Process for preparing 1,4-dibenzodiazepines via Buchwald-Hartwig chemistry

Abstract

The present application provides a one-pot catalytic process which involves the formation of 1,4-dibenzodiazepines from o-haloaldimines (either pre-formed or formed in situ) of formula (I) and o-haloanilines of formula (II) via a palladium catalyzed Buchwald-Hartwig reaction and a cyclization sequence, to afford the 1,4-dibenzodiazepine products of formula (III). The present application describes the preparation of the 1,4-dibenzodiazepine products of formula (III) from simple commercial raw materials by efficient processes. ##STR00001##

Claims

1. A process for the catalytic one-pot synthesis of products of formula (III) from substrates of formula (I) and (II) respectively, ##STR00015## wherein, X represents a halogen group or a triflate group (OTf); R represents, an alkyl or aryl group; R.sup.1 and R.sup.3 represent a hydrogen, a saturated alkyl, allyl, vinyl or cycloalkyl group, or an aryl group, or an OH, tiol, amino, nitro, cyano, aldehyde, ketone, ester, thioester, carboxylic acid, carbamate, ether or a thioeter group; R.sup.2 represents a hydrogen, an alkyl, allyl, vinyl or aryl group; comprising the use of an active palladium catalyst, at a loading of between 0.1 and 5 mol %, wherein the reaction is conducted by adding a palladium complex, a ligand at a loading of between 0.25 and 10 mol %, and a base in a solvent.

2. The process according to claim 1, wherein the active catalyst is prepared by adding the ligand to the palladium complex in a dry solvent, under an inert atmosphere and allowing the mixture to stir up to 24 h with a temperature range from 50 to 130 C.

3. The process according to claim 1, wherein the palladium complex used is selected from the group consisting of Pd(OAc).sub.2, PEPPSI-iPr catalyst, Pd.sub.2(dba).sub.3.CHCl.sub.3, [Pd(TFA).sub.2], PdCl.sub.2(dppf), Pd(PPh.sub.3).sub.4, cationic palladium (II) complexes and PdNHCs.

4. The process according to claim 1, wherein the reaction solvent used is selected from the group consisting of: toluene, dimethyl ether, diethyl ether, 1,4-dioxane, acetonitrile, chloroform, DMF, DMA and NMP.

5. The process according to claim 1, wherein the ligand is a monophosphane type ligand.

6. The process according to claim 1, wherein the base is selected from the group consisting of triethylamine, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, CaCO.sub.3, Ba(OH).sub.2, KOAc, DIPA, K.sub.3PO.sub.4, NMM, DBU, KOH, KF, Cs.sub.2CO.sub.3, and KOtBu.

7. The process according to claim 1, wherein the substrate of formula (I) is pre-formed or formed in situ.

8. The process according to claim 1, wherein the reaction is run under an inert atmosphere.

9. The process according to claim 1, wherein the reaction temperature ranges between 50 and 130 C.

10. The process according to claim 1, wherein the halogen group is selected from the group consisting of Br, Cl and I.

Description

EXAMPLES

(1) General Catalytic Procedure for the Synthesis of Dibenzodiazepines

(2) The reactions were performed under a nitrogen atmosphere using a Radleys 12 position carousel reactor station. Pd(OAc).sub.2 (2.5 mol %), SPhos (5.0 mol %), o-bromoarylimines, o-bromoarylamines, Cs.sub.2CO.sub.3 (2 equivs) and THF were added to the reaction tube. The reactions were performed at 100 C. for 18 h. The reactions were monitored by TLC, to follow the disappearance of the starting materials. After completion, the mixture was allowed to cool to room temperature. The reaction mixture was filtered with celite and the solvent removed under reduced pressure and then purified by column chromatography using 9:1 Hexane/EtOAc, to give the following pure compounds 1-11.

