Synthesis of 5-alkyl-4-amino-2-(trifluoromethyl)pyridines and their transformation into trifluoromethylated 1H-pyrazolo[4,3-c]pyridines

Article abstract of DOI:10.1016/S0040-4020(01)00024-2

5-Alkyl-4-amino-2-(trifluoromethyl)pyridines were prepared in good yields starting from the corresponding pyridinols either using condensation with tosyl isocyanate or by alkylation with 2-chloroacetamide and subsequent Smiles type rearrangement. The cyclisation of diazonium salts, generated from 5-alkyl-4-amino-2-(trifluoromethyl)pyridines, afforded trifluoromethylated 1H-pyrazolo[4,3-c]pyridines.

Full text of DOI:10.1016/S0040-4020(01)00024-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2051±2055
Synthesis of 5-alkyl-4-amino-2-(tri¯uoromethyl)pyridines and
their transformation into tri¯uoromethylated
1H-pyrazolo[4,3-c]pyridines
Vladimir I. Tyvorskii,a,p Denis N. Bobrov,a Oleg G. Kulinkovich,a Kourosch Abbaspour Tehranib
and Norbert De Kimpeb
aDepartment of Organic Chemistry, Belarussian State University, Fr. Scorina Av., 4, 220050 Minsk, Belarus
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 17 October 2000; revised 5 December 2000; accepted 21 December 2000
AbstractÐ5-Alkyl-4-amino-2-(tri¯uoromethyl)pyridines were prepared in good yields starting from the corresponding pyridinols either
using condensation with tosyl isocyanate or by alkylation with 2-chloroacetamide and subsequent Smiles type rearrangement. The cyclisa-
tion of diazonium salts, generated from 5-alkyl-4-amino-2-(tri¯uoromethyl)pyridines, afforded tri¯uoromethylated 1H-pyrazolo[4,3-c]pyri-
dines. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
formicins,8,9 the antihyperuricemic drug allopurinol,10 and
also possess interesting pharmacological properties as anti-
hypertensive11 and antidepressive agents.12
4-Aminopyridine (fampridine) is one of the most useful
heterocyclic amines, which has important applications
both in organic synthesis and in medicinal chemistry.
Recently, 2-tri¯uoromethylated fampridine has been
prepared by nitration and subsequent reduction of
2-(tri¯uoromethyl)pyridine N-oxide,1 and used for the
synthesis of biologically active compounds.1,2 Related
4-amino-2-(tri¯uoromethyl)pyridines, bearing an alkyl
substituent at the 3 (or 5)-position of the heteroaromatic
ring, are suitable precursors of fused nitrogen-containing
heterocycles,3±5 but only fragmentary data concerning the
preparation and properties of such amines are available in
the literature.5
2. Results and discussion
To accomplish the conversion of 5-alkyl-2-(tri¯uoro-
methyl)-4H-pyran-4-ones 1a±c6 into 4-aminopyridines
5a±c, compounds 1a±c were treated initially with aqueous
ammonia in boiling MeOH or i-PrOH; the expected 4-pyri-
dinols 2a±c were obtained in 83±94% yield. Following our
procedure7 for the preparation of 5-arylated congeners of
5a±c, pyridinols 2a±c were condensed with tosyl iso-
cyanate in toluene at re¯ux and the resulting tosylamido-
pyridine intermediates 3a±c were hydrolysed with hot 90%
H2SO4 to the desired 4-aminopyridines 5a±c in 86±88%
yield (Scheme 1, method A).
We have previously reported that 4-amino-5-aryl-2-
(tri¯uoromethyl)pyridines are accessible from the corre-
sponding 4H-pyran-4-ones and were successfully converted
to tri¯uoromethylated benzo[c][1,6]naphthyridines.6,7 The
present work was undertaken to extend these investigations
in order to prepare 5-alkyl-4-amino-2-(tri¯uoromethyl)-
pyridines 5 which were then employed for the synthesis
of pyrazolo[4,3-c]pyridines 7. Such heteroaromatic
compounds, along with their [3,4-c]fused analogues, are
structurally related to some biologically active purine type
heterocycles like, for example, the nucleoside antibiotics
Although this route to alkylated 4-aminopyridines 5a±c is
quite ef®cient, our intention was to elaborate a more general
approach excluding harsh acidic conditions at the work-up
stage and potentially allowing the preparation of analogues
of 5a±c with acid sensitive functional groups. Toward this
end, a simpli®ed two-step procedure, proposed earlier13 for
the preparation of 2-aminopyridines from 2(1H)-pyridi-
nones via a rearrangement of the intermediate 2-(2-pyridyl-
oxy)acetamides under basic conditions, was employed for
the synthesis of 4-aminopyridines 5a±c. To our knowledge,
such transformation of 4-pyridinols to 4-aminopyridines has
not been reported previously.14
Keywords: 4H-pyran-4-ones; 4-aminopyridines; 1H-pyrazolo[4,3-c]pyri-
dines; Smiles rearrangement.
