Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists

Article abstract of DOI:10.1021/jm990199u

A novel series of N-(phenylalkyl)cinnamides related to N-(4- phenylbutyl)-3,4-dihydroxy-β-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The N- (phenylalkyl)cinnamides are selective antagonists of NR1(A)/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC₅₀ value of 77 nM and > 1000-fold selectivity with respect to NR1(A)/2A and NR1(A)/2C receptors. Potency at α₁ adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1(A)/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.

Full text of DOI:10.1021/jm990199u

3412
J . Med. Chem. 1999, 42, 3412-3420
Str u ctu r e-Activity Rela tion sh ip of N-(P h en yla lk yl)cin n a m id es a s Novel NR2B
Su btyp e-Selective NMDA Recep tor An ta gon ists
Amir P. Tamiz,† Sui Xiong Cai,‡ Zhang-Lin Zhou,‡ Po-Wai Yuen,§ Robert M. Schelkun,§ Edward R. Whittemore,‡
Eckard Weber,‡ Richard M. Woodward,*,‡ and J ohn F. W. Keana*,†
Department of Chemistry, University of Oregon, Eugene, Oregon 97403, CoCensys Inc., 213 Technology Drive,
Irvine, California 92618, and Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, Michigan 48106
Received April 22, 1999
A novel series of N-(phenylalkyl)cinnamides related to N-(4-phenylbutyl)-3,4-dihydroxy-â-
cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized
and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and
subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three
binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination
with either NR2A, NR2B, or NR2C. The N-(phenylalkyl)cinnamides are selective antagonists
of NR1A/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxy-
cinnamide (16) has an IC50 value of 77 nM and >1000-fold selectivity with respect to NR1A/2A
and NR1A/2C receptors. Potency at R1 adrenergic receptors is low for the four cinnamides tested.
Inhibition of NR1A/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase
inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and
structurally diverse framework for designing new NR2B-selective NMDA antagonists as
potential CNS therapeutics.
In tr od u ction
Glutamate-induced hyperexcitation of N-methyl-D-
aspartate (NMDA) receptors results in neuronal death
in a variety of acute and chronic neurodegenerative
diseases.1 NMDA antagonists may find clinical use in
the treatment of neurological disorders.1 In particular,
interaction between the dopamine and glutamate sys-
tems in the basal ganglia of the brain may have
therapeutic relevance to the treatment of Parkinson’s
disease.2 Development of clinically useful NMDA an-
tagonists as drugs, however, has been hampered by
dose-limiting side effects which include memory deficits,
neurotoxicity, psychotomimetic behaviors, and a narrow
therapeutic index with respect to sedation.3
In recent years it has become clear that NMDA
receptors are heterooligomeric assemblies of at least two
types of polypeptide subunits: NR1, found in eight
isoforms, and NR2, found as four distinct subtypes
(NR2A-NR2D).4 Subunit composition of native recep-
tors in adult mammalian brain differs significantly from
F igu r e 1. Potent antagonists of the NR2B subtype of the
NMDA receptor. Compounds 1, 2, and 5 were tested as
racemates; only one enantiomer of 1 and 5 is shown.
region to region.5 In addition, NMDA receptor subtypes
differ in both pharmacological and physiological proper-
ties. These differences suggest that the subtype-selectiv-
ity profile for NMDA antagonists may be an important
determinant of therapeutic efficacy and side effects.
Ifenprodil (1, originally designed as an antihypertensive
agent; Figure 1) was the first selective NR1/2B antago-
nist discovered. Ifenprodil is reported to reduce allo-
sterically the frequency of opening of NMDA receptor
cloned NR1A/2B receptors expressed in oocytes is ∼0.1
µM.7 Using ifenprodil as a starting point, several
structurally related NR2B-selective antagonists such as
Ro 25-6981 (2),8 CP 101,606 (3),9 Co 101677 (4),7 and
nylidrin (5)10 have been described. A number of these
compounds have been reported to have neuroprotective
channels by way of a site or sites distinct from the
effects in animal models of focal cerebral ischemia
glutamate, glycine, or ion channel sites.6 The IC50 for
without themselves inducing neurotoxicity or showing
behavioral liability in drug discrimination studies.6,8,9
In a detailed study of molecular mechanism, Kew and
* To whom correspondence should be addressed.
† University of Oregon.
co-workers have shown that ifenprodil has a ∼50-fold
‡ CoCensys, Inc.
§ Parke-Davis Pharmaceutical Research.
higher affinity for agonist-bound states of the NMDA
10.1021/jm990199u CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/05/1999

SAR of N-(Phenylalkyl)cinnamides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3413
Sch em e 1a
receptor as compared to resting states.11 This feature
may also contribute to the desirable side effect profile
of these subtype-selective antagonists.
As part of a screening effort to find novel subtype-
selective NMDA antagonists, we recently identified
N-(2-(4-hydroxyphenyl)ethyl)-4-chlorocinnamide (27) as
a potent and selective antagonist at NR1A/2B recep-
tors.12 Subsequent screening identified a related cinna-
mide, N-(4-phenylbutyl)-3,4-dihydroxy-â-cyanocinna-
mide (6), as another potent antagonist. Cinnamide 6 is
a potent epidermal growth factor receptor tyrosine
kinase (EGFR-K) inhibitor with high antiproliferative
activity.13 Herein we elaborate the structure-activity
relationship (SAR) around cinnamides 6 and 27. A
series of substituted N-(phenylalkyl)cinnamides were
prepared and assayed for inhibition at three putative
subtypes of NMDA receptors: NR1A in combination
with either NR2A, NR2B, or NR2C. The potency and
selectivity of the antagonists were assessed by func-
tional assays in Xenopus oocytes expressing recombi-
nant NMDA receptors.7 Cinnamide 16 was the most
potent among these cinnamides tested, exhibiting low
nanomolar potency (IC50 ) 77 nM) for the NR1A/2B
subunit combination and >1000-fold selectivity with
respect to NR1A/2A and NR1A/2C.
Ch em istr y
â-Cyanocinnamides (9, 11-15, and 30-31) were
prepared using modifications of known methodology
(method A).14 The other cinnamides were synthesized
by one of three general methods: direct reaction of a
cinnamic acid with the appropriate amine in the pres-
ence of CDI in THF (method B) or DCC and HOBT in
DMF (method C) or reaction of a cinnamyl chloride7,12,14
with the appropriate amine in the presence of trieth-
ylamine (method D). Cinnamide 36 was prepared by
alkylation of amide 27 with tert-butyl bromoacetate
followed by hydrolysis of the ester intermediate in TFA
(Scheme 1). N-Protection of tyramine (37) with benzyl
chloroformate followed by alkylation with N,N-dieth-
yliodoacetamide gave amide 38. Hydrogenolysis of
amide 38 with Pd/C (20%) followed by BH3‚SMe2 reduc-
tion gave amine 39. Reaction of amine 39 with 4-chlo-
rocinnamyl chloride as in method A gave cinnamide 40.
