Synthesis and characterization of norbornanediol isomers and their fluorinated analogues

Article abstract of DOI:10.1021/jo0513156

Fluorinated norbornene monomers exhibit the requisite properties for inclusion in 157 nm photoresists, but traditional addition and radical polymerizations with these monomers have failed. Norbornanediols provide an alternate route to these materials via condensation polymerization, and methods have been developed for the efficient synthesis of the exo-2-syn-T- and endo-2-exo-3-dihydroxynorbornanes. Synthesis of the fluorinated analogues is complicated by steric and electronic effects; however, a high-yielding synthesis of endo-2-exo-3-dihydroxynorbornane bearing a 5-endo-[2,2-bis(trifluoromethyl) hydroxyethyl] substituent is reported.

Full text of DOI:10.1021/jo0513156

SCHEME 1. Synthesis and Phosgene Condensation of
2-exo-3-exo-Norbornanediol
Synthesis and Characterization of
Norbornanediol Isomers and Their Fluorinated
Analogues
Scott M. Grayson, Brian K. Long, Shiro Kusomoto,
Brian P. Osborn, Ryan P. Callahan,
Charles R. Chambers, and C. Grant Willson*
Department of Chemistry and Biochemistry,
UniVersity of Texas, Austin, Texas 78712
willson@che.utexas.edu
ReceiVed June 27, 2005
tion polymerization was sought. Norbornanediols offer a number
of attractive opportunities for the preparation of such polymers,
for example, via condensation with phosgene to yield polycar-
bonates.
Although synthetic routes from norbornene to the 2,3-dihy-
droxy-5 and 2,7-dihydroxy6,7 norbornane have been reported,
much of this chemistry is not viable for fluorine-substituted nor-
bornane systems as the synthetic methods do not provide suf-
ficient yields or purity of the monomers. The preparation of
fluorinated norbornane compounds most easily proceeds through
the Diels-Alder reaction of cyclopentadiene with a fluorinated
alkene, which have been previously investigated.4 In this study
norbornene was used as a model to develop routes to the corres-
ponding diols. After the synthesis was optimized for norbornene,
these routes were investigated with the incorporation of fluor-
inated substituents. It was soon discovered that, in most cases,
the hydrocarbon norbornene was not an appropriate model for
the fluorinated monomers.
Fluorinated norbornene monomers exhibit the requisite
properties for inclusion in 157 nm photoresists, but traditional
addition and radical polymerizations with these monomers
have failed. Norbornanediols provide an alternate route to
these materials via condensation polymerization, and methods
have been developed for the efficient synthesis of the exo-
2-syn-7- and endo-2-exo-3-dihydroxynorbornanes. Synthesis
of the fluorinated analogues is complicated by steric and
electronic effects; however, a high-yielding synthesis
of endo-2-exo-3-dihydroxynorbornane bearing a 5-endo-
[2,2-bis(trifluoromethyl)hydroxyethyl] substituent is reported.
The continued drive to miniaturize microelectronic devices
has been accomplished by printing the circuit elements with
ever-decreasing wavelengths of light.1 Leading edge manufac-
turing is now done with 193 nm light, and many are pursuing
exposure at 157 nm. Polynorbornenes are of particular interest
as the basis for the design of photoresists due to their unique
set of desirable properties, including high glass transition tem-
peratures, high resistance to reactive ion etching, low UV absor-
bance, and relative ease of synthesis.2 However, at 157 nm, even
aliphatic hydrocarbons such as polynorbornene absorbs strongly.3
Fortunately, introduction of fluorinated substituents into the
norbornane skeleton provides materials with sufficient transpar-
ency to be used at this wavelength,4 but the most transparent
of the fluorine-substituted norbornene monomers resists addition
polymerization initiated by classical catalysts.2 Therefore, an
alternate route to fluorinated norbornene polymers by condensa-
The most straightforward route from norbornene, 1, to a
norbornane diol is oxidative dihydroxylation. The cis-diol can
be obtained by oxidation with either permagnate6 or osmium
tetraoxide. As reported for a range of reactions with the alkene
functionality of norbornene,8 the higher steric hindrance on the
endo face leads to a strong preference for the exo-diol isomer
2. While the synthetic route to the monomer is a single step,
all attempts to prepare a polycarbonate by condensation with
phosgene yielded exclusively the cyclic carbonate 3. Attempts
to carry out the ring-opening polymerization of 3 using either
acid or Sn(Oct)2 catalysts also failed;9 therefore, efforts shifted
toward the synthesis of a norbornenediol with regiochemistry
that precluded the formation of the cyclic carbonates, specifi-
cally, the trans-2,3-norbornanediol (Scheme 1).
