Enabling the synthesis of perfluoroalkyl bicyclobutanes via 1,3 γ-silyl elimination

Article abstract of DOI:10.1021/ol200121f

Two new bicyclobutanes were prepared from cyclobutyl systems by a novel, solvolytic, carbocation-based methodology. An electron-withdrawing perfluoroalkyl group at the incipient cationic center enhances neighboring-group participation of the γ-silyl group

Full text of DOI:10.1021/ol200121f

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1646–1649
Enabling the Synthesis of Perfluoroalkyl
Bicyclobutanes via 1,3 γ-Silyl Elimination
Christopher B. Kelly,‡ Allison M. Colthart,§ Brad D. Constant,† Sean R. Corning,†
Lily N. E. Dubois,† Jacqueline T. Genovese,† Julie L. Radziewicz, Ellen M. Sletten,^
Katherine R. Whitaker,# and Leon J. Tilley*,†
Department of Chemistry, Stonehill College, 320 Washington Street, Easton,
Massachusetts 02357, United States
ltilley@stonehill.edu
Received January 14, 2011
ABSTRACT
Two new bicyclobutanes were prepared from cyclobutyl systems by a novel, solvolytic, carbocation-based methodology. An electron-
withdrawing perfluoroalkyl group at the incipient cationic center enhances neighboring-group participation of the γ-silyl group, inducing
facile, remarkably selective 1,3-elimination yielding only bicyclobutanes. The method unlocks potential access to a host of EWG-substituted
strained rings and a potential new method for the synthesis of trifluoromethylcyclopropanes.
The preparation of [1.1.0]bicyclobutane, 3, by Wiberg,1
represented a milestone in the syntheses of strained organic
systems. Since then, traditional Wurtz coupling or other
anionic-type ring-closure methods have been used in the
preparation of 3 and its derivatives.2 To date, however, the
trifluoromethyl derivative of 3 has not been prepared by
these or any other methods, likely due to the tendency of
the CF3 moiety to eliminate fluoride under anionic
conditions.3 Herein we report the first synthesis of 1-
(trifluoromethyl)bicyclo[1.1.0]butane, 9a, via novel catio-
nic bridgehead bond formation methodology utilizing
electron-withdrawing-group (EWG) enhanced γ-silyl eli-
mination. Despite the expected large strain energy4 of 9a,
the reaction gives bridgehead bond formation free of side
products.
Under solvolytic conditions, γ-silyl substrates are known
to form cyclopropanes via 1,3 γ-silyl elimination as a
consequence of strong neighboring-group participation by
the back lobe of the C-Si bond to the γ-silyl substituent
(otherwise known as “percaudal” participation).5 While the
W conformation (Figure 1) maximizes the propensity for
ring closure, even under ideal circumstances cyclopropanes
are formed in very low yield and are not the major pro-
ducts.6 In contrast, our new methodology combines the
destabilizing effect of an R-CF3 group with the electron-
releasing effects of a γ-silyl substituent in order to induce
selective 1,3 γ-silyl elimination under mild conditions. With
‡ Present address: University of Connecticut, Department of Chem-
istry, 55 North Eagleville Road, Unit 3060, Storrs, Connecticut 06269-
3060.
§ Present address: Brandeis University, Department of Biochemistry, 415
South Street, Waltham, Massachusetts 02454.
† Stonehill College.
Present address: Chemic Laboratories, 480 Neponset Street, Bldg. 7,
Canton, Massachusetts 02021.
(4) Rozental, E.; Azran, C.; Basch, H.; Hoz, S. Can. J. Chem. 1999,
77, 527.
^ Present address: Department of Chemistry, University of California,
Berkeley, B84 Hildebrand Hall #1460, Berkeley, California 94720-1460.
# Present address: University of Wisconsin;Madison, Department of
Chemistry, 1101 University Avenue, Madison, Wisconsin 53706.
(1) Wiberg, K. B.; Lampmann, G. M. Tetrahedron Lett. 1963, 2173.
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Am. Chem. Soc. 1971, 93, 130. (c) Rifi, M. R. J. Am. Chem. Soc. 1967, 89,
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r
10.1021/ol200121f
Published on Web 03/02/2011
2011 American Chemical Society

retention or β-silyl elimination, in agreement with Creary’s
findings.12 However, we subsequently found (Scheme 1)
that in situ pyrolysis13 of the tosylate, 2, did yield 3, albeit in
very low yield (2.5% by 1H NMR).
