Alternative approach to 1,2,4-triazole-3-carboxamides

Article abstract of DOI:10.1080/00397910802661000

The conversion of trichloromethyl and tribromomethyltriazoles to the corresponding carboxamide derivatives is described. The trihalomethyl analogs are straightforward to make and react readily with a range of amines to produce carboxamides. The strategy a

Full text of DOI:10.1080/00397910802661000

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Alternative Approach to 1,2,4-
Triazole-3-carboxamides
David Ellis a
a Pfizer Global Research and Development ,
Sandwich, Kent, UK
Published online: 16 Jun 2009.
To cite this article: David Ellis (2009) Alternative Approach to 1,2,4-Triazole-3-
carboxamides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:14, 2585-2595, DOI:
10.1080/00397910802661000
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Synthetic Communications1, 39: 2585–2595, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802661000
Alternative Approach to 1,2,4-Triazole-3-
carboxamides
David Ellis
Pfizer Global Research and Development, Sandwich, Kent, UK
Abstract: The conversion of trichloromethyl and tribromomethyltriazoles to the
corresponding carboxamide derivatives is described. The trihalomethyl analogs
are straightforward to make and react readily with a range of amines to produce
carboxamides. The strategy avoids the problems of decarboxylation associated
with the use of triazole acids.
Keywords: 1,2,4-Triazole carboxamides, triazole carboxylic acids, trihalomethy-
loxadiazoles
We required
a
more convenient access to 3-amino- and
3-carboxamido-1,2,4-triazoles.[1]
Our established route, though robust, introduced the required amine
variation in the first step. The rapid production of analogs was therefore
hampered (Scheme 1).
In our hands, an alternative approach via the displacement of an
activated leaving group such as chlorine had previously proved
Received August 20, 2008.
This paper is dedicated to the memory of Olga Wallace, a fine young chemist.
Address correspondence to David Ellis, Discovery Chemistry, Pfizer Global
Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.
E-mail: david.ellis@pfizer.com
2585

2586
D. Ellis
Scheme 1. Original synthesis of 5-amino-1,2,4-triazoles.
unsuccessful (Scheme 2), despite the frequent use of this strategy in
heterocyclic chemistry.[2]
The literature indicated that the trichloromethyl group has some uti-
lity as a leaving group in this type of process with a variety of hetero-
cycles,[3] though it has not been reported for 1,2,4-triazoles and its main
use seems to be as a carboxylic acid surrogate.[4] This approach would
require the requisite 3-trichloromethyl substituted 1,2,4-triazole A, which
was synthesized by the well-established treatment of the corresponding
1,3,4-oxadiazole with an amine under acid catalysis[5] (Scheme 3).
The first attempt to convert A into an aminotriazole with piperidine
was not successful, and the corresponding amide was produced instead
(Scheme 4). This process appears unreported for 1,2,4-triazoles though
occasionally is seen in six-membered heterocyclic systems[6] and also in
a pyrazole template.[7] However, the conditions reported for the pyrazole
template (refluxing ethanol) were unsuccessful for the triazole template.
This appeared to be a general process, and after optimization, a small
series of amides was synthesized rapidly using pyridine as a solvent and
4-dimethylaminopyridine as a catalyst (see Table 1). This alternative
result was regarded as useful because previous attempts to access the
Scheme 2. Attempted displacement strategy.

1,2,4-Triazole-3-carboxamides
2587
Scheme 3. Synthesis of trichloromethyl-1,2,4-triazoles.
Scheme 4. Initial trial displacement reaction.
corresponding carboxylic acids had been thwarted by decarboxylation
upon hydrolysis of the corresponding esters.[8]
The examples in the table show that the process tolerates some
variety in the amine component.
Table 1. Reaction of trichloromethyltriazole A with various amines
Compound
Amine
Yield (%)
28
1
2
41
3
4
33
26
5
6
17
19