(4) Trinque, B. C.; Chambers, C. R.; Osborn, Br. P.; Callahan, R. P.;
Lee, G. S.; Kusumoto, S.; Sanders, D. P.; Grubbs, R. H. Conley, W. E.;
Willson, C. G. J. Fluorine Chem. 2003, 122, 17. Tran, H. V.; Hung, R. J.;
Chiba, T.; Yamada, S.; Mrozek, T.; Hsieh, Y.-T.; Chambers, C. R.; Osborn,
B. P.; Trinque, B. C.; Pinnow, M. J.; Sanders, D. P.; Connor, E. F.; Grubbs,
R. H.; Conley, W.; MacDonald, S. A.; Willson, C. G. J. Photopolym. Sci.
Technol. 2001, 14, 669.
(1) Levinson, H. J. Principles of Microlithography, 2nd ed.; SPIE
Press: Bellingham, WA, 2005.
(2) Saunders: D. P.; Connor, E. F.; Grubbs, R. H.; Hung, R. J.; Osborn,
B. P.; Chiba, T.; MacDonald, S. A.; Willson, C. G.; Conley, W.
Macromolecules 2003, 36, 1534. Barnes, D. A.; Benedikt, G. M.; Goodall,
B. L.; Huang, S. S.; Kalamarides, H. A.; Lenhard, S.; McIntosh, L. H.;
Selvy, K. T.; Shick, R. A.; Rhodes, L. F. Macromolecules 2003, 36, 2623.
Benedikt, G. M.; Elce, E.; Goodall, B. L.; Kalamarides, H. A.; McIntosh,
L. H.; Rhodes, L. F.; Selvy, K. T.; Andes, C.; Oyler, K.; Sen, A.
Macromolecules 2002, 35, 8978. Lipian, J.; Mimna, R. A.; Fondran, J. C.;
Yandulov, D.; Shick, R. A.; Goodall, B. L.; Rhodes, L. F.; Huffman, J. C.
Macromolecules 2002, 35, 8969. Mathew, J. P.; Reinmuth, A.; Melia, J.;
Swords, N.; Risse, W. Macromolecules 1996, 29, 2755.
(5) Heyns, K.; Rudiger, G.; Paulsen, H. Chem. Ber. 1972, 105, 1019.
Taylor, J. E. Synthesis 1985, 1142.
(6) Kwart, H.; Vosburgh, W. G. J. Am. Chem. Soc. 1954, 76, 5400.
(7) Walborsky, H. M.; Loncrini, D. F. J. Am. Chem. Soc. 1954, 76, 5396.
Crandall, J. K. J. Org. Chem.. 1964, 29, 2830. Shealy, Y. F.; Clayton, J. D.
J. Am. Chem. Soc. 1969, 91, 3075. Tenaglia, A.; Terranova, E.; Waegell,
B. Tetrahedron Lett. 1990, 31, 1157. Kotsuki, H.; Kataoka, M.; Nishizawa,
H. Tetrahedron Lett. 1993, 34, 4031.
(3) Kunz, R. R.; Bloomstein, T. M.; Hardy, D. E.; Goodman, R. B.;
Downs, D. K.; Curtin, J. E. Proc. SPIE 1999, 3678, 13.
