A facile synthesis and chemoselective reactions of dihydrothiouracils

Article abstract of DOI:10.1055/S-0032-1317133

A highly efficient procedure was devised for the synthesis of 3-(3-arylthioureido)propanoic/butanoic acid and its cyclization to (3-ary1/3-ary1-6-methyl)-2-thioxotetrahydropyrimidin-4(1H)-one derivatives. Carbonyl diimidazole proved to be a very effective coupling reagent for the cyclization. Studies carried out to examine the ambident nature of the thioamide moiety towards substitution reactions demonstrated the preference for alkylation at sulfur, and acylation and 1,4-addition at nitrogen. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0032-1317133

LETTER
▌2357
lAetteFr acile Synthesis and Chemoselective Reactions of Dihydrothiouracils
Synthesis and Reactions of Dihydrothiouracils
Varun Kumar, Gopal L. Khatik, Anang Pal, Mohan R. Praneeth, Sanjay Bhattarai, Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
Fax +91(172)2214692; E-mail: vn74nr@yahoo.com
Received: 06.06.2012; Accepted: 24.07.2012
The reported methods for the formation of 3-(3-arylthiou-
Abstract: A highly efficient procedure was devised for the synthe-
reido)propanoic acid and its subsequent cyclization using
sis of 3-(3-arylthioureido)propanoic/butanoic acid and its cycliza-
POCl3 or acetic/propanoic anhydride8–12 affords only low
yields of 3-aryl-2-thioxotetrahydropyrimidin-4(1H)-ones,
tion to (3-aryl/3-aryl-6-methyl)-2-thioxotetrahydropyrimidin-
4(1H)-one derivatives. Carbonyl diimidazole proved to be a very ef-
fective coupling reagent for the cyclization. Studies carried out to while side-products were obtained in considerable
examine the ambident nature of the thioamide moiety towards sub-
stitution reactions demonstrated the preference for alkylation at sul-
fur, and acylation and 1,4-addition at nitrogen.
amounts. With our interest in developing new synthetic
methodologies for heterocyclic compounds,13 a highly ef-
ficient and economic strategy was developed for the syn-
thesis of 2-thioxotetrahydropyrimidin-4(1H)-ones, at
ambient temperature. The need for purification by chro-
Key words: uracils, amino esters, carbonyl diimidazole, thioamide,
ambident nucleophile
matography was also eliminated, preventing solvent wast-
age as well. The course of the reaction involves the one-
pot synthesis of 3-(3-arylthioureido)propanoic/butanoic
acids and their subsequent cyclization using carbonyl di-
imidazole (CDI) to afford the products in excellent yields.
The pyrimidinone moiety is an important constituent of
the genetic materials RNA and DNA, in the form of nitro-
gen bases uracil, thymine and cytosine.1 Many drugs, for
example 5-fluorouracil, uramustine, floxuridine, lamivu-
dine, telbivudine, sorivudin, trifluridine, alogliptin and
aminometradine, contain pyrimidinones as the pharmaco-
phore.2,3 Associated with diverse biological properties,
various structural modifications have been carried out on
the pyrimidinone moiety in the search for more potent de-
rivatives. Their analogues, dihydrothiouracils and their
homologues, the thiohydantoins, are well known for their
biological properties, pharmaceutical applications and
agricultural importance.4–6 Among the dihydrothiouracils,
the 3-aryl derivatives were extensively studied for their
usefulness in treating atherosclerotic conditions such as
dyslipoproteinemias and coronary heart disease.5 These
scaffolds are also known to possess anticonvulsant, anti-
cancer, antibacterial, insecticidal and herbicidal proper-
ties.5,6 The applications of thioxotetrahyropyrimidin-
4(1H)-ones is not only limited to the biological field but
have also been extended to chemical reactions as organo-
catalysts.7 Thus, the extensive biological properties and
applications have revealed a need for more efficient syn-
theses of these molecules and their derivatives.
