Facile synthesis of TMS-protected trifluoromethylated alcohols using trifluoromethyltrimethylsilane (TMSCF3) and various nucleophilic catalysts in DMF

Article abstract of DOI:10.1021/jo060835d

Organofluorine compounds are becoming increasingly important in different fields, such as material science, agro chemistry, and the pharmaceutical industry. Nucleophilic trifluoromethylation is one of the widely used methods to incorporate a trifluoromethyl moiety into organic molecules. We have carried out extensive studies to develop varieties of easily accessible nucleophilic catalysts to promote such reactions. TMS-protected trifluoromethylated alcohols were prepared from both aldehydes and ketones in excellent yields using catalytic amount of amine N-oxide. Carbonate and phosphate salts also showed efficient catalytic activity toward this reaction. These reactions were highly solvent dependent, and DMF was found to be the most suitable one among the various solvents studied. All these reactions proceeded under very mild conditions, giving clean products and avoiding the use of any fluoride initiators or expensive catalysts, and extremely water-free conditions. The mechanism for the reaction is discussed in detail. DFT calculations were performed on the possible reaction intermediates using the Gaussian 03 program at B3LYP/6-311+G* level to support the proposed mechanism.

Full text of DOI:10.1021/jo060835d

Facile Synthesis of TMS-Protected Trifluoromethylated Alcohols
Using Trifluoromethyltrimethylsilane (TMSCF ) and Various
3
Nucleophilic Catalysts in DMF
G. K. Surya Prakash,* Chiradeep Panja, Habiba Vaghoo, Vijayalakshmi Surampudi,
Roman Kultyshev, Mihirbaran Mandal, Golam Rasul, Thomas Mathew, and George A. Olah
Donald P. and Katherine B. Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, 837 Bloom Walk, Los Angeles, California 90089-1661
gprakash@usc.edu
ReceiVed April 20, 2006
Organofluorine compounds are becoming increasingly important in different fields, such as material science,
agro chemistry, and the pharmaceutical industry. Nucleophilic trifluoromethylation is one of the widely
used methods to incorporate a trifluoromethyl moiety into organic molecules. We have carried out extensive
studies to develop varieties of easily accessible nucleophilic catalysts to promote such reactions. TMS-
protected trifluoromethylated alcohols were prepared from both aldehydes and ketones in excellent yields
using catalytic amount of amine N-oxide. Carbonate and phosphate salts also showed efficient catalytic
activity toward this reaction. These reactions were highly solvent dependent, and DMF was found to be
the most suitable one among the various solvents studied. All these reactions proceeded under very mild
conditions, giving clean products and avoiding the use of any fluoride initiators or expensive catalysts,
and extremely water-free conditions. The mechanism for the reaction is discussed in detail. DFT
calculations were performed on the possible reaction intermediates using the Gaussian 03 program at
B3LYP/6-311+G* level to support the proposed mechanism.
3
4
Introduction
al., became the Ruppert-Prakash reagent, after our group has
5
extensively used it as a versatile reagent to incorporate a
Fluorine, because of its unique electronic property and its
size, quite often imparts specific beneficial properties to organic
trifluoromethyl group into organic compounds by nucleophilic
activation. Fluoride sources, such as TBAF, TBAT, TMAF, or
CsF, have been widely used as nucleophilic initiators for the
trifluoromethylation reaction of different electrophiles for the
1
molecules. Fluoroorganics have important applications in
different fields, such as material science, agro chemistry, and
the pharmaceutical industry. Significant work has been carried
out in past decade to incorporate a fluorinated moiety in organic
molecules. TMSCF3, which was first prepared by Ruppert et
2
6
3
past several years by different groups, including our own.
However, the reactions are not catalytic with respect to the
initiators used. Further, these initiators are very sensitive to
moisture.
(
1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (b) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004.
(3) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 24,
2195.
(
2) Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr., Eds. Fluorine-
(4) (a) Large-Radix, S.; Billard, T.; Langlois, B. R. J. Fluorine Chem.
2003, 124, 147. (b) Stahly, G. P.; Bell, D. R. J. Org. Chem. 1989, 54,
2873. (c) Also see: Thayer, A. M. Chem. Eng. News 2006, June 5, p 15.
Containing Molecules: Structure, ReactiVity, Synthesis, and Applications;
VCH: New York, 1988.
