2-(2-Hydroxyaryl)cinnamic amides: a new class of axially chiral molecules

Article abstract of DOI:10.1016/j.tet.2006.07.019

The syntheses of several differently substituted amides formally derived from a chiral amine, either E-2-(2-hydroxyphenyl)cinnamic acid or both E- and Z-2-(2-hydroxynaphthyl)cinnamic acid, are reported. These molecules display a restricted rotation about

Full text of DOI:10.1016/j.tet.2006.07.019

Tetrahedron 62 (2006) 8943–8951
2-(2-Hydroxyaryl)cinnamic amides: a new class of axially
chiral molecules
Chiara Marelli,a Chiara Monti,b Simona Galli,a Norberto Masciocchia and Umberto Piarullia,
*
aDipartimento di Scienze Chimiche e Ambientali, Universitaꢀ degli Studi dell’Insubria, Via Valleggio, 11, I-22100 Como, Italy
bDipartimento di Chimica Organica e Industriale, Universitaꢀ degli Studi di Milano, Via Venezian, 21, I-20133 Milano, Italy
Received 20 April 2006; revised 14 June 2006; accepted 6 July 2006
Available online 28 July 2006
Abstract—The syntheses of several differently substituted amides formally derived from a chiral amine, either E-2-(2-hydroxyphenyl)-
cinnamic acid or both E- and Z-2-(2-hydroxynaphthyl)cinnamic acid, are reported. These molecules display a restricted rotation about the
1
C2–Caryl bond. The barriers to rotation about the C2–Caryl bond were measured by the dynamic H NMR and were found to vary between
11.8 and 24.5 kcal molꢀ1, depending on the substitution. In particular, E-2-(2-hydroxynapthyl)cinnamic amides, displayed a high barrier to
rotation (DGzc¼24.4 kcal molꢀ1) and could be isolated in both diastereomerically pure forms at room temperature. The X-ray structure of one
E-2-(2-hydroxynapthyl)cinnamic amide, was resolved, enabling for the determination of the absolute configuration of the chiral axis (aR).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
As a part of the project aimed at synthesizing new chiral
structures to be used as ligands in catalytic asymmetric
applications, we decided to investigate the chiral 2-(2-
hydroxyaryl)cinnamic amides 1 (Fig. 1), obtained from the
coupling of the corresponding 2-(2-hydroxyaryl) cinnamic
acids and a chiral primary amine. These molecules were cho-
sen since they possess several potential sites of diversity (R1,
R2, R3 and Ar), which allow for the fine-tuning of their steric,
electronic and conformational properties. In addition, we
were also intrigued by the fact that they were structurally
reminiscent of biaryl compounds and might display
restricted rotation about the C2–Caryl bond and, depending
on the energetic barrier to rotation, be resolved into two
diastereomeric atropisomeric forms.
Axial chirality represents one of the most interesting stereo-
chemical features of modern synthetic chemistry. Axially
chiral molecules are often used as versatile auxiliaries or
as ligands in transition-metal promoted asymmetric synthe-
sis,1 and nature offers a large number of representatives of
this class of compounds, with, in many cases, interesting
pharmacological activities.2 Axial chirality is often associ-
ated with atropisomerism and atropisomers, i.e., with the
stereoisomers resulting from hindered rotation about single
bonds, where the barrier to rotation is high enough to allow
for the isolation of the conformers. The condition for the
existence of atropisomerism has been defined as one where
stereoisomers can be isolated and have a half-life of at least
1000 s.3 The most extensively studied class of atropisomers
is biaryls,4 especially with respect to the substitution
required for restricted rotation. Reported examples of other
classes of atropisomeric molecules include: substituted
styrenes,5 axially chiral amides (e.g., anilides,6 benzamides7
and 1-naphthamides8), o-substituted arylcarbinols of the
Ar–C(OH)R2 type,9 5,6-disubstituted-3,4-dihydro-1H-pyridin-
2-ones,10 o-substituted N-aryl-4-alkyl-thiazoline-2-thiones11
and substituted N-(2-hydroxynaphthalen-1yl)-N,N0-diacyl-
hydrazines.12
Herein we report the syntheses of several differently
substituted amides of general type 1 (Fig. 1) derived from
2-(2-hydroxyphenyl)cinnamic and 2-(2-hydroxynaphthyl)-
cinnamic acid. The barriers to rotation about the C2–Caryl
bond were experimentally determined for both the phenyl
and naphthyl derivatives by dynamic 1H NMR methods
O
O
R1*
H
R1*
H
Ar
R2
Ar
N
OH
N
OH
R2
R3
R3
1
1
R1*NH = chiral amine
Keywords: Axial chirality; Cinnamic acid; Atropisomerism.
* Corresponding author. Tel.: +39 031 238 6444; fax: +39 031 238 6449;
e-mail: umberto.piarulli@uninsubria.it
Figure 1. General structure and atropisomeric behaviour of amides 1, and
their similarity to biaryl compounds (dashed lines).
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.019

8944
C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
and were found to be significantly lower than those ob-
served in biaryls bearing similar substitution pattern. In
particular, E-2-(2-hydroxynapthyl)cinnamic amides, dis-
played a high barrier to rotation (DGzc>24.4 kcal molꢀ1
)
and both diastereomerically pure forms could be isolated
at room temperature. The X-ray structure of one E-2-(2-
hydroxynapthyl)cinnamic amide, was determined and the
absolute configuration of the chiral axis assigned.
2. Results and discussion
The syntheses of 2-(2-hydroxyphenyl)cinnamic amides 3
were performed using 2-hydroxyphenylacetic acid, as a start-
ing material, which was converted into lactones 2a–c
(Scheme 1 and Table 1), through a Perkin condensation
with different aromatic aldehydes.13
Figure 2. Ortep representation (30% probability level) of the X-ray molec-
ular structure of lactone E-2a. Carbon, grey; hydrogen, light grey; oxygen,
red.
COOH
OH
O
O
NHR O
RNH2
Ar
Ph
Ph
a)
O
O
O
Ph
NH2
+
2a Ar = C6H5 (62%)
2b Ar = o-MeO-C6H4 (86%)
2c Ar = p-NO2-C6H4 (35%)
2a
O
O
RNH2
R
O
N
H
O
N
H
OH
Ph
Ar
OH
b)
4
3a Ar = C6H5 (84%)
3b Ar = o-MeO-C6H4 (41%)
3c Ar = p-NO2-C6H4 (74%)
Scheme 2. Proposed mechanism for the reaction of lactone 2 with amines.
In order to favour the opening of lactone 2 with respect to the
Michael addition, which is the first step of the tandem con-
jugate addition retro-Mannich sequence, 2-hydroxypyridine
was employed as a proton transfer catalyst.14 Under these
conditions, good yields of amides 3 were obtained as separa-
ble mixtures of E and Z isomers (Table 1).
Scheme 1. (a) AcONa (1 equiv), ArCHO (1 equiv), Ac2O, reflux, 6 h and (b)
(R)-1-phenylethylamine (2 equiv), 2-hydroxypyridine (0.2 equiv), THF, rt,
72 h.
