synthesis of oxadiazoles, thiadiazoles and...
TRANSCRIPT
INTRODUCTION
INTRODUCTION
Importance and a review on methods of syntheses ofpyrroles, pyrazoles, oxazoles, thiazoles, imidazoles,
1,3,4-oxadiazoles and 1,3,4-thiadiazoles
INTRODUCTION
A study on heterocyclic compounds is of great interest in pharmaceutical arena. This
has catalyzed the discovery and development of much new heterocyclic chemistry and
methods. In fact, one of the reasons for the widespread use of heterocyclic compounds is that
their structures can be suitably manipulated to achieve a required modification in function.
Besides, knowledge of heterocyclic chemistry is useful in biosynthesis and in drug
metabolism as well. Indeed, pharmaceutical and agrochemical industries have made rapid and
significant progresses to quench the quest of organic chemists in discovering and developing
suitable heterocyclic compounds for the benefit of mankind. Thus, heterocyclic chemistry
attracts scientists working not only in the area of natural products but also synthetic organic
chemistry. The pesticidal, potential chemotherapeutic, fungicidal and antiviral properties have
been the reasons for the upsurge in interest and development of these heterocyclic compounds
in general and pyrroles, pyrazoles, oxazoles, thiazoles, imidazoles, oxadiazoles and
thiadiazoles in particular. In this perspective, “A study on the synthesis and bioassay of
heterocyclic compounds” has been taken up.
Pyrroles are one of the most important classes of heteroaromatic compounds which
are components of a structural fragment of many biologically active natural products and
pharmaceutical agents. The naturally occurring polyamide antibiotics- netropsin (1),
distamycin (2), netamsa (3) and 4-aminopyrrole-2-carboxylates have been served as principal
compounds for constructing a diverse series of DNA-binding ligands exhibiting antibiotic,
antiviral and oncolytic properties.1,2 The distamycin dimers containing terephthalic linkage
display promising anti-HIV activity.3,4 Moreover, pyrroles are of pharmacological relevance
due to their anti-inflammatory and analgesic properties. The prominent examples are
keterolac (4), tolmetin (5), amtolmetin (6) and indomethacin (7).5 Sunitinib6 (8) is a multi-
targeted receptor tyrosine kinase inhibitor useful for the treatment of renal cell carcinoma and
gastrointestinal stromal tumor.
2
N
Me
NH
N
Me
O
NH
NH
NH2
O
NH
NH
NH2
O NH
NH
NH2
O NH
N
Me
NH
N
Me
O NH
N
Me
O
NH
H
O
1
2
N
MeO
NH
O
O
O
OMe
MeO
Me
CO2H
N
MeO
Cl
O NH
NH
Me
Me
O
NH
O
N
CO2H
N
MeO
Me
N
NH
NH
N
NH
NH
SO2Me
OMe
O O
N
Me
NH
O Me
NH
NH2
O
O
N CO2H
6
7 8
5
43
Pyrroles are also abundant as constituents of natural products and have broad
synthetic utility in both materials science and medicine.7,8 Pyrrole containing pharmaceuticals
include the cholesterol-lowering drug lipitor (9). Di Santo et al.9 reported pyrrolnitrin (10)
and some related nitropyrroles as antifungal agents.10
3
Cl
NH
Cl
NO2
O
NH
F
N
OHOH
HO2C
109
Furthermore, pyrrole derivatives have emerged as chemotherapeutic agents potentially
useful for inhibiting the activities of M. tuberculosis, M. avium complex, a pathogen that
greatly contributes to the death of AIDS patients.11 Zomepirac12 (11), a pyrrole derivative is
an orally effective non-steroidal anti-inflammatory drug (NSAID) that has antipyretic action,
whereas obatoclax13 (12) is in phase II clinical trials for the treatment of leukemia,
lymphoma, myelofibrosis and mastocytosis. Viminol14 (13) has both antitussive and analgesic
effects.
NH
NH
N
Me
Me
OMe Cl
N
OH
N
N
Me
Me
O
Cl
HO2C
12 1311
Pharmacologically, pyrazole and its derivatives represent one of the prominent classes
of heterocyclic compounds. Pyrazoles and annelated pyrazoles (14,15) show antimicrobial
activity.15 Pyrazole and its N-substituted derivatives are also potential inhibitors and
deactivators of liver alcohol dehydrogenase. Difenamizole (16) exhibits analgesic activity
greater than aspirin. The fluorinated pyrazoles possess high biological activities as herbicides,
fungicides, insecticides, analgesics, antipyretics and anti-inflammatory agents.16,17 The
trifluoro derivatives of pyrazoles (17) are about 0.5% as effective as an amoebicide,
comparable with emetin and metronidazole.
NNH
RO
N
N
R
SCF3
Me NNH
Me
NN
NH
O
NMeMe
Me
Ph
Ph
14 15 16 17
4
Muzolimine (18), a substituted 2-pyrazolin-5-one is a highly active diuretic. It differs
from other diuretics as it contains neither sulfonamide nor carboxyl group. Substituted 3,5-
pyrazolidinediones such as phenylbutazone (19), oxyphenbutazone (20), sulfinpyrazone (21),
bendazac (22), benzpiperylon (23), benzydamine (24) etc. are some of the important anti-
inflammatory agents.18 In addition, lonazolac (25), deracoxib (26), kebuzone (27) and
tepoxalin (28) are non-steroidal anti-inflammatory drugs which are approved for veterinary
use to treat osteoarthritis and hip dysplasia.
NN
n-Bu O
ONN
Me
Cl
Cl
NH2
O
18 19
NN
n-Bu O
O
OHCH2Ph
NN
O
O
OH
SOO
NN
O
O
Ph
20 21 22
NN
OH
Cl
O
Ph
CH2Ph
NN
O(CH2)
3NMe
2
NHNO
N
Me
PhPh
23 24 25
NNO
O
O
Ph
Ph
NN
F
FF
MeO
SO2NH2
NN
Cl
OMe
NOH
O
26 27 28
5
Further, a variety of pyrazole derivatives are synthesized as a new class of
COX-1 / COX-2 inhibitors. Although COX-2 inhibitors possess anti-inflammatory properties,
their greatest effects appear to be associated with pain relief and symptoms of osteoarthritis.
Therefore, it may be postulated that moderately selective COX-2 inhibitors are a safer
alternative to the patients with cardiovascular disease. It is found that celecoxib (29) has no
effect on platelet aggregation and did not reduce increased PG levels in cerebrospinal fluid.5
In fact, this is being used at present as an effective anti-inflammatory drug. Further,
mepiprazole (30) is a minor tranquilizer used for the treatment of anxiety neuroses.
NH
N
N
N
ClNN CF3
Br
H2NO2S
3029
The oxazole scaffold has found widespread utility in medicinal chemistry and is
present in a number of natural products. 2-Phenylamino-2-oxazoline and their derivatives
exhibit local anesthetic, sedative, blood pressure depressant and gastric fluid secretion
inhibitory effect and find application in the treatment of hypertonia and ulcers (31).19 2-(1-
Naphthylamino)oxazolines are useful as potentiators for anesthetics, hypnotics, narcotics and
analgesics.20 Apart from these, 2,4-disubstituted oxazoles and 2-oxazolines possess anti-
inflammatory, analgesic and antipyretic properties (32,33).20,21
N
O Ar
O
X
R R12
R
R
N
O
Me
Me
R2
1
N
ONH
R
R
R3
1
3131
33
2
32
Besides, acyl oxazolines have antiviral properties (34).22 4-Oxazoline acetic acid
derivatives show antidiabetic activity (35).23 Moreover, some of the oxazoline derivatives
viz., 5-alkoxy-4-methyl oxazoles are used as intermediates for drugs and vitamin B6 (36).24
Some 2,4- and 2,5-disubstituted oxazolines find applications as insecticides, acaricides,
fungicides, pesticides and nematocides (37,38).25,26
6
N
O
CO2H
R R
( )n
1 O
N
OR
Me
R1
O
N
S
Br
F
F
N
O
R'
R
R
O
N
R
R
R
35 36
3837
34
1
2
3
4
R(CH2)nOm
Rilmenidine (39), a 2-amino-2-oxazoline derivative stores adrenergic and imidazoline
receptor agonist activity and is used as an antihypertensive agent.27 The mycobactins (40)28
and vibriobactins (41)29 which contain one and two hydroxyphenyl oxazoline units
respectively, possess antibiotic activity. The oxazole ring is also present in tandem arrays in
natural products including a monochloro-bioxazole moiety in the cytotoxic agent
diazonamide A (42)30 and a 4,2-linked bioxazole in the antiviral agent hennoxazole A (43).31
2-Indolyl-5-aryl-2-oxazolines exhibit anticancer activity through inhibition of tubulin
polymerization by binding at the colchicines site (44).32
X
OH
O
NNH
O
R
O
O
R
O
NH
N
OOH
N
OH
O
R
O
N
NH
( )
( )Y
40
39
N O
NH
N NH
OO
OH
OH
OH
OH
O
ON
OH
OH N
O
NH
Cl
N
O
NH
ONH
O
NH2 Cl
OHOOH
41 42
7
N
ON
Me
OMe
OMe
OMe
O
OH
HOMe OMe
O
Me Me
N
O
Me
N
43 44
Apart from these, some oxazoline containing drugs are pemoline (45),33 to treat
attention-deficit hyperactivity disorder and narcolepsy, fenozolone (46), a psychoactive drug
and reclazepam (47), a sedative and anxiolytic drug.34 Oxaprozin (48) is a NSAID,35 used to
relieve the inflammation, swelling, stiffness and joint pain associated with osteoarthritis
and rheumatoid arthritis.
NH
O
O
NH N
O NH Me
O
N
O
O
N NCl
Cl
OHO
N
O
45 46 47 48
Thiazoles are the principal core structures present in a variety of natural products and
have acquired significance due to a wide variety of medicinal and biological properties
associated with them. Their wide range of antitumor, antiviral and antibiotic activities as well
as their ability to bind to proteins, DNA and RNA has fueled numerous synthetic and
biological investigations.36-39 Notable examples are thiangazole (49)40 and curacin A (50)41
which shows antiviral and antiproliferative activities, respectively.42 In fact, thiangazole
together with the related tantazoles, viz., tantazole B (51) constitute a unique family of
biologically interesting alkaloids, which show structures based on the linear fusion of four or
five successive 2,4-disubstituted thiazoline / oxazole rings terminating in a 2-cinnamyl or
2-isopropyl thiazoline.43 Besides, amino 2-thiazoline derivatives possess local anesthetic,
analgesic, anti-inflammatory and radio protective properties.44,45
8
N
S
S
NMe
Me
O
N
NHMe
O
Me
N
S
Me
11
8
5
49
S
NN
S
Me Me
N S
S
N MeMe
O
N
O NHMe
Me
NS
H Me
Me
H
OMe
H
50 51
7 132
19
2-Thiazoline derivatives are also effective as insect repellents, insecticides and
fungicides against Penicillium lumber mold and Aspergillus niger.46 2-Substituted
thiothiazolines and 2-alkyl, aryl and vinyl thiazolines find applications as herbicides,
bactericides, fungicides, insecticides and nematocides (52-54).47,48 It is observed that 1- and
2-naphthyl 2-thiazolines are more active nematocides than tetraamisole.49 In addition, trans
4,5-dihydrothiazoles (55) are intermediates for the development of anticancer agents and
bactericides.50
RH2CS S
N
S
N
RS OR1
S
N
R
N
SRH
RH
CH2X
52 53 54 55
1 2
1
Moreover, aminophenyl thiazolines and oxazolines are used as local anesthetics and
have more effectiveness and low toxicity to procaine,51 a natural product which contains
thiazole ring.52 Mycothiazole has anthelmintic activity (56).53 Sulfathiazole (57) is an
antibacterial agent.54 Some pyrazine containing thiazolines and thiazolidinones have
antimicrobial properties (58,59).55 Aerugine, 2-aryl-4-hydroxymethyl-2-thiazoline possess
antibiotic activity (60).56 The epothilones (61) like taxanes prevent cancer cells from dividing
by interfering with tubulin.57 Phthalylsulfathiazole (62), a sulfonamide drug is a broad
9
spectrum antimicrobial that can treat different types of infections including intestinal.
Febuxostat (63) is a urate lowering drug, an inhibitor of xanthine oxidase used in the
treatment of hyperuricemia and gout.58 Clomethiazole (64) is sedative and hypnotic drug
which prevents symptoms of acute alcohol withdrawal. Ritonavir (65) is an antiretroviral
drug and find applications to treat HIV infection and AIDS.
N
SMeMe
OH
NH
O
MeO
SOO
NH
N
S
NH2
56 57
N
N
S
N
R
NNH
O
O
R
N
N
S
N
R
NNH
O
O
O OH N
S
CH2OH
58 59 60
S
N
Me
Me
O
O OH O
OH
OR
O
NH
S
O
O
OH
O
S
N
NH
61 62
S
NMe
OH
O O
N
Cl S
NMe
NH
NH
N
NH
O
OH O
O
Me S
N
O
N
S
63 64
65
Furthermore, thiazolines constitute a family of compounds known for their usage in
flavor chemistry.59 More than 30 thiazoline structures have been identified from natural
sources,60 in particular in cooked meat59 and in certain exotic fruits such as litchis.61
10
Imidazole nucleus exhibits broad spectrum of cardiovascular activities eg.,
medetomidine (66), idazoxan (67), moxonidine (68) and clonidine (69) are α2-adrenoceptor
agonists.62 Mebendazole (70),63 oxibendazole (71),64 albendazole (72)65,66 and fenbendazole
(73) are benzimidazole drugs used to treat infestations by worms including pinworms,
roundworms, tapeworms, hookworms and whipworms. Triclabendazole (74) display high
efficacy against both immature and adult liver flukes. Omeprazole (75),67,68 rabeprazole
(76),68 dexlansoprazole (77)69 and esomeprazole (78)70 are proton pump inhibitors used in the
treatment and maintenance of patients with erosive oesophagitis and non-erosive gastro-
oesophageal reflux disease.
N
NH O
ONH
N
N
N
NH
N
NH
Cl
NH
N
NH
Cl
Cl
66 67 68 69
N
NH
NH
O O
OMe
N
NHO
MeNH
O
OMe
N
NH
S
MeO
Cl
Cl
Cl NH
NS
O
N
Me
Me
OMe
MeO
N
NH
NH
O
OS
NH
NNH
O
S
MeO
70 71
74 75
72
73
NH
NS
O
N
Me O(CH2)3OMe
NH
NS
O
N
Me O
CF3
..
N
Me
Me
SO
N
NH
OMe
MeO
76 77 78
11
Besides, pimozide (79)71 is an antipsychotic drug and mibefradil (80)72 find
application for the treatment of hypertension and chronic angina pectoris.
N
N
NH
F
F
O
F
O
O
N
NH
N
MeO
79 80
1,3,4-Oxadiazoles have attracted interest in medicinal chemistry as surrogates of
carboxylic acids, esters and carboxamides. In fact, 1,3,4-oxadiazoles and their benzal
derivatives (81) possess analgesic,73 anti-inflammatory,74 antimicrobial75 and hypoglycemic76
activities. Indeed, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole (82) and 5-(2-
naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione (83) have superior anti-inflammatory
profile with low gastric ulceration.77
O
NN
O CH
R
N CH OMe
C15H31
R
O
NN
ONH
Me
N
NHN
OS
Me
1
81
82 83
Moreover, benzylthiophenyl / phenoxyphenyl-1,3,4-oxadiazoles (84) display
anticonvulsant and antidepressant properties.78 Zibotentan79 (85) is an anticancer agent which
is in phase III clinical trial for prostate cancer. Raltegravir80 (86) is an antiretroviral drug.
