Study on selectivity in the reaction of 2-substituted pyridinium-N-imines with dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1016/j.tetlet.2016.01.092

Reactions of 2-X-pyridinium-N-imines (X = F, Cl, Br, CN, OPh, NH₂, N-morpholine) with dimethyl acetylenedicarboxylate (DMAD) have been studied. In the case of X = Cl, Br, CN, OPh both 7-substituted- and 7-H-pyrazolo[1,5-a]pyridines are formed. The 7-H/7-X ratio usually increases with the growing solvent polarity. The reaction of N-amino-2-iminopyridine with DMAD gives substituted pyrido[1,2-b][1,2,4]triazine.

Full text of DOI:10.1016/j.tetlet.2016.01.092

Accepted Manuscript
Study on selectivity in the reaction of 2-substituted pyridinium-N-imines with
dimethyl acetylenedicarboxylate
Vyacheslav I. Supranovich, Aleksey Yu. Vorob’ev, Gennady I. Borodkin, Yury
V. Gatilov, Vyacheslav G. Shubin
PII:
S0040-4039(16)30093-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.092
TETL 47256
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 November 2015
18 January 2016
26 January 2016
Please cite this article as: Supranovich, V.I., Vorob’ev, A.Y., Borodkin, G.I., Gatilov, Y.V., Shubin, V.G., Study
on selectivity in the reaction of 2-substituted pyridinium-N-imines with dimethyl acetylenedicarboxylate,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.092
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Study on selectivity in the reaction of 2-substituted pyridinium-N-
imines with dimethyl acetylenedicarboxylate
Vyacheslav I. Supranovicha,b, Aleksey Yu. Vorob’eva,b, Gennady I. Borodkina,b,*, Yury V. Gatilova,b,
Vyacheslav G. Shubina
aVorozhtsov Novosibirsk Institute of Organic Chemistry, Acad. Lavrentiev Ave. 9, Novosibirsk, 630090, Russia
bNovosibirsk State University, Pirogov st. 2, Novosibirsk, 630090, Russia
Abstract
Reactions of 2-X-pyridinium-N-imines (X = F, Cl, Br, CN, OPh, NH2, N-morpholine) with dimethyl
acetylenedicarboxylate (DMAD) have been studied. In the case of X = Cl, Br, CN, OPh both 7-
substituted- and 7-H-pyrazolo[1,5-a]pyridines are formed. The 7-H/7-X ratio usually increases with the
growing solvent polarity. The reaction of N-amino-2-iminopyridine with DMAD gives substituted
pyrido[1,2-b][1,2,4]triazine.
Keywords: 1,3-Dipolar cycloaddition, N-Amine salts, Pyrazolo[1,5-a]pyridines, Selectivity, C-X bond
cleavage, DFT calculations.
Introduction
The pyrazolo[1,5-a]pyridine motif is an important heterocyclic core which has received much
attention as a scaffold for drug design.1,2,3,4,5 The most common method for pyrazolo[1,5-a]pyridine
preparation is the 1,3-dipolar cycloaddition reaction of pyridinium-N-imines with acetylenes and
substituted alkenes.6 Such imines are usually generated in situ from N-aminopyridinium salts. Although
studies have been published on this reaction, only a few reports concerning the reactivity of 2-substituted
pyridinium-N-imines have appeared to date. Some 2-substituted pyridinium-N-imines and their
benzologues are known to give tetraazaanthracenes by dimerization.7,8 2-Methyl-, 2-trifluoromethyl- and
2-methoxypyridinium-N-imines were successfully applied for the preparation of 7-substituted
pyrazolo[1,5-a]pyridines.3,9,10,11 However, the reaction of 2-methyl-N-ethoxycarbonylpyridinium-N-imine
with DMAD gave the ipso-addition product, which was unstable and spontaneously rearranged.12 2-
Ethoxycarbonylpyridinium-N-imine reacted with benzyl phenylpropiolate and methyl propiolate to yield
the corresponding 7-ethoxycarbonylpyrazolo[1,5-a]pyridines.13,14 Alvarez-Builla and coworkers reported
an extensive study on the reactivity of some 2-ethoxycarbonylpyridinium-N-imines.13,15 In the reaction
with olefinic dipolarophiles these imines acted as formal 1,4-dipoles and afforded substituted pyrido[1,2-
b]pyridazin-9-ium-4-olates or their 1,2-dihydroderivatives. Such reactions proceed via N-C2 ipso-addition
with subsequent rearrangement of the ipso-cycloadduct. In a few cases, these intermediates also gave
pyrazolo[1,5-a]pyridines after elimination of the CO2Et group. In our previous work 2,2′-bipyridinium-
N,N′-diimines and acetylenes were also found to undergo 1,3-dipolar ipso-cycloaddition with subsequent
* Corresponding author. Tel.: +7 (383) 330 7651; fax: +7 (383) 330 9752.
E-mail address: gibor@nioch.nsc.ru (G.I. Borodkin).

