CuTC mediated coupling of 6,7-disubstituted benzothiazoles

Article abstract of DOI:10.3987/COM-06-10809

A synthesis of the halogeno derivatives of substituted benzothiazoles (2-6) is described, and dimerization using copper in different oxidation states is examined. Dimerization of iododerivatives (2) and (4) by copper(I) thiophen-2-carboxylate (CuTC) mediated coupling afforded the corresponding o,o'-disubstituted bibenzothiazoles (7) and (S) in excellent yield.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10809

HETEROCYCLES, Vol. 68, No. 9, 2006
1909
HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1909 - 1916. © The Japan Institute of Heterocyclic Chemistry
Received, 12th June, 2006, Accepted, 14th July, 2006, Published online, 18th July, 2006. COM-06-10809
CuTC MEDIATED COUPLING OF 6,7-DISUBSTITUTED
BENZOTHIAZOLES
Livio Racanè,a Vesna Traliꢀ-Kulenoviꢀ,*a Gordana Pavloviꢀ,a and Grace
Karminski-Zamolab
aDepartment of Applied Chemistry, Faculty of Textile Technology, University of
Zagreb, Prilaz baruna Filipoviꢀa 30, 10000 Zagreb Croatia. vtralic@ttf.hr
bDepartment of Organic Chemistry, Faculty of Chem. Eng. and Technology,
University of Zagreb, Maruliꢀev trg 20, 10000 Zagreb, Croatia
Abstract – A synthesis of the halogeno derivatives of substituted benzothiazoles
(2-6) is described, and dimerization using copper in different oxidation states is
examined. Dimerization of iododerivatives (2) and (4) by copper(I)
thiophen-2-carboxylate (CuTC) mediated coupling afforded the corresponding
o,o’-disubstituted bibenzothiazoles (7) and (8) in excellent yield.
INTRODUCTION
Benzothiazoles represent structural units frequently found in a broad range of organic compounds,
including natural product, pharmaceuticals, dyes and other functional synthetic compounds.1
Consequently, methods for functionalization and expansion of heterocyclic moiety would find application
in various scientific disciplines. Due to the fact that many natural and commercial interesting molecules
contain several bounded aromatic ring, aryl-aryl bond formation is one of the most important tools of
modern organic synthesis.2
Arylation of benzothiazoles using palladium as catalyst was efficiently carried out mostly in position 2,
while 6-bromo-2-methylbenzothiazole was coupled with arylzinc chloride in position 6.3 Furthermore,
direct arylation in position 2 with iodoarene was achieved with cobalt and Cu2O as catalyst.4
In connection with our studies on the synthesis and properties of substituted benzothiazoles,5 we turned
our attention on the preparation and homocoupling of 6,7-disubstituted benzothiazoles, one of
substituents being halogen, by copper in different oxidation states. The copper(I) thiophen-2-carboxylate
(CuTC) promoted reductive homocoupling reaction was chosen because it successfully coupled aryl,
heteroaryl, and alkenyl iodides and bromides bearing a coordinating ortho-substituent at ambient

1910
HETEROCYCLES, Vol. 68, No. 9, 2006
temperature in high yield.6 In addition CuTC can be easily prepared on multigram scale from
thiophene-2-carboxilic acid and Cu2O, and handled without any special precaution.
RESULTS AND DISCUSSION
Preparation of 6,7-disubstituted benzothiazoles as starting compounds for homocoupling reaction is
shown in Scheme 1.
