An Efficient Selective Reduction of Aromatic Azides to Amines Employing BF₃·OEt₂/NaI: Synthesis of Pyrrolobenzodiazepines

Abstract

A selective and facile method for the reduction of aromatic azides to amines by employing borontrifluoride diethyl etherate and sodium iodide. This methodology has been applied towards the preparation of biologically important imine-containing pyrrolobenzodiazepines and their dilactams through intramolecular reductive-cyclization process. In this protocol the reagent systems are amenable for the generation of solution-phase combinatorial synthesis.

Key words

pyrrolo[2,1-c][1,4]benzodiazepines - boron trifluoride diethyl etherate - sodium iodide - intramoleculor reductive-cyclization

References and Notes

• 1 Scriven EFV. Turnbull K. Chem. Rev.  1988,  88:  297 
• 2 Smith SC. Heathcock CH. J. Org. Chem.  1992,  57:  6379 
• 3 McDonald FE. Danishefsky SJ. J. Org. Chem.  1992,  57:  7001 
• 4a Ito M. Koyakumaru K. Takaya TH. Synthesis  1995,  376 
• 4b Rao HSP. Siva P. Synth. Commun.  1994,  24:  549 
• 4c Alverez SG. Fisher GB. Singavam B. Tetrahedron Lett.  1995,  36:  2567 
• 4d Molina P. Diaz I. Tarraga A. Tetrahedron  1995,  51:  5617 
• 4e Ramesha AR. Bhat S. Chandrasekaran S. J. Org. Chem.  1995,  60:  7682 
• 4f Capperucci A. Degl’Innocenti A. Funicello M. Mauriello G. Scafato P. Spagnolo P. J. Org. Chem.  1995,  60:  2254 
• 4g Kamal A. Reddy BSP. Reddy BSN. Tetrahedron Lett.  1996,  37:  6803 
• 4h Huang Y. Zhang Y. Wang Y. Tetrahedron Lett.  1997,  38:  1065 
• 5 Molander GA. Chem. Rev.  1992,  92:  29 
• 6a Kamal A. Rao MV. Laxman N. Ramesh G. Reddy GSK. Curr. Med. Chem.: Anti-Cancer Agents  2002,  2:  215 
• 6b Kamal A. Reddy KL. Devaiah V. Shankaraiah N. Reddy DR. Mini-Rev. Med. Chem.  2006,  6:  53 
• 6c Kamal A. Reddy KL. Devaiah V. Shankaraiah N. Rao MV. Mini-Rev. Med. Chem.  2006,  6:  71 
• 8 Thurston DE. In Molecular Aspects of Anticancer Drug-DNA Interactions   Vol. 1:  Neidle S. Waring MJ. The Macmillan Press Ltd; London: 1993.  p.54 
• 9 Thurston DE. Bose DS. Chem. Rev.  1994,  94:  433 
• 7 Kamal A. Shankaraiah N. Reddy KL. Devaiah V. Tetrahedron Lett.  2006,  47:  4253 
• 10 Kneko T. Wong H. Doyle TW. Rose WC. Brander WT. J. Med. Chem.  1985,  28:  388 
• 11 Blackburn BK. Lee A. Baier M. Kohl B. Olivero AG. Matamoros R. Robarge KD. McDowell RS. J. Med. Chem.  1997,  40:  717 
• 12 Wright WB. Brabander HJ. Greenblatt EN. Day IP. Hardy RA. J. Med. Chem.  1978,  21:  1087 
• 13 Di Martino G. Massa S. Corelli F. Pantaleoni G. Fanini D. Palumbo G. Eur. J. Med. Chem.  1983,  18:  347 
• 14 Karp GM. Manfredi MC. Guaciaro MA. Ortlip CL. Marc P. Szamosi IT. J. Agric. Food Chem.  1997,  45:  493 
• 15a Kaneko T. Wong H. Doyle TW. J. Antibiotics  1984,  37:  300 
• 15b Kamal A. Reddy BSP. Reddy BSN. Tetrahedron Lett.  1996,  37:  2281 
• 15c Jones GB. Davey CL. Jenkins TC. Kamal A. Kneale G. Neidle S. Webster GD. Thurston DE. Anti-Cancer Drug Des.  1990,  5:  249 
• 15d Kaneko T. Wong H. Doyle TW. Tetrahedron Lett.  1983,  24:  5165 
• 16 Kamal A. Howard PW. Reddy BSN. Reddy BSP. Thurston DE. Tetrahedron  1997,  53:  3223 
• 17a Thurston DE. Bose DS. Chem. Rev.  1994,  94:  433 
• 17b Kamal A. Rao MV. Reddy BSN. Khim. Geterotsikl. Soedin. (Chem. Heterocycl. Compd.)  1998,  1588 
• 17c Kamal A. Rao NV. Chem. Commun.  1996,  385 
• 18a Carbateas PM. inventors; US  3,732,212.  ; Chem. Abstr. 1973, 79, P42570x
• 18b Carbateas PM. inventors; US  3,763,183.  ; Chem. Abstr. 1973, 79, P146567t
• 18c Carbateas PM. inventors; US  3,860,600.  ; Chem. Abstr. 1975, 83, P58892x
• 18d Reddy BSP. PhD Thesis   Osmania University; India: 1995. 

