One-pot, three-component reaction using modified Julia reagents: A facile synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles in a wet organic solvent

Article abstract of DOI:10.1021/co5001597

A new one-pot, three component reaction involving the use of Julia reagent, aldehyde, and sodium azide was developed for the efficient synthesis of N-unsubstituted 1,2,3-triazoles. This reaction could be carried out under mild reaction conditions without any precaution, and broad scope of substrates, both respect to Julia reagents and aldehydes, could be applied in this reaction system in generation of a small library of title compounds.

Full text of DOI:10.1021/co5001597

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Technology Note
A One-pot, Three-component Reaction Using Modified
Julia Reagents: A Facile Synthesis of 4,5-Disubstituted
1,2,3-(NH)-Triazoles in a Wet Organic Solvent
Huihui Chai, Ruiqiang Guo, Wei Yin, Linping Cheng, Renhua Liu, and Changhu Chu
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co5001597 • Publication Date (Web): 28 Jan 2015
Downloaded from http://pubs.acs.org on January 29, 2015
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A One-pot, Three-component Reaction Using
Modified Julia Reagents: A Facile Synthesis of 4,5-
Disubstituted 1,2,3-(NH)-Triazoles in a Wet Organic
Solvent
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Huihui Chai, Ruiqiang Guo, Wei Yin, Linping Cheng, Renhua Liu and Changhu Chu*
School of Pharmacy, Shanghai Key Laboratory of New Drug Design, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China
ABSTRACT: A new one-pot three component reaction
involving the use of Julia reagent, aldehyde and sodium
azide was developed for the efficient synthesis of N-
unsubstituted 1,2,3-triazoles. This reaction could be
carried out under mild reaction conditions without any
N
NH
N
O
S
N
S
10% ammonium acetate
methanol:H2O=95:5(v:v)
R2CHO
NaN3
R2
+
R1
O
O
O
R1
precaution, and broad scope of substrates, both respect to Julia reagents and aldehydes, could be applied in this reaction system in
generation of a small library of title compounds.
KEYWORDS: multicomponent reaction, Julia reagent, 1,2, 3-triazoles, sodium azide, one pot
1, 2, 3-triazole derivatives are attractive target compounds, which have been utilized as dyes,
photostabilizers, agrochemicals, pharmaceutically active ingredients and biochemicals, as well as
intermediate in chemical synthesis.1 So far, many synthetic methods for achieving this ring
system have been developed for different purposes. Among these methods, a typical click
reaction, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is undoubtedly the most
1,2
powerful strategies.
Besides Cu(I) catalysts, other transition metal catalysts, such as
ruthenium,3 palladium 4 and zinc 5 in combination with different reaction systems, have also been
utilized to promote the formation of 1,2,3-triazoles. Furthermore, other protocols,
including the use of non-transition metal catalysts, such as tetrabutylammonium fluoride
(TBAF),6 tetraalkylammonium hydroxide or potassium tert-butoxide,7 small organic molecules
and organic bases,8 even heat promoted [3+ 2] cycloaddition reactions9 and catalyst free strain-
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promoted alkyne-azide cycloaddition (SPAAC) have been developed.10 However, most of these
methods afforded 1-substituted 1,2,3-triazoles, and only a few of them gave N-unsubstituted
1,2,3-triazoles, which could be further derivatized to 2-substituted 1,2,3-triazoles.11 On the other
hand, a multicomponent reaction (MCR), which was first reported in 1838 by Laurent and
Gerhardt, is an attractive synthetic strategy in drug discovery research, since it provides easy and
rapid access to large libraries of organic compounds with diverse substitution patterns. Since the
Strecker amino-acid synthesis reaction in 1850, many named reactions, such as Mannich,
Hantzsch, Biginelli, Tietze, Robinson–Schopf, Grieco, Ugi, etc were incorporated into MCRs,12
and some MCRs were developed for obtaining 1,2,3-triaoles. 11a,13 It still is of great importance to
develop new MCRs, which may offer greater possibilities for molecular diversity per step with a
minimum of synthetic time and effort. Furthermore, the efficient construction of the ring
structure without using transition metal catalysts is also an essential issue both in pharmaceutical
synthesis and bioconjugation. Therefore, construction of heterocyclic systems with simple
organic molecules by MCRs is highly desired.