Fenadiazole (87) is a hypnotic drug with a unique oxadiazole based structure. In addition to
their utility as bioactive molecules, 1,3,4-oxadiazoles are useful intermediates in organic
synthesis81 particularly as electron deficient azadienes in inverse electron demand Diel’s-
Alder reaction.82,83
12
NN
O
SO
O
N
NH
N
N
Me
OMe
ON
N
Me
N
N
O
O
NH
NH O
Me
Me
FOHMe
NN
O
OH
O
NN
O
F
R
85
86 87
84
1,3,4-Thiadiazoles are a class of heterocycles which have attracted significant interest
in medicinal chemistry. Oleson et al.84 reported the antitumor activity of 2-substituted 1,3,4-
thiadiazoles (88) since then much work has been done on these compounds.85 In fact, high
antileukemic activity is demonstrated for 1-(2,6-dichlorophenyl)-N,N'-di(1,3,4-thiadiazol-2-
yl)methylenediamine (89) which is designated as a selected agent by the National Cancer
Institute, USA.86 The ureido derivatives of 1,3,4-thiadiazoles also exhibit antileukemic
property. The carbonic anhydrase inhibitors of sulfonamide type such as acetazolamide (90)
and methazolamide (91) are extensively used in clinical medicine in the management of
diverse diseases viz., glaucoma,87-89 oedema,89 epilepsy,90 mountain sickness,91 gastric
ulcers,92 neurological disorders,87,93 acid-base disequilibria87,94 etc. Another compound from
this class of pharmacological agents, benzolamide (92) an orphan drug occupies a special
place among the known carbonic anhydrase inhibitors.95
S
NN
NH
Me
O
S
NN
NH
S
NNCl
Cl
NH
SO OS
NN
NH
Me
ONH2
88 89 90
13
SO O
NMe
O
S
NN
Me
NH2 SO O
S
NN
SOO
NH
PhNH2
91 92
Some nitroimidazolyl-1,3,4-thiadiazoles (93) possess antituberculosis activity.96 In
addition to these, 1,3,4-thiadiazole derivatives exhibit antibacterial,97 antifungal,97,98
cardiotonic,99 antitubercular,100 antidepressant,101,102 anti-inflammatory, analgesic77,103 and
antiparasitic activities.104 In fact, cefazolin (94), a first generation cephalosporin and ceftezole
(95) are used as antibiotic drugs.
S
NN
N
N
S(O) R
Me
O2N n
93
S
NN
N
NN
NS
N
NH
O
O
H
OOH
S S
NN
N
NN
NS
N
NH
O
O
H
OOH
S
94 95
Non-steroidal anti-inflammatory drugs (NSAIDS) are widely utilized for the treatment
of pain, fever and inflammation particularly arthritis. Among the most popular NSAIDS,
diclofenac (96) is one of the top 200 drugs. Replacement of carboxylic acid group of
diclofenac with heterocycles viz., 1,3,4-oxadiazoles and 1,3,4-thiadiazoles (97) exhibit an
interesting profile of anti-inflammatory activity with significant reduction in their ulcerogenic
effect.105
X
NN
NH
R
ClCl
NH
ClCl
O
OH
X = O / S
96 97
14
PYRROLES
I. Formation of carbon heteroatom bonds
Pyrroles were prepared by a well known method of Paal-Knorr condensation of 2,5-
diketones with primary amines or ammonia106 (Eqn.1). Since then, a large number of 2,5-
disubstituted pyrroles bearing an aromatic or heterocyclic substituent in position 1 were
reported by the reaction of hexane-2,5-dione, phenacylacetone and 1,2-dibenzoylethane with
three isomeric picolylamines, 2-aminomethyl-6-methylpyridine and β-diethylaminoethyl ester
of anthranilic acid.107
+EtNH2
EtO2C(CH2)2 N
Et
(CH2)2CO2Et(CH2)2CO2EtEtO2C(CH2)2 O O
Eqn. 1
Tetrasubstituted pyrroles were reported in a regiospecific manner by a two step
sequence involving Diel’s-Alder reaction of 2-oxo-3-butenoate with 2-alkoxy-1,3-pentadiene
derivatives followed by ozonolysis and Paal-Knorr cyclization108 (Eqn.2). Microwave-
assisted Paal-Knorr cyclization was also carried out with 1,4-diketoesters in the presence of
different amines.109
TIPSO
Me
+ O
CH2ORMe
TIPSO
CH2OR
O
N
NHPhth
Me
CH2OR
OTIPSO
(ii) O3 (iii) N-Aminophthalimide(i) Eqn. 2
i ii
iii
Pyrroles were also synthesized using iodine-catalyzed and montmorillonite KSF-clay
induced Paal-Knorr method. The reaction was performed by mixing the clay with a solution
of amine and ketone in dichloromethane and evaporating the solvent under reduced
pressure.110 The skeletal rearrangement of γ,γ-dialkyl-γ-amino-α,β-unsaturated carbonyl
compounds in the presence of organoaluminum Lewis acid gave substituted pyrroles through
Paal-Knorr type cyclization111 (Eqn.3).
15
Ar NH
R'
O
RRNR
Ar
R'
R
N
N
AlMe
Tf
Tf
i, ii
(i) / Toluene (ii) 1N HCl / Toluene Eqn. 3
The microwave-assisted one-pot procedure for the synthesis of alkyl substituted
pyrroles was reported by a two-component coupling of chloroenones and amines on the
surface of silica gel112 (Eqn.4). Pyrroles were also obtained from β-alkynyl ketones and
amines in the presence of silver trifluoromethanesulfonate or a mixture of gold (I) chloride,
silver trifluromethanesulfonate and triphenylphosphine.113
R R
NH2
N
R R
RR
Cl
O
+
(i) SiO2 / MW
i1 2
1 2
3
Eqn. 4
3
An efficient alkenylation of amides with 1,4-diiodo-1,3-dienes afforded substituted N-
acylpyrroles in the presence of CuI as catalyst, caesium carbonate as base and rac-trans-N,N'-
dimethylcyclohexane-1,2-diamine as ligand114 (Eqn.5). Besides, an acid promoted cyclization
reaction of sulfanyl substituted allenic aldehydes with amines gave pyrrole derivatives115
(Eqn.6). An intermolecular amination and Pd(II) catalyzed intramolecular hydroamidation of
1,3,5-triphenylpent-2-en-4-ynyl acetate yielded polysubstituted pyrroles116 (Eqn.7).
I I
RR
RR
NH2R
O
N
R R
RO
RR+
1
23
41
23
4
5
5 i
(i) CuI / ligand / Cs2CO3 / Dioxane Eqn. 5
O
RR
H
R S
R NR SR
R
RR
R NH2
1
2
3
4
5
(i) TsOH. H2O / CH2Cl2
i1
2
3 4
Eqn. 6
+5
16
AcOR
R
R
R
NHR
R
R
R
R
N R
R
RR
R
1
2 3
4
1
2 3
4
5
1
2 3
4
5
i
(i) PdCl2 / KCl Eqn. 7
+ 5R NH2
Rare-earth metal triflates are frequently used as potent environmentally benign Lewis
acids, which have the advantages of low toxicity, high stability, ease to handle, recover from
water and efficient catalysis in green media such as water, ionic liquids, super critical CO2
and solvent free conditions as well as solid supported synthesis.117 In fact, a ytterbium (III)
triflouromethanesulfonate (Yb(OTf)3) catalyzed synthesis of pyrrole derivatives from
-diketone and hydrazide proceeded from moderate to excellent yield118 (Eqn.8).
Me NHNH2
O
MeMe
O
O
N
NHMe
O
MeMe+
i
(i) Yb(OTf)3Eqn. 8
In addition to these, AlCl3-catalyzed [4+1] cycloaddition between
,-unsaturated imidoyl cyanides and isocyanides furnished polysubstituted
2-amino-5-cyanopyrroles. The former compounds were prepared from the respective ,-
unsaturated aldehydes, amines and trimethylsilyl cyanide (TMSCN) by
2-iodoxybenzoic acid (IBX) / tetrabutylammonium bromide (TBAB) mediated oxidative
Strecker reaction119 (Eqn.9). Acylvinylketoximes obtained from ketoximes and
acylacetylenes in the presence of triphenylphosphine on heating rearranged to 2- or 3-
acylpyrroles120 (Eqn.10).
H
O
R
R
H
H
NR
R
R
NC
N
R
NHR
R R
NC
1
3
4
2
i ii
1
2
3
Eqn. 9
+
R3NH2
TMSCN
(i) IBX / TBAB / MeCN (ii) AlCl3 / R4NC / Toluene
1
2
+
17
R
NOH
R
OO
Ph
ON
R
R
O
O
Ph
NR
H
R
Ph
O
O
ON
R
R
H
O
Ph
i
ii
+
(i) Ph3P / CH2Cl2 (ii)
+
Eqn. 10
1 1
1 1
II. Formation of 3,4- and C-N bonds
The reaction of -aminoketones with acetylenic ester resulted in pyrroles via a
Michael type addition121 (Eqn.11). The three component reaction of dialkyl
acetylenedicarboxylates, primary amines and β-nitrostyrene in the presence of iron (III)
chloride afforded tetrasubstituted pyrroles122 (Eqn.12). Substituted pyrroles were also
developed via the one-pot domino reactions of arylamines, acetylenedicarboxylates and
3-phenacyclideneoxindoles. The reaction mechanism involved the sequential Michael
addition and ring closure of the in situ generated β-active enamino ester.123 (Eqn.13).
+Me
O
NH2.HCl
PhNH
Me
OH
Ph
CO2Me
CO2Me NH
Me
Ph CO2Me
CO2Me
CO2Me
CO2Me
Eqn. 11(i) NaOAc / MeOH (ii) HCl / MeOH
i ii
N
CO2R
CO2R
Ar
R
R NH2
CO2R
CO2RAr
NO2
Eqn. 12
+
(i) FeCl3 (40 mol%) / Toluene
i+
1
1
1
1
18
CO2R
CO2RNH
O
O
NRO2C
NH
O
RO2CArNH2 + +
Ar'
R'
Ar'
i
R'
Ar
(i) AcOH Eqn. 13
Furthermore, pentasubstituted pyrroles were also reported by a one-pot reaction of
,-unsaturated carbonyl compounds, amines and nitroalkanes on the surface of silica in the
absence of solvent under microwave irradiation124 (Eqn.14). The reaction of amines,
aldehydes, diketone and nitroalkane under catalyst-free condition using ionic liquid as a
reaction medium or in the presence of NiCl2·6H2O produced substituted pyrroles.125,126
(Eqn.15). A novel three-component direct synthesis of substituted pyrroles was reported from
substituted anilines, nitrostyrene and 1,3-diketone in the presence of (diacetoxyiodo)
benzene127 (Eqn.16).
Me NO2R
O
R
RN
RR
R
R
Me
Eqn. 14
R4NH2 ++
(i) SiO2 / MW
i
2
3
1
4
3
2
1
H
O
MeNO2
O O
NH
O
R1NH2R2
+++
R1
R2
(i) [Hbim]BF4
i
Eqn. 15
O O
NMe
O
Me
NO2
R1NH2 ++
R1
R2
(i) DIB / EtOH
iR2
Eqn. 16
Besides, palladium-catalyzed cyclization of alkynes and 2-amino-3-iodoacrylates
furnished highly functionalized pyrroles regioselectively128 (Eqn.17). Similarly,
triphenylphosphine-promoted reaction between dialkyl acetylenedicarboxylates and
19
hydroxyethanones gave pyrrole derivatives.129 The Sonogashira coupling reaction of 2-
bromoprop-2-en-1-amine with phenylacetylene in the presence of CuI and Pd(PPh3)2Cl2
produced 1,2,4-trisubstituted pyrroles.130 Gallium(III) triflate was also used as catalyst to
promote the cyclization.131 The reaction of benzil with dimethyl acetylenedicarboxylate and
ammonium acetate in the presence of triphenylphosphine resulted in highly substituted
pyrrole derivative132 (Eqn.18).
ONHR
O
IR
N R
R
RR
O
O
R
R
1
2
+
1
2
4
i
(i) Pd(OAc)2 / LiCl / K2CO3 / DMF Eqn. 17
33
4
NH
CO2Me
CO2Me
Ph
Ph
CO2Me
CO2MeO
O
PhPh
Eqn. 18
+
(i) Ph3P / NH4 OAc / MeCN
i
The regiospecific synthesis of 4-alkoxy-2-trifluoromethylpyrroles from 5-azido-4-
alkoxy-1,1,1-trifluoropent-3-en-2-ones was reported by an Aza-Wittig cyclization in the
presence of triphenylphosphine in tetrahydrofuran133 (Eqn.19).
F3C
O OR
N3
N
H
F3C
OR
(i) Ph3P / THF Eqn. 19
i
Apart from these, tri and tetrasubstituted pyrroles were prepared from vinyl azides and
1,3-dicarbonyl compounds in the presence of Mn(III) complexes134,135 (Eqn.20). Symmetric
pyrrole-2,5-dicarboxylate derivatives were prepared by Ti(IV) mediated oxidative
dimerization of 2-azidocarboxylic esters.136 The regioselective synthesis of polysubstituted
pyrroles were developed by the reaction of α-azido chalcones with 1,3-dicarbonyl compounds
in the presence of indium trichloride137 (Eqn.21).
20
N3 Me
O O
OEtN Me
CO2Et
H
+ i
(i) Mn(OAc)3.2H2O / AcOH / MeOH Eqn. 20
O
N3
OO
NH
O OR1
R3
R4
R1 R2R3 R4
+i
(i) InCl3 / H2O / MW /Eqn. 21
R2
In addition, substituted pyrroles were directly produced from ,-unsaturated imines
and acid chlorides mediated by triphenylphosphine. The reaction proceeded by an
intramolecular Wittig pathway and provided one-step access to a diverse range of pyrrole
derivatives138 (Eqn.22).
R R
R
NR
R Cl
O
N
R
R R
RR1
2
3
+ 5
1
2
34
5i
(i) PPh3 / Et3N Eqn. 22
4
The reaction of propargyl vinyl ethers with aromatic amines resulted in substituted
pyrroles where the reaction proceeded through silver (I) catalyzed propargyl-Claisen
rearrangement, an amine condensation, and a gold (I) catalyzed 5-exo-dig heterocyclization139
(Eqn.23). Propargylic glycinates in the presence of silver nitrate undergo 5-endo-dig
cyclization and produced hydroxydihydropyrroles which on subsequent in situ dehydration
resulted in pyrrole derivatives140 (Eqn.24). Polyethylene glycol (PEG-400) was found to be
an inexpensive non-toxic and effective medium for one-pot three-component synthesis of
pyrrole derivatives from phenacyl bromides, primary amines and dialkyl
acetylenedicarboxylates141 (Eqn.25). The reaction of propargylic carbonates with β-enamino
esters in the presence of palladium catalyst afforded tetrasubstituted pyrroles142 (Eqn.26).
21
O
O
Me
OEt
Ph
N
O
OEtMe
Me
R
Ph
(i) AgSbF6 (ii) R4NH2 (iii) (Ph3P)AuCl
4
i, ii, iii
Eqn. 23
R
OH
R
TsHN
CO2MeN
R
R CO2Me
Ts
i1 12
2
(i) 10% AgNO3-SiO2 / CH2Cl2 Eqn. 24
RBr
OCO2R
CO2RN
R
R
CO2R
CO2R+ R NH2
+i
(i) PEG - 400 / Eqn. 25
2
2
2
2
1
1
OCO2Bn
Ph
ONHRO2S
OMeN
SO2R
Ph
MeO2C
N
PhMeO2C
+ +i
(i) Pd2(dba)3 / CHCl3 / THF /
Ts
Eqn. 26
The reaction of 3,5-diphenylpent-2-en-4-ynal with phenylhydroxylamine in the
presence of triethylamine and CuCl in dimethylformamide yielded pyrrole derivatives. The
former compound was obtained from bromovinyl aldehyde by Sonogashira coupling143
(Eqn.27). A copper-catalyzed reaction of amine with but-2-ynedioate resulted in pyrrole-
2,3,4,5-tetracarboxylate144 (Eqn.28).
