Sequential perfluoroalkylation and asymmetric reduction of nitriles triggered with perfluoroalkyl titanates: catalytic asymmetric synthesis of perfluoroalkyl amines

Article abstract of DOI:10.1016/j.tetlet.2009.12.140

Highly enantio-enriched perfluoroalkyl amines are shown to be synthesized by perfluoroalkylation and asymmetric reduction of nitriles. Perfluoroalkylation of nitriles can be attained by the Lewis acidic perfluoroalkyl titanate reagents to give acyclic ket

Full text of DOI:10.1016/j.tetlet.2009.12.140

Tetrahedron Letters 51 (2010) 1371–1373
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Tetrahedron Letters
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Sequential perfluoroalkylation and asymmetric reduction of nitriles
triggered with perfluoroalkyl titanates: catalytic asymmetric synthesis
of perfluoroalkyl amines
*
Koichi Mikami , Tatsushi Murase, Lili Zhai, Susumu Kawauchi, Yoshimitsu Itoh, Shigekazu Ito
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantio-enriched perfluoroalkyl amines are shown to be synthesized by perfluoroalkylation and
asymmetric reduction of nitriles. Perfluoroalkylation of nitriles can be attained by the Lewis acidic per-
fluoroalkyl titanate reagents to give acyclic ketimines. Catalytic asymmetric hydrogenation of the acyclic
ketimines affords the perfluoroalkyl amine products in up to 93% ee.
Received 7 December 2009
Revised 24 December 2009
Accepted 24 December 2009
Available online 7 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor T.V. RajanBabu for
his 60’s birthday on February 5th.
Organofluorine compounds have attracted great interest be-
cause of promising applications in biological and material science
in recent years.1 Organofluorine compounds now constitute more
than 40% of pharmaceuticals on the top market and about 80% in
pipelines of new drug candidates. A new term, ‘fluorine scan’2 is
thus coined for the drug design. In sharp contrast, the methodolog-
ical aspect of organofluorine chemistry, as the development of new
methods to introduce fluorine, is still under development.
Chiral perfluoroalkyl amines potentially bear significant impor-
tance as biological targets due to the unique properties of perfluo-
roalkyl groups.3 However, enantio-enriched perfluoroalkyl amines
have generally been difficult to prepare and, hence, there are only
limited number of approaches to those chiral perfluoroalkyl com-
pounds.4 A simple approach to the enantio-enriched perfluoroalkyl
amines is the catalytic asymmetric hydrogenation of perfluoroalkyl
imines. Although its simplicity, there are two major obstacles in
the catalytic asymmetric reduction of the ketimines:5 (1) the ster-
eoselective preparation of perfluoroalkyl ketimines, and (2) the
catalytic asymmetric hydrogenation of the resultant ketimines.
The problem in synthesizing perfluoroalkyl ketimines associates
with the preparation of perfluoroalkyl ketonic precursors by per-
fluoroalkyl metal reagents and (Z/E)-control of the ketimines de-
rived thereof. However, the perfluoroalkyl metal reagents have
Recently, we reported the generation of stable perfluoroalkyl
(Rf ꢀ) titanate-type reagents and a new type of reaction, namely,
tandem8 reductive9 perfluoroalkylation of esters (Eq. 1).10 Herein
we report an advanced reaction sequence of catalytic asymmetric
reduction and perfluoroalkylation triggered with the addition of
the Lewis acidic titanate reagents to nitriles, which possess the
same oxidation level as esters (Eq. 2):
RfTi(OiPr)4MgBr
O
OH
Rf
O
ð1Þ
R'
R
Rf
R
R
O
N-
NH2
ð2Þ
RCN
*
R
Rf
R
Rf
The Lewis acidic perfluoroalkyl titanate reagents can be reactive
to nitriles, hopefully in the same tandem reductive perfluoroalky-
lation manner.10 However, when the perfluoroalkyl titanate re-
agents were reacted with nitriles at room temperature, only
perfluoroalkyl ketones (1) were obtained quantitatively (Table 1)
rather than the tandem reductive perfluoroalkylation product,
namely perfluoroalkyl amines (2) after acidic work-up with 1N
HCl (entries 1–3). These results indicate the formation of perfluoro-
alkyl imine intermediates. Without titanium tetra(iso-propoxide),
the Grignard reagent did not give the perfluoroalkyl ketone (entry
4), even in the presence of the Lewis acidic cerium reagent.11
The imine intermediates were then isolated (Scheme 1). After
perfluoroalkylation of nitrile with the perfluoroalkyl titanate
reagent, acetic anhydride was added to give the perfluoroalkyl ket-
imine in good isolated yield, as a single (Z)-isomer. The (Z)-geom-
etry of perfluoroalkyl ketimines was proven by the 1H–19F NOESY
spectra. The formation of the single (Z)-isomer is attributable to
hyperconjugative interaction of the lone electron pair of the
generally been recognized unstable because of the
a- or b-metal
fluoride elimination.6 The catalytic asymmetric hydrogenation of
perfluoroalkyl acyclic imines is the other issue, which has been rec-
ognized to be difficult to give high enantioselectivity due to the pe-
culiar organofluorine1,5 and acyclic imine5 functional groups.
* Corresponding author. Tel.: +81 3 5734 2142; fax: +81 3 5734 2776.
E-mail address: mikami.k.ab@m.titech.ac.jp (K. Mikami).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.140

