2D 1H and 13C NMR conformational studies of thienopyridines and carboline biarylic compounds

Article abstract of DOI:10.1016/j.saa.2009.06.060

In this paper, we report on conformational studies of biarylic compounds, as prepared through the well-known aza-Wittig methodology. The conformational studies were mainly realized by bidimensional (2D) nuclear magnetic resonance spectroscopy (NMR) and NO

Full text of DOI:10.1016/j.saa.2009.06.060

Spectrochimica Acta Part A 74 (2009) 515–525
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
2D 1H and 13C NMR conformational studies of thienopyridines and carboline
biarylic compounds
D. Coronaa,∗, E. Díazb,∗, H. Barriosb, E. Sánchezb, C. Alvaradob, C.K. Jankowskic, A. Guzmánb
a Centro de Investigación en Química Sustentable, Facultad de Química, Universidad Autónoma del Estado de México, Toluca Estado de México, 50200, Mexico
b Instituto de Química, Universidad Nacional Autónoma de México, Circuito exterior, Coyoacan, Distrito Federal, 04510, México, Mexico
c Departement de chimie et biochimie, Université de Moncton, Moncton, N.B., E1A 3E9 Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we report on conformational studies of biarylic compounds, as prepared through the well-
known aza-Wittig methodology. The conformational studies were mainly realized by bidimensional (2D)
nuclear magnetic resonance spectroscopy (NMR) and NOESY experiments. The conformational behav-
ior showed that these biarylic compounds display an orthogonal symmetry and adopt a characteristic
arrangement around the pivotal bond. Molecular modeling calculations were performed to support
Received 20 November 2008
Received in revised form 23 June 2009
Accepted 30 June 2009
Keywords:
NOESY
Aza-Wittig
Thienopyridin
Carboline
structure conformations.
© 2009 Elsevier B.V. All rights reserved.
1. Introduction
the reaction between an aromatic iminophosphorane intermedi-
ate and an aromatic aldehyde [6–8]. Such strategies are mostly
The conformational behavior of the molecules is one of the most
important subjects in biological chemistry, because conformation
is strongly related to biological activity [1]. Conformational stud-
ies have been performed on biarylic derivatives whose aromatic
units are linked through a rotationally hindered biaryl axis due to
steric factors [2,3]. It is well accepted that, if two planar groups are
connected by one central bond, and the ground state is not planar,
then the molecule possess axial chirality (provided that neither of
the two planes are symmetrical to a plane involving this central
bond). If the rotation barrier is small, then as the rotation around
the symmetry axis accelerates, the magnetic environment of the
nuclei becomes interchangeable, and the averaging takes place; this
leads to the apparent racemization of the chiral compound. The
most typical examples of such racemization can be found in the
biphenyl series [4,5]. The same principle can be applied to other
non-planar molecules. The magnitude of the energy for the rota-
tional barriers can be evaluated approximately in terms of steric
effects. Biphenyls constitute a unique system in which introduc-
tion of a substituent in o,oꢀ positions can influence the transition
state for a given conformer affecting its ground state energy.
The preparation of biarylic heterocyclic compounds has been
performed using different methodologies, some of which involve
directed towards the construction of nitrogen-containing hetero-
cycles [8–11]. The readily available iminophosphorane (prepared
from azides) [12] and their aza-Wittig reaction with a wide vari-
ety of carbonyls [13–15] and heterocumulene [16–18] compounds
provide a valuable method for the regiospecific construction of
carbon–nitrogen double bonds [19–21].
Recently, our group applied this methodology to build a variety
of molecular skeletons, and to study their conformational behavior
by NMR [22,23].
2. Results and discussion
Iminophosphoranes were obtained by condensation reactions
between ethyl azido acetate and various aromatic aldehydes 1–5.
The Staudinger reaction with triphenyl phosphine produces the cor-
responding iminophosphoranes 6–10 with moderated yields for a
two-step synthesis (Table 1). From an aza-Wittig reaction between
aromatic aldehydes 11–18 and the iminophosphorane intermedi-
ates 6–10, the biarylic compounds 19–31 were synthesized (yields
shown in Table 2) (Scheme 1).
The biarylic compounds 19–31 (Fig. 1) prepared using the aza-
Wittig methodology shows a variable steric hindrance between
the two aromatic moieties linked through the aforementioned piv-
otal bond. The compounds 19–21 are derivatives of thienopyridines
with either one or two aromatic moieties, while derivatives 22–30
are tricyclic aromatic compounds linked to mono- or bicyclic aro-
matic moieties.
∗
Corresponding authors. Tel.: +52 5 56224421; fax: +52 5 56162217.
E-mail addresses: barrios@servidor.unam.mx (D. Corona),
maudiaz@servidor.unam.mx (E. Díaz).
1386-1425/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2009.06.060

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D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
Table 1
ported by COSY and NOESY experiments as described in Section
4.
Iminophosphoranes 6–10 obtained by Staudinger reaction.
The assignments of the 13C resonances of the synthesized
products were carried out in CDCl3 by determining the sig-
nal multiplicities from DEPT experiment. The complete 1H and
13C assignments of the molecules were achieved by means of
proton–carbon correlation methods, for example the HSQC and
HMBC spectra, in order to complete the full assignments.
In order to demonstrate dipolar interactions between key pro-
tons through the space, we performed a phase sensitive NOESY
experiment in CDCl3. The interatomic distances of selected protons
were calculated from NMR data.
Ar1
Phosphonate
Yield (%)a
5-Methylthiophen-2-yl (1)
N-Methylindol-2-yl (2)
N-Benzyl-2-carboethoxvthieno[2,3-b]pyrrol-5-yl (3)
5-Chlorothieno[2,3-b]pyridin-2-yl (4)
6-Methylthieno[2,3-b]quinol-2-yl (5)
6
7
8
9
10
63
70
75
40
35
a
Two steps.
Table 2
Biarylic compounds obtained through the TAWERS reaction.