N
S
H2N
1. HSO3NO
2. KI
Br2/HOAc
ICl
N
S
N
S
N
S
H2N
H2N
I
Br
I
5
3
1
KNO3/H2SO4
CH3COCl
CH3COCl
N
S
N
S
N
S
I
H3COCHN
H3COCHN
NO2
I
Br
6
2
4
Scheme 1
There are two ways for preparation of substituted 6- or- 7-halogenobenzothiazoles from readily accessible
6-aminobenzothiazole. Diazotization with nitrosylsulfate in acetic acid followed by Sandmeyer reaction
gave 6-iodobenzothiazole (1) in moderate yield (54 %). Although 6-iodobenzothiazole has been
previously mentioned as a reagent in one patent7 there exist no literature data on the preparation and
characterization of this compound. Therefore, the synthesis and X-Ray structure characterization of
6-iodobenzothiazole is given in this article. Nitration of 1 with KNO3 in sulfuric acid gave
6-iodo-7-nitrobenzothiazole (2) in yield of 80 %. Halogenation of starting 6-aminobenzothiazole afford
6-amino-7-iodobenzothiazole (3) and 6-amino-7-bromobenzothiazole (5),8 respectively. The yield of

HETEROCYCLES, Vol. 68, No. 9, 2006
1911
compound (3) strongly depends on the method of preparation and purification. Thus, we found that
iodination with ICl in acetic acid affords 3 in low yield (cca 30 %) opposite to iodination with ICl in
diluted HCl giving good yield (70 %). Purification of compound (3) was performed using dry column
chromatography, as not time consuming method for purification of large quantities of crude product. The
amino derivatives (3) and (5) were transformed into corresponding acetyl derivatives,
6-acetylamino-7-iodobenzothiazole (4), and 6-acetylamino-7-bromobenzothiazole (6), respectively. Our
approach to the homocoupling of substitueted benzothiazoles (2), (4), and (6) is outlined in Scheme 2.
Cu/DMF
NO2
S
N
S
CuTC/NMP
N
N
I
S
O2N
NO2
2
7
N
CuTC/NMP
CuTC/NMP
S
N
H3COCHN
I
S
H3COCHN
S
4
NHCOCH3
N
N
S
8
H3COCHN
Br
6
Scheme 2
Attempt to form C-C bond between two benzothiazole using the Ullmann coupling reaction of
6-iodo-7-nitrobenzothiazole (2) with activated copper in DMF was unsuccessful. In analogy to oxidative
homocoupling of substituted 2-aminonaphtalene,9 we tried to couple 6-aminobenzothiazole directly using
Cu(II)-salts. This method was unsuccessful, too. Homocoupling of substituted benzothiazole was
successful when CuTC promoted method was used. Thus, iodo derivatives (2) and (4) were homocoupled
in NMP with 2.5 eq CuTC at room temperature in very good yield (90 %). Isolation of

1912
HETEROCYCLES, Vol. 68, No. 9, 2006
7,7’-dinitro-6,6’-bibenzothiazole (7) and 6,6’-diacetylamino-7,7’-bibenzothiazole (8) was quite simple.
Pouring the reaction mixture in diluted ammonia provided compounds (7) and (8) in almost pure form. In
spite of the fact homocoupling of bromoaryl derivative is described in literature,6 we didn’t succeed to
couple the compound (6) with CuTC/NMP. We carried out the homocoupling at 70° C, and prolonged
reaction time (5 days) but only the bromo derivative (6) was regenerated from reaction mixture.
1
13
The structures of new compounds were confirmed by elemental analysis, IR, H, and C NMR spectra,
while structures of 1 and 7 were also additionally confirmed by X-Ray structure analysis on single
crystals. The X-Ray molecular structures of 1 and 7 are shown in Figures 1a and 1b, respectively.
The molecule of 6-iodobenzothiazole (1) is planar (Figure 1a). Molecular geometry is as expected.
Nitro groups in the molecule of 7,7'-dinitro-6,6'-bibenzothiazole (7) are in trans position (Figure 1b). The
molecule is not planar with the dihedral angle between planes calculated through two benzothiazole ring
atoms of 70.4(1)o.
(a)
(b)
Figure 1. ORTEP drawings of molecular structures of 1 and 7
We can conclude that successful CuTC promoted homocoupling is carried out only with iodo-substituted
benzothiazoles (2) and (4) in excellente yield.
