A convenient method for preparation of 2-amino-4,6-diphenylnicotinonitrile using HBF4 as an efficient catalyst via an anomeric based oxidation: A joint experimental and theoretical study

Article abstract of DOI:10.1016/j.molstruc.2017.02.083

Experimental and computational studies in the synthesis of 2-amino-4,6-diphenylnicotinonitrile using HBF₄ as an oxidizing promoter catalyst under mild and solvent free conditions were carried out. The suggested anomeric based oxidation (ABO) me

Full text of DOI:10.1016/j.molstruc.2017.02.083

Accepted Manuscript
A convenient method for preparation of 2-amino-4,6-diphenylnicotinonitrile using
HBF as an efficient catalyst via an anomeric based oxidation: A joint experimental
4
and theoretical study
Mohammad Ali Zolfigol, Mahya Kiafar, Meysam Yarie, Avat(Arman) Taherpour,
Thomas Fellowes, Amber Nicole Hancok, Ako Yari
PII:
S0022-2860(17)30242-9
10.1016/j.molstruc.2017.02.083
MOLSTR 23477
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 October 2016
Revised Date: 5 January 2017
Accepted Date: 22 February 2017
Please cite this article as: M.A. Zolfigol, M. Kiafar, M. Yarie, A.(A.) Taherpour, T. Fellowes, A. Nicole
Hancok, A. Yari, A convenient method for preparation of 2-amino-4,6-diphenylnicotinonitrile using HBF
4
as an efficient catalyst via an anomeric based oxidation: A joint experimental and theoretical study,
Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.02.083.
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ACCEPTED MANUSCRIPT
A convenient method for preparation of 2-amino-4,6-diphenylnicotinonitrile
using HBF as an efficient catalyst via an anomeric based oxidation: A joint
4
experimental and theoretical study
*
a
a
a
*b,c
Mohammad Ali Zolfigol, Mahya Kiafar, Meysam Yarie, Avat(Arman) Taherpour ,Thomas
d
e
b
Fellowes , Amber Nicole Hancok , Ako Yari
H+
NH OAc
4
O
H
NC
NC
H N
-
H2
HBF4
H
O
N
H N
N
2
2
NC
CN
H
BF4-
2
4
-Amino-4,6-diphenylnicotinonitriles were synthesized by using HBF as oxidizing promoter
catalyst. The suggested anomeric based oxidation mechanism was supported by experimental
and theoretical evidences.
a
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, P.O. Box:
6
517838683, Iran. E-mail: zolfi@basu.ac.ir, & mzolfigol@yahoo.com, Fax: +98 8138257407; Tel: +98 8138282807
b
Department of Organic Chemistry, Razi University, Kermanshah, P.O. Box: 67149-67346, Iran.
c
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. E-Mail:
avatarman.taherpour@gmail.com
d
School of Chemistry, University of Melbourne, Parkville Victoria 3010, Australia.
School of Chemistry and Bio21 Institute, The University of Melbourne, Victoria 3052, Australia.
e

