Chiral Lewis base promoted trichlorosilane reduction of ketimines. An enantioselective organocatalytic synthesis of chiral amines

Article abstract of DOI:10.1016/j.tet.2009.06.015

The reduction of the carbon-nitrogen double bond is an important transformation. Here we report our studies on a family of chiral organic catalysts able to promote the stereoselective reduction of ketimines with trichlorosilane. The very cheap, metal-free catalysts were easily prepared in one step from commercially available products, namely a chiral aminoalcohol and picolinic acid derivatives. The catalyst structure was extensively modified in a study that allowed to identify an extremely active species, able to promote the reduction on a large variety of substrates with high efficiency (up to 95% ee). A three component methodology has been also developed, where the enantiomerically enriched amine was isolated after performing the reaction by mixing a ketone and an amine in the presence of trichlorosilane and the catalyst. Its synthetic potentiality was demonstrated by employing the present metal-free catalytic procedure in the preparation of (S)-metolachlor, a potent and widely used herbicide.

Full text of DOI:10.1016/j.tet.2009.06.015

Tetrahedron 65 (2009) 6354–6363
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral Lewis base promoted trichlorosilane reduction of ketimines.
An enantioselective organocatalytic synthesis of chiral amines
*
Stefania Guizzetti, Maurizio Benaglia , Franco Cozzi, Rita Annunziata
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Golgi 19-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The reduction of the carbon–nitrogen double bond is an important transformation. Here we report our
studies on a family of chiral organic catalysts able to promote the stereoselective reduction of ketimines
with trichlorosilane. The very cheap, metal-free catalysts were easily prepared in one step from com-
mercially available products, namely a chiral aminoalcohol and picolinic acid derivatives. The catalyst
structure was extensively modified in a study that allowed to identify an extremely active species, able to
promote the reduction on a large variety of substrates with high efficiency (up to 95% ee). A three
component methodology has been also developed, where the enantiomerically enriched amine was
isolated after performing the reaction by mixing a ketone and an amine in the presence of trichlorosilane
and the catalyst. Its synthetic potentiality was demonstrated by employing the present metal-free cat-
alytic procedure in the preparation of (S)-metolachlor, a potent and widely used herbicide.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 February 2009
Received in revised form 20 April 2009
Accepted 4 June 2009
Available online 10 June 2009
Keywords:
Pyridine N-oxides
Organocatalysis
Monoterpenes
Allyltrichlorosilane
Epoxide opening
1. Introduction
enantioselective imine reductions and reductive amination pro-
cesses.4 Two methodologies have been successfully developed; in
Chiral amines are ubiquitous in a variety of bioactive molecules
such as alkaloids, natural products, drugs, pharmaceuticals and
agrochemicals. Therefore it is not surprising that the development
of a catalytic stereoselective process for the preparation of enan-
tiomerically enriched amines is attracting an increasing interest
both at the academic and the industrial levels.1 The reduction of
ketimines represents a powerful and widely used transformation
for the generation of a new nitrogen-bearing stereocenter. How-
ever the few efficient chiral catalytic organometallic systems cur-
rently available suffer from some drawbacks.2 Indeed, the catalysts
are generally quite expensive species, typically constituted by an
enantiomerically pure ligand (whose synthesis may be costly, long
and difficult), and a metal species, in many cases a precious and
toxic metal, whose leaching can contaminate the product. A solu-
tion to some of these problems can be represented by the use of
metal-free catalysts. The advent of organocatalysis over the last few
years has led to the discovery and development of new activation
modes and novel transformations, sometimes complementary to
those established in the field of organometallic catalysis.3
one approach, binaphthol-derived phosphoric acids were success-
fully employed as catalytic activators in the reduction of ketimines
by using a dihydropyridine-based Hantzsch ester type reagent as
the reducing agent. However, it must be noted that the procedure
involves the use of high molecular weight and quite expensive
compounds as catalysts and it requires separation of the oxidized
form of the Hantzsch ester from the reaction product.5 Another
methodology exploits trichlorosilane as the reducing species, that
needs to be activated by co-ordination with Lewis bases, such as
N,N-dimethylformamide, acetonitrile, trialkylamines, to generate
a hexacoordinated hydridosilicate acting as the actual reducing
agent.6 Among the employed Lewis bases activators, N-formyl de-
rivative of amino acids have so far played a major role. Derivatives
of this type have been shown to promote the reduction, in some
cases with high enantioselectivity.7 Recently other chiral N-form-
amide derivatives were prepared from commercially available (S)-
pipecolinic acid and enantiopure 2-amino-1,2-diphenylethanol,
and successfully employed in the reduction of ketimines.8 In ad-
dition to formamides, it was shown that quinoline, isoquinoline
and pyridine-derived chiral oxazolines may be efficient promoters
for the addition of trichlorosilane to ketones and imines.9 The
stereoselective reduction of a broad range of N-aryl ketimines was
also catalyzed in the presence of a chiral sulfinamide featuring
a stereogenic sulfur atom.10 However many of these systems
present some drawbacks, due to the stability of the activators, or
their difficult synthesis and limited applicability, and to sometimes
In this context, the reduction of carbon–nitrogen double bonds
has been the subject of an intense research activity that has allowed
the development of efficient organocatalytic methods to perform
* Corresponding author. Tel.: þ39 0250314171; fax: þ39 0250314159.
E-mail address: maurizio.benaglia@unimi.it (M. Benaglia).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.015

S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
6355
Me
unsatisfactory levels of chemical and stereochemical efficiency.
Finally N-picolinoylpyrrolidine derivatives were also reported to
act as promoters for this reaction.11
Me
N
Me
N
Me
N
Me
Ph
N
Me
Ph
Me
Ph
Me
Ph
N
N
N
O
O
O
O
OH
OH
OMe
OH
Despite all these reported methods, however, the development
of a really efficient system, of general applicability and suitable for
large scale preparations is still a task of extreme interest. It is clear
now that organocatalysis has entered a new phase; many funda-
mental reactions of organic chemistry can now be run in the
presence of metal-free promoters, but the challenge today is to
design novel organocatalysts of great efficiency, low cost, high
stability and capable to promote enantioselective reactions on
a wide variety of substrates. In other words, the real challenge is the
development of metal-free catalysts of interest for industrial
applications.12
2
4
1
3
Ph
H
N
N
Me
Ph
Me
N
N
N
N
O
O
O
Ph
OH
OH
Ph
OH
6
5
7
Ph
Ph
Me
Ph
N
N
Me
N
N
N
N
N
N
O
O
O
OH
Ph
OH
Ph
OH
O
Ph
Ph
Ph
OH
Ph
Ph
11
8
9
10
In this context we wish to report here our studies on a low cost
catalytic system, easily prepared from commercially available
products, able to promote the enantioselective reduction of carbon–
nitrogen double bonds with trichlorosilane with great efficiency.
Ph
Ph
Ph
N
Me
N
N
N
N
N
O
O
O
OH
OH
Ph
OH
12
13
14
2. Results and discussion
H
N
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
N
2.1. Catalyst structure/activity study
N
O
O
Ph
OH
OH
16
O
OH
15
17
Our project aimed to the development of structurally simple
chiral Lewis bases as catalysts for the enantioselective reduction of
imines with trichlorosilane; the catalysts should be obtained by
modification of an inexpensive, commercially available, enantio-
pure material whose manipulation must be kept to minimum.13 We
were specially attracted by Matsumura’s work on picolinamides as
chiral promoters for the imine reduction11 and we decided to focus
our attention onto a wide class of catalysts prepared by simple
condensation of a chiral aminoalcohol with picolinic acid or its
derivatives.14 At that time Zhang reported in a preliminary com-
munication the use of ephedrine and pseudoephedrine-derived
picolinamides in the reduction of N-aryl and N-benzyl ketimines
promoted by trichlorosilane.15
Ph
Ph
N
N
N
N
N
N
N
N
O
O
O
O
OH
21
OH
OH
OH
19
18
20
Chart 1. Chiral catalysts for enantioselective reduction of imines.
N
HN
cat. (10 mol%)
HSiCl3
We decided to study in detail this class of organocatalyst. In
a single step procedure several derivatives were synthesized simply
by reaction of picolinic acid and different enantiomerically pure
amino alcohols mediated by condensing agents or by reaction of
picolinoyl chloride and the amino alcohol (see Experimental sec-
tion) (Scheme 1).
Scheme 2. Enantioselective reduction of N-phenyl imine of acetophenone.
The results of these exploratory experiments are reported in
Table 1 and Table 2. By running the reaction at 0 ꢀC in dichloro-
methane in the presence 10 mol % amount of N-picolinoylamide of
(1R,2S)-ephedrine 1 the (R) product was isolated after 15 h in
quantitative yield and 77% ee (entry 1, Table 1), in accordance with
Zhang’s result.15 The high chemical efficiency and the good level of
enantioselectivity showed by catalyst 1 are very interesting in light
of the low cost of ephedrine as the source of absolute stereocontrol
in the reduction. On this basis we undertook a detailed in-
vestigation of the structure–activity relationship of this kind of
organocatalysts. First benzamide 2 was prepared where the pyridyl
group has been replaced by phenyl ring. In the hypothesis that both
the nitrogen atom of picolinoyl group and the carbonyl oxygen play
a fundamental role in the activation of trichlorosilane by co-
ordination of silicon atom catalyst 2 was expected to perform worse
than 1. Indeed, compound 2 promoted the reaction in 40% yield and
only 27% ee.
