Synthesis of novel bis(β-aminocarbonyl) compounds and some β-aminocarbonyls by catalyst-free multicomponent Mannich reactions

Article abstract of DOI:10.1007/s13738-013-0340-3

A highly diastereoselective catalyst-free multicomponent Mannich reaction between cyclohexanone, aromatic aldehydes and amines in cyclohexane is described. The double Mannich reaction of diamines and two equivalents of aldehydes and cyclohexanone gave the

Full text of DOI:10.1007/s13738-013-0340-3

J IRAN CHEM SOC (2014) 11:685–692
DOI 10.1007/s13738-013-0340-3
ORIGINAL PAPER
Synthesis of novel bis(b-aminocarbonyl) compounds and some
b-aminocarbonyls by catalyst-free multicomponent Mannich
reactions
•
H. Eshghi M. Rahimizadeh F. Eshkil
•
•
•
M. Hosseini M. Bakavoli M. Sanei-Ahmadabad
•
Received: 2 March 2013 / Accepted: 1 September 2013 / Published online: 13 September 2013
Ó Iranian Chemical Society 2013
Abstract A highly diastereoselective catalyst-free mul-
ticomponent Mannich reaction between cyclohexanone,
aromatic aldehydes and amines in cyclohexane is descri-
bed. The double Mannich reaction of diamines and two
equivalents of aldehydes and cyclohexanone gave the
novel bis(b-aminocarbonyl) compounds. Reactions pro-
ceeded in good to high yields with an excellent diastere-
oselectivity. The best selectivity was obtained where there
are weak electron donating and electron-withdrawing
groups on the aldehyde. The rate formation of Mannich
product is decreased when strong electron-withdrawing
groups and/or electron-releasing groups are present on
aldehyde. In these cases only the corresponding imines are
obtained in moderate to high yields. Aromatic diamines are
more suitable than aliphatic diamines in this reaction.
Usually, aliphatic diamines only produce the corresponding
imines albeit in high yields.
Introduction
Multicomponent reactions (MCRs) have become a signif-
icant part of today’s arsenal of methods in combinatorial
chemistry due to their valuable features such as atom
economy, straightforward reaction design, and the oppor-
tunity to construct target compounds by the introduction of
several diversity elements in a single chemical event [1–3].
Typically, purification of products resulting from MCRs is
simple since all the organic reagents employed are con-
sumed and incorporated into the target compound [4].
A Mannich-type reaction is a multicomponent reaction of a
non-enolizable aldehyde, a primary or secondary amine, and
an enolizable carbonyl compound to afford the corresponding
b-amino carbonyl compound [5]. These b-amino carbonyl
compounds are important synthetic intermediates for the
synthesis of various pharmaceuticals and natural products [6]
and have found wide application in organic synthesis.
Keywords Bis(b-aminocarbonyl) compounds ꢀ
Mannich reaction ꢀ Combinatorial chemistry ꢀ
Catalyst free
The Mannich reaction is one of the most widely used
chemical transformations for the construction of nitrogen-
containing compounds [7]. With the increasing occurrence
of nitrogen in drugs and natural products, highly asym-
metric variants of the Mannich reaction are desirable [8].
Moreover, a catalytic diastereo- and enantioselective
reaction would be the most efficient means of constructing
this class of compounds because the chirality-controlling
element is used in limited quantities [9]. Several strategies
are available for the diastereoselective synthesis of b-
amino carbonyl compounds, using different catalysis
methods including organocatalysis [10], transition-metal
catalysis [11], BrAnsted [12] and Lewis acid [13] catalysis,
phase-transfer catalysis [14], HPA catalysis [15], bioca-
talysis [16] and ionic liquid catalysis [17].
The manuscript has been presented at the ‘‘1st National Conference
on Multi-Component Reaction’’ in Institute of Science and High
Technology and Environmental sciences, Graduate University of
Advanced Technology, Kerman, Iran, 2012.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0340-3) contains supplementary
material, which is available to authorized users.
H. Eshghi (&) ꢀ M. Rahimizadeh ꢀ F. Eshkil ꢀ M. Hosseini ꢀ
M. Bakavoli ꢀ M. Sanei-Ahmadabad
Department of Chemistry, School of Sciences, Ferdowsi
University of Mashhad, 91775-1436 Mashhad, Iran
e-mail: heshghi@um.ac.ir
In this work, we report for the first time, a catalyst-free
method for the three-component Mannich reaction of
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J IRAN CHEM SOC (2014) 11:685–692
Scheme 1 Bis(b-
R'
R'
aminocarbonyl) compounds
from the double Mannich
reactions
H
R
O
NH2
O
O
HN
O
HN
Cyclohexane
Catalyst-free, r.t
R'
R
R
syn
anti
R
R
O
H
R
O
X
X
cyclohexane
Catalyst-free, r.t
N
H
N
H
H2N
NH2
O
O
X= Aryl, Biaryl, (CH2)2
R= H, 4-Cl, 2-Cl, 4-CH3
aromatic aldehydes and aromatic amines with cyclohexa-
none to afford the anti Mannich product with high diaste-
reoselectivity. The catalyst-free synthesis of novel bis(b-
aminocarbonyl) compounds from the double Mannich
reactions between cyclohexanone, aromatic aldehydes and
diamines is also investigated (Scheme 1).
with crystallization by aqueous ethanol. The products were
characterized by comparison of their physical data with
those of known samples or by their 1H NMR, FT-IR
spectral data and elemental analysis.***
2-[Anilino(phenyl)methyl]-1-cyclohexanone (1)
C19H21NO (crystalline light brown solid) 65 %; m.p.
