Sterically controlled stereoregulation in aldol reactions of 3-aryl-1-alkyl dihydrothiouracils

Article abstract of DOI:10.1055/s-0031-1289889

Aldol reactions of 3-aryl-1-alkyl dihydrothiouracils were investigated with respect to the orientation of the exocyclic group at N1, electronic effects of the aryl substituent at N3 and the steric demands of the electrophile. The reactions highlight the preference for formation of the anti aldol diastereomer with increasing steric constraints of the reactants. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289889

LETTER
2997
Sterically Controlled Stereoregulation in Aldol Reactions of 3-Aryl-1-alkyl
Dihydrothiouracils
A
ldol Reactions of
a
3-Aryl-1-a
r
lkyl
D
ih
u
ydrothiourac
n
ils Kumar, Gopal L. Khatik, Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Sector 67, Mohali, Punjab 160 062, India
E-mail: vn74nr@yahoo.com
Received 19 July 2011
aspects of the heterocycle and the effects of the substitu-
ents on the diastereoselectivity have not been investigat-
ed. With the limited substrate variation, the scope of the
reaction was also not considered.7 Widely known for its
Abstract: Aldol reactions of 3-aryl-1-alkyl dihydrothiouracils were
investigated with respect to the orientation of the exocyclic group at
N1, electronic effects of the aryl substituent at N3 and the steric de-
mands of the electrophile. The reactions highlight the preference for
formation of the anti aldol diastereomer with increasing steric con- applications in pharmaceutical and agricultural fields,8 we
straints of the reactants.
decided to choose the structurally constrained 1,3-disub-
stituted dihydrothiouracil, for a detailed investigation. Si-
multaneously, efforts to functionalize this substrate also
stemmed from our interests in developing new biological-
ly active heterocycles,9 including dihydrothiouracils, as a
part of our ongoing cancer research program. This model
was expected to help in the understanding of the origin of
stereoselectivity arising from steric and conformational
control.
Key words: aldol reaction, cyclization, aldehyde, dihydrothio-
uracils, stereoselectivity
With the aim of inducing stereoselectivity in carbon–
carbon bond formation, aldol reactions have attained par-
amount importance.1 Over the last few decades, stereose-
lectivity in these reactions have been explored with
increased impetus, providing new routes to the desired
diastereomers.2 Numerous reports and theoretical ratio-
nalizations on the diastereoselectivity have helped in the
total synthesis of several natural products.3 These studies
have demonstrated that analysis of the transitions states,
especially of acyclic carbonyl substrates, can allow the
stereochemistry of the product to be predicted with rea-
sonable accuracy.4 In contrast, reactions with cyclic car-
bonyl compounds seem to be more complex, as observed
with lactams, lactones and thiazolidinones,5 for which the
outcome of the reaction largely depends on the conforma-
tion adopted by the ring. Since the rotational freedom of
sp3 hybridized carbon atoms endows cyclic systems with
flexibility, we focused our attention on highly rigid mole-
cules containing sp2 carbon atoms, preferably linked to
heteroatoms6 as this would restrict the conformational
variants considerably. Thoughts in this direction led us to
consider uracils, which have attained wide recognition in
both the chemical and biological realms. The aldol reac-
tion of dihydrouracils for the chain extension of glycer-
aldehyde has been reported, but the conformational
This paper discusses the aldol reactions of 3-aryl-1-alkyl
dihydrothiouracils, where the steric influence of the elec-
trophile and the conformational effects of the cyclic eno-
late on diastereoselectivity were examined. A facile
synthetic route to 3-aryl-1-alkyl dihydrothiouracils (4) in-
volves the condensation of b-amino esters (2) with aryl
isothiocyanates (3). b-Amino esters can be prepared by a
conventional aza-Michael addition of amines to methyl
acrylate (1) through electrophilic activation induced by
lithium perchlorate in a polar protic medium.10 Subse-
quent condensation with aryl isothiocyanates mediated by
a Lewis acid in acetonitrile (Scheme 1) affords 3-aryl-1-
alkyl dihydrothiouracils, in short reaction time9a–c
(Table 1). In general, the reactions afforded the desired
products with good yields, however, the reaction with me-
thyl 3-(tert-butylamino)propanoate failed, probably be-
cause of steric hindrance. Aldol reactions were then
performed to examine the reactant parameters on a model
reaction of 3-(4-chlorophenyl)-1-alkyl dihydrothiouracil
with 4-fluorobenzaldehyde (Table 2). The reaction of the
lithium enolate, having an E geometry due to structural
R2
R2
S
R1
NCS
R1
R1
H2N
3i–iii
MeO
O
MeO
O
HN
N
N
Et3N, LiClO4
MeCN, reflux
LiClO4, MeOH
O
1
2a–d
4a(i)–d(iii)
Scheme 1 One-pot synthesis of 3-aryl-1-alkyl dihyrothiouracils
SYNLETT 2011, No. 20, pp 2997–3001
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289889; Art ID: B13611ST
© Georg Thieme Verlag Stuttgart · New York