Single-crystals of lactone E-2a (Ar¼Ph) suitable for an
X-ray data collection were obtained from a saturated
solution of AcOEt/hexane. In the solid state, the fused rings
of lactone E-2a show a very limited deviation from
coplanarity, with a t1 torsional angle (Fig. 2) of less than
5ꢁ. A more pronounced deviation from planarity is observed
at torsion t2 (Fig. 2), reaching a value of about 12ꢁ.
2-(2-Hydroxynaphthyl)cinnamic amides 7 were prepared
starting from b-naphthol (Scheme 3), which was trans-
formed into lactone 5,15 and then subjected to Perkin con-
densation using several aromatic aldehydes. Lactones 6
were obtained as mixtures of E and Z isomers (Table 1).
X-ray quality crystals of lactone E-6a (Ar¼Ph) were
obtained from a saturated solution of AcOEt/hexane. The solid
state molecular structure of lactone E-6a is substantially
similar to that of E-2a, with the notable exception of an
enhanced deviation from co-planarity, the t1 between the naph-
tholic aromatic ring and the exocyclic double bond being
The opening of lactones 2 was then performed, using
(R)-1-phenylethylamine. Simple aminolysis of lactone 2a
in several solvents (DCM, toluene, THF) almost led to
the exclusive formation of 2-hydroxy phenylacetamide 4
[R¼(R)-1-phenylethylamine], probably through a tandem
Michael retro–Mannich sequence (Scheme 2).
Table 1. Synthesis of lactones 2 and 5, and amides 3 and 7
Entry
Ar
Lactone
Yield (%)
E/Z
R
R/S
Amide
Yield (%)
E/Z
aS/aR
1
2
3
4
5
6
C6H5
2a
2b
2c
6a
6a
6b
62
86
35
62
62
45
85/15
100/0
100/0
25/75
25/75
0/100
Ph
Ph
Ph
Ph
Chx
Ph
R
R
R
R
S
3a
3b
3c
7a
7b
7c
84
41
74
71
88
68
75/25
100/0
76/24
34/66
39/61
0/100
—
—
—
1.2/1
1/1.3
—
o-MeO–C6H4
p-NO2–C6H4
C6H5
C6H5
o-MeO–C6H4
R

C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
8945
O
O
Ar
O
O
a)
b)
c)
-Naphthol
5 (64%)
6a Ar = C6H5 (62%)
6b Ar = o-MeO-C6H4 (45%)
O
O
Ar
O
N
R
N
R
N
R
Ar
Ar
H
H
H
OH
OH
OH
+
+
(aR)-E-7a Ar = C6H5, R = Ph (11%)
(aR)-E-7b Ar = C6H5, R = Chx (19%)
Z-7a Ar = C6H5, R = Ph (47%)
Z-7b Ar = C6H5, R = Chx (54%)
Z-7c Ar = o-MeO-C6H, R = Ph (68%)
(aS)-E-7a Ar = C6H5, R = Ph (13%)
(aS)-E-7b Ar = C6H5, R = Chx (12%)
Scheme 3. (a) Glyoxal (7 equiv), KOH (1 equiv), H2O, 30 ꢁC, 4.5 h; (b) AcONa (1 equiv), RCHO (1 equiv), Ac2O, reflux, 6 h and (c) nBuLi (3 equiv),
RCH(CH3)NH2 (2.5 equiv), THF, rt, 1 h, ꢀ40 ꢁC, 6 (1 equiv), 2 h.
about 26ꢁ. At variance, the t2 dihedral angle is only margin-
ally lowered to ca. 10ꢁ. Attempts to open lactones 6 by
reaction with amines in various solvents and in the presence
of 2-hydroxypyridine met with limited success and the major
isolated products were the 2-hydroxynaphthylacetamides
derived from the conjugate addition retro-Mannich mecha-
nism described above. To overcome this problem, we rea-
soned that the hardness of the amine nucleophile had to be
increased, in order to favour the attack to the carbonyl of
the lactone with respect to the Michael addition.
fixed stereocenter of (R)-1-phenylethylamine, resulted to
be aR.
Circular dichroism (CD) curves were measured for com-
pounds aR-E-7a and aS-E-7b (Fig. 4): two nearly mirror
image curves were obtained for the two compounds. In the
case of aR-E-7a, an intense positive band at 228 nm (D3 +14),
a negative band at 264 mn (D3 ꢀ8) and a weak positive
band at 333 nm (D3 +1.7), were observed. In particular the
exciton band at about 228 nm has been attributed to the
1
long axis polarized Bb transition of naphthalene,16 while
This was achieved by first deprotonating the amines, (R)-
1-phenylethylamine or (S)-1-ethylcyclohexylamine, with
nBuLi and then adding the lithium amide solution to
a cold solution of the lactone (Scheme 3). In this way, no
2-hydroxynaphthylacetamide was detected, and good yields
of amides 7 were obtained as separable mixtures of one Z
isomer and two atropisomeric E isomers (Table 1 and
Scheme 3). X-ray quality crystals of amide aR-E-7a (Ar¼Ph
and R¼Ph) were obtained from a saturated solution of
AcOEt/hexane. The solid state structure of amide aR-E-7a
shows that, in the crystal, the molecule adopts a staggered
conformation with a dihedral angle of ca. 89ꢁ between the
naphtholic ring and the unsaturated amide plane (Fig. 3).
The absolute configuration of the chiral axis, based on the
the band at 264 nm is probably due to the absorption of
the cinnamic moiety.17 These two chromophores are ori-
ented perpendicularly to each other and can be described
as two interacting orthogonal dipoles. The strong positive–
negative exciton is in agreement with a positive helicity18
and with the aR absolute configuration of the chiral axis,
as shown also by the X-ray molecular structure. A negative
band at 228 nm (D3 ꢀ6), a positive band at 262 mn (D3 +3)
and a weak negative band at 335 nm (D3 ꢀ0.6), were
observed for aS-E-7b. In this case a negative–positive
exciton is indicative of a negative helicity and of the aS
configuration of the chiral axis.
A study of the barrier to rotation about the C2–Caryl bond was
then undertaken for all the amides synthesized. Kinetic data
Figure 3. Ortep representation (30% probability level) of the X-ray molec-
ular structure in amide aR-E-7a. Carbon, grey; hydrogen, light grey; nitro-
gen, blue; oxygen, red.
Figure 4. CD spectra of aR-E-7a (red curve) and aS-E-7b (black curve)
showing nearly enantiomeric behaviour.

8946
C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
Table 2. Coalescence temperature and activation parameters of the con-
figurationally unstable amides 3a–c and Z-7a–c
Table 3. Activation parameters of amides (aR)-E-7a–b in CDCl3 at 298 K
Entry
Compound
kc (sꢀ1
)
DGz (kcal molꢀ1
)
Entry
Amide
Tc (K)
kc (sꢀ1
)
DGz (kcal molꢀ1
)
1
2
(aR)-E-7a
(aR)-E-7b
6.40ꢂ106
24.4
24.5
1
2
3
4
5
6
3a
3b
3c
Z-7a
Z-7b
Z-7c
243
245
248
298
303
303
120.6
72.5
96.7
88.4
48.3
193.6
11.8
12.2
12.2
14.8
15.3
14.6
7.85ꢂ106
rates of (aR)-E-7a and (aR)-E-7b were followed at 298 K,
by monitoring the time-dependent first-order variation of
1
the relative intensities of the H NMR spectra in CDCl3.
