Pd-catalyzed regioselective arylation on the C-5 position of N-aryl 1,2,3-triazoles

Article abstract of DOI:10.1021/jo5026145

We herein report a highly efficient method for the arylation at the C-5 position of N-aryl 1,2,3-triazoles via a direct palladium catalyzed arylation reaction. The optimal reaction conditions required a combination of Pd(OAc)₂ and tris(o-tolyl)

Full text of DOI:10.1021/jo5026145

Subscriber access provided by Purdue University Libraries
Article
Pd-catalyzed reigoselective arylation on C-5 position of N-aryl 1,2,3-Triazoles
K. Durga Bhaskar Yamajala, Shaibal Banerjee, and Mahendra Patil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5026145 • Publication Date (Web): 24 Feb 2015
Downloaded from http://pubs.acs.org on March 2, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 25
The Journal of Organic Chemistry
1
2
3
4
Pd-catalyzed Reigoselective Arylation on C-5 position of N-aryl 1,2,3-
5
6
7
8
Triazoles
K. Durga Bhaskar Yamajala1, Mahendra Patil*2 and Shaibal Banerjee∗1
1Department of Applied Chemistry, Defence Institute of Advanced Technology (DU), Girinagar,
Pune-411025, India.
9
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
2Department of Chemistry, Centre for Excellence in Basic Sciences, Health Centre, University of
Mumbai, Vidyanagari Campus, Kalina, Santacruz(E), Mumbai 400098, India
∗Author for Correspondence: Tel: +91-20-24304164, Fax: +91-20-24389411
E-mail: shaibal.b2001@gmail.com, mahendra.patil@cbs.ac.in
TOC graphics
Abstract:
We herein report a highly efficient method for the arylation at C-5 position of N-aryl 1,2,3-
Triazoles via a direct palladium catalyzed arylation reaction. The optimal reaction conditions
required a combination of Pd(OAc)2 and tris(o-tolyl)phosphine as catalyst, Cs2CO3 as the
base under inert atmosphere. A variety of C-5 substituted N-aryl 1,2,3-Triazoles were
prepared using these conditions with yields in the 70-88% range. Regioselective C-5
arylations were also performed on 1,4-disubstituted 1,2,3-triazoles. The regioselectivity in
triazole substitution at C-5 position was confirmed by single crystal XRD. In addition,
computational investigations of key steps of the catalytic cycle using the density functional
theory (DFT) have provided the rationale for the selective C-5 arylation of N-aryl 1,2,3-
Triazoles.
Key words: Triazoles, arylation, catalysis, DFT calculations, C-5 regioselectivity
Page 1 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
5
6
Introduction
7
8
9
1,2,3-Triazoles and its derivative have a wide range of applications in biological science as
HIV protease inhibitors, anti cancer drugs (like 1,2,3-triazolo[4,5-d] pyrimidines),
antituberculosis drugs, antifungal agents, antibacterial drugs (like 5-(4-methyl-1,2,3-
triazole)methyl oxazolidinones) as well as in material science as energetic materials,
lubricants, dyes and photostabilisers.1,2 Unique properties of 1,2,3-triazole such as rigidity
and stability of triazole core in vivo, hydrogen bonding capability, dipole moment are
considered as decisive factors for their improved biological activity.3 Owing to the
importance of triazole compounds especially in biological sciences, various synthetic
approaches for the construction of triazole have been developed in the recent years.4 For
instances, Hüisgen’s 1,3-dipolar [3+2]-cycloaddition of azides and alkynes is one of the
popular methods for the synthesis of triazole core.5 Generally towards the synthesis of 1,2,3-
triazoles, chemists have either used commercially available alkynes or prepared in-situ
alkynes by typical procedures.6 However, these methods usually provide a mixture of
regioisomeric products and require a strong electron withdrawing group on the alkyne
moiety. Besides, these methods have limited scope for substitution at post-triazole stage and
also the choice of substituents depends on the feasibility of cycloaddition. Consequently,
significant efforts have been undertaken towards regioselective synthesis of substituted 1,2,3-
trizaoles. These methods include metallation of the triazole and subsequent addition of
electrophile,7 cross-coupling of 5-halo-1,2,3-triazoles,8 reaction of azides with bromo-
magnesium acetylides followed by addition of electrophile.9
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
Page 2 of 25
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
Reaction 1: Synthesis of C-5 substituted 1,2,3-triazole by ruthenium catalysis
4
5
6
7
8
9
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
Despite these remarkable advances, generally applicable methods for the regioselective
synthesis of substituted 1,2,3-triazoles are still desirable. Recently, Pd-catalyzed direct
arylation and heteroarylation have emerged as a valuable alternative to the conventional
methods used for the functionilzation of heterocycle.10 The direct Pd-catalyzed arylation
reactions have also shown to be efficient in functionlization of 1,2,4-triazole11 as well as 1,4-
disubstituted 1,2,3-triazole.12 However, to best of our knowledge, reports on the
regioselective arylation of 1,2,3-triazoles are extremely scanty in the literature.
Reaction 2: Synthesis of C-5 substituted 1,2,3-triazole by Pd catalysis
In this article, we describe a straightforward method for the synthesis of C-5 substituted N-
aryl 1,2,3-triazole using a direct Pd-catalyzed arylation reaction. The reactions proceeded
efficiently in the presence of catalytic amount of Pd(OAc)2 and tris(o-tolyl)phosphine to give
desired products in good yields. In addition, through DFT calculations, we have provided a
detailed explanation for the regioselective C-5 arylation of N-aryl 1,2,3-triazoles.
Results and discussion
Initial screening reactions were performed with Pd catalyst under ligand free condition (table
1), but full consumption of starting material (1a) was not observed. Thereafter, combinations
of Pd catalyst and pivalic acid medium were tried to maximise product yield. When arylation
Page 3 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
5
6
7
8
9
reaction was performed with Pd(OAc)2 (10 mol%) and phosphine ligand (PPh3) (20 mol%) it
gave enhanced yield (50%). By using the PPh3 ligand, the starting material was not consumed
totally, so that by replacing PPh3 ligand with slightly electron rich and steric ligand like
tris(o-tolyl)phophine gave good yield of the product (72%). This method was found to be
more efficient and high reigoselectivity was obtained for C-5 arylation on N-aryl substituted
1,2,3-triazole. It was found that the C-5 arylation, on mono-substituted 1,2,3-triazole with
aryl iodide in the presence of Pd(OAc)2, tris(o-tolyl)phosphine and Cs2CO3 under inert atm,
offered C-5 arylated triazoles in good yields. Changing the base to K2CO3 from Cs2CO3 did
not show any effect on the rate of reaction and offered slightly lower yield. This reaction
proceeded smoothly with electron deficient(4-nitrophenyl), electron rich (m-anisole) and
bulky (1-naphthyl) aryl iodides presumably via mechanism shown in the scheme 1.13
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
Table 1: Optimization of reaction conditions
Thus, a variety of aryl-substituted 1,2,3-triazoles, containing electron withdrawing aryl
groups and electron donating aryl groups on nitrogen, were shown to proceed to C-5 arylation
successfully (Table 1). It indicates, a variety of functional groups such as methoxy, nitro,
methyl and trifluoromethyl tolerated these conditions.
Page 4 of 25
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
By using above condition, highly reigoselective C-5 arylated triazoles were synthesized. N-
phenyl 1,2,3-triazole (1b) having two characteristic proton peaks at δ 7.86 and 8.01 ppm on
the triazole ring. After arylation on 1b with Pd catalyst, arylated product 1(ba) was obtained.
