Asymmetric transfer hydrogenation of ketimines with trichlorosilane: Structural studies

Article abstract of DOI:10.1055/s-0028-1088045

We report structural and mechanistic studies on the organocatalytic asymmetric transfer hydrogenation of ketimines with trichlorosilane. Amines were obtained in good yields and moderate enantioselectivities. Both experiment and computation were utilized to provide an improved understanding of the mechanism. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088045

SPECIAL TOPIC
1531
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane:
Structural Studies
A
symmetric Tra
h
nsfe
r
H
ydro
i
genatio
g
n
of
K
etimin
u
es
w
ith Tric
o
hlorosilane Zhang, Parham Rooshenas, Heike Hausmann, Peter R. Schreiner*
Institut für Organische Chemie, Justus-Liebig-Universität Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
Fax +49(641)9934309; E-mail: prs@org.chemie.uni-giessen.de
Received 7 February 2009
generate amines, but the substrate scope was limited to al-
iphatic and aromatic aldimines.17 Unfortunately, chiral
thiourea derivatives fail to promote the hydride transfer
from Hantzsch esters to ketimines. As part of our efforts
in the development of organocatalytic methods for the re-
duction of ketimines, we turned our attention to trichlo-
rosilane as an alternative organic reducing agent.18
Inspired by the reduction of aldehydes, ketones, as well as
imines with the combination of trichlorosilane and N,N-
dimethylformamide, the Matsumura group were the first
to develop chiral N,N-dimethylformamide analogues,
namely N-formylproline derivatives, as effective activa-
tors for asymmetric reductions of ketimines using trichlo-
rosilane as the reducing agent, giving the corresponding
amines in moderate enantiomeric excess.9 Later, signifi-
cant improvement of the enantiomeric excess was
achieved by Malkov et al. by using a new N-methyl-L-va-
line derived Lewis basic organocatalyst.12 Since then,
considerable efforts have been devoted to the develop-
ment of this transformation and a rapid evolution of cata-
lyst structures has been made by Matsumura,8,9
Malkov,10–12 Sun,13–15 and others.16 Among others, the key
structure features of most catalysts are N-formyl amino
acid derived carboxamides (1, Figure 1). We initiated our
research by a systematic investigation of the influence of
nonaromatic R groups in N-formylproline (2, Figure 1) on
the enantiomeric excesses of ketimine reductions with
trichlorosilane as the reductant. Although plausible mech-
anisms have been proposed, no details are available at this
stage, which makes the rational design and development
of efficient catalysts difficult. Herein, we report our re-
sults on structural studies regarding the aliphatic R
groups. Mechanistic studies utilizing computational
methods are employed, with the hope of an improved un-
derstanding of this highly practical transformation.
Abstract: We report structural and mechanistic studies on the orga-
nocatalytic asymmetric transfer hydrogenation of ketimines with
trichlorosilane. Amines were obtained in good yields and moderate
enantioselectivities. Both experiment and computation were uti-
lized to provide an improved understanding of the mechanism.
Key words: amines, Lewis bases, organocatalysis, transfer hydro-
genation, trichlorosilane
The importance of chiral amines lies in their propensity to
be fundamentally important building blocks of natural
products, drugs, as well as agrochemicals.1 The asymmet-
ric reduction of imines with a chiral catalyst represents a
direct and most appealing approach to enantiomerically
enriched amines and the development of asymmetric cat-
alysts for such processes has been the focus of recent re-
search efforts.2 However, in contrast to the well-developed,
effective, and industrially relevant asymmetric reductions
of olefins and ketones, the corresponding imine reduc-
tions are less advanced.3 Among various catalytic meth-
ods, hydrogenation or transfer hydrogenation of ketimines
with a chiral transition metal catalyst system is currently
one of the most accessible protocols.4 Parallel to the quest
for more efficient metal catalysts, the discovery of ‘green’
catalysts has become another focal point.5 As a conse-
quence, impressive progress has been made recently in the
development of organic catalysts for the enantioselective
transfer hydrogenation of ketimines using Hantzsch dihy-
dropyridine or trichlorosilane as the hydride donor in con-
junction with a chiral organocatalyst that activates the
substrate or the reductant (Scheme 1).6–16
EtO2C
Me
CO2Et
or
HSiCl3
NR3
R2
NHR3
N
H
Me
*
R1
R1
R2
chiral organocatalyst
R2
O
H
N
R1
H
Scheme 1 Organocatalytic asymetric transfer hydrogenation of
imines
N
R3
N
HN
R
O
O
O
H
1
2
Our studies revealed that electron-poor thiourea deriva-
tives can activate imines by hydrogen bonding and thus
promote the hydrogen transfer from Hantzsch esters to
Figure 1 General structure of the a-amino acid derived catalysts
Our search for chiral organic activators for trichlorosilane
was initially based on the following general consider-
ations: (1) N-formylproline provides the basic chiral mod-
ule, with the carboxy group converted into an amide that
bears a variety of aliphatic R groups; (2) N-formylproline
SYNTHESIS 2009, No. 9, pp 1531–1544
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0028-1088045; Art ID: C00809SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

1532
Z. Zhang et al.
SPECIAL TOPIC
derived diastereomeric activators involving more than droxy-1H-benzotriazole hydrate (HOBt) and 1-[3-
one chiral center;19 (3) extension to other amino acids (dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
such as valine or pipecolinic acid scaffolds; (4) introduc- ride (EDCI) as coupling reagents (Scheme 2). This meth-
tion of N-formylproline to an axially chiral scaffold; (5) od is applicable to all primary aliphatic amines, namely
preparation of 1,3-dicarbonyl N-formamide as potential compounds 2a–k. The same strategy was also employed
‘six ring’ activators; (6) comparison with known catalysts. for the synthesis of L-pipecolinic acid derived N-form-
On the basis of these considerations, a series of com- amide 3.
pounds was designed and prepared (Figure 2).
R
The synthesis of proline-derived formamides started with
HCOOH
Ac2O
RNH2
COOH
COOH
the formylation of proline in the presence of acetyl anhy-
dride and formic acid, which afforded N-formylproline in
90% yield. The carboxy group of the latter derivative was
then converted into a series of secondary amides by reac-
tion with the respective primary amines, employing 1-hy-
HOBt, EDCI
N
H
N
N
O
O
O
H
H
2a–k
Scheme 2 Synthesis of catalysts 2a–k
H
N
H
N
H
N
N
N
N
O
O
O
H
O
H
O
H
O
2a
2b
2c
H
N
H
N
H
N
N
N
N
O
O
O
H
O
H
O
H
O
2d
2e
2f
HN
HN
O
O
H
N
N
N
O
O
O
O
N
O
O
H
H
O
H
O
2g
2h
2i
O
O
O
O
O
O
H
N
N
HN
N
HN
N
O
O
O
H
H
H
O
2j
3
2k
H
Me
Me
O
N
O
O
H
N
O
Me
H
N
O
N
HN
Me
Fmoc
O
H
O
5a
5b
4
H
N
O
H
N
Me
N
H
O
OH
O
NH
S
O
N
H
O
H
N
N
O
H
6
7
8
O
Figure 2 Potential catalysts prepared for this study
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1533
The synthesis of 4 commenced with N-methylation of the
Boc-protected L-valine 9 with iodomethane in the pres-
ence of sodium hydride, which afforded the Boc-protected
N-methylvaline 10. The latter was then converted into 11
through the reaction of 1-aminoadamantane with the
mixed anhydride, generated in situ from 10 and methyl
chloroformate. Boc deprotection with trifluoroacetic acid
was followed by formylation with formic acid and acetic
anhydride to produce 4 (Scheme 3). The known com-
pounds 7 and 8 were prepared according to the literature
protocols.12,20
OMe
N
OMe
COOH
(1)
O
1. (COCl)2, DMF, CH2Cl2
2. MeNHCHO, pyridine
56%
O
Me
5a
H
H
Me
N
O
1. SOCl2, CH2Cl2, reflux
2. MeNHCHO, pyridine
COOH
NHFmoc
O
NHFmoc
18%
5b
(2)
Scheme 4 Preparation of potential ‘six ring’ activators 5a,b
O
O
MeI, NaH
N
O
OH
O
HN
O
OH
O
O
O
THF, r.t., 24 h
H
N
N
10
1. ClCO2Me, Et3N
THF, 0 °C, 1 h
9
O
COOH
N
1. ClCO2Me, Et3N
THF, 0 °C, 1 h
H
N
O
2.
N
O
NH2
O
2.
