Transition metal-free steric controlled one-pot synthesis of highly substituted N-amino 1,2,3-triazole derivatives via diazo transfer reaction from β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2016.04.112

An efficient, simple protocol for the one-pot synthesis of N-amino 1,2,3-triazole from β-keto esters has been described. This method involves diazo transfer reaction into in situ generated hydrazones using imidazole sulfonyl azide as the nitrogen source.

Full text of DOI:10.1016/j.tetlet.2016.04.112

Accepted Manuscript
Transition metal-free steric controlled one - pot synthesis of highly substituted
N-amino 1, 2, 3-triazole derivatives via diazo transfer reaction from β-keto esters
Rajendran Nagarajan, Jayadevan Jayashankaran, Lourdusamy Emmanuvel
PII:
S0040-4039(16)30495-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.112
TETL 47612
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 February 2016
28 April 2016
29 April 2016
Please cite this article as: Nagarajan, R., Jayashankaran, J., Emmanuvel, L., Transition metal-free steric controlled
one - pot synthesis of highly substituted N-amino 1, 2, 3-triazole derivatives via diazo transfer reaction from β-keto
esters, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.112
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Transition metal-free steric controlled one - pot synthesis of highly substituted
N-amino 1, 2, 3-triazole derivatives via diazo transfer reaction from β-keto
esters
Graphical Abstract:
An efficient, simple protocol for the one- pot synthesis of N-amino 1, 2, 3 – triazole from β-keto
esters has been described. This method involves diazo transfer reaction into in situ generated
hydrazones using imidazole sulfonyl azide as the nitrogen source. This protocol does not involve
any transition metal and can be regarded as general method for the synthesis of N-amino 1, 2, 3 –
triazole from hydrazones.

Transition metal free steric controlled one - pot synthesis of highly substituted
N- amino 1, 2, 3-triazole derivatives via diazo transfer reaction from β-keto
esters
Rajendran Nagarajana, Jayadevan Jayashankaranb, Lourdusamy Emmanuvela*
a
School of Science and Humanities, Department of Chemistry, Karunya University, Karunya
Nagar, Coimbatore, 641114, India
E-mail:emmanuvel@karunya.edu
Fax: 0422-2615615 Ph: +919042678370
b Syngene International Ltd, Biocon Park , Plot 2&3, Bommasandra Industrial Estate - Phase-
IV, Bommasandra-Jigani Link Road, Bangalore 560 099, India
Keywords: N-amino 1, 2, 3-triazole, diazo transfer, metal free reaction, one-pot synthesis.
1, 2, 3-triazoles and their derivatives have recently received a considerable interest in organic
synthesis and drug discovery.1 They find applications in various fields such as optical
brighteners,2 dyes,3 active pharmaceutical ingredients,4 agrochemicals,5 etc. Several 1, 2, 3-
triazole derivatives have been found to possess biological activities such as anti-HIV, anti-
microbial, anti-allergic, anti-fungal, anti-convulsant, etc.6 Recently, N-amino 1,2,3-triazole
derived ionic liquids had been studied for their use as high energy material.7 After the discovery
of regio selective 1,3 dipolar cycloaddition (Huigen’s cycloaddition) of organic azide with
alkynes or their precursors in the presence of catalyst to get 1,2,3-triazole,8 one of the most
studied click reactions, a large number of triazoles had been synthesized and screened for their
potential applications. In spite of this click reaction being considered as a versatile method to
obtain 1-alkyl or aryl 1, 2, 3-triazoles, this method cannot be employed to obtain N-amino 1, 2,
3-triazoles. And also, the reaction of azides with internal alkynes is less explored and results in

