A SiCl4-ZnCl2 induced general, mild and efficient one-pot, three-component synthesis of β-amido ketone libraries

Article abstract of DOI:10.1016/j.tetlet.2007.06.128

A general, mild and efficient protocol for the synthesis of β-amido ketone libraries was achieved utilizing tetrachlorosilane and zinc chloride in dichloromethane at ambient temperature via a one-pot, three-component condensation of various aldehydes, ket

Full text of DOI:10.1016/j.tetlet.2007.06.128

Tetrahedron Letters 48 (2007) 6199–6203
A SiCl4–ZnCl2 induced general, mild and efficient one-pot,
three-component synthesis of b-amido ketone libraries
Tarek A. Salama,* Saad S. Elmorsy, Abdel-Galel M. Khalil and Mohamed A. Ismail
Chemistry Department, Faculty of Science, Mansoura University, 35516-Mansoura, Egypt
Received 3 May 2007; revised 12 June 2007; accepted 20 June 2007
Available online 27 June 2007
Abstract—A general, mild and efficient protocol for the synthesis of b-amido ketone libraries was achieved utilizing tetrachlorosilane
and zinc chloride in dichloromethane at ambient temperature via a one-pot, three-component condensation of various aldehydes,
ketones and nitriles.
ꢀ 2007 Elsevier Ltd. All rights reserved.
b-Amido ketones are important building blocks and
intermediates in synthesis, for example, they are impor-
tant precursors of heterocycles1 as well as of b-amino
alcohols, which are common units in both natural and
synthetic biologically or pharmacologically important
compounds.2 Multicomponent coupling reactions3
(MCRs) are attractive for parallel synthesis as large
arrays of compounds with diverse substitution patterns
can be prepared in one-step, often in high yields, under
mild conditions. MCRs are powerful tools in modern
drug discovery and allow fast, automated and high
throughput synthesis of diverse structural scaffolds
required in the search of novel therapeutic molecules.
Recently, a number of reports have described the syn-
thesis of b-acetamido ketones through multicomponent
condensation of aryl aldehydes, enolizable ketones,
acetyl chloride and acetonitrile catalyzed by CoCl2,4
benzonitrile, no other nitriles have been used in such
condensations. Therefore, the introduction of new and
efficient methods for this multicomponent reaction are
still required. Towards this goal, and in continuation
of our investigations9 on the development and applica-
tions of new in situ reagents derived from tetrachloro-
silane (TCS)10 in organic synthesis, we have developed
an efficient, general and convenient protocol for the
one-pot synthesis of b-amido ketones. The reaction
proceeds via a three-component reaction of various
aldehydes, ketones and nitriles including alkyl, aralkyl,
aryl and a,b-unsaturated nitriles as well as cyano esters
utilizing the inexpensive and readily available tetra-
chlorosilane–zinc chloride reagent10e in dichlorometh-
ane at room temperature without using acetyl chloride.
An equimolar mixture of benzaldehyde, acetophenone
and acetonitrile in dichloromethane was allowed to react
in the presence of TCS (4 equiv) and ZnCl2 (2 equiv) at
room temperature to furnish the corresponding b-acet-
amido ketone 4a in good yield (Table 1, entry 1). In
order to create a library of compounds, we have reacted
various ketones, aldehydes, and nitriles to afford a
diverse set of b-amido ketones (Scheme 1, Table 1).
6
Montmorillonite K-10 clay5 or SiO2–H2SO4 under
thermal conditions or by using ZrOCl2Æ8H2O7 or BiCl3
generated in situ from BiOCl and acetyl chloride8 at
room temperature. Although, these protocols are valu-
able, they lack the generality to produce arrays of b-ami-
do ketones as they are restricted to acetonitrile giving
the corresponding b-acetamido ketones,4–8 and only
one example of a b-benzamido ketone was prepared
by this method involving benzonitrile in a long time
(36 h).7 To our knowledge, except for acetonitrile or
As seen from the results in Table 1 and Scheme 2, the
reaction proved to be general and tolerated a variety
of functional groups on the aromatic aldehydes, includ-
ing chlorine, methyl and methoxy as well as sterically
hindered aldehydes such as naphthaldehyde (Table 1,
entries 2–4 and 7). A unique example of heteroaryl as
well as a,b-unsaturated aldehydes was introduced through
the MCR of 3-formylchromone with acetophenone and
Keywords: Tetrachlorosilane; Zinc chloride; One-pot three-component
synthesis; b-Amido ketones.
