Design and synthesis of potential β-sheet nucleators via Suzuki coupling reaction

Article abstract of DOI:10.1016/j.tet.2007.09.071

Three series of compounds characterized by biphenylic structure were synthesized in order to develop new scaffolds able to induce β-sheet folding in the peptides. Microwave flash heating was used in order to shorten reaction times and to enhance the obtained yields. Simulated annealing molecular dynamics simulations demonstrated that some of the compounds were capable of adopting a 15-membered intramolecularly hydrogen-bonded conformation, which supports an antiparallel β-sheet structure.

Full text of DOI:10.1016/j.tet.2007.09.071

Tetrahedron 63 (2007) 12779–12785
Design and synthesis of potential b-sheet nucleators
via Suzuki coupling reaction
Elisa Perissutti, Francesco Frecentese, Antonio Lavecchia, Ferdinando Fiorino, Beatrice Severino,
*
Francesca De Angelis, Vincenzo Santagada and Giuseppe Caliendo
Dipartimento di Chimica Farmaceutica e Tossicologica, Universitaꢀdi Napoli ‘‘Federico II’’, Via D. Montesano 49, 80131 Naples, Italy
Received 7 June 2007; revised 5 September 2007; accepted 27 September 2007
Available online 29 September 2007
Abstract—Three series of compounds characterized by biphenylic structure were synthesized in order to develop new scaffolds able to induce
b-sheet folding in the peptides. Microwave flash heating was used in order to shorten reaction times and to enhance the obtained yields.
Simulated annealing molecular dynamics simulations demonstrated that some of the compounds were capable of adopting a 15-membered
intramolecularly hydrogen-bonded conformation, which supports an antiparallel b-sheet structure.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reported by Hirschmann and co-workers in their work on
cyclic somatostatin analogues.6
The secondary structure of peptides and proteins is critical
for their bioactivities. Several examples are reported in the
literature of molecular mimics of specific secondary struc-
tures by means of non-peptidic scaffolds.1–3 In particular,
the mechanism of b-sheet folding and the basis for sheet
stability are under investigation in several laboratories using
a variety of creative approaches.4 The b-sheet structure is
currently an interesting target because of its poor abundance
with respect to a-helical secondary structure; our lack of
knowledge about b-sheets is due, in part, to difficulties in-
herent in creating a well defined peptide model system for
the detailed study of b-sheet formation in aqueous media.5
Here, we describe the development of a series of compounds
characterized by a general structure reported in Figure 1,
which have been designed to replace the backbone of a b-turn
and reverse the peptide chain direction via a hydrogen-
bonded hydrophobic cluster conformation to initiate b-hair-
pin folding.
The new molecules have a common scaffold, characterized
by a biphenyl-based amino acid structure with the carboxyl
and amino functions in the ortho positions, substituted with
electron withdrawing or donating substituents. The introduc-
tion of these substituents is important because in this way we
can introduce some pharmacologically relevant functional
groups in an unconventional position of the peptide.
Although studies on the conformational properties of pep-
tides have enhanced our understanding of b-sheet structure,
the approach is limited because of competitive intra- and
inter-molecular foldings, which lead to heterogeneous
b-sheet structures. Our goal was to develop a new reliable
strategy to prepare monomeric b-hairpin structures that
can accommodate considerable a-amino acid sequence
variations.
The synthetic approach for the development of these new
compounds has involved the use of microwave flash heating
in order to shorten reaction times and to increase the
obtained yields.7 In fact, during recent years, our interests
were mainly directed to advances in the syntheses of pepti-
domimetics and particularly to the application of microwave
irradiation in the field of peptide chemistry.7,8
However, the conformational properties of known b-turn
sequences do not appear to be sufficient to effect b-hairpin
folding, given what is currently known about the process.
Therefore, several laboratories are interested in designing
unnatural amino acid templates in order to initiate b-sheet
folding, taking advantage of the template concept first
R3
R2
R1
R4
NH2
n
n COOX
X= H; CH3; n= 0, 1, 2
Keywords: b-Sheet mimetics; Microwave irradiation; Suzuki coupling.
* Corresponding author. Tel.: +39 81 678648; fax: +39 81 678649; e-mail:
santagad@unina.it
Figure 1. General structure of b-sheet nucleators.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.071

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E. Perissutti et al. / Tetrahedron 63 (2007) 12779–12785
We developed three series of compounds, indicated as 3a–3f,
4a–4f and 5a–5f, respectively, characterized by the carboxy-
lic and the amino groups directly bond to the phenyl ring or
by one or two additional methylene groups, respectively.
then transferred into a sealed tube and irradiated by micro-
wave for a total time of 30 min. Microwave power was set
at 300 W and the temperature kept at 150 ꢀC for 30 min.
The main aspect of our procedure was that a short irradiation
time of the reaction mixture furnished the final compounds
in 30 min, with quite good yields in a single step procedure.
Our efforts in the development of biphenyl structures started
from the consideration that similar structures were reported
in the literature as able to induce the b-sheet conformation;6
this was obtained through a H-bond, generating a 13- or 15-
membered ring, that favored the b-sheet moiety. Moreover,
compound 4a was already reported as a dipeptide b-turn
mimetic and this was consistent with predictions made by
molecular modeling calculations.10
The yields of compounds 3a–3f, 4a–4f, and 5a–5f are sum-
marized in Table 1.
