Practical methylation procedure for (1H)-1,2,4-triazole

Article abstract of DOI:10.1080/00397910701820319

Conversion of (1H)-1,2,4-triazole to its sodium salt with methanolic sodium methoxide is followed by reaction with iodomethane. A scalable approach that overcomes problems associated with water-soluble starting material and water-soluble product combined continuous extraction (chloroform/water) with a final short-path distillation under a controlled vacuum to obtain spectroscopically pure 1-methyl-1,2,4-triazole in 63% yield. Adaptation to microwave synthesis conditions, while providing a faster reaction time, offers no product yield or purification advantages over the conventional approach described. Conversions of this product to related derivatives such as 1,4-dimethyl-1,2,4-triazolium iodide and 1-methyl-1,2,4-triazolium hydrochloride are readily achieved. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701820319

This article was downloaded by: ["University at Buffalo Libraries"]
On: 08 October 2014, At: 06:37
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Practical Methylation Procedure for
(
1H)‐1,2,4‐Triazole
a
b
b
John L. Belletire , Robert A. Bills & Scott A. Shackelford
a
ERC Incorporated, Air Force Research Laboratory, Edwards Air Force Base ,
California, USA
b
Air Force Research Laboratory , Space and Missile Propulsion Directorate,
Propellants Branch, Edwards Air Force Base , California, USA
Published online: 15 Feb 2008.
To cite this article: John L. Belletire , Robert A. Bills & Scott A. Shackelford (2008) Practical Methylation
Procedure for (1H)‐1,2,4‐Triazole, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:5, 738-745, DOI: 10.1080/00397910701820319
To link to this article: http://dx.doi.org/10.1080/00397910701820319
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
Synthetic Communications , 38: 738–745, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701820319
Practical Methylation Procedure
for (1H)-1,2,4-Triazole
1
John L. Belletire, Robert A. Bills, and Scott A. Shackelford
2
2
1
ERC Incorporated, Air Force Research Laboratory, Edwards Air Force
Base, California, USA
2
Air Force Research Laboratory, Space and Missile Propulsion
Directorate, Propellants Branch, Edwards Air Force Base,
California, USA
Abstract: Conversion of (1H)-1,2,4-triazole to its sodium salt with methanolic sodium
methoxide is followed by reaction with iodomethane. A scalable approach that
overcomes problems associated with water-soluble starting material and water-
soluble product combined continuous extraction (chloroform/water) with a final
short-path distillation under a controlled vacuum to obtain spectroscopically pure
1
-methyl-1,2,4-triazole in 63% yield. Adaptation to microwave synthesis conditions,
while providing a faster reaction time, offers no product yield or purification advan-
tages over the conventional approach described. Conversions of this product to
related derivatives such as 1,4-dimethyl-1,2,4-triazolium iodide and 1-methyl-1,2,4-
triazolium hydrochloride are readily achieved.
Keywords: 1-methyl-1,2,4-triazole, regioselective alkylation, sequential continuous
extraction, short-path distillation, 1,2,4-triazole sodium salt
INTRODUCTION
A large body of published chemistry has emerged pertaining to heterocycles
[1]
containing multiple nitrogen atoms within the ring system. The alkylation
of amide-anions derived from such heterocycles with various alkyl halides
Received in the USA September 14, 2007
Address correspondence to Scott A. Shackelford, Air Force Research Laboratory,
Propellants Branch, 10 East Saturn Blvd., Building 8451, Edwards Air Force Base,
CA 93524, USA. E-mail: scott.shackelford@edwards.af.mil
7
38

Practical Methylation Procedure for (1H)-1,2,4-Triazole
739
provides useful methodology for the preparation of valuable reaction products
from relatively inexpensive starting materials. Illustrating this approach, and
made more significant by their utility in numerous agrichemical and
[
2]
medicinal applications, alkylations of 1,2,4-triazoles have been widely
or an alter-
[3–5]
examined. Past reports using a direct methylation process
[
6]
native deamination strategy provided promising background methodology.
