NMR and conformational studies of new 5-phenylpyrrole-carboxamide derivatives

Article abstract of DOI:10.1002/mrc.2524

The ¹H and ¹³C NMR resonances of 22 5-(5-substituted-2-nitrophenyl)-¹H-pyrrole-2-carboxamides, 22 5-(5-substituted-2-aminophenyl)-¹H-pyrrole-2-carboxamides, and 9 5-phenyl-¹H-pyrrole-2-carboxamides we

Full text of DOI:10.1002/mrc.2524

Spectral Assignments and Reference Data
Received: 19 June 2009
Revised: 31 August 2009
Accepted: 2 September 2009
Published online in Wiley Interscience: 9 October 2009
(www.interscience.com) DOI 10.1002/mrc.2524
NMR and conformational studies of new
5-phenylpyrrole-carboxamide derivatives
´
´
´
Luisa C. Lopez-Cara, M. Jose Pineda de las Infantas, M. Dora Carrion,
´
M. Encarnacion Camacho, Miguel A. Gallo, Antonio Espinosa
and Antonio Entrena∗
The 1H and 13C NMR resonances of 22 5-(5-substituted-2-nitrophenyl)-1H-pyrrole-2-carboxamides, 22 5-(5-substituted-
2-aminophenyl)-1H-pyrrole-2-carboxamides, and 9 5-phenyl-1H-pyrrole-2-carboxamides were assigned completely using
the concerted application of one- and two-dimensional experiments (DEPT, gs-HMQC and gs-HMBC). NOE studies and
c
conformational analysis confirm the preferred conformations of such compounds. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: NMR; 1H; 13C; HMQC; HMBC; NOEDIFF; 5-phenyl-1H-pyrrole-2-carboxamides
Introduction
respectively, by treatment with NH4Cl/NH4OH.[5] In all other cases,
the ester moiety of compounds 2a–c was previously hydrolyzed
(NaOH, then AcOH),[6] transformed into the corresponding
acyl chloride (SOCl2),[7] and treated with the appropriated
amine (R2NH2/TEA)[8] to yield the corresponding N-substituted
carboxamide. Finally, compounds 26–47 were obtained by
reduction of the nitro group in the corresponding derivative
4–25, performed by treatment with Fe/FeSO4.[9]
A similar procedure was used in the synthesis of compounds
48–56, starting from cinnamaldehyde 1d, which was converted
into 5-phenyl-1H-pyrrole-2-carboxylic acid 3. Reaction of 1d with
ethyl azidoacetate followed by a pyrolysis yielded ethyl 5-phenyl-
1H-pyrrole-2-carboxylate which was further hydrolyzed (NaOH,
then AcOH) to give compound 3. Treatment of 3 with SOCl2 and
R2NH2/TEA yields the final compounds 48–56.
Nitric oxide synthase (NOS), the enzyme responsible of the
transformation of L-arginine in nitric oxide, is an interesting
target in the development of new compounds with potential
therapeutic interest. In particular, the inducible isoform of this
enzyme, inducible nitric oxide synthase (iNOS), is implicated in
some diseases such us septic shock[1] and rheumatoid arthritis.[2]
In a recent paper, the synthesis and biological evaluation of
some 5-phenyl-1H-pyrrole-2-carboxamide derivatives 26–47 as
new inhibitors of the iNOS have been described.[3]
Although the structures of these derivatives have been
determined by means of standard spectroscopic techniques (1H
and 13C NMR, MS), a detailed NMR study has been performed
in some of them, in order to unequivocally corroborate their
structures.
In this paper, we describe the assignment of each signal in the
1H and 13C NMR spectra in compounds 26–47, using one- and
two-dimensional NMR techniques. The spectra of nitro derivatives
4–25, the direct precursors in the synthetic pathway, are also
included. Conformational analysis and NOEDIFF experiments
performed on some of these compounds allow determination of
their preferred conformations. Finally, the 1H and 13C NMR spectra
of 9 new 5-phenyl-1H-pirrole-2-carboxamides 48–56, described
herein for the first time, are also included.
NMR Techniques
The 1H NMR and 13C NMR spectra were recorded on a Bruker
AMX 300 spectrometer, operating at 300.160 MHz for 1H and
75.479 MHz for 13C, respectively, with a 5 mm 13C/1H dual Wilmad
probe (No. 528-PP), and the sample temperature was maintained
constant at 297 K. In almost all cases, samples were dissolved in
CDCl3 at concentrations of ca 27 mg ml−1, and the central peak
of CDCl3 signals [7.26 ppm (1H) and 77.0 ppm (13C)] was used
as internal standard. In some cases, samples were dissolved in
(CD3)2CO, CD3OD, and DMSO at concentrations of ca 27 mg ml−1
.
Synthesis
The following parameters were used in DEPT experiments: PW
(135◦), 9.0 µs; recycle time, 1 s; 1/2J(CH) = 4 ms; 65 536 data points
acquired and transformed from 1024 scans; spectral width, 15 KHz;
and line broadening, 1.3 Hz.
Scheme 1 represents the previously reported synthetic pathway
followedinthepreparationofcompounds26–47.[3] Thesynthesis
begins with the reaction of 2-nitro-cinnamaldehyde derivatives
1a–c with ethyl azidoacetate, followed by a thermolysis, to
yield the corresponding nitrophenylpyrrole derivatives 2a–c.
