An enolate-mediated regioselective synthesis of 1,2,3-triazoles via azide-aldehydes or ketones [3+2]-cycloaddition reactions in aqueous phase

Article abstract of DOI:10.1016/j.tetlet.2020.151662

A synthetic route for the direct conversion of arylazides into the corresponding trizoles via phase transfer catalyst-assisted [3+2] cycloaddition reaction under basic conditions in aqueous medium is reported. This synthetic methodology, which offers high

Full text of DOI:10.1016/j.tetlet.2020.151662

Journal Pre-proofs
An enolate-mediated regioselective synthesis of 1,2,3-triazoles via azide-alde-
hydes or ketones [3+2]-cycloaddition reactions in aqueous phase
Anupam Tripathi, Chandrashekhar V. Rode, Jordi Llop, Subhash P. Chavan,
Sameer M. Joshi
PII:
S0040-4039(20)30081-2
DOI:
https://doi.org/10.1016/j.tetlet.2020.151662
TETL 151662
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
28 October 2019
19 January 2020
21 January 2020
Please cite this article as: Tripathi, A., Rode, C.V., Llop, J., Chavan, S.P., Joshi, S.M., An enolate-mediated
regioselective synthesis of 1,2,3-triazoles via azide-aldehydes or ketones [3+2]-cycloaddition reactions in aqueous
phase, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151662
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An enolate-mediated regioselective synthesis of 1,2,3-triazoles via azide-aldehydes or ketones
[3+2]-cycloaddition reactions in aqueous phase
Anupam Tripathi,a Chandrashekhar V. Rode,b Jordi Llop,c Subhash P. Chavan a* and Sameer M.
Joshiad

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An enolate-mediated regioselective synthesis of 1,2,3-triazoles via azide-
aldehydes or ketones [3+2]-cycloaddition reactions in aqueous phase
Anupam Tripathi,a Chandrashekhar V. Rode,b Jordi Llop,c Subhash P. Chavan a* and Sameer M. Joshiad
a. Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008, India.
a. Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
b. Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr HomiBhabha Road, Pune 411008, India
c. Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Paseo Miramón 182, 20014 San Sebastián, Spain.
d At present: Department of Oncology, Wayne State University, Detroit, Michigan 48202, United States
*E-mail: Sameer M. Joshi (sameer.joshi3@wayne.edu), Subhash P. Chavan (sp.chavan@ncl.res.in). Electronic Supplementary Information (ESI) available:
Characterization details of 1,2,3-triazoles by 1H and 13C NMR. See DOI: 10.1039/x0xx00000x
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A synthetic route for the direct conversion of arylazides into the corresponding trizoles via phase
transfer catalyst-assisted [3+2] cycloaddition reaction under basic conditions in aqueous medium
is reported. This synthetic methodology, which offers high yields and excellent regioselectivity
for varieties of triazoles at 100 °C for 24 hr- 48 hr and this ‘greener’ synthesis constitutes an
alternative to the previously reported well established click reactions.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
click chemistry
azides + aldehydes or ketones
triazoles
water
———
 Corresponding author.; e-mail: sameer.joshi3@wayne.edu (S. M. Joshi)

2
Tetrahedron
Click chemistry involving Huisgen [3+2] cycloaddition of alkynes and azides under thermal conditions to obtain 1,2,3-
triazoles has been widely used for more than a century [1,2], and has been extensively applied to the preparation of 1,4- and
1,5-disubstituted 1,2,3-triazoles, which find application in a broad range of industrial and societal sectors [3]. Early works to
achieve regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles was carried out by Meldal and Sharpless’ groups using
copper catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) reactions [4], while regioselective synthesis of 1,5-disubstituted
1,2,3-triazoles can be carried out by ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) reactions [5]. Very recently,
nickel-catalyzed azide−alkyne cycloaddition (NiAAC) to yield 1,5-disubstituted 1,2,3-triazoles in aqueous media has been
described [6].