two regio isomers.9 This poor regioselectivity limits the application of Huisgen’s reaction to
apply for the synthesis of 4, 5-disubstituted 1,2,3-triazoles.9
N-amino 1,2,3-triazoles, a relatively less explored class of triazoles mainly due to lack of
practical method to access them, may be of greater interest as the functionalization would be
easier and the extra N-H group would be expected to form hydrogen bonding with biological
systems. As far our knowledge, direct introduction of nitrogen atom to the 1-position of 1, 2, 3-
triazole (N-N bond formation) has not been reported till date. The most convenient method for
the synthesis of N-amino 1, 2, 3-triazole involves MnO2 mediated oxidation of glyoxal derived
dihydrazones (Fig.1).10 However, this method is not convincing for substituted triazole
derivatives as the product selectivity is poor in non-symmetrical 1,2-dicarbonyl compounds,
which limits the substrate scope of this method.11 Another approach that involves spontaneous
1,5 electro cyclization of α-diazo hydrazones of α-diazo semicarbazones prepared via
condensation of diazo compounds with hydrazines or semicarbazides respectively have also been
reported.12,15 Hence, the search for a simple practical method to obtain 1, 2, 3-triazole with
nitrogen heteroatom at 1-position would be appreciated. In this communication we report the
synthesis of highly substituted N-amino 1, 2, 3-triazole derivatives via diazo transfer reaction to
β-keto ester derived hydrazones in one pot process.
Fig. 1: Synthesis of N-amino 1, 2, 3- triazole
Recently, we found that diazo transfer reaction in oxime ethers results in N-alkoxy 1, 2, 3-
triazoles as the minor product and the corresponding diazo compound in major quantity.13 We
envisaged that introduction of a bulkier group on nitrogen atom of imine may control the product
selectivity and result in N-hetro atom substituted 1,2,3-triazole exclusively or as major product.
Accordingly, when the hydrazone 2 derived from ethyl acetoacetate (1) by reacting with
NH2NH-Boc, was treated with imidazole sulfonyl azide in the presence of DBU in CH3CN:
Toluene (1:1) gave the corresponding N-amino 1, 2, 3- triazole derivative 3 as the only product

in 72% yield after column purification (Scheme 1). Unlike our earlier observation, α-diazo
hydrazone 4 was not observed.
Scheme-1: Synthesis of N-amino 1,2,3-triazole
In order to optimize the reaction condition, we carried out the reaction with several sulfonyl
azides and bases in different solvent system and the results are tabulated (Table-1). Hydrazone
was prepared by reacting ethyl acetoacetate with NH2NHBoc in toluene and found to be unstable
and got converted back to β-keto ester when toluene was removed under rotary evaporator. To
overcome this problem, 4o molecular sieves was added and the reaction mixture was directly
taken to the next step without workup.
Among the sulfonyl azides, both 4-toluene sulfonyl azide and imidazole sulfonyl azide gave
comparable yields (Entry1 and 5; Table-1). Yet, we prefered imidazole sulfonyl azide as diazo
transfer reagent since the by-product is water soluble. Equal volume of toluene and CH3CN was
found to be the best reaction medium. When toluene was employed as the only solvent the yield
was poor (Entry 8). Removal of toluene under reduced pressure partially hydrolyzed the C=N
bond and resulted in considerable amount of ethyl 2-diazo acetoacetate upon diazo transfer
reaction (Entry 7; Table-1). Among the bases screened for the diazo transfer reaction, DBU was
found to give better yield than Et3N and N,N-diisopropylethylamine.
Table-1: Screening of sulfonyl azides, bases and solvent for diazo transfer reactiona

Entry
Sulfonyl azide
TsN3
Base
Et3N
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
CH3CN: Toluene
CHCl3: Toluene
CH3CN: Toluene
CH3CN: Toluene
CH3CN: Toluene
CH3CN: Toluene
CH3CN
63
42c
40
MsN3
Et3N
4-NO2PhSO2N3
Imid-SO2N3
Imid-SO2N3
Imid-SO2N3
Imid-SO2N3
Imid-SO2N3
Et3N
Et3N
58
DBU
DIPEA
DBU
DBU
72
32
25(21)d
Toluene
19
aReaction condition: i) NH2NHBoc (3 mmol), substrate (3 mmol), 4o MS (1 g), Toluene (10
ml), 60 ºC for 3 h then 25 ºC for 21 h. ii) sulfonyl azide (3.6 mmol), base (3.6 mmol), solvent
b
c
(20 ml). Yield refers to isolated yield by column chromatography. Freshly prepared from
MsCl was used. dYield of the ethyl 2-diazo acetoacetate.
In order to study the substrate scope of this method, 14 several β-keto esters were subjected to this
reaction and the results are given in table 2. From the table, we can find that β-keto esters gave
the desired product in good yields irrespective of the ester groups (Entry a-c; table 2). It is
surprising to observe that conformationally locked cyclic β-keto lactones gave better yields
(Entry g-j; Table- 2) than non-cyclic β-keto esters. β-keto lactones were found to be stable under
the reaction condition and the ring opening was not observed. Not only β-keto esters, but also
cyclic 1, 3-diones (Entry e and f; Table-2) underwent this transformation in good yield.
However, non-cyclic 1, 3 dione such as acetyl acetone failed to give the desired product.
Table-2: Synthesis of N- amino 1, 2, 3-triazole via diazo transfer reactiona
Entry
Substrate
Product (3)
Yield (%)b
R= Et; 68
R=Bn; 72
R=Me; 65
a
b
c

