Highly regioselective synthesis of 1,3,5-trisubstituted 1,2,4-triazole derivatives

Article abstract of DOI:10.1080/00397911.2010.525678

The synthesis of 1,3,5-trisubstituted-1,2,4-triazoles is described. The key reaction is the thermal cyclization of an amidrazone intermediate with the aminal of an aromatic aldehyde. The method allows a variety of functionalities to be incorporated to add diversity to the initial templates.

Full text of DOI:10.1080/00397911.2010.525678

This article was downloaded by: [Mount Allison University 0Libraries]
On: 07 May 2013, At: 07:40
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
Highly Regioselective Synthesis of 1,3,5-
Trisubstituted 1,2,4-Triazole Derivatives
David Ellis a & Aurelio Arias-Wood b
a Discovery Chemistry, Pfizer Global Research and Development,
Sandwich, Kent, UK
b Imperial College, London, UK
Published online: 20 Apr 2011.
To cite this article: David Ellis & Aurelio Arias-Wood (2011): Highly Regioselective Synthesis of 1,3,5-
Trisubstituted 1,2,4-Triazole Derivatives, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 41:11, 1703-1712
To link to this article: http://dx.doi.org/10.1080/00397911.2010.525678
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
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.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 41: 1703–1712, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.525678
HIGHLY REGIOSELECTIVE SYNTHESIS OF 1,3,5-
TRISUBSTITUTED 1,2,4-TRIAZOLE DERIVATIVES
David Ellis1 and Aurelio Arias-Wood2
1Discovery Chemistry, Pfizer Global Research and Development,
Sandwich, Kent, UK
2Imperial College, London, UK
GRAPHICAL ABSTRACT
Abstract The synthesis of 1,3,5-trisubstituted-1,2,4-triazoles is described. The key reaction
is the thermal cyclization of an amidrazone intermediate with the aminal of an aromatic
aldehyde. The method allows a variety of functionalities to be incorporated to add diversity
to the initial templates.
Keywords Aminals; hydrazones; regioselective; thermal cyclization; 1,2,4-triazole
The 1,2,4-triazole template A (Fig. 1) was required as part of a medicinal chemistry
program.
Several approaches to 1,3,5-trisubstituted 1,2,4-triazoles are known, but most
lack a wider generality in synthesis. Some methods require the synthesis of specific
hydrazines for use in a cyclization process, which may not be an attractive option
when a variety of substituents is required.[1] Alkylation of 3,5-disubstituted 1,2,4-
triazoles can lead to regioisomeric products that require separation by some
means.[2] Other methods lack wider generality because of the use of intermediates
that have lengthy syntheses[3] or require harsh reagents or conditions.[4]
A search of the literature revealed a 1,2,4-triazole by-product B in some work
directed to the synthesis of triazaphospholes. This work utilized the cyclization of an
amidrazone 1 with tris-dimethylaminophosphine[5] (Scheme 1). The authors
suggested that breakdown of the amidrazone during the reaction gave rise to benzal-
dehyde, which reacted further with tris-dimethylaminophosphine to give the aminal.
Received June 30, 2010.
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
1703

1704
D. ELLIS AND A. ARIAS-WOOD
Figure 1. Initial triazole target.
This then reacted with the amidrazone to produce the triazole B along with the
triazaphosphole. This hypothesis was then proved in a separate experiment when
amidrazone 1 was reacted with the tetramethylaminal of benzaldehyde in refluxing
toluene to produce triazole B in 90% yield.
The conditions of the triazole-forming reaction are noteworthy for their sim-
plicity, mildness, good yield, and regioselectivity. However, there are no reports of
this reaction being used to make triazoles. This made us initially uncertain of the
general applicability to the synthesis of the required triazoles. The reaction formed
the basis of our own attempts to synthesize triazole A and later expand the process
to include a variety of substituents.
Retrosynthetic analysis of triazole A is shown in Scheme 2.
Aminal fragment 4 would be available from the corresponding commercially
available aldehyde[6] while the amidrazone 5 can be conveniently derived from the
hydrazone of benzaldehyde 6 and thioimidate 7. The latter can be accessed by
S-alkylation of the commercially available thioamide 8.[7] The simple nature of the
fragments in this synthesis suggested that other substituents could be easily intro-
duced to produce a triazole synthesis of wider generality. The amidrazone fragment
5 already contains four of the atoms in the final triazole ring and is easily assembled
in two steps under mild conditions[8] (Scheme 3).
Reaction of commercially available thioamide 8 with MeI in acetone at ambi-
ent temperature smoothly furnished the thioimidate salt, which was isolated by a
simple filtration. Subsequent reaction with the hydrazone of benzaldehyde 6 in
EtOH gave a clean reaction to yield the amidrazone 5. A simple aqueous=organic
Scheme 1. Original literature synthesis with triazole by-product.