All final compounds were isolated as crystalline solids.
a
Reagents: (i) tert-butyl bromoacetate, EtOH; (ii) TFA; (iii)
benzyl chloroformate, NaHCO3; (iv) N,N-diethyliodoacetamide,
K2CO3; (v) Pd/C (20%), H2 (50 psi), EtOH; (vi) BH3‚SMe2, THF;
(vii) 4-chlorocinnamyl chloride.
F igu r e 2. Receptor features presumed important for the
binding of cinnamide antagonists at the NR1A/2B subtype.
Intramolecular distances (Å) between atoms were measured
on the fully extended conformer of 16, the most potent of the
cinnamides investigated. Calculations were at the semiem-
pirical (AM1) level.
Biologica l Eva lu a tion
Potency and subunit selectivity were assayed by
electrical recordings in Xenopus oocytes expressing three
binary combinations (NR1A expressed in combination
with either NR2A, NR2B, or NR2C) of cloned rat NMDA
receptor subunits. The steady-state IC50 values were
determined by curve fitting to concentration-inhibition
data pooled from 2-7 separate experiments (Table 1).
The methodology has been detailed earlier.7,10 In the
following discussion we consider only the high potency
inhibition of NR1A/2B receptors. The compounds tested
in this series are essentially inactive at the other two
subtypes of NMDA receptors tested. Binding of selected
cinnamides at R1 adrenergic receptors was determined
using the [3H]prazosin binding assay described by
Wright et al.15
ing: (a) the optimal distance and the spatial orientation
between the two aromatic rings (A- and B-rings, see
Figure 2) required for high potency; (b) the contribution
of the cinnamide carbon-carbon double bond and the
cyano group in the cinnamide moiety to potency; (c) the
effect of changes in substitution patterns on the aro-
matic rings; (d) the importance of the amide functional
group for the antagonist/receptor interaction.
â-Cyanocinnamides 6 and 7 show submicromolar
binding at the NR1A/2B subunit (Table 1). Keeping the
cinnamide moiety constant in 6-10, we see that the
NR1A/2B potency of these molecules increases with an
increase in the length of the alkyl chain connecting the
A-ring to the nitrogen atom of the amide group. The
potency is severely compromised when the chain length
is shorter than two atoms as illustrated by the inactivity
of cinnamides 9 and 10. Removal of the 3-OH group in
Str u ctu r e-Activity Rela tion sh ip
The SAR was conducted to determine the primary
structural determinants of potency in this series includ-

3414 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Tamiz et al.
Ta ble 1. Functional Antagonism of Reference Compounds and Substituted Cinnamides at NMDA Receptor Subtypes

SAR of N-(Phenylalkyl)cinnamides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3415
Ta ble 1 (Continued)
a
IC50 values ((SEM) were determined by electrical assays in Xenopus oocytes expressing the NMDA receptor combinations. For methods
and analyses, see refs 7 and 10. Values were obtained from at least three oocytes for NR1A/2B and at least two oocytes for the other
subunit combinations, except for 9, 13, 14, 17, and 36 where values were obtained from one or two oocytes. Due to solubility limitations,
b
>100 signifies <20% inhibition at 30 µM or <50% inhibition at 100 µM. NR1C/2A and NR1C/2B values, respectively, are taken from ref
d
g
8. c Not applicable or not tested. See ref 14. e See Experimental Section. f X ) CH2COOH. Y ) CH2CH2NEt2.
Ch a r t 1
secondary amide group in the linking chain is not
required for potent binding. Removal of the double bond
in the linking chain in 16 gives 21 and a 6-fold drop in
potency. The carbon-carbon double bond may be in-
volved in an electrostatic interaction with the receptor
pocket, or it merely constrains the geometry of the
antagonist, hence making the overall interaction with
the receptor thermodynamically more favorable (Figure
2). Surprisingly, ketone 2216 is only about 10-fold less
potent than amides 20 and 21.
The SAR in the n ) 2 series (cinnamides 8, 23-36,
and 40) is similar to that observed in the n ) 4 series.
Removal of the 3-OH group and the R-CN group in 8
gives cinnamide 23 and results in a small change in
potency. This finding supports the notion that the 3-OH
and R-CN groups are not required for activity. Addition
of a 4-Cl in the A-ring in 23 gives 24 and a >4-fold
increase in potency. This trend is opposite to that
observed in the n ) 4 series (16 vs 17). However,
replacing the B-ring 4-OH in 23 with a 4-Cl results in
an inactive compound (35), further demonstrating the
importance of the B-ring 4-OH group. Interestingly,
introduction of a 4-OH on the A-ring in 23 gives 25 and
results in 14-fold loss in potency. Surprisingly, cinna-
mide 26, with a 4-OH group on the A-ring instead of
the B-ring (23), is 2-fold more potent than 23. Appar-
ently the NR1A/2B receptor contains two hydrophobic
pockets both of which bind phenyl groups, however, only
one of which requires a hydrogen bond-donating/accept-
ing interaction (Figure 2). Thus there is only a slight
difference in potency between 23 and its transposed
analogue 26.
6 gives 11 and results in a 2-fold increase in potency.
By contrast, removal of the 4-OH group in 6 results in
complete loss of potency as seen with 15. Similarly,
removal of the 4-OH group in 11 and 16 gives 14 and
18, respectively, and renders the molecules essentially
inactive. Substitution of the 4-OH group in 11 with a
4-chloro (12) or 4-fluoro (13) atom also renders the
molecules inactive and further demonstrates the im-
portance of the 4-OH group for potency. Removal of the
R-cyano group in 11 gives 16 which is the most potent
compound in this series. Similarly, removal of the
R-cyano group in 14 gives 18 and a 3-fold increase in
potency. Cinnamide 16 is 7-fold more potent than the
R-cyano derivative 6. It appears that the R-cyano group
is not a major determinant of potency in n ) 4 series.
Piperidine-based cinnamide 20 (Chart 1), a rigidified
analogue of 16, was found to have similar potency to
that of 16. Hence the rigidification in the alkyl chain of
the antagonist is well-tolerated. This is consistent with
prototypic molecules such as ifenprodil. The high po-
tency of 20 also indicates that the hydrogen atom of the
Introduction of a 4-Cl group in the A-ring of 26 results
in cinnamide 27, the most potent cinnamide in the n )
2 series. Cinnamide 27 is 4-fold more potent than 26.
While introduction of an R-CN group in the n ) 4 series
results in a 3-fold decrease in potency (16 vs 11), the
presence of an R-CN group in the n ) 2 series reduces
the potency by 20-fold (29 vs 27). Introduction of a â-CN
group in the n ) 2 series (30 vs 27 and 31 vs 26)
decreases the potency more than an R-CN group does.

