Synthesis of 4-Substituted Chlorophthalazines ... - ACS Publications

Article pubs.acs.org/joc

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones Hanh Nho Nguyen,*,† Victor J. Cee,‡ Holly L. Deak,† Bingfan Du,† Kathleen Panter Faber,†,⊥ Hakan Gunaydin,§ Brian L. Hodous,†,∥ Steven L. Hollis,§ Paul H. Krolikowski,§ Philip R. Olivieri,† Vinod F. Patel,†,# Karina Romero,† Laurie B. Schenkel,† and Stephanie D. Geuns-Meyer† Departments of †Chemistry Research and Discovery and §Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, Massachusetts 02142, United States ‡ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States S Supporting Information *

ABSTRACT: Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i−9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b−1v via reaction with hydrazine, followed by chlorination with POCl3. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,Ndimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a−15c via the proposed ring expansion of 3-vinyl-3hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a−16d and 2-pyrazolyl benzohydrazides 17a−17g rather than the expected alkynyl phthalazinones.

■

INTRODUCTION Phthalazine is a common heterocycle present in a wide range of potential therapeutics for the treatment of cancer,1−7 inflammation,3,8−10 epilepsy,11 diabetes,12 cerebrovascular/circulation disorders,13 and chronic obstructive pulmonary disease.14 We desired a general method to synthesize 4-substituted heteroaryl chlorophthalazines 1a for rapid preparation of aurora kinase inhibitors.1 Several methods for the preparation of 4-aryl and 4-alkyl substituted chlorophthalazines have been reported previously, but all suffer from significant drawbacks. For example, these substrates can be synthesized via Negishi15 and Suzuki− Miyaura16,17 monocoupling of 1,4-dichlorophthalazine. Unfortunately, bis-coupling of organozinc/organoboron reagents with 1,4-dichlorophthalazine reduces the yield of the desired monocoupling product and can require tedious chromatographic purification. 1,4-Dichlorophthalazine can also be transformed into 4-substituted chlorophthalazines by Friedel−Crafts reaction.18,19 © 2012 American Chemical Society

However, there are a limited number of suitable Friedel− Crafts substrates 2a (e.g., electron-rich aromatic rings). 4-Substituted chlorophthalazines can also be prepared as shown in Scheme 1.2,5,20−22 The key 2-keto benzoic acids 3a can be prepared from phthalic anhydride (4a) via the Friedel−Crafts reaction22−24 or through a metalation route,25−29 which expands the scope to aryl, heteroaryl, and alkyl substrates. However, even at low temperature (−70 to −78 °C), bisaddition of the organolithium and Grignard reagents 5a to phthalic anhydride (4a) can lead to isobenzofuranones 6a, often hampering the purification and the yield.26,28,29 The bisaddition byproduct 6a may be minimized by adding 5a to excess 4a (inverse addition order) at even lower temperature (−100 °C)26,28 or by employing organocuprate reagents that must be generated from 5 equiv of Received: February 9, 2012 Published: March 29, 2012 3887

dx.doi.org/10.1021/jo3000628 | J. Org. Chem. 2012, 77, 3887−3906

The Journal of Organic Chemistry

Article

Scheme 1. Reported Methods for the Synthesis of 4-Substituted Chlorophthalazines 1a from Phthalic Anhydride (4a)

Scheme 2. Proposed Three-Step Method to Prepare 4-Substituted Chlorophthalazines 1a from Phthalimide 8a

organomagnesium reagents.30 These limitations prompted us to develop an alternative, efficient, and general method to prepare 4-substituted aryl/heteroaryl/alkyl chlorophthalazines. Enders, Deniau, and co-workers have shown that N,Ndimethylaminophthalimide (8a) undergoes selective monoreduction with NaBH4.31−33 They also showed the addition of organometallic reagents to 8a.34 For example, 8a reacted with phenylmagnesium bromide to provide 3-phenyl-3-hydroxyisoindolinones.35 We were also aware that 9a could be transformed into phthalazinone 7a.35,36 From these observations, we envisioned a general three-step protocol for the synthesis of 4-aryl/heteroaryl/alkyl chlorophthalazines 1a from N,N-dimethylaminophthalimide (8a) (Scheme 2).37

Table 1. Selective Monoaddition of Aryl Lithium 5b to Phthalic Anhydride (4a) and Phthalimides 8a−8e

■

RESULTS AND DISCUSSION The selective monoaddition of organometallic reagents to phthalic anhydride (4a), phthalimides 8a−8e, tetrahydrophthalimide 8f, and maleimide 8g is illustrated in Tables 1 and 2. Compounds 8a−8g were prepared from reaction of the corresponding cyclic anhydrides with the substituted hydrazines, O-methylhydroxylamine, or amines in refluxing toluene in the presence of a catalytic amount of p-TsOH with a Dean− Stark apparatus for removing water azeotropically. In agreement with previous reports,26,28,29 bisaddition of pyridinyl lithium 5b to phthalic anhydride (4a) was observed, and isobenzofuranone 6b was isolated in 12% yield along with the desired monoaddition product 3-hydroxyisobenzofuranone 10a, which was isolated in only 25% yield (Table 1, entry 1). In contrast, selective monoaddition of pyridinyl lithium 5b to N,N-dimethylaminophthalimide (8a) was achieved, and 9b was isolated in 67% yield (Table 1, entry 2).34 Variations to the experimental procedure such as addition of 8a to anion 5b at −78 °C or using diethyl ether as the solvent instead of THF provided similar yields (60−70%). Screening of other phthalimides 8b−8e also revealed only monoaddition products 9c−9f (Table 1, entries 3−6). In addition, tetrahydrophthalimide 8f and maleimide 8g were both suitable substrates (Table 2, entries 1 and 2). Besides

Table 2. Selective Monoaddition of Organometallic Reagents to Tetrahydrophthalimide 8f and Maleimide 8g

(6-methylpyridin-2-yl)lithium (5b), benzylmagnesium bromide (5c) and phenyl lithium (5d) were also suitable nucleophiles. However, diethylzinc, a weaker nucleophile, did not react with phthalimide 8a even at room temperature (data not shown). 3888



Article

Scheme 3. Proposed Mechanism for the Addition of Aryl Lithium to 4a, 8a, and 8d

The significant differences observed between phthalic anhydride and phthalimides with regard to mono- and bisaddition of organometallic reagents deserves further comment (Scheme 3). Presumably, bisaddition arises from ring opening of the initially formed alkoxy-isobenzofuranone 11a, leading to diaryl ketone 11b, which reacts with the organometallic reagent to give 6b. The lack of bisaddition products in reactions of the analogous N,N-dimethylaminophthalimide 8a and N-methylphthalimide 8d suggests that ring opening is substantially reduced, although it is also possible that the ring-opened intermediates 11d and 11f, if produced, are much less reactive than 11a. Ab initio calculations (B3LYP/6-31+G(d)) of the relative equilibrium free energies of 11a/b, 11c/d, and 11e/f support the former hypothesis: ring-opened intermediate 11b is favored over 11a by 7.4 kcal/mol, while ring-closed intermediates 11c and 11e are favored over the corresponding ring-opened intermediates 11d and 11f by 9.1 and 12.8 kcal/mol, respectively. Overall, the reaction of (6-methylpyridin-2-yl)lithium (5b) to N,N-dimethylaminophthalimide (8a) provided selective monoaddition product 9b in good yield. In addition, 8a is a stable solid that can easily be made on large scale from commercially available phthalic anhydride (4a). Therefore, N,N-dimethylaminophthalimide (8a) was chosen as the electrophile for further studies. The scope of the organometallic reagent was explored next. The organolithium reagents were generated using standard conditions including lithium−halogen exchange or direct lithiation of heterocycles and alkynes. Grignard reagents were obtained from commercial sources. Table 3 shows moderate to excellent yields of isoindolinones containing six- (9i−9m) and five-membered (9n−9u) ring heterocycles, substituted benzenes (9v−9z), alkyls (9aa and 9ab), cycloalkyls (9ac and 9ad), aromatic alkynes (9ae−9ag), silyl alkynes (9ah38 and 9ai), and alkyl alkynes (9aj−9am). A limitation to the scope of the general reaction was discovered when exploring vinylic organometallic reagents. Reaction of vinyl magnesium bromide 12a and 8a afforded a 1:3 mixture of vinyl hydroxyisoindolinones 13a and ringexpanded dihydrobenzoazepinedione 15a in 16% yield. Dihydrobenzoazepinediones 15b and 15c were isolated when propenylmagnesium bromide 12b and phenylvinyl lithium 12c were used. Attempts to improve the isolated yield of 15a−15c by changing the temperature or addition order were not successful. HMBC connectivities and ROESY cross-peaks confirmed the structure of 15a−15c. We postulate that the ring-expansion products are more likely to be generated via a [1,3]-shift of a chelated lithium vinylic hydroxyisoindolinone (INT A) rather than through an intramolecular Michael addition of an enone (INT B) to form the strained sevenmembered ring (INT C) (Scheme 4). With a series of isoindolinones in hand, the chlorophthalazine syntheses were completed (Table 4). The transformation of hydroxyisoindolinones 9b, 9i−9z, 9aa, and 9ad to

Table 3. Preparation of 3-Substituted 3-Hydroxyisoindolin1-ones 9i−9ama

a

Anion sources. Lithium−halogen exchange: 9i−9 m, 9p, 9v−9z. Direct lithiation with n-BuLi and TMEDA: 9n and 9o, 9q. Direct lithiation with n-BuLi: 9r−9u, 9ae −9am. Grignard reagent: 9aa −9ad. bBr−Li exchange to form 9l was more efficient in Et2O than in THF.39 It was possible that (5-chloropyridin-2-yl)lithium was insoluble and thus more stable in Et2O. cFor the synthesis of 9n and 9o, lithiation of 3-methylthiophene with n-BuLi alone gave a 3:1 mixture of C5:C2 lithiointermediates. The presence of TMEDA improved this ratio to 9:1, and we were able to prepare up to 90% yield of 9n and 9o in a 9:1 ratio.40,41

phthalazinones 7b−7v with hydrazine proceeded cleanly (Step 1).36 Chlorination of phthalazinones 7b−7v with excess 3889



Article

Scheme 4. Formation and Proposed Mechanism of Dihydrobenzoazepinediones 15a−15c

as no Lewis acid was present.45,46 In Path A, which would lead to major isomer 19d, the more nucleophilic hydrazine nitrogen47−49 undergoes conjugate addition to the activated alkyne. We believe that alkynyl hydroxyisoindolinone contains a “masked” ynone.50 The allene 19b can then rearrange to (Z)-βhydrazine enone 19c, which can undergo cyclodehydration to afford the major pyrazolyl benzohydrazide 19d. The regioselectivity was similar to the reactions between hydrazines and ynones.43,44 If hydrazine was used, benzohydrazides 19d could be hydrolyzed by the liberated water from the previous step to give the pyrazolyl benzoic acid 19f, possibly via a tricyclic 19e that could be formed from the more nucleophilic free NH-pyrazole.

POCl3 afforded chlorophthalazines 1b−1v in good yields (Step 2). For the mixture of 1h and 1i, the major isomer 1h could be cleanly separated by recrystallization with EtOAc. The structures of both phthalazinone isomers 7h and 7i and chlorophthalazine 1h were confirmed by NMR analyses. Overall, the three-step protocol to prepare aryl/heteroaryl/ alkyl chlorophthalazines 1b−1v from N,N-dimethylaminophthalimide (8a) was straightforward. For phenylethynyl hydroxyisoindolinone 9ae, reaction with 15 equiv of hydrazine in refluxing ethanol yielded 58% of 2-pyrazolyl benzoic acid 16a instead of the anticipated alkynyl phthalazinone (data not shown). Further optimization revealed that a complete conversion of 9ae to 16a could also be achieved with 3 equiv of anhydrous hydrazine in THF at room temperature (Table 5, entry 1).42 The generality of the reaction was demonstrated in the preparation of n-butyl, cyclopropyl, and tert-butylpyrazole benzoic acids (entries 2−4). Interestingly, for monoalkyl hydrazines, a similar reaction with alkynyl hydroxyisoindolinone occurred but provided the pyrazole benzohydrazides rather than the pyrazole carboxylic acids. No reaction took place between methylhydrazine and 9ae in THF at room temperature, but heating to 80 °C afforded a 23:1 regioisomeric mixture of pyrazolyl benzohydrazides 17a:18a (Table 5, entry 5). The formation of the major regioisomer 17a is consistent with literature reports for the reaction of monoalkyl hydrazines and ynones.18,43,44 The same conditions were also used to prepare a 13:1 mixture of 17b:18b (entry 6). When methyl, n-butyl, and isobutyl hydrazines reacted with either alkyl or aryl alkynyl isoindolinones under similar conditions, only the major regioisomers 17a−17g were isolated (entries 7−11). The structures of pyrazolyl benzohydrazides 17a, 17e, and 17g were confirmed by 2D-NMR analyses. In addition, structures of 17a, 17b, and 17g were unambiguously determined by single crystal X-ray structure. All structures showed R1 and R2 were adjacent to one another, confirming the pyrazolyl structures of compounds 17a−17g. Scheme 5 shows the proposed mechanism for the formation and regioselectivity for the formation of 2-pyrazolyl benzohydrazides and 2-pyrazolyl benzoic acids. Since alkynyl phthalazinone 19g was not obtained, Michael addition of hydrazine to alkynyl hydroxyisoindolinone is likely the predominant pathway. Hydrohydrazination of 19a is unlikely

■

CONCLUSIONS

■

EXPERIMENTAL SECTION

Here we disclose a general three-step synthesis of 4-substituted chlorophthalazines from N,N-dimethylaminophthalimide. N,NDimethylaminophthalimide ensured clean monoaddition of organometallic reagents. Intramolecular chelation and predominant ring-closed hydroxyisoindolinone might have prevented bisaddition of organometallic reagents. A wide variety of alkyl, aryl, and heteroaryl chlorophthalazines were prepared in good yields. This methodology did not provide a suitable route to vinyl and alkynyl chlorophthalazines; instead, transformations of vinyl and alkynyl hydroxyisoindolinones uncovered novel routes to dihydrobenzoazepinediones and 2-pyrazolyl benzohydrazides/benzoic acids, respectively.

Unless indicated otherwise, all materials were obtained from commercial suppliers and used without further purification. Dry organic solvents (THF, dioxane, toluene, etc.) were commercially available. Organometallic reagents such as alkyl lithiums and Grignard reagents were purchased and were handled under an argon or a nitrogen atmosphere. Anhydrous hydrazine and substituted hydrazines and their vapors can be flammable and explosive in the presence of heat, flame, sparks, contaminants, and oxidizers including air. Quenching of POCl3 with aqueous base at low temperature can cause a delayed exotherm. Monitoring the internal temperature during the workup is advised. Chlorophthalazines hydrolyze over time at rt; therefore, they should be used immediately. To minimize hydrolysis, they should be stored under vacuum or in a desiccator. 3890



Article

Table 4. Preparation of Chlorophthalazines 1b−1v

Table 5. Preparation of 2-Pyrazolyl Benzoic Acids 16a−16d and 2-Pyrazolyl Benzohydrazides 17a−17g

a THF, rt. bTHF, 80 °C. c23:1 mixture of regioisomers. d13:1 mixture of regioisomers.

DCM or CHCl3, and 1−2 drops of the solution was applied on a 2 mm × 2 mm square diamond, brazed into a tungsten carbide disk. After DCM or CHCl3 had evaporated, the IR spectrum was acquired and processed. 1H NMR, 13C NMR, and 19F NMR spectra were recorded on a NMR instrument at ambient temperature. For 1H NMR and 13C NMR spectra, chemical shifts are reported in ppm unit, relative to residual deuterated solvent peaks. Data are reported as follows: chemical shift (multiplicity, coupling constants, and number of protons). The abbreviations for multiplicity are s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, sep = septet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were determined on a high-resonance electrospray timeof-flight mass spectrometer in positive electrospray ionization (ESI) mode. Masses are reported in units of mass over charge (m/z) to four decimal places. Melting points were obtained from a melt-temp apparatus and were uncorrected. All yields reported refer to isolated yields of compounds estimated to be greater than 95% purity as determined by HPLC and 1H NMR. Compounds described in the literature were characterized by comparison of their melting points and 1 H and/or 13C NMR spectra to the previously reported data. The procedures in this section are representative, and thus the yields may differ from those reported in tables. All calculations were computed in the gas phase by the HF/ 6-31+G(d) method.51 Thermal corrections were computed at room temperature. All energies are reported in kcal/mol. General Procedure To Prepare Phthalimide and Maleimide. 2-(Dimethylamino)isoindoline-1,3-dione (8a).52−54 In a round-bottom flask were added isobenzofuran-1,3-dione (5.0 g, 34 mmol), N,N-dimethylhydrazine (2.9 mL, 37 mmol), and toluene (75 mL). Then p-toluenesulfonic acid monohydrate

Reactions were monitored by thin layer chromatography or using LC−MS with UV detection at 254 nm and a low-resonance electrospray mode (ESI). Medium pressure liquid chromatography (MPLC) was performed with normal phase silica gel (35−60 μm) columns and UV detection at 254 nm. IR spectra were recorded and are reported in wavenumbers (cm−1). The sample was dissolved in 3891



Article

Scheme 5. Proposed Mechanism for the Formation of 2-Pyrazolyl Benzohydrazide 19d and 2-Pyrazolyl Benzoic Acid 19f

2-(Dimethylamino)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (8f). Following the general procedure to prepare 8a, 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (2.3 g, 15 mmol) was allowed to react with N,N-dimethylhydrazine (1.4 mL, 18 mmol) in toluene (33 mL) in the presence of p-TsOH·H2O (0.14 g, 0.74 mmol) for 4.5 h at 125 °C. Following similar workup procedure, the product was obtained as a yellow solid (2.6 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ 2.91 (s, 6H), 2.32−2.28 (m, 4H), 1.77−1.74 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 169.6, 139.9, 44.9, 21.2, 19.8. FT-IR (thin film, cm−1) 2943, 1712. MS calcd for C10H14N2O2 [M]+ = 194, found [M + H]+ = 195. HRMS calcd for C10H14N2O2 [M + H]+ = 195.1128, [M + Na]+ = 217.0948, found [M + H]+ = 195.1132, [M + Na]+ = 217.0955. Mp = 42−43 °C. 1-(Dimethylamino)-3,4-dimethyl-1H-pyrrole-2,5-dione (8g). Following the general procedure to prepare 8a, 3,4-dimethylfuran-2,5dione (3.1 g, 25 mmol) was allowed to react with N,Ndimethylhydrazine (2.1 mL, 28 mmol) in toluene (55 mL) in the presence of p-TsOH·H2O (0.24 g, 1.2 mmol) for 4.5 h at 125 °C. Following similar workup procedure, a viscous yellow liquid was obtained (3.7 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 2.87 (s, 6H), 1.91. (s, 6H). 13C NMR (101 MHz, CDCl3) δ 170.4, 135.7, 44.8, 8.6. FT-IR (thin film, cm−1) 1705. MS calcd for C8H12N2O2 [M]+ = 168, found [M + H]+ = 169. HRMS calcd for C8H12N2O2 [M + H]+ = 169.0972, [M + Na]+ = 191.0791, found [M + H]+ = 169.0992, [M + Na]+ = 191.0796. 3-Hydroxy-3-(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one (10a) and 3,3-Bis(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one (6b). In a dry round-bottom flask were added 2-bromo-6-methylpyridine (0.44 mL, 3.8 mmol) and THF (6.4 mL). The reaction was purged with argon and cooled to −78 °C. n-BuLi (1.6 mL, 4.0 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of isobenzofuran-1,3-dione (0.68 g, 4.6 mmol) in 5 mL of THF at −30 °C over a period of 45 min. After 15 min, the temperature was warmed to rt. After another 30 min, LC− MS showed the desired product at 1.564 min as [M + H]+ = 242, bisaddition lactone at 2.244 min as [M + H]+ = 317, and bisaddition benzoic acid at 1.257 min as [M + H]+ = 335. The ratio of monoaddtion product:bisaddition lactone:bisaddition benzoic acid was 1:8.4:3.2. The reaction was quenched with 2 mL of MeOH and concentrated to give a yellow oil. The residue was purified further by using 70:30 Hex/EtOAc and 90:10 DCM to provide two products. The first series of fractions gave an off-white solid that corresponded to the monoaddition product. 1H NMR and 13C NMR of the off-white solid in DMSO were complicated possibly because the carboxylic acid (ring open) was in equilibrium with the lactone (ring closed). FT-IR (thin film) of the off-white solid was also complicated, but the IR spectrum showed the OH-carboxylic acid and carbonyl stretching frequencies. A second series of fractions gave an offwhite solid. 1H NMR and LC−MS showed the bis-addition product. On the FT-IR spectrum, there was no evidence for OH-carboxylic acid or the alcohol stretching frequencies. Therefore, the bis-addition product existed in the lactone form.