d
77
e
f
R=H; 76
R= Me; 72
g
h
86
88
92
83
i
j
a Reaction condition: i) β Keto ester (3 mmol), NH2NHBoc (3 mmol), Toluene (9 ml), 4o
MS, 60 oC, 3 h then rt for 21 h; ii) imidazole sulfonyl azide (3.3 mmol) Toluene:CH3CN
(1:1), DBU (3.3 mmol) 2 h; bisolated yield from column chromatography.
Cunha, A.C et.15 al have followed a different approach to synthesize N aryl-amino-1, 2, 3-
triazole derivatives 7 that involves hydrazone formation between aryl hydrazine and ethyl 2-
diazo acetoacetate (5) and its 1,5-electro cyclization (Route A, Scheme-2). However, in the case

of NH2NHBoc, contrary to many aryl hydrazines,14 this route did not lead to Boc protected N-
amino 1,2,3-triazole 7 even after reacting and diazo compound 5 in MeOH for 24 h. Moreover
the yield of triazoles 7 decreased when electron deficient aryl hydrazine15 was employed and
completely failed to give triazole with 2, 4-dinitro phenyl hydrazine.
On the other hand, we were able to extend our present protocol for the synthesis of N-aryl
amino 1, 2, 3-triazole derivatives more conveniently with improved yields. Accordingly, the
hydrazone 6 was prepared from ethyl acetoacetate (1) and aryl hydrazine in quantitative yields
and subjected to diazo transfer reaction using imidazole sulfonyl azide and DBU in acetonitrile
to get 7 in excellent yields (Route B; Scheme-2). However, this route cannot be used with
phenyl hydrazine as the condensation with ethyl acetoacetate does lead to a subsequent
cyclization to give 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one.
Yield (%) of 7
RNHNH2
(7 a) R = Ph
Route A
70%
Route B
16
-
(7 b) R = 2,4-(NO2)2Ph No reaction
(3 a) R = Boc No reaction
90
68
Scheme-2: Synthetic approaches to N aryl-amino-1, 2, 3-triazole

Mechanistically, it is very clear that the diazo compound 6 formed in the reaction was unstable
and underwent spontaneous 1, 5-electro cyclization17 triggered by the lone pair of electron on
imine nitrogen (Fig-2). Resonance effect of diazo group destroys the stereo chemistry of the
hydrozones and result in triazole as the only product.
In conclusion we have developed a simple method for the synthesis of N-amino 1, 2, 3-
triazole derivatives via steric controlled diazo transfer reaction. These derivatives can readily be
functionalized and can be screened for their biological activities. This method is free from
transition metal and can be referred as general procedure for the synthesis of N-amino-1, 2, 3-
triazole from hydrazones.
Acknowledgments:
The authors thank DST/SERB, New Delhi, India, for Fast Track financial support to carry
out this research work. The authors also thank Dr. J. Daphy Louis Lovenia, Director, School of
Science and Humanities and Dr. K. Parameswari, Head of the Department, Department of
Chemistry for their constant support and encouragement.
References and notes:
1
(a) Benjamin, S.; Ulrich, S. S. Chem. Soc. Rev. 2014, 43, 2522. (b) Benson, F. R.; Savell, W.
L. Chem. Review. 1950, 46, 1. (c) Antonino, L.; Riccardo, D.; Francesco, M.; Alessio, T.;
Annamaria, M.; Giampaolo, B.; Anna, M. A. Eur. J. Org. Chem. 2014, 16, 3289. (d)
Marcus, B.; Ian, R. B. Beilstein. J. Org. Chem. 2015, 11, 1194. (e) Moses, J. E.; Moorhouse,
A. D. Chem. Soc. Rev. 2007, 36, 1249. (f) Finn, M. G.; Fokin. V. V. Chem.Rev. 2010, 39,