Compound 2c was treated with CH3I under basic conditions
and in the presence of 18-crown-6 ether to yield compound 2d.[4]
Two alternative procedures were employed in the synthesis
of nitrocarboxamide derivatives 4–25 from compounds 2a–d.
Compounds 9, 14, 19, and 20 were directly obtained from 2a–d,
∗
´
Correspondenceto:Antonio Entrena,DepartamentodeQuímicaFarmaceutica
´
y Organica, Facultad de Farmacia, Universidad de Granada, c/Campus de
Cartuja, s/n. 18071 Granada, Spain. E-mail: aentrena@ugr.es
´
´
Departamento de Química Farmaceutica y Organica, Facultad de Farmacia,
Universidad de Granada, 18071 Granada, Spain
c
Magn. Reson. Chem. 2009, 47, 1101–1109
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

L. C. Lo´pez-Cara et al.
Scheme 1. General synthetic pathway for compounds 4–56.
The HMQC spectra were recorded using the standard Bruker
software, and resulted from a 256 × 1024 data matrix size with
16–64 scans for t1, depending on the sample concentration, an
inter-pulse delay of 3.2 ms, and a 5 : 3:4 gradient combination.[10]
The long-range 1H-13C HMBC was recorded using the sequence
described by Bax and Morris,[11] with delay values optimized for
3J(CH) of 5.5 Hz; 16 scans were measured for 512 values of t1 to
give a total data matrix of 512 × 2048 complex points. The carbon
and proton spectral widths were 20 and 4.2 kHz, respectively.
One-dimensional NOE difference experiments were measured
with irradiation time of 4 s in series of eight scans with alternating
on-andoff-resonance.Theirradiatingpowerwassetlowtoachieve
selectivity.
Tables 1–3 show the 1H NMR signals of each proton for
compounds 4–56, while Tables 4–6 show the corresponding
13C NMR chemical shifts for the same molecules.
1H NMR signals have been identified by means of the above
mentioned combined techniques.
In the three series of compounds (nitrophenyl-pyrroles 4–25,
aminophenyl-pyrroles 26–47, and phenyl-pyrroles 48–56, re-
spectively) 1H NMR and 13C NMR signals are similar, and small
differences are observed when the experiments were performed
in different solvents.
HMQC and HMBC experiments were performed on some
compounds of each series, and the results of these experiments
have been extrapolated to the other compounds.
HMQC experiments performed on compounds 5, 13 and 22
allowed the unequivocal assignment of the tertiary carbon atoms
chemical shifts C-3ꢁ, C-4ꢁ, C-5ꢁ, and C-6ꢁ in the nitrophenyl-
pyrrole derivatives. These atoms show signals in ranges of
123.85–127.57 (C-3ꢁ), 113.55–130.80 (C-4ꢁ), 132.16–162.54 (C-5ꢁ),
and 115.98–133.55 ppm.
Results and Discussion
Structural elucidation of compounds 4–56 has been made by
routine 1H and 13C NMR techniques. Nevertheless, a definitive
determination of all signals needs the use of several NMR
techniques as follows: (i) DEPT experiments to determine the
multiplicity of 13C signals; (ii) gs-HMQC spectra to determine
the 13C resonances of the tertiary, secondary, and primary
carbons; (iii) gs-HMBC sequences to assign the signals of
quaternary carbons via two- and three-bond interactions; and
(iv) NOE experiments to determine the preferred conformations in
solutions.
NOEDIFF experiments performed in compound 13 (R1 = Cl,
R2 = c-C3H5) indicate the existence of NOE between both the
ꢁ
benzene C6 –H (δ 7.58 ppm) atom and the pyrrole H-4 proton
(δ 6.52 ppm), on the one hand, and between the pyrrole H-3
atom (δ 6.34 ppm) and the amide NH proton, on the other. These
NOEs demonstrate the spatial proximity of both pairs of atoms in
the preferred conformation of this molecule, and confirm the 1H
signals assignment to H-3 and H-4.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 1101–1109

Spectral Assignments and Reference Data
c
Magn. Reson. Chem. 2009, 47, 1101–1109
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

L. C. Lo´pez-Cara et al.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 1101–1109

Spectral Assignments and Reference Data
HMBC experiment performed on compound 13 indicates
that H-4 signal (δ 6.34 ppm) is correlated with the 13C sig-
nal at δ 129.82 ppm, while H-3 signal (δ 6.52 ppm) is corre-
lated with the 13C signal at δ 129.42 ppm, and consequently
these signals can be assigned to C-5 and C-2, respectively.
HMBC spectrum of compound 13 also indicates a correlation
between the 13C signal at δ 148.07 ppm and the signals of
H-3ꢁ (δ 7.74 ppm), on the one hand, and between the 13C
signal at δ 139.86 ppm and the signals of H-4ꢁ (δ 7.37 ppm)
and H-6ꢁ (δ 7.58 ppm), on the other. These correlations in-
dicate that these signals can be assigned to C-2ꢁ and C-5ꢁ,
and that the signal at δ 129.51 ppm should be assigned to
C-1ꢁ.
