Synthesis, structural, conformational and pharmacological study of some amides derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9α-amine

Article abstract of DOI:10.1016/j.molstruc.2010.03.061

Some mono-substituted amides (2-5) derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9α-amine were synthesized and studied by IR, ¹H and ¹³C NMR spectroscopy. The crystal structure of 3-methyl-2,4-diphenyl-9α-(3,5-dichlorobenzamido)-3-azabicyclo[3.3.1]nonane (3) was determined by X-ray diffraction. NMR data showed that all compounds adopt in CDCl₃ a preferred flattened chair-chair conformation with the N-CH₃ group in equatorial disposition. X-ray data agreed with this conformation in the case of compound 3. IR data revealed that compounds 2 and 3 present a C{double bond, long}O?HN intermolecular bond in the solid state. This conclusion was also confirmed by X-ray data of compound 3. In the case of compound 5, IR results suggested intermolecular NH?N-heterocyclic bonding. On the contrary, in the pyrazine derivative (4), IR, ¹H and ¹³C NMR data showed the presence of an intramolecular NH?N1″-heterocyclic hydrogen bond in the solid state and solution. Moreover, NMR and IR data showed a preferred trans disposition for the NH-C{double bond, long}O group. NMR also revealed free rotation of the -NH-CO-R group around C9-NH bond. Pharmacological assays on mice were drawn to evaluate analgesic activity.

Full text of DOI:10.1016/j.molstruc.2010.03.061

Journal of Molecular Structure 976 (2010) 190–195
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structural, conformational and pharmacological study of some amides
derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9a-amine
b
a
a
I. Iriepa a, , J. Bellanato , E. Gálvez , B. Gil-Alberdi
*
a Departamento de Química Orgánica, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
b Instituto de Estructura de la Materia, C.S.I.C., Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Some mono-substituted amides (2–5) derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]
nonan-9
-amine were synthesized and studied by IR, 1H and 13C NMR spectroscopy. The crystal structure
Received 18 January 2010
Received in revised form 22 March 2010
Accepted 22 March 2010
a
of 3-methyl-2,4-diphenyl-9
by X-ray diffraction.
a-(3,5-dichlorobenzamido)-3-azabicyclo[3.3.1]nonane (3) was determined
Available online 27 March 2010
NMR data showed that all compounds adopt in CDCl3 a preferred flattened chair–chair conformation
with the N-CH3 group in equatorial disposition. X-ray data agreed with this conformation in the case
of compound 3.
Keywords:
3-Methyl-2,4-diphenyl-3-azabicyclo[3.3.1]
IR data revealed that compounds 2 and 3 present a C@Oꢀ ꢀ ꢀHN intermolecular bond in the solid state.
This conclusion was also confirmed by X-ray data of compound 3. In the case of compound 5, IR results
suggested intermolecular NHꢀ ꢀ ꢀN-heterocyclic bonding. On the contrary, in the pyrazine derivative (4),
IR, 1H and 13C NMR data showed the presence of an intramolecular NHꢀ ꢀ ꢀN100-heterocyclic hydrogen bond
in the solid state and solution. Moreover, NMR and IR data showed a preferred trans disposition for the
NH–C@O group. NMR also revealed free rotation of the –NH–CO–R group around C9–NH bond.
Pharmacological assays on mice were drawn to evaluate analgesic activity.
nonan-9
Amides
Infrared spectroscopy
NMR spectroscopy
Conformational analysis
a-amine derivatives
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
The 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9a-amine
(1) was previously synthesized by reduction of the corresponding
oxime with sodium in ethanol [1]. Reaction of 1 with the corre-
sponding carboxylic acid in the presence of dicyclohexylcarbodiim-
ide (DCC) and dimethylaminopiridine (DMAP) as catalyst led to the
amides (2, 4, 5) (method A) [2]. Compound 3 was prepared by
reaction of the bicyclic amine (1) with 2,5-dimethylbenzoyl chloride
in presence of triethylamine (method B) [3].