p
Corresponding author. Tel.: 1375-017-2265609; fax: 1375-017-
2264998; e-mail: tyvorskii@chem.bsu.unibel.by
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00024-2

2052
V. I. Tyvorskii et al. / Tetrahedron 57 (2001) 2051±2055
Scheme 1.
Thus, the reaction of pyridinols 2a±c with 2-chloroacet-
amide in the presence of potassium carbonate in DMF at
50±608C followed by heating at 140±1508C with an
additional portion of potassium carbonate directly produced
the target 4-aminopyridines 5a±c in a one-pot procedure in
86±89% yield (Scheme 1, method B). This transformation
of compounds 2a±c apparently proceeds through the forma-
tion of 2-(4-pyridyloxy)acetamides 4a±c, which underwent
a Smiles type rearrangement upon heating with base.15 In
the case of pyridinol 2a, intermediate acetamide 4a was
isolated, when the alkylation of compound 2a was
performed in boiling acetone and smoothly converted into
aminopyridine 5a under the action of potassium carbonate
in DMF at re¯ux (Scheme 2).
analysis of crude 7a also revealed the presence of the
diazo-coupling product of compound 7a with diazonium
salt 6a. In order to minimise this side reaction, the generated
6a±c were slowly added to a large excess of cold,
vigorously stirred aqueous sodium acetate. In this way,
pyrazolopyridines 7a±c were obtained in 40±77% yield.
It should be noted that a series of pyrazolo[3,4-c]pyridines
has been prepared previously by nitrosation of 3-acetamido-
4-methylpyridines, and subsequent rearrangement and
cyclisation of the N-nitroso compounds produced.4,5,9
Under similar conditions, N-acylated 4-amino-3-methyl-
pyridines were found to give the corresponding pyra-
zolo[4,3-c]pyridines in poor yield.5
The 4-aminopyridines 5a±c prepared were readily
converted into the corresponding pyrazolo[4,3-c]pyridines
7a±c via a simple and practical procedure as follows
(Scheme 3). 5-Alkyl-4-aminopyridines 5a±c were diazo-
tized in a conventional manner by the action of sodium
nitrite in 50% sulphuric acid. Treatment of the diazonium
salts 6a±c thus formed with aqueous sodium acetate
solution gave the desired tri¯uoromethylated pyrazolo[4,3-
c]pyridines 7a±c as high-melting crystalline materials
which can be puri®ed by sublimation in vacuo. Spectral
All new compounds were characterised by spectral and
microanalytical data. Mass spectra of compounds 7a±c
showed the molecular ion as the base peak. As expected,
in the 1H NMR spectra of compounds 7a±c, signals
assigned to the pyridine protons are signi®cantly shifted
down®eld (Ddˆ0.78±1.19 ppm) compared to the pyridine
precursors 2a±c, 5a±c.4
In conclusion, practical routes to 5-alkyl-4-amino-2-
(tri¯uoromethyl)pyridines 5 starting from the corresponding
Scheme 2.
Scheme 3.

V. I. Tyvorskii et al. / Tetrahedron 57 (2001) 2051±2055
2053
4H-pyran-4-ones were developed. Diazotisation of 5-alkyl-
ated 4-aminopyridines, followed by sodium acetate treat-
ment of the obtained diazonium salts, offers a convenient
procedure for the synthesis of tri¯uoromethylated pyra-
zolo[4,3-c]pyridines.
158.83 (CCH3), 162.68 (C±OH). EIMS (70 eV) m/z (rel.
int.) 191 (M1, 100), 176 (5), 172 (12), 171 (17), 163 (7),
162 (26), 148 (6), 142 (9), 128 (10), 102 (24), 94 (10), 91
(7), 81 (21), 75 (11), 69 (11), 67 (12), 55 (17), 53 (23), 51
(19), 42 (34), 39 (20). Anal. Calcd for C8H8F3NO: C, 50.27;
H, 4.22. Found: C, 50.38; H, 4.39.