The Eyring equation was used to derive the DGzc values
from the rate constants kc (Table 3).
and energy barriers of interconversion of configurationally
labile compounds have been conveniently investigated,
among others, by means of dynamic NMR.19 The free
energy barriers to internal rotation in the phenol-substituted
amides 3a–c and Z-7a–c were estimated from their variable
temperature 1H NMR spectra by measuring the coalescence
temperature of the N–H signal (Table 2). The rate constants
kc were calculated from the relationship kc¼pDn/O2, and the
free energies of activation (DGzc) were derived by substitut-
ing kc into the Eyring equation.19
When comparing the values of the barrier to rotation for
compounds 3a–c and Z-7a–c to those observed for 2,20,6
trisubstituted biphenyls20 and 1,10,10 trisubstituted-2,20-
binaphthyls21 (actually, both amides 3a–c and Z-7a–c
are reminiscent of a trisubstituted biaryl chiral axis, see
Fig. 1), it can be noted that the former are significantly lower.
A similar behaviour is found in amides E-7a–b with respect
to tetrasubstituted biaryl moieties. In fact, slowly intercon-
verting atropisomeric biaryls have been observed, particu-
larly, when associated to 2,20,6 trisubstituted biphenyls,
and 1,10,10 trisubstituted-2,20-binaphthyls, depending on
the size of the substituents, but in general tetrasubstituted
biarlys are configurationally stable compounds. In the case
of our 2-(2-hydroxyaryl)cinnamic amides, the rather low
barrier to rotation and the relatively fast atropisomerization
process can be explained assuming that, in the lower energy
transition state for rotation, the carboxamide moiety is not
coplanar with the double bond, thus facilitating the rotation
about the C2–Caryl bond.22
For amides 3a–c, the NMR experiments were run in CD2Cl2
and, as a general trend, the signals are well resolved at
298 K, broaden in the 253–233 K range and split below
233 K yielding two sets of signals (Fig. 5). The values for
DGzc are less than 12.2 kcal molꢀ1 (Table 2, entries 1–3)
and are in agreement with the free rotation of the two substit-
uents about the chiral axis at room temperature. For amides
Z-7a–c, the NMR experiments were performed in CDCl3
and the coalescence is observed near room temperature,
with a single set of well resolved signals above 313 K and
two completely resolved sets of signals below 243 K
(Fig. 4). The DGzc are comprised between 14.6 and
15.3 kcal molꢀ1 (Table 2, entries 4–6).
3. Conclusions
The barriers to rotation for amides E-7a–b were also
investigated. In this case, in variable temperature H NMR
1
The syntheses of several differently substituted chiral
amides formally derived from a chiral amine, either E-2-
(2-hydroxyphenyl)cinnamic acid (3a–c) or both E- and
Z-2-(2-hydroxynaphthyl)cinnamic acid (7a–c), are reported.
These molecules display a restricted rotation about the C2–
Caryl bond and, depending on their barrier to rotation, can
be isolated in two atropisomeric forms. The barriers to rota-
tion about the C2–Caryl were measured by dynamic 1H NMR
studies, the coalescence temperature was not reached even
upon heating a DMSO-d6 sample to 413 K. The atrop-
isomers are stable enough to be isolated at room tempera-
ture, although it was noticed that both diastereomerically
pure atropisomers slowly equilibrated to a 1/1 mixture of
the aR and aS atropisomers, upon standing in solution
(24 h in CDCl3) at room temperature. The transformation
and were found to vary between 11.8 and 24.5 kcal molꢀ1
,
depending on the substitution. In particular, E-2-(2-hydroxy-
napthyl)cinnamic amides 7 displayed a high barrier to
rotation (DGzc>24.4 kcal molꢀ1) and could be isolated in
both diastereomerically pure forms at room temperature.
The X-ray structure of one E-2-(2-hydroxynapthyl)cinnamic
amide, (aR)-E-7a, was resolved, allowing the determination
of the absolute configuration of the chiral axis. The applica-
tion of these new chiral structures as chiral organic catalysts
and ligands for enantioselective metal catalyzed reactions is
now actively being investigated in our laboratories.
4. Experimental
4.1. General
Figure 5. Variable temperature 1H NMR spectra of amides 3a (left) and
Z-7a.
All manipulations requiring anhydrous conditions were car-
ried out in flame-dried glassware, with magnetic stirring, and

C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
8947
under an atmosphere of purified nitrogen. All aldehydes
were distilled before use. All other commercially available
reagents were used as received. Anhydrous solvents were
purchased from commercial sources and withdrawn from
the container by syringe, under a slightly positive pressure
of nitrogen. Reactions were monitored by analytical thin-
layer chromatography (TLC) using silica gel 60 F254 pre-
coated glass plates (0.25 mm thickness). Visualization was
accomplished by irradiation with a UV lamp and/or staining
with a permanganate solution. Flash column chromato-
graphy was performed using silica gel 60 A, particle size
40–64 mm, following the procedure by Still and co-
workers.23 Melting points are uncorrected. Proton NMR
spectra were recorded on a 400 MHz spectrometer. Proton
chemical shifts are reported in parts per million (d) with
the solvent reference relative to tetramethylsilane (TMS)
employed as an internal standard (CDCl3 d 7.26 ppm). Car-
bon NMR spectra were recorded on a 400 spectrometer
operating at 100.56 MHz, with complete proton decoupling.
Carbon chemical shifts are reported in parts per million (d)
with the solvent reference relative to (TMS) employed as
an internal standard (CDCl3 d 77.0 ppm). Infrared spectra
were recorded on a standard Infrared spectrophotometer;
peaks are reported in cmꢀ1. Optical rotation values were
measured on an automatic polarimeter with 1-dm cell at
the sodium D line. CHN-analyses were performed using
a Perkin Elmer 2400 Series II CHNS/O Analyzer. CD spec-
tra were recorded at 298 K on a Jasco J-500C spectro-
polarimeter, in acetonitrile, in a 0.01-cm cell in the range
220–400 nm.
0.09 mmꢀ1. The structure was solved by direct methods
and refined by full-matrix least-squares, with final R and
wR values of 0.047 for 1171 reflections with I>2sI, and
0.111 for 1928 reflections, respectively. All the crystallo-
graphic data presented in the manuscript (excluding struc-
ture factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 602856. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk].
