Preparation of (phenyldifluoromethyl)- and (phenoxydifluoromethyl)-silanes by magnesium-promoted carbon-chlorine bond activation

Article abstract of DOI:10.1055/s-2004-829533

Treatment of α-chloro-α,α-difluorotoluene and α-chloro-α,α-difluoroanisole with chlorotrimethylsilane in the presence of magnesium in DMF led to their corresponding trimethylsilyl derivatives. These compounds are able to transfer their fluorinated group to various electrophilic substrates (carbonyl compounds, disulfides, phenyl isocyanate).

Full text of DOI:10.1055/s-2004-829533

LETTER
1759
Preparation of (Phenyldifluoromethyl)- and (Phenoxydifluoromethyl)-silanes
by Magnesium-Promoted Carbon-Chlorine Bond Activation
P
reparatio
é
n of
(
Pheny
r
ldifluor
ô
omethyl)- an
m
d
(Phenoxydifluoro
e
methyl)-silanes Guidotti,a François Metz,b Marc Tordeux,a Claude Wakselman*a
a
SIRCOB-CNRS, Bâtiment Lavoisier, Université de Versailles, 45 avenue des Etats-Unis, 78035 Versailles, France
b
Rhodia, Centre de Recherche de Lyon, 85 avenue des Frères Perret, 69192 Saint-Fons Cedex, France
Fax +33(1)39254452; E-mail: Wakselma@chimie.uvsq.fr
Received 16 March 2004
In order to find an alternative synthesis, which could be
more easily scaled up, we have examined Gilman’s proce-
dure for the formation of reagent 2. Similarly, we have
studied the transformation of a-chloro-a,a-difluoro-
Abstract: Treatment of a-chloro-a,a-difluorotoluene and a-chloro-
a,a-difluoroanisole with chlorotrimethylsilane in the presence of
magnesium in DMF led to their corresponding trimethylsilyl deriv-
atives. These compounds are able to transfer their fluorinated group
to various electrophilic substrates (carbonyl compounds, disulfides, anisole (5) in analogous conditions in order to obtain the
phenyl isocyanate).
unknown (phenoxy-difluoromethyl)trimethylsilane (3,
Figure 2).
Key words: fluorine, alkyl halides, silicon, magnesium, nucleo-
philic additions
CF2SiMe3
OCF2SiMe3
(Perfluoroalkyl)trimethylsilanes 1 (Figure 1) have attract-
ed considerable interest because these reagents are able to
transfer their fluorinated group to electrophilic substrates
in the presence of fluoride ion sources or t-BuOK.
3
2
Figure 2
Attempts to apply Gilman’s procedure to the synthesis of
silyl derivatives 2 and 3 in THF either at room tempera-
ture or at reflux were unsuccessful.
F3C
SiMe3
n
F3C SiMe3
F
F
However mixing halide 4 with magnesium metal (2 equiv)
and trimethylsilyl chloride (4 equiv) in DMF10–13 at room
temperature led to the formation of 2 (Scheme 2). This
exothermic reaction was nearly quantitative. After hydro-
lysis and concentration of the mixture under reduced pres-
sure, the crude product was purified by chromatography
on silica gel.14
1
1a
Figure 1
The well-known Ruppert reagent 1a (n = 0) can be formed
by different routes.1,2 Its use as a trifluoromethylating
agent has been well described. Otherwise, reagents 1 bear-
ing a long perfluoroalkyl chain (n>0) have been prepared
by Gilman from their corresponding bromides or iodides
by action of magnesium metal in THF in the presence of
trimethylsilyl chloride3,4 (Scheme 1).
Mg
R
CF2SiMe3
+ Me3SiCl
CF2Cl
R
DMF, r.t.
R = Ph : 2
R = PhO : 3
R = Ph : 4
R = PhO : 5
THF
Scheme 2
RfSiMe3
RfI + Mg + Me3SiCl
–78 °C
Rf = CF3(CF2)n; n > 0; X = I, Br.
