Cs2.5H0.5PW12O40 catalyzed diastereoselective synthesis of β-amino ketones via three component Mannich-type reaction in water

Article abstract of DOI:10.1016/j.tet.2010.06.052

A series of insoluble salts of Keggin heteropoly compounds were prepared and used as catalysts for the Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone in water. Among them, Cs_2.5H_0.5PW ₁₂O₄₀ showed excellent catalytic activity. Effects of surfactant, catalyst loading and temperature were studied to introduce the best reaction condition. The optimized reaction conditions were extended to Mannich reaction of various aldehydes, ketones, and amines in water. This rapid procedure afforded structurally divers β-amino ketones with major anti diastereoselectivity. Additionally, four new compounds were reported. The catalyst was recovered and reused for subsequent runs.

Full text of DOI:10.1016/j.tet.2010.06.052

Tetrahedron 66 (2010) 6858e6863
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cs2.5H0.5PW12O40 catalyzed diastereoselective synthesis of
three component Mannich-type reaction in water
b-amino ketones via
,
b
,
a
a
a,b
Ezzat Rafiee a , Sara Eavani , Fereshte Khajooei Nejad , Mohammad Joshaghani
*
a Faculty of Chemistry, Razi University, Kermanshah 67149, Iran
b Kermanshah Oil Refining Company, Kermanshah, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of insoluble salts of Keggin heteropoly compounds were prepared and used as catalysts for the
Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone in water. Among them,
Cs2.5H0.5PW12O40 showed excellent catalytic activity. Effects of surfactant, catalyst loading and temper-
ature were studied to introduce the best reaction condition. The optimized reaction conditions were
extended to Mannich reaction of various aldehydes, ketones, and amines in water. This rapid procedure
Received 24 March 2010
Received in revised form 29 May 2010
Accepted 21 June 2010
Available online 25 June 2010
afforded structurally divers
compounds were reported. The catalyst was recovered and reused for subsequent runs.
Ó 2010 Elsevier Ltd. All rights reserved.
b-amino ketones with major anti diastereoselectivity. Additionally, four new
Keywords:
Mannich reaction
b-Amino ketone
Aqueous media
Cs2.5H0.5PW12O40
€
Bronsted acid
R2
R1
1. Introduction
O
NH O
R3
Catalyst
R3
R1CHO + R2NH2
+
R4
One of the important goals in organic chemistry is the
development of new methodologies for the synthesis of function-
alized biologically active compounds with structural diversity from
simple and readily available precursor molecules.
R4
Scheme 1. Three-component Mannich reaction.
b
-Amino carbonyl compounds are important intermediates for
various pharmaceutical and natural product syntheses including
-amino alcohols,
-amino acids, and lactams.1e3 Among the var-
ious methods for the synthesis of these compounds, Mannich-type
reaction constitutes a method of choice in many cases due to its
versatility.4
pursued. In this context, we focused on the development of reus-
able heteropoly acid (HPA) catalyst to perform this transformation
under milder reaction conditions and to enhance the generality of
the reaction.
b
b
Numerous versions of the Mannich reaction have been
developed to overcome drawbacks associated with the classical
Mannich reaction. One of the efficient routes is to conduct a one-pot
three-component reaction of an aldehyde, an amine and a ketone
2. Results and discussion
The pKa of HPAs is lower than that of the conventional solid
acid catalysts.17 Therefore, they are generally active catalysts,
which allow efficient operation under mild conditions. Owing to
inherent advantages of HPAs, heterogeneous acid catalysis by
these compounds has the potential of a great economic reward
and green benefits. In order to achieve this goal, one way is to
exchange their protons with large alkali metal cations such as Kþ,
Csþ, or [(n-Bu)4N]þ to form insoluble salts.18
Taking the above into account, a series of HPA-salts with varied
cations and different catalytic mechanisms were prepared and their
catalytic activities were evaluated in the Mannich reaction of benzal-
dehyde(1.0 mmol), aniline(1.0 mmol), andcyclohexanone (1.0 mmol).
Without addition of catalyst, the reactionproceeds via imine formation
(Scheme 1) with the assistance of ultrasound irradiation5 or using
9
Lewis acids,6e8 Lewis base, Bronsted acids,10e14 organocatalyst15 or
€
praline16 to catalyze the reaction.
Despite the merits of these methodologies, problems recycling
and reusing of the catalysts, harsh reaction conditions, toxicity or
difficulty in product separation remain concerns. Therefore, the
search for new readily available green catalysts is still being actively
* Corresponding author. Tel./fax: þ98 831 427 4559; e-mail addresses:
ezzat_rafiee@yahoo.com, e.rafiei@razi.ac.ir (E. Rafiee).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.052

E. Rafiee et al. / Tetrahedron 66 (2010) 6858e6863
6859
through the condensation of benzaldehyde and aniline, and no
products from the aldol reaction and Mannich-type reaction were
observed (Table 1, entry 1). The formation of imine was confirmed by
using 1H NMR and performing the condensation between benzalde-
hyde and aniline as a control reaction. This result indicates that the
catalyst is necessary to produce a Mannich product.
