Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

Article abstract of DOI:10.1016/j.tet.2007.10.010

The synthesis of atropisomeric 2-substituted benzamides 2a-e, 3a-e, and 4a-e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic ¹H NMR spectroscopic studies of benzamides 2b-d, 3b-d, and 4b-d i

Full text of DOI:10.1016/j.tet.2007.10.010

Tetrahedron 63 (2007) 12655–12664
Synthesis and dynamics of atropisomeric
(S)-N-(a-phenylethyl)benzamides
c
a
b
Gabriela Huelgas,a,b Sylvain Bernes, Mario Sanchez, Leticia Quintero,
ꢀ
ꢁ
Eusebio Juaristi,d Cecilia Anaya de Parrodia, and Patrick J. Walsh
*
e
a
´
ꢁ
Universidad de las Americas Puebla, Departamento de Ciencias Quımico-Biologicas,
ꢁ
Santa Catarina Maꢁrtir s/n, Cholula, Puebla 72820, Mexico
Benemerita Universidad Autoꢁnoma de Puebla, Facultad de Ciencias Quꢁımicas, Puebla, Puebla 72570, Mexico
b
´
cUniversidad Autoꢁnoma de Nuevo Leoꢁn, Facultad de Ciencias Quꢁımicas, Mexico
dDepartamento de Quꢁımica, Centro de Investigacioꢁn y de Estudios Avanzados
´
´
del Instituto Politecnico Nacional, Mexico, D.F. 07000, Mexico
eP. Roy and Diana T. Vagelos Laboratories, University of Pennsylvania, Department of Chemistry,
231 South 34th Street, Philadelphia, PA 19104-6323, USA
Received 9 August 2007; revised 29 September 2007; accepted 2 October 2007
Available online 6 October 2007
Abstract—The synthesis of atropisomeric 2-substituted benzamides 2a–e, 3a–e, and 4a–e, and characterization by X-ray structure analysis of
2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic 1H NMR spectroscopic studies of benzamides 2b–d, 3b–d, and 4b–d indicate that only two
of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of
activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal molꢀ1. Benzamides ArCON[(S)-phenethyl]2 (2e, 3e, and 4e),
exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal molꢀ1
.
The highest rotation barriers were observed for the ortho-nitro derivatives 2a–e. Molecular calculations at the semiempirical level (PM3MM)
gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal molꢀ1, respectively, which are comparable to the experimental
values.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
benzamides, and naphthamides entails diastereoselective re-
actions with stoichiometric chiral auxiliaries.12–15 Enantio-
selective methods to prepare such compounds, however, are
emerging16–21 and will likely inspire new investigations in
this area.
Compounds presenting chiral axes, such as BINOL and
BINAP, have played an important role in the development
of asymmetric catalysis and are considered to be privileged
ligands.1–3 These ligands are chiral due to restricted rotation
about the central C–C bonds, whose rotational barriers are
sufficiently high to allow isolation and use at high tempera-
tures without racemization.4–7
One of the aims of our research is to prepare non-biaryl atro-
pisomeric benzamides that are suitable ligands for use in
asymmetric catalysis. The most significant hurdle in the ap-
plication of such ligands is the preparation of chiral building
In contrast to atropisomeric biaryl ligands, efforts to perform
catalytic asymmetric reactions with non-biaryl atropisomers
have attracted less attention. The perpendicular architecture
of atropisomeric anilides, benzamides, and naphthamides ef-
fectively exert control over the formation of new stereogenic
centers.8–11 Themostcommonroutetoatropisomericanilides,
blocks that contain enantioenriched atropisomers.13,22,23
A
strategy that has been successfully utilized to circumvent
this synthetic challenge involves installation of a stereogenic
center near an axis that exhibits hindered rotation. Ideally,
the rotational barrier is not sufficiently high to allow isola-
tion of stereochemically stable atropisomers at temperatures
necessary to perform enantioselective reactions. The central
chirality will influence the relative energies of the inter-
converting diastereomeric conformations of the atropiso-
mers. If the bound ligand’s chiral axis is positioned close
to the metal center, it may have a significant impact on the
enantioselectivity of reactions at the metal. In other words,
Keywords: Atropisomers; Chiral ligands; Variable temperature NMR; Semi-
empirical theoretical calculations.
* Corresponding author. Tel.: +52 222 229 2670; fax: +52 222 229 2419;
e-mail: cecilia.anaya@udlap.mx
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.010

12656
G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
the central chirality can cause the atropisomeric group to
preferentially adopt one of the chiral conformations and
this chiral conformation can be used in the transfer of asym-
metry to the substrate.7,24–26 In their pioneering work, Mino
et al. prepared chiral P/O chelating ligands containing sec-
ondary amides and a phosphine (Scheme 1).27 Although
the stereogenic center is far removed from the metal binding
site, the ligated catalyst gave up to 85% enantioselectivity in
the palladium catalyzed asymmetric allylation reaction. This
enantioselectivity is impressive, especially when compared
to the slightly lower enantioselectivity observed when
a closely related PO ligand with a fixed atropisomeric amide
was used in this reaction.23
2. Results and discussion
2.1. Synthesis of (S)-N-(a-phenylethyl)benzamides
2a–e, 3a–e, and 4a–e
The secondary amines 1a and 1b were prepared from (S)-
a-phenylethylamine by N-alkylation with 2-iodo-propane
and benzyl bromide, respectively. Reactions were per-
formed in DMPU in the presence of Na2CO3, according
to the procedure described in the literature (85–90% yield,
Scheme 2, A).30
R
A
NH2
NH
i
+
R
X
Ph
Ph
1a, 85% yield, R = iPr
1b, 90% yield, R = CH2Ph
O
O
MeO
Ph
OMe
Ph
OMe
OAc
[(allyl)PdCl]2
O
O
R' CH2
iii
B
+
R' CH
Ph
L*
O
NH2
ii
N
Ph
Ph
Ph
NH
MeO
OMe
*
+
R'
H
Ph
Ph
PPh2 O
5c - d
1c, 81% yield,
L* =
N
H
R' = (1-Naphthyl)
1d, 72% yield,
R' = (9-Anthracenyl)
Ph
Pd
Ph
C
Ph
Ph
Ph
OMe
Ph2
Ph
Ph2P
P
O
NH
O
N
O
NH
NH2
iv
v
OMe
+
Pd
Ph
Ph
HN
Ph
5e
Ph
Ph
Ph
1e, 35% yield
Scheme 1.
Scheme 2. Reagents and conditions: (i) Na2CO3, DMPU, D; (ii) K2CO3/
EtOH–H2O (80:20), rt, 12 h; (iii) NaBH4/MeOH, rt, 6 h; (iv) (1)
Ti(Oi-Pr)4 (3 equiv); (2) H2/Pd–C 10% (0.5 mol %), 12 h; (v) (1) HCl
5% aq, D, recrystallization; (2) NaOH 1 M.
In this work, we set out to prepare a series of N/O ligands
that would bind to metals upon deprotonation. Given the
importance of the (S)-a-phenylethylamino group in asym-
metric synthesis,28,29 we chose to use this chiral auxiliary
as the source of central chirality. We report herein the syn-
thesis of ortho-substituted benzamides 2a–e, 3a–e, and
4a–e (Fig. 1) from secondary N-[(S)-a-phenylethyl]amines
1a–e. The structures of benzamides 2d, 2e, 3c, 3e, 4c, and
4e were determined by X-ray crystallography, allowing as-
signment of the absolute configuration of the chiral axis in
the solid state. We have also studied the dynamics of atrop-
isomerization in these compounds, both by variable temper-
Amines 1c, 1d, and 1e were prepared from 1-naphthylalde-
hyde, 9-anthracenylaldehyde, and acetophenone, respec-
tively, via the corresponding imines 5c, 5d, and 5e followed
by reduction. Thus, reaction of 1-naphthylaldehyde or 9-
anthracenylaldehyde with (S)-a-phenylethylamine and K2CO3
in EtOH/H2O (80:20) at room temperature afforded interme-
diate aldimines 5c and 5d. The aldimines were reduced with
NaBH4 in MeOH at room temperature (overall yield 72–
81%, Scheme 2, B). According to the procedure described
in the literature,31 reaction of acetophenone with (S)-a-phen-
ylethylamine in the presence of 3 equiv of Ti(Oi-Pr)4, fol-
lowed by in situ reduction of the ketimine 5e with H2/Pd–C
(5 mol %), afforded a diastereomeric mixture (78:22 dr).