2588
D. Ellis
Scheme 5. Amidation reaction with tribromomethyltriazole.
The modest yields in the process may be due to chlorine being a poor
leaving group, hence the greater temperatures and long reaction times.
Bromine is a better leaving group, and the tribromomethyl group was
tried in this conversion. Further literature work revealed[6] that the tri-
bromomethyl group could be converted more easily to amides than the
trichloromethyl analog in a six-membered heterocyclic system. Therefore,
the tribromomethyl 1,2,4-triazole B was synthesized, and its conversion
to amides was examined (Scheme 3, R ¼ Br).
The conversion of triazole B to a small series of amides proceeded
well under milder conditions than the trichloromethyl analog A. The
reactions showed a much cleaner profile upon heating at 60–70ꢀC in
acetonitrile with Hunig’s base. Yields of amide products also appeared
to be more acceptable when compared to those obtained with the
trichloromethyl analogs (Scheme 5, Table 2).
Table 2. Reaction of tribromomethyltriazole B with various amines
Compound
Amine
Yield (%)
48a
7
8
9
53b
72
aEe of compound 7 is 95.4% (rt 12.9 min).
bEe of compound 8 is 94% (rt 17.1 min). Determined on Chiralpak
IA column with Heptane=IPA as eluent. This indicates that the chiral
integrity has been maintained for these amines.

1,2,4-Triazole-3-carboxamides
2589
In summary, an alternative approach to 1,2,4-triazole-3-carboxa-
mides has been found using the conversion of the tribromomethyl group
with a variety of amines under mild conditions. This opens up further
possibilities for this little used functional group interconversion.
EXPERIMENTAL
Proton nuclear magnetic resonance spectra (1H NMR) data were obtained
using a Varian 400-MHz Mercury spectrometer. Low-resolution mass
spectral data were recorded on a Waters ZQ ESCI spectrometer. The
quoted ions refer to the composition of the lowest isotopic mass. Column
chromatography was performed using Merck silica gel 60 (230–400 mesh).
2-Methoxymethyl-5-trichloromethyl-1,3,4-oxadiazole
Preparation
Trichloroacetic anhydride (6.22 g, 20.14 mmol) was added dropwise over
5 min to methoxyacetic hydrazide (2.00 g, 19.21 mmol) with stirring under
nitrogen at room temperature. (A mild exotherm was noted.) After stirring
for 1 h, phosphorus oxychloride was added dropwise, and the resulting
solution was heated to 110ꢀC for 2 h. The reaction mixture was then cooled
and evaporated to dryness. The residue was dissolved in ethyl acetate
(30 ml), washed with saturated sodium bicarbonate solution (3 ꢁ 10 ml)
and brine (10 ml), dried over MgSO4, filtered, and evaporated. The residue
was purified by chromatography on silica gel using CH2Cl2=MeOH as
eluent (100=0–97=3) to yield the product as a clear oil (1.72 g, 38%).
Data
1H NMR (400 MHz, CDCl3) d 3.5 (s, 3H), 4.75 (s, 2H). APCI þ ve m=z
231=233=235 MHþ (three-chlorine pattern).
3-Methoxymethyl-4-(2-methoxy-5-pyridyl)-5-trichloromethyl-
1,2,4-triazole
Preparation
5-Amino-2-methoxypyridine (1.07 g, 8.62 mmol) was added to a solution
of 3-methoxymethyl-5-trichloromethyl-1,3,4-oxadiazole (1.33 g, 5.74

