Direct Reductive Cyclocondensation of the Nitro Group with the Amido

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives Michał Tryniszewski,†,‡ Robert Bujok,† Piotr Cmoch,† Roman Gańczarczyk,‡ Irena Kulszewicz-Bajer,‡ and Zbigniew Wróbel*,† †

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 00-266 Warsaw, Poland Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland

‡

J. Org. Chem. Downloaded from pubs.acs.org by TULANE UNIV on 02/03/19. For personal use only.

S Supporting Information *

ABSTRACT: A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.

minophosphoranes, first reported in 1919 by Staudinger and Meyer,1 are a valuable class of compounds that have found numerous applications in organic synthesis. Their initial application, still being of certain importance in chemistry, was hydrolysis to amines.1,2 The great significance of iminophosphoranes is mainly associated with their ylide character. This makes them powerful reagents for the formation of carbon− nitrogen double bonds in reactions with carbonyl groups. This aza-Wittig reaction is particularly valuable when both reacting functions are in the same molecule, as it leads to cyclocondensation forming a new heterocyclic ring. There is an extensive and rich literature devoted to such reactions, and the topic does not seem to be exhausted yet.3 The most common method to prepare aryliminophosphoranes is the Staudinger reaction of azides with phosphines.2,4 The coupling of amines and phosphines with the presence of oxidants such as halogenating agents,5 azodicarboxylates,6 or ethylenedicarboxylates7 have also been reported. Formation of aryliminophosphoranes from nitrogen groups with nitrogen on higher oxidation state are rare. These are generally more complex and less selective processes with dominating subsequent reactions of intermediate nitrenes such as cyclizations and rearrangements.8 This is true for nitro as well as for nitroso groups. In our work published in 2014 we found that the reaction of 2-nitrosodiarylamines with PPh3 proceeded under very mild conditions and that the corresponding iminophosphoranes were formed in very good yields.9 Because of the presence of ortho arylamino substituent they turned out to be versatile starting materials in the synthesis of nitrogen-containing heterocyclic frameworks, guided mainly by aza-Wittig condensation.9,10 Later we proved that the corresponding iminophosporanes can also be synthesized from 2-nitrodiaryl-

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© XXXX American Chemical Society

amines, although the reaction requires elevated temperature.11 The finding prompted us to employ this reaction and the iminophosphoranes so formed for the synthesis of heterocyclic compounds based on 1,4-dibenzodiazepine scaffold. A few prominent examples of them are shown in Figure 1.

Figure 1. Prominent dibenzodiazepines drugs.

We were particularly focused on clozapine,12 its derivatives, and analogues containing dialkylamino substituent at C11. Numerous methods for the synthesis of clozapine and its analogues (Scheme 1) consist in the formation of the intermediate diazepinone scaffold (path a−c) followed by one- or two-steps introduction of the amino group.13 The most standard path (path b)13a−c,e−g uses suitably substituted nitrodiarylamines as starting materials. The formation of the seven-membered ring that way requires the prior reduction of the nitro group. Our idea was to shorten the whole process by direct cyclocondensation of 2-nitrodiarylamines bearing appropriate 2′-dialkylamido group, using trivalent phosphorus reagents. This yielded the desired 11-dialkylamino-1,4-dibenzodiazeReceived: October 23, 2018

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DOI: 10.1021/acs.joc.8b02682 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

In a preliminary testing reaction sequence copper-catalyzed reaction of 2-bromo-5-chloronitrobenzene (1a) with anthranilic acid was performed. This was followed by the conversion of N-(4-chloro-2-nitro)anthranilic acid to amide 3a, which, by heating at 150 °C with an excess of PPh3,11 was transformed into iminophosphorane 4a in 79% yield. The latter was then cyclized in neat PPh3 to give clozapine (5a) in 65% yield after 4 d at 230 °C (Scheme 3).

Scheme 1. Known and Proposed Synthetic Routes Leading to 11-Dialkylamino-1,4-dibenzodiazepines

Scheme 3. Synthesis of Clozapine via aza-Wittig Cyclocondensation of the Iminophosphorane 4a

pines in an uncatalyzed, metal-free, reductive process. The approach relies on the intermediate formation of aryliminoaminophosphoranes directly from the nitro group followed by their aza-Wittig condensation with the suitably positioned dialkylamido function (Scheme 2).14

The conditions, namely, molten PPh3 and no other solvent, were chosen for both steps to test the possibility of avoiding isolation of the iminophosphorane intermediate. Indeed, when 3a was stirred with an excess of PPh3 at 230 °C for 4 d a slightly higher yield, as compared to the combined yield of both steps, was obtained. Some modifications of the reaction conditions were then examined, particularly to lower the temperature and eliminate the cumbersome excess of PPh3 (Table 1).

Scheme 2. Complete Route from Simple Nitroarenes to 11Dialkylaminodibenzodiazepines via Iminophosphoranes

Table 1. Modifications of the One-Pot Reaction 3a → 5a entry

P(III) reagent

temp (°C)

1 2 3 4 5 6

PPh3 PPh3 PBu3 P(NMe2)3 P(NMe2)3 P(OEt)3

150 230 150 150 200 150

3 1 2 1 1 1

time

yield, %

h d (4 d) d d d d

0a 31 (60) 82 0b 0c 0c

a

79% of 4a was isolated. b28% of the corresponding iminophosphorane 4b was isolated. cMulticomponent mixture.

The presented method makes use of a feature of the nitro group that activates the ortho halogens for substitution according to the SNAr or the Ullmann scheme on the very first step and undergoes final reductive cyclocondensation. To achieve the goal cyclocondensation of the iminophosphorane function with the amide group is accomplished. Amides are not typical carbonyl reagents in the aza-Wittig condensations. Nevertheless, intramolecular reactions of iminophosphoranes with amido groups have some literature references cited in reviews.3 While most of them refer to the reactions of imido group, in a few cases true amido group was engaged.15 In no respective case was the starting iminophosphorane obtained from the nitro compounds. As a rule they were synthesized from azides in the Staudinger reaction.

The use of tri-n-butylphosphine instead of Ph3P (Table 1, entry 3) was especially beneficial, since the reaction gave a higher yield of the product at a lower temperature. Moreover, the excess of the phosphorus reagent and its oxide could be, for the most part, removed under vacuum after the reaction. Other trivalent phosphorus compounds were ineffective. Hexamethylphosphorous triamide reacted to form corresponding iminophosphorane 4b, which was not prone to cyclization. In the reaction of trialkyl phosphite a complex product mixture was formed. The best conditions found for the cyclization of 3a (entry 3) were applied for the synthesis of a number of 1,4dibenzodiazepines (Scheme 4). Unexpectedly, the reaction of the amides of relatively smaller steric bulkiness (i.e., pyrrolidinamide derivatives 3c, 3h, and B


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satisfactory yields were achieved by applying a higher temperature, 220 °C (shown in parentheses in Scheme 4). On the other hand, the exceptionally bulky amide group in 3r completely prevented cyclization at 150 °C. The intermediate iminophosphorane 4c was the only isolated product in 50% yield. The cyclization took place at 220 °C; however, the yield of 5r was rather moderate. The higher temperature turned out to be beneficial for the reactions of N-methylpiperazinamide 3i but gave lower yield in the case of 3l. Apparently, the final yield of 5 is a result of a competition between the desired reductive cyclization and some destructive processes, mostly significant at higher temperature. The reaction was effective for both carbocyclic and heterocyclic nitroamides. This is exemplified by the synthesis of olanzapine (5s), its derivative 5t, and pyridobenzodiazepines 5u and 5v. It also seems to be insensitive to both electron-withdrawing and -donating substituents, at least within the explored range. Starting amides 3a−r were prepared from the appropriate 2bromonitroarenes following the general synthetic path (Scheme 2). In the case of amides 3s and 3t, precursors of olanzapine derivatives, better results were attained when the nucleophilic substitution of fluorine in 2-fluoronitrobenzene with 2-amino-5-methyltiophene-3-carboxylic acid ethyl ester16 was followed by hydrolysis of the ester group. The acid was transformed into amides 3s and 3t via standard procedures (Scheme 5). In regard to pyridine derivatives 3u and 3v,

Scheme 4. Synthesis of 11-Dialkylaminodibenzodiazepines from Nitroamidesa

Scheme 5. Synthesis of Nitroamides 3s−va

a

NR2 stays for N-methylpiperazine (3s and 3u) or for morpholine (3t and 3v).

corresponding 2-iodobenzamides were prepared first, then coupled with 2-amino-3-nitropyridine (for details of the amides preparation see the Experimental Section). In summary, a rather unexplored intramolecular aza-Wittig condensation of iminophosphoranes with amides was employed for the short and convenient synthesis of 11dialkylaminodibenzodiazepines and their heteroanalogues. The starting iminophosphoranes could be prepared in situ from the corresponding nitro compounds in a metal-free reductive process with triaryl- or trialkylphosphines.