EXPERIMENTAL
Melting points were determined on a Kofler hot stage microscope and are uncorrected. IR spectra were
1
recorded on a Nicolet Magna 760 spectrophotometer in KBr discs. H and 13C NMR spectra were
recorded on either a Varian Gemini 300 or a Brucker Avance DPX 300 spectrometer. Chemical shifts (δ)
are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and
coupling constants (J) are given in hertz (Hz). Elemental analyses were carried out in the Microanalytical
laboratory at the Rudjer Boskovic Institute. All compounds were routinely checked by TLC with Merck
silica gel 60F-254 glass plates.
6-Amino-7-bromobenzothiazole (5) was prepared according to the literature procedure.8

HETEROCYCLES, Vol. 68, No. 9, 2006
1913
6-Iodobenzothiazole (1) To the mixture of concd H2SO4 (45 mL) and NaNO2 (3.04 g, 44 mmol)
prepared at 70 °C, cooled to 40 °C, 6-aminobenzothiazole (6.0 g, 40 mmol) in acetic acid (80 mL) was
added and stirred at rt for 30 min. The stirred solution of KI (7.32 g, 44 mmol) in water (70 mL) was
heated at 70 °C, and the previously prepared diazonium salt was added. After 30 min the reaction mixture
was poured on ice and the crystals of crude product were filtered off, washed with water and dissolved in
CHCl3. The CHCl3 solution was treated with 10 % Na2S2O3, washed with water and dried. The solvent
was evaporated, and the residue was crystallized from cyclohexane. Yield of colorless crystals was 5.54 g
(53.3 %), mp 79-80 °C. IR (KBr, cm-1): 3043, 1578, 1427, 1386, 861, 816, 799. 1H NMR (DMSO-d6, 300
MHz) δ: 9.35 (s, 1H), 8.61 (d, 1H, J=1.6 Hz), 7.88 (d, 1H, J=8.5 Hz), 7.88 (dd, 1H, J=1.7 Hz, J=8.6 Hz).
13C NMR (DMSO-d6, 75 MHz), δ: 157.5, 152.9, 136.6, 135.3, 131.3, 125.2, 91.2. Anal. Calcd for
C7H4NIS: C, 32.20; H, 1.54; N, 5.36. Found: C, 32.34; H, 1.58; N, 5.21.
6-Iodo-7-nitrobenzothiazole (2) The 6-iodobenzothiazole (1) (10.5 g, 40 mmol) was added to a stirred
solution of KNO3 (8.4 g, 83 mmol) in concd H2SO4 (45 mL), and stirred at rt for 4 d. Reaction mixture
was poured on crushed ice, and neutralized with ammonia. The obtained crystals were filtered off,
washed with water and crystallized from toluene/cyclohexane (charcoal). Yield of pale yellow crystals
was 9.94 g (80.8 %), mp 188-189 °C. IR (KBr, cm-1): 1587, 1508, 1325, 1301, 855. 1H NMR (DMSO-d6,
13
300 MHz), δ: 9.52 (s, 1H), 8.34 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=8.4 Hz). C NMR (DMSO-d6, 75
MHz), δ: 160.4, 154.4, 145.4, 140.1, 131.2, 128.8, 88.7. Anal. Calcd for C7H3N2O2IS: C, 27.47; H, 0.99;
N, 9.15. Found: C, 27.30; H, 1.02; N, 9.32.
