The first example of a diastereoselective thio-Ugi reaction: A new synthetic approach to chiral imidazole derivatives

Article abstract of DOI:10.1021/jo071030o

(Chemical Equation Presented) The first example of a diastereoselective thio-Ugi reaction with chiral α-methylbenzylamine is described. The reaction results in formation of two diastereomers of thioamides, the major of which was isolated. We have found that under similar conditions stereochemical results of the thio-Ugi reaction are opposite to stereochemical results of the Ugi reaction. Several chiral thioamides were synthesized. The reaction of thioamides with ammonia results in substituted amidines, which can be cyclized to imidazole derivatives in aqueous HCl. The synthesis of chiral imidazole derivatives was elaborated. Using certain approaches, both isomers of a key synthon in the synthesis of SB203386 (an orally bioactive HIV-1 protease inhibitor) were prepared. The scope, limitations, and stereochemistry of the approach are discussed.

Full text of DOI:10.1021/jo071030o

The First Example of a Diastereoselective Thio-Ugi Reaction:
A New Synthetic Approach to Chiral Imidazole Derivatives
Anton V. Gulevich, Elizabeth S. Balenkova, and Valentine G. Nenajdenko*
Department of Chemistry, Moscow State UniVersity, Leninskije gory, 119992 Moscow, Russia
nen@acylium.chem.msu.ru
ReceiVed May 16, 2007
The first example of a diastereoselective thio-Ugi reaction with chiral R-methylbenzylamine is described.
The reaction results in formation of two diastereomers of thioamides, the major of which was isolated.
We have found that under similar conditions stereochemical results of the thio-Ugi reaction are opposite
to stereochemical results of the Ugi reaction. Several chiral thioamides were synthesized. The reaction
of thioamides with ammonia results in substituted amidines, which can be cyclized to imidazole derivatives
in aqueous HCl. The synthesis of chiral imidazole derivatives was elaborated. Using certain approaches,
both isomers of a key synthon in the synthesis of SB203386 (an orally bioactive HIV-1 protease inhibitor)
were prepared. The scope, limitations, and stereochemistry of the approach are discussed.
Introduction
with lithiated imidazoles.4 Several imidazoles can be obtained
starting from amino acids.2,5 Several MCR approaches to
imidazoles based on the TosMIC were described recently.6
Consequently, new, efficient methodology for the preparation
of imidazole derivatives would provide a valuable tool to
synthetic organic chemists. This research is concerned with the
development of a new synthetic approach to imidazole deriva-
tives, based on the Ugi reaction.
Imidazole is a common heterocyclic fragment of many
biologically important small molecules, such as histidine,
histamine, adenine, etc. There are also many effective pharma-
ceutical compounds and drugs containing the imidazole residue
(Scheme 1).1 Imidazoles containing a 2-aminoalkyl residue (for
example B or C) are important building blocks for the synthesis
of different natural products such as SB203386 (A) is an orally
bioactive HIV-1 protease inhibitor.2 2-Arylaminoalkylimidazoles
D (benzhydrylamine derivatives) containing an imidazole
residue are interesting drug-like substances for medicinal
chemistry.
There is no general method for the synthesis of different
functionalized imidazole derivatives. Several protected 2-ami-
noalkylimidazoles have been prepared by reaction of imidazo-
lium ylides (generated from N-substituted imidazole and Boc2O)
with imines.3 Another method is based on reaction of imines
The four-component Ugi reaction belongs to the most
interesting diversity-generating reactions of modern organic and
combinatorial chemistry. One of the most important applications
of the Ugi reaction is the synthesis of the different type of
heterocycles.7 The thio-Ugi reaction (the Ugi MCR with
thioacids) is an important approach to various thioamides8 which
have been used as amide bond surrogates in a number of
(4) Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2005, 61, 11148-
11155.
(5) Chen, J. J.; Zhang, Y.; Hammond, S.; Dewdney, N.; Ho, T.; Lin, X.;
Browner, M. F.; Castelhano, A. L. Bioorg. Med. Chem. Lett. 1996, 6, 1601-
1606.
(6) (a) Sisko, J. J. Org. Chem. 1998, 63, 1516-1524. (b) Sisko, J.;
Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.
Chem. 2000, 65, 1516-1524. (c) Sisko, J.; Mellinger, M. Pure Appl. Chem.
2002, 74, 1349-1357.
(7) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17-89.
* To whom correspondence should be addressed. Tel.: +7 495 939 2276.
Fax: +7 495 932 8846.
(1) Grimment, M. R. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Ed.; Pergamon Press: Oxford, 1996; Vol. 3.
(2) Pridgen, L. N.; Mokhallalti, M. K.; McGuire, M. A. Tetrahedron
Lett. 1997, 38, 1275-1278.
(3) Zificsak, C. A.; Hlasta, D. J. Tetrahedron Lett. 2005, 46, 4789-
4792.
10.1021/jo071030o CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/13/2007
7878
J. Org. Chem. 2007, 72, 7878-7885

A DiastereoselectiVe Thio-Ugi Reaction
SCHEME 1. Imidazole Derivatives in Nature and Medicine
SCHEME 2. New Synthetic Approach to Imidazole Derivatives
SCHEME 3. Synthesis of the Thiopeptides
biologically active peptides and incorporated into different
natural molecules.9 Asymmetric multicomponent reactions
(AMCR) have a great importance and interest for chemists.10
The thio-Ugi reaction has various synthetic applications, but
no diastereoselectivity of the reactions has been investigated.
However, development of diastereoselective thio-Ugi MCR can
open new possibilities for organic and medicinal chemistry.
TABLE 1. Influence of Amine Component
Results and Discussion
entry
R1
R2
product
yield, %
1
2
3
4
5
6
7
Bn
4-ClPh
4-ClPh
4-ClPh
i-Pr
i-Pr
i-Pr
2a
2b
2c
2d
2e
2f
45
53
50
64
66
65
83
It has been demonstrated that the Ugi reaction with thioacids
is an important approach to various thioamides. Thioamides are
valuable precursors for many synthetic purposes. It is known
that thioamides react with ammonia,11 amines,12 hydroxy-
lamine,13 acetamide,14 hydrazine,15 and other nucleophiles.
Recently, Kazmaier developed an effective method for synthesis
of the thiazole derivatives. The approach is based on the Ugi
reaction with thioacids and 2,2-dimethoxyethylisocyanide, fol-
lowed by cyclization under microwave irradiation using TMSI.16
In this paper, we elaborate a new effective method for the
synthesis of imidazoles bearing an aminoalkyl fragment in the
2-position. The synthesis is based on high reactivity of the
thioamide bond in thiopeptides toward nucleophiles. We
proposed that the thiopeptides prepared by the Ugi reaction using
2,2-dimethoxyethylisocyanide can be converted to amidines by
treatment with ammonia.11 Subsequent heterocyclization and
deprotection of nitrogen can open an effective synthetic way to
imidazole derivatives (Scheme 2).17
First, we decided to investigate the synthetic scope and
limitations of the thio-Ugi reaction to prepare thioamides 2. The
influence of the amine and aldehyde components on the yield
of the target thiopeptides was studied for this aim (Scheme 3).
We have investigated the influence of the amine component
on the reaction using model 4-chlorobenzaldehyde or the
isobutyraldehyde, isocyanide 1, and thioacetic acid (Table 1).
We found that target thioamides 2a-g could be prepared
PhCH2CH2
3,5-Me2Ph
3-indolylCH2CH2
cyclohexyl
Mea
i-Pr
2g
a Hydrochloride was used.
generally in good yield with alkyl amines and electron-rich
anilines. Anilines bearing electron-withdrawing groups (for
example, 4-F-aniline and 4-NO2-aniline) and sterically hindered
alkyl amines (t-BuNH2) were almost unreactive in this process.
Second, using a model benzylamine, isocyanide 1, and
thioacetic acid, we investigated the relationship between the
(10) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-
1634.