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EXPERIMENTAL SECTION

General Information. Melting points were recorded in open capillary and are uncorrected. The 1H, 13C, and 15N NMR spectra of all compounds studied were measured at temperature 298 K (if not otherwise stated) in CDCl3 or deuterated dimethyl sulfoxide (DMSOd6) solutions with a Varian vnmrs-600 [equipped with a 600 MHz PFG Auto XID (1H/15N-31P 5 mm) indirect probehead] or Varian vnmrs-500 [equipped with a 500 MHz PFG Auto XDB (1H-19F/

All reactions were performed in 1.0 mmol scale at 150 °C and/or at 220 °C. Yields attained at 220 °C shown in parentheses.

a

3m as well as n-butylamide 3o) gave noticeably lower yields than other amides. For the reactions of such compounds, C


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1H), 7.51−7.56 (m, 1H), 7.64−7.67 (m, 1H), 7.95 (dd, J = 7.8, 1.6 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H), 11.24 (br s, 1H), 13.38 (br s, 1H). 13 C{1H} NMR (125 MHz, DMSO-d6) δ 56.3, 101.1, 108.6, 119.9, 120.3, 122.8, 129.2, 130.4, 132.2, 134.0, 141.6, 141.7, 165.1, 168.9. MS (EI) m/z: (%) 288 (83, [M+]), 224 (100), 196 (63), 153 (31). HRMS (EI) m/z: Calcd for C14H12N2O5 [M+] 288.0746; Found 288.0751. Preparation of 5-Methyl-2-[(2-nitrophenyl)amino]thiophene-3-carboxylic Acid (2g). Ethyl 5-methyl-2-[(2nitrophenyl)amino]thiophene-3-carboxylate16 (584 mg, 2.0 mmol) and LiOH·H2O (420 mg, 10 mmol) in a mixture of tetrahydrofuran (THF; 10 mL), MeOH (5 mL), and H2O (5 mL) was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness, treated with 10% aqueous HCl (50 mL), and extracted with EtOAc (3 × 100 mL). The extract was dried (Na2SO4), and the solvent was evaporated to obtain 554 mg (100% yield) of the acid as red solid (mp 208−210 °C dec) 1H NMR (500 MHz, DMSO-d6) δ 2.37 (d, J = 0.9 Hz, 3H), 6.91 (d, J = 0.9 Hz, 1H), 7.14 (ddd, J = 8.3, 7.2, 0.9 Hz, 1H), 7.77 (ddd, J = 8.6, 7.2, 1.4 Hz, 1H), 7.90 (dd, J = 8.6, 0.9 Hz, 1H), 8.22 (dd, J = 8.3, 1.4 Hz, 1H), 11.72 (br, 1H), 12.9 (br s, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 14.9, 114.8, 117.3, 121.4, 124.0, 125.5, 127.1, 135.7, 136.8, 137.7, 150.2, 165.8. MS (EI) m/z: (%) 278 (85, [M+]), 214 (100), 186 (39), 140 (34). HRMS (EI) m/z: Calcd for C12H10N2O4S [M+] 278.0361; Found 278.0361. General Procedure for the Synthesis of Amides 3a−t. To a solution of N-(2-nitroaryl)-ortho-aminoaryl acid 1 (3.0 mmol) in toluene (9.0 mL) was added SOCl2 (0.4 mL), and the mixture was heated at 90 °C for 3 h. After the mixture was cooled, the volatile components were evaporated under reduced pressure. The residue was dissolved in 1,2-dichloroethane (10 mL), and the solvent was evaporated. This operation was repeated twice. The obtained crude acid chloride was dissolved in DCM (30 mL), and an excess (ca. 1.2 mL) of the appropriate amine was added. After the small exothermic effect ceased, the mixture was left at room temperature overnight; then the solvent was evaporated, and the product was isolated by column chromatography. If not stated otherwise, DCM then DCM/ MeOH 20:1 mixture was used as the eluent. N-(4-Chloro-2-nitrophenyl)-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine (3a). Orange precipitate, mp 149−150 °C dec (lit.21 149 °C), 1.05 g, 93% yield. 1H NMR (500 MHz, CD2Cl2) δ 2.26−2.38 (m, 5H), 2.46 (br s, 2H), 3.42 (br s, 2H), 3.79 (br s, 2H), 7.22 (d, J = 9.3 Hz, 1H), 7.23−7.27 (m, 1H), 7.34 (dd, J = 9.3, 2.5 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.40−7.45 (m, 2H), 8.19 (d, J = 2.5 Hz, 1H), 9.70 (s, 1H). 13C{1H} NMR (125 MHz, CD2Cl2) δ 41.6, 45.8, 47.0, 54.5, 55.1, 118.0, 123.0, 124.0, 125.5, 125.9, 128.4, 130.4, 130.8, 134.1, 135.6, 136.1, 140.6, 167.6. MS (EI) m/z: (%) 376 (17), 374 (37, [M+]), 229 (41), 99 (46). 70 (100). HRMS (EI) m/z: Calcd for C18H1935ClN4O3 [M+] 374.1146; Found 374.1144. N-(4-Chloro-2-nitrophenyl)-N-[2-(morpholin-4-ylcarbonyl)phenyl]amine (3b). Eluent: hexane/EtOAc 1:1. Orange precipitate, mp 155−156 °C, 1.08 g, 100% yield. 1H NMR (600 MHz, 351.3 K, DMSO-d6) δ 3.43 (br s, 4H), 3.51 (br s, 4H), 7.20 (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 7.1, 1.8 Hz, 1H), 7.42 (dd, J = 7.4, 1.1 Hz, 1H), 7.47−7.52 (m, 2H), 7.54 (dd, (J = 9.2, 2.5 Hz, 1H), (d, J = 2.5 Hz, 1H), 9.45 (br s, 1H). 13C{1H} NMR (150 MHz, 351.3 K, DMSO-d6) δ 41.7, 47.3, 66.1, 119.1, 121.4, 124.3, 125.0, 125.3, 128.1, 130.2, 130.4, 133.7, 135.7, 136.1, 140.3, 166.9. MS (EI) m/z: (%) 363 (16), 361(41, [M+]), 315 (33), 228 (100). HRMS (EI) m/z: Calcd for C17H1635ClN3O4 [M+] 361.0829; Found 361.0826. N-(4-Chloro-2-nitrophenyl)-N-[2-(pyrrolidin-1-ylcarbonyl)phenyl]amine (3c). Eluent: hexane/EtOAc from 9:1 to 2:1. Orange solid, mp 135−137 °C, 844 mg, 81% yield. 1H NMR (500 MHz, CD2Cl2) δ 1.72−1.89 (m, 4H), 3.26−3.52 (m, 4H), 7.11 (dt, J = 7.5, 1.2 Hz, 1H), 7.27−7.39 (m. 5H), 8.09 (dd, J = 2.4, 0.5 Hz, 1H), 10.06 (br s, 1H). 1H NMR (600 MHz, 353.1 K, DMSO-d6) δ 1.81 (br s, 4H), 3.36 (br s, 4H), 7.25−7.28 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.45−7.50 (m, 3H), 7.54 (dd, J = 9.0, 2.5 Hz, 1H), 8.10 (d, J = 2.5 Hz), 9.71 (br s, 1H). 13C{1H} NMR (150 MHz, CD2Cl2) δ 24.7, 26.6, 46.2, 49.6, 118.9, 122.7, 123.0, 124.5, 126.1, 128.6, 130.5, 130.9,

15N-31P 5 mm) direct probehead] using tetramethylsilane (TMS) as internal standard. Concentration of all solutions used for measurements was ∼20 mg of compounds in 0.6 mL of solvent. The structures of the compounds studied were determined/confirmed by interpretation of the 1H, 13C, one-dimensional (1D) NOESY spectra and two-dimensional (2D) heteronuclear 1H−13C (1H−15N) HSQC, HMBC NMR spectra. Proton connectivities were derived from COSY and 1D NOESY spectra. 13C Resonances corresponding to carbons with directly attached protons were assigned using results of interpretation of the HSQC experiments, whereas HMBC spectra were used to assign resonances of the quaternary carbons and to validate the connectivities established by the other spectra and also to check overlapping of several signals. Mass spectra (electron impact (EI), 70 eV) were obtained on an AutoSpec Premier (Waters) spectrometer. For electrospray ionization (ESI) measurements a Maldi SYNAPT G2-S HDMS (Waters) was used. Accurate mass measurements were obtained using magnetic sector mass analyzer (EI) or time-of-flight (TOF) analyzer (ESI). Silica gel Merck 60 (230−400 mesh) was used for column chromatography. When required for the melting point measurements, analytical samples of products were recrystallized from a suitable solvent. Dimethylformamide (DMF) was dried over CaH2, distilled, and stored over molecular sieves. All commercial reagents were used without additional purification. Known 2-(2-nitrophenyl)aminobenzoic acids 2a,17 2b,18a 2c,19 2e,20 and 2f20 were prepared according to the literature (lit.). The spectral data of the known compounds 2 not available in the literature. 2-[(4-Trifluoromethyl-2-nitrophenyl)amino]benzoic Acid (2b). Yellow solid, mp 221−223 °C (lit.18b 225−226 °C). 1H NMR (500 MHz, DMSO-d6) δ 7.24 (ddd, J = 8.5, 6.4, 2.6 Hz, 1H), 7.59−7.64 (m, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 9.0, 2.1 Hz, 1H), 8.00−8.03 (m, 1H), 8.41 (d, J = 1.6 Hz, 1H), 11.29 (s, 1H), 13.50 (br s, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 119.58, 119.64 (q, JFC = 34 Hz), 121.1, 121.3, 123.9 (q, JFC = 272 Hz), 124.1, 124.5 (q, JFC = 4 Hz), 132.0 (q, JFC = 3 Hz), 132.2, 134.0, 135.4, 140.6, 142.4, 168.8. MS (EI) m/z: (%) 326 (72, [M+]), 262 (100), 234 (42). Highresolution mass spectrometry (HRMS) (EI) m/z: Calcd for C14H9F3N2O4 [M+] 326.0514; Found 326.0507. 2-[(5-Chloro-2-nitrophenyl)amino]benzoic Acid (2e). Orange solid, mp 224−226 °C (AcOH) (lit.20 228−229 °C). 1H NMR (500 MHz, DMSO-d6) δ 7.07 (dd, J = 9.1, 2.2 Hz, 1H), 7.13−7.18 (m, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.56−7.59 (m, 2H), 7.96−7.98 (m, 1H), 8.15 (d, J = 9.1 Hz, 1H), 11.11 (s, 1H), 13.46 (br s, 1H). 13 C{1H} NMR (125 MHz, DMSO-d6) δ 118.0, 120.1, 120.2, 120.5, 123.3, 128.8, 132.3, 134.2, 135.6, 140.2, 140.8, 141.4, 168.9. MS (EI) m/z: (%) 292 (47, [M+]), 228 (100), 200 (41). HRMS (EI) m/z: Calcd for C13H935ClN2O4 [M+] 292.0251; Found 292.0245. 5-Chloro-2-[(5-chloro-2-nitrophenyl)amino]benzoic Acid (2f). Orange solid, mp 253−256 °C (lit.20 257−258 °C). 1H NMR (500 MHz, DMSO-d6) δ 7.11 (dd, J = 9.1, 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.59−7.64 (m, 2H), 7.93 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 11.08 (s, 1H), 13.85 (br s, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 118.0, 120.6, 120.9, 121.3, 125.9, 128.2, 130.8, 133.4, 133.6, 139.2, 140.2, 140.3, 167.4. MS (EI) m/z: (%) 328 (37), 326 (57, [M+]), 264 (74), 262 (100), 234 (41). HRMS (EI) m/z: Calcd for C13H835Cl2N2O4 [M+] 325.9861; Found 325.9858. Preparation of 2-[(5-Methoxy-2-nitrophenyl)amino]benzoic Acid (2d). 2-Iodobenzoic acid (2.73 g, 11.0 mmol) and 2-nitro-5methoxyaniline (1.68 g, 10.0 mmol) were dissolved in dry DMF (10 mL); then CuI (573 mg, 3.0 mmol) and K2CO3 (1.656 g, 12 mmol) were added, and the mixture was stirred at 120 °C for 3 h. The solvent was removed by evaporation in vacuo; the resulting residue was acidified to a pH of ∼4 with 2 M hydrochloric acid and extracted with dichloromethane (DCM; 2 × 50 mL). The extract was dried with Na2SO4; the solvent was evaporated, and the crude residue was purified by column chromatography (SiO2, DCM/methanol 20:1) to give 1.85 g, 64% yield of the product as a yellow solid, mp 229−230 °C (EtOH). 1H NMR (500 MHz, DMSO-d6) δ 3.77 (s, 3H), 6.59 (dd, J = 9.5, 2.5 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 7.09−7.13 (m, D