Among triazoles, 1,4-diaryl-5-methyl(alkyl)-1,2,3-triazoles have shown promise in the pharmaceutical sector. However, the
development of regioselective synthetic procedures for
their preparation has not been thoroughly explored. One alternative involves the reaction of metal acetylide (metal= Li, Mg,
Zn or Te) with an organic azide and its subsequent in situ reaction with an electrophile to form a metalated triazole with
reverse selectivity and high reactivity [7]. Palladium- or copper-catalyzed reactions [8], in the presence of arylboronic acid or
aryltrifluoroborates [9], and reaction of aryl azides with active methylenes or symmetrical ketones at high temperature have
also been described [10]. Of note, most of the above mentioned methods employ costly or non-commercial substrates instead of
using simple starting materials such as phenylacetaldhyde or arylacetones.
a) Previous work: organic solvents
b) Previous work: water
c) Present study: water
Scheme 1. (a) Reaction reported in previous work [11]. When R1=R3=Ph and R2=H, yield = 5% in water; (b) similar kind of work in water [12a]
and (c) reaction reported in this work, When R1=R3=Ph and R2=H, yield = 77% and When R2=Ph, yield = 95%.
Organocatalytic azide-aldehyde [11] and azide-ketone [13a,14]
reactions using [3+2] cycloaddition to furnish 1,4-disubstituted 1,2,3-triazoles have been reported. However, their application
is limited to organic solvents. Previous attempts to conduct the reaction in aqueous media show limited scope (i.e. simple
ketones such as cyclohexanone), and require the use of organocatalysts with long aliphatic chains [12a]. The outcome becomes
more dramatic when translated to cycloaddition reactions involving azides and aldehydes. For example, 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted azide-aldehyde reaction results in less than 5% yields in water (Scheme 1a)
[11]. Still, the use of water as the solvent as reported by Yeung et al [12a] would be highly desirable to achieve environmental-
friendly, easy to scale up synthetic routes. Recently, we have described the preparation of 13N-labelled azides [15], triazoles [16]
,
and tetrazoles [17] under catalytic conditions. In continuation of our work, we here present a azide-aldehydes or ketones [3+2]-
cycloaddition reactions for the synthesis of triazoles in water as a green solvent (Scheme 1b).
Initially, the reaction between phenyl azide and phenyl acetaldehyde was assayed as a model reaction using different bases,
catalysts and reaction conditions, and using water as the only solvent. In the absence of catalyst, the formation of the desired
triazole was not observed (Table 1, entries 1 and 3), and identical results were obtained when only TBAHS was added as the
catalyst (Table 1, entry 2). Simultaneous addition of KOH and K2CO3 resulted in the formation of the corresponding triazole
in trace amount (Table 1, entry 4).
Previous works have shown that phase transfer catalyst (PTC) such as TBAHS can be used under aqueous basic conditions to
achieve metal-free reactions of amides with peroxides [18]. Therefore, we decided to explore the suitability of this catalyst to
achieve the desired triazole. In the presence of TBAHS, moderate yields (64%, 61% and 69%) were obtained when
potassium, sodium and caesium carbonates, respectively, were used as the base, and the reaction was conducted at 100°C for

3
24 h (Table 1, Entries 5-7). These values decreased to 25% and 42% when sodium and potassium bicarbonates were used
respectively (Table 1, Entries 8 and 9).The addition of a stronger base such as NaOH resulted in yields equivalent to those
obtained with carbonates (61%; Table 1, entry 10), although this value increased to 77% when KOH was used (Table 1, entry
11). The use of alternative catalysts including tetrabutylammonium bromide (TBAB) and tetrabutylammonium iodide (TBAI)
resulted in slightly lower yields (66% and 62%, respectively; Table 1, Entries 12 and 13).
