Regioselective unusual formation of spirocyclic 4-{2′-benzo(2′, 3′-dihydro)furo}-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole by 4-exo-trig aryl radical cyclization and rearrangement

Article abstract of DOI:10.1021/ol061531g

4-(2′-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b] indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished exclusively the 4-{2′-benzo(2′,3′-dihydro)furo}-9-methyl-2,3, 9-trihydrothiopyrano[2,3-b]indoles in exce

Full text of DOI:10.1021/ol061531g

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4059-4062
Regioselective Unusual Formation of
Spirocyclic
4-{2′-Benzo(2′,3′-dihydro)furo}-
9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole
by 4-exo-trig Aryl Radical Cyclization
and Rearrangement
K. C. Majumdar* and S. Alam
Department of Chemistry, UniVersity of Kalyani, Kalyani 741235, India
kcm_ku@yahoo.co.in
Received June 22, 2006
ABSTRACT
4-(2
′
-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished
-benzo(2 ,3 -dihydro)furo -9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles in excellent yield (75 80%) via 4-exo-trig cyclization,
exclusively the 4-
{2′
′
′
}
−
opening of the oxetene ring, and 5-endo-trig cyclization.
The use of C-C bond forming aryl radical cyclization for
the construction of heterocyclic rings is an important reaction
in synthetic organic chemistry.1 There are some reports on
the synthesis of oxygen-containing heterocyclic compounds
by aryl radical cyclization.2 A pentenyl radical (1) can cyclize
either in a 4-exo-trig manner or in a 5-endo-trig manner to
give radicals 2 and 3, respectively (eq 1, Scheme 1). In the
4-exo-trig process, however, the ring opening and cyclization
between 2 and 1 is reversible due to the high degree of strain
present in the four-membered ring 2,3 which usually shifts
the equilibrium to the starting radical 1. On the other hand,
the 5-endo-trig process is recognized as a disfavored process
due to stereoelectronic disadvantage in the attack of the
(1) (a) Todd, M. H.; Ndubaku, C.; Bartlett, P. A. J. Org. Chem. 2002,
67, 3985. (b) Zhou, S.-Z.; Bommezijn, S.; Murphy, J. A. Org. Lett. 2002,
4, 443. (c) Turiso, F. G.-L.; Curran, D. P. Org. Lett. 2005, 7, 151. (d)
Ishibashi, H.; Ohata, K.; Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 547. (e) Escolano, C.; Jones, K. Tetrahedron Lett.
2000, 41, 8951. (f) Escolano, C.; Jones, K. Tetrahedron 2002, 58, 1453.
(g) Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 4237. (h) Lizos, D. E.;
Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117 (i) Majumdar, K. C.;
Biswas, A.; Mukhopadhyay, P. P. Synthesis 2003, 2385. (j) Majumdar, K.
C.; Mukhopadhyay, P. P.; Biswas, A. Tetrahedron Lett. 2005, 46, 6655.
(2) (a) Smith, T. W.; Butler, G. B. J. Org. Chem. 1978, 43, 6. (b)
Bowman, W. R.; Mann, E.; Parr, J. J. Chem. Soc., Perkin Trans. 1 2000,
2991. (c) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.; Sarkar, S.;
Ghosh, S. K.; Biswas, P. Tetrahedron 2003, 59, 2151. (d) Zhang, W.; Pugh,
G. Tetrahedron Lett. 2001, 42, 5613.
Scheme 1. Two modes of Cyclization of the Pentenyl Radical
and the Related Aryl Radical
10.1021/ol061531g CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/01/2006