1231. (g) Hawker, C. J.; Wooley, K. L. Science, 2005, 309, 1200. (h) Donnelly, K. F.;
Petronilho, A.; Albrecht, M. Chem. Commun. 2013, 49, 1145. (i) Gulevich, A. V.; Dudnik,
A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084.
2
(a) Dougherty, E. M.; Guthrie, K. P.; Shapiro, M. Biological Control. 1996, 7, 71. (b)
Daniel, L.; Florian, G.; Brigitte, H.; Berthold, S.; Christian, H.; Georg, A.; Reider.;
Johannes, F. Cryst. Growth Des. 2014, 14, 1018. (c) Nicholas, W. S.; Annabel, A.;
Christopher, M. B.; Sergei, V. D. Bio-chem. Biophys. Res. Commun. 2010, 391, 1455.
(a) Byungkwon, J.; Sung, Y. K.; Jung, Y. D. Dyes. Pigm. 2012, 94, 217. (b) Julian, J. L.;
Plainfield.; Robert, S. L.; Bound, B.; Harold, M. F.; Somerville, N . J. U.S. Patent. 1958,
2,865,916. (c) Lanter, J. J. Soc. Dyers Colourists. 1966, 82, 125.
3
4
5
(a) Nadeem, S.; Waquar, A.; Shamsher, A. M.; Ruhi, A.; Sanjay.; Jainb, B. A.; Jawaid, A.
Int. J. Phrm. Sci. Rev.Res. 2011, 8, 161. (b) Simon, C.; Pranatharthi, H. C. J. Antimicrob.
Chemother. 2010, 65, 410.
(a) Varsha, P. S.; Indu, S. S.; Kaushik, B.; Pallavi, N. W.; Sanjay, D. S. J. Agric. Food.
Chem. 2015, 63, 10736. (b) Wechsler, K.; Rombourg, M.; Bindler, F.; Exinger, A.; Breuzin,
C. Intern. J. Enb. imn. Anal. Che. 1996, 65, 277; (c) Euro. Food. Saft. Auth. J. 2009, 7,
1167.
6
(a) Derek, R. B.; Caroline, J. M. R.; Harry, S.; Barbara A, S. J. Med. Chem. 1984, 27, 223.
(b) Pankaja, K.; Kadaba. J. Med. Chem. 1988, 31, 196. (c) Sandip, G. A.; Suleman, R. M.;
Vandana, S. P.; Chem. Asian. J. 2011, 6, 2696. (d) Alessandro, K. J.; Vitor, F. F.; Thiago,
M. L. S.; Gabrielle, G.; Souza, F.; Viviane, M.; Juliana, L. A.; Maria C. B. V. S.; Anna, C.
C. Bioorg. Med. Chem. 2011, 19, 1860.
7
8
(a) Ghule, V. D. Comp. Theor. Chem. 2012, 992, 92. (b) Ghule, V. D. J. Phys. Chem. A.
2012, 116, 9391. (c) Koguchi, S.; Izawa, K. ACS Comb. Sci. 2014, 16, 381. (d)
J. Mater. Chem. A, 2013, 1, 585.
(a) Huisgen, R. In 1, 3-Dipolar Cycloaddition Chemistry In Padwa, A., Ed.; Wiley: New
York, 1984; pp 1–176 Chapter 1; (b) Amblard, F.; Cho, J, H.; Schinazi, R. F. Chem. Rev.
.
2009, 109, 4207. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev., 2007, 36, 1249. (d)
Wu, L. -Y.; Xie, Y. -X.; Chen, Z. -S.; Niu, Y. -N.; Liang, Y. -M. Synlett. 2009, 9, 1453. (e)
Smith, C. D.; Greaney, M. F. Org. Lett, 2013, 15, 4826. (f)

