Annulation of the Cyclohexane Ring by Tandem Free Radical Alkylation of a Nonactivated δ-carbon Atom-Intramolecular Carbanion Cycloalkylation

Article abstract of DOI:10.1021/ol0062401

formula presented Annulation of the cyclohexane ring by a combination of free radical and ionic reactions sequences was achieved. Free radical alkylation of the remote nonactivated δ-carbon atom involves addition of δ-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates, to radicophilic olefins, while the polar sequence involves enolate anions as intermediates which undergo a cycloalkylation reaction. Thus, the cyclohexane ring was constructed using diverse acyclic and cyclic structures as precursors of alkoxy radicals.

Full text of DOI:10.1021/ol0062401

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3769-3772
Annulation of the Cyclohexane Ring by
Tandem Free Radical Alkylation of a
Nonactivated δ-Carbon
Atom−Intramolecular Carbanion
Cycloalkylation
Goran Petrovic and Zivorad Cekovic*
Faculty of Chemistry, UniVersity of Belgrade, Studentski trg 16, P.O Box 158,
11000 Belgrade, Serbia, YugoslaVia
zcekoVic@.chem.bg.ac.yu
Received June 21, 2000 (Revised Manuscript Received September 21, 2000)
ABSTRACT
Annulation of the cyclohexane ring by a combination of free radical and ionic reactions sequences was achieved. Free radical alkylation of
the remote nonactivated δ-carbon atom involves addition of δ-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates,
to radicophilic olefins, while the polar sequence involves enolate anions as intermediates which undergo a cycloalkylation reaction. Thus, the
cyclohexane ring was constructed using diverse acyclic and cyclic structures as precursors of alkoxy radicals.
Recently we discovered that δ-carbon radicals, generated by
1,5-hydrogen transfer in alkoxy radical intermediates, un-
dergo intermolecular addition to activated olefins with the
introduction of a functionalized alkyl chain at a remote
nonactivated carbon atom.1-3 In these sequential free radical
reactions, hydroxy compounds possessing an electron-
withdrawing group at the 6-position are obtained, offering
the possibility for cyclohexane ring closure by an intra-
molecular alkylation reaction involving enolate anions.
combination of a free radical sequence of reactions and an
intramolecular carabanion alkylation reaction (Scheme 1).
Scheme 1
Herein a new method for the construction of the cyclo-
hexane ring by free radical δ-alkylation of nonactivated
carbon atoms and a subsequent anionic cyclization reaction,
which could be complementary to the Robinson annulation,
is described. Thus, starting from alkyl benzenesulfenate 1
as a precursor of alkoxy radicals and activated olefin 2,
annulation of cyclohexane ring 4 was achieved by a
(1) Petrovic, G.; Cekovic, Z. Tetrahedron Lett. 1997, 38, 627. Petrovic,
G.; Cekovic, Z. Tetrahedron 1999, 55, 1377.
(2) Petrovic, G.; Saicic, R. N.; Cekovic, Z. Tetrahedron Lett. 1997, 38,
7107.
This cyclohexane ring annulation methodology was veri-
fied using various structurally different alkyl arenesulfenates
as alkoxy radical precursors. Thus, substituted cyclohexane
(3) Petrovic, G.; Saicic, R. N.; Cekovic, Z. Synlett 1999, 635.
10.1021/ol0062401 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000

Table 1. Annulation of the Cyclohexane Ring by a Free Radical and Carbanionic Sequence of Reactions Using Methyl Vinyl Ketone
as the Activated Olefin
derivatives (5 and 6) were obtained by using open chain alkyl
arenesulfenates and methyl vinyl ketone as an activated
(radicophilic) olefin, while decaline derivative 4 was obtained
from 2-cyclohexylethyl benzenesulfenate. By the appropriate
selection of starting compounds, a spirobicyclohexane de-
rivative (8) was prepared, and annulation of a cyclohexane
ring on adamantane (9) and the steroid skeleton (10) was
achieved (all results are summarized in Table 1.).
Alkyl arenesulfonates 11 were used as precursors of alkoxy
radicals 12.1,4 The alkylation of the nonactivated δ-carbon
atom was carried out by irradiation of the alkyl arene-
sulfenates in the presence of tributyltin hydride and 10 molar
3770
Org. Lett., Vol. 2, No. 24, 2000