10.1021/jo060835d CCC: $33.50 © 2006 American Chemical Society
6
806
J. Org. Chem. 2006, 71, 6806-6813
Published on Web 08/11/2006

Synthesis of TMS-Protected Trifluoromethylated Alcohols
3
SCHEME 1. CF Transfer to Aldehydes Using
Trimethylamine N-Oxide as a Catalyst in DMF
FIGURE 1. Nucleophilic catalysts containing oxygen.
pyridine N-oxide, p-chloropyridine N-oxide, N,N-dimethylpyr-
idine N-oxide, and trimethylamine N-oxide. During our earlier
studies, we were able to develop an efficient catalytic method
for the preparation of TMS-protected trifluoromethylated alco-
hols from a variety of aldehydes using trimethylamine N-oxide
as a recoverable nucleophilic catalyst. This methodology is
applicable for base-sensitive substrates. The work has been
On the other hand, considerable advancement has been
made during the past few years for the Lewis base catalyzed
reactions, using silylated reagents. Recently, trifluorometh-
7
ylation has been studied using nucleophilic catalysts, such as
8
9
tri-tert-butyl phosphine, N-heterocyclic carbene (NHC), and
molecular sieves 10 in DMF or DMSO. Among the Lewis base
catalysts, oxygen-containing nucleophiles are more efficient due
to the high bond strength as well as the kinetic lability of the
silicon-oxygen bond. Therefore, oxygen-containing nucleo-
philes are suitable initiators or catalysts in TMSCF3 chemistry.
5
m
recently published.
In the previous methodology, our catalyst loading was too
high. To overcome this problem, we began to investigate this
reaction under different conditions. Finally, while trying to study
the effect of solvent on the rate of the reaction, we found that
DMF as a solvent has a very significant effect on the reaction
rate (Scheme 1). The catalyst loading can be reduced 10-fold
1
Metal alkoxides have been used in trifluoromethylation reac-
tions using TMSCF3, but due to their high basicity, they are
not suitable in most cases. Hence, a search for milder oxygen-
containing nucleophiles, which are catalytic in nature, less basic,
cost-effective, and simple to use, has been carried out. Herein,
we report our results obtained from our recent studies on
nucleophilic trifluoromethylation with milder oxonucleophiles
(from 50 to 5 mol %). For reactions in DMF, the amount of
TMSCF3 used can also be reduced further with substantial
increase in product yields. We can even further reduce the
loading of the catalyst to 2 mol %. However, more time is
required to complete the reaction. Table 1 shows the results for
the reaction of different aldehydes with TMSCF3 using trimeth-
ylamine N-oxide as a catalyst and DMF as the solvent.
(Figure 1).
Results and Discussion
To validate our outlined approach, we have screened the
reactivity of commercially available amine oxides, such as
TABLE 1. CF3 Transfer to Aldehydes Using Trimethylamine
N-Oxide as a Catalyst in DMF
(
5) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393. (b) Prakash, G. K. S.; Ramaiah, R. Synlett 1991, 643.
c) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757. (d) Prakash,
G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett.
000, 2, 3173. (e) Prakash, G. K. S.; Tongco, E. C.; Mathew, T.; Vankar,
(
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Y. D.; Olah, G. A. J. Fluorine Chem. 2000, 101, 199. (f) Prakash, G. K.
S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2000, 40, 589. (g)
Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77. (h) Prakash,
G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 589. (i) Prakash, G. K.
S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847. (j) Prakash, G. K. S.;
Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2002,
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7, 3718. (k) Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124,
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538. (l) Mloston, G.; Prakash, G. K. S.; Olah, G. A.; Heimgartner, H.
HelV. Chim. Acta 2002, 85, 1644. (m) Prakash, G. K. S.; Mandal, M.; Panja,
C.; Mathew, T.; Olah, G. A. J. Fluorine Chem. 2003, 123, 61.
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Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001, 66, 2572. (c)
Petrov, V. A. Tetrahedron Lett. 2000, 41, 6959. (d) Li, N. S.; Tang, X. P.;
Piccirilli, J. Org. Lett. 2001, 3, 1025. (e) Sevenard, D. V.; Kirsch, P.;
R o¨ schenthaler, G. V.; Movchun, V. N.; Kolomeitsev, A. A. Synlett 2001,
3
79. (f) Benayood, F.; Abouabdellah, A.; Richard, C.; Bonnet-Delpon, D.;
B je gue, J. P.; Levasseur, D.; Boutaud, O.; Schuber, F. Tetrahedron Lett.
