New access to the 1H-pyrazolo[4,3-c]pyridine core from bis-acetylenic-N- benzoylhydrazones

Article abstract of DOI:10.1016/j.tet.2003.11.036

1H-pyrazolo[4,3-c]pyridines were obtained from bis-acetylenic-N- benzoylhydrazones using aqueous ammonia.

Full text of DOI:10.1016/j.tet.2003.11.036

Tetrahedron 60 (2004) 933–938
New access to the 1H-pyrazolo[4,3-c]pyridine core from
bis-acetylenic-N-benzoylhydrazones
a
Laurent Commeiras,a Samuel C. Woodcock,a Jack E. Baldwin,a Robert M. Adlington,
,
*
Andrew R. Cowleyb and Peter J. Wilkinsona
aDyson Perrins Laboratory, University of Oxford, South Parks Road, OX1 3QY Oxford, UK
bChemical Cristallography, University of Oxford, South Parks Road, OX1 3QR Oxford, UK
Received 12 September 2003; revised 22 October 2003; accepted 13 November 2003
Abstract—1H-pyrazolo[4,3-c]pyridines were obtained from bis-acetylenic-N-benzoylhydrazones using aqueous ammonia.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
c]pyridine core are ring closure of the pyridine ring of a
functionised pyrazole or ring closure of the pyrazole ring of
a functionalised pyridine.3 Herein we report a new synthesis
of the pyrazolo[4,3-c]pyridine core based on an unusual one
step tandem ring closure and rearrangement of bis-
acetylenic N-acylated hydrazones using aqueous ammonia.
Bicyclic hetero-aromatic compounds are well known for
their wide range of biological activity. For example the
3-furylindazole YC-1 (1) (Fig. 1) is now considered as a
lead compound in the design of novel indazole derivatives
potentially useful for treatment of various diseases linked to
smooth muscle relaxation including cardiovascular
insufficiency and erectile dysfunction.1 The related pyrazol-
opyridines, which comprise five isomers [3,4-b], [3,4-c],
[4,3-c], [4,3-b] and [1,5-a], were shown to display high
biological activity; pyrazolo[4,3-c]pyridine 2 derivatives
have use as angiotensin II antagonists and Bay 41-2272 (3)
has been introduced as a novel orally available agent which
directly stimulates soluble guanylate cyclase (sGC) and
sensitizes it to its physiological stimulator, nitric oxide.2
2. Results and discussion
Our initial aim was the synthesis of the nine membered ring
compound 4, starting from the commercially available 1,4-
bis(trimethylsilyl)-1,3-butadiyne 8 as outlined in Scheme 1.
The planned synthesis of 4 called for ammonolysis of a bis-
acetylenic N-acetylated hydrazone 5 followed by a 9-endo-
dig cyclisation.4
The usual synthetic routes towards the pyrazolo[4,3-
Our synthesis (Scheme 2) began with the commercially
Figure 1.
Keywords: 3-Furylindazole; Angiotensin II antagonist; Pyrazole ring; 1H-Pyrazolo[4,3-c]pyridine.
*
Corresponding author. Tel.: þ44-1865-275-671; fax: þ44-1865-275-632; e-mail address: jack.baldwin@chem.ox.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.036

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L. Commeiras et al. / Tetrahedron 60 (2004) 933–938
Scheme 1. Retrosynthetic analysis.
available 1,4-bis(trimethylsilyl)-1,3-butadiyne 8, which
upon treatment with acetyl chloride and anhydrous
aluminium trichloride in CH2Cl2 furnished the correspond-
ing ketone 9 in quantitative yield.5 The acetylenic ketone 9,
upon reaction with phenylhydrazine or substituted
analogues in MeOH was converted into the corresponding
hydrazones 10, 11, 12 and 13 as separable mixtures of Z and
E isomers. The structure of both of these isomers were
confirmed by the intensity of the 1H NMR NOE interactions
between the methyl protons and the N–H proton. However,
it was found that the hydrazones E-11, E-12 and E-13 was
relatively unstable, and upon standing in CDCl3 for a few
hours, were cleanly converted to their corresponding
Z-isomer (Fig. 2). E-10 was found to be stable under these
conditions and no isomerisation was observed. Thus, the
next step of the synthesis was performed with the
Z-compounds Z-10, Z-11, Z-12 and Z-13 which upon
treatment with benzoyl chloride and anhydrous aluminium
trichloride in refluxing of CH2Cl2 gave, in fair yields, the
corresponding N-benzoyl compounds.6 Unfortunately
hydrazone Z-10 was degraded and no N-benzoylated
product was observed. However Z-11, Z-12 and Z-13 gave
15, 16 and 17 in 71, 36 and 56% yields, respectively.
