Highly anti-anti selective synthesis of bis-β-amino ketones via three-component direct Mannich-type reaction of terephthalaldehyde catalyzed by ZrOCl2·8H2O

Article abstract of DOI:10.1007/s13738-012-0175-3

At room temperature, zirconium oxychloride (ZrOCl₂· 8H₂O) efficiently catalyzes the direct Mannich-type reaction of a variety of in situ generated bis-imines using terephthalaldehyde and anilines with ketones in a three-component reaction at room temperature. The reaction proceeds rapidly and affords the corresponding bis-β-amino ketones in good-to-high yields with good-to-excellent anti-anti selectivity.

Full text of DOI:10.1007/s13738-012-0175-3

J IRAN CHEM SOC (2013) 10:421–427
DOI 10.1007/s13738-012-0175-3
ORIGINAL PAPER
Highly anti–anti selective synthesis of bis-b-amino ketones
via three-component direct Mannich-type reaction
of terephthalaldehyde catalyzed by ZrOCl ꢀ8H O
2
2
Bagher Eftekhari-Sis
Mohammad Bonyad-Bagheri
•
Mahnaz Saraei
•
Received: 2 May 2012 / Accepted: 3 October 2012 / Published online: 23 October 2012
Ó Iranian Chemical Society 2012
Abstract At room temperature, zirconium oxychloride
(
Mannich reactions have been reported by several groups as
an efficient method to prepare b-amino carbonyl com-
pounds [11–23].
ZrOCl ꢀ8H O) efficiently catalyzes the direct Mannich-
2
2
type reaction of a variety of in situ generated bis-imines
using terephthalaldehyde and anilines with ketones in a
three-component reaction at room temperature. The
reaction proceeds rapidly and affords the corresponding
bis-b-amino ketones in good-to-high yields with good-
to-excellent anti–anti selectivity.
Due to the easy availability [24], and low toxicity [25],
ZrOCl ꢀ8H O, a metal-oxo chloride, has recently attracted
2
2
much attention in organic transformations [26–28].
In continuation of our work on Mannich reaction [27,
29], in this paper we described a simple and environmen-
tally benign method for the synthesis of bis-b-amino
ketones 4 via three-component direct Mannich-type reac-
tion of terephthalaldehyde, 1,4-benzenedicarbaldehyde, 2
with ketones 1 and aniline derivatives 3 in the presence of
ZrOCl ꢀ8H O as catalyst in EtOH at room temperature
Keywords Mannich-type reaction ꢀ Bis-b-amino ketones ꢀ
Zirconium oxychloride ꢀ Terephthalaldehyde
2
2
Introduction
(Scheme 1).
b-Amino carbonyl compounds are widely found in natural
and unnatural products, which exhibit biological activity
Experimental section
[
1], such as anti-inflammatory [2] and antimicrobial
activities [3]. Among the most important routes to the
synthesis of this class of compounds, the Mannich reaction
is a classical method for the preparation of b-amino car-
bonyl compounds [1, 4, 5] and has been one of the most
important basic reactions in organic chemistry for its use in
natural product and pharmaceutical synthesis [6–10].
However, the classical Mannich reaction suffers from
number of serious disadvantages such as drastic reaction
conditions and the long reaction times [4, 5], the catalytic
General
All chemicals were purchased and used without any further
purification. NMR spectra were recorded at 400 MHz for
proton and at 100 MHz for carbon nuclei in (CDCl or
3
DMSO-d ). All aldehydes, and amines were employed, are
6
commercially available.
General reaction procedure
To a solution of terephthalaldehydes (0.5 mmol) and anilines
B. Eftekhari-Sis (&)
(1 mmol) in EtOH (5 ml), ketones (1.5 mmol) and
Department of Chemistry, Faculty of Science, University
of Maragheh, P.O. Box 55181-83111, Maragheh, Iran
e-mail: eftekharisis@maragheh.ac.ir
ZrOCl ꢀ8H O (15 mol %) were added successively at room
2
2
temperature (20–25 °C) and stirred at the same temperature.