1372
K. Mikami et al. / Tetrahedron Letters 51 (2010) 1371–1373
Table 1
Table 3
Reaction of perfluoroalkyl titanate reagents with nitriles
Effect of chiral ligands
[C4F9Ti(OiPr)4MgBr]
-
Ti (OiPr)4
NHAc
N
O
NH2
C4F9
R C4F9
(X eq.)
NAc
C4F9
RCN
H2 (45 atm)
[BINAPs-Ir]+BArF
CH2Cl2, r.t., 20 h
Et2O, r.t.
*
Ph
C4F9
R
C4F9
R
-
Ph
1
2
Entry
R
X (equiv)
Yielda (%)
1
2
1
2
PhCH2CH2
PhCH2CH2
Ph
Ph
2.5
4.0
4.0
4.0
—
—
—
—
Quant.
72
—
Entry
Ligand
Yielda (%)
eeb (%)
3
1c
2c
3d
4d
(S)-BINAP
94
93
95
92
88 (R)
90 (S)
93 (S)
88 (S)
4b
(R)-tolBINAP
(R)-xylBINAP
(R)-SEGPHOS
a
Determined by 19F NMR using BTF as an internal standard.
Without Ti(OiPr)4.
b
a
b
c
Isolated yields.
Determined by HPLC (CHIRAL CELL OJ-H).
5 mol % of the catalyst.
[C4F9Ti(OiPr)4MgBr] (2.5eq.)
CN
d
3 mol % of the catalyst.
Ph
Et2O, r.t., 2 h
P
P
N
N
P2O (2.5 eq.)
r.t., 1 h
mines with iridinium complexes with BINAP (Ir+-BINAPs/BArFꢀ),
which generally provide only low enantioselectivity for non-fluori-
nated acyclic ketimines.13 In sharp contrast, the perfluoroalkyl
ketimines gave the acyclic perfluoroalkyl sec-amine in high yield
and more significantly with high enantioselectivity (Table 3, entry
1). The chiral ligands, BINAP derivatives, were then screened in the
hydrogenation of the model substrate. When tolBINAP was used,
the perfluoroalkyl amine was obtained in good yield and higher
enantioselectivity (entry 2). The xylBINAP complex gave the high-
est yield and enantioselectivity (entry 3).
Ph
C4F9
R
Rf
P=Ac: 57% NMR yield
53% isolated yield
single isomer
P=Boc: 78% NMR yield
(A)
Scheme 1.
nitrogen into the
r* orbital of the C–C bond between imine and
perfluoroalkyl group (A).12 Even a generally employable Boc pro-
tecting group can also be introduced to give the Boc-protected per-
fluoroalkyl ketimine in good yield.
The absolute configuration of the (R)-(+)-perfluorobutyl phen-
ethyl amine (88% ee: Table 3, entry 1) was first deduced by com-
parison of the optical rotation of the de-protected (R)-(+)-
Several nitriles were then examined to give the protected (Z)-
perfluoroalkyl ketimines (Table 2). In the case of aliphatic nitrile,
acyclic perfluoroalkyl ketimines (CnF2n+1(CnH2n+1)C@NAc) were ob-
tained (entry 2). Other perfluoroalkyl groups such as C3F7 and C6F13
could also be introduced into the perfluoroalkyl ketimines (entries
3 and 4). In the case that a Boc protecting group is employed, the
corresponding Boc-protected perfluoroalkyl ketimines were ob-
tained in good yields after aqueous rather than acidic work-up (en-
tries 5 and 6). Even when R is sterically demanding and electron-
withdrawing aromatic group,11 the corresponding imine was also
obtained in good yield (entry 5).
hydrochloride salt (½a D25
+10.8) with (S)-(ꢀ)-trifluoromethyl amine
ꢁ
(½a 2D5
ꢀ15.2). Furthermore, the authentic sample of (R)-(+)-perfluo-
ꢁ
robutyl phenethyl amine (½a D25
ꢁ
+11.5: hydrochloride salt) was pre-
