Tandem Aza Michael Addition-Vinylogous Nitroaldol Condensation: Construction of Highly Substituted N-Fused 3-Nitropyrazolopyridines

Article abstract of DOI:10.1021/acs.joc.8b00746

A base-mediated tandem aza-Michael addition-vinylogous nitroaldol condensation has been described between 3,5-dialkyl 4-nitropyrazoles and alkynyl ketones/aldehydes. This transition metal-free atom economical transformation occurred via C-N and C=C bond formations in one step with the elimination of water. The construction of a variety of highly substituted N-fused 3-nitropyrazolopyridine derivatives has been demonstrated with good yields. Good to excellent regioselectivities have been achieved with unsymmetrically substituted 4-nitropyrazoles.

Full text of DOI:10.1021/acs.joc.8b00746

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Article
Tandem Aza Michael Addition#Vinylogous Nitroaldol Condensation:
Construction of Highly Substituted N-Fused 3-Nitropyrazolopyridines
Owk Obulesu, V Murugesh, Battu Harish, and Surisetti Suresh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00746 • Publication Date (Web): 21 May 2018
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Tandem Aza Michael Addition―Vinylogous Nitroaldol
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Condensation: Construction of Highly Substituted N-Fused 3-
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Nitropyrazolopyridines
Owk Obulesu,†,‡ V. Murugesh,†,‡ Battu Harish,†,‡ and Surisetti Suresh*,†,‡
†Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT),
Hyderabad 500 007, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 025, India
ABSTRACT: A base-mediated tandem aza-Michael addition―vinylogous nitroaldol
condensation has been described between 3,5-dialkyl 4-nitropyrazoles and alkynyl
ketones/aldehydes. This transition metal-free atom economical transformation occurred via C–N
and C=C bond formations in one step with the elimination of water. The construction of a variety
of highly substituted N-fused 3-nitro-pyrazolopyridine derivatives has been demonstrated with
good yields. Good to excellent regioselectivities have been achieved with unsymmetrically
substituted 4-nitropyrazoles.
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INTRODUCTION
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N-Fused heterocycles, essentially comprising of at least two structural N-heterocyclic ring
motifs, have received much attention as these compounds have exhibited excellent biological
activities and represent several marketed therapeutics.1 Among them pyrazolo[1,5-a]pyridine
derivatives have displayed a wide range of potential biological activities that may become
suitable for "privileged" compounds in drug discovery research programs. Substituted N-
fused/bridged pyrazolopyridine derivatives that possess a wide range of potential biological
activities are depicted in Figure 1.2 Eg. 3-Amino substituted pyrazolo[1,5-a]pyridine E2508 is an
antagonist of Corticotropin Releasing Factor-1 (CRF1) receptor and has been proved to possess
excellent drug properties to advance into clinical trials for the treatment of stress related
disorders (Figure 1).2e Therefore the construction of pyrazole fused pyridines has been a topic of
interest to organic chemists.3
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The reported methods to access the N-fused pyrazolopyridine skeleton, broadly, fall in to two
strategies: (i) construction of pyrazole on a pyridine ring and (ii) construction of pyridine on a
pyrazole ring (Scheme 1a,b). There have been several reports on the former strategy that use the
specifically prepared pyridine reagents including N-aminated pyridines and 2-substituted
pyridines as precursors.4 However, these precursors are not readily accessible besides the
synthesis of N-aminated pyridines is associated with the generation of by-products.5 Hence the
pyridine part is scarcely substituted in this strategy. The substituted pyrazolopyridine derivatives
are generally synthesized using expensive/unfriendly transition metal catalysts through the
functionalization/derivatization of the appropriate pyrazolo[1,5-a]pyridines.6
Concerning the later strategy, the reported methods using this strategy are very few that deal
with the intramolecular cyclization of specially substituted pyrazole precursors.7 Further these
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precursors were prepared using multi-step synthesis. Intermolecular approach was reported for
the synthesis of pyrazolo[1,5-a]pyridine derivatives from the reaction of 3-aryl substituted
pyrazole-5-carbaldehydes and 4-bromocrotonates.8 However, the pyrazole precursors were
synthesized using multi-step processes.
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N-fused pyrazolopyridine system in circles
F3CO
SOMe
H
N
O
N
OMe
B
antitubercular agent2b
N
SO2
N
N
H
N
HO
O
A
H
antimalarial agent2a
N
N
O
N
.
pTsOH
O
N
N
O
Cl
N
H
MeO
N
OMe
N
N
O
N
MeO
F3C
E (E2508)
C
D
useful in the treatment of
stress related disorders2e
melatonin receptor ligand2c
hepatitis C
replication inhibitor2d
Figure 1. Selected biologically active substituted N-fused pyrazolopyridine derivatives.
RESULTS AND DISCUSSION
Recently, we have reported transition metal (TM)-catalyzed arylation–cyclization strategies for
the synthesis of various fused heterocycles.9 Herein, alternatively, we report the development of
TM-free strategy for the synthesis of N-fused pyrazolopyridine derivatives. We envisaged the
direct construction of pyridine ring structure on a pyrazole ring from an intermolecular reaction
between 3,5-dialkyl substituted 4-nitropyrazoles 1 and alkynyl ketones/aldehydes 2, harnessing
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their innate reactivity profiles (Scheme 1c). The proposed strategy involves tandem aza-Michael
addition of 4-nitropyrazole to alkynyl carbonyl compound followed by vinylogous nitroaldol
condensation of γ-active methyl(-ene) group of 4-nitropyrazole and carbonyl group on alkyne
(Scheme 1c).
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Scheme 1. Strategies for the construction of N-fused pyrazolopyridines and Present tandem
strategy.
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Accordingly, we have performed the reaction of readily accessible 3,5-dimethyl-4-
nitropyrazole 1a and alkynyl ketone 2a in the presence of different bases like KOH, KOtBu, and
NaH―unfortunately, none of these reactions gave the expected product but most of the starting
materials were recovered unreacted (Table 1, entries 1-3). Gratifyingly, use of potassium
carbonate as a base gave excellent yields of the desired product 3a via tandem aza-Michael
addition―vinylogous nitroaldol condensation (Table 1, entries 4-5). We have also screened
different bases (Table 1, entries 6-7), various solvents and reaction conditions in this
transformation (for an extensive optimization survey, see Supporting Information). It turned out
that K2CO3 in DMSO at 120 oC was found to be the best condition from the optimization survey.
Note that this transformation works well at room temperature albeit required prolonged reaction
time (Table 1, entry 8). This transformation was not successful in the absence of the base (Table
1, entry 9) or in the presence of a catalytic amount (20 mol%) of the base.
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Table 1. Optimization study.a
Entry
Base
KOH
KOtBu
NaH
Temp (oC)
120
Time (h)
% yield of 3a
1
2
3
2
2
2
―
―
―
120
120
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K2CO3
K2CO3
NaHCO3
Cs2CO3
K2CO3
―
120
120
120
120
RT
2
4
86
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85
―
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120
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (1.65 mmol), DMSO = dimethyl sulfoxide (2 mL).
After identifying the set of optimized conditions, we turned to study the generality of the
present tandem aza-Michael addition―vinylogous nitroaldol condensation (Scheme 2). We have
used 4-nitropyrazoles containing symmetrical alkyl groups at 3-, 5-positions and variously
substituted alkynyl carbonyl compounds. Reactions of 3,5-dimethyl- and 3,5-diethyl-4-
nitropyrazoles (1a and 1b) with 1,3-diphenylprop-2-yn-1-one 2a provided good to excellent
yields of the corresponding pyrazolopyridine derivatives 3a-b. Reactions with 1-(naphthalen-1-
yl)-3-phenylprop-2-yn-1-one 2b gave moderate to good yields of the pyrazolopyridines 3c-d.