O
O
NH2
14
12
NH2
64%
THF, r.t., 12 h
13
H
r.t., 16 h, reflux, 3 h
O
O
O
1. TFA
r.t., 1 h
H
N
N
N
HN
O
N
H
HN
O
O
2. HCO2H, Ac2O
r.t., 12 h
1. TFA, r.t., 1 h
O
4
2. HCO2H, Ac2O, r.t.
11
H
N
41%
80%
N
Scheme 3 Synthesis of catalyst 4
O
H
O
6
76%
The synthesis of 5a started with the conversion of (R)-2-
methoxy-2-phenylacetic acid into the acyl chloride with
oxalyl chloride in the presence of catalytic amounts of
Scheme 5 Synthesis of axially chiral catalyst 6
N,N-dimethylformamide, followed by reaction with N- Our initial study began with the reduction of ketimine 15a
methylformamide (Scheme 4, equation 1). The phenylala- (derived from acetophenone and aniline) with trichloro-
nine-derived formamide 5b prepared through the same silane in dichloromethane at 0 °C in the presence of the
procedure did not give the corresponding product due to potential catalysts (10 mol%) (Table 1). In general, reduc-
side reactions. An alternative method for the conversion tion of 15a with trichlorosilane gives the amines in good
of Fmoc-protected L-phenylalanine into the acyl chloride to high yields; 5a and 5b are exceptions. Variation of the
was carried out with thionyl chloride, followed by reac- molecular size of the amide functionality in the catalysts
tion with N-methylformamide, giving the desired product,
albeit in low yield (Scheme 4, equation 2).
had a large effect on the stereochemical outcome. The
enantioselectivities increased when the substituents
changed from cyclohexane to diamantane (Table 1, en-
tries 1–3), however, catalyst 2e, from 9-aminotriaman-
tane, was found to be slightly less efficient, affording the
product in lower yield with 65% ee (Table 1, entry 5), in-
dicating the importance of steric interaction between the
amide functionality and substrate for the reaction out-
come. Catalysts involving additional stereogenic centers
did not result in higher enantioselectivities. The configu-
ration of the a-position in proline is crucial for the abso-
lute configuration of the corresponding product (Table 1,
entries 8 and 9, 10 and 11). ‘Six ring’ activators such as
The synthesis of 6 commenced with conversion of Boc-
protected L-proline 12 into the active anhydride interme-
diate, generated in situ from 12 and methyl chloroformate,
followed by reaction with (+)-(R)-1,1¢-binaphthyl-2,2¢-di-
amine (13) to give product 14 (64%). Boc-deprotection
with trifluoroacetic acid followed by formylation with a
mixed anhydride, generated in situ from formic acid and
acetic anhydride, to produce the desired axially chiral ac-
tivator 6 (Scheme 5).
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1534
Z. Zhang et al.
SPECIAL TOPIC
1,3-dicarbonyl formamides 5a and 5b proved to be slug- solvents generally gave lower enantioselectivities, the re-
gish catalysts, which suggests that the proposed simulta- action run in dichloromethane proceeded smoothly and
neous coordination of two carbonyls with one silyl group gave the highest enantioselectivities. Interestingly, when
may not be correct (Table 1, entries 17 and 18). Interest- the reaction was run at –18 °C or at room temperature, the
ingly, catalyst 3, derived from L-pipecolinic acid and 1- enantiomeric excess of product 16a decreased to 45% and
aminoadamantane, gives the product in racemic form 58% (Table 2, entries 8 and 9), while the yields were al-
(Table 1, entry 12). According to the literature, N-forma- most unchanged. Toluene was found to afford the same
mide catalysts derived from L-pipecolinic acid exhibited level of enantioselectivity as dichloromethane at –18 °C
significantly higher reactivities and selectivities than their (Table 2, entry 10). The lower enantioselectivities ob-
congeners derived from L-proline.14 This unexpected phe- tained in diethyl ether and tetrahydrofuran clearly indicate
nomenon prompted us to investigate the enantiomeric pu- that the reaction requires nonpolar solvents (Table 2, en-
rity of L-pipecolinic acid, which is, however, very high.
tries 5 and 6). As expected, no enantioselectivity was ob-
served when the reaction was run in N,N-
dimethylformamide (Table 2, entry 7). A slight concen-
tration effect was also observed. Reactions carried out at
lower concentrations give somewhat higher enantioselec-
tivities.
Next, we examined the influence of other reaction param-
eters such as temperature, solvent, as well as concentra-
tions on the reaction outcome in the presence of 2b as the
catalyst (Table 2). All three reaction parameters proved to
be important. While reactions carried out in highly polar
With optimized reaction conditions established, we at-
tempted to elucidate if there is an electronic effect on the
enantioselectivity by substitution of the phenyl ring with
electron-donating and electron-withdrawing groups in the
para position. Structure 2b was chosen as the catalyst
(Table 3). Disappointingly, the electronic substituent ef-
fects are negligible, with the only exception that electron-
Table 1 Catalyst Screening for the Reduction of 15a with Trichlo-
rosilanea
Ph
Ph
HSiCl3 (2.0 equiv)
N
HN
*
catalyst (0.1 equiv)
CH2Cl2, 0 °C
Ph
Ph
15a
16a
Entry
1
Catalyst
2a
2b
2c
2d
2e
2f
Yieldb (%) eec (%)
Configd
Table 2 Solvents, Temperature, and Concentrations Surveyeda
79
85
81
78
52
87
83
78
78
70
76
80
89
82
91
82
43
39
42
63
68
60
65
65
61
28
45
30
15
0
R
R
R
R
R
R
R
R
S
Ph
Ph
HSiCl3 (2.0 equiv)
N
HN
2
2b (0.1 equiv)
Ph
Ph
*
3
15a
16a
4
Entry
1
15a [M] Temp (°C) Solvent
Yieldb (%) eec (%)
5
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
4.0
2.0
0.2
0.04
0
0
CH2Cl2
CHCl3
toluene
xylenes
THF
82
81
78
85
79
75
85
80
80
78
79
77
75
79
81
63
49
50
43
34
33
0
6
2
7
2g
2h
2i
3
0
8
4
0
9
5
0
10
11
12
13
14
15
16
17
18
2j
R
S
6
0
Et2O
2k
3
7
0
DMF
–
8
r.t.
–18
–18
–18
0
CH2Cl2
CH2Cl2
toluene
THF
58
45
45
31
55
57
65
67
4
54
86
95
30
0
R
S
9
7
10
11
12
13
14
15
8
S
6
S
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5a
5b
–
0
0
–
0
a Conditions: 15a (0.2 mmol), catalyst (10 mol%), HSiCl3 (2 equiv),
CH2Cl2, 0 °C.
0
b Yield of isolated product.
a Conditions: 15a (0.2 mmol), 2b (10 mol%), HSiCl3 (2 equiv).
b Yield of isolated product.
c Determined by chiral GC or HPLC analysis.
d Absolute configuration from comparison with literature data.12
c Determined by chiral GC or HPLC analysis.
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1535
Table 3 Substrate Scopea
R2
R2
HSiCl3 (2.0 equiv)
N
HN
2b (0.1 equiv)
R1
R1
*
CH2Cl2, 0 °C
15
16
Entry Ketimine R1
R2
Yieldb
(%)
eec
(%)
1
2
3
4
5
6
7
15a
15b
15c
15d
15e
15f
Ph
Ph
85
88
80
95
88
66
78
63
55
63
52
57
53
37
Ph
4-MeOC6H4
3,5-Me2C6H4
4-MeOC6H4
4-ClC6H4
Ph
4-MeC6H4
4-MeC6H4
4-F3CC6H4
4-F3CC6H4
4-MeOC6H4
4-ClC6H4
15g
Figure 3 Part of the ROESY spectrum of compound 2c
a Conditions: 15a (0.2 mmol), 2b (10 mol%), HSiCl3 (2 equiv),
CH2Cl2, 0 °C.
1
In the H NMR spectrum of a 1:2 mixture of catalyst 2b
and trichlorosilane, shift of ~0.1 ppm to downfield was
only observed for the corresponding signal of the form-
amide proton in the cis conformation, no formamide pro-
ton shift was found for the trans conformation, suggesting
that cis conformation of proline-derived catalysts may
play a crucial role in promoting the reduction with trichlo-
rosilane (Figure 4). In addition, the reduction of imine 15a
with trichlorosilane in the presence of catalysts 2b, 3, and
4 afforded 16a in high yield with 63, 0, and 53% ee, re-
spectively. The product generated with 2b had the oppo-
site configuration to that catalyzed by 4, although the
configurations of the catalysts were identical. Interesting-
ly, no enantiomeric excess was observed with catalyst 3.
These results suggest that the crucial enantiodifferentiat-
ing steps for proline, pipecolinic acid, and valine-derived
catalysts may be different.
b Yield of isolated product.
c Determined by chiral HPLC analysis.
deficient phenyl groups decreased the enantioselectivity
to 37% (Table 3, entry 7).
The 1H NMR spectra of all N-formamide catalysts display
a doubling of resonances. These two sets of signals are
commonly assigned to conformers containing the cis and
trans stereochemistry about the tertiary amide C–N bond
(Scheme 6).29 Rotation about such bonds is slow on the
NMR timescale and the conformer ratio can be measured
by integration of 1H NMR spectra. We found that the val-
1
ue of Ktrans/cis = [trans]/[cis], as determined by H NMR
spectroscopy, is >1 (CDCl3). Hyperconjugative delocal-
ization of a nonbonding pair of electrons (n) from the
formyl oxygen into the C–O bond and the intramolecular
hydrogen bonding between amide and N-formyl oxygen
might be the primary factors that contribute to the signifi-
cant extent of the trans-isomer. The cis and trans 1H res-
onances of the N-formamide catalysts were identified by
using ROESY spectroscopy. The observation of a ROE
cross peak between the formyl-H and C5-CH2 1indicates
the trans-isomer (Figure 3). Unfortunately, the H signal
of the N-formyl group of the cis/trans-isomers of com-
pound 2c appeared overlapped at d = 8.27 ppm. We ob-
served that the expected ROE signal between the formyl-
H and the C5-CH2 for the trans-isomer of 2c at
d(1H) = 3.58–3.47 ppm. The cross signals between the
NH signals indicate chemical exchange due to the cis/
trans isomerization.