The one-pot strategy for the synthesis of dihydro-
thiouracils by electrophilic activation using lithium
perchlorate13a,b works well for the cyclocondensation of
aryl isothiocyanates with activated β-amino esters such as
ethyl 3-(alkylamino)propanoate, but fails in the case of
ethyl 3-aminopropanoate, affording instead ethyl 3-(3-
arythioureido)propanoate as the sole product. The cycli-
zation of the intermediate ethyl 3-[3-(4-chlorophe-
nyl)thioureido]propanoate 3′aa was tried (Scheme 1) with
different bases in order to enhance the nucleophilicity of
the nitrogen N3 attached to the phenyl group, but the re-
sults were disappointing. Attempts to cyclize ethyl 3-[3-
(4-chlorophenyl)thioureido]propanoate under acidic con-
ditions using 6 M HCl in MeOH and acetic acid at 100 °C
afforded only the transesterification product. However,
the same reaction conditions led to the formation of the
cyclized product for cases in which an N-alkylthioureido
substituent was present instead of an N-aryl substituent.8
This prompted us to reinvestigate the reaction by cycliza-
tion of the 3-(3-arylthioureido)propanoic acid instead of
6 M HCl, MeOH
Cl
Cl
O
Cl
AcOH, 100 °C
S
S
EtO
H
X
N
N
N
H
NH
O
NH2
O
NCS
base
EtO
1a
2a
4aa
3'aa
Scheme 1 Formation of 3-(4-chlorophenyl)-2-thioxotetrahydro pyrimidin-4(1H)-one
SYNLETT 2012, 23, 2357–2362
Advanced online publication: 31.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317133; Art ID: ST-2012-D0601-L
© Georg Thieme Verlag Stuttgart · New York

2358
V. Kumar et al.
LETTER
R2
R1
R1
R2
O
NH2
R3
S
R3
O
1) 10 M KOH, MeOH
2) 1 M HCl
+
EtO
N
N
OH
H
H
NCS
3aa–3fa R3 = H
3ab–3fb R3 = Me
2a R3 = H
2b R3 = Me
1a–f
Scheme 2 One-pot synthesis of 3-(3-arylthioureido)propanoic/butanoic acids
the ester. Reported methods for the synthesis of 3-(3-aryl- corresponding 2-thioxotetrahydropyrimidin-4(1H)-one
thioureido)propanoic acid involves the direct condensa- was explored under different reaction conditions. It was
tion of aryl isothiocyanate with 3-aminopropanoic acid in anticipated that activation of the carboxylic acid by incor-
aqueous NaOH for 24 h at 20 °C, but suffer from major porating a good leaving group on the acyl carbon would
disadvantages such as poor yield, short reaction time, and facilitate attack by the nitrogen N3 on the carbonyl carbon
difficulty in purification.5d Therefore, we attempted an al- to afford the cyclized product.
ternate procedure for the synthesis of thioureido acid by
To our dismay, neither the acid chloride nor the anhydride
condensation of aryl isothiocyanate with ethyl 3-amino-
afforded quantitative yields of the product. Carbodiimides
propanoate and subsequent hydrolysis. Interestingly, a so-
are known to afford different heterocycles by carbonyl in-
lution of ethyl 3-aminopropionate and 4-chlorophenyl
sertion and acyl activation reactions.14 We decided, there-
isothiocyanate in N,N-dimethylformamide (DMF), when
fore, to employ coupling reagents, and N,N-
reacted with aqueous NaOH, underwent condensation fol-
dicyclohexylcarbodiimide (DCC) afforded the desired
lowed by hydrolysis in eight hours, affording a good yield
product in moderate yield. However, removal of the dicy-
clohexyl urea formed during the course of reaction from
the product was difficult. Alternatively, the coupling re-
of 3-[3-(4-chlorophenyl)thioureido]propanoic acid 3aa in
a one-pot process. The reaction was then optimized by us-
ing different solvents and varying concentrations of the
agent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
base, and the best result was obtained in two hours by
(EDC) did not show any significant improvement in yield
using 10 M KOH in methanol. The reaction conditions
from that obtained with DCC, in addition to the fact that
employing stoichiometric quantities of the reagent was
were then applied to different β-amino esters and aryl iso-
thiocyanates (Scheme 2), which afforded the potassium
also not economical. Quite surprisingly, when the cycliza-
salts of the 3-(3-arylthioureido)propanoic/butanoic acids.
tion was attempted using carbonyl diimidazole (CDI), the
Acidification of the carboxylate salt by 1 M HCl led to
product was afforded in a few minutes with excellent
precipitation of the free acid (Table 1), which was subject-
yields15 (Scheme 3). Evaporation of the solvent under re-
ed to cyclization without further purification. The cycliza-
duced pressure followed by addition of water led to pre-
tion of 3-(3-arylthioureido)propanoic/butanoic acid to the
cipitation of the desired product. The pure product was
isolated simply by filtration and no further purification
was required. Based on the success of this reaction, the
conditions were then applied to various thioureido acids
and excellent yields of products were obtained in all cases
(Table 2).
