Second Supplements to the 2nd Edition of Rodd's Chemistry

of Carbon Compounds, Vol.IV C/D, edited by M. Sainsbury

9 1998 Elsevier Science B.V. All rights reserved.

173

Chapter 18b
OXADIAZOLES AND THIADIAZOLES
M.SAINSBURY
1. OXADIAZOLES
(a) General chemistry
A comprehensive review of the metallation and halogen-metal exchange
reactions of 1,2,3-and 1,2,4-triazoles, tetrazoles, 1,2,3-, 1,2,4-, 1,2,5-, and
1,3,4-oxadiazoles, and 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-thiadiazoles and the
reactions of the resulting organometallic derivatives, particularly lithiated
derivatives, has been written by M.R.Grimmett and B.Iddon (Heterocycles,
1995, 41, 1525).
~J (C-C) Spin-spin coupling constants have been recorded for oxadiazoles
and thiadiazoles, as well as for other five-membered heterocycles. These
couplings show a clear distinction between carbon-carbon bonds which are
formally either double or single. There seems to be no correlation of the
couplings with the bond lengths concerned, in spite of some apparent trends.
Potential applications of the couplings are discussed in assessing the
aromaticity of five-membered heterocycles (M.Witanowski and Z.Biedrzyeka, Magn. Reson. Chem., 1994, 32, 62).
Equilibrium topologies and harmonic force fields have been determined for
1,2,5-oxadiazole, 1,2,5-thiadiazole and 1,2,5-selenadiazole. Scaled quantummechanical (SOM) force fields have been calculated, using experimental data
available from the literature, for the three heterocycles and some of their
isotopomers. Infra red absorption intensifies have been calculated using
computed dipole derivative tensors and an assignment of the experimental to
the calculated frequencies made, firstly on symmetry grounds and then
mainly according to frequency order. The calculated vibrational spectra for
the molecules by the scaled MP2 force fields are only slightly better than
those calculated by corresponding SCF methods (A.A.Elazhary, Acta Chem.
Scand., 1995, 49, 11).

174

(b) 1,2,3-Oxadiazoles
These are the least common of the oxadiazole group of heterocycles and the
literature relating to them is rather sparse; nonetheless, a compound claimed
to be the fh-st 1,2,3-oxadiazole to be isolated in the pure state, naphth[2,3-d]
[1,2,3]oxadiazole (2), has been prepared from 3-hydroxynaphthalene-2diazonium tetrafluoroborate (1) (A.Blocher and K.-P.Zeller, Angew. Chem.,
Int. Ed. Engl., 1991, 30, 1476).

o
(~)

(2)

This compound on photolysis in methanol yields 2-(methoxycarbonyl)indene

(4) formed by a Wolff rearrangement, plus 2-naphthol. The latter compound
is formed from the intermediate carbene (3) by hydrogen abstraction from the
solvent. Other solvents than methanol (e.g. water or cyclohexane) can also
be used, but regardless of the solvent, experiments with (2) bearing [~3C] at
C-9 show that there is no randomisation of the label in the photolysis
products. This rules out the participation of naphth[2,3-b]oxirene (5) as a
reactive intermediate (idem, Chem. Ber., 1994, 127, 551).
The reactions at the aryl tings of some ortho-substituted N-arylsydnones with
electrophiles has been studied (K.Turnbull, T.L.Biackbum and D.B.McClure,
J. Het. Chem., 1994, 31, 1631). The sydnone (6) on acid mediated hydrolysis
affords the indazolone (7) (F.Dumitrascu, M.Plaveti and D.Raileanu, Rev.
Roum. Chem., 1991, 36, 917).
4-Formyl-3-phenylsydnone (8) undergoes decarboxylation on treatment with
base, but reacts with enolates of methyl ketones to afford aldol products.
These dehydrate to enones (9) (W.J.Hung et al., Chin. Chem. Soc. (Taipei),
1993, 40 385).
Tropolone (11) adds to 3-phenylsydnone (10) to give the adduct (12), this
readily decomposes by oxidation and loss of carbon dioxide to yield the
pyrazolotropolone (13) (H.Kato et al., J. Chem. Soc., Perkin Trans 1, 1993,
1617).

175
hD

(2)

-N 2

N2
~..O

MeOH

(3)

~o.

C~

I McOH

C~

~co~
(4)

(5)

~+

CO2H

,~~~
.o
(6)

I%O
n+
(7)

176
Ph
N.

CHO

0~ . . .

o-

Ph, + CH=CHCOR
N%

MeCOR_
NaOMe

N, O,~.. O-

(9)

(8)

Ph
Ph

(10)

+ ~0

(11)

N~~x~O

(12)

Ph

(13)

(c) 1,2,4-Oxadiazoles
(i) Synthesis
N-Ethoxycarbonyl-N'-cyanoguanidine (1) reacts with hydroxylamine hydrochloride to afford 3-ethoxy-5-ureido-1, 2, 4-oxadiazole (2) and 5-amino-3ethoxycarbonyl-l,2,4-oxadiazole (3). On alkaline hydrolysis (2) gives 5amino-3-ethoxy-l,2,4-oxadiazole (4), whereas (3) affords the alkali metal
salt of 5-amino-3-carboxy-l,2,4-oxadiazole (5) (T.Suyama et al., Nippon
Kagaku Kaishi, 1993, 1359).
Further work has shown that the thioacetal (6, R = SMe) reacts with
hydroxylamine to give 5-amino-3-methylthio-l,2,4-oxadiazole (7, R = SMe),
whereas diethyl N-cyanocarbonimidate under the same reaction conditions
affords 3-amino-5-ethoxy-l,2,4-oxadiazole (7, R = OEt). The reaction of S-ethyl
N-cyano-thiocarbamate (8) with hydroxylamine yields 3-amino-l,2,4oxadiazolin-5(2H)-one (9) [T.Suyama, N.Ozawa and N.Suzuki, Bull. Chem.
Soc. (Japan), 1994, 67, 307].

177
EtO
O

NHaOH EtO

~ NHCN
HN
(I)

N"O2"" NHCONI't2
(3)

(2)
~ o t NaOH

1-I20~ NaOH

EtO
N-O,9~NH2

O
(4)

R
~-~N-CN

NH2OH
~))

NI-L~OH
(8)

N-o, NH ,
(7)

(6)

NCNHCOSEt

(5)

H2N~__N
H~N-0"~O
(9)

A simple synthesis of 5-substituted-l,2,4-oxadiazole-3-carboxylates starts

from N-aroylglycines (10), which are transformed with phosphorus
oxychloride in DMF into 2-aryl-4-dimethylaminomethylenoxazol-5(4H)-ones
(11). Ring opening gives acids (12), which after hydrolysis and treatment
with hydroxylamine can be converted into the 5-aryl-l,2,4-oxadiazole-3carboxylic acids (13) (M.Kmetic and B.Stanovnik, J. Het. Chem., 1995, 32,
1563).

178

/---N

POCI3

H02C 0 ,)2,,As DMF~

H
Or 0 ~/l-.Ar'

(10)

"

H02C o ~ - A r

(11)

(12)

H02C

(t3)
3,5-Bis(thien-2-yl)- 1,2,4-oxadiazole (15) is formed by the ultrasonication of
the O-acylamidoxime (14) in the presence of alumina. Other analogues can
be synthesised through the microwave irradiation of amidoximes and
isopropenyl acetate in the presence of KSF (B.Oussaid et al., Phosphorus
Sulfur Silicon, 1993, 85, 23; Syn. Commun., 1995, 25, 1451).
~ _ _ ~ O-N~ N ~

ultrasound
A1203~

(14)

O~__~N~
(15)

3,5-Diaryl-l,2,4-oxadiazoles (17) are available through the oxidation of Nbenzylamidoximes (16) with potassium permanganate in the presence of
alkali (B.I. Buzykin, Russian J. Gen. Chem,, 1993, 63, 1829). More
generally, related compounds (19) are obtained from amidoximes (18) and
acid chlorides by acylation and cyclisation with concomitant elimination of
hydrogen chloride and water (K.E.Andersen, A.S.Jorgensen and
C.Braestrup, Eur. J. Med. Chem., 1994, 29, 393; for another illustration of
this type of procedure see G.D.Diana et al., J. Med. Chem., 1994, 37, 2421).
Ar
H
X~/N/
N. O ~-~Ph

KMnO,
~alkali
~"

Ar
X~/N
N. O'3.. Ph
--

H
(16)

(17)

179

Me

Me

N.

"

OH

(18)

N- O,;')"" R
(19)

The reaction of amidoximes with cyanoguanidine in the presence of Lewis

acids affords 3-substituted 5-guanidino-l,2,4-oxadiazoles. A study of the
reaction of 15N-labelled chloroacetamidoxime with cyanoguanidine shows
that the formation of the oxadiazole ring occurs via the elimination of the
amino group from the amidoxime fragment (V.N.Yarovenko et al., Russian
Chem. Bull., 1994, 43, 114).
1,2,4-Oxadiazoles can be synthesised by reacting the methyl esters of Bocprotected L-amino acids (Ala, Gly, Asp, Phe, Ser, Arg, Cys, and Pro), and an
amidoxime (RC(NHOH)NH2) in the presence of sodium hydride in
THF/DCM (S.Borg et al., Eur. J. Med. Chem., 1993, 28, 801). This work
paved the way for the construction of heterocyclic amino acid mimetics,
useful as building blocks in the synthesis of modified peptides. In the followup work symmetrical anhydrides (20) of different Boc-protected amino acids
were reacted with ethoxycarbonylamidoxime (21) in pyridine. On heating the
reaction mixtures cyclocondensation occurs to form the 1,2,4-oxadiazoles
(22). The reaction conditions were chosen to allow for the formation of
products with high enantiopurity. In the same paper the synthesis of 1,3,4oxadiazoles (24) (formed by the cyclodehydration of N-diacylhydrazines
(23) with thionyl chloride and pyfidine) is also described (S. Borg et al., J.
Org. Chem., 1995, 60, 3112) (this is a standard approach to such
compounds, see later).

EtO~CI)F_~
RCO.O.OCR +

(20)

HzNC(NHOH)CO2Et

(21)

N. ~ " R
O
(22

180

SOC12

N- N

pyridine

RCONHNHCOCO,Et

(23)

c%Et

(24)

The 1,3-dipolar cycloaddition of nitrones with numerous multiply bonded

compounds provides an efficient route to many types of five-membered
heterocycles (see, for example, H.Mohrle and J.Lessel, Z. Naturforsch. Sect.
B., 1992, 47, 1333; R.Neidlein and S.Li, Syn. Commun., 1995, 25, 2379).
With of nitriles as co-reactants cycloaddition gives 1,2,4-oxadiazoles and
illustrations are provided by the reactions of benzonitriles with 4azahomoadamant-4-ene N-oxide (25), with 2,2-dimethyl-3,4-dihydro-2Hpyrrole N-oxide (26), and with N-(benzylidene)aniline N-oxide (27). The
reactions normally need heat and often take more than 12 h at high pressure
to afford the corresponding 2,3-dihydro-l,2,4-oxadiazoles. With acetonitrile
as the dipolarophile even longer reaction times are required (up to 15 days).
However, the use of an activated nitrile, e.g., methyl cyanoformate, permits
much shorter reaction times and milder conditions (typically 25-89 ~
(Y.Yu, M.Ohno and S.Eguchi, Chem. Commun., 1994, 331; Yu et al.,
Synthesis, 1995, 498; J. Chem. Soc., Perkin 1, 1995, 1417; 2197).
Photolysis of benzene/tetranitromethane in dicbloromethane or acetonitrile
with light of ~. > 435 nm gives different types of product depending upon the
solvent and the temperature. These are mainly nitrotoluenes and nitro
phenols, but in acetonitrile solution at +20 ~ a low yield (1.7%) of 5methyl-3-(4-nitrophenyl)-l,2,4-oxadiazole is obtained. The origin of this
compound is probably a cycloaddition reaction between 4-nitrobenzonitrile
N-oxide and acetonitrile (L.Eberson et al., Acta Chem. Scand., 1994, 48,
347).
When photoactivated by visible light the benzylcobaloximes (28) react with
an alkyl nitrite to give oximes. Hydrogen abstraction from these products,
probably by nitric oxide, allows the formation of an azine dioxide (29), which
partially decomposes to the appropriate nitrile oxide (30). Finally a reaction
between the nitfile oxide and its precursor (29) yields a 3,5-diaryl-l,2,4oxadiazole (31) (M.Kijima, K.Nakazato and T.Sato, Chem. Letters, 1994,
347).

