Radical cascade involving a 5-endo-trig cyclization of α-amidoyl radicals

Article abstract of DOI:10.1016/S0040-4039(01)02200-6

Bu₃SnH-mediated radical reactions of aryl bromides 4 gave pyrrolo[1,2-b]- and isoindolo[2,1-b]isoquinoline derivatives 11 through a radical cascade process involving a 6-endo-trig cyclization of an aryl radical and a 5-endo-trig cyclization of

Full text of DOI:10.1016/S0040-4039(01)02200-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 473–475
Radical cascade involving a 5-endo-trig cyclization of
a-amidoyl radicals
Hiroyuki Ishibashi,* Atsuko Ishita and Osamu Tamura
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 6 September 2001; accepted 16 November 2001
Abstract—Bu SnH-mediated radical reactions of aryl bromides 4 gave pyrrolo[1,2-b]- and isoindolo[2,1-b]isoquinoline derivatives
3
1
1 through a radical cascade process involving a 6-endo-trig cyclization of an aryl radical and a 5-endo-trig cyclization of an
a-amidoyl radical. © 2002 Elsevier Science Ltd. All rights reserved.
Radical cascade approaches to polycyclic compounds
are now widely used in organic and natural products
syntheses. To evaluate the synthetic utility of new
radical reactions, these methods have frequently been
applied to radical cascade processes. We recently
reported the first example of a 6-endo selective aryl
radical cyclization onto a simple alkenic bond. Enam-
examined the radical cascades of a range of N-acryloyl
congeners 4 to determine the feasibility of using a
5-endo-trig radical cyclization of a-amidoyl radicals 5.
In this paper, we describe the viability of this sequence
for the synthesis of pyrrolo[1,2-b]- and isoindolo[2,1-
1
3
b]isoquinolines.
ides 1, on treatment with Bu SnH in the presence of
We initiated our investigation by examining the cycliza-
tion of enamide 4a, which was prepared from amine 7
according to the procedure illustrated in Scheme 2. A
3
2
ACN (azobiscyclohexanecarbonitrile) in boiling tolu-
ene, underwent 6-endo-trig aryl radical cyclization to
give tetrahydroisoquinolines 3 via intermediate a-ami-
toluene solution of 4a was treated at reflux with a
2
doyl radicals 2 (Scheme 1). In the present study, we
solution of 1.5 equiv. of Bu SnH and a catalytic
3
Br
Bu3SnH
•
N
ACN
N
R
R
N
R
O
O
O
1
2
3
Br
R1
R2
R1
R1
•
N
5-endo-trig
Products
N
N
R2
• R2
O
O
O
5
6
1
2
4
4
4
4
4
a: R = R = H
1
2
b: R = Me, R = H
1
2
c: R = H, R = Me
1
2
d: R = R = Me
1
2
e: R , R = –(CH2)4–
Scheme 1.
Keywords: aryl halides; enamides; cyclisation; radical and radical reactions.
*
Corresponding author. Fax: +81 76 234 4476; e-mail: isibasi@dbs.p.kanazawa-u.ac.jp
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02200-6

