An efficient synthesis of β-acylureas via a three-component, one-pot synthesis using TCS/ZnCl2

Article abstract of DOI:10.1016/j.tetlet.2011.01.066

A simple and efficient one-pot, three-component synthesis of new trisubstituted ureas containing diastereotopic protons is achieved via the reaction of aromatic aldehydes, aromatic ketones, and dimethyl cyanamide using a TCS/ZnCl₂ reagent mixtu

Full text of DOI:10.1016/j.tetlet.2011.01.066

Tetrahedron Letters 52 (2011) 1448–1451
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An efficient synthesis of b-acylureas via a three-component, one-pot
synthesis using TCS/ZnCl2
⇑
Tamer K. Khatab , Khairy A. M. El-Bayouki, Wahid M. Basyouni
Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient one-pot, three-component synthesis of new trisubstituted ureas containing diaste-
reotopic protons is achieved via the reaction of aromatic aldehydes, aromatic ketones, and dimethyl
cyanamide using a TCS/ZnCl2 reagent mixture at room temperature.
Received 8 November 2010
Revised 27 December 2010
Accepted 14 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b-Acylureas
Tetrachlorosilane
Multicomponent reactions
In multicomponent reactions (MCRs), three or more substrates
react in a single reaction vessel to form new products that contain
structural units of all the components. These types of reactions are
important in organic and medicinal chemistry because they allow
highly sophisticated polyfunctional molecules to be obtained
through simple one-pot procedures. Multicomponent reactions
have been successfully employed to generate highly diverse com-
binatorial libraries for high-throughput screening of biological
and pharmacological activities.1–5 The use of three or more build-
ing blocks in a one-pot, high-yielding multicomponent reaction
leads to a wide structural and functional diversity combined with
excellent combinatorial efficiency. Industrial and academic re-
search has made use of MCR strategies as efficient and cost-effec-
tive tools for combinatorial synthesis.6–8 The development of novel
MCRs is a challenging task since one has to consider not only the
reactivity match of the starting materials but also the reactivity
of the intermediate molecules generated in situ, their compatibil-
ity, and their compartmentalization.9
novel multicomponent reactions using a binary catalyst derived
from TCS as an in situ reagent,13 we have developed an efficient
protocol for the synthesis of 1,1-dimethyl-3-(3-oxo-1,3-diphenyl-
propyl)urea (4aa) in good yield. The reaction occurs via
a
three-component, one-pot reaction between benzaldehyde (1a),
acetophenone (2a), and dimethyl cyanamide (3) using TCS/ZnCl2
in methylene chloride as the solvent at room temperature
(Scheme 1).
As a part of an ongoing study to investigate the optimum con-
ditions for these reactions, we studied the efficacy of the promoter
type, molar ratio, and solvent. The results obtained are summa-
rized in Table 1.
It was found that the best results were obtained by using a
1:1:1:3 ratio of aldehyde, acetophenone, dimethyl cyanamide,
and TCS/ZnCl2, respectively, in CH2Cl2 (Table 1, entry 3). These re-
sults prompted us to explore the potential of this protocol for the
synthesis of various trisubstituted ureas. The results are summa-
rized in Scheme 2 and Table 2.
Urea derivatives have been reported as an important class of
compounds in organic, bioorganic, supramolecular, and medicinal
chemistry.10 A few reports are available on the synthesis of
b-acylureas by reacting amines with phosgene or substituted isocy-
anates10,11 which are considered as highly toxic and unstable mate-
rials. In the present work, we describe a new practical approach for
the synthesis of some novel trisubstituted urea derivatives.
Many reagents have been derived from tetrachlorosilane
(TCS).12 In continuation of our investigations on the synthesis of
novel alicyclic and heterocyclic compounds, and the design of
From the results obtained it was apparent that the reaction time
was shorter and the yield was higher for the one-pot condensa-
tions of aldehydes or acetophenones containing an electron-donat-
ing group (CH3), relative to the unsubstituted reactants. However,
1a
CHO
O
O
O
i)
CH3
CH3
CH3
CH3
+
NC N
N
N
H
4aa
2a
3
Reagents and conditions: i) TCS/ZnCl2, CH2Cl2, r.t.
⇑
Corresponding author. Tel.: +20 233371010; fax: +20 237601877.
E-mail address: tamer_khatab@hotmail.com (T.K. Khatab).
Scheme 1. Synthesis of 1,1-dimethyl-3-(3-oxo-1,3-diphenylpropyl)urea 4aa.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.066

