Trichloromethyltrimethylsilane, sodium formate, and dimethylformamide: A mild, efficient, and general method for the preparation of trimethylsilyl- protected 2,2,2-trichloromethylcarbinols from aldehydes and ketones

Article abstract of DOI:10.1021/jo070180w

(Chemical Equation Presented) New conditions for the preparation of trimethylsilyl-protected 2,2,2-trichloromethylcarbinols 2 from aldehydes and ketones are reported. Compounds 2, which are important intermediates in organic synthesis, were obtained in excellent yields by use of a combination of trichloromethyltrimethylsilane (TMSCCI₃), and a catalytic amount of sodium formate (HCOONa) in dimethylformamide (DMF). Substrates bearing highly sensitive protecting groups have been successfully subjected to our conditions. We also describe a one-pot procedure that gives direct access to 2,2,2-trichloromethylcarbinols 3. This methodology avoids the use of strong bases usually required for the synthesis of 3 (Wyvratt et al. J. Org. Chem. 1987, 52, 944; Aggarwal and Mereu, J. Org. Chem. 2000, 65, 7211).

Full text of DOI:10.1021/jo070180w

tions.3 Compounds 3 have mainly been used for the formation
of R-fluoro acids,3b R-hydroxy acids,3c,d R-amino acids,3c,d
epoxides,3e vinyl dichlorides,3f and terminal alkynes.3g Our group
reported transformation of 2,2,2-trichloromethylcarbinols 3 into
2-haloalk-2(Z)-en-1-ols and 1-chloro-1(Z)-alkenes,3h and more
recently a ring expansion/homologation-aldehyde condensation
cascade sequence with cyclic trichloromethylcarbinols.3i
Although trifluoromethyl group transfer to carbonyl com-
pounds has been thoroughly studied with trifluoromethyltrim-
ethylsilane (TMSCF3, Ruppert’s reagent),4 only a few methods
for the preparation of 2 by mean of a trichloromethyl-providing
reagent are reported in the literature.5 Trichloromethyltrimeth-
ylsilane (TMSCCl3),5b,c,d,g trimethylsilyl trichloroacetate (Cl3-
CCO2TMS),5e,f or a combination of trimethylsilyl chloride
(TMSCl) and carbon tetrachloride (CCl4) have been used
successfully.5a Base catalysis with various F- sources [tris-
(diethylamino)sulfonium difluoromethylsilicate (TASF),5b,c,f
potassium fluoride (KF),5f and tetrabutylammonium fluoride
(TBAF)5g] or potassium carbonate (K2CO3)5e are the most
efficient and widely used reaction conditions described.
In the course of our studies, a general method for the
preparation of 2 under mild conditions compatible with both
acid- and base-sensitive substrates was needed. In this respect
the reported methods showed some restrictions. Indeed, the
diversity and sensitivity of the substrates, aldehydes and ketones,
studied in the previous reports are limited. This observation
prompted us to investigate new reaction conditions for the
formation of 2 using the readily accessible TMSCCl3.6
Trichloromethyltrimethylsilane, Sodium Formate,
and Dimethylformamide: A Mild, Efficient, and
General Method for the Preparation of
Trimethylsilyl-Protected
2,2,2-Trichloromethylcarbinols from Aldehydes
and Ketones
Je´re´my Kister and Charles Mioskowski*
Laboratoire de Synthe`se Bio-Organique, UMR 7175--LC1,
Faculte´ de Pharmacie, UniVersite´ Louis Pasteur, 74 Route du
Rhin, BP 24, 67401 Illkirch Graffenstaden, France
mioskow@aspirine.u-strasbg.fr
ReceiVed February 1, 2007
First, acetophenone was used as a model substrate for the
screening of various bases as catalyst for the formation of 2
(Table 1). Fluorine-, phosphorus-, and oxygen-based as well as
nitrogen-based Lewis bases were explored. All reactions led to
the clean formation of 2, although with variable yields. After
workup the crude mixture was composed of product 2 and the
starting acetophenone. It turned out that both TBAF and KF
led to low conversion in dimethylformamide (DMF) (Table 1,
entries 2 and 3). Phosphorus-based catalysts were inefficient
(Table 1, entries 4-6). Among the different nitrogen-donor
Lewis bases used, TBD was the most efficient (Table 1, entry
New conditions for the preparation of trimethylsilyl-protected
2,2,2-trichloromethylcarbinols 2 from aldehydes and ketones
are reported. Compounds 2, which are important intermedi-
ates in organic synthesis, were obtained in excellent yields
by use of a combination of trichloromethyltrimethylsilane
(TMSCCl3), and a catalytic amount of sodium formate
(HCOONa) in dimethylformamide (DMF). Substrates bear-
ing highly sensitive protecting groups have been successfully
subjected to our conditions. We also describe a one-pot
procedure that gives direct access to 2,2,2-trichloromethyl-
carbinols 3. This methodology avoids the use of strong bases
usually required for the synthesis of 3 (Wyvratt et al. J. Org.
