O -iodoxybenzoic acid mediated oxidative desulfurization initiated domino reactions for synthesis of azoles

Article abstract of DOI:10.1021/jo2025509

A systematic exploration of thiophilic ability of o-iodoxybenzoic acid (IBX) for oxidative desulfurization to trigger domino reactions leading to new methodologies for synthesis of different azoles is described. A variety of highly substituted oxadiazoles, thiadiazoles, triazoles, and tetrazoles have been successfully synthesized in good to excellent yields, starting from readily accessible thiosemicarbazides, bis-diarylthiourea, 1,3-disubtituted thiourea, and thioamides.

Full text of DOI:10.1021/jo2025509

Article
pubs.acs.org/joc
o-Iodoxybenzoic Acid Mediated Oxidative Desulfurization Initiated
Domino Reactions for Synthesis of Azoles
Pramod S. Chaudhari, Sagar P. Pathare, and Krishnacharaya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
S
* Supporting Information
ABSTRACT: A systematic exploration of thiophilic ability of
o-iodoxybenzoic acid (IBX) for oxidative desulfurization to
trigger domino reactions leading to new methodologies for
synthesis of different azoles is described. A variety of highly
substituted oxadiazoles, thiadiazoles, triazoles, and tetrazoles
have been successfully synthesized in good to excellent yields,
starting from readily accessible thiosemicarbazides, bis-diary-
lthiourea, 1,3-disubtituted thiourea, and thioamides.
planned and various methods were developed, as summarized
in Scheme 1, and are discussed here case by case.
INTRODUCTION
■
Azoles are of paramount importance to medicinal chemistry
and pharmaceutical industry in numerous ways and find wide
applications in agricultural and material research.1 Despite
myriad synthetic methods available in the literature, the advent
of new efficient and short routes to access them is of practical
significance and is most welcome. In the past two decades,
hypervalent organoiodine(V) reagents have emerged as
versatile reagents for organic transformations with far reaching
synthetic applicability.2 They find wide applications in the field
of medicinal and natural product research due to their mild
oxidative property and carbon−carbon and carbon−heteroa-
tom bond-forming ability.3 According to recent literature,
hypervalent iodine reagents have been used for desulfurization
purposes,4 but o-iodoxybenzoic acid (IBX)−sulfur chemistry, in
particular, is less explored, and few significant transformations
reported are deprotection of dithianes.5 New transformations
revealed by our group include oxidation of sulfides to
sulfoxides,6 ring expansion of dihydro-1,4-dithiins and dihy-
dro-1,4-dithiepines to the corresponding 1,3-dithiolanes and
1,3-dithianes,7 oxidative dimerization of thioamides to 1,2,4-
thiadiazoles,8 and more recently, oxidative desulfurization of
1,3-disubstituted thioureas to carbodiimides.9 With the knowl-
edge acquired through these investigations on IBX−sulfur
interactions and considerable potential of carbodiimide
methodology for construction of various nitrogen containing
heterocycles, we envisaged and developed a one-pot synthesis
of azoles.
2-Amino-1,3,4-oxadiazoles 3. It was envisaged that
intramolecular oxidative cyclization reactions on to carbodii-
mide A, generated from thiosemicarbazides 2, could lead to
formation of 2-amino-1,3,4-oxadiazoles 3 due to favorable
entropy requirement (Scheme 1, Route I). Under similar
conditions, bis-diarylthioureas 4 could lead to formation of 2,5-
diamino-1,3,4-thiadiazoles 5 through intramolecular cyclization
reaction via carbodiimide intermediate B (Scheme 1, Route II).
2-Amino-1,3,4-oxadiazoles are useful chemical entities and
exhibit a broad spectrum of biological activities such as anti-
inflammatory,10a analgesic,10a hypertensive,10a diuretic,10a anti-
convulsant,10b muscle relaxant,10c antineoplastic,10d insectici-
dal,10e and herbicidal activities.10f Apart from their latent
potential in medicinal and agricultural chemistry, they also find
applications in the field of materials science such as
photosensitizers, liquid crystals, and electron-transporting
layers in organic light emitting diodes (LEDs).11 Despite
wide applications, the development of mild and efficient
methods for their synthesis has received less attention. General
methods reported in the literature for synthesis of 2-amino-
1,3,4-oxadiazoles can be classified into two categories: (i)
cyclodehydration of semicarbazides,12 including use of
dehydrating agents such as POCl3, SOCl2, concentrated
H2SO4, the Burgess reagent, Appel conditions, and phospho-
nium reagents and (ii) cyclodesulfurization of thiosemicarba-
zides,13 by use of I2/NaOH, tosyl chloride, alkylating agents
such as methyl iodide and ethyl bromoacetate, carbodiimides,
mercuric salt, and lead oxide. These approaches suffer from one
or the other drawbacks such as harsh reaction conditions,
RESULTS AND DISCUSSION
■
We reasoned that intra- and intermolecular trapping of
generated carbodiimide by different nucleophiles could lead
to construction of azoles. With this reasoning, present work was
Received: December 22, 2011
Published: March 16, 2012
© 2012 American Chemical Society
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Scheme 1. IBX-Mediated Domino Reactions and Synthesis of Azoles
a
Table 1. Optimization of Reaction Conditions for Preparation of 3d
b
entry
hypervalent iodine reagent
TEA (equiv)
time (min)
yield (%)
1
2
3
4
5
6
7
DIB
IBX
nil
nil
nil
2
360
360
360
10
78
68
65
84
96
80
70
DMP
DIB
IBX
DMP
IBX
2
10
2
10
1
60
a
Reaction conditions: thiosemicarbazide 2d (0.5 g, 1.75 mmol), hypervalent iodine reagent (1.75 mmol), and triethylamine in an appropriate
b
amount in DCM (10 mL) were stirred for the mentioned time, and temperature was maintained at 0 °C. Isolated yield.
multiple byproduct formation, and use of corrosive and toxic
reagents. The use of a o-iodoxybenzoic acid (IBX)/triethyl-
amine (TEA) system addresses many of these problems.
