Synthesis of chiral β-amino acid derivatives by asymmetric hydrosilylation with an imidazole derived organocatalyst

Article abstract of DOI:10.1016/j.tet.2012.04.084

The organocatalysed asymmetric hydrosilylation of a number of N-aryl and alkyl β-substituted enamino esters proceeds in generally good yield and enantioselectivity. Crucial to obtaining high yield and selectivity was the addition of benzoic acid as an additive and under these conditions, both N-alkyl and N-aryl substituents were well tolerated. β-Aryl and alkyl substituents were evaluated and a model proposed to account for the experimental observations based upon enamine tautomerisation and conformational preferences of the reactive ketimine intermediate.

Full text of DOI:10.1016/j.tet.2012.04.084

Tetrahedron 68 (2012) 5522e5532
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral
b-amino acid derivatives by asymmetric hydrosilylation with
an imidazole derived organocatalyst
*
Simon Jones , Xianfu Li
Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The organocatalysed asymmetric hydrosilylation of a number of N-aryl and alkyl b-substituted enamino
Received 31 January 2012
Received in revised form 3 April 2012
Accepted 23 April 2012
esters proceeds in generally good yield and enantioselectivity. Crucial to obtaining high yield and se-
lectivity was the addition of benzoic acid as an additive and under these conditions, both N-alkyl and N-
aryl substituents were well tolerated. b-Aryl and alkyl substituents were evaluated and a model proposed
to account for the experimental observations based upon enamine tautomerisation and conformational
preferences of the reactive ketimine intermediate.
Available online 30 April 2012
Keywords:
Hydrosilylation
Asymmetric synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
b-amino acid
Organocatalyst
1. Introduction
findings with 2-picolinamide catalysts, although it was not until
their follow-up work in 2011 that the applicability to
Optically active
building blocks for the synthesis of
b
-amino acids and their derivatives are key
-peptides, -lactams and
a-substituted substrates was comprehensively demonstrated and
b
b
observations were made of the need to use unpurified solvent to
facilitate generation of HCl needed to promote tautomerisation.
Nakajima’s group was the first to use Lewis basic bis-phosphine
oxides and pyridine-N-oxides to affect competitive 1,4- and
related biologically active compounds, with a wide variety of
methods having been reported for their preparation.1 Catalytic
methods include the use of transition-metals, organocatalysts,
and biocatalysts, and more recently, several groups have reported
the use of chiral Lewis-bases for the trichlorosilane mediated
1,2-reduction pathways of structurally related N-acyl-b-enamino
ketones in up to 81% ee.6 Subsequent work by Benaglia has
demonstrated the use of phosphinamide catalysts for the re-
asymmetric reduction of b
-enamino esters.2 These advances stem
from efforts from a number of research groups to extend the
substrate scope of such catalysts derived from formamides, pico-
linoylamides, phosphine oxides and sulfoxides as activators of
trichlorosilane for the catalytic asymmetric reduction of
ketimines.3
duction of b-aryl N-benzyl and N-p-methoxybenzyl b-enamino
esters in generally good yield, with an enantiomeric excess of up
to 83%, which could be increased further by the use of an addi-
tional stereodirecting group in the substrate.7 A recent report by
the same group has examined the use of picolinamide catalysts to
effect the same transformation with similar results. Interestingly,
neither Nakajima nor Benaglia report the use of additives to
augment the yield and/or selectivity. However, recent work from
Sun has shown that additives, in particular precisely measured
quantities of water, are essential for ensuring high yields and ees
ꢀ
ꢁ
Malkov and Kocovsky first reported the reduction of
b
-enamino esters and nitriles in 2008 using the commercially
available SigamideÒ chiral formamide catalyst.4 The addition of
acetic acid was deemed essential to buffer the reaction medium
and promote isomerisation to the reactive ketimine tautomer.
Using these conditions, a range of
yphenyl enamines were reduced in excellent yield with an en-
antiomeric excess ranging from 59 to 90%. -Substituted
b
-aryl and alkyl N-p-methox-
in the reduction of N-alkyl b-enamino esters promoted by sul-
fonamide catalysts.8
a
We recently reported the development of an imidazole-based
organocatalyst able to catalyse the asymmetric reduction of a vari-
ety of ketimines in excellent yields and enantioselectivities at very
low catalyst loading,9 and more recently reported the extension of
this catalyst to the direct reductive amination of ketones with both
aromatic and aliphatic amines.3c Herein, we describe the applica-
substrates were also found to react with exceptional levels of
diastereoselectivity. Later that year,5 Zhang published similar
* Corresponding author. Tel.: þ44 (0)114 222 9483; fax: þ44 (0)114 222 9346;
e-mail address: simon.jones@sheffield.ac.uk (S. Jones).
tion to the reduction of b-enamino esters with this catalyst.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.084

S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
5523
2. Results and discussion
-Enamino ester 2a was used as a model substrate for initial
There appears to be a tentative correlation between the enantio-
selectivity of these reactions with the pKa of the aniline or amine,
since the more basic species generally provide products with
higher enantioselectivity. Thus, electron donating nitrogen sub-
stituents are likely to facilitate the rate of equilibration of the en-
amine to its reactive ketimine tautomer and any subsequent
isomerisation. Since it is well recognized that the enantioselectiv-
ities obtained in trichlorosilane processes are independent of the
ratio of the initial ketimine geometries, facile equilibration is a pre-
requisite for high selectivity (Fig. 1).
b
evaluation of the reduction conditions (Scheme 1). Under the initial
reaction conditions, the process suffered from poor reproducibility
in terms of both yields and enantioselectivity, however, this prob-
lem could not be overcome by addition of acetic acid or water as
noted by other groups (Table 1, entries 1e3). Sub-stoichiometric
amounts of other Brønsted acids including salicylic acid, benzoic
acid and phenol were then investigated in the presence of 10 mol %
catalyst (Table 1, entries 4e11). High reactivity was observed when
0.2 equiv of salicylic acid was used as an additive but low enan-
tioselectivity was observed (Table 1, entry 4). Using 0.2 equiv of
benzoic acid or phenol also improved the reactivity slightly and
gave good enantioselectivity (Table 1, entries 5 and 6). However,
further increasing the amount of benzoic acid additive to 0.3 equiv
rendered a sharp decrease in enantioselectivity (Table 1, entry 7).
Higher enantioselectivity could be achieved when using less
equivalents of additive, but this did lead to a drop in yield (Table 1,
entries 8e10). The optimum ratio of catalyst to additive was found
to be 0.2 equiv of catalyst 1 with 0.1 equiv of benzoic acid as an
additive (Table 1, entry 11). Using these conditions, product 2a was
isolated in 76% yield and 91% ee after 10 h at 0 ꢀC (Table 1, entry 11).
Scheme 2. Application of optimized conditions.
The ketimine tautomer then adopts a preferred conformation
that places the nitrogen substituent anti to the aryl ring, which
maximizes the conjugation between the aryl and C]N p-systems.
This conformation must also locate the ester functionality at 90ꢀ to
the sp2 system to minimize interactions between this group and
Scheme 1. Initial substrate for optimization studies in Table 1.
Table 1
both the nitrogen substituent and aryl ring. Such a conformation
that then places the ester remote from the catalyst is important,
since Sun demonstrated that the selectivity in these processes is
independent of the size of the ester functionality.8 Molecular
modelling of a simple representative iminium ion supports this
hypothesis, clearly showing a low-energy conformation with these
key features (Fig. 2). Note that the face selectivity in this proposed
model is then analogous to that proposed for the reduction of
acetophenone derivatives by Matsumura.10
a
Optimization of initial reaction conditions for Scheme 1
Entry
1 (equiv)
Additive (equiv)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
None
AcOH (1)
H2O (1)
10
10
10
10
10
10
10
10
24
10
10
55
90
74
87
68
70
83
60
62
58
76
84
42
51
65
85
83
75
88
88
91
91
Salicylic acid (0.2)
PhCOOH (0.2)
PhOH (0.2)
PhCOOH (0.3)
PhCOOH (0.1)
PhCOOH (0.1)
PhCOOH (0.05)
PhCOOH (0.1)
9
10
11
Table 2
Substrate scope of reaction described in Scheme 2
a
Compound 2a (0.5 mmol), HSiCl3 (2 mmol), CH2Cl2 (1 mL) at 0 ꢀC.
Refers to isolated product.
Determined by chiral phase HPLC.
Entry
R1
R2
Product
Yielda (%)
eeb (%)
b
c
1
2
3
4
5
6
7
8
4-MeOC6H4
Ph
4-MeC6H4
4-FC6H4
2-MeC6H4
2-MeOC6H4
PhCH2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
76
64
69
59
53
41
57
59
75
70
66
50
27
56
63
44
91
85
87
71
86
13
93
94
92
91
90
82
3
With optimized conditions in-hand, a representative series of
-enamino esters were prepared by standard methods and used in
this reaction. In the first instance, series of differentially
N-substituted -phenyl enamine substrates were examined
(Scheme 2, Table 2, entries 1e8). Most delivered the desired
product with enantioselectivities over 85% (entries 1e3, 5, 7 and 8),
notably including N-methyl and N-benzyl substrates. The absolute
configuration of the products was confirmed by comparison with
literature specific rotations where possible or by structural analogy.
Two anomalies were observed with p-fluorophenyl (entry 4) and
o-methoxyphenyl (entry 6). Since high enantioselectivities can be
obtained with nitrogen protecting groups of varied size (Me vs Ph),
the origin of the selectivity is more likely to lie in electronic factors.
b
a
Me
b
9
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
2-Thienyl
4-NO2C6H4
2-MeC6H4
PhCH2
Me
10
11
12
13
14
15
16
30
20
56
i-Pr
a
Refers to isolated product.
Determined by chiral phase HPLC, except entry 15 where integration of signals
b
in the 1H NMR spectrum after addition of mandelic acid was employed.

5524
S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
since no additives were employed in this work, their role in influ-
encing the data cannot be ruled out.
Since the N-p-methoxyphenyl group delivered one of the best
yields and enantioselectivities, it was then used to probe the effect of
varying the substituent in the
b-position (Table 2, entries 9e16). In
general, nearly all -aryl substituents gave good yield and enantio-
b
selectivity (Table 2, entries 9e12), except for the o-methylphenyl de-
rivative (Table 2, entry 13). In this case, the conversion obtained is in-
line with that observed for the background reaction, and this, coupled
with the low ee, indicates that the catalyst cannot bind to this sub-
strate due to the steric requirements of the o-methyl group (Fig. 3).