Note

The Journal of Organic Chemistry 135.0, 135.7, 137.2, 140.4, 167.6. MS (EI) m/z: (%) 345 (28, [M+]), 299 (37), 229 (77), 230 (100),215 (38). HRMS (EI) m/z: Calcd for C17H1635ClN3O3 [M+] 345.0880; Found 345.0880. N-{2-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-N-[2-nitro-4(trifluoromethyl)phenyl]amine (3d). Eluent: EtOAc. Orange precipitate, mp 103−105 °C, 1.03 g, 86% yield. 1H NMR (500 MHz, CD2Cl2) δ 2.22−2.29 (m, 5H), 2.39 (br s, 2H), 3.39 (br s, 2H), 3.72 (br s, 2H), 7.31−7.35 (m, 1H), 7.36−7.42 (m, 2H), 7.48−7.51 (m, 2H), 7.61 (dd, J = 9.0, 1.9 Hz, 1H), 8.51 (d, J = 1.2 Hz, 1H), 10.06 (br s, 1H). 13C{1H} NMR (125 MHz, CD2Cl2) δ 41.7, 45.6, 47.3, 54.5, 55.1, 117.1, 119.5 (q, JFC = 34 Hz), 123.5 (q, JFC = 271 Hz), 124.5, 124.6 (q, JFC = 4.2 Hz), 125.8, 128.2, 130.3, 131.2, 131.5 (q, JFC = 3.3 Hz), 132.9, 135.7, 144.2, 167.2. MS (EI) m/z: (%) 408 (50, [M+]), 263 (53), 99 (45), 70 (100). HRMS (EI) m/z: Calcd for C19H19F3N4O3 [M+] 408.1409; Found 408.1407. N-[2-(Morpholin-4-ylcarbonyl)phenyl]-N-[2-nitro-4(trifluoromethyl)phenyl]amine (3e). Eluent: hexane/EtOAc from 9:1 to 2:1. Orange precipitate, mp 108−111 °C, 789 mg, 67% yield. 1H NMR (600 MHz, CD2Cl2) δ 3.35−3.75 (m, 8H), 7.31−7.34 (m, 1H), 7.37−7.41 (m, 2H), 7.47−7.52 (m, 2H), 7.60 (dd, J = 8.8, 2.1 Hz, 1H), 8.50 (d, J = 1.2 Hz, 1H), 10.09 (br s, 1H). 13C{1H} NMR (150 MHz, CD2Cl2) δ 42.6, 48.3, 67.1, 117.5, 120.1 (q, JFC = 34 Hz), 123.9 (q, JFC = 271 Hz), 124.8, 125.0 (q, JFC = 4 Hz), 126.2, 128.7, 130.9, 131.0, 131.9 (q, JFC = 3 Hz), 133.4, 136.2, 144.4, 167.8. MS (EI) m/z: (%) 395 (36, [M+]), 376 (10), 349 (30), 263 (100), 262 (72). HRMS (EI) m/z: Calcd for C18H16F3N3O4 [M+] 395.1093; Found 395.1096. N-[2-(Morpholin-4-ylcarbonyl)phenyl]-N-(2-nitrophenyl)amine (3f). Orange precipitate, mp 111−112 °C, 930 mg, 95% yield. 1H NMR (500 MHz, CDCl3) δ 3.31−3.93 (m, 8H), 6.84 (ddd, J = 8.5, 7.0, 1.2 Hz, 1H), 7.23 (td, J = 7.5, 1.2 Hz, 1H), 7.28 (dd, J = 8.7, 1.0 Hz, 1H), 7.36 (dd, J = 7.5, 1.2 Hz, 1H), 7.38−7.44 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 8.20 (dd, J = 8.7, 1.5 Hz, 1H), 9.73 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 42.3, 47.7, 66.8, 116.4, 118.5, 123.7, 125.0, 126.7, 128.3, 130.2, 130.4, 134.3, 135.5, 136.5, 141.6, 168.0. MS (EI) m/z: (%) 327 (44, [M+]), 281 (30), 195 (100). HRMS (EI) m/z: Calcd for C17H17N3O4 [M+] 327.1219; Found 327.1224. N-{2-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-N-(2nitrophenyl)amine (3g). Red crystals, mp 114−115 °C (EtOAc/ hexane), 878 mg, 86% yield. 1H NMR (500 MHz, CDCl3) δ 2.32 (s, 3H), 2.30−2.55 (m, 4H), 3.44 (br s, 2H), 3.81 (br s, 2H), 6.83 (ddd, J = 8.3, 6.9, 1.0 Hz, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (td, J = 8.7, 1.0 Hz, 1H), 7.36 (dd, J = 7.6, 1.5 Hz, 1H), 7.37−7.44 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 8.19 (dd, J = 8.3, 1.5 Hz, 1H), 9.69 (s, 1H). 13 C{1H} NMR (125 MHz, CDCl3) δ 41.4, 45.7, 46.8, 54.4, 54.9, 116.5, 118.4, 123.9, 125.1, 126.7, 128.3, 130.3, 130.5, 134.3, 135.5, 136.4, 141.8, 167.8. MS (EI) m/z: (%) 340 (61, [M+]), 194 (66), 99 (52), 70 (100). HRMS (EI) m/z: Calcd for C18H20N4O3 [M+] 340.1535; Found 340.1551. N-(2-Nitrophenyl)-N-[2-(pyrrolidin-1-ylcarbonyl)phenyl]amine (3h). Red crystals, mp 117−120 °C (EtOAc/hexane), 805 mg, 86% yield. 1H NMR (500 MHz, CDCl3) δ 1.91 (br s, 4H), 3.22−3.71 (m, 4H), 6.82 (ddd, J = 8.4, 6.4, 1.7 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.35−7.44 (m, 4H), 7.46 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 9.96 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 24.6, 26.0, 46.0, 49.0, 116.8, 118.3, 122.8, 124.3, 126.6, 128.1, 130.1, 131.2, 134.6, 135.3, 136.6, 141.4, 167.7. MS (EI) m/z: (%) 311 (50, [M+]), 265 (51), 195 (100). HRMS (EI) m/z: Calcd for C17H17N3O3 [M+] 311.1270; Found 311.1266. N-(5-Methoxy-2-nitrophenyl)-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine (3i). Yellow crystals, mp 98−101 °C (EtOAc/hexane), 765 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 2.23−2.31 (m, 5H), 2.37 (br s, 2H), 3.35 (br s, 2H), 3.72 (br s, 2H), 3.77 (s, 3H), 6.37 (dd, J = 9.4, 2.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), J = 7.27 (td, J = 7.4, 1.7 Hz, 1H), 7.39 (dd, J = 7.4, 0.9 Hz, 1H), 7.42−7.48 (m, 2H), 8.17 (d, J = 9.4 Hz, 1H), 9.90 (br s, 1H). 13 C{1H} NMR (125 MHz, CDCl3) δ 41.7, 46.0, 47.1, 54.5, 55.0, 55.8, 98.1, 106.9, 124.5, 125.6, 128.1, 128.5, 128.9, 130.2, 131.5, 135.7, 144.4, 165.4, 167.7. MS (EI) m/z: (%) 370 (34, [M+]), 335 (17), 225 (77), 70 (100). HRMS (EI) m/z: Calcd for C19H22N4O4 [M+] 370.1641; Found 370.1642.