In general, the neutral salts of HPA gave poor yields in com-
€
parison with acidic salts, indicating that a Bronsted acid is clearly
involved in the process (Table 1, entries 2e11). Obviously, tungsten
containing heteropoly compounds exhibited higher reactivity in
comparison with the molybdenum analogs. CsxH3-xPW12O40 cata-
lysts showed better results in comparison with others and the
highest activity was achieved upon partially substitution of HPA
protons with Cs stoichiometry equal to 2.5 (Table 1, entries 8e10).
Thus, Cs2.5H0.5PW12O40 (Cs2.5PW) was selected as the best catalyst
for further investigation.
Table 1
Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone in the presence
of various catalysts
Since the reactants were insoluble in water, we decided to
examine the use of a surfactant to solubilize the hydrophobic
substrates. In the presence of cationic surfactants, CPB and CTAB,
the product yield was decreased (Table 2, entries 1 and 2). It may be
due to the positively charged micellar interface, which provided an
unfavorable electrostatic interaction with protonated imine present
in water solution, thus decreasing the yield compared to the same
reaction carried out in the absence of surfactant (Table 1, entry 10).
Triton X-100 also did not afford the desired product (Table 2, entry
3) this neutral surfactant formed two immiscible layers, so was not
effective in this reaction. Anionic surfactants afforded the desired
product in a modest yield (Table 2, entries 4e6). They formed
a white muddy reaction mixture and this colloidal dispersion in the
presence of the substrates leads to efficient catalysis. However,
addition of these surfactants only slightly improved the yield (in
comparison with entry 10, Table 1). Additionally, these surfactants
produce colloidal dispersion by emulsion formation as a result of
which, phase separation was difficult. Hence, further studies were
performed in the presence of Cs2.5PW without the addition of
surfactant.
Ph
CHO
O
NH2
Catalyst (0.04 g)
NH O
Ph
+
+
+
N
Ph
H2O (5mL), r.t.
80 min
Ph
Entry
Catalyst
Yielda (%)
Ph
Ph
Ph
NH O
N
Ph
1
2
3
4
5
6
7
8
d
38
49
75
74
81
72
60
44
31
7
0
38
19
17
11
10
26
50
64
86
15
K5CoW12O40
[(n-Bu)4N]5PMo2W9O39 (Sn2þ$H2O)
[(n-Bu)4N]3PMo2W9O39 (Sn4þ$H2O)
[(n-Bu)4N]3PMo2W9O39 (Ti4þ$H2O)
[(n-Bu)4N]5PMo2W9O39 (Zn2þ$H2O)
[(t-Bu)4N]4PW11CoO39
Cs2H1PW12O40
9
10
11
Cs1H2PW12O40
Cs2.5H0.5PW12O40
Cs2.5H0.5PMo12O40
56
a
Table 2
Isolated yield.
Effect of surfactants in Mannich-type reaction of benzaldehyde, aniline, and
cyclohexanone
Ph
K5CoW12O40 is the most important example of an HPA, based
on a d-transition-metal heteroatom, that is, used as electron-
transfer catalyst in some organic transformations.19 The poor
catalytic performance of K5CoW12O40 indicated that this conver-
sion is not proceed via electron-transfer mechanism (Table 1, entry
2). Metal substituted HPAs afforded the desired product only in
low yields while the imine product was obtained in good yield
(Table 1, entries 3e7). Presumably, they act as Lewis acids (LA) to
catalyze nucleophilic attack on the carbonyl group of benzalde-
hyde by aniline, as well as serving as dehydrating agents to fa-
cilitate the removal of water and formation of the corresponding
imine (Scheme 2). In the next step, the carbonyl group of ketone
should be activated by the coordination of oxygen atom with the
LA sites of the catalyst to form an enolate, which then reacts with
the imine leading to the formation of the Mannich product. It
seems that metal substituted HPAs catalyze the imine formation
preferentially over the Mannich reaction due to their low ability to
coordinate ketone.
CHO
O
NH2
NH O
NH O
Ph
Cs2.5PW (0.04 g)
+
N
+
+
Ph
H2O (5 mL), 80 min
Surfactant (0.02 g/mL)
Ph
Entry Surfactant
Yielda (%)
Ph
Ph
Ph
N
Ph
1
2
Cetylpyridium bromide (CPB)
Cetyltrimethylammonium bromide
(CTAB)
Poly(ethylene glycol) mono [4-(1,1,3, 69
3-tetramethylbutylphenyl)
71
65
26
31
3
0
ether (Triton X-100)
4
5
6
Sodium octyl sulfate (SOS)
Sodium decyl sulfate (SDeS)
Sodium dodecyl sulfate (SDS)
Trace
11
Trace
82
85
84
a
Isolated yield.