000, 41, 6367. (g) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
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2
(
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620. (c) Denmark, S.
E.; Coe, D. E.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161.
(d) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K. T. J. Am. Chem.
Soc. 1996, 118, 7404. (e) Denmark, S. E.; Wong, K. T.; Stavenger, R. A.
J. Am. Chem. Soc. 1997, 119, 2333. (f) Iseki, K.; Mizuno, S.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron Lett. 1998, 39, 2767. (g) Iseki, K.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron: Asymmetry 1998, 9, 2889. (h) Nakajima, M.;
Saito, M.; Shiro, M.; Hashimoto, S. I. J. Am. Chem. Soc. 1998, 120, 6419.
(
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i) Denmark, S. E.; Stavenger, R. A.; Wong, K. T. J. Org. Chem. 1998, 63,
18. (j) Denmark, S. E.; Stavenger, R. A. J. Org. Chem. 1998, 63, 9524.
(
(
k) Mukaiyama, T.; Nakagawa, T.; Fujisawa, H. Chem. Lett. 2003, 32, 56.
l) Nakagawa, T.; Fujisawa, H.; Nagata, Y.; Mukaiyama, T. Chem. Lett.
2
004, 33, 1016.
8) Mizuta, S.; Shibata, N.; Sato, T.; Fujimoto, H.; Nakamura, S.; Toru,
T. Synlett 2006, 267.
9) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.; Senanayake,
C. H. Org. Lett. 2005, 7, 2193.
10) Iwanami, K.; Oriyama, T. Synlett 2006, 112.
(
(
(
J. Org. Chem, Vol. 71, No. 18, 2006 6807

Prakash et al.
TABLE 2. CF3 Transfer to Ketones Using Trimethylamine
N-Oxide as a Catalyst in DMF
TABLE 4. Effect of Solvents in K2CO3-Catalyzed Reaction
entry
solvents
time
5 min
overnight
10 h
48 h
1 h
conv. (%)
yield (%)
86
i
ii
iii
iv
v
DMF
THF
100
60
100
<5
100
100
THF + DMF (4:1)
80
DCM
DCM + DMF (4:1)
DMSO
78
78
vi
5 min
TABLE 5. CF3 Transfer to Aldehydes Using K2CO3 as a Catalyst
in DMF
a
The rest is starting material. b Yields are calculated on the basis of
conversion.
TABLE 3. Various Useful Nucleophilic Catalysts in
Trifluoromethylation
entry
catalyst
K2CO3
Na2CO3
Li2CO3
CH3COONa
HCOOAg
KHCO3
NaHCO3
(NH4)2CO3
time
conv. (%)
i
ii
5 min
30 min
16 h
20 min
15 min
3 days
3 days
100
100
100
100
100
90
iii
iv
v
vi
vii
viii
80
R,â-Unsaturated aldehyde (Table 1, 4i) exclusively gives 1,2-
addition product (Table 1, 5i). Pyridine N-oxide can also act as
a catalyst for this reaction. However, as shown in our previous
study, trimethylamine N-oxide is found to be the most efficient
amine N-oxide catalyst. In our earlier report, we mentioned that
reactions of ketones do not progress under similar conditions.
Present investigations on aromatic ketones containing an
electron-withdrawing group showed substantial improvement
when DMF was used as the solvent. However, reaction of
ketones having an electron-donating group is sluggish toward
this reaction. The results are shown in Table 2.
N-oxide catalyst in situ from the precursor amine. We first
prepared the amine N-oxide in situ following the conventional
procedure using MCPBA and then performed the CF3 transfer
reaction in one pot. Interestingly, the reaction was found to be
11
Encouraged by these results, we decided to explore this
reaction further and perform the reaction by forming the amine
6808 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of TMS-Protected Trifluoromethylated Alcohols
TABLE 6. CF3 Transfer to Ketones Using K2CO3 as a Catalyst in DMF
a
Silylenol ether (5-10%) of the corresponding ketones was obtained.
complete within a few minutes. To rationalize this significant
rate acceleration, we performed several control reactions and
found that K2CO3 (which was used as a base) was responsible
for the rate enhancement.
tion. However, the efficiency of carbonates as catalysts for CF3
transfer from TMSCF3 in DMF has not been explored much.