The ammonium chloride salts were formed and the (S,S)-
product was obtained by fractional crystallization of the dia-
stereomeric mixture. The free amine 1e was liberated upon
reaction with 1 M NaOH (35% overall yield, Scheme 2, C).
1
1
ature H nuclear magnetic resonance spectroscopy (VT H
NMR), and computationally using semiempirical methods
(PM3MM).
2a−e; Z = NO2
ortho-Nitrobenzamides 2a–e were prepared by addition of
the secondary amines 1a–e (1 equiv) to ortho-nitrobenzoyl
chloride (1.4 equiv) in dichloromethane in the presence of
triethylamine (74–86% yield, Scheme 3). The resulting nitro
derivatives 2a–e were reduced to the corresponding anilines
3a–e with iron powder (16 equiv) in 20% aqueous acetic
acid in EtOH (81–95% yield, Scheme 3). Finally, ortho-(sul-
fonamido)benzamides 4a–e were prepared by addition of
para-tert-butylbenzensulfonyl chloride (2 equiv) to a solu-
tion of anilines 3a–e (1 equiv) in pyridine at 25 ꢁC, affording
4a–e in 69–89% yield (Scheme 3).
Ph
Z
3a−e; Z = NH2
(S)
4a−e; Z = NHSO2-p-C6H4-t-Bu
N
R
O
R
Benzamide
a
b
c
d
e
i-Pr
PhCH2
(1-Naphthyl)CH2
(9-Anthracenyl)CH2
(S)-PhMeCH
Figure 1. ortho-Substituted N-[(S)-a-phenylethyl]benzamides.

G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
12657
Ph
NO2
O
R
o-NO2-C6H4-COCl
NH
(S)
(S)
Ph
N
R
Et3N/CH2Cl2/rt/2 h
NO2
(Sa,S,S)-2e
H
H
74−86%
Me
Ph
2a−e
1a−e
N
O
Fe/ AcOHaq 20%
EtOH/reflux/5 h
81−95%
Me
Ph
Ph
NH2
(S)
H2N
H
N
R
O
(Ra,S,S)-3e
3a−e
p-t-Bu-C6H4-SO2Cl
Py/rt/12 h
Me
Ph
O
N
69−89%
H
Me
Ph
SO2
t-Bu
(Sa,S,S)-4e
Ph
N
H
Me
Ph
H
(S)
SO2
N
R
O
N
H
4a−e
N
H
O
Ph Me
Scheme 3.
t-Bu
Figure 3. Solid state structures of (Sa,S,S)-2-nitro-N,N-bis-(a-phenylethyl)-
benzamide 2e, (Ra,S,S)-2-amino-N,N-bis(a-phenylethyl)benzamide 3e, and
(Sa,S,S)-2-(4-tert-butylphenylsulfonamido)-N,N-bis(a-phenylethyl)benz-
amide 4e illustrating the conformations about the atropisomeric amides. Dis-
order in the t-Bu group of 4e is not shown, but can be found in the structure
report.
Benzamides 2d, 2e, 3c, 3e, 4c, and 4e were crystallized and
afforded X-ray quality crystals. The solid state structures
were determined and are illustrated in Figure 2 (2d, 3c,
O2N
O
and 4c) and Figure 3 (2e, 3e, and 4e). Each compound was
detected in the collected crystallized material as a single di-
astereomer in the solid state. The configurations about the
atropisomeric axes were assigned from the solid state struc-
tures as (Ra,S,E) for 2d, 3c, and 4c. The configurations of 2e,
3e, and 4e were assigned as (Sa,S,S), (Ra,S,S), and (Sa,S,S),
respectively.
N
H
Ph
Me
(Ra,S,E)-2d
Ph
H
Me
2.2. VT NMR experiments on ortho-substituted
benzamides
N
O
H2N
With the tertiary amides in hand, we initiated studies to
examine their solution dynamics. Variable temperature H
(Ra,S,E)-3c
1
NMRspectroscopywasperformedonortho-substitutedbenz-
amide derivatives 2a–e, 3a–e, and 4a–e to determine the num-
ber of conformers observable in solution and their relative
populations. The NMR spectra of the benzamides containing
Ni-Pr groups (2a, 3a, and 4a) were complicated due to over-
lapping resonances and were not amenable to our analysis.
Ph
Me
H
N
O
HN
SO2
Each of the ortho-substituted benzamides 2b–d, 3b–d, and
4b–d potentially has four diastereomers, by a possible re-
striction in the rotation around the Ph–CO and NH–CO
bonds. These conformers interconvert by rotation about the
N–CO amide bond and/or rotation about the Ar–CO bond
(Fig. 4). In contrast, rotation about the [(S)-phenyl-
ethyl]2N–CO amide bond in 2e, 3e, and 4e is degenerate
and only two diastereomers are possible (Fig. 5).
(Ra,S,E)-4c
t-Bu
Figure 2. Solid state structures of (Ra,S,E)-N-(anthracen-9-ylmethyl)-2-
nitro-N-(a-phenylethyl)benzamide 2d, (Ra,S,E)-2-amino-N-(naphthalen-1-
ylmethyl)-N-(a-phenylethyl)benzamide 3c, and (Ra,S,E)-2-(4-tert-butyl-
phenylsulfonamido)-N-(naphthalen-1-ylmethyl)-N-(a-phenylethyl)benz-
amide 4c illustrating the conformations about the atropisomeric amides.
Compound 4c crystallized with acetone included in the unit cell, which is
omitted for clarity.
To examine the efficiency with which the central chirality
biases the stereochemistry of the atropisomeric axes, the

12658
G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
aryl ring, over the amino and sulfonamido groups. Rotation
about the Ar–CO bond probably causes simultaneous rota-
tion of the Ar–NO2 from the electronically preferred orien-
tation parallel to the aromatic ring. In contrast, the bulky
sulfonyl group can orient away from the amide carbonyl to
avoid unfavorable interaction during the Ar–CO rotation.
Another contributing factor could be stabilization of the
transition state to rotation about the Ar–CO bond by forma-
tion of a hydrogen bond between the N–H of the ortho-sub-
stituent (H2N– or H–N–SO2Tol and the amide carbonyl).
N-CO rotation
Ph
Z
Z
R
Me
N
R
O
N
O
Me
(Sa,S,Z)
(Sa,S,E)
Ph
Ar-CO rotation
Ar-CO rotation
N-CO rotation
Ph
Z
Z
Free energy of activation of interconversion of configura-
tionally labile compounds has been investigated by means
of dynamic NMR spectroscopy.32,33 To measure the free en-
R
N
Me
N
R
O
O
Me
(Ra,S,E)
(Ra,S,Z)
Ph
1
ergy of activation (DGz) by variable temperature H NMR,
Figure 4. Conformational interconversions of 2a–d, 3a–d, and 4a–d.
the coalescence temperature method can be used. The
coalescence temperature (Tc, K) is the lowest temperature
at which the two rotamers merge (Table 2). The free energy
of activation (DGz;, kcal molꢀ1) is derived using the Eyring
equation and the rate constant (kc, sꢀ1, Eqs. 1 and 3).32
Ar-CO rotation
Ph
Z
Ph
Z
Me
N
O
Me
N
O
pffiffiffi
Ph
Me
(Ra,S,S)
ꢀ
Ph
(Sa,S,S)
Me
kc ¼ pDn 2 ¼ 2:22Dn
ð1Þ
ð2Þ
Figure 5. Conformational interconversions of 2e, 3e, and 4e.
