Tandem reductive perfluoroalkylation of esters with perfluoroalkyl titanate-type reagents

Article abstract of DOI:10.1021/ja074642z

The generation of stable perfluoroalkyl titanate-type reagents and their new type of reaction, tandem reductive perfluoroalkylation of esters, are shown to give perfluoroalkylated sec-alcohols in up to quantitative yield. Copyright

Full text of DOI:10.1021/ja074642z

Published on Web 08/30/2007
Tandem Reductive Perfluoroalkylation of Esters with Perfluoroalkyl
Titanate-Type Reagents
Koichi Mikami,* Tatsushi Murase, and Yoshimitsu Itoh
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
Received June 25, 2007; E-mail: mikami.k.ab@m.titech.ac.jp
Organofluorine compounds have attracted current interest because
of late but rich blooming in biological and material science.1
However, perfluoroalkyl metal reagents have generally been
recognized unstable and difficult to prepare because of the facile
R- or â-metal fluoride (M-F) elimination.2 Herein, we report the
generation of stable perfluoroalkyl (Rf-) titanate-type reagents and
their new type of reaction, namely tandem (domino)3 reductive4
perfluoroalkylation of esters (eq 1). The present report can thus be
recognized as a significant advance toward the common use of
stable perfluoroalkyl metal reagents with new type of reactivity.
We have already reported that the metal enolates of R-trifluo-
Figure 1. The 3D structures of Ti-, Ti-ate- and Li-enolates: the bond
romethyl (CF3) ketones can be generated quantitatively without
defluorination using TiCl4 and Et3N in spite of the strong affinity
of Ti and F.5 The structures of Li-, Ti-, and Ti-ate enolates of R-CF3-
acetone were thus clarified by DFT calculation6,7 (Figure 1).
In the Li-case, strong interaction between Li and fluorine is
observed in the s-cis configuration, and defluorination can be
recognized to readily take place. In the Ti-enolate, the Ti-O-C
angle is 170.2°, and Ti-F interaction cannot be observed.8 In the
Ti-ate enolate, in contrast, the Ti-O-C bond has no more linearity
but s-trans configuration with respect to the fluorine group.
Therefore, Ti-F interaction cannot be observed. The s-trans
configuration of the Ti-ate enolate probably stems from the
electronic and steric repulsion between Ti-ate complex and CF3.
With this stable form of Ti-ate enolates, we thought that
perfluoroalkyl titanate-type reagents might also be stable to prevent
R- or â-F-elimination. Therefore, the corresponding perfluoroalkyl
titanate-type reagents were prepared; First perfluoroalkyl Grignard
reagent was prepared at -78 °C,9 and titanium tetra(iso-propoxide)10
was added. The perfluoroalkyl titanate-type reagent was then reacted
with benzaldehyde at room temperature to give perfluoroalkyl
alcohol in 93% isolated yield (eq 2). Without titanium tetra(iso-
propoxide), the Grignard reagent did not give the alcohol at that
temperature. We have thus developed stable perfluoroalkyl metal
reagents.
lengths are in Å, the bond angles (italics) are in degrees.
Scheme 1
The time course of this reductive perfluoroalkylation of the ester
was traced (Figure 2). In the reaction of the ester substrate (green
squares), the corresponding ketone intermediate (orange triangle)
was first observed. With decrease of the ketone intermediate (orange
triangle), the perfluoroalkylated sec-alcohol product (blue circle)
was finally obtained. The tandem4 sequence of this reductive
perfluoroalkylation of esters via the ketone intermediate was thus
proven.
Formation of the sec-alcohol can be rationalized by the Meer-
wein-Pondrov-Valley reduction of the ketone intermediate with
isopropoxide. Indeed, treatment of the ketone with the perfluoroalkyl
titanate-type reagent gave the sec-alcohol (Scheme 2).13,14
Several esters were then investigated (Table 1). Other perfluo-
roalkyl groups such as C3F7 and C6F13 could also be introduced
into the reductive perfluoroalkylation products in high yields (76
and 87%, respectively) (entries 2 and 3). Even when R2 is a
sterically demanding phenyl group, the tandem product was also
obtained in good yield (88%) (entry 4). With electron withdrawing
or donating groups (4-CF3 and 4-OMe), the reductive perfluoro-
alkylation products were formed in high yields (84% and 72%)
(entries 5 and 6). In the case of sterically demanding 1- and
2-naphthyl groups, the reductive perfluoroalkylation products were
also obtained in excellent yields (94% and 99%) (entries 7 and 8).
