Unexpected cleavage of the Cpy-Cpybond in the reaction of 2,2′-bipyridine N,N′-diimines with acetylenes

Article abstract of DOI:10.1016/j.tetlet.2014.08.015

An unusual cleavage of the C_py-C_pybond in the reaction of 2,2′-bipyridine N,N′-diimine and its C-methyl substituted derivatives with acetylenes is described. The effect of the solvent on the yield of 7,7′-bipyrazolo[1,5-a]pyridine-2,2′,3,3′-tetracarboxylates and the products of cleavage of the C_py-C_pybond has been studied. The mechanism of the cleavage reaction is discussed on the basis of DFT calculations.

Full text of DOI:10.1016/j.tetlet.2014.08.015

Tetrahedron Letters 55 (2014) 5377–5380
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected cleavage of the Cpy–Cpy bond in the reaction
of 2,20-bipyridine N,N0-diimines with acetylenes
Vyacheslav I. Supranovich a,b, Gennady I. Borodkin a,b, , Aleksey Yu. Vorob’ev a,b, Vyacheslav G. Shubin a
⇑
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Acad. Lavrentiev Ave. 9, 630090, Russia
b Novosibirsk State University, Pirogov St. 2, 630090, Russia
a r t i c l e i n f o
a b s t r a c t
An unusual cleavage of the Cpy–Cpy bond in the reaction of 2,20-bipyridine N,N0-diimine and its C-methyl
substituted derivatives with acetylenes is described. The effect of the solvent on the yield of 7,70-bipyraz-
olo[1,5-a]pyridine-2,20,3,30-tetracarboxylates and the products of cleavage of the Cpy–Cpy bond has been
studied. The mechanism of the cleavage reaction is discussed on the basis of DFT calculations.
Ó 2014 Elsevier Ltd. All rights reserved.
Article history:
Received 30 May 2014
Revised 11 July 2014
Accepted 6 August 2014
Available online 13 August 2014
Keywords:
1,3-Dipolar cycloaddition
N-Amine salts
Pyrazolo[1,5-a]pyridines
DFT calculations
C
sp2–Csp2 bond cleavage
Pyrazolo[1,5-a]pyridine derivatives are an important class of
that this reaction was completely analogous with the behavior of
pyridine N-imines, though the yield of the adduct was very low
(8%). However, we have found that the 1,3-dipolar cycloaddition
is accompanied by cleavage of the Cpy–Cpy bond.
When salts 1a–c were treated with K2CO3 and reacted with
DMAD, products of both normal 1,3-dipolar cycloaddition (2a–c)
and unexpected C–C0-bipyridyl bond cleavage (3a–d) were formed
(Scheme 1).18
nitrogen-containing heterocycles with a wide range of biological
activities such as diuretic,1 antiplatelet,2 antiviral,3 and anti-ische-
mic.4 Substituted pyrazolo[1,5-a]pyridines act as ligands for a
number of receptors, for example, D3, D4, 5HT3, melatonin, and
adenosine A1.1,5–7 Pyrazolopyridines are found among numerous
systems that affect the central nervous system. The dopamine D3
receptor subtype is associated with several neuropathologies such
as schizophrenia, unipolar major depression, attention-deficit dis-
order, and Parkinson’s disease.7a
Insertion of the electron-donor methyl groups at the 4,40 and
5,50 positions of the pyridine rings had no significant effect on
the ratio of the expected cycloaddition products 2 and fragmenta-
tion products 3 (Table 1, in the Supplementary material). The ratio
of the products 2 and 3 depends on the solvent used. When toluene
was used as the solvent, bipyridyls 4a,b were also obtained. It was
also observed that when an argon atmosphere was used instead of
air, no appreciable effect on the yield of 2a and ratio of 2a/3a
occurred (Table 2, entries 3 and 4 in the Supplementary material).
Acetylenes other than DMAD behaved similarly under the same
reaction conditions (Scheme 2) (cf. Ref. 24).
Due to the importance of pyrazolo[1,5-a]pyridine derivatives as
substructures in drug design, many efforts have been devoted to
the development of efficient protocols for their preparation.3b,5–17
The most commonly used method for the synthesis of pyrazol-
o[1,5-a]pyridines is via 1,3-cycloaddition of pyridine N-imines
with alkyne or alkene derivatives.3b,5–17 Over the past four decades,
the 1,3-dipolar properties of N-imines have been investigated
intensively.7d,9,10,12–17
However, information on the behavior of N,N0-diimines in this
reaction is quite limited. Tamura et al. reported that N,N0-dia-
A theoretical study based on DFT analysis26 at the RI-B3LYP/
6-31G(d,p) level of theory with the SMD solvation model27 was
performed to examine the possible mechanism of the reaction,
and to find a reaction path that accounts for the abnormal behavior
of the N,N0-diimino-2,20-bipyridyl salts (Scheme 3 and Fig. 1 in the
Supplementary material).28
mino-4,40-dimethyl-2,20-bipyridinium
dimesitylenesulfonate
underwent reaction with dimethyl acetylenedicarboxylate
(DMAD) under basic conditions to give a 1:2 adduct.17 It was found
The complete process for the formation of the abnormal product
3a is highly exothermic. It is very probable that the rate-limiting
⇑
Corresponding author. Tel.: +7 (383) 330 7651; fax: +7 (383) 330 9752.
