The use of cyclohexyl isocyanide in the esterification of N-benzoyl α-amino acids derivatives

Article abstract of DOI:10.3184/174751911X13129847175330

The N-benzoyl of α,β-dehydroamino acids that were obtained by condensation of N-benzoylglycine and an aldehyde, were esterified with an alcohol in high yield using cyclohexyl isocyanide to activate the carboxylic acid under neutral conditions.

Full text of DOI:10.3184/174751911X13129847175330

468 RESEARCH PAPER
AUGUST, 468–470
JOURNAL OF CHEMICAL RESEARCH 2011
The use of cyclohexyl isocyanide in the esterification of N-benzoyl
α-amino acids derivatives
Alireza Hassanabadia*, Mohammad Anary-Abbasinejadb, Atefeh Ahmadi Niric and
Rozita Feizpoorb
aDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
cDepartment of Chemistry, Islamic Azad University, Karaj Branch, Karaj, Iran
The N-benzoyl of α,β−dehydroamino acids that were obtained by condensation of N-benzoylglycine and an aldehyde,
were esterified with an alcohol in high yield using cyclohexyl isocyanide to activate the carboxylic acid under neutral
conditions.
Keywords: cyclohexyl isocyanide, esterification, α-amino acids, α,β-dehydro-α-amino acids, alcohols
The synthesis of α,β-dehydro-α-amino acids is important in
the context of peptide-derived chemotherapeutics.1–4 The sub-
stitution of proteinogenic α-amino acids by α,β-dehydro-α-
amino acid residues usually affects markedly the physiological
activity of peptides, changing their secondary structure and
increasing their resistance to protease catalyzed hydrolysis.5–7
The hydrogenation of α,β-dehydro-α-amino acids using
Wilkinson-type chiral catalysts is one of the general methods
for the enantioselective synthesis of α-amino acids.1,2,8–11
α,β-Dehydro-α-amino acid derivatives have been obtained by
the Wittig reaction, starting from easily accessible N-acyl-α-
triphenylphosphonioglycinates as precursors of ylides12 or by
the Wadsworth–Emmons variant.13–16
The addition reactions to isocyanides has been of particular
interest. For example the reaction of hydrogen halides to iso-
cyanides at low temperatures has been reported to produce
haloimines.17 The reaction of organic acids, such as Meldrum’s
acid18 or 1,1,1-trifluoro-2,3-pentandiones,19 with isocyanides
has also been reported. Isocyanides react with two equivalents
of carboxylic acids to afford the corresponding carboxylic acid
derivatives.17 Recently it has been reported that the reaction
of isocyanides with sulfonic acids lead to the corresponding
sulfonamides.20 A similar reaction was also reported between
isocyanides and carboxylic acids in methanol as solvent to
yield the corresponding carboxamides.21
Compounds 6b,c, 7b–f and 8 were all new compounds and
their structures were deduced from their elemental analyses
and spectral data.
An X-ray crystallographic study has shown29 that the stereo-
chemistry of the double bond that was formed during conden-
sation of 3 with the aldehydes has the Z-configuration in 6.
The 1H NMR spectra of products 7a–f revealed the restricted
rotation around the carbon–carbon double bond and with
the 13C NMR spectra were consistent with the presence of
only one isomer (Z-isomer). Thus the NMR spectra were in
agreement with the proposed structures.30
The 1H NMR spectrum of compound 8 exhibited one sharp
line at δ = 3.79 ppm for the proton of methoxy group. The
NH was coupled with methine proton to give a doublet (3JHH
=
8.5 HZ) at 6.63 ppm. After addition of D2O the signal assigned
to the NH proton disappeared. The two methyl groups are
diastereotopic and showed distinct signals in the NMR spectra
of compound 8 (Scheme 2). Two doublets (3JHH = 6.5 Hz) at
1.00 and 1.02 ppm and multiplets at 2.29 ppm were observed