(11) (a) Shankaran, K.; Donnelly, K. L.; Shah, S. K.; Guthikonda, R.
N.; MacCoss, M.; Humes, J. L.; Pacholok, S. G.; Grant, S. K.; Kellyc, T.
M.; Wong, K. K. Bioorg. Med. Chem. Lett. 2004, 14, 4539-4544. (b)
Plevachuk, N. E.; Komaritsa, I. P. Chem. Heterocycl. Cmpd. (Engl. Transl.)
1970, 6, 144-1545.
(12) (a) Chambon, M.; Boucherle, A. Bull. Soc. Chim. Fr. 1954, 907-
910. (b) Baguley, M. E.; Evidge, J. A. J. Chem. Soc. 1957, 709-717. (c)
Mazharuddin, M.; Thyagarajan, G. Tetrahedron 1969, 25, 517-525.
(13) (a) Behringer, M. Justus Liebigs Ann. Chem. 1957, 607, 67-76.
(b) Roslaya, G. I. Chem. Heterocycl. Compd. (Engl. Transl.) 1968, 4, 326-
327. (c) Millen, M. H.; Waters, W. A. J. Chem. Soc. 1968, 408-411. (d)
Bushey, D. F.; Florenca, F. C. J. Org. Chem. 1980, 45, 4198-4206.
(14) Elion, G. B.; Mueller, S.; Hitchings, G. H. J. Am. Chem. Soc. 1959,
81, 1898-1901.
(8) Kolb, J.; Beck, B.; Almstetter, M.; Heck, S.; Herdtweck, E.; Do¨mling,
A. Mol. DiV. 2003, 6, 297-313.
(9) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; Wiley-
VCH: Weinheim, Germany, 2002; Chapter 7, pp 339-378.
J. Org. Chem, Vol. 72, No. 21, 2007 7879

Gulevich et al.
SCHEME 5. Investigation of the Stereoselectivity
SCHEME 4. Synthesis of Imidazolesa
a A R2 ) Ar, NH4OAc/EtOH, reflux; B R2 ) Alk, NH4OAc/EtOH/
NH3(aq), reflux.
TABLE 3. Imidazoles, Obtained by Acidic Cyclization
TABLE 2. Influence of Carbonyl Component, R1 ) Bn
thioa-
entry mide
yield,
method product %
entry
R2
R3
product
yield, %
R1
R2
8
9
4-ClPh
Ph
H
H
H
H
H
H
H
2a
2h
2i
2j
2k
2l
2m
2n
2o
2p
45
52
57
60
15
25
75
55
53
48
18
19
20
21
2a Bn
4-ClPh
4-Cl-Ph
i-Pr
A
A
B
B
4a
4b
4f
61
72
63
64
2b PhCH2CH2
2f Me
2g
10
11
12
13
14
15
16
17
3-MePh
4-MeOPh
4-NO2Ph
2-thienyl
i-Pr
-(CH2)5-
-(CH2)4-
i-Pr
4g
22
23
24
25
2h Bn
2i Bn
2j Bn
2m Bn
Ph
A
A
A
B
4h
4i
4j
67
61
59
69
3-MePh
4-MeOPh
i-Pr
4m
TABLE 4. Investigation of the Diastereoselectivity (R,S/S,S)
structure of carbonyl compounds and the yield of the thiopep-
tides (Table 2). It was found that the effect of the structure of
the carbonyl component on the reaction was very important.
Benzaldehydes without an electron-withdrawing group (entries
8-11) and aliphatic aldehydes and ketones (entries 14-17)
reacted smoothly. In general, the thio-Ugi reaction is a common
and effective approach to different thioamides. However, in the
case of electron-poor and heteroaromatic aldehydes, yields were
lower (entries 12 and 13). Owing to steric sensitivity of the
thio-Ugi reaction, acetophenone and diphenylketone did not give
any Ugi products.
0.01 mol/L
0.1 mol/L
1 mol/L
-22 °C
0 °C
20 °C
1.42
1.78
1.54
2.56
1.14
1.53
2.02
1.72
1.69
SCHEME 6. Determination of the Absolute
Stereochemistrya
With these endothiopeptides 2 in hand, we began our
investigations toward the imidazole synthesis. Transformation
of thioamides in amidines is a well-known process.13 We tested
several reagents, such as NH3(gas), NH3(aq), NH4Cl/EtOH, NH3-
(aq)/HgO, NH3(aq)/(Hg(OAc)2), and NH4OAc/EtOH, and found
that NH4OAc in ethanol was the most effective reagent for such
amidine 3 synthesis (Method A). If a thiopeptide contained alkyl
residue (2f, 2g, 2m), addition of aqueous ammonia in the
reaction mixture was necessary (Method B). Amidine 3 (R1 )
Bn, R2 ) 4-ClPh) was isolated in a yield of 82% and was
a Conditions: (a) Hg(OAc)2/EtOH; (b) HCl (6 M), reflux, 12 h.
concentrated HCl was accomplished by cleavage of the acetyl
group and gave directly unprotected 2-aminoalkylimidazoles 4
in good yield (Table 3). A few thioamides, such as the R,R-
disubstituted thioamides 2n-p, prepared from ketones or labile
in acidic conditions, and compounds 2d and 2l were not stable
and decomposed completely. In general, this method allows
synthesis of 2-aminoalkylimidazoles with different alkyl or aryl
substitutes.
The thio-Ugi reaction has various synthetic applications, but
no diastereoselective modification of the reaction has been
investigated. A major obstacle to provide stereoinduction by
the Ugi reaction is that it consequently follows sometimes
different mechanisms under specific conditions.18 Chiral amines
1
characterized by H NMR and 13C NMR spectra. Using 3, we
have investigated several reagents for cyclization (AcOH, CF3-
COOH, NH4Cl, HCl, and others) and found that HCl (concd)
was the reagent of choice.
Amidines are not very stable compounds, and they can be
transformed without isolation directly to imidazole derivatives
by reflux in aqueous HCl. This permitted the development of
short and straightforward syntheses of imidazoles directly from
thio-Ugi products (Scheme 4). Reactions of the thioamides with
NH4Cl followed by cyclization of the amidines by reflux in
(15) (a) Polivka, Z.; Holubek, J.; Svatek, E.; Dlabac, A.; Pusek, D.;
Collect. Czech. Chem. Commun. 1983, 48, 1465-1476. (b) Bock, M. G.;
DiPrado, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F. J. Med. Chem.
1988, 31, 176-181. (c) Walser, A.; Flynn, T.; Mason, C. J. Heterocycl.
Chem. 1991, 28, 1121-1125. (d) Kawakami, Y.; Kitani, H.; Yuasa, S.;
Abe, M.; Moriwaka, M. Eur. J. Med. Chem. Chim. Ther. 1996, 31, 683-
692.
(17) (a) Dirlam, J. P.; James, R. B.; Shoop, E. V. J. Org Chem. 1982,
47, 2196-2199. (b) Matthews, D. P.; Whitten, J. P.; Mc Carthy, J. R.
Synthesis 1986, 336-337. (c) Brown, R. S.; Clewley, R. G. J. Org. Chem.
1987, 52, 1216-1218. (d) Merrett, J. H.; Spurden, W. C.; Thomas, A. W.;
Tong, B. P.; Whitcombe, I. W. J. Chem. Soc., Perkin Trans. 1 1988, 61-
68. (e) Galeazzi, E.; Guzman, A.; Nava, J. L.; Liu, Y.; Maddox, M. L.;
Muchowski, J. M. J. Org. Chem. 1995, 60, 1090-1092. (f) Huang, L. F.;
Bauer, L. J. Heterocycl. Chem. 1997, 34, 1123-1130. (g) Reader, V. A.
Synlett 1998, 1077-1078.
(16) Kazmaier, U.; Ackerman, S. Org. Biomol. Chem. 2005, 3, 3184-
3187.