Fig. 1. Effect of the N-substituent on selectivity.
Fig. 3. Possible steric interaction preventing catalyst binding with substrate (Table 2,
entry 13).
All of the three b-alkyl substituents evaluated (Table 2, entries
14e16) gave low enantioselectivities, which improved slightly with
increasing steric bulk. With the smaller groups, such as methyl and
benzyl, there is essentially no difference in the size of the two alkyl
groups to dictate a preference for one ketimine geometry. Only when
the size differential starts to increase, as with the iso-propyl group, is
there sufficient bias of one ketimine geometry to facilitate selectivity.
In summary, catalyst 1 can facilitate the reduction of a range of N-
alkyl and N-aryl enamino esters with generally good yield and
enantioselectivity. With the information provided from this study
and observations noted by other groups, it seems likely that the key
stereocontrol event in this reaction is the equilibration of the en-
amine to a preferred ketimine form. Here stereoselective reduction
may then occur on the basis of classic large versus small steric dis-
crimination of the substituents such as in the model proposed by
Matsumura (Fig. 4).10 More detailed mechanistic studies are currently
being carried out and will be the subject of a future publication.
Fig. 2. Modelled low-energy conformer of reaction intermediate.
The exception to this hypothesis is then the o-methoxyphenyl
derivative (entry 6), which despite having similar basicity to the p-
methoxyphenyl derivative delivers the lowest enantioselectivity. It
is also interesting to note the reduction of the corresponding
ketimine proceeds with excellent selectivity, although in low yield,
whilst the analogous 2-methyl derivative provides product with
both good yield and selectivity (Scheme 3). This evidence strongly
supports a synergistic role of the oxygen atom and the adjacent
carbonyl group, perhaps through stabilisation of the enamine tau-
tomer, thus inhibiting the rate of the tautomerisation process. It is
important to note that only one other report has investigated the
role of the nitrogen protecting group in this type of reaction, and
high enantioselectivities were obtained in all cases.5b However,
Fig. 4. Possible model for the observed selectivity applying Matsumura’s model.
3. Experimental
3.1. General experimental
Unless stated otherwise, all solvents were obtained from
a Grubbs dry solvent system and glassware were flame dried and
cooled under vacuum before use. Petroleum ether refers to the
Scheme 3. Reduction of 2-substituted N-aryl ketimines/enamines.

S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
5525
boiling fraction between 40 and 60 ꢀC. All chemicals were used as
received without further purification unless otherwise stated. An-
alytical thin layer chromatography (TLC) was performed using
Merck 60 F254 precoated silica gel plates. Subsequent to elution,
plates were visualized using UV radiation (254 nm); further visu-
alization was possible by staining with a basic solution of potassium
(2ꢂArCH), 129.2 (ArCH), 133.6 (ArC), 136.1 (ArC), 155.9 (ArC), 159.9
(C]CH), 170.3 (CO). Data were in accordance with the literature.
3.2.2. (Z)-Ethyl 3-phenyl-3-(phenylamino)acrylate 2b.11
permanganate or silica supported iodine. Flash chromatography
ꢂ
was performed using silica gel 40e63
m
60 A (Fluorochem Limited).
Silica gel chromatography columns were typically packed as slurry
and equilibrated with the appropriate solvent system prior to use.
1H and 13C NMR spectra were recorded on Bruker 400 MHz or
250 MHz spectrometer at ambient temperature unless otherwise
Obtained by general procedure A using 1.2 equiv amine, and
purified using 100% petroleum ether eluent as a white solid (1.00 g,
34%); mp 72e74 ꢀC (lit.11 65e66 ꢀC); Rf (10% EtOAc/petroleum
ether) 0.90; dH (250 MHz, CDCl3) 1.34 (t, 3H, J 7.2, CH3CH2), 4.22 (q,
2H, J 7.2, CH2), 5.01 (s, 1H, CH), 6.65e6.70 (m, 2H, 2ꢂArCH),
6.89e6.96 (m, 1H, ArCH), 7.07e7.13 (m, 2H, 2ꢂArCH), 7.26e7.38 (m,
5H, 5ꢂArCH), 10.32 (br s, 1H, NH); dC (63 MHz, CDCl3) 14.6 (CH3),
59.3 (CH2), 91.3 (C]CH), 122.2 (2ꢂArCH), 123.0 (ArCH), 128.3
(2ꢂArCH), 128.4 (2ꢂArCH), 128.6 (2ꢂArCH), 129.4 (ArCH), 136.1
(ArC), 140.1 (ArC), 159.1 (C]CH), 170.1 (CO). 1H NMR data were in
accordance with the literature.
stated. Chemical shifts for 1H NMR spectra are reported as
d
in units
0.0) and relative
7.26, singlet). Coupling constants (J)
are reported in hertz. Data for 13C NMR are reported as
in parts per
million downfield from SiMe4 0.0) and relative to the signal of
chloroform-d ( 77.0, triplet). Mass spectra (m/z) were recorded on
of parts per million (ppm) downfield from SiMe4 (
d
to the signal of chloroform-d (
d
d
(d
d
a ‘Waters’-LCT for Electrospray (ES). Infrared spectra were recorded
on a PerkineElmer 1600 FT-IR as thin film from a solution in
dichloromethane or chloroform. Specific rotations were performed
at room temperature on an Optical Activity Ltd. AA-10 automatic
polarimeter at 589 nm (Na D-line) at 20 ꢀC and [
a]D values are given
3.2.3. (Z)-Ethyl 3-phenyl-3-(4-methylphenylamino)acrylate 2c.12
in 10ꢁ1 deg cm2 gꢁ1. Melting points were measured on a Gallen-
kamp apparatus and are uncorrected. Elemental analysis was per-
formed on a PerkineElmer 2400 CHNS/O Series II apparatus.
Enantioselectivities were determined by high performance liquid
chromatography (HPLC) analysis employing a Gilson HPLC chain
with an ABI Analytical Spectroflow 783 UV detector at
l 254 nm
unless specified otherwise, using a mixture of hexane and ipa
(propan-2-ol) as the mobile phase and Chiralcel OD-H, Chiralcel OJ,
Obtained by general procedure A using 1.2 equiv amine, and
purified using 100% petroleum ether eluent, followed by re-
crystallization from petroleum ether as a white solid (1.51 g, 53%
yield); mp 72e74 ꢀC (not reported in literature); Rf (20% EtOAc/
petroleum ether) 0.60; dH (400 MHz, CDCl3) 1.34 (t, 3H, J 7.1,
CH3CH2), 2.23 (s, 3H, CH3), 4.23 (q, 2H, J 7.1, CH2), 4.98 (s, 1H, CH),
6.59 (d, 2H, J 7.6, 2ꢂArCH), 6.90 (d, 2H, J 7.6, 2ꢂArCH), 7.28e7.38 (m,
5H, 5ꢂArCH), 10.28 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.6 (CH3),
20.7 (CH3), 59.2 (OCH2), 90.4 (C]CH), 122.4 (2ꢂArCH), 128.3
(2ꢂArCH), 128.4 (2ꢂArCH), 129.2 (2ꢂArCH), 129.3 (ArCH), 132.6
(ArC), 136.2 (ArC), 137.8 (ArC), 159.4 (C]CH), 170.2 (CO). Data were
in accordance with the literature.
Kromasil 3-Cellucoat OD, Phenomenex Lux 3
mm Amylase-2 or
Phenomenex Lux 3 m Cellulose-1 column as the stationary phase.
m
Mobile phase flow, unless specified otherwise, was 1.0 mL/min.
Absolute configuration of the products was determined by com-
parison with compounds previously published. Catalyst 1 was
prepared by established literature methods.9
3.2. General procedure A for the preparation of
esters
b-enamino
A mixture of
b-ketoester (10 mmol), amine (1.1e1.5 equiv,
specified for each compound) and p-TsOH (0.1 mmol) in ethanol
(25 mL) was heated at reflux for overnight. The mixture was then
cooled to room temperature and the solvent was evaporated under
reduced pressure. The residue was purified by chromatography on
3.2.4. (Z)-Ethyl 3-(4-fluorophenylamino)-3-phenylacrylate 2d.13
silica gel with eluents as noted to give the b-enamino ester.
3.2.1. (Z)-Ethyl 3-(4-methoxyphenylamino)-3-phenylacrylate 2a.4b
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5%/25% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from diethyl ether/petroleum
ether as a white solid (1.67 g, 59% yield); mp 75e77 ꢀC (not
reported in literature); Rf (25% diethyl ether/petroleum ether) 0.70;
dH (400 MHz, CDCl3) 1.34 (t, 3H, J 7.1, CH3CH2), 4.23 (q, 2H, J 7.1, CH2),
5.02 (s, 1H, CH), 6.64e6.68 (m, 2H, 2ꢂArCH), 6.78e6.82 (m, 2H,
2ꢂArCH), 7.28e7.38 (m, 5H, 5ꢂArCH), 10.26 (br s, 1H, NH); dC
(100 MHz, CDCl3) 14.5 (CH3), 59.3 (CH2), 91.0 (C]CH), 115.3 (d, JCeF
22.7, 2ꢂArCH), 124.0 (d, JCeF 7.9, 2ꢂArCH), 128.3 (2ꢂArCH), 128.5
(2ꢂArCH),129.5 (ArCH),135.7 (ArC),136.5 (ArC),159.0 (d, JCeF 242.8,
ArCF), 159.3 (C]CH), 170.2 (CO); dF (235 MHz, CDCl3) ꢁ119.9. Data
were in accordance with the literature, although 19F NMR not
reported, or JCeF values and multiplicities in 13C NMR data.
