A one-pot, ugi four-component synthesis of 2(3H)-oxazolone 4-carboxamides

Article abstract of DOI:10.1055/s-2007-992372

Ugi reaction between arylglyoxals, anilines, cyclohexyl isocyanide and trichloroacetic acid in dichloromethane, in the presence of molecular sieves, afforded 2(3H)-oxazolone 4-carboxamides in good yields by a one-pot process that involved an in situ spontaneous cyclization of the Ugi product through an intermediate ketone enolate and the chloroacetate carbonyl group. The synthesis is based on the ability of the trichloroacetyl group to function as a masked carbonic acid surrogate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992372

LETTER
33
A One-Pot, Ugi Four-Component Synthesis of 2(3H)-Oxazolone
4-Carboxamides
O
ne-Pot, Ugi Four-C
o
.ponent Syn
G
thesis of 2(3
H
)
-Ox
a
azolone 4-
r
Carboxa
c
a
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n 09001 Burgos, Spain
E-mail: ttorroba@ubu.es
b
Dipartimento di Chimica Organica ‘Ugo Schiff’, Università degli Studi di Firenze, 50019 Sesto Fiorentino (FI), Italy
Fax +34(947)258831; E-mail: stefano.marcaccini@unifi.it
Received 28 September 2007
tremely powerful synthetic tools for the preparation of
structurally diverse complex molecules, such as heterocy-
clic compounds with elaborate substitution patterns, con-
strained peptides, peptide mimetics, and pseudopeptides.5
Abstract: Ugi reaction between arylglyoxals, anilines, cyclohexyl
isocyanide and trichloroacetic acid in dichloromethane, in the pres-
ence of molecular sieves, afforded 2(3H)-oxazolone 4-carbox-
amides in good yields by a one-pot process that involved an in situ
spontaneous cyclization of the Ugi product through an intermediate As a new contribution of this methodology, we report in
ketone enolate and the chloroacetate carbonyl group. The synthesis
is based on the ability of the trichloroacetyl group to function as a
masked carbonic acid surrogate.
this paper a new one-pot synthesis of 3,5-diaryl-2(3H)-ox-
azolone 4-carboxamides by the Ugi reaction between
arylglyoxals 1, anilines 2, cyclohexyl isocyanide (3), and
Key words: isocyanide, arylglyoxal, trichloroacetic acid, oxazolo-
trichloroacetic acid (4), followed by spontaneous in situ
ne
cyclization reaction of the presumably initially formed
Ugi products (Scheme 1).
Arylglyoxals 1 were prepared in good yields by the gen-
The aryloxazolone moiety is found in the structure of
eral method of Riley and Gray,6 following the modifica-
some nonsteroidal anti-inflammatory drugs that are potent
tion by Arnold and Fuson,7 to prevent the formation of the
and selective COX-2 inhibitors,1 but oxazolones with a
glyoxal hydrate. Thus, a mixture of freshly distilled aryl-
carboxyl group at the 4-position are relatively uncommon,
glyoxal 1a–e (1 equiv) and aniline 2a–e (1.2 equiv) in
which is somewhat surprising considering that the ox-
dichloromethane was stirred at room temperature in the
azolone moiety incorporates dense functionality and great
presence of 3 Å molecular sieves for ten minutes. Then
utility in synthesis.2 Very few syntheses of 2(3H)-ox-
cyclohexyl isocyanide8 (3; 1 equiv) and anhydrous
azolone-4-carboxylic acid derivatives have been report-
trichloroacetic acid (4; 1 equiv) were added and the mix-
ed.3 The rather complex and non-general reported
ture was stirred at room temperature for two days. Filtra-
methodologies could have hindered the availability of this
tion of the molecular sieves and evaporation of the solvent
nucleus for practical applications such as the well-known
afforded a sticky residue that was stirred with diethyl
ones developed for the dihydro compounds, namely
ether until solid N-cyclohexyl 3,5-diaryl-2(3H)-oxazolo-
2-oxo-4-oxazolidinecarboxylic acid derivatives.4 We
ne 4-carboxamides 5a–m were obtained in good yields
have recently shown that the sequences of classical Ugi or
(61–89%; Table 1).9
Passerini isocyanide multicomponent reactions, followed
by post-condensation transformations, constitute ex-
R1
O
O
O
H
NH2
NC
NH
CH2Cl2
CO2H
Cl3C
+
+
+
O
N
R3
3 Å MS, 2 d
R1
R2
O
3
4
5a–m
1a–e
2a–e
R2
R3
1a: R1 = H
1b: R1 = Me
1c: R1 = Cl
1d: R1 = OMe
1e: R1 = F
2a: R2 = H; R3 = H
2b: R2 = Me; R3 = H
2c: R2 = OMe; R3 = H
2d: R2 = Cl; R3 = H
2e: R2 = H; R3 = Cl
Scheme 1
SYNLETT 2008, No. 1, pp 0033–0036
x
x.