4-Pheny-1-(2-phenylacetyl) thiosemicarbazide 2d was used
as a model substrate, and reaction conditions were optimized
with different hypervalent iodine reagents, moles of TEA, time,
and results, as summarized in Table 1.
Suitability of other solvents such as DMSO, acetonitrile, ethyl
acetate, and THF were investigated, and all were found
suitable; however, the reaction was clean in the case of DCM.
We tested other hypervalent reagents viz. Dess−Martin
periodinane (DMP) and diacetoxyiodobenzene (DIB) with or
without combination of triethylamine, and in all cases yield of
3d was lower compared to that obtained with IBX (Table 1,
entries 1, 3, 4, and 6). It should be noted that yield of reaction
was significantly reduced with decrease in equivalents of
triethylamine employed (Table 1, entries 5 and 7). The overall
results reflected the IBX/TEA system to be superior for this
transformation.
To explore the scope of the reaction, several 2-amino-1,3,4-
oxadiazoles 3 were successfully synthesized in good to excellent
yields, and results are given in Table 2. In general, all the
reactions were fast and completed in just 10 min, giving
comparable yields irrespective of the nature of substituent on
the aromatic rings (Table 2, entries 3f−3i). It is well-known
that IBX can oxidize phenol to corresponding quinone (even at
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a
Table 2. Substrate Scope for 2-Amino-1,3,4-oxadiazoles 3
a
Optimized reaction conditions: thiosemicarbazide (1 equiv), IBX (1 equiv), and TEA (2 equiv) were stirred in DCM for 10 min at 0 °C. Yields are
1
isolated; products were characterized by mp, IR, H NMR, and MS (ESI).
0 °C); however, we did not observe any such oxidation product
(Table 2, entries 3g and 3h) indicating high chemoselectivity.
The present method efficiently extended for synthesis of
methyl 5-(2-(1-methyl-1H-indol-3-yl)ethylamino)-1,3,4-oxadia-
zole-2-carboxylate (Table 2, entry 3m), a common intermediate
employed as heterodiene by Boger et al. for synthesis of vinca
alkaloids.14
Scheme 2. Representative Postulated Mechanism of
Desulfurization for Synthesis of 2-Amino-1,3,4-oxadiazoles
and Role of TEA
According to recent literature on desulfurization by hyper-
valent iodine reagents,4,9 herein, we would postulate
representative reaction mechanism of desulfurization for
synthesis of 2-amino-1,3,4-oxadiazoles 3 as shown in Scheme 2.
Initially, intermediate Y is formed by nucleophilic attack of
sulfur on electrophilic iodine assisted by triethylamine. Then,
intermediate Y could follow two paths, i.e., path “a”, where
nucleophilic displacement of sulfur by oxygen leading to
cyclization followed by tautomerization giving oxadiazole, or in
the case of path “b”, formation of carbodiimide intermediate A
followed by cyclization. The precipitation of elemental sulfur
supports the proposed mechanism. The role of TEA, a base,
was considered to be dual: to solublize IBX in DCM and
facilitate transformations at different steps by activation of
hydrazides/thisemicarbazides.
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2,5-Diamino-1,3,4-thiadiazoles 5. Drug resistance has
become a serious problem in the treatment of infectious
diseases caused by bacteria, fungi, and viruses. The search for
new antimicrobial agents is one of the most challenging tasks to
medicinal chemists. In particular, 1,3,4-thiadiazoles have been
widely employed in drug discovery programs because of their
versatile biological properties such as antimicrobial, antituber-
culosis, anti-inflammatory, anticonvulsant, antioxidant, and
antifungal properties.15 Numerous methods are available in
the literature16 for preparation of 1,3,4-thiadiazoles employing
different precursors. However, there are only a few methods
based on oxidative cyclization of bis-diaryl thioureas 4 because
formation of number of byproducts is a major concern.
Methods based on alkali-catalyzed thermal cyclization of bis-
diaryl thiourea 4 results in very low yield of 2,5-diamino-1,3,4-
thiadiazole 5, and modification using microwave heating did
not show any improvement; instead, the reaction mass was
messy, posing difficulty in separation.17 In the past few years,
desulfurizing agents viz. chloranil, bromonil,18 and very recently
iodine19 are utilized for this transformation; however, good
yields have been observed only in the case of iodine-based
methods. In our approach, we utilized IBX/TEA system for
desulfurization leading to a new method for preparation of 2,5-
diamino-1,3,4-thiadiazoles 5 starting from bis-diaryl thioureas 4,
and the results are summarized in Table 3.