(0.32 g, 1.7 mmol) was added. The Dean−Stark apparatus and a condenser were attached. The mixture was refluxed for 4 h. After cooling to rt, toluene was removed under a reduced pressure to afford a residue. The crude product was dissolved in DCM, washed with satd NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford a light yellow solid, 2-(dimethylamino)isoindoline-1,3dione (6.1 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (m, 4H), 2.89 (s, 6H). MS calcd for C10H10N2O2 [M]+ = 190, found [M + H]+ = 191. 2-(Pyrrolidin-1-yl)isoindoline-1,3-dione (8b). Following the general procedure to prepare 8a, isobenzofuran-1,3-dione (2.3 g, 15 mmol) was allowed to react with pyrrolidin-1-amine hydrochloride (2.1 g, 17 mmol) in toluene (34 mL) in the presence of p-TsOH·H2O (0.15 g, 0.76 mmol) for 4.5 h at 125 °C. Similar workup provided a crude product. This material was passed through a pad of silica gel with the aid of 70:30 Hex/EtOAc to afford 2-(pyrrolidin-1yl)isoindoline-1,3-dione as a beige solid (1.1 g, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.85−7.81 (m, 2H), 7.74−7.70 (m, 2H), 3.39−3.36 (m, 4H), 2.05−1.99 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.6, 136.3, 134.5, 123.5, 52.4, 24.3. FT-IR (thin film, cm−1) 2986, 1702. MS calcd for C12H12N2O2 [M]+ = 216, found [M + H]+ = 217. HRMS calcd for C12H12N2O2 [M + H]+ = 217.0972, [M + Na]+ = 239.0791, found [M + H]+ = 217.0985, [M + Na]+ = 239.0798. Mp = 146−148 °C. 2-Methoxyisoindoline-1,3-dione (8c). Following the general procedure to prepare 8a, isobenzofuran-1,3-dione (2.3 g, 15 mmol) was allowed to react with methoxyamine hydrochloride (1.9 g, 23 mmol) in toluene (34 mL) in the presence of p-TsOH·H2O (0.14 g, 0.76 mmol) for 4.5 h at 125 °C. Following similar workup procedure, a white solid was obtained (2.0 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ 7.83−7.80 (m, 2H), 7.76−7.73 (m, 2H), 4.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.2, 134.4, 128.8, 123.5, 65.8. FT-IR (thin film, cm−1) 1799, 1732. MS calcd for C9H7NO3 [M]+ = 177, found [M + H]+ = 178. HRMS calcd for C9H7NO3 [M + H]+ = 178.0499, [M + Na]+ = 200.0318, found [M + H]+ = 178.0517, [M + Na]+ = 200.0337. Mp =139−140 °C (lit.55 mp =142−143 °C). 2-Methylisoindoline-1,3-dione (8d). This compound was commercially available. 2-Isopropylisoindoline-1,3-dione (8e). Following the general procedure to prepare 8a, isobenzofuran-1,3-dione (1.3 g, 8.4 mmol) was allowed to react with propan-2-amine (0.79 mL, 9.3 mmol) in toluene (19 mL) in the presence of p-TsOH·H2O (0.080 g, 0.42 mmol) for 5 h at 125 °C. Following similar workup procedure, a white solid was obtained (1.5 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.81−7.78 (m, 2H), 7.69−7.67 (m, 2H), 4.52 (sep, J = 7.1 Hz, 1H), 1.48 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 168.4, 133.8, 132.1, 123.0, 43.0, 20.2. FT-IR (thin film, cm−1) 2979, 1699. MS calcd for C11H11NO2 [M]+ = 189, found [M + H]+ = 190. HRMS calcd for C11H11NO2 [M + H]+ = 190.0863, [M + Na]+ = 212.0682, found [M + H]+ = 190.0869, [M + Na]+ = 212.0687. Mp = 81−82 °C. 3892



Article

3-Hydroxy-3-(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one (10a) and 2-(2-Methylpicolinoyl)benzoic Acid. A mixture of the lactone and the carboxylic acid were obtained (0.23 g, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.85−7.83 (m, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.71−7.69 (m, 1H), 7.48−7.29 (m, 4H), 7.21−7.19 (m, 1H), 3.70 (m, 1H), 2.23 (s, 3H). 13C NMR was complicated. FT-IR (thin film, cm−1) 3500−2500 (br), 1720, 1670, 1592, 1564. MS calcd for C14H11NO3 [M]+ = 241, found [M + H]+ = 242. HRMS calcd for C14H11NO3 [M + H]+ = 242.0812, [M + Na]+ = 264.0631, found [M + H]+ = 242.0833, [M + Na]+ = 264.0664. Mp > 250 °C. 3,3-Bis(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one (6b). The bisaddition product was obtained as an off-white solid (0.15 g, 12% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.69 (td, J = 7.4, 1.0 Hz, 1H), 7.56−7.51 (m, 3H), 7.37 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.5 Hz, 2H), 2.48 (6H). 13C NMR (101 MHz, CDCl3) δ 170.2, 158.1, 158.0, 151.3, 136.7, 133.5, 129.0, 126.8, 125.5, 124.8, 122.4, 118.1, 24.5 (one carbon was not accounted for). 13C NMR (151 MHz, CDCl3) δ 170.2, 158.1, 158.0, 151.3, 136.7, 133.5, 129.0, 126.8, 125.5, 124.8, 122.4, 118.1, 90.8, 24.5. FT-IR (thin film, cm−1) 1773. MS calcd for C20H16N2O2 [M]+ = 316, found [M + H]+ = 317. HRMS calcd for C20H16N2O2 [M + H]+ = 317.1285, [M + Na]+ = 339.1104, found [M + H]+ = 317.1317, [M + Na]+ = 339.1125. Mp = 169−170 °C. General Procedure To Prepare Heteroaryl Hydroxyisoindolinone. 2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b). In a dry round-bottom flask were added 2-bromo-6-methylpyridine (66 μL, 0.58 mmol) and THF (1.2 mL). The reaction was purged with argon and cooled to −78 °C. n-BuLi (0.24 mL, 0.61 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2-(dimethylamino)isoindoline-1,3-dione (0.17 g, 0.87 mmol) in 2 mL of THF that was previously submerged in a cold bath at −78 °C for 2 min. After 15 min at −78 °C, the temperature was warmed to −30 °C. After 1 h, LC−MS showed the product at 1.535 min. The reaction was warmed to rt and quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The product was purified by performing a column chromatography on silica gel eluting with 85:15 DCM/(90:10:1 DCM/ MeOH/NH4OH) to afford 2-(dimethylamino)-3-hydroxy-3(6-methylpyridin-2-yl)isoindolin-1-one as a yellow solid (0.11 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.78−7.64 (m, 3H), 7.54−7.45 (m, 2H), 7.17−7.13 (m, 2H), 3.33 (s, 1H), 2.76 (s, 6H), 2.31 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.9, 157.6, 156.6, 147.3, 137.2, 132.3, 130.8, 129.0, 122.46, 122.49, 122.0, 118.9, 91.0, 44.4, 23.9. FT-IR (thin film, cm−1) 3324 (br), 2954, 2884, 1704, 1460, 1344. MS calcd for C16H17N3O2 [M]+ = 283, found [M + H]+ = 284. HRMS calcd for C16H17N3O2 [M + H]+ = 284.1394, [M + Na]+ = 306.1213, found [M + H]+ = 284.1395, [M + Na]+ = 306.1205. Mp = 142−143 °C. 3-Hydroxy-3-(6-methylpyridin-2-yl)-2-(pyrrolidin-1-yl)isoindolin1-one (9c). In a dry round-bottom flask were added 2-bromo-6methylpyridine (0.20 mL, 1.7 mmol) and THF (2.9 mL). The reaction was purged with argon and cooled to −78 °C. n-BuLi (0.73 mL, 1.8 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2-(pyrrolidin-1-yl)isoindoline-1,3-dione (0.45 g, 2.1 mmol) in 5.0 mL of THF. After 15 min, the temperature was warmed to rt. After 30 min, LC−MS showed the product at 1.654 min as [M + H]+ = 310. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The product was purified by performing a column chromatography on silica gel eluting with 70:30 DCM/(90:10:1 DCM/MeOH/NH4OH) to afford 3-hydroxy3-(6-methylpyridin-2-yl)-2-(pyrrolidin-1-yl)isoindolin-1-one as a yellow foam (0.30 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 7.87−7.86 (m, 1H), 7.60−7.50 (m, 3H), 7.22−7.21 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 3.49−3.44 (m, 2H), 3.11−3.05 (m, 2H), 2.72 (s, 3H), 1.91−1.79 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 165.8, 156.1, 155.4, 145.8, 137.2,

132.2, 130.8, 129.1, 122.7, 122.4, 122.2, 117.2, 88.7, 51.5, 23.8, 23.5. FTIR (thin film, cm−1) 3324 (br), 1986, 2874, 1703. MS calcd for C18H19N3O2 [M]+ = 309, found [M + H]+ = 310. HRMS calcd for C18H19N3O2 [M + H]+ = 310.1550, [M + Na]+ = 332.1370, found [M + H]+ = 310.1563, [M + Na]+ = 332.1374. Mp = 146−147 °C. 3-Hydroxy-2-methoxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9d). In a dry round-bottom flask were added 2-bromo-6methylpyridine (0.20 mL, 1.7 mmol) and THF (2.9 mL). The reaction flask was purged with argon and cooled to −78 °C. n-BuLi (0.73 mL, 1.8 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2methoxyisoindoline-1,3-dione (0.37 g, 2.1 mmol) in 5.0 mL of THF at −30 °C over a period of 45 min. After 15 min at −30 °C, the temperature was warmed to rt. After 30 min, LC−MS showed the product at 1.571 min as [M + H]+ = 271. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The residue was purified by performing a column chromatography on silica gel eluting with 70:30 Hex/EtOAc to afford a white solid, 3-hydroxy-2-methoxy-3-(6methylpyridin-2-yl)isoindolin-1-one (0.26 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ 7.86−7.84 (m, 1H), 7.53−7.40 (m, 4H), 7.23− 7.21 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 3.94 (s, 3H), 2.64 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.2, 156.7, 153.9, 144.9, 138.1, 133.1, 129.7, 128.9, 123.5, 123.4, 122.4, 117.4, 89.3, 65.7, 24.0. FT-IR (thin film, cm−1) 3309 (br), 1721. MS calcd for C15H14N2O3 [M]+ = 270, found [M + H]+ = 271. HRMS calcd for C15H14N2O3 [M + H]+ = 271.1077, [M + Na]+ = 293.0897, found [M + H]+ = 271.1081, [M + Na]+ = 293.0897. Mp = 112−114 °C. 3-Hydroxy-2-methyl-3-(6-methylpyridin-2-yl)isoindolin-1-one (9e). In a dry round-bottom flask were added 2-bromo-6methylpyridine (0.20 mL, 1.7 mmol) and THF (5.8 mL) under an argon atmosphere. The reaction was purged with argon and cooled to −78 °C. Then n-butyllithium (0.73 mL, 1.8 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2-methylisoindoline-1,3-dione (0.30 g, 1.8 mmol) in 5.0 mL of THF. After 15 min, the temperature was warmed to rt. LC− MS showed product as [M − OH]+ = 237 and [2M + Na]+ = 531. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. After hexanes was added to the oily residue, a beige solid precipitated out. The solid was filtered off with the aid of cold hexanes and dried under vacuum to afford a beige solid, 3-hydroxy-2-methyl-3(6-methylpyridin-2-yl)isoindolin-1-one (0.33 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.56−7.47 (m, 3H), 7.27−7.17 (m, 3H), 6.70 (d, J = 7.5 Hz, 1H), 2.75 (s, 3H), 2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.7, 156.8, 155.2, 147.6, 138.4, 132.3, 131.5, 129.5, 123.4, 123.2, 122.3, 117.3, 89.0, 24.1, 23.5. FT-IR (thin film, cm−1) 3297 (br), 1700. MS calcd for C15H14N2O2 [M]+ = 254, found [M − OH]+ = 237 and [2M + Na]+ = 531. HRMS calcd for C15H14N2O2 [M + H]+ = 255.1128, [M + Na]+ = 277.0948, found [M + H]+ = 255.1129, [M + Na]+ = 277.0945. Mp = 133−134 °C. 3-Hydroxy-2-isopropyl-3-(6-methylpyridin-2-yl)isoindolin-1-one (9f). 2-Bromo-6-methylpyridine (0.13 mL, 1.2 mmol) and THF (3.9 mL) were added into a dry round-bottom flask under an argon atmosphere. The reaction was purged with argon and cooled to −78 °C. Then n-butyllithium (0.49 mL, 1.2 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2-isopropylisoindoline-1,3-dione (0.23 g, 1.2 mmol) in 5.0 mL of THF. After 15 min, the temperature was warmed to rt. LC− MS showed the product at 1.740 min as [M − OH]+ = 265 and [2M + Na]+ = 587. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. The product was purified by performing a column chromatography on silica gel eluting with 75:25 Hex/EtOAc to afford a viscous colorless oil, 3-hydroxy-2-isopropyl-3-(6-methylpyridin-2yl)isoindolin-1-one (0.19 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.83−7.81 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.49−7.43 (m, 2H), 3893



Article

[M + Na]+ = 306.1213, found [M + H]+ = 284.1403, [M + Na]+ = 306.1201. Mp = 73−74 °C. 2-(Dimethylamino)-3-hydroxy-3-(4-methylpyridin-2-yl)isoindolin-1-one (9j). Following the general procedure to prepare 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1one (9b), this compound was prepared using 2-bromo-4-methylpyridine (6.5 mL, 58 mmol) and THF (97 mL), n-BuLi (24 mL, 61 mmol), 2-(dimethylamino)isoindoline-1,3-dione (13 g, 70 mmol) in 70 mL of THF. The crude product was triturated in hexanes until the solid precipitated out of the solution. The solid was filtered off with the aid of hexanes and dried under vacuum to afford 2-(dimethylamino)-3-hydroxy3-(4-methylpyridin-2-yl)isoindolin-1-one (12 g, 70% yield). The second batch was obtained from the filtrate. After concentration of the filtrate, the residue was purified by column chromatography eluting with 80:20 DCM/(90:10:1 DCM/MeOH/ NH4OH) to afford a yellow solid (1.0 g, 6% yield). The overall yield was 76%. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.65−7.63 (m, 1H), 7.52−7.46 (m, 2H), 7.16−7.10 (m, 3H), 2.70 (s, 6H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.8, 158.3, 148.2, 147.59, 147.57, 132.3, 130.9, 128.9, 123.8, 122.52, 122.49, 121.9, 90.7, 44.3, 20.8. FT-IR (thin film, cm−1) 3436 (br), 1655, 1024. MS calcd for C16H17N3O2 [M]+ = 283, found [M + H]+ = 284; [2M + Na]+ = 589. HRMS calcd for C16H17N3O2 [M + H]+ = 284.1394, [M + Na]+ = 306.1213, found [M + H]+ = 284.1413; [M + Na]+ = 306.1248. Mp = 150−152 °C. 2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-3-yl)isoindolin-1one (9k). Following the general procedure to prepare 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this compound was prepared using 5-bromo-2-methylpyridine (0.4 g, 2.3 mmol) and THF (7.8 mL), n-BuLi (9.8 mL, 2.4 mmol; 2.5 M in THF), 2-(dimethylamino)isoindoline-1,3-dione (0.66 g, 3.5 mmol) in 15 mL of THF. The product was triturated with hexanes to afford a yellow solid, 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-3-yl)isoindolin-1-one (0.50 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.46−8.45 (d, 1H), 7.72−7.70 (m, 1H), 7.61−7.51 (m, 3H), 7.22− 7.18 (m, 2H), 7.11 (s, 1H), 2.73 (s, 6H), 2.44 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.9, 156.9, 146.8, 146.7, 134.0, 132.4, 132.0, 129.6, 129.0, 122.6, 121.8, 88.6, 44.2, 23.2. FT-IR (thin film, cm−1) 3100 (br), 2956, 2885, 1702, 1467, 1343. MS calcd for C16H17N3O2 [M]+ = 283, found [M + H]+ = 284. HRMS calcd for C16H17N3O2 [M + H]+ = 284.1394, [M + Na]+ = 306.1213, found [M + H]+ = 284.1419, [M + Na]+ = 306.1247. Mp = 164−165 °C. 3-(5-Chloropyridin-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin1-one (9l). Following the general procedure to prepare 2-(dimethylamino)3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this compound was prepared using 2-bromo-5-chloropyridine (3.5 g, 18 mmol) and Et2O (73 mL), n-BuLi (7.7 mL, 19 mmol; 2.5 M in THF), 2-(dimethylamino)isoindoline-1,3-dione (4.2 g, 22 mmol) in 20 mL of THF. The product was purified by performing a column chromatography eluting with 80:20 Hex/EtOAc to afford a brown solid, 3-(5-chloropyridin2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (2.0 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.01 (s, 2H), 7.67 (d, J = 6.6 Hz, 1H), 7.52 (quin, J = 7.0 Hz, 2H), 7.27 (s, 1H), 7.18 (d, J = 6.6 Hz, 1H), 2.72 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.7, 157.4, 147.0, 136.6, 132.4, 130.8, 130.2, 129.1, 123.5, 122.6, 122.0, 90.4, 44.4. FT-IR (thin film, cm−1) 3332 (br), 3053, 2954, 2884, 1686. MS calcd for C15H14ClN3O2 [M]+ = 303, found [M + H]+ = 304. HRMS calcd for C15H14ClN3O2 [M + H]+ = 304.0847, [M + Na]+ = 326.0667, found [M + H]+ = 304.0856, [M + Na]+ = 326.0673. Mp = 137−139 °C. 2-(Dimethylamino)-3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin1-one (9m). Following the general procedure to prepare 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this compound was prepared using 2-bromo-6-methoxypyridine (2.0 mL, 16 mmol) and THF (27 mL), n-BuLi (6.7 mL, 17 mmol; 2.5 M in THF), 2-(dimethylamino)isoindoline-1,3-dione (3.6 g, 19 mmol). The crude product was triturated in hexanes to provide an off-white solid, 2-(dimethylamino)-3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin-1one (4.2 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (m, 1H), 7.65 (dd, J = 7.0, 1.0 Hz, 1H), 7.58−7.45 (m, 3H), 7.15 (dd, J = 7.0, 1.0 Hz, 1H), 7.11 (s, 1H), 6.72 (dd, J = 7.0, 1.0 Hz, 1H), 3.52

