Diastereoselective synthesis of 5-iminooxazolines and their subsequent transformation to α,α-disubstituted dipeptide esters: A formal [4+1] cycloaddition reaction of cyclohexyl isocyanide and Z-alkyl-α-benzoyl amino-acrylates

Article abstract of DOI:10.1016/j.tet.2012.06.073

A novel atom economical diastereoselective synthesis of 5-iminooxazolines and their subsequent transformation to α,α-disubstituted dipeptide esters is described. Heating a mixture of cyclohexyl isocyanide and Z-α-benzoyl amino-acrylic acid alkyl esters un

Full text of DOI:10.1016/j.tet.2012.06.073

Tetrahedron 68 (2012) 8046e8051
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective synthesis of 5-iminooxazolines and their subsequent
transformation to
reaction of cyclohexyl isocyanide and Z-alkyl-
a
,
a
-disubstituted dipeptide esters: a formal [4þ1] cycloaddition
a
-benzoyl amino-acrylates
,
b
,
a
c
d
Abbas Ali Esmaeili a , Shima Shahmansouri , Azizollah Habibi , Ali Reza Fakhari
*
a Chemistry Department, University of Birjand, Birjand, Iran
b Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
c Faculty of Chemistry, University of Tarbiatmoallem, 15719-14911 Tehran, Iran
d Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, G.C., PO Box 19396-4716, Evin, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2012
Received in revised form 28 May 2012
Accepted 18 June 2012
Available online 23 June 2012
A novel atom economical diastereoselective synthesis of 5-iminooxazolines and their subsequent
transformation to -disubstituted dipeptide esters is described. Heating a mixture of cyclohexyl iso-
cyanide and Z- -benzoyl amino-acrylic acid alkyl esters under solvent-free conditions, afforded 5-
iminooxazolines, which, upon specifications provided
a,a
a
a
,a
-disubstituted dipeptide esters in good yield.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5-Iminooxazolines
a
-Amidoacrylates
Cyclohexyl isocyanide
[4þ1] Cycloaddition
Solvent-free synthesis
1. Introduction
side effects, and improving the half-life of compound by minimiz-
ing enzymatic degradation.8
Peptide containing drugs typically present higher bactericidal
strength and a lower tendency for generating resistance compared
to common antibiotics, such as penicillin and sulfonamides. Nev-
ertheless, the use of peptide drugs is limited due to their low
metabolic stability and poor pharmacokinetic properties.1e3 The
fast degradation by proteases, low lipophilicity, and the lack of di-
rect transition into cells systems, are the major disadvantages of
peptide drugs. Cell membranes generally resist the transport of
most peptides, and peptide drugs are rapidly excreted through the
liver and kidney. Conformational flexibility of peptides, which, al-
lows a peptide to bind to more than one receptor, leads to un-
desired side effects, creating another problem.4,5 Incorporation of
Isocyanides have been recognized as crucial building blocks in
modern organic synthesis.9 This unusual reactivity offers constructs
substituted heterocyclic compound and has attracted significant at-
tention in recent years. This reactivity involves the a-addition of both
nucleophiles and electrophiles on the same carbon atom of the
functional group.9a Five-membered, nitrogen-containing heterocy-
cles are found in a broad number of biologically active compounds.10
In terms of five-membered ring construction, a [4þ1] mode, in which
1,3-conjugated systems act as four-atom assembling units, were
reported as an interesting reaction of isocyanides. A variety of these
[4þ1] cycloaddition reactions involving a wide range of substrates,
such as a,b
-unsaturated carbonyl compounds,11 quinonemethides,12
conformationally constrained amino acids, such as
a,
a-di-
thioxothiamides,13 azadienes,14 and vinyl isocyanates,15 with iso-
cyanides have been carried out. Among five-membered nitrogen-
containing heterocycles, the 5-iminooxazolines, are infrequently
reported in the literature, and besides its hydrolysis to dipeptides,
little is known about their chemistry. Moreover, they are valuable
substituted -amino acids into key positions of peptides chains is
a
an efficient strategy to retard proteolytic degradation and to sta-
bilize secondary structure motifs.6,7 As a result of such activities,
the advantage of the modification of natural peptides has been
showed by increasing the potency, and selectivity, decreasing the
synthetic intermediates due to the ease of hydrolyses to
a,a-di-
substituted dipeptide esters. Recently, Burger et al. reported that
imines of hexafluoroacetone and methyl 3,3,3-trifluoropyruvate, can
able to undergo [4þ1] cycloaddition with
a,a-disubstituted-a-iso-
cyanatoesters, leading to the 5-iminooxazolines, which can be easily
* Corresponding author. Tel.: þ98 511 8797022; fax: þ98 511 8796416; e-mail
addresses: abesmaeili@ferdowsi.um.ac.ir, aa_esmaeili@yahoo.com (A.A. Esmaeili).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.073

A.A. Esmaeili et al. / Tetrahedron 68 (2012) 8046e8051
8047
Table 2
Syntheses of
iminooxazolines 6 with alcoholic hydrochloric acid
hydrolyzed under mild acidic conditions to give the corresponding
-disubstituted dipeptide esters.16 In 2007, Zhu et al.17 reported that
three-component reaction of -disubstituted -isocyanoacetamide
a
,
a
-disubstituted
a
-amino acid amides
7
fromhydrolysis of 5-
a,a
a,a
a
with an aldehyde and an amine, providing access to 5-
iminooxazolines, which can be readily transformed into cyclic di-
peptides under mild acidic conditions.
In last decade, the development in the field of solvent-free re-
actions have provided organic chemists with new simple efficient
synthetic routes of great promise.18
As part of our ongoing efforts on the development of new ap-
proaches to the preparation of heterocyclic compounds,19 we report
herein a new and efficient manner for synthesis of 5-iminoxazoline
Product
X1
X2
R
Yield (%)a
7a
7b
7c
7d
H
H
H
H
NO2
NO2
CN
Pr
Bu
Me
i-Pr
55
85
96
75
with potency transform to
a,a-disubstituted a-amino acid de-
rivatives. To the best of our knowledge, the formation of 5-
iminooxazolines from the reaction of cyclohexyl isocyanide and
CN
a
Isolated yields.
Z-
studies.
For this purpose, we have utilized
a-benzoylamino acrylates were unprecedented at the time of our
a-amidoacrylates building
solvent-free condition at 190 ꢀC. The reaction was completed
within 0.5 h to produce (5Z)-ethyl 4-(4-nitrobenzyl)-5-(cyclo-
hexylimino)-4,5-dihydro-2-phenyloxazole-4-carboxylate 6a in 55%
yield (Table 1, entry 1). To explore the scope of this reaction further,
Z-alkyl 2-(benzamido)-3-(4-X2-phenyl)acrylates 4, were used un-
der similar conditions; however the reaction did not proceed for
X2¼H and X2¼EDG. It is worth noting that an electron withdrawing
group on the para position of Ph-CH]moiety (X2¼EWG) had an
important role in the reaction pathway and presence of this moiety
is essential for reaction to proceed. Two other isocyanides, tert-
butylisocyanide and 1,1,3,3-tetramethylbutylisocyanide were also
examined, but no conversion occurred.
block 4, (Scheme 1) resulting from the Erlenmeyer reaction of ar-
omatic aldehydes with hippuric acid followed by an oxazolone ring
opening alcoholysis, in the reaction with cyclohexyl isocyanide at
140e210 ꢀC, under solvent-free conditions (Table 1). On the basis of
our experience in the introduction of 5-iminooxazolines 6, we
decided to test these five-membered rings scaffolds with the goal
of obtaining
a small library N-benzoyl-N-cyclohexyl phenyl-
alaninamides as peptidomimetics scaffold 7 (Table 2).
