A new method of reducing 2-mercapto-substituted 1,3,4-oxadizoles: Synthesis of acylhydrazine derivatives

Article abstract of DOI:10.2174/157017810791514670

A new method has been developed for the synthesis of acylhydrazines 5a-g by the reduction of unsymmetrical 1,3,4-oxadiazoles 4a-g by using sodium borohydride/acetic acid combination. Later on, acylhydrazines 5a-g were converted to their corresponding sulfonamide derivatives 6a-d.

Full text of DOI:10.2174/157017810791514670

Letters in Organic Chemistry, 2010, 7, 411-414
411
A New Method of Reducing 2-Mercapto-Substituted 1,3,4-Oxadizoles:
Synthesis of Acylhydrazine Derivatives
Muhammad Zareefa, Rashid Iqbal†,a, Javid Hussain Zaidi*,a, Muhammad Arfana, Muhammad Alib
and Khalid M. Khan*,b
aDepartment of Chemistry, Quaid-i- Azam University, Islamabad 45320, Pakistan
bH. E. J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi 75270, Pakistan
Received August 14, 2008: Revised March 11, 2010: Accepted March 30, 2010
Abstract: A new method has been developed for the synthesis of acylhydrazines 5a-g by the reduction of unsymmetrical
1,3,4-oxadiazoles 4a-g by using sodium borohydride/acetic acid combination. Later on, acylhydrazines 5a-g were
converted to their corresponding sulfonamide derivatives 6a-d.
Keywords: Acylhydrazine derivatives, benzenediazasulfonamides, 1,3,4-oxadiazole, sodium acytoxyborohydride.
INTRODUCTION
diborane? Since, this has been demonstrated that the
transitory reducing specie of the reaction between sodium
borohydride and acetic acid is sodium acyloxyborohydride
[1].
Several methods have been reported for the reduction of
amides to their corresponding amines. These methods
involve lithium aluminum hydride, diborane, lithium
trimethoxy aluminum hydride, aluminum hydride, sodium
borohydride-pyridine,
sodium
borohydride-aluminum
RESULTS AND DISCUSSION
chloride, lithium cyanoborohydride, sodium borohydride-
glyme and sodium borohydride-triethyloxonium fluoroborate
[1]. Many reports have appeared in literature for the
combined use of sodium borohydride and carboxylic acids as
an effective and versatile reducing pair [2]. This reagent
system is used to carry out a wide range of reductions of
nitrogen- and oxygen-based functionalities [1c,3].
Combination of borohydrides and carboxylic acids forms
acyloxyborohydrides which generates robust reducing
species. The particular combination of NaBH4 and acetic
acid, well-known as Gribble conditions, is commonly used to
effect non-enantioselective reductions of ketones and imines.
It is worth noting that crystal structure of compound 6a
and the antibacterial activities of the acylhydrazine
derivatives 6a-d are already reported earlier by our research
group [9,10]. Since, the method for the synthesis of
acylhydrazines from oxadiazoles by means of monosodium
acyloxyborohydride is new one; it is worthy to elucidate the
chemistry of the reaction as oxadiazole formation of
hydrazides which is found to be a good protecting method.
We intended to reduce carboxamides containing 1,3,4-
oxadiazole 4a-g into their corresponding amines by using
sodium borohydride in acetic acid in a 1:1 molar ratio
(sodium monoacyloxyborohydride) [1]; however, it came up
as a surprise that 1,3,4-oxadiazole nucleus has been reduced
instead to the corresponding acyl hydrazine derivatives. To
the best of our knowledge, there is only one report on the
reductions of 1,3-oxazoles and 1,3,4-oxadiazoles to acyl
hydrazines by using mercury (Hg) electrode and several
symmetrical 1,3,4-oxadiazoles had been reduced by this
methodology [11].
It has been reported that the reaction of sodium
borohydride and carboxylic acids in a molar ratio of 1:1
produces 1 equivalent of hydrogen along with the formation
of sodium monoacyloxyborohydrides; however, the
reduction with this specie does not occur at room
temperature [4-6].
Marshal et al. [7] reported the hydroboration of 1-hexene
with sodium borohydride and acetic acid. Later, the
procedure was also verified by Hach [8] and he found that it
is extremely useful hydroboration reagent. However, it was
not clear that the reducing specie in this method is actually
We assume that acyl hydrazine derivatives may be
masked/protected as their 1,3,4-oxadiazole derivatives which
can be deprotected by using sodium monoacyloxyboro-
hydride. Hydride cleavage of this important heterocyclic
class of compounds has opened up a new avenue for the
methodology development in organic chemistry. The new
method is simple, straight forward, easily executable and
affords high yields of the corresponding acylhydrazines.
*Address correspondence to these authors at the Department of Chemistry,
Quaid-i- Azam University, Islamabad 45320, Pakistan; Tel: 0092-51-
90642107; Fax: 0092-51-90642241; E-mail: javid_zaidi@yahoo.com
H. E. J Research Institute of Chemistry, International Center for Chemical
and Biological Sciences, University of Karachi 75270, Pakistan; Tel:
00922134824910; Fax: 00922134819018.; E-mail: khalid.khan@iccs.edu,
hassaan2@super.net.pk
In this communication, we describe the conversion of
1,3,4-oxadiazole 4a-4g into their corresponding acylhydr-
azines by using sodium borohydride in acetic acid (in 1:1
molar ratio) under reflux (Scheme 1).
†Deceased in 2008.
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