Increasing the quantity of Cs2.5PW from 0.04 to 0.12 g did not
improve the result to a greater extent while with a lesser amount
(0.02 g), the reaction remained incomplete (Table 3, entries 1e3).
Thus, 0.04 g of Cs2.5PW is the suitable choice for catalyst loading.
The effect of temperature was also studied. Faster reactions oc-
curred on increasing the temperature but the product yield de-
creased at high temperatures possibly because the Mannich base is
unstable at elevated temperatures (Table 3, entries 5 and 6). As can
be seen, by using of 2 equiv of cyclohexanone, the desired product
Scheme 2. Metal substituted HPAs catalyzed imine formation.

6860
E. Rafiee et al. / Tetrahedron 66 (2010) 6858e6863
Table 3
all cases (Table 4, entries 1e9). It was found that while reaction
worked well with 2 equiv of aromatic ketones, the use of 5 equiv
was required in the case of cyclohexanone for reaction completion
Optimization of reaction conditions in the presence of Cs2.5PW
Ph
Ph
CHO
O
NH2
NH O
Ph
(Table 4, entries 5, 7, and 9). It may be due to the low activity of a-
Cs2.5PW
N
+
+
+
hydrogen of cyclohexanone. To our surprise, aliphatic aldehyde
and amines as substrates afforded the corresponding products in
good yield (Table 4, entries 18 and 19), as previous approaches
gave negative results, or very poor yields, for similar
reactions.14,20,21
Ph
H2O (5 mL)
Entry
Cs2.5PW
(g)
Ketone
(equiv)
Temp
(ꢀC)
Time
(min)
Yielda (%)
Many unique structures can be attained when three or more
reactants were combined in a single step to afford new compounds
possessing the combined features of the building blocks. Encour-
aged by the above excellent results, we decided to investigate the
reaction of structurally diverse substrates in order to obtain the
new compounds 17e20 (Table 5). These compounds containing
reactive functionalities for further elaboration of new molecular
system and they will most likely to be useful for the synthesis of
biologically active molecules.
Ph
Ph
NH O
N
Ph
Ph
1
2
3
4
5
6
7
8
0.02
0.04
0.08
0.12
0.04
0.04
0.04
0.04
1
1
1
1
1
1
2
3
25
25
25
25
50
80
25
25
80
80
80
80
40
40
30
30
25
7
12
9
73
75
72
86
88
88
10
Trace
94
A possible mechanism of the Mannich-type reaction in the
Trace
Trace
€
95
presence of Cs2.5PW as a Bronsted acid catalyst is proposed
a
(Scheme 3). The reaction proceeded typically through the imine
formation of the aldehyde and amine, protonation of the imine, and
the attack of the enol derived from the ketone to the protonated
imine, leading to the formation of Mannich product.
Isolated yield.
was obtained in excellent yield within short reaction time while
more than 2 equiv had no effect on product yield (Table 3, entries 2,
7, and 8).
To exam the reusability of the catalyst, 0.4 g of Cs2.5PW was
added to
a
mixture of benzaldehyde (10 mmol), aniline
The results in entry 7 of Table 3 became particularly in-
teresting. From 1H NMR spectra, the ratio of Mannich-product/
imine was 94:6 after 30 min of mixing. Thus, these optimized
conditions were extended to a series of aldehydes, ketones and
amines to explore the generality of this catalytic system
(Table 4).
(10 mmol), and cyclohexanone (20 mmol) in water. Then the
mixture was stirred. After 30 min, water was removed from the
mixture to leave residue. Then, the residue was dissolved in
30 mL diethyl ether to isolate the catalyst via centrifugation. The
isolated catalyst was washed with diethyl ether and used for
catalyzing the next reaction cycle. In a test of five cycles, the
Table 4
Synthesis of various b-amino ketones via three component Mannich reaction
R2
NH O
O
Cs2.5PW (0.04 g)
R3
+
R1CHO +
R2NH2
R1
R4
R4
H2O (5 mL), r.t.