Ph
H CHO
Ph
N
Ph O
Ph
Ph
+ PhNHOH
(i) CuCl / Et3N / DMF Eqn. 27
22
NEtO2C
EtO2C CO2Et
CO2Et
NH2
CO2Et
CO2Et
i
(i) Cu / O2
C6H4p-Me
+
Eqn. 28
III. Formation of 2,3- and 4,5- bonds
The preparation of pyrroles constitutes one of the major synthetic uses of tosylmethyl
isocyanide (TosMIC). The TosMIC based synthesis of pyrroles comprises the base induced
reaction of TosMIC with a Michael acceptor or a base induced reaction of an activated
methyl compound with 1-isocyano-1-tosyl-1-alkene (Eqn.29). Thus, the reaction of ,-
unsaturated compounds with TosMIC led to 3,4-disubstituted pyrroles145-148 (Eqn.30).
RCHO
REWG
R
Tos
NCNH
EWGR
(i) MeEWG (ii) TosMIC Eqn. 29
i
i
ii
ii
(EWG = Electron withdrawing group)
PhCO2Me
NH
CO2MePh
Eqn. 30(i) TosMIC / NaH / DMSO / Et2O
i
The reaction of olefins having two different electron withdrawing substituents with
TosMIC proceeded regiospecifically.149 On the other hand, treatment of alkynyl Michael
acceptors with TosMIC resulted in 2-tosylpyrroles150 (Eqn.31). The [2+3] cycloaddition of
,-unsaturated nitriles to methyl isocyanoacetate provided a regioselective synthesis of 2-
substituted 3,4-diarylpyrroles151 (Eqn.32). The 3-aryl- and 3,4-diarylpyrroles were also
obtained by the reaction of aryl alkenes with TosMIC.152 The coupling of chromone-3-
carboxaldehyde with TosMIC in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in tetrahydrofuran followed by deformylation yielded substituted pyrroles.153
23
R CO2Me +NH
R
Tos
CO2Me
N
R
Tos
RCO2Me
CO2Me
Eqn. 31
i
(i) TosMIC / DBU / DMF
Ar
Ar'
NC NH
Ar'Ar
CO2Me
Eqn. 32(i) CNCH2CO2Me / tBuOK
i
3,4-Disubstituted pyrroles were also synthesized by cyclocondensation of aryl styryl
sulfones and benzyl styryl sulfones with TosMIC154 (Eqn.33). However, phenyl vinyl sulfone
under similar conditions afforded 3-benzenesulfonylpyrrole and 2-(2-benzylsulfonylethyl)-4-
benzenesulfonylpyrrole.154
SO O
Ph
N
H
Ar( )n
SPhO O
Ar( )n
Eqn. 33
i
(i) TosMIC / NaH / DMSO / Et2O n = 0, 1
On the other hand, the reaction of bischalcones with TosMIC in the presence of
sodium hydride in dimethyl sulfoxide and ether furnished 3'-aryl-1'-(4-aryl-1H-pyrrol-3-yl)-
prop-2'-enone. Attempts to prepare bis pyrrolyl ketones using two equivalents of TosMIC
were not successful. However, bis pyrrolyl ketones were obtained by the treatment of
pyrrolylprop-2'-enones with one equivalent of TosMIC155 (Eqn.34). In a much similar way,
the Michael acceptors, 1-arylsulfonyl-2-styrylsulfonylethenes were also used as synthons to
develop bis pyrroles.156 Adopting similar methodology, unsymmetrical bischalcones were
also subjected to 1,3-dipolar cycloaddition reaction with TosMIC. The reaction proceeded in
a regiospecific manner resulted in the formation of 4-aryl-3-(3'-phenyl-2'-methyl-2'-
propenone)-1H-pyrrole.157 The olefin and ester functionalities in E-arylsulfonyl-
ethenesulfonylacetic acid methyl ester and E-aroylethenesulfonylacetic acid methyl ester
were also exploited to develop pyrrolyl oxazolines and thiazolines.158,159
24
O
Ar ArN
ArO
Ar
H
NN
ArO
Ar
H H
(i) TosMIC / NaH / DMSO / Et2O
i i
Eqn. 34
The 1,3-dipolar cycloaddition of polarized ketene S,S- and N,S-acetals to carbanions
derived from activated methylene isocyanides led to the formation of 2,3,4-trisubstituted
pyrroles160 (Eqn.35). Amido substituted Horner-Wadsworth-Emmons reagents also served as
precursors to 1,3-dipoles for the preparation of pyrroles.161 The reaction of 3-
phenacylideneoxindoles with tosylmethyl isocyanide produced pyrrole derivatives.162
SMe
SMeH
O2N NH
SMeO2N
CO2Et
NH
SMeO2N
Tos
(i) :C=NCH2CO2Et / DBU / DMF / N2
(ii) :C=NCH2Tos / DBU / DMF / N2Eqn. 35
i
ii
IV. Miscellaneous methods.
The coupling of enyne-imines with Fisher carbene complexes led to the formation of
alkenylpyrrole derivatives163 (Eqn.36). The regioselective reaction of phenyl α-bromovinyl
sulfone with glycine ester Schiff base in the presence of a catalytic amount of AgOAc and
excess DBU yielded pyrrole carboxylate.164 (Eqn.37.). A gold (I) catalyzed acetylenic
Schmidt reaction of homopropargyl azides also resulted in substituted pyrroles165 (Eqn.38).
N
Bu
H
NMe2N
NMe2
Bu
Me
OMei
(i) Me(OMe)C=Cr(CO)5
Eqn. 36
25
SO2
Br
N
O
OMeNH O
OMe
RR
(i) THF / AgOAc / DBU / RT
+i
Eqn. 37
BTSO
N3
Ph
Ph
N
H
H
OSTBPh
Ph
i
(i) (dppm)Au2Cl2 / AgSbF6 / MeNO2
Eqn. 38
2,5-Disubstituted and 2,4,5-trisubstituted pyrroles were synthesized from dienylazides
in the presence of a catalytic amount of ZnI2 or Rb2(O2CC3F7)4166 (Eqn.39). Dirhodium salts
efficiently catalyze the three component reaction of an imine, diazoacetonitrile and an
activated alkynyl to form substituted 1,2-diarylpyrroles. The transition metal catalyzed
decomposition of diazo compound in the presence of an imine presumably generated a
transient azomethine ylide that involved in cycloaddition with dipolarophiles167 (Eqn.40).
Gold (I) catalyzed cyclization of pentenyl allyl tosylamides resulted in substituted pyrroles
via aza-Claisen type mechanism168 (Eqn.41).
RCO2R
R N3NH
R CO2R
R
1
2
3
1
2
3
(i) ZnI2 / CH2Cl2Eqn. 39
i
R H
NR
H
N2
CNCO2R
CO2R
N
R
R
RO2C CO2R
+ +
2
2
Eqn. 40
1
1
22
i
(i) Rh(II) / CH2Cl2
NH
RR
N
RR
Tos
1 2
Tos
1 2
i
(i) Ph3PAuNTf2 / CH2Cl2 Eqn. 41
26
The Mukiyama-Michael type heterocyclization of Danishefsky’s diene with 1,2-diaza-
1,3-butadienes led to substituted pyrroles169 (Eqn.42). A regioselective synthesis of
tetrasubstituted pyrroles was reported via the classic 1,3-dipolar cycloaddition of ,-
unsaturated benzofuran-3-one and azalactones followed by spontaneous decarboxylation170
(Eqn.43). Ultrasonic exposure of an amine with 2,5-dimethoxytetrahydrofuran in the
presence of a catalytic amount of Bi(NO3)3·5H2O furnished corresponding pyrroles171
(Eqn.44). The reaction of mesoionic 1,3-oxazolino-5-olates with various sulphur ylides
proceeded via nucleophilic addition followed by opening of the oxazole ring and subsequent
cyclization to multisubstituted pyrroles172 (Eqn.45).
RN
NCOR
R
OSiMe3
OMe
N
NHR
O
RCO
R1
2
3 + 1
23
4
1
2
3
Eqn. 42
O
N
R O
R
O
O
RR
NH
OOH
R R
R
R
+
12
3
41
2
3 4
i
(i) MW
Eqn. 43
OMeO OMe N
R
RNH2
(i) Bi(NO3)3.5H2O /
+
)))
i
Eqn. 44
O
N
Me
OPh
COCF3
N
MeS CF3
Ph
Me
N
CF3
Ph
Me
+i
ii
+
-
(i) Me3S+I- / Base(ii) AcOH Eqn. 45
27
PYRAZOLINES
I. Hydrazine based reactions
The pyrazoline was first reported in 1894 by Curtius and Wirsing173 by the
spontaneous reaction of acrolein with hydrazine (Eqn.46). In fact, the cyclocondensation of
different ,-unsaturated ketones having alkyl, aromatic and heteroaromatic substituents with
hydrazine, its alkyl and aryl derivatives resulted in 2-pyrazolines.174-176 The former
compounds were also obtained from chalcone dibromide and phenylhydrazine177 (Eqn.47).
NNH
H
O
NH2NH2
Eqn. 46+
Ar
Ph
Ar'N
N Ar Ar'
O
Br
Br
Ar Ar'
O
Eqn. 47
i ii
(i) PhNHNH2.HCl / Pyridine or NBS / CCl4 (ii) PhNHNH2.HCl / DMF
The reaction of -arylsulfonylchalcones with hydrazine hydrate afforded 3,5-diaryl-4-
arylsulfonyl-2-pyrazolines178 (Eqn.48). Furthermore, several bis (2-pyrazolines) were
reported by the treatment of 1,3 and 1,4-phenylene bischalcones179,180 and bis (cinnamoyl)
phenols181 with hydrazine hydrate and its alkyl derivatives (Eqn.49).
ArSO2
Ar'CO H
Ar
ArN
N
R
Ar'ArSO2
RNHNH2+
+ RNHNH2Ar
O
Ar
O
ArN
N
R
ArN
N
R
Eqn. 48
Eqn. 49
Moreover, the reaction of bifunctional olefins, 1-aroyl-2-arylsulfonylethenes with
hydrazine hydrate and phenylhydrazine produced 5-arylsulfonyl-3-aryl-2-pyrazolines182
(Eqn.50). Similarly, acetyl / propyl / sulfonamido pyrazolines carrying a pyrazole moiety
were synthesized by the cyclocondensation of α,β-unsaturated pyrazolyl compounds with
hydrazine hydrate183 / hydrazinobenzenesulfonamide.184 The cyclocondensation of
benzofuran chalcones with norfloxacin and mefenamic acid hydrazides resulted in
28
benzofuran 2-pyrazolines.185 Substituted 2-pyrazolines were also obtained by the reaction of
isoniazid with chalcones.186
RNHNH2ArSO2
NN
R
Ar'
SOO
ArAr'
O
+
Eqn. 50
In addition to these, 3-naphthalenyl-1,5-diphenyl-2-pyrazolines were prepared from
1-naphthyl-3-phenyl-2-propen-1-one and phenylhydrazine hydrochloride.187 The N-
substituted thiocarbamoyl-3-phenyl-2-pyrazolines were also reported by the reaction of
Mannich bases with N-4-substituted thiosemicarbazides. The Mannich bases were in turn
obtained by the Mannich reaction of various ketones with formaldehyde and dimethylamine
hydrochloride188 (Eqn.51). The cyclocondensation of 1,4-phenylene bischalcone with
substituted thiosemi-carbazides led to the formation of thiocarbamoyl bispyrazoline
derivatives189 (Eqn.52).
XMe
O
XN
O
Me
MeNH2
NH
R
S
NN R
S
XClH.
Me2NH.HCl
O O
PhPhC RNH2NH
S
NN N
N
Ph Ph
C CR SR S
+ +
+
i
ii
Eqn. 51(i) EtOH / HCl / (ii) MeOH / NaOH /
(HCHO)n
+
(i) NaOH / EtOH Eqn. 52
i
Substituted 2-pyrazolines were also prepared by the cyclocondensation of different
chalcones with isonicotinic acid hydrazide190 (Eqn.53). The reaction of 1,1,1-trifluoro-4-
indolylbut-3-en-2-one with 4-sulfamylphenylhydrazine hydrochloride yielded 5-indolyl-1-(4-
sulfamylphenyl)-3-trifluoromethylpyrazolines, the effective COX-2 inhibitors191 (Eqn.54).
29
X3C R
O OMeN
N
ROH
X3C
ON
N
O
NH
NH2
+i
(i) MeOH Eqn. 53
NN
CF3
NH
SO2NH2
NH
CF3
O
X
NH
NH2
NH2SO2
X
+i
Eqn. 54(i) EtOH /
Besides, pyrazoles were efficiently synthesized from β-dimethylaminovinylacetones
and hydrazine sulfate in solid state on grinding in the presence of p-toluenesulfonic acid192
(Eqn.55). Multisubstituted pyrazoles were efficiently prepared by cyclocondensation of
β-thioalkyl-α,β-unsaturated ketones with substituted hydrazines193 (Eqn.56).
R N
O
R Me
Me
NH
NR
R
+ i
(i) p-TSA
NH2NH2.H2SO4
Eqn. 55
1
1
NN
O
SEt
+
Eqn. 56
R2R1
R3NHNH2
R1
R2
R3
i
KOBu or AcOH /(i) t
The cyclization of fluoroalkylated 3,5-dioxoesters with hydrazine in glacial acetic
acid afforded substituted pyrazolines.194 The cyclocondensation of ethyl acetoacetate with
phenylhydrazine afforded 3-methyl-1-phenyl-1H-pyrazol-5-ol which was treated with
phosphorus oxychloride in dimethylformamide to get 5-chloro-3-methyl-1-phenyl-1H-
pyrazole-4-carbaldehyde195 (Eqn.57).
30
NN
Me
OHO
O O
NN
Me
Cl
CHO
POCl3 DMFPhNHNH2 / C2H5OH conc. HCl /Eqn. 57
10%NaOH(i)
i
(ii) /
ii
/
The reaction of substituted araldehydes with vinylmagnesium bromide gave the
corresponding allylic alcohols which were further oxidized with Jones reagent to enone
derivatives. Reaction of the latter compounds with hydrazine produced 4,5-dihydro-1H-
pyrazoles196 (Eqn.58).
CHO
NO2
R1
NO2
OH
R1
NO2
O
R1
NO2
NHN
R1
BrMgCH=CH2 THF NH2NH2Eqn. 58
i ii
iii
(i) / (ii) CrO3 / Acetone (iii) / EtOH
Synthesis of some new 3,5-diamino-4-(4'-fluorophenylazo)-1-aryl / heteroaryl
pyrazoles was reported by the treatment of aryl / heteroarylhydrazines with 2-[(4-
fluorophenyl)hydrazono]malononitrile in refluxing ethanol197 (Eqn.59). Cyclization of
different aryl and heteroaryl hydrazones by Vilsmeier-Haack reaction afforded pyrazole
carbaldehydes.198,199
NH2F FN
H
NNC
NC
NN
NH2NH2
R
NN
FRNHNH2NaNO2, HCl CH2(CN)2 / NaOAc Eqn. 59
EtOH /(i)
i
(ii)
ii
/ /
31
On the other hand, the reaction of 3-aryldiazenylpentane-2,4-dione with
hydrazinobenzothiazole resulted in 1-(6'-chlorobenzothiazol-2-yl)-3,5-dimethyl-4-(arylazo)-
pyrazole200 (Eqn.60).