ACCEPTED MANUSCRIPT
A convenient method for preparation of 2-amino-4,6-diphenylnicotinonitrile
using HBF as an efficient catalyst via an anomeric based oxidation: A joint
4
experimental and theoretical study
*
a
a
a
*b,c
Mohammad Ali Zolfigol, Mahya Kiafar, Meysam Yarie, Avat(Arman) Taherpour ,Thomas
d
e
b
Fellowes , Amber Nicole Hancok , Ako Yari
a
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, P.O. Box:
6
517838683, Iran. E-mail: zolfi@basu.ac.ir, & mzolfigol@yahoo.com, Fax: +98 8138257407; Tel: +98 8138282807
b
Department of Organic Chemistry, Razi University, Kermanshah, P.O. Box: 67149-67346, Iran.
c
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. E-Mail:
avatarman.taherpour@gmail.com
d
School of Chemistry, University of Melbourne, Parkville Victoria 3010, Australia.
School of Chemistry and Bio21 Institute, The University of Melbourne, Victoria 3052, Australia.
e
Abstract
Experimental and computational studies in the synthesis of 2-amino-4,6-diphenylnicotinonitrile
using HBF as an oxidizing promoter catalyst under mild and solvent free conditions were
4
carried out. The suggested anomeric based oxidation (ABO) mechanism is supported by
experimental and theoretical evidence. The theoretical study shows that the intermediate isomers
with 5R- and 5S- chiral positions have suitable structures for the aromatization through an
anomeric based oxidation in the final step of the mechanistic pathway.
Keywords: HBF , 2-amino-4,6-diphenylnicotinonitrile, anomeric based oxidation, experimental
4
and theoretical study , solvent free conditions.
Introduction
After the discovery of the anomeric effect (The Edward-Lemieux effect) by J.T. Edward in 1955,
it attracted the attention of a generation of chemists, leading to a great deal of research in this
area [1]. It was found that despite unfavorable steric and solvation effects, the axial conformer of
2
-methoxy-tetrahydro-2H-pyran is more stable than the equatorial conformer. An explanation for
this unusual preference is based on stereoelectronic effects involving the oxygen’s lone pair [2].
The obtained data from the study on the anomerization equilibria of the fully acetylated
derivatives of the aldohexopyranoses confirmed the stereoelectronic effect for these equilibria
[3].
The anomeric effect is a stabilizing phenomenon and refers to the tendency of an electronegative
substituent in the structure of the pyranoid ring at C1 position to prefer the axial rather than
equatorial orientation [1]. Since the original definition, it has become clear that the anomeric
effect is not restricted to the aforementioned interpretation in the context of carbohydrate
chemistry and could be an explanation for the preference of the gauche- over the anti-orientation
in Newman projections of other compounds [1]. Anomeric interactions can also explain the
stereochemical selectivity in radical reactions [4] and conformational preferences in N-alkoxy

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cyclic hydroxylamines, bisoxo-substituted amines, ONO systems and N-alkoxy-N-chloroureas
[5-8].
A striking example of the anomeric effect can be observed in the activation and fixation of some
small molecules like H , CO, NO, N O and CO at N-heterocyclic carbene centers [9]. The
2
2
2
interaction of lone-pair electrons of the nitrogen atoms with the carbene center, stabilize this
intermediate in the activation and the fixation process.
In some cases, like the Cannizzaro reaction and tricyclic orthoamide, the anomeric effect can
cause the generation of hydrogen gas through a hydride transfer. These examples show that the
anomeric effect can contribute to the mechanistic aspects of certain reactions [10,11]. In light of
this, we have recently introduced a new term, “anomeric based oxidation (ABO)” for the
mechanistic interpretation of the aromatization of some nitrogen-containing heterocyclic
compounds. As depicted in Scheme 1 and 2, in the final steps of the presented mechanisms for
the synthesis of the 1,4-dihydropyrano-[2,3-c]-pyrazole derivatives and 2,4,6-triarylpyridines,
the lone pair of the nitrogen atom can promote the hydride transfer leading to the liberation of H2
from substrate molecules [12,13].
Scheme 1. The anomeric based oxidation effect in the aromatization of 1,4-dihydropyrano-[2,3-c]-pyrazole
1
2
derivatives
Scheme 2. The anomeric based oxidation effect in the aromatization of 1,4-dihydropyrano-[2,3-c]-pyrazole
1
3
derivatives
In order to develop our concept of "anomeric based oxidation" (ABO) in the aromatization of
heterocyclic molecules, we have looked for suitable compounds that possess the necessary
structural properties. In addition to the above compounds (Schemes 1 and 2), we found that the
2
-amino-4,6-diphenylnicotinonitrile 1 is a suitable target molecule for this purpose. The 2-
amino-4,6-diphenylnicotinonitrile derivatives contain pyridine ring systems which possess wide
chemotherapeutic and pharmaceutical applications such as IKK-b inhibitors [14], A2Aadenosine
receptor antagonists [15], and potent inhibitors of HIV-1 integrase [16]. As a consequence of the
biological and therapeutic significance of these heterocyclic molecules, a number of methods
have been developed for their preparation [17-25].