4.1.2. 3-[1-(2-Methoxy-phenyl)-meth-(E)-ylidene]-
3H-benzofuran-2-one (2b). 2-Hydroxyphenylacetic acid
(1 equiv, 9.85 mmol, 1.50 g) was treated with sodium ace-
tate (1 equiv, 9.85 mmol, 1.35 g), 2-methoxy-benzaldehyde
(1 equiv, 9.85 mmol, 1.35 mL) and acetic anhydride
(7 mL) at reflux temperature for 6 h. Water (70 mL) was
then added to the hot mixture followed by vigorous stirring
overnight. Concentrated HCl (10 mL) was added and the
mixture was warmed at 60 ꢁC for 5 h. The product was
then extracted with toluene and the organic phase was suc-
cessively washed with brine and dried over Na2SO4. Evapo-
ration of the solvent gave the crude product, which was then
purified by flash chromatography on silica gel (CH2Cl2/
hexane¼75/25) affording the desired product as a yellow
solid (2.13 g, 86% yield), mp¼123 ꢁC. IR (Nujol):
nmax¼1782, 1723, 1634, 1594, 1316, 1295, 1255, 1165,
1126, 1075, 1021, 967, 876, 773, 745; 1H NMR
(400 MHz, CDCl3): d¼8.07 (s, 1H, CH), 7.76 (d,
J¼7.6 Hz, 1H, ArH), 7.65 (d, J¼7.7 Hz, 1H, ArH), 7.49
(dd, J1¼7.8 Hz, J2¼7.9 Hz, 1H, ArH), 7.33 (dd,
J1¼7.8 Hz, J2¼7.8 Hz, 1H, ArH), 7.13 (d, J¼8.1 Hz, 1H,
ArH), 7.01–7.09 (m, 3H, ArH), 3.91 (s, 3H, CH3); 13C
NMR (400 MHz, CDCl3): d¼169.4, 158.7, 154.7, 137.8,
132.9, 130.9, 130.0, 123.9, 123.5, 123.1, 122.7, 122.1,
120.6, 111.5, 111.4, 56.0; C16H12O3 calcd. C 76.19, H
4.76; found: C 76.07, H 4.57.
4.1.1. 3-[1-Phenyl-meth-(E)-ylidene]-3H-benzofuran-
2-one (2a). NaHCO3 (1 equiv, 32.9 mmol, 2.80 g) was
dissolved in 50 mL of water. 2-Hydroxyphenylacetic acid
(1 equiv, 32.9 mmol, 5 g) was added to the mixture to obtain
a yellow solution. The system was stirred vigorously and
warmed at 50 ꢁC for 2 h. The solvent was evaporated under
reduced pressure affording a white solid and the last traces of
water were azeotropically removed by evaporation with
toluene (2ꢂ30 mL) and drying under vacuum. Sodium
2-hydroxyphenylacetate (5.60 g, 32.0 mmol) was treated
with benzaldehyde (3.4 mL, 33.6 mmol) and acetic anhy-
dride (13 mL) at reflux temperature for 6 h. The hot mixture
was then added to water and stirred vigorously overnight.
HCl concentrated was added and the mixture was warmed
at 60 ꢁC for 5 h. The product was then extracted with toluene
and successively precipitated with petroleum ether at
ꢀ15 ꢁC affording the lactone 2a as an orange solid
(2.14 g, 62% yield), mp¼88 ꢁC. IR (nujol): nmax¼1782,
1769, 1629, 1607, 1293, 1240, 1148, 1121, 1082, 1080,
1022, 967, 932, 877, 757, 754, 732, 703; 1H NMR
(400 MHz, CDCl3): d¼7.90 (s, 1H, CH), 7.75 (d, J¼
7.7 Hz, 1H, ArH), 7.69–7.72 (m, 2H, ArH), 7.48–7.54 (m,
3H, ArH), 7.37 (dddd, J1¼8.1 Hz, J2¼7.3 Hz, J3¼1.2 Hz,
J4¼1.2 Hz, 1H, ArH), 7.16 (d, J¼8.1 Hz, 1H, ArH), 7.06
(dd, J1¼7.8 Hz, J2¼7.5 Hz, 1H, ArH); 13C NMR
(400 MHz, CDCl3): d¼169.2, 154.9, 141.3, 134.4, 131.4,
131.0, 129.8, 129.3, 124.1, 123.2, 122.6, 122.2, 111.6;
C15H10O2 calcd. C 81.07, H 4.54; found: C 79.96, H 4.46.
4.1.3. 3-[1-(4-Nitro-phenyl)-meth-(E)-ylidene]-
3H-benzofuran-2-one (2c). 2-Hydroxyphenylacetic acid
(1 equiv, 9.85 mmol, 1.5 g) was treated with sodium
acetate (1 equiv, 9.85 mmol, 1.35 g), 4-nitro-benzaldehyde
(1 equiv, 9.85 mmol, 1.50 mL) and acetic anhydride
(7 mL) at reflux temperature for 6 h. The hot mixture
was then poured into water (70 mL) and stirred vigorously
overnight. Concentrated HCl (10 mL) was added and the
mixture was warmed at 60 ꢁC for 5 h. The product was
then extracted with toluene and the organic phase was
successively washed with brine and dried over Na2SO4.
Evaporation of the solvent gave the crude product, which
was then purified by flash chromatography on silica gel
(hexane/AcOEt¼70/30) affording the desired product
as a yellow solid (0.92 g, 35% yield), mp¼189 ꢁC. IR
(Nujol): nmax¼1780, 1613, 1588, 1524, 1515, 1343,
1319, 1239, 1145, 1123, 1079, 880, 774, 751, 698; 1H
NMR (400 MHz, CDCl3): d¼8.38 (d, J¼8.5 Hz, 2H,
ArH), 7.86 (s, 1H, CH), 7.85 (d, J¼8.2 Hz, 2H, ArH),
7.57 (d, J¼7.7 Hz, 1H, ArH), 7.43 (dd, J1¼8.0 Hz,
J2¼7.7 Hz, 1H, ArH), 7.19 (d, J¼8.0 Hz, 1H, ArH),
7.08 (dd, J1¼7.7 Hz, J2¼7.7 Hz, 1H, ArH); 13C NMR
(400 MHz, CDCl3): d¼168.3, 155.5, 148.8, 140.9, 137.2,
132.6, 131.8, 130.4, 124.6, 124.4, 123.3, 121.4, 112.1;
X-ray crystallographic data of 2a. Orthorhombic, space
˚
group Pcab, a¼9.855(1), b¼12.208(2), c¼18.268(3) A,
3
V¼2197.8(6) A , Z¼8, r¼1.343 g/cm3, m(Mo Ka)¼
˚

8948
C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
C15H9NO4 calcd C 67.41, H 3.37, N 5.24; found: C 67.23,
H 3.25, N 5.14.
4.3. 1H-Naphtho[2,1-b]furan-2-one (5)
The compound was prepared following a literature pro-
cedure.14 The analytical data were in agreement with those
reported.
4.2. General procedure for the synthesis of
2-(2-hydroxyphenyl)cinnamic amides
A solution of lactone (1 equiv, 1.35 mmol), (R)-1-phenyl-
ethylamine (2 equiv, 2.70 mmol, 350 mL) and 2-hydroxy-
pyridine (0.2 equiv, 0.27 mmol, 28 mg) in THF (24 mL)
was stirred at room temperature for 3 d. The reaction
mixture was then hydrolyzed with HCl 1 M and extracted
with AcOEt (12ꢂ3 mL). The combined organic layers
were washed with brine and then dried over Na2SO4. After
evaporation of the solvent in vacuo, the crude product was
purified by flash chromatography on silica gel.