Next, the ring closure of the N-benzoylated hydrazones with
aqueous ammonia was attempted.
However, after exposure of compounds 15, 16 and 17 to
Scheme 2. (a) MeCOCl, AlCl3, DCM, 0 8C; (b) NH2NHR, MeOH; (c) PhCOCl, AlCl3, DCM, reflux; (d) 33% aq. NH3, EtOH, 85 8C.

L. Commeiras et al. / Tetrahedron 60 (2004) 933–938
935
amidine moiety on the terminal alkyne.4 However, under the
reaction conditions, further reaction of 22 with another
equivalent of ammonia presumably gives rise to 23 which
undergoes consecutive 5-endo-dig pyrazole cyclisation
followed by thermal 6pe disrotary ring closure and
elimination of ammonia to form the isolated pyrazolo[4,3-
c]pyridine compounds. An alternative mechanism, which
does not require a nine membered ring, is also a possibility
(Scheme 4).
3. Conclusion
A concise novel route to the pyrazolo[4,3-c]pyridine core by
an unusual mechanistic pathway has been developed.
4. Experimental
4.1. General
All solvents and reagents were purified by standard
techniques reported in Perrin, D. D.; Amarego, W. L. F.
Purification of laboratory chemicals, 3rd ed.; Pergamon:
Oxford, 1988 or used as supplied from commercial sources
as appropriate. Solvents were removed under reduced
pressure using a Buchi R110 or R114 Rotavapor fitted
with a water or dry ice condenser as necessary. Final traces
of solvent were removed from samples using an Edwards
E2M5 high vacuum pump with pressures below 2 mmHg.
All experiments were carried out under inert atmosphere
Figure 2.
ethanolic aqueous ammonia,7 the corresponding pyra-
zolo[4,3-c]pyridines 18, 19 and 20 were obtained, rather
than the nine membered ring 4. The structure of these
compounds was confirmed by X-ray analysis of 198 and by
further spectral comparison of 18 and 20 to 19.
To explain the formation of the pyrazolo[4,3-c]pyridines
from the corresponding hydrazones, we propose the
following mechanistic rationale (Schemes 3 and 4). In
Scheme 3, the first step is the formation of the imino-
hydrazone 219 followed by 9-endo-dig cyclisation of the
1
unless otherwise stated. H NMR spectra were recorded at
400 MHz using Bruker DPX400. For 1H spectra recorded in
CDCl3, chemical shifts are quoted in parts per million (ppm)
and are referenced to the residual solvent peak. The
Scheme 3.

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L. Commeiras et al. / Tetrahedron 60 (2004) 933–938
Scheme 4.
following abbreviations are used: s, singlet; d, doublet; t,
triplet; m, multiplet; b, broad. Data are reported in the
following manner: chemical shift (integration, multiplicity,
coupling constant if appropriate). Coupling constants (J) are
reported in Hertz to the nearest 0.5 Hz. 13C NMR spectra
were recorded at 100 MHz using Bruker DPX400
instrument. Carbon spectra assignments are supported by
DEPT-135 spectra, 13C–1H (HMQC and HMBC) corre-
lations where necessary. Chemical shifts are quoted in ppm
and are referenced to the appropriate residual solvent peak.
Flash column chromatography was carried out using
Sorbsile C60 (40–63 mm, 230–40 mesh) silica gel. Thin
layer chromatography was carried out on glass plates pre-
coated with Merck silica gel 60 F254 which were visualised
by quenching of UV fluorescence or by staining with 10%
w/v ammonium molybdate in 2 M sulphuric acid or 1% w/v
potassium permanganate in aqueous alkaline solution
followed by heat, as appropriate. Melting points were
recorded using a Cambridge Instruments Gallene III Kofler
Block melting apparatus or a Buchi 510 capillary apparatus
and are uncorrected. Infrared spectra were recorded either as
a thin film between NaCl plates or as a KBr disc (as
indicated) on a Perkin–Elmer Paragon 1000 Fourier
Transform spectrometer with internal referencing. Absorp-
tion maxima are reported in wavenumbers (cm21). High
resolution mass spectrometry was measured on a Waters
2790-Micromass LCT electrospray ionisation mass spec-
trometer and on a VG autospec chemical ionisation mass
spectrometer.