Chem. 1987, 52, 944; Aggarwal and Mereu, J. Org. Chem.
2000, 65, 7211).
(3) (a) For a review, see Reeve, W. Synthesis 1971, 131-138. (b)
Khrimian, A. P.; Oliver, J. E.; Waters, R. M.; Panicker, S.; Nicholson, J.
M.; Klun, J. A. Tetrahedron: Asymmetry 1996, 7 (1), 37-40. (c) Corey,
E. J.; Link, J. O. Tetrahedron Lett. 1992, 33 (24), 3431-3434. (d) Corey,
E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114 (5), 1906-1908. (e) Corey
E. J.; Helal, C. J. Tetrahedron Lett. 1993, 34 (33), 5227-5230. (f) Li, J.;
Xu, X.; Zhang, Y. Tetrahedron Lett. 2003, 44, 9349-9351. (g) Wang, Z.;
Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.; Fortunak, J. M.; Confalone,
P. N. J. Org. Chem. 2000, 65, 1889-1891. (h) Baati, R.; Barma, D. K.;
Falck, J. R.; Mioskowski, C. Tetrahedron Lett. 2002, 43, 2183-2185. (i)
Falck, J. R.; He, A.; Reddy, L. M.; Kundu, A.; Barma, D. K.; Bandyo-
padhyay, A.; Kamilia, S.; Akella, R.; Bejot, R.; Mioskowski, C. Org. Lett.
2006, 8 (20), 4645-4647.
Trimethylsilyl-protected 2,2,2-trichloromethylcarbinols 2 are
valuable intermediates in organic synthesis and are involved in
a variety of transformations.1 Indeed, they are known precursors
of (Z)-2-chloroalk-2-en-1-ols,1a R-chloroketones, vinyl dichlo-
rides, and terminal alkynes.1b Moreover, trimethylsilyl (TMS)
deprotection of 22 gives access to 2,2,2-trichloromethylcarbinols
3, which have been subjected to numerous chemical transforma-
(4) For reviews, see (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV.
1997, 97, 757-786. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
56, 7613-7632.
(5) (a) Brunner, H.; Wimmer, P. J. Organomet. Chem. 1986, 309, C4-
C6. (b) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107, 4085-4087.
(c) Fujita, M.; Obayashi, M.; Hiyama, T. Tetrahedron 1988, 44 (13), 4135-
4145. (d) Gisch, J. F.; Landgrebe, J. A. J. Org. Chem. 1985, 50, 2050-
2054. (e) Renga, J. Tetrahedron Lett. 1985, 26 (9), 1175-1178. (f) de Jesus,
M. A.; Prieto, J. A.; del Valle, L.; Larson, G. L. Synth. Commun. 1987, 17
(9), 1047-1051. (g) Wang, P. C. (The Dow Chemical Company). U.S.
Patent 4634787, 1987.
(1) (a) Takai, K.; Kokumai, R.; Nobunaka, T. Chem. Commun. 2001,
1128-1129. (b) Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet.
Chem. 1975, 97, 355-374.
(2) (a) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107, 4085-
4087. (b) Renga, J. M.; Pen-Chung, W. Tetrahedron Lett. 1985, 26 (9),
1175-1178. (c) Deleris, G.; Dunogues, J.; Barbin, P.; Calas, R.; Bardone,
M.-C.; Guyonnet, J.-C. Eur. J. Med. Chem.: Chim. Ther. 1981, 16 (6),
533-537.
(6) Hergott, H. H.; Simchen, G. Synthesis 1980, 626-627.