Several diaryl substituted alkynyl ketones containing halogen, electron withdrawing and electron
donating groups on the aryl moieties have been used in this tandem process to furnish the
corresponding highly substituted pyrazolo[1,5-a]pyridine derivatives 3e-u in moderate to high
yields. The reaction of 1a and 1,1,1-trifluoro-4-phenylbut-3-yn-2-one 2p afforded the
corresponding pyrazole fused pyridine 3v in 42% yield. The reactions of 3,5-dialkyl 4-
nitropyrazoles 1a-b and alkynyl ketones 2q-r having aryl, alky substituents provided good yields
of the corresponding N-fused pyrazolopyridines 3w-y. The reaction of 1a and hex-3-yn-2-one 2s
afforded the corresponding pyrazole fused pyridine 3z in 53% yield.
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Scheme 2. Reaction of 3,5-dimethyl- and 3,5-diethyl-4-nitropyrazoles and alkynyl ketones.a
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[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.65 mmol), DMSO (2 mL).
We have also used alkynyl ketones 2t-v―containing heteroaryl moieties like 2-, 3-pyridyl
and 2-thiophenyl―in the tandem aza-Michael addition―vinylogous nitroaldol condensation
process of 3,5-dimethyl-4-nitropyrazole 1a to furnish the corresponding pyrazolo[1,5-a]pyridines
3aa-ac in good yields (Scheme 3).
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Scheme 3. Reaction of 3,5-dimethyl-4-nitropyrazole and alkynyl ketones bearing
heterocycles.a
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[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.65 mmol), DMSO (2 mL).
Later we checked the scope of the present tandem reaction using 4-nitropyrazoles 1c-e
containing unsymmetrical alkyl groups at 3-, 5-positions and variously substituted alkynyl
carbonyl compounds 2a-b, 2g-h, 2w (Scheme 4). The corresponding pyrazolo[1,5-a]pyridines
3ad-3aj were isolated in moderate to very good yields. It is interesting to note that the products
3ad-3ai were isolated with excellent regioselectivity resulting from the participation of less
sterically hindered methyl group at 5-position of the pyrazole in the vinylogous nitroaldol
condensation process.
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Scheme 4. Reaction of unsymmetrical 3,5-disubstituted 4-nitropyrazoles and alkynyl
ketones.a
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R1
R1
N
NO2
NO2
O
K2CO3
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N
R3
+
N
DMSO, 120 oC, 4 h
R2
N
2
R2
H
1
R3
1c: R1 = CH2CHMe2; 1d: R1 = Et; 1e: R1 = CF3
2w: R2 = Ph, R3 = C6H4-p-Br
3
NO2
NO2
NO2
NO2
N
N
N
N
N
N
N
N
3ae, 63%
3ad, 83%
3af, 60%
3ag, 72%
OMe
Br
F3C
NO2
NO2
NO2
N
N
N
N
N
N
F
3aj, 67%
3ah, 51%
3ai, 34%
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.65 mmol), DMSO (2 mL).
We have also used alkynyl aldehydes like 3-phenylpropiolaldehyde 2x in the tandem aza-
Michael addition―vinylogous nitroaldol condensation process of 3,5-dimethyl- and 3,5-diethyl-
4-nitropyrazoles 1a-b to furnish the corresponding pyrazolo[1,5-a]pyridines 3ak and 3al in 63%
and 55% yields, respectively (Scheme 5).
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Scheme 5. Reaction of 1a-b and 2x.a
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[a] Reaction conditions: 1 (0.5 mmol), 2x (0.5 mmol), K2CO3 (1.65 mmol), DMSO (2 mL).
When
the
unsymmetrical
3-ethyl-5-methyl-4-nitro-1H-pyrazole
1d
and
3-
phenylpropiolaldehyde 2x reacted, two regioisomers 3am and 3am' were obtained in 3:1 ratio,
respectively (Scheme 6a). It is reasonable to believe that the formation of isomer 3am' resulted
from the tautomerization of 3-ethyl-5-methyl-4-nitro-1H-pyrazole 1d to 5-ethyl-3-methyl-4-
nitro-1H-pyrazole 1da.10 The major product being resulted from the participation of less
sterically congested 5-methyl substituent of 1d in the vinylogous nitroaldol condensation process
(Scheme 6b).
Scheme 6. Reaction of 1d and 2x.a
NO2
NO2
NO2
O
K2CO3
N
N
+
H
+
N
N
N
DMSO, 120 oC, 4 h
N
H
Ph
Ph
Ph
2x
1d
3am', 15%
3am, 42%
[a] Reaction conditions: 1d (0.5 mmol), 2x (0.5 mmol), K2CO3 (1.65 mmol), DMSO (2 mL).
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Scheme 6b.
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NO2
NO2
NO2
2a
N
N
N
N
N
K2CO3
N
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H
H
Ph
1d
Ph
O
3am
, 42%
NO2
NO2
2a
N
NO2
N
N
N
H
O
K2CO3
N
Ph
N
Ph
H
1da
3am', 15%
It is worth mentioning that the present tandem aza-Michael addition―vinylogous nitroaldol
condensation process worked well at gram scale to provide 2-methyl-3-nitro-5,7-
diphenylpyrazolo[1,5-a]pyridine 3a in high yield (Scheme 7).
Scheme 7. Gram scale synthesis of product 3a.a
[a] Reaction conditions: 1a (10 mmol), 2a (10 mmol), K2CO3 (33 mmol), DMSO (25 mL).
We became interested to test carboxylate as an electron withdrawing group instead of nitro
group at the 4-position of 3,5-dimethylpyrazole. Accordingly, the reaction of ethyl 3,5-dimethyl-
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1H-pyrazole-4-carboxylate 1f and 1,3-diphenylprop-2-yn-1-one 2a was conducted in the
5
6
o
presence of K2CO3 in DMSO at 120 C for 4 h. We have observed the formation of the
7
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9
corresponding aza-Michael adduct 4 and pyrazolo[1,5-a]pyridine 5 in very low yields (Scheme
8a) . The reaction of 3,4,5-trimethyl-1H-pyrazole 1g, having methyl group at 4-position, and 2a
was conducted in DMSO in the presence of K2CO3. In this reaction the corresponding aza-
Michael adduct 6 was observed in low yield (Scheme 8b). The above experiments suggest that
the present tandem process is more efficient with strong EWG like nitro group at the 4th position
on pyrazole. The reaction of N-methyl substituted 3,5-dimethyl-4-nitropyrazole 1h and 2a was
not successful to give any vinylogous nitroaldol condensation product while most of the pyrazole
remain unreacted (Scheme 8c).
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Scheme 8. Reactions of 1f-h and 2a.
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The 3-nitro group of the pyrazolo[1,5-a]pyridine 3a was reduced to give the corresponding 3-
amino pyrazolo[1,5-a]pyridine 7 derivative in good yield without further purification. The
reaction was also conducted on gram scale to give moderate yield of the product 7 (Scheme 9).
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Scheme 9. Reduction of nitro group in 3a.
