Microwave-assisted synthesis of N-arylglycines: Improvement of sydnone synthesis

Article abstract of DOI:10.3987/COM-05-10574

Reactions of anilines with ethyl bromoacetate under microwave irradiation have afforded N-arylglycines that are subsequently converted to their N-nitroso derivatives with a combination of silica chloride or periodic acid, wet SiO₂ and sodium nitrite in CH₂Cl₂ with satisfactory yields. In the final step, the use of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a new and effective reagent for dehydration of N-nitroso-N-arylglycines to sydnones was successfully examined.

Full text of DOI:10.3987/COM-05-10574

HETEROCYCLES, Vol. 68, No. 1, 2006
175
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 175 – 181. © The Japan Institute of Heterocyclic Chemistry
Received, 26th September, 2005, Accepted, 30th November, 2005, Published online, 2nd December, 2005. COM-05-10574
MICROWAVE-ASSISTED
SYNTHESIS
OF
N-ARYLGLYCINES:
IMPROVEMENT OF SYDNONE SYNTHESIS
Davood Azarifar,*a Hassan Ghasemnejad Bosra,a Mohammad-Ali Zolfigol,a and
Mahmood Tajbakshb
aChemistry Department, School of Science, Bu-Ali Sina University, Postal Code
65174, Hamadan, Iran
bChemistry Department, Faculty of Science, Mazandaran University, Babolsar,
Iran
*Corresponding author; Fax: +98-811-8272404, e-mail: azarifar@basu.ac.ir
Abstract- Reactions of anilines with ethyl bromoacetate under microwave
irradiation have afforded N-arylglycines that are subsequently converted to their
N-nitroso derivatives with a combination of silica chloride or periodic acid, wet
SiO2 and sodium nitrite in CH2Cl2 with satisfactory yields. In the final step, the
use of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a new and effective reagent
for dehydration of N-nitroso-N-arylglycines to sydnones was successfully
examined.
Sydnones such as 4 are dipolar heterocycles and archetypal members of the class of compounds known
as mesoionic1 which were first prepared by Earl and his co-workers in 1935.2 Sydnones are of a
biological importance: inter alia sydnones have been used efficaciously as antibacterial,3 antitumour,4
antimalarial,5 anti-inflamatory,6 and antihypertensive7 agents. Their activity as MAO (monoamine
oxidase) inhibitors has also been reported.8 Sydnones can also undergo a variety of transformations
including electrophilic aromatic substitution (at the 4-position, if unsubstituted),1,9-14 cleavage with HCl to
form hydrazines2 or heterocycles,15 hydrolysis with hot alkali to regenerate the N-nitrosamino acids16 and
1,3-dipolar cycloadditions to form pyrazoles or related species.17 Sydnones (4) constitute a well-
investigated intrinsically neutral substances which are normally prepared by dehydration of N-
nitrosamino acids.18
In a total preparative scheme to the sydnones (4a-j), we wish herein to report some useful modifications
in an easy synthesis of N-arylglycines (2a-j) from microwave-assisted reactions of the anilines (1a-j) with
ethyl bromoacetate in the presence of SiO2 and their subsequent conversion to the sydnones (4a-j)