As continuation of our studies on the synthesis of heterocyclic
compounds with potential therapeutic activity, we report in this pa-
per the synthesis and the structural study of a series of amides (2–5)
derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9a-
amine (1) by IR and NMR spectroscopy. The unambiguous assign-
ment of all proton and carbon resonances was achieved by double
resonance experiments. The structure and conformation of 3-
methyl-2,4-diphenyl-9a-(3,5-dichlorobenzamido)-3-azabicyclo
[3.3.1]nonane (3) in the solid state was determined by X-ray
diffraction.
2.2. NMR spectra
2. Experimental
NMR spectra of compounds 2–5 were recorded on a Varian
UNITY-300 Spectrometer. The 1H NMR spectra of CDCl3 solutions
(about 4% w/v) were obtained at 300 MHz using spectral width
of 4000 Hz in 24 K memory and acquisition time of 3.0 s over 64
transients. Resolution enhancement (LB = ꢁ0.80, GF = 0.60 and
GFS = 0.20) was followed by zero filling into 32 K memory prior
to Fourier transformations. The double resonance experiments in
CDCl3 involved the use of conventional irradiation.
2.1. Synthesis
Compounds 2–5 were prepared by two general methods illus-
trated in Scheme 1.
* Corresponding autor. Address: Departamento de Química Orgánica, Facultad de
Farmacia, Universidad de Alcalá de Henares, Ctra. Madrid–Barcelona, Km 33,600, E-
28871 Alcalá de Henares (Madrid), Spain. Tel.: +34 91 885 4651; fax: +34 91 885
4686.
The 13C NMR spectra were obtained at 75.429 MHz at a spectral
width of 16,501 Hz in 64 K memory, acquisition time of 1s and
relaxation delay of 1s, using CDCl3 solutions (20% w/v).
E-mail address: isabel.iriepa@uah.es (I. Iriepa).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.03.061

I. Iriepa et al. / Journal of Molecular Structure 976 (2010) 190–195
191
CH3
Ph
CH3
Ph
N
2'
N
1'
Hax
Hax
3
RCOOH, DCC/DMAP
Hax
4
5
4
Ph
2
Method A
2
7
5
6
6
H
Heq
H
Heq
RCOCl, Et3N
1
1
8
9
9
8
Method B
N
O
Hax
Hax
NH2
1
H
R
5''
8''
1''
1''
4''
2''
4''a
3''
2''
2''
3''
6''
7''
2''
3''
1''
6''
5''
3''
6''
5''
N
R:
N
6''
4''
8''a
N
CH3
H3C
Cl
Cl
4''
5''
4''
1''
4
5
2
3
Yield
88%
84%
74%
60%
Scheme 1. Synthesis of amides 2–5.
2.3. IR spectra
splittings of 4.5 and 13.4 Hz due to the couplings with H7eq,
H6(8)eq and H7ax, respectively. The H6(8)eq signal appears as a dou-
blet of doublets with splittings of 5.3 and 13.4 Hz due to the cou-
pling with H7ax and H6(8)ax, respectively. The 3J H6(8)eq–H7ax is
very small and could not be established due to the low resolution
of the corresponding signal.
On saturating the H6(8)eq and H7eq signals (1.43–1.45 ppm),
H7ax and H6(8)ax simplify to a triplet and an apparent doublet,
respectively.
The IR spectra for compounds 2–5 were recorded on a Perkin-
Elmer FTIR 1725X spectrophotometer, assisted by a computer, in
the solid state (KBr) in the 4000–400 cmꢁ1 and in CDCl3 solution
(ꢂ0.15 M) in the 4000–900 cmꢁ1 region using 0.2 mm NaCl cells.
Spectra for very dilute CCl4 solution were taken in the 4000–
2500 cmꢁ1 region with 4 cm quartz cells. The reported wavenum-
bers are estimated to be accurate to within 3 cmꢁ1
.