A plausible tentative mechanism can be proposed for the present tandem aza-Michael
addition―vinylogous nitroaldol condensation. In the presence of base 3,5-dialkyl 4-
nitropyrazole 1 would add on to the alkynyl carbonyl compound 2 in aza-Michael addition
fashion to give intermediate I. The base would abstract the acidic proton present on the active γ-
methylene group, activated by a nitro group through conjugation, to provide intermediate II that
can act as a C-nucleophile. The vinylogous nitroaldol condensation process would finally give
the product 3 via intermediate III with the loss of a water molecule (Scheme 10, path a).
Alternatively, the reaction may go through initial vinylogous nitroaldol condensation
intermediate IV followed by intramolecular 1,8-conjugate addition (Scheme 10, path b).
However, this path may be ruled out since the reaction of 1,3,5-trimethyl-4-nitro-1H-pyrazole 1h
did not provide a vinylogous nitroaldol condensation product.
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Scheme 10. Plausible reaction mechanism.
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CONCLUSIONS
In summary, we have developed and demonstrated a new tandem reaction process involving
base-mediated aza Michael addition―vinylogous nitroaldol condensation process between 3,5-
dialkyl substituted 4-nitropyrazoles and alkynyl aldehydes or ketones. The advantages of this
transformation being the formation of C–N and C=C bonds in one step and atom economic with
the generation of water as the only by-product. This process furnished highly substituted 3-
nitropyrazolo[1,5-a]pyridine derivatives in moderate to high yields. Further studies are underway
on the application of the developed method for selected target oriented synthesis.
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EXPERIMENTAL SECTION
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All the reactions were performed using oven-dried standard glassware or screw-caped vials. The
reactions are stirred magnetically and monitored by analytical thin layer chromatography (TLC).
TLC was made by silica gel 60 F254, and UV lamp was used as visualizing agent. Iodine, 5%
aqueous potassium permanganate solution were used as a developing agents followed by heating.
Purification of products was performed using column chromatography on silica gel (60-120,
100-120 and 230-400 mesh) where it is required. Hexane/ethyl acetate were used as eluents. The
solvents were removed by rotary evaporator at 40-45 oC under reduced pressure. All the reagents
and solvents were purchased from commercial suppliers. Melting points reported in this work are
uncorrected. The IR spectra were recorded on a FT-IR spectrophotometer by dissolving the
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sample in chloroform or as KBr pellet. H-NMR spectra were recorded on 300, 400 and 500
MHz instruments. Chemical shifts (δ) are reported in parts per million (ppm) with the reference
solvent and the internal standards (TMS = 0; CDCl3 = 7.26). The following abbreviations were
used to explain the multiplicity of the spectra (s = singlet, d = doublet, dd = doublet of doublet, t
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= triplet, q = quartet, sep = septet, m = multiplet). C-NMR spectra were recorded on 75, 100,
and 125 MHz spectrometers. The mass spectral analyses were carried out using Electrospray
Ionization (ESI) techniques and high resolution mass spectra (HRMS) were recorded on a
Orbitrap Mass Spectrometer or QSTAR XL Hybrid MS/MS mass spectrometer.
General procedure for the synthesis of pyrazolo[1,5-a]pyridine derivatives (0.5 mmol
scale) 3a-3am':- 3,5-Dialkyl 4-nitro-1H-pyrazole 1 (0.5 mmol), K2CO3 (1.65 mmol, 227 mg),
alkynyl carbonyl compound 2 (0.5 mmol) were taken into a 10 mL screw cap vial and added
DMSO (2 mL). The reaction vial was placed in a metal heating block, gradually heated to 120 oC
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and stirred at the same temperature for 4 h. The reaction mixture was cooled to room
temperature, diluted with water and extracted with ethyl acetate (2 x 20 mL). The organic phase
was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed in
vacuo to afford a crude residue. The residue was purified by flash column chromatography
(hexane/EtOAc, 95:5) on silica gel to afford pyrazolo[1,5-a]pyridine derivatives 3a-3am'.
2-Methyl-3-nitro-5,7-diphenylpyrazolo[1,5-a]pyridine 3a:- Pale yellow solid, 152 mg,
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(0.462 mmol), 92%, Rf = 0.6 (EtOAc/Hexane, 5:95); MP 158-160 C; IR (CHCl3) 741, 928,
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1214, 1476, 1549, 1635, 3019 cm-1; H-NMR (400 MHz, CDCl3) δ = 2.78 (s, 3H), 7.40 (d, J =
2.0 Hz, 1H), 7.48-7.51 (m, 1H), 7.52-7.55 (m, 2H), 7.55-7.60 (m, 3H), 7.77-7.79 (m, 2H), 7.88-
7.91 (m, 2H), 8.57 (d, J = 2.0 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 114.0, 115.8,
127.3, 128.7, 129.3, 129.5, 129.7, 130.5, 131.7, 137.4, 138.8, 141.6, 144.2, 151.9; MS (ESI) m/z
330 [M+H]+; HRMS (ESI, m/z): calcd for C20H16N3O2 [M+H]+ 330.1237, found 330.1239.
2-Ethyl-4-methyl-3-nitro-5,7-diphenylpyrazolo[1,5-a]pyridine 3b:- Pale yellow solid, 134
o
mg, (0.375 mmol), 75%, Rf = 0.6 (EtOAc/Hexane, 5:95); MP 118-120 C; IR (CHCl3) 747,
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1214, 1471, 1526, 2921, 3020 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.36 (t, J = 7.4 Hz, 3H),
2.53 (s, 3H), 3.10 (q, J = 7.5 Hz, 2H), 7.08 (s, 1H), 7.40-7.45 (m, 2H), 7.46-7.49 (m, 2H), 7.49-
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7.55 (m, 4H), 7.85-7.89 (m, 2H); C{1H}NMR (100 MHz, CDCl3) δ = 12.6, 18.3, 21.8, 118.4,
124.1, 125.5, 128.4, 128.5, 128.7, 129.3, 129.7, 129.9, 132.1, 137.7, 138.6, 138.8, 143.9, 156.1;
MS (ESI) m/z 358 [M+H]+; HRMS (ESI, m/z):calcd for C22H20N3O2 [M+H]+ 358.1550, found
358.1557.
2-Methyl-5-(naphthalen-1-yl)-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3c:- Yellow solid,
o
169 mg, (0.445 mmol), 89%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 168-170 C; IR (CHCl3)
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758, 1157, 1380, 1477, 1549, 1636, 2853, 2923, 3058 cm-1; H-NMR (500 MHz, CDCl3) δ =
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2.80 (s, 3H), 7.54 (s, 1H), 7.56-7.62 (m, 5H), 7.87-7.99 (m, 5H), 8.01 (d, J = 8.6 Hz, 1H), 8.26
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(s, 1H), 8.70 (s, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 114.2, 115.9, 123.7, 124.5,
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126.9, 127.0, 127.2, 127.8, 128.6, 128.7, 129.2, 129.8, 130.5, 131.8, 133.5, 133.6, 134.6, 138.8,
141.7, 144.1, 151.9; MS (ESI) m/z 380 [M+H]+ HRMS (ESI, m/z): calcd for C24H18N3O2
[M+H]+, 380.1393 found 380.1402.
