Cyclization by intramolecular carbolithiation of alkyl- and vinyllithiums prepared by reductive lithiation: Surprising stereochemistry in the lithium oxyanion accelerated cyclization

Article abstract of DOI:10.1021/ja027988c

The versatility of intramolecular carbolithiation of simple alkenes to yield cyclopentylmethyllithiums by unconjugated organolithiums is greatly increased (1) by generating the organolithiums by reductive lithiation of phenyl thioethers with aromatic radi

Full text of DOI:10.1021/ja027988c

Published on Web 09/20/2002
Cyclization by Intramolecular Carbolithiation of Alkyl- and Vinyllithiums
Prepared by Reductive Lithiation: Surprising Stereochemistry in the Lithium
Oxyanion Accelerated Cyclization
Kai Deng, Ahlem Bensari, and Theodore Cohen*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received August 2, 2002
Scheme 1
The intramolecular addition of alkyl- and vinyllithiums to
unactivated alkenes is rapidly growing in popularity as a preparative
method for cyclopentylmethyllithiums, their heterocyclic analogues
and, less effectively, the corresponding six-membered rings.1
However, despite the highly significant work of Bailey and others,
the method still has considerable limitations. A major one is the
lack of general methods for preparing the organolithium. For the
most part, the generation methods can only be used for primary
organolithiums or those with special stabilizing features such as
adjacent heteroatom groups that direct lithiations or sp2 character
Scheme 2
of the carbon atom bearing the lithium. In most cases, the
organolithium is produced by halogen-lithium or tin-lithium
exchange or by heteroatom-directed lithiation. Another limita-
tion is the paucity of functionality in the cyclized product in most
cases.
We now demonstrate the potential for very greatly extending
the versatility of this cyclization method (1) by generating the
organolithiums by reductive lithiation of phenyl thioethers with
aromatic radical anions such as lithium 1-dimethylaminonaphtha-
lenide (LDMAN) and 4,4′-di-tert-butylbiphenylide (LDBB)2,3 and
(2) by using allylic or homoallylic alcohol groups on the receiving
alkene. This type of reductive lithiation allows virtually any kind
of organolithium to be generated, usually in a connective manner.
Furthermore, the allylic or homoallylic oxyanionic groups on the
alkene greatly accelerate the reaction and lead in most cases to
completely stereoselectiVe cyclization at -78°. Of course, the
cyclization product contains the useful alcohol function in addition
to the lithiomethyl group.
Scheme 3
Scheme 4
Scheme 1 shows what was, when it was performed, the first
example of a tertiary carbanionic cyclization4 and it occurs at a far
lower temperature than that at which such cyclizations are usually
performed. It should be noted that the unique properties of sulfur
allow rapid construction of the substrates 1 from the thioacetals of
acetaldehyde and acetone. The high trans selectivity in the
cyclization of the secondary organolithium derived from 1a was
also found by Bailey for the same organolithium produced, however,
by I-Li exchange.5
The versatility of reductive lithiation of phenyl thioethers in
carbanionic cyclizations is further illustrated by generation of the
fused cyclopentenylmethyllithium precursor of 6 in a three-pot
sequence by ring-closure of vinyllithium 5, derived from 4, which
is itself readily produced from 3.6,7 (Scheme 2).8
case. A single isomer is produced; the same cis stereochemistry
between the metallomethyl group and the oxyanionic group is
manifested in the Mg case.
As illustrated in Scheme 4,10 an allylic lithium oxyanionic group
has a powerful accelerating effect in the intramolecular carbometa-
lation by an unconjugated alkyllithium. Most intramolecular car-
bolithiations using primary alkyllithiums are performed in hexane/
ether mixtures at room temperature. One of the strong advantages
of the use of reductive lithiation is that it allows organolithium
generation in THF in which cyclizations of primary alkyllithiums
occur at -30°.3c However, the presence of the lithium oxyanionic
group allows cyclization of primary as well as tertiary alkyllithiums
to occur in THF at -78°.
Recent work from this laboratory has demonstrated that in the
cases of lithium-9a and magnesium-ene9b cyclizations, an allylic
oxyanionic group on the alkene being carbometalated not only
facilitates the cyclization but also exerts stereochemical control,
sometimes quite high, as shown in Scheme 3 for the lithium-ene
However, the most surprising result in Scheme 4 is that the single
diastereomers isolated in all four cases have the oxygen function
and the function derived from the CH2Li group on the opposite
side of the cyclopentane ring. The directing effect of the lithium
* To whom correspondence should be addressed. E-mail: cohen@pitt.edu.
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J. AM. CHEM. SOC. 2002, 124, 12106-12107
10.1021/ja027988c CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5
directing effect of allylic and homoallylic lithium oxyanionic groups
should greatly increase the versatility of intramolecular carbolithia-
tion for cyclizations.
Acknowledgment. This material is based upon work supported
by the National Science Foundation under Grant No. 0102289. We
are grateful to Dr. Fu-Tyan Lin for help in NMR spectroscopy,
Dr. Kasi Somayajula for help with the mass spectra, and MDL
Information Systems and DuPont Pharmaceutical for generous
software and database support.
Scheme 6