Scheme 1. Bicyclobutane via 1,3 γ-Silyl Elimination
Figure 1. Silyl-promoted percaudal participation to yield 1,3
C-C bond formation.
the relative ease of incorporation of silicon into organic
compounds,7 exploration of EWG-directed γ-silyl elimina-
tion as a viable synthetic tool has the potential to provide
avenues to desirable trifluoromethylcyclopropyl groups
which have been described as important motifs for enhan-
cing lipophilicity in pharmaceutical targets.8 Current meth-
ods of preparation of these cyclic moieties are quite limited.9
Some time ago, we speculated10 that the W conformation
of the cis-cyclobutyl system might be sufficiently favorable
to lead to the formation of 3 from 1,3 γ-silyl elimination
under solvolysis conditions. Siehl et al. found conforma-
tionally dependent γ-silyl stabilization of the cyclobutyl
system during rearrangement of the 1-(tert-butyldimethyl-
silyl)bicyclobutonium ion to the 3-endo-(tert-butyldimeth-
silyl)dimethylsilylbicyclobutonium ion at -115 ꢀC.11 More
recently, during the course of our investigations, Creary
et al. reported evidence of percaudal participation during
solvolyses of cis-3-(trimethylsilyl)cyclobutyl systems (un-
substituted, R-methyl, R-phenyl). However, Creary did not
observe the formation of 3.12
Subsequent to the apparent lack of facile 1,3-elimination
in the solvolysis of unsubstituted silylcyclobutyl systems,
we postulated that the installation of an EWG at the R-
carbon could increase percaudal participation and favor
bicyclobutane formation.
Indeed, Gassman14 has suggested that enhancement of
neighboring-group participation in carbocations can be
accomplished by the installation of an R-CF3 or other
EWG such as CN. Additionally, during our own mechan-
istic studies on acyclic R-CF3 substituted γ-trimethylsilyl
systems, we observed enhanced γ-silyl participation in
electron-deficient cations.15 With these encouraging pre-
cedents, we embarked on the synthesis of 9a (Scheme 2).
A [2 þ 2]-cyclization of vinyltrimethylsilane, 4, with
dichloroketene, generatedin situ from trichloroacetyl chlo-
ride, and subsequent dehalogenation of the dichlorocyclo-
butyl ketone 5 gave cyclobutanone 6 in yields comparable
to the literature.16,17 Trifluoromethylation of 6 by the
Prakash method18 produced 7a. By analogy to hydride
reductions and other 1,2-additions to cyclobutanones,2b,12
we expected the major isomer of trifluoromethylation to be
the 1s, 3s “cis” (with respect to the Me3Si and the OH)
isomer as opposed to the 1r, 3r “trans” (with respect to the
Me3Si and the OH) isomer. Indeed, using 19F{1H}
HOESY9 (Figure 2) and 1H{1H} NOESY NMR (see
Supporting Information) the identity of the major isomer
in the product was confirmed to be 1s, 3s, with a 94:6 1s,
3s:1r, 3r ratio as determined by 1H NMR (and GC-MS).
The tosylate 8a was prepared from 7a by deprotonation
with KH and subsequent reaction with p-toluenesulfonic
anhydride.
We had also examined the products of solvolytic stu-
dies10a,b of various unsubstituted cis-3-(trimethylsilyl)cyc-
lobutyl substrates and obtained only substitution with
(7) For some reviews on organosilicon chemistry, see: (a) Organic
Chemistry VI: From Molecules to Materials; Auner, N.; Weiss, J., Eds.;
WILEY-VCH: Weinheim, 2005. (b) The Chemistry of Organic Silicon
Compounds; Rappaport, Z.; Apeloig, Y., Eds.; WILEY-VCH: Weinheim,
2001; Vol. 3. (c) Brook, M. A. Silicon in Organic, Organometallic, and
Polymer Chemistry; WILEY-VCH: Weinheim, 1999. (d) Taylor, P. C. Annu.
Rep. Prog. Chem., Sect. B: Org. Chem. 2009, 105, 75. (e) Barton, T. J.;
Boudjouk, P. Organosilicon Chemistry: A Brief Overview. In Silicon-
Based Polymer Science: A Comprehensive Resource; Zeigler, J. M.,
Gordon Fearon, F. W., Eds.; Advances in Chemistry Series, Vol. 224;
American Chemical Society: Washington, DC, 1989; pp 3-46.