elimination affording 7-H-pyrazolo[1,5-a]pyridines along with 7,7’-bis-(pyrazolo[1,5-a]pyridine)
derivatives.16
Thus, there is only limited knowledge on the applicability of 2-substituted pyridinium-N-imines for the
preparation of 7-substituted pyrazolo[1,5-a]pyridines. The influence of even common substituents such as
halogens, CN, OR or NH2 on the reaction selectivity is unknown. The aim of this work is a study of
solvent and substituent effect on the selectivity of the reaction of 2-substituted pyridinium-N-imines with
DMAD.
Results and discussion
Salts 1a-g were prepared by N-amination of the corresponding pyridines with O-
mesitylenesulfonylhydroxylamine. Since 1e was found to be unstable, it was used without purification
immediately after preparation. 2-Nitropyridine was found to not undergo N-amination. Salts 1a-g were
reacted with DMAD under basic conditions. Similar to our previous study,16 formation of pyrazolo[1,5-
a]pyridine 317 from 1a-f was observed along with cycloaddition products 2a-f (Scheme 1). Salt 1a with
the electron withdrawing CN-group gave noticeably less of the normal cycloaddition product 2a, than
compounds 1b-d having π-donating substituents. Interestingly, polar solvents typically increased the ratio
of 3:2 (Table 1).
Scheme 1. Reaction of N-aminopyridinium salts 1a-f with DMAD.
Table 1. Impact of the solvent on the yields and ratios of 3 and 2a-d for the reaction of N-aminopyridinium salts
1a-d with DMADa
Solvent
Toluene
3 2db
3 2a
3 2b
3 2c
39 24 (1.6)
3 21 (0.1)
5 21 (0.2)
6 27 (0.2)
Acetonitrile 79 14 (5.6)
12 52 (0.2)
31 35 (0.9)
16 25 (0.6)
5 39 (0.1)
26 40 (0.6)
17 33 (0.5)
6 64 (0.1)
14 50 (0.3)
19 49 (0.4)
DMF
66 12 (5.5)
60 7 (8.6)
DMSO
aSalt 1a-d (0.20 mmol), DMAD (0.22 mmol), K2CO3 (1.0 mmol), solvent (5 mL), 24 h.
Yields (%) and ratios (in parentheses) of 3:2a-d were determined by 1H NMR analysis of
b
the corresponding reaction mixture. 2-Phenoxypyridine was observed in the reaction
mixture.
For salt 1e only traces of 2e and 3 were found while in the case of 1f complex mixtures were
obtained without any detectable quantities of either 2f or 3. The only identifiable component of these
mixtures was 2-(N′-morpholino)-pyridine. Salt 1d under the reaction conditions led to a considerable
amount (8-19%) of 2-phenoxypyridine in addition to 2d and 3. 2-Phenoxypyridine formation may be

caused by the decreased acidity of 1d owing to the π-donating effect of the phenoxy group. This may
result in the presence of salt 1d together with its N-imine form in the reaction mixture of which the former
may be reduced by intermediate 4 according to Scheme 2. If this assumption is true, use of a stronger base
would result in an increase of 2d formation.
Scheme 2. Possible pathway for the formation of 2-phenoxypyridine.
Indeed, when the reaction was performed with 2.0 eq. of t-BuOK in CH3CN 38% of 2d, 3% of 3 and only
5% of 2-phenoxypyridine were formed. The use of chloranil as oxidant increased the yield of 2d to 68%.
Oxidation with chloranil also increased the yields of 2b,c in acetonitrile. Though the 3/2b ratio was the
lowest in toluene, the mixture of products obtained from 1b in acetonitrile was cleaner and contained a
higher quantity of 2b allowing its easy isolation (35%). Similarly, the reaction of 1c with DMAD in
acetonitrile led to 2c with 52% isolated yield.
The reaction of salt 1g with DMAD led to pyrido[1,2-b][1,2,4]triazine 6 in 60% yield. No
pyrazolo[1,5-a]pyridines were found in the reaction mixture. The molecular structure of 6 was confirmed
by single crystal X-ray analysis18 (Figure 1). Its formation is likely to proceed through initial DMAD
addition to the N-NH2-group of imine 5 (Scheme 3).
Scheme 3. Possible pathway for the formation of pyrido[1,2-b][1,2,4]triazine 6.