Supporting Information Available: Experimental procedures and
compound characterization (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Reviews: Bailey, W. F.; Ovaska, T. V. In AdVances in Detailed
Reaction Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT.;
Vol. 3, 1994; p 251-273. Mealy, M. J.; Bailey, W. F. J. Organomet.
Chem. 2002, 646, 59-67. Clayden, J. Organolithiums: SelectiVity for
Synthesis; Pergamon Press: New York, 2002; pp 293-335. The earliest
reports of such cyclizations involved Grignard reagents and are due to
the pioneering work of Richey: (b) Richey, H. G., Jr.; Rees, T. C.
Tetrahedron Lett. 1966, 36, 4297-4301. Kossa, W. C., Jr.; Rees, T. C.;
Richey, H. G., Jr. Tetrahedron Lett. 1971, 3455-3458.
Scheme 7
Scheme 8
(2) Reviews: Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152-161.
Cohen, T. In Heteroatom Chemistry; Block, E., Ed.; VCH Publishers:
New York, 1990; Chapter 7, pp 129-142. For a review of the special
method that uses a catalytic amount of the aromatic and a large excess of
lithium, see Ramo´n, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225-237.
(3) The only other examples of intramolecular carbolithiation of nonconjugated
alkyllithiums prepared by reductive lithiation are by (a) Broka, C. A.;
Shen, T. J. Am. Chem. Soc. 1989, 111, 2981-84, in which phenyl
thioethers are substrates (two examples), (b) Rychnovsky, S. D.; Hata,
T.; Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3, 807-810, in which
a nitrile was the substrate (one example), and (c) Yus, M.; Ortiz, R.;
Huerta, F. F. Tetrahedron Lett. 2002, 43, 2957-2960, in which an alkyl
chloride was the substrate. In 3c, very special conditions were required
for the tertiary case. References 3a and 3b appeared after we had completed
much of our work described herein.
oxyanionic group is complete and in the opposite sense to that in
the case of intramolecular allylmetallic carbometalations.11
Even a cyclobutanol, 12, can be generated by this method in a
three-flask reaction from commercial reactants (Scheme 5). The
stereochemistry is again exclusively trans.
As shown in Scheme 6, an sp2 organolithium is subject to the
same type of stereochemical control by an allylic lithium oxyanionic
group but with somewhat less stereoselectivity. Substrate 13 is
produced in one-pot from methyl isobutyrate.12 Note that the alkene
linkage is exo to the five-membered ring unlike the endo alkene
that is produced upon cyclization of 5.
In the cases of lithium oxyanionic participation in Schemes 3-6,
the allylic lithium oxyanionic group is positioned such that it is a
ring substituent in the cyclized organolithium. The type of allylic
lithium oxyanionic participation shown in Scheme 7, in which the
alcohol function is positioned exo to the ring, is seen to be equally
effective at promoting cyclization. The substrate 18 was readily
prepared by alkylation13 of the dianion of methallyl alcohol with
3-phenylthio-1-bromopropane.14
As shown in Scheme 8, a homoallylic lithium oxyanion placed
exo to the forming ring is even more effective than the allylic
lithium oxyanionic group derived from 8 (Scheme 4) in accelerating
the cyclization, and the stereochemistry of the product is still trans.
The substrate 20 was readily prepared by reduction of the carboxylic
acid obtained by alkylation15 of the dianion of crotonic acid with
3-phenylthio-1-bromopropane.14 On the other hand, we observed
an apparent retardation of cyclization when the homoallylic lithium
oxyanion was a substituent on the forming ring.
(4) Very recently, Rychnovsky3b and Yus3c reported one tertiary example each
by reductive lithiation of, respectively, a nitrile and a chloride.
(5) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc.
1987, 109, 2442-2448. This lone secondary example proceeded in only
44% yield.
(6) Cohen T.; Doubleday, M. D. J. Org. Chem. 1990, 55, 4784-86.
(7) Use of Montmorillonite clay for the production of 3: Labiad, B.; Villemin,
D. Synthesis 1989, 143-44; use of a cuprate for regiocontrol in the
allylation: Giner, J. L.; Margot, C.; Djerassi, C. J. Org. Chem. 1989, 54,
2117-2125.
(8) Cyclization of the cyclohexenyllithium, generated by the Shapiro reaction
from 2-homoallylated cyclohexanone, gives a different regioisomer of 5:
Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. J. Am. Chem.
Soc. 1988, 110, 4788-4796.
(9) (a) Cheng, D.; Knox, K. R.; Cohen, T. J. Am. Chem. Soc. 2000, 122,
412-13. (b) Cheng, D.; Zhu, S.; Yu, Z.; Cohen, T. J. Am. Chem. Soc.
2001, 123, 30-34.
(10) The substrates 7 are prepared in one-flask reactions from commercial
materials; Chen, F.; Mudryk, B.; Cohen, T. Tetrahedron 1999, 55, 3291-
3304.
(11) We suspect that the lithium oxyanions can participate in a nucleophilic
fashion in metallo-ene cyclizations, which proceed via 6-center transition
states, but prefer participation in an electrophilic fashion in alkyllithium
cyclizations, which proceed via 4-center transition states. This concept
will be further elaborated in a full article.
(12) Cohen, T.; Gapinski, R. E.; Hutchins, R. R. J. Org. Chem. 1979, 44, 3599-
3601.
(13) Lipshutz, B. H.; Sharma, S.; Dimock, S. H.; Behling, J. R. Synthesis 1992,
191-195.
(14) Bakuzis, P.; Bakuuzis, M. L.; Fortes, C. C.; Santos, R. J. Org. Chem.
1976, 41, 2769-2770.
(15) Aurell, M. J.; Gil, S.; Mestres, R., Parra, M.; Parra, L. Tetrahedron 1998,
54, 4357-4366.
The combined powers of reductive lithiation of phenyl thioethers
to prepare substrates and of the accelerating and remarkable
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