T. K. Khatab et al. / Tetrahedron Letters 52 (2011) 1448–1451
1449
Table 1
the presence of electron-withdrawing substituents (Cl, Br) led to
longer reaction times and lower yields (Tables 2).
Effect of promoters and solvents on the yield and reaction time for the one-pot
synthesis of 1,1-dimethyl-3-(3-oxo-1,3-diphenylpropyl)urea (4aa)
The structures of the obtained b-acylureas were elucidated by
Entry
Promoter (mmol)
Solvent
Time (h)
Yield (%)
spectroscopic methods. The IR spectra showed peaks at
m = 3396–
3295, 1689–1660, and 1633–1623 cmÀ1 corresponding to NH,
COCH2, and the urea carbonyl (CH3)2NCONH groups, respectively.
The 1H NMR spectra of the synthesized products revealed singlets
for –N(CH3)2, two double doublets and mutiplet signals for the dia-
stereotopic protons (CH2CH), and broad NH signals. The 13C NMR
spectrum of compound (4ab) showed two characteristic signals
at d = 199.21 for the ketone (CO) and at 144.28 for the urea
[(CH3)2NCONH] carbonyl groups, at 142.31–125.83 for CArH,
1
2
3
4
5
6
7
8
9
TCS/ZnCl2 (10)
TCS/ZnCl2 (20)
TCS/ZnCl2 (30)
TCS/ZnCl2 (30)
TCS/ZnCl2 (30)
TCS (30)
ZnCl2 (30)
TCS/SnCl2 (30)
TCS/FeCl3 (30)
CH2Cl2
CH2Cl2
CH2Cl2
THF
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
10
6
20
20
30
30
30
30
50
65
85
35
40
20
15
45
32
CH3
O
H3O+
O
Ar O
O
3
Ar'
O
N
CH
N 3
CH3
+
Ar'
N
Ar
H
Ar' CH3
i)
N
H
CH3
Ar
4aa-4ad
4ba-4bd
4ca
1a, Ar = Ph-
2a, Ar' = Ph-
1b, Ar = 4-F-C6H4-
1c, Ar = 4-Cl-C6H4-
1d, Ar = 3-Br-C6H4-
1e, Ar = 2-thienyl
1f, Ar = naphthyl
2b, Ar' = 4-CH3-C6H4-
2c, Ar' = 4-Cl-C6H4-
2d, Ar' = 4-Br-C6H4-
4da-4dd
4ea
4fa
Reagents and conditions: i) TCS/ZnCl2, CH2Cl2, r.t.
Scheme 2. Synthesis of trisubstituted ureas.
Table 2
Reaction of dimethyl cyanamide (3) with various aldehydes 1 and ketones 2
Entry
Aldehyde
Ketone
Product
Time (h)
6
Yield (%)
85
O
O
1
1a
2a
CH3
N
H
N
CH3
O
O
2
1a
2b
5
89
CH3
N
N
H
CH3
H3C
Cl
O
O
O
3
4
1a
1a
2c
8
80
78
CH3
N
N
CH3
H
O
F
2d
10
CH3
N
H
N
CH3
Br
5
6
7
1b
1b
1b
2a
2b
2c
8
7
9
87
88
O
O
CH3
N
H
N
CH3
F
O
O
CH3
N
N
CH3
H
H3C
F
O
O
85
CH3
N
N
H
CH3
Cl
(continued on next page)