O
O
N
CHO
X2
CO2R
X1
O
O
The structures of compounds 6aej were deduced from their
elemental analysis, mass, IR, and high-field 1H and 13C NMR spectra
(see Supplementary data). The mass spectrum of 6a displayed the
molecular ion peak at m/z 435, which is in agreement with the
proposed structure. The IR spectrum of this compound showed
b
a
N
H
CO H
+
2
N
H
X1
X1
4
3
X2
1
2
X2 = CN, NO2
R = Me, Et, n-Pr
X2
i-Pr, n-Bu
absorption bands due to the one NO2 group at 1347, and 1518 cmꢁ1
,
Scheme 1. General synthesis of alkyl Z-a-benzoylamino acrylate, reagent: (a)
CH3CO2Na/Ac2O and (b) RONa, ROH.
two C]N groups at 1645, 1738 cmꢁ1 and the carbonyl group at
1748 cmꢁ1. The 1H NMR spectrum of 6a, exhibited mutiplet signals
for the cyclohexyl ring (
stereotopic methylene protons of CH2Ph moity
3.69 ppm), a mutiplet for NCH of cyclohexyl ring (
d
¼1.09e1.75 ppm), two doublet for dia-
Table 1
Syntheses of 5-iminooxazolines 6 from reaction of Z-
alkyl esters 4 and cyclohexyl isocyanide 5
a
-benzoyl amino-acrylic acid
(d
¼3.52 and
d
¼3.59 ppm),
H
a singlet for methoxy group (
d
¼3.77 ppm), and two multiplets for
CO2R
O
the aromatic protons (
d
¼7.36e7.46 and 7.50e7.99 ppm). The 1H-
N
O
decoupled 13C NMR spectrum of 6a showed 20 distinct resonances
in agreement with the suggested structure, partial assignment of
these resonances is given in the experimental section. Charactristic
13C NMR signals were showed due to one ester carbonyl at
N
H
150-180 O
Solven-free
C
RO
X1
:C
N
+
N
X1
O
5
4
6
X2
X2
d
¼154.02 and two C]N groups at
d
¼163.6 and 168.3. The 1H and
13C NMR of 6bej are similar to those for 6a except for ester and
aromatic moieties. Unambiguous evidence for the structure and
stereochemistry of 6d was obtained from a single-crystal X-ray
analysis. An ORTEP22 diagram of 6d is shown in Fig. 1. The
Product
X1
X2
R
T (ꢀC)a
Time (h)
Yieldb
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
CN
CN
CN
CN
CN
Me
Et
Pr
i-Pr
Bu
Me
Et
190
175
175
180
150
175
155
170
210
140
185
193
0.5
1.5
2
2.5
6
1
1.25
2
1.25
2.5
0.25
2.5
55%
79%
93%
60%
54%
69%
52%
78%
68%
65%
51%
40%
Pr
i-Pr
Bu
Me
Pr
6j
6k
6l
OMe
OMe
NO2
NO2
a
Reaction Temperature.
Isolated yields.
b
2. Results and discussion
In a model reaction, Z-methyl-2-(benzamido)-3-(4-nitrophenyl)
acrylate 4,20,21 and cyclohexyl isocyanide were stirred under
Fig. 1. Single-crystal X-ray structure (ORTEP) of 6d.

8048
A.A. Esmaeili et al. / Tetrahedron 68 (2012) 8046e8051
stereochemistry was deduced from the crystallographic data and
the same configuration was assumed for the other products on
account of their NMR spectroscopic similarities.
incorporated into the desired 5-iminooxazolines, that is, this re-
action is 100% atom-economic; (2) A formal [4þ1] Cycloaddition
reaction of cyclohexyl isocyanide and Z-alkyl-a-benzoyl amino-
A mechanistic rationalization for this reaction is provided in
Scheme 2. Initially, isomerization of species 4, gives N-benzoyli-
mine intermediate 7, followed by [4þ1] cycloaddition reaction with
cyclohexyl isocyanide affords the products (path A). Addition of
acrylates, provides an efficient route to diastereoselective synthe-
sis of 5-Iminooxazolines in good yeilds; (3) The use of simple and
ready available isocyanide along with the simplicity of its method
makes it a novel route for syntheses of 5-iminooxazolines.
isocyanide 5 to
intramolecular cyclization rapidly produces product 6 (path B). The
efficient conversion of -amidoacrylate 4, involving electron
windrowing (EW) substituent in the para position of phenyl group
(X2¼NO2 and CN), supported the mechanism reaction sequence
outlines in path B.
a-amidoacrylate 4, forms intermediate 8, then
3. Experimental
3.1. General
a
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. Elemental analyses for C, H, and N
were performed using a Heraeus CHNeO-Rapid analyzer. IR spectra
were measured on a PerkineElmer 783 infrared spectrophotome-
ter. 1H and 13C NMR spectra were measured with BRUKER DRX-300
AVANCE spectrometer at 300.13 and 75.46 MHz, respectively. Mass
spectra were recorded on a Shimadzu GCeMS-QP5050 mass
spectrometer operating at an ionization potential of 70 eV iso-
cyanides were obtained from Merck (Germany) and Fluka (Buchs,
Switzerland), (Z)-alkyl 2-(benzamido)-3-aryl acrylates (a-amidoa-
crylate) prepared by known method20,21 and all materials were
used without further purification. The purity of the products and
the progress of the reactions were accomplished by TLC on silica-
gel polygram SILG/UV254 plates.
3.2. General procedure for the synthesis of products 6
(Z)-Alkyl 2-(benzamido)-3-aryl acrylate (1 mmol) was placed in
a capped test tube, and was heated to its melting point. Then
cyclohexyl isocyanide (1 mmol) was added. The mixture was stirred
for 5 min, then the temperature was increased to those stated and
stirring was continued for an appropriate time (Table 1). The re-
action mixture was cooled to room temperature. Pure product 6
was isolated by preparative plate chromatography eluted with n-
hexane:EtOAc.
Scheme 2. Proposed mechanisms for the formation of compound 6.
The synthetic scope of this new reaction is increased by the
potential for hydrolysis of the 5-iminooxazolines. For instance,
hydrolysis of 5-iminooxazolines 6c, 6e, 6f and 6i with alkoholic
hydrochloric acid16 at room temperature provides corresponding
a,a-disubstituted a-amino acid esters 7aed in good yields (Table 2).
