Catalyst-Free Regioselective N2 Arylation of 1,2,3-Triazoles Using Diaryl Iodonium Salts

Article abstract of DOI:10.1021/acs.orglett.9b02140

The widespread application of 1,2,3-triazoles in pharmaceuticals has resulted in substantial interest toward developing efficient postmodification methods. Whereas there are many postmodification methods available to obtain N¹-substituted 1,2,3-triazoles, developing a selective and convenient protocol to synthesize N²-aryl-1,2,3-triazoles has been challenging. We report a catalyst-free and regioselective method to access N²-aryl-1,2,3-triazoles in good to excellent yields (66-97%). This scalable postmodification protocol is effective for a wide range of substrates.

Full text of DOI:10.1021/acs.orglett.9b02140

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalyst-Free Regioselective N2 Arylation of 1,2,3-Triazoles Using
Diaryl Iodonium Salts
Sahar Roshandel, Maiko J. Lunn, Golam Rasul, Daniel Sylvinson Muthiah Ravinson, Suresh C. Suri,
and G. K. Surya Prakash*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
90089-1661, United States
S
* Supporting Information
ABSTRACT: The widespread application of 1,2,3-triazoles in pharma-
ceuticals has resulted in substantial interest toward developing efficient
postmodification methods. Whereas there are many postmodification
methods available to obtain N1-substituted 1,2,3-triazoles, developing a
selective and convenient protocol to synthesize N2-aryl-1,2,3-triazoles has
been challenging. We report a catalyst-free and regioselective method to
access N2-aryl-1,2,3-triazoles in good to excellent yields (66−97%). This
scalable postmodification protocol is effective for a wide range of substrates.
he extensive biological activities of 1,2,3-triazoles including
Recently, the research groups of Olofsson22 and Stuart23 have
Tanticancer, anti-inflammatory, and antibacterial character- reported the regiospecific N arylation of amines using diaryl
iodonium salts, which eliminates the need to use toxic and
expensive transition-metal catalysts to form a C−N bond
(Scheme 1a). The reaction proceeds through the formation of a
istics have led to the frequent utilization of this scaffold in
medicinal chemistry.1 Regioselective copper-2,3 and ruthenium-
catalyzed4 cycloaddition of azides and alkynes was reported in
2002 and 2007, giving easy access to 1,4- and 1,5-substituted
1,2,3-triazoles, respectively. Since then, many practical methods
have been developed for the postmodification of 1,2,3-triazoles
to provide N1-substituted 1,2,3-triazoles.5 On the contrary, only
a few synthetic methods have been reported to access N2-
substituted 1,2,3-triazoles6−10 despite their promising biological
activities.11−13 N2-Aryl-1,2,3-triazole-containing molecules dis-
play interesting biological activities. For example, they have been
used in a potent dual orexin receptor antagonist for the
treatment of primary insomnia.14 The simplest approach to
access such N2-substituted triazole motifs would be through the
postmodification of readily available 1,2,3-triazoles. However,
the existing postmodification methods that produce N2-aryl-
1,2,3-triazoles in a regioselective manner suffer significant
drawbacks. For instance, the regioselectivity of the reaction
can be controlled by using sterically hindering groups on the C4
and C5 positions of NH-1,2,3-triazoles.15−19 Whereas such
protocols are selective toward N2 substitution, they unavoidably
suffer from a limited substrate scope. The research groups of
Shi20 and Buchwald21 have independently developed protocols
that use Cu- and Pd-based catalysts, respectively, to conduct the
arylation of NH-1,2,3-triazoles. Despite the high N2 selectivity
and wide substrate range of these methods, there are drawbacks,
such as the cost and toxicity associated with the use of transition-
metal catalysts. The presence of even traces of metal impurities
in marketed drugs creates a significant challenge for using such
catalysts in the pharmaceutical industry. Therefore, it is desirable
to move toward developing regioselective metal-free method-
ologies to access such biologically valuable 1,2,3-triazole motifs
with potential applications in the pharmaceutical industry.
Scheme 1. (a) Metal-Free Arylation of Amines with Diaryl
Iodonium Salts by Stuart and Olofsson Research Groups and
(b) N2 Arylation of 1,2,3-Triazoles with Diaryl Iodonium
a
Salts
a
TMP: 1,3,5-trimethoxyphenyl.