The reaction mixture was solidified rapidly and stirred for
additional 1 h. After completion of the reaction, monitored by
TLC (hexane:ethylacetate; 7:3), crude solid was isolated by
M. Saraei ꢀ M. Bonyad-Bagheri
Department of Chemistry, Payame Noor University,
P.O. Box 19395-3697, Tehran, Iran
123

4
22
J IRAN CHEM SOC (2013) 10:421–427
Scheme 1 ZrOCl
catalyzed Mannich-type
2
ꢀ8H
2
O-
reaction of terephthalaldehyde
0
13
simple filtration and washed with hexane to afford the 2,2 -
1,4-phenylenebis[(arylamino)methylene]}diketones.
CH2,c-Hex), 1.64–1.99 (4 9 m, 12H, CH2,c-Hex) ppm.
C
{
NMR (100 MHz, CDCl ): d 211.1, 142.2, 139.1, 128.0,
3
1
1
2
27.9, 126.5, 126.4, 126.3, 126.2, 118.6, 116.4, 116.2,
11.6, 111.1, 111.0, 56.6, 56.5, 56.2, 56.1, 41.2, 30.7, 26.8,
5.8, 23.1 ppm. C H Cl N O (549.53): calcd. C 69.94,
Spectroscopic data of compounds:
3
2
34
2 2 2
0
H 6.24, N 5.10; found C 7.01, H 6.17, N 5.01.
2
clohexanone (4a) FT-IR (KBr, cm ): 3,404, 3,379 (N–
,2 -{1,4-Phenylenebis[(phenylamino)methylene]}dicy-
-
1
0
2,2 -{1,4-Phenylenebis[(4-chlorophenylamino)methy-
lene]}dicyclohexanone (4c) FT-IR (KBr, cm ): 3,377,
H), 3,020, 2,935, 2,862 (C–H), 1,697 (C=O), 1,600 (C=C),
1
,504 (C–N). H NMR (400 MHz, CDCl ): d 7.30–7.33
-1
1
3
3,338 (N–H), 3,031, 2,937, 2,862 (C–H), 1,699 (C=O),
1
(
m, 4H, CHPhenylene), 7.07–7.12 (m, 4H, CH ), 6.63–6.70
Ph
1,596 (C=C), 1,496 (C–N). H NMR (400 MHz, CDCl ): d
3
(
m, 2H, CH ), 6.52–6.59 (m, 4H, CH ), 4.81–4.82 (m,
Ph Ph
7.23–7.26 (m, 4H, CHPhenylene), 6.97–7.01 (m, 4H, CHAr),
6.39–6.45 (m, 4H, CH ), 4.79 (s, br. 1.44H, NHanti), 4.71
m, 0.56H, CHsyn), 4.52 (s, br. 0.56H, NHsyn), 4.48 (d,
J = 5.9 Hz, 1.44H, CHanti), 2.73–2.74 (m, 2H, CHc-Hex),
2.31–2.38 (m, 4H, CH2,c-Hex), 1.58–2.01(4 9 m, 12H,
0
.68H, CHsyn, anti–syn), 4.72 (s, br. 2H, NH), 4.59–4.61
Ar
[
2 9 d: (d, J = 6.76 Hz, 0.68H, CHanti, anti–syn), (d,
J = 6.78 Hz, 0.89H, CHanti, anti–anti),], 2.75–2.79 (m,
H, CHc-Hex), 2.32–2.46 (m, 4H, CH2,c-Hex), 1.84–2.07
(
2
(
2 9 m, 6H, CH2,c-Hex), 1.61–1.77 (2 9 m, 6H, CH2,c-Hex
1
ppm. C NMR (100 MHz, CDCl ): d 211.3, 139.6, 128.0,
)
13
CH2,c-Hex) ppm. C NMR (100 MHz, CDCl ): d 211.84,
3
3
3
211.8, 210.3, 145.0, 144.9, 144.8, 139.3, 139.24, 139.20,
1
1
2
7
27.9, 126.6, 126.35, 126.30, 116.6, 116.3, 112.9, 112.5,
12.4, 56.7, 56.3, 56.29, 55.8, 55.4, 41.4, 40.8, 30.4, 30.3,
6.9, 23.8, 22.7 ppm. C H N O (480.64): calcd. C
1
1
27.8, 127.7, 126.6, 126.56, 126.5, 126.33, 126.3, 126.26,
26.2, 121.0, 120.97, 120.94, 114.1, 113.6, 57.0, 56.2,
3
2
36
2
2
56.1, 56.0, 55.1, 41.4, 41.0, 30.7, 30.67, 30.61, 27.5, 27.4,
6.9, 25.9, 23.7, 22.9 ppm. C H Cl N O (549.53):
9.96, H 7.55, N 5.83; found C 79.91, H 7.54, N 5.69.