Under the same conditions, no reaction occurred with the
less reactive halide 5. It was necessary to use a large ex-
cess of trimethylsilyl chloride (10 equiv) and to heat the
mixture at 55 °C, in order to obtain the reagent 3.15 The
yield was limited to 60% owing to the formation of a by-
product C6H5OCF2H. Moreover, neat 3 is less stable than
neat 2. Its decomposition on standing was occasionally
observed and led to olefins 6 and 7 as a mixture of geo-
metrical isomers,16 probably by dimerisation of a carbenic
intermediate17,18 (Scheme 3). Usually, the reagent was
kept in a DMF solution.
Scheme 1
Lastly, the synthesis of other (fluoroalkyl)-trimethylsi-
lanes have also been reported. (Phenyldifluoromethyl)tri-
methylsilane 2 (Figure 2) was obtained from a-chloro-
a,a-difluoro-toluene 4 by action of samarium diiodide
and trimethylsilyl chloride in THF in the presence of
HMPA.5–7 An electrochemical method has also been re-
ported for its preparation from trifluoromethylbenzene.8,9
Bordeau et al.9 have shown that reagent 2 is able to intro-
duce the difluorobenzyl group into organic molecules by
addition to carbonyl compounds. Thus, they described a
rapid access to a,a-gem-difluoroalcohols.8,9 After devel-
SYNLETT 2004, No. 10, pp 1759–1762
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829533; Art ID: G07904ST
© Georg Thieme Verlag Stuttgart · New York
0
9
.0
8
.2
0
0
4

1760
J. Guidotti et al.
LETTER
O
PhOCF2TMS
PhOCF2
PhOCF
+
Me3Si
1) MeOH, MeOK, 80 °C
2) HCl
PhCF2CO2Me
91%
PhCF2
NHPh
Scheme 4
PhOCF2
F
+
Despite its lack of stability, reaction with carbonyl com-
pounds gave the corresponding gem-difluoroalcohols
with moderate to good yields (Table 2, entry 7–9). Use of
3 as a precursor of gem-difluoroamide was also examined
(entry 10). Results were similar to those obtained with
reagent 2.
PhO
F
F
PhOCF
OPh
6 + 7 (mixture of isomers)
Scheme 3
The starting chlorides 4 and 5 are available as secondary
products in the chlorine to fluorine exchange reaction by
hydrogen fluoride used generally to produce trifluoro-
methylated compounds. They can also be prepared in
good yields by reaction of pyridinium poly(hydrogen
fluoride) with the trichloromethylated precursors.22 The
present study shows that (phenyldifluoro-methyl)trimeth-
ylsilane 2 can be prepared from 4 by Gilman’s procedure
provided that the reaction is performed in a dipolar aprotic
solvent such as DMF. This procedure allows the replace-
ment of expensive samarium diiodide (and carcinogenic
HMPA)5,6 by magnesium metal. Use of 2 as a difluoro-
alkylating agent has been extended to disulfides and iso-
cyanates. In the same way, a new building block, the
(phenyl-difluoromethoxy)trimethylsilane 3, is available
oping a new and easy synthesis of 2, we wondered if it was
possible to extend the previous results of the literature to
other electrophiles such as disulfides or isocyanates. Re-
sults are summarised in Table 1. In our hands, reagent 2
reacted with benzaldehyde, as described by Bordeau and
co-workers, to give 2,2-difluoro-1,2-diphenylethanol in
good yield (entry 2).19 Other aldehydes gave similar re-
sults (entry 1 and 3). Reaction of reagent 2 with disulfides
(entry 4 and 5), led to gem-difluorothioethers, which are
versatile building blocks in synthesis.20 Lastly, reaction of
2 with phenyl isocyanate led to the corresponding amide
(entry 6). After hydrolysis, the gem-difluoroester,21 which
can also be considered as an interesting building block for
the introduction of the difluorobenzyl moiety into com-
plex molecules, was obtained in nearly quantitative yield
(Scheme 4).
–
from 5. Its use as a ‘PhOCF2 ’ anion equivalent in reaction
with different electrophiles, such as aldehydes or phenyl
isocyanate was also demonstrated.