T-shaped intermediate, from which the desired N-arylated
product is formed by reductive elimination. Inspired by their
work, we wondered whether the diaryl iodonium salts can be
utilized for the regioselective arylation of 1,2,3-triazoles, being
particularly interested in N2 substitution. Given that diaryl
iodonium salts are bench-stable and can be easily synthesized
from inexpensive reagents (iodoarenes or arenes), replacing
conventional catalysts with these salts would provide a metal-
free and cost-effective protocol to obtain N2-aryl-1,2,3-triazoles.
Received: June 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02140
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We started our investigation with 4-phenyl-1,2,3-triazole (1a)
as the model substrate and phenyl(2,4,6-trimethoxyphenyl)-
iodonium trifluoroacetate (2a) as the model diaryl iodonium
salt. When 1a (0.2 mmol; 1 equiv) was treated with 2a (2 equiv)
in the presence of sodium carbonate (1.2 equiv) in toluene for
24 h at 100 °C (Table 1, entry 1), the formation of N1- and N2-
With the optimized conditions in hand providing 94% of the
desired N2 product (Table 1, entry 9), we investigated the
efficacy of this reaction for various NH-1,2,3-triazoles. Initially,
the reaction efficacy for various C4-substituted 1,2,3-triazoles
(Schemes 2, 3a−e) was tested to explore the effect of C4
Scheme 2. Substrate Scope of Regioselective N2 Arylation of
a
a
Table 1. Optimization of Reaction Conditions
Various NH-1,2,3-Triazoles Using 2a
2a
Na2CO3
(equiv)
T
(°C)
b
b
c
entry (equiv)
solv
%X1a
3a/4a
%Y3a
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
1.6
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.6
0
100
100
100
100
75
50
25
100
100
100
100
toluene
DMF
100
100
100
100
92
84
80
100
100
100
70
89:11
85:15
64:36
83:17
81:19
68:32
68:32
92:8
85
79
56
78
75
62
61
88
94
82
45
CH3CN
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
95:5
85:15
56:44
a
0.2 mmol 1a was treated with the indicated amount of 2a and
Na2CO3 in 2 mL of anhydrous and degassed solvent under argon. 1a
and 2a were prepared according to the previously reported procedures
b
by our group24 and Stuart’s group,25 respectively. % conversion of 1a
c
and ratio of 3a to 4a were determined by GC−MS. Isolated yield of
3a.
aryl-substituted triazoles was observed, along with 100%
consumption of the starting substrate. Excitingly, we observed
excellent regioselectivity toward the formation of the N2-
substituted triazole 3a (N2/N1 = 89:11), which was isolated
through chromatography in 85% yield.
a
0.2 mmol 1, 0.24 mmol 2a, and 0.24 mmol sodium carbonate in 2
b
mL of anhydrous and degassed toluene under argon. Reaction was
conducted on a 2 mmol scale.
Obtaining such high regioselectivity without the use of any
metal catalyst and directing groups is unprecedented, and it
encouraged us to further explore the optimum reaction
conditions to produce N2-aryl-1,2,3-triazoles with even higher
selectivity. When we changed the reaction solvent from toluene
to other more polar solvents, such as DMF, CH3CN, or dioxane,
a decrease in the regioselectivity of the reaction was observed
(Table 1, entries 1−4). Reducing the reaction temperature to
75, 50, and 25 °C also had an adverse impact on both the
conversion and the selectivity of the reaction (Table 1, entries
5−7). Whereas poor N2 selectivity was still observed at lower
temperatures, our results showed that heating is crucial for
achieving a high regioselectivity.
Decreasing the 2a amount during the reaction from 1.6 equiv
to 1.4 equiv increased the selectivity for 2a to 95%, along with
94% isolated yield. With regards to sodium carbonate, a decrease
in its amount from 1.2 to 0.6 equiv decreased the 3a selectivity,
whereas 2a conversion still remained 100%. Finally, the reaction
also proceeded in the absence of any Na2CO3 base additive.