By irradiation of the H6(8)ax signal (1.32 ppm), H7ax simplifies
to a doublet of triplets and H6(8)eq simplifies to an apparent dou-
blet due to the coupling with H7ax, 3J H6(8)eq-H7eq is very small
and only an estimated value (<2 Hz) could be deduced taking into
account the W1/2 of each line of the doublet.
3. Results and discussion
3.1. NMR spectra
With all the data the following coupling constants can be
deduced:
3.1.1. Spectral analysis and assignment
2J H6(8)eq ꢁ H6(8)ax, 3J H6(8)ax ꢁ H7ax, 3J H6(8)ax ꢁ H7eq and 3J
H6(8)eq ꢁ H7ax. The other coupling constants have been measured
directly on the spectra. The values are in Table 1.
Assignment of proton resonances for compounds 2–5 was made
on the basis of our previous studies for related systems [4–9]. The
1H NMR spectra of compounds 2–5 showed great similarity in rela-
tion to the bicyclic systems. The values of the proton magnetic
parameters were deduced by analysis of the respective spin sys-
tems and are listed in Table 1.
The singlet at 2.01 ppm has been assigned to the N–CH3 protons
in all compounds.
The aromatic protons corresponding to the phenyl groups in
two and four positions appear unresolved at 7.06–7.90 ppm. With
respect to the aryl substituents attached to the amido groups, the
orto aromatic protons with respect to the nitrogen atoms, in com-
pounds 4 and 5, appear at higher chemical shifts (9.43–8.74 ppm)
in comparison with the other aromatic protons (8.13–7.41 ppm).
For the assignment of the 13C NMR chemical shifts (Table 2),
substituent steric and electronic effects and our previous studies
of related compounds [4–9] were taken into consideration.
Regarding the C@O groups, the highest carbon value corre-
sponds to compound 2 where two methyl (electron-donating) sub-
stituents are present in the aromatic ring. On the contrary, with the
electron-withdrawing substituents (compounds 3–5) the values of
the carbon chemical shifts decrease.
In the 1H NMR spectra of compounds 2–5 the signals corre-
sponding to H9, H1(5), H2(4)ax, H7ax, the N–CH3 group and the aro-
matic protons appear well differentiated.
The H9 signal is a doublet of triplets owing to the coupling with
H1(5) and the amide proton. H2(4)ax signal appears as a doublet
due to the coupling with H1(5). The H7ax signal appear as a quar-
tet of triplets because |2J(H7ax ꢁ H7eq)| ꢂ J(H6(8)ax ꢁ H7ax).
3
The H6(8)eq, H6(8)ax and H7eq signals are partially overlapped.
To clarify the assignments of the signals and to deduce the pro-
ton magnetic parameters, double resonance experiments in CDCl3
for 3 were performed at 300 MHz.
By irradiation of the H7ax signal at 2.62 ppm, the signal corre-
sponding to H6(8)eq simplifies to a doublet with splitting of
13.4 Hz due to the coupling with H6(8)ax
.
By irradiation of the H1(5) signal at 2.05 ppm, the doublet of
triplets corresponding to H9 simplifies to a doublet and the doublet
corresponding to H2(4)ax simplifies to a singlet. The triplet of trip-
lets at 1.32 ppm [H6(8)ax] becomes a triplet of doublets with
3.1.2. Conformational study
We used the NMR technique to analyse the conformations of
these compounds and the following general features were
deduced:

192
I. Iriepa et al. / Journal of Molecular Structure 976 (2010) 190–195
Table 1
1H NMR Chemicals shifts (d, ppm) and multiplicities (J, Hz) for 2–5 in CDCl3.