Table 1 Syntheses of 3-(3-Arylthioureido)propanoic/butanoic Acids
Entry R1
R2
R3
Time (h) Yield (%) Product
1
2
Cl
H
H
1.6
2.0
1.8
2.2
2.4
2.5
1.5
1.8
2.1
2.3
2.2
2.5
85
88
87
91
93
84
90
84
84
87
91
83
3aa
3ba
3ca
3da
3ea
3fa
Our interests then focused on the substitution reactions of
3-aryl-2-thioxtetrahydropyrimidin-4(1H)-ones. It was ex-
pected that these compounds can tautomerize to the corre-
F
Cl
H
3
CN
Cl
Cl
H
sponding
3-aryl-2-mercapto-5,6-dihydropyrimidin-
4
CF3
CF3
CF3
H
H
4(3H)-ones (Scheme 4). An energy comparison of the tau-
tomers 4aa and 4′aa by ab initio calculations, performed
using Gaussian B3 LYP with basis set 6-31G* (d,p),
showed that the thioxo form 4aa was more stable than the
corresponding imine form 4′aa.16 This was substantiated
by 13C NMR spectra, which showed a peak at δ = 180.1
ppm corresponding to the thione carbon.
5
CN
NO2
Cl
H
6
H
7
Me
Me
Me
Me
Me
Me
3ab
3bb
3cb
3db
3eb
3fb
8
F
Cl
The molecular electrostatic potential map for 4aa showed
a high electron density on the sulfur atom.17 Therefore, it
is expected that the substitution reactions of these deriva-
tives should proceed through sulfur instead of nitrogen.
Consequently, a reaction of 3-(4-chlorophenyl)-2-thiox-
tetrahydropyrimidin-4(1H)-one, when tried with benzyl
9
CN
Cl
Cl
10
11
12
CF3
CF3
CF3
CN
NO2
Synlett 2012, 23, 2357–2362
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis and Reactions of Dihydrothiouracils
2359
R2
O
R2
R1
S
R1
N
N
S
R3
O
N
H
N
N
N
N
N
OH
O
R3
MeCN, r.t.
H
H
4aa–4fa R3 = H
4ab–4fb R3 = Me
3aa–3fa R3 = H
3ab–3fb R3 = Me
Scheme 3 Cyclization of 3-(3-arylthioureido)propanoic/butanoic acids using CDI
Cl
Cl
Table 2 Syntheses of 3-Aryl-2-thioxotetrahydropyrimidin-4(1H)-
ones
S
SH
N
NH
N
N
Entry
R1
R2
R3
Time
(min)
Yield Product
(%)
O
O
4aa
4'aa
1
2
Cl
H
H
10
15
15
20
20
20
15
10
15
20
20
20
90
84
89
82
84
85
93
86
84
81
82
86
4aa
4ba
4ca
4da
4ea
4fa
Scheme 4 Tautomeric forms of 3-(4-chlorophenyl) dihydrothiouracil
F
Cl
H
3
CN
Cl
Cl
H
bromide in CH2Cl2 using triethylamine at room tempera-
ture, afforded the S-benzyl derivative (Scheme 5).
4
CF3
CF3
CF3
H
H
5
CN
NO2
Cl
H
For optimization, the reaction was conducted with a range
of bases, solvents, and electrophiles, as shown in Table 3.