Scheme 2
equiv of methyl vinyl ketone as the activated olefin 2.5 The
and converted to the corresponding ketone enolate anions
16. In the presence of a suitably disposed sulfonate leaving
group, an intramolecular alkylation takes place and cyclo-
hexane ring 17 is formed with an exocyclic electron-
withdrawing group.9 We propose that 8-endo-cycloalkylation,
with the formation of the cyclooctane ring, could also occur
if the formation of the enolate anion is performed under
kinetic conditions.10
Cycloalkylation reaction of the open chain or cyclic
sulfonate esters 15 with appropriate positions and stereo-
chemical orientation of the reacting centers is a favorable
reaction. However, when the stereochemical relations are not
suitable for intramolecular alkylation, an elimination occurs
as a side reaction to give unsaturated products.
The importance of stereochemistry in the cycloalkylation
reaction was observed in the reaction of the enolate anion
18, derived from a compound obtained by δ-alkylation of
(-)-menthyl benzenesulfenate with methyl vinyl ketone.
Possesing an equatorial leaving group, the enolate anion 18
does not undergo a substitution reaction but rather undergoes
an elimination reaction to give the unsaturated compound.11
To carry out the cycloalkylation reaction, the hydroxyl group
in the δ-alkylated product obtained from (-)-menthyl
benzenesulfenate was epimerized to the axial position (via
the p-nitrobenzoate ester).12 The enolate anion 19, derived
from the corresponding keto-methanesulfonate with an axial
leaving group, undergoes intramolecular substitution to give
the bicylic product 7. However, in addition to the bicyclic
product 7, the unsaturated compound 20 was also formed as
a product of the elimination reaction (yields of 53% and 34%,
δ-carbon radicals 13, generated by 1,5-hydrogen transfer in
the alkoxy radical 12,6 undergo intermolecular addition to
give δ-alkylated products 14 (Scheme 2).1,7 Products of the
free radical alkylation at the δ-carbon atom were isolated
and fully characterized.
The hydroxyl group in the alkylated products 14 was
converted to the corresponding toluenesulfonate or meth-
anesulfonate ester 15 by reaction with sulfonyl chlorides in
pyridine.8 In the next step, the sulfonate esters were reacted
with sodium hydride in DME under equilibrium conditions
(4) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem. Soc., Chem.
Commun. 1989, 1202.
(5) Typical experiment: A solution of 3-cyclohexylpropyl-O-p-nitroben-
zenesulfenate ester (0.15 g; 0.51 mmol), methyl vinyl ketone (0.35 g; 5.1
mmol; 10 equiv excess), and tributyltin hydride (0.16 g; 0.55 mmol) in
benzene (40 mL) was irradiated at rt with visible light (xenon lamp 250
W, λ > 300 nm or by UV lamp) for 1 h in an argon atmosphere. After
reaction was completed, the benzene was evaporated and the residual oil
was dissolved in ether (50 mL) and washed with an aqueous NaF solution
(0.5 g in 10 mL). The ethereal solution was separated and the aqueous
solution extracted with ether (2 × 20 mL). The ethereal solutions were
dried (anhydrous Na2SO4), and by evaporation of the ether, an oily alkylation
product was obtained, which was dissolved in toluene and purified by dry
flash chromatography using petroleum ether:acetone 95:5 as eluent. 4-[(3-
Hydroxypropyl)cyclohexyl]butan-2-one was obtained as a pale yellow oil
(50 mg; 47% yield). IR (film): 3405, 1713, 1596, 1519, 1459, 1416, 1358,
1
1339, 1164, 1057, 1018, 964, 918, 852, 822 cm-1. H NMR (CDCl3, 200
MHz) δ: 0.91 (t, J ) 7.2 Hz, 2H), 1.21-1.61 (m, 14H), 1/93 (s, broad,
1H), 2.16 (s, 3H), 2.29-2.38 (m, 2H), 3.61 (t, J ) 6.4 Hz, 2H). 13C NMR
(CDCl3, 50 MHz) δ: 210.01, 63.52, 37.71, 35.58, 33.92, 3252, 30.42, 29.88,
27.67, 26.92, 26.27. 26.09, 21.41. The hydroxy ketone was converted to
the corresponding tosylate which was treated with sodium hydride in DME
to give 1-spiro[5.5]undec-2-ylethanone (8) as a colorless oil (10 mg; 77%
yield). IR (film): 1709, 1451, 1372, 1354, 1270, 1236, 1189, 1164, 964,
903, 843 cm-1. 1H NMR (CDCl3, 200 MHz) δ: 0.89-1.90 (m, 18H), 2.13
(s, 3H), 2.50 (tt, Jaa ) 12.2 Hz, Jae ) 3.4 Hz, 1H). 13C NMR (CDCl3, 50
MHz) δ: 212.84 (C), 46.68 (CH), 41.82, 38.75, 35.83 (CH2), 32.65 (C),
32.14, 28.71 (CH2), 27.93, (CH3), 26.78, 21.47. 20.67 (CH2). MS (CI): 195
(M + 1) 100%.
(6) Mihailovic, M. Lj.; Cekovic, Z. Synthesis 1970, 209. Kalvoda, J.;
Heusler, K. Synthesis 1971, 501. Barton, D. H. R. Pure and Appl. Chem.
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51, 7095. Tsunoi, S.; Ryu, I.; Okuda, T.; Tanaka, M.; Komatsu, M.; Sonoda,
N. J. Am. Chem. Soc. 1998, 120, 8692. Dorigo, A. E.; Houk, K. N. J. Org.
Chem. 1988, 53, 1650.
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M. J. Org. Chem. 1983, 48, 4241.
(9) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: 1991; Vol. 3, Chapter 1 and references
therein. Caine, D. In Carbon-Carbon Bond Formation; Augustune, R. L.,
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Org. Lett., Vol. 2, No. 24, 2000
3771