N-(5-Methoxy-2-nitrophenyl)-N-[2-(morpholin-4-ylcarbonyl)phenyl]amine (3j). Yellow crystals, mp 186−188 °C (toluene/ hexane), 990 mg, 96% yield. 1H NMR (500 MHz, CDCl3) δ 3.41 (br s, 2H), 3.53 (br s, 2H), 3.62−3.75 (m, 4H), 3.76 (s, 3H), 6.38 (dd, J = 9.5, 2.6 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 7.26 (td, J = 7.3, 1.5 Hz, 1H), 7.38 (dd, J = 7.6, 1.0 Hz, 1H), 7.41−7.48 (m, 2H), 8.18 (d, J = 9.5, 1H), 9.90 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 42.2, 47.6, 55.8, 66.7, 98.2, 106.9, 124.4, 125.6, 128.1, 128.5, 129.1, 130.4, 131.0, 135.8, 144.3, 165.5, 167.9. MS (EI) m/z: (%) 357 (43, [M+]), 311 (45), 225 (100), 224 (77), 211 (45), 196 (55). HRMS (EI) m/z: Calcd for C18H19N3O5 [M+] 357.1325; Found 357.1326. N-(5-Chloro-2-nitrophenyl)-N-[2-(morpholin-4-ylcarbonyl)phenyl]amine (3k). Orange crystals, mp 153−154 °C (EtOAc/ MeOH), 846 mg, 78% yield. 1H NMR (500 MHz, CDCl3) δ 3.41 (br s, 2H), 3.51−3.85 (m, 6H), 6.79 (dd, J = 9.0, 2.1 Hz, 1H), 7.24 (d, J = 2.1, Hz, 1H), 7.26−7.31 (m, 1H), 7.36−7.39 (m, 1H), 7.45−7.49 (m, 2H), 8.16 (d, J = 9.0 Hz, 1H), 9.87 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 42.3, 47.8, 66.8, 115.5, 118.7, 124.1, 125.6, 128.2, 128.4, 130.4, 130.6, 132.6, 136.0, 142.2, 142,5, 167.7. MS (EI) m/z: (%) 363 (16), 361 (41, [M+]), 317 (19), 315 (44), 231 (52), 229 (100). HRMS (EI) m/z: Calcd for C17H1635ClN3O4 [M+] 361.0829; Found 361.0829. N-(5-Chloro-2-nitrophenyl)-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine (3l). Orange crystals, mp 120−124 °C (EtOAc/hexane), 1120 mg, 99% yield. 1H NMR (500 MHz, CDCl3) δ 2.27 (s, 3H), 2.24−3.34 (m, 2H), 2.41 (br s, 2H), 3.39 (br s, 2H), 3.37 (br s, 2H), 6.76 (dd J = 9.0, 2.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.25−7.29 (m, 1H), 7.35−7.38 (m, 1H), 7.43−7.65 (m, 2H), 8.15 (d, J = 9.0 Hz, 1H), 9.82 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 41.8, 46.0, 47.2, 54.6, 55.1, 115.6, 118.6, 124.3, 125.7, 128.1, 128.3, 130.4, 131.0, 132.5, 135.8, 142.2, 142.7, 167.5. MS (EI) m/z: (%) 376 (16), 374 (41, [M+]), 231 (22), 229 (45), 99 (51), 70 (100). HRMS (EI) m/z: Calcd for C18H1935ClN4O3 [M+] 374.1146; Found 374.1149. N-(5-Chloro-2-nitrophenyl)-N-[2-(pyrrolidin-1-ylcarbonyl)phenyl]amine (3m). Brown crystals, mp 141−142 °C (EtOAc/ hexane), 1059 mg, 97% yield. 1H NMR (500 MHz, CDCl3) δ 1.85− 2.00 (m, 4H), 3.35−3.65 (m, 4H), 6.77 (dd, J = 9.0, 2.1 Hz, 1H), 7.23 (td, J = 7.3, 1.0 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.41−7.50 (m, 3H), 8.15 (d, J = 9.0 Hz, 1H), 10.13 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 24.4, 26.1, 45.9, 49.1, 115.9, 118.5, 123.1, 124.9, 128.1, 128.3, 130.4, 131.3, 132.9, 136.1, 142.0, 142.3, 167.3. MS (EI) m/z: (%) 347 (15), 345 (42, [M+]), 299 (61), 229 (100), 215 (59), 200 (57). HRMS (EI) m/z: Calcd for C17H1635ClN3O3 [M+] 345.0880; Found 345.0883. 2-[(5-Chloro-2-nitrophenyl)amino]-N,N-dimethylbenzamide (3n). Yellow solid, mp 96−98 °C, 423 mg, 88% yield. 1H NMR (600 MHz, DMSO-d6) δ 2.91 (s, 3H), 2.93 (s, 3H), 6.94 (dd, J = 9.1, 2.2 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.45 (dd, J = 7.6, 1.2 Hz, 1H), 7.49−7.56 (m, 2H), 8.15 (d, J = 9.1 Hz, 1H), 9.83 (s, 1H). 13C{1H} NMR (150 MHz, DMSO-d6) δ 34.8, 39.1, 116.3, 118.9, 124.5, 125.6, 128.70, 128.73, 130.8, 131.2, 132.9, 136.3, 141.2, 142.5, 168.4. MS (EI) m/z: (%) 321 (23), 319 (57, [M+]), 273 (63), 229 (95), 228 (100), 200 (58). HRMS (EI) m/z: Calcd for C15H1435ClN3O3 [M+] 319.0724; Found 319.0718. N-Butyl-2-[(5-chloro-2-nitrophenyl)amino]benzamide (3o). Yellow powder, mp 129−130 °C, 499 mg, 96% yield. 1H NMR (600 MHz, DMSO-d6) δ 0.86 (t, J = 7.4 Hz, 3H), 1.29 (sext, J = 7.4 Hz, 2H), 1.45 (quin, J = 7.3 Hz, 2H), 3.22 (q, J = 7.0 Hz, 2H), 6.98 (dd, J = 9.1, 2.2 Hz, 1H), 7.24 (td, J = 7.7, 1.2 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.52 (td, J = 7.2, 1.5 Hz, 1H), 7.56 (dd, J = 8.1, 1.0 Hz, 1H), 7.67 (dd, J = 7.9, 1.2 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 8.60−8.64 (m, 1H) (the amide proton difficult to be observed). 13C{1H} NMR (150 MHz, DMSO-d6) δ 14.1, 20.0, 31.4, 39.1, 116.6, 119.2, 122.3, 124.4, 127.8, 128.8, 129.4, 131.8, 134.0, 138.3, 141.0, 141.6, 167.7. MS (EI) m/z: (%) 349 (22), 347 (57, [M+]), 303 (45), 301 (88), 228 (100), 200 (58). HRMS (EI) m/z: Calcd for C17H1835ClN3O3 [M+] 347.1037; Found 347.1046. N-{4-Chloro-2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-N-(5chloro-2-nitrophenyl)amine (3p). Yellow crystals, mp 149−151 °C E


Note

The Journal of Organic Chemistry (hexane/EtOAc), 1056 mg, 86% yield. 1H NMR (500 MHz, CDCl3) δ 2.29 (s, 3H), 2.32 (br s, 2H), 2.43 (br s, 2H), 3.41 (br s, 2H), 3.76 (br s, 2H), 6.80 (dd, J = 9.1, 2.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.39−7.44 (m, 2H), 8.16 (d, J = 9.1 Hz, 1H), 9.7 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 44.5, 48.6, 49.9, 57.1, 57.7, 118.2, 121.7, 128.2, 130.8, 130.9, 133.2, 133.7, 135.1, 135.4, 137.1, 144.9, 145.0, 168.7. MS (EI) m/z: (%) 410 (26), 408 (34, [M+]), 265 (24), 263 (31), 70 (100). HRMS (EI) m/z: Calcd for C18H1835Cl2N4O3 [M+] 408.0756; Found 408.0767. N-[4-Chloro-2-(morpholin-4-ylcarbonyl)phenyl]-N-(5-chloro-2nitrophenyl)amine (3q). Orange crystals, mp 128−129 °C (hexane/ MeOH), 901 mg, 96% yield. 1H NMR (600 MHz, CDCl3) δ 3.39 (br s, 2H), 3.53−3.85 (m, 6H), 6.80 (dd, J = 9.1, 2.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.40−7.44 (m, 2H), 8.15 (d, J = 9.1 Hz, 1H), 9.75 (s, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 42.3, 47.7, 66.7 (2 × H2C-O), 115.5, 119.2, 125.3, 128.2, 128.2, 130.4, 130.7, 132.8, 134.6, 136.8, 142.1, 142.4, 166.2. MS (EI) m/z: (%) 397 (46), 395 (67, [M+]), 351 (28), 349 (42), 265 (82), 263 (100). HRMS (EI) m/z: Calcd for C17H1535Cl2N3O4 [M+] 395.0440; Found 395.0454. 2-[(5-Chloro-2-nitrophenyl)amino]-N,N-diisopropylbenzamide (3r). Yellow crystals, mp 157−158 °C (EtOAc/hexane), 360 mg, 63% yield. 1H NMR (500 MHz, DMSO-d6) δ 0.85 (br s, 3H), 1.08 (br s, 3H), 1.19 (br s, 3H), 1.41 (br s, 3H), 3.45−3.55 (m, 1H), 3.65−3.75 (m, 1H), 6.92 (dd, J = 9.1, 2.2 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 7.36−7.40 (m, 2H), 7.49−7.54 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 9.50 (s, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 20.1, 20.5, 20.6, 20.8, 45.3, 51.1, 115.5, 118.5, 126.4, 126.9, 127.0, 128.7, 130.0, 132.0, 134.2, 135.3, 141.5, 143.4, 167.7. MS (EI) m/z: (%) 377 (8), 375 (22, [M+]), 231 (46), 229 (100). HRMS (EI) m/z: Calcd for C19H2235ClN3O3 [M+] 375.1350; Found 375.1346. N-{5-Methyl-3-[(4-methylpiperazin-1-yl)carbonyl]thien-2-yl}-N(2-nitrophenyl)amine (3s). Brown solid, mp 106−107 °C, 985 mg, 91% yield. 1H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H), 2.32−2.37 (m, 4H), 2.45 (s, 3H), 3.59 (br s, 4H), 6.61−6.63 (m, 1H), 6.86 (ddd, J = 8.6, 7.0, 1.1 Hz, 1H), 7.38 (dd, J = 8.6, 1.1 Hz, 1H), 7.43− 7.48 (m, 1H), 8.20 (dd, J = 8.5, 1.5 Hz, 1H), 10.02 (s, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 15.5, 46.0, 54.9, 116.3, 118.7, 123.3, 126.4, 127.4, 133.8, 133.9, 135.9, 139.2, 141.9, 164.7 (one pair of pyrrolidine signals not separated, the other one too broad to be visible). MS (EI) m/z: (%) 360 (100, [M+]), 303 (52), 215 (53), 214 (52). HRMS (EI) m/z: Calcd for C17H20N4O3S [M+] 360.1256; Found 360.1252. N-[5-Methyl-3-(morpholin-4-ylcarbonyl)thien-2-yl]-N-(2nitrophenyl)amine (3t). Yellow crystals, mp 158−159 °C, 860 mg, 83% yield. 1H NMR (600 MHz, CDCl3) δ 2.45 (d, J = 1.0 Hz, 3H), 3.57−3.65 (m, 8H), 6.60−6.62 (m, 1H), 6.88 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 7.40 (dd, J = 8.6, 1.1 Hz, 1H), 7.47 (ddd, J = 8.6, 7.0, 1.4 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz, 1H), 10.11 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 15.5, 44.9 (2 × CH2−N), 66.8 (2 × CH2−O), 116.2, 118.9, 123.1, 126.5 (CH−CNO2 and C-CO), 132.8, 133.8, 135.9, 139.8, 141.7, 164.9. MS (EI) m/z: (%) 347 (82, [M+]), 214 (100), 186 (31). HRMS (EI) m/z: Calcd for C16H17N3O4S [M+] 347.0940; Found 347.0929. Synthesis of N-{2-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-3-nitropyridin-2-amine (3u). 1-(2-Iodobenzoyl)-4-methylpiperazine. To a solution of 2-iodobenzoic acid (3.70 g, 14.92 mmol) in DCM (30 mL) oxalyl chloride (5 mL) was added slowly at 0 °C followed by a few drops of DMF. The reaction mixture was stirred at room temperature for 2 h. The volatile materials were removed in vacuo, and the resulting residue was dissolved in DCM (30 mL) and cooled to ca. 0 °C, and N-methylpiperazine (3.6 mL, 33 mmol) was added. The reaction was left overnight at room temperature; then water was added, the layers separated, and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic extracts were dried (Na2SO4), and the solvent was evaporated. The crude product was used without purification. Obtained 4.90 g (100% yield) as yellow solid, mp 103−104 °C (lit.22 104−106 °C). 1H NMR (500 MHz, CDCl3) δ 2.30−2.36 (m,