O
O
Ktrans/cis
N
N
HN
HN
R
R
H
O
O
H
Figure 4 Determination of reaction intermediate by 1H NMR
trans conformer
cis conformer
Scheme 6 Catalyst conformers
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1536
Z. Zhang et al.
SPECIAL TOPIC
Few mechanistic details on this reaction are known at this
stage. Malkov and co-workers proposed a transition struc-
ture, however, without accompanying computations.10
We utilized computations to elucidate the mechanism fur-
ther. All structures were optimized employing density
functional theory (DFT) using the B3PW91 combination
of functionals.21 A standard cc-pVDZ basis set,22 as im-
plemented in the GAUSSIAN 03 suite of programs23 was
used in all cases. All stationary points were characterized
as minima or transition structures by computing analytical
second derivatives; the reported energies include zero-
point vibrational energy (ZPVE) corrections, unless noted
otherwise.
To explore the role of the catalyst we first considered the
uncatalyzed reaction of trichlorosilane (C1) with ketimine
C2 leading to N-silylated product C3. The large activation
‡
enthalpy for this reaction (DH0 = 40 kcal/mol) arises
from the unfavorable four-electron/four-center (4c/4e)
transition structure TS1 (Figure 5). The overall reaction is
highly exothermic for the formation of C3, which is hy-
drolyzed during workup. As the employed catalysts all
display S=O or C=O functionalities, a reasonable propos-
al for the catalytic activity of these groups is indeed their
coordination to the silicon atom.12
We modeled this situation by first examining complex
formation between C1 and model catalysts N-methylfor-
mamide (C4) and N,N-dimethylformamide (C5). Reac-
tion of C1 with C4 gives intermediate C1·C4a (DH0 =
–3.3 kcal/mol, Figure 5). C1·C4a reacts to C1·C4b
(DH0‡= 6.6 kcal/mol), which reduces C2 through TS2
(DH0 = 31.2 kcal/mol). Although coordination of the
amide group of C4 to C1 lowers the barrier for the hydride
transfer, this barrier is still too high because of the unfa-
vorable 4c/4e transition structure (Figure 6).
Similarly, the reaction of C1 and C5 gives rise to the for-
mation of C1·C5a (DH0 = –3.2 kcal/mol) and finally
C1·C5b (DH0 = 6.2 kcal/mol), which reacts with C2
Figure 6 The potential energy hypersurface for the reduction of C2
with C1 catalyzed with (a) C4 and (b) C5 at B3PW91/cc-pVDZ with
relative enthalpies DH0 in kcal/mol (DG in parentheses); the opti-
mized geometries for TS2 and TS3 computed at the same level of
theory are also shown with selected bond lengths in Å.
‡
through TS3 (DH0 = 31.8 kcal/mol, Figure 6).24
Malkov et al. reported low yields for the reactions apply-
ing catalysts in the absence of a secondary amide hydro-
gen.10 Hence we considered another pathway for a
Figure 5 The potential energy hypersurface for the reaction of C1 and C2 at B3PW91/cc-pVDZ with relative enthalpies DH0 and relative
Gibbs free energies DG (in parentheses) in kcal/mol; the optimized geometries for TS1, C1·C4a, and C1·C4b computed at the same level of
theory are also shown with selected bond lengths in Å.
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1537
reduction catalyzed with C4 leading to C1·C4a and
C1·C4b and finally through transition structure TS4,
which emphasizes the role of the secondary amide hydro-
gen and avoids the unsuitable 4c/4e binding situation
(Figure 7). The activation barrier for this reaction is much
lower compared with the other paths shown above
‡
(DH0 = 10.3 kcal/mol). In TS4 silicon is pentacoordinat-
ed; the oxygen atom of the catalyst takes an equatorial po-
sition, as does the hydride. The basic nitrogen attracts the
amide proton of C4, which increases the nucleophilicity
of the oxygen atom, and leads to a shorter Si–O bond (1.72
Å) compared to the same bond in C1·C4b (2.17 Å). This
promotes hydride transfer onto C2 and results in the for-
mation of the amine C6 and silylated amide C7. The NBO
analysis shows a positive charge on the formal proton
(+0.455) and a smaller negative charge on the formal hy-
dride (–0.156). Therefore, this reduction can be described
as the addition of a formal H+/H– pair onto a double
bond.25 The subsequent reaction of C6 and C7 regenerates
catalyst C4 and forms C3.
Considering the structural features of some of the experi-
mentally employed catalysts with two amide groups, we
also discovered a path leading to an intermediate complex
C1·C4·C4 with two molecules of C4 coordinating to the
silicon of trichlorosilane. This reaction is slightly exother-
mic (DH0 = –1.9 but DG = 21.3 kcal/mol). The Si–Cl
bonds lengthen up to 2.28 Å (for the upper axial chlorine),
which facilitates the formation of an octahedral geometry
for the hypervalent silicon in C1·C4·C4 (Figure 8). It re-
acts with C2 through TS5, in the same manner as men-
tioned above for TS4, and eventually leads to C3 through
Figure 8 The geometries for C1·C4·C4 and TS5 at B3PW91/
ccpVDZ with selected bond lengths in Å
We assume a similar reaction pattern for reductions cata-
lyzed with proline derivatives, which we have modeled
with C8 (Figure 9). The stable trans-conformer C9 is,
however, favored relative to the catalytically active cis-
conformer C8 (DG = 4.8 kcal/mol). C8 reacts with C1 to
‡
a low activation barrier (DH0 = 6.4 kcal/mol).
Figure 7 The potential energy hypersurface for reduction of C2 catalyzed with C4 through TS4 at B3PW91/cc-pVDZ with relative DH0 in
kcal/mol (relative DG in parentheses); the geometry for TS4 is also given with selected bond lengths in Å (selected NBO charges in parentheses)
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1538
Z. Zhang et al.
SPECIAL TOPIC
Figure 9 The computed potential energy hypersurface for the reduction of C2 with C1 catalyzed with C8 with relative DH0‡ in kcal/mol (re-
lative DG values in parentheses), as well as the optimized geometry for TS6 (with selected bond lengths in Å) at the B3PW91/cc-pVDZ level
of theory.
give C1·C8a (DH0 = –3.6 kcal/mol). This initially formed ic acid for asymmetric reductions of ketimines with
complex evolves through C1·C8b (DH0 = 6.0 kcal/mol) to trichlorosilane to afford the corresponding secondary
C1·C8c (DH0 = 8.9 kcal/mol). Compared with C1·C8b, amines. Enantioselectivities up to 68% ee were observed
the Si–O bond is fully developed in C1·C8c (1.70 Å), in the presence of catalyst 2c formed by N-formyl-L-pro-
whereas the axial Si–Cl bond lengthens from 2.14 to 3.24 line and 1-aminodiamantane. Variations in the catalyst
Å. The carbon of the formamide group attracts the depart- structures clearly demonstrate the dominant role of the
ing chlorine (Figure 10). This could explain the impor- amino acids scaffold for the mode of action in the enan-
tance of formamide functionality, as observed tiodifferentiating step. Mechanistic studies by means of
experimentally.12 Further rotation around the Si–O–C–N DFT computations reveal that the catalyst not only coor-
dihedral angle (from 178.6° to 161.6°) leads to C1·C8d dinates to trichlorosilane, but also reacts as a proton donor
(DH0 = 4.9 kcal/mol). C1·C8d reacts with C2 through in the crucial transition structure. Indeed, the catalytic re-
‡
TS6 with a low barrier (DH0 = 2.9 kcal/mol) to form C6 duction of ketimines with trichlorosilane can be described
and C10, which finally give C3 and C8.
as a formal H+/H– transfer to the C=N double bond. Fur-
ther work will be directed to elaborate the mechanism as-
pects and to develop more efficient catalysts.
In summary, we have designed a series of novel chiral or-
ganocatalysts derived from proline, valine, and pipecolin-
Figure 10 The geometries for C1·C8a–C1·C8d at B3PW91/cc-pVDZ with selected bond lengths in Å
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1539
Unless otherwise noted, all materials were obtained from commer-
cial suppliers and were used without further purification. Solvents
for chromatography were of technical grade and were distilled prior
to use. Solvents used in the reactions were reagent grade and were
distilled from the indicated drying agents: toluene (P2O5), CH2Cl2
(P2O5), benzene (Na), Et2O (Na), MeCN (P2O5), 1,4-dioxane (Na),
DMF (CaH2), CHCl3 (P2O5), THF (Na). For TLC, silica gel coated
aluminum plates (Merck, silica gel 60 F254) were used and chro-
matograms were visualized by irradiation with UV light at 254 nm.