*
Corresponding author. Fax: +2 050 2246781; e-mail: tasalama@
yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.128

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T. A. Salama et al. / Tetrahedron Letters 48 (2007) 6199–6203
Table 1. SiCl4–ZnCl2 induced one-pot, three-component reaction of aldehydes with ketones and nitriles giving the corresponding b-amido ketones
Entry
R1
R2
R3
R4
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Ph
4-ClC6H4
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
PhCH2
PhCH2
PhCH2
PhCH2
Ph
Ph
Ph
Ph
Ph
CH2@CH–
CH2@CH–
CH2@CH–
CH2@CH–
CH2@CH–
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
Me
4a
4b
4c
4d
4e
4f
8
9
10
9
71
69
72
74
70
73
66
62
65
68
66
67
60
61
63
61
62
66
64
67
65
68
70
72
71
69
65
87
67
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
2-Naphthyl
2-Chromonyl
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
Ph
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
2-Naphthyl
4-MeOC6H4
8
11
10
13
11
10
13
12
20
18
17
18
16
12
11
11
12
10
11
10
11
10
12
18
13
4g
5
6a
6b
6c
6d
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
9a
9b
9c
9d
10
11
12
Ph
4-MeC6H4
4-MeC6H4
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
Ph
4-MeC6H4
4-MeC6H4
1-Tetralone
1-Tetralone
1-Benzosuberone
—
Me
a Isolated yields after column chromatography except for product 11, purified by recrystallization from EtOH.
O
nitrile, the MCRs of aldehydes and ketones with aralkyl,
aryl and a,b-unsaturated nitriles as well as with cyano-
esters were studied. Phenylacetonitrile, benzonitrile,
acrylonitrile and ethyl cyanoacetate were chosen as rep-
resentative examples. In all the cases studied, the reac-
tion proceeded smoothly under the above conditions
giving the corresponding b-amido ketones, typically
within 12 h, except for the reaction with benzonitrile
where reaction times of up to 20 h were required, which
might be attributed to steric factors as well as to the low
nucleophilicity of benzonitrile (Table 1, entries 13–17).
O
HN
R4
O
O
TCS/ZnCl2
CH2Cl2, r.t.
R3
R4 CN
+
+
R1
H
R2
R2
R1
R3
3
2
1
4-10,12
Scheme 1.
acetonitrile, which gave b-acetamido ketone 5 in moder-
ate yield (Table 1, entry 8). It is appeared that the reac-
tion with a-substituted enolisable ketones (entries 27
and 29) proceeds in a diastereoselective manner, how-
ever, we could not state which diastereoisomer is pre-
ferred at moment. Further investigations on the
diastereoselectivity of the process are currently in pro-
gress in our lab. With respect to the ketones, the present
reaction tolerated aryl methyl ketones as well as carbo-
cyclic ketones such as 1-tetralone and 1-benzosuberone
(Table 1, entries 27 and 29) giving the respective b-ami-
do ketones in moderate yields. As with aldehydes, the
present procedure works well with sterically hindered
ketones (Table 1, entries 27 and 29). However, using
two sterically hindered components in this reaction gave
only the corresponding enone. Thus, the MCR of 1-tetr-
alone with 2-naphthaldehyde and acetonitrile gave
exclusively 2-naphthylidene-1-tetralone 11 even when
using an excess of TCS and ZnCl2 for a longer reaction
time (up to 8 equiv, Table 1, entry 28). The reaction was
successful with a variety of nitriles. Thus, besides aceto-
To optimize the reaction conditions, we examined the
reaction in various solvents. CH2Cl2 was found to be
the most effective solvent while donor solvents such as
diethyl ether completely inhibited the reaction. SnCl2
as a Lewis acid was examined and similar results were
obtained but it was less effective than ZnCl2. It is note-
worthy to mention that no reaction was observed in the
absence of either the Lewis acid or SiCl4.
