An efficient and diastereoselective synthesis of hydrazino amides via a novel one-pot three-component reaction

Article abstract of DOI:10.1016/j.tet.2013.02.056

An efficient one-pot three-component synthesis of a series of α-hydrazino amides, obtained in high diastereoselectivity and yield, was realized starting from cyclic ketones, hydrazides, and isocyanides in the presence of 10 mol % p-TsOH in ethanol at room temperature. The synthetic protocol was optimized and the observed diastereoselectivity was measured using ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2013.02.056

Tetrahedron 69 (2013) 3480e3485
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient and diastereoselective synthesis of hydrazino amides via
a novel one-pot three-component reaction
,
b
a,c
Sorour Ramezanpour a, Saeed Balalaie a , Frank Rominger , Hamid Reza Bijanzadeh
*
a Peptide Chemistry Research Center, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b
€
Organisch-Chemisches Institut der Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
c Department of Chemistry, Tarbiat Modares University, PO Box 141115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot three-component synthesis of a series of
a-hydrazino amides, obtained in high
Received 16 November 2012
Received in revised form 31 January 2013
Accepted 18 February 2013
Available online 24 February 2013
diastereoselectivity and yield, was realized starting from cyclic ketones, hydrazides, and isocyanides in
the presence of 10 mol % p-TsOH in ethanol at room temperature. The synthetic protocol was optimized
and the observed diastereoselectivity was measured using 1H NMR spectroscopy.
Ó 2013 Published by Elsevier Ltd.
Dedicated to Dr. M. Vahid Dastjerdi for her
brilliant contribution in Iranian health
system
Keywords:
a
a
-Hydrazino amides
-Hydrazino pseudopeptides
One-pot three-component reaction
Isocyanide-based multicomponent reaction
Diastereoselectivity
1. Introduction
hydrazones with an isocyanide and trifluoroacetic acid.6 The Ugi
reaction is the best known isocyanide-based multicomponent
Hydrazides constitute an important class of biologically active
organic compounds.1 Hydrazides and their condensation products
have displayed diverse range of biological activities including an-
ticonvulsant, antidepressant, anti-inflammatory, antimalarial, an-
ticancer, antimicrobial, anti-HIV and tuberculostatic activities.2
Prescribed agents featuring the hydrazide scaffold include the an-
tidepressant isocarboxazid (MarplanÒ) and the antitubercular iso-
niazid. Hydrazides have also been used as important intermediates
in synthesis of various heterocyclic compounds3 and peptidomi-
metic and peptide backbones (e.g., azapeptides, azatides, hydrazino
peptides and many more other compounds).4
reaction (IMCR), offering facile access to diverse compound
libraries.7
IMCRs can be considered one of the breakthrough reaction
classes of the last century.8 IMCRs are advantageous due to features
such as atom economy, simple experimental procedures, mild re-
action conditions, execution of reactions in green reaction media
like water or ethanol, high yields, and their one-pot character.9
Therefore, IMCRs have attracted much attention because of the
advantages that they offer to the field of combinatorial chemistry.10
Although the great utility of isocyanide-based multicomponent
reactions in the synthesis of heterocyclic compounds, stereo-
chemical control still represents a challenge.11 Usually in Passerini
and Ugi reactions a new stereogenic center is generated, but most
reactions reported so far suffer from low or absence of stereo-
selectivity.12 Consequently, developing methods to make these re-
actions more diastereoselective is an important goal.
Although to the best of our knowledge, hydrazino amides5 are
useful in preparing more proteolytically stable analogues of
natural bioactive pseudopeptides with preserved biological ac-
tivity, the reports are very scarce on synthesis of hydrazino
peptides. Some time ago Krasavin et al. reported the synthesis of
hydrazino pseudopeptide motifs via Ugi reaction of N-acyl
This investigation is a continuation of our previous studies on
isocyanide-based multicomponent reactions13 and deals with the
diastereoselective synthesis of hydrazino pseudopeptide motifs
through the novel one-pot three-component reaction of cyclic ke-
tones, hydrazides, and isocyanides (Scheme 1).
* Corresponding author. Fax: þ98 21 2285 3650; e-mail address: balalaie@
kntu.ac.ir (S. Balalaie).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.02.056

S. Ramezanpour et al. / Tetrahedron 69 (2013) 3480e3485
3481
Scheme 1. Diastereoselective synthesis of hydrazine amide motifs through the novel three-component reaction of cyclic ketones, hydrazides, and isocyanides.