2998
V. Kumar et al.
LETTER
limitations, afforded a diastereomeric mixture of syn and ed by the observation that no substantial change in diaste-
anti aldols with poor selectivity, irrespective of which reoselectivity occurred when the substituent on N1 was
lithium base was employed.
varied from ethyl to n-propyl and n-butyl (Table 2). On
the other hand, the results obtained when the n-propyl
group was changed to an isopropyl group indicated the or-
igin of stereoregulation induced by the steric effects of a
simple positional isomerism. With the isopropyl group on
N1, the electronic effect of the substituent on N3 was ex-
amined. The diastereoselectivity remained unchanged, re-
gardless of the nature of the substituent on the aryl ring
(Scheme 3, products 8–10), suggesting that the substitu-
ents on the aryl ring at N3 did not make any major contri-
bution to the stereoelectronic effects of the transition
state.
Table 1 Reactions of b-Amino Esters with Aryl Isothiocyanates
Entry
R1
R2
Cl
Cl
Cl
Cl
Br
H
Time (h) Yield (%) Product
1
2
3
4
5
6
Et
1.0
2.5
1.5
2.5
2.5
3.0
84
78
76
72
80
81
4a(i)
4b(i)
4c(i)
n-Pr
n-Bu
i-Pr
i-Pr
i-Pr
4d(i)
4d(ii)
4d(iii)
To delineate the steric influence of the electrophile, reac-
tions of the dihydrothiouracil 4d(i) were carried out with
various aromatic aldehydes (Scheme 3). It was observed
that the reactions with substituted benzaldehydes afforded
inseparable diastereomeric mixtures of syn and anti aldols
without appreciable differences in selectivity, with varia-
tions of the substituent on the aromatic ring (Scheme 3,
products 11–14). To assign the relative configuration, ab
initio energy minimization calculations were performed
for the syn and anti aldol diastereomers of 8 using Gauss-
ian B3LYP with basis set 6-31G* (d,p);11 the dihedral an-
gles were computed for the vicinal protons at C5 and C7
from the optimized structures (Figure 1). A correlation of
the dihedral angles and 1H NMR spectra of the diastereo-
meric mixture (see the Supporting Information) indicated
that the syn diastereomer had a vicinal coupling constant
(J = 3.56 Hz) corresponding to a dihedral angle of 67°,
and the anti diastereomer had a coupling constant (J =
8.04 Hz) consistent with a dihedral angle of 163°. The as-
sumptions drawn on the relative configuration were fur-
ther confirmed by analysis of aldol diastereomers, which
were separated as the corresponding acetate derivatives
syn-8¢ and anti-8¢.
Table 2 Effect of Substituents at N1 and Lithium Bases on Aldol
Reactions of 3-(4-Chlorophenyl)-1-alkyl Dihydrothiouracils
(Scheme 2, R2 = Cl)
Entry
1
R1
Base
Time (h) Yield (%) anti:syna
Et
BuLi
2.0
2.5
1.5
1.5
2.5
2.5
2.5
2.2
2.0
1.5
2.0
1.5
65
70
80
58
68
75
68
60
75
68
77
85
56:44
58:42
56:44
56:44
55:45
56:44
55:45
56:44
57:43
68:32
68:32
72:28
2
Et
LDA
3
Et
LHMDS
BuLi
4
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
i-Pr
i-Pr
i-Pr
5
LDA
6
LHMDS
BuLi
7
8
LDA
9
LHMDS
BuLi
10
11
12
LDA
LHMDS
a Ratio of diastereomers was determined by 1H NMR analysis.
From the relatively modest result obtained, LHMDS was
chosen for further optimization trials (Scheme 2). Reac-
tions carried out to understand the steric and/or conforma-
tional influence exerted by the exocyclic substituent at N1
indicated no significant bearing on the selectivity from a
linear expansion of the alkyl chain. This was demonstrat-
Figure 1 Energy-optimized structures of 4d(i), syn aldol 8 and anti
aldol 811
R2
R2
S
S
R2
R1
R1
1
N
3
N
4
3
N
4
1
N
S
2
2
LHMDS, THF, –78 °C
R1
H
H
+
6
N
N
6
H
O
O
O
5
5
H
H
F
O
HO
7
7
HO
F
F
anti
syn
Scheme 2 Aldol reactions of 3-aryl-1-alkyl dihydrothiouracil with 4-fluorobenzaldehyde
Synlett 2011, No. 20, 2997–3001 © Thieme Stuttgart · New York