7880 J. Org. Chem., Vol. 72, No. 21, 2007

A DiastereoselectiVe Thio-Ugi Reaction
SCHEME 7. Stereoselectivity of the Ugi and Thio-Ugi Reactiona
a Isolated yields: 2s (the less polar) 35%; 2u (the less polar) 26%; 2v (the more polar) 54%; 2y (the less polar) 28%; and 2z (the more polar) 50%.
SCHEME 8a
the reagents. It should be noted that the dependence is not linear.
The best ratio of diastereomers (2q/2r 2.56) was observed in
0.1 M MeOH solution at -22 °C (Table 4). The ratio of the
isomers was determined by GCMS analysis of the reaction
mixtures. According to the 1H NMR spectrum, we assigned the
configuration of 2q and 2r by chemical shift of the CH(OMe)2
proton. R,S- and S,R-diastereomers have δ 4.68, and S,S- and
R,R-diastereomers have δ 4.51 (see below). Unfortunately, the
diastereomers could not be separated by column chromatogra-
phy. We postulated that replacement of thioacetic acid by
thiobenzoic acid would permit us to isolate pure diastereomers.
a Conditions: (a) Hg(OAc)2, EtOH/H2O, rt.
have been used several times to control the formation of a new
stereogenic center in Ugi-4CR.19 The most common amine for
this aim was chiral R-methylbenzylamine, both enantiomers of
which were commercially available substances. Therefore, we
decided to investigate the stereochemistry of the thio-Ugi
reaction to develop a new diastereoselective approach toward
imidazole synthesis. Using (S)-R-methylbenzylamine as a model
amine (Scheme 5), we investigated the dependence of stereo-
selectivity of the model reaction by temperature and concentra-
tions of the reagents (all components were mixed in equimolar
amounts). We found that the ratio of diastereoisomers depends
significantly an both from temperature and concentrations of
Fortunately, the reaction with thiobenzoic acid under the
particular conditions resulted in two isomers (2:1 according
GCMS). The major isomer 2s (the more polar product) was
isolated by column chromatography in a yield of 35%. To
confirm the stereochemistry, the major product 2s was converted
to D-valine by transformation of the thioamide to an amide,
followed by acidic hydrolysis, giving this amino acid with [R]D
-26.04 (c 0.42 M, 6 M HCl), in agreement with the literature
data (Scheme 6).20
Consequently, the major product 2s of the thio-Ugi reaction
is the R,S-diastereomer. This result did not correlate with the
usual stereochemical result of the Ugi reaction, the major
product of which is the S,S-diastereomer (under the same
conditions, T ) -20 °C, c ) 0.1 M, MeOH).21
(18) Zhu, J.; Biename´, H. Multicomponent Reactions; Wiley: Weinheim,
Germany, 2005.
(19) (a) Ugi, I.; Offerman, K. Angew. Chem., Int. Ed. Engl. 1963, 2,
624. (b) Ugi, I.; Offerman, K.; Herlinger, H.; Marquarding, D. L. Ann. Der
Chemie 1967, 709, 1-10. (c) Ugi, I.; Kaufhold, G. L. Ann. Der Chemie
1967, 709, 11-28. (d) Madsen, U.; Frydenvang, K.; Ebert, B.; Johansen,
T. N.; Krogsgaard-Larsen, P. J. Med. Chem. 1996, 39, 183-190. (e)
Ahmadian, H.; Neilsen, B.; Bra¨uner-Osborne, H.; Johansen, T. N.; Stensbøl,
T. B.; Sløk, F. A.; Sekiyama, N.; Nakanishi, S.; Krogsgaard-Larsen, P.;
Madsen, U. J. Med. Chem. 1997, 40, 3700-3705. (f) Kelly, C. L.; Lawrie,
W. M. K.; Morgan, P.; Willis, C. L. Tetrahedron Lett. 2000, 41, 8001-
8005. (g) Hebach, C.; Kazmaier, U. J. Chem. Soc., Chem. Commun. 2003,
596-597.
We decided to study the stereochemistry of the Ugi reaction
and thio-Ugi under the same conditions (Scheme 7) to compare
(20) See for example: Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa,
K.; Naito, T. J. Org. Chem. 2000, 65, 176-185.
(21) (a) Ugi, I.; Offerman, K.; Herlinger, H.; Marquarding, D. L. Ann.
Der Chemie 1967, 709, 1-10. (b) Kelly, C. L.; Lawrie, W. M. K.; Morgan,
P.; Willis, C. L. Tetrahedron Lett. 2000, 41, 8001-8005.
J. Org. Chem, Vol. 72, No. 21, 2007 7881

Gulevich et al.
SCHEME 9. Possible Mechanisms of the Ugi and Thio-Ugi Reactions
SCHEME 10. Synthesis of Chiral Imidazole Derivativesa
the stereochemical results. Unexpectedly, we observed inversion
of the stereoselectivity upon replacement of benzoic acid by
thiobenzoic acid. Specific chemical shift of the CH(OMe)2
proton could be used for assignment of the absolute stereo-
1
chemistry of 2s-v by H NMR analysis and characterization
of the absolute stereochemistry of the products of Ugi and thio-
Ugi reactions. Specific δ values of the thio product are 4.69
for R,S- and S,R- (2s) and 4.51 for R,R- and S,S-diastereomers
(2t), while for similar Ugi products, they are 4.49 (2u) and 4.27
(2v), respectively. These δ values can be used for assignment
of the absolute stereochemistry in cases of thioamides with other
substituents on the asymmetric center.
Additional verification of these unexpected results was done
using tert-butyl isocyanide (Scheme 7). To examine the ratio
of diastereomers, we transformed the crude mixture of thioa-
mides 2w and 2x to the mixture of oxo compounds 2y and 2z,
which could be isolated by column chromatography (Scheme
8). The major isomer in the mixture of amides was 2y, and the
major isomer in the mixture of thioamides was 2w. This result
confirms again the inversion of stereochemical preference in
the thio-Ugi reaction. The assignment of the absolute stereo-
a Conditions: (a) T ) -22 °C; C ) 0.1 M in MeOH; (b) NH4OAc,
NH3, EtOH, reflux; (c) HCl (concd), reflux.
salts with the imine 5 (Mechanism A) without further nucleo-
philic addition to the iminium center. Thereafter, an isocyanide
attack occurs from the less sterically hindered side, and product
7 having the S configuration is formed. In the case of the thio-
Ugi reaction (Mechanism B), the much more nucleophilic
thiocarboxylate attacks 8 from the less sterically hindered side,
and intermediate (R)-9 is formed. Furthermore, an SN2-type
nucleophilic substitution with inversion of configuration of the
formed stereocenter results in 10 as the R-isomer. Therefore,
thioamide (R)-11 is formed as the major diastereomer.
1
chemistry of 2y and 2z was based on H NMR chemical shift
values for tert-butyl groups. Empirically, the chemical shift
values for the tert-butyl groups of R,S- and S,R-forms of this
compounds were in the range of δ 1.3-1.4, whereas chemical
shifts for R,R- and S,S-diastereomers were δ 1.1.22 We detected
by 1H NMR spectra of the mixture of 2w and 2x (predominance
2w) that tert-butyl groups in thioamides also have specific δ
values, namely, δ 1.60 for R,S- and S,R- (2w) and δ 1.43 for
R,R- and S,S-diastereomers (2x). This NMR data can be used
for further configuration assignment.
We propose that preferable formation of the R-diastereomer
in the thio-Ugi reaction with (S)-R-methylbenzylamine can be
explained in the detailed view of mechanism of the reaction.
There are a number of mechanisms of the Ugi reaction
described.17 We believe that the mechanisms of Ugi and thio-
Ugi reactions are different (Scheme 9). Carboxylic acids form
Using a diastereoselective method for the synthesis of chiral
thioamides 2s (-R,S) and 2λ (-S,R), we were successful in
obtaining both isomers of 4p, the key synthon in the synthesis
of SB203386 (an orally bioactive HIV-1 protease inhibitor;
Scheme 10). During acidic cyclization (6 M aq HCl, reflux),
the R-methylbenzyl group, unlike the benzyl group, was
removed, and the reaction led directly to the target imidazole
in moderate yield. It should be noted that the proposed method
of synthesis of the 4p is rather short, simple, and very
competitive compared to literature approaches. Starting from
both enantiomers of R-methylbenzylamine, both R- and S-
enantiomers of 4p can be prepared very easily.