The structures of compounds 7aed were deduced from their
elemental analysis, mass, IR, and high-field 1H and 13C NMR spectra
(see Supplementary data). The mass spectrum of 7a displayed the
molecular ion peak at m/z 481, which is in agreement with the
proposed structure. The IR spectrum of this compound showed two
NH groups at 3349, absorption bands due to the one NO2 group at
3.2.1. Methyl (5Z)-5-(cyclohexylimino)-4-(4-nitrobenzyl)-2-phenyl-
4,5-dihydro-1,3-oxazole-4-carboxylate (6a). Brown oil, 0.24 g, Yield
55%. Rf (25% EtOAc/n-hexane) 0.34; IR (KBr) (nmax, cmꢁ1): 1748 (C]
O), 1738, 1645 (C]N), 1518, 1347 (NO2). Anal. calcd for C24H25N3O5
(436): C, 66.19; H, 5.79; N, 9.65% found: C, 65.88; H, 5.82; N, 9.68%
MS (EI, 70 eV): m/z (%)¼436 (Mþþ1, 1.46), 435 (Mþ, 4.36), 376
(MþꢁCH3CO2, 2.59), 299 (MþꢁCH2C6H4NO2, 23.13), 217 (Mþþ1-
C6H11eCH2C6H4NO2, 41.19), 105 (PhCO, 100),77 (Ph, 19.81). 1H
NMR (300.13 MHz, CDCl3): dH¼1.09e1.75 (10H, m, 5 CH2 of cyclo-
1320, and 1500 cmꢁ1, two carbonyl groups at 1654 and 1725 cmꢁ1
.
The 1H NMR spectrum of 7a, exhibited triplet signal of OCH2CH2CH3
at 0.88 ppm, mutiplet signals for the cyclohexyl ring and
OCH2CH2CH3
methylene protons of CH2Ph moiety (
a mutiplets for NCH of cyclohexyl ring (
¼3.59 ppm), a doublet for
(
d
¼1.15e1.97 ppm), two diastereotopic doublet for
2
d
¼3.64 and 4.13 ppm),
hexyl), 3.52 (1H, d, JHH¼13.4 Hz, CHAHBC6H4NO2), 3.59 (1H, m,
2
d
HCeN), 3.69 (1H, d, JHH¼13.4 Hz, CHAHBC6H4NO2), 3.77 (3H, s,
NHCH (
aromatic protons
d
¼6.20 ppm), a singlet for NH-CO (7.62 ppm), along with the
OCH3), 7.36e7.47 (4H, m, arom), 7.50e7.55 (1H, m, arom), 7.86 (2H,
3
(d
¼7.36e7.46 and 7.5e7.99 ppm). The 1H-
m, arom), 7.99 (2H, d, JHH¼8.70 Hz, arom). 13C NMR (75.47 MHz,
decoupled 13C NMR spectrum of 7a showed 22 distinct resonances
in agreement with the recommended structure, partial assignment
of these resonances is given in the experimental section. Char-
CDCl3): dC¼24.5, 24.6, 25.5, 33.3, 33.5 (5 CH2 of cyclohexyl), 40.6
(CH2eC6H4NO2), 53.5 (OCH3), 58.0 (HCeN), 76.7 (C), 122.8 (2
CHarom), 125.4 (Carom), 128.1, 128.7, 131.9 (3 CHarom), 133.2 (CHarom),
142.4 (Carom), 147.1 (Carom), 154.0 (C]O), 163.6, 168.3 (2C]N).
actristic 13C NMR signals were due to two ester carbonyl at
d
¼154.0
and 166.4 and one ester carbonyl group at
NMR of 7bed are similar to those for 7a except for ester and aro-
matic moieties.
d
¼170.7. The 1H and 13
C
3.2.2. Ethyl
(5Z)-5-(cyclohexylimino)-4-(4-nitrobenzyl)-2-phenyl-
4,5-dihydro-1,3-oxazole-4-carboxylate(6b). Yellow crystal, 0.35 g,
In summary, we have introduced a new and efficient method for
the diastereoselective synthesis of 5-iminooxazolines, which could
be easily hydrolyzed under alcoholic acidic conditions to afford the
Yield 79%; mp: 104e106 ꢀC. Rf (50% EtOAc/n-hexane) 0.47; IR (KBr)
(
nmax, cmꢁ1): 1745 (C]O),1730, 1639 (C]N),1514,1341 (NO2). Anal.
Calcd for C25H27N3O5 (449): C, 66.80; H, 6.05; N, 9.35%, found: C,
67.12; H, 6.24; N, 9.45%. MS (EI, 70 eV): m/z (%)¼449 (Mþ, 1.17), 376
(MþeCH3CH2CO2, 1.98), 313 (MþeCH2C6H4NO2, 8.45), 231 (Mþþ1-
C6H11eCH2C6H4NO2, 14.57), 105 (PhCO, 100), 77 (Ph, 22.60). 1H
corresponding a,a-disubstituted a-amino acid esters with the po-
tential to undergo further hydrolysis for incorporation into key
position of peptides for use in the retardation of proteolytic deg-
radation and to stabilize secondary structure motifs. Main advan-
tages of our method are: (1) All atoms of two reactants are
3
NMR (300.13 MHz, CDCl3): dH¼1.23 (3H, t, JHH¼7.1 Hz, CH2CH3),
1.26e1.82 (10H, m, 5 CH2 of cyclohexyl), 3.52 (1H, d, 2JHH¼13.5 Hz,

A.A. Esmaeili et al. / Tetrahedron 68 (2012) 8046e8051
8049
2
CHAHBeC6H4NO2), 3.60 (1H, m, HCeN), 3.69 (1H, d, JHH¼13.5 Hz,
CHAHBeC6H4NO2), 4.15 (1H, m, OCHAHBCH3), 4.33 (1H, m,
OCHAHBCH3), 7.37e7.44 (4H, m, arom) 7.53 (1H, m, arom), 7.87 (2H,
OCHAHBeCH3CH2CH2), 7.37e7.45 (4H, m, arom), 7.54 (1H, m, arom),
7.86 (2H, m, arom), 7.99 (2H, d, 3JHH¼8.63 Hz, arom) ppm 13C NMR
(75.47
MHz,
CDCl3):
dC¼13.6
(OCH2CH2CH2CH3), 18.9
d, JHH¼7.3 Hz, arom), 7.99 (2H, d, JHH¼8.6 Hz, arom). 13C NMR
(75.47 MHz, CDCl3): dC¼14.0 (OCH2CH3), 24.5, 24.6, 25.6, 33.3, 33.5,
(5 CH2 of cyclohexyl), 40.4 (CH2eC6H4NO2), 57.9 (OCH2CH3), 62.5
(HCeN), 76.7 (C), 122.8 (2 CHarom), 125.5 (Carom), 128.1, 128.7, 131.8
(6 CHarom), 132.8 (Carom), 142.6 (CHarom), 147.1 (Carom), 154.3 (C]O),
163.6, 167.7 (2C]N).
(OCH2CH2CH2CH3), 24.6, 24.6, 25.6 (3 CH2 of cyclohexyl), 30.4
(OCH2CH2CH2CH3) 33.3, 33.5 (2 CH2 of cyclohexyl), 40.4
(CH2eC6H4NO2), 57.9 (OCH2CH2CH2CH3), 66.3 (HCeN), 77.1 (C),
122.8 (2 CHarom), 125.5 (Carom), 128.1, 128.7, 131.9 (6 CHarom), 132.8
(Carom),142.6 (CHarom),147.0 (Carom),154.2 (C]O),163.6,167.8 (2C]
N).
3
3
3.2.3. n-Propyl (5Z)-5-(cyclohexylimino)-4-(4-nitrobenzyl)-2-
phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (6c). Brown solid,
0.43 g, Yield 93%; mp: 108e110 ꢀC. Rf (50% EtOAc/n-hexane) 0.50; IR
(KBr) (nmax, cmꢁ1): 1747 (C]O),1729,1638 (C]N),1515,1341 (NO2).