1H), 2.36 (s, 3H), 2.47−2.56 (m, 2H), 2.57−2.63 (m, 1H), 3.19− 3.26 (m, 1H), 3.30−3.36 (m, 1H), 3.82−3.92 (m, 2H), 7.11 (td, J = 7.9, 7.4, 1.5 Hz, 1H), 7.23 (dd, J = 7.4, 1.5 Hz, 1H), 7.42 (td, J = 7.4, 1.1 Hz, 1H), 7.86 (dd, J = 7.9, 1.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 41.5, 46.0, 46.7, 54.4, 55.0, 92.5, 127.0, 128.3, 130.2, 139.2, 142.2, 169.2. To a solution of 1-(2-iodobenzoyl)-4-methylpiperazine (711 mg, 2.16 mmol) and 2-amino-3-nitropyridine (685 mg, 5.0 mmol) in DMF (6.0 mL) was added CuI (480 mg, 2.5 mmol) and K2CO3 (690 mg, 5.0 mmol). The mixture was stirred at 120 °C for 3 h. After it was cooled, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic solution was evaporated, and the residue was chromatographed (SiO2, hexane/ ethanol) to obtain 3u as a yellow solid, mp 96−97 °C 603 mg, 80% yield. 1H NMR (600 MHz, CDCl3) δ 2.24 (br s, 5H, two signals overlapped), 2.44 (br s, 2H), 3.42 (br s, 2H), 3.80 (br s, 2H), 6.84 (dd, J = 8.2, 4.5 Hz, 1H), 7.17 (td, J = 7.5, 1.0, 1H), 7.29 (dd, J = 7.6, 1.4 Hz, 1H), 7.40−7.43 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 4.5, 1.7 Hz, 1H), 8.51 (dd, J = 8.2, 1.8 Hz, 1H), 10.57 (br s, 1H). 13 C{1H} NMR (150 MHz, CDCl3) δ 41.9, 46.0, 47.4, 54.6, 55.3, 114.3, 124.20, 124.24, 127.4, 128.2, 129.3, 129.8, 135.5, 135.7, 149.8, 154.6, 168.3. HRMS (ESI−) m/z: Calcd for C17H18N5O3 [M − H]− 340.1410; Found 340.1403. Synthesis of N-[2-(Morpholin-4-ylcarbonyl)phenyl]-3-nitropyridin-2-amine (3v). 4-(2-Iodobenzoyl)morpholine.23 Following the procedure described for 1-(2-iodobenzoyl)-4-methylpiperazine, 2iodobenzoic acid (1.40 g, 5.67 mmol) in DCM (10 + 30 mL), oxalyl chloride (3 mL), two drops of DMF, and morpholine (3.0 mL, 30 mmol) were used. The product was obtained as a colorless solid, 1.70 g, 95% yield. N-[2-(Morpholin-4-ylcarbonyl)phenyl]-3-nitropyridin-2-amine (3v). This was prepared following the procedure described for 3u, using 4-(2-iodobenzoyl)morpholine (1.26 g, 3.96 mmol), 2-amino-3nitropyridine (685 mg, 5.0 mmol), CuI (570 mg, 3.0 mmol), and K2CO3 (760 mg, 5.5 mmol) in DMF (10 mL). After 6 h of heating the reaction mixture was worked out as previously (as in the case of 3u) to obtain 3v as orange powder, mp 156−157 °C dec, 578 mg, 44% yield. 1H NMR (600 MHz, CDCl3) δ 3.32−3.96 (m, 8H), 6.87 (dd, J = 8.3, 4.5 Hz, 1H), 7.19 (td, J = 7.4, 0.9 Hz, 1H), 7.30 (dd, J = 6.1, 1.6 Hz, 1H), 7.44 (td, J = 7.9, 1.6 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.45 (dd, J = 4.5, 1.8 Hz, 1H), 8.54 (dd, J = 8.3, 1.8 Hz, 1H), 10.60 (s, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 42.4, 48.0, 66.8, 114.4, 124.2, 124.3, 127.4, 127.6, 129.4, 130.1, 135.6, 135.8, 149.8, 154.6, 168.5. MS (EI) m/z: (%) 328 (1, [M+]), 242 (100), 196 (67), 167 (52), 140 (36). HRMS (EI) m/z: Calcd for C16H16N4O4 328.1172; Found 328.1178. Preparation of N-{4-Chloro-2-[(triphenylphosphoranylidene)amino]phenyl}-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine (4a). Compound 3a (375 mg, 1.0 mmol) and triphenylphosphine (3.1 g, 12 mmol) were melted and heated at 150 °C for 3 h. After the mixture was cooled, the product was isolated by column chromatography (SiO2, DCM, then DCM/MeOH 30:1) to afford 4a as yellow solid, mp 108−112 °C, 477 mg, 79% yield. 1H NMR (500 MHz, CDCl3) δ 2.15 (s, 3H), 2.22 (br s, 4H), 3.25−3.88 (m, 4H), 6.35 (dd, J = 2.1, 1.1 Hz, 1H), 6.55 (dd, J = 8.4, 2.1 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 8.4, 2.7 Hz, 1H), 7.22 (dd, J = 7.5, 1.5 Hz, 1H), 7.24−7.29 (m, 1H), 7.45−7.56 (m, 10H), 7.73− 7.80 (m, 6H), 8.03 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 41.8, 45.9, 47.2, 54.8, 112.8 (d, JPC = 1 Hz), 116.6, 117.3, 119.1 (d, JPC = 10 Hz), 119.6, 123.4, 125.8, 127.7, 128.7 (d, JPC = 12 Hz), 129.8, 130.1 (d, JPC = 100 Hz), 131.91 (d, JPC = 3 Hz), 132.6 (d, JPC = 10 Hz), 135.6 (d, JPC = 20 Hz), 140.6, 140.9, 169.3. MS (EI) m/z: (%) 604 (100, [M+]), 534 (40), 505 (47), 262 (68), 183 (75). HRMS (EI) m/z: Calcd for C36H3435ClN4OP 604.2159; Found 604.2177. General Procedure for the Synthesis of Dibenzodiazepines 5. An ampule, equipped with a Teflon stopcock, was filled with nitroamide 3 (1.0 mmol) and n-Bu3P (3.0 mL) and was heated at 150 or 220 °C for 48 h. After the reaction was complete a majority of nBu3P was removed under reduced pressure at ca. 100 °C. The residue was separated by column chromatography (SiO2, DCM/MeOH 20:1 F