The diamide derivatives 6a, 7a, and 8a (Fig. 2), derived from
compounds 3a, 4a, and 5a, respectively, were studied by
molecular modeling in an effort to evaluate their potential
abilities for b-sheet nucleation as well as to probe their intra-
molecular hydrogen-bonding preferences.
Molecular modeling calculations have demonstrated that
compounds 5a–5f are capable of adopting a 15-membered
intramolecularly hydrogen-bonded conformation, which
should support an antiparallel b-sheet structure. These results
The conformational space available to these structures is lim-
ited by the restricted rotation about the interaromatic single
1
are in consonance with FTIR and variable temperature H
NMR spectroscopic studies performed on the diamide deriv-
ative of a similar compound, the [30-(2-aminoethyl)-2-biphe-
nyl]propionic acid,9 which suggested that this compound is
capable of promoting hydrogen-bonded conformations so
as to facilitate b-sheet structure formation in CH2Cl2.
Table 1. Substituents and obtained yields of compounds 3a–3f, 4a–4f
and 5a–5f
Compound
n
X
R1
R2
R3
R4
Yielda (%)
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
0
0
0
0
0
0
1
1
1
1
1
1
2
2
2
2
2
2
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF3
H
CH3
H
H
H
CF3
H
CH3
H
H
H
CF3
H
CH3
H
H
H
H
NO2
H
H
CF3
H
H
NO2
H
H
CF3
H
H
NO2
H
H
CF3
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
H
CH3
H
34
17
34
29
24
19
37
15
36
30
22
23
39
20
38
33
23
25
2. Results and discussion
The syntheses of biphenyl structures with the proposed
features were described in the literature as composed of
several synthetic steps.10
H
In our approach, instead, we developed the one pot synthesis
of biphenyl compounds 3a–3f, 4a–4f, and 5a–5f (Scheme 1)
optimizing the conditions of the Suzuki coupling.11
CH3
CH3
H
H
H
H
CH3
CH3
R3
R2
R1
R4
R4
CsCO3
/
R3
R2
NH2
a
(PH3P)Pd
nCOOX
OH
nNH2
Br
All the reactions were performed three times and the reaction time and
yields given are the average values.
n
+
DMF /
H20 ; MW
B
n
COOX
OH
R1
3a-3f
4a-4f
5a-5f
1
2
X= H, CH3
n = 0, 1, 2
O
l
d
e
c
H
N
H
b
H
b
N
H
O
Scheme 1. General synthetic procedure of compounds 3a–3f, 4a–4f, and
5a–5f via Suzuki coupling reaction.
HH
HH
O
c
a
a
H
H
H
N
N
H
m
f
g
O
Since the examples of Suzuki reactions with aniline halide
substrates are quite limited in the literature, several reaction
conditions were tried.12 The best results were obtained in
aqueous media using cesium carbonate as base; these condi-
tions were the best also for the development of benzylaminic
or phenylethyl aminic derivatives. The presence of electron
withdrawing or donating substituents allowed us to inves-
tigate their role in the Suzuki coupling. Reactions and
conditions are reported in Scheme 1.
6a
7a
d
e
h
H
N
H
b
HH
O
c
H
N
a
HH
H
g
f
i
O
8a
The reactions were carried out using a microwave oven
(ETHOS 1600, MilestoneÒ) especially designed for organic
synthesis. The boronic acid 1 and the appropriate aniline
halide or phenyl alkyl halide 2 were dissolved in a mixture
of DMF/water in a 5:1 ratio. The reaction mixture, added
with cesium carbonate and the palladium catalyst, was
Figure 2. Parameters affecting conformational flexibility and constraint in
the diamide derivatives of 6a, 7a, and 8a, designed as b-sheet nucleators.
In the biphenyl derivatives, flexibility is provided by free rotation about
bonds a, d, e, f, g, h, and i, and constraint is imposed by restricted rotation
about bonds l and m, steric clashes b and c between substituents ortho to the
interaromatic bond, and possible hydrogen bond between the NH and CO
amide groups.

E. Perissutti et al. / Tetrahedron 63 (2007) 12779–12785
12781
Figure 3. Stereoview of the most highly populated conformation cluster derived from simulated annealing MD calculations for the diamide b-sheet nucleator
8a. The hydrogen bond, which contributes to form a 15-membered ring between the NH and CO amide groups, is shown as a yellow line. For reasons of clarity
only the heavy atoms (C: green, N: blue, O: red) and amide protons (white) are shown.
bond a due to a balance of opposing effects. Overlap of the p
systems of the rings favors their coplanarity, whereas steric
clashes between substituents ortho to the interaromatic link-
age such as hydrogen atoms and the CO and NH groups (b
and c) disfavor coplanarity. Because the amides are directly
attached to the aromatic system in compound 6a, rotation
about bonds l and m is expected to be constrained to dihedral
angles of ꢁ25ꢀ between the plane of the amide and that of the
aromatic ring. These values for the dihedral angle were ob-
served in a search of relevant small-molecule crystal struc-
tures in the Cambridge database, and can be explained by
the balance of two opposing forces. Finally, the conformation
of the biphenyl system should allow hydrogen bonding to oc-
cur between the NH and CO amide groups. Such a hydrogen
bond corresponds to that between residues i and i+3 of a
b-hairpin, and its presence would provide further conforma-
tional constraint on the system.
