Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of N ^β-Fmoc-Amino Alkyl Isonitriles from N ^β-Fmoc-Amino Alkyl Thioformamides

Abstract

Synthetically useful N ^β-Fmoc amino alkyl isonitriles are prepared conveniently from N ^β-Fmoc amino alkyl thioformamides via a cyanogen bromide mediated dehydrosulfurization. The reaction is fast, clean, and yields are good.

Key words

N ^β-Fmoc-amino alkyl thioformamides - isonitriles - dehydrosulfurization - cyanogen bromide

References and Notes

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47

The two dipeptide thioformamides were synthesized in to verify the optical purity of N ^β-Fmoc-amino alkyl thiofor mamides 1. For this, 1b was treated with 20% Et₂NH in CH₂Cl₂ to deprotect the Fmoc group. The resulting amino-free N ^β-(1-amino alanine)-thioformamide was coupled both d and l isomers of Fmoc-Phg-OH using EDC/separately to obtain 1k and 1l. The ^¹H NMR spectra of both Fmoc-l-Phg-Ala-Ψ[CH₂NHCHS] and Fmoc-d-Phg-Ala-Ψ[CH₂NHCHS] showed distinct methyl group doublets at δ = 1.13, 1.14 ppm and δ = 1.21, 1.23, respectively. However, the mixture of epimers prepared by coupling amino-free N ^β-(1-amino alanine)-thioformamide with epimeric mixture of Fmoc
(l/d)-Phg-OH had two separate doublets corresponding to each diastereomer. This clearly confirmed the optical purity of thioformamides.

48

The mechanism of the dehydrosulforization of thioformamides using CNBr is given in Scheme  [³] .

Scheme 3

49

Typical Experimental Procedure for 1a-j To a stirred solution of N ^β-Fmoc amino alkyl formamide 5
(1 mmol) in THF (5 mL), P₂S₅ (0.7 mmol) was added. The reaction mixture was subjected to ultrasonication for 15 min. After the completion of reaction (TLC), the solvent was evaporated in vacuo, and the crude was purified by a flash chromatography to obtain the thioformamides as solids.

50

Selected Spectroscopic Data. Compound 1b: ^¹H NMR (400 MHz, CDCl₃): δ = 1.30 (d, 3 H, J = 6.53 Hz), 2.65 (d, 2 H), 3.90 (m, 1 H), 4.20 (t, 1 H, J = 13.04 Hz), 4.41 (d, 2 H, J = 6.62 Hz), 5.01 (br, 1 H), 7.31 (t, 2 H, J = 14.79 Hz), 7.39 (t, 2 H, J = 14.69 Hz), 7.57 (d, 2 H, J = 7.21 Hz), 7.76 (d, 2 H, J = 7.48 Hz), 8.20 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.44, 46.83, 47.18, 56.18, 66.83, 122.24, 124.93, 127.08, 128.17, 141.34, 143.66, 155.77, 139.31.
Compound 1j: ^¹H NMR (400 MHz, CDCl₃): δ = 2.39-2.65 (m, 2 H), 3.12-3.51 (m, 2 H), 3.1 (m, 1 H), 4.10 (t, 1 H, J = 6.90 Hz), 4.12 (d, 2 H, J = 7.2 Hz), 4.74 (s, 2 H), 5.56 (br, 1 H), 7.15-7.80 (m, 13 H), 8.25 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃; CCl₄): δ = 36.91, 43.06, 46.82, 51.89, 65.83, 69.82, 119.15, 124.90, 126.25, 127.53, 128.12, 128.24, 141.67, 143.53, 143.81, 156.38, 139.22, 171.58.
Compound 1k: ^¹H NMR (400 MHz, CDCl₃): δ = 1.14 (d, 3 H, J = 5.0 Hz), 2.65-3.16 (m, 2 H), 4.05-4.20 (m, 3 H), 4.22 (d, 2 H, J = 8.0 Hz), 6.65 (br, 1 H), 6.88 (br, 1 H), 7.28-7.48 (m, 8 H), 7.56 (d, 2 H, J = 4.0 Hz), 7.74 (d, 2 H, J = 8.0 Hz), 8.16 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.12, 43.09, 45.86, 53.69, 58.29, 67.18, 125.34, 126.22, 127.09,127.77, 128.01, 128.40, 128.63, 135.54, 141.30, 143.75, 159.14, 156.29, 138.9.

51

Typical Experimental Procedure for 2a-j A solution of N ^β-Fmoc amino alkyl thioformamide 1 (1 mmol) in dry CH₂Cl₂ (10 mL) was cooled to 0 ˚C, NMM
(2 mmol) and CNBr (1.5 mmol) were added, and the reaction mixture was stirred at this temperature for 30 min. After completion of reaction, it was diluted with CH₂Cl₂ (10 mL) and was washed with H₂O, brine, and dried over anhyd Na₂SO₄. The solvent was evaporated under reduced pressure followed by chromatographic purification (silica gel, 100-200 mesh, 20% EtOAc in hexane) to afford the desired isonitriles 2 in excellent yield and purity as stable solids.

52

Selected Spectroscopic Data
Compound 2c: IR (KBr): ν_max = 1715, 2149 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.81 (br, 2 H), 3.12-3.65 (m, 2 H), 3.95 (br, 1 H), 4.12 (br, 1 H), 4.29 (d, 2 H, J = 4.0 Hz), 5.15 (br, 1 H), 7.17 (m, 9 H), 7.44 (d, 2 H, J = 8.0 Hz), 7.69 (d, 2 H, J = 8.0 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 37.30, 44.39, 47.19, 50.79, 66.99, 120.10, 125.04, 127.15, 127.35, 127.84, 129.03, 129.10, 135.98, 141.38, 143.65, 155.55, 158.45. Compound 2f: IR (KBr) ν_max = 1710, 2151 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.20-2.71 (m, 2 H), 3.00-3.59 (m, 4 H), 4.00 (br, 1 H), 4.12 (d, 1 H, J = 7.8 Hz), 4.41 (br, 2 H), 6.02 (s,1 H), 7.00-7.74 (m, 13 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 32.10, 36.21, 44.00, 46.85, 49.12, 53.34,66.88, 119.90, 124.82, 126.95, 127.08, 127.83, 128.15, 136.77, 141.00, 143.13, 155.11, 158.10.
Compound 2l: IR (film/pellet) ν_max = 1715, 2151 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.24 (d, 3 H, J = 4.0 Hz), 3.12-3.79 (m, 2 H), 3.87-4.10 (m, 3 H), 4.11 (d, 2 H, J = 8.0 Hz), 5.09 (br, 1 H), 5.89 (br, 1 H), 7.28-7.48 (m, 8 H), 7.56 (d, 2 H, J = 4.0 Hz), 7.74 (d, 2 H, J = 8.0 Hz), 8.18 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.00, 43.69, 46.42, 54.10, 57.95, 67.10, 119.77, 125.45, 127.22, 127.75, 128.53, 128.40, 128.63, 135.09, 141.30, 143.75, 154.94, 156.49, 170.97.