radical center of 1 at the alkenic bond.4 So, there have been
few reports on either 5-endo-trig5 or 4-exo-trig6 radical
cyclization of the pentenyl radical and related species. The
four-membered ring is known to possess a higher degree of
strain and generally 5-endo-trig cyclization becomes facile
over 4-exo-trig cyclization. The substituents and temperature
also control the mode of cyclization.7 But a higher degree
of stability of the four-membered radical intermediate
sometimes favors the 4-exo-trig cyclization.8 Here we have
examined whether 4-exo-trig or 5-endo-trig cyclization would
be facile for an aryl radical of the type 4 (eq 2, Scheme 1).
The required precursors for our present study 4-(2′-
bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano-
[2,3-b]indoles (10a-f) were synthesized in 80-86% yield
by the thio-Claisen rearrangement of 2-(4′-aryloxybut-2′-
ynylthio)-1-methylindoles (9a-f). The compounds 9a-f in
turn were prepared in 90-94% yield by the reaction of
1-methylindoline-2-thione (7) and 1-aryloxy-4-chlorobut-2-
yne (8a-f) under phase transfer catalysis conditions, using
benzyltriethylammonium chloride (BTEAC) as a phase
transfer catalyst (Scheme 2).
lower activation energy perhaps due to lower aromaticity of
the pyrrole ring of the indole moiety. The sulfides 9a-f on
refluxing in chlorobenzene (132 °C) for 1 h afforded the
compounds 10a-f (Scheme 2).
Formation of the products 10 may be explained10 by an
initial [3,3] sigmatropic rearrangement of the sulfide segment
in substrates 9 followed by enolization to give the allenyl-
ene-thiols (12) which may then undergo [1,5] H shift and
6π-electrocyclic ring closure to afford the endocyclic inter-
mediate 4-aryloxymethyl-9-methyl-2,9-dihydrothiopyrano-
[2,3-b]indole (14, not isolated). These may then undergo
tautomerism to give the exocyclic double bonded11 compound
10 (Scheme 3).
Scheme 3. Mechanism of thio-Claisen Rearrangement
Scheme 2. Preparation of Sulfides and Enol Ethers
The products 10 contain a suitably placed o-bromoaryl
group with respect to the double bond of the enol ether.
Therefore, compound 10a was treated with Bu3SnH (1.1
equiv) in toluene at 80 °C in the presence of a radical initiator
(AIBN, 0.5 equiv) for 4 h. A white crystalline solid 15a,12
mp 156-158 °C, was obtained in 80% yield (Scheme 4).
Scheme 4. Aryl radical Cyclization of Enol Ethers
The sulfides 9a-f contain the but-2-ynylindole-2-yl sulfide
moiety as well as the arylprop-2-ynyl ether moiety. The thio-
Claisen rearrangement9 in the sulfide moiety may require
(3) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato, T.; Ikeda,
M. J. Org. Chem. 1995, 60, 1276 and references therein.
(4) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(5) (a) Majumdar, K. C.; Sarkar, S.; Bhattacharrya, T. Tetrahedron 2003,
59, 4309. (b) Bommezijn, S.; Martin, C. G.; Kennedy, A. R.; Lizos, D.;
Murphy, J. A. Org. Lett. 2001, 3, 3405. (c) Ishibashi, H.; Nakamura, N.;
Sato, T.; Takeuchi, M.; Ikeda, M. Tetrahedron Lett. 1991, 32, 1725. (d)
Bogen, S.; Gulea, M.; Fensterbank, L.; Malacria, M. J. Org. Chem. 1999,
64, 4920. (e) Gao, J.; Rusling, J. F. J. Org. Chem. 1998, 63, 218. (f)
Ishibashi, H.; Fuke, Y.; Yamashita, T.; Ikeda, M. Tetrahedron: Asymmetry
1996, 7, 2531. (g) Goodall, K.; Parsons, A. F. Tetrahedron Lett. 1997, 37,
491.
(6) (a) Castle, K.; Hau, C.-S.; Sweeney, J. B.; Tindall, C. Org. Lett. 2003,
5, 757. (b) Piccardi, P.; Modena, M.; Cavalli, L. J. Chem. Soc. C 1971,
3959. (c) Belletire, J. L.; Hagedorn, C. E.; Ho, D. M.; Krause, J. Tetrahedron
Lett. 1993, 34, 797. (d) Ishibashi, H.; Kameoka, C.; Ueda, R.; Kodama,
K.; Sato, T.; Ikeda, M. Synlett 1993, 649. (e) Ishibashi, H.; Kameoka, C.;
Kodama, K.; Ikeda, M. Tetrahedron 1996, 52, 489. (f) Ishibashi, H.;
Kodama, K.; Kameoka, C.; Kawanami, H.; Ikeda, M. Tetrahedron 1996,
52, 13867. (g) Ishibashi, H.; Kameoka, C.; Kodama, K.; Kawanami, H.;
Hamada, M.; Ikeda, M. Tetrahedron 1997, 53, 9611.
The structure of the product 15a was confirmed by its
single-crystal X-ray diffraction study (Figure 1) and was
characterized as 4-{2′-benzo(2′,3′-dihydro)furo}-9-methyl-
2,3,9-trihydrothiopyrano[2,3-b]indole.
4060
Org. Lett., Vol. 8, No. 18, 2006