(8) Brown, H. C.; Kawakami, J. H.; Liu, K. T. J. Am. Chem. Soc. 1973,
95, 2209.
10.1021/jo0513156 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/10/2005
J. Org. Chem. 2006, 71, 341-344
341

SCHEME 2. Acid-Catalyzed 2-exo-3-exo-Epoxynorbornane
Ring-Opening Products
Previously reported techniques for the synthesis of trans-2,3-
dihydroxynorbornane are limited to the Raney nickel isomer-
ization of the cis-2,3-dihydroxynorbornanes (2).5 Our attempts
to repeat this work invariably gave mixtures regardless of the
source of the catalyst, and the isomerization failed on the
fluorinated norbornanes, so an alternative procedure was sought.
exo-2-exo-3-Epoxynorbornane is readily accessible by oxida-
tion of norbornene, but attempts to ring-open the unsubstituted
epoxynorbornane 5a under acidic aqueous conditions yielded a
mixture of products due to norbornyl cation rearrangements
(Scheme 2).7 The epoxide ring opening was monitored by GC-
MS to determine the time-dependent product distribution and
was found initially to yield a complex mixture of dihydroxy-
and chlorohydroxynorbornanes10 (see Figure 1), the chief
constituents being the exo-2-syn-7-dihydroxynorbornane (6) and
exo-2-chloro-syn-7-hydroxynorbornane (7), as well as the
desired trans-2,3-diol (8). Each of these products was isolated
by column chromatography, and the structures were proved by
X-ray crystallography. Separation of the isomers required
difficult, tedious chromatography, but increasing the reaction
time to 1 day led to isomerization to the thermodynamically
favored exo-2-syn-7-dihydroxynorbornane (6). Because the
primary impurities after 1 day were norbornyl ether oligomers,
the product (6) could be purified easily by sublimation.
Confirmation of the regiochemistry of 6 was verified by reaction
with phosgene, which yielded the cyclic carbonate at temper-
atures above 0 °C. Although this diol was successfully
condensed with phosgene at low temperatures to yield a
polycarbonate polymer, attempts to ring-open fluorinated ep-
oxynorbornanes under these and other acidic conditions led to
a complex mixture of inseparable isomers.
The ring opening of 2-exo-3-exo-epoxynorbornanes under
basic conditions should preclude carbocation rearrangements,
but this reaction is complicated instead by steric hindrance
inhibiting nucleophilic attack from the endo-face. A range of
basic aqueous conditions were investigated using hydroxide ion
as the nucleophile, but these reactions yielded only starting
material. Nucleophilic attack of the unsubstituted epoxide, 5a,
could only be achieved using potassium benzyloxide, which
afforded a 30% yield of 9 after 10 days at 150 °C. Reaction
with potassium benzyloxide at temperatures below 130 °C
yielded only starting material, while temperatures above 160°
led to degradation of the material. The benzyl group of 9 was
readily removed by palladium catalyzed hydrogenolysis to afford
FIGURE 1. Product distribution of acid-catalyzed epoxynorbornane
ring opening
SCHEME 3. Base Catalyzed 2-exo-3-exo-Epoxynorborn-
ane Ring-Opening Products
a racemic mixture of the trans-2,3-norbornanediol, 8. The crystal
structure of the di(phenyl carbamate) after reaction of the diol
with phenylisocyanate. Condensation with phosgene yielded the
corresponding polycarbonate without formation of the cyclic
carbonate, making the trans-diol the most attractive route to
production of fluorinated norbornane condensation polymers.
The details of the polymerizations will be reported elsewhere.
Unfortunately, attempts to open the fluorinated norbornene
epoxides 5b and 5c with potassium benzyloxide at 150 °C failed,
and increasing the temperature led to decomposition of the
starting material (Scheme 3).