By analogy with reagent 2, use of the new (difluoro-
alkyl)trimethylsilyl compound 3 as a PhOCF2 group pre-
cursor has been studied. Results are given in Table 2.
Table 1 Preparation and NMR Characteristics of Difluorinated Compounds 8a–f
Entry Silylated
Compound
Electrophile
Product
Yield 1H NMR (CDCl3)
19 F NMR
[d in ppm]
[%]
[d in ppm]
1
2
8a
60
1.01 (t, 3 H, 3JHH = 7 Hz)
1.31–1.46 (m, 2 H)
–108.8; –108.9
ABX JFF = 249 Hz
O
H
OH
Ph
1.98 (d, 1 H, OH, 3JHH = 6 Hz)
3.81–3.95 (m, 1 H)
F
F
F
7.44–7.52 (m, 5 H, HAr
)
2
3
2
2
8b9
8c
77
93
2.72 (d, 1 H, OH, 3JHH = 3 Hz)
5.07 (dt, 1 H, 3JFH = 9 Hz)
–107.2
apparent s
OH
O
Ph
Ph
Ph
H
H
Ph
7.20–7.42 (m, 10 H, HAr
)
F
2.63 (d, 1 H, OH, 3JHH = 6 Hz)
5.10 (dt, 1 H, 3JFH = 15 Hz)
6.34 (m, 2 H)
–107.6, 107.7
ABX JFF = 248 Hz
O
OH
O
O
F
F
7.38–7.40 (m, 6 H)
4
5
6
2
2
2
PhSSPh
8d24
8e
83
18
32
7.45–7.60 (m, 6 H, HAr
7.70–7.85 (m, 4 H, HAr
)
)
–72.3
–72.4
Ph
S
Ph
F
F
PhCH2SSCH2Ph
PhNCO
1.56 (s, 2 H)
7.36–7.64 (m, 10 H, HAr
Ph
Ph
S
Ph
)
F
F
8f25
7.17–7.70 (m, 10 H, HAr
8.12 (s, 1 H, NH)
)
–103.0
O
Ph
N
F
F
H
Synlett 2004, No. 10, 1759–1762 © Thieme Stuttgart · New York

LETTER
Preparation of (Phenyldifluoromethyl)- and (Phenoxydifluoromethyl)-silanes
1761
Table 2 Preparation and NMR Characteristics of Difluorinated Compounds 9a–d
Entry Silylated
Compound
Electrophile
Product
Yield
[%]
1H NMR (CDCl3)
[d in ppm]
19 F NMR
[d in ppm]
7
3
9a
70
1.13 (t, 3 H, 3JHH = 7 Hz)
1.73 (m, 2 H)
1.91 (m, 1 H, OH)
3.92 (m, 1 H)
–84.2
apparent s
O
H
OH
O
Ph
F
F
7.19–7.39 (m, 5 H, HAr
)
8
9
3
3
9b
9c
80
40
2.87 (d, 1 H, OH, 3JHH = 3 Hz)
5.12 (td, 1 H, 3JHF = 6 Hz)
7.13–7.60 (10 H, HAr, M)
–82.4
apparent s
OH
O
O
Ph
Ph
H
H
Ph
F
F
2.82 (d, 1 H, OH, 3JHH = 6 Hz)
5.14 (td, 1 H, 3JHF = 7 Hz)
6.43–6.58 (m, 2 H)
–81.8
apparent s
OH
O
O
Ph
O
O
F
F
7.18–7.50 (m, 6 H)
10
3
PhNCO
9d
30
7.21–7.44 (m, 8 H, HAr
)
–77.6
O
7.60–7.64 (d, 2 H, HAr, 3JHH = 7 Hz)
8.14 (s, 1 H, NH)
O
Ph
Ph
N
H
F
F
(13) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J. Org.
Chem. 2001, 66, 7216.