MilestoneÒ) especially designed for organic synthesis.
Microwave reactions were performed in sealed tubes and a
microwave program that was composed by appropriate
ramping and holding steps was selected. The temperature
of the stirred reaction mixture was monitored directly by a
microwave-transparent fluoroptic probe inserted into the
reaction mixture; irradiation time and power were monitored
with the ‘easyWAVE’ software package.
3.2. Chemistry
All reactions were followed by thin layer chromatography
carried out on Merck silica gel 60 F254 plates with fluores-
cent indicator and the plates were visualized with UV light
(254 nm). Preparative chromatographic purifications were
performed using silica gel column (Kieselegel 60). Melting
points were determined using a Kofler hot-stage apparatus.
Elemental analyses were carried out on a Carlo Erba model
1
By simulated annealing molecular dynamics (MD) simulation
over 5000 ps, the stability of the b-hairpin pattern was investi-
gated in the gas phase for compounds under discussion.
1106. The structures were verified spectroscopically by H
NMR, 13C NMR, IR, and ESI-MS; in 13C NMR of fluori-
nated compounds, carbon–fluorine decoupling was applied.
Spectra were recorded on a Varian Mercury Plus 400 MHZ
instrument. Chemical shifts are given as d; the solvent was
DMSO-d6. The following abbreviations are used to describe
peak patterns when appropriate: s (singlet), d (doublet), br s
(broad singlet), t (triplet). Mass spectra of the final products
were performed on LCQ Thermoquest-Ion trapmass spec-
trometry. IR spectra were recorded on Thermo Nicolet
5700 FT-IR spectrometer.
Whereas diamides 6a and 7a do not fold into a stable hairpin
structure over the trajectory of the MD simulation, the
b-hairpin pattern remains stable for diamide 8a (most popu-
lated cluster with 88% occupancy along the trajectory).
As depicted in Figure 3, the diamide derivative 8a is capable
of adopting a 15-membered intramolecularly hydrogen-
bonded conformation, which should support an antiparallel
b-sheet structure. These results are consistent with FTIR
and variable temperature 1H NMR spectroscopic studies per-
formed on the diamide derivative of a similar compound, the
[30-(2-aminoethyl)-2-biphenyl]propionic acid,9 which sug-
gested that this compound is capable of promoting hydro-
gen-bonded conformations so to facilitate b-sheet structure
formation in CH2Cl2.
3.3. General procedure for the microwave synthesis of
compounds 3a–3f, 4a–4f, and 5a–5f
The boronic acid 1 (2.22 mmol) and the appropriate aniline
halide or phenyl alkyl halide 2 (1.48 mmol) were dissolved
in a mixture of DMF/water (5:1 v/v). Cesium carbonate
(5.92 mmol) and tetrakis (triphenylphosphine) palladium
catalyst (0.044 mmol) were added to the reaction mixture
that was stirred for 5 min at room temperature. The reaction
was then transferred into a sealed vial specifically designed
for reactions with high pressure. The mixture was irradiated
at 150 ꢀC by microwave for 30 min at 300 W. The solvent
was removed under reduced pressure and the residue ob-
tained was taken up in dichloromethane and extracted (three
3. Experimental section
3.1. Microwave equipment and conditions
The synthetic steps performed by microwave irradiation
were carried out using a microwave oven (ETHOS 1600,

12782
E. Perissutti et al. / Tetrahedron 63 (2007) 12779–12785
times) with NaHCO3 5% and brine. The organic phase was
dried over Na2SO4, filtered, and dried in vacuo. The mixture
was purified over an opened silica gel column affording final
compounds 3a–3f, 4a–4f, and 5a–5f.