7.30 (s, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.13−7.11 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 3.51 (quin, J = 7.1 Hz, 1H), 2.67 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.8, 156.3, 156.0, 147.7, 138.0, 132.5, 132.1, 129.4, 123.3, 122.9, 122.1, 118.0, 89.7, 44.5, 24.1, 20.7, 20.1. FT-IR (thin film, cm−1) 3311 (br), 2976, 1694. MS calcd for C17H18N2O2 [M]+ = 282, found [M − OH]+ = 265 and [2M + Na]+ = 587. HRMS calcd for C17H18N2O2 [M + H]+ = 283.1441, [M + Na]+ = 305.1261, found [M + H]+ = 283.1445, [M + Na]+ = 305.1270. 3-Benzyl-2-(dimethylamino)-3-hydroxy-2,3,4,5,6,7-hexahydroisoindol-1-one (9g). In a dry round-bottom flask were added 2-(dimethylamino)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.31 g, 1.6 mmol) and THF (7.7 mL). The reaction was purged with argon and cooled to −78 °C. Benzylmagnesium bromide (1.2 mL, 1.5 mmol) in 5.0 THF was added via a syringe. After 15 min, the temperature was warmed to rt. LC−MS showed the product at 1.96 min as [M + H]+ = 285. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. Hexanes were added followed by a small amount of Et2O. White solid precipitated out of the solution. The solid was filtered off with the aid of cold hexanes and dried under vacuum to provide a sticky off-white solid, 3-benzyl-2-(dimethylamino)-3hydroxy-2,3,4,5,6,7-hexahydroisoindol-1-one (0.30 g, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.28−7.20 (m, 5H), 3.30 (d, J = 14.1 Hz, 1H), 3.11 (d, J = 14.1 Hz, 1H), 2.95 (s, 7H), 2.11−2.06 (m, 3H), 1.91−1.80 (m, 1H), 1.69−1.50 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 169.2, 152.9, 135.5, 132.8, 129.8, 128.2, 126.9, 90.8, 45.7, 41.8, 22.1, 21.9, 21.6, 19.5. FT-IR (thin film, cm−1) 3330, 2940, 1678. MS calcd for C17H22N2O2 [M]+ = 286, found [M + H]+ = 287. HRMS calcd for C17H22N2O2 [M + H]+ = 287.1754, [M + Na]+ = 309.1574, found [M + H]+ = 287.1771, [M + Na]+ = 309.1594. 1-(Dimethylamino)-5-hydroxy-3,4-dimethyl-5-phenyl-1H-pyrrol2(5H)-one (9h). 1-(Dimethylamino)-3,4-dimethyl-1H-pyrrole-2,5dione (0.40 g, 2.4 mmol) and THF (7.5 mL) were added into a dry round-bottom flask under an argon atmosphere. The reaction was purged with argon and cooled to −78 °C. Then phenyl lithium (1.3 mL, 2.3 mmol; 1.8 M in di-n-butylether) at 0 °C was added via a syringe. After 15 min, the temperature was warmed to rt. LC−MS showed the product at 1.792 min as [M + H]+ = 247. The reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. The product was purified by performing a column chromatography on silica gel eluting with 60:40 Hex/EtOAc to afford a white solid, 1-(dimethylamino)-5-hydroxy-3,4-dimethyl-5-phenyl-1H-pyrrol2(5H)-one (0.39 g, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.43− 7.28 (m, 5H), 3.43, (s, 1H), 2.79 (s, 6H), 1.84 (s, 3H), 1.65 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 170.2, 150.7, 138.0, 128.34, 128.29, 128.13, 126.1, 91.3, 45.3, 10.1, 8.1. FT-IR (thin film, cm−1) 3351 (br), 2951, 2882, 1686. MS calcd for C14H18N2O2 [M]+ = 246, found [M + H]+ = 247. HRMS calcd for C14H18N2O2 [M + H]+ = 247.1441, [M + Na]+ = 269.1261, found [M + H]+ = 247.1465, [M + Na]+ = 269.1272. Mp = 198−199 °C. 2-(Dimethylamino)-3-hydroxy-3-(5-methylpyridin-2-yl)isoindolin-1-one (9i). Following the general procedure to prepare 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1one (9b), this compound was prepared using 2-bromo-5-methylpyridine (1.0 g, 5.8 mmol) and THF (9.7 mL), n-BuLi (2.4 mL, 6.1 mmol; 2.5 M solution in THF), 2-(dimethylamino)isoindoline-1,3dione (1.3 g, 7.0 mmol) in 10 mL of THF. The product was purified by performing a column chromatography eluting with 85:15 DCM/ (90:10:1 DCM/MeOH/NH4OH) to afford a viscous yellow oil (1.4 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.50−7.47 (m, 1H), 7.19−7.12 (m, 3H), 6.82−6.80 (m, 1H), 6.70 (br s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 2.50 (s, 6H), 2.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.6, 153.4, 147.5, 146.0, 138.0, 133.5, 132.6, 131.2, 129.6, 122.8, 122.6, 120.1, 88.8, 45.0, 18.1. FT-IR (thin film, cm−1) 3337 (br), 1700. MS calcd for C16H17N3O2 [M]+ = 283, found [M + H]+ = 284. HRMS calcd for C16H17N3O2 [M + H]+ = 284.1394, 3894



Article

(s, 3H), 2.77 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 165.8, 162.4, 156.3, 147.3, 139.8, 133.2, 130.8, 128.9, 122.4, 121.8, 114.8, 109.6, 90.7, 52.5, 44.4. MS calcd for C16H17N3O3 [M]+ = 299, found [M + H]+ = 300; [2M + Na]+ = 621. HRMS calcd for C16H17N3O3 [M + H]+ = 300.1343, found [M + H]+ = 300.1337. Mp = 142 °C. 2-(Dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin1-one and 2-(Dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)isoindolin-1-one (9n and 9o).40,41,56,57 Under a nitrogen atmosphere, n-BuLi (1.3 mL, 3.4 mmol) was added into a solution of TMEDA (0.55 mL, 3.7 mmol) in Et2O (3.1 mL) at rt. Then 3-methylthiophene (0.29, 3.1 mmol) was added via a syringe. The mixture was heated to reflux under a nitrogen atmosphere for 5 min. The reaction was cooled to rt, and the whole was cannulated into a mixture of 2-(dimethylamino)isoindoline-1,3-dione (0.70 g, 3.7 mmol) in ether (10 mL). The solution became milky. After 15 min, LC−MS showed product at 1.913 min as [M + H]+ = 289. The ratio of regioisomers could not be determined from LC−MS at this point. TLC showed one intense spot. The reaction was quenched slowly with brine. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The residue was purified by performing a column chromatography eluting with 80:20 DCM/(90:10:1 DCM/MeOH/NH4OH) to afford a light yellow solid (0.96 g, 90% yield). HPLC showed a 9:1 mixture of two isomers. Minor isomer 9o, 2-(dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)isoindolin-1-one, was at 6.156 min. Major isomer 9n, 2-(dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-1one, was at 6.335 min. MS calcd for C15H16N2O2S [M]+ = 288, found [M + H]+ = 289. A small amount of the mixture was purified by HPLC for characterization of both isomers. This mixture was carried on to the next step. 2-(Dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin1-one (9n). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.3 Hz, 1H), 7.56−7.46 (m, 2H), 7.42−7.40 (m, 1H), 6.86 (m, 2H), 4.04 (br s, 1H), 2.95 (s, 6H), 2.21 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.0, 145.4, 143.1, 137.1, 132.4, 129.5, 127.6, 122.8, 122.6, 121.1, 88.7, 45.2, 15.4. 13C NMR (151 MHz, CDCl3) δ 166.3, 145.8, 143.4, 139.4, 137.4, 132.7, 129.8, 128.0, 123.1, 122.9, 121.4, 89.0, 45.5, 15.7. FT-IR (thin film, cm−1) 3315 (br), 1689. MS calcd for C15H16N2O2S [M]+ = 288, found [M + H]+ = 289. HRMS calcd for C15H16N2O2S [M + Na]+ = 311.0825, found [M + Na]+ = 311.0835. Mp = 157−159 °C. 2-(Dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)isoindolin1-one (9o). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.3 Hz, 1H), 7.56−7.46 (m, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H), 6.78 (d, J = 3.0 Hz, 1H), 3.80 (br s, 1H), 2.80 (s, 6H), 2.51 (s, 3H). FT-IR (thin film, cm−1) 3282, 1686. MS calcd for C15H16N2O2S [M]+ = 288, found [M + H]+ = 289. HRMS calcd for C15H16N2O2S [M + Na]+ = 311.0825, found [M + Na]+ = 311.0800. Mp = 163−165 °C. 2-(Dimethylamino)-3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin1-one (9p). A solution of 2-bromo-5-methylthiophene (0.60 mL, 5.3 mmol) in THF (11 mL) was purged with nitrogen and cooled to −78 °C. n-Butyllithium (2.2 mL, 5.5 mmol; 2.5 M in THF) was added, and the mixture was stirred under nitrogen for 30 min. The resulting solution was cannulated into a flask containing a solution of 2-(dimethylamino)isoindoline-1,3-dione (1.5 g, 7.9 mmol) in THF (16 mL) at −78 °C under a nitrogen atmosphere. The reaction was allowed to warm to −30 °C over 1 h, at which point LC−MS showed complete conversion of 2-bromo-5-methylthiophene to product. The reaction was quenched by careful addition of saturated aqueous NH4Cl. The whole was diluted with dichloromethane and water, and the layers were separated. The aqueous portion was extracted with dichloromethane, and the combined organics were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography eluting with 0−2% MeOH in dichloromethane to provide a light yellow solid, 2-(dimethylamino)-3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin-1-one (1.2 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.68−7.65 (m, 1H), 7.63−7.59 (m, 1H), 7.57−7.51 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.69−6.66 (m, 1H), 6.65− 6.62 (m, 1H), 2.81 (s, 6H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSOd6) δ 165.0, 147.3, 141.6, 139.3, 132.7, 129.49, 129.46, 125.0, 124.7, 123.0, 122.1, 88.4, 44.7, 14.9. FT-IR (thin film, cm−1) 3347, 3215, 1673. MS calcd for C15H16N2O2S [M]+ = 288, found [M + H]+ = 289. HRMS calcd

for C15H16N2O2S [M + H]+ = 289.1005, [M + Na]+ = 311.0825, found [M + H]+ = 289.1022, [M + Na]+ = 311.0838. Mp = 138−140 °C. 2-(Dimethylamino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindolin-1-one (9q). n-BuLi (5.9 mL, 15 mmol) was added slowly into a solution of THF (18 mL) in TMEDA (2.2 mL, 15 mmol) at 0 °C. After 30 min at 0 °C, 2-ethylthiophene (1.5 g, 13 mmol) was added slowly. The whole was warmed to rt and heated to 50 °C for 30 min. After cooling down to 0 °C, the solution was cannulated slowly into a cold mixture of 2-(dimethylamino)isoindoline-1,3-dione (2.5 g, 13 mmol) in 30 mL of ether at 0 °C. After warming to rt for 15 min, the reaction was quenched slowly with saturated aqueous NH4Cl and brine. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a brown oil. The product was purified by performing column chromatography on silica gel eluting with 70:30 Hex/EtOAc to afford 2-(dimethylamino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindolin-1one (3.2 g, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.3 Hz, 1H), 7.63−7.51 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.70 (d, J = 3.8 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 2.81 (s, 6H), 2.76 (q, J = 7.3 Hz, 2H), 1.20 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.0, 147.3, 146.8, 141.2, 132.7, 129.5, 129.4, 124.8, 123.1, 122.8, 122.1, 88.4, 44.6, 22.8, 15.8. FT-IR (thin film, cm−1) 3265 (br), 2963, 2879, 1679. MS calcd for C16H18N2O2S [M]+ = 302, found [M + H]+ = 303. HRMS calcd for C16H18N2O2S [M + H]+ = 303.1162, [M + Na]+ = 325.0981, found [M + H]+ = 303.1177, [M + Na]+ = 325.0988. Mp = 104−105 °C. 3-(Benzo[b]thiophen-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9r). To a solution of benzo[b]thiophene (0.75 g, 5.6 mmol) in 19 mL of THF at −78 °C was added n-BuLi (2.4 mL, 5.9 mmol; 2.5 M in hexanes). The reaction was allowed to stir for 15 min at −78 °C and was warmed to 0 °C for 30 min. The reaction was cooled back to −78 °C, and a solution of 2-(dimethylamino)isoindoline-1,3-dione (1.1 g, 5.9 mmol) in 5 mL of THF was added via a cannula over 5 min. The resulting yellow solution was allowed to stir for 15 min and was warmed to rt. A precipitate was formed. After 30 min, the reaction was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with brine (1x), dried over sodium sulfate, filtered, and concentrated in vacuum to give an oil. Purification by silica gel chromatography (MPLC, 80 g, 0−50% EtOAc in hexanes) provided 1.7 g of a white foam. Recrystallization from a 2:1 mixture of hot H2O/ ACN provided 3-(benzo[b]thiophen-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (1.2 g, 64% yield) as white crystals. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 - 7.93 (m, 1 H), 7.77 - 7.82 (m, 1 H), 7.72 (d, J = 7.0 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.3 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.37 (s, 1 H), 7.29 - 7.36 (m, 3 H), 2.83 (s, 6 H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.0, 146.9, 145.4, 139.2, 138.9, 132.9, 129.7, 129.5, 124.4, 124.2, 123.8, 123.1, 122.3, 122.3, 122.0, 88.5, 44.7. FT-IR (thin film, cm−1) 3277, 1682. HRMS calcd for C18H17N2O2S [M + H]+ = 325.1011, found [M + H]+ = 325.1005. Mp = 168.8−169.5 °C. 2-(Dimethylamino)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1one (9s). Following the procedure to prepare 2-(dimethylamino)-3hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (9t), this compound was prepared using 5-methylthiazole (0.66 g, 6.6 mmol) and THF (13 mL), n-BuLi (2.8 mL, 6.9 mmol), 2-(dimethylamino)isoindoline1,3-dione (1.9 g, 9.9 mmol) in 15 mL of THF. The product was purified by trituration with hexanes to afford an orange solid, 2-(dimethylamino)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1-one (1.4 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.75−7.73 (m, 1H), 7.67−7.57 (m, 2H), 7.63 (s, 1H), 7.43 (d, 1H), 7.37−7.36 (m, 1H), 2.86 (s, 6H), 2.50 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.1, 165.3, 145.9, 140.3, 135.0, 132.7, 130.0, 129.6, 122.83, 122.2, 89.1, 44.5, 11.5. FT-IR (thin film, cm−1) 3100 (br), 2954, 2885, 1710, 1464, 1442, 1341. MS calcd for C14H15N3O2S [M]+ = 289, found [M + H]+ = 290. HRMS calcd for C14H15N3O2S [M + H]+ = 290.0958, [M + Na]+ = 312.0777, found [M + H]+ = 290.0988, [M + Na]+ = 312.0780. Mp = 160−161 °C. General Procedure To Prepare Thiazole Hydroxyisoindolinones. 2-(Dimethylamino)-3-hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (9t). In a dry round-bottom flask, a solution of 3895



Article

23 mmol) in THF (20 mL), n-butyllithium (25 mL; 1.04 M solution in hexanes), 2-(dimethylamino)isoindoline-1,3-dione (5.4 g, 28 mmol) and THF (15 mL). The product was purified by MPLC silica gel chromatography using 0−100% (90:10 MeOH/CH2Cl2) in DCM to yield 3-(4-tert-butylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1one (4.2 g, 55% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.68−7.66 (m, 1H), 7.56−7.48 (m, 2H), 7.35−7.33 (m, 2H), 7.29−7.26 (m, 2H), 7.17−7.15 (m, 1H), 6.90 (s, 1H), 2.73 (s, 6H), 1.25 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ ppm 165.3, 149.9, 147.9, 136.7, 132.4, 129.8, 128.8, 125.8, 124.4, 122.7, 121.8, 89.8, 44.3, 34.0, 30.9. FT-IR (thin film, cm−1) 3310 (br), 2954, 2867, 1681, 1466, 1360. MS calcd for C20H24N2O2 [M]+ = 324.4, found [M + H]+ = 325.1. HRMS calcd for C20H24N2O2 [M + H]+ = 325.1911, [M + Na]+ = 347.1730, found [M + H]+ = 325.1924, [M + Na]+ = 347.1746. Mp = 68−69 °C. 2-(Dimethylamino)-3-hydroxy-3-m-tolylisoindolin-1-one (9x). Following the general procedure to prepare 3-(4-chlorophenyl)-2(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this compound was prepared using 1-bromo-3-methylbenzene (1.1 mL, 8.8 mmol) and THF (15 mL), n-BuLi (3.7 mL, 9.2 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.9 g, 9.9 mmol) in 15 mL of THF. The product was purified by trituration with hexanes to afford 2(dimethylamino)-3-hydroxy-3-m-tolylisoindolin-1-one (1.8 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.76−7.74 (m, 1H), 7.47−7.44 (m, 2H), 7.30 (s, 1H), 7.23−7.19 (m, 3H), 7.13−7.12 (m, 1H), 4.03 (s, 1H), 2.85 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 167.1, 147.0, 139.3, 138.3, 133.0, 130.5, 129.7, 129.4, 128.5, 127.1, 123.6, 123.4, 123.2, 100.0, 45.5, 21.8. FT-IR (thin film, cm−1) 3317, 2954, 1686, 1611, 1468, 1447, 1360. MS calcd for C17H18N2O2 [M]+ = 282, found [M + H]+ = 283. HRMS calcd for C17H18N2O2 [M + H]+ = 283.1441, [M + Na]+ = 305.1261, found [M + H]+ = 283.1467, [M + Na]+ = 305.1292. Mp = 160−161 °C. 2-(Dimethylamino)-3-hydroxy-3-(3-(trifluoromethyl)phenyl)isoindolin-1-one (9y). Following the general procedure to prepare 3(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this compound was prepared using 1-bromo-3-(trifluoromethyl)benzene (0.61 mL, 4.4 mmol) and THF (7.4 mL), n-BuLi (1.9 mL, 4.7 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.7 g, 8.9 mmol) in 15 mL of THF. The product was purified by trituration with hexanes to afford 2-(dimethylamino)-3-hydroxy-3-(3(trifluoromethyl)phenyl)isoindolin-1-one (1.1 g, 74% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.76−7.74 (m, 1H), 7.55−7.61 (m, 2H), 7.50−7.44 (m, 3H), 7.19−7.21 (d, 1H), 4.23 (s, 1H), 2.82 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 167.0, 146.4, 140.8, 133.4, 131.3, 130.4, 130.2, 130.1, 129.1, 125.7, 125.6, 123.7, 123.6, 123.2, 90.5, 45.6. FT-IR (thin film, cm−1) 3318, 1687, 1468, 1446, 1328, 1167, 1126. MS calcd for C17H15F3N2O2 [M]+ = 336, found [M + H]+ = 337. HRMS calcd for C17H15F3N2O2 [M + H]+ = 337.1158, [M + Na]+ = 359.0978, found [M + H]+ = 337.1161, [M + Na]+ = 359.0988. Mp = 113−114 °C. 3-(4-Chloro-3-methoxyphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9z). Following the general procedure to prepare 3-(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this compound was prepared using 4-bromo-1-chloro-2methoxybenzene (1.2 g, 5.4 mmol) and THF (9.0 mL), n-BuLi (23 mL, 5.7 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.1 g, 6.0 mmol) in 10 mL of THF. The product was purified by recrystallization with a mixture of DCM/hexanes to afford the first batch as white crystals, 3-(4-chloro-3-methoxyphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.62 g, 34% yield). A second batch was obtained from the mother liquor by column chromatography eluting with 60:40 Hex/EtOAc to afford an off-white solid (0.14 g, 8% yield). The overall yield was 42%. 1H NMR (400 MHz, CDCl3) δ 7.82−7.80 (m, 1H), 7.56−7.49 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.24−7.23 (m, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.1, 2.1 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 1H), 2.93 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 166.6, 155.0, 146.2, 139.4, 133.0, 130.03, 129.95, 129.8, 123.3, 122.78, 122.7, 119.2, 110.3, 90.4, 56.2, 45.4. FT-IR (thin film, cm−1) 3332 (br), 2958, 2885, 1687. MS calcd for C17H17ClN2O3 [M]+ = 332, found [M + H]+ = 333. HRMS calcd for C17H17ClN2O3