LETTER
Aldol Reactions of 3-Aryl-1-alkyl Dihydrothiouracils
2999
R2
R1
R2
R2
R1
R2
S
H
S
H
R2
S
H
S
H
R1
R1
S
LHMDS,
THF, –78 °C
LHMDS,
N
N
H
R1
N
N
H
THF, –78 °C
N
N
H
N
N
H
N
N
O
+
O
O
H
O
O
O
R3
R4
R3
O
R4
R3
H
HO
O
HO
HO
HO
R4
H
anti
R3
syn
anti
R2
LHMDS
THF, –78 °C
syn
R1
Et
R2
R4
Product
Yield (%), anti:syn
R1
Et
Product
Cl
Cl
Cl
Cl
Br
H
Cl
Cl
Cl
Cl
F
H
80, 71:29
84, 56:44
78, 57:43
82, 72:28
86, 71:29
80, 70:30
82, 70:30
78, 72:28
84, 70:30
72, 71:29
5
Yield (%), anti:syn
n-Pr
6
F
F
F
F
F
H
H
H
H
H
H
H
H
15
16
Cl
Cl
80, 71:29
80, 86:14
n-Bu
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
7
i-Pr
8
9
R2
10
11
12
13
14
S
H
Br
Me
H
R1
N
O
N
OMe OMe
H
HO
anti
R1
Product
R2
Yield (%), anti:syn
Et
i-Pr
Cl
Cl
76, anti only
80, anti only
17
18
Scheme 3 Steric effects of electrophiles on aldol reactions with dihydrothiouracils
The 1H NMR spectra of the acetate derivatives displayed 4a(i) with 2-naphthaldehyde towards the anti aldol 15 was
vicinal coupling constants of J = 5.12 and 6.92 Hz, respec- inferior; whereas the reaction with 9-anthraldehyde af-
tively, for the syn and anti diastereomers (Figure 2). Se- forded the anti aldol 17 only. This observation augments
lectivity towards the anti aldol was highly impressive with the fact that the combination of steric effects imparted by
polyaromatic aldehydes. 2-Naphthaldehyde demonstrated the substituent at N1 and the bulky electrophile controls
diastereoselectivity (86:14) in favor of the anti aldol 16, the stereochemical outcome. Reaction of 4d(i) with a ster-
whereas 9-anthraldehyde gave the anti aldol 18 exclusive- ically bulky aliphatic aldehyde (e.g., tert-butyraldehyde)
ly. With an ethyl group at N1, the aldol reactions of 4a(i) afforded a mixture of syn and anti diastereomers, which
with polyaromatic aldehydes gave interesting results. In were inseparable either as the aldol adduct or as its acetate
comparison with 4d(i), the selectivity for the reaction of derivative.
Figure 2 1H NMR spectra of syn-8¢ and anti-8¢
Synlett 2011, No. 20, 2997–3001 © Thieme Stuttgart · New York

