Heteroaryl radicals: A furyl radical in the synthesis of the tricyclic framework of eremophilane sesquiterpenoids

Article abstract of DOI:10.1055/s-2005-871925

Studies on the intramolecular addition of thieno and furan radicals to alkenyl groups are reported. The radicals undergo a 6-endo-trig selective cyclization to alkenyl systems resulting in a linearly annulated tricyclic moiety. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-2005-871925

LETTER
1951
Heteroaryl Radicals: A Furyl Radical in the Synthesis of the Tricyclic
Framework of Eremophilane Sesquiterpenoids
H
eteroarylRa
a
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(322)2282252; E-mail: jkray@chem.iitkgp.ernet.in
Received 3 May 2005
Abstract: Studies on the intramolecular addition of thieno and
furan radicals to alkenyl groups are reported. The radicals undergo
a 6-endo-trig selective cyclization to alkenyl systems resulting in a
O
O
O
H
OH
H
linearly annulated tricyclic moiety.
A
Glaucescenolide
Key words: radical reactions, cyclizations, furans, terpenoids
Scheme 1
The use of radical reactions, and in particular a radical
reaction cyclization sequence, has been of great interest to
organic chemists.1 Organotin-mediated intramolecular
aryl–radical cyclizations have emerged as useful synthetic
methods for benzo-fused ring structures.2 Ring closures of
aryl radicals, as in the case of alkyl radicals, readily pro-
ceed via 5-exo and 6-exo pathways, generating five- and
six-membered rings.3 Ghatak and co-workers4a–e reported
a potentially useful route to certain linearly benzannulated
six- to nine-membered ring structures through Bu3SnH-
induced endo-trig aryl–radical cyclizations. Pyridine-
ring-fused six-, seven-, and eight-membered-ring annulat-
ed polycyclic compounds were also synthesized very re-
cently;4f also homolytic reactions for the heteroaromatic
series were investigated.5 There is also precedent for
radical ipso-type substitution onto aryl rings.6
As a part of our ongoing investigation into the generation
and reactions of radicals formed from heteroaromatic
compounds, we prepared 2-bromo-3-bromomethyl
thiophene derivatives 2, which could serve as radical pre-
cursors. Bromination of 2-bromo-3-methyl thiophene
with NBS in carbon tetrachloride afforded compound 2 in
very good yield.
The desired alkene 6 was derived from Hagemann’s ester
1. We initially converted 1 to 5 by adapting a known
three-step procedure.12 Wittig olefination of the ketone 5
with a phosphonium salt and BuLi in THF furnished
compound 6 in 68% yield. The radical cyclization of 6 in
refluxing benzene with Bu3SnH and a catalytic amount of
AIBN at high dilution afforded 5,5-dimethyl-
4,4a,5,6,7,8,8a,9-octahydro-naphtho[2,3-b]thiophene (7)
in 60% yield as the only isolable product (Scheme 2).
The furanoeremophilanes, bearing a furan moiety fused to
the decalin core, belong to a structurally diverse class of
sesquiterpenoids. The linearly fused furan ring is em-
bodied in a large number of natural products, particularly,
in some insect anti-feeding compounds such as petasal-
bine, ligularone, atractylon etc.,7 which possess unique
structural features; this has triggered the synthesis of such
compounds.8,9 However, to date there have been no re-
ports on the synthesis of furanoeremophilane frameworks
through radical cyclization. In 2002 Perry et al.10 isolated
a bioactive natural product, Glaucescenolide, which con-
tains a novel carbon skeleton. Very recently Takikawa et
al.11 have synthesized Glaucescenolide in vitro using
tricyclic intermediate A (Scheme 1). Amongst various
approaches aimed at the synthesis of these types of skele-
tons, we examined the possibilities of using radical reac-
tions, as they usually avoid acidic or basic conditions,
which is a prerequisite for handling such systems.
Unfortunately, when we attempted to convert 3-methyl-
furan to 2-bromo-3-bromomethylfuran by the same pro-
cedure we could not isolate the desired compound, as it
Br
O
S
O
S
S
Br
Br
(i)
EtO2C
EtO2C
3
2
1
(ii)
Br
Br
CH2
Br
O
O
S
(iv)
S
(iii)
6
4
5
H
H
(v)
S
7
Scheme 2 Reagents and conditions: (All the reactions were carried
under an argon atmosphere) (i) t-BuOK, t-BuOH, reflux, 10 h (63%);
(ii) KOH, EtOH–H2O, reflux, 8 h (49%); (iii) Me2CuLi, BF3·Et2O,
Et2O, –50 °C (15 min), then –30 °C (1 h) (71%); (iv) Ph3P+CH3I–, Bu-
Li, THF, –30 °C to r.t. (3 h) (68%); (v) Bu3SnH, AIBN, benzene, re-
flux, 8 h, (60%).
SYNLETT 2005, No. 12, pp 1951–1953
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871925; Art ID: G15205ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
8
.2
0
0
5