2. Results and discussion
obtained yields for the model reaction were 79, 30, and 20%, re-
spectively. According to these results, ethanol was the most optimal
solvent. Consequently, the optimal reaction conditions were as
follows: catalyst, p-TsOH; catalyst amount, 10 mol %; reaction me-
dia, ethanol. The scope of the reaction was studied using different
starting materials after determining the best reaction conditions.
The results are summarized in Table 2.
In our initial study, 4-tert-butylcyclohexanone 1i was treated
with benzhydrazide 2i and tert-butylisocyanide 3i in ethanol at
room temperature as a model reaction, but the desired product was
not obtained even after heating the reaction mixture to 80 ꢀC.
However, when the reaction was performed in the presence of
catalytic amount (10%) of p-toluene sulfonic acid, the desired
product 4i was obtained in 79% yield (Scheme 2).
Meanwhile, the reaction of a variety of different aromatic al-
dehydes with benzhydrazide and tert-butylisocyanide was exam-
Scheme 2. The model reaction for the synthesis of 4i.
In an effort to optimize the reaction, reaction conditions were
investigated by adding catalytic amounts (10 mol %) of different
type of catalysts including metal catalysts; zinc chloride/zirconium
oxychloride, and Brønsted acid catalysts: phosphorous acid, p-tol-
uene sulfonic acid, camphor sulfonic acid, ascorbic acid, S-1,1-
binaphthyl-2,2-diylhydrogen phosphate (Table 1).
ined. However, these reactions only led to formation of imine and
the nucleophilic attack of isocyanide didn’t occur.
We believe that the reaction is diastereoselective. This claim was
checked with investigation of the model reaction (4i). After the
completion of the reaction, the mixture was evaporated and the 1H
NMR data of the crude product showed the existence of two di-
astereomers. The ratios of diastereomers were also assigned based
on the peak area for the eNHeNHeCO, which resonated at
d 9.42
Table 1
and 9.60 ppm for axial and equatorial positions in two di-
astereomers. The ratio of distinguished peaks was 86:14. The ratios
of the diastereomers were also characterized for other products in
the same way and were included in Table 2. Two diastereomers
have different solubility in ethanol. They could be separated by
crystallization. The mixture was crystallized in minimum of ethanol
as the solvent. The major diastereomer was crystallized and the
other one was soluble in ethanol. The crystalline form was filtered
and its 1H NMR showed the existence of single diastereomer. The
diastereoselectivity of the model reaction was analyzed using 1H
NMR spectroscopy of the crude product mixture.
Effect of metal catalysts and Brønsted acid catalysts on the formation of hydrazino
amide 4i
Entry Catalysts
Catalyst [%] Yielda [%]
1
2
3
4
5
6
7
p-TsOH
ZrOCl2
ZnCl2
H3PO3
10
10
10
10
10
10
79
20
Trace
80
80
Camphor sulfonic acid
Ascorbic acid
S-1,1-Binaphthyl-2,2-diylhydrogenphosphate 10
Trace
30
a
In all cases time of reactions was 24 h, except using p-TsOH time of reaction was
16 h.
The yields of the reactions were reported according to the
amount of purified single major diastereomer 4aen as the single
purified diastereomer. The structures of the products 4aen were
deduced from their IR, 1H NMR, and 13C NMR spectra. For example,
the 1H NMR spectrum of 4i consisted of multiplet signals for the
The best result among these catalysts was achieved with p-tol-
uene sulfonic acid. Another essential factor, which affects the per-
formance of a catalytic reaction is the amount of catalyst used. In
order to optimize the catalyst amount, different amounts of p-tol-
uene sulfonic acid were used. In the presence of 5, 10, 20, 30% of
p-TsOH, the yield of hydrazino pseudopeptide 4i obtained was 40,
79, 80, and 80%, respectively. The best result was obtained with
10 mol % of p-toluene sulfonic acid catalyst. The model reaction was
carried out in three different solvents (EtOH, toluene, and THF) the
methylene groups of cyclohexyl ring at
for NH at 5.30 ppm and multiplet was observed at
7.45e7.94 ppm for aromatic protons and eNH (tert-butyl) of
amide and a doublet for amide proton of NHeNHeCOPh at
9.40 ppm. Data arising from a combined analysis of 2D HeH COSY
allowed us to assign signals of the 1H NMR spectrum of compound
d 0.83e1.80 ppm, a doublet
d
a
d
d

3482
S. Ramezanpour et al. / Tetrahedron 69 (2013) 3480e3485
Table 2
4i. 2D HeH-COSY spectrum was used to determine the relationship
between eNHeNHeCO and the other eNH amide proton.