ꢀ
DGz ¼ 2:303RTcð10:319 þ log Tc kcÞ
NMR spectra were recorded at temperatures that freeze out
individual conformers. The 200 MHz 1H NMR spectra of the
ortho-nitrobenzamides exhibited resonances for two diaste-
reomers at room temperature (Table 1, entries 1–4). The ra-
tio of the diastereomers in DMSO-d6 was found to range
from about 1:1 for 2e to 3:1 for 2d. At room temperature,
only a single species was observed for compounds 3b–
d and 4b–d, suggesting that interconversion of the con-
formers was rapid at this temperature on the NMR timescale.
The ratios of diastereomers of the ortho-amino- and ortho-
sulfonylaminobenzamides were, therefore, measured in
CDCl3 at temperatures between ꢀ50 and ꢀ60 ꢁC (Table 1,
entries 5–12). Although there are four possible diastereo-
meric atropisomers for each benzamide 2b–d, 3b–d, and
4b–d, we observed only two of them by VT NMR (Fig. 4).
In these cases the ratio of conformers ranged from 1:1 to
1:4. The higher rotational barriers of the ortho-nitrobenz-
amides are primarily attributed to the effective size of the
ortho-nitro group, which lies roughly in the plane of the
ꢀ
DGz ¼ 4:569 ꢂ 10ꢀ3Tcð10:319 þ log Tc kcÞ
ð3Þ
The 1H NMR experiments with ortho-nitrobenzamides 2b–e
were conducted in DMSO-d6. At room temperature, reso-
nances for two diastereomers were observed. The coales-
cence temperatures for ortho-nitrobenzamides 2b–e were
reached upon heating the sample in the probe of the NMR
spectrometer to temperatures between 75 and 105 ꢁC. The
measured free energies of activation ranged from 17.6 to
18.9 kcal molꢀ1 (Table 2, entries 1–4). The coalescence tem-
peratures for ortho-amino- and ortho-sulfonylaminobenz-
amides 3b–e and 4b–e were reached on cooling samples in
CDCl3 between ꢀ40 and 0 ꢁC. On the basis of these VT
NMR experiments, free energies of activation were calcu-
lated for 3b–e and 4b–e and found to be 11.5–
13.5 kcal molꢀ1 (Table 2, entries 5–12).
Table 1. Populations of diastereoisomeric atropisomers of amides 2b–e, 3b–e, and 4b–e
Entry
Z
R
Solvent
T (ꢁC)
Ratio
1, 2b
2, 2c
3, 2d
4, 2e
5, 3b
6, 3c
7, 3d
8, 3e
9, 4b
10, 4c
11, 4d
12, 4e
NO2
NO2
NO2
NO2
NH2
NH2
NH2
NH2
CH2Ph
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
+25
+25
+25
+25
ꢀ50
ꢀ53
ꢀ60
ꢀ60
ꢀ50
ꢀ50
ꢀ60
ꢀ60
0.60:0.40
0.67:0.33
0.75:0.25
0.56:0.44
0.73:0.27
0.71:0.29
0.67:0.33
0.50:0.50
0.60:0.40
0.58:0.42
0.65:0.35
0.56:0.44
CH2(1-naphthyl)
CH2(9-anthracenyl)
(S)-CHCH3Ph
CH2Ph
CH2(1-naphthyl)
CH2(9-anthracenyl)
(S)-CHCH3Ph
CH2Ph
NHSO2p-C6H4-t-Bu
NHSO2p-C6H4-t-Bu
NHSO2p-C6H4-t-Bu
NHSO2p-C6H4-t-Bu
CH2(1-naphthyl)
CH2(9-anthracenyl)
(S)-CHCH3Ph
CDCl3
CDCl3
CDCl3

G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
Table 2. VT NMR studies of benzamides 2b–e, 3b–e, and 4b–e
12659
Entry
Solvent
d1 (ppm)
d2 (ppm)
Dv (Hz)
kc (sꢀ1
)
Tc (ꢁC)
DGz (kcal molꢀ1 a
)
1, 2b
2, 2c
3, 2d
4, 2e
5, 3b
6, 3c
7, 3d
8, 3e
9, 4b
10, 4c
11, 4d
12, 4e
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
1.642
1.694
7.442
4.847
1.588
4.600
4.830
1.929
3.904
1.304
4.842
1.392
1.443
1.473
7.167
4.710
1.381
4.222
4.714
1.736
3.725
1.265
4.747
1.324
39.8
44.2
55.0
27.4
41.4
75.6
23.2
38.6
35.8
7.8
88.4
98.1
122.1
60.8
91.9
167.8
51.5
85.6
79.5
17.3
42.2
30.2
105
95
85
75
ꢀ20
ꢀ10
ꢀ20
ꢀ40
0
ꢀ10
ꢀ20
ꢀ40
18.9
18.3
17.6
17.6
12.4
12.6
12.7
11.5
13.5
13.8
12.8
12.5
CDCl3
CDCl3
CDCl3
19.0
13.6
Errorꢃ0.3 kcal molꢀ1
.
a
2.3. Computational calculations of bond rotation on
tertiary aromatic amides
on the amide nitrogens. The structures were calculated at
the semiempirical PM3MM level, implemented in Gaussian
’03.34 The transition state for rotation of the Ar–CO bond of
3e was found to contain a hydrogen bond between the oxy-
gen of the carbonyl and the amino N–H. Hydrogen bond dis-
To gain further insight into the dynamic processes observed
by VT NMR, we performed computations on benzamides 2e
and 3e. These benzamides were chosen because they have
very different barriers to interconversion of the diastereo-
meric atropisomers. Furthermore, the calculations are sim-
plified by the equivalence of the two N,N-dialkyl groups
˚
tances for the O/H and N–H bonds of 2.48 and 1.71 A,
respectively, were used.
The minimum energies of the diastereoisomeric conformers
were located by calculating the energies at different angles
between the aryl and carbonyl groups. We observed that the
lowest energy rotamer for compound 2e had the (Sa,S,S)
stereochemistry (Table 3). In contrast, the lowest energy con-
formation of benzamide 3e exhibited the opposite configura-
tion of the chiral axis (Table 3). The minimum energy
conformers located computationally are the same as those
found in the solid state structures of 2e and 3e (Fig. 6). The
calculated relative energies (Table 3) are in agreement with
Table 3. Relative energies of diastereomeric conformations and comparison
of experimental and calculated barriers of interconversiona
b
Entry
E (Sa,S,S)
E (Ra,S,S)
DGzexp
DGzcalcd
1, 2e
2, 3e
0
0.0917
1.709
0
17.6
11.5
23.6
12.4
All the values are given in kcal molꢀ1
The experimental data were obtained by VT NMR spectroscopy.
.
a
b
(Ra,S,S)-2e
TS-2e
(Sa,S,S)-2e
(Sa,S,S)-3e
TS-3e
(Ra,S,S)-3e
Figure 6. Calculated structures of diastereomeric conformations and transition states of benzamides 2e and 3e.

12660
G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
the populations of the diastereomers measured by 1H NMR
(Table 1, entries 4 and 8), which showed a preferential confor-
mation for 2e. The transition state structures were also calcu-
lated and the free energies of activation were found to be 23.6
and 12.4 kcal molꢀ1 for 2e and 3e, respectively (Table 3). The
calculated free energies of activation showed a good correla-
tion with the experimental values obtained by VT NMR.
10.0 mmol) was then added and the mixture was stirred over-
night at room temperature. The reaction mixture was evapo-
rated under vacuum until the aldimine 5c gets precipitated as
a yellow solid, which was filtered and washed with a mixture
of EtOH/H2O (80:20) to provide 2.58 g of 5c (9.90 mmol,
99% yield). A magnetically stirred suspension of 5c
(1.70 g, 6.50 mmol) in absolute methanol (30 mL) was
cooled to 0 ꢁC and treated with sodium borohydride
(0.740 g, 19.5 mmol) for 15 min. The resulting mixture
was stirred at rt for 6 h. The reaction was quenched by
slow addition of water, washed with 25 mL of H2O, ex-
tracted with 3ꢂ25 mL of dichloromethane, and the com-
bined organic phase was dried with magnesium sulfate.
The solvent was then removed under reduced pressure and
the product 1c (2.11 g, 81% yield) was recovered.
Approach to the transition states TS-2e and TS-3e was found
to occur with simultaneous rotation around the Caryl–N bond
of nitro and the amino groups (Fig. 6).