3.1.5. 5-Ethyl-2-(tri¯uoromethyl)-4-pyridinol (2c). 83%.
Mp 128±1298C (cyclohexane±toluene, 1:1); IR (CHCl3)
3. Experimental
3.1. General
1
3565, 3400, 1640 (weak), 1605 cm21; H NMR (CDCl3) d
1.27 (t, Jˆ7.5 Hz, 3H), 2.72 (q, Jˆ7.5 Hz, 2H), 7.18 (s, 1H),
8.12 (s, 1H), 11.01 (brs, 1H). EIMS (70 eV) m/z (rel. int.)
191 (M1, 49), 190 (12), 177 (8), 176 (100), 172 (7), 128 (6),
126 (15), 101 (4), 78 (5), 69 (6), 68 (3), 55 (4), 53 (13), 52
(8), 51 (11), 50 (4), 39 (13). Anal. Calcd for C8H8F3NO: C,
50.27; H, 4.22. Found: C, 50.35; H, 4.41.
IR spectra were measured on a Specord 75 IR (CCl4 or
CHCl3 solution) or a UR 20 (KBr) spectrophotometer. H
1
and 13C NMR spectra were recorded on a Bruker AC-200
spectrometer at 200 and 50.3 MHz, respectively, with Me4Si
as the internal standard. Mass spectra were obtained on a
Shimadzu QP-5000 GC/MS spectrometer. Melting points are
uncorrected. All chemicals were reagent grade; solvents were
dried and distilled prior to use. 5-Methyl-2-(tri¯uoromethyl)-
4H-pyran-4-one (1a) and 5,6-dimethyl-2-(tri¯uoromethyl)-
4H-pyran-4-one (1b) were prepared as previously reported.6
3.1.6. Preparation of 4-aminopyridines 5a±c. Method A.
Tosyl isocyanate (2.7 mL, 17.5 mmol) was added in one
portion to a suspension of 4-pyridinols 2a±c (10 mmol) in
20 mL of dry toluene. The reaction mixture was then heated
at re¯ux for 9 h. The solution was cooled to 08C, and 90%
sulphuric acid (3.0 mL) was added. The two-phase mixture
was stirred at 608C for 16 h. After cooling to 08C, crushed
ice (10 g) was added followed by 46% aqueous sodium
hydroxide (8.7 mL). The precipitated sodium sulphate was
then ®ltered off and washed thoroughly with CH2Cl2. The
®ltrate was extracted with CH2Cl2 (10 mL£5). The
combined organic phases were stirred at re¯ux with
50 mL of 15% HCl for 30 min. The organic layer was sepa-
rated and washed with 10 mL of 15% HCl. The combined
aqueous acid phases were treated with 46% aqueous sodium
hydroxide until alkaline, extracted with CH2Cl2 (10 mL£5),
the extract being washed with brine and dried over Na2SO4.
After evaporation of the solvent, the residue was recrystal-
lised to obtain 4-aminopyridines 5a,b or diluted with ether
and ®ltered through a short pad of silica gel to provide, after
concentration, 4-aminopyridine 5c.
3.1.1. 5-Ethyl-2-(tri¯uoromethyl)-4H-pyran-4-one (1c).
This compound was prepared from 2-acetyl-2-ethyl-
oxirane16 in 36% overall yield according to the previously
described two-step procedure.6 1c: bp 68±698C/10 mmHg;
nD ˆ1.4393; IR (CCl4) 1675, 1640, 1605 cm21; H NMR
(CDCl3) d 1.18 (t, Jˆ7.5 Hz, 3H), 2.45 (q, Jˆ7.5 Hz, 2H),
6.71 (s, 1H), 7.74 (s, 1H). EIMS (70 eV) m/z (rel. int.) 192
(M1, 77), 191 (100), 177 (4), 164 (9), 145 (9), 139 (17), 123
(3), 95 (44), 75 (9), 69 (47), 54 (8), 53 (88), 52 (11), 51 (18),
50 (9), 41 (16), 40 (6), 39 (90), 38 (11). Anal. Calcd for
C8H7F3O2: C, 50.01; H, 3.67. Found: C, 50.19; H, 3.83.