R1
R1
R
R
R2
NH
OH
R2
N
HO
N
N
+
R3
O
O
R3
R4
OH
R4
Scheme 1. General scheme for the synthesis of chiral picolinamides.
Some of the structurally diversified organocatalysts synthesized
and employed to promote the trichlorosilane reduction of keti-
mines are reported in Chart 1.
The N-phenyl imine of acetophenone was selected as model
substrate to investigate the catalytic behaviour of compounds 1–21
in the reaction with trichlorosilane under different conditions of
solvent and temperature. (Scheme 2) After preliminary experi-
ments, chlorinated solvents were found to be the medium of choice
for this kind of transformation.
In a typical procedure, to a stirred solution of catalyst and the
imine in the proper solvent and temperature conditions under ni-
trogen, trichlorosilane was added drop wise by means of a syringe.
After usual aqueous work up allowed to isolate the crude product.
As already reported15 the relative stereochemistry of the
aminoalcohol stereocenters and the presence of the hydroxyl
groups played a decisive role in controlling the stereochemistry;
indeed also in our hands the already known catalysts15 3 and 4
performed less efficiently. The result seems to point out at an active
role of the OH group in controlling the stereochemical outcome of
the trichlorosilane mediated reduction, possibly by a H-bond
mediated coordination of the imine nitrogen with the hydroxyl

6356
S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
Table 1
We moved our attention also to the modification of the picoli-
noyl moiety. A selection of ephedrine-derivatives obtained by
condensation with picolinic acids bearing different substituents in
positions 3, 4 or 6 of the pyridine ring is shown in Chart 2. The new
catalysts were evaluated in the usual test reduction of acetophe-
none imine under the same experimental conditions employed for
compounds 1–21.
Enantioselective reduction of N-phenyl imine of acetophenone performed in DCM at
ꢀC with 10 mol % amount of catalyst
0
Entry
Catalyst
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
98
40
98
98
98
98
98
76
98
41
81
94
98
98
98
73
98
98
96
98
92
77 (R)
27 (R)
28 (R)
59 (R)
<5
11 (S)
50 (R)
<5
I
Cl
Me
N
Me
N
Me
N
Me
Ph
Me
Ph
Me
Ph
N
N
N
O
9
9
60 (R)
<5
O
O
OH
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
10
11
12
13
14
15
16
17
18
19
20
21
10 (R)
25 (R)
21 (S)
16 (S)
<5
40 (R)
15 (S)
10 (R)
7 (R)
24
22
23
Me
N
Me
N
Me
Ph
Me
Ph
N
Cl
N
O
O
OH
OH
26
25
30 (R)
37 (R)
Br
N
Cl
N
Me
N
a
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
b
Me
N
Me
N
Me
N
Me
Ph
Me
Ph
Me
Ph
Table 2
O
O
O
OH
28
Chart 2. Modified Chiral catalysts for reduction of imines.
OH
OH
27
Enantioselective reduction of N-phenyl imine of acetophenone performed with
10 mol % amount of catalyst
29
Entry
Catalyst
Solvent
Temp
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
1
1
DCM
CHCl3
DCM
DCM
DCM
CHCl3
CHCl3
CHCl3
CHCl3
0 ꢀ
0 ꢀ
0
0 ꢀ
C
C
ꢀC
98
98
8
97
91
95
98
47
49
77 (R)
82 (R)
77 (R)
71 (R)
75 (R)
78 (R)
73 (R)
61 (R)
57 (R)
22
23
23
23
24
25
26
From the results collected in Table 2 it was clear that a sub-
stituent in position 3 did not seem to influence the reactivity or the
stereochemical behavior of the catalyst. Indeed compounds 22, 23
and 24, bearing a 3-methyl, chloro and iodo substituted pyridine
ring respectively, promoted the reaction in similar yields and
enantioselectivities comparable to those of catalyst 1 (up to 77% ee).
As general observation these catalysts usually performed better in
chloroform than in dichloromethane (see for example entry 1 vs 2
in Table 2, but also entry 5 vs 6), while the lowering of the reaction
temperature often did not bring any substantial modification in the
enantioselectivity and not in a predictable way.16
A substitution at the 6 position on the pyridine was shown to be
deleterious for the stereochemical efficiency of the catalyst; 6-
chloro and 6-methyl picolinamides 25 and 26 promoted the re-
ductionwith lower enantioselectivities than 1 (entries 8–9, Table 2).
On the other hand the introduction of an appropriate sub-
stituent in the 4 position of the pyridine moiety was decisive to
improve catalyst efficiency. Indeed specially 4-bromo and 4-chloro
picolinic derivatives 28 and 29 showed remarkable catalytic prop-
erties (Table 3). Working at 0 ꢀC in dichloromethane with catalyst
29 the chiral amine was obtained in quantitative yield and 83% ee;
enantioselectivity was increased up to 88% by working in chloro-
form. A further improvement was observed by performing the re-
action at ꢁ20 ꢀC when enantioselectivity reached 95% with no
C
ꢁ20 ꢀC
ꢁ20 ꢀ
ꢁ20 ꢀ
ꢁ20 ꢀ
ꢁ20 ꢀ
C
C
C
C
a
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
b
group of the aminoalcohol. Finally the catalyst obtained starting
from ( )-nor-ephedrine 5 was tested and it showed to promote the
reduction with excellent chemical yield but without any stereo-
control (entry 5, Table 1).
L
Having identified the pyridine ring, free hydroxyl group and N-
alkyl substitution in the aminoalcohol portion as key structural
elements, necessary to secure good stereocontrol, the effect of
different substituents at the nitrogen atom and at the two stereo-
centers was then studied. N-Benzyl derivative 6 catalyzed the re-
action in only 10% ee (isomer R was obtained as major isomer),
while compound 7 bearing an isopropyl group was able to afford
the (S) isomer in lower enantiomeric excess than compound 1 (50%
vs 77%, entries 7 vs 1).
From the data collected with catalysts 8–11 it was shown that
only structure 9 was able to assure a good level of enantioselectivity
(60% ee, entry 9, Table 1), that however was slightly inferior than
that observed with 1. This clearly indicates once again that a N-alkyl
derivative behaved better than a N-benzyl one and that increasing
the steric hindrance at the stereocenter bearing the OH group does
not bring to any improvement of enantioselectivity. The activity of
molecules 12–14 with one stereocenter only was also investigated
but no improvement in the stereoselectivity was observed (entries
12–14). The same held true with compounds 15–17 obtained by
condensation of picolinic acid with 1,2-diphenyl amino ethanol.
Finally very disappointing results were observed also working with
both trans and cis enantiomerically pure aminoindanol derivatives
18–21 (entries 18–21, Table 1).
Table 3
Enantioselective reduction of N-phenyl imine of acetophenone performed with
10 mol % amount of catalyst
Entry
Catalyst
Solvent
Temp
Yielda (%)
eeb (%)
1
2
3
4
5
27
29
29
29
28
CHCl3
DCM
CHCl3
CHCl3
CHCl3
ꢁ20 ꢀ
C
98
98
98
98
95
80 (R)
83 (R)
88 (R)
95 (R)
93 (R)
0
ꢀC
0 ꢀ
C
ꢁ20 ꢀ
C
C
ꢁ20 ꢀ
a
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
b

S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
6357
erosion of the chemical yield, being the reduction product isolated
basically in quantitative yield (entries 2–4 of Table 3). Also 4-bromo
picolinic acid derivative 28 was able to promote the reaction with
high chemical and stereochemical efficiency (93% ee, entry 5).
It is worth mentioning that not only the stereochemical ability
but also the chemical activity of 4-chloropicolinic acid derivative 29
was superior to that of picolinamide 1. The performances of the two
catalysts at different loadings were investigated and the results
collected in Table 4. When the ketimine reduction was performed at
0 ꢀC in chloroform in the presence of 10 mol % amount of catalyst 1
the product was isolated in 83% ee; by lowering the catalyst loading
0 ꢀC in chloroform in the presence of 1 or 29 afforded the corre-
sponding chiral alcohol in 86% yield and 65% ee, and 80% yield and
66% ee, respectively.18
H
Cl
N
O
Me
Cl
Me
O
H
O
Me
Cl
H
Me
Cl
O
N
H
Me
H
H
Me
N
N
N
Cl
N
Cl
picolinamide of (L) ephedrine still showed to efficiently catalyze the
reaction even in 5% or even 1 mol % amount, affording the chiral
amine in 88% and 86% yield respectively after 15 h; however a small
but significant decrease of enantioselectivity was observed, from
83% to 78% and 70% (entries 1, 3 and 4 of Table 4). 4-Chloropicolinic
acid derivative 29 proved to be a superior catalyst, able to maintain
a very high chemical efficiency and a satisfactory stereoselectivity
even at low catalyst loadings. Indeed by employing 5 mol % amount
of 29 it was possible to obtain the product in 93% yield after only 2 h
and unchanged enantioselectivity (entry 5, Table 4).