(22) (a) Marquarding, D.; Hoffman, P.; Heitzer, H.; Ugi, I. J. Am. Chem.
Soc. 1970, 92, 1969-1971. (b) Semple, J. E.; Wang, P. S.; Lysenko, Z.;
Joullie´, M. M. J. Am. Chem. Soc. 1980, 102, 7505-7510.
7882 J. Org. Chem., Vol. 72, No. 21, 2007

A DiastereoselectiVe Thio-Ugi Reaction
(m, 1H), 4.62 (t, J ) 5.6 Hz, 1H), 7.01 (s, 1H), 7.10-7.22 (m,
2H), 7.35 (d, J ) 8.1 Hz, 2H), 8.2 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.2, 20.3, 22.5, 25.2, 28.0, 47.2, 54.1, 77.2, 100.9, 111.3,
111.8, 118.4, 119.5, 122.1, 122.5, 127.0, 136.2, 173.2, 202.7. Anal.
Calcd for C21H31N3O3S: C, 62.19; H, 7.70. Found: C, 62.40; H,
7.64.
Conclusion
In conclusion, we have studied for the first time a diastereo-
selective thio-Ugi reaction and investigated the influence of
reaction conditions on the stereoselectivity. Chiral thioamides
were prepared, and their absolute stereochemistry was deter-
mined. It was found that stereochemistry of the thio-Ugi reaction
was opposite to the Ugi reaction. On the basis of one method
of synthesis of the thioamides, we developed a new effective
synthetic approach to imidazole derivatives. Starting from chiral
thioamides, both isomers of chiral imidazole 4p, a key synthon
in the synthesis of SB203386, were synthesized. The scope,
limitations, and stereochemistry of the approach were discussed.
N-Cyclohexyl-N-(1-{[(2,2-dimethoxyethyl)amino]carbono-
thioyl}-2-methylpropyl)acetamide (2e): yield 66%; yellow oil;
Rf 0.50 (2:1 hexanes/ethyl acetate); IR (film) 3430, 2950, 1740
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.81 (d, J ) 6.5 Hz, 3H),
1.03 (d, J ) 6.5 Hz, 3H), 1.10-1.33 (m, 4H), 1.47-1.75 (m, 4H),
1.82-1.92 (m, 2H), 2.15 (s, 3H), 2.87-2.99 (m, 1H), 3.35 (s, 3H),
3.36 (s, 3H), 3.42-3.50 (m, 1H), 3.69-3.69 (m, 1H), 3.77-3.87
(m, 2H), 4.57 (t, J ) 5.56, 1H); 13C NMR (100 MHz, CDCl3) δ
20.5, 21.0, 23.3, 24.7, 25.8, 26.0, 27.7, 31.1, 32.7, 47.1, 53.5, 53.8,
60.9, 76.2, 100.6, 173.1, 204.4. Anal. Calcd for C17H32N2O3S: C,
59.27; H, 9.36. Found: C, 59.04; H, 9.46.
Experimental Section
Preparation of Isocyanide 1. Isocyanide 1 was obtained by a
literature procedure from aminoacetaldehyde dimethylacetal as a
colorless liquid: yield 64%; bp 30 °C (1 Torr). Attention, heating
isocyanide 1 at a temperature higher than 60 °C can proVoke an
explosion. Spectroscopic data correlated with literature data.15
General Procedure for Thio-Ugi Reaction. An aldehyde (1
mmol) and an amine (1 mmol) were dissolved in methanol (5 mL)
and stirred for 15 min at rt. Then the reaction mixture was cooled
to 0 °C, and the thioacetic acid (1 mmol) and isocyanide 1 (1 mmol)
were added. The mixture stood overnight at room temperature. The
solvent was removed in vacuo, and the crude product was purified
by column chromatography.
Investigation of the Stereoselectivity. Investigation of the
stereoselectivity was carried out according to a general procedure
for a thio-Ugi reaction using (S)-R-methylbenzylamine with dif-
ferent temperatures and concentration. Crude mixtures were
analyzed by GCMS.
N-(1-{[(2,2-Dimethoxyethyl)amino]carbonothioyl}-2-methyl-
propyl)-N-methylacetamide (2f): yield 71%; colorless oil; Rf 0.55
1
(2:1 hexanes/ethyl acetate); IR (film) 2950, 1740 cm-1; H NMR
(400 MHz, CDCl3) δ 0.84 (d, J ) 6.5 Hz, 3H), 0.93 (d, J ) 6.5
Hz, 3 H), 2.07 (s, 3H), 2.47-2.60 (m, 1H), 3.04 (s, 3H), 3.34 (s,
3H), 3.35 (s, 3H), 3.75-3.85 (m, 2 H), 3.82-3.90 (m, 1H), 4.52
(t, J ) 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.8, 19.7,
22.2, 27.6, 46.4, 54.1, 77.4, 100.8, 172.6, 201.4. Anal. Calcd for
C12H24N2O3S: C, 52.15; H, 8.75. Found: C, 52.17; H, 8.54.
N-[2-(3,4-Diethoxyphenyl)ethyl]-N-(1-{[(2,2-dimethoxyethyl)-
amino]carbonothioyl}-2-methylpropyl)acetamide (2g): yield 83%;
yellow oil; Rf 0.55 (2:1 hexanes/ethyl acetate); IR (film) 2950, 1750
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.90 (d, J ) 6.5 Hz, 3H),
1.04 (d, J ) 6.5 Hz, 3H), 1.36-1.45 (m, 6H), 2.00 (s, 3H), 2.70-
3.00 (m, 3H), 3.36 (s, 3H), 3.37 (s, 3H), 3.55-3.75 (m, 1H), 3.83-
3.92 (m, 3H), 4.00-4.07 (m, 4H), 4.58 (t, J ) 5.5 Hz, 1H), 6.65-
6.80 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 14.8, 20.2, 25.3,
28.0, 35.2, 44.4, 47.1, 54.0, 54.6, 64.6, 64.7, 77.3, 100.8, 113.7,
114.4, 121.0, 130.7, 147.5, 148.8, 173.1, 202.5. Anal. Calcd for
C23H38N2O5S: C, 60.76; H, 8.42. Found: C, 60.40; H, 8.64.
N-Benzyl-N-{2-[(2,2-dimethoxyethyl)amino]-1-phenyl-2-
thioxoethyl}acetamide (2h): yield 52%; colorless oil; Rf 0.55 (2:1
hexanes/ethyl acetate); IR (film) 2960, 1740 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.19 (s, 3H), 3.34 (s, 3H), 3.36 (s, 3H), 3.75-
3.90 (m, 2H), 4.42-4.46 (m, 1H), 6.02 (s, 1H), 7.0-7.09 (m, 2H),
7.12-7.35 (m, 8H), 8.5 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 22.8, 47.2, 52.7, 54.3, 54.3, 70.6, 100.9, 126.6, 127.4, 127.7,
128.4, 128.5, 130.1, 133.7, 138.2, 172.8, 201.0. Anal. Calcd for
C21H26N2O3S: C, 65.26; H, 6.78. Found: C, 65.36; H, 6.49.