117–118 °C; 1H NMR (CDCl3, 100 MHz, d ppm): 1.4–2.3
(m, 6H), 2.3–2.6 (m, 2H), 2.6–2.9 (m, 1H), 4.65 (d, 1H,
J = 7.5 Hz, anti), 6.3–6.8 (m, 3H), 6.9–7.75 (m, 7H); IR
(KBr disk):3,330 (s, NH), 3,023 (w), 2,934 (m), 1,702 (s,
C=O), 1,602 (s), 1,497 (s), 1,279 (m), 754 (m),
Experimental
General: All solvents, reagents and compounds were pur-
chased from Merck and Fluka companies. NMR spectra
were recorded on ASPECT 3000 Brucker-100 MHz and
Avance Brucker-400 MHz spectrometers. All chemical
shifts in NMR experiments are reported as ppm and were
referenced to residual solvent. FT-IR spectra were recorded
on AVATAR-370-FT-IR ThermoNicolet. All mass spectra
were scanned on a Varian Mat CH-7 at 70 eV. Reaction
was monitored by TLC using silica gel plates and the
products were identified by comparison of their spectra and
physical data with those of the authentic samples. Melting
points were measured on an Electrothermal 9100
apparatus.
703(m) cm-1
.
2-[Phenyl(3-toluidino)methyl]-1-cyclohexanone (2)
C20H23NO (powder light brown solid) 45 %; m.p.
120–122 °C; 1H NMR (CDCl3, 100 MHz, d ppm): 1.5–2.2
(m, 6H), 2.2 (s, 3H), 2.2–2.6 (m, 2H), 2.6–3.1 (m, 1H),
2.5–3.5 (br, NH), 4.6 (d, 0.19H, J = 7.5 Hz, anti), 4.8 (d,
0.81H, J = 4.8 Hz, syn), 6.1–6.5 (m, 3H), 6.95 (t, 1H,
J = 7 Hz), 7.1–7.6 (m, 5H). IR (KBr disk): 3,386 (s, NH),
3,022 (w), 2,957 (m), 1,696 (s, C=O), 1,603 (s), 1,525 (s),
Typical procedure for the synthesis of b-
aminocyclohexanones (1–6)
1,444 (s), 1,310 (m), 781(s), 702 (s) cm-1
.
2-[(4-Chlorophenyl)(3-toluidino)methyl]-1-cyclohexanone
(3)
A mixture of aromatic amine (1.0 mmol), aromatic alde-
hyde (1.0 mmol) and cyclohexanone (1.2 mmol) in
cyclohexane (1 mL) was stirred at room temperature and
the completion of the reaction was monitored by TLC.
After completion of the reaction petroleum ether (1 mL)
was added and the mixture was filtered by suction and
dried in air. The crude product obtained was used to
determine the isomer ratio by NMR spectroscopy without
further purification. Further purification was performed
C20H22ClNO (crystalline light brown solid) 45 %; m.p.
127–128 °C; 1H NMR (CDCl3, 100 MHz, d ppm): 1.4–2.1
(m, 6H), 2.2 (s, 3H), 2.3–2.7 (m, 2H), 2.7–3.2 (m, 1H), 4.55
(d, 1H, J = 7.5 Hz, anti), 6.3–6.8 (m, 3H), 7.05 (t, 1H,
J = 7 Hz), 7.32 (AB-q, 4H). IR (KBr disk): 3,349 (s, NH),
3,039 (w), 2,940 (m), 1,703 (s, C=O), 1,606 (m), 1,489 (m),
780 (m) cm-1
.
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J IRAN CHEM SOC (2014) 11:685–692
687
2-[(3-Nitrophenyl)(4-toluidino)methyl]-1-cyclohexanone
(4)
performed with crystallization by hot ethyl acetate and
then ethanol.
N1,N4-Bis(cyclohexyl-2-one(phenyl)methyl)benzene-1,4-
diamine (7)
C20H22N2O3 (powder light brown solid) 62 %; m.p.
136–138 °C; 1H NMR (CDCl3, 400 MHz, d ppm):
1.50–1.90 (m, 3H), 1.9–2.2 (m, 3H), 2.21 (s, 3H), 2.3–2.5
(m, 2H), 2.85–2.95 (m, 1H), 4.73 (d, 0.48H, 5.2 Hz, anti),
4.86 (d, 0.52H, 4.4 Hz, syn), 6.48 (d, 2H, 8.4 Hz), 6.93 (d,
2H, J = 8.0 Hz), 7.49 (t, 1H, J = 8.0 Hz), 7.80 (d, 1H,
J = 7.2 Hz), 8.09 (d, 1H, J = 8 Hz), 8.28 (s, 1H); 13C
NMR (CDCl3, 100 MHz, d ppm): 20.38, 20.40, 24.46,
24.99, 27.21, 27.85, 29.23, 31.98, 42.41, 42.53, 56.37,
57.12, 57.33, 57.91, 113.69, 114.21, 122.23, 122.36,
122.54, 127.31, 127.55, 129.32, 129.38, 129.72, 129.80,
133.72, 134.25, 144.36, 144.66, 148.41, 210.90 (syn),
212.03 (anti); IR (KBr disk): 3,383 (s, NH), 2,932 (m),
1,704 (C=O, syn), 1,697 (C=O, anti), 1,616 (m), 1,518 (s),
1
C32H36N2O2 (powder dark green solid) H NMR (CDCl3,
100 MHz, d, ppm): 7.1–7.8 (m, 10H), 6.5–6.8 (m, 4H),
4.6–4.75 (d, 0.4H, syn), 4.2–4.35 (d, 1.6H, anti), 4–5 (b,
2H, NH), 2.9–3.1 (m, 2H), 1.5–2.3 (m, 12H), 1.2–1.5 (m,
4H). 13C NMR (CDCl3, 100 MHz, d, ppm): 213.1 (anti
isomers), 157, 156.3, 146.2, 141.8, 141.6, 137.0, 136.7,
136.2, 136.0, 132.4 130.8, 130.6, 130.4, 130.0, 128.8,
128.7, 128.6, 128.5,128.4, 128.2, 127.3, 122.4, 122.3,
116.9, 115.9, 114.0, 58.2, 57.4, 41.9, 31.5, 2,805, 28.0,
23.75, 23.0. IR (KBr disk): 3,403 (s, NH), 3,374 (s, NH),
3,059 (w), 3,026 (w), 2,949 (m), 2,859 (m), 1,692 (s, C=O),
1,346 (s), 811 (s), 711 (m) cm-1
.