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Results and Discussion
Recently, we have introduced a new concept entitled "Anomeric Based Oxidation" (ABO).
1
2,13
In
an ABO reaction, the major driving force is aromatization supported by stereoelectronic effects.
In order to demonstrate this, we synthesized 2-amino-4,6-diphenylnicotinonitrile 1, via one-pot
four component reaction of benzaldehyde, acetophenone, malononitrile and ammonium acetate
using HBF as an oxidizing promoter catalyst under mild and solvent free conditions (Scheme 3).
4
To verify that ABO was occurring in the synthesis of 2-amino-4,6-diphenylnicotinonitrile 1, the
reaction was carried out under N atmosphere. The obtained results show no change in the yields
2
and the reaction times. The related intermediate 7 has two nitrogen atoms that can contribute to
the resonance through their unshared electrons and interact with the anti-bonding orbital of C-H
(σ*C-H orbital). The delocalization of the electrons through the ring leads to the weakening of the
C-H bond, promoting hydride transfer and the generation of molecular hydrogen (H2).
Scheme 3. The preparation of the 2-amino-4,6-diphenylnicotinonitrile in the presence of catalytic amount of HBF4
as oxidizing promoter catalyst
-
+
4 4 2 3 2
Modeling of the reactions of HBF (as its hydrated form [BF ] [H O ] ) as an oxidizing catalyst
with the R- and S- isomers of intermediate 7 was performed using the Spartan ‘10 package [26].
The calculations on the structures of the R- and S- isomers of intermediate 7, the different
positions of the transition states (TS) of the reactions, intermediates and the product were
undertaken using a DFT-B3LYP/6-31G* method [26]. The transition states were obtained by
reaction coordinate methods. The HF/6-31G* was applied for initial optimization of the precisely
transition states and then DFT-B3LYP/6-31G** performed for final optimization of the
transition states as well as the reactants and the intermediates. The vibration frequencies were
checked for optimized TS structures. The supplementary data (S1), shows selected structural data
(
bond length (Å), bond angle (°) and torsional angle (°)) of the precursors (intermediate 7; R- and
-
+
S- isomers), the transition states with different orientations of the [BF ] [H O ] as oxidizing
4
2
3
2
agent with respect to the R- and S- isomers of the precursors, intermediates and the product. In
-
+
Figure 1 we show the optimized structures of [BF ] [H O ] as an oxidizing agent.
4
2
3
2

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-
+
Figure 1: Structure of the oxidizing promoter catalyst: [BF ] [H O ]
2
4
2
3
Figure 2 shows the optimized structures of the "R" and "S" enantiomers of intermediate 7. Table
shows the calculated Mulliken bond orders (MBO) in intermediate 7. The data show that the
1
MBO of C5-H6 bond for the isomers with 5R- and 5S- chiral positions of intermediate 7 are 0.93
and 0.91, respectively. It seems that the S-isomer is more likely than the R-isomer to take part in
the ABO reaction in the first step of the reaction, as the MBO is smaller by 0.02. The DFT
calculations show that in the R- and S- isomers of intermediate 7 the MBO of C5-C7 due to the
anomeric effect were calculated at 0.95 for both isomers. It seems that the N2-C3-C4-C5-H6
pathway for electron transfer facilitates electron ring currents and satisfies the Hückel
requirement for aromaticity in the heterocyclic ring. There appears to be an anomeric effect via
outside electron transfer (N10-C9-C8-C5-H6), but there are no electron ring currents or sextet for
the heterocyclic ring in comparison to the inside electron transfer. The MBO of C9-N10 was
calculated to be 1.03, which is much smaller than 2.00 as the simple B.O. of a double bond. The
2
DFT calculation has shown pyramidality for the NH group in intermediate 7. The lower MBO
for C8-C9 (1.57) than C3-C4 (1.77) demonstrated another pathway (N2-C9-C8-C5-H6) for
electron transfer. In this pathway, the MBO of N2-C9 and C9-C8 were calculated to be 0.99 and
1
.57, respectively. This pathway is not only better suited for electron ring currents and the
aromatic electronic sextet for the heterocyclic ring, but also allows the NH and NH groups to
2
better participate in the anomeric effect on C5-H6 bond. The inside (N2-C3-C4-C5-H6) pathway
of electron transfer (red pathway in figure of Table 1) includes: n →π*
and πC3-C4→σ*C5-C6.
N2
C3-C4
The other inside electron transfer pathway (N2-C9-C8-C5-H6) includes: n →π*
and πC9-
N2
C9-C8
C8→σ*C5-C6 electron conjugations. The outside (N10-C9-C8-C5-H6) pathway of electron
conjugation (blue pathway in figure of Table 1) includes: nN10→π*C9-C8 and πC9-C8→σ*C5-C6
.

