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Synthesis and Cyclization of Benzothiazole:
Review
Article · January 2010
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Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
JCPR 2010; 2010; 3(1): 13-23
© 2010 Medipoeia
Received: 30/04/2010
Revised: 25/06/2010
Accepted: 18/07/2010
Synthesis and Cyclization of Benzothiazole: Review
Akhilesh Gupta and Swati Rawat
ABSTRACT
Akhilesh Gupta
Kunwar Haribamsh Singh College of
Pharmacy, Jaunpur (U.P.) India.
Swati Rawat
Shri Bhagwan College of Pharmacy,
Dr. Y. S. Khedkar Marg, N-6,
CIDCO, Aurangabad (M.S.) (India)
, Goli Divakar and Manoj K. Jangid
Objective: Benzoheterocycles such as benzothiazoles, benzimid azoles and benzoxazoles can serve
as unique and versatile scaffolds for experimental drug design. Among the all benzohaterocycles,
benzothiazole has considerable place in research area especially in synthetic as well as in
pharmaceutical chemistry because of its potent and significant pharmacological activities. Since, a
wide range of methods are available for synthesizing benzothiazole nucleus and its derivatives but a
real need exists for new procedures that support many kinds of structural diversity and various
substitution. The present review deals with the common methods adopted and reported to focus the
synthesis as well as cyclisation of benzothiazole nucleus.
Keywords: Benzohaterocycles, Benzothiazole, Cyclization
1. INTRODUCTION
Benzothiazole is a privileged bicyclic ring system. Due to its potent and significant
biological activities it has great pharmaceutical importance; hence, synthesis of this compound is
of considerable interest. The small and simple benzothiazole nucleus if present in compounds
involved in research aimed at evaluating new products that possess interesting biological activities.
2-substitued benzothiazole has emerged in its usage as a core structure in the diversified
therapeutically applications. The studies of structure–activity relationship interestingly reveal that
change of the structure of substituent group at C-2 position commonly results the change of its
bioactivity. Among those 2-substituted benzothiazole derivatives with fluorine substituted
molecules have already received considerable attention due to their potential bioactivities (Jian
Haoa et al.; 2007). Since most of the benzothiazole derivatives were reported for their diversified
activity viz., antitumor, antitubercular, antimalarial, anticonvulsant, anthelmintic, analgesic, antiinflammatory, antifungal, a topical carbonic anhydrase inhibitor and an antihypoxic (Hutchison et
al., 2003; Latrofa et al., 2005; Yoshida et al., 2005; Latrofa et al., 2005; Caryolle et al., 1990)
In 1887, 2 substituted benzothiazole was first synthesized by A. W. Hofmann then
because of diversified activity as well as simple cyclization mechanism number of synthetic routes
have been adopted and reported.
Correspondence:
Akhilesh Gupta
Kunwar Haribamsh Singh College of
Pharmacy, Jaunpur (U.P.) India.
Mobile No: +91-8149631905
E-mail:
akhileshgupta81@rediffmail.com
2-substitutedbenzothiazoles are most commonly synthesized via one of two major routes:
the most common direct method involves the condensation of an ortho-amino thiophenol with a
substituted aromatic aldehyde, carboxylic acid, acyl chloride or nitrile. This method, however, is
often not appropriate for manysubstituted 2-arylbenzothiazoles due to the difficulties encountered
in the synthesis of the readily oxidisable 2-amino thiophenols bearing substituent groups. The
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
other methods used extensively in the laboratories which are based
on the potassium ferricyanide (Jacobsen cyclization) radical
cyclization of thiobenzanilides which involve cyclization onto
either carbon atom ortho to the anilido nitrogen produces only one
product, hence, the Jacobsen cyclization is a highly effective
strategy for benzothiazole synthesis e.g. for the synthesis of 6substituted benzothiazoles, radical cyclization of the 3-fluoro- or
3,4-difluoro-substituted thiobenzanilides (Ben-Alloum et al.,
1997). A similar mixture of regioisomeric products from the
Jacobsen cyclization has also been observed by Roe and Tucker for
the synthesis of 5- and 7-fluoro-2-phenylbenzothiazoles (Roe et al.,
1965).
