New approach to 3,3-difluoroallyl alcohol

Article abstract of DOI:10.1016/j.jfluchem.2012.08.001

A new difluoroalkene with a triethylsilyl group, 4,4-difluoro-3- (triethylsilyl)- but-3-en-1-ol (1), was synthesized as a new building block for 1,1-difluoro-1-alkenes. Treatment of 1 with sodium hydride in the presence of a catalytic amount of p-methoxyphenol induced SiCsp² bond dissociation. Subsequent addition of an aldehyde to the reactive intermediate afforded 3,3-difluoroallyl alcohol (9). The reaction was accelerated by added p-methoxyphenol.

Full text of DOI:10.1016/j.jfluchem.2012.08.001

Journal of Fluorine Chemistry 144 (2012) 114–117
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
New approach to 3,3-difluoroallyl alcohol
Masaaki Omote a, Tatsuya Miake a, Atsushi Tarui a, Kazuyuki Sato a, John T. Welch b,
Itsumaro Kumadaki a, Akira Ando a,
*
a Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata 573-0101, Japan
b Department of Chemistry, The University at Albany – SUNY, 1400 Washington Ave., Albany, NY 12222, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
A new difluoroalkene with a triethylsilyl group, 4,4-difluoro-3-(triethylsilyl)- but-3-en-1-ol (1), was
synthesized as a new building block for 1,1-difluoro-1-alkenes. Treatment of 1 with sodium hydride in
the presence of a catalytic amount of p-methoxyphenol induced Si–Csp2 bond dissociation. Subsequent
addition of an aldehyde to the reactive intermediate afforded 3,3-difluoroallyl alcohol (9). The reaction
was accelerated by added p-methoxyphenol.
Received 8 June 2012
Received in revised form 2 August 2012
Accepted 11 August 2012
Available online 5 September 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
3,3-Difluoroallyl alcohol
1,1-Difluoro-1-alkenes
Triethyl(alkenyl)silane
1. Introduction
2. Result and discussion
Fluorinated olefins have attracted much attention, especially for
use in medicinal chemistry as bioisosteres [1]. Particularly notable
are compounds with an exo-difluoromethylene moiety that can act
as chemically stable bioisosteres of an aldehyde or ketone, being
inherently reactive electrophiles [2,1c,1d]. Many studies on the
bioisosteric propensity of exo-difluoromethylene-containing sugars
and related compounds have been reported [3,1c]. For exo-
difluoromethylene unit construction, ketones were shown to react
with CF2 carbene from sodium chlorodifluoroacetate [4]. This
reaction and its variants are the method of choice with appropriate
substrates. On the other hand, a variety of building blocks have been
developed for a convenient access to 2,2-difluoroalkenes. In 1981,
the first preparation of 2,2-difluorovinyllithium from gaseous 1,1-
difluoroethene accelerated the search for such building blocks [5,6].
We considered that 1,1-difluorovinyl-2-triethylsilyl compound, 1,
could generate a 2,2-difluorovinyl anion species on treatment with
sodiumhydridethroughintramolecularbonddissociationofSi–Csp2
bond. The resulting 2,2-difluorovinyl anion could react with
aldehydes to generate a 3,3-difluoroallyl alcohol scaffold with a
tethered hydroxyethyl chain capable of delivering a variety of
substructures. Herein, we wish to report a new pathway to 3,3-
difluoroallyl alcohols that are amenable to a variety of synthetic
transformations (Fig. 1).
Preparation of 1, from 2,2,2-trifluoroethanol, 4, was possible in
the moderate yields appropriate for gram-scale synthesis. Treat-
ment of 4 with excess LDA induced retro Brook rearrangement to
give silyl ketone 5 [7]. Subsequently, the
a,b-unsaturated ester 6
was constructed by Horner–Wadsworth–Emmons olefination of 5
[8]. The terminal hydrogen on difluorocarbon in 6 was sufficiently
acidic that deprotonation with LDA to dienolate anion followed by
acidification gave 7. Addition of TMSCl to trap the LDA-generated
dienolate increased the yield of 7. Reduction of the ester group of 7
produced 1 that was the precursor required for further transfor-
mations (Scheme 1).