NN
COMe
COMeR N
SNH
NH2Cl N
NN
SClMe
MeN N R
Eqn. 60
+
AcOH(i)
i
II. Diazomethane based reactions
The 1,3-dipolar cycloaddition of diazomethane to a double bond was
also a versatile method for the preparation of 2-pyrazolines. Azzarello201 prepared
2-pyrazolines by the cycloaddition of diazomethane to ethylene under very gentle conditions.
Thus, the addition of diazomethane to styrene,202 allyl chloride203 and 1,1-diphenylethanol204
also furnished substituted 2-pyrazolines (Eqn.61).
CH2N2N
NH
+
Eqn. 61
In fact, the cycloaddition of diazomethane and its simple analogs to unsaturated
compounds provided an access to the synthesis of 1- and 2-pyrazolines205 (Eqn.62).
Consequently, the addition of diazomethane to various Michael acceptors such as ,-
unsaturated aldehydes, ketones, acid and their derivatives, nitriles, nitroolefins, steroids and
heterocyclic systems was studied178,206-208 (Eqn.63).
NNH
R COR
NN
R CORRCH=CHCOR
NNCH2
+_
Eqn. 62
+
111
+
RCH=CH
O2N Me
NO
O2N Me
NO
R
NNH
CH2N2
Eqn. 63
32
Besides these, sulfonyl activated olefins have also been used as substrates in 1,3-
dipolar cycloaddition reactions. Helder et al.207 reported sulfonyl-2-pyrazolines by two
different methods. In one method, divinyl sulfone was treated with diazomethane in the
presence of a base, triethylamine to get bis(2-pyrazolin-3-yl)sulfone. In another method,
diazomethane was added to divinyl sulfone, wherein bis(1-pyrazolin-3-yl) sulfone was
obtained which on treatment with triethylamine isomerized to 2-pyrazoline (Eqn.64). They
have also prepared 3-phenylsulfonyl 1- and 2-pyrazolines from phenyl vinyl sulfone and 3,4-
(dimethylsulfonyl)-2-pyrazoline from cis-1,2-bis(methylsulfonyl) ethene (Eqn.65). This
methodology was supported by the addition of diazomethane to arylvinylsulfones in the
presence of a base where only 2-pyrazolines were obtained152 (Eqn.66). Contrary to these, the
reaction of vinyl sulfides with diazomethane produced 1-pyrazolines only.209
SOO
SOO
NH
NNH
N
SOO
NN
NN
(i) CH2N2 / Et3N (ii) CH2N2 (iii) Et3N
i
Eqn. 64
ii
iii
NNH
SO2MeMeSO2H H
MeSO2 SO2MeN
N
MeSO2 SO2Me
CH2N2
SO2Ar
NNH(i) Et3N
CH2N2SOO
Ar
+
Eqn. 65
+i
Eqn. 66
On the other hand, the addition of diazomethane to ,-unsaturated fluoroalkyl
sulfones yielded N-methyl-2-pyrazoline derivatives. This indicated that the initially formed
1-pyrazoline presumably isomerized to 2-pyrazoline, which underwent N-methylation in the
presence of excess diazomethane.210 Under similar conditions, the cycloaddition of
diazomethane to -arylsulfonylchalcones furnished 4-aryl-5-aroyl-5-arylsulfonyl-2-
pyrazolines178 (Eqn.67). Likewise, treatment of 1-aroyl-2-arylsulfonylethenes and 1,2-
33
bis(arylsulfonyl)ethenes with diazomethane under different conditions resulted in a variety of
pyrazolines and pyrazoles.211
Ar'CO
ArSO2CHAr'' CH2N2
NH
N
Ar''
Ar'CO
ArSO2+
Eqn. 67
In addition to these, cycloaddition of diazomethane to Z,E- and E,E-
bis(styryl)sulfones produced a mixture of (4-aryl-2-pyrazolin-3-yl)styrylsulfones and bis (4-
aryl-2-pyrazolin-3-yl)sulfones as minor and major products. The J values of the former
indicated that in Z,E-bis(styryl)sulfones, the addition took place at Z-position only. However,
the mono pyrazolines on further reaction with diazomethane afforded the same bis(2-
pyrazolin-3-yl)sulfones212 (Eqn.68).
H Ar'
Ar H
NH
N
SOO
(i) CH2N
2
Ar Ar'
NH
NNH
N
SOO
HH
Ar
H
H
Ar'
SOO
+
Eqn. 68
i
i
Treatment of 1-arylsulfonyl-2-styrylsulfonylethenes with two moles of diazomethane
in the presence of triethylamine gave a mixture of mono- and bis- 2-pyrazolines. On the other
hand, the addition of excess diazomethane produced only bis- 2-pyrazolines.213 In a much
similar way, a variety of bispyrazolinyl sulfones were prepared from bis(2-arylsulfonyl-
ethenyl)-[1,1']sulfones.213 Silicon and tin 3-, 3,5-, and 3,4,5-metalated pyrazoles were
reported by 1,3-dipolar cycloaddition of N-phenylsydnone or trimethylsilyldiazomethane to
silyl, disilyl and silylstannylacetylenes214 (Eqn.69). The tandem catalytic cross-coupling /
electrocyclization of enoltriflates and diazoacetates in the presence of Pd(PPh3)4 and N-
methylmorpholine led to the formation of pyrazoles215 (Eqn.70).
NN
R SiMe3
Me3Si
H
Me3Si CHN2SiMe
3R
(i) THF /
+i
Eqn. 69
34
R'
OTf
R''
O CO2R
N2N
NH
R'
RO2C
R''
O
Eqn. 70
+
(i) Pd(PPh3)4 / NMM / DMF
i
Some new bisheterocycles-pyrazolyl oxadiazoles were prepared by cycloaddition of
diazomethane to styryl arylsulfonylmethyl / arylmethanesulfonylmethyl-1,3,4-oxadiazoles.216
(Eqn.71).
Ar
NH
N
SO O
N N
OAr
ArS
OO
O
NN
Ari
(i) CH2N2 / Et3N / Et2O Eqn. 71
( )n( )n
n = 0, 1
A new class of bispyrazolines were reported from activated bisolefins by 1,3-dipolar
cycloaddition reaction of diazomethane and cyclocondensation of hydrazine hydrate217-219
(Eqn.72).
ArCO
X
COAr
NNH
X
NNH
ArCO
ArNNH
X H
COArH
ArCO
Eqn. 72
i
(i) CH2N2 / Et3N / Et2O (ii) N2H4.H2O
ii
X = S / SO2
The cyclocondensation of arylaminosulfonylacetic acid hydrazide with Z-styryl-
sulfonylacetic acid led to substitiuted oxadizoles. Interconversion of oxadiazoles to
thiadaizoles was effected with thiourea. The olefin moiety present in these compounds was
utilized to develop pyrazoles by 1,3-dipolar cycloaddition of diazomethane220 (Eqn.73).
Apart from these, sulfone linked pyrazolyl oxadiazoles and thiadiazoles were developed from
Z-styrylsulfonylacetic acid and E-arylsulfonylethenesulfonylacetic acid. The olefin moiety
was subjected to 1,3-dipolar cycloaddition with diazomethane and acid moiety for oxadiazole
and thiadiazole rings in the presence of appropriate nucleophiles.221,222
35
SOO
SOO
O
NN
NH
R R
H H
SOO
SOO
S
NN
NH
R R
SO O
NH
NH
NH2
RO OH
OR
SOO
NH
N
SOO
SOO
X
NN
NH
R R
SOO
SOO
X
NN
NH
R R
+
i
ii
iii, iv
X = O or SEqn. 73
(i) POCl3
(ii) NH2CSNH2 / THF
(iii) CH2N2 / Et3N / Et2O(iv) Chloranil / Xylene
The 1,3-dipolar cycloaddition of diazomethane to 1-arylsulfonylethylsulfonyl-2-
arylethenes produced 3,4-disubstituted 2-pyrazolines which on dehydrogenation with
chloranil resulted in the corresponding pyrazoles.223 Pyrazolyl 1,3,4-oxadiazoles and 1,3,4-
thiadiazoles were also reported from arylaminosulfonylacetic acid hydrazide and aryl-
sulfonylethenesulfonylacetic acid followed by cycloaddition of diazomethane224 (Eqn.74).
NH
N
SOO
SOO
X
NN
NH
R
SOO
R
SO O
NH
NH
NH2
RO
SOO
SOO
O
NN
NH
R
SO O
R
SO O
R
SOO
OH
O
SOO
SOO
S
NN
NH
R
SO O
R
SOO
SOO
X
NN
NH
R
SO O
R
(iii) CH2N2 / Et3N / Et2O(iv) Chloranil / Xylene
iii, iv
X = O / S
+
(i) POCl3
(ii) NH2CSNH2 / THF
i
ii
Eqn. 74
Styrene-ω-sulfonalides were also used to prepare pyrazolyl sulfonamides by the
cycloaddition of diazomethane followed by dehydrogenation225 (Eqn.75).
SO O
NH
R
R
SOO
NH
NN
Me
R R
i
ii
(i) CH2N2 / Et3N / Et2O (ii) Chloranil / Xylene Eqn. 75
36
III. Nitrile imine based reactions
The 1,3-dipolar cycloaddition offers a convenient one step route for the construction
of manifold five membered heterocycles.226 Among 1,3-dipoles known, nitrile imines have
been used for the preparation of pyrazolines. The nitrile imines can be generated by (i)
treatment of hydrazonoyl halides with base,227 (ii) thermolysis or photolysis of either 2,5-
diphenyltetrazoles,228 oxathiadiazolines,229 1,3,4-oxadiazolin-2-ones,230 sydnones,231 sodium
salt of -nitroaldehyde hydrazones or pyridinium betamines,232 (iii) dehydrogenation of
aldehyde hydrazone with lead tetraacetate,233 (iv) auto-oxidation of an aldehyde hydrazone
with triethylamine234 etc.
The reaction of diaryl nitrile imines and olefins was a facile method for the
stereoselective and regioselective synthesis of 2-pyrazolines or pyrazoles.227,235 The reaction
of benzonitrile N-phenylimide with ,-unsaturated ketones gave a mixture of regioisomers
in 40:60 ratio236 (Eqn.76). The regioselectivity of phenylaminocarbonyl-N-arylnitrile imines
with electron deficient and electron rich dipolarophiles was also studied. Thus, cycloaddition
of former to benzalmalononitrile led to pyrazole derivative.237 (Eqn.77). Highly
regioselective synthesis of 3-bromopyrazolines was reported by the addition of bromonitrile
imines to alkenes.238
PhNHCO
NN
Ph
Ph
CN
H
H PhNHCO
NN
Ph
Ph
CN
NN
PhPh
MeOC
Ph
NN
PhMeOC
Ph
Ph
C NPhNPh_+
Me
O
Ph
NH
NNH
Ph
O
Cl
Ph
PhCN
CN
Eqn. 77
Eqn. 76
++
+
The reaction of aliphatic and aromatic aldehyde hydrazones with olefins in the
presence of chloramine-T afforded 2-pyrazolines239 (Eqn.78). The cycloaddition of nitrile
imines generated in situ from araldehyde phenylhydrazones in the presence of chloramine-T
to ,-unsaturated ketones and sulfones also provided 2-pyrazolines. The aromatization of
latter compounds with chloranil furnished pyrazoles.240 Adopting similar methodology,
37
sulfonyl pyrazolines were prepared from aryl styryl sulfones.241 Contrary to this, 1,3-dipolar
cycloaddition of nitrile imines to bifunctional olefins, 1-aroyl-2-arylsulfonylethenes and 1,2-
diaroylethenes produced a mixture of 2-pyrazoline and pyrazole derivatives in which it was
presumed that chloramine-T also acts as a reagent for aromatization242 (Eqn.79).
(i) Chloramine-T / EtOH
R'R
H
NNZ
Z
R'
R
NN
(i) Chloramine-T / EtOH
Ar''
ArCO XAr'
PhNN
Ar''
ArCO XAr'
PhN
NAr X
O
Ar'Ar'' N
NH
Ph
i+
Eqn. 78
+
Eqn. 79
+i
iX = CO / SO2
On the other hand, the 1,3-dipolar cycloaddition of nitrile imines generated from
araldehyde phenylhydrazones to 1,5-diaryl-1,4-pentadien-3-ones in the presence of
chloramine-T resulted in a mixture of mono and bis pyrazolines. However, in the presence of
excess chloramine-T only bis pyrazolines were prepared. Aromatization of latter compounds
with chloranil in xylene gave corresponding pyrazoles.243 Similarly, mono and bis pyrazolinyl
sulfones were obtained by the treatment of E,E-bis(styryl)sulfones, 1-aroyl-2-
styrylsulfonylethenes and 1-arylsulfonyl-2-styrylsulfonylethenes with nitrile imines generated
from araldehyde phenylhydrazones in the presence of chloramine-T.244,245 Unsymmetrical
bischalcones were also exploited to obtain a new class of bis pyrazolines adopting similar
methodology.157,246
2-Pyrazolines were also reported by the cycloaddition reaction of nitrile imines
generated from hydrazonoyl chlorides with acrylonitrile or α-bromo-cinnamaldehyde.247,248
The solvent free 1,3-dipolar cycloaddition reaction of methyl acrylate and nitrile imines
generated in situ by the oxidation of araldehyde phenylhydrazones with di(acetoxy)iodo-
benzene under microwave irradiation resulted in 2-pyrazolines249 (Eqn.80).
NN
Ar
Ph
CO2MeAr NNH
PhCO
2Me
Eqn. 80
+ i
(i) Di(acetoxy)iodobenzene / Silica gel / MW
38
Some novel oxo-linked bisheterocycles viz., pyrrolyl pyrazolines were reported by
1,3-dipolar cycloaddition of tosylmethyl isocyanide (ToSMIC) to bis chalcones and
bis(styryl)sulfones followed by the addition of diazomethane or nitrile imines155,156 (Eqn.81).
The regioselective reaction of methyl 3-aryl-2-(E-arylethenesulfonyl)acrylate with
tosylmethyl isocyanide followed by functionalization of olefin moiety with diazomethane,
nitrile imines and nitrile oxides led to some new sulfone linked pyrrolyl pyrazoles and
isoxazoles.250
O
Ar Ar N
ArO
Ar
H
NN
N
ArO
Ar
H H
NN
N
ArO
H
Ar
Ar'Ph
ii
iii
i
Eqn. 81
(i) TosMIC / NaH / Et2O + DMSO (ii) CH2N2 / Et3N / Et2O(iii) Ar'-CH=NNHPh / Chloramine-T / MeOH
Regioselective 1,3-dipolar cycloaddition of nitrile imines with 5-arylidene-2-
arylimino-4-thiazolidinones afforded the corresponding 1,3,4-triaryl-5-N-arylpyrazole
carboxamides251 (Eqn.82). The 1,3,4-trisubstituted pyrazole was prepared by the reaction of
N,N-dimethylaminopropenone with hydrazonyl chloride in the presence of triethylamine252
(Eqn.83).
N
S
Ar
Ar1
N
Ar
O
Ar2 NNH
Cl
PhN
N
Ar1
NHAr
Ar2
Ph
O
Eqn. 82
+ i
(i) Toluene / or MW
NN
Ar
PhOC COMe
NNH
Cl
ArMeOCN
O
Me
MePh
Eqn. 83Dioxane / Et3N /(i)
i+
39
OXAZOLES
I. From nitriles
The rhodium-catalyzed reaction of diazoaldehyde ester with nitriles afforded oxazoles
directly253 (Eqn.84). Similar reaction of dimethyl diazomalonate with nitriles in the presence
of rhodium(II) acetate produced oxazoles.254 The reaction of aminopropanedinitrile p-
toluenesulfonate with acid chlorides gave trisubstituted oxazoles255 (Eqn.85). Apart from
these, trisubstituted oxazoles were reported by the reaction of benzonitrile with aromatic
ketones in the presence of mercury(II) p-toluenesulfonate under microwave irradiation 256
(Eqn.86).