A regiospecific synthesis of 2-arylbenzothiazoles
unsubstituted in the phenyl ring was developed through the use of a
bromo substituent ortho to the anilido nitrogen and formation of a
benzyne intermediate followed by intramolecular cyclization. A
similar strategy has been developed for the synthesis of wide range
of 7-substituted benzothiazoles via directed ortho metallation
followed by benzyne formation and subsequent cyclization
(Stanetty et al 1996). These strategies, however, were found to be
incompatible with the nitro functionality on the aryl ring and do
not represent a general route to functionalised 2arylbenzothiazoles (Hutchinson et al., 2000; Shi et al., 1996).
2) Jacobsen cyclisation
Jacobson and Frankenbacher synthesized 2-substituted
benzothiazole by heating of azobenzene with carbon disulfide
in a sealed tube at 2500C for 5 hours. The product melted at
1740C but was identical with Hofmann's 1-mercaptobenzothiazole. The disulfide obtained by the oxidation of this
product with potassium dichromate in acetic acid solution after
recrystallization from benzene melted at 1860C. Jacobson and
Frankenbacher further reported synthesis and cyclization of 2substituted benzothiazole by use of potassium ferricyanide
with sodium hydroxide (Jacobson 1886).
Min Wang synthesized 4-fluorinated 2-phenylbenzothiazoles
(fig. 02) which include benzylation of starting material 3hydroxy- 4-methoxybenzaldehyde was achieved by the
protection of phenolic hydroxyl group with benzyl bromide to
provide 3-benzloxy-4-methoxybenzaldehyde. Oxidation of this
compound using sodium chlorite provided 3-benzloxy-4methoxybenzoic acid which reacted with thionyl chloride to
give
3-benzloxy-4-methoxybenzoyl
chloride.
2Fluorobenzamides
N-(2-fluorophenyl)3-benzloxy-4methoxybenzamide
and
N-(2-fluorophenyl)-3,4dimethoxybenzamide were prepared by condensation of 3benzloxy-4-methoxybenzoyl chloride, or commercially
available starting material 3, 4-dimethoxybenzoyl chloride
with 2-fluoroaniline. The benzamides were converted to their
thiobenzamides
N-(2fluorophenyl)-3-benzloxy-4methoxythiobenzamide
and
N-(2-fluorophenyl)-3,
4dimethoxythiobenzamide with Lawesson’s reagent in
hexamethylphosphoramide
(HMPA).
Cyclization
of
thiobenzamides by a modified method of Jacobson thioanilide
radical cyclization using potassium ferricyanide and aqueous
sodium hydroxide gave 4-fluorobenzothiazoles4-fluoro-2-(3benzloxy-4-methoxyphenyl) benzothiazole (Min Wang et al.,
2006).
2. SYNTHESIS AND CYCLIZATION OF
BENZOTHIAZOLE
Recently, several new methods have been reported, some
of the most common methods for the synthesis of 2 substituted
benzothiazole are as follows
1) Hofmann Method
1-Mercapto-benzothiazole (fig. 01) was first obtained by A.
W. Hofmannin an attempt to prepare the disulfhydryl
derivative of thiocarbanilide by the action of carbon disulfide
on o-aminophenol. He obtained the same substance by the
action of sodium hydro- sulfide on chlorophenyl mustard oil
(1-chloro-benzothiazole). The product thus obtained, after
recrystallization from alcohol, melted at 1790C and was easily
oxidized to a disulfide melting at 1800C. Hofmann also noted
formation of 2- anilinobenzothiazole from the reaction of 2aminothiophenol and phenyl isothiocyanate (Hofmann et al.,
1887).
3) Bromine as catalyst
Recently several methods reported which utilize bromine as
catalyst. Basically cyclization with bromine achieved by oxidation
of aniline, substituted aniline and arylthiourea in acid or
chloroform with alkali thiocyanate.