2
3
2
34
2 2 2
0
calcd. C 69.94, H 6.24, N 5.10; found C 69.92, H 6.19, N
4.98.
2
,2 -{1,4-Phenylenebis[(2-chlorophenylamino)methy-
1
-
lene]}dicyclohexanone (4b) FT-IR (KBr, cm ): 3,396
N–H), 3,060, 3,028, 2,943, 2,862 (C–H), 1,701 (C=O),
(
0
2,2 -{1,4-Phenylenebis[(3,4-dichlorophenylamino)meth-
ylene]}dicyclohexanone (4d) FT-IR (KBr, cm ): 3,375
1
1
7
6
,595 (C=C), 1,506 (C–N). H NMR (400 MHz, CDCl ): d
.28 (s, 4H, CHPhenylene), 7.19–7.23 (m, 2H, CH ), 6.88–
Ar
-1
3
(N–H), 3,029, 2,931, 2,858 (C–H), 1,697 (C=O), 1,595
1
.95 (m, 2H, CH ), 6.52–6.56 (m, 2H, CH ), 6.38–6.44
Ar Ar
(
C=C), 1,508 (C–N). H NMR (400 MHz, CDCl ): d
3
(
m, 2H, CH ), 5.40–5.43 (m, 2H, NH), 4.61–4.65 (m, 2H,
Ar
7.23–7.25 (m, 4H, CHPhenylene), 7.06–7.09 (m, 2H, CHAr),
6.53–6.55 (m, 2H, CH ), 6.32–6.38 (m, 2H, CH ),
CHanti), 2.78–2.82 (m, 2H, CHc-Hex), 2.30–2.42 (m, 4H,
Ar
Ar
Scheme 2 Mannich-type
reaction of bis-imine 5
1
23

J IRAN CHEM SOC (2013) 10:421–427
423
4
.65–4.67 (m, 4H, NH and CHanti), 2.75–2.77 (m, 2H, CHc-
CHsyn,c-pent), 2.43–2.49 (m, 1.7H, CHanti,c-pent), 2.25–2.35
(m, 2H, CH2,c-pent), 2.01–2.10 (m, 2H, CH2,c-pent),
1.78–1.87 (m, 4H, CH2,c-pent), 1.63–1.73 (m, 4H, CH2,c-
Hex), 2.26–2.42 (m, 4H, CH2,c-Hex), 1.86–2.01 (2 9 m, 8H,
1
CH2,c-Hex), 1.45–1.69 (m, 4H, CH2,c-Hex) ppm. C NMR
3
1
3
(
100 MHz, CDCl ): d 211.1, 142.2, 139.1, 128.0, 127.9,
pent) ppm. C NMR (100 MHz, DMSO-d ): d 218.13,
3
6
1
1
2
5
26.5, 126.4, 126.3, 126.2, 118.6, 116.4, 116.2, 111.6,
11.1, 111.0, 56.6, 56.5, 56.2, 56.1, 41.2, 30.7, 26.8, 25.8,
3.1 ppm. C H Cl N O (618.42): calcd. C 62.15, H
218.1, 217.6, 147.7, 147.6, 139.9, 139.8, 128.7, 128.6,
127.1, 127.0, 126.3, 116.0, 113.1, 112.9, 56.1, 53.9, 53.7,
25.0, 24.9, 23.5, 19.9 ppm. C H N O (452.59): calcd. C
3
2
32
4
2
2
30 32 2 2
.22, N 4.53; found C 62.18, H 5.20, N 4.38.