1450
T. K. Khatab et al. / Tetrahedron Letters 52 (2011) 1448–1451
Table 2 (continued)
Entry
Aldehyde
Ketone
Product
Time (h)
10
Yield (%)
82
F
O
O
8
9
1b
2d
CH3
N
H
N
CH3
Br
Cl
1c
2a
9
77
O
O
CH3
N
N
H
CH3
Br
O
O
10
11
12
1d
1d
1d
2a
2b
2c
11
10
12
78
83
75
CH3
N
H
N
CH3
Br
O
O
CH3
N
N
CH3
H
H3C
Br
O
O
CH3
N
H
N
CH3
Cl
Br
O
O
13
14
15
1d
1e
1f
2d
2a
2a
12
8
72
80
70
CH3
N
H
N
CH3
Br
S
O
O
CH3
N
H
N
CH3
O
O
12
CH3
N
N
H
CH3
4. (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907; (b) Dondoni, A.; Massi, A. Acc.
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(see also the Supplementary data).
In conclusion, the synthesis of b-acylureas containing diastereo-
topic protons in good to excellent yields via the MCR of dimethyl
cyanamide, an aromatic ketone, and an aromatic aldehyde using
a binary reagent (TCS/ZnCl2) and methylene chloride as solvent
has been described.14 The reaction products were characterized
by IR, MS, 1H NMR, 13C NMR, and elemental analysis.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.066.
12. (a) Massa, A.; De Sio, V.; Villano, R.; Acocella, M. R.; Palombi, L.; Sellitto, G.;
Peduto, A.; Filosa, R.; De Capraris, P.; Scettri, A. Synthesis 2009, 643–649; (b)
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4602–4605; (c) Curti, C.; Sartori, A.; Battistini, L.; Rassu, G.; Zanardi, F.;
Casiraghi, G. Tetrahedron Lett. 2009, 50, 3428–3431; (d) Dash, B. P.; Satapathy,
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Reference and notes
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C.; Elmorsy, S. S. Monatsh. Chem. 2003, 134, 1241–1252; (b) Elmorsy, S. S.;
Badawy, D. S.; Khatab, T. K. Phosphorus, Sulfur, Silicon Relat. Elem. 2005, 180,
109–116; (c) Elmorsy, S. S.; Badawy, D. S.; Khatab, T. K. Phosphorus, Sulfur,
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14. In a dry two-necked round bottomed flask equipped with a rubber septum, a
magnetic stirring bar, and a condenser, a mixture of ketone (5 mmol), aldehyde
(5 mmol), dimethyl cyanamide (5 mmol), anhydrous ZnCl2 (15 mmol), in
CH2Cl2 (20 ml) was allowed to stir with exclusion of moisture at room
temperature for 5 min. Tetrachlorosilane (15 mmol) was then added and the
mixture was stirred for the specified time (Table 2). The mixture was poured
onto ice-cold H2O (ꢀ100 ml), neutralized with aq Na2CO3, extracted with CHCl3
(3 Â 30 ml) and the extract was dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the obtained residue was purified by
preparative thin layer chromatography to give products 4. 1,1-Dimethyl-3-(3-
oxo-1,3-diphenylpropyl)urea (4aa) Rf 0.33 (pet. ether/EtOAc, 2:1), mp 164–
6 °C. IR (KBr)
: 3332, 3062, 2926, 1686, 1626, 1533. 1H NMR dH (500 MHz,
CDCl3): 2.92 (s, 6H, 2CH3), 3.41–3.46 (dd, 1H, J = 16.4, 6.1 Hz, CH2CH), 3.71–
3.75 (dd, 1H, J = 16.4, 5.3 Hz, CH2CH), 5.41–5.42 (m, 1H, CH2CH), 5.81 (b, 1H,
NH), 7.22–8.08 (m, 10H, ArH). MS (EI 70 eV) m/z: 296 (M+), 224, 191, 72. Anal.
Calcd for C18H20N2O2 (296.15): C, 72.95; H, 6.80; N, 9.45. Found: C, 72.87; H,
6.77; N, 9.41. 1,1-Dimethyl-3-(3-oxo-1-phenyl-3-p-tolylpropyl)urea (4ab) Rf
m
0.32 (pet. ether/EtOAc, 2:1), mp 118 °C. IR (KBr) m: 3297, 3046, 2929, 1662,
1624, 1523. 1H NMR d (300 MHz, CDCl3): 2.40 (s, 3H, CH3), 2.95 (s, 6H, 2CH3),
3.38–3.45 (dd, 1H, J = 16.5, 5.7 Hz, CH2CH), 3.66–3.73 (dd, 1H, J = 16.4, 5.4 Hz,
CH2CH), 5.40–5.41 (m, 1H, CH2CH), 5.91 (br s, 1H, NH), 7.17–7.82 (m, 9H, ArH).
13C NMR d (75 MHz, CDCl3): 199.21 (C@O), 144.28 ((CH3)2NCONH), 142.31–
125.83 (10 ArC), 51.58 (CH2), 43.62 (CHNH), 36.15 (2CH3), 21.60 (CH3). MS (EI
70 eV) m/z: 310 (M+), 222, 119, 72. Anal. Calcd for C19H22N2O2 (310.39): C,
73.52; H, 7.14; N, 9.03. Found: C, 73.45; H, 7.12; N, 9.00. 3-[3-(4-
Chlorophenyl)-1-(4-fluorophenyl)-3-oxopropyl]-1,1-dimethylurea (4bc) Rf
0.26 (pet. ether/EtOAc, 2:1), mp 147 °C. IR (KBr) m: 3320, 3064, 2927, 1688,
1624, 1535. 1H NMR d (200 MHz, CDCl3): d (ppm) 2.69 (s, 6H, 2CH3), 3.15–3.18
(dd, 1H, J = 16, 6.2 Hz, CH2CH), 3.41–3.43 (dd, 1H, J = 16, 5.2 Hz, CH2CH), 5.12–
5.15 (m, 1H, CH2CH), 5.43 (br s, 1H, NH), 6.70–7.71 (m, 8H, ArH). MS (EI 70 eV)
m/z: 348 (M+), 276, 139, 72. Anal. Calcd for C18H18ClFN2O2 (348.8): C, 61.98; H,
5.20; N, 8.03. Found: C, 61.93; H, 5.16; N, 8.00.