Discovery of chiral catalysts by asymmetric activation for highly enantioselective diethylzinc addition to imines: Using racemic and achiral diimines as effective activators

Article abstract of DOI:10.1016/j.tetasy.2005.07.014

A library of chiral zinc complexes formed in situ by the combination of achiral and racemic diimines with 3,3′-di(3,5-ditrifluoromethylphenyl)- BINOL and diethylzinc were evaluated in the asymmetric addition of diethylzinc to N-acylimines. In the presence of 10 mol % of chiral ligand 4 and racemic diimine 5, high enantioselectivities of up to 97% ee and yields of up to 96% were achieved for a wide range of aromatic imines in dichloromethane at -30°C.

Full text of DOI:10.1016/j.tetasy.2005.07.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2901–2907
Discovery of chiral catalysts by asymmetric activation for
highly enantioselective diethylzinc addition to imines: using
racemic and achiral diimines as effective activators
Hua Liu,a,b Hai-Le Zhang,a,b Shuang-Jun Wang,a,b Ai-Qiao Mi,a,b
Yao-Zhong Jianga,b and Liu-Zhu Gonga,b,
*
aKey Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China
bGraduate School of Chinese Academy of Sciences, Beijing, China
Received 6 June 2005;accepted 12 July 2005
Available online 26 August 2005
Abstract—A library of chiral zinc complexes formed in situ by the combination of achiral and racemic diimines with 3,30-di(3,5-ditri-
fluoromethylphenyl)-BINOL and diethylzinc were evaluated in the asymmetric addition of diethylzinc to N-acylimines. In the pres-
ence of 10 mol % of chiral ligand 4 and racemic diimine 5, high enantioselectivities of up to 97% ee and yields of up to 96% were
achieved for a wide range of aromatic imines in dichloromethane at À30 °C.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
these catalytic processes, the zinc complex of [2.2]-para-
cyclophane-based N,O-ligand-catalyzed addition of
diorganozinc to N-acylimines is the only case, which
does not require an additional transition metal besides
zinc, and gives high enantioselectivity (up to 95% ee).7
In sharp contrast, a large number of N,O-ligands, in
particular amino alcohols, have been used in the cata-
lytic asymmetric addition of dialkylzincs to C@O
bonds.9 Thus, the design of new efficient catalysts for
catalytic asymmetric dialkylzinc additions to imines is
of fundamental importance. Asymmetric activation has
become an important platform for engineering chiral
catalysts to activate carbonyl substrates, however, this
concept has rarely been applied to the development of
chiral catalysts for asymmetric nucleophilic additions
to imines.10 Recently, we found a zinc complex that
was generated in situ by the combination of 3,30-
di(3,5-ditrifluoromethylphenyl)-BINOL 2 and enantio-
merically pure diimines 1a with diethylzinc, which cata-
lyzed the addition of diethylzinc to acylimines in high
enantioselectivities (up to 94% ee) (Fig. 1).11 The major
drawback of this process is the use of an enantiomeri-
cally pure diimine as the activator. We also observed
that the use of 1b, the enantiomer of 1a, to activate
the zinc complex of 2 gave the same enantioselectivity
as 1a, indicating that the enantiomeric excess or the
configuration of the diimine might be unnecessary for
The synthetic usefulness of enantiomerically pure
amines in the preparation of biologically active com-
pounds,1 and as resolving reagents and auxiliaries for
asymmetric synthesis2 has stimulated great interest in
the development of efficient methods for preparing such
molecules asymmetrically.3 The catalytic asymmetric
addition of organometallic reagents to C@N bonds is
amongst the most important reactions for the synthesis
of optically active amines. The enantioselective addition
of simple diorganozinc reagents to imines has recently
received much attention,4–8 because of the good toler-
ance of various functionalities with respect to organo-
lithiums and Grignard reagents. Although considerable
effort has been focused on this approach, stoichiometric
amounts of chiral ligands were usually required to ob-
tain high conversion and enantioselectivity4 until a small
number of chiral catalysts or ligands were recently dis-
covered for the catalytic asymmetric addition of simple
diorganozincs to N-sulfonylimines,5 N-arylimines,6 N-
acylimines,7 and N-diphenylphosphinoylimines.8 Of
*
Corresponding author. Fax: +86 28 85223978;e-mail: gonglz@
dcioc.ac.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.014

2902
H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
CF3
Ph
N
Ph
N
Ph
N
Ph
N
CF3
CF3
OH
OH
1b
1a
2
CF3
Figure 1. The previously reported enantiomerically pure diimines and a BINOL derivative for building up combined zinc catalysts.11
Ph
N
Ph
N
N
N
N
N
N N
N
N
R
R R
R
4
R
3
R
R
R
R
5
R
6
7
Figure 2. Achiral and racemic diimines evaluated as activators in this study.