412 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Zareef et al.
O
CS2
N
N
N
N
BrCH2CO2Et
NaHCO3 aq.
NH2
R1
N
OEt
H
R1
O
S
R1
O
SH
EtOH, KOH
O
1a-g
2a-g
3a-g
NH3 (g), EtOH
N
NaBH4/Acetic acid
Dioxane, reflux, 2 h
N
O
H
N
NH2
R1
O
S
R1
N
CH3.HCl
H
HCl (g), CHCl3
O
5a-g
R2
4a-g
Et3N, DMAP
CHCl3, 24 h
SO2Cl
R2
Compounds 1-5
O
O2S
N
a) R1 = C6H5
b) R1 = 3-CH3-C6H4
c) R1 = 3-OCH3-C6H4
d) R1 = 2-Cl-C6H4
e) R1 = 3-Cl-C6H4
f) R1 = 4-Cl-C6H4
g) R1 = 3-Pyridyl
R1
N
CH3
H
6a-d
6a) R1 = C6H5
6b) R1 = C6H5
6c) R1 = 3-Cl-C6H4 R2 = CH3
6d) R1 = 3-Cl-C6H4 R2 = Cl
R2 = CH3
R2 = Cl
Scheme 1. Synthesis of acylhydrazine derivatives 5a-g and their corresponding sulfonamide derivative.
The conversion of 1,3,4-oxadiazole into their
corresponding acylhydrazines by using sodium borohydride
in acetic acid has been studied in detail to evaluate the
general applicability of the method (Scheme 1). The method
has been found to be easily executable and provides high
yields. The products were separated as hydrochloride salts.
The resulting acylhydrazine hydrochlorides 5a-g were then
reacted with various sulfonylchlorides in the presence of
triethylamine and N,N-dimethylaminopyridine (DMAP) to
get benzenediazasulfonamides 6a-d. All the synthesized
compounds were characterized satisfactorily by elemental
analysis, IR, 1H NMR, 13C NMR and mass spectral data.
1106 elemental analyzer. Thin layer chromatography (TLC)
was performed on precoated silica gel 60 F254 aluminum
sheets (Merck).
General Procedure for the Synthesis of Benzenediazasul-
fonamides (6a-d)
To a stirred suspension of sodium borohydride (50
mmol) and corresponding oxadiazole derivative 4a-g (10
mmol) in 1,4-dioxane (25 mL), acetic acid (50 mmol) in
dioxane (10 mL) was added over a period of 10 minutes at
°
10 C, the resulting mixture was stirred under reflux for 1.5-
2.5 h [1]. The progress of the reaction was monitored by
TLC (pet. Ether : EtOAc, 2:1). After completion of reaction,
the solvent was removed in vacuo and the excess reagent
was decomposed with water and extracted with chloroform
(3 x 50 mL). Combined organic extract was washed with
water and dried over anhydrous sodium sulfate. The
resulting chloroform layer was treated with dry HCl and the
mixture was evaporated in vacuo, the residues were
crystallized from methanol-ether to corresponding acylhy-
drazine hydrochlorides 5a-g. The resulting acylhydrazine
hydrochlorides were used without further purification in the
next step for the synthesis of corresponding benzenediaza-
sulfonamides 6a-d. Appropriate acylhydrazine hydrochloride
5 (2 mmol), triethylamine (4 mmol) and DMAP (25 mg) in
anhydrous chloroform were stirred at room temperature for
fifteen minutes. An appropriate sulfonyl chloride (2.2
mmol), dissolved in anhydrous chloroform was then added
In conclusion, acylhydrazides can be masked as their
oxadiazole derivatives which can easily be deprotected by
the use of sodium monoacyloxyborohydride in good yields.
GENERAL EXPERIMENTAL
Melting points were determined on a Gallenkamp digital
melting point apparatus and were uncorrected. IR spectra
were recorded in KBr disc on a FT-IR model FTS 3000 MX
spectrometer. NMR spectra were recorded in Acetone-d6,
DMSO-d6 or CDCl3 on a Bruker (300, 400 and 500 MHz;
13C, 75 MHz) spectrophotometer. The chemical shifts of
proton signals are in parts per million (ppm) downfield from
tetramethylsilane (TMS) as an internal standard. EI-MS
spectra were recorded on MAT 311A mass spectrometer (EI
at 70eV). Elemental analysis was performed on a Carlo Erba