HMQC experiments performed on compounds 28, 32, and 46
allowed the unequivocal assignment of the tertiary carbon atoms
chemical shifts C-3ꢁ, C-4ꢁ, C-5ꢁ, and C-6ꢁ in the aminophenyl-pyrrole
derivatives. These atoms resonate in ranges of 119.60–116.57 (C-
3ꢁ),114.91–132.15(C-4ꢁ),118.43–154.46(C-5ꢁ),and113.64–132.07
(C-6ꢁ) ppm.
NOEDIFF experiments performed on compound 32 (R1 = Cl,
R2 = CH3) indicate the spatial proximity of both H-4 and H-6ꢁ
and of H-3 and the NH amide group. The similarity of the NOEs
observed in compounds 13 and 32 indicates that the preferred
conformations in both molecules should be very similar.
Finally, in the phenyl-pyrrole derivatives HMQC experiments
performed on compound 50 allowed the unequivocal assignment
of the tertiary carbon atoms chemical shifts C-2ꢁ, C-3ꢁ, C-4ꢁ, C-5ꢁ,
and C-6ꢁ. These atoms show signals in ranges of 128.42–129.10
(C-3ꢁ, C-5ꢁ), 126.89–128.17 (C-4ꢁ), and 124.49–127.74 (C-2ꢁ, C-6ꢁ)
ppm. The quaternary carbons have been perfectly identified
with HMBC experiment performed on compound 50. In this
experiment it can be observed that the 13C signal at δ 135.77 ppm
is correlated with the signals of H-3 (δ 6.54 ppm), H-2ꢁ, and H-6ꢁ
(δ 7.53 ppm), indicating that this carbon should be C-5. On the
other hand, H-3ꢁ and H-5ꢁ signals (δ 7.29 ppm) are correlated with
the 13C signal at δ 131.98 ppm, and this carbon should be C-1ꢁ.
Consequently, the other quaternary carbon C-2 resonates at δ
126.90 ppm.
Figure 1. (a–d) The four more stable conformers found for compound
41. Relative energies are expressed in kcal/mol. (e) The most stable
conformer found for compound 43. Distances (expressedin Angstrom) are
compatibles with the NOE observed in compounds 13 and 32.
Tripos force field[12] implemented in the Sybyl program[13]
was employed in the conformational analysis of compounds 41
and 43. In both compound, the phenyl-pyrrole and the pyrrole-
carboxamide bonds were scanned using an interval of 10◦. In
compound 43 the NH–cyclopropyl bond was also scanned using
the same interval. The so obtained conformations were minimized
and compared with each other in order to identify the more stable
conformers of these molecules.
In order to get more insight into the relative stability of
each conformer, the more stable conformations were optimized
by means of Gaussian 98 program[14] using the Hartree–Fock
Hamiltonian at a 6–31G∗∗ level. Both methodologies give similar
geometries and energy values for the more stable conformers.
Figure 1 shows the four conformations found for compound
41. It can be observed that the expected coplanarity of the
benzene and pyrrole moieties as a result of the conjugation
between both rings is broken (the dihedral angle defined by both
rings is about 40◦) by the presence of the 2ꢁ-NH2. The energy
differences between conformations I and II or III and IV are small,
indicating that the nonbonding interactions between the 2ꢁ-NH2
and the pyrrole NH (conformers I and III) are quite similar to
that of 2ꢁNH2 and pyrrole C4-H (conformers II and IV). Finally,
s-cis configuration is preferred for the bond between the pyrrole
ring and the carboxamide moiety (conformers I and III), probably
because of higher interactions between the pyrrole NH and the
terminal NH2 group in conformations II and IV.
Neither the N-Alkylation of the amide moiety nor the substi-
tution in C5ꢁ modifies significantly the conformational behavior
of these series of compounds. In this sense, the N-alkylation
only increases the number of rotamers around the N–R bond,
and all the resulting conformations can be classified into four
families similar to those of the conformers found for compound
41. Figure 1 also shows, as an example, the most stable con-
former of compound 43, which is similar to conformation I
obtained for compound 41. It can be observed that the cal-
ꢁ
culated distances between the benzene C6 –H and the pyrrole
H-4 atoms (2.6 Å), and between the pyrrole H-3 and the amide
NH atoms (2.4 Å) are compatible with the observed NOE above
described for compounds 13 and 32, indicating that this type
of conformation is the preferred one of these molecules in
solution.
Compounds 20 and 42 bear a N1-methyl substituent and,
consequently, the existence of a higher rotational barrier around
the bond linking the pyrrole and the phenyl moieties can be
expected. These molecules have been optimized by means of
Gaussian 98 program, and the rotational barriers have been
studied by scanning the angle formed by both rings (ω151 2
ꢁ ꢁ ),
using the Hartree–Fock Hamiltonian at a 6–31G∗∗ level.
c
Magn. Reson. Chem. 2009, 47, 1101–1109
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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L. C. Lo´pez-Cara et al.