R3
1a-14n
Entry
R1
R2
R3
R4
Ketone
(equiv)
Product
Time
(min)
Yield
(%)a
anti/syn
Ref.
ratiob
1
2
3
4
5
6
7
8
Ph
Ph
Ph
e(CH2)4e
e(CH2)4e
e(CH2)4e
e(CH2)4e
e(CH2)4e
e(CH2)4e
e(CH2)4e
e(CH2)4e
2
2
2
2
5
2
5
2
5
2
2
2
2
2
2
2
2
2
2
1
2
3
4
4
5
5
6
6
7
8
9
10
11
12
13
14
15
16
30
170
120
90
200
165
210
60
120
40
50
50
50
30
20
50
40
200
130
94
76
71
45
96
45
81
55
84
92
89
91
82
93
81
80
89
66
64
66:34
64:36
67:33
d
20
20
20
21
21
21
21
20
20
20
21
21
20
20
20
20
20
14
14
4-CleC6H4
4-CleC6H4
4-CleC6H4
4-CleC6H4
Ph
Ph
Ph
Ph
4-MeOeC6H4
4-NO2eC6H4
4-NO2eC6H4
3-NO2eC6H4
3-NO2eC6H4
2-Furyl
62:38
d
58:42
d
9
2-Furyl
e(CH2)4e
54:46
d
10
11
12
13
14
15
16
17
18
19
4-MeOeC6H4
4-MeOeC6H4
4-CleC6H4
4-NO2eC6H4
4-CleC6H4
4-MeeC6H4
Ph
Ph
n-C3H7
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
4-CleC6H4
4-CleC6H4
Ph
Ph
Ph
Ph
Ph
Ph
d
d
d
d
d
4-MeeC6H4
4-CleC6H4
Ph
d
d
d
n-C4H9
Ph
d
a
Isolated yield.
b
anti/syn-ratio measured by 1H NMR spectroscopy analysis of the crude reaction mixture.
In the cases of
b
-amino-cyclohexanones, stereoselectivity was
change of product yield is minimal, indicating that Cs2.5PW is
stable and reusable (Fig. 1). Only trace amounts of imine were
observed in all runs.
determined by 1H NMR spectroscopy and by comparison with
known compounds. The selectivity for anti-isomer was favored in

E. Rafiee et al. / Tetrahedron 66 (2010) 6858e6863
6861
Table 5
Synthesis of new Mannich products
Entry
Aldehyde
Amine
Ketone or alcohol
Product
Time (min)/yield (%)a
O
CHO
NH2
NH O
O
1b
180/85
220/70
O
O
O
O
17
O
N
O
O
CHO
CHO
CHO
O
O
2b
N
H
O
O
18
N
O
N
3b,c
NH O
70/60
85/90
NH2
O
O
O
O
19
O
O
N
O
OH
4d
OH
N
H
O
20
a
Isolated yield.
b
c
Reaction conditions: aldehyde (1 mmol), ketone (2 mmol), amine (1 mmol), catalyst (0.04 g), H2O (5 mL), room temperature.
Catalyst (0.12 g) was used in this reaction.
Reaction conditions: aldehyde (1.3 mmol),
d
b
-naphthol (1 mmol), amine (1 mmol), catalyst (0.04 g), H2O (5 mL), room temperature.
3. Conclusion
Cs2.5PW as heterogeneous catalyst showed effective catalytic
activity in the synthesis of -amino ketones via three component
b
R1CHO
O
R2NH
+
2
R3
Mannich reaction in water. The good yields, mild conditions, low
catalyst loading and convenient operations as well as no formation
of by-products, such as aldol or deamination products made it
believable that this protocol would play important role in the
synthesis of natural products.
R4
H+
R4
R2
R1
H
O
R2
H+
NH
O
-H+
N
R4
+
4. Experimental section
4.1. General
R3
R3
R1
Scheme 3. Proposed mechanism.
H3PMo12O40, [(n-C4H9)4N]Br, [(t-C4H9)4N]Br, Cs2CO3, TiCl4, SnCl4,
KCl, HOAc, H3PO4, sodium molybdate and sodium tungstate were
obtained from Merck and SnCl2 from Fluka were used as supplied.
H3PW12O40, Co(OAc)2$4H2O and potassium persulfate purchased
from Aldrich. CPB, CTAB, Triton X-100, SOS, SDeS, and SDS were
obtained from Aldrich and used as received without further purifi-
cation. The organic materials were commercially available and
purchased from Fluka, Merck, and Aldrich chemical companies.
1H NMR spectra were recorded on a Bruker Avance 200 MHz
NMR spectrometer with CDCl3 as solvent and TMS as internal
standard. IR spectra were recorded with KBr pellets or Nujol using
a Shimadzu 470 spectrophotometer. Melting points were de-
termined using a digital Gallenkamp apparatus.
100
80
60
40
20
0
4.2. Synthesis of catalysts
1
2
3
Run
4
5
The synthesis of [(n-Bu)4N]5PMo2W9O39 (Sn2þ$H2O), [(n-
Bu)4N]3PMo2W9O39 (Sn4þ$H2O), [(n-Bu)4N]3PMo2W9O39 (Ti4þ$H2O),
Figure 1. Reusability of Cs2.5PW catalyst (after 30 min).