N-Benzyl-N-[2-[(2,2-dimethoxyethyl)amino]-1-(3-methylphe-
nyl)-2-thioxoethyl]acetamide (2i): yield 57%; colorless oil; Rf 0.55
N-Benzyl-N-{1-(4-chlorophenyl)-2-[(2,2-dimethoxyethyl)amino]-
2-thioxoethyl}acetamide (2a): yield 45%; yellow oil; Rf 0.55 (2:1
hexanes/ethyl acetate); IR (film) 2950, 1740 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.22 (s, 3H), 3.35 (s, 3H), 3.38 (s, 3H), 3.80-
3.85 (m, 2H), 4.5-4.8 (m, 3H), 6.04 (s, 1H), 7.03-7.08 (m, 2H),
and 7.15-7.28 (m, 7 H); 13C NMR (100 MHz, CDCl3) δ 22.6,
47.0, 52.3, 54.2, 69.8, 100.7, 126.3, 127.1, 128.2, 128.3, 130.2,
133.7, 134.0, 136.8, 172.8, 201.1. Anal. Calcd for C21H25-
ClN2O3S: C, 59.92; H, 5.99. Found: C, 59.97; H, 5.84.
N-{1-(4-Chlorophenyl)-2-[(2,2-dimethoxyethyl)amino]-2-thiox-
oethyl}-N-(2-phenylethyl)acetamide (2b): yield 53%; white solid;
mp 89-90 °C; Rf 0.50 (2:1 hexanes/ethyl acetate); IR (film) 2950,
1
1740 cm-1; H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 2.45-
2.55 (m, 1H), 2.75-2.85 (m, 1H), 3.34 (s, 3H), 3.36 (s, 3H), 3.54-
3.65 (m, 1H), 3.70-3.90 (m, 3H), 4.57 (t, J ) 5.3 Hz, 1 H), 6.04
1
(2:1 hexanes/ethyl acetate); IR (film) 2960, 1730 cm-1; H NMR
(s, 1H), 7.03-7.08 (m, 2c), 7.14-7.37 (m, 7c), 9.0 (br s, 1H); 13
C
(400 MHz, CDCl3) δ 2.15 (s, 3H), 2.18 (s, 3H), 3.32 (s, 3H), 3.35
(s, 3H), 3.82 (s, 2H), 4.45-4.80 (m, 3H), 6.17 (s, 1H), 6.90-7.20
(m, 9H), 8.2 (br s, 1H); 13C NMR (400 MHz, CDCl3) δ 21.3, 22.7,
47.2, 52.7, 54.4, 70.6, 101.0, 126.1, 126.5, 127.0, 128.3, 129.2,
130.1, 135.0, 138.2, 145.9, 157.9, 172.9, 202.5. Anal. Calcd for
C22H28N2O3S: C, 65.97; H, 7.05. Found: C, 65.90, H, 6.95.
N-Benzyl-N-{2-[(2,2-dimethoxyethyl)amino]-1-(4-methoxyphe-
nyl)-2-thioxoethyl}acetamide (2j): yield 60%; colorless oil; Rf 0.55
NMR (100 MHz, CDCl3) δ 22.3, 36.0, 47.4, 52.5, 54.3, 72.4, 100.9,
126.7, 128.6, 128.7, 128.8, 129.4, 134.4, 137.6, 138.8, 172.2, 201.0.
Anal. Calcd for C22H27ClN2O3S: C, 60.75; H, 6.26. Found: C,
60.70; H, 6.24.
N-Benzyl-N-[2-[(2,2-dimethoxyethyl)amino]-1-(3,5-dimeth-
ylphenyl)-2-thioxoethyl]acetamide (2c): yield 50%; colorless oil;
Rf 0.60 (2:1 hexanes/ethyl acetate); IR (film) 2950, 1740 H cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.89 (s, 3H), 2.25 (s, 6H), 3.37 (s,
3H), 3.38 (s, 3H), 3.80-3.90 (m, 2H), 4.60 (t, J ) 4.7 Hz, 1 H),
5.88 (s, 1H), 7.14-7.37 (m, 7H), 9.0 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 21.1, 23.7, 47.3, 54.3, 76.2, 100.9, 117.6, 125.9,
128.5, 129.7, 130.1, 134.0, 139.4, 142.6, 172.2, 200.4. Anal. Calcd
for C22H27ClN2O3S: C, 60.75; H, 6.26. Found: C, 60.50; H, 6.04.
N-(1-{[(2,2-Dimethoxyethyl)amino]carbonothioyl}-2-methyl-
propyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide (2d): yield 64%;
yellow oil; Rf 0.55 (2:1 hexanes/ethyl acetate); IR (film) 3450, 2950,
1
(2:1 hexanes/ethyl acetate); IR (film) 2950, 1740 cm-1; H NMR
(400 MHz, CDCl3) δ 2.12 (s, 3H), 3.32 (s, 3H), 3.34 (s, 3H), 3.71
(s, 3H), 3.77-3.85 (m, 2H), 4.50-4.80 (m, 3H), 6.17 (s, 1H), 6.67
(d, J ) 7.6, 2H), 6.95 (d, J ) 7.6, 2H), 7.10-7.20 (m, 5H), 8.11
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.8, 47.2, 52.0, 54.4,
55.2, 70.1, 101.0, 113.8, 126.4, 127.0, 128.3, 130.7, 159.5, 172.8,
202.2. Anal. Calcd for C22H28N2O4S: C, 63.44; H, 6.78. Found:
C, 63.38; H, 6.66.
N-Benzyl-N-{2-[(2,2-dimethoxyethyl)amino]-1-(4-nitrophenyl)-
2-thioxoethyl}acetamide (2k): yield 15%; colorless oil; Rf 0.55
1
1740 cm-1; H NMR (400 MHz, CDCl3) δ 0.90 (d, J ) 6.6 Hz,
1
3H), 1.04 (d, J ) 6.6 Hz, 3H), 2.01 (s, 3H), 2.82-3.20 (m, 3H),
3.39 (s, 6H), 3.45-3.55 (m, 2H), 3.67-3.80 (m, 2H), 3.85-3.97
(2:1 hexanes/ethyl acetate); IR (film) 2950, 1750 cm-1; H NMR
(400 MHz, CDCl3) δ 2.28 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.70-
J. Org. Chem, Vol. 72, No. 21, 2007 7883

Gulevich et al.
3.90 (m, 2H), 4.55-4.60 (m, 1H), 4.75 (s, 2H), 5.90 (s, 1H), 7.12-
7.34 (m, 7H), 8.03 (d, J ) 8.9, 2H), 9.1 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 22.9, 47.4, 54.2, 54.3, 72.6, 100.7, 123.4, 127.4,
128.2, 128.3, 128.9, 142.8, 147.2, 172.8, 199.4. Anal. Calcd for
C21H25N3O5S: C, 58.45; H, 5.84. Found: C, 58.58; H, 5.76.
N-Benzyl-N-{2-[(2,2-dimethoxyethyl)amino]-1-(2-thienyl)-2-
thioxoethyl}acetamide (2l): yield 25%; colorless oil; Rf 0.55 (2:1
hexanes/ethyl acetate); IR (film) 2970, 1740 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.12 (s, 3H), 3.34 (s, 3H), 3.35 (s, 3H), 3.70-
3.90 (m, 2H), 4.48-4.57 (m, 1H), 4.70-4.81 (m, 2H), 6.17 (s,
1H), 6.83 (m, 1H), 6.93 (m, 1H), 7.03-7.08 (m, 2H), 7.15-7.25
(m, 4H), 8.30 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.7,
47.3, 54.2, 54.3, 66.8, 101.0, 126.4, 126.6, 127.3, 127.4, 128.5,
129.4, 137.1, 140.1, 172.5, 200.5. Anal. Calcd for C19H24N2O3S2:
C, 58.14; H, 6.16. Found: C, 58.04; H, 6.26.