20
1
3.1.2. Conversion of pyranones 1a±c into pyridinols 2a±
c. To a solution of starting pyranones 1a±c (10 mmol) in
5 mL of MeOH (compounds 1a and 1c) or i-PrOH
(compound 1b), 25% aqueous ammonia (1.9 mL,
25 mmol) was added. The resulting solution was heated at
re¯ux for 12±36 h. After evaporation of the solvent under
reduced pressure, the solid residue was recrystallised to
afford compounds 2a±c as white crystals.
Method B. 2-Chloroacetamide (0.94 g, 10 mmol), potassium
carbonate (3.45 g, 25 mmol) and sodium iodide (0.04 g,
0.25 mmol) were added to a solution of 4-pyridinols 2a±c
(10 mmol) in 25 mL of dry DMF. The stirred reaction
mixture was heated at 50±608C for 30 h. Then, a fresh
portion of potassium carbonate (3.45 g, 25 mmol) was
added and the mixture was heated at 140±1508C for 8 h.
The bulk of the DMF was evaporated under reduced pres-
sure, the residue diluted with 10 mL of water and extracted
with ether (10 mL£5). The combined organic extracts were
washed with brine and dried over Na2SO4. Evaporation of
the solvent afforded pure 4-aminopyridines 5a±c, identical
in all aspects with samples obtained according to method A.
3.1.3. 5-Methyl-2-(tri¯uoromethyl)-4-pyridinol (2a).
94%. Mp 143±1448C (toluene); IR (CHCl3) 3555, 1637
1
(weak), 1600 cm21; H NMR (CDCl3) d 2.29 (s, 3H), 7.22
(s, 1H), 8.18 (s, 1H), 11.86 (brs, 1H). 13C NMR (DMSO-d6)
d
12.73 (CH3), 107.15 (s, CHvCCF3), 121.91 (q,
Jˆ274 Hz, CF3), 123.98 (CCH3), 146.10 (q, Jˆ33 Hz,
CCF3), 151.40 (CHvCCH3), 163.33 (C±OH). EIMS
(70 eV) m/z (rel. int.) 177 (M1, 100), 176 (13), 159 (9),
158 (14), 157 (19), 148 (10), 128 (7), 108 (18), 102 (17),
101 (9), 81 (16), 80 (11), 79 (11), 75 (12), 69 (10), 68 (15), 63
(10), 55 (12), 53 (32), 52 (14), 51 (12), 39 (10). Anal. Calcd
for C7H6F3NO: C, 47.47; H, 3.41. Found: C, 47.61; H, 3.58.
3.1.7. 4-Amino-5-methyl-2-(tri¯uoromethyl)pyridine (5a).
87% method A; 89% method B, white crystals. Mp 109±
1108C (cyclohexane±toluene, 1:1); IR (CCl4) 3500, 3405,
1
1620 cm21; H NMR (CDCl3) d 2.17 (s, 3H), 4.47 (brs,
3.1.4. 5,6-Dimethyl-2-(tri¯uoromethyl)-4-pyridinol (2b).
94%. Mp 137±1388C (cyclohexane±benzene, 1:1); IR
2H), 6.89 (s, 1H), 8.19 (s, 1H). 13C NMR (CDCl3) d 13.67
(CH3), 105.67 (q, Jˆ2.5 Hz, CHvCCF3), 119.30 (CCH3),
122.10 (q, Jˆ274 Hz, CF3), 146.95 (q, Jˆ33 Hz, CCF3),
150.18 (CHvCCH3), 152.60 (C±NH2). EIMS (70 eV) m/z
(rel. int.) 176 (M1, 100), 175 (22), 157 (11), 156 (25), 148 (5),
129 (5), 107 (12), 101 (4), 81 (5), 80 (54), 78 (5), 75 (5), 69
1
(CHCl3) 3570, 3400, 1645 (weak), 1590 cm21; H NMR
(CDCl3) d 2.20 (s, 3H), 2.49 (s, 3H), 6.99 (s, 1H), 8.07
(brs, 1H). 13C NMR (DMSO-d6) d 10.66 (CH3), 22.40
(CH3), 105.62 (q, Jˆ2.5 Hz, CHvCCF3), 121.53 (CCH3),
121.97 (q, Jˆ274 Hz, CF3), 144.23 (q, Jˆ33 Hz, CCF3),

2054
V. I. Tyvorskii et al. / Tetrahedron 57 (2001) 2051±2055
(6), 66 (5), 63 (8), 54 (10), 53 (15), 52 (17), 41 (8), 40 (6), 39
(19). Anal. Calcd for C7H7F3N2: C, 47.73; H, 4.01. Found: C,
47.87; H, 4.18.
