A facile method for preparation of optically active hydantoin

Article abstract of DOI:10.1246/cl.2003.372

Treatment of N-(4-nitrophenoxycarbonyl)amino acid amide, which was prepared from amino acid amide and 4-nitrophenyl chloroformate, under weakly basic conditions proceeded to afford the corresponding hydantoin. A direct conversion of amino acid amide into

Full text of DOI:10.1246/cl.2003.372

372
Chemistry Letters Vol.32, No.4 (2003)
A Facile Method for Preparation of Optically Active Hydantoin
Jun-ichi Yamaguchi,ꢀ Masakazu Harada, Takahito Kondo, Takeshi Noda, and Takayuki Suyamaꢀ
Department of Applied Chemistry, Faculty of Engineering, Kanagawa Institute of Technology, Shimo-ogino, Atsugi, Kanagawa
243-0292
(Received January 15, 2003; CL-030045)
Treatment of N-(4-nitrophenoxycarbonyl)amino acid amide,
which was prepared from amino acid amide and 4-nitrophenyl
chloroformate, under weakly basic conditions proceeded toafford
the corresponding hydantoin. A direct conversion of amino acid
amide into hydantoin without isolation of N-(4-nitophenoxycar-
bonyl)amino acid amide was also accomplished.
amounts of NaHCO3 in dry MeCN at room temperature for 3 h
(Table 1).10 Unfortunately, because it was difficult to purify (S)-3
from a small amount of 4-nitrophenol by chromatography on
silica-gel, (S)-3 was isolated by reprecipitation with ethyl acetate-
hexane only. Therefore, the yields of (S)-3 remained moderate.
Table 1. Preparation of (S)-3 from (S)-2
R3
Run
R1
R2
Substrate Product Yield/%
2aa
2ba
2cb
2da
3a
3b
3c
3d
84
76
71
78
Hydantoins and their synthesis by the action of carbonyl
compounds have been known since early in the 20th century.1
Recently, it has been found that hydantoins play an important role
in medicinal activities such as fibrinogen receptor antagonist and
leukocyte function-associated antigen-1 (LFA-1) antagonist.2
Therefore, many synthetic methods have been reported in the past
10 years and can be classified into two types: 1) cyclization of N-
carbamoyl amino acid ester under basic or acidic conditions,3 2)
cyclization of N-alkoxy or phenoxycarbonyl amino acid amide.4
However, racemization check of the synthesized hydantoin has
hardly been reported.
4-Nitrophenyl N-substituted carbamates5;6 as well as 4-
nitrophenyl esters7 and carbonates8 are known as activated esters
and react with amines to produce ureas, carboxamides, and
carbamates, respectively. Among them, 4-nitrophenyl N-substi-
tuted carbamates generate the corresponding isocyanates on
treatment with alkali or amine.9 From the above reports, we
expected that treatment of N-(4-nitrophenoxycarbonyl)amine
bearing a nucleophilic group with alkaline would generate the
corresponding isocyanate, which will transform into the corre-
sponding cyclic compound by its intramolecular cyclization. In
this communication, we wish to report a convenient method for
preparation of (S)-hydantoin (1) from (S)-amino acid amide (2)
via formation of N-(4-nitrophenoxycarbonyl)amino acid amide
(3) under weakly basic conditions (Scheme 1).
1
2
3
4
CH2Ph
CH2Ph
CH2Ph
H
H
H
H
Ph
(CH2)2Ph
Ph
-(CH2)3-
aHCl salt. b4-Toluenesulfonic acid salt.
Next, we examined the degradation of (S)-3 under basic
conditions to prepare (S)-1. It was found that treatment of 3 with
1.0 equimolar amount of NaHCO3 in H2O-MeCN at room
temperature for 3 h afforded (S)-1 (Table 2). All of the reaction
mixture changed from colorless into yellow instantly when an
aqueous NaHCO3 was added to a MeCN solution of (S)-3. This
phenomenon shows that degradation of (S)-3 and generation of 4-
nitrophenol are very fast. Since formation of the corresponding
isocyanate of (S)-3d derived from proline is impossible, we
suspected that no transformation of (S)-3d into (S)-1d proceeded.
Although the reaction rate was slow, (S)-1d was obtained. This
fact indicated that (S)-1d would be given in another reaction
pathway.