3416 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Tamiz et al.
Ta ble 2. Selected Cinnamides: R1 Data and Comparison of
Moving the hydroxy group in 27 from the para to the
meta (32) or ortho (33) position also reduces potency
∼20-fold. Replacing the 4-OH group in 27 with a 4-Cl
(34) or hydrogen (35) atom results in inactive molecules.
Replacement of the 4-OH group with an oxyacetic acid
group (i.e. 36) or a 2-dimethylaminoethoxy group (i.e.
40) also renders the molecules inactive.
Functional Antagonism of NR1A/2B Receptors with Inhibitory
Activities toward Two Tyrosine Kinases
IC50 (µM)
autophosphorylation
Compd
No.
a
R1
1A/2Bb
EGFRc ErbB2/neuc
d
1
6
7
8
9
10
16
20
28
0.100 ( 0.036 0.11 ( 0.01
-
-
>500
35
We note that the series of N-(phenylalkyl)cinnamides
described herein has a similar SAR to that of other
series of subtype-selective NMDA receptor antago-
nists.6,8,9,17 In earlier work concerning a series of bis-
(phenylalkyl)amines, we reported that the 4-OH group
in the phenyl ring is important for potency. In that
series a bis(phenylalkyl)amine without the 4-OH group
is 100-fold less active than the corresponding amine
with the 4-OH group.7 Chenard et al.9a also made
similar observations in a related series of subtype-
selective NMDA receptor antagonists; however, the
potency of compounds in their series was measured
using a different assay.
>100
-
0.56 ( 0.07
0.66 ( 0.14
1.7 ( 0.49
45
5
0.7
<0.625
0.1
1.25
-
-
-
-
23
13.5
42
-
-
-
-
-
90 ( 33
>100
>100
>100
0.077 ( 0.009
0.12 ( 0.02
19 ( 2.8
a
Single determination using [3H]prazocin as described in ref
b
15 except for the value for 1 which was taken from ref 18. IC50
values are taken from Table 1. c IC50 values are taken from ref
d
13b. Not tested.
Con clu sion
For the current series of cinnamide-based subtype-
selective NMDA receptor antagonists, the primary
determinants of potency at the NR2B containing NMDA
receptors are (1) the phenolic 4-OH group (Figure 2)
which presumably serves as a H-bond donor; (2) the
length of the linking chain from the nitrogen atom of
the cinnamide moiety to the B-ring; (3) an electrostatic
interaction between the receptor and the amide func-
tional group in the linking chain; (4) rigidification of the
linker through inclusion of a double bond. Our data
demonstrate that neither the piperidine ring of the
ifenprodil-based antagonists nor the basic nitrogen atom
in the linking chain are necessary for high potency and
selectivity. Potency at R1 adrenergic receptors is low,
and inhibition of NR1A/2B receptors does not correlate
with EGFR and ErbB2/neu tyrosine kinase activity. The
N-(phenylalkyl)cinnamides constitute a novel series of
subtype-selective NMDA receptor antagonists that ex-
tends the framework for designing novel NR1A/2B-
selective antagonists as clinically useful CNS therapeu-
tics.
Amide 16 (IC50 0.077 µM) is the most potent N-
(phenylalkyl)cinnamide in the present study. An 8-atom
spacer connects the A- and B-phenyl groups, giving the
molecule an overall length of ∼17.5 Å (Figure 2). In the
case of 23 and its transposed analogue 26, a 6-atom
spacer connects the two phenyl groups. Potencies are
significantly less than that of 16 but are improved by
lengthening the molecules with a 4-Cl group (24 and
27, respectively). An optimal length of ∼17.5 Å and a
similar structural motif were observed with the bis-
(phenylalkyl)amines, as exemplified by the most potent
member of that series, Co 101677 (4, IC50 0.008 µM).7
The optimal distance (7.8 Å) between the (basic) nitro-
gen atom and the oxygen of the hydroxy group in 4 is
shorter than in cinnamide 16 (∼8.9 Å) and may be
responsible for the 9-fold lower potency of 16 compared
to 4. Though there is no clear evidence that different
series of NR2B subtype-selective antagonists share a
common binding site, the general similarities in the SAR
of cinnamides, bis(phenylalkyl)amines, and 1,4-disub-
stituted piperidines suggest that all of these compounds
may interact with the NR1/2B receptors at the same or
overlapping sites.6,8,9,17
Exp er im en ta l Section
Gen er a l. Cinnamic acids were purchased from commercial
sources or were prepared using published procedures.7,12,14
Compounds 1 and 5-8 were purchased from commercial
sources. Reagents and solvents were purchased from com-
mercial suppliers and used as received. All starting materials
were commercially available unless otherwise indicated. Melt-
ing points were taken on a Mel-Temp apparatus and are
uncorrected. Tetrahydrofuran (THF) was distilled from blue
sodium benzophenone ketyl solution. Column chromatography
was performed in the flash mode on Davisil silica gel (200-
425 mesh). Yields are of purified product and are not opti-
Ifenprodil (1) is a potent R1 adrenergic receptor
antagonist.18 It was therefore of interest to compare
selected cinnamides to ifenprodil in terms of competitive
binding with [3H]prazosin as the radioligand. As the
data in Table 2 indicates, cinnamides 6, 16, 20, and 28
are essentially inactive in the [3H]prazosin binding
assay.
The inhibitory activities of cinnamides 6-10 toward
epidermal growth factor receptor (EGFR) tyrosine ki-
nase (HER1) and ErbB2/neu tyrosine kinase (HER2)
have been reported.13b This invites a comparison with
the functional antagonism by these cinnamides (termed
tyrphostins in ref 13b) of NR1A/2B containing NMDA
receptors (Table 2). While 6 is the most potent NR1A/
2B antagonist in this series, it is the least potent EGFR
and ErbB2/neu tyrosine kinase antagonist. The least
potent NR1A/2B antagonist, 10, is nearly 200-fold less
potent than 6. However, as an EGFR tyrosine kinase
antagonist, 10 is 4-fold more potent than 6. Apparently,
there is little correlation between NR1A/2B antagonism
and inhibitory activity toward these tyrosine kinases.
1
mized. H NMR spectra were recorded on a Varian Inova 310
MHz spectrometer; chemical shifts are reported in δ units
referenced to residual proton signals of the deuterated solvents
(chloroform-d1, 7.26; dimethyl-d6 sulfoxide, 2.49; methyl alcohol-
d4, 3.31), and coupling constants are reported in Hz.
P r ep a r a tion of N-(P h en yla lk yl)cin n a m id es (Gen er a l
P r oced u r e, Meth od A): N-Ben zyl-3,4-d ih yd r oxy-r-cya n o-
cin n a m id e (9). Benzylamine (3.0 g, 28 mmol) and ethyl
cyanoacetate (4.7 g, 42 mmol) in CH3CN (20 mL) were
magnetically stirred at reflux for 4 h. The solvent was removed
in vacuo to give an oil which solidified upon standing.