SYNTHESIS OF 1,3,5-TRISUBSTITUTED 1,2,4-TRIAZOLES
1705
Scheme 2. Retrosynthetic analysis of the triazole A.
workup gave the free base of the amidrazone as a solid, which was pure enough for
subsequent reactions.
N,N0-Dimethylaminal 4 was easily prepared by addition of a toluene solution
of 4-benzyloxy-3-methoxybenzaldehyde to a solution of tris-dimethylaminoarsine
in toluene.[9] A precipitate of As2O3 formed rapidly, and workup consisted of fil-
tration and evaporation of the filtrate giving the aminal 4 as a clear oil, sufficiently
pure for further reaction (Scheme 4).
To complete the synthesis of the triazole template A, the amidrazone 5 and
aminal 4 were refluxed in toluene for 3 h. A simple aqueous=organic workup fol-
lowed by column chromatography yielded the protected derivative of the desired
triazole template A as a single regoisomer. The protecting group was removed by tri-
fluoroacetic acid=dichloromethane (TFA=DCM) to furnish the required triazole A
(Scheme 5).
Some early work in this area had established that neither aldehydes nor acetals
were suitable to achieve this cyclization. Only the aminal gave a clean, rapid reac-
tion. However, we were aware that utilization of arsenic-containing reagents for
the synthesis of aminals would not endow the method with wide acceptance. We
therefore sought an alternative method for the preparation of these intermediates.
Aminals of aromatic aldehydes are frequently made by heating the aldehyde and
40% aqueous dimethylamine at 50–60 ꢀC for several hours.[10] This protocol did not
work well with 4-benzyloxy-3-methoxybenzaldehyde where very poor conversions
were obtained. Further studies on aminal formation used p-bromobenzaldehyde.
Scheme 3. Synthesis of the amidrazone.

1706
D. ELLIS AND A. ARIAS-WOOD
Scheme 4. Synthesis of the aminal.
This aldehyde was chosen as it would be less electronically compromised and yet still
yield triazole targets with useful functionality for further reactions. This aldehyde
reacted well with 40% aqueous dimethylamine solution at 50 ꢀC to produce the cor-
responding aminal. Simple evaporation of the solvent and azeotropic drying of the
residue with toluene produced the aminal as a clear oil, which was sufficiently pure
for subsequent use. Some residual aldehyde was seen by NMR. This could be easily
estimated, and allowances were made in the subsequent step with the prior knowl-
edge that it would not participate in the cyclization to the triazole.
A simpler and more rapid method was found later.[11] It is known that aro-
matic aldehydes can be transformed into their aminals with dimethylaminotrimethyl-
silane catalyzed by trimethylsilyltrifluoromethane sulfonate in DCM at 0 ꢀC. This
procedure was followed for pyridine-3-carboxaldehyde 9 and a good yield of the
aminal 10 was obtained under these mild conditions (Scheme 6).
Scheme 5. Final cyclization to the triazole.
Scheme 6. Alternative synthesis of aminals.