period of 10 min to an ice cooled solution of 4-amino-
pyridines 5a±c (5 mmol) in 4.2 mL of 50% H2SO4. During
the addition of the NaNO2 solution, the reaction mixture was
vigorously stirred and the temperature was maintained at
0±58C. The resulting clear solution was added dropwise
over a period of 30 min to vigorously stirred 20% aqueous
sodium acetate (80 mL), cooled to 0±58C. After the addi-
tion, the reaction mixture was allowed to warm at room
temperature and stirred for 1 h. The resulting yellow±
orange suspension was extracted with ethyl acetate. The
combined organic extracts were washed with NaHCO3,
brine, and dried over Na2SO4. Evaporation of the solvent
gave an orange solid which on sublimation in vacuo (180±
2008C, 10 mmHg) afforded pyrazolopyridines 7a±c as pale
yellow crystals. Recrystallisation gave analytical samples of
7a±c as white crystals.
3.1.8. 4-Amino-5,6-dimethyl-2-(tri¯uoromethyl)pyridine
(5b). 88% method A; 86% method B, white crystals. Mp
94±958C (cyclohexane±benzene, 1:1); IR (CCl4) 3505,
1
3410, 1620 cm21; H NMR (CDCl3) d 2.10 (s, 3H), 2.51
(s, 3H), 4.30 (brs, 2H), 6.78 (s, 1H). EIMS (70 eV) m/z (rel.
int.) 190 (M1, 100), 189 (14), 175 (4), 171 (11), 170 (42),
162 (5), 149 (4), 129 (6), 102 (7), 95 (5), 81 (6), 80 (62), 78
(6), 77 (6), 69 (7), 67 (7), 66 (7), 54 (11), 52 (16), 51 (12), 42
(17), 41 (11), 39 (12). Anal. Calcd for C8H9F3N2: C, 50.53;
H, 4.77. Found: C, 50.69; H, 4.93.
3.1.9. 4-Amino-5-ethyl-2-(tri¯uoromethyl)pyridine (5c).
86% method A; 87% method B, pale yellow oil; IR
1
(CCl4) 3515, 3425, 1630 cm21; H NMR (CDCl3) d 1.17
3.1.13. 6-(Tri¯uoromethyl)-1H-pyrazolo[4,3-c]pyridine
(7a). 64%. Mp 238±2398C (i-PrOH±toluene, 1:1); IR
(t, Jˆ7.5 Hz, 3H), 2.54 (q, Jˆ7.5 Hz, 2H), 4.57 (brs, 2H),
6.89 (s, 1H), 8.18 (s, 1H). EIMS (70 eV) m/z (rel. int.) 190
(M1, 48), 176 (8), 175 (100), 171 (4), 169 (3), 148 (1), 128
(2), 125 (5), 94 (2), 78 (2), 75 (2), 69 (3), 63 (1), 54 (2), 52
(5), 51 (3), 42 (1), 41 (2), 39 (5). Anal. Calcd for C8H9F3N2:
C, 50.53; H, 4.77. Found: C, 50.70; H, 4.95.
1
(KBr) 3300±2700, 1630, 1505 cm21; H NMR (DMSO-
d6) d 8.07 (s, 1H), 8.51 (s, 1H), 9.28 (s, 1H), 14.02 (brs,
1H). 13C NMR (DMSO-d6) d 103.72 (q, Jˆ3 Hz,
CHvCCF3), 121.68 (Cquat), 122.63 (q, Jˆ273 Hz, CF3),
134.42 (CHvN±NH), 141.11 (q, Jˆ33 Hz, CCF3), 142.17
(C±NH), 145.95 (CHvN). EIMS (70 eV) m/z (rel. int.) 187
(M1, 100), 168 (12), 137 (11), 118 (33), 94 (3), 91 (12), 81
(6), 75 (4), 69 (10), 66 (6), 64 (25), 63 (13), 62 (10), 52 (17),
51 (4), 40 (7), 39 (7). Anal. Calcd for C7H4F3N3: C, 44.93;
H, 2.15. Found: C, 45.08; H, 2.26.