(3) ##STR00004##

(4) 5H-Dibenzo[b,e][1,4]diazepine): From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and 2-bromoaniline (0.258 g), according to the general procedure, the title compound was obtained as a yellow solid (0.20 g, 70%) m.p. 124.0-124.5 C. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.06-7.12 (m, 2H, ArH), 7.33-7.37 (m, 2H, ArH), 7.42-7.46 (m, 1H, ArH), 7.62-7.66 (m, 2H, ArH), 8.33 (dd, J=6.6 and 2.0 Hz, 1H, ArH), 8.76 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 118.5 (C), 120.0 (CH), 126.3 (C), 127.2 (CH), 128.0 (CH), 128.5 (CH), 129.7 (CH), 133.0 (CH), 133.2 (CH), 133.4 (CH), 134.4 (C), 150.5 (C), 160.8 (HCN) ppm. MS (ESI TOF) m/z: 195.2 (M.sup.++H).

(5) ##STR00005##

(6) 2-Fluoro-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromo-5-fluorobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.3 mmol) and 2-bromoaniline (0.224 g), according to the general procedure, the title compound was obtained as a yellow solid (0.40 g, 76%) m.p. 107.2-108.8 C. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.05-7.14 (m, 3H, ArH), 7.34-7.38 (m, 1H, ArH), 7.58-7.67 (m, 2H, ArH), 8.03-8.06 (m, 1H, ArH), 8.70 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 116.0 (d, J=24 Hz, CH), 118.7 (C), 119.8 (CH), 120.2 (d, J=23 Hz, CH), 127.6 (CH), 128.6 (CH), 133.3 (CH), 134.6 (d, J=7.5 Hz, CH), 136.3 (C), 146.1 (C), 150.0 (C), 159.6 (HCN), 162.3 (d, J=239.7 Hz, CF) ppm. MS (ESI TOF) m/z: 213.21 (M.sup.++H).

(7) ##STR00006##

(8) 2-Methoxy-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromo-5-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.4 mmol) and 2-bromoaniline (0.241 g), according to the general procedure the title compound was obtained as a brown semi-solid (0.222 g, 76%). .sup.1H NMR (400 MHz, CDCl.sub.3): 3.87 (s, 3H, OMe), 6.91-6.94 (m, 1H, ArH), 7.04-7.10 (m, 2H, ArH), 7.31-7.35 (m, 1H, ArH), 7.47-7.49 (m, 1H, ArH), 7.62-7.64 (m, 1H, ArH), 7.84-7.85 (m, 1H, ArH), 8.69 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 55.8 (OMe), 118.0 (CH), 119.9 (CH), 120.7 (CH), 127.2 (CH), 128.4 (C), 128.5 (CH), 132.6 (C), 133.1 (CH), 133.9 (CH), 134.0 (C), 134.8 (C), 150.2 (C), 160.6 (HCN) ppm. MS (ESI TOF) m/z: 225.27 (M.sup.++H).

(9) ##STR00007##

(10) 3-Methoxy-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.4 mmol) and 2-bromoaniline (0.241 g), according to the general procedure the title compound was obtained as a brown solid/oil (0.218 g, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3): 3.87 (s, 3H, OMe), 6.95-7.08 (m, 3H, ArH), 7.31-7.35 (m, 1H, ArH), 7.62-7.64 (m, 1H, ArH), 7.89-7.91 (m, 1H, ArH), 8.27-8.29 (m, 1H, ArH), 8.66 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 55.9 (OMe), 114.6 (CH), 118.1 (CH), 120.0 (CH), 124.9 (CH), 126.8 (C), 128.5 (CH), 128.9 (C), 130.6 (CH), 131.0 (C), 132.6 (C), 133.2 (CH), 156.8 (C), 159.9 (HCN) ppm. MS (ESI TOF) m/z: 225.27 (M.sup.++H).