Precipitation (EtOAc) resulted in 3.28 g (67%) of an off-white
powder corresponding to N-benzylcyanoacetamide as an in-
termediate: 1H NMR (DMSO) δ 3.68 (s, 2H), 4.27 (d, J ) 6,

SAR of N-(Phenylalkyl)cinnamides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3417
2H), 7.2-7.4 (m, 5H), 8.71 (s, 1H). A mixture of N-benzylcy-
anomethylamide (1.3 g, 7.5 mmol), 3,4-dihydroxybenzaldehyde
(1.1 g, 8.2 mmol), and piperidine (catalytic, 5 drops) was
magnetically stirred at reflux for 3 h. Flash chromatography
(EtOAc) followed by two recrystallizations (H2O/EtOH) yielded
the title compound as a white powder, 0.8 g (36%): mp 207-
208 °C; 1H NMR (DMSO) δ 4.39 (d, J ) 5.7, 2H), 6.88 (d, J )
8.7, 1H), 7.2-7.4 (m, 6H), 7.53 (d, J ) 1.8, 1H), 7.97 (s, 1H),
8.83 (t, J ) 6, 1H), 9.81 (bs, 2H). Anal. (C17H14N2O3) C, H, N.
The following compounds (11-15) were prepared by the
method described for 9 using the appropriate combination of
the reagents.
obtained 82 mg (9%) of 16 as a white solid: mp 140-141 °C;
1H NMR (CDCl3 + DMSO) δ 1.4-1.5 (m, 4H), 2.54 (t, J ) 7.2,
2H), 3.25 (q, J ) 6.2, 2H), 6.17 (d, J ) 15.9, 1H), 6.35 (bs, 1H),
6.72 (d, J ) 8.4, 2H), 7.07 (d, J ) 7.2, 1H), 7.15 (d, J ) 6.6,
2H), 7.2-7.3 (m, 3), 7.40 (d, J ) 15.6, 1H), 9.02 (s, 1H). Anal.
(C19H21NO2) C, H, N.
N-(4-Hyd r oxycin n a m yl)-4-ben zylp ip er id in e (20). From
4-hydroxycinnamic acid (494 mg, 3.01 mmol), CDI (488 mg,
3.01 mmol), and 4-benzylpiperidine (614 mg, 3.50 mmol) was
obtained 184 mg (19%) of 20 as a white solid: mp 138-140
°C; 1H NMR (CDCl3) δ 1.22 (m, 2H), 1.77 (m, 3H), 2.57 (m,
3H), 3.05 (m, 1H), 4.11 (m, 1H), 4.70 (m, 1H), 6.13 (m, 1), 6.75
(d, J ) 15.6, 1H), 6.85 (d, J ) 8.4, 2H), 7.15 (d, J ) 6.6, 2H),
7.31 (m, 3H), 7.40 (d, J ) 8.7, 2H), 7.60 (d, J ) 15.3, 1H). Anal.
(C21H23NO2) C, H, N.
N -(4-P h e n y lb u t y l)-3-(4-h y d r o x y p h e n y l)p r o p io n a -
m id e (21). From 3-(4-hydroxyphenyl)propionic acid (499 mg,
3.01 mmol), CDI (488 mg, 3.01 mmol), and 4-phenylbutylamine
(498 mg, 3.34 mmol) was obtained 86 mg (10%) of 21 as a white
solid: mp 71-72 °C; 1H NMR (CDCl3) δ 1.47 (m, 2H), 1.57
(m, 2H), 2.41 (t, J ) 7.5, 2H), 2.60 (t, J ) 7.2, 2H), 2.88 (t,
J ) 7.2, 2H), 3.23 (q, J ) 6.6, 2H), 5.29 (s, 1H), 5.38 (s, 1H),
6.72 (d, J ) 8.1, 2H), 7.04 (d, J ) 8.4, 2H), 7.17 (m, 3H), 7.29
(m, 2H). Anal. (C19H23NO2) C, H, N.
N-(2-(4-Hyd r oxyp h en yl)eth yl)cya n oa ceta m id e. From
ethyl cyanoacetate (4.10 g, 36.3 mmol) and tyramine (5.00 g,
36.5 mmol) was obtained 3.48 g (47%) of the title compound
as a yellow solid: mp 150-152 °C; 1H NMR (DMSO) δ 2.55 (t,
J ) 7.2, 2H), 3.18 (t, J ) 7.2, 2H), 3.54 (s, 1H), 6.62 (d, J )
8.1, 2H), 6.94 (d, J ) 8.4, 2H), 8.23 (s, 1H), 9.16 (s, 1H).
N-(2-(4-Hyd r oxyp h en yl)eth yl)-4-ch lor o-r-cya n ocin n a -
m id e (29). From N-(2-(4-hydroxyphenyl)ethyl)cyanoacetamide
(600 mg, 2.77 mmol) and 4-chlorobenzaldehyde (600 mg, 4.25
mmol) was obtained 823 mg (60%) of 29 as a white solid: mp
170-171 °C; 1H NMR (DMSO) δ 2.65 (t, J ) 7.2, 2H), 3.16
(2H), 6.63 (d, J ) 8.4, 2H), 6.96 (d, J ) 8.1, 2H), 7.60 (d, J )
8.4, 2H), 7.89 (d, J ) 8.7, 2H), 8.10 (s, 1H), 8.50 (t, 1H), 9.17
(bs, 1H). Anal. (C18H15ClN2O2) C, H, N.
N-(4-P h en ylbu tyl)cya n oa ceta m id e. A solution of ethyl
cyanoacetate (8.0 g, 7.5 mL, 70 mmol) and 4-phenylbutylamine
(10 g, 67 mmol) was allowed to stir at 100 °C for 10 h without
a condenser. The residue was then purified by flash chroma-
tography to give N-(4-phenylbutyl)cyanoacetamide as a yellow
1
solid, 10 g (69%): mp 50-52 °C; H NMR (CDCl3) δ 1.65 (m,
4H), 2.65 (m, 2H), 3.31 (m, 2H), 3.35 (s, 2H), 6.07 (bs, 1H),
7.2-7.3 (m, 5H).
N-(4-P h en ylbu tyl)-4-h yd r oxy-r-cya n ocin n a m id e (11).
From 4-hydroxybenzaldehyde (0.61 g, 5.0 mmol) and N-(4-
phenylbutyl)cyanoacetamide (1.2 g, 5.5 mmol) was obtained
0.81 g (51%) of 11 as a yellow solid: mp 143-145 °C; 1H NMR
(CDCl3) δ 1.67 (m, 4H), 2.66 (m, 2H), 3.43 (m, 2H), 6.12 (bs,
1H), 6.33 (s, 1H), 6.93 (d, J ) 8.7, 2H), 7.2-7.3 (m, 5H), 7.87
(d, J ) 8.7, 2H), 8.23 (s, 1H). Anal. (C20H20N2O2) C, H, N.