d (ppm)a
2
3
4
5
H9
4.58 (dt)
4.56 (dt)
4.60 (dt)
4.73 (dt)
3J H9 ꢁ H1(5) = 2.9
3.80 (d)
3J H9 ꢁ H1(5) = 3.0
3.79 (d)
3J H9 ꢁ H1(5) = 3.2
3.80 (d)
3J H9 ꢁ H1(5) = 3.1
3.84 (d)
H2(4)ax
H7ax
3J H2(4)ax ꢁ H1(5) = 3.4
2.61 (qt)
3J H2(4)ax ꢁ H1(5) = 3.3
2.62 (m)
3J H2(4)ax ꢁ H1(5) = 3.2
2.61 (qt)
3J H2(4)ax ꢁ H1(5) = 3.2
2.61 (qt)
3J H6(8)ax ꢁ H7ax = 14.6
3J H6(8)eq ꢁ H7ax = 6.1
2.01 (s)
3J H6(8)ax ꢁ H7ax = 13.4
3J H6(8)eq ꢁ H7ax = 5.3
2.01 (s)
3J H6(8)ax ꢁ H7ax
3J H6(8)ax ꢁ H7ax = 13.4
3J H6(8)eq ꢁ H7ax = 5.3
2.01 (s)
b
3J H6(8)eq ꢁ H7ax
b
N–CH3
2.01 (s)
H1(5)
2.05 (brs)
2.05 (brs)
2.05 (brs)
2.13 (brs)
(W1/2 ꢄ 9 Hz)
(W1/2 ꢄ 9 Hz)
(W1/2 ꢄ 8 Hz)
(W1/2 ꢄ 8 Hz)
H6(8)ax
H7eq
1.35 (tt)
1.32 (tt)
1.41 (m)
1.31 (m)
3J H6(8)ax ꢁ H1(5) = 4.4
1.41 (m)
3J H6(8)ax ꢁ H1(5) = 4.5
1.43 (m)
3J H6(8)ax ꢁ H1(5)b
1.41 (m)
3J H6(8)ax ꢁ H1(5)b
1.36 (m)
2J H7ax ꢁ H7eq = ꢁ14.6
3J H6(8)ax ꢁ H7eq = 4.4
1.41 (m)
2J H7ax ꢁ H7eq = ꢁ13.4
3J H6(8)ax ꢁ H7eq = 4.5
1.45 (m)
2J H7ax ꢁ H7eq
2J H7ax ꢁ H7eq = ꢁ13.4
b
3J H6(8)ax ꢁ H7eq
3J H6(8)ax ꢁ H7eq
b
b
H6(8)eq
1.41 (m)
1.50 (m)
b
b
2J H6(8)ax ꢁ H6(8)eq = ꢁ14.6
3J H6(8)eq ꢁ H1(5)<2c
6.44 (d)
2J H6(8)ax ꢁ H6(8)eq = ꢁ13.4
3J H6(8)eq ꢁ H1(5)<2c
6.42 (d)
2J H6(8)ax ꢁ H6(8)eq
2J H6(8)ax ꢁ H6(8)eq
3J H6(8)ax ꢁ H1(5)b
3J H6(8)ax ꢁ H1(5)b
6.53 (d)
NH
8.31 (d)
3J H9 ꢁ NH = 8.1
3J H9 ꢁ NH = 8.1
3J H9 ꢁ NH = 8.4
3J H9 ꢁ NH = 8.3
CH3
H20–H60
H200
2.35 (s)
–
–
–
7.06–7.89
7.34 (s)
7.14–7.84
7.10–7.90
–
7.22–7.88
7.60 (d)
8.90 (d)
4J H200 ꢁ H400 = 1.9
–
3J H200 ꢁ H300 = 4.4
7.41 (d)
H300
H400
H500
H600
–
9.43 (d)
4J H300 ꢁ H500 = 1.6
7.12 (s)
–
7.48 (t)
–
–
4J H400 ꢁ H600 = 1.9
–
8.50 (dd)
8.13 (d)
3J H500 ꢁ H600 = 2.4
8.74 (d)
3J H500 ꢁ H600 = 8.3
7.60 (ddd)
7.34 (s)
7.60 (d)
3J H600 ꢁ H700 = 7.8
4J H600 ꢁ H800 = 1.5
7.75 (ddd)
H700
H800
–
–
–
–
–
–
3J H700 ꢁ H800 = 7.9
4J H500 ꢁ H700 = 1.5
8,18 (dd)
5J H500 ꢁ H800 = 1.2
The d values were deduced from the first order analysis of the corresponding system protons with an error of 0.05 ppm.
a
Abbreviations: brs, broad singlet; d, doublet; dd, doublet of doublets; ddd, double doublet of doublets; dt, doublet of triplets; m, multiplet; qt, quartet of triplets; s,
singlet; t, triplet; tt, triplet of triplets.
b
Not determined due to the low resolution of the signal.
