Palladium-Catalyzed Decarboxylative ortho-Acylation of Anilines with

20 hours ago - (19) Moreover, 3aa could be used to prepare the NH-free acridone 5aa in 82% yield through Cu-catalyzed intramolecular C(sp2)–H aminat...
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Article Cite This: ACS Omega 2018, 3, 4187−4198

Palladium-Catalyzed Decarboxylative ortho-Acylation of Anilines with Carbamate as a Removable Directing Group Qi-Li Li,† Zhong-Yuan Li,† and Guan-Wu Wang*,†,‡ †

CAS Key Laboratory of Soft Matter Chemistry, Collaborative Innovation Center of Chemistry for Energy Materials (iChEM), Hefei National Laboratory for Physical Sciences at Microscale, and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China S Supporting Information *

ABSTRACT: An efficient palladium-catalyzed decarboxylative ortho-acylation of anilines with α-oxocarboxylic acids has been realized by using carbamate as a directing group (DG). The reaction proceeds smoothly with high regioselectivity to afford diverse acylation products of aniline derivatives in moderate to good yields under mild conditions. This transformation exhibits broad substrate scope and highly functional group tolerance. In addition, the employed DG can be easily removed to give the corresponding 2-amino aromatic ketones. Importantly, several transformations of the synthesized ortho-acylated anilines into several synthetically valuable products have been demonstrated for their utilities.

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INTRODUCTION Over the past decades, transition-metal-catalyzed direct C−H functionalization with high atom economy has been significantly developed as one of the most powerful and straightforward strategies to construct complex target molecules from relatively simple materials.1 Among them, functional group-directed C−H activation protocols are particularly useful, owing to regioselective functionalizations of ubiquitous C−H bonds in organic molecules at the desired positions.2 Nitrogencontaining heterocycles such as pyridine, pyrimidine, and so forth have proven to be a subclass of the most efficient directing groups (DGs) in organic synthesis, but their synthetic utilities were significantly compromised because of the difficulty in removing or modifying these DGs after the desired transformations.3 Therefore, new methods have been developed to exploit a variety of removable DGs in recent years, thereby making these methods more useful in organic synthesis.4 For example, phenol carbamates have been investigated as substrates with removable DGs for many C−H activation transformations including alkenylation,5 arylation,6 borylation,7 halogenation,8 and oxygenation.9 Unlike phenol carbamates, aniline carbamates bearing the intrinsic carbamate functionality as the potential DGs have been rarely explored in transitionmetal-catalyzed C−H activation reactions.10 In 2014, the Li group disclosed a Pd-catalyzed ortho-C−H arylation of aniline carbamates, which was the first investigation by using carbamates as DGs for sp2 C−H activation (Scheme 1A).11a Later, Moghaddam and co-workers reported the Pd-catalyzed ortho-halogenation of aniline carbamates under mild conditions (Scheme 1B).11b Unfortunately, there have been no other examples, although aniline carbamates have exhibited great advantages for C−H activation reactions as removable DGs. © 2018 American Chemical Society

Scheme 1. (A) Pd-Catalyzed ortho-C−H Arylation of Aniline Carbamates; (B) Pd-Catalyzed ortho-Halogenation of Aniline Carbamates; and (C) Pd-Catalyzed ortho-C−H Acylation of Aniline Carbamates

Meanwhile, aniline carbamates are crucial structural motifs in natural products and play important and ubiquitous roles in pharmaceutical12 and therapeutic compounds.13 Thus, synthetically useful methods for the diversified functionalizations of aniline carbamates via direct C−H activations are highly desirable. On the other hand, transition-metal-catalyzed ligand-directed ortho-acylation in arenes using acyl surrogates has attracted Received: March 8, 2018 Accepted: April 4, 2018 Published: April 13, 2018 4187

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ACS Omega Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

oxidant

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23c 24d 25c,e 26c,f 27c,g 28c,h 29c 30c 31c 32c,i

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(CH3CN)2Cl2 Pd(PhCN)2Cl2 Pd(OAc)2

(NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 K2S2O8 Na2S2O8 oxone BQ Ag2O (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8

additive

solvent, temp (°C)

yieldb (%) 21 15 trace trace

PTSA PivOH D-CSA TfOH TFA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA PTSA

DCE, 30 DCM, 30 diglyme, 30 CH3CN, 30 dioxane, 30 toluene, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 30 DCE, 25 DCE, 35 DCE, 40 DCE, 45 DCE, 50 DCE, 60 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45 DCE, 45

10 trace trace trace trace 42 22 24 21 trace 32 56 62 67 58 50 71 57 65 68 68 70 67 8 trace 63

a Reaction conditions: 1a (0.10 mmol), 2a (0.18 mmol), catalyst (0.01 mmol), (NH4)2S2O8 (0.20 mmol), additive (0.05 mmol), and DCE (1.0 mL), 24 h. bIsolated yields based on 1a. cAdditive (0.075 mmol). dAdditive (0.10 mmol). e2a (0.16 mmol). f2a (0.20 mmol). gReaction for 22 h. h Reaction for 26 h. iCatalyst (0.005 mmol).

intense attention as a reliable tool at the frontier of acylation chemistry.14 The α-oxocarboxylic acids have been used to a great extent as convenient acyl sources with remarkable success.15 However, some of the previously used DGs are difficult to modify or remove.16 Therefore, the development of a removable DG-assisted acylation is highly demanded. To the best of our knowledge, the Pd-catalyzed decarboxylative acylation of sp2 C−H bonds with aniline carbamates as the DG have never been reported. With a continuation of our interest in developing more C−H bond activation protocols,17 herein we disclose the first example of the Pd-catalyzed decarboxylative acylation of anilines with α-oxocarboxylic acids by using carbamate as a removable DG (Scheme 1C).

