Synthesis of functionalized pseudopeptides through five-component sequential Ugi/nucleophilic reaction of N-substituted 2-alkynamides with hydrazides

Article abstract of DOI:10.1021/jo4003294

Five-component sequential Ugi/nucleophilic addition reaction of aromatic aldehydes, primary amines, propiolic acid, isocyanides, and hydrazides has been developed in order to access polyfunctional pseudopeptides. The reaction may proceed through formation

Full text of DOI:10.1021/jo4003294

Article
pubs.acs.org/joc
Synthesis of Functionalized Pseudopeptides through
Five-Component Sequential Ugi/Nucleophilic Reaction
of N‑Substituted 2‑Alkynamides with Hydrazides
Shokoofeh Maghari,† Sorour Ramezanpour,† Saeed Balalaie,*,† Fatemeh Darvish,† Frank Rominger,‡
and Hamid Reza Bijanzadeh†,§
†Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416 Tehran, Iran
‡Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
§Department of Biophysics, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
S
* Supporting Information
ABSTRACT: Five-component sequential Ugi/nucleophilic
addition reaction of aromatic aldehydes, primary amines,
propiolic acid, isocyanides, and hydrazides has been developed
in order to access polyfunctional pseudopeptides. The reaction
may proceed through formation of N-substituted 2-alkynamides
as intermediates. This process is found to be mild and
operationally simple with broad substrate scope.
lanthanides,13 actinides,14 and titanium.15 Restrictions in these
previous works include lack of generality, limited functional
group tolerance, lengthy synthetic sequences, and harsh reaction
conditions.
INTRODUCTION
■
Development of strategies for the facile construction of highly
functionalized molecules with a diverse range of complexity via
multicomponent reactions has recently attracted much attention
and is now widely recognized as a first choice opportunity in the
To the best of our knowledge, there are a limited number of
reports of direct addition of hydrazides to alkynes in the
preparation of macromolecules with a high bond-forming
literatures.6,16 In continuation of our research for the con-
struction of new polyfunctional compounds through multi-
component reactions, we became interested in synthesis of
pseudopeptides via the addition of hydrazides to alkynamides.
Herein we report a novel approach for the synthesis of func-
tionalized psedopeptides through sequential Ugi/nucleophilic
addition reactions. The reactions were carried out in a “one-pot”
two-step process (Scheme 1).
efficiency (BFE) under simple and mild reaction conditions.1
To accomplish this purpose, a combination of multicomponent
reaction with an efficient post transformation, typically a ring
formation process or nucleophilic addition,2 has been proven to
be a powerful tool for the synthesis of highly functionalized
compounds.
To develop an efficient sequential multicomponent reaction,
selecting functionalized starting materials has an essential role.
For example, in light of our recent research reports, Ugi 4-CR
reaction of aromatic aldehydes, primary amines, propiolic acid,
and isocyanides leading to N-substituted 2-alkynamides has
further applications in nucleophilic addition and stereoselective
synthesis of enaminones and dithiocarbamates.3
We have recently initiated a research program to develop
transition-metal-free efficient sequential Ugi/nucleophilic addi-
tion reactions as a promising approach for nucleophilic addition
of hydrazides to N-substituted 2-alkynamides. The direct
addition of primary or secondary amines to alkynes is known
as hydroamination reaction, which needed metal catalysts.4 This
approach is an atom-efficient route to new, synthetically useful,
and biologically significant organonitrogen compounds.5,6
Although it is thermodynamically favorable, the high activation
barrier for the hydroamination reaction under normal conditions
means a catalyst is required to make the reaction practical.7
Several catalysts have been utilized for this reaction such
as calcium,8 rhodium,9 palladium,10 iridium,6,11 ruthenium,12
RESULTS AND DISCUSSION
■
The transition-metal-catalyzed hydroamination of alkynes with
amines is a well-known process, which represents a promising
arena for initial studies toward the development of a sequential
process between activated alkynamides and hydrazides. In the
first step, we tried to obtain our desired product by direct
addition of benzhydrazide (6a) to Ugi 4-CR intermediate 5a in
the presence of DIEA in MeOH, without any catalyst or
separation of intermediate. Unfortunately, neither strategy was
ultimately successful. The results indicate that methanol in the
presence of base was added as nucleophile to the active triple
bond and functionalized methyl vinyl ether was produced instead
of expected product I (Scheme 2).