1952
S. K. Mal et al.
LETTER
polymerized readily at room temperature.13 The analo-
gous 3-bromo-2-chloromethylfuran was stable and
alkylation of Hagemann’s ester 1 with 3-bromo-2-chlo-
romethylfuran and t-BuOK in t-BuOH under reflux af-
forded compound 9 as a viscous yellow oil in 58% yield.
Hydrolysis and decarboxylation of 9 with KOH/EtOH–
H2O furnished 2-(3-bromofuran-2-ylmethyl)-3-methyl-
cyclohex-2-enone (10) in 48% yield. The saturated ketone
11 was synthesized from the cyclohexenone derivative 10
with Gilman’s reagent (Me2CuLi). Wittig olefination of
the ketone 11 resulted in the formation of 3-bromo-2-(2,2-
dimethyl-6-methylenecyclohexylmethyl)furan (12) in
67% yield.
Radical cyclization14 of the unsaturated bromofuran 12
with Bu3SnH initiated with a catalytic amount of AIBN in
refluxing benzene at high dilution afforded exclusively
the cyclohexane-ring-annulated furan 13 as the only isol-
able product (Scheme 3). The assigned structures of 7 and
13 were established by spectral and elemental analyses.15
The trans-geometry of the newly generated ring junction
was derived from the spectral data and by analogy with
known compounds.4e
References
(1) (a) Malacria, M. Chem. Rev. 1996, 96, 289. (b) Parsons, P.
J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
(c) McCarrol, A. J.; Walton, J. C. Angew. Chem. Int. Ed.
2001, 40, 2224. (d) Renaud, P.; Sibi, M. P. Radicals in
Organic Synthesis, Vol. 1; Wiley-VCH: Weinheim, 2001.
(e) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis,
Vol. 2; Wiley-VCH: Weinheim, 2001.
(2) For reviews, see (a) Giese, B.; Kopping, B.; Göbel, T.;
Dickhaut, T.; Thoma, G.; Kulicke, K. J.; Trach, F. Org.
React. (N.Y.) 1996, 48, 301. (b) RajanBabu, T. V. In
Encyclopedia of Reagents for Organic Synthesis, Vol. 7;
Paquette, L., Ed.; Wiley: New York, 1995, 5016.
(c) Jaseperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev.
1991, 91, 1237. (d) Aldabbagh, F.; Bowman, W. R.
Contemp. Org. Synth. 1997, 4, 261. (e) Banik, B. K. Curr.
Org. Chem. 1999, 3, 469.
(3) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996. (b) Majumdar,
K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron 2004,
60, 6239.
(4) (a) Ghosh, A. K.; Mukhopadhyaya, J. K.; Ghatak, U. R. J.
Chem. Soc., Perkin Trans. 1 1997, 2747; and references
cited therein. (b) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U.
R. J. Org. Chem. 1994, 59, 2687. (c) Ghosh, A. K.; Ghosh,
K.; Pal, S.; Ghatak, U. R. J. Chem. Soc., Chem. Commun.
1993, 809. (d) Ghosh, K.; Ghosh, A. K.; Ghatak, U. R. J.
Chem. Soc., Chem. Commun. 1994, 629. (e) Pal, S.;
Mukherjee, M.; Podder, D.; Mukherjee, A. K.; Ghatak, U. R.
J. Chem. Soc., Chem. Commun. 1991, 1591. (f) Maiti, S.;
Achari, B.; Mukhopadhyay, R.; Banerjee, A. J. Chem. Soc.,
Perkin Trans. 1 2002, 1769.
(5) (a) Vernin, G.; Metzger, J.; Parkanyi, C. J. Org. Chem. 1975,
40, 3183. (b) Benati, L.; Capella, L.; Montevecchi, P. C.;
Spagnolo, P. J. Org. Chem. 1995, 60, 7941. (c) Roy, S. C.;
Rana, K. K.; Guin, C. J. Org. Chem. 2002, 67, 3242.
(d) Mayer, S.; Bambaoud, J. P.; Guillou, O. Tetrahedron
1998, 54, 8753. (e) Martinez-Barrasa, V.; de Viedma, A. G.;
Burgos, C.; Alvarez-Builla, J. Org. Lett. 2000, 2, 3933.
(6) (a) Kyei, A. S.; Tchabanenko, K.; Baldwin, J. E.; Adlington,
R. M. Tetrahedron Lett. 2004, 45, 8931. (b) Nandi, A.;
Mukhopadhyay, R.; Chattopadhyay, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 24, 3346. (c) Sloan, C. P.; Cuevas, J.
C.; Quesnelle, C.; Snieckus, V. Tetrahedron Lett. 1988, 29,
4685. (d) Demircan, A.; Parsons, P. J. Eur. J. Org. Chem.
2003, 1729. (e) Parsons, P. J.; Penverne, M.; Pinto, I. L.
Synlett 1994, 721. (f) Parsons, P. J.; Demircan, A. Synlett
1998, 1215. (g) Ghosh, T.; Hart, H. J. Org. Chem. 1989, 54,
5073.
Br
O
O
Br
(i)
Cl
EtO2C
O
EtO2C
CH2
O
O
8
9
1
(ii)
Br
Br
Br
O
(iii)
(iv)
O
O
O
12
11
10
H
(v)
O
13
H
Scheme 3 Reagents and conditions: (All the reactions were carried
out under an argon atmosphere) (i) t-BuOK, t-BuOH, reflux, 12 h
(58%); (ii) KOH, EtOH–H2O, reflux, 8 h (48%); (iii) Me2CuLi,
BF3·Et2O, Et2O, –50 °C (15 min), then –30 °C (1 h) (75%); (iv)
Ph3P+CH3I–, BuLi, THF, –30 °C to r.t., 3 h (67%); (v) Bu3SnH, AIBN,
benzene, reflux, 8 h, (46%).
In conclusion, it has been shown that it is possible to
generate radicals at the C-2 position of thiophene and C-3
position of the furan ring and for these to undergo
intramolecular cyclization reactions to provide a quick
access to a range of interesting natural and unnatural
tricyclic frameworks. Further investigations on the gener-
ality of this type of endo-selective heteroaryl–radical
cyclization, as a potential synthetic gateway to a variety of
new ring-fused heterocyclic structures of general interest,
are in progress.
(7) (a) Ishii, H.; Tozyo, T.; Minato, H. Tetrahedron 1965, 21,
2605. (b) Musman, M.; Tanaka, J.; Higa, T. J. Nat. Prod.
2001, 64, 111.
(8) (a) Shanmugham, M. S.; White, J. D. Chem. Commun. 2004,
44. (b) Honan, M. C. Tetrahedron Lett. 1985, 26, 6393; and
references cited therein. (c) Yamakawa, K.; Satoh, T. Chem.
Pharm. Bull. 1978, 26, 3704. (d) Cooper, J. A.; Cornwall,
P.; Dell, C. P.; Knight, D. W. Tetrahedron Lett. 1988, 29,
2107.
(9) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In Total Synthesis of Natural Products, Vol. 5;
ApSimon, J., Ed.; Wiley: New York, 1983, 202.
(10) Scher, J. M.; Burgess, E. J.; Lorimer, S. D.; Perry, N. B.
Tetrahedron 2002, 58, 7875.
Acknowledgment
(11) Takikawa, H.; Ueda, K.; Sasaki, M. Tetrahedron Lett. 2004,
45, 5569.
(12) Mal, S. K.; Kar, G. K.; Ray, J. K. Tetrahedron 2004, 60,
2805.
Financial support from DST, CSIR & UGC (New Delhi) (for a
fellowship to S.M. and S.S.) is gratefully acknowledged.
Synlett 2005, No. 12, 1951–1953 © Thieme Stuttgart · New York