controlling the enantioselectivity. Thus, we further
speculated that racemic and achiral imines might acti-
vate the zinc complex of 2 as efficiently as enantiomeri-
cally pure diimines. Walsh et al. have used a similar
strategy to engineer catalysts for the addition of diethyl-
zinc to aldehydes.12 To advance our speculation, and
inspired by WalshÕs work,12 we report herein, the
evaluation of combined zinc catalysts of racemic and
achiral imines 3–7 (Fig. 2) with 3,30-di(trifluoromethyl-
phenyl)-BINOL 2 for the catalytic asymmetric addition
of diethylzinc to imines. As a result, we discovered a new
efficient catalyst, which promotes the reaction with
excellent enantioselectivities of up to 97% ee.
The meso-diimines 4 and 5a derived, respectively, from
(1R,2S)-1,2-diphenyl-ethane-1,2-diamine and cis-cyclo-
hexane-1,2-diamine are fundamentally different from
achiral imines 3 since they have stereocenters, but as
seen in Table 2, they activated the zinc complex of 2
as effectively as achiral diimines 3. The combined zinc
complexes of 2 with meso-diimines 4a–c showed a sub-
stituent effect with regard to the enantioselectivity, sim-
ilar to the findings with simple achiral diimines 3a–e as
activators. Diimine 4b, which bears a bulky 2,4,6-tri-
methylphenyl group, in combination with diethylzinc
and ligand 2 led to a zinc complex, which catalyzed
the model reaction with lower enantioselectivity (entry
2, 82% ee) relative to the results with its structural ana-
logues 4a and 4c. With ligand 4c derived from benzalde-
hyde, a high enantioselectivity of 92% ee similar to that
reported previously with 1a, an enantiomerically pure
diastereomer of 4c,11 was observed. Thus, as we specu-
lated, neither the enantiomeric purity nor configuration
of the diimine activator is very important for the stereo-
control of the combined catalyst. In the presence of
diimine 5a derived from cis-cyclohexane-1,2-diamine
and 2,6-dichlorobenzaldehyde the enantioselectivity is
93% ee (entry 4).
2. Results and discussion
Achiral diimies 3–7 were prepared in high yields by the
condensation of the corresponding diamines with alde-
hydes following a reported procedure.12 Initially, we
screened simple achiral ligands 3 for activating the zinc
complex of 2. The resulting combined zinc complexes
were used to catalyze the asymmetric addition of dieth-
ylzinc to 4-bromophenylacylimine 9a in 1,2-dichloroeth-
ane at À25 °C.11 As shown in Table 1, the achiral
ligands are highly efficient at activating the zinc complex
of 2. Thus, product 10a was obtained in high yields with
the zinc complex of 2 by adding achiral diimines 3a–e.
The size of the substituent on the diimine ligands dra-
matically affects the enantioselectivity. The use of a
diimine with bulky substituents resulted in both a
comparably low yield and enantioselectivity (entry 2,
61% yield, 38% ee). Among this series of achiral diimine
activators 3a–e, 3e can be considered a better ligand,
which in combination with diethylzinc and 2, catalyzed
the model reaction in high yield and enantioselectivity
(entry 5, 82% yield, 92% ee). However, a very low
enantioselectivity of 21% ee was obtained with the zinc
complex of 2 in the absence of any diimine activator
(entry 6).
Racemic diimines 6a–d, which were derived from race-
mic trans-cyclohexane-1,2-diamine, were also used for
the activation of the chiral zinc complex of 2 (Table 2,
entries 5–9). The substituent-effects on both catalytic
activity and enantioselectivity are similar to those with
achiral ligands 3 and 4 based on the experimental data
shown in Table 2, entries 5–8. With diimine 6b, which
bears a bulkier substituent, a lower enantioselectivity
(entry 6, 87% ee) was seen than with its structural ana-
logues 6a and 6c–d (entries 5, 7 and 8, 91–94% ee).