Commonly, dissociation of Si–Csp2 bond is effected by
treatment with a fluoride or oxide anion [9]. In the case of 1,
the Si–Csp2 bond could be dissociated by the intramolecular
assistance of alkoxide ion through 5 membered ring formation like
intermediate 2 [10]. We explored the possibility of the Si–Csp2
bond dissociation by conducting the reaction of 1 with NaH in
several classes of solvents. Difluorovinyl anion generated was
quenched by the addition of an aldehyde to afford a 3,3-
difluoroallyl alcohol.
The results are summarized in Table 1. THF and CH2Cl2 were
inferior solvents for the reaction. Meanwhile, DMF and DMPU
were viable solvents for generation of adduct 9a. Interestingly, the
presence of small portions of water in the solvent increased the
yield of 9a around 30% along with a considerable amount of 10
(entry 8, Table 1). The result prompted us to investigate the effect
of an additional hydroxide ion on this reaction system.
* Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 850 7020.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.08.001

M. Omote et al. / Journal of Fluorine Chemistry 144 (2012) 114–117
115
Fig. 1. Si–Csp2 bond dissociation strategy through intramolecular assistance of alkoxide ion.
Scheme 1. Synthesis of 1.
Table 1
Intramolecular Si–Csp2 bond dissociation reaction and subsequent trapping of the generated carbanion.
.
Entry
Solvent
Temp. (8C)
Time (h)
Yield
(%) 9aa
Yield
(%) 10a
1b
2c
3b
4c
5b
6c
7b
8c
THF
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0
12
12
12
12
12
1.5
12
1.5
nr
nr
nr
nr
CH2Cl2
DMF
11
36
8
7
20
23
60
DMPU
0 to rt
0
30
a
Isolated yield.
b
c
Anhydrous solvent was used.
Solvent was used without dehydration.
Addition of an equimolar amount of hydroxide ion improved
the reaction slightly in both solvents (entries 1 and 3 in Table 2),
while a catalytic amount of hydroxide ion accelerated the reaction
markedly to yield a 71% of 9a with suppression of the generation of
10 (entry 4). On the basis of these findings, a search for more
suitable additives was conducted (see Table 2). p-Methoxyphen-
oxide ion was the most expedient additive producing an optimal
yield of 9a with formation of 10 notably suppressed (entry 7)
(Table 3).
To determine the optimal condition, the influence of the
alkoxide counter cation was also investigated. Neither potassium
nor lithium hydride, was more effective than sodium hydride, with
both cations retarding the reaction by comparison.
Table 2
Acceleration effect of oxide anion on the reaction.
Entry
Additive (equiv)
NaH
Solvent
Yield
Yield
(equiv)a
(%) 9ab
(%) 10b
1
2
3
4
5
6
7
8
9
H2O (1.0)
2.5
DMF
33
35
39
71
59
74
76
66
64
55
35
57
16
15
9
H2O (0.25)
1.75
2.5
H2O (1.0)
DMPU
H2O (0.25)
1.75
1.75
1.75
1.75
1.75
1.75
EtOH (0.25)
CF3CH2OH (0.25)
p-MeO–C6H4OH (0.25)
PhOH (0.25)
5
10
11
Subsequently, the scope and limitation of the reaction with
several aromatic and aliphatic aldehydes under the optimized
conditions were explored. The reaction with the more electron-
rich p-anisaldehyde proceeded in only 56% yield (entry 3, Table 4),
p-NO2–C6H4OH (0.25)
a
Same amount of NaH with additive was added extra for the generation of
corresponding oxide anion in the reaction media.
b
Isolated yield.