The conformational study by the 2D NMR NOESY shows, for
almost all derivatives, an orthogonal pattern appearing as two
biarylic units with restricted rotation through their pivotal bond
for example, C4–C3ꢀ for compound 19 (19–28, Figs. 2 and 3). Never-
theless, for compounds derived from the 2-quinolincarboxaldehyde
(compounds 29–31), the conformational study specified a spe-
cial geometry between two aromatic moieties. This observation is
similar to one previously reported by us, and supported by X-ray
crystallography studies for the case of 6-carboethoxy-2-methyl-4-
(2ꢀ-quinolin)thieno[3,2-c]pyridine [22].
For derivative 19, NOESY experiment detected dipolar correla-
tion between protons H-3/H-4ꢀ (2.39 Å), as well as, the correlation
corresponding to aldehydic protons H-6ꢀ/H-4ꢀ (2.57 Å). From the
NMR data, we calculated the minimum conformational energy as
well as the dihedral angle between two planes determinated by
3a-4 and 3ꢀ-4ꢀ (Table 3).
Phosphonate
Aldehyde (Ar2)
Compound
Yield (%)
77
6
5-Chloro-1-methyl-2-
formylpyrrol-4-carboxaldehyde
(11)
2,6-Dichloro-3-formylpyrido-5-
carboxaldehyde
19
6
6
20
21
72
83
(12)
5-Chlorothieno[2,3-b]pyrido-2-
carboxaldehyde
(13)
Phthaldehyde (14)
Thiophen-2,3-dicarboxaldehyde
(15)
Thiophen-2,3-dicarboxaldehyde
(15)
2-Carbomethoxythieno[2,3-
b]pyrido-5-carboxaldehyde
(16)
2,3-Thiophendicarboxaldehyde
(15)
2,3-Thiophendicarboxaldehyde
(15)
7
7
22
23
84
92
7
9
24
25
92
77
8
8
26
27
75
75
For dihalogenated derivative 20, using the diagonal and
cross-peaks from H-3 and H-4ꢀ we were able to identify a dipo-
lar interaction between these protons (3.02 Å). An additional
correlation observed was that between aldehydic proton H-7ꢀ
(ı = 10.4 ppm) with the H-4ꢀ proton at ı = 8.38 ppm (2.23 Å). Geo-
metrical parameters can be observed in Table 3.
7
7
9
Quinoline-4-carboxaldehyde (17)
Quinoline-2-carboxaldehyde (18)
Quinoline-2-carboxaldehyde (18)
Quinoline-2-carboxaldehyde (18)
28
29
30
31
91
85
84
62
10
The derivative 21 represent an aromatic heterocompound
formed by two moieties of thienopyridines linked through C-2ꢀ/C-4
bond. The phase sensitive NOESY spectrum displays strong corre-
lations between H-4ꢀ/H-3ꢀ (2.87 Å), as well as the helpful spatial
correlation between H-3/H-3ꢀ (2.13 Å).
Finally, compound 31 is an aromatic tetracycle joined to an aro-
matic moiety formed by another two cycles. It is expected that
compounds of this class will display a hindered rotation due to
steric factors. We have previously studied this class of phenom-
ena, focusing on a particular conformational behavior of these
molecules [22,23].
Since the derivatives 19–31 (Fig. 1) may be of some pharma-
ceutical interest, it appeared attractive to study their detailed
conformational data, taking into account the restricted rotation
that may occurs through the pivotal bond between both aromatic
moieties.
In order to obtain a molecular-level insight into these interest-
ing effects, we performed 2D NMR conformational studies of the
biarylic units from thienopyridines and carboline derivatives.
First, the molecules obtained were identified using high-
resolution NMR 1D and 2D techniques. All the assignments
given are self-consistent and unambiguous, and particularly sup-
For compound 22, the 1H NMR recorded in CDCl3 displayed
the chemical shift for the conformational and relevant protons
within a highly overlapped area. In order to overcome this difficulty,
NOESY experiment for the compound 22 was recorded instead
in C6D6. Under these conditions, the 1D 1H NMR 500 MHz more
clearly displayed the key NOESY signals, which provides evidence
of compound 22’s conformational behavior. The assignment of the
chemical shift of the protons for this compound began with NOESY
spectrum using the diagonal peak of the N-Me at ı = 2.80 with the
cross-peaks at ı = 6.83 (H-6) separated by 2.29 Å as well as that due
to H-4 (ı = 8.25) separated by 2.28 Å. Other relevant dipolar corre-
lations were observed between the aldehydic proton H-7ꢀ (ı = 10.1)
and the proton H-3ꢀ, as well as that assigned to H-9 at ı = 7.40. The
most important dipolar correlation which enabled us to get confor-
Scheme 1. Synthesis of biarylic compounds.

D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
517
Fig. 1. Biarylic compounds 19–31 of this study.
mational evidence for the compound 22, was the one between H-9
(ı = 7.40) with H-6ꢀ (ı = 7.56), 2.68 Å (Table 3).
ı = 7.70, 23 with the H-8 ı = 7.01, 23 as well as, for H-9 at ı = 7.60, 24
with H-8 at ı = 6.94, 24.
Similarly to compound 22, for the mixture of compounds 23
and 24, the NMR in CDCl3 solution displays highly overlapped the
aromatic protons signals. However, when we recorded the mixture
23 and 24 in a CDCl3/C6D6 1:1 solution, it was possible to isolate
the particular chemical shifts of the compounds 23 from those due
to 24 and established their ratio at 1:1. For example, both aldehydic
protons display a 5J long range coupling with one of the thiophenic
protons confirmed by COSY spectrum. It was for example observed
the 5␴ bond correlation between aldehydic protons (C-6ꢀ) at ı = 10.1
(d, 5J = 1.0, 23) with H-5ꢀ ı = 7.24, 23. The second aldehydic proton at
ı = 9.80 (br, 24) was correlated with the proton at ı = 6.97 (H-5ꢀ 24),
respectively. Through NOESY spectrum we were also able to observe
diagonal peaks of H-9 of 23 at ı = 7.69 with cross-peaks of aldehydic
protons at ı = 10.1, 23 as well as the signal at ı = 7.28. However, the
signal due to H-9 of 24 at ı = 7.60 displayed only dipolar correlation
with aldehydic proton at ı = 9.80, 24. In the same spectrum it was
possible to observe less relevant dipolar correlation between H-9
The protons on C4 and C6 for 23 (8.26 s, and 7.08 d, respectively)
and 24 (8.24, s and 7.03 d) both were assigned through the cross-
peaks of their chemical shift using as diagonal peaks those due to
N-Me group at ı = 3.14, 23 and 3.10, 24.