A revised synthetic approach was developed, taking into
consideration the sensitivity of norbornanes to strongly acidic
conditions and the steric blockage of the endo face. The 2-exo-
3-exo-norbornanediol was readily accessible in high yields
through osmium tetraoxide dihydroxylation so a synthetic route
was devised by which one of the hydroxyls would be protected
while the stereochemistry of the other was inverted. This was
achieved by protecting the cis-endo-diol via a p-toluenesulfonic
acid-catalyzed condensation with benzaldehyde dimethyl acetal.
When this reaction was carried out in an ice bath under reduced
pressure, the exo-isomer 10 was formed exclusively. A single
hydroxyl group was deprotected by reaction with DIBAL,11 and
oxidation of the product 11 with PCC afforded 2-exo-benzy-
loxynorbornan-3-one, 12. Reduction of exo-benzyloxynorbor-
nanone with sodium borohydride afforded 61% of the trans
isomer 13 but regenerated 39% of the cis isomer 11. The
stereoselectivity for this reaction is reduced significantly when
compared to the reduction of unsubstituted norbornanone, as a
result of the bulky benzyl ether on the exo face; however,
(9) Lo¨wenhielm, P.; Claesson, H.; Hult, A. Macromol. Chem. Phys. 2004,
205, 1489. Shibasaki, Y.; Sanda, F.; Endo, T. Macromolecules 2000, 33,
3630. Kricheldorf, H. R.; Jenssen, J. J. Macromol. Sci. Chem. 1989, A26,
631.
(11) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593; Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29,
4085.
(10) McDonald, R. N.; Tabor, T. E. J. Org. Chem. 1968, 33, 2934.
342 J. Org. Chem., Vol. 71, No. 1, 2006

SCHEME 4. Alternative Synthesis of
ing the hydroxyl group with a benzyl ether resulting in greatly
reduced regioselectivity.
2,3-trans-Norbornanediola
Oxidation using PCC afforded a nearly quantitative yield of
the norbornanone 18, which was converted to the endo-alcohol
19 by reduction with superhydride. This reduction was signifi-
cantly more stereoselective than that of the unsubstituted ketone
(12) because of the presence of the bulky hexafluorobutanol
group on the endo face. Finally, catalytic hydrogenolysis of the
benzyl protecting group afforded the target compound 20. The
relative stereochemistry of the three substituents was confirmed
by X-ray crystallography.
Due to the steric and electronic effects of fluorine incorpora-
tion into the norbornene ring structure, previously reported
techniques for the synthesis of many norbornene diols failed to
provide an effective route to fluorinated analogues. A high
yielding, multistep route has been developed to provide synthetic
access to the fluorinated norbornanediol, 20, in 79% overall
yield. The unfluorinated trans-2-endo-3-exo-norbornanediol
condenses with phosgene to afford poly(norbornene carbonate)
and studies of this polymer and its fluorinated analogues are
presently underway to evaluate their use as 157 nm photo resists.
a Key: (a) PhCH(OCH3)2, PhCH3, 0 °C, 10 Torr; (b) DIBAL, PhCH3;
(c) PCC, CH2Cl2; (d) superhydride, THF 0 °C; (e) Pd/C, H2, EtOH/EtOAc.