R1
R1
H
1) ArOCOCl, NaHCO3,
dry MeCN
R2
N
R2
R3
O
N
N
H
O
N
2) adding H2O
R3
O
Free or HX salt
H-AA-NHR2
2
1
According to the method for the preparation of 4-nitrophenyl
carbamate,5 (S)-3 was prepared by reaction of (S)-2 with 4-
nitrophenyl chloroformate in the presence of 2.0 equimolar
Ph
H
N
Ph
O
H
N
N
N
H
H
O
O
R1
O
R1
ArOCOCl, NaHCO3
dry MeCN
H
H
5
R2
N
N
N
R3
ArO
N
R2
R3
H
Scheme 2.
O
O
Free or HX salt
H-AA-NHR2
2
Table 2. Transformation of (S)-3 into (S)-hydantoin (1)
R3
3
Run
R1
R2
Substrate Product Yield/%a
R1
R1
1
2
3
4
CH2Ph
CH2Ph
CH2Ph
H
H
H
H
Ph
(CH2)2Ph
Ph
3a
3b
3c
3d
1a
1b
1c
1d
92
99
93
80b
NaHCO3
O
O
N
C
HN
O
N
MeCN-H2O
R2=H
O
HN
R3
-(CH2)3-
R3
aThe structures of these compounds were supported by IR, Mass,
and 1HNMR spectra. bThe starting material (3d) was recovered in
14% yield.
4
1
Ar=4-NO2-C6H4-
Scheme 1.
Copyright ꢀ 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.4 (2003)
373
In comparing the reaction conditions of 4-nitrophenoxycar-
bonylation of 2 and cyclization of 3, the only difference is the
presence or absence of water. Further, no degradation of 3
occurred under dry conditions even if excess amounts of NaHCO3
existed. From the above results, 3 was prepared from 2 and 4-
nitrophenyl chloroformate in the presence of excess amounts of
NaHCO3 in dry MeCN, and then only addition of water to the
reaction mixture gave 1 (Scheme 2, Table 3).11 However, in the
case of Run 6, the intramolecular cyclization will be retarded by
steric hindrance of the tert-butyl group, so that water may attack
2-isocyanatocarboxamide (4f) to regenerate 2f, which reacts with
4 to give urea (5). The yield of 1f was improved when 1.0
equimolar amount of triethylamine was used instead of water
(Run 7).
addition-elimination process.
In conclusion, we have developed one-pot preparation of
hydantoins from amino acid amide utilizing decomposition of 4-
nitrophenyl N-substituted carbamate under weakly basic condi-
tions without racemization.
References and Notes
1
E. C. Wagner and M. Bizer, Org. Synth., 1955, 323, and
references there cited therein.
2
H. U. Stilz, B. Jablonka, M. Just, J. Knolle, E. F. Paulus, and G.
Zoller, J. Med. Chem., 39, 2118 (1996); T. A. Kelly, D. D.
Jeanfavre, D. W. McNeil, J. R. Woska, Jr., B.-J. Bormann, and
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Itoi, Y. Takamatsu, T. Kinoshita, T. Okazaki, K. Kawakubo, M.
Shindo, T. Honma, M. Tohjigamori, and T. Haneishi, J.
Antibiot., 44, 293 (1991).
Table 3. One-pot preparation of (S)-1 from (S)-2
R2
3
K.-H. Park, E. Abbate, S. Najdi, M. Olmstead, and M. J. Kurth,
Chem. Commun., 1998, 1679; A. Boeijen, J. A. W. Kruijtzer,
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Run
R1
R3
Producta Yield/% E.e./%b
1c
2c
3d
4c
5c
6c
7c
8d
CH2Ph
CH2Ph
CH2Ph
H
H
H
Ph
(S)-1a
(S)-1b
96
94
96
68f
92
28g
78h
96
>99
>99
>99
>99
>99
>99
>99
98
H (CH2)2Ph (S)-1c
-(CH2)3-
Ph
Pr
t-Bu
t-Bu
Ph
(S)-1d
(S)-1e
(S)-1f
(S)-1f
(S)-1g
(S)-1h
CH2Ph
CH2Ph
CH2Ph
i-Pr
H
H
H
H
´
Ellmerer-Muller, A. Tako, N. Maslouh, and W. Bannwarth,
¨
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(1999).
9d CH2-3-indolyl H
10e CH2OBut
Pr
96
92
90
>99
99
>99
4
B. A. Dressman, L. A. Spangle, and S. W. Kaldor, Tetrahedron
Lett., 37, 937 (1996); X.-Y. Xiao, K. Ngu, C. Chao, and D. V.
Patel, J. Org. Chem., 62, 6968 (1997).