9
1
We observed that in H-NMR of 1(ba), δ 8.01 ppm peak has disappeared on triazole ring.
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
Similarly for 1,4-disubstituted 1,2,3-triazole (1h) which have only one characteristic peak on
triazole ring at δ 7.81ppm, on arylation the triazole ring proton of (1ha) peak disappeared. It
indicates the arylation occurred at C-5 position. The C-5 centre of N-aryl substituted 1,2,3-
triazole has greater nucleophilic character compared to the C-4. The electropositive nature of
C-4 was observed clearly in 1H-NMR spectra, C-4 proton have more δ value compared to C-5
15
proton, it indicates polarisable character of respective carbons. Whereas, N-NMR of 1jb, it
has showed three nitrogen peaks in the spectrum at δ -130.85 (Ν1), -31.88 (Ν2) and -17.13
(N3) respectively. It was observed that the intensity N1 peak is low as compare to other two
nitrogen atoms, because it was attached to aromatic ring and tertiary nitrogen atom. This peak
(N1) was confirmed by 15N-HMBE NMR spectra.
Table 2: C-5 arylation of N-aryl substituted 1,2,3-triazole
Page 5 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
5
6
7
8
9
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
Similarly, by using this same condition on 1,4-disubstituted 1,2,3-triazole, C-5 arylation was
achieved in good yields (Table 3). It can be inferred that this reaction even works smoothly at
highly hindered substitutions in the vicinity of C-5. It showed the C5 centre more favourable
site for arylation in comparison to C-4.
Page 6 of 25
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
4
Table 3: Arylation on C-5 position of 1,4-disubstituted 1,2,3-triazole
5
6
7
8
9
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
The proposed catalytic cycle for the Pd-catalyzed arylation of N-aryl 1,2,3-triazole is shown
in the Scheme 1. 13,14 In the first step, phosphine ligand reduces the Pd(II) species to Pd (0)
active species (A), subsequently, aryl palladium intermediate (B) is generated through
oxidative addition of aryl iodide to Pd(0). The coordination of base to intermediate (B)
followed by C-H bond activation via CMD pathway gives tri-coordinated Pd intermediate.
Reductive C–C coupling in the final step affords a desired C-5 arylated triazole by releasing
the Pd (0) species to complete the catalytic cycle.
Page 7 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
Pd(II)
R
4
5
6
7
N N
ArX
N
Ar
Pd(0)L
R1
A
8
Ar-Pd(L)-X
B
9
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
Cs2CO3
CsI
L
Ar Pd
L
R1
R
N
Ar Pd
O
N
N
O
O
Cs
C
L
CsHCO3
O
H
Ar Pd
O
R
R
N
N
N
O
R1
H
Cs
N
N
N
R1
R= Aryl groups
R1= H, alkyl or aryl
CMD Transition state
Scheme 1: Proposed catalytic cycle for the Pd catalyzed arylation of N-aryl 1,2,3-triazole.
The C-5 arylated triazole structure was confirmed by single crystal XRD (ccdc deposited
number CCDC 1032133). In the crystal structure of the 1fa shown in the figure 1, the two
substituents are placed on vicinal atoms (N-1 & C-5) and away from the each other in the
same plane of the triazole ring. It indicates the new C5-C6 bond has been formed between
triazole carbon (C-5) and aryl iodide (C-6). The bond length of C-C bond is 1.47 A° and bond
angle between C-C-C and C-C-N are 128.56° & 127.72° respectively. The central triazole
ring appears planar without much distortion because of remote spatial orientation of the
substituents.
Page 8 of 25
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
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
Figure 1. ORTEP single crystal XRD of 1fb
Computational Studies
The Pd-catalyzed arylation reaction described in this work is highly regioselective and
provides C-5 substituted 1,2,3 triazole as a major product. To gain better insights into the
origin of the regioselectivity of the reaction, computational investigations on key steps of the
catalytic cycle shown in the scheme 1 were carried out using the DFT methods. To save
computational time, we have considered trimethyl phosphine Pd(Pd-PMe3) instead of tris(o-
tolyl)phosphine Pd as a Pd(0) active species and triazole 1b as a model substrate for our
calculations. Experimentally, tris(o-tolyl)phosphine is used as a ligand. The bulkiness of
tri(o-tolyl)phosphine may prevent double or more coordination to the palladium in the
catalytic cycle. So we restricted our calculations to a mono-trimethyl phosphine Pd(0) active
species. All energies are calculated relative to preceding intermediate as well as separated
reactants. The calculated free energies and activation free energies of intermediates and
transition states, respectively, obtained at the M06L levels are summarized in the scheme 2.
Page 9 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
5
6
7
8
9
Ph
N
PMe3
PMe3
Pd
Cs2CO3
PhI
PMe3
Pd
N
N
Pd
O
Ph
O
Ph
O
Me3P-Pd
H
TS(A
B)
∆
G = 0.3 (-12.0)
Ph
I
∆
G = -36.0 (-72.0)
O
O
Ph
A
CsI
O
B
N
∆
G = -8.8 (-36.0)
Cs
Cs
N
N
C
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
D
TS(DC4
E)
TS(DC5
F)
∆
G = 25.8(-46.2)
∆
G = 30.2(-41.0)
PMe3
PMe3
Pd
PMe3
O
Pd
Ph
O
Ph
Pd
Ph
O
-CsHCO3
HO
O
N
∆
G = 28.8 (-33.7)
Ph
HO
Cs
N
N
N
N
Cs
N
N
N
N
Ph
F
E
Ph
I)
G
TS(G
∆
G = 34.1 (-38.8)
-CsHCO3
Me3P-Pd
∆
G = 5.0(-28.8)
PMe3
Pd
Ph
Me3P-Pd
Ph
Ph
Ph
N
N
Ph
N
TS(H
J)
N
N
N
N
∆
G = 6.9(-31.9)
N
N
Ph
C-4 arylated Triazole
I
J
H
C-5 arylated Triazole
Scheme 2. Intermediates involved in the Pd-catalyzed arylation of N-aryl 1,2,3 triazole. Free
energies and activation free energies computed relative to preceding reacting complexes or
intermediate are shown. Parenthesise values indicate free energies and activation free
energies computed relative to separated Pd active species A, 1b, iodobenzene and Cs2CO3
On the basis of catalytic cycle shown in the scheme 1, Pd-catalyzed arylation involves four
key steps namely, oxidative addition, ligand exchange, C-H bond activation and reductive
elimination. We began our computational investigation with oxidative addition of
iodobenzene to mono-ligated trimethylphosphine Pd active species (A). Initial coordination
of iodobenzene to A leads to an intermediate in which, Pd coordinates to C–I bond of
iodobenzene. The initial coordination of iodobenzene to A is predicted to be exoergic by 12.3
Page 10 of 25
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
kcal/mol. Intermediate undergoes oxidative addition via TS(A→B) to afford a three
coordinated Pd species (B) with a marginal barrier of 0.3 kcal/mol. Prior to deprotonation
7
8
2-
step, it is expected that carbonate ion (CO3 ) coordinates to the B by replacing halide ion.
9
The substitution of I- by carbonate ion in B provides tetra-coordinated Pd intermediate C, and
the process of halide exchange by carbonate ion in B is found to be exoergic by 8.8 kcal/mol.