3000
V. Kumar et al.
LETTER
To address the mechanistic issue of kinetic versus thermo- formed, thereby validating the stereochemical assump-
dynamic pathways, the pure anti and syn aldols 8, ob- tions drawn from the transition-state models.
tained by hydrolysis of the corresponding acetate
In conclusion, the stereochemical outcome of the aldol
derivatives, were subjected to retro-aldol reactions under
reactions of 3-aryl-1-alkyl dihydrothiouracils signifies an
basic conditions (LHMDS). The anti and syn diastereo-
enhancement in diastereoselectivity arising from moder-
ate to high steric interactions between the electrophiles
mers remained intact, with no traces of the other diastere-
omer even after several hours of reaction. Retro-
and a geometrically constrained heterocyclic enolate,
aldolization under acidic conditions (HCl) also gave sim-
while the electronic effects are regulated.
ilar results. These observations demonstrate that the reac-
tions proceed by a kinetic mechanism, and not through a
thermodynamic pathway.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Based on these results, transition-state models are pro-
posed for the reaction, taking into consideration the geom-
etry of the substrate and the conformation adopted.
Structure optimization and energy minimization11 were
performed for 4d(i), and the optimized structure is illus-
trated in Figure 1. In transition state TS-1, leading to the
formation of the anti aldol, the hydrogen atoms at C5 and
C7 share a trans relationship, whereas they have a cis dis-
position in transition state TS-2 (Figure 3). As demon-
strated by the transition-state models, when RY is
hydrogen, there is almost equal probability of forming syn
and anti aldols, since a stereofacial discrimination is not
possible with the steric and electronic factors remaining
equivalent for TS-1 and TS-2. This fact holds experimen-
tally true for unbranched aliphatic substituents at N1, af-
fording poor diastereoselectivity with ethyl, n-propyl, and
n-butyl groups (Scheme 3, products 5–7). However, with
the isopropyl group as the substituent at N1, the steric ef-
fect imparted by the electrophile favors TS-1 over TS-2,
leading to the formation of the anti aldol. This can be bet-
ter understood from the perspective of the 1,2-interaction
between the aldehyde substituent and the dihydrothiou-
racil ring. The 1,2-interaction is prominent in the six-
membered cyclic transition state TS-2 where the substitu-
ents at C5 and C7 are disposed in an equatorial–axial man-
ner, while this relation becomes diequatorial in TS-1, with
a resultant decrease in the torsional strain as the dihedral
angle shifts from gauche to anti. These attributes, arising
from steric interactions of the electrophile and the substit-
uent at N1, dictate the stereochemistry of the aldol adduct
Acknowledgment
We thank the Department of Science and Technology, Government
of India for the research funding and the University Grants Com-
mission for a research fellowship to V.K. We are also grateful to the
Centre for Pharmacoinformatics, NIPER, S. A. S. Nagar for use of
the computational facilities.
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Synlett 2011, No. 20, 2997–3001 © Thieme Stuttgart · New York

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independent calculations were perfectly in agreement with
the structure of the molecule, as confirmed by single crystal
X-ray diffraction analysis, see reference 9b. (b) The present
studies involve another molecule of the same template, and
the structure was optimized by ab initio calculation using
Gaussian B3LYP.
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