Therefore, we decided to revisit this arena and studied the
trifluoromethylation reaction using different carbonate and
bicarbonate salts as catalysts. The results are shown in Table
3.
Reactions are found to be quantitative in the presence of
catalysts i-v listed in Table 3. However, proton-containing
catalysts (vi-viii) show low efficiency (no reaction was
observed for (NH4)2CO3, Table 3, entry viii). Recently, the use
of lithium acetate as a catalyst in similar reactions has been
After a thorough literature search, we found a recent report
1
2
by Yan et al. where K2CO3 had been used as a catalyst in a
cyano-silylation” reaction. In the case of CF3 transfer, there
“
13
were some initial reports of using carbonate salts as initiators
with trifluoromethyltriethylsilane in DMF with limited applica-
(11) (a) O’Neil, I. A.; Miller, N. D.; Barkley, J. V.; Low, C. M. R.;
Kalindjian, S. B. Synlett 1995, 617. (b) O’Neil, I. A.; Miller, N. D.; Barkley,
J. V.; Low, C. M. R.; Kalindjian, S. B. Synlett 1995, 619.
(13) Nelson, D. W.; O’Reilly, N. J.; Speier, J.; Gassman, P. G. J. Org.
Chem. 1994, 59, 8157 and references therein.
(12) Bin, H.; Yan, L.; Xiaoming, F.; Guolin, Z. Synlett 2004, 10, 1776.
J. Org. Chem, Vol. 71, No. 18, 2006 6809

Prakash et al.
TABLE 7. Phosphate Salts as Nucleophilic Catalysts
TABLE 8. CF3 Transfer to Aldehydes Using Phosphate (3) as a
Catalyst in DMF
amount
(mol%) time
TMSCF3
(equiv) yield (%)
entry
phosphate
i
ii
iii
iv
K3PO4
K2HPO4‚3H2O
KH2PO4
5
5
5
2
2 h
30 min
16 h
1.5
1.5
1.5
1.2
86
85
80
92
-
+
(OMe)2P(O)(O )( NBu4)
5 min
SCHEME 2. CF
Catalyst in DMF
3
Transfer to Aldehydes Using K
2
CO
3
as a
discussed by Mukayama and co-workers.14 Since K2CO3 gave
the best result (Table 3, entry i), we decided to explore its role
in the CF3 transfer reactions in different solvent systems.
The bidentate nature of K2CO3 makes it different and unique
from other well-known monodentate initiators or catalysts used
so far for CF3 transfer reactions. We performed the trifluoro-
methylation reactions with a catalytic amount of K2CO3 using
different solvent systems (Table 4). DMF, in this case also,
appeared to be the most efficient solvent (Table 4, entry i). The
high dielectric constant of DMF may be playing an important
role in stabilizing the reaction transition state, which in turn
makes the reaction more facile. Thus, we found that DMSO
also behaves similarly toward this reaction (Table 4, entry vi).
Both aldehydes and ketones undergo this reaction, giving only
the trimethylsilyl-protected trifluoromethylated alcohols, and no
deprotected alcohols were observed. Scheme 2 and Tables 5
and 6 illustrate the scope of this reaction using K2CO3 as the
catalyst. Aldehydes containing both electron-withdrawing as
well as electron-donating groups undergo CF3 transfer efficiently
(Table 5). In the case of ketones, significant variation was
observed (Table 6, entries m and n). Furthermore, enolizable
ketones (Table 6, entries o-q) were found to give small amounts
of silylenol ethers as byproducts.
phosphate catalysts, which could be more useful in different
synthetic applications, where metal salts are less preferred.
We anticipated that the phosphate catalyst (3), which is
prepared easily following the literature procedure,15 would be
a suitable candidate as an effective nucleophilic catalyst due to
its enhanced solubility in DMF. Catalyst 3 turned out to be
excellent and gave very promising results for the trifluoro-
methylation reaction. The results for the reaction with aldehydes
To overcome the enolization problem associated with eno-
lizable ketones in the presence of the basic catalyst, we began
to explore the catalytic efficiency of less basic salts, such as
nitrate, sulfate, or phosphates. Phosphate salts were found to
be very effective catalysts for the CF3 transfer reaction, keeping
the enolization to a minimum (Table 9, entries o-q). We probed
the catalytic activity of the mono-, di-, and tribasic potassium
phosphates for the trifluoromethylation reaction of 9-anthral-
dehyde (4h) in DMF, and the results are shown in Table 7.
