Difluoromethyl Phenyl Sulfone as a Selective Difluoromethylene Dianion Equivalent: One-Pot Stereoselective Synthesis of anti-2,2-Difluoropropane-1,3-diols

Article abstract of DOI:10.1002/anie.200352172

Intramolecular charge-charge repulsion rather than traditional steric control is responsible for the high diastereoselectivity (up to 94% de) obtained in tBuOK-induced difluoromethylenation of aldehydes 1 with difluoromethyl phenyl sulfone (2) to give symmetrical and unsymmetrical anti-2,2-difluoropropane-1,3-diols 3.

Full text of DOI:10.1002/anie.200352172

Communications
Difluoromethylenation
Difluoromethyl Phenyl Sulfone as a Selective
Difluoromethylene Dianion Equivalent: One-Pot
Stereoselective Synthesis of anti-2,2-
Difluoropropane-1,3-diols**
G. K. Surya Prakash,* Jinbo Hu, Thomas Mathew, and
George A. Olah
That more and more organofluorine compounds have been
found to display biological effects such as mimicry, blocking,
polarity, and lipophilicity is attributed to the unique proper-
[
1]
ties of the fluorine atom. For instance, the CꢀF bond mimics
the CꢀHbond because of its similar bond length, and the
difluoromethylene group is isosteric and isopolar to an
[
2]
ethereal oxygen atom. Hence, the synthesis of fluorine-
containing analogues of bioactive natural products is of great
interest because of their potential applications in the phar-
[
3]
maceutical industry. Since anti-1,3-diol functionality is a
fundamental unit in many naturally occurring compounds, its
stereoselective preparation is attractive to synthetic organic
[
4]
chemists. anti-2,2-Difluoropropane-1,3-diols 3 are a group
of interesting compounds, but not much is known about their
synthesis. To the best of our knowledge, the only reported
method to synthesize these compounds is by diasteroselective
Meerwein–Pondorff–Verley reduction of a,a-difluoro-b-hy-
[
5]
droxy ketones. The disadvantage of this approach is the
need to prepare the a,a-difluoro-b-hydroxy ketone precur-
sors.
In 1997, we reported the preparation of difluorobis(tri-
methylsilyl)methane (TMSCF TMS) as a potential difluoro-
2
ꢀ
ꢀ
[2]
methylene dianion (“ CF ”) equivalent.
However,
2
TMSCF TMS was found only to couple with one equivalent
2
of an aldehyde, for example, with benzaldehyde to give 2,2-
[
2]
difluoro-1-phenylethanol (after acid hydrolysis).
We recently disclosed alkoxide- and hydroxide-induced
nucleophilic trifluoromethylation of nonenolizable carbonyl
compounds and disulfides by using trifluoromethyl sulfone or
[
6]
sulfoxide. The chemistry is based on the nucleophilic attack
by alkoxide (commonly potassium tert-butoxide) or hydrox-
ide on the sulfur center of trifluoromethyl phenyl sulfone (4a)
or sulfoxide (4b) to release
Scheme 1, Eq. (1)]. We assumed that a similar type of SꢀC
bond cleavage could occur with difluoromethyl phenyl
a trifluoromethyl anion
[
[*] Prof. Dr. G. K. S. Prakash, Dr. J. Hu, Dr. T. Mathew,
Prof. Dr. G. A. Olah
Loker Hydrocarbon Research Institute and
Department of Chemistry
University of Southern California
University Park, Los Angeles, CA 90089-1661 (USA)
Fax: (+1)213-740-6270
E-mail: gprakash@usc.edu
[
**] Support of our work by Loker Hydrocarbon Research Institute is
gratefully acknowledged. Professor G. Rasul is thanked for his help
with preliminary theoretical calculations.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5
216
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DOI: 10.1002/anie.200352172
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Angewandte
Chemie
selectively (see Scheme 2). An excess of tBuOK
facilitates completion of SꢀC bond-cleavage
process, which is similar to our previous obser-
vations with the trifluoromethyl sulfone
[
6]
system. Furthermore, the formation and con-
sumption of PhSCF H (14) with time (Table 1,
2
entries e and f) indicate that there is an equili-
brium between anionic species 16 and 14 with
protonation/deprotonation by tBuOH/tBuOK.