A
B
R- product
S- product
Figure 1. Proposed model of stereoselection for enantioselective reduction of N-aryl
ketoimines.
2.2. General applicability
4-Chloropicolinamide of (1R,2S)-ephedrine 29 was then se-
lected as the catalyst of choice and employed in a series of exper-
iments aimed to test its general applicability to substituted N-aryl
imine of alkyl-aryl ketones (Scheme 3).
Table 4
Catalyst efficiency of compounds 1 and 29 in chloroform in the reduction of N-
phenyl imine of acetophenone
Entry
Catalyst
Cat. Load.
Time
Temp
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
1
29
1
10%
10%
5%
1%
5%
1%
10%
1%
15 h
15 h
15 h
15 h
2 h
0 ꢀ
0 ꢀ
C
C
98
98
88
86
93
90
98
98
77
83 (R)
88 (R)
78 (R)
70 (R)
88 (R)
86 (R)
95 (R)
88 (R)
90 (R)
R'
R'
cat. (10 mol%)
0
0
0
0
ꢀC
ꢀC
ꢀC
ꢀC
N
HN
1
CHCl3
HSiCl3
29
29
29
29
29
Ar
R
Ar
R
2 h
15 h
15 h
4 h
ꢁ20 ꢀC
ꢁ20 ꢀC
1%
ꢁ20 ꢀ
C
30
Ar= naphthyl, R=Me, R'=H
Ar= 4-CF3-C6H4 R=Me, R'=H
Ar= Ph; R=Me, R'=2-OMe
Ar= Ph; R=Me, R'=4-OMe
Ar= Ph, R=Et, R'=H
35
a
31
32
33
34
,
36
37
38
39
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
b
Even by working with 1 mol % amount catalyst 29 offered a re-
ally interesting performance, promoting the reduction in 90% yield
after only 2 h (entry 6, Table 4). By comparing the catalytic behavior
of catalysts 1 and 29 it was observed once again that while the use
of 1 mol % of catalyst 1 at ꢁ20 ꢀC did not bring to any improvement
in the enantioselectivity, 4-chloropicolinic acid derivative 29
maintained a high level of efficiency leading to the product after
only 4 h in 77% yield and still 90% ee (entry 9, Table 4).
Scheme 3. Enantioselective reduction of N-aryl imine of different ketones.
Different N-aryl ketimines were reduced with trichlorosilane in
the presence of 10 mol % of catalyst 1 in CHCl3 at 0 ꢀC and catalyst
29 at ꢁ20 ꢀC (Table 5).
Table 5
The screening of systematically modified organocatalysts of this
family led to identify the key structural factors that influence their
catalytic properties and to propose a tentative model of stereo-
selection observed in the reaction promoted by picolinamide de-
rivatives. In this model pyridine nitrogen and CO amidic group of
picolinamide activate trichlorosilane by coordination; the hydrogen
atom of hydroxyl group plays a fundamental role in coordinating the
imine through hydrogen bonding. The presence of two stereogenic
centers on the aminoalcohol moiety with the correct relative con-
figuration such as in (1R,2S)-(ꢁ) ephedrine is necessary to stereo-
direct the imine attack by trichlorosilane. The methyl groups on the
amide nitrogen and on the stereocenter in position 2 of the amino-
alcohol chain apparently have the optimum size for maximizing the
enantiodifferentiation of the process. In the proposed stereo-
selection model A, leading to the major enantiomer, the steric
interaction between the pyridine ring and N-aryl group is much less
significant than that observed in adduct B, that is thus disfavored.17
The importance of the role played by the substituent at the
imine nitrogen was supported by the observation that the same
organocatalysts were able to promote the enantioselective re-
duction of aryl-alkyl ketones in lower enantioselectivity Figure 1
For instance the reaction of acetophenone with trichlorosilane at
Enantioselective catalytic reduction of imines 30–34
Entry
Catalyst
Imine
Yielda (%)
eeb (%)
1c
2
3
4
5
6
7
8
1
29
1
29
1
29
1
29
1
29
30
30
31
31
32
32
33
33
34
34
95
95
98
85
98
98
98
98
90
91
82
95
77
91
83
82
87
91
71
81
9
10
a
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
Reaction run at ꢁ20 ꢀC with 10 mol % of catalyst.
b
c
With all the substrates both catalysts displayed a high catalytic
activity, affording the products very often in quantitative yields. In
terms of enantioselectivity, catalyst 29 performed generally better
than catalyst 1, often leading to products in more than 90% enantio-
selectivities.19 For example, with imine 30, catalyst 29 was able to
catalyze the reduction in 95% ee (entries 1–2, Table 5). This is also
the case for imine 31 (entries 3–4, Table 5) and, more importantly, of

6358
S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
N-4-methoxyphenyl imine 33; the chiral amine 38 was isolated in
quantitative yield and 91% ee. It must be noted that both products 37
and 38 represent potential precursors of primary amines, since both
the ortho-methoxyphenyl ring as well as the para-methoxyphenyl
moiety are easily removed by oxidative degradation of the anisol ring.
Zhang has already reported that ephedrine-derived picolina-
mide 1 was also active in the reduction of N-benzyl imines.15
(Scheme 4, Eq. a) In our hands imine 40 of acetophenone was re-
duced by reaction with trichlorosilane in the presence of 10% of
catalyst 1 at 0 ꢀC in 85% yield and 71% ee (entry 1, Table 6). Also for
this substrate, 4-chloropicolinamide 29 promoted the reaction in
better yield and enantioselectivities, performing at its best at
ꢁ20 ꢀC in dichloromethane; under these conditions chiral amine
41, direct precursor of a primary amine, was synthesized in quan-
titative yield and 80% ee (entry 4, Table 6).
to maintain a very high level of enantioselectivity (entry 9, Table 6).
The wide applicability and generally high stereochemical efficiency
shown by ephedrine-based picolinamides in the enantioselective
reduction of both N-aryl and N-alkyl ketoimines is remarkable
considering the extremely simple preparation and the low cost of
such a class of organocatalysts.
Catalyst 29 was also successfully employed in the enantiose-
lective reduction of a cyclic N-alkyl imine, a structural motif of great
interest in view of future possible application in pharmaceutical
chemistry. The reduction of 2-phenyl-(3,4-5,6-tetrahydro)-pyri-
dine promoted by 4-chloropicolinic derivative 29 afforded the
corresponding cyclic amine in 98% yield and 81% ee.
Another positive feature is represented by the possibility to
recover and reuse the catalyst. After a simple aqueous work up the
crude reaction mixture is often constituted by just the product and
the catalyst. An easy purification through a short plug of silica al-
lows to separate the product from the organocatalyst that was re-
covered in higher than 95% yield, and recycled with no loss of
chemical and stereochemical efficiency.
R
R
HN
N
cat. (10 mol%)
(a)
HSiCl3
2.3. Three component methodology
41 R= Bn
43 R= Bu
The development of a three component version of the reaction
was also explored; we reasoned that since the preparation of the
ketimines is not straightforward and requires long reaction times
and relatively high temperatures, the possibility to perform an
enantioselective reductive amination process starting directly from
a ketone/amine mixture would be very attractive and would make
the methodology even more synthetically appealing.
40 R= Bn
42 R= Bu
HN
N
PhLi
cat. (10 mol%)
HSiCl3
CN
(b)
Br
Asymmetric reductive amination of ketones has been performed
with organometallic as well as with organic catalysts.22 However it
must be noted that a reductive multicomponent methodology for
the trichlorosilane promoted reduction has been so far un-
derdeveloped.23 One of the reasons may be that a reductive ami-
nation process mediated by trichlorosilane competes with ketone
reduction, since also these substrates are easily reduced by HSiCl3
in the presence of by Lewis bases, even at low temperatures. For
instance the reduction of acetophenone promoted by 1 afforded the
corresponding alcohol in 86% at 0 ꢀC, 64% at ꢁ20 ꢀC and 55% yield at
ꢁ40 ꢀC after 12 h only in dichloromethane.18
Scheme 4. Enantioselective reduction of N-benzyl and N-alkyl imines.
Table 6
Enantioselective catalytic reduction of imines 40–42
Entry
Catalyst
Imine
Solvent
Temp
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9c
1
40
40
40
40
42
42
42
42
42
DCM
DCM
CHCl3
DCM
DCM
DCM
CHCl3
CHCl3
CHCl3
0 ꢀ
C
85
98
98
98
95
98
98
98
77
71
77
78
80
70
77
91
83
87
29
29
29
1
29
29
29
29
ꢁ20 ꢀC
0 ꢀ
C
0
0
0
ꢀC
ꢀC
ꢀC
A detailed study allowed us to find the correct experimental
conditions and to develop a successful organocatalyzed reductive
amination starting from a ketone and an aromatic amine. The re-
action of acetophenone and aniline was investigated as model
transformation (Scheme 5).