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Figure 2: The structures of the "5R" and "5S" epimers of intermediate 7. The energy level differences of the epimers
-
1
(
2.9 kcal mol ) and the barrier energy of inversion on N2-atom for the interconversion of the two isomers (about 1
-1
kcal mol ) have obtained very low. So, the energies have approximately considered with equal energy levels.
Table 1: The bond orders of the resonance process in intermediate 7 for the anomeric effect on C5-H6 bond in the
different pathways.
6
H
7
5
NC
4
3
8
.
.
..
N
9
2
H N
1
0
2
1
H
Structures
and
pathways
Bond Orders
C9-N10
C8-C9
C5-C8
C5-C7
C5-H6
C4-C5
C3-C4
N2-C3
N2-C9
H1-N2
R-Isomer
S-Isomer
R-NH
1.04
1.04
1.03
1.03
1.03
1.04
1.57
1.56
1.55
1.55
1.55
1.56
0.97
0.98
0.97
0.98
0.97
0.98
0.95
0.95
0.94
0.94
0.94
0.95
0.91
0.93
0.93
1.10
1.10
1.10
0.97
0.97
0.97
0.97
0.97
0.97
1.77
1.77
1.76
1.77
1.77
1.77
0.91
0.97
0.97
0.97
0.97
0.97
0.99
0.99
0.99
0.99
0.99
0.99
0.87
0.88
0.89
0.89
0.89
0.88
S-NH
R-NH2
S-NH2
The isomers with 5R- and 5S- chiral positions have trans- and cis- structures respect to N2-atom,
-1
respectively. The energy level differences of the epimers (2.9 kcal mol ) and the barrier energy
-1
of inversion on N2-atom for the interconversion of the two isomers (about 1 kcal mol ) have
obtained very low. So, the energies have approximately considered with equal energy levels.
This point could be important when the isomers react with the structure of HBF (as its hydrated
4
-
+
4 2 3 2
form [BF ] [H O ] ). The interactions like electrostatic attractions and H-bonding between the