SCHEME 5. Preparation of Fluorinated Norbornane
Monomera
Experimental Section
2-(exo-2-exo-3-Dihydroxybicyclo[2.2.1]heptan-5-ylmethyl)-
1,1,1,3,3,3-hexafluoro-2-propan-2-ol (15). To a round-bottom flask
containing 116 g of bicyclo[2.2.1]hept-5-en-2-ylmethyl-1,1,1,3,3,3-
hexafluoropropan-2-ol were added 1350 mL of THF, 150 mL of
water, and 60 g of N-morpholine oxide. The reagents were stirred
until dissolved and the reaction vessel was lowered into a water
bath. Then 43 mL of a 2.5 wt % solution of osmium tetraoxide
was added, and the reaction mixture was stirred at room temperature
for 12 h. The solution was reduced in vacuo, and the aqueous
mixture extracted 3 times with ethyl acetate. The organic layers
were combined, reduced in vacuo, and purified by filtration through
a plug of silica gel. The filtrate was then reduced in vacuo, dissolved
in a minimal amount of ethyl acetate, and precipitated into
dichloromethane yielding 117.6 g of a slightly yellowish powder
(91% yield): 1H NMR (CDCl3) 0.66, (m, 1H), 1.16 (d, 1H, J )
10.2, Hz), 1.7-1.9 (m, 3H), 2.0-2.1 (m, 2H), 2.09 (s, 1H), 2.13
(m, 1H), 3.60 (d, 1H, J ) 6.0 Hz), 3.93 (d, 1H, J ) 6.0 Hz); 13C
NMR (CDCl3) 32.4, 33.9, 34.0, 34.5, 45.5, 49.9, 70.3, 75.7, 77.5
(m, JC-F ) 28 Hz), 125.1 (dq, JC-F ) 16.8, 287 Hz); 19F NMR
a Key: R ) CH2C(CF3)2OH (a) OsO4, NMO, THF; (b) PhCH(OCH3)2,
PhCH3, 0 °C, 10 Torr; (c) DIBAL, PhCH3 (d) PCC, CH2Cl2; (e)
superhydride, THF 0 °C; (f) Pd/C, H2, EtOH/EtOAc.
reduction with the more stereoselective superhydride afforded
the desired isomer 13 in a 91% yield. The benzyl protecting
group was quantitatively removed by hydrogenolysis to afford
the target model compound 8 (Scheme 4).
The 2,2-bis(trifluoromethyl)hydroxyethyl substituent was
investigated because it is sufficiently transparent for 157 nm
lithography, and is aqueous base soluble. The endo-alkene 14
was oxidized with osmium tetraoxide and precipitated into
dichloromethane to afford the cis-diol 15. The large steric bulk
of the fluorinated substituent assured solely exo dihydroxylation.
Benzylidene protection was carried out with p-toluenesulfonic
acid as the acid catalyst. If the reaction was carried out at room
temperature under reduced pressure rather than in refluxing
toluene, the exo-benzylidene protected diol 16 was isolated in
nearly quantitative yields (Scheme 5). The structure was verified
by X-ray crystallography.
A single hydroxyl group on 16 was deprotected by reaction
with 6 equiv of DIBAL, and although two regioisomers from
this reaction were observed by GC, carrying out this reaction
under high dilution (5 µM in substrate) provided a 91% yield
of a single racemate. X-ray crystallography verified that the
deprotection occurred at the hydroxyl â to the HFA substituent,
yielding 17. It is proposed that cleavage occurs in the observed
position because of anchimeric assistance from the free hydroxyl
group of the fluorinated substituent (Scheme 6). The first
equivalent of DIBAL acts to deprotonate this acidic hydroxyl
and provides a tethered Lewis acid which preferentially activates
the â-ether toward cleavage by a second hydride. Such assistance
by free hydroxyls during the DIBAL deprotection of benzylidene
groups has been reported previously for threitol systems.12
Additional support for this mechanism was obtained by protect-
(CDCl3) -77.5, (q, 3F, JF-F ) 10.0 Hz), -78.7, (q, 3F, JF-F
)
10.0 Hz); LRMS (EI) m/z 308 (3, M+), 290 (10), 272 (15), 261
(20), 248 (25), 237 (50), 95 (65), 81 (65), 67 (65), 57 (100); HRMS
([M + H]+ calcd ) 309.0925, found ) 309.0926); FTIR ν ) 3385,
2970, 2880, 1416, 1203, 1033 cm-1. Anal. Calcd for C11H14F6O3:
C, 42.87; H, 4.58; F, 36.98. Found: C, 42.90; H, 4.60.
1,1,1,3,3,3-Hexafluoro-2-(4-phenyl-3,5-dioxatricyclo[5.