Obtained by general procedure A using 1.0 equiv amine, and
purified using 5% EtOAc/petroleum ether eluent, followed by re-
crystallization from EtOAc/petroleum ether as a yellow solid
(1.80 g, 60%); mp 102e105 ꢀC (lit.4b 96e98 ꢀC); Rf (10% EtOAc/pe-
troleum ether) 0.60; dH (250 MHz, CDCl3) 1.33 (t, 3H, J 7.1, CH3CH2),
3.72 (s, 3H, OCH3), 4.22 (q, 2H, J 7.1, CH2), 4.95 (s, 1H, CHCO), 6.65
(app. s, 4H, 4ꢂArCH), 7.24e7.37 (m, 5H, 5ꢂArCH), 10.25 (br s, 1H,
NH); dC (63 MHz, CDCl3) 14.6 (CH3), 55.3 (OCH3), 59.2 (OCH2), 89.6
(C]CH), 113.9 (2ꢂArCH), 124.3 (2ꢂArCH), 128.3 (2ꢂArCH), 128.4

5526
S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
3.2.5. (Z)-Ethyl 3-phenyl-3-(2-methylphenylamino)acrylate 2e.14
3.2.8. (Z)-Ethyl 3-(methylamino)-3-phenylacrylate 2h.15
Obtained by general procedure A using methanaminium acetate
(2.0 equiv), and purified using a 3%/20% EtOAc/petroleum ether
gradient eluent as light yellow oil (1.22 g, 55%); Rf (50% EtOAc/pe-
troleum ether) 0.50; nmax (thin film, cmꢁ1) 3296, 2978, 1650, 1613,
1595, 1574; dH (400 MHz, CDCl3) 1.30 (t, 3H, J 7.1, CH3CH2), 2.79 (d,
3H, J 5.2, NCH3), 4.16 (q, 2H, J 7.1, CH2), 4.62 (s, 1H, CH), 7.28e7.43
(m, 5H, 5ꢂArCH), 8.52 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.6
(CH3), 31.4 (CH3N), 58.6 (CH2), 84.8 (C]CH), 127.8 (2ꢂArCH), 128.3
(2ꢂArCH),129.1 (ArCH),135.9 (ArC),165.6 (C]CH),170.6 (C]O); m/
z (TOF ESþ) 206.1172 (MHþ, C12H16NO2 requires 206.1181). Only bp,
nmax and signal of dH 4.61 ppm are reported in the literature.
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5%/20% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from diethyl ether/petroleum
ether as a light yellow solid (1.16 g, 41%); mp 103e105 ꢀC (not
reported in literature); Rf (25% diethyl ether/petroleum ether) 0.70;
dH (400 MHz, CDCl3) 1.35 (t, 3H, J 7.1, CH3CH2), 2.45 (s, 3H, CH3), 4.24
(q, 2H, J 7.1, OCH2), 5.06 (s, 1H, CH), 6.35 (d, 1H, J 7.8, ArCH), 6.83 (td,
1H, J 7.8, 1.2, ArCH), 6.88 (td, 1H, J 7.4, 1.0, ArCH), 7.16 (d, 1H, J 7.4,
ArCH), 7.26e7.35 (m, 5H, 5ꢂArCH), 10.17 (br s, 1H, NH); dC
(100 MHz, CDCl3) 14.6 (CH3CH2), 18.2 (CH3C), 59.3 (CH2), 90.8 (C]
CH), 123.5 (ArCH), 123.9 (ArCH), 125.8 (ArCH), 128.1 (2ꢂArCH),
128.3 (2ꢂArCH), 129.4 (ArCH), 130.2 (ArC), 130.4 (ArCH), 136.2
(ArC), 139.0 (ArC), 159.8 (C]CH), 170.3 (CO). Data were in accor-
dance with the literature, although 13C NMR signals below 128 ppm
have been omitted.
3.2.9. (Z)-Ethyl 3-(4-methoxyphenylamino)-3-(4-methylphenyl)ac-
rylate 2i.
3.2.6. (Z)-Ethyl 3-(2-methoxyphenylamino)-3-phenylacrylate 2f.14
Obtained by general procedure A using 1.06 equiv amine, and
purified using a 10%/20% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from diethyl ether/petroleum
ether as yellow crystals (1.27 g, 41% yield); mp 78e80 ꢀ. Found C
73.24, H 6.62, N 4.43; C19H21NO3 requires C 73.29, H 6.80, N 4.50; Rf
Obtained by general procedure A using 1.2 equiv amine, and
purified using a 5% EtOAc/petroleum ether eluent, followed by re-
crystallization from petroleum ether as yellow crystals (1.21 g,
40%); mp 90e91 ꢀC (lit.14 105 ꢀC); Rf (20% EtOAc/petroleum ether)
0.60; dH (400 MHz, CDCl3) 1.34 (t, 3H, J 7.1, CH3CH2), 3.93 (s, 3H,
OCH3), 4.24 (q, 2H, J 7.1, CH2), 5.02 (s, 1H, CH), 6.25 (dd, 1H, J 7.5, 1.0,
ArCH), 6.52e6.56 (m, 1H, ArCH), 6.84e6.91 (m, 2H, 2ꢂArCH),
7.28e7.40 (m, 5H, 5ꢂArCH), 10.29 (br s, 1H, NH); dC (100 MHz,
CDCl3) 14.6 (CH3CH2), 55.7 (OCH3), 59.3 (CH2), 91.6 (C]CH), 110.5
(ArCH), 120.0 (ArCH), 121.8 (ArCH), 122.9 (ArCH), 128.0 (2ꢂArCH),
128.4 (2ꢂArCH), 129.4 (ArCH), 129.6 (ArC), 136.4 (ArC), 150.5 (ArC),
158.4 (C]CH), 169.9 (CO). Data were in accordance with the
literature.
(25% diethyl ether/petroleum ether) 0.50; nmax (thin film, cmꢁ1
)
3251, 2978, 1653, 1615, 1513; dH (400 MHz, CDCl3) 1.34 (t, 3H, J 7.1,
CH3CH2), 2.34 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.22 (q, 2H, J 7.1, CH2),
4.94 (s, 1H, CH), 6.65e6.69 (m, 4H, 4ꢂArCH), 7.09 (d, 2H, J 8.0,
2ꢂArCH), 7.23 (d, 2H, J 8.0, 2ꢂArCH), 10.23 (br s, 1H, NH); dC
(100 MHz, CDCl3) 14.6 (CH3), 21.3 (CH3), 55.3 (OCH3), 59.1 (CH2),
89.3 (C]CH), 113.9 (2ꢂArCH), 124.2 (2ꢂArCH), 128.3 (2ꢂArCH),
129.0 (2ꢂArCH), 133.1 (ArC), 133.7 (ArC), 139.3 (ArC), 155.8 (ArC),
160.0 (C]CH), 170.4 (CO); m/z (TOF ESþ) 312 (100, MHþ), 266 (10).
3.2.10. (Z)-Ethyl 3-(4-methoxyphenyl)-3-(4-methoxyphenylamino)
acrylate 2j.4a
3.2.7. (Z)-Ethyl 3-(benzylamino)-3-phenylacrylate 2g.8
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5%/10% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from petroleum ether/diethyl
ether as a white solid (1.17 g, 42% yield); mp 71e72 ꢀC (lit.8
66e67 ꢀC); dH (400 MHz, CDCl3) 1.33 (t, 3H, J 7.1, CH3CH2), 4.21 (q,
2H, J 7.1, OCH2), 4.32 (d, 2H, J 6.5, NCH2), 4.75 (s, 1H, CH), 7.22e7.44
(m, 10H, 10ꢂArCH), 9.00 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.7
(CH3), 48.4 (NCH2), 58.8 (OCH2), 86.6 (C]CH), 126.9 (2ꢂArCH),
127.3 (ArCH), 127.9 (2ꢂArCH), 128.5 (2ꢂArCH), 128.7 (2ꢂArCH),
129.3 (ArCH), 136.1 (ArC), 139.4 (ArC), 164.7 (C]CH), 170.4 (CO).
Data were in general accordance with the literature, although no
signals above 140 ppm were reported in the 13C NMR data.
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 10%/20% diethyl ether/petroleum ether gradient
eluent as a brown, sticky oil (1.63 g, 50% yield); Rf (20% diethyl
ether/petroleum ether) 0.40; dH (400 MHz, CDCl3) 1.33 (t, 3H, J 7.1,
CH3CH2), 3.74 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.20 (q, 2H, J 7.1,
OCH2), 4.93 (s, 1H, CH), 6.65e6.69 (m, 4H, 4ꢂArCH), 6.80 [(AX)2, 2H,
2ꢂArCH], 7.26 [(AX)2, 2H, 2ꢂArCH], 10.21 (br s, 1H, NH); dC
(100 MHz, CDCl3) 14.6 (CH3), 55.2 (OCH3), 55.3 (OCH3), 59.1 (CH2),
88.9 (C]CH), 113.7 (2ꢂArCH), 113.9 (2ꢂArCH), 124.3 (2ꢂArCH),
128.2 (ArC), 129.8 (2ꢂArCH), 133.8 (ArC), 155.7 (ArC), 159.7 (ArC),
160.4 (C]CH), 170.4 (CO). Data were in accordance with the liter-
ature, although a solid is reported rather than an oil.

S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
5527
3.2.11. (Z)-Ethyl
3-(4-methoxyphenylamino)-3-(2-thienyl)acrylate
CDCl3) 14.6 (CH3), 19.5 (CH3), 55.3 (OCH3), 59.1 (CH2), 88.1 (C]CH),
113.9 (2ꢂArCH), 122.9 (2ꢂArCH), 125.8 (ArCH), 129.0 (ArCH), 130.3
(2ꢂArCH), 133.1 (ArC), 135.5 (ArC), 135.9 (ArC), 155.8 (ArC), 160.2
(C]CH), 170.5 (CO). Data were in accordance with the literature.
2k.4b
3.2.14. (Z)-Ethyl 3-(4-methoxyphenylamino)-4-phenylbut-2-enoate
2n.
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5%/20% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from petroleum ether as yel-
low crystals (1.36 g, 45% yield); mp 54e56 ꢀC (lit.4b 52e53 ꢀC); Rf
(20% EtOAc/petroleum ether) 0.70; dH (400 MHz, CDCl3) 1.34 (t, 3H,
J 7.1, CH3CH2), 3.77 (s, 3H, OCH3), 4.22 (q, 2H, J 7.1, CH3O), 5.15 (s, 1H,
CH), 6.73 [(AX)2, 2H, 2ꢂArCH], 6.83 [(AX)2, 2H, 2ꢂArCH], 6.92 (dd,
1H, J 5.0, 3.7, ArCH), 7.01 (dd, 1H, J 3.7, 1.2, ArCH), 7.30 (dd, 1H, J 5.0,
1.2, ArCH), 10.05 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.6 (CH3), 55.4
(OCH3), 59.3 (OCH2), 89.5 (CH), 114.0 (2ꢂArCH), 125.3 (2ꢂArCH),
127.1 (ArCH), 127.6 (ArCH), 129.0 (ArCH), 133.5 (ArC), 137.6 (ArC),
153.0 (ArC),156.5 (C]CH),170.1 (CO). Data were in accordance with
the literature.