4.4. 1-[1-Phenyl-meth-(E)-ylidene]-1H-naphtho[2,1-b]-
furan-2-oneD1-[1-phenyl-meth-(Z)-ylidene]-1H-
naphtho[2,1-b]furan-2-one (6a)
1H-Naphtho[2,1-b]furan-2-one (1 equiv, 10.15 mmol,
1.87 g) was treated with sodium acetate (1 equiv,
10.15 mmol, 1.38 g), benzaldehyde (1 equiv, 10.15 mmol,
1.03 mL) and acetic anhydride (7 mL) at reflux temperature
for 6 h. The hot mixture was added to water (120 mL) and
stirred vigorously overnight. The mixture was then acidified
with concentrated HCl (15 mL) keeping the system under
magnetic stirring at 60 ꢁC for 5 h. The reaction mixture
was cooled and the product was extracted in toluene, drying
the organic phase over Na2SO4. Evaporation of toluene gave
the crude product, which was purified by flash chromato-
graphy on silica gel (hexane/AcOEt¼8/2) affording the
desired product as a yellow solid (1.68 g, 62% yield) and
as a 1/3 mixture of E and Z diastereomers.
4.2.1. (E)-2-(2-Hydroxy-phenyl)-3-phenyl-N-((R)-1-
phenyl-ethyl)-acrylamide (3a). Pale orange solid (0.29 g,
63% yield). IR (Nujol): nmax¼3397, 1644, 1612, 1595,
1
1514, 1293, 1247, 1234, 1015, 937, 750, 702; H NMR
(400 MHz, CDCl3): d¼7.74 (s, 1H, CH), 7.31–7.35 (m,
3H, ArH), 7.24–7.27 (m, 3H, ArH), 7.13–7.21 (m, 3H,
ArH), 7.03–7.10 (m, 4H, ArH), 6.90–6.95 (m, 1H, ArH),
6.20 (d, J¼7.9 Hz, 1H, NH), 5.18 (m, 1H, CH), 1.44 (d,
J¼6.9 Hz, 3H, CH3); 13C NMR (400 MHz, CDCl3):
d¼168.2, 154.9, 143.2, 139.0, 134.7, 131.3, 131.1, 130.5,
129.4, 129.1, 128.7, 127.9, 127.8, 126.3, 122.3, 121.6,
117.9, 49.8, 22.3; [a]D ꢀ25.6 (c 0.50, CHCl3); C23H21NO2
calcd C 80.19, H 7.01, N 3.90; found: C 79.80, H 6.87, N
3.96.
IR (Nujol): nmax¼1771, 1610, 1573, 1523, 1262, 1139, 1106,
1
987, 889, 853, 801, 765, 740, 688; H NMR (400 MHz,
CDCl3): d¼8.37 (d, J¼8.6 Hz, 1H, ArH), 8.30 (s, 1H,
CH), 8.09 (s, 1H, CH), 8.04–8.07 (m, 2H, ArH), 7.95 (d,
J¼8.7 Hz, 2H, ArH), 7.89 (d, J¼8.8 Hz, 1H, ArH), 7.86
(d, J¼8.3 Hz, 1H, ArH), 7.69 (ddd, J1¼7.6 Hz, J2¼7.1 Hz,
J3¼1.3 Hz, 1H, ArH), 7.35–7.53 (m, 12H, ArH), 7.16
(ddd, J1¼7.8 Hz, J2¼7.7 Hz, J3¼1.1 Hz, 1H, ArH), 6.99
(d, J¼8.5 Hz, 1H, ArH); 13C NMR (400 MHz, CDCl3):
170.2, 155.0, 153.1, 143.1, 140.7, 135.7, 134.0, 133.6,
132.4, 131.9, 131.6, 131.5, 131.1, 130.7, 130.6, 129.8,
129.1, 128.7, 127.5, 127.2, 125.2, 125.1, 123.7, 123.1,
122.5, 112.1, 112.0; C19H12O2 calcd C 83.82, H 4.41; found:
C 83.46, H 4.34.
4.2.2. (E)-2-(2-Hydroxy-phenyl)-3-(2-methoxy-phenyl)-
N-((R)-1-phenyl-ethyl)-acrylamide (3b). Yellow solid
(0.06 g, 41% yield), mp¼125 ꢁC. IR (Nujol): nmax¼3410,
3402, 3125, 1653, 1600, 1522, 1292, 1252, 1163, 1105,
1024, 759, 750, 698; 1H NMR (400 MHz, CDCl3): d¼7.88
(s, 1H, CH), 7.23–7.37 (m, 6H, ArH), 7.18 (dd, J1¼7.8 Hz,
J2¼7.8 Hz, 1H, ArH), 7.02 (d, J¼8.2 Hz, 1H, ArH), 6.96
(d, J¼7.6 Hz, 1H, ArH), 6.84–6.75 (m, 3H, ArH), 6.62
(dd, J1¼7.5 Hz, J2¼7.5 Hz, 1H, ArH), 6.28 (d, J¼7.8 Hz,
1H, NH), 5.26–5.19 (m, 1H, CH), 1.51 (d, J¼6.9 Hz, 3H,
CH3); 13C NMR (400 MHz, CDCl3): d¼169.3, 158.2,
155.2, 143.2, 133.7, 132.8, 131.2, 130.8, 130.5, 130.3,
129.1, 127.8, 126.5, 123.8, 122.7, 121.0, 120.7, 117.9,
110.8, 55.8, 49.8, 22.2; [a]D ꢀ10.1 (c 0.11, CHCl3);
C24H23NO3 calcd C 77.21, H 6.17, N 3.75; found: C
76.87, H 6.16, N 3.65.
X-ray crystallographic data of 6a. Orthorhombic, space
˚
group Pcab, a¼7.932(4), b¼13.908(10), c¼24.500(17) A,
3
V¼2703(3) A , Z¼8, r¼1.338 g/cm3, m(Mo Ka)¼
˚
0.09 mmꢀ1. The structure was solved by direct methods
and refined by full-matrix least-squares, with final R and
wR values of 0.068 for 971 reflections with I>2sI, and
0.145 for 2458 reflections, respectively. CCDC No. 602857.
4.2.3. (E)-2-(2-Hydroxy-phenyl)-3-(4-nitro-phenyl)-N-
((R)-1-phenyl-ethyl)-acrylamide (3c). Yellow solid
(0.07 g, 56% yield), mp¼70 ꢁC. IR (Nujol): nmax¼3404,
3240, 1651, 1614, 1599, 1518, 1343, 1289, 1109, 1043,
4.5. 1-[1-(2-Methoxy-phenyl)-meth-(E)-ylidene]-1H-
naphtho[2,1-b]furan-2-one (6b)
1H-Naphtho[2,1-b]furan-2-one (1 equiv, 4.54 mmol, 0.83 g)
was treated with sodium acetate (1 equiv, 4.54 mmol,
0.37 g), 2-methoxy-benzaldehyde (1 equiv, 4.54 mmol,
0.62 g) and acetic anhydride (6 mL) at reflux temperature
for 6 h. The hot mixture was added to water (120 mL) and
stirred vigorously overnight. The mixture was then acidified
with HCl (15 mL) keeping the system under magnetic stir-
ring at 60 ꢁC for 5 h. A brown precipitate was formed. The
reaction mixture was cooled and the product was extracted
in toluene, drying the organic phase over Na2SO4. Evapora-
tion of toluene gave the crude product, which was purified by
flash chromatography on silica gel (hexane/AcOEt¼75/25)
1
1014, 852, 833, 758, 700; H NMR (400 MHz, CDCl3):
d¼8.04 (br s, 1H, OH), 7.96 (d, J¼8.4 Hz, 2H, ArH), 7.65
(s, 1H, CH), 7.25–7.35 (m, 6H, ArH), 7.14 (d, J¼8.3 Hz,
2H, ArH), 7.06 (d, J¼8.1 Hz, 1H, ArH), 6.86–6.94 (m,
2H, ArH), 6.28 (d, J¼7.9 Hz, 1H, NH), 5.14–5.21 (m, 1H,
CH), 1.46 (d, J¼6.8 Hz, 3H, CH3); 13C NMR (400 MHz,
CDCl3): d¼167.8, 155.0, 147.6, 142.8, 141.6, 136.3,
135.6, 131.7, 130.9, 130.8, 130.0, 129.2, 127.9, 126.3,
123.8, 121.7, 121.4, 118.2, 50.0, 22.1; [a]D ꢀ15.5 (c 0.15,
CHCl3); C23H20N2O4 calcd C 71.13, H 5.15, N 7.22; found:
C 70.84, H 5.06, N 7.03.