Anal. calcd for C26H29N3O5 (463): C, 67.37; H, 6.31; N, 9.07% found:
C, 67.47; H, 6.32; N, 9.25%. MS (EI, 70 eV): m/z (%)¼464 (Mþþ1,1.53),
463 (Mþ, 3.93), 376 (MþꢁCO2CH2CH2CH3, 4.92), 327
(MþꢁCH2C6H4NO2, 15.90), 245 (Mþþ1-C6H11eCH2C6H4NO2, 22.50),
105 (PhCO, 100), 77 (Ph, 14.48). 1H NMR (300.13 MHz, acetone-d6):
3.2.6. Methyl (5Z)-5-(cyclohexylimino)-4-(4-cyanobenzyl)-2-phenyl-
4,5-dihydro-1,3-oxazole-4-carboxylate (6f). Yellow crystal, 0.29 g,
Yield 69%; mp: 102e104 ꢀC. Rf (25% EtOAc/n-hexane) 0.38; IR (KBr)
(
nmax, cmꢁ1): 2213 (CN), 1748 (C]O), 1730, 1639 (C]N). Anal. calcd
for C25H25N3O3 (415): C, 72.27; H, 6.06; N, 10.11% found: C, 72.51; H,
6.23; N, 10.28%. MS (EI, 70 eV): m/z (%)¼416 (Mþþ1, 3.81), 415 (Mþ,
5.84), 400 (MþꢁCH3, 0.58), 356 (MþꢁCO2CH3, 3.29), 299
(MþꢁCH2C6H4CN, 35.04), 217 (Mþþ1-C6H11eCH2C6H4CN, 61.82),
105 (PhCO, 100), 77 (Ph, 20.28). 1H NMR (300.13 MHz, CDCl3):
3
dH¼0.88 (3H, t, JHH¼7.4 Hz, OCH2CH2CH3), 1.28e1.81 (12H, m, 5
dH¼1.21e1.76 (10H, m,
5 CH2 of cyclohexyl), 3.47 (1H, d,
2
CH2 of cyclohexyl, OCH2CH2CH3), 3.51 (1H, d, JHH¼13.5 Hz,
2JHH¼13.5 Hz, CHAHBeC6H4CN), 3.56 (1H, m, HCeN), 3.64 (1H, d,
2JHH¼13.5 Hz, CHAHBeC6H4CN), 3.77 (3H, s, OCH3), 7.32 (2H, d,
3JHH¼8.0 Hz, arom), 7.41e7.45 (4H, m, arom), 7.51e7.56 (1H, m,
arom), 7.87 (2H, d, 3JHH¼7.3 Hz, arom). 13C NMR (75.47 MHz, CDCl3):
dC¼24.55, 24.7, 25.6, 33.3, 33.5 (5 CH2 of cyclohexyl), 41.0
(CH2C6H4CN), 53.5 (OCH3), 58.0 (HCeN), 76.7 (C), 111.0 (CN), 118.8,
125.5 (2Carom), 128.1, 128.7, 131.5, 131.8 (8 CHarom), 132.9 (Carom),
140.3 (CHarom), 154.1(C]O), 163.5, 168.3 (2C]N).
2
CHAHBeC6H4NO2), 3.66 (1H, m, HCeN), 3.70 (1H, d, JHH¼13.5 Hz,
CHAHBeC6H4NO2), 4.07 (1H, m, OCHAHBCH2CH3), 4.22 (1H, m,
OCHAHBCH2CH3), 7.47e7.53 (4H, m, arom), 7.61 (1H, m, arom),
7.90e7.94 (2H, m, arom), 8.04e7.08 (2H, m, arom). 13C NMR
(75.47 MHz, acetone-d6): dC¼10.5 (OCH2CH2CH3), 22.5
(OCH2CH2CH3), 25.0, 25.0, 26.3, 34.1, 34.5 (5 CH2 of cyclohexyl),
40.9 (CH2-C6H4NO2), 58.2 (OCH2CH2CH3), 68.2 (HCeN), 77.5 (C),
123.4 (2 CHarom), 126.6 (Carom), 128.8, 129.7, 133.0 (6 CHarom), 133.7
(Carom), 143.8 (CHarom), 148.0 (Carom), 155.1 (C]O), 164.2, 168.5
(2C]N).
3.2.7. Ethyl (5Z)-5-(cyclohexylimino)-4-(4-cyanobenzyl)-2-phenyl-
4,5-dihydro-1,3-oxazole-4-carboxylate (6g). Yellow precipitation,
0.22 g, Yield 52%; mp: 117e118 ꢀC. Rf (25% EtOAc/n-hexane) 0.40; IR
(KBr) (nmax, cmꢁ1): 2218 (CN), 1745 (C]O), 1728, 1640 (C]N). Anal.
Calcd for C26H27N3O3 (429): C, 72.71; H, 6.34; N, 9.78% found: C,
73.00; H, 6.46; N, 9.87%. MS (EI, 70 eV): m/z (%)¼430 (Mþþ1, 1.18),
429 (Mþ, 6.13), 400 (MþꢁCH2CH3, 1.16), 356 (MþꢁCH2CH3CO2, 5.35),
313 (MþꢁCH2C6H4CN, 23.55), 231 (Mþþ1-C6H11eCH2C6H4CN,
37.29), 105 (PhCO, 100), 77 (Ph, 15.12). 1H NMR (300.13 MHz, CDCl3):
dH¼1.11e2.01 (13H, m, 5 CH2 of cyclohexyl, OCH2CH3), 3.48 (1H, d,
2JHH¼13.49 Hz, CHAHBeC6H4CN), 3.57 (1H, m, HCeN), 3.65 (1H, d,
2JHH¼13.5 Hz, CHAHBeC6H4CN), 4.17 (1H, m, OCHAHBCH3), 4.34 (1H,
3.2.4. Isopropyl (5Z)-5-(cyclohexylimino)-4-(4-nitrobenzyl)-2-
phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate(6d). Yellow crystals,
0.28 g, Yield 60%; mp: 140e143 ꢀC. Rf (40% EtOAc/n-hexane) 0.46;
IR (KBr) (nmax, cmꢁ1): 1742 (C]O), 1732, 1637 (C]N), 1514, 1339
(NO2). Anal. calcd for C26H29N3O5 (463): C, 67.37; H, 6.31; N, 9.07%
found: C, 67.15; H, 6.12; N, 9.21% MS (EI, 70 eV): m/z (%)¼464
(Mþþ1, 1.83), 463 (Mþ, 3.74), 376 (Mþꢁ(CH3)2CHCO2, 7.71), 327
(MþꢁCH2C6H4NO2, 12.57), 245 (Mþþ1-C6H11, CH2C6H4NO2, 7.97),
105 (PhCO, 100), 77 (Ph, 15.12). 1H NMR (300.13 MHz, acetone-d6):
3
3
3
dH¼1.18 (3H, d, JHH¼6.3 Hz, CH3), 1.21 (3H, d, JHH¼6.23 Hz, CH3),
m, OCHAHBCH3), 7.31e7.59 (7H, m, arom), 7.88 (2H, d, JHH¼7.5 Hz,
1.26e1.76 (10H, m, 5 CH2 of cyclohexyl), 3.49 (1H, d, 2JHH¼13.4 Hz,
arom). 13C NMR (75.47 MHz, CDCl3): dC¼14.0 (OCH2CH3), 24.6, 24.6,
25.6, 33.3, 33.6 (5 CH2 of cyclohexyl), 40.8 (CH2C6H4CN), 57.9
(OCH2CH3), 62.5 (HCeN), 76.7 (C), 110.9 (CN), 118.9, 125.6 (2Carom),
128.1, 128.7, 131.4, 131.8 (8 CHarom), 132.8 (Carom), 140.4 (CHarom),
154.3 (C]O), 163.5, 167.8 (2C]N).
