Novel intramolecular (4 + 1) and (4 + 2) annulations of halopolyenes by cascade radical reaction

Article abstract of DOI:10.1021/ol0002323

(matrix presented) Free radical reaction of vinyl iodides having dinenoate function in the presence of tributyltin hydride or tris(trimethylsilyl)silane caused a sequential cyclization reaction to produce (4 + 1) and (4 + 2) annulated compounds by means o

Full text of DOI:10.1021/ol0002323

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3579-3581
Novel Intramolecular (4 + 1) and
(4 + 2) Annulations of Halopolyenes by
Cascade Radical Reaction
,†
Kiyosei Takasu,* Jun-ichi Kuroyanagi, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received August 14, 2000
ABSTRACT
Free radical reaction of vinyl iodides having dinenoate function in the presence of tributyltin hydride or tris(trimethylsilyl)silane caused a
sequential cyclization reaction to produce (4 + 1) and (4 + 2) annulated compounds by means of a cascade radical reaction. Stereogenic
centers of the cascade reaction were highly controlled. On the contrary, the cathodic electrolysis of the vinyl iodides afforded monocyclic
compounds.
Intramolecular annulation reactions of polyenes have received
much attention as a powerful methodology to construct bi-
or polycyclic framework in organic synthesis and have been
utilized as key reactions for the total synthesis of natural
products.1 Diels-Alder reaction, 1,3-dipolar addition, and
[2 + 2] cycloaddition have been intensely explored. Recently,
the annulation methods catalyzed by transition metals,2,3 for
example, cobalt,3a rhodium,3b and palladium,3c have been
exceedingly developed. We have been interested in the
intramolecular annulation reactions, such as the intramo-
lecular double Michael reaction4 and the Michael-aldol
† E-mail: kay-t@mail.pharm.tohoku.ac.jp.
(1) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Per-
gamon Press: Oxford, 1990.
(2) For a review, see: Leutens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49-92.
(3) Representative examples. (a) Cobalt: Dzwiniel, T. L.; Etkin, N.;
Stryker, J. M. J. Am. Chem. Soc. 1999, 121, 10670-10641. (b) Rhodium:
O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998, 443-
445. Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love,
J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121, 10442-10443. (c)
Palladium: Trost, B. M.; Chan, D. M. J. Am. Chem. Soc. 1982, 104, 3733-
3735.
(4) (a) For a review, see: Ihara, M.; Fukumoto, K. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1010-1022. (b) Ihara, M.; Makita, K.; Takasu, K. J.
Org. Chem. 1999, 64, 1259-1264. (c) Takasu, K.; Mizutani, M.; Noguchi,
M.; Makita, K.; Ihara, M. J. Org. Chem. 2000, 65, 4112-4119 and
references cited therein.
reaction,5 to construct polycyclic skeletons. In the above
reactions, a nucleophilic function of substrates changes
character to that of an electrophile after the initial reaction,
and an electrophilic group acts as a nucleophile in a second
reaction. That is, the reaction center moves stepwise from
one functional group back to the same one via other
functional groups. We applied the concept for the cascade
radical reactions6,7 (Figure 1). We envisaged that the vinyl
radical can act as both radical donor and acceptor during
(5) (a) Ihara, M.; Ohnishi, M.; Takano, M.; Makita, K.; Taniguchi, N.;
Fukumoto, K. J. Am. Chem. Soc. 1992, 114, 4408-4410. (b) Takasu, K.;
Ueno, M.; Ihara, M. Tetrahedron Lett. 2000, 41, 2145-2148 and references
cited therein.
(6) For reviews of cascade radical reactions, see: (a) Curran D. P. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack,
M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 818-827. (b) Jasperse,
C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 7-1286. (c)
Malacria, M. Chem. ReV. 1996, 96, 289-306.
(7) For recent examples of cascade radical reactions, see: (a) Journet,
M.; Malacria, M. J. Org. Chem. 1994, 59, 6885-6886. (b) Devin, P.;
Fensterbank, L.; Malacria, M. J. Org. Chem. 1998, 63, 6764-6765. (c)
Haney, B. P.; Curran, D. P. J. Org. Chem. 2000, 65, 2007-2013.
(8) (a) Takasu, K.; Kuroyanagi, J.; Katsumata, A.; Ihara, M. Tetrahedron
Lett. 1999, 40, 6277-6280. (b) Toyota, M.; Yokota, M.; Ihara, M.
Tetrahedron Lett. 1999, 40, 1551-1554.
(9) (a) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto,
K. J. Org. Chem. 1996, 61, 677-684. (b) Katsumata, A.; Takasu, K.; Ihara,