2590
D. Ellis
mmol) in glacial acetic acid (10 ml). The resulting solution was heated at
100ꢀC for 2 h. The cooled reaction mixture was evaporated to dryness.
The residue was dissolved in ethyl acetate (25 ml), washed with saturated
sodium bicarbonate solution (2 ꢁ 10 ml), 10% aqueous citric acid solution
(2 ꢁ 10 ml); and brine (10 ml); dried over MgSO4; filtered; and evapo-
rated. The residue was purified by chromatography on silica gel using
ethyl acetate–pentane as eluent (0=100–100=0) to yield the product as a
white solid (1.72 g, 54%).
Data
1H NMR (400 MHz, CDCl3) d 3.35 (s, 3H), 4.07 (s, 3H), 4.53 (s, 2H),
6.85–6.95 (m, 1H), 7.25–7.35 (m, 1H), 7.84 (s, 1H). APCI þ ve m=z
337=339=341 MHþ (three-chlorine pattern).
Conversion of Trichloromethyltriazole A into an Amide 1
Representative Procedure
2-Phenylethylamine (143 mg, 1.18 mmol) was added to a solution of
the trichloromethyltriazole A (200 mg, 0.59 mmol) in pyridine (3 ml).
4-Dimethylaminopyridine (15 mg, 0.11 mmol) was added, and the
resulting solution was heated to 100ꢀC for 18 h under nitrogen. The
cooled reaction mixture was evaporated and partitioned between ethyl
acetate (10 ml) and water (5 ml). The organic phase was separated,
washed with 1 M HCl (2 ꢁ 5 ml), saturated NaHCO3 solution, and
brine (5 ml); dried over MgSO4; filtered; and evaporated. The residue
was purified by chromatography on silica gel using CH2Cl2=MeOH
as eluent (100=0–98=2) to furnish the product as a white solid
(61 mg, 28%).
Data
1H NMR (400 MHz, CDCl3) d 2.87 (t, 2H), 3.30 (s, 3H), 3.62 (q, 2H),
4.00 (s, 3H), 4.42 (s, 2H), 6.85 (d, 1H), 7.17–7.32 (m, 5H), 7.40–7.55
(m, 1H), 7.55 (d, 2H), 8.10 (s, 1H). APCI þ ve m=z 368 MHþ. The fol-
lowing examples in this series were made by similar means.
Compound 2. d 3.35 (s, 3H), 3.65–3.85 (m, 6H), 4.00 (s, 3H), 4.10–4.25
(m, 2H), 4.45 (s, 2H), 6.65–6.80 (m, 2H), 6.85–6.90 (br d, 1H),
7.55–7.65 (m, 2H), 8.10 (s, 1H), 8.20–8.25 (br d, 1H). m=z 410 MHþ.

1,2,4-Triazole-3-carboxamides
2591
Compound 3. d 3.32 (s, 3H), 3.78 (q, 2H), 4.00 (s, 3H), 4.05–4.12 (m, 2H),
4.42 (s, 2H), 6.85–6.98 (m, 4H), 7.25–7.32 (m, 2H), 7.52–7.58 (br d, 1H),
7.75–7.87 (br t, 1H), 8.12 (s, 1H). m=z 384 MHþ.
Compound 4. d 2.85 & 3.05 (t, 2H), 3.22 & 3.32 (s, 3H), 3.66 & 4.10 (t,
2H), 3.95 & 4.00 (s, 3H), 4.40 & 4.45 (s, 2H), 6.77 & 6.83 (d, 1H),
7.10–7.35 (m, 6.5H), 7.60 (br d, 0.5H), 7.87 & 8.08 (s, 1H) (rotamers
present in spectrum). m=z 382 MHþ.
Compound 5. d 2.00–2.20 (m, 1H), 2.30–2.50 (m, 1H), 3.30 & 3.33 (s, 3H),
3.38–3.65 (m, 2H), 3.80–4.12 (m, 2H), 4.00 (s, 3H), 4.32–4.40 (m, 0.5H),
4.42 & 4.45 (s, 2H), 4.55–4.62 (m, 0.5H), 6.85 (d, 1H), 7.20–7.38 (m, 5H),
7.57–7.63 (m, 1H), 8.06–8.10 (m, 1H). m=z 394 MHþ.
Compound 6. d 1.75–1.95 (m, 3H), 2.00–2.15 (m, 1H), 3.15–3.25 (m, 1H),
3.35 (s, 3H), 3.55–3.65 (m, 1H), 4.00 (s, 3H), 4.45 (s, 3H), 4.45–4.60 (m,
1H), 5.10 (s, 2H), 6.85 (d, 1H), 7.08–7.13 (m, 1H), 7.20–7.32 (m, 3H), 7.65
(dd, 1H), 8.13 (s, 1H). m=z 436 MHþ.
N-Acetyl-N0-tribromoacetylhydrazine
Preparation
A solution of tribromoacetyl chloride (4.46 g, 14.20 mmol) in 3 ml of
acetonitrile was added to a stirred, ice-cold solution of acetic hydra-
zide (1.00 g, 13.50 mmol) and pyridine (1.28 g, 16.20 mmol) in acetoni-
trile (10 ml) dropwise over 5 min under nitrogen. The resulting dark
solution was allowed to warm to room temperature. After 1 h the
reaction mixture was evaporated to low volume and partitioned
between dichloromethane and water. A precipitate formed, which
was filtered, washed with small portions of dichloromethane and
water, and dried under vacuum to yield the product as a white solid
(2.00 g, 42%).
Data
1H NMR (400 MHz, CDCl3) d 2.00 (s, 3H), 9.50–9.90 (br s, 1H),
10.10–10.40 (br s, 1H). APCIꢂve m=z 349–355 MꢂHþ for three-bromine
pattern.

