Preparation of differentiated diamides of 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-2,6- and -3,6-dicarboxylic acids suitable for parallel synthesis

Article abstract of DOI:10.1007/s10593-011-0840-y

1,3-Dipolar cycloaddition of a bicyclic sydnone to a propargylic acid amide affords 4,5,6,7-tetra-hydropyrazolo[1,5-a]pyridine-2,6- and -3,6-dicarboxylic acid monoamides which are further converted to corresponding differentiated diamides.

Full text of DOI:10.1007/s10593-011-0840-y

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
PREPARATION OF DIFFERENTIATED DIAMIDES OF
4,5,6,7-TETRAHYDROPYRAZOLO[1,5-a]PYRIDINE-
2,6- AND -3,6-DICARBOXYLIC ACIDS
SUITABLE FOR PARALLEL SYNTHESIS
E. Erdmane1, R. Zemribo1*
1,3-Dipolar cycloaddition of a bicyclic sydnone to a propargylic acid amide affords 4,5,6,7-tetra-
hydropyrazolo[1,5-a]pyridine-2,6- and -3,6-dicarboxylic acid monoamides which are further converted
to corresponding differentiated diamides.
Кeywords: sydnones, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridines, 1,3-dipolar cycloaddition.
The pyrazole core represents an important class of nitrogen-containing heterocycles since it is a stuctural
element of natural products [1] and pharmaceutically active compounds [2–4]. The bicyclic pyrazole motif is a
fragment of numerous biologically active compounds [5–8]. The partially saturated bicyclic pyrazole system,
4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, has found use as a scaffold in drug research [9, 10] and agrochemi-
cals [11].
Within the medicinal chemistry program in our laboratories, we considered a diversity-oriented library
synthesis around this scaffold, specifically, the synthesis of differentiated diamides of 4,5,6,7-tetra-
hydropyrazolo[1,5-a]pyridine-2,6-dicarboxylic acid 1a and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3,6-di-
carboxylic acid 1b. The literature search revealed that only few structural modifications of 4,5,6,7-tetra-
hydropyrazolo[1,5-a]pyridine [12], the corresponding 2-carboxylic acid derivatives [13, 14], and boranes [14]
are known. Furthermore, 6-substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine derivatives have not been
reported.
Two principally distinct synthetic routes towards 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine derivatives
have been reported. Route A is based on the hydrogenation of pyrazolo[1,5-a]pyridines 3a,b [9, 10], and route B
– on the pyrazole ring closure by 1,3-dipolar cycloaddition of bicyclic sydnone 6 to propargylic acid derivatives.
Retrosynthetic analysis of target compounds showed that for route A, an intermediate pyrazolo[1,5-a]pyridine-
2- or -3-carboxylic acid derivatives 4a,b would be required. Pyrazolo[1,5-a]pyridine-2-carboxylic acid
derivatives 4a are synthesized by 1,3-dipolar cycloaddition of 1-aminopyridinium species 5 to acetylene
dicarboxylic acid esters and subsequent monodecarboxylation [15], whereas the corresponding
_______
*To whom correspondence should be addressed, e-mail: ronalds@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga, LV-1006, Latvia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.7, 992–997, July, 2011. Original article
submitted April 19, 2011.
0009-3122/11/4707-0811©2011 Springer Science+Business Media, Inc.
811

