Mechanistic studies on α-trifluoromethylation of ketones via silyl enol ethers and its application to other carbonyl compounds

Article abstract of DOI:10.1021/jo9004348

(Chemical Equation Presented) Synthesis of α-CF₃ carbonyl compounds has been recognized to be difficult up to now because the polarization of CF₃^δ--I^δ+ is opposite to that of CH₃^δ+-I^δ-, and this makes it difficult to introduce CF₃⁺ unit to enolates. We recently reported an effective R-trifluoromethylation of ketones by using Et ₂Zn with Rh catalyst, but the mechanism has not fully been cleared. Now, we carried out the detailed mechanistic studies and found the involvement of a highly reactive alkylrhodium complex which derived from Et₂Zn and RhCl(PPh₃)₃ in this α-trifluoromethylation. Furthermore, this α-trifluoromethylation was applied to other types of carbonyl compounds in good yields.

Full text of DOI:10.1021/jo9004348

Mechanistic Studies on r-Trifluoromethylation of Ketones via Silyl
Enol Ethers and Its Application to Other Carbonyl Compounds
Kazuyuki Sato, Takashi Yuki, Ryoji Yamaguchi, Tetsuya Hamano, Atsushi Tarui,
Masaaki Omote, Itsumaro Kumadaki, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan UniVersity, 45-1, Nagaotoge-cho, Hirakata,
Osaka 573-0101, Japan
aando@pharm.setsunan.ac.jp
ReceiVed February 25, 2009
Synthesis of R-CF3 carbonyl compounds has been recognized to be difficult up to now because the
+
polarization of CF3δ--Iδ+ is opposite to that of CH3δ+-Iδ-, and this makes it difficult to introduce CF3
unit to enolates. We recently reported an effective R-trifluoromethylation of ketones by using Et2Zn with
Rh catalyst, but the mechanism has not fully been cleared. Now, we carried out the detailed mechanistic
studies and found the involvement of a highly reactive alkylrhodium complex which derived from Et2Zn
and RhCl(PPh3)3 in this R-trifluoromethylation. Furthermore, this R-trifluoromethylation was applied to
other types of carbonyl compounds in good yields.
Introduction
romethylation,3 which uses CF2X2/Zn or Cd. These reactions
gave the corresponding cross-coupling products. Taking advan-
tage of their trifluoromethylation, many kinds of reactions for
introducing a CF3 group into various organic molecules have
been developed, especially using nucleophilic trifluoromethy-
lation.4 For example, CF3-TMS on treatment with a fluoride
ion, by Prakash et al., or CF3-I on treatment with tetrakis(di-
methylamino)ethylene (TDAE), by Dolbier et al., reacted with
Organofluorine compounds have attracted much attention
because of their important applications in medicines, pesticides,
and/or liquid crystalline materials. Thus, many chemists have
concentrated their efforts on their synthesis for many years.1
Among those studies, trifluoromethylation of various aryl or
alkyl halides is one of the most fascinating reactions as
represented by Kobayashi-Kumadaki’s trifluoromethylation,2
which uses CF3Cu derived from CF3-X, and Burton’s trifluo-
(3) Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014–
5015.
(4) For a review for the nucleophilic trifluoromethylation reagents, see:
Langlois, B. R.; Billard, T.; Roussel, S. J. Fluorine Chem. 2005, 126, 173–179,
and references cited therein.
(5) For the nucleophilic trifluoromethylation by using CF3-TMS, see: (a)
Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111,
393–395. (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984–989. (c) Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. Org.
Synth. 1995, 72, 232–240. (d) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
56, 7613–7632. (e) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001,
112, 123–131.
(6) For the nucleophilic trifluoromethylation by using CF3-I with TDAE, see:
(a) A¨ıt-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. R., Jr. Org. Lett.
2001, 3, 4271–4273. (b) Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267–3269.
(c) Xu, W.; Dolbier, W. R., Jr. J. Org. Chem. 2005, 70, 4741–4745. (d) Pooput,
C.; Dolbier, W. R., Jr.; Medebielle, M. J. Org. Chem. 2006, 71, 3564–3568.
