Gem-difluorinated homoallyl alcohols, β-hydroxy ketones, and syn- and anti-1, 3-diols via γ,γ-difiuoroallylboronates

Article abstract of DOI:10.1021/ol800069z

γ,γ-Difluoroallylboronates have been prepared from trifluoroethanol and utilized for the allylboration of a variety of aldehydes to provide gem-difluorinated homoallylic alcohols. α-Chiral aldehydes were allylborated in 4:1-13:1 diastereoselectivity favoring the anti-isomer. A representative series of difluorinated hydroxyl enol ethers were converted to the corresponding α, α-difluoro-β-hydroxy ketones. Diastereoselective reduction of one of these to either syn- and anti-1,3-diol was also studied.

Full text of DOI:10.1021/ol800069z

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1195-1198
Gem-Difluorinated Homoallyl Alcohols,
-Hydroxy Ketones, and syn- and
anti-1,3-Diols via
-Difluoroallylboronates
â
γ,γ
P. Veeraraghavan Ramachandran* and Anamitra Chatterjee
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue
UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received January 10, 2008
ABSTRACT
γ
,
γ
-Difluoroallylboronates have been prepared from trifluoroethanol and utilized for the allylboration of a variety of aldehydes to provide
gem-difluorinated homoallylic alcohols. -Chiral aldehydes were allylborated in 4:1 13:1 diastereoselectivity favoring the anti-isomer. A
-difluoro- -hydroxy ketones. Diastereoselective
r
−
representative series of difluorinated hydroxyl enol ethers were converted to the corresponding
reduction of one of these to either syn- and anti-1,3-diol was also studied.
r,r
â
Fluorine often influences the delivery and metabolism of
pharmaceuticals.1 Geminal difluoromethylated molecules are
valued intermediates and targets in drug design owing to their
unique biological properties, such as enzyme inhibition.1 The
preparation of fluoro-aromatic and trifluoromethylated ali-
phatic compounds are becoming commonplace, whereas
gem-difluorinated aliphatic compounds warrant further de-
velopment.2 Allylation is frequently utilized by synthetic
chemists for stitching together simple and complex natural
and unnatural molecules.3 The preparation and reaction of
gem-difluorinated homoallyl alcohols via allylmetals, such
as allylsilanes,4 -lithium,5 -tin,6 -zinc,7 -indium,8 etc. have
been described. Although allylboranes are readily synthesized
and possess demonstrated advantages,9 there has been no
report of fluorine-containing allylboranes or -boronates.
Herein we describe the first synthesis of γ,γ-difluoroallyl-
boronates from trifluoroethanol and their applications for
tailored gem-difluorinated synthons.
Allylboranes can be prepared via transmetalation, hy-
droboration of allenes, Pd-catalyzed addition of boron to 1,3-
dienes, allylic acetates, conjugate-addition elimination, and
homologation of vinylmetals.9 The availability of a variety
of fluorovinylmetals10 encouraged us to adopt the homolo-
gation approach for fluoroallylboranes. We sought to utilize
Nakai’s alkoxydifluorovinyllithium, readily accessed from
trifluoroethanol,11 for the eventual synthesis of difluorinated
synthons (Scheme 1).
(1) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(2) (a) Romanenko, V. D.; Kukhar, V. P. Chem. ReV. 2006, 106, 3868.
(b) Ma, J. A.; Cahard, D. Chem. ReV. 2006, 105, 4581. (c) Tozer, M. J.;
Herpinb, T. F. Tetrahedron 1996, 52, 8619.
(3) (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (b)
Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c) Hoffmann, R. W.
Chem. ReV. 1989, 89, 1841.
(4) (a) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107, 4085. (b)
Fujita, M.; Obayashi, M.; Hiyama, T. Tetrahedron 1988, 44, 4135.
(5) (a) Seyferth, D.; Simon, R. M.; Sepelak, D. J.; Klein, H. A. J. Org.
Chem. 1980, 45, 2273. (b) Seyferth, D.; Simon, R. M.; Sepelak, D. J.; Klein,
H. A. J. Am. Chem. Soc. 1983, 105, 4634.
(8) Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T.; Nemoto, H.
Tetrahedron 2000, 56, 8275.
(9) For a review on pinane-based versatile “allyl” borane reagents, see:
Ramachandran, P. V. Aldrichim. Acta 2002, 35, 23.
(10) Burton, D. J.; Yang, Z. Y.; Morken, P. A. Tetrahedron 1994, 50,
2993.
(6) Seyferth, D.; Wursthorn, J. J. Organomet. Chem. 1979, 182, 455.
(7) Yang, Z.; Burton, D. J. J. Org. Chem. 1991, 56, 1037.
(11) (a) Tanaka, K.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1978,
19, 4809. (b) Nakai, T.; Tanaka, K.; Ishikawa, N. Chem. Lett. 1976, 1263.
10.1021/ol800069z CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