(11) ##STR00008##

(12) 3-Methoxy-5H-dibenzo[b,e][1,4]diazepin-2-ol: From N-(2-bromo-5-hydroxy-4-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.3 mmol) and 2-bromoaniline (0.224 g), according to the general procedure the title compound was obtained as a colorless oil (0.225 g, 72%). .sup.1H NMR (400 MHz, CDCl.sub.3): 3.96 (s, 3H, OMe), 4.06 (br s, 1H, OH), 5.68 (br s, 1H, NH), 7.03-7.09 (m, 3H, ArH), 7.31-7.35 (m, 1H, ArH), 7.62-7.64 (m, 1H, ArH), 7.91 (s, 1H, ArH), 8.62 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 56.5 (OMe), 114.5 (CH), 114.9 (CH), 120.0 (CH), 127.0 (CH), 128.5 (CH), 132.7 (C), 133.3 (CH), 144.2 (C), 145.5 (C), 150.3 (C), 150.6 (C), 151.8 (C), 160.1 (HCN) ppm. MS (ESI TOF) m/z: 241.27 (M.sup.++H).

(13) ##STR00009##

(14) 8-(Trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and 2-bromo-4-(trifluoromethyl)aniline (0.360 g), according to the general procedure the title compound was obtained as a yellow semi-solid (0.178 g, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.10-7.12 (m, 1H, ArH), 7.37-7.46 (m, 2H, ArH), 7.59-7.67 (m, 2H, ArH), 7.90 (br s, 1H, ArH), 8.30-8.33 (m, 1H, ArH), 8.62 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 125.7 (q, J=7.0 Hz, CH), 126.6 (CH), 127.3 (CH), 129.7 (q, J=260.0 Hz, CF.sub.3), 129.2 (C), 130.0 (q, J=3.8 Hz, CH), 130.3 (q, J=6.8 Hz, CH), 132.1 (q, J=30.0 Hz, CCF.sub.3), 133.7 (CH), 133.9 (CH), 147.1 (C), 153.7 (C), 158.0 (C), 162.2 (HCN) ppm. MS (ESI TOF) m/z: 263.24 (M.sup.++H).

(15) ##STR00010##

(16) 7-Methyl-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and 2-bromo-5-methylaniline (0.279 g), according to the general procedure the title compound was obtained as a white oil (0.203 g, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3): 2.36 (s, 3H, CH.sub.3), 6.86-6.93 (m, 2H, ArH), 7.32-7.36 (m, 1H, ArH), 7.41-7.46 (m, 1H, ArH), 7.49.7.51 (m, 1H, ArH), 7.62-7.67 (m, 1H, ArH), 8.30-8.33 (m, 1H, ArH), 8.74 (br s, 1H, HCN) ppm. MS (ESI TOF) m/z: 209.27 (M.sup.++H).

(17) ##STR00011##

(18) 7-Nitro-5H-dibenzo[b,e][1,4]diazepine (4ad): From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and 2-bromo-5-nitroaniline (0.326 g), according to the general procedure the title compound was obtained as a yellow solid (0.215 g, 60%) m.p. 139.3-139.7 C. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.40-7.46 (m, 2H, ArH), 7.67 (dd, J=1.2 and 8.0 Hz, 1H, ArH), 7.82 (d, J=8.8 Hz, ArH), 7.89 (d, J=2.8 Hz, ArH), 7.96 (dd, J=2.8 and 8.8 Hz, ArH), 8.31 (dd, J=1.2 and 8.0 Hz, ArH), 8.82 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 114.6 (CH), 121.3 (CH), 126.0 (C), 126.8 (C), 128.1 (CH), 129.8 (CH), 133.6 (CH), 133.7 (C), 133.8 (CH), 133.9 (CH), 148.1 (C), 151.5 (C), 162.8 (HCN) ppm. MS (ESI TOF) m/z: 240.23 (M.sup.++H).