Table 3. 1H NMR signal assignments for compounds 48–56 δ (in ppm), in CDCl3. Multiplicities and coupling constants (Hz) are given in parentheses
Compound
H-1
H-3
H-4
H-2ꢁ
H-3ꢁ
H-4ꢁ
H-5ꢁ
H-6ꢁ
CONH
48b
49b
50
51c
52c
53c
54
11.22 (bs) 7.49 (m)
11.58 (bs) 7.50 (m)
10.08 (bs) 6.54 (d, 4.5)
10.59 (bs) 6.66 (d, 3.0)
9.83 (bs) 6.53 (d, 3.0)
6.87 (d, 1H, 3) 7.86 (m)
7.49 (m)
7.50 (m)
7.29 (m)
7.35 (m)
7.44 (m)
7.43 (m)
7.27 (m)
7.31 (m)
7.38 (m)
7.38 (m)
7.17 (m)
7.25 (m)
7.34 (m)
7.33 (m)
7.27 (m)
7.31 (m)
7.49 (m)
7.50 (m)
7.29 (m)
7.35 (m)
7.44 (m)
7.43 (m)
7.27(m)
7.31 (m)
7.86 (m)
7.86 (m)
7.53 (m)
7.63 (m)
7.70 (m)
7.71 (m)
7.63 (m)
7.64 (m)
7.60 (bs)
7.74 (bs)
5.92 (bs)
6.18 (m)
6.92 (d, 3.5)
6.44 (d, 4.5)
6.51 (d, 3.0)
6.05 (d, 3.0)
7.86 (m)
7.53 (m)
7.63 (m)
7.70 (m)
6.18 (m)
a
a
7.43 (m)
6.67 (dd, 3.0) 7.71 (m)
9.71 (bs) 6.46 (d, 3.0)
10.32 (bs) 7.31 (m)
6.39 (d, 3.0)
6.51 (d, 3.0)
7.63 (m)
7.64 (m)
5.67 (d,7.0)
5.73 (bs)
55b
56b
11.27 (bs) 7.88–6.99 (m) 7.88–6.99 (m) 7.88–6.99(m) 7.88–6.99 (m) 7.88–6.99 (m) 7.88–6.99 (m) 7.88–6.99(m) 8.06 (bs)
a Not observable. b CO(CD3)2, c CD3OD as solvent. 1H signals for the R2 substituents: 48, CH3: 2.85 (d, 6.0); 49, CH2CH3: 3.33 (m), 1,14 (t, 6.0); 50,
CH2CH2CH3: 3.33 (m, 2H), 1.54 (m, 2H); 0.89 (t, 6.0); 51, CH2CH2CH2CH3: 3.39 (m, 2H), 1.56 (m, 2H); 1.35 (m, 2H); 0.92 (t, 6.0); 52, c-C3H5: 2.82 (m, 1H),
0.84–0.60 (m, 4H); 53, c-C4H7: 4.40 (m, 1H), 2.32, 2.08, 1.76 (3m, 6H), 54, c-C5H9: 4.23 (m, 1H), 1.99–1.30 (m, 8H), 55, c-C6H11: 3.75 (m, 1H), 1.97–1.50
(m, 5H); 0.92–0.65 (m, 5H); 56, H2ꢁꢁ-H6ꢁꢁ: 7.88–6.99 (m); CH2: 4.54 (d, 2.6).
Table 4. 13C NMR chemical shifts of compounds 4–25 δ (in ppm), in CDCl3
Compound
C-2
C-3
C-4
C-5
C-1ꢁ
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-6ꢁ
CONH
OCH3
4
127.47
127.57
127.31
127.59
128.23
128.16
129.28
128.30
128.22
129.42
126.62
128.48
128.57
127.83
128.94
128.72
127.73
129.49
127.64
127.94
128.03
128.16
109.71
109.49
109.98
109.62
110.15
110.12
111.96
111.67
111.83
113.17
112.23
109.15
109.13
109.59
109.88
110.74
108.99
110.65
109.91
109.74
109.66
109.24
111.12
111.16
111.26
111.03
110.42
111.07
111.60
109.92
109.73
111.53
111.41
110.66
110.77
111.14
110.18
114.23
113.37
111.24
110.98
110.91
110.90
111.21
130.37
130.29
130.49
130.40
130.49
130.32
130.70
128.46
130.48
129.82
129.62
128.83
128.85
129.33
129.30
132.92
134.39
130.16
129.73
129.56
129.53
129.20
129.55
129.49
129.41
129.55
129.56
129.36
129.69
128.36
128.36
129.51
128.92
126.00
126.02
126.27
126.48
127.81
127.73
127.17
126.44
126.42
126.46
125.96
141.68
141.73
141.68
141.66
141.82
141.73
148.51
146.74
148.69
148.07
147.87
147.83
147.86
148.73
148.90
149.99
151.14
149.65
148.73
148.73
148.70
147.86
127.26
127.27
127.31
127.20
127.57
126.80
127.12
125.83
125.90
127.18
126.62
123.84
123.85
124.34
123.89
124.80
124.84
124.63
124.21
124.18
124.21
123.87
113.55
113.63
113.63
113.63
113.60
113.70
129.37
128.10
128.17
129.51
128.92
128.15
128.17
128.41
128.34
128.72
130.80
129.12
128.27
128.20
128.19
128.26
162.50
162.51
162.54
162.48
162.49
162.47
138.77
138.47
138.57
139.86
138.28
132.29
132.31
132.34
132.18
133.05
134.25
132.92
132.18
132.16
132.17
132.34
116.39
116.23
116.29
116.18
116.30
115.98
132.17
131.04
130.88
132.25
131.56
131.22
131.22
130.84
131.32
131.32
133.55
132.03
131.08
131.08
131.01
131.26
161.72
160.99
162.54
160.69
160.72
162.09
162.47
160.82
160.72
163.53
162.69
160.72
160.01
160.79
160.55
169.51
164.13
162.49
159.90
160.56
160.04
160.20
56.05
5
56.05
6
56.07
7
56.04
8a
55.71
9a
55.67
10a
11
12
13
14a
15c
16c
17a
18a
19b
20a
21a
22
23
24
25b
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
a CO(CD3)2, b CD3OD, c DMSO as solvent.