x
x.
2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-992372; Art ID: G30307ST
© Georg Thieme Verlag Stuttgart · New York

34
M. García-Valverde et al.
LETTER
Table 1 Synthesis of Oxazolones 5a–m
We then applied the same methodology to 1f·H2O and
2a,b, 3 and 4, from which oxazolones 5n–o were obtained
in 69–72% yields (Scheme 3). Therefore the presence of
an additional equivalent of water had no influence on the
reaction yields if sufficient 3 Å molecular sieves were
present to absorb water produced during the Ugi conden-
sation.
5
R1
R2
R3
Yield (%) Yield (%)
3 Å MS amine (2 equiv)
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
85
89
72
88
83
71
69
88
81
62
61
62
65
64
58
56
61
56
55
51
65
61
52
49
53
51
H
Me
OMe
H
H
MeO
OH
Me
Me
Me
Me
Cl
O
OH
+
Me
OMe
Cl
2a,b
+
3
O
CH2Cl2
NH
+
4
3 Å MS, 2 d
5g
5h
5i
O
N
5n–o
H
OMe
O
5n, R2 = H (69%)
5o, R2 = Me (72%)
Cl
Me
OMe
OMe
H
1f
R2
5j
Cl
Scheme 3
5k
5l
OMe
OMe
F
The presence of water has been reported to accelerate the
Ugi reaction11 but in our case, in the absence of 3 Å mo-
lecular sieves, a mixture of 1a (1 equiv), 2b (1 equiv), 3 (1
equiv) and 4 (1 equiv) in dichloromethane, stirred for two
days at room temperature, afforded 5b in 31% yield. MS
of the reaction residue showed distinct peaks of cyclohex-
ylformamide, tolyl trichloroacetamide and deacylated Ugi
product. In the same way, reaction of 1c (1 equiv), 2a,d,e
(1 equiv), 3 (1 equiv) and 4 (1 equiv) in isopropyl ether,
stirred for two days at room temperature, produced the
deacylated Ugi products 7a–c (35–48%) as the main prod-
ucts, showing only traces of the oxazolones by MS of the
reaction residue (Scheme 4, Table 2).12
5m
H
The recrystallized products were easily characterized by
the usual spectroscopic and analytical techniques. Single
crystal X-ray diffraction of one of the samples, 5b, con-
firmed the oxazolone structure.10
We supposed that the expected Ugi products 6a–m were
initially formed under the reaction conditions, subse-
quently undergoing spontaneous cyclization by attack of
the ketone enolate onto the chloroacetate carbonyl group,
consequently eliminating chloroform and affording irre-
versibly the oxazolones 5a–m (Scheme 2). The high solu-
bility of the products in dichloromethane prevented the
usual precipitation of the Ugi products, thus allowing a
smooth cyclization to the products. This reaction is an ex-
ample of the known ability of the trichloroacetyl group to
function as a masked carbonic acid surrogate.5b
NH2
Cl
O
O
H
R3
O
i-Pr2O
R2
2a,d,e
NC
N
O
r.t., 2 d
H
HN
R3
R2
Cl3C CO2H
R1
Cl
1a–e
1
3
4
7a–c
+
2a–e
+
O
H
N
CH2Cl2
– CHCl3
Scheme 4
5a–m
N
O
3 Å MS, 2 d
3
H
Cl3C
+
4
Table 2 Synthesis of Deacylated Products 7a–c
R3
O
7
R2
H
R3
H
Yield (%)
R2
6a–m (not isolated)
7a
7b
7c
35
42
48
Scheme 2
Cl
H
H
Cl
To extend the scope of the reaction we then performed the
reaction by using two commercial arylglyoxal hydrates,
1e·H2O and 1f·H2O. First, hydrate 1e·H2O was subjected
to the above-described reaction conditions, from which
oxazolone 5m was obtained in comparable yield (63%).