(19) ##STR00012##

(20) 5H-dibenzo[b,e][1,4]diazepine-7-carbonitrile: From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.25 g, 0.74 mmol) and 3-amino-4-bromobenzonitrile (0.146 g), according to the general procedure, the title compound was obtained as a yellow semi-solid (0.085 g, 53%). .sup.1H NMR (400 MHz, CDCl.sub.3): 3.68 (br s, 1H, NH), 7.11 (d, J=8.0 Hz, ArH), 7.38-7.48 (m, 2H, ArH), 7.63-7.67 (m, 2H, ArH), 7.93 (d, J=1.6 Hz, ArH), 8.29 (dd, J=2.0 and 7.8 Hz, ArH), 8.74 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 110.5 (C), 117.7 (C), 118.3 (C), 120.6 (CH), 126.7 (C), 128.1 (CH), 129.8 (CH), 132.5 (CH), 133.6 (CH), 133.7 (C), 133.8 (CH), 136.6 (CH), 154.7 (C), 162.5 (HCN) ppm.

(21) ##STR00013##

(22) 8-Fluoro-6-methyl-5H-dibenzo[b,e][1,4]diazepine: From N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.5 mmol) and 2-bromo-4-fluoro-6-methylaniline (0.304 g), according to the general procedure, the title compound was obtained as a yellow solid (0.251 g, 74%) m.p. 78.4-79.0 C. .sup.1H NMR (400 MHz, CDCl.sub.3): 2.22 (s, 3H, CH.sub.3), 6.69-6.95 (m, 1H, ArH), 7.21-7.23 (m, 1H, ArH), 7.36-7.45 (m, 2H, ArH), 7.54-7.66 (m, 1H, ArH), 8.27-8.29 (m, 1H, ArH), 8.67 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 29.8 (CH.sub.3), 116.6 (d, J=21.7 Hz, CH), 117.6 (d, J=24.9 Hz, CH), 126.2 (C), 128.0 (CH), 129.2 (CH), 131.5 (C), 133.1 (CH), 133.4 (CH), 134.3 (C), 138.5 (C), 146.5 (C), 159.0 (d, J=244.7 Hz, CF), 165.1 (HCN) ppm. MS (ESI TOF) m/z: 227.26 (M.sup.++H).

(23) ##STR00014##

(24) 8-Fluoro-2-methoxy-6-methyl-5H-dibenzo[b,e][1,4]diazepine):

(25) From N-(2-bromo-5-methoxybenzylidene)-4-methylbenzenesulfonamide (0.50 g, 1.4 mmol) and 2-bromo-4-fluoro-6-methylaniline (0.276 g), according to the general procedure the title compound was obtained as a yellow solid (0.216 g, 62%) 68.5-69.2 C. .sup.1H NMR (400 MHz, CDCl.sub.3): 2.22 (s, 3H, CH.sub.3), 3.88 (s, 3H, OMe). 6.91.6.98 (m, 2H, ArH), 7.21-7.24 (m, 1H, ArH), 7.51-7.53 (m, 1H, ArH), 7.80-7.81 (m, 1H, ArH), 8.63 (br s, 1H, HCN) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 19.3 (CH.sub.3), 55.9 (OMe), 112.4 (CH), 116.5 (d, J=21.7 Hz, CH), 117.1 (C), 117.4 (d, J=26.9 Hz, CH), 120.8 (CH), 123.4 (C), 131.5 (d, J=8.2 Hz, C), 134.1 (CH), 134.7 (d, J=3.1 Hz, C), 146.4 (C), 159.0 (d, J=244.6 Hz, CF), 159.3 (C), 165.0 (HCN) ppm. MS (ESI TOF) m/z: 257.28 (M.sup.++H).

(26) Naturally, the present application is by no means restricted to the embodiments described in this document, and a person with average skills in the art might predict many possibilities of altering the same without departing from the general idea, as defined in the claims.

(27) Accordingly, the scope of the present application is to be construed in accordance with the substance defined by the following claims.

(28) Abbreviations

(29) DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DIPA Diisopropylamine DMA Dimethylacetamide NHC N-Heterocyclic Carbene NMM N-Methylmorpholine NMP N-Methylpiperidine PEPPSI catalyst Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation SPhos 2-Dicyclohexylphosphino-2,6-dimethoxybiphenyl TBAAc Tetrabutylammonium acetate Tf Triflate (trifluoromethylsulfonyl) TFA Trifluoroacetic acid XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

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