79.61, H 7.13, N 6.19; found C 79.53, H 7.15, N 5.97.
0
0
2
lene]}dicyclohexanone (4e) FT-IR (KBr, cm ): 3,375,
,2 -{1,4-Phenylenebis[(4-bromophenylamino)methy-
-
4,4 -(1,4-Phenylene)bis[4-(phenylamino)butan-2-one]
1
-1
(6) FT-IR (KBr, cm ): 3,392 (N–H), 3,051, 3,018,
3
1
7
6
4
4
2
,336 (N–H), 3,028, 2,935, 2,862 (C–H), 1,701 (C=O),
1
2,933, 2,885 (C–H), 1,708 (C=O), 1,600 (C=C), 1,514 (C–
1
,591 (C=C), 1,494 (C–N). H NMR (400 MHz, CDCl ): d
N). H NMR (400 MHz, CDCl ): d 7.31 (s, 4H, CH
3
3
Pheny-
.27–7.29 (m, 4H, CHPhenylene), 7.14–7.17 (m, 4H, CHAr),
), 7.08 (t, J = 7.8 Hz, 4H, CH ), 6.67 (t, J = 7.3 Hz,
Ph
lene
.39–6.44 (m, 4H, CH ), 4.85 (s, br. 1.46H, NHanti),
Ar
2H, CH ), 6.53 (d, J = 7.8 Hz, 4H, CH ), 4.82 (t,
Ph Ph
.72–4.75 (m, 0.54H, CHsyn), 4.57 (m, 0.54H, NHanti),
.50 (m, 1.46H, CHanti), 2.76–2.81 (m, 2H, CHc-Hex),
.33–2.44 (m, 4H, CH2,c-Hex), 1.57–2.04 (4 9 m, 12H,
J = 6.4 Hz, 2H, CH–N), 4.41 (s, br. 2H, NH), 2.89 (d,
1
J = 6.4 Hz, 4H, CH ), 2.06 (s, 6H, CH ) ppm. C NMR
3
2
3
(100 MHz, CDCl ): d 206.1, 145.7, 140.6, 128.1, 125.7,
3
1
3
CH2,c-Hex) ppm. C NMR (100 MHz, CDCl ): d 211.8,
116.8, 112.7, 52.9, 50.0, 29.7 ppm. C H N O (400.51):
26 28 2 2
3
2
1
1
5
2
10.3, 145.0, 144.9, 144.8, 139.3, 139.24, 139.20, 127.8,
27.7, 126.6, 126.56, 126.5, 126.33, 126.3, 126.26,
26.2, 121.0, 120.97, 120.94, 114.1, 113.6, 57.0, 56.2,
6.1, 56.0, 55.1, 41.4, 41.0, 30.7, 30.67, 30.61, 27.5,
7.4, 26.9, 25.9, 23.7, 22.9 ppm. C H Br N O
calcd. C 77.97, H 7.05, N 6.99; found C 78.05, H 7.05, N
6.71.
0
Mixture of 2,2 -[1,4-Phenylenebis(azanediyl)]bis(phe-
nylmethylene)dicyclohexanone (9) (40 %) and bis-imine
3
2
34
2
2
2
-1
0 (60 %) FT-IR (KBr, cm ): 3,400 (N–H), 3,058,
1
(
638.43): calcd. C 60.20, H 5.37, N 4.39; found C 60.17,
3
,024, 2,943, 2,862 (C–H), 1,691 (C=O, C=N), 1,616
1
H 5.33, N 4.53.