10.1021/jo070180w CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/20/2007
J. Org. Chem. 2007, 72, 3925-3928
3925

TABLE 1. Catalyst Screening for the Formation of 2na
TABLE 2. Effect of Solvent, Concentration, Amount of Catalyst,
a
and Amount of TMSCCl3
entry
catalyst
yieldb (%)
TMSCCl3
(equiv)
time
(h)
yieldb
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
none
TBAF
KF
(Ph)3P
(Ph)3PdO
(Bu)3P
TBD
DBU
(i-Pr)2EtN
DMAP
pyridine N-oxide
DMPU
0
22
29
11
5
entry
solvent (conditions)
toluene
CH2Cl2
THF
CH3CN
DMSO
1
2
3
4
5
1.2
1.2
1.2
1.2
1.2
14
14
14
14
14
31
62
61
5
36
7c
9
23
8
6
7
8
1.2
1.2
1.2
DMF (5 mL)
DMF (2 mL)
DMF (0.5 mL)
4
4
4
71
81
83
11
17
9
1.2
DMF (at 0 °C)
4
69
10
11
12
1.2
1.2
1.2
DMF (HCOONa, 5 mol %)
DMF (HCOONa, 20 mol %)
DMF (HCOONa, 30 mol %)
1
1
1
80
81
86
14
15
16
17
18
19
20
21
22
23
sodium phenolate
sodium benzoate
lithium acetate
65
70
70
74
61
44
83
84d
80
82
13
14
15
16
17
1.3
1.4
1.5
1.6
2.0
DMF
DMF
DMF
DMF
DMF
1
1
1
1
1
87
91
96
96
94
sodium acetate
potassium acetate
sodium trichloroacetate
sodium formate
sodium formate
potassium formate
cesium formate
a Reaction conditions: acetophenone (0.5 mmol), sodium formate (0.05
mmol, 10 mol % unless otherwise stated), solvent (1 mL, unless otherwise
stated), 20 °C unless otherwise stated. b Isolated yields.
a Reaction conditions: acetophenone (0.5 mmol), TMSCCl3 (0.6 mmol,
1.2 equiv), catalyst (0.05 mmol, 10 mol %), and DMF (1 mL), 4 h at 20
°C. b Isolated yields. c R-Trimethylsiloxystyrene formed in 35% yield.
d Reaction for 1 h.
formation, as high yields were achieved in each of these
examples. Aliphatic aldehyde 1d (Table 3, entry 4) gave access
to product 2d in high yield. Starting with R,â-unsaturated
aldehyde 1e (Table 3, entry 5), product 2e arising from the 1,2-
addition was regiospecifically obtained as the single product
of the reaction. The reaction works equally well with hetero-
cyclic compounds 1g and 1h (Table 3, entries 7 and 8). Our
reaction conditions were then applied to para-substituted ben-
zaldehydes containing different protecting groups (Table 3,
entries 9-12). Acetate-, trimetylsilyl-, and tert-butoxycarbonyl-
protected 4-hydroxybenzaldehyde were selected as both base-
and acid-sensitive groups.7 4-Acetoxybenzaldehyde 1i (entry 9)
gives access to product 2i in 82% yield when a reduced amount
of TMSCCl3 is used (method B). The yield for the formation
of 2i dropped to 68% when the regular conditions (method A)
were used due to partial phenol deprotection. Under the
optimized condition, 1j was very efficiently converted into the
bis-protected product 2j (as shown by the crude NMR).
Nevertheless, the purification of 2j proved to be difficult due
to the high instability of the phenolic TMS group. Indeed,
purification by column chromatography on silica gel or alumina
led to complete phenol deprotection and to 2k in quantitative
yield (entry 11). Vacuum distillation was ineffective and product
degradation occurred. Use of preparative HPLC with a reverse-
phase column and the absence of water in the eluent was the
only efficient method to purify 2j in 75% yield (entry 10).
Product 2l bearing a carbonate group was formed in quantitative
yield (entry 12). In the case of ketoaldehyde 1m, a chemose-
lectivity problem had to be overcome in order to form product
2m (entry 13). Once again, method B provided the desired
product in 88% yield, whereas 2m was obtained in 60% yield
7). Interestingly, under the reaction conditions, DBU led to
R-proton abstraction on acetophenone (Table 1, entry 8) and to
the subsequent formation of the trimethylsilyl enol ether in 35%
yield. Higher yields were obtained with sodium phenolate (Table
1, entry 14), and most of all with carboxylate-derived catalysts
(Table 1, entries 15-23). Salts of formic acid provided
comparable results (Table 1, entries 20-23), and sodium formate
(Table 1, entry 21) was selected for further investigation.