13C signals for the R2 substituent: 4, CH3: 26.21; 5, CH2CH2CH3: 41.23, 23.08, 11.42; 6, c-C3H5: C-1ꢁꢁ: 22.72, C-2ꢁꢁ –C-3ꢁꢁ, 6.86; 7, c-C5H9: C-1ꢁꢁ:
51.27, C-2ꢁꢁ,C-5ꢁꢁ: 33.25, C-3ꢁꢁ,C-4ꢁꢁ: 23.81; 8, CH2Ph: C-1ꢁꢁ: 139.90, C-2ꢁꢁ, C-6ꢁꢁ: 128.34; C-4ꢁꢁ: 127.57; C-3ꢁꢁ, C5ꢁꢁ: 126.86, CH2: 42.72; 10, CH3: 26.55; 11,
CH2CH3: 34.51, 15.04; 12, CH2CH2CH2CH3: 39.36, 31.36, 20.17, 13.84; 13, c-C3H5: C-1ꢁꢁ: 24.07, C-2ꢁꢁ, C-3ꢁꢁ; 8.24; 15, CH3: 25.46; 16, CH2CH3: 33.28, 14.98;
17, CH2CH2CH3: 41.27, 23.15, 11.49; 18, CH2CH2CH2CH3: 38.66, 31.89, 19.92, 13.30; 20, N–CH3: 34.06; 21, c-C3H5: C1ꢁꢁ: 23.21, C-2ꢁꢁ, C-3ꢁꢁ: 6.40; 22,
c-C4H7: C-1ꢁꢁ: 44.69, C-2ꢁꢁ, C-4ꢁꢁ: 31.45, C-3ꢁꢁ: 15.18; 23 c-C5H9: C-1ꢁꢁ: 51.24, C-2ꢁꢁ, C-5ꢁꢁ: 33.27; C-3ꢁꢁ, C-4ꢁꢁ: 23.80; 24, c-C6H11: C-1ꢁꢁ: 48.22, C-2ꢁꢁ, C-6ꢁꢁ: 33.35;
C-3ꢁꢁ, C5ꢁꢁ: 25.57, C-4ꢁꢁ: 24.96; 25, CH2Ph: C-1ꢁꢁ: 139.77, C-3ꢁꢁ, C-5ꢁꢁ: 128.16; C-4ꢁꢁ: 127.10; C-2ꢁꢁ, C6ꢁꢁ: 126.63, CH2: 41.84.
Figure 2 shows the more stable conformers obtained for
each compound, and it can be observed that the higher steric
interactions originated by the N–Me substituent increase the
angle formed by the benzene and the pyrrole rings (90◦
and 70◦ in compounds 20 and 74, respectively). Figure 2
also shows the energy variation during the rotation around
perpendicular to the benzene ring, while the maxima correspond
to conformations with both rings almost coplanar. When the value
of the torsional angle ω151 2
ꢁ
ꢁ is 360◦ the N-methyl substituent
is orientated toward the 2ꢁ-NO2 or 2ꢁ-NH2 groups, and the
energy barrier is higher and similar in both compounds. A
value of about 180◦ for the torsional angle ω151 2
ꢁ ꢁ indicates
the torsional angle ω151 2
ꢁ
ꢁ . Both molecules show two minima
a conformation with the pyrrole H-4 near to the 2ꢁ-NO2
or 2ꢁ-NH2 groups, and in this case the energy barrier is
smaller.