(400 MHz, CDCl3) 0.21 (9H, s), 2.33 (3H, s); 13C NMR
(100 MHz, CDCl3) 20.7, 32.7, 73.6, 74.8, 85.7, 97.5, 183.3;
HRMS found 165.0732 (MHþ), C9H13OSi requires
165.0736.
4.2. General procedure for the preparation of 10–13
4.2.1. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, 2-nitro-
phenylhydrazone (Z-10) and E-6-trimethylsilanyl-hexa-
3,5-diyn-2-one, 2-nitrophenylhydrazone (E-10). To a
solution of 6-trimethylsilanyl-hexa-3,5-diyn-2-one
9
(1.00 g, 6.09 mmol) in MeOH (16 mL) was added, at 0 8C,
2-nitrophenyl-hydrazine (1.03 g, 6.70 mmol). The solution
was stirred at 0 8C and followed by TLC. After disappear-
ance of starting material (approximately 4 h), the mixture
was evaporated under vacuum. Water (20 mL) and CH2Cl2
(20 mL) were added, the aqueous layer extracted with
CH2Cl2 (2£20 mL) and the combined organic extracts were
washed with saturated aqueous NaCl solution (15 mL),
dried over MgSO4 and concentrated under vacuum. The
crude product was purified by flash chromatography (SiO2,
1:9 to 3:7, CH2Cl2/light petroleum) to give, in 83% yield
(1.52 g), 77% of Z-10 and 23% of E-10. Z-10: mp¼104 8C;
n
max (KBr disc/cm21) 3300, 2090, 1615, 1503, 1344, 1141,
1
1075; H NMR (400 MHz, CDCl3) 0.26 (9H, s), 2.21 (3H,
s), 6.86 (1H, bt, J¼8.0 Hz), 7.51 (1H, bt, J¼8.0 Hz), 7.81
(1H, d, J¼8.5 Hz), 8.17 (1H, d, J¼8.5 Hz), 11.59 (1H, bs);
13C NMR (100 MHz, CDCl3) 20.5, 22.2, 67.5, 85.9, 86.8,
98.3, 116.4, 118.9, 126.0, 129.1, 131.4, 136.1, 140.9; HRMS
found 300.1178 (MHþ), C15H18N3O2Si requires 300.1168.
E-10: mp¼85 8C; nmax (KBr disc/cm21) 3304, 2198, 2098,
4.1.1. 6-Trimethylsilanyl-hexa-3,5-diyn-2-one (9). To a
solution of 1,4-bis(trimethylsily)-1,3-butadiyne (5.30 g,
27.26 mmol) in CH2Cl2 (50 mL) at 0 8C was added acetyl
chloride (2.14 mL, 29.98 mmol) then anhydrous aluminium
trichloride (3.99 g, 29.98 mmol). The reaction was stirred
further 30 min at 0 8C and quenched with a mixture of 10%
aqueous hydrochloric acid and ice (50 mL, 1/1). The
aqueous phase was extracted with CH2Cl2 (3£50 mL), and
the combined organic extracts were washed with saturated
NaHCO3 solution (50 mL), dried over MgSO4, and
concentrated under vacuum to afford the crude product.
Purification by flash column chromatography (SiO2, 1:9 to
4:6, CH2Cl2/light petroleum) furnished in quantitative yield
1
1613, 1499, 1313, 1275, 1147, 1069; H NMR (400 MHz,
CDCl3) 0.23 (9H, s), 2.16 (3H, s), 6.92 (1H, bt, J¼8.0 Hz),
7.55 (1H, bt, J¼8.0 Hz), 7.89 (1H, bd, J¼8.5 Hz), 8.16 (1H,
bd, J¼8.5 Hz), 11.02 (1H, bs); 13C NMR (100 MHz,
CDCl3) 20.4, 17.3, 74.8, 75.5, 87.4, 93.4, 116.6, 119.8,
125.9, 131.9, 132.1, 136.5, 140.6; HRMS found 300.1168
(MHþ), C15H18N3O2Si requires 300.1168.