However, after 24 h, only 70% 1a conversion was observed. Also,
the selectivity of the reaction to produce 3a decreased
significantly (3a/4a 56:44) in the absence of Na2CO3.
substitution on the regioselectivity of the reaction. Interestingly,
the reaction proceeded with excellent N2 regioselectivity for all
C4-substituted substrates, regardless of their electronic nature.
Furthermore, the cyano group (3d) as well as the cyclopropyl
group (3e) was well tolerated under the reaction conditions, and
isolated yields of 80 and 97% were obtained for their
corresponding products, respectively. Next, we explored the
effect of both C4 and C5 disubstitution on the regioselectivity
and yield of the reaction. Towards this endeavor, disubstituted
1,2,3-triazoles were reacted with 2a under the reaction
conditions.
Initially, we screened benzotriazole because the previously
reported N2 arylation methods were not successful in obtaining
any regioselectivity with benzotriazole as the substrate.20,21
However, with our protocol, we observed high N2 selectivity and
obtained the corresponding N2 product (3f) in 85% yield. This
is particularly exciting because N-substituted benzotriazoles are
highly sought-after moieties in pharmaceuticals,26,27 and, to the
best of our knowledge, this is the only protocol that provides
easy access to N2-aryl-benzotriazole in a regioselective manner.
Among other disubstituted triazoles, both 4-ethyl-5-phenyl and
B
DOI: 10.1021/acs.orglett.9b02140
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
−NO2 in the para position, affording the corresponding N2
products 5(b−d) in high yield (75, 78, and 89%, respectively).
In the case of 5d, with p-NO2 substitution, the reaction was
conducted at 65 °C because we observed the decomposition of
the diaryl iodonium salt at elevated temperatures. We also found
that this reaction proceeds smoothly with diaryl iodonium salts
containing mildly activating moieties such as −CH3 (5i). Apart
from the phenyl ring, the pyridinyl ring can also be used for this
arylation because product 5e was obtained in high N2 selectivity
and excellent yield. Thus 4-substitutions in the iodonium salt
aryl ring and the presence of a heterocycle do not inhibit the
reaction or alter the product selectivity to a significant degree.
On the contrary, the selectivity was drastically influenced by
ortho substitutions on the aryl ring, as in the case of 2g, we
observed an almost 1:1 ratio of N1 and N2 products. The lack of
selectivity is presumably due to the steric hindrance of ortho
substituents on the aryl group. To further examine the effect of
ortho substitution on the selectivity, 2h and 2i with o-Me and m-
Me groups, respectively, were exposed to the reaction
conditions. As anticipated, the ortho-methyl-substituted 2h
offered poor N2 selectivity, whereas the meta-methyl-substituted
2i afforded the corresponding N2 product (5i) with high
selectivity.
Scheme 3. Substrate Scope of Regioselective N2 Arylation of
1a Using Various Diaryl Iodonium Salts
a
To gain a better insight into the reaction mechanism and the
reason for the N2 regioselectivity of the reaction, we conducted
DFT calculation studies of the plausible intermediates and
transition states. On the basis of our findings, we postulate that
the regioselective N2 arylation of 1,2,3-triazoles proceeds
through a ligand-exchange, process followed by reductive
elimination to furnish the thermodynamically favored N2-aryl-
1,2,3-triazole. During the initial ligand-exchange process, the
CF3COO− ligand coordinated to the iodine center is replaced by
the triazole moiety. The triazole can coordinate to the iodine in
two possible ways: through N1 (IB; on right) or N2 coordination
(IA; on left) (Scheme 4). The relative energies of the two
competing routes (I and II) based on the DFT calculations are
shown in Scheme 4a. According to our calculations, the IA
intermediate is 2.86 kcal/mol more stable than the IB
intermediate. This energy difference indicates that at any time
the concentration of IA is slightly more than that of IB in the
reaction mixture. The comparison of relative energies of
transition states (ΔΔG‡ = 0.22 kcal/mol) illustrates that the
formation of N1 product is kinetically favored, as we observed
during the reaction optimization process. However, when the
relative energy of the N2 products (A + C) is compared with that
of the N1 products (B + C), the former is significantly (by 4.96
kcal/mol) more stable (Scheme 2a). These calculations
demonstrate that the formation of N2 product is thermodynami-
cally favored. As a result, the arylation protocol gives the N2-
substituted products with high selectivity at higher temper-
atures. Similarly, in the case of ortho-substituted aryls, where we
observed poor N2 selectivity, our calculation shows that N1
product and N2 product are, respectively, kinetically and
thermodynamically favored (Scheme 4b). To get thermody-
namic control, we conducted the reactions at 120 °C and,
indeed, the N2 selectivity (5g and 5h) increased at elevated
temperatures, and we were able to obtain the N2 products in 57
and 77% yield, respectively.
