The synthesis of Aminobenzothiazoles from 2,3-biaryl-5-anilino-Δ3-1,2,4-thiadiazolines

Article abstract of DOI:10.1081/SCC-120021031

2-Amidinobenzothiazoles 4 can be prepared in high yields by a thermally-promoted rearrangement of thiadiazolium salts 1 or thiadiazolines 2. Addition of base to the rearrangement of the thiadiazolium salts can improve the yields by the prior conversion of the thiadiazolium salts to the corresponding thiadiazoline free bases. The rearrangement of the thiadiazolines may go through an electrophilic aromatic substitution or free radical pathway.

Full text of DOI:10.1081/SCC-120021031

This article was downloaded by: [The University of Manchester Library]
On: 10 October 2014, At: 12:34
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
The Synthesis of Aminobenzothiazoles from 2,3-
Biaryl-5-anilino-Δ3-1,2,4-thiadiazolines
Kevin Pan a & Allen B. Reitz a
a Drug Discovery Division , The R.W. Johnson Pharmaceutical Research Institute , Spring
House, Pennsylvania, USA
Published online: 17 Aug 2006.
To cite this article: Kevin Pan & Allen B. Reitz (2003) The Synthesis of Aminobenzothiazoles from 2,3-Biaryl-5-
anilino-Δ3-1,2,4-thiadiazolines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:12, 2053-2060, DOI: 10.1081/SCC-120021031
To link to this article: http://dx.doi.org/10.1081/SCC-120021031
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2053–2060, 2003
The Synthesis of Aminobenzothiazoles from
2,3-Biaryl-5-anilino-"3-1,2,4-thiadiazolines
*
Kevin Pan and Allen B. Reitz
Drug Discovery Division, The R.W. Johnson
Pharmaceutical Research Institute, Spring House,
Pennsylvania, USA
ABSTRACT
2-Amidinobenzothiazoles 4 can be prepared in high yieldsby a
thermally-promoted rearrangement of thiadiazolium salts 1 or
thiadiazolines 2. Addition of base to the rearrangement of the
thiadiazolium salts can improve the yields by the prior conversion
of the thiadiazolium salts to the corresponding thiadiazoline free
bases. The rearrangement of the thiadiazolines may go through an
electrophilic aromatic substitution or free radical pathway.
*Correspondence: Kevin Pan, Drug Discovery Division, The R.W. Johnson
Pharmaceutical Research Institute, Welsh and McKean Roads, P.O. Box 776,
Spring House, PA 19477-0776, USA; Fax: þ86(21)6360-1892; E-mail:
kpan@shpl.com.cn.
2053
DOI: 10.1081/SCC-120021031
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2054
Pan and Reitz
5-Amino-1,2,4-thiadiazoles, either in the form of salts (thiadia-
zolium salts 1) or free bases (thiadiazolines 2), can be synthesized
from readily accessible amidinothioureas 3 using a variety of oxidizing
[2]
agentsusch aselemental halogen,s
N-chlorosuccinimide (NCS),[3]
or diethyl azodicarboxylate (DEAD).[4] Ashsown in Sch. 1, when
bromine[3,5] or N-bromosuccinimide (NBS)3 were used as the oxidizing
agents, 2-amidinobenzothiazoles 4 could be obtained at yieldsashigh
as 85%. Kurzer and Sanderson had reported the isomerization of
2-aryl-5-arylamino-3-arylimino-Á3-1,2,4-thiadiazolines5 to 2-guanidino-
benzothiazoles 6.[6] We hereby report our studies investigating the
rearrangement of 2,3-biaryl-5-anilino-Á3-1,2,4-thiadiazolium bromides
1 or thiadiazolines 2 to 2-amidinobenzothiazoles 4 to demons-
trate that thismethod isa viable meansof preparing compoundsof
type 4.
Thiadiazolium bromides 1 were incubated in dimethyl sulfoxide
at 65ꢀC for 16 h at a concentration of 1.0 mg/mL (Method A).[7]
The crude reactionswere analyzed by LC/MS, and the reusltswere
compared to the LC retention times of the starting materials.
Compounds 1a to 1g all generated products 4 (Table 1). In the
cases of 1a, 1e, and 1g, there were no thiadiazolium bromides
which remained after thisperiod of time, whereas 1b–d, and 1f
still had some thiadiazolium bromide starting material. 1h and 1i did
not show any reaction because the 2- and 6-positions of the aniline
ring were blocked. The stability of 1j and 1k suggested that the rear-
rangement reaction require both a proton and an aryl ring on the 5-
amino nitrogen. The free base of 1f wasprepared by treating the
corresponding thiourea with N-chlorosuccinimide and followed by
the extraction from saturated NaHCO3 aqueousoslution, and was
then converted to other acid addition salts. The resulting
thiadiazolium salts were subjected to the incubation condition
(Method A), and the extent of formation of 4f wasfound to
be dependent on the strength of the acids (Fig. 1). The free base
thiadiazoline 2f and the salts of the weaker acids, such as succinic
and phosphoric acids, were completely transformed to 4f. The strong
acid salts, such as those from sulfuric acid, HCl, and HBr, displayed
partial conversion of between 55% to 65% under the same reaction
conditions. When 3.0 mol-equiv. of triethylamine was added to the
reaction in dimethyl sulfoxide at 65ꢀC for 16 h (Method B),[8] 4a–g
were synthesized in good to excellent yields (60–97%).
Based on the above observations, we suggest that the rearrange-
ment might start from the thiadiazolines 2, ashsown in Sch. 2. The
stability of 1j might be due to the N-methyl group blocking the

