A one-pot chemoselective S-alkylation and acetylation of thiohydantoins using the alkyl orthoformate-ZnCl2-Ac2O reagent system

Article abstract of DOI:10.1016/j.tetlet.2008.07.020

The chemoselective S-alkylation of 2-thiohydantoins is reported. The methodology involves the use of alkyl orthoformates (trimethyl and triethyl) as alkylating agents, which in the presence of Ac₂O and ZnCl₂ chemoselectively alkylate the thio group whilst other nucleophilic groups present in the thiohydantoins are acetylated simultaneously in moderate to high yields. A plausible mechanism for this reaction is delineated.

Full text of DOI:10.1016/j.tetlet.2008.07.020

Tetrahedron Letters 49 (2008) 5475–5479
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A one-pot chemoselective S-alkylation and acetylation of thiohydantoins
using the alkyl orthoformate–ZnCl2–Ac2O reagent system
*
Ravi Kumar, Prem M. S. Chauhan
Medicinal and Process Chemistry Division, Central Drug Research Institute , Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemoselective S-alkylation of 2-thiohydantoins is reported. The methodology involves the use of
alkyl orthoformates (trimethyl and triethyl) as alkylating agents, which in the presence of Ac2O and ZnCl2
chemoselectively alkylate the thio group whilst other nucleophilic groups present in the thiohydantoins
are acetylated simultaneously in moderate to high yields. A plausible mechanism for this reaction is
delineated.
Received 30 April 2008
Revised 27 June 2008
Accepted 3 July 2008
Available online 6 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
S-Alkylation
Acetylation
2-Thiohydantoins
Orthoformate
ZnCl2
Thiohydantoins and their derivatives represent an important
class of biologically active molecules having broad medicinal (anti-
cancer,1 anticonvulsant,2 antidiabetic,3 antimicrobial,4 antiarry-
thmic,5 hypolipidemic6 and hypotensive7) and agrochemical8
(herbicidal and fungicidal) applications. Furthermore, many thio-
hydantoins are responsible for inhibition of fatty acid hydrolases,9
glycogen phosphorylases,10 amylases11 and serine proteases.12
Thiohydantoins are useful synthons in natural product synthe-
sis. Complex natural products such as the tetracyclic core of stylo-
guanidine (1) and hymenialdisine (2), and bioactive heterocycles
possesing a glycociamidine ring are commonly synthesized from
their corresponding thiohydantoins. Conversion of 2-thiohydanto-
ins to substituted glycociamidines is usually carried out in two
steps; first thioalkyation of the thiohydantoin and then nucleo-
philic substitution of the thioalkyl group with a suitable nucleo-
phile.13–18 In general, thioalkylation is accomplished using alkyl
halides which are toxic, dangerous, carcinogenic and nonselec-
tive.19,20 Hence, there remains a need for an efficient protocol for
chemoselective S-alkylation of 2-thiohydantoins using surrogate
alkyl halide reagents (Fig. 1).
Orthoesters are commonly used in the preparation of ketals and
acetals.21–23 However, in recent years, increased interest has
H2N
N
O
HN
O
CbzN
O
NH
N
N
Br
HN
NH
N
NHBn
H
O
NHBn
1
2
Tetracyclic core of the complex hexacyclic
bisguanidine alkaloid styloguanidine.13
Hymenialdisine14b
Figure 1. Structures of the tetracyclic core of styloguanidine (1) and hymenialdisine (2).
* Corresponding author. Tel.: +91 9415106859; fax: +91 522 2223405.
E-mail address: prem_chauhan_2000@yahoo.com (P. M. S. Chauhan).
CDRI Communication No. 7501.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.020

5476
R. Kumar, P. M. S. Chauhan / Tetrahedron Letters 49 (2008) 5475–5479
Table 1
Chemoselective S-alkylation and acetylation of 2-thiohydantoins
Entry
Substrate
Orthoformate
Product
Yield (%)
Time (h)
O
O
Ac
H
1
78a
6
N
H
O
N
S
S
4a
N
NH
O
O
5
5a
Br
Ac
Br
O
O
O
H
N
2
72b
8
H
N
S
S
4a
NH
N
O
O
6a
6
OAc
OH
O
O
O
Ac
3
69b
7
H
H
N
N
S
S
4a
N
NH
O
O
O
7
7a
O
O
O
O
Ac
4
71a
8
H
4a
H
N
N
S
S
N
NH
O
O
8
8a
O
O2N
O2N
O
O
Ac
H
5
6
7
N
88a
65a
82b
4
H
N
S
S
NH
N
4a
O
O
9
9a
Cl
Cl
O
O
O
Ac
H
7
H
N
N
S
S
4a
N
NH
O
O
10
10a
O
Ac
O
O
H
N
N
18
H
S
S
NH
N
4a
O
O
11
11a