(10 mol %) and (NH4)2S2O8 (2.0 equiv) in 1,2-dichloroethane (DCE) at 30 °C for 24 h. To our delight, the desired product 3aa was isolated in 21% yield (Table 1, entry 1). Encouraged by this initial result, we then optimized the reaction conditions including solvents, oxidants, additives, palladium catalysts, reaction temperature, and reaction time, and the selected results are summarized in Table 1. Firstly, solvent screening experiments demonstrated that dichloromethane (DCM), diglyme, acetonitrile (CH3CN), dioxane, and toluene were much less efficient than DCE (entries 2−6 vs entry 1). Then, the effectiveness of the oxidant was examined. Compared to other oxidants such as K2S2O8, Na2S2O8, oxone, BQ, and Ag2O, (NH4)2S2O8 was the most suitable oxidant in this reaction (entries 7−11 vs entry 1). After that, different sorts of additives had been investigated. When 0.5 equiv of p-toluenesulfonic acid (PTSA) was added to this reaction, the yield was dramatically improved to 42% (entry 12). The addition of other additives, such as pivalic acid (PivOH), D-camphorsulfonic acid (D-CSA),

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RESULTS AND DISCUSSION Our investigation began with decarboxylative coupling of methyl phenylcarbamate (1a) with phenylglyoxylic acid (2a, 1.8 equiv) as the model reaction in the presence of Pd(OAc)2 4188

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ACS Omega trifluoromethanesulfonic acid (TfOH), and trifluoroacetic acid (TFA), to the reaction resulted in reduced yields of 3aa (entries 13−16 vs entry 12). Next, we examined the influence of the reaction temperature. Decreasing the temperature to 25 °C suppressed the reaction efficiency and provided 3aa in 32% yield (entry 17). Increasing the temperature to 35, 40, or 45 °C led to an improvement of the yield up to 67% (entries 18−20). However, no better result could be obtained by further increasing the temperature to 50 and 60 °C (entries 21 and 22). We were pleased to find that the yield could be improved to 71%, when the amount of PTSA was increased to 0.75 equiv (entry 23). Nevertheless, the yield decreased slightly as the amount of PTSA was further increased to 1.0 equiv (entry 24). Subsequently, varying the amount of 2a proved to be fruitless (entries 25 and 26). Furthermore, the effect of the reaction time was also studied. The experimental results indicated that shorter or longer reaction time was not beneficial either (entries 27 and 28). To identify the impact of different kinds of palladium catalysts, experiments with several palladium salts were performed. The yield of 3aa was not enhanced with other palladium catalysts including Pd(TFA)2, Pd(CH3CN)2Cl2, and Pd(PhCN)2Cl2 (entries 29−31 vs entry 23). Finally, we attempted to decrease the catalyst loading to 5 mol %, and the target product was obtained in only 63% yield (entry 32). Therefore, the optimized conditions of the Pd-catalyzed decarboxylative ortho-acylation of 1a with 2a were determined as shown in entry 23. With the optimized reaction conditions in hand, we turned our attention to investigate the substrate scope of aniline carbamates. As shown in Table 2, the reactions proceeded smoothly to afford ortho-acylation products 3aa−pa in moderate to good yields with temperature variations in some cases. Aniline carbamates 1b and 1c with para-substituted electron-donating groups (Me and t-Bu) gave the corresponding products 3ba and 3ca in 53 and 54% yields, respectively. Halogen-substituted aniline carbamates 1d−f were compatible with our optimal reaction conditions. In particular, the fluorosubstituted aniline carbamate 1d gave the corresponding product 3da in 78% yield. It should be pointed out that the acylation could tolerate the electron-withdrawing group CF3 at the para-position and provided 3ga in a moderate yield of 51%. To our delight, meta-substituted electron-rich or electrondeficient aniline carbamates exhibited good regioselectivity and gave products 3ha−ma in 45−81% yields. Even the reaction with the iodo-substituted aniline carbamate delivered the expected product 3la in 61% yield. It is of interest to note that the halo group in products 3da−fa and 3ia−la may be utilized as the handle for further functionalization. Unfortunately, ortho-substituted aniline carbamates failed to provide the desired product under the current catalyst system, presumably due to the steric hindrance. Moreover, 3,4disubstituted aniline carbamate 1n was also compatible and gave the corresponding product 3na in 53% yield. Furthermore, the methyl carbamate group could be replaced by the ethylcarbamate group and still afforded a good yield (70%) of 3oa. Additionally, phenyl phenylcarbamate (1p), a substrate with both phenol and aniline carbamate functionalities, showed complete selectivity for functionalization of the aniline moiety (3pa), rather than the previously established reactivity selectively at the phenol moiety.6b,18 To further examine the substrate scope and limitations, various α-oxocarboxylic acids were investigated under the optimized reaction conditions. As shown in Table 3, various α-

Table 2. Substrate Scope for the Acylation of Aniline Carbamates 1a−p with Phenylglyoxylic Acid (2a)a,b

a

Reaction conditions: 1a (1b−p, 0.30 mmol), 2a (0.54 mmol), Pd(OAc)2 (0.03 mmol), (NH4)2S2O8 (0.60 mmol), PTSA (0.225 mmol), DCE (3.0 mL), at 45 °C for 24 h unless otherwise noted. b Isolated yields based on 1. cReaction at 60 °C.

oxocarboxylic acids containing different functional groups in the aromatic ring showed good reactivity to give the corresponding products in moderate to good yields with temperature variations in some cases. The acylation could tolerate with either electron-rich or electron-deficient groups including the OMe, Me, and halogen groups at the paraposition, affording the desired products 3ab−ag in 42−60% yields. Similarly, meta-substituted phenylglyoxylic acids worked well to give the desired products 3ah−am in 50−70% yields. The reaction could also be extended to ortho-substituted phenylglyoxylic acids to afford 3an−aq in 56−70% yields. When 2-(naphthalene-1-yl)-2-oxoacetic acid (2r) was employed as the acyl source, the corresponding product 3ar was obtained in 51% yield. Finally, the disubstituted phenylglyoxylic acids also proved to be feasible for this procedure and provided products 3as−au in 50−59% yields. We then explored the synthetic utility of synthesized orthoacylated aniline carbamates; we conducted further transformations of the representative 3aa to provide several synthetically valuable products (Scheme 2). For example, 3aa could react with (ethoxyethynyl)lithium to synthesize the multifunctionalized indole 4aa in 81% yield.19 Moreover, 3aa could be used to prepare the NH-free acridone 5aa in 82% yield through Cu-catalyzed intramolecular C(sp2)−H amination and simultaneous removal of the DG.20 Subsequently, the removal of the DGs was examined. By following previously reported alkaline conditions,21 the removal of the methyl carbamate group could be realized to produce (24189

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ACS Omega Table 3. Substrate Scope for the Acylation of Aniline Carbamate 1a with α-Oxocarboxylic Acids 2b−ua,b

Scheme 2. Removal of the DGs and Transformations of 3aa, 3oa, and 3pa

previous literature,17d,25 a plausible mechanism for this Pdcatalyzed C−H acylation is depicted in Scheme 4. At first, this transformation is believed to start with the formation of a sixmembered palladacycle A by the ortho-palladation of 1 with a Pd(II) species. Then, A undergoes oxidative coupling with the acyl radical B, which is produced by decarboxylation of 2 in the presence of (NH4)2S2O8,17d to furnish the Pd(III) intermediate C.26 The intermediate C is subsequently oxidized by (NH4)2S2O8 to provide a Pd(IV) intermediate D.26 Finally, the acylated product 3 is generated by reductive elimination of the intermediate D, and a Pd(II) species is released simultaneously to complete the catalytic cycle.

