Indium-mediated reaction of 3-bromo-3,3-difluoropropene and bromodifluoromethylacetylene derivatives with aldehydes

Article abstract of DOI:10.1016/S0040-4020(00)00749-3

Aldehydes reacted with 3-bromo-3,3-difluoropropene at the α-position in the presence of indium to afford 1-substituted-2,2-difluorobut-3-en-1-ols. Ketones and other electrophiles are inert under the examined conditions. The reaction of bromodifluoromethyl

Full text of DOI:10.1016/S0040-4020(00)00749-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8275±8280
Indium-Mediated Reaction of 3-Bromo-3,3-di¯uoropropene and
Bromodi¯uoromethylacetylene Derivatives with Aldehydes
*
Masayuki Kirihara, Tomofumi Takuwa, Shinobu Takizawa, Takefumi Momose
and Hideo Nemoto
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 31 July 2000; accepted 25 August 2000
AbstractÐAldehydes reacted with 3-bromo-3,3-di¯uoropropene at the a-position in the presence of indium to afford 1-substituted-2,2-
di¯uorobut-3-en-1-ols. Ketones and other electrophiles are inert under the examined conditions. The reaction of bromodi¯uoromethyl-
acetylene derivatives with an aldehyde in the presence of indium provided di¯uorohomopropargylic alcohols. These reactions ef®ciently
proceeded in polar solvents (water, DMF) under mild conditions. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
We found that the gem-di¯uoroallylindium generated from
3-bromo-3,3-di¯uoropropene and indium reacts with alde-
hydes to afford gem-di¯uorohomoallyl alcohols in high
yields under mild conditions, which was described in a
preliminary communication.15 We now report the full
details and further results of this reaction.
The di¯uoromethylene moiety (CF2) is a key structural unit
in many ¯uorinated compounds of biological and pharma-
ceutical signi®cance.1 This group has been recognized as an
isopolar±isosteric substitute for oxygen and used as one
strategy for the modi®cation of biologically active
compounds.2±6 Some procedures have been developed to
introduce CF2 into organic compounds.1
The coupling of the gem-di¯uoroallylic metal species with
carbonyl compounds is one of the most important pro-
cedures since the resulting gem-di¯uorohomoallyl alcohols
have an alkene moiety capable of conversion into other
functionalities. Seyferth reported the reaction of carbonyl
compounds with (gem-di¯uoroallyl)lithium, available
from either the lithium±halogen exchange of 3-bromo-
3,3-di¯uoropropane7,8 or metal exchange of the (di¯uoro-
allyl)trimethyltin9 with butyllithium at low temperature
(2958C) in tetrahydrofuran gave gem-di¯uorohomoallyl
alcohols in moderate to high yields.
Hiyama found that the treatment of (a,a-di¯uoroallyl)-
silane10 or (g,g-di¯uoroallyl)silane11,12 with ¯uoride or
with t-butoxide in the presence of a carbonyl compound
ef®ciently afforded gem-di¯uorohomoallyl alcohols. Burton
reported that aldehydes and ketones reacted with 3-bromo-
3,3-di¯uoropropene in the presence of the acid-washed zinc
powder at 08C to room temperature to afford gem-di¯uoro-
homoallyl alcohols in moderate yields (Scheme 1).13,14
Keywords: indium and compounds; ¯uorine and compounds.
* Corresponding author. Tel.: 181-76-434-7533; fax: 181-76-434-4656;
e-mail: kirihara@ms.toyama-mpu.ac.jp
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00749-3

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M. Kirihara et al. / Tetrahedron 56 (2000) 8275±8280
Scheme 2.
Results and Discussion
In the presence of indium, 3-bromo-3,3-di¯uoropropene (1)
ef®ciently reacted with aldehydes (2) at room temperature to
afford gem-di¯uorohomoallyl alcohols (3) (Scheme 2).
These results are summarized in Table 1.
Scheme 3.
was not an effective solvent (entry 3). Only the CF2 terminus
of 1 attacked the carbonyl of the aldehydes (a-attack).
These results were in contrast with the indium mediated
allylations using 1-substituted 3-bromopropenes which
attack carbonyls at their g-position.20±22
The products were obtained in high yields in DMF. As in the
case of conventional indium-mediated allylations,16±19
water was also an excellent solvent for this reaction. This
result was in sharp contrast to other gem-di¯uoroallylations
which are required anhydrous conditions. Tetrahydrofuran
Table 1. Indium-mediated di¯uoroallulation of 3-bromo-3,3-di¯uoropropene with aldehydes
pA single isomer was obtained. The stereochemistry of 3g has not yet been determined.