R. Kumar, P. M. S. Chauhan / Tetrahedron Letters 49 (2008) 5475–5479
5477
Table 1 (continued)
Entry
Substrate
Orthoformate
Product
Yield (%)
Time (h)
O
O
Ac
H
H
O
8
81a
6
N
N
S
S
NH
N
O
4b
O
5b
5
OH
OAc
O
O
O
Ac
72b
7
H
9
H
N
N
S
S
4b
NH
N
O
O
7b
7
O
O
O
O2N
O2N
Ac
H
10
90a
4
H
N
N
S
S
NH
N
4b
O
O
9
9b
Br
Br
Ac
O
O
O
H
N
11
74b
8
H
N
S
S
NH
N
4b
O
O
6b
6
O
O
O
Ac
H
H
12
83b
18
N
N
S
S
N
NH
11
O
O
4b
11b
O
O
O
Ac
Ac
13
82b
15
H
N
N
S
S
NH
12
N
4a
O
O
11a
Ac
H
O
N
O
O
N
S
S
14
65a
18
H
NH
N
O
O
4a
3
(continued on next page)
3a

5478
R. Kumar, P. M. S. Chauhan / Tetrahedron Letters 49 (2008) 5475–5479
Table 1 (continued)
Entry
Substrate
Orthoformate
Product
Yield (%)
Time (h)
Ac
N
Ac
O
O
N
S
S
67a
18
S
15
H
O
NH
O
N
O
4a
3a
13
H
N
Ac
N
O
O
O
16
40b
16
S
H
NH
O
N
O
4a
14a
14
a
Purified by filtration.
Purified by column chromatography.
b
focused on alkyl orthoformates as alternative reagents to alkyl
halides for safer and selective alkylation protocols. In particular,
Selva’s group recently developed a one-pot procedure for highly
selective mono-C-methylation of arylacetonitrile using trimethyl
orthoformate (TMOF) as the methylating agent.24 Earlier, the same
group reported that O-, S- and C-methylation of phenol, thiophenol
and phenylacetonitrile, respectively, could be carried out using
TMOF as the methylating agent.25 Several TMOF-mediated N-
methylations of aromatic amines and imidazole-like compounds
have also been cited in the literature.26–28
In our endeavour to synthesize some key nitrogen heterocycles,
it was observed that S-methylation and N-acetylation of 5-phe-
nylmethylene-2-thiohydantoin (5) occurred on treatment with tri-
methyl orthoformate in Ac2O and ZnCl2 in one-pot. Herein, we
report a one-pot chemoselective S-alkylation of 2-thiohydantoins
and simultaneous acetylation of nucleophilic centres in the same
molecule using alkyl orthoformates in Ac2O and ZnCl2. To the best
of our knowledge, there have been no reports on this type of
reaction.
Initial investigations were focused on chemoselective S-alkyl-
ation of 5-substituted-2-thiohydantoins using 5-phenylmethyl-
ene-2-thiohydantoin (5) as the model substrate. At 100 °C,
1 equiv of ZnCl2 was required for a 5:1 solution of trimethyl ortho-
formate (4a) and Ac2O to convert completely 5-phenylmethylene-
2-thiohydantoin (5) into its S-methyl N-acetyl derivative 5a.
It was found that in the absence of either Ac2O or ZnCl2 the
reaction failed to furnish the desired product. In order to explore
whether substituents on the phenyl ring affected the reactivity of
5-phenylmethylene-2-thiohydantoins (PMHs), diversely phenyl
substituted PMHs29 were reacted with TMOF in Ac2O and ZnCl2.
The results listed in Table 1 demonstrate that substituents on the
phenyl ring do not affect the reactivity of PMHs towards S-alkyl-
ation. 5-(2-Nitrobenzylidene)-2-thioxoimidazolidin-4-one (9)
reacted surprisingly rapidly with alkyl orthoformates to give the
highest yields of products (Scheme 1).
To investigate the chemoselectivity of the reagent system, we
carried out the reaction of 5-(4-hydroxybenzylidine)-2-thiooxo-
imidazolidin-4-one (7) with TMOF in Ac2O and ZnCl2 which
resulted in N-, O-acetylated, S-methylated product 7a. TLC analysis
of the reaction of 5-benzyl-2-thiohydantoin with reference
compound (12) provided an insight into the reaction mechanism
indicating that acetylation precedes alkylation. Based on the above
observation, we propose that ZnCl2 mediated acetylation is fol-
lowed by nucleophilic attack of the S-nucleophile of 1-acetylated
2-thiohydantoin at the alkoxy carbon (not the carboxylic carbon)
Ac
H
ZnCl2 Ac2O
R
N
N
S
S
R
H
N
H
N
3a
O
O
O
O
O
R
R
3
4
Scheme 1. General scheme for the chemoselective S-alkylation and acetylation of
2-thiohydantoins.
Cl2Zn
O
O
O
H
R
Ac
O
H
O
R
Ac
N
N
S
H
S
N
O
O
R
H
O
- CH3COOH
S
N
N
O
H
O
H
N
R
H
ZnCl2
O
12
11
R
5a
5b
R = -H
R = -CH3
R = - H, -CH3
Scheme 2. Proposed mechanism for the S-alkylation and acetylation of 2-thiohydantoins.

