Sequential free radical reactions with xanthates: Cyclopentane ring annulation

Article abstract of DOI:10.1055/s-1998-1946

In the presence of electron-rich alkenes, electro- and ambiphilic homoallylic radicals, generated by homolytic decomposition of the corresponding xanthates, undergo annulation with inverse electron-demand, and afford cyclopentane derivatives in moderate t

Full text of DOI:10.1055/s-1998-1946

December 1998
SYNLETT
1435
Sequential Free Radical Reactions with Xanthates: Cyclopentane Ring Annulation
V. Maslak, Æ. »ekoviÊ and R. N. SaiËiÊ*
Faculty of Chemistry, University of Belgrade, Studentski trg 16, P. O. Box 158, 11000 Belgrade, and ICTM, Center for Chemistry, Njegoseva 12,
Belgrade, Yugoslavia
Fax: (+) 381 11 636 061; E-mail: rsaicic@chem.bg.ac.yu
Received 31 August 1998
Abstract: In the presence of electron-rich alkenes, electro- and
ambiphilic homoallylic radicals, generated by homolytic decomposition
of the corresponding xanthates, undergo annulation with inverse
electron-demand, and afford cyclopentane derivatives in moderate to
good yields.
than the initial one 2, thermodynamically favourable group transfer
reaction is expected to proceed efficiently, with the formation of the
final product 6, and regeneration of 2 which continues the chain.
Starting compound 1 acts as both the radical precursor and transfer
agent. The absence of an external transfer agent is essential for the
success of the overall sequence, as the intermolecular addition of
stabilized radical 2 is not expected to be very fast; however, the transfer
step being reversible and degenerate, it does not compete with the
addition, and gives the initial radical 2 long enough life-time to undergo
even relatively slow reactions.
Free-radical reactions owe a significant part of their increasing
popularity in the synthetic community to the possibility of sequencing,
i.e. of performing multiple structural transformations via radical
1
intermediates in a one-pot reaction. A particularly useful application of
this principle is a free radical annulation which allows for the
construction of 5-membered carbocycles by an addition/cyclization
tandem, starting from two acyclic, unsaturated fragments, and formally
represents a synthetic equivalent of a homopolar 3+2 cycloaddition
2
(Scheme 1). However, due to the inherently nucleophilic character of
simple alkyl radicals, sequential reactions of this type have mostly been
restricted to electron-rich radicals and electron-deficient alkenes as the
reaction partners. Radical additions with inverse electron demand
(electron-deficient radicals with electron-rich alkenes) are possible, but
incompatible with most widely used (rapid) chain transfer agents, like
tributyltin hydride or thiohydroxamic esters: electron-withdrawing
substituents at
a radical centre stabilise the radical, decelerate
intermolecular addition, and favour its direct reaction with a transfer
agent instead. Annulations with inverse electron demand have been
successfully performed when electrophilic 3-butenyl radicals were
generated from vinylcyclopropanes (via the fragmentation of the
3
corresponding cyclopropylmethyl radicals), and also in the reactions of
propargyl and allyl α-iodomalonates and malonodinitriles with electron-
rich alkenes, under the conditions of iodine transfer, which afforded
4
Scheme 2
cyclopentane derivatives in good yields. However, some of the
aforementioned radical precursors are unstable and somewhat difficult
to prepare and purify. We endeavoured to investigate the alternative
methods of generation of carbon radicals for annulation reactions with
reversed electronic requirements, using readily available and stable
radical precursors, which would also be applicable to monosubstituted
radicals. In that respect, group-transfer reactions of xanthates seemed
To test the feasibility of this conception, four xanthate precursors, with
one or two electron-withdrawing groups at the proradical carbon atom
were prepared (Scheme 3). While 7 and 8 were obtained according to
6
previously described methods, ester and malonate xanthate derivatives
10 and 12 were synthesised directly from 9 and 11, by the reactions of
5
promising.
7
their enolates with diethyl dithiobis(thioformate) 13. This is a direct
way of transforming carbanionic centres into proradical ones, resulting
in the "umpolung" of active methylene compounds.
Given the known sensitivity of xanthates to UV light, the first annulation
experiment was performed by simply irradiating a deaerated solution of
7 in 5 mol eq of allyl acetate, (in an NMR tube), by a 250 W high
pressure mercury lamp (Method A). Under these conditions the
consumption of the starting xanthate was complete within 45 min.
Purification of the reaction mixture by column chromatography afforded
the desired cyclopentane derivative 15b in 59% isolated yield (Scheme
Scheme 1
8
4, R= CH OAc, Z= CO Et). The generality of this procedure was then
2
2
tested by submitting various combinations of xanthate precursors 7, 8,
10, 12, and alkene acceptors 14a-f to the same reaction conditions: in all
cases cyclopentane derivatives were isolated in moderate to good yields.
The results of these experiments are summarised in Table 1. The longest
reaction times and the lowest yields were observed when cyclopentene
14f was used as a radicophilic acceptor, which can be explained by the
The principle of the envisaged annulation sequence is displayed in
Scheme 2. In the presence of electron-rich alkene 3, electron-deficient
initial radical 2, formed from 1 under homolytic conditions, should
undergo addition/cyclization sequence giving rise to cyclopentylmethyl
radical 5. As the final radical 5 is non-stabilized and much more reactive