181

R NyO

"'6

(25)

N+-o

Ar

,3--

A CN

~ ~

N-O

Ar
R

(26)
OI N+
Ph ~ "Ph

Ph

ArCN

N-O

~~

(27)

ArCH2Co(dmH)2py + RNO2
(28)
ArCNO + (29)

(30)

ArCH=N(O)N(O)=CHAr
(29)

Ar
N. O~ " Ar
(30

The acylation of phenylnitromethane with acetyl chloride in the presence of 2amidoimidazolidin-4-one (32) affords the 4-(1,2,4-oxadiazol-5-yl)methyl- 1,2,4oxadiazol-5(4H)-one (33). The mechanism of this reaction again appears to
involve 1,3-dipolar cycloaddition of benzonitrile oxide (generated from the nitro
compound) with an imine. The last intermediate results from N-3-C-2 cleavage
of the imidazolidinone (32). Reactions of this type have gene, ality and also takes
place with other aliphatic nitro compounds (K.Harada, J.Yokoyama and S.Zen,
Nippon Kagaku Kaishi, 1995, 47).

182

PhCI-I2NO2 +

H
N"

MeCOCI

"~NH

NaOMe

ON
I

Ph

/~---N

~-0

Ph

(32)

(33)

For example, (Z)-N-aryl[1,2,4]oxadiazolyl-N-[(methylcarbamoyl)methyl]benzamidoximes (35) are prepared from the N-methylimidazolidinone (34) in
reactions with primary nitroalkanes and acetyl chloride (K.Harada et al.,
Chem. Pharm. Bull. Tokyo, 1992, 40, 1610).
OX~...NMe

NaOMe

|
N...-x

Ar-----~N-t3

['NH~ NH MeOH HN_f _OMe

Ar

"-

N ' O "NI-I""CONHMe

(34)
Ar
Ar~N-O
-

N. ~)'-...Nr~CONHMe
O

MeOH

"~ NOH
AI"
(35)

A reaction between the isocyanate (37) and benzonitrile oxide (36) results in
the production of a mixture of the 1,2,4-oxadiazolinone (38) and the 3imino-1,4,2-dioxazoline (39) (A.A. Esipenko et al., Zh. Org. Khim, 1991,
27, 1262).
Ph
PhCNO + CISO2NCO
(36)
(37)

"

SO2C1

N, , ~ O
O
(38)

Ph
+

NSO2CI
O
(39)

183
A potential route to 1,2,4-oxadiazolines is the cycloaddition of nitrile oxides
and alkyl N-(diphenylmethylene)-0c, B-dehydroamino acids (40), but there is
the problem of selectivity. In practice the position of attack by the nitrile
oxide is govemed by the nature and the stereochemistry of the B-substituent(s) on the alkene bond of the ethenimine and either isoxazolines (41)
or 1,2,4-oxadiazolines (42) are produced. However, the additions are not
normally random and often proceed with both high site and regioselectivity.
Thus, isoxazolines are favoured when C-methylene compounds (40, 1R = 2R
= H) are used (C.Balsamini et al., J. Het. Chem., 1992, 29, 1593).
1R ~R
RO2C

BR
3RCNO
~

phL

RO2C~ O '
Ph

1R-~."2R

~
~R
ROzC- - N~ N

or

PhN~N

Ph- ~ O"
Ph

Ph
(40)

(41)

(42)

1,2,4-Oxadiazolium hexachloroantimonates (45) are obtained through the

cycloaddition of nitfilium salts (44) and mesitonitrile oxide (43) (R.Abu-E1
Halawa, P.B.Shrestha-Dawadi and J.C.Jochims, Chem. Ber., 1993, 126,

107).
R

Ar

+N!
-O
(43)

t
N+

II

Ar
SbC16 -

N.

IR

(44)

SbCI6 (45)

Ar = mesityl
The above synthesis has general applicability, but a less versatile approach to
oxadiazolium salts is the reaction of 4-oxo-l,3-benzoxazinium perchlorate
(46) with hydroxylamine hydrochloride. This leads to a 3-(2-hydroxyphenyl)
derivative (47) (Yu I.Ryabukhin, A.Yu Yeliseeva and K.Ph.Suzdalev, Khim.
Geterotsikl. Soedin., 1992, 280).

184
o

N
i~Oi ~

HC1

~.

Me
N_+' ~X

clo2

"o

(46)

M~

CIO4

(47)

(ii) Chemical reactions including bond-switching rearrangements

Catalytic hydrogenation of 5-substituted 3-(2-aminobenzyl)-l,2,4-oxadiazoles
(48) gives 2-acylaminoindoles (50). In common with previously known
chemistry, the initial step is hydrogenolysis of the heterocyclic ring to afford an
N-acylguanidine intermediate (49), which then recycles with loss of ammonia
(I.Bata et al., Chem. Ber., 1993, 126, 1835).
~ o - .

(49)

(48)

NHCOR
I

(50)
1,2,4-Oxadiazolines (51) on treatment with trifluoroacetic anhydride give the
corresponding 1,3,4-oxadiazoles (54), through N-acylation and subsequent
rearrangement (52 --, 53) (A.Q.Hussein et al., Heterocycles, 1994, 38, 981).
The photoinduced molecular rearrangements of 1,2,4- and 1,2,5-oxadiazoles
has been reviewed (N.Vivona and S.Buscemi, Heterocycles, 1995, 41,
2095). It is also well known (see N.Vivona et al., Adv. Het. Chem., 1993,
56, 49) that Z-1,2,4-oxadiazole oximes (56) rearrange to 3-aminofurazans

185

(57), whereas the E-isomers (55) only rearrange if the reaction conditions
permit E-to-Z isomerisation first. Similarly, the acid promoted rearrangement
of the oxime (58) eventually gives the aminofurazan (59, R = H) [via the Zisomer and then (59, R = CF3CO)]. In the absence of acid the starting oxime
cannot isomerise and an alternative reaction may ensue leading to the
nitrosopyrazole (60) [V.G.Andrianov and A.V.Eremeev, Chem. Her.
Compd., (Engl. Transl.), 1990, 26, 1199; also see V.G.Andrianov,
V.S.Semenikhina and A.V.Eremeev, Khim. Geterotsikl. Soedin, 1991,827].

NHPh

NHPh

H-N~0 Ar

NHPh

TFAA

benzene
R

R o" "e "~

R'LoN"~ ~

CFs

(5D

CF 3

(52)

(53)

NHPh
N,#[',O
Ar
(54)

RCOR

CF3CONI-I2

186
1R

R L ~ ~ N --N/

1R

OH

RCONH
OH

m ~

N..N

(57)

(56)

(55)

1R

CH=NNMe2
RNH

CF3CONH

CH=NNMe2

N..N
0

CF3"~" O"N

NO
N
I

NMe2
(59)

(60)

(58)

Related work by the same group of chemists (Khim. Geterotsikl. Soedin.,

1992, 687; 967) shows that the chlorooxime (61) combines with methylhydrazine to give the hydrazidoximes (62) and (63). The last compound may
rearrange to the 1,2,5-oxadiazole (64). However, the chlorohydroxylamine
(65) reacts with acrylonitrile to give the adduct (67), through the agency of
the nitrile oxide (66). These results are described in a series of papers which
exemplify the reactions of heteroaryl nitrile oxides with nucleophiles and/or
with dipolarophiles (for example, see V.I.Kelarev et al., Zh. Org. Khim.,
1993, 9, 763).

N
CI
O[~N ~ N

MeNHNH2
~1~

~,N MelN-NH2
Me
~O~..~~~q.,. OH + "N~N
O ~ / ~ ~ NN NI-I2

OH
(61)

Ht9
(62)

(63)

H Me
MeCO'-N N"NI-I2
i

h(

N..N
0
(64)

187
- 0

CN

+N'

I~N

~-- N

Base

A,

CI~=CHCN I~

OH ~

/~

~~"

N. .N
O

N. .N
O

N..N
O

(65)

(66)

(67)

In pursuit of studies to determine the effect of the structure of the side chain
upon mechanism and reactivity in mononuclear heterocyclic rearrangements,
the conversion of some N-(5-phenyl-l,2,4-oxadiazol-3-yl)-N'-arylformamidines (68) to 3-(N-benzoylamino)-l,2,4-triazoles (69) in dioxane-water has
been studied. The reactivities of the substrates were then compared with
those of arylhydrazones of 3-benzoyl-5-phenyl-l,2,4-oxadiazole and of 3arylureido-5-phenyl-l,2,4-oxadiazoles in similar bond switching processes
(V.Frenna et al., J. Chem. Soc., Perkin. Trans. 2, 1993, 1339).
H.

.N ~
(68)

(69)

The isomerism of 4-acylamino-3-aryl-l,2,4-oxadiazolidines (70) to 2-aryl-5chloromethyl-l,3,4-oxadiazoles (71) by the standard bond switching mechanism has also been recorded (M.M.Elabadelah et al., J. Het. Chem., 1991,
28, 1229).
R

N-N

N-N

- RCOR

N- N

A . o C%Cl

Ar
(70)

(71)

188
Isomerism of the side chain double bond of 3-styryl-l,2,4-oxadiazole (72)
occurs under irradiation with ultraviolet light; further rearrangement and
photoinduced cyclisation then affords the isoquinoline (73) (S.Buscemi,
G.Cusmano and M.Gruttaduaria, J. Het. Chem., 1990, 27, 861).

N- N' ' ' ~ f Ph hu

N- N""~

hu

Hl

Ph~ ,N-.Nt~
0

(72)

(73)

Disubstituted amino-E-oximes (74) also undergo acid promoted isomerisation to give the Z-forms (75), which can then be rearranged by
treatment with base at 120-140 ~ C to give the 4-amino-2,1,3-oxadiazoles
(76). Interestingly, the monosubstituted amino-E-oximes (74, R = H) also
rearrange under basic conditions (see N.Vivona et al., Adv. Het. Chem.,
1993, 56, 49).

~R.
R-N OH
I'I2N~/'k==N
~ )H+
)
N"O.N

(74)

1R
R-N"
1"12N~=~NOH

N.O"N
(75)

HO .NH2R
HO" "N~7=~N" 1R
N- .N
O

(76)

(d) 1,2,5-Oxadiazoles and benzo-l,2,5-oxadiazoles (furazans and

benzofurazans)
(i) Synthesis
3,4-Dinitrofurazan (1, R = NO2) can be obtained through the cyclodimerisation of nitroformonitrile oxide. The starting compound is itself available
through the dehydration of dinitromethane (I.V.Ovchinnikov, N.N.Mahova
and L.I.Khmel'nitskii, lzv. Akad. Nauk, Ser. Khim., 1995, 722).