(1) (a) Organofluorine Chemistry: Techniques and Synthons; Chambers,
R. D., Ed.; Springer: Berlin, 1997. (b) Hiyama, T., Kanie, K., Kusumoto, T.,
Morizawa, Y., Shimizu, M.; Organofluorine Compounds: Chemistry and
Applications; Springer-Verlag: Berlin, Heidelberg, 2000. (c) Mikami, K.; Itoh,
Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1–16. (d) Ma, J.-A.; Cahard, D. Chem.
ReV. 2004, 104, 6119–6146. (e) Fluorine-Containing Synthons; Soloshonok,
V. A., Ed.; ACS Symposium Series No. 911; American Chemical Society:
Washington, D.C., 2005. (f) Uneyama, K. Organofluorine Chemistry; Blackwell
Publishing: Oxford, 2006. (g) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007,
128, 975–996.
(2) (a) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 10, 4095–4096.
(b) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. Tetrahedron Lett. 1979, 20,
4071–4072.
10.1021/jo9004348 CCC: $40.75
Published on Web 04/14/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3815–3819 3815

Sato et al.
TABLE 1. r-Trifluoromethylation Using Silyl Enol Ethers of
Various Ketones
SCHEME 1. Zn-Mediated Rh-Catalyzed
r-Trifluoromethylation of Ketones
carbonyl compounds to afford trifluoromethylated carbinols.5,6
In additioin, a CF3 radical derived from CF3-I with SmI2 or
Et3B was added to olefins.7
Although there are a number of methods for introducing a
CF3 unit to an organic molecule as mentioned above, it is
difficult to introduce a CF3 group at the R-position of carbonyl
compounds. One of the most simple methods is the use of
electrophilic trifluoromethylating reagents such as trifluoro-
methyl chalcogenium salts,8 but their insolubility in most organic
solvents inhibits their common use in organic synthesis. Another
method is the use of radical trifluoromethylation protocols, but
this method leads to low yields and requires special equipment
or techniques in some cases.9-11
a Isolated yield. b Diastereomeric ratio was calculated from 19F NMR.
c
19F NMR yield calculated from benzotrifluoride (BTF). d Total yield of
diastereomeric mixture. e 3c was obtained in 15% as a by-product. f The
dimer (4d) was isolated in the yield as the diastereomeric mixture.
Recently, we have reported a Zn-mediated Rh-catalyzed
R-trifluoromethylation of ketones via silyl enol ethers (2)
(Scheme 1).12 This reaction proceeded smoothly and made it
possible to use the aromatic silyl enol ethers that could not be
used in Mikami’s procedure.13 However, the mechanism of this
effective R-trifluoromethylation of ketones was still unclear. This
fact drove to investigate the reaction mechanism. We report
herein the result of the mechanistic studies on the R-trifluo-
romethylation and the further application to other carbonyl
compounds.
TABLE 2. Examination about SET Mechanism
RhCl(PPh3)3
(mol %)
entry
additive
none
none
O2
amount
25 mL
time (h) yielda (%)
1
2
3
4
5
6
7
2
none
none
0.5
24
3
1.5
18
81
16
45
79
42
84
76
2
2
2
2
galvinoxyl 4 mol %
galvinoxyl 1 equiv
Results and Discussion
Mechanistic Studies on r-Trifluoromethylation. In a previ-
ous report, we disclosed an R-trifluoromethylation of ketones
via silyl enol ethers (2) using Et2Zn in the presence of
RhCl(PPh3)3 (Table 1).12 Various R-CF3 ketones (3) for which
synthesizing was difficult came to be easily obtained by using
this method.
In this R-trifluoromethylation, we initially had assumed a
participation of the SET mechanism, since a dimer product (4d)
was obtained in an excellent yield on the R-trifluoromethylation
TEMPO
TEMPO
4 mol %
1 equiv
1.5
5
a
19F NMR yield calculated from benzotrifluoride (BTF).
of 1-phenyl-1-trimethylsiloxyethylene (2d) as shown in entry
4 of Table 1. In fact, Mikami’s procedure was a radical
R-trifluoromethylation of ketones by using Li, Ti, or Zn enolates
assisted Et3B/O2.13 Furthermore, Chen et al. also reported Pd(0)-
induced addition of Rf-X to alkenes via a SET mechanism.14
Thus, we tried to confirm the involvement of radical mechanism
using the 1-(trimethylsiloxy)cyclohexene (2a) as a substrate
(Table 2).