6-Amino-7-iodobenzothiazole (3) A solution of ICl (15.0 g, 0.1 mol) in diluted HCl (18 mL of concd
HCl and 60 mL of water) was added to a solution of 6-aminobenzothiazole (12 g, 80 mmol) in diluted
HCl (9 mL of concd HCl and 120 mL of water). Reaction mixture was stirred at rt for 1 h and neutralized
with saturated solution of NaHCO3. The crude product was purified by dry column chromatography on
SiO2 with petrolether/AcOEt 8/2 to give colorless crystals 15.9 g (72.0 %), mp 130-132 °C. IR (KBr,
1
cm-1): 3448, 3359, 3050, 1611, 1586, 1540, 1465, 1449, 1387, 868, 844, 811. H NMR (DMSO-d6, 300
MHz), δ: 9.01 (s, 1H), 7.76 (d, 1H, J= 8.7 Hz), 6.95 (d, 1H, J=8.7 Hz), 5.56 (s, 2H). 13C NMR (DMSO-d6,
75 MHz), δ: 148.8, 148.2, 143.6, 142.8, 123.7, 114.7, 70.2. Anal. Calcd for C7H5N2IS: C, 30.45; H, 1.38;
N, 10.15. Found: C, 30.63; H, 1.46; N, 9.88.
6-Acetylamino-7-iodobenzothiazole (4) To a stirred mixture of 6-amino-7-iodobenzothiazole (3) (2.75 g,
10 mmol), and Et3N (1.4 mL) in 1,2-dichlorethane, acetyl chloride (1.5 mL, 20 mmol) was added
dropwise. The reaction mixture was stirred at rt for 1 h, and the crude product was filtered off, washed

1914
HETEROCYCLES, Vol. 68, No. 9, 2006
with 1,2-dichlorethane and dried. The product was suspended in water, filtered off and crystallized from
EtOH/ CHCl3 (1/1). Yield of colorless crystals was 2.95 g (92.8 %), mp 244 °C. IR (KBr, cm-1): 3265,
1658, 1526, 1462, 1377. 1H NMR (DMSO-d6, 300 MHz), δ: 9.74 (s, 1H), 9.47 (s, 1H), 8.06 (d, 1H, J=8.7
Hz), 7.52 (d, 1H, J=8.7 Hz), 2.10 (s, 3H). 13C NMR (DMSO-d6, 75 MHz), δ: 168.6, 155.4, 148.0, 142.6,
138.2, 125.6, 122.6, 87.3, 23.2. Anal. Calcd for C9H7N2OIS: C, 33.98; H, 2.22; N, 9.88. Found: C, 34.12;
H, 2.38; N, 8.67.
6-Acetylamino-7-bromobenzothiazole (6) To a stirred mixture of 6-amino-7-bromobenzothiazole (5)
(2.30 g, 10 mmol), and Et3N (1.4 mL) in chloroform (150 mL), acetyl chloride (1.5 mL, 20 mmol) was
added dropwise. The reaction mixture was stirred at rt for 1 h, and the solution was washed with water,
dried and evaporated to a volume of 15 mL. After cooling overnight the obtained colorless crystals were
1
filtered off. Yield was 2.23 g (82.4 %), mp 204 °C. IR (KBr, cm-1): 3245, 1672, 1649, 1529, 1384. H
NMR (DMSO-d6, 300 MHz), δ: 9.79 (s, 1H), 9.44 (s, 1H), 8.07 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=8.7 Hz),
13
2.12 (s, 3H). C NMR (DMSO-d6, 75 MHz), δ: 168.7, 149.7, 137.4, 134.4, 125.8, 121.9, 23.1. Anal.
Calcd for C9H7N2OBrS: C, 39.87; H, 2.60; N, 10.33. Found: C, 39.79; H, 2.71; N, 10.48.
7,7'-Dinitro-6,6'-bibenzothiazole (7) To a solution of 6-iodo-7-nitrobenzothiazole (2) (3.02 g, 10 mmol)
in NMP (40 mL), CuTC (4.7 g, 25 mmol) was added under N2. The flask was stoppered, and the reaction
mixture was stirred at rt for 2 h. The mixture was poured in aq. NH3 (10 % 500 mL), and the product was
filtered off, washed with diluted NH4OH, and water. Crystallization from xylene yielded 1.66 g (92.7 %)
1
of pale yellow crystals, mp 312-313 °C. IR (KBr, cm-1): 3043, 1603, 1514, 1323, 1308, 860, 851. H
13
NMR (DMSO-d6, 600 MHz), δ: 9.65 (s, 2H), 8.56 (d, 2H, J=8.2 Hz), 7.68 (d, 2H, J=8.2 Hz). C NMR
(DMSO-d6, 151 MHz), δ: 161.4, 154.6, 140.1, 133.9, 130.4, 129.3, 129.2. Anal. Calcd for C14H6N4O4S2:
C, 46.92; H, 1.69; N, 15.63. Found: C, 47.11; H, 1.44; N, 15.41.