1,588 (s), 1,516 (s), 1,440 (m), 758 (m), 702 (m) cm-1
.
Elemental analysis for C32H36N2O2: calcd % (C, 79.96; H,
7.55; N, 5.83). Found %: (C, 79.79; H, 7.51; N, 8.63). MS
(m/z): 480, 470, 451, 442, 359 (base peak), 280, 271, 256,
215, 194, 150, 127, 114, 90, 65.
2-[(4-Chlorophenyl)(4-toluidino)methyl]-1-cyclohexanone
(5)
C20H22ClNO (crystalline light brown solid) 45 %; m.p.
125–126 °C; 1H NMR (CDCl3, 100 MHz, d ppm): 1.5–2.1
(m, 6H), 2.17 (s, 3H), 2.25–2.5 (m, 2H), 2.6–2.9 (m, 1H),
4.6 (d, 1H, J = 7.5 Hz, anti), 6.4 (d, 2H, J = 9 Hz), 6.9 (d,
2H, J = 9 Hz), 7.26 (AB-q, 4 H); IR (KBr disk): 3,349 (s,
NH); 3,051 (w), 2,940 (m), 1,703 (s, C=O), 1,607 (s), 1,490
N1,N4-Bis(cyclohexyl-2-one(4-
methylphenyl)methyl)benzene-1,4-diamine (8)
1
C34H40N2O2 (powder dark green solid) H NMR (CDCl3,
100 MHz, d, ppm): 7.1–7.6 (m, 8H), 6.6–6.8 (m, 4H), 4.6
(d, 2H, anti), 3.4–4.1 (b, 2H, NH), 2.7–3.1 (m, 2H), 2.2–2.5
(m, 4H, s, 6H, CH3), 1.6–2.1 (m, 12H). 13C NMR (CDCl3,
100 MHz, d, ppm): 213 (anti isomers), 159.7, 157.0, 156.3,
150.0, 146.1, 145.1, 143.1, 142.0, 141.9, 141.1, 141.0,
138.9, 138.5,136.9,136.8, 133.7, 130.5, 129.6, 129.5,
129.4, 129.2, 129.0,128.8, 128.5, 127.2, 122.3,122.2,
121.9, 115.6, 114.1, 57.9, 57.5, 41.8, 31.3, 28.6, 28.0, 23.6,
21.7, 21.6, 21.5, 21.1. IR (KBr disk): 3,402 (s, NH), 3,026
(w), 2,941(m), 2,855 (m), 1,693 (s, C=O), 1,605 (s), 1,511
(s), 1,492 (m), 887 (m), 811(m) cm-1. Elemental analysis
for C34H40N2O2: calcd % (C, 80.28; H, 7.93; N, 5.51).
Found %: (C, 79.89; H, 7.51; N, 5.42). MS (m/z): 508, 494,
392, 389, 311, 309 (base peak), 208, 155, 90, 65.
(m), 827 (m), 781 (s) cm-1
.
2-[Anilino(2-chlorophenyl)methyl]-1-cyclohexanone (6)
C19H20ClNO (crystalline light brown solid) 54 %; m.p.
150–152 °C; 1H NMR (CDCl3, 100 MHz, d ppm): 1.6–2.2
(m, 6H), 2.3–2.5 (m, 2H), 2.7–3.1 (m, 1H), 4.7–5.3 (br,
NH), 4.90 (d, 1H, J = 5.0 Hz, syn), 6.5–6.7 (m, 3H),
6.9–7.2 (m, 3H), 7.2–7.4 (m, 4H); IR (KBr disk): 3,386 (s,
NH), 3,022 (w), 2,957 (m), 1,696 (s, C=O), 1,603 (s), 1,525
(m), 1,444 (m), 780 (s), 702 (s) cm-1. Elemental analysis
for C19H20ClNO: calcd % (C, 72.72; H, 6.42; N, 4.46).
Found %: (C, 72.89; H, 6.51; N, 4.23).
N1,N4-Bis(cyclohexyl-2-one(4-
Typical procedure for the synthesis of bis(b-
aminocarbonyl) compounds (7–14)
chlorophenyl)methyl)benzene-1,4-diamine (9)
1
C32H34Cl2N2O2 (powder green solid) H NMR (CDCl3,
A mixture of diamine (1.0 mmol), aromatic aldehyde
(2.0 mmol) and cyclohexanone (2.4 mmol) in cyclohex-
ane (2.0 mL) was stirred at room temperature and the
progress of the reaction was monitored by TLC. After
completion of the reaction petroleum ether (b.p.