The best catalyst among those with diimines 4–6 as acti-
vators was the zinc complex of 2 combined with diimine
6d, which was derived from racemic trans-cyclohexane-
1,2-diamine and naphthalene-2-carbaldehyde. An ee
value of as high as 94% was observed with this catalyst

H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
Table 1. Screening simple achiral diimine activators 3a–ea
2903
O
O
O
N
H
HN
H
HN
H
10 mol% 2 and 3
Et2Zn, DCE, -25 o
C
Et2Zn
H
SO2Tol
Br
Br
Yieldb (%)
Br
8a
10a
9a
Entry
1
Activators
R
eec (%)
3a
71
61
75
38
Me
2
3b
Me
Me
Cl
3
4
3c
3d
81
73
90
84
Cl
5
6
3e
82
66
92
21
—
—
a Unless otherwise specified, the reaction was performed on a 0.1 mmol scale with 3 equiv diethylzinc (1.0 M in hexane) in 1,2-dichloroethane at
À25 °C for 36 h.
b Isolated yield based on the imine precursor 8a.
c Determined by GC.
(entry 8). The best enantioselectivity of 96% ee was
obtained at À30 °C in dichloromethane (entry 9).
zinc complexes.12 In those cases, diimines based on
meso-diamines and biphenyl-2,20-diamine with a flexible
chirality are more enantioselective than the simple
diimines. In terms of the yield and enantioselectivity,
diimines 5a and 6d can be considered better ligands.
Biphenyl-2,20-diamine-based achiral diimines 7a–d were
also examined. These achiral diimines, in which the axial
chirality is generated when they coordinate with chiral
transition metal complexes,12,13 are distinct from simple
achiral ligands 3. As shown in Table 3, this class of achi-
ral ligands shows different trends in the substituent effect
on the enantioselectivity from the achiral diimines 3–5a
and racemic diimines 6. The lowest enantioselectivity
(27% ee) was obtained with the diimine derived from
naphthalene-2-carbaldehyde (entry 3). A high enantiose-
lectivity of 91% ee was also induced in the presence of
diimine 7b, which is derived from 2,6-dichlorobenzalde-
hyde (entry 2).
The combined catalyst of diethylzinc, 3,30-di(3,5-bistri-
fluoromethylphenyl)-BINOL and either 5a or 6d was
subsequently extended to a range of imine precursors
bearing either electron-donating or electron-withdraw-
ing groups with 10 mol % loading under optimal condi-
tions. The results are summarized in Table 4. These
catalysts generally show high enantioselectivity for the
imines tested regardless of the electronic-nature and ste-
ric hindrance of the substituent. With the exception of
N-benzylidene-formamide 9d, ee values of 90–97% were
obtained with the remaining imines. Interestingly, these
catalysts are more enantioselective than those with
enantiomerically pure diimine 1a as the activator.11
The results obtained with diimines 4–7 confirm that a
chiral backbone is unnecessary for the enantioselectiv-
ity;in contrast, an appropriate substituent is crucial
for the catalytic performance of the combined zinc com-
plexes. For example, the catalysts derived from 3e, 4c,
5a, 6d, and 7b, which contain a distinct backbone, all
promoted the model reaction with high enantioselectiv-
ities (91–94% ee). These observations are apparently dif-
ferent from those for the asymmetric addition of
diethylzinc to aldehydes catalyzed by similar combined
In summary, the combined catalysts of diethylzinc, 3,30-
di(3,5-bistrifluoromethylphenyl)-BINOL 2 and diimines
derived from achiral and racemic diamines were for the
first time screened for their ability to catalyze the asym-
metric catalytic addition of diethylzinc to N-acylimines.
meso-Diimine 5a and racemic diimine 6d are two of bet-
ter ligands for activating the zinc complex of 2. High

2904
H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
Table 3. Screening the diimine activators 7 with flexibly axial chiralitya
Table 2. Screening meso and racemic diimine activators 4–6a
Entry
1
Activators
R
Yieldb (%)
eec (%)
Entry
Activators
R
Yieldb (%)
eec (%)
Me
Cl
1
7a
77
84
4a
78
88
Me
Me
Cl
Cl
Me
2
7b
82
91
2
4b
63
82
Cl
Me
Me
3
4
7c
7d
65
70
27
53
3
4
4c
5a
82
83
92
93
Cl
NO2
a Unless otherwise specified, the reaction is the same as that illustrated
in Table 1.