Synlett. 2007, 19, 3037. (g) Belskaya, N.; Subbotina, J.;
Lesogorova, S. Top. Heterocycl. Chem. 2015, 40, 51.
9
(a) Vsevolod, V. R.; Luke, G. G.; Valery, V. F.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596. (b) Brant, C. B.; Sridhar, N.; Lars, K. R.; Li, Z.; Haitao, Z.; Zhenyang, L.;
Guochen, J.; Valery V. F. J. Am. Chem. Soc. 2008, 130, 8923. (c) Masoud, F.; Mojtaba, A.;
Alireza, P. A. Cat. Comm. 2016, 76, 72.
10 (a) Qiu, H. L.; Yu, C. Li.; Ya, Y. L.; Zhu, W.; Wei, L.; Cai, Q.; Si, P. P. J. Mater. Chem.,
2012, 22, 666. (b) Greg, K.; Greg, D.; Kerri, T.; Leslie, H.; Tommy, H. J. Heterocyclic
Chem. 2005, 42, 19. (c) Alexandrou, N. E.; Adamopoulos, S. Synthesis., 1976, 7, 482. (d)
Bargamov, G. G.; Bargamova, M. D. J. Fluorine Chem., 1996, 79, 45.
11 (a) Stephanidou, J. S.; Varella, E.; Micromastoras, E. D.; Alexandrou, N. E. J. Hetrocyclic
Chem., 1979, 16, 1373. (b) Benedetti, F.; Bozzini, S.; Forchiassin, M.; Nardin, G.; Pitacco,
G.; Russo, C.; Valetin, E. J. Heterocyclic Chem. 1989, 26, 301.
12 (a) Sezer, O.; Dabak, K.; Akar, A.; Anac, O. Helv. Chim. Acta., 1996, 79, 449. (b) Jordao, A.
K.; Ferreira, V. F.; Souza, T. M. L.; Faria, G. G. S.; Machado, V.; Abrantes, J. L.; Souza, M.
C. B. V.; Cunha, A. C. Bioorg. Med. Chem., 2011, 19, 1860.
13 (a) Lourdusamy, E.; Yao, L.; Park. C. M. Angew. Chem. Int. Ed. 2010, 49, 7963. (b)
Kuruba, B. K.; Shariff, N.; Vasanthkumar, S.; Emmanuvel, L. Synth. Commun., 2015, 45,
2454.
14 General Procedure for the synthesis of N-amino 1, 2, 3 triazole: A two neck round
bottom flask was charged with β-keto ester (3 mmol), NH2NHBoc (3.3 mmol), toluene (10
ml), 4 o MS (1g) and was heated at 60 oC for 3 h then at 25 oC for 21 h. After confirming the
formation of hydrazone by TLC, the reaction mixture was cooled to -20 oC and a solution of
imidazole sulfonyl azide (3.3 mmol) in CH3CN (10 ml) was added followed by DBU (3.3
mmol). After 2 h the reaction was quenched with water, diluted with ethyl acetate washed
with water, brine, dried over anhydrous Na2SO4. The organic layer was concentrated under
reduced pressure to get the crude product which was purified by column chromatography
(silica gel) using pet.ether/ethyl acetate (90:10) to get pure compound. Spectral data for
tert-butyl
(6-(4-nitrophenyl)-4-oxo-6,7-dihydropyrano[3,4-d][1,2,3]triazol-1(4H)-
o
yl)carbamate (3j): Yellow solid , 83% (0.933 g ); m.p 102 C, IR (ν, cm-1): 3250, 2982,
1752, 1606, 1524, 1349, 1276, 1158, 1039. 1H NMR (300 MHz, CDCl3): δ 9.56 (s, 1H), 8.30

(d, 2H, J = 9 Hz), 7.74 (d, 2 H, J = 9 Hz), 5.93 (dd, J =12, 4.2 Hz), 3.49 (s, 1H), 3.35 (s,
13
1H), 1.15 (s, 9H). C NMR (75 MHz, CDCl3): δ 159.03, 152.90, 143.86, 142.35, 132.40,
127.30, 124.12, 84.64, 77.50, 28.03. HR-MS: Calculated=375.3268, found= 375.3259.
15 Jordao, A. K.; Afonso, P. P.; Ferreira, V. F.; Souza, M. C. B. V.; Almeida, M. C. B.;
Beltrame, C. O.; Paiva, D. P.; Wardell, S. M. S. V.; Wardell, J. L.; Tiekink, E. R. T.;
Clarissa R. Damaso, C. R.; Cunha, A. C. Eur. J. Med. Chem. 2009, 44, 3777.
16 Hydrazone formation resulted in 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one which can be
subjected to diazo transfer reaction
17 (a) Vogel, M.; Lippmann, E. J. Prakt. Chem. 1989, 331, 75. (b) Raghavendra, M. S.; Lam,
Y. Tetrahedron Lett. 2004, 45, 6129. (c) Jones, G.; Ollivierre, H.; Fuller, L. S.; Young, J. H.
Tetrahedron, 1991, 47, 2851. (d) Augusti, R.; Kascheres, C. Tetrahedron, 1994, 50, 6723.

Highlights:
1) One pot synthesis of N-amino 1, 2, 3-triazole derivatives.
2) Transition metal free protocol.
3) It involves different approach from usual azide alkyne cyclization.