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In our previous work, a type of substituted vinyl sulfones were prepared through the
Ti(Oi-Pr)4 mediated Knoevenagel condensation between benzothiazol-2-yl sulfones (BT sulfone,
Julia reagent) and aldehydes with good yields and exclusively E isomers, which could rapidly
react with sodium azide to afford 4,5-disubstituted-(NH)-1,2,3-triazoles with high yield.14
However, this (NH)-1,2,3-triazoles synthesis procedure was time consuming requiring two
independent steps. Furthermore, the Ti(Oi-Pr)4 is a moisture sensitive reagent, thus the
Knoevenagel condensation reaction should be run in a dry solvent under an inert atmosphere. In
addition, a laborious workup is required because of the amorphous precipitate of titanic acid
formed upon hydrolysis. In spite of these disadvantages, it was noticeable that the irreversible
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1,3-dipolar cycloaddition reaction between vinyl sulfones and sodium azide in polar solvents and
can be carried out under mild condition without any precautions. Likewise, the Knoevenagel
condensation can be catalyzed by ammonium salts in alcoholic solvent. Furthermore, Julia
reagents can be readily prepared. Based on the facts mentioned above, it was assumed that an
ammonium catalyzed Knoevenagel condensation between aldehyde and BT sulfone could gave a
vinyl sulfone, which subsequently would react with sodium azide by an irreversible 1,3-dipolar
cycloaddition and elimination the benzothiazol sulfonyl group to drive the preceding equilibrium
to the product side (of course, the elimination of the sulfone part of the group in the Julia reagent
is not atom efficient).Our interest in developing a new, more efficient method for the synthesis
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of functional 4,5-disubstituted-(NH)-1,2,3-triazoles encouraged us to test the three component
reaction between Julia reagents, aldehydes and sodium azide with ammonium acetate as the
catalyst. Herein, we would like to describe an efficient method for obtaining 4,5-disubstituted-
(NH)-1,2,3-triazoles (Scheme 1). This process, which has a broad scope both in respect to the
Julia reagents and aldehydes, is experimentally simple, and affords the target compounds in
moderate to excellent yield without a complicated purification step. Different ammonium salts,
such as ammonium acetate, ammonium chloride, ammonium carbonate, ammonium formate,
ammonium nitrate et. al. could be used for this reaction. Additionally, alcoholic solvents, such as
methanol and ethanol are preferred solvents (Table 1, Entries 1 and 2). Polar aprotic solvents,
including N,N-dimethylformamide (DMF), N,N-dimethyl acetamide (DMA), tetrahydrofuran
(THF), ethyl acetate (EtOAc) and dimethyl sulfoxide (DMSO) can also be used in this reaction
as well, however neither the selectivity nor conversion is satisfactory (Table 1, Entries 4, 6, 7, 8
and 11). When chloroform, dichloromethane and water were used as solvent, no reaction was
detectable (Table 1, Entries 5, 9 and 10). In addition, since the reaction is not sensitive to
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moisture, a small amount of water (about 5%) accelerates it due to sodium azide’s high aqueous
solubility (Table 1, Entry 3), 95% aqueous methanol was used in all the rest of multicomponent
reactions. A control experiment was also carried out without using ammonium acetate as the
catalyst resulting in a lower selectivity and yield (Table 1, Entry 12).