6862
E. Rafiee et al. / Tetrahedron 66 (2010) 6858e6863
and [(Bu)4N]5PMo2W9O39 (Zn2þ$H2O) were started with the prepa-
ration of -K7PMo2W9O39$19H2O from -Na8HPW9O34$24H2O and
sodium molybdate, according to the procedure described pre-
viously.22 [(t-Bu)4N]4 PW11CoO39 and CsxH3-xPW12O40 catalysts
were prepared according to our previously published paper.22
K5CoW12O40 catalyst were prepared and purified by literature
procedures.23
2938, 1673, 1597, 1500 cmꢁ1
; dH (200 MHz, CDCl3 major/
a
b
minor¼54:46) 7.29e7.10 (3H, m, furyl), 6.71e6.61 (3H, m, aro-
matic), 6.26e6.17 (2H, m, aromatic), 4.88 (0.46H, d, J 4.8 Hz, NHCH),
4.82 (0.54H, d, J 5.4 Hz, NHCH), 4.5 (1H, br s, NH), 2.99e2.89 (1H, m,
C(O)CH), 2.40e1.60 (8H, m, CH2).
4.4.7. Compound 7. Yield (0.30 g, 92%),
150e152 ꢀC; Rf (25% ethyl acetate/hexane) 0.53; nmax (KBr) 3387,
3021, 1668 cmꢁ1
dH (200 MHz, CDCl3) 7.93e7.55 (3H, m, aromatic),
a white solid, mp
4.3. Typical procedure for Mannich reaction
;
7.46e7.35 (4H, m, aromatic), 7.11e6.86 (4H, m, aromatic), 6.70e6.54
(3H, m, aromatic), 4.96(1H, t, J6.4 Hz, NHCH), 3.77(3H, s, OCH3), 3.54
(1H, d, J 6.4 Hz, C(O)CH2), 3.34 (1H, d, J 6.4 Hz, C(O)CH2).
Typically, to a mixture of aldehyde (1 mmol), amine (1 mmol) and
ketone (2 or 5 mmol), and H2O (5 mL), catalyst (0.04 g) was added.
The reaction mixture was vigorously stirred for the period of time
listed in the Tables. Progress of the reaction was monitored by TLC.
The resulting solid substance was filtered off and diethyl ether was
added to dissolve of the target product. After filtration, the filtrate
was concentrated at room temperature to generate the crude
product. The crude products were purified either by crystallization
from ethanol or by column chromatography on silica-gel using ethyl
acetate/hexane as eluent. Known products (1e16) were identified by
comparing of their spectral data with those of the authentic
samples.20,21
4.4.8. Compound 8. Yield (0.33 g, 89%), a pale yellow solid, mp
149e151 ꢀC; Rf (25% ethyl acetate/hexane) 0.55; nmax (KBr) 3381,
3020, 1669 cmꢁ1
; dH (200 MHz, CDCl3) 7.90e7.42 (5H, m, aromatic),
7.33e7.01 (4H, m, aromatic), 6.87e6.45 (4H, m, aromatic), 4.90 (1H,
t, J 7.4 Hz, NHCH), 4.57 (1H, br s, NH), 3.77 (3H, s, OCH3), 3.50e3.35
(2H, m, C(O)CH2).
4.4.9. Compound 9. Yield (0.34 g, 91%),
155e157 ꢀC; Rf (25% ethyl acetate/hexane) 0.50; nmax (KBr) 3378,
3020, 1668 cmꢁ1
dH (200 MHz, CDCl3) 7.93e7.94 (d, 2H, J 4.6 Hz),
a yellow solid, mp
;
4.4. Characterization of compounds 1e20
7.59e7.44 (5H, m, aromatic), 7.31e7.05 (4H, m, aromatic), 6.50 (2H,
d, J 8.2 Hz, aromatic), 4.95 (1H, t, J 4.6 Hz, NHCH), 3.47e3.36 (2H, m,
C(O)CH2).
4.4.1. Compound 1. Yield (0.26 g, 94%),
136e138 ꢀC; Rf (25% ethyl acetate/hexane) 0.49; nmax (KBr) 3386,
2939, 1689, 1500 cmꢁ1
a white solid, mp
;
dH (200 MHz, CDCl3 major/minor¼68:32)
4.4.10. Compound 10. Yield (0.28 g, 82%),
107e110 ꢀC; Rf (25% ethyl acetate/hexane) 0.49; nmax (KBr) 3410,
3020, 1663, 1349 cmꢁ1
dH (200 MHz, CDCl3) 8.14e7.82 (4H, m, ar-
a white solid, mp
7.43e7.31 (5H, m, aromatic), 7.21e6.43 (5H, m, aromatic), 4.84
(0.34H, d, J 4.0 Hz, NHCH), 4.76 (0.66H, d, J 7.2 Hz, NHCH), 2.93e2.84
(1H, m, C(O)CH), 2.44e2.22 (2H, m, C(O)CH2),1.86e1.53 (6H, m, CH2).