Hugerschoff in early 1900s synthesed 2-aminobenzothiazole
(fig. 03) and found that an arylthiourea can be cyclized with
liquid bromine in chloroform to form a 2aminobenzothiaozles. (Hugerschoff 1901)
N
NH2
S
Johanson
and
Hamillton
prepared
2-amino-6ethylmercaptobenzothiazole (fig. 04) by oxidation of 4Methylmecaptophenylthiourea with bromine as a catalyst
(Johanson et al., 1949).
fig. 01
14
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
OCH 3
OCH 3
OH
OBn
Benzyl Bromide, K 2CO 3
DMF, 650CDMF,
DMF, 650C
O
H
O
H
NaClO 2,H2NSO 3H
AcOH, 180C AcOH, 180C
OCH 3
OCH 3
OBn
OBn
SOCl 2, Toluene
1000C1000C
1000C
O
Cl
O
OH
2 Fluoroaniline, Et 3N
CH2Cl 2
OCH 3
OCH 3
OR
OR
Lawesson's reagent
F
F
HMPA, 1000C HMPA, 1000C
O
NH
S
NH
K
NaOH, 900C NaOH, 900C
F
OR
N
OCH
S
fig. 02
15
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
Stuckwisch used potassium thiocyanate to cyclize psubstituted aniline into 2-amino-6-substituted benzothiazole
(fig. 05) in the presence of bromine as a catalyst (Stuckwisch,
C.G. 1949).
Jeng Li et al prepared 6-substituted-2-aminobenzothiazole (fig.
07) by cyclizations of p-substituted anilines with the help of
ammonium thiocyanate and bromine (Jeng et al., 1981)
Alaimo and coworkers prepared 2-amino-5, 6-dichloro and 2amino-6, 7-dichlorobenzothiazole (fig. 06) by cyclization of
suitable substituted aniline with help of thiocyanogen (Alaimo
et al., 1971).
NH2
NH 2SCN
N
NH2
Br 2
X
S
X
X = Cl, Br, F,CH 3
fig. 07
Br 2, CHCL 3
S
Naim et al. synthesized 2-aminobenzoyhiazole-6-carboxalic
acid and 2-amino-6-substituted-carbonyl benzothiazoles (fig.
08) by reaction of the corresponding 4-substituted anilines
with potassium thiocyanate followed by oxidative cyclizations
of the resultant thioureas with bromine (Naim et al., 1991).
NH2
KSCN
N
NH2
fig. 03
NH2
S
NH
S
Br 2
S
NH2
Br 2
X
S
N
S
X
R
R
NH2
CHCL 3
NH2
KSCN
N
R= OH, O, alkyls
X= CO
fig. 04
fig. 08
Dogruer, D. S and coworkers prepared 2-amino-6-fluoro-7chlorobenzothiazole (fig. 09) by cyclization of 3-chloro-4fluoroaniline and potassium thiocyanate in presence of
catalytic bromine (Dogruer D. S. et al., 1998). It is also
synthesized by using similar method and materials by Nargund
et al (Nargund et. al., 1999).
O
O
Br 2
NH2
N
NH2
NH2
KSCN
Cl
Br 2
fig. 09
Cl
Patel and Agravat were synthesized various 4(5 or 6)substituted-2-aminobenzothiazoles (fig. 10) through reaction
of 4(5 or 6)-substituted anilines with ammonium thiocyanate
and bromine (Patel et al., 2006).
Cl
NH2
S
F
Cl
Cl
NH2
Br 2, Acitic acid
F
fig. 05
Thioyanogen
N
KSCN
S
S
NH2
Cl
N
N
NH 4SCN
fig. 06
R
NH2
Br 2
fig. 10
16
NH2
R
S
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
5) Benzene as a catalyst
Jimonet et al. synthesized various substituted-2benzothiazolamines derivatives (fig. 11) by different methods.
One-pot reaction of appropriate anilines with thiocyanogen
generated from bromine and alkaline thiocyanate in acetic acid
medium lead to formation of the desired product in good to
moderate yields (Jimonet et al., 1991)
Tweit et al reported cyclizations of isothiocyanates to 2aminobenzothiazole (fig. 15) in presence of benzene (Tweit et
al., 1970).
NH2
N
RNCS
Matsui et. al. prepared 6-substituted-2-aminobenzothiazoles
(fig. 12) by the reaction of 4-substituted anilines with
potassium thiocyanate in presence of bromine (Matsui, M. et
al., 1998).