N-(4-P h en ylb u t yl)-4-ch lor o-r-cya n ocin n a m id e (12).
From 4-chlorobenzaldehyde (0.70 g, 5.0 mmol) and N-(4-
phenylbutyl)cyanoacetamide (1.2 g, 5.5 mmol) was obtained
0.83 g (49%) of 12 as a white solid: mp 115-117 °C; 1H NMR
(CDCl3) δ 1.64 (m, 4H), 2.67 (m, 2H), 3.46 (m, 2H), 6.33 (bs,
1H), 7.20-7.32 (m, 5H), 7.48 (d, J ) 8.4, 2H), 7.88 (d, J ) 8.4,
2H), 8.27 (s, 1H). Anal. (C20H19ClN2O) C, H, N.
N-(4-P h en ylbu tyl)-4-flu or o-r-cyan ocin n am ide (13). From
4-fluorobenzaldehyde (0.62 g, 5.0 mmol) and N-(4-phenylbu-
tyl)cyanoacetamide (1.2 g, 5.5 mmol) was obtained 0.80 g (50%)
of 13 as a yellow solid: mp 82-84 °C; 1H NMR (CDCl3) δ 1.67
(m, 4H), 2.67 (m, 2H), 3.46 (m, 2H), 6.32 (bs, 1H), 7.79 (m,
7H), 7.95 (m, 2H), 8.28 (s, 1H). Anal. (C20H19FN2O) C, H, N.
N-(4-P h en ylbu tyl)-r-cya n ocin n a m id e (14). From benz-
aldehyde (0.53 g, 5.0 mmol) and N-(4-phenylbutyl)cyanoac-
etamide (1.2 g, 5.5 mmol) was obtained 0.45 g (31%) of 14 as
a white solid: mp 75-77 °C; 1H NMR (CDCl3) δ 1.68 (m, 4H),
2.67 (m, 2H), 3.46 (m, 2H), 6.35 (bs, 1H), 7.2-7.3 (m, 5H), 7.52
(m, 3H), 7.92 (d, J ) 6.9, 2H), 8.33 (s, 1H). Anal. (C20H20N2O‚
0.15H2O) C, H, N.
P r ep a r a tion of N-(P h en yla lk yl)cin n a m id es (Gen er a l
P r oced u r e, Meth od C): N-(2-(4-Ch lor op h en yl)eth yl)-4-
h yd r oxycin n a m id e (24). A solution of 4-hydroxycinnamic
acid (800 mg, 4.88 mmol), 1,3-dicyclohexylcarbodiimide (1.08
g, 5.22 mmol), and 1-hydroxybenzotriazole (846 mg, 6.26 mmol)
in DMF (20 mL) was stirred at room temperature for 3 h. To
the solution was then added 2-(4-chlorophenyl)ethylamine (915
mg, 5.86 mmol), and the reaction mixture was stirred at 80
°C for 12 h. The precipitate was removed by filtration, and
the filtrate was diluted with H2O (310 mL). The solid precipi-
tate was collected by filtration and crystallized (EtOAc) to give
24 as a colorless solid, 1.04 g (96%): mp 197-199 °C; 1H NMR
(DMSO) δ 1.90 (t, J ) 9.0, 2H), 2.55 (t, J ) 6.3, 2H), 5.54 (d,
J ) 15.9, 1H), 5.94 (d, J ) 8.7, 2H), 6.2-6.6 (m, 7H), 7.14 (bs,
1H), 8.99 (bs, 1H). Anal. (C17H16ClNO2) C, H, N.
N-(4-P h en ylbu tyl)-3-h yd r oxy-r-cya n ocin n a m id e (15).
From 3-hydroxybenzaldehyde (0.61 g, 5.0 mmol) and N-(4-
phenylbutyl)cyanoacetamide (1.2 g, 5.5 mmol) was obtained
1
1.2 g (74%) of 15 as a white solid: mp 183-185 °C; H NMR
(CDCl3) δ 1.48 (m, 4H), 2.49 (m, 2H), 3.23 (m, 2H), 6.8-7.2
(m, 11H), 7.99 (m, 1H). Anal. (C20H20N2O2) C, H, N.
The following compounds (17, 23, 25, 30, and 31) were
prepared by the method described for 23 using the appropriate
combination of the reagents.
P r ep a r a tion of N-(P h en yla lk yl)cin n a m id es (Gen er a l
P r ocedu r e, Meth od B): N-(4-P h en ylbu tyl)cin n am ide (18).
A solution of cinnamic acid (445 mg, 3.00 mmol) and CDI (486
mg, 3.00 mmol) in THF (15 mL) was stirred at room temper-
ature for 0.5 h. 4-Phenylbutylamine (551 mg, 3.69 mmol) was
added, and the mixture was stirred at room temperature
overnight. The solution was diluted with H2O (50 mL) and
EtOAc (40 mL). The organic phase was separated and washed
with 0.1 N HCl (3 × 15 mL), dried over MgSO4, and evaporated
in vacuo to give a white solid. Crystallization (diethyl ether)
gave the title compound 18 as a white solid, 313 mg (36%):
N-(4-(4-Ch lor op h en yl)bu tyl)-4-h yd r oxycin n a m id e (17).
From 4-hydroxycinnamic acid (446 mg, 2.72 mmol), 1,3-
dicyclohexylcarbodiimide (560 mg, 2.72 mmol), 1-hydroxyben-
zotriazole (367 mg, 2.72 mmol), and 4-(chlorophenyl)butyl-
amine (500 mg, 2.72 mmol) was obtained 80 mg (9%) of 17 as
1
a white solid: mp 162-164 °C; H NMR (DMSO) δ 1.3-1.6
(m, 4H), 2.57 (t, J ) 6.9 Hz, 2H), 3.14 (q, J ) 6.6 Hz, 2H),
6.32 (d, J ) 15.9, 1H), 6.75 (t, J ) 8.4, 2 H), 7.1-7.4 (m, 7H),
7.94 (t, J ) 6.0, 1H), 9.81 (bs, 1H). Anal. (C19H20NO2Cl) C, H,
N.
1
mp 62-63 °C; H NMR (CDCl3) δ 1.56-1.70 (m, 4H), 2.66 (t,
J ) 7.2, 2H), 3.41 (q, J ) 6.3, 2H), 5.61 (bs, 1H), 6.36 (d, J )
15.6, 1H), 7.1-7.5 (m, 10H), 7.62 (d, J ) 15.3, 1H). Anal.
(C19H21NO) C, H, N.