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5%/10% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from diethyl ether/petroleum
ether as white needle-like crystals (1.17 g, 56% yield), mp 70e72 ꢀC.
Found C 73.52, H 6.78, N 4.47; C19H21NO3 requires C 73.29, H 6.80, N
4.50; Rf (25% diethyl ether/petroleum ether) 0.40; nmax (thin film,
cmꢁ1) 3028, 2977, 1651, 1613, 1514; dH (400 MHz, CDCl3) 1.30 (t, 3H,
J 7.1, CH3CH2), 3.52 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 4.16 (q, 2H, J 7.1,
OCH2), 4.62 (s, 1H, CH), 6.81 [(AX)2, 2H, 2ꢂArCH], 6.96 [(AX)2, 2H,
2ꢂArCH], 7.03e7.06 (m, 2H, 2ꢂArCH), 7.18e7.26 (m, 3H, 3ꢂArCH),
10.15 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.6 (CH3), 38.7 (CH2), 55.4
(OCH3), 58.8 (OCH2), 86.1 (C]CH), 114.1 (2ꢂArCH), 126.6 (ArCH),
127.8 (2ꢂArCH), 128.4 (2ꢂArCH), 128.9 (2ꢂArCH), 131.8 (ArC), 137.0
(ArC), 157.8 (ArC), 162.4 (C]CH), 170.7 (CO); m/z (TOF ESþ) 312.1610
(MHþ, C19H22NO3 requires 312.1600).
3.2.12. (Z)-Ethyl 3-(4-methoxyphenylamino)-3-(4-nitrophenyl)acry-
late 2l.
3.2.15. (Z)-Ethyl 3-(4-methoxyphenylamino)but-2-enoate 2o.16
Obtained by general procedure A using 1.5 equiv amine, and
purified by slow cooling of the reaction mixture, filtration and
washing with diethyl ether as yellow needle-like crystals (2.80 g,
82% yield); mp 126e128 ꢀC. Found C 63.29, H 5.26, N 8.17;
C18H18N2O5 requires C 63.15, H 5.30, N 8.18; nmax (thin film, cmꢁ1
)
3258, 2979, 1658, 1615, 1591, 1514; dH (400 MHz, CDCl3) 1.35 (t, 3H, J
7.1, CH3CH2), 3.73 (s, 3H, OCH3), 4.24 (q, 2H, J 7.1, CH2), 5.00 (s, 1H,
CH), 6.64e6.69 (m, 4H, 4ꢂArCH), 7.51 (d, 2H, J 7.5, 2ꢂArCH), 8.14 (d,
2H, J 7.5, 2ꢂArCH), 10.17 (br s, 1H, NH); dC (100 MHz, CDCl3) 14.5
(CH3), 55.3 (OCH3), 59.6 (CH2), 91.3 (C]CH), 114.2 (2ꢂArCH), 123.6
(2ꢂArCH), 124.8 (2ꢂArCH), 129.3 (2ꢂArCH), 132.7 (ArC), 142.7
(ArC), 148.0 (ArC), 156.4 (ArC), 157.2 (C]CH), 169.8 (CO); m/z (TOF
ESþ) 343.1290 (MHþ, C18H19N2O5 requires 343.1294).
Obtained by general procedure A using 1.5 equiv amine and
heating at reflux for 3 h, and purified using a 20% diethyl ether/
petroleum ether eluent, followed by recrystallization from petro-
leum ether as white needle-like crystals (1.55 g, 66% yield), mp
42e44 ꢀC (lit.17 44.5e45.5 ꢀC); Rf (25% diethyl ether/petroleum
ether) 0.30; dH (400 MHz, CDCl3) 1.31 (t, 3H, J 7.2, CH3 CH2), 1.91 (s,
3H, CH3), 3.83 (s, 3H, OCH3), 4.17 (q, 2H, J 7.2, CH2), 4.67 (s, 1H, CH),
6.69 [(AX)2, 2H, 2ꢂArCH], 7.05 [(AX)2, 2H, 2ꢂArCH], 10.17 (br s, 1H,
NH); dC (100 MHz, CDCl3) 14.6 (CH3), 20.1 (CH3), 55.4 (OCH3), 58.6
(CH2), 84.7 (C]CH), 114.2 (2ꢂArCH), 126.8 (2ꢂArCH), 132.1 (ArC),
157.5 (ArC), 160.0 (C]CH), 170.5 (CO). Data were in accordance with
the literature.
3.2.13. (Z)-Ethyl 3-(4-methoxyphenylamino)-3(2-methylphenyl)ac-
rylate 2m.4b
3.2.16. (Z)-Ethyl 3-(4-methoxyphenylamino)-4-methylpent-2-enoate
2p.4b
Obtained by general procedure A using 2.0 equiv amine, and
purified using a 5%/20% diethyl ether/petroleum ether gradient
eluent, followed by recrystallization from diethyl ether/petroleum
ether as a white solid (0.43 g, 11%); mp 58e61 ꢀC (lit.4b 51e53 ꢀC);
Rf (20% EtOAc/petroleum ether) 0.40; dH (400 MHz, CDCl3) 1.34 (t,
3H, J 7.1, CH3CH2), 2.13 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 4.22 (q, 2H, J
7.1, CH2CH3), 4.72 (s, 1H, CH), 6.57e6.62 (m, 4H, 4ꢂArCH), 7.08 (d,
1H, J 7.4, ArCH), 7.18e7.23 (m, 1H, ArCH), 7.24e7.27 (m, 1H, ArCH),
7.32 (dd, 1H, J 7.4, 1.5, ArCH), 10.51 (br s, 1H, NH); dC (100 MHz,
Obtained by general procedure A using 1.5 equiv amine, and
purified using a 5% diethyl ether/petroleum ether eluent to remove
excess amine. The resulting mixture was distilled under reduced
pressure to remove excess volatiles, and the residue solidified on

5528
S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
standing to provide product as a white solid (1.10 g, 42% yield); mp
37e39 ꢀC (lit.4b 36e38 ꢀC); dH (400 MHz, CDCl3) 1.08 [d, 6H, J 6.8,
CH(CH3)2], 1.32 (t, 3H, J 7.1, CH3), 2.73 (hept, 1H, J 6.8, CH), 3.83 (s,
3H, CH3), 4.17 (q, 2H, J 7.1, CH2), 4.73 (s, 1H, CH]C), 6.89 [(AX)2, 2H,
2ꢂArCH], 7.05 [(AX)2, 2H, 2ꢂArCH], 10.19 (br s, 1H, NH); dC
(100 MHz, CDCl3) 14.6 (CH3), 22.0 (2ꢂCH3), 28.4 (CH), 55.4 (OCH3),
58.7 (CH2), 80.3 (C]CH), 114.3 (2ꢂArCH), 127.8 (2ꢂArCH), 131.8
(ArC),157.7 (ArC),171.1 (C]CH),171.3 (CO). Data were in accordance
with the literature.
1.0, CHCl3) 85% ee; lit.16
[
a
]
ꢁ1.3 (c 1.0, CHCl3) 92.3% ee; Rf (25%
D
diethyl ether/petroleum ether) 0.40; dH (400 MHz, CDCl3) 1.22 (t,
3H, J 7.2, CH3CH2), 2.81 (dd, 1H, J 14.8, 6.8, CHH), 2.85 (dd, 1H, J
14.8, 6.8, CHH), 4.07e4.19 (m, 2H, OCH2), 4.65 (br s, 1H, NH), 4.86
(t, 1H, J 6.8, NCH), 6.59 (d, 2H, J 7.8, 2ꢂArCH), 6.69 (t, 1H, J 7.4,
ArCH), 7.12 (t, 2H, J 7.4, 2ꢂArCH), 7.23e7.29 (m, 1H, ArCH),
7.33e7.37 (m, 2H, 2ꢂArCH), 7.40e7.42 (m, 2H, 2ꢂArCH); dC
(100 MHz, CDCl3) 14.2 (CH3), 42.9 (CH2), 55.0 (NCH), 60.8 (OCH2),
113.7 (2ꢂArCH), 117.8 (ArCH), 126.3 (2ꢂArCH), 127.5 (ArCH), 128.8
(2ꢂArCH), 129.2 (2ꢂArCH), 142.2 (ArC), 146.8 (ArC), 171.1 (CO).
Enantiomeric excess was determined by chiral phase HPLC (Phe-
3.3. General procedure B for the reduction of
esters
b-enamino
nomenex Lux 3 m ,
m Cellulose-1) 5% ipa in hexane@1 mL minꢁ1
tR¼12.2 min (major), 12.8 min (minor). Data were in accordance
b-Ketoester (0.5 mmol), catalyst 1 (0.1 mmol), benzoic acid
with the literature.
(0.05 mmol) and dry dichloromethane (1 mL) were added into
a 20 mL Schlenk tube. The mixture was stirred until complete
dissolution, then cooled to 0 ꢀC and trichlorosilane (0.2 mmol) was
added by syringe. The resulting mixture was left to stir for 10 h at
0 ꢀC. The reaction mixture was diluted with CH2Cl2 (20 mL),
quenched with water (2 mL) and followed by addition of aqueous
sodium hydroxide (1 M, 20 mL). This mixture was stirred until the
precipitate was completely dissolved and no gas was evolved. The
organic phase was separated and the aqueous phase was extracted
with CH2Cl2 (2ꢂ20 mL). The combined organic phases were
washed with brine (20 mL) and dried over MgSO4. Filtration and
concentration gave the crude product, which was purified by
chromatography on silica gel using a 2e20% solution of diethyl
ether in petroleum ether.
3.3.3. (S)-Ethyl 3-phenyl-3-(4-methylphenylamino)propanoate 3c.