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N
NH
N
R2CHO
O
S
N
S
10% ammonium acetate
methanol:H2O=95:5(v:v)
R2
2
+
R1
O
NaN3
3
O
R1
O
4
1
Scheme 1 One-pot multicomponent synthesis of 4,5-disubstituted-(NH)-1,2,3-triazole
O
S
O
S
N
S
N
S
OEt
O
O
O
O
O
2
N
1
O
O
S
N
S
S
S
NH
O
O
Br
O
O
MeO
3
4
Figure 1. Diversity of Julia reagents 1{1-4}
OMe
Cl
F
Cl
OMe
OMe
OMe
Cl
F
NO2
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
2
3
4
6
7
1
5
8
CHO
CHO
CHO
CHO
CHO
S
CHO
O
CHO
6
7
8
CHO
9
13
14
10
15
11
12
16
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Figure 2. Diversity of aldehydes 2{1-16},
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Table 1 Screening of reaction solvent a
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N
NH
N
O
N
PhCHO
NaN3
10% ammonium acetate
solvent , 4h
Ph
S
+
S
OEt
O
O
OEt
O
Entry
solvent
Conversion (%)
Selectivity (%)b
Yield (%)
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2
3
4
5
6
7
8
9
EtOH
MeOH
MeOH:H2O(95:5)
DMSO
H2O
100
100
100
100
0
100
100
70
87
95
98
45
0
51
33
53
0
87
95
98
45
0
51
33
37
0
DMA
DMF
THF
CH2Cl2
0
10
11
12c
CHCl3
EtOAc
MeOH:H2O(95:5)
0
40
90
0
28
51
0
11
45
a, reaction conditions: benzaldehyde (58mg, 0.55mmol), Julia reagent(143mg, 0.5mmol) and
sodium azide (49mg, 0.75mmol), ammonium acetate(4mg, 0.05mmol); reaction time:4h;
temperature: 30oC. 2mL commercial solvent was used directly without any further purification.
Conversion, selectivity and yield are determined by GC; b, selectivity is the percent of target
coumpound in all of products; c, ammonium acetate was not used.
After screening various combinations of reagents, an optimized procedure for obtaining 4, 5-
disubstituted-(NH)-1, 2, 3-triazoles was achieved. The Julia reagents contain three diverse
functionalities, an ester, a ketone and an amide (Figure 1), aldehydes include aromatic aldehydes
with electronic donating and electronic withdrawing groups, heterocyclic aldehyde and alkyl
aldehyhdes (Figure 2). As depicted in Table 2, the reactions preceeded in moderate to excellent
yield (55% to 99%). The substituent on the aldehydes did not significantly distinguish the
yields. Furthermore, the three types of Julia reagents, containing ester, amide or ketone
combined with sodium azide, reacted with the aldehydes to form the corresponding (NH)-1, 2, 3-
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triazoles, though the reactivity of the amide is a little weaker than the ester and ketone (Table 2,
Entries 24 and 25). Hence, by varying both the Julia reagents and aldehydes, a wide variety of
4,5-disubstituted-(NH)-1,2,3-triazoles could be readily prepared. Furthermore, the reaction
mechanism study displayed that it is difficult to drive the Knoevenagel condensation to
completion in the presence of 10% mol amount of ammonium acetate. After 24 hours at 30oC,
only a small amount of Julia reagent was transformed to the corresponding vinyl sulfone. Thus
the 1,3-dipolar cycloaddition between the vinyl sulfone and sodium azide drove the three
component reaction forward. Also, the equilibrium between ammonium acetate and sodium
azide likely affords some ammonium azide, which is the more active nucleophile toward the
vinyl sulfone. This would explain the catalytic role of ammonium acetate in this reaction. A
plausible mechanism is shown in Scheme 2. (Caution: ammonium azide is highly volatile at or
near room temperature, and both ammonium azide and sodium azide are very shock sensitive.
They have been known to spontaneously explode.)