189

3,4-Diaminofurazan (1, R = NH2) is safely and cheaply synthesised by the

action of hydroxylamine hydroehloride and aqueous sodium hydroxide upon
glyoxime to form diaminoglyoxime. This product is then cyclodehydrated by
treatment with potassium hydroxide to yield the diaminofurazan
(A.Gunasekaran et al., J. Het. Chem., 1995, 32, 1405). The availability of
this compound allows the preparation of high-density "energetic"
compounds. Thus, when it is reacted with formaldehyde and potassium Nmethylsulfamate in water, followed by treatment with nitric acid and acetic
anhydride, the tetranitro compound (2) is obtained in 55% yield
(A.S.Ermakov et al., Izv. Akad. Nauk, Ser. Khim., 1995, 719).
NO2 NO2
R

(i)HCHO/MeNHSO3K
/---N
N---~
.......
,
Me-N
~
N-Me
(ii) HNO 3 / Ac20
NO 2 N.o.N
NO 2

N..N
O

(R = NH2)

(I)

(2)

Bicyclic furazans are often formed by the oxidative cyclisation of 2-amino

nitrosoarenes or analogous heterocycles. An example is the synthesis of the
pyrimidinofurazan (4) from (3) (E.I.Ivanov et al., Zh. Org. Khim., 1992, 28,
422).
o

~
.o

.j
(3)

~
.o..J
(4)

(ii) Reactions
Dicyanofuroxan (5), when heated at 550 ~ undergoes cycloreversion to
afford dicyanogen mono-N-oxide (6) (T.Pasinszki and N.P.C.Westwood, J.
Chem. Soc., Chem. Commun., 1995, 1901; Pasinszki, G.Ferguson and
Westwood, J. Chem. Soc., Perkin Trans. 2, 1996, 179).

190
NC
N

CN
N

heat
~D-

2 NC-CNO

"O" "O
(5)

(6)

Benzofuroxan (7) when irradiated with light from a high pressure mercury
lamp with a Pyrex filter in acetonitrile solution containing a little water gives
1H-azepine-2,7-dione (11) (M.Hasegawa and T.Takabatake, J. Het. Chem.,
1991, 28, 1079). The authors suggest the reaction proceeds through the
formation of the intermediates (8) - (10) en route to the final product.
Irradiation from a low pressure lamp also caused the formation of the
azepinedione, but now it is accompanied by 6H-furazano[4,5-c]carbazole Noxide (12) (an unanticipated result!).

---

O
H20

~N...
-O

(7)

+ -

N. h-o
O -----~
+

(8)

0
-

N
O

O,C

~ N H
~
~ ~ - - - NHOH [
O
(lo)

(9)

oN
H

O
(1~)

(12)

Photolysis of the 1,2,5-oxadiazole (13) in the presence of ammonia gives 3amino-5-phenyl-1,2,4-oxadiazole (14); the amino group of the product stems
from the ammonia, rather than from the original oxadiazole (S.Buscemi et
al., Heterocycles, 1992, 34, 2313).

191
Ph

h(' NHCOPh

s.

O"
(13)

N-O';;"~Ph
(14)

A mild reductive cleavage of benzofuroxans to 2-nitroanilines occurs when

they are treated with ferrous sulfate in aqueous DMSO (A.M.Gasco,
C.Medana and A.Gasco, Syn. Commun., 1994, 24, 2707).

(e) 1,3,4-Oxadiazoles
(i) Synthesis
1,3,4-Oxadiazoles are generally synthesised by the dehydration of N,N'diacylhydrazines and there are numerous examples of this approach in the
current literature, using different reaction conditions and reagents. Some
have already been mentioned in the previous sections, but for others see:
M.M.Girges, Arzneim Forsch., 1994, 44, 490; E.Jedlovska and J.Lesko, Syn.
Commun., 1994, 24, 1879; E.Jedlovska and E.Gavlokova, Coll. Czech.
Chem, Commun., 1994, 59, 1892; Z.-J.Ren, E.Jiang and H.-B.Zhou, Youji
Hauxi, 1995, 15, 2; B.Oussaid et al., Syn. Commun., 1995, 25, 1451; S.Borg
et al., J. Org. Chem., 1995, 60, 3112; also see P.Reynaud et al., J. Het.
Chem., 1992, 29, 991. Unexpectedly, whereas the dehydration of N,N'dialkanoylbutanohydrazides (1) gives 5,5"-dialkyl-2,2"-(1,2-ethandiyl)bis(1,3,4-oxadiazoles (2), the aroyl analogues (3) produce 2,5-diaryl-l,3,4oxadiazoles (10), presumably via a series of diazine intermediates (4,5,6) and
then dehydration of the diacyldiamine (7). A by-product is succinic acid (9)
formed by hydrolysis of the diazine (8) (H.Tashoush, M.Altalib and N.Odeh,
Liebigs Ann. Chem., 1992, 291).

192

POCl 3

CH212

N
O

N-N

~
R MeCN

[CH2

(1)

(3)

(2)
0

N-N

POC13

ArCONHNH()H(4)

Ar

,
0

ao S ' Y

(5)

_..

(6)
HO

Ar

Ar

(7)
_

,,NH

225
(8)

H20"x,~

H+

(9) H O H
O

N - N

(10)

2-Ethylsulfonyl-5-trifluoromethyl-l,3,4-oxadiazole (12, R = SO2Et) is

synthesised by the cyclodehydration of the N-thioethoxycarbonyl-N'trifluorocetylhydrazine (11, R - SEt) with phosphorus pentoxide. Similarly
obtained is 2,5-bis(trifluoromethyl)-l,3,4-oxadiazole (12, R = CF3). Both
compounds react with various angle strained cycloalkenes (13) (and also
cycloalkynes) by [4 + 2]-cycloaddition to give adducts (14), which have
varying stability (AG.Seitz and C.Geringhaus, Pharmazie, 1994, 49,102).

193

(13)

P20'

N--N

N--N

O O
(11)

(12)
O

CF 3

tt
(14)

The preparation of a series of 3,5-di-*butyl-4-hydroxyphenyl)-ethyl, ethylene

or methyleneoxy linked 1,3,4-oxadiazoles (or 1,3,4-thiadiazoles) has been
reported (M.Santagati, Pharmazie, 1994, 49, 880). The starting compounds
can be amino derivatives, such as the oxadiazole (16). This last compound is
obtained from the acylhydrazide (15), which can be cyclised by a variety of
reagents, including formic acid - cyanogen bromide. Phosgene gives the
oxadiazolinone (17) (J.B.Kramer, D.H.Boschelli and D.T. Connor, J. Het.
Chem., 1994, 31, 1439).

H O ~ ~ . . ff

v- - O

__./

/I

COC12

(15)
/

(i) HCO2H
~(ii)BrCN
NaHCO3
N-N

N-N "H
HO

__~

(~7)

"~

OX~" NH2
(16)

194
There is also interest in bi(1,3,4-oxadiazol-2-yl) derivatives, linked through
biphenyl spacers, as emitter and carrier transport materials in organic
electroluminescence cells. Yet again the synthesis of these compounds
involves the cyclodehydration of the appropriate N,N'-diacylhydrazines
(Y.Hamada et al., Nippon Kagaku Kaishi, 1991, 1540). Some new
polyfluorinated 1,3,4-oxadiazoles, such as 2,5-bis(trifluoromethyl)-l,3,4oxadiazole, have been obtained through the cyclodehydration of the
appropriate N,N'-diacylhydrazines. Some aspects of their cycloaddition
reactions have been analysed and the energies of the frontier orbitals,
calculated by the MNDO method, indicate a LUMO-dependent pathway
(N.V.Vasiliev et al., J. Fluor. Chem., 1993, 65, 227). Aromatic
poly(oxadiazole)s form a class of heterocyclic polymers that show excellent
thermal and chemical stability. Also, their electrical and optoelectrical
properties are of interest. A short review summarising recent studies on
aromatic poly(oxadiazole)s at the former Institute of Polymer Chemistry in
Teltow-Seehof is provided by B.Schulz and E.Leibnitz (Acta Polymerica,
1992, 43, 343). New syntheses are discussed and the structures of poly(pphenylene-l,3,4-oxadiazole) in solution, as well as in solid state, are
described. In addition, the electrochemical behaviour and the dynamicmechanical properties of these types of compounds are surveyed.
A multidentate macrocycle (18) containing two 1,3,4-oxadiazole units,
bonded through C-2 and C-5 by hydroxybenzalimino groups, has been
synthesised to study its propensity to form coordination complexes with
metal ions. Once more, the five membered heterocyclic Unit is obtained
through the cyclodehydration of a suitable diacylhydrazide precursor (M.A.
Perez and J.M.Bermejo, J. Org. Chem., 1993, 58, 2628).
o
HO
N

2
(18)

195
An improved synthesis of 5-aryl-3-methyl-l,3,4-oxadiazoles (20) is claimed
through the oxidative cyclisation of 1-aroyl-2,4-dimethylthiosemicarbazides
(19) with mercuric oxide in methanol as the reagent. Yields range from 5481% (J.M.Kane and M.A.Staeger, Syn. Commun., 1992, 22, 1).
Me
!
H, N" N ~ NHMe HgO

J.

Ar"-~O
(19)

MeOH

Ar

Me
N- N
NMe
O
(20)

Ar = Ph, 3-CF3C6H4, 4-tBuC6H4, 4-C1C6H4, etc.

Another oxidative cyclisation is implicit in the reaction of acetone
benzoylhydrazone (21) with phenyliodonium acetate in methanol, this gives
2-methoxy-5,5-dimethyl-2-phenyl-l,3,4-oxadiazoline (22) (R.Yang and
L.Dai, J. Org. Chem., 1993, 58, 3 381).
HN-N
Ph----~ \ p M e
O Me
(21)

PhI(OAc)2
~
MeOH

Ph N=N Me
MeO)/,,O,)(
Me
(22)

In another related preparation, the oxidative cyclisation of acetone Nmethoxycarbonylhydrazone with lead tetraacetate in methanol gives unstable
2,2-dimethoxy-5,5-dimethyl-l,3,4-oxadiazoline (23). On thermolysis this
compound gives tetramethoxyethene (25), through the intermediacy of
dimethoxycarbene (24), plus acetone and nitrogen (M.E1-Saidi et al., J.
Amer. Chem. Soc., 1992, 114, 8751).

196

M e O ~ = ~ ( Me
MeO

Me

heat
- N 2

MeO
>:
MeO

o=<

Me

Me

(24)

(23)

MeO

)=< OMe

MeO

OMe

(25)
(ii) Other reactions
The thermolysis of the oxadiazole (23) in the presence of buckminsterfullerene, C~, allows the entrapment of dimethoxycarbene which is produced and
thus a 6-6-ring-bridged dimethoxymethanofullerene (26), with a closed transannular bond, is formed in 32% yield (L.Isaacs and F.Diederich, Helv. Chim.
Acta, 1993, 76, 2454).