2
CHAHBeC6H4NO2), 3.67 (1H, m, HCeN), 3.68 (1H, d, JHH¼13.4 Hz,
3
CHAHBC6H4NO2), 5.06 (1H, sep, JHH¼6.24 Hz, (CH3)2CHCO2),
7.47e7.53 (4H, m, arom), 7.61 (1H, m, arom), 7.90e7.93 (2H, m,
arom), 8.04e8.08 (2H, m, arom). 13C NMR (75.47 MHz, acetone-d6):
dC¼21.5, 21.6 [(CH3)2CHCO2], 25.0, 26.4, 34.1, 34.3, (5 CH2 of cyclo-
hexyl), 40.8 (CH2eC6H4NO2), 58.1 [(CH3)2CHCO2], 70.6 (HC-N), 77.5
(C), 123.4 (2 CHarom), 126.7 (Carom), 128.8, 129.7, 133.0 (6 CHarom),
133.7 (Carom), 144.0 (CHarom), 148.0 (Carom), 155.2 (C]O), 164.1, 167.9
(2C]N).
3.2.8. n-Propyl (5Z)-5-(cyclohexylimino)-4-(4-cyanobenzyl)-2-
phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (6h). Yellow solid,
0.34 g, Yield 78%; mp: 122e125 ꢀC. Rf (25% EtOAc/n-hexane) 0.38; IR
(KBr) (nmax, cmꢁ1): 2208 (CN), 1741 (C]O), 1731, 1641 (C]N). Anal.
Calcd for C27H29N3O3 (443): C, 73.11; H, 6.59; N, 9.47% found: C, 73.33;
H, 6.72; N, 9.39%. MS (EI, 70 eV): m/z (%)¼444 (Mþþ1, 2.15), 443 (Mþ,
4.63), 400 (MþꢁCH2CH2CH3, 1.22), 356 (MþꢁCO2CH2CH2CH3, 6.16),
327 (MþꢁCH2C6H4CN, 20.27), 245 (Mþþ1-C6H11, CH2C6H4CN, 30.29),
3.2.5. n-Butyl (5Z)-5-(cyclohexylimino)-4-(4-nitrobenzyl)-2-phenyl-
4,5-dihydro-1,3-oxazole-4-carboxylate (6e). Yellow precipitation,
0.26 g, Yield 54%; mp: 99e101 ꢀC. Rf (40% EtOAc/n-hexane) 0.41; IR
(KBr) (nmax, cmꢁ1): 1740 (C]O), 1726, 1640 (C]N), 1512, 1335
(NO2). Anal. Calcd for C27H31N3O5 (477): C, 67.91; H, 6.54; N, 8.80%
found: C, 68.01; H, 6.34; N, 8.71%. MS (EI, 70 eV): m/z (%)¼478
(Mþþ1, 1.72), 477 (Mþ, 3.68), 376 (MþꢁCO2CH2CH2CH2CH3, 4.75),
341 (MþꢁCH2C6H4NO2, 13.97), 259 (MþꢁC6H11eCH2C6H4NO2,
105 (PhCO,100), 77 (Ph, 16.24). 1H NMR (300.13 MHz, CDCl3):
d¼0.88
3
(3H, t, JHH¼7.4 Hz, OCH2CH2CH3), 1.21e1.78 (12H, m, 5 CH2 of
cyclohexyl, OCH2CH2CH3), 3.48 (1H, d, 2JHH¼13.5 Hz,
2
CHAHBeC6H4NO2), 3.58 (1H, m, HCeN), 3.65 (1H, d, JHH¼13.4 Hz,
CHAHBeC6H4NO2), 4.06 (1H, m, OCHAHBCH2CH3), 4.23 (1H, m,
OCHAHBCH2CH3), 7.33 (2H, d, 3JHH¼8.1 Hz, arom), 7.42e7.46 (4H, m,
arom), 7.54 (1H, m, arom), 7.87 (2H, d, 3JHH¼7.3 Hz, arom). 13C NMR
(75.47 MHz, CDCl3): dC¼10.2 (OCH2CH2CH3), 21.8 (OCH2CH2CH3),
24.6, 24.7, 25.6, 33.3, 33.5 (5 CH2 of cyclohexyl), 40.7 (CH2eC6H4CN),
57.9 (OCH2CH2CH3), 67.9 (HCeN), 76.7 (C), 110.8 (CN), 118.9, 125.6
17.05), 105 (PhCO, 100), 77 (Ph, 11.70). 1H NMR (300.13 MHz, CDCl3):
3
d
¼0.87 (3H, t, OCH2CH2CH2CH3, JHH¼7.37 Hz), 1.21e1.78 (14H, m,
2
5CH2 of cyclohexyl, OCH2CH2CH2CH3), 3.52 (1H, d, JHH¼13.51 Hz,
CHAHBeC6H4NO2), 3.59 (1H, m, HCeN), 3.70 (1H, d, 2JHH¼13.48 Hz,
CHAHBeC6H4NO2), 4.11 (1H, m, OCHAHBCH3CH2CH2), 4.28 (1H, m,

8050
A.A. Esmaeili et al. / Tetrahedron 68 (2012) 8046e8051
(2Carom),128.1, 128.7, 131.4, 131.8 (8 CHarom), 132.8 (Carom), 140.4
(CHarom), 154.3 (C]O), 163.5, 167.9 (2C]N).
solid, 0.19 g, Yield 40%; mp: 58.5e61.5 ꢀC. Rf (25% EtOAc/n-hexane)
0.45; IR (KBr) (nmax, cmꢁ1): 1739 (C]O), 1712, 1621 (C]N), 1512,
1335 (NO2). Anal. Calcd for C27H31N3O6 (493): C, 65.71; H, 6.33; N,
8.51% found: C, 66.01; H, 6.22; N, 8.62%. MS: m/z (%)¼493 (Mþ,
1.03), 407 (MþꢁCO2CH2CH2CH3, 39.28), 358 (Mþþ1e CH2C6H4NO2,
87.50), 274 (MþꢁCO2CH2CH2CH3eMeO-PhCO, 66.07), 135
(MeOePhCO, 100). 1H NMR (300.13 MHz, CDCl3): dH¼0.88 (3H, t,
3JHH¼7.5 Hz, OCH2CH2CH3), 1.21e1.69 (1.78) (10H, m, 5 CH2 of
cyclohexyl), 3.51 (1H, d, 2JHH¼13.5 Hz, CHAHBeC6H4NO2), 3.55e3.60
3.2.9. Isopropyl (5Z)-5-(cyclohexylimino)-4-(4-cyanobenzyl)-2-
phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (6i). Brown solid,
0.30 g, Yield 68%; mp: 130e133 ꢀC. Rf (30% EtOAc/n-hexane) 0.50; IR
(KBr) (nmax, cmꢁ1): 2213 (CN),1743 (C]O),1730,1640 (C]N).). Anal.