A reasonable mechanism for the present reaction may
proceed as depicted in Scheme 3 in an aldol-type11
way followed by amidoalkylation.12 The addition of
nucleophiles to the ketones is promoted by co-ordina-
tion of a Lewis acid to the carbonyl group enhancing
the electrophilicity of this moiety.13 On the other hand,
use of ZnCl2 as a radical initiator as well as a chelating
agent has been documented.14 Therefore, a reaction
pathway that involves activation of the ketones by SiCl4

T. A. Salama et al. / Tetrahedron Letters 48 (2007) 6199–6203
6201
O
O
O
O
HN
O
HN
O
O
HN
O
R
R'
R
R'
R"
5
4a;
R = R' = R'' = H
4b; R = R'' = H, R' = Cl
4c;
6a;
R = H, R' = Me
6b; R = H, R' = OMe
R = R'' = H, R' = Me
6c;
6d;
R = Me, R' = Me
R = Me, R' = OMe
4d; R = R'' = H, R' = OMe
4e; R = R' = Me, R'' = H
4f;
R = Me, R' = OMe, R'' = H
4g;R = H, R, R'' = -(CH = CH)2-
O
O
O
O
O
HN
O
HN
O
O
HN
Ph
R
R'
R
R'
R
R'
8a;
R = H, R' = Me
8b; R = H, R' = OMe
8c;
9a;
R = H, R' = Me
7a;
R = H, R' = Cl
9b; R = H, R' = OMe
7b; R = H, R' = Me
R = Me, R' = H
8d; R = Me, R' = Me
8e;
9c;
R = Me, R' = Me
7c;
7d;
R = H, R' = OMe
R = Me, R' = H
9d; R = Me, R' = OMe
R = Me, R' = OMe
7e; R = Me, R' = Me
O
O
O
HN
O
HN
O
OMe
10
12
11
Scheme 2.
Cl
Si Cl3
R3
SiCl3
R3
O
O
O
+
O
ZnCl2
ZnCl2
- HCl
R3
+
R1
H
+
R2
Cl
R2
SiCl4
R2
Cl
Si
O
Cl
Cl
Zn
Cl
O
Cl
O
Cl
Cl
O
Cl
Zn
Cl
Zn
R3
Cl3Si
Zn
R3
R2
- OSiCl3
R2
O
O
+
R2
Cl3Si Cl
R1
R1
R2
R1
O
R3
R3
A
R1
B
R4
O
Cl
SiCl4
+
Cl
O
O
HN
R4
Cl
Cl
O
Zn
Zn
R3
H2O
N
N
R4
CN
SiCl4
+
R1
R2
R1
R2
R1
R2
R3
R4
R3
Scheme 3.
is reasonable in analogy to the Me3SiX assisted addi-
tion.15 We presume that the mechanism is formally
analogous to the Lewis acid-catalyzed addition of silyl
enol ethers to carbonyl compounds. Indeed, the reac-
tion may proceed via the prior complexation of the
–CO– with ZnCl2 according to the well established Zim-
merman–Traxler chair-like transition state model16 to
afford the corresponding silyl zinc chelate A,17 which is
tually the desired b-amido ketone after aqueous work-
up.
According to the proposed mechanism, the reaction may
be viewed as a new route to b-amido ketones via a mild
tandem aldol-amidoalkylation reaction sequence. It is
noteworthy to mention that only a few examples of
b-amido ketones of type 6 and 7 have previously been
prepared via multi-step routes under harsh conditions.18
converted to silyl zinc chelate B. On the other hand, as
18a
with SnCl4
SiCl4 may co-ordinate with nitriles acti-
vating addition of the nitrile to the silyl zinc chelate B
In conclusion, we have reported SiCl4–ZnCl2 as a read-
ily available and inexpensive reagent for the efficient
in a manner similar to the Ritter reaction19 giving even-

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T. A. Salama et al. / Tetrahedron Letters 48 (2007) 6199–6203
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libraries through a tandem aldol-amidoalkylation reac-
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is convenient and applicable to a wide variety of alde-
hydes, ketones and nitriles, which should make it
amenable to high throughput synthesis of combinatorial
libraries for potential drug development.
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Acknowledgement
We thank Dr. A. F. Abdel-Razik (NRC, Cairo) for
mass spectroscopic assistance.
References and notes
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ZnCl2: To
a solution of anhydrous ZnCl2 (1.35 g,
10 mmol) in CH2Cl2 (20 ml) were added aldehyde
(5 mmol), ketone (5 mmol) and nitrile (5 mmol). The
reaction mixture was stirred at ambient temperature for
10 min, SiCl4 (2.4 ml, 20 mmol) was added and the
reaction mixture was stirred with exclusion of moisture.