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Table 2. Scope of the three component reaction
N
NH
N
R2CHO
O
S
N
S
10% ammonium acetate
methanol:H2O=95:5(v:v)
R2
2
+
R1
O
NaN3
3
O
R1
O
4
1
product
Entry
1
Yield (%)a Entry
product
N NH
Yield (%)a
85
NH
98
14
N
N
N
6
OEt
O
4{1,14}
OEt
O
4{1,1}
NH
N
N
NH
2
93
15
95
OMe
N
N
7
OEt
O
4{1,15}
OEt
MeO
O
4{1,2}
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NH
N
N
NH
N
3
4
90
88
16
17
80
88
OMe
N
MeO
8
OEt
O
4{1,16}
OEt
O
4{1,3}
NH
H
N
Cl
N
10
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N
N
N
OEt
Cl
O
4{1,4}
O
4{2,1}
OMe
N
NH
N
5
94
18
82
N
NH
N
MeO
Cl
O
4{1,5}
OEt
O
4{2,3}
N NH
N
NH
N
6
7
80
99
19
20
84
65
N
6
O
4{1,6}
OEt
O
4{2,14}
N
F
NH
N
NH
N
N
7
F
O
O
4{1,7}
OEt
4{2,15}
H
NO2
8
9
99
80
21
22
85
70
N
NH
N
N
N
N
Br
Br
Br
O
O
OEt
4{1,8}
4{3,1}
H
N
N
NH
N
N
N
O
O
O
4{1,9}
N
OEt
NH
4{3,11}
H
10
74
23
84
N
N
N
N
S
O
OEt
4{1,10}
O
4{3,13}
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N
NH
N
N
NH
N
11
91
24
25
60
55
O
O
OEt
O
NH
4{1,11}
OMe
10
11
12
13
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15
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O
4{4,1}
NH
N
N
NH
12
13
94
60
O
N
N
NH
O
OEt
O
O
OMe
4{1,12}
O
4{4,3}
NH
N
N
OEt
O
4{1,13}
a Reaction conditions: aldehyde (1.1mmol), Julia reagent (1 mmol) and sodium azide (1.5mmol),
ammonium acetate (8mg, 0.1mmol); Temperature: 30oC. 2mL 95% aqueous methanol
(methanol:water = 95:5, v:v) was used. The yields are for the isolated product
Explosive !
-N N+ N-NH4
+
CH3CO2Na
+
NaN3
CH3CO2NH4
+
O
S
O
N
S
Ph
N
S
ammonium acetate
slow
S
+
PhCHO
OEt
N
OEt
O
O
O
O
N
N
N
N-
N
Ph
O
elimination
fast
O
S
N
S
OEt
O
O
OEt
N
NH
N
OEt
O
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Scheme 2 Plausible mechanism for the multicomponent reaction
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Conclusion
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In summary, the ammonium catalyzed three component reaction described here provides a direct,
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simple, highly selective and efficient method for the synthesis of 4,5-disubstituted-(NH)-1,2,3-
triazoles, in which the Knoevenagel condensation and 1,3-dipolar cycloaddition was combined in
one pot without any precaution. Starting from commercial and readily available reagent, 4,5-
disubstituted-(NH)-1,2,3-triazoles with several functional groups can be prepared conveniently,
which is quite useful for construction of small focused library.
EXPERIMENTAL SECTION
Azides can be very explosive compounds and should be handled with care. Aldehydes were
distilled before use. Ammonium acetate, ammonium chloride, ammonium nitrate, ammonium
carbonate, ammonium formate, sodium azide, and methanol, as well as other starting materials
were commercially available and used without further purification. Melting Points were obtained
1 13
with a Reichert Thermovar apparatus and are uncorrected. H NMR spectra and C NMR were
1
13
recorded on Bruker Avance 400 spectrometers (400MHz for H NMR, and 125 MHz for C
NMR); Chemical shifts were reported in δ(ppm) and coupling constants (J) in hertz, relative to
the internal standard of tetramethylsilane (TMS). All infrared (IR) spectra were recorded using a
KBr disc or coating on a Nicolet 6700 spectrometer. Mass spectra were performed on a GCT
Premier spectrometer under electron impact (EI). Thin layer chromatography (TLC) was
performed on 10-40µm silica plates and column chromatographic purifications were performed
on 300-400 mesh silica gel.
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General procedure for the one-pot multicomponent synthesis of 4,5-disubstituted-(NH)-
5
6
1,2,3-triazole
7
8
9
a solution of the modified Julia reagents ethyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (286mg,
1mmol), benzaldehyde (116mg, 1.1mmol), sodium azide (98mg, 1.5mmol) and ammonium
acetate (8mg, 0.1mmol) in 2mL methanol(contaning 5% water) was stirred at 30℃ for 4h. The
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reaction was detected by thin layer chromatography (TLC). After the Julia reagent was
consumed out, the solvent was removed by evaporation and the residue was purified by a flash
column on silica gel to afford compound 4{1,1} in 98% yield.
