Heteroannulation through copper catalysis: A novel cyclization leading to a highly regio- and stereoselective synthesis of 2-substituted benzothiazolines

Article abstract of DOI:10.1021/ol990165g

(matrix presented) 3-(2-Aminophenylthio)prop-1-yne 8 reacted with aryl iodides 9-18 under palladium-copper catalysis leading to the disubstituted alkynes 19-28 which after tosylation underwent a novel cyclization under copper catalysis to 2-substituted be

Full text of DOI:10.1021/ol990165g

ORGANIC
LETTERS
2000
Vol. 2, No. 3
235-238
Heteroannulation through Copper
Catalysis: A Novel Cyclization Leading
to a Highly Regio- and Stereoselective
Synthesis of 2-Substituted
Benzothiazolines†
Bidisha Nandi and Nitya G. Kundu*
Department of Organic Chemistry, Indian Association for the CultiVation of Science,
JadaVpur, Calcutta - 700032, India
ocngk@mahendra.iacs.res.in
Received July 15, 1999
ABSTRACT
3-(2-Aminophenylthio)prop-1-yne 8 reacted with aryl iodides 9−18 under palladium−copper catalysis leading to the disubstituted alkynes 19−
28 which after tosylation underwent a novel cyclization under copper catalysis to 2-substituted benzothiazolines 29−38. The expected 3-(arylidine)-
2,3-dihydrobenzothiazines were not obtained.
Palladium-catalyzed reactions1 have been of immense interest
for both carboannulation2 and heteroannulation processes.3
Our own interest in this area has been in the use of terminal
alkynes under palladium-copper catalysis to generate ben-
zofused heterocyclic structures, with one heteroatom only,
e.g. benzofurans,4a phthalides,4b quinolines,4c isoindolines,4d
and isobenzofurans,4e structures which are an integral part
of many naturally occurring and biologically active com-
pounds.5
† This paper is dedicated to late Professor Phanindra Chandra Dutta, Head
(1951-1977), Department of Organic Chemistry, Indian Association for
the Cultivation of Science, Jadavpur, Calcutta-700032, India, on the occasion
of the Golden Jubilee Celebration of the department in January 2000.
(1) For general references, see: (a) Heck, R. F. Org. React. 1982, 27,
345. (b) Heck, R. F. Palladium Reagents in Organic Synthesis, Academic
Press: London, 1985. (c) Daves, G. D., Jr.; Hallberg, A. Chem. ReV. 1989,
89, 1433. (d) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester,
1995.
Subsequently, we have developed a variation of the above
procedure to synthesize benzofused heterocyclic structures
with two heteroatoms which would be of biological interest
(Schemes 1 and 2).6,7
In continuation of those studies we felt that 3-(2-ami-
nophenylthio)prop-1-yne 8 would react with aryl iodides
(2) For selective references on carboannulation, see: (a) Ihle, N. C.;
Heathcock, C. H. J. Org. Chem. 1993, 58, 560. (b) Larock, R. C.; Doty,
M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579. (c) Trost, B. M.; Tanoury,
G. J.; Lautens, M.; Chan, C.; McPherson, D. T. J. Am. Chem. Soc. 1994,
116, 4255. (d) Ma, S.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 6345.
(e) Tietze, L. F.; Nobel, T.; Spescha, M. J. Am. Chem. Soc. 1998, 120,
8971.
Scheme 1. Synthesis of
(Z)-2-(Arylidene)-2,3-dihydro-1,4-benzodioxin and
(Z)-2-(Arylidene)-2,3-dihydronaphtho[2,3-b]dioxin
(3) For selective references on heteroannulation, see: (a) Arcadi, A.;
Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581. (b) Negishi,
E.-i.; Coperet, C.; Ma, S.; Lion, S.-Y.; Lire, F. Chem. ReV. 1996, 96, 365.
(c) Bouyssi, D.; Caviechioli, M.; Balme, G. Synlett 1997, 944. (d) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. Larock, R. C.; Yum,
E. K.; Refvik, M. D. J. Org. Chem.1998, 63, 7652. Larock, R. C.; Han, X.
J. Org. Chem. 1999, 64, 1875. Roesch, K. R.; Larock, R. C. Org. Lett.
1999, 4, 553. Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
10.1021/ol990165g CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/11/2000