R. Kumar, P. M. S. Chauhan / Tetrahedron Letters 49 (2008) 5475–5479
5479
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of the orthoformate resulting in S-alkylation (Scheme 2). This was
supported by the fact that when triethyl orthoformate (TEOF) was
used instead of TMOF, S-ethylation took place along with N-acety-
lation (entries 8–12). 5-Benzyl (11) and 5-methyl-2-thiohydantoin
(14) also gave the expected products (11a) and (14a), respectively,
but were less reactive in comparison to their 5-methylene counter-
parts. Unsubstituted 2-thiohydantoin (3) yielded 1-acetyl-2-meth-
ylsulfanyl-4-imidazolidinone (3a) but the product of the reaction
of 2-thiohyantoin (3) with TEOF in Ac2O and ZnCl2 was too unsta-
ble to be purified by column chromatography. 1-Methyl-2-thio-
hydantoin gave a complex mixture of products, whilst 1-acetyl-
2-thiohydantoin (13) reacted smoothly to furnish 1-acetyl-2-
methylsulfanyl-4-imidazolidinone (3a) in moderate yield. PMHs
5–10 gave better yields in comparison to 5-alkyl-2-thiohydantoins
(11, 12 and 14). Another interesting observation was that the ac-
tive methylene group of 2-thiohydantoin (3) did not react with
orthoformates, however, similar cyclopentendiones are known to
react with orthoesters via their active methylene group.30
In conclusion, we have developed a highly chemoselective one-
pot S-alkylation (methylation, ethylation) and acylation protocol of
thiohydantoins.31 This new protocol should help to expedite the
overall synthetic process and reduce the labour involved in total
syntheses of natural products. This method could be used for deriv-
atization of natural products for medicinal chemistry purposes as it
chemoselectively alkylates the thio group whilst any other nucleo-
philic groups are acetylated. It may also be useful for the alkyaltion
of thiohydantoin molecules containing oxidation prone functional
groups, in which case oxidative nucleophilic substitution14a of
the thio group will not be possible.
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General experimental procedure: ZnCl2 (1.2 equiv, 1.2 mmol) was
added to a mixture of 2 ml of acetic anhydride and 10 ml of trialkyl
orthoformate at 100 °C. The resulting mixture was stirred for 5 min
and then the 2-thiohydantoin (1 mmol) was added. The reaction
was monitored by TLC analysis. After completion, the reaction
mixture was cooled to room temperature and 20 ml of water was
added. In most cases, a precipitate formed which was filtered
and dried. In some cases (entries 2, 3, 11–13 and 16) a precipitate
was not formed after addition of water. In these cases, the reaction
mixture was neutralized with saturated sodium bicarbonate solu-
tion and extracted with DCM (15 ml ꢀ 3). The combined organic
