II

General Synthetic Methods

for Thiazole and Thiazolium Salts
GASTON VERNIN
Laboratoire de Chimie Organique, Faculti des Sciences et Techniques de Saint-Jerome,
Marseille, France

1. Introduction. . . . . . . . . . . . . ... . . . . . . . . . . . . . . .
1. Various Types of Thiazole Ring Closure. . . . . . . . . . . . . . . .

II. Thiazoles from a-Halocarbonyl Compounds and Derivatives. Hantzsch's Synthesis, and Related Condensation (Type I) . . . . . . . . . . . . . . . . .
1. Reaction with Thioamides . . . . . . . . . . . . . . . . . . . . . .
A. Chloroaceta1dehyde and Derivatives (Thiazole and its 2-Monosubstituted
Derivatives
B. Higher a-Haloaldehydes (5- and 2,5-Disubstituted Thiazoles)
C. a-Haloketones and Derivatives . . . . . . . . . . .
D. Hantzsch's Synthesis Mechanism. . . . . . . . . . .
2. Reaction with N-Substituted Thioamides (Thiazolium Salts)
3. Reaction with Thiourea . . . . . . . . . . . . . . . .
A. a-Halocarbonyl Compounds and Derivatives: 2-Aminothiazoles .
B. Mechanism
4. Reaction with N-Substituted Thioureas
A. N-Monosubstituted Thioureas .
B. Dithiobiuret
C N,N-Disubstituted Thioureas. .
D. Thiosemicarbazides and Thiosemicarbazones.
5. Reaction with Salts and Esters of Thiocarbamic Acid: 2-Hydroxythiazoles
and Derivatives
6. Reaction with Salts and Esters of Dithiocarbamic Acid: 2-Mercaptothiazole
Derivatives and 2-Thiazolyl Sulfides
A. 2-Mercaptothiazole Derivatives.
B. 2-Thiazolyl Sulfides.
C. Mechanism
...
165

166
167
169
169
169
172
175
209
211
213
213
232
232
232
244
244
249
258
260
260
266
269

166

General Synthetic Methods for Thiazole and Thiazolium Salts

Ill. Thiazoles from Rearrangement of the a-Thiocyanatoketones (Type Ib).

271
1. Acid or Alkaline Hydrolysis . .
271
2. Action of Dry Hydrogen Halides
273
3. Action of Labile Sulfur. . . . .
276
4. Action of Labile Nitrogen . . .
278
IV. Thiazoles from Acylaminocarbonyl Compounds and Phosphorus Pentasulfide
and Related Condensations (Gabriel's Synthesis (Type Ill). . . . . . . . . . 278
V. Thiazoles from aAminonitriles (Cook-Heilbron's Synthesis) (Type II). . . . 284
1. Salts and Esters of Dithioacids: 5-Aminothiazole Derivatives and Related
Condensatior.s. . . . . . . . . . . . . . . . . . . . .
284
2. Carbon Disulfide: 2-Mercapto-S-aminothiazole Derivatives.
286
3. Carbon Oxysulfide: 2-Hydroxy-S-aminothiazole Derivatives.
288
4. Isothiocyanates: 2,S-Diaminothiazole Derivatives . . .
289
VI. Thiazoles from Nitriles and a-Mercaptoketones or Acids: 2,4-Disubstituted
291
and 4-Hydroxythiazole Derivatives. . . . . . . .
1. a-Mercaptoketones . . . . . . . . . . . . . . . .
291
2. a-Mercaptoacids: 4-Hydroxythiazole Derivatives . . .
293
3. 2,4-Diaminothiazoles from a-Halonitriles and Thiourea
296
VII. Miscellaneous Reactions. . . .
297
1. 2-Aminothiazole Derivatives .
297
2. 4-Aminothiazole Derivatives .
301
3. 5-Hydroxythiazole Derivatives.
303
4. 4,5-Dihalogenothiazoles and 2,4,5-Trihalogenothiazoles
304
5. 4-Tosylthiazoles
305
6. Alkylthiazoles .
305
7. Cyanothiazoles.
306
8. Miscellaneous .
306
308
VIII. Thiazoles from Other Heterocyclic Compounds
1. Thiazoles from ~-3-Thiazoles .
308
2. Thiazoles from Oxazoles . .
309
3. Thiazoles from Isothiazoles .
310
IX. References. . . . . .
310