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CONCLUSIONS In summary, we have developed an efficient palladiumcatalyzed acylation of anilines with high regioselectivity by utilizing carbamate as a removable DG via C−H activation strategy. This protocol can be applied to a wide range of aniline carbamates and α-oxocarboxylic acids with both electrondonating and electron-withdrawing groups. Additionally, this protocol is also compatible with halogen functional groups, which offer a potential for further structural modification. Importantly, the synthesized ortho-acylated anilines can be further converted to indoles and acridones, and the protecting carbamate group can be easily removed to provide the 2-amino aromatic ketones, which could be further transformed to quinoline and quinazoline derivatives.

a Reaction conditions: 1a (0.30 mmol), 2b (2c−u, 0.54 mmol), Pd(OAc)2 (0.03 mmol), (NH4)2S2O8 (0.60 mmol), PTSA (0.225 mmol), and DCE (3.0 mL), at 45 °C for 24 h unless otherwise noted. b Isolated yields based on 1. cReaction at 60 °C.

aminophenyl)(phenyl)methanone (6aa) in 93% yield. Additionally, ethyl and phenyl carbamate moieties of 3oa and 3pa could also be removed efficiently by using tetrabutylammonium fluoride (TBAF).22 Furthermore, 6aa could react with NH4OAc and benzylic C−H bond of toluene to synthesize 2,4-diphenylquinazoline (7aa) in 78% yield under the KI− TBHP conditions.23 In addition, 6aa could be efficiently transformed to 2-methyl-4-phenylquinoline (8aa) by reacting with acetone in 92% yield.24 In order to understand the reaction mechanism of this transformation, a radical trapping experiment was explored (Scheme 3). When the radical scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) was added to the reaction system of 1a and 2a under the optimized conditions, only a trace amount of 3aa was detected; meanwhile the acyl radicalTEMPO adduct 9 was isolated in 38% yield. This result indicated that the reaction probably involved a free radical process. On the basis of the above experimental result and the

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EXPERIMENTAL SECTION General Information. NMR spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1H NMR; 101 MHz for 13C NMR). Chemical shifts (δ) were reported in ppm reference to an internal TMS standard or the DMSO-d6 residual peak (δ 2.50) for 1H NMR. Chemical shifts of 13C NMR were determined relative to residual CDCl3 at δ 77.16 ppm. Data for 1H NMR and 13C NMR are represented as follows: chemical shift (δ, ppm) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad). High-resolution mass spectra (HRMS) were measured with FTMS-electrospray ionization (ESI) in a positive mode. 2a was purchased from TCI and used directly. All of other 4190

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ACS Omega Scheme 3. Radical Trapping Experiment for the Formation of 3aa

Scheme 4. Plausible Reaction Mechanism

Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 3.77 (s, 3H), 2.28 (s, 3H); C NMR (101 MHz, CDCl3): δ 199.43, 154.55, 138.94, 138.51, 135.06, 133.70, 132.43, 130.84, 129.99 (2C), 128.41 (2C), 123.23, 120.19, 52.42, 20.78; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1132. Methyl(2-benzoyl-4-(tert-butyl)phenyl)carbamate (3ca). By following the general procedure, the reaction of 1c (62.6 mg, 0.30 mmol) with 2a (81.0 mg, 0.54 mmol) gave 3ca (50.3 mg, 54% yield). Yellow oil. 1H NMR (400 MHz, CDCl3): δ 10.10 (br, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.74−7.69 (m, 2H), 7.62−7.57 (m, 2H), 7.54 (d, J = 2.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 3.77 (s, 3H), 1.25 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 199.40, 154.53, 144.08, 138.84, 138.29, 132.50, 131.36, 130.39, 130.09 (2C), 128.32 (2C), 122.85, 119.92, 52.39, 34.30, 31.21 (3C); HRMS (ESI): calcd for C19H22NO3 [M + H]+, 312.1594; found, 312.1604. Methyl(2-benzoyl-4-fluorophenyl)carbamate (3da). By following the general procedure, the reaction of 1d (50.7 mg, 0.30 mmol) with 2a (80.7 mg, 0.54 mmol) gave 3da (64.2 mg, 78% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 9.97 (br, 1H), 8.38 (dd, J = 9.2, 4.9 Hz, 1H), 7.73−7.69 (m, 2H), 7.62 (tt, J = 7.4, 1.3 Hz, 1H), 7.53−7.47 (m, 2H), 7.32−7.27 (m, 1H), 7.23 (dd, J = 8.9, 3.0 Hz, 1H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.03 (d, JC−F = 1.0 Hz), 156.61 (d, JC−F = 243.5 Hz), 154.54, 138.04, 137.00 (d, JC−F = 3.0 Hz), 132.96, 129.99 (2C), 128.61 (2C), 124.33 (d, JC−F = 6.0 Hz), 122.23 (d, JC−F = 7.0 Hz), 121.20 (d, JC−F = 22.1 Hz), 119.28 (d, JC−F = 23.1 Hz), 52.58; HRMS (ESI): calcd for C15H13NO3F [M + H]+, 274.0874; found, 274.0882.