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HETEROCYCLES, Vol. 68, No. 1, 2006
through their intermediate formation of N-nitrosoglycines (3a-j) (Scheme 1). As shown in Table 1, the
results obtained from the reactions of the anilines (1a-j) with ethyl bromoacetate indicate that the
application of the microwave irradiation can considerably increase the efficiency of these reactions to
produce the N-arylglycines (2a-j) in satisfactory yields (89-95%) and reduce the reaction times when
compared with the classical thermal conditions.
Scheme 1
BrCH CO Et
NaNO / SiO -Cl (or H IO )
2 2 5 6
1) NaOH
2) HCl
2
2
ArNHCH2CO2H
ArNH2
ArNHCH2CO2Et
SiO , MW
Wet SiO (w/w 50%)
2
2
2a-j
1a-j
Ar
H
N
Ar-N-CH2CO2H
DBH
+
CH Cl
N
2
2
O
NO
O
3a-j
4a-j
(a) Ar = C H ; (b) Ar = 2-MeC H ; (c) Ar = 4-MeC H ; (d) Ar = 4-MeOC H ; (e) Ar = 2-NO C H ; (f) Ar = 4-NO C H ;
6
5
6
4
6
4
6
4
2
6
4
2 6 4
(g) Ar = 4-ClC H ; (h) Ar = 2,4-Cl C H ; (i) Ar = 4-BrC H ; (j) Ar = 2-MeOC H
6
4
2
6
3
6
4
6 4
Table 1: Silica-supported conversion of the anilines (1a-j) to the N-arylglycines (2a-j) with ethyl
bromoacetate under microwave irradiation condition.
Producta
Yield (%)b
Entry
Substrate
Reaction Time
mp (˚C)
MW (min) Thermal (h)
MW Thermal
1
2
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
7.0
8.0
5.0
4.0
5.3
5.0
4.8
7.2
6.3
4.3
21.0
16.0
15.0
14.0
15.5
15.0
14.0
24.0
18.0
15.0
93
85
90
89
87
90
91
83
88
85
65
52
66
49
48
53
56
51
57
47
83
121
132
135
140
165
102
98
3
4
5
6
7
1g
1h
1i
2g
2h
2i
8
9
105
118
10
1j
2j
a
1
Products were characterized on the basis of their physical, IR and H-NMR spectral analysis and by direct
comparison with literature data, (2a),2 (2b, 2h),18 (2c, 2f, 2g),19 (2d, 2e, 2j),20 (2i).21 bPurified Yields.
In the next stage of our preparative scheme to the sydnones (4a-j), we have examined a mild and
heterogeneous method to nitrosate the N-arylglycines (2a-j) to the N-nitrosoglycines (3a-j). N-Nitrosation
of glycines is a well-established reaction used in synthesis of sydnones.22 Nitrous acid generated from
treatment of sodium nitrite with strong mineral acids in water or aqueous alcohol is the most generally

HETEROCYCLES, Vol. 68, No. 1, 2006
177
employed reagent in nitrosation reactions.23 In this work, we have examined the combination of NaNO2
with silica chloride (I) or H5IO6 (II) in the presence of wet SiO2 (w/w 50%) in CH2Cl2 as an efficient and
simple reagent for nitrosation of the N-arylglycines (2a-j) prepared in the preceding stage (Scheme 1)
under mild and heterogeneous condition. The results obtained from these reactions are summarized in
Tables 2 and 3. It is to mention that this reagent has been previously reported for the nitrosation of
secondary amines.24,25
Table 2: Nitrosation of the N-arylglycines (2a-j) (2 mmol) with a combination of silica chloride (I) and
NaNO2 in the presence of wet SiO2 (w/w 50%) in CH2Cl2 at 0-5 ˚C.
Producta
Yield (%)b
Entry
Substrate
Reagent (I) (gr)
Time (h)
mp (˚C)
1
2
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
0.6
0.5
0.4
0.5
0.5
0.6
0.6
0.7
0.6
0.5
2.5
2.0
2.2
1.7
2.1
2.0
2.3
2.0
2.4
90
92
93
92
91
93
95
88
90
89
72
111
120
121
132
148
91
3
4
5
6
7
2g
2h
2i
3g
3h
3i
8
89
9
96
10
2j
3j
1.8
110
a
1
Products were characterized on the basis of their physical, IR and H-NMR spectral analysis and by
direct comparison with literature data, (3a),2 (3b, 3h),18 (3c, 3f, 3g),19 (3d, 3e, 3j),20 (3i).21 bPurified
Yields.
Dehydration of N-nitroso-N-arylglycines to their corresponding sydnones with trifluroacetic anhydride in
CH2Cl2 has been previously reported.2,20,26,27
In connection with our ongoing studies on 1,3-dibromo-5,5-dimethylhydantoin (DBH) as an efficient and
versatile reagent used in various transformations,28-30 we successfully examined DBH as a more robust
and less expensive reagent in the final step of scheme 1 to effectively convert the N-nitroso-N
arylglycines (a-j) to the sydnones (4a-j) in CH2Cl2 under mild conditions in high yields (85-94%) (Table
4). A possible mechanism proposed for these cyclization reactions by DBH is shown in Scheme 2.
Scheme 2
O
Br
Br
N
N
O
Ar
Ar
N
O
Ar
O
Br
H
Br
N
+
N
N
H
H
N
N
N
H
N
O
N
OH
N
+
+
+
-
OBr
OH
O
O
O
O
O
O
3a-j
4a-j