Reaction of benzaldehyde (1a) and sulfone 2/
tBuOK in DMF is much more intriguing and
rewarding (see Scheme 3). Similar to the reac-
tion with diphenyl disulfide, PhSO CF H
2
2
(
(
1.0 equiv)/tBuOK (3.0 equiv) reacts with 1a
2.0 equiv) at ꢀ508C!RT over 90 min to gen-
1
9
erate monosubstituted product 17 ( F NMR:
4
1% yield), as earlier shown by Stahly in
[
8]
aqueous NaOH, and disubstituted product 3a
1
9
(
(
F NMR: 58% yield, anti/syn = 98/1). When 2
1.0 equiv)/tBuOK (4.0 equiv) reacted with
Scheme 1. Mechanistic considerations. R=H, alkyl group. E, E’=electrophiles, such
as disulfides and aldehydes.
PhCHO (3.0 equiv) at ꢀ508C!RT for 8 h with
sulfone
2
(PhSO CF H). The
Table 1: Difluoromethylenation of PhSSPh with 2.
2
2
chemistry of 2 is even more inter-
esting than that of 4a [Scheme 1,
Eq. (2)]. It is known that the
hydrogen atom of the CF Hgroup
2
in compound 2 is rather acidic, and
a common base such as sodium
methoxide or even aqueous
sodium hydroxide can deprotonate
it in an equilibrium mode to gen-
[
a]
Entry
Reactant ratio [equiv]
Reaction time
Product yield [%]
2
tBuOK
11
12
13
14
a
1
1
2.5
1
1
1
1.0
1.5
2.0
3.0
3.5
3.5
4.0
1.0
1.0
14 h
2.0
2.0
2.0
2.0
30 min
50 min
76
91
0
3
5
6
b
c1
d
e
f
g
ꢀ
[7,8]
64
22
14
44
erate PhSO CF2 (6).
In 1989,
2
4 h
4 h
15 h
4 h
41
0
0
14
16
3
Stahly showed that anion 6, gener-
ated in situ, can react with alde-
hydes to give difluoromethylated
carbinols in aqueous NaOHin the
84
97
99
1
0
0
19
[a] Yields were determined by F NMR spectroscopy with PhOCF as the internal standard.
3
presence of
agent.
a
phase-transfer
However, he did not
observe any SꢀC bond cleavage in aqueous NaOH(RT,
h). Obviously, aqueous NaOHis not nucleophilic enough to
[
8]
4
activate the SꢀC bond scission, and with hydroxide or
alkoxide the deprotonation of difluoromethyl sulfone 2 is
much faster than SꢀC bond cleavage. Thus, by use of an
appropriate alkoxide such as tBuOK that acts both as a base
and a nucleophile, sulfone 2 might react stepwise with two
electrophiles to give new difluoromethylene-containing prod-
ucts [Scheme 1, Eq. (2)]. Thus, difluoromethyl phenyl sulfone
2
can be regarded as a selective difluoromethylene dianion
2
ꢀ
(
“CF2 ”) synthon.
With the above considerations in mind, we first treated
the PhSO CF H/tBuOK system with diphenyl disulfide
2
2
(
PhSSPh) as an electrophile. The results are shown in
Table 1. By using different reactant ratios, both monosubsti-
tution product 12 and disubstitution product 13 can be
obtained at room temperature with high selectivity (Table 1,
entries b and g). This result confirms our previous assumption
that the reactivities of deprotonation and SꢀC bond cleavage
are different, and that these two steps can be controlled
Scheme 2. Stepwise formation of 12 and 13.
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Communications
intermediate 18, which further reacts with p-chlorobenzalde-
hyde 1b to give unsymmetrical anti-2,2-difluoropropane-1,3-
diol 20 (after hydrolysis) with high diastereoselectivity.