(
C=C), 1,514 (C–N). H NMR (400 MHz, CDCl ): d
3
0
2,2 -{1,4-Phenylenebis[(4-butylphenylamino)methy-
-
lene]}dicyclohexanone (4f) FT-IR (KBr, cm ): 3,342
8.41–8.52 (4 9 s, 2H, CH=N, E,E, E,Z and Z,Z of 10),
7.46–7.94 and 7.34–7.38 (5 9 m, 10H, CH , 10),
1
Ph
(
(
N–H), 3,022, 2,927, 2,860 (C–H), 1,701 (C=O), 1,614
1
C=C), 1,519 (C–N). H NMR (400 MHz, CDCl3):
7.41–7.43 (m, 4H, CH , 9), 7.30–7.34 (m, 4H, CH , 9),
Ph Ph
7.20–7.24 (m, 2H, CH , 9), 7.11–7.13 (m, 4H, CH
Ph Pheny-
d = 7.28 (s, 4H, CHPhenylene), 6.86 (d, J = 8.4 Hz, 4H,
CH ), 6.43 (d, J = 8.4 Hz, 4H, CH ), 4.52–4.57 (m, 4H,
NH and CHanti), 2.67–2.70 (m, 2H, CHc-Hex), 2.42 (t,
lene, 10), 6.71–6.73 and 6.57–6.59 (2 9 m, 4H, CHPheny-
lene, 9), 4.82–4.83 (d, J = 4.3 Hz, 0.4H, CHsyn, 9),
4.62–4.64 (d, J = 7.0 Hz, 1.6H, CHanti, 9), 2.79–2.81 (m,
2H, CHc-Hex, 9), 2.42–2.45 (m, 2H, CH2c-Hex, 9),
2.32–2.39 (m, 4H, CH2,c-Hex, 9), 1.62–1.93 (2 9 m, 10H,
CH2,c-Hex, 9) ppm.
Ar
Ar
J = 7.6 Hz, 4H, CH2,n-Bu), 2.27–2.40 (m, 4H, CH2,c-Hex),
1
.80–1.89 (m, 8H, CH2,c-Hex), 1.59–1.67 (m, 4H, CH2,c-
Hex), 1.48 (quintet, J = 7.9 Hz, 4H, CH2,n-Bu), 1.29 (sextet,
J = 7.3 Hz, 4H, CH2,n-Bu), 0.88 (t, J = 7.3 Hz, 6H, CH3,n-
1
3
Bu) ppm. C NMR (100 MHz, DMSO-d ): d 211.2, 145.8,
6
1
40.8, 129.3, 129.1, 128.9, 128.3, 127.2, 121.1, 112.9,
Results and discussion
5
6.3, 55.8, 33.9, 33.5, 30.5, 27.9, 22.7, 21.7, 13.8 ppm.
C H N O (592.85): calcd. C 81.04, H 8.84, N 4.73;
40 52 2 2
The ZrOCl ꢀ8H O-catalyzed Mannich-type reaction
2
2
found C 81.11, H 8.83, N 4.47.
was first studied using bis-imine, N,N’-[1,4-phenylene-
bis(methylidene)]dianiline 5, that was treated with
cyclohexanone in EtOH in the presence of catalytic
0
2
,2 -{1,4-Phenylenebis[(phenylamino)methylene]}dicy-
-
1
clopentanone (4g) FT-IR (KBr, cm ): 3,380 (N–H),
,051, 3,022, 2,960, 2,879 (C–H), 1,724 (C=O), 1,600
3
amount of ZrOCl
2
ꢀ8H
2
O at room temperature and the
1
0
(
C=C), 1,506 (C–N). H NMR (400 MHz, CDCl ): d
corresponding bis-b-amino ketone, 2,2 -{1,4-phenylene-
bis[(phenylamino)methylene]}dicyclohexanone 4a, was
isolated in high yield (63 %), with excellent anti–anti
selectivity. Consequently, a one-pot sequence involving
the formation of the bis-imine and its in situ Mannich
reaction was investigated. The overall reaction is shown
in Scheme 2.