0 ꢀ
C
ꢁ20 ꢀ
C
0 ꢀ
C
a
Yields determined after chromatographic purification.
b
c
Enantiomeric excess determined by HPLC on chiral stationary phase.
Reaction was performed with 1 mol % amount of catalyst.
O
cat. (10 mol%)
HN
+
HSiCl3
Even better results were obtained in the enantioselective re-
H2N
duction of N-alkyl imines.20 It is worth mentioning that an efficient
organocatalyzed reduction of N-alkyl substituted ketoimines has
been described for the first time only very recently.21 Previously
only two examples were reported where the catalyst was shown to
be stereochemically inefficient, affording the product as racemic
mixture7b or in low enantioselectivity.10a
Scheme 5. Enantioselective reductive amination process.
When an equimolar mixture of ketone and aniline was reacted in
the presence of 10 mol % amount of catalyst 1 and 3.5 mol equiv of
trichlorosilane for 48 h at 0 ꢀC in dichloromethane the chiral amine
was recovered in only 50% yield along with 10% of 1-phenyl-1-
ethanol. The enantioselectivity was comparable to that obtained in
the direct reduction of N-phenyl imine of acetophenone (78% ee,
entry 1, Table 7). A longer reaction time increased the yield of both
the chiral amine and the undesired alcohol (entry 2). However, by
working on the stoichiometry of the reagents it was possible to
secure better results; an increase of the aniline equivalents was
found to be crucial for obtaining only amine in good yields and
However ephedrine-based picolinamides promoted the reaction
of N-butyl imine of acetophenone 42 in excellent yields and
pleasingly in high stereoselectivities. While the reaction run at 0 ꢀC
in dichloromethane with 1 afforded the product 43 in 95% yield and
70% ee, with catalyst 29 the N-butyl amine 43 was isolated in
quantitative yield and 77% ee (entries 5–6, Table 6).
Under the best conditions (chloroform, 0 ꢀC, 24 h) 4-chloro
picolinic derivative 29 promoted the reduction in 98% yield and 91%
ee (entry 7, Table 6). It was demonstrated that it was possible to
carry out the reaction with just 1 mol % amount of catalyst and still

S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
6359
unchanged enantioselectivity. After 24 h the reductive amination
process successfully lead to the chiral amine in quantitative yield
and 76% ee at 0 ꢀC in chloroform (entry 5). However a reaction time
as short as six hours gave the product in 87% (entry 7). Also in the
three components reaction catalyst 29 proved to be really efficient.
Working with this catalyst at 0 ꢀC the product was obtained in
quantitative yield and 83% ee, that was further increased up to 87%
enantioselectivity byperforming the reaction at ꢁ20 ꢀC, with no loss
of chemical efficiency (entries 8–9, Table 7). The reductive amina-
tion methodology was also applied to other substrates (Table 8).
methoxyacetone 44 was first explored (Scheme 6). After 15 h at
0 ꢀC in dichloromethane catalyst 1 derived from (1S,2R)-(þ)
ephedrine afforded the product in quantitative yield and 65% ee
(Table 9, entry 1). The catalyst performed better in chloroform;
when the reaction temperature was lowered from 0 ꢀC to ꢁ20 ꢀC,
the product was obtained in 75% yield and 75% ee (entry 3). Based
on these promising results the methodology was employed in the
enantioselective reduction of imine 46 to afford chiral amine 47, an
immediate precursor of metolachlor. Under the best conditions
(CHCl3, ꢁ20 ꢀC, 15 h, entry 5, Table 9) the product was isolated in
53% yield and 72% ee, that is a 86:14 enantiomeric ratio, very similar
to that of the commercial product. In this case catalyst 29 afforded
comparable results and led to the formation of product 47 at ꢁ20 ꢀC
in 67% yield and 70% ee (entry 7, Table 9).
Table 7
Reductive amination process for the synthesis of N-phenyl-1-phenylethylamine at
0
ꢀC
Entry
Catalyst
Aniline
(equiv)
Solvent
Time
Yielda
(%)
Yielda
alcohol (%)
eeb (%)
R
N
R
1
2
3
4
5
6
7
8
9c
1
1
1
1
1
1
1
29
29
1
1
DCM
DCM
DCM
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
48 h
72 h
72 h
72 h
24 h
12 h
6 h
50
67
78
96
98
94
87
98
98
10
29
12
d
d
d
d
d
d
78
78
77
77
76
75
75
83
87
N
Me
Ph
N
O
1.5
2.5
2.5
2.5
2.5
2.5
2.5
HN
OH
MeO
MeO
HSiCl3
15h
72 h
40 h
R = Me 44
R = Et 46
R = Me 45
R = Et 47
a
Yields determined after chromatographic purification.
b
c
Enantiomeric excess determined by HPLC on chiral stationary phase.
Reaction performed at ꢁ20 ꢀC.
Scheme 6. Enantioselective reduction of N-aryl imine of methoxyacetone.
Table 8
Reductive amination process for the synthesis of N-4-methoxyphenyl 1-phenyl
ethylamine 38
Table 9
Enantioselective reduction of N-aryl imine of methoxyacetone
Entry
Catalyst
Temperature
Solvent
Time
Yielda (%)
eeb (%)
Entry
Catalyst
Imine
Solvent
Temp
0 ꢀ
Yielda (%)
eeb (%)
1
2
3
1
29
29
0 ꢀ
0 ꢀ
C
C
DCM
DCM
CHCl3
12 h
72 h
90 h
15
90
80
73
77
87
1
2
3
4
5
6
7
1
1
1
1
1
29
29
44
44
44
46
46
46
46
DCM
DCM
C
98
80
75
84
53
68
67
65
70
75
67
72
55
70
0
ꢀC
ꢁ20 ꢀC
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
ꢁ20 ꢀ
C
C
C
0 ꢀ
C
a
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
ꢁ20 ꢀ
b
0 ꢀ
C
ꢁ20 ꢀ
For example also 4-methoxyaniline was reacted with aceto-
a
phenone in the presence of catalyst 29 (10 mol %) under different
experimental conditions to afford the chiral amine 38 (Scheme 3),
immediate precursor of a primary amine. In this case longer re-
action times were required in order to have high yields of the
product. By working in chloroform at ꢁ20 ꢀC 4-chloro picolinamide
derivative was able to catalyze the synthesis of amine 38 in 80%
yield and 87% ee (entry 3, Table 8).
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC on chiral stationary phase.
b
To the best of our knowledge this is the first organocatalytic
example of reduction for an industrially relevant compound oc-
curring with efficiency comparable to the existing organometallic
process.
Since the preparation of the imine precursor for these important
chiral amines is quite difficult and it requires long reaction times,
the development of a three component reductive amination pro-
cess was especially attractive. We were pleased to find that when
a mixture of methoxyacetone and 2-ethyl, 6-methyl aniline was
reacted at 0 ꢀC in chloroform for 70 h with 10 mol % amount of
picolinamide 1 and 3.5 mol equiv of trichlorosilane, chiral amine 47
was obtained in 86% yield and 70% ee (Scheme 7).
As a synthetic application of the present methodology, a syn-
thesis of (S)-metolachlor was attempted. This is a very popular
herbicide belonging to the class of a-chloroacetanilides. Since 1996,
a mixture of metolachlor constituted by 88% of the (S)-isomer and
12% of the (R)-isomer is commercialized by Syngenta (Chart 3). The
preparation on ton scale of the enantiomerically enriched product
relies on the enantioselective imine reduction through an ex-
tremely active and efficient, but very expensive iridium-chiral fer-
rocenyl phosphine complex.24
The use of picolinamides 1 and 29 as organocatalysts in the
enantioselective reduction of N-2,6-dimethylphenyl imine of
O
cat. (0.1 eq)
+
MeO
HN
H2N
72 h, CHCl3
HSiCl3
MeO
O
O
Scheme 7. Multicomponent enantioselective organocatalyzed preparation of an im-
mediate precursor of metolachlor.
Cl
Cl
N
N
MeO
MeO
3. Conclusion
(R) - Metolachlor
(S) - Metolachlor
In conclusion, we have studied and developed a new class of
metal-free chiral catalysts able to promote the enantioselective
Chart 3. Metolachlor: a potent herbicide.

6360
S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
reduction of ketimines mediated by trichlorosilane with high
chemical and stereochemical efficiency.25 The organocatalysts have
several positive features: they are easily prepared, by a single
condensation step, from commercially available compounds; they
are low cost catalysts, the source of stereocontrol being a very
cheap and largely available aminoalcohol, such as ephedrine; the
reduction of carbon–nitrogen double bond is performed under very
mild reaction conditions and with an extremely simple experi-
mental procedure. The catalytic methodology can be applied to
a large variety of substrates; noteworthy the ephedrine-derived
picolinamides promoted the reduction not only of N-aryl but also of
N-alkyl ketimines; the catalyst could be used in loading as low as
1 mol %. A convenient enantioselective organocatalytic three com-
ponent methodology was also developed; the reductive amination
process, starting simply by a mixture of a ketone and an aryl amine,
opens an easy access to chiral amines with a straightforward ex-
perimental methodology. All these positive features make the
present catalytic method in principle suitable also for large scale
applications; its synthetic potentiality was demonstrated by suc-
cessfully employing the present metal-free catalytic procedure in
the preparation of (S)-metolachlor, a potent and widely used
herbicide.