The effect of the concentrations of the catalyst and the base was also investigated. While lowering the concentrations of
catalyst and base to 10 mol% and 0.21 mmol, respectively, resulted in moderately lower yields (45%; Table 1, entry 14), an
increase in the amount of both the base and the catalyst did not positively affect the yield (Table 1, entry 15). Later, the effect
of the temperature was also explored. Our results clearly show that lower reaction temperatures dramatically decrease
reaction yields (Table 1, entries 16 and 17).
We next explored the substrate scope of our reaction by reacting a variety of carbonyl compounds with phenyl azide (Table
2). Aliphatic aldehydes did not yield the desired triazoles under our experimental conditions (Table 2, entries 3 and 4),
probably due to the lower acidic character of the alpha methylene groups, which hampers the formation of the enolate
intermediate. However, the formation of the product was achieved when hydrocinnamaldehyde was used, in spite of the
presence of one additional methylene group (59%, Table 2, entry 2).The reaction was also unsuccessful in the case of
aliphatic esters (Table 2, entries 5 and 6). Finally, we explored the reactivity of ketones and almost quantitative yields were
obtained (Table 2, entries 7 and 8). As in the case of esters, the enolate ion is resonance-stabilised in ketones. However, the
negative charge of the conjugate base of the ester is stabilized by the same oxygen atom whose lone pair is involved in the
resonance, resulting in a lower effectiveness. Overall, this results in a higher stability of the conjugate base of the ketone,
leading to the formation of a more acidic compound which favours the formation of the triazole.
Table 1 Optimization of reaction between arylazide and aldehyde[a]
Entry
1
2
3
4
5
6
7
8
Base[b]
none
none
K2CO3
KOH
K2CO3
Na2CO3
Cs2CO3
NaHCO3
KHCO3
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Catalyst[c]
none
TBAHS
none
t/h
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
T/°C
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
Yield(%)[d]
0
0
0
K2CO3
10
64
61
69
25
42
61
77
66
62
45
75
48
21
TBAHS
TBAHS
TBAHS
TBAHS
TBAHS
TBAHS
TBAHS
TBAB
9
10
11
12
13
14[e]
15[f]
16
17
TBAI
TBAHS
TBAHS
TBAHS
TBAHS
RT
[a] All reactions were carried out with 1a (0.21 mmol), 2a (0.21 mmol) in presence of TBAHS (0.042 mmol) and KOH (0.42 mmol) in water
(1.0 mL); [b] 0.42 nmol; [c] 0.042 nmol; [d] Isolated yields after column chromatography; [e] catalyst- 10 mol% and KOH- 0.21 mmol; [f]
catalyst- 30 mol%; TBAHS: Tetrabutyl ammonium hydrogen sulfate; TBAB: Tetrabutylammonium bromide; TBAI: Tetrabutylammonium
iodide.
Table 2 Scope of carbonyl compounds[a]

4
Tetrahedron
Yield
Entry
Substrate 2
Carbonyl
Product
R3
Ph
R2
H
H
H
H
compd
2a
2b
2c
2d
2e
2f
2g
2h
(%)[b]
77
59
0
0
0
0
95
94
1
2[c]
3
4
5
6
7
8
3aa
3ab
3ac
3ad
3ae
3af
PhCH2
Me(CH2)2
Me(CH2)3
MeCO
MeCO
Ph
OCH2CH3
OCH3
Ph
3ag
3ah
4-ClC6H4
CH3
[a] All reactions were carried out with 1a (0.21 mmol), 2 (0.21 mmol) in presence of TBAHS (0.042 mmol) and KOH (0.42 mmol) in water
(1.0 mL) at 100 °C for 24 hr. [b] Isolated yields after column chromatography. [c] Reaction time: 48 hr.