R,â-Unsaturated ester substrate (R1 ) PhCHdCH) also provided
the 1,2-reductive perfluoroalkylation product in 73% yield, without
formation of the 1,4-product (entry 9). Even in the case of enolizable
esters bearing R-protons (Bn, n-C7H15), the reductive perfluoro-
Esters were then examined. Surprisingly, the perfluoroalkyl
titanate-type reagent reacted with benzoate ester to give a “reduc-
tive” perfluoroalkylation product, sec-alcohol in quantitative yield
(Scheme 1), because ordinary alkyl titanate-type reagents were
unreactive therewith.11 By contrast, the perfluoroalkyl lithium
reagents have been reported to give ketones or the tert-alcohols
thereof.12
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J. AM. CHEM. SOC. 2007, 129, 11686-11687
10.1021/ja074642z CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Science, Okazaki, Japan is greatly acknowledged. This work was
supported by a Grant-in-Aid for Scientific Research on Priority
Areas “Advanced Molecular Transformations of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Complete ref 6; detailed
experimental procedure; Cartesian coordinates of the calculation model.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Figure 2. The change of products with time progress.
Scheme 2
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Table 1. Tandem Reductive Perfluoroalkylation of Esters.
(4) (a) Tandem reductive amination was quite recently reported: Storer, R.
I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 84. (b) Review on asymmetric reductive amination: Tararov, V. I.;
Borner, A. Synlett 2005, 203. (c) Tandem reduction-reductive alkylation
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alkyl tris(dialkylamino)titanium reagents: Schiess, M.; Seebach, D. HelV.
Chim. Acta 1982, 65, 2598-2602.
entry
R1
R2
Rf
yield [%]a
1
2
3
4
5
6
7c
8
9
10c
11c
Ph-
Ph-
Ph-
Ph-
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
C4F9
C3F7
C6F13
C4F9
C4F9
C4F9
C4F9
C4F9
C4F9
C4F9
C4F9
quantb
76
87
88b
84
72
94
99
73
4-CF3-C4H4-
4-MeO-C4H4-
1-Naph-
2-Naph-
(E) -PhCHdCH-
Bn
(5) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am. Chem. Soc. 2004, 126, 13174-
13175.
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6-31G* for others) was adopted. For Ti-ate-enolate, B3LYP/631+LAN
(LANL2DZ for Ti, 6-31+G* for others) was adopted. (a) Hay, P. J.; Wadt,
W. R. J. Chem. Phys. 1985, 82, 270-283. (b) Wadt, W. R.; Hay, P. J. J.
Chem. Phys. 1985, 82, 284-298. (c) Hay, P. J.; Wadt, W. R. J. Chem.
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Schleyer, P.; Pople, J. A. Ab initio Molecular Orbital Theory; Wiley: New
York, 1986 and references cited therein.
41
51
nC7H15
a Isolated yield. b Determined by 1H NMR. c Reaction run using 6.0 equiv
of C4F9Ti(OiPr)4MgBr for 20 h.
(8) Donation of the lone electron pair of the oxygen to the empty d-orbital of
Ti causes the linear multiple bonding (see ref 5).
alkylation products were obtained though in moderate yields (41%
and 51%, respectively) (entries 10 and 11).
(9) McBee, E. T.; Roberts, C. W.; Meiners, A. F. J. Am. Chem. Soc. 1957,
79, 335-337.
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Scheffold, R., Ed.; Verlag: Frankfurt, Germany, 1983; Vol. 3, pp 217-
354. (b) Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer-Verlag: Berlin, 1986.
(11) Alkyl titanate-type reagents prepared from RMgBr (R ) methyl or ethyl)
and Ti(OiPr)4 did not give any adduct of benzoate at room temperature
for 3 h.
(12) Gassman, P. G.; O’Reilly, N. J. J. Org. Chem. 1987, 52, 2481-2490.
(13) This reaction mechanism can also be supported by the formation of the
perfluoroalkyl adduct of acetone which is derived from isopropoxide.
(14) When aluminium tri(iso-propoxide) was used for the reaction of perfluo-
roalkyl metal-ate reagent with aldehyde, no perfluoroalkylation took place.
We have reported the generation of stable perfluoroalkyl titanate-
type reagents and the new type of reaction, tandem reductive
perfluoroalkylation of esters to give fluoroalkyl sec-alcohols. Further
application to the “enantioselective” synthesis could provide highly
enantio-enriched organofluorine compounds with high physiological
activity and remarkable physical properties.
Acknowledgment. Dedicated to Prof. Frederick E. Ziegler for
his great contribution to synthetic organic chemistry. Generous
allotment of computational time from the Institute for Molecular
JA074642Z
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