4.1.1.2. General procedure B. A stirred solution of the picolinic acid
(1 mol equiv) or its derivatives in thionyl chloride (1 mL/mmol
substrate) was refluxed for 2 h, then the solvent was evaporated
under vacuum; the residue, dissolved in THF (2 mL) with a few
drops of DMF, was added to a solution of chiral aminoalcohol
(1 mol equiv) and TEA (3 mol equiv) in THF; the reaction mixture
was stirred for 12 h at reflux. The organic phase was quenched with
aqueous saturated solution NaHCO3, and brine. The organic phase
was then dried over Na2SO4, filtered and concentrated under vac-
uum to give the crude product. Purification by flash chromatogra-
phy afforded the products.
4.1.1.3. Catalyst 1 (procedure A).
6
3
5
7
1
Me
N
8
H
4
Me
N
9
O
10
11
OH
H
2
9'
10'
Following procedure A, starting from (1R,2S)-ephedrine
(1.2 mmol, 0.198 g) catalyst 1 was isolated as white solid (70% yield,
0.189 g) (purification through silica gel, eluent: 99:1 CH2Cl2/
CH3OH).
4. Experimental
4.1. General methods
Rotamer 1. 1H NMR (300 MHz, CDCl3):
d 8.53 (s, 1H, 4), 7.85–7.65
(m, 1H, 6), 7.55–7.45 (m, 1H, 7), 7.40–7.30 (m, 1H, 5), 7.30–7.25 (m,
All reactions were carried out in oven-dried glassware with
magnetic stirring under nitrogen atmosphere, unless otherwise
stated. Dry solvents were purchased by Fluka and stored under
nitrogen over molecular sieves (bottles with crown cap). Reactions
were monitored by analytical thin-layer chromatography (TLC)
using silica gel 60 F254 pre-coated glass plates (0.25 mm thickness)
and visualized using UV light or phosphomolibdic acid. Proton NMR
spectra were recorded on spectrometers operating at 200, 300 or
500 MHz respectively. Proton chemical shifts are reported in ppm
5H, 9, 90, 10, 100, 11), 4.81 (d, J¼4.6 Hz, 1H, 2), 4.35 (br s, 1H, 1), 2.8 (s,
3H, 3), 1.33 (d, J¼4.9 Hz, 3H, 8). 13C NMR (75 MHz, CDCl3):
d 169,
154.2, 147.3, 141.5, 137.4, 128.2 (2C), 127.4, 126.7 (2C), 124.5, 123.1,
76.1, 58.3, 29.7, 14.5. Rotamer 2. 1H NMR (300 MHz, CDCl3):
d 8.53 (s,
1H, 4), 7.78–7.73 (m, 1H, 6), 7.53–7.47 (m, 1H, 7), 7.40–7.36 (m, 1H,
5), 7.30–7.25 (m, 5H, 9, 90, 10, 100, 11), 5.09 (br s, 1H, 2), 4.57 (br s, 1H,
1), 2.87 (s, 3H, 3), 1.28 (d, J¼4.8 Hz, 3H, 8). 13C NMR (75 MHz,
CDCl3): d 169.8, 154.8, 148.3, 142.1, 137.1, 128.2 (2C), 127.1, 126.3 (2C),
124.5, 124.3, 76.4, 58.6, 35, 11.2. IR (DCM): nC]O¼1725 cmꢁ1
.
(d
) with the solvent reference relative to tetramethylsilane (TMS)
25
Mp¼99–101 ꢀC. [
a
]
ꢁ19 (c 0.55 g/100 mL, DCM, ¼589 nm). Mass
l
employed as the internal standard (CDCl3,
d
¼7.26 ppm). The fol-
D
(ESIþ): m/z¼271 [M]þ, 293 [MþNa]þ. Anal. Calcd for C16H18N2O2: C,
lowing abbreviations are used to describe spin multiplicity:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad
signal, dd¼doublet of doublets. 13C NMR spectra were recorded on
300 or 500 MHz spectrometers operating at 75 and 125 MHz re-
spectively, with complete proton decoupling. Carbon chemical
71.09; H, 6.71; N, 10.36. Found: C, 71.15; H, 6.57; N, 10.35.
4.1.1.4. Catalyst 2.
9'
3
shifts are reported in ppm (d) relative to TMS with the respective
10
8
1
Me
N
4
solvent resonance as the internal standard (CDCl3,
d
¼77.0 ppm).
H
9
Me
Optical rotations were obtained on a polarimeter at 589 nm using
a 5 mL cell with a length of 1 dm. HPLC for ee determination was
performed on Agilent 1100 instruments under the conditions
reported below. Mass spectra (MS) were performed on a hybrid
quadrupole time of flight mass spectrometer equipped with an ESI
ion source. Microwave-accelerated reactions were performed in
CEM Discover class S instrument.
8'
5
O
OH
6
7
12
H
2
5'
6'
To a solution of (1R,2S)-ephedrine (1.2 mmol, 0.198 g), TEA
(1.2 mmol, 0.165 mL) and DMAP (10 mg) in dry THF a solution of
benzoyl chloride (1 mmol, 0.140 g) in THF was slowly added
dropwise. The mixture was stirred for 12 h at room temperature.
The obtained residue, after evaporation of solvent, was purified by
silica gel flash chromatography (eluent: 100 mL of 7:3 hexane/ethyl
acetate, then 300 mL of 6:4 hexane/ethyl acetate) allowed to obtain
as white solid 2 (98% yield, 0.26 g).
4.1.1. Synthesis of the catalysts
4.1.1.1. General procedure A. To a stirred solution of the picolinic
acid (1 mol equiv) or its derivatives in chloroform (5 mL/mmol
substrate) kept under nitrogen at 0 ꢀC, chloroform solutions of 1-
[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride
(EDC, 1.2 mol equiv), and 1-hydroxybenzotriazole (HOBT,
1.2 mol equiv), and aminoalcohol (1.2 mol equiv) were added in this
order (the volume of each added solution was 1–3 mL; the total
final volume of the solution was 8–25 mL). The reaction was stirred
at room temperature overnight, and concentrated under vacuum to
give the crude product. Purification by flash chromatography
afforded the products.
Rotamer 1. 1H NMR (300 MHz, CDCl3): 7.4–7.1 (m, 10H, 8, 80, 9,
d
90, 10, 5, 50, 6, 60, 7), 6.98 (s, 1H, 12), 4.81 (s, 1H, 2), 4. 5 (br s, 1H, 1),
2.6 (s, 3H, 3), 1.33 (d, J¼5.5 Hz, 3H, 4). Rotamer 2. 1H NMR (300 MHz,
CDCl3): d
7.4–7.1 (m, 10H, 8, 80, 9, 90, 10, 5, 50, 6, 60, 7), 6.90 (s, 1H, 12),
4.5 (s,1H, 2), 4.3 (br s,1H,1), 2.9 (s, 3H, 3),1.4 (d, J¼5.1 Hz, 3H, 4). 13C
NMR (75 MHz, CDCl3):
d 168, 155.2, 141.3, 141.0, 137.4, 128.3 (2C),
128.0, 127.7 (2C), 126.5 (2C), 124.5 (2C), 123.1, 120.1 (2C), 77.1, 59.3,

S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
6361
25
30.7, 15.5. IR (DCM): nC]O¼1700 cmꢁ1. Mp¼122–124 ꢀC. [
a
]
DCM,
l
¼589 nm). HMRS Mass (ESIþ): m/z¼[MþH]þ calcd for
D
ꢁ140.6 (c 0.46 g/100 mL, DCM,
l
¼589 nm). Mass (ESIþ): m/z¼270
C16H17BrN2O2 348.0473, found 348.0469 [MþH]þ.
4.1.1.7. Catalyst 29 (procedure B).
[M]þ. Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
75.85; H, 7.12; N, 5.15.
Cl
4.1.1.5. Catalyst 4.
3
5
4
7
1
Me
N
6
8
3
Me
N
H
5
Me
9
7
N
1
8
H
4
O
Me
9
N
10
11
OH
6
H
O
2
10
11
OMe
9'
12
10'
H
2
9'
10'
Starting from (1R,2S) ephedrine (1.2 mmol, 0.198 g) and 4-
choloropicolinic chloride (1 mmol, 0.180 g) catalyst 29 was isolated
as white solid (71% yield, 0.21 g) (purification through silica gel,
eluent: 400 mL of 98:2 CH2Cl2/MeOH, 600 mL of 95:5 CH2Cl2/
MeOH, then 400 mL of 9:1 CH2Cl2/MeOH).
Compound 1 (0.5 mmol, 0.135 g) was added to a suspension of
50% NaH (0.55 mmol, 26.4 mg) in THF (3 mL) and the mixture was
stirred at room temperature for 2 h. MeI (1 mmol, 0.142 g) was
added and the resulting mixture was stirred for 20 h. The residue
obtained after evaporation of solvent was purified by silica gel flash
chromatography (eluent: 200 mL of 9:1 CH2Cl2/CH3OH). Com-
pound 4 was isolated as white solid (29% yield, 47 mg).