3
7
.32–7.33 and 7.28–7.30 (2 9 m, 3.4H, CHanti–anti, Pheny-
lene), 7.24–7.30 (m, 0.6H, CHanti–syn, Phenylene), 7.03–7.08
(
m, 4H, CH ), 6.62–6.67 (m, 2H, CH ), 6.50–6.55 (m,
Ph Ph
4
0
0
H, CH ), 5.17 (s, br. 1.4H, NHanti–anti), 4.71–4.72 (m,
Ph
.3H, CHsyn), 4.47–4.50 (m, 1.7H, CHanti), 2.95–2.96 (s, br.
.6H, NHanti–anti and NHanti–syn) 2.68–2.69 (m, 0.3H,
123

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J IRAN CHEM SOC (2013) 10:421–427
Table 1 Yields and
stereoselectivity of the Mannich
products
Stereoselectivityb
anti–anti/anti–syn (or syn–syn)
Entry Ketone
Aniline
Product, yield (%)a
O
NH2
1
4a, 63
56/43
>98/2
61/39
100/0
63/37
100/0
–
O
NH2
Cl
2
4b, 51
4c, 87
4d, 20
4e, 56
4f, 65
–c
O
NH2
3
Cl
O
Cl
Cl
NH2
NH2
NH2
NH2
4
O
5
Br
O
6
n-Bu
MeO
O
7
O
NH2
8
–c
–
Me
O
NH2
9
–c
–
a
Yields refer to isolated
products
O
NH2
NH2
b
Stereoselectivity (anti–anti/
anti–syn/syn–syn) was measured
10
4g, 58
85/15
1
by analysis of the H NMR
O
spectrum of the crude reaction
mixture
11
–c
–
c
The corresponding imine was
obtained after 24 h
Mannich reactions of cyclic ketones and different
substituted anilines with terephthalaldehyde 2 were carried
out by sequentially adding of 3 equiv. of ketones and
As shown in Table 1, entries 2–5, halogenated anilines
work well in ZrOCl ꢀ8H O-catalyzed Mannich-type reac-
2
2
tion with 2 and cyclohexanone. Anilines with electron-
releasing groups show different reactivity under Mannich
reaction condition; with moderate electron-releasing group
1
0 mol % of ZrOCl ꢀ8H O to the solution of 0.5 mmol
2
2
of terephthalaldehyde 2 and 2 equiv. of aniline in EtOH
at room temperature under stirring, and the reaction
was allowed to continue at the same temperature and
n
in para position such as p- Bu-aniline reaction took place
and corresponding bis-b-amino ketone 4f was obtained in
65 % yield with high anti–anti selectivity, but in ortho
position such as o-toluidine, corresponding bis-imine was
isolated as only product after 24 h. Strongly electron-
releasing group in para position such as methoxy group
(p-anisidine) resulted to the formation of corresponding
bis-imine. Similarly, other cyclic ketones, cyclopentanone
and cycloheptanone, were subjected to Mannich-type
0
corresponding 2,2 -{1,4-phenylenebis[(phenylamino)meth-
ylene]}diketones 4 were obtained in good to high yields. A
number of examples of the ZrOCl ꢀ8H O-catalyzed direct
2
2
Mannich-type reaction of 2 with cyclic ketones and ani-
lines are listed in Table 1. The structure of compounds 4a–
1
g was established using IR, H NMR, C NMR and CHN
13
analyses.
1
23

J IRAN CHEM SOC (2013) 10:421–427
425
Fig. 1 Identification and
measurement of
1
stereoselectivity by H NMR
spectroscopy
Scheme 3 Mannich-type
reaction of terephthalaldehyde
with n-butyl amine and
cyclohexanone
Scheme 4 ZrOCl
2
ꢀ8H
2
O-
catalyzed Mannich-type
reaction of terephthalaldehyde
with acetone
reaction, and cyclopentanone underwent the reaction rap-
idly due to the more acidity of a-proton rather than
cyclohexanone, but in the case of cycloheptanone, bis-
imine was isolated after 24 h.
center of the anti–syn and/or syn–syn isomers with low
intensity.
n
ZrOCl ꢀ8H O-catalyzed Mannich reaction of BuNH ,
2
2
2
as an aliphatic amine, with 2 and cyclohexanone was
investigated and the bis-imine 5 was obtained as only
products over long reaction times (Scheme 3).