(263
The PE spectra of the 1,3,4-oxadiazoline (27), and certain 1,3,4-thiadiazolines have been recorded and, based on HAM/3, MNDO, AM1, and
PM3 calculations, the ionisation potentials have been assigned to specific
molecular orbitals. During the gas-phase thermolysis of (27) the extrusion of
nitrogen occurs at 400-460 ~ leading to a reactive species, which cyclizes
to the oxirane (28). At higher temperatures and on flash vacuum pyrolysis
consecutive reactions may lead to smaller acyclic molecules. In the case of
the thiadiazole (29) the thioxirane (30) is produced, which at higher
temperatures eliminates sulfur and gives bis(cyclohexyl) (31) (M.K.Kinderman et al., Chem. Ber., 1993, 126, 2675).

197
OMe
OMe
~ = NOMe460C,
o~
~ O~oMe 600C~ "~O/"" >750C~ /~ + ~ ' O
(27)

(28)
+" ~ + ~"0 /
0
4+c

-(29)

. N2

- H2S
(30)

(31)

When 5-phenyl-2-benzylthio-l,3,4-oxadiazole is heated at ca. 250 ~ in a

sealed tube COz, HzS, 1-120, benzyl thiocyanate, benzonitrile, benzyl sulfide,
aniline, benzamide, benzaldehyde, 2-mercaptoquinazolinone, dibenzyl,
stilbene, and tetraphenylthiophene are produced. Pyrolysis of 5-phenyl-2phenacylthio-1,3,4-oxadiazole gives similar results, as well as the formation
of phenacyl thiocyanate. Pyrolysis of 5-(2-hydroxyphenyl)-2-benzylthio1,3,4-oxadiazole gives 2-hydroxybenzonitrile, 2-hydroxybenzamide and 5-(2hydroxyphenyl)-l,3,4-oxadiazole (A.A.Atalla et al., Phosphorus Sulfur
Silicon., 1994, 233).
The reaction of 5-aryl-l,3,4-oxadiazole-2(3H)-thiones (32) with N-phenylbenzohydrazonoyl chloride (33) in either benzene or ethanol, in the presence
of triethylamine, at room temperature gives 3,5-diphenyl-l,3,4-thiadiazol2(3H)-one benzoylhydrazone derivatives (36). Two mechanisms are possible:
the first is the reaction of benzonitrilium N-phenylimide with the S-atom to
give the thiohydrazonate esters (34), which then afford the spirocycles (35).
Ring-chain tautomerism then allows the formation of the products (36). The
second requires the addition of the dipolar species across the thione group to
give the spirocycles directly. Since intermediates of the type (34) are not
detected the evidence, thus far, favours the second route (I.M.Abbass et al.,
J. Chem. Res. Synop., 1994, 308).

198
N-N
PhC(CI)=NNHPh
~S
(33)
Ar"~ O
I*
N.r
Ar~X/O'~ S
Et3N
ph" H
(32)
(34)
H
N-N"

IPhC(CI)=NNHPh
Et3N

O,xjN-N

N-N

ph.-N-N
(35)

Ph

(36)

New 3-acylamino-2-oxazolidinone derivatives (38) are obtained in good

yields by reactions of 5-aryl (or benzyl)-3-(2-hydroxyethyl)-l,3,4-oxadiazol2(3H)-ones (37) with sodium ethoxide. When the side chain cannot act as the
internal nucleophile, for example in the case of the ester (39), then the
heterocycle is opened by attack of ethoxide ion at the ring carbonyl and the
carbamates (40) are produced (R.Milcent, B.Yver and G.Barbier, J. Het.
Chem., 1993, 30, 905).
N_N/-~
R~X/o,~O O'H

~ ~NaOEt
,
(i)

(ii) H+

(37)
N-N

r~
H'N- s ~.,O

R"~O O
(38)

/'" CO2Et

R'~o'~O
(39)

(i) NaOEt

H.
/"'-CO2Et
N=N

(ii) H:
(40)

199

(iii) Theoretical considerations

Ab-initio transition structures for the Diels-Alder reaction of 1.3,4oxadiazoles with cyanoethylenes and heterodienophiles, together with the
general reactivity and exo-lone pair effects in such cycloadditions have been
generated and studied (B.S.Jursic and Z.Zdrakovski, Absr. Papers Amer.
Chem. Soc., 1994, 207, Pt.1, 149-Comp.). In addition, transition structures
for Diels-Alder reactions of 1,3,4-oxadiazole with formaldehyde,
formaldimine, diazenes, and nitrosyl hydride have been deduced by ab initio
molecular orbital calculations. Formaldehyde and exo hydrogen formaldimine
have a higher activation energy than ethene addition to 1,3,4-oxadiazole,
while the others have similar or lower activation energies. Transition
structures that have an endo nitrogen or oxygen lone electron pair have
higher energies than the corresponding structures with the exo lone pair. The
opposite effect is obtained when a hydrogen is attached to nitrogen, the endo
hydrogen decreases the energy of the transition, structure. The exo-lone-pair
preference for formaldimine is 7.0 kcal/mol, for cis-diazene 16.6 kcal/mol,
and for nitrosyl hydride 9.0 kcal/mol estimated by MP2/6-31G*. These
preferences are the result of the electrostatic repulsion between the nitrogen
lone pair and the oxadiazole pi-electrons and electrostatic attraction between
the hydrogen bound to nitrogen and the oxadiazole pi-electrons (B.S.Jursic
and Z.Zdravkovski, J. Org. Chem., 1994, 59, 3015).
The transformation of 2-acetyl-5-substituted-tetrazoles into the corresponding 1,3,4-oxadiazoles has been studied by MOPAC semi-empirical and
by GAUSSIAN ab initio methods. Two mechanisms, one with two transition
states and the other with three, are elucidated by MOPAC. The first, which
is supported by PM3 and MNDO calculations requires a two-step, almost
concerted mechanism, (1) the elimination of a nitrogen molecule from the
tetrazole ring and (2) formation of the oxadiazole product from an openchain intermediate through bonding between C5 and the acetyl oxygen atom.
The second mechanism, supported by AM1 and MINDO/3 arguments
subdivides the elimination reaction of the nitrogen molecule into two steps:
f'trst breaking the N4-C5 and then the N2-N3 bonds. However, HF/STO-3G
and HF/3-21G ab initio methods tend to confirm the first mechanism where
two bonds are breaking almost simultaneously.
Despite these disagreements the transition state that represents the product
formation from an open-chain intermediate is quite similar for all methods

200

studied. The semi-empirical calculation of this transition state is possible only

if it is assumed that it has biradical character. The activation energies
calculated by PM3 seem to be insensitive to the nature of the substituents
(B.S.Jursic and Z.Zdravkovski, Theochem. J. Mol. Struct., 1994, 115, 241).

2. THIADIAZOLES
a. 1,2,3-Thiadiazoles

(i) Synthesis
The Hurd-Mori reaction of ot-substituted-X hydrazones of acetone (1) with
thionyl chloride gives 4-methyl-5-X-1,2,3-thiadiazoles (2) and /or 4-Xmethylene-l,2,3-thiadiazoles (3). The balance between (2) and (3) reflects
the relative ease of acid catalysed enolisation of methyl or X-methylene units
in the starting material. In a follow-up study similar reaction conditions
employed on N-ethoxycarbonyl- (or p-toluenesulfonyl-) hydrazones of 1,2alkanediones gave 5L1,2,3-thiadiazolin-l-ones (4) as the sole isolable
products. Upon treatment of (4) with hydrogen chloride the 1,2,3thiadiazole (6) is formed, possibly via the tautomer of (4) and a bicyclic
intermediate (5) (M.Fujita et al., Heterocycles, 1993, 39, 33; 1995, 41,
2413).
3-Arylazopropenamides (7; 2R = NH2, or NHEt, X -- H) on treatment, firstly
with KSCN and bromine, and then with perchloric acid give 1,2,3thiadiazolium salts (8) [methyl esters (7, 2R -- OMe) react in a similar way
and afford (8, 2R = OMe)]. The amido products can also be formed by
reacting 3-arylazo-2-halopropenamides (7, X = halogen, rather than H)
directly with KSCN/HOAc (G.Lutze et al., J. Prakt. Chem., 1993, 335,
169).

201

"

- 2HCI

N--~

N.s2

(2)

N_~

SOC12

NNHCO2Et

_:%

N,S.~ X

II

(1)

,CH2X

Mc

y,N,

Y H
"

Me

socl,

Me

(3)

NNHCO2Et____x

ii--

- 2HC1

EtO2C"N'H ~Me

EtO2C.N, S~.Me
O (4)

II

F
N. //x..

- EtOH

.-

EtO2C" SH Me

L~O
N~

(5)

- 1202

NNH2

N'$~Me
(6)

~R

~R

Ar"

etc.
0

(7) X=H
X=

Hal

HZ

At"+ - S

~
Z"

(8)

The tosylhydrazone of indanone (9) when treated with thionyl chloride gives
8H-indeno[1,2-d]- 1,2,3-thiadiazole (10), oxidation of which affords the
ketone (11). The phenylhydrazone (12) of this last compound when reacted
with Meerwein's salt and then with a base gives a mixture of the methylated
compounds (13) and (14) (G. L'abb6 et al., J. Het. Chem., 1992, 29, 461).

202
0
i, TsNHNH2
,,

ii, SOCI 2

(10)

(9)
NNHPh

(11)
N=N

M~OBF4 -

.Ph

,s
N-N.

- .Ph
N-N
+

(13)

02)

-.

Me
(14)

Me

(ii) Reactions
Methylation of the hydrazones (15) either gives the mesoionic 1,2,3thiadiazole (16), or the tetraazathiapentalene (17), depending upon the
reagent and the conditions. Other examples of selective methylations are
noted for the corresponding oximes (15, NOH instead of NNHPh)
(G.L'abb6 et al., J. Chem. Soc., Perkin 1, 1992, 1755).
Ph/
Me N. ~
4----N-N (R = Ph)
Ph
(17)

N ~

M%OBF' Me
N.NHPh
(R -- C02Me)

(15)

CO2Me
S

NPh
(16)

Although the thiadiazolium salt (18) fails to react with nucleophiles such as
ammonia, it combines with activated methylene ketones (19, R --- alkyd and
esters (19, R = OEt) in the presence of base to give the corresponding 5methylidene derivatives (L'abb6 et al., J. Chem. Soc., Perkin 1, 1994, 2545;
2895).

203
Bu

1RCH2COR

Me'~N-S,~" CI

base"

N--~
Me" "S 11

BF4
(18)

(19)

Under the influence of ultraviolet fight 1,2,3-thiadiazole extrudes nitrogen

and gives thioketene as the primary product; this then rearranges to ethyne
thiol and thiirene (B.D.Larsen et al., Acta Chem. Scand., 1992, 46, 482).
Photolysis of thiadiazole (21), formed by the reaction of disulfur dichloride
with the dihydrazone (20), produces a biradical (22), which can be trapped
with the thiacycloheptyne (23) to give (24). This product has two masked
tbutyl groups and reductive desulfurisation of it with Raney nickel affords
2,3,4,5-tetra-%utylthiophene (25) (A.W.Krebs et al., Tetrahedron Lett.,
1992, 5947).