Note

The Journal of Organic Chemistry → 10:1) to obtain pure 5. In a few cases (5b, 5c, 5k, and 5p) additional purification on a chromatography column (SiO2, hexane/ EtOAc) was performed. 8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine13g (5a). White powder, mp 180−182 °C (lit.24 182.8 °C), 262 mg, 80% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 3H), 2.51 (br s, 4H), 3.48 (br s, 4H), 4.90 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.1 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.24−7.31 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.1, 47.2, 55.0, 120.0, 120.1, 123.0, 123.1, 123.4, 126.7, 129.0, 130.3, 131.9, 140.4, 141.8, 152.7, 162.8. MS (EI) m/z: (%) 328 (8), 326 (23, [M+]) 258 (38), 256 (92, [M+]), 245 (46), 243 (100), 227 (51). HRMS (EI) m/z: Calcd for C18H1935ClN4 [M+] 326.1298; Found 326.1298. 8-Chloro-11-morpholin-4-yl-5H-dibenzo[b,e][1,4]diazepine (5b). Yellow powder, mp 174−176 °C (lit.25 169−170 °C), 270 mg, 86% yield obtained at 150 °C. 1H NMR (600 MHz, CD2Cl2) δ 3.43 (br s, 4H), 3.72−3.79 (m, 4H), 5.09 (br s, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 8.3, 2.4 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 7.03−7.08 (m, 2H), 7.30 (dd, J = 7.9, 1.5 Hz, 1H), 7.34 (dt, J = 6.0, 1.5 Hz, 1H). 13 C{1H} NMR (150 MHz, CD2Cl2) δ 48.5, 67.1, 120.56, 120.61, 123.5, 123.6, 126.8, 129.1, 130.6, 132.5, 141.1, 153.4, 163.5 (one signal missing). MS (EI) m/z: (%) 315 (39), 314 (62), 313 (83, [M+]), 312 (100), 228 (52), 192 (56). HRMS (EI) m/z: Calcd for C17H1635ClN3O [M+] 313.0982; Found 313.0982. 8-Chloro-11-pyrrolidin-1-yl-5H-dibenzo[b,e][1,4]diazepine (5c). Pale yellow powder, mp 147−150 °C, 237 mg, 79% yield obtained at 220 °C. 1H NMR (600 MHz, CD2Cl2) δ 1.76−2.11 (m, 4H), 3.18−3.76 (m, 4H), 4.98 (br s, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 8.2, 2.4 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 7.03 (dt, J = 7.6, 0.9 Hz, 1H), 7.21−7.37 (m, 2H). 13C{1H} NMR (150 MHz, CD2Cl2) δ 25.9, 49.6, 120.0, 120.4, 122.0, 123.1, 125.4, 126.5, 129.0, 130.0, 131.6, 140.6, 143.3, 152.6, 161.0. MS (EI) m/z: (%) 297 (100, [M+]), 296 (85), 268 (69), 228 (64), 192 (46). HRMS (EI) m/z: Calcd for C17H16N335Cl [M+] 297.1033. Found 297.1020. 11-(4-Methylpiperazin-1-yl)-8-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (5d). Pale yellow powder, mp 197−200 °C (lit.26 193−194 °C), 260 mg, 72% yield obtained at 150 °C. 1H NMR (500 MHz, CD2Cl2) δ 2.32 (s, 3H), 2.49 (br s, 4H), 3.47 (br s, 4H), 5.20 (br s, H), 6.81 (d, J = 8.0 Hz, 1H), 6.89 (dd, J = 8.0, 0.5 Hz, 1H), 7.06 (dt, J = 7.6, 0.9 Hz, 1H), 7.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.27−7.31 (m, 2H), 7.34 (dt, J = 7.6, 1.5 Hz, 1H). 13C{1H} NMR (125 MHz, CD2Cl2) δ 45.8, 47.2, 54.9, 119.4, 119.9 (q, JFC = 3.8 Hz), 120.2, 123.2, 123.5, 123.8 (q, JFC = 3.5 Hz), 124.4 (q, JFC = 271 Hz), 126.0 (q, JFC = 32 Hz), 131.2, 132.0, 140.9, 145.1, 152.1, 162.9. MS (EI) m/ z: (%) 360 (27, [M+]), 290 (93), 277 (100), 261 (57), 241 (33), 192 (41). HRMS (EI) m/z: Calcd for C19H19F3N4 [M+] 360.1562; Found 360.1552. 11-Morpholin-4-yl-8-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (5e). Pale yellow powder, mp 149−151 °C, 282 mg, 81% yield obtained at 150 °C. 1H NMR (600 MHz, CDCl3) δ 3.46 (br s, 4H), 3.77−3.83 (m, 4H), 5.08 (br s, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 7.04 (dt, J = 7.7, 0.9 Hz, 1H), 7.12 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (dd, J = 7.7, 1.5 Hz, 1H), 7.30−7.34 (m, 2H). 13 C{1H} NMR (150 MHz, CDCl3) δ 48.0, 66.8, 119.4, 120.3, 120.5 (q, JFC = 3.8 Hz), 123.1, 123.3, 124.2 (q, JFC = 272 Hz), 124.3 (q, JFC = 3.8 Hz), 126.5 (q, JFC = 32 Hz), 130.3, 132.2, 140.4, 144.8, 152.2, 163.1. MS (EI) m/z: (%) 347 (70, [M+]), 346 (100), 262 (43), 192 (33). HRMS (EI) m/z: Calcd for C18H16F3N3O [M+] 347.1245. Found 347.1237. 11-Morpholin-4-yl-5H-dibenzo[b,e][1,4]diazepine (5f). Yellow solid, mp 200−203 °C (lit.25 201−202 °C), 150 mg, 54% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 3.42 (br s, 4H), 3.77−3.81 (m, 4H), 4.94 (s, 1H), 6.70 (dd, J = 6.4, 1.3 Hz, 1H), 6.81−6.84 (m, 1H), 6.89 (dt, J = 7.6, 1.5 Hz, 1H), 6.95−7.01 (m, 2H), 7.09 (dd, J = 7.6, 1.3 Hz, 1H), 7.25−7.30 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 48.2, 66.9, 119.1, 119.4, 120.0, 122.8, 123.2, 124.0, 124.3, 127.2, 130.2, 131.8, 141.8, 153.3, 162.6. MS (EI) m/z: (%) 279 (81, [M+]), 278 (100), 210 (38), 194 (57), 193 (53),

192 (48). HRMS (EI) m/z: Calcd for C17H17N3O [M+] 279.1372; Found 279.1366. 11-(4-Methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (5g). Brown crystals, mp 184−185 °C (acetone/hexane) (lit.26 182−184 °C), 209 mg, 72% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 2.51 (br s, 4H), 3.46 (br s, 4H), 4.93 (s, 1H), 6.69 (dd, J = 7.8, 1.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.87 (td, J = 7.6, 1.3 Hz, 1H), 6.94−7.00 (m, 2H), 7.08 (dd, J = 7.8, 1.3 Hz, 1H), 7.24−7.29 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.2, 47.3, 55.1, 119.3, 120.0, 122.7, 123.6, 123.7, 124.2, 127.2, 130.3, 131.6, 140.5, 141.8, 153.2, 162.4 (aliphatic signals not fully separated). MS (EI) m/z: (%) 292 (33, [M+]), 222 (100), 209 (96), 193 (,89). HRMS (EI) m/z: Calcd for C18H20N4 [M+] 292.1688; Found 292.1687. 11-Pyrrolidin-1-yl-5H-dibenzo[b,e][1,4]diazepine (5h). Yellow crystals, mp 163−165 °C (Et2O), 194 mg, 74% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 1.92 (br s, 4H), 3.54 (br s, 4H), 4.88 (s, 1H), 6.70 (dd, J = 7.7, 1.2 Hz, 1H), 6.79−6.84 (m, 2H), 6.74−7.00 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 7.25 (td J = 7.8, 1.2 Hz, 1H), 7.30 (dd, J = 7.8, 1.2 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 25.6, 49.5, 119.3, 119.7, 122.5, 122.7, 124.3, 124.8, 127.0, 129.8, 131.1, 140.9, 141.5, 152.6, 160.5 (two pairs of pyrrolidine signals not separated). MS (EI) m/z: (%) 263 (100, [M+]), 234 (76), 194 (85). HRMS (EI) m/z: Calcd for C17H17N3 [M+] 263.1422; Found 263.1421. 7-Methoxy-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (5i). Yellow crystals, mp 224−225 °C, 218 mg, 68% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 3H), 2.52 (br s, 4H), 3.41 (br s, 4H), 3.73 (s, 3H), 4.89 (s, 1H), 6.28 (d, J = 2.6 Hz, 1H), 6.54 (dd, J = 8.6, 2.8 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.99 (dt, J = 7.4, 0.8 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 7.6, 1.4 Hz, 1H), 7.28−7.31 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.2, 47.4, 55.1, 55.5, 105.5, 109.1, 119.9, 122.9, 123.7, 127.9, 130.4, 131.5, 133.8, 142.4, 152.5, 156.7, 161.6 (two pairs of piperazine signals not separated). MS (EI) m/z: (%) 322 (51, [M+]), 252 (89), 239 (100), 223 (72). HRMS (EI) m/z: Calcd for C19H22N4O [M+] 322.1794; Found 322.1801. 7-Methoxy-11-morpholin-4-yl-5H-dibenzo[b,e][1,4]diazepine (5j). Yellow crystals, mp 122−124 °C (Et2O), 276 mg, 89% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 3.37 (br s, 4H), 3.73 (s, 3H), 3.77−3.82 (m, 4H), 4.92 (br s, 1H), 6.28 (d, J = 2.7 Hz, 1H), 6.55 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.98− 7.02 (m, 2H), 7.26−7.31 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 48.3, 55.5, 66.9, 105.6, 109.1, 120.0, 123.0, 123.3, 128.0, 130.3, 131.7, 133.5, 142.5, 152.7, 157.0, 161.8 (two pairs of morpholine signals not separated). MS (EI) m/z: (%) 309 (100, [M+]), 278 (23), 224 (58). HRMS (EI) m/z: Calcd for C18H19N3O2 [M+] 309.1477; Found 309.1476. 7-Chloro-11-morpholin-4-yl-5H-dibenzo[b,e][1,4]diazepine (5k). Yellow crystals, mp 182−184 °C (acetone/hexane), 274 mg, 87% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 3.43 (br s, 4H), 3.77−3.82 (m, 4H), 4.94 (br s, 1H), 6.73 (br s, 1H), 6.82−6.85 (m, 1H), 6.93 (dd, J = 8.4, 2.2 Hz, 1H), 6.98−7.01 (m, 1H), 7.03 (dt, J = 7.5, 0.9 Hz, 1H), 7.26−7.33 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 48.05, 66.8, 119.4, 120.2, 123.2, 123.3, 124.2, 128.0, 128.8, 130.3, 132.0, 138.9, 142.5, 152.5, 162.6 (two pairs of morpholine signals not separated). MS (EI) m/z: (%) 315 (26), 314 (51), 313 (78, [M+]), 312 (100), 228 (57), 192 (58). HRMS (EI) m/z: Calcd for C17H1635ClN3O [M+] 313.0982; Found: 313.0972. 7-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (5l). Brown crystals, mp 132−135 °C (acetone/hexane) (lit.26 178−179 °C), 264 mg, 80% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 3H), 2.52 (br s, 4H), 3.47 (br s, 4H), 4.89 (s, H), 6.71 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.92 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (d, J = 8.4, 1H), 7.0, 7.04 (m, 1H), 7.26−7.32 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.1, 47.3, 55.0, 119.3, 120.1, 123.2, 123.5, 124.1, 127.9, 128.5, 130.3, 131.8, 139.2, 142.4, 152.3, 162.4 (two pairs of piperazine signals not separated). MS (EI) m/z: (%) 328 (15), 326 (34, [M+]), 256 (100), G