(7) (a) Lu, X.; Ma, S.; Zhu, J. Tetrahedron Lett. 1988, 29, 5129–5130. (b)
Takeyama, Y.; Ichinose, Y.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1989,
30, 3159–3162. (c) Yajima, T.; Nagano, H.; Saito, C. Tetrahedron Lett. 2003,
44, 7027–7029.
(8) (a) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156–2164.
(b) Umemoto, T. Chem. ReV. 1996, 96, 1757–1777. (c) Ma, J.-A.; Cahard, D. J.
Org. Chem. 2003, 68, 8726–8729.
(9) For the trifluoromethylation of silyl and germyl enolates of esters and
ketones, see: (a) Miura, K.; Taniguchi, M.; Nozaki, K.; Oshima, K.; Utimto, K.
Tetrahedron Lett. 1990, 31, 6391–6394. (b) Miura, K.; Takeyama, Y.; Oshima,
K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 1542–1553.
(10) For the trifluoromethylation of lithium enolate of imides, see: (a) Iseki,
K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169–2170. (b) Iseki,
K.; Nagai, T.; Kobayashi, Y. Tetrahedron: Asymmetry 1994, 5, 961–974.
(11) For the trifluoromethylation of enamines, see: (a) Cantacuze`ne, D.;
Dorme, R. Tetrahedron Lett. 1975, 25, 2031–2034. (b) Cantacuze`ne, D.;
Wakselman, C.; Dorme, R. J. Chem. Soc., Perkin Trans. 1 1977, 1365–1371.
(c) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186–5191. (d)
Semisch, C.; Margaretha, P. J. Fluorine Chem. 1986, 30, 471–475.
(12) Sato, K.; Yuki, T.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A.
Tetrahedron Lett. 2008, 49, 3558–3561.
(13) (a) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7, 649–651. (b) Itoh, Y.;
Mikami, K. Org. Lett. 2005, 7, 4883–4885. (c) Itoh, Y.; Mikami, K. Tetrahedron
2006, 62, 7199–7203. (d) Mikami, K.; Tomita, Y.; Ichikawa, Y.; Amikura, K.;
Itoh, Y. Org. Lett. 2006, 8, 4671–4673. (e) Itoh, Y.; Houk, K. N.; Mikami, K.
J. Org. Chem. 2006, 71, 8918–8925.
Although the yield was very low and a long reaction time
was needed, this reaction gave 3a even in the absence of the
Rh catalyst (entry 2). Since a dialkylzinc such as Et2Zn is
generally not a good radical source, the need to add an additive
such as O2 has been recognized for the generation of alkyl
radical,15 and the yield of 3a also improved slightly as expected
(entry 3). However, although these results suggested the
participation of the SET mechanism, the addition of a catalytic
amount of radical scavengers such as galvinoxyl or TEMPO to
(14) Chen, Q.-Y.; Yang, Z.-Y.; Zhao, C.-X.; Qiu, Z.-M. J. Chem. Soc., Perkin
Trans. 1 1988, 563–567.
(15) (a) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett.
1998, 39, 6335–6336. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P.
J. Org. Chem. 1999, 64, 9189–9193. (c) Bertrand, M. P.; Coantic, S.; Feray, L.;
Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56, 3951–3961. (d) Yamada, K.;
Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002,
4, 3509–3511.
3816 J. Org. Chem. Vol. 74, No. 10, 2009

Mechanistic Studies on R-Trifluoromethylation of Ketones
FIGURE 2. Reaction mechanism of Zn-mediated Rh-catalyzed R-tri-
fluoromethylation of carbonyl compounds
FIGURE 1. Zn-mediated Rh-catalyzed R-trifluoromethylation of 2b.
SCHEME 2. Examination of r-Fluoroalkylation Using
(Rf)2Zn
and the formation of them is also strongly supported in this
reaction. In particular, the key intermediate must be the Rh-Et
complex (7) in this case, because the use of Me2Zn instead of
Et2Zn also gave the R-trifluoromethylated product (3a) in a good
yield (2 h, 66%). In addition, the catalytic effect of Et2Zn was
hardly detected in this reaction (0.5 equiv of Et2Zn: 55%, 0.1
equiv of Et2Zn: 18%).