N-(2-P h en yleth yl)-4-h ydr oxycin n am ide (23). From 4-hy-
droxycinnamic acid (1.0 g, 6.1 mmol), 1,3-dicyclohexylcarbo-
diimide (1.3 g, 6.3 mmol), 1-hydroxybenzotriazole (0.9 g, 6.7
mmol), and 2-phenylethylamine (0.8 g, 6.3 mmol) was obtained
1.4 g (88%) of 23 as a solid: mp 143-145 °C; 1H NMR (DMSO)
δ 2.75 (t, J ) 7.2, 2H), 3.38 (t, J ) 6.6, 2H), 6.35 (d, J ) 15.6,
1H), 6.75 (d, J ) 8.4, 1H), 7.2-7.4 (m, 6H), 8.0 (t, J ) 5.4 2H),
9.82 (s, 1H). Anal. (C17H17NO2) C, H, N.
The following compounds (16, 20, 21, and 29) were prepared
by the method described for 17 using the appropriate combina-
tion of the reagents.
N-(4-P h en ylbu tyl)-4-h ydr oxycin n am ide (16). From 4-hy-
droxycinnamic acid (492 mg, 3.00 mmol), CDI (496 mg, 3.05
mmol), and 4-phenylbutylamine (490 mg, 3.25 mmol) was

3418 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Tamiz et al.
N-(2-(4-Hydr oxyph en yl)eth yl)-4-h ydr oxycin n am ide (25).
From 4-hydroxycinnamic acid (1.00 g, 6.01 mmol), 1,3-dicy-
clohexylcarbodiimide (0.99 g, 7.32 mmol), 1-hydroxybenzo-
triazole (0.99 g, 7.32 mmol), and tyramine (1.00 g, 7.32 mmol)
was obtained 1.54 g (89%) of 25 as a solid: mp 247-248 °C;
1H NMR (DMSO) δ 2.59 (t, J ) 7.2, 2H), 6.32 (d, J ) 15.6,
1H), 6.62 (d, J ) 8.4, 2H), 6.72 (d, J ) 8.4, 2H), 6.95 (d, J )
8.5, 2H), 7.23 (d, J ) 15.6, 1H), 7.32 (d, J ) 8.4, 2H), 7.96 (m,
1H), 9.15 (bs, 1H), 9.75 (bs, 1H). Anal. (C17H17NO3) C, H, N.
N-(2-(4-Hyd r oxyp h en yl)eth yl)-4-ch lor o-â-cya n ocin n a -
m id e (30). 4-Chloro-â-cyanocinnamate potassium salt14b (1.0
g, 4.1 mmol) was dissolved in 2 N HCl (100 mL) and extracted
with EtOAc (3 × 50 mL). The combined EtOAc layers was
dried over Na2SO4 and evaporated in vacuo to give the
corresponding acid as a white powder. From 4-chloro-â-
cyanocinnamic acid (400 mg, 1.63 mmol), 1,3-dicyclohexylcar-
bodiimide (370 mg, 1.79 mmol), 1-hydroxybenzotriazole (269
mg, 2.12 mmol), and tyramine (364 mg, 2.12 mmol) was
obtained 583 mg (94%) of 30 as a white solid: mp > 250 °C;
1H NMR (DMSO) δ 2.66 (t, J ) 6.8, 2H), 6.68 (d, J ) 8.4, 2H),
7.00 (d, J ) 8.1, 2H), 7.31 (s, 1H), 7.59 (d, J ) 8.7, 2H), 7.68
(d, J ) 8.4, 2H), 8.52 (s, 1H), 9.16 (s, 1H). Anal. (C18H15ClN2O2)
C, H, N.
N-(2-(4-Hyd r oxyp h en yl)eth yl)-â-cya n ocin n a m id e (31).
Potassium â-cyanocinnamate14b (1.00 g, 4.74 mmol) was dis-
solved in 2 N HCl (100 mL) and extracted with EtOAc (3 × 50
mL). The combined EtOAc layers were dried over Na2SO4 and
evaporated in vacuo to give the corresponding acid. From
â-cyanocinnamic acid (0.87 g, 5.05 mmol), 1,3-dicyclohexyl-
carbodiimide (1.11 g, 5.40 mmol), 1-hydroxybenzotriazole (0.76
g, 5.60 mmol), and tyramine (1.15 g, 6.06 mmol) was obtained
150 mg (10%) of 31 as a transparent solid: mp 169-171 °C;
1H NMR (DMSO) δ 2.63 (t, J ) 5.5, 2H), 3.33 (t, J ) 5.4, 2H),
6.65 (d, J ) 6.8, 2H), 7.00 (d, J ) 6.8, 2H), 7.27 (s, 1H), 7.5-
7.6 (m, 5H), 8.51 (s, 1H), 9.16 (s, 1H). Anal. (C18H16N2O2) C,
H, N.
precipitate was collected by filtration and crystallized (EtOH)
to yield a transparent solid (1.7 g, 75%) corresponding to 2,5-
dichlorocinnamic acid as an intermediate: 1H NMR (CDCl3)
δ 6.67 (d, J ) 16.2, 2H), 7.45 (d, J ) 8.7, 2H), 7.53 (d, J ) 8.4,
2H), 7.71 (d, J ) 15.9, 2H), 8.01 (s, 1H). 2,5-Dichlorocinnamic
acid (3.3 g, 15 mmol) was dissolved in SOCl2 (5 mL), and the
solution was stirred at reflux for 12 h. The SOCl2 was removed
in vacuo to give a white powder. This powder was dissolved
in CH2Cl2 (2 × 10 mL), and the solvent was removed in vacuo
to give a white powder. This powder (0.39 g, 1.81 mmol) was
added to a solution of tyramine (0.55 g, 3.99 mmol) in CH3CN
(15 mL), and the mixture was stirred at reflux for 3 h. The
precipitate was collected by filtration and purified by flash
chromatography (CHCl3/EtOAc, 9:1) to give the title compound
1
28 as a white solid, 0.217 g (36%): mp 174-175 °C; H NMR
(CDCl3 + 5% DMSO) δ 2.47 (t, J ) 7.2, 2H), 3.20 (q, J ) 6.3,
2H), 6.70 (d, J ) 15.8, 1H), 6.46 (d, J ) 8.4, 2H), 6.73 (d, J )
8.1, 2H), 6.95 (d, J ) 8.7, 1H), 7.05 (d, J ) 8.6, 1H), 7.55 (d,
J ) 15.7, 1H), 8.45 (s, 1H). Anal. (C17H15Cl2NO2) C, H, N.
N-(2-(3-Hyd r oxyp h en yl)eth yl)-4-ch lor ocin n a m id e (32).