The pair of thiophenic protons for 23, at ı = 7.24 (dd, 5J = 1.5,
3J = 5.0 H-5ꢀ) and ı = 7.28 (d, 3J = 5.0, H-4ꢀ); and those due to thio-
phenic moiety of 24, ı = 6.97 (dd, 5J = 1.0, 3J = 5.5, H-5ꢀ) and ı = 7.62
(d, 3J = 5.5, H-4ꢀ) complete the assignment.
The data obtained by Gaussian molecular modeling calculations
enable us to evaluate for compounds 23 and 24, using NOESY spec-
trum data conformational energy as well as torsional angles as
depicted in Table 3.
The most striking conformational behavior was observed for
compound 25. From the data of NOESY spectrum, the diagonal-
cross-peak H-4 to both H-6ꢀ and H-4ꢀ as well as the usual dipolar
correlation between H-4ꢀ with H-3ꢀ, it was possible to evaluate
the minimum energy and the corresponding dihedral angle (50.0◦)

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D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
Fig. 2. NOESY experiment of the compound 25.
between 4b-5, 5ꢀ-6ꢀ (Table 4). The interatomic distances between
protons are: H-4/H-6ꢀ = 2.58 Å; H-4/H-4ꢀ = 4.28 Å; H-3ꢀ/H-4ꢀ = 2.71 Å.
For the isomeric pair of compounds 26 and 27 obtained in 2:1
ratio, the phase sensitive NOESY experiment enable the structural
assignment by dipolar correlations between H-3 at ı = 7.80 ppm for
derivative 26 which displays a cross-peak (doublet 3J = 5.0 Hz at
ı = 7.64 ppm H-4ꢀ). This last signal correlates also with H-5ꢀat ı = 7.91
(dd 5J = 1.2, 3J = 5.0). For the compound 27, the protons H-5ꢀ and H-
4ꢀ display only cross-peak to each other at ı = 7.74 ppm (H-5ꢀ) and
ı = 7.53 ppm (H-4ꢀ). From the NOESY data it was deduced for the
pair 26 and 27 that in an orthogonal conformation for derivative
26 a dihedral angle between 3b-4, 3ꢀ-4ꢀ carbons is 39.0◦ and from
a dipolar correlation between H-3/H-4ꢀ an internuclear distance of
2.43 Å.
For the derivative 27, it was obtained the dihedral angle between
3b-4, 3ꢀ-1ꢀ carbons of 43.0◦ with interatomic distance H-4ꢀ/H-5ꢀof
2.65 Å.
Similarly for derivative 28, the phase sensitive NOESY sug-
gested a non-coplanar conformation where both aromatic moieties
displays a dihedral angle between 9b-1, 4ꢀ-3ꢀ carbons of 57.0◦. Con-
sequently, we were able to observe for H-9 three different dipolar
correlations, with H-8 (strong), H-3ꢀ (medium) and finally with H-5ꢀ
(weak) with internuclear distances of H-3ꢀ/H-9 = 2.67 Å, H-5ꢀ/H-
9 = 4.9 Å, respectively (Fig. 3).
Additional relevant nOe correlations were observed for the
cross-peaks for H-6 and H-4 where the diagonal peak for the N-Me
at ı = 4.00 helped the unambiguous assignment of the remaining
proton signals (H-13/H-6 = 2.49 Å; H-13/H-4 = 2.26 Å).
Fig. 3. NOESY of compound 28.

D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
519
Fig. 4. Chemical shifts modification observed in CDCl3 for compound 29. (a) After 5 min; (b) 60 min; (c) 24 h (partial spectrum).
The derivative 29 1D 1H NMR, displayed a special behav-
ior (Fig. 4). It was noted that the chemical shifts due to H-4ꢀ
(ı = 8.42), H-3ꢀ (ı = 8.42), H-9 (ı = 8.50) and H-8ꢀ (ı = 8.28) were
shifted slightly with time in the chloroformic solution (for exam-
ple H-4ꢀ ꢀı = 0.05 ppm, H-9 ıꢀ = −0.11 ppm and H-8 ıꢀ = 0.08 ppm,
respectively). The initial spectrum (Fig. 4) enabled us to detect
through the NOESY experiment several important dipolar correla-
tions and to deduce its conformation. For example, the key element
for the conformational assignment of compound 29 was the dipo-
lar correlation between H-9 with H-8ꢀ which left the molecule with
predictable dihedral angle as 22.0◦ and internuclear distance H-
9/H-8ꢀ as 2.67 Å.
were observed even after one week in solution. However, in deuter-
ated chloroform for compound 31, which displayed strong acidic
effect as described in Table 4 and Fig. 5, the addition of a drop
of base (TEA) showed that all protons went back to their original
positions.
With respect to the conformational behavior of the molecule
31, the key element deduced from the NOESY spectrum was the
relevant dipolar correlation between H-8ꢀwith H-5 (3.07 Å, Fig. 6).
The other important correlations, signals that help to unambigu-
ously assign the remaining protons were the diagonal peak due to
methyl 15 with the cross-peaks of the signals due to H-8 and H-6
(2.55 Å and 2.44 Å, respectively).
For the chloroderivative 30, its NOESY spectra clearly displayed
dipolar correlation between the protons H-4 and H-8ꢀ. From the
NOESY data it was possible to estimate a H-4/H-8ꢀ through space
distance of 2.96 Å with conformational parameters depicted in
Table 3.
The conformational evidences as deduced from the NOESY
spectrum of 31, enabled us to estimate the interatomic distances
for selected protons; for example, 2.49 Å for H-5/H-6; and 2.56 Å
for H-4ꢀ/H-5ꢀ. In order to explain the long-range dipolar correla-
tion between H-5/H-8ꢀ, in the absence of observable correlation
between H-6/H-8ꢀ the dihedral angle between the planes of the
two aromatic rings should be of 35.0◦, this matched with the
minimum energy calculated for this molecule (see Table 3 and
Fig. 6).