Although previous investigations often concentrated on alkylations with
higher-molecular-weight electrophiles rather than on synthesizing the
methyl homolog, the simple reaction to obtain the monomethyl derivative,
1
-methyl-1,2,4-triazole from (1H)-1,2,4-triazole presents experimental
problems for which a focused solution has not been addressed. A procedural
approach is herein provided that partially achieves these goods:
1
.
counters the appreciable water solubility of both the starting material and
the desired reaction product,
2
3
4
.
.
.
reduces regiochemical scrambling in the alkylation product,
minimizes overalkylation (i.e., quaternization), and
overcomes similar vapor pressure properties of both the 1-methyl-1,2,4-
triazole product and the (1H)-1,2,4-triazole reactant.
Because these challenges are common to the methylation of other low-
molecular-weight heterocycle substrates, our process should have consider-
able generality.
RESULTS AND DISCUSSION
By effectively solubilizing the reactants, intermediates, and products,
methanol serves as a polar protic solvent well suited for alkylation of (1H)-
1
,2,4-triazole 1. Screening of possible bases for removal of the acidic
proton prior to alkylation revealed that triethylamine was too weak to effec-
tively deprotonate the triazole, instead affording an intractable postalkylation
mixture largely consisting of (1H)-1,2,4-triazole, recovered triethylamine, and
triethylmethylammonium iodide. In contrast, an equivalent of sodium
methoxide, introduced as a 25% w:w solution in methanol, led to efficient
[
3–5]
deprotonation
when the reaction mixture was warmed (568C) for 2 h.
Although the sodium salt 2 of (1H)-1,2,4-triazole is commercially available,
in situ preparation of the anion is a trivial operation that allows the less
expensive triazole free base to be employed as starting material. Methylation
involves the dropwise addition of iodomethane to a precooled solution of the
sodio-intermediate, while maintaining the temperature using both an external
cooling bath and the electrophile’s rate of addition to control the considerable
exotherm. The reaction mixture is then allowed to stir for 19 h with gentle
heating at reflux. In range-finding experiments, heating the iodomethane/
triazole mixture for 6 h at reflux led to ꢀ10% recovered unreacted starting

740
J. L. Belletire, R. A. Bills, and S. A. Shackelford
material, whereas heating the iodomethane/sodio-triazole reaction mixture
for 72 h at 458C gave a crude reaction mixture essentially identical to the
1
9-h variant. A simple atmospheric distillation to concentrate the reaction
mixture to a viscous residue is performed using a short-path column.
Although this operation minimizes codistillation of the somewhat volatile
alkylation product, an actual test comparison using a rotary evaporator
under a modest vacuum (75 mbar) with a rt water bath afforded only a
modest (4%) decrease in yield. Upon isolation of the concentrated residue,
1
H NMR of the crude syrup demonstrated that the organic components
included the desired final product 1-methyl-1,2,4-triazole 3 (93%), ꢀ2% of
starting material 1, ꢀ2% of the undesired regioisomer 4, and ꢀ2% of the quar-
ternary bis-alkylation salt 5.
Structures
Efficient workup and purification of the reaction mixture encompassed a
sequence of simple operations. The reaction residue is diluted with a
minimum volume of water (in practice, 33 mL of water per 10 g of the
starting material) to remove the inorganic salts as well as small amounts
of very water-soluble by-products. Using a small continuous extraction
apparatus, the water solution is extracted with 170–200 mL of chloroform
with heating at reflux maintained for 22.5 h. Cooling of the system, separ-
ation and drying of the chloroform layer, filtration, and careful removal of
the chloroform can be achieved on a rotary evaporator equipped with a rt
water bath and operating at a modest vacuum (75 mbar). Alternatively,
and for best yields, distillation of the chloroform through a Vigreaux
column at atmospheric pressure affords a mobile oil whose proton NMR
exhibits essentially complete absence of starting material 1, regioisomer 4,
and quaternization product 5 (see structures shown in Scheme 1). The
presence of several very small baseline peaklets in the proton NMR of the
Scheme 1.