6,6'-Diacetylamino-7,7'-bibenzothiazole (8) To a solution of 6-acetylamino-7-iodobenzothiazole (4)
(3.22 g, 10 mmol) in NMP (35 mL), CuTC (4.7 g, 25 mmol) was added under N2. The flask was
stoppered, and the reaction mixture was stirred at rt for 3 days. The mixture was poured in aq. NH3 (10 %
500 mL), and the obtained product was filtered off, washed with diluted NH4OH, and water.
Crystallization from DMF yielded 1.69 g (88.5 %) of colorless crystals, mp >300 °C. IR (KBr, cm-1):
3448, 3245, 3074, 1683, 1593, 1523, 1279. 1H NMR (DMSO-d6, 300 MHz), δ: 9.33 (s, 2H), 9.16 (s, 2H),
13
8.15 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.6 Hz), 1.77 (s, 6H). C NMR (DMSO-d6, 75 MHz), δ: 168.8,
150.2, 135.0, 133.8, 124.6, 124.0, 122.9, 23.0. Anal. Calcd for C18H14N4O2S2: C, 56.53; H, 3.69; N, 14.65.
Found: C, 56.48; H, 3.78; N, 14.43.

HETEROCYCLES, Vol. 68, No. 9, 2006
1915
X-Ray Crystallographic Structure Determination of 1 and 7
The data collection for both structures were carried out on Xcalibur four-circle kappa geometry
single-crystal diffractometer with Xcalibur Sapphire 3 CCD detector by applying the CrysAlis Software
system, Version 171.23 at 296 K.10 Structure solutions were determined by direct method with the
SHELXS program.11 The coordinates and anisotropic thermal displacement parameters for all
non-hydrogen atoms were refined by the least-squares methods based on F2 using the SHELXL97
program.12 The coordinates of the hydrogen atoms belonging to the phenyl and thiazolyl ring carbon
atoms were generated at ideal geometrical positions [Csp2-H 0.93 Å, Uiso(H) = 1.2 Ueq(C) ] and refined
applying the riding model. The molecular graphics were done using the PLATON98 program.13
Compound (1): C7H4NIS, Mr = 261.08, monoclinic, P 21/a, a = 12.3861(12) Å, b = 4.6598(4) Å, c =
13.9082(12) Å, β = 95.919(7)o, V = 798.46(12) Å3, Z = 4, Dc = 2.172 g cm-3, µ = 4.2 mm-1, F(000) =
488, No. measured reflections = 8831, No. independent reflections (Rint) = 1725 (0.124), No. refined
parameters = 92, No. observed reflections with I ≥ 2σ(I) = 1649, R = 0.0447, wR = 0.1152, R (all data) =
0.0466, wR (all data) = 0.1130, S = 1.12.
Compound (7): C14H6N4O4S2, Mr = 358.37, orthorombic, P bca, a = 8.4932(7) Å, b = 14.0757(10) Å, c =
24.2363(18) Å, V = 2897.4(4) Å3, Z = 8, Dc = 1.643 g cm-3, µ = 0.4 mm-1, F(000) = 1456, No. measured
reflections = 34022, No. independent reflections (Rint) = 3142 (0.067), No. refined parameters = 217, No.
observed reflections with I ≥ 2σ(I) = 3095, R = 0.0721, wR = 0.1344, R (all data) = 0.0739, wR (all data)
= 0.1336, S = 1.38.