(PPh3)2PdCl2 (3 mol %), CuI (6 mol %), and triethylamine-
(4 equiv) in acetonitrile as solvent.8 Bis-triphenylphosphine
palladium chloride was found to be the catalyst of choice
whereas cuprous iodide was found to be an essential
cocatalyst. Carrying out the reaction in acetonitrile in the
presence of triethylamine as a base gave the optimum yields
(59-80%) (see Table 1) and reactions that were independent
Scheme 2. Synthesis of
(Z)-N-Aryl-2-arylidene-2,3-dihydrobenzo-1,4-oxazines
Table 1. Reaction of 3-(2-Aminophenylthio)prop-1-yne 8 with
Aryl Iodides 9-18 under Palladium-Copper Catalysis To Yield
the Disubstituted Alkynes 19-28 (Scheme 3)
9-18 under palladium-copper catalysis and subsequent
cyclization would lead to 3-(arylidene)-2,3-dihydrobenzothi-
azines 39. However, we found that the terminal alkyne 8
indeed reacted with the aryl iodides 9-18 to yield the
disubstituted alkynes 19-28 which, however, in the form
of the tosylates underwent a novel cyclization with cuprous
iodide in triethylamine to 2-styryl-N-tosylbenzothiazolines
29-38 rather than to the expected 3-(arylidene)-2,3-dihy-
drobenzothiazines 39 (Scheme 3).
Scheme 3. Synthesis of 2-Styryl-N-tosylbenzothiazolines
29-38a
of substitution on the aryl iodides. When 2,5-diiodothiophene
17 was used, the dialkynyl thiophene 27 was also obtained
in good yield.
a Reagents and conditions: (a) (PPh3)2PdCl2 (3 mol %), CuI (6
mol %), Et3N, CH3CN, room temperature, 24 h; (b) p-TsCl, py,
CH2Cl2, room temperature, 10 h; (c) CuI (40 mol %), Et3N, THF,
reflux, 36 h.
In contrast to our observations on the synthesis of
2-arylidene-2,3-dihydrobenzodioxins 3, where palladium-
catalyzed reactions and cyclization leading to the benzo-
dioxins took place in a single step (Scheme 1), the cyclization
of the disubstituted alkynes 19-28 did not take place in a
single step under palladium-copper catalysis. We observed
that the free amines 19-28 did not cyclize under various
conditions. However, the corresponding tosylates could be
cyclized with cuprous iodide (40 mol %) in the presence of
triethylamine in tetrahydrofuran with a 36 h reflux.9 As we
have mentioned, cyclization did not lead to the expected
benzothiazines 39 but surprisingly to the 2-substituted
The reaction of aryl iodides 9-18 with alkyne 8 was
carried out under very mild conditions by stirring the mixture
at room temperature (25-30 °C) for 24 h in the presence of
(4) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem.
Soc., Chem. Commun. 1992, 41. Kundu, N. G.; Pal, M.; Mahanty, J. S.;
De, M. J. Chem. Soc., Perkin Trans. 1, 1997, 2815. (b) Kundu, N. G.; Pal,
M. J. Chem. Soc. Chem. Commun. 1993, 86. Kundu, N. G.; Pal, M.; Nandi,
B. J. Chem. Soc., Perkin Trans. 1 1998, 561. (c) Kundu, N. G.; Mahanty,
J. S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34, 1625. Mahanty, J. S.;
De, M.; Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397. (d) Khan, M.
W.; Kundu, N. G. Synlett 1997, 1435. (e) Khan, M. W.; Kundu, N. G.
Synlett 1999, 435.
(5) For references on naturally occurring and biologically active ben-
zofurans, phthalides, quinolines, isoindolinones, and isobenzofurans, see
references cited in 4a-e.
(6) Chowdhury, C.; Kundu, N. G. Chem. Commun 1996, 1067. Chowdhury,
C.; Chaudhuri, G.; Guha, S.; Mukherjee, A. K.; Kundu, N. G. J. Org. Chem.
1998, 63, 1863.
(8) When the tosylate of 8 was used under similar conditions or with
excess CuI (40 mol %), neither disubstituted alkynes 19-28 nor cyclic
products 29-38 could be obtained.
(9) The use of less CuI led to lower yieldssfor example with 19, use of
6 mol % of CuI gave 10% yield, similarly 20 mol % gave 30% yield, 30
mol % gave 45% yield, and 40 mol % gave 67% yield of 29. Higher
percentages of CuI led to a decline in yield. Also, the use of KOH in the
cyclization step did not give any cyclic product, with the detosylated amines
being recovered.
(7) Chaudhuri, G.; Chowdhury, C.; Kundu, N. G. Synlett 1998, 11, 1273.
236
Org. Lett., Vol. 2, No. 3, 2000