2.1.02,6]dec-8-ylmethyl)propan-2-ol (16). To a round-bottomed
flask containing 109.3 g of 15 were added 200 mL of toluene and
78 g of benzaldehyde dimethoxyacetal. The reaction vessel was
cooled in an ice bath to 0 °C, 7.5 g of p-toluenesulfonic acid was
added, and the reaction mixture was stirred under reduced pressure.
After 3 h, the reaction was washed with sodium bicarbonate and
extracted with dichloromethane. The organic extracts were com-
bined, reduced in vacuo, and filtered through a plug of silica gel to
afford 140 g a white amorphous solid (99% yield): 1H NMR
(mixture of R and S isomers) 0.60, (m, 1H), 1.21 (m, 1H), 1.84
(dd, 1H, J ) 8.0, 15.0 Hz), 1.9-2.0 (m, 2H), 2.03 (dd, 1H, J )
6.4, 15.0 Hz), 2.21 (m, 1H, J ) 6.0 Hz), 2.42 (m, 1H J ) 4.2 Hz),
2.51(d, 1H, J ) 3.8 Hz), 3.22 (s, 1H), 4.06 (d, 1H J ) 5.9 Hz),
4.35 (d, 1H, J ) 5.8 Hz), 5.56 (s, 1H), 7.3-7.4 (m, 3H), 7.5-7.6
(m, 2H); 13C NMR 30.5, 31.7, 32.0, 33.5, 40.7, 45.0, 76.5 (m, JC-F
) 29.0 Hz), 78.5, 82.6, 102.7, 123.1 (q, JC-F ) 5.0, 287 Hz), 126.8,
(12) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Hirama, M.;
Ogasawara, K. Synthesis 1986, 811.
J. Org. Chem, Vol. 71, No. 1, 2006 343

SCHEME 6. Proposed Mechanism for Regioselective Deprotection of 16
128.4, 129.6, 136.0; 19F NMR -76.7, (q, 3F, JF-F ) 10.2 Hz),
-78.0, (q, 3F, JF-F ) 10.2 Hz); LRMS (EI) m/z 395 (100, M -
1+), 349 (10), 273 (15), 105 (80), 91 (60); HRMS ([M + H]+ calcd
) 397.1222, found ) 397.1238); FTIR ν ) 3338, 3040, 2962, 2879,
1460, 1403, 1214, 1143, 1063 cm-1. Anal. Calcd for C18H18F6O3:
C, 54.55; H, 4.58; F, 28.76. Found: C, 54.58; H, 4.62.
warmed to room temperature and stirred for 12 h. The reaction
mixture was cooled to 0 °C and quenched by addition of con-
centrated aqueous NaHSO4. The resulting solution was extracted
twice with dichloromethane, and the organic fractions were com-
bined and reduced in vacuo. The product was isolated by chroma-
tography on silica, (eluent 11% ethyl acetate 89% hexane) as a
mixture of enantiomers (yield 99%): 1H NMR 1.18 (d, 1H, J )
11 Hz), 1.20 (d, 1H, J ) 11 Hz), 1.33 (m, 1H), 1.54 (m, 1H), 1.94
(dd, 1H, J ) 5.5, 15 Hz), 2.02 (m, 1H), 2.25 (s, 1H), 2.37 (s, 1H),
2.47 (t, 1H, J ) 13 Hz), 4.54 (d, 1H, J ) 9.5 Hz), 4.90 (d, 1H, J
) 9.5 Hz), 7.2-7.4 (m, 5H); 13C NMR 34.4, 38.0, 39.3, 39.5, 46.4,
2-(exo-2-Benzyloxy-exo-3-hydroxybicyclo[2.2.1]heptan-5-yl-
methyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (17). To a round-
bottomed flask containing 14.0 g of 16 diluted in 500 mL of toluene
was added 214 mL of DIBAL (1.5 M solution in toluene) dropwise.
The reaction mixture stirred at room temperature for 12 h and cooled
to 0 °C, and the excess DIBAL was quenched by adding 0.3 M aq
solution of Rochelle’s salt dropwise until evolution of gas ceased.