Cl
b Isolated yield based on the imine precursor 8a.
c Determined by GC.
Cl
5
6
6a
6b
88
73
92
87
Cl
LET MX-1E FT-IR. Mass spectra were recorded on a
Brucker BioTOF Q. Elemental analyses were carried
out using Carlo Erba-1106 Analyzer. Chiral GC analy-
ses were performed on a VARIAN CP-3380 using a
CP-Chirasil Dex column.
Me
Me
Me
All reactions were conducted in a flame-dried glassware
under an atmosphere of dry argon. All chemicals and
solvents were used as received unless otherwise stated.
THF (Na, benzophenone), toluene (Na, benzophenone),
CH2Cl2(CaH2), ClCH2CH2Cl(CaH2) were distilled
under argon from the drying agent indicated. The N-for-
myl-a-(p-tolylsulfonyl)-benzylamines were prepared
according to the literature procedures.14 The absolute
configurations of amides 10 were assigned by the com-
parison of specific rotations with the literature values.7a
7
8
9
6c
6d
6d
88
83
89
91
94
96d
a Unless otherwise specified, the reaction is the same as that illustrated
in Table 1.
b Isolated yield based on the imine precursor 8a.
c Determined by GC.
3.2. Synthesis of new achiral diimines 3a–e, 4a–c, 5,
7a–c12b and 6a–d
d The reaction was performed at À30 °C in dichloromethane.
3.2.1. General procedure. The diamine (1.00 mmol) and
the corresponding aldehyde (2.00 mmol) were dissolved
in methanol (10 mL) and stirred under reflux for 5 h
to produce a precipitate. The reaction mixture was
cooled down to room temperature and the Schiff base
isolated by filtration and purified by recrystallization
from a solvent mixture of dichloromethane and hexane.
enantioselectivities of up to 97% ee and high yields of up
to 96% were obtained for a wide range of aromatic imi-
nes. These results confirm that the enantiomeric purity
of the diimines is unnecessary for the catalytic perfor-
mance of the combined catalysts. Thus, our finding
may provide some insight into the development of new
catalysts for asymmetric addition to imines.
3.2.2. N,N0-Bis(2,6-dichlorobenzylidiene)-( )-trans-1,2-
diaminocyclohexane 6a. Yield: 87%;white solid,
1
mp133–136 °C; H NMR (300 MHz, CDCl3): d (ppm)
3. Experimental
1.53 (m, 4H), 1.88 (m, 6H), 3.60 (m, 2H), 7.16 (t,
J = 7.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 8.47 (s, 2H);
13C NMR (75 MHz, CDCl3): d (ppm) 24.20, 32.83,
74.89, 128.56, 129.91, 132.85, 134.80, 156.53.
3.1. General methods
1H and 13C NMR spectra were recorded on a Brucker-
300 (300/75 MHz) spectrometer. Optical rotations were
measured with a Perkin–Elmer 341 Polarimeter in a
10 cm cell with the solvent indicated. Melting points
were measured on an electrothermal digital melting
point apparatus. IR spectra were recorded on a NICO-
3.2.3.
N,N0-Bis(2,4,6-trimethylbenzylidiene)-( )-trans-
1,2-diaminocyclohexane 6b. Yield: 85%;white solid,
1
mp 142–145 °C; H NMR (300 MHz, CDCl3): d (ppm)
1.50 (m, 2H), 1.83 (m, 8H), 2.23 (s, 6H), 2.24 (s, 12H),

H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
Table 4. Asymmetric addition of diethylzinc to iminesa
2905
O
O
O
HN
H
HN
H
N
H
Et2Zn
10 mol% 2 and 5a or 6d
Ar
Ar
SO2Tol
Ar
H
Et2Zn
8
10
9
Entry
Imines 9 (Ar)
Methodb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
4-BrC6H4 9a
3-BrC6H4 9b
3-ClC6H4 9c
C6H5 9d
4-ClC6H4 9e
4-MeC6H4 9f
4-MeOC6H4 9g
4-CNC6H4 9h
4-CF3C6H4 9i
4-MeO2CC6H4 9j
A
A
A
B
A
B
89
91
91
90
96
90
91
84
93
71
96
97
95
88
94
91
90
92
94
93
B
A
A
A
a Unless otherwise specified, the reaction was performed on a 0.2 mmol scale with 3 equiv diethylzinc (1.0 M in hexane).