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HETEROCYCLES, Vol. 68, No. 1, 2006
Table 3: Nitrisation of N-arylglycines (2a-j) (2 mmol) with a combination of H5IO6 (II) and NaNO2 in
the presence of wet SiO2 (w/w 50%) in CH2Cl2 at 0-5 ˚C.
Yieldb
(%)
mp
Producta
Entry
Substrate
Reagent (II)
Time (h)
(gr)
(˚C)
1
2
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
1.8
1.6
1.8
1.7
1.6
1.7
1.5
1.6
1.7
1.8
2.3
1.9
2.0
1.9
2.2
2.0
2.3
2.1
2.2
1.7
88
92
90
94
89
91
94
90
90
89
72
111
120
121
132
148
91
3
4
5
6
7
2g
2h
2i
3g
3h
3i
8
89
9
96
10
2j
3j
110
a
1
Products were characterized on the basis of their physical, IR and H-NMR spectral analysis and by
direct comparison with literature data, (3a),2 (3b, 3h),18 (3c, 3f, 3g),19 (3d, 3e, 3j),20 (3i).21 bPurified
Yields.
Table 4: Dehydrative cyclization of the N-nitroso-N-arylglycines (3a-j) to the corresponding sydnones (4a-j) by
DBH in CH2Cl2 at 0-5 ˚C.
Entry
1
Producta
mp (˚C)
IR (KBr) (cm-1)
1H-NMR (CDCl3) (ppm)
Yield (%)b
4a
87
134
3110, 1760, 941, 735
6.38 (s, 1H, CHsyd), 7.40-6.60 (m,
5H, Ar)
2
3
4b
4c
4d
4e
4f
80
78
88
82
86
81
86
88
89
98
144
126
147
184
113
95
3100, 1770, 940, 730
3110, 1760, 940, 735
3100, 1770, 940, 730
3120, 1780, 950, 740
3119, 1775, 944, 738
3110, 1760, 940, 730
3120, 1768, 945, 737
3119, 1762, 943, 730
3117, 1755, 940, 750
2.40 (s, 3H, CH3), 6.47 (s, 1H,
CHsyd), 7.60-7.20 (m, 4H, Ar)
2.20 (s, 3H, CH3), 6.31 (s, 1H,
CHsyd), 7.70-7.20 (m, 4H, Ar)
4
4.20 (s, 3H, CH3), 6.53 (s, 1H,
CHsyd), 7.60-7.10 (m, 4H, Ar)
5
6.67 (s, 1H, CHsyd), 8.40-7.60 (m,
4H, Ar)
6
6.60 (s, 1H, CHsyd), 8.20-7.40 (m,
4H, Ar)
7
4g
4h
4i
6.57 (s, 1H, CHsyd), 7.90-7.30 (m,
4H, Ar)
8
6.71 (s, 1H, CHsyd), 8.40-7.60 (m,
3H, Ar)
9
138
97
6.52 (s, 1H, CHsyd), 7.80-7.10 (m,
4H, Ar)
10
4j
4.30 (s, 3H, CH3), 6.50 (s, 1H,
CHsyd), 7.90-7.30 (m, 6H, Ar)
aProducts were characterized on the basis of their physical, IR and 1H-NMR spectral analysis and by direct
comparison with literature data, (4a),2 (4b, 4h),18 (4c, 4f, 4g),19 (4d, 4e, 4j),20 (4i).21 bPurified yields.