Column chromatography was performed using J. T. Baker (particle
size 0.063–0.200 mm). Solvent mixtures are understood as volume/
volume. All the imines except imine 15g and all the amines are
known compounds and their NMR data were in agreement with
those in the literature.7,11,15,26,27
brine and dried (anhyd MgSO4), filtered, and evaporated. Purifica-
tion using flash column chromatography (silica gel, hexane–EtOAc,
20:1) afforded the product as a colorless oil. The ee values were de-
termined by chiral HPLC or chiral GC. Representative data are giv-
en for 16g.
N-(4-Chlorophenyl)-1-[4-(trifluoromethyl)phenyl]ethanamine
(16g)
1
Light yellow oil; yield: 78%. H NMR data are in agreement with
the literature data.28 The enantiomers were analyzed by chiral
HPLC (Daicel Chiralpak IB, hexane–i-PrOH, 98:2, 0.70 mL/min):
tR = 15.9 and 27.1 min; 37% ee.
IR (KBr): 3425, 2972, 2928, 1601, 1499, 1326 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.56 (d, J = 8.1 Hz, 2 H), 7.45 (d,
J = 8.1 Hz, 2 H), 7.03 (d, J = 9.0 Hz, 2 H), 6.43 (d, J = 9.0 Hz, 2 H),
4.48 (q, J = 6.9 Hz, 1 H), 4.10 (br s, 1 H), 1.54 (d, J = 6.9 Hz, 3 H).
All 1D and 2D NMR experiments were performed on a Bruker
Avance 400 MHz or 600 MHz NMR spectrometer equipped with a
5 mm BBO probe at 295 K. The data were collected and processed
by TOPSPIN software (Bruker) running on a PC with Microsoft
Windows XP. The 2D experiments were performed using Bruker
N-Formyl Amino Acids; General Procedures
N-Formyl-L-proline29
1
standard pulse sequences and parameters. H and 13C chemical
L-Proline (4.0 g, 34.8 mmol) was dissolved in 98% HCO2H (50 mL)
and the resulting soln was cooled to 0 °C. The cooled soln was add-
ed to a mixture of Ac2O (40 mL, 436 mmol) in 98% HCO2H (50
mL) at 0 °C. The resulting soln was allowed to warm to r.t. over-
night. The solvent was then removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 30
g, 10% MeOH–CHCl3). Fractions containing N-formyl-L-proline
were pooled, and the solvent was removed under reduced pressure
to yield the product (4.5 g, 90%) as a clear oil.
1H NMR (400 MHz, CDCl3): d = 8.26 (s, 1 H, COOH), 8.22 (s, 0.6
H, CHO), 8.18 (s, 0.4 H, CHO), 4.45–4.42 (m, 1 H), 3.63–3.77 (m,
1 H), 3.45 (t, J = 7.22 Hz, 1 H), 2.29–2.20 (m, 2 H), 1.87–2.08 (m,
2 H).
shifts were referred to the solvent signal signals (CDCl3) at d = 7.24
and 77, respectively. HRMS were recorded on a Thermo Finnigan
MAT 95. GC-MS analyses were carried out with a Quadrupol-MS
HP MSD 5971 (EI) and HP 5890A gas chromatograph equipped
with a J & W scientific fused silica GC column (30 m × 0.250 mm,
0.25 micron DB-5MS stationary phase: 5% phenyl and 95% methyl
silicone) using He as carrier gas; T-program standard 60–250 °C
(15 °C/min heating rate), injector and transfer line 250 °C. Chiral
gas chromatography (GC) analyses were performed on a Hewlett-
Packard 5890 gas chromatography using a Hydrodex-b-6-TBDM
column. Chiral HPLC analyses were performed on a Chirapak IB
column. Optical rotations were measured using a 5-mL cell with a
1-dm path length on a Jasco P-2000 digital polarimeter.
13C NMR (100 MHz, CDCl3): d = 173.7, 173.6, 163.2, 162.2, 58.9,
56.6, 46.8, 44.1, 29.4, 29.0, 23.6, 22.5.
1-(Aryl1)-N-(aryl2)ethanimines 15; General Procedure
A 50-mL round-bottomed flask was filled with NaHCO3 (50.0
mmol), a ketone (10.0 mmol), an amine (10.0 mmol), and activated
molecular sieves (4 Å, 8.0 g) in anhyd toluene (10.0 mL). The mix-
ture was heated at 80 °C for 12 h under an argon atmosphere. The
mixture was filtered through Celite and washed with CH2Cl2. The
filtrate was then evaporated and the crude product was further puri-
fied by recrystallization from appropriate solvents or by distillation.
N-Formyl-D-proline30
D-Proline (600 mg, 5.21 mmol) was dissolved in 85% HCO2H (11
mL) and cooled to 0 °C. Ac2O (3.6 mL) was added and the resulting
mixture was stirred at r.t. for 2 h. Ice cold H2O (4.2 mL) was then
added and the solvent was removed under reduced pressure. The
residue pale yellow oil was purified by flash column chromatogra-
phy (10% MeOH–CHCl3) to give the product (663.9 mg, 89%) as a
colorless oil.
1H NMR (400 MHz, CDCl3): d = 8.54 (s, 1 H), 8.21 (s, 0.6 H), 8.18
(s, 0.4 H), 4.35–4.40 (m, 1 H), 3.56–3.64 (m, 1 H), 3.46 (app triplet,
J = 7.22 Hz, 1 H), 2.14–2.25 (m, 1 H), 1.83–2.06 (m, 3 H).
N-(4-Chlorophenyl)-1-[4-(trifluoromethyl)phenyl]ethanimine
(15g)
Purified by recrystallization (pentane); light yellow crystalline sol-
id.
IR (KBr): 1628, 1485, 1327, 1139, 848 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 8.4 Hz, 2 H), 7.70 (d,
J = 8.4 Hz, 2 H), 7.33 (m, 2 H), 6.73 (m, 2 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.2, 173.8, 163.2, 167.2, 59.2,
57.0, 47.0, 44.3, 29.3, 23.9, 22.8.
13C NMR (100 MHz, CDCl3): d = 165.1, 149.6, 142.3, 132.4 (q,
J = 33.0 Hz), 129.2, 129.0, 128.6, 127.6, 125.3 (q, J = 3.7 Hz),
120.6, 17.7.
HRMS: m/z [M]+ calcd for C15H11ClF3N: 297.05266; found:
276.05330.
N-Formyl-L-pipecolinic Acid31
Ac2O (0.662 mL, 7.0 mmol) was added dropwise to a stirred and
cooled (0–5 °C) soln of L-pipecolinic acid (129.2 mg, 1.0 mmol) in
98% HCO2H (1.0 mL). Stirring was continued at r.t. for 1 h. H2O
(0.8 mL) was added and the soln was evaporated to dryness to give
crude product (125 mg) as a yellow oil, which was purified by flash
column chromatography (10% MeOH–CHCl3) to yield the product
(97 mg, 62%) as a colorless oil.
1-(Aryl1)-N-(aryl2)ethanamines 16; General Procedure for Cat-
alytic Hydrosilylation
All reactions were performed in oven-dried Schlenk flasks unless
otherwise stated. Under an argon atmosphere, HSiCl3 (40 mL, 0.4
mmol) was added dropwise to a stirred soln of imine (0.2 mmol) and
the catalyst (0.02 mmol) in anhyd CH2Cl2 at 0 °C, and the mixture
was allowed to stir overnight at the same temperature. The reaction
was quenched with sat. NaHCO3 soln (5 mL) and the product was
extracted with EtOAc (3 × 15 mL). The extract was washed with
(R)-N-(2-Hydroxybenzyl)-2-methylpropane-2-sulfinamide (8)20
To a stirred soln of (+)-(R)-2-methylpropane-2-sulfinamide (121.2
mg, 1.0 mmol) in anhyd toluene (5 mL) at 45 °C was added anhyd
KHSO4 (272 mg, 2.0 mmol) and salicylaldehyde (213 mL, 2.0
mmol). After 24 h, the mixture was filtered and concentrated under
high vacuum to afford sulfimine as a white–yellow solid (224 mg).
The solid was dissolved in THF (10 mL) and NaBH4 (57 mg, 1.5
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1540
Z. Zhang et al.
SPECIAL TOPIC
mmol) was added. Once the addition was completed, the mixture
became yellow and was stirred at 0 °C for an additional 2 h; the soln
turned colorless. Sat. aq NH4Cl was added to quench the reaction
and the resulting mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated to give the crude product as a colorless oil (260 mg),
which was purified by flash column chromatography (silica gel,
hexane–EtOAc, 2:1) to yield 8 (156 mg, 69%) as a white solid. The
resulting solid was recrystallized (EtOAc–hexanes) to afford highly
pure 8 as needles.
20 h. The mixture was diluted with EtOAc (250 mL) and washed
successively with H2O (100 mL), cold 0.5 M HCl (2 × 100 mL), sat.