The best result was obtained with potassium carbonate as
base and DMF as solvent18 (Table 3, entries 1–10). The re-
action proceeded well with activated and sterically less
demanding electrophiles, whereas the bulky tert-butyl
bromide did not afford the product. Hence, it is evident
that the ambident nucleophile reacts with alkyl halides by
an SN2 reaction mechanism through the sulfur atom. In all
these cases, a characteristic signal near δ = 150 ppm was
observed in the 13C NMR spectra, indicative of the C=N
bond. Interestingly, when the reaction of 3-(4-chlorophe-
nyl)-2-thioxotetrahydropyrimidin-4(1H)-one was con-
ducted with acyl chloride the reaction occurred on the
nitrogen atom and not on the sulfur. Reactions were car-
6
H
7
CH3
CH3
CH3
CH3
CH3
CH3
4ab
4bb
4cb
4db
4eb
4fb
8
F
Cl
9
CN
Cl
Cl
10
11
12
CF3
CF3
CF
CN
NO2
ried out with a range of acid chlorides under the optimized
conditions with NaH as base and THF as solvent19 (Table
3, entries 12–14). The 13C NMR spectra revealed a peak at
Cl
R
N
S
R
X
N
K2CO3, DMF
O
5a–f
Cl
S
O
Cl
H
S
O
N
N
R
Cl
N
N
R
NaH, THF
O
4aa
O
6a–c
O
OMe
Cl
S
O
R
N
N
OMe
K2CO3, DMF
R
O
7a–b
Scheme 5 Chemoselective reactions of 3-(4-chlorophenyl)-2-thioxotetrahydropyrimidin-4(1H)-one
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2357–2362

2360
V. Kumar et al.
LETTER
on the nature of electrophile. The formation of the prod-
ucts can be explained on the basis of the HSAB principle.
The alkyl halides are soft in nature and hence attack by the
softer atom of the ambident nucleophile led to the S-alkyl-
ated product. The S-alkylations are also preferred on ste-
ric grounds and because of the higher partial charge and
better polarizability of the 3p orbital. On the other hand,
the acid chlorides, being hard in nature, undergo acylation
reactions on the nitrogen. With α,β-unsaturated esters, re-
actions of 2-thioxotetrahydropyrimidin-4(1H)-one pro-
ceed at the harder nitrogen atom. The conjugation of the
C=C bond with the ester group increases the electrophilic
character at the β-carbon of the Michael acceptor, leading
to a partial positive charge and hence a much harder site
than the alkyl halides. Thus, the reaction can be expected
to occur on the harder atom of the ambident nucleophile
through strong coulombic interactions, affording the N-
substituted product.21
Table 3 Reactions of 3-(4-Chlorophenyl)-2-thioxotetrahydropyrim-
idin-4(1H)-one with Electrophiles
Entry Base
Solvent Electrophile
Time Yield Product
(h) (%)
Br
1
Et3N
CH2Cl2
2.0 68
5a
O
O
O
Br
Br
Br
2
3
4
5
6
Et3N
NaH
NaH
CH2Cl2
THF
2.0 65
2.0 70
1.8 72
1.0 88
1.5 85
5b
5a
5b
5a
5b
Br
THF
To conclude, an economic and efficient method has been
developed for the synthesis of 3-aryl-2-thioxtetrahydro-
pyrimidin-4(1H)-ones. The chemoselectivity of the thio-
amide moiety was investigated as an ambident
nucleophile in S-alkylation, and N-acylation and 1,4-ad-
dition.
Br
K2CO3 DMF
K2CO3 DMF
Acknowledgment
Me
Me
Br
7
8
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
6.0 82
8.0 76
1.5 88
2.0 80
5c
5d
5e
5f
Me
We thank the Department of Science and Technology, Government
of India for the research funding and the University Grants Com-
mission for a fellowship to V.K.
Br
Br
9
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
O
O
r
t
iornat
10
Br
EtO
Me
References and Notes
11
12
13
Et3N
NaH
NaH
CH2Cl2
2.0
–
–
Cl
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O
THF
THF
2.0 70
6a
6b
Me
Me
Cl
O
12.0 78
Cl
Cl
O
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14
15
16
NaH
THF
12.0 75
5.0 70
5.0 55
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OMe
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Me
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Synlett 2012, 23, 2357–2362
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arora, V.; Wongvipat, J.; Smith-Jones, P. M.; Yoo, D.;
Synthesis and Reactions of Dihydrothiouracils
2361
MS (APCI): m/z [M + H]+ calcd for C10H9ClN2OS: 241.02;
found: 241.13. 1H NMR (400 MHz, DMSO-d6): δ = 2.81–
2.85 (m, 2 H), 3.47–3.51 (m, 2 H), 7.16 (d, J = 8.4 Hz, 2 H),
7.43 (d, J = 8.4 Hz, 2 H), 10.01 (br s, 1 H). 13C NMR (100
MHz, DMSO-d6): δ = 30.96, 37.89, 128.80, 132.05, 132.63,
138.71, 167.76, 181.48.