RCH, Benzene
SH
NH
R
S
fig. 15
N
Alkaline thiocynate
R
NH2
NH2
Br 2, Acetic acid
6) Benzyltrimethylammonium tribromide as catalyst
S
R
Jordan et al. used Benzyltrimethylammonium tribromide
(PhCH2NMe3Br3), is an electrophilic bromine source for the
conversion
of
substituted
arylthioureas
to
2aminobenzothiazoles under mild conditions in a variety of
solvents with good yields. One of the key benefits for this
reagent when compared with molecular bromine in ease of
addition and handling, which minimizes the risk of forming
brominated side products. They have extended the use of this
reagent to a direct, one-pot synthesis of 2aminobenzothiazoles (fig. 16) from either aryl isothiocyanate
and anilines or tetrabutylammonium thiocyanate and anilines
(Jordan et al., 2003).
fig. 11
NH2
KSCN
N
NH2
Br 2 AcOH
R
S
R
fig. 12
Francisco Lopez-Calahorra reported reaction of benzoyl
chloride with ammonium thiocyanate initially gave benzoyl
isothiocyanate, which underwent addition with 3-fluoroaniline
to
form
3-fluorophenylthiourea.
2-amino-5fluorobenzothiazole (fig. 13) was obtained from the
cyclization with bromine (Francisco et al., 2004).
NH
F
NH2
R
NH
F
NH
Benzoyl cloride
NH2
S
R
fig. 16
S
F
7) Copper- and palladium-catalyzed cyclization
Batey et al. reported the synthesis of 2-aminobenzoyhiazoles
through analogous C-S bond forming methodologies. They
formed the intramolecular C-S bond with the help of copperand palladium-catalyzed. Copper- and palladium-catalyzed
intramolecular C-S bond formation by cross-coupling between
aryl halide and thioureas functionality is demonstrated for the
synthesis of 2-aminobenzothiazoles (fig. 17) (Batey et al.,
2003).
N
NH2
S
fig. 13
4) Sulfuric acid as a catalyst
X
Allen used sodium thiocyanate and cyclize p-substituted
aniline into 2-amino-6-substituted benzothiazole (fig. 14) in
the presence of sulfuric acid which act as a catalyst (Allen et
al., 1942).
R
NH
S
N
R2
R1
CU & Pd
R1
N
Toluene
N
R
S
R2
fig. 17
8) Chloroformamidinium salts
N
NaSCN
NH2
N
PhCH 2NMeBr 3
O
NH2
BR 2, CH 2Cl 2, 320C
R
SH
NH2
NH2
H2SO 4
R
S
El-Faham et. al. synthesized 2-aminobenzothiazoles
derivatives by using efficient reagents that is
Chloroformamidinium salts which allowed to react with o-
fig. 14
17
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
R2
SH
R1
Cl
+
R1
NH2
N
R3
N PFe
R2
R4
R4 PFe
N
R3
N
S
NH2
R1
H
N
R3
NH
N
S
S
N
R3
N
R4
R2
R4
fig. 18
10) Lawesson’s reagent
substituted aniline to form 2- aminobenzothiazole (fig. 18) (ElFaham et al., 2006).
Serdons. K. reported synthesis of benzothiazole in which oanisidine was first reacted with p-nitrobenzoyl chloride to
form N-2’-methoxyphenyl-4-nitrobenzamide. The amide was
then converted to the thiobenzamide using Lawesson’s reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane- 2,4disulphide) which is a useful thiation reagent to replace the
carbonyl oxygen atoms of ketones, amides and esters by
sulphur. In the presence of potassium ferricyanide, it cyclized
to the 2-(4’- nitrophenyl)-benzothiazole (fig. 20) (Serdons et
al., 2009).
9) Appel’s salt
Chi B. Vu synthesized benzothiazole nucleus throug
cyclisation which involve reaction of 2-Bromo-4-nitroaniline
with 4,5-dichloro-1,2,3-dithiazol-1-ium chloride, also referred
to as Appel’s salt, to form (Z)-2-bromo-N-(4-chloro- 5H1,2,3-dithiazol-5-ylidene)-4-nitroanilin. This intermediate
could be cyclized to the desired benzothiazole (fig. 19) (Chi et
al., 2009).