40–60 °C, 1 mL) was added, the mixture was filtered by
suction, solid product was obtained that is suitable for
spectroscopic application. Further purification was
100 MHz, d, ppm): 7.2–7.4 (AB-q, 4H), 7.1 (d, 4H,
J = 7.5 Hz), 6.5 (d, 4H, J = 7.5 Hz), 4.6 (d, 2H, anti), 4.3
(bd, 2H, NH), 2.7–2.9 (m, 2H), 2.2–2.6 (m, 4H), 1.5–2.1
(m, 8H), 1.3 (m, 4H). 13C NMR (CDCl3, 100 MHz, d,
ppm): 215 (anti isomers), 154, 136, 132, 129, 128, 122,
116, 114, 53, 52, 43, 32, 27, 24. IR (KBr disk): 3,415 (s,
NH), 2,945 (w), 2,863 (m), 1,696 (s, C=O), 1,517 (s), 1,487
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(s), 1,297 (m), 826 (m) cm-1. Elemental analysis for
C32H34Cl2N2O2: calcd % (C, 69.94; H, 6.24; N, 5.10).
Found %: (C, 70.81; H, 6.51; N, 5.21). MS (m/z): 549, 515,
473, 435, 350, 307, 229 (base peak), 215, 153, 125, 92, 65,
43, 29.
27.07, 24.84, 23.90, 23.52, 23.38, 23.05, 21.68, 21.44,
21.10. IR (KBr disk): 3,407 (s, NH), 3,026 (w), 2,925,
2,858 (m), 1,702 (s, C=O), 1,603 (s), 1,505 (s), 1,274 (m),
1,140 (m), 818(m) cm-1
.
Elemental analysis for
C40H44N2O2: calcd % (C, 82.15; H, 7.58; N, 4.79).
Found %: (C, 82.05; H, 7.46; N, 4.45). MS (m/z): 584, 574,
546, 469, 387, 364, 299, 284 (base peak), 257, 193, 166,
151, 115, 91, 28.
40
N4,N Bis(cyclohexyl-2-one(phenyl)methyl)biphenyl-4,40-
diamine (10)
0
1
C38H40N2O2 (powder light green solid) H NMR (CDCl3,
N4,N4 Bis(cyclohexyl-2-one(4-
400 MHz, d, ppm): 7.84 (s, imine impurity), 7.18–7.65 (m,
6H), 6.56 (dt, 4H, J = 8, 2.5 Hz), 4.8–4.9 (three d of syn
isomers (1:2:4) 2H, J = 6 Hz, 37 %), 4.63–4.7 (three d of
anti isomers (1:1:7), 2H, J = 7.2 Hz, 63 %), 4–5 (b, 2H,
NH), 2.98 [dt, 2H(major isomer), J = 8, 2.0 Hz], 2.87 [dt,
2H(minor isomer), J = 7.5, 2.5 Hz], 2.7–2.83 (m, other
isomers, 2H), 2.45 [m, 4H(minor isomer, 37 %)], 2.39 [m,
4H(major isomer, 63 %)], 1.5–2.1 (m, 8H), 1.3 (m, 4H).
13C NMR (CDCl3, 100 MHz, d, ppm): 212.9 (anti iso-
mers), 211.4 (syn isomers), 145.97, 145.69, 141.81, 136.97,
136.22, 136.01, 135.62, 130.40, 130.33, 128.77, 128.62,
128.56, 128.50, 128.41, 128.37, 127.53, 127.53, 127.28,
127.19, 127.09, 126.99, 115.44, 114.29, 113.87, 113.82,
58.09, 57.53, 57.37, 56.67, 42.43, 42.02, 41.77, 40.38,
31.28, 29.73, 28.98, 28.68, 28.49, 27.91, 27.06, 24.87,
23.92, 23.63, 23.42, 23.05. IR (KBr disk): 3,393 (s, NH),
3,022 (w), 2,936, 2,859 (m), 1,701 (s, C=O), 1,613 (s),
1,504 (s), 1,448 (m), 813 (m), 701(m) cm-1. Elemental
analysis for C38H40N2O2: calcd % (C, 81.98; H, 7.24; N,
5.03). Found %: (C, 82.09; H, 7.41; N, 4.95). MS (m/z):
556, 523, 469, 444, 348, 271, 183 (base peak), 127, 114,
91, 41, 28.
cholorophenyl)methyl)biphenyl-4,40-diamine (12)
C38H38Cl2N2O2 (powder light green solid,) 1H NMR
(CDCl3, 100 MHz, d, ppm): 7.1–7.6 (m, 12H), 6.5–6.65
(m, 4H), 4.75–4.9 (d, 0.74H, syn), 4.55–4.7 (d, 1.26H,
anti), 4.3 (bd, 2H, NH), 2.6–3.1 (m, 2H), 1.2–2.45 (m,
16H). 13C NMR (CDCl3, 100 MHz, d, ppm): 212.9 (anti
isomers), 211.4 (syn isomers),154.6, 136.4, 135.8, 134.3,
131.6, 131.5, 129.5, 128.9, 128.7, 128.6, 122.4, 115.6,
114.0, 57.7, 57.3, 42.2, 42.0, 31.7, 28.4, 27.9, 26.9, 24.1,
22.8. IR (KBr disk): 3,393 (s, NH), 3,026 (w), 2,936, 2,863
(m), 1,701 (s, C=O), 1,612 (s), 1,503 (s), 1,281 (m), 814
(m), 701(m) cm-1. Elemental analysis for C38H38Cl2N2O2:
calcd % (C, 72.95; H, 6.12; N, 4.48). Found %: (C, 72.09;
H, 6.03; N, 4.12). MS (m/z): 625, 350, 271, 215, 184 (base
peak), 167, 129, 115, 92, 67, 29.