Next, with sodium formate as catalyst, the reaction conditions
were optimized (Table 2). Screening of different solvents
revealed that only polar solvents led to the formation of 2n
(Table 2, entries 1-5); no product was observed with toluene
or dichloromethane (Table 2, entries 1 and 2), probably because
of sodium formate’s low solubility. Variation of the substrates
concentration from 0.25 to 1 mol/L (Table 2, entries 6-8) did
not significantly affect the yield of the reaction. The catalyst
amount, from 5 to 30 mol %, (Table 2, entries 10-12) had
also a minimum impact on the product formation. However,
the critical parameter appeared to be the amount of TMSCCl3
(Table 2, entries 13-17). The maximum yield was reached with
1.5 equiv of TMSCCl3; higher quantities of the reagent did not
change the outcome of the reaction.
The optimized conditions were then applied to various
aldehydes and ketones (Table 3) to establish the scope and
limitations of the reaction. First we studied aldehydes reactivity.
Benzaldehyde derivatives were used to analyze both the
electronic and the steric effects of phenyl ring substituents (Table
3, entries 2, 3, and 6). The presence of electron-donating (entry
2) and -withdrawing groups (entry 3) as well as a sterically
demanding group (entry 6) had no effect on the product
(7) Greene, T. W.; Wuts, P. P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: Weinheim, Germany, 1999; pp
246-292.
3926 J. Org. Chem., Vol. 72, No. 10, 2007

TABLE 3. Formation of Trimethylsilyl-Protected 2,2,2-Tricloromethylcarbinols 2 from Aldehydes and Ketonesa
a Reaction conditions for method A: carbonyl derivative (0.5 mmol), TMSCCl3 (0.75 mmol, 1.5 equiv), sodium formate (0.05 mmol, 10 mol %), and
DMF (1 mL), 1 h at 20 °C. b Isolated yields. c Method B: same as method A, except TMSCCl3 (0.6 mmol, 1.2 equiv). d Partial TMS deprotection occurred
during the purification by preparative HPLC. e TMS deprotection occurred during the purification by flash chromatography on silica gel.
only along with the bisaddition product 2m′ (30%) when method
A was used. Excellent yields were also obtained with the
different ketones studied (Table 3, entries 14-20): hindered
(entries 18 and 20), aliphatic (entry 15), R,â-unsaturated (entry
16), heterocyclic (entry 19), and cyclic ketones (entry 17) gave
the desired product 2 with yields superior to 75%.
Finally we investigated the one-pot formation of 2,2,2-
trichloromethylcarbinol 3 from aldehydes 1a and 1l and ketone
1n by combining the TMSCCl3/HCOONa methodology with a
mild TMS deprotection procedure. Compounds 3 are usually
prepared by base-promoted addition of chloroform to aldehydes
or ketones.8a,b Even the latest reported methodologies involve
relatively strong bases (KOH8a or DBU8b), which narrows their
scope of application. We thought that the use of the one-pot
process would represent an interesting alternative route for the
synthesis of 3. Table 4 summarizes the results obtained on three
substrates for the two-step one-pot synthesis of compound 3.
Starting from aldehydes (Table 4, entries 1 and 2), the desired
products 3 were obtained in high yields. Boc-protected aldehyde
1l was used in order to test the stability of an acid-sensitive
group under our reaction conditions and no deprotected product
was observed. Nevertheless, ketone 1n was less reactive (Table
4, entry 3), and both higher temperature and longer reaction
time were required for satisfactory conversion.
In conclusion, after the screening of various Lewis bases,
we found that sodium formate was an efficient catalyst for the
formation of trimethylsilyl-protected 2,2,2-trichloromethyl-
carbinols 2. Optimized reaction conditions were applied to a
collection of aldehydes and ketones, and products 2 were formed
in high yields. Finally, a one-pot TMSCCl3 addition/TMS
deprotection process was described leading to 2,2,2-trichloro-
methylcarbinols 3. An asymmetric version of this reaction is
currently under investigation in our laboratory.
(8) (a) Wyvratt, J. M.; Hazen, G.; Weinstock, L. M. J. Org. Chem. 1987,
52, 944-945. (b) Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65,
7211-7212.