116
M. Omote et al. / Journal of Fluorine Chemistry 144 (2012) 114–117
Table 3
diisopropylamine (2,1 mL, 15.0 mmol) in THF (50 mL) at 0 8C
Effect of counter cation on the reaction.
and the mixture was stirred for 30 min. To the mixture was added
solution of 6 (3.6 g, 13.6 mmol) in THF (10 mL) over 30 min. After
stirring for further 30 min at 0 8C, TMSCl (1.92 mL, 15.0 mmol) was
added slowly into the reaction mixture and whole was stirred for
1 h at room temperature. The reaction mixture was poured into
ice-cold aqueous 10% HCl, extracted with Et2O and organic layer
was dried over anhydrous MgSO4. After evaporation of the solvent,
the residue was purified by column chromatography (SiO2,
EtOAc:hexane = 5:95) to give 7 (3.24 g, 90%). 7: A colorless oil.
Entry
Base
Temp. (8C)
Time (h)
Yield (%) 9aa
1
2
3
NaH
KH
0
1.5
1.5
24
76
37
57
0
LiH
0 to rt
a
Isolated yield.
Table 4
Scope and limitation of the reaction.a
1H NMR (400 MHz, CDCl3)
J = 8.0 Hz, 9H), 1.26 (t, J = 7.1 Hz, 3H), 2.98 (t, J = 0.4 Hz, 2H), 4.14 (q,
J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
: 2.9 (dd, J = 1.7,
d: 0.67 (q, J = 8.0 Hz, 6H), 0.95 (t,
Entry
8
RCHO
Ph-
9
Yield (%)b
d
1
2c
3
8a
8a
8b
8c
8d
8e
8e
8f
9a
76
42
56
31
35
nd
23
51
1.6 Hz), 7.1, 14.1, 31.2 (dd, J = 8.1, 5.1 Hz), 60.8, 73.9 (dd, J = 35.4,
5.3 Hz), 157.3 (dd, J = 306.3, 282.6 Hz), 171.1 (dd, J = 3.9, 2.6 Hz);
9a
9b
9c
9d
9e
9e
9f
p-MeO–C6H4–
p-CF3–C6H4–
2-Pyridyl
19F NMR (90 MHz, CDCl3)
d
: À7.8 (d, J = 31.0 Hz, 1F), À15.4 (d,
4
5
J = 31.0 Hz, 1F); IR (neat) nmax 2964, 1742 cmÀ1; MS m/z = 235
(M+À29).
6
Isopropyl
7c
8c
Cyclohexyl
4.3. Synthesis of 4,4-difluoro-3-(triethylsilyl)but-3-en-1-ol (1)
a
Reaction was conducted with p-methoxyphenol (0.25 equiv) and NaH
(1.75 equiv).
b
Isolated yield.
Under an argon atmosphere, a solution of 7 (2.65 g, 10.0 mmol)
in Et2O (10 mL) was added slowly to a suspension of LiAlH4
(507 mg, 13.2 mmol) in Et2O (100 mL) at 0 8C. After stirring for
30 min at room temperature, the reaction mixture was poured into
ice-cold aqueous 10% HCl, extracted with Et2O and organic layer
was dried with anhydrous MgSO4. After evaporation of the solvent,
the residue was purified by column chromatography (SiO2,
EtOAc:hexane = 20:80) to give 1 (1.82 g, 82%). 1: A colorless oil.
c
Reaction was conducted with p-methoxyphenol (0.25 equiv) and NaH
(0.30 equiv).
a yield lower than that of benzaldehyde. The chemical yield of the
reaction was also reduced with the electron deficient aromatic
aldehydes p-trifluoromethylbenzaldehyde and 2-pyridinecarbox-
aldehyde (entries 4 and 5). With aliphatic aldehydes bearing an a-
hydrogen, aldol condensation predominated. The desired product
was not obtained. The difficulties encountered with aliphatic
aldehydes could be ameliorated slightly by reducing the amount of
NaH (entry 7). Application of this approach to cyclohexanecar-
baldehyde which was susceptible to aldol condensation in the
basic media led to formation of 9f of 51%.