In all these reactions water may act as the acid component
in the presence of the strongly acidic trichloroacetic acid,
but the action of water can be minimized in alkaline envi-
Synlett 2008, No. 1, 33–36 © Thieme Stuttgart · New York

LETTER
A One-Pot, Ugi Four-Component Synthesis of 2(3H)-Oxazolone 4-Carboxamides
35
ronment. Thus, in the presence of two equivalents of start-
ing aniline, a mixture of arylglyoxals 1a–e (1 equiv),
anilines 2a–e (2 equiv), cyclohexyl isocyanide (3; 1
equiv) and trichloroacetic acid (4; 1 equiv) in dichlo-
romethane, stirred for two days, afforded the same oxazo-
lones 5a–m, although in lower yields (Table 1). On the
other hand, in the presence of two equivalents of trichlo-
roacetic acid, a mixture of reagents 1b (1 equiv), 2b (1
equiv) and 3 (1 equiv) in methanol, stirred at room tem-
perature for three days, afforded exclusively the Ugi prod-
uct 6e, probably due to the fact that its solubility was
sufficiently low to precipitate in the reaction environment
as it was formed (Scheme 5).13
References and Notes
(1) Michaelidou, A. S.; Hadjipavlou-Litina, D. Chem. Rev.
2005, 105, 3235.
(2) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 2005,
61, 8073.
(3) (a) Yamashita, M.; Lee, S.-H.; Koch, G.; Zimmermann, J.;
Claphama, B.; Janda, K. D. Tetrahedron Lett. 2005, 46,
5495. (b) Okonya, J. F.; Hoffman, R. V.; Johnson, M. C.
J. Org. Chem. 2002, 67, 1102; and references therein.
(4) See, for example: (a) Fraunhoffer, K. J.; White, M. C. J. Am.
Chem. Soc. 2007, 129, 7274. (b) Luppi, G.; Lanci, D.;
Trigari, V.; Garavelli, M.; Garelli, A.; Tomasini, C. J. Org.
Chem. 2003, 68, 1982. (c) Holden, K. G.; Mattson, M. N.;
Cha, K. H.; Rapoport, H. J. Org. Chem. 2002, 67, 5913.
(d) Falb, E.; Nudelman, A.; Gottlieb, H. E.; Hassner, A. Eur.
J. Org. Chem. 2000, 645. (e) Xi, N.; Alemany, L. B.;
Ciufolini, M. A. J. Am. Chem. Soc. 1998, 120, 80.
(f) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson,
T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed. 1998,
37, 2700.
(5) (a) Marcaccini, S.; Torroba, T. In Multicomponent
Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH:
Weinheim Germany, 2005, Chap. 2, 33–75. (b) Ignacio, J.
M.; Macho, S.; Marcaccini, S.; Pepino, R.; Torroba, T.
Synlett 2005, 3051. (c) Sañudo, M.; Marcaccini, S.; Basurto,
S.; Torroba, T. J. Org. Chem. 2006, 71, 4578.
Me
1b
O
+
MeOH
Et3N
2b
+
3
+
5e
N
O
H
CH2Cl2
r.t., 3 d
(68%)
N
Cl3C
1 h
(quant.)