Obtained by general procedure B as a white solid (98 mg, 69%
yield, 87% ee); mp 58e60 ꢀC; [
a
]
ꢁ5.7 (c 0.7, CHCl3) 87% ee.
D
Found C 76.09, H 7.38, N 4.72; C18H21NO2 requires C 76.29, H 7.47,
N 4.94; Rf (25% diethyl ether/petroleum ether) 0.40; nmax (thin
film, cmꢁ1) 3392, 2981, 1728, 1618, 1520; dH (400 MHz, CDCl3)
1.22 (t, 3H, J 7.2, CH3CH2), 2.22 (s, 3H, CH3), 2.80 (dd, 1H, J 14.7,
7.0, CHH), 2.84 (dd, 1H, J 14.7, 7.0, CHH), 4.08e4.19 (m, 2H, OCH2),
4.48 (br s, 1H, NH), 4.83 (t, 1H, J 7.0, NCH), 6.52 (d, 2H, J 7.5,
2ꢂArCH), 6.95 (d, 2H, J 7.5, 2ꢂArCH), 7.25e7.29 (m, 1H, ArCH),
7.33e7.37 (m, 2H, 2ꢂArCH), 7.40e7.42 (m, 2H, 2ꢂArCH); dC
(100 MHz, CDCl3) 14.2 (CH3), 20.4 (CH3), 43.0 (CH2), 55.3 (NCH),
60.8 (OCH2), 113.9 (2ꢂArCH), 126.3 (2ꢂArCH), 127.0 (ArCH), 127.4
(ArC), 128.8 (2ꢂArCH), 129.7 (2ꢂArCH), 142.5 (ArC), 144.6 (ArC),
171.2 (CO); m/z (TOF ESþ) 284 (MHþ, 100). Enantiomeric excess
3.3.1. (S)-Ethyl 3-(4-methoxyphenylamino)-3-phenylpropanoate
3a.4b
was determined by chiral phase HPLC (Phenomenex Lux 3 mm
Cellulose-1) 5% ipa in hexane@1 mL minꢁ1, tR¼9.5 min (minor),
11.7 min (major).
Obtained by general procedure B as a white solid (114 mg, 76%
yield, 91% ee); mp 68e70 ꢀC (lit.4b 51e53 ꢀC); [
a
]
ꢁ5.7 (c 0.7,
D
CHCl3) 91% ee; lit.4b
[a
]
ꢁ5.6 (c 1.0, in CHCl3) 92.3% ee; Rf (25%
3.3.4. (S)-Ethyl 3-phenyl-3-(4-fluorophenylamino)propanoate 3d.
D
diethyl ether/petroleum ether) 0.30; dH (400 MHz, CDCl3) 1.22 (t,
3H, J 7.1, CH3CH2), 2.75e2.85 (m, 2H, CH2), 3.72 (s, 3H, OCH3),
4.09e4.16 (m, 2H, OCH2), 4.33 (br s, 1H, NH), 4.77 (t, 1H, J 6.7, NCH),
6.55 [(AX)2, 2H, 2ꢂArCH], 6.72 [(AX)2, 2H, 2ꢂArCH], 7.24e7.28 (m,
1H, ArCH), 7.32e7.40 (m, 4H, 4ꢂArCH); dC (100 MHz, CDCl3) 14.2
(CH3), 43.0 (CH2), 55.7 (NCH), 56.0 (OCH3), 60.8 (OCH2), 114.8
(2ꢂArCH), 115.2 (2ꢂArCH), 126.3 (2ꢂArCH), 127.4 (ArCH), 128.7
(2ꢂArCH), 141.0 (ArC), 142.5 (ArC), 152.3 (ArC), 171.3 (CO). Enan-
tiomeric excess was determined by chiral phase HPLC (Phenom-
Obtained by general procedure B as a white solid (84 mg, 59%
yield, 71% ee); mp 50e52 ꢀC; [
a
]
D þ10 (c 1.2, CHCl3) 71% ee. Found C
70.75, H 6.29, N 4.77; C17H18FNO2 requires C 71.06, H 6.31, N 4.87; Rf
(25% diethyl ether/petroleum ether) 0.50; nmax (thin film, cmꢁ1
enex Lux
3 mm ,
Cellulose-1) 5% ipa in hexane@1 mL minꢁ1
)
tR¼13.3 min (minor), 17.7 min (major). Data were in accordance
3393, 2982, 1727, 1510; dH (400 MHz, CDCl3) 1.22 (t, 3H, J 7.2,
CH3CH2), 2.78 (dd, 1H, J 14.8, 7.9, CHH), 2.83 (dd, 1H, J 14.8, 5.5,
CHH), 4.10e4.17 (m, 2H, CH2), 4.51 (br s, 1H, NH), 4.75e4.79 (m, 1H,
NCH), 6.49e6.52 (m, 2H, 2ꢂArCH), 6.80e6.84 (m, 2H, 2ꢂArCH),
7.25e7.39 (m, 5H, 5ꢂArCH); dC (100 MHz, CDCl3) 14.1 (CH3), 42.9
(CH2), 55.7 (NCH), 60.8 (OCH2), 114.6 (d, JCeF 7.5, 2ꢂArCH), 115.6 (d,
JCeF 22.3, 2ꢂArCH), 126.3 (2ꢂArCH), 127.5 (ArCH), 128.8 (2ꢂArCH),
142.1 (ArC), 143.2 (ArC), 156.0 (d, JCeF 235.4, ArCF), 171.2 (CO); dF
(235 MHz, CDCl3) ꢁ127.6; m/z (TOF ESþ) 288.1393 (MHþ,
C17H19FNO2 requires 288.1400). Enantiomeric excess was de-
with the literature.
3.3.2. (S)-Ethyl 3-phenyl-3-(phenylamino)propanoate 3b.16
termined by chiral phase HPLC (Phenomenex Lux 3
5% ipa in hexane@1 mL minꢁ1
tR¼9.4 min (minor), 11.7 min
(major).
mm Cellulose-1)
Obtained by general procedure B as a white solid (86 mg, 64%
,
yield, 85% ee); mp 74e76 ꢀC (no literature mp reported); [
a]D 0 (c

S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
5529
3.3.5. (S)-Ethyl 3-(2-methylphenylamino)-3-phenylpropanoate 3e.
assumed to be 1, CHCl3) for R isomer; Rf (20% diethyl ether/pe-
troleum ether) 0.20; dH (400 MHz, CDCl3) 1.21 (t, 3H, J 7.1,
CH3CH2), 2.12 (br s, 1H, NH), 2.64 (dd, 1H, J 15.5, 5.2, CHH), 2.74
(dd, 1H, J 15.5, 8.8, CHH), 3.57 (d, 1H, J 13.2, NCHH), 3.67 (d, 1H, J
13.2, NCHH), 4.09e4.15 (m, 3H, NCH and OCH2), 7.23e7.40 (m,
10H, 10ꢂArCH); dC (100 MHz, CDCl3) 14.2 (CH3), 43.2 (CH2), 51.4
(NCH2), 58.9 (NCH), 60.5 (OCH2), 126.9 (ArCH), 127.2 (2ꢂArCH),
127.5 (ArCH), 128.3 (2ꢂArCH), 128.4 (2ꢂArCH), 128.6 (2ꢂArCH),
140.3 (ArC), 142.6 (ArC), 171.8 (CO). Enantiomeric excess was
Obtained by general procedure B as a colourless oil (75 mg, 53%
determined by chiral phase HPLC (Phenomenex Lux
3 mm
Cellulose-1) 5% ipa in hexane@1 mL minꢁ1 at
l
210 nm,
yield, 86% ee); [
a
]
þ25.3 (c 1.5, CHCl3) 73% ee. Found C 76.35, H
D
7.83, N 4.94; C18H23NO2 requires C 76.29, H 7.47, N 4.94; Rf (15%
diethyl ether/petroleum ether) 0.60; nmax (thin film, cmꢁ1) 3419,
2980, 1728, 1606, 1588; dH (400 MHz, CDCl3) 1.23 (t, 3H, J 7.1,
CH3CH2), 2.28 (s, 3H, CH3), 2.84 (dd, 1H, J 14.5, 7.7, CHH), 2.89 (dd,
1H, J 14.5, 5.5, CHH), 4.11e4.17 (m, 2H, OCH2), 4.65 (br s, 1H, NH),
4.88 (dd, 1H, J 7.7, 5.5, NCH), 6.41 (d,1H, J 8.0, ArCH), 6.65 (t,1H, J 7.3,
ArCH), 6.99 (t,1H, J 8.0, ArCH), 7.08 (d,1H, J 7.3, ArCH), 7.25e7.29 (m,
1H, ArCH), 7.33e7.42 (m, 4H, 4ꢂArCH); dC (100 MHz, CDCl3) 14.2
(CH3), 17.6 (CH3), 43.2 (CH2), 55.0 (NCH), 60.9 (OCH2), 111.2 (ArCH),
117.3 (ArCH), 122.3 (ArC), 126.2 (2ꢂArCH), 127.0 (ArCH), 127.4
(ArCH), 128.8 (2ꢂArCH), 130.1 (ArCH), 142.3 (ArC), 144.8 (ArC), 171.3
(CO); m/z (TOF ESþ) 284.1644 (MHþ, C18H22NO2 requires 284.1651).
Enantiomeric excess was determined by chiral phase HPLC (Phe-
tR¼6.8 min (minor), 9.6 min (major). NMR data have only been
previously reported in acetone-d6.
3.3.8. (S)-Ethyl 3-(methylamino)-3-phenylpropanoate 3h.