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2-Ethyl-4-methyl-5-(naphthalen-1-yl)-3-nitro-7-phenylpyrazolo[1,5-a]pyridine
3d:-
o
Yellow solid, 118 mg, (0.289 mmol), 58%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 160-162 C;
IR (CHCl3) 751, 1214, 1463, 1666, 2853, 2923, 2955, 3019 cm-1; 1H-NMR (500 MHz, CDCl3) δ
= 1.38 (t, J = 7.5 Hz, 3H), 2.58 (s, 3H), 3.12 (q, J = 7.5 Hz, 2H), 7.18 (s, 1H), 7.51-7.58 (m, 6H),
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7.88-7.94 (m, 5H), 7.97 (d, J = 8.4 Hz, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 12.6, 17.9,
21.8, 119.0, 125.3, 125.9, 126.3, 126.8, 126.9, 128.4, 128.6, 128.8, 129.7, 129.9, 131.2, 131.9,
133.6, 136.5, 137.4, 138.4, 142.4, 155.9; MS (ESI) m/z 408 [M+H]+ HRMS (ESI, m/z): calcd
for C26H22N3O2 [M+H]+ 408.1712 found 408.1707.
7-([1,1'-Biphenyl]-4-yl)-2-methyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3e:- yellow
o
solid, 164 mg, (0.404 mmol), 81%, Rf = 0.6 (EtOAc/Hexane, 30:70); MP 234-236 C; IR
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(CHCl3) 763, 1286, 1474, 1546, 1632, 2855, 2922 cm-1; H-NMR (400 MHz, CDCl3) δ = 2.81
(s, 3H), 7.39-7.57 (m, 7H), 7.67-7.69 (m, 2H), 7.78-7.80 (m, 4H), 7.99-8.01 (m, 2H), 8.57 (d, J =
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2.0 Hz, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 113.9, 115.7, 127.2, 127.3, 127.4,
129.0, 129.4, 130.2, 137.3, 138.8, 140.1, 141.3, 143.4, 144.2, 151.9; MS (ESI) m/z 406 [M+H]+
HRMS (ESI, m/z):calcd for C26H20N3O2 [M+H]+ 406.1550, found 406.1559.
5-(4-Chlorophenyl)-2-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3f:- Pale yellow
solid, 110 mg, (0.303 mmol), 61%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 172-174 oC; IR (CHCl3)
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756, 1161, 1471, 1548, 1635, 2923, 3061 cm-1; H-NMR (500 MHz, CDCl3) δ = 2.78 (s, 3H),
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7.34 (d, J = 2.0 Hz, 1H), 7.50-7.52 (m, 2H), 7.57-7.58 (m, 3H), 7.71-7.72 (m, 2H), 7.88-7.90 (m,
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2H), 8.53 (d, J = 2.0 Hz, 1H); C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 113.9, 115.4, 128.6,
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128.7, 129.6, 129.7, 130.6, 131.6, 135.8, 135.9, 138.7, 141.8, 142.8, 152.1; MS (ESI) m/z 364
[M+H]+; HRMS (ESI, m/z): calcd for C20H15N3O2Cl [M+H]+ 364.0847, found 364.0846.
5-(4-Chlorophenyl)-2-ethyl-4-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3g:- Pale
yellow solid, 131 mg, (0.335 mmol), 67%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 166-168 oC; IR
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(CHCl3) 764, 1198, 1473, 1532, 1612, 2932, 2973 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.34
(t, J = 7.5 Hz, 3H), 2.51 (s, 3H), 3.10 (q, J = 7.5 Hz, 2H), 7.02 (s, 1H), 7.34-7.37 (m, 2H), 7.46-
7.49 (m, 2H), 7.51-7.54 (m, 3H), 7.83-7.87 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ = 12.5,
18.3, 21.8, 117.9, 124.1, 125.6, 128.4, 128.9, 129.7, 130.0, 130.6, 131.9, 134.6, 137.2, 137.6,
138.8, 142.6, 156.1; MS (ESI) m/z 392 [M+H]+; HRMS (ESI, m/z): calcd for C22H19N3O2Cl
[M+H]+ 392.1160, found 392.1162.
5-(2-Chlorophenyl)-2-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3h:- Yellow solid,
o
160 mg, (0.44 mmol), 88%, Rf = 0.34 (EtOAc/Hexane, 10:90); MP 148-150 C; IR (CHCl3)
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753, 1160, 1292, 1334, 1407, 1544, 1634, 2923, 3056 cm-1; H NMR (400 MHz, CDCl3) δ =
2.79 (s, 3H), 7.31 (d, J = 1.9 Hz, 1H), 7.40-7.42 (m, 2H), 7.48-7.51 (m, 1H), 7.53-7.57 (m, 4H),
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7.89-7.91 (m, 2H), 8.40 (d, J = 1.9 Hz, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 117.0,
118.2, 123.8, 127.4, 128.6, 129.7, 130.2, 130.3, 130.4, 131.0, 131.5, 132.3, 137.2, 138.3, 140.6,
142.6, 151.7; MS (ESI) m/z 364 [M+H]+; HRMS (ESI, m/z):calcd for C20H15ClN3O2 [M+H]+
364.0847, found 364.0871.
2-Methyl-3-nitro-5-(3-nitrophenyl)-7-phenylpyrazolo[1,5-a]pyridine 3i:- Pale yellow
solid, 116 mg, (0.310 mmol), 62%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 176-178 oC; IR (CHCl3)
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742, 981, 1283, 1449, 1527, 1634, 2928 cm-1; H-NMR (400 MHz, CDCl3) δ = 2.80 (s, 3H),
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7.40 (d, J = 2.0 Hz, 1H), 7.58-7.63 (m, 3H), 7.76 (t, J = 8.0 Hz, 1H), 7.89-7.94 (m, 2H), 8.14 (d,
J = 8.4 Hz, 1H), 8.36 (dd, J1 = 2.4 Hz, J2 = 7.6 Hz, 1H), 8.62 (d, J = 2.0 Hz, 2H); 13C{1H}NMR
(100 MHz, CDCl3) δ = 14.9, 114.6, 115.1, 122.2, 124.1, 128.8, 129.7, 130.5, 130.8, 131.3, 133.2,
138.6, 139.2, 141.2, 142.2, 148.9, 152.2; MS (ESI) m/z 375 [M+H]+; HRMS (ESI, m/z): calcd
for C20H14N4O4Na [M+Na]+; 397.0907, found 397.0932.
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2-Ethyl-4-methyl-3-nitro-5-(3-nitrophenyl)-7-phenylpyrazolo[1,5-a]pyridine 3j:- Pale
yellow solid, 153 mg, (0.379 mmol), 76%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 170-172 oC; IR
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(CHCl3) 774, 1125, 1484, 1533, 1617, 2930, 3058 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.36
(t, J = 7.5 Hz, 3H), 2.53 (s, 3H), 3.11 (q, J = 7.5 Hz, 2H), 7.05 (s, 1H), 7.53-7.56 (m, 3H), 7.70
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(t, J = 7.8 Hz, 1H ), 7.76-7.78 (m, 1H), 7.85-7.88 (m, 2H), 8.30-8.34 (m, 2H); C{1H}NMR
(100 MHz, CDCl3) δ = 12.5, 18.3, 21.8, 117.5, 123.3, 124.2, 124.4, 125.8, 128.6, 129.7, 129.8,
130.3, 131.7, 135.4, 139.2, 140.6, 140.9, 148.4, 156.3; MS (ESI) m/z 403 [M+H]+; HRMS (ESI,
m/z): calcd for C22H19N4O4 [M+H]+ 403.1400, found 403.1399; C22H18N4O4Na [M+Na]+
425.1220, found 425.1218.