SYNTHESIS OF 1,3,5-TRISUBSTITUTED 1,2,4-TRIAZOLES
1707
Once reliable methods had been established for aminal synthesis, attention
turned to variation of the amidrazone fragment. The benzaldehyde originally used
was readily replaced by other aromatic aldehydes such as p-bromobenzaldehyde,
pyridine-3-carboxaldehyde, and furan-3-carboxaldehyde. The hydrazones were
synthesized in the same manner from the aldehyde and hydrazine hydrate. The
thioamide fragment was also varied to include methoxythioacetamide, which would
furnish a useful masked alcohol substituent. After alkylation of these thioamides
with MeI as before, the thioimidate salts reacted smoothly with the hydrazones to
produce a range of amidrazones. A simple chromatographic purification was needed
for the products (Table 1).
Reaction of the amidrazones with the aminals proceeded as before to give the
expected 1,3,5-trisubstituted 1,2,4-triazoles in acceptable yields. A simple chromato-
graphy was required to give pure products, with the excess aminals always eluting
first. The triazoles synthesized are shown in the table along with spectroscopic data
(Table 2). All triazoles were produced as a single isomer. Extensive NMR profiling of
Table 1. NMR data for the amidrazones
Amidrazone
NMR data
d (CDCl3) 1.72–1.85 br s, 2H, 3.43 s, 3H, 4.15 s, 2H,
7.28–7.33 m, 1H, 8.03–8.08m, 1H, 8.35 s, 1H, 8.60 m,
1H, 8.90 s, 1H. ESIMS: m=z 193 [MH]þ.
d (CDCl3) 1.46 s, 9H, 3.95 m, 2H, 5.12–5.30 br m, 1H,
5.65–6.05 br m, 2H, 7.28–7.35 m, 1H, 8.05–8.10 m, 1H,
8.38 s, 1H, 8.58–8.63 m, 1H, 8.90 s, 1H. ESIMS: m=z
222 [M ꢁ tBu]þ.
d (CDCl3) 1.50–1.70 br s, 2H, 3.42 s, 3H, 4.12 s, 2H,
6.80 s, 1H, 7.42 s, 1H, 7.70 s, 1H, 8.30 s, 1H. ESIMS:
m=z 182 [MH]þ.
d (CDCl3) 1.46 s, 9H, 3.88–3.95 m, 2H, 5.10–5.25 br m,
1H, 5.60–5.75 br m, 2H, 6.79 s, 1H, 7.42 s, 1H, 7.70 s,
1H, 8.30 s, 1H. ESIMS: m=z 211 [M ꢁ tBu]þ.
d (DMSO-d6) 1.38 s, 9H, 3.67–3.75 m, 2H, 6.30–6.85 br
m, 2H, 6.88–6.95 br m, 1H, 7.68 m, 2H, 7.77 m, 2H,
8.23 s, 1H. ESIMS: m=z 355=357 [MH]þ 1 Br pattern.

1708
D. ELLIS AND A. ARIAS-WOOD
Table 2. NMR data on final triazoles
Entry
Triazole
NMR data
d (CDCl3) 1.43 s, 9H, 4.40–4.53m, 2H, 5.10–5.30
br m, 1H, 5.35 s, 2H, 7.27–7.30 m, 1H, 7.40 d
(J ¼ 8.15 Hz), 2H, 7.50–7.58 m, 1H, 7.62 d
(J ¼ 8.15 Hz), 2H, 8.45 s, 1H, 8.55–8.62 m, 1H.
ESIMS: m=z 388=390 [M ꢁ tBu]þ 1 Br pattern.
42% yield (amorphous solid).
1
d (CDCl3) 3.50 s, 3H, 4.60 s, 2H, 5.40 s, 2H,
7.25–7.35 m, 1H, 7.42 d (J ¼ 8.30 Hz), 2H,
7.53–7.58 m, 1H, 7.62 d (J ¼ 8.30 Hz), 2H,
8.46 s, 1H, 8.56–8.60 m, 1H. ESIMS: m=z
359=361 [MH]þ 1 Br pattern. 33% yield (glass).
2
d (CDCl3) 1.42 s, 9H, 4.30–4.55 br m, 2H,
5.15–5.35 m, 3H (inc s for 3H @ 5.30), 7.00 d
(J ¼ 8.10 Hz), 1H, 7.35 s, 0.5H, 7.38–7.42 m,
1.5H, 7.45–7.50 m, 2H, 7.57–7.65 m, 2H.
ESIMS: m=z 377=379 [M ꢁ tBu]þ 1Br pattern.
33% yield (glass).
3
d (CDCl3) 3.50 s, 3H, 4.60 s, 2H, 5.20 s, 2H, 7.05
d (J ¼ 8.10 Hz), 1H, 7.30–7.65 m, 6H. 59% yield
(glass).
4
(Continued )