Figure 1. Single crystal X-ray determined structure of pyrido[1,2-b][1,2,4]triazine 6. Displacement ellipsoids are
drawn at the 50% probability level.
As could be seen from the Table 1, direct cyclization of 2-CN-piridinium-N-imine and DMAD
cannot be employed for the satisfactory preparation of 2a. However, the well-developed method of
haloaryl cyanation can be used to obtain 2a from 2b with moderate yield (Scheme 4).19
Scheme 4. Preparation of 2a by cyanation of 2b.
Acetylenes less active than DMAD (ethyl propiolate and methyl phenylpropiolate) led to complex
reaction mixtures, where tetraazaanthracene (7)7 was present in large quantities (Scheme 5).
Scheme 5. Formation of tetraazaanthracene 7 from 1a-d.
The formation of 2 and 3 most likely proceeds via one of two possible mechanisms (Scheme 6). The
first is a concerted 1,3-dipolar cycloaddition. The N-C6 cycloaddition leads to intermediate 8 which could
isomerize into 8' before giving 2 by oxidation. Ipso N-C2 cycloaddition gives intermediate 9 which could
isomerize into 9′ before giving 3 by elimination. The second one is the stepwise addition of DMAD with
the formation of intermediate 10 which could undergo ring closure at both the C2 and C6 positions. The
possibility of the equilibrium between the two sets of intermediates, which are on the pathway to 2 and 3,
was checked by excluding oxygen from the reaction.

Scheme 6. Possible pathway for the formation of pyrazolo[1,5-a]pyridines 2 and 3 from pyridinium-N-imines.
Keeping the reaction mixture under an argon atmosphere did not affect the products ratio even when
heated. This suggests the absence of equilibrium between intermediates 8 and 9 using the given
conditions and therefore irreversibility of the cycloaddition first stage.
To gain more insight into this reaction we performed theoretical studies based on DFT calculations
at the B3LYP/6-31+G* level of theory with SMD solvation in the GAMESS.20,21,22 The HOMO topology
of 2-CN-pyridinium-N-imine and other imines (see ESI) reveals the possibility of both N-C2 and N-C6
cycloaddition. Transition states corresponding to the concerted cycloaddition of DMAD to the 2-CN- and
2-Cl-pyridinium-N-imines were located. The C-N and C-C bond lengths (Figure 2) in all structures
indicate an early polar transition state formation. This is quite opposite to our previous study of DMAD
and 2,2′-bipiridinium-N,N′-diimine cycloaddition when the latter transition state was observed.16 As could
be seen from Table 2, N-C2 cycloaddition is favorable in most cases. The experimental observations of
the solvent influence on the 3/2a,c reaction selectivity qualitatively correspond to the calculations. The
calculations showed intermediate 10 to be highly energetic (Figure 3, diagram b). Also, the barrier of its
formation is notably higher than energy of TS1 and TS2 (Figure 3, diagram a). As could be seen from
energetic diagram, addition of DMAD to imine is highly exothermic.
TS1
TS2
TS3
Figure 2. Structures of calculated transition states for the reaction of 1a with DMAD resulting in 2a and 3
formation. Bond lengths are given in Å.

(a)
(b)
Figure 3. Energetic diagrams of the 2-CN-pyridinium-N-imine and DMAD cycloaddition pathways (free energies
are given in kJ/mol).
Table 2. Difference in activation free energies of 8 and 9 (X = CN, Cl) formation
∆∆G≠ = ∆G≠ (TS1) - ∆G≠ (TS2),
Calculated 3:2a,c ratio
kJ/mol
Solvent
(at 298K)
X = CN
X = CN
1.55
X = Cl
-3.98
-1.22
1.91
X = Cl
0.2
gas phase
toluene
1.9
2.3
5.1
4.9
5.1
2.02
0.6
acetonitrile
DMF
4.03
2.2
3.94
1.37
1.7
DMSO
4.03
1.37
1.7
Conclusion
In summary, the reaction of 2-X-pyridinium-N-imines (X = F, Cl, Br, CN, OPh, NH2, N-
morpholine) with DMAD has been studied. Competition of the sites at positions 2 and 6 for cyclization is
general for the 1,3-dipolar cycloaddition of 2-substituted pyridinium-N-imines. The nature of the
substituent considerably affects the selectivity of the reaction. Polar solvents typically increase the ratio of
unsubstituted product to substituted products. The reaction of N-amino-2-aminopyridinium salt with
DMAD under basic conditions gives methyl 2-(2-oxo-2H-pyrido[1,2-b][1,2,4]triazin-3-yl)acetate.

Acknowledgments
This study was performed with financial support from the Russian Foundation for Basic Research
(projects No. 11-03-00205-а, 12-03-31322-mol-a), and the Russian Academy of Sciences (Project No.
5.1.4).
Supplementary data
Supplementary data associated with this article can be found in the online version.

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Graphical Abstract (for review)
Graphical abstract
Study on the selectivity in the reaction of 2-substituted
pyridinium-N-imines with dimethyl acetylenedicarboxylate
Vyacheslav I. Supranovich, Aleksey Yu. Vorob’ev, Gennady I. Borodkin, Yury V.
Gatilov,Vyacheslav G. Shubin