Received: February 19, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Pseudopeptides (7a−g) via Sequential Ugi/Nucleophilic Addition Reactions
Scheme 2. Attempted Addition of Benzhydrazide to N-Substituted 2-Alkynamides 5a
Scheme 3. Synthesis of Pseudopeptide (7a) via Addition of Benzhydrazide to N-Substituted 2-Alkynamide (5a)
After failing to conduct this reaction in MeOH, we sought to
replace the solvent of the nucleophilic addition sequence with a
non-nucleophilic solvent. Fortunately, use of DCE as solvent
leads to completion of the reaction. Ugi 4-CR was carried out in
MeOH, and after evaporation of the solvent, without separating
the Ugi 4-CR intermediate (5a), addition of benzhydrazide (6a,
1.2 equiv) was performed in the presence of (1equiv) DIEA as
the base in DCE.
We envisioned the functionalized vinyl hydrazide I (Scheme 2)
produced from hydroamination of N-substituted 2-alkynamide 5a
with benzhydrazide (6a) but 1H NMR and X-ray crystallographic
analysis proved structure of hydrazone 7a as the sole product
(Scheme 3).
has high affinity toward nucleophilic addition, and the reaction
could proceed without any catalyst or separation of intermediate
5a. Following the formation of Ugi 4-CR intermediate (5a),
benzhydrazide (6a) was added as nucleophile to the active triple
bond and substrate I was formed. Then enamine−imine
tautomerization converted compound I to hydrazone 7a as
1
sole product. Structure of compound 7a was assigned by H
NMR spectroscopy with highly characteristic peaks with ABX
pattern at 2.91−3.09 ppm for diastereotopic hydrogens.
X-ray crystallographic data confirmed the structure of the
product 7a. Figure 1 shows ORTEP structure of the compound
7a and molecular associations which were caused by the
intramolecular hydrogen bondings.
The proposed mechanism for the synthesized of hydrazone 7a
After optimization of reaction conditions, the scope of the
is shown in Scheme 4. The Ugi-4CR with an active triple bond
reaction was extended to other N-substituted-2-alkynamides and
B
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Proposed Mechanism for Synthesis of Pseudopeptide (7a)
Figure 1. ORTEP structure and intramolecular association of compound 7a.
different types of hydrazides as nucleophiles. The results are
summarized in Table 1.
In another attempt, phenylpropiolic acid and methylpropiolic
acid were used for the synthesis of desired N-substituted
2-alkynamides, but addition of hydrazides as nucleophiles was
not successful and the Ugi-4CR was unactive to nucleophilic
addition.
The products 7a−g are functionalized hydrazones which are
the same as the metal-catalyzed hydroamination reaction
product.6 Under metal-free reaction conditions, the formation
of hydrazones could be obtained with good yields because of
intramolecular hydrogen bondings and stabilized molecular
associations. Next, to gain more insight into the reaction
mechanism and broaden the chemical library of products,
we investigated the addition of 3-phenylpropiolhydrazide and
p-toluenesulfonhydrazide to the Ugi-4CR 5a intermediate, which
leads to vinyl hydrazides with different configurations (Scheme 5).
As can be seen in Scheme 5, addition of 3-phenyl-
propiolhydrazide (6d) to Ugi-4CR intermediate 5a produced
pseudopeptide 7h, which contained the vinyl hydrazide group
with Z configuration. The appearance of doublets at 5.22 and
6.22 ppm with J = 7.3 Hz for vinylic protons and also the
deshielded chemical shift (δ 10.51 ppm) for NH reveals the
formation of the Z configuration of compound 7h. This data
could confirm efficient intermolecular hydrogen bondings. When
p-toluenesulfonhydrazide was used as nucleophile, the prod-
uct showed characteristic peaks at δ 5.15 and 7.88 ppm with
J = 12.9 Hz, which confirms the E configuration of compound 7i.
It seems that selective formation of E configuration is due to the
C
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Synthesis of Pseudopeptides via 5-Component Sequential Ugi/Nucleophilic Addition
a
Reactions condition: aromatic aldehydes (1 mmol), primary amines (1 mmol), propiolic acid (1 mmol), isocyanides (1 mmol), hydrazide
b
(1.2 mmol), DIEA (1 mmol). Monitored after 3−4 days.
thermodynamically more stable intermediate and there is not
intermolecular hydrogen bonding.
Seemingly, the nature of hydrazides plays an important role in
the appearance and type of hydrogen bondings and intra-
molecular associations and leads to formation of products with
different stereoselectivity.
