Synthesis of 2-chloromethyl-5-aryl-, 2-chloromethyl-5-(5-methyl-2-furyl)-, and 2-chloromethyl-5-(1,5-dimethyl-2-pyrrolyl)-1,3,4-oxadiazoles from tetrazole derivatives

Article abstract of DOI:10.1007/s11167-005-0389-6

Acetylation of 5-aryltetrazoles, 5-(5-methyl-2-furyl)tetrazole, and 5-(1,5-dimethyl-2-pyrrolyl)tetrazole with chloroacetyl chloride was studied.

Full text of DOI:10.1007/s11167-005-0389-6

Russian Journal of Applied Chemistry, Vol. 78, No. 5, 2005, pp. 773 775. Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 5,
2005, pp. 787 789.
Original Russian Text Copyright
2005 by Baranov, Tsypin, Malin, Laskin.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of 2-Chloromethyl-5-aryl-, 2-Chloromethyl-
5-(5-methyl-2-furyl)-, and 2-Chloromethyl-5-(1,5-dimethyl-
2-pyrrolyl)-1,3,4-oxadiazoles from Tetrazole Derivatives
A. B. Baranov, V. G. Tsypin, A. S. Malin, and B. M. Laskin
Prikladnaya Khimiya Russian Scientific Center, St. Petersburg, Russia
Received October 26, 2004
Abstract Acetylation of 5-aryltetrazoles, 5-(5-methyl-2-furyl)tetrazole, and 5-(1,5-dimethyl-2-pyrrolyl)tetra-
zole with chloroacetyl chloride was studied.
1,3,4-Oxadiazoles are key fragments of various
drugs, from antiviral agents to antidepressants; they
are used as organic scintillators and are components
of specialty polymerizing formulations, etc. [1].
120 C. Following the procedures from [8 10], we
prepared 5-phenyltetrazole I, 5-(2-chlorophenyl)tetra-
zole II, 5-(2-nitrophenyl)tetrazole III, 5-(2-ethoxy-
phenyl)tetrazole IV, 5-(3-methylphenyl)tetrazole V,
5-(2,4-dimethoxyphenyl)tetrazole VI, 5-(3,4,5-tri-
methoxyphenyl)tetrazole VII, and also previously un-
known 5-(1,5-dimethyl-2-pyrrolyl)tetrazole VIII and
5-(5-methyl-2-furyl)tetrazole IX. The reaction condi-
tions, yields, melting points, and analytical data for
VIII, IX, and products of their further transformations
The goal of this study is the development of a one-
pot procedure for preparing 5-aryl-2-chloromethyl-
1,3,4-oxadiazoles and previously unknown 2-chloro-
methyl-5-(5-methyl-2-furyl)- and 2-chloromethyl-5-
(1,5-dimethyl-2-pyrrolyl)-1,3,4-oxadiazoles from ap-
propriate tetrazole derivatives. These 1,3,4-oxadia-
zoles are of interest as biologically active substances
and reagents for further fine organic synthesis. Simi-
larly to other 1,3,4-oxadiazoles [2], they can be in-
volved in the peptide synthesis by the subsequent
reactions with amino acids.
1
(X XVIII) are given in Table 1, and the H NMR
data, in Table 2.
H
N
NaN + NH Cl
N
N
4
3
RCN
R
+ NaCl
NH
+
,
3
DMF
N
2,5-Disubstituted 1,3,4-oxadiazoles of various
structures can be prepared by several procedures. The
starting compounds can be carboxylic acids and hy-
drazine; they are converted into diacylhydrazides via
several intermediates. The cyclodehydration of diacyl-
I IX
R4
R = R3
Me
Me
,
,
.
hydrazides under the action of POCl yields 1,3,4-
N
Me
VIII
3
O
R1
I VII
R2
oxadiazoles; these compounds can also be prepared
by cyclodehydration of diaroylhydrazines and diacyl-
hydrazines under the action of various dehydrating
agents (organic acid anhydrides, PCl , H SO [2 5]).
IX
3
1
2
3
4
1
2
4
R = R = R = R = H (I); R = Cl, R = R = R =
1
2
3
2
4
1
5
2
4
H (II); R = NO , R = R = R = H (III); R = OEt,
2
2
3
1
4
3
1
3
4
A procedure developed in [6] for preparing 2,5-di-
aryl-1,3,4-diazoles by the reactions of tetrazoles with
benzoyl chlorides in o-xylene or toluene on heating
was applied here to the synthesis of 2-chloromethyl-
5-aryl-, 2-chloromethyl-5-(5-methyl-2-furyl)-, and
2-chloromethyl-5-(1,5-dimethyl-2-pyrrolyl)-1,3,4-oxa-
diazoles from tetrazoles and chloroacetyl chloride.
R = R = R = H (IV); R = Me, R = R = R = H
2
4
2
3
(V); R = R = OMe, R = R = H (VI); R = R =
4
R
= OMe (VII).
From tetrazoles I IX, we prepared 2-chloromethyl-
5-phenyl-1,3,4-oxadiazole X, 2-chloromethyl-5-(2-
chlorophenyl)-1,3,4-oxadiazole XI, 2-chloromethyl-5-
(2-nitrophenyl)-1,3,4-oxadiazole XII, 2-chloromethyl-
Tetrazoles are prepared starting from aromatic and 5-(2-ethoxyphenyl)-1,3,4-oxadiazole XIII, 2-chloro-
heterocyclic nitriles [7]. Their azidation with NaN is
methyl-5-(3-methylphenyl)-1,3,4-oxadiazole XIV,
2-chloromethyl-5-(2,4-dimethoxyphenyl)-1,3,4-oxadi-
3
performed in the presence of NH Cl in DMF at 110
4
1070-4272/05/7805-0773 2005 Pleiades Publishing, Inc.