;
omatic), 7.65e7.49 (4H, m, aromatic), 6.73e6.70 (4H, m, aromatic),
7.13 (2H, m, aromatic), 5.12 (1H, t, J 6.1 Hz, NHCH), 3.52 (2H, d, J
6.1 Hz, C(O)CH2).
4.4.2. Compound 2. Yield (0.24 g, 76%), a pale yellow solid, mp
137e138 ꢀC; Rf (25% ethyl acetate/hexane) 0.45; nmax (KBr) 3378,
2951, 1676, 1510 cmꢁ1
7.55e7.21 (5H, m, aromatic), 6.60e6.51 (4H, m, aromatic), 4.67
(0.36H, d, J 4.0 Hz, NHCH), 4.57 (0.64H, d, J 7.2 Hz, NHCH), 2.72e2.65
(1H, m, C(O)CH), 2.32e2.29 (2H, m, C(O)CH2),1.92e1.60 (6H, m, CH2).
;
dH (200 MHz, CDCl3 major/minor¼64:36)
4.4.11. Compound 11. Yield (0.31 g, 93%),
116e117 ꢀC; Rf (25% ethyl acetate/hexane) 0.51; nmax(KBr) 3376,
3020, 1667 cmꢁ1
dH (200 MHz, CDCl3) 7.89e7.66 (2H, m, aromatic),
a white solid, mp
;
7.35e7.05 (7H, m, aromatic), 6.89e6.71 (3H, m, aromatic),
6.48e6.31 (2H, m, aromatic), 4.99 (1H, t, J 5.6 Hz, NHCH), 4.57 (1H,
br s, NH), 3.49e3.38 (2H, m, C(O)CH2).
4.4.3. Compound 3. Yield (0.25 g, 71%), a pale yellow solid, mp
132e134 ꢀC; Rf (25% ethyl acetate/hexane) 0.48; nmax (KBr) 3362,
2964, 1703, 1512 cmꢁ1
;
dH (200 MHz, CDCl3 major/minor¼67:33)
4.4.12. Compound 12. Yield (0.26 g, 81%),
131e132 ꢀC; Rf (25% ethyl acetate/hexane) 0.56; nmax(KBr) 3400,
3020, 1678 cmꢁ1
dH (200 MHz, CDCl3) 7.90 (2H, m, aromatic),
a white solid, mp
7.27e6.99 (4H, m, aromatic), 6.85e6.43 (4H, m, aromatic), 4.75
(0.33H, d, J 4.8 Hz, NHCH), 4.59 (0.67H, d, J 6.4 Hz, NHCH), 3.78 (3H,
s, OCH3), 2.69 (1H, m, C(O)CH), 2.43e2.32 (m, 2H, C(O)CH2),
1.93e1.81 (4H, m, CH2), 1.68e1.63 (2H, m, CH2).
;
7.56e7.39 (5H, m, aromatic), 7.09e6.85 (4H, m, aromatic),
6.65e6.51 (3H, m, aromatic), 5.76 (1H, t, J 6.8 Hz, NHCH), 3.71 (3H, s,
OCH3), 3.58e3.46 (2H, m, C(O)CH2).
4.4.4. Compound 4. Yield (0.35 g, 96%),
169e171 ꢀC; Rf (25% ethyl acetate/hexane) 0.43; nmax (KBr) 3386,
3021, 1673, 1527, 1348 cmꢁ1
dH (200 MHz, CDCl3 major/
minor¼62:38) 8.18e7.57 (4H, m, aromatic), 7.05e6.41 (4H, m, ar-
omatic), 4.80 (0.38H, d, J 5.8 Hz, NHCH), 4.64 (0.62H, d, J 7.2 Hz,
NHCH), 2.86e2.83 (1H, m, C(O)CH), 2.48e2.30 (2H, m, C(O)CH2),
2.10e2.01 (2H, m, CH2), 1.95e1.58 (4H, m, CH2).
a white solid, mp
4.4.13. Compound 13. Yield (0.25 g, 80%),
138e139 ꢀC; Rf (25% ethyl acetate/hexane) 0.47; nmax(KBr) 3380,
3020, 1665 cmꢁ1
dH (200 MHz, CDCl3) 7.76 (2H, m, aromatic),
7.40e7.14 (8H, m, aromatic), 6.80e6.41 (4H, m, aromatic), 4.91 (1H,
m, NHCH), 3.49e3.41 (2H, m, C(O)CH2), 2.40 (3H, s, CH3).