AUTHOR INFORMATION
Changhu Chu, to whom correspondence should be addressed
†School of Pharmacy, Shanghai Key Laboratory of New Drug Design, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China.
Fax: +86-21-64250627; Email: chuch@ecust.edu.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
We acknowledge the financial support from the National Natural Science Foundation of China
(No. 21172072, No. 21372081).
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ASSOCIATED CONTENT
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Supporting Information
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Further details on the experimental and isolation procedures, spectral data, and copies of 1H and
13C NMR spectra for all synthesized compounds. This information is available free of charge via
the Internet at http://pubs.acs.org/
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References and Notes
1. Selected reviews: (a) Holub, J. M.; Kirshenbaum, K. Tricks with Clicks: Modification of
Peptidomimetic Oligomers via Copper-Catalyzed Azide-Alkyne [3+2] Cycloaddition. Chem.
Soc. Rev. 2010, 39, 1325-1337. (b) Meldal, M.; Tornøe, C. W. Cu-Catalyzed Azide-Alkyne
Cycloaddition. Chem. Rev. 2008, 108, 2952-3015. (c) Moorhouse, A. D.; Moses, J. E. Click
Chemistry and Medicinal Chemistry: A Case of “Cyclo-addition”. ChemMedChem. 2008, 3,
715-723. (d) Moses, J. E.; Moorhouse, A. D. The Growing Applications of Click Chemistry.
Chem. Soc. Rev. 2007, 36, 1249-1262.
2. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen
Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and
Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. (b) Kamata, K.; Nakagawa,
Y.; Yamaguchi, K.; Mizuno, N. 1,3-Dipolar Cycloaddition of Organic Azides to Alkynes by
a Dicopper-Substituted Silicotungstate. J. Am. Chem. Soc. 2008, 130, 15304-15310. (c)
Ozcubukcu, S.; Ozkal, E.; Jimeno, C.; Pericas, M. A. A Highly Active Catalyst for Huisgen
1,3-Dipolar Cycloadditions Based on the Tris(triazolyl)methanol-Cu(I) Structure. Org. Lett.
2009, 11, 4680-4683. (d) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry:
ACS Paragon Plus Environment
11

ACS Combinatorial Science
Page 12 of 15
1
2
3
4
Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40,
5
6
2004-2021.
7
8
9
3. (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V.
V.; Jia, G. Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides. J. Am. Chem.
Soc. 2005, 127, 15998-15999. (b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.;
Zhao, H.; Lin Z.; Jia, G.; Fokin, V. V. Ruthenium-Catalyzed Azide-Alkyne Cycloaddition:
Scope and Mechanism. J. Am. Chem. Soc. 2008, 130, 8923-8930.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. (a) Zhou, J.; He, J.; Wang, B.; Yang, W.; Ren, H. 1,7-Palladium Migration via C-H
Activation, Followed by Intramolecular Amination: Regioselective Synthesis of
Benzotriazoles. J. Am. Chem. Soc. 2011, 133, 6868-6870. (b) Barluenga, J.; Valdes, C.;
Beltran, G.; Escribano, M.; Aznar, F. Developments in Pd Catalysis: Synthesis of 1H-1,2,3-
Triazoles from Sodium Azide and Alkenyl Bromides. Angew. Chem. Int. Ed. 2006, 45, 6893-
6896. (c) Zhang, W.; Kuang, C.; Yang, Q. Palladium-Catalyzed One-Pot Synthesis of 4-
Aryl-1H-1,2,3-Triazoles from Anti-3-Aryl-2,3-Dibromopropanoic Acid and Sodium Azide.
Synthesis. 2010, 283-287.
5. Meng, X.; Xu, X.; Gao, T.; Chen, B. Zn/C-Catalyzed Cycloaddition of Azides and Aryl
Alkynes. Eur. J. Org. Chem. 2010, 5409-5414.