J. Org. Chem, Vol. 72, No. 10, 2007 3927

TABLE 4. One-Pot Formation of 2,2,2-Trichloromethylcarbinols
3a
General Procedure for the One-Pot Formation of 2,2,2-
Trichloromethylcarbinols 3. To a DMF solution (1 mL) of
TMSCCl3 (0.144 g, 0.75 mmol) were added the carbonyl derivative
(0.5 mmol) and HCOONa (3.4 mg, 0.05 mmol). The reaction
mixture was stirred at room temperature for 1 h. MeOH (1 mL)
and a 1 N HCl solution (1 mL, 1 mmol) were added, the reaction
mixture was stirred at room temperature for 1 h and then poured
into a half-saturated NH4Cl solution (30 mL), and the product was
extracted with Et2O (3 × 10 mL). The combined organic layers
were washed with H2O (20 mL) and brine (20 mL), dried over
anhydrous MgSO4, filtered, and concentrated on a rotary evaporator.
The crude residue was purified by silica gel flash chromatography
(cyclohexane/EtOAc 8:2) to afford the pure product.
[2,2,2-Trichloro-1-(4-nitrophenyl)ethoxy]trimethylsilane (2c).
Yield 99% as a light yellow solid, purification by flash chroma-
tography (cyclohexane/CH2Cl2 95:5); mp 74-75 °C; 1H NMR (300
MHz, CDCl3) δ 8.25-8.21 (m, 2H), 7.81-7.78 (m, 2H), 5.20 (s,
1H), 0.13 (s, 9H); 13C (75 MHz, CDCl3) δ 148.3, 144.0, 130.4,
122.7, 101.5, 84.0, -0.1; IR (neat) 2963, 1520, 1348, 1255, 1100,
889, 844, 778, 761, 753 cm-1; Elemental analysis calcd for C11H14-
Cl3NO3Si: C, 38.55; H, 4.12; N, 4.09. Found: C, 38.64; H, 4.04;
N, 3.99.
tert-Butyl 4-(2,2,2-trichloro-1-hydroxyethyl)phenyl carbonate
(3l). Yield 85% as a white solid after purification by flash
chromatography (cyclohexane/ethyl acetate 8:2); mp 150-151 °C;
1H NMR (300 MHz, CDCl3) δ 7.61-7.58 (d, J ) 8.7 Hz, 2H),
7.20-7.17 (d, J ) 8.7 Hz, 2H), 5.15 (s, 1H), 3.52 (s, 1H), 1.56 (s,
9H); 13C (75 MHz, CDCl3) δ 151.67, 151.63, 132.3, 130.3, 120.6,
102.9, 83.9, 83.8, 27.6; IR (neat) 3447, 2986, 1726, 1370, 1316,
1222, 1154, 1084, 808, 781, 621 cm-1; Elemental analysis calcd
for C13H15Cl3O4: C, 45.71; H, 4.43. Found: C, 45.69; H, 4.47.
a Reaction conditions: (i) carbonyl derivative (0.5 mmol), TMSCCl3 (0.75
mmol, 1.5 equiv), sodium formate (0.05 mmol, 10 mol %), and DMF (1
mL), 1 h at 20 °C; (ii) 1 N HCl (1 mL, 2 equiv) and MeOH (1 mL), 1 h
at 20 °C. b Isolated yields. c (ii) 12 h at 50 °C.
Experimental Section
General Procedure for the Formation of Trimethylsilyl-
Protected 2,2,2-Tricloromethylcarbinols 2. To a DMF solution
(1 mL) of TMSCCl3 (0.144 g, 0.75 mmol) were added the carbonyl
derivative (0.5 mmol) and HCOONa (3.4 mg, 0.05 mmol). The
reaction mixture was stirred at room temperature for 1 h and then
poured into a half-saturated NH4Cl solution (20 mL), and the
product was extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with H2O (20 mL) and brine (20 mL),
dried over anhydrous MgSO4, filtered, and concentrated on a rotary
evaporator. The crude residue was purified by silica gel flash
chromatography (cyclohexane/CH2Cl2 or EtOAc) to afford the pure
product.
Acknowledgment. This work was supported by the Minis-
te`re de´le´gue´ a` l’Enseignement Supe´rieur et a` la Recherche. We
are grateful to Dr. Meunier Ste´phane for his helpful advice.
Supporting Information Available: General information, ana-
lytical data, and 1H and 13C spectra of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070180W
3928 J. Org. Chem., Vol. 72, No. 10, 2007