Using dipolar correlations observed from NOESY experiments,
with compounds 19–31, the conformational studies were per-
formed upon the relevant diagonal/cross-peaks. These data and
some other dipolar correlations, including the dihedral angles
and the calculated minimum energy deduced from the NMR fea-
tures deduced from the 2D NMR spectra, are summarized in
Table 3.
For the compound 31, with its two nitrogen atoms in the vicinity
of the pivotal bond between two aromatic moieties, it was observed
through its 1H NMR spectrum that for some protons their chemi-
cal shift was slowly changing, displaying relevant chemical shift
difference within 60 min to 24 h period of time. From this obser-
vation of the proton signals for the initial/final spectra we have
deduced that this was due to the acidity of the NMR solvent (CDCl3)
and the structure involved the ammonium salt formation on N-10.
The resonance forms depicted in Fig. 5 resume where the elec-
tron deficient carbons could be placed as detailed in Table 4. The
protons that underwent the major induced acid effect after the
protonation on N-l0 are H-5, H-6, H-8 and H-9 [24]. Some addi-
tional 1H NMR experiment was also performed on compounds 29
and 31. When the spectra for both compounds were recorded in
perdeuterated benzene no relevant differences of chemical shifts
The lowest energy conformation can be estimated after the min-
imization of the NMR data via the semi-empirical method. In the
same operation, the torsional angle formed by two aromatic sys-
tems could also be calculated.

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D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
Fig. 5. Resonance forms of protonated compound 31.
Fig. 6. NOESY of compound 31.

D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
521
Table 4
NMRtimedependingdataforcompound31 inCDCl3 (500 MHz). Chloroforminduced
chemical shifts.
␦H (ppm)
5 min
60 min
24 h
One week
ꢀı (ppm)
H-1
H-5
H-6
H-8
H-9
H-3ꢀ
H-4ꢀ
H-5ꢀ
H-6ꢀ
H-7ꢀ
H-8ꢀ
8.73
8.69
7.34
7.64
8.05
8.25
8.53
8.05
7.74
7.88
8.16
8.73
8.77
7.36
7.66
8.09
8.26
8.54
8.06
7.76
7.88
8.17
8.76
9.12
7.47
7.77
8.32
8.35
8.58
8.08
7.80
7.92
8.22
8.78
9.40
7.56
7.87
8.50
8.42
8.64
8.10
7.82
7.95
8.28
+0.05
+0.71
+0.22
+0.23
+0.45
+0.17
+0.11
+0.05
+0.08
+0.07
+0.12
This angle gives a precise idea about the conformation adopted
by the biarylic rotating systems, as in compounds 19–31, and is
as such, it is valuable additional tool for completely characterizing
these molecules.
Calculationswereprocessedwithsemi-empiricalChemBioDraw
Ultra® 3D version 11.0 and with Gaussian 03’. Together these pro-
grams allowed us to calculate the dihedral angles and evaluate the
corresponding rotational energy for the conformation with the low-
est energy minimized. Data are presented in Table 3.
2.1. Comparison of NMR assisted computational data
2.1.1. Conformational analysis and computational details
The NOE experiments are now used in analysis of molecular
structure and dynamics, for both small molecules and macro-
molecules. Although NOEs are often treated qualitatively as static
phenomena, the observed effects are usually a time average of
contributing structures, and must be interpretated cautiously. Fur-
thermore, differences in relaxation behavior can change the nature
of the observed effects. Dipolar cross-relaxation gives rise to the
NOE, and it is necessary to suppress other relaxation mechanisms
as much as possible in order to maximize the weak effects such as
intramolecularNOEs. The typical detectionlimit observed fornuclei
with intermediate relaxation times under the best circumstances,
with minimal effect from other relaxation mechanism [27] is ∼5 Å.
The NOESY experiments provides structural information
through the NOE cross-peaks, whose magnitudes are inversely pro-
portional to the sixth power of the interproton distance (r) in space
(1/r6).
Because of the fact that, the most of the compounds studied
herein, are formed by two aromatic moieties linked by a piv-
otal bond they adopt specific orientations to reduce the stereo
violations. The systematic search started from the dihedral angle
measured from specific conformations obtained by rotation about
this pivotal bond. This could define the relative orientation of the
substituents on the biphenyl-like scaffold.
Compared to the NOE patterns we retain for calculations only the
conformations which are consistent with the experimental NMR
data and subjected to the following calculations:
(i) Semi-empirical ChemBioDraw Ultra® 3D version 11.0 MM2
simulations and energy minimization with any constraint. The
conformation with the lowest energy was chosen as the start-
ing structure for a systematic search of the representative
dihedral angles.
(ii) The lowest energy conformations should fit the NOE data.
(iii) Inthefinalstepweusedquantumchemicalcalculationthrough
Gaussian 03 with Density Function Theory (DFT) (with a step
size of 5–10◦, respectively).

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D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
Fig. 7. Compound 25.
In order to have a clearer picture of the conformation of com-
(c) The rotational barrier between points A and B was calculated as
11.79 kJ/mol.
(d) Energy difference between points
ꢀE = 0.28 kJ/mol.
pounds 19–31 two dihedral angles were defined which involved
atoms adjacent to the pivotal bond (ꢁ and ω). The dihedral
angles ꢁ and ω were scanned simultaneously, the systematic
searching began from this selected geometry. Through DFT cal-
culations we were able to draw the different energy curve for
each compound (see Table 3 and Figs. 7 and 8) with the rela-
tive potential energy (kJ/mol) being plotted as a function of the
dihedral angle ꢁ leading to detailed analysis of compounds 25 and
28.
A
and D shown a
The optimized structures of conformers A and B using density
functional theory (B3LYP/6-31G):
The optimized structures of conformers: A, B, C and D using DFT
density functional theory (B3LYP/6-31G):
(a) Relative potential energy (kJ/mol) of conformers from 28 as a
function of dihedral angle ꢁ with the Hartree units and angular
angle step of 5◦.
(b) Relative potential energy (kJ/mol) of conformers from 28 as a
function of dihedral angle obtained from a system search anal-
ysis with a step size 10◦.
(a) Relative potential energy (kJ/mol) of conformers from 25 as
a function of dihedral angle ꢁ with Hartree units and angular
angle step of 5◦.
(b) Relative potential energy (kJ/mol) of conformers from 25 as a
function of dihedral angle obtained from a system search anal-
ysis with a step size of 10◦.