Next step involves an entry of substrate 1b in the catalytic cycle. The coordination of 1b to C
leads to η1 – C – Pd coordinated complex D which further enables deprotonation of C4 / C5
proton of 1b presumably assisted by C-H bond activation. The mechanism of Pd catalyzed
reactions involving C–H bond activation has been extensively investigated using
computational methods, and four different routes have been proposed for the C–H bond
activation which includes oxidative addition of C- H bond, electrophilic aromatic
substitution, concerted metallation-deprotonation (CMD) and σ-bond metathesis pathway.15
In most of the reactions, CMD pathway represents the preferred pathway for the C–H bond
activation and deprotonation step.16 In present reaction also, the CMD route for the
deprotonation of C-4 or C-5 proton of 1b seems to be relevant pathway since it involves the
coordination of base (carbonate) to the Pd complex. Transition states (TSs) for the
deprotonation of C-4 (TS(DC4→E)) and C-5 proton (TS(DC5→F)) of substrate 1b
corresponding to CMD pathway were located at the M06L level and shown in the figure 2.
The computed activation barrier (30.2 kcal/mol) for the TS(DC4→E) is found to be higher
compared to the barrier (25.8 kcal/mol) for the TS(DC5→F). Calculations clearly favour the
deprotonation at the C-5 position of 1b which is in accordance with the experimental
observations.
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
Page 11 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
4
5
6
7
8
9
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
TS(DC4→E)
TS(DC5→F)
Figure 2. C–H activation transition states corresponding to CMD pathway.
The optimized structures of transition states TS(DC4→E) and TS(DC5→F) are provide in
Figure 2. It is noticed that the formation of Pd····C(substrate) bond and the cleavage of
C····H bond occur in a fairly concerted manner as can be seen from the corresponding
distances (2.35 and 1.38 Å in TS(DC4→E); 2.29 and 1.30 Å in TS(DC5→F) ). These TSs are
further confirmed by the intrinsic reaction coordinate (IRC) calculations. It has been shown
that the interaction between catalyst and substrate and distortion in structures of catalyst and
substrate at the CMD transition state can be crucial factors in controlling selectivity of
reaction.17 Hence, to identify the contribution of distortion and interaction energies of Pd-
complex C (catalyst) and 1b(substrate), distortion/interaction analysis was performed on the
TS(DC4→E) and TS(DC5→F). In this approach, the interaction energy Eint between C and 1b
in the transition state and the distortion energies Edis associated with C and 1b in the
transition states compared to their ground state geometries were evaluated. Results of
distortion/interaction analysis are summarized in Figure 2. The interaction energy (Eint) at the
TS(DC4→E) is found to be 14.2 kcal/mol higher than the interaction energy (Eint) at the
TS(DC5→F). However, the stabilizing interactions is compensated by the high distortion
energies of C and 1b in the TS(DC4→E). The total distortion energy (Edis) associated with
Page 12 of 25
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
TS(DC4→E) is estimated to be 19.5 kcal/mol higher than the total distortion energy (Edis)
associated with TS(DC5→F). Overall, deprotonation in the TS(DC5→F) is more favourable
than the deprotonation in TS(DC4→E) mainly because of lower degree of distortions in C and
substrate 1b at the TS(DC5→F) as compared to their ground state geometries.
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
In the next step, the intermediates E and F release CsHCO3 to form tri-coordinated Pd
complexes G and H, respectively. Finally, reductive C–C coupling occurs in G and H via
three membered transition states (TS(G→I) and TS(H→J)) to release the C-4 and C-5
arylated triazole, respectively. The computed barriers for this step are less than 7 kcal/mol.
After releasing arylated product, the active catalytic species Pd(0)L is regenerated to
complete the catalytic cycle.
Conclusion
We have demonstrated a straightforward method for the synthesis of C-5 substituted N-aryl
1,2,3-triazoles. By using combination of Pd(OAc)2 and tris(o-tolyl)phosphine as catalyst,
arylation of N-aryl 1,2,3-triazole have been achieved regiospecifically at the C-5 position of
triazoles. The scope of this method further extended for the arylation of 1,4-disubstituted
1,2,3-trizaole. The origin of C-5 selectivity of the reaction has been revealed by means of
theoretical investigations of catalytic cycle of the reaction, results of which are in agreement
with experimental outcomes. The distortion/interaction analysis on the CMD transition states
suggested that energetic cost associated with the distortion of substrate and Pd-catalyst at the
transition state can be a crucial factor in discrimination of two transition states which leads to
the isomeric products.
Page 13 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
Experimental section:
4
5
6
7
8
9
General procedure: A solution of azide (1.00 eq) and Trimethysilyl (TMS)-acetylene (1.5 eq)
were taken in MeOH/H2O (1:1 ratio 5 mL) in 50 mL round bottom flask. CuSO4 (0.1 eq),
Sodium Ascorbate (0.2 eq) and K2CO3 (2.0 eq) were added and then reaction mixture was
closed tightly with stopper and stirred rapidly for 24 hr. Upon completion of reaction, the
reaction mixture was diluted with EtOAc and the organic layer was separated. This was
washed with water, brine and dried over Na2SO4. The filtrate was concentrated under
vacuum, afforded crude product. The crude product was purified by column chromatography
by using silica gel (100-200 mesh) with hexane: EtOAc as elutant.
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
By using above mentioned procedure the following triazoles compounds from 1a to 1j were
prepared.
1-(4-nitrophenyl)-1H-1,2,3-triazole23 (1a): Yield: 245 mg (70%), H NMR (300MHz, δ
1
13
ppm 7.93 (s, 1 H) 8.02 (d, J=9.06 Hz, 2 H) 8.14 (s, 1 H) 8.45 (t, J=1.00 Hz, 2 H). C NMR
(126MHz, CDCl3); δ ppm 120.8, 121.8, 125.8, 135.5, 141.4. IR (Neat, cm-1): 2918, 2850,
1596, 1515, 1335, 1234, 1027, 851.
1
1-phenyl-1H-1,2,3-triazole23 1(b): Yield: 390 mg (68%), H NMR (500MHz, CDCl3), δ
ppm 7.45 ppm (s, 1 H). 7.51 - 7.56 (m, 2 H), 7.75 (dd, J=1.1 Hz, 8.7, 2 H), 7.86 (d, J=0.9
13
Hz, 1 H), 8.00 (d, J=1.2 Hz, 1 H), C NMR (126MHz, CDCl3); δ ppm 120.9, 121.9, 128.9,
129.9, 134.6, 137.2.
1
1-(p-tolyl)-1H-1, 2, 3-triazole24 (1c): Yield: 369 (62%), H NMR (500MHz, CDCl3), δ ppm
2.42 (s, 3 H) 7.32 (d, J =8.41 Hz, 2 H) 7.59 - 7.64 (m, 2 H) 7.83 (d, J =1.01 Hz, 1 H) 7.95
13
(d, J =1.01Hz, 1 H). C NMR (126MHz, CDCl3); δ ppm 21.3, 120.8, 121.9, 130.44, 134.5,
134.9, 139.0. IR (Neat, cm-1): 3129, 2991, 1737, 1518, 1319, 1113, 1039, 809.
1
4-(1H-1, 2, 3-triazol-1-yl)pyridine (1e): Yield: 218 mg (71%), H NMR (500MHz,
CDCl3); δ ppm 7.78 - 7.73 (m, 2 H), 7.91 (d, J = 1.3 Hz, 1 H), 8.12 (d, J = 1.3 Hz, 1 H),
8.83 - 8.78 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 114.0, 121.3, 135.3,143.2, 151.9.