According to this result, it is clear that two eNH protons have
One-pot three-component reaction of cyclic ketones, hydrazides, and isocyanides for
the synthesis of hydrazino amides 4aen
correlation at
d 5.30 and 9.40 ppm, which could confirm the re-
lation between eNH of amide and amine (eNHeNHeCO). Another
amide proton resonates at d 7.94 ppm, which shows that there is no
correlation with other protons. The proton decoupled 13C NMR
spectrum of 4i showed 14 distinct resonances in agreement with
the proposed structure.
Meanwhile, for two samples 4d and 4k the single crystals were
obtained and the ORTEP structure could confirm their structure
(Fig. 1). The X-ray data for two single crystals 4d, 4k showed
clearly the orientation of the substituent and this was evidence to
confirm getting the single diastereomer.
The possible mechanism for the formation of product is shown
in Scheme 3. It is conceivable that the initial event is the formation
of imine. In the presence of acid catalyst it could convert to its
iminium salt, which is more active compared to its imine form.
Therefore, the presence of p-toluene sulfonic acid could facilitate
the addition of isocyanide, and without adding the acid catalyst the
reaction doesn’t proceed and the imine is the final product. There
are two possibilities for the addition of isocyanides to iminium ion.
The transition state for axial attack suffers from steric strain be-
tween 1,3 axial hydrogens and the incoming isocyanide reagent.
But addition of isocyanide through equatorial attack is more suit-
able with low steric effect 6i. The final step is water nucleophilic
addition on the activated nitrile moiety and formation of com-
pound 4i.
3. Conclusion
In summary, we have reported a novel multicomponent reaction
led to diastereoselective synthesis of hydrazine pseudopeptide
derivatives. The desired products 4aen were formed in good yields
upon mixing readily available substrates in the presence of 10 mol %
p-toluene sulfonic acid catalyst. The broad scope, operational sim-
plicity, practicability, high yields and mild reaction conditions
render it an attractive approach for the generation of different
hydrazino amides and hydrazine pseudopeptides. Moreover, these
products can be used for the synthesis of hydrazino acids, amino
amides, and also azapeptides.
aIn all cases, the yields of isolated single diastereomer are reported.
4k
4d
Fig. 1. ORTEP structure of compounds 4d and 4k.

S. Ramezanpour et al. / Tetrahedron 69 (2013) 3480e3485
3483
Scheme 3. Proposed mechanism for the synthesis of hydrazino amides 4aen through isocyanide three-component reaction.
4. Experimental section
4.1. General
7.51 (t, 1H, J 7.0 Hz, HAr), 7.71 (d, 2H, J 7.0 Hz, HAr), 8.16 (d, 1H, J
7.5 Hz, NH), 9.42 (s, 1H, NH); dC (125 MHz, DMSO-d6) 20.7, 22.7,
24.6, 25.3, 26.4, 29.8, 32.2, 34.0, 39.3,47.5, 64.3, 127.5, 128.3, 131.3,
133.7, 167. 6, 174.0; HRMS (ESI): [MþH]þ found 358.2495.
C21H32N3O2 requires 358.2496. [MþNa]þ found 380.2315.
C21H31N3NaO2 requires 380.2317.
Commercially available materials were used without further
purification. Melting points were determined on an Electrothermal
9100 apparatus and were uncorrected. IR spectra were obtained on
an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR
spectra were run on Bruker DRX-500 AVANCE, DRX-300 AVANCE
spectrometers at 500 and 300 MHz for 1H NMR,125 and 75 MHz for
13C NMR. DMSO-d6 was used as solvent. High-resolution mass
spectra were recorded on Mass-ESI-POS (Apex Qe-FT-ICR in-
strument) spectrometer.
4.2.3. Compound 4c: (1SR,3SR)-N-cyclohexyl-3-methyl-1-(2-(thio-
phene-2-carbonyl)hydrazinyl) cyclohexanecarboxamide. Yield 254 mg,
70% as a white solid; mp 208e211 ꢀC; Rf (33% EtOAc/hexane) 0.31;
nmax (KBr) 3293, 3239, 3090,1618 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.83
(br s, 3H, eCH3), 1.09e1.73 (m, 19H, HeCyclohexyl), 3.31e3.40 (m,1H,
eCHN), 5.28 (s, 1H, NH), 7.13 (s, 1H, Hethiophene), 7.76 (m, 2H,
Hethiophene), 8.11 (s, 1H, NH), 9.31 (br s, 1H, NH); dC (125 MHz,
DMSO-d6) 24.5, 24.9, 25.0, 25.3, 26.3, 29.6, 32.1, 33.1, 34.0, 47.4, 64.3,
127.8, 128.6, 131.0, 137.8, 162.0, 173.9; HRMS (ESI): [MþH]þ found
364.2056. C19H30N3O2S requires 364.2057. [MþNa]þ found 386.1876.
C19H29N3NaO2S requires 386.1877.