Note


°C), 130 mg, 41% yield obtained at 150 °C. 1H NMR (600 MHz, CDCl3) δ 2.30 (d, J = 1.0 Hz, 3H), 2.35 (s, 3H), 2.49−2.53 (m, 4H), 2.53 (br s, 4H), 4.97 (s, 1H), 6.28 (d, J = 1.0 Hz, 1H), 6.59 (dd, J = 7.7, 1.1 Hz, 1H), 6.86 (td, J = 7.6, 1.4 Hz, 1H), 6.95 (dt, J = 7.6, 1.2 Hz, 1H), 7.01 (dd, J = 7.7, 1.2 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 15.4, 46.0, 46.7, 55.0, 118.9, 119.5, 122.9, 123.8, 124.7, 128.1, 129.1, 140.9, 142.4, 151.8, 157.6 (two pairs of piperazine signals not separated). MS (EI) m/z: (%) 312 (35, [M+]), 242 (100), 229 (74), 213 (57). HRMS (EI) m/z: Calcd for C17H20N4S [M+] 312.1409; Found: 312.1405. 2-Methyl-4-morpholin-4-yl-10H-thieno[2,3-b][1,5]benzodiazepine (5t). Brown solid, mp 177−178 °C (dec), 180 mg, 60% yield obtained at 220 °C. 1H NMR (600 MHz, CDCl3) δ 2.31 (d, J = 1.0 Hz, 3H), 3.49−3.55 (m, 4H), 3.77−3.80 (m, 4H), 5.07 (br s, 1H), 6.29 (d, J = 1.0 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.89 (td, J = 7.7, 1.4 Hz, 1H), 6.97 (dt, J = 7.6, 1.4 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 15.4, 47.7, 66.9, 119.0, 122.7, 124.2, 124.7, 128.1, 129.3, 140.3, 142.7, 152.4, 152.5, 158.0 (two pairs of morphline signals not separated). MS (EI) m/z: (%) 299 (100, [M+]), 268 (24), 242 (31), 214 (69). HRMS (EI) m/z: Calcd for C16H17N3OS [M+] 299.1092; Found: 299.1087. 6-(4-Methylpiperazin-1-yl)-11H-pyrido[2,3-b][1,4]benzodiazepine (5u). Brown crystals, mp 154−158 °C dec (hexane/ EtOAc), 106 mg, 36% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 2.36 (s, 3H), 2.53 (br s, 4H), 3.50 (br s, 4H), 5.86 (s, 1H), 6.89−6.91 (m, 2H), 7.00 (t, J = 7.3 Hz, 1H), 7.26−7.35 (m, 3H), 7.80 (dd, J = 4.8, 1.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.0, 47.4, 54.9, 120.1, 120.6, 122.7, 123.0, 130.2, 132.1, 134.3, 134.9, 141.7, 150.8, 153.0, 163.1 (two pairs of piperazine signals not separated). MS (EI) m/z: (%) 293 (28, [M+]), 223 (100), 210 (99), 194 (70). HRMS (EI) m/z: Calcd for C17H19N5 [M+] 293.1640; Found 293.1645. 6-Morpholin-4-yl-11H-pyrido[2,3-b][1,4]benzodiazepine (5v). Yellow crystals, mp 205−206 °C (hexane/EtOAc), 100 mg, 34% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 3.46 (br s, 4H), 3.78−3.80 (m, 4H), 5.98 (br s, 1H), 6.90−6.95 (m, 2H), 7.00 (dt, J = 7.3, 1.0 Hz, 1H), 7.27−7.35 (m, 3H), 7.81 (dd, J = 4.9, 1.5 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 48.2, 66.8, 120.2, 120.7, 122.7, 122.8, 130.2, 132.3, 134.5, 134.8, 141.8, 150.9, 153.0, 163.3 (two pairs of morpholine signals not separated). MS (EI) m/z: (%) 280 (70, [M+]), 279 (100), 195 (32), 194 (35). HRMS (EI) m/ z: Calcd for C16H16N4O [M+] 280.1324; Found 280.1318. Compound 4b. Obtained in the reaction of 3a and P(NMe2)3 following the general procedure. Isolated as a contaminated compound after unsuccessful trials of purification, brown solid, 144 mg, 28% yield. 1H NMR (500 MHz, CDCl3) δ 2.13−2.48 (m, 4H), 2.21 (s, 3H), 2.68 (d, JPH = 9.7 Hz, 18H), 3.25−3.85 (m, 4H), 6.53 (dd, J = 8.5, 2.2 Hz, 1H), 6.59−6.62 (dd, J = 2.2, 0.9 Hz, 1H), 6.84 (td, J = 7.6, 0.9 Hz, 1H), 7.08 (dd, J = 8.3, 2.8 Hz, 1H), 7.16 (dd, J = 7.6, 1.4 Hz, 1H), 7.21−7.25 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.64 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 37.4 (d, JPC = 3 Hz), 45.8, 53.8, 54.7, 54.8, 112.6, 115.8, 117.5, 119.5, 119.6 (d, JPC = 6 Hz), 123.7, 125.7, 127.7, 129.8, 134.7 (d, JPC = 21 Hz), 140.8 (compound contaminated, two aromatic signals missing). MS (EI) m/z: (%) 507 (39), 505 (100, [M+]), 435 (48), 406 (26), 135 (98). HRMS (EI) m/z: Calcd for C24H3735ClN7OP [M+] 505.2486; Found 505.2479. 2-({5-Chloro-2-[(tributylphosphoranylidene)amino]phenyl}amino)-N,N-diisopropylbenzamide (4c). Colorless crystals, mp 131−132 °C, 290 mg, 53%. 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 9H), 0.92−1.19 (m, 6H), 1.33−141 (m, 6H), 1.44− 1.59 (m, 9H), 1.69 (br s, 3H), 1.78−1.90 (m, 6H), 3.35−3.55 (m, 1H), 3.76−3.97 (m, 1H), 6.40−6.49 (m, 1H), 6.51−6.59 (m, 1H), 6.86 (t, J = 7.3 Hz, 1H), 7.10 (dd, J = 7.3, 1.4 Hz, 1H), 7.12−7.15 (m, 1H), 7.22 (td, J = 7.3, 1.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.60 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 13.5, 20.7, 24.0, 24.2 (JPC = 14 Hz), 26.2 (JPC = 62 Hz), 45.6, 50.8, 112.1, 117.4, 118.3, 119.4, 120.1, 121.2, 126.1, 128.8, 129.6, 138.3, 138.5, 139.5, 170.0. MS (EI) m/z: (%) 547 (46), 545 (100, [M+]), 502 (28), 446 (16),