Practical Methylation Procedure for (1H)-1,2,4-Triazole
741
residue as well as a pale yellow color are evidence for trace amounts of
polymer. Final purification is accomplished when the residual oil is
subjected to a short-path distillation at constant moderate vacuum (70
mbar) with external oil-bath heating and isolation of the center cut. A
practical source of constant reduced pressure involves simply disconnecting
the original flexible tubing connection between the B u´´ chi vacuum controller
assembly and the actual B u´´ chi rotary evaporator apparatus and then recon-
necting that flexible tubing to the vacuum takeoff of the all-glass distillation
system. Trapping of the distilled product in an ice–salt water bath causes the
distillate to freeze into a snow-white solid. Thawing provides an approxi-
mate melting point of 3–58C for this sample. By reference to a standard
pressure/temperature (P/T) nomagraph, the published boiling point of
[
3]
1
-methyl-1,2,4-triazole, 177–1788C at 755 mm Hg, and our observed
boiling-point parameters at moderate pressure, 74–788C at 70 mbar, are in
agreement. Distillation at oil pump vacuum (0.1–0.3 mm Hg), both by
reference to the P/T nomagraph and by actual trial, occurs inconveniently
at temperatures colder than rt. Replication consistency is illustrated by
two consecutive methylations at a scale of 10 g of (1H)-1,2,4-triazole
starting material that gave 62.5% and 63.1% overall yields of distilled, spec-
troscopically pure 3.
Microwave experiments conducted using
a
Biotage/Personal
ChemistryTM Initiator apparatus sought to optimize the alkylation procedural
parameters. It was found that deprotonation of a 14.5-mmol sample of
the starting material could be accomplished using an equivalent of the
2
5
5% w/w methanolic sodium methoxide solution with heating to 658C for
min in a 5-mL sealed microwave reaction vessel within the microwave
apparatus. After cooling the reaction mixture in an ice bath to 0–38C,
uncrimping the reaction assembly, layering of the requisite neat iodo-
methane, and recrimping the 5-mL reaction vessel, the reaction vessel was
reinserted into the microwave apparatus. The reaction mixture was then
subjected to a second microwave heating at a set point of 908C for a total
overall heating cycle of 8 min. In this cycle, an initial very rapid (ꢀ15 s
in duration) exotherm to 1148C was followed by re-equilibration to 908C
within 200 s. After cooling to rt, removal of the methanol on a rotary evap-
orator afforded a viscous gelatinous residue, which was then subjected to
extraction with six 5-mL portions of reagent-grade chloroform. The
w
combined chloroform washes were filtered through a bed of Celite and
evaporated at reduced pressure to a solvent-free residue with a recovery of
0
.78 g. This residue is essentially identical in composition to that obtained
1
by the aforementioned conventional reaction procedure. Thus, by H NMR
integration, the microwave-derived crude product contains an amount
equal to, or greater than, 93% of the desired 1-Me-1,2,4-triazole 3 along
with 1.5–2.7% each of the starting (1H)-1,2,4-triazole 1, the 4-Me-1,2,4-
triazole regioisomer 4, and the quarternary 1,4-di-Me-1,2,4-triazolium
iodide 5. Final purification of the crude isolate could then be accomplished

742
J. L. Belletire, R. A. Bills, and S. A. Shackelford
as described previously. Although the microwave runs permit a much faster
reaction than the previous pot-boiler approach, we observed no advantage
with respect to the impurity profile, nor are the microwave runs easily
scalable to the 10-g level.
With convenient access to multigram samples of pure 1-methyl-1,2,4-
triazole, our own synthetic work required that this material be transformed
into several additional compounds. Two examples are given that afford the
ionic solids 5 and 6. Product 5 is obtained by reaction of the 1-methyl-
1,2,4-triazole with an excess of iodomethane. Because the light-sensitive,
highly crystalline 1,4-dimethyl-1,2,4-triazolium iodide 5 rapidly darkens
from white to grayish-green under fluorescent illumination, during all stages
of 5’s preparation, workup, and storage, the apparatus should be protected
from direct light by wrapping with aluminium foil. However, it is found
that somewhat darkened samples of 5 are still suitable for use as a chemical
intermediate. Reaction of 3 with 12M aqueous hydrochloric acid in
methanol at rt conveniently provides, after removal of volatiles, the crystal-
line, but hygroscopic, 1-methyl-1,2,4-triazolium hydrochloride 6.