4 (2 equiv)
O
Me
6e
(6) Phenylglyoxal: (a) Riley, H. A.; Gray, A. R. Org. Synth.,
Coll. Vol. II; Wiley: New York, 1943, 509. (b) Riley, H. A.;
Gray, A. R. Org. Synth. 1935, 15, 67. (c) p-Chlorophenyl-
glyoxal: Muccioli, G. G.; Wouters, J.; Charlier, C.; Scriba,
G. K. E.; Pizza, T.; Di Pace, P.; De Martino, P.; Poppitz, W.;
Poupaert, J. H.; Lambert, D. M. J. Med. Chem. 2006, 49,
872. (d) p-Methoxyphenylglyoxal: Fodor, G.; Kovacs, O.
J. Am. Chem. Soc. 1949, 71, 1045. (e) p-Methylphenyl-
glyoxal: De Meester, J. W. G.; van der Plas, H. C.;
Middelhoven, W. J. J. Heterocycl. Chem. 1987, 24, 441.
(f) p-Fluorophenylglyoxal: Joshi, K. C.; Dubey, K.; Dandia,
A. Heterocycles 1981, 16, 1545.
Scheme 5
The obtained Ugi product 6e was a stable solid,14 but
when treated with triethylamine (2 equiv) in dichlo-
romethane at room temperature for one hour, it afforded
quantitatively the corresponding oxazolone 5e
(Scheme 5). Under the same conditions, a mixture of 1b
(1 equiv), 2a (1 equiv), 3 (1 equiv) and 4 (2 equiv) afford-
ed the corresponding oxazolone 5a in 62% yield, indicat-
ing that the cyclization was also catalyzed by acid.
Because of the uncertainty of the results, this method was
not further studied. Some of the reported oxazolones were
remarkably fluorescent in acetonitrile solution. As a rep-
resentative example, the colorless (λmax = 287 nm, e = 2 ×
104 Lmol–1cm–1) oxazolone 5f (10–4 M in MeCN) fluo-
resced at 432 nm and 462 nm (λex = 298 nm).
(7) Arnold, R. T.; Fuson, R. C. J. Am. Chem. Soc. 1936, 58,
1295.
(8) (a) Gokel, W.; Widera, R. P.; Weber, W. P. Org. Synth.,
Coll. Vol. VI; Wiley: New York, 1988, 232. (b) Gokel, W.;
Widera, R. P.; Weber, W. P. Org. Synth. 1976, 55, 96.
Alternative procedure: (c) Ugi, I.; Meyr, R.; Lipinski, M.;
Bodesheim, F.; Rosendahl, F. Org. Synth., Coll. Vol. V;
Wiley: New York, 1973, 300. (d) Ugi, I.; Meyr, R.;
Lipinski, M.; Bodesheim, F.; Rosendahl, F. Org. Synth.
1961, 41, 13.
(9) Synthesis of 2 (3H)-Oxazolone 4-Carboxamides 5a–m:
A mixture of freshly distilled arylglyoxal (1 mmol), the
corresponding arylamine (1.2 mmol) and activated 3 Å MS
(1 g) in CH2Cl2 (10 mL) was stirred at r.t. for 10 min. Then
cyclohexyl isocyanide (110 mg, 1 mmol) and anhyd tri-
chloroacetic acid (162 mg, 1 mmol) were consecutively
added and the mixture was stirred at r.t. for 2 d, then filtered
and the solvent was evaporated under reduced pressure. The
sticky residue was stirred with Et2O (10 mL) until a solid
separated. The solid was filtered and recrystallized from the
appropriate solvent.
In summary, we have described the synthesis of new N-
cyclohexyl 3,5-diaryl-2(3H)-oxazolone 4-carboxamides
by means of a very simple one-pot Ugi four-component
condensation followed by spontaneous cyclization to the
final products. The reaction employs all commercial or
easily available starting materials, is performed under
very simple experimental conditions and does not require
chromatographic workup, but only recrystallization of the
products, therefore being appropriate for combinatorial
schemes.
