New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

Article abstract of DOI:10.3762/bjoc.13.80

An efficient and operationally simple synthesis of 7-deuteropyrazolo[1,5-a]pyridine and 7-deutero-1,2,4-triazolo[1,5-a]pyridine derivatives using α-H/D exchange of 1-aminopyridinium cations in basic D₂O followed by a 1,3-cycloaddition of acetylenes and nitriles is presented. A high regioselectivity and a high degree of deuterium incorporation were achieved. The procedure was applied for several 4-R-1-aminopyridinium cations (R = H, Me, OMe).

Full text of DOI:10.3762/bjoc.13.80

New approach toward the synthesis of deuterated
pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines
Aleksey Yu. Vorob’ev*1,2, Vyacheslav I. Supranovich1,2, Gennady I. Borodkin1,2
and Vyacheslav G. Shubin1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 800–805.
1Vorozhtsov Novosibirsk Institute of Organic Chemistry, Acad.
Lavrentiev Ave. 9, Novosibirsk, 630090, Russia and 2Novosibirsk
State University, Pirogov st. 2, Novosibirsk, 630090, Russia
doi:10.3762/bjoc.13.80
Received: 09 February 2017
Accepted: 09 April 2017
Published: 02 May 2017
Email:
Aleksey Yu. Vorob’ev* - vor@nioch.nsc.ru
Associate Editor: J. Aubé
* Corresponding author
© 2017 Vorob’ev et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
deuteration; 1,3-dipolar cycloaddition; pyrazolo[1,5-a]pyridine;
1,2,4-triazolo[1,5-a]pyridine
Abstract
An efficient and operationally simple synthesis of 7-deuteropyrazolo[1,5-a]pyridine and 7-deutero-1,2,4-triazolo[1,5-a]pyridine de-
rivatives using α-H/D exchange of 1-aminopyridinium cations in basic D2O followed by a 1,3-cycloaddition of acetylenes and
nitriles is presented. A high regioselectivity and a high degree of deuterium incorporation were achieved. The procedure was
applied for several 4-R-1-aminopyridinium cations (R = H, Me, OMe).
Introduction
Isotopically labeled compounds find broad applications in applied in the development of FIXa [11], PI3K [12], EGFR [13]
studies of chemical and biochemical reaction mechanisms and and PDE [14] inhibitors and dopamine receptor ligands [15].
metabolism pathways. Deuterium is the most common used The nonselective PDE3,4 inhibitor ibudilast (MN-166) has been
isotopic label in mechanistic studies. Deuterated organic com- marketed in Japan for over 25 years for treating asthma and
pounds are widely used in biological [1] and pharmacological post-stroke patients [16]. 1,2,4-Triazolo[1,5-a]pyridines show
[2-5] investigations. In the last years deuteration became also an antifungal [17], antitumor [18], and cytotoxic [19] activities.
efficient tool in drug design [6].
Both types of heterocyclic cores are readily available from
N-aminopyridium salts and related pyridinium-N-imines via
Pyrazolo[1,5-a]pyridine and 1,2,4-triazolo[1,5-a]pyridine scaf- 1,3-cycloaddition reaction [20] or intramolecular ring closure
folds attracted significant attention to the medicinal chemistry [21-24]. The importance of these cores for medical chemistry
community during the past decade. For example, pyrazolo[1,5- studies suggests that isotopically labeled pyrazolo[1,5-
a]pyridine derivatives were used in the design of antiviral [7,8], a]pyridines and triazolo[1,5-a]pyridines could be of interest.
antimalarial [9] and antitubercular [10] agents. Also they were Recently, deuterium-labeled pyridinium-N-imines were applied
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Beilstein J. Org. Chem. 2017, 13, 800–805.
to mechanistic studies of the conversion to pyrazolo[1,5-
a]pyridines [25,26]. Such labeled N-imines were obtained
starting from commercially available pyridine-d5. Since substi-
tuted deuterated pyridines are less accessible new mild and
simple methods of deuterium introduction into the pyridine ring
are of great interest. The N-aminopyridinium cation has been
shown to undergo a fast H/D exchange at the α-position of the
pyridine ring [27]. Pyridine-N-imines could also be deuterated
under significantly harder conditions [28,29]. In the present
study we report mild and effective syntheses of 7-deuteropyra-
Figure 1: pKa values for N-aminopyridinium cation hydrogen atoms
according to DFT M06-2X 6-31+G(d,p) calculations.