NH2
O 2N
Br
+
S
+
Cl
S
N
N
THF; RT
N
Cl
Cl
O 2N
Br
S S
Cul; Pyridine; 110*
N
CN
O 2N
fig. 19
18
S
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
NO 2
COCL
NH
+
R1 O
R
R
NO 2
R = 2 OCH 3, 5 OCH 3, 3 OCH 3
R1 = H, 2Cl, 2 Br
1,4 Dioxane
Lewesson"s Reagent
Reflux for 3 hrs
NO 2
NaOH, c 2H5OH
N
K3Fe(CN) 6 90*C, 2hr
NH
NO 2
S
R
NMP,NaH 110*C, 12hr
R
S
R1
R = 4 OCH 3, 5 OCH 3, 7 OCH 3
fig. 20
R2
R1
OH
N
R1
R2
4 PPA, 2000C4
4 PPA, 2000C
+
CH2CL2, DCC
N
NH
NH2
O
O
Lawessons Reagent
Toluene, Rreflux
R1
R1
R2
H2O / EtOH, NaOH
N
N
K 3Fe(CN) 6
S
R2
N
NH
S
fig. 21
19
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
mmol) and bakers’ yeast (2 g), were stirred at room
temperature for 24 h in DCM. After completion of the
reaction, bakers’ yeast was filtered through a bed of Celite,
and the filtrate was concentrated under reduced pressure. On
cooling, the solid product obtained was separated and
crystallized from ethanol to afford the pure benzothiazole.
Bakers’ yeast is a known source of extracellular enzymes.
These enzymes might be accelerating the cyclocondensation of
2-aminothiophenol and aldehydes by forming either an initial
enzyme–2- aminothiophenol non-covalent complex or an
enzyme–aldehyde complex, resulting in intermediate
benzothiazolines. The coenzymes, nicotinamide adenosine
dinucleotide
/flavin
adenosinedinucleotide-dependent
oxidoreductase available in bakers’ yeast, may be catalyzing
Stephen O. synthesized (pyridinyl) benzothiazole (fig. 21)
using palladium complexes through 4-tert-butylpicolinic acid,
4-tert-butyl aniline, DCC, 4-PP and CH2Cl2 to produce 2-tertButyl-pyridine-2-carboxylic acid (4-tert-butylphenyl)-amide
which on rection with Lawesson’s reagent produces
carbothionic acid and finally cyclisized to benzothiazole by
potassium ferrocyanate (Stephen et al 2007).
11) Bakers’ yeast to catalyze cyclization
Umesh R. Pratap successfully employed bakers’ yeast to
catalyze the condensation of 2-aminothiophenol and aldehydes
in DCM to yield 2-substituted benzothiazoles (fig. 22) in
moderate to good yields under mild reaction condition. A
mixture of an aldehyde (8 mmol), 2-aminothiophenol (8
CHO
SH
Baker's yeast
+
N
CH2Cl 2, rt
NH2
S
CHO
SH
+
NH2
(Enzyme)
CH2Cl 2, rt
S H
N
H
Enzyme
FAD
N
S
+
fig. 22
Enzyme
20
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
SH
F
NH2
CF 3COOH, PPh 3
N
Et 3N (excess)
CCl
N
H
CF3
F
N
N
SH
NBS / CCl 4
N
+
Sunlamp / Refluxing
NH2
NH
N
NH2
S
N
fig. 24
N
CF 2Br
N
H
fig. 23
O
OH
N
R
OH
N
-
S
HOOC
S
NH2
HOOC
OH
H
N
R
O
-
H
NH2
O
H
N
COOH
H
N
S
S
HOOC
HOOC
NH2
R
S
HOOC
NH2
CHO
CHO
R
NH2
fig. 25
formation of bromodifluoromethyl benzo-1,3- diazoles(fig. 23)
(Fenglian et al 2007).
the aromatization by dehydrogenation involving hydride ion
transfer and the subsequent abstraction of a proton. The
second step could be a rate determining step. The intermediate
may have better solubility in DCM compared to other
solvents, thus permitting better interaction with the cofactors
resulting in high yields of the benzothiazoles (Umesh et al
2009).
13) Micellaneous Methods
Yong-Qian Wu et. al. used Di(imidazole-1-yl)methanimine for
formation of nitrogen containing heterocyclic nucleus.