1
1-(4-(trifluoromethyl)phenyl)-1H-1, 2, 3-triazole25 (1f): Yield: 220 mg (52%), H NMR
(500MHz, CDCl3); δ ppm 7.67 - 7.76 (m, 2 H) 7.90 (d, J =0.92 Hz, 1 H) 7.97 - 8.01 (m, 1 H)
8.05 (d, J =0.61 Hz, 1 H) 8.07 (d, J=1.22 Hz, 1 H). 13C NMR (126MHz, CDCl3); δ ppm
117.3, 117.8, 121.7, 123.7, 125.3 - 125.6, 130.6, 134.9, 137.4. IR (Neat, cm-1): 3128, 2924,
2854, 1486, 1339, 1235, 1173, 1034, 895.
Page 14 of 25
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1-(3-methoxyphenyl)-1H-1, 2, 3-triazole25 (1g): Yield: 185 mg (63%), H NMR (500MHz,
CDCl3); δ ppm 3.89 (s, 3 H), 6.98 (ddd, J = 0.8, 2.5, 8.4 Hz, 1 H), 7.29- 7.25 (m, 1 H), 7.36
(t, J = 2.3 Hz, 1 H), 7.45 - 7.39 (m, 1 H), 7.84 (d, J = 1.0 Hz, 1 H), 7.99 (d, J = 1.2 Hz, 1
H). 13C NMR (126MHz, CDCl3); δ ppm 55.6, 106.5, 112.5, 114.6, 121.8, 130.5, 134.4, 138.1,
160.6. IR (Neat, cm-1): 3126, 2924, 2852, 1607, 1455, 1164, 1124, 1097, 1031, 992,
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
1
4-cyclopropyl-1-phenyl-1H-1,2,3-triazole 1(h): Yield: 373 mg (65%), H NMR (500MHz,
CDCl3) : δ ppm 1.02 - 0.96 (m, 2 H), 1.10 - 1.04 (m, 2 H), 2.07 (m, 1 H), 7.81 (s, 1 H),
7.99 - 7.94 (m, 2 H), 8.44 - 8.39 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 6.7, 8.0,
113.39, 117.6, 120.1, 125.5, 126.4, 141.3, 147.0, 152.0. IR (Neat, cm-1): 3097, 3003, 2923,
2852, 1595, 1512, 1408, 1223, 1110, 854. HRMS: [M+H]+: Calculated for C11H11N4O2 :
231.0882 found 231.0899
1-(naphthalen-1-yl)-1H-1,2,3-triazole26 (1i): Yield: 569 mg (66%), H NMR (500MHz,
1
CDCl3); δ ppm 7.53 - 7.62 (m, 5 H) 7.94 - 7.99 (m, 3 H) 8.04 (brs. 1 H). 13C NMR
(126MHz, CDCl3) δ ppm 122.3, 123.6, 125.01, 126.3, 127.11, 127.9, 128.3, 128.7, 130.4,
133.8, 134.1. IR (Neat, cm-1): 3125, 2925, 2855, 1598, 1471, 1312, 1228, 1018, 772.
1-(naphthalen-1-yl)-4-phenyl-1h-1,2,3-triazole27 (1j): Yield : 801 mg (81%), H NMR
1
(500MHz, CDCl3); δ ppm 7.38 - 7.44 (m, 1 H) 7.51 (t, J =7.74 Hz, 2 H) 7.55 - 7.69 (m, 4 H)
7.73 (d, J =7.74 Hz, 1 H) 7.96 - 8.03 (m, 3 H) 8.06 (d, J =8.08 Hz, 1 H) 8.18 (s, 1 H). C
NMR (126MHz, CDCl3); δ ppm 122.5, 123.7, 125.1, 125.9, 127.2, 128.0, 128.4, 128.5,
128.6, 129.1, 130.4, 130.6, 133.8, 134.3, 147.8. IR (Neat, cm-1): 3134, 2944, 1600, 1426,
1378, 1074, 1025, 910.
13
General procedure for the synthesis of compounds 1,4-dsubstituted of 1,2,3-triazoles: To
a dried 2-neck round bottom flask, were added mono-substituted 1,2,3-triazole (1.0 eq), aryl
iodide (1.2 eq), Cs2CO3 (2.0 eq) and tris(o-tolyl)phosphine (20 mol%) and DMF (3.0 mL).
Then reaction mixture was degassed for 10 min at room temperature. After that Pd(AcO2)2
(10 mole%) was added to the reaction mixture and closed reaction setup was put under N2
atmosphere. The reaction mixture (RM) was stirred at room temperature for 5 min, and then
heated slowly upto 100°C for 20 hr. RM was periodically monitored by TLC. After
completion of reaction, the RM was diluted with EtOAc and washed with water (twice), the
organic layer was separated and again washed with brine solution. The organic layer was
Page 15 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
4
5
6
7
8
dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum,
afforded crude product. The crude product was purified by column chromatography by using
silica gel (100-200 mesh) with hexane: EtOAc as eluant.
9
By using above mentioned procedure the following triazole compounds from 1aa to 1jb were
prepared.
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
1-(4-nitrophenyl)-5-phenyl-1H-1,2,3-triazole28(1aa): Yield: 101 mg (72%) , M. P. ; 157 -
160 °C; 1H NMR (500MHz, CDCl3); δ ppm 7.23 - 7.26 (m, 2 H) 7.39 - 7.49 (m, 3 H) 7.55 -
13
7.62 (m, 2 H) 7.89 (s, 1 H) 8.26 - 8.36 (m, 2 H). C NMR (126MHz, CDCl3); δ ppm 125.1,
125.5, 126.3, 128.9, 129.5, 130.2, 134.4, 138.2, 141.5, 147.7. IR (Neat, cm-1): 3082, 2924,
2857, 1600, 1517, 1343, 1237, 1040, 983, 851. HPLC (20% Acetonitile in water, flow rate
0.5 mL/min) tR = 15.00 min (major).
1,5-bis(4-nitrophenyl)-1H-1,2,3-triazoles29(1ab): Yield: 107 mg (69%), M.P. : 187 -190 °C;
1H NMR (500MHz, CDCl3); δ ppm 7.45 - 7.48 (m, 2 H) 7.57 - 7.60 (m, 2 H) 8.01 (s, 1 H)
8.28 - 8.31 (m, 2 H) 8.35 - 8.38 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 124.7, 125.5,
125.7, 129.8, 132.5, 135.1, 148.1, 148.6. IR (Neat, cm-1): 3108, 2922, 1342, 1108, 1038, 981,
849. [M+H]+: Calculated for C14H9N5O4: 312.0733 found 312.0734. HPLC (20% Acetonitile
in water, flow rate 0.5 mL/min) tR = 10.05 min (minor),11.5 min (major).
5-(3-methoxyphenyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (1ac): Yield: 109 mg (72%),
M.P. : 96 -98 °C; 1H NMR (500MHz, CDCl3); δ ppm 3.78 (s, 3 H), 6.82 -6.77 (m, 2 H), 7.01
- 6.97 (m, 1 H), 7.33 (s, 1 H), 7.63 - 7.59 (m, 2 H), 7.89 (s, 1 H), 8.31 (d, J = 9.1 Hz, 2 H).
13C NMR (126MHz, CDCl3); δ ppm 55.6, 114.8, 115.3, 117.5, 121.2, 125.0, 125.4, 130.6,
134.4, 138.1, 141.5, 147.7, 160.2. IR (Neat, cm-1): 3012, 2924, 2853, 1590, 1342, 1227,
1111, 853. [M+H]+: Calculated for C15H12N4O3 : 297.0988 found 297.0985. Anal. Calcd for
C15H12N4O3: C, 60.81; H, 4.08; N, 18.91. Found: C, 59.90; H, 4.1; N, 18.58.