N-((1R)-1-{[(2,2-Dimethoxyethyl)amino]carbonyl}-2-methyl-
propyl)-N-[(1S)-1-phenylethyl]benzamide (2u): yield 26%; color-
less oil; Rf 0.6 (2:1 hexanes/ethyl acetate); IR (film) 2950, 1740
cm-1; 1H NMR (400 MHz) δ 0.31 (d, J ) 6.6 Hz, 3H), 0.76 (d, J
) 6.6 Hz, 3H), 1.55 (d, J ) 7.1 Hz, 3H), 2.87-3.00 (m, 1H), 3.20-
3.40 (m, 2H), 3.37 (s, 3H), 3.36 (s, 3H), 3.50-3.60 (m, 1H), 4.49
(t, J ) 5.6 Hz, 1H), 5.06 (q, J ) 7.1 Hz, 1H), 7.27-7.35 (m, 5H),
7.42-7.52 (m, 5H), 8.4 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 17.4, 19.7, 19.8, 24.3, 53.0, 53.7, 59.1, 68.7, 101.9, 125.5, 128.4,
128.4, 128.9, 129.3, 137.7, 138.4, 173.4, 173.8; [R]20 -87.48 (c
D
0.05 M, MeOH). Anal. Calcd for C24H32N2O4: C, 69.88; H, 7.82.
Found: C, 69.70; H, 7.53.
N-((1S)-1-{[(2,2-Dimethoxyethyl)amino]carbonyl}-2-methyl-
propyl)-N-[(1S)-1-phenylethyl]benzamide (2v): yield 54%; color-
less oil, crystallizes on standing; mp 110-112 °C; Rf 0.4 (2:1
hexanes/ethyl acetate); IR (film) 2950, 1740 cm-1; 1H NMR (400
MHz) δ 1.00 (d, J ) 6.6 Hz, 3H), 1.10 (d, J ) 6.6 Hz, 3H), 1.65
(d, J ) 6.8 Hz, 3H), 3.00-3.15 (m, 2H), 3.39 (s, 3H), 3.40 (s,
3H), 4.27 (t, J ) 5.8 Hz, 1H), 5.13 (q, J ) 6.8 Hz, 1H), 7.7-7.35
(m, 5H), 7.48-7.60 (m, 5H), 8.4 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 16.7, 19.8, 20.7, 26.6, 40.2, 52.8, 54.0, 58.1, 69.5, 101.8,
N-Benzyl-N-(1-{[(2,2-dimethoxyethyl)amino]carbonothioyl}-
2-methylpropyl)acetamide (2m): yield 75%; colorless oil; Rf 0.55
1
(2:1 hexanes/ethyl acetate); IR (film) 2950, 1740 cm-1; H NMR
(400 MHz, CDCl3) δ 0.68 (d, J ) 6.5 Hz, 3H), 0.93 (d, J ) 6.3
Hz, 3H), 2.11 (s, 3H), 2.70-2.90 (m, 1H), 3.42 (s, 6H), 3.77-
3.83 (m, 2H), 3.82-3.90 (m, 1H), 4.55-4.65 (m, 3H), 7.20-7.35
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 20.2, 23.0, 23.1, 28.2,
30.9, 44.4, 46.9, 54.0, 100.8, 127.1, 172.6, 128.6, 135.1, 173.5,
201.8. Anal. Calcd for C18H28N2O3S: C, 61.33; H, 8.01. Found:
C, 61.17; H, 8.04.
126.3, 127.5, 128.3, 128.9, 130.0, 137.3, 138.5, 173.6, 179.9; [R]20
D
-12.77 (c 0.05 M, MeOH). Anal. Calcd for C24H32N2O4: C, 69.88;
H, 7.82. Found: C, 69.80; H, 7.77.
N-{(1R)-1-[(tert-Butylamino)carbonyl]-2-methylpropyl}-N-
[(1S)-1-phenylethyl]benzamide (2y): yield 28%; colorless oil; Rf
0.6 (2:1 hexanes/ethyl acetate); IR (film) 2960, 1760 cm-1; 1H NMR
(400 MHz) δ 0.30 (d, J ) 6.5 Hz, 3H), 0.77 (d, J ) 6.5 Hz, 3H),
1.37 (s, 9H), 1.57 (d, J ) 7.1 Hz, 3H), 2.85-2.95 (m, 1H), 3.05
(d, J ) 10.9 Hz, 1H), 5.11 (q, J ) 7.1 Hz, 1H), 7.23-7 35 (m,
5H), 7.42-7.55 (m, 5H), 8.2 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 17.6, 19.7, 19.8, 27.5, 28.7, 50.5, 59.3, 70.2, 125.4, 128.4,
128.7, 129.1, 129.3, 137.8, 138.5, 172.4, 173.1. Anal. Calcd for
C24H32N2O2: C, 75.75; H, 8.48. Found: C, 75.55; H, 8.28 (lit.22).
N-((1S)-1-{[(2,2-Dimethylpropyl)amino]carbonyl}-2-methyl-
propyl)-N-[(1S)-1-phenylethyl]benzamide (2z): yield 50%, color-
less oil; Rf 0.5 (2:1 hexanes/ethyl acetate); IR (film) 2960, 1760
cm-1; 1H NMR (400 MHz) δ 1.00 (d, J ) 6.6 Hz, 3H), 1.07 (d, J
) 6.6 Hz, 3H), 1.15 (s, 9H), 1.62 (d, J ) 6.8 Hz, 3H), 2.95-3.20
(m, 2H), 5.11 (q, J ) 6.8 Hz, 1H), 7.15-7 30 (m, 5H), 7.45-7.60
(m, 5H), 8.3 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.5, 19.7,
19.8, 20.6, 27.5, 28.6, 50.4, 59.2, 70.1, 125.4, 128.3, 128.6, 129.0,
129.3, 137.8, 138.4, 172.4, 173.1. Anal. Calcd for C24H32N2O2: C,
75.75; H, 8.48. Found: C, 76.00; H, 8.69 (lit.22).
N-((1S)-1-{[(2,2-Dimethoxyethyl)amino]carbonothioyl}-2-me-
thylpropyl)-N-[(1R)-1-phenylethyl]benzamide (2λ): yield 35%;
colorless oil; Rf 0.4 (3:1 hexanes/ethyl acetate); IR (film) 2940,
1750 cm-1; 1H NMR (400 MHz) δ 0.37 (d, J ) 6.7 Hz, 3H), 0.87
(d, J ) 6.7 Hz, 3H), 1.69 (d, J ) 7.1, 3H), 2.90-3.00 (m, 1H),
3.43 (s, 3H), 3.42 (s, 3H), 3.77-3.82 (m, 1H), 3.97-4.05 (m, 2H),
4.69 (t, J ) 5.6 Hz, 1H), 5.12 (q, J ) 7.1 Hz, 1H), 7.20-7.55 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 19.0, 20.3, 20.6, 28.3, 47.2,
53.5, 54.0, 60.2, 75.2, 100.6, 128.5, 128.6, 128.9, 129.0, 129.5,
137.5, 138.23, 174.42, 205.42; [R]20D +177.02 (c 0.05 M, MeOH).
Anal. Calcd for C24H32N2O3S: C, 67.26; H, 7.53. Found: C, 67.33;
H, 7.66.
General Procedure for Hydrolysis of Thioamides: To the
solution of thioamide 2s (1 mmol) in ethanol was added a solution
of the Hg(OAc)2 (318 mg, 1 mmol) in water (1 mL). The reaction
mixture was stirred overnight, black precipitate was filtered off,
and filtrate was evaporated and purified by column chromatography.
The yield of amide 2u was about 60%.