CONCLUSIONS
■
We have introduced a facile and efficient free-metal-catalyzed
approach for nucleophilic addition of hydrazide to N-substituted-
2-alkynamides which leads to functionalized psudopeptides
containing hydrazones (7a−g) and vinyl hydrazide (7h−j)
groups with high diversity and different stereoselectivity. The
type of hydrazide could affect the configuration of vinyl
The proposed mechanism for the synthesis of compounds 7h,i
is shown in Scheme 6.
D
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 5. Synthesis of Vinyl Hydrazide Pseudopeptides 7h−i
using SADABS17 based on the Laue symmetry of the reciprocal space,
μ = 0.08 mm−1, Tmin = 0.98, Tmax = 0.99; structure solved by direct
methods and refined against F2 with a full-matrix least-squares algorithm
using the SHELXTL (Version 2008/4) software package;17 342
parameters refined; hydrogen atoms were treated using appropriate
riding models, except for the hydrogens at the nitrogen atoms N1 and
N9, which were refined isotropically, Flack absolute structure parameter
0.0(15), goodness of fit 1.08 for observed reflections; final residual
values R1(F) = 0.038, wR(F2) = 0.095 for observed reflections, residual
electron density −0.15 to 0.14 e Å−3. CCDC 922255 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(E)-3-(2-Acetylhydrazono)-N-(2-(cyclohexylamino)-2-oxo-1-phe-
nylethyl)-N-phenylpropanamide (7b): isolated yield 70% (303 mg);
mp 210−211 °C; IR (KBr, cm−1) ν = 3267, 3062, 1676, 1553; 1H NMR
(300 MHz, DMSO-d6) δ 0.95−1.22 (m, 5H), 1.49−1.81 (m, 5H), 1.95
(s, 3H), 2.79− 2.99 (ABX, 2H, J = 16.9 Hz), 3.54−3.67 (m, 1H), 6.02
(s, 1H, CH), 7.02−7.43 (m, 11H, CH), 7.99 (d, 1H, J = 6.3 Hz), 10.95
(s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 20.2, 21.4, 24.5, 24.7, 25.2,
25.3, 32.2, 47.9, 63.5, 127.6, 127.8, 128.4, 129.1, 130.1, 130.9, 135.2,
139.2, 141.6, 167.0, 168.5, 171.3; HR-MS (ESI) calcd for C25H31N4O3
[M + H]+ 435.23983, found 435.23969, calcd for C25H30N4NaO3
[M + Na]+ 457.22142, found 457.22135.
hydrazides. These features were exploited through the develop-
ment of five-component sequential Ugi/Nucleophilic addition
reaction. Several advantages, such as mild reaction conditions,
simple and easy workup procedure, atomic economy, and high
BFE are discussed.
EXPERIMENTAL SECTION
■
General Experimental Details. Commercially available materials
were used without further purification. High-resolution mass spectra
were recorded on a Mass-ESI-POS (Apex Qe-FT- ICR instrument)
spectrometer.
General Procedure for the Synthesis of the Pseudopeptides
7a−j. To a solution of aldehyde 1 (1 mmol) in methanol (5 mL) was
added the primary amine 2 (1 mmol), and the reaction mixture was
stirred at room temperature for 1 h. Then, propiolic acid 3 (1 mmol) was
added, and stirring was continued for 15 min, followed by addition of
isocyanides 4 (1 mmol); the solution was stirred for 24 h at room
temperature. The solvent was removed in vacuo, and DCE was added to
the residue. Then hydrazide 7 (1.2 mmol) and DIEA (1 mmol)
were added to the mixture. The reaction mixture was stirred at 50 °C for
3−4 days. The progress of the reaction was monitored using TLC
(n-hexane−EtOAc 1:2). The precipitate which formed in the mixture of
reaction was filtered off and washed with CH2Cl2.