Scheme 5. Plausible Mechanism for the Formation of
Table 2. Copper-Catalyzed Cyclization of the Tosylates of the
Disubstituted Alkynes 19-28 to the 2-Substituted
Benzothiazolines 29-38 (Scheme 3)
2-Styrylbenzothiazolinesa
a Reagents and conditions: (a) reduction of PdII to Pd0 with
alkynes and Et3N; (b) CuI, Et3N; (c) tosylation with p-TsCl-py;
(d) isomerization to an allene with CuI, Et3N; (e) nucleophilic attack
on the allene (F) to generate the N-tosyl-2-styrylbenzothiazolines
(29-38).
formation of ArPdX [B] through oxidative addition of Pd0
[A] (generated from PdII) to ArX,14 (ii) transmetalation of
ArPdX with the Cu salt of 8 generating the alkynyl palladium
species [D], (iii) extrusion of Pd0 to yield the disubstituted
alkynes 19-28, (iv) tosylation of the free amine to [E], and
(v) isomerization to the allenic intermediates15 [F] which then
cyclize to the (E)-2-styrylbenzothiazolines 29-38.
In conclusion, we have described a palladium-copper-
catalyzed reaction of 3-(2-aminophenylthio)prop-1-yne with
a terminal acetylenic moiety with readily available aryl
iodides. This has resulted in the formation of a number of
disubstituted alkynes which under copper catalysis underwent
an interesting rearrangement and subsequent cyclization to
(E)-2-substituted benzothiazolines. Only five-membered het-
eroannulation took place when the styryl group at C-2 was
in the E-configuration. No six-membered heteroannulated
compounds were observed. We believe this is the first
reported palladium-copper-catalyzed general procedure for
benzothiazolines 29-38 in fairly good yields (Table 2). The
structures of the benzothiazolines 29-38 follow from their
analytical and spectroscopic data.10 The presence of two
vinylic hydrogens at δ 6.25 and 6.69 (J ) 15 Hz) indicated
the E-configuration of the double bond.
Additional evidences regarding the structures of the
benzothiazolines follow (i) from the conversion of 2-styryl-
N-tosylbenzothiazoline 29 to 2-styrylbenzothiazole 4011
(74%) by treatment with potassium tert-butoxide in DMF
and (ii) from the conversion of 2-(m-chlorostyryl) benzothia-
zoline 31 to m-chlorocinnamaldehyde 41 (73%) by treatment
with silver nitrate in Et3N-phosphate buffer according to
the procedure of Corey and Boger12 (Scheme 4) and (iii)
also from X-ray diffraction studies on 30.13
Mechanistically, the formation of benzothiazolines in-
volves the following steps (as shown in Scheme 5): (i)
1
(10) Typical H NMR data for compound 29 (300 MHz, CDCl3, TMS,
Scheme 4. Detosylation of 29 to 2-Styrylbenzothiazole 40 and
Conversion of 31 to m-Chlorocinnamaldehyde 41a
25 °C): δ ) 2.32 (s, 3H, ArCH3), 6.2 (q, J1 ) 15 Hz, J2 ) 6 Hz, 1H,
-CHdCHPh), 6.25 (d, J ) 6 Hz, 1H.; -CHCHdCHPh), 6.69 (d, J ) 15
Hz, 1H; -CHdCHPh), 7.02-7.3 (m, 10H, ArH), 7.46 (d, J ) 9 Hz, 2H,
ArH), 7.72 (d, J ) 9 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3, TMS, 25
°C): δ 21.516, 68.958, 120.87, 122.620, 125.321, 125.638, 126.853, 126.911,
127.367, 128.047, 128.374, 129.376, 130.650, 132.572, 134.539, 136.897,
144.243.
(11) Styrylbenzothiazole 40 was identical with an authentic sample (mp
111 °C) (synthesized according to the procedure of Brown D. M.; Kon, G.
A. R. J. Chem. Soc. 1948, 2147) by comparison of IR and 1H NMR spectra.
(12) Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 5.
(13) To be reported in detail elsewhere.
(14) Sonogashira, K.; Tohda, Y.; Hagihara, Y. Tetrahedron Lett. 1975,
4476.
(15) Theron, F.; Verry, M.; Vessiere, R. Rearrangement involving
acetylenes. In The chemistry of the carbon-carbon triple bond, Part I,
Chapter 10; Patai, S., Ed.; J. Wiley and Sons: Chichester, 1978; p 381.
a Reagents and conditions: (a) K-OBut in DMF; (b) AgNO3 in
Et3N-phosphate buffer (ph 7).
Org. Lett., Vol. 2, No. 3, 2000
237