A suspension of amide 2u (1 mmol) was refluxed in 6 M HCl
(3 mL) for 6 h. A precipitate was filtered off. The reaction mixture
was evaporated, and the residue was dissolved in H2O (5 mL) and
extracted with CH2Cl2 (2 × 5 mL). After evaporation of the aqueous
phase, recrystallization of the residue (H2O) afforded D-valine: yield
11%; [R]20D -26.04 (c 0.42 M, 6 M HCl). The 1H NMR spectrum
and melting point correlated with literature data.19
N-Benzyl-N-(1-{[(2,2-dimethoxyethyl)amino]carbonothioyl}-
cyclohexyl)acetamide (2n): yield 55%; white solid; mp 112-113
°C (lit.15 115 °C); Rf 0.55 (2:1 hexanes/ethyl acetate); IR (film)
1
2950, 1740 cm-1; H NMR (400 MHz, CDCl3) δ 1.10-1.22 (m,
1H), 1.35-1.60 (m, 5H), 1.85-1.93 (m, 2H), 2.06 (s, 3H), 2.83-
2.92 (m, 2H), 3.40 (s, 6H), 3.83 (t, J ) 5.3 Hz, 2H), 4.60 (t, J )
5.3 Hz, 1H), 4.73 (s, 2H), 7.20-7.35 (m, 5H), 9.0 (br s, 1H); 13C
NMR (100 MHz, CDCl3) δ 22.8, 24.7, 25.2, 35.1, 47.3, 49.8, 54.1,
69.3, 101.1, 125.9, 127.1, 128.8, 138.8, 174.5, 205.5. Anal. Calcd
for C20H30N2O3S: C, 63.46; H, 7.99. Found: C, 63.31; H, 7.82.
N-Benzyl-N-(1-{[(2,2-dimethoxyethyl)amino]carbonothioyl}-
cyclopentyl)acetamide (2o): yield 53%; colorless oil, crystallized
on standing; mp 96-97 °C; Rf 0.55 (2:1 hexanes/ethyl acetate); IR
1
(film) 2950, 1740 cm-1; H NMR (400 MHz, CDCl3) δ 1.52-
1.63 (m, 4H), 1.87-1.98 (m, 2H), 1.99 (s, 3H), 2.87-2.97 (m,
2H), 3.36 (s, 6H), 3.79 (t, J ) 5.3 Hz, 2H), 4.55 (t, J ) 5.3 Hz,
1H), 4.72 (s, 2H), 7.15-7.35 (m, 5H), 8.8 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 23.5, 22.0, 37.9, 47.3, 52.0, 53.9, 77.3, 100.7,
125.3, 126.9, 128.7, 138.6, 174.0, 205.9. Anal. Calcd for
C19H28N2O3S: C, 62.61; H, 7.74. Found: C, 62.41; H, 7.65.
N-Benzyl-N-(1-benzyl-4-{[(2,2-dimethoxyethyl)amino]-
carbonothioyl}piperidin-4-yl)acetamide (2p): yield 48%; color-
less oil; Rf 0.55 (2:1 hexanes/ethyl acetate); IR (film) 2950, 1750
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.02 (s, 3H), 2.05-2.20 (m,
4H), 2.67 (d, J ) 11.6 Hz, 2H), 3.13 (d, J ) 11.6 Hz, 2H), 3.35 (s,
2H), 3.41 (s, 6H), 3.86 (t, J ) 5.3 Hz, 2H), 4.62 (t, J ) 5.3 Hz,
1H), 4.71 (s, 2H), 7.20-7.35 (m, 10H), 9.2 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 30.9, 34.6, 47.4, 50.0, 58.2, 62.4, 77.2,
105.8, 121.8, 125.9, 128.0, 128.5, 128.7, 128.8, 135.3, 136.4, 167.3,
203.4. Anal. Calcd for C26H35N3O3S: C, 66.49; H, 7.51. Found:
C, 66.31; H, 7.52.
N-((1R)-1-{[(2,2-Dimethoxyethyl)amino]carbonothioyl}-2-me-
thylpropyl)-N-[(1S)-1-phenylethyl]benzamide (2s): yield 37%;
colorless oil; Rf 0.4 (3:1 hexanes/ethyl acetate); IR (film) 2940,
1750 cm-1; 1H NMR (400 MHz) δ 0.37 (d, J ) 6.7 Hz, 3H), 0.87
(d, J ) 6.7 Hz, 3H), 1.69 (d, J ) 7.1, 3H), 2.90-3.00 (m, 1H),
3.43 (s, 3H), 3.42 (s, 3H), 3.77-3.82 (m, 1H), 3.97-4.05 (m, 2H),
4.70 (t, J ) 5.6 Hz, 1H), 5.12 (q, J ) 7.1 Hz, 1H), 7.20-7.55 (m,
10H), 10.4 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.0, 20.3,
20.6, 28.3, 47.2, 53.5, 54.0, 60.2, 75.2, 100.6, 128.5, 128.6, 128.9,
129.0, 129.5, 137.5, 138.23, 174.42, 205.42; [R]20D -174.16 (c 0.05
M, MeOH). Anal. Calcd for C24H32N2O3S: C, 67.26; H, 7.53.
Found: C, 67.26; H, 7.33.
7884 J. Org. Chem., Vol. 72, No. 21, 2007

A DiastereoselectiVe Thio-Ugi Reaction
N-Benzyl-N-{1-(4-chlorophenyl)-2-[(2,2-dimethoxyethyl)amino]-
2-iminoethyl}acetamide 3: Thioamide 2a (1 mmol) was dissolved
in ethanol (10 mL). Then NH4OAc (2 g) was added. The reaction
mixture was refluxed overnight. The solvent was removed in vacuo
above 40 °C. The solid residue was treated with 1 M aq K2CO3.
The mixture was extracted with 1 M aq H2Cl2, dried over K2CO3,
and the solvent was removed in vacuo. The amidine 3 was obtained
(82%) as a gray solid: mp 160-165 °C; Rf 0.55 (2:1 hexanes/
N-Benzyl-N-[1H-imidazol-2-yl(phenyl)methyl]amine (4h):
Method A; yield 67%; gray solid; mp 119-120°C; Rf 0.5 (4:1:0.1
1
acetonitrile/methanol/NH3(aq)); IR (Nujol) 3120 cm-1; H NMR
(400 MHz, CDCl3) δ 3.3 (br s, NH), 5.74 (s, 2H), 6.94-7.02 (m,
2H), 7.23-7.30 (m, 3H), 7.37-7.50 (m, 7H), 9.1 (br s, 1H); 13C
NMR (100 MHz, CDCl3) δ 50.5, 77.2, 120.4, 121.8, 125.2, 126.3,
128.6, 129.3, 129.8, 130.5, 133.4, 136.6. Anal. Calcd for
C17H17N3: C, 77.54; H, 6.51. Found: C, 77.16; H, 6.15.
1
ethyl acetate); IR (Nujol) 2950, 1740 cm-1; H NMR (400 MHz,
N-Benzyl-N-[1H-imidazol-2-yl(3-methylphenyl)methyl]-
amine (4i): Method A; yield 61%; gray crystals; mp 130-131°C;
Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3110
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 3.3 (br s, NH),
5.70 (s, 2H), 6.97-6.99 (m, 2H), 7.14-7.33 (m, 5H), 7.52 (s, 2H),
9.1 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.4, 50.5, 77.2,
120.2, 122.0, 124.0, 125.1, 126.2, 126.4, 128.7, 129.3, 129.6, 131.3,
133.5, 136.3, 139.9. Anal. Calcd for C18H18ClN3: C, 69.34; H, 5.82.
Found: C, 69.50; H, 5.63.
CDCl3) δ 2.42 (s, 3H), 3.34 (d, J ) 6.2 Hz, 1H), 3.50 (s, 6H), 4.43
(d, J ) 5.3 Hz, 2H), 4.95 (t, J ) 5.5 Hz, 1H), 5.12 (s, 2H), 6.87-
6.95 (m, 2H), 7.30-7.35 (m, 5H), 7.46 (d, J ) 8.6, 2H); 13C NMR
(100 MHz, CDCl3) δ 11.5, 47.3, 48.9, 56.6, 77.0, 103.1, 125.37,
128.4, 128.8, 129.3, 131.7, 133.9, 134.3, 139.2, 147.0, 172.7. Anal.
Calcd for C21H26ClN3O3: C, 62.45; H, 6.49. Found: C, 62.38; H,
6.56.
General Procedure for Imidazole Synthesis. Method A: A
thiopeptide (1 mmol) was dissolved in ethanol (10 mL). Then NH4-
OAc (2 g) was added. The reaction mixture was held at reflux
overnight, and the solvent was removed in vacuo above 40 °C.