H (CH2)2Ph (S)-1i
11e CH2CO2But H (CH2)3Ph (S)-1j
aThe structures of these compounds were supported by IR, Mass,
5N. Choy, K. Y. Moon, C. Park, Y. C. Son, W. H. Jung, H.-I.
Choy, C. S. Lee, C. R. Kim, and H. Yoon, Org. Prep. Proced.
Int., 28, 173 (1996).
1
b
and H NMR spectra. E.e. was determined by HPLC. Condi-
tions: Run 1; column, Chiralpak WH (Daicel Chemical Indus-
tries, Ltd.), 1.0 mL/min of 0.25mmoldm ꢂ3 CuSO4, detection,
254 nm, other Runs; column, Sumichiral OA-4700 (Sumika
Chemical Analysis Service, Ltd.), 1.0 mL/min of hexane:E-
tOH=9:1, detection, 254 nm. cHCl salt. d4-Toluenesulfonic acid
6
B. Raji, J. M. Kassir, and T. P. Kogan, Bioorg. Med. Chem. Lett.,
8, 3043 (1998); Q. Liu, N. W. Luedtke, and Y. Tor, Tetrahedron
Lett., 42, 1445(2001).
7
8
M. Bodanszky, Nature, 175, 685 (1955); M. Bodanszky and V.
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798.
e
f
salt. Free amine. The starting material (3d) was recovered in
14% yield. gUrea (5) was obtained as a main product.
hTriethylamine (1.0 equiv.) was used instead of water and the
reaction mixture was stirred for 12 h after adding Et3N. Urea (5)
was obtained in 21% yield.
9
H. L. Bender and R. B. Homer, J. Org. Chem., 30, 3975(1965);
F. M. Menger and L. E. Glass, J. Org. Chem., 39, 2469 (1974).
It has been reported that racemic-1a has a melting point of
186 ꢁC12 and (S)-1a has a melting point of 181-183 ꢁC13 or
182 ꢁC.14 Although the melting point (185-186 ꢁC) of synthesized
racemic-1a according to the literature was the same as that of the
reported one, the melting point of (S)-1a obtained by our
procedure was 171-172 ꢁC, andwas apparently different from that
of the reported (S)-1a. Therefore, we undertook a racemization
check of synthesized 1 by HPLC. A peak corresponding to the
optically active hydantoin was identified by comparison with the
standard hydantoin derived from racemic- or (R)-amino acid run
under identical conditions (Table 3). It was found that the present
reaction proceeded without racemization under the reaction
conditions.
Similar to degradation of 4-nitrophenyl N-methylcarbamate
under basic conditions, it is assumed that the present reaction will
mainly proceed through theinitial formation of 4by treatment of 3
with NaHCO3 in MeCN-H2O. Isocyanate (4), in turn, gives the
corresponding hydantoin (1) by its cyclization (elimination-
addition process). Since formation of 4 is impossible when 2d is
used as the starting material, the reaction will proceed by an
10 3a: mp 132 ꢁC (decomp.); 3b: mp 136 ꢁC (decomp.); 3c: mp
127-128 ꢁC (decomp.); 3d: mp 137-138 ꢁC.
11 One-pot preparation of 1: to a suspension of amino acid amide
(0.3 mmol) and NaHCO3 (0.9 mmol) in dry MeCN (5mL) was
added 4-nitrophenyl chloroformate (0.3 mmol) at room tem-
perature. After being stirred for approximately 3 h, water (3 mL)
was added and the reaction mixture was stirred for approxi-
mately 3 h. After removal of MeCN under reduced pressure, the
organic materials were extracted with EtOAc. The organic layer
was washed with 5% K2CO3 solution and brine successively,
and was dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by preparative TLC
1
on silica-gel and hydantoin 1 was isolated. (S)-1a: H NMR
(300 MHz, DMSO-d6) d 2.96 (1H, dd, J ¼ 6:6 and 13.9 Hz),
3.12 (1H, dd, J ¼ 4:4 and 13.9 Hz), 4.23 (1H, dd, J ¼ 4:4 and
6.6 Hz), 7.20-7.30 (5H, m), 7.35 (1H, brs), 10.28 (1H, brs).
12 F. Lippich, Hoppe-Seyer’s Z. Physiol. Chem., 90, 124 (1914).
13 H. D. Dakin and H. W. Dudley, J. Biol. Chem., 17, 29 (1914).
14 T. Suzuki, K. Igarashi, K. Hase, and K. Tuzimura, Agric. Biol.
Chem., 37, 411 (1973).