Calcd for C27H29N3O3 (443): C, 73.11; H, 6.59; N, 9.47% found: C,
72.81; H, 6.45; N, 9.60%. MS (EI, 70 eV): m/z (%)¼443 (Mþ, 1.03), 356
(Mþꢁ(CH3)2CHCO2, 3.97), 327 (MþꢁCH2C6H4CN, 5.21), 245 (Mþþ1-
C6H11eCH2C6H4CN, 5.61), 77 (Ph, 21.42). 1H NMR (300.13 MHz, ac-
etone-d6): dH¼1.17 [3H, AB system, 3JHH¼6.3 Hz, OCH(CH3)A(CH3)B],
1.20 [3H, AB system, 3JHH¼6.3 Hz, OCH(CH3)A(CH3)B],1.25e1.81 (10H,
m, 5 CH2 of cyclohexyl), 3.43 (1H, d, 2JHH¼13.5 Hz, CHAHBeC6H4CN),
3.62 (1H, d, 2JHH¼13.5 Hz, CHAHBC6H4CN), 3.68 (1H, m, HCeN), 5.05
[1H, sep., 3JHH¼6.2 Hz, OCH(CH3)2], 7.43 (2H, d, 3JHH¼8.2 Hz, CHarom),
7.51 (4H, m, arom), 7.61 (1H, m, arom), 7.91 (2H, m, arom). 13C NMR
(75.47 MHz, acetone-d6): dC¼21.6, 21.6 (OCH(CH3)2), 25.0, 26.3, 34.1,
34.2, (5 CH2 of cyclohexyl), 41.1 (CH2eC6H4CN), 58.0 (OCH(CH3)2),
70.5 (HCeN), 77.5 (C), 111.5 (CN), 119.2, 126.7 (2Carom),128.7, 129.7,
132.2, 132.8 (8 CHarom), 133.7 (Carom), 141.7 (CHarom), 155.2 (C]O),
164.0, 167.9 (2C]N).
2
(1H, m, HCeN), 3.68 (1H, d, JHH¼13.5 Hz, CHAHBeC6H4NO2), 3.85
(3H, s, CH3O), 4.03e4.11 (1H, m, OCHAHBCH2CH3), 4.20e4.28 (1H,
3
m, OCHAHBCH2CH3), 6.91 (2H, d, JHH¼8.6 Hz, arom), 7.39 (2H, d,
3
3JHH¼8.4 Hz, arom), 7.82 (2H, d, JHH¼8.5 Hz, arom), 7.99 (2H, d,
3JHH¼8.2 Hz, arom). 13C NMR (75.47 MHz, CDCl3): dC¼10.2
(OCH2CH2CH3), 21.8 (OCH2CH2CH3), 24.6, 24.7, 25.6, 33.3, 33.6 (5
CH2 of cyclohexyl), 40.4 (CH2eC6H4NO2), 55.5 (OCH3), 57.9
(OCH2CH2CH3), 67.9 (HCeN), 76.6 (C), 114.1 (2 CHarom), 117.6 (Carom),
122.8, 130.0, 131.9 (6 CHarom), 142.8, 147.0 (3Carom), 154.5 (C]O),
163.3, 168.1 (2C]N) ppm.
3.3. General procedure for the synthesis of 7a
A solution of 6 (1 mmol) in corresponding alcohol (3 mL) was
stirred with 4 drops of 1 N HCl at rt. The progress of the reaction
was monitored by TLC (ethyl acetate/hexanes). After evaporation of
the solvent, the residue was dissolved in methylene chloride and
washed with NaHCO3 solution, with water and dried over Na2SO4.
After evaporation of the solvent, produce the desired products 7.
3.2.10. n-Butyl (5Z)-5-(cyclohexylimino)-4-(4-cyanobenzyl)-2-
phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (6j). Yellow solid,
0.29 g, Yield 65%; mp: 124e126 ꢀC. Rf (40% EtOAc/n-hexane) 0.44;
IR (KBr) (nmax, cmꢁ1): 2213 (CN), 1748 (C]O), 1722, 1642 (C]N).
Anal. Calcd for C28H31N3O3 (457): C, 73.50; H, 6.83; N, 9.18% found:
C, 73.64; H, 6.94; N, 9.34%. MS (EI, 70 eV): m/z (%)¼458 (Mþþ1,
1.24), 457 (Mþ, 2.25), 356 (MþꢁCO2CH2CH2CH2CH3, 4.05), 341
(MþꢁCH2C6H4CN, 12.18), 259 (Mþþ1-C6H11eCH2C6H4CN, 21), 105
(PhCO, 100), 77 (Ph, 25.02). 1H NMR (300.13 MHz, CDCl3): dH¼0.87
3.3.1. N-Benzoyl-N-cyclohexyl-4-nitro-a-(propoxycarbonyl) phenyl-
alaninamide (7a). Yellow solid, 0.27 g, Yield 55%; mp: 162e164 ꢀC.
IR (KBr) (nmax, cmꢁ1): 3349 (NH), 1725, 1654 (C]O), 1500, 1320
(NO2). Anal. Calcd for C26H31N3O6 (481): C, 64.85; H, 6.49; N, 8.73%
found: C, 65.03; H, 6.50; N, 8.5%. MS: m/z (%)¼481 (1.03) [Mþ], 356
(29.09) (Mþþ1-C6H11NHCO), 279 (54.53) (MþꢁC6H11NHCOePh),
137 (100) (CH2C6H4NO2), 105 (55.62) (PhCO). 1H NMR (300.13 MHz,
CDCl3): dH¼0.88 (3H, t, 3JHH¼7.5 Hz, OCH2CH2CH3), 1.15e1.99 (12H,
3
(3H, t, JHH¼7.3 Hz, OCH2CH2CH2CH3), 1.25e1.78 (14H, m, 5 CH2 of
2
cyclohexyl, OCH2CH2CH2CH3), 3.47 (1H, d, JHH¼13.5 Hz,
2
CHAHBeC6H4NO2), 3.57 (1H, m, HCeN), 3.65 (1H, d, JHH¼13.5 Hz,
CHAHBeC6H4NO2), 4.10 (1H, m, OCHAHBCH3CH2CH2), 4.28 (1H, m,
3
OCHAHBCH3CH2CH2), 7.32 (2H, d, JHH¼8.18 Hz, arom), 7.41e7.46
2
(4H, m, arom), 7.54 (1H, m, arom), 7.85e7.88 (2H, m, arom). 13C
NMR (75.47 MHz, CDCl3): dC¼13.7 (OCH2CH2CH2CH3), 18.9
(OCH2CH2CH2CH3), 24.6, 24.7, 25.6 (3 CH2 of cyclohexyl), 30.4
(OCH2CH2CH2CH3), 33.3, 33.5 (2 CH2 of cyclohexyl), 40.7
(CH2eC6H4CN), 57.88 (OCH2CH2CH2CH3), 66.24 (HCeN), 77.1 (C),
110.8 (CN), 118.6, 125.6 (2Carom),128.1, 128.7, 131.4, 131.8 (8 CHarom),
132.8 (Carom), 140.5 (CHarom), 154.3 (C]O), 163.5, 167.9 (2C]N).
m, 5 CH2 of cyclohexyl, OCH2CH2CH3), 3.64 (1H, d, JHH¼14.0 Hz,
CHAHBeC6H4NO2), 3.71e3.82 (1H, m, HCeN), 4.13 (1H, d,
2JHH¼14.0 Hz, CHAHBeC6H4NO2), 4.14e4.25 (2H, m, OCH2CH2CH3),
3
3
6.20 (1H, d, JHH¼8.0 Hz, CHNH), 7.24 (2H, t, JHH¼8.7 Hz, arom),
7.45 (2H, m, arom), 7.55 (1H, m, arom), 7.62 (1H, s, NH), 7.74 (2H, m,
arom), 8.07 (2H, d, JHH¼8.7 Hz, arom). 13C NMR (75.47 MHz,
3
CDCl3): dC¼10.3 (OCH2CH2CH3), 21.8 (OCH2CH2CH3), 24.6, 24.7,
25.3, 32.7, 32.9 (5 CH2 of cyclohexyl), 38.7 (CH2eC6H4NO2), 49.5
(HCeN), 66.7 (C), 68.6 (OCH2CH2CH3), 123.4, 127.0, 128.8, 130.8 (8
CHarom), 132.2 (CHarom), 133.4, 142.9, 147.3 (3Carom), 164.5, 166.4,
170.2 (3C]O).