5-(naphthalen-1-yl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (1ad): Yield: 198 mg (80%), M.P.
: 131 – 134 °C 1H NMR (500MHz, CDCl3): δ ppm 7.40 (dd, J=7.0, 1.2 Hz, 1 H), 7.45 - 7.50
(m, 1 H), 7.50 - 7.53 (m, 2 H), 7.53 - 7.59 (m, 3 H), 7.96 (d, J=8.2 Hz, 1 H), 8.01 (s, 1 H),
8.03 (d, J=8.2 Hz, 1 H), 8.12 - 8.17 (m, 2 H). 13C NMR (126MHz, CDCl3): δ ppm 123.7
124.0, 124.3, 124.8, 125.3, 127.0, 127.7, 128.9, 129.0, 130.9, 131.4, 133.7, 136.1, 141.3,
147.2. IR (Neat, cm-1): 3058, 2934, 2854, 1597, 1474, 1232, 1015, 962, 802. Anal. Calcd for
C18H12N4O2: C, 68.35; H, 3.82; N, 17.71; O, 10.12. Found: C,67.92; H, 3.83, N, 17.63.
1
1,5-diphenyl-1H-1,2,3-triazole30 (1ba) 154: Yield: 111 mg (76%), M.P. : 109 – 112 °C; H
NMR (500MHz, CDCl3); δ ppm7.21 - 7.25 (m, 2 H) 7.33 - 7.36 (m, 1 H) 7.36 - 7.39 (m, 4
H) 7.43 - 7.46 (m, 3 H) 7.87 (s, 1 H). 13C NMR (126MHz, CDCl3); δ ppm 125.4, 126.9,
Page 16 of 25
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
128.8, 129.1, 129.4, 129.6, 133.6, 136.8, 137.9. IR (Neat, cm-1): 3061, 2923, 1596, 1493,
1452, 1233, 1128, 984, 835. HPLC (20% Acetonitile in water, flow rate 0.5 mL/min) tR =
12.86 min (major),17.88 min (minor).
6
7
8
9
5-(4-nitrophenyl)-1-phenyl-1H-1,23-triazole31 (1bb): Yield: 135 mg (75%); M.P.: 139 -141
°C; 1H NMR (500MHz, CDCl3); δ ppm 7.33 - 7.37 (m, 2 H) 7.40 - 7.43 (m, 2 H) 7.46 - 7.52
(m, 3 H) 7.99 (s, 1 H) 8.19 - 8.22 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 124.3, 125.5,
129.5, 129.9, 130.1, 133.2, 134.4, 135.8, 136.2, 148.1. HPLC (20% Acetonitile in water, flow
rate 0.5 mL/min) tR = 7.13 min (major).
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
1
5-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1ca) : Yield 119 mg (82%); M.P.:75 -77 °C; H
NMR (500MHz, CDCl3); δ ppm 2.40 (s, 3 H) 7.22 - 7.25 (m, 6 H) 7.33 - 7.37 (m, 3 H) 7.85
13
(s, 1 H). C NMR (126MHz, CDCl3); δ ppm 21.4, 125.2, 127.1, 128.8, 129.0, 129.3, 130.1,
133.5, 134.3, 137.8, 139.5. IR (Neat, cm-1): 2922, 2857, 1452, 1276, 1232, 1044, 984, 823.
HPLC (20% Acetonitile in water, flow rate 0.5 mL/min) tR = 11.27 min (major),14.71 min
(minor).
5-(4-nitrophenyl)-1-(p-tolyl)-1H-1,2,3-triazole (1cb): Yield: 117 mg (66%); M.P. : 71 -73
°C, 1H NMR (500MHz, CDCl3); δ ppm 2.40 - 2.47 (m, 3 H) 7.20 - 7.25 (m, 2 H) 7.26 - 7.30
(m, 2 H) 7.39 - 7.44 (m, 2 H) 7.98 (s, 1 H) 8.19- 8.23 (m, 2 H). 13C NMR (126MHz,
CDCl3); δ ppm 21.4, 124.3, 125.3, 129.4, 130.5, 133.4, 133.7, 134.2, 135.8, 140.4, 148.1., IR
(Neat, cm-1): 3114, 2921, , 1334, 1230, 1192, 1037, 986, 809. [M+H]+: Calculated for
C15H12N4O2: 281.1039 found 281.1033. HPLC (20% Acetonitile in water, flow rate 0.5
mL/min) tR = 11.16 min (major),13.2 min (minor).
1
5-(3-methoxyphenyl)-1-(p-tolyl)-1H-1,2,3-triazole (1cc): Yield: 123 mg (72%); H NMR
(500MHz, CDCl3); δ ppm 2.40 (s, 3 H) 3.70 (s, 3 H) 6.75 (dd, J =2.44, 1.53 Hz, 1 H) 6.79 -
6.82 (m, 1 H) 6.90 (ddd, J =8.39, 2.59, 0.92 Hz, 1 H) 7.23 - 7.27 (m, 5 H) 7.85 (s, 1 H). 13C
NMR (126MHz, CDCl3); δ ppm 21.4, 55.4, 114.3, 114.9, 120.8, 121.1, 125.2, 128.2, 130.1,
133.5, 134.4, 137.7, 139.6, 159.8. [M+H]+: Calculated for C16H15N3O: 266.1293 found
266.1301. HPLC (20% Acetonitile in water, flow rate 0.5 mL/min) tR = 5.00 min (major)
5-phenyl-1-(o-tolyl)-1H-1,2,3-triazole32 (1da) : Yield: 109 mg (75%); M.P. : 71 -73 °C; 1H
NMR (500MHz, CDCl3); δ ppm 1.96 (s, 3 H), 7.20 - 7.16 (m, 2 H), 7.34 - 7.27 (m, 6 H),
13
7.44 - 7.40 (m, 1 H), 7.95 (s, 1H). CNMR(126MHz, CDCl3); δ ppm 17.7, 126.8, 127.2,
127.8, 129.0, 129.3, 130.0, 130.3, 131.5, 132.5, 135.4, 136.1, 138.8. IR (Neat, cm-1): 3055,
2924, 2858, 1492, 1231, 1122, 984, 834. HPLC (20% Acetonitile in water, flow rate 0.5
mL/min) tR = 13.75 min (major),19.65 min (minor).
4-(5-phenyl-1H-1,2,3-triazole-1-yl)pyridine33 (1ea): Yield: 121 mg (84%); M.P. : 199 -201
1
°C; H NMR (500MHz, CDCl3); δ ppm 7.31 - 7.26 (m, 2 H), 7.38 - 7.35 (m, 2 H), 7.51 -
7.43 (m, 3 H), 7.88 (s, 1 H), 8.76 - 8.68 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 118.3,
126.2, 128.8, 129.3, 129.9, 134.4, 137.8, 143.4, 151.3. IR (Neat, cm-1): 2922, 2852, 1587,
Page 17 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
5
1452, 1406, 1224, 1132, 1049. HPLC (20% Acetonitile in water, flow rate 0.5 mL/min) tR =
3.5 min (minor), 6.3 min (major).