Obtained by general procedure B, except purified using
a 20%/100% diethyl ether/petroleum ether gradient eluent, as
nomenex Lux 3
tR¼10.1 min (major), 13.8 min (minor).
m ,
m Cellulose-1) 5% ipa in hexane@1 mL minꢁ1
a colourless oil (61 mg, 59% yield, 94% ee); [
a
]
ꢁ25 (c 1.3,
D
CHCl3) 94% ee; Rf (diethyl ether) 0.10; nmax (thin film, cmꢁ1
)
3345, 2978, 1731, 1453; dH (400 MHz, CDCl3) 1.22 (t, 3H, J 7.1,
CH3CH2), 1.70 (br s, 1H, NH), 2.29 (s, 3H, NCH3), 2.63 (dd, 1H, J
15.5, 5.4, CHH), 2.73 (dd, 1H, J 15.5, 8.5, CHH), 3.98 (dd, 1H, J 8.5,
5.4, NCH), 4.12 (q, 2H, J 7.1, OCH2), 7.28e7.36 (m, 5H, 5ꢂArCH); dC
(100 MHz, CDCl3) 14.1 (CH3CH2), 34.4 (CH3), 42.8 (CH2), 60.5
(OCH2), 61.5 (NCH), 127.1 (2ꢂArCH), 127.4 (ArCH), 128.5
(2ꢂArCH), 142.4 (ArC), 171.9 (CO); m/z (TOF ESþ) 208.1345 (MHþ,
C12H18NO2 requires 208.1338). Enantiomeric excess was de-
termined by comparison of the integrals in the 1H NMR spec-
trum in CDCl3 of the diastereomeric salts formed by addition of
3.3.6. (S)-Ethyl 3-(2-methoxyphenylamino)-3-phenylpropanoate
3f.18
Obtained by general procedure B as a colourless oil (61 mg, 41%
excess L-mandelic acid. Compound reported in the literature, but
with no NMR data.
yield, 13% ee); [
a]
D þ3.0 (c 2.3, CHCl3) 13% ee; lit.18
[
a
]
D ꢁ19 (c 1.2,
CHCl3) 83% ee for R isomer; Rf (20% diethyl ether/petroleum ether)
0.60; dH (400 MHz, CDCl3) 1.22 (t, 3H, J 7.2, CH3CH2), 2.83 (dd, 1H, J
14.6, 6.7, CHH), 2.88 (dd, 1H, J 14.6, 6.7, CHH), 3.90 (s, 3H, OCH3),
4.07e4.19 (m, 2H, OCH2), 4.87 (q, 1H, J 6.7, NCH), 5.10 (d, 1H, J 6.7,
NH), 6.45 (d, 1H, J 7.7, ArCH), 6.65 (td, 1H, J 7.7, 1.5, ArCH), 6.74 (td,
1H, J 7.7, 1.4, ArCH), 6.79 (dd, 1H, J 7.8, 1.2, ArCH), 7.24e7.28 (m, 1H,
ArCH), 7.73e7.36 (m, 2H, 2ꢂArCH), 7.40e7.42 (m, 2H, 2ꢂArCH); dC
(100 MHz, CDCl3) 14.1 (CH3), 43.3 (CH2), 54.9 (NCH), 55.5 (OCH3),
60.7 (OCH2), 109.5 (ArCH), 111.2 (ArCH), 116.9 (ArCH), 121.2 (ArCH),
126.3 (2ꢂArCH), 127.4 (ArCH), 128.7 (2ꢂArCH), 136.8 (ArC), 142.5
(ArC), 146.9 (ArC), 171.0 (CO). Enantiomeric excess was determined
3.3.9. (S)-Ethyl 3-(4-methoxyphenylamino)-3-(4-methylphenyl)prop-
anoate 3i.
Obtained by general procedure B as a colourless oil (118 mg,
by chiral phase HPLC (Phenomenex Lux 3 mm Cellulose-1) 5% ipa in
75%, yield, 92% ee); [
a
]
ꢁ19.4 (c 0.62 in CHCl3) 92% ee. Found C
D
hexane@1 mL minꢁ1, tR¼15.3 min (minor), 19.3 min (major). Data
72.94, H 7.75, N 4.43; C19H23NO3 requires C 72.82, H 7.40, N
4.47; Rf (20% diethyl ether/petroleum ether) 0.30; nmax (thin
film, cmꢁ1) 3386, 2983, 1731, 1513, 1239; dH (400 MHz, CDCl3)
1.22 (t, 3H, J 7.1, CH3CH2), 2.23 (s, 3H, CH3), 2.78 (d, 2H, J 6.8,
CH2), 3.72 (s, 3H, OCH3), 4.07e4.18 (m, 2H, OCH2), 4.28 (br s, 1H,
NH), 4.74 (t, 1H, J 6.8, NCH), 6.54 [(AX)2, 2H, 2ꢂArCH], 6.72
[(AX)2, 2H, 2ꢂArCH], 7.14 (d, 2H, J 7.8, 2ꢂArCH), 7.27 (d, 2H, J 7.8,
2ꢂArCH); dC (100 MHz, CDCl3) 14.2 (CH3), 21.1 (CH3), 43.0 (CH2),
were in accordance with the literature.
3.3.7. (S)-Ethyl 3-(benzylamino)-3-phenylpropanoate 3g.8
55.7 (NCH
&
CH3O), 60.7 (OCH2), 114.8 (2ꢂArCH), 115.2
(2ꢂArCH), 126.2 (2ꢂArCH), 129.4 (2ꢂArCH), 137.0 (ArC), 139.5
(ArC), 141.2 (ArC), 152.3 (ArC), 171.3 (CO); m/z (TOF ESþ)
314.1750 (MHþ, C19H24NO3 requires 314.1756). Enantiomeric
excess was determined by chiral phase HPLC (Phenomenex Lux
Obtained by general procedure B as a colourless oil (81 mg,
3
m
m Cellulose-1) 5% ipa in hexane@1 mL minꢁ1, tR¼11.6 min
57% yield, 93% ee); [
a
]
ꢁ41 (c 1.5, acetone) 93% ee; lit.8 þ34 (c
(minor), 12.8 min (major).
D

5530
S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
3.3.10. (S)-Ethyl 3-(4-methoxyphenylamino)-3-(4-methoxyphenyl)
115.2 (2ꢂArCH), 124.0 (2ꢂArCH), 127.4 (2ꢂArCH), 140.2 (ArC), 147.3
(ArC), 150.3 (ArC), 152.7 (ArC), 170.6 (CO); m/z (TOF ESþ) 345.1435
(MHþ, C18H21N2O5 requires 345.1450). Enantiomeric excess was
determined by chiral phase HPLC (Chiralpak IA) 10% ipa in
hexane@1 mL minꢁ1, tR¼27.9 min (minor), 30.5 min (major).
propanoate 3j.4b
3.3.13. (S)-Ethyl 3-(4-methoxyphenylamino)-3-(2-methylphenyl)prop-
anoate 3m.4b
Obtained by general procedure B as a colourless oil (115 mg, 70%
yield, 91% ee); [
a]
D ꢁ20 (c 1.0, CHCl3) 91% ee; lit.4b
[a
]
D ꢁ17.9 (c 1.0
in CHCl3) 88% ee; Rf (20% diethyl ether/petroleum ether) 0.20; dH
(400 MHz, CDCl3) 1.22 (t, 3H, J 7.1, CH3CH2), 2.74e2.83 (m, 2H, CH2),
3.72 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.09e4.17 (m, 2H, OCH2), 4.28
(br s, 1H, NH), 4.73 (t, 1H, J 6.8, NCH), 6.55 [(AX)2, 2H, 2ꢂArCH], 6.73
[(AX)2, 2H, 2ꢂArCH], 6.88 [(AX)2, 2H, 2ꢂArCH], 7.30 [(AX)2, 2H,
2ꢂArCH]; dC (100 MHz, CDCl3) 14.2 (CH3), 43.0 (CH2), 55.2 (NCH),
55.4 (OCH3), 55.7 (OCH3), 60.7 (OCH2), 114.1 (2ꢂArCH), 114.8
(2ꢂArCH), 115.2 (2ꢂArCH), 127.4 (2ꢂArCH), 134.5 (ArC), 141.1 (ArC),
152.3 (ArC), 158.8 (ArC), 171.3 (CO). Enantiomeric excess was de-
Obtained by general procedure B as a light yellow oil (42 mg, 27%
yield, 3% ee); [
a
]D 0(c1.0, CHCl3) 3% ee; lit.4b
[a]D þ1.4 (c1.0, CHCl3) 79%
ee; Rf (20% diethyl ether/petroleum ether) 0.40; dH (400 MHz, CDCl3)
1.23 (t, 3H, J 7.2, CH3CH2), 2.48 (s, 3H, CH3), 2.68 (dd, 1H, J 14.8, 8.4,
CHH), 2.77 (dd, 1H, J 14.8, 5.1, CHH), 3.72 (s, 3H, OCH3), 4.08e4.19 (m,
2H, OCH2), 4.27 (br, s,1H, NH), 4.96 (dd,1H, J 8.4, 5.1, NCH), 6.48 [(AX)2,
2H, 2ꢂArCH], 6.72 [(AX)2, 2H, 2ꢂArCH], 7.15e7.21 (m, 3H, 3ꢂArCH),
7.40e7.44 (m, 1H, ArCH); dC (100 MHz, CDCl3) 14.2 (CH3), 19.1 (CH3),
41.3 (CH2), 52.4 (NCH), 55.7 (OCH3), 60.8 (OCH2),114.8 (2ꢂArCH),114.9
(2ꢂArCH),125.2 (ArCH),126.6 (ArCH),127.2 (ArCH),130.8 (ArCH),135.0
(ArC), 140.2 (ArC), 141.1 (ArC), 152.3 (ArC), 171.3 (CO). Enantiomeric
termined by chiral phase HPLC (Phenomenex Lux 3 mm Cellulose-1)
5% ipa in hexane@1 mL minꢁ1, tR¼12.9 min (minor), 14.1 min (ma-
jor). Data were in accordance with the literature.
3.3.11. (S)-Ethyl 3-(4-methoxyphenylamino)-3-(thienyl)propanoate
3k.4b
excess was determined by chiral phase HPLC (Phenomenex Lux 3 mm
Cellulose-1) 5% ipa in hexane@1 mL minꢁ1, tR¼10.2 min (minor),
15.6 min (major). Data were in accordance with the literature.
3.3.14. (S)-Ethyl 3-(4-methoxyphenylamino)-4-phenylbutanoate 3n.