3. Conclusion
In summary, we prepared a series of atropisomeric benz-
amides (2a–e, 3a–e, and 4a–e) from secondary amines 1a–e
in overall yields of 41–72%. The dynamics of bond rotation
have been evaluated by VT NMR techniques. In each case,
only two of the four possible diastereoisomeric conformers
were observed. We found that the rate of interconversion
of the diastereoisomeric conformations is almost completely
dependent on the nature of the ortho-substituent. The nature
of the N–R group has little impact on the rotational barriers.
Furthermore, simulation of rotational barriers about the
Ar–CO and CO–NRR0 bonds at the PM3MM level suggests
gearing of the ortho-substituent (NO2 or NH2) with rotation
about the Ar–CO bond. We obtained only low to moderate
diastereoselectivity and we surmise that the chiral amines
are not enough stereo-differentiating to promote chiral atrop-
isomerism. With a better understanding of the stereochem-
ical dynamics of these atropisomeric benzamides, we are
now positioned to prepare a second generation of atropiso-
meric benzamides and examine their use as ligands in cata-
lytic asymmetric reactions.
4.4.1. Data for (S)-(naphthalen-1-ylmethyl)-a-phenyleth-
ylamine (1c).35 Afforded a pale yellow liquid (82% yield);
1
[a]2D0 ꢀ31.2 (c 1, CHCl3); H NMR (CDCl3, 200 MHz)
d¼1.36 (d, 3H, 3J¼6.6 Hz), 1.64 (br, 1H, NH), 3.86 (q, 1H,
3J¼6.6 Hz), 3.96 (d, 1H, 2J¼13.2 Hz), 4.05 (d, 1H,
2J¼12.8 Hz), 7.18–7.23 (m, 1H), 7.25–7.30 (m, 2H), 7.32–
7.43 (m, 6H), 7.66–7.71 (m, 1H), 7.75–7.80 (m, 1H), 7.93–
7.97 (m, 1H); 13C{1H} NMR (CDCl3, 50 MHz) d¼25.2,
50.0, 58.7, 123.5, 125.1, 125.3, 125.6, 125.8, 126.5, 126.7,
127.4, 128.1, 128.3, 131.4, 133.5, 135.8, 145.1; IR (film)
cmꢀ1: 3318, 3048, 2966, 2907, 2849, 1596, 1508, 1490,
1449, 1396, 1367, 1302, 1261, 1202, 1161, 1114, 1079,
1020, 908, 855, 779, 697, 597, 550; HRMS-ES+ m/z found
261.1516 [(M)+; calcd 261.1517 for C19H19N].
4.4.2. Data for (S)-1-(naphthalen-1-ylmethylene)-a-
phenylethylamine (5c).36 Afforded a light yellow powder
(99% yield), mp 59.8–60.0 ꢁC; [a]D20 ꢀ 49.2 (c 1, CHCl3);
3
1H NMR (CDCl3, 200 MHz) d¼1.58 (d, 3H, J¼6.6 Hz),
3
4.40 (q, 1H, J¼6.6 Hz), 7.14–7.17 (m, 1H), 7.26 (q, 4H,
3J¼7.4 Hz), 7.42 (t, 2H, 3J¼7.0 Hz), 7.62 (d, 1H,
4. Experimental section
4.1. General methods
3
3J¼8.2 Hz), 7.72 (d, 2H, J¼7.0 Hz), 8.72 (s, 1H), 8.97 (d,
3
1H, J¼8.6 Hz); 13C{1H} NMR (CDCl3, 50 MHz) d¼25.9,
71.0, 124.2, 124.6, 125.5, 126.1, 126.3, 126.6, 128.0, 128.8,
130.4, 130.8, 131.0, 132.8, 137.9, 144.7, 158.4; IR (film)
cmꢀ1: 3084, 3037, 2966, 2919, 2861, 1690, 1631, 1613,
1590, 1502, 1484, 1443, 1390, 1361, 1232, 1173, 1114,
1073, 1014, 973, 902, 832, 797, 767, 691; HRMS-ES+ m/z
found 259.1365 [(M)+; calcd 259.1361 for C19H17N].
NMR spectra were obtained on a 300 MHz Fourier trans-
form spectrometer at the University of Pennsylvania and
a 200 MHz at the Universidad de las Americas Puebla
NMR facilities. 1H NMR spectra were referenced to tetrame-
thylsilane; 13C{1H} NMR spectra were referenced to resid-
ual solvent.
Secondary amine 1d and aldimine 5d were prepared accord-
ing to the procedure outlined above.
4.2. (S)-N-(iso-Propyl)-a-phenylethylamine (1a)
Amine 1a was prepared according to the literature proce-
dure.30
4.4.3. Data for (S)-(anthracen-9-ylmethyl)-a-phenylethyl-
amine (1d). Afforded a yellow powder (73% yield), mp
82.0 ꢁC; [a]2D0 ꢀ37.3 (c 1, CHCl3); 1H NMR (CDCl3,
3
4.3. (S)-N-(Benzyl)-a-phenylethylamine (1b)
200 MHz) d¼1.37 (d, 3H, J¼6.6 Hz), 1.68 (br, 1H, NH),
3
2
4.02 (q, 1H, J¼6.6 Hz), 4.39 (d, 1H, J¼12.4 Hz), 4.49
(d, 1H, 2J¼12.2 Hz), 7.29–7.50 (m, 9H), 7.87–7.92 (m,
2H), 8.05–8.09 (m, 2H), 8.28 (s, 1H); 13C{1H} NMR
(CDCl3, 50 MHz) d¼25.3, 44.6, 59.7, 123.9, 124.6, 125.7,
126.7, 126.8, 126.9, 128.3, 128.8, 129.9, 131.2, 131.5,
145.2; IR (film) cmꢀ1: 3343, 3047, 2960, 2910, 2848,
1613, 1601, 1582, 1507, 1488, 1447, 1364, 1326, 1214,
1126, 1102, 1039, 1020, 989, 958, 889, 845, 783, 759,
727, 702, 646, 603; HRMS-ES+ m/z found 312.1737
[(M+H)+; calcd 312.1752 for C23H22N].
Amine 1b was prepared according to the literature proce-
dure.30
4.4. (S)-(Naphthalen-1-ylmethyl)-a-phenylethylamine
(1c)35,36
(S)-a-Phenylethylamine (1.21 g, 10.0 mmol) and solid
K2CO3 (1.38 g, 10.0 mmol) were dissolved in 13.5 mL of
H2O and 50.0 mL of EtOH. 1-Naphthaldehyde (1.56 g,

G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
12661
4.4.4. Data for (S)-(anthracen-9-ylmethylene)-a-phenyl-
ethylamine (5d). Afforded a yellow powder (99% yield),
4.5.3. Data for (S)-N-(naphthalen-1-ylmethyl)-2-nitro-N-
(a-phenylethyl)benzamide (2c). Afforded a pale yellow
foamy solid (86% yield), mp 97.8–98.0 ꢁC; [a]D20 ꢀ71.0 (c
1
mp 118.0 ꢁC; [a]D20 ꢀ12.4 (c 1, CHCl3); H NMR (CDCl3,
200 MHz) d¼1.81 (d, 3H, 3J¼6.6 Hz), 4.84 (q, 1H,
3J¼6.6 Hz), 7.21–7.28 (m, 1H), 7.30–7.48 (m, 6H), 7.55–
7.59 (m, 2H), 7.94–7.99 (m, 2H), 8.39–8.44 (m, 3H), 9.47
(s, 1H); 13C{1H} NMR (CDCl3, 50 MHz) d¼26.0, 72.1,
124.5, 124.9, 126.3, 126.5, 126.8, 128.3, 128.5, 128.9,
129.6, 130.9, 140.5, 144.3, 158.2; IR (film) cmꢀ1: 3072,
3025, 2966, 2919, 2860, 1637, 1513, 1484, 1443, 1378,
1296, 1255, 1155, 1114, 1067, 1014, 961, 897, 867, 838,
791, 756, 732, 697, 657, 609; HRMS-ES+ m/z found
310.1596 [(M+H)+; calcd 310.1596 for C23H20N].