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-
+
isomer structures and specially the endo orientation (A) of [BF
condition for different rate of the isomer reactions. The calculated structures of the transition
states ([TS] and [TS] ) for the first step of the ABO reaction in the R- and S- isomers of
intermediate 7 with [BF ] [H O ] are presented in Figure 4. In the reactions, the isomers with
4 2 3 2
] [H O ] has made the
R
S
-
+
4
2
3
2
-
+
5
R- and 5S- chiral positions of intermediate 7 with [BF ] [H O ] the bond lengths of C5-H6
4 2 3 2
and H6…H8 in the more stable transition state (TS(A); the isomers with 5R chiral positions)
were obtained as 1.889 and 0.784Å, respectively. These bond lengths in the less stable transition
state (TS(B); the isomers with 5S chiral positions) were obtained as: 1.611 and 0.849Å,
respectively. See supplementary data (S1), (S2) and Figure 3. The DFT calculations shows that
the endo-orientation is more stable than the exo-orientation for [TS] and [TS] . The hydrogen
R
S
bonds and dipole-dipole interactions between the reactants in the endo-orientation is stronger
+
than in the exo-orientation. The supplementary data (S3) shows the structures of the H
-
+
attractions step from intermediate 8 by [BF ] [H O ] .
4
2
3
2
Figure 3: Two structures of the transition states ([TS] of endo orientation (A) and of exo orientation (B)) for the first
-
+
step of the intermediate 7 oxidation reactions with [BF ] [H O ] . The structure (A) is more stable than (B).
4
2
3
2
-1
The reaction diagram and free energies (in kcal mol ) of the anomeric based oxidation of
-
+
intermediate 7 by [BF ] [H O ] is shown in Figure 6. The DFT results demonstrated that the
4
2
3
2
#
-
+
∆
G of R- and S- isomers of intermediate 7 with [BF ] [H O ] in the endo-orientation are 31.7
and 43.8 kcal mol , respectively. The DFT calculations show that the endo-orientation is more
stable than exo-orientation for [TS] and [TS] . The results have shown that the ∆G of the
isomers with 5R- and 5S- chiral positions of intermediate 7 with [BF ] [H O ] in the exo-
orientation are 39.1 and 45.1 kcal mol , respectively. The differences between the free activation
energies (∆∆G ) for the endo- and exo-orientations reactions were obtained 12.4 and 6.8 kcal
mol , respectively. See Figure 4.
4 2 3 2
-1
#
R
S
-
+
4
2
3
2
-
1
#
-1
-
+
#
The oxidation reactions by [BF ] [H O ] for the exo-orientation (with ∆G =39.1 (5R) and 45.1
(
4
2
3
2
-1
5S) kcal mol ) has the highest reaction rate among the different calculated situations. As
mentioned before, the calculated Mulliken bond order (MBO) of C5-H6 for 5R-isomer is 0.02
less that 5S-isomer and it could be the reason of the higher reactivity of the 5R-isomer compared

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to the 5S-isomer on the basis of the anomeric effect in intermediate 7 structure. The DFT
calculated free energies of the reactant and the product (∆GTotal) of the oxidation reactions for the
isomers with 5R- and 5S- chiral positions of intermediate 7 were calculated to be -20.6 and -20.3
-1
kcal mol , respectively. See the free energies table of Figure 4. The DFT-B3LYP/6-31G* show
that the 5S-isomer is more stable than 5R-isomer of intermediate 7, but the reaction of the R-
isomer is faster because of the lower Mulliken bond order of C5-H6 due to the anomeric effect.
#
∆
G
∆G
B
Energy Data
#
-
1
∆∆G
(
kcal mol )
R-7
S-7
R-7
S-7
-
+
[
BF
4
]
2
[H
3
O ]
2
(Out)
39.1
45.1
43.8
6.8
-18.7
-18.7
-18.4
-18.4
-
+
[
BF
4
]
2
[H
3
O ]
2
(In)
31.7*
12.4

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-
Figure 4: The reaction diagram of intermediate 7 oxidation reaction on the basis of anomeric effect by [BF
4
+
]2
[H O ] agent. For exo (A) and endo (B) orientation. The calculated values of ∆G
(S and R isomers) are: -20.6
Total
3
2
-1
and -20.3 kcal mol , respectively. *The highest rate of the oxidation reaction.
-
+
The suggested mechanistic pathway, as described in Scheme 4, shows that [BF ] [H O ] can
4
2
3
2
act as oxidizing promoter catalyst and activate acetophenone and benzaldehyde as electrophilic
species to yield the related intermediate 2 and 3, respectively by the reaction with in-situ
generated NH (from ammonium acetate) and malononitrile. The reaction between these two
3
intermediates afford intermediate 4 that can convert to the intermediate 7 through a sequence of
tautomerization, cyclization and again tautomerization. As depicted in Scheme 4, the
intermediate 7 has an appropriate structure with two active nitrogen atoms that can release their
unpaired electrons in resonance and interact with the anti-bonding orbital of C-H (σ*C-H orbital).
Finally, the intermediate 7 undergoes anomeric based oxidation to yields the desired aromatized
product 1.
NC
NC
NC
CN
CN
NC
NC
H
HN
N
H N
2
O
H N
2
NH
NH
NC
O
NH
H
H
NC
H
N
N
N
NC
H
NC
H
H N
NH2
H N
2
2
H
NC
NH
NH2
NH
NH2
N
NC
NC
NC
H
H N
N
2
NH2
Scheme 4. A plausible mechanistic pathway for the synthesis of 2-amino-4,6 diphenylnicotinonitrile in the presence
-
+
[
4 2 3 2
BF ] [H O ] as oxidizing promoter catalyst