A limit value was estimated taking into account the W1/2 values of the corresponding signals.
c
Table 2
13C Chemicals shifts (d, ppm) for 2–5 in CDCl3.
ꢃ In CDCl3 solution, these compounds adopt a flattened chair–
d (ppm)a
2
3
4
5
chair conformation with the N–CH3 groups in equatorial
positions.
C9
52.62
73.89
44.18
40.12
20.26
20.72
21.23
167.23
142.90
127.50b
128.24
126.68
135.08
124.54
138.32
132.99
–
53.20
73.86
44.16
39.94
20.13
20.66
–
52.50
73.87
44.18
40.15
20.29
20.59
–
162.17
142.77
127.08b
128.22
126.73
–
53.20
73.88
44.16
40.09
20.14
20.63
–
166.58
142.61
127.20b
128.33
126.86
–
149.55
118.34
129.64
124.48
125.07
125.07
130.21
C2(4)
N–CH3
C1(5)
C7
C6(8)
CH3
ꢃ The cyclohexane ring is more flattened than the piperidine
moiety.
ꢃ The phenyl groups are near coplanar with respect to C–H2(4)ax;
the shapes of the multiplets due to proton aromatic signals
account for a distinct conformation of the phenyl groups (due
to restricted phenyl spinning).
C@O
C10
164.28
142.84
c
ꢃ The conjugated amido group lies in a plane nearly coincident
with the symmetry plane of the bicycle; in this conformation,
the carbonyl group occupies a cis disposition with respect to
H9, therefore the amido group is in a trans form.
ꢃ Free rotation of the amido group around the C9–NH bond can be
deduced.
C20(60)
C30(50)
C40
128.28
126.84
137.84
125.48
135.53
131.33
–
135.53
125.48
–
C100
C200
142.48
147.25
–
C300
C400
ꢃ
1H NMR data indicate an intramolecular hydrogen bond
C400a
C500
–
138.32
124.54
–
–
–
144.36d
144.56d
–
N–Hꢀ ꢀ ꢀN100-heterocyclic in compound 4 in CDCl3 solution.
C600
C700
C800
–
–
–
–
130.21
c
C800a
These conclusions are supported by the following experimental
data:
a
b
c
Error of 0.05 ppm.
Broad signal.
Not determined owing to the low resolution of the signal.
These values may be interchanged.
In the 1H NMR spectra, the W1/2 value (8–9 Hz) for the H1(5)
signals is in agreement with previously reported values for a flat-
tened chair–chair conformation in related bicyclic systems [4–9].
d

I. Iriepa et al. / Journal of Molecular Structure 976 (2010) 190–195
193
For a boat disposition of one of these rings, the signal correspond-
ing to H1(5) would be an apparent doublet with a coupling con-
stant about 18 Hz [10].
compound 4 (see Table 1) can be attributed to the anisotropic ef-
fect exerted by the intramolecularly bonded pyrazine moiety over
H6(8)ax
.