benzyl 2,2-difluorovinyl ether. Indeed, the yield could be
further improved to 82% by utilizing distilled 1.
Scheme 1. Retrosynthesis of Difluoro-Synthons
This new difluoroallylboration was then extended to a
variety of aromatic, aliphatic, and fluorinated aldehydes.
Electron-donating (4b) or withdrawing (4c-d) groups
on the phenyl ring, the steric bulk of the aliphatic aldehydes
(4f-j), or fluorine substitution (4e, 4k) did not have a
noticeable effect on the yields. All reacted within 1-5 h,
except the bulky pivaldehyde (4i), which required 30 h for
completion. This prompted a solvent study15 and examination
of pentane, toluene, and dichloromethane revealed that the
reaction proceeded faster in these solvents. Noticeably,
reagent 1 was consumed by all of the aldehydes almost
instantaneously in pentane. The results are summarized in
Table 1.
Initially, we examined the homologation12 of tosyloxydi-
fluorovinyllithium (2′),13 prepared from trifluoroethanol
tosylate, with diisopropyl iodomethylboronate14 at -78 °C.
Gratifyingly, the resultant “ate complex” (3′) (11B NMR
spectrum: δ 2 ppm, singlet), upon warming to room
temperature (rt), displaced the iodide with the tosyloxydif-
luorovinyl group to furnish the desired allylboronate (1′)
within 12 h (Scheme 2, 11B: δ 28 ppm). Subsequent
Having standardized the reagent preparation and reaction
conditions, the diastereoselectivity of the difluoroallylbora-
tion of chiral aldehydes was probed. (S)-3-(tert-butyldim-
ethylsilyloxy)-2-methylpropanal (4l), (R)-2,2-dimethyl-1,3-
dioxolane-4-carbaldehyde (4m), and (R)-2-phenylpropanal
(4n) underwent allylboration instantly at rt to provide the
product alcohols with diastereoselectivity in the range 4:1
to 13:1 (Table 1, entry 12-14). The upfield resonance of
the CF2 group for the major isomers of 5l-n in the 19F NMR
spectra revealed them to be anti on the basis of literature
report.16 The diastereomers of 5l were separated by column
chromatography to characterize the isomers. Conversion of
the major isomer to the corresponding 3,5-dinitrobenzoate
and examination by X-ray crystallography (Figure 1) con-
firmed it to be anti.
Scheme 2. Preparation and Reaction of
γ,γ-Difluoroallyl-Boronates
allylboration of benzaldehyde (4a) revealed no reaction at
rt, but proceeded to completion in 24 h under refluxing THF
(11B NMR shift from δ 28 to 18 ppm). Aqueous workup
provided the corresponding difluorinated homoallylic alcohol
5′a in 60% yield.
Presuming that the slow rate of allylboration could be the
consequence of decreased electron-density on the alkene due
to the tosyl group, we sought to commence the synthesis of
the allylboronate with trifluoroethanol bearing other protect-
ing groups. Due to the ease of its removal, benzyl 2,2,2-
trifluoroethyl ether was treated with two equiv of n-butyl-
lithium in THF to provide the difluorovinyllithium (2). This
underwent facile homologation with diisopropyl iodometh-
ylboronate within 1 h to provide â-benzyloxy-γ,γ-difluoro-
allylboronate 1. An accelerated allylboration of 4a was
achieved in situ, within 1 h at rt, and an aqueous workup
provided 3-benzyloxy-2,2-difluoro-1-phenyl-3-buten-1-ol (5a)
in 45% isolated yield. The yield of the in situ allylboration
could be improved to 76% by preparing the reagent 1 from
Figure 1. X-ray crystal structure of 3,5-dinitrobenzoate of the
major isomer of 5l.
Ishihara and co-workers have reported the synthesis of
R,R-difluorinated-â-hydroxy ketones via the aldol reaction
(15) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990,
55, 1868.
(16) Zhang, X.; Xia, H.; Dong, X. C.; Jin, J.; Meng, W. D.; Qing, F. L.
J. Org. Chem. 2003, 68, 9026.
(17) Kuroboshi, M.; Ishihara, T. Tetrahedron Lett. 1987, 28, 6481.
(18) Hydrogenation of the protected alcohol (5a) resulted in a 1:1 mixture
of syn and anti diol which were separated as their cyclic acetal and
characterized fully.
(12) Wuts, P. G. M.; Thompson, P. A.; Callen, G. R. J. Org. Chem.
1983, 48, 5398.
(13) (a) Ichikawa, J.; Kaneko, M.; Yokota, M.; Itonaga, M.; Yokoyama,
T. Org. Lett. 2006, 8, 3167. (b) Ichikawa, J.; Sonoda, T.; Kobayashi, H.
Tetrahedron Lett. 1989, 30, 1641.
(14) (a) Soundararajan, R.; Li, G.; Brown, H. C. J. Org. Chem. 1996,
61, 100. (b) Wallace, R. H.; Zong, K. K. Tetrahedron Lett. 1992, 33, 6941.
1196
Org. Lett., Vol. 10, No. 6, 2008