SYNTHESIS OF 1,3,5-TRISUBSTITUTED 1,2,4-TRIAZOLES
1709
Table 2. Continued
Entry
Triazole
NMR data
d (CDCl3) 1.44 s, 9H, 4.40–4.55 m, 2H, 5.15–5.30
br m, 1H, 5.35 s, 2H, 7.05 d (J ¼ 8.10 Hz), 2H,
7.38–7.44 m, 1H, 7.48 d (J ¼ 8.10 Hz), 2H,
7.85–7.90 m, 1H, 8.70–8.75 m, 1H, 8.80 s, 1H.
ESIMS: m=z 388=390 [M ꢁ tBu]þ 1 Br pattern.
11% yield. (glass) (chromatographed twice).
5
d (CDCl3) 1.46 s, 9H, 4.40–4.53 m, 2H,
5.10–5.35 m, 3H (inc s for 2H @ 5.30), 7.05 d
(J ¼ 8.16 Hz), 2H, 7.38–7.50 m, 6H. ESIMS:
m=z 421=423=425 [M ꢁ tBu]þ 1Cl=1Br pattern.
65% yield (amorphous solid).
6
analog 2 confirmed the anticipated regiochemistry as shown. Carbon-13, hetero-
nuclear multiple bond correlations (HMBC), and heteronuclear multiple quantum
correlations (HMQC) NMR experiments were performed to establish the structure
and hence the regioselectivity of the process.
CONCLUSION
A general approach to the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has
been described. The desired regioselectivity has been confirmed by NMR studies.
The method was successfully used in the preparation of a key target and related ana-
logs containing substituents of value in medicinal chemistry. The method consists of
several steps, but all are simple and mild. Initial studies utilizing an alternative
aminal synthesis suggest that the method may have a broad applicability for such
templates. The advantages over other methods include the avoidance of synthesizing
particular hydrazines, the use of harsh reagents such as antimony pentachloride,
cryogenic temperatures, and forcing thermal conditions.
EXPERIMENTAL
1
All H NMR spectra were obtained on a 400-MHz Varian Mercury spec-
trometer using either CDCl3 or dimethylsufoxide (DMSO-d6) as solvents. The
chemical shifts are reported in parts per million (ppm) relative to the deuterated sol-
vent. Mass spectra were recorded on an Agilent 1100 series liquid chromatograph=
mass spectrometer (LC=MS) in the electrospray=atmospheric pressure (ES=AP)

1710
D. ELLIS AND A. ARIAS-WOOD
ionization modes. All chromatography was performed using Merck silica gel using a
gradient elution profile unless otherwise stated. Thin-layer chromatography (TLC)
was performed using Merck TLC plates.
Representative Synthesis of the Hydrazones
To an ice-cold solution ofhydrazine hydrate (0.94 g, 18.8 mmol) in EtOH (10 mL)
was added a solution of benzaldehyde (2.00 g, 18.8 mmol) in EtOH (10 mL) dropwise
under nitrogen over 10 min. The resulting solution was allowed to warm to ambient
temperature. After 5 h, the solution was evaporated, and the residue was partitioned
between EtOAc (30 mL) and water (15 mL). The organic phase was separated,
washed with brine (15 mL), dried over MgSO4, filtered, and evaporated to yield
the product as a pale yellow oil, which solidified on storage in the freezer. Yield:
1
1.56 g, 66%; H NMR (400 MHz, CDCl3): d ¼ 5.30–5.65 (br s, 2H), 7.25–7.40 (m,
3H), 7.50–7.58 (m, 2H), 7.75 (s, 1H).
Data for the Hydrazones
Hydrazone of p-bromobenzaldehyde. 1H NMR (400 MHz, CDCl3):
d ¼ 5.40–5.70 (br s, 2H), 7.42 (d, 2H), 7.50 (d, 2H), 7.70 (s, 1H).
Hydrazone of furan-3-carboxaldehyde. 1H NMR (400 MHz, CDCl3):
d ¼ 5.15–5.60 (br s, 2H), 6.68 (s, 1H), 7.40 (s, 1H), 7.52 (s, 1H), 7.70 (s, 1H).
Hydrazone of pyridine-3-carboxaldehyde. 1H NMR (400 MHz, CDCl3):
d ¼ 5.50–5.85 (br s, 2H), 7.20–7.28 (m, 1H), 7.70 (s, 1H), 7.85–7.90 (m, 1H), 8.50
(br s, 1H), 8.66 (s, 1H).
Representative Synthesis of the Aminals
Trimethylsilyl-trifluoromethanesulfonate (61 mg, 50 mL, 0.28 mmol) was added
dropwise as a solution in 3 mL DCM to an ice-cold solution of pyridine-3-
carboxaldehyde (1 g, 9.34 mmol) and N,N-dimethylaminotrimethylsilane (2.3 g,
3.10 mL, 19.6 mmol) in DCM (7 mL), and the resulting solution was allowed to
warm to ambient temperature. After 18 h the reaction mixture was washed with
water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated to
yield the product, which was sufficiently pure for further use. Yield: 1.56 g; 93% clear
1
oil. H NMR (400 MHz, CDCl3): d ¼ 2.07 (s, 12H), 3.40 (s, 1H), 7.20–7.25 (m, 1H),
7.50 (d, 1H), 8.40 (s, 1H), 8.46 (d, 1H).
Aminal of P-Bromobenzaldehyde
1H NMR (400 MHz, CDCl3): d ¼ 2.10 (s, 12H), 3.38 (s, 1H), 7.10 (d, 2H), 7.46
(d, 2H).
Representative Synthesis of the Thioimidates
Methyl iodide (556 mg, 3.92 mmol) was added in one portion to an ice-cold
solution of N-t-butoxycarbonylaminothioacetamide (497 mg, 2.61 mmol) in acetone