3-carboxylic acid derivatives 4b are obtained in the reaction of compound 5 with propiolic acid derivatives
[15, 16]. Therefore route A is not appropriate for parallel synthesis. This consideration, together with potential
problems associated with differentiation of two carboxylic acids/ester/amide functionalities, prompted us to
choose route B as synthetically more attractive.
R2
R4
R1
N
N
R3
N
O
1a,b
R2
R2
O
B
A
R1
R1
O
+
N
N
N
N
N
N
RO2C
HO2C
MeO2C
6
3a,b
2a,b
R2
O
OH
X
R1
+
NH
N
N
NH2
N
MeO2C
Br
Br
4a,b
7
5
1, 2 a R1 = CONR5R6, R2 = H; b R1 = H, R2 = CONR5R6;
3, 4 a R1 = CO2R, R2 = H; b R1 = H, R2 = CO2R; R = alkyl
Route B is based on 1,3-dipolar cycloaddition of sydnones 6 to acetylenes. Although successful
1,3-dipolar cycloaddition of sydnone 6 to olefins [17], acetylenes [18], and propargylic acid esters [13, 19] is
documented, there is no literature precedent of such reaction with propargylic acid amides. To enable the
differentiation of the carboxylic amide at the 2- or 3-position from the ester at 6-position, we chose sydnone 6
1,3-dipolar cycloaddition to propargylic amides as our approach.
The synthesis of key intermediate 2 began with the preparation of piperidine-2,5-dicarboxylic acid
5-methyl ester (7). According to the literature procedure [20], pyridine-2,5-dicarboxylic acid dimethyl ester (8)
can be hydrogenated to piperidine 9 and then converted to compound 7.
CO2Me
O
NH
H2, PtO2
AcOH
OH
AcOH
CO2Me
N
CO2Me
9
7
CO2H
CO2Me
NaOH
MeOH
N
H2, Pd/C
AcOH
8
CO2Me
10
812

Although the described method is suitable for preparation of compound 7, we found that saturation of
the pyridine ring of compound 10 in the last step is more convenient. Dimethyl ester 8 was converted to
monomethyl ester 10 [21] and then hydrogenated to provide the target piperidine 7, which was used without
purification.
Sydnone 6 was readily prepared in two steps. Piperidine-2-carboxylic acid 7 was converted to N-nitroso-
piperidine 11, treatment of which with trifluoroacetic anhydride (TFAA) according to the literature procedure
[13, 17] led to sydnone 6. 1,3-Dipolar cycloaddition of sydnone 6 to 1-piperidin-1-yl-propynone (12) led to the
formation of two regioisomers 13a and 13b, which were easily separated by column chromatography on silica
gel to give the desired compounds 13a and 13b in ~1:2 ratio in overall yield of 30% in four steps. The alkaline
hydrolysis of esters 13a and 13b led to the key intermediates 14a and 14b in good yield.
O
N
NaNO2
HCl
CO2H
TFAA
THF
12
6
7
O
N
N
m-xylene
H2O
MeO2C
11
O
N
O
N
+
N
N
N
N
MeO2C
MeO2C
13a
13b
LiOH
LiOH
THF
H2O
THF
H2O
O
N
O
N
N
HO2C
N
N
N
14b
HO2C
14a
Et2NH, EDC
HOBt, TEA
DMF
Et2NH, EDC
HOBt, TEA
DMF
O
O
N
N
N
N
Et2NOC
N
N
Et2NOC
15b
15a
The obtained acids 14a and 14b can be used in the parallel synthesis of different amides, which we ex-
emplified by preparing diethylamides 15a and 15b.
In conclusion, a method for preparing differentiated diamides of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyri-
dine-2,6- and -3,6-dicarboxylic acids, suitable for parallel synthesis, has been elaborated.
813

EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury (200 MHz, compounds 13a,b, 14a,b) and Varian
MR (400 MHz, compounds 15a,b) spectrometers in CDCl3. Chemical shifts are referenced to HMDS as the
internal standard ( = 0.05 ppm) or using the signal of the residual protonated solvent ( = 7.26 ppm). High-
resolution mass spectra analyses were performed using a Micromass Q-TOF Micro quadrupole time-of-flight
high-resolution mass spectrometer with ESI ionization. Leucine enkephalin was used as internal lock mass for
accurate mass calculation (m/z 566.2771). LC-mass spectra analyses were performed on a Shimadzu Prominence
system connected to the Applied Biosystems API 2000 mass spectrometer (atmospheric pressure ionization).
Reagents and solvents were purchased from Aldrich, Acros and Alfa Aesar Chemical Industries. Pyri-
dine-2,5-dicarboxylic acid 5-methyl ester hydrogen chloride (10) was prepared from pyridine-2,5-dicarboxylic
acid dimethyl ester (8) according to the literature procedure [21].
2-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylic Acid Methyl
Ester (13a) and 3-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-6-carboxylic Acid
Methyl Ester (13b). Pyridine-2,5-dicarboxylic acid 5-methyl ester hydrogen chloride (10) (2.0 g, 9.2 mmol)
was dissolved in a mixture of AcOH (40 ml) and MeOH (5 ml), and 10% Pd/C (0.53 g, 0.5 mmol) was added.
Hydrogenation was carried out at room temperature at 10 atm for 24 h. The reaction mixture was filtered
through Celite, washed with EtOAc, and evaporated to give 0.77 g of the piperidine-2,5-dicarboxylic acid
5-methyl ester (7) as a white solid which was used without purification in the next step. LC–MS, m/z: 188
[M+H]+.
To a solution of methyl ester 7 in water (5 ml) at 0°C, concentrated hydrochloric acid (0.6 ml) was
added, followed by NaNO2 (0.885 g, 12.8 mmol) in small portions. The mixture was stirred at 0°C for 1 h,
extracted with CHCl3, dried over Na2SO4, filtered, and evaporated under reduced pressure at 30–35°C. The
residue containing 1-nitroso-piperidine-2,5-dicarboxylic acid 5-methyl ester (11) was immediately used in
the next step.
To a stirred solution of compound 11 in dry THF (20 ml) at 0°C under argon atmosphere, a solution of
trifluoroacetic anhydride (1 ml, 7 mmol) in THF (5 ml) was added dropwise. The mixture was stirred at 0°C for
5 h and then 16 h at room temperature. The solvent was evaporated and the crude material diluted with EtOAc
and stirred with anhydrous K2CO3 (1 g). The mixture was filtered through a pad of silica gel, and the filtrate was
evaporated. The obtained brownish oil containing 6-(methoxycarbonyl)-4,5,6,7-tetra-hydro[1,2,3]oxadiazolo-
[3,4-a]pyridin-8-ium-3-olate (6) was used in the next step without purification.
To a stirred solution of compound 6 in m-xylene (5 ml), propargylic acid amide 12 [22] (1.26 g,
9.2 mmol) was added, the reaction mixture was heated at 140°C for 8 h and evaporated; the residue was purified
by flash chromatography on silica gel (eluent hexane–ethyl acetate, 1:1 to 1:4) to obtain 0.55 g of compound
13a and 0.25 g of compound 13b as oils. The overall yield of both products together was 30% (over 4 steps).
1
Compound 13a. H NMR spectrum, , ppm (J, Hz): 1.49–1.65 (6H, m, 3',4',5'-CH2 piperidine);
1.85-2.05 (1H, m) and 2.20–2.26 (1H, m, 5-CH2); 2.74–3.06 (3H, m, 4-CH2, 6-CH); 3.63–3.74 (4H, m, 2',6'-CH2
piperidine); 3.71 (3H, s, OCH3); 4.22 (1H, dd, J = 13.2, J = 8.8) and 4.37 (1H, dd, J = 13.2, J = 5.9, 7-CH2);
6.25 (1H, s, H-3). Found: m/z 292.1659 [M+H]+. C15H22N3O3. Calculated: M 292.1661.
1
Compound 13b. H NMR spectrum, , ppm (J, Hz): 1.58–1.63 (6H, m, 3',4',5'-CH2 piperidine);
1.87-2.06 (1H, m) and 2.25–2.34 (1H, m, 5-CH2); 2.82–3.21 (3H, m, 4-CH2, 6-CH); 3.56–3.62 (4H, m, 2',6'-CH2
piperidine); 3.74 (3H, s, OCH3); 4.24 (1H, dd, J = 13.2, J = 8.8) and 4.40 (1H, dd, J = 13.2, J = 5.9, 7-CH2);
7.48 (1H, s, H-2). Found: m/z 292.1659 [M+H]+. C15H22N3O3. Calculated: M 292.1661.
2-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylic Acid (14a). To
a solution of 13a (58 mg, 0.20 mmol) in THF (1 ml), water (3 ml) was added followed by LiOH·H2O (9 mg,
0.22 mmol), and the mixture was stirred at room temperature for 2 h. The THF was evaporated, and the water
layer was acified with 10% HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered,
1
and evaporated to give 55 mg (99%) of the desired acid 14a as a yellow oil. H NMR spectrum, , (ppm)
814