M. Kirihara et al. / Tetrahedron 56 (2000) 8275±8280
8277
All the other gem-di¯uoroallylic metal species have also
been reported to react with carbonyl compounds at the
CF2 terminus.7±14 Tonachini and Canepa investigated
di¯uoroallyllithium for various levels using the ab initio
theory, and concluded the structure of 4 to be the most
stable.23 They also calculated the addition reaction of form-
aldehyde with (1,1-di¯uoroallyl)lithium, and the a-attack is
signi®cantly preferred. The transition structure 5 is 17 kcal/
mol higher in energy than 6 (Scheme 3).24
Scheme 4.
This indium-mediated gem-di¯uoroallylation might proceed
through sesqui(di¯uoroallyl)indium(III) sesquibromide (7)
or di¯uoroallylindium(I) (8) as shown in Scheme 3, and
²
they attacked the aldehyde in a way similar to di¯uoroallyl-
lithium (Scheme 4).
As noted in entries 8±10 of Table 1, the reaction with the
a,b-unsaturated aldehydes (2e,f) exclusively gave the 1,2-
adducts (3e,f). For the aldehyde (2g), only one diastereo-
isomer was obtained.
Interestingly, ketones, acid chlorides and epoxides did not
react with 1 under these reaction conditions. For the
Scheme 5.
Table 2.
²
Recently, Chan et al. reported that allyl bromide reacted with indium to
afford allylindium(I) in aqueous media.25