of cis amides and carboxylic acids in medicinal chemistry with
tunable liphophilicity. This class of compounds has great
potential as NAD(P)H oxidase inhibitors,20 glucokinase
activators,21 hepatitis C virus (HCV) protease S3 inhibitors,22
calcitonine gene-related peptide receptor antagonist,23 and
synthetic intermediates for bioactive molecules.24 Synthetic
methods for 1,5-disubstituted tetrazoles based on metal
catalyzed coupling reactions of 5-chloro-1-phenyltetrazole via
Suzuki−Miyaura−Negishi pathway and more recently by direct
C−H arylation/alkenylation of 1-substituted tetrazoles show
promising results.25 Other methods include reaction of
secondary amides or thioamides with PCl5/HN3, TMSN3/
Ph3P/DEAD, and TMSN3/Et3N/Hg(II); however, these
methods suffer from long reaction times, tedious workup, and
use of toxic metals.26 A good number of methods are known for
synthesis of 1,5-disubtituted tetrazoles; however, because of
their importance, development of new and efficient synthetic
methods remains an attractive area of research. We explored
our approach and scope of the reaction with synthesis of aryl
and heteroaryl tetrazoles, and results are given in Table 4. High
a
Table 4. Substrate Scope for 1,5-Disubstituted Tetrazoles 7
Table 3. Representative Examples for 2,5-Diamino-1,3,4-
a
thiadiazoles 5
a
Optimized reaction conditions: thiourea (1 equiv) was added to a
stirred solution of IBX (1 equiv)/TEA (3 equiv) in DMF for 10 min,
and then NaN3 (3 equiv) was added portionwise, and stirring was
continued for 3 h at rt. Yields are isolated; products are characterized
1
by mp, IR, H NMR, and MS (ESI).
a
Optimized reaction conditions: bis-diarylthiourea 4 (1 equiv), IBX (1
equiv), and TEA (2 equiv) were stirred in DCM for 10 min at 0 °C.
Yields are isolated, and products are characterized by mp, IR, 1H
NMR, and MS (ESI).
yields were observed in the case of 1,5-diaryl tetrazoles (Table
4, entries 7a, 7b, and 7e), whereas yields were on the lower side
in the case of tetrazoles when one of the substituent R1 is alkyl
(Table 4, entries 7d and 7f). A noteworthy feature is the
stability of the acid-sensitive furan moiety under the reaction
conditions (Table 4, entries 7e and 7f).
5-Aminotetrazoles 9. After successful synthesis of 1,5-
disubstituted tetrazoles, we premised that intermolecular
trapping of carbodiimide intermediate D, generated by
oxidative desulfurization of 1,3-disubstituted thioureas, by
external nucleophiles such as sodium azide and hydrazides
could lead to corresponding 5-aminotetrazoles 9 and 1,2,4-
triazoles 10 (Scheme 1, Route IV), respectively. 5-Amino-
tetrazoles constitute an important class of compounds that
possess widespread applications such as high energy density
materials,27 useful ligands,28 and important synthetic inter-
The reactions were carried out under the same conditions
employed for synthesis of 2-amino-1,3,4-oxadiazoles 3. High
yield was observed with bis-diaryl thiourea containing electron-
donating substituent (Table 3, entry 5b), while yield was
somewhat lower observed with electron-withdrawing substitu-
ent (Table 3, entry 5d).
Synthesis of Tetrazoles. 1,5-Disubstituted Tetrazoles 7.
It is quite logical that desulfurization of thioamides 6 with IBX/
TEA system would be expected to give 1,5-disubstituted
tetrazoles 7 via nucleophilic displacement of IBX activated
complex C by azide ion and subsequent electrocyclization
(Scheme 1, Route III). Tetrazoles are considered as bioisosteres
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mediates in pharmaceutical and natural product research.29
Methods for synthesis of 5-(substituted amino) tetrazoles are
divided into four main categories:30 (i) amino group or ring
functionalization of 5-aminotetrazole, (ii) the nucleophilic
substitution of a leaving group in the 5-position of tetrazole
with amines, (iii) reactions of aminoguanidine derivatives with
sodium nitrite, and (iv) various azide-mediated tetrazole ring
constructions including addition of azide to carbodiimides,
cynamides, and nucleophilic substitution by azide ion on
chloroformamidines, aminoiminomethanesulfonic acid, and di-
and trisubstituted (benzotriazolyl)-carboximidamides. Our
approach falls under the category viz. azide-mediated tetrazole
ring construction starting from 1,3-disubstituted thiourea via
carbodiimide intermediacy, whereas those approaches reported
in the literature totally relied on the use of mercury or lead salts
for desulfurization. More recently, the same transformation has
been reported by using molecular iodine. It shows promising
results but with the limitation of not being applicable for
synthesis of molecules such as N,1-dialiphatic-1H-tetrazol-5-
amines.18 For the development of our method, the reaction was
optimized, taking 1-butyl-3-phenylthiourea 8b (R2 = phenyl
and R3 = butyl, Table 5) as a model substrate with respect to
followed by addition of NaN3 (3 equiv) portionwise with
continued stirring for 3 h at rt, we synthesized various 5-
aminotetrazoles 9 in good to excellent yields, as shown in Table
5.
1-Phenyl-5-aminotetrazole from the terminal phenylthiourea
was obtained in good yield (Table 5, entry 9a). High yields of
N,1-disubstituted tetrazoles were observed in cases where
thioureas were substituted at least with one aromatic nucleus
(Table 5, entries 9b−9f), while yields were moderate in the
case of dialiphatic substituted thioureas (Table 5, entries 9g and
9h). It should be mentioned here that formation of
regioisomeric tetrazoles is possible in the case of unsymmetri-
cally substituted thioureas. The possible preponderance of the
observed regioisomers, N-aryl substituted tertrazoles (Table 5,
entries 9a−9f) and others, could be due to the difference in the
pKas of the precursor amines attached to the thioureas.19 The
guanidyl intermediate E (Scheme 1, Route IV), formed with
protonation of more basic amine (higher pKa) with imine
group on the other side and vice versa following the attack by
azide group on to the first formed unsymmetrical carbodiimide,
undergoes electrocyclization giving products where the amine
having lower pKa goes to the ring nitrogen and the other amine
having higher pKa is part of the exocyclic nitrogen.