1, CHCl3); H NMR (DMSO-d6, T¼175 ꢁC, 200 MHz)
1
d¼1.62 (d, 3H, 3J¼4.8 Hz), 4.92 (d, 1H, 2J¼16.6 Hz),
5.17 (d, 1H, 2J¼17.2 Hz), 5.34 (br, 1H), 7.21–7.85 (m,
15H), 8.08 (br, 1H); 13C{1H} NMR (DMSO-d6,
T¼185 ꢁC, 50 MHz) d¼17.2, 44.1, 55.5, 121.0, 122.8,
123.3, 123.5, 123.7, 124.3, 125.6, 125.8, 126.4, 126.6,
126.8, 128.3, 129.0, 130.2, 131.3, 131.7, 132.2, 138.5,
143.8, 165.8; IR (film) cmꢀ1: 3060, 2990, 2931, 2872,
1631, 1572, 1525, 1484, 1443, 1408, 1378, 1343, 1314,
1261, 1208, 1149, 1073, 1020, 991, 850, 785, 756, 703;
HRMS-ES+ m/z found 433.1541 [(M+Na)+; calcd
433.1528 for C26H22N2O3Na].
4.4.5. (S,S)-Bis(a-phenylethyl)amine (1e). Amine 1e was
prepared according to the literature procedure.31
4.5.4. Data for (Ra,S,E)-N-(anthracen-9-ylmethyl)-2-
nitro-N-(a-phenylethyl)benzamide (2d). Afforded a pale
yellow solid (74% yield), mp 161.8–162 ꢁC; [a]D20 ꢀ83.9
4.5. General procedure for the preparation of 2-nitro-
benzamides (2a–e)
1
(c 1, CHCl3); H NMR (DMSO-d6, T¼165 ꢁC, 200 MHz)
2
A solution of the secondary amine 2a–e (3.00 mmol), and
triethylamine (6.00 mmol) in dichloromethane (10 mL)
was slowly added to an ice cooled solution of 2-nitrobenzoyl
chloride (4.20 mmol) in dichloromethane (10 mL). The re-
sulting mixture was allowed to warm to rt and stirred for
2 h. The solution was quenched with 25 mL of H2O, ex-
tracted with 3ꢂ25 mL of dichloromethane, and the com-
bined organic phase was dried with magnesium sulfate.
The solvent was then removed under reduced pressure and
the 2-nitro-benzamides were recovered. The crude products
were purified by flash chromatography on deactivated silica
gel (Et3N/SiO2¼2.5% v/v, hexanes/EtOAc (80:20) to afford
2a–e.
d¼1.34 (br, 3H), 4.95 (br, 1H), 5.54 (d, 1H, J¼15.0 Hz),
2
5.74 (d, 1H, J¼15.0 Hz), 7.00–7.08 (m, 5H), 7.34–7.60
(m, 7H), 7.98–8.12 (m, 5H), 8.43 (s, 1H); 13C{1H} NMR
(DMSO-d6, T¼165 ꢁC, 50 MHz) d¼16.0, 40.7, 54.5,
122.5, 122.7, 123.2, 124.4, 125.1, 125.4, 125.8, 126.1,
126.2, 126.6, 127.2, 128.0, 129.3, 129.4, 131.5, 132.1,
137.9, 143.4, 165.6; IR (film) cmꢀ1: 3048, 2989, 1631,
1572, 1531, 1448, 1417, 1345, 1252, 1219, 1159, 1028,
991, 889, 854, 788, 734, 698, 624; recrystallized from
hexanes/EtOAc (1:1); yellow prism, 0.60ꢂ0.38ꢂ
0.28 mm3, C30H24N2O3. Monoclinic, P21, a¼12.0572(12),
b¼6.1558(13), c¼15.8216(19) A, b¼95.225(7)ꢁ, Z¼2,
˚
rcalcd¼1.308 g cmꢀ3. A set of 6838 reflections was collected
˚
at T¼296(1) K using Mo Ka radiation (l¼0.71073 A,
4.5.1. Data for (S)-N-iso-propyl-2-nitro-N-(a-phenyl-
ethyl)benzamide (2a). Afforded white crystals (78% yield),
Bruker P4 diffractometer), corresponding to 2qmax¼55ꢁ.
For the refinement of 318 parameters, 2923 independent re-
flections (Friedel pairs merged, Rint¼0.0189) were used,
without neither restraints nor constraints (SHELXTL 5.10
package).37 All H atoms were placed in idealized positions
and refined using a standard riding model. The absolute con-
figuration of the chiral center was assigned as S-C11. Final R
indices: R1¼0.0337 for 2509 reflections with I>2s(I) and
wR2¼0.0923 for all data. CCDC deposition number:
601708. Structure factors and raw files are available on re-
quest to authors. HRMS-ES+ m/z found 483.1698
[(M+Na)+; calcd 483.1685 for C30H24N2O3Na].
1
mp 161.8–162.0 ꢁC; [a]D20 ꢀ112.3 (c 1, CHCl3); H NMR
(DMSO-d6, T¼175 ꢁC, 200 MHz) d¼1.21 (d, 3H,
3J¼7.4 Hz), 1.41 (d, 3H, 3J¼6.6 Hz), 1.76 (d, 3H,
3J¼6.6 Hz), 3.69 (m, 1H, 3J¼6.6 Hz), 4.79 (q, 1H,
7.0 Hz), 7.21–7.56 (m, 5H), 7.62–7.89 (m, 3H), 8.17 (t,
13
1H, 3J¼7.6 Hz); C{1H} NMR (DMSO-d6, T¼175 ꢁC,
50 MHz) d¼17.5, 19.6, 19.7, 44.5, 53.8, 122.9, 125.2,
125.5, 126.0, 126.3, 128.0, 132.6, 170.1; IR (film) cmꢀ1
:
3060, 2978, 2931, 2872, 1637, 1572, 1525, 1478, 1437,
1349, 1261, 1190, 1138, 1096, 1061, 1026, 967, 908, 850,
785, 756, 703, 662; HRMS-ES+ m/z found 313.1540
[(M+H)+; calcd 313.1552 for C18H21N2O3].
4.5.5. Data for (Sa,S,S)-2-nitro-N,N-bis(a-phenylethyl)-
benzamide (2e). Afforded colorless crystals (80% yield),
1
4.5.2. Data for (S)-N-benzyl-2-nitro-N-(a-phenylethyl)-
benzamide (2b). Afforded yellow crystals (82% yield),
mp 150.0–151.0 ꢁC; [a]D20 ꢀ48.9 (c 1, CHCl3); H NMR
(DMSO-d6, T¼165 ꢁC, 200 MHz) d¼1.56 (br, 1H), 1.80
(d, 5H, 3J¼6.6 Hz), 4.85 (br, 2H), 7.16 (d, 3J¼1.6 Hz,
8H), 7.25–7.55 (m, 3H), 7.70 (m, 1H), 7.82 (t, 1H,
3J¼7.8 Hz), 8.19 (d, 1H, 3J¼8.0 Hz); 13C{1H} NMR
(DMSO-d6, T¼165 ꢁC, 50 MHz) d¼17.6, 18.0, 54.7,
123.2, 125.3, 125.8, 125.9, 126.1, 126.3, 126.5, 126.6,
1
mp 92.0–92.3 ꢁC; [a]D20 ꢀ104.9 (c 1, CHCl3); H NMR
(DMSO-d6, T¼175 ꢁC, 200 MHz) d¼1.60 (d, 3H,
3J¼6.2 Hz), 4.23 (dd, 1H, J0¼15.8 Hz, J00¼2.8 Hz), 4.66
2
(d, 1H, J¼15.6 Hz), 5.32 (br, 1H), 7.16–7.34 (m, 10H),
7.46–7.50 (m, 1H), 7.55–7.70 (m, 2H), 8.09–8.13 (m, 1H);
13C{1H} NMR (DMSO-d6, T¼175 ꢁC, 50 MHz) d¼17.1,
47.1, 55.0, 122.7, 125.0, 125.6, 125.9, 126.2, 126.5, 126.6,
128.2, 131.3, 132.2, 136.3, 138.5, 143.9, 165.6; IR (film)
cmꢀ1: 3060, 3025, 2978, 2931, 2872, 1637, 1572, 1525,
1490, 1437, 1408, 1343, 1261, 1202, 1143, 1073, 1026,
991, 961, 914, 850, 785, 750, 697; HRMS-ES+ m/z found
361.1568 [(M+H)+; calcd 361.1552 for C22H21N2O3].
