The 5-endo-trig cyclization of gem-difluoroolefins with sp3 carbon nucleophiles: Synthesis of 1-fluorocyclopentenes

Article abstract of DOI:10.1246/cl.2002.282

A disfavored 5-endo-trig cyclization is accomplished in gemdifluoroolefins with sp³ carbon nucleophiles, generated via the lithium - iodine exchange reaction of 1, 1-difluoro-5-iodo-1-pentenes with tert-butyllithium, to afford 1-fluorocyclopentenes.

Full text of DOI:10.1246/cl.2002.282

282
Chemistry Letters 2002
The 5-endo-trig Cyclization of gem-Difluoroolefins with sp3 Carbon Nucleophiles:
Synthesis of 1-Fluorocyclopentenes
Junji Ichikawaꢀ, Kotaro Sakoda, and Yukinori Wada
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received November 9, 2001;CL-011128)
A disfavored 5-endo-trig cyclization is accomplished in gem-
presence of a palladium catalyst and CuI, followed by deprotec-
tion of the MOM group to afford 3a–e.11 Thus obtained alcohols 3
were transformed into the desired iodides 4a–e11 via their
mesylates (Table 1).
difluoroolefins with sp3 carbon nucleophiles, generated via the
lithium–iodine exchange reaction of 1,1-difluoro-5-iodo-1-pen-
tenes with tert-butyllithium, to afford 1-fluorocyclopentenes.
The 5-endo-trig cyclization is well known, according to
Baldwin’s rules, to be a disfavored process for the construction of
five-membered rings.1 This is considered to be due to the severe
distortions required in the reaction geometry. Although success-
ful examples of radical-initiated2 and electrophile-driven3 ring
closures of this type have been reported in recent years,
nucleophile-driven 5-endo-trig cyclizations are still rarely
observed in synthetic chemistry.4{6
Most nucleophilic 5-endo-trig ring closures that have been
reported are effected by heteronucleophiles. Carbocyclizations,
which would have great potential as effective C–C bond-forming
reactions, are mostly limited to a few examples of addition of
stabilized sp2 carbanions (anions ꢀ to cyano or carbonyl groups)
to electrophilic double bonds such as (1) olefins activated by
sulfonyl, cyano, nitro, or carbonyl groups, (2) imines, and (3) a ꢁ-
allylpalladium system.4c{h,6d One exception to our knowledge is
the cyclization of a 2-cyclohexenone bearing an alkyl anion
generated by electrochemical reduction, which is remarkably
facilitated in microemulsions.4i
In our recent publications, we have reported the nucleophilic
5-endo-trig cyclizations of gem-difluoroolefins bearing N-, O-,
and S-nucleophiles, providing ring-fluorinated heterocycles such
as indoles, pyrrolines, furans, and thiophenes in high yields.5 This
five-membered ring formation proceeds via intramolecular
vinylic substitution of fluorine,7;8 based on our concept of gem-
difluoroolefins: (i) the highly polarized C–C double bond which
allows disfavored 5-endo addition and (ii) the successive
elimination of fluoride ion which suppresses the reverse ring
opening.6
Thus, we turned our attention to 5-endo-trig cyclization of
gem-difluoroolefins with an sp3 carbon nucleophile to broaden the
scope of this cyclization. For the generation of sp3 carbanion,
metal–halogen exchange was adopted. The substrates were
designed to be gem-difluoroolefins bearing an iodine substituent
and subjected to the ring-forming reaction. Herein we wish to
report the results of our studies on the synthesis of 1-
fluorocyclopentenes by this cyclization.9
According to the reported procedure for lithium–halogen
exchange of primary alkyl iodides,12 1,1-difluoro-5-iodo-4-
methyl-2-phenyl-1-pentene 4d was treated with 2.2 molar
amount of tert-butyllithium (1.4 mol dmꢁ3 in pentane) in diethyl
ether–hexane at ꢁ78 ꢂC. The reaction was quenched at ꢁ78 ꢂC to
give the cyclized product, 1-fluorocyclopentene 5d11 in 28%
yield along with a 28% yield of the reduced product 6d, which
confirmed the generation of the carbanion (Entry 1, Table 2). The
cyclization was effectively promoted by allowing the reaction
mixture to stand at room temperature for 1 h, improving the yield
up to 69% (Entry 2).13 Some other solvent systems were
examined, however in vain (Entries 3–5). In diethyl ether direct
replacement of the fluorine by tert-butyllithium occurred to give
7d in 10% yield (Entry 4). Addition of HMPA (2 molar amount)