0
N4,N4 Bis(cyclohexyl-2-one(2-
cholorophenyl)methyl)biphenyl-4,40-diamine (13)
C38H38Cl2N2O2 (powder dark green solid) 1H NMR
(CDCl3, 100 MHz, d, ppm): 7.1–7.7 (m, 12H), 6.5–6.7 (m,
4H), 4.9 (d, 2H, syn), 4.3 (bd, 2H, NH), 2.6–3.1 (m, 2H),
1.2–2.4 (m, 16H). 13C NMR (CDCl3, 100 MHz, d, ppm):
211.4 (syn isomers), 134.1, 131.8, 130.6, 129.7, 129.0,
128.3, 127.9, 127.3, 127.1, 126.3, 121.6, 115.5, 113.5,
55.4,28.4, 26.9, 24.0, 23.8.IR (KBr disk): 3,384 (s, NH),
3,025 (w), 2,926, 2,850 (m), 1,705 (s, C=O), 1,612 (s),
1,503 (s), 1,280 (m), 813 (m), 753 (m) cm-1. Elemental
analysis for C38H38Cl2N2O2: calcd % (C, 72.95; H, 6.12;
N, 4.48). Found %: (C, 72.79; H, 6.33; N, 4.41). MS (m/z):
625, 341, 306, 263, 220, 185 (base peak), 167, 128, 115,
91, 67, 29.
0
N4,N4 Bis(cyclohexyl-2-one(4-
methylphenyl)methyl)biphenyl-4,40-diamine (11)
C40H44N2O2 (powder green solid) 1H NMR (CDCl3,
400 MHz, d, ppm): 7.8–7.85 (imine impurities), 7.47 [d,
2H(major isomer), J = 8.2 Hz], 7.25 [d, 2H(major iso-
mer), J = 8 Hz], 7.1–7.4 (m, 6H), 6.55 (d, 4H,
J = 8.2 Hz), 4.79 [d, 2H(syn, 20 %), J = 4.4 Hz], 4.67 [d,
2H(anti, 20 %), J = 6.8 Hz], 4.62 [d, 2H(anti, 60 %)],
4.5–5 (b, 2H, NH), 2.96 [dt, 2H(major isomer), J = 5 Hz],
2.86 [dt, 2H(minor isomer), J = 4.5 Hz], 2.7–2.84 (m,
other minor isomers), 2.3–2.5 (m, 4H), 2.42 [s, 3H(CH3,
major isomer)], 2.41 [s, 3H(CH3, minor isomer)], 2.23 [s,
3H(CH3, minor isomer)], 1.6–2 (m, 12H), 1.296 (m, 4H).
13C NMR (CDCl3, 100 MHz, d, ppm): 213.06, 145.72,
138.84, 138.72, 136.90, 136.76, 135.85, 135.52, 133.24,
130.51, 130.48, 129.58, 129.52, 129.21, 129.16, 129.13,
128.88, 128.87, 127.61, 127.43, 127.15, 126.96, 126.82,
121.46, 121.30, 114.26, 113.81, 57.78, 57.59, 56.72, 42.44,
41.69, 40.30, 31.17, 29.74, 29.03, 28.81, 28.56, 27.61,
N1,N2-Bis(cyclohexyl-2-one(2-
chlorophenyl)methyl)ethylene-1,2-diamine (14)
C28H34Cl2N2O2 (brown oil) 1H NMR (CDCl3, 400 MHz, d,
ppm): 7.57 (b, 2H, OH aldol), 7.54 (bs, 2H, enone), 7.1–7.45
(m, H, Ar), 5.51 (m, 1H, syn aldol, 70 %), 5.45 (m, 1H, anti
aldol, 30 %), 5.21 (bs, syn Mannich, 83 %), 5.1 (bs, anti
Mannich, 17 %), 3.5–4 (b, NH), 2.7 (m, 2H), 2.58 (t, 2H,
J = 8 Hz), 2.35 (t, 2H, J = 8 Hz), 1.55–2.0 (m, cyclohexyl
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J IRAN CHEM SOC (2014) 11:685–692
689
40
N4,N -bis(4-nitrobenzylidene)-[1,10-biphenyl]-4,40-
protons), 1.44 (m, 4H). 13C NMR (CDCl3, 100 MHz, d,
ppm): 212.1 (Mannich carbonyl), 201.7 (aldol carbonyl),
147.74, 143.11, 130.81, 130.45, 129.63, 129.50, 129.35,
129.29, 129.09, 128.65, 124.66, 117.07, 64.38, 61.95, 58.45,
55.17, 52.51, 49.21, 48.62, 47.42, 45.52, 44.55, 42.00, 40.67,
33.93, 33.71, 28.97, 27.27, 27.17, 23.92. IR (KBr disk):
3,374 (s, NH), 3,064 (w), 2,928, 2,854 (m), 1,707 (s, C=O),
1,689 (s), 1,606 (s), 1,467 (m), 11,436 (m), 1,255(m), 1,141
(m), 1,034 (s), 748 (s) cm-1. Elemental analysis for
C28H34Cl2N2O2: calcd % (C, 67.06; H, 6.83; N, 5.59).