4.2. General procedure for the synthesis of
amides
a-hydrazino
To a solution of ketone 1 (1 mmol), hydrazide 2 (1 mmol) and
isocyanide 3 (1.2 mmol) in 5 mL EtOH was added p-TSOH$H2O
(0.02g, 10 mol %). The mixture was stirred for 16e32 h at ambient
temperature. After completion of the reaction, as indicated by TLC
(ethyl acetate/n-hexane, 1:3), the product was precipitated by ad-
dition of 10 mL of diisopropylether. The precipitate was filtered off
and then crystallized from ethanol.
4.2.4. Compound 4d: (1SR,4SR)-1-(2-benzoylhydrazinyl)-N-cyclo-
hexyl-4-methylcyclohexane carboxamide. Yield 268 mg, 75% as
a white solid; mp 242e244 ꢀC Rf (33% EtOAc/hexane) 0.32; nmax
(KBr) 3296, 3230, 3089,1626 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.87 (d,
3H, J 4.0 Hz, eCH3), 1.05e1.72 (m, 19H, HeCyclohexyl), 3.31e3.34
(m, 1H, eCHN), 5.32 (d, 1H, J 3.5 Hz, NH), 7.44 (t, 2H, J 7.5 Hz, HeAr),
7.52 (t, 1H, J 7.5 Hz, HeAr), 7.71 (d, 2H, J 7.5 Hz, HeAr), 8.15 (d, 1H, J
8.0 Hz, NH), 9.37 (d, 1H, J 3.5 Hz, NH); dC (125 MHz, DMSO-d6) 22.4,
24.5, 25.3, 29.2, 30.4, 31.3, 32.1, 47.4, 63.1, 127.4, 128.2, 131.3, 133.6,
167.4, 174.0; HRMS (ESI): [MþH]þ found 358.2489. C21H32N3O2
requires 358.2489. [MþNa]þ found 380.2308. C21H31N3NaO2 re-
quires 380.2308.
4.2.1. Compound 4a: (1SR,4SR)-1-(2-benzoylhydrazinyl)-4-tert-
butyl-N-cyclohexylcyclohexane carboxamide. Yield 271 mg, 68% as
a white solid; mp 240e243 ꢀC; Rf (33% EtOAc/hexane) 0.33; nmax
(KBr) 3296, 3224, 3091, 1650, 1627 cmꢁ1
; dH (500 MHz, DMSO-d6)
0.83 (s, 9H, t-Bu), 0.93e1.79 (m, 19H, HCyclohexyl), 3.29e3.40 (m, 1H,
CHN), 5.30 (d, 1H, J 4.0 Hz, NH), 7.45 (t, 2H, J 7.5 Hz, HAr), 7.52 (t,1H, J
7.5 Hz, HAr), 7.71 (d, 2H, J 7.5 Hz, HAr), 8.15 (d, 1H, J 7.5 Hz, NH), 9.39
(d, 1H, J 4.0 Hz, NH); dC (125 MHz, DMSO-d6) 21.6, 24.5, 25.2, 27.5,
30.9, 32.1, 32.2, 47.0, 47.5, 63.2, 127.4, 128.2, 131.2, 133.6,167.3, 174.1;
HRMS (ESI): [MþH]þ found 400.2964. C24H38N3O2 requires
400.2964.