Based on these results, we propose the formation of a highly
reactive Rh-Et complex (7), which derived from Rh-X catalyst
and Et2Zn, in the mechanism of R-trifluoromethylation (Figure
2). Namely, the oxidative addition of CF3-I onto 7 to form a
Rh(III) complex (9) was followed by the coordination onto the
π-bond of silyl enol ether. On subsequent addition of the CF3
unit into the olefin, another Rh(III) complex (11) which suffered
the reductive elimination was formed to give the desired R-CF3
product (3) along with loss of ethyltrimethylsilane (TMS-Et)
or trimethylsilane (TMS-H) with ethylene.
the reaction mixture did not affect the yield of 3a significantly
(entries 4 and 6). Furthermore, the desired product (3a) was
obtained even in the presence of a stoichiometric amount of
the scavengers, although the yield was decreased slightly owing
to formation of a complex mixture as shown in entries 5 and 7.
These results mean that SET mechanism was not the main
pathway in this Rh-catalyzed reaction.
r-Trifluoromethylation of Esters via Ketene Silyl Acetals.
We found out the reaction mechanism of the R-trifluoromethy-
lation. Our proposed mechanism suggests that various silyl enol
ethers will be able to be used in this reaction. In fact, the reaction
could also apply to ketene silyl acetals (5) as already mentioned.
Then, we attempted to synthesize of R-CF3 esters (12) via ketene
silyl acetals in place of silyl enol ethers (2). Generally, an ester
group is stable, and can be easily transformed to other functional
groups. Thus, synthesis of R-CF3 esters is very important, but
only a few methods are known for their synthesis.18
In addition, the R-trifluoromethylation using 6-methyl-1-
(trimethylsiloxy)cyclohexene (2b) gave the desired product (3b)
along with a sizable amount of isomerized side product (3c) as
shown in Table 1. Isomerization of olefins by Rh catalyst is
well-known, and our result strongly suggests the coordination
of a Rh complex onto the π-bond of silyl enol ether (Figure 1).
On the other hand, we had also assumed the formation of
(CF3)2Zn or CF3ZnX from CF3-I (1a) and Et2Zn. We found that
the reaction could apply to ketene silyl acetals (5) which derived
from esters, as shown below. In addition, when C4F9-I (1b) was
used in place of CF3-I, the desired R-Rf carbonyl compound
was obtained (eq 1 in Scheme 2). We tried the reaction by using
(C4F9)2Zn, which was synthesized according to Naumann’s
procedure,16 but the desired product (6a) could not be obtained
at all in the absence of Rh catalyst (eq 2 in Scheme 2). This
means that the (Rf)2Zn is not involved as an active species and
the formation of a Rh complex that derived from Et2Zn is
fundamental to give the R-CF3 ketone (3).
First, according to the previous procedure (method A),12 we
examined the reaction with 2-(trimethylsiloxy)-4H-chromene
(5a) as the substrate (Table 3). As shown in entries 1-3,
lowering the reaction temperature to 0 °C from room temper-
ature increased the yield of R-CF3 ester (12a), but further cooling
to -30 °C decreased the yield. Next, we tried method B for
the simplification of the procedure. Namely, the mixture of CF3-I
(1a) and 5a in the presence of RhCl(PPh3)3 was treated with
Et2Zn. As expected, there were no significant differences in the
yields (compare entry 4 with entry 2 of method A). We then
examined the amount of the Rh catalyst (entries 4-7). Like as
the previous results, the reaction gave the product only in a
trace amount in the absence of RhCl(PPh3)3 as shown in entry
We already reported that treatment of RhCl(PPh3)3 with Et2Zn
immediately gave Rh-Et complex (7) or Rh-H complex (8),17
(16) Naumann, D.; Schorn, C.; Tyrra, W. Z. Anorg. Allg. Chem. 1999, 625,
827–830.