Table 3 Substrate scope[a]
3ag, 95%
3ah, 94%
3ai, 92%
3aj, 82%
3ak, 79%
3al, 75%
3am, 82%
3an, 43%
3bg, 78%
3bh, 81%
3ck, 90%
3bj, 90%
3cl, 82%
3cg, 79%
3ci, 89%
3cm, 87%
3dg, 88%
3dj, 91%
3dk, 81%
3dl, 89%

5
3dm, 91%
3em, 84%
3eg, 77%
3eh, 87%
3el, 90%
[a] All reactions were carried out with 1 (0.21 mmol), 2 (0.21 mmol) in presence of TBAHS (0.042 mmol) and KOH (0.42 mmol) in water (100
°C, 24 hr).
Table 4 Substrate that doesn’t work[a]
3ao, 0%
3ap, 0%
3fg, 0%
[a] All reactions were carried out with 1 (0.21 mmol), 2 (0.21 mmol) in presence of TBAHS (0.042 mmol) and KOH (0.42 mmol) in water (100
°C, 24 hr).
Encouraged by these results, we investigated the reactivity of different ketones (Table 3, 2g-2n) with different arylazides
(Table 3, 1a-1e). Cycloaddition reactions proceeded smoothly, irrespective of the electronic properties of the substituents on
the aromatic rings. The presence of both electron withdrawing groups such as chloro and bromo at the p- position (Table 3,
3cg-3dm), electron-donating groups like methyl moieties at the p- position (Table 3, 3eg-3em), or electron-neutral groups
(Table 3, 3ag-3an) on the phenyl azide yielded the corresponding triazoles in very good yields. Notably, high yields were also
obtained with benzyl azide (Table 3, 3bg-3bj).
The effect of substituents on the ketone was also explored. When substituted phenyl acetones were used, good yields were
obtained irrespective of the substituents on the aromatic rings. The presence of electron withdrawing groups such as chloro
and trifluoromethyl at the p-and m-positions, resulted in 94% and 75% yields, respectively (Table 3, 3ah and 3al). Similar
results were obtained with electron donating groups such as methoxy at the p- position of the phenyl rings (Table 3, 3am,
3cm, 3dm and 3em) In addition, aromatic ketones containing two methoxy groups also did not affect the reaction rate and
which delivers corresponding triazoles in higher yields. (3ak, 3ck and 3dk). 1-Phenyl-2-butanone also resulted in excellent
yields (Table 3, 3ai and 3ci). Pleasingly, the best yield was obtained with 2-Phenylacetophenone, which afforded the desired
triazole in 95% isolated yield (Table 3, 3ag). However, 4-acetyl pyridine having low reactivity since lack of extra methylene
group next to carbonyl group which afforded corresponding triazole only in 43% yield (Table 3, 3an). As expected, alkyl
ketones, namely 2-butanone and 2- octanone, did not yield the formation of the triazole (Table 4, 3ao and 3ap), due to the low
acidic character of alpha-methylene groups in comparison with aromatic ketones, which hampers the formation of the enolate
ion for the subsequent [3+2] cycloaddition reaction. Also reaction was unsuccessful, when it is performed in presence of
sulfonylazides (Table 4, 3fg). The results in Table 3 demonstrate the broad scope of this synthetic approach covering a
structurally diverse group of aryl azides 1(a-e) and aromatic ketones 2(g–n). It is worth mentioning that, the high yields are
even more impressive considering that water was the only solvent. Overall, our methodology has proven robust and
demonstrated by the preparation of twenty-seven different triazoles, fourteen of them reported for the first time.
The exact reaction mechanism remains to be explored. However, we hypothesize that the reaction of phase transfer
catalyst (PTC) with aldehyde/ketone 2 under basic conditions, forms the enolate ion intermediate 4 or 4’, which subsequently
reacts with R1-N3 (1) rapidly to yield the 1,2,3-triazoline adduct 5 via concerted or stepwise [3+2] cycloaddition amination-
cyclization reaction.[11,13a] Adduct 5 then yields the corresponding 1,2,3-triazole 3 by loss of a water molecule (dehydration)
(Scheme 2).
Scheme 2. Plausible reaction mechanism.