Colourless crystal (plate), dimensions 1.04ꢂ0.32ꢂ0.07 mm3,
ꢀ
crystal system monoclinic, space group P21/c, Z¼8, a¼9.7842(6) A,
ꢀ
ꢀ
b¼17.6143(11) A, c¼23.5526(16) A,
a
¼90ꢀ,
b
¼97.886(2)ꢀ,
g
¼90ꢀ,
3
ꢀ
V¼4020.7(4) A ,
r
¼1.188ꢀg/cm3, T¼200(2) K, qmax¼25.12ꢀ, radiation
ꢀ
Mo K
a,
l
¼0.71073 A, 0.3
u
-scans with CCD area detector, covering
the asymmetric unit in reciprocal space with a mean redundancy of
ꢀ
4.71and a completeness of 99.4% to a resolution of 0.84A, 34,173
4.2.2. Compound 4b: (1SR,3SR)-1-(2-benzoylhydrazinyl)-N-cyclo-
hexyl-3-methylcyclohexane carboxamide. Yield 214 mg, 60% as
a white solid; mp 217e220 ꢀC; Rf (33% EtOAc/hexane) 0.32; nmax
reflections measured, 7116 unique (R(int)¼0.0443), 4935 observed
(I>2s(I)), intensities were corrected for Lorentz and polarization
(KBr) 3292, 3228, 3088, 1653, 1623 cmꢁ1
; dH (500 MHz, DMSO-d6)
effects, an empirical absorption correction was applied using
SADABS14 based on the Laue symmetry of the reciprocal space,
0.82 (d, 3H, J 5.0 Hz, Me), 1.04e1.74 (m, 19H, HeCyclohexyl),
3.42e3.44 (m, 1H, CHN), 5.32 (s, 1H, NH), 7.44 (t, 2H, J 7.0 Hz, HAr),
m
¼0.08 mmꢁ1, Tmin¼0.92, Tmax¼0.99, structures of 4d and 4k solved

3484
S. Ramezanpour et al. / Tetrahedron 69 (2013) 3480e3485
by direct methods and refined against F2 with a full-matrix least-
squares algorithm using the SHELXTL (Version 2008/4) software
package,15 493 parameters refined, hydrogen atoms were treated
using appropriate riding models, except of those at the nitrogen
atoms, which were refined isotropically, goodness of fit 1.07 for
observed reflections, final residual values R1(F)¼0.047, wR(F2)¼
0.104 for observed reflections, residual electron density ꢁ0.19 to
2958, 1631 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.83 (s, 9H, t-Bu),
0.91e0.96 (m,1H, Hecyclohexyl),1.18 (s, 9H, t-Bu), 1.31e1.80 (m, 8H,
Hecyclohexyl), 5.30 (d, 1H, J 3.0 Hz, NH), 7.45 (t, 2H, J 7.5 Hz, HeAr),
7.52 (t, 1H, J 7.5 Hz, HeAr), 7.72 (d, 2H, J 7.5 Hz, HeAr), 7.94 (s, 1H,
NH), 9.40 (s, 1H, NH); dC (125 MHz, DMSO-d6) 21.7, 27.5, 28.2, 30.9,
32.2, 47.1, 49.5, 63.6, 127.5, 128.2, 131.2, 133.7, 167.4, 174.6; HRMS
(ESI): [MþH]þ found 374.2803. C22H36N3O2 requires 374.2803.
[MþNa]þ found 396.2623. C22H35N3NaO2 requires 396.2624.
ꢀꢁ3
0.17 e A . CCDC 910985 contains the supplementary crystallo-
graphic data for this paper.
4.2.10. Compound 4j: (1SR,4SR)-N-tert-butyl-4-ethyl-1-(2-
isonicotinoylhydrazinyl)cyclohexane carboxamide. Yield 242 mg,
70% as awhite solid; mp 235e238 ꢀC; Rf (33% EtOAc/hexane) 0.3; nmax
4.2.5. Compound 4e: (1SR,4SR)-N-cyclohexyl-4-methyl-1-(2-(thio-
phene-2-carbonyl)hydrazinyl)cyclohexane carboxamide. Yield 253 mg,
70% as a white solid; mp 215e216 ꢀC; Rf (33% EtOAc/hexane) 0.4; nmax
(KBr) 3295, 3252, 3077, 1634 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.84 (t,
(KBr) 3352, 3299, 3240, 1630, 1616 cmꢁ1
;
dH (500 MHz, DMSO-d6)
3H, J 7.0 Hz, eCH3),1.07e1.76 (m, 20H, Hecyclohexyl,CH2eCH3, t-Bu),
5.43 (s,1H, NH), 7.61 (d, 2H, J 5.0 Hz, Hepyridyl), 7.85 (s,1H, NH), 8.70
(d, 2H, J 5.0 Hz, Hepyridyl), 9.62 (s, 1H, NH); dC (125 MHz, DMSO-d6)
11.4, 26.9, 28.2, 29.2, 30.3, 38.1, 49.5, 63.9, 121.6, 140. 8, 150.1, 165.8,
174.3; HRMS (ESI): [MþH]þ found 347.2441. C19H31N4O2 requires
347.2441.