0.69 (ethyl acetate/petroleum ether 5:5); nmax (KBr) 3437,
1
3328, 2936, 1712, 1436, 1316, 1279, 1071, 758 cmꢂ1; H
NMR (400 MHz, DMSO-d6): d 2.78 (s, 3H), 3.31 (s, 3H),
7.24 (1H, t, J 7.7 Hz), 7.47 (1H, t, J 7.7 Hz), 7.63 (1H, t, J
7.9 Hz), 7.84 (1H, d, J 7.7 Hz), 8.30 (1H, d, J 7.9 Hz),
8.37 (1H, d, J 7.9 Hz), 8.49 (1H, d, J 7.7 Hz), 11.67 (br s,
NH); 13C NMR (DMSO-d6): d 15.5, 39.0, 116.8, 118.2,
122.9, 123.3, 123.9, 126.3, 128.1, 128.6, 130.3, 133.5,
134.9, 137.2, 161.5; MS: 242 (MH+), 264 (MꢂNa), 280
(MꢂK). Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N,
5.81. Found: C, 74.52; H, 7.01; N, 5.90.
3.3.1. 2-(2-Aminophenyl)benzoic acid (3a). Yield 107 mg,
34%, white powder, mp 133–135 ꢀC; Rf 0.52 (n-hexane/
ethyl acetate 6:4); nmax (KBr) 3425, 3321, 2956, 2852,
1
1686, 1619, 1258, 1084, 795 cmꢂ1; H NMR (400 MHz,
DMSO-d6): d 7.24 (1H, t, J 8.0 Hz), 7.34 (1H, d, J
8.0 Hz), 7.47 (1H, t, J 8.0 Hz), 7.63 (1H, t, J 7.8 Hz), 7.84
(1H, t, J 7.8 Hz), 8.30 (1H, d, J 8.0 Hz), 8.37 (1H, d, J
7.8 Hz), 8.49 (1H, d, J 7.8 Hz), 9.62 (br s, 1H, OH), 11.67
(br s, NH); 13C NMR (DMSO-d6): d 116.8, 118.2, 122.9,
123.3, 123.9, 126.3, 128.1, 128.6, 130.3, 133.5, 134.9,
137.2, 161.5; MS: 214 (MH+), 236 (MꢂNa), 252 (MꢂK).
Anal. Calcd for C13H11NO2: C, 73.23; H, 5.20; N, 6.57.
Found: C, 73.19; H, 5.23; N, 6.52.
3.3.6. 2-(2-Amino-4-(trifluoromethyl)phenyl)methylben-
zoate (3f). Yield 83 mg, 19%, white powder, mp 121–
123 ꢀC; Rf 0.85 (petroleum ether/ethyl acetate 7:3); nmax
(KBr) 3437, 3359, 2948, 2859, 1718, 1417, 1253, 1066,
780 cmꢂ1; 1H NMR (400 MHz, DMSO-d6): d 3.30 (s, 3H),
7.28 (s, 1H), 7.32 (1H, d, J 8.0 Hz), 7.65 (1H, t, J 7.7 Hz),
7.81 (1H, t, J 7.7 Hz), 8.28 (1H, d, J 8.0 Hz), 8.34 (1H, d,
J 7.7 Hz), 8.47 (1H, d, J 7.7 Hz), 11.67 (br s, NH); 13C
NMR (DMSO-d6): d 39.0, 116.8, 118.2, 122.9, 123.3,
123.9, 124.2, 126.3, 128.1, 128.6, 130.3, 133.5, 134.9,
137.2, 161.5; MS: 296 (MH+), 318 (MꢂNa), 334 (MꢂK).
Anal. Calcd for C15H12F3NO2: C, 61.02; H, 4.10; N, 4.74.
Found: C, 61.03; H, 4.18; N, 4.68.
3.3.2. 2-(2-Amino-5-(trifluoromethyl)phenyl)benzoic
acid (3b). Yield 71 mg, 17%, white powder, mp 168–
170 ꢀC; Rf 0.73 (ethyl acetate/petroleum ether 5:5); nmax
(KBr) 3423, 3320, 2932, 2850, 1678, 1410, 1239, 1118,
1
794 cmꢂ1; H NMR (400 MHz, DMSO-d6): d 7.34 (1H, d,
J 7.9 Hz), 7.47 (s, 1H), 7.63 (1H, t, J 7.8 Hz), 7.84 (1H, t,
J 7.8 Hz), 8.30 (1H, d, J 7.9 Hz), 8.37 (1H, d, J 7.8 Hz),
8.49 (1H, d, J 7.8 Hz), 9.58 (br s, 1H, OH), 11.64 (br s,
NH); 13C NMR (DMSO-d6): d 116.8, 118.2, 122.9, 123.3,
123.9, 124.5, 126.3, 128.1, 128.6, 130.3, 133.5, 134.9,
137.2, 161.5; MS: 282 (MH+), 304 (MꢂNa), 320 (MꢂK).
Anal. Calcd for C14H10F3NO2: C, 59.79; H, 3.58; N, 4.98.
Found: C, 60.01; H, 3.60; N, 5.02.
3.3.7. 2-(2-(2-Aminomethyl)phenyl)acetic acid (4a). Yield
132 mg, 37%, white powder, mp 139–141 ꢀC; Rf 0.86 (di-
ethyl ether/n-hexane 8:2); nmax (KBr) 3027, 2933, 2844,
1
1719, 1641, 1432, 1231, 1150, 866, 723 cmꢂ1; H NMR
(400 MHz, DMSO-d6): d 3.41 (s, 2H), 3.90 (s, 2H), 7.22
(1H, t, J 7.8 Hz), 7.32 (1H, d, J 7.8 Hz), 7.43 (1H, t, J
7.8 Hz), 7.61 (1H, t, J 7.5 Hz), 7.82 (1H, t, J 7.5 Hz), 8.28
(1H, d, J 7.8 Hz), 8.35 (1H, d, J 7.5 Hz), 8.47 (1H, d, J
7.5 Hz), 9.66 (br s, OH), 11.79 (br s, NH); 13C NMR
(DMSO-d6): d 41.6, 45.9, 117.1, 118.4, 123.2, 123.7,
124.3, 126.8, 128.4, 129.0, 130.5, 133.8, 135.2, 137.6,
161.8; MS: 241 (MH+), 264 (MꢂNa), 280 (MꢂK). Anal.
Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found:
C, 74.28; H, 6.82; N, 5.80.
3.3.3. 2-(2-Amino-4-(nitro)phenyl)benzoic acid (3c).
Yield 130 mg, 34%, white powder, mp 159–161 ꢀC; Rf
0.82 (petroleum ether/ethyl acetate 7:3); nmax (KBr) 3424,
3320, 2935, 2852, 1690, 1618, 1507, 1329, 1258, 1088,
791 cmꢂ1; 1H NMR (400 MHz, DMSO-d6): d 7.47 (s, 1H),
7.56 (1H, d, J 8.2 Hz), 7.85 (1H, t, J 8.2 Hz), 8.07 (1H, t, J
8.2 Hz), 8.37 (1H, d, J 8.2 Hz), 8.49 (1H, d, J 7.9 Hz),
8.50 (1H, d, J 7.9 Hz), 9.32 (br s, 1H, OH), 11.72 (br s,
NH); 13C NMR (DMSO-d6): d 117.1, 118.5, 123.1, 123.6,
124.1, 126.5, 128.4, 128.9, 130.5, 133.7, 135.0, 137.4,
161.7; MS: 259 (MH+), 281 (MꢂNa), 297 (MꢂK). Anal.
Calcd for C13H10N2O4: C, 60.47; H, 3.90; N, 10.85. Found:
C, 60.53; H, 3.92; N, 10.95.
3.3.8. 2-(2-(2-Aminomethyl)-5(trifluoromethyl)phenyl)-
acetic acid (4b). Yield 69 mg, 15%, white powder, mp
156–158 ꢀC; Rf 0.85 (ethyl acetate/petroleum ether 5:5);
nmax (KBr) 3026, 2963, 1708, 1465, 1241, 1136, 1029,
754 cmꢂ1; 1H NMR (400 MHz, DMSO-d6): d 3.41 (s, 2H),
3.90 (s, 2H), 7.34 (1H, d, J 7.9 Hz), 7.47 (s, 1H), 7.63 (1H,
t, J 7.8 Hz), 7.84 (1H, t, J 7.8 Hz), 8.30 (1H, d, J 7.9 Hz),
8.37 (1H, d, J 7.8 Hz), 8.49 (1H, d, J 7.8 Hz), 9.58 (br s,
1H, OH), 11.64 (br s, NH); 13C NMR (DMSO-d6): d 41.6,
45.9, 116.8, 118.2, 122.9, 123.3, 123.9, 124.5, 126.3,
128.1, 128.6, 130.3, 133.5, 134.9, 137.2, 161.5; MS: 310
(MH+), 332 (MꢂNa), 348 (MꢂK). Anal. Calcd for
C16H14F3NO2: C, 62.13; H, 4.56; N, 4.53. Found: C,
62.25; H, 4.83;N, 4.62.
3.3.4. 2-(2-Amino-5-(methyl)phenyl)benzoic acid (3d).
Yield 97 mg, 29%, white powder, mp 108–110 ꢀC; Rf 0.69
(n-hexane/ethyl acetate 6:4); nmax (KBr) 3422, 3318, 2875,
1686, 1417, 1274, 793 cmꢂ1; 1H NMR (400 MHz, DMSO-
d6): d 2.35 (s, 3H), 7.35 (1H, d, J 8.0 Hz), 7.48 (s, 1H),
7.64 (1H, t, J 7.8 Hz), 7.85 (1H, t, J 7.8 Hz), 8.31 (1H, d, J
8.0 Hz), 8.38 (1H, d, J 7.8 Hz), 8.50 (1H, d, J 7.8 Hz),
9.43 (br s, 1H, OH), 11.42 (br s, NH); 13C NMR (DMSO-
d6): d 24.6, 116.8, 118.3, 122.9, 123.4, 123.8, 126.1,
128.2, 128.8, 130.4, 133.3, 134.7, 137.4, 161.5; MS: 228
(MH+), 250 (MꢂNa), 266 (MꢂK). Anal. Calcd for
C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 74.05;
H, 5.82; N, 6.23.
3.3.9. 2-(2-(2-Aminomethyl)-4(nitro)phenyl)acetic acid
(4c). Yield 152 mg, 36%, white powder, mp 181–183 ꢀC;
Rf 0.88 (petroleum ether/ethyl acetate 7:3); nmax (KBr)
3026, 2931, 1713, 1526, 1344, 1315, 1283, 1056,
785 cmꢂ1; 1H NMR (400 MHz, DMSO-d6): d 3.41 (s, 2H),
3.90 (s, 2H), 7.47 (s, 1H), 7.56 (1H, d, J 8.2 Hz), 7.85 (1H,
t, J 8.2 Hz), 8.07 (1H, t, J 7.9 Hz), 8.37 (1H, d, J 8.2 Hz),
3.3.5. 2-(2-Amino-3-(methyl)phenyl)methylbenzoate
(3e). Yield 86 mg, 24%, white powder, mp 191–193 ꢀC; Rf

E. Perissutti et al. / Tetrahedron 63 (2007) 12779–12785
12783
8.49 (1H, d, J 7.9 Hz), 8.50 (1H, d, J 7.9 Hz), 9.32 (br s, 1H,
OH), 11.72 (br s, NH); 13C NMR (DMSO-d6): d 41.6, 45.9,
117.1, 118.5, 123.1, 123.6, 124.1, 126.5, 128.4, 128.9, 130.5,
133.7, 135.0, 137.4, 161.7; MS: 287 (MH+), 309 (MꢂNa),
325 (MꢂK). Anal. Calcd for C15H14N2O4: C, 62.93; H,
4.93; N, 9.79. Found: C, 63.03; H, 4.90; N, 9.56.