In conclusion, we have developed a simple, versatile, and green route for enolate-mediated azide-aldehyde or ketone [3+2]-
cycloaddition reaction which enables the synthesis of 1,4-disubstituted 1,2,3-triazoles containing a variety of functional

6
Tetrahedron
groups with excellent regioselectivity using water as the only solvent. This water-compatible and phase transfer catalyst
(PTC)-assisted catalytic synthetic approach described here provides a stepping stone towards a greener organic synthesis in
pharmaceutical industries.
Experimental:
1, 4-Diphenyl-1H-1, 2, 3-triazole (3aa): Typical procedure
In an ordinary glass tube equipped with a magnetic stirring bar, to phenylacetaldehyde (25.2 mg, 0.21 mmol, 1 equiv.), TBAHS (14 mg,
0.042 mmol, 20 mol %) and potassium hydroxide (23 mg, 0.42 mmol, 2 equiv.) were added successively in Milli-Q water (1.0 mL) at
room temperature. Finally, corresponding phenylazide (25mg, 0.21 mmol, 1 equiv.) was added to above reaction mixture. This reaction
mixture was stirred at room temperature for 2 minutes which was subsequently heated for 24 hours at 100 °C. The reaction progress
was monitored by TLC and after consumption of starting aldehyde, reaction mixture was cooled to room temperature. The crude
reaction mixture was extracted with ethyl acetate (3 x 7 mL). These combined mixtures of organic layers were dried over sodium
sulfate, filtered and concentrated. Pure product 3aa was obtained by column chromatography (silica gel, mixture of ethyl
acetate/petroleum ether) and was isolated as a white solid. 35 mg, 77% yield. 1,4,5-Triphenyl-1H-1,2,3-triazole (3ag): Typical
procedure
In an ordinary glass tube equipped with a magnetic stirring bar, to 2-Phenylacetophenone (41.2 mg, 0.21 mmol, 1 equiv.), TBAHS (14
mg, 0.042 mmol, 20 mol %) and potassium hydroxide (23 mg, 0.42 mmol, 2 equiv.) were added successively in Milli-Q water (1.0 mL)
at room temperature. Finally, corresponding phenylazide (25mg, 0.21 mmol, 1 equiv.) was added to above reaction mixture. This
reaction mixture was stirred at room temperature for 2 minutes which was subsequently heated for 24 hours at 100 °C. The reaction
progress was monitored by TLC and after consumption of starting ketone, reaction mixture was cooled to room temperature. The crude
reaction mixture was extracted with ethyl acetate (3 x 7 mL). These combined mixtures of organic layers were dried over sodium
sulfate, filtered and concentrated. Pure product 3ag was obtained by column chromatography (silica gel, mixture of ethyl
acetate/petroleum ether) and was isolated as a white solid. 59 mg, 95% yield. This particular reaction was also reproducible in tap
water.
Acknowledgments
SMJ acknowledges the generous funding for the award of the National Post-Doctoral Fellow (N-PDF; File No. PDF/2017/001235). AT
thanks CSIR, New Delhi, for the award of a research fellowship. JL acknowledges financial support from the Spanish MINECO
(CTQ2017-87637-R).
Appendix A. Supplementary data
Supplementary to this article can be found online at http://dx.doi.org/10.1016/j.tetlet.2019.
References
[1]
(a) J.-F. Lutz, Angew. Chem. 119 (2007) 1036;
(b) J.-F. Lutz,Angew. Chem. Int. Ed. 46 (2007) 1018;
(c) N. J. Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem. Soc. 127 (2005) 11196.
(a) R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, (1984);
(b) W.-Q. Fan, A. R. Katritzky, C. W. Rees, E. F. V. Scriven in Comprehensive Heterocyclic Chemistry II, Pergamon, Oxford, (1996).