NaHCO3 (2 × 100 mL), and brine (100 mL) and dried (MgSO4), fil-
tered, and evaporated to afford crude product (884 mg) as a yellow
oil, which was purified by column chromatography (silica gel,
CHCl3–MeOH, 20:1) to give 2b (585 mg, 40%) as a white solid.
IR (KBr): 3306, 2906, 2849, 1684, 1639, 1539, 1384, 612 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.24 (s, 1 H,
CHO), 6.68 and 5.53 (2 s, br, 1 H, NH), 4.34–4.37 and 4.17–4.20
(2 q, J = 3.75 Hz, 1 H), 3.40–3.61 (m, 2 H), 2.36–2.43 (m, 0.7 H),
1.77–2.16 (m, 13.3 H), 1.62 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.3, 169.1, 162.3, 162.1, 61.6,
58.5, 56.4, 56.2, 46.9, 44.4, 41.5, 41.3, 39.3, 39.1, 38.9, 38.85, 38.8,
38.7, 38.6, 38.1, 37.8, 37.4, 37.3, 37.2, 37.0, 36.8.
[a]D20 –86.8 (c 0.45, EtOAc).
1H NMR (400 MHz, CDCl3): d = 8.64 (s, 1 H), 7.03–7.06 (m, 2 H),
6.70–6.80 (m, 2 H), 4.25–4.30 (m, 2 H), 4.08–4.14 (m, 1 H), 1.17
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 155.7, 129.6, 129.5, 124.0, 119.6,
116.4, 56.2, 46.9, 22.6.
HRMS: m/z [M]+ calcd for C16H24N2O2: 276.18323; found:
276.18317.
(S)-2-[(tert-Butoxycarbonyl)(methyl)amino]-3-methylbutanoic
Acid (10)
(2S)-N-Cyclohexyl-1-formylpyrrolidine-2-carboxamide (2a)
Following the typical procedure for 2b on a 0.50 mmol scale using
CyNH2 (1.2 equiv). After workup, the crude product was purified
by column chromatography (silica gel, CHCl3–MeOH, 15:1) to give
2a (75 mg, 7%) as a white solid.
NaH (60% dispersion in mineral oil; 3.0 g, 138 mmol) was added in
small portions to a stirred soln of (S)-2-[(tert-butoxycarbonyl)ami-
no]-3-methylbutanoic acid (9, 3.0 g, 13.8 mmol) and MeI (19.6 g,
138 mmol) in anhyd THF (60 mL) at 0 °C. The mixture was allowed
to stir at r.t. for 24 h under an argon atmosphere. The reaction was
then quenched with H2O (15 mL), EtOAc (10 mL) was added, and
the soln was evaporated in vacuo. The residue was diluted in H2O
(300 mL) and washed with EtOAc (150 mL). The aqueous soln was
acidified to pH 3.5 with 5% citric acid soln and extracted with
EtOAc (200 mL). The extract was washed with brine (100 mL),
dried (anhyd MgSO4), and evaporated in vacuo to give 10 as a yel-
low oil, which was used in the following step without further puri-
fication.
IR (KBr): 3288, 2985, 2933, 2852, 1668, 1646, 1554, 1373, 691
cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.27 (s, 1 H,
CHO), 6.89 and 5.84 (2 s, br, 1 H, NH), 4.41–4.44 and 4.29–4.32 (2
quintets, J = 3.83 Hz, 1 H), 3.63–3.79 (m, 1 H), 3.43–3.61 (m, 2 H)
2.43–2.50 (m, 0.8 H), 1.05–2.24 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 170.2, 169.2, 162.3, 162.2, 61.0,
58.0, 48.5, 48.3, 46.9, 44.4, 33.1, 33.0, 32.8, 32.7, 30.4, 26.9, 25.5,
25.4, 24.8, 24.6, 24.2, 22.8.
HRMS: m/z [M]+ calcd for C12H20N2O2: 224.15193; found:
224.15179.
(S)-2-[(tert-Butoxycarbonyl)(methyl)amino]-N-(3,5-dimethyl-
phenyl)-3-methylbutanamide
ClCO2Me (0.55 mL, 7.15 mL) was added dropwise to a stirred soln
of 10 (1.40 g, 6.05 mmol) and Et3N (1.0 mL, 7.15 mmol) in anhyd
THF (30 mL) at 0 °C under an argon atmosphere and the mixture
was stirred at this temperature for 2 h. The precipitation was re-
moved by filtration in vacuo and the filtrate was added dropwise to
a soln of 3,5-dimethylaniline (1.06 mL, 8.5 mmol) and Et3N (1.0
mL, 7.15 mmol) in anhyd THF (30 mL) at 0 °C. The mixture was
allowed to stir at r.t. overnight under an argon atmosphere and the
solvent was then removed under reduced pressure. The residue was
purified using flash column chromatography (silica gel, hexane–
EtOAc, 4:1) to afford the product (958 mg) as a yellow oil.
1-Formyl-N-(pentacyclo[7.3.1.14,12.02,7.06,11]tetradecan-1-
yl)pyrrolidine-2-carboxamide (2c)
Following the typical procedure for 2b on a 0.50 mmol scale using
1-aminodiamantane (1.0 equiv). After workup, the crude product
was purified by column chromatography (silica gel, CHCl3–MeOH,
15:1) to give 2c (116 mg, 71%) as a white solid; mp 191 °C.
IR (KBr): 3311, 2899, 2852, 1676, 1640, 1534, 1395, 629 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.24 (s, 1 H,
CHO), 6.70 and 5.56 (2 s, br, 1 H, NH), 4.38–4.41 and 4.20–4.22 (2
m, 1 H), 3.43–3.58 (m, 2 H), 2.39–2.43 (m, 0.8 H), 1.38–2.18 (m,
22 H).
13C NMR (100 MHz, CDCl3): d = 170.0, 168.9, 162.2, 162.1, 61.4,
58.5, 52.3, 51.9, 46.9, 44.3, 44.3, 41.5, 41.4, 30.5, 29.4, 29.36, 26.9,
24.2, 22.9.
(S)-N-(3,5-Dimethylphenyl)-2-[formyl(methyl)amino]-3-meth-
ylbutanamide (7)
(S)-2-[(tert-Butoxycarbonyl)(methyl)amino]-N-(3,5-dimethylphe-
nyl)-3-methylbutanamide (344 mg, 1.03 mmol) was dissolved in
TFA (2.0 mL) at r.t. After 1 h, the mixture was evaporated in vacuo,
the residue was dissolved in 98% HCO2H (1.5 mL) and the resulting
soln was cooled to 0 °C. Ac2O (0.68 mL, 7.21 mmol) was added
dropwise and the mixture was allowed to stir at r.t. overnight. The
solvent was then removed by reduced pressure. Purification using
column chromatography (silica gel, hexanes–EtOAc, 1:1) afforded
7 (175 mg) as a colorless oil.
HRMS: m/z [M]+ calcd for C20H28N2O2: 328.21453; found:
328.21329.
1-Formyl-N-(pentacyclo[7.3.1.14,12.02,7.06,11]tetradecan-4-
yl)pyrrolidine-2-carboxamide (2d)
Following the typical procedure for 2b on a 0.50 mmol scale using
4-aminodiamantane (1.0 equiv). After workup, the crude product
was purified by column chromatography (silica gel, CHCl3–MeOH,
20:1) to give 2d (108 mg, 66%) as a white solid. The resulting prod-
uct was purified again with column chromatography (silica gel,
hexane–EtOAc, 2:1) to obtain highly pure product (98 mg, 60%) as
a white solid; mp 214 °C.
(2S)-N-(1-Adamantyl)-1-formylpyrrolidine-2-carboxamide
(2b); Typical Procedure
Et3N (1.12 mL, 8.02 mmol) was added dropwise to a cooled (0 °C)
soln of N-formyl-L-proline (760 mg, 5.35 mmol) in anhyd CH2Cl2
(50 mL). 1-Aminoadamantane (970.4 mg, 6.4 mmol) was added,
followed by HOBt (1.07 g, 6.96 mmol) and EDCI (1.33 g, 6.96
mmol). The mixture was stirred at 0 °C for 1 h, and then at r.t. for
IR (KBr): 3439, 3303, 2884, 2849, 1682, 1638, 1536, 1461, 1348,
1232, 1051, 630 cm–1.