M. Heterocycles 1999, 51, 733-736.
10.1021/ol0002323 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Scheme 2
Figure 1.
a Bu3SnH and AIBN were added dropwise over 1 h. b Hydride
and AIBN were added dropwise over 2 h.
the same reaction. Recently we reported cascade radical
reactions of halopolyenes, which involved (2 + 1) annulation,
utilizing this feature.8 Herein, we describe (4 + 1) and (4 +
2) annulation reactions of iodoolefins tethered with dienoate
function as novel radical cascade reactions.
In an initial experiment, we examined the radical reaction
of dienoate 1 under two conditions, use of tributyltin hydride
(TBTH)-AIBN as a radical generator or cathodic electroly-
sis9 mediated by nickel(II) cyclam (Scheme 1). Dienoate 1
of 4 was slowly added a benzene solution of TBTH (1.2
equiv) and AIBN (0.5 equiv) over 1 h. After an additional 2
h of reflux, bicyclic product 5 and monocyclic 6 were
obtained in 40 and 20% yields, respectively (run 1). The
slower addition (over 2 h) of the reagents afforded only 5 in
63% yield as a single diastereomer (run 2).10 When tris-
(trimethylsilyl)silane (TTMSH) was used as a radical source
in the presence of AIBN, a result similar to that above was
obtained (run 3). The transformation resulted in a cascade
5-exo, 6-endo cyclization process to give the isoindole
skeleton, that is, an intramolecular (4 + 2) annulation has
occurred. No reaction of 4 proceeded without radical sources
under reflux conditions in benzene (entry 4), that is, the (4
+ 2) annulation is not the result of a Diels-Alder reaction.
On the contrary, indirect cathodic electrolysis11 of 4 provided
only 6 in 85 and 86% yields at ambient temperature or at
100 °C, respectively (runs 5 and 6). The structures of 512
and 612 were assigned on the basis of 1D and 2D NMR
spectroscopies.
Scheme 1
Modification of the substrate in the vicinity of the
iodovinyl moiety, however, has induced a different mode of
annulation. The treatment of 7, which has a longer tether
a Bu3SnH and AIBN were added dropwise over 1 h.
(10) General procedure for the reaction with TBTH: To a stirred
solution of the vinyl iodide (40 µmol) in degassed benzene (20 mL) were
added dropwise a solution of Bu3SnH (48 µmol) and AIBN (20 µmol) in
benzene (4 mL) over 2 h using a syringe pump under reflux. After being
stirred for 2 h, the solution was concentrated. The resulting residue was
chromatographed on silica gel (4:1 v/v).
was chosen as a probe because the radical deiodation of 1
followed by cyclization would generate the intermediate 2
possessing the stabilized captodative radical (acylvinyl
radical), which can be expected to introduce succeeding
radical cyclization. However, both of the conditions afforded
only monocyclic product 3, which has a trans-â,γ-unsatur-
ated ester moiety. The result suggested that the captodative
radical intermediate was produced after the first cyclization
stage, but the sequential cyclization would be prohibited by
the trans geometry of the intermediate.
We considered that the introduction of a bulky substituent
at the â-position would control the desired configuration of
the intermediates to promote sequential cyclization. The
radical reactions of â-phenyl-substituted dienoate 4 were
summarized in Scheme 2. To a refluxing benzene solution
(11) The electrolysis was carried out under conditions similar to those
of ref 8a.
(12) Spectral data for compound 5: colorless needles (from Et2O); mp
176-178 °C; IR (neat) ν 2950, 1730, 1340, 1160, 1090, 660 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 7.74 (d, J ) 8.5 Hz, 2H), 7.34-7.16 (m, 7H),
5.88 (dd, J ) 4.9, 1.8 Hz, 1H), 3.69 (m, 2H), 3.53 (dd, J ) 10.1, 6.7 Hz,
1H), 3.38 (s, 3H), 3.13 (dd, J ) 10.1, 1.8 Hz, 1H), 3.05 (t, J ) 9.7 Hz,
1H), 2.81 (m, 1H), 2.43 (s, 3H), 2.36 (m, 1H), 1.92 (dt, J ) 13.4, 4.9 Hz,
1H), 1.54 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 174.1, 143.4, 140.7,
137.8, 133.7, 129.7, 128.3, 127.5, 127.3, 125.5, 53.1, 51.9, 51.7, 44.6, 38.3,
35.1, 28.6, 21.5; MS m/z 411 (M+). Anal. Calcd for C23H25NO4S: C, 67.13;
H, 6.12; N, 3.42; S, 7.79. Found: C, 66.99; H, 6.28; N, 3.36; S, 7.88.
Compound 6: colorless oil; IR (neat) ν 2950, 1730, 1590, 1340, 1160,
1090, 660 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J ) 8.0 Hz, 2H),
7.33-7.27 (m, 5H), 7.12 (dd, J ) 7.4, 2.2 Hz, 2H), 5.25 (d, J ) 9.5 Hz,
3580
Org. Lett., Vol. 2, No. 23, 2000