the synthesis of various 2-substituted benzothiazolines. Also
since benzothiazolines have profound biological activities,16
we believe our method will be of interest to many synthetic
organic and medicinal chemists as a new general method
for the synthesis of 2-substituted benzothiazolines.17,18
India, New Delhi, under Grant 01(1385)/95/EMR-II to N.G.K.;
B.N. was a JRF and then an SRF in the above project.
Supporting Information Available: Characterization
data for products 29, 31, 40, and 41. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support has been provided by the
Council of Scientific and Industrial Research, Government of
(16) For general references, see: Metzer, J. V. Thiazoles and their Benzo
derivatives. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 6, p 235. (b) As
antihypertensive, anticoagulant, and calcium agonist: Iwao, J.; Iso, I.; Oya,
M. Jpn. Kokai Tokyo Koho JP6183, 175, Chem. Abstr. 1986, 105, 208865e.
Yamamoto, K.; Fujita, K.; Tabasi, K.; Kawashima, Y.; Kato, E.; Oya, M.;
Iso, T.; Iwao, J. J. Med. Chem. 1988, 31, 919. (c) As anticonvulsant,
vasodilators, and blood platelet aggregation inhibitors: Santen Pharmaceuti-
cal Co. Ltd. Jpn. Kokai, Tokyo Koho, JP 5967, 27 [8467, 276]; Chem. Abstr.
1985, 102, 6464a. Ucar, H.; Vanderpoorten, K.; Cacciaguerra, S.; Spam-
pinato, S.; Stables, J. P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge, J.;
Poupaert, J. H. J. Med. Chem. 1998, 41, 1138. (d) As antifungal agents:
Singh, R. V. Main Group Metal Chem. 1990, 13, 55; Chem. Abstr. 1992,
116, 2555. (e) Kanoongo, N.; Singh, R. V.; Tandon, J. P. Ind. J. Chem.,
Sect. A 1990, 29A, 560; Chem. Abstr. 1990, 113, 164355x.
OL990165G
residue was extracted with CHCl3 (2 × 25 mL) and H2O (20 mL). The
CHCl3 layer was washed with H2O (3 × 10 mL) and dried (anhydrous
Na2SO4). After removal of solvent, the residue was chromatographed on
silica gel (60-120 mesh), with the eluant being 5% ethyl acetate in light
petroleum (60-80 °C), to yield the disubstituted alkynes 19-28.
(18) General Procedure for Cyclization: The disubstituted alkynes
were tosylated with p-TsCl (1.2 equiv) in the presence of pyridine (2.0
equiv) in CH2Cl2. The tosylates (0.76 mmol) were cyclized to benzothia-
zolines with CuI (40 mol %) in Et3N (3.06 mmol) by being refluxed in
THF (10 mL) for 36 h under an argon atmosphere. After removal of solvent,
the residue was treated with H2O (10 mL) and extracted with CHCl3 (3 ×
50 mL). The CHCl3 extracts were combined, washed with H2O (3 × 10
mL), and dried (anhydrous Na2SO4) and the solvent was removed. The
residue was purified by column chromatography on silica gel (60-120
mesh), with the eluant being 5% ethyl acetate in light petroleum (60-80
°C). Compound 29 was crystallized from chloroform-petroleum ether (60-
80 °C), mp 154 °C.
(17) General Experimental Conditions: Aryl iodides 9-18 (3.6 mmol)
in CH3CN (5 mL) were stirred at rt with (PPh3)2PdCl2 (3 mol %) and CuI
(6 mol %) in the presence of Et3N (14.4 mmol) under a nitrogen atmosphere
for 1/2 h. Acetylenic compound 8 (3.67 mmol) in CH3CN (2 mL) was added,
and the solution was stirred at rt for 24 h. After removal of solvent, the
238
Org. Lett., Vol. 2, No. 3, 2000