4
74
H. Ishibashi et al. / Tetrahedron Letters 43 (2002) 473–475
amount of ACN in toluene over a period of 3.5 h to
give a complex mixture of products, from which three
products, 8a, 9a, and 10a, were isolated in 11, 13 and
4c acts as an effective radical-stabilizing group for the
1 2
radical 6 (Scheme 1: R =H, R =Me) generated by
5-endo-trig cyclization of a-amidoyl radical 5. The
methyl group might also prevent the formation of the
6-exo cyclization product such as 9 due to steric
reasons.
4
4
3
% yields, respectively (Scheme 3). Unfortunately,
enamide 4a gave no expected radical cascade product.
Formation of 9a and 10a might be a result of 6-exo and
7-endo aryl radical cyclizations with the N-acryloyl
group, respectively. The N-crotonoyl congener 4b also
Encouraged by the success in obtaining the radical
cascade product 11c from 4c, we next turned our
attention to the tiglyl derivative 4d. Treatment of 4d
gave no radical cascade product and afforded only the
6
-endo and 6-exo aryl radical cyclization products 8b
and 9b in 39 and 28% yields, respectively. In this
instance, no 7-endo cyclization product 10b was formed
with Bu SnH/ACN in boiling toluene gave 8d, 10d and
3
11d in 18, 3 and 57% yields, respectively (Scheme 4).
1
(
Scheme 3).
The H NMR spectrum of 11d indicated it to be a
mixture of two stereoisomers in a ratio of ca. 3:2. The
N-crotonoyl derivative 4b, having a b-methyl sub-
stituent on the acryloyl group, gave no 5-endo-trig
cyclization product, indicating that the b-methyl sub-
stituent does not play a part in effecting the 5-endo-trig
cyclization of a-amidoyl radicals. In this context, it is of
interest that the yield of 11d (57%) was much higher
than that of 11c (26%). Similarly, enamide 4e afforded
The reason for the low overall yield of 8a and 9a is
obscure at the moment, since the starting enamide 4a
and the products 8a and 9a were relatively stable in
boiling toluene and only a limited quantity of the
simple reduction product was formed.
We soon found, however, that treatment of the N-
4
methacryloyl congener 4c with Bu SnH/ACN gave the
isoindolo[2,1-b]isoquinoline derivative 11e in 36% yield
3
expected radical cascade product, 1,2,3,5,10,10a-hexa4-
hydro-2-methylpyrrolo[1,2-b]isoquinolin-3-one (11c),
in 26% yield as a mixture of two stereoisomers in a
ratio of ca. 3:2, together with 8c and 10c in 25 and 8%
yields, respectively (Scheme 4).
as a single stereoisomer, along with 8e and trans-10e in
5
31 and 4% yields, respectively (Scheme 5). The stereo-
chemistry of 11e, as depicted in Scheme 5, was con-
firmed by NOE experiments.
5
-endo-trig Ring-closure has been recognized as a
Formation of 11c strongly suggests that the methyl
substituent at the a-position of the N-acryloyl group of
stereoelectronically disfavored process not only for het-
erolytic reactions, but also for homolytic cyclizations.
6
O
SPh
Br
SPh
1) MCPBA
R1 2) heat
NaHCO3
R1
Br
Cl
R2
4a-e
NH
NEt3
N
R2
7
O
Scheme 2.
R
CH2R
Br
Bu3SnH
ACN
R
R
O
O
N
toluene
reflux
N
N
N
O
O
4a: R = H
8a: R = H (11%)
9a: R = H (13%)
10a: R = H (3%)
4b: R = Me
8b: R = Me (39%)
9b: R = Me (28%)
10b: R = Me (0%)
Scheme 3.
R
Br
Me
H
1
R
Bu3SnH
R
R
0a
1
ACN
toluene
reflux
O
N
N
N
N
Me
Me
2
Me
O
O
8c: R = H (25%)
8d: R = Me (18%)
O
4
c: R = H
10c: R = H (8%)
10d: R = Me (3%)
11c: R = H (26%)
11d: R = Me (57%)
4d: R = Me
Scheme 4.