layers were dried over sodium sulfate and concentrated in vacuo.
The residue was purified by column chromatography using DCM
as the eluent.
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31. Representative analytical data for 1-acetyl-5-benzylidene-2-methylsufanyl-4-
imidazolidinone (5a): mp: 172–174 °C; Recrystallization solvent: Chloroform;
1H NMR (300 MHz, CDCl3): d = 8.18 (dd, 2H, J = 9.6 Hz, J0 = 2 Hz), 7.46-7.43 (m,
3H), 7.00 (s, 1H), 2.67 (s, 3H), 2.64 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 169.74, 167.87, 163.17, 137.22, 134.27, 132.53, 130.80, 129.75, 129.55,
Acknowledgements
129.10, 126.04, 25.11, 14.89 ppm. IR (KBr)
m
= 1747.6, 1712.0, 1706.5, 1634.4,
ESMS: m/z = 219
1597.4, 1495.9, 1371.0, 1291.5, 1215.7, 767.0 cmꢁ1
.
We acknowledge SAIF, CDRI for providing analytical data. R.K.
thanks the Council of Scientific and Industrial Research, India for
a Senior Research Fellowship and Sharad Porwal for his invaluable
support.
(M+1ꢁAc). Anal. Calcd for C13H12N2O2S (260.06): C, 59.98; H, 4.65; N, 10.76.
Found: C, 59.89; H, 4.60; N, 10.68.
Compound (7a): mp: 185–187 °C; 1H NMR (300 MHz, CDCl3): d = 8.20 (d, 2H,
J = 8.7 Hz), 7.18 (d, 2H, J = 9 Hz), 6.96 (s, 1H), 2.67 (s, 3H), 2.62 (s, 3H), 2.34 (s,
3H) ppm; 13C NMR (75 MHz, CDCl3) d = 169.38, 169.32, 167.34, 162.95, 151.92,
136.72, 133.30, 131.62, 124.28, 121.87, 24.68, 21.01, 14.47 ppm. IR (KBr)
m
= 1750.5, 1723.5, 1638.9, 1598.1, 1490.7, 1374.4, 1279.5, 1206.9, 1167.7,
References and notes
918.7 cmꢁ1. ESMS: m/z = 277 (M+1ꢁAc). Anal. Calcd for C15H14N2O4S (318.07):
C, 56.59; H, 4.43; N, 8.80. Found: C, 56.52; H, 4.40; N, 8.73.
1. (a) Shih, R. U.; Wu, J.; Liu, Y.; Liang, Y. C.; Lin, S. Y.; Sheu, M. T.; Lee, W. S.
Biochem. Pharmacol. 2004, 67, 67–75; (b) Takahashi, A.; Matsuoka, H.;
Yamada, K.; Uda, Y. Food Chem. Toxicol. 2005, 43, 521–528; (c) Al-Obaid, A.
A.; El-Subagh, H. I.; Khodair, A. I.; Elmazar, M. M. A. Anti-Cancer Drugs 1996, 7,
873–880.
2. Chui, W.-K.; Wong, T.-H.; Thenomozhiyal, J. C. J. Med. Chem. 2004, 47, 1527–
1535.
3. Poitout, L.; Thurieau, C.; Brault, V. WO01/09090; Chem. Abstr. 2001, 134,
163050.
Compound (7b): mp: 178–180 °C; 1H NMR (300 MHz, CDCl3): d = 8.19 (d, 2H,
J = 9 Hz), 7.18 (d, 2H, J = 8.7 Hz), 6.95 (s, 1H), 3.25 (q, 2H, J = 7.4 Hz), 2.67 (s,
3H), 2.35 (s, 3H), 1.50 (t, 3H, J = 7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3)
d = 168.83, 166.88, 162.14, 151.73, 136.60, 132.90, 131.45, 123.59, 121.80,
95.80, 25.48, 24.59, 20.82, 13.03 ppm. IR (KBr)
m = 1751.6, 1727.2, 1638.6,
1598.1, 1487.4, 1372.5, 1272.5, 1206.2, 1167.8, 915.8 cmꢁ1. ESMS: m/z = 291
(M+1ꢁAc). Anal. Calcd for C16H16N2O4S (332.08): C, 57.82; H, 4.85; N, 8.43.
Found: C, 57.58; H, 4.68; N, 8.25.