The diphosphate was found to be more reactive, may be due to
its water of crystallization, which helps to increase its solubility
in DMF (Table 7, entry ii). So far, to our best knowledge,
phosphate salts have not been used as catalysts in trifluoro-
methylation reactions. Subsequently, we looked for metal-free
(Scheme 3) and ketones are summarized in Tables 8 and 9,
respectively. The amount of the silylenol ethers formed from
enolizable ketones using phosphate catalyst 3 is less compared
to that obtained from the K2CO3-catalyzed reaction (Table 9,
entries o-q).
Mechanism
We have already discussed the mechanism of trifluoro-
methylation using trimethylamine N-oxide as a catalyst in our
(
14) (a) Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005,
3
4, 88. (b) Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005,
4, 422. (c) Kawano, Y.; Mukaiyama, T. Chem. Lett. 2005, 34, 894. (d)
3
Kawano, Y.; Kaneko, N.; Mukaiyama, T. Chem. Lett. 2006, 35, 304.
(15) Phan, M. R.; Poulter, C. D. J. Org. Chem. 2001, 66, 6705.
6810 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of TMS-Protected Trifluoromethylated Alcohols
TABLE 9. CF3 Transfer to Ketones Using Phosphate (3) as a Catalyst in DMF
a
Silylenol ether (1-6%) of the corresponding ketones was obtained.
SCHEME 3. CF
3
Transfer to Aldehydes Using Phosphate
trigonal bipyramidal intermediate i. This intermediate i can form
the hexavalent intermediate ii by further expanding the valency
of silicon, which has a low-lying empty d orbital. Our theoretical
study on intermediate ii supports such a possibility. Subse-
quently, either the pentavalent (i) or the hexavalent intermediate
(3) as a Catalyst in DMF
(ii) can undergo attack by the aldehydes or ketones to form the
second set of intermediates (iii and iv), which can then decom-
pose to give the product and regenerate the catalyst. Alterna-
tively, both the anionic centers in the catalyst can simultaneously
previous publication.5m A possible mechanism for the bidentate,
potassium carbonate catalyzed reaction is shown in Scheme 4.
It is important to note that free alcohol was never obtained even
after using an excess of the catalysts, which itself supports the
true catalytic (vide supra) nature of the reaction. As indicated
in Scheme 4, we can envision route “a”, wherein only a single
anionic center is involved in the attack of TMSCF3 to form the
attack two molecules of TMSCF to give rise to a double
3
trigonal bipyramidal intermediate (v), wherein the carbonate can
occupy the axial positions of both the trigonal bipyramids.
Intermediate v can further react with two molecules of carbonyl
compounds to give the intermediate vi from which trifluoro-
J. Org. Chem, Vol. 71, No. 18, 2006 6811

Prakash et al.
SCHEME 4. Possible Mechanism with Potassium Carbonate as Catalyst
methylated product is formed with regeneration of the catalyst.
This path is illustrated in Scheme 4 through route “a+b”.
Calculations on intermediate v also support the possibility of
such a complex formation. The reaction can proceed via any
one of the routes described above or by a combination of both
the routes.
On the other hand, monobasic phosphate catalyzed reactions
can proceed in a similar fashion as described for the trimeth-
ylamine N-oxide catalyzed reaction. With tri- and dibasic
phosphates (Table 7, entries i and ii), we can think of similar
mechanisms as mentioned for the potassium carbonate catalyzed
reaction. Use of bidentate or tridentate catalysts can open up
new possible mechanistic pathways for the trifluoromethylation
reactions using TMSCF3.
Calculations of the Structure of the Complex of TMSCF3
and CO3
2
-
Calculations were performed using the Gaussian 03 pro-
1
6
gram. The geometry optimizations and vibrational frequency
calculations were performed at the B3LYP/6-311+G* level.