Thus silanes 2 and 3 complete the arsenal of reagents,
which are able to incorporate the gem-difluoromethylene
unit into organic molecules.23
(14) Preparation of 2: To anhyd DMF (20 mL) were added
magnesium powder (0.486 g, 20 mmol) and chlorotri-
methylsilane (5.07 mL, 40 mmol) under argon. Then a-
chloro-a,a-difluorotoluene(4) (1.625 g, 10 mmol) was added
dropwise. The reaction was very exothermic and the mixture
was stirred until it turned brown. After hydrolysis, the
mixture was extracted with Et2O and the organic layer
washed with H2O, dried over MgSO4 and then purified by
flash chromatography on silica gel using pentane as eluent to
afford 1.96 g of a colourless liquid identified as 2 (98% from
PhCF2Cl). 13C NMR (50 MHz, CDCl3): d = –4.9, 124.6 (t,
3JCF = 7 Hz), 128.2, 128.8, 131.8 (t, 1JCF = 265 Hz), 138.2 (t,
2JCF = 20 Hz).
(15) Preparation of 3: In the same way, (phenoxydifluoro-
methyl)trimethylsilane was synthesised by reaction of a-
chloro-a,a-difluoroanisole(5) (1.785 g, 10 mmol),
magnesium powder (0.486 g, 20 mmol) and chlorotrimethyl-
silane (12.67 mL, 100 mmol). The reaction mixture was
stirred and heated (55 °C) until it turned brown. Treatment
and purification are the same as for compound 2. Reagent 3
was isolated as a colourless liquid (60% from PhOCF2Cl).
19F NMR (282 MHz, CDCl3): d = –75.2 (s); 1H NMR (300
MHz, CDCl3): d = 0.33 (s, 9 H, CH3), 7.18–7.39 (m, 5 H,
Ar-H). 13C NMR (50 MHz, CDCl3): d = –4.7, 122.1, 125.0,
129.1, 131.1 (t, 1JCF = 268 Hz), 150.6 (t, 4JCF = 5 Hz). MS:
m/z (%) = 216 (11)[M+] 197 (2) [M+ – F] 77 (100), [ Ph] 73
(43) [SiMe3]. Degradation of 3 into olefins 6 and 7
sometimes occurs and does not allow an accurate elemental
analysis.
Acknowledgment
We thank Rhodia for financial support (grant to J.G) and Dr. Karen
Wright for advice during the composition of this manuscript.
References
(1) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613; and
references cited therein.
(2) Surya Prakash, G. K.; Hu, J.; Olah, G. A. J. Org. Chem.
2003, 68, 4457.
(3) Gilman, H. J. Organomet. Chem. 1975, 100, 83.
(4) Farnham, W. B. Synthetic Fluorine Chemistry; Olah, G. A.;
Chambers, R. D.; Surya Prakash, G. K., Eds.; Wiley and
Sons Inc.: New York, 1992, 247.
(5) Yoshida, M.; Suzuki, D.; Iyoda, M. Chem. Lett. 1994, 2357.
(6) Yoshida, M.; Suzuki, D.; Iyoda, M. J. Chem. Soc., Perkin
Trans. 1 1997, 643.
(7) This method is reported to give an almost quantitative yield.
In our hands, the yield was limited to 20%, even with
carefully distilled solvents.
(8) Clavel, P.; Léger-Lambert, M.-P.; Biran, C.; Serein-Spirau,
F.; Bordeau, M.; Roques, N.; Marzouk, H. Synthesis 1999, 5,
829.
(9) Clavel, P.; Lessene, G.; Biran, C.; Bordeau, M.; Roques, N.;
Trévin, S.; de Montauzon, D. J. Fluorine Chem. 2001, 107,
301.
(16) Olefin 6: 19F NMR (188 MHz, CDCl3): d = –128.6 (s). 1H
NMR (200 MHz, CDCl3): d = 7.16–7.43 (m, 10 H, Ar-H).
Olefin 7: 19F NMR (188 MHz, CDCl3): d = –122.5 (s). 1H
NMR (200 MHz, CDCl3): d = 7.12–7.39 (m, 5 H, Ar-H).