308 (MꢂK). Anal. Calcd for C17H19NO2: C, 75.81; H,
7.12; N, 5.20. Found: C, 75.22; H, 7.32; N, 5.44.
3.3.14. 3-2-(2-(2-Aminomethyl)-5(trifluoromethyl)phe-
nyl)propionic acid (5b). Yield 100 mg, 20%, white powder,
mp 178–180 ꢀC; Rf 0.87 (ethyl acetate/petroleum ether 5:5);
nmax (KBr) 3022, 2948, 1710, 1612, 1286, 1183, 802 cmꢂ1
;
3.3.10. 2-(2-(2-Aminomethyl)-5(methyl)phenyl)acetic
acid (4d). Yield 113 mg, 30%, white powder, mp 123–
125 ꢀC; Rf 0.76 (n-hexane/ethyl acetate 6:4); nmax (KBr)
1H NMR (400 MHz, DMSO-d6): d 2.64 (2H, t, J 8.6 Hz),
2.82 (2H, t, J 8.3 Hz), 3.41 (2H, t, J 8.6 Hz), 3.90 (2H, t, J
8.3 Hz), 7.34 (1H, d, J 7.9 Hz), 7.47 (s, 1H), 7.63 (1H, t, J
7.8 Hz), 7.84 (1H, t, J 7.8 Hz), 8.30 (1H, d, J 7.9 Hz), 8.37
(1H, d, J 7.8 Hz), 8.49 (1H, d, J 7.8 Hz), 9.58 (br s, 1H,
OH), 11.64 (br s, NH); 13C NMR (DMSO-d6): d 26.9,
31.8, 36.7, 36.9, 116.8, 118.2, 122.9, 123.3, 123.9, 124.5,
126.3, 128.1, 128.6, 130.3, 133.5, 134.9, 137.2, 161.5;
MS: 338 (MH+), 360 (MꢂNa), 376 (MꢂK). Anal. Calcd
for C18H18F3NO2: C, 64.09; H, 5.38; N, 4.15. Found: C,
64.16; H, 5.22;N, 4.33.
1
3034, 2942, 1712, 1636, 1478, 1137, 816 cmꢂ1; H NMR
(400 MHz, DMSO-d6): d 2.35 (s, 3H), 3.41 (s, 2H), 3.90
(s, 2H), 7.35 (1H, d, J 8.0 Hz), 7.48 (s, 1H), 7.64 (1H, t, J
7.8 Hz), 7.85 (1H, t, J 7.8 Hz), 8.31 (1H, d, J 8.0 Hz), 8.38
(1H, d, J 7.8 Hz), 8.50 (1H, d, J 7.8 Hz), 9.43 (br s, 1H,
OH), 11.42 (br s, NH); 13C NMR (DMSO-d6): d 24.6,
41.6, 45.9, 116.8, 118.3, 122.9, 123.4, 123.8, 126.1, 128.2,
128.8, 130.4, 133.3, 134.7, 137.4, 161.5; MS: 256 (MH+),
278 (MꢂNa), 294 (MꢂK). Anal. Calcd for C16H17NO2: C,
75.27; H, 6.71; N, 5.49. Found: C, 75.13; H, 6.73; N, 5.54.
3.3.15. 3-2-(2-(2-Aminomethyl)-4(nitro)phenyl)pro-
pionic acid (5c). Yield 177 mg, 38%, white powder, mp
142–144 ꢀC; Rf 0.92 (petroleum ether/ethyl acetate 7:3);
nmax (KBr) 3031, 2961, 1703, 1528, 1346, 1258, 1083,
3.3.11. 2-(2-(2-Aminomethyl)-3(methyl)phenyl)acetate
(4e). Yield 88 mg, 22%, white powder, mp 138–140 ꢀC; Rf
0.76 (ethyl acetate/petroleum ether 5:5); nmax (KBr) 3021,
1
769 cmꢂ1; H NMR (400 MHz, DMSO-d6): d 2.64 (2H, t,
1
2927, 1737, 1613, 1310, 1221, 1030, 745 cmꢂ1; H NMR
J 8.6 Hz), 2.82 (2H, t, J 8.3 Hz), 3.41 (2H, t, J 8.6 Hz),
3.90 (2H, t, J 8.3 Hz), 7.47 (s, 1H), 7.56 (1H, d, J 8.2 Hz),
7.85 (1H, t, J 8.2 Hz), 8.07 (1H, t, J 7.9 Hz), 8.37 (1H, d, J
8.2 Hz), 8.49 (1H, d, J 7.9 Hz), 8.50 (1H, d, J 7.9 Hz),
9.32 (br s, 1H, OH), 11.72 (br s, NH); 13C NMR (DMSO-
d6): d 26.9, 31.8, 36.7, 36.9, 117.1, 118.5, 123.1, 123.6,
124.1, 126.5, 128.4, 128.9, 130.5, 133.7, 135.0, 137.4,
161.7; MS: 315 (MH+), 337 (MꢂNa), 353 (MꢂK). Anal.