EXPERIMENTAL
Equipment was generally dried in a glassware oven at 1008C for several hours
before use. All solvents were Sigma-Aldrich reagent grade. Starting materials
were purchased from Sigma-Aldrich and from Spectrum. NMR spectra were
taken on a Bruker 400-MHz spectrometer. IR spectra were taken on a Nicolet
6700 FTIR equipped with an HATR optical system.
1-Methyl-1,2,4-triazole (3)
To a 250-mL, three-necked round-bottom reaction flask (RBRF) equipped
w
with a 1-inch Teflon -clad magnetic stirring bar, a rubber septum, a 50-
mL constant pressure addition funnel, a reflux condenser, and a nitrogen inlet,
were added methanol (Sigma-Aldrich, reagent grade, 75 mL) and (1H)-1,2,4-
triazole 1 (Spectrum, MW 69.04, 10.00 g, 144.84 mmol). [Spectral data of
1
starting material: H (400.13 MHz, DMSO-d6, DMSO ¼ 2.500 ppm); 13.800
(br s, 1H), 8.299 (s, 2H)]. With ice-bath cooling and under a gentle
nitrogen purge, a commercial solution of sodium methoxide in methanol
[
Sigma-Aldrich, 25% w:w (den. ¼ 0.943 g/mL), 33.1 mL (31.21 g of
solution ¼ 7.803 g of actual NaOMe); MW 54.02; 144.45 mmol (thus, the
limiting reagent)] was added dropwise. Using an oil bath, the reaction mixture
was heated (internal T ¼ 568C) for 2 h. The flask was then cooled with an
external ice bath. Under gentle nitrogen purge and with continued ice-bath
cooling of the reaction flask, neat iodomethane [Sigma-Aldrich, MW 141.94,
10.1 mL (den. ¼ 2.28 g/mL), 23.03 g, 162.24 mmol, (handle with care: toxic

Practical Methylation Procedure for (1H)-1,2,4-Triazole
743
and volatile)] was added dropwise over 1 h. The ice bath was removed and was
replaced with an oil bath. The reaction mixture was heated at gentle reflux under
a nitrogen atmosphere for 19 h and then cooled to room temperature. Upon
substituting a glass stopper for the Liebig condenser and replacement of the
addition funnel by a short-path distillation apparatus, the methanol was
distilled using oil-bath heating and atmospheric pressure. To the resulting
thick semisolid residue (predominantly NaI) remaining in the flask,
deionized water (33 mL) was added, and the mixture was swirled to
produce a homogeneous solution. This was then loaded into a 250-mL con-
tinuous extraction apparatus (Sigma-Aldrich, Z126926) and 190 mL of
chloroform (Sigma-Aldrich, reagent grade) was added. Under nitrogen, the
immiscible solutions were subjected to continuous extraction with
refluxing chloroform for 22.5 h. After the two-phase mixture had cooled to
room temperature, the layers were separated. The original yellow color of
the water layer had now completely disappeared, and the chloroform layer
had acquired a faint yellow tint. The chloroform layer was dried over
MgSO , filtered, and, using the short-path distillation apparatus, the chloro-
4
form layer was distilled in portions at atmospheric pressure from a 200-mL,
one-neck, round-bottom reaction flask. The residue (11.11 g, 92.6% crude
yield) was then transferred to a 50-mL, one-neck, round-bottom flask
w
equipped with a 0.5-inch Teflon -clad magnetic stir bar and a short-path dis-
tillation apparatus. A tared receiver was used as the initial recovery flask. The
distillation apparatus was connected to a vacuum system consisting of a B u¨ chi