128.3, 132.1, 132.7, 132.9, 139.1, 164.4; IR (film) cmꢀ1
:
3062, 3031, 2980, 2942, 1639, 1574, 1527, 1496, 1430,
1346, 1319, 1280, 1260, 1204, 1156, 1086, 1008, 1024,
964, 876, 853, 791, 753, 697, 666; recrystallized from hex-
anes/Et2O (1:1); colorless block, 0.60ꢂ0.38ꢂ0.36 mm3,
C23H22N2O3. Orthorhombic, P212121, a¼8.669(4),
b¼12.327(7), c¼18.410(8) A, Z¼4, rcalcd¼1.264 g cmꢀ3
.
˚

12662
G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
A set of 4549 reflections was collected at T¼296(2) K using
a colorless solid (88% yield); [a]2D0 ꢀ52.2 (c 1, CHCl3);
3
1H NMR (CDCl3, 200 MHz) d¼1.43 (d, 3H, J¼7.0 Hz),
˚
Mo Ka radiation (l¼0.71073 A, Siemens P4 diffractome-
2
ter), corresponding to 2qmax¼52ꢁ. For the refinement of
256 parameters, 50 independent reflections 2276 (Friedel
pairs merged, Rint¼0.0651) were used, without neither re-
straints nor constraints (SHELXTL 5.10 package).37 All H
atoms were placed in idealized positions and refined using
a standard riding model. The absolute configurations of the
chiral centers were assigned as S-C8, S-C16 assuming an un-
changed configuration for the chiral starting material during
the synthesis. Final R indices: R1¼0.0511 for 1432 reflec-
tions with I>2s(I) and wR2¼0.1649 for all data. CCDC de-
position number: 623376. Structure factors and raw files are
available on request to authors. HRMS-ES+ m/z found
375.1713 [(M+H)+; calcd 375.1709 for C23H23N2O3].
4.39–4.44 (m, 3H), 5.40 (d, 1H, J¼16.0 Hz), 5.57 (q, 1H,
3
3J¼6.2 Hz), 6.66–6.75 (m, 2H), 7.14 (t, 1H, J¼7.2 Hz),
3
7.21–7.47 (m, 9H), 7.71 (t, 1H, J¼4.8 Hz), 7.78–7.84 (m,
3H); 13C{1H} NMR (CDCl3, 50 MHz) d¼18.5, 44.3, 57.3,
116.9, 117.3, 120.6, 122.5, 123.7, 125.0, 125.3, 125.7,
126.6, 127.0 127.2, 127.3, 128.3, 128.5, 130.3, 133.3,
139.9, 145.3, 171.7; IR (film) cmꢀ1: 3412, 3331, 3248,
3048, 2978, 2931, 1613, 1596, 1490, 1449, 1408, 1308,
1261, 1149, 1073, 1026, 996, 791, 756, 650; recrystallized
from hexanes/EtOAc (1:1); colorless prism, 0.6ꢂ0.4ꢂ
0.2 mm3, C26H24N2O. Monoclinic, P21, a¼9.2527(11),
b¼10.607(3), c¼10.9807(12) A, b¼90.579(8)ꢁ, Z¼2,
˚
rcalcd¼1.173 g cmꢀ3. A set of 2664 reflections was collected
˚
at T¼296(1) K using Mo Ka radiation (l¼0.71073 A,
4.6. General procedure for the preparation of 2-amino-
benzamides (3a–e)
Bruker P4 diffractometer), corresponding to 2qmax¼50ꢁ.
For the refinement of 272 parameters, 2007 independent re-
flections (Friedel pairs merged, Rint¼0.0123) were used,
without neither restraints nor constraints (SHELXTL 5.10
package).37 H atoms of the NH2 functionality were found
in a difference map and refined with free coordinates and
isotropic displacement parameters. Other H atoms were
placed in idealized positions and refined using a standard
riding model. The absolute configuration of the chiral center
was assigned as S-C11. Final R indices: R1¼0.0411 for 1689
reflections with I>2s(I) and wR2¼0.1166 for all data.
CCDC deposition number: 601709. Structure factors and
raw files are available on request to authors. HRMS-ES+
m/z found 403.1774 [(M+Na)+; calcd 403.1786 for
C26H24N2ONa].
A solution of the 2-nitrobenzamides 2a–e (1.00 mmol) and
5% acetic acid solution (17 mL) in EtOH/H2O (80:20) was
treated with iron powder (16.0 mmol). The resulting solution
was then heated under reflux for 5 h with vigorous stirring.
The mixture was cooled in an ice bath followed by addition
of 20% aqueous NaHCO3 (20 mL) and dichloromethane
(50 mL). The resulting mixture was filtered over Celite, ex-
tracted with 3ꢂ25 mL of dichloromethane, and the com-
bined organic phase was dried over magnesium sulfate.
After filtration the solvent was removed under reduced pres-
sure. The crude product was purified by flash chromato-
graphy on deactivated silica gel (Et3N/SiO2¼2.5% v/v,
hexanes/EtOAc (80:20)) to afford the products 3a–e.
4.6.4. Data for (S)-2-amino-N-(anthracen-9-ylmethyl)-N-
(a-phenylethyl)benzamide (3d). Afforded a yellow solid
(95% yield), mp 80.0–80.1 ꢁC; [a]D20 ꢀ144.7 (c 1.0,
CHCl3); 1H NMR (CDCl3, 200 MHz) d¼0.64 (d, 3H,
3J¼7.0 Hz), 4.47 (br, 2H, NH), 5.07–5.14 (m, 2H), 6.23
(d, 1H, 2J¼15.4 Hz), 6.59–6.74 (m, 2H), 6.94–6.98 (m,
2H), 7.06–7.20 (m, 5H), 7.27–7.42 (m, 4H), 7.89–7.93 (m,
4H), 8.32 (s, 1H); 13C{1H} NMR (CDCl3, 50 MHz)
d¼17.7, 39.7, 57.1, 116.7, 117.3, 121.1, 124.2, 124.6,
125.7, 126.9, 127.0, 127.7, 128.0, 128.7, 129.2, 130.2,
130.5, 131.0, 139.0, 145.1, 172.0; IR (film) cmꢀ1: 3454,
3357, 3052, 2977, 1733, 1615, 1587, 1493, 1449, 1410,
1334, 1253, 1158, 1027, 992, 887, 843, 789, 731; HRMS-
ES+ m/z found 453.1922 [(M+Na)+; calcd 453.1943 for
C30H26N2ONa].
4.6.1. Data for (S)-2-amino-N-iso-propyl-N-(a-phenyl-
ethyl)benzamide (3a). Afforded a colorless liquid (95%
yield); [a]2D0 ꢀ140.8 (c 1, CHCl3); 1H NMR (CDCl3,
300 MHz) d¼1.05 (d, 3H, 3J¼6.7 Hz), 1.38 (d, 3H,
(br, 2H), 4.91 (q, 1H, 3J¼6.9 Hz), 6.65–6.71 (m, 2H), 7.05–
7.09 (m, 2H), 7.17–7.18 (m, 1H), 7.19–7.23 (m, 2H), 7.26–
7.33 (m, 2H); 13C{1H} NMR (CDCl3, 75 MHz) d¼17.8,
20.5, 21.3, 48.3, 57.1, 117.2, 118.2, 126.2, 127.5, 127.7,
128.4, 130.0, 144.4, 170.9; IR (film) cmꢀ1: 3436, 3342,
3213, 3049, 2966, 2931, 2872, 1619, 1590, 1490, 1455,
1361, 1325, 1261, 1196, 1178, 1138, 1096, 1026, 967, 908,
855, 820, 785, 756, 697, 644; HRMS-ES+ m/z found
305.1639 [(M+Na)+; calcd 305.1630 for C18H22N2ONa].