Acknowledgment
N-Cyclohexyl-2-oxo-3,5-diphenyl-2,3-dihydrooxazole-4-
carboxamide (5a): colorless crystals (308 mg, 85%); mp
230–231 °C (i-Pr2O–i-PrOH). 1H NMR (400 MHz, CDCl3):
d = 0.85–0.93 (m, 2 H), 0.98–1.10 (m, 1 H), 1.18–1.29 (m, 2
H), 1.50–1.61 (m, 3 H), 1.64–1.74 (m, 2 H), 3.73–3.81 (m, 1
H), 5.45 (d, J = 8.0 Hz, 1 H), 7.38–7.49 (m, 8 H), 7.76–7.79
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 24.4 (CH2), 25.1
(CH2), 32.1 (CH2), 48.6 (CH), 119.1 (Cq), 125.5 (CHAr),
We gratefully acknowledge financial support from the Dirección
General de Investigación of Spain (Project ref. CTQ2006-15456-
C04-04BQU) and Junta de Castilla y León, Consejería de Educa-
ción y Cultura, y Fondo Social Europeo (Project ref. BU013A06).
We thank SCAI of the University of Burgos for solving the structure
of 5b by single-crystal X-ray diffraction.
Synlett 2008, No. 1, 33–36 © Thieme Stuttgart · New York

36
M. García-Valverde et al.
LETTER
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: +44(1223)336033; email: deposit@ccdc.cam.ac.uk.
(11) (a) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004,
126, 444. (b) See also: Mironov, M. A.; Ivantsova, M. N.;
Mokrushin, V. S. Mol. Divers. 2003, 6, 193.
(12) Synthesis of Deacylated Ugi Products 7a–c; General
Procedure: A mixture of p-chlorophenylglyoxal (169 mg,
1 mmol) and the corresponding arylamine (1 mmol) in
i-Pr2O (10 mL) was stirred at r.t. for 10 min. Then cyclo-
hexyl isocyanide (110 mg, 1 mmol) and anhyd trichloro-
acetic acid (163 mg, 1 mmol) were consecutively added and
the mixture was stirred at r.t. for 2 d. The solid residue was
filtered and then recrystallized from the i-Pr2O–i-PrOH
mixture.
126.1 (Cq), 126.3 (CHAr), 128.5 (CHAr), 128.7 (CHAr), 129.4
(CHAr), 129.6 (CHAr), 133.7 (Cq), 139.1 (Cq), 152.5 (Cq),
157.1 (Cq). IR (KBr): 3254, 1770, 1630 cm–1. MS (EI): m/z
(%) = 362 (69) [M+], 279 (100). HRMS (EI): m/z calcd for
C22H22N2O3: 362.1630; found: 362.1632. Anal. Calcd for
C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C, 72.97; H,
6.16; N, 7.67.
3-(4-Chlorophenyl)-N-cyclohexyl-2-oxo-5-p-tolyl-2,3-
dihydrooxazole-4-carboxamide (5g): colorless crystals
(284 mg, 69%); mp 232–233 °C (i-Pr2O–i-PrOH). 1H NMR
(400 MHz, CDCl3): d = 0.93–1.10 (m, 3 H), 1.20–1.34 (m, 2
H), 1.55–1.63 (m, 3 H), 1.75–1.79 (m, 2 H), 2.39 (s, 3 H),
3.75–3.84 (m, 1 H), 5.61 (d, J = 8.2 Hz, 1 H), 7.22–7.25 (m,
2 H), 7.32–7.35 (m, 2 H), 7.40–7.44 (m, 2 H), 7.57–7.59 (m,
2 H). 13C NMR (100 MHz, CDCl3): d = 21.7 (Me), 24.8
(CH2), 25.4 (CH2), 32.6 (CH2), 49.0 (CH), 118.4 (Cq), 123.3
(Cq), 126.9 (CHAr), 127.1 (CHAr), 129.7 (CHAr), 129.8
(CHAr), 132.8 (Cq), 134.4 (Cq), 140.0 (Cq), 140.7 (Cq), 152.7
(Cq), 157.2 (Cq). IR (KBr): 3282, 1774, 1663, 1635, 1495
cm–1. MS (EI): m/z (%) = 412 (16) [M+ + 2], 410 (57) [M+],