In conclusion, potassium tert-butoxide-induced difluoro-
methylenation with difluoromethyl phenyl sulfone enables us
to synthesize both symmetrical and unsymmetrical anti-2,2-
difluoropropane-1,3-diols with high diastereoselectivity (up
to 94% de). This unusual type of high diastereoselectivity was
obtained by means of an intramolecular charge–charge
repulsion effect rather than the traditional steric control
(based on Cram's rule). Difluoromethyl phenyl sulfone can be
used as a selective synthon for the difluoromethylene dianion
ꢀ
ꢀ
(
CF ), which can couple with two electrophiles (e.g.,
2
1
9
Scheme 3. Reaction of PhCHO (excess) and 2/tBuOK. [a] F NMR for
diphenyl disulfide or nonenolizable aldehydes) to give new
difluorinated products. Since difluoromethyl phenyl sulfone
can be readily prepared from inexpensive chemicals such as
3
19
anti isomer: d=ꢀ120.9 ppm (pseudo t, J(F,H)=11.4 Hz, 2F). [b]
F
NMR: d=ꢀ104.4 ppm (dd, J=238.0, 2.8 Hz, 1F); d=ꢀ119.8 ppm
(
dd, J=238.0, 21 Hz, 1F).
activation by tBuOK, alkoxide 17b is formed in
situ and undergoes SꢀC bond fission to generate
dianionic intermediate 18, which can react with
a further equivalent of benzaldehyde to form
disubstituted anti-diol 3a in excellent yield
1
9
(
F NMR: 92%, isolated product: 82%) and
high diastereoselectivity (anti/syn = 97/3, de =
4%). The observed high diastereoselectivity
9
can be interpreted by a charge–charge repulsion
effect during the second addition (Scheme 4).
To the best of our knowledge, this may be the
first time that high diastereoselectivity has been
achieved in the reaction of a dianion with
another, neutral electrophile under the influ-
ence of an intramolecular charge–charge repul-
sion effect (during product formation) rather
than the traditional steric control
Scheme 4. Proposed mechanism of diastereoselective formation of 3a from PhCHO
and 2/tBuOK.
[
9,10]
(
based on Cram's rule).
Table 2 demonstrates the appli-
Table 2: Preparation of 2,2-difluoropropane-1,3-diols 3 from aldehydes 1(3 equiv) and difluoromethyl
phenyl sulfone 2 (1 equiv) with tBuOK (4 equiv) in DMF at ꢀ508C!RT.
cation of this methodology to the
synthesis of various 2,2-difluoro-
propane-1,3-diols with high stereo-
selectivity from nonenolizable
[a]
[b]
Entry
Substrate 1
Product 3
Yield [%]
anti/syn
de [%]
a
82
97:3
94
[
11]
aldehydes.
The yields of diols
are a bit lower for electron-rich
aldehydes (entries d and g), prob-
ably due to the relative instability
of the corresponding dianion inter-
mediates.
b
c
78
70
52
94:6
96:4
94:6
88
92
88
Besides symmetrical anti-2,2-
difluoropropane-1,3-diols,
this
d
new methodology can also be
used to synthesize unsymmetrical
anti-2,2-difluoropropane-1,3-diols.
Scheme 5 shows an example of this
type of synthesis. Difluoro(phenyl-
sulfonyl)methyl-substituted alco-
hol 17a can be easily obtained
and isolated by Stahly's approach
e
f
69
75
63
97:3
96:4
93:7
94
92
86
g
[
8]
in high yield. Activation of 17a
with tBuOK generates the dianion
1
9
[a] Yields of isolated product. [b] anti/syn ratios were determined by F NMR spectroscopy.