6. (a) D'Ambrosio, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. TBAF-Catalyzed [3+2]
Cycloaddition of TMSN3 to 3-Nitrocoumarins under SFC: An Effective Green Route to
Chromeno [3,4-d][1,2,3]Triazol-4(3H)-Ones. Green Chem. 2005, 7, 874-877. (b) Amantini,
D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Zunino, E.; Vaccaro, L. Synthesis of 4-Aryl-1H-
1,2,3-Triazoles through TBAF-Catalyzed [3+2] Cycloaddition of 2-Aryl-1-Nitroethenes with
ACS Paragon Plus Environment
12

Page 13 of 15
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
TMSN3 under Solvent-Free Conditions. J. Org. Chem. 2005, 70, 6526-6529. (c) Gao, Y.;
Lam, Y., [3 + 2] Cycloaddition Reactions in the Synthesis of Triazolo[4,5-b]pyridin-5-ones
and Pyrrolo[3,4-b]pyridin-2-ones. J. Comb. Chem. 2008, 10, 327–332.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. (a) Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V. Transition-
Metal-Free Catalytic Synthesis of 1,5-Diaryl-1,2,3-Triazoles. Org. Lett. 2010, 12, 4217-4219.
(b) Wu, L.; Chen, Y.; Tang, M.; Song, X.; Chen, G.; Song, X.; Lin, Q. Potassium Tert-
butoxide Promoted Cycloaddition Reaction for the Synthesis of 1,5-Disubstituted 1,2,3-
Triazoles from Aromatic Azides and Trimethylsiyl-protected Alkynes. Synlett. 2012, 23,
1529-1533.
8. (a) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Organocatalytic Enamide-Azide
Cycloaddition Reactions: Regiospecific Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles.
Chem. Eur. J. 2011, 17, 3584-3587. (b) Berkel, S. S. V.; Brauch, S.; Gabriel, L.; Henze, M.;
Stark, S.; Vasilev, D.; Wessjohann, L. A.; Abbas, M.; Westermann, B. Traceless
Tosylhydrazone-Based Triazole Formation: A Metal-Free Alternative to Strain-Promoted
Azide-Alkyne Cycloaddition. Angew. Chem. Int. Ed. 2012, 51, 5343-5346. (c) Sengupta, S.;
Duan, H.; Lu, W.; Petersen, J. L.; Shi, Xi. One Step Cascade Synthesis of 4,5-Disubstituted-
1,2,3-(NH)-Triazoles. Org. Lett. 2008, 10, 1493-1496.
9. (a) Roque, D. R.; Neill, J. L.; Antoon, J. W.; Stevens, E. P. Synthesis of 1,2,3-Triazoles by
Cycloadditions of Azides with Enol Ethers. Synthesis. 2005, 2497-2502. (b) Quiclet-Sire, B.;
Zard, S. Z. The Synthesis of 1,2,3-Triazoles from Nitroalkenes-Revisited. Synthesis. 2005,
3319-3326. (c) Ponpandian, T.; Muthusubramanian, S.; Rajagopal, S. Sequential [3+2]
ACS Paragon Plus Environment
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ACS Combinatorial Science
Page 14 of 15
1
2
3
4
Cycloaddition/Air Oxidation Reactions: Triazoloyl Ion Assisted Oxidative Cleavage of
5
6
Alkynes. Eur. J. Org. Chem. 2013, 3974-3977.
7
8
9
10. (a) Lutz, J. Copper-Free Azide-Alkyne Cycloadditions: New Insights and Perspectives.