Found %: (C, 66.89; H, 6.51; N, 5.24). MS (m/z): 501, 409,
352, 299, 235, 186 (base peak), 128, 116, 40.
diamine (16)
C26H18N4O4 (powder orange solid) 1H NMR (CDCl3,
100 MHz, d, ppm): 8.6 (s, 2H), 8.3 (d, 4H), 8.1 (d, 4H), 7.7
(d, 4H), 7.3 (d, 4H). 13C NMR (CDCl3, 100 MHz, d, ppm):
129.5, 127.8, 124.1, 121.7.
Result and discussion
As previously reported [18], when we use ferric hydrogen
sulfate (10 mol %) as an inorganic heterogeneous catalyst
in ethanol, the three-component Mannich reaction gave
moderate diastereoselectivity (anti:syn = 67:33). We also
found that the synthesis of b-aminocarbonyl compounds
from three-component Mannich reaction could also be
carried out without a catalyst in ethanol. In the present
work, we decided to explore Mannich reactions between
aniline (1.0 eq), benzaldehyde (1.0 eq) and cyclohexanone
(1.2 eq) as a model reaction to optimize the reaction con-
ditions in the absence of any catalyst. We used freshly
distilled materials in these reactions to minimize the
chances of any impurity catalysis. Benzaldehyde was
washed carefully with sodium bicarbonate solution to
remove any benzoic acid impurity. The results of reactions
in the presence of polar and non-polar solvents are shown
in Table 1. This reaction took place faster in protic solvents
such as ethanol and methanol in the absence of catalyst but
the diastereoselectivity was low (Table 1, entries 1 and 2).
0
N4,N4 Bis(cyclohexyl-2-one(4-
methoxyphenyl)methyl)biphenyl-4,40-diamine (15)
1
C40H44N2O4 (powder dark green solid) H NMR (CDCl3,
400 MHz, d, ppm): 7.47 [d, 2H(major isomer), J =
8.2 Hz], 7.25 [d, 2H(major isomer), J = 8 Hz], 7.1–7.4 (m,
6H), 6.55 (d, 4H, J = 8.2 Hz), 4.79 [d, 2H (syn, 30 %),
J = 4.4 Hz], 4.62 [d, 2H (anti, 70 %), J = 6.8 Hz], 4.5–5
(b, 2H, NH), 2.96 [dt, 2H(major isomer), J = 5 Hz], 2.86
[dt, 2H(minor isomer), J = 4.5 Hz], 2.7–2.84 (m, other
minor isomers), 2.3–2.5 (m, 4H), 2.42 [s, 3H(CH3, major
isomer)], 2.41 [s, 3H(CH3, minor isomer)], 2.23 [s,
3H(CH3, minor isomer)], 1.6–2 (m, 12H), 1.296 (m, 4H).
13C NMR (CDCl3, 100 MHz, d, ppm): 213.06, 211, 149.9,
145.2, 130.7, 128.6, 128.2, 127.2, 127.1, 123.7, 123.6,
114.3, 113.7, 57.9, 57.0, 56.2, 42.5, 42.0, 32.1, 27.0, 25.7,
25.0, 24.5.
Table 1 Catalyst-free diastereoselective three-component Mannich reaction of aniline and benzaldehyde with cyclohexanone
O
H
NH2
O
O
HN
O
HN
Condition, rt
+
+
+
anti
syn
a) Isolated Yield. b) Determined by 1HNMR Spectroscopy. c) No reaction.
Entry
Solvent
Yield (%)a
Anti::synb
Time (h)
1
2
3
4
5
6
7
8
a
Ethanol
72
60:40
0.5
0.5
Methanol
Acetonitrile
Pyridine
70
60:40
NRc
NR
NR
65
–
12
–
12
12
12
20
12
Dichloromete
Cyclohexane
Petroleum ether
Neat
–
[99:\1
[99:\1
–
60
NR
b
Isolated yield, determined by H NMR spectroscopy, no reaction
1
c
123

690
J IRAN CHEM SOC (2014) 11:685–692
Table 2 Scope of catalyst-free three-component Mannich reaction of aromatic amines and aldehydes with cyclohexanone
R
R
O
H
NH2
O
O
HN
O
HN
Cyclohexane
+
+
+
rt, catalyst-free
R
R'
R'
R'
1-6
anti
syn
Entry
R
R0
Product (yield %)a
Anti:synb
Time (h)
M.p. (lit. m.p.)/ °C
1
2
3
4
5
6
7
8
9
a
H
H
1 (65)
2 (45)
[99:\1
19:81
[99:\1
48:52
[99:\1
1[:99\
–
12
24
24
24
48
48
48
24
72
117–118 (116–118 [21])
120–122 (123–124 [22])
127–128 (127–128 [18])
136–138 (136–137 [18])
125–126 (125–126 [18])
150–152 (150–151 [23])
132–134 (188–190 [24])c
122–124 (134–135 [25])
130–132 (125–127 [26])
3-Me
3-Me
4-Me
4-Me
H
H
4-Cl
3 (45)
3-NO2
4-Cl
4 (62)
5 (45)
2-Cl
6 (54)
2-Cl
4-Cl
4-NO2
4-NO2
4-NO2
1
Imine (80)
Imine (75)
Imine (70)
–
4-OMe
–
b
c
Isolated yield, determined by H NMR, for it’s hydrochloride salt
In other polar aprotic solvents such as acetonitrile and
pyridine the reaction failed (Table 1, entries 3–5). The use
of a protic solvent may catalyze this reaction by hydrogen
bonding or proton transfer. On the other hand, in non-polar
solvents such as cyclohexane and petroleum ether, the
reaction took place slowly but with high diastereoselec-
tivity (Table 1, entries 6 and 7). It seems that the solubility
of the reactants, iminium intermediate and products is low
in non-polar cyclohexane solvent. Also, this reaction did
not proceed under catalyst-free and solvent-free conditions
(Table 1, entry 8). So, it seems that the enol concentrations
in non-polar solvents increase and promote the reaction. On
the other hand, the less solubility of products assists the
reaction compellation in these non-polar solvents. The
precise percent of enol present at equilibrium is solvent
dependent. For example, for ethyl acetoacetate, the amount
of enol is higher in non-polar solvents (15–30 %) such as
carbon tetrachloride and benzene than in more polar sol-
vents such as water and acetone (5 % enol in acetone, 1 %
enol in water) [19, 20].