3-(4-Chlorophenyl)-6-methyl-2-thioxotetrahydropyrim-
idin-4(1H)-one (4ab): Yield: 93%; white solid; mp 249–
251 °C. MS (APCI): m/z [M + H]+ calcd for C11H11ClN2OS:
255.03; found: 255.13. 1H NMR (400 MHz, DMSO-d6): δ =
1.26 (d, J = 6.4 Hz, 3 H), 2.66–2.73 (m, 1 H), 2.84–2.89 (m,
1 H), 3.86–3.87 (m, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.44 (d,
J = 8.4 Hz, 2 H), 10.06 (br s, 1 H). 13C NMR (100 MHz,
DMSO-d6): δ = 19.75, 38.10, 45.41, 128.85, 132.03, 132.68,
138.63, 167.57, 180.87.
Kwon, A.; Wasielewska, T.; Welsbie, D.; Chen, C. D.;
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(18) General procedure for alkylation reaction: To a solution
of 3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one (1.0
mmol) in DMF (5 mL) was added K2CO3 (1.6 mmol)
followed by alkyl halide (1.1 mmol). The reaction mixture
was stirred at room temperature and monitored by TLC.
After completion of the reaction, the solution was
concentrated under reduced pressure and the crude product
was precipitated from water. The product was purified by
column chromatography on silica gel (60–120 mesh;
hexane–EtOAc, 85:15).
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2-(Benzylthio)-3-(4-chlorophenyl)-5,6-
dihydropyrimidin-4(3H)-one (5a): Yield: 88%; white
solid; mp 180–182 °C. MS (APCI): m/z [M + H]+ calcd for
C17H15ClN2OS: 331.07; found: 331.12. 1H NMR (400 MHz,
DMSO-d6): δ = 2.69 (t, J = 7.3 Hz, 2 H), 3.86 (t, J = 7.3 Hz,
2 H), 4.12 (s, 2 H), 7.11–7.15 (m, 2 H), 7.20–7.27 (m, 5 H),
7.35–7.40 (m, 2 H). 13C NMR (100 MHz, DMSO-d6): δ =
30.96, 36.83, 44.56, 124.47, 128.54, 129.20, 129.43, 131.02,
133.93, 135.43, 136.04, 154.77, 168.87.
(13) (a) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966.
(b) Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A.
Org. Biomol. Chem. 2010, 8, 4960. (c) Khatik, G. L.; Pal, A.;
Mobin, S. M.; Nair, V. A. Tetrahedron Lett. 2010, 51, 3654.
(d) Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.;
Venugopalan, P.; Nair, V. A. Eur. J. Med. Chem. 2011, 46,
3291. (e) Chouhan, M.; Senwar, K. R.; Sharma, R.; Grover,
V.; Nair, V. A. Green Chem. 2011, 13, 2553. (f) Khatik, G.
L.; Khurana, R.; Kumar, V.; Nair, V. A. Synthesis 2011,
3123. (g) Sharma, R.; Chouhan, M.; Nair, V. A. Tetrahedron
Lett. 2010, 51, 2039. (h) Kumar, V.; Khatik, G. L.; Nair, V.
A. Synlett 2011, 2997. (i) Kumar, V.; Pal, A.; Khatik, G. L.;
Nair, V. A. Tetrahedron: Asymmetry 2012, 23, 434.
(j) Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.; Nair, V. A.
Bioorg. Med. Chem. Lett. 2012, 22, 1912. (k) Khatik, G. L.;
Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442.
(19) General procedure for acylation reaction: A solution of
NaH (1.2 mmol) in THF (10 mL) was cooled to 0 °C and 3-
aryl-2-thioxotetrahydropyrimidin-4(1H)-one (1.0 mmol)
was added. The reaction mixture was stirred for 30 min, then
acyl chloride (1.1 mmol) was added. The reaction was
monitored by TLC and, after completion, quenched with
water and extracted into ethyl acetate. The organic layer was
dried and concentrated to provide a gummy compound,
which, upon purification by column chromatography on
silica gel (60–120 mesh; hexane–EtOAc, 85:15), afforded
the pure product.