and two maxima during the rotation. The minima correspond
to the more stable conformers with the pyrrole ring almost
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 1101–1109

Spectral Assignments and Reference Data
Table 5. 13C NMR chemical shifts of compounds 26–47 δ (in ppm), in CDCl3
Compound
C-2
C-3
C-4
C-5
C-1ꢁ
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-6ꢁ
CONH
OCH3
26
126.07
126.24
125.87
127.26
127.09
124.98
127.51
127.46
126.63
127.37
127.07
126.01
126.10
126.11
126.18
119.56
126.91
125.81
125.99
126.24
126.36
126.56
109.97
109.73
110.41
112.18
113.33
111.86
110.15
110.23
109.66
110.64
111.56
109.74
109.68
109.69
109.52
106.42
113.45
110.25
109.79
109.52
109.63
111.88
109.03
109.04
109.49
108.56
109.92
109.27
108.75
108.66
109.40
108.75
108.86
108.95
108.90
108.87
108.88
103.84
108.82
108.99
108.94
108.87
108.91
108.32
133.28
133.19
133.50
132.99
135.03
134.33
131.48
131.47
131.80
131.68
131.97
133.16
133.19
133.19
133.20
128.79
135.40
133.46
133.36
133.12
133.08
132.45
119.98
119.13
119.90
118.73
121.14
119.68
119.37
119.30
119.93
119.42
119.29
118.35
118.38
118.35
118.42
112.81
118.08
118.31
118.41
118.41
118.62
118.43
136.77
136.00
136.85
139.23
139.05
136.99
144.20
144.13
141.95
144.18
144.19
143.67
143.70
143.73
143.78
138.35
145.56
143.73
143.71
143.72
143.36
140.00
118.96
119.13
118.99
117.96
119.60
118.94
117.29
117.20
118.02
117.32
117.40
116.72
116.67
116.57
116.71
111.41
118.08
116.67
116.69
116.68
116.79
116.68
114.94
114.91
114.96
114.88
115.89
115.05
127.67
127.60
128.46
127.70
127.76
128.86
128.81
128.76
128.85
123.54
132.15
128.87
128.84
128.82
128.77
128.00
153.51
153.64
153.50
151.75
154.46
153.36
121.37
121.28
124.02
121.47
121.94
119.22
119.16
119.06
119.18
113.84
120.01
119.14
119.17
119.17
119.32
118.43
113.64
113.66
113.69
113.84
114.70
113.72
128.28
128.19
128.46
128.28
128.24
128.86
128.87
128.82
128.89
123.65
132.07
128.87
128.89
128.85
128.92
129.06
161.79
161.13
158.85
160.47
163.58
162.83
161.29
160.60
160.98
161.91
162.29
161.76
161.03
161.12
161.09
157.35
163.84
162.55
160.12
160.73
160.24
160.63
55.90
27
55.87
28
55.89
29c
30b
31
55.92
56.21
55.87
32a
33a
34
35a
36a
37
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
38
39
40
41
42b
43
44
45
46
47a
a CO(CD3)2, b CD3OD, c DMSO as solvent.
13C signals for the R2 substituents: 26, CH3: 26.27; 27, CH2CH2CH3: 41.26, 23.17, 11.45; 28, c-C3H5: C-1ꢁꢁ: 22.71, C-2ꢁꢁ, C-3ꢁꢁ: 7.01; 29, c-C5H9: C-1ꢁꢁ: 50.89,
C-2ꢁꢁ,C-5ꢁꢁ: 32.84, C-3ꢁꢁ,C-4ꢁꢁ: 24.11; 30, CH2Ph: C-1ꢁꢁ: 140.50, C-2ꢁꢁ, C6ꢁꢁ: 129.50; C-4ꢁꢁ: 128.10; C-3ꢁꢁ, C5ꢁꢁ: 128.47, CH2: 43.93; 32, CH3: 25.21; 33, CH2CH3:
33.70, 14.53; 34, CH2CH2CH2CH3: 39.32, 31.99, 20.19, 13.87; 35, c-C3H5: C-1ꢁꢁ: 22.56, C-2ꢁꢁ,C-3ꢁꢁ: 5.59; 37, CH3: 26.27; 38, CH2CH3: 34.40, 15.18, 39,
CH2CH2CH3: 41.17, 23.17, 11.46; 40, CH2CH2CH2CH3: 39.29, 31.97, 20.18, 13.85; 42, N–CH3: 33.92; 43, c-C3H5: C1ꢁꢁ: 22.67, C-2ꢁꢁ, C-3ꢁꢁ: 6.94; 44, c-C4H7:
C-1ꢁꢁ: 44.76, C-2ꢁꢁ, C-4ꢁꢁ: 31.76, C-3ꢁꢁ: 15.20; 45, c-C5H9: C-1ꢁꢁ: 51.25, C-2ꢁꢁ, C-5ꢁꢁ: 33.40; C-3ꢁꢁ, C-4ꢁꢁ: 23.85ꢁꢁ; 46, c-C6H11: C-1ꢁꢁ: 48.23, C-2ꢁꢁ, C-6ꢁꢁ: 33.40; C-3ꢁꢁ,
C-4ꢁꢁ, C5ꢁꢁ: 25.00; 47, CH2Ph: C-1ꢁꢁ: 140.00, C-2ꢁꢁ, C6ꢁꢁ: 128.31; C-4ꢁꢁ: 126.76; C-3ꢁꢁ, C5ꢁꢁ: 127.27, CH2: 41.98.