I. INTRODUCTION
The first syntheses of the thiazolic ring were made at the end of the
nineteenth century when the initial research was carried out by scientists
such as Hantzsch, Hubacher, Traumann, Miolatti, Tcherniac, and Gabriel.
Together with the derivatives of pyridine, the thiazoles soon constituted
an important part of heterocyclic chemistry, as much from the point of
view of the initial research as from the practical aspect. Their biological
and pharmaceutical interest is in fact important as they appear in the
composition of certain vitamins such as vitamin B 1 (thiamine) and in the
penicillins. Reduced thiazoles serve in the study of polypeptides and
pruteins and occur as structural units in compounds of biological significance, for example, firefly luciferins and in antibiotics bacitracin A and

thiostrepton. Equally some derivatives of the 2-aminothiazoles are used

as fungicides, pesticides, and bacteriocides, other possess mitodepressive
and mitostatic properties (698), and a large range of 2-amino (and
hydrazino) 5-nitrothiazoles (nitridazole) are devoid of schistosomicidal
activity (727).
Certain Schiff bases derived from 2-amino-5-phenylthiazole and their
reduction products show diuretic properties (661). Others such as
rhodanines are used as intermediates in the synthesis of amino acids,
peptides, and purines. In industry, several mercaptothiazole derivatives
serve to accelerate the vulcanization of rubber, and alkyl- and acylthiazoles are known to be interesting flavoring agents (711, 785). Finally,
derivatives of thiazoles are also to be found in certain natural products: a
new amino acid incorporating the thiazole ring has been recently isolated
from the fungus Xerocomus substomentosus (662).
In this chapter we intend to outline the general methods by which the
thiazolic ring is synthetized from open-chain compounds. The conversion
of one thiazole compound to another is not discussed here, but in
appropriate later chapters. Thus the conversion of thiazole carboxylic
acids, halogeno-, amino-, hydroxy-, and mercaptothiazoles, to the corresponding unsubstituted thiazoles is treated in Chapters IV through VII,
respectively.
These subjects have been reviewed up the year 1975 in various works.
Prij's Card Index (363) of thiazole compounds provides swift access to
information on individual compounds. Syntheses of thiazoles have been
carefully reviewed by Wiley et al. (361), and in 1957 the subject was dealt
with in an excellent survey by Sprague and Land (448).
This list was usefully supplemented in 1970, 1973, and 1975 by the
publications of Kurzer (699), and a number of books on penicillin contain
much information on the reduced thiazole system (312,540).
Asinger and Offermanns (607) have reviewed the chemistry of d-3
thiazolines, and Ohta and Kato's (663) comprehensive survey on sydnones includes a section of mesionic thiazoles (d. Chapter VIII).
In our study, literature coverage has been extended to 1976. If important omissions have occurred, I ask the indulgence of the reader.

1. Vmous Types of Tbiazole Ring Closure

Several methods for the synthesis of thiazole compounds are available,
which can be classified into the partial structures illustrated in Scheme 1.
The first of these structures (Ia) is by far the most useful and versatile of
all the thiazole syntheses. By a judicious choice of reactants it allows

168

General Synthetic Methods for Thiazole and Thiazolium Salts

alkyl, aryl, aralkyl, or heterocyclic substituents to be placed in anyone of

the 2-, 3-, 4-, or 5-positions of the ring. This method, better known by
the name of the German chemist Hantzsch who originated it in 1887,
involves the condensation of a compound bearing the two heteroatoms on
the same carbon with a compound bearing one halogen and one carbonyl
function on two neighboring carbons. A great variety of compounds may
serve as nucleophilic reagent in this reaction, such as thioamide, thiourea,
ammonium thiocarbamate or dithiocarbamate, and derivatives. The two
carbon fragments may be a-halocarbonyl compounds or their functional
derivatives. This synthetic method has been the subject of thiazole
research for a hundred years and is one of the classic reaction of thiazole
chemistry. Its importance is clearly reflected by its continued wide use. A
variant of this method Ib was introduced by Tcherniac who cyclized
a-thiocyanatoketones (obtained from a-haloketones and metal thiocyanates) to thiazoles under the action of labile hydrogen compounds.
This reaction leads to thiazoles variously substituted in the 2-position,
depending on the experimental conditions. Although this method has
been studied rather extensively, it has limited scope and frequently fails
to give thiazoles.
The thiazole ring can be obtained directly by other methods, but they
have limited aprlication. An example is the synthesis of Cook and
Heilbron using a-aminonitriles or a-aminoamides and carbon disulfide
(or thioacid derivatives) as reactants of type II.
The reaction of phosphorus pentasulfide with a-acylamino carbonyl
compounds of type lila also yields thiazoles. Even more commonly, a
mercaptoketone is condensed with a nitrile of type IVa or amercaptoacids or their esters with Schiff bases. This ring closure is limited
to the thiazolidines. In the Va ring-closure type, f3-mercaptoalkylamines
serve as the principal starting materials, and ethylformate is the reactant
that supplies the carbon at the 2-position of the ring. These syntheses
constitute the most important route for the preparation of many
thiazolidines and 2-thiazolines. In the Vb type of synthesis, one of the
reactant supplies only the carbon at the 5-position of the resultant
thiazole. Then in these latter years new modern synthetic methods of
thiazole ring have been developed (see Section 7; also Refs. 515, 758,
807, 812, 822).