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1541
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.22 (s, 1 H,
CHO), 6.65 and 5.49 (2 s, br, 1 H, NH), 4.33 and 4.16 (2 dd, J = 7.8,
3.9 Hz, 1 H), 3.37–3.59 (m, 2 H), 2.34–2.41 (m, 0.8 H), 1.65–2.14
(m, 22 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 169.2, 162.2, 162.1, 61.4,
58.5, 51.2, 50.7, 46.9, 44.3, 42.0, 41.9, 38.5, 38.4, 37.3, 37.2, 36.4,
36.3, 30.4, 26.8, 25.6, 25.4, 24.1, 22.8.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.24 and 8.21
(2 s, 1 H, CHO), 7.72–7.76 (m, 3 H), 7.64 (s, 1 H), 7.50 and 6.31 (2
d, J = 8.0 Hz, 1 H, NH), 7.28–7.44 (m, 3 H), 5.24 and 5.13 (2 m, 1
H), 4.50 and 4.30 (2 dd, J = 7.7, 3.6 Hz, J = 8.2, 3.3 Hz, 1 H), 3.44–
3.53 (m, 1 H), 3.33–3.40 (m, 1 H), 1.62–2.16 (m, 4 H), 1.51 and
1.48 (2 d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 169.2, 162.4, 162.3, 140.9,
139.9, 133.4, 133.3, 132.8, 132.6, 128.8, 128.4, 128.0, 127.9, 127.7,
127.6, 126.4, 126.1, 126.08, 125.7, 124.6, 124.45, 124.43, 124.3,
61.0, 58.0, 49.4, 49.0, 46.9, 44.4, 30.4, 29.7, 26.7, 24.2, 22.9, 22.6,
21.4.
HRMS: m/z [M]+ calcd for C20H28N2O2: 328.21453; found:
328.21512.
N-(Heptacyclo[7.7.1.13,15.01,12.02,7.04,13.06,11]octadecan-9-yl)-1-
formylpyrrolidine-2-carboxamide (2e)
HRMS: m/z [M]+ calcd for C18H20N2O2: 296.15193; found:
Following the typical procedure for 2b on a 0.50 mmol scale using
9-aminotriamantane (1.0 equiv). After workup, the crude product
was purified by column chromatography (silica gel, CHCl3–MeOH,
20:1) to give 2e (164 mg) as a colorless oil. The resulting product
was purified again with column chromatography (silica gel, hex-
ane–EtOAc, 2:1) to obtain highly pure product (121 mg, 64%) as a
white solid; mp 191 °C.
296.15029.
Benzyl (2S)-2-{[(2S)-1-Formylpyrrolidin-2-ylcarbonyl]amino}-
3-methylbutanoate (2h)
Following the typical procedure for 2b on a 1.0 mmol scale using L-
valine benzyl ester hydrochloride (1.0 equiv), and Et3N (4.3 equiv).
After workup, the crude product was purified by column chroma-
tography (silica gel, CHCl3–MeOH, 15:1) to give 2h (232 mg, 67%)
as a colorless oil.
IR (KBr): 3453, 3290, 3051, 2968, 2873, 1679, 1643, 1540, 1425,
1387, 1333, 1264, 1232, 1221, 1196, 1083, 1058, 1025, 992, 782,
647, 509, 457 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.20 (s, 1 H,
CHO), 6.67 and 5.50 (2 s, br, 1 H, NH), 4.33 and 4.16 (2 dd, J = 8.0,
4.2 Hz, 1 H), 3.37–3.58 (m, 2 H), 2.35–2.42 (m, 0.8 H), 1.75–2.14
(m, 10 H), 1.56–1.63 (m, 10 H), 1.49 (s, 2 H), 1.37 (s, 2 H), 1.24 (s,
2 H).
IR (KBr): 3305, 3064, 2966, 2878, 1740, 1661, 1540, 1383, 1193,
751, 700 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.25 and 8.21
(2 s, 1 H, CHO), 7.24–7.38 (m, 6 H), 5.03–5.15 (m, 2 H), 4.41–4.54
(m, 2 H), 3.42–3.60 (m, 2 H), 2.39 and 2.13 (2 m, 2 H), 1.78–2.04
(m, 3 H), 0.75–0.85 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 169.2, 162.3, 162.1, 61.4,
58.5, 52.3, 51.9, 48.7, 48.6, 46.9, 45.75, 45.74, 45.64, 45.62, 44.8,
44.7, 44.3, 41.9, 41.8, 41.7, 39.1, 39.0, 38.0, 37.8, 37.7, 37.6, 37.4,
37.3, 34.9, 34.8, 34.7, 34.6, 34.1, 34.0, 30.5, 27.25, 27.18, 26.8,
24.2, 22.9.
13C NMR (100 MHz, CDCl3): d = 171.5, 171.4, 171.2, 170.3, 162.1,
162.0, 135.5, 135.1, 128.8, 128.7, 128.6, 128.57, 128.5, 128.4,
128.3, 127.0, 125.1, 120.2, 109.4, 85.1, 67.3, 66.9, 60.8, 57.8, 57.6,
57.1, 46.9, 44.3, 31.1, 31.0, 30.5, 27.0, 24.2, 22.9, 19.1, 19.08, 17.6,
17.5.
HRMS: m/z [M]+ calcd for C24H32N2O2: 380.24638; found:
HRMS: m/z [M]+ calcd for C18H24N2O4: 332.17306; found:
380.24370.
332.17052.
(2S)-1-Formyl-N-[(R)-1-phenylethyl]pyrrolidine-2-carbox-
amide (2f)
Benzyl (2S)-2-{[(R)-1-Formylpyrrolidin-2-ylcarbonyl]amino}-
3-methylbutanoate (2i)
Following the typical procedure for 2b on a 0.50 mmol scale using
(R)-a-methylbenzylamine (1.2 equiv). After evaporation of the sol-
vent, the residue was directly purified by column chromatography
(silica gel, CHCl3–MeOH, 20:1) to give 2f (96 mg, 78%) as a white
solid; mp 103 °C.
Following the typical procedure for 2b with N-formyl-D-proline
(1.0 equiv), L-valine benzyl ester hydrochloride (1.0 equiv), and
Et3N (4.3 equiv). After workup, the crude product was purified by
column chromatography (silica gel, CHCl3–MeOH, 15:1) to give 2i
(76 mg, 23%) as a colorless oil.
IR (KBr): 3284, 2982, 2966, 1649, 1528, 1376, 768, 706, 544 cm–1.
IR (film): 3294, 3034, 2965, 2877, 1740, 1661, 1539, 1382, 670
cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.23 and 8.22
(2 s, 1 H, CHO), 7.40 and 6.21 (2 d, J = 6.6 Hz, 1 H, NH), 7.14–7.29
(m, 5 H), 5.04–5.11 and 4.94–5.01 (2 m, 1 H), 4.46–4.49 and 4.28–
4.31 (2 dd, J = 7.7, 3.6 Hz, 1 H), 3.46–3.56 (m, 1 H), 3.34–3.42 (m,
1 H), 2.42–2.50 (m, 0.8 H), 1.70–2.12 (m, 3.5 H), 1.63 (s, 0.7 H),
1.43 and 1.40 (2 d, J = 7.37 Hz, 3 H).
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.21 and 8.13
(2 s, 1 H, CHO), 7.45 and 6.38 (2 d, J = 9.2 Hz, 1 H, NH), 7.26 (m,
5 H), 4.97–5.15 (m, 2 H), 4.50 (m, 1 H), 4.34 and 4.43 (m, 1 H), 3.44
and 3.31 (2 m, 2 H), 2.14 and 2.40 (2 m, 2.7 H), 1.72–1.94 (m, 3.3
H), 0.75–0.89 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.3, 169.1, 162.4, 162.3, 143.5,
142.6, 128.8, 128.6, 127.6, 127.0, 125.9, 125.8, 61.0, 57.9, 49.2,
48.9, 46.9, 44.4, 30.4, 26.7, 24.1, 22.9, 22.7, 21.5.
HRMS: m/z [M]+ calcd for C14H18N2O2: 246.13628; found:
246.13662.
13C NMR (100 MHz, CDCl3): d = 171.5, 171.4, 171.3, 171.2, 171.1,
170.3, 162.3, 162.0, 135.5, 135.4, 135.0, 128.6, 128.5, 128.4, 128.3,
128.27, 128.24, 128.19, 128.17, 124.9, 120.0, 109.3, 85.0, 67.1,
66.7, 66.6, 60.6, 59.2, 57.5, 57.4, 57.3, 57.0, 48.0, 46.6, 44.2, 30.8,
30.6, 30.5, 26.8, 26.7, 24.8, 23.9, 22.7, 22.2, 19.0, 17.44, 17.39.
HRMS: m/z [M]+ calcd for C18H24N2O4: 332.17306; found:
(2S)-1-Formyl-N-[(R)-1-(2-naphthyl)ethyl]pyrrolidine-2-car-
boxamide (2g)
332.17072.
Following the typical procedure for 2b on a 0.50 mmol scale using
(R)-1-methyl-2-naphthylethylamine (1.2 equiv). After evaporation
of the solvent, the residue was directly purified by column chroma-
tography (silica gel, CHCl3–MeOH, 20:1) to give 2g (120 mg, 81%)
as a white solid.
(2S)-N-[(4S,5R)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-1-
formylpyrrolidine-2-carboxamide (2j)
Following the typical procedure for 2b on a 0.5 mmol scale using
(4S,5R)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-amine (1.0 equiv).
After workup, the crude product was purified by column chroma-
IR (KBr): 3313, 2972, 1673, 1642, 1534, 1398, 752 cm–1.
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1542
Z. Zhang et al.
SPECIAL TOPIC
tography (silica gel, CHCl3–MeOH, 20:1) to give 2j (78 mg, 47%)
as a white solid.
