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

Ahmed Kamal; N. Shankaraiah; N. Markandeya; Ch. Sanjeeva Reddy

doi:10.1055/s-2008-1072742

LETTER

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

Ahmed Kamal*^a, N. Shankaraiah^a, N. Markandeya^b, Ch. Sanjeeva Reddy*^b
^a Chemical Biology, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax: +91(40)927193189; e-Mail: ahmedkamal@iict.res.in;
^b Department of Chemistry, Kakatiya University, Warangal 506009, A.P., India
Fax: +91(870)2439600; e-Mail: chsrkue@yahoo.in;

Abstract

All articles of this category

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

Full Text

References

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.