(E)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyl-3-(2-
(thiophene-2-carbonyl)hydrazono)propanamide (7c): isolated yield
63% (316 mg); mp 205−207 °C; IR (KBr, cm−1) ν = 3267, 3064, 1657,
1552; 1H NMR (300 MHz, DMSO-d6) δ 0.98−1.17 (m, 5H), 1.40−1.75
(m, 5H), 2.95−3.22 (m, 2H), 3.50−3.80 (m, 1H), 6.07 (s, 1H), 6.66−
7.11 (m, 10H), 7.41 (brs, 1H), 7.79−7.94 (m, 4H), 11.50 (brs, 1H, NH,
pro-Z), 11.62 (brs, 1H, NH, pro-E); 13C NMR (75 MHz, DMSO-d6) δ
24.5, 24.6, 25.1, 32.2, 47.9, 63.6, 127.2, 127.6, 127.8, 128.4, 128.7, 130.1,
130.9, 131.7, 135.2, 138.2, 139.2, 146.7, 168.5, 168.9, 169.8; HR-MS
(ESI) calcd for C28H31N4O3S [M + H]+ 503.21193, found 503.21180,
calcd for C28H30N4NaO3S [M + Na]+ 525.19340, found 525.19335.
(E)-3-(2-Benzoylhydrazono)-N-(2-(cyclohexylamino)-2-oxo-1-
(thiophene-2-yl)ethyl)-N-phenylpropanamide (7d): isolated yield
47% (235 mg); mp 215−217 °C; IR (KBr, cm−1) ν = 3245, 3065,
(E)-3-(2-Benzoylhydrazono)-N-(2-(cyclohexylamino)-2-oxo-1-
phenylethyl)-N-phenylpropanamide (7a): isolated yield 72% (357
mg); mp 210−213 °C; IR (KBr, cm−1) ν = 3255, 3071, 2931, 1553; 1H
NMR (300 MHz, DMSO-d6) δ 0.96−1.23 (m, 5H), 1.50−1.76 (m, 5H),
3.00 (ABX, 2H, J = 16.7, 4.5 Hz), 3.48−3.70 (m, 1H), 6.05 (s, 1H),
7.05−7.14 (m, 10H), 7.37−7.55 (m, 3H), 7.78−7.84 (m, 3H), 7.12 (d,
1H, J = 7.1 Hz), 11.62 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 24.5,
24.6, 25.7, 32.2, 48.0, 63.6, 127.6, 128.0, 128.4, 130.1, 130.9, 131.7,
133.3, 135.2, 139.2, 146.9, 162.8, 168.5, 168.7; HR-MS (ESI) calcd for
C30H33N4O3 [M + H]+ 497.25510, found 497.25518, calcd for
C30H32N4NaO3 [M + Na]+ 519.23689, found 519.23685.
Colorless crystal (needle): dimensions 0.24 × 0.15 × 0.07 mm3, crys-
tal system orthorhombic, space group Aba2, Z = 8, a = 17.2631(12) Å,
b = 35.327(3) Å, c = 8.9843(6) Å, α = 90°, β = 90°, γ = 90°, V =
5479.1(7) Å3, ρ = 1.204 g/cm3, T = 200(2) K, θmax= 26.52 deg, radiation
Mo Kα, λ = 0.71073 Å, 0.5 deg ω-scans with CCD area detector,
covering the asymmetric unit in reciprocal space with a mean
redundancy of 9.18 and a completeness of 99.5% to a resolution of
0.80 Å, 28519 reflections measured, 3028 unique (R(int) = 0.0363),
2670 observed (I >2σ(I)). Intensities were corrected for Lorentz and
polarization effects; an empirical absorption correction was applied
1
2932, 1654; H NMR (300 MHz, DMSO-d6) δ 1.00−1.23 (m, 5H),
1.50−1.80 (m, 5H), 3.00 (ABX, 2H, J = 17.0, 5.4 Hz), 3.47−3.60 (m,
1H), 5.74 (s, 1H), 6.90−7.45 (m, 10H), 7.50−7.53 (m, 1H), 7.75−7.84
(m, 2H), 8.08 (d, 1H, J = 7.2 Hz), 11.63 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 24.5, 24.6, 25.1, 31.7, 32.1, 35.3, 48.1, 66.1, 127.1,127.6,
127.8, 128.4,128.8, 130.1, 130.8, 131.7, 135.2, 138.2, 139.2, 146.7, 166.5,
167.7, 168.4; HR-MS (ESI) calcd for C28H31N4O3S [M + H]+
E
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 6. Proposed Mechanism for Synthesis of Pseudopeptides 7h−j
503.21155, found 503.21148, calcd for C28H30N4NaO3S [M + Na]+
525.19355, found 525.19331.