Supplementary material
CCDC 610516 & 610517 contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(0)1223-336033; email: deposit@ccdc.cam.ac.uk]. Structure factors table is available from the
authors.
ACKNOWLEDGEMENTS
The support of the Ministry of Science and Technology, Republic of Croatia (Project No 125005, and
119633) is gratefully acknowledged.
REFERENCES
1. (a) J. C. Day, L. C. Tisi, and M. J. Bailey, Luminiscence, 2004, 19, 8. (b) G. P. Gunavardana, S.
Kohomoto, S. P. Gunasekera, O. J. McConnell, and F. E. Koehn, J. Am. Chem. Soc., 1988, 110,
4856. (c) N. Ashizawa and T. Aotsuka, Drugs Future, 1998, 23, 521. (d) C. O. Leong, M. Suggitt,

1916
HETEROCYCLES, Vol. 68, No. 9, 2006
D. J. Swaine, M. C. Bibby, M. F. G. Stevens, and T. D. Bradshaw, Mol. Cancer Therapeutics,
2004, 3, 1565. (e) M. Humphreys, N. Hall, D. A. S. Phillips, and J. A. Taylor, Dyes and Pigments,
2003, 59, 193. (f) A. Lochart, L. Ye, D. B. Judd, A. T. Merritt, P. N. Lowe, J. L. Morgersten, G.
Hong, A. D. Gee, and J. Brown, J. Bio. Chem., 2005, 280, 7677.
2. J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, and M. Lemaire, Chem. Rev., 2002, 102, 1359.
3. (a) Y. Heo, Y. S. Song, B. T. Kim, and J. N. Heo, Tetrahedron Lett., 2006, 47, 3091. (b) V. J.
Majo, J. Prabhakaran, J. J. Mann, and J. S. D. Kumar, Tetrahedron Lett., 2003, 44, 8535. (c) A.
Yokooji, T. Okazawa, T. Satoh, M. Miura, and M. Nomura, Tetrahedron, 2003, 59, 5685. (d) S.
Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, and M. Nomura, Bull. Chem. Soc. Jpn., 1998, 71,
467. (e) N. A. Bumagin, A. F. Sokolova, and I. P. Beletskaya, Russ. Chem. Bull., 1993, 42, 1926.
4. (a) B. Sezen and D. Sames, Org. Lett., 2003, 5, 3607. (b) J. Chodowska-Palacka and M. Nilsson,
Synthesis, 1974, 128.
5. (a) L. Racanè, R. Stojković, V. Tralić-Kulenović, and G. Karminski-Zamola, Molecules, 2006, 11,
325. (b) V. Tralić-Kulenović, L. Racanè, and G. Karminski-Zamola, Sectroscopy Lett., 2003, 36,
43. (c) L. Racanè, V. Tralić-Kulenović, L. Fišer-Jakić, D. W. Boykin, and G. Karminski-Zamola,
Heterocycles, 2001, 55, 2085.
6. S. Zhang, D. Zhang, and L. S. Liebskind, J. Org. Chem., 1997, 62, 2312.
7. D. S. Rosen, Y. L. Zhang, R. N. Henrie, B. J. Dugan, T. M. Zydowsky, S. Zhang, and I. Shulman,
2004, WO2004010761.
8. E. R. Ward and C. H. Williams, J. Chem. Soc., 1965, 2248.
9. Š. Vyskočil, M. Smrčina, M. Lorenc, I. Tišlerova, R. D. Brooks, J. J. Kulagowski, V. Langer, L. J.
Ferrugia, and P. Kočovsky, J. Org. Chem., 2001, 66, 1359.
10. Oxford Diffraction (2004). Oxford Diffraction Ltd., Xcalibur CCD system, CrysAlis Software
system, Version 171.23.
11. G. M. Sheldrick, Acta Cryst., 1990, A46, 467.
12. G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures. University of
Göttingen, Germany, 1997.
13. A. L. Spek, Acta Cryst., 1990, A46, 34.