and molecular sieves.17 Having prepared a variety of R,R-
difluorinated â-hydroxyl enol benzyl ethers in high yields,
we undertook their conversion to a representative series of
R,R-difluorinated-â-hydroxy ketones for further conversion
to either the syn or anti-2,2-difluoro-1,3-diols.18 While
reagents, such as BF3-Et2O, 6N HCl, ceric ammonium
nitrate, and DDQ debenzylated in poor to moderate yields,
Na in liquid NH3 provided the highest yield for the hydroxy
Table 1. Difluoroallylboration of Aldehydes with 1ba
19
ketone. Thus, the treatment of 5a with Na in liquid NH3
yielded 78% of the â-hydroxy ketone 6a. This protocol was
then extended to include 5b, 5h, and 5i. The corresponding
hydroxy ketones were obtained in 75-82% yields (Scheme 3).
Scheme 3. Preparation of R,R-Difluoro-â-hydroxy Ketones
Diastereoselective reduction of â-hydroxyketones is a well
studied topic in organic chemistry.20 Kuroboshi and Ishihara
had conducted a systematic study on the diastereoselective
reduction of R,R-difluoro-â-hydroxy ketones to prepare the
corresponding syn- and anti-1,3-diols, utilizing DIBALH in
the presence of ZnCl2-TMEDA and triisopropoxyaluminum,
respectively.21 They had observed that contrary to the
reduction of non-fluorinated systems, anti-selective reagents
DIBALH afforded the syn-diol predominantly and tetram-
ethylammonium triacetoxyborohydride provided a complex
mixture.
A variety of reducing agents were examined for the
reduction of 6a and the results are summarized in Table 2.
Confirming Ishihara’s results, we achieved the syn-diol (syn-
7a) in high yields by reduction with DIBALH in the presence
Table 2. Diastereoselective Reduction of R,
R-difluoro-â-hydroxy Ketone 6a
entry
reducing agent
temp (°C) time, h yielda syn/antib
1
2
3
4
5
6
7
Me4N(OAc)3BH
Na(OAc)3BH
Al(OiPr)3
LiAl(tBuO)2H2
NaBH4/Et3B/MeOH
DIBAL-H/NMO
DIBALH/ZnCl2-
TMEDA
-40
-40
rt
-78
rt
24
24
48
6
4
8
90
92
94
85
88
89
92
25:75
20:80
19:81
59:41
76:24
87:13
93:7
a Reactions were carried out in pentane at rt with 1.2 equiv reagent within
5 min. b Isolated yield of pure product. c syn/anti ratio determined using
19F NMR spectrum of the crude reaction mixture.
-78
-78
8
a Isolated yield of pure product. b Ratio determined by 19F NMR of the
crude reaction mixtures of the corresponding acetals.
of chlorodifluoromethyl ketones in the presence of zinc, a
catalytic amount of copper(I) chloride or silver(I) acetate,
Org. Lett., Vol. 10, No. 6, 2008
1197