6
7
8
9
5-phenyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (1fa): Yield: 109 mg (81%);
1
M.P. : 110 -113 °C; H NMR (500MHz, CDCl3); δ ppm 7.20 - 7.25 (m, 2 H) 7.34 - 7.44 (m,
3 H) 7.49 - 7.58 (m, 2 H) 7.67 - 7.73 (m, 2 H) 7.85 - 7.89 (m, 1H). 13C NMR (126MHz,
CDCl3); δ ppm 122.05, 122.3, 125.8, 126.1, 126.4, 128.2, 128.8, 129.3, 129.8, 130.2, 132.1,
132.3, 133.9, 137.1, 138.0. 19F NMR (376MHz, CDCl3): δ ppm -62.95; IR (Neat, cm-1):
3068, 2924, 2855, 1601, 1520, 1462, 1262, 1170, 1063. [M+H]+: Calculated for C15H10F3N3:
290.0827 found 231.0819. Anal. Calcd for C15H10F3N3: C, 62.28; H, 3.48; N, 14.53.
Found: C, 62.00; H, 3.12; N, 14.17.
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
5-(4-nitrophenyl)1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (1fb): Yield: 110 mg (
1
71%); M.P. : 133 -136 °C; H NMR (500MHz, CDCl3); δ ppm 7.41 - 7.46 (m, 2 H) 7.49 (d,
J =7.93 Hz, 1 H) 7.62 (t, J =7.93 Hz, 1 H) 7.75 (s, 1 H) 7.77 - 7.81 (m, 1 H) 8.01 (s, 1 H)
13
8.24 - 8.29 (m, 2 H). C NMR (126MHz, CDCl3); δ ppm 122.4, 124.5, 126.7, 128.3, 129.6,
19
130.6, 134.7, 136.0, 136.6, 148.4. F NMR (376MHz, CDCl3): δ ppm -62.95; IR (Neat, cm-
1): 3061, 2924, 2854, 1601, 1520, 1461, 1323, 1171, 1062, 999. [M+H]+: Calculated for
C15H9F3N4O2: 335.0756 found 335.0744. Anal. Calcd for C15H9F3N4O2: C, 53.90; H, 2.71;
N, 16.76. Found: C, 54.20; H, 3.0; N, 16.94.
1-(3-methoxyphenyl)-5-phenyl-1H-1,2,3-triazole (1ga): Yield: 108 mg (84%); M.P. : 85 -
88 °C; 1H NMR (500MHz, CDCl3); δ ppm3.75 (s, 3 H) 6.88 (ddd, J = 0.9, 2.0, 7.9 Hz, 1
H), 6.99 - 6.93 (m, 2 H), 7.26 - 7.23 (m, 2 H), 7.29 (t, J = 8.1 Hz, 1 H), 7.38 - 7.32 (m, 3
H),7.85 (s, 1 H). 13C NMR (126MHz, CDCl3); δ ppm 55.7, 110.8, 115.6, 117.5, 127.0, 128.8,
129.0, 129.4, 130.2, 133.6, 137.7, 137.9, 160.3. Anal. Calcd for C15H13N3O: C, 71.70; H,
5.21; N, 16.72;. Found: C, 71.49; H, 5.2; N, 16.9.
4-cyclopropyl-1-(4-nitrophenyl)-5-diphenyl-1H-1,2,3-triazole (1ha): Yield: 150 mg
(86%); M.P. : 127 -130 °C; 1H NMR (500MHz, CDCl3); δ ppm 0.95 - 1.01 (m, 2 H) 1.11 -
1.17 (m, 2 H) 1.87 (tt, J =8.41, 5.05 Hz, 1 H) 7.25 - 7.31 (m, 2 H) 7.43 -7.48 (m, 3 H) 7.48 -
7.53 (m, 2 H) 8.20 - 8.28 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 6.3, 8.1, 124.9,
124.9, 127.1, 129.4, 129.7, 129.8, 134.1, 141.7, 147.3, 148.3. IR (Neat, cm-1): 3087, 2956,
2853, 1597, 1500, 1277, 1058, 991, 854. [M+H]+: Calculated for C17H15N4O2: 307.1195
found 307.1196. Anal. Calcd for C17H14N4O2 : C, 66.66; H, 4.61; N, 18.29. Found: C,
67.02; H, 5.1; N, 18.62.
4-cyclopropyl-5-(3-methoxyphenyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (1hb): Yield: 196
mg (89%); M.P.: 139 -141 °C; 1H NMR (500MHz, CDCl3); δ ppm 8.29 - 8.24 (m, 2 H), 7.57
Page 18 of 25
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
- 7.52 (m, 2 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.00 (dd, J = 0.9, 2.6, Hz, 1H), 6.87 - 6.81 (m, 2
H), 3.80 (s, 3 H), 1.94 - 1.87 (m, 1 H), 1.18 - 1.13 (m, 2 H), 1.03 - 0.97 (m, 2 H). C NMR
(126MHz, CDCl3); δ ppm 6.2, 7.9, 55.4, 114.6, 115.6, 122.0, 124.7, 128.1, 130.4, 133.8,
137.5, 141.5, 147.1, 148.2, 160.0. IR (Neat, cm-1): 2922, 2852, 1595, 1342, 1283, 1051, 907,
852. [M+H]+: Calculated for C18H17N4O3: 337.1300 found 337.1271. Anal. Calcd for
C18H16N4O3: C, 64.28; H, 4.79; N, 16.66; O, 14.27 Found: C, 64.09; H, 4.7; N, 16.04.
13
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
1-(naphthalen-1-yl)-5-phenyl-1H-1,2,3-triazole34 (1ia): Yield: 132 mg (72%); M.P. : 120 -
123 °C; 1H NMR (500MHz, CDCl3); δ ppm 7.11 - 7.15 (m, 2 H) 7.15 - 7.21 (m, 2 H) 7.21 -
7.26 (m, 1 H) 7.38 (d, J =8.54 Hz, 1 H) 7.41 - 7.57 (m, 4 H) 7.93 - 8.03 (m, 2 H) 8.04 (s, 1
H). 13C NMR (126MHz, CDCl3); δ ppm 122.7, 125.1, 125.6, 126.5, 127.2, 127.9, 128.0,
128.4, 128.9, 129.3, 129.9, 130.7, 132.6, 133.2, 134.3, 139.8. IR (Neat, cm-1): 3058, 2934,
2854, 1597, 1474, 1232, 1015, 962, 802. HPLC (20% Acetonitile in water, flow rate 0.5
mL/min) tR = 11.58 min (minor).14.77 min (major), 20.07 min (minor).
1-(naphthalen-1-yl)-4,5-diphenyl-1H-1,2,3-triazole (1ja): Yield: 159 mg (83%); M.P. : 161
1
-163 °C; H NMR (500MHz, CDCl3); δ ppm 7.09 - 7.14 (m, 2 H) 7.14 - 7.20 (m, 2 H) 7.21 -
7.26 (m, 1 H) 7.32 - 7.40 (m, 5 H) 7.42 - 7.57 (m, 5 H) 7.68 - 7.72 (m, 2 H) 7.88 - 7.96 (m, 2
H). 13C NMR (126MHz, CDCl3); δ ppm 122.7, 124.9, 125.8, 127.1, 127.5, 127.9, 128.1,
128.3, 128.7, 128.9, 129.4, 129.7, 130.2, 130.6, 130.9, 132.9, 134.1, 136.1, 144.2. IR (Neat,
cm-1): 3058, 2924, 2854, 1600, 1445, 1162, 1021, 917, 801. [M+H]+: Calculated for C24H17N3
: 348.1501 found 348.1497. Anal. Calcd for C24H17N3: C, 82.97; H, 4.93; N, 12.10. Found:
C, 82.63; H, 4.94; N, 11.89.