Rotamer 1. 1H NMR (300 MHz, CDCl3):
d 8.35–8.30 (m, 1H, 4),
7.29–7.20 (m, 3H, 5, 10, 100), 7.25–7.18 (m, 1H, 11), 7.08 (d, J¼6.1 Hz,
2H, 9, 90), 6.48 (br s, 1H, 7), 4.63 (d, J¼4.0 Hz, 1H, 2), 4.12–4.06 (m,
1H, 1), 2.86 (s, 3H, 3), 1.31 (d, J¼6.7 Hz, 3H, 8). 13C NMR (75 MHz,
Rotamer 1. 1H NMR (300 MHz, CDCl3):
d 8.59 (s, 1H, 4), 7.70–7.65
(m, 1H, 6), 7.49–7.39 (m, 2H, 9, 90), 7.38–7.35 (m, 1H, 11), 7.35–7.31
(m, 2H,10,100), 7.30–7.25 (m,1H, 5), 7.08 (d, J¼7.5 Hz,1H, 7), 4.36 (d,
J¼5.5 Hz, 1H, 2), 4.20–4.15 (m, 1H, 1), 3.27 (s, 3H, 12), 3.12 (s, 3H, 3),
CDCl3):
d 167.9, 155.4, 148.3, 144.9, 141.7, 128 (2C), 127.6, 126.1 (2C),
124.3, 124.1, 75.2, 58.8, 28.8, 14.2. Rotamer 2. 1H NMR (300 MHz,
CDCl3): d
8.33–8.28 (m, 1H, 4), 7.45–7.35 (m, 2H, 9, 90), 7.33–7.27 (m,
3H, 7, 10, 100), 7.25–7.20 (m, 1H, 5), 7.22–7.18 (m, 1H, 11), 5.11–5.01
1.36 (d, J¼6.5 Hz, 3H, 8). 13C NMR (75 MHz, CDCl3):
d 169, 154, 148,
(m, 1H, 2), 4.60–4.50 (m, 1H, 1), 2.80 (s, 3H, 3), 1.25 (d, J¼7 Hz, 3H,
139.5, 136, 128.4 (2C), 127.9, 126.8 (2C), 124.1, 124, 86.1, 58.6, 57.1,
8). 13C NMR (75 MHz, CDCl3):
d 168.1, 155.8, 149.1, 145, 141.8, 128
28.6, 13.5. Rotamer 2. 1H NMR (300 MHz, CDCl3):
d 8.59 (s, 1H, 4),
(2C), 127.3, 126.1 (2C), 124.3, 123.3, 75.9, 57.6, 34.2, 11.1. Mp¼139–
7.80–7.73 (m, 1H, 6), 7.35–7.25 (m, 2H, 5, 7), 7.30–7.25 (m, 1H, 11),
7.30–7.20 (m, 2H, 10, 100), 7.08 (d, J¼7.6 Hz, 2H, 9, 90), 4.80–4.70 (m,
1H, 1), 4.57 (d, J¼4.5 Hz, 1H, 2), 3.32 (s, 3H, 12), 2.92 (s, 3H, 3), 1.36
25
141 ꢀC. IR (DCM): nC]O¼1721 cmꢁ1. [
a
]
D
ꢁ36.06 (c 0.244 g/100 mL,
DCM,
l
¼589 nm). HRMS Mass (ESIþ): m/z¼[MþNa]þ calcd for
C16H17ClN2O2 327.0871, found 327.0869 [MþNa]þ.
(d, J¼5.5 Hz, 3H, 8). 13C NMR (75 MHz, CDCl3):
d 168.5, 154, 148, 140,
136, 128.4 (2C), 127.7, 127.1 (2C), 124, 122.5, 86.1, 57.1, 55.5, 31.3, 11.7.
25
IR (DCM): nC]O¼1720 cmꢁ1. Mp¼81–91 ꢀC. [
a
]
ꢁ35.31 (c 0.32 g/
4.1.2. General procedures for reduction reaction
D
100 mL, DCM,
l
¼589 nm). Mass (ESIþ): m/z¼285. Anal. Calcd for
4.1.2.1. Imine reduction. General procedure. To a stirred solution of
catalyst (0.1–0.01% mol/eq mmol) in the chosen solvent (2 mL), the
imine (1 mmol/eq) was added. The mixture was then cooled to the
chosen temperature and trichlorosilane (3.5 mmol/eq) was added
drop wise by means of a syringe. After stirring at the proper tem-
perature, the reaction was quenched by the addition of a saturated
aqueous solution of NaHCO3 (1 mL). The mixture was allowed to
warm up to room temperature and water (2 mL) and dichloro-
methane (5 mL) were added. The organic phase was separated and
the combined organic phases were dried over Na2SO4, filtered, and
concentrated under vacuum at room temperature to afford the
crude product. If necessary, the amine was purified by flash chro-
matography. Yields and enantiomeric excesses for each reaction are
indicated in the Tables. The assignment of absolute configuration to
the predominant isomer formed in each reaction rests on com-
parison of sign of optical rotation with those reported in the
literature.
C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C, 71.83; H, 7.11; N,
9.81.
4.1.1.6. Catalyst 28 (procedure A).
Br
3
5
6
1
Me
N
8
H
4
Me
N
9
O
10
11
OH
7
H
2
9'
10'
Starting from(1R,2S) ephedrine(1.2 mmol, 0.198 g)and4-bromo-
picolinic acid (1 mmol, 0.2 g) catalyst 28 was isolated as white solid
(60% yield, 0.21 g) (purification through silica gel, eluent: 500 mL of
97:3 CH2Cl2/MeOH).
Rotamer 1. 1H NMR (300 MHz, CDCl3):
d
8.30 (d, J¼5.3 Hz, 1H, 4),
4.1.2.2. Three component reaction. General procedure. Amine
(2.5 mmol/eq), ketone (1 mmol/eq) and trichlorosilane (3.5 mmol/
eq) in the chosen solvent (2 mL) were stirred for 30 min and then
the catalyst (0.1 mmol/eq) was added. After stirring at the chosen
temperature the reaction was quenched by the addition of a satu-
rated aqueous solution of NaHCO3 (1 mL). The mixture was allowed
to warm up to room temperature and water (2 mL) and dichloro-
methane (5 mL) were added. The organic phase was separated and
the combined organic phases were dried over Na2SO4, filtered, and
concentrated under vacuum at room temperature to afford the
crude product. If necessary, the amine was purified by flash chro-
matography. Yields and enantiomeric excesses for each reaction are
7.55–7.48 (m, 1H, 5), 7.35–7.28 (m, 3H, 10, 100, 11), 7.25–7.15 (m, 3H,
6, 9, 90), 4.75 (d, J¼6.6 Hz,1H, 2), 4.28–4.22 (m,1H, 1), 2.89 (s, 3H, 3),
1.36 (d, J¼6.7 Hz, 3H, 8). 13C NMR (75 MHz, CDCl3):
d 167.7, 155.1,
148, 141.4, 133.7, 128.1 (2C), 127.8, 127.4, 126.2 (2C), 126.1, 75.6, 58.6,
29.2, 14.4. Rotamer 2. 1H NMR (300 MHz, CDCl3):
d
8.30 (d, J¼5.3 Hz,
1H, 4), 7.55–7.45 (m, 3H, 5, 9, 90), 7.40–7.35 (m, 2H, 10, 100), 7.35–
7.30 (m, 1H, 11), 7.25–7.18 (m, 1H, 6), 5.05 (d, J¼3.8 Hz, 1H, 2), 4.65–
4.55 (m, 1H, 1), 2.86 (s, 3H, 3), 1.33 (d, J¼3.1 Hz, 3H, 8). 13C NMR
(75 MHz, CDCl3): d 168.2, 155.6, 148.9, 141.7, 133.6, 128.1 (2C), 127.8,
127.4, 126.2 (2C), 126.1, 76.3, 58.3, 34.7, 11.1. IR (DCM):
25
nC]O¼1723 cmꢁ1. Mp¼143–145 ꢀC. [
a
]
ꢁ24.12 (c 0.23 g/100 mL,
D

6362
S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
indicated in the Tables. The assignment of absolute configuration to
the predominant isomer formed in each reaction rests on com-
parison of sign of optical rotation with those reported in the
literature.
4.1.3.6. N-(1-Phenylpropyl)aniline (39). This product was purified
with a 98:2 hexane/ethyl acetate mixture as eluent. Its 1H NMR data
were in agreement with those reported in the literature.26
1H NMR (300 MHz, CDCl3):
d 7.31 (m, 4H), 7.25–7.18 (m,1H), 7.07
(t, J¼7.50 Hz, 2H), 6.62 (t, J¼6.90 Hz, 1H), 6.50 (d, J¼6.90 Hz, 2H),
4.21 (t, J¼6.70 Hz, 1H), 4.05 (br s, 1H), 1.81 (m, 2H), 0.94 (t,
J¼6.70 Hz, 3H).