than 4, with TBTH or TTMSH in the presence of AIBN
afforded bicyclic product 812 as a sole stereoisomer (runs 1
and 2 in Scheme 3). The reaction of 10, which has a cis-
It was found that the mode of annulation was highly
dependent on the substrates. Structural reinforcement of the
intermediates that were formed after the first radical cycliza-
tion would be important for the regio- and stereoselectivity
in the second cyclization step. Although the detailed reaction
mechanism must still be clarified, possible conformations
of the intermediates can drawn to explain the substrate-
controlled selectivity observed (Figure 2). At the second
Scheme 3
a Hydride and AIBN were added dropwise over 2 h.
iodovinyl function, under the same conditions gave a
diastereomeric mixture of 11 (R:â ) 3:2) (runs 1 and 2,
Scheme 4). Both of the reactions using TBTH or TTMSH
Figure 2. Transition state model.
cyclization step in the reaction of 4, the regioselective 6-endo
addition was predominant over 5-exo addition. On the other
hand, the trajectory from 7 and 10 was preferentially 5-exo.
The difference of the regioselectivity might be caused by
the conformational rigidity of the pyrrolidine or piperidine
ring. The diastereoselectivity for the reaction of 4 could be
induced from the steric repulsion between the phenyl
substituent and the ester moiety (see 13A and 13B). Thus,
the less repulsive conformation 13A conceded the isoindole
5. The stereoselective production of 8 from 7 would be
mainly derived from the repulsion among the phenyl ring,
the ester group, and the axially oriented hydrogen on the
piperidine ring (see 14A and 14B).
Scheme 4
a Diastereomeric ratio; R:â ) 3:2. b Hydride and AIBN were
In summary, we have developed a novel ring formation
method based on the cascade radical reaction. The reaction
provides (4 + 2) or (4 + 1) annulated compounds, whose
regio- and stereoselectivities were highly dependent on the
structure of the substrates. Further studies for the generaliza-
tion of the methodology and the development of more than
three-step cascade radical reactions are under investigation.
added dropwise over 2 h.
proceeded via a tandem 6-exo, 5-exo cyclization to furnish
(4 + 1) cycloadducts. On the other hand, the electrolysis of
7 and 10 afforded monocyclic products 9 and 12, respectively
(runs 3 in Schemes 3 and 4).
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Encouragement of Young Scientists (No.
12771347) from the Ministry of Education, Science, Sports
and Culture, Japan.
1H), 4.94 (m, 2H), 3.96 (d, J ) 15.0 Hz, 1H), 3.69 (dd, J ) 15.0, 1.9 Hz,
1H), 3.60-3.55 (m, 4H), 3.34 (s, 2H), 3.24 (m, 1H), 2.84 (t, J ) 9.5 Hz,
1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.6, 147.4, 143.8, 139.0,
138.2, 132.9, 129.8, 128.6, 128.5, 128.0, 127.8, 127.7, 108.4, 53.4, 51.9,
51.8, 44.2, 43.2, 21.5; MS m/z 411 (M+); HRMS m/z calcd for C23H25-
NO4S 411.1503, found 411.1483. Compound 8: colorless oil; IR (neat) ν
2950, 1720, 1590, 1330, 1220, 1150, 1090, 750 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.66 (d, J ) 8.2 Hz, 2H), 7.38-7.24 (m, 7H), 6.34 (s, 1H), 3.83
(d, J ) 12.5 Hz, 1H), 3.66 (s, 3H), 3.55 (m, 1H), 3.41 (s, 1H), 2.94 (br s,
1H), 2.53 (dd, J ) 12.5, 4.2 Hz, 1H), 2.43 (s, 3H), 2.46-2.34 (m, 1H),
1.97 (td, J ) 12.5, 4.2 Hz, 1H), 1.46 (d, J ) 12.5 Hz, 1H), 1.05 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 172.8, 1435, 140.6, 134.9, 133.5, 132.1,
129.7, 128.5, 127.8, 127.6, 125.4, 63.1, 51.8, 49.4, 44.8, 43.3, 42.7, 34.7,
21.5, 19.2; MS m/z 425 (M+); HRMS m/z calcd for C24H27NO4S 425.1659,
found 425.1679.
Supporting Information Available: Synthetic procedures
for key substrates and characterization data for selected
compounds 3-12. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0002323
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