SYNTHESIS OF 1,3,5-TRISUBSTITUTED 1,2,4-TRIAZOLES
1711
(5 mL). The resulting mixture was allowed to warm to ambient temperature. After
18 h, the mixture was filtered, and the precipitate was washed with ether and dried
to furnish the product. Yield: 753 mg, 87%; amorphous white solid. 1H NMR
(400 MHz, CDCl3): d ¼ 1.38 (s, 9H), 1.80–2.60 (br s, 2H), 2.70 (s, 2H), 4.35 (s,
2H), 6.35–6.42 (br s, 1H). There was evidence of rotamers in this spectrum, as is
often seen with the Boc group.
Thioimidate of Methoxyacetic Acid Thioimidate
1H NMR (400 MHz, CDCl3): d ¼ 2.80 (s, 3H), 3.42 (s, 3H), 4.60 (s, 2H).
Representative Amidrazone Formation
A solution of benzaldehyde hydrazone (74 mg, 0.62 mmol) in EtOH (2 mL)
dropwise was added to a stirred ice-cold solution of S-methyl-N-t-butoxycarbonyl-
aminoacetylthioimidate and hydriodide salt (205 mg, 0.62 mmol) in EtOH (3 mL)
over 2 min. The solution was allowed to warm to rt. After 18 h, the solvent was eva-
porated, and the residue was partitioned between EtOAc (10 mL) and 1 M NaOH
(5 mL). The organic layer was separated, washed with brine (5 mL), dried over
MgSO4, filtered, and evaporated. The residue was triturated with ether and filtered
to give the product as a white solid. Yield: 160 mg, 94%. 1H NMR (400 MHz,
CDCl3): d ¼ 1.46 (s, 9H), 3.95 (s, 2H), 5.15–5.30 (br s, 1H), 5.60–6.00 (br s, 2H),
7.35–7.40 (m, 3H), 7.70–7.75 (m, 2H), 8.38 (s, 1H). MS (APCI þ ve): m=z
(%) ¼ 221 (100%) [MHþ ꢁ tBu],
Representative Cyclization Procedure
A solution of the aminal (2 eq, 2 mmol) in toluene (2 mL) was added to a sol-
ution of an amidrazone (1 mmol, 1 eq) in toluene (8 mL). The resulting solution was
heated to reflux under nitrogen for 3–5 h. The solution was then evaporated to dry-
ness. The residue was purified by column chromatography using EtOAc=pentane or
DCM=MeOH mixtures. Data on the final triazoles produced is included in Table 2.
REFERENCES
1. For syntheses requiring specific hydrazines, see (a) Buzykin, B. I.; Bredikhina, Z. A. An
approach to 1-aryl-1,2,4-triazoles. Synthesis 1993, 59–61; (b) Su, W.; Yang, D.; Li, J.
Novel process for synthesis of 1,2,4-triazoles: Ytterbium triflate–catalyzed cyclization
of hydrazonyl chlorides with nitriles. Synth. Commun. 2005, 35(11), 1435–1440; (c)
Kuberkar, S. V. Simple route for the synthesis of 1,3,5-trisubstituted-s-triazoles. Ind. J.
Chem. B 1991, 30, 78–79.
2. For examples of nonspecific alkylation, see (a) Katritzky, A. R.; Qi, M.; Feng, D.; Zhang,
G.; Griffith, M. C.; Watson, K. Synthesis of 1,2,4-triazole-functionalized solid support
and its use in the solid-phase synthesis of trisubstituted 1,2,4-triazoles. Org. Lett. 1999,
1(8), 1189–1191; (b) Parmar, K.; Suthar, B.; Prajapati, S.; Suthar, A. Synthesis and bio-
logical activity of novel 1,3,5-trisubstituted 1,2,4-triazole derivatives. J. Het. Chem. 2010,
47(1), 156–161; (c) Garfunkle, J.; Ezzili, C.; Rayl, T. J.; Hochstatter, D. G..; Hwang, I.;