In all cases, the 2J[H2(4)ax ꢁ H1(5)] value of ca. 3 Hz accountsfor a
dihedral angle of about 60° according to the Karplus relationship
[11]. In compounds 2, 3, 3J [H2(4)ax ꢁ H1(5)] ꢂ 3.3 Hz is smallerthan
3J [H6(8)ax ꢁ H1(5)] ꢂ 4.5 Hz and consequently the H2(4)ax–C–C–
H1(5) dihedral angle is greater than H6(8)ax–C–C–H1(5); this fact
is in close agreement with a flattened chair conformation for the
cyclohexane ring. Moreover, 3J [H6(8)ax ꢁ H1(5)] ꢂ 4.5 Hz is greater
than 3J [H6(8)eq ꢁ H1(5)] (<2) and 3J [H6(8)ax ꢁ H7eq] ꢂ 4.5 Hz is
greater than 3J[H6(8)eq ꢁ H7eq] (<2); therefore, the H6(8)eq–C–C–
H1(5) and H6(8)eq–C–C–H7eq dihedral angles are greater than
H6(8)ax–C–C–H1(5) and H6(8)ax–C–C–H7eq, respectively; these re-
sults confirm the distortion of the cyclohexane ring.
3.2. IR spectra
Table 3 shows the infrared frequencies (cmꢁ1) with the corre-
sponding assignments of the bands appearing in the NH and dou-
ble bond stretching regions.
Compound 2 in the solid state (KBr) showed a medium infrared
band at 3283 cmꢁ1 which is assigned to the intermolecularly
bonded NH group (see later). This band shifted to 3455 cmꢁ1 and
3462 cmꢁ1 in CDCl3 (0.06 M) and in CCl4 (0.0003 M), respectively,
due to the formation of free N–H groups. However, a small propor-
tion of bonded molecules remained even at high dilution. In the
The N–CH3 13C chemical shifts of compounds 2–5 of about
44 ppm (Table 2) agree with the values found in equatorial N–
CH3 substituted piperidines [4–9,12].
literature [16] the m (N–H) band of secondary amides in the
3340–3270 cmꢁ1 region in the solid state was assigned to a trans
bonded structure while a band in the 3220–3140 cmꢁ1 region
was attributed to the bonded band of a cis complex. Moreover,
for free N–H groups the frequency ranges given are 3470 cmꢁ1
for the trans and 3440–3420 cmꢁ1 for the cis structure. Therefore,
in accordance with 1H NMR data, IR results for compound 2 reveal
that the preferred conformation of this compound for the –NH–
CO– system is trans.
Furthermore, in the 13C NMR spectra, the twin-chair conforma-
tion is confirmed by the C2(4) (73.86–73.89 ppm) and C6(8)
(20.59–20.72 ppm) chemical shifts in agreement with previous
work [4–9]. For a boat conformation, the carbon signals would be
shifted to a higher field because of the steric compressing effect
due to the eclipsing between H2(4)ax ꢁ H1(5) and H6(8)ax ꢁ H1(5)
hydrogen atoms.
In addition, by comparing the NMR results of the a-epimers (2–
5) with those of their corresponding b-epimers [5], we can deduce
that they adopt similar preferred conformations with some slightly
In KBr two bands appeared in the carbonyl amide region at
1637 and 1622 cmꢁ1 and upon dilution in CDCl3 a strong band ap-
peared at 1652 cmꢁ1, indicating that C@O groups are implicated in
intermolecular hydrogen bonding with N–H groups (NHꢀ ꢀ ꢀO@C). In
the related b-compound the intermolecular hydrogen bond was
confirmed by the results obtained by cooling the sample at the li-
quid air temperature which showed a decrease of both N–H and
C@O stretching frequencies, as expected [5].
differences. The values
and
dC6(8)(b-epimers)-C6(8)(2–5) ꢂ 7 ppm can be attributed to
the steric syn-diaxial effect exerted by the axial amido group on
H2(4)ax for b-epimers and on H6(8)ax for -epimers (2–5). Besides,
the effect on H6(8)ax is greater for -epimers due to greater distor-
tion of the cyclohexane ring in comparison with the piperidine one.
The
D
dC2(4)(2–5)–C2(4)(b-epimers) ꢂ 5 ppm
D
a
a
A very strong band at 1534 cmꢁ1 (1510 cmꢁ1 in CDCl3) is as-
signed to the amide II band and according to the literature the
presence of this band confirms the trans conformation of the –
NH–CO– system [17].