Obtained by general procedure B as a colourless oil (110 mg, 66%
yield, 90% ee); [
a
]
D ꢁ15 (c 1.0, CHCl3) 90% ee; lit.4b ꢁ9.1 [
a]D (c 1.0)
70% ee; Rf (20% diethyl ether/petroleum ether) 0.20; dH (400 MHz,
CDCl3) 1.25 (t, 3H, J 7.1, CH3CH2), 2.90 (dd, 1H, J 15.2, 6.5, CHH), 2.94
(dd, 1H, J 15.2, 6.5, CHH), 3.75 (s, 3H, OCH3), 4.16 (q, 2H, J 7.1, OCH2),
4.23 (br s, 1H, NH), 5.09 (t, 1H, J 6.5, NCH), 6.67 [(AX)2, 2H, 2ꢂArCH],
6.78 [(AX)2, 2H, 2ꢂArCH], 6.94e7.19 (m, 2H, 2ꢂArCH), 7.20 (dd, 1H, J
5.0, 1.2, 2ꢂArCH); dC (100 MHz, CDCl3) 14.2 (CH3), 42.6 (CH2), 52.3
(NCH), 55.7 (OCH3), 60.8 (OCH2), 114.8 (2ꢂArCH), 115.8 (2ꢂArCH),
123.8 (ArCH), 124.2 (ArCH), 126.8 (ArCH), 140.6 (ArC), 147.3 (ArC),
152.9 (ArC), 170.9 (CO). Enantiomeric excess was determined by
Obtained by general procedure B as a light yellow oil (88 mg,
56% yield, 30% ee); [
a
]
þ2.3 (c 1.3, CHCl3) 30% ee; Rf (25% diethyl
D
ether/petroleum ether) 0.20; nmax (thin film, cmꢁ1) 3371, 2981,
2934, 1728, 1512; dH (400 MHz, CDCl3) 1.26 (t, 3H, J 7.1, CH3CH2),
2.44 (dd, 1H, J 15.3, 6.3, CHH), 2.51 (dd, 1H, J 15.3, 6.0, CHH), 2.87
(dd,1H, J 13.6, 7.2, CHH), 2.97 (dd,1H, J 13.6, 5.1, CHH), 3.64 (br s, 1H,
NH), 3.78 (s, 3H, OCH3), 4.01e4.07 (m, 1H, NCH), 4.14 (q, 2H, J 7.1,
OCH2), 6.66 [(AX)2, 2H, 2ꢂArCH], 6.82 [(AX)2, 2H, 2ꢂArCH],
7.19e7.33 (m, 5H, 5ꢂArCH); dC (100 MHz, CDCl3) 14.2 (CH3), 38.3
(CH2), 40.0 (CH2), 52.6 (NCH), 55.8 (OCH3), 60.5 (OCH2), 115.0
(2ꢂArCH), 115.5 (2ꢂArCH), 126.6 (ArCH), 128.5 (2ꢂArCH), 129.5
(2ꢂArCH), 137.9 (ArC), 140.9 (ArC), 152.5 (ArC), 172.0 (CO); m/z (TOF
ESþ) 314.1749 (MHþ, C19H24NO3 requires 314.1756). Enantiomeric
excess was determined by chiral phase HPLC (Phenomenex Lux
chiral phase HPLC (Phenomenex Lux 3 mm Cellulose-1) 10% ipa in
hexane@1 mL minꢁ1, tR¼10.6 min (minor), 13.0 min (major). Data
were in accordance with the literature.
3.3.12. (S)-Ethyl 3-(4-methoxyphenylamino)-3-(4-nitrophenyl)prop-
anoate 3l.
3
m
m Cellulose-1) 10% ipa in hexane@1 mL minꢁ1, tR¼8.7 min
(major), 9.8 min (minor).
3.3.15. (S)-Ethyl 3-(4-methoxyphenylamino)butanoate 3o.16
Obtained by general procedure B as an orange oil (87 mg, 50%
yield, 82% ee); [
a
]
D ꢁ23 (c 0.8, CHCl3) 82% ee; Rf (20% diethyl ether/
petroleum ether) 0.40; nmax (thin film, cmꢁ1) 3386, 2983, 1730,
1514; dH (400 MHz, CDCl3) 1.22 (t, 3H, J 7.2, CH3CH2), 2.81 (dd, 1H, J
15.1, 6.5, CHH), 2.84 (dd, 1H, J 15.1, 6.5, CHH), 3.71 (s, 3H, OCH3), 4.14
(q, 2H, J 7.2, OCH2), 4.48 (br s, 1H, NH), 4.86 (t, 1H, J 6.5, NCH), 6.49
[(AX)2, 2H, 2ꢂArCH], 6.72 [(AX)2, 2H, 2ꢂArCH], 7.58 [(AX)2, 2H,
2ꢂArCH], 8.19 [(AX)2, 2H, 2ꢂArCH]; dC (100 MHz, CDCl3) 14.1 (CH3),
42.3 (CH2), 55.5 (NCH), 55.6 (OCH3), 61.1 (OCH2), 114.9 (2ꢂArCH),
Obtained by general procedure B as a light yellow oil (75 mg, 63%
yield, 20% ee); [
a
]D 0 (c 1.0, CHCl3) 20% ee; lit.16
[
a
]D ꢁ4.0 (c 0.5, MeOH)
93.8% ee; Rf (20% diethyl ether/petroleum ether) 0.10; dH (400 MHz,

S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
5531
CDCl3) 1.27 (d, 3H, J 6.4, CH3), 1.28 (t, 3H, J 7.2, CH3CH2), 2.42 (dd, 1H, J
15.0, 6.8, CHH), 2.62 (dd,1H, J 15.0, 6.8, CHH), 3.51 (br s,1H, NH), 3.77 (s,
3H, OCH3), 3.83e3.91 (m,1H, NCH), 4.16 (q, 2H, J 7.2, OCH2), 6.64[(AX)2,
2H, 2ꢂArCH], 6.80 [(AX)2, 2H, 2ꢂArCH]; dC (100 MHz, CDCl3) 14.2
(CH3), 20.7 (CH3), 41.0 (CH2), 47.3 (NCH), 55.7 (OCH3), 60.4 (OCH2),114.9
(2ꢂArCH), 115.5 (2ꢂArCH), 141.0 (ArC), 152.4 (ArC), 172.0 (CO). Enan-
tiomeric excess was determined by chiral phase HPLC (Phenomenex
(48%), mp 49e50 ꢀC (not reported in literature); dH (400 MHz, CDCl3)
2.13 (3H, s, CH3), 2.20 (3H, s, CH3), 6.88 (dd, 1H, J 7.8, 1.0, ArCH), 7.03
(ddd,1H, J 8.7, 7.6, 1.2, ArCH), 7.19e7.25 (m, 2H, 2ꢂArCH), 7.46e7.51 (m,
3H, 3ꢂArCH), 8.02e8.05 (m, 2H, 2ꢂArCH); dC (63 MHz, CDCl3) 17.5
(CH3), 17.8 (CH3), 118.5 (ArCH), 123.3 (ArCH), 126.4 (ArCH), 127.2
(2ꢂArCH), 128.4 (2ꢂArCH), 130.4 (ArCH), 130.5 (ArCH), 139.5 (2ꢂArC),
150.4 (ArC), 164.9 (C]N). Data were in accordance with the literature.
Lux 3
m
m Cellulose-1) 5% ipa in hexane@1 mL minꢁ1, tR¼10.2 min
(minor),10.9 min (major). Data were in accordance with the literature.
3.5. General procedure D for the reduction of ketimines
3.3.16. Ethyl 3-(4-methoxyphenylamino)-4-methylpentanoate 3p.4b
Imine (1 mmol), catalyst 1 (0.01 mmol) and dry CH2Cl2 (0.5 mL
or 1 mL) were introduced into an oven-dried 25 mL two-necked
flask or an oven-dried carousel tube. The mixture was stirred un-
til complete dissolution, then cooled to 0 ꢀC and trichlorosilane
(2 mmol, 0.2 mL) was added by syringe over 5e10 s. The reaction
mixture was left to stir for the desired time. Aqueous hydrochloric
acid (1 M, ca. 2 mL) was added, which led to gas evolution and
precipitation, followed by CH2Cl2 (20 mL) and aqueous sodium
hydroxide (1 M, 20 mL). This mixture was stirred until the pre-
cipitate was completely dissolved. The organic phases were sepa-
rated and the aqueous phase was extracted with CH2Cl2 (2ꢂ20 mL).
The combined organic phases were washed with brine (20 mL) and
dried over MgSO4. Filtration and concentration gave the product
that could be purified by chromatography column on silica gel
using a 2e10% solution of diethyl ether or ethyl acetate in petro-
leum ether. Racemic samples of compound were obtained by this
procedure, using N-formylpyrrolidine (0.1 mmol) as catalyst.
Obtained by general procedure B as a light yellow oil (58 mg,
44% yield, 56% ee); [
a]
D þ20 (c 1.0, CHCl3) 56% ee; lit.4b
[
a]
D þ21.3 (c
1.0, CHCl3) 59% ee; Rf (25% diethyl ether/petroleum ether) 0.30; dH
(400 MHz, CDCl3) 0.95 (d, 3H, J 6.8, CH3CH), 1.00 (d, 3H, J 6.8,
CH3CH), 1.23 (t, 3H, J 7.1, CH3CH2), 1.86e1.98 [m, 1H, (CH3)2CH], 2.43
(dd,1H, J 14.8, 7.3, CHH), 2.52 (dd,1H, J 14.8, 5.3, CHH), 3.46 (br s,1H,
NH), 3.61e3.65 (m, 1H, NCH), 3.76 (s, 3H, OCH3), 4.10 (q, 2H, J 7.1,
OCH2), 6.63 [(AX)2, 2H, 2ꢂArCH], 6.78 [(AX)2, 2H, 2ꢂArCH]; dC
(100 MHz, CDCl3) 14.2 (CH3), 18.6 (CH3), 18.7 (CH3), 31.7 (CH), 36.9
(CH2), 55.8 (OCH3), 57.2 (NCH), 60.4 (OCH2), 114.9 (2ꢂArCH), 115.0
(2ꢂArCH), 141.9 (ArC), 152.1 (ArC), 172.4 (CO). Enantiomeric excess
3.5.1. (S)-2-Methoxy-N-(1-phenylethyl)aniline 5a.19
was determined by chiral phase HPLC (Phenomenex Lux 3 mm
Cellulose-1) 5% ipa in hexane@1 mL minꢁ1, tR¼9.1 min (minor),
9.9 min (major). Data were in accordance with the literature.