b Method A: The reaction was performed with diimine 6d as an activator in dichloromethane at À30 °C;Method B: The reaction was performed with
diimine 5a as an activator in 1,2-dichloroethane at À25 °C.
c Isolated yield based on products 10 and imine precursors 8.
d Determined by GC and the absolute configuration is assigned as R by comparison of the specific rotations with those in the literature.7
20
D
3.42 (m, 2H), 6.77 (s, 4H), 8.54 (s, 2H); 13C NMR
(75 MHz, CDCl3): d (ppm) 20.58, 21.04, 24.52, 33.56,
75.61, 129.11, 132.24, 137.32, 138.18, 160.22.
white solid, mp 97–100 °C; ½aŠ ¼ þ144.3 (c 0.26
CHCl3);The 1H NMR shows a 6.6:1 mixture of two
rotamers (rotation of the N-formyl group in solution),
major rotamer: H NMR (300 MHz, CDCl3): d (ppm)
1
3.2.4. N,N0-Bis(benzylidiene)-( )-trans-1,2-diaminocyclo-
hexane 6c. Yield: 81%;white solid, mp 141–143 °C; 1H
NMR (300 MHz, CDCl3): d (ppm) 1.50 (m, 4H), 1.87
(m, 6H), 3.41 (m, 2H), 7.31 (m, 6H), 7.58 (m, 4H),
8.21 (s, 2H); 13C NMR (75 MHz, CDCl3): d (ppm)
24.44, 32.91, 73.76, 127.86, 128.32, 130.16, 136.31,
160.98.
0.95 (t, J = 7.4 Hz, 3H, CH3), 1.77–1.89 (m, 2H, CH2),
4.97 (q, J = 7.4 Hz, 1H, CH), 6.09 (br s, 1H, NH),
7.39 (d, J = 8.3 Hz, 2H, HAr), 7.59 (d, J = 8.3 Hz, 2H,
HAr), 8.21 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d (ppm) 10.73, 29.04, 53.38, 112.11, 127.48, 131.98,
140.21, 160.56;HRESI-MS (positive ion) C 10H12BrNO
([M+H]+) requires 263.9994. Found 263.9988;IR
(KBr): m = 3322 (s), 1661 (s), 1520 (s) cmÀ1. Anal. Calcd
for C10H12BrNO: C 49.61, H 5.00, N 5.79. Found: C,
49.30;H, 4.94;N, 5.66. Enantiomeric excess: 96%, deter-
mined by GC (CP-Chirasil Dex column, Tc = 180 °C,
H2 = 12 Psi, S-isomer, tR = 8.68 min and R-isomer,
tR = 8.92 min).
3.2.5. N,N0-Bis(2-naphthylidiene)-( )-trans-1,2-diamino-
cyclohexane 6d. Yield: 90%;white solid, mp 196–
200 °C; 1H NMR (300 MHz, CDCl3): d (ppm) 1.55
(m, 4H), 1.93 (m, 6H), 3.51 (m, 2H), 7.41 (m, 4H),
7.73 (m, 6H), 7.86 (m, 4H), 8.37 (s, 2H); 13C NMR
(75 MHz, CDCl3): d (ppm) 24.51, 33.00, 73.93, 123.87,
126.16, 126.77, 127.65, 128.15, 128.45, 129.39, 132.95,
133.91, 134.41, 161.15.
3.3.1.
N-[1-(3-Bromophenyl)propyl]formamide
10b.
20
Yield: 91%;colorless oil; ½aŠ ¼ þ109.8 (c 1.33, CHCl3);
D
1H NMR shows a 4.9:1 mixture of two rotamers (rota-
3.3. General procedure for the asymmetric diethylzinc
addition to imines
tion of the N-formyl group in solution), major rotamer:
1H NMR (300 MHz, CDCl3):
d (ppm) 0.92 (t,
J = 7.4 Hz, 3H, CH3), 1.76–1.90 (m, 2H, CH2), 4.91
(q, J = 7.4 Hz, 1H, CH), 6.00 (br s, 1H, NH), 7.12–
7.42 (m, 4H, HAr), 8.19 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.72, 29.14, 53.39, 122.91,
125.56, 129.55, 130.40, 130.71, 144.16, 160.63;HRESI-
MS (positive ion) C10H12BrNO ([M+H]+) requires
263.9994. Found 263.9985;IR (KBr): m = 3276 (s),
1660 (s), 1534 (s) cmÀ1. Enantiomeric excess: 97%, deter-
mined by GC (CP-Chirasil Dex column, Tc = 180 °C,
H2 = 12 Psi, S-isomer, tR = 6.93 min and R-isomer,
tR = 7.15 min).