In the case of compound 3 the infrared spectrum in the solid
state showed a
D
d H6(8)eq(b-epimers) ꢁ H6(8)eq
(
a
-epimers) ꢂ 0.2 ppm is
attributed to the W arrangement of the equatorial protons with re-
spect to the amido group in the first case; consequently, these pro-
tons would be more sensitive to the inductive deshielding effect
[13].
m ,
(N–H) medium intensity band at 3279 cmꢁ1
which was shifted to 3449 cmꢁ1 in CDCl3 and to 3457 cmꢁ1 in
CCl4. In the carbonyl amide region two bands appeared in the spec-
trum of the solid at 1639 and 1617 cmꢁ1 and one band at
1663 cmꢁ1 in CDCl3 solution. These results agree with results for
compound 2 and are interpreted in the same way. Furthermore,
X-ray data confirm the trans NH–CO structure and the presence
of a double NHꢀ ꢀ ꢀO@C hydrogen bond amide system defining
chains along the z axis in the crystal (d Nꢀ ꢀ ꢀO = 2.930 (5) Å; d
Oꢀ ꢀ ꢀH = 2.1 (1) Å; <N–Hꢀ ꢀ ꢀO@C = 155 (5)°).
Owing to the small differences in the chemical shifts of the H7ax
and H2(4)ax among compounds 2–5 and related systems [4–8], we
can conclude that the positions adopted by the phenyl groups in
2–5 will be the same as those found in the related systems, with
near coplanarity with respect to C–H2(4)ax as it was also observed
in the crystal structure of 3.
The differences
0.2 ppm and
d [H6(8)ax(2–5) ꢁ H6(8)ax(1)(1.49 ppm)] ꢂ 0.1 ppm
can be attributed not only to the -effect exerted by the amido
D
d[H2(4)ax(2–5) ꢁ H2(4)ax(1)(3.59 ppm)] ꢂ
D
r
Contrary to the infrared results obtained for compounds 2 and
group, but also to the decreasing anisotropic effect exerted by the
lone pair of the nitrogen atom when the amino group changes into
an amido group [4].
3, in the case of 4 the m
N–H stretching frequency at 3404 cmꢁ1
in the solid did not change much upon dilution in CDCl3
(3401 cmꢁ1) or CCl4 (3411 cmꢁ1), indicating the existence of intra-
molecular bonding, in this case between the NH group and the vic-
inal heterocyclic nitrogen (NHꢀ ꢀ ꢀN), forming a five member ring as
it has also been deduced from 1H NMR results (see before). Conse-
quently, the amide I band (1681 cmꢁ1 in KBr) did not increase on
dilution in CDCl3 (1671 cmꢁ1). The intramolecular bond was also
present in the related b-epimer, this conclusion being confirmed
by cooling the solid sample at the liquid air temperature: no
change was observed in the NH and C@O stretching frequencies
[5].
The
D
d [H9(2–5) ꢁ H9(1)(3.27 ppm)] value of 1.5 ppm can be
partially attributed to the
p
deshielding effect exerted by the car-
bonyl group over H9, confirming the cis disposition between this
group and H9.
The equivalence of the C1 and C5 protons and C6 and C8 pro-
tons and also of the C1 and C5, and C6 and C8 accounts for free
rotation of the amido group around the C9-NH group [14,15].
In compound 4, the signal corresponding to the N–H amide pro-
ton appears as a doublet centered at 8.3 ppm while in compounds 2,
3 and 5 the doublet appears at 6.4–6.5 ppm. This fact indicates that
the amide proton is hydrogen bonded in CDCl3 solution (see IR re-
sults), in this case forming a five member ring through an intramo-
lecular bond with the vicinal heterocyclic nitrogen (N100, Scheme 1).
