Catalytic activity of 1,3-dibromo-5,5-dimethylhydantoin (DBH) in the one-pot transformation of N-arylglycines to N-arylsydnones in the presence of NaNO2/Ac2O under neutral conditions: Subsequent bromination of these sydnones to their

Article abstract of DOI:10.1055/s-2006-926380

1,3-Dibromo-5,5-dimethylhydantoin (DBH) has been found to efficiently catalyze the one-pot conversion of various N-arylglycines through N-nitrosation and cyclization to sydnones in combination with NaNO₂ and Ac ₂O in high yields (80-

Full text of DOI:10.1055/s-2006-926380

PAPER
1123
Catalytic Activity of 1,3-Dibromo-5,5-dimethylhydantoin (DBH) in the
One-Pot Transformation of N-Arylglycines to N-Arylsydnones in the Presence
of NaNO2/Ac2O under Neutral Conditions: Subsequent Bromination of these
Sydnones to their 4-Bromo Derivatives
Conversionof
N
-A
a
rylglycines
v
to
N
-Arylsy
o
dnones od Azarifar,* Hassan Ghasemnejad-Bosra
Department of Chemistry, School of Science, Bu-Ali Sina University, 65174 Hamadan, Iran
Fax +98(811)8272404; E-mail: azarifar@basu.ac.ir
Received 17 October 2005; revised 18 November 2005
In connection with our ongoing studies on 1,3-dibromo-
Abstract: 1,3-Dibromo-5,5-dimethylhydantoin (DBH) has been
found to efficiently catalyze the one-pot conversion of various N-
arylglycines through N-nitrosation and cyclization to sydnones in
combination with NaNO2 and Ac2O in high yields (80–94%) under
5,5-dimethylhydantoin (DBH) as a versatile and conve-
nient reagent used in various transformations,16–19 and
also in order to avoid the drawbacks generally caused by
mild and neutral conditions. Also, it was shown that DBH can the use of strong acidic media in nitrosation reactions, we
conveniently promote the bromination of these sydnones to their
4-bromo substituted congeners in excellent yields in DMF at room
temperature.
wish, herein, to report on the use of DBH as a more robust
and efficient catalyst for the one-pot conversion of N-
arylglycines to sydnones under neutral conditions. In this
work, we have observed that 1,3-dibromo-5,5-dimethyl-
Key words: nitrosation, N-arylglycines, sydnones, 1,3-dibromo-
5,5-dimethylhydantoin (DBH), bromination
hydantoin (DBH) can efficiently catalyze the conversion
of N-arylglycines 1a–j to sydnones 2a–j using sodium ni-
trite and acetic anhydride in CH2Cl2 with satisfactory
Sydnones such as 2 are unique archetypal members of that
class of heterocyclic compounds known as mesoionic.1
Sydnones were first prepared by Earl and Mackney in
1935,2 and the greatest interest in them, ever since, stems
from their biological activity as antibacterial,3 antitumor,4
antimalarial,5 anti-inflammatory,6 and antihypertensive7
agents. Sydnones, also undergo a variety of transforma-
tions including electrophilic aromatic substitution at the
4-position (if unsubstituted),8 1,3-dipolar cycloaddition
reactions to form pyrazoles or related species9 and cleav-
age to hydrazines2 or heterocycles10 when treated with
HCl. The ease with which these compounds undergo elec-
trophilic aromatic substitutions is apparently similar to
that of furan1 and 3-arylsydnones 2 generally react with
electrophiles to yield the corresponding 4-substituted de-
rivatives. In the case of 3-arylsydnones, substitutions with
a vast majority of electrophiles occur exclusively at the
sydnone ring and not at the 3-aryl ring. This is probably
attributable to deactivation of the aryl substituent by the
electron-withdrawing effect of the sydnone ring N-3 posi-
tion that bears a substantial fractional positive charge.11,12
yields (80–94%) (Scheme 1, Table 1). In reliance on the
previously reported action of acetic anhydride in the cy-
clization of N-nitrosoglycines to sydnones,2 we propose a
possible mechanism for these reactions in five steps as
shown in Scheme 2, in which the cyclization (step 4) of
the intermediate N-nitrosoglycines is, probably, activated
by acetyl hypobromite generated from the reaction of ace-
tic anhydride with hypobromous acid.
N
DBH, NaNO2, Ac2O
ArNHCH2CO2H
N
in CH2Cl2, 0–5 °C
O
O
2a–j
1a–j
Scheme 1
Among the aromatic substitution reactions of the syd-
nones, bromination reaction has attracted special inter-
ests. A number of methods including Br2/Ac2O,21 Br2/
NaHCO3 (and Br2/KBr),22 Br2/NaOAc23, and NBS24 have
been developed for the preparation of the 4-bromosyd-
nones 3 from their 4-unsubstituted precursors. Most of
these methods suffer from certain disadvantages includ-
ing the use of expensive reagents, severe reaction condi-
tions, low yields of the products, and problematic removal
and recovering of the catalysts employed. In this regard,
we were prompted to examine the DBH as a more robust
and efficient reagent in the continuation of our research
for bromination of 3-arylsydnones 2a–j. The results ob-
tained indicate the successful bromination of 3-arylsyd-
nones 2a–j to their 4-bromo derivatives 3a–j using DBH
in DMF at room temperature in good to excellent yields
under mild conditions (Scheme 3).
Sydnones are intrinsically neutral substances that are nor-
mally prepared by dehydrative cyclization of N-nitros-
amino acids.13 N-Nitrosamino acids used in the synthesis
of sydnones are themselves prepared from N-nitrosation
of amino acids. N-Nitrosation is a well-known reaction in
organic synthesis14 that is usually accomplished with ni-
trous acid, generated by treatment of sodium nitrite with
an aqueous mineral acid.15
SYNTHESIS 2006, No. 7, pp 1123–1126
x
x
.
x
x
.2
0
0
6
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926380; Art ID: Z20005SS
© Georg Thieme Verlag Stuttgart · New York

