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

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Synlett 2008(9): 1297-1300
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;

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Publication History

Received 20 November 2007
Publication Date:
07 May 2008 (online)

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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

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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).

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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.