6150
V. Kumar et al. / Tetrahedron Letters 52 (2011) 6148–6151
O
medicinal chemistry. The important features of the reaction are
solvent-free conditions and easy work-up procedure which make
the reaction convenient and eco-friendly.
O
P
BuO
P
O
C
OBu
NH
O
P
R1
R2
N
CH
1
C N
OBu
HX
HO
OBu
OBu
R1
N
COOMe
OBu
CH
R2
Supplementary data
COOMe
5
R1
R2
O
Supplementary data associated with this Letter can be found, in
OH
O
C
O
N
O
R1
R2
N
H+/
-CH3OH
NH
C
R
N
NH2
O
P
P
OBu
BuO
O
N
H
CH
CH
OBu
OBu
R1
COOMe
References and notes
COOMe
3
6
1. (a) Ware, E. Chem. Rev. 1950, 46, 403; (b) Avendano, C.; Trigo, G. G. Adv.
Heterocycl. Chem. 1985, 38, 177; (c) Meusel, M.; Gütschow, M. Org. Prep. Proc.
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Igarashi, T.; Minami, N. Chem. Pharm. Bull. 1992, 40, 1823.
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Haneishi, T. J. Chem. Soc Perkin. Trans. 1 1991, 1637; (b) Mirza, S. Chem. Abstr.
1992, 117, 8356; (c) Mio, S.; Ichinose, R.; Goto, K.; Sugai, S.; Sato, S. Tetrahedron
1991, 47, 2111; (d) Mio, S.; Shiraishi, M.; Sugai, S.; Haruyama, H.; Sato, S.
Tetrahedron 1991, 47, 2121; (e) Mio, S.; Kumagawa, Y.; Sugai, S. Tetrahedron
1991, 47, 2133; (f) Chemla, P. Tetrahedron Lett. 1993, 34, 7391; (g) Harrington,
P. M.; Jung, M. E. Tetrahedron Lett. 1994, 35, 5145.
Scheme 2. Mechanism for the formation of 3.
O
NC
NC
2
NH
N
H2C
7
C N
N
100 oC, 2 h
O
COOMe
8 = CN at 3 position (Yields: 84%)
9 = CN at 4 position (Yields: 86%)
Scheme 3. Comparative reactivity of nitrile and cyanamide group.
1. NaHCO3 (aq.)
2
COOMe
3. (a) Lavrador, K.; Guillerm, D.; Guillerm, G. Bioorg. Med. Chem. Lett. 1998, 8,
1629; (b) Tellier, F.; Acher, F.; Brabet, I.; Pin, J.-P.; Azerad, R. Bioorg. Med. Chem.
1998, 6, 195.
N
N
COOMe
100 oC, 1 h
2. CNBr, Et2O
10 oC, rt, 1 h
N
H.HCl
O
O
N
H
CN
11
10
4. (a) David, S. S.; O’Shea, V. L.; Kundu, S. Nature 2007, 447, 941; (b)
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Chem. 1999, 42, 1027; (c) Tellier, F.; Acher, F.; Brabet, I.; Pin, J. P.; Azerad, R.
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Conway, S. J. Org. Biomol. Chem. 2008, 6, 988.
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A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937; (e) Nefzi, A.; Ostresh, J. M.;
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R.; Loupy, A. Synthesis 2002, 75; (d) Lin, M.-J.; Sun, C.-M. Tetrahedron Lett. 2003,
44, 8739.
12
(Biphasic reaction)
Scheme 4. Synthesis of bicyclohydantoin 12.
As, it is evident that the free amino acid esters are known to be
susceptible to undergo self-condensation to form diketopipera-
zines and polycondensation products due to the intramolecular
reaction between amine and ester group.17 In an alternative ap-
proach, proline methyl ester was in situ converted into 11 from
10 without isolation. In biphasic reaction, proline methyl ester
hydrochloride and cyanogen bromide were dissolved in water
and diethyl ether, respectively.18 To this immiscible solution, a sat-
urated solution of sodium bicarbonate was added to neutralize 10
into proline methyl ester which reacts with cyanogen bromide in
organic layer to give 11. Conversion of 11 into 12 was carried out
by following our present method (Scheme 4).19
We have also successfully attempted to synthesize bis-hydanto-
ins. Bis-hydantoin with methylene (13) and ether (14) pivotal was
synthesized with good yields under similar reaction conditions as
shown in Scheme 5. This indicates the expansion of our method
for the development of chemically useful products which could
find its application in supramolecular chemistry.20
In summary, a new strategy for the synthesis of hydantoins has
been developed to give the products in quantitative yields with
high purity. Synthesis of wide varieties of hydantoins with pri-
mary, secondary, tertiary, cyclic, and aryl groups represents an
impressive library. The reaction is also of practical importance
for the synthesis of bis-hydantoins and bicyclohydantoin which
may open attractive avenues in supramolecular chemistry and
10. (a) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220; (b) Maiti, B.;
Chanda, K.; Sun, C.-M. Org Lett. 2009, 11, 4826; (c) Zhang, W.; Lu, Y. Org. Lett.
2003, 5, 2555; (d) Gallienne, E.; Muccioli, G. G.; Lambert, D. M.; Shipman, M.
Tetrahedron Lett. 2008, 49, 6495; (e) Riviere, J.; Bergeron, F.; Tremblay, S.;
Gasparutto, D.; Cadet, J.; Wagner, J. R. J. Am. Chem. Soc. 2004, 126, 6548; (f)
Olimpieri, F.; Bellicci, M. C.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 2009,
6179; (g) Murray, R. G.; Whitehead, D. M.; Start, F. L.; Conway, S. J. Org. Biomol.
Chem. 2008, 6, 988.
11. (a) Kumar, V.; Kaushik, M. P. Chem. Lett. 2005, 34, 1230; (b) Kumar, V.; Kaushik,
M. P. Tetrahedron Lett. 2005, 46, 8121; (c) Kumar, V.; Kaushik, M. P. Chem. Lett.
2006, 35, 312; (d) Kumar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 1457; (e)
Kumar, V.; Kaushik, M. P. Synth. Commun. 2006, 36, 2385; (f) Kumar, V.;
Kaushik, M. P. Synlett 2007, 2937; (g) Kumar, V.; Kaushik, M. P. Bull. Chem. Soc.
Jpn. 2008, 81, 160.
X
X
NC
CN
N
N
N
N
CH2
2, 100 oC
2 hr
CH2
O
O
O
O
COOMe
N
COOMe
N
H
H
X= CH2 (13)
X= O (14)
12. Kumar, V.; Kaushik, M. P.; Mazumdar, A. Eur. J. Org. Chem 2008, 1910.
Scheme 5. Synthesis of bis-hydantoins.