3
3J¼6.8 Hz), 1.60 (d, 3H, J¼6.9 Hz), 3.40 (br, 1H), 3.78
4.6.2. Data for (S)-2-amino-N-benzyl-N-(a-phenylethyl)-
benzamide (3b). Afforded a colorless liquid (81% yield);
4.6.5. Data for (Ra,S,S)-2-amino-N,N-bis(a-phenylethyl)-
benzamide (3e). Afforded colorless crystals (82% yield),
1
1
[a]2D0 ꢀ127.7 (c 1, CHCl3); H NMR (CDCl3, 200 MHz)
mp 115.0–116.0 ꢁC; [a]D20 ꢀ43.1 (c 1, CHCl3); H NMR
d¼1.46 (d, 3H, 3J¼7.0 Hz), 3.91 (d, 1H, 2J¼15.4 Hz),
4.30 (br, 2H, NH), 4.84 (d, 1H, 2J¼15.0 Hz), 5.44 (br,
1H), 6.62–6.69 (m, 2H), 7.03–7.29 (m, 12H); 13C{1H}
NMR (CDCl3, 50 MHz) d¼18.7, 46.3, 56.1, 116.6, 117.1,
120.6, 126.3, 126.4, 126.7, 126.9, 127.1, 127.8, 128.1,
130.0, 138.4, 139.6, 144.8, 171.3; IR (film) cmꢀ1: 3448,
3229, 3064, 3019, 2970, 2933, 1609, 1590, 1483, 1442,
1397, 1294, 1156, 1025, 751, 686; HRMS-ES+ m/z found
353.1639 [(M+Na)+; calcd 353.1631 for C22H22N2ONa].
(CDCl3, 200 MHz) d¼1.78 (d, 6H, J¼7.4 Hz) 3.92 (br,
3
2H, NH), 4.88 (q, 2H, 3J¼7.0 Hz), 6.67–6.76 (m, 2H);
7.07–7.15 (m, 12H) 13C{1H} NMR (CDCl3, 50 MHz)
d¼19.3, 56.0, 116.5, 117.6, 123.2, 125.7, 126.8, 127.7,
129.4, 140.2, 143.8, 169.9; IR (film) cmꢀ1: 3444, 3348,
3060, 3029, 2977, 2939, 1616, 1494, 1452, 1430, 1320,
1206, 1156, 1096, 1024, 966, 884, 793, 749, 697; recrystal-
lized from hexanes/Et2O; colorless prism, 0.6ꢂ0.4ꢂ
0.4 mm3, C23H24N2O. Monoclinic, P21, a¼8.6721(17),
ꢁ
˚
b¼9.555(2), c¼12.031(2) A, b¼104.235(8) , Z¼2, rcalcd
¼
4.6.3. Data for (Ra,S,E)-2-amino-N-(naphthalen-1-yl-
methyl)-N-(a-phenylethyl)benzamide (3c). Afforded
1.184 g cmꢀ3. A set of 3847 reflections was collected at
˚
T¼296(1) K using Mo Ka radiation (l¼0.71073 A, Siemens

G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
12663
P4 diffractometer), corresponding to 2qmax¼49.98ꢁ. 1803
independent reflections (Friedel pairs merged, Rint¼0.0241)
were used for the refinement of 243 parameters, without nei-
ther restraints nor constraints (SHELXTL 5.10 package).37
H atoms of the NH2 functionality were found in a difference
map and refined with free coordinates and isotropic displace-
ment parameters. Other H atoms were placed in idealized
positions and refined using a standard riding model. The ab-
solute configurations of the chiral centers were assigned as
S-C11, S-C19. Final R indices: R1¼0.0314 for 1737 reflec-
tions with I>2s(I) and wR2¼0.0861 for all data. CCDC de-
position number: 623377. HRMS-ES+ m/z found 367.1783
[(M+Na)+; calcd 367.1786 for C23H24N2ONa].
88.2–88.3 ꢁC; [a]D20 ꢀ21.8 (c 1, CHCl3); 1H NMR (CDCl3,
300 MHz) d¼1.22 (s, 9H) 1.38–1.43 (m, 3H), 4.43 (d, 1H,
2J¼16.8 Hz), 5.40 (br, 1H), 6.62–6.71 (m, 1H), 7.17–7.41
(m, 15H), 7.41–7.67 (m, 4H), 8.51 (br, 1H, NH); 13C{1H}
NMR (CDCl3, 75 MHz) d¼18.3, 29.9, 31.2, 35.3, 58.6,
117.7, 123.2, 125.5, 126.0, 126.2, 126.4, 127.2, 127.4,
127.6, 127.8, 127.9, 128.2, 128.8, 129.1, 131.3, 132.7,
133.8, 137.3, 140.1, 156.9, 171.2; IR (film) cmꢀ1: 3272,
3060, 2966, 2872, 1619, 1602, 1490, 1449, 1396, 1337,
1267, 1208, 1161, 1108, 1090, 1020, 920, 791, 756, 697,
620; recrystallized from hexanes/acetone (2:1); colorless
plate, 0.60ꢂ0.38ꢂ0.06 mm3, C36H36N2O3S (C3H6O)1.5
.
Monoclinic, P21, a¼14.1816(19), b¼9.4551(17), c¼
15.476(3) A, b¼106.429(15) , Z¼2, rcalcd¼1.108 g cmꢀ3
.
ꢁ
˚
4.7. General procedure for preparation of 2-(4-tert-
butylphenylsulfonamido)benzamides (4a–e)
A set of 9391 reflections was collected at T¼296(1) K using
˚
Mo Ka radiation (l¼0.71073 A, Bruker P4 diffractometer),
corresponding to 2qmax¼50ꢁ. Raw data were corrected for
a significant intensity decay of ca. 16% suffered by the sam-
ple during data collection, and absorption effects. 3733 inde-
pendent reflections (Friedel pairs merged, Rint¼0.0482)
were used for the refinement of 455 parameters, correspond-
ing to a model including restrained geometry for the solvent
molecules (SHELXTL 5.10 package).37 H atoms were
placed in idealized positions and refined using a standard
riding model. The absolute configuration of the chiral center
was assigned as S-C11. Final R indices: R1¼0.0741 for 2522
reflections with I>2s(I) and wR2¼0.1822 for all data.
CCDC deposition number: 601710. Structure factors and
raw files are available on request to authors. HRMS-ES+
m/z found 599.2366 [(M+Na)+; calcd 599.2344 for
C36H36N2O3NaS].
para-tert-Butylbenzensulfonyl chloride (0.200 mmol) was
added to a solution of 3a–e (0.100 mmol) in pyridine
(2 mL). The mixture was then stirred overnight at room tem-
perature and the pyridine was removed under high vacuum.
Aqueous HCl (0.20 M, 15 mL) was added to the residue,
which was then extracted with 3ꢂ25 mL of dichloromethane
and the combined organic phase was dried with magnesium
sulfate. The solvent was then removed under reduced pres-
sure. The crude product was purified by flash chromato-
graphy on deactivated silica gel (Et3N/SiO2¼2.5% v/v,
hexanes/EtOAc (91:9)) to afford the products 4a–e.