The resulting solution was extracted twice with dichloromethane,
and the organic fractions were combined and reduced in vacuo.
The desired product was isolated by chromatography on silica,
(eluent 20% ethyl acetate 80% hexane) as a mixture of enantiomers
(yield 91%): 1H NMR (mixture of R and S isomers) 0.50 (m, 1H),
1.18 (m, 1H), 1.76 (dd, 1H, J ) 1.6, 10.4 Hz), 1.8-2.0 (m, 3H),
2.11 (m, 1H), 2.23 (d, 1H, J ) 4.6 Hz), 2.35 (d, 1H, J ) 2.6 Hz),
3.46 (d, 1H, J ) 6.2 Hz), 3.70 (m, 1H), 4.10 (d, 1H, J ) 6.2 Hz),
4.54 (d, 1H, J ) 11.7 Hz), 4.61 (d, 1H, J ) 11.7 Hz), 6.05 (s, 1H),
7.2-7.4 (m, 5H); 13C NMR 32.1, 32.3, 33.6, 34.0, 40.8, 48.0, 70.3,
73.1, 77.1 (m, JC-F ) 28.4 Hz), 82.3, 124.1 (q, JC-F ) 287, 6.2
50.3, 77.5, 77.6, 81.2, 82.7 (m, JC-F ) 28.4 Hz) 123.1 (dq, JC-F
)
21.3, 288 Hz), 133.4, 133.6, 134.1, 144.6; 19F NMR -73.9, (q,
3F, JF-F ) 10.0 Hz), -75.3, (q, 3F, JF-F ) 10.0 Hz); LRMS (EI)
m/z 398 (1, M+), 289 (30), 261 (65), 91 (100); HRMS ([M + H]+
calcd ) 399.1395 found ) 399.1407); FTIR ν ) 3460, 3230, 3022,
2960, 2883, 1456, 1202, 1163, 1052 cm-1. Anal. Calcd for
C18H20F6O3: C, 54.27; H, 5.06; F, 28.62. Found: C, 54.34; H, 5.08.
2-(exo-2-endo-3-Dihydroxybicyclo[2.2.1]heptan-5-ylmethyl)-
1,1,1,3,3,3-hexafluoropropan-2-ol (20). To a 100 mL cylindrical
glass sleeve was added a stirbar, 1.30 g of 19, 50 mL of 1:1 ethanol/
ethyl acetate, and 40 mg of 10% Pd/C. The sleeve was placed inside
a stainless steel Parr reactor and charged with 400 psi of H2. The
reaction vessel was stirred vigorously for 12 h, at which point the
reactor was depressurized, refreshed with an additional 20 mg of
Pd/C, recharged to 400 psi of H2, and stirred for an additional 12
h. The reaction vessel was then depressurized and reaction mixture
filtered through a Whatman 0.2 µm PTFE filter to remove the Pd/C
catalyst. The clear solution was reduced in vacuo to yield the
racemic product as a white amorphous solid: yield 99%; 1H NMR
1.31 (ddt, 1H, J ) 1.4, 2.2, 10.7 Hz), 1.39 (dt, 1H, J ) 2.0, 10.7
Hz), 1.58 (ddd, 1H, J ) 2.4, 5.8, 12.5 Hz), 1.73 (dt, 1H, J ) 4.8,
11.5 Hz), 2.02 (m, 1H), 2.1-2.3 (m, 3H), 2.31 (m, 1H), 2.5 (b,
2H), 3.94 (ddd, 1H, J ) 1.4, 4.4, 9.2 Hz), 4.01 (ddd, 1H, J ) 1.3,
4.6, 9.0 Hz); 13C NMR 28.8, 33.5, 34.4, 35.0, 43.8, 45.7, 69.1,
72.2, 77.9 (m, JC-F ) 28.4 Hz) 125.1 (dq, JC-F ) 22.6, 288 Hz);
19F NMR (CDCl3) -76.1, (q, 3F, JF-F ) 10.4 Hz), -80.4, (q, 3F,
JF-F ) 10.4 Hz); LRMS (EI) m/z 308 (5, M+), 290 (20), 272 (25),
261 (30), 248 (40), 237 (75), 95 (75), 57 (100); HRMS ([M + H]+
calcd ) 309.0925, found ) 309.0912); FTIR ν ) 1049, 1150, 1200,
2885, 2959, 3227, 3360 cm-1. Anal. Calcd for C11H14F6O3: C,
42.87; H, 4.58; F, 36.98. Found: C, 43.17; H, 4.56.