1124
D. Azarifar, H. Ghasemnejad-Basra
PAPER
Table 1 Conversion of N-Arylglycines 1a–j to Sydnones 2a–j
Entry
Producta
Ar
Time (h)
Yield (%)b
Mp (°C)
Found
Reported20,21
1
2
2a
2b
2c
2d
2e
2f
2-CH3C6H4
4-CH3C6H4
2-CH3OC6H4
4-CH3OC6H4
2-NO2C6H4
4-NO2C6H4
4-ClC6H4
12.0
11.0
11.5
10.5
16.0
14.0
11.5
16.0
11.0
10.0
87
85
90
92
80
82
87
83
90
94
98
144
97
97
145
97
3
4
126
147
183
113
95
125
148
184
113
96
5
6
7
2g
2h
2i
8
2,4-Cl2C6H3
4-BrC6H4
9
138
134
137
135
10
2j
C6H5
a All the isolated products were characterized on the basis of their physical properties and 1H NMR, 13C NMR and IR spectra and by direct
comparison with literature data.20,21
b Isolated yields.
using a 90 MHz JEOL FT NMR spectrometer. All melting points
were determined on a Büchi 530 melting point apparatus and are un-
corrected.
The transformations 2 → 3 were conducted using around
two equivalents of the reagent DBH in DMF and, in all
cases, the reactions completed in less than three hours at
room temperature. The 4-bromo compounds 3a–j were
obtained in 94–99% yields (Table 2) after precipitation of
the reagent, flash column chromatography (to remove po-
lar impurities), and recrystallization from ethanol.
Conversion of N-Arylglycines 1a–j to Sydnones 2a–j with
NaNO2/Ac2O Catalyzed by DBH; General Procedure
To a magnetically stirred solution of N-arylglycine 1 (2 mmol) in
CH2Cl2 (40 mL), was added 1,3-dibromo-5,5-dimethylhydantoin
(DBH) (1.6 mmol), NaNO2 (0.17 g, 2.5 mmol), and Ac2O (0.31 g,
3 mmol) at 0–5 °C. After the completion of the reaction in 10–16 h
(Table 1) as monitored by TLC, the mixture was poured into H2O (5
mL), and then solid NaHCO3 was added cautiously with stirring to
Chemicals were obtained from Merck and Fluka chemical compa-
nies. IR spectra were recorded using a Shimadzu 435-U-04 spectro-
photometer (KBr pellets) and NMR spectra were obtained in CDCl3
O
O
Br
Br
Br
N
N
N
N
–
Na
Br+NO2
+
NaNO2
NO+
+
Step 1:
O
O
_
_
Br+NO2
BrO
–
+
Step 2:
Step 3:
+ NO+
+ BrO-
HOBr
+
ArN(NO)CH2CO2H
Ar
ArNHCH2CO2H
1a–j
Ar
O
N
N
N
+ (Ac2O + HOBr)
– AcOH
AcOBr
Ac
O
Step 4:
Step 5:
BrO–
+
N
O
OH
OH
O
Ar
H
Ar
H
N
N
+ BrO–
OAc
OH
HOAc
HOBr
+
+
+
N
N
O
O
O
2a–j
Scheme 2
Synthesis 2006, No. 7, 1123–1126 © Thieme Stuttgart · New York