774
BARANOV et al.
Table 1. Reaction conditions, melting points, elemental analyses, and yields of VIII XVIII
Reaction conditions
Found, %
H
Calculated, %
Com-
pound
Yield,
%
mp, C
Formula
T,
C
, h
C
N
C
H
N
VIII
IX
X
115 120
110 115
115 120
14
5
5
188 187
174 175
119 120,
(129 131 [2])
120 122,
(93 94 [3])
71 72,
51.50
48.04
55.48
5.51
4.02
3.55
42.91 C7H9N5
37.30 C6H6N4O
14.42 C9H7ClNO2
51.53 5.52 42.95
48.00 4.00 37.33
55.53 3.60 14.40
81
85
86
XI
120 125
105 110
4
4
47.12
45.10
2.60
2.50
12.20 C9H6Cl2N2O
17.52 C9H6ClN3O3
47.16 2.62 12.22
45.09 2.51 17.54
87
83
XII
(65 68 [3])
75 76
XIII
XIV
XV
115 120
110 115
120 125
120 125
3
5
4
8
55.30
57.52
51.85
50.60
4.60
4.31
4.31
4.56
11.73 C11H11ClN2O2 55.34 4.61 11.74
13.41 C10H9ClN2O 57.55 4.32 13.43
11.00 C11H11ClN2O3 51.87 4.32 11.0
9.86 C12H13ClN2O4 50.62 4.57 9.84
84
86
93
89
61 62
143 145
120 122,
(215 [3])
76 78
XV
XVII
XVIII 110 115
110 115
10
5
51.03
48.35
4.72
3.52
19.85 C9H10ClN3O
14.10 C8H7ClN2O2
51.06 4.73 19.86
48.36 3.53 14.11
80
92
88 89
Table 2. 1H NMR spectra pf V XVI in DMSO-d6
1H NMR spectrum, , ppm
other signals
Compound
CH2Cl
VIII
2.28 s (3H, CH3), 3.93 s (3H, NCH3), 5.91 d (1H, pyrrole), 6.69 d (1H, pyrrole), 16.06 s
(1H, NH-tetrazole)
IX
2.42 s (3H, CH3), 6.26 d (1H, furan), 7.06 d (1H, furan), 16.40 s (1H, NH-tetrazole)
X
4.90 s (2H) 7.33 7.94 m (5H, phenyl)
XI
4.97 s (2H) 7.31 7.93 m (4H, phenyl)
XII
XIII
XIV
XV
XVI
XVII
XVIII
5.01 s (2H) 7.87 8.18 m (4H, phenyl)
5.11 s (2H) 4.18 q (2H, OCH2), 1.37 t (3H, CH3), 7.10 7.84 m (4H, phenyl)
5.12 s (2H) 2.42 s (3H, CH3), 7.45 7.85 m (4H, phenyl)
4.73 s (2H) 3.91 s (3H, OCH3), 3.92 s (3H, OCH3), 6.91 7.59 m (3H, phenyl)
4.98 s (2H) 3.90 s (6H, OCH3), 3.78 s (3H, OCH3), 7.22 s ((2H), phenyl)
4.71 s (2H) 6.02 d (1H, pyrrole), 6.80 d (1H, pyrrole), 3.93 s (3H, NCH3), 2.29 s (3H, CH3)
4.99 s (2H) 6.35 d (1H, furan), 7.17 d (1H, furan), 2.44 s (3H, CH3)
azole XV, 2-chloromethyl-5-(3,4,5-trimethoxyphenyl)-
1,3,4-oxadiazole XVI, and also previously unknown
2-chloromethyl-5-(1,5-dimethyl-2-pyrrolyl)-1,3,4-oxa-
diazole XVII and 2-chloromethyl-5-(5-methylfuryl)-
1,3,4-oxadiazole XVIII. These compounds are poten-
tially bioactive and are of considerable interest as
drug precursors.
R4
R = R3
Me
Me
,
,
.
N
Me
O
R1
4
R2
X XVI
XVIII
XVII
H
1
2
3
1
2
3
4
N
R = R = R = R = H (X); R = Cl, R = R = R =
N
N
1
2
3
4
1
N
N
O
CH2 Cl
H (XI); R = NO , R = R = R = H (XII); R =
2
R
CH2 Cl
+ HCl
R
+
2
3
4
2
1
3
OEt, R = R = R = H (XIII); R = Me, R = R =
O
Cl
N
I IX
4
1
3
2
4
X XIII
R = H (XIV); R = R = OMe, R = R = H (XV);
2
3
4
,
R
= R = R = OMe (XVI).
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 5 2005