On completion (TLC monitoring of the progress of the
reaction), the mixture was poured onto water (100 ml),
extracted with CH2Cl2 (2 · 50 ml) and the combined
organic extract dried over anhydrous MgSO4, evaporated
and the residue chromatographed on silica gel using pet.
ether–ethyl acetate (2:1) as eluent to give pure b-amido
ketones. Spectral data for representative examples of b-
amido ketones are listed below.
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N-(3-Chromonyl-3-oxo-3-phenylpropyl)-acetamide 5: mp
188–190 ꢁC. Rf = 0.22, (pet. ether/AcOEt 1:1); IR (KBr)
m 3311, 3078, 2920, 1679, 1643, 1575, 1545, 1465, 1402,
1359, 1319, 1282, 1222, 1161, 1143, 990, 810, 759,
692 cmÀ1 1H NMR (300 MHz, CDCl3): d 8.20 (s, 1H),
;
8.13 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.64 (t,
J = 7.6 Hz, 1H), 7.41–7.50 (m, 4H), 7.39 (s, 1H), 7.21 (t,
J = 6.9 Hz, 1H, NH exchanged with D2O), 5.52 (q,
J = 4.45 Hz, 1H), 3.80 (dd, J = 3.97, 17.5 Hz, 1H), 3.50
(dd, J = 3.97, 17.6 Hz, 1H), 1.96 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 198.29, 180.13, 169.39, 155.87,
149.23, 136.48, 133.29, 132.19, 129.17, 128.53, 127.09,
124.43, 123.62, 114.54, 113.21, 49.62, 43.31, 23.23; Anal.
Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found:
C, 71.76; H, 5.07; N, 4.22.

T. A. Salama et al. / Tetrahedron Letters 48 (2007) 6199–6203
6203
N-[1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl]-2-pheny-
lacetamide 6b: mp 131–132 ꢁC. Rf = 0.18, (pet. ether/
AcOEt 2:1); IR (KBr) m 3275 (NH), 3064, 3030, 2926,
1686 (CO), 1646 (CONH), 1613, 1550, 1513, 1450, 1358,
1H), 5.61 (m, 2H), 3.77 (dd, J = 6, 16 Hz, 1H), 3.42 (dd,
J = 6, 16 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 198.61, 164.13, 144.32, 139.81, 134.13,
133.07, 131.19, 128.20, 128.03, 127.94, 126.87, 126.32,
49.52, 43.08, 21.61, 21.39; Anal. Calcd for C20H21NO2: C,
78.15; H, 6.89; N, 4.56. Found: C, 78.02; H, 7.03; N, 4.33.
N-[1-(4-Methylphenyl)-3-oxo-3-(4-methylphenyl)propyl]-
2-carbethoxyacetamide 9c: mp 104–106 ꢁC. Rf = 0.41, (pet.
ether/AcOEt 2:1); IR (KBr) m 3283 (NH), 3092, 2980, 1745
(COOEt), 1683 (CO), 1650 (CONH), 1608, 1564, 1515,
1249, 1200, 1177, 1030, 993, 757, 693 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 7.83 (d, J = 7.8 Hz, 2H), 7.52 (t,
J = 7.2 Hz, 1H), 7.42–7.2 (m, 7H), 7.18 (d, J = 8.7 Hz,
2H), 6.74 (m, 3H), 5.48 (q, J = 6.3 Hz, 1H), 3.7 (s, 3H),
3.62 (dd, J = 5.5, 16.6 Hz, 1H), 3.52 (s, 2H), 3.29 (dd,
J = 5.5, 16.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
198.1, 170.21, 158.61, 136.49. 134.76, 133.24, 132.82,
129.18, 128.76, 128.51, 127.98, 127.48, 127.08,
113.8,55.06, 49.51, 43.62, 43.3; MS (m/z, %): 373 (M+,
40.8), 374 (M++1, 14), 254 (100), 223 (53), 19 (100); Anal.
Calcd for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found:
C, 77.12; H, 6.17; N, 3.51.