3.1.10. 2-[5-Methyl-2-(tri¯uoromethyl)-4-pyridyloxy]-
acetamide (4a). 2-Chloroacetamide (0.94 g, 10 mmol),
potassium carbonate (3.45 g, 25 mmol) and sodium iodide
(0.04 g, 0.25 mmol) were added to a solution of 4-pyridinol
2a (1.77 g, 10 mmol) in 35 mL of dry acetone. The stirred
reaction mixture was heated at re¯ux for 48 h and cooled to
room temperature. The salts were ®ltered off and washed
thoroughly with acetone. The ®ltrate and washings were
combined and evaporated under reduced pressure. The resi-
due was recrystallised to give 1.64 g (70%) of compound 4a
as colourless crystals. Mp 175±1778C (i-PrOH±toluene,
3.1.14. 4-Methyl-6-(tri¯uoromethyl)-1H-pyrazolo[4,3-c]-
pyridine (7b). 77%. Mp 181±1838C (toluene); IR (KBr)
1
3300±2600, 1620, 1605, 1510 cm21; H NMR (DMSO-d6)
d 2.83 (s, 3H), 7.86 (s, 1H), 8.52 (s, 1H), 13.91 (brs, 1H).
13C NMR (DMSO-d6) d 21.98 (CH3), 101.50 (CHvCCF3),
121.00 (Cquat), 122.62 (q, Jˆ273 Hz, CF3), 134.27
(CHvN±NH), 140.81 (q, Jˆ33 Hz, CCF3), 142.08 (C±
NH), 155.12 (CH3±CvN). EIMS (70 eV) m/z (rel. int.)
201 (M1, 100), 182 (10), 181 (18), 180 (5), 173 (2), 162
(14), 161 (8), 154 (28), 135 (3), 131 (5), 127 (11), 105 (10),
91 (5), 81 (7), 78 (7), 77 (7), 75 (5), 69 (10), 66 (7), 62 (6),
52 (12), 51 (12), 50 (7), 39 (10). Anal. Calcd for C8H6F3N3:
C, 47.77; H, 3.01. Found: C, 47.89; H, 3.19.
1
3:2); IR (CHCl3) 3520, 3400, 1700, 1575 cm21; H NMR
(DMSO-d6) d 2.27 (s, 3H), 4.77 (s, 2H), 7.30 (s, 1H), 7.51
(brs, 1H), 7.57 (brs, 1H), 8.44 (s, 1H). 13C NMR (DMSO-d6)
d
12.96 (CH3), 66.82 (CH2), 104.25 (q, Jˆ2.5 Hz,
CHvCCF3), 121.78 (q, Jˆ274 Hz, CF3), 125.76 (CCH3),
146.45 (q, Jˆ33 Hz, CCF3), 151.00 (CHvCCH3), 163.22
(C±O), 169.00 (CvO). EIMS (70 eV) m/z (rel. int.) 234
(M1, 31), 215 (7), 191 (19), 190 (16), 176 (23), 161 (8),
160 (23), 141 (15), 140 (6), 113 (8), 110 (5), 83 (10), 75 (5),
69 (6), 65 (6), 63 (16), 59 (100), 58 (30), 53 (6), 51 (6), 44
(70), 42 (12), 39 (24). Anal. Calcd for C9H9F3N2O2: C,
46.16; H, 3.87. Found: C, 46.28; H, 3.98.
3.1.15. 3-Methyl-6-(tri¯uoromethyl)-1H-pyrazolo[4,3-c]-
pyridine (7c). 40%. Mp 274±2768C (ethyl acetate); IR
1
(KBr) 3300±2600, 1630, 1495 cm21; H NMR (DMSO-
d6) d 2.64 (s, 3H), 7.96 (s, 1H), 9.22 (s, 1H), 13.58 (br s,
1H). 13C NMR (DMSO-d6) d 11.76 (CH3), 103.24 (q,
Jˆ3 Hz, CHvCCF3), 120.85 (Cquat), 122.62 (q, Jˆ273
Hz, CF3), 141.16 (q, Jˆ33 Hz, CCF3), 142.91 (CH3±
CvN±NH and C±NH), 145.20 (CHvN). EIMS (70 eV)
m/z (rel. int.) 201 (M1, 100), 200 (79), 182 (9), 174 (4),
173 (11), 154 (3), 150 (3), 147 (2), 132 (4), 91 (4), 78 (4),
77 (4), 75 (7), 69 (8), 66 (4), 64 (9), 52 (9), 51 (8), 50 (6), 42
(8), 39 (4). Anal. Calcd for C8H6F3N3: C, 47.77; H, 3.01.