pared4a,4b to confirm the absolute configuration.
Several ketimines were then investigated to afford highly enan-
tio-enriched perfluoroalkyl amines (Table 4). Even with pseudo-
symmetric perfluoroalkyl ketimines (CnF2n+1(CnH2n+1)C@NAc), the
chiral half-perfluoroalkylated amines were obtained with high
enantioselectivities (92%, 90%, and 93% ee, respectively) (entries
2–4). When the Boc protecting group was employed
(Rf(R)C@NBoc), the perfluoroalkyl amines were also obtained in
high enantioselectivities (entries 5 and 7). Even in the case of ste-
rically demanding and electron-withdrawing benzonitrile-derived
imine (CnF2n+1(Ph)C@NBoc), the use of acidic trifluoroethanol as a
The highly enantio-selective synthesis of chiral sec-amines was
realized by the catalytic asymmetric hydrogenation of the keti-
Table 2
Synthesis of the perfluoroalkyl imines
Table 4
Asymmetric hydrogenation of perfluoroalkyl imines
P
NP
Rf
NHP
H2 (45 atm)
[xylBINAPs-Ir]+BArF
CH2Cl2, r.t.
[RfTi(OiPr)4MgBr] (2.5eq.)
N
P2O (2.5 eq.)
-
*
RCN
R
R
Rf
R
Rf
Et2O, r.t., 2 h
r.t., 1 h
Entry
P
R
Rf
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
Ac
PhCH2CH2
C4H9
C3H7
C6H13
PhCH2CH2
C6H5
C4F9
C4F9
C3F7
C3F7
C4F9
C4F9
C4F9
95
88
97
90
87
67
52
93
92
90c
93
93
15
90d
Ac
Ac
Ac
Boc
Boc
Boc
Entry
P
R
Rf
Yielda (%)
1
2
3
4
5
6
Ac
Ac
Ac
Ac
Boc
Boc
PhCH2CH2
C4H9
C3H7
C6H13
Ph
C4F9
C4F9
C3F7
C6F13
C4F9
C4F9
57(53)
51
51
56(56)
78
73
C6H5
a
b
c
Isolated yields.
Determined by HPLC (CHIRAL CELL OJ-H).
Determined by chiral GC (CP-Chirasil-Dex CB).
In CF3CH2OH.
PhCH2CH2
Determined by 19F NMR using BTF as an internal standard. The values in the
parentheses referred to isolated yields.
a
d

K. Mikami et al. / Tetrahedron Letters 51 (2010) 1371–1373
1373
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(A’)
Figure 1. MP2/6-311+G(d,p) optimized geometry: F (blue), H (white), C (gray), N
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90% ee) (entry 7). Hydrogen bonding of the carbonyl protection and
perfluoroalkyl groups of the ketimines with acidic trifluoroethanol
may additionally exert to fix the (Z)-imine geometry (vide infra),14
leading to the increase in enantioselectivity. Otherwise, only low
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311+G(d,p) (Fig. 1). The optimized structure (A0) shows multi-
hydrogen bonding sites in the complex. The primary interaction
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with the perfluoroalkyl fluorine atoms (2.879 Å and 2.926 Å,
respectively). Although these non-bonding distances are longer
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1.47 Å),1a the ‘hydrogen bonding’ network14 including the weak
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the first successful catalytic asymmetric hydrogenation of acyclic
simple perfluoroalkyl ketimines even with the generally employ-
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