E-mail address: gibor@nioch.nsc.ru (G.I. Borodkin).
http://dx.doi.org/10.1016/j.tetlet.2014.08.015
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5378
V. I. Supranovich et al. / Tetrahedron Letters 55 (2014) 5377–5380
MeO2C
CO2Me
X
4
X
N
3
2
N
CO2Me
X
5
5
4
7
NH2
N
DMAD
K2CO3
3
6
6
X
X
N
+
+
1
N
NH2
CO2Me
N
5
2
1
6
N
N
N
N
4
1
-
X
X
2MesSO3
3 CO2Me
2
MeO2C
4a-c
2a-c
1a-c
X = H (a)
3a-d
X = H (a)
X = H (a)
X = H (a)
4-Me (b)
4,4'-Me2 (b)
5,5'-Me2 (c)
4,4'-Me2 (b)
5,5'-Me2 (c)
4,4'-Me2 (b)
5,5'-Me2 (c)
5-Me (c)
6-Me (d)
Scheme 1. The reaction of N,N0-diamino-2,20-bipyridinium salts 1a–c with dimethyl acetylenedicarboxylate (DMAD).
Ph
NH2
N
Ph
CO2Me
N
N
N
N
MeO2C
Ph
+
Ph
N
NH2
N
N
CO2Me
K2CO3, CH3CN
CO2Me
6 (18%)
-
2MesSO3
5 (26%)
1a
NH2
N
N
N
CO2Et
N
N
+
CO2Et
N
NH2
EtO2C
N
N
K2CO3, CH3CN
CO2Et
(59%)
-
8
2MesSO3
7
(26%)
1a
Scheme 2. The reaction of N,N0-diamino-2,20-bipirydinium dimesitylenesulfonate (0.1 mmol) with methyl 3-phenylpropiolate (0.24 mmol) or ethyl propiolate (0.24 mmol)
and K2CO3 (1.0 mmol).
NH
N
N
N
CO2Me
CO2Me
NH
N
CO2Me
CO2Me
TSA
(23.9 kcal/mol)
CO2Me
N
NH
CO2Me
NH
+
H2N
N
N
ΔE 0 kcal/mol
ΔE -29.8 kcal/mol
ΔE -43.4 kcal/mol
TSB
(7 kcal/mol)
N
N
N
N
CO2Me
+
CO2Me
+
NH2
N
N
-
NH
CO2Me
CO2Me
ΔE -62.2 kcal/mol
C
ΔE -82.6 kcal/mol
Scheme 3. A possible mechanism for the formation of dimethylpyrazolo[1,5-a]pyridine-2,3-di-carboxylate, energetic barriers (in parentheses) and relative
DE values.
step is the [3+2] cycloaddition and the reaction steps involving the
transfer of a proton have a very small energetic barrier. The TSA
transition state does not correspond to a bipolar complex. This is
proved by the distances between the reaction centers (r NCDMAD
2.10 Å, r C2CDMAD 1.86 Å). IRC calculations connect the computed
transition structure TSA with the cycloadduct. Therefore, even
though the TSA transition complex has significantly different
NCDMAD and C2CDMAD bonds, the cycloaddition proceeds according
to a one-step mechanism. It is assumed that carbene C undergoes
rearrangement into a pyridinium N-imine, which reacts with DMAD
to yield pyrazolopyridine 3a as well.
The HOMO and LUMO topology of 2,20-bipyridinium-N,N0-
dimines formed from 1a–c and DMAD under basic conditions
reveals the possibility of cycloaddition at both the N1, C2 and
N1, C6 atoms to form cycloadducts (Fig. 2 in the Supplementary
material). Small differences in the energies of the HOMO and the
C2, C6 coefficients of the diimines explain the similarity in their
chemical behavior.