1527; 1H NMR (300 MHz, DMSO-d6) δ 1.22 (s, 9H), 2.9−3.00 (ABX,
2H,16.5 Hz), 6.00 (s, 1H), 6.10−7.30 (m, 11H), 7.40−7.92 (m, 6H),
11.61 (s, 1H); 13C NMR(75 MHz, DMSO-d6) δ 28.4, 50.30, 63.8, 127.1,
127.5, 127.8, 128.4, 129.9, 130.1, 130.9, 131.6, 131.6, 133.3, 135.5, 139.3,
147.0, 162.7, 168.5, 168.9, 169.8; HR-MS (ESI) calcd for C28H31N4O3
[M + H]+ 471.23953, found 471.23945, calcd for C28H30N4NaO3
[M + Na]+ 493.22129, found 493.22124.
(E)-3-(2-Benzoylhydrazono)-N-(2-(cyclohexylamino)-2-oxo-1-
phenylethyl)-N-(4-isopropylphenyl)propanemide (7g): isolated yield
63% (279 mg); mp 187−190 °C; IR (KBr, cm−1) ν = 3270, 3060, 2930,
1655, 1540; 1H NMR (300 MHz, DMSO-d6) δ 0.82−1.50 (m, 5H), 1.08
(d, 6H, J = 6 Hz,), 1.50−1.90 (m, 5H), 2.74−2.78 (m, 1H), 2.70−3.20
(ABX, 2H, J = 17.1, 4.4 Hz), 3.48−3.60 (m, 1H), 6.00 (s, 1H), 7.90−7.30
(m, 7H), 7.45−7.55 (m, 5H), 7.70−7.90 (m, 3H), 7.96 (d, 1H, J = 7.1 Hz),
11.62 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 23.7, 24.5, 24.6, 25.2, 30.9,
32.1, 47.9, 63.5, 126.2, 127.0, 127.5, 127.7, 128.2, 128.4, 129.8, 130.1, 130.6,
131.6, 133.2, 135.4, 136.8, 147,.0 147.9, 162.7, 168.4, 168.8; HR-MS (ESI)
(E)-N-(2-(Cyclohexylamino)-2-oxo-1-(thiophene-2-yl)ethyl)-N-
phenyl-3-(2-(thiophene-2-carbonyl)hydrazono)propanamide (7e):
isolated yield 52% (279 mg); mp 228−230 °C; IR (KBr, cm−1) ν =
3359, 3267, 3075, 2933, 1685, 1527;1 H NMR (300 MHz, DMSO-d6) δ
1.00−1.35 (m, 5H), 1.40−1.90 (m, 5H), 2.49−2.69 (m, 2H), 3.72 (m,
1H), 5.84 (s, 1H), 6.70−6.85 (m, 1H), 6.90−7.00 (m, 3H), 7.11−7.18
(m, 5H), 7.41 (d, 1H, J = 4.6 Hz), 7.63 (d, 1H), 7.75 (d, 1H, J = 4.8 Hz),
7.99 (d, 1H, J = 7.3 Hz), 9.98 (s, 1H, NH, pro-Z), 9.99 (s, 1H, NH,
pro-E); 13C NMR (75 MHz, DMSO-d6) δ 24.7, 25.3, 31.7, 32.0, 35.4,
49.3, 65.7, 126.2, 126.4, 127.3, 127.5, 127.9, 128.3, 129.3, 130.9, 136.8,
137.5, 140.7, 161.3, 166.5, 171.3; HR-MS (ESI) calcd for C26
H29N4O3S2 [M + H]+ 509.16909, found 509.16884, C26H28N4NaO3S2
[M + Na]+ 531.15104, found 531.15080.
(E)-3-(2-Benzoylhydrazono)-N-(2-(tert-butylamino)-2-oxo-1-phe-
nylethyl)-N-phenylpropanamide (7f): isolated yield 40% (188 mg);
mp 200−201 °C; IR (KBr, cm−1) ν = 3359, 3267, 3075, 2933, 1655,
F
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
calcd for C33H39N4O3 [M + H]+ 539.30347, found 539.30320, calcd for
C33H38N4−NaO3 [M + Na]+ 561.28481, found 561.28463.
2007, 72, 2151−2160. (c) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem.
2009, 74, 3109−3115. (d) Corres, N.; Delgado, J. J.; García-Valverde,
M.; Marcaccini, S.; Rodríguez, T.; Rojo, J.; Torroba, T. Tetrahedron
2008, 64, 2225−2232. (e) Bararjanian, M.; Balalaie, S.; Rominger, F.;
Movassagh, B.; Bijanzadeh, H. R. J. Org. Chem. 2010, 75, 2806−2812.