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Conclusion
In summary, the synthesis of 2-amino-4,6-diphenylnicotinonitrile 1 using HBF as oxidizing
4
promoter catalyst under mild and solvent free conditions was investigated. Also, in addition to
the experimental efforts, the theoretical study has demonstrated that the isomers with 5R- and
5
S- chiral positions of intermediate have suitable structures for the aromatization through an
anomeric based oxidation (ABO) in the final step of the mechanistic pathway. The theoretical
aspects of the preparation of 2-amino-4,6-diphenylnicotinonitrile using HBF as an efficient
4
catalyst via the anomeric based oxidation (ABO) mechanism have investigated. We think that the
proposed mechanism has potential for entering into the graduate text book in the future.
Experimental
General
All chemicals were purchased from Merck chemical company. The structural confirmation of
known products was done by comparison of their physical properties and spectral data with their
reported authentic samples in the literature. The progress of the reaction and the purity of the
1
product were monitored using TLC using silica gel SIL G/UV 254 plates. The H NMR (400
1
3
MHz) and C NMR (100 MHz) spectra were recorded on a Bruker spectrometer in DMSOd6,
using TMS as internal standard and the chemical shifts are expressed in δ ppm. Melting points
were determined by Buchi B-545 apparatus in open capillary tubes and are uncorrected. An
4
aqueous solution of HBF (40% W/W) was used.
General procedure for the synthesis of 2-amino-4,6-diphenylnicotinonitrile
To a round bottom flask containing a mixture of benzaldehyde (1 mmol, 0.106 g), acetophenone
(
1 mmol, 0.120 g), malononitrile (1 mmol, 0.066 g), and ammonium acetate (3 mmol, 0.23 g), a
-
+
4 2 3 2 4
catalytic amount of [BF ] [H O ] (0.46 mmol of HBF , 0.1 g of solution) as oxidizing promoter
o
catalyst was added. Then, the resulting mixture was stirred under solvent free condition at 90 C
for appropriate times under air or nitrogen atmosphere. The progress of the reaction was
monitored using TLC with a mixture of n-hexane and ethyl acetate as the eluent. Upon
completion of the reaction, the mixture was cooled to room temperature. 5 mL of distillated
water was added to the reaction mixture and decanted after few minutes in order to remove
excess ammonium acetate. The desired product was obtained by recrystallization from ethanol
with good yield.
Spectral data
2
-amino-4,6-diphenylnicotinonitrile (1)
o
29
Melting point: 187-188 C, [186-187]
-1
FT-IR (KBr): υ(cm ) = 3466, 3305, 3180, 2206, 1638, 1573, 1423, 1370, 1259, 755, 698.
1
H NMR (DMSO-d
6 2
, 400 MHz): δ (ppm) = 7.06 (s, 2H,NH ), 7.29 (s, 1H, aromatic), 7.52 (m,
8
H, aromatic), 8.14 ( s, 2H, aromatic).
1
3
6
C NMR (DMSO-d , 100 MHz): δ (ppm) = 86.6, 109.2, 117.0, 127.2, 128.3, 128.6, 128.7,
1
29.6, 130.1, 137.0, 137.5, 154.9, 128.6, 160.9.

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Acknowledgements
We thank Bu-Ali Sina University and Iran National Science Foundation (INSF) for financial
support (The Grant Number: 95831207) to our research group.
References
[
[
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ACCEPTED MANUSCRIPT
•
The synthesis of 2-amino-4,6-diphenylnicotinonitrile using HBF as oxidizing
4
promoter catalyst under mild and solvent free conditions was investigated.
•
•
HBF is a commercially available low cost reagent.
4
Our recently new introduced concept entitled "anomeric based oxidation" (ABO)
was developed for the final step of the described synthesis and it was also
approved using theoretical studies.
•
We think that the proposed mechanism have potential for entering into the
graduate text book in the future.