Hz), 128.2, 128.4, 129.0, 138.3; 19F NMR -76.0, (q, 3F, JF-F
)
10.0 Hz), -78.5, (q, 3F, JF-F ) 10.0 Hz); LRMS (EI) m/z 395 (2,
M+), 289 (45), 261 (90), 91 (100); HRMS ([M + H]+ calcd )
399.1395, found ) 399.1391); FTIR ν ) 3489, 3208, 3034, 2965,
2877, 1453, 1207, 1140, 1090 cm-1. Anal. Calcd for C18H20F6O3:
C, 54.27; H, 5.06; F, 28.62. Found: C, 54.37; H, 5.04.
2-(exo-2-Benzyloxybicyclo[2.2.1]hept-3-on-5-ylmethyl)-
1,1,1,3,3,3-hexafluoropropan-2-ol (18). To a round-bottomed flask
containing 12.3 g of 17 diluted in 500 mL of dichloromethane was
added 14.0 g of pyridium chlorochromate. The reaction mixture
was stirred at room temperature for 12 h, after which time it was
filtered through a plug of silica gel with ethyl acetate as eluent.
The solvent was removed in vacuo to yield 12.1 g of a lightly
brownish viscous liquid (yield 98%): 1H NMR 1.14 (m, 1H), 1.67
(m, 1H), 1.94 (m, 1H), 2.05 (m, 1H), 2.2-2.3 (m, 2H), 2.49 (m,
1H), 2.53 (m, 1H), 2.65 (m, 1H), 3.19 (s, 1H), 3.58 (d, 1H, J )
2.8 Hz), 4.62 (d, 1H, J ) 12 Hz), 4.77 (d, 1H, J ) 12 Hz), 7.2-
7.4 (m, 5H); 13C NMR 31.5, 32.2, 33.2, 35.7, 46.2, 49.2, 72.7, 77.1
(m, JC-F ) 28.4 Hz), 123.3 (q, JC-F ) 288, 20.0 Hz), 128.2, 128.3,
128.7, 138.4, 214.3; 19F NMR -75.2 (q, 3F, JF-F ) 10.0 Hz), -79.1
(q, 3F, JF-F ) 10.0 Hz); LRMS (EI) m/z 290 (15), 259 (20), 247
(15), 91 (100); HRMS ([M + H]+ calcd ) 397.1221, found
)397.1238); FTIR ν ) 3336, 2971, 2882, 1744, 1454, 1250, 1086
cm-1. Anal. Calcd for C18H18F6O3: C, 54.55; H, 4.58; F, 28.76.
Found: C, 54.47; H, 4.56.
Acknowledgment. We gratefully acknowledge the Welch
Foundation and International SEMATECH for financial support
of this work and Prof. Eric Anslyn for helpful discussions.
Supporting Information Available: Experimental details and
characterizational data for compounds 2, 6, and 8-13, as well as
crystallographic data for 8, 16, 17, 19, and 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
2-(exo-2-Benzyloxy-endo-3-hydroxybicyclo[2.2.1]heptan-5-yl-
methyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (19). A round-bot-
tomed flask containing 0.169 g of 18 was diluted in 6 mL of THF
and cooled to 0 °C. To this solution was added 1.1 mL of lithium
triethylborohydride (1 M solution in THF), and the reaction was
JO0513156
344 J. Org. Chem., Vol. 71, No. 1, 2006