327 (84), 119 (100). HRMS (EI): m/z calcd for
3-(4-Chlorophenyl)-N-cyclohexyl-3-oxo-2-(phenyl-
amino)propionamide (7a): colorless crystals (130 mg,
35%); mp 164–165 °C (i-Pr2O–i-PrOH). 1H NMR (400
MHz, CDCl3): d = 0.89–1.13 (m, 3 H), 1.20–1.32 (m, 2 H),
1.48–1.83 (m, 5 H), 3.57–3.68 (m, 1 H), 5.31 (d, J = 3.0 Hz,
1 H), 5.43 (d, J = 3.0 Hz, 1 H), 6.68–6.71 (m, 2 H), 6.80–6.85
(m, 2 H), 7.21–7.24 (m, 2 H), 7.44–7.46 (m, 2 H), 8.21–8.23
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 24.5 (CH2), 24.6
(CH2), 25.2 (CH2), 32.4 (CH2), 32.5 (CH2), 48.6 (CH), 66.6
(CH), 113.8 (CHAr), 119.4 (CHAr), 128.7 (CHAr), 129.5
(CHAr), 131.8 (CHAr), 132.3 (Cq), 140.9 (Cq), 145.5 (Cq),
165.8 (Cq), 193.0 (Cq). IR (KBr): 3390, 3298, 1695, 1654
cm–1. MS (EI): m/z (%) = 372 (7) [M+ + 2], 370 (24) [M+],
245 (100), 231 (99), 104 (69). HRMS (EI): m/z calcd for
C21H23ClN2O2: 370.1448; found: 370.1443. Anal. Calcd for
C21H23ClN2O2: C, 68.01; H, 6.25; N, 7.55. Found: C, 67.94;
H, 5.95; N, 7.48.
C23H23ClN2O3: 410.1397; found: 410.1382. Anal. Calcd for
C23H23ClN2O3: C, 67.23; H, 5.64; N, 6.82. Found: C, 67.28;
H, 5.67; N, 6.77.
5-(4-Chlorophenyl)-N-cyclohexyl-2-oxo-3-phenyl-2,3-
dihydrooxazole-4-carboxamide (5h): colorless crystals
(349 mg, 88%); mp 224–226 °C (dec., i-Pr2O–i-PrOH). 1H
NMR (400 MHz, CDCl3): d = 0.78–0.88 (m, 2 H), 0.98–1.08
(m, 1 H), 1.18–1.30 (m, 2 H), 1.51–1.68 (m, 5 H), 3.71–3.79
(m, 1 H), 5.37 (d, J = 8.0 Hz, 1 H), 7.38–7.49 (m, 7 H), 7.75–
7.77 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 24.6 (CH2),
25.4 (CH2), 32.5 (CH2), 48.9 (CH), 119.5 (Cq), 125.0 (Cq),
125.9 (CHAr), 128.0 (CHAr), 129.0 (CHAr), 129.2 (CHAr),
129.9 (CHAr), 131.7 (Cq), 133.9 (Cq), 135.9 (Cq), 139.2 (Cq),
152.5 (Cq), 157.1 (Cq). IR (KBr): 3305, 1789, 1658, 1632
cm–1. MS (EI): m/z (%) = 398 (24) [M+ + 2], 396 (100) [M+],
313 (59), 315 (19). HRMS (EI): m/z calcd for C22H21ClN2O3:
396.1241; found: 396.1233. Anal. Calcd for C22H21ClN2O3:
C, 66.58; H, 5.33; N, 7.06. Found: C, 66.53; H, 5.29; N, 7.01.
3-(3-Chlorophenyl)-N-cyclohexyl-5-(4-methoxyphenyl)-
2-oxo-2,3-dihydrooxazole-4-carboxamide (5l): colorless
crystals (265 mg, 62%); mp 240–241 °C (dec., i-Pr2O–i-
PrOH). 1H NMR (400 MHz, CDCl3): d = 0.86–1.30 (m, 5 H),
1.53–1.61 (m, 3 H), 1.75–1.79 (m, 2 H), 3.77–3.83 (m, 1 H),
3.85 (s, 3 H), 5.49 (d, J = 8.4 Hz, 1 H), 6.94–6.96 (m, 2 H),
7.32–7.41 (m, 4 H), 7.67–7.69 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 24.7 (CH2), 25.4 (CH2), 32.6 (CH2), 48.9
(CH), 55.6 (Me), 114.5 (CHAr), 117.5 (Cq), 118.6 (Cq), 123.9
(CHAr), 126.0 (CHAr), 128.7 (CHAr), 128.8 (CHAr), 130.5
(CHAr), 135.2 (Cq), 152.5 (Cq), 157.2 (Cq), 161.2 (Cq). IR
(KBr): 3418, 3247, 1773, 1661, 1632, 1607 cm–1. MS (EI):
m/z (%) = 428 (13) [M+ + 2], 426 (47) [M+], 135 (100).