A flame-dried vial (10 mL) was charged with ligand 2
(14.2 mg, 0.02 mmol), activator 6d (7.8 mg, 0.02 mmol)
and N-[4-bromophenylbenzyl(toluene-4-sulfonyl)meth-
yl]formamide 8a (74 mg, 0.2 mmol). After the vial was
flushed with argon, CH2Cl2 (1.0 mL) was added. After
the mixture was stirred at À30 °C for 30 min, diethylzinc
(0.7 mL, 0.7 mmol, 1 M in hexane) was added. After
being stirred at À30 °C for 36 h, the reaction was
quenched with HCl (2.0 M, 2 mL). The organic layer
was washed with 2.0 M HCl, brine and dried over
Na2SO4. After removal of the solvent in vacuo, the res-
idue was purified by column chromatography on silica
gel (PE–acetone = 5:1) to give the analytically pure N-
[1-(4-Bromophenyl)propyl]formamide 10a. Yield: 89%;
3.3.2.
N-[1-(3-Chlorophenyl)propyl]formamide
10c.
20
Yield: 91%;colorless oil; ½aŠ ¼ þ114.8 (c 1.46, CHCl3);
D
1H NMR shows a 4.4:1 mixture of two rotamers

2906
H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
(rotation of the N-formyl group in solution), major
rotamer: HNMR (300 MHz CDCl3): d (ppm) 0.92 (t,
3.3.6. N-[1-(4-Methoxyphenyl)propyl]formamide 10g.7a
20
1
Yield: 91%;colorless oil; ½aŠ ¼ þ132.6 (c 0.39, CHCl3);
D
J = 7.4 Hz, 3H, CH3), 1.74–1.91 (m, 2H, CH2), 4.93
(q, J = 7.7 Hz, 1H, CH), 5.88 (br s, 1H, NH), 7.11–
7.32 (m, 4H, HAr), 8.27 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.72, 29.12, 53.42, 125.07,
126.74, 127.80, 130.11, 134.70, 143.83, 160.60;IR
(KBr): m = 3276 (s), 1660 (s), 1534 (s) cmÀ1. Enantio-
meric excess: 95%, determined by GC (CP-Chirasil
Dex column, Tc = 180 °C, H2 = 12 Psi, S-isomer, tR =
4.61 min and R-isomer, tR = 4.73 min).
1H NMR shows a 3.1: 1 mixture of two rotamers (rota-
tion of the N-formyl group in solution), major rotamer:
1H NMR (300 MHz, CDCl3):
d (ppm) 0.91 (t,
J = 7.4 Hz, 3H, CH3), 1.74–1.90 (m, 2H, CH2), 3.79 (s,
3H, OCH3), 4.92 (q, J = 7.8 Hz, 1H, CH), 5.85 (br s,
1H, NH), 6.88 (d, J = 8.7 Hz, 2H, HAr), 7.22 (d,
J = 8.7 Hz, 2H, HAr), 8.17 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.78, 29.07, 53.12, 55.41,
114.20, 127.89, 133.89, 159.04, 160.49. Enantiomeric ex-
cess: 90%, determined by GC (CP-Chirasil Dex column,
Tc = 175 °C, H2 = 12 Psi, S-isomer, tR = 8.67, R-iso-
mer, tR = 8.88 min).
3.3.3. N-(1-Phenylpropyl)formamide 10d.7a Yield:
20
D
1
90%;colorless oil; ½aŠ ¼ þ126.2 (c 0.48, CHCl3); H
NMR shows a 3.2:1 mixture of two rotamers (rotation
of the N-formyl group in solution), major rotamer: H
1
3.3.7.
N-[1-(4-Cyanophenyl)propyl]formamide
10h.