Di(imidazole-1-yl)methanimine was synthesized by treating
cyanogens bromide with imdazole. The reaction complete
smoothly with 2-substituted anilines, regardless of their
nucleophilicity and this may suggest that second imidazole
displacement is not the rate-limiting step due to the strong
tendency towards cyclizations(fig. 24) (Yong-Qian et.
al.2003).
Alessandra Napolitano has reported cyclisation of
benzothiazole by oxidation of 1, 4-benzothiazine species
12) One-pot intramolecular cyclization
Fenglian Ge synthesized benzothiazole derivative according to
Uneyama’s preparation of fluorinated imidoyl chlorides to the
efficient synthesis of various 2-trifluoromethyl and 2difluoromethyl substituted benzo-1,3-diazole derivatives via a
rapid and mild one-pot intramolecular cyclization process.
Subsequent bromination of 2-difluoromethyl benzo- 1,3diazole products by the photolysis with NBS leads to the
21
Journal of Current Pharmaceutical Research 2010; 3(1): 13-23
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derivative by degradation of pheomelanins with alkaline hydrogen
peroxide. Tetrahedron Lett 1996b 37, 6799–6802.
Nargund, L.V.G., Hendery, Anthelmintic activity of 8-Fluoro-9-substituted
(1,3)-. Benzothiazolo(5,1-b)-1,3,5-triazoles on Pheretima postuma.
Indian Drugs, 1999; 36: 137-139.
Patel, N. B. and Agravat, S. N., Synthesis and microbial studies of 2-[(3'Trifluoromethylphenyl)
amino]-3-[N1-(substituted
benzothiazolyl)
carbonyl] pyridinesOrient. J. Chem., 2006; 22: 333.
Patrick J., François A., Michel B., Jean-Charles B., Alain B., Yvette B.,
Marie-Annick C., Adam D., Gilles D., Claudine Do H., Marie-Hélène
D., Jean Marie D., Pierre G., Claude G., Eliane H., Bernard J., Roselyne
K., Sylvie G., Philippe H., Pierre M. L., Joseph Le B., Mireille M., JeanMarie M., Conception N., Martine P., Odile P., Jeremy P., Jean R.,
Michel R., Jean-Marie S., and Serge M. Synthesis and in Vivo
“Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines and 3-
which then undergo nucleophilic attack of the hydroxyl anion
at C-2 to afford a transient bemithioketal, invoked in the
alkali-induced ring contraction of 2H-1, 4- benzooxazines.
Then undergo rearrangement and oxidation. Further oxidation
and aromatization of intermediate yield eventually 2- carboxy4-hydroxy-6-(2 -amino-2 -carboxyethyl) benzothiazole (fig.
25) (Alessandra et al 1996).
5. CONCLUSION
Benzothiazole belongs to an important class of
heterocyclic compounds and exhibits a wide range of biological
properties and due to its potent activities, thus the synthesis of
benzothiazole is an area of current interest. Several methods for the
synthesis and cyclization of benzothiazole have been reported such
as Hofmann Method Jacobson synthesis and oxidation by bromine,
sulphuric acid, benzyltrimethylammoniumtribromide, copper and
palladium, chloroformamidium salt, Appel’s salt to facilitate
formation of the thiyl radical from the thiobenzamide, which
cyclizes with loss of a hydrogen atom and Baker’s yeast
cyclization to produce the benzothiazole. Since, individual method
has their own advantages and disadvantages, but the most common
classical methods for the synthesis of benzothiazole are based on
cyclization of thiobenzamides (Jacobson synthesis) which involves
the use of potassium ferricyanide with sodium hydroxide and
cyclization of substituted aniline in the presence of potassium
thiocyanate achied through oxidation by bromine. The cyclization
as well as structural elaboration in lead optimization, the points of
attachment on the benzoheterocycle can be through a number of
atoms on either the benzene or heterocyclic rings. In general, the
formation of heteroatom linkages between any points on the
benzoheterocyclic nucleus for example, any aromatic, lipid-like,
peptide, heterocyclic or even carbohydrate appendage may take
advantage of S, and N nucleophilicity. However, the formation of
carbon–carbon bonds to the benzoheterocyclic nucleus from these
appendages may be more involved, particularly in the presence of
sensitive heteroatom functionality on the heterocyclic portion of
the nucleus.
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