(468 mg, ca. 2.6 mmol) and EDCI (500 mg, 2.6 mmol). The mixture
was stirred at 0 °C for 1 h, and then at r.t. for 20 h. The mixture was
diluted with EtOAc (100 mL) and washed successively with H2O
(40 mL), cold 0.5 M HCl (2 × 40 mL), sat. NaHCO3 (2 × 40 mL),
and brine (40 mL) and dried (MgSO4), filtered, and evaporated to
afford crude product (750 mg), which was purified by column chro-
matography (silica gel, hexane–EtOAc, 6:1) to give 11 (585 mg,
80%) as a colorless oil.
IR (KBr): 3253, 2984, 2873, 1676, 1651, 1552, 1378, 1204, 1076,
700 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.20 and 7.76
(2 s, 1 H, CHO), 7.37 and 6.36 (2 d, J = 8.8 Hz, 1 H, NH), 7.15–7.32
(m, 5 H), 5.17 and 5.10 (2 s, 1 H), 3.96–4.22 (m, 3 H), 3.78 and 3.75
(2 s, 1 H), 3.37–3.49 (m, 2 H), 1.62–2.00 (m, 4 H), 1.46–1.51 (m, 6
H).
13C NMR (100 MHz, CDCl3): d = 170.8, 169.9, 162.0, 161.9, 138.6,
138.1, 128.4, 128.3, 128.1, 127.8, 127.5, 125.7, 125.2, 125.1, 99.6,
99.5, 77.4, 77.1, 76.7, 72.2, 71.6, 64.6, 64.4, 64.3, 60.4, 57.5, 47.4,
47.3, 46.7, 45.5, 44.2, 30.4, 29.8, 29.6, 23.9, 22.7, 18.6, 18.5.
Compound 11 (364.5 mg, 1.0 mmol) was then treated with 20%
TFA in CH2Cl2 (10 mL). After stirring at r.t. for 1 h, the soln was
concentrated under reduced pressure to give the TFA salt as an oil,
which was dissolved in 98% HCO2H (1.5 mL). The soln was cooled
down to 0 °C, Ac2O (0.68 mL, 7.21 mmol) was added dropwise at
this temperature. The resulting mixture was allowed to stir at r.t.
overnight and then evaporated to dryness. The residue was purified
by column chromatography (silica gel, hexane–EtOAc, 2:1) to give
4 (121 mg, 41%) as a colorless oil.
HRMS: m/z [M] calcd for C18H24N2O4: 332.17306; found:
331.16577 [M – 1]+.
(2R)-N-[(4S,5R)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-1-
formylpyrrolidine-2-carboxamide (2k)
IR (KBr): 3525, 3457, 3279, 2966, 2908, 2850, 1672, 1650, 1562,
1063 cm–1.
Following the typical procedure for 2b with N-formyl-D-proline
(0.5 mmol) and (4S,5R)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-
amine (1.0 equiv). After workup, the crude product was purified by
column chromatography (silica gel, CHCl3–MeOH, 20:1) to give
2k (78 mg, 47%) as a white solid.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.05 and 8.03
(2 s, 1 H, CHO), 5.70 and 5.39 (2 s, 1 H, NH), 4.08 and 3.13 (2 d,
J = 11.3 Hz, 1 H), 2.89 and 2.82 (2 s, 3 H), 2.19–2.32 (m, 1 H), 1.98
(s, 3 H), 1.90 (s, 6 H), 1.59 (s, 6 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.76
(d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.1, 167.8, 163.6, 163.1, 69.2,
62.4, 53.4, 52.5, 52.1, 41.4, 41.38, 36.3, 36.2, 31.2, 29.5, 29.4, 29.2,
27.2, 26.7, 25.3, 19.7, 19.4, 18.9, 18.5.
IR (KBr): 3253, 2984, 2873, 1676, 1651, 1552, 1378, 1204, 1076,
700 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.04 and 8.02
(2 s, 1 H, CHO), 7.70 and 6.38 (2 d, J = 9.2 Hz, 1 H, NH), 7.14–7.29
(m, 5 H), 5.18 and 5.10 (2 s, 1 H), 4.49 and 4.40 (2 d, J = 7.7 Hz, 1
H), 4.04–4.22 (m, 2 H), 3.77–3.85 (m, 1 H), 3.35 and 3.25 (2 m, 1
H), 3.06 and 2.87 (2 m, 1 H), 2.21 (m, 0.7 H), 1.46–1.97 (m, 10 H).
HRMS: m/z [M]+ calcd for C17H28N2O2: 292.21453; found:
292.21292.
(R)-N-Formyl-2-methoxy-N-methyl-2-phenylacetamide (5a)
To (R)-2-methoxy-2-phenylacetic acid (166.2 mg, 1.0 mmol) and
DMF (1 drop) in anhyd CH2Cl2 (3 mL) was added dropwise oxalyl
chloride (186.1 mL, 2.2 mmol). The resulting soln was stirred at r.t.
for 2 h. After removal of the solvent and excess oxalyl chloride un-
der reduced pressure, the residue was dissolved in anhyd CH2Cl2 (2
mL) and cooled to –5 °C under ice-salt bath. Anhyd pyridine (97.7
mL, 1.2 mmol) was dropwise added, followed by dropwise addition
of a soln of N-methylformamide (64.3 mL, 1.1 mmol) in anhyd
CH2Cl2 (2 mL). The reaction was allowed to stir at r.t. for 2 h. The
solvent was then removed in vacuo, and the residue was purified by
column chromatography (silica gel, hexane–EtOAc, 3:1) to afford
the product 5a (115 mg, 56%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 170.7, 170.4, 169.6, 162.1, 162.0,
139.1, 138.9, 138.3, 128.4, 128.3, 127.7, 127.1, 127.0, 125.5, 125.4,
125.2, 124.9, 124.8, 99.7, 99.5, 71.6, 71.3, 71.1, 64.6, 64.4, 64.1,
62.2, 60.7, 59.0, 57.2, 47.6, 47.4, 47.2, 47.0, 46.8, 46.5, 46.1, 45.5,
44.1, 31.6, 30.0, 29.7, 29.6, 26.2, 26.0, 24.5, 23.5, 22.3, 22.0, 18.6,
18.5.
HRMS: m/z [M] calcd for C18H24N2O4: 332.17306; found:
331.16303 [M – 1]+.
(2S)-N-(1-Adamantyl)-1-formylpiperidine-2-carboxamide (3)
Following the typical procedure for 2b with N-formyl-L-pipecolinic
acid (0.62 mmol) and 1-aminoadamantane (1.2 equiv). After work-
up, the crude product was purified by column chromatography (sil-
ica gel, CHCl3–MeOH, 15:1) to give 3 (145 mg, 81%) as a white
solid; mp 123 °C.
IR (film): 3386, 2994, 2940, 2830, 1726, 1675, 1283, 1075, 700
cm–1.
1H NMR (400 MHz, CDCl3): d = 9.27 (s, 1 H, CHO), 7.26–7.35 (m,
5 H) 5.17 (s, 1 H), 3.43 (s, 3 H), 3.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.7, 163.4, 134.7, 129.1, 129.0,
126.2, 85.0, 58.0, 26.6.
HRMS: m/z [M]+ calcd for C11H13NO3: 207.08899; found:
207.08919.
IR (KBr): 3418, 2911, 2850, 1690, 1667, 1653, 1503, 1410, 549
cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 8.01 (s, 1 H,
CHO), 5.61 and 5.52 (2 s, br, 1 H, NH), 4.8 and 4.01 (2 d, J = 5.6
Hz, 1 H), 4.31 and 3.46 (2 dd, J = 13.3, 3.0 Hz, 1 H), 3.16 and 2.63
(2 td, J = 13.0, 3.0 Hz, 1 H), 2.43 and 2.2 (2 m, 1 H), 2.00 (s, 3 H),
1.60–1.92 (m, 16 H), 1.27–1.5 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 168.8, 168.0, 162.4, 162.3, 58.1,
53.4, 52.4, 51.9, 51.3, 44.3, 41.6, 41.5, 41.3, 38.6, 36.3, 36.2, 36.1,
29.6, 29.5, 29.3, 29.2, 26.8, 25.7, 25.1, 24.5, 21.2, 20.9.
Anal. Calcd for C11H13NO3 (207.22): C, 63.76; H, 6.32; N, 6.76.
Found: C, 63.34; H, 6.33; N, 6.58.
(9H-Fluoren-9-yl)methyl (S)-1-[Formyl(methyl)amino]-1-oxo-
3-phenylpropan-2-ylcarbamate (5b)
HRMS: m/z [M]+ calcd for C17H26N2O2: 290.19888; found:
290.19754.