4-methylthiazole (1.5 g, 15 mmol) in THF (25 mL) was purged with argon. The whole was cooled to −78 °C. n-BuLi (6.4 mL, 16 mmol) was added via a syringe. After 30 min at −78 °C, the reaction was allowed to warm to 0 °C. After 30 min, the whole was cooled back to −78 °C. Then, the anion was cannulated into a solution of 2-(dimethylamino)isoindoline-1,3-dione (3.2 g, 17 mmol) in 20 mL of THF at −30 °C. After 15 min, the temperature was warmed to rt, quenched slowly with saturated aqueous NH4Cl, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. Trituration with hexanes afforded a beige solid, 2-(dimethylamino)-3-hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (3.4 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 6.7 Hz, 1H), 7.61−7.52 (m, 3H), 7.30 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 1.0 Hz, 1H), 2.80 (s, 6H), 2.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 165.2, 151.9, 145.8, 132.7, 130.0, 129.6, 122.8, 122.2, 115.7, 89.0, 44.4, 16.8. FT-IR (thin film, cm−1) 3300 (br), 2956, 2887, 1690. MS calcd for C 14 H 15 N 3 O 2 S [M]+ = 289, found [M + H]+ = 290. HRMS calcd for C14H15N3O2S [M + H]+ = 290.0958, [M + Na]+ = 312.0777, found [M + H]+ = 290.0968, [M + Na]+ = 312.0775. Mp = 137−139 °C. 2-(Dimethylamino)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindolin-1-one (9u). Following the general procedure to prepare 2-(dimethylamino)-3-hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (9t), this compound was prepared using 4,5-dimethylthiazole (2.0 g, 18 mmol) and THF (29 mL), n-BuLi (7.4 mL, 19 mmol), 2-(dimethylamino)isoindoline-1,3-dione (3.7 g, 19 mmol) in 20 mL of THF. The product was purified by trituration with hexanes to afford a yellow solid, 2-(dimethylamino)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindolin-1one (3.7 g, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.79−7.77 (m, 1H), 7.55−7.48 (m, 2H), 7.35−7.33 (m, 1H), 5.39 (s, 1H), 2.95 (s, 6H), 2.34 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.4, 163.7, 147.5, 144.9, 132.8, 130.1, 129.3, 123.2, 122.8, 88.6, 45.4, 14.7, 11.5. FTIR (thin film, cm−1) 3305 (br), 1690. MS calcd for C15H17N3O2S [M]+ = 303, found [M + H]+ = 304. HRMS calcd for C15H17N3O2S [M + H]+ = 304.1114, [M + Na]+ = 326.0934, found [M + H]+ = 304.1130, [M + Na]+ = 326.0964. Mp = 183−185 °C. General Procedure To Prepare Substituted Phenyl Hydroxyisoindolinones. 3-(4-Chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v). In a dry round-bottom flask, a solution of 1-bromo-4-chlorobenzene (9.2 g, 48 mmol) and THF (80 mL) was cooled to −78 °C. n-BuLi (20 mL, 50 mmol) was added via a syringe. After 30 min, the anion was cannulated into a solution of 2-(dimethylamino)isoindoline-1,3-dione (10 g, 53 mmol) in 100 mL of THF (the SM precipitated out of the solution at low temp) over a period of 45 min. After 15 min at −78 °C, the temperature was warmed to rt. After 1 h, the reaction was quenched slowly with saturated aqueous NH4Cl (10 mL). After concentration, the residue was dissolved with DCM (50 mL), and brine (20 mL) was added. The organic layer was separated. The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give a viscous colorless oil. Trituration with hexanes afforded the first batch as white solid (9.9 g, 68% yield). The second batch (0.51 g, 3.5% yield) was obtained from the filtrate. 1H NMR (400 MHz, CDCl3) δ 7.76−7.74 (m, 1H), 7.52−7.45 (m, 2H), 7.41−7.37 (m, 2H), 7.33−7.30 (m, 2H), 7.20−7.17 (m, 1H), 3.87 (s, 1H), 2.84 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 166.6, 146.3, 137.8, 134.4, 133.0, 130.2, 129.8, 128.5, 127.9, 123.3, 122.9, 90.2, 45.3. FT-IR (thin film, cm−1) 3303 (br), 1678. MS calcd for C16H15ClN2O2 [M]+ = 302, found [M + H]+ = 303. HRMS calcd for C16H15ClN2O2 [M + H]+ = 303.0895, [M + Na]+ = 325.0714, found [M + H]+ = 303.0900, [M + Na]+ = 325.0735. Mp = 133−134 °C. 3-(4-tert-Butylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1one (9w). Following the general procedure to prepare 3-(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this compound was prepared using 1-bromo-4-tert-butylbenzene (4.1 mL, 3896



Article

yield). 1H NMR (400 MHz, DMSO-d6) δ 7.60−7.57 (m, 2H), 7.50− 7.48 (m, 2H), 6.29 (s, 1H), 5.77 (s, 1H), 2.90 (s, 6H), 2.13−2.05 (m, 2H), 1.80−1.77 (m, 1H), 1.61−1.50 (m, 2H), 1.33−0.94 (m, 5H). 13C NMR (151 MHz, DMSO-d6) δ 165.2, 145.2, 131.8, 130.9, 128.8, 122.8, 121.9, 92.2, 44.5, 42.3, 27.7, 26.8, 26.2, 26.0, 25.6. FT-IR (thin film, cm−1) 3365 (br), 2930, 2833, 1688. MS calcd for C16H22N2O2 [M]+ = 274, found [M + H]+ = 275. HRMS calcd for C16 H22 N2O2 [M + H]+ = 275.1754, [M + Na]+ = 297.1573, found [M + H]+ = 275.1771, [M + Na]+ = 297.1582. Mp = 139−140 °C. General Procedure To Prepare Alkynyl Hydroxyisoindolinones. 2-(Dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al). In a dry round-bottom flask were added 3,3-dimethylbut-1-yne (0.40 g, 4.9 mmol) and THF (8.1 mL). After purging with argon and cooling to −78 °C, n-BuLi (2.0 mL, 5.1 mmol) was added via a syringe. After 30 min at −78 °C, a solution of 2-(dimethylamino)isoindoline-1,3-dione (0.93 g, 4.9 mmol) in 10 mL of THF at rt was added into the anion over a period of 15 min. After another 15 min, the temperature was warmed to rt. After 1 h at rt, the reaction was quenched slowly with saturated aqueous NH4Cl (15 mL). The product was extracted with Et2O (3 × 30 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give an oil. Trituration with hexanes afforded a white solid, 2-(dimethylamino)3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (1.1 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.3 Hz, 1H), 7.62−7.56 (m, 2H), 7.48 (td, J = 6.8, 1.5 Hz, 1H), 4.12 (s, 1H), 3.05 (s, 6H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 165.3, 144.0, 132.7, 129.8, 122.9, 122.6, 93.0, 82.1, 75.4, 45.2, 30.5, 27.3. FTIR (thin film, cm−1) 3315 (br), 2970, 1690. MS calcd for C16H20N2O2 [M]+ = 272, found [M + H]+ = 273. HRMS calcd for C16H20N2O2 [M + H]+ = 273.1598, [M + Na]+ = 295.1417, found [M + H]+ = 273.1620, [M + Na]+ = 295.1447. Mp = 179−181 °C. 2-(Dimethylamino)-3-hydroxy-3-(phenylethynyl)isoindolin-1-one (9ae). Following the general procedure to prepare 2-(dimethylamino)3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this compound was prepared using 1-ethynylbenzene (0.54 mL, 4.9 mmol) and THF (8.2 mL), n-BuLi (2.1 mL, 5.1 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.0 g, 5.4 mmol) in 20 mL of THF. The product was purified by performing a column chromatography on silica gel eluting with 75:25 Hex/EtOAc to afford an off-white solid, 2-(dimethylamino)-3-hydroxy-3-(2-phenylethynyl)isoindolin-1-one (1.2 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.62 (td, J = 7.5, 1.2 Hz, 1H), 7.51 (td, J = 8.6, 1.0 Hz, 1H), 7.45−7.42 (m, 2H), 7.35−7.29 (m, 3H), 4.58 (s, 1H), 3.12 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.3, 143.5, 132.9, 131.8, 130.1, 130.0, 129.1, 128.3, 123.1, 122.8, 121.4, 85.4, 84.0, 82.4, 45.4. FT-IR (thin film, cm−1) 3315 (br), 1690. MS calcd for C18H16N2O2 [M]+ = 292, found [M + H]+ = 293. HRMS calcd for C18H16N2O2 [M + H]+ = 293.1285, [M + Na]+ = 315.1104, found [M + H]+ = 293.1306, [M + Na]+ = 315.1121. Mp = 145−146 °C. 2-(Dimethylamino)-3-hydroxy-3-(pyridin-2-ylethynyl)isoindolin1-one (9af). Following the general procedure to prepare 2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this compound was prepared using 2-ethynylpyridine (0.66 g, 6.4 mmol) and THF (11 mL), n-BuLi (2.7 mL, 6.7 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.3 g, 7.0 mmol) in 15 mL of THF. The product was purified by performing a column chromatography eluting with 30:70 Hex/EtOAc to afford an orange solid, 2-(dimethylamino)3-hydroxy-3-(2-(pyridin-2-yl)ethynyl)isoindolin-1-one (0.94 g, 50% yield). This analogue must be stored cold to prevent decomposition. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 4.1 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.67 (td, J = 7.6, 1.7 Hz, 1H), 7.61 (td, J = 8.6, 1.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.30−7.26 (m, 1H), 5.48 (br s, 1H), 3.14 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.1, 149.6, 142.9, 141.5, 136.0, 132.6, 129.6, 129.84, 129.76, 127.1, 123.2, 122.8, 85.4, 82.4, 81.9, 45.1. FT-IR (thin film, cm−1) 3059 (br), 1703. MS calcd for C17H15N3O2 [M]+ = 293, found [M + H]+ = 294. HRMS calcd for C17H15N3O2 [M + H]+ = 294.1237, [M + Na]+ = 316.1057, found [M + H]+ = 294.1249, [M + Na]+ = 316.1056. Mp: crystallized at 73−78 °C and melted at 109−110 °C.

[M + H]+ = 333.1001, [M + Na]+ = 355.0820, found [M + H]+ = 333.1024, [M + Na]+ = 355.0833. Mp = 178−179 °C. General Procedure To Prepare Alkyl/Cycloalkyl Hydroxyisoindolinones. 2-(Dimethylamino)-3-hydroxy-3-isopropylisoindolin-1-one (9aa). In a dry round-bottom flask were added 2-(dimethylamino)isoindoline-1,3-dione (2.8 mg, 15 mmol) and THF (16 mL). After cooling to −78 °C, isopropylmagnesium chloride (4.9 mL, 9.7 mmol; 2 M solution in diethyl ether) was added via a syringe over 10 min. After 30 min at −78 °C, the reaction was warmed to rt. After 30 min, the reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow solid. The product was purified by column chromatography eluting with 85:15 DCM/(90:10:1 DCM/MeOH/NH4OH) to afford a white solid, 2-(dimethylamino)-3-hydroxy-3-isopropylisoindolin-1-one (2.1 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.1 Hz, 2H), 7.53−7.49 (m, 2H), 6.31 (s, 1H), 2.91 (s, 6H), 2.49 (sep, J = 6.8 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H), 0.53 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.3, 144.8, 131.3, 131.1, 128.9, 122.81, 121.9, 92.6, 44.5, 32.2, 17.4, 17.0. FT-IR (thin film, cm−1) 3362 (br), 2960, 2876, 1682. MS calcd for C13H18N2O2 [M]+ = 234, found [M + H]+ = 235. HRMS calcd for C13H18N2O2 [M + H]+ = 235.1441, [M + Na]+ = 257.1269, found [M + H]+ = 235.1454, [M + Na]+ = 257.1269. The solid melted at 69−70 °C to form a glass, which was then recrystallized. It eventually melted again at 166−167 °C. 3-Benzyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9ab). Following the general procedure to prepare 2-(dimethylamino)-3hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was prepared using 2-(dimethylamino)isoindoline-1,3-dione (0.76 g, 4.0 mmol) and THF (5.5 mL), benzylmagnesium chloride (2.5 mL, 3.3 mmol; 1.3 M solution in THF). The product was purified using 60:40 Hex/EtOAc to afford a light yellow foam, 3-benzyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.49 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 2.7 Hz, 1H), 7.43 (td, J = 7.3, 1.0 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.29−7.26 (m, 3H), 7.19−7.15 (m, 2H), 6.75 (d, J = 7.3 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 3.28 (s, 1H), 3.06 (s, 6H), 2.91 (d, J = 13.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 165.8, 143.9, 135.3, 131.7, 130.8, 129.4, 128.0, 127.0, 123.6, 122.9, 90.1, 45.7, 43.5. FT-IR (thin film, cm−1) 3351 (br), 2953, 2885, 1683. MS calcd for C17H18N2O2 [M]+ = 282, found [M + H]+ = 283. HRMS calcd for C17H18N2O2 [M + H]+ = 283.1441, [M + Na]+ = 305.1261, found [M + H]+ = 283.1453, [M + Na]+ = 305.1284. Mp = 133−134 °C. 3-Cyclopropyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9ac). Following the general procedure to prepare 2-(dimethylamino)3-hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was prepared using 2-(dimethylamino)isoindoline-1,3-dione (1.0 g, 5.3 mmol) and THF (8.0 mL), cyclopropylmagnesium bromide (9.6 mL, 4.8 mmol; 0.5 M in THF). The product was purified by performing a column chromatography on silica gel eluting with 70:30 Hex/EtOAc to afford a white solid, 3-cyclopropyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.75 g, 67% yield). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 1H), 7.52−7.41 (m, 3H), 3.49 (s, 1H), 2.99 (s, 6H), 1.31−1.21 (m, 1H), 0.86 (sex, J = 5.3 Hz, 1H), 0.68−0.61 (m, 1H), 0.47−0.40 (m, 1H), 0.36−0.29 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 165.6, 144.5, 132.0, 130.8, 129.4, 122.9, 122,4, 88.6, 45.3, 17.6, 1.42, 0.41. FT-IR (thin film, cm−1) 3332, 2952, 1675. MS calcd for C13H16N2O2 [M]+ = 232, found [M + H]+ = 233. HRMS calcd for C13H16N2O2 [M + H]+ = 233.1285, [M + Na]+ = 255.1104, found [M + H]+ = 233.1302, [M + Na]+ = 255.1115. Mp = 169−170 °C. 3-Cyclohexyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9ad). Following the general procedure to prepare 2-(dimethylamino)3-hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was prepared using 2-(dimethylamino)isoindoline-1,3-dione (1.2 g, 6.4 mmol) and THF (8.9 mL), cyclohexylmagnesium bromide (6.4 mL, 5.3 mmol; 18% in THF). The product was purified using 85:15 DCM/ (90:10:1 DCM/MeOH/NH4OH) to afford a light yellow foam, 3cyclohexyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (1.3 g, 87% 3897



Article

δ 7.6 (d, J = 7.6 Hz, 1H), 7.64−7.58 (m, 2H), 7.49 (td, J = 7.3, 1.5 Hz, 1H), 4.19 (s, 1H), 3.07 (s, 6H), 1.09−0.99 (m, 21H). 13C NMR (101 MHz, CDCl3) δ 165.5, 143.6, 132.9, 130.0, 130.1, 123.1, 122.7, 103.2, 86.4, 81.9, 45.4, 18.5, 11.1. FT-IR (thin film, cm−1) 3317, 2944, 2866, 1693. MS calcd for C21H32N2O2Si [M]+ = 372, found [M + H]+ = 373. HRMS calcd for C21H32N2O2Si [M + H]+ = 373.2306, [M + Na]+ = 395.2125, found [M + H]+ = 373.2332, [M + Na]+ = 395.2152. Mp = 134−135 °C. 2-(Dimethylamino)-3-(hex-1-ynyl)-3-hydroxyisoindolin-1-one (9aj). Following the general procedure to prepare 2-(dimethylamino)3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this compound was prepared using hex-1-yne (0.68 mL, 6.1 mmol) and THF (10 mL), n-BuLi (2.6 mL, 6.4 mmol), 2-(dimethylamino)isoindoline1,3-dione (1.3 g, 6.7 mmol) in 15 mL of THF. The product was recrystallized in hexanes to yield light yellow crystals, 2-(dimethylamino)-3-(hex-1-ynyl)-3-hydroxyisoindolin-1-one (1.6 g, 95% yield). 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.4 Hz, 1H), 7.63−7.57 (m, 2H), 7.48 (td, J = 7.1, 1.5 Hz, 1H), 4.06 (s, 1H), 3.07 (s, 6H), 2.23 (t, J = 7.1 Hz, 2H), 1.49 (quin, J = 7.3 Hz, 2H), 1.39 (sex, J = 8.1 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.3, 143.9, 132.8, 129.8, 123.0, 122.6, 85.6, 82.1, 76.7, 45.3, 30.2, 21.9, 18.3, 13.5. FT-IR (thin film, cm−1) 3319, 2955, 2932, 2872, 2239, 1687. MS calcd for C16H20N2O2 [M]+ = 272, found [M + H]+ = 273. HRMS calcd for C16H20N2O2 [M + H]+ = 273.1598, [M + Na]+ = 295.1417, found [M + H]+ = 273.1610, [M + Na]+ = 295.1422. Mp = 87−88 °C. 2-(Dimethylamino)-3-hydroxy-3-(4-hydroxybut-1-ynyl)isoindolin-1-one (9ak). Following the general procedure to prepare 2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1one (9al), this compound was prepared using but-3-yn-1-ol (0.16 mL, 2.1 mmol) and THF (3.6 mL), n-BuLi (1.8 mL, 4.4 mmol), 2-(dimethylamino)isoindoline-1,3-dione (0.43 g, 2.2 mmol) in 10 mL of THF. The product was purified by performing a column chromatography eluting with 60:40 Hex/EtOAc to afford a sticky off-white solid, 2-(dimethylamino)-3-hydroxy-3-(4-hydroxybut-1-ynyl)isoindolin-1-one (0.43 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 1H), 7.65−7.60 (m, 2H), 7.51 (t, J = 4.3 Hz, 1H), 4.60 (s, 1H), 3.76 (distorted t, J = 5.6 Hz, 2H), 3.08 (s, 6H), 2.75 (br s, 1H), 2.52 (distorted t, J = 4.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 165.6, 144.1, 133.3, 130.3, 130.0, 123.3, 122.9, 83.0, 82.2, 78.8, 60.9, 45.6, 23.3. FT-IR (thin film, cm−1) 3304 (br), 2956, 2885, 2245, 1688. MS calcd for C14H16N2O3 [M]+ = 260, found [M + H]+ = 261. HRMS calcd for C14H16N2O3 [M + H]+ = 261.1234, [M + Na]+ = 283.1053, found [M + H]+ = 261.1257, [M + Na]+ = 283.1067. 3-(Cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin1-one (9am). Following the general procedure to prepare 2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this compound was prepared using ethynylcyclopropane (0.57 g, 6.1 mmol; 70% by wt. in toluene) and THF (10 mL), n-BuLi (2.5 mL, 6.4 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.2 g, 6.3 mmol) in 10 mL of THF. Trituration with hexanes afforded a yellow solid, 3(2-cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (1.2 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.61−7.55 (m, 2H), 7.47 (td, J = 7.4, 1.8 Hz, 1H), 4.38 (br s, 1H), 3.04 (s, 6H), 1.30−1.23 (m, 1H), 0.81−0.67 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 165.3, 143.9, 132.7, 129.83, 129.79, 122.9, 122.6, 88.3, 82.1, 71.8, 45.2, 8.23, −0.10. FT-IR (thin film, cm−1) 3316 (br), 2245, 1689. MS calcd for C15H16N2O2 [M]+ = 256, found [M + H]+ = 257. HRMS calcd for C15H16N2O2 [M + H]+ = 257.1285, [M + Na]+ = 279.1104, found [M + H]+ = 257.1313, [M + Na]+ = 279.1118. Mp = 133−134 °C. General Procedure To Prepare Phthalazinones. 4-(6-Methylpyridin-2-yl)phthalazin-1(2H)-one (7b). 2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (3.2 g, 11 mmol), EtOH (11 mL), and hydrazine (5.3 mL, 168 mmol) were added into a round-bottom flask. A nitrogen balloon was attached on top of the condenser. After refluxing overnight, the reaction was cooled to rt. An off-white solid precipitated out of the solution. After cooling to 0 °C, water was added slowly. The solid was filtered off with the aid of water and dried under vacuum to afford a white solid, 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