,.
I-IaNN" / / N ~

Et3N

(2o)

S
(21)

-.J
(22)

s
3)

Ni/A1

(24)

(25)

3-Amido-2-chloro-l,2,3-thiadiazoles are susceptible to nucleophilic substitution by amines and hydrazines to afford 2-amino and 2-hydrazinyl
derivatives, respectively. 2-Thiols are obtainable directly from the 2-amino

204

compounds by reactions with thiolates (Y.Y.Morzherin, E.V.Tarasov and

V.V.Baklulev, Khim. Geterotsikl. Soedin., 1994, 554), however, treatment
of 5-amino-4-thioamido-l,2,3-thiadiazoles (26) with sodium ethoxide effects
ring opening and affords sodium diazocarbodithiomidates (27) (E.F.Dankova et al., Khim. Geterotsikl. Soedin., 1992, 979).
S

Ar~ N H ~- / N
I.I2N..-K,S, N
(26)

NaOEt
~

Ar'N~"~N 2

Na+ I_I2N~ , S
Ar = 4-MeOC6H4
(27)

(b) 1,2,4-Thiadiazoles
(i) Synthesis
A new synthesis of 5-amino-3-phenyl-l,2,4-thiadiazoles (3) is achieved by
thermolysis of 1-thiocarbamoyl-5-phenyltetrazoles (2), prepared from the
reaction of N-thiocarbamoylbenzimidoyl chloride (1) and sodium azide (K.
Rosenbaum, S. Goldenberg, and G. Weber, J. Prakt. Chem., 1992, 334,
283).
C1
N

)=s

N-N

Ph

R2N
(1)

NaN3

"

N. ~ P h
N

Ph

heat

g
N

"RzN
(2)

RzN
(3)

Treatment of N-substituted N'-chlorobenzamidines (4) with potassium Smethyl cyanimidodithiocarbonate (5) gives 5-[N-(cyano)imino]-l,2,4-thiadiazoles in moderate yield (7), via the intermediacy of (6). The N-unsubstituted analogues cyclise by an alternative pathway and form 3-imino derivatives (8) instead (H.Sonnenschein et al., Liebigs Ann. Chem., 1992, 287).

205
HN
"~N.s)~".- SMe
NH (8)

=H
Ar

NC.
NCI

N
\~----SMe
KS
(6)

(4)
(5)
Ar

NCN

/MESH
R

N.S-'~ NCN
(7)

Sulfur bearing heterocycles possessing an exocyclic imine function o~- to the

sulfur atom can react as masked 1,3-dipoles. These heterocycles include 4methyl-l,2,3,4-thiatriazolin-5-imines, bearing a cyanopropyl, o-cyanobenzyl
or o-cyanomethyl)benzyl group at the exocyclic imine function, which when
thermolysed give fused 1,2,4-thiadiazoles via an intramolecular cycloaddition
-elimination process. In the example shown below the imine (10) was formed
by the N-methylation of the thiatriazole (9) and then deprotonation of the
product with base. On heating, elimination of nitrogen and cycloaddition the
imine (10) gives the bicyclic thiadiazole (11) (G.L'abb6 and S.Leurs, J.
Chem. Soc., Perkin Trans. 1, 1992, 181).

N-N
I~. ~ S cx~NH'~
n
(9)

Me

(i) Me3OBF4 N-N"

"
~v
1~'"s'~N~"A
(ii) NaOH
N
(10)

- N2
.-'-

N"Me
A
S~b/
(11)

206
The oxidative cyclisation of 1-aroyl-5-methyl-2-thiobiurets (12) with alkaline hydrogen peroxide gives 5-aroylamino-2-methyl-2H-1,2,4-thiadiazol-3ones (13) (N.S.Cho, H.I.Shoh and C.Parkanyi, J. Her. Chem., 1991, 28,
1645). A similar cyclisation of the corresponding des-5-methyl thiobiurets
can be achieved with bromine as the oxidant, but in this case the product 3ones equilibrate with the appropriate 3-hydroxy-l,2,4-thiadiazoles (idem,
ibid., p. 1725).
H

1-I2021,

R=H

HO

N'_.
N
._._x
O
_~NHCOAr
NaOH
R"N-s
~NHCOAr
R'N S
H
(12)
(13)

N"S~ NHCOAr

Fused 1,2,4-thiadiazoles are formed in high yield by the reactions of o>

cyanoalkylamines with thiocarbamoyl isothiocyanates and oxidation of the
intermediate dithiobiurets with bromine-pyridine. Two examples are shown
below (G. L'abbt, B.D'hooge and W.Dehaen, J. Chem. Soc:, Perkin Trans.
1, 1996, 225):

(1) ~N~II
N

R2NNCSNCS H~,(N~INI

Br2
~pyridine
~

R-zN' ' ~ s SH

(2)

R2NNCSNCS~~'

R2N"j~S

~ \N~-~
---s

Br2/ pyridine
9
R = Ipr

N~~
N ' ~ S. N

N.~S .N
D~,r

&
S

1,2,4-Thiadiazol-5-ones (16) are formed by reacting hydroxamidines (14)

with thiophosgene and rearrangement of the product thiones (15) by

207
treatment with copper. These can be converted into the corresponding
thiones (17) by reaction with phosphorus pentasulfide, but a more direct
route to the thiones (18) is to treat the amidines (14, R = H) with carbon
disulfide. S-Methylation of the thiones (18) is possible using either
diazomethane, dimethyl sulfate, or methyl iodide, giving 5-methylthio-l,2,4thiadiazoles (19) (H.Agirbas, Y.Durust and D.Sumengen, Phosphorus,
Sulfur Silicon, 1992, 66, 321).

Ph

HO"

Ph

S~ , , o . N

(14)

R
"- O ~

(15)

CS2 " ~

Ph

Ph

P,S,

S oN

Ph

"S ~ s -

(16)

(17)
Ph

CI_I2N2

SJ,,s.N

" M S. s.N

(18)

(19)

Cyclization of nitrile sulfides (22), generated in situ from 1,3,4-oxathiazole2-ones (21) by thermolysis, with tosyl cyanide, or with ethyl cyanoformate,
afford 5-tosyl- or 5-ethoxycarbonyl-3-aryl-l,2,4-thiadiazoles (23), respectively (P.C.Unangst et al., J. Med. Chem, 1992, 35, 3691).
RN.
O_/_/
N "S ~
(21)

heat
~),"
- CO2

RCNS
(22)

NCCOzEt._
"-

R
N
.,
N. S ~ CO2Et
(23)

(ii) Bond-switching rearrangements

Bond-switching rearrangements using the propensity of sulfur to assume a
hypervalent state are commonly observed for thiadiazoles. Indeed a study of
the ring/chain (diazomine/triazole) equilbria of several diazomethyl and
diazoester substituted thiadiazoles and triazoles has been reported. The

208

ability of the diazo compounds to exist in the triazole form decreases in the
order thiazole > 1,3,4-thiazole > 1,2,4-thiadiazole and also, diazomethyl >
diazoester. The effects of temperature, solvents and substituents of the ring
have been analysed (G.L'abbr, I.Luyten, and S.Toppet; J. Het. Chem, 1992,
29, 713). Fused 1,2-4-thiadiazoles (25) are obtained when 5-[(Ncyanoalkyl)imino]-4-methyl-l,2,3,4-thiatriazoles (24) are thermolysed at 75
~ in ethanol (G.L'abb6 and S.Leurs, Tetrahedron, 1992, 48, 7505),
however when the tether is a N-(2-methylcyano)phenyl unit [as in (26)]
cyclisation occurs onto the aromatic ring giving rise to a benzothiazole (e.g.
27).

I/r-13
N

"

\E/go

-N,

N S ,)L.NM e
I
N=N

,v_

N - S . / ~ NMe

(24)

(25)

_ N2
\(~

N SI~'NMe
I
I
N~N
(26)

NHMe
(27)

The reaction of azidoalkyl nitriles and acyl isothiocyanates affords

dihydrothiatriazoles (28), which decompose to 1,2,4-oxathiazole-3-imines
(29) in principle these should then undergo an isomerisation to afford 5imino-l,2,4-thiadiazoles (30) (L'abbr, I.Sannen and W.Dehaen, J. Chem.
Soc., Perkin Trans. 1, 1993, 27).

209

///

[-1-]
n
tN r,,.N
~N.....S

Me

"N2.~

//~N.]n

Me
S---O

(28)

(29)
,,._

i1,,.-

o
(30)
The 5-imino-2H-1,2,4-thiadiazole (31) reacts with trichloroacetonitrile to
afford the tautomeric 1,2,4-thiadiazoles (33) and (34), through the
intermediacy and rearrangement of the imine (32) (G.L'abb6, E.Albecht and
S.Toppet, J. Het. Chem., 1992, 29, 1317).

Ph

(32)

(31)

Ph
N'~

NHMe

N~

C13CIJ~N"S

C13c.~N "s

(33)

(34)

Ph
NMe

Similar bond-switching rearrangements via a hypervalent sulfur atom occur

during the reactions of bicyclic thiadiazoles and an exchange of nitrile units
has been observed [i.e. (35) ~ (36)] (L.L.Lai et al., J. Chem. Soc. Perkin
Trans.1, 1993, 1753).

210

R-CN +

~r "'~

1R'~N'S

N~ /l ~
~c,-~" ~ S"N
~
N

~,r

'R-CN +

NfSyR
s"N

(35)

(36)

Similarly, 5-anilino-2-benzyl-3-oxo-~54-1,2,4-thiadiazoline (37) combines with

ketenes (or isothiocyanates or carbon disulfide) and nitriles to give the
products [(38) appropriate X and Y groups] and (39), respectively. N,N'Ditolylcarlxxtiimide reacts to give the addition product (40, Ar = 4MeC6I~), which only partly rearranges into (41, Ar = 4-MeC6I~) the
amount increasing as the temperature is increased (G.L'abb6 and E.Albrecht,
J. Het. Chem., 1992, 29, 451).
Ph

R
.N

Ng's
/~- NHBn

NI-IPh
.~

Ph

)r- Bn

,~

N s

(39)

Y
.X

/~'---NHBn
(38)
O

(37)
I ArN=C=NAr
Ph

NAr

N~/.,,S N H A r ~
/~'--lqBn
O
(41)

Ph
x

NAr

N,~s.N--Ar
/~-'-NHBn
O
(40)

2-Benzyl-5-chloro-l,2,4-thiadiazol-3-one (42) and 2-aminobenzyl cyanide

(43) in ethanol containing triethylamine affords the intermediate (44) which,
through yet another example of bond switching, gives the
indolinothiadiazoline (45) (L'abb6 et al., Tetrahedron, 1994, 50, 7019).

211

0
Bn

.N

"S

x.~--C1

.- I

0~,, ,N

EtOH
NC

(42)

/N--S.
Bn

N
(44)

(43)

Bn

NI-I S. /~--~
N

(45)
(iii) Reactions with nucleophiles
The products (47) of the addition of nucleophiles (i.e. alcohols, amines) to
the cyano group of 5-(cyanoimino)thiadiazolines (46) (for synthesis see H.
Sonnenschein et al., Liebigs Ann. Chem., 1992, 287) undergo a BoultonKatritzky rearrangement, followed by the elimination of a nitrile from the
intermediate (48) to give thiadiazoles (49). In the case of the bicyclic
thiadiazoloazepine (50) a mixture of the unrearranged iminothiadiazoline
(51) and the nitrile (53) is formed. The last compound being generated via
ring opening of the imine (52) (idem, ibid., 1994, 1177).

tR

~R

2R

2R

~R

2R

HNu
N, S' ~ N C N

N.S~

~~"

,~ N
HN S'N~"Nu

HN" -Nu
(46)

(47)

(48)

1RCN
w-

212
~R

H..N"
(Nu = OMe or NMe2; 1R and 2R aryl = and/or alkyl)
S'N~',,Nu
(49)

N-S
N ' ~ NCN

NH
HNu
v

(5~)

(50)

N /~Nu

(52)

_N

H~Nu

(53)

(c) 1,2,5-Thiadiazoles
(i) Synthesis
The first cyclic bis(imino)fluorosulfinate (2), has been synthesised. This
compound is formed when 3,3,4,4-tetrafluoro-l,2,5-thiadiazoline (1) is
reacted with tris(dimethylamino)sulf'mium difluorotrimethy!silide (E.Lork,
G.Knitter and R.Mews, J. Chem. Soc., Chem. Commun., 1995, 1437).