(8) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(13) For an example of 1,3-elimination via pyrolysis, see: Sonnen-
berg, F. M.; Stille, J. K. J. Org. Chem. 1966, 31, 3441.
(14) (a) Gassman, P. G.; Hall, J. B. J. Am. Chem. Soc. 1984, 106,
4267. (b) Gassman, P. G.; Doherty, M. M. J. Am. Chem. Soc. 1982, 104,
3742. (c) Nelson, D. W.; O’Reilly, N. J.; Speier, J.; Gassman, P. G. J.
Org. Chem. 1994, 59, 8157. (d) Gassman, P. G.; Tidwell, T. T. Acc.
Chem. Res. 1983, 16, 279.
(15) Mercadante, M. A. Synthesis of Trifluoromethyl Ketones and
the Solvolysis of Beta-Deuterium Labeled Trifluoromethyl Sulfonates.
Undergraduate Senior Thesis, Stonehill College, Easton, MA, 2010.
(16) (a) Danheiser, R.; Sard, H. Tetrahedron Lett. 1983, 24, 23.
(b) Hassner, A.; Dillon, J. L., Jr. J. Org. Chem. 1983, 48, 3382.
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(10) (a) Colthart, A. M.; Dubois, L. N.; Tilley, L. J. Presented at the
239th National Meeting of the American Chemical Society, San Fran-
scisco, CA, March 21-25, 2010, Poster CHED 1086. (b) Tilley, L. J.; Kelly,
C. B.; Dubois, L. N. E.; Constant, B. D.; Colthart, A. M. Presented at the
238th National Meeting of the American Chemical Society, Washington, DC,
August 16-20, 2009; Poster CHED 297. (c) Whitaker, K.; Radziewicz, J.
Presented at the 233rd National Meeting of the American Chemical Society,
Chicago, IL, March 25-27, 2007; Poster CHED 733.
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Org. Lett., Vol. 13, No. 7, 2011
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Scheme 2. Preparation and Solvolysis of 8a and 8b
Figure 2. 19F{1H}HOESY of cyclobutanol 7a. The red numbers
correspond to the intensity of the cross peak per proton nor-
malized to the weakest signal.
which apparently forms a low-boiling azeotrope with the
TFE and/or 9a. Conducting the reaction in 40T changed
the major byproduct to the higher boiling silanol, 10.
Careful fractionation using a salt-water ice-cooled con-
denser and receiving flask left only small amounts of 10
and TFE in the crude product. Dissolving the crude
distillate in 1,1,2-trichloroethane, washing with water,
and redistillation affordedpure9a(97 mol % by 1H NMR)
as a volatile, colorless liquid in 40% yield.
Solvolysis of 8a was performed in deuterated aqueous
trifluoroethanol (TFE) ranging from 40% to 100% by
weight (40T-100T) using various proton scavengers in-
cluding pyridine, pyridine-d6, 2,6- lutidine, or 2,4,6-colli-
dine. 1H NMR analysis of the solvolysis products showed,
after approximately 12 h, complete and sole conversion
of 1s, 3s 8a to 9a and the expected byproducts of the 1,
3-elimination: trimethylsilanol,19 10, and 2,2,2-trifluor-
oethoxytrimethylsilane, 11.20 Peaks of 9a in the spectra
were similar to those of 3,21 with the expected slight
downfield shifts. Yields as determined by 1H NMR ranged
from 86 to 94%.
The ease of formation of 9a and 9b demonstrates the
utility of EWGs to enhance 1,3 C-C bond formation via
the γ-silyl effect as well as to stabilize highly strained
systems by the so-called “perfluoroalkyl effect,”22 which
protects the product by preventing electrophilic degrada-
tion and raising activation energies of isomerization.22a
The Baeyer strain of 9aiscalculatedtobe more than8 kcal/
mol lower than 3 and 2.6 kcal/mol lower than bicyclobu-
tane-1-carbonitrile.4 Indeed, we have found that 9a can be
stored indefinitely in a sealed vial in the freezer without
decomposition. The cyano analog has been reported to
polymerize spontaneously at room temperature.23 In-
Despite complete conversion, yields were somewhat less
than quantitative, likely resulting from a combination of
the unreactivity of the 1r, 3r isomer as well as the volatility
of the product 9a (see Supporting Information). We also
prepared and solvolyzed the pentafluoroethyl analog 8b,
1
terestingly, we have also noted in the H NMR that
there is a significant downfield shift on the bridgehead H
from 9a to 9b, while the exo-H shifts upfield, and the
endo-H remains virtually unchanged (see Supporting
Information). Thus, there must be a large influence of
the electron-withdrawing substituent on the electron
density of the bridgehead bond.
