Bromodimethylsulfonium Bromide (BDMS)-Catalyzed Synthesis of 1,5-Benzodiazepines Using a Multi-Component Reaction Strategy

This work is dedicated to the late Dr. Uttara Debi who was compassionate and amicable in nature.

Abstract

A new approach for the synthesis of multi-functionalized 1,5-benzodiazepines is developed starting from o-phenylenediamines, β-keto esters and aromatic aldehydes utilizing a one-pot, three-component strategy employing bromodimethylsulfonium bromide as the catalyst. The simple reaction procedure, good yields, mild reaction conditions and applicability to a wide range of substrates are some of the salient features of this protocol.

Key words

multi-component reactions - 1,5-benzodiazepines - o-phenylenediamines - bromodimethylsulfonium bromide

• References and Notes

• 1a Randall O, Kappel B In Benzodiazepines . Garattini S, Mussini E, Randall LO. Raven Press; New York: 1973: 27
• 1b Schütz H In Benzodiazepines . Springer; Heidelberg: 1982
• 2 Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell GF, Veber DF, Anderson PS. J. Med. Chem. 1988; 31: 2235
• 3a Patchett AA, Nargund RP. Annu. Rep. Med. Chem. 2000; 35: 289
• 3b Triggle DJ. Cell. Mol. Neurobiol. 2003; 23: 293
• 3c DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA. Comb. Chem. High Throughput Screening 2004; 7: 473
• 3d Poupaert J, Carato P, Colacino E. Curr. Med. Chem. 2005; 12: 877
• 4a Smalley RK In Comprehensive Organic Chemistry . Vol. 4. Barton D, Ollis WD, Sammes PG. Pergamon; Oxford: 1979: 600
• 4b Landquist JK In Comprehensive Heterocyclic Chemistry . Vol. 1. Katritzky AR, Rees CW, Meth-Cohn O. Pergamon; Oxford: 1984: 166
• 5 Knabe J, Büch HP, Bender S. Arch. Pharm. 1995; 328: 59
• 6 Atwal KS, Bergey JL, Hedberg A, Moreland S. J. Med. Chem. 1987; 30: 635
• 7 Di Braccio M, Grossi G, Roma G, Vargiu L, Mura M, Marongiu ME. Eur. J. Med. Chem. 2001; 36: 935
• 8 Fader LD, Bethell R, Bonneau P, Bös M, Bousquet Y, Cordingley MG, Coulombe R, Deroy P, Faucher A.-M, Gagnon A, Goudreau N, Grand-Maître C, Guse I, Hucke O, Kawai SH, Lacoste J.-E, Landry S, Lemke CT, Malenfant E, Mason S, Morin S, O’Meara J, Simoneau B, Titolo S, Yoakim C. Bioorg. Med. Chem. Lett. 2011; 21: 398
• 9 Harris RC, Straley JM US Pat., 1,537,757, 1968 Chem. Abstr., 1970, 73, 100054w
• 10a Aversa MC, Ferlazzo A, Giannetto P, Kohnke FH. Synthesis 1986; 230
• 10b Chimirri A, Grasso S, Ottana R, Romeo G, Zappala M. J. Heterocycl. Chem. 1990; 27: 371
• 11 Zhu J, Bienaymé H. Multicomponent Reactions . Wiley-VCH; Weinheim: 2005
• 12a Nardi M, Cozza A, Maiuolo L, Oliverio M, Procopio A. Tetrahedron Lett. 2011; 52: 4827 ; and references cited therein
• 12b Goswami S, Hazra A, Jana S. J. Heterocycl. Chem. 2009; 46: 861
• 12c Feng S.-E, Xu F, Shen Q. Chin. J. Chem. 2008; 26: 1163
• 13 Ried W, Torinus E. Chem. Ber. 1959; 92: 2902
• 14a Radatz CS, Silva RB, Perin G, Lenardão EJ, Jacob RG, Alves D. Tetrahedron Lett. 2011; 52: 4132 ; and references cited therein