F F
F~-..- F

+
(Me2F03SMe3SiF2
._

F F
F-~-~F

N.~S,..,N

N,,"S'.,,N
!
F

(1)

(2)

+
(Me2N)3S

213
The synthesis of tricyclic 1,2,5-thiadiazole derivatives (e.g. 5) has been
described, some of which show non-ohmic behaviour. The synthesis of (5)
involves a Homer-Wittig reaction of the dione (3) with two equivalents of
the carbanion derived from the phosphonate ester (4) (Y.Yamashita et al., J.
Org. Chem., 1992, 57, 5517; J. Chem. Soc., Chem. Commun., 1993, 1803).
O
.N

N.

S><~S (4)
H- "PO(OMe)2

~ ~ .

base

N'-S'~'S-" N
\--I

(3)

(,5)

This work has been extended to the synthesis of 7-(1,3-dithiol-2-ylidene)-4methyl-4,7-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine (6), which has good
electron donating ability and forms a highly conducting charge-transfer
complex with tetracycanoquinodimethane (K.Ono et al., J. Chem. Soc.,
Chem. Commun., 1994, 899).

N...N
S

(6)
N-Methyltrimethylsilyl tt-aminoacetamides (7) react with sulfur dioxide,
generated from thionyl chloride and water, to give 1,2,5-thiadiazol-3-ones
(11) in moderate yields. A possible mechanism involves the initial formation
of sulfinylamine intermediates (8), which after cyclization to (10) and loss of
TMSOH give 4-aryl-l,2,5-thiadiazol-3(2H)-ones (11) (W.H.W.Lunn and
J.K.Shadle, Tetrahedron, 1992, 48, 8615).

214

R,...NH N H

so,:,I

~1.I20
~

TMS
(7)
TMSCI

o
-TMSCI

R -'NH ,,N

R--NH ,N'-TMS
(~S.cI
(8)

o, , ~
~/
R~'N.s-.N
I
OTMS
(10)

- TMSOH

%-(Ar
(9)

~r

R"N's" N
(11)

Following earlier work (J.Cho and K.Kim, J. Het. Chem., 1992, 29, 1433), it
has been shown that when dibromomethyl aryl ketones are heated with
tetrasulfur tetranitride ($4N4) at 115 ~ without a solvent, 3-amido-4-aryl1,2-5-thiadiazoles (12) are formed as the major products (12-71%) and 3,5diaroyl-l,2,4-thiadiazoles (13) as minor products. The major products are
transformed into the minor ones by oxidation with m-chloroperbenzoic acid
in chloroform at room temperature, whereas reduction with sodium
borohydride in chloroform-ethanol at room temperature gives 3-amino-4aryl- 1,2,5-thiadiazoles (14) (71-93%). Treatment of 3-(3-amido)-4-(3-nitrophenyl)-l,2,5-thiadiazoles with either sodium hydroxide in aqueous dioxane
at reflux, or sodium hydride in chloroform at room temperature effects
hydrolysis and gives 3-amino-4-(3-nitrophenyl)-l,2,5-thiadiazole (K.Kim,
J.Cho and S.C.Yoon, J. Chem. Soc., Perkin 1, 1995, 253).
Thionyl chloride and pyridine react with 2,3-diamino-l,4-naphthoquinone
(15) to form the naphthoquin0no-l,2,5-thiadiazole (16), but it is much
simpler to react 1,4-naphthoquinone (17) directly with the trithiatriazole
chloride (18) in a one-step procedure. Evidence is put forward to support the
hypothesis that NSC1, or a related thiazyl derivative, is the reactive species
that brings about the transformations. 2,3,5,6-Tetrachloro-l,4-quinone (19)
reacts with $4N4 and gives the di-(1,2,5-thiadiazolo)quinone (20). In like
vein, a reaction between 2,3-dichloro-1,4-naphthoquinone (21) and $4N4 and
pyridine yields (16). But when a mixture of the dichloronaphthoquinone (21),
anthra-l,4-quinone (22) and S4I-h are heated in benzene containing 25 molar

215

equivalents of pyridine a 73% yield of the tetracyclic thiadiazole (23) is

obtained. The reaction fails if 2,3-dichloro-l,4-naphthoquinone is not
present (S.H.Shi et al., J. Org. Chem., 1995, 60, 1285).

.~~
N, ,N

NaB~

~~

mCPBA

N,s,N

(14)

(12)

~N

N,S..~COAr
(13)

O
SOCI2

S
N

pyridine
O
(15)

O
(16)

CI
'
+

N~,S-N
a
IJ

~P"

(16)

cI'S"N "S'C1 pyridine

0
(17)
0
CI~C1

(18)
0

$4N4
I,..._
IT

CI" ~'~ "Cl

O
(19)

pyridine

s,N~r
o
(20)

216

s~,
(16)

C1

pyridine

O
(21)
o
(21)

s
pyridine
0
(22)

0
(23)

4H,5H-Benzo[1,2-c;3,4-c']bis[1,2,5]thiadiazole-4,5-dione (26), prepared by

the oxidation of 4-bromobenzobis[1,2,5]thiadiazole (24) with nitric acid, can
be subsequently converted into 5,6-dihydroxybenzenetetramine dihydrochloride (27,R =H) by reduction, whereas oxidation cleaves the benzene ring,
giving the bis(thiadiazole) dicarboxylic acid (25). The dione (26) is a versatile
starting compound for the synthesis of a range of other products, such as Oalkyl derivatives of the tetraamine (27), the pentacycle (28), the dihydric
phenol (29) and the di(thiadiazole (30) (S.Mataka et al., Chem. Ber, 1993,
126, 2767).

217
N-S
O

N-S
N

HNO3 R

N-S
Cr(VI)~ HO2C-"~/
.- HO2C~,,~

.,
O" ~ " N

(R=Br)

N-S
(26)

]~ -N

(R=OH)

-N

N--S

N.-S

(24)

(2.6)

N-S

r~
2HC1

N- " ~ " N
N-S
(28)
1,2-phenylenediamine
~'~

SnB-I~

o" "~ "N

Et2NOH
N--S
/
(26)

N-S
HO

N-S

R0- y
-NH~
NI-L2
(27)

aq. alkali
~

N-'S.
-0 2

HO-'~ "N
N-S
(29)

N--S
(3o)

Examples of multiple thiadiazolo-fused naphthalenes are known including

(32), (34) and (35), they can be synthesised by reacting orthodihydoxynaphthalenes (e.g. 31) with tetrasulfur tetranitride. They are useful
in that upon reduction, usually with tin and hydrochloric acid, they give
polyaminonaphthalenes (e.g. 33) (S. Mataka et al., Heterocycles, 1992, 33,
791; Bull. Chem. Soc. Jpn, 1992, 65, 2221).

218
N-S

OH N4S4,-'- ~

OH

~l

N~

Sn / HCI._.

N-S
(32)

(31)

N-,f

N-'S
hl

S-N

S-N

(33)
N-S

r~~ r , , ~

N"S
(34)

(35)

A fluorescent compound (37) is formed as a by-product when 8-amino-3,4dihydro-7-nitroso-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (36) is reduced

with sodium hydrosulfite. The main product is the diamine (38) (P.Pecorari
et al., J. Het. Chem., 1992, 29, 1449).
0

ONI ~ N I ~

S NariS03

N~N~

(36)

0
S

HaNI ~ N ~

(37)

(38)

The known compound 1,2,5-thiadiazole-3,4-dicarbonitrile (39) reacts with

oxygen, sulfur and nitrogen containing nucleophiles to give the monoimino
products (40) preferentially, however, bis addition compounds (41) are
sometimes also formed (E.H.MCrkved, H.Kjosen and S.M.Neset, Acta
Chem. Scand., 1994, 48, 372).
NC

CN

N.. ,.N
S

(39)

NC

C0{)=NH

N.. ,.N
S

(40)
R = OMe,NHAr,SPh,SBn,SEt

HN=(R)CC ( R ) = N H
N., ,,N
S

(41)

R = OMe,NHOH,NHBu

219
A new sulfamide chiral auxiliary, 3,4-diphenyl-l,2,5-thiadiazolidinone 1,1dioxide (42) derived from trans-stilbene is efficient in titanium-mediated
asymmetric aldol reactions and as the titanium enolate reacts with aldehydes
to give syn aldol adducts (43) with high stereoselection (95:5). Conversion
of the adducts into [3-hydroxyesters (44) can then be readily achieved
(K.H.Ahn, D.J.Yoo and J.S.Kim, Tetrahedron Lett., 1992, 33, 6661).
Ph

Ph

RCHO

Sd, ~
o

Ph
Ph
_-= ~ ' ~
R.~~..N
. N . .IA . R

steps

HO

OH

(43)

(42)

several steps

MeO~~.j

[I

OH
(44)

(d) 1,3,4-Thiadiazoles
(i) Synthesis
As for 1,3,4-oxadiazoles, cyclodehydration is the normal method for the
synthesis of 1,3,4-thiadiazoles. In this case thiosemicarbazides are the usual
starting materials. Thus, A.A.Eleman and J.Lehmann (Monatsh. Chem.,
1994, 125, 587) have used this approach to obtain 5-adamant-1-yl-2-amino1,3,4-thiadiazoles from adamantylcarbonylthiosemicarbazides. Similarly
oxazolyl derivatives are obtained by the cyclodehydration of the appropriate
thiosemicarbazides with phosphorus pentoxide (A.Shafiee et al., J. Het.
Chem., 1995, 32, 1235). For further examples also see (M.Dobosz and A.
P.-Stec, Acta Pol. Pharm., 1995, 52, 103; F.Firoozi et al., J. Het. Chem.,
1995, 32, 123; W.J.Gottstein et al., J. Het. Chem., 1995, 32, 1235).