2592
D. Ellis
3-Methyl-5-tribromomethyl-1,3,4-oxadiazole
Preparation
Phosphorus oxychloride (1.4 g, 9.06 mmol, 845 ml) was added dropwise
as a solution in acetonitrile (2 ml) to refluxing solution of
a
N-acetyl-N0-tribromoacetylhydrazine (1.60 g, 4.53 mmol) in acetonitrile
(10 ml) under nitrogen. After 4 h, the reaction mixture was cooled to room
temperature and evaporated to dryness. The residue was treated with ice
to produce a white solid that was filtered, washed with water, and dried
under vacuum to yield the product as a white solid (1.30 g, 85%).
Data
1H NMR (400 MHz, CDCl3) d 2.62 (s, 3H). APCI þ ve m=z 350–356
MNHþ4 for three-bromine pattern. Anal. calcd. for C4H3Br3N2O: C,
14.34; H, 0.90; N, 8.36. Found: C, 14.20; H, 0.89; N, 8.23.
3-Methyl-4-(2-methoxy-5-pyridyl)-5-tribromomethyl-1,2,4-triazole
Preparation
5-Amino-2-methoxypyridine (343mg, 2.76 mmol) was added to a solution
of 3-methyl-5-tribromomethyl-1,3,4-oxadiazole (617 mg, 1.84mmol) in
glacial acetic acid (5ml). The resulting solution was heated at 60ꢀC for 4 h
and then left at room temperature overnight. The reaction mixture was eva-
porated to dryness, and the residue was azeotroped with toluene (2ꢁ 5 ml).
The residue was partitioned between dichloromethane (30ml) and water
(10ml). The organic phase was separated washed with saturated sodium
bicarbonate solution (10 ml), 10% aqueous citric acid solution (2 ꢁ 10ml),
and brine (10 ml); dried over MgSO4; filtered; and evaporated. The residue
was dissolved in refluxing methanol (20ml) and decolorized with charcoal.
After filtration and evaporation, a white solid was produced. This was tri-
turated in ether, filtered, washed with fresh ether, and dried under vacuum
to yield the product as a white solid (350 mg, 44%).
Data
1H NMR (400 MHz, CDCl3) d 2.25 (s, 3H), 4.00 (s, 3H), 6.90–6.95 (d,
1H), 7.65–7.70 (d, 1H), 8.30 (s, 1H). APCI þ ve m=z 439=441=443=445
MHþ (three-bromine pattern).