(17) (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Lett. 2004, 6,
4359–4361. (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Synth. 2006,
83, 177–183. (c) Sato, K.; Ishida, Y.; Murata, E.; Oida, Y.; Mori, Y.; Okawa,
M.; Iwase, K.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A. Tetrahedron 2007,
63, 12735–12739.
(18) (a) Molines, H.; Wakselman, C. J. Fluorine Chem. 1987, 37, 183–189.
(b) Duan, J.-X.; Su, D.-B.; Chen, Q.-Y. J. Fluorine Chem. 1993, 61, 279–284.
(c) Hagooly, A.; Rozen, S. Chem. Commun. 2004, 594–595.
J. Org. Chem. Vol. 74, No. 10, 2009 3817

Sato et al.
TABLE 3. Optimization of Reaction Conditions
TABLE 5. r-Trifluoromethylation Using Other Silyl Enol Ethers
RhCl(PPh3)3
(mol %)
entry
method
A
time (h)
T (°C)
yielda (%)
1
2
3
4
5
6
7
2
2
2
2
1
4
0
0.5
1
24
1
1.5
1
24
rt
0
-30
0
0
0
0
69
76
37
77
70
78
trace
B
a
19F NMR yield calculated from benzotrifluoride (BTF).
a Isolated yield.
TABLE 4. r-Trifluoromethylation Using Various Ketene Silyl
Acetals
enough space for introduction of the CF3 group due to its high
planarity. In entries 7 and 8, the ketene silyl acetals which have
alkoxy group also gave the products in moderate yields. On
the other hand, the substrate (5c) did not give the product at
all. The reason for this decreased reactivity might be attributed
to the aromatization by the trimethylsilylation of coumaranone.
For the same reason, trimethyl(phenoxy)silane did not give the
product.
r-Trifluoromethylation of Other Carbonyl Compounds.
Next, we investigated the R-trifluoromethylation of other
carbonyl compounds. These results are summarized in Table
5. As shown in entry 1, the R-trifluoromethylation of an amide
proceeded smoothly and gave the corresponding product (13a)
in a moderate yield, even though it has two substituents on the
R-position. An R-CF3 aldehyde (14) was also obtained in a
moderate yield as shown in entry 2. Furthermore, the reaction
could be also applied to the synthesis of an R-CF3 thioester
(15) in a moderate yield (entry 3). It is well-known that amide
group is found frequently in bioactive compounds such as
peptides. However, there are a few methods for synthesizing
R-CF3 amides to the best of our knowledge.19 Furthermore, the
R-trifluoromethylation of aldehydes or thioesters has hardly ever
reported, while most of them suffer cross-coupling reactions
with sp2-halides to give R-CF3 enals.20 This reaction is from
the above results very useful because it could be applied to the
directly synthesis of R-CF3 carbonyl compounds.
In the last part, we tried to synthesize of R-CF3 secondary
amides. As already known, it is difficult to synthesize and to
purify the N,O-silyl ketene acetals owing to the lone pair on
the nitrogen that makes them less stable. In particular, the
synthesis of them from the corresponding secondary amides is
rarely reported owing to the influence of amide hydrogen. Thus,
it is easily anticipated that the synthesis of R-CF3 secondary
amides would be difficult by using this reaction. However, we
thought the difficulty would be overcome by transamidation with
an R-CF3 ester and a primary amine. Thus, the R-CF3 ester
b
a Isolated yield. 19F NMR yield calculated from benzotrifluoride
(BTF).
7. It is clear that the Rh catalyst was also playing an important
role in this reaction.
In the next step, various substrates were examined on the
basis of the condition in entry 4 of Table 3. The results are
summarized in Table 4. All of the reactions smoothly proceeded.
As shown in entries 1, 2, and 4-6, the ketene silyl acetals which
have an aryloxy group gave the desired R-CF3 esters in good
yields. Also in this reaction, the more crowded the reaction
centers were, the lower the yields were as shown in entries 4-6.
However, it was interesting that the highly crowded product
(12b) with a CF3-attached quaternary carbon was obtained in a
good yield as shown in entry 2. The substrate (5b) might have
(19) (a) Chen, Q.; Wu, S. J. Chem. Soc., Chem. Commun. 1989, 705–706.
(b) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169–70.