a
Table 5. Substrate Scope for 5-Aminotetrazoles 9
Synthesis of 3-Amino-1,2,4-triazoles 10. As an exten-
sion of this study, we explored the preparation of 3-amino-
1,2,4-triazoles 10 from 1,3-disubtituted thioureas 8 (Scheme 1,
Route IV). Triazoles show a wide range of biological activities
such as antifungal,31 antimicrobial,32 antiviral,33 anti-inflamma-
tory,34 antiasthmatic,35 and antiproliferative36 activities and are
also used as amide bond isostere for design of receptor ligands
in order to enhance their pharmacokinetic properties.37
Synthesis of 3-amino-1,2,4-triazole has been accomplished
from thiourea using mercury(II) and more recently silver salts
as a key reagent for the desulfurization purpose.38 Other
methods, based on solid phase synthesis strategy using acid
hydrazide resin and amidines in the presence of molecular
sieves, acylated amidrazones obtained from N-resin bound
thioamides on subsequent cyclization in presence of acetic acid,
suffer from drawbacks such as harsh reaction conditions and
longer reaction times.39 To explore the scope of our method,
we tested various 1,3-disubstituted thioureas 8 with formyl
hydrazide, and results are shown in Table 6. Good yields of
triazoles were observed with electron-donating substituent
(Table 6, entry 10b) as compared to electron-withdrawing
substituent (Table 6, entry 10c). Further exploration of this
transformation to exploit its potential is underway.
In conclusion, we have demonstrated the multifaceted use of
a homogeneous IBX/TEA system for construction of azoles in
one pot via oxidative desulfurization approach from easy to
prepare starting materials. In the literature, many of these
reactions were carried out by using toxic heavy metals. In the
present approaches, (i) intramolecular trapping of in situ
generated carbodiimide-like intermediate from thiosemicarba-
zides and bis-diarylthioureas by oxygen and sulfur nucleophile,
respectively, provide an access to a range of 2-amino/thio-1,3,4-
oxadiazoles and 2,5-diamino-1,3,4-oxadiazoles in an excellent
yield, and (ii) intermolecular trapping of in situ generated
carbodiimide from thioamide and thiourea by azide and
hydrazide nucleophiles leads to highly substituted tetrazoles
and triazoles in moderate to good yields. Because of rapid
access to highly substituted N-containing heterocycles by these
approaches and occurrence of these heterocycles in natural
a
Optimized reaction conditions: thiourea (1 equiv) was added to a
stirred solution of IBX (1 equiv)/triethylamine (3 equiv) in DMF for
10 min, and then NaN3 (3 equiv) was added portionwise, and stirring
was continued for 3 h at rt. In the cases of 9e and 9g, a mixture of
regioisomeric tetrazoles was obtained. Yields are isolated, and products
1
are characterized by mp, IR, H NMR, and MS (ESI).
moles of TEA and NaN3 and time (refer to Table S1,
Supporting Information (SI)). We screened different solvents
such as DMSO, DMF, acetonitrile, DCM, and THF, but the
reaction was clean and high yielding in DMF. With the
optimized conditions of reacting thiourea (1 equiv), IBX (1
equiv), and triethylamine (3 equiv) in DMF for 10 min
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were dried over Na2SO4 and evaporated to afford the crude product,
which was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate combination) to afford 0.42 g of 7a
as a white solid in 82% yield. The product was confirmed by mp, IR,
1H NMR, and ESI-MS.
Table 6. Representative Examples for 3-(Substituted
Amino)-1,2,4-triazoles 10
a
General Experimental Procedure for Preparation of 5-
Aminotetrazole (9a−9h). 1,3-Disubstituted thiourea 8b (0.5 g,
2.59 mmol) was added to a stirred solution of IBX (0.72 g, 2.59
mmol)/TEA (1 mL, 7.77 mmol) in DMF (10 mL) for 5 min. Then,
NaN3 (0.5 g, 7.77 mmol) was slowly added to the reaction mixture
with continued stirring for 3 h at rt. After completion, the reaction
mixture was poured into a saturated solution of NaHCO3 (20 mL).
The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried over Na2SO4 and evaporated to
afford the crude product, which was purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate combination) to
afford 0.5 g of 4b as a white solid in 90% yield. The product was
1
confirmed by mp, IR, H NMR, and ESI-MS.
General Experimental Procedure for Preparation of 3-
Amino-1,2,4-triazole (10a−10c). 1,3-Diphenyl thiourea (0.5 g,
2.19 mmol) was added to a stirred solution of IBX (0.65 g, 2.19
mmol)/TEA (1 mL, 7.11 mmol) in DMF (10 mL) for 5 min. Then,
NaN3 (0.45 g, 7.04 mmol) was slowly added to the reaction mixture
with continued stirring for 3 h at rt. After completion, the reaction
mixture was poured into a saturated solution of NaHCO3 (20 mL).
The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried over Na2SO4 and evaporated to
afford the crude product, which was purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate combination) to
afford 0.37 g of 10a as a white solid in 72% yield. The product was
a
Optimized reaction conditions: thiourea (1 equiv) was added to a
stirred solution of IBX (1 equiv)/triethylamine (3 equiv) in DMF for
10 min, and then HCONHNH2 (3 equiv) was added portionwise, and
stirring was continued for 3 h at rt. Yields are isolated, and products
1
are characterized by mp, IR, H NMR, and MS (ESI).
1
products and active pharmaceutical ingredients, we are hopeful
that these one-pot methods will hold great potential.
confirmed by mp, IR, H NMR, and ESI-MS.
5-Phenyl-1,3,4-oxadiazole-2-amine (3a). Yield 92%: white
solid, mp 246−248 °C (lit. 244−247 °C); IR (KBr, thin film) νmax
1
(cm−1) 3365, 3290, 3059, 1596, 1490, 1448; H NMR (300 MHz,
EXPERIMENTAL SECTION
■
DMSO-d6) δ 7.81 (br s, 2H, NH2), 7.64 (m, 1H), 7.58 (d, J = 8.2 Hz,
2H), 7.29 (d, J = 8.2 Hz, 2H); MS (ESI) m/z (M + H)+ 161.87.