1,2,4-Triazole-3-carboxamides
2593
Conversion of Tribromomethyltriazole B into Amide 7
Representative Procedure
Di-isopropylethylamine (103 mg, 0.80 mmol) was added to a solution of
the tribromomethyltriazole B (101 mg, 0.23 mmol) and S-2-methyl-2-
phenylethylamine (62 mg, 0.45 mmol) in acetonitrile (3 ml). The resulting
solution was refluxed for 6 h under nitrogen. The cooled reaction mixture
was evaporated and partitioned between ethyl acetate (10 ml) and water
(5 ml). The organic phase was separated, washed with 1 M HCl (2 ꢁ 5 ml),
saturated NaHCO3 solution, and brine (5 ml); dried over MgSO4,
filtered, and evaporated. The residue was purified by chromatography
on silica gel using EtOAc=pentane as eluent (20=80–100=0) to furnish
the product as a white solid (39 mg, 48%).
Data
1H NMR (400 MHz, CDCl3) d 1.27 (d, 3H), 2.35 (s, 3H), 2.95–3.05 (m,
1H), 3.35–3.50 (m, 1H), 3.55–3.65 (m, 1H), 4.00 (s, 3H), 6.88 (d, 1H),
7.15–7.35 (m, 6H), 7.40–7.45 (br d, 1H), 8.10 (s, 1H) m=z 352 MHþ.
The other examples in this series were made by similar means.
Compound 8. d 1.27 (d, 3H), 2.35 (s, 3H), 2.95–3.05 (m, 1H), 3.35–3.50
(m, 1H), 3.55–3.65 (m, 1H), 4.00 (s, 3H), 6.88 (d, 1H), 7.15–7.35 (m,
6H), 7.40–7.45 (br d, 1H), 8.10 (s, 1H) m=z 352 MHþ.
Compound 9. d 2.36 (s, 3H), 3.13 & 3.55 (s, 3H), 3.82 (t, 1H), 3.93 & 3.98
(s, 3H), 4.10 (t, 1H), 4.27 (s, 2H), 6.75–6.88 (m, 3H), 6.92–7.00 (m, 1H),
7.25–7.32 (m, 2H), 7.47–7.55 (m, 1H), 8.02–8.08 (m, 1H) m=z 368 MHþ.
REFERENCES
1. Brown, A. D.; Calabrese, A. A.; Ellis, D.; Watson, L. Substituted triazole
derivatives, WO 2005121152 (2005); Brown, A. D.; Ellis, D.; Smith, C. R.
Substituted triazole derivatives, WO 2005028452 (2005).
2. For some typical recent examples, see Gentile, G.; Di Fabio, R.; Pavone, F.;
Sabbatini, F. M.; St-Denis, Y.; Zampori, M. G.; Vitulli, G.; Worby, A. Novel
substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 recep-
tor antagonists. Bioorg. Med. Chem. Lett. 2007, 17, 5218–5221; Montgomery,
C. P.; Parker, D.; Lamarque, L. Effective and efficient sensitisation of
terbium luminescence at 355 nm with cell permeable pyrazolyl-1-azaxanthone