22
NMR (300 MHz, CDCl3): d (ppm) 1.04 (t, J = 7.4 Hz,
3H, CH3), 1.91–2.04 (m, 2H, CH2), 5.08 (q,
J = 7.4 Hz, 1H, CH), 6.13 (br s, 1H, NH), 7.35–7.49
(m, 5H, HAr), 8.31 (s, 1H, CHO); 13C NMR (75 MHz,
CDCl3): d (ppm) 10.79, 29.18, 53.85, 126.70, 127.62,
Yield: 84%;colorless oil; ½aŠ ¼ þ49.3 (c 1.75, CHCl3);
D
1H NMR shows a 6.5:1 mixture of two rotamers (rota-
tion of the N-formyl group in solution), major rotamer:
1H NMR (300 MHz, CDCl3):
d (ppm) 0.90 (t,
J = 7.4 Hz, 3H, CH3), 1.77–1.87 (m, 2H, CH2), 4.97
(q, J = 7.4 Hz, 1H, CH), 5.97 (br s, 1H, NH), 7.37–
7.40 (d, J = 8.3 Hz, 2H, HAr), 7.60–7.64 (d,
J = 8.3 Hz, 2H, HAr), 8.22 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.66, 29.01, 53.70, 118.77,
127.44, 132.66, 147.28, 160.71;HRESI-MS (positive
ion) C11H12N2O ([M+H]+) requires 211.0842. Found
211.0849;IR (KBr): m = 3250 (s), 2227 (s), 1665 (s),
1550 (s) cmÀ1. Enantiomeric excess: 92%, determined
by GC (CP-Chirasil Dex column, Tc = 180 °C, H2 =
12 Psi, S-isomer, tR = 23.31, R-isomer, tR = 23.74 min).
128.82, 141.67, 160.59;Minor rotamer:
1HNMR
(300 MHz, CDCl3): d (ppm) 1.07 (t, J = 7.4 Hz, 3H,
CH3), 1.91–2.04 (m, 2H, CH2), 4.48 (q, J = 7.4 Hz,
1H, CH), 6.55 (br s, 1H, NH), 7.35–7.49 (m, 5H,
HAr), 8.24 (d, J = 11.9 Hz, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.79, 30.42, 58.21, 126.30,
127.86, 129.00, 141.67, 164.60. Enantiomeric excess:
88%, determined by GC (CP-Chirasil Dex column,
Tc = 160 °C, H2 = 12 Psi, S-isomer, tR = 4.77 min and
R-isomer, tR = 4.89 min).
3.3.4.
N-[1-(4-Chlorophenyl)propyl]formamide
10e.
3.3.8. N-[1-(4-(Trifluoromethyl)phenyl)propyl]formamide
10i. Yield: 93%;white solid, mp 85–88
20
Yield: 96%;white solid, mp 97–100 °C; ½aŠ ¼ þ130.6
°C;
D
(c 0.68, CHCl3); 1H NMR shows a 3.9:1 mixture of
two rotamers (rotation of the N-formyl group in solu-
20
1
½aŠ ¼ þ91.5 (c 0.82, CHCl3); H NMR shows a 4.8:1
miDxture of two rotamers (rotation of the N-formyl
group in solution), major rotamer: 1H NMR
(300 MHz, CDCl3): d (ppm) 0.90 (t, J = 7.4 Hz, 3H,
CH3), 1.80–1.89 (m, 2H, CH2), 5.00 (q, J = 7.4 Hz,
1H, CH), 5.92 (br s, 1H, NH), 7.38–7.40 (d,
J = 8.3 Hz, 2H, HAr), 7.58–7.60 (d, J = 8.3 Hz, 2H,
HAr), 8.21 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d (ppm) 10.37, 28.81, 53.26, 125.57, 126.40, 126.71,
145.47, 160.35;HRESI-MS (positive ion) C 11H12F3NO
([M+H]+) requires 254.0763. Found 254.0787;IR
(KBr): m = 3323 (s), 1662 (s), 1523 (s) cmÀ1. Enantio-
meric excess: 94%, determined by GC (CP-Chirasil
Dex column, Tc = 175 °C, H2 = 12 Psi, S-isomer,
tR = 3.24, R-isomer, tR = 3.39 min).