From 4-chlorocinnamyl chloride (1.50 g, 7.50 mmol) and 2-(3-
hydroxyphenyl)ethylamine (1.43 g, 8.24 mmol) was obtained
0.92 g (41%) of 32 as a white solid: mp 141-142 °C; 1H NMR
(CDCl3) δ 2.83 (t, J ) 6.8, 2H), 3.65 (q, J ) 6.5, 2H), 5.68 (bs,
1H), 5.96 (bs, 1H), 6.27 (d, J ) 15.4, 1H), 6.7-6.8 (m, 3H),
7.19 (t, J ) 7.6, 1H), 7.31 (d, J ) 8.7, 2H), 7.38 (d, J ) 8.7,
2H), 7. 56 (d, J ) 15.4, 1H). Anal. (C17H16ClNO2) C, H, N.
N-(2-(2-Hyd r oxyp h en yl)eth yl)-4-ch lor ocin n a m id e (33).
From 4-chlorocinnamyl chloride (1.57 g, 7.83 mmol) and 2-(2-
hydroxyphenyl)ethylamine (1.50 g, 8.64 mmol) was obtained
1.92 g (81%) of 33 as a white solid: mp 178-179 °C; 1H NMR
(DMSO) δ 2.8-3.0 (m, 2H), 3.5-3.6 (m, 2H), 6.13 (bs, 1H), 6.34
(d, J ) 15.4, 2H), 6.83 (dt, J ) 7.4, 1.2, 1H), 6.91 (dd, J ) 8.1,
1.2, 1H), 7.07 (dd, J ) 7.5, 1.7, 1H), 7.16 (dt, J ) 7.7, 1.7, 1H),
7.34 (d, J ) 8.4, 2H), 7.43 (d, J ) 8.4, 2H), 7.51 (s, 1H), 7.65
(d, J ) 15.7, 1H). Anal. (C17H16ClNO2) C, H, N.
N-(2-(4-Ch lor op h en yl)et h yl)-4-ch lor ocin n a m id e (34).
From 4-chlorocinnamyl chloride (600 mg, 3.00 mmol) and 2-(4-
chlorophenyl)ethylamine (557 mg, 3.58 mmol) was obtained
895 mg (94%) of 34 as a crystalline solid: mp 171-173 °C; 1H
NMR (DMSO) δ 2.76 (t, J ) 7.2, 2H), 3.40 (t, J ) 7.2, 2H),
6.62 (d, J ) 15.9, 1H), 7.2-7.6 (m, 9H), 8.18 (bs, 1H). Anal.
(C17H15Cl2NO) C, H, N.
P r ep a r a tion of N-(P h en yla lk yl)cin n a m id es (Gen er a l
P r oced u r e, Meth od D): N-(2-(4-Hyd r oxyp h en yl)eth yl)-
cin n a m id e (26). A mixture of cinnamyl chloride (500 mg, 3.00
mmol) and tyramine (1.00 g, 7.50 mmol) in DMF (20 mL) was
stirred at 80 °C for 3 h. The mixture was diluted with H2O
(310 mL), and the solution was stirred overnight. The precipi-
tate was collected by filtration. Crystallization (EtOAc) re-
sulted in the title compound 26 as a crystalline solid, 497 mg
1
N-(2-P h en yleth yl)-4-ch lor ocin n a m id e (35). From 4-chlo-
rocinnamyl chloride (1.09 g, 5.42 mmol) and phenylethylamine
(839 mg, 6.93 mmol) was obtained 1.29 g (94%) of 35 as a
colorless solid: mp 148-150 °C; 1H NMR (DMSO) 2.76 (t, J )
9.2, 2H), 3.39 (t, J ) 9.3, 2H), 6.58 (d, J ) 15.9, 1H), 7.2-7.6
(m, 1H). Anal. (C17H16ClNO) C, H, N.
(62%): mp 186-187 °C; H NMR (DMSO) δ 1.79 (t, J ) 7.5,
2H), 2.45 (t, J ) 7.5, 2H), 5.78 (d, J ) 15.6, 1H), 5.84 (d, J )
8.4, 2H), 6.17 (d, J ) 8.1, 2H), 6.5-6.6 (m, 4H), 6.71 (d, J )
8.4, 1H), 7.31 (m, 2H), 8.33 (bs, 1H). Anal. (C17H17NO2) C, H,
N.
The following compounds (19, 27, 28, 32, 34, and 35) were
prepared by the method described for 23 using the appropriate
combination of the reagents.
N-[2-(4-(2-Ca r boxym eth yl-1-oxy)p h en yl)eth yl]-4-ch lo-
r ocin n a m id e (36). A mixture of cinnamide 27 (0.49 g, 1.62
mmol), K2CO3 (1.12 g, 8.10 mmol), and tert-butyl bromoacetate
(0.53 mL, 3.28 mmol) in absolute EtOH (12 mL) was stirred
at reflux for 3 h. The solid was removed by filtration and
washed with EtOAc (2 × 31 mL). The filtrate was evaporated
in vacuo, and the residue was purified by chromatography
(EtOAc/hexanes, 3:10) to give 0.17 g (25%) of the title
compound, a colorless oil, as an intermediate: 1H NMR (CDCl3)
δ 2.81 (t, J ) 6.84, 2H), 3.60 (q, J ) 6.4, 2H), 4.47 (s, 2H),
5.65 (t, J ) 5.4, 1H), 6.26 (d, J ) 15.6, 1H), 6.7-6.8 (m, 2H),
6.80 (d, J ) 7.6, 1H), 7.18 (m, 1H), 7.28 (d, J ) 8.6, 2H), 7.37
(d, J ) 8.6, 2H), 7.52 (d, J ) 15.6, 1H). A solution of the N-[2-
(4-(2-tert-butylcarboxymethyl-1-oxy)phenyl)ethyl]-4-chlorocin-
namide (0.17 g, 0.41 mmol) in TFA (3 mL) was stirred at room
temperature overnight. TFA was evaporated in vacuo to give
a colorless oil. The oil was dissolved in EtOAc (20 mL) and
evaporated in vacuo to give the title compound 36 as a white
solid, 0.13 g (88%): mp 126-127 °C; 1H NMR (DMSO) δ 2.75
(t, J ) 7.4, 2H), 3.40 (q, J ) 6.8, 2H), 4.65 (s, 2H), 6.62 (d,
J ) 15.9, 1H), 6.74 (dd, J ) 8.2, 2.7, 1H), 6.7-6.8 (m, 2H),
7.21 (t, J ) 7.8, 1H), 7.40 (d, J ) 15.9, 1H), 7.47 (d, J ) 8.7,
N-(4-P h en ylbu tyl)-2,5-d ich lor ocin n a m id e (19). From
2,5-dichlorocinnamyl chloride (364 mg, 1.68 mmol) and 4-
phenylbutylamine (499 mg, 3.35 mmol) was obtained 478 mg
1
(47%) of 19 as a white solid: mp 88-90 °C; H NMR (CDCl3)
δ 1.8 (m, 4H), 2.68 (t, J ) 6.9, 2H), 3.40 (q, J ) 6.6, 2H), 5.60
(bs, 1H), 6.32 (d, J ) 15.6, 1H), 7.0-7.5 (m, 8H), 7.87 (d, J )
18, 1H). Anal. (C19H19Cl2NO) C, H, N.