4.2.2. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, 4-nitro-
phenylhydrazone (Z-11) and E-6-trimethylsilanyl-hexa-
3,5-diyn-2-one, 4-nitrophenylhydrazone (E-11). Prepared
as above for E,Z-10 using 9 (798 mg, 4.86 mmol) in MeOH
(13 mL) and 4-nitrophenylhydrazine (818 mg, 5.34 mmol).
The crude product was purified by flash chromatography
(4.48 g) the desired ketone 9 as an oil. nmax (film/cm21
2963, 2206, 2097, 1678, 1252, 1236, 847; 1H NMR
)

L. Commeiras et al. / Tetrahedron 60 (2004) 933–938
937
(SiO2, 4:6 to 7:3, CH2Cl2/light petroleum) to give, in 89%
yield (1.30 g), 67% of Z-11 and 33% of E-11. Z-11:
mp¼95 8C; nmax (KBr disc/cm21) 3288, 2094, 1594, 1498,
92.7, 108.4, 115.9, 119.3, 127.7, 130.2, 144.6, 149.3; HRMS
found 300.1167 (MHþ), C15H18N3O2Si requires 300.1168.
1
1319, 1268, 1140, 1109; H NMR (400 MHz, CDCl3) 0.26
4.3. General procedure for the preparation of 15–17
(9H, s), 2.17 (3H, s), 7.09 (2H, d, J¼9.0 Hz), 8.16 (2H, d,
J¼9.0 Hz), 8.66 (1H, bs); 13C NMR (100 MHz, CDCl3)
20.5, 22.0, 67.0, 85.9, 86.7, 98.4, 112.4, 126.2, 126.6,
141.0, 148.6; HRMS found 298.1005 (M2Hþ),
C15H16N3O2Si requires 298.1012. E-11: mp¼153 8C; nmax
(film/cm21) 3306, 2196, 2097, 1595, 1502, 1325, 1260,
1150, 1108; 1H NMR (400 MHz, CDCl3) 0.22 (9H, s), 2.08
(3H, s), 7.15 (2H, d, J¼9.0 Hz), 8.04 (1H, bs), 8.15 (2H, d,
J¼9.0 Hz); 13C NMR (100 MHz, CDCl3) 20.4, 16.4, 74.4,
75.5, 87.4, 93.2, 113.0, 126.1, 129.5, 141.5, 148.4; HRMS
found 298.1012 (M2Hþ), C15H16N3O2Si requires
298.1012.
4.3.1. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, N-ben-
zoyl-4-nitrophenylhydrazone (15). To a stirred solution of
Z-11 (200 mg, 0.67 mmol) in CH2Cl2 (4 mL) was added, at
0 8C, benzoyl chloride (0.077 mL, 0.67 mmol) then AlCl3
(89 mg, 0.67 mmol). The solution was stirred at 0 8C for
15 min then heating to reflux and followed by TLC. After
disappearance of starting material (approximately 2 h), the
reaction was quenched with 10% aqueous HCl. The aqueous
layer was extracted with CH2Cl2 (3£10 mL), the combined
organic layers were dried over MgSO4 and concentrated
under vacuum. The crude product was purified by flash
chromatography (SiO2, 3:7 Et2O/light petroleum) to give 15
4.2.3. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, phenyl-
hydrazone (Z-12) and E-6-trimethylsilanyl-hexa-3,5-
diyn-2-one, phenylhydrazone (E-12). Prepared as above
for E,Z-10 using 9 (291 mg, 1.77 mmol) in MeOH (5 mL)
and phenylhydrazine (0.191 mL, 1.95 mmol). The crude
product was purified by flash chromatography (SiO2, 1:9 to
3:7, CH2Cl2/light petroleum) to give, in 74% yield
(335 mg), 65% of Z-12 and 35% of E-12. Z-12:
mp¼33 8C; nmax (KBr disc/cm21) 3301, 2199, 2095,
1600, 1504, 1247, 1150, 1088; 1H NMR (400 MHz,
CDCl3) 0.30 (9H, s), 2.17 (3H, s), 6.92 (1H, bt,
J¼7.5 Hz), 7.09 (2H, bd, J¼8.5 Hz), 7.29 (2H, bdd,
J¼8.5, 7.5 Hz), 8.40 (1H, bs); 13C NMR (100 MHz,
CDCl3) 20.4, 21.7, 68.4, 85.7, 86.5, 96.9, 113.2, 120.8,
121.2, 129.4, 143.7; HRMS found 255.1312 (MHþ),
C15H19N2Si requires 255.1318. E-12: mp¼45 8C; nmax
(KBr disc/cm21) 3301, 2195, 2095, 1601, 1504, 1252,
1150, 1073; 1H NMR (400 MHz, CDCl3) 0.23 (9H, s), 2.03
(3H, s), 6.94 (1H, bt, J¼7.5 Hz), 7.12 (2H, bd, J¼8.0 Hz),
7.28 (2H, bt, J¼8.0 Hz), 7.58 (1H, bs); 13C NMR
(100 MHz, CDCl3) 20.3, 15.9, 73.0, 76.8, 88.0, 91.9,
113.7, 121.6, 124.8, 129.4, 143.5; HRMS found 255.1315
(MHþ), C15H19N2Si requires 255.1318.