after the lithiation of 4d decreased the yield of 5d (Entry 5).
Having obtained the optimum conditions as shown above, the
cyclization of several other 1,1-difluoro-5-iodo-1-pentenes 4 was
examined and the results are shown in Table 3.11 The substrates
The starting materials 4 were easily prepared as outlined
below by using the one-pot sequence that we have previously
established for a wide range of gem-difluoroolefins.10 2,2-
Difluorovinylboranes 2 were prepared in situ from 2,2,2-
trifluoroethyl p-toluenesulfonate 1 and trialkylboranes generated
by hydroboration of MOM ethers of allyl and metallyl alcohols.
The coupling reactions of 2 with aryl iodides were achieved in the
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
283
Thomas, J. Chem. Soc., Chem. Commun., 1976, 736;J. E. Baldwin,
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2
For recent reports, see: A. F. Parsons, C. R. Acad. Sci., Ser. IIC:
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3405 (2001) and references therein.
3
4
For recent reports, see: A. D. Jones, D. W. Knight, and D. E. Hibbs,
J. Chem. Soc., Perkin Trans. 1, 2001, 1182 and references therein.
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After our findings on the unusual reactivity of gem-difluoroolefins
in 5-endo-trig cyclization,5 examples based on the same concept as
ours have been reported: a) T. Yamazaki, S. Hiraoka, J. Sakamoto,
and T. Kitazume, J. Phys. Chem. A, 103, 6820 (1999). b) Z.-G.
Wang and G. B. Hammond, J. Org. Chem., 65, 6547 (2000). c)
P. L. Coe, J. Burdon, and I. B. Haslock, J. Fluorine Chem., 102, 43
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5
6
7
8
9
gem-Difluoroolefins are susceptible to nucleophilic substitution for
the vinylic fluorine via addition–elimination processes. The attack
of nucleophiles is governed to occur exclusively at the difluoro-
methylene carbon so that the fluorines are placed at the position ꢂto
the electron-rich carbon in the transition state to avoid electron-pair
repulsion.
‘‘Organofluorine Chemistry, Principles and Commercial Applica-
tions,’’ ed. by R. E. Banks, B. E. Smart, and J. C. Tatlow, Plenum
Press, New York (1994), p 57;V. J. Lee, ‘‘Conjugate Additions of
Reactive Carbanions to Activated Alkenes and Alkynes,’’ in
‘‘Comprehensive Organic Synthesis,’’ ed. by B. M. Trost, Perga-
mon Press, Oxford (1991), Vol. 4, p 69.
bearing no subutituents on the 4-position gave better results
(Entries 1 vs 4 and 3 vs 5). Concerning para-substituents on the 2-
phenyl group, electron-withdrawing and electron-donating
groups caused little effect on the cyclization (Entries 2, 3, and
5).14
The synthesis of 1-monofluorinated cycloalkenes is limited to the
following method via difluorination of cyclic ketones and
dehydrofluorination: D. R. Strobach and G. A. Boswell, Jr., J.
Org. Chem., 36, 818 (1971).
In conclusion, 5-endo-trig cyclizations of gem-difluoro-
olefins are successfully achieved by not only intramolecular
heteronucleophiles but also sp3 carbon nucleophiles, to which
much less attention has been paid in such ring closure. By this
carbocyclization, the scope of the intramolecular substitution of
gem-difluoroolefins has been expanded in terms of five-
membered ring formation.
10 J. Ichikawa, J. Fluorine Chem., 105, 257 (2000) and references
therein.
1
11 All new compounds were fully characterized by H, 19F, and 13
C
NMR, IR, MS, and combustion analysis (ꢃ0:3%) and/or HRMS.
12 W. F. Bailey and E. R. Punzalan, J. Org. Chem., 55, 5404 (1990);
E. Negishi, D. R. Swanson, and C. J. Rousset, J. Org. Chem., 55,
5406 (1990).
13 When 1,1-difluoro-2-phenyl-1-hexene was treated with butyl-
lithium (1.1 mol. amt.) under the same reaction conditions as those
for 4, the intermolecular substitution of the butyl group for the
vinylic fluorine occurred to give the E=Z mixture (E=Z ¼ 70=30) of
products in 69% yield.7
We dedicate this article to Professor Teruaki Mukaiyama on
the occasion of his 75th birthday.
References and Notes
1
14 1,1-Difluoro-2-(3-iodopropyl)-4-phenyl-1-pentene underwent no
cyclization on treatment with tert-butyllithium (2.2 mol. amt.)
under the same reaction conditions as those for 4.
J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734;J. E.
Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, and R. C.