Moreover, the results of our study are in sharp contrast
to previous solvolytic studies of other tertiary γ-silyl
systems in which participation of the silyl substituent was
1
with similar results. By H NMR, 9b was formed exclu-
sively, in 85-91% yield.
For further characterization, we conducted a large-scale
solvolysis of 8a in aqueous TFE. While 9a formed just as
readily in the small scale studies, isolation was complicated
by losses due to the volatility (bp 28 ꢀC) of 9a and by
difficulty in separation of the TMS ether byproduct, 11,
(22) (a) Lemal, D. M.; Dunlap, L. H., Jr. J. Am. Chem. Soc. 1972, 94,
6562. (b) Grayston, M W.; Lemal, D. M. J. Am. Chem. Soc. 1976, 98,
1278. (c) Wirth, D.; Lemal, D. M. J. Am. Chem. Soc. 1982, 104, 847.
(d) Lemal, D. M.; Staros, J. V.; Austel, V. J. Am. Che. Soc. 1969, 91,
3373.
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Chem. 2003, 41, 625.
(19) 1H NMR: Zafrani, Y.; Gerchonov, E.; Columbus, I. J. Org.
Chem. 2007, 72, 7014.
(20) 1H NMR: Lee, B.; Kim, J. H.; Lee, H.; Ahn, B. S.; Cheong, M.;
Kim, H. S.; Kim, H. J. Fluorine Chem. 2007, 128, 110.
(21) 1H NMR: Wurthrich, K.; Meiboom, S.; Snyder, L. C. J. Chem.
Phys. 1970, 52, 230.
1648
Org. Lett., Vol. 13, No. 7, 2011

either nearly nonexistent24 or insufficient to effect bridge-
head bond formation by silyl elimination.12 We propose
that the exclusivity of 9a as the only solvolysis product
results from a combination of factors, as shown in our
proposed mechanism (Figure 3).
which possess the proper W conformation reacted com-
pletely, while the endo-sickle-like 1r, 3r isomers failed to
react during the reaction time. Indeed, the peaks for the
1
minor isomer, which were partially obscured in the H
NMR spectra of the initial reaction mixtures, became
unmasked as the reaction proceeded and the major isomer
was consumed, giving further support to a conformation-
ally dependent mechanism and partially explaining the
nonquantitative yields seen in the solvolyses.
We present the first documented case of using enhanced
γ-silyl interactions via an “electron-deficient” cation to
synthesize novel bicyclobutanes. This method represents a
potential new way to prepare a variety of highly strained,
high-energy, bridgehead polycyclic hydrocarbons contain-
ing electron-withdrawing groups as well as a potential new
way to prepare trifluoromethylcyclopropanes. We are
currently investigating the effectiveness of this methodol-
ogy for cyclopropanation in acyclic systems, as well as the
scope of the reaction in terms of other EWGs.
Figure 3. Proposed reaction mechanism for formation of 9a.
Increased electron demand at the cationic center due to
the R-EWG causes increased participation of the silyl
group. The greater degree of bonding character between
the R- and γ-carbons as well as the amplified positive
charge character (and therefore increased electrophilicity)
of the silicon allow for more facile abstraction of the silyl
group by nucleophilic solvent molecules. The reduction of
positive charge and the increase in steric bulk at the
R-carbon precludes pathways for rearrangement or
substitution.
Acknowledgment. This work was supported by Stone-
hill College and by the Office of Naval Research (Award
Number N0014-08-1-1160). We thank Dr. Chris Canlas of
the University of California, Berkeley for his assistance
with the 19F{1H} HOESY spectroscopy and Barbara
Anzivino, Dr. Louis Liotta, and Dr. Pamela Lombardi
of Stonehill College, and the Stonehill College Chemistry
Department for helpful discussions.
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectra of the com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
As expected, the reaction appears to be highly confor-
mationally dependent. The 1s, 3s isomers of 8a and 8b
(24) Tilley, L. J.; Shiner, V. J., Jr. J. Phys. Org. Chem. 1999, 12, 564.
Org. Lett., Vol. 13, No. 7, 2011
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