reagents were purchased from Adamas-beta, J&K, Alfa Aesar, Energy Chemical and used directly. 1a−p and 2b−u were prepared according to the reported protocols.27 The solvents were purchased from Sinopharm Chemical Reagent Co. Ltd (SCRC) and used directly. Products were purified by flash chromatography on 200−300 mesh silica gel. General Procedure for the Palladium-Catalyzed Decarboxylative ortho-Acylation of Aniline Carbamates with α-Oxocarboxylic Acids. A mixture of 1 (0.30 mmol), Pd(OAc)2 (10 mol %), α-oxocarboxylic acid 2 (0.54 mmol), (NH4)2S2O8 (0.60 mmol), PTSA (0.225 mmol), and DCE (3.0 mL) in a 25 mL tube was heated at 45 or 60 °C for 24 h. Once completion, the reaction was cooled to room temperature. Then, the mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in vacuo. Product 3 was isolated by column chromatography over silica gel using a mixture of petroleum ether and ethyl acetate (v/v = 10:1) as the eluent. Methyl(2-benzoylphenyl)carbamate (3aa).28 By following the general procedure, the reaction of 1a (45.4 mg, 0.30 mmol) with 2a (80.7 mg, 0.54 mmol) gave 3aa (54.1 mg, 71% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.30 (br, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.72−7.66 (m, 2H), 7.62−7.52 (m, 3H), 7.51−7.45 (m, 2H), 7.06−6.99 (m, 1H), 3.79 (s, 3H). Methyl(2-benzoyl-4-methylphenyl)carbamate (3ba). By following the general procedure, the reaction of 1b (49.4 mg, 0.30 mmol) with 2a (80.7 mg, 0.54 mmol) gave 3ba (42.4 mg, 53% yield). Yellow oil. 1H NMR (400 MHz, CDCl3): δ 10.09 (br, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.72−7.67 (m, 2H), 7.59 (tt, J = 7.4, 1.3 Hz, 1H), 7.51−7.46 (m, 2H), 7.38 (dd, J = 8.5, 2.0

13

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ACS Omega Methyl(2-benzoyl-4-chlorophenyl)carbamate (3ea). By following the general procedure, the reaction of 1e (55.6 mg, 0.30 mmol) with 2a (82.5 mg, 0.54 mmol) gave 3ea (63.8 mg, 74% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.10 (br, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.72−7.68 (m, 2H), 7.63 (tt, J = 7.4, 1.2 Hz, 1H), 7.54−7.48 (m, 4H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.15, 154.30, 139.51, 138.09, 134.07, 132.97, 132.75, 129.99 (2C), 128.66 (2C), 126.50, 124.22, 121.66, 52.65; HRMS (ESI): calcd for C15H13NO335Cl [M + H]+, 290.0579; found, 290.0588. Methyl(2-benzoyl-4-bromophenyl)carbamate (3fa). By following the general procedure, the reaction of 1f (68.7 mg, 0.30 mmol) with 2a (81.0 mg, 0.54 mmol) at 60 °C gave 3fa (59.6 mg, 60% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.10 (br, 1H), 8.34 (d, J = 8.7 Hz, 1H), 7.72−7.65 (m, 3H), 7.65−7.61 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 3.79 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 198.03, 154.22, 139.98, 138.06, 136.93, 135.62, 132.97, 129.99 (2C), 128.65 (2C), 124.57, 121.91, 113.72, 52.65; HRMS (ESI): calcd for C15H13NO379Br [M + H]+, 334.0073; found, 334.0083. Methyl(2-benzoyl-4-(trifluoromethyl)phenyl)carbamate (3ga). By following the general procedure, the reaction of 1g (65.9 mg, 0.30 mmol) with 2a (90.2 mg, 0.6 mmol) gave 3ga (49.7 mg, 51% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.41 (br, 1H), 8.61 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.72−7.67 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.39, 154.13, 143.99, 137.98, 133.14, 130.84 (q, JC−F = 3.5 Hz), 130.53 (q, JC−F = 3.5 Hz), 129.97 (2C), 128.74 (2C), 123.77 (q, JC−F = 271.7 Hz), 123.26 (q, JC−F = 33.5 Hz), 122.29, 120.12, 52.81; HRMS (ESI): calcd for C16H13NO3F3 [M + H]+, 324.0842; found, 324.0852. Methyl(2-benzoyl-5-methylphenyl)carbamate (3ha). By following the general procedure, the reaction of 1h (49.5 mg, 0.30 mmol) with 2a (81.6 mg, 0.54 mmol) gave 3ha (49.7 mg, 50% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.50 (br, 1H), 8.28 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.50−7.41 (m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 3.79 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.32, 154.51, 145.85, 141.35, 139.21, 134.11, 132.14, 129.79 (2C), 128.32 (2C), 122.21, 120.29, 120.20, 52.43, 22.32; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1133. Methyl(2-benzoyl-5-fluorophenyl)carbamate (3ia). By following the general procedure, the reaction of 1i (50.6 mg, 0.30 mmol) with 2a (80.9 mg, 0.54 mmol) gave 3ia (61.2 mg, 75% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.71 (br, 1H), 8.26 (dd, J = 11.9, 2.5 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.61−7.55 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 6.74−6.67 (m, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.56, 166.21 (d, JC−F = 253.6 Hz), 154.15, 144.03 (d, JC−F = 13.1 Hz), 138.91, 136.51 (d, JC−F = 11.1 Hz), 132.32, 129.61 (2C), 128.43 (2C), 118.72, 108.45 (d, JC−F = 22.1 Hz), 106.85 (d, JC−F = 28.2 Hz), 52.61; HRMS (ESI): calcd for C15H13NO3F [M + H]+, 274.0874; found, 274.0882. Methyl(2-benzoyl-5-chlorophenyl)carbamate (3ja). By following the general procedure, the reaction of 1j (55.5 mg, 0.30 mmol) with 2a (80.9 mg, 0.54 mmol) gave 3ja (70.3 mg, 81% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.46 (br, 1H), 8.53 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51−7.45 (m, 3H), 6.99 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.63, 154.10, 142.27, 140.81, 138.56, 134.87, 132.56, 129.76 (2C), 128.47