1436
LETTERS
SYNLETT
Almost all cyclized products were obtained and isolated as inseparable
mixtures of diastereoisomers. However, in some cases it was possible to
separate a single diastereoisomer by careful column chromatography,
and fully assign all signals in the NMR spectra. The lack of
stereoselectivity observed in these reactions reflects the inherent
Scheme 3
increased steric hindrance of 1,2-disubstituted alkene (entries 8, 9, 13,
and 18). Annulation reactions could also be performed, with comparable
efficiency, with chemical initiation (Method B), but cleaner reactions
9
6
reactivity of the corresponding ∆ -hexenyl radicals 4, and it is unlikely
and superior yields were obtained when the reactions were promoted by
a visible light irradiation at room temperature (Method C). With
that the diastereoselectivity could be significantly improved by changing
the reaction conditions. We hoped, however, that the reactions of cyclic
precursors and/or cyclic alkene acceptors, leading to the formation of
10
respect to radical annulations with normal electronic requirements, two
features are of note: a) reactions can be run at high concentrations of
reactants; b) no second addition of the final radical 4 to radicophilic
alkene occurs (in "standard" annulation procedures preventing this step
requires further sophistication of the reaction sequence, through the
introduction of β-elimination as the final step, stabilization of the final
radical, etc.).
bicyclic frameworks, might proceed with
a higher level of
stereoselectivity, due to additional conformational constraints in
11
transition states for both cyclization and group-transfer steps. In that
respect, it is noteworthy that the reaction of malonate derivative 12 with
cyclopentene proceeded with complete stereoselectivity, and afforded a
12
single isomer 16c (tentatively assigned as "all cis") in 30% isolated
yield (entry 18). The reaction of 10 with allyl acetate afforded 17b as a
1:1 mixture of diastereoisomers (entry 19; 8 diastereoisomers with cis
ring junction are possible); other bicyclic products, however, were
obtained as complex mixtures of diastereoisomers. Surprisingly, cyclic
xanthate precursor 10 failed to react with cyclopentene, probably due to
increased steric hindrance.
To summarise, homoallylic xanthates can serve as synthetically useful
precursors of electrophilic alkyl radicals for annulation reactions with
inverse electron demand. The ready availability of these compounds,
very mild reaction conditions, and the simplicity of the experimental
procedure make the described protocol a potentially useful complement
to the already known methods for the construction of cyclopentane
derivatives.
References and notes
1.
a) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp
715; b) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. Organic Reactions, 1996, 48, 301; c)
Jasperse, J. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91,
1237; d) Malacria, M. Chem. Rev. 1996, 96, 289.