Vac 500 diaphragm pump and a B u¨ chi V805 pressure controller. The vacuum
was adjusted to a pressure of 87 mbar, and the oil bath was kept at 658C. Over
2
h, only a trace of material (0.1 g) consisting of a mixture of chloroform,
water, and 1-methyl-1,2,4-triazole could be condensed. The recovery flask
was replaced with a tared fresh one-neck 25-mL receiver. The vacuum was
decreased to 70 mbar, and the oil bath was warmed to 1318C (subsequently,
the oil bath gradually was warmed to 1408C). At 1318C oil-bath temperature,
the product now began to distill into the clean receiver and did so over a bp
range of 74–788C. (Because of the on-and-off cycling of the diaphragm
pump, the internal pressure of the system showed approximately a 10%
fluctuation around 70 mbar, and the actual overall temperature range for
the distillation was 71–948C, but almost all the material distilled between
7
4 and 788C.) During the distillation, the recovery flask was cooled in a
ice/salt/water bath kept at approx. 288C, thereby allowingthe distillate to crys-
tallize into a snow-white solid, which, in turn, remelted at approximately 3–58C
on warming. Upon thawing, the distillate is a colorless mobile liquid that
1
weighed 7.57 g (63.1% yield), No extraneous peaks are visible in the H or
1
3
1
C NMR; spectral data: H (400.13 MHz, DMSO-d6, DMSO ¼ 2.500 ppm)
1
3
d ¼ 8.454 (s, 1H), 7.943 (s, 1H), 3.863 (s, 3H); C (100.61 MHz, proton
decoupled, DMSO-d6, DMSO-C ¼ 39.510) d ¼ 151.362, 144.445, 35.679; IR
partial listing: 3113.3, 3015.2, 2945.7, 1585.0, 1515.6, 1437.9, 1413.4, 1339.8,
21
1
266.3, 1205.0, 1143.7. 1070.1 cm .

744
J. L. Belletire, R. A. Bills, and S. A. Shackelford
1,4-Dimethyl-1,2,4-triazolium Iodide (5)
To a 100-mL, one-neck RBRF equipped with a rubber septum,
-methyl-1,2,4-triazole (MW 83.09, 2.6133 g, 31.45 mmol), methanol
Sigma-Aldrich, reagent grade, 5.0 mL), and iodomethane [Sigma-Aldrich,
1
(
MW 141.94, density ¼ 2.28 g/mL, 9.804 g (4.30 mL), 69.07 mmol (signifi-
cant excess, handle with care: toxic and volatile)] were added. The reaction
flask was flushed with nitrogen, the apparatus was wrapped with alunimium
foil, and the clear homogeneous liquid was allowed to stand for 96 h at rt,
whereupon the solution had become very faintly green in color. Volatiles
were removed on a rotary evaporator with the last traces of solvent taken
off on a high-vacuum system (0.01 torr for several hours), whereupon the
resulting viscous syrup gradually crystallized to a light yellow solid. Tritura-
tion with anhydrous diethyl ether afforded off-white granular crystals 6.5770 g
(
82.0%). Because the crystals turn from white to light grayish-green after 1–2
days of exposure to laboratory-level fluorescent lighting, they should be
stored in an amber bottle or in a flask protected from laboratory light by
1
a layer of aluminum foil. Spectral data: H (400.13 MHz, DMSO-d6,
DMSO ¼ 2.500 ppm) d ¼ 10.052 (s, 1H), 9.149 (s, 1H), 4.064 (s, 3H),
1
3
3
.902 (s, 3H);
C
(100.62 MHz, proton decoupled, DMSO-d6,
DMSO-C ¼ 39.510) d ¼ 145.106, 143.206, 38.787, 34.235; IR partial
listing: 3019.3, 2974.3, 2945.7, 1585.0, 1540.1, 1442.0, 1417.5, 1364.4,
1286.7, 1237.7, 1164.1, 1066.1, 984.3 cm
2
1
.