HETEROCYCLES, Vol. 68, No. 1, 2006
179
EXPERIMENTAL
Chemicals were obtained from Merck and Fluka chemical companies. IR spectra were recorded using a
Shimadzu 435-U-04 spectrophotometer (KBr pellets) and NMR spectra were obtained in CDCl3 using a 90
MHz JEOl FT NMR spectrometer. All melting points were determined on a Büchi 530 melting point
apparatus, and reported uncorrected.
Step 1: Preparation of N-arylglycines (2)
To a stirred mixture of ethyl bromoacetate (1.70 mg, 10 mmol) and SiO2 (5 g), was added the aniline (1)
(10 mmol), and the resulting mixture was irradiated (300 Watt) for a few min (Table 1) at rt. The
resulting solid mixture was washed with water (3x10 mL), filtered, and then treated with 10% aqueous
solution of sodium hydroxide (10 mL) in ethanol (2 mL) for 10 min under reflux until the complete
dissolution occurred. The mixture was allowed to cool to rt, acidified with aqueous HCl (0.1 %), then
extracted with CH2Cl2 (2x20 mL), and the extract was dried over anhydrous MgSO4, evaporated in vacuo
and finally recrystallized from ethanol to yield the pure corresponding N-arylglycines (2) (Table 1).
Step 2: N-Nitrosation of the N-arylglycines (2) to the N-nitroso-N-arylglycines (3)
(i) To a mixture of the N-arylglycine (2) (2 mmol) and silica chloride (Table 2) was added wet SiO2 (w/w
50 %) (0.4 g) and NaNO2 (0.2 g, 3 mmol) in CH2Cl2 (10 mL) and the resulting mixture was vigorously
stirred at 0-5 ºC for a few h (Table 2). After the completion of the reaction that was monitored by TLC,
the resulting reaction mixture was extracted with dichloromethane (2x20 mL), dried over anhydrous
MgSO4, and then evaporated under reduced pressure to yield the N-nitrosoarylglycine (3) which was
purified by recrystallization from ethanol (Table 2). The structures of these compounds were established
1
on the basis of their IR, H-NMR and 13C-NMR spectral analysis and direct comparison with the
literature data.2,18-21
(ii) In a flask, a suspension of the N-arylglycine (2) (2 mmol), H5IO6 (Table 3), wet SiO2 (w/w 50 %) (0.4
g) and NaNO2 (0.2 g, 3 mmol) in CH2Cl2 (10 mL) was stirred at 0-5 ºC for a few h (Table 3). After the
completion of the reaction that was monitored by TLC using EtOH/petroleum ether (1:8), the reaction
mixture was filtered, then the filterate dried over anhydrous MgSO4, and evaporated in vacuo to leave a
solid residue which was recrystallized from ethanol to yield highly pure N-nitrosoarylglycine (3) (Table
3).
Step 3: Cyclization of the N-nitroso-N-arylglycine (3) to the sydnones (4)
To a magnetically stirred solution of the N-nitrosoglycine (3) (5 mmol) in CH2Cl2 (5 mL), was added 1,3-
dibromo-5,5-dimethylhydantoin (DBH) (1.45 mg, 5 mmol) at 0-5 ºC . After 4 h, the reaction mixture was
poured into water (5 mL), and then solid sodium bicarbonate was added cautiously with stirring to
remove the remaining glycines. The organic layer was separated, dried over anhydrous MgSO4, and then

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HETEROCYCLES, Vol. 68, No. 1, 2006
evaporated in vacuo to leave the solid product (4), which was further purified by recrystallization from
1
ethanol. These products were characterized on the basis of their IR and H-NMR spectral data given in
the Table 4 and with direct comparison with literature data.2,18-21
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