PAPER
Conversion of N-Arylglycines to N-Arylsydnones
1125
Table 2 Bromination of 3-Arylsydnones 2a–j to their 4-Bromo Derivatives 3a–j
Entry
Substrate
Ar
Producta
Time (h)
Yield (%)b
Mp (°C)
Found
Reported8,25,26
1
2
2a
2b
2c
2d
2e
2f
2-CH3C6H4
4-CH3C6H4
2-CH3OC6H4
4-CH3OC6H4
2-NO2C6H4
4-NO2C6H4
4-ClC6H4
3a
3b
3c
3d
3e
3f
2.1
2.0
2.3
2.2
2.6
2.5
2.2
2.7
2.1
2.0
98
99
97
99
96
90
97
95
96
94
96
88
97
89
3
110
106
112
154
93
110
107
113
154
94
4
5
6
7
2g
2h
2i
3g
3h
3i
8
2,4-Cl2C6H3
4-BrC6H4
90
91
9
98
97
10
2j
C6H5
3j
139
140
a All the isolated products were characterized on the basis of their physical properties and 1H NMR, 13C NMR and IR spectra and by direct
comparison with literature data.8,25,26
b Isolated yields.
O
(3) (a) Brooks, P.; Walker, J. J. Chem. Soc. 1959, 4409.
Br
Br
(b) Ackermann, E. Pharmazie 1967, 22, 537; Chem. Abstr.
1968, 68, 28171.
(4) Kier, L. B.; Roche, E. B. J. Pharm. Sci. 1967, 56, 149.
(5) McCaustland, D. J.; Burton, W. H.; Cheng, C. C. J.
Heterocycl. Chem. 1971, 8, 89.
O
N
N
Ar
Ar
Br
H
Br
4
3 N
N
N
NH
O
+
5
2 N
N
DMF, r.t.
O
O
O
O
1
O
(6) (a) Pala, G.; Mantegani, A.; Coppi, G.; Genova, R. Chim.
Ther. 1969, 4, 31; Chem. Abstr. 1969, 71, 3328.
(b) Kamiya, T.; Saito, Y.; Teraji, T. Fujisawa Pharm. Co.,
Ltd., Japanese Patent 7232073, 1972; Chem. Abstr. 1973,
78, 42592.
3a–j
2a–j
Scheme 3
remove the remaining glycines. The resulting mixture was filtered,
the filtrate was extracted with CH2Cl2, and then the organic layer
was separated, dried, and evaporated in vacuo to leave the solid
product 2, which was further purified by recrystallization from
EtOH (Table 1). These products were characterized on the basis of
their physical properties and also by their IR and 1H NMR spectra
with direct comparison with the literature data.20,21
(7) Saito, Y.; Kamiya, T. Takeda Chem. Ind. Ltd., Japanese
Patent 7010510, 1970; Chem. Abstr. 1970, 73, 14853.
(8) Turnbull, K. J. Heterocycl. Chem. 1985, 22, 965.
(9) Huisgen, R.; Grashey, R.; Gotthardt, H.; Schmidt, R. Angew.
Chem. 1962, 74, 29.
(10) Gelvin, C. R.; Turnbull, K. Helv. Chim. Acta 1992, 75, 1931.
(11) Tin-Lok, C.; Miller, J.; Stansfield, F. J. Chem. Soc. 1964,
1213.
Bromination of Sydnones 2a–j with DBH; General Procedure
To a stirred solution of 3-arylsydnone 2a–j (1 mmol) in DMF (3
mL) was added DBH (0.548 g, 2 mmol), and the mixture was al-
lowed to stir for 2.0–2.7 h at r.t. After complete conversion of the
substrate as indicated by TLC, the mixture was poured into ice wa-
ter, and extracted with CH2Cl2 (2 × 25 mL). The combined CH2Cl2
extracts were dried (MgSO4) and the solvent was evaporated under
reduced pressure to leave a brown residue, which was recrystallized
from EtOH (95%) to yield pure tan crystals of 3a–j in 94–99%
yields (Table 2).
(12) Turnbull, K.; Blackburn, T. L.; Miller, J. J. Heterocycl.
Chem. 1996, 33, 485.
(13) Thoman, C. J.; Voaden, D. J. Org. Synth. Coll. Vol. V;
Wiley: New York, 1973, 962.
(14) Williams, D. L. H. In The Chemistry of Functional Groups,
The Chemistry of Amino, Nitroso, Nitro and Related Groups,
Supplement F2; Patai, S., Ed.; Wiley: Chichester, 1996,
665–682.
(15) Shriner, R. L.; Reynold, T. L.; Fuson, C.; Curtin, D. Y.;
Morrill, T. C. The Systematic Identification of Organic
Compounds, 6th ed.; Wiley: New York, 1980, 220–223.
(16) Azarifar, D.; Zolfigol, M. A.; Maleki, B. Synthesis 2004,
1744.
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1126
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PAPER
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Synthesis 2006, No. 7, 1123–1126 © Thieme Stuttgart · New York