4.1.2.3. General procedure for the synthesis of imines 30, 31, 32, 33,
34, 40, 4226. In a typical experiment: amine (1 equiv) was reacted
in toluene with ketone (1 equiv) in the presence of montmorillonite
The enantiomeric excess was determined by HPLC on a Chiralcel
(250 mg for 5 mmol of reagent) in
a
microwave reactor
IB column (99:1 hexane/isopropanol; flow rate: 0.8 mL/min; l
254 nm): tS¼7.9 min, tR¼8.5 min.
(PW¼200 W; T¼130 ꢀC; time: 4 h and 30 min). The product was
purified by fractional distillation at P¼1 mbar: the starting material
distilled at about 120 ꢀC, the desired product at about 160 ꢀC.
4.1.3.7. N-Benzyl-1-phenylethanamine (41). This product was puri-
fied with a 8:2 hexane/ethyl acetate mixture as eluent. Its 1H NMR
data were in agreement with those reported in the literature.26
4.1.3. Characterization of products
1H NMR (300 MHz, CDCl3):
d 7.38–7.24 (m, 10H), 3.82 (q,
4.1.3.1. N-(1-Phenylethyl)aniline. This product was purified with
a 98:2 hexane/ethyl acetate mixture as eluent. Its 1H NMR data
were in agreement with those reported in the literature.26
J¼6.50 Hz, 1H), 3.67, (d, J¼7.00 Hz, 1H, A proton of AB system), 3.60
(d, J¼7.00 Hz, 1H, B proton of AB system), 1.57 (br s, 1H), 1.37 (d,
J¼6.50 Hz, 3H).
1H NMR (300 MHz, CDCl3):
d
7.35–7.10 (m, 5H), 7.01 (t,
The enantiomeric excess was determined by HPLC on a Chiralcel
ODH column (99:1 hexane/isopropanol; flow rate: 0.8 mL/min;
J¼7.80 Hz, 2H), 6.57 (t, J¼6.60 Hz, 1H), 6.44 (d, J¼7.90 Hz, 2H), 4.41
(q, J¼6.70 Hz, 1H), 3.94 (br s, 1H), 1.41 (d, J¼6.70 Hz, 3H).
l¼210 nm): tR¼7.8 min, tS¼8.4 min.
The enantiomeric excess was determined by HPLC on a Chiralcel
IB column (99:1 hexane/isopropanol; flow rate: 0.8 mL/min;
4.1.3.8. N-(1-Phenylethyl)butan-1-amine (43). This product was
purified with a 8:2 hexane/ethyl acetate mixture as eluent. Its 1H
NMR data were in agreement with those reported in the literature.7
l¼254 nm): tS¼9.3 min, tR¼10.4 min.
4.1.3.2. N-(1-(Naphthalen-2-yl)ethyl)aniline (35). This product was
purified with a hexane/ethyl acetate 98:2 mixture as eluent. It had
1H NMR data in agreement with those reported in the literature.26
1H NMR (300 MHz, CDCl3):
d
7.3–7.1 (m, 5H), 3.73 (q, J¼6.50 Hz,
1H), 2.45–2.35 (m, 2H), 1.40–1.30 (m, 2H), 1.32 (d, J¼6.50 Hz, 3H),
1.22–1.15 (m, 2H), 0.79 (t, J¼7.50 Hz, 3H).
1H NMR (300 MHz, CDCl3):
d
7.91–7.86 (m, 4H), 7.55–7.45 (m,
The enantiomeric excess was determined by analysis of the
acetamide obtained by reaction of the isolated amine with acetic
anhydride at room temperature for 12 h.
3H), 7.1 (t, J¼7.70 Hz, 2H), 6.80–6.60 (m, 3H), 4.6 (q, J¼6.80 Hz, 1H),
3.97 (br s, 1H), 1.6 (d, J¼6.80 Hz, 3H).
The enantiomeric excess was determined by HPLC on a Chiralcel
OD column (98:2 hexane/isopropanol; flow rate: 1 mL/min;
1H NMR (300 MHz, CDCl3):
J¼6.70 Hz, 1H), 5.0
2.1
d
7.45–7.35 (m, 5H), 6.0 (q,
*
(q, J¼6.80 Hz, 1H), 3.3–2.8 (m, 2H), 2.2 (s, 3H),
l¼254 nm): tS¼14.7 min, tR¼15.7 min.
*
(s, 3H), 1.6 (d, J¼6.70 Hz, 3H), 1.5 (d, J¼6.580 Hz, 3H), 1.45–1.35
*
(m, 2H), 1.25–1.10 (m, 2H), 0.8 (t, J¼6750 Hz, 3H).
4.1.3.3. N-(1-(4-(Trifluoromethyl)phenyl)ethyl)aniline (36). This pro-
duct was purified with a 98:2 hexane/ethyl acetate mixture as el-
uent. Its 1H NMR data were in agreement with those reported in the
literature.7
The enantiomeric excess was determined by HPLC on a Chiralcel
IB column (9:1 hexane/isopropanol; flow rate: 0.8 mL/min;
l
210 nm): tR¼8.5 min, tS¼9.4 min.
1H NMR (300 MHz, CDCl3):
d
7.51 (d, J¼7.80 Hz, 2H), 7.41 (d,
4.1.3.9. 2-Phenylpiperidine. The imine was prepared following the
procedure reported below:27
J¼7.70 Hz, 2H), 7.02 (t, J¼6.90 Hz, 2H), 6.59 (t, J¼6.80 Hz, 1H), 6.38
(d, J¼6.90 Hz, 2H), 4.46 (q, J¼6.50 Hz, 1H), 3.97 (br s, 1H), 1.46 (d,
J¼6.50 Hz, 3H).
PhLi (1.13 equiv, solution 1.9 M), was added dropwise to a solu-
tion of 5-bromovaleronitrile (1 equiv) in dry benzene (0.1 M). The
resulting solution was refluxed for 20 h, cooled and quenched with
1 mL of water. The organic solution was dried (MgSO4) and the
solvents were removed under reduced pressure. The oily residue
was separated by chromatography on neutral alumina (eluent:
400 mL of 97:3 hexane/AcOEt, then 300 mL of 95:5 hexane/AcOEt).
The enantiomeric excess was determined by HPLC on a Chiralcel
OD column (9:1 hexane/isopropanol; flow rate: 1 mL/min;
l¼254 nm): tS¼9.9 min, tR¼12.4 min.
4.1.3.4. 2-Methoxy-N-(1-phenylethyl)aniline (37). This product was
purified with a 98:2 hexane/ethyl acetate mixture as eluent. Its 1H
NMR data were in agreement with those reported in the literature. 7
1H NMR (300 MHz, CDCl3):
d 7.90–7.70 (m, 2H), 7.50–7.30 (m,
3H), 3.80–3.70 (m, 2H), 2.70–2.60 (m, 2H), 1.90–1.80 (m, 2H), 1.75–
1H NMR (300 MHz, CDCl3):
d 7.43–7.26 (m, 6H), 6.80–6.72 (m,
1.60 (m, 2H). Mass (ESIþ): m/z¼160.2.
2H), 6.66 (d, J¼7.50 Hz, 1H), 6.40 (d, J¼7.50 Hz, 1H), 4.53 (q,
The reduction product was purified with a 98:2 CH2Cl2/MeOH
mixture as eluent. Its 1H NMR data were in agreement with those
reported in the literature.28
J¼6.50 Hz, 1H), 3.93 (s, 3H), 1.60 (d, J¼6.50 Hz, 3H).
The enantiomeric excess was determined by HPLC on a Chiralcel
IB column (99:1 hexane/isopropanol; flow rate: 0.8 mL/min;
1H NMR (300 MHz, CDCl3):
d 7.38–7.20 (m, 5H), 3.65–3.55 (m,
l
¼254 nm): tS¼7.3 min, tR¼9.5 min.
1H), 3.22–3.18 (m, 1H), 2.85–2.75 (m, 1H), 1.90–1.48 (m, 6H).
The enantiomeric excess was determined by analysis of tri-
fluoroacetamide obtained by reaction of the isolated amine with
trifluoroacetic anhydride at 0 ꢀC for 3 h.
4.1.3.5. 4-Methoxy-N-(1-phenylethyl)aniline (38). This product was
purified with a 98:2 hexane/ethyl acetate mixture as eluent. Its 1H
NMR data were in agreement with those reported in the literature.7
1H NMR (300 MHz, CDCl3):
d
7.44–7.35 (m, 5H), 6.0 (q,
(d,
(m, 1H), 3.45–3.35
1H NMR (300 MHz, CDCl3):
d
7.43–7.26 (m, 5H), 6.73 (d,
J¼6.65 Hz,1H), 5.4
*
(q, J¼6.55 Hz,1H), 4.4 (d, J¼6.65 Hz,1H), 3.8
*
J¼8.00 Hz, 2H), 6.58 (d, J¼8.00 Hz, 2H), 4.46 (q, J¼6.90 Hz, 1H), 3.74
J¼6.55 Hz, 1H), 3.20–3.00 (m, 1H), 2.66–2.55
*
(s, 3H), 1.58 (d, J¼6.90 Hz, 3H).