(2C), 121.44, 120.71, 119.75, 52.63; HRMS (ESI): calcd for C15H13NO335Cl [M + H]+, 290.0579; found, 290.0587. Methyl(2-benzoyl-5-bromophenyl)carbamate (3ka). By following the general procedure, the reaction of 1k (68.9 mg, 0.30 mmol) with 2a (89.9 mg, 0.6 mmol) gave 3ka (70.0 mg, 70% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.40 (br, 1H), 8.70 (d, J = 1.8 Hz, 1H), 7.68−7.64 (m, 2H), 7.63− 7.57 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.5, 1.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.84, 154.16, 142.15, 138.57, 134.85, 132.68, 129.85 (2C), 129.56, 128.55 (2C), 124.50, 122.84, 121.24, 52.70; HRMS (ESI): calcd for C15H13NO379Br [M + H]+, 334.0073; found, 334.0083. Methyl(2-benzoyl-5-iodophenyl)carbamate (3la). By following the general procedure, the reaction of 1l (83.3 mg, 0.30 mmol) with 2a (81.5 mg, 0.54 mmol) at 60 °C gave 3la (69.5 mg, 61% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.30 (br, 1H), 8.89 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.01, 154.15, 141.57, 138.48, 134.53, 132.71, 130.55, 129.88 (2C), 128.83, 128.54 (2C), 121.84, 102.39, 52.68; HRMS (ESI): calcd for C15H13NO3127I [M + H]+, 381.9935; found, 381.9945. Methyl(2-benzoyl-5-(trifluoromethyl)phenyl)carbamate (3ma). By following the general procedure, the reaction of 1m (65.8 mg, 0.30 mmol) with 2a (81.0 mg, 0.54 mmol) at 60 °C gave 3ma (44.1 mg, 45% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.13 (br, 1H), 8.78 (s, 1H), 7.73−7.69 (m, 2H), 7.68−7.61 (m, 2H), 7.51 (td, J = 7.6, 1.9 Hz, 2H), 7.29 (dd, J = 8.2, 1.1 Hz, 1H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.47, 154.21, 141.22, 138.01, 135.36 (q, JC−F = 33.2 Hz), 133.73, 133.20, 130.11 (2C), 128.65 (2C), 125.26, 123.46 (q, JC−F = 273.7 Hz), 117.78 (q, JC−F = 4.0 Hz), 117.17 (q, J C−F = 4.0 Hz), 52.76; HRMS (ESI): calcd for C16H13NO3F3 [M + H]+, 324.0842; found, 324.0849. Methyl(2-benzoyl-4,5-dichlorophenyl)carbamate (3na). By following the general procedure, the reaction of 1n (65.6 mg, 0.30 mmol) with 2a (80.9 mg, 0.54 mmol) at 60 °C gave 3na (51.6 mg, 53% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.23 (br, 1H), 8.66 (s, 1H), 7.69−7.60 (m, 4H), 7.51 (t, J = 7.5 Hz, 2H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.54, 154.01, 140.23, 138.83, 137.91, 134.44, 133.06, 129.82 (2C), 128.72 (2C), 124.81, 122.16, 121.68, 52.79; HRMS (ESI): calcd for C15H12NO335Cl2 [M + H]+, 324.0189; found, 324.0194. Ethyl(2-benzoylphenyl)carbamate (3oa). By following the general procedure, the reaction of 1o (49.6 mg, 0.30 mmol) with 2a (81.0 mg, 0.54 mmol) gave 3oa (56.2 mg, 70% yield). Yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.25 (br, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.72−7.68 (m, 2H), 7.61−7.51 (m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.02 (td, J = 8.1, 1.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.40, 153.98, 141.12, 138.82, 134.30, 133.68, 132.43, 129.96 (2C), 128.36 (2C), 122.88, 121.12, 120.00, 61.35, 14.59; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1131. Phenyl(2-benzoylphenyl)carbamate (3pa). By following the general procedure, the reaction of 1p (64.1 mg, 0.30 mmol) with 2a (81.1 mg, 0.54 mmol) at 60 °C gave 3pa (58.3 mg, 61% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.66 (br, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.64−7.55 (m, 3H), 7.50 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.7 Hz, 4192

DOI: 10.1021/acsomega.8b00441 ACS Omega 2018, 3, 4187−4198

Article

ACS Omega

mmol) with 2g (149.2 mg, 0.54 mmol) at 60 °C gave 3ag (48.5 mg, 42% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.23 (br 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.58 (td, J = 8.6, 1.4 Hz, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.04 (td, J = 7.9, 0.9 Hz, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.50, 154.38, 141.12, 138.12, 137.69 (2C), 134.67, 133.45, 131.38 (2C), 122.51, 121.37, 120.17, 100.07, 52.55; HRMS (ESI): calcd for C15H13NO3127I [M + H]+, 381.9935; found, 381.9941. Methyl(2-(3-methoxybenzoyl)phenyl)carbamate (3ah). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2h (97.7 mg, 0.54 mmol) at 60 °C gave 3ah (39.2 mg, 50% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.25 (br, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.60−7.52 (m, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.25−7.19 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.17, 159.57, 154.43, 140.99, 140.10, 134.38, 133.71, 129.35, 122.96, 122.64, 121.27, 120.00, 118.77, 114.35, 55.59, 52.49; HRMS (ESI): calcd for C16H16NO4 [M + H]+, 286.1074; found, 286.1081. Methyl(2-(3-methylbenzoyl)phenyl)carbamate (3ai). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 mmol) with 2i (89.3 mg, 0.54 mmol) gave 3ai (56.2 mg, 70% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.28 (br, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.59−7.49 (m, 3H), 7.46 (d, J = 7.3 Hz, 1H), 7.41−7.32 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.65, 154.43, 140.95, 138.86, 138.28, 134.24, 133.71, 133.21, 130.34, 128.19, 127.22, 123.10, 121.24, 119.97, 52.45, 21.46; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1133. Methyl(2-(3-fluorobenzoyl)phenyl)carbamate (3aj). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 mmol) with 2j (93.7 mg, 0.54 mmol) gave 3aj (48.7 mg, 59% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.24 (br, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.48−7.43 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.32−7.25 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.91 (d, JC−F = 2.0 Hz), 162.48 (d, JC−F = 248.4 Hz), 154.37, 141.21, 140.86 (d, JC−F = 6.0 Hz), 134.77, 133.60, 130.09 (d, JC−F = 7.0 Hz), 125.71 (d, JC−F = 3.0 Hz), 122.38, 121.38, 120.12, 119.42 (d, JC−F = 21.1 Hz), 116.71 (d, JC−F = 23.1 Hz), 52.54; HRMS (ESI): calcd for C15H13NO3F [M + H]+, 274.0874; found, 274.0883. Methyl(2-(3-chlorobenzoyl)phenyl)carbamate (3ak). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2k (99.6 mg, 0.54 mmol) at 60 °C gave 3ak (44.5 mg, 51% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.25 (br, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.62−7.48 (m, 4H), 7.42 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.90, 154.35, 141.25, 140.49, 134.83, 134.67, 133.60, 132.33, 129.74, 129.71, 127.99, 122.30, 121.42, 120.12, 52.55; HRMS (ESI): calcd for C15H13NO335Cl [M + H]+, 290.0579; found, 290.0586. Methyl(2-(3-bromobenzoyl)phenyl)carbamate (3al). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2l (123.5 mg, 0.54 mmol) gave 3al (54.5 mg, 55% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.26 (br, 1H), 8.43 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.64−7.55 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 3.79 (s, 3H);