a white solid, mp
;
;
4.4.14. Compound 14. Yield (0.30 g, 89%), a pale yellow solid, mp
119e120 ꢀC; Rf (25% ethyl acetate/hexane) 0.49; nmax(KBr) 3380,
4.4.5. Compound 5. Yield (0.26 g, 81%),
163e165 ꢀC; Rf (25% ethyl acetate/hexane) 0.24; nmax(KBr) 3386,
3021, 1673, 1527, 1348 cmꢁ1
dH (200 MHz, CDCl3 major/
minor¼58:42) 8.26e8.24 (1H, m, aromatic), 8.09e8.07 (1H, m, ar-
omatic), 7.80e7.12 (4H, m, aromatic), 6.70e6.52 (3H, m, aromatic),
4.86 (0.42H, d, J 4.0 Hz, NHCH), 4.84 (0.58H, d, J 5.2 Hz, NHCH),
2.89e2.86 (1H, m, C(O)CH), 2.42e2.34 (2H, m, C(O)CH2), 2.08e1.95
(3H, m, CH2), 1.79e1.58 (3H, m, CH2).
a white solid, mp
3020, 1685 cmꢁ1
; dH (200 MHz, CDCl3) 7.85e7.66 (3H, m, aromatic),
;
7.48e7.35 (4H, m, aromatic), 7.29e7.08 (5H, m, aromatic), 6.48 (2H,
m, aromatic), 4.90 (1H, t, J 6.3 Hz, NHCH), 3.48 (2H, m, C(O)CH2).
4.4.15. Compound 15. Yield (0.21 g, 66%),
93e95 ꢀC; Rf (25% ethyl acetate/hexane) 0.38; nmax(KBr) 3385,
3020, 1685, 1495, 1378 cmꢁ1
dH (200 MHz, CDCl3) 7.88e7.38 (5H,
a white solid, mp
;
m, aromatic), 7.10e6.55 (5H, m, aromatic), 4.65 (1H, m, NHCH),
3.51e3.44 (2H, m, C(O)CH2), 1.48 (2H, m, CH2CH2CH), 1.33 (2H, m,
CH3CH2CH2), 0.96 (3H, t, J 6.8 Hz, CH3CH2).
4.4.6. Compound 6. Yield (0.23 g, 84%),
a white solid, mp
120e121 ꢀC; Rf (25% ethyl acetate/hexane) 0.46; nmax (KBr) 3362,

E. Rafiee et al. / Tetrahedron 66 (2010) 6858e6863
6863
4.4.16. Compound 16. Yield (0.20 g, 64%),
98e101 ꢀC; Rf (25% ethyl acetate/hexane) 0.41; nmax(KBr) 3382,
3020, 1668, 1489, 1383 cmꢁ1
dH (200 MHz, CDCl3) 7.89e7.34 (5H,
a
white solid, mp
(1H, s, OH), 7.98e6.11 (9H, m, aromatic), 5.35 (1H, s, CHN),
3.68e2.55 (8H, m, CH2).
;
m, aromatic), 7.21e7.08 (5H, m, aromatic), 4.89 (1H, m, NHCH),
3.50e3.43 (2H, m, C(O)CH2), 2.89 (1H, br s, NH), 2.55 (2H, m,
CH2CH2NH), 1.41 (2H, m, CH2CH2CH2), 1.35 (2H, m, CH3CH2CH2),
1.03 (3H, t, J 6.8 Hz, CH3CH2).
Acknowledgements
The authors thank the Razi University Research Council and
Kermanshah Oil Refining Company for support of this work.
4.4.17. Compound 17. Yield (0.27 g, 85%),
a white solid, mp
Supplementary data
135e138 ꢀC; [found: C, 72.47; H, 7.90; N, 4.52. C19H25NO3 requires
C, 72.35; H, 7.99; N, 4.44%]; Rf (25% ethyl acetate/hexane) 0.18;
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.052.
nmax(KBr) 3374, 3021, 1744, 1683 cmꢁ1
; dH (200 MHz, CDCl3)
7.34e7.11 (5H, m, aromatic), 4.85 (1H, m, NHCH), 4.42e4.31 (2H, t, J
8.3 Hz, OCH2), 3.66 (1H, m, CHC(O)), 3.59e3.42 (2H, m, C(O)CH2),
3.29e3.34 (1H, m, NHCH), 2.89e2.75 (2H, m, CH2), 1.92e1.31 (10H,
m, cyclohexyl).
References and notes
1. Simplício, A. L.; Clancy, J. M.; Gilmer, J. F. Int. J. Pharm. 2007, 336, 208e214.
2. Mandloi, D.; Joshi, S.; Khadikarc, P. V.; Khosla, N. Bioorg. Med. Chem. Lett. 2005,
15, 405e411.