H
O
N2
O
EtO C NR
O
N
R
O
EtO+
(i) Rh2(OAc)4 (cat.) /
i
Eqn. 84
H C
NH3OTs
CN
CNR Cl
O
O
N
RNH2
NC
+i
(i) 1-Methyl-2-pyrrolidinone Eqn. 85
RR
O
C NPh
R
O
N
R' Ph+
i
(i) Hg(OTs)2 / MW
1
1
Eqn. 86
The Ritter reaction of γ-hydroxy-α,β-alkynoic esters in the presence of arylnitriles
furnished 5-oxazoleacetic acid derivatives257 (Eqn. 87). 2,4,5-Trisubstituted oxazoles were
prepared via a tandem Ugi / Robinson-Gabriel sequence from 2,4-dimethoxybenzylamine,
arylglyoxal, an acid and a nitrile258 (Eqn.88).
O
R
OH
OEt
O
N
R
RO
EtOR C N
2
(i) H2SO4
i1
1
2
Eqn. 87
+
40
NH2
MeO OMe
OH
O
O
Ar
O O
N
Ar
NH
O
R C N2
+
+
+
R1
(i) Ugi Reaction(ii) Robinson-Gabrieln Reaction
i
ii
Eqn. 88
R2
R1
The reaction of alkyl and aryl ketones with oxone and trifluoromethanesulfonic acid
in the presence of iodoarene in acetonitrile provided substituted oxazoles259,260 (Eqn.89).
Moreover, the [2+2+1] annulation of terminal alkyne, nitrile and an oxygen atom from an
oxidant in the presence of Gold-catalyst resulted in 2,5-disubstituted oxazoles261 (Eqn.90).
The amino acid derived propargylic amides were cyclized in the presence of Au(III) catalyst
to oxazoles262 (Eqn.91).
O
N
MeAr
R
MeCNi
(i) ArI / TfOH / Oxone / 0 oC(ii) Ar1COCH2R / MeCN /
ii 1
Eqn. 89
Me( )8
Me O
N
Me
(i) [Au] / [O]
i( )8
Eqn. 90
+ MeCN
NH
Me
BocHN
O
Me
O
NBr
Me
Me
BocHN
i
(i) AuCl3 / CHCl3
(ii) Br2 /
ii
Eqn. 91
A quarternary ammonium hydroxide ion exchange resin catalyzed the reaction of p-
tolylsulfonylmethyl isocyanide with aromatic aldehydes to give 5-aryloxazoles263 (Eqn.92).
In addition, the Nef-isocyanide coupling between acyl chloride and isocyanide afforded a
nitrilium ylide intermediate which in the presence of base cyclized to 2,5-disubstituted
oxazole.264 However, a one-pot synthesis of 2,5-disubstituted oxazoles was reported by the
41
reaction of benzyl halides and acyl chloride. The isocyanide generated in situ reacted with
acyl chlorides in the presence of base to afford the desired oxazoles265 (Eqn.93).
SO O
NC
SOO
O
N
Ar O
N
Ar
SOO
Hi +
(i) ArCHO / Base Eqn. 92
R Br R NCO
N
RR
i ii
(i) AgCN / KCN / TEBAC / MeCN /(ii) R2COCl / 2,6-Lutidine
112
1
Eqn. 93
II. From amides
The cyclocondensation between cinnamamide and ethyl bromopyruvate under
Hantzsch-type conditions produced the oxazole derivative266 (Eqn.94). The sequential
treatment of carbonyl compounds with [hydroxyl-(2,4-dinitrobenzenesulfonyloxy)iodo]-
benzene (HDNIB) and amides under solvent-free microwave irradiation also furnished
trisubstituted oxazoles267 (Eqn.95). Besides, the reaction of isocyanoacetamides with
aldehydes and ketones gave 2-substituted-5-aminooxazoles268 (Eqn.96).
NH2
O
Ph Br
O
O
OEt
O
OEtN
OPh
+i
(i) NaHCO3 / THF (ii) (CF3CO)2O Eqn. 94
RR
O
ODNs
RR
O R
O
N
R R
i ii1 1
2
2
2
1
3
(i) HDNIB / MW (ii) R3CONH 2 / MW Eqn. 95
O
N
R3
R4
R2R1N
NR2
O
NOSi R3
R3
R4
R2R1NCONNC R1R2 iii
i) R3R4CO / R3SiCl (ii) R3R4CO / HNR1R2Eqn. 96
42
The Harrison’s procedure of addition of benzyl cyanamide procured by the treatment
of cyanogen bromide with benzylamine, to a dimer of dihydroxyacetone in the presence of
sodium hydroxide afforded 2-aminooxazole269 (Eqn.97). The triflic anhydride mediated
cyclodehydration of N-acylamino esters produced oxazole in one-pot transformation270
(Eqn.98).
NH
N
OH OH
O O
N
NH
OHBnBnNH2 + BrCN
iBn
+ ii
(i) Na2CO3 (ii) Cat. NaOH Eqn. 97
O O
NH
R
R
OMeO
N
R
R
MeOi
(i) Tf2O / Base
1
2
1
2
Eqn. 98
In addition, 5-vinyloxazoles were prepared by the reaction of α–chloroglycinate with
dimethylaluminium acetylide of phenylpropargyl ether271 (Eqn.99). Besides, the oxidative
cycloisomerization of propargyl amides in the presence of phenyliodine(III)diacetate [PIDA]
in acetic acid or AuCl3 provided 2,5-disubstituted oxazoles262,272,273 (Eqn.100). Di and
trisubstituted 2-aryloxazoles were also prepared by Yb(OTf)3 catalyzed cyclization of
trisubstituted propargylic alcohols with aryl amides274 (Eqn.101).
R NH
O Cl
CO2EtMe2Al
OPh O
N
R
EtO2C
+
Eqn. 99
NH
O O
N
OAcR1
R1i
(i) PIDA / AcOH Eqn. 100
Ar NH2
O
O
N
Ar
R
R
R
R
OH
R
R
(i) Yb(OTf)3 / PhMe /
+i1
2
3
1
2
3
Eqn. 101
43
Moreover, 2,5-disubstituted oxazole-4-carboxylates were obtained from methyl ester
of N-acyl-β-halodehydroaminobutyric acid derivatives in the presence of DBU in
acetonitrile275 (Eqn.102).
R NH
O X
CO2Me
O
N
R
MeO2Ci
(i) DBU / MeCNEqn. 102
A silver-mediated one-step synthesis of di- and trisubstituted oxazoles was reported
from primary amides and activated β–bromo-α-ketones276,277 (Eqn.103). Apart from these,
the reaction of phenacyl benzoate with ammonium acetate in acetic acid afforded a mixture of
2,4-diphenyloxazole and 2,4-diphenylimidazole278 (Eqn.104). The cyclization of azidoaryl
esters with ammonium acetate in acetic acid led to corresponding oxazoles279 (Eqn.105).
R NH2
O
BrR
O
R R
O
N
RR+
i1
1
2
23
3
(i) AgSbF6 / DCE / MW Eqn. 103
O
O
O
PhPh
O
N
Ph
Ph
NH
N
Ph
Ph
+i
(i) NH4OAc / AcOHEqn. 104
O
R
O
ClR
O
O
OPh
Ph
R
N
O
Ph
Ph
R
R1 i
(i) SOCl2 /(ii) Benzoin / Pyridine / DMAP(iii)NH4OAc / AcOH /
ii
iii
R = 4-N3
= 3-N3
Eqn. 105
44
III. From oxazolines
The 2-oxazolines were oxidized to oxazoles in the presence of
N-bromosuccinamide / peroxide or light or by Kharasch-Sosnovsky reaction.280,281 Similarly,
thiazoline esters gave the respective thiazoles281 ( Eqn.106).
X
N
RR
RO2C
X
N
RR
RO2C
(i) t-BuOOCOPh / CuBr / PhH /
i
X = O / S
2 1 2 1
Eqn. 106
IV. From azirines
Ring opening and selective cleavage of N-C double bond of aminoazirines282,283 and
phosphorus substituted azirines284 can be achieved with carboxylic acids. In fact, the reaction
of phosphorylated azirines with carboxylic acids followed by the cyclization of corresponding
adducts resulted in phosphorylated oxazoles 284,285 (Eqn.107). The photoisomerization of
azirine derivatives also led to oxazoles286 (Eqn.108).
N
R' PR
O
P
O
N
R' R
R
O
RR
i
(i) RCO2H (ii) Ph3P / C2Cl6 / Et3N
ii
Eqn. 107
N
Cl
COPh
MeO2C O
NCl
CO2MePh
Cl
N
O
PhCO2Mei
(i)
-+
Eqn. 108
V. From methyl ketones
An I2-promoted domino oxidative synthesis of 2,5-disubstituted oxazoles was
reported from methyl ketones and benzyl amine287 (Eqn.109).
ONH2
O
N
PhR1 R1+i
(i) I2 / DMSO /Eqn. 109
45
THIAZOLES
I. From thiourea derivatives
The Hantzsch synthesis of 2-aminothiazoles was based on the reaction of thiourea
derivatives with α–haloketones288,289 (Eqn.110). The condensation of amidines with
isothiocyanates afforded amidinothioureas. The latter compounds on subsequent treatment
with α–bromo ketones led to S-alkylated intermediate which yielded thiazoles via base
catalyzed ring closure process290 (Eqn.111).
RBr
O N
S NHR'
R
NH2 NHR'
S
+
Eqn. 110
R NH
NHR
NH S
21
S
N
NHR
R
R
O
2
1
3
R N NHR
NH S
R O
21
3
-NH3R NH2
NH2 . ClN=C=S i ii
DBU.HBr
(i) DMF / DBU (ii) DMF / DBU / R3COCH2Br
-
++
1
Eqn. 111
R2
Cyclodextrins, the cyclic oligosaccharides have generated interest as enzyme models
due to their ability to bind substrates selectively and catalyze chemical reactions by
supramolecular catalysis involving the reversible formation of host-guest complexes with the
substrates by non-covalent bonding as in enzyme complexation process.291 In fact, the
aqueous phase preparation of thiazoles and aminothiazoles was reported from phenacyl
bromides and thioamide / thiourea in the presence of β-cyclodextrin292 (Eqn.112).
OBr
X
H
O
R NH2
SN
S R
X
+ i
(i) H2OEqn. 112
The N-acylglycinamides prepared by the reaction of phenylglycinamide with various
acid chlorides in the presence of N-ethylmorpholine (NEM), were dithionated to get
bis(thioamide) intermediates using Lawesson’s reagent or Belleau’s reagent. The bis
46
(thioamide) derivatives on subsequent treatment with trifluoroacetic anhydride (TFAA)
afforded thiazoles having trifluoroacetamide moiety293 (Eqn.113). The thiazoles and
aminothiazoles were also reported by the treatment of phenacyl bromides with thioamides /
thiourea in the presence of ammonium-12-molybdophosphate.294 The reaction of chalcone
derivatives with thiourea yielded substituted 2-aminothiazoles295 (Eqn.114).
NH2
NH2
O
Ph
R NH
NH2
O
O
Ph
R NH
NH2
S
S
Ph
N
S RNH
CF3
OPh
i ii
iii
(i) RCOCl / Pyridine / NEM (ii) Lawesson's reagent or Belleau's reagent (iii) TFAA / CH2Cl2 Eqn. 113
OF3C
F3CS
N
NH2
F3C
F3CNH2
S
NH2
i
(i) EtOH
+
Eqn. 114
2-Aminothiazoles were prepared by the reaction of ketones with thiourea using silica
chloride as effective heterogeneous catalyst.296 The coupling of α-diazoketones with thiourea
in the presence of copper (II) triflate produced the corresponding 2-aminothiazoles297
(Eqn.115).
S
N
NH2
PhO
PhN2 NH2 NH2
Si
(i) Cu(OTf)2
+
Eqn. 115
A highly efficient and facile method for the synthesis of substituted 2-aminothiazoles
in water from phenacyl bromides and thiourea derivatives was reported by Srinivasan et
al.,298 (Eqn.116). 2-Aminothiazoles were also prepared in one-step from isothiocyanates via
thiourea formation followed by cycloisomerization in an intramolecular thia-Michael
fashion299 (Eqn.117). Besides, the reaction of isothiocyanates with secondary amines
provided thiazoles300 (Eqn.118). A one-pot synthetic protocol for the synthesis of thiazoles
47
was reported from alkynes via in situ formation of 2,2-dibromo-1-phenylethanone and
thiourea in the presence of β-cyclodextrin54 (Eqn.119).
ArBr
O
NH2NHR
S
S
N
NHR
Ar
+i
(i) H2OEqn. 116
S
N
NHR
R
EtO2CCO2Et
R
HCl.H2N
2
N=C=S
(i) Et3N / THF
1
2
+
Eqn. 117
R1
N=C=S
O
S
N
O
R2 R1
R1
R2 NR4R5
(i) R4R5NH
i
Eqn. 118
N
S
NH2
NH2 NH2
S
Ar +i
(i) NBS / CD / H2OEqn. 119
The synthesis of bis(diamino)thiazoles was achieved by the reaction of
bis(bromoacetyl)benzene with 1-alkyl or aryl-3-(N-nitroamidino)thioureas in the presence of
triethylamine301 (Eqn.120). Apart from these, bisthiazolylamine was prepared by the reaction
between chloroacetaldehyde and dithiobiuret302 (Eqn.121).
RHN NH
NHNO2
S NH
Br
Br
O
O
O
O
N
SN
S
NHR
NH2
RHN
NH2
+
(i) Et3N / DMF /
i
Eqn. 120
48
ClH
O
S NH
S
NH2NH2
NH
S
NN
S
+ i
Eqn. 121(i) EtOH
3-Aryl-2-chloropropanal obtained by the reaction of arenediazonium chlorides with
acrolein in the presence of copper (II) chloride, reacted with substituted thioureas to afford
thiazole derivatives303 (Eqn.122).
O
H
O
Cl
H
RNH
S
NR'R
N2 Cl
R
i
+ -
NH
NH2
SR'
+ ii
Eqn. 122(i) CuCl2 / Me2CO-H2O (ii)
The bromination of acetophenone in PEG-400 in the presence N-bromosuccinimide
generated α-bromo ketones in situ which in the presence thiourea derivatives cyclized to 2-
amino-4-arylthiazoles.304 The reaction of methyl ketones and unsaturated methyl ketones with
thiourea in the presence of I2/CuO yielded 2-aminothiazoles.305 4-Thienylthiazoles were
synthesized by the reaction of 2-bromothienylethanone with thiourea and substituted
thioamides306 (Eqn.123). The cyclocondensation of p-toluenesulfonylthiosemicarbazide with
α-halocarbonyl compounds produced p-toluenesulfonylhydrazinothiazoles307 (Eqn.124).
NH2 R
S
SCl Cl
O
Br
S
S
N
R
Cl
Cl
+
Eqn. 123
49
SOO
NH
NH
NH2
S
S
N
SOO
NH
NH
R
R
1
2R
RX
O 1
2
i
SOO
S
N
NN
R
R
O
O
+
(i) DMF / Me2CO (ii) Ac2OEqn. 124
ii2
1
Apart from these, substituted thiazoles and imidazoles were reported by the reaction
of α-tosyloxy ketones with a variety of thioamides and amidines308 (Eqn.125). Zeolite H-beta
facilitated the reaction of α-chloroacetyl chloride with 1,2-bistrimethylsilyl acetylene to give
corresponding silylbut-3-yn-2-one which on treatment with thioacetamide afforded
trimethylsilylethynyl thiazole. The coupling reaction of latter with heteroaryl halides under
modified Sonogashira reaction conditions resulted in alkynyl substituted thiazole
derivatives309 (Eqn.126). A one-pot method for the synthesis of 2-aminothiazoles was
reported from isothiocyanates, amidines/guanidines and halomethylenes310 (Eqn.127).