Table 6. 13C NMR chemical shifts for compounds 48–56 δ (in ppm), in CDCl3
Compound
C-2
C-3
C-4
C-5
C-1ꢁ
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-6ꢁ
CONH
48a
49a
50
51b
52b
53b
54
125.93
126.11
126.90
128.43
129.93
128.38
129.70
125.13
128.79
110.88
111.22
110.35
112.56
112.21
112.23
110.34
112.26
111.31
109.66
109.82
107.49
106.89
110.47
111.24
108.28
110.06
105.97
133.91
135.63
135.77
135.83
136.15
134.10
135.05
135.04
139.83
130.72
130.70
131.98
132.28
130.62
130.67
130.68
130.70
130.67
127.56
127.61
124.94
124.49
127.05
127.02
127.01
126.98
127.74
128.64
128.63
129.10
128.71
128.42
128.43
128.99
128.43
128.56
127.81
127.85
127.46
126.89
127.64
127.61
128.17
127.58
127.87
128.64
128.63
129.10
128.71
128.42
128.43
128.99
128.43
128.56
127.56
127.61
124.94
124.49
127.05
127.02
127.01
126.98
127.74
160.72
160.30
161.46
162.47
160.50
160.50
160.13
160.60
160.12
55a
56a
a CO(CD3)2, b CD3OD as solvent.
13C signals for the R2 substituents: 48, CH3: 25.40; 49, CH2CH3: 34.18, 14.98; 50, CH2CH2CH3: 41.47, 23.39, 11.66; 51, CH2CH2CH2CH3:
39.04, 31.76, 20.05, 13.05, 52, c-C3H5: C-1ꢁꢁ: 21.24, C-2ꢁꢁ –C-3ꢁꢁ: 5.44; 53, c-C4H7: C-1ꢁꢁ: 44.89, C-2ꢁꢁ, C-4ꢁꢁ: 30.64, C-3ꢁꢁ: 14.80; 54, c-C5H9: C-1ꢁꢁ: 51.56, C-2ꢁꢁ,
C-5ꢁꢁ: 33.52; C-3ꢁꢁ, C-4ꢁꢁ: 23.89ꢁꢁ, 56, c-C6H11: C-1ꢁꢁ: 48.85, C-2ꢁꢁ, C-6ꢁꢁ: 32.81; C-3ꢁꢁ, C5ꢁꢁ: 25.28, C-4ꢁꢁ: 25.28; 56, CH2Ph: C-1ꢁꢁ: 143.48, C-3ꢁꢁ, C5ꢁꢁ: 128.68; C-4ꢁꢁ:
127.13; C-2ꢁꢁ, C6ꢁꢁ: 127.52, CH2: 42.67.
These data indicate that the rotation around the bond linking Experimental
the benzene and pyrrole rings is not free and that the value of
energy barrier is about 20 kcal/mol.
Rotation around the benzene–pyrrole bond also implies the
rotation of the 2ꢁ-NO2 or 2ꢁ-NH2 groups in order to allow both rings
Preparation of α-azido-5-phenyl-2,4-pentadienoic acid ethyl
ester
To a stirred solution of ethyl azidoacetate (69.12 mmol) and
to be almost coplanar. Consequently, the conjugation between
these groups and the benzene ring is broken, and this is another
reason for the high energy barrier calculated for both molecules.
cinnamadehyde 1d (13.43 mmol) in dry ethanol, a solution of
sodium ethanolate (70 mmol of Na in 60 ml of dry ethanol)
was added dropwise. The reaction mixture was stirred under
c
Magn. Reson. Chem. 2009, 47, 1101–1109
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

L. C. Lo´pez-Cara et al.
Figure 2. (a, b) The more stable conformers found for compound 20 and 42, respectively; (c) Variation of the energy (kcal/mol) during the rotation of the
torsional angle ω151 2 in both compounds 20 and 42.
ꢁ
ꢁ
argon atmosphere at −20 ◦C for 4.5 h, and then poured into
water. The aqueous mixture was extracted with ethyl acetate
(3 × 50 ml), and the combined organic layers were dried
(Na2SO4), filtered, and concentrated to yield a crude material,
which was recrystallized from methanol/diethyl ether or ethyl
acetate/hexane. This compound is unstable and spontaneously
tends to cyclize to yield 5-phenyl-1H-pyrrole-2-carboxylic acid
ethyl ester, and for this reason was not isolated.
mixture was stirred at 65–80 ◦C for 5 h. After this period, the
mixture was concentrated to dryness, yielding a brown solid (the
acyl chloride) that was dissolved in CH2Cl2 (10 ml), and a solution
of the appropriated amine (R3NH2, 2 mmol) and TEA (3 mmol)
in CH2Cl2 (3 ml) was added dropwise. The reaction mixture was
stirred for 3 h at room temperature, washed with H2O several
times, and the combined aqueous layers extracted with CH2Cl2
(3 × 50 ml). The combined organic layers were dried (Na2SO4),
filtered, concentrated, and the residue recrystallized or purified by
flash chromatography.
Preparation of 5-phenyl-1H-pyrrole-2-carboxylic acid ethyl
ester
5-Phenyl-1H-pyrrole-2-carboxylic acid methylamide (48)
The α-azido-5-phenyl-2,4-pentadienoic acid ethyl ester was
suspended in p-xylene and heated at 100 ◦C for 24 h. Evaporation
of the solvent allows the isolation of 5-phenyl-1H-pyrrole-2-
carboxylic acid ethyl ester as a white solid after recrystallization
from ethyl acetate/hexane.
(17%); mp 207 ◦C; MS (LSIMS) m/z 201.3546. (M + H)+, Calcd. Mass
for C12H13N2O 201.0923
5-Phenyl-1H-pyrrole-2-carboxylic acid ethylamide (49)
(22%); mp 172 ◦C; MS (LSIMS) m/z 237.1010 (M + Na)+, Calcd. Mass
for C13H14N2ONa 237.1003.