The solid residue was dissolved in concd HCl (10 mL). The reaction
mixture was held at reflux overnight, and the solvent was removed
in vacuo. The residue was made alkaline with saturated K2CO3
solution (10%), and the product was extracted with CH2Cl2 (3 ×
10 mL). After drying the organic layer over K2CO3, the solvent
was removed in vacuo, and the crude product was purified by
column chromatography.
N-Benzyl-N-[1H-imidazol-2-yl(4-methoxyphenyl)methyl]-
amine (4j): Method A; yield 59%; white solid; mp 114-115 °C;
Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3110
1
cm-1; H NMR (400 MHz, CDCl3) δ 3.24 (s, 3H), 5.77 (s, 2H),
6.91-7.00 (m, 2H), 7.20-7.30 (m, 3H), 7.36-7.49 (m, 6H), 9.1
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 50.5, 77.2, 120.2, 121.8,
123.0, 126.2, 128.7, 129.4, 129.5, 130.0, 133.1, 135.8, 136.4. Anal.
Calcd for C18H19N3O: C, 73.69; H, 6.53. Found: C, 73.79; H, 6.20.
Method B: A thiopeptide (1 mmol) was dissolved in ethanol
(10 mL). Then NH4OAc (2 g) and aq NH3 (2 mL) were added.
The reaction mixture was refluxed for 40 h, and the solvent was
removed in vacuo above 40 °C. Further treatment was according
to Method A.
N-Benzyl-N-[1-(1H-imidazol-2-yl)-2-methylpropyl]amine (4m):
Method B; yield 69%; white solid; mp 127-130 °C; Rf 0.5 (4:1:
0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3130 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.25 (d, J ) 6.9 Hz, 6H), 3.05-3.15 (m,
3H), 5.69 (s, 2H), 6.97-7.03 (m, 2H), 7.25-7.35 (m, 3H), 7.40
(s, 2H), 8.9 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 24.5,
49.8, 77.2, 119.9, 121.8, 125.9, 128.7, 129.4, 133.0, 135.2. Anal.
Calcd for C14H19N3: C, 73.33; H, 8.35. Found: C, 73.07; H, 8.25.
N-Benzyl-N-[(4-chlorophenyl)(1H-imidazol-2-yl)methyl]-
amine (4a): Method A; yield 61%; gray solid; mp 115-117 °C;
Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3130
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.3 (br s, NH), 5.60 (s, 2H),
6.87-7.03 (m, 2H), 7.25-7.45 (m, 7H), 7.56 (s, 2H), 9.0 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 50.7, 77.2, 120.3, 121.9, 123.6,
126.2, 128.7, 129.4, 130.0, 130.5, 133.2, 136.8, 136.8. Anal. Calcd
for C17H16ClN3: C, 68.57; H, 5.32. Found: C, 68.40; H, 5.05.
N-[(4-Chlorophenyl)(1H-imidazol-2-yl)methyl]-2-phenyletha-
namine (4b): Method A; yield 72%; gray solid; mp 130-131°C;
Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3110
[(1R)-1-(1H-Imidazol-2-yl)-2-methylpropyl]amine (R)-4p:
Method B; yield 34%; yellow oil; Rf 0.5 (4:1:0.1 acetonitrile/
1
methanol/NH3(aq)); IR (Nujol) 3140 cm-1; H NMR (400 MHz,
CDCl3) δ 0.91 (d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.8 Hz, 3H), 1.9
(br s, 2H), 2.15-2.25 (m, 1H), 4.10 (d, J ) 5.3 Hz, 1H), 7.22 (d,
J ) 3.0 Hz, 1H), 7.70 (d, J ) 3.0 Hz, 1H); 13C NMR (100 MHz,
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.84 (t, J ) 6.1 Hz, 2H),
CDCl3) δ 17.2, 19.4, 34.8, 59.6, 118.3, 142.3, 176.7; [R]20 -2.4
D
3.03 (br s, NH), 4.72 (t, J ) 6.1 Hz, 2H), 6.75-6.80 (m, 2H),
7.10-7.20 (m, 3H), 7.28 (d, J ) 8.4 Hz, 2H), 7.35-7.40 (m, 2H),
7.46 (d, J ) 8.4 Hz, 2H), 8.9 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 35.5, 49.0, 77.2, 120.3, 121.5, 123.8, 127.6, 129.0, 130.1,
130.6, 135.5, 136.3, 36.8. Anal. Calcd for C18H18ClN3: C, 69.34;
H, 5.82. Found: C, 69.50; H, 5.63.
(c 0.027 M, MeOH). Anal. Calcd for C7H13N3: C, 60.40; H, 9.41.
Found: C, 60.80; H, 9.67.
[(1S)-1-(1H-Imidazol-2-yl)-2-methylpropyl]amine(S)-4p:Method
B; yield 36%; yellow oil; Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3-
1
(aq)); IR (Nujol) 3140 cm-1; H NMR (400 MHz, CDCl3) δ 0.91
N-[1-(1H-Imidazol-2-yl)-2-methylpropyl]-N-methylamine (4f):
Method B; yield 63%; white solid; mp 130-131°C; Rf 0.5 (4:1:
0.1 acetonitrile/methanol/NH3(aq)); IR (Nujol) 3140 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.35 (d, J ) 7.1 Hz, 6H), 3.10-3.25 (m,
3H), 4.01 (s, 3H), 7.35 (s, 2H), 8.8 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.9, 24.4, 33.5, 77.2, 119.6, 121.3, 128.9. Anal. Calcd
for C8H15N3: C, 62.71; H, 9.87. Found: C, 63.00; H, 10.12.
N-[2-(3,4-Diethoxyphenyl)ethyl]-N-[1-(1H-imidazol-2-yl)-2-
methylpropyl]amine (4g): Method B; yield 64%; gray solid; mp
123-124°C; Rf 0.5 (4:1:0.1 acetonitrile/methanol/NH3(aq)); IR
(d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.8 Hz, 3H), 1.9 (br s, 2H),
2.15-2.25 (m, 1H), 4.10 (d, J ) 5.3 Hz, 1H), 7.22 (d, J ) 3.3 Hz,
1H), 7.70 (d, J ) 3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
17.2, 19.4, 34.8, 59.6, 118.3, 142.3, 176.7; [R]20D +2.8 (c 0.03 M,
MeOH). Anal. Calcd for C7H13N3: C, 60.40; H, 9.41. Found: C,
60.74; H, 9.57.
Acknowledgment. Financial support from Russian Science
Support Foundation is gratefully acknowledged. The authors
would like to thank Dr. B. V. Lokshin for the optical rotation
measurements.
1
(Nujol) 3140 cm-1; H NMR (400 MHz, CDCl3) δ 1.24 (d, J )
6.9 Hz, 6H), 1.33 (t, J ) 7.1 Hz, 3H), 1.38 (t, J ) 7.1 Hz, 3H),
2.75-2.85 (m, 2H), 2.90 (s, 1H), 3.00 (t, J ) 6.9 Hz, 2H), 3.92 (q,
J ) 7.1 Hz, 2H), 4.05 (q, J ) 7.1 Hz, 2H), 4.57 (t, J ) 6.9 Hz,
2H), 6.42 (d, J ) 8.0 Hz, 1H), 6.51 (s, 1H), 6.70 (d, J ) 8.0 Hz,
1H), 7.35 (s, 2H), 8.6 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ
14.7, 21.2, 24.3, 35.8, 48.4, 64.5, 64.7, 77.3, 113.7, 114.1, 121.0,
121.7, 128.2, 129.0, 134.6, 148.3, 149.1. Anal. Calcd for
C19H29N3O2: C, 68.85; H, 8.82. Found: C, 68.80; H, 8.60.
Supporting Information Available: 1H and 13C NMR spectral
data of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO071030O
J. Org. Chem, Vol. 72, No. 21, 2007 7885