(c) The rotational barrier between lowest energy points was calcu-
lated as 13.9 kJ/mol.

D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
523
Fig. 8. Compound 28.
3. Conclusion
natural products, chiral auxiliaries and catalysis. Thus is not sur-
prising that significant advances in the synthesis of new biarylic
compounds have been performed.
The conformational analysis of these compounds as performed
by a combination of NMR spectroscopy and quantum chemical cal-
culation, shows an excellent agreement between two approaches
to conformational analysis. The structure calculation of compounds
19–31 was conducted using molecular dynamics (MD) simulation
and Gaussian 03 for quantum chemical calculation in order to have
a clearer picture of the preferred conformations adopted by several
rotationally hindered biarylic compounds.
On the other hand, the NMR experiment results in particularly
the phase sensitive NOESY, when applied to the analysis of several
biarylic derivatives in solution, displayed an excellent agreement
with the data published in our previous work [22].
We were able to establish a complete conformational profile for
several thienopyridines and indole derivatives. The NOESY data,
when compared with the results of molecular modeling calcula-
tions afforded complementary features for description of molecules
that have two aromatic moieties with limited rotation around the
pivotal bond. The major conformation in solution is the one that
presents with a minimal conformational energy. The interatomic
distances of selected protons as calculated from NMR data fully
agreed with the assignments presented in this study.
4. Experimental
Melting points were determined with a Kofler hot stage and they
are uncorrected. 1H and 13C spectra were recorded using a Varian
Unity 300 for routine experiments and Varian Unity 500 spectrom-
eters for 2D experiments (NOESY, HSQC, and HMBC). The 1H and
13C chemical shifts (ı) are given in ppm relative to TMS as internal
standard (0.00 ppm). For analytical purpose the mass spectra were
recorded on a JEOL JMS-5X 10217 in EI/PI mode, 70 eV, 200 ◦C using
the direct inlet probe. Only molecular ion (m/z) values are reported.
IR spectra were recorded on a Nicolet Magna 55-X FT instrument.
Aldehydes used in the preparation of compounds 6–7, 23–25,
27–31 were purchased from Aldrich and used as received. The alde-
hydes used to synthesized compounds 8–10, 19–22, 25–26, were
prepared according to the literature [28].
4.1. General procedure for the reaction between aldehydes and
iminophosphoranes
On the other hand, the axis of a biaryl which is rotationally hin-
dered and thus stereogenic is the structurally, conformationally and
stereochemically decisive element of a steadily growing number of
A mixture of 0.1 mmol of the iminophosphorane intermediate
6–10 and 0.1 mmol of the corresponding aromatic aldehyde (Ar2)
in 2 mL of 1,2-dichlorobenzene was refluxed for 12–16 h. The mix-

524
D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
(%): 364 (M+; 12). 1H NMR 500 MHz (C6D6/CDCl3 1:1) ı (ppm): 1.19
(t, 3H, J = 7.0 Hz; H-12); 3.10 (s, 3H, H-13); 4.355 (q, 2H, J = 7.0 Hz;
H-10); 6.94 (ddd, 1H; J = 7.5, 8.0, 1.0 Hz; H-8); 7.28 (dd, 1H, J = 7.5,
7.5, 1.0 Hz; H-7); 7.03 (br d 7.5; H-6); 7.60 (ddd 1.0,1.5,8.0 H-9);
7.62 (d, J = 5.5 H-4ꢀ); 7.97 (d, 1H, J = 5.5 Hz; H-5ꢀ); 8.245 (s, 1H, H-4);
9.80 (s, 1H, H-6ꢀ). 13C NMR 75 MHz (CDCl3) ı (ppm): 14.4 (C-12);
29.6 (C-13); 62.1 (C-11); 106.5 (C-4); 109.5 (C-6); 121.5 (C-8); 122.3
(C-9b); 122.3 (C-9); 125.9 (C-5ꢀ); 127.3 (C-4ꢀ); 128.5 (C-7); 134.0
(C-9a); 139.4 (C-2ꢀ); 143.5 (C-4aꢀ); 144.2 (C-3ꢀ); 145.5 (C-5a); 147.9
(C-1); 165.8 (C-10); 185.2 (C-6ꢀ).
ture was allowed to reach room temperature and then purified by
column chromatography (silica gel, 70–230 mesh) yielding in all
cases white solids.
4-(2-Chloro-5-formyl-1-methyl-1H-pyrrol-3-yl)-6-
ethoxycarbonyl-2-methyl-thieno[3,2-c]
pyridine
(19).
m.p.
214–216 ◦C, yield 77%. C17 H15O3N2SCl; MW: 362.83; C, 56.27;
H, 4.17; Cl, 9.77; N, 7.72; O 13.23; S, 8.84. MS (E.I.) m/z (%): 362
(M+; 40), 364 (M++2; 13). 1H NMR 500 MHz (CDCl3) ı (ppm): 1.45
(t, 3H, J = 7.0 Hz; H-10); 2.68 (d, 2H; J = 1.5 Hz; H-11); 3.97 (s, 3H;
H-7ꢀ); 4.47 (q, 2H, J = 7.0 Hz; H-9); 7.08 (s, 1H; H-4ꢀ); 7.4 (dd, 1H;
J = 1.5, 0.5 Hz; H-3); 8.49 (d, 1H; J = 0.5 Hz; H-7); 9.94 (s, 1H; H-6ꢀ).
13C NMR 125 MHz (CDCl3) ı (ppm): 14.3 (C-10); 16.4 (C-11); 32.0
(C-7ꢀ); 61.7 (C-9); 110.7 (C-4ꢀ); 118.1 (C-7), 120.6 (C-3ꢀ); 121.1 (C-3);
136.8 (C-3a); 140.4 (C-2ꢀ); 144.4 (C-4); 146.0 (C-5ꢀ); 146.9 (C-6);
148.6 (C-7a); 165.3 (C-8); 184.1 (C-6ꢀ).
3-Chloro-5-(2-methoxycarbonyl-thieno[2,3-b]pyridin-5-yl)-
7-methoxycarbonyl-thieno[2,3-b:4,5-cꢀ]dipyridine
(25).
m.p.