Found: C, 47.92; H, 3.17.
3.1.11. Transformation of compound 4a to 4-amino-
pyridine 5a. Compound 4a (1.50 g, 6.4 mmol) was
dissolved in 25 mL of dry DMF, then potassium carbonate
(3.45 g, 25 mmol) was added and the mixture was re¯uxed
for 8 h. The bulk of the DMF was evaporated under reduced
pressure, the residue diluted with 5 mL of water and
extracted with ether (10 mL£5). The combined organic
extracts were washed with brine and dried over Na2SO4.
Evaporation of the solvent afforded 1.04 g (92%) of
4-aminopyridine 5a as white crystals.
Acknowledgements
3.1.12. General procedure for the synthesis of 1H-pyra-
zolo[4,3-c]pyridines 7a±c. A solution of NaNO2 (0.38 g,
5.5 mmol) in 0.7 mL of water was added dropwise over a
We are indebted to INTAS (project 97-0217) for ®nancial
support of this work.

V. I. Tyvorskii et al. / Tetrahedron 57 (2001) 2051±2055
2055
7. Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; De
Kimpe, N.; Aelterman, W. Tetrahedron 2000, 56, 7313±7318.
8. Milhavet, J.-C.; Gueiffer, A.; Bernal, S.; Teulade, J.-C.
Heterocycles 1999, 51, 1661±1667.
References
1. Webber, S. E.; Bleckman, T. M.; Attard, J.; Deal, J. G.;
Kathardekar, V.; Welsh, K. M.; Webber, S.; Janson, C. A.;
Matthews, D. A.; Smith, W. W.; Freer, S. T.; Jordan, S. R.;
Bacquet, R. J.; Howland, E. F.; Booth, C. L. J.; Ward, R. W.;
Hermann, S. M.; White, J.; Morse, C. A.; Hilliard, J. A.;
Bartlett, C. A. J. Med. Chem. 1993, 36, 733±746.
2. Cox, J. M.; Gillen, K. J.; Ellis, R. M.; Vohra, S. K.; Smith, S.
C.; Matthews, I. R. PCT Int. Appl. WO 96 37, 466, 1996;
Chem. Abstr. 1997, 126, 104006t.
9. Maracos, P.; Pouli, N.; Wise, D. S.; Townsend, L. B. Synlett
1997, 561±562.
10. (a) Ellis, A.; Li, C. G.; Rand, M. J. Eur. J. Pharmacol. 1998,
356, 41±47. (b) Ovcharova, I. M.; Zasosova, I. M.; Gerchikov,
L. N.; Golovchinskaya, E. S.; Liberman, S. S. Khim.-Farm.
Zh. 1973, 7 (N11), 57±59; Chem. Abstr. 1974, 80, 47949h.
11. Ratcliffe, A. H.; Masek, B. B. PCT Int. Appl. WO 94 03,453,
1994; Chem. Abstr., 1994, 120, 270465n.
3. Greenhill, J. V. Pyrazoles with fused six-membered hetero-
cyclic ring. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon
Press: Oxford, 1984; Vol. 5, pp 305±343 (Part 4A).
4. Chapman, D.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1980,
2398±2404.
12. Shutske, G. M.; Kapples, K. J.; Tomer, J. D. US Patent
5,264,576, 1993; Chem. Abstr. 1994, 120, 217669f.
13. Narsaiah, B.; Sivaprasad, A.; Venkataratnam, R. V. J. Fluorine
Chem. 1994, 67, 87±90.
14. For the similar conversion of 4-quinolinol into 4-aminoquino-
line in 27% yield, see: Wiedner, J. J.; Peet, N. P. J. Heterocycl.
Chem. 1997, 34, 1857±1860.
5. Michaely, W. J.; Curtis, J. K.; Knudsen, C. G. US Patent
5,300,478, 1994; Chem. Abstr. 1994, 121, 57503n.
6. Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; De
Kimpe, N.; Abbaspour Tehrani, K. Tetrahedron 1998, 54,
2819±2826.
15. Coutts, I. G. C.; Southcott, M. R. J. Chem. Soc., Perkin Trans.
1 1990, 767±771.
16. Reusch, W.; Djerassi, C. Tetrahedron 1967, 23, 2893±2909.