N-(2-(4-Hyd r oxyp h en yl)eth yl)-4-ch lor ocin n a m id e (27).
From 4-chlorocinnamyl chloride (267 mg, 1.33 mmol) and
tyramine (532 mg, 3.88 mmol) was obtained 195 mg (49%) of
27 as a transparent white solid: mp 164-167 °C; 1H NMR
(DMSO) δ 2.06 (t, J ) 7.2, 2H), 3.18 (m, 2H), 6.55 (d, J ) 7.2,
1H), 6.63 (d, J ) 8.1, 2H), 6.96 (d, J ) 8.1, 2H), 7.33 (d, J )
15.9, 1H), 7.42 (d, J ) 8.1, 2H), 7.23 (d, J ) 8.4, 2H), 8.12 (bs,
1H). Anal. (C17H16ClNO2) C, H, N.
N -(2-(4-H y d r o x y p h e n y l)e t h y l)-2,5-d ic h lo r o c in n a -
m id e (28). A mixture of 1,4-dichloro-2-iodobenzene (2.8 g,
10 mmol), acrylic acid (0.9 g, 12 mmol), palladium(II) acetate
(22 mg, 0.10 mmol), and Et3N (2.6 g, 26 mmol) in CH3CN (4
mL) was heated under N2 in a sealed tube at 100 °C for 1 h.
The reaction was allowed to cool to room temperature and
diluted with HCl (10% in H2O, 250 mL). The resulting colorless
2H), 7.58 (d, J ) 8.7, 2H), 8.22 (t, J ) 5.6, 1H). Anal. (C19H18
ClNO4) C, H, N.
-

SAR of N-(Phenylalkyl)cinnamides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3419
N,N-Diet h yl-2-(4-(2-N-b en zyloxyca r b a m ylet h yl)p h e-
n oxy)a ceta m id e (38). To a mixture of tyramine (37; 2.00 g,
14.6 mmol) and NaHCO3 (1.26 g, 15.0 mmol) in THF/H2O (100
mL, 1:1) cooled at 0 °C was added dropwise benzyl chlorofor-
mate (2.2 mL, 14.6 mmol), and the reaction mixture was
allowed to warm to room temperature and stirred overnight.
The organic layer was separated, and the aqueous layer was
extracted with CHCl3 (2 × 75 mL) and THF (2 × 75 mL). The
combined organic layers were washed with brine (75 mL) and
evaporated in vacuo to give an oil. Column chromatography
(EtOAc/hexanes, 1:4 then 1:1) resulted in 2.31 g (60%) of
N-(benzyloxycarbonyl)-2-(4-hydroxyphenyl)ethylamine, a color-
less oil, as an intermediate: 1H NMR (CDCl3) δ 2.70 (t, J )
7.0, 2H), 3.38 (q, J ) 6.8, 2H), 4.75 (bs, 1H), 5.06 (s, 2H), 5.34
(s, 1H), 6.72 (d, J ) 8.6, 2H), 6.99 (d, J ) 8.1, 2H),7.3-7.4 (m,
5H). A mixture of N,N-diethyliodoacetamide (1.21 g, 5.02
mmol), N-(benzyloxycarbonyl)-2-(4-hydroxyphenyl)ethylamine
(1.31 g, 4.79 mmol), K2CO3 (1.38 g, 9.98 mmol), and a catalytic
amount of 18-crown-6 in THF (60 mL) was stirred at reflux
for 18 h. N,N-Diethyliodoacetamide (0.6 g, 2.5 mmol) was
added, and the mixture was further stirred at reflux for 24 h.
The reaction mixture was cooled to room temperature. The
resulting solids were filtered and washed with THF (2 × 50
mL). The filtrate was evaporated in vacuo to give an orange
oil. Column chromatography (EtOAc/hexanes, 3.5:10) resulted
in the title compound 38 as a colorless oil, 2.16 g (92%): 1H
NMR (CDCl3) δ 1.10 (t, J ) 7.1, 3H), 1.17 (t, J ) 7.1, 3H),
2.71 (t, J ) 6.8, 2H), 3.3-3.4 (m, 6H), 4.72 (bs, 1H), 4.61 (s,
2H), 5.05 (s, 2H), 6.84 (d, J ) 8.6, 2H), 7.05 (d, J ) 8.3, 2H),
7.2-7.3 (m, 5H).
N,N-Diet h yl-2-(4-(2-a m in oet h yl)p h en oxy)et h yla m in e
(39). A mixture of N,N-diethyl-2-(4-(2-N-benzyloxycarbamyl-
ethyl)phenoxy)acetamide (38) (2.17 g, 5.64 mmol) and 20%
Pd/C (200 mg) in absolute EtOH (100 mL) was shaken on a
Parr flask under H2 (50 psi) for 4.5 h. The catalyst was
removed by filtration, and the filtrate was evaporated in vacuo
to give 1.32 g (93%) of N,N-diethyl-2-(4-(2-aminoethyl)phe-
noxy)acetamide, a colorless oil, as an intermediate: 1H NMR
(CDCl3) δ 1.10 (t, J ) 7.3, 3H), 1.17 (t, J ) 7.3, 3H), 1.81 (bs,
2H), 2.65 (t, J ) 6.8, 2H), 2.89 (t, J ) 6.8, 2H), 3.35 (quin,
J ) 7.1, 4H), 4.61 (s, 2H), 6.84 (d, J ) 8.6, 2H), 7.07 (d, J )
8.6, 2H). A mixture of N,N-diethyl-2-(4-(2-aminoethyl)phe-
noxy)acetamide (1.32 g, 5.27 mmol) and BH3‚SMe2 (1.6 mL,
16.0 mmol) in THF (120 mL) was stirred at reflux for 6 h. The
reaction mixture was cooled to 0 °C and quenched by dropwise
addition of MeOH (20 mL). The solvent was evaporated in
vacuo to give an oil. The oil was dissolved in 1 N HCl (50 mL)
and extracted with CHCl3/EtOAc (50 mL, 1:1). The pH was
adjusted to 10-11 with K2CO3 and extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried over Na2-
SO4, filtered through a cotton wool, and evaporated in vacuo
to give the title compound 39 as a colorless oil, 0.83 g (66%):
1H NMR (CDCl3) δ 1.03 (t, J ) 7.1, 6H), 2.60 (q, J ) 7.1, 2H),
2.63 (q, J ) 6.6, 2H), 2.83 (t, J ) 6.4, 2H), 2.88 (t, J ) 6.6,
2H), 3.99 (t, J ) 6.2, 2H), 6.80 (d, J ) 7.8, 2H), 7.05 (d, J )
7.8, 2H).
odology and Dr. L. Zhang for the preparation of cRNA.
Financial support to the University of Oregon was
provided by CoCensys, Inc.
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