C-N

C S/C

C'S/C

I
C S/C

Ia

Ib

II

Hantzsch (1887)

Tcherniac (1919)

Cook and Heilbronn (1947)

C-N

C-N

C S C

C S.. . C

I
I
C-.. S C

IIIb

IIIe

C-N

IlIa

Gabriel (1910)

C-N

C,S C

C S C

C,S C

IVa

IVb

Va
Gabriel (1916)

Erlenmeyer (1943)

C-N

I
C S.. . C

I
C'S.. . C

Vb

VI
Dubs (1974)

Hartke and Seib (1971)

Scheme 1. Various types of ring closure for the thiazoles, thiazolines, and thiazolidines.

II. THIAZOLES FROM a -HALOCARBONYL COMPOUNDS

AND DERIVATIVES. HANTZSCH'S SYNTHESIS, AND RELATED CONDENSATION (TYPE I)
The cyclization of a-halocarbonyl compounds is carried out
with a great variety of reactants including thioamides, thioureas, their
mono- or disubstituted derivatives, and salts and esters of monothioearbamie acid, leading to variously substituted thiazoles.
1. Reaction witb Tbioamides

A. Chloroacetaldehyde and Derivatives (Thiazole and its 2Monosubstituted Derivatives) (Table II-I)
Thiazole itself (3), R) = H, can be obtained by condensing chloroacetaldehyde (1) and thioformamide (2), R) = H (39, 127).
HCO
HzN
I
+
I
CHzCI S=C-R)
1

-----+

2
Scheme 2

~JRl
3

TABLE II-l.

2-SUBSTITUTED THlAZOLES
N=:J[H
Rt---ll I H
S
Yield (%) Ref.

Rt

Conditions"

CI, PzS s, dioxane, or CICHzCH(CI)OMe,

H 20, 40-50C
CICHzCH(CI)OEt, heat
BrCHzCH(Br)OEt, PzS s , MgC03 , heat 4060C; CI or Br, P 2SS ' C6 H 6 , (AC)20, heat

21-25

BrCHzCH(Br)OEt, PzSs , heat, 40-60C

Br, PzS s, dioxane, MgC03 , heat 40-60C
BrCHzCH(Br)OEt or CI, PzS s, dioxane
MgC03 , heat 4o--60C
CI, PzS s , heat
BrCHzCH(Br)OEt or CI, P2 SS ' dioxane,
MgC03 heat 40-60C and then 80-100C
BrCH 2CH(BrjOEt or Ct, P 2 SS , dioxane
BrCHzCH(Br)OEt, P 2SS ' dioxane, MgC0 3
heat 40-50C and then 80-100C
CI, heat

50
26-50
39-62

CI or Br, C 6 H6 , reflux 2 hr
Cl or Br, heat
CI or Br, P 2SS ' dioxane, heat
Cl, abs. alcohol, reflux
Br, PzS s, dioxane, heat
CICHz(Cl)OEt, AcONa, heat,
Br, abs. alcohol, piperidine (drops),
CI, abs. alcohol, MgC03 , reflux 10 hr
BrCH 2CH(Br)OEt, abs. alcohol, MgC03 ,
reflux 5 hr
BrCH2CH(Br)OEt, abs. alcohol, MgC0 3 ,
reflux 5 hr
BrCH 2 CH(Br)OEt, abs. alcohol, MgC0 3 ,
reflux 5 hr
CI in excess, reflux 10-12 hr
CI in excess, reflux 10-12 hr
CI in excess, reflux 10-12 hr
CI in excess, reflux 10-12 hr
BrCH 2CH(OEt)2
CICH 2CH(CI)OEt
BrCH 2 CH(OEt)2' alcohol, reflux