RR
OTs
O
R NH2
X N
X
R
R R
i
(i) / Water
+12
3
1
23
X = S, NH
Eqn. 125
ClCl
O
Si Si
Si
O
Cl
SiN
S
N
SR
+i ii
(i) Zeolite H-beta / CH2Cl2
(ii) Thioacetamide / DMF(iii) L-Proline / PdCl2(PPh3)2 / CuI / K2CO3
Eqn. 126
iii
S
N
NHS
N
NH
NRR
N=C=SNRR
NHX
R2
R2R1
i
(i) DMF
+R1
R1
R2R3
R3
Eqn. 127
50
The α-bromo ketones were transformed into the corresponding α-thiocyanato ketone
by treating with sodium thiocyanate which in the presence of primary amine in the same pot
produced 2-aminothiazoles311 (Eqn.128).
O
BrR
N
S NHR'
R
i
(i) NaSCN / EtOH / (ii) R'NH2 / EtOH /
ii
Eqn. 128
The reaction of α-bromo ketone with potassium thiocyanate in the presence of silicon
dioxide afforded α-thiocyano ketone which reacted with alumina-supported amino acetate to
give 2-aminothiazole312,313 (Eqn.129). A multi-component solution-phase protocol was
reported to prepare 2-aminothiazoles from α-bromocarbonyl compounds and amines in the
presence of trimethylsilyl isothiocyanate314 (Eqn.130). A one-pot reaction of an aldehyde
with 2-amino-2-cyanoacetamide in the presence of elemental sulfur produced thiazole
derivatives315 (Eqn.131). 2,4,5-Trisubstituted thiazoles were developed by cyclocondensation
of β-substituted methylaminoenones with thionyl chloride. The enones were readily
accessible from corresponding methylamines and monothio-1,3-diketones316 (Eqn.132).
O
BrPh
PhS
N
NHR
Ph
Ph
i
(i) KSCN / SiO2-RNH3OAc / Al2O3 / PhH / Eqn. 129
Br
OS
O N
S
N
N
Si-N=C=S
H-N=C=SR1
R2
R1
R2 HNR3
R4
R1
R2
R3
R4
(i) EtOH(ii) Base
i
ii
Eqn. 130
51
R H
O
NH2
NH2
NO
S
N
NH2
R
O
NH2
+i
(i) S8 / Base / Eqn. 131
NH
MeO
O
N
SO
MeO
i
(i) SOCl2 / Base Eqn. 132
II. From oxidation of 2-thiazolines
A variety of protocols were reported for the oxidation of thiazoline to thiazole viz.,
activated manganese dioxide,317-319 nickel oxide,320,321 trichlorobromomethane in the presence
of DBU.322,323 Apart from these, environment-benign oxidation by molecular oxygen was also
used for the conversion of thiazolines to thiazoles324 (Eqn.133).
S
N
R
R'O2C
S
N
R
R'O2C
i
(i) Air or O2 Eqn. 133
52
IMIDAZOLES
I. From amidines
Lawson reported that the reaction between cyanamide and 2-amino-
acetaldehydeacetals followed by acid catalyzed cyclization produced 2-aminoimidazoles 325
(Eqn.134). 1-Aryl-2-phenylimidazoles were synthesized by the reaction of silyl enolethers
with N-chloro-N'-arylbenzamidines in the presence of pyridine326 (Eqn.135).
NH2 C N NH2
OR
OR
NH2
OR
NH
NH
OR
NH
N
NH2
+i ii
(i) (ii) Acid Eqn. 134
Me3Si O CH CH R
NH
Cl
Ph
R1
N
N
PhR
R1
2
2+
i
(i) CHCl3 / / Pyridine Eqn. 135
An alkylation-cyclization sequence involving the use of amidine and α-bromo-
aldehyde was employed to prepare imidazoles in a highly regioselective manner.327
(Eqn.136). 1,2-Diarylimidazoles were synthesized by the reaction of thioamides with
dimethyl acetylenedicarboxylate in dichloromethane at room temperature328 (Eqn.137).
NH
NH
Ph
PhBr
O
CHON
N
PhOHC
Ph
+
i-Pri
(i) K2CO3 / CHCl3 / H2O Eqn. 136
NH
SN R
Ph
N
NR
PhMeO2CCO
2Me
CO2Me
i+
(i) CH2Cl2Eqn. 137
53
A hetero-Cope rearrangement was used as key reaction in a two-step synthesis of
imidazoles.329 Specifically, oxime was reacted with a two-fold excess of imidoyl chloride in
the presence of triethylamine to afford amidine. This compound readily underwent the hetero-
Cope rearrangement in refluxing toluene in the presence of p-toluenesulfonic acid to give
tetrasubstituted imidazoles329 (Eqn.138). A Stille-type coupling was also used as a key step in
the synthesis of 2,4,5-triarylimidazole from 4-(bromoacetyl)pyridine hydrobromide and
benzamidine330 (Eqn.139).
Ph
Ph NOHN
O
N
NH
PhPh
Ph
Ph
N
NPh
Ph PhCl
N
Ph
+i ii
(i) Et3N / THF (ii) p-TsOH / PhMe /
2
Eqn. 138
HBr.N
O
Br
NH2
NH
Ph NH
N
NPh+
i
(i) DMF /Eqn. 139
The reaction of 2-aminoacetaldehyde dimethylacetal with O-methylisourea in the
presence of sulfuric acid resulted in 2-aminoimidazoles331 (Eqn.140). α-Aminocarbonyl
derivatives obtained from α-amino acids on reaction with isothiocyanates produced
N-substituted cyclic thioureas. Oxidative or reductive desulfurization of the latter led to
imidazole derivatives332 (Eqn.141). The direct CuCl-mediated reaction of nitriles with α-
aminoacetals gave substituted imidazoles by intermolecular as well as intramolecular
cyclization333 (Eqn.142).
NH2
OR
OR NH
N
NH2
NH
NH2
OMe
ORNH
NH2
OR
NH
+i ii
(i) H2O / (ii) H2SO4 / PH 2.5 / Eqn. 140
54
RNH
O
R
CO2EtCl
-
R N S
N
R
REtO2C
1
2
N=C=SN
N
R
EtO2C
RN
NR
EtO2C
R
iii or iv
(i) EtOH / Et3N / 10% PPTS / PhMe (ii) 1:3 t-BuOH / H2O /(iii) Raney Nickel / EtOH (iv) / H2O2 / AcOH Eqn. 141
+i or ii
+
1
2
3
R3 or
1
3
2 2
N
N
R
R
NH
NR
OR OR
R
i
2
1C N
RNH
OR
ORii
(i) CuCl (ii) HCl
1
2
R1 +
Eqn. 142
2
4,5-Diamino-1,2-diarylimidazoles were synthesized by the reaction of 1,2-
diaminoethenes with N-aryl-N'-chlorobenzamidines in boiling dichloromethane or chloroform
in the presence of an equimolar amount of pyridine, followed by oxidation of the resulting
trans-4,5-diamino-1,2-diaryl-4,5-dihydroimidazoles with chloranil 334 (Eqn.143).
N
NH
N
N
H
Y
Y
Ph
R1
NH
Cl
Ph
R1
N
N
N
Y
Ph
R1
N
N
N
Y
Ph
N
Y
R1
N
Y
N
Y
CHCH ii
+i
(i) CHCl2 or CHCl3 / Pyridine (ii) Chloranil / PhH / PhMe /
+
Eqn. 143
II. From carbonyl compounds
Substituted imidazoles were prepared by cyclocondensation reaction between 1,2-
dicarbonyl compounds, aldehydes, 1,2-aminoalcohols and ammonium acetate335 (Eqn.144).
The addition of substituted aminoalcohols to thioamide and subsequent-oxidation with
pyridinium dichromate (PDC) produced imidazoles.336
55
R
NH2 OH
R
N
N
R
R
OH
i
(i) HCHO / OHC-CHO / NH3 source / MeOH /
1
1
2
2
Eqn. 144
Indium trichloride trihydrate was found to be a mild and effective catalyst for the one-
pot, three component synthesis of substituted imidazoles from 1,2-dicarbonyl compounds,
aldehydes and ammonium acetate337 (Eqn.145). 2,4,5-Trisubstituted and 1,2,4,5-
tetrasubstituted imidazoles were reported by one-pot condensation of benzil with a variety of
aldehydes, aromatic primary amines and ammonium acetate using PEG-400 as reaction
medium.338 L-Proline was also employed as a catalyst in this reaction.338-340 A one-pot four-
component synthesis of 1,2,4-trisubstituted imidazoles was reported from phenacyl bromide,
an aldehyde, a primary amine and ammonium acetate under solvent-free conditions341
(Eqn.146).
R O
R O
NH
N
R
R
R+ R2CHO + NH4OAc
(i) InCl3.3 H2O / MeOH
i
1
1 21
1
Eqn. 145
N
NAr
R
ArArBr
O
+ NH4OAc
(i) Solvent-free /
+RNH2
iAr2CHO +
1
1
2
Eqn. 146
Cu(II) nitrate impregnated Zeolite was also used as an efficient supported reagent for
the rapid one-pot synthesis of substituted imidazoles from 1,2-diketones, aldehydes, primary
amines and ammonium acetate.342 1,4-Diazabicyclo[2.2.2]octane (DABCO) was also
effectively catalyzed the above reaction.343 Ammonium molybdate was used as a catalyst for
the synthesis of trisubstituted imidazoles from benzil, araldehydes and ammonium acetate
under solvent free conditions using microwave irradiation344 (Eqn.147).
56
O
OPh
Ph NH
N
Ar
Ph
Ph+ 2 NH4OAc
(i) (NH4)6Mo7O24.4H2O / M W
+ArCHOi
Eqn. 147
3-Methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate, a Bronsted acidic
ionic liquid, was used as an efficient, green and reusable catalyst for the synthesis of
tetrasubstituted imidazoles using benzil, an aromatic aldehyde, and a primary amine in the
presence of ammonium acetate under solvent-free conditions.345 Eco-friendly synthesis of
imidazoles was reported by one-pot reaction of benzil or benzoin, ammonium acetate and
araldehydes in water in the presence of 1-methylimidazolium trifluoroacetate346 (Eqn.148). A
series of 12-phosphotungstic acid (PWA) supported on various porous carriers such as silica,
alumina, titania, clay and carbon were prepared and their catalytic performance was evaluated
in the synthesis of imidazoles in solvent-free conditions. It was found that PWA supported on
silica showed higher activity compared to other catalysts.347 ZnO was also an effeicient,
readily available and reusable catalyst for the one-pot synthesis of tetrasubstituted and
trisubstituted imidazoles.348 A simple one-pot four-component synthetic method was reported
for the preparation of tetrasubstituted imidazole derivatives from benzil, aromatic aldehydes,
primary amines and ammonium acetate in the presence of Preyssler-type heteropoly acid
catalyst.349 p-Toluenesulfonic acid, sulphanilic acid, NiCl2∙6H2O were also used as catalysts
in the above reaction.350-352 Ultrasound irradiation of benzoin or benzil, an aldehyde and
ammonium acetate using diethyl bromophosphate (DEP) as a mild oxidant produced 2,4,5-
triarylimidazoles353 (Eqn.149).
O
OH
Ph
Ph
NH
NR
Ph
Ph
O
OPh
Ph
RCHO+i
(or) + NH4OAc
(i) [Hmim]TFA / H2O
2
Eqn. 148
57
O
OPh
PhNH
NPh
Ph
CHO
R
R
+ NH4OAc
(i) DEP / )))) Eqn. 149
i+
The α-bromoketones on treatment with amidines resulted in imidazoles. The former
compounds were prepared from N-protected α-aminoacids which were converted into
α-diazoketones and consequently into α-bromoketones354 (Eqn.150).
OH
O
NH OCH2Ph
O
RCH2N2
O
NH OCH2Ph
O
RCH2Br
O
NH OCH2Ph
O
R
NH OCH2Ph
O
R
NNH
Ph
iiii ii
(i) THF / EtOCOCl / Et3N / CH2N2 / Et2O(ii) HBr / AcOH(iii) Benzamidine.HCl / THF / H2O / K2CO3
Eqn. 150
Brodereck and Theilig355 reported symmetrical and unsymmetrical 4,5-diaryl-
imidazoles by the reaction of a large molar excess of formamide with the appropriate benzoin
or 2-amino-1,2-diarylethanones355-362 (Eqn.151).
NH
NAr
ArNH
NAr
Ar
OAr
Ar OH
+
1
2
iHCONH2
Eqn. 151
1
21
2
(i)
III. From diazabutadiene
The reaction of 4-thiomethyl-1,3-diazabuta-1,3-dienes with Simmon's-Smith reagent
generated from diiodomethane and a zinc-copper couple in ether underwent an unusual 1,4-
methylene transfer to yield imidazole derivatives363 (Eqn.152). The disubstituted imidazoles
were produced via the dimerization of aryl glyoxal imino generated from α-azidoketones in
the presence of potassium ethylxanthate364 (Eqn.153).
58
R
N
N SMe
R
Ph
R
N
N SMe
R
PhH2C
Zn
I
CH2
I
N
N
R
Ph
SMeR
H N
N
R
Ph
R
(i) CH2I2 / Zn(Cu) / Et2O / THF
i
1 1
1
1
Eqn. 152
R
O
N3 O SK
S
NH
N
R
R
O
NH
NR
O
R+
i
(i) i-PrOH /
2
Eqn. 153
+
IV. By cycloaddition
The van Leusen group found that the base-induced [3+2] cycloaddition of TosMIC to
N-(arylidene)anilines in a protic medium followed by concomitant elimination of p-
toluenesulfinic acid gave 1,5-diarylimidazoles.365-369 (Eqn.154)
N
N
Ar
Ar
1
2CH NAr Ari
(i) TosMIC / K2CO3 / MeOH / DME
12
Eqn. 154
Similarly 1,2,5-triarylimidazoles were prepared in a single operation from N-tosyl-
methylimino compounds and aldimines370 (Eqn.155 ).
TsCH2NSMe
PhN
Ar
R
1
N
N
Ar Ph
R
1
+i
(i) NaH / DME / DMSO Eqn. 155
59
OXADIAZOLES
I. From hydrazone derivatives
1,3,4-Oxadiazoles were reported by the reaction of acylhydrazines with cyanogen
bromide371 (Eqn.156). Cyclocondensation of hydrazides with imidate hydrochlorides also
resulted in 1,3,4-oxadiazole derivatives372 (Eqn.157). The reaction of monoacylhydrazines
with azirine led to the formation of 1,3,4-oxadiazoles. The reaction presumably proceeds by
the addition of acylhydrazine to the imino group of azirine followed by cleavage of the
resulting aziridine to form an amidine which then cyclized to oxadiazole by the loss of
dimethylamine373 (Eqn.158).