3.4. General procedure C for the preparation of ketimines
ꢂ
Activated 4 A molecular sieves (20 g), toluene (40 mL), ketone
(50 mmol) and amine (60 mmol) were introduced into a 100 mL
flask. The mixture was stirred at room temperature for 24 h and
filtered. The imines were purified by distillation under reduced
pressure to remove volatiles, leaving the pure product as residue.
Prepared according to general procedure D (80 mg, 35%, 96% ee)
as a white solid, mp 78e80 ꢀC (not reported in literature); [
a]
D
þ78.3 (c 0.6, ethyl acetate) 96% ee; lit.19
[
a]
ꢁ32.3 (c 1.03, CHCl3)
D
97% ee for R isomer; Rf (5% EtOAc/petroleum ether) 0.80; dH
(400 MHz, CDCl3) 1.57 (d, 3H, J 6.8, CH3), 3.91 (s, 3H, OCH3), 4.49 (q,
1H, J 6.8, NCH), 4.68 (br s, 1H, NH), 6.36 (dd,1H, J 7.6, 1.6, ArCH), 6.63
(td, 1H, J 7.6, 1.9, ArCH), 6.70 (td, 1H, J 7.5, 1.6, ArCH), 6.77 (dd, 1H, J
7.8,1.9, ArCH), 7.20e7.41 (m, 5H, 5ꢂArCH); dC (CDCl3,100 MHz) 25.3
(CH3), 54.3 (NCH), 55.5 (CH3O), 109.4 (ArCH), 111.2 (ArCH), 116.4
(ArCH), 121.3 (ArCH), 126.0 (2ꢂArCH), 126.9 (ArCH), 128.7
(2ꢂArCH), 137.3 (ArC), 145.6 (ArC), 146.7 (ArC). Enantiomeric excess
was determined by chiral phase HPLC (Kromasil 3-Cellucoat OD-H),
0.2% ipa in hexane@1 mL minꢁ1, tR¼7.5 min (major), 10.6 min (mi-
nor). Data were in accordance with the literature.
3.4.1. 2-Methoxy-N-(1-phenylethylidene)benzenamine 4a.19
Prepared according to general procedure C as a yellow oil (44%); dH
(250 MHz, CDCl3) 2.20 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.80 (dd, 1H, J
7.5, 1.7, ArCH), 6.94e7.01 (m, 2H, 2ꢂArCH), 7.07e7.14 (m, 1H, ArCH),
7.44e7.49 (m, 3H, 3ꢂArCH), 8.01e8.05 (m, 2H, 2ꢂArCH); dC (63 MHz,
CDCl3) 17.8 (CH3), 55.7 (OCH3),111.8 (ArCH),120.7 (ArCH),121.1(ArCH),
124.3 (ArCH), 127.4 (2ꢂArCH), 128.4 (2ꢂArCH), 130.5 (ArCH), 139.6
(ArC), 140.8 (ArC), 149.1 (ArC), 167.0 (C]N). Data were in accordance
with the literature, except a yellow solid was previously noted.
3.5.2. (S)-2-Methyl-N-(1-phenylethyl)aniline 5b.21
3.4.2. 2-Methyl-N-(1-phenylethylidene)benzenamine 4b.20
Prepared according to general procedure D (135 mg, 64%, 97% ee)
as a white solid, mp 42e44 ꢀC (not reported in literature); [
a]D þ60.8
(c 1.09, CHCl3) 97% ee; lit.21
[a]
þ14 (c 0.5, CHCl3) 25% ee; Rf (5%
D
Prepared according to general procedure C, followed by recrystal-
EtOAc/petroleum ether) 0.60; dH (400 MHz, CDCl3) 1.59 (d, 3H, J 6.7,
CH3), 2.26 (s, 3H, ArCH3), 3.88 (br s, 1H, NH), 4.56 (q, 1H, J 6.7, NCH),
lisation from diethyl ether/petroleum ether 40e60 ꢀC as a yellow solid

5532
S. Jones, X. Li / Tetrahedron 68 (2012) 5522e5532
Yuan, W.; Liu, B.; Zhang, X. J. Org. Chem. 2011, 76, 9109e9115; (c) Gautier, F.-M.;
Jones, S.; Li, X.; Martin, S. J. Org. Biomol. Chem. 2011, 9, 7860e7868; (d) Xue, Z.-
Y.; Jiang, Y.; Peng, X.-Z.; Yuan, W.-C.; Zhang, X.-M. Adv. Synth. Catal. 2010, 352,
2132e2136; (e) Wang, Z. Y.; Zhou, L.; Lu, X. X.; Sun, J. Chin. Sci. Bull. 2010, 55,
1726e1728.
6.39 (d,1H, J 8.1, ArCH), 6.62 (t,1H, J 7.2, ArCH), 6.98 (t,1H, J 7.7, ArCH),
7.01 (d, 1H, J 7.2, ArCH), 7.25 (t, 1H, J 7.1, ArCH), 7.33e7.40 (m, 4H,
4ꢂArCH); dC (100 MHz, CDCl3) 17.7 (ArCH3), 25.4 (CH3), 53.4 (NCH),
111.1 (ArCH), 116.9 (ArCH), 121.6 (ArC), 125.9 (2ꢂArCH), 126.9 (ArCH),
127.1 (ArCH), 128.7 (2ꢂArCH), 130.1 (ArCH), 145.2 (ArC), 145.4 (ArC).
Enantiomeric excess was determined by chiral phase HPLC (Kromasil
3-Cellucoat OD-H), 3% ipa in hexane@1 mL minꢁ1, tR¼4.1 min (ma-
jor), 7.0 min (minor). Data were in accordance with the literature.
ꢀ
ꢀ
ꢁ
4. (a) Malkov, A. V.; Vrankova, K.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2009, 74,
ꢀ
ꢁ
ꢀ
ꢁ
5839e5849; (b) Malkov, A. V.; Stoncius, S.; Vrankova, K.; Arndt, M.; Kocovsky, P.
Chem.dEur. J. 2008, 14, 8082e8085.
5. (a) Jiang, Y.; Chen, X.; Zheng, Y.; Xue, Z.; Shu, C.; Yuan, W.; Zhang, X. Angew. Chem.,
Int. Ed. 2011, 50, 7304e7307; (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, 9864e9867.
6. Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun. 2009, 3585e3587.
7. (a) Guizzetti, S.; Benaglia, M.; Bonsignore, M.; Raimondi, L. Org. Biomol. Chem.
2011, 9, 739e743; (b) Bonsignore, M.; Benaglia, M.; Annunziata, R.; Celentano,
G. Synlett 2011, 1085e1088.
3.6. Molecular modelling
8. Wu, X.; Li, Y.; Wang, C.; Zhou, L.; Lu, X.; Sun, J. Chem.dEur. J. 2011, 17,
2846e2848.
9. Gautier, F. M.; Jones, S.; Martin, S. J. Org. Biomol. Chem. 2009, 7, 229e231.
10. Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47,
3751e3754.
All electronic structure calculations were performed using the
SMP version of the Gaussian 09 program package (rev. A2)22 with
the B3LYP functional method.23 Gaussian was compiled using the
Portland Compiler version 8.0-6 with the Gaussian-supplied ver-
sion of BLAS24 and ATLAS25 on the EMT64 architecture. In all cal-
culations we used the 6-311G** basis set on all atoms.26 All
calculations were run in vacuo on the enantiomeric series to that
depicted in this manuscript. All minimum energy structures found
have indeed zero imaginary frequencies.
11. Zhang, Z.-H.; Yin, L.; Wang, Y.-M. Adv. Synth. Catal. 2006, 348, 184e190.
€
12. Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlaander, M.; Skrydstrup, T.
Org. Lett. 2009, 11, 4208e4211.
13. Cao, H.; Wang, X.; Jiang, H.; Zhu, Q.; Zhang, M.; Liu, H. Chem.dEur. J. 2008, 14,
11623e11633.
14. Park, M.-S.; Lee, J.-I. Bull. Korean Chem. Soc. 2004, 25, 1269e1272.
15. Sano, T.; Horiguchi, Y.; Toda, J.; Imafuku, K.; Tsuda, Y. Chem. Pharm. Bull. 1984,
32, 497e503.
16. Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343e5345.
17. Lin, J.; Zhang, L.-F. Monatsh. Chem. 2007, 138, 77e81.
18. Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600e3603.
Acknowledgements
ꢀ ꢁ
19. Mrsic, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am. Chem. Soc. 2009, 131,
We would like to thank the University of Sheffield for support.
8358e8359.
20. Chen, D.; Wang, Y.; Klankermayer, J. Angew. Chem., Int. Ed. 2010, 49,
9475e9478.
21. Tagashira, J.; Imao, D.; Yamamoto, T.; Ohta, T.; Furukawa, I.; Ito, Y. Tetrahedron:
Asymmetry 2005, 16, 2307e2314.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.084.
22. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Car-
icato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg,
J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Naka-
jima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J.
E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S.
S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09
Revision A.02; Gaussian: Wallingford, CT, USA, 2009.
23. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
24. Dongarra, J. J.; Croz, J. D.; Hammarling, S.; Duff, I. S. ACM Trans. Math. Software
1990, 16, 1e17.
25. Whaley, R. C.; Petitet, A.; Dongarra, J. Parallel Comput. 2001, 27, 3e25.
26. McLean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639e5648.
References and notes
1. For reviews, see: (a) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656e1691; (b) Sleebs, B. E.; Van Nguyen,
T. T.; Hughes, A. B. Org. Prep. Proced. Int. 2009, 41, 429e478; (c) Enantioselective
Synthesis of b-Amino Acids, 2nd ed; Juaristi, E., Soloshonok, V. A., Eds.;; John
Wiley & Sons: Hoboken, NJ, 2005; (d) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42,
4290e4299; (e) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991e8035; (f) Juaristi,
E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983e1004; (g) Cardillo, G.; Tomasini,
C. Chem. Soc. Rev. 1996, 25, 117e128.
2. Weickgenannt, A.; Oestreich, M. ChemCatChem 2011, 3, 1527e1529.
3. For a review, see Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem. 2010, 5529e5541;
For work published subsequently, see: (a) Kashiwagi, T.; Kotani, S.; Sugiura, M.;
Nakajima, M. Tetrahedron 2011, 67, 531e539; (b) Chen, X.; Zheng, Y.; Shu, C.;
€