(3) (a) Bararjanian, M.; Balalaie, S.; Rominger, F.; Movassagh, B.;
Bijanzadeh, H. R. Mol. Divers. 2011, 15, 583−594. (b) Barajanian, M.;
Balalaie, S.; Movassagh, B.; Bijanzadeh, H. R. Tetrahedron Lett. 2010, 51,
3277−3279.
(Z)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyl-3-(2-
(3-phenylpropioloyl)hydrazinyl)acrylamide (7h): isolated yield 45%
(234 mg); mp 217−220 °C; IR (KBr, cm−1) ν = 3255, 3071, 2931, 2175,
1
1650, 1553; H NMR (300 MHz, DMSO-d6) δ 0.9−1.40 (m, 5H),
1.50−1.90 (m, 5H), 3.50−3.65 (m, 1H), 5.22 (d, 1H, J = 7.2 Hz), 5.84
(brs, 1H), 6.11 (s, 1H), 6.22 (d, 1H, J = 7.4 Hz), 6.96−7.52 (m, 15H),
8.05 (brs, 1H), 10.51 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 24.6,
24.8, 25.2, 32.2, 48.0, 63.4, 94.3, 126.9, 127.7, 127.6, 128.6, 128.7, 130.2,
130.7, 135.9, 139.8, 144.3, 161.8, 166.3, 168.6; HR-MS (ESI) calcd for
C32H33N4O3 [M + H]+ 521.25634, found 521.25608, calcd for
C32H32N4NaO3 [M + Na]+ 543.23691, found 543.23799.
(4) (a) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron
2000, 56, 5157−5162. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2000, 122, 9546−9547. (c) Tillack, A.; Garcia Castro, I.; Hartung,
C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541−2543.
(E)-N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenyl-3-(2-
tosylhydrazinyl)acrylamide (7i): isolated yield 65% (354 mg); mp
214−217 °C; IR (KBr, cm−1) ν = 3271, 3085, 2929, 1653, 1599; 1H NMR
(300 MHz, DMSO-d6) δ 0.93−1.30 (m, 5H), 1.50−1.80 (m, 5H), 2.38
(s, 3H), 3.55−3.58 (m, 1H), 4.87 (s, 2H), 5.15 (d, 1H, J = 12.9 Hz), 6.13 (s,
1H), 6.90−7.01 (m, 10H), 7.43 (d, 2H, J =8.1Hz), 7.67 (d, 2H, J = 8.2 Hz),
7.88 (d, 1H, J = 12.9 Hz), 7.95 (d, 1H, J = 7.7 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 21.1, 24.5, 24.7, 25.2, 32.1, 32.3, 47.9, 63.5, 99.5, 127.3, 127.4,
127.7, 127.7, 128.1, 130.1, 131.1, 132.9, 135.8, 139.3, 141.0, 144.7, 165.4,
168.8; HR-MS (ESI) calcd for C30H35N4O4S [M + H]+ 547.23916, found
547.23888, C30H34N4NaO4S [M + Na]+ 569.22079, found 569.22057.
(E)-N-(2-(Cyclohexylamino)-2-oxo-1-(thiophene-2-yl)ethyl)-N-
phenyl-3-(2-tosylhydrazinyl)acrylamide (7j): isolated yield 60% (331
mg); mp 223−225 °C; IR (KBr, cm−1) ν = 3271, 3085, 2929, 1653,
1599; 1H NMR (300 MHz, DMSO-d6) δ 0.94−1.30 (m, 5H), 1.40−1.80
(m, 5H), 3.33 (s, 3H), 3.40−3.60 (m, 1H), 4.87 (s, 2H), 5.13 (d, 1H, J =
12.8 Hz), 6.35 (s, 1H), 6.76−6.78 (m, 2H), 7.04−7.15 (m, 5H), 7.29 (d,
2H, J = 4.2 Hz), 7.43 (d, 2H, J = 7.9 Hz), 7.66 (d, 2H, J = 8.1 Hz), 7.88
(d, 1H, J = 12.9 Hz), 8.00 (d, 1H, J = 7.7 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 21.1, 24.5, 24.6, 25.2, 32.1, 48.0, 58.4, 99.2, 126.1, 127.4,
127.7, 128.3, 129.1, 129.8, 130.1, 130.3, 130.8, 132.9, 137.6, 141.1, 144.7,
165.3, 168.0; HR-MS (ESI) calcd for C28H33N4O4S2 [M + H]+
553.19531, found 553.19515, calcd for C28H32N4NaO4S2 [M + Na]+
575.17729, found 575.17709.