1712
D. ELLIS AND A. ARIAS-WOOD
Boger, D. L. Optimization of the central heterocycle of a-ketoheterocycle inhibitors of
fatty acid amide hydrolase. J. Med. Chem. 2008, 51(15), 4392–4403; (d) Baumgartner,
C.; Brandli, L.; Diederich, F. Synthesis of 1,2,4-trisubstituted imidazoles and 1,3,5-
trisubstituted 1,2,4-triazoles. Heterocycles 2008, 76(1), 401–428.
3. (a) Al-Soud, Y. A.; Al-Dweri, M. N.; Al-Masoudi, N. A. Synthesis, antitumor, and anti-
viral properties of some 1,2,4-triazole derivatives. Farmaco 2004, 59(10), 775–783; (b)
Meng, Q.; Bai, H.; Li, Z.; Wang, Q.; Tao, F. A facile approach to 4,5-dihydro[1,2,4]tria-
zolo[3,2-d][1,5]benzoxazepines. Synthesis 2007, 1629–1634.
4. (a) Al-Soud, Y. A.; Al-Masoudi, N. A.; Ferwanah, A. E.-S. Synthesis and properties of
new substituted 1,2,4-triazoles: Potential antitumor agents. Bioorg. Med. Chem. 2003,
11(8), 1701–1708; (b) Kuberkar, S. V.; Bhosale, V. N.; Vartale, S. P.; Badne, S. G.
Synthesis and some novel reactions of 8-chloro-2H-[1,2,4]triazino[3,4-b][1,3]
benzothiazole-3,4-dione and 6-chloro-2-hydrazino-1,3-benzothiazole. J. Chem. Res.
2005, 10, 632–635; (c) Paulvannan, K.; Chen, T.; Hale, R. An improved synthesis of
1,2,4-triazoles using Ag2CO3. Tetrahedron 2000, 56(41), 8071–8076; (d) Huisgen, R.;
Grashey, R.; Seidel, M.; Wallbillich, G.; Knupfer, H.; Schmidt, R. 1,3-Dipolar additions,
II: Synthesis of 1,2,4-triazoles from nitrilimines and nitriles. Ann. Chem. 1962, 653,
105–113.
5. Lopez, L.; Majoral, J. P.; Meriem, A.; N’Gando M’Pondon, T.; Navech, J.; Barrans, J.
Synthesis of the first examples of 1H- and 4H-1,2,4,3k,3-triazaphospholes via unexpected
ring-contraction reactions. Chem. Commun. 1984, 3, 183–185.
6. Available from Sigma-Aldrich, Gillingham, Dorset, UK, catalog no. 163619.
7. Available from Maybridge Chemical Company, catalog no. MO07925.
8. Rostamizadeh, S.; Keshavarz, H. A facile route to amino-azines. J. Chem. Res. 2000, 5,
226–227.
9. Weingarten, H.; White, W. A. Amination of aldehydes and ketones by tris(dimethylami-
no)arsine and tetrakis(dimethylamino)titanium. J. Org. Chem. 1966, 31(12), 4041–4042.
10. Betschart, C.; Schmidt, B.; Seebach, D. Scope of the reductive coupling of aromatic aldi-
mines using low-valent titanium reagents to form 1,2-diarylethylenediamines. Helv. Chim.
Acta 1988, 71(8), 1999–2021.
11. Aube, P.; Christot, I.; Combret, J. C.; Klein, J. L. Trimethylsilanes, III: Characterization
of an addition compound with aldehydes; preparation of aminals and b-dialkylamino-b-
aryl esters in aprotic media. Bull. Chim. Soc. Fr. 1988, 6, 1009–1014.