0.87 (d, 3H, J 4.0 Hz, eCH3), 1.07e1.69 (m, 19H, HeCyclohexyl),
3.39e3.41 (m, 1H, eCHN), 5.29 (s, 1H, NH), 7.12 (t, 1H, J 4.0 Hz,
Hethiophene), 7.75 (d, 1H, J 5.0 Hz, Hethiophene), 7.81 (d, 1H, J
3.3 Hz, Hethiophene), 8.14 (d, 1H, J 8.0 Hz, NH), 9.29 (s, 1H, NH); dC
(125 MHz, DMSO-d6) 22.3, 24.7, 25.3, 29.2, 30.4, 31.3, 32.1, 47.4, 63.1,
127.9, 128.6, 131.0, 137.8, 161.9, 174.0; HRMS (ESI): [MþH]þ found
364.20555. C19H30N3O2S requires 364.20561.
4.2.11. Compound 4k: (1SR,3SR)-1-(2-benzoylhydrazinyl)-N-tert-
butyl-3-methylcyclohexane carboxamide. Yield 261 mg, 79% as
a white solid; mp 202e204 ꢀC; Rf (33% EtOAc/hexane) 0.43; nmax
4.2.6. Compound
hexylcyclopentane. Yield 253 mg, 77% as
200e202 ꢀC; Rf (33% EtOAc/hexane) 0.4; nmax (KBr) 3295, 3224,
3087, 1625 cmꢁ1
dH (500 MHz, DMSO-d6) 1.04e1.91 (m, 18H,
4f:
(1SR)-1-(2-benzoylhydrazinyl)-N-cyclo-
a
white solid; mp
(KBr) 3310, 3284, 3100, 3050, 3010, 1638 cmꢁ1
; dH (500 MHz,
DMSO-d6) 0.82 (d, 3H, J 7.0 Hz, eCH3), 1.17 (s, 9H, t-Bu), 1.18e1.80
(m, 8H, Hecyclohexyl), 2.40e2.48 (m, 1H, Hecyclohexyl), 5.31 (s,
1H, NH), 7.11e7.20 (m, 1H, HeAr), 7.50e7.60 (m, 2H, HeAr), 7.69 (d,
2H, J 8.0 Hz, HeAr), 7.93 (s, 1H, NH), 9.40 (s, 1H, NH); dC (125 MHz,
DMSO-d6) 20.7, 22.6, 26.4, 27.1, 28.2, 29.6, 34.0, 49.5, 51.1, 64.7,
125.5, 127.5, 128.1, 128.2, 131.2, 133.8, 167.6, 174.0; HRMS (ESI):
[MþH]þ found 332.2335. C19H30N3O2 requires 332.2336. [MþNa]þ
found 354.2155. C19H29N3NaO2 requires 354.2156. Colourless
crystal (needle), dimensions 0.89ꢂ0.09ꢂ0.07 mm3, crystal system
;
HeCyclopentyl, Cyclohexyl), 3.45e3.47 (m, 1H, eCHN), 5.19 (d, 1H, J
3.5 Hz, NH), 7.45 (t, 2H, J 7.5 Hz, HeAr), 7.52 (t, 1H, J 7.5 Hz, HeAr),
7.75 (d, 2H, J 7.5 Hz, HeAr), 8.27 (d, 1H, J 7.5 Hz, NH), 9.55 (d, 1H, J
3.5 Hz, NH); dC (125 MHz, DMSO-d6) 24.6, 24.7, 25.3, 32.2, 34.7, 47.6,
72.4, 127.4, 128.4, 131.4, 133.4, 167.4, 173.7; HRMS (ESI): [MþH]þ
found 330.2178. C19H28N3O2 requires 330.2179. [MþNa]þ found
352.1998. C19H27N3NaO2 requires 352.1999.
ꢀ
ꢀ
3
ꢀ
monoclinic, space group P21/c, Z¼4, a¼10.961(2) A, b¼18.093(3) A,
ꢀ
ꢀ
4.2.7. Compound 4g: (1SR,4SR)-ethyl 4-(2-benzoylhydrazinyl)-4-
(cyclohexylcarbamoyl)piperidine-1-carboxylate. Yield 345 mg, 83% as
a white solid; mp 176e177 ꢀC; Rf (33% EtOAc/hexane) 0.45; nmax (KBr)
c¼9.6927(19) A,
a
¼90ꢀ,
b
¼99.845(5)ꢀ,
g
¼90 , V¼1893.9(6) A ,
r
l
¼1.162 g/cm3, T¼200(2) K, qmax¼25.03ꢀ, radiation Mo
Ka,
ꢀ
ꢀ
¼0.71073 A, 0.3
u-scans with CCD area detector, covering the
3283, 3229, 3086, 1699, 1624 cmꢁ1
;