SYNTHESIS OF 2-CHLOROMETHYL-5-ARYL-, 2-CHLOROMETHYL-...
775
1,3,4-Oxadiazoles X XVIII were prepared in 80
93% by a one-pot procedure involving the reaction of
I IX with chloroacetyl chloride in o-xylene at 110
120 C for 3 10 h. The structures of VIII XVIII were
distilled off at 20 mm Hg. The remaining solution was
slowly poured with cooling into 10% NaOH. The pre-
cipitate thus formed was filtered off, dried in air, and
recrystallized from ethanol.
1
confirmed by elemental analysis and H NMR spec-
troscopy. The melting points given in the literature for
X XII and XVI are different and depend on the syn-
thesis procedure. We determined the melting points of
VIII XVIII (Table 1) on a PTP device at a heating
CONCLUSION
5-Aryl- and 5-heteryltetrazoles react with chloro-
acetyl chloride in o-xylene to form 5-aryl-2-chloro-
methyl-1,3,4-oxadiazoles, 2-chloromethyl-5-(1,5-di-
methyl-2-pyrrolyl)-1,3,4-oxadiazole, and 2-chloro-
methyl-5-(5-methyl-2-furyl)-1,3,4-oxadiazole in 80
93% yields.
1
rate of 1 deg min .
EXPERIMENTAL
1
The H NMR spectra were recorded on a DPX-300
spectrometer (300 MHz), solvent DMSO-d , internal
6
REFERENCES
reference TMS. The elemental analysis was performed
on a Hewlett Packard automatic C, H, N analyzer.
The melting points were determined on a PTP device.
The TLC analyses were performed on Silufol UV-254
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3
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3
furan and 3 g of NH Cl. The mixture was cooled, and
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4
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oxadiazole XVII, and 2-chloromethyl-5-(5-methyl-
2-furyl)-1,3,4-oxadiazole XVIII. A 5-g portion of
I IX was dissolved in 30 ml of o-xylene. The solution
was heated with stirring to 30 40 C, and 3.6 g of
chloroacetyl chloride in 10 ml of o-xylene was added.
The mixture was cooled, and excess o-xylene was
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 5 2005