282–283 ◦C, yield 77%. C21H12O4N3S2Cl; MW: 469.92; C, 53.67; H,
2.57; Cl, 7.54; N, 8.94; O, 13.62; S, 13.65. MS (E.I.) m/z (%): 469 (M+;
22), 471 (M++2; 7). 1H NMR 300 MHz (CDCl3) ı (ppm): 4.02 (s, 3H,
H-9ꢀ); 4.07 (s, 3H, H-11); 7.58 (d, 1H; J = 2.5 Hz; H-4); 8.12 (s, 1H;
H-3ꢀ); 8.5 (d, 1H, J = 2.5 Hz; H-4ꢀ); 8.64 (d, 1H, J = 2.5 Hz; H-2); 8.76
(s, 1H; H-8); 8.94 (d, 1H, J = 2.5 Hz; H-6ꢀ). 13C NMR 75 MHz (CDCl3)
ı (ppm): 52.9 (C-9ꢀ); 53.3 (C-11); 119.3 (C-8); 127.6 (C-5ꢀ); 127.9
(C-3ꢀ); 128.6 (C-4a); 131.3 (C-4); 131.9 (C-3); 132.2 (C-2ꢀ); 133.4
(C-4ꢀ); 135.4 (C-3aꢀ); 144.2 (C-7); 148.8 (C-6ꢀ); 149.0 (C-2); 149.8
(C-8a); 150.2 (C-4b); 153.3 (C-5); 159.8 (C-9a); 163.9 (C-8ꢀ); 165.1
(C-10); 165.5 (C-7aꢀ).
4-(2,6-Dichloro-5-formyl-pyridin-3-yl)-6-ethoxycarbonyl-2-
methyl-thieno[3,2-c]pyridine (20). m.p. 203–204 ◦C, yield 72%.
C17 H12O3N2SCl2; MW: 395.26; C, 51.66; H, 3.06; Cl, 17.94; N, 7.09;
O, 12.14; S, 8.11. MS (E.I.) m/z (%): 394 (M+: 16) 396 (M++2; 9), 398
(M++4; 4). 1H NMR 500 MHz (CDCl3) ı (ppm): 1.46 (t, 3H; J = 7.0 Hz;
H-10); 2.65 (d, 3H; J = 1.0 Hz; H-11); 4.5 (q, 2H; J = 7.0 Hz; H-9); 6.83
(qt, 1H, J = 1.0 Hz; H-3); 8.38 (s, 1H; H-4ꢀ); 8.67 (d, 1H, J = 0.5 Hz;
H-7); 10.4 (s, 1H,; H-7ꢀ). 13C NMR 125 MHz (CDCl3) ı (ppm): 14.
3 (C-10); 16.4 (C-11); 62.0 (C-9); 119.8 (C-7); 119.9 (C-3); 127.8
(C-3ꢀ); 134.8 (C-5ꢀ); 137.2 (C-3a); 141.1 (C-6); 141.8 (C-4ꢀ); 147.6
(C-7a); 147.9 (C-4); 147.3 (C-2); 152.1 (C-2ꢀ); 153.5 (C-6ꢀ); 165.1
(C-8); 187.6 (C-7ꢀ).
6-Carboethoxy-2-carbomethoxy-8-benzyl-4-(2-formyl-thiophen-
3-yl)-8-thia-5,8-diazacyclopenta
b]pyrrolo[3,2-c]pyridine (26). m.p. 246–248 ◦C, yield 75%.
26H20O5N2S2; MW: 504.57; C, 61.89; H, 4.0; N, 5.55; O, 15.85; S,
[a]-indene-5-aza-thieno[2,3-
C
12.71. MS (E.I.) m/z (%): 504 (M+; 22). NMR 1H 300 MHz (CDCl3) ı
(ppm): 1.48 (t, 3H, J = 7.0 Hz, H-11); 3.90 (s, 2H, H-13); 4.52 (q, 2H,
J = 7.0 Hz; H-10); 5.53 (s, 2H; H-14); 7.14–7.34 (m, 5H; H16-H20);
7.64 (d, 1H, J = 5.0 Hz; H-4ꢀ); 7.91 (dd, 1H, J = 5.0, 1.2 Hz; H-5ꢀ); 7.80
(s, 1H, H-3); 8.4 (s, 1H, H-7); 10.14 (d J = 1.2, 1H, H-6ꢀ).
4-(5-Chloro-thieno[2,3-b]pyridin-2-yl)-6-ethoxycarbonyl-2-
methyl-thieno[3,2-c]pyridine (21). m.p. 251–253 ◦C, yield 83%.
C18 H13O2N2S2Cl; MW: 388.89; C, 55.59; H, 3.37; Cl, 9.12; N, 7.2; O,
8.23; S, 16.49. MS (E.I.) m/z (%): 388 (M+: 40) 390 (M++2; 13). 1H
NMR 500 MHz (CDCl3) ı (ppm): 1.5 (t, 3H; J = 7.0 Hz; H-10); 2.65
(d, 3H; J = 1.0 Hz; H-11); 4.5 (q, 2H; J = 7.0 Hz; H-9); 7.66 (m, 1H,
H-3); 7.87 (s, 1H; H-3ꢀ); 8.08 (d, 1H, J = 2.0 Hz; H-4ꢀ); 8.55 (d, 1H,
J = 2.0 Hz; H-6ꢀ); 8.67 (d, 1H, J = 1.0, Hz; H-7). 13C NMR 125 MHz
(CDCl3) ı (ppm): 14.3 (C-10); 16.6 (C-11); 61.9 (C-9); 118.8 (C-7);
120.6 (C-3ꢀ); 120.6 (C-3); 128.5 (C-5ꢀ); 130.5 (C-4ꢀ); 145.7 (C-4);
135.2 (C-3a); 140.7 (C-2ꢀ); 134.2 (C-3aꢀ); 146.3 (C-6ꢀ); 146.3 (C-6);
147.8 (C-2); 149.2 (C-7a); 160.1 (C-7aꢀ); 165.2 (C-8).
8-Benzyl-8H-6-carboethoxy-2-carbomethoxy-4-(3-formyl-
thiofen-2-yl)-5-aza-thieno[2,3-b]pirrolo[3,2-c]pyridine (27). m.p.