withdrawing groups such as NO2 at the para or meta
positions of the benzaldehyde disfavored the Mannich
reaction and only the corresponding imines are obtained in
moderate to high yields. Interestingly, with this EWG on
aldehyde (3-NO2), only one example of Mannich reaction
without significant diastereoselectivity is obtained when an
ERG is present at the aromatic amine (Table 2, entry 4).
In view of these findings, we decided to synthesise a
more complex Mannich reaction using a diamine (1 eq), an
aromatic aldehyde (2 eq) and cyclohexanone (2.4 eq)
under catalyst-free conditions in cyclohexane as a non-
polar solvent. The results of this investigation which led to
the synthesis of novel bis(b-aminocarbonyl) compounds
are shown in Table 3. As it can be seen in some examples
only the anti stereoisomer is obtained (Table 3, entries 2
and 3), while in other examples selectivity is lower and
some syn isomer is also formed. Interestingly, the 2-chlo-
robenzaldehyde yielded only the syn isomer (Table 3,
entries 7 and 8). The weak electron-withdrawing or elec-
tron-releasing groups on benzaldehyde enhance the reac-
tion rate and the diastereoselectivity. The presence of
strong electron-withdrawing or electron-releasing groups
on benzaldehyde disfavored the Mannich reaction and only
the corresponding imines are obtained. Aromatic diamines
are more suitable than aliphatic diamines in these reactions.
Ethylene diamines usually gave the corresponding imines
in high yields.
When the reaction conditions were optimized on the
model reaction, the effect of various electron-withdrawing
and electron-releasing groups on the aldehyde and aniline
was studied. As summarized in Table 2, in some examples
the only stereoisomer obtained is anti, while with 2-Cl
benzaldehyde syn isomer is exceptionally obtained
(Table 2, entry 2). The weak electron-withdrawing groups
on benzaldehyde such as 4-Cl favored this diastereoselec-
tive reaction. However, the presence of strongly electron-
The most plausible mechanism for these one-pot reac-
tions is the formation of the imine from the amine and
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J IRAN CHEM SOC (2014) 11:685–692
691
Table 3 Synthesis of bis(b-aminocarbonyl) compounds under catalyst-free conditions
R
R
O
H
R
O
cyclohexane, r.t
Catalyst-free
H
N
H
X N
H2N X NH2
+
+
O
O
7-14
Entry
X
R
Product (yield %)a
Anti:syn
Time (h)
M.p. (°C)
1
2
3
4
5
6
7
8
9
10
a
C6H4
H
7 (72)
8 (70)
80:20
[99:\1
[99:\1
63:37
80:20
67:33
1:99
24
48
48
24
24
48
48
48
48
48
98
C6H4
4-CH3
4-Cl
H
114–116
112–113
119
C6H4
9 (67)
Biphenyl
Biphenyl
Biphenyl
Biphenyl
(CH2)2
10 (78)
11 (68)
12 (65)
13 (62)
14 (65)
15 (75)
16 (83)
4-CH3
4-Cl
2-Cl
2-Cl
108
129
96–97
Oily
17:83
67:33
Imine
Biphenyl
Biphenyl
4-OCH3
4-NO2
250
239
Isolated yield
a-
b-
C N
Ar'
Ar CHO
Ar' NH2
+
Ar
H
Ar'
O
O
HN
Ar
Ar'
N
Ar
C
H
+
H
Ar'
H
O
H
H
O
Ar'
Ar
O
Ar'
O
N
Ar'
N
N
N
Ar
H
H
H
Ar
Ar
H
Ar'
Ar
Ar'
Ar'
Ar
Ar'
NH
O
NH
O
NH
O
NH
O
Ar
Ar
anti
syn
anti
syn
a
b
c
d
Fig. 1 Suggestive transition states related to Mannich reaction in cyclohexane and catalyst-free condition a anti product from anti imine b syn
product from anti imine c anti product from syn imine d syn product from syn imine
aldehyde, followed by nucleophilic addition of the enol to
imine. Mechanistically, it seems likely that cyclohexane
does not play any role in transition state of reaction. Also
low solubility of the reactants, iminium intermediate and
product in this solvent is not the determining factor in the
observed diastereoselectivity. It seems that the enol con-
centration in non-polar solvents is higher and promotes the
reaction. On the other hand, the less solubility of products
123

692
J IRAN CHEM SOC (2014) 11:685–692
catalyst-free diastereoselective multicomponent Mannich
reaction using a diamine, an aromatic aldehydes and
cyclohexanone in a non-polar solvent is described. The
advantage of our method is the moderate to high yield and
excellent selectivity in a simple setup and workup proce-
dure under catalyst-free conditions. Also, we compared
polar and non-polar solvent in reactivity and stereo selec-
tivity of this reaction.
H
H
H
O
O
'
Ar
N
'
Ar
N
H
Ar
Ar
anti
Fig. 2 Electronic effect of transition state
assists the reaction compellation in this non-polar solvent.
