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DOI: 10.1055/s-0029-1219583
Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of N β-Fmoc-Amino Alkyl Isonitriles from N β-Fmoc-Amino Alkyl Thioformamides
Publication History
Publication Date:
16 March 2010 (online)
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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
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References and Notes
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.
The mechanism of the dehydrosulforization of thioformamides using CNBr is given in Scheme [³] .
![](https://www.thieme-connect.de/media/synlett/201007/d276_s3.gif)
Scheme 3
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.
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.
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.
Selected Spectroscopic
Data
Compound 2c: IR (KBr): νmax = 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) νmax = 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) νmax = 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.