1
The anti–anti selectivity was determined by H NMR
spectroscopy, using the intensities of the Ha and Ha’
(
Fig. 1). It is well known that the chemical shift of H and
a
Also, Mannich reaction of terephthalaldehyde and ani-
line with acyclic ketone such as acetone in the presence of
ZrOCl ꢀ8H O in EtOH at room temperature was investi-
H signals in syn form were down-field shifted from that in
a’
1
the case of anti form [27]. For instance, in the H NMR
2
2
0
spectrum of 2,2 -{1,4-phenylenebis[(phenylamino)methy-
gated. When 3 equiv. of acetone was treated with 0.5 mmol
lene]}dicyclopentanone 4 g, the signals at d = 4.46-
of 2 and 2 equiv. of aniline under the Mannich reaction
0
4
.50 ppm (J = 6.1 and 5.8 Hz) are attributed to the anti–
anti and anti center of the anti–syn isomers, while the one
at 4.71-4.72 ppm (J = 3.9 Hz) is attributed to the syn
conditions, the corresponding bis-b-amino ketone, 4,4 -
(1,4-phenylene)bis[4-(phenylamino)butan-2-one] 6, was
obtained in 75 % yield (Scheme 4).
123

4
26
J IRAN CHEM SOC (2013) 10:421–427
diastereotopic protons, H and H , separately, appeared as
0
a
a
a triplet at 4.82 ppm with J = 6.4 Hz. So it is concluded
that, the H and H are not diastereotopics arising from
a
a’
achirality of structure by center of symmetry (Fig. 2).
As shown in Scheme 5, also, the synthesis of bis-amino
ketones by the Mannich-type reaction of p-phenylenedi-
amine 8 was investigated, in which 3 equiv. of cyclohex-
anone was treated with 0.5 mmol of 8 and 2 equiv. of
benzaldehyde in EtOH in the presence of 10 mol % of
0
ZrOCl ꢀ8H O at room temperature and 2,2 -[1,4-phenyl-
2
2
enebis(azanediyl)]bis(phenylmethylene)dicyclohexanone 9
was obtained in 53 yield with 60 % anti–anti selectivity.
1
The stereoselectivity was determined by H NMR spectra
of the crude products mixture. In addition to Mannich
adduct, the bis-imine 10 was determined in the reaction
1
mixture using H NMR spectrum. The ratio of 9/10 was
1
determined to be 40/60 using H NMR spectrum of the
1
Fig. 2 A The H NMR of 7 showing diastereotopic relationship
crude product mixture.
1
. B The H NMR of 6 showing the existence of the
between H
c
and H
center of symmetry
c
0
Conclusions
1
The structure of 6 was confirmed by its IR, H NMR,
1
3
C NMR and CHN analyses. H and Ha
a
0
, however, which
In conclusion, three-component Mannich-type reactions of
terephthalaldehyde, anilines, and ketones are efficiently
catalyzed by ZrOCl ꢀ8H O to afford bis-b-amino ketones
were expected to be diastereotopic and appear in different
chemical shifts as two doublet of doublets via coupling
2
2
with each other and H (as shown in the case of 7 as a
b
in good-to-high yields. We have found that anti–anti
selectivity was observed in the ZrOCl ꢀ8H O-catalyzed
model compound), appear at the same chemical shift at
2
2
2.89 ppm as doublet with J = 6.4 Hz, which has arisen
from the coupling only with H . However, H was expected
Mannich-type reaction of cyclic ketones and in situ gen-
erated bis-imines in short reaction times, at room temper-
ature in EtOH.
b
b
to appear as a doublet of doublets via coupling with
Scheme 5 ZrOCl
2
ꢀ8H
2
O-
catalyzed Mannich-type
reaction of
p-phenylenediamine 8
1
23

J IRAN CHEM SOC (2013) 10:421–427
427
Acknowledgments The authors would like to thank the research
council of the Payam Noor University and University of Maragheh for
financial supports.
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