(J, Hz): 1.50–1.74 (6H, m, 3',4',5'-CH2 piperidine); 2.01–2.28 (2H, m, 5-CH2); 2.70–3.07 (3H, m, 4-CH2, 6-CH);
3.69–3.77 (4H, m, 2',6'-CH2 piperidine); 4.24–4.38 (2H, m, 7-CH2); 6.30 (1H, s, H-3); 7.78 (1H, br. s, OH).
Mass spectrum, m/z: 278 [M+H]+.
3-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylic Acid (14b) was
synthesized in the same manner as compound 14a from ester 13b (65 mg, 0.22 mmol) to give 48 mg (78%) of
1
acid 14b as a yellow oil. H NMR spectrum, , ppm (J, Hz): 1.50–1.75 (6H, m, 3',4',5'-CH2 piperidine);
1.98-2.29 (2H, m, 5-CH2); 2.81–3.18 (3H, m, 4-CH2, 6-CH); 3.51–3.70 (4H, m, 2',6'-CH2 piperidine); 4.26–4.44
(2H, m, 7-CH2); 7.51 (1H, s, H-2); 7.78 (1H, br. s, OH). Mass spectrum, m/z: 278 [M+H]+.
2-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylic Acid Diethyl-
amide (15a). To a solution of acid 14a (55 mg, 0.20 mmol), HOBt·H2O (41 mg, 0.24 mmol), EDC (46 mg,
0.24 mmol) in DMF (1.5 ml), diethylamine (25 l, 0.24 mmol) and TEA (30 l, 0.24 mmol) were added. The
mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted
with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue
was purified by flash chromatography on silica gel (eluent hexane–ethyl acetate, 1:1) to give 18 mg (27%) of the
desired compound 15a as an oil. 1H NMR spectrum, , ppm (J, Hz): 1.14 (3H, t, J = 7.4, NCH2CH3); 1.23 (3H, t,
J = 7.4, NCH2CH3); 1.57–1.70 (6H, m, 3',4',5'-CH2 piperidine); 2.03–2.09 (2H, m, 5-CH2); 2.73–2.82 (1H, m,
6-CH); 3.02 (1H, dt, J = 16.8, J = 4.3, 4-CH); 3.07–3.15 (1H, m, 4-CH); 3.31–3.53 (4H, m, 2NCH2CH3);
3.64-3.72 (2H, m) and 3.78–3.85 (2H, m, 2',6'-CH2 piperidine); 4.24–4.33 (2H, m, 7-CH2); 6.32 (1H, s, H-3).
Found: m/z 333.2281 [M+H]+. C18H29N4O2. Calculated: M 333.2291.
3-(Piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carboxylic Acid Diethyl-
amide (15b) was synthesized in the same manner as compound 15a from acid 14b (48 mg, 0.17 mmol).
Compound 15b was obtained as a yellow oil, yield 21 mg (36%). 1H NMR spectrum, , ppm (J, Hz): 1.13 (3H,
t, J = 7.4, NCH2CH3); 1.22 (3H, t, J = 7.4, NCH2CH3); 1.59–1.71 (6H, m, 3',4',5'-CH2 piperidine); 1.97–2.11
(2H, m, 5-CH2); 2.89–2.96 (1H, m, 6-CH); 3.06–3.14 (1H, m, 4-CH); 3.19 (1H, ddd, J = 18.0, J = 5.5, J = 2.4,
4-CH); 3.27–3.46 (4H, m, 2 NCH2CH3); 3.60–3.62 (4H, m, 2',6'-CH2 piperidine); 4.23–4.33 (2H, m, 7-CH2);
7.48 (1H, s, H-2). Found: m/z 333.2281 [M+H]+. C18H29N4O2. Calculated: M 333.2291.
This work was supported by European Social Fund (No. 2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
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