5-(3-methoxyphenyl)-1-(naphthalene-1-yl)-4-phenyl-1H-1,2,3-triazole (1jb): Yield: 171
1
mg (82%); H NMR (500MHz, CDCl3); δ ppm 3.44 (s, 3 H) 6.61 (dd, J =2.44, 1.60 Hz, 1
H) 6.68 - 6.78 (m, 2 H) 7.07 (t, J =7.91 Hz, 1 H) 7.29 -7.41 (m, 4 H) 7.42 - 7.57 (m, 4 H)
7.69 - 7.76 (m, 2 H) 7.86 - 7.98 (m, 2 H). 13C NMR (126MHz, CDCl3); δ ppm 55.1, 114.8,
115.4, 122.3, 122.8, 124.9, 125.8, 127.1, 127.5, 127.9, 128.2, 128.3, 128.7, 130.0, 130.3,
130.6, 130.9, 132.9, 134.1, 135.9, 144.2, 159.6. IR (Neat, cm-1): 3058, 2924, 2854, 1600,
1445, 1211, 1162, 1021, 917, 801. [M+H]+: Calculated for C25H19N3O: 378.1601 found
378.1595. Anal. Calcd for C25H19N3O: C, 79.55; H, 5.07; N, 11.13. Found: C, 79.18; H,
5.06; N, 10.73.
Computational Methods
All calculations were performed with the Gaussian09 quantum chemical programs.18 Density
functional theory was applied throughout using the M06L functional.19 For geometry
optimizations, the DFT calculations employed the 6-311G** basis set for C, H, N, O, P 20 and
Page 19 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
5
6
7
8
9
the Lanl2dz effective core potential and the associated double-ζ basis set for Pd and Cs.21
Geometry optimizations were carried out in the gas phase without any constraints. The
optimized stationary points were characterized as local minima or transition structures by
harmonic force constant analysis, and intrinsic reaction coordinate (IRC) calculations were
performed to verify the transition state structures. 22
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
Acknowledgments
The authors would like to thank the Vice Chancellor, DIAT for providing the infrastructural
facilities. Financial support from ER&IPR, DRDO towards “DRDO-DIAT programme on
Nano Materials”, New Delhi is gratefully acknowledged.
Supporting Information
NMR (1H, 13C, 19F, 15N) spectra S3 – S22, HPLC graphs S23-S29, Single crystal XRD data
S29-S32, Computational Studies data S33 – S38.
References:
(1) (a) Massarotti, A.; Aprile, S.; Mercalli, V.; Grosso, E. D.; Grosa, G.; Sorba, G.; Cesare
Tron, G.; ChemMedChem. 2014, 9, 2497. (b) Lauria, A.; Delisi, R.; Mingoia, F.; Terenzi, A.;
Martorana, A.; Barone, G.; Almerico, A. M.; Eur. J. Org. Chem. 2014, 16, 3289. (c) Lauria,
A; Delisi, R.; Mingoia, F.; Terenzi, A.; Martorana, A.; Barone, G.; Almerico, M.; Eur. J.
Org. Chem. 2014, 3289. (d) Kotha, S.; Goyal, D.; Bitra, A.; Thota, N.; Kruger, G.;
Anand, R.; RSC Adv., 2013, 3, 24447. (e) Dippold, A. A.; Klapötke, T. M.; Chem. Eur.-J.
2012, 18, 16742. (f) Agalave, S. G.; Maujan, S. R.; Pore, V. S.; Chem. Asian J. 2011, 6,
2696. (g) Finley, T.; Montgomery, J. A.; The Chemistry of Heterocyclic Compounds,
Triazoles 1,2,3. John Wiley & Sons, 2009. (h) Xue , H.; Gao , H.; Twamley, B.; and Shreeve,
J. M.; Chem. Mater., 2007, 19, 1731. (i) Kallander, L. S. Chen, Q. Lu. W.; Tomaszek, T.;
Yang, G.; Tew, D.; Meek, T. D.; Hofman, G. A.; Schulz-Pritchard, C. K.; Smith, W. W.;
Page 20 of 25
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Janson, C. A.; Ryan, M. D.; Zhang, G. F.; Johanson, K. O.; Kirkpatrick,R. B.; Ho, T. F.;
Fisher, P. W.; Matterm, M. R.; Johnson, R. K.;Hansbury, M. J.; Winkler, J. D.; Ward, K. W.;
Veber, D. F.; Thompson. S. K.; J. Med. Chem. 2005, 48, 5644. (j) Tome, A. C.; Sci. Synth.
2004, 13, 415. (k) Melo, J. O. F.; Donnici, C. L.; Augusti, R.; Lopes, M. T. P.; Mikhailovskii,
A. G.; Heterocycl. Commun. 2003, 9, 235. (l) Baures, P. W.; Org. Lett. 1999, 1, 249.
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
(2) (a) Palmer, L. M.; Janson, C. A.; Smith, W. W.; PCT Int. Appl. 2005, p. 347,
CODEN:PIXXD2 WO 2005016237A22050224, CAN: 142:256748. (b) Kallander, L. S.;
Thompson, S. K.; PCT Int. Appl. 2001, p.44, CODEN: PIXXD2WO 2001078723A1
20011025, CAN: 135:331429.
(3) (a) Kamal, A.; Shankaraiah, N.; Devaiah,V.; Reddy, K. L.; Juvekar, A.; Sen, S.; Kurian,
N.; Zingde, S.; Bioorg. Med. Chem. Lett. 2008, 18, 1468. (b) Holla, B. S.; Mahalinga, M.;
Karthikeyan, M. S.; Poojary, B.; Akberali, P.M.; Kumari, N.S. Eur.; J. Med. Chem. 2005, 40,
1173.
(c) Kolb, H. C.; Sharpless, K. B.; Drug Discov. Today 2003, 8, 1128.
(4) (a) Barral, K.; Moorhouse, A. D.; Moses, J. E.; Org. Lett., 2007, 9, 1809. (b) Zhang, L.;
Chen, X.; Xue, P.; Sum, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G.; J.
Org. Chem. Soc. 2005, 127, 15998. (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B.; Angew. Chem., Int. Ed. 2002, 41, 2596. (d) Torne, C. W.; Christensen, C.;
Meldai, M.; J. Org. Chem. 2002, 67, 3057.
(5) (a) Hüisgen, R. In 1,3-Dipolr Cycloaddition Chemistry, Padwa, A., Ed., Wiley: New
York, 1984: pp1-176.(b) Huisgen, R.; Angew. Chem. Int. Ed. Engl. 1963, 2, 265.
(6) (a) Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J.; Synthesis, 2004, 59. (b)
Müller, S.; Liepold, B., Roth, G. J.; Bestmann, H. J.; Synlett, 1996, 521. (c) Gilbert, J. C.;
Weerasooriya, U.; J. Org. Chem., 1982, 47, 1837.
Page 21 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
5
6
7
8
9
(7) (a) Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.; Begtrup, M.; Synthesis 1998,
1181. (b) Ohta, S.; Kawasaki, I.; Uemura, T.; Yamashita, M.; Yoshioka, T.; Yamaguchi, S.;
Chem. Pharm. Bull. 1997, 45, 1140. (c) Uhlmann, P.; Felding, J.; Vedsø, P.; Begtrup, M.; J.
Org. Chem. 1997, 62, 9177. (d) Holzer, W.; Ruso, K. J.; Hetrocycl. Chem. 1992, 29, 1203.