In compound 5 the spectrum of the solid showed a
m
N–H band
at about 3330 cmꢁ1 and a strong band at 1658 cmꢁ1 with a shoul-
der at about 1640 cmꢁ1. The
m
N–H band was shifted to 3437 cmꢁ1
in CDCl3 and to 3445 cmꢁ1 in CCl4. However, the amide I band
(1658 cmꢁ1) did not change much in CDCl3 (1662 cmꢁ1) and the
frequency of the amide II band was 1515 cmꢁ1 in both media. As
Moreover, the
D
d [H6(8)ax(4)-H6(8)ax(2, 3, 5)] value (ꢂ0.1 ppm)
and the fact that H6(8)ax and H6(8)eq are isochronous for

194
I. Iriepa et al. / Journal of Molecular Structure 976 (2010) 190–195
Table 3
Infrared frequencies (cmꢁ1) of compounds 2–5.
Compound
2
Medium
KBr
m
(N–H) free
Bonded
Amide I
Ring
Amide II
1534 vs
3283 ma
1637 m
1622 s
1601 sb
1595 sb
CDCl3
CCl4
3455 w
3462 w
3320 vvw
3322 vvw
1652 s-vs
1604 sb
1510 vs
c
c
c
3
4
KBr
3279 m
1639 s
1617 vs
1663 s
1602 vwb
1566 vsb
1601 vwb
1540 vs
CDCl3
3449 w
3457 w
3330 vvw
1509 vs
c
1568 s
c
c
CCl4
KBr
3340 vvw
3404 w-md
1681 vs
1628 we
1601 vwe
1578 we
1601 we
1520 vs
CDCl3
3401 wd
1671 vs
1529 sh
1580 we
1523 vs
c
c
c
CCl4
KBr
3411 w-md
3330 w
5
1658 vs
1640 sh
1602 vwe
1585 we
1496 se
1515 s
CDCl3
3437 w
3445 w
3323 vvw
3335 vvw
1662 s
1602 we
1584 we
1515 vs
1497 se
c
c
c
CCl4
a
b
c
Abbreviations; s, strong; m, medium; w. weak, v, very; sh, shoulder.
Aromatic ring.
Not measured.
Intramolecular bond.
Heterocycle.
d
e
in the related b-epimer [5] infrared results of 5 suggest intermolec-
ular bonding between the N–H and the basic nitrogen of the quin-
oline ring (NHꢀ ꢀ ꢀN) in the solid state.
the contrary, IR results for compound 5 suggested NHꢀ ꢀ ꢀN-hetero-
cyclic intermolecular bonding.
Compound
4 shows the presence of an intramolecular
NHꢀ ꢀ ꢀN100-heterocyclic hydrogen bond in the solid state and in
non-polar solvents.
3.3. Pharmacology
With respect to the analgesic activity, compound 5 is the most
active compound showing peripheral effect, although non-signifi-
cant central effect.
Pharmacology assays on mice were performed with compounds
2–5 to evaluate drug-induced gross behavioral alteration. Both the
writhing test [18] and hot-plate test [19] were applied to evaluate
analgesic activity.
Acknowledgements
With respect to the analgesic activity, compounds 2–4
[10 mg Kgꢁ1 (i.p)] showed a partial antinociceptive effect in the
acetic acid writhing test in the mouse but this appeared to be
non-statistically significant activity when we compared it with
the degree of protection afforded by acetylsalicylic acid
[200 mg Kgꢁ1 (p.o.)] or diclofenac [10 mg kgꢁ1 (p.o)]. However,
compound 5 [10 mg Kgꢁ1 (i.p.)] showed a statistically significant
activity with a degree of protection similar to acetylsalicylic acid
or diclofenac. When the hot-plate test was used, compounds 2–5
did not achieve the grade of activity showed by morphine
[8 mg Kgꢁ1 (i.p.)]. These results indicate that compound 5 would
exhibit peripheral but no significant central analgesic effect.
The authors thank Dr. A. Orjales (FAES S.A Laboratories, Bilbao,
Spain) for the pharmacological studies. We also thank Dr. J. Sanz-
Aparicio (Instituto Rocasolano, Departamento de Rayos X, CSIC,
Madrid, Spain) for the X-Ray measurements.
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4. Conclusions
Some amides (2–5) derived from 3-methyl-2,4-diphenyl-3-aza-
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