a
0.2 mmol 1a, 0.24 mmol 2, and 0.24 mmol sodium carbonate in 2
b
mL of anhydrous and degassed toluene under argon. Reaction was
conducted at 65 °C because at higher temperatures decomposition of
the corresponding diaryl iodonium salt was observed. Yields reported
c
in parentheses are obtained at 120 °C.
4,5-diphenyl triazole were arylated at the N2 position with high
selectivity, and 80 and 78% of their corresponding products were
isolated, respectively. Subsequently, triazole containing steri-
cally hindering moieties on both C4 and C5 (trimethylsilyl and
naphthyl groups, respectively) was subjected to the reaction
conditions. We discovered that the reaction performed well in all
cases (3(g−i,k)), and high N2 selectivity was obtained
regardless of the steric bulk of the substituents. The ester
moiety was also well tolerated under the reaction conditions and
afforded the corresponding product 3j in 87% yield. Thus it
seems that the substitution in the four and five positions of the
triazole does not significantly influence the yield and selectivity
of reaction. In the case of NH-1,2,3-triazole, without any
substitution on the triazole ring, the reaction proceeded slower
as compared with 1a, and 79% 1l conversion was achieved after
24 h. Nonetheless, the reaction was highly N2-selective, similar
to the other substrates (isolated yield 75%). This proves that the
N2 selectivity is not directed by the steric hindrance of C4 or C5
substitutions. Rather, it is more likely that the N2-substituted
product is thermodynamically favorable compared with the N1-
substituted product, as will be evident from the results of our
density functional theory (DFT) calculations presented vide
infra. Finally, the scalability of this protocol was investigated
with substrate 1a on a 2 mmol scale. The reaction performed
well on the higher scale and afforded the corresponding N2
product (3a) in 80% yield.
In conclusion, we have successfully developed a scalable,
transition-metal/catalyst-free methodology that provides easy
access to N2-aryl-1,2,3-triazoles in a highly regioselective
manner. Moreover, this postmodification method arguably
presents a cost-effective protocol to synthesize N2-aryl-1,2,3-
Subsequently, we investigated the effect of different diaryl
iodonium salts on the reaction efficiency and selectivity using 1a
as the model triazole substrate (Scheme 3). The reaction
proceeded with high selectivity with diaryl iodonium salts
containing deactivating moieties such as −COOR, −CF3, and
C
DOI: 10.1021/acs.orglett.9b02140
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. (a) Plausible Reaction Mechanism of N2 Arylation
of 1,2,3-Triazoles with DFT Calculations of the Potential
Intermediates and Transition States and (b) DFT
ACKNOWLEDGMENTS
Financial support by the Loker Hydrocarbon Research Institute
is gratefully acknowledged.
■
Calculations of the Potential Intermediates and Transition
a
States for the ortho-Substituted Aryls
REFERENCES
■
(1) Dheer, D.; Singh, V.; Shankar, R. Bioorg. Chem. 2017, 71, 30−54.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41 (14), 2596−2599.
(3) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67
(9), 3057−3064.
(4) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9
(26), 5337−5339.
(5) John, J.; Thomas, J.; Dehaen, W. Chem. Commun. 2015, 51 (54),
10797−10806.
(6) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125 (26), 7786−7787.
(7) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10 (15),
3171−3174.
(8) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng, X.; Zhao, M.; Chen, B. Org.
Lett. 2012, 14 (1), 26−29.
(9) Wang, K.; Chen, P.; Ji, D.; Zhang, X.; Xu, G.; Sun, J. Angew. Chem.,
Int. Ed. 2018, 57 (38), 12489−12493.