H. Ishibashi et al. / Tetrahedron Letters 43 (2002) 473–475
475
H
H
H
Bu3SnH
H
O
ACN
toluene
reflux
11b
11a
7
4e
a
N
N
N
trans-10e: 4%
H
O
O
8
e: 31%
11e: 36%
Scheme 5.
However, not unnaturally, several exceptions to this
39, 75–78; (d) Baker, S. R.; Parsons, A. F.; Wilson, M.
Tetrahedron Lett. 1998, 39, 2815–2818; (e) Davies, D. T.;
Kapur, N.; Parsons, A. F. Tetrahedron Lett. 1998, 39,
4397–4400; (f) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.;
Zard, A. Z. Tetrahedron Lett. 1998, 39, 8995–8998; (g)
Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, A. Z.
Tetrahedron 1998, 54, 1029–1040; (h) Ikeda, M.; Ohtani,
S.; Yamamoto, T.; Sato, T.; Ishibashi, H. J. Chem. Soc.,
Perkin Trans. 1 1998, 1763–1768; (i) Ikeda, M.; Ohtani, S.;
Sato, T.; Ishibashi, H. Synthesis 1998, 1803–1806; (j) Clark,
A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh,
J. P. Tetrahedron Lett. 1999, 40, 8619–8623; (k) Cassayre,
J.; Zard, S. Z. Synlett 1999, 501–503; (l) Baker, S. R.;
Burton, K. I.; Parsons, A. F.; Pons, J.-F.; Wilson, M. J.
Chem. Soc., Perkin Trans. 1 1999, 427–436; (m) Ikeda, M.;
Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1999, 1949–
7
,8
guideline have been discovered. Quite recently, the
first example of 5-endo-trig cyclization of an a-amidoyl
9,10
radical has also been reported.
Although many
examples are required to determine the factors involved
in effecting the 5-endo-trig cyclization of a-amidoyl
radicals, the present method may be useful for the
synthesis of poly-heterocyclic compounds.
References
1. For reviews, see: Malacria, M. Chem. Rev. 1996, 96,
2
89–306; McCarrol, A. J.; Walton, J. C. Angew. Chem., Int.
Ed. Engl. 2001, 40, 2225–2248.
2
3
. Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura,
O. Chem. Commun. 2000, 1527–1528.
. During the course of the present study, Murphy et al.
reported a radical cascade reaction involving a 5-exo-trig
cyclization of an aryl radical and a 5-endo-trig cyclization
of the resulting alkyl radical, see: Bommezijn, S.; Martin,
C. G.; Kennedy, A. R.; Lizos, D.; Murphy, J. A. Org. Lett.
1
1
956; (n) Ishibashi, H.; Toyao, A.; Takeda, Y. Synlett 1999,
468–1470; (o) Ishibashi, H.; Matsukida, H.; Toyao, A.;
Tamura, O.; Takeda, Y. Synlett 2000, 1497–1499; (p)
Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.;
Muraoka, O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett.
2001, 42, 1729–1732. See also references cited therein.
2
001, 3, 3405–3407.
8
. For other 5-endo-trig cyclizations, see: (a) Gimisis, T.;
Chatgilialoglu. J. Org. Chem. 1996, 61, 1908–1909; (b)
Yamamoto, Y.; Ohno, M.; Eguchi, S. J. Org. Chem. 1996,
4
. Spectroscopic data for products (diagnostic data only). 9a:
−
1 1
IR (CHCl ) 1675 cm ; H NMR (CDCl , 270 MHz) l 1.53
3
3
(
(
d, 3H, J=7.3 Hz, Me), 3.65 (q, 1H, J=7.3 Hz, 4-H), 4.55
dd, 1H, J=9.2, 1.3 Hz), 4.64 (dd, 1H, J=16.2, 1.3 Hz),
61, 9264–9271; (c) Journet, M.; Rouillard, A.; Cai, D.;
−
1
Larsen, R. J. Org. Chem. 1997, 62, 8630–8631; (d) Cai, Y.;
Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1998,
7
.58 (dd, 1H, J=16.2, 9.2 Hz). 10a: IR (CHCl ) 1670 cm ;
3
1
H NMR (CDCl , 270 MHz) l 3.05 (br t, 2H, J=ca. 7 Hz),
3
467–475; (e) Nonami, Y.; Baran, J.; Sosnicki, J.; Mayr, H.;
3
.25 (br t, 2H, J=ca. 7 Hz), 4.46 (dd, 1H, J=9.2, 1.3 Hz),
Masuyama, A.; Nojima, M. J. Org. Chem. 1999, 64,
4060–4063; (f) Bogen, S.; Gulea, M.; Fensterbank, L.;
Malacria, M. J. Org. Chem. 1999, 64, 4920–4925; (g)
Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999,
4
.63 (dd, 1H, J=16.2, 1.3 Hz), 7.37 (dd, 1H, J=16.2, 9.2
−
1 1
Hz). 11c: IR (CHCl ) 1675 cm ; H NMR (CDCl , 270
MHz) l 1.27 (d, 3H, J=6.9 Hz, Me for both isomers A
and B), 1.35–1.46 (m, 3/5H, one of 1-H for isomer A),
1
3
3
.94–2.15 (m, 2/5×3H, 1-H and 2-H for isomer B), 2.52–
.70 (m, 3/5×3H, one of 1-H, 2-H and one of 10-H for
6
4, 7081–7093; (h) Orito, K.; Uchiito, S.; Satoh, Y.;
Tatsuzawa, T.; Harada, R.; Tokuda, M. Org. Lett. 2000,
, 307–310; (i) Clive, D. L. J.; Yang, W.; MacDonald, A.
C.; Wang, Z.; Cantin, M. J. Org. Chem. 2001, 66, 1966–
983. See also references cited therein.
2
isomer A), 3.61–3.74 (m, 3/5H, 10a-H for isomer A),
2
3
.72–3.84 (m, 2/5H, 10a-H for isomer B). 11e: IR (CHCl )
3
−
1 1
1
675 cm ; H NMR (CDCl , 270 MHz) l 2.18 (dq, 1H,
3
1
J=4.3, 6.9 Hz, 11a-H), 2.53 (q, 1H, J=6.9 Hz, 7a-H), 3.46
dt, 1H, J=11.6, 4.3 Hz, 11b-H).
9
. Gribble et al. reported that hexahydropyrrolo[3,4-
b]indoles were obtained from 2-bromo-3-carboxamides
(
5
6
7
. A small quantity of cis-10e was also obtained as a mixture
of the simple reduction product.
through a Bu SnH-mediated 1,5-radical translocation pro-
3
cess followed by 5-endo-trig cyclization of the resulting
a-amidoyl radicals onto the indole C-2 position. See:
Gribble, G. W.; Fraser, H. L.; Badenock, J. C. Chem.
Commun. 2001, 805–806.
. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
7
36–738.
. For effective 5-endo-trig cyclizations of N-vinylic car-
bamoylmethyl radicals, see: (a) Ishibashi, H.; Nakamura,
N.; Sato, T.; Takeuchi, M.; Ikeda, M. Tetrahedron Lett.
10. For unsuccessful examples of 5-endo-trig radical cycliza-
tion of a-amidoyl radicals, see: Burnet, D. A.; Choi, J.-K.;
Fart, D. J.; Tsai, Y-.M. J. Am. Chem. Soc. 1984, 106,
8201–8209; Beckwith, A. L. J.; Boate, D. R. Tetrahedron
Lett. 1985, 26, 1761–1764.
1
991, 32, 1725–1728; (b) Sato, T.; Nakamura, N.; Ikeda,
K.; Okada, M.; Ishibashi, H.; Ikeda, M. J. Chem. Soc.,
Perkin Trans. 1 1992, 2399–2407; (c) Ishibashi, H.;
Higuchi, M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1998,