Angew. Chem. Int. Ed. 2008, 47, 2182-2184. (b) Jewett, J. C.; Bertozzi C. R. Cu-Free Click
Cycloaddition Reactions in Chemical Biology. Chem. Soc. Rev. 2010, 39, 1272-1279. (c)
Prescher, J. A.; Bertozzi, C. R. Chemistry in Living Systems. Nature Chem. Bio. 2005, 1, 13-
21.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11. (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Synthesis of Triazoles from Nonactivated
Terminal Alkynes via the Three-Component Coupling Reaction Using a Pd(0)-Cu(I)
Bimetallic Catalyst. J. Am. Chem. Soc. 2003, 125, 7786-7787. (b) Li, J.; Wang, D.; Zhang, Y.;
Li, J.; Chen, B. Facile One-Pot Synthesis of 4,5-Disubstituted 1,2,3-(NH)-Triazoles through
Sonogashira Coupling/1,3-Dipolar Cycloaddition of Acid Chlorides, Terminal Acetylenes,
and Sodium Azide. Org. Lett. 2009, 11, 3024-3027. (c) Gao, Y.; Lam, Y. [3+2]
Cycloaddition Reactions in the Solid-Phase Synthesis of 1,2,3-Triazoles. Org. Lett. 2006, 8,
3283-3285. (d) Kalisiak, J; Sharpless, K. B.; Fokin, V. V. Efficient Synthesis of 2-
Substituted-1,2,3-triazoles. Org. Lett. 2008, 10, 3171-3174. (e) Ponpandian, T.;
Muthusubramanian, S. Tandem Knoevenagel-[3+2] cycloaddition-elimination reactions: one-
pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles. Tetrahedron Lett. 2012, 53, 59-63.
12. (a) Syamala, M. Recent Progress in Three-Component Reactions. Org. Prep. Proced. Int.
2009, 41, 1-68. (b) D’Souza, D. M.; Mueller, T. J. J. Multi-Component Syntheses of
Heterocycles by Transition-Metal Catalysis. Chem. Soc. Rev. 2007, 36, 1095-1108. (c)
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Page 15 of 15
ACS Combinatorial Science
1
2
3
4
Kakuchi, R.; Theato, P. Three-Component Reactions for Post-Polymerization Modifications.
5
6
ACS Macro Lett. 2013, 2, 419-422.
7
8
9
13. (a) Jin, G.; Zhang, J.; Fu, D.; Wu, J.; Cao, S. One-Pot Three-Step Synthesis of 1,4,5-
Trisubstituted 1,2,3-Triazoles Starting from Primary Alcohols. Eur. J. Org. Chem. 2012,
5446-5449. (b) Friscourt, F.; Boons, G. One-Pot Three-Step Synthesis of 1,2,3-Triazoles by
Copper-Catalyzed Cycloaddition of Azides with Alkynes formed by a Sonogashira Cross-
Coupling and Desilylation. Org. Lett. 2010, 12, 4936-4939. (c) Pokhodylo, N. T.; Matiychuk,
V. S.; Obushak, M. D. One-Pot Multicomponent Synthesis of 1-Aryl-5-Methyl-N-R2-1H-
1,2,3-Triazole-4-Carboxamides: An Easy Procedure for Combinatorial Chemistry. J. Comb.
Chem. 2009, 11, 481-485. (d) Thomas, J.; John,J.; Parekh, N.; Dehaen, W. A Metal-Free
Three-Component Reaction for the Regioselective Synthesis of 1,4,5-Trisubstituted 1,2,3-
Triazoles. Angew. Chem. Int. Ed. 2014, 53, 10155-10159. (e) Francisco, A.; Yanina, M.;
Gabriel, R.; Miguel, Y. Copper-Catalysed Multicomponent Click Synthesis of 5-Alkynyl
1,2,3-Triazoles under Ambient Conditions. Synlett. 2012, 23, 2179-2182.
10
11
12
13
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17
18
19
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25
26
27
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35
36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14. (a) Yang, J.; Yin, W.; Liu, R.; Chu, C. Facile Synthesis of 4,5-Disubstituted 2H-1,2,3-
Triazoles by Catalyst-free Cycloaddition between Substituted Vinyl Sulfones and Sodium
Azide under Ambient Conditions. Chin. J. Chem. 2012, 30, 2786-2790. (b) Yang, J.; Yin, W.;
Liu, R.; Chu, C. Ti(Oi-Pr)4 Mediated Olefination between Julia Reagent and Aldehydes under
Mild Conditions: Facile Synthesis of Vinyl Sulfones. J. Chin. Chem. Soc. 2013, 60, 412-417.
Notes: Both sodium azide and ammonium azide are very explosive compounds, which should be
handled with great care.
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