5-(4-Methoxyphenyl)-2-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3k:- Yellow
o
solid, 117 mg, (0.325 mmol), 65%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 190-192 C; IR
(CHCl3) 744, 1214, 1380, 1448, 1606, 3019 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 2.77 (s, 3H),
3.89 (s, 3H), 7.02-7.07 (m, 2H), 7.36 (d, J = 2.1 Hz, 1H), 7.55-7.60 (m, 3H), 7.70-7.76 (m, 2H),
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7.84-7.91 (m, 2H), 8.16 (d, J = 1.9 Hz, 1H); C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 55.5,
113.0, 114.7, 115.4, 128.6, 128.7, 129.7, 130.4, 131.8, 138.9, 141.5, 143.8, 151.9, 160.9; MS
(ESI) m/z 360 [M+H]+; HRMS (ESI, m/z): calcd for C21H18N3O3 [M+H]+ 360.1342 found
360.1349.
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3l:-
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Yellow solid, 124 mg, (0.320 mmol), 64%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 176-178 C;
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IR (CHCl3) 758, 1029, 1252, 1478, 1511, 1599, 2925 cm-1; H-NMR (400 MHz, CDCl3) δ =
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1.36 (t, J = 7.5 Hz, 3H), 2.53 (s, 3H), 3.10 (q, J = 7.4 Hz, 2H), 3.88 (s, 3H), 7.02 (d, J = 8.4 Hz,
2H), 7.07 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.49-7.54 (m, 3H), 7.82-7.90 (m, 2H); 13C{1H}NMR
(100 MHz, CDCl3) δ = 12.6, 18.3, 21.6, 55.3, 114.0, 118.5, 123.9, 125.3, 128.4, 129.7, 129.9,
130.6, 131.0, 132.1, 137.8, 138.5, 143.5, 156.0, 159.6, 159.7; MS (ESI) m/z 388 [M+H]+;
HRMS (ESI, m/z): calcd for C23H22N3O3 [M+H]+ 388.1655 found 388.1659.
7-(4-Fluorophenyl)-2-methyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3m:- Yellow solid,
o
108 mg, (0.311 mmol), 62%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 188-190 C; IR (CHCl3)
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768, 1159, 1379, 1477, 1549, 1635, 2852, 2925 cm-1; H-NMR (400 MHz, CDCl3) δ = 2.80 (s,
3H), 7.23-7.28 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.47-7.58 (m, 3H), 7.75-7.79 (m, 2H), 7.89-
7.94 (m, 2H), 8.56 (d, J = 2.0 Hz, 1H); 13C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 114.1, 115.6,
115.7, 115.9, 123.7, 127.3, 127.7, 127.8 (J = 12.0 Hz), 129.3, 129.6, 131.8 (J = 8.17 Hz), 137.3,
138.8, 140.5, 144.2, 151.9, 162.6, 165.1; MS (ESI) m/z 348 [M+H]+; HRMS (ESI, m/z): calcd
for C20H15FN3O2 [M+H]+ 348.1142 found 348.1141.
7-(4-Chlorophenyl)-2-methyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3n:- Yellow solid,
o
105 mg, (0.289 mmol), 58%, Rf = 0.42 (EtOAc/Hexane, 10:90); MP 142-144 C; IR (CHCl3)
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768, 1159, 1291, 1379, 1447, 1549, 1634, 2856, 2925, 2961, 3056 cm-1; H NMR (500 MHz,
CDCl3) δ = 2.78 (s, 3H), 7.38 (d, J = 2.0 Hz, 1H), 7.50-7.57 (m, 5H), 7.75-7.79 (m, 2H), 7.84-
7.88 (m, 2H), 8.57 (d, J = 2.0 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 114.3, 115.7,
127.3, 128.6, 128.9, 129.3, 129.6, 130.1, 131.0, 136.6, 137.2, 138.8, 140.3, 144.1, 151.9;MS
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(ESI) m/z 364 [M+H]+; HRMS (ESI, m/z): calcd for C20H15ClN3O2 [M+H]+, 364.0847, found
364.0849.
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7-(2-Chlorophenyl)-2-methyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3o:- Yellow solid,
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o
140 mg, (0.38 mmol), 77%, Rf = 0.30 (EtOAc/Hexane, 10:90); MP 198-200 C; IR (CHCl3)
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760, 1163, 1284, 1326, 1439, 1549, 1633, 2924, 3070 cm-1; H NMR (500 MHz, CDCl3) δ =
2.73 (s, 3H), 7.35 (d, J = 1.9 Hz, 1H), 7.45-7.55 (m, 6H), 7.59-7.60 (m, 1H), 7.77-7.79 (m, 2H),
8.61 (d, J = 2.1 Hz, 1H); 13C{1H}NMR (125 MHz, CDCl3) δ = 14.8, 114.7, 116.6, 123.7, 127.0,
127.3, 129.3, 129.6, 130.1, 131.3, 131.4, 131.5, 134.2, 137.2, 138.3, 138.9, 143.6, 151.9; MS
(ESI) m/z 364 [M+H]+; HRMS (ESI, m/z):calcd for C20H15ClN3O2 [M+H]+ 364.0847, found
364.0871.
2-Methyl-3-nitro-5-phenyl-7-(p-tolyl)pyrazolo[1,5-a]pyridine 3p:- Yellow solid, 140 mg,
o
(0.408 mmol), 82%, Rf = 0.6 (EtOAc/Hexane, 10:90); MP 185-187 C; IR (CHCl3) 766, 1291,
1477, 1549, 1634, 2855, 2926, 3043 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 2.47 (s, 3H), 2.78 (s,
3H), 7.36-7.40 (m, 3H), 7.46-7.50 (m, 1H), 7.51-7.56 (m, 2H), 7.73-7.82 (m, 4H), 8.54 (d, J =
13
2.1 Hz, 1H); C{1H}NMR (125, MHz, CDCl3) δ = 14.9, 21.5, 113.7, 115.5, 123.6, 127.3,
128.8, 129.3, 129.4, 129.5, 129.6, 137.5, 138.8, 140.8, 141.7, 144.2, 151.9; MS (ESI) m/z 344
[M+H]+; HRMS (ESI, m/z): calcd for C21H18N3O2 [M+H]+ 344.1399, found 344.1409.
7-(4-(tert-Butyl)phenyl)-2-methyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3q:- Yellow
o
solid, 150 mg, (0.389 mmol), 78%, Rf = 0.4 (EtOAc/Hexane, 10:90); MP 172-174 C; IR
(CHCl3) 768, 1291, 1379, 1447, 1509, 1635, 2855, 2926, 3057 cm-1; H-NMR (500 MHz,
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CDCl3) δ = 1.40 (s, 9H), 2.79 (s, 3H), 7.39 (d, J = 2.1 Hz, 1H), 7.55-7.45 (m, 3H), 7.61-7.57 (m,
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2H), 7.79-7.73 (m, 2H), 7.89-7.84 (m, 2H), 8.53 (d, J = 2.1 Hz, 1H); C{1H}NMR (125 MHz,
CDCl3) δ = 14.9, 31.2, 34.9, 113.7, 115.6, 123.6, 125.7, 127.3, 128.7, 129.3, 129.4, 129.5, 137.5,
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138.8, 141.6, 144.2, 151.5, 153.8; MS (ESI) m/z 386 [M+H]+; HRMS (ESI, m/z): calcd for
C24H24N3O2 [M+H]+ 386.1869, found 386.1874.