246–248 ◦C, yield 75%. C26H20O5N2S2; MW: 504.57; C, 61.89; H,
4.00; N, 5.55; O, 15.85; S, 12.71. MS (E.I.) m/z (%): 504 (M+; 22).
1H NMR 300 MHz (CDCl3) ı (ppm): 1.48 (t, 3H, J = 7.0 Hz; H-11);
3.86 (s, 3H, H-13); 4.53 (q, 2H, J = 7.0 Hz; H-10); 5.53 (s, 2H; H-14);
7.14–7.34 (m, 5H; H16-H20); 7.73 (d, 1H, J = 5.3 Hz; H-4ꢀ); 7.53 (dd,
1H, J = 5.0, 0.75 Hz; H-5ꢀ); 7.83 (s, 1H; H-3); 8.41 (s, 1H, H-7); 9.94
(br s, 1H; H-6ꢀ).
5-Methyl-3-carboethoxy-1-quinol-4-yl-5H-pyrido[4,3-b]indole
(28). m.p. 274–276 ◦C, yield 91%. C24H19O2N3; MW: 381.42; C,
75.57; H, 5.02; N, 11.02; O, 8.39. MS (E.I.) m/z (%): 381 (M+; 75).
1H NMR 300 MHz (CDCl3) ı (ppm): 1.44 (t, 3H, J = 7.2 Hz, H-12);
4.0 (s, 3H, H-13); 4.52 (q, 2H, J = 7.2 Hz; H-11); 6.73 (dd, 1H, J = 1.2,
8.1, Hz; H-9); 6.93 (m, 1H, H-8); 7.34 (ddd, 1H, J = 1.2, 8.1 Hz; H-6ꢀ);
7.47 (m, 2H, H-6, H-7); 7.53 (dd, 1H, J = 8.1, 0.9 Hz; H-5ꢀ); 7.66 (d,
1H, J = 4.5 Hz; H-3ꢀ); 7.71 (ddd, 1H, J = 8.4, 1.5 Hz; H-7ꢀ); 8.26 (d, 1H,
J = 8.1 Hz; H-8ꢀ); 8.38 (s, 1H, H-4); 9.1 (d, 1H, J = 4.5 Hz; H-2ꢀ). 13C
NMR 75 MHz (CDCl3) ı (ppm): 14.3 (C-12); 29.5 (C-13); 61.9 (C-11);
106.1 (C-4); 109.2 (C-6); 120.0 (C-9a); 120.2 (C-9b); 121.0 (C-8);
121.5 (C-3ꢀ); 122.6 (C-9); 125.8 (C-5ꢀ); 126.5 (C-4a); 126.6 (C-5aꢀ);
127.1 (C-6ꢀ); 127.9 (C-7); 129.2 (C-8ꢀ); 129.9 (C-7ꢀ); 142.1 (C-4a);
143.6 (C-3); 145.4 (C-5a); 146.4 (C-4ꢀ); 148.0 (C-8aꢀ); 149.7 (C-2ꢀ),
150.2 (C-1); 166.0 (C-10).
5-Methyl-3-carboethoxy-1-quinol-2-yl-5H-pyrido[4,3-b]indole
(29). m.p. 179–180 ◦C, yield 83%. C24H19O2N3; MW: 381.42; C,
75.57; H, 5.02; N, 11.02; O, 8.39. MS (E.I.) m/z (%): 381 (M+; 85);
309 (100). 1H NMR 300 MHz (CDCl3) ı (ppm): 1.44 (t, 3H, J = 7.5 Hz,
H-12); 3.99 (s, 3H, H-13); 4.52 (q, 2H, J = 7.5 Hz; H-11); 7.20 (ddd,
J = 1.2, 7.2, 7.2 Hz; H-8); 7.50 (d, 1H, J = 7.2 Hz; H-6); 7.65 (ddd, 1H,
J = 1.2, 6.9, 6.9 Hz; H-7); 7.70 (ddd, 1H, J = 6.9, 1.5 Hz; H-6ꢀ); 7.84
(ddd, 1H, J = 1.5, 6.9 Hz; H-7ꢀ); 7.98 (dd, 1H, J = 8.4, 1.5 Hz; H-5ꢀ);
8.40 (s, 1H, H-4); 8.36 (d, 1H J = 8.4 Hz; H-8ꢀ); 8.39 (dd, 1H, J = 8.1,
1.2 Hz; H-9); 8.40 (d, 1H, J = 4.5 Hz; H-3ꢀ); 8.47 (d, 1H, J = 4.5 Hz;
5-Methyl-3-carboethoxy-1-(2-formylphenyl)-carboline (22). m.p.
199–201 ◦C, yield 84%. C22H18 O3N2; MW: 358.38; C, 73.73; H, 5.06;
N, 7.82; O, 13.39. MS (E.I.). m/z (%): 358 (M+; 3). 1H NMR 300 MHz
(CDCl3) ı (ppm): 1.47 (t, 3H, J = 7.0 Hz, H-12); 4.01 (s, 3H, H-13); 4.54
(q, 2H, J = 7.0 Hz; H-11); 7.01 (m, 2H; H-8, H-9); 7.49 (m, 2H; H-6, H-
7); 7.67 (m, 3H, H-4ꢀ, H-5ꢀ, H-6ꢀ); 8.18 (d, 1H, J = 8.0 Hz; H-3ꢀ); 8.33 (s,
1H, H-4); 9.79 (s, 1H, H-7ꢀ). 13C NMR 75 MHz (CDCl3) ı (ppm): 14.4
(C-12); 29.5 (C-13); 62.0 (C-11); 105.9 (C-4); 109.3 (C-6); 120.6 (C-
9b); 121.1 (C-8); 122.3 (C-9); 128.0 (C-7); 128.1 (C6ꢀ); 129.4 (C-4ꢀ);
130.6 (C-3ꢀ); 133.9 (C-5ꢀ); 134.5 (C-9a); 142.2 (C-4a); 143.2 (C-3);
145.3 (C-5a); 150.9 (C-1); 166.0 (C-10); 191.3 (C-7ꢀ).