(14) (a) Olimpieri, F.; Fustero, S.; Volonterio, A.; Zanda, M.
Synthesis 2010, 651. (b) Sundaram, G. S. M.; Venkatesh, C.;
Ila, H.; Junjappa, H. Synlett 2007, 251. (c) Kolasa, T.;
Miller, M. J. Tetrahedron 1989, 45, 3071.
(15) General procedure for the preparation of 3-aryl-2-
thioxotetrahydropyrimidin-4(1H)-ones: Aryl
1-Acetyl-3-(4-chlorophenyl)-2-
thioxotetrahydropyrimidin-4(1H)-one (6a): Yield: 70%;
light-yellow solid; mp 192–194 °C; MS (APCI): m/z [M +
H]+ calcd for C12H11ClN2O2S: 283.03; found: 282.88. 1H
NMR (400 MHz, DMSO-d6): δ = 2.70 (s, 3 H), 2.99 (t,
J = 6.6 Hz, 2 H), 4.23 (t, J = 6.6 Hz, 2 H), 7.07 (d, J =
8.3 Hz, 2 H), 7.45 (d, J = 8.5 Hz, 2 H). 13C NMR (100 MHz,
DMSO-d6): δ = 27.60, 33.19, 40.82, 129.69, 130.38, 134.78,
137.08, 166.90, 174.03, 182.58.
isothiocyanate (3.0 mmol) was dissolved in methanol (20
mL) and β-amino ester (3.0 mmol) was added, followed by
10 M KOH (2 mL). The reaction mixture was stirred at 20 °C
for 2 h. After completion of the reaction, the solution was
concentrated under reduced pressure and then neutralized by
1 M HCl until precipitation occurred. The product obtained
was filtered and dried to give the desired acid. The acid was
dissolved in acetonitrile (15 mL) and CDI (4.0 mmol) was
added. The reaction mixture was stirred for 20 min (progress
was monitored by TLC). Upon completion, the reaction
mixture was concentrated and the product was precipitated
in water, filtered, dried and recrystallized in methanol.
3-(4-Chlorophenyl)-2-thioxotetrahydropyrimidin-
4(1H)-one (4aa): Yield: 90%; white solid; mp 201–203 °C;
(20) General procedure for 1,4-addition reaction: A procedure
similar to the preparation of 3-aryl-2-(alkylthio)-5,6-
dihydropyrimidin-4(3H)-ones was adopted for the aza-
Michael reactions.
Methyl 3-[3-(4-chlorophenyl)-4-oxo-2-
thioxotetrahydropyrimidin-1(2H)-yl]propanoate (7a):
Yield: 70%; light-brown liquid. MS (APCI): m/z [M + H]+
calcd for C14H15ClN2O3S: 327.06; found: 327.03. 1H NMR
(400 MHz, DMSO-d6): δ = 2.82–2.84 (m, 4 H), 3.64 (s, 3 H),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2357–2362

2362
V. Kumar et al.
LETTER
3.84 (t, J = 6.5 Hz, 2 H), 4.10 (t, J = 6.5 Hz, 2 H), 6.96–6.99
(m, 2 H), 7.30–7.33 (m, 2 H). 13C NMR (100 MHz, DMSO-
d6): δ = 31.58, 31.90, 46.88, 51.80, 52.04, 129.26, 130.74,
134.23, 137.77, 166.60, 172.53, 181.04.
2001, 6, 557. (c) Fava, A.; Iliceto, A.; Bresadola, S. J. Am.
Chem. Soc. 1965, 87, 1045. (d) Robinson, R. S.; Dovey, M.
C.; Gravestock, D. Eur. J. Org. Chem. 2005, 505. (e) Fang,
G. F.; Kim, G.; Danishefsky, G. Tetrahedron Lett. 1989, 30,
3625.
(21) (a) Fathalla, W.; Cajan, M.; Pazdera, P. Molecules 2000, 5,
1210. (b) Fathalla, W.; Cajan, M.; Pazdera, P. Molecules
Synlett 2012, 23, 2357–2362
© Georg Thieme Verlag Stuttgart · New York