(a) A. C. Tome, Sci. Synth. 13 (2004) 415;
[2]
[3]
(b) L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G. Yang, D. Tew, T. D. Meek, G. A. Hofmann, C. K. Schulz-Pritchard, W.W. Smith, C. A. Janson,
M. D. Ryan, G. F. Zhang, K. O. Johanson, R. B. Kirkpatrick, T. F. Ho, P.W. Fisher, M. R. Mattern, R. K. Johnson, M. J. Hansbury, J. D. Winkler,
K.W. Ward, D. F. Veber, S. K. Thompson, J. Med. Chem. 48 (2005) 5644;
(c) A. Lauria, R. Delisi, F. Mingoia, A. Terenzi, A. Martorana, G. Barone, A. M. Almerico, Eur. J. Org. Chem. (2014) 3289.
(a) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057;
(b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 41 (2002) 2596;
(c) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 114 (2002) 2708.
For RuAAC and IrAAC click reactions, see: (a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharpless, V. V. Fokin, G. Jia, J. Am.
Chem. Soc. 127 (2005) 15998;
[4]
[5]
(b) S. Ding, G. Jia, J. Sun, Angew. Chem. 126 (2014) 1908;
(c) S. Ding, G. Jia, J. Sun, Angew. Chem. Int. Ed. 53 (2014) 1877.
[6]
[7]
[8]
W. G. Kim, M. E. Kang, J. B. Lee, M. H. Jeon, S. Lee, J. Lee, B. Choi, P. M. S. D. Cal, S. Kang, J. M. Kee, G. J. L. Bernardes, J. U. Rohde, W.
Choe, and S. Y. Hon; J. Am. Chem. Soc. 139 (2017) 12121.
(a) A. Krasin´ ski, V. V. Fokin, K. B. Sharpless, Org. Lett. 6 (2004) 1237;
(b) C. D. Smith, M. F. Greaney, Org. Lett. 15 (2013) 4826.
(a) L. Ackermann, H. K. Potukuchi, D. Landsberg, R. Vicente, Org. Lett. 10 (2008) 3081;
(b) L. Ackermann, A. Althammer, S. Fenner, Angew. Chem. Int. Ed. 48 (2009) 201;
(c) L. Ackermann, A. Althammer, S. Fenner, Angew. Chem. 121 (2009) 207.
[9]
(a) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, V. V. Fokin, Angew. Chem. Int. Ed. 48 (2009) 8018;
(b) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, V. V. Fokin, Angew. Chem. 121 (2009) 8162.
(a) D. B. Ramachary, K. Ramakumar, V. V. Narayana, Chem. Eur. J. 14 (2008) 9143;
(b) D. B. Ramachary, A. B. Shashank, Chem. Eur. J. 19 (2013) 13175;
[10]
(c) W. Li, Q. Jia, Z. Du, J. Wang, Chem. Commun., 49 (2013) 10187.
[11]
[12]
D. B. Ramachary, A. B. Shashank, S. Karthik, Angew. Chem. Int. Ed. 53 (2014) 10420.
(a) D. K. J. Yeung, T. Gao, J. Huang, S. Sun, H. Guo, and J. Wang, Green Chem., 15 (2013) 2384;
(b) L. J. T. Danence, Y. Gao, M. Li, Y. Huang, J. Wang, Chem. Eur. J. 17 (2011) 3584;
(c) L. Wang, S. Peng, L. J. T. Danence, Y. Gao, J. Wang, Chem. Eur. J. 18 (2012) 6088;

7
(d) N. Seus, L. C. Goncalves, A. M. Deobald, L. Savegnago, D. Alves, M. W. Paixao, Tetrahedron 68 (2012) 10456;
(e) W. Li, Q. Jia, Z. Du, J. Wang, Chem. Commun. 49 (2013) 10187;
(f) D. K. J. Yeung, T. Gao, J. Huang, S. Sun, H. Guo, J. Wang, Green Chem. 15 (2013) 2384;
(g) N. Seus, B. Goldani, E. J. Lenardão, L. Savegnago, M. W. Paixão, D. Alves, Eur. J. Org. Chem. (2014) 1059;
(h) W. Li, Z. Du, J. Huang, Q. Jia, K. Zhang, J. Wang, Green Chem. 16 (2014) 3003;
(i) W. Li, Z. Du, K. Zhang, J. Wang, Green Chem. 17 (2015) 781; (j) Q. Jia, G. Yang, L. Chen, Z. Du, J. Wei, Y. Zhong, J. Wang, Eur. J. Org. Chem.