1409, 1361, 1234, 1151, 1034, 811 cmÀ1
;
1H NMR
(200 MHz, CDCl3): d 8.1 (d, J = 6 Hz, 1H), 7.87 (d,
J = 7.8 Hz, 2H), 7.30(d, J = 7.6 Hz, 4H), 7.17 (d, J =
7.4 Hz, 2H), 5.62 (q, J = 6.4 Hz, 1H), 4.25 (q, J = 7 Hz,
2H), 3.75 (dd, J = 5.2, 16.4 Hz, 1H), 3.46 (m, 1H), 3.39 (s,
2H), 2.47 (s, 3H), 2.37 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H); 13
C
N-[1-(4-Methylphenyl)-3-oxo-3-phenylpropyl]-benzamide
7b: mp 172–173 ꢁC. Rf = 0.4, (pet. ether/AcOEt 2:1); IR
(KBr) m 3279 (NH), 3071, 2955, 1683 (CO), 1642 (CONH),
1599, 1578, 1446, 1405, 1359, 1303, 1198, 1264, 1226, 1157,
NMR (75 MHz, CDCl3): d 198.81, 171.52, 168.10, 141.07,
139.18, 135.17, 133.54, 128.27, 128.13, 128.00, 126.12,
49.36, 43.72, 42.25, 56.31, 21.41, 21.23, 19.42; MS (m/z, %):
367 (M+, 27), 368 (M++1, 8), 322 (4), 276 (7), 253 (19), 252
(100), 236 (12), 221 (18), 134 (39), 119 (87); Anal. Calcd for
C22H25NO4: C, 71.91; H, 6.86; N, 3.81. Found: C, 71.68;
H, 6.77; N, 3.87.
1
1083, 983, 800, 761, 650, 600 cmÀ1; H NMR (300 MHz,
CDCl3): d 7.91 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz,
2H), 7.58 (d, J = 5.3, 1H, NH), 7.47 (m, 6H), 7.31 (m, 2H),
7.10 (d, J = 7.8 Hz, 2H), 5.73 (q, J = 5.1 Hz, 1H), 3.86 (dd,
J = 5.5, 16.95 Hz, 1H), 3.51 (dd, J = 5.5, 16.95 Hz, 1H),
2.28 (s, 3H); 13C NMR (75 MHz, CDCl3): d 198.00, 170.24,
137.73, 136.91, 136.35, 134.76, 133.28, 129.23, 129.17,
128.81, 128.54, 128.01, 127.14, 126.18, 49.73, 43.25, 20.92;
Anal. Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08.
Found: C, 80.22; H, 6.02; N, 3.79.
2-[N-Acetylamino(4-methoxyphenyl)methyl]-1-benzosube-
rone 12: mp 166 ꢁC. Rf = 0.3, (pet. ether/AcOEt 1:1); IR
(KBr) m 3356, 2997, 2933, 2860, 1675, 1606, 1514, 1449,
1371, 1299, 1276, 1244, 1185, 1115, 1031, 980, 843,
582 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 7.61 (d,
J = 9.3 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.34 (t,
J = 7.5 Hz, 1H), 7.19 (m, 4H), 6.77 (d, J = 8.4 Hz, 2H),
5.31 (dd, J = 3.9, 9.3 Hz, 1H), 3.50 (m, 1H), 3.76 (s, 3H),
3.00 (m, 2H), 2.20 (m, 1H), 2.06 (s, 3H), 1.90 (m, 2H), 1.60
(m, 1H); 13C NMR (75 MHz, CDCl3): d 207.18, 169.65,
158.36, 142.68, 139.65, 133.31, 131.41, 130.11, 127.83,
127.64, 126.33, 113.61, 55.07, 53.77, 53.58, 33.83, 29.07,
25.30, 23.44; Anal. Calcd for C21H23NO3: C, 74.75; H,
6.87; N, 4.15. Found: C, 74.38; H, 7.10; N, 4.09.
N-[1-(4-Methylphenyl)-3-oxo-3-(4-methylphenyl)propyl]-
acrylamide 8d: mp 102–103 ꢁC. Rf = 0.51, (pet. ether/
AcOEt 1:1); IR (KBr) m 3264 (NH), 3059, 2920, 1680 (CO),
1651 (CONH), 1411, 1360, 1268, 1181, 992, 810, 732 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 7.82 (d, J = 8 Hz, 2H),
7.24 (d, J = 10 Hz, 4H), 7.11 (d, J = 8 Hz, 2H), 6.82 (d,
J = 6 Hz, 1H), 6.31 (dd, J = 5.4, 16.5 Hz, 1H), 6.11 (m,