5
218
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Angew. Chem. Int. Ed. 2003, 42, 5216 –5219

Angewandte
Chemie
7
.5 mmol) in DMF (5 mL) at ꢀ508C. The reaction flask
was then sealed, and the reaction mixture was then stirred
at ꢀ508C for 1 h, followed by stirring at ꢀ508C!RT
overnight. The reaction mixture was quenched with ice
water (20 mL), and extracted with diethyl ether (3 ꢀ
20 mL). The combined ethereal phase was washed with
a saturated aqueous solution of NH Cl, and then with
4
water. After drying over MgSO , the diethyl ether solvent
4
was removed under vacuum. The crude product was
further purified by chromatography on a silica gel column
(hexanes/ethyl acetate 9/1, then 1/1) to give 2,2-difluoro-
1,3-diphenyl-1,3-propanediol as a white crystalline solid,
(
541 mg, 82% yield, anti/syn = 97/3, determined by
1
9
1
F NMR). anti isomer: HNMR ([D ]actone): d = 5.27
6
1
9
(
m, 4H), 7.28–7.50 ppm (m, 10H); F ([D ]acetone): d =
6
ꢀ
120.9 ppm (dd, J = 11 Hz, J = 11 Hz, 2F); HRMS (DCI/
+
NH ): m/z calcd for C H F NO [M+NH ]: 282.1305,
3
15 18
2
2
4
Scheme 5. Synthesis of unsymmetrical anti-2,2-difluoropropane-1,3-diol 20.
found: 282.1304.
[
[
12] G. K. S. Prakash, J. Hu, G. A. Olah, J. Org. Chem. 2003,
8, 4457 – 4463, and references therein.
13] J. Hu, Ph.D. Dissertation, University of Southern Cal-
6
[
12,13]
CF ClHor CF Br ,
this new methodology provides a
2
2
2
convenient and efficient synthetic tool for many potential
applications.
ifornia, 2002.
Received: June 18, 2003 [Z52172]
Keywords: alcohols · CꢀC coupling · diastereoselectivity ·
.
fluorine
[
1] Organofluorine Compounds. Chemistry and Applications (Ed.:
T. Hiyama), Springer, New York, 2000.
[
2] A. K. Yudin, G. K. S. Prakash, D. Deffieux, M. Bradley, R. Bau,
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[
3] J. McCarthy, Utility of Fluorine in Biologically Active Molecules,
th
ACS Fluorine Division Tutorial, 219 National ACS Meeting,
(
San Francisco), 2000.
[
[
4] S. Masamune, W. Choy, Aldrichimica Acta 1982, 15, 47 – 64.
5] M. Kuroboshi, T. Ishihara, Bull. Chem. Soc. Jpn. 1990, 63, 1185 –
1
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[
3
[
[
[
7] J. Hine, J. J. Porter, J. Am. Chem. Soc. 1960, 82, 6178 – 6181.
8] P. Stahly, J. Fluorine Chem. 1989, 43, 53 – 66.
9] Recently, two groups reported the control of stereoselectivity by
electrostatic repulsion. a) In 1997, Mall and Stamm reported that
electrostatic repulsion by the charged tail of a radical controls
the stereochemistry of coupling with the anthracenide radical
anion: T. Mall, H. Stamm, J. Chem. Soc. Perkin Trans. 2 1997,
2135 – 2140. b) In 2001, Uneyama et al. reported control of
diastereoselectivity by electrostatic repulsion between the
negative charge density on a trifluoromethyl group and that of
electron-poor aromatic rings: T. Katagiri, S. Yamaji, M. Handa,
M. Irie, K. Uneyama, Chem. Commun. 2001, 2054 – 2055; T.
Katagiri, K. Uneyama, Chirality 2003, 15, 4 – 9.
[
[
10] DFT calculations (B3LYP6-31G**//B3LYP6-31G* + ZPE level)
on 3,3-difluoro-2,4-pentanediolate dianion as a model showed
ꢀ1
the anti structure to be 5.5 kcalmol more stable than the
corresponding syn structure. Furthermore, the absence of
changes in the anti/syn diol ratios on prolonged treatment with
base indicate lack of product reversibility.
11] Typical procedure for tBuOK-induced difluoromethylenation:
The reaction was commonly carried out in a Schlenk flask under
an argon atmosphere. A solution of tBuOK (1.12 g, 10 mmol) in
DMF (5 mL) was added to solution of difluoromethyl phenyl
sulfone (2, 480 mg, 2.5 mmol) and benzaldehyde (800 mg,
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