(2015) 3435;
(k) X. Xu, Z. Shi, W. Li, New J. Chem. 40 (2016) 6559;
(l) W. Li, J. Wang, Angew. Chem. 126 (2014) 14410;
(m) W. Li, J. Wang, Angew. Chem. Int. Ed. 53 (2014) 14186;
(n) S. S. V. Ramasastry, Angew. Chem. 126 (2014) 14536;
(o) S. S. V. Ramasastry, Angew. Chem. Int. Ed. 53 (2014) 14310;
(p) C. G. S. Lima, A. Ali, S. S. van Berkel, B. Westermann, M. W. Paixão, Chem. Commun. 51 (2015) 10784;
(q) J. John, J. Thomas, W. Dehaen, Chem. Commun. 51 (2015) 10797;
(r) D. González-Calderón, A. Fuentes-Benítes, E. Díaz-Torres, C. A. González-González, C. González-Romero, Eur. J. Org. Chem. (2016) 668;
(s) X. Zhou, X. Xu, K. Liu, H. Gao, W. Wang, W. Li, Eur. J. Org. Chem. (2016) 1886;
(t) X. Zhou, X. Xu, Z. Shi, K. Liu, H. Gao, W. Li, Org. Biomol. Chem. 14 (2016) 5246.
[13] (a) A. B. Shashank, S. Karthik, R. Madhavachary, and D. B. Ramachary, Chem.–Eur. J., 20 (2014) 16877;
(b) D. B. Ramachary, G. Jagjeet, P. Swamy, and G. S. Reddy, Eur. J. Org. Chem. (2017) 459;
(c) D. B. Ramachary, G. S. Reddy, P. Swamy, and G. Jagjeet, ChemCatChem, 9 (2017) 263;
(d) K. Anebouselvy, D. B. Ramachary, Click Reactions in Organic Synthesis (2016) 99;
(e) D. B. Ramachary, P. M. Krishna, J. Gujral, G. S. Reddy, Chem. Eur. J. 21 (2015) 16775;
(f) P. M. Krishna, D. B. Ramachary, S. Peesapati, RSC Adv., 5 (2015) 62062.
[14]
[15]
[16]
[17]
[18]
M. Belkheira, D. El Abed, J.-M. Pons and C. Bressy, Chem.–Eur. J., 17 (2011) 12917.
S. M. Joshi, A. De Cózar, V. Gómez-Vallejo, J. Koziorowski, J. Llop and F. P. Cossío, Chem. Commun., 51 (2015) 8954.
S. M. Joshi, V. Gómez-Vallejo, V. Salinas and J. Llop, RSC Adv., 6 (2016) 109633.
S. M. Joshi, R. B. Mane, K. R. Pulagam, V. Gómez-Vallejo, J. Llop and C. Rode, New J. Chem., 41 (2017) 8084.
X. Yao, X. Weng, K. Wang, H. Xiang and X. Zhou, Green Chem., 20 (2018) 2472.
Declaration of interests
✔The authors declare that they have no known competing financialinterestsor personal relationships that
could have appeared to influence the work reported in this paper.
✔The authors declare the following financial interests/personal relationships which may be considered as potential
competing interests:

8
Tetrahedron
 Click Chemistry: Azide-Aldehyde/Ketone
 Excellent Regioselectivity
 High Efficiency
 Broad Substrate Scope
 Green Solvent
Highlights
Bullet points
click chemistry
azides + aldehydes or ketones
triazoles
water