1H NMR (400 MHz, CDCl3)
J = 8.0 Hz, 9H), 1.42 (bs, 1H), 2.25 (tt, J = 7.2, 1.2 Hz, 2H), 3.60 (t,
J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
: 3.1 (dd, J = 1.7,
d: 0.67 (q, J = 8.0 Hz, 6H), 0.95 (t,
d
1.6 Hz), 7.2, 29.0 (dd, J = 6.7, 3.5 Hz), 62.2 (dd, J = 3.4, 2.5 Hz), 75.4
(dd, J = 30.0, 5.4 Hz), 156.8 (dd, J = 305.6, 281.6 Hz); 19F NMR
(90 MHz, CDCl3)
d
: À8.7 (d, J = 36.0 Hz, 1F), À12.5 (d, J = 36.0 Hz,
1F); IR (neat) nmax 3336, 2960, 1690, 1468, 1420, 1228, 1050,
720 cmÀ1; MS m/z = 193 (M+À29).
3. Conclusion
In summary, a new difluorovinyl anion source 1 was prepared
from readily available 2,2,2-trifluoroethanol. Reaction of 1 with
NaH in the presence of an aldehyde afforded 9. The reaction was
accelerated by the addition of a catalytic amount of p-methox-
yphenoxide with the generation of 10 suppressed. Although the
reaction proceeded in moderate yield, the structural features of 9
that allow diverse synthetic transformations are fascinating. The
mechanistic studies required for a more complete understanding
of this reaction are currently under investigation.
4.4. Typical procedure for the synthesis of 9
Under an argon atmosphere, p-methoxyphenol (19 mg,
0.15 mmol) was added into a suspension of NaH (60% dispersion
in mineral oil, 50.4 mg, 1.05 mmol) in DMPU (2.4 mL). To the
suspension, a solution of 1 (133.3 mg, 0.6 mmol) and benzalde-
hyde (151
mL, 1.2 mmol) was added in DMPU (0.6 mL) over 1 h at a
temperature of ice cooling. After stirring for 30 min, the reaction
mixture was poured into saturated aqueous solution of NaHCO3,
extracted with Et2O and organic layer was dried with anhydrous
MgSO4. After evaporation of the solvent, the residue was separated
by column chromatography to give 9.
4. Experimental
4.1. General
2-(Difluoromethylene)-1-phenylbutane-1,4-diol (9a): A col-
orless solid; Mp = 73.0–74.0 8C. 1H NMR (400 MHz, CDCl3)
d: 1.85–
1H NMR and 13C NMR spectra were recorded on JNM-GX400
and JEOL-ECA-600SN spectrometers. 19F NMR spectrum was
recorded on Hitachi FT-NMR R-90H spectrometer. Chemical shifts
of 1H NMR and 13C NMR are reported in ppm from tetramethylsi-
lane (TMS) as an internal standard. Chemical shifts of 19F NMR are
1.95 (m, 1H), 2.21–2.29 (m, 1H), 3.53 (td, J = 10.4, 3.6 Hz, 1H), 3.60
(bs, 1H), 3.64–3.70 (m, 1H), 4.84 (bs, 1H), 5.64–5.66 (m, 1H), 7.23–
7.37 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
: 25.6, 61.2, 67.9 (dd,
J = 3.5, 2.3 Hz), 91.6 (dd, J = 13.9, 13.8 Hz), 125.4, 127.3, 128.3,
141.6, 154.8 (dd, J = 289, 289 Hz); 19F NMR (90 MHz, CDCl3)
d
:
reported in ppm from ethyl
a
,
a,
a
-trifluorotoluene as an internal
À29.2 to À30.8 (m, 2F); IR (KBr)
n
max 3300, 2948, 1742 cmÀ1; MS
standard. Mass spectra were obtained on JEOL JMS-700T spec-
trometer. Melting points were measured on Yanagimoto micro
melting point apparatus MP-S3.
m/z = 214 (M+); HRMS m/z M+ calcd. for C11H12F2O2: 214.081;
found: 214.080.