(191 mg) in 71% yield. Mp¼76 8C; nmax (KBr disc/cm21
)
2189, 2090, 1676, 1520, 1344, 1255, 1227, 1171, 1065; 1H
NMR (400 MHz, CDCl3) 0.17 (9H, s), 2.20 (3H, s), 7.35–
7.48 (5H, m), 7.62 (2H, m), 8.21 (2H, bd, J¼9.0 Hz); 13C
NMR (100 MHz, CDCl3) 20.7, 24.2, 68.3, 85.2, 86.7,
100.1, 124.4, 126.1, 128.1, 129.6, 131.5, 134.4, 145.7,
146.9, 149.9, 169.4; HRMS found 404.1409 (MHþ),
C22H22N3O3Si requires 404.1430.
4.3.2. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, N-ben-
zoylphenylhydrazone (16). Prepared as above for 15 using
Z-12 (200 mg, 0.79 mmol) in CH2Cl2 (5 mL), benzoyl
chloride (0.091 mL, 0.79 mmol) and AlCl3 (104 mg,
0.79 mmol). The crude product was purified by flash
chromatography (SiO2, 2:8 Et2O/light petroleum) to give
16 as an oil (103 mg) in 36% yield. nmax (film/cm21) 2193,
2097, 1670, 1597, 1490, 1339, 1252, 1148, 1073; 1H NMR
(400 MHz, CDCl3) 0.19 (9H, s), 2.23 (3H, s), 7.20–7.40
(8H, m), 7.61 (2H, m); 13C NMR (100 MHz, CDCl3) 20.6,
24.4, 68.7, 85.2, 86.1, 98.3, 127.6, 127.8, 128.0, 129.0,
129.4, 130.6, 135.3, 141.4, 168.9; HRMS found 359.1590
(MHþ), C22H23N2OSi requires 359.1580.
4.3.3. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, N-ben-
zoyl-3-nitrophenylhydrazone (17). Prepared as above for
15 using Z-13 (210 mg, 0.70 mmol) in CH2Cl2 (5 mL),
benzoyl chloride (0.081 mL, 0.70 mmol) and AlCl3 (94 mg,
0.70 mmol). The crude product was purified by flash
chromatography (SiO2, 3:7 Et2O/light petroleum) to give
17 as an oil (159 mg) in 56% yield. nmax (film/cm21) 2097,
1673, 1531, 1350, 1252, 1078; 1H NMR (400 MHz, CDCl3)
0.17 (9H, s), 2.17 (3H, s), 7.29–7.47 (3H, m), 7.54 (1H, m,
J¼8.0 Hz), 7.57 (1H, bdt, J¼8.0, 2.0 Hz), 7.63 (2H, m),
8.10 (1H, bdt, J¼8.0, 2.0 Hz), 8.15 (1H, bt, J¼2.0 Hz); 13C
NMR (100 MHz, CDCl3) 20.8, 24.2, 68.3, 85.2, 86.7, 99.9,
122.2, 122.3, 128.0, 129.5, 129.7, 131.3, 132.5, 134.3,
142.3, 147.3, 148.4, 169.6; HRMS found 404.1445 (MHþ),
C22H22N3O3Si requires 404.1430.