2-(Dimethylamino)-3-hydroxy-3-((3-hydroxyphenyl)ethynyl)isoindolin-1-one (9ag). Following the general procedure to prepare 2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1one (9al), this compound was prepared using 3-ethynylphenol (0.50 g, 4.2 mmol) and THF (15 mL), n-BuLi (3.4 mL, 8.6 mmol), 2-(dimethylamino)isoindoline-1,3-dione (0.84 g, 4.4 mmol) in 10 mL of THF. The product was purified by performing a column chromatography eluting with 60:40 Hex/EtOAc to afford an off-white solid, 2-(dimethylamino)-3-hydroxy-3-(2-(3-hydroxyphenyl)ethynyl)isoindolin-1-one (0.75 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.29 (br s, 1H), 7.14 (t, J = 8.1 Hz, 1H), 6.95−6.88 (m, 3H), 4.80 (br s, 1H), 3.09 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.8, 156.0, 143.4, 133.2, 130.2, 129.7, 129.6, 124.0, 123.2, 122.1, 122.9, 118.6, 117.1, 84.7, 84.1, 82.6, 45.3. FT-IR (thin film, cm−1) 3314 (br), 1688. MS calcd for C18H16N2O3 [M]+ = 308, found [M + H]+ = 309. HRMS calcd for C18H16N2O3 [M + H]+ = 309.1334, [M + Na]+ = 331.1053, found [M + H]+ = 309.1300, [M + Na]+ = 331.1055. Mp = 134−135 °C. 2-(Dimethylamino)-3-hydroxy-3-((trimethylsilyl)ethynyl)isoindolin-1-one (9ah). Following the general procedure to prepare 2(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1one (9al), this compound was prepared using ethynyltrimethylsilane (0.86 mL, 6.1 mmol) and THF (10 mL), n-BuLi (2.6 mL, 6.4 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.3 g, 6.7 mmol) in 15 mL of THF. Because the anion formed was so thick, normal addition was used. Trituration with hexanes afforded a white solid, 2-(dimethylamino)-3-hydroxy-3-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (0.89 g, 51% yield). A second batch was obtained from the mother liquor as a white solid (0.82 g, 47% yield). The overall yield was 98%. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.4 Hz, 1H), 7.65−7.58 (m, 2H), 7.50 (td, J = 7.1, 1.5 Hz, 1H), 4.12 (s, 1H), 3.07 (s, 6H), 0.17 (s, 9H). 13C NMR in CDCl3 showed a complex mixture of product probably due to C−O silyl migration. FT-IR (thin film, cm−1) 3301 (br) 2960, 1693. MS calcd for C15H20N2O2Si [M]+ =288, found [M + H]+ =289. HRMS calcd for C15H20N2O2Si [M + H]+ = 289.1367, [M + Na]+ = 311.1186, found [M + H]+ = 289.1374, [M + Na]+ = 311.1183. Mp = 194−195 °C. 2-(Dimethylamino)-3-ethynyl-3-hydroxyisoindolin-1-one (9ah′). To shed light on the complex 13C NMR, desilylation with TBAF was performed. Tetrabutylammonium fluoride (0.27 mL, 1.0 mmol; 1.0 M in THF) was added into a cold solution of 2-(dimethylamino)3-hydroxy-3-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (0.20 g, 0.69 mmol) in THF (1.4 mL) at 0 °C. After 15 min, the reaction was warmed to rt and quenched with saturated aqueous NH4Cl. The product was extracted with Et2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The product was purified further by performing a column chromatography eluting with 60:40 Hex/EtOAc to afford a white solid. 1H NMR showed product cleanly. However, 13C NMR in CDCl3 again was complex. 13C NMR in DMSO-d6 confirmed product, 2-(dimethylamino)-3-ethynyl-3hydroxyisoindolin-1-one (0.12 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.76 (td, J = 7.6, 1.3 Hz, 1H), 7.64−7.60 (m, 2H), 7.56 (td, J = 7.3, 1.2 Hz, 1H), 4.07 (s, 1H), 3.09 (s, 6H), 2.63 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 164.4, 144.9, 133.1, 129.9, 129.1, 122.8, 122.2, 81.5, 81.3, 74.2, 44.5. FT-IR (thin film, cm−1) 3291 (br), 1691. MS calcd for C12H12N2O2 [M]+ = 216, found [M + H]+ = 217. HRMS calcd for C12H12N2O2 [M + H]+ = 217.0972, [M + Na]+ = 239.0791, found [M + H]+ = 217.0983, [M + Na]+ = 239.0796. Mp = 165−166 °C, decomposed. 2-(Dimethylamino)-3-hydroxy-3-((triisopropylsilyl)ethynyl)isoindolin-1-one (9ai). Following the general procedure to prepare 2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1one (9al), this compound was prepared using ethynyltriisopropylsilane (0.46 g, 2.5 mmol) and THF (4.2 mL), n-BuLi (1.1 mL, 2.6 mmol), 2-(dimethylamino)isoindoline-1,3-dione (0.53 g, 2.8 mmol) in 5 mL of THF. The product was purified by performing a column chromatography eluting with 80:20 Hex/EtOAc to afford a white solid, 2-(dimethylamino)-3-hydroxy-3-(2-(triisopropylsilyl)ethynyl)isoindolin-1-one (0.67 g, 71% yield). 1H NMR (400 MHz, CDCl3) 3898



Article

(2.6 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (br s, 1H), 8.46−8.41 (m, 2H), 8.02−7.95 (m, 3H), 7.72 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 2.67 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.4, 157.1, 153.7, 144.1, 137.7, 133.4, 131.6, 128.7, 128.0, 127.5, 125.8, 123.2, 121.2, 24.1. FT-IR (thin film, cm−1) 2918, 2850, 1674. MS calcd for C14H11N3O [M]+ = 237, found [M + H]+ = 238. HRMS calcd for C14H11N3O [M + H]+ = 238.0975, found [M + H]+ = 238.0970. Mp = 242−243 °C. 4-(5-Methylpyridin-2-yl)phthalazin-1(2H)-one (7c). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)3-hydroxy-3-(5-methylpyridin-2-yl)isoindolin-1-one (0.45 g, 1.6 mmol), ethanol (1.6 mL), and hydrazine (0.75 mL, 24 mmol). Similar workup provided a white solid, 4-(5-methylpyridin-2-yl)phthalazin1(2H)-one (0.35 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.62 (s, 1H), 8.44 (d, J = 6.8 Hz, 1H), 8.35 (d, J = 6.8 Hz, 1H), 7.95−7.77 (m, 4H), 2.44 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.3, 151.7, 149.2, 145.7, 137.7, 133.6, 133.5, 131.5, 129.3, 128.4, 127.8, 126.6, 123.8, 18.4. FT-IR (thin film, cm−1) 1672. MS calcd for C14H11N3O [M]+ = 237, found [M + H]+ = 238. HRMS calcd for C14H11N3O [M + H]+ = 238.0975, [M + Na]+ = 260.0794, found [M + H]+ = 238.0984, [M + Na]+ = 260.0795. Mp = 247− 248 °C. 4-(4-Methylpyridin-2-yl)phthalazin-1(2H)-one (7d). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)one (7b), this compound was prepared using 2-(dimethylamino)-3hydroxy-3-(4-methylpyridin-2-yl)isoindolin-1-one (0.50 g, 1.8 mmol), hydrazine (1.1 g, 35 mmol) and ethanol (8.8 mL). Similar workup provided 1-chloro-4-(4-methylpyridin-2-yl)phthalazine as a light yellow solid (0.39 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.59−8.58 (d, 1H), 8.36−8.31 (m, 2H), 7.91−7.84 (m, 2H), 7.66 (s, 1H), 7.36−7.35 (M, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.2. 154.0, 148.1, 148.0, 143.8, 133.0, 131.3, 128.4, 127.7, 127.2, 125.5, 124.4, 124.4, 20.4. FT-IR (thin film, cm−1) 3180, 3045, 1660, 1604, 1557, 1471, 1336. MS calcd for C14H11N3O2 [M]+ = 237, found [M + H]+ = 238. HRMS calcd for C14H11N3O2 [M + H]+ = 238.0975, [M + Na]+ = 260.0794, found [M + H]+ = 238.1007, [M + Na]+ = 260.0823. Mp = 238−239 °C. 4-(6-Methylpyridin-3-yl)phthalazin-1(2H)-one (7e). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)one (7b), this compound was prepared using 2-(dimethylamino)-3hydroxy-3-(6-methylpyridin-3-yl)isoindolin-1-one (0.50 g, 1.8 mmol), hydrazine (1.1 mL, 35 mmol), and ethanol (8.8 mL). Similar workup provided a yellow solid, 4-(6-methylpyridin-3-yl)phthalazin-1(2H)-one (0.40 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.65 (s, 1H), 8.35 (m, 1H), 7.92 (m, 3H), 7.67 (m, 1H), 7.45−7.43 (m, 1H), 2.58 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.8, 158.1, 148.5, 143.6, 136.7, 133.3, 131.4, 128.5, 127.7, 127.4, 125.9, 125.7, 122.3, 23.5. FT-IR (thin film, cm−1) 2917, 2849, 2357, 1652, 1558, 1539, 1455. MS calcd for C14H11N3O [M]+ = 237, found [M + H]+ = 238. HRMS calcd for C14H11N3O [M + H]+ = 238.0975, [M + Na]+ = 260.0794, found [M + H]+ = 238.1000, [M + Na]+ = 260.0816. Mp > 250 °C. 4-(5-Chloropyridin-2-yl)phthalazin-1(2H)-one (7f). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)one (7b), this compound was prepared using 3-(5-chloropyridin-2-yl)-2(dimethylamino)-3-hydroxyisoindolin-1-one (2.0 g, 6.6 mmol), ethanol (6.6 mL), and hydrazine (3.1 mL, 99 mmol). Similar workup provided an off-white solid, 4-(5-chloropyridin-2-yl)phthalazin-1(2H)-one (1.0 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.5 Hz, 1H), 8.39− 8.32 (m, 2H), 8.12 (dd, J = 6.1, 2.5 Hz, 1H), 7.93−7.86 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 159.3, 152.9, 147.1, 142.8, 137.4, 133.4, 131.7, 131.3, 128.3, 127.9, 127.3, 125.9, 125.4. FT-IR (thin film, cm−1) 1688, 1668. MS calcd for C13H8ClN3O [M]+ = 257, found [M + H]+ = 258. HRMS calcd for C13H8ClN3O [M + H]+ = 258.0429, [M + Na]+ = 280.0248, found [M + H]+ = 258.0414, [M + Na]+ = 280.0249. Mp > 250 °C. 4-(6-Methoxypyridin-2-yl)phthalazin-1(2H)-one (7g). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin-1-one (4.2 g, 14 mmol),

ethanol (18 mL), and hydrazine (7 mL, 0.21 mol). Similar workup provided 4-(6-methoxypyridin-2-yl)phthalazin-1(2H)-one (2.4 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ 12.91 (s, 1H), 8.64 (d, J = 7.3 Hz, 1H), 8.33 (dd, J = 7.4, 1.1 Hz, 1H), 7.95−7.86 (m, 3H), 7.44 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 7. Eight Hz, 1H), 3.91 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.6, 159.4, 151.9, 143.6, 140.2, 133.4, 131.5, 128.6, 127.9, 127.2, 125.9, 117.0, 110.7, 53.3. MS calcd for C14H11N3O2 [M]+ = 253, found [M + H]+ = 254; [2M + Na]+ = 529. HRMS calcd for C14H11N3O2 [M + H]+ = 254.09240, found [M + H]+ = 254.09267. Mp = 249 °C. 4-(4-Methylthiophen-2-yl)phthalazin-1(2H)-one (7h) and 4-(3Methylthiophen-2-yl)phthalazin-1(2H)-one (7i). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)one (7b), these compounds was prepared using a mixture of 2(dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-1one and 2-(dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)isoindolin-1-one (7.7 g, 27 mmol) from the previous step, EtOH (27 mL), and hydrazine (13 mL, 0.40 mol). Following similar workup procedure provided a mixture of phthalazinones that were separated by prep-HPLC. 4-(4-Methylthiophen-2-yl)phthalazin-1(2H)-one (7h). Major isomer was obtained as a brown solid (2.9 g, 45% yield). 1H NMR showed the desired isomer. Two singlets for thiophene were evident at 7.2 and 7.1 ppm. 1H NMR (600 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.99 (t, J = 7.2 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 2.31 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 158.9, 140.4, 137.9, 136.7, 134.0, 131.9, 130.8, 128.3, 127.8, 126.30, 126.27, 122.9, 15.6. FT-IR (thin film, cm−1) 2928, 1655. HRMS calcd for C13H10N2OS [M]+ = 242.0514, found [M + H]+ = 243.0537. Mp = 238−239 °C. 4-(3-Methylthiophen-2-yl)phthalazin-1(2H)-one (7i). Minor isomer was obtained as a brown solid (0.93 g, 14% yield). 1H NMR (600 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.33 (dd, J = 7.2, 0.6 Hz, 1H), 7.94−7.88 (m, 2H), 7.69 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 2.09 (s, 3H). 13C NMR (151 MHz, DMSOd6) δ 159.6, 140.8, 137.6, 134.3, 132.3, 130.6, 130.0, 129.8, 127.9, 126.90, 126.87, 126.4, 15.0. COSY (600 MHz, DMSO-d6) showed two doublets at 7.54 and 7.10 ppm that were correlated with one another. FT-IR (thin film, cm−1) 1659. HRMS calcd for C13H10N2OS [M + H]+ = 243.0514, found [M + H]+ = 243.0536. mp =208−209 °C. 4-(5-Methylthiophen-2-yl)phthalazin-1(2H)-one (7j). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin-1-one (1.1 g, 0.40 mmol), hydrazine (0.19 mL, 59 mmol) and 4.0 mL of EtOH. Similar workup provided a white solid, 4-(5-methylthiophen-2-yl)phthalazin-1(2H)one (0.82 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.50−8.39 (m, 1H), 8.14−8.04 (m, 1H), 7.83−7.69 (m, 2H), 7.20−7.17 (m, 1H), 6.82−6.71 (m, 1H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 142.5, 141.1, 134.3, 133.7, 131.7, 129.4, 128.8, 128.3, 127.1, 126.6, 125.8, 15.4. FT-IR (thin film, cm−1) 2891, 1660, 1334. MS calcd for C13H10N2OS [M]+ = 242, found [M + H]+ = 243. HRMS calcd for C13H10N2OS [M + H]+ = 243.0587, found [M + H]+ = 243.0581. Mp = 191−194 °C. 4-(5-Ethylthiophen-2-yl)phthalazin-1(2H)-one (7k). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindolin-1-one (3.2 g, 11 mmol), EtOH (21 mL), and hydrazine (5.0 mL, 0.16 mol). Similar workup provided a light yellow solid, 4-(5-ethylthiophen-2yl)phthalazin-1(2H)-one (2.3 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 12.8, (s, 1H), 8.34 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.98−7.88 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 3.8 Hz, 1H), 2.88 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4, 148.6, 140.4, 134.2, 133.9, 131.8, 123.4, 128.3, 127.8, 126.2, 126.1, 124.4, 22.7, 15.8. FT-IR (thin film, cm−1) 1662. MS calcd for C14H12N2OS [M]+ = 256, found [M + H]+ = 257. HRMS calcd for C14H12N2OS [M + H]+ = 257.0743, [M + Na]+ = 279.0563, found [M + H]+ = 257.0752, [M + Na]+ = 279.0568. Mp = 198− 200 °C. 3899



Article

[M + Na]+ = 279.0296, found [M + H]+ = 257.0480, [M + Na]+ = 279.0301. Mp > 250 °C. 4-(4-tert-Butylphenyl)phthalazin-1(2H)-one (7q). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 3-(4-tertbutylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (3.5 g, 11 mmol), ethanol (11 mL), and anhydrous hydrazine (5.2 mL, 0.16 mol). Similar workup provided 4-(4-tert-butylphenyl)phthalazin1(2H)-one as an off-white solid (2.6 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.35−8.32 (m, 1H), 7.92−7.86 (m, 2H), 7.72−7.70 (m, 1H), 7.58−7.51 (m, 4H), 1.35 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ ppm 159.2, 151.4, 146.3, 133.5, 132.2, 131.5, 129.0, 127.9, 126.6, 126.0, 125.3, 34.5, 31.1. FT-IR (thin film, cm−1) 2950, 2865, 1659, 1605, 1492, 1455, 1341. MS calcd for C18H18N2O [M]+ = 278.3, found [M + H]+ = 279.1. HRMS calcd for C18H18N2O [M + H]+ = 279.1492, [M + Na]+ = 301.1311, found [M + H]+ = 279.1504, [M + Na]+ = 301.1319. Mp > 250 °C. 4-m-Tolylphthalazin-1(2H)-one (7r). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-3hydroxy-3-m-tolylisoindolin-1-one (1.00 g, 0.35 mmol), hydrazine (2.2 mL, 71 mmol), and EtOH (18 mL). Similar workup provided 4m-tolylphthalazin-1(2H)-one as a light yellow solid (0.73 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.34−8.32 (m, 1H), 7.89−7.87 (m, 2H), 7.68−7.66 (m, 1H), 7.45−7.43 (m, 4H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.6, 146.9, 138.3, 135.2, 134.0, 132.0, 130.2, 130.0, 129.4, 128.8, 128.3, 127.0, 126.8, 126.5, 21.4. FT-IR (thin film, cm−1) 2900, 1669, 1341. MS calcd for C15H12N2O [M]+ = 236, found [M + H]+ = 237. HRMS calcd for C15H12N2O [M + H]+ = 237.1022, found [M + H]+ = 237.1033. Mp = 210−211 °C. 4-(3-(Trifluoromethyl)phenyl)phthalazin-1(2H)-one (7s). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (7b), this compound was prepared using 2(dimethylamino)-3-hydroxy-3-(3-(trifluoromethyl)phenyl)isoindolin1-one (0.80 g, 2.4 mmol), hydrazine (1.5 mL, 48 mmol), and ethanol (12 mL). Similar workup provided 4-(3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one as a light yellow solid (0.61 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.36−8.34 (m, 1H), 7.93−7.87 (m, 5H), 7.82−7.78 (m, 1H), 7.61−7.65 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 160.0, 145.5, 136.6, 134.2, 134.0, 132.2, 130.1, 130.0, 129.7, 129.2, 128.3, 126.6, 126.3, 126.0, 125.8. FTIR (thin film, cm−1) 3178, 3032, 2359, 2337, 1695, 1652, 1558, 1324. MS calcd for C15H9F3N2O [M]+ = 290, found [M + H]+ = 291. HRMS calcd for C15H9 F3N2O [M + H]+ = 291.0740, [M + Na]+ = 313.0559, found [M + H]+ = 291.0762, [M + Na]+ = 313.0577. Mp = 259−260 °C. 4-(4-Chloro-3-methoxyphenyl)phthalazin-1(2H)-one (7t). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (7b), this compound was prepared using 3-(4chloro-3-methoxyphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1one (0.76 g, 2.3 mmol), ethanol (4.6 mL), and hydrazine (1.1 mL, 34 mmol). Similar workup provided 4-(4-chloro-3-methoxyphenyl)phthalazin-1(2H)-one as a light yellow solid (0.53 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (br s, 1H), 8.34 (m, 1H), 7.91 (m, 2H), 7.75 (m, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.16 (d, J = 7.9 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.2, 154.5, 145.5, 135.3, 133.7, 131.7, 129.8, 128.9, 127.8, 126.6, 126.0, 122.3, 121.8, 113.8, 56.3. FT-IR (thin film, cm−1) 1695. MS calcd for C15H11ClN2O2 [M]+ = 286, found [M + H]+ = 287. HRMS calcd for C15H11ClN2O2 [M + H]+ = 287.0582, [M + Na]+ = 309.0401, found [M + H]+ = 287.0604, [M + Na]+ = 309.0416. Mp >250 °C. 4-Isopropylphthalazin-1(2H)-one (7u). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-3-hydroxy3-isopropylisoindolin-1-one (2.1 g, 8.8 mmol), ethanol (8.8 mL), and hydrazine (4.1 mL, 0.13 mol). An additional 3 mL of anhydrous hydrazine was added to ensure complete consumption of starting material. Similar workup provided a white solid, 4-isopropylphthalazin-1(2H)-one (1.5 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.29

4-(Benzo[b]thiophen-2-yl)phthalazin-1(2H)-one (7l). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 3-(benzo[b]thiophen-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.70 g, 2.3 mmol), and hydrazine (1.1 mL, 35 mmol) in 2.3 mL EtOH. Similar workup provided 4-(benzo[b]thiophen-2-yl)phthalazin-1(2H)one as a gray solid (0.61 g, 95% yield). 1H NMR (400 MHz, DMSOd6) δ ppm 13.02 (s, 1H), 8.26−8.51 (m, 2H), 7.82−8.16 (m, 5H), 7.30−7.59 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ ppm 158.9, 140.1, 139.7, 138.9, 137.5, 134.1, 132.0, 128.1, 127.7, 126.3, 126.0, 125.4, 125.3, 124.7, 124.5, 122.2. FT-IR (thin film, cm−1) 3155, 1656. HRMS calcd for C16H11N2OS [M + H]+ = 279.0592, found [M + H]+ = 279.0588. Mp = 246−247 °C. 4-(5-Methylthiazol-2-yl)phthalazin-1(2H)-one (7m). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1-one (0.92 g, 0.32 mmol), hydrazine (0.20 mL, 64 mmol), and ethanol (16 mL). Similar workup provided 4-(5-methylthiazol-2-yl)phthalazin-1(2H)-one as a light yellow solid (0.70 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.35−9.33 (m, 1H), 8.31−8.29 (m, 1H), 8.01−7.97 (m, 1H), 7.92−7.87 (m, 1H), 7.72−7.71 (m, 1H), 2.50 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.5, 159.2, 141.5, 137.7, 135.7, 133.9, 131.9, 127.6, 127.3, 127.0, 126.0, 11.5. FT-IR (thin film, cm−1) 3028, 2896, 1665, 1607, 1577, 1450, 1336. MS calcd for C12H9N3OS [M]+ = 243, found [M + H]+ = 244. HRMS calcd for C12H9N3OS [M + H]+ = 244.0539, [M + Na]+ = 266.0359, found [M + H]+ = 244.0560, [M + Na]+ = 266.0380. Mp = 230 °C. 4-(4-Methylthiazol-2-yl)phthalazin-1(2H)-one (7n). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)one (7b), this compound was prepared using 2-(dimethylamino)-3hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (3.4 g, 12 mmol), ethanol (23 mL), and hydrazine (5.5 mL, 0.17 mol). Similar workup provided 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one as a light yellow solid (2.4 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 9.41 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.06−8.02 (m, 1H), 7.93 (t, J = 7.3 Hz, 1H), 7.44 (s, 1H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.3, 159.2, 153.0, 137.7, 134.0, 131.9, 127.6, 127.3, 127.0, 126.0, 116.2, 17.1. FT-IR (thin film, cm−1) 1656. MS calcd for C12H9N3OS [M]+ = 243, found [M + H]+ = 244. HRMS calcd for C12H9N3OS [M + H]+ = 244.0539, [M + Na]+ = 266.0359, found [M + H]+ = 244.0561, [M + Na]+ = 266.0373. Mp > 250 °C. 4-(4,5-Dimethylthiazol-2-yl)phthalazin-1(2H)-one (7o). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindolin-1-one (3.7 g, 12 mmol), ethanol (25 mL), and hydrazine (5.8 mL, 0.19 mol). Similar workup provided 4-(4,5-dimethylthiazol-2-yl)phthalazin-1(2H)one as a light yellow solid (3.1 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.0 (s, 1H), 9.38 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.02−7.99 (m, 1H), 7.90 (t, J = 7.4 Hz, 1H), 2.38 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.3, 159.1, 148.9, 137.6, 133.9, 131.8, 128.8, 127.6, 127.3, 127.1, 125.9, 14.8, 10.9. FT-IR (thin film, cm−1) 1663. MS calcd for C13H11N3OS [M]+ = 257, found [M + H]+ = 258. HRMS calcd for C13H11N3OS [M + H]+ = 258.0696, [M + Na]+ = 280.0515, found [M + H]+ = 258.0724, [M + Na]+ = 280.0528. Mp > 250 °C. 4-(4-Chlorophenyl)phthalazin-1(2H)-one (7p). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin1(2H)-one (7b), this compound was prepared using 3-(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9.9 g, 33 mmol), ethanol (65 mL), and hydrazine (15 mL, 0.49 mol). An additional 5 mL of hydrazine was added to ensure complete consumption of starting material. Similar workup provided a light yellow solid, 4-(4-chlorophenyl)phthalazin-1(2H)-one (7.9 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (br s, 1H), 8.35−8.33 (m, 1H), 7.92−7.87 (m, 2H), 7.68−7.60 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 159.2, 145.3, 133.9, 133.8, 133.6, 131.7, 131.2, 128.8, 128.6, 127.8, 126.3, 126.1. FT-IR (thin film, cm−1) 1670. MS calcd for C14H9ClN2O [M]+ = 256, found [M + H]+ = 257. HRMS calcd for C14H9ClN2O [M + H]+ = 257.0476, 3900