R NH
NH2
O
O
NN
R NH2
(i) CNBr / Eqn. 156
i
O
N N
R NHRR HN
NH2 Cl
OEtR N
H
NH2
O
(i) KOH / MeOH / Eqn. 157
+i
1
+
1
-
N
Me2NR N
H
NH2
O
O
NN
R
NH2(i) DMF / Eqn. 158
+i
The cyclodehydration of acylhydrazines in the presence of dehydrating agents
produced corresponding oxadiazoles. A wide range of reagents viz., phosgene, carbonyl
diimidazole, chloroformate, carbon disulfide, thiophosgene, isocyanide dichloride,
phosphorus pentoxide etc. were used for cyclization.374,375 In fact, 2-chloro-1,3-dimethyl-4,5-
dihydroimidazolium chloride was an effective dehydrating agent for condensation and
subsequent cyclization of acylhydrazines and carboxylic acids to 1,3,4-oxadiazoles376
(Eqn.159).
R NH
NH2
O
O
NN
R R
NMe
N ClMe
Cl(i) / Et3N / CH2Cl2+ Eqn. 159
+1
i1R CO2H
60
The combination of PPh3 / CCl4 was proved as a useful variation of the Mitsunobu
reaction and acts as an effective and mild dehydrating agent for the formation of 1,3,4-
oxadiazoles.377 The cyclization of diacylhydrazines using triphenylphosphine and
hexachloroethane in the presence of Hunig’s base led to the formation of tetrasubstituted
alkenyl-1,3,4-oxadiazoles.378 Moreover, 1,3,4-oxadiazoles were obtained by BF3·Et2O
promoted cyclodehydration of 1,2-diacyl / diaroylhydrazines prepared in situ from the
corresponding acid chlorides and hydrazine379 (Eqn.160).
OO
NH NH
R R
N N
OR R
R
Cl
O
Eqn. 160
iNH2NH2 + ii2
(i) Dry dioxane (ii) BF3.Et2O / Dry dioxane
A rapid and green synthesis of 2,5-disubstituted 1,3,4-oxadiazoles was reported by the
reaction of different acyl hydrazides with orthoesters in the presence of silica sulfuric acid
under solvent free conditions.380 The solid supported Nafion®NR50 was the most efficient
catalyst for the synthesis of 1,3,4-oxadiazoles381 (Eqn.161). Ceric ammonium nitrate (CAN)
in PEG-400 was also used as a non-volatile and ecofriendly catalytic medium for the green
synthesis of 2,5-disubstituted 1,3,4-oxadiazoles.382 The reaction of aryl and heteroaryl acids
with different aryl acid hydrazides in phosphorus oxychloride resulted in 2,5-disubstituted
1,3,4-oxadiazoles.383,384 It was reported that the reaction of heteroaryl acid hydrazide with
appropriate aromatic acids in the presence of phosphorus oxychloride gave the corresponding
oxadiazoles385,386 (Eqn.162).
NHNH2
O
R
N N
OR
R
REqn. 161
+i 1
(i) Nafion NR50 / MW
1R C(OEt)3
S
N
NHNH2
OO
NN
RS
N
R OH
O
Eqn. 162
i
(i) POCl3
+
An efficient synthesis of 2-styryl-1,3,4-oxadiazoles under microwave irradiation was
reported by cyclocondensation of cinnamic acid hydrazide and triethylorthoesters387
61
(Eqn.163). The reaction of 1-cyanoformamidineacrylic acid hydrazide with 2-vinyl-5-amino-
1,3,4-oxadiazole was accomplished in the presence of pyridine.388 -Cyanobenzylidene-
hydrazides obtained from S,S-dialkyl acetals of aromatic aldehydes on heating underwent
intramolecular cyclocondensation by the loss of HCN to give 1,3,4-oxadiazoles389 (Eqn.164).
NHNH2
O
Ph
O
OO
RO
N N
RPh+
i
(i) MW / AcOH Eqn. 163
ArNNH
R
O
CN O
N N
ArR
(i) DMSO / Eqn. 164
i
Apart from these, the acid activation with carbonyldiimidazole (CDI) followed by
coupling with acylhydrazine and dehydration in the same pot with triphenylphosphine and
tetrabromomethane provided the corresponding 1,3,4-oxadiazoles.390 The reaction of benzoic
acid derivatives with (N-isocyanimino)triphenylphosphorane also produced 1,3,4-
oxadiazoles391 (Eqn.165). The one-pot reaction of primary amine, aromatic carboxylic acid
and chloroacetone in the presence of (isocyanimino)triphenylphosphorane led to the
formation of 1,3,4-oxadiazoles via an intramolecular Aza-wittig reaction392 (Eqn.166).
X
Y
OH
O
O
NN
X
Y
Ph3P=ON N CPh3P-+
Eqn. 165
+i
+
(i) CH2Cl2
O
ClAr OH
O
N N CPh3PO
NN
Ar
Cl
NHR
Ph3P=O-+
RNH2
Eqn. 166
i
(i) CH2Cl2
++ + +
Symmetrical and unsymmetrical 1,3,4-oxadiazoles were prepared by the reaction of
aryl / benzylsulfonylacetic acid hydrazides with aryl / benzylsulfonylacetic acids in the
presence of phosphorus oxychloride. The oxadiazoles were interconverted to thiadiazoles by
treating with thiourea in tetrahydrofuran.393,394 Adopting similar methodology, quinazoline
62
substituted 1,3,4-oxadiazoles were also prepared from hydrazides and acids.395 The acid
hydrazides were converted into differently substituted oxadiazoles by cyclization with
substituted benzoic acid in the presence of phosphorus oxychloride and also with carbon
disulfide under basic conditions396,397 (Eqn.167). Iodobenzene diacetate was also utilized as a
catalyst to promote oxidative cyclization of pyrazolylaldehyde N-acylhydrazones.398
O
NHNH2
O
R
R
O
NN
O
Ar
R
O
NN
O
SH
Eqn. 167
i
ii
(i) ArCO2H / POCl3 (ii) CS2 / K2CO3
In addition to these, bisheterocycles - pyrazolyl oxadiazoles were synthesized from
arylsulfonylacetic acid hydrazide and benzylsulfonylacetic acid hydrazide by reaction with
cinnamic acid in the presence of phosphorus oxychloride. The olefin moiety in
styryloxadiazoles was used to develop pyrazoline ring by 1,3-dipolar cycloaddition of
diazomethane.399 Benzimidazolyl oxadiazoles were prepared by the reaction of
imidazolylthioacetic acid hydrazide with differently substituted aromatic acids in the
presence of phosphorus oxychloride400 (Eqn.168). The oxadiazoles were also obtained from
aminosulfonylacetic acid and different carboxylic acid hydrazides. Interconversion of
oxadiazoles to thiadiazoles was effected in the presence of thiourea.401 Further, E-aryl-
sulfonylethenesulfonylacetic acid was exploited to develop bisheterocycles pyrazoles in
combination with oxadiazoles and thiadiazoles in the presence of different carboxylic acid
hydrazides.222
63
NH2
NH2NH
NSH
NH
N
S
O
OEt
NH
N
S NHNH2
OO
NN
R'S
NH
N
Cl
O
OEt
Eqn. 168
i ii
iii
iv
(i) CS2 / NaOH / EtOH (ii) EtOH(iii) NH2NH2.H2O / EtOH (iv) R'COOH / POCl3
+
The oxidative cyclization of bisaroylhydrazones of isophthaldehyde and
terephthaldehyde with lead(IV) acetate furnished 1,3- and 1,4-bis-[5-aryl-1,3,4-oxadiazol-2-
yl]benzene.402 Bromine, chloramine-T and bis (trifluoroacetoxy)iodobenzene were also
employed as oxidizing agents to convert acylhydrazones into 1,3,4-oxadiazole
derivatives.403-406 In a similar way, treatment of acylhydrazines with araldehydes in the
presence of ceric ammonium nitrate gave acylhydrazones which underwent oxidative
cyclization to 1,3,4-oxadiazoles407 (Eqn.169). Sodium bisulfite also promotes the reaction of
hydrazide with aromatic aldehyde by the elimination of water followed by cyclization to
substituted 1,3,4-oxadiazoles.408
R NH
NH2
O
R CHOR N
H
N R
O
O
NN
R R
(i) CAN / EtOH / (ii) CAN Eqn. 169
+ 1 1
1
i ii
The electrolysis of benzohydrazide in the presence of potassium hydroxide as the
base, platinum as the anode and cathode, KI as the electrolyte and 60mA as the reaction
electrolytic current resulted in 1,3,4-oxadiazozles409 (Eqn.170).
O
NN
Ar ArAr NH
NH2
O
KI / KOH / MeOH Eqn. 170(i)
i
A series of 5-(alkyl-(1H-indol-3-yl))-2-substituted 1,3,4-oxadiazoles were efficiently
synthesized by oxidative cyclization of N'-benzylidene-(1H-indol-3-yl)alkane hydrazides and
araldehydes using di(acetoxy)iodobenzene410 (Eqn.171). The condensation reaction between
benzohydrazides and thiophene-2-carbaldehyde led to substituted benzoylhydrazone. The
64
reaction of latter with di(acetoxy)iodobenzene in dichloromethane produced 1,3,4-
oxadiazoles. 411
NH
O
NH
NH2NH
O
NN
R
Eqn. 171(i) EtOH / DIB /
( )n ( )ni
+ RCHO
CH2Cl2
A one-pot cyclodeselenization reaction of isoselenocyanates and hydrazides in
dimethylformamide yielded 2-amino-1,3,4-oxadiazoles412 (Eqn.172).
R NH
O
NH2 O
NN
NH
RR
RN
CSe
Eqn. 172(i) DMF
i1 1+
The vinyl substituted 1,3,4-oxadiazoles were prepared using o-nitrophenyl sulfoxide
precursor via syn-elimination reaction using sodium acetate in tetrahydrofuran413 (Eqn.173).
S
ONO2
OEt S NHNH2
ONO
2
S
NO2
O
NNR
S
NO2
O
NNR
O
O
NNR
NH2NH
2. H
2O / EtOH
RCOOH / POCl3
m-CPBA
NaOAc / THF Eqn. 173
i ii
iii
iv
(i)
(ii)
(iii)
(iv)
II. From thiosemicarbazone derivatives
Acylthiosemicarbazides were cyclized to 1,3,4-oxadiazoles in the presence of lead or
mercuric oxide by the loss of hydrogen sulfide414 (Eqn.174). On the other hand, pyrolysis of
S-methyl derivative of 1-benzoylthiourea resulted in 2-amino-5-phenyl-1,3,4-oxadiazole by
the elimination of methyl mercaptan415 (Eqn.175). 5-Substituted 2-amino-1,3,4-oxadiazoles
were also synthesized by treating 1-acylthiosemicarbazides with PbO. Apart from these,
HgO, Pb3O4, CuSO4, dicyclohexylcarbodiimide (DCC)416 or I2 / NaOH417,418 were also used
as cyclizing reagents.419 In fact, carbodiimides were found to be effective reagents to promote
the cyclization of these compounds.420
65
NHNH
NH2
SO
Ph
Ph
(i) Pb3O4
Ph
PhO
NN
NH2
Eqn. 174
i
NHNH
SMe
NHO
PhO
NN
Ph NH2
Eqn. 175
i
(i)
The dehydrative cyclization of 2-acylhydrazides bound to the polymeric support using
trifluoroacetic acid anhydride gave oxadiazoles.421 The tosyl chloride and pyridine mediated
cyclization of thiosemicarbazide also gave 1,3,4-oxadiazole.422 Apart from these, 5-
substituted 2-amino-1,3,4-oxadiazoles were prepared by oxidative cyclization of respective
thiosemicarbazides using 1,3-dibromo-5,5-dimethylhydantoin as the primary oxidant in the
presence of potassium iodide423 (Eqn.176).
Ar Cl
O NH NH
NH2
Ar O S O
NN
Ar NH2
Eqn. 176
i ii
(i) NH2CSNHNH2 / THF (ii) NaOH / KI / iPrOH / 1,3-Dibromo-5,5-dimethylhydantoin
The electro-oxidative cyclization of arylthioesmicarbazides obtained from the
corresponding acylhydrazines and isothionates on the platinum electrode in the presence of
lithium perchlorate as an electrolyte gave 5-aryl-2-(arylamino)-1,3,4-oxadiazoles424
(Eqn.177).
R NH
NH2
O
O
NN
R NH
R
R NH
NH
O NH
S
R1
i1 2
2
1
ii
(i) R2NCS (ii) Electrocyclization Eqn. 177
III. Miscellaneous methods
The conversion of tetrazoles to 1,3,4-oxadiazoles in the presence of acylating agents
was first reported by Stolle425 and then by Huisgen et al.426 The reaction of phenyltetrazole
with p-nitrobenzoyl chloride in pyridine resulted in 2,5-disubstituted 1,3,4-oxadiazole427
(Eqn.178). Moreover, the cycloaddition of nitrile imines generated from tetrazoles by the loss
of nitrogen to isocyanates or ketones afforded 1,3,4-oxadiazole derivatives.428 Further, 1,2,4-
oxadiazoles having amino or hydroxyl groups at 3-position on irradiation rearranged to 1,3,4-
oxadiazoles429 (Eqn.179).
66
NNH
N N
Ph
O
Cl
NO2
O
NN
NO2
Ph
Eqn. 178
+
(i) Pyridine
i
O
NN
RPhON
N
Ph
R
hv(i) MeOH / Eqn. 179
i
Substituted 1,2,4-triazine-3-ones undergo ring contraction in the presence of bromine
to yield 1,3,4-oxadiazoles430 (Eqn.180). In addition to these, substituted oxadiazoles were
prepared in a relay synthesis from triazolylbenzamidines and acid chlorides or anhydrides431
(Eqn.181).
O
PhO
NN
NHMeN
NHN
O
MeOH
Ph
Eqn. 180
i
(i) Br2 / NaOAc / AcOH
NN
NN
NH2
Ph
O
N N
RN
NH
N
PhEqn. 181(i) RCOCl
+i
On the other hand, 1,3,4-oxadiazoles were also synthesized by the addition of carbene
to diacyldiimide. The [4+1] cycloaddition of dibromocarbene generated from
phenyltrihalomercurial reagent to azodibenzoyl yielded 2-bromo-5-phenyl-1,3,4-
oxadiazole432 (Eqn.182). In addition to these, treatment of aldazines with organic iodine (III)
reagents viz., bis (trifluoroacetoxy)iodobenzene at room temperature provided 2,5-
disubstituted 1,3,4-oxadiazoles433 (Eqn.183).
NN
O
O
PhPh
O
NN
BrPh
Eqn. 182(i) PhHg CBr3
i
R NN R
O
NN
R R
Eqn. 183
i
(i) Bis(trifluoroacetoxy)iodobenzene
1
1
67
THIADIAZOLES
I. From thiosemicarbazone derivatives
The oxidative cyclization of benzalthiosemicarbazone with ferric chloride resulted in
2-amino-5-phenyl-1,3,4-thiadiazole434 (Eqn.184). Adopting similar methodology, 2-anilino-
and 2-methylamino-5-phenyl-1,3,4-thiadiazoles were reported from 4-phenyl- and 4-
methylbenzalthiosemicarbazones.434,435 It was observed that the reactivity of calcium
ferricyanide was similar to ferric chloride.436 In fact, 2-(p-aminobenzenesulfonamido)-5-
methyl-1,3,4-thiadiazole was prepared from the corresponding thiosemicarbazone in the
presence of calcium ferricyanide.436 The sydnonyl substituted thiadiazole derivatives were
also reported by the reaction of thiosemicarbazones with ferric chloride.437 Similarly,
oxidative cyclization of araldehyde thiosemicarbazones in the presence of ammonium ferric
sulphate gave 1,3,4-thiadiazoles.438 Formic acid was also used for the cyclodehydration of
acylthiosemicarbazides.439 In addition, 2-amino-5-trifluoromethyl-1,3,4-thiadiazoles were
prepared by the reaction of 4,4-disubstituted thiosemicarbazides with trifluoroacetic acid440
(Eqn.185).