2H), 7.25 (d, J = 6.6 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 199.58, 152.18, 150.69, 140.58, 138.72, 134.50, 133.84, 132.64 (2C), 130.06 (2C), 129.51 (2C), 128.47 (2C), 125.82, 123.24, 121.81 (2C), 120.20; HRMS (ESI): calcd for C20H16NO3 [M + H]+, 318.1125; found, 318.1134. Methyl(2-(4-methoxybenzoyl)phenyl)carbamate (3ab). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2b (97.7 mg, 0.54 mmol) at 60 °C gave 3ab (39.2 mg, 46% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 9.96 (br, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 8.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.63, 163.40, 154.42, 140.27, 133.60, 132.89, 132.68 (2C), 131.04, 129.12, 121.30, 120.21, 113.66 (2C), 55.62, 52.41; HRMS (ESI): calcd for C16H16NO4 [M + H]+, 286.1074; found, 286.1080. Methyl(2-(4-methylbenzoyl)phenyl)carbamate (3ac). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2c (89.9 mg, 0.54 mmol) gave 3ac (48.3 mg, 60% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.19 (br, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.58−7.51 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.03 (td, J = 8.1, 1.0 Hz, 1H), 3.78 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.00, 154.43, 143.39, 140.73, 136.02, 134.01, 133.44, 130.28 (2C), 129.07 (2C), 123.37, 121.24, 120.04, 52.43, 21.76; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1132. Methyl(2-(4-fluorobenzoyl)phenyl)carbamate (3ad). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 mmol) with 2d (91.3 mg, 0.54 mmol) gave 3ad (46.4 mg, 56% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.12 (br, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.7, 5.4 Hz, 2H), 7.60−7.54 (m, 1H), 7.50 (dd, J = 7.9, 1.4 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H), 7.05 (dd, J = 7.6, 0.8 Hz, 1H), 3.79 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 197.70, 165.41 (d, JC−F = 254.6 Hz), 154.37, 140.84, 134.91 (d, JC−F = 4.0 Hz), 134.35, 133.24, 132.66 (d, JC−F = 9.1 Hz, 2C), 122.99, 121.37, 120.23, 115.60 (d, JC−F = 22.1 Hz, 2C), 52.50; HRMS (ESI): calcd for C15H13NO3F [M + H]+, 274.0874; found, 274.0883. Methyl(2-(4-chlorobenzoyl)phenyl)carbamate (3ae). By following the general procedure, the reaction of 1a (45.5 mg, 0.30 mmol) with 2e (99.4 mg, 0.54 mmol) gave 3ae (48.2 mg, 56% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.19 (br, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (ddd, J = 8.6, 7.5, 1.4 Hz, 1H), 7.49 (dd, J = 7.9, 1.5 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.04 (td, J = 7.9, 1.1 Hz, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.04, 154.37, 141.04, 138.95, 137.08, 134.59, 133.38, 131.41 (2C), 128.75 (2C), 122.67, 121.38, 120.20, 52.53; HRMS (ESI): calcd for C15H13NO335Cl [M + H]+, 290.0579; found, 290.0586. Methyl(2-(4-bromobenzoyl)phenyl)carbamate (3af). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 mmol) with 2f (123.1 mg, 0.54 mmol) at 60 °C gave 3af (52.4 mg, 53% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.20 (br, 1H), 8.42 (d, J = 8.5 Hz, 1H), 7.64−7.54 (m, 5H), 7.49 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.19, 154.35, 141.07, 137.53, 134.62, 133.40, 131.71 (2C), 131.48 (2C), 127.51, 122.56, 121.37, 120.17, 52.53; HRMS (ESI): calcd for C15H13NO379Br [M + H]+, 334.0073; found, 334.0082. Methyl(2-(4-iodobenzoyl)phenyl)carbamate (3ag). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 4193

DOI: 10.1021/acsomega.8b00441 ACS Omega 2018, 3, 4187−4198

Article

ACS Omega C NMR (101 MHz, CDCl3): δ 197.76, 154.33, 141.23, 140.68, 135.23, 134.82, 133.58, 132.59, 129.93, 128.41, 122.63, 122.25, 121.42, 120.10, 52.54; HRMS (ESI): calcd for C15H13NO379Br [M + H]+, 334.0073; found, 334.0083. Methyl(2-(3-(trifluoromethyl)benzoyl)phenyl)carbamate (3am). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2m (117.7 mg, 0.54 mmol) gave 3am (51.9 mg, 54% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.27 (br 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J = 6.6 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.87, 154.35, 141.36, 139.52, 135.00, 133.49, 133.01, 131.11 (q, JC−F = 33.2 Hz), 129.03, 128.82 (q, JC−F = 3.4 Hz), 126.58 (q, JC−F = 3.7 Hz), 123.71 (q, JC−F = 272.7 Hz), 122.13, 121.50, 120.24, 52.56; HRMS (ESI): calcd for C16H13NO3F3 [M + H]+, 324.0842; found, 324.0851. Methyl(2-(2-methoxybenzoyl)phenyl)carbamate (3an). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2n (98.0 mg, 0.54 mmol) gave 3an (47.9 mg, 56% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 11.09 (br, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.50−7.40 (m, 2H), 7.28−7.26 (m, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 200.29, 156.81, 154.59, 141.79, 135.12, 134.76, 131.86, 129.41, 129.08, 122.40, 121.24, 120.63, 119.03, 111.50, 55.76, 52.46; HRMS (ESI): calcd for C16H16NO4 [M + H]+, 286.1074; found, 286.1081. Methyl(2-(2-methylbenzoyl)phenyl)carbamate (3ao). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2o (90.3 mg, 0.54 mmol) gave 3ao (56.7 mg, 70% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 11.09 (br, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.56 (td, J = 8.7, 1.5 Hz, 1H), 7.42−7.35 (m, 2H), 7.31−7.22 (m, 3H), 6.95 (td, J = 8.1, 1.1 Hz, 1H), 3.82 (s, 3H), 2.28 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 202.55, 154.48, 142.07, 139.51, 135.92, 135.36, 134.72, 130.97, 130.18, 127.84, 125.45, 122.17, 121.36, 119.24, 52.50, 19.82; HRMS (ESI): calcd for C16H16NO3 [M + H]+, 270.1125; found, 270.1133. Methyl(2-(2-fluorobenzoyl)phenyl)carbamate (3ap). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2p (91.6 mg, 0.54 mmol) gave 3ap (47.9 mg, 58% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.86 (br, 1H), 8.51 (d, J = 8.5 Hz, 1H), 7.61−7.51 (m, 2H), 7.51− 7.42 (m, 2H), 7.27 (td, J = 8.0, 1.0 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 7.00 (td, J = 8.1, 1.0 Hz, 1H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 196.74, 159.47 (d, JC−F = 251.6 Hz), 154.43, 141.82, 135.60, 134.35 (d, JC−F = 1.0 Hz), 132.98 (d, JC−F = 8.0 Hz), 130.26 (d, JC−F = 2.0 Hz), 127.84 (d, JC−F = 15.1 Hz), 124.42 (d, JC−F = 4.0 Hz), 122.08, 121.51, 119.33, 116.40 (d, JC−F = 21.1 Hz), 52.54; HRMS (ESI): calcd for C15H13NO3F [M + H]+, 274.0874; found, 274.0881. Methyl(2-(2-chlorobenzoyl)phenyl)carbamate (3aq). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2q (99.7 mg, 0.54 mmol) gave 3aq (50.6 mg, 58% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 11.06 (br, 1H), 8.55 (d, J = 8.5 Hz, 1H), 7.58 (td, J = 8.5, 1.2 Hz, 1H), 7.49−7.40 (m, 2H), 7.40−7.29 (m, 3H), 6.96 (td, J = 8.1, 1.0 Hz, 1H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.86, 154.41, 142.38, 139.02, 135.90, 134.73, 131.16, 130.97, 130.15, 128.69, 126.85, 121.48, 121.10, 119.18, 52.54; HRMS