(10) Zhu, L.-L.; Tian, L.; Zhang, H.; Xiao, L.; Luo, W.; Cai, B.; Wang,
H.; Wang, C.; Liu, G.; Pei, C.; Wang, Y. Adv. Synth. Catal. 2018, 361
(5), 1117−1123.
́
(11) Bretner, M.; Baier, A.; Kopanska, K.; Najda, A.; Schoof, A.;
Reinholz, M.; Lipniacki, A.; Piasek, A.; Kulikowski, T.; Borowski, P.
Antivir. Chem. Chemother. 2005, 16 (5), 315−326.
(12) Paluchowska, M. H.; Bugno, R.; Charakchieva-Minol, S.;
́
́
Bojarski, A. J.; Tatarczynska, E.; Chojnacka-Wojcik, E. Arch. Pharm.
(Weinheim, Ger.) 2006, 339 (9), 498−506.
(13) Vankadari, S. R.; Mandala, D.; Pochampalli, J.; Tigulla, P.; Valeru,
A.; Thampu, R. Med. Chem. Res. 2013, 22 (12), 5912−5919.
(14) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.;
McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.; Bednar,
R. A.; Lemaire, W.; et al. J. Med. Chem. 2010, 53 (14), 5320−5332.
(15) Chen, Y.; Liu, Y.; Petersen, J. L.; Shi, X. Chem. Commun. 2008, 0
(28), 3254−3256.
(16) Wang, X.; Sidhu, K.; Zhang, L.; Campbell, S.; Haddad, N.;
Reeves, D. C.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2009,
11 (23), 5490−5493.
a
TMP: 1,3,5-trimethoxyphenyl.
(17) Wang, X.; Zhang, L.; Krishnamurthy, D.; Senanayake, C. H.;
Wipf, P. Org. Lett. 2010, 12 (20), 4632−4635.
(18) Zhang, L.; Li, Z.; Wang, X.; Yee, N.; Senanayake, C. H. Synlett
2012, 23 (7), 1052−1056.
triazoles because it moves away from the use of costly and toxic
transition-metal catalysts. Additionally, the isolable byproduct of
the reaction, iodo-2,4,6-trimethoxybenzene, can be recycled to
synthesize back the diaryl iodonium salts. Therefore, we believe
that the work presented here provides a convenient and green
method to furnish biologically valuable N2-aryl-1,2,3-triazoles.
(19) Motornov, V. A.; Tabolin, A. A.; Novikov, R. A.; Nelyubina, Y. V.;
Ioffe, S. L.; Smolyar, I. V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2017,
2017, 6851−6860.
(20) Liu, Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi, X. Org. Lett. 2008,
10 (23), 5389−5392.
(21) Ueda, S.; Su, M.; Buchwald, S. L. Angew. Chem. 2011, 123 (38),
9106−9109.
ASSOCIATED CONTENT
■
S
* Supporting Information
(22) Purkait, N.; Kervefors, G.; Linde, E.; Olofsson, B. Angew. Chem.,
Int. Ed. 2018, 57 (35), 11427−11431.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02140.
(23) Sandtorv, A. H.; Stuart, D. R. Angew. Chem., Int. Ed. 2016, 55
(51), 15812−15815.
Experimental procedures, NMR spectra, and character-
ization data (PDF)
(24) Roshandel, S.; Suri, S. C.; Marcischak, J. C.; Rasul, G.; Prakash,
G. K. S. Green Chem. 2018, 20 (16), 3700−3704.
(25) Carreras, V.; Sandtorv, A. H.; Stuart, D. R. J. J. Org. Chem. 2017,
82 (2), 1279−1284.
AUTHOR INFORMATION
■
(26) Dawood, K. M.; Abdel-Gawad, H.; Rageb, E. A.; Ellithey, M.;
Mohamed, H. A. Bioorg. Med. Chem. 2006, 14 (11), 3672−3680.
(27) Rezaei, Z.; Khabnadideh, S.; Pakshir, K.; Hossaini, Z.; Amiri, F.;
Assadpour, E. Eur. J. Med. Chem. 2009, 44 (7), 3064−3067.
Corresponding Author
*E-mail: gprakash@usc.edu (G.K.S.P.).
ORCID
G. K. Surya Prakash: 0000-0002-6350-8325
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b02140
Org. Lett. XXXX, XXX, XXX−XXX