for the two methyl groups protons and methine proton respec-
tively. The other methine proton resonates at 4.80 ppm as a
3
double doublet (3JHH = 8.5 Hz, JHH = 6.5 Hz). The aromatic
protons resonate between 7.27 and 7.82 ppm as multiplets.
Two signals were observed for the methyl groups at 17.97 and
19.67 ppm in the 13C NMR spectrum of compound 8. The
methine carbons resonated at 34.44 and 57.45 ppm. Four
signals were observed between 127.07 and 134.29 ppm for
aromatic carbons and the carbonyl carbons were observed at
167.38 and 172.67 ppm. The IR spectrum of compound 8 also
supported the suggested structure. Strong absorption bands
were observed at 3335, 1741 and 1641 cm−1 respectively for
the NH, ester and amide groups.
On the basis of the well established chemistry of isocya-
nides32–35 the formation of compound 8 can be rationalised as
shown in Scheme 3. Protonation of cyclohexyl isocyanide by
the carboxyl group followed by the nucleophilic addition
of the conjugate anion 10 on the nitrilium cation 11 led to
the iminoester 12. Cyclisation of 12 gave intermediate 13.
Nucleophile attack on 13 produced 8.
The present method has the advantage that the reaction is
performed under neutral conditions, and the components can
be mixed without any activation or modification.
In summary, we report that three-component reaction
between N-benzoyl α,β-dehydro-α-amino acid derivatives or
N-bezoylamino acids and cyclohexyl isocyanide in different
alcohols as solvent, afforded a simple route for synthesis of
N-acyl-α,β-dehydro-α-amino acid esters.
Isocyanides alone have been shown to activate phosphoric
22
acid derivatives in pyridine. Esterification of α-amino acid
derivatives has also been reported.26–28
Results and discussion
In this paper, we report the synthesis of α-substituted α-amino
esters starting from the natural amino acids, glycine and
( )valine.
The amino group of glycine was protected with the benzoyl
group as N-benzoyl glycine 3. The 2-phenyl-4H-oxazol-5-one
(4), was condensed with an aldehyde to form the oxazolones 5
which was then hydrolysed to the corresponding acids 6.
The acids 6 were treated with cyclohexyl isocyanide in
different alcohols as solvent as shown in Scheme 1. These
reaction afforded a simple route for the synthesis of N-acyl-
α,β-dehydro-α-amino acid esters 7 under neutral condition
in high yield. The reaction of N-benzoyl glycine or ( )valine
1a under the same conditions afforded N-acyl-α-substituted
α-amino acid esters 8.
When the acid 6 was added to different alcohols as a solvent
in the absence of cyclohexyl isocyanide, no product was
detected.
Compounds 5a, 6a and 7a were known and our m.p. and 1H
NMR spectroscopic data of compounds are in agreement with
previously reported NMR data.12,23–25,29,31
Experimental
Melting points were determined with an Electrothermal 9100 appara-
tus. Elemental analyses were performed using a Costech ECS 4010
* Correspondent. E-mail:ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2011 469
Scheme 1 Reagents and conditions: (i) NaOH(10%), HCl; (ii) Ac2O/ AcO−; (iii) ArCHO; (iv) NaOH/ H2O/ CH3OH; (v) H+/H2O;
(vi) Cyclohexyl isocyanide/ROH, reflux, 1h.
CHNS-O analyser at the analytical laboratory of the Islamic Azad
University Yazd branch. Mass spectra were recorded on a Finnigan-
MAT 8430 mass spectrometer operating at an ionisation potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
1H and 13C NMR spectra were recorded on Bruker DRX-500 Avance
spectrometer at solution in CDCl3 using TMS as internal standard.
The chemicals used in this work were purchased from Fluka (Buchs,
Scheme 2 Compound 8 is racemic.
Switzerland) and were used without further purification.
Scheme 3 Suggested mechanism for formation compound 8.