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Aminobenzothiazoles
2055

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2056
Pan and Reitz
Table 1. Rearrangement of thiadiazolium salts 1a–1h in DMSO at 65ꢀC with
methodsA and B to generate 4-amidinobenzothiazoles 4.
Method A
purityb of 4
Method B
R4 (% of remaining 1) isolated yieldc
No.
R1
R2
R3(R30)a
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
Ph
H
H
61% (0)
46% (27%)
71% (3%)
42% (11%)
76% (0)
56%
80%
61%
89%
78%
95%d
97%d
0
2-OMePh
2-ClPh
Ph
H
2-MeO
2-Cl
H
Ph
H
2-OMe 2-OMe Ph
H
56% (28%)
100% (0)
0 (100%)
0 (100%)
0 (100%)
0 (100%)
1g
1h
1i
2-OMe 2-OMe 3,5-F-Ph
2-OMe 2-OMe 2,6-F-Ph
2-OMe 2-OMe 2-Cl-6-Me-Ph
H
H
H
0
1j
1k
2-Me
H
H
H
4-OMePh
Bn
Me
H
—
—
aR30 were the substitutions on the phenyl rings.
bThe percentageswere calculated based to the peak area integration of analytical
HPLC traces.
cThe yieldswere calculated after the purification from semi-preparative HPLC.
dNo purification isneeded.
formation of thiadiazoline 2j from thiadiazolium bromide 1j. The
results in Fig. 1 also support the relative importance of thiazolines
2 in the reaction pathway because the weak acid salts can equilibrate
to 2f more readily, and hence 4f could be generated quantitatively.
We reasoned that addition of a base to the reaction mixture might
increase the rate of the rearrangement. Rearrangement of 1f
became significantly slower in ethanol or water, or at low temperatures
and pH.
The mechanism of the isomerization of 5 to 6 waspropoesd to
proceed via aqueoushydrolyissby addition of water to the 2-N and