(5) (a) Muller, T. E. Tetrahedron Lett. 1998, 39, 5961−5962.
̈
(b) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675−704. (c) Alonso,
̈
F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079−3160.
(d) Panda, N.; Raghavender, M. J. Org. Chem. 2012, 77, 9407−9412.
(e) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68,
8079−8146.
(6) (a) Dabb, S. L.; Messerle, B. A. Dalton Trans. 2008, 6368−6371.
(b) Zhao, J.; Zheng, Z.; Bottle, S.; Chou, A.; Sarina, S.; Zhu, H. Chem.
Commun 2013, 49, 2676−2678.
(7) (a) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104−114.
(b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004,
43, 3368−3398.
(8) (a) Datta, S.; Roesky, P. W.; Blechert, S. Organometallics 2007, 26,
4392−4394. (b) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem.
Soc. 2005, 127, 2042−2043.
(9) Hartung, C. G.; Tillack, A.; Trauthwein, H.; Beller, M. J. Org. Chem.
2001, 66, 6339−6343.
(10) (a) Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570−4571. (b) Jones, G. C.; Beard, W. Q.; Hauser, C.
R. J. Org. Chem. 1963, 28, 199−203.
(11) Dabb, S. L.; Ho, J. H. H.; Hodgson, R.; Messerle, B. A.; Wagler, J.
Dalton Trans. 2009, 634−642.
(12) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed.
1999, 38, 3222−3225.
(13) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757−1771.
(b) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770−3772.
(14) (a) Straub, T.; Haskel, A.; Neyroud, T. G.; Kapon, M.;
Botoshansky, M.; Eisen, M. S. Organometallics 2001, 20, 5017−5035.
(b) Haskel, A.; Straub, T.; Eisen, M. S. Organometallics 1996, 15, 3773−
3775. (c) Straub, T.; Frank, W.; Reiss, G. J.; Eisen, M. S. Dalton Trans.
1996, 2541−2546.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, X-ray crystallographic data, and copies
of IR, 1H NMR,13C NMR, and also HRMS (ESI) spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(15) (a) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305−
2308. (b) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123,
2923−2924. (c) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed.
1999, 38, 3389−3391. (d) Bytschkov, I.; Doye, S. Eur. J. Org. Chem.
2003, 2003, 935−946. (e) Shi, Y.; Ciszewski, J. T.; Odom, A. L.
Organometallics 2001, 20, 3967−3969. (f) Cao, C.; Ciszewski, J. T.;
Odom, A. L. Organometallics 2001, 20, 5011−5013. (g) Sweeney, Z. K.;
Salsman, J. L.; Andersen, R. A.; Bergman, R. G. Angew. Chem., Int. Ed.
2000, 39, 2339−2343. (h) Polse, J. L.; Andersen, R. A.; Bergman, R. G. J.
Am. Chem. Soc. 1998, 120, 13405−13414. (i) Baranger, A. M.; Walsh, P.
J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753−2763. (j) Walsh, P.
J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708−
1719.
AUTHOR INFORMATION
Corresponding Author
*E-mail: balalaie@kntu.ac.ir.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.B. gratefully acknowledges Iranian National Science Foundation
(INSF) for financial support. We also thank the Iranian Ministry of
Health and Medical Education and also the Presidential Office
Deputy of Science and Technology for financial support.
(16) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853−2856.
(17) (a) Sheldrick, G. M. Bruker Analytical X-ray-Division, Madison,
WI, 2008. (b) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122.
REFERENCES
■
(1) (a) Domling, A. InMulticomponent Reactions; Zhu, J., Bienayme, H.,
̈
Eds.; Wiley-VCH: Weinheim, 2005; p 76−94. (b) Slobbe, P.; Ruijler, E.;
Orru, R. V. A. Med. Chem. Commun 2012, 3, 1189−1218. (c) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234−
6246. (d) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
̈
3083−3155.
(2) (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.;
Herdtweck, E.; Domling, A. Org. Lett. 2003, 5, 1047−1050. (b) Banfi, L.;
̈
Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem.
G
dx.doi.org/10.1021/jo4003294 | J. Org. Chem. XXXX, XXX, XXX−XXX