N,5-Diphenyl-1,3,4-oxadiazole-2-amine (3b). Yield 92%: white
solid, mp 218−220 °C (lit. 218−220 °C); IR (KBr, thin film) νmax
General Methods. All products are well-known compounds and
were characterized by comparing physical and spectral properties with
literature values. 1H NMR spectra were recorded on 300 and 400 MHz
spectrometer in CDCl3 and DMSO-d6.
1
(cm−1) 3385, 3059, 1560, 1495, 1440; H NMR (400 MHz, DMSO-
General Experimental Procedure for Preparation of 2-
Amino/thio-1,3,4-oxadiazole (3a−3m). Thiosemicarbazide 2d
(0.5 g, 1.75 mmol) was added over a cooled, temperature ∼0 °C,
and stirred solution of IBX (0.49 g, 1.75 mmol) and TEA (0.5 mL, 3.5
mmol) in dichloromethane (10 mL). The mixture was stirred at 0 °C
for 10 min. The reaction was then quenched with saturated aqueous
NaHCO3 and extracted with dichloromethane (3 × 10 mL). The
combined organic layers were dried over Na2SO4 and evaporated to
afford the crude product, which was purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate combination) or
recrystallization to afford 0.42 g of 3d as a white solid in 96% yield.
d6) δ 7.02 (t, J = 7.3 Hz, 1H), 7.33 (dd, J = 7.3, 7.5 Hz, 2H), 7.40 (m,
3H), 7.60−7.65 (m, 2H), 7.95 (m, 2H), 9.66 (s, 1H, NH); MS (ESI)
m/z (M + H)+ 237.90.
N-Ethyl-5-phenyl-1,3,4-oxadiazole-2-amine (3c). Yield 86%:
white solid, mp 129−130 °C (lit. 128−130 °C); IR (KBr, thin film)
νmax (cm−1) 3305, 3050, 1560, 1475, 1420; 1H NMR (400 MHz,
CDCl3) δ 1.42 (t, J = 8.2 Hz, 3H), 3.50 (q, J = 8.2 Hz, 2H), 5.41 (bs,
1H), 7.45 (m, 3H), 7.91 (d, J = 7.3 Hz, 2H); MS (ESI) m/z (M + H)+
190.20.
5-Benzyl-N-phenyl-1,3,4-oxadiazole-2-amine (3d). Yield 96%:
white solid, mp 179−180 °C (178−180 °C); IR (KBr, thin film) νmax
(cm−1) 3325, 3030, 1540, 1485, 1440; 1H NMR (400 MHz, CDCl3) δ
7.30 (1H, m), 7.45−7.50 (m, 7H), 7.93 (d, J = 7.4 Hz, 2H), 4.61 (d,
2H), 5.20 (bs, 1H); MS (ESI) m/z (M + H)+ 252.13.
N,5-Dibenzyl-1,3,4-oxadiazol-2-amine (3e). Yield 90%: white
solid, mp 122−124 °C (lit. 120−122); IR (KBr, thin film) νmax (cm−1)
3332, 3030, 1545, 1465, 1420; 1H NMR (300 MHz, DMSO-d6) δ 4.01
(s, 2H), 4.33 (s, 2H), 7.22 (dd, J = 7.5, 8.3 Hz, 2H), 7.52 (m, 3H),
7.26 - 7.29 (dd, J = 7.5, 8.4 Hz, 2H), 7.34 −7.37 (m, 3H), 8.01 (t, 1H,
NH); MS (ESI) m/z (M + 1)+ 266.28.
N-Benzyl-5-o-tolyl-1,3,4-oxadiazol-2-amine (3f). Yield 88%:
white solid, mp 125−127 °C (lit. 126−128 °C); IR (KBr, thin film)
νmax (cm−1) 3325, 3025, 1570, 1445, 1428; 1H NMR (300 MHz,
DMSO-d6) δ 2.53 (s, 3H), 4.45 (s, 2H), 7.25−7.29 (dd, J = 6.8, 3.6,
2H), 7.41−7.34 (m, 2H), 7.35−7.37 (d, J = 7.2, 8.2 Hz, 2H), 7.40 (m,
1H), 7.68−7.70 (d, J = 7.2 Hz, 2H), 8.3 (t, 1H); MS (ESI) m/z (M)+
265.20 (M)+.
2-(5-(Phenylamino)-1,3,4-oxadiazol-yl)phenol (3g). Yield
92%: white solid, mp 223−224 °C (lit. 223−224 °C); IR (KBr, thin
film) νmax (cm−1) 3325, 3020, 1560, 1485, 1440; 1H NMR (300 MHz,
DMSO-d6) δ 6.97−7.03 (dd, J = 7.4, 3 Hz, 2H), 7.04−7.07 (m, 1H),
1
The product was confirmed by mp, IR, H NMR, and ESI-MS.
General Experimental Procedure for Preparation of 2,5-
Diamino-1,3,4-thiadiazole (5a−5d). Bis-diaryl thiurea 4a (0.5 g,
1.65 mmol) was added over a cooled, temperature ∼0 °C, and stirred
solution of IBX (0.49 g, 1.65 mmol) and TEA (0.5 mL, 3.5 mmol) in
dichloromethane (10 mL). The mixture was stirred at 0 °C for 10 min.
The reaction was then quenched with saturated aqueous NaHCO3 and
extracted with dichloromethane (3 × 10 mL). The combined organic
layers were dried over Na2SO4 and evaporated to afford the crude
product, which was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate combination) to afford 0.38 g of 5a as
1
a white solid in 86% yield. The product was confirmed by mp, IR, H
NMR, and ESI-MS.