LETTER
Heteroaryl Radicals
1953
(13) Prugh, J. D.; Huitric, A. C.; McCarthy, W. C. J. Org. Chem.
1964, 29, 1991.
(15) Spectral data of representative compounds.
5,5-Dimethyl-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-
b]thiophene (7)
(14) Radical cyclization of 6 and 12 with Bu3SnH
To a solution of 6 or 12 (50 mg, 0.227 mmol or 0.245 mmol)
in degassed anhyd benzene (30 mL) heated under reflux
were added Bu3SnH (1.5 equiv) and AIBN (5 mg, 0.02
mmol) in degassed anhyd benzene (20 mL) slowly by
syringe pump. The addition of Bu3SnH was carried out over
2 h and the mixture was heated under reflux for 8 h. The
solvent was removed under reduced pressure, Et2O (20 mL)
and a sat. aq solution of KF (20 mL) were added to the
residue; the whole mixture was stirred at r.t. for 24 h. The
organic phase was separated, washed with brine, dried, and
concentrated. Purification was carried out by
1H NMR (CDCl3, 200 MHz): d = 0.88 (s, 3 H), 0.96 (s, 3 H),
1.25–1.59 (m, 8 H), 2.27–2.41 (m, 2 H), 2.62–2.88 (m, 2 H),
6.73 (d, 1 H, J = 5.11 Hz), 7.02 (d, 1 H, J = 5.11 Hz); MS
(EI, 70 ev): m/z = 220 (M+); Anal. Calcd for C14H20S: C,
76.30; H, 9.15. Found: C, 76.45; H, 9.25.
8,8-Dimethyl-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-
b]furan (13)
1H NMR (CDCl3, 200 MHz): d = 0.88 (s, 3 H), 0.96 (s, 3 H),
1.21–1.58 (m, 8 H), 1.71–2.71 (m, 4 H), 6.15 (br s, 1 H), 7.22
(br s, 1 H); ESI-MS: m/z = 205.12 [M + H]+; Anal. Calcd for
C14H20O: C, 82.30; H, 9.87. Found: C, 82.65; H, 9.76.
chromatography(hexane).
Synlett 2005, No. 12, 1951–1953 © Thieme Stuttgart · New York