3.2.11. Methyl (5Z)-5-(cyclohexylimino)-2-(4-methoxyphenyl)-4-(4-
nitrobenzyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (6k). Brown oil,
0.24 g, Yield 51%. Rf (30% EtOAc/n-hexane) 0.37; IR (KBr) (nmax
,
cmꢁ1): 1735 (C]O),1726, 1612 (C]N),1510,1320 (NO2). Anal. Calcd
for C25H27N3O6 (465): C, 64.50; H, 5.85; N, 9.03% found: C, 64.20; H,
5.95; N, 8.96%. MS (EI, 70 eV): m/z (%)¼465 (Mþ, 4.13), 450
(MþꢁCH3, 2.58), 406 (MþꢁCO2CH3, 3.29), 344 (MþꢁCH2C6H4OMe,
25.04), 105 (PhCO, 100), 77 (Ph, 23.28). 1H NMR (300.13 MHz,
CDCl3): dH¼1.15e1.74 (10H, m, 5 CH2 of cyclohexyl), 3.50 (1H, d,
2JHH¼13.4 Hz, CHAHBC6H4NO2), 3.57 (1H, m, HCeN), 3.66 (1H, d,
2JHH¼13.4 Hz, CHAHBC6H4NO2), 3.76 (3H, s, OCH3), 3.82 (3H, s,
3. 3. 2. N-Benzoyl-
nitrophenylalaninamide (7b). Yellow Oil, 0.43 g, Yield 85%. IR (KBr)
nmax, cmꢁ1): 3354 (NH), 1653, 1730 (C]O), 1502, 1345 (NO2). Anal.
a-(butoxycarbonyl)-N-cyclohexyl-4-
(
Calcd for C28H33N3O6 (495): C, 65.44; H, 6.71; N, 8.48% found: C,
65.63; H, 6.54; N, 8.31%. MS: m/z (%)¼495 (Mþ, 1.75), 370 (Mþþ1-
C6H11NHCO, 42.11), 296 (MþꢁC6H11NHCO, OCH2CH2CH2CH3,
29.82), 149 (CH2CH2C6H4NO2, 100), 105 (PhCO, 75.43). 1H NMR
(300.13 MHz, CDCl3): dH¼0.86 (3H, t, 3JHH¼7.4 Hz, OCH2CH2CH2CH3),
1.12e1.94 (14H, m, 5 CH2 of cyclohexyl, OCH2CH2CH2CH3), 3.64 (1H,
3
3
CO2CH3), 6.90 (2H, d, JHH¼8.9 Hz, arom), 7.37 (1H, d, JHH¼8.6 Hz,
3
3
arom), 7.80 (2H, d, JHH¼8.8 Hz, arom), 7.98 (2H, d, JHH¼8.6 Hz,
arom). 13C NMR (75.47 MHz, CDCl3): dC¼24.6, 24.7, 25.6, 33.3, 33.5
(5 CH2 of cyclohexyl), 40.7 (CH2eC6H4NO2), 53.4 (CO2CH3), 55.5
(OCH3), 57.9 (HCeN), 76.5 (C), 114.1 (2 CHarom), 117.6 (Carom), 122.8,
130.0, 131.9 (6 CHarom), 142.6, 147.0 (3Carom), 154.3 (C]O), 163.3,
168.5 (2C]N) ppm.
2
d, JHH¼14.0 Hz, CHAHBeC6H4NO2), 3.71e3.83 (1H, m, HCeN), 4.13
2
(1H, d, JHH¼14.1 Hz, CHAHBeC6H4NO2), 4.18e4.26 (2H, m,
3
OCH2CH2CH2CH3), 6.2 (1H, d, JHH¼8.0 Hz, CHNH), 7.2 (2H, d,
3JHH¼8.6 Hz, arom), 7.4e7.6 (3H, m, arom), 7.6 (1H, s, NH), 7.74 (2H, d,
3
3JHH¼7.2 Hz, arom), 8.1 (2H, d, JHH¼8.6 Hz, arom). 13C NMR
(75.47
MHz,
CDCl3):
dC¼13.5
(OCH2CH2CH2CH3),
18.9
3.2.12. Propyl (5Z)-5-(cyclohexylimino)-2-(4-methoxyphenyl)-4-(4-
(OCH2CH2CH2CH3), 24.6, 24.7, 25.3 (3 CH2 of cyclohexyl), 30.3
(OCH2CH2CH2CH3), 32.7, 32.9 (2 CH2 of cyclohexyl), 38.7
nitrobenzyl)-4,5-dihydro-1,3-oxazole-4-carboxylate
(6l). Brown

A.A. Esmaeili et al. / Tetrahedron 68 (2012) 8046e8051
8051
(CH2eC6H4NO2), 49.5 (HCeN), 66.7 (C),66.8 (OCH2CH2CH2CH3),
References and notes
123.4, 127.0, 128.8, 130.8 (8 CHarom),132.2 (CHarom),133.4,142.9,147.3
(3Carom), 164.5, 166.4, 170.2 (3C]O).
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G. R.; Clarc, J. D.; Dunbar, J. B., Jr.; Smith, G. D.; Zabrocki, J.; Redlinski, A. S.;
Leplawy, M. T. Int. J. Pept. Protein Res. 1988, 32, 544e555.
3.3.3. N-Benzoyl-4-cyano-N-cyclohexyl-a-(methoxycarbonyl) phe-
nylalaninamide (7c). Yellow Oil, 0.43 g, Yield 96%. IR (KBr) (nmax
,
cmꢁ1): 3354 (NH), 2213 (CN), 1735, 1649 (C]O). Anal. Calcd for
C25H27N3O4 (433): C, 69.27; H, 6.28; N, 9.69% found: C, 69.01; H,
6.44; N, 9.78%. MS: m/z (%)¼433 (1.03) [Mþ], 308 (24.06) (Mþþ1-
C6H11NHCO), 230 (44.53) (MþꢁC6H11NHCO, Ph), 137 (100)
(CH2C6H4NO2), 105 (55.62) (PhCO). 1H NMR (300.13 MHz, CDCl3):
dH¼1.16e1.92 (10H, m,
5 CH2 of cyclohexyl), 3.61 (1H, d,
2JHH¼14.0 Hz, CHAHBeC6H4CN), 3.75 (1H, m, HCeN), 3.81 (3H, s,
7. Lombardi, A.; De Simone, G.; Galdiero, S.; Nastri, F.; Di Costanzo, L.; Makihira,
K.; Yamada, T.; Pavone, V. Biopolymers 2000, 53, 182e188.