NNH
NH2
S
Ph
NN
SNH2Ph
Eqn. 184
i
(i) FeCl3
R2N NH
NH2
S
R2N NH
NH
S
CF3
O
S
NN
F3C NR2
i
(i) TFA R2N = (a) morpholino, (b) piperidino, (c) 1-pyrrolidinyl Eqn. 185
In yet another route, 1,3,4-thiadiazoles were prepared from thiosemicarbazides and
ethyl orthoformate.441 However, in the presence of excess ethyl orthoformate, N,N-bis(1,3,4-
thiadiazol-2-yl)formamidine was obtained (Eqn.186). The treatment of oxazole carbonitriles
with alkyl or arylisothiocyanates produced thiosemicarbazidooxazoles which on heating in
dioxane gave 1,3,4-thiadiazolylacetonitriles.442 Besides, 2-substituted 5-phenyl-1,3,4-
thiadiazoles and 1,3,4-oxadiazoles were reported by the reaction of 1,4-disubstituted
thiosemicarbazides with ethenetetracarbonitrile in dimethylformamide443 (Eqn.187).
68
NH2 NH
NH2
S
HC(OEt)3
N N
S NH2
N N
S
N N
S N NH
(i) (ii) Excess HC(OEt)3 / Eqn. 186
+
i
ii
NHNH
NHR
SO
PhS
NN
NHRPh
CN
CN
NC
NC
O
NN
NHRPh
Eqn. 187
i
/ DMF(i)
+
The reaction of thiosemicarbazide or acid hydrazide with carbon disulfide in the
presence of potassium hydroxide or sodium carbonate led to the corresponding potassium salt
which on heating cyclized to 1,3,4-thiadiazole derivatives.444,445 (Eqn.188). The
heterocyclization of dithizone or dinaphthyl thiocarbazone with carbon disulfide yielded 3,5-
disubstituted 1,3,4-thiadiazole-2-thiones.446
S
N N
Cl SH
Cl
O
NH
NH2
Cl
O
NH
NH
SK
S
Eqn. 188
i ii
(i) KOH / CS2 / EtOH (ii) H2SO4
+-
In addition to these, alkyl / acylthiosemicarbazides in the presence of conc. H2SO4
cyclized to 1,3,4-thiadiazoles.447 Similarly, treatment of 3,5-disubstituted pyrazolyl acetate
with hydrazine hydrate resulted in hydrazide derivative which on reaction with
phenylisothiocyanate produced thiosemicarbazide. Chemoselective heterocyclization of latter
with conc. H2SO4 led to the formation of 1,3,4-thiadiazole448 (Eqn.189). The reaction of
araldehydes, hydrazine hydrate and aryl isothiocyanates followed by oxidative cyclization of
in situ generated thiosemicarbazones with ferric ammonium sulfate (FAS) gave 1,3,4-
thiadiazoles449 (Eqn.190).
69
(i) NH2NH2 (ii) PhNCS (iii) conc. H2SO4
R'
N N
R
NH
NH2
OR'
N N
RO
OEt
R'
N N
R
S
NN
NHPh
R'
N N
R
NH
NH
NH
O
S
Ph
Eqn. 189
i ii
iii
S
NN
Ar NH
Ar'ArCHO H2NNH2.H2O Ar'NCS Ar NNH
NH
S
Ar'
(i) MeOH / (ii) FAS / MeOH / Eqn. 190
+ii
+i
2,5-Disubstituted 1,3,4-thiadiazoles were prepared by the reaction of acid hydrazide
with isothiocyante in the presence of triethylamine450 (Eqn.191). The long chain alkenoic
acid hydrazides on reaction with phenyl isocyanate and phenyl isothiocyanate led to the
corresponding semicarbazides and thiosemicarbazides which in the presence of phosphorus
oxychloride and acetic anhydride yielded 1,3,4-oxadiazoles and 1,3,4-thiadiazoles,
respectively.451 The cyclocondensation of imidazothiazolyl thiosemicarbazides in the
presence of conc. H2SO4 produced imidazothiazolyl-1,3,4-thiadiazoles.452 Likewise, thiazolyl
thiadiazoles were reported by cyclocondensation of hydrazine carboxamides in the presence
of conc. H2SO4.453
NH
NH2
O
S=C=N
NO2 S
NN
NH
NO2
+
(i) Et3N
i
Eqn. 191
The reaction of ethyl 4-(benzoylamino)benzoate with hydrazine hydrate gave the
corresponding acid hydrazide. Treatment of latter compound with aryl isothiocyanate
provided 4-aryl-1-[4-(benzoylamino)benzoyl]thiosemicarbazides which were cyclized in the
presence of an acid to 5-(4-aminophenyl)-2-(arylamino)-1,3,4-thiadiazoles454 (Eqn.192).
70
NHPh
O NH
NH2
O
NHPh
ONH
NH
O
NH
S
R
H2SO4
S
NN
NH
NH2
R
Eqn. 192R1NCS / EtOH
1
1
(i)
i
(ii) /
ii
A one-pot three component reaction of araldehyde, phenylisothiocyanate and
hydrazine hydrate in water under combined microwave and ultrasound irradiation in the
presence of FeCl3 produced 2,5-disubstituted 1,3,4-thiadiazole455 (Eqn.193).
CHO
R
NCS
S
NN
NH
R
FeCl3, H2O / CMUI Eqn. 193
+ NH2NH2.H2O
+i
/(i)
The reaction of stearohydrazide with potassium thiocyanate afforded
thiosemicarbazide derivative. Treatment of latter with potassium iodide and iodine in the
presence of sodium hydroxide furnished 1,3,4-oxadiazol-2-amine. On the other hand,
cyclization in the presence of conc. H2SO4 resulted in 1,3,4-thiadiazol-2-amine456 (Eqn.194).
R NH
NH2
O
KSCN / HCl
R NH
NH
O
NH2
S
O
NN
R NH2
S
NN
R NH2
KI / I2 / NaOH H2SO4 / NH4OH Eqn. 194(i)
i
(ii)
ii
(iii)
iii
II. From hydrazone derivatives
Unsymmetrical 1,3,4-thiadiazoles were reported by Stolle’s method. 2-Benzhydryl-5-
phenyl-1,3,4-thiadiazole and 2-methyl-5-phenyl-1,3,4-thiadiazole were obtained from N-
diphenylacetyl-N-benzoylhydrazine and N-acetyl-N-benzoylhydrazine in the presence of
71
phosphorus pentasulfide.457 The one pot synthesis of 1,3,4-thiadiazoles was carried out by the
reaction of various acid hydrazides with triethyl orthoformate, triethyl orthopropionate and
triethyl orthobenzoate in the presence of phosphorus pentasulfide in alumina381 (Eqn.195).
The reaction of p-tolualdehyde hydrazone with disulfur dichloride in the presence of DBU
gave 2,5-di(p-tolyl)-1,3,4-thiadiazole along with p-tolualdehyde azine (Eqn.196). However,
phenyldiazomethane under identical conditions resulted in 2,5-diphenyl-1,3,4-thiadiazole in
high yield.458
NHNH2
O
R
N N
SR
R
(i) P4S10 / Al2O3 / MW / 120 Co
+i 1
Eqn. 195
R C(OEt)31
S
NN
Tol
-Tol
H
NNH2
(i) DBU / Base / CH2Cl2
-Tol
H
N
NH
Eqn. 196
++ S2Cl2 -Tolpp-
pi
-Tolp
p
5-Substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were also prepared by the
reaction of bis(2,4-dihydroxythiobenzoyl)sulfoxide with hydrazides or carbazates459
(Eqn.197). The one pot reaction of an acid and acid hydrazide with phosphorus pentasulfide
or Lawesson’s reagent in the presence of propylphosphonic anhydride and triethylamine also
afforded 2,5-disubstituted 1,3,4-thiadiazoles460 (Eqn.198).
S
NN
R / OR
OHOH
NH2NH
RO / R
O
S O
S
S
OH
OH
OH
OH Eqn. 197
+
OH
OR
S
NN
RRNHNH2
OR
Eqn. 198
+
(i) Propylphosphonic anhydride / Et3N / Lawesson's reagent (or) P2S5
1
i1
72
Besides, thiadiazoles were prepared by the reaction of N,N-diaroylhydrazines with
Lawesson’s reagent followed by treatment with P4S10.461 Thionation of N,N-diacylhydrazines
with fluorous analogue of the Lawesson’s reagent produced 1,3,4-thiadiazoles462 (Eqn.199).
NHNH
R R'O O S
NN
R R'
Eqn. 199
i
(i) Fluorous Lawesson's reagent
Treatment of thioaroylhydrazines with aromatic aldehydes yielded 2,3-dihydro-1,3,4-
thiadiazoles.463 Similarly, the reaction of thiocarbonylhydrazines with imino ether
hydrochlorides gave 1,3,4-thiadiazoles464 (Eqn.200). The alkoxycarbonyl derivatives of
substituted thiadiazoles were also prepared by the treatment of thiohydrazides with alkyl
oxalyl chlorides465 (Eqn.201).
R NH
S
NH2
S
NN
R
R
Cl
R
Cl
NH2 Cl
EtO
NH
NH
O
S
NH2
R RS
NN
NH
O
OR'
O
ClOR'
O
O
Eqn. 2002
11 ( )n
+
2
( )n
.
Eqn. 201
+
A facile one pot synthesis of 2,5-disubstituted 1,3,4-thiadiazoles was reported by
ultrasonication of a mixture of 1-naphthylacetyl chloride, NH4CNS, dichloromethane and
PEG-400 in the presence of N-arylglycine hydrazides466 (Eqn.202).
CH2COCl CH2CON=C=S
S
NN
NH
NHAr
O
i ii
Eqn. 202(i) NH4CNS / PEG-400 / CH2Cl2 / US (ii) ArNHCH2CONHNH2 / US
III. Miscellaneous methods
Bithiourea and substituted bithiourea were converted to 1,3,4-thiadiazoles by several
methods. Treatment of bithiourea with HCl, phosgene and other reagents produced 1,3,4-
thiadiazoles.467 Bithiourea was also cyclized to 2,5-diamino-1,3,4-thiadiazole in the presence
73
of 30% hydrogen peroxide468 (Eqn.203). It was observed that cyclization of bithiourea was
also effected in the presence of alkali. Thus, the reaction of 1-anilino-6-phenylbithiourea with
20% alkali gave 2,5-disubstituted 1,3,4-thiadiazole. Monothiobiureas also undergo
cyclization in a similar manner to bithioureas. However, the former compounds led to
aminohydroxythiadiazoles instead of mercapto derivatives.
N N
S NH2NH2
NHNH
NH2
SSNH2
Eqn. 203(i) H2O2
i
Apart from these, interconversion of 2-mercapto-5-(4-pyridyl)-1,3,4-oxadiazole to
2-hydroxy-5-(4-pyridyl)-1,3,4-thiadiazole was effected in the presence of conc. HCl469
(Eqn.204). The reaction of 1,3,4-oxadiazole with thiourea in THF in an inert atmosphere also
furnished 1,3,4-thiadiazole470 (Eqn.205).
O
NN
N
SH S
NN
N
OH
Eqn. 204(i) conc. HCl
i
O
NN
R'R S
NN
R'R
(i) Thiourea / THF Eqn. 205
i
Common route for the synthesis of oxadiazoles and thiadiazoles
The synthesis of oxadiazoles and thiadiazoles was accomplished from a common
intermediate, sulfonylacetic acid via acid hydrazide. The methyl ester of phenacylsulfonyl-
acetic acid and benzylsulfonylacetic acid on treatement with hydrazine hydrate in the
presence of pyridine furnished the corresponding acid hydrazides. The potassium
dithiocarbazate of acid hydrazides on refluxion in acetic acid cyclized to thiadiazoles. Acid
catalyzed hydrolysis of the former compounds led to oxadiazoles471,472 (Eqn.206).
74
SO O
RO
NHNH2
N
O
N
SHS
O OR
N
S
N
SHS
O OR
SO O
RO
NHNHCS K-
S
+( )n ( )n
( )n( )n
i
ii
(i) CS2 / KOH / EtOH (ii) H+ (iii) AcOH
Eqn. 206
iii
Apart from these, phenacylsulfonylacetic acid methyl ester was also used to develop
bisheterocycles, 1,2,3-selenadiazolyl / thiadiazolyl / diazaphosphonyl oxadiazoles and
thiadiazoles exploiting -ketomethylene and ester functionalities473 (Eqn.207). Furthermore,
the methyl ester of E-styrylsulfonylacetic acid, aroylethenesulfonylacetic acid and
arylsulfonylethenesulfonylacetic acid were also used as synthons to develop bisheterocycles-
pyrazolyl / pyrrolyl oxadiazoles and thiadiazoles adopting similar methodology474,475
(Eqn.208). The cyclocondensation of arylsulfonylethylsulfonylacetic acid hydrazide and
benzylsulfonylethylsulfonylacetic acid hydrazide with aromatic acid in the presence of
phosphorus oxychloride led to 2,5-disubstituted oxadiazole. Interconversion of oxadiazole to
thiadiazole was effected with thiourea476 (Eqn.209).
SOO
NN
Se
NN
S SH
RNN
O SHS
OO
NN
Se
R
SOO
NN
Se
O
NHNH2
R
SOO
NN
Se
O
NHNHCS K
R
S
(i) CS2 / KOH / EtOH / US (ii) HCl / H2O (iii) AcOH
ii iii
Eqn. 207
- +i
75
SOO
S
H
H
O
OMeAr
OO
NN
SS
OO
NH
SHS
OO
Ar
SOO
NH
O
NHNHCS KS
OO
Ar
S
SOO
NH
O
OMeS
OO
Ar
SOO
NH
O
NHNH2
SOO
Ar
NN
OS
OO
NH
SHS
OO
Ar
(i) TosMIC / NaH / Et2O / DMSO (ii) NH2NH2 / Pyridine / EtOH(iii) CS2 / KOH / EtOH / US (iv) HCl / H2O (v) AcOH
iv v
- +
i ii
iii
Eqn. 208
SO O
SOO
NHNH2
O
R
O
NN
SO O
SOO
ClR
S
NN
SO O
SOO
ClR
(i) 2-ClC6H4COOH / POCl3 (ii) NH2CSNH2 / THF
ii
i( )n( )n
( )n
n = 0 or 1 Eqn. 209
The sulfonamidomethane pyrazolyl oxadiazoles and pyrazolyl thiadiazoles were
prepared by the reaction of arylsulfonylaminoacetic acid hydrazide with E-cinnamic acid
followed by treatment with diazomethane and aromatization.477 Adopting similar
methodology different acid hydrazides viz., arylaminosulfonylacetic acid hydrazides,
arylsulfonylaminosulfonylacitic acid hydrazides and a variety of acids such as Z- and E-
styrylsulfonylacetic acids, E-aroylethenesulfonylacetic acids were exploited to construct
multifunctional pyrrolyl / pyrazolyl / oxadiazoles and thiadiazoles.478-480 (Eqn.210).
76
SO O
NH
NH
NH2
RO
SOO
SOO
O
NN
NH
R RH
H O
SO O
R
OH
O
O
SOO
SOO
S
NN
NH
R R
O
+
(i) POCl3
(ii) NH2CSNH2 / THF
i
ii
NH
SOO
SOO
X
NN
NH
R
R
O
SOO
SOO
X
NN
NH
R
NH
N
R
NH
N
SOO
SOO
X
NN
NH
R
R
O
SOO
SOO
X
NN
NH
R R
O
v,vi
iii
iv,vi
(v) NH2NH2.H2O / MeOH(vi) Chloranil / Xylene
(iii) TosMIC / NaH / DMSO / Et2O(iv) CH2N2 / Et3N / Et2O
X = O / S
Eqn. 210