2-(Difluoromethylene)-1-(4-methoxyphenyl)butane-1,4-di-
ol (9b): A colorless oil. 1H NMR (400 MHz, CDCl3)
d: 1.88–1.99 (m,
4.2. Synthesis of ethyl 4,4-difluoro-3-(triethylsilyl)but-3-enoate (7)
1H), 2.22–2.30 (m, 1H), 3.54 (td, J = 10.0, 3.2 Hz, 1H), 3.60 (bs, 1H),
3.65–3.72 (m, 1H), 3.80 (s, 3H), 4.52 (bs, 1H), 5.62 (s, 1H), 6.87 (d,
Under an argon atmosphere, n-butyllithium (9.4 mL, 1.60 M
J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d:
in hexane, 15.0 mmol) was added slowly to a solution of
25.6, 55.3, 61.4 (dd, J = 3.3, 1.6 Hz), 67.7 (dd, J = 5.0, 2.5 Hz), 91.7

M. Omote et al. / Journal of Fluorine Chemistry 144 (2012) 114–117
117
(dd, J = 13.3, 13.3 Hz), 113.7, 126.6, 133.7 (dd, J = 5.0, 2.5 Hz), 154.6
(dd, J = 298, 298 Hz), 158.8; 19F NMR (90 MHz, CDCl3)
: À28.7 to
À30.1 (m, 2F); IR (neat) max 3344, 2936, 1742, 1622, 1416, 1330,
1164, 860 cmÀ1; MS m/z = 244 (M+); HRMS m/z M+ calcd. for
4.11 (m, 1H); 13C NMR (100 MHz, CDCl3)
J = 2.3 Hz), 26.3, 28.6, 29.6, 41.2 (t, J = 2.0 Hz), 61.7 (dd, J = 3.3,
2.5 Hz), 71.7 (d, J = 5.0 Hz), 89.8 (dd, J = 14.0, 14.0 Hz), 154.6 (dd,
J = 288, 288 Hz); 19F NMR (90 MHz, CDCl3)
2F); IR (KBr) nmax 3332, 2928, 1740, 1450, 1266, 1212, 1024,
690 cmÀ1; MS m/z = 220 (M+); HRMS m/z M+ calcd. for C11H18F2O2:
220.127; found: 220.128.
d
: 25.7, 25.8, 26.0 (d,
d
n
d
: À28.0 to À29.2 (m,
C12H14F2O3: 244.091; found: 244.092.
2-(Difluoromethylene)-1-(4-(trifluoromethyl)phenyl)bu-
tane-1,4-diol (9c): A colorless oil. 1H NMR (400 MHz, CDCl3)
d:
1.79–1.90 (m, 1H), 2.29 (dq, J = 15.2, 3.2 Hz, 1H), 3.60 (td, J = 10.4,
3.6 Hz, 1H), 3.72–3.78 (m, 1H), 3.80 (bs, 2H), 5.69 (s, 1H), 7.47 (d,
J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d:
References
25.5, 61.3, 67.6 (dd, J = 4.9, 3.3 Hz), 91.2 (dd, J = 15.0, 14.1 Hz),
127.4 (q, J = 272 Hz), 125.3 (q, J = 4.2 Hz), 125.9, 129.5 (q, J = 32 Hz),
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d: 0.00
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(s, 3F), À27.8 to À29.2 (m, 2F); IR (neat) nmax 3388, 2940, 1742,
1622, 1416, 1330, 1172, 856 cmÀ1; MS m/z = 282 (M+); HRMS m/z
M+ calcd. for C12H11F5O2: 282.068; found: 282.069.