General Experimental Procedure for Preparation of 1,5-
Disubstituted Tetrazole (7a−7f). Thioamide 6a (0.5 g, 2.34 mmol)
was added to a stirred solution of IBX (0.65 g, 2.34 mmol)/TEA (1
mL, 7.11 mmol) in DMF (10 mL) for 5 min. Then, NaN3 (0.45 g,
7.04 mmol) was slowly added to the reaction mixture with continued
stirring for 3 h at rt. After completion, the reaction mixture was poured
into a saturated solution of NaHCO3 (20 mL). The aqueous layer was
extracted with ethyl acetate (3 × 15 mL). The combined organic layers
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7.32 (m, 1H), 7.35−7.38 (m, J = 7.6, 2 Hz, 1H), 7.38−7.43 (dd, J =
7.6, 2 Hz, 2H), 7.59−7.67 (m, 2H), 10.20 (s, 1H) 10.74 (s, 1H); MS
(ESI) m/z (M − H)+ 252.73.
1-Cyclohexyl-5-phenyl-1H-tetrazole (7d). Yield 74%: mp 131−
133 °C (lit. 131−133 °C); IR (KBr, thin film) νmax (cm−1) 2928, 1640,
1520, 1165, 1040; 1H NMR (400 MHz, CDCl3) δ 1.25−1.40 (m, 4H),
1.60 (m, 2H), 1. 95−2.14 (q, J = 8.3 Hz, 4H), 4.20 (quin, J = 8.4 Hz,
1H), 7.40 (dd, 1H), 7.60 (m, 2H), 7.85 (m, 1H); MS (ESI) m/z (M +
H)+ 229.27.
2-(5-(Benzylamino)-1,3,4-oxadiazol-yl)phenol (3h). Yield
94%: white solid, mp 129−130 °C (lit. 128−130 °C); IR (KBr, thin
film) νmax (cm−1) 3315, 3040, 1530, 1485, 1428; 1H NMR (300 MHz,
DMSO-d6) δ 4.49 (s, 2H), 6.93−7.03 (dd, J = 7.8, 3.2 Hz, 2H), 7.24
(m, 1H), 7.30 (m, 1H), 7.33−7.37 (m, J = 8.2, 7.4 Hz, 1H), 7.55−7.69
(dd, J = 8.2, 2.2 Hz, 2H), 7.95−7.97 (m, 2H), 8.53 (s, 1H), 10.10 (s,
1H); MS (ESI) m/z (M − H)+ 266.20.
5-(Furan-2-yl)-1-phenyl-1H-tetrazole (7e). Yield 80%: IR (KBr,
1
thin film) νmax (cm−1) 3030, 1650, 1545, 1170, 1020, 1069; H NMR
(400 MHz, CDCl3) δ 7.55−7.68 (m, 3H), 7.45−7.52 (m, 3H), 7.20−
7.28 (m, 1H), 7.0−7.1 (m, 1H); MS (ESI) m/z (M + H)+ 213.62.
1-Cyclohexyl-5-(furan-2-yl)-1H-tetrazole (7f). Yield 74%: mp
58−60 °C (lit. 58−60 °C); IR (KBr, thin film) νmax (cm−1) 2928,
N-Benzyl-5-(2-chlorophenyl)-1,3,4-oxadiazol-2-amine (3i).
Yield 92%: white solid, mp 119−120 °C (lit. 118−120 °C); IR
1
1
(KBr, thin film) νmax (cm−1) 3345, 3030, 1540, 1475, 1430; H NMR
1650, 1510, 1145, 1020; H NMR (400 MHz, CDCl3) δ 1.20−1.40
(m, 4H), 1.75−1.80 (m, 2H), 1. 95−2.14 (m, 4H), 4.80 (m, 1H), 6.45
(m, 1H), 6.65 (m, 1H), 7.25 (m, 1H); MS (ESI) m/z (M − H)+
217.74.
(300 MHz, DMSO-d6) δ 8.46 (br s, 1H), 4.45 (s, 2H), 7.25−7.33 (dd,
J = 6.8, 1.8 Hz, 2H), 7.36−7.47 (m, J = 6.8, 1.8, 8.2 Hz, 2H), 7.50 (dd,
J = 8.2, 2.1 Hz, 2H), 7.60−7.82 (m, 3H); MS (ESI) m/z (M +H)+
286.00.
1-Phenyl-1H-tetrazol-5-amine (9a). Yield 71%: white solid, mp
165−168 °C (lit. 166−168 °C); IR (KBr, thin film) νmax (cm−1) 3329,
3158, 2983, 1659, 1594, 1578, 1498, 1460, 1317, 1141, 1130, 1093; 1H
NMR (400 MHz, DMSO-d6 + CDCl3) δ 6.82 (bs, 2H), 7.51−7.55 (m,
5H); MS (ESI) m/z (M + H)+ 162.07.
N-Benzyl-5-(2-nitrophenyl)-1,3,4-oxadiazol-2-amine (3j).
Yield 94%: yellow solid, mp 123−125 °C (123−126 °C); IR (KBr,
1
thin film) νmax (cm−1) 3365, 3050, 1545, 1459, 1420, 1350; H NMR
(300 MHz, DMSO-d6) δ 4.48 (s, 2H), 7.25 (dd, J = 6.8, 3 Hz, 2H),
7.39 (m, 3H), 8.00−8.03 (d, J = 9 Hz, 2H), 8.32−8.35 (d, J = 9 Hz,
2H), 8.62 (t, 1H); MS (ESI) m/z (M − H)+ 295.27.