1
tion), major rotamer: H NMR (300 MHz, CDCl3): d
(ppm) 0.93 (t, J = 7.4 Hz, 3H, CH3), 1.78–1.90 (m,
2H, CH2), 4.93 (q, J = 7.4 Hz, 1H, CH), 5.76 (br s,
1H, NH), 7.21–7.24 (d, J = 6.7 Hz, 2H, HAr), 7.30–
7.32 (d, J = 6.7 Hz, 2H, HAr), 8.21 (s, 1H, CHO); 13C
NMR (75 MHz, CDCl3): d (ppm) 10.70, 29.09, 53.37
(t, CH), 128.13, 129.03, 133.43, 140.17, 160.71. Anal.
Calcd for C10H12ClNO: C, 60.76;H, 6.12;N, 7.09.
Found C, 60.58;H, 6.08;N, 7.06. Enantiomeric excess:
94%, determined by GC (CP-Chirasil Dex column,
Tc = 180 °C, H2 = 12 Psi, S-isomer, tR = 5.82 min and
R-isomer, tR = 5.95 min).
3.3.5. N-[1-p-Tolypropyl]formamide 10f.7a Yield: 90%;
20
1
colorless oil; ½aŠ ¼ þ122.3 (c 0.54, CHCl3); HNMR
3.3.9. 4-(1-Formylaminopropyl)benzoic acid methyl ester
shows a 3.3:1 mDixture of two rotamers (rotation of the
N-formyl group in solution), major rotamer: H NMR
20
10j.7a 71%;white solid, mp 139–141 °C; ½aŠ ¼ þ41 (c
D
1
1
0.57, CHCl3); H NMR shows a 5.1:1 mixture of two
(300 MHz, CDCl3): d (ppm) 0.91 (t, J = 7.4 Hz, 3H,
CH3), 1.73–1.87 (m, 2H, CH2), 2.33 (s, 3H, ArCH3),
4.93 (q, J = 7.7 Hz, 1H, CH), 5.84 (br s, 1H, NH),
7.10–7.19 (m, 4H, HAr), 8.18 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3): d (ppm) 10.78, 21.19, 29.12, 53.60,
126.64, 129.52, 137.34, 138.64, 160.50. Enantiomeric
excess: 91%, determined by GC (CP-Chirasil Dex
column, Tc = 160 °C, H2 = 12 Psi, S-isomer, tR = 6.45
min and R-isomer, tR = 6.60 min).
rotamers (rotation of the N-formyl group in solution),
major rotamer: H NMR (300 MHz, CDCl3): d (ppm)
1
0.92 (t, J = 7.1 Hz, 3H, CH3), 1.80–1.90 (p,
J = 7.3 Hz, 2H, CH2), 3.91 (s, 3H, CO2CH3), 5.00 (q,
J = 7.6 Hz, 1H, CH), 5.91 (br s, 1H, NH), 7.34 (d,
J = 8.5 Hz, 2H, HAr), 7.99 (d, J = 8.3 Hz, 2H, HAr),
8.23 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3): d
(ppm) 10.68, 29.15, 52.34, 53.65, 126.70, 130.10,
130.18, 146.87, 160.63, 166.92. Enantiomeric excess:

H. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2901–2907
2907
Jiang, F.;Zhang, X.-M.;Gong, L.-Z.;Mi, A.-Q.;Cui, X.;
93%, determined by GC (CP-Chirasil Dex column,
Tc = 175 °C, H2 = 12 Psi, S-isomer, tR = 15.28, R-iso-
mer, tR = 15.94 min).
Jiang, Y.-Z.;Wu, Y.-D. Chem. Eur. J. 2004, 10, 1481.
5. (a) Fujihara, H.;Nagai, K.;Tomioka, K. J. Am. Chem.
Soc. 2000, 122, 12055;(b) Soeta, T.;Nagai, K.;Fujihara,
H.;Kuriyama, M.;Tomioka, K. J. Org. Chem. 2003, 68,
9723.
6. (a) Porter, J. R.;Traverse, J. F.;Hoveyda, A. H.;Snapper,
M. L. J. Am. Chem. Soc. 2001, 123, 984;(b) Porter, J. R.;
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Acknowledgements
We are grateful for financial support from NSFC (Pro-
jects 203900505 and 20325211).
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5940;(b) Hermanns, N.;Dahmen, S.;Bolm, C.;Bra ¨se, S.
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