December 1998
SYNLETT
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2.
a) Clive, D. L. J.; Angoh, A. G. Chem. Commun. 1985, 980; b)
Calcd. for C H O S : C: 51.70; H: 6.94; S: 18.40; Found: C:
15 24 5 2
51.56; H: 7.00; S: 18.37.
SaiËiÊ, R. N.; »ekoviÊ, Æ. Tetrahedron Lett. 1986, 5893; c)
Barton, D. H. R.; da Silva, E.; Zard, S. Z. Chem. Commun. 1988,
285; d) Curran, D. P.; van Elburg, P. Tetrahedron Lett. 1989, 2501;
e) SaiËiÊ, R. N.; »ekoviÊ, Æ. Tetrahedron 1992, 48, 8975;
multiple annulations: f) SaiËiÊ, R. N.; »ekoviÊ, Æ. Tetrahedron
Lett. 1994, 7845; g) Ferjancic, Z.; SaiËiÊ, R. N.; »ekoviÊ, Æ.
Tetrahedron Lett. 1997, 4165.
9.
Method B: A deaerated solution of 7 (250 mg; 1 mmol) and 14f
(680 mg; 10 mmol) in benzene (5 ml) was heated to reflux under
an argon atmosphere, while dilauroyl peroxide (20 mg) was added
every 2 h. After 10 h the reaction was complete (TLC). The
solvent was removed under reduced pressure and the product
purified by column chromatography on SiO (eluent: toluene) to
afford 121 mg (38%) of 16a as a light-yellow oil. H-NMR: 4.63
(q, J=7, 2H); 4.1 (q, J=7, 2H); 3.24 (dd, J =13, J =7.2, 1H); 3.11
2
1
3.
a) Feldman, K. S.; Romanelli, A. L.; Ruckle, R. E.; Jean, G. J.
Org. Chem. 1992, 57, 100; b) Feldman, K. S.; Romanelli, A. L.;
Ruckle, R. E.; Miller, R. F. J. Am. Chem. Soc. 1988, 110, 3300; c)
Miura, K.; Fugama, K.; Oshima, K.; Utimoto, K. Tetrahedron
Lett. 1988, 5135; d) Singleton, D. A.; Church, K. M. J. Org.
Chem. 1990, 55, 4780; e) Feldman, K. S.; Uong, A. K. K.
Tetrahedron Lett. 1990, 823.
1
2
(dd, J =13, J =7.8, 1H); 2.77 (m, 1H); 2.6-2.2 (m, 5H); 2.12-2.0
1
2
(m, 3H); 1.8-1.62 (m, 3H); 1.42 (t, J=7, 3H); 1.26 (t, J=7, 3H);
13
C-NMR: 215.14; 170.18; 69.79; 60.36; 50.26; 47.94; 46.93;
40.19; 37.66; 34.44; 33.82; 27.2; 27.0; 14.27; 13.75; IR : 2953;
2866; 1729; 1217; 1181; 1051; MS/CI (isobutane): 317 (M+1).
film
10. Method C: In a Pyrex, external water-cooled reactor, a deaerated
solution of 12 (180 mg; 0.56 mmol) and 14a (720 mg; 5.6 mmol)
in benzene (0.6 ml) was irradiated for 1.5 h with a 250W xenophot
sun-lamp focalized light, with stirring, under an argon
atmosphere. After the evaporation of solvent, the product was
4.
a) Curran, D. P.; Seong, C. M. Tetrahedron 1992, 48, 2157; b)
Curran, D. P.; Seong, C. M. Tetrahedron 1992, 48, 2175; c)
Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang, C.-
T. J. Am. Chem. Soc. 1989, 111, 8872.
purified by column chromatography on SiO (eluent: toluene) to
afford 148 mg (72%) of 15i as a light-yellow oil. H-NMR: 4.63
(q, J=7.1, 2H); 4.2 (2 x q, 4H); 3.83 (m, 1H); 3.5 (m, 1H); 3.36-
5.
6.
7.
8.
Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672; Angew.
Chem. 1997, 109, 724.
2
1
a) Phillips, D. D. J. Am. Chem. Soc. 1954, 76, 5385; b) Bridges, A.
J.; Whitham, G. H. J. Chem. Soc. Perkin Trans 1, 1975, 1603.
3.21 (dd+q, 3H); 2.65 (dd, J =14.4, J =1.6, 1H); 2.47-2.3 (m, 3H);
1
2
2.2 (dd, J =14.4, J =4.2, 1H); 1.42 (t, J=7, 3H); 1.32-1.21 (2 x t,
1
2
13
Oida, T. in: Encyclopedia of Reagents for Organic Synthesis, Ed.
Paquette, L. A., John Wiley & Sons, 1995, Vol 3, pp 2070.
6H); 1.12 (t, J=7, 3H); C-NMR: 215.2; 172.6; 171.7; 79.8; 69.8;
63.8; 61.6; 61.4; 58.6; 43.2; 38.6; 37.3; 34.7; 15.2; 13.9 (2 x CH );
3
1
13.7; IR : 3020; 2982; 1728; 1217; 1159; 1114; MS/CI
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H-NMR: 4.65 (q, J=7 Hz, 2H); 4.2-4.0 (q+m, 4H); 3.5-3.0 (series
(isobutane): 393 (M+1); Anal. Calcd. for C
H O S : C: 52.02;
17 28 6 2
of m, 2H); 2.82 (app. quint., J=8.8, 1H); 2.55-2.35 (m, 2H); 2.25-
2.05 (m, 2H); 2.08 (s, 3H); 1.9-1.7 (m, 2H); 1.42 (t, J=7, 3H); 1.25
H: 7.19; S: 16.34; Found: C: 52.29; H: 7.30; S: 16.29.
13
11. Curran, D. P.; Porter, N.; Giese, B. Stereochemistry of Radical
Reactions, VCH: Weinheim, 1995.
(t, J=7.2, 3H); C-NMR: 214.5; 175.4; 170.8; 69.8; 64.2; 60.4;
41.9; 40.5; 40.3; 36.6; 34.7; 31.8; 20.8; 14.0; 13.6; IR : 2980;
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1734; 1230; 1113; 1050; MS/CI (isobutane): 349 (M+1); Anal.
12. Ref. 11, p. 51-71.