19

General Procedure for Azido Reductions
The substituted aromatic azides were dissolved in MeCN (15 mL), BF₃·OEt₂ (2.0 equiv), NaI (50 mol%) was added and then solvent stirred at r.t. for 10-80 min to afford reductively cyclized products. The reaction mixture was quenched with aq Na₂S₂O₃ followed by neutralization with aq NaHCO₃ soln. The mixture was extracted with EtOAc (3 × 35 mL) and the combined organic extracts dried over anhyd Na₂SO₄. The solvent was evaporated under vacuum and the residue purified by column chromatography through SiO₂ (60-120 mesh) eluting with EtOAc-hexane (yields as shown in Tables 1-3).

20

Selected Data
Compound 2h: ¹H NMR (200 MHz, CDCl₃): δ = 7.35-7.45 (m, 5 H), 7.22 (s, 1 H), 6.15 (s, 1 H), 5.47-5.90 (br s, 2 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.83 (s, 3 H). MS (EI): m/z = 287 [M⁺].
Compound 4a: ¹H NMR (200 MHz, CDCl₃): δ = 8.05 (d, J = 7.43 Hz, 1 H), 7.79 (d, J = 4.46 Hz, 1 H), 7.53 (t, J = 6.69 Hz, 1 H), 7.28-7.38 (m, 2 H), 3.36-3.94 (m, 3 H), 2.26-2.38, (m, 2 H), 2.02-2.16 (m, 2 H). MS (EI): m/z = 200 [M⁺]. [α]_D ²⁶ +343 (c 0.4, CHCl₃).
Compound 4b: ¹H NMR (400 MHz, CDCl₃): δ = 8.00-8.05 (m, 1 H), 7.00-7.80 (m, 1 H), 7.40-7.60 (m, 1 H), 7.20-7.30 (m, 1 H), 3.40-3.90 (m, 3 H), 1.90-2.50 (m, 7 H). MS (EI): m/z = 214 [M⁺].
Compound 4e: ¹H NMR (200 MHz, DMSO-d ₆): δ = 7.84 (d, 1 H, J = 7.32), 7.12-7.26 (m, 1 H), 6.95 (d, 1 H, J = 5.01 Hz), 6.70-7.80 (m, 2 H), 4.92 (d, 1 H, J = 4.81 Hz), 4.17-4.26 (m, 1 H), 4.02 (m, 1 H), 3.50-3.75 (m, 2 H), 1.95-2.10 (m, 1 H), 1.70-1.80 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 166.5, 150.2, 144.6, 133.5, 131.7, 131.4, 128.6, 125.2, 71.0, 56.6, 52.0, 39.5. MS (EI): m/z 216 [M⁺]. HRMS: m/z calcd for C₁₂H₁₂N₂O₂: 216.2358; found: 216.2361.
Compound 6a: ¹H NMR (200 MHz, CDCl₃): δ = 9.22 (br s, 1 H), 7.96-8.08 (d, 1 H, J = 8.03 Hz), 7.42-7.58 (t, 1 H, J = 8.03, 7.03 Hz), 7.21-7.28 (m, 1 H), 7.03-7.07 (d, 1 H, J = 8.03 Hz), 4.05-4.09 (d, 1 H, J = 6.57 Hz), 3.75-3.86 (m, 1 H), 3.51-3.65 (m, 1 H), 2.71-2.82 (m, 1 H), 1.85-2.15 (m, 3 H). MS (EI): m/z = 216 [M⁺]. HRMS: m/z calcd for C₁₂H₁₂N₂O₂: 216.2358; found: 216.2363.
Compound 6f: ¹H NMR (200 MHz, DMSO-d ₆): δ = 7.84 (d, 1 H, J = 7.3 Hz), 7.12-7.26 (m, 1 H), 6.95 (d, 1 H, J = 5.0 Hz), 6.70-6.80 (m, 2 H), 4.92 (d, 1 H, J = 4.8 Hz), 4.17-4.26 (m, 1 H), 4.02-4.10 (m, 1 H), 3.50-3.75 (m, 2 H), 1.95-2.10 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 166.5, 150.2, 144.6, 133.5, 131.7, 131.4, 128.6, 125.2, 71.0, 56.6, 52.0, 39.5. MS (EI): m/z = 232 [M⁺]. HRMS: m/z calcd for C₁₂H₁₂N₂O₃: 232.2352; found: 232.2358.
Compound 6j: ¹H NMR (200 MHz, CDCl₃): δ = 10.10 (s, 1 H), 7.26-7.40 (m, 6 H), 6.49 (s, 1 H), 5.10 (s, 2 H), 3.98-4.01 (d, 1 H, J = 6.44 Hz), 3.91 (s, 3 H), 3.65-3.75 (m, 1 H), 3.42-3.50 (m, 2 H), 2.65-2.75 (m, 1 H), 1.90-2.00 (m, 2 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 171.2, 166.5, 152.2, 146.6, 137.2, 131.4, 129.5, 128.6, 118.3, 113.4, 106.8, 71.0, 68.5, 56.6, 54.0, 35.8. MS (EI): m/z = 368 [M⁺]. HRMS: m/z calcd for C₂₀H₂₀N₂O₅: 368.3824; found: 368.3831.