C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
8949
affording the desired product as an orange solid (1.47 g, 45%
yield).
(400 MHz, CDCl3): d¼8.32 (s, 1H, CH), 7.90 (d,
J¼8.9 Hz, 1H, ArH), 7.88 (d, J¼7.7 Hz, 1H, ArH), 7.69 (d,
J¼8.2 Hz, 1H, ArH), 7.39–7.48 (m, 2H, ArH), 7.00–7.29
(m, 11H, ArH), 5.84 (d, J¼7.8 Hz, 1H, NH), 5.13–5.21
(m, 1H, CH), 1.24 (d, J¼6.9 Hz, 3H, CH3); 13C NMR
(400 MHz, CDCl3): d¼166.3, 151.8, 143.3, 142.5, 134.4,
132.8, 131.6, 130.3, 130.0, 129.7, 129.0, 128.9, 128.0,
127.6, 126.7, 126.2, 124.6, 124.2, 118.6, 114.0, 49.6,
22.1; [a]D +93.2 (c 0.19, CHCl3); C27H23NO2 calcd C
82.44, H 5.85, N 3.56; found: C 80.71, H 6.17, N 3.32.
Mp¼157 ꢁC. IR (Nujol): nmax¼1775, 1599, 1524, 1292,
1254, 1112, 1001, 1020, 973, 807, 780, 744; 1H NMR
(400 MHz, CDCl3): d¼8.58 (s, 1H, ArH), 8.38 (d,
J¼8.5 Hz, 1H, ArH), 8.19 (d, J¼7.7 Hz, 1H, ArH), 7.92
(d, J¼8.2 Hz, 1H, ArH), 7.86 (d, J¼8.7 Hz, 1H, ArH),
7.67 (dd, J1¼7.4 Hz, J2¼7.9 Hz, 1H, ArH), 7.52–7.45 (m,
2H, ArH), 7.34 (d, J¼8.7 Hz, 1H, ArH), 7.08 (dd,
J1¼7.6 Hz, J2¼7.6 Hz, 1H, ArH), 6.99 (d, J¼8.3 Hz, 1H,
ArH), 3.96 (s, 3H, CH3); 13C NMR (400 MHz, CDCl3):
d¼166.7, 158.6, 152.8, 141.5, 138.7, 132.9, 132.4, 131.9,
131.5, 130.5, 128.9, 128.7, 125.1, 123.0, 122.8, 120.5,
117.4, 112.0, 110.8, 56.1; C20H14O3 calcd C 79.47, H
4.63; found: C 79.44, H 4.50.
4.6.3. (Z)-2-(2-Hydroxy-naphthalen-1-yl)-3-phenyl-N-
((R)-1-phenyl-ethyl)-acrylamide (Z-7a). 0.43 g, 47%
yield, mp¼81 ꢁC. IR (Nujol): nmax¼3320, 3056, 1618,
1512, 1510, 1260, 1232, 1225, 975, 950, 819, 751, 698; 1H
NMR (400 MHz, CDCl3, 313 K): d¼7.99 (d, J¼8.5 Hz,
1H, ArH), 7.84 (d, J¼8.1 Hz, 1H, ArH), 7.78 (d,
J¼8.9 Hz, 1H, ArH), 7.25–7.51 (m, 11H, ArH), 7.09–7.11
(m, 2H, ArH), 6.85 (s, 1H, CH), 6.05 (d, J¼7.3 Hz, 1H,
NH), 5.13–5.20 (m, 1H, CH), 1.39 (d, J¼6.9 Hz, 3H,
CH3); 13C NMR (400 MHz, CDCl3, 313 K): d¼171.2,
153.9, 141.9, 138.1, 135.2, 133.4, 130.7, 129.8, 129.2,
129.1, 129.0, 128.9, 128.7, 128.0, 127.0, 123.7, 123.3,
120.4, 118.1, 50.0, 21.1; [a]D ꢀ26.1 (c 0.15, CHCl3);
C27H23NO2 calcd C 82.44, H 5.85, N 3.56; found: C
80.99, H 5.88, N 3.34.
4.6. 2-(2-Hydroxy-naphthalen-1-yl)-3-phenyl-N-((R)-1-
phenyl-ethyl)-acrylamide (7a)
nBuLi (1.6 M in hexanes 4.31 mL, 6.90 mmol) was slowly
added to a solution of (R)-1-phenylethylamine (0.742 mL,
5.75 mmol) in anhydrous tetrahydrofuran (14 mL), in
a Schlenk tube, under nitrogen, at 0 ꢁC. After stirring for
1 h the mixture was cooled to ꢀ40 ꢁC and lactone 6a
(626 mg, 2.30 mmol) was added. The reaction mixture was
stirred at ꢀ40 ꢁC for 2 h, quenched with 1 M HCl (42 mL)
and extracted with AcOEt. The organic phase was washed
with brine and dried over Na2SO4. The crude product was
purified by flash chromatography giving three pale yellow
solids.
4.7. N-((S)-1-Cyclohexyl-ethyl)-2-(2-hydroxy-naphtha-
len-1-yl)-3-phenyl-acrylamide (7b)
nBuLi (1.6 M in hexanes 3.80 mL, 5.94 mmol) was slowly
added to
a solution of (S)-1-cyclohexyl-ethylamine
4.6.1. (E)-2-(2-Hydroxy-naphthalen-1-yl)-3-phenyl-N-
((R)-1-phenyl-ethyl)-acrylamide [(aR)-E-7a]. 0.10 g,
11% yield, mp¼180 ꢁC. IR (Nujol): nmax¼3403, 3397,
3115, 1650, 1600, 1582, 1342, 1276, 1247, 1211, 1158,
1079, 992, 955, 821, 775, 751, 699, 692; 1H NMR
(400 MHz, CDCl3): d¼8.30 (s, 1H, CH), 7.90 (d,
J¼8.9 Hz, 1H, ArH), 7.85–7.88 (m, 1H, ArH), 7.60–7.63
(m, 1H, ArH), 7.39–7.41 (m, 2H, ArH), 7.29 (d, J¼8.4 Hz,
1H, ArH), 7.16–7.21 (m, 4H, ArH), 6.97–7.10 (m, 6H,
ArH), 5.82 (d, J¼7.8 Hz, 1H, NH), 5.15–5.20 (m, 1H,
CH), 1.31 (d, J¼6.9 Hz, 3H, CH3); 13C NMR (400 MHz,
CDCl3): d¼166.5, 151.8, 143.3, 142.4, 134.4, 132.8,
131.6, 130.2, 130.0, 129.6, 129.0, 128.9, 128.8, 128.0,
127.5, 126.8, 126.1, 124.6, 124.4, 118.6, 114.0, 49.6, 22.3;
[a]D ꢀ200.4 (c 0.15, CHCl3); C27H23NO2 calcd C 82.44,
H 5.85, N 3.56; found: C 80.71, H 6.17, N 3.32.