220

There is considerable interest in macrocycles containing five-membered

heterocyclic units. Thus, b i s - o r tris- (1,3,4-thiadiazolidine) derivatives
connected by aliphafic or aromatic bridges have been targeted. In the case of
some ether linked compounds the precursors (e.g., 3) are formed from
methyl 2-methyldithiocarbazate (1) and bis(chloro-carbonylmethyl) ether (2).
After cyclisation with acetic anhydride and perchloric acid, reaction of the
diperchlorate salt (4) with triethylamine and 3-aminopropanol (5) gives the
diol (6). This compound can then be used to form macrocycles, through
intermolecular cyclodehydration reactions (P.Molina et al., Heterocycles
1993, 36, 1263).
For related work utilising other spacer units between the heterocycles see
Molina et al. (J. Org. Chem., 1994, 59, 3665). 2-(~Aminoalkyl)-l,3,4thiadiazoles can be synthesised by the reactions of lactam acetals, or lactim
ethers, with thiohydrazides. These reactions afford unusual zwitterionic
tautomers (8) of lactam thioacylhydrazones (7). In acidic solution, most of
them undergo reversible ring-chain transformations to spiro compounds (9)
and thence to novel 2-(~aminoalkyl)-l,3,4-thiadiazoles (10). Some
compounds of the last type can be isolated as salts (U.Radics et al., Chem.
Ber., 1992, 125, 1389).
3-Acetyl-4-hydroxy-5-methyl-2H-pyran-2-one thiosemicarbazone (11, R =
H) is transformed into 2-(acetylamino)-5-methyl-l,3,4-thiadiazole (12) by
treatment with acetic anhydride and triethylamine. In this reaction cyclisation
of the thiadiazole ring is accompanied by loss of 4-hydroxy-5-methylpyran-2one. However, when (11, R = Ph) is the substrate the oxygen heterocycle is
retained giving the 2-(pyran-2-on-3-yl)-l,3,4-thiadazoline (13) (L.Somogyi,
Liebigs Ann. Chem., 1995, 721).
Thioarylmethylenetriphenylphosphoranes (15) react with benzonitrile imines
(14) to give hydrazonotriphenylphosphonono thiolates (17) via
thiadiazolidines (16). The thiolates under more rigorous conditions undergo
intramolecular Wittig cyclisation and expulsion of triphenylphosphine sulfide
to afford pyrazoles (18) (L.Capuano, S.Dreschler and V.Huch, Liebigs Ann.
Chem., 1993, 125).
S-Methyl iminodithiocarbazates (19) undergo oxidative cyclisation when
treated with DDQ in benzene to afford 2-methylthio-l,3,4-thiadiazoles (20)
(A.A.Hassan, Bull. Soc. Chim. Fr., 1994, 131, 424).
A variety of 5-alkyl-2-mercapto-l,3,4-thiadiazoles have been prepared by
metallation of commercially available 2-mercapto-5-methyl-t,3,4-thiadiazole

221

with excess "BuLi and reaction with electrophiles (S.Connolly and K.Hardy;
Synlett, 1993, 533).
In the case of thiadiazolidine-2,5-dithione (21), however, a reaction with
ethyl chloroacetate yields the S-alkylthiothiadiazolinethione (22) as the initial
product, which undergoes further S-alkylation with propyl bromide to
produce the di-(S-alkyl)thiadiazole (23) (A.R.Katritzky et al., J. Het. Chem.,
1991, 28, 1139).

Me

Me.
N_NH2

CI

Toluene

CI

S
(1)
Ac20
HCIO4

heat

H
H
Me
NN-N
M e S A N ~ " " O~
~"~ SMe
SO
O S
9

(3)

(2)
Me. +
N-N

+ Me
N-N

Me'~OH

MeS ~/~ S,~.,,- O ~ - J ~ S~.-, SMe

Et3N

2 CIO4
(4)

Me.
N-N

Me
N-N
Me

OH

OH

(6)

(5)

222
1R

1R
NH

-.

-s)~N'NH~
2R' +

(7)

(8)
N-N

-NH

2~
(10)

(9)

HO
,,~

N-N

C(Me)=NNHCSNHR

Me-"~S ~ N H A c
Me" "0" "O
(11)

Ac20 ~t
Et3N

Et3N

(12)
Ph

"N" Ac

AcO

S "~

Me" -0- "0

(~3)

223

Ph

Ar
+

pph s
PPh3
(15)

(14)

Ph
N- N~NNAr

(16)

O2N'- ~

- Ph3PS

N- N

Ph

[
+ PPh3
(17)

(18)

R.,.,~N. h y

SMe
S

DDQ
Phil "-

N-N
R'~'~'S ~'~ SMe

(19)

H N- N"H

C1CH2CO2Et
~ ~ ,

S~s 3~s Ko~,o.

(21)

(20)

H'N-N

PrBr

S~s ~sc~c~

Ko~oH

(22)
N-N
P r S " ~ S~

SCI-I2CO2Et

(23)

Diquaternary salts of 1,3,4-thiadiazole are prepared by treatment of the

thiadiazoles with an alkylating reagent, such as trialkyloxonium

224

tetrafluoroborate. In addition, cyclisation of N,N'-dialkyl-N,N'-dithioacylhydrazines (24) with two equivalents of triethyloxonium tetrafluoroborate gives 2,3,4,5-tetrasubstituted 1,3,4-thiadiazolium di(tetrafluoroborate) salts (27), in 50-80% yields. The reaction may involve Smonoalkylation at one of the thione units to give (25) and 1,5electrocyclization to the corresponding thiadiazoline. Next, a second
ethylation at the ethylthio group yields intermediates (26) from which
elimination of diethyl sulfide provides access to the salts (27)
(N.M.Przheval'skii, I.V.Magedov and V.N.Drozd, Synthesis, 1993, 463).

2R
"N-N"

~R

2R

aR/

4R

BF4-

(24)
Et2S
-

3R -~

+ N-N +

(25)
ZR\
3R
s
+N-N+

(26)

2BE 4-

1 R - ~ s ~/~4R
2BF 4(27)

The reactions of N'-phenylthioformohydrazide (28) with carbonyl

compounds, such as aliphatic, aromatic and heterocyclic aldehydes in the
presence of trimethylsilyl chloride proceed easily to afford the corresponding
2,2'-substituted-2,3-dihydro-3-phenyl-l,3,4-thiadiazoles (30) in good yields
under mild conditions. The hydrazones (29) are intermediates in this process
(Y.Matsubara et al., Chem. Pharm. Bull., 1994, 42, 373).

HN-'NHPh

PhCHO

N-NHPh

"~S

~t~
TMSC1

~ "~Ph
S OTMS

(28)

(29)

- TMSOH
~l~

N-N

Ph

~" " ~ P h
S
(30)

225
Unexpectedly, the condensation of 4-methyl-4-phenyl-3-thiosemicarbazide
(31) with a methyl ketone, under acidic conditions yields alkylidenamino-2,5dithiobiureas (32), rather than the thiosemicarbazones (33). The pydct-2-yl
analogue (34) on treatment with propionitrile containing a trace of acetic
acid gives the corresponding 1,3,4-thiadiazole-2-yl hydrazone (35)
(J.P.Scovill and D.L.Klayman, Phosphorus, Sulfur, and Silicon, 1991, 63,
273).

Me
/L~

Me

NNH- N-ph
i

R N'r

H~'
S

HH
'

Me
'

Me

N-N'tr'N'P"
S

HM e , ,
Y N'Ph
S

(32)

(31)
Me N,,NHs H
HN_Nff
N ' P, h ' Me,
S

(33)

EtCN~

N-N
M ~ ~ N"HN" ~ S~N'Meph,

HOAc

(34)

(35)

5- (Dialkylthio)-3-(4-chlorobenzoyl)-2,3-dihydro-2-methyl- 1,3,4-thiadiazoles
(37) are obtained from the reaction of 4-chlorobenzoyl chloride with the
hydrazones (36) obtained by the condensation of dialkylthio(thiocarbonyl)hydrazides with ethyl pyruvate, ethyl acetoacetate, or ethyl
levulinate (K.Toyooka et al., Heterocycles, 1991, 32, 1813).

H"N- N
ArCOCI
R2S~:~S ~,X~Me
.~
(CH2)nCO2R
(36)

N-N "COAr
R2S.~s ~ M e
~(CH2)nCO2R
(37)

226
The thiosemicarbazones of araldehydes (38, R = H or Me) exhibit chain-ring
tautomerism with thiadiazolines (39) in trifluoroacetic acid solution
(K.N.Zelenin et al., Khim. Geterotsikl. Soedin., 1992, 1689). Similarly, the
protonated thiosemicarbazones of alkanals in trifluoroacetic acid exist as an
equilibrium mixture of three protonated components: 1,2,4-triazolines (40)
(5-10%), thiosemicarbazones (41) (5-10%), and 1,3,4-thiadiazolines (42)
(80-90%). In the case of the thiosemicarbazones of p-anisaldehyde (41, 1R =
4-MeOC6I-h) the corresponding protonated 1,2,4-triazolines were not
observed (K.N.Zelenin et al., Tetrahedron, 1993, 49, 5327).
H
.

N-N
Ar" HS

N-N
NHR2

x------

Ar

CF~CO~

CF~CO,

(38)

H
2R
H....k + "
N-N

'RTt- N
H

....
m%

(39)

IR

~,R
'~-N ~

H,

x----"

2R

1- N-N"

S"
i

(40)

(41)

(42)

N,N'-Diaryloxalodihydrazonoyl dihalides (43) react with potassium

thiocyanate or thiourea and yield the hitherto unknown bi(4-5dihydrothiadiazol-5-imine) derivatives (46). In these reactions the initial
products are assumed to be (44) and (45), respectively, formed by halogen
displacement by the nucleophilic reagents. Reactions of the bi(thiadiazoles)
(46) with acetic anhydride, benzoyl chloride and nitrous acid yield the
corresponding N-acetyl, N-benzoyl and N-nitroso derivatives (A.M.Farag et
al., Tetrahedron, 1994, 50, 5091).

227
(ii) Some ring fused 1,3,4-thiadiazoles
An aza Wittig-type reaction of the iminophosphorane (47), from 3-amino-4phenylthiazole-2-(3H)-thione, with aromatic isothiocyanates gives the
mesoionic thiazolo[2,3-b]-l,3,4-thiadiazoles (48). Similar reactions with
aliphatic isothiocyanates afford the zwitterionic derivatives (49). The
iminophosphorane in reactions with aliphatic isocyanates and acyl chlorides,
yields N,N'-bisheteroarylguanidines (50) and thiazolo[2,3,b]- 1,3,4-thiazolium
salts (51), respectively (P.Molina, A.Arques, and A.Alias, Tetrahedron,
1992, 48, 1285).

NH.N

Hal

.am) ~ N--NH
(43)

Ar

~Ncs~/

KSCN

At.

NH
NH'N
S
'
~
N
H~
,)-%

~N'~-S

gr,

S--CN

,~-~,

N--NH

I-IN

NH-N
NC-S

N--NH
Ar

"Ar
(44)

(45)

/
Ar-N.N

S ~ NH

HN/~S

N'N-Ar

'k--(,
(46)

228

Ph

Ph

Ph

N...pph3

N Ar

(47)

(48)

AL

(49)

NR
N&SI
R

Sv.s
]
R

(50)

Ph

CI

(51)

Semicarbazide (52) and ethyl thiocyanate gives rise to the corresponding

thioimidate (53) and thence the thiadiazole (54), which, without isolation,
can be reacted with ethyl acetoacetate and polyphosphoric acid to yield the
thiadiazolopyridone (55) (S.S.Shukurov et al., Khim. Geterotsikl. Soedin.,
1992, 1148). The same group of chemists record that 4-amino-5-methyl1,2,4-triazole-3-thione (56) when reacted with benzyl thiocyanate in polyphosphoric acid gives 3-methyl-(6-benzylthio)-l,2,4-triazolo[3,4-b][1,3,4]thiadiazole (57) (idem, lzv. Akad. Nauk, Ser. Khim., 1993, 231). The
preparation of several other fused 1,3,4-thiazoles has been reported. Thus,
4-amino-3-(2-benzofuranyl)-5-mercapto-1,2,4-triazoles can be ring closed to
give s-triazolo-fused derivatives (58) (G.A.E.Saraf, Indian J. Chem., 1992,
31B, 167). 2-(Ethylarylamino)-l,3,4-thiadiazolo[3,2-b]indazoles (59) are
formed by triethylphosphite mediated deoxygenative cyclization of 2arylamino-5-(2-nitrophenyl)-l,3,4-thiadiazoles (V.R.K.Reddy, P.S.N.Reddy,
and C.V.Ratnam, ibid., p. 499) and 1,3,4-thiadiazolo[3,2-b]-l,2,3-thiazolo[4,5-d]pyrimidin-9(3H)-ones (60) are synthesised from 5-substituted 1,3,4thiadiazol-2-amine (N.Suzuki et al., Chem. Pharm. Bull., 1992, 40, 357).