Preparation of 5-phenyl-1H-pyrrole-2-carboxylic acid 3
Ethyl 5-phenyl-1H-pyrrole-2-carboxylate (2.04 mmol) was stirred
and dissolved in 1 N NaOH solution (4.08 mmol) at 100 ◦C, glacial
AcOH (4.08 mmol) was then added, and the solution was stirred at
room temperature for 1 h. The solution was extracted with ethyl
acetate (3×50 ml), and the combined organic layers were washed
with water, dried (Na2SO4), filtered, and concentrated to yield a
crude material that was recrystallized from ethyl acetate/hexane.
5-Phenyl-1H-pyrrole-2-carboxylic acid propylamide (50)
(62%); mp 135–137 ◦C; MS (LSIMS) m/z 251.1162 (M + Na)+, Calcd.
Mass for C14H16N2ONa 251.1160.
5-Phenyl-1H-pyrrole-2-carboxylic acid butylamide (51)
(22%); mp 115 ◦C; MS (LSIMS) m/z 265.1311(M + Na)+, Calcd. Mass
for C15H18N2ONa 265.1317
Preparation of 5-phenyl-1H-pyrrole-2-carboxylic acid alky-
lamide 48–51
5-Phenyl-1H-pyrrole-2-carboxylic acid cyclopropylamide (52)
SOCl2 (11 mmol)wasaddedtoasolutionof5-phenyl-1H-pyrrole-2-
carboxylic acid 3 (1 mmol) in dry CH3CN (30 ml), and the reaction
(12%); mp 197 ◦C; MS (LSIMS) m/z 249.7465 (M + Na)+, Calcd. Mass
for C14H14N2O Na 249.1192
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 1101–1109

Spectral Assignments and Reference Data
5-Phenyl-1H-pyrrole-2-carboxylicacid cyclobutylamide (53)
[3] L. C. Lo´pez-Cara,M. E. Camacho,M. D. Carrio´n,V. Tapias,M. A. Gallo,
G. Escames, D. Acun˜a-Castroviejo, A. Espinosa, A. Entrena, Eur. J.
Med. Chem. 2009, 44, 2655.
[4] W. C. Guida, D. J. Mathre, J. Org. Chem. 1980, 45, 3172.
[5] D. D. Davey, J.Org. Chem. 1987, 52, 4379.
(23%); mp 250 ◦C; MS (LSIMS) m/z 263.2437 (M + Na)+, Calcd. Mass
for C15H16N2ONa 263.1385
[6] H. McKennis Jr, L. B. Turnbull, E. R. Bowman, E. Tamaki, J.Org. Chem.
5-Phenyl-1H-pyrrole-2-carboxylicacid cyclopentylamide (54)
1963, 28, 383.
[7] G. H. Coleman, G. Wichols, C. M. Mc Closekey, H. D. Anspon, Org.
Syn. Coll. 1963, 3, 712.
[8] P. J. Garratt, R. Jones, D. A. Tocher, J. Med. Chem. 1995, 38, 1132.
[9] J. Zhu, R. Beugelmans, S. Bourdet, J. Chastanet, G. Roussi, J. Org.
Chem. 1995, 60, 6389.
(18%), mp 239 ◦C; MS (LSIMS) m/z 255.1498 (M + H)+, Calcd. Mass
for C16H19N2O 255.1497
5-Phenyl-1H-pyrrole-2-carboxylicacid cyclohexylamide (55)
[10] A. Bax, G. A. Morris, J. Magn. Reson. 1981, 42, 501.
[11] R. E. Hurd, B. K. John, J. Magn. Reson. 1991, 91, 648.
[12] SYBYL Molecular Modeling Software, Tripos Inc.: St. Louis, S.
Hanley Road; M 63144-2913; www.tripos.com. 1699.
[13] M. Clark, R. D. Cramer III, N. Van Opdenbosch, J. Comput. Chem.
1989, 10, 982.
(20%); mp 213–215 ◦C; MS (LSIMS) m/z 291.6500(M + Na)+, Calcd.
Mass for C17H20N2ONa 291.1600.
5-Phenyl-1H-pyrrole-2-carboxylicacid bencylamide (56)
[14] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman,
V. G. Zakrzewski,
J. A. Montgomery, Jr.,
(21%); mp 57 ◦C; MS (LSIMS) m/z 299.6856 (M + Na)+, Calcd. Mass
R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels,
K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi,
R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford,
J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma,
D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman,
J. Cioslowski, J. V. Ortiz, A. G. Baboul, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin,
D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
C. Gonzalez, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
for C18H16N2ONa 299.1356.
Acknowledgements
This work was partially supported by grants from the Ministerio de
Ciencia y Tecnología (SAF2005-07991-C02-02) and from the Junta
de Andalucia (P06-CTS-01941).
M. W. Wong,
J. L. Andres,
C. Gonzalez,
M. Head-Gordon,
E. S. Replogle, J. A. Pople, Gaussian 98, Revision A.7, Gaussian,
Inc., Pittsburgh PA, 1998.
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c
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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www.interscience.wiley.com/journal/mrc