Article

(d, J = 8.1 Hz, 1H), 8.21 (t, J = 7.1 Hz, 1H), 8.15 (t, J = 7.1 Hz, 1H), 7.98 (s, 1H), 7.55 (d, J = 4.6 Hz, 1H), the methyl group was overlapped with the DMSO peaks. MS calcd for C14H10ClN3 [M]+ = 255 Found [M + H]+ = 256. HRMS calcd for C14H10ClN3 [M + H]+ = 256.0636, found [M + H]+ = 256.0622. 1-Chloro-4-(6-methylpyridin-3-yl)phthalazine (1e). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(6-methylpyridin-3-yl)phthalazin-1(2H)-one (0.15 g, 0.63 mmol) and POCl3 (0.71 mL, 7.6 mmol). Similar workup provided 1-chloro-4-(6-methylpyridin-3yl)phthalazine (0.12 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.21−8.01 (m, 4H), 7.51 (d, J = 7.7 Hz, 1H), 2.61 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.0, 158.5, 154.6, 150.0, 138.3, 135.2, 135.0, 128.8, 127.3, 127.2, 125.9, 125.6, 123.5, 24.6. FT-IR (thin film, cm−1) 1599, 1389, 1353, 1291. MS calcd for C14H10ClN3 [M]+ = 255, found [M + H]+ = 256. HRMS calcd for C14H10ClN3 [M + H]+ = 256.0636, [M + Na]+ = 278.0456, found [M + H]+ = 256.0627, [M + Na]+ = 278.0441. Mp = 186−187 °C. 1-Chloro-4-(5-chloropyridin-2-yl)phthalazine (1f). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(5-chloropyridin-2-yl)phthalazin-1(2H)-one (1.6 g, 6.2 mmol) and phosphoryl trichloride (9.8 mL, 0.11 mol). Similar workup provided a brown solid, 1-chloro-4-(5-chloropyridin-2-yl)phthalazine (1.4 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.41 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.05−7.93 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 155.9, 155.6, 153.2, 147.6, 137.2, 133.6, 133.3, 133.2, 127.6, 126.8, 126.6, 126.5, 125.3. FT-IR (thin film, cm−1) 1574, 1557, 1295. MS calcd for C13H7Cl2N3 [M]+ = 275, found [M + H]+ = 276, [2M + Na]+ = 575. HRMS calcd for C13H7Cl2N3 [M + H]+ = 276.0090, [M + Na]+ = 297.9909, found [M + H]+ = 276.0089, [M + Na]+ = 297.9910. Mp = 180−182 °C. 1-Chloro-4-(6-methoxypyridin-2-yl)phthalazine (1g). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(6-methoxypyridin-2-yl)phthalazin-1(2H)-one (2.8 g, 11 mmol) and POCl3 (12 mL, 0.13 mol). Similar workup provided a tan solid, 1-chloro-4(6-methoxypyridin-2-yl)phthalazine (3.0 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.07−8.00 (m, 2H), 7.88−7.81 (m, 2H), 6.99 (d, J = 7.9 Hz, 1H), 4.01 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.9, 156.9, 154.6, 151.7, 140.4, 134.3, 127.4, 126.4, 125.6, 124.9, 118.4, 111.7, 80.7, 53.5. MS calcd for C14H10ClN3O [M]+ = 271, found [M + H]+ = 272; [2M + Na]+ = 565. HRMS calcd for C14H10ClN3O [M + H]+ = 272.0585, [M + Na]+ = 294.0421, found [M + H]+ = 272.0600; [M + Na]+ = 294.0421. Mp > 250 °C. 1-Chloro-4-(4-methylthiophen-2-yl)phthalazine (1h). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(4-methylthiophen-2-yl)phthalazin-1(2H)-one (2.8 g, 12 mmol) and POCl3 (19 mL, 0.20 mol). Similar workup provided a tan solid, 1-chloro-4-(4methylthiophen-2-yl)phthalazine (2.8 g, 93% yield). Note: If a mixture of phthalazinones 7h and 7i was carried on to this chlorination step, the major isomer 1-chloro-4-(3-methylthiophen-2-yl)phthalazine 1h could be separated cleanly from the minor isomer 1i by recrystallization with EtOAc. 1H NMR (400 MHz, CDCl3) δ 8.58− 8.55 (m, 1H), 8.42−8.39 (m, 1H), 8.08−8.01 (m, 2H), 7.57 (d, J = 1 Hz, 1H), 7.25 (distorted t, 1H), 2.41 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 153.98, 153.93, 138.7, 136.3, 133.7, 133.5, 132.9, 126.6, 126.5, 126.4, 125.8, 125.6, 15.8. The structure was confirmed by 2D NMR. FT-IR (thin film, cm−1) 1609, 1290. HRMS calcd for C13H9ClN2S [M]+H+ = 261.0175, found [M + H]+ = 261.0248. Mp = 155− 156 °C. 1-Chloro-4-(3-methylthiophen-2-yl)phthalazine (1i). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(3-methylthiophen-2-yl)phthalazin-1(2H)-one (3.1 g, 13 mmol) and phosphoryl trichloride (20 mL, 0.22 mol). Similar workup provided a yellow solid, 1-chloro-4-(3-methylthiophen-2-yl)phthalazine (3.2 g, 94% yield).

(d, J = 7.5 Hz, 1H), 8.06 (s, J = 8.3 Hz, 1H), 7.95 (t, J = 7.3 Hz, 1H), 7.85 (t, J = 7.0 Hz, 1H), 3.58 (sep, J = 6.3 Hz, 1H), 1.29 (d, J = 6.5 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) 159.2, 150.0, 133.5, 131.2, 128.7, 127.8, 126.1, 124.7, 39.5, 21.4. FT-IR (thin film, cm−1) 3178, 3052, 2968, 2929, 1656, 1594, 1468, 1350, 1158, 1017, 781, 752, 686. MS calcd for C11H12N2O [M]+ = 188, found [M + H]+ = 189; [2M + H]+ = 399.1. HRMS calcd for C11H12N2O [M + H]+ = 189.1022, [M + Na]+ = 211.0842, found [M + H]+ = 189.1070; [M + H]+ = 211.0888. Mp = 164−165 °C. 4-Cyclohexylphthalazin-1(2H)-one (7v). Following the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (7b), this compound was prepared using 3-cyclohexyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (1.3 g, 4.7 mmol), ethanol (4.7 mL), and hydrazine (4.4 mL, 0.14 mol). Similar workup procedure provided an off-white solid, 4-cyclohexylphthalazin-1(2H)-one (0.96 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.90−7.75 (m, 3H), 3.12 (distorted t, J = 11.3 Hz, 1H), 2.00−1.31 (m, 10H). 13C NMR (101 MHz, DMSO-d6) 159.2, 149.6, 13.4, 131.2, 128.7, 127.8, 126.1, 124.6, 40.2, 38.5, 31.6, 25.9. MS calcd for C14H16N2O [M]+ = 228, found [M + H]+ = 229; [2M + H]+ = 479. HRMS calcd for C14H16N2O [M + H]+ = 229.1335, [M + Na]+ = 251.1155, found [M + H]+ = 229.1368; [M + Na]+ = 251.1189. FT-IR (thin film, cm−1) 3178, 3049, 2928, 2853, 1657, 1449, 1346, 783, 768, 684. Mp = 201−202 °C. General Procedure To Prepare Chlorophthalazines. 1-Chloro4-(6-methylpyridin-2-yl)phthalazine (1b). A dry round-bottom flask equipped with a stirring bar and a reflux condenser was charged with 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (0.78 g, 3.3 mmol) and POCl3 (11 mL, 0.12 mol). After refluxing for 18 h, excess POCl3 was removed under vacuum with the aid of toluene. The residue was cooled to 0 °C and basicified with cold 6 N NaOH until pH = 9. Occasionally, ice was added to keep the mixture cold. It is very critical to keep the reaction mixture cold during the work up at all times to avoid the hydrolysis of the product back to phthalazinone. Stirring, agitation, and sonication would eventually provide a solid. This solid was filtered and washed quickly with ample amount of water. The solid was quickly transferred into a flask and dried under vacuum to afford a white solid (0.67 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 9.3, 1.5 Hz, 1H), 8.40 (dd, J = 9.6 Hz, 7.8 Hz, 1H), 7.92−8.07 (m, 3H), 7.87 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 2.73 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 157.8, 137.9, 133.4, 133.2, 127.9, 127.2, 125.2, 124.0, 122.8, 77.4, 77.2, 77.0, 76.7, 24.4. FT-IR (thin film, cm−1) 3070, 1597, 1532, 1458, 1393, 1285, 832, 775. MS calcd for C14H10ClN3 [M]+ = 255, found [M + H]+ = 256. HRMS calcd for C14H10ClN3 [M + H]+ = 256.0636, found [M + H]+ = 256.0630. Mp = 138−140 °C. 1-Chloro-4-(5-methylpyridin-2-yl)phthalazine (1c). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(5-methylpyridin-2-yl)phthalazin-1(2H)-one (0.35 g, 1.5 mmol) and POCl3 (1.7 mL, 18 mmol). Similar workup provided a grayish green solid, 1-chloro-4-(5-methylpyridin-2-yl)phthalazine (0.17 g, 45% yield). 1H NMR (600 MHz, DMSO-d6) δ 8.72 (d, J = 7.8 Hz, 1H), 8.0 (s, 1H), 8.31 (d, J = 3.6 Hz, 1H), 8.06−8.04 (m, 1H), 8.03−7.98 (m, 2H), 7.80 (dd, J = 7.8, 1.2 Hz, 1H), 2.44 (s, 3H). 13C NMR (151 MHz, DMSOd6) δ 156.6, 154.4, 151.4, 148.7, 137.6, 133.9, 133.4, 133.3, 127.5, 126.4, 125.7, 124.55, 124.51, 17.9. FT-IR (thin film, cm−1) 1570, 1352, 1292. MS calcd for C14H10ClN3 [M]+ = 255, found [M + H]+ = 256. HRMS calcd for C14H10ClN3 [M + H]+ = 256.0636, [M + Na]+ = 278.0456, found [M + H]+ = 256.0659, [M + Na]+ = 278.04602. Mp = 182 °C. 1-Chloro-4-(4-methylpyridin-2-yl)phthalazine (1d). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using with 4-(4methylpyridin-2-yl)phthalazin-1(2H)-one (0.39 g, 1.6 mmol) and POCl3 (31 mL, 0.33 mol). Similar workup provided 1-chloro-4-(4methylpyridin-2-yl)phthalazine (0.30 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.1 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.41 3901



Article

H NMR (400 MHz, CDCl3) δ 8.40−8.38 (m, 1H), 8.05−7.95 (m, 3H), 7.52 (d, J = 5.1 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 2.20 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.5, 154.7, 138.9, 133.52, 133.50, 130.5, 129.8, 128.2, 127.23, 127.22, 126.1, 125.5, 15.2. FT-IR (thin film, cm−1) 1548, 1520, 1435, 1289, 732. MS calcd for C13H9ClN2S [M]+ = 260, found [M + H]+ = 261. HRMS calcd for C13H9ClN2S [M + H]+ = 261.0247, [M + Na]+ = 283.0067, found [M + H]+ = 261.0267, [M + Na]+ = 283.0076. Mp = 152−153 °C. 1-Chloro-4-(5-methylthiophen-2-yl)phthalazine (1j). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(5-methylthiophen-2-yl)phthalazin-1(2H)-one (0.79 g, 3.3 mmol) and POCl3 (11 mL, 114 mmol). Similar workup provided 1-chloro-4-(5methylthiophen-2-yl)phthalazine (0.81 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.45−8.38 (m, 1H), 8.29−8.23 (m, 1H), 7.95−7.86 (m, 2H), 7.41 (d, J = 4.0, 1H), 6.86−6.81 (m, 1H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.1, 153.5, 144.8, 135.3, 133.5, 133.2, 130.5, 126.4, 126.4, 126.3, 125.6, 125.4, 15.6. FT-IR (thin film, cm−1) 3073, 2917. MS calcd for C13H9ClN2S [M]+ = 260, found [M + H]+ = 261. HRMS calcd for C13H9ClN2S [M + H]+ = 261.0248, [M + Na]+ = 283.0057, found [M + H]+ = 261.0244, [M + Na]+ = 283.0057. Mp = 103−107 °C. 1-Chloro-4-(5-ethylthiophen-2-yl)phthalazine (1k). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(5-ethylthiophen-2-yl)phthalazin-1(2H)-one (3.2 g, 13 mmol) and phosphoryl trichloride (17 mL, 0.19 mol). Similar workup provided a light yellow solid, 1-chloro-4-(5-ethylthiophen-2-yl)phthalazine (2.7 g, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 8.55−8.52 (m, 1H), 8.38−8.36 (m, 1H), 8.04−7.99 (m, 2H), 7.54 (d, J = 3.5 Hz, 1H), 6.97 (d, J = 3.8 Hz, 1H), 2.98 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.9, 153.3, 152.3, 134.5, 133.4, 133.1, 130.3, 126.2, 126.1, 125.4, 124.4, 23.5, 15.7. FT-IR (thin film, cm−1) 2967, 1470. MS calcd for C14H11ClN2S [M]+ = 274, found [M + H]+ = 275. HRMS calcd for C14H11ClN2S [M + H]+ = 275.0404, [M + Na]+ = 297.0223, found [M + H]+ = 275.0407, [M + Na]+ = 297.0218. Mp = 104−105 °C. 1-(Benzo[b]thiophen-2-yl)-4-chlorophthalazine (1l). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(benzo[b]thiophen-2-yl)phthalazin-1(2H)-one (0.50 g, 1.8 mmol) in phosphorus oxychloride (2.9 mL, 31 mmol). This product was purified by silica gel chromatography (MPLC, 40-g cartridge, 30−100% EtOAc in hexanes) to afford 1-(benzo[b]thiophen-2-yl)-4-chlorophthalazine (0.31 g, 58% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 - 8.76 (m, 1H), 8.37 - 8.46 (m, 1H), 8.31 (s, 1H), 8.21 - 8.27 (m, 2H), 8.07 8.14 (m, 1H), 8.01 - 8.07 (m, 1H), 7.44 - 7.56 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ ppm 153.7, 153.7, 140.0, 139.8, 137.5, 135.0, 134.5, 128.1, 126.2, 126.1, 125.7, 125.4, 125.3, 125.0, 124.9, 122.4. FT-IR (thin film, cm−1) 1520, 1289, 1280, 984. HRMS calcd for C16H9ClN2S [M + H]+ = 297.0250, found [M + H]+ = 297.0249. Mp = 165−167 °C 2-(4-Chlorophthalazin-1-yl)-5-methylthiazole (1m). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one (0.20 g, 0.82 mmol) and POCl3 (0.92 mL, 9.9 mmol). Similar workup provided 1-chloro-4(4-methylthiazol-2-yl)phthalazine (0.19 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 9.65−9.63 (m, 1H), 8.27−8.25 (m, 1H), 8.00− 7.92 (m, 2H), 7.68 (s, 1H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.5, 154.8, 150.2, 142.0, 138.2, 134.1, 133.3, 127.4, 126.0, 125.2, 124.9, 11.8. FT-IR (thin film, cm−1) 1519, 1442, 1341, 1289, 1112. MS calcd for C12H8ClN3S [M]+ = 261, found [M + H]+ = 262. HRMS calcd for C12H8ClN3S [M + H]+ = 262.0200, [M + Na]+ = 284.0020, found [M + H]+ = 262.0213, [M + Na]+ = 284.0013. Mp = 151−152 °C. 1-Chloro-4-(4-methylthiazol-2-yl)phthalazine (1n). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one (2.4 g, 9.9 mmol) and phosphoryl trichloride (14 mL, 0.15 mol). Similar workup provided a brown solid, 1-chloro-4-(4-methylthiazol-2-yl)phthalazine (2.4 g, 94% yield).