2594
D. Ellis
macrocyclic complexes. Chem. Commun. 2007, 37, 3841–3843; Zimmermann,
P. J.; Buhr, W.; Brehm, C.; Palmer, A. M.; Feth, M. P.; Senn-Bilfinger, J.;
Simon, W.-A. Novel indanyl-substituted imidazo[1,2-a]pyridines as potent
reversible inhibitors of the gastricHþ=Kþ-ATPase. Bioorg. Med. Chem. Lett.
2007, 17, 5374–5378; Han, X.; Civiello, R.; Pin, S. S.; Burris, K.; Balanda,
L. A.; Knipe, J.; Ren, S.; Fiedler, T.; Browman, K. E.; Macci, R.; Taber,
M. T.; Zhang, J.; Dubowchik, G. M. An orally active corticotropin releasing
factor
1 receptor antagonist from 8-aryl-1,3a,7,8-tetraaza-cyclopenta[a]
indenes. Bioorg. Med. Chem. Lett. 2007, 17, 2026–2030; Hu, L.-Y.; Lei, H.
J.; Du, D.; Johnson, T. R.; Fedij, V.; Kostlan, C.; Yue, W. S.; Lovdahl, M.; Li,
J. J.; Carroll, M.; Dettling, D.; Asbill, J.; Fan, C.; Wade, K.; Pocalyko, D.;
Lapham, K.; Yalamanchili, R.; Samas, B.; Vrieze, D.; Ciotti, S.; Krieger-Burke,
T.; Sliskovic, D.; Welgus, H. Synthesis and biological evaluation of
amino-pyridines as androgen receptor antagonists for stimulating hair growth
and reducing sebum production. Bioorg. Med. Chem. Lett. 2007, 17, 5693–5697;
Watterson, S. H.; Chen, P.; Zhao Y.: Gu, H. H.; Murali Dhar, T. G.; Xiao, Z.;
Ballentine, S. K.; Shen, Z.; Fleener, C. A.; Rouleau, K. A.; Obermeier, M.; Yang,
Z.; McIntyre, K. W.; Shuster, D. J.; Witmer, M.; Dambach, D.; Chao, S.; Mathur,
A.; Chen, B.-C.; Barrish, J. C.; Robl, J. A.; Townsend, R.; Iwanowicz.
Acridone-based inhibitors of inosine 50–monophosphate dehydrogenase: Discov-
ery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-
yl)pyridine-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxa-
mide (BMS-566419). J. Med. Chem. 2007, 50, 3730–3742.
3. Kreutzberger, A. J. Reactions of trichloromethyl-1,3,5-triazine derivatives with
amines. J. Am. Chem. Soc. 1957, 79, 2629–2633; Kober, E. J. Conversion of tri-
chloromethyl groups into dichloromethyl groups. J. Org. Chem. 1961, 26,
2270–2271; Elnagdi, M. H.; Fahmy, S. M.; Hafez, E. A. A.; Elmoghayar,
M. R. H.; Amer, S. A. R. Pyrimidine derivatives and related compounds: A
novel synthesis of pyrimidines, pyrazolo[4,3-d]pyrimidines, and isoxazo-
lo[4,3-d]pyrimidines. J. Heterocycl. Chem. 1979, 16, 1109–1111; Elnagdi, M.
H.; Elfahham, H. A.; Ghozlan, S. A. S.; Elgemeie, G. E. H. Activated nitriles
in heterocyclic synthesis: A new procedure for the synthesis of pyrimidine deri-
vatives. J. Chem. Soc., Perkin Trans. 1 1982, 11, 2667–2670; Mencarelli, P.;
Mattioli, M. Reactions of 4-(trihalomethyl)quinazolines with aliphatic amines:
Role of the halogen atom and of the amine on the reaction pattern. J. Org.
Chem. 1990, 55, 776–778; Mylari, B. L.; Oates, P. J.; Zembrowski, W. J.; Beebe,
D. A.; Conn, E. L.; Linhares, J. C.; Withbroe, G. J. A sorbitol dehydrogenase
inhibitor of exceptional in vivo potency with a long duration of action: 1-R-
{4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)-2R,6S-dimethylpiperazin-1-yl]pyrimidin-
2-yl}ethanol. J. Med. Chem. 2002, 45, 4398–4401; Werbel, L. M.; Elslager, E. F.;
Hess, C.; Hutt, M. P. Antimalarial activity of 2-(substituted amino)-4,6-
bis(trichloromethyl)1,3,5triazines and N-(chlorophenyl)-N0-[4-(substituted amino)-
6-(trichloromethyl)-1,3,5-triazin-2-yl]guanidines. J. Med. Chem. 1987, 30, 1943–1948.
4. For a typical example, see Le Fave, G. M.; Scheurer, P. G. Some reactions of
the trifluoromethyl group in the benzotrifluoride series, II: Alcoholysis. J. Am.
Chem. Soc. 1950, 72, 2464–2465.

1,2,4-Triazole-3-carboxamides
2595
5. Carlsen, P. H. J.; Jorgensen, K. B. Synthesis of unsymmetrically substituted
4H-1,2,4-triazoles. J. Heterocycl. Chem. 1994, 31, 805–807; Reitz, D. B.;
Finkes, M. J. Reaction of 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole with
primary amines: Synthesis of 4-substituted-3,5-bis(trifluoromethyl)-4H-1,2,4-
triazoles. J. Heterocyl. Chem. 1989, 26, 225–230; Brown, A. D.; Calabrese,
A. A.; Ellis, D.; Watson, L. Substituted triazole derivatives, WO 2005121152
(2005); Brown, A. D.; Ellis, D.; Smith, C. R. Substituted triazole derivatives,
WO 2005028452 (2005).
6. Mencarelli, P.; Mattioli, M. Reactions of 4-(trihalomethyl)quinazolines with
aliphatic amines: Role of the halogen atom and of the amine on the reaction
pattern. J. Org. Chem. 1990, 55, 776–778.
7. Martins, M. A. P.; Emmerich, D.; Beck, P.; Cunico, W.; Pereira, C. M. P.;
Sinhorin, A. P.; Brondani, S.; Peres, R.; Teixeira, M. V. M.; Bonacorso,
H. G.; Zanatta, N. One-pot synthesis of pyrazole-5-(3)-carboxyamides. Synth.
Commun. 2004, 34, 1915–1923.
8. Brown, T. B. Personal communication.