Under an argon atmosphere, SOCl2 (0.729 mL, 10.0 mmol) was
added to a suspension of Fmoc-Phe-OH (387.4 mg, 1.0 mmol) in
anhyd CH2Cl2 (5 mL). The resulting mixture was refluxed for 2 h
and the solvent was then removed under reduced pressure. The res-
idue was re-evaporated 3 times with addition of CH2Cl2 to give a
white solid. The white solid was dissolved in anhyd CH2Cl2 (2 mL)
and hexane was added to cause precipitation, which was filtered,
(2S)-N-(1-Adamantyl)-2-[formyl(methyl)amino]-3-methyl-
butanamide (4)
Et3N (0.4 mL, 3.0 mmol) was added dropwise to a cooled (0 °C)
soln of 10 (462.6 mg, 2.0 mmol) in anhyd CH2Cl2 (20 mL). 1-Ami-
noadamantane (302.4 mg, 2.0 mmol) was added, followed by HOBt
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane
1543
washed with hexane several times, and dried in a desiccator in
vacuo to give the corresponding chloride as a white solid.
127.9, 127.6, 127.1, 127.0, 126.5, 125.8, 125.4, 125.0, 123.9, 123.4,
61.0, 58.4, 58.3, 58.0, 57.6, 46.0, 45.9, 45.7, 43.8, 43.4, 30.1, 29.9,
29.7, 28.3, 27.8, 27.6, 26.8, 26.7, 23.6, 23.5, 23.0, 22.4, 22.1, 21.7,
20.7.
HRMS: m/z [M]+ calcd for C32H30N4O4: 534.22616; found:
Fmoc-Phe-Cl (276 mg, 0.68 mmol) was dissolved in anhyd CH2Cl2
(2 mL) and cooled to 0 °C, followed by the addition of pyridine (66
mL, 0.82 mmol). To the resulted soln was dropwise added a soln of
N-methylformamide (43.7 mL, 0.75 mmol) in anhyd CH2Cl2 (2 mL).
The reaction was allowed to stir at r.t. overnight. The mixture was
diluted with EtOAc (25 mL), washed with H2O (10 mL), cold 0.5 M
HCl (2 × 10 mL), sat. aq NaHCO3 (2 × 10 mL), and brine (10 mL),
dried (MgSO4), filtered, and evaporated to give crude product as an
oil, which was purified by column chromatography (silica gel, hex-
ane–EtOAc, 3:1) to afford the product 5b (52 mg, 18%) as a white
solid.
534.22622.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are cartesian coordinates for all stationary points found on the hy-
persurfaces, tables of absolute energies, and geometries for the
structures C1·C5a and C1·C5b.
IR (KBr): 3346, 1694, 1665, 1533, 760, 742, 701 cm–1.
1H NMR (400 MHz, CDCl3, cis and trans forms): d = 9.00 and 8.55
(2 s, 1 H, CHO), 7.04–7.71 (m, 16 H) 5.02 (m, 1 H), 4.29–4.39 (m,
2 H), 3.01 (d, J = 7.1 Hz, 2 H), 2.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.6, 155.6, 143.4, 143.3, 140.6,
136.3, 129.0, 127.9, 127.2, 126.6, 126.3, 124.8, 124.7, 119.4, 67.2,
54.1, 47.1, 39.7, 27.1.
Acknowledgment
Generous financial support by the Deutsche Forschungsgemein-
schaft (SPP 1179) is gratefully acknowledged. Z.Z. thanks the
Deutsche Akademische Austauschdienst and the Justus-Liebig Uni-
versity for fellowships. We thank Hartmut Schwertfeger and Anika
Merz for the preparation of 1-aminodiamantane, 4-aminodiaman-
tane, as well as 9-aminotriamantane, and BASF for the kind dona-
tion of some amine substrates.
HRMS: m/z [M]+ calcd for C26H24N2O4: 428.17306; found:
428.17208.
(2S)-1-(tert-Butoxycarbonyl)-N-[(R)-2¢-{[(2S)-1-(tert-butoxy-
carbonyl)pyrrolidin-2-ylcarbonyl]amino}-1,1¢-binaphthyl-2-
yl]pyrrolidine-2-carboxamide (14)
References
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To a soln of Boc-L-proline (12, 344.4 mg, 1.6 mmol) and Et3N
(223.2, 1.6 mmol) in anhyd THF (8.0 mL) was added dropwise
ClCO2Me (123.6 mL, 1.6 mmol) at 0 °C under an argon atmosphere.
After stirring for 1 h, (+)-(R)-1,1¢-binaphthyl-2,2¢-diamine (13,
227.4 mg, 0.8 mmol) was introduced in small portions. The result-
ing soln was continued to stir at 0 °C for 1 h, at r.t. for 16 h, and then
at reflux for 3 h. After filtration and removal of solvents under re-
duced pressure, the residue was dissolved in a small amount of
CH2Cl2 and purified by column chromatography (silica gel, hex-
ane–EtOAc, 1:1) to afford 14 (347 mg, 64%) as a white solid.
1H NMR (400 MHz, CDCl3): d = 7.00–8.54 (m, 14 H), 3.92–4.08
(m, 2 H), 2.92 (s, br, 2 H), 2.42 (s, br, 2 H), 1.77 (s, br, 4 H), 1.49
(s, br, 3 H), 1.09 (s, br, 20 H).
(4) Representative recent examples for asymmetric ketimine
hydrogenation and transfer hydrogenation: (a) Haraguchi,
N.; Tsuru, K.; Arakawa, Y.; Itsuno, S. Org. Biomol. Chem.
2009, 7, 69. (b) Li, C. Q.; Wang, C.; Villa-Marcos, B.; Xiao,
J. L. J. Am. Chem. Soc. 2008, 130, 14450. (c) Li, C. Q.;
Xiao, J. L. J. Am. Chem. Soc. 2008, 130, 13208.
(d) Matharu, D. S.; Martins, J. E. D.; Wills, M. Chem. Asian
J. 2008, 3, 1374. (e) Reetz, M. T.; Bondarev, O. Angew.
Chem. Int. Ed. 2007, 46, 4523. (f) Wang, Y. Q.; Lu, S. M.;
Zhou, Y. G. J. Org. Chem. 2007, 72, 3729. (g) Zhu, S. F.;
Xie, J. B.; Zhang, Y. Z.; Li, S.; Zhou, Q. L. J. Am. Chem.
Soc. 2006, 128, 12886. (h) Yang, Q.; Shang, G.; Gao, W.;
Deng, J.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 3832.
(5) Wang, C.; Wu, X. F.; Xiao, J. L. Chem. Asian J. 2008, 3,
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13C NMR (100 MHz, CDCl3): d = 171.4, 170.9, 154.8, 153.6, 134.4,
132.1, 131.2, 129.8, 128.4, 127.8, 125.8, 124.9, 124.4, 121.0, 120.3,
80.1, 61.8, 61.3, 60.4, 46.8, 46.3, 31.0, 29.6, 28.1, 24.0, 23.2, 21.1,
14.2.
(2S)-N-[(R)-2¢-{[(2S)-1-formylpyrrolidin-2-ylcarbonyl]amino}-
1,1¢-binaphthyl-2-yl]-1-formylpyrrolidine-2-carboxamide (6)
Compound 14 (243 mg, 0.36 mmol) was then treated with 20% TFA
in CH2Cl2 (4 mL). After stirring at r.t. for 1 h, the soln was concen-
trated under reduced pressure to give the TFA salt as a white solid,
which was dissolved in 98% HCO2H (1.5 mL). The soln was cooled
down to 0 °C, Ac2O (1 mL) was added dropwise at the same tem-
perature. The resulting mixture was allowed to stir at r.t. overnight,
and then evaporated to dryness. The yellow residue was purified by
column chromatography [silica gel, CH2Cl2–MeOH, 50:1 (100
mL), 40:1 (100 mL) 30:1 (100 mL), 20:1 (200 mL)] to afford 6 (146
mg, 76%).
(6) For reviews see: (a) Ouellet, S. G.; Walji, A. M.; Macmillan,
D. W. C. Acc. Chem. Res. 2007, 40, 1327. (b) Connon, S. J.
Org. Biomol. Chem. 2007, 5, 3407. (c) You, S. L. Chem.
Asian J. 2007, 2, 820.
IR (KBr): 3380, 3250, 3055, 2974, 2878, 1657, 1502, 819 cm–1.
(7) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.;
Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005, 44,
7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 84.
1H NMR (400 MHz, CDCl3): d = 8.36 (s, 0.4 H, CHO), 7.80–8.15
(m, 7 H), 7.05–7.47 (m, 7 H), 3.95–4.22 (m, 2 H), 1.18–2.02 (m, 8
H), 2.54–3.18 (m, 4 H).
13C NMR (150 MHz, CDCl3): d = 170.8, 170.0, 169.4, 166.7, 164.0,
163.1, 161.4, 159.5, 158.6, 155.9, 134.6, 134.3, 134.0, 133.5, 132.5,
132.4, 132.2, 132.1, 132.0, 131.9, 131.6, 129.6, 129.5, 129.2, 128.3,
(8) Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y.
Tetrahedron Lett. 2006, 47, 3751.
Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York

1544
Z. Zhang et al.
SPECIAL TOPIC
(9) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.;
Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525.
(10) Malkov, A. V.; Stončius, S.; MacDougall, K. N.; Mariani,
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Synthesis 2009, No. 9, 1531–1544 © Thieme Stuttgart · New York