dH (500 MHz, DMSO-d6) 1.16 (t,
asymmetric unit in reciprocal space with a mean redundancy of
4.14 and a completeness of 99.7% to a resolution of 0.84 A, 14,447
ꢀ
3H, J 6.5 Hz, eCH3),1.03e1.87 (m,14H, HeCyclohexyl), 3.32e3.45 (m,
3H, eCHN, eCHaxN), 3.55e3.62 (m, 2H, eCHeqN), 4.02 (q, 2H, J
7.0 Hz, eOCH2), 5.62 (d,1H, J 4.0 Hz, NH), 7.46 (t, 2H, J 7.5 Hz, HeAr), 7.
52 (t, 1H, J 7.5 Hz, HeAr), 7.73 (d, 2H, J 7.5 Hz, HeAr), 8.12 (d, 1H, J
7.5 Hz, NH), 9.57 (d, 1H, J 4.0 Hz, NH); dC (125 MHz, DMSO-d6) 14.6,
24.6, 25.2, 30.4, 30.7, 32.0, 47.6, 60.5, 62.0, 127.4, 128.3, 131.4, 133.4,
154.6, 167.4, 172.6; HRMS (ESI): [MþH]þ found 417.2500. C22H33N4O
requires 417.2501. [MþNa]þ found 439.2319. C22H32N4NaO4 requires
439.2320.
reflections measured, 3334 unique (R(int)¼0.1909), 2680 observed
(I>2s(I)), 235 parameters refined, hydrogen atoms were treated
using appropriate riding models, except of H2, H3, and H5 at the
nitrogen atoms, which were refined isotropically, goodness of fit
1.11 for observed reflections, final residual values R1(F)¼0.088,
wR(F2)¼0.199 for observed reflections, residual electron density
ꢀꢁ3
ꢁ0.31 to 0.52 e A . CCDC 910986 contains the supplementary
crystallographic data for this paper.
4.2.8. Compound 4h: (1SR,4SR)-ethyl 4-(cyclohexylcarbamoyl)-4-(2-
(thiophene-2-carbonyl)hydrazinyl)piperidine-1-carboxylate. Yield
320 mg, 76% as a white solid; mp 205e206 ꢀC; Rf (33% EtOAc/
4.2.12. Compound 4l: (1SR,4SR)-1-(2-benzoylhydrazinyl)-N-tert-
butyl-4-methylcyclohexane carboxamide. Yield 264 mg, 80% as
a white solid; mp 241e243 ꢀC; Rf (33% EtOAc/hexane) 0.42; nmax
hexane) 0.40; nmax (KBr) 3289, 3081, 2926, 1704, 1650 cmꢁ1
;
dH
(500 MHz, DMSO-d6) 1.16 (t, 3H, J 6.5 Hz, eCH3), 1.07e1.85 (m,
14H, ecyclohexyl), 3.34e3.49 (m, 3H, eCHN, eCHaxN),
(KBr) 3332, 3290, 3256, 1640, 1629 cmꢁ1
; dH (500 MHz, DMSO-d6)
0.86 (d, 3H, J 2.5 Hz, eCH3), 1.18 (s, 9H, t-Bu), 1.29e1.71 (m, 9H,
HeCyclohexyl), 5.31 (d, 1H, J 3.0 Hz, NH), 7.45 (t, 2H, J 7.5 Hz, HeAr),
7.52 (t, 1H, J 7.5 Hz, HeAr), 7.71 (d, 2H, J 7.5 Hz, HeAr), 7.92 (s, 1H,
NH), 9.35 (s, 1H, NH); dC (125 MHz, DMSO-d6) 22.3, 28.2, 29.3, 30.4,
31.4, 49.5, 63.5, 127.4, 128.2, 131.2, 133.7, 167.4, 174.5; HRMS
(ESI):[MþH]þ found 332.2334. C19H30N3O2 requires 332.2334.
[MþNa]þ found 354.2154. C19H29N3NaO2 requires 354.2154.
H
3.52e3.59 (m, 2H, eCHeqN), 4.02 (q, 2H, J 6.5 Hz, eOCH2), 5.58 (s,
1H, NH), 7.71 (t, 1H, J 4.0 Hz, Hethiophene), 7. 77 (d, 2H, J 4.0 Hz,
Hethiophene), 8.08 (d, 1H, J 7.5 Hz, NH), 9.50 (s, 1H, NH), 9.56 (s,
1H, NH); dC (125 MHz, DMSO-d6) 14.6, 24.5, 25.2, 30.4, 30.8, 32.0,
47.5, 60.6, 62.0, 127.9, 128.6, 131.2, 137.6, 154.6, 161.9, 172.6;
HRMS (ESI): [MþH]þ found 423.2063. C20H31N4O4S requires
423.2064. [MþNa]þ found 445.1882. C20H30N4NaO4S requires
445.1883.