(c) Xiao, J.-C.; Chen, Q.-Y. J. Fluorine Chem. 2003, 123, 189–195.
(20) (a) Paratian, J. M.; Labbe, E.; Sibille, S.; Perichon, J. J. Organomet.
Chem. 1995, 489, 137–143. (b) Kamigata, N.; Udodaira, K.; Shimizu, T.
Phosphorus, Sulfur Silicon Relat. Elem. 1997, 129, 155–168. (c) Nowak, I.;
Robins, M. J. J. Org. Chem. 2007, 72, 2678–2681.
3818 J. Org. Chem. Vol. 74, No. 10, 2009

Mechanistic Studies on R-Trifluoromethylation of Ketones
SCHEME 3. Synthesis of r-Trifluoromethylated Secondary
Amides
mL) was immediately added. The reaction mixture was allowed to
warm to room temperature and was stirred for 0.5 h. The resulting
mixture was quenched with 10% HCl and extracted with Et2O. The
Et2O layer was washed with satd NaCl and dried over MgSO4. The
solvent was removed in vacuo, and then benzotrifluoride (BTF)
was added to the residue. The yield was calculated from the
integration ratio of the 3 and BTF on 19F NMR.
General Procedure for the Synthesis of r-CF3 Esters (12)
(Method B). To a solution of RhCl(PPh3)3 (2 mol %) and ketene
silyl acetal (5, 1.0 mmol) in DME (5 mL) was added CF3-I (1a,
ca. 1 mL at -78 °C) at -40 °C. After the mixture was warmed to
0 °C, 1.0 M Et2Zn in hexane (1 mL, 1.0 mmol) was slowly added,
and the mixture was stirred for 1 h at the same temperature. The
resulting mixture was quenched with 10% HCl and extracted with
Et2O. The Et2O layer was washed with satd NaCl and dried over
MgSO4. The solvent was removed in vacuo, and then benzotrif-
luoride (BTF) was added in the residue. The yield was calculated
from the integration ratio of the 12 and BTF on 19F NMR. After
the calculation, the residue was purified by column chromatography
(CHCl3/hexane ) 1:1) to give 12.
General Procedure for the Synthesis of r-CF3 Secondary
Amides (13b or 13c). A solution of phenyl 3,3,3-trifluoropropionate
(12d, 0.5 mmol) and a primary amine (0.7 mmol) in toluene (2
mL) was refluxed until the disappearance of 12d on the GLC
analysis. The resulting mixture was quenched with 10% HCl and
extracted with AcOEt. The AcOEt layer was washed with satd NaCl
and dried over MgSO4. The solvent was removed in vacuo, and
the residue was purified by column chromatography to give the
product.
(12d), synthesized by our reaction, was treated with primary
amines to give the corresponding R-CF3 secondary amides (13b
and 13c) in good yields (Scheme 3).
Conclusions
In conclusion, we clarified the reaction mechanism based on
detailed mechanistic studies, where the highly reactive alkyl-
rhodium complex that derived from Et2Zn and RhCl(PPh3)3
played a very important role in this R-trifluoromethylation.
Furthermore, we carried out the synthesis of various R-CF3
carbonyl compounds. The R-trifluoromethylation reaction is one
of the most important reactions not only in organofluorine
chemistry but also in medicinal chemistry. Thus, we hope this
reaction is used in various fields.
Experimental Section
Acknowledgment. We gratefully acknowledge TOSOH F-
TECH, Inc., for the generous gift of CF3I.
General Procedure for the r-Trifluoromethylation of
Ketones. The reaction procedure which was used for the mecha-
nistic study was followed according to the previous report (method
A).12 Namely, to a solution of TMS enol ether (2, 1.0 mmol) in
DME (3 mL) was added a solution of 1.0 M Et2Zn in hexane (1.0
mmol) gradually at 0 °C and stirred for 1 h at this temperature.
After the reaction mixture was cooled to -30 °C, CF3-I (1a, ca.
1 mL at -78 °C) was introduced through a gas inlet tube, and then
a solution of RhCl(PPh3)3 (2 mol%) and an additive in DME (2
Supporting Information Available: Detailed experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO9004348
J. Org. Chem. Vol. 74, No. 10, 2009 3819