8278
M. Kirihara et al. / Tetrahedron 56 (2000) 8275±8280
compound (2h) bearing both aldehyde and ketone function-
alities, 1 chemoselectively reacted with the aldehyde
carbonyl to provide 3h (Scheme 5).
temperature. The reaction mixture was then quenched
with 10% HCl and extracted with ether (3£20 ml). The
combined organic extract was dried over anhydrous sodium
sulfate, ®ltered, and the solvent was removed in vacuo. The
residue was puri®ed using chromatography on silica gel (n-
hexane±ethyl acetate) to give 3.
These results are in contrast with those of the other gem-
di¯uoroallylations,7±14 where little or no difference was
observed between the aldehydes and ketones, and also
with conventional allylindiums,16±20 which have been
found to react with a wide varaiety of ketones and acid
halides.
2,2-Di¯uoro-1-phenylbut-3-en-1-ol (3a). The spectral data
for this sample were identical with those in the literature.14
2,2-Di¯uoro-1-(p-hydroxyphenyl)but-3-en-1-ol (3b). A
colorless oil. IR (neat) cm21: 3363, 3267; 1H NMR
(CDCl3) d: 2.47 (1H, d, Jˆ2.7 Hz), 4.83 (1H, td, Jˆ10.0,
2.2 Hz), 5.07 (1H, s), 5.46 (1H, d, Jˆ10.0 Hz), 5.57 (1H, d,
Jˆ17.0 Hz), 5.75±5.88 (1H, m), 6.81 (2H, d, Jˆ8.2 Hz),
7.27 (2H, d, Jˆ8.2 Hz); 19F NMR (CDCl3) d: 2108.65
(1F, dt, JFFˆ246.0 Hz, JFHˆ10.0 Hz), 2110.23 (1F, dt,
JFFˆ246.0 Hz, JFHˆ10.0 Hz); MS (m/z) 200 (M1);
HRMS calcd for C10H10F2O2 (M1): 200.0649, found
200.0630.
We then examined the reaction of the bromodi¯uoromethyl-
acetylene derivatives (9) with aldehydes in the presence of
indium. The CF2 terminus of 9 attacked the carbonyl of the
aldehydes (a-attack) exclusively to give gem-di¯uorohomo-
propargyl alcohols (10). These results are summarized in
Table 2.
³
The allenes (100) were not obtained in all cases. These
results are in contrast to the indium-mediated reaction of
g-substituted propargyl bromides with aldehydes which
affords allenes.27 Although the yields of 10 were not high
for the reaction using indium metal, 10 was obtained in
moderate yields in the reaction using the combination of
indium chloride (InCl3) and Sn.22
1-(p-Bromophenyl)-2,2-di¯uorobut-3-en-1-ol (3c).
A
colorless oil. IR (neat) cm21: 3420; H NMR (CDCl3) d:
2.54±2.63 (1H, br), 4.88 (1H, td-like), 5.48 (1H, d,
Jˆ10.0 Hz), 5.58 (1H, d, Jˆ18.0 Hz), 5.74±5.91 (1H, m),
7.29 (2H, d, Jˆ8.2 Hz), 7.49 (2H, d, Jˆ8.2 Hz); 19F NMR
(CDCl3) d: 2107.85 (1F, dt, JFFˆ246.0 Hz, JFHˆ10.0 Hz),
2109.20 (1F, dt, JFFˆ246.0 Hz, JFHˆ10.0 Hz); MS (m/z)
262 (M1); HRMS calcd for C10H9BrF2O (M1): 261.9804,
found 261.9808.
1
Conclusion
In the presence of indium, 3-bromo-3,3-di¯uoropropene
chemoselectively reacted with aldehydes to provide gem-
di¯uorohomoallyl alcohols. gem-Di¯uorohomopropargyl
alcohols were obtained in the reaction of bromodi¯uoro-
methylacetylene derivatives with aldehydes in the presence
of indium or InCl3±Sn. These reaction ef®ciently proceeded
in polar solvents (water, DMF) under very mild conditions.
3,3-Di¯uorododec-1-en-4-ol (3d). A colorless oil. IR (neat)
1
cm21: 3420; H NMR (CDCl3) d: 0.87 (3H, t, Jˆ6 Hz),
1.10±1.90 (14H, m), 2.00±2.15 (1H, m), 3.71±3.80 (1H,
br), 5.53 (1H, d, Jˆ10.0 Hz), 5.70 (1H, d, Jˆ17.0 Hz),
5.82±6.06 (1H, m); 19F NMR (CDCl3) d: 2109.15 (1F,
dt, JFFˆ249.0 Hz, JFHˆ10.0 Hz), 2112.70 (1F, dt,
JFFˆ249.0 Hz, JFHˆ10.0 Hz); MS (m/z) 220 (M1); HRMS
calcd for C12H22F2O (M1): 220.1639, found 220.1756.
Experimental
The infrared spectra (IR) were measured using a Perkin±
Elmer 1600 series FT-IR spectrophotometer. The H- and
3,3-Di¯uorodeca-1,5-dien-4-ol (3e). A colorless oil. IR
(neat) cm21: 3404; 1H NMR (CDCl3) d: 0.89 (3H, t,
Jˆ7.0 Hz), 1.25±1.43 (4H, m), 2.03±2.12 (3H, m), 4.24±
4.27 (1H, br), 5.43±6.04 (5H, m); 19F NMR (CDCl3) d:
2109.75 (1F, dt, JFFˆ249.0 Hz, JFHˆ10.0 Hz), 2111.78
(1F, dt, JFFˆ249.0 Hz, JFHˆ10.0 Hz); MS (m/z) 190 (M1),
113 (M12CF2CHCF2); HRMS calcd for C10H16F2O (M1):
190.1169, found 190.1122.
1
19F NMR spectra were obtained using a JEOL GX270,
Varian Gemini 300 or Varian UNITY plus 500 instrument
1
with tetramethylsilane (for H) and chlorotri¯uoromethane
(for 19F) as the internal standards. The mass spectra (MS)
and high-resolution mass spectra (HR-MS) were measured
on a JEOL JMS D-200 spectrometer. Column chroma-
tography was performed on silica gel (Merck Kieselgel
60). 3-Bromo-3,3-di¯uoropropene (1) was purchased from
Kanto Chemical Co. Bromodi¯uoromethylacetylene deriva-
tives (9) were prepared according to the literature.28
4,4-Di¯uoro-1-phenylhexa-1,5-dien-3-ol (3f). The spectral
data for this sample were identical with those in the litera-
ture.14
4,4-Di¯uoro-2-phenylhex-5-en-3-ol (3g). The spectral data
General procedure for the indium-mediated coupling of
aldehydes with 1
for this sample were identical with those in the literature.14
7,7-Di¯uoro-6-hydroxy-1-phenylnon-8-en-1-one (3h). A
colorless oil. IR (neat) cm21: 3446, 1684; 1H NMR
(CDCl3) d: 1.41±2.17 (7H, m), 3.00 (2H, t, Jˆ6.5 Hz),
3.75±3.89 (1H, m), 5.54 (1H, d, Jˆ10.0 Hz), 5.72 (1H, d,
Jˆ18.0 Hz), 5.89±6.07 (1H, m), 7.44±7.97 (5H, m); 19F
NMR (CDCl3) d: 2108.93 (1F, dt, JFFˆ248.0 Hz, JFHˆ
10.0 Hz), 2112.84 (1F, dt, JFFˆ248.0 Hz, JFHˆ10.0 Hz);
A suspension consisting of an aldehyde (0.50 mmol), 1
(76 ml, 0.75 mmol), powdered indium (86 mg, 0.75 mmol)
and DMF (or water) (5 ml) was stirred for 3 h at room
³
A similar regioselectivity was reported in the zinc-mediated reaction of 9
with aldehydes.26