4.2.4. Z-6-Trimethylsilanyl-hexa-3,5-diyn-2-one, 3-nitro-
phenylhydrazone (Z-13) and E-6-trimethylsilanyl-hexa-
3,5-diyn-2-one, 3-nitrophenylhydrazone (E-13). Prepared
as above for E,Z-10 using 9 (1.00 g, 6.09 mmol) and
3-nitrophenylhydrazine hydrochloride (1.27 g, 6.70 mmol)
at reflux in MeOH (16 mL) for 4 h. The crude product was
purified by flash chromatography (SiO2, 2:8 to 5:5, CH2Cl2/
light petroleum) to give, in 50% yield (915 mg), 71% of
Z-13 and 29% of E-13. Z-13: mp¼90 8C; nmax (KBr disc/
cm21) 3295, 2206, 2100, 1618, 1529, 1344, 1256, 1143,
1
1094; H NMR (400 MHz, CDCl3) 0.25 (9H, s), 2.14 (3H,
s), 7.31 (1H, bdt, J¼8.0, 2.0 Hz), 7.34 (1H, bd, J¼8.0 Hz),
7.67 (1H, bdt, J¼8.0, 2.0 Hz), 7.88 (1H, bt, J¼2.0 Hz), 8.49
(1H, bs); 13C NMR (100 MHz, CDCl3) 20.6, 21.8, 67.4,
86.0, 86.3, 97.8, 107.8, 115.1, 118.7, 124.3, 130.0, 144.7,
149.3; HRMS found 300.1179 (MHþ), C15H18N3O2Si
requires 300.1168. E-13: mp¼205 8C; nmax (KBr disc/
cm21) 3334, 2196, 1622, 1530, 1342, 1253, 1173, 1073; 1H
NMR (400 MHz, CDCl3) 0.22 (9H, s), 2.07 (3H, s), 7.40
(1H, bd, J¼8.0 Hz), 7.43 (1H, bdt, J¼8.0, 2.0 Hz), 7.73 (1H,
bdt, J¼8.0, 2.0 Hz), 7.81 (1H, bs), 7.92 (1H, bt, J¼2.0 Hz);
13C NMR (100 MHz, CDCl3) 20.4, 16.2, 73.8, 75.9, 87.6,
4.4. General procedure for the preparation of 18–20
4.4.1. 3-Methyl-1-(4-nitro-phenyl)-4-phenyl-1H-pyra-
zolo[4,3-c]pyridine (18). A solution of 15 (87 mg,
0.22 mmol) in EtOH (9 mL) and 33% aq. NH3 (9 mL) was
heated at 85 8C in a sealed tube for 4 h. The solvent was then
removed under vacuum. Water (5 mL) and CH2Cl2 (5 mL)

938
L. Commeiras et al. / Tetrahedron 60 (2004) 933–938
were added, the aqueous layer was extracted with CH2Cl2
(3£10 mL), the combined organic layers were dried over
MgSO4 and concentrated under vacuum. The crude product
was purified by flash chromatography (SiO2, 5:5 to 10:0
Et2O/light petroleum) to give 18 (36 mg) in 51% yield.
Acknowledgements
We thank Roche for funding (L. C.)
1
Mp¼144 8C; nmax (KBr disc/cm21) 1523, 1344, 1058; H
NMR (400 MHz, CDCl3) 2.33 (3H, s), 7.52–7.54 (3H, m),
7.59–7.63 (2H, m), 7.65 (1H, d, J¼6.0 Hz), 7.95 (2H, d,
J¼9.0 Hz), 8.42 (2H, d, J¼9.0 Hz), 8.59 (1H, d, J¼6.0 Hz);
13C NMR (100 MHz, CDCl3) 15.2, 104.0, 120.5, 121.7,
125.5, 128.4, 129.4, 129.4, 138.8, 143.7, 144.6, 145.5,
145.7, 147.1, 157.4; HRMS found 331.1196 (MHþ),
C19H15N4O2 requires 331.1195.
References and notes
1. Hun-Kung, H.; Shu-Hui, J.; Pei-Yin, H.; Yu-Chih, L.; Chien-
Huang, L.; Che-Ming, T.; Wen-Sen, L. Bio. Pharm. 2003, 66,
263. and ref. therein.