zolo[1,5-a]pyridine and 7-deutero-1,2,4-triazolo[1,5-a]pyridine for both N–H and C–H hydrogens possibly due to the electron-
derivatives by H/D exchange of 1-aminopyridinium cations fol- donating effect of the methoxy group. These quantum chemical
lowed by the reaction with acetylenes and nitriles.
data together with Zoltewicz’s work [27] suggest 7-deuterium-
labeled pyrazolo[1,5-a]pyridines could be obtained from
N-aminopyridium salts through an H/D exchange in basic D2O
Results and Discussion
N-Aminopyridinium salts are easily available via direct solution followed by the cycloaddition reaction with acetylenes
N-amination of parent pyridines. Salt 1a was prepared by (Scheme 1).
N-amination of pyridine with hydroxylamine-O-sulfonic acid
followed by the reaction with HBF4 according to a previously In the first step, the H/D exchange in 1a has been performed
described method [30]. Salts 1b,c were prepared by direct with a 0.67 M solution of K2CO3 in D2O at 80 °C for 5 min.
N-amination of the corresponding pyridines with O-mesitylsul- After D2O evaporation and the reaction with dimethyl
fonylhydroxylamine. In view of difficulties in obtaining experi- acetylenedicarboxylate (2a, DMAD) in MeCN D-labeled pyra-
mental pKa values of different positions of pyridinium cations zolo[1,5-a]pyridine 3 was obtained in 70% yield (Table 1). The
we carried out DFT calculations [31] at the M06-2X deuteration at room temperature even for 24 h led to a signifi-
6-31+G(d,p) [32] level of theory with SMD [33] solvation cantly lower degree of deuteration (DD, 20%).
(Figure 1, see also Supporting Information File 1).
Salt 1b gave the corresponding 5-CD3-7-D-pyrazolopyridine 5
As expected, in all cases the NH2 group is the most acidic. The along with a 93% DD for the methyl group after two runs in
NH2 group is usually ≈12–13 pKa units more acidic than α-C–H D2O. The 4-methoxy derivative 1c slowly underwent an H/D
hydrogens. However, the difference in pKa of NH2 and CH3 exchange at the 2-position of the pyridinium ring probably by
groups of the 4-methyl-1-aminopyridinium cation is not so high reason of a lower acidity due to the electron-donating effect of
and the NH2 group is only 2.7 units more acidic. 1-Aminopyri- the methoxy group. Thus, 5-methoxypyrazolopyridine 6 was
dinium and 4-methyl-1-aminopyridinium cations have similar obtained in 25% yield with a DD of only 58%. A higher DD of
pKa values for NH2 and α-C–H groups. The 4-methoxy-N- 6 could be achieved by increasing the reaction time, however,
aminopyridinium cation possesses significantly lower acidity the yield of pyrazolopyridine decreased possibly due to the
Scheme 1: H/D exchange of N-aminopyridinium salts 1a–c and their reaction with acetylenes.
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Beilstein J. Org. Chem. 2017, 13, 800–805.
Table 1: Synthesis of deuteropyrazolo[1,5-a]pyridine derivativesa.
Product and
Yield (%)
Product and
Yield (%)
D content (%)b
D content (%)b
70
87
63
34c
3
6
5
7
19d
8, 9
aH/D-exchange: salt 1a–c (0.20 mmol), K2CO3 (1.0 mmol), D2O (1.5 mL), 80 °C, 5 min; 1,3-cycloaddition: acetylene compound (0.2 mmol), MeCN
(5 mL), chloranil (0.15 mmol), rt, 1 h. bD content (%) was determined by 1H NMR. cDD and yield after two runs in D2O. dDD and yield after H/D
exchange for 1 h in D2O at 80 °C.
hydrolysis of the methoxy group. The 4-dimethylamino-substi- ethyl propiolate (2c) was used 2,7-dideuteropyrazolo[1,5-
tuted pyridinium-N-amine salt (anion MesSO3−) did not a]pyridine 8 was formed along with monodeuterated product 9.