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Aminobenzothiazoles
2057
Figure 1. Generation of 4f from 1f in various acid salt forms; (a) Incubation at
1.0 mg/mL in DMSO at 65ꢀC for 16 h; (b) The percentageswere calculated from
the integration of peak area on HPLC analysis compared with 1f prepared
[9]
independently; (c) The pKa valueswere obtained from Ref.
1-S atoms, followed by elimination of water from the hydroxyl group on
sulfur and the ortho-hydrogen from the 5-anilino phenyl ring which
provided the observed benzothiazole products.[6] Since there isno water
present in the reactions we studied, this mechanism can be excluded. As
shown in Sch. 1, we propose two possible pathways for the conversion of
thiadiazolines 2 to the products 4. Pathway I involvesan electrophilic
aromatic ring substitution, whereas pathway II starts from the
breakdown of the labile N-S bond in 2 and proceedsby a radical
mechanism. Pathway I can be used to explain the stability of 1k because,
after forming thiadiazoline 2k, methylene substitution on the phenyl ring
is not as activating as amino substitution, and therefore electrophilic
aromatic substitution does not occur. Pathway II can still occur in this
case since the methylene group prevents the delocalization of the radical
on the nitrogen to the 5-aminobenzyl ring, although the resulting product
would be a six-member ring.
In summary, we have discovered the rearrangement of 2,3-biaryl-
5-anilino-Á3-1,2,4-thiadiazolium bromidesor thiadiazolinesto 2-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2058
Pan and Reitz
Scheme 2.
amidinobenzothiazoles. The mechanism of the reaction may go
through an electrophilic aromatic ring substitution or a free radical
pathway. We have shown that 2-amidinobenzothiazoles 4 can be
synthesized in good yields by adding base to the thiadiazolium salts
1 in dimethyl sulfoxide at an elevated temperature or directly from
thiadiazolines 2. The amidinobenzothiazolesthat are prepared in this
manner would be expected to have useful pharmaceutical or other
biological properties if screened broadly against a variety of suitable
protein targets.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Aminobenzothiazoles
2059
ACKNOWLEDGMENT
The authorswould like to thank Dr. DennisHlatsa for uesful
discussions, support, and encouragement, and Diane Gauthier for
performing many of the NMR experiments.
REFERENCES
1. Author’s current address: Shanghai Hutchison Pharmaceuticals,
Suite 1107, Hua Sheng Building, 399 Jiu Jiang Road, Shanghai,
China, P.R., Postal Code: 200001.
2. Goerdeler, J.; Lobach, W. Reaction of 5-imino-Á3-1,2,4-thiadiazo-
lineswith heterocumulenes. Chem. Ber. 1979, 112, 517–531.
3. Chetia, J.P.; Mazumder, S.N.; Mahahan, M.P. One-pot synthesis of
2-aryl-3-phenyl(benzyl)-5-phenylimino-Á4-1,2,4-thiadiazolinesuisng
N-Chlorosuccinimide. Synthesis 1985, 83–84.
4. Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki, T.;
Furukawa, M. Oxidative heterocyclization using diethyl azodia-
carboxylate. Synthesis 1990, 1020–1023.
5. Bohrisch, J.; Patzel, M.; Grubert, L.; Liebscher, J. Synthesis of
S,N-heterocyclesfrom N-thioacyllactamimines. Phos. Sulfur Silicon
1993, 84, 253–256.
6. Kurzer, F.; Sanderson, P.M. Thiadiazoles. Part X. The synthesis
and isomerisation of 2-aryl-5-arylamino-3-arylmino-Á4-1,2,4-
thiadiazolines. J. Chem. Soc. 1960, 3240–3249.
7. Experimental procedure for the synthesis of 4f (Method A): 1f
(0.500 g, 1.06 mmol) was dissolved in 60 mL of DMSO. The solution
washeated at 65 ꢀC for 16 h. DMSO wasremoved by GeneVac
(Model: HT-12). The resulting crude was purified by semi-preparative
HPLC column. 235 mg of 4f was isolated as a TFA salt at a yield of
43.9%. Compound 4f had the same molecular ions as the thiadiazo-
lium cations 1f on the ESI-MS spectroscopy except that 4f had
1
fragment of the benzothiazole. H NMR of 6f in acetone-d6 at r.t.
showed a typical rotameric splitting of the two ortho-methoxy
protonsinto four peaksand the complexity of the aromatic protons.
Upon heating, the H NMR of 3f in DMSO-d6 (80ꢀC) showed the
1
collapse of the four methoxy proton peaks into two peaks and the
simplification of peaks in the aromatic area. 1H TOCSY NMR in
DMSO-d6 at 80ꢀC showed that one of the ortho-protonson the
anilinophenyl ring disappeared, indicating ring closure at the
ortho-position. 13C-1HMBC, HETCOR, and COSY NMR

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2060
Pan and Reitz
spectroscopy obtained in DMSO-d6 (80ꢀC) were used to assign the
1H NMR peaksasfollowed (chemical shiftsin ppm):
8. Experimental procedure of the synthesis for 4f (Method B): 1f
(0.500 g, 1.06 mmol) was dissolved in 10 mL of TEA (0.444 mL,
3.19 mmol) in DMSO. The solution was heated at 65ꢀC for 16 h.
DMSO was removed by GeneVac. The resulting yellow crystalline
solid was dissolved in 20 mL of saturated aqueous NaHCO3, and was
extracted with EtOAc. The organic layerswere dried over Na SO4,
2
and 418 mg (95% yield) of pure 4f wasobtained without purification.
Anal. calcd: C, 67.84; H, 4.92; N, 10.79; S, 8.23. Found: C, 67.59; H,
4.99; N, 10.60; S, 7.87.
9. (1) Gordon, A.J.; Ford, R.A. The Chemist’s Companion: A Handbook
of Practical Data, Techniques, and References; Wiley: New York,
1972; 58 pp; (2) Dean, J.A. Lange’s Handbook of Chemistry, 13th Ed.;
McGraw-Hill: New York, 1985; 5 pp.
Received October 1, 2002