2. Straub, A.; Stasch, J.-P.; Alonso-Alija, C.; Benet-Buchholz, J.;
Ducke, B.; Feurer, A.; Furstner, C. Bioorg. Med. Chem. Lett.
2001, 11, 781. and ref. therein.
4.4.2. 3-Methyl-1-phenyl-4-phenyl-1H-pyrazolo[4,3-
c]pyridine (19). Prepared as above for 18 using 16
(100 mg, 0.28 mmol), EtOH (10 mL) and 33% aq. NH3
(10 mL). The crude product was purified by flash chroma-
tography (SiO2, 5:5 to 10:0 Et2O/light petroleum) to give 18
3. (a) Hardy, C. R. The chemistry of pyrazolopyridines. Advances
in Heterocyclic Chemistry; Academic: London, 1984; Vol. 36.
p 343. (b) Townsend, L. B.; Wise, D. S. Bicyclic 5–6 systems:
three heteroatoms 2:1. Comprehensive heterocyclic chemistry
II; Pergamon: Oxford; 1996, Vol. 7, p 283..
(59 mg) in 74% yield. Mp¼68 8C; nmax (KBr disc/cm21
)
4. Nuclephilic attack onto an activated acetylene via a 9-endo-dig
cyclisation has been observed elsewhere, see for example,
Deslongchamps, P.; Roy, B. L. Can. J. Chem. 1986, 64, 2068.
5. (a) Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37,
45. (b) Stang, P. J.; Ladika, M. Synthesis 1981, 29.
6. Rojahn, C. A. Chem. Ber. 1922, 55, 291.
1561, 1508, 1443, 1241, 1053; 1H NMR (400 MHz, CDCl3)
2.34 (3H, s), 7.38 (1H, bt, J¼7.5 Hz), 7.47–7.56 (5H, m),
7.53 (1H, d, J¼6.0 Hz), 7.62–7.65 (2H, m), 7.68–7.70 (2H,
m), 8.48 (1H, d, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
15.1, 103.9, 119.6, 122.8, 127.2, 128.2, 129.0, 129.4, 129.7,
139.2, 139.3, 143.5, 144.5, 144.8, 156.9; HRMS found
286.1344 (MHþ), C19H16N3 requires 286.1344.
7. Daneshtalab, M.; Tehrani, M. H. H. Heterocycles 1984, 22,
1095.
8. The atomic coordinates for 19 are available upon request from
the Cambridge Crystallographic Data Centre, University
Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW
(Deposit number CCDC 211595). The crystallographic
numbering system differs from that used in the test; therefore
any request should be accompanied by the full literature citation
of this paper.
4.4.3. 3-Methyl-1-(3-nitro-phenyl)-4-phenyl-1H-pyra-
zolo[4,3-c]pyridine (20). Prepared as above for 18 using
17 (90 mg, 0.22 mmol), EtOH (9 mL) and 33% aq. NH3
(9 mL). The crude product was purified by flash chroma-
tography (SiO2, 5:5 to 10:0 Et2O/light petroleum) to give 20
(38 mg) in 52% yield. Mp¼129 8C; nmax (KBr disc/cm21
)
1566, 1534, 1346; 1H NMR (400 MHz, CDCl3) 2.34 (3H, s),
7.51–7.55 (3H, m), 7.60–7.63 (3H, m), 7.74 (1H, t,
J¼8.0 Hz), 8.10 (1H, bdd, J¼8.0, 2.0 Hz), 8.21 (1H, bdd,
J¼8.0, 2.0 Hz), 8.58 (1H, d, J¼6.0 Hz), 8.62 (1H, t,
J¼2.0 Hz); 13C NMR (100 MHz, CDCl3) 15.2, 103.6,
117.0, 120.1, 121.3, 127.6, 128.3, 129.3, 129.4, 130.7,
138.8, 140.5, 143.6, 145.5, 146.4, 149.1, 157.3; HRMS
found 331.1187 (MHþ), C19H15N4O2 requires 331.1195.
9. Proto-desilylation of trimethylsilyl-acetylenes under aqueous
base is a known reaction, see for example Baldwin, J. E.;
Adlington, R. M.; Wilkinson, P. J.; Marquez, R.; Adamo, M. F.
A. Heterocycles 2003, 59, 81.