2
OCH3), 4.06 (1H, d, JHH¼14.0 Hz, CHAHBeC6H4CN), 6.22 (1H, d,
3JHH¼9.0 Hz, CHNH), 7.16 (2H, d, 3JHH¼8.1 Hz, arom), 7.42e7.57 (5H,
m, arom), 7.61 (1H, s, NH), 7.74 (2H, d, 3JHH¼7.2 Hz, arom). 13C NMR
(75.47 MHz, CDCl3): dC¼24.6, 24.7, 25.3, 32.6, 32.8 (5 CH2 of
cyclohexyl), 38.9 (CH2eC6H4CN), 49.5 (HCeN), 53.8 (C), 66.7
(OCH3), 111.3 (CN), 118.7 (Carom), 127.1, 128.8, 130.7, 132.0 (8 CHarom),
132.2 (CHarom), 133.3, 140.6 (2Carom), 164.4, 166.4, 170.8 (3C]O).
8. Peggion, C.; Crisma, M.; Formaggio, F.; Toniolo, C.; Wright, K.; Wakselman, M.;
Mazaleyrat, J.-P. Biopolymers 2002, 63, 314e324.
€
9. For reviews on isocyanides in organic synthesis, see: (a) Domling, A.; Ugi, I. An-
gew. Chem., Int. Ed. 2000, 39, 3168e3210; (b) Josien, H.; Ko, S.-B.; Bom, D.; Curran,
D. P. Chem.dEur. J.1998, 4, 67e83; (c) Saegusa, T.; Ito, Y. Synthesis 1975, 291e300.
10. (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045e1075; (b) Gilchrist, T.
L. J. Chem. Soc., Perkin Trans. 1 1998, 615e628; (c) Nobuyoshi, A.; Akihiko, O.;
Chikara, M.; Tatsuya, T.; Masami, O.; Hiromitsu, S. J. Med. Chem. 1999, 42,
2946e2960; (d) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005,
44, 606e609; (e) Torok, M.; Abid, M.; Mhadgut, S. C.; Torok, B. Biochemistry
2006, 45, 5377e5383.
3.3.4. N-Benzoyl-4-cyano-N-cyclohexyl-a-(isopropoxycarbonyl)
11. Ito, Y.; Kato, H.; Saegusa, T. J. Org. Chem. 1982, 47, 741e743.
phenylalaninamide (7d). Yellow solid, 0.35 g, Yield 75%; mp:
175e177 ꢀC, IR (KBr) (nmax, cmꢁ1): 3349 (NH), 2213 (CN), 1731, 1653
(C]O). Anal. Calcd for C27H31N3O4 (461): C, 70.26; H, 6.77; N, 9.10%
found: C, 70.35; H, 6.84; N, 9.21%. MS: m/z (%)¼461 (Mþ, 3.57), 336
(Mþþ1-C6H11NHCO, 87.50), 276 [MþꢁC6H11NHCO, OCH(CH3)2,
63.63], 231 (CH2C6H4NO2, PhCO, 32.72), 105 (PhCO, 100).1H NMR
(300.13 MHz, CDCl3): dH¼1.10e1.96 [16H, m, 5 CH2 of cyclohexyl,
12. Nair, V.; Menon, R. S.; Vinod, A. U.; Viji, S. Tetrahedron Lett. 2002, 43, 2293e2295.
13. Morel, G.;Marchand, E.;Sinbandhit,S.;Carlier, R.Eur. J. Org.Chem. 2001, 6655e6662.
14. Atlan, V.; Buron, C.; El Kaïm, L. Synlett 2000, 489e490.
15. Rigby, J. H.; Deur, C.; Heeg, M. J. Tetrahedron Lett. 1999, 40, 6887e6890.
€
16. Koksch, B.; Mutze, K.; Osipov, S. N.; Golubev, A. S.; Burger, K. Tetrahedron Lett.
2000, 41, 3825e3828.
17. Pirali, T.; Cesare Tron, G.; Masson, G.; Zhu, J. Org. Lett. 2007, 9, 5275e5278.
18. Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003.
19. (a) Esmaeili, A. A.; Bodaghi, A. Tetrahedron 2003, 59, 1169e1171; (b) Esmaeili, A.
A.; Darbanian, M. Tetrahedron 2003, 59, 5545e5548; (c) Esmaeili, A. A.; Zen-
degani, H. Tetrahedron 2005, 61, 4031e4034; (d) Esmaeili, A. A.; Amini, S.;
Bodaghi, A. Synlett 2007, 1452e1454; (e) Esmaeili, A. A.; Nasseri, M. A.; Vesa-
lipoor, H.; Bijanzadeh, H. ARKIVOC 2008, xv, 343e349; (f) Esmaili, A. A.; Vesa-
lipoor, H. Synthesis 2009, 1635e1638.
2
(CH3)2CHO], 3.58 (1H, d, JHH¼14.0 Hz, CHAHBeC6H4CN), 3.77 (1H,
2
m, HCeN), 4.05 (1H, d, JHH¼14.0 Hz, CHAHBeC6H4CN), 5.13 [1H,
sep, 3JHH¼6.3 Hz, (CH3)2CHO], 6.16 (1H, d, 3JHH¼8.2 Hz, CHNH), 7.17
(2H, d, 3JHH¼8.26 Hz, arom), 7.42e7.57 (6H, m, arom, NH), 7.71 (2H,
m, arom). 13C NMR (75.47 MHz, CDCl3): dC¼21.4, 21.5 [(CH3)2CHO],
24.7, 24.7, 25.3, 32.7, 32.9 (5 CH2 of cyclohexyl), 38.8 (CH2eC6H4CN),
49.3 (HCeN), 66.7 (C), 70.8 [(CH3)2CHO], 111.2 (CN), 118.7 (Carom),
126.9, 128.8, 130.7, 132.0 (8 CHarom), 132.1 (CHarom), 133.7, 140.9
(2Carom), 164.6, 166.4, 169.5 (3C]O).
20. Mesaik, M. A.; Rahat, S.; Khan, K. M.; Ullah, Z.; Choudhary, M. I.; Murad, S.;
Ismail, Z.; Rahman, A.; Ahmada, A. Bioorg. Med. Chem. 2004, 12, 2049e2057.
21. Cleary, T.; Brice, J.; Kennedy, N.; Chavez, F. Tetrahedron Lett. 2010, 51, 625e628.
22. Crystal data for 6d C26H29N3O5 (CCDC 823597): MW¼463.52, monoclinic, space
ꢀ
ꢀ
ꢀ
a
group ’P 21/c, a¼10.440(2) A, b¼14.726(3) A, c¼16.917(3) A,
¼90.00 ¼105.
b
3
ꢀ
3
59(3),
dimension 0.5ꢂ0.6ꢂ0.4 mm, radiation, Mo K
intensity data were collected at 120(2) K with a Bruker APEX area-detector
diffractometer, and employing /2 scanning technique, in the range of
direct
g
¼90.00, V¼2505.1(9) A , Z¼4, Dc¼1.229 mg/m , F (000)¼984, crystal
ꢀ
a
(
l¼0.71073 A), 2.45ꢃ2 ꢃ29.19,
q
u
q
ꢁ14ꢃhꢃ10, ꢁ19ꢃkꢃ20, ꢁ23ꢃlꢃ23; the structure was solved by
a
Supplementary data
method, all non-hydrogen atoms were positioned and anisotropic thermal
parameters refined from 4456 observed reflections with R (into)¼0.1750 by
a full-matrix least-squares technique converged to R¼0.1358and Raw¼0.3567
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.073.
[I>2s(I)].