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7-(4-Fluorophenyl)-5-(4-methoxyphenyl)-2-methyl-3-nitropyrazolo[1,5-a]pyridine 3r:-
yellow solid, 116 mg, (0.307 mmol), 62%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 206-208 oC; IR
(CHCl3) 753, 827, 1157, 1379, 1473, 1537, 1636, 2851, 2921 cm-1; 1H-NMR (400 MHz, CDCl3)
δ = 2.77 (s, 3H), 3.89 (s, 3H), 7.03-7.08 (m, 2H), 7.23-7.30 (m, 3H), 7.33 (d, J = 2.1 Hz, 1H),
7.70-7.76 (m, 2H), 7.87-7.93 (m, 2H), 8.51 (d, J = 2.1 Hz, 1H); 13C{1H}NMR (125 MHz,
CDCl3) δ = 14.9,.55.5, 113.0, 114.8, 115.3, 115.9 (J = 13.3 Hz), 123.5, 128.5, 129.4, 131.8 (J =
8.8 Hz), 138.9, 140.4, 143.8, 151.9, 161.0.; MS (ESI) m/z 378 [M+H]+; HRMS (ESI, m/z): calcd
for C21H17FN3O3 [M+H]+ 378.1248, found 378.1252.
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2-Methyl-3-nitro-5-(3-nitrophenyl)-7-(p-tolyl)pyrazolo[1,5-a]pyridine 3s:- Pale yellow
solid, 101 mg, (0.260 mmol), 52%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 182-184 oC; IR (CHCl3)
1285, 1474, 1532, 1616, 2927, 2960 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 2.48 (s, 3H), 2.80 (s,
3H), 7.38 (d, J = 2.0 Hz, 1H), 7.39 (s, 1H), 7.41 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.81 (s, 1H),
7.82 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.35 (dd, J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 8.58 (d, J = 2.0 Hz,
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1H), 8.60 (d, J = 1.8 Hz, 1H); C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 21.6, 114.3, 114.8,
122.2, 124.0, 128.4, 129.5, 129.6, 130.5, 133.2, 138.6, 139.3, 141.2, 141.3, 142.4, 148.9, 152.2;
MS (ESI) m/z 389 [M+H]+; HRMS (ESI, m/z): calcd for C21H17N4O4 [M+H]+ 389.1244, found
389.1249.
2-Ethyl-4-methyl-3-nitro-5-(3-nitrophenyl)-7-(p-tolyl)pyrazolo[1,5-a]pyridine 3t:- Pale
yellow solid, 136 mg, (0.326 mmol), 65%, Rf = 0.5 (EtOAc/Hexane, 5:95); MP 178-180 oC; IR
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(CHCl3) 981, 1127, 1458, 1526, 1629, 2927, 2960 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.36
(t, J = 7.5 Hz, 3H), 2.45 (s, 3H), 2.52 (s, 3H), 3.11 (q, J = 7.5 Hz, 2H), 7.02 (s, 1H), 7.34 (d, J =
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8.0 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.75-7.78 (m, 3H), 8.29-8.33 (m, 2H); 13C{1H}NMR (100
MHz, CDCl3) δ = 12.6, 18.3, 21.5, 21.8, 117.2, 123.3, 124.1, 129.3, 129.6, 129.8, 135.4, 135.5,
139.3, 140.6, 141.0, 148.4, 156.2; MS (ESI) m/z 417 [M+H]+; HRMS (ESI, m/z): calcd for
C23H21N4O4 [M+H]+ 417.1518, found 417.1518.
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7-(4-tert-Butylphenyl)-2-methyl-3-nitro-5-(3-nitrophenyl)pyrazolo[1,5-a]pyridine 3u:-
yellow solid, 150 mg, (0.348 mmol), 70%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 168-170 oC; IR
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(CHCl3) 757, 809, 1026, 1158, 1296, 1346, 1475, 1535, 1635, 2867, 2928 cm-1; H-NMR (400
MHz, CDCl3) δ = 1.41 (s, 9H), 2.82 (s, 3H), 7.40-7.41 (m, 1H), 7.60-7.63 (m, 2H), 7.75 (t, J =
8.0 Hz, 1H), 7.87-7.90 (m, 2H), 8.10-8.14 (m, 1H), 8.32-8.37 (m, 1H), 8.59-8.61 (m, 2H);
113C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 31.2, 34.7, 114.2, 115.0, 122.1, 124.0, 125.8, 128.3,
129.4, 130.4, 133.2, 138.6, 139.3, 141.3, 142.3, 148.9, 152.1, 154.2; MS (ESI) m/z 431 [M+H]+;
HRMS (ESI, m/z): calcd for C24H23N4O4 [M+H]+ 431.1713, found 431.1720.
2-Methyl-3-nitro-7-phenyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine 3v:- Yellow solid,
68 mg, (0.212 mmol), 42%, Rf = 0.4 (EtOAc/Hexane, 10:90); MP 144-146 oC; IR (CHCl3) 694,
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767, 887, 1036, 1078, 1171, 1270, 1306, 1378, 1402, 1549, 1646, 2852, 2923 cm-1; H-NMR
(400 MHz, CDCl3) δ = 2.80 (s, 3H), 7.29-7.31 (m, 1H), 7.57-7.60 (m, 3H), 7.87-7.90 (m, 2H),
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8.65 (s, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 111.7, 114.5 ( J = 4.5 Hz), 121.6,
123.8, 125.0, 128.8, 129.7, 130.6, 131.1, 132.3 ( J = 34 Hz), 137.3, 142.7, 152.3; MS (ESI) m/z
322 [M+H]+; HRMS (ESI, m/z): calcd for C15H11F3N3O2 [M+H]+ 322.0797, found 322.0787.
5-tert-Butyl-2-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3w:- Wine red solid, 115
mg, (0.372 mmol), 74%, Rf = 0.6 (EtOAc/Hexane, 5:95); MP 134-136 oC; IR (CHCl3) 742, 928,
1214, 1382, 1413, 1638, 3019 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 1.45 (s, 9H), 2.75 (s, 3H),
7.17 (d, J = 2.2 Hz, 1H), 7.54-7.59 (m, 3H), 7.82-7.86 (m, 2H), 8.30 (d, J = 2.2 Hz, 1H);
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13C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 30.7, 35.7, 112.6, 115.5, 123.2, 128.6, 129.7, 130.3,
132.1, 138.5, 140.9, 151.7, 155.9; MS (ESI) m/z 310 [M+H]+; HRMS (ESI, m/z): calcd for
C18H20N3O2 [M+H]+ 310.1550, found 310.1543; C18H19N3O2Na [M+Na]+ 332.1369, found
332.1364.
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5-tert-Butyl-2-ethyl-4-methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3x:- Yellow solid,
108 mg, (0.320 mmol) 64%, Rf = 0.6 (EtOAc /Hexane, 5:95); MP 138-140 oC; IR (CHCl3) 742,
928, 1214, 1382, 1472, 1542, 1638, 3019 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.32 (t, J = 7.6
Hz, 3H), 1.54 (s, 9H), 2.69 (s, 3H), 3.03 (q, J = 7.6 Hz, 2H), 7.20 (s, 1H), 7.51-7.55 (m, 3H),
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7.80-7.84 (m, 2H); C{1H}NMR (100 MHz, CDCl3) δ = 12.7, 19.4, 21.7, 31.1, 36.4, 115.9,
125.1, 125.2, 128.5, 129.7, 129.8, 132.6, 137.8, 138.1, 151.1, 156.2; MS (ESI) m/z 338 [M+H]+;
HRMS (ESI, m/z): calcd for C20H24N3O2 [M+H]+ 338.1863, found 338.1859.