V. I. Supranovich et al. / Tetrahedron Letters 55 (2014) 5377–5380
MeO2C
5379
CO2Me
X
N
X
X
N
X
(a)
X
(b)
N
N
X
N
N
NH2
N
4 a-c
X = H (a)
4-Me (b)
5-Me (c)
(c)
MeO2C
CO2Me
X
MeO2C
CO2Me
X
N
N
N
(d)
X
N
2a (X=H)
49%
N
N
2b (X=5,5'-Me2) 41%
2c (X=4,4'-Me2) 44%
X
N
MeO2C
H2N
CO2Me
2a-c
Scheme 4. The stepwise synthesis of 2a–c from bipyridyls 4a–c. Reagents and conditions: (a) MesSO3NH2, CH2Cl2, rt; (b) DMAD, K2CO3/MeCN, chloranil, rt; (c) MesSO3NH2/
CH2Cl2, MeOH, rt; (d) DMAD, K2CO3/MeCN, chloranil, rt.
Alberti, M. J.; Badiang, J. G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.;
In order to increase the yields of 2a–c, we attempted to use a
Chamberlain, S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753.
stepwise synthesis and chloranil as the oxidant (Scheme 4).30
9. Valenciano, J.; Cuadro, A. M.; Vaquero, J. J.; Alvarez-Builla, J.; Palmeiro, R.;
The isolated yields of products 2a–c over four steps were 49%,
41%, and 44%, respectively.
Castaño, O. J. Org. Chem. 1999, 64, 9001.
10. Tamura, Y.; Sumida, Y.; Miki, Y.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1975,
406.
11. Elsner, J.; Boeckler, F.; Davidson, K.; Sugden, D.; Gmeiner, P. Bioorg. Med. Chem.
2006, 14, 1949.
In conclusion, the [3+2] cycloaddition of N,N0-dimino-2,20-bipy-
ridyls with alkynes is accompanied by C–C0-bipyridyl bond cleav-
12. Johnston, K. A.; Allcock, R. W.; Jiang, Z.; Collier, I. D.; Blakli, H.; Rosair, G. M.;
Bailey, P. D.; Morgan, K. M.; Kohno, Y.; Adams, D. R. Org. Biomol. Chem. 2008, 6,
175.
13. Mousseau, J. J.; Bull, J. A.; Ladd, C. L.; Fortier, A.; Roman, D. S.; Charette, A. B. J.
Org. Chem. 2011, 76, 8243.
age.
A possible mechanism for this unexpected reaction
supported by DFT calculations is presented. In addition, an efficient
four-step approach to 7,70-bipyrazolo[1,5-a]-2,20,3,30-tetracarboxy-
lates has been developed starting from 2,20-bipyridines. As a devel-
opment of this work, we are now studying the behavior of various
2-substituted pyridine N-imines in this cycloaddition reaction.
14. Tarabová, D.; Titiš, J.; Prónayová, N.; Gatial, A.; Krutošíková, A. Arkivoc 2010, ix,
269.
15. Hoashi, Y.; Takai, T.; Kotani, E.; Koike, T. Tetrahedron Lett. 2013, 54, 2199.
16. Tamura, Y.; Ikeda, M. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic Press: New York, 1981; Vol. 29, pp 71–139.
17. Tamura, Y.; Miki, Y.; Ideda, M. J. Heterocycl. Chem. 1973, 10, 447.
18. The preparation and spectral data for the mesitylenesulfonates of dications
1a,b and tetramethyl-5,50-dimethyl-7,70-bipyrazolo[1,5-a]pyridine-2,20,3,30-
tetracarboxylate have been reported previously.17,19,20 The dimesitylenesulf-
onate of dication 1c was prepared by a similar method.
Acknowledgements
This study was performed with financial support from the
Russian Foundation for Basic Research (Projects No. 11-03-00205-a,
12-03-31322-mol-a), and the Russian Academy of Sciences (Project
No. 5.1.4).
Reactions of 1a–c with acetylenes: To a solution of 1 (0.10 mmol) in MeCN
(3 mL) were added with stirring the acetylene derivative (0.24 mmol) in MeCN
(2 mL) and K2CO3 (l.0 mmol). The solution was stirred at room temperature for
24 h and evaporated. The products were extracted with CHCl3 with the use of a
Soxhlet-type extractor; the solvent was evaporated and the resulting oil
analyzed by 1H NMR (in CDCl3). The structures of the products were confirmed
by 1H and 13C NMR spectroscopy, IR spectroscopy, and mass spectrometry (see
the Supplementary data). The NMR spectra of compounds 3, 6, and 8 were
consistent with the literature data.21–25
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
015.
19. Takeuchi, H.; Hayakawa, S.; Tanahashi, T.; Kobayashi, A.; Adachi, T.; Higuchi, D.
J. Chem. Soc., Perkin Trans. 2 1991, 847.
20. Borodkin, G. I.; Vorob’ev, A. Yu.; Supranovich, V. I.; Gatilov, Yu. V.; Shubin, V. G.
J. Mol. Struct. 2013, 1035, 441.
21. Anderson, P. L.; Hasak, J. P.; Kahle, A. D.; Paolella, N. A.; Shapiro, M. J. J.
Heterocycl. Chem. 1981, 18, 1149.