4.7.1. Data for (S)-2-(4-tert-butylphenylsulfonamido)-N-
iso-propyl-N-(a-phenylethyl)benzamide (4a). Afforded
pale yellow crystals (69% yield), mp 78.3–78.5 ꢁC; [a]D20
1
ꢀ76.5 (c 1, CHCl3); H NMR (CDCl3, 300 MHz) d¼1.17
4.7.4. Data for (S)-N-(anthracen-9-ylmethyl)-2-(4-tert-
butylphenylsulfonamido)-N-(a-phenylethyl)benzamide
(4d). Afforded a yellow powder (77% yield), mp 116.0–
3
3
(d, 3H, J¼6.5 Hz), 1.26 (d, 3H, J¼6.0 Hz), 1.31 (s, 9H),
1.63 (br, 3H), 3.58 (br, 1H), 4.87 (br, 1H), 7.03 (t, 1H,
3J¼7.4 Hz), 7.22–7.36 (m, 6H), 7.48 (d, 2H, J¼8.6 Hz),
116.5 ꢁC; [a]D20 ꢀ127.6 (c 1, CHCl3); H NMR (CDCl3,
3
1
7.56 (d, 2H, 3J¼8.0 Hz), 7.86 (d, 2H, 3J¼8.0 Hz), 8.28 (br,
1H, NH); 13C{1H} NMR (CDCl3, 75 MHz) d¼18.2, 20.7,
21.5, 31.2, 35.3, 50.0, 123.4, 126.4, 127.2, 127.5, 128.7,
130.5, 136.1, 137.7, 156.9; IR (film) cmꢀ1: 3272, 3060,
2966, 2872, 1613, 1594, 1484, 1443, 1396, 1326, 1273,
1161, 1114, 1085, 1014, 926, 837, 756, 697, 620; HRMS-
ES+ m/z found 501.2196 [(M+Na)+; calcd 501.2188 for
C28H34N2O3NaS].
300 MHz) d¼0.61(d, 3H, J¼6.5 Hz), 1.22 (s, 9H), 4.96
3
(q, 1H, 3J¼6.5 Hz), 5.21 (d, 1H, 2J¼14.5 Hz), 6.08 (d, 1H,
2J¼14.5 Hz); 6.98–7.03 (m, 3H), 7.23–7.33 (m, 6H), 7.47–
7.58 (m, 8H), 7.91–7.02 (m, 4H), 8.43 (s, 1H), 8.65 (br,
1H, NH); 13C{1H} NMR (CDCl3, 75 MHz) d¼17.1, 29.9,
31,2, 35.3, 56.9, 118.8, 122.8, 124.1, 124.9, 125.2, 126.5,
126.7, 127.1, 127.2, 127.5, 128.3, 128.7, 129.4, 131.1,
131.2, 131.5, 136.9, 137.3, 139.2, 157.0, 171.5; IR (film)
cmꢀ1: 3327, 3056, 3023, 2966, 2872, 1613, 1539, 1493,
1449, 1399, 1334, 1254, 1169, 1113, 1082, 1027, 993,
925, 834, 755, 733, 699; HRMS-ES+ m/z found 649.2532
[(M+Na)+; calcd 649.2501 for C40H38N2O3NaS].
4.7.2. Data for (S)-N-benzyl-2-(4-tert-butylphenylsulfon-
amido)-N-(a-phenylethyl)benzamide (4b). Afforded a yel-
low powder (70% yield), mp 80.2–80.5 ꢁC; [a]D20 ꢀ85.1 (c
1
1.0, CHCl3); H NMR (CDCl3, 200 MHz) d¼1.28 (s, 9H),
1.50 (d, 3H, 3J¼6.6 Hz), 3.64 (m, 1H), 3.93 (d, 1H,
4.7.5. Data for (Sa,S,S)-2-(4-tert-butylphenylsulfon-
amido)-N,N-bis(a-phenylethyl)benzamide (4e). Afforded
colorless crystals (79% yield), mp 153.0–154.0 ꢁC; [a]D20
2J¼15.8 Hz), 5.38 (br, 1H), 6.96 (m, 1H), 7.13–7.38 (m,
3
14H), 7.55 (d, 1H, J¼7.6 Hz), 7.74–7.79 (m, 2H), 8.42
(br, 1H, NH); 13C{1H} NMR (CDCl3, 50 MHz) d¼19.3,
31.9, 35.9, 49.8, 57.8, 119.9, 122.8, 125.8, 126.6, 126.8,
127.6, 128.2, 128.5, 130.6, 135.9, 136.6, 137.6, 139.3,
156.0, 170.2; IR (film) cmꢀ1: 3272, 3049, 3025, 2954,
2872, 1619, 1596, 1490, 1449, 1402, 1331, 1279, 1202,
1161, 1085, 920, 750, 697, 620; HRMS-ES+ m/z found
549.2205 [(M+Na)+; calcd 549.2188 for C32H34N2O3NaS].
ꢀ38.8 (c 1, CHCl3); H NMR (CDCl3, 200 MHz) d¼1.31
1
3
3
(s, 9H), 1.73 (d, 6H, J¼7.0 Hz), 4.91 (q, 2H, J¼6.6 Hz),
7.00–7.04 (m, 2H), 7.08–7.17 (m, 4H), 7.19–7.28 (m, 8H),
7.42–7.48 (m, 2H), 7.77–7.82 (m, 2H), 8.60 (br, 1H, NH);
13C{1H} NMR (CDCl3, 50 MHz) d¼19.6, 31.7, 35.8, 56.4,
119.8, 122.9, 126.0, 126.1, 126.7, 127.2, 127.3, 128.0,
129.9, 135.2, 137.1, 139.6, 156.0, 168.6; IR (film) cmꢀ1
:
3060, 3031, 2965, 2869, 1598, 1493, 1451, 1435, 1324,
1281, 1203, 1166, 1113, 1087, 1024, 968, 925, 792, 757,
698; recrystallized from hexanes/Et2O; colorless irregular,
0.6ꢂ0.6ꢂ0.4 mm3, C33H36N2O3S. Tetragonal, P41212,
4.7.3. Data for (Ra,S,E)-2-(4-tert-butylphenylsulfon-
amido)-N-(naphthalen-1-ylmethyl)-N-(a-phenylethyl)-
benzamide (4c). Afforded a yellow powder (89% yield), mp

12664
G. Huelgas et al. / Tetrahedron 63 (2007) 12655–12664
˚
16. Rios, R.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10272–10273.
17. Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002,
67, 8682–8684.
a¼13.3920(13), b¼13.3920(13), c¼34.679(4) A, Z¼8,
rcalcd¼1.155 g cmꢀ3. A set of 10,777 reflections was col-
lected at T¼296(1) K using Mo Ka radiation (l¼
˚
0.71073 A, Siemens P4 diffractometer), corresponding to
2qmax¼50.02ꢁ. For the refinement of 388 parameters, 5301
independent reflections (Rint¼0.0670) were used
(SHELXTL 5.10 package).37 H atoms were placed in ideal-
ized positions and refined using a standard riding model. The
t-Bu group is strongly disordered and was modeled with two
positions for each methyl group. The absolute configurations
of the chiral centers were assigned as S-C11, S-C19, and
confirmed by refinement of a Flack parameter, x¼0.08(17),
based on non-merged Friedel pairs. Final R indices:
R1¼0.0637 for 2908 reflections with I>2s(I) and
wR2¼0.1900 for all data. CCDC deposition number:
623378. Structure factors and raw files are available on
request to authors. HRMS-ES+ m/z found 563.2350
[(M+Na)+; calcd 563.2344 for C33H36N2O3NaS].
18. Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003, 14,
587–592.
19. Chan, V.; Kim, J. G.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. Org.
Lett. 2004, 6, 2051–2053.
20. Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T.
J. Am. Chem. Soc. 2005, 127, 3676–3677.
21. Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006,
4586–4587.
22. Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org.
Chem. 2000, 65, 7033–7040.
23. Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron: Asymmetry
2001, 12, 695–698.
24. Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802–
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25. Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2002, 124, 6929–6941.
26. Honda, A.; Waltz, K.; Carroll, P. J.; Walsh, P. J. Chirality 2003,
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Acknowledgements
27. Mino, T.; Kashihara, K.; Yamashita, M. Tetrahedron:
Asymmetry 2001, 12, 287–291.
We thank CONACYT, Consejo Nacional de Ciencia y
ꢁ
Tecnologıa (Project No. V39500-Q). C.A.P. thanks the
ꢁ
28. Juaristi, E.; Escalante, J.; Leon-Romo, J. L.; Reyes, A.
Tetrahedron: Asymmetry 1998, 9, 715–740.
Petroleum Research Fund (Summer Scholar Grant No.
41805-AC-1), and G.H. thanks CONACYT Grant No
144893. P.J.W. acknowledges the US National Science
Foundation (CHE-0615210) for support of this work.
ꢁ
29. Juaristi, E.; Leon-Romo, J. L.; Reyes, A. Tetrahedron:
Asymmetry 1999, 10, 2441–2495.
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