M. Kirihara et al. / Tetrahedron 56 (2000) 8275±8280
8279
MS (m/z) 268 (M1); HRMS calcd for C15H18F2O2 (M1):
268.1275, found 268.1263.
273.0 Hz, JFHˆ7.9 Hz), 295.54 (1F, dd, JFFˆ273.0 Hz,
JFHˆ10.2 Hz); MS (m/z) 284 (M1); HRMS calcd for
C18H14F2O (M1): 284.1013, found 284.1025.
General procedure for the indium-mediated coupling of
aldehydes with 9
3,3-Di¯uoro-1-phenyltridec-1-yn-4-ol (10e). A colorless
1
oil. IR (neat) cm21: 3446, 2925, 2855, 2242; H NMR
(CDCl3) d: 0.78±0.83 (3H, m), 1.19±1.76 (16H, m), 3.82
(1H, dd, Jˆ17.8, 6.8 Hz), 7.25±7.47 (5H, m); 19F NMR
(CDCl3) d: 294.76 (1F, dd, JFFˆ273.0 Hz, JFHˆ10.2 Hz),
296.34 (1F, dd, JFFˆ273.0 Hz, JFHˆ10.2 Hz); MS (m/z)
308 (M1); HRMS calcd for C19H26´F2O (M1): 264.1326,
found 264.1328.
A suspension consisting of an aldehyde (2) (0.50 mmol), 9
(0.75 mmol), powdered indium (86 mg, 0.75 mmol) and
DMF (or water) (5 ml) was stirred at room temperature
for 3 h and then stirred at 808C for 12 h. The reaction
mixture was quenched with 10% HCl and extracted with
ether (3£20 ml). The combined organic extract was dried
over anhydrous sodium sulfate, ®ltered, and the solvent was
removed in vacuo. The residue was puri®ed using chroma-
tography on silica gel (n-hexane±ethyl acetate) to give 10.
Acknowledgements
This work was supported in part by the foundation of
Toyama Daiichi Bank and the Foundation for the Promotion
of Higher Education in Toyama Prefecture.
General procedure for the indium trichloride/tin-
mediated coupling of aldehydes with 9
A suspension consisting of an aldehyde (2) (0.50 mmol), 9
(0.75 mmol), indium trichloride (147 mg, 0.50 mmol), tin
(59 mg, 0.50 mmol) and water (5 ml) was stirred at room
temperature for 3 h and then stirred at 808C for 12 h. The
reaction mixture was then quenched with 10% HCl and
extracted with ether (3£20 ml). The combined organic
extract was dried over anhydrous sodium sulfate, ®ltered,
and the solvent was removed in vacuo. The residue was
puri®ed using chromatography on silica gel (n-hexane±
ethyl acetate) to give 10.
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