(m, 1H), 2.1–2.0 (m, 2H), 1.5–1.3 (m, 3H).
The enantiomeric excess was determined by HPLC on a Chiralcel
ODH column (98:2 hexane/isopropanol; flow rate 0.8 mL/min;
The enantiomeric excess was determined by HPLC on a Chiralcel
OD column (98:2 hexane/isopropanol; flow rate: 0.8 mL/min;
l¼230 nm): tR¼13.6 min, tS¼15.5 min.
l¼210 nm): tS¼6.7 min, tR¼7.3 min.

S. Guizzetti et al. / Tetrahedron 65 (2009) 6354–6363
6363
Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 14, 3045; (d) Wu, P.; Wang, Z.;
Cheng, M.; Zhou, L.; Sun, J. Tetrahedron 2008, 64, 11304.
9. Malkov, A. V.; Liddon, A. J. P. S.; Ramı´rez-Lo´ pez, P.; Bendova´, L.; Haigh, D.;
4.1.3.10. N-(1-Methoxypropan-2-yl)-2,6-dimethylaniline (45). This
product was purified with a 98:2 hexane/ethyl acetate mixture as
eluent. Its 1H NMR data were in agreement with those reported in
the literature.29
ˇ
´
Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432.
10. (a) Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 25, 5913; (b) Pei,
D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal. 2008, 350, 619.
11. (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura,
Y. Tetrahedron Lett. 2001, 42, 2525; (b) Onomura, O.; Kouchi, Y.; Iwasaki, F.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751.
1H NMR (300 MHz, CDCl3):
d
7.0 (d, J¼7.50 Hz, 2H), 6.8 (t,
J¼7.50 Hz, 1H), 3.40–3.30 (m, 7H), 2.2 (s, 6H), 1.2 (d, J¼6.90 Hz, 3H).
The enantiomeric excess was determined by HPLC on a Chiralcel
12. Asymmetric Organic Catalysis; Berkessel, A., Groger, H., Eds.; Wiley-VCH:
Weinheim, 2005; See also in: Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2006.
13. Guizzetti, S.; Benaglia, M.; Cozzi, F.; Rossi, S.; Celentano, G. Chirality 2009, 21, 233.
14. Guizzetti, S.; Benaglia, M. European Patent Application November 30 2007;
PCT/EP/2008/010079, November 27, 2008.
15. While we were proceeding with the European Patent application (see Ref. 14)
and completing the experiments for submitting the present manuscript
a communication was published: Zheng, H.; Deng, J.; Lin, W.; Zhang, X. Tetra-
hedron Lett. 2007, 48, 7934.
16. For catalyst 1 several experiments of reduction reactions run at low tem-
perature did not show any improvement in the stereoselection of the
process.
17. For a discussion on the relative basicity of pyridine ring as function of the
substituents see: The fact that 4 chloro picolinamide 29 behaved better than 4-
methyl picolinamide 27 seems to suggest that electronic factors play a major
role in fine tuning the catalytic activity and determining an optimum ar-
rangement of the catalyst-trichlorosilane-imine adduct. Brotzel, F.; Kempf, B.;
Singer, T.; Zipse, H.; Mayr, H. Chem.dEur. J. 2007, 13, 336.
OD column (99.5:0.5 hexane:isopropanol; flow rate 0.8 mL/min;
254 nm): tR¼9.7 min, tS¼11.6 min.
l
4.1.3.11. 2-Ethyl-N-(1-methoxypropan-2-yl)-6-methylaniline (47). This
product was purified with a 98:2 hexane/ethyl acetate mixture as
eluent. Its 1H NMR data were in agreement with those rerported in
the literature.29
1H NMR (300 MHz, CDCl3):
d
7.00 (d, J¼7.80 Hz, 2H), 6.8 (t,
J¼7.80 Hz, 1H), 3.25–3.05 (m, 7H), 2.7 (q, J¼5.80 Hz, 2H), 2.2 (s, 3H),
1.3 (t, J¼5.80 Hz, 3H), 1.2 (d, J¼6.70 Hz, 3H).
The enantiomeric excess was determined by HPLC on a Chiralcel
OD column (99.5:0.5 hexane/isopropanol; flow rate 0.8 mL/min;
l¼254 nm): tR¼7.8 min, tS¼9.1 min.
Acknowledgements
18. Further details about the enantioselective reduction of aryl-alkyl ketones will
be reported (manuscript in preparation).
19. Since in his report (Ref. 15) Zhang normally used catalyst 1 in 20 mol % amount,
for sake of comparison we preferred to report in Table 5 the results obtained by
us by employing both catalysts 1 and with 29 at 10%. In our hands catalyst 1
performed often better at 0 ꢀC than at lower temperature.
20. Guizzetti, S.; Benaglia, M. European Patent Application. n.EP07023240.0, Sep-
tember 22, 2008.
Financial support from MIUR (Rome) within the national project
‘Nuovi metodi catalitici stereoselettivi e sintesi stereoselettiva di
molecole funzionali’ is gratefully acknowledged by M.B.
References and notes
21. Wang, C.; Wu, X.; Zhou, L.; Sun, J. Chem.dEur. J. 2008, 14, 8789.
22. Enantioselective reductive amination: selected references for organometallic
systems: (a) Reetz, M. T.; Bondarev, O. Angew. Chem., Int. Ed. 2007, 46, 4523;
(b) Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett. 2006, 8, 1229 for
organic catalysts: see Ref. 4 and; (c) Rueping, M.; Antonchick, A. P.; Theiss-
mann, T. Angew. Chem., Int. Ed. 2006, 45, 3683; (d) Zhou, J.; List, B. J. Am.
Chem. Soc. 2007, 129, 7498; (e) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 84; For a recent biocatalytic reductive
animation see: Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Roz-
zell; Kroutil, W. Angew. Chem., Int. Ed. 2008, 47, 9337.
23. Kocovsky has already described a one pot procedure which involves the in situ
preparation of imine followed by trichlorosilane-mediated reduction (see Ref.
7d). With those formammide-based catalysts it was shown that the ketone
reduction was slower than imine reduction. However with our catalytic sys-
tems only a fine tuning of the experimental conditions allowed to efficiently
perform the reductive amination process.
1. (a) Tararov, V. L.; Borner, A. Synlett 2005, 203; (b) Blaser, H.-U.; Malan, C.; Pugin,
B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103; (c) See
also: Nugent, T. C.; Ghosh, A. K.; Wachamure, V. N.; Mohanty, R. R. Adv. Synth.
Catal. 2006, 348, 1289 and references cited therein.
2. Blaser, H.-U.; Pugin, B.; Spindler, F.; Thommen, M. Acc. Chem. Res. 2007, 40, 1240
and references cited therein. For a special issue on hydrogenation and transfer
hydrogenation see: Krische, M. J. Sun, Y. Eds.; Acc. Chem. Res. 2007, 40.
3. Reviews: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (b)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (c) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
4. Ouellet, S. G.; Walji, A.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327 and
references cited therein.
5. Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407.
6. Reviews: (a) Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem. Rev. 2008,
252, 492; (b) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
24. Blaser, H.-U. Adv. Synth. Catal. 2002, 344, 17. See also Ref. 2.
ˇ
´
25. For two recent contributions about the enantioselective synthesis of
b-amino
7. (a) Malkov, A. V.; Mariani, A.; MacDougal, K. N.; Kocovsky, P. Org. Lett. 2004, 6,
ˇ
acids involving the use of trichlorosilane see: (a) Malkov, A. V.; Stoncius, S.;
Vrankova, K.; Arndt, M.; Kocovsky, P. Chem.dEur. J. 2008, 14, 8082; (b) Zheng,
H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin, W.-Q.; Yuan, W.-C.; Zhang, X.-M.
Chem.dEur. J. 2008, 14, 9864.
2253; (b) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.; McGeoch,
ˇ
´
G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264; (c) Malkov, A. V.; Figlus, M.;
Stoncius, S.; Kocovsky, P. J. Org. Chem. 2007, 72, 1315; (d) Malkov, A. V.; Stoncius,
S.; Kocovsky, P. Angew. Chem., Int. Ed. 2007, 46, 3722; (e) Malkov, A. V.; Figlus,
ˇ
ˇ
´
ˇ
ˇ
´
ˇ
´
26. Samec, J. S. M.; Ba¨ckvall, J.-E. Chem.dEur. J. 2002, 8, 2955.
M.; Kocovsky, P. J. Org. Chem. 2008, 73, 3985; See also: (f) Matsumura, Y.; Ogura,
K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 17, 3789.
27. Gallulo, V.; Dimas, L.; Zezza, C. A.; Smith, M. B. Org. Prep. Proced. Int. 1989, 21, 297.
28. Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952.
29. Dorta, R.; Broggini, D.; Kissner, R.; Togni, A. Chem.dEur. J. 2004, 10, 4546.
8. (a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 5, 999; (b)
Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem. Commun. 2007, 2977; (c) Wang, Z.;