H NMR (400 MHz, CDCl3) δ 9.84 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.10−8.01 (m, 2H), 7.15 (s, 1H), 2.64 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.9, 155.2, 154.6, 150.5, 134.1, 133.4, 127.7, 126.2, 125.4, 125.0, 117.7, 17.4. FT-IR (thin film, cm−1) 3090, 1520, 1461, 1289. MS calcd for C12H8ClN3S [M]+ = 261, found [M + H]+ = 262. HRMS calcd for C12H8ClN3S [M + H]+ = 262.0200, [M + Na]+ = 284.0020, found [M + H]+ = 262.0203, [M + Na]+ = 284.0016. Mp = 152−153 °C. 1-Chloro-4-(4,5-dimethylthiazol-2-yl)phthalazine (1o). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(5-methylthiazol-2-yl)phthalazin-1(2H)-one (3.1 g, 13 mmol) and phosphoryl trichloride (18 mL, 0.19 mol). Similar workup provided a pink solid, 1-chloro-4-(4,5-dimethylthiazol-2-yl)phthalazine (2.9 g, 82% yield). 1 H NMR (400 MHz, CDCl3) δ 7.6 (d, J = 7.6 Hz, 1H), 7.1 (d, J = 7.1 Hz, 1H), 8.00 (t, J = 7.6 Hz, 2H), 2.49 (s, 3H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.8, 154.9, 150.71, 150.67, 134.1, 133.3, 131.4, 128.0, 126.4, 125.6, 125.1, 15.1, 11.6. FT-IR (thin film, cm−1) 1521, 1463, 1289. MS calcd for C13H10ClN3S [M]+ = 275, found [M + H]+ = 276. HRMS calcd for C13H10ClN3S [M + H]+ = 276.0357, [M + Na]+ = 298.0176, found [M + H]+ = 276.0327, [M + Na]+ = 298.0177. Mp = 148−150 °C. 1-Chloro-4-(4-chlorophenyl)phthalazine (1p). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(4chlorophenyl)phthalazin-1(2H)-one (7.9 g, 31 mmol) and phosphoryl trichloride (43 mL, 0.46 mol). Similar workup provided light a yellow solid, 1-chloro-4-(4-chlorophenyl)phthalazine (8.4 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.1 Hz, 1H), 8.06−7.94 (m, 3H), 7.70 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.2, 154.7, 136.1, 133.7, 133.5, 133.4, 131.4, 129.0, 127.0, 126.6, 126.3, 125.6. FT-IR (thin film, cm−1) 1597, 1402, 1351, 1291, 1093. MS calcd for C14H8Cl2N2 [M]+ = 274, found [M + H]+ = 275. HRMS calcd for C14H8Cl2N2 [M + H]+ = 275.0137, [M + Na]+ = 296.9957, found [M + H]+ = 275.0155, [M + Na]+ = 296.9974. Mp = 199−200 °C. 1-(4-tert-Butylphenyl)-4-chlorophthalazine (1q). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-(4-tertbutylphenyl)phthalazin-1(2H)-one (2.6 g, 9.3 mmol), phosphorus oxychloride (8.7 mL, 93 mmol). Similar workup provided light yellow precipitate that was further purified by trituration with ethyl acetate to yield 1-(4-tert-butylphenyl)-4-chlorophthalazine (1.6 g, 58% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39−8.37 (m, 1H), 8.21−8.17 (m, 1H), 8.14−8.10 (m, 1H), 8.08−8.06 (m, 1H), 7.69−7.64 (m, 4H), 1.38 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ ppm 159.99, 152.33, 140.61, 134.40, 134.21, 132.15, 129.76, 126.94, 126.56, 125.46, 125.36, 124.92, 78.72, 54.87, 34.61, 31.06. MS calcd for C18H17ClN2 [M]+ = 296.8, found [M + H]+ = 297.1. HRMS calcd for C18H17ClN2 [M + H]+ = 297.1153, [M + Na]+ = 319.0973, found [M + H]+ = 297.1155, [M + Na]+ = 319.0968. Mp = 138−139 °C. 1-Chloro-4-m-tolylphthalazine (1r). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-m-tolylphthalazin-1(2H)-one (0.50 g, 2.1 mmol) and POCl3 (65 g, 0.42 mol). Similar workup provided 1-chloro-4-m-tolylphthalazine (0.45 g, 84% yield). 1H NMR (400 MHz, CDCl3) δ 8.38−8.36 (d, 1H), 8.09−8.07 (d, 1H), 8.02, 7.98 (m, 1H), 7.94−7.90 (m, 1H), 7.54 (s, 1H), 7.50−7.43 (m, 2H), 7.38−7.36 (m, 1H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.1, 154.0, 138.1, 134.8, 132.8, 132.8, 130.3, 130.0, 128.1, 126.9, 126.8, 126.7, 125.9, 125.0, 21.1. FT-IR (thin film, cm−1) 1525, 1423, 1379, 1352, 1290. MS calcd for C15H11ClN2 [M]+ = 254, found [M + H]+ = 255. HRMS calcd for C15H11ClN2 [M + H]+ = 255.0684, [M + Na]+ = 277.0544, found [M + H]+ = 255.0700, [M + Na]+ = 277.0544. Mp = 118−119 °C. 1-Chloro-4-(3-(trifluoromethyl)phenyl)phthalazine (1s). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2yl)phthalazine (1b), this compound was prepared using 4-(3(trifluoromethyl)phenyl)phthalazin-1(2H)-one (0.50 g, 1.7 mmol) and phosphoryl oxychloride (53 g, 0.35 mol). Similar workup provided

1

1

3902



Article

room temperature over time. 1H NMR (400 MHz, CDCl3) of the dihydrobenzoazepinedione 15a δ 7.85 (dt, J = 8.4, 1.0 Hz, 1H), 7.59−7.50 (m, 3H), 3.74−3.71 (m, 2H), 2.96−2.93 (m,2H), 2.81 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 202.2, 167.1, 135.6, 133.9, 132.3, 131.4, 129.8, 127.7, 45.1, 44.8, 44.0. FT-IR (thin film, cm−1) 2950, 2887, 1765, 1688, 1650. MS calcd for C12H14N2O2 [M]+ = 218, found [M + H]+ = 219. HRMS calcd for C12H14N2O2 [M + H]+ = 219.1128, [M + Na]+ = 241.0948 , found [M + H]+ = 219.1152, [M + Na]+ = 241.0955. 2-(Dimethylamino)-4-methyl-3,4-dihydro-2H-benzo[c]azepine1,5-dione (15b). In a dry round-bottom flask were added 2-(dimethylamino)isoindoline-1,3-dione (0.43 g, 2.3 mmol) and THF (3.4 mL). After purging with argon and cooling to −30 °C, prop-1-en-2ylmagnesium bromide (4.1 mL, 2.1 mmol; 0.50 M in THF) was added. After 15 min, the whole was warmed to rt. After 30 min, the reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The product was purified by column chromatography on silica gel eluting with 50:50 Hex/EtOAc to afford a white solid (80 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 3.60 (d, J = 6.8 Hz, 2H), 3.09 (m, 1H), 2.86 (s, 6H), 1.21 (d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 206.5, 167.4, 135.9, 133.4, 132.0, 131.5, 129.5, 127.8, 52.4, 49.7, 43.8, 15.4. 2D-NMR confirmed the dihydrobenzoazepinedione structure. FT-IR (thin film, cm−1) 2948, 2887, 1688, 1653. MS calcd for C13H16N2O2 [M]+ = 232, found [M + H]+ = 233. HRMS calcd for C13H16N2O2 [M + H]+ = 233.1285, [M + Na]+ = 255.1104, found [M + H]+ = 233.1300, [M + Na]+ = 255.1123. Mp = 59−60 °C. 2-(Dimethylamino)-4-phenyl-3,4-dihydro-1H-benzo[c]azepine1,5(2H)-dione (15c). In a dry round-bottom flask were added 1-(1bromovinyl)benzene (0.28 mL, 2.2 mmol) and THF (7.3 mL). After purging with argon and cooling to −78 °C, n-butyllithium (0.92 mL, 2.3 mmol) was added. After 30 min, the anion was cannulated into a solution of 2-(dimethylamino)isoindoline-1,3-dione (0.46 g, 2.4 mmol) in 10 mL of THF at −30 °C. After 15 min, the whole was warmed to rt. After 30 min, the reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The product was purified by column chromatography on silica gel eluting with 60:40 Hex/EtOAc to afford a sticky white solid that was purified further by RPLC to afford a light yellow sticky solid (240 mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 7.5, 1.2 Hz, 1H), 7.60 (td, J = 7.3, 1.0 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.34−7.29 (m, 3H), 7.14− 7.12 (m, 2H), 4.31 (dd, J = 12.3, 3,8 Hz, 1H), 4.18 (t, J = 14.7 Hz, 1H), 3.76 (dd, J = 14.7, 3.8 Hz, 1H), 2.91 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 204.0, 167.1, 136.5, 136.3, 133.1, 131.9, 131.7, 129.4, 128.8, 127.8, 127.7, 127.4, 60.5, 52.1, 43.8. 2D-NMR confirmed the dihydrobenzoazepinedione structure. FT-IR (thin film, cm−1) 2951, 2889, 1690, 1653. MS calcd for C18H18N2O2 [M]+ = 294, found [M + H]+ = 295. HRMS calcd for C18H18N2O2 [M + H]+ = 295.1441, [M + Na]+ = 317.1261 , found [M + H]+ = 295.1474, [M + Na]+ = 317.1275. Preparation of Pyrazoles. 2-(5-Phenyl-1H-pyrazol-3-yl)benzoic Acid (16a). Conditions A. 2-(Dimethylamino)-3hydroxy-3-(2-phenylethynyl)isoindolin-1-one (0.12 g, 4.0 mmol), ethanol (8.1 mL), and hydrazine (1.9 mL, 61 mmol) were added into a round-bottom flask equipped with a condenser. The whole was refluxed under argon. After 5 h, the reaction was cooled to rt and concentrated under reduced pressure to afford a solid. The solid was triturated with hexanes and a small amount of ether. Sonication for 1 h provided an off-white solid that was filtered off with the aid of cold hexanes. The product, 2-(5-phenyl-1Hpyrazol-3-yl)benzoic acid was obtained as a light yellow solid (0.62 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 8.3, 1.2 Hz, 2H), 7.72 (dd, J = 7.8, 1.3 Hz, 1H), 7.60 (dd, J = 7.6, 1.5 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.36−7.25 (m, 3H), 7.08 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 173.7, 149.4, 144.9, 140.2,

1-chloro-4-(3-(trifluoromethyl)phenyl)phthalazine (0.40 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.43−8.41 (d, 1H), 8.08− 8.04 (m, 1H), 8.01−7.98 (m, 3H), 7.94−7.92 (m, 1H), 7.85−7.83 (m, 1H), 7.71−7.75 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 159.2, 155.2, 136.5, 134.0, 133.8, 133.6, 129.6, 127.2, 126.8, 126.6, 126.0, 125.5, 122.8. FT-IR (thin film, cm−1) 1380, 1362, 1325, 1309, 1290. MS calcd for C15H8ClF3N2 [M]+ = 308, found [M + H]+ = 309. HRMS calcd for C15H8ClF3N2 [M + H]+ = 309.0401, [M + Na]+ = 331.0220, found [M + H]+ = 309.0431, [M + Na]+ = 331.0248. Mp = 160 °C. 1-Chloro-4-(4-chloro-3-methoxyphenyl)phthalazine (1t). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2yl)phthalazine (1b), this compound was prepared using 4-(4-chloro3-methoxyphenyl)phthalazin-1(2H)-one (0.53 g, 1.8 mmol) and phosphoryl trichloride (2.6 mL, 28 mmol). Similar workup provided a gray solid, 1-chloro-4-(4-chloro-3-methoxyphenyl)phthalazine (0.52 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.1 Hz, 1H), 8.11−7.95 (m, 3H), 7.56 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 3.98 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.0, 155.1, 154.4, 134.4, 133.20, 132.18, 129.8, 126.7, 126.4, 126.1, 125.3, 124.4, 122.5, 113.5, 56.0. FT-IR (thin film, cm−1) 1577. MS calcd for C15H10Cl2N2O [M]+ = 304, found [M + H]+ = 305. HRMS calcd for C15H10Cl2N2O [M + H]+ = 305.0243, [M + Na]+ = 327.0062, found [M + H]+ = 305.026, [M + Na]+ = 327.009. Mp = 237−238 °C. 1-Chloro-4-isopropylphthalazine (1u). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-isopropylphthalazin1(2H)-one (0.60 g, 3.2 mmol) and POCl3 (3.6 mL, 38 mmol). Similar workup provided a light yellow solid, 1-chloro-4-isopropylphthalazine (0.57 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.8, 1H), 8.06 (d, J = 2.8, 1H), 7.96−7.92 (m, 1H), 7.86−7.82 (m, 1H), 3.58−3.55 (m, 1H), 1.26 (d, J = 5.8, 6H). 13C NMR (101 MHz, DMSO-d6) δ 153.5, 145.0, 134.1, 133.3, 126.2, 125.1, 124.7, 38.9. 21.9, 21.4. FT-IR (thin film, cm−1) 2970, 2931, 2872, 1292. MS calcd for C11H11ClN2 [M]+ = 206, found [M + H]+ = 207. HRMS calcd for C11H11ClN2 [M + H]+ = 207.0684, [M + Na]+ = 229.0503, found [M + H]+ = 207.0689, [M + Na]+ = 229.0487. Mp = 73−74 °C 1-Chloro-4-cyclohexylphthalazine (1v). Following the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b), this compound was prepared using 4-cyclohexylphthalazin1(2H)-one (0.85 g, 3.7 mmol) and POCl3 (10 mL, 0.11 mol). Similar workup provided a light yellow solid (1.7 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.49−8.45 (m, 1H), 8.33−8.26 (m, 1H), 8.18− 8.14 (m, 2H), 3.68−3.62 (m, 2H), 2.72−2.68 (m, 1H), 1.96−1.71 (m, 4H), 1.61−1.47 (m, 2H), 1.36−1.29 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 159.2, 149.6, 133.4, 131.2, 128.7, 127.8, 126.1, 124.7, 39.9, 39.1, 38.5, 25.8. FT-IR (neat, cm−1) 2924, 2853, 1600, 997. MS calcd for C14H15ClN2 [M]+ = 246, found [M + H]+ = 247. HRMS calcd for C14H15ClN2 [M + H]+ = 247.0997, [M + Na]+ = 269.0816, found [M + H]+ = 247.0996; [M + Na]+ = 269.0801. Mp = 150−152 °C. Synthesis of Dihydrobenzoazepinediones. 2-(Dimethylamino)-3,4-dihydro-1H-benzo[c]azepine-1,5(2H)-dione (15a) and 2-(Dimethylamino)-3-hydroxy-3-vinylisoindolin-1-one (13a). In a dry roundbottom flask were added 2-(dimethylamino)isoindoline-1,3dione (0.48 mg, 2.5 mmol) and THF (11 mL). After purging with argon and cooling to −78 °C, vinylmagnesium bromide (2.3 mL, 2.3 mmol; 0.5 M in THF) at 0 °C was added via a syringe. After 15 min, the whole was warmed to rt. After 30 min, the reaction was quenched slowly with saturated aqueous NH4Cl. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. The product was purified by column chromatography on silica gel eluting with 70:30 DCM/(90:10:1 DCM/MeOH/NH4OH) to afford a white solid. The product was purified further with RPLC. Fractions containing the product were combined and washed with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to afford a light yellow solid. 1H NMR showed a 3:1 ratio of 15a:13a (80 mg, 16% yield). This mixture decomposed at 3903



Article

C14H16N2O2 [M + H]+ = 245.1285, found [M + H]+ = 245.1283. Mp > 250 °C. N′,N′-Dimethyl-2-(1-methyl-5-phenyl-1H-pyrazol-3-yl)benzohydrazide (17a). Conditions C. 2-(Dimethylamino)-3-hydroxy3-(phenylethynyl)isoindolin-1-one (80 mg, 0.27 mmol), THF (0.27 mL), and methylhydrazine (73 μL, 1.4 mmol) were added into a sealed tube. The tube was sealed and heated to 80 °C. After 16 h, LC−MS showed the hydrazide product. The whole was concentrated. The product was purified by performing column chromatography eluting with 70:30 DCM/(90:10:1 DCM/MeOH/ NH4OH). The product was purified further by RPLC. Fractions containing the product were combined and concentrated. The water residue was passed through a 5-g SCX column with the aid of MeOH. The product was eluted with a solution of 2 M NH3 in methanol. The filtrate was concentrated to afford N′,N′-dimethyl-2-(1-methyl-5phenyl-1H-pyrazol-3-yl)benzohydrazide as an off-white solid (55 mg, 63% yield). LC−MS confirmed product. HPLC showed 96% pure, 23:1 ratio of major:minor isomer. 1H NMR in CDCl3 confirmed the product. 1H NMR (400 MHz, CDCl3) δ 7.67−7.62 (m, 2H), 7.50− 7.38 (m, 8H), 6.55 (s, 1H), 3.95 (s, 3H), 2.59 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 167.7, 149.2, 144.8, 131.2, 130.14, 130.05, 129.3, 128.8, 128.74, 128.72, 128.67, 128.63, 127.9, 106.4, 47.2, 37.6. 2D NMRs confirmed the pyrazole structure. FT-IR (thin film, cm−1) 3201 (br), 2951, 1658. MS calcd for C19H20N4O [M]+ = 320, found [M + H]+ = 321. HRMS calcd for C19H20N4O [M + H]+ = 321.1710, found [M + H]+ = 321.1707. Mp = 44−45 °C. 2-(5-(3-Hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17b). Following conditions C using 2(dimethylamino)-3-hydroxy-3-((3-hydroxyphenyl)ethynyl)isoindolin1-one (80 mg, 0.26 mmol), THF (0.26 mL), and methylhydrazine (69 μL, 1.3 mmol), 2-(5-(3-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)N′,N′-dimethylbenzohydrazide was obtained as an off-white solid (44 mg, 50% yield). HPLC showed a 13:1 ratio of major:minor isomer. 1H NMR (400 MHz, CDCl3) δ 7.67−7.57 (m, 2H), 7.45 (td, J = 7.7, 1.5 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 7.25−7.23 (m, 1H), 6.91−6.80 (m, 4H), 6.41 (s, 1H), 3.83 (s, 3H), 2.54 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 168.5, 157.0, 148.8, 144.9, 133.8, 131.2, 131.0, 130.2, 129.8, 129.2, 128.6, 127.9, 119.9, 116.2, 115.8, 106.0, 47.1, 37.5. FTIR (thin film, cm−1) 300−2700 (br), 1643, 1584. MS calcd for C19H20N4O2 [M]+ = 336, found [M + H]+ = 337. HRMS calcd for C19H20N4O2 [M + H]+ = 337.1659, found [M + H]+ = 337.1657. Mp = 89−90 °C. 2-(5-Butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17c). Following conditions C using 2-(dimethylamino)-3-(hex-1ynyl)-3-hydroxyisoindolin-1-one (80 mg, 0.29 mmol), THF (0.29 mL), and methylhydrazine (78 μL, 1.5 mmol), 2-(5-butyl-1methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained as an off-white solid (50 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (td, J = 7.7, 0.9 Hz, 2H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.36 (td, J = 7.5, 1.4 Hz, 1H), 6.74 (br s, 1H), 6.24 (s, 1H), 3.83 (s, 3H), 2.61 (distorted t, J = 7.5 Hz, 1H), 2.54 (s, 6H), 1.66 (m, 3H), 1.44 (sex, J = 7.5 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.7, 148.7, 144.3, 134.2, 131.6, 129.9, 129.2, 128.7, 127.7, 104.8, 47.2, 36.2, 30.6, 25.3, 22.4, 13.8. 2D-NMR confirmed the pyrazole structure. FT-IR (thin film, cm−1) 3209 (br), 2955, 2869, 1664, 1546. MS calcd for C17H24N4O [M]+ = 300, found [M + H]+ = 301. Calcd for C17H24N4O [M + H]+ = 301.2023, found [M + H]+ = 301.2021. Mp = 130−131 °C. 2-(5-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17d). Following conditions C using 3-(cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (80 mg, 0.31 mmol), THF (0.31 mL), and methylhydrazine (83 μL, 1.6 mmol), 2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained as a light yellow solid (34 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.7, 1.2 Hz, 1H), 7.56 (dd, J = 7.7, 0.9 Hz, 1H), 7.43 (td, J = 7.7, 1.5 Hz, 1H), 7.36 (td, J = 7.4 1.2 Hz, 1H), 6.05 (s, 1H), 3.96 (s, 3H), 2.58 (s, 6H), 1.76−1.72 (m, 1H), 1.02−0.99 (m, 2H), 0.72−0.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.7, 148.6, 146.3, 134.0, 131.5, 130.0, 129.3, 128.8, 127.8, 103.1, 47.0, 36.4, 6.8, 6.1. FT-IR (thin film, cm−1) 3208 (br), 2952, 1659, 1555. MS calcd for C16H20N4O [M]+ = 284, found [M + H]+ = 285.