undergo an H/D exchange under the present conditions. Both The deuterium atom may appear in position 2 of compound 8 in
4-CO2Me-substituted pyridinium-N-amine and N-aminoiso- two different ways (Scheme 2). The first one includes
quinolinium mesitylenesulfonates failed deuteration owing to deuterium atom migration from position 3a to position 2 in
the formation of insoluble compounds in basic D2O solution. cycloadduct 10 (path a) with the formation of intermediate 11
which, on further oxidation, gives product 8. Intermediate 11 is
Ethyl phenylpropiolate (2b) reacts similar to DMAD with the the most stable isomer among other dihydro intermediates ac-
formation of the corresponding 7-D-pyrazolopyridine 7. When cording to quantum chemistry calculations by the M-06-2X
Scheme 2: Possible pathways for the formation of 8.
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Beilstein J. Org. Chem. 2017, 13, 800–805.
6-31G+(d,p) method (Figure 2) and 3a -> 2 hydrogen atom except the fact that t-BuOK was used instead of KOH for KOD
migration is a highly exothermic process. However, the forma- generation to achieve a higher degree of deuteration. The reac-
tion of 11 is probably kinetically unfavorable due to the prohib- tion yielded the corresponding 7-D-triazolo[1,5-a]pyridines
ited 1,3-hydrogen shift. Thus, no NMR signals corresponding to with high D content at position 7. However, an H/D exchange at
11 were found in the reaction mixture before oxidation. Another the methyl group was also observed with only moderate DD.
possible way of deuterium-atom incorporation includes the H/D
exchange between the ND-group and the Csp–H hydrogen of
ethyl propiolate before the formation of cycloadduct 12 (path
b). Rearrangement of 12 into 13 and further oxidation leads to
pyrazolopyridine 8.
In order to explore this approach for the synthesis of deutero-
1,2,4-triazolo[1,5-a]pyridines the reaction of 1a and MeCN in
basic D2O solution was studied (Scheme 3, Table 2). The previ-
Scheme 3: Synthesis of deutero 1,2,4-triazolo[1,5-a]pyridines.
ously reported conditions for such a reaction were applied [18]
Figure 2: Relative stability of 3-CO2Et-substituted dihydropyrazolo[1,5-a]pyridines by the M06-2X 6-31+G(d,p) method in kJ/mol.
Table 2: Synthesis of deutero 1,2,4-triazolo[1,5-a]pyridinesa.
D content (%)b
Yield (%)
D content (%)b
Yield (%)
40
40
14
16
15
17
42
46
aConditions: salt 1a (0.20 mmol), RCN (0.2 mmol), t-BuOK (1.0 mmol), D2O (1.5 mL), rt, overnight under air. bD content (%) was determined by
1H NMR.
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Conclusion
We have developed an efficient protocol for the synthesis of
deuterium labeled pyrazolo[1,5-a]pyridines and triazolo[1,5-
a]pyridines. Readily available and cheap D2O was employed as
the deuterium source. The established system displays notable
efficacy under mild reaction conditions in a short reaction time.
A comparative assessment of the pKa values of different posi-
tions of N-aminopyridinium cations by DFT calculations allows
predicting the direction of deuterium exchange. We assume that
this method could also be extended to tritium labelling of phar-
maceutically interesting compounds for medicinal applications.
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Supporting Information
12.Kendall, J. D.; Marshall, A. J.; Giddens, A. C.; Tsang, K. Y.; Boyd, M.;
Frédérick, R.; Lill, C. L.; Lee, W.-J.; Kolekar, S.; Chao, M.; Malik, A.;
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Med. Chem. Commun. 2014, 5, 41–46. doi:10.1039/C3MD00221G
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Mellor, M. J.; Orme, J. P.; Perkins, D.; Perkins, P.; Richmond, G.;
Smith, P.; Ward, R. A.; Waring, M. J.; Whittaker, D.; Wells, S.;
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Supporting Information File 1
Experimental part, NMR spectra, and quantum calculation
details.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-80-S1.pdf]
Acknowledgements
Financial support from the Russian Foundation for Basic
Research (projects Nos. 11-03-00205-а and 12-03-31322-mol-
a), and the Chemistry and Materials Science Department of the
Russian Academy of Sciences (project No. 5.1.4) is gratefully
acknowledged.
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