2-(Difluoromethylene)-1-(pyridin-2-yl)butane-1,4-diol (9d):
A colorless oil. 1H NMR (400 MHz, CDCl3)
d: 1.79–1.89 (m, 1H),
2.31–2.39 (m, 1H), 3.51–3.65 (m, 2H), 3.70 (bs, 1H), 5.45 (bs, 1H),
5.59 (s, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H),
7.75 (td, J = 8.0, 2.4 Hz, 1H), 8.55 (dd, J = 4.8, 1.2 Hz, 1H); 13C NMR
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(100 MHz, CDCl3) d: 26.5 (d, J = 1.8 Hz), 61.0 (dd, J = 3.3, 1.7 Hz),
67.9 (dd, J = 5.8, 3.2 Hz), 90.5 (dd, J = 13.1, 12.3 Hz), 120.8, 122.8,
137.3, 147.9, 155.4 (dd, J = 288, 288 Hz), 158.8 (dd, J = 3.0, 2.5 Hz);
19F NMR (90 MHz, CDCl3)
À28.0 (dd, J = 42.6, 3.5 Hz, 1F); IR (neat) nmax 3296, 2932, 1742,
1596, 1440, 1272, 1054, 752 cmÀ1; MS: m/z = 215 (M+); HRMS m/z
M+ calcd. for C10H11F2NO2: 215.076; found: 215.076.
d
: À27.0 (ddd, J = 42.6, 4.2, 2.3 Hz, 1F),
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3-(Difluoromethylene)-5-methylhexane-1,4-diol (9e): A col-
orless solid; Mp = 40.0–41.0 8C. 1H NMR (400 MHz, CDCl3)
d: 0.77
(d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.71–1.86 (m, 1H), 2.09–
2.20 (m, 1H), 2.37–2.46 (m, 1H), 3.29 (bs, 2H), 3.59 (td, J = 10.4,
3.6 Hz, 1H), 3.75–3.82 (m, 1H), 3.97 (d, J = 9.6 Hz, 1H); 13C NMR
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Journal of Organic Chemistry 65 (2000) 5342–5349;
(100 MHz, CDCl3)
90.1 (dd, J = 14.3, 14.3 Hz), 154.5 (dd, J = 288, 288 Hz); 19F NMR
(90 MHz, CDCl3)
d: 18.4, 19.2, 32.1, 61.5–61.7 (m), 72.7–73.0 (m),
(b) S.E. Denmark, R.F. Sweis, Journal of the American Chemical Society 123 (2001)
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d
: À28.2 to À28.5 (m, 2F); IR (KBr) nmax 3340,
2972, 1742, 1468, 1266, 1212, 1026, 700 cmÀ1; MS m/z = 180 (M+);
HRMS m/z M+ calcd. for C8H14F2O2: 180.096; found: 180.096.
1-Cyclohexyl-2-(difluoromethylene)butane-1,4-diol (9f): A
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(c) Y. Nakao, J. Chen, H. Imanaka, T. Hiyama, Y. Ichikawa, W.-L. Duan, R. Shintani,
T. Hayashi, Journal of the American Chemical Society 129 (2007) 9137–9143;
(d) R. Shintani, Y. Ichikawa, T. Hayashi, J. Chen, Y. Nakao, T. Hiyama, Organic
Letters 9 (2007) 4643–4645.
colorless solid; Mp = 107.0–108.0 8C. 1H NMR (400 MHz, CDCl3)
d:
0.76–0.89 (m, 1H), 0.92–1.05 (m, 1H), 1.09–1.31 (m, 3H), 1.42–1.55
(m, 2H), 1.63–1.83 (m, 3H), 2.04–2.20 (m, 2H), 2.37–2.46 (m, 1H),
3.07 (bs, 2H), 3.63 (td, J = 10.0, 2.8 Hz, 1H), 3.77–3.84 (m, 1H), 4.05–