133.6, 129.6, 128.6, 127.8, 127.7, 127.2, 127.1, 126.0, 125.1, 100.9. 2D-NMR confirmed the pyrazole structure. FT-IR (thin film, cm−1) 3361−2962 (br), 1540. MS calcd for C16H12N2O2 [M]+ = 264, found [M + H]+ = 265. HRMS calcd for C16H12N2O2 [M + H]+ = 265.1972, [M + Na]+ = 287.0791, found [M + H]+ = 265.1996, [M + Na]+ = 287.0807. Mp > 250 °C. 2-(5-Phenyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16a·HCl). Conditions B. 2-(Dimethylamino)-3-hydroxy-3-(2phenylethynyl)isoindolin-1-one (40 mg, 0.14 mmol), THF (0.27 mL), and hydrazine (14 μL, 0.41 mmol) were added into a sealed tube. After stirring at rt for 16 h, LC−MS showed a complete conversion to the pyrazole carboxylic acid. The whole was diluted with 1 mL of water and acidified dropwise with 2 N aqueous HCl to pH = 1. White solid precipitated out of the solution and collected by filtration with the aid of water to afford 2-(5-phenyl-1H-pyrazol-3-yl)benzoic acid hydrochloride (27 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 2H), 7.78 (distorted d, J = 7.3 Hz, 2H), 7.70−7.50 (m, 3H), 7.45 (distorted t, J = 7.8 Hz, 3H), 7.34 (distorted t, J = 7.2 Hz, 1H), 6.85 (br s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.8, 130.9, 130.4, 129.4, 128.9, 128.6, 127.8, 125.0, 124.8, 101.7. All 14 carbons were not accounted for because peaks appeared broad. FT-IR (thin film, cm−1) 3500−2500 (br), 1548. MS calcd for C16H12N2O2 [M]+ = 264, found [M + H]+ = 265. HRMS calcd for C16H12N2O2 [M + H]+ = 265.0972, found [M + H]+ = 265.1004. Mp > 250 °C. In order to confirm both the products from the original and modified conditions were the same, both samples were subjected to LC−NMR using D2O/CAN buffer as an eluent. Both spectra were the same; therefore, both samples were in different forms. The conditions B utilized aqueous HCl in the workup, and two hydrogens were detected in the carboxylic region (12−14 ppm). Therefore, conditions B yielded the product as the HCl salt. 2-(5-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16b). Following conditions B using 2-(dimethylamino)-3-(hex-1-ynyl)-3hydroxyisoindolin-1-one (60 mg, 0.22 mmol), anhydrous hydrazine (21 μL, 0.66 mmol), and THF (0.44 mL), 2-(5-butyl-1H-pyrazol-3yl)benzoic acid hydrochloride was isolated as a yellow solid (42 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.68 (br s, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.52−7.46 (m, 2H), 7.37 (td, J = 7.4, 1.2 Hz, 1H), 6.21 (s, 1H), 2.60 (t, J = 7.5 Hz, 2H), 1.59 (quin, J = 7.7 Hz, 2H), 1.35 (sex, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 170.4, 147.8, 145.2, 132.7, 131.5, 129.9, 128.7, 128.0, 127.0, 102.2, 30.9, 25.0, 21.7, 12.6. FT-IR (thin film, cm−1) 3500− 2500 (br), 3056, 2930, 1695. MS calcd for C14H16N2O2 [M]+ = 244, found [M + H]+ = 245. HRMS calcd for C14H16N2O2 [M + H]+ = 245.1285, [M + Na]+ = 267.1104 , found [M + H]+ = 245.1300, [M + Na]+ = 267.1123. 2-(5-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16c). Following conditions B using 3-(2-cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (60 mg, 0.23 mmol), anhydrous hydrazine (22 μL, 0.70 mmol), and THF (0.47 mL), 2-(5-cyclopropyl1H-pyrazol-3-yl)benzoic acid hydrochloride was isolated as a yellow solid (40 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 2H), 7.58−7.46 (m, 3H), 7.37 (td, J = 7.4, 1.2 Hz, 1H), 6.11 (s, 1H), 1.93−1.89 (m, 1H), 0.94−0.90 (m, 2H), 0.71−0.67 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 168.4, 149.8, 146.6, 132.0, 131.1, 130.2, 129.4, 129.1, 128.8, 102.0, 8.78, 6.94. FT-IR (thin film, cm−1) 3500−2500 (br), 1696. MS calcd for C13H12N2O2 [M]+ = 228, found [M + H]+ = 229. HRMS calcd for C13H12N2O2 [M + H]+ = 229.0972, found [M + H]+ = 229.0973. Mp > 250 °C. 2-(5-tert-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16d). Following conditions B using 2-(dimethylamino)-3-(3,3-dimethylbut1-ynyl)-3-hydroxyisoindolin-1-one (60 mg, 0.22 mmol), anhydrous hydrazine (28 μL, 0.66 mmol), and THF (0.44 mL), 2-(5-tert-butyl1H-pyrazol-3-yl)benzoic acid hydrochloride was obtained as a light yellow solid (41 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (br s, 2H), 7.52−7.46 (m, 2H), 7.36 (td, J = 7.6, 1.1 Hz, 1H), 6.24 (s, 1H), 1.29 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 170.4, 154.3, 147.3, 132.7, 131.5, 129.8, 128.6, 127.9, 127.0, 99.9, 30.7, 30.1. FT-IR (thin film, cm−1) 3500−2500 (br), 2962, 1695. MS calcd for C14H16N2O2 [M]+ = 244, found [M + H]+ = 245. HRMS calcd for 3904



■

HRMS calcd for C16H20N4O [M + H]+ = 285.1710, found [M + H]+ = 285.1710. Mp = 132−133 °C. 2-(5-tert-Butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17e). Following conditions C using 2-(dimethylamino)-3(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (80 mg, 0.29 mmol), THF (0.29 mL), and methylhydrazine (78 μL, 1.5 mmol), 2-(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained as an off-white solid (14 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 5.6, 1.1 Hz, 1H), 7.54 (dd, J = 6.8, 1.5 Hz, 1H), 7.42 (td, J = 7.6, 1.5 Hz, 1H), 7.35 (td, J = 7.5, 1.3 Hz, 1H), 6.71 (br s, 1H), 6.21 (s, 1H), 4.01 (s, 3H), 2.51 (s, 6H), 1.39 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 167.6, 152.1, 148.0, 134,2, 131.5, 129.9, 129.3, 128.8, 127.7, 104.3, 47.2, 39.4, 31.2, 29.6. 2D-NMR confirmed the pyrazole structure. FT-IR (thin film, cm−1) 3180 (br), 2959, 2215, 1652, 1600. MS calcd for C17H24N4O [M]+ = 300, found [M + H]+ = 301. HRMS calcd for C17H24N4O [M + H]+ = 301.2023, found [M + H]+ = 301.2015. Mp = 156−157 °C. 2-(1-Butyl-5-phenyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17f). Following conditions C using 2-(dimethylamino)-3-hydroxy3-(phenylethynyl)isoindolin-1-one (80 mg, 0.27 mmol), THF (0.27 mL), and butylhydrazine (0.12 g, 1.4 mmol), 2-(1-butyl-5-phenyl-1H-pyrazol-3yl)-N′,N′-dimethylbenzohydrazide was obtained as a viscous colorless oil (76 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.68−7.63 (m, 2H), 7.49−7.38 (m, 8H), 6.50 (s, 1H), 4.18 (t, J = 7.5 Hz, 2H), 2.60 (s, 6H), 1.84 (quin, J = 7.7 Hz, 2H), 1.27 (sex, J = 7.6 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.7, 149.2, 144.7, 131.5, 130.5, 130.1, 129.4, 128.9, 128.79, 128.77, 128.69, 128.6, 127.9, 106.5, 49.5, 47.2, 32.7, 19.8, 13.6. FT-IR (thin film, cm−1) 3197 (br), 3038, 2955, 2871, 1652, 1600. MS calcd for C22H26N4O [M]+ = 362, found [M + H]+ = 363. HRMS calcd for C22H26N4O [M + H]+ = 363.2179, found [M + H]+ = 363.2180. 2-(5-Cyclopropyl-1-isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide (17g). Following conditions A using 3-(2-cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.30 g, 1.2 mmol), EtOH (2.34 mL), and 1-isobutylhydrazine (0.52 g, 5.9 mmol), 2-(5-cyclopropyl-1-isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained as a white solid (0.24 g, 63% yield). 1 H NMR (400 MHz, CDCl3) δ 7.57−7.55 (m, 2H), 7.41 (td, J = 7.4, 1.4 Hz, 1H), 7.33 (td, J = 7.7, 1.2 Hz, 1H), 6.56 (br s, 1H), 6.00 (s, 1H), 4.01 (d, J = 7.5 Hz, 2H), 2.49 (s, 6H), 2.39−2.31 (sep, 1H), 1.75−1.68 (m, 1H), 0.99−0.94 (m, 8H), 0.69−0.65 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.7, 148.6, 146.3, 134.2, 131.8, 129.9, 129.4, 128.7, 127.8, 102.6, 56.5, 47.2, 29.7, 20.2, 7.41, 6.35. FT-IR (thin film, cm−1) 3205, 2958, 2871, 1660, 1550. MS calcd for C19H26N4O [M]+ =326, found [M + H]+ = 327. HRMS calcd for C19H26N4O [M + H]+ = 327.2179, [M + Na]+ = 349.1999, found [M + H]+ = 327.2209, [M + Na]+ = 349.2004. Mp = 126−127 °C. Following conditions C using 3-(cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (80 mg, 0.31 mmol), THF (0.31 mL), and isobutylhydrazine (0.14 mg, 1.6 mmol), 2-(5-cyclopropyl-1isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained as a white solid (102 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.43 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 6.02 (s, 1H), 4.02 (d, J = 7.6 Hz, 2H), 2.53 (s, 6H), 2.37 (sep, 1H), 1.77−1.70 (m, 1H), 1.01−0.97 (m, 8H), 0.71−0.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.7, 148.6, 146.3, 134.1, 131.7, 130.0, 129.4, 128.7, 127.7, 102.6, 56.4, 47.1, 29.6, 20.1, 7.4, 6.3. 2D-NMR confirmed the pyrazole structure. FT-IR (thin film, cm−1) 3208, 2957, 2871, 1657, 1600. MS calcd for C19H26N4O [M]+ = 326, found [M + H]+ = 327. HRMS calcd for C19H26N4O [M + H]+ = 327.2179, found [M + H]+ = 327.2177. Mp = 122−123 °C.

■

Article

AUTHOR INFORMATION

Corresponding Author

*Corresponding author. Tel.: +1 617 444 5254; fax: +1 617 577 9822; e-mail: [email protected]. Present Addresses ∥

Blueprint Medicines, 215 First Street, Cambridge, MA 02142. University of California, San Francisco, CA 94143. # Sanofi-Aventis, Cambridge, MA 02139. ⊥

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We would like to thank Cary Fridrich, Kritti Modi, and Dr. Jay Larrow for the synthesis of 2-(dimethylamino)isoindoline-1,3dione; Matt Potter and Larry Miller for the purification; Dr. Richard J. Staples for the crystallography; and Dr. Margaret Y. Chu-Moyer for proofreading this manuscript.

■

REFERENCES

(1) Cee, V. J.; Schenkel, L. B.; Hodous, B. L.; Deak, H. L.; Nguyen, H.; Olivieri, P. R.; Romero, K.; Bak, A.; Be, X.; Bellon, S.; Bush, T. L.; Cheng, A.; Chung, G.; Coats, S.; Eden, P.; Gallant, P.; Gu, Y.; Huang, X.; Kendall, R.; Lin, J.; Morrison, M.; Patel, V. F.; Radinsky, R.; Rose, P.; Ross, S.; Sun, J.-R.; Tang, J.; Zhao, H.; Payton, M.; Geuns-Meyer, S. D. J. Med. Chem. 2010, 53, 6368−6377. (2) Bold, G.; Altmann, K.-H.; Frei, J.; Lang, M.; Manley, P. W.; Traxler, P.; Wietfeld, B.; Brueggen, J.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Furet, P.; Hofmann, F.; Martiny-Baron, G.; Mestan, J.; Roesel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss, E.; Emmenegger, R.; Laesser, L.; Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. M. J. Med. Chem. 2000, 43, 2310−2323. (3) Tasker, A.; Zhang, D.; Cao, G.-Q.; Chakrabarti, P. P.; Falsey, J. R.; Herberich, B., J.; Hungate, R., W.; Pettus, L., H.; Reed, A.; Rzasa, R., M.; Sham, K. K. C.; Thaman, M., C.; Xu, S. WO2006094187A2, 2006. (4) Jost Lorenz, M.; Gschwind, H.-P.; Jalava, T.; Wang, Y.; Guenther, C.; Souppart, C.; Rottmann, A.; Denner, K.; Waldmeier, F.; Gross, G.; Masson, E.; Laurent, D. Drug Metab. Dispos. 2006, 34, 1817−1828. (5) Kaizerman, J. A.; Aaron, W.; An, S.; Austin, R.; Brown, M.; Chong, A.; Huang, T.; Hungate, R.; Jiang, B.; Johnson, M. G.; Lee, G.; Lucas, B. S.; Orf, J.; Rong, M.; Toteva, M. M.; Wickramasinghe, D.; Xu, G.; Ye, Q.; Zhong, W.; McMinn, D. L. Bioorg. Med. Chem. Lett. 2010, 20, 4607−4610. (6) Bastian, J. A.; Hipskind, P. A.; Sall, D. J.; Wilson, T. (Eli Lilly and Company, USA) WO2010062507A1, 2010. (7) Hipskind, P. A.; Takakuwa, T. (Eli Lilly and Company, USA) WO2009134574A2, 2009. (8) Herberich, B.; Cao, G.-Q.; Chakrabarti, P. P.; Falsey, J. R.; Pettus, L.; Rzasa, R. M.; Reed, A. B.; Reichelt, A.; Sham, K.; Thaman, M.; Wurz, R. P.; Xu, S.; Zhang, D.; Hsieh, F.; Lee, M. R.; Syed, R.; Li, V.; Grosfeld, D.; Plant, M. H.; Henkle, B.; Sherman, L.; Middleton, S.; Wong, L. M.; Tasker, A. S. J. Med. Chem. 2008, 51, 6271−6279. (9) Achmatowicz, M.; Thiel, O. R.; Wheeler, P.; Bernard, C.; Huang, J.; Larsen, R. D.; Faul, M. M. J. Org. Chem. 2009, 74, 795−809. (10) Thiel, O. R.; Achmatowicz, M.; Bernard, C.; Wheeler, P.; Savarin, C.; Correll, T. L.; Kasparian, A.; Allgeier, A.; Bartberger, M. D.; Tan, H.; Larsen, R. D. Org. Process Res. Dev. 2009, 13, 230−241. (11) Sivakumar, R.; Kishore Gnanasam, S.; Ramachandran, S.; Thomas Leonard, J. Eur. J. Med. Chem. 2002, 37, 793−801. (12) Davis, J. L.; Mayer, M. J.; Josien, H. B. (Schering Corporation, USA). WO2010091176A1, 2010. (13) Iwase, N.; Morinaka, Y.; Tamao, Y.; Kanayama, T.; Yamada, K. EP534443A1, 1993. (14) Haack, T.; Fattori, R.; Napoletano, M.; Pellacini, F.; Fronza, G.; Raffaini, G.; Ganazzoli, F. Bioorg. Med. Chem. 2005, 13, 4425−4433.

ASSOCIATED CONTENT

S Supporting Information *

1

H NMR spectra for all compounds; NMR analyses of 7h, 7i, 1h, 15a, 15b, 15c, 17a, 17e, and 17g; ORTEP structures, crystal data, and atomic coordinates of 17a, 17b, and 17g; CIF files of 17a, 17b, and 17g. This material is available free of charge via the Internet at http://pubs.acs.org. 3905



Article

(41) Asselin, S. M.; Bio, M. M.; Langille, N. F.; Ngai, K. Y. Org. Process Res. Dev. 2010, 14, 1427−1431. (42) Liang, J. T.; Mani, N. S.; Jones, T. K. J. Org. Chem. 2007, 72, 8243−8250. (43) Dirat, O.; Clipson, A.; Elliott, J. M.; Garrett, S.; Brian Jones, A.; Reader, M.; Shaw, D. Tetrahedron Lett. 2006, 47, 1729−1731. (44) Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43−52. (45) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304−2307. (46) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853−2856. (47) Rothgery, E. F. Kirk-Othmer Encycl. Chem. Technol.(5th Ed.) 2005, 13, 562−607. (48) Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205−213. (49) Al-Hajjar, F. S.; Sabri, S. S. J. Heterocycl. Chem. 1986, 23, 727− 729. (50) Chang, K.-T.; Choi, Y. H.; Kim, S.-H.; Yoon, Y.-J.; Lee, W. S. J. Chem. Soc., Perkin Trans. 1 2002, 207−210. (51) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R. H., J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A., Gaussian 03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004. (52) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P. Tetrahedron: Asymmetry 2003, 14, 2253−2258. (53) Saito, Y.; Sakamoto, T.; Kikugawa, Y. Synthesis 2001, 2, 221− 224. (54) Deniau, E.; Enders, D. Tetrahedron Lett. 2000, 41, 2347−2350. (55) Niyaz-Khan, M.; Ariffin, A. React. Kinet. Catal. Lett. 2003, 78, 193−200. (56) Uchida, K.; Matsuoka, T.; Kobatake, S.; Yamaguchi, T.; Irie, M. Tetrahedron 2001, 57, 4559−4565. (57) Rahman, L. US2005085492A1, 2005.

(15) Lucas, B. S.; Aaron, W.; An, S.; Austin, R. J.; Brown, M.; Chan, H.; Chong, A.; Hungate, R.; Huang, T.; Jiang, B.; Johnson, M. G.; Kaizerman, J. A.; Lee, G.; McMinn, D. L.; Orf, J.; Powers, J. P.; Rong, M.; Toteva, M. M.; Uyeda, C.; Wickramasinghe, D.; Xu, G.; Ye, Q.; Zhong, W. Bioorg. Med. Chem. Lett. 2010, 20, 3618−3622. (16) Cee, V. J.; Deak, H. L.; Du, B.; Geuns-Meyer, S. D.; Hodous, B. L.; Nguyen, H. N.; Olivieri, P. R.; Patel, V. F.; Romero, K.; Schenkel, L.(Amgen Inc., USA). WO2007087276A1, 2007, Chemical Indexing Equivalent to 151:148333 (US). (17) Duncton, M. A. J.; Piatnitski Chekler, E. L.; Katoch-Rouse, R.; Sherman, D.; Wong, W. C.; Smith, L. M.; Kawakami, J. K.; Kiselyov, A. S.; Milligan, D. L.; Balagtas, C.; Hadari, Y. R.; Wang, Y.; Patel, S. N.; Rolster, R. L.; Tonra, J. R.; Surguladze, D.; Mitelman, S.; Kussie, P.; Bohlen, P.; Doody, J. F. Bioorg. Med. Chem. 2009, 17, 731−740. (18) Smith, C. D.; Tchabanenko, K.; Adlington, R. M.; Baldwin, J. E. Tetrahedron Lett. 2006, 47, 3209−3212. (19) Knoepfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682−9683. (20) Kassab, E. A. Egypt. J. Chem 2005, 48, 183−199. (21) Raposo, M. M. M.; Sampaio, A. M. B. A.; Kirsch, G. J. Heterocycl. Chem. 2005, 42, 1245−1251. (22) Bele, C.; Darabantu, M. Heterocycl. Commun. 2003, 9, 641−646. (23) Mahmoodi, N. O.; Salehpour, M. J. Heterocycl. Chem. 2003, 40, 875−878. (24) Tedjamulia, M. L.; Tominaga, Y.; Castle, R. N.; Lee, M. L. J. Heterocycl. Chem. 1983, 20, 1143−1148. (25) Fieser, L. F.; Hershberg, E. B. J. Am. Chem. Soc. 1937, 59, 2331− 2335. (26) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1976, 41, 1268− 1269. (27) Acosta, A.; de la Cruz, P.; De Miguel, P.; Diez-Barra, E.; de la Hoz, A.; Langa, F.; Loupy, A.; Majdoub, M.; Martin, N.; et al. Tetrahedron Lett. 1995, 36, 2165−2168. (28) Koyanagi, J.; Yamamoto, K.; Nakayama, K.; Tanaka, A. J. Heterocycl. Chem. 1994, 31, 1303−1304. (29) Yamaguchi, M.; Kamei, K.; Koga, T.; Akima, M.; Kuroki, T.; Ohi, N. J. Med. Chem. 1993, 36, 4052−4060. (30) Rahman, M. T.; Nahar, S. K. J. Organomet. Chem. 1992, 425, 201−208. (31) Deniau, E.; Enders, D. Tetrahedron 2001, 57, 2581−2588. (32) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P. Tetrahedron: Asymmetry 2005, 16, 875−881. (33) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry 2003, 14, 2625−2632. (34) Deniau, E.; Enders, D. Tetrahedron Lett. 2000, 41, 2347−2350. (35) Gavish, M.; Veenman, J. A.; Shterenberg, A.; Marek, I. (Technion Research and Development Foundation Ltd., Israel) WO2008023357, 2008. (36) Saito, Y.; Sakamoto, T.; Kikugawa, Y. Synthesis 2001, 221−224. (37) Nguyen, H. N.; Romero, K.; Olivieri, P.; Schenkel, L.; Du, B.; Cee, V.; Hodous, B.; Deak, H.; Panter, K.; Fridrich, C.; Modi, K.; Larrow, J.; Hollis, S.; Potter, M.; Miller, L.; Geuns-Meyer, S.; Patel, V. Abstracts of Papers, 235th ACS National Meeting, New Orleans, LA, United States, April 6−10, 2008; American Chemical Society: Washington, DC, 2008, ORGN-469. This oral presentation had presented part of this work. On February 28, 2008, Gavish et al. published a patent describing a similar approach to chlorophenylphthalazines. (38) Proton NMR in CDCl3 confirmed the 2-(dimethylamino)-3hydroxy-3-((3-hydroxyphenyl)ethynyl)isoindolin-1-one; however, 13C NMR showed a complex mixture of products, likely due to C−O silyl migration. The product was further confirmed by desilylation with TBAF. The desilylated product, 2-(dimethylamino)-3-ethynyl-3hydroxyisoindolin-1-one, had very clean 1H and 13C NMR spectra. (39) Lehmann, U.; Henze, O.; Schluter, A. D. Chem.Eur. J. 1999, 5, 854−859. (40) Gronowitz, S.; Cederlund, B.; Honrnfeldt, A.-B. Chemica Scripta 1974, 5, 217−226. 3906


Synthesis of 4-Substituted Chlorophthalazines ... - ACS Publications

Recommend Documents