2
-
Complexation of TMSCF3 with CO3 leads to ii, which was
found to be a stable minimum at the B3LYP/6-311+G* level
(Figure 2). The complexation energy was found to be 63.7 kcal/
mol at the B3LYP/6-311+G*//B3LYP/6-311+G* + ZPE (zero-
point vibrational energy, scaled by a factor of 0.96) level. The
Cs symmetry structure ii contains a six-coordinate silicon atom
involving four carbon and two oxygen atoms. The Si-O bond
distance of ii is 1.925 Å. The Si-C (CF3) bond length of ii is
2
.171 Å, 0.172 Å longer than the Si-C (axial CH3) bond,
To rationalize the various mechanistic pathways, we per-
indicating relatively more nucleophilic character of the CF3
group compared to the CH3 group.
formed DFT calculations at the B3LYP/6-311+G* level for
complexation of TMSCF3 with CO32
-
.
1
7
NBO charges of the structure ii were also calculated. In ii,
2
-
the CO3 group as a whole bears -1.46 of charge, which
2-
indicates that -0.54 of charge was transferred from CO3 to
the TMSCF3 group upon complexation. In ii, the CF3 group as
a whole bears -0.61 charge, and the CH3 on average -0.51 of
charge. This again indicates the relatively more nucleophilic
nature of the CF3 group compared to the CH3 group.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford CT, 2004.
FIGURE 2. B3LYP/6-311+G* calculated structure of ii.
812 J. Org. Chem., Vol. 71, No. 18, 2006
6

Synthesis of TMS-Protected Trifluoromethylated Alcohols
Conclusions
In summary, a new generation of nucleophilic catalysts has
been explored for the facile trifluoromethylation reaction of
carbonyl compounds. Trimethylamine N-oxide has been used
successfully as an effective catalyst in the nucleophilic trifluo-
romethylation reactions, and its catalytic property has been
improved further by using DMF as a solvent. The reactions with
carbonates and phosphates are fast, insensitive to moisture, and
very clean in nature. TMS-protected alcohols were obtained as
sole products in high yields in most of the cases. Further, DFT
calculations were performed on the possible reaction intermedi-
ates using the Gaussian 03 program at B3LYP/6-311+G* level
to support the possible mechanism of the trifluoromethylation
reaction.
Experimental Section
General Procedure for the Addition of TMSCF
Ketone under Nucleophilic Catalysis in DMF. Aldehyde/ketone
1 mmol) and TMSCF (neat) in dry DMF (3 mL) were placed in
3
to Aldehyde/
(
3
a 25 mL round-bottom flask (or a 30 mL vial). To this solution
was added nucleophilic catalyst, and the mixture was stirred
vigorously at room temperature. Completion of the reaction was
monitored by TLC and GCMS. The reaction mixture was then
poured in brine solution (15 mL) and extracted with diethyl ether
FIGURE 3. B3LYP/6-311+G* calculated structure of v.
Further complexation of ii with another molecule of TMSCF3
leads to v, which was also found to be a stable minimum at the
B3LYP/6-311+G* level (Figure 3). The complexation energy
was found to be 44.2 kcal/mol at the B3LYP/6-311+G*//
B3LYP/6-311+G* + ZPE level. The C2V symmetry structure
v contains two five-coordinate silicon atoms. The Si-O bond
distance in v is 1.895 Å. The Si-C (CF3) bond length in v is
(
3 × 30 mL). Combined organic layers were finally washed with
brine solution, dried over anhydrous Na SO , and then solvent was
2
4
removed under reduced pressure. The crude product was further
purified by chromatography (using 9:1 hexanes/ethyl acetate solvent
system) to afford pure TMS-protected alcohols.
Acknowledgment. Dedicated to Professor Karl O. Christe
on the occasion of his 70th birthday. Support of our work by
Loker Hydrocarbon Research Institute is gratefully acknowl-
edged.
2
.176 Å, about 0.26 Å longer than the Si-C (CH3) bond,
indicating relatively more nucleophilic character of the CF3
group compared to the CH3 group. NBO charges of the structure
v were also calculated. In v, the CO32- group as a whole bears
-
1.45 of charge, which indicates that -0.55 of charge was
Supporting Information Available: Experimental procedure,
2-
transferred from CO3 to two TMSCF3 groups upon complex-
ation.
1
13
19
spectral data, and copies of H NMR, C NMR, F NMR spectra
of the TMS-protected trifluoromethylated alcohols. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
8
99.
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