References and notes
1. Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.;
Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem. 1999, 42, 779.
2. Ohmuro, S.; Sasahara, T.; Taga, F.; Ohkubo, H.; Uchida, H. Arzneimittelforschung
1992, 42, 43.
3. (a) Allen, S. H.; Johns, B. A.; Gudmundsson, K. S.; Freeman, G. A.; Boyd, F. L., Jr.;
Sexton, C. H.; Selleseth, D. W.; Creech, K. L.; Moniri, K. R. Bioorg. Med. Chem.
2006, 14, 944; (b) Johns, B. A.; Gudmundsson, K. S.; Allen, S. H. Bioorg. Med.
Chem. Lett. 2007, 17, 2858.
22. Sasaki, T.; Kanematsu, K.; Kakehi, A. J. Org. Chem. 1971, 36, 2978.
23. Miki, Y.; Nakamura, N.; Hachiken, H.; Takemura, S. J. Heterocycl. Chem. 1989, 26,
1739.
24. Wu, C.; Wang, Q.; Zhao, J.; Li, P.; Shi, F. Synthesis 2012, 44, 3033.
25. Boekelheide, V.; Fedoruk, N. A. J. Org. Chem. 1968, 33, 2062.
26. Sholl, D. S.; Steckel, J. A. Density Functional Theory. A Practical Introduction;
Wiley: Hoboken, 2009.
27. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378.
28. The stationary points were fully optimized using the GAMESS suite of
programs.29 Harmonic vibrational frequencies were calculated at the B3LYP/
6-31G(d,p) level in order to characterize stationary points (minima and saddle
points). Intrinsic reaction coordinate (IRC) calculations were performed from
the transition states to determine which state connects the cycloadduct. For
estimation of the solvation effects the solvation model based on solute electron
density (SMD) was used.27 Acetonitrile was chosen as the model solvent.
29. Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen,
J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.;
Montgomery, J. A., Jr. J. Comput. Chem. 1993, 14, 1347.
4. Kishi, Y.; Ohta, S.; Kasuya, N.; Sakita, S.; Ashikaga, T.; Isobe, M. Cardiovasc. Drug
Rev. 2001, 19, 215.
5. Koike, T.; Takai, T.; Hoashi, Y.; Nakayama, M.; Kosugi, Y.; Nakashima, M.;
Yoshikubo, S.-I.; Hirai, K.; Uchikawa, O. J. Med. Chem. 2011, 54, 4207.
6. Löber, S.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 97.
7. (a) Löber, S.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2002, 12, 2377; (b)
Hansen, J. B.; Weis, J.; Suzdak, P. D.; Eskesen, K. Bioorg. Med. Chem. Lett. 1994, 4,
695; (c) Bettinetti, L.; Schlotter, K.; Hübner, H.; Gmeiner, P. J. Med. Chem. 2002,
45, 4594; (d) Mousseau, J. J.; Fortier, A.; Charette, A. B. Org. Lett. 2010, 12, 516.
8. (a) Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Samano, V. A.;
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L.; Moniri, K. R. Bioorg. Med. Chem. 2005, 13, 2397; (b) Stevens, K. L.; Jung, D. K.;
30. General procedure for the stepwise synthesis of 2a–c: A solution of 2,20-bipyridyl
4 (1.0 mmol) and O-mesitylsulfonylhydroxylamine (MesSO3NH2) (1.5 mmol)

5380
V. I. Supranovich et al. / Tetrahedron Letters 55 (2014) 5377–5380
in CH2Cl2 (5 mL) was stirred at room temperature for 2.5 h. After the
(1.5 mmol) in CH2Cl2 (3 mL) was added. The mixture was stirred for 3 h and
then Et2O (10 mL) and hexane (5 mL) were added. The resulting oil was
decanted and then dried under reduced pressure. The residue was dissolved in
MeCN (3 mL). K2CO3 (5.0 mmol) and then after 5 min, DMAD (1.0 mmol) were
added. After stirring at room temperature for 1.5 h, chloranil (0.5 mmol) was
added. The mixture was stirred for 2 h and then allowed to stand overnight.
The solvent was evaporated and the residue was purified by chromatography
on alumina (eluent CHCl3) to afford product 2.
completion of the reaction, Et2O (10 mL) was added and the resulting
residue was dissolved in MeCN (3 mL). K2CO3 (5.0 mmol), and then after
5 min, DMAD (1.0 mmol) were added to the solution. After stirring at room
temperature for 4 h, chloranil (0.5 mmol) was added. The mixture then was
stirred for 2 h and then allowed to stand overnight. The solvent was evaporated
and the residue was purified by chromatography on alumina (eluent CHCl3).
The crystalline product was dissolved in MeOH (1 mL) and MesSO3NH2