4.4.18. Compound 18. Yield (0.21 g, 70%),
a
white solid, mp
€
€
3. Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601e635.
4. Kleinmann, E. F. ComprehensiveOrganic Synthesis; Pergamon: New York, NY,1991.
5. Zeng, H.; Li, H.; Shao, H. Ultrason. Sonochem. 2009, 16, 758e762.
6. Ramalingam, S.; Kumar, P. Catal. Commun. 2008, 9, 2445e2448.
7. Dai, Y.; Li, B. D.; Quan, H. D.; Lü, C. X. Chin. Chem. Lett. 2010, 21, 31e34.
8. Loh, T. P.; Liung, S. B. K. W.; Tan, K. L.; Wei, L. L. Tetrahedron 2000, 56, 3227e3237.
9. Wu, H.; Chen, X.; Wan, Y.; Ye, L.; Xin, H.; Xu, H.; Yue, C.; Pang, L.; Ma, R.; Shi, D.
Tetrahedron Lett. 2009, 50, 1062e1065.
122e125 ꢀC; [found: C, 67.40; H, 6.95; N, 4.70. C17H21NO4 requires
C, 67.31; H, 6.98; N, 4.62%]; Rf (25% ethyl acetate/hexane) 0.21;
nmax(KBr) 3019, 1752, 1685, 1272, 1238, 1085 cmꢁ1
; dH (200 MHz,
CDCl3) 7.09e7.30 (5H, m, aromatic), 4.87 (1H, m, NHCH), 4.42e4.28
(2H, t, J 8.3 Hz, OCH2), 3.64 (1H, m, CHC(O)), 3.79 (4H, m, CH2OCH2),
3.57e3.38 (2H, m, C(O)CH2), 2.91e2.73 (6H, m, CH2).
10. Dong, F.; Jun, L.; Xin-Li, Z.; Zu-Liang, L. Catal. Lett. 2007, 116, 76e80.
11. Dong, F.; Zhenghao, F.; Zuliang, L. Catal. Commun. 2009, 10, 1267e1270.
12. Sahoo, S.; Joseph, T.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2006, 244, 179e182.
13. Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965e1967.
14. Azizi, N.; Torkiyan, L.; Saidi, M. R. Org. Lett. 2006, 8, 2079e2082.
15. Teo, Y. C.; Lau, J. J.; Wu, M. C. Tetrahedron: Asymmetry 2008, 19, 186e190.
16. Pandey, J.; Anand, N.; Tripathi, R. P. Tetrahedron 2009, 65, 9350e9356.
17. Timofeeva, M. N.; Matrosova, M. M.; Maksimov, G. M.; Likholobov, V. A. Kinet.
Catal. 2001, 42, 785e790.
4.4.19. Compound 19. Yield (0.19 g, 60%), a colorless oil; [found: C,
70.42; H, 6.18; N, 4.60. C19H20N2O3 requires C, 70.35; H, 6.21; N,
8.64%]; Rf (43% ethyl acetate/hexane) 0.23; nmax (Nujol) 3381, 3021,
1748, 1679 cmꢁ1
; dH (200 MHz, CDCl3) 8.46e7.35 (4H, m, aromatic),
7.25e7.11 (5H, m, aromatic), 4.83 (1H, m, NHCH), 4.45e4.29 (4H, m,
CH2), 3.66 (1H, m, CHC(O)), 3.59e3.42 (2H, m, C(O)CH2), 2.89e2.75
(2H, m, CH2).
18. Okuhara, T.; Watanabe, H.; Nishimura, T.; Inumaru, K.; Misono, M. Chem. Mater.
2000, 12, 2230e2238.
19. Rafiee, E.; Azad, A. Bioorg. Med. Chem. Lett. 2007, 17, 2756e2759.
20. Yi, W. B.; Cai, C. J. Fluorine Chem. 2006, 127, 1515e1521.
21. Shen, W.; Wang, L. M.; Tian, H. J. Fluorine Chem. 2008, 129, 267e273.
22. Rafiee, E.; Zolfagharifar, Z.; Joshaghani, M.; Eavani, S. Appl. Catal., A 2009, 365,
287e291.
4.4.20. Compound 20. Yield (0.28 g, 90%), an orange solid, mp
184e188 ꢀC; [found: C, 73.62; H, 6.17; N, 4.61. C19H19NO3 requires C,
73.77; H, 6.19; N, 4.53%]; Rf (43% ethyl acetate/hexane) 0.15; nmax
23. Rafiee, E.; Tangestaninejad, S.; Habibi, M. H.; Mirkhani, V. Synth. Commun. 2004,
34, 3673e3681.
(KBr) 3264, 1595, 1271, 1236, 1080 cmꢁ1
; dH (200 MHz, CDCl3) 13.98