Calcd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found:
C, 64.75; H, 5.83; N, 9.02.
(400 MHz, DMSO-d6): d 2.78 (s, 3H), 3.31 (s, 3H), 3.41
(s, 2H), 3.90 (s, 2H), 7.24 (1H, t, J 7.7 Hz), 7.47 (1H, t, J
7.7 Hz), 7.63 (1H, t, J 7.9 Hz), 7.84 (1H, d, J 7.7 Hz), 8.30
(1H, d, J 7.9 Hz), 8.37 (1H, d, J 7.9 Hz), 8.49 (1H, d, J
7.7 Hz), 11.67 (br s, NH); 13C NMR (DMSO-d6): d 15.5,
39.0, 41.6, 45.9, 116.8, 118.2, 122.9, 123.3, 123.9, 126.3,
128.1, 128.6, 130.3, 133.5, 134.9, 137.2, 161.5; MS: 270
(MH+), 292 (MꢂNa), 308 (MꢂK). Anal. Calcd for
C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.64;
H, 7.19; N, 5.36.
3.3.16. 3-2-(2-(2-Aminomethyl)-5(methyl)phenyl)pro-
pionic acid (5d). Yield 138 mg, 33%, white powder, mp
158–160 ꢀC; Rf 0.83 (n-hexane/ethyl acetate 6:4); nmax
(KBr) 3024, 2956, 1709, 1611, 1489, 1168, 879,
793 cmꢂ1; 1H NMR (400 MHz, DMSO-d6): d 2.35 (s, 3H),
2.64 (2H, t, J 8.6 Hz), 2.82 (2H, t, J 8.3 Hz), 3.41 (2H, t, J
8.6 Hz), 3.90 (2H, t, J 8.3 Hz), 7.35 (1H, d, J 8.0 Hz), 7.48
(s, 1H), 7.64 (1H, t, J 7.8 Hz), 7.85 (1H, t, J 7.8 Hz), 8.31
(1H, d, J 8.0 Hz), 8.38 (1H, d, J 7.8 Hz), 8.50 (1H, d, J
7.8 Hz), 9.43 (br s, 1H, OH), 11.42 (br s, NH); 13C NMR
(DMSO-d6): d 24.6, 26.9, 31.8, 36.7, 36.9, 116.8, 118.3,
122.9, 123.4, 123.8, 126.1, 128.2, 128.8, 130.4, 133.3,
134.7, 137.4, 161.5; MS: 284 (MH+), 306 (MꢂNa), 322
(MꢂK). Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N,
4.94. Found: C, 76.33; H, 7.41; N, 4.86.
3.3.12. 2-(2-(2-Aminomethyl)-4(trifluoromethyl)phenyl)-
acetate (4f). Yield 110 mg, 23%, white powder, mp 166–
168 ꢀC; Rf 0.91 (petroleum ether/ethyl acetate 7:3); nmax
(KBr) 3039, 2931, 1743, 1618, 1458, 1283, 1119, 776 cmꢂ1
;
1H NMR (400 MHz, DMSO-d6): d 3.30 (s, 3H), 3.41 (s,
2H), 3.90 (s, 2H), 7.28 (s, 1H), 7.32 (1H, d, J 8.0 Hz), 7.65
(1H, t, J 7.7 Hz), 7.81 (1H, t, J 7.7 Hz), 8.28 (1H, d, J
8.0 Hz), 8.34 (1H, d, J 7.7 Hz), 8.47 (1H, d, J 7.7 Hz), 11.67
(br s, NH); 13C NMR (DMSO-d6): d 39.0, 41.6, 45.9, 116.8,
118.2, 122.9, 123.3, 123.9, 124.2, 126.3, 128.1, 128.6,
130.3, 133.5, 134.9, 137.2, 161.5; MS: 324 (MH+), 346
(MꢂNa), 362 (MꢂK). Anal. Calcd for C17H16F3NO2: C,
63.15; H, 4.99; N, 4.33. Found: C, 63.32; H, 4.73; N, 4.52.