(17) Dimerisation of the analogous chlorophenoxycarbene has
been reported.13
(10) DMF has already been used for the formation of fluorinated
organometallic intermediates.12
(11) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189; and
references cited therein.
(12) Transformation of 1,4-bis(trifluoromethyl)benzene into a-
trimethylsilyl-a,a,a¢,a¢,a¢-pentafluoroxylene by Gilman’s
procedure in DMF has been reported.13 However, these
conditions are not efficient when the aromatic ring is
substituted by only one trifluoromethyl group.
(18) Brük, W.; Dürr, H. Angew. Chem., Int. Ed. Engl. 1982, 21,
916.
(19) Preparation of difluorinated compounds 8 and 9:
–
Fluoride source [KF or (n-Bu4N+, Ph3SnF2 ), 0.5 mmol),
DMF (5 mL) and the electrophile (10 mmol) were
Synlett 2004, No. 10, 1759–1762 © Thieme Stuttgart · New York

1762
J. Guidotti et al.
LETTER
introduced, in that order, into a round bottomed flask under
argon. The difluoroalkyltrimethysilylated reagent was then
added in one portion. The solution was stirred. Evolution of
the mixture was followed by 19F NMR. After consumption
of the silylated compound, the mixture was poured onto 20
mL of HCl (0.5 M) and stirred for 20 min. The aqueous layer
was extracted with Et2O and the resulting organic phase was
washed with brine, an iced sat. NaHCO3 aq solution and
again with brine. The organic phases were dried over MgSO4
and concentrated under vacuum. Alcohols were obtained in
their O-silylated form; deprotection was achieved by an
acidic treatment [HCl 35% (0.2 mL) in EtOH (10 mL)]. See
Table 1 and Table 2 for 1H NMR and 19F NMR data.
Compound 8b: 13C NMR (75 MHz, CDCl3): d = 76.9 (t,
2JCF = 31 Hz), 121.2 (t, 1JCF = 248 Hz), 126.3 (t, 3JCF = 6
Hz), 127.8, 127.9, 128.0, 128.6, 130.0, 133.8 (t, 2JCF = 26
Hz), 135.8. IR: 3431, 3057, 3032 cm–1. MS: m/z (%) = 127
(26) [PhCF2], 107 (88) [PhCHOH], 77 (51) [Ph]. Anal.
Calcd for C14H12F2O: C, 71.79%; H, 5.13%. Found: C,
71.69%; H, 5.03%. The spectral data agree with those
reported in the literature.8,9 Compound 8f: isolated as a white
solid, mp 102 °C. 13C NMR (75 MHz, CDCl3): d = 114.8 (t,
1JCF = 254 Hz), 120.3, 125.6 (t, 3JCF = 6 Hz), 125.7, 128.7,
129.2, 131.1, 132.6 (t, 2JCF = 25 Hz), 135.8, 149.3, 161.9 (t,
2JCF = 31 Hz). IR: 3334, 3057, 1685 cm–1. MS: m/z (%) =
247 (78) [M+], 127 (76) [PhCF2], 120 (67) [PhNHC(O)], 92
(79) [PhNH], 77 (41) [Ph]. Anal. Calcd for C14H11F2ON: C,
68.00%; H, 4.45%. Found: C, 68.21%; H, 4.47%.
(20) Billard, T.; Langlois, B. R.; Medebielle, M. Tetrahedron
Lett. 2001, 42, 3463.
(21) Middleton, K. J.; Bingham, E. M. J. Org. Chem. 1980, 45,
2883.
(22) Saint-Jalmes, L. PCT Int. Appl. WO97 43,231, 1998; Chem.
Abstr. 1998, 128, 365773r.
(23) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(24) Yagupolskii, L. M.; Korinko, V. A. J. Gen. Chem. USSR
1969, 39, 186.
(25) Yagupolskii, L. M.; Belinskaya, R. V. J. Gen. Chem. USSR
1958, 28, 750.
Synlett 2004, No. 10, 1759–1762 © Thieme Stuttgart · New York