1-(2-Formyl-thiophen-3-yl)-3-carboethoxy-5-methyl-5H-
pyrido[4,3-b]indole (23). m.p. 212–213 ◦C, yield 92%. C20H16O3N2S;
MW: 364.41; C, 65.92; H, 4.43, N, 7.69, O, 13.17, S, 8.80. MS (E.I.).
m/z (%): 364 (M+; 12). NMR 1H 500 MHz (CDCl3/C6D6 1:1) ı (ppm):
1.20 (t, 3H, J = 7.0 Hz; H-12); 3.14 (s, 3H, H-13); 4.36 (q, 2H, J = 7.0 Hz;
H-11); 7.01 (ddd, 1H; J = 7.5, 8.0, 1.0 Hz; H-8); 7.69 (ddd, J = 1.0, 1.5,
8.0 H-9), 7.28 (d, J = 5.5 H-4ꢀ); 7.24 (d, 1H, J = 5.5 Hz; H-5ꢀ); 8.26 (s,
1H, H-4); 10.1 (s, 1H, H-6ꢀ); 7.33 (ddd J = 1.0, 7,5, 8.0; H-7); 7.08
(brd, J = 8, H-6). 13C NMR 75 MHz (CDCl3) ı (ppm): 14.4 (C-12); 29.6
(C-13); 62.1 (C-11); 106.1 (C-4); 109.5 (C-6); 120.5 (C-9b); 121.4
(C-8); 122.5 (C-9); 128.3 (C-7); 130.7 (C-4ꢀ); 133.9 (C-5ꢀ); 134.0
(C-9a); 141.6 (C-3); 142.2 (C-4a); 143.5 (C-2ꢀ); 144.2 (C-3ꢀ); 145.7
(C-5a); 146.8 (C-1); 165.9 (C-10); 184.1 (C-6ꢀ).
1-(3-Formyl-thiophen-2-yl)-3-carboethoxy-5-methyl-5H-
pyrido[4,3-b]indole (24). m.p. 212–213 ◦C, yield 92%. C20H16O3N2S;
MW: 364.41; C, 65.92; H, 4.43; N, 7.69; O, 13.17; S, 8.80; MS (E.I.) m/z

D. Corona et al. / Spectrochimica Acta Part A 74 (2009) 515–525
525
H-4ꢀ). 13C NMR 75 MHz (CDCl3) ı (ppm): 14.4 (C-12); 29.5 (C-13);
61.9 (C-11); 106.2 (C-4); 108.8 (C-6); 119.9 (C-9b); 128.2 (C9a);
121.0 (C4ꢀa); 120.9 (C-8); 142.7 (C-4a); 122.4 (C-9); 125.6 (C-3ꢀ);
127.2 (C-6ꢀ); 127.8 (C-5ꢀ); 128.1 (C-7); 129.2 (C-8ꢀ); 130.0 (C-7ꢀ);
137.3 (C-4ꢀ); 142.7 (C-4a); 146.9 (C8aꢀ); 146.6 (C-5a); 146.9 (C-3);
152.0 (C-1); 157.7 (C-2ꢀ); 166.1 (C-10).*Spectra recorded after one
week into CDCl3 solution.
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(1994) 2740.
3-Chloro-5-(quinolin-2-yl)-7-methoxycarbonyl-thieno[2,3-b:4,5-
cꢀ]dipyridine (30). m.p. 295–297 ◦C, yield 84%. C21H12O2N3SCl;
MW: 405.85; C, 62.15; H, 2.98; Cl; 8.74; N, 10.35; O, 7.88; S, 7.90.
MS (E.I.) m/z (%): 405.0 (M+, 60); 407 (M++2; 40). 1H NMR 200 MHz
(CDCl3) ı (ppm): 4.08 (s, 3H; H-12); 7.71 (ddd, 1H, J = 1.2, 7.6 Hz;
H-6ꢀ); 7.86 (ddd, 1H, J = 1.4, 7.6 Hz: H-7ꢀ); 8.0 (dd, 1H, J = 1.4, 7.5 Hz;
H-5ꢀ); 8.13 (d, 1H, J = 7.6 Hz; H-8ꢀ); 8.28 (d, 1H, J = 8.6; H-3ꢀ); 8.48 (d,
1H, J = 2.3 Hz; H-4); 8.51 (d, 1H, J = 8.6; H-4ꢀ); 8.64 (d, 1H, J = 2.3 Hz;
H-2); 8.76 (s, 1H; H-8).
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Chabard, D. Dauphin, J. Org. Chem. 59 (1994) 6413.
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1035.
7-Methyl-4-quinolin-2-yl-11-tia-3,10–diaza-benzo[b]fluorene 2-
carboxyic acid ethyl ester (31). m.p. 220–222 ◦C, yield 62%.
C22H19O2N3S; MW: 449.11; C, 72.14; H, 4.26; N, 9.35; O, 7.12; S, 7.13.
MS (E.I.) m/z (%): 449 (M+90). 1H NMR 500 MHz (CDCl3) ı (ppm):
1.50 (t, 3H; J = 7.2 Hz; H-14); 2.56 (s, 3H; J = 1.0 Hz; H-15); 4.58 (q, 2H;
J = 7.2 Hz; H-13); 7.55 (s, 1H; H-6); 7.81 (ddd, 1H, J = 8.0, 1.8 Hz; H-6ꢀ);
7.95 (ddd, 1H, J = 1.8, 8.0 Hz; H-7ꢀ); 8.10 (dd, 2H, J = 8.0, 1.8 Hz, H-5ꢀ);
8.28 (dd, 1H; J = 8.0, 1.8 Hz; H-8ꢀ); 8.41 (d. 1H; J = 8.5 Hz; H-3ꢀ); 8.80
(s, 1H; H-4); 8.49 (d, 1H, J = 8.5 Hz; H-9); 8.63 (d, 1H; J = 8.5 Hz, H-
4ꢀ); 7.90 (d, 1H; J = 8.5 Hz; H-8) *Spectrum recorded after one week
into CDCl3 solution.
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Acknowledgements
We would thank SNI-CONACyT and UAEM (2005) respectively
for financial support of this work. Our special thanks go to M.Sc.
Hector Rios, Ph.D. Ma Isabel Chavez, Ph.D. B. Quiroz, Ing. L. Velasco
and Chemist R. Patin˜o for technical support.
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