Synthesis of Acylhydrazine Derivatives
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
413
to the reaction mixture drop wise. The reaction mixture was
stirred at room temperature for 24 h. The progress of the
reaction was monitored by TLC (MeOH : CHCl3, 1:2). After
reaction completion, the reaction mixture was washed with
saturated solution of sodium bicarbonate, brine and water
followed by extraction with chloroform (2 x 25 mL).
Combined organic layers were dried over anhydrous Na2SO4
and concentrated under vacuum. The isolated product was
purified by recrystallization from aqueous ethanol (30%).
NMR (Acetone-d6, 500 MHz): ꢀ 3.31 (NCH3), 7.51 (d, 1H, J
= 8.0 Hz, ArH), 7.58-7.62 (m, 1H, ArH), 7.68 (d, 1H, J = 8.0
Hz, ArH), 7.78 (d, 2H, J = 8.5 Hz, ArH), 7.99 (s, 1H, ArH),
7.97 (d, 2H, J = 8.5 Hz, ArH), 9.67 (br. s, 1H, NH); EIMS:
m/z (rel. abund. %) 359 (M+, 17), 295 (3), 246 (2), 212 (17),
185 (2), 184 (5), 183 (50), 172 (27), 156 (4), 155 (61), 140
(21), 139 (100), 111 (37), 75 (5), 65 (12); Anal. calcd. for
C14H12N2O3SCl2 (359.2276): C, 46.81; H, 3.37; N, 7.81;
Found: C, 46.77; H, 3.39; N, 7.75.
N-benzoyl-Nꢀ-methyl-Nꢀ-(4-methylbenzenesulfonyl)hydra-
zine (6a)
ACKNOWLEDGEMENT
Yield = 81%; M.p. = 190-191 C; IR ꢁmax cm-1: 3254
(NH), 3053 (CH-Ar), 1672 (C=O), 1354, 1157 (SO2); H
°
This work was financially supported by the Higher
Education Commission (HEC) Pakistan under the National
Research Program for Universities.
1
NMR (Acetone-d6, 500 MHz): ꢀ 2.43 (s, 3H, CH3-Ar), 3.19
(s, 3H, NCH3), 7.41 (d, 2H, J = 8.0 Hz, ArH), 7.44-7.56 (m,
5H, ArH), 7.79 (d, 2H, J = 7.95 Hz, ArH), 9.55 (br. s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz): ꢀ 21.1, 41.5, 127.5,
127.8, 128.2, 128.5, 129.5, 137.3, 139.1, 139.2, 177.7;
EIMS: m/z (rel. abund. %) 305 (M+, 22), 304 (6), 160 (7),
258 (5), 256 (6), 212 (7), 198 (4), 183 (3), 156 (4), 155 (9),
150 (17), 149 (100), 139 (8), 119 (12), 106 (46), 105 (100),
103 (2), 91 (35), 77 (92), 76 (3), 65 (10); Anal. calcd. for
C15H16N2O3S (304.3646): C, 59.19; H, 5.31; N, 9.20; Found:
C, 59.23; H, 5.28; N, 9.26.
NOTE
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(NH), 3031 (CH-Ar), 1675 (C=O), 1356, 1158 (SO2); H
°
1
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(br. s, 3H, NCH3), 7.28 (d, 2H, J = 7.9 Hz, ArH), 7.40 (d,
1H, J = 8.0 Hz, ArH), 7.49 (d, 1H, J = 7.8 Hz, ArH), 7.54-
7.58 (m, 1H, ArH), 7.72 (d, 2H, J = 8.1 Hz, ArH), 7.81 (d,
1H, J = 7.6 Hz, ArH), 7.95 (br. s, 1H, ArH), 9.62 (s, 1H,
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(6), 212 (5), 186 (2), 185 (17), 184 (12), 183 (51), 172 (37),
156 (4), 155 (21), 142 (5), 141 (61), 140 (16), 139 (100), 111
(27), 91 (53), 75 (6), 65 (12); Anal. calcd. for
C15H15N2O3SCl (338.8096): C, 53.18; H, 4.46; N, 14.17;
Found: C, 53.21; H, 4.42; N, 14.15.
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1

414 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
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