243 (97), 227 (59), 192 (67). HRMS (EI) m/z: Calcd for C18H1935ClN4 [M+] 326.1298; Found: 326.1307. 7-Chloro-11-pyrrolidin-1-yl-5H-dibenzo[b,e][1,4]diazepine (5m). Yellow crystals, mp 122−124 °C (hexane/Et2O), 225 mg, 76% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 1.92 (br s, 4H), 3.54 (br s, 4H), 4.91 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.91 (dd, J = 8.6, 2.3 Hz, 1H), 6.98−7.03 (m, 2H), 7.24− 7.31 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 25.6, 49.3, 119.2, 119.7, 122.9, 124.2, 125.0, 127.2, 127.8, 129.7, 131.2, 140.1, 142.1, 151.8, 160.5 (two pairs of pyrrolidine signals not separated). MS (EI) m/z: (%) 299 (47), 297 (100, [M+]), 270 (38), 268 (74), 230 (36), 228 (73). HRMS (EI) m/z: Calcd for C17H1635ClN3 [M+] 297.1033; Found: 297.1033. 7-Chloro-N,N-dimethyl-5H-dibenzo[b,e][1,4]diazepin-11-amine (5n). Yellow crystals, mp 188−189 °C (acetone/hexane), 194 mg, 71% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 2.99 (s, 6H), 4.87 (s, 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 7.8, 1.0 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.02 (td, J = 7.8, 1.0 Hz, 1H), 7.24 (dd, J = 7.8, 1.5 Hz, 1H), 7.29 (td, J = 7.8, 1.5 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 39.6, 119.2, 120.0, 123.0, 123.8, 124.1, 127.8, 127.9, 130.5, 131.5, 139.8, 142.1, 151.9, 162.7. HRMS (ESI) m/z: Calcd for C15H1535ClN3 [M + H]+ 272.0955. Found 272.0956. N-Butyl-7-chloro-5H-dibenzo[b,e][1,4]diazepin-11-amine (5o). Brown crystals, mp 105−107 °C (acetone/hexane), 216 mg, 72% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.4 Hz, 3H), 1.46 (sext, J = 7.4 Hz, 2H), 1.62−1.69 (m, 2H), 3.48− 3.53 (m, 2H), 4.57 (br s, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.4, 2.3 Hz, 1H), 6.97−7.01 (m, 2H), 7.28 (td, J = 7.8, 1.2 Hz, 1H), 7.30−7.33 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 13.9, 20.4, 31.4, 41.7, 119.3, 119.4, 123.2, 124.1, 126.2, 127.57, 127.64, 127.9, 131.9, 140.1, 141.8, 152.2, 158.5. MS (EI) m/z: (%) 301 (25), 299 (91, [M+]), 270 (33), 256 (52), 243 (100), 192 (59). HRMS (EI) m/z: Calcd for C17H1835ClN3 [M+] 299.1189; Found: 299.1188. 2,7-Dichloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (5p). Yellow crystals, mp 126−129 °C (acetone/hexane) (lit.27 178−180 °C), 285 mg, 79% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 3H), 2.51 (br s, 4H), 3.44 (br s, 4H), 4.88 (s, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.4, 2.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.23−7.28 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 46.1, 47.3, 54.9, 119.3, 121.4, 124.4, 125.0, 128.1, 128.6, 128.8, 129.8, 131.7, 138.9, 141.9, 150.7, 161.0 (two pairs of piperazine signals not separated). MS (EI) m/z: (%) 362 (8), 360 (13, [M+]), 290 (39), 277 (77), 226 (38), 70 (100). HRMS (EI) m/z: Calcd for C18H1835Cl2N4 [M+] 360.0909; Found: 360.0913. 2,7-Dichloro-11-morpholin-4-yl-5H-dibenzo[b,e][1,4]diazepine (5q). Yellow crystals, mp 206−208 °C (acetone/hexane), 279 mg, 80% yield obtained at 150 °C. 1H NMR (500 MHz, CDCl3) δ 3.41 (br s, 4H), 3.77−3.82 (m, 4H), 4.90 (br s, 1H), 6.95 (dd, J = 8.4, 2.2 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 48.1, 66.7, 119.4, 121.5, 124.5, 124.7, 128.2, 128.7, 129.2, 129.8, 131.8, 138.6, 142.0, 150.9, 161.1 (two pairs of morpholine signals not separated). MS (EI) m/z: (%) 349 (55), 348 (82), 347 (73, [M+]), 346 (100), 262 (50), 226 (59). HRMS (EI) m/z: Calcd for C17H1535Cl2N3O [M+] 347.0592; Found: 347.0578. 7-Chloro-N,N-diisopropyl-5H-dibenzo[b,e][1,4]diazepin-11amine (5r). Yellow crystals, mp 154−155 °C (EtOH/H2O), 117 mg, 35% yield obtained at 220 °C. 1H NMR (500 MHz, CDCl3) δ 1.39 (br s, 12H), 3.72 (sep, J = 6.6 Hz. 2H), 4.80 (br s, 1H), 6.69 (s, 1H), 6.78−7.05 (m, 4H), 7.15−7.30 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 21.7, 48.6, 119.0, 120.2, 123.0, 123.9, 126.0, 126.8, 127.4, 129.2, 131.0, 139.8, 141.8, 151.5, 160.6 (two methylene and four methyl signals not separated). MS (EI) m/z: (%) 327 (27, [M+]), 286 (46), 284 (100), 227 (41), 192 (48). HRMS (EI) m/z: Calcd for C19H2235ClN3 [M+] 327.1502; Found: 327.1501. 2-Methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine (5s). Brown solid, mp 197−198 °C (lit.28 193−194 H


Note

The Journal of Organic Chemistry 404 (18). HRMS (EI) m/z: Calcd for C31H49N335ClOP [M+] 545.3302; Found 545.3305.

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Ketenimines Bearing 1,3-Oxathiane Units. Computational Assessment of the Experimental Diastereoselection. Tetrahedron 2012, 68, 4672. (d) Burns, C. T.; Shang, S.; Thapa, R.; Mashuta, M. S. Synthesis of Air-Stable Zwitterionic 2-Phosphiniminium-arenesulfonates. Tetrahedron Lett. 2012, 53, 4832. (e) Casimiro, M.; Iglesias, M. J.; Lopez Ortiz, F.; Roces, L.; Garcia-Granda, S. Directed Ortho-Lithiation of Aminophosphazenes: an Efficient Route to the Stereoselective Synthesis of P-Chiral Compounds. Org. Lett. 2013, 15, 2378. (5) (a) Llamas-Saiz, A. L.; Foces-Foces, C.; Elguero, J.; Molina, P.; Alajarin, M.; Vidal, A. Iminophosphorane-Substituted Proton Sponges. Part 2. Preparation and Crystal Structure of Four Phosphoranylideneammonionaphthalene Derivatives. J. Chem. Soc., Perkin Trans. 2 1991, 2, 1667. (b) Zeng, F.; Alper, H. Tandem Palladium-Catalyzed Addition/Cyclocarbonylation: An Efficient Synthesis of 2-Heteroquinazolin-4(3H)-ones. Org. Lett. 2010, 12, 1188. (6) Adib, M.; Sheikhi, E.; Deljoush, A. Reaction Between Triphenylphosphine and Aromatic Amines in the Presence of Diethyl Azodicarboxylate: an Efficient Synthesis of Aryliminophosphoranes under Neutral and Mild Conditions. Tetrahedron 2011, 67, 4137. (7) Yavari, I.; Adib, M.; Hojabri, L. Vinyltriphenylphosphonium Salt Mediated Serendipitous Synthesis of Aryliminophosphoranes. Tetrahedron 2002, 58, 7213. (8) (a) Bunyan, P. J.; Cadogan, J. I. G. 7. The Reactivity of Organophosphorus Compounds. Part XIV. Deoxygenation of Aromatic C-Nitroso-Compounds by Triethyl Phosphite and Triphenylphosphine: a New Cyclisation Reaction. J. Chem. Soc. 1963, 42. (b) Dyatkin, B. L.; Mochalina, E. P.; Konstantinov, Y. S.; Sterlin, S. R.; Knunyants, I. L. Reaction of Perfluoronitrosoalkanes with Esters of Phosphorous acid. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1967, 16, 2200. (c) Cadogan, J. I. G. Reduction of Nitro- and Nitroso-Compounds by Tervalent Phosphorus Reagents. Q. Rev., Chem. Soc. 1968, 22, 222. (9) Łukasik, E.; Wróbel, Z. Simple Synthesis of 2-Aminoaryliminophosphoranes from N-Aryl-2-nitrosoanilines and Their Application in 2-Aminobenzimidazole Synthesis. Synlett 2014, 25, 217. ( 1 0 ) ( a ) Ł u k a s i k , E . ; W r ó b e l , Z . 2 - ( A r y l a m i n o ) aryliminophosphoranes as Easily Available and Convenient Starting Materials in the Synthesis of 1,2,3-Benzotriazoles. Synlett 2014, 25, 1987. (b) Łukasik, E.; Wróbel, Z. Quaternization of 2-(Arylamino)aryliminophosphoranes. A Route to N,N′-Disubstituted 2-Aminodiarylamines and Unsymmetrically Substituted 1-Aryl-1,2,5,6-tetrahydro-1,6-benzodiazocines. ARKIVOC 2016, No. iv, 67. (c) Łukasik, E.; Wróbel, Z. Aryliminophosphoranes as Key Intermediates in the OnePot Synthesis of 1-Aryl-1,3-dihydro-2H-benzimidazol-2-ones from NAryl-2-nitrosoanilines and Carbon Dioxide under Mild Metal-Free Conditions. Synthesis 2016, 48, 1159. (d) Łukasik, E.; Wróbel, Z. A New Approach to the Synthesis of 1-Arylbenzimidazole-2-thiones from Nitroarenes and Anilines through Halogen-Free Substitution of Hydrogen via Iminophosphorane Intermediates. Synthesis 2016, 48, 263. (11) Łukasik, E.; Wróbel, Z. 2-(Arylamino)aryliminophosphoranes from 2-Nitrodiarylamines. Heteroat. Chem. 2016, 27, 372. (12) Wenthur, C. J.; Lindsley, C. W. Classics in Chemical Neuroscience: Clozapine. ACS Chem. Neurosci. 2013, 4, 1018. (13) (a) Wander, S. A. A. Diazepine and Thiazepine Compounds. Br. Patent BR980,853, 1961. (b) Wander, S. A. A. Procédé de Préparation d’Amidines de la Série des 5-Dibenzo-[b,e] [1,4]diazépines. Fr. Patent FR1,334,944, 1963. (c) Hunziker, F.; Shmutz, J. 11-Basic Substituted Dibenzodiazepines and Dibenzothiazepines. U. S. Patent US3,539,573(A), 1970. (d) Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C. Palladium-Mediated Approach to Dibenzo[b,e][1,4]diazepines and Benzopyrido-Analogues. An Efficient Synthesis of Tarpane. Tetrahedron 2005, 61, 61. (e) Joshua, A. V.; Sharma, S. K.; Strelkov, A.; Scott, J. R.; Martin-Iverson, M. T.; Abrams, D. N.; Silverstone, P. H.; McEwan, A. J. B. Synthesis and Biodistribution of 8-Iodo-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]-diazepine: Iozapine. Bioorg. Med. Chem. Lett. 2007, 17, 4066. (f) Leyva-Perez, A.; Cabrero-Antonino, J. R.; Corma, A. Bifunctional

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02682. 1 H NMR and 13C{1H} NMR spectra of the products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Piotr Cmoch: 0000-0002-8413-9290 Irena Kulszewicz-Bajer: 0000-0002-7936-5138 Zbigniew Wróbel: 0000-0002-9609-7067 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. A. Kwast from Institute of Organic Chemistry, Polish Academy of Sciences, and Dr. B. K. Wilk from Monmouth Univ. for their invaluable help in the preparation of the manuscript.

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REFERENCES

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Note


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Direct Reductive Cyclocondensation of the Nitro Group with the Amido

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