HRMS (EI): m/z calcd for C23H23ClN2O4: 426.1346; found:
426.1329. Anal. Calcd for C23H23ClN2O4: C, 64.71; H, 5.43;
N, 6.56. Found: C, 64.66; H, 5.38; N, 6.51.
(13) For a complete discussion about the effect of reagents and
solvents in the Ugi reaction, see: Marcaccini, S.; Torroba, T.
Nature Prot. 2007, 2, 632.
(14) Synthesis of N-Cyclohexyl-3-oxo-3-p-tolyl-2-(2,2,2-
trichloro-N-p-tolylacetamido)propionamide (6e): A
mixture of p-tolylglyoxal (148 mg, 1 mmol) and p-toluidine
(107 mg, 1 mmol) in MeOH (10 mL) was stirred for 10 min,
and then cyclohexyl isocyanide (110 mg, 1 mmol) and anhyd
trichloroacetic acid (327 mg, 2 mmol) were consecutively
added. The mixture was stirred at r.t. for 3 d, cooled at 0 °C
overnight, then filtered, and the collected solid was recrys-
tallized from MeOH, from which product 6e was obtained as
colorless crystals (347 mg, 68%); mp 210–212 °C (MeOH).
1H NMR (400 MHz, CDCl3): d = 0.73–1.28 (m, 5 H), 1.65–
1.41 (m, 5 H), 2.34 (s, 3 H), 2.42 (s, 3 H), 3.50–3.61 (m, 1
H), 6.10 (d, J = 7.8 Hz, 1 H), 6.27 (s, 1 H), 7.10 (d, J = 8.5
Hz, 2 H), 7.28 (d, J = 8.1 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H),
7.86 (d, J = 8.1 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d =
21.2 (Me), 21.8 (Me), 24.4 (CH2), 24.5 (CH2), 25.3 (CH2),
32.0 (CH2), 32.3 (CH2), 48.6 (CH), 71.1 (CH), 93.0 (Cq),
127.8 (Cq), 128.5 (CHAr), 129.0 (CHAr), 129.6 (CHAr), 131.2
(CHAr), 132.9 (Cq), 135.8 (Cq), 139.7 (Cq), 145.2 (Cq), 161.1
(Cq), 162.8 (Cq), 194.1 (Cq). IR (KBr): 3242, 1771, 1631,
744 cm–1. MS (EI): m/z (%) = 512 (0.7) [M+ + 4], 510 (3.4)
[M+ + 2], 508 (2.5) [M+], 391 (27), 390 (100), 307 (45), 119
(92). HRMS (EI): m/z calcd for C25H27Cl3N2O3: 508.1056;
found: 508.1087. Anal. Calcd for C25H27Cl3N2O3: C, 58.89;
H, 5.34; N, 5.49. Found: C, 58.83; H, 5.28; N, 5.43.
(10) Crystal Data for Compound 5b: C23H24N2O3, MW =
376.44, orthorhombic, P212121, a = 9.038(5) Å, b = 10.536
(5) Å, c = 21.916(11) Å, a = 90°, b = 90°, g = 90°; V =
2087.1(18) Å3, Z = 4, Dcalc = 1.198 gcm–1, m(Mo–Ka) = 0.080
mm–1. Colorless prism (0.30 × 0.20 × 0.10 mm3), 19410
measured reflections, 3658 independent (Rint = 0.0968),
2247 observed [I > 2s(I)]. R1 = 0.1434, wR2 = 0.2444 (all
data). CCDC 664815 contains the supplementary
Synlett 2008, No. 1, 33–36 © Thieme Stuttgart · New York

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