470 JOURNAL OF CHEMICAL RESEARCH 2011
Preparation of compounds 7b–f; general procedure
Benzyl 2-(benzamido)-3-(4-chlorophenyl)acrylate (7f): Yield: 80%;
yellow powder, m.p. 174–178 °C, IR (KBr)(νmax, cm−1): 3227 (NH);
1721 (C=O, ester); 1649 (C=O, amide). Anal. Calcd for C23H18ClNO3:
C, 70.50; H, 4.63; N, 3.57. Found: C, 70.31; H, 4.40; N, 3.76%. MS
To a magnetically stirred solution of 6 (2 mmol) in 10 mL alcohol was
added dropwise cyclohexyl isocyanide (2 mmol) The reaction mixture
was then stirred for 1 h at reflux temperature. The solvent was evapo-
rated at reduced pressure. The residue was precipitated, filtered
and washed with diethyl ether to give the pure product 7. Compound
3, 5 and 6 were prepared as previously described in the literature.29
Compounds 5a, 6a and 7a were known compounds.12,23–25,29,31
1
(m/z, %): 391 (M+, 3). H NMR (500 MHz, CDCl3): δ 5.05 (2H, s,
OCH2), 7.33 (1 H, s, CHolefinic), 7.27–7.80 (14H, m, aromatic), 7.82
(1H, s, NH). 13C NMR (125.8 MHz, CDCl3): δ 66.63 (OCH2), 124.47,
127.76, 128.09, 128.49, 128.68, 128.87, 129.00, 129.19, 129.26,
130.64, 131.31, 132.54, 132.85, 133.77, 135.51 135.70, (16C olefinic
and aromatic), 165.57 (C=O amide), 166.09 (C=O ester).
Preparation of compounds 8; general procedure
Methyl 2-(benzamido)-3-methylbutanoate (8): Yield: 84%; white
powder, m.p. 174–176 °C, IR (KBr)(νmax, cm−1): 3335 (NH), 1741
(C=O, ester), 1641 (C=O, amide). Anal. Calcd for C13H17NO3: C,
66.36; H, 7.28; N, 5.95. Found: C, 66.50; H, 7.41; N, 5.80%. MS (m/z,
%): 235 (M+, 20). 1H NMR (500 MHz, CDCl3): δ 1.00 and 1.02 (6H,
2d, 3JHH = 6.5 Hz, 2CH3), 2.29 (1H, m, CH(Me)2), 3.79 (3H, s, OCH3),
4.80 (1H, dd, 3JHH = 8.5 Hz, 3JHH = 6.5 Hz, CH), 6.63 (1H, d, 3JHH = 8.5
Hz, NH), 7.27–7.82 (5H, m, aromatic). 13C NMR (125.8 MHz, CDCl3):
δ 17.97 and 19.67 (2CH3), 31.63 (CH), 52.25 (OCH3), 57.41 (CHN),
127.07, 128.61, 131.73, 134.29 (4C aromatic), 167.38 (C=O amide),
172.67 (C=O ester).
To a magnetically stirred solution of the N-benzoyld of α-amino acids
3a (2 mmol) in 10 mL alcohol was added dropwise cyclohexyl
isocyanide (2 mmol) The reaction mixture was then stirred for 1 h
at reflux temperature. The solvent was removed under reduced pres-
sure and the residue was purified by silica-gel column chromatogra-
phy using hexane-ethyl acetate as eluent. The solvent was removed
under reduced pressure to afford the product 8.
Compound 5a had a m.p. 161–163 °C (lit. 165–166 °C), 6a had
a m.p. 180–182 °C (lit. 185–186 °C) and 7a had a m.p. 145–147 °C
(lit. 162–163 °C).
2-Benzoylamino-3-(4-chlorophenyl)acrylic acid (6b): Yellow
powder, m.p. 191–193 °C, IR (KBr)(νmax, cm−1): 3211 (NH); 1655
(C=O, amide). Anal. Calcd for C16H12ClNO3: C, 63.69; H, 4.01; N,
4.64. Found: C, 63.52; H, 4.14; N, 4.73%. MS (m/z, %): 301 (M+, 5).
1H NMR (500 MHz, CDCl3): δ 7.41 (1 H, s, CHolefinic), 7.31–7.88 (9H,
m, aromatic), 7.90 (1H, s, NH). 13C NMR (125.8 MHz, CDCl3):
δ 123.94, 129.09, 129.36, 129.57, 130.56, 131.15, 132.70, 133.08,
133.92, 135.77 (10C olefinic and aromatic), 165.69 and 166.45
(2C=O).
Received 22 June 2011; accepted 9 August 2011
Paper 1100698 doi: 10.3184/174751911X13129847175330
Published online: 29 August 2011
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3
t JHH = 7 Hz, CH3), 4.39 (2H, q, JHH = 7 Hz, OCH2), 7.53 (1 H, s,
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