38-84
10-60

Me

Et
iso-Pr
n-Pr
iso-Bu

tert-Bu
Neopentyl
CH 2 (CH 2 )9CH=CH 2
HqCH 3 )C0 2Ph
Bz
CHzCHzPh
CHCHPh
Cyclohexyl
Ph

o-MeC6 H4
m-MeC6 H 4
p-MeC6 H 4

o-BrC6 H4
m-BrC6 H4
p-BrC6 H4
p-CIC6 H4
p-MeOC6 H 4
p-EtOC 6 H 4
m- and
p-AcC6 H 4
3,4-(CH z0 2 )C6 H 3 BrCH 2CH(OEth
3,4-(HO)2C6 H 3
BrCHzCH(OEt)z
CONHNH 2
CI, 30 min at 100C

39
30-49

39, 127,455
4, 10, 22, 175
578
4, 10, 15, 22,
285, 578
578
285, 578
285, 578

49
45

578
578, 711

56
20

578
578

63

195

44
4-10
72
82
58

75,595
595
285
649
15
264
641
641
738
336
654
646
336, 646, 738
141, 738
75, 221
101
569

30

75
75, lOl
444

" CI or Br designates the corresponding a-chloro or a-bromo-aldehyde or ketone; P 2 SS

designates thioamides formed in situ from amides.

170

II. Thiazoles from a -Halocarbonyl Compounds and Derivatives

171

This reaction is explosive and proceeds in low yield (= 21 %) because of

the instability of the thioformamide that is destroyed as soon as it is
cyclized with 1 (113,491). The thioformamide is better prepared directly
in the reaction mixture by condensing phosphorus pentasulfide and formamide at room temperature, in dioxane solution, according to reaction 1
(491,492),
HCONH z + l/5P zSs ~ HCSNH z

(1)

but secondary reactions can occur:

HCONH z + PzOs~ HCN + 2HP0 3

(2)

HCSNH z ~ HCN + HzS

(3)

Another difficulty in this reaction lies in the preparation of pure

chloroacetaldehyde. The low yield observed is due to simultaneous formation of by-products (polyhalogenation). So vinylchloride was used as a
starting material for this synthesis (449). A simpler method is to react
chlorine with vinylchloride in aqueous solution and then to dehydrate the
semihydrated chloroacetaldehyde by distillation through a column of
calcium chloride heated to 70 to 90C (451).
When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz's
method (222), 2-substituted thiazoles are obtained (4, 10,22,175).
For example, with thioacetamide prepared in situ in dioxane solution at
45C, Cottet and Metzger (578) prepared the 4-methylthiazole (3), R 1 =
Me, in 39% yield, while Erlenmeyer et ai. (285) obtained a similar result
in benzene and acetic anhydride.
Cyclohexyl, benzyl, and phenethylthioamides give a low yield (4 to
10%) of the corresponding 2-substituted thiazoles (595,649).
With arylthioamides except for some nitrothiobenzamides (101), yields
are usually higher than those obtained above, due to the increased
stability of these amides under acidic conditions (3), R j = Ph, yield 70 to
82% (264, 285, 336, 483, 578, 641). In this case, cyclizations are carried
out several hours to reflux, in absolute alcohol, in the presence of melted
sodium acetate and few drops of piperidine.
Aromatic thioamides can be prepared as described in the literature by
different ways, either by S ~ 0 exchange between the corresponding
benzamides and phosphorus pentasulfide in pyridine solution in the
presence of triethylamine (65,646) as strong base, or by action of HzS on
the appropriate nitrile with pyridine and triethylamine solvents using the
method of Fairfull et al. (34,374, 503). In this reaction, thioacetamide in
acidic medium can also be used as a HzS generator with dimethylformamide as the solvent (485).

172

General Synthetic Methods for Thiazole and Thiazolium Salts

It is also possible to start from chloroacetaldehyde derivatives such as

1,2-dihalogeno ethyl acetate: yields can reach 90% (356). These compounds can be easily obtained by addition of halogen to the double bond
of vinylacetate at 0 to woe.
Aliphatic thioamides cyclized with a,l3-dibromoether in the presence of
MgC0 3 as base, yield the corresponding 2-alkylthiazoles in the 20 to
60% range (578).
a-Bromoacetal condensed with thiobenzamide (513) also give 2phenylthiazole. But thiazole is very often prepared by indirect methods.
Among them, deamination of 2-aminothiazole (49), subsequent reduction
of the diazo compound using hypophosphorus acid, or the reduction of 2halogenothiazoles (mainly the 2-chloro derivatives) by acetic acid and zinc
according to the method of Mac Lean and Muir (175) are most commonly
used. Another method by which thiazole can be indirectly synthetized is
by oxidation of 2-mercaptothiazole (77% yield) (135,203).
Therefore, the synthesis of the unsubstituted heterocycle is usually
more difficult to realize than that of its derivatives.