N-Butyl-1-phenyl-1H-tetrazol-5-amine (9b). Yield 90%: white
solid, mp 105−107 °C (lit. 104−105 °C); IR (KBr, thin film) νmax
1
(cm−1) 3320, 1652, 1530, 1560, 1468, 1315, 1160, 1043; H NMR
N-Benzyl-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amine (3k).
Yield 94%: white solid, mp 139−140 °C (lit. 137−139 °C); IR
(400 MHz, CDCl3) δ 0.95 (t, J = 8.4 Hz, 3H), 1.4 (m, J = 8.4 Hz, 2H),
1.65 (m, J = 8.2 Hz, 2H), 3.45 (t, J = 8.2 Hz, 2H), 4.30 (bs, 1H),
7.45−7.60 (m, 5H); MS (ESI) m/z (M)+ 218.50.
1
(KBr, thin film) νmax (cm−1) 3345, 3030, 1540, 1475, 1430; H NMR
(300 MHz, DMSO-d6) δ 4.47 (s, 2H), 7.23−7.25 (dd, J = 6.9, 3.1 Hz,
2H), 7.28−7.39 (m, 3H), 7.69−7.71 (d, J = 5.7 Hz, 2H), 8.70−8.72
(d, J = 5.7 Hz, 2H), 8.63 (t, 1H); MS (ESI) m/z (M + H)+ 253.10.
N-Ethyl-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amine (3l). Yield
92%: white solid, mp 131−132 °C (131−132 °C); IR (KBr, thin film)
νmax (cm−1) 3350, 3030, 1567, 1460, 1410; 1H NMR (300 MHz,
DMSO-d6) δ 3.23−3.30 (q, J = 7.2 Hz, 2H), 1.14−1.19 (t, J = 7.2 Hz,
3H), 7.68−7.70 (d, J = 5.7 Hz, 2H), 8.69−8.71 (d, J = 5.7 Hz, 2H),
7.98 (t, 1H); MS (ESI) m/z (M − H)+ 189.07.
1-Phenyl-N-propyl-1H-tetrazol-5-amine (9c). Yield 88%: IR
(KBr, thin film) νmax (cm−1) 3310, 1620, 1545, 1440, 1325, 1110,
1
1020; H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 8.3 Hz, 3H), 1.65
(m, J = 8.3, 2H), 3.50 (t, J = 8.1 Hz, 2H), 4.25 (bs, 1H), 7.50−7.65
(m, 5H); MS (ESI) m/z (M + H)+ 204.10.
N,1-Diphenyl-1H-tetrazol-5-amine (9d). Yield 94%: white solid,
mp 158−160 °C (lit. 158−159 °C); IR (KBr, thin film) νmax (cm−1)
3340, 1650, 1520, 1430, 1340, 1145, 1050; 1H NMR (400 MHz,
CDCl3) δ 6.35 (bs, 1H), 7.10 (dd, J = 7.5, 3.1 Hz, 2H), 7.40 (dd, J =
7.4, 2.8 Hz, 2H), 7.50 (m, 3H), 7.70 (m, 3H); MS (ESI) m/z (M +
H)+ 238.93 (M +H)+.
Methyl 5-[(2-(1-Methyl-1H-indol-3-yl)ethyl)amino]-1,3,4-ox-
adiazole-2-carboxylate (3m). Yield 94% white solid, mp143−145
°C (lit. 144−146 °C); IR (KBr, thin film) νmax (cm−1) 3430, 1740,
1635, 1515, 1068; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz,
1H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (m, 1H), 7.18 (t, 1H), 6.95 (s,
1H), 5.45 (s, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.73 (m, 2H), 3.15 (t,
2H); MS (ESI) m/z (M − H)+ 298.90.
N-Benzyl-1-phenyl-1H-tetrazol-5-amine (9e). Yield 86%: IR
(KBr, thin film) νmax (cm−1) 3330, 1650, 1525, 1460, 1342, 1125,
1
1010; H NMR (400 MHz, CDCl3) δ 4.70 (m, 2H), 6.25 (bs, 1H),
7.20 (dd, J = 7.6, 2.6 Hz, 2H), 7.30 (m, 3H), 7.35 (m, 3H), 7.50 (dd, J
= 7.2, 3.1 Hz, 2H); MS (ESI) m/z (M + H)+ 252.73.
N2,N5-Diphenyl-1,3,4-thiadiazole-2,5-diamine (5a). Yield 86%:
white solid, mp 239−241 °C (lit. 239−242 °C); IR (KBr, thin film)
νmax (cm−1) 3341, 1556, 1470, 1420, 1152; 1H NMR (300 MHz,
CDCl3+DMSO-d6) δ 6.80 (dd, J = 7.2, 2.1 Hz, 1H), 7.20 (m, 3H),
8.45 (s, 2H); MS (ESI) m/z (M + H)+ 269.16.
N-Cyclohexyl-1-phenyl-1H-tetrazol-5-amine (9f). Yield 92%:
white solid, mp 129−131 °C (lit. 128−130 °C); IR (KBr, thin film)
νmax (cm−1) 3332, 1670, 1550, 1430, 1310, 1165, 1030; 1H NMR (400
MHz, CDCl3) δ 1.20 (m, 2H), 1.40−1.45 (m, J = 8.1, 8.5 Hz, 4H),
1.65−1.80 (m, J = 8.1, 8.5 Hz, 4H), 3.80 (quin, J = 8,1 Hz, 1H), 4.10
(bs, 1H), 7.45 (dd, J = 7.6 Hz, 2.9 Hz, 2H), 7.60 (m, J = 7.6, 7.6, 2.9
Hz, 3H); MS (ESI) m/z (M − H)+ 242.16.