229

EtSCN

H2N-N~s

H
N-N S

.._

" EtSIJ~S ~),,N

(54)

NI~
(53)

(52)

N-N

O
MeCOCH2CO2Et

N-N~

PPA
(55)

Mei~._N. NI_I2
N. N"~S

BnSCN
~PPA
~

Met~._N-N,,,,~SBn
N. N/,)-----S

H
(56)

(57)

Ar

s
(58)

N.N N.
(59)

(60)

N-(2,3-Dihydro-2-thioxo-l,3,4-thiadiazol-5-yl)benzamides (61) react with

hydrazonyl halides in ethanol solution containing triethylamine to give
transient adducts of the type (62), which cyclise to spirocycles (63). The
latter undergo ring-chain tautomerism and yield 3,5-disubstituted 1,3,4thiadiazo-2(3H)-one 4-aroylthiosemicarbazoles (64). This chemistry is
similar to that exhibited by the corresponding 1,3,4-oxadiazoline-2-thiones
(M.A. Abdallah et al., J. Chem. Res. Synop., 1995, 370).

230

N _ N .'H

N-N

RC(C1)=NHPh

ArCONH~/S,~'~ S

ArCONHJ~ S ' ~ s

.N__--{

F__~N

PhNH
R
(62)

(61)
H

N-N

N-N

coNH- s -'-s
PhN.~..~~"~ R

S PhN~. N/'-,~ R

(63)

(64)

(iii) Reactions
Alkenes from thiadiazoles
A generally applicable procedure for the synthesis of highly strained alkenes
is the thermal, two-fold extrusion of nitrogen and sulfur (or selenium) from
1,3,4-thiadiazolines (or selenadiazoles). Thus, the 1,3,4-thiadiazolines (66)
can be prepared by treatment of a ketone with hydrogen sulfide and then
with hydrazine. Oxidation in situ converts the initially formed thiadiazolidines (65) into the thiadiazolines, thus minimising azine formation.
Extrusion of nitrogen from thiadiazolines (66) by heating in THF or CHC13
at reflux yields the thiiranes (67), which when treated with triphenylphosphine gives the corresponding alkenes (68) (L.R.Collaza and
F.S.Guziec, Jr., J. Org. Chem., 1994, 58, 43).

RCOR

H
H
'N-N"

(i) H2S

N=N

[0]

R,,,~S,, ~

(ii) NH2NH2
,9

(65)
~~.heat
" N2

R~_~ R
H

(67)

(66)

Ph3P,~-

H
(68)

231
Phenyldiazomethane in toluene at room temperature reacts selectively at the
thione group of the thiazolinethione (69, R = Bn) affording the spirocyclic
derivative (70). This undergoes extrusion of nitrogen to give (71) and from
this compound sulfur is then lost yielding the 2-methylidene-2,3dihydrothiazole (72), as a mixture of cis and trans isomers. However, in the
case of the phenyl analogue (69, R = Ph) the product is the thiadiazole (73)
generated presumably by ring-chain tautomerism from a related spirocyclic
intermediate (M.Petit et al., Helv. Chim. Acta, 1994, 77, 1076).

Me
N--~Me

Me Me
N'--~ N=N

N2CHPh
R - Bn

Me Me
N'--~

- N2

Ph

Ph

(69)

(70)

(71)

M~/Me-s

Me N-N
H

Bn

Ph
H-'N

Ph
(72)

/~ S
Ph

(73)

There are other examples of alkene formation through tandem extrusion of

N2 and a chalcogen. Selenadiazoles have been used, but with varying
success. Thus, although the selenone (75) reacts with the diazoalkane (74) to
form the selenadiazoline (76), it is a thermally stable crystalline solid and on
pyrolysis it fails to yield the strained alkene (77), presumably due to steric
effects in the alkene. Instead, reterocyclization and decomposition products
are obtained (P.R. Brooks et al., J. Org. Chem., 1993, 58, 5900).

232

S:

Se

S:

S: N=N

S:

$...(74)

(75)

(76)

~ ~ S S:
:
- N~

_/.
- Se

S
(77)

Thermolysis and photolysis of 2-alkylidene-l,3,4-selenadiazolines and their

sulfur analogues have also been investigated. Here, thermal decomposition of
the selenadiazoline (78) initiates denitrogenation and affords the selenone
(80) and a carbene (79). The latter rearranges to 3,3-dimethyl-l-trimethylsilylpent-4-en-l-yne (81). On photolysis at ~m,~360 nm in benzene solution
(78) gives a biradical intermediate, generated by cleavage of the C-Se bond,
which combines with the solvent and is thus converted into the bicyclic
selenahexanes (82) and (83) in low yield (N.Choi et al., Tetrahedron, 1993,
59, 1189).
It is reasonable that the tellurium analogues, telluradiazolines, would also be
suitable substrates for the two-fold extrusion methodology. Indeed, novel
A3-1,3,4-telluradiazolines (e.g. 84) are known. This compound has been
prepared from 1,1,3,3-tetramethylindanone hydrazone by reaction with
tellurium dichloride in the presence of triethylamine. It is probable that this
reaction involves 1,3-dipolar cycloaddition of the appropriate telluroketone
with diazo compounds, both generated in situ (R.Okazaki, M.Minoura and
T.Kawashima, Chem. Lett., 1993, 1047).

233

"ea'

-N 2

Se

~'~
(79)

(78)

(80)

h~ ~ C 6 H 6

/~
TMS

N--N
(82)

--Ph

e~p.

TMS

(81)

N--N
(83)

(84)

Other reactions
2-Alkyl-3,5-diphenyl-l,3,4-thiadiazolium perchlorates (e.g. 85) react with
triethylamine to give the corresponding methine bases (86), which on
hydrolysis ring open and form N2-alkanoyl-N~-phenylbenzothiohydrazides
(87) (T.Mohammad and M.S.Gibson, Phosphorus Sulfur Silicon., 1992, 70,
243).

234
Ph
N- N"+
p h - ~ S~ " ~
(85)

.Ph
N=N

EhN
"
CIO4-

ph-~s%

.Ph
NH-N

H20
"

(86)

ph'~s 0 %
(87)

2-[(4-Methoxyphenyl)azo]-l,3,4-thiadiazole (88, R = Me) exhibits a single

protolytic equilibrium for which the pK, value has been evaluated, and the
structure of the protonated species has been determined. The compound
hydrolyses from the monoprotonated substrate by a A-S(E)2 mechanism of
the SNAr type to give 2-[4-hydroxyphenyl)azo]-l,3,4-thiadiazole (88, R -- H)
(K.A.Ogunjobi, J. Org. Chem., 1994, 59, 3386).
N-N

RO
(88)

Allylic Grignard reagents (90) easily react through addition and elimination
with 2,5-bis(methylthio)-l,3,4-thiadiazole (89) to give the 2,5-disubstituted
thiadiazole (91). A similar overall substitution of a methylthio group occurs
in reactions of the Grignard reagents and 5-methylthio-l,3,4-thiadiazol2(3H)-thione leading to the mono substituted analogues (92) (J.Laduranty
and L. Miginiac J. Orgmet. Chem., 1994, 464, 1).

235
3R

~' N-N 3R~ -CH2

H.C~'~-,/

---~
N-N. ~
MeS ,,s__SMe + 'R ~
(89)

MgC1

2R 1R

ll~

(91)

(90)
N-N ~"~ C H 2
S" 172R

(92)
When 5-alkylthio-l,3,4-thiadiazole-2-thiones (93) are arylated by reactions
with 9-chloroacridine in pyridine, acting both as solvent and as base, attack
occurs at the N-3 site to give the derivatives (94), but if the sodium salts (95)
are presynthesised and then reacted with chloroacridine 2-acridinylthio-5alkylthio-1,3,4-thiadazoles (96) are produced (P.Amiel et al., Can. J. Chem.,
1995, 73, 1258).

H'N-N
S ~ " S)~"S-R

1R. N-N

1RCI
pyridine

S ~:~"S~ "

(93)
N-N
NaS...~S)~ S_ R

S-R

(94)
1RCI
~)"

N-N
xR_S..-~ S ) ~

(95)

S-R

(96)
1R = 9-acridinyl

(e) Selenadiazoles
Some examples of these heterocycles have already been discussed (section
2d, iii); in general they exhibit the same types of reactions as the
corresponding thiadiazoles.

236
1,2,3-Selenadiazoles are commonly synthesised by reacting semicarbazones
with selenium dioxide. For example, the thiacyclooctane derivatives (2) and
(3), and (5) and (6) are obtained in this way from the appropriate
semicarbazones (1) and (4). The reactions are highly regiospecific and the
product ratios depend upon the proportions of E/Z isomers in the starting
materials (H.Schumacher and H.Meier, Z. Naturforsch. Sect. B, 1992, 47,
563).

Se.N
~~~:NNHCON" Se02~. ~ N ~ N
"~S

(1)

~-'S

Se/

(2)

(4)

S" "

(5)

~'-S

(3)

~.~ISe..N

~:~NNHCONI-I2SeO2 ~ N
S--"

+ ~N

"Se
(6)

Disubstituted 1,2,4- (7) and 1,3,4-selenadiazoles (9) behave as cyclic

azadienes bridged by a selenium atom and undergo thermally mediated [4+2]
cycloadditions with reactive dienophiles, such as dimethyl acetylenedicarboxylate (DMAD). The adducts extrude selenium and give
pyrimidine (8) or pyrazine derivatives (10), respectively (Y.Takikawa et al.,
Chem. Lett., 1991, 2043). The 1,2,5-selenadiazole (12), formed from the
pyrimidine (11) by selenium dioxide oxidation, undergoes reduction with zinc
and acetic acid to give the diamine (13), a substrate from which pyrroles (e.g.
14) are available through reactions with 1,3-diketones (T.Ueda et al., J.
Chem. Soc., Perkin Trans. 1, 1994, 2201).

237
R

R >.N

DMAD

N. S:~"-.R

CO2Me

~CO2Me
R

(7)
Ph

(8)
Ph

P h ' ~ I~C02Me

DMAD

N. .N
Se
(9)

Ph

N
(lo)

Ph. N ~ I ~ ? ~,SeO2

CO2Me

Ph- N %

(11)

N.

Zn/HOAc.._ Ph"N ' ~ N t[~ /

(12)
MeCOCH2COMe'"

Me
Ac
~~N
PhNHCO
Me
H
(14)

(13)

2,1,3-Ben zoselenadiazoles can be readily formed from 1,2phenylenediamines, by treatment with selenium dioxide and reconverted back
to the diamines with equal ease by reduction and loss of selenium. This is
used as a means of protecting sensitive 1,2-phenylenediamines. Subsequent
removal of selenium from the selenadiazoles is possible by reduction with
hydrogen iodide (W.Tian and P.Grivas, J. Het. Chem., 1992, 29, 1305).