1-Methyl-1,2,4-triazolium Hydrochloride (6)
To a 100-mL one-neck RBRF equipped with a rubber septum, 1-methyl-1,2,4-
triazole (MW 83.09, 1.2443 g, 14.975 mmol), methanol (Sigma-Aldrich,
reagent grade, 5.0 mL), and conc. aqueous HCl (J. T. Baker, 12 M,
1.25 mL, 15 mol) were added. The reaction flask was flushed with nitrogen,
and the clear homogeneous liquid was allowed to stand for 96 h at rt to
afford a colorless reaction mixture. Volatiles were removed on a rotary evap-
orator, and the resulting semisolid was pumped for several hours on a vacuum
line (0.03 torr). Trituration with anhydrous diethyl ether afforded moderately
hygroscopic white granular crystals. After rapid filtration on a Buchner funnel
under a flooding dry nitrogen atmosphere (provided by an inverted plastic
funnel), the crystals can be obtained solvent-free (1.5082 g, 84.2%) by
1
pumping on a high vacuum line (final P ¼ 0.01 torr). Spectral data: H
(
400.13 MHz, DMSO-d6, DMSO ¼ 2.500 ppm) d ¼ 14.602 (br s, 1H),
1
.845 (s, 1H), 8.879 (s, 1H), 4.006 (s, 3H); C (100.62 MHz, proton
3
9
decoupled, DMSO-d6, DMSO-C ¼ 39.510) d ¼ 145.140, 142.366, 37.714;
IR partial listing: 3383.0, 3150.1, 3113.3, 2986.3, 2925.3, 2884.4, 1564.6,
1527.8, 1429.7, 1364.4, 1262.2, 1151.9, 984.3, 939.4, 865.8 cm
2
1
.

Practical Methylation Procedure for (1H)-1,2,4-Triazole
ACKNOWLEDGMENTS
745
The authors acknowledge the Office of Naval Research (ONR, Project
Number N0001406MP20093) and the Air Force Research Laboratory
(AFRL/RZSP, Edwards AFB, CA) for their generous financial support.
REFERENCES
1
. Heterocyclic chemistry encompasses a vast area of knowledge. For a general
overview and introduction to the discipline, the following books are useful: (a)
Paquette, L. A. Principles of Modern Heterocyclic Chemistry; W. A. Benjamin:
New York, 1968; (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science: London, 2000.
2. The chemistry and practical applications of triazoles are well-developed. For
several highly selected examples, among many publications, see Temple, C.
1,2,4-Triazoles. (a) Montgomery, J. A. In The Chemistry of Heterocyclic
Compounds; Montgomery, J. A., Ed.; John Wiley & Sons: New York, 1981;
Vol. 37; (b) Turnbull, K. Five-membered ring systems with more than one N
Atom. Prog. Heterocycl. Chem. 1998, 10, 153–171; (c) Garratt, P. J. 1,2,4-
Triazoles. In Comprehensive Heteroaromatic Chemistry II; Katritzky, A. R.,
Rees, C. W., and Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 4,
pp. 127–163, 905–1006; (d) Koltin, Y.; Hitchcock, C. A. The search for new
triazole antifungal agents. Curr. Opin. Chem. Biol. 1997, 1, 176–182;
(
7
e) Terrell, C. L. Antifungal agents, part II: the azoles. Mayo Clin. Proc. 1999,
4, 78–100; (f) Richardson, K.; Brammer, K. W.; Marriott, M. S.; Troke, P. F.
Activity of UK-49,858, a bistriazole derivative, against experimental infections
with Candida albicans and Trichophyton mentagrophytes. Antimicrob. Agents
Chemother. 1985, 27, 832–835; (g) Heeres, J.; Hendrickx, R.; Van Cutsem, J.
Antimycotic azoles, 6: synthesis and antifungal properties of terconazole, a
novel triazole ketal. J. Med. Chem. 1983, 26, 611–613.
3
4
. Atkinson, M. R.; Polya, J. B. Triazoles, part II: N-Substitution of some 1,2,4-
triazoles. J. Chem. Soc. 1954, 141–145.
. Mirzael, Y. R.; Twamley, B.; Shreeve, J. M. Syntheses of 1-alkyl-1,2,4-triazoles
and the formation of quaternary 1-alkyl-4-polyfluoralk-1,2,4-triazolium salts
leading to ionic liquids. J. Org. Chem. 2002, 67, 9340–9345.
5. Bulger, P. G.; Cottrell, I. F.; Cowdon, C. J.; Davies, A. J.; Dolling, U.-H. An inves-
tigation into the alkylation of 1,2,4-triazole. Tetrahedron Lett. 2000, 41,
1297–1301.
6. Astleford, B. A.; Goe, G. L.; Keay, J. G.; Scriven, E. F. V. Synthesis of 1-alkyl
1,2,4-triazoles: a new one-pot regiospecific procedure. J. Org. Chem. 1989, 54,
731–732.