Scheme 5. Mechanism of Aryl Radical Cyclization
Figure 1. X-ray crystal structure of 15a.
Substrates 10b-f under similar treatment gave the prod-
ucts 15b-f in 75-80% yield (Table 1). Surprisingly we
failed to obtain here the expected product 16 and or 17
(Scheme 4) as 16 type product was obtained in the case of
another enol ether.5a
In case of the aryl radical cyclization of 10, formation of
the products 15 is quite unusual. It may be noted that initially
Table 1. Yield of Aryl Radical Cyclization Products 15a-f
generated aryl radical 18 could have undergone either
5-endo-trig or 4-exo-trig cyclization at the enol ether part
of the diene 10. The 5-endo-trig cyclization would have
generated the radical 19, which would have provided 16, or
4-exo-trig cyclization could have generated the four-
membered radical intermediate 20, which could have yielded
17. The other less probable options were 6-exo-trig versus
7-endo-trig onto the ene-amine part of the diene 10.
However, none of these options can explain the formation
of 15.
(7) (a) Ikeda, M.; Ohtani, S.; Yamamoto, T.; Sato, T.; Ishibashi, H. J.
Chem. Soc., Perkin Trans. 1 1998, 1763. (b) Ishibashi, H.; Higuchi, M.;
Ohba, M.; Ikeda, M. Tetrahedron Lett. 1998, 39, 75. (c) Ponaras, A. A.;
Zaim, O. Tetrahedron Lett. 1993, 34, 2879.
(8) (a) Ishibashi, H.; Kodama, K.; Higuchi, M.; Muraoka, O.; Tanabe,
G.; Takeda, Y. Tetrahedron 2001, 57, 7629. (b) Sato, T.; Nakamura, N.;
Ikeda, K.; Okada, M.; Ishibashi, H.; Ikeda, M. J. Chem. Soc., Perkin Trans.
1 1992, 2399. (c) Fremont, S. L.; Belletire, J. L.; Ho, D. M. Tetrahedron
Lett. 1991, 32, 2335. (d) Araki, Y.; Endo, T.; Arai, Y.; Tanji, M.; Ishido,
Y. Tetrahedron Lett. 1989, 30, 2829. (e) Gill, G. B.; Pattenden, G.; Reynolds,
S. J. Tetrahedron Lett. 1989, 30, 3229.
(9) (a) Majumder, K. C.; Kundu, U. K.; Ghosh, S. K. Org. Lett. 2002,
4, 2629. (b) Majumdar, K. C.; Bandyopadhyay, A.; Biswas, A. Tetrahedron
2003, 59, 5289.
(10) Majumdar, K. C.; De, R. N.; Khan, A. T.; Chattopadhyay, S. K.;
Dey, K.; Patra, A. J. Chem. Soc., Chem. Commun. 1988, 777.
(11) (a) Majumdar, K. C.; Jana, G. H. Synthesis 2001, 924. (b) Majumdar,
K. C.; Ghosh, S. Tetrahedron 2001, 57, 1589. (c) Majumdar, K. C.;
Bhattacharyya, T. Synthesis 2001, 1568.
(12) 1H NMR (CDCl3, 300 MHz): δH 2.15-2.25 (dt, 1H, J ) 13, 2.1
Hz, -SCH2CH2), 2.66-2.73 (ddd, 1H, J ) 13.4, 6, 1.6 Hz, -SCH2SCH2),
3.03-3.10 (ddd, 1H, J ) 12.7, 6, 2.1 Hz, -SCH2CH2), 3.17-3.22 (d, 1H,
J ) 16.3 Hz, ArCH2), 3.38-3.47 (dt, 1H, J ) 12.8, 1.6 Hz, -SCH2CH2),
3.63 (s, 3H, -NCH3), 3.98-4.04 (d, 1H, J ) 16.3 Hz, ArCH2), 6.75-7.38
(m, 8H, ArH).13C NMR (CDCl3, 125 MHz): δC 25.66, 30.28, 39.31, 42.10,
84.97, 108.84, 109.41, 110.08, 118.87, 120.39, 120.75, 121.34, 125.43,
126.48, 126.96, 128.79, 133.38, 138.00, 159.06. MS: m/z 307 (M+).
Org. Lett., Vol. 8, No. 18, 2006
4061

The formation of 15 is explicable by a 4-exo-trig cycliza-
tion of the initially generated aryl radical 18 at the enol ether
part of the diene to give the more stable radical 20 rather
than radical 19. The stability is due to the overlapping of
the p-orbital of the radical center of 20 with the neighboring
π-system of the indole moiety. The highly strained oxetene
ring may undergo ring opening leading to the formation of
a resonance stabilized aryloxy radical 21 rather than aryl
radical 18. The aryloxy radical 21 may then undergo 5-endo-
trig cyclization to give stable benzylic radical 22 followed
by abstraction of a hydrogen radical to afford the unusual
product 15 (Scheme 5).
It may therefore be concluded that the furan ring in 15 is
formed not via initial 5-endo-trig cyclization but through the
occurrence of an initial 4-exo-trig cyclization followed by
5-endo-trig cyclization of the resultant aryloxy radical
intermediate formed by the opening of the oxetene ring of
the radical intermediate. We have been able to achieve the
successful synthesis of spirocyclic indole annulated oxygen
heterocyclic compounds in excellent yield by aryl radical
cyclization. The methodology described here is mechanisti-
cally interesting and synthetically useful and exhibits ap-
preciable regioselectivity.
Acknowledgment. We thank the CSIR (New Delhi) for
financial assistance. One of us (S.A.) is grateful to UGC
(New Delhi) for a Senior Research fellowship. We are
thankful to Dr. A. T. Khan, IITG, for XRD of compound
15a. We also thank the DST (New Delhi) for providing UV-
VIS and IR spectrometers under the DST-FIST program.
1
Supporting Information Available: H NMR spectra for
compounds 15a-f, 13C NMR spectra for compounds 15a,b,
mass spectra for compounds 15a,b,d,e, and crystallographic
information files (in CIF firmat) for compound 15a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061531G
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Org. Lett., Vol. 8, No. 18, 2006