5-(tert-Butyl)-7-(4-(tert-butyl)phenyl)-2-methyl-3-nitropyrazolo[1,5-a]pyridine
3y:-
o
Yellow solid, 136 mg, (0.372 mmol), 75%, Rf = 0.4 (EtOAc/Hexane, 10:90); MP 152-154 C;
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IR (CHCl3) 768, 1159, 1379, 1447, 1549, 1634, 2856, 2925, 3056 cm-1; H-NMR (500 MHz,
CDCl3) δ = 1.39 (s, 9H), 1.44 (s, 9H), 2.76 (s, 3H), 7.15-7.21 (m, 1H), 7.53-7.62 (m, 2H), 7.77-
13
7.84 (m, 2H), 8.25-8.31 (m, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 14.9, 30.6, 31.2, 34.9,
35.6, 112.3, 115.3, 123.0, 125.6, 129.3, 132.8, 138.5, 140.8, 151.6, 153.5, 155.9; MS (ESI) m/z
366 [M+H]+; HRMS (ESI, m/z): calcd for C22H28N3O2 [M+H]+ 366.2182, found 366.2200.
7-Ethyl-2,5-dimethyl-3-nitropyrazolo[1,5-a]pyridine 3z:- Yellow solid, 58 mg, (0.264
o
mmol), 53%, Rf = 0.6 (EtOAc/Hexane, 20:80); MP 142-144 C; IR (CHCl3) 769, 1055, 1294,
1458, 1551, 2853, 2924 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.44 (t, J = 7.5 Hz, 3H), 2.51 (s,
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3H), 2.77 (s, 3H), 3.17 (q, J = 7.5 Hz, 2H), 6.77 (s, 1H), 8.01 (s, 1H); C{1H}NMR (75 MHz,
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CDCl3) δ = 11.2, 14.7, 21.8, 23.7, 115.0, 115.5, 138.0, 143.0, 143.9, 151.2; MS (ESI) m/z 220
[M+H]+; HRMS (ESI, m/z): calcd for C11H14N3O2 [M+H]+ 220.1080, found 220.1080.
2-Methyl-3-nitro-7-phenyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyridine 3aa:- Pale yellow
solid,105 mg, (0.318 mmol), 63%, Rf = 0.4 (EtOAc/Hexane, 5:95); MP 154-156 oC; IR (CHCl3)
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770, 1125, 1413, 1508, 1636, 2824, 3065, 3125 cm-1; H-NMR (500 MHz, CDCl3) δ = 2.77 (s,
3H), 7.37 (d, J = 2.0 Hz, 1H), 7.46-7.56 (m, 1H), 7.57-7.60 (m, 3H), 7.89-7.91 (m, 2H), 8.08-
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8.10 (m, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.75 (s, 1H), 9.03 (s, 1H); C{1H}NMR (75 MHz,
CDCl3) δ = 14.9, 115.0, 117.0, 123.7, 124.8, 125.8, 127.4, 129.3, 129.6, 136.5, 137.3, 139.0,
139.4, 144.2, 149.3, 150.1, 151.8; MS (ESI) m/z 331 [M+H]+; HRMS (ESI, m/z): calcd for
C19H15N4O2 [M+H]+ 331.1189, found 331.1208.
2-Methyl-3-nitro-5-phenyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyridine 3ab:- Pale yellow
solid, 98 mg, (0.296 mmol), 60%, Rf = 0.4 (EtOAc/Hexane, 5:95); MP 152-155 oC; IR (CHCl3)
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773, 1124, 1414, 1509, 1600, 2825, 3066, 3126 cm-1; H-NMR (300 MHz, CDCl3) δ = 2.83 (s,
3H), 7.45-7.57 (m, 4H), 7.84 (d, J = 6.8 Hz, 2H), 7.91-7.97 (m, 1H), 8.10 (d, J = 2.2 Hz, 1H),
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8.63-8.65 (m, 2H), 8.83 (d, J = 3.3 Hz, 1H); C{1H}NMR (100 MHz, CDCl3) δ = 14.9, 114.9,
116.9, 124.7, 125.8, 127.4, 129.2, 129.5, 136.5, 137.3, 138.9, 139.4, 144.3, 149.2, 150.0, 151.7;
MS (ESI) m/z 331 [M+H]+; HRMS (ESI, m/z): calcd for C19H15N4O2 [M+H]+ 331.1189, found
331.1208.
2-Methyl-3-nitro-7-phenyl-5-(thiophen-2-yl)pyrazolo[1,5-a]pyridine 3ac:- Yellow solid,
o
120 mg, (0.36 mmol), 72%, Rf = 0.30 (EtOAc/Hexane, 10:90); MP 192-194 C; IR (CHCl3)
761, 1006, 1283, 1332, 1459, 1543, 1629, 2923, 3092 cm-1; H NMR (500 MHz, CDCl3) δ =
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2.76 (s, 3H), 7.18-7.19 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.49 (dd, J1 = 1.0 Hz, J2 = 5.0 Hz, 1H),
7.75-7.59 (m, 3H), 7.62 (dd, J1 = 1.0 Hz, J2 = 5.0 Hz, 1H), 7.86-7.88 (m, 2H), 8.53 (d, J = 1.9 Hz,
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1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 14.8, 111.8, 114.3, 126.4, 128.2, 128.6, 128.7, 129.7,
130.5, 131.5, 137.3, 138.7, 140.4, 141.7, 151.9; MS (ESI) m/z 336 [M+H]+; HRMS (ESI,
m/z):calcd for C18H14SN3O2 [M+H]+ 336.0801, found 336.0821.
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2-iso-Butyl-3-nitro-5,7-diphenylpyrazolo[1,5-a]pyridine 3ad:- Pale yellow solid, 154 mg,
o
(0.415 mmol), 83%, Rf = 0.6 (EtOAc/hexane, 5:95); MP 126-128 C; IR (CHCl3) 761, 1285,
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1439, 1552, 1634, 2921, 3019 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.02 (d, J = 6.7 Hz, 6H),
2.26 (sep, J = 6.8 Hz, 1H), 3.08 (d, J = 7.1 Hz, 2H), 7.41 (d, J = 2.1 Hz, 1H), 7.47-7.50 (m, 1H),
7.52-7.55 (m, 2H), 7.55-7.59 (m, 3H), 7.76-7.79 (m, 2H), 7.90-7.92 (m, 2H), 8.58 (d, J = 2.0 Hz,
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1H); C{1H}NMR (100 MHz, CDCl3) δ = 22.6, 27.7, 36.8, 114.2, 115.8, 123.5, 127.3, 128.6,
129.3, 129.5, 129.7, 130.4, 137.5, 138.9, 144.1, 144.2, 154.7; MS (ESI) m/z 372 [M+H]+;
HRMS (ESI, m/z): calcd for C23H22N3O2 [M+H]+ 372.1706, found 372.1709.