(8) Deng, J.; Wu, Y. -M.; Chen, Q. -Y.; Synthesis, 2005, 2730.
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
(9) Krasinski, A.; Fokin, V. V.; Sharpless, K. B.; Org. Lett. 2004, 6, 1237.
(10) (a) Campeau, L. –C.; Stuart, D. R.; Fagnou, K.; Aldrich. Chim. Acta 2007, 40, 35. (b)
Dauglis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. –N.; Lazareva, A. Synlett 2006, 3382.
(c) Sergin, I. V.; Gevorgyan, V.; Chem. Soc. Rev. 2007, 36, 1173. (d) Alberico, D. Scott, M.
E.; Lauten, M.; Chem. Rev. 2007, 107, 174.
(11) Chiong, H. A.; Daugulis, O.; Org. Lett.; 2007, 9, 1449.
(12) (a) Ackermann, L.; Vicente, R.; Org. Lett., 2009, 11, 4922. (b) Chuprakov, S.;
Chernyak, N.; . Dudnik, A. S.; and Gevorgyan, V.; Org. Lett. 2007, 9, 2333.
(13) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F.; Org. Lett. 2003,
5, 301.
(14) (a) Lane, B. S.; Brown, M. A.; Sames, D.; J. Am. Chem. Soc. 2005, 127, 8050. (b)
Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M.; J. Am. Chem. Soc. 2002, 124, 5286. (c)
McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar, F,; Org.
Lett. 2001, 3, 1677. (d) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.;
Bull. Chem. Soc. Jpn. 1998, 71, 467. (e) Aoyagi, Y.; Inoue, A.; Koizumi, A.; Hashimoto, R.;
Tokunaga, K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.;
Akita, Y.; Ohta, A.; Heterocycles 1992 ,33, 257. (f) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba,
M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y.; Heterocyles 1990 ,31,
1951.
Page 22 of 25
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
(15) (a) Gorelsky, S. I.; Coord. Chem. Rev. 2013, 257, 153. (b) Balcells, D.; Clot, E.;
Eisenstein, O.; Chem. Rev., 2010, 110, 749 and references cited therein.
7
8
9
(16) Selected examples: (a) Yang, Y. -F.; Cheng, G. J.; Liu, P. Leow, D.; Sun, T. -Y. Chen,
P.; Zhang, X.; Y. J. -Q.; Wu. Y. -D.; Houk, K. N.; J. Am. Chem. Soc. 2014, 136, 344. (b)
Goresky, S. I.; Lapointe, D.; Fagnou, K.; J. Am. Chem. Soc. 2008, 130, 10848. (c) Garcia-
Caudrado, D. Braga, A. A. C.; Maseras, F.; Echavarren, A. M.; J. Am. Chem. Soc. 2006, 128,
1066. (d) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J.; Clot, E. Baudoin,
O.; J. Am. Chem. Soc. 2005, 130, 15157. (e) Davies, D. L.; Donald, S. M. A.; Macgregor, S.
A.; J. Am. Chem. Soc. 2005, 127, 13754.
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
(17) (a) Anil Kumar, K.; Kannaboina, P. Dhaked, D. K. Vishwakarma, R. A.; Bharatam, P.
V.; Das, P.; Org. Biomol. Chem. 2015, 13, 1481. (b) Potavathri, S.; Pereire, K. C.; Gorelsky,
S. I.; Pike, A.; lebris, A. P.; DeBoef, B.; J. Am. Chem. Soc. 2010, 132, 14676. (c) Xi, P.;
Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J.; J. Am. Chem. Soc. 2010, 132,
1822.
(18) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R . Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.
A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.;. Nakajima, T. Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A. Jr.,
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S. ; Tomasi, J.; Cossi, M.; Rega, N.;. Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V. Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J. ; Dapprich, S.; Daniels, A.
Page 23 of 25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
6
D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian, Inc.,
Wallingford CT, 2013.
7
8
9
(19) (a) Zhao, Y.; Truhlar, D. G.; Theor. Chem. Acc. 2008, 120, 215. (b) Zhao, Y. Schultz, N.
E.; Truhlar, D. G.; J. Chem. Phys. 2005, 123, 161103.
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
(20) (a) Blaudeau, J. -P. McGrath, M. P.; Curtiss, L. A.; Radom, L.; J. Chem. Phys. 1997,
107, 5016. (b) Curtiss, L. A.; McGrath, M. P.; Blaudeau, J. -P.; Davis, N. E.; Binning Jr., R.
C., Radom, L.; J. Chem. Phys. 1995, 103, 6104. (c) McGrath, M. P.; Radom, L.; J. Chem.
Phys. 1991, 94, 511. (d) Binning Jr., R. C.; Curtiss, L. A.; J. Comp. Chem. 1990, 11, 1206.
(e) Raghavachari, K.; Trucks, G. W.; J. Chem. Phys. 1989, 91, 1062. (f) McLean, A. D.;
Chandler, G. S.; J. Chem. Phys. 1980, 72, 5639. (g) Raghavachari, K. Binkley, J. S.; Seeger,
R. Pople, J. A.; J. Chem. Phys. 1980, 72, 650 (h) Wachters, A. J. H.; J. Chem. Phys. 1970, 52,
1033. (i) Hay, P. J.; J. Chem. Phys. 1977, 66, 4377.
(21) (a) Hay, P. J.; Wadt, W. R.; J. Chem. Phys. 1985, 82, 270. (b) Wadt, W. R.; Hay, P. J.; J.
Chem. Phys. 1985, 82, 284. (c) Hay, P. J.; Wadt, W. R.; J. Chem. Phys. 1985, 82, 299.
(22) (a) Gonzalez, C.; Schlegel, H. B.; J. Phys. Chem. 1990, 94, 5253. (b) Gonzalez, C.;
Schlegel, H. B.; J. Chem. Phys. 1989, 90, 2154.
(23) Jiang, Y.; Kuang, C.; Yang, Q.; Synlett 2009, 3163.
(24) Wu, L.; Yan, B.; Yang, G; Chen, Y.; Heterocycl. Commun.. 2013, 19, 397.
(25) Jiang,Y.; Kuang, C.; Yang, Q.; Tetrahedron 2011, 67, 289.
(26) Xu, M.; Kuang, C.; Wang, Z.; Yang, Q.; Jiang, Y.; Synthesis 2011, 223.
(27) Zhou, C. T.; Cui, X.; Li, J.; Liu, A.; Liu, L.; Guo, Q.; Tetrahedron Lett. 2007, 48,
3525.
(28) Ski, A. K.; Fokin, V. V.; Sharpless, K. B.; Org. Lett. 2004, 6, 1237.
(29) Kadaba, P. K.; Synthesis 1978, 694.
(30) Hong, L.; Lin, W.; Zhang, F.; Liu, R.; Zhou, X.; Chem. Commun., 2013, 49, 5589.
Page 24 of 25
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
(31) Wang, Y.C.; Xie, Y. Y.; Qu, H. E.; Wang, H. S.; Pan, Y. M. Huang, F. P.; J. Org. Chem.
2014, 79, 4463.
6
7
(32) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V.; Org. Lett. 2007, 9, 5337.
8
9
(33) Chattopadhyay, B.; Rivera Vera, C. I.; Chuprakov, S.; Gevorgyan, V.; Org. Lett. 2010,
12, 2166.
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
(34) Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X. Angew. Chem. Int. Ed. 2013, 52,
13265.
Page 25 of 25
ACS Paragon Plus Environment