(ESI): calcd for C15H13NO335Cl [M + H]+, 290.0579; found, 290.0586. Methyl(2-(2-naphthoyl)phenyl)carbamate (3ar). By following the general procedure, the reaction of 1a (45.7 mg, 0.30 mmol) with 2r (108.5 mg, 0.54 mmol) gave 3ar (46.7 mg, 51% yield). Colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.24 (br, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.95−7.88 (m, 3H), 7.82 (d, J = 8.5 Hz, 1H), 7.64−7.52 (m, 4H), 7.05 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.21, 154.42, 140.92, 135.97, 135.21, 134.23, 133.65, 132.20, 131.68, 129.47, 128.51, 128.39, 127.91, 127.04, 125.72, 123.34, 121.35, 120.12, 52.46; HRMS (ESI): calcd for C19H16NO3 [M + H]+, 306.1125; found, 306.1132. Methyl(2-(2,4-dimethylbenzoyl)phenyl)carbamate (3as). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2s (97.0 mg, 0.54 mmol) gave 3as (42.3 mg, 50% yield). Yellow oil. 1H NMR (400 MHz, CDCl3): δ 10.17 (bs, 1H), 8.39 (d, J = 8.7 Hz, 1H), 7.55−7.52 (m, 2H), 7.50 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.34 (s, 3H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 199.21, 154.45, 142.11, 140.70, 136.88, 136.47, 133.92, 133.46, 131.16, 129.54, 127.98, 123.55, 121.22, 120.04, 52.42, 20.12, 19.87; HRMS (ESI): calcd for C17H17NO3 [M + H]+, 284.1287; found, 284.1291. Methyl(2-(2,4-difluorobenzoyl)phenyl)carbamate (3at). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2t (100.8 mg, 0.54 mmol) gave 3at (45.2 mg, 52% yield). White oil. 1H NMR (400 MHz, CDCl3): δ 10.71 (br, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.58 (td, J = 8.6, 1.3 Hz, 1H), 7.53−7.43 (m, 2H), 7.05−6.97 (m, 2H), 6.91 (td, J = 9.3, 2.3 Hz, 1H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 195.36, 164.80 (dd, JC−F = 254.6, 11.1 Hz), 160.29 (dd, JC−F = 255.6, 12.1 Hz), 154.35, 141.68, 135.61, 133.93 (d, JC−F = 2.0 Hz), 132.00 (dd, JC−F = 10.1, 4.0 Hz), 124.15 (dd, JC−F = 15.1, 4.0 Hz), 122.15, 121.55, 119.48, 112.0 (dd, JC−F = 21.6, 3.5 Hz), 104.82 (t, JC−F = 25.2 Hz), 52.54; HRMS (ESI): calcd for C15H12NO3F2 [M + H]+, 292.0780; found, 292.0789. Methyl(2-(2,4-dichlorobenzoyl)phenyl)carbamate (3au). By following the general procedure, the reaction of 1a (45.6 mg, 0.30 mmol) with 2u (118.1 mg, 0.54 mmol) gave 3au (57.4 mg, 59% yield). White solid. 1H NMR (400 MHz, CDCl3): δ 10.96 (br, 1H), 8.55 (d, J = 8.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 197.72, 154.32, 142.41, 137.37, 136.64, 136.14, 134.48, 132.05, 130.08, 129.70, 127.30, 121.52, 120.86, 119.28, 52.57; HRMS (ESI): calcd for C15H12NO335Cl2 [M + H]+, 324.0189; found, 324.0196. Synthesis and Characterization of Product 4aa.19 nBuLi (1.6 M in THF, 1.0 mL, 4.0 equiv) was added slowly to ethoxyacetylene (40 w/v % in hexane, 0.3 mL, 4.0 equiv) in THF (1.6 mL) at −78 °C, and the mixture was stirred at the same temperature for 2 h and then at 0 °C for another 2 h. Then, the reaction mixture was re-cooled to −78 °C before adding 3aa (100.1 mg in 1.6 mL THF, 0.4 mmol, 1.0 equiv). The mixture was then stirred at −78 °C for 1 h and at room temperature for 2 h. Then, 1.0 N HCl (5.0 mL) was added to the reaction mixture at 0 °C and stirred for 40 min at room temperature. The mixture was extracted with EtOAc, and the combined extract was washed with brine and then dried over Na2SO4. After the removal of the solvent under vacuum, the product 4aa (90.3 mg, 81% yield) was obtained as a yellow gum

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DOI: 10.1021/acsomega.8b00441 ACS Omega 2018, 3, 4187−4198