(0.74 mL, 4.95 mmol) in anhydrous tetrahydrofuran, in
a Schlenk tube, under nitrogen, at 0 ꢁC. After stirring for
1 h the mixture was cooled to ꢀ40 ꢁC and lactone 6a
(540 mg, 1.98 mmol) was added. The reaction mixture was
stirred at ꢀ40 ꢁC for 2 h, quenched with HCl 1 M (42 mL)
and extracted with AcOEt. The organic phase was washed
with brine and dried over Na2SO4. The product obtained
was purified by flash chromatography giving three different
pale yellow solids.
4.7.1. (E)-N-((S)-1-Cyclohexyl-ethyl)-2-(2-hydroxy-
naphthalen-1-yl)-3-phenyl-acrylamide [(aR)-E-7b].
0.09 g, 15% yield, mp¼70 ꢁC. IR (Nujol): nmax¼3410,
3171, 1652, 1600, 1506, 1344, 1282, 1206, 958, 820, 749,
1
690, 668; H NMR (400 MHz, CDCl3): d¼8.30 (s, 1H,
CH), 7.90 (d, J¼8.9 Hz, 1H, ArH), 7.86 (d, J¼7.6 Hz, 1H,
ArH), 7.64 (d, J¼8.3 Hz, 1H, ArH), 7.37–7.43 (m, 2H,
ArH), 7.29 (d, J¼8.9 Hz, 1H, ArH), 7.02–7.15 (m, 5H,
ArH), 5.44 (d, J¼8.9 Hz, 1H, NH), 3.85–3.95 (m, 1H, CH),
1.47–1.65 (m, 5H, CyH), 1.01–1.16 (m, 4H, CyH), 0.85–
0.89 (m, 4H, CH3), 0.62–0.71 (m, 1H, CH3); 13C NMR
(400 MHz, CDCl3): d¼166.5, 151.8, 141.9, 134.6, 132.8,
131.5, 130.2, 129.8, 129.6, 128.9, 128.8, 128.0, 127.1,
124.5, 124.2, 118.5, 114.3, 50.5, 43.1, 29.5, 28.9, 26.7,
26.4, 18.0; [a]D ꢀ57.9 (c 0.39, CHCl3); C27H29NO2 calcd
C 81.40, H 7.04, N 3.52; found: C 78.43, H 7.56, N 3.15.
X-ray crystallographic data of (aR)-E-7a. Monoclinic, space
˚
group P21, a¼10.014(6), b¼10.129(3), c¼21.348(15) A,
3
3
ꢁ
˚
b¼99.30(6) , V¼2137(2) A , Z¼4, r¼1.223 g/cm , m(Mo
Ka)¼0.08 mmꢀ1. The structure was solved by direct
methods and refined by full-matrix least-squares, with final
R and wR values of 0.063 for 2160 reflections with I>2sI,
and 0.117 for 4114 reflections, respectively. CCDC No.
602858.
4.6.2. (E)-2-(2-Hydroxy-naphthalen-1-yl)-3-phenyl-N-
((R)-1-phenyl-ethyl)-acrylamide [(aS)-E-7a]. 0.12 g, 13%
yield, mp¼181 ꢁC. IR (Nujol): nmax¼3399, 3150, 1651,
1593, 1576, 1537, 1516, 1504, 1342, 1285, 1246, 1209,
1141, 1080, 923, 955, 822, 766, 754, 692; 1H NMR
4.7.2. (E)-N-((S)-1-Cyclohexyl-ethyl)-2-(2-hydroxy-
naphthalen-1-yl)-3-phenyl-acrylamide [(aS)-E-7b].
0.07 g, 19% yield, mp¼179 ꢁC. IR (Nujol): nmax¼3399,
3227, 1652, 1605, 1595, 1511, 1351, 1246, 1205, 1143,

8950
C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
827, 749, 690; 1H NMR (400 MHz, CDCl3): d¼8.31 (s, 1H,
CH), 7.90 (d, J¼8.9 Hz, 1H, ArH), 7.86 (d, J¼7.9 Hz,
1H, ArH), 7.67 (d, J¼8.2 Hz, 1H, ArH), 7.37–7.46 (m,
2H, ArH), 7.27 (d, J¼8.9 Hz, 1H, ArH), 7.16–7.21 (m, 1H,
ArH), 7.05–7.12 (m, 4H, ArH), 6.04 (br s, 1H, OH), 5.36
(d, J¼9.0 Hz, 1H, NH), 3.88–3.97 (m, 1H, CH), 1.48–1.60
(m, 3H, CyH), 1.23–1.38 (m, 3H, CyH), 0.68–1.10 (m, 7H,
CyH), 0.33–0.42 (m, 1H, CyH); 13C NMR (400 MHz,
CDCl3): d¼166.3, 151.5, 141.9, 134.5, 132.8, 131.5,
130.2, 129.9, 129.6, 129.0, 128.8, 127.9, 127.1, 124.6,
118.4, 114.2, 50.2, 43.3, 29.4, 28.3, 26.6, 26.4, 26.3, 18.2;
[a]D +154.8 (c 0.12, CHCl3); C27H29NO2 calcd C 81.40, H
7.04, N 3.52; found: C 78.43, H 7.56, N 3.15.
Partial financial support by the Fondazione CARIPLO is
also acknowledged. We also like to thank Dr. L. Santagostini
(University of Milano) for running the CD spectra and
for helpful discussions on their interpretation, and Prof.
C. Gennari (University of Milano) for inspiring discussions.
References and notes
1. MCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809–3844.
2. Bringmann, G.; G€unther, C.; Ochse, M.; Schupp, O.; Tasler, S.
Progress in the Chemistry of Organic Natural Products; Herz,
W., Falk, H., Kirby, G. W., Moore, R. E., Eds.; Springer: Wien,
2001; Vol. 82, pp 1–249.
4.7.3. (Z)-N-((S)-1-Cyclohexyl-ethyl)-2-(2-hydroxy-
naphthalen-1-yl)-3-phenyl-acrylamide (Z-7b). 0.41 g,
54% yield, mp¼168 ꢁC. IR (Nujol): nmax¼3333, 3150,
1602, 1555, 1305, 1258, 1218, 1204, 1169, 1146, 1107,
3. Oki, M. Top. Stereochem. 1983, 14, 1–81.
4. Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44,
5384–5427.