The most probable transition states which can explain the
diastereoselectivity of the reaction are shown in Fig. 1.
The general belief on the mechanism of the three-
component reactions is that the catalyst plays its role
mostly in the second step of the mechanism. It can also
effect on the rate of enol formation and nucleophilic
addition of enol to aldimine. It is proposed that it mostly
control the diastereoselectivity of the reaction by control-
ling the stereochemistry of the transition state. As it shown
in Fig. 1, transition states a and c formed by a simple
hydrogen bonding are more favorable from a steric point of
view. These transition states will give the anti isomer.
Transition states b and d are highly hindered and so unli-
kely to be formed. These highly energetic transition states
will lead to syn isomer. According to this mechanism if the
cis-imine is formed the anti product is formed (Fig. 1. c).
While if the trans-imine is formed, steric effect is the major
factor in transition state equilibrium. (Fig. 1. a, b).
Acknowledgments We are grateful to Ferdowsi University of
Mashhad Research Council for their financial support of this work
(Grants: P9-89:30-08-89 and 3/18528-11-05-90).
References
1. P.A. Wender, S.T. Handi, D.L. Wright, Chem. Ind. 765 (1997)
2. H. Sharghi, R. Khalifeh, A.R. Salimi Beni, J. Iran. Chem. Soc. 7,
275 (2010)
3. H. Sharghi, R. Khalifeh, F. Moeini, M.H. Beyzavi, A. Salimi
Beni, M.M. Doroodmand, J. Iran. Chem. Soc. 8, s89 (2011)
4. A. Domling, A. Ugi, Angew. Chem. Int. Ed. 39, 3169 (2000)
5. S. Kobayashi, Y. Mori, J.S. Fossey, M.M. Salter, Chem. Rev.
111, 2626 (2011)
6. F. Davis, A. Zhang, Y.G. Anilkumar, J. Org. Chem. 68, 8061
(2003)
7. B.M. Trost, L.R. Terrell, J. Am. Chem. Soc. 125, 338 (2003)
8. M. Hatano, T. Horibe, K. Ishihara, Org. Lett. 12, 3502 (2010)
9. Z. Rezaei, H. Firouzabadi, N. Iranpoor, A. Ghaderi, M.R. Jafari,
A.A. Jafari, H.R. Zare, Eur. J. Med. Chem. 44, 4266 (2009)
10. X. Zheng, Y. Quan, Y. Wang, Eur. J. Org. Chem. (3), 515 (2010)
11. J. Xia, R. Qiu, S. Yin, X. Zhang, S. Luo, C. Au, K. Xia, W.
Wong, J. Organomet. Chem. 695, 1487 (2010)
12. G. Lu, C. Cai, Catal. Commun. 11, 745 (2010)
13. D. Hong, Y. Yang, Y. Wang, X. Liu, Synlett (7), 1107 (2009)
14. A.A. Jafari, F. Moradgholi, F. Tamaddon, Eur J Org Chem (8),
1249 (2009)
15. B. Das, A.S. Kumar, B.R. Kanth, Synth. Commun. 39, 3111
(2009)
16. T. He, K. Li, M. Wu, X. Fang, N. Wang, H. Wang, C. Li, X. Lu,
J. Mol. Cat B Enzym. 67, 189 (2010)
17. R. Strivastava, Catal. Lett. 139, 17 (2010)
We proposed that the transition state is chair like and
both enol and imine self-assembled with hydrogen bonding
at transition state. The modified transition state illustrated
in Fig. 2 shows that the electronic effect is one of the major
factors that control the diastereoselectivity of product.
When we use the methyl group on aniline, the diastere-
oselectivity improve because of increasing basicity of
imine for both base-catalyzed enol formation and also
efficient hydrogen bonding in this transition state. In fact,
with imines containing methyl substitution on aniline ring,
the electronic density of transition state depicted in Fig. 2
improved and hydrogen bonding of nitrogen to enol will
occur and diastereoselectivity proceeds toward anti isomer
(Table 2, entries 2, 3 and 5). When the nitro group is
located on benzaldehyde the electronic density and basicity
of imine decreased as well as its solubility in non-polar
solvent, and only corresponding imines were obtained.
18. H. Eshghi, M. Rahimizadeh, M. Hosseini, A. Javadian-Saraf,
Monatsh. Chem. 144, 197 (2013)
19. K.D. Grande, S.M. Rosenfield, J. Org. Chem. 45, 1626 (1980)
20. S.G. Mills, P. Beak, J. Org. Chem. 50, 1216 (1985)
21. K. Gong, D. Fang, H. Wang, Z. Liu, Monatsh. Chem. 138, 1195
(2007)
22. N.S. Kozlov, G.V. Vorobeva, Vestsi Akad Navuk BSSR. Ser
Khim Navuk 4, 107 (1968)
23. F. Nemati, A.S. Fakhaei, A. Amoozadeh, Y. Saeidi Hayeniaz,
Synth. Commun. 41, 3695 (2011)
24. D. Liotta, A.D. Baker, S. Goldstein, N. Goldman, F. Weinstein-
Lanse, D. Felsen-Reingold, R. Engel, J. Org. Chem. 39, 2718
(1974)
25. T. Asano, H. Furuta, H. Hofmann, R. Cimiraglia, Y. Tsuno, M.
Fujio, J. Org. Chem. 58, 4418 (1993)
26. M. Zarei, M. Mohamadzadeh, Tetrahedron 67, 5832 (2011)
Conclusions
In conclusion, we present in this paper a completely dia-
stereoselective three-component Mannich reaction by a
catalyst-free condition in a non-polar solvent. Also,
123