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ACS Omega

TBHP (82 μL, 0.6 mmol) was added, and then, the reaction mixture was stirred at 90 °C for another 20 h. After completion of the reaction, the reaction mixture was cooled to room temperature and then directly purified by flash column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (v/v = 20:1 to 10:1) as the eluent to afford the desired product 7aa (66.1 mg, 78% yield) as a white solid. 2,4-Diphenylquinazoline (7aa).30 1H NMR (400 MHz, CDCl3): δ 8.72−8.68 (m, 2H), 8.18−8.11 (m, 2H), 7.92−7.86 (m, 3H), 7.63−7.49 (m, 7H). Synthesis and Characterization of Product 8aa.24 A mixture of 2-aminophenyl ketone 6aa (394.0 mg, 2.0 mmol) and acetone (0.5 mL) in 20% KOH ethanol solution (10.0 mL) was refluxed overnight at 85 °C. Then, the reaction mixture was quenched with hydrochloric acid (1.0 N) and extracted three times with EtOAc (3 × 20 mL). The combined organic layer was washed with brine once and dried over Na2SO4. The organic phase was concentrated under vacuum and purified by a chromatographic column over silica gel using a mixture of petroleum ether and ethyl acetate(v/v = 10:1−6:1) as the eluent, giving 8aa (404.1 mg, 92%) as a light yellow solid. 2-Methyl-4-phenylquinoline (8aa).31 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70−7.64 (m, 1H), 7.54−7.44 (m, 5H), 7.44−7.38 (m, 1H), 7.22 (d, J = 2.3 Hz, 1H), 2.77 (d, J = 1.2 Hz, 3H). Trapping Experiment with TEMPO. A mixture of aniline carbamate 1a (45.6 mg, 0.30 mmol), phenylglyoxylic acid (2a) (90.0 mg, 0.54 mmol), Pd(OAc)2 (7.0 mg, 0.03 mmol), (NH4)2S2O8 (136.9 mg, 0.6 mmol), PTSA (38.9 mg, 0.225 mmol), and TEMPO (93.7 mg, 0.6 mmol) in DCE (2.0 mL) was stirred at 45 °C for 24 h. After this, the reaction was cooled to room temperature. Then, the mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in vacuum. Product 9 (54.1 mg, 38% yield based on 2a) was isolated by column chromatography over silica gel using a mixture of petroleum ether and ethyl acetate (v/v = 10:1) as the eluent. 2,2,6,6-Tetramethylpiperidin-1-yl Benzoate (9).26 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 1.84−1.65 (m, 3H), 1.63− 1.55 (m, 2H), 1.51−1.41 (m, 1H), 1.28 (s, 6H), 1.12 (s, 6H).

by column chromatography over silica gel using a mixture of petroleum ether and ethyl acetate (v/v = 10:1) as the eluent. Methyl 2-Formyl-3-phenyl-1H-indole-1-carboxylate (4aa). 1 H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.59−7.47 (m, 6H), 7.32 (t, J = 7.6 Hz, 1H), 4.10 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 182.70, 152.01, 137.55, 134.49, 132.32, 130.77, 130.71 (2C), 129.19, 128.91, 128.62 (2C), 128.38, 124.20, 122.46, 115.43, 54.71; HRMS (ESI): calcd for C17H13NO3Na [M + Na]+, 302.0793; found, 302.0789. Synthesis and Characterization of Product 5aa.20 A Schlenk tube was charged with 3aa (104.0 mg, 0.4 mmol), CuI (15.6 mg, 0.08 mmol), and DMSO (2.4 mL). The mixture was stirred at 120 °C under air for 48 h. The reaction was cooled down to room temperature, diluted with ethyl acetate, washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and dried under vaccum. The product 5aa (64.1 mg, 82% yield) was obtained as a yellow solid by column chromatography over silica gel using a mixture of petroleum ether and ethyl acetate (v/v = 3:1) as the eluent. Acridin-9(10H)-one (5aa).20 1H NMR (400 MHz, DMSOd6): δ 11.74 (s, 1H), 8.23 (d, J = 8.1 Hz, 2H), 7.73 (ddd, J = 7.7, 7.1, 1.5 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H). Removal of Carbamate DGs and Characterization of 6aa. The removal of the methyl carbamate DG was performed according to a literature procedure.21 3aa (103.5 mg, 0.46 mmol) was dissolved in 8.0 mL methanol, to which was added 4.0 mL of 40% aqueous KOH. The solution was then refluxed for 4 h. Once completion, the reaction was diluted with water (10.0 mL) and extracted with ethyl acetate (3 × 20 mL). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was then purified by flash chromatography using a mixture of petroleum ether and ethyl acetate (v/v = 10:1) to yield (2aminophenyl) (phenyl)methanone 6aa (84.1 mg, 93%) as a yellow solid. (2-Aminophenyl) (phenyl)methanone (6aa).29 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.48−7.41 (m, 3H), 7.29 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.09 (br, 2H). Removal of the Ethyl and Phenyl Carbamate DGs was Accomplished Using a Second Set of the Literature Procedure.11b 3oa or 3pa (0.4 mmol) was dissolved in 2.0 mL of dry THF. To this solution, under a gentle stream of nitrogen gas, was added with TBAF (for the ethyl carbamate 3oa, 2.0 mmol; for the phenyl carbamate 3pa, 0.48 mmol, both as a 1.0 M solution in THF). The reaction vessel was then sealed. The reaction containing 3oa was refluxed for 6 h, while the reaction containing 3pa was stirred at room temperature for 30 min. Once completion, each reaction was quenched with water (2.0 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum. The obtained residue was purified by flash chromatography using a mixture of petroleum ether and ethyl acetate (v/v = 10:1) to yield (2aminophenyl) (phenyl)methanone (6aa) (64.8 mg, 82% and 68.6 mg, 87%, respectively) as a yellow solid. Synthesis and Characterization of Product 7aa.23 To a solution of 2-aminophenyl ketone 6aa (59.8 mg, 0.3 mmol) in toluene (1.5 mL) were added NH4OAc (70.1 mg, 0.9 mmol) and KI (15.8 mg, 0.09 mmol), followed by 70% aqueous TBHP (82 μL, 0.6 mmol). The reaction mixture was stirred in a Schlenk tube at 90 °C. After 4 h, the remaining 70% aqueous

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00441. NMR spectra of 3aa−pa, 3ab−au, 4aa−8aa, and 9 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guan-Wu Wang: 0000-0001-9287-532X Notes

The authors declare no competing financial interest.

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REFERENCES

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