5. (a) Anderson, J. E.; Hazlehurst, C. J. J. Chem. Soc., Chem.
Commun. 1980, 1188–1189; (b) Anderson, J. E.; Barkel,
D. J. D.; Cooksey, C. J. Tetrahedron Lett. 1983, 24, 1077–
1080.
6. Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T.
J. Am. Chem. Soc. 2005, 127, 3676–3677.
7. (a) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M.
Org. Chem. 2000, 65, 7033–7040; (b) Honda, A.; Waltz,
K. M.; Carroll, P. J.; Walsh, P. J. Chirality 2003, 15, 615–
621.
1
1000, 919, 885, 819, 818, 753, 699, 639, 635; H NMR
(400 MHz, CDCl3): d¼10.62 (br s, 1H, OH), 7.97 (d,
J¼8.4 Hz, 1H, ArH), 7.84 (d, J¼8.1 Hz, 1H, ArH), 7.78 (d,
J¼8.9 Hz, 1H, ArH), 7.50–7.56 (m, 3H, ArH), 7.35–7.45
(m, 4H, ArH), 7.29 (d, J¼8.9 Hz, 1H, ArH), 6.84 (s, 1H,
CH), 5.60 (br s, 1H, NH), 3.78–3.90 (m, 1H, CH), 1.60–
0.73 (m, 11H, CyH), 0.93 (d, J¼6.5 Hz, 3H, CH3); 13C
NMR (400 MHz, CDCl3): d¼171.6, 153.9, 137.7, 133.2,
130.3, 129.7, 129.2, 129.0, 128.9, 127.1, 125.0, 123.6,
123.3, 120.5, 117.5, 50.9, 43.0, 29.3, 29.2, 26.6, 26.4, 16.8;
[a]D +36.5 (c 0.20, CHCl3); C27H29NO2 calcd C 81.40, H
7.04, N 3.52; found: C 78.43, H 7.56, N 3.15.
8. (a) Dai, W.-M.; Yeung, K. K. Y.; Liu, J.-T.; Zhang, Y.;
Williams, I. D. Org. Lett. 2002, 4, 1615–1618; (b) Chan, V.;
Gon Kim, J.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. Org. Lett.
2004, 6, 2051–2053; (c) Dai, W.-M.; Zhang, Y.; Zhang, Y.
Tetrahedron: Asymmetry 2004, 15, 525–535.
4.8. (E)-2-(2-Hydroxy-naphthalen-1-yl)-3-(2-methoxy-
phenyl)-N-((R)-1-phenyl-ethyl)-acrylamide (Z-7c)
9. Casarini, D.; Coluccini, C.; Lunazzi, L.; Mazzanti, A. J. Org.
Chem. 2005, 70, 5098–5102.
nBuLi (1.6 M in hexanes 0.62 mL, 0.99 mmol) was slowly
added to a solution of (R)-1-phenylethylamine (0.107 mL,
0.83 mmol) in anhydrous tetrahydrofuran, in a Schlenk
tube, under nitrogen, at 0 ꢁC. After stirring for 1 h the mix-
ture was cooled to ꢀ40 ꢁC and lactone 6b (100 mg,
0.33 mmol) was added. The reaction mixture was stirred at
ꢀ40 ꢁC for 2 h, quenched with HCl 1 M (7 mL) and
extracted with AcOEt. The organic phase was washed with
brine and dried over Na2SO4. The crude product was purified
by flash chromatography giving a greenish-yellow solid
(0.10 g, 68% yield), mp¼65 ꢁC. IR (Nujol): nmax¼3406,
3292, 3061, 3031, 2974, 2931, 1665, 1617, 1602, 1538,
1510, 1463, 1336, 1250, 1114, 1026, 821, 753, 700, 623;
1H NMR (400 MHz, CDCl3, 313 K): d¼10.50 (br s, 1H,
OH), 8.18 (d, J¼8.4 Hz, 1H, ArH), 7.81 (d, J¼8.0 Hz, 1H,
ArH), 7.77 (d, J¼8.9 Hz, 1H, ArH), 6.85–7.61 (m, 13H,
ArH), 6.18 (br s, 1H, NH), 5.00–5.07 (m, 1H, CH), 3.83–
3.90 (m, 3H, CH3), 1.35–1.27 (m, 3H, CH3); 13C NMR
(400 MHz, CDCl3, 313 K): d¼171.1, 157.3, 153.9, 135.2,
133.6, 130.2, 130.0, 129.7, 129.0, 128.7, 127.7, 126.8,
126.5, 124.2, 123.1, 121.5, 120.4, 111.2; [a]D ꢀ31.7 (c
0.28, CHCl3); C28H25NO3 calcd C 79.43, H 5.91, N 3.31;
found: C 78.51, H 5.95, N 3.16.
€
10. (a) Jabin, I.; Monnier-Benoit, N.; Le Gac, S.; Netchitaılo, P.
Tetrahedron Lett. 2003, 44, 611–614; (b) Le Gac, S.;
Monnier-Benoit, N.; Doumampouom Metoul, L.; Petit, S.;
Jabin, I. Tetrahedron: Asymmetry 2004, 15, 139–145.
11. Vanthuyne, N.; Andreoli, F.; Fernandez, S.; Roman, M.;
Roussel, C. Lett. Org. Chem. 2005, 2, 433–443.
12. Brandes, S.; Bella, M.; Kjoersgaard, A.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 1147–1151.
13. Czaplicki, S.; Kostanecki, S. V.; Lampe, V. Chem. Ber. 1909,
42, 827–838.
14. Bringmann, G.; Breuning, M.; Tasler, S.; Endress, H.; Ewers,
C. L. J.; Gobel, L.; Peters, K.; Peters, E.-M. Chem.—Eur. J.
1999, 5, 3029–3038.
15. Kito, T.; Yoshinaga, K.; Yamaye, M.; Mizobe, H. J. Org. Chem.
1991, 56, 3336–3339.
16. (a) Casarini, D.; Rosini, C. J. Org. Chem. 2003, 68, 1815–1820;
(b) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M.
Tetrahedron 2004, 60, 4451–4458 and references therein.
17. Cinnamic acid displays a strong UV absorption at 266 nm
(log 3 5.35).
18. Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257–
263.
19. Oki, M. Application of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH: Weinheim, 1985.
Acknowledgements
20. Meyers, A. I.; Himmelsbach, R. J. J. Am. Chem. Soc. 1985, 107,
682–685.
We gratefully acknowledge MIUR for financial support and
for a PhD fellowship to C.M. (Progetto Giovani 2003).
21. Baker, R. W.; Brkic, Z.; Sargent, M. V.; Skelton, B. W.; White,
A. H. Aust. J. Chem. 2000, 53, 925–938.

C. Marelli et al. / Tetrahedron 62 (2006) 8943–8951
8951
22. The atropisomerization process was also simulated by
molecular mechanics (SPARTAN ’02, Wavefunction,
Inc., Irvine, CA) in the case of amide aR-E-7a. The
of the slight rotation of the amide residue (with concom-
itant partial loss of conjugation) during the interconver-
sion process.
computed barrier (only
the experimental value), clearly indicated the assistance
a
few kcal molꢀ1 higher than
23. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.