B. Higher a-Haloaldehydes (5- and 2,5-Disubstituted Thiazoles,

Table II-2.).
The cyclization of a-haloaldehydes (4) with thioformamide has
been reported (4, 10, 12, 22, 506); the products are 5-alkyl- or
arylthiazoles (5), R 1 = H, R 2 = alkyl or aryl (Table 11-2).
TABLE II-2. S-ALKYL (OR ARYL) THIAZOLES AND 2,S-ALKYLARYL
THIAZOLES

rr----v-:

l~S/-

Yield
(%) Ref.

R1

R,

Conditions

Me

CI, P2 S" dioxane, heal

Br, P 2 S" dioxane, MgC03 , heat

Et

H
H
H
H
H
H

CH,OH
(CH 2 hOH
iso-Pr
tert-Bu
C02 Me
Ph

Br, P 2 S" dioxane, MgC03 , heat

20 mn al 40-50C and then 5 hr at
80-100C
36
Ct, heat
65
CI, heat
30-40
Br, heat
7-20
Br, heat
Ct, heat
CI, abs. alcohol, heat or R 2 CH(Br)CH(Br)OEt 10-15
Br, P 2 S" dioxane, MgC0 3 , heat.

0.

8-30 245, 364, 455

30-60 4, 10, 22, 219, 286,
492,506,512
37-50 492, 512

587
587
492, 512
492, 512
359
75, 101, 189, 503
127,519,641

TABLE B-2 (continued)

Yield
R,

R2

Conditions

Me

Me

CI, or
Br, P2S" dioxane, MgC03 , heat
Br, P 2SS , dioxane, MgC03 , heat
Br, P,S" dioxane, MgC0 3 , heat
Br, P,S" dioxane: MgCO" heat
Br, P,S" dioxane, MgC03 , heat
Br, P,S" dioxane, MgC03 , heat
Br, P,S" dioxane, MgC03 , heat
Br, P,Ss, dioxane, MgC03 , heat
Br, P,S., dioxane, MgC03 , heat
Br, P2S" dioxane, MgC03 , heat
Br, P 2 S" dioxane, MgCO" heat
Br, P2 S" dioxane, MgC03 , heat
Br, P 2 S" dioxane, MgC03 , heat
CI or Br, heat
Br, abs. alcohol, heat
Br
Br
Br, abs. alcohol, heat
CI, abs. alcohol, MgC03
2 hr at 4Q-80C and then reflux 5 hr
Br, abs. alcohol, MgC03 , 2 hr at
4Q-80C and then reflux 5 hr
Br, abs. alcohol, MgC03 , 2 hr
at 4o--80C artd then reflux 5 hr
CI,
Br, abs. alcohol, MgC03 , heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Br, abs. alcohol, heat
Cl, water bath, 1.5 hr
Cl or Br or BrCH,CH(Br)OEt

Et
iso-Pr
lert-Bu
Me
Et
iso-Pr
lert-Bu
Me
Et
iso-Pr
lerl-Bu
Me
Me
Me
Me
Bz
CH=CH-Ph
Ph

Me
Me
Me
Et
Et
Et
Et
iso-Pr
iso-Pr
iso-Pr
iso-Pr
lerl-Bu
C02Et
Ph
p-HOC.H..
Me
Ph
Me

Ph

Et

Ph

iso-Pr

Ph
Ph
p-FC.a.
o-ClC.a.
p-ClC.H.
m-IC.H..
p-02NC.H.
p-Biphenylyl
Ph
,,-Naphthyl
,,-Thienyl
I3-Pyridyl
'Y- Pyridyl
C02Me
C02 Et

C02 Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
,,-naphthyl
Ph
Ph
Ph
Ph
C02Me
Me

(%) Ref

11
40
I1
82

15
175, 285, 492, 512
492, 512
492, 512
492,512
492, 512
492, 512
492, 512
492, 512
492, 512
492, 512
492, 512
492, 512
492, 512
145
450
450
294
374
641

54

641

45

641

37
50
62
12
56
38
13
59
28
54
23
62
21
35

196
519
457
457
457
457
457
457
457
457
457
457
457
383
201, 208, 210,
236,245

44
61
74.5
74
37
42
72.5
68.5
35.5
35
40
30.5
13

See Table II-I.

H-CO
HzN
I
+
I
Rz-CHX S=C-R 1

----+

N
r
R/'S)R
5

Scheme 3

173