respectively). It is well-known that the intramolecular
cycloalkylation reaction is less favorable when the leaving
group (i.e., sulfonate ester group) is attached to a secondary
carbon atom and the elimination of the leaving group
becomes a serious side reaction.11
Scheme 3
The 1,3-disubstituted cyclohexane derivative 6 obtained
by the described sequence of reactions from an open chain
nonbranched alkyl benzenesulfenate, such as n-octyl ben-
zenesulfenates, has cis-stereochemistry because the “axial”
interaction of the substituents disfavor the transition state
leading to trans-1,3-disubstituted cyclohexane derivatives.
One stereoisomer, 4, was also obtained in the annulation of
the cyclohexane ring starting from 2-(cyclohexyl)ethyl p-
nitrobenzenesulfenate and methyl vinyl ketone because the
addition of the intermediary cyclohexane-centered radical (of
type 13) to the methyl vinyl ketone preferentially takes place
from the equatorial side to give the trans diequatorial
intermediary product, which upon cycloalkylation gives the
trans-decaline derivative 4 (see Scheme 1 and Table 1.).
Annulation of a cyclohexane ring into the steroid skeleton
was realized by the free radical alkylation of the C-18 angular
methyl group of pregnene-20â-O-p-nitrobenzenesulfenate
derivative by methyl vinyl ketone followed by the intra-
molecular alkylation of the intermediary keto mesylate. Thus,
ring E was constructed and the 18,20-ethanopregnene 10
derivative was obtained in 25.6% overall yield (Table 1).
The intermediary products of the free radical δ-alkylation,
the tosylates and mesylates, as well as the products of
annulation were completely characterized.
arenesulfenates 23 (Scheme 3). The cyclohexane derivatives,
21, formed by applying this methodology contain only an
exocyclic electron-withdrawing group. Herein the presented
method could be complementary to the Robinson annulation
of the cyclohexenone ring,14 24, which also requires two
fragments: conjugated and saturated ketones 26 and 25 and
two procarbanionic carbon atom (Scheme 4).
Scheme 4
The described sequence of free radical and carbanion
reactions offers a new method for annulation of a cyclohex-
ane ring which requires two fragments: an activated olefin
(i.e., Michael acceptor) and a four-carbon-atom chain, 22,
with a proalkoxy radical functional group, preferably alkyl
Supporting Information Available: General experimen-
tal procedures and full characterization for compounds 5, 6,
and 8. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) Curran, D. P.; Eichenberger, E.; Collis, M.; Roepel, M. G.; Thoma,
G. J. Am. Chem. Soc. 1994, 116, 4279. Schubert, S.; Renaud, P.; Carrupt,
P.-A.; Schenk, K. HelV. Chim. Acta 1993, 76, 2473.
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R. E. Synthesis 1976, 777. Bergman, E. D.; Gingberg, D.; Pappo, R. Org.
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5934.
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