4.2.13. Compound 4m: (1SR,4SR)-ethyl 4-(2-benzoylhydrazinyl)-4-
(tert-butylcarbamoyl) piperidine-1-carboxylate. Yield292mg, 75% as
a white solid; mp 184e187 ꢀC; Rf (33% EtOAc/hexane) 0.4; nmax (KBr)
4.2.9. Compound 4i: (1SR,4SR)-1-(2-benzoylhydrazinyl)-N-4-di-tert-
butylcyclohexane carboxamide. Yield 298 mg, 80% as a white solid;
mp 197e200 ꢀC; Rf (33% EtOAc/hexane) 0.34; nmax (KBr) 3290, 3066,
3420, 3363, 3143,1620,1570cmꢁ1
;dH (500MHz, DMSO-d6)1.17e1.30
(m, 3H, CH3), 1.20 (s, 9H, t-Bu), 1.65e1.72 (m, 2H, eCHax), 1.75e1.85
(m, 2H, eCHeq), 3.25e3.45 (m, 2H, eCHaxN), 3.58e3.60 (m, 2H,

S. Ramezanpour et al. / Tetrahedron 69 (2013) 3480e3485
3485
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4465e4468; (b) Moulin, A.; Demange, L.; Ryan, J.; Mousseaux, D.; Sanchez, P.;
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Vanderesse, R. Peptides containing C/N/O amide bond replacement. In Hou-
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metics; Thieme: Stuttgart, Germany, 2002; Vol. E22c, pp 423e457.
5. (a) Huang, X.; Roemer, E.; Sattler, I.; Moellmann, U.; Christner, A.; Grabley, S.
Angew. Chem., Int. Ed 2006, 45, 3067e3072; (b) Miller, E. D.; Kauffman, C. A.;
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eCHeqN), 4.02 (q, 2H, J 7.5 Hz, eOCH2), 5.62 (br s,1H, NH), 7.46 (t, 2H, J
7.5 Hz, HeAr), 7. 53 (t,1H, J 7.5 Hz, HeAr), 7.72 (d, 2H, J 7.5 Hz, HeAr),
7.88 (s, 1H, NH), 9.56 (s, 1H, NH); dC (125 MHz, DMSO-d6) 14.6, 27.1,
28.1, 30.5, 49.7, 55.8, 60.6, 62.4, 125.5,127.4, 128.3, 131.4, 133.5, 154.7,
167.4, 173.3; HRMS (ESI): [MþH]þ found 391.2345. C20H31N4O4 re-
quires 391.2345. [MþNa]þ found 413.2167. C20H30N4NaO4 requires
413.2169.
4.2.14. Compound 4n: (1R,2SR,4S)-2-(2-benzoylhydrazinyl)-N-tert-
butyl-1,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxamide. Yield
243 mg, 90% as a white solid; mp 198e200 ꢀC; Rf (33% EtOAc/
hexane) 0.45; nmax (KBr) 3167, 3013, 2941, 1660, 1645 cmꢁ1
; dH
(300 MHz, DMSO-d6) 0.75 (s, 6H, 2-CH3), 0.90 (s, 9H, t-Bu),0.98 (s,
3H, eCH3), 1.15e1.80 (m, 4H, 2-CH2), 1.87e2.00 (m, 1H, eCH), 2.10
(d, 1H, J 17.0 Hz, eCH), 2.60 (d, 1H, J 17.0 Hz, eCH), 3.30 (br s, 1H,
NH), 7.45 (br s, 3H, HeAr), 7.78 (br s, 3H, HeAr, eNH), 10.19 (s, 1H,
NH); dC (75 MHz, DMSO-d6) 11.5, 18.5, 19.3, 26.9, 32.4, 34.7,43.4,
47.6, 52.6, 127.6, 128.3, 131.2, 134.3, 163.1, 173.3; HRMS (ESI):
[MꢁC5H10NO]þ found 271.1805. C17H23N2O requires 271.1805.
[MꢁC5H10NOþNa]þ found 293.16246. C17H22N2NaO requires
293.16243. [2MꢁC5H10NOþNa]þ found 563.3356. C34H44N4NaO2
requires 563.3356.
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Acknowledgements
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S.B. gratefully acknowledges Iran National Science Foundation
(INSF). We are also thanking Iranian Ministry of Health and Me-
dicinal Education and also Presidential Office Deputy of Science and
Technology for financial support.
11. Orru, R. V. A.; Ruijter, E. Synthesis of Heterocycles via Multicomponent Reactions
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.056.
References and notes
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