• 14b Jacob RG, Radatz CS, Rodrigues MB, Alves D, Perin G, Lenardão EJ, Savegnago L. Heteroat. Chem. 2011; 22: 180
• 14c Ghorbani-Vaghei R, Veisi H. Mol. Diversity 2010; 14: 249
• 14d Shaabani A, Rezayan AH, Keshipour S, Sarvary A, Ng SW. Org. Lett. 2009; 11: 3342
• 14e Climent MJ, Corma A, Iborra S, Santos LL. Chem. Eur. J. 2009; 15: 8834
• 15a Shobha D, Chari MA, Selvan ST, Oveisi H, Mano A, Mukkanti K. J. Org. Chem. 2012; 77: 4484
• 15b Maiti G, Kayal U, Karmakar R, Bhattacharya RN. Tetrahedron Lett. 2012; 53: 1460
• 16a Fujioka H, Murai K, Kubo O, Ohba Y, Kita Y. Org. Lett. 2007; 9: 1687
• 16b Murai K, Nakatani R, Kita Y, Fujioka H. Tetrahedron 2008; 64: 11034
• 16c Sotoca E, Constantieux T, Rodriguez J. Synlett 2008; 1313
• 16d Sotoca E, Allais C, Constantieux T, Rodriguez J. Org. Biomol. Chem. 2009; 7: 1911
• 16e Lal M, Basha RS, Sarkar S, Khan AT. Tetrahedron Lett. 2013; 54: 4264
• 17a Choudhury LH, Parvin T, Khan AT. Tetrahedron 2009; 65: 9513
• 17b Khan AT, Parvin T, Choudhury LH. J. Org. Chem. 2008; 73: 8398
• 17c Khan AT, Basha RS, Lal M. Tetrahedron Lett. 2011; 52: 5157
• 17d Khan AT, Choudhury A, Ali S, Khan MM. Tetrahedron Lett. 2012; 53: 4852
• 18 1,5-Benzodiazepines; General Procedure In an oven-dried 25 mL round-bottomed flask was added the requisite o-phenylenediamine (1.0 mmol) and β-keto ester (1.0 mmol) in DCE (3 mL). Next, bromodimethylsulfonium bromide (10 mol%) was added and the mixture was stirred at r.t. After 15 min, the aromatic aldehyde (1.0 mmol) was added and the mixture was heated at 55 °C for the appropriate amount of time. Following completion (TLC), the solvent was removed on a rotary evaporator. The residue was extracted with CH₂Cl₂ (2 × 10 mL), washed with H₂O (10 mL) and dried over anhydrous Na₂SO₄. The solution was filtered, concentrated in vacuo and the residue purified by column chromatography (EtOAc–hexane, 5:95) to provide the 1,5-diazepine product. (Z)-Ethyl 2-(4-Phenyl-4,5-dihydro-1H-benzo[b][1,4]-diazepin-2(3H)-ylidene)acetate (4a) Yield: 0.213 g (75%); yellow solid; mp 73–77 °C. IR (KBr): 1158, 1455, 1618, 1637, 2923, 3415, 3467 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (t, J = 7.2 Hz, 3 H, -CH₃), 2.54 (dd, J = 14, 4.4 Hz, 1 H, -CH₂), 2.70 (dd, J = 14, 9.2 Hz, 1 H, -CH₂), 3.7 (br s, 1H, -NH), 4.1–4.2 (m, 2 H, -OCH₂), 4.61 (s, 1 H, =CH), 4.85 (dd, J = 9.2, 4 Hz, 1 H, -CH), 6.76–6.79 (m, 1 H, Ar-H), 6.85–6.94 (m, 1 H, Ar-H), 6.96–7.05 (m, 2 H, Ar-H), 7.28–7.32 (m, 1 H, Ar-H), 7.32–7.39 (m, 4 H, Ar-H), 10.24 (s, 1 H, -NH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.75, 40.52, 59.05, 65.33, 82.42, 121.01, 121.80, 122.74, 125.19, 126.29 (2 C), 128.18, 129.03 (2 C), 130.11, 138.11, 145.07, 158.83, 170.52.HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀N₂O₂: 309.1598; found: 309.1594. Anal. Calcd for C₁₉H₂₀N₂O₂: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.06; H, 6.59; N, 9.02.