3.3.13. 3-2-(2-(2-Aminomethyl)phenyl)propionic acid
(5a). Yield 155 mg, 39%, white powder, mp 138–140 ꢀC;
Rf 0.92 (diethyl ether/n-hexane 8:2); nmax (KBr) 3026,
3.3.17. 3-2-(2-(2-Aminomethyl)-3(methyl)phenyl)propa-
noate (5e). Yield 101 mg, 23%, white powder, mp 188–
190 ꢀC; Rf 0.84 (ethyl acetate/petroleum ether 5:5); nmax
(KBr) 3039, 2963, 1743, 1640, 1312, 1239, 1088,
2963, 2850, 1706, 1686, 1584, 1475, 1271, 796, 768 cmꢂ1
;
1H NMR (400 MHz, DMSO-d6): d 2.64 (2H, t, J 8.6 Hz),
2.82 (2H, t, J 8.3 Hz), 3.41 (2H, t, J 8.6 Hz), 3.90 (2H, t, J
8.3 Hz), 7.22 (1H, t, J 7.8 Hz), 7.32 (1H, d, J 7.8 Hz), 7.43
(1H, t, J 7.8 Hz), 7.61 (1H, t, J 7.5 Hz), 7.82 (1H, t, J
7.5 Hz), 8.28 (1H, d, J 7.8 Hz), 8.35 (1H, d, J 7.5 Hz),
8.47 (1H, d, J 7.5 Hz), 9.62 (br s, OH), 11.71 (br s, NH);
13C NMR (DMSO-d6): d 26.9, 31.8, 36.7, 36.9, 117.1,
118.4, 123.2, 123.7, 124.3, 126.8, 128.4, 129.0, 130.5,
133.8, 135.2, 137.6, 161.8; MS: 270 (MH+), 292 (MꢂNa),
1
796 cmꢂ1; H NMR (400 MHz, DMSO-d6): d 2.64 (2H, t,
J 8.6 Hz), 2.78 (s, 3H), 2.82 (2H, t, J 8.3 Hz)3.31 (s, 3H),
3.41 (2H, t, J 8.6 Hz), 3.90 (2H, t, J 8.3 Hz), 7.24 (1H, t, J
7.7 Hz), 7.47 (1H, t, J 7.7 Hz), 7.63 (1H, t, J 7.9 Hz), 7.84
(1H, d, J 7.7 Hz), 8.30 (1H, d, J 7.9 Hz), 8.37 (1H, d, J
7.9 Hz), 8.49 (1H, d, J 7.7 Hz), 11.67 (br s, NH); 13C
NMR (DMSO-d6): d 15.5, 26.9, 31.8, 36.7, 36.9, 116.8,
118.2, 122.9, 123.3, 123.9, 126.3, 128.1, 128.6, 130.3,

12784
E. Perissutti et al. / Tetrahedron 63 (2007) 12779–12785
133.5, 134.9, 137.2, 161.5; MS: 298 (MH+), 320 (MꢂNa),
336 (MꢂK). Anal. Calcd for C19H23NO2: C, 76.73; H,
7.80; N, 4.71. Found: C, 76.65; H, 7.92; N, 4.76.
Universita degli Studi di Napoli ‘‘Federico II’’. The assis-
tance of the staff has been gratefully appreciated.
ꢀ
References and notes
3.3.18. 3-2-(2-(2-Aminomethyl)-4(trifluoromethyl)phe-
nyl)propanoate (5f). Yield 130 mg, 25%, white powder,
mp 113–115 ꢀC; Rf 0.66 (petroleum ether/ethyl acetate
9:1); nmax (KBr) 3036, 2970, 1740, 1602, 1438, 1259,
1. Ball, J. B.; Andrews, P. R.; Alewood, P. J. FEBS Lett. 1990,
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1132, 738 cmꢂ1; H NMR (400 MHz, DMSO-d6): d 2.64
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3. Huffman, W. F.; Callahan, J. F.; Eggleston, D. S.; Newlander,
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(2H, t, J 8.6 Hz), 2.82 (2H, t, J 8.3 Hz), 3.30 (s, 3H), 3.41
(2H, t, J 8.6 Hz), 3.90 (2H, t, J 8.3 Hz), 7.28 (s, 1H), 7.32
(1H, d, J 8.0 Hz), 7.65 (1H, t, J 7.7 Hz), 7.81 (1H, t, J
7.7 Hz), 8.28 (1H, d, J 8.0 Hz), 8.34 (1H, d, J 7.7 Hz),
8.47 (1H, d, J 7.7 Hz), 11.67 (br s, NH); 13C NMR
(DMSO-d6): d 26.9, 31.8, 36.7, 36.9, 39.0, 116.8, 118.2,
122.9, 123.3, 123.9, 124.2, 126.3, 128.1, 128.6, 130.3,
133.5, 134.9, 137.2, 161.5; MS: 352 (MH+), 374 (MꢂNa),
390 (MꢂK). Anal. Calcd for C19H20F3NO2: C, 64.95; H,
5.74; N, 3.99. Found: C, 64.90; H, 5.80; N, 3.91.
3.4. Molecular modeling studies
Molecular modeling and graphics manipulations were per-
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three steps: the molecules were fast heated at 1200 K and
then were cooled to 0 K over the first 1000 ps, annealed at
this temperature for the next 1000 ps and slowly cooled
over the next 3000 ps. After cooling, the final conformation
obtained was energy-refined using a conjugated gradient
algorithm with a final gradient of 0.001 kcal/mol as the con-
vergence criteria. The structures that lie within 5 kcal/mol of
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analyzed further. The obtained minima were compared and
clustered into families according to their heavy atom root
mean square values Intramolecular amide–amide hydrogen
bonds were monitored, the existence of a hydrogen bond
being defined by a maximum distance of 0.25 nm between
the hydrogen and the acceptor atoms and a minimum angle
of 135ꢀ between the donor, hydrogen, and acceptor.
Acknowledgements
The NMR and MS spectra were performed at ‘Centro
di Ricerca Interdipartimentale di Analisi Strumentale’,

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