of ZnCl2-TMEDA and also with DIBALH-NMO.22 Never-
theless, anti-7a was obtained predominantly with both
tetramethylammonium and sodium triacetoxyborohydride
(entry 1 and 2). Meerwein-Ponndorf-Verely reduction pro-
vided primarily the anti-isomer, whereas reduction under
Narasaka’s conditions23 with sodium borohydride in the
presence of triethylborane and methanol provided the syn-
product as the major isomer.
In conclusion, the preparation of difluorinated allylborating
agents in high yield and purity via the homologation of
lithiated difluorovinyl ethers derived from trifluoroethanol
has been described. A variety of aldehydes, including
R-chiral aldehydes, were successfully allylborated almost
instantly in pentane at rt to provide the gem-difluorinated
homoallylic alcohols in good yields.24 A representative series
of difluorinated hydroxyl enol ethers were converted to the
corresponding R,R-difluoro-â-hydroxy ketones, and one of
these ketones was further reduced to either syn- and anti-
1,3-diol in high diastereoselectivity. This methodology can
be applied to the efficient preparation of various gem-
difluoro-containing molecules, including sugars and lactones.
This chemistry is currently being used to prepare chiral
reagents, synthons, and targets.
Supporting Information Available: Experimental details
and spectral data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800069Z
(24) The preparation and representative reaction of 1 is as follows. (a)
Preparation of benzyl-2,2,2-trifluoroethyl ether: Trifluoroethanol (20 g, 14.6
mL, 200 mmol) was added, slowly, to a suspension of NaH in THF (200
mL) (8.72 g, 55% dispersion in mineral oil, 200 mmol) at 0 °C and warmed
to rt. When the hydrogen evolution ceased, benzyl bromide (30.8 g, 21.5
mL, 180 mmol) was added and refluxed for 3 h. The organic solvents were
removed and the residue was washed with ether and the combined organics
were washed with brine, dried (anhydrous MgSO4), concentrated, and
distilled to provide benzyl-2,2,2-trifluoroethyl ether as a colorless liquid
(32 g, 94%). bp 80 °C/30 Torr. (b) Preparation of 1-benzyloxy-2,2-
difluoroethene: Under vigorous stirring, at -100 °C, the above benzyl-
2,2,2-trifluoroethyl ether (7.6 g, 40 mmol) was added, slowly over a period
of 20 min, to a solution of n-BuLi (40 mL, 2.5 M solution in hexane, 100
mmol) in THF (120 mL) and kept stirring for another 2 h. The dark-red
solution was quenched with methanol (12 mL) at this temperature, followed
by the addition of aqueous saturated NH4Cl solution (40 mL). The solution
was warmed to rt and diluted with diethyl ether (200 mL). The ether layer
was separated and the aqueous layer was washed with ether (3 × 20 mL).
The combined ether layer was washed with brine, dried (anhydrous MgSO4),
and evaporated. The residue was distilled to yield 1-benzyloxy-2,2-
difluoroethene as a colorless viscous liquid (5.2 g, 76%). bp. 70 °C/30 Torr.
(c) Preparation of â-benzyloxy-γ,γ-difluoroallylboronate (1): n-BuLi (12.2
mL, 2.5 M solution in hexane, 30.4 mmol) was added, slowly at -78 °C,
to a solution of 1-benzyloxy-2,2-difluoroethene (5.2 g, 30.4 mmol) in THF
(60 mL) and at that temperature for 20 min. Diisopropyl iodomethylboronate
(8.2 g, 30.4 mmol) was added slowly, at -78 °C, to the resultant red
solution, left stirred for 0.5 h, allowed to warm to rt, and continued to stir
for 2 h. The solvents were removed under vacuo, and the residue was
triturated with dry pentane (30 mL). The supernatant was filtered through
a short bed of celite under inert atmosphere. The residue was washed with
pentane (4 × 20 mL), and the combined organics was concentrated and
distilled to yield â-benzyloxy-γ,γ-difluoroallylboronate (1) as a colorless
liquid. bp. 79-82 °C/0.2 Torr. (d) Representative procedure for allylbo-
ration: Allylboronate 1 (2.2 mL of 1 M solution in pentane, 2.2 mmol)
was added to a solution of benzaldehyde (0.21 mL, 2 mmol) in pentane.
Upon completion (11B NMR spectroscopy: δ 28 to 18 ppm, 2 min), the
reaction was quenched with 2 mL of sat. NH4Cl solution. The product was
extracted with ether (3 × 20 mL), dried (Na2SO4), concentrated, and purified
by flash silica gel chromotography (hexane:ethyl acelate ) 4:1) to yield
homoallylic alcohol 5a ( 0.48 g, 82 %) as a colorless viscous liquid.
Acknowledgment. Financial support from the Herbert C.
Brown Center for Borane Research is gratefully acknowl-
edged.
(19) Reist, E. J.; Bartuska, V. J.; Goodman, L. J. Org. Chem. 1964, 29,
3725.
(20) Brown, H. C.; Ramachandran, P. V. In Reductions in Organic
Chemistry; ACS Sym. Ser. 641; Abdel Magid, A. F., Ed.; American
Chemical Soc.: Washington, DC, 1996; Chapter 1.
(21) Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 1185.
(22) Ramachandran, P. V.; Reddy, M. V.; Rudd, M. T. Chem. Commun.
1999, 1979.
(23) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233.
1198
Org. Lett., Vol. 10, No. 6, 2008