2-iso-Butyl-5-(naphthalen-1-yl)-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3ae:- Yellow
o
solid, 133 mg, (0.315 mmol), 63%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 142-144 C; IR
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(CHCl3) 750, 1214, 1449, 1625, 1662, 2853, 2924, 2955, 3019 cm-1; H-NMR (500 MHz,
CDCl3) δ = 1.03 (d, J = 6.7 Hz, 6H), 2.27 (sep, J = 6.8 Hz, 1H), 3.09 (d, J = 7.1 Hz, 2H), 7.54 (d,
J = 2.1 Hz, 1H), 7.54-7.61 (m, 5H), 7.86-7.90 (m, 1H), 7.90-7.92 (m, 1H), 7.93-7.98 (m, 3H),
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8.00 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H); C{1H}NMR (125 MHz,
CDCl3) δ = 22.6, 27.7, 36.8, 114.4, 115.9, 124.5, 126.9, 127.0, 127.2, 127.8, 128.6, 129.2, 129.8,
130.4, 131.8, 133.5, 133.6, 134.7, 139.0, 141.6, 143.9, 154.7; MS (ESI) m/z 422 [M+H]+;
HRMS (ESI, m/z): calcd for C27H24N3O2 [M+H]+ 422.1869, found 422.1867.
2-iso-Butyl-5-(4-methoxyphenyl)-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3af:- Yellow
o
solid, 120 mg, (0.299 mmol), 60%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 150-152 C; IR
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(CHCl3) 695, 762, 829, 1156, 1260, 1298, 1377, 1470, 1544, 1633, 2927 cm-1; H-NMR (500
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MHz, CDCl3) δ = 1.02 (d, J = 6.7 Hz, 6H), 2.25 (sep, J = 6.8 Hz, 1H), 3.07 (d, J = 7.1 Hz, 2H),
3.89 (s, 3H), 7.02-7.11 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.54-7.58 (m, 3H), 7.72-7.76 (m, 2H),
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7.88-7.93 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H); C{1H}NMR (125 MHz, CDCl3) δ = 22.7, 27.6,
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36.9, 55.5, 113.2, 114.7, 115.4, 128.5, 129.7, 130.3, 131.9, 139.1, 141.4, 143.7, 154.6, 160.9;
MS (ESI) m/z 402 [M+H]+; HRMS (ESI, m/z): calcd for C24H24N3O3 [M+H]+ 402.1812, found
402.1813.
5-(4-Bromophenyl)-2-iso-butyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3ag:- Yellow
o
solid, 162 mg, (0.360 mmol), 72%, Rf = 0.4 (EtOAc/Hexane, 10:90); MP 147-149 C; IR
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(CHCl3) 767, 1159, 1291, 1379, 1447, 1635, 2863, 2926, 3055 cm-1; H-NMR (500 MHz,
CDCl3) δ = 1.02 (d, J = 6.7 Hz, 6H), 2.26 (sep, J = 6.8 Hz, 1H), 3.08 (d, J = 7.1 Hz, 2H), 7.33-
7.36 (m, 1H), 7.54-7.59 (m, 3H), 7.66 (q, J = 8.5 Hz, 4H), 7.89-7.91 (m, 2H), 8.55 (s, 1H);
13C{1H}NMR (125 MHz, CDCl3) δ = 22.6, 27.7, 36.7, 114.1, 115.3, 123.5, 124.1, 128.6, 128.8,
129.7, 130.5, 131.7, 132.5, 136.4, 138.9, 141.7, 142.7, 154.7; MS (ESI) m/z 450 [M+H]+;
HRMS (ESI, m/z): calcd for C23H21BrN3O2 [M+H]+ 450.0817, found 450.0818.
7-(4-Fluorophenyl)-2-iso-butyl-3-nitro-5-phenylpyrazolo[1,5-a]pyridine 3ah:- Yellow
o
solid, 100 mg, (0.257 mmol), 51%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 158-160 C; IR
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(CHCl3) 768, 838, 1158, 1293, 1376, 1474, 1548, 1635, 2869, 2928 cm-1; H-NMR (500 MHz,
CDCl3) δ = 1.02 (d, J = 6.7 Hz, 6H), 2.25 (sep, J = 6.8 Hz, 1H), 3.07 (d, J = 7.1 Hz, 2H), 7.23-
7.28 (m, 2H), 7.23-7.28 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.47-7.51 (m, 1H), 7.52-7.56 (m, 2H),
7.75-7.78 (m, 2H), 7.89-7.94 (m, 2H), 8.58 (d, J = 2.0 Hz, 1H); 13C{1H}NMR (125 MHz,
CDCl3) δ = 22.6, 27.6, 36.7, 114.3, 115.6, 115.9, 129.4 ( J = 32 Hz), 131.8 ( J = 8.17 Hz), 137.4,
138.9, 140.5, 144.1, 154.6, 162.8, 164.8; MS (ESI) m/z 390 [M+H]+; HRMS (ESI, m/z): calcd
for C23H21FN3O2 [M+H]+ 390.1612, found 390.1616.
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The Journal of Organic Chemistry
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2-Ethyl-3-nitro-5,7-diphenylpyrazolo[1,5-a]pyridine 3ai:- Yellow solid, 59 mg, (0.172
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mmol), 34%, Rf = 0.6 (EtOAc /Hexane, 20:80); MP 158-159 C; IR (CHCl3) 756, 1287, 1442,
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1547, 1633, 2925, 2979, 3057 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.38 (t, J = 7.4 Hz, 3H),
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3.21 (q, J = 7.5 Hz, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.47-7.58 (m, 6H), 7.76-7.78 (m, 2H), 7.91-
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7.93 (m, 2H), 8.58 (d, J = 2.0 Hz, 1H); C{1H}NMR (75 MHz, CDCl3) δ = 12.2, 22.0, 114.1,
115.8, 127.3, 128.6, 129.3, 129.5, 129.8, 130.4, 131.8, 137.5, 139.0, 141.7, 144.2, 156.7; MS
(ESI) m/z 344 [M+H]+; HRMS (ESI, m/z): calcd for C21H18N3O2 [M+H]+ 344.1393, found
344.1419; C21H17N3O2Na [M+Na]+ 366.1213, found 366.1238.
3-Nitro-5,7-diphenyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine 3aj:- Yellow solid, 128
o
mg, (0.334 mmol), 67%, Rf = 0.6 (EtOAc/Hexane, 30:70); MP 256-258 C; IR (CHCl3) 761,
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1293, 1452, 1580, 1637, 3049 cm-1; H-NMR (400 MHz, CDCl3) δ = 7.53-7.60 (m, 7H), 7.77-
7.80 (m, 2H), 7.88-7.91 (m, 2H), 8.63 (d, J = 2.0 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ =
114.3, 117.3, 118.3, 121.9, 127.4, 128.8, 129.5, 129.8, 136.8, 139.2, 140.2, 140.5, 142.4, 145.6;
MS (ESI) m/z 384 [M+H]+; HRMS (ESI, m/z): calcd for C20H13F3N3O2 [M+H]+ 384.0954,
found 384.0970.
2-Methyl-3-nitro-7-phenylpyrazolo[1,5-a]pyridine 3ak:- Light brown colour solid, 80 mg,
(0.316 mmol), 63%, Rf = 0.6 (EtOAc / Hexane, 20:80); MP 165-167 oC; IR (CHCl3) 756, 1294,
1480, 1535, 1630, 2854, 2924 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 2.77 (s 3H), 7.15 (dd, J1 =
1.3 Hz, J2 = 7.3 Hz, 1H), 7.55-7.57 (m, 3H), 7.68-7.72 (m, 1H), 7.84-7.86 (m, 2H), 8.37 (dd, J1 =
1.4 Hz, J2 = 8.8 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 14.8, 116.3, 117.2, 128.6, 129.6,
130.4, 130.9, 131.7, 138.6, 141.7, 151.4; MS (ESI) m/z 254 [M+H]+; HRMS (ESI, m/z): calcd
for C14H12N3O2 [M+H]+ 254.0924, found 254.0931.
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