1-Benzyl-N-propyl-1H-tetrazol-5-amine (9g). Yield 80%: IR
(KBr, thin film) νmax (cm−1) 3345, 1650, 1550, 1430, 1310, 1135,
1050; 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 5H), 5.32 (s, 2H), 3.74
(bs, 1H), 3.31 (m, 2H), 1.51 (m, 2H), 0.8 (m, 3H); MS (ESI) m/z (M
+ H)+ 218.62.
N,1-Dicyclohexyl-1H-tetrazol-5-amine (9h). Yield 92%: white
solid, mp 202−204 °C (lit. 204−2−5 °C); IR (KBr, thin film) νmax
(cm−1) 3340, 1442, 1350, 1120, 1040; 1H NMR (400 MHz, CDCl3) δ
1.15 (m, J = 8.1, 6H), 1.40 (m, J = 8.2 Hz, 4H), 1.45−1.60 (m, J = 8.5
Hz, 6H), 1.70−1.85 (m, J = 7.9 Hz, 4H), 3.50 (m, 2H), 4.10 (bs, 1H);
MS (ESI) m/z (M + H)+ 250.80.
N-4-Diphenyl-4H-1,2,4-triazole-3-amine (10a). Yield 72%: mp
216−218 °C (lit. 214−216 °C); IR (KBr, thin film) νmax (cm−1) 3315,
1650, 1548, 1492, 1453, 1020; 1H NMR (400 MHz, DMSO-d6) δ 6.85
(dd, J = 7.2, 3.1 Hz, 1H), 7.20 (d, J = 7.4 Hz, 2H), 7.40 (dd, J = 7.2,
7.4 Hz, 2H), 7.60 (m, 5H), 8.50 (bs, 1H); MS (ESI) m/z (M + H)+
237.47.
N2,N5-Bis(4-methoxyphenyl)-1,3,4-thiadiazole-2,5-diamine
(5b). Yield 92%: white solid, mp 235−238 °C (lit. 235−237 °C); IR
1
(KBr, thin film) νmax (cm−1) 3331, 1540, 1450, 1440, 1050, 1152; H
NMR (300 MH, CDCl3+DMSO-d6) δ 3.80 (s, 6H), 6.80 (d, J = 8.2
Hz, 4H), 7.45 (d, J = 8.2 Hz, 4H), 8.15 (s, 2H); MS (ESI) m/z (M +
H)+ 329.41.
1,5-Diphenyl-1H-tetrazole (7a). Yield 82%: white solid, mp
142−143 °C (lit. 142−143 °C); IR (KBr, thin film) νmax (cm−1) 1640,
1
1510, 1145, 1030; H NMR (400 MHz, CDCl3) δ 7.15 (dd, J = 8.1,
2.8 Hz, 1H), 7.40 (dd, J = 8.2, 7.5 Hz, 2H), 7.67 (dd, J = 8.2, 2.8 Hz,
2H), 7.45 (m, 3H), 7.90 (dd, J = 8.1, 2.3 Hz, 2H); MS (ESI) m/z (M
+ H)+ 223.93.
5-(4-Methoxyphenyl)-1-phenyl-1H-tetrazole (7b). Yield 84%;
1
IR (KBr, thin film) νmax (cm−1) 1660, 1550, 1125, 1010; H NMR
(400 MHz, CDCl3) δ 3.80 (s, 3H), 6. 95 (d, J = 7.6 Hz, 2H), 7.45 (d, J
= 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.90 (m, 3H); MS (ESI) m/z
(M + H)+ 253.20.
1-Benzyl-5-phenyl-1H-tetrazole (7c). Yield 76%: white solid,
mp 90−92 °C (lit. 88−90 °C); IR (KBr, thin film) νmax (cm−1) 1660,
1
1550, 1135, 1010; H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 7.20
N-4-Bis(4-methoxyphenyl)-4H-1,2,4-triazol-3amine (10b).
Yield 80%: mp 184−186 °C (lit. 183−184 °C); IR (KBr, thin film)
νmax (cm−1) 3335, 1630, 1560, 1478, 1460, 1046; 1H NMR (400 MHz,
(m, 2H), 7.40−7.50 (m, 5H), 7.75−7.80 (m, 3H); MS (ESI) m/z (M
− H)+ 236.90.
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Article
DMSO-d6) δ 3.70 (s, 3H), 3.80 (s, 3H), 6.80 (d, J = 8.2 Hz, 2H), 7.10
(d, J = 8.2 Hz, 2H), 7.40 (m, 3H), 8.20 (s, 1H), 8.16 (d, 2H); MS
(ESI) m/z (M + H)+ 297.43.
Martynaitis, V.; Holzer, W.; Manelinckx, S.; De Kimpe, N.; Sackus, A,
S. Tetrahedron 2006, 62, 3309 and references cited therein.
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N,4-Bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (10c). Yield
70%: mp 224−226 °C (lit. 226−228 °C); IR (KBr, thin film) νmax
1
(cm−1) 3345, 1660, 1510, 1458, 1430, 1056; H NMR (400 MHz,
DMSO-d6) δ 7.30 (d, J = 7.3 Hz, 2H), 7.50 (m, 4H), 7.70 (d, J = 7.6
(14) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Table S1, spectroscopic data of all product entries in Tables
1
1−4 with their H NMR, MS (ESI) copies, and supporting
references. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Hassan, A. A.; Mourad, A. F. E.; El-Shaieb, K. M.; Abou-Zied, A.
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AUTHOR INFORMATION
Corresponding Author
*Fax: +91-22-33611020. Tel.: +91-22-33611111. E-mail:
kgap@rediffmail.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors (P.S.C. and S.P.P.) appreciate the financial support
provided by the University Grant Commission (UGC), India.
We are thankful to University of Mumbai and IIT Mumbai for
Spectral analysis. We are also thankful to M/S Omkar
Chemicals, India for the generous gift of IBX.
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