Regiospecific Synthesis of N 2-Aryl 1,2,3-Triazoles from 2,5-Disubstituted Tetrazoles via Photochemically Generated Nitrile Imine Intermediates

Article abstract of DOI:10.1055/s-0034-1379010

The synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles was achieved under photochemical conditions. This simple and mild one-step reaction provides regiospecific access to 2,4,5-substituted 1,2,3-triazoles via a nitrile imine intermediate. Syntheses of alkyl and heterocylic derivatives were also investigated.

Full text of DOI:10.1055/s-0034-1379010

2480▌
LETTER
lRetteergiospecific Synthesis of N2-Aryl 1,2,3-Triazoles from 2,5-Disubstituted
Tetrazoles via Photochemically Generated Nitrile Imine Intermediates
N2-Aryl 1,2,3-Triazoles
Sam Stewart,a Robert Harris,*a Craig Jamieson*b
a
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
E-mail: Robert.M.Harris@gsk.com
b
University of Strathclyde, Department of Pure and Applied Chemistry, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL,
UK
E-mail: Craig.Jamieson@strath.ac.uk
Received: 24.06.2014; Accepted after revision: 31.07.2014
bon disulfide11 and hydrogen sulfide12 yield the triazole.
Abstract: The synthesis of N2-aryl 1,2,3-triazoles from 2,5-disub-
Butler et al. favoured the oxidation to 1,2,3-triazolium-1-
stituted tetrazoles was achieved under photochemical conditions.
aminides and subsequent reduction to triazoles using toxic
This simple and mild one-step reaction provides regiospecific ac-
cess to 2,4,5-substituted 1,2,3-triazoles via a nitrile imine interme-
lead oxide and phosphorus trichloride, respectively.13
diate. Syntheses of alkyl and heterocylic derivatives were also Most recently, Guru et al. have shown an efficient and re-
investigated.
giospecific copper-catalysed formation of triaryl 1,2,3- or
1,2,4-triazoles from arylhydrazones under aerobic condi-
Key words: photochemistry, regioselectivity, tetrazole, triazole,
indazole
tions.14
A) synthesis of N2-aryl 1,2,3-triazoles by post-triazole arylation
Ar
1,2,3-triazoles are an important class of heterocycles due
to a number of useful properties. N2-Alkyl and -acyl
1,2,3-triazoles act as PPAR agonists1 and as selective CB1
receptor antagonists.2 N2-Aryl 1,2,3-triazoles have appli-
cation as β3-adrenergic receptor agonists;3 but more
uniquely, have photonic properties which make them suit-
able as biocompatible UV/blue-light emitting dyes4 and
inhibitors of polymer degradation.5 However, issues of re-
gioselectivity between the N1 and N2 position means that
the synthesis of N2-substituted 1,2,3-triazoles remains a
challenge. Herein, we will focus on synthesis of N2-aryl
1,2,3-triazoles.
H
N
N
N
N
N
N
R1
R2
R1
R2
2
1
B) synthesis of N2-aryl 1,2,3-triazoles via bis(arylhydrazones)
Ar
NH
Ar
N
Ar
N
Ar
N
R2
N
N
N
N
N
R1
N
R1
R2
R1
R2
HN
Ar
4
3
2
N2-Aryl 1,2,3-triazoles 2 are synthesized via two main
pathways: A) arylation of NH-1,2,3-triazoles 1 or B) rear-
rangement of bis(arylhydrazones) 3 via 1,2,3-triazolium
1-aminides 4 (Scheme 1).
Scheme 1 Common routes to N2-aryl 1,2,3-triazoles
In an effort to synthesise pyrazoline adducts 8 to serve as
probes for the intracellular visualisation of alkene-tagged
systems 7, we unexpectedly isolated 2,4,5-triaryl 1,2,3-
triazoles 9 from 2,5-diaryl tetrazoles 5 (Scheme 2). Previ-
ous accounts had reported the formation of tetrazine 10
from the dimerisation of the nitrile imine intermediate 6,
in contrast to the triazoles isolated in the current study.15,16
Shi et al. reported a regioselective copper-catalysed, or
SNAr-mediated, N2-arylation utilising bulky ligands or
bulky 4,5-substituents.6 Palladium catalysis has also been
reported for this application.7 Chen et al. have demonstrat-
ed the generation of 1,2,3-NH-triazoles followed by regio-
selective arylation using one-pot, multicomponent
reactions starting from a variety of molecules.8–10 Howev-
er, the scope of these SNAr reactions was limited to elec-
tron-poor substrates.
A survey of the literature revealed few examples of con-
verting 2,5-diaryl tetrazoles into triazoles under photo-
chemical conditions.17,18 Using a recently developed
methodology for the copper-catalysed synthesis of 2,5-di-
aryl tetrazoles19 we decided to investigate the scope of this
reaction. Accordingly, 2,5-diaryl tetrazoles 5a–q were
prepared from 5-aryl NH-tetrazoles 11 and aryl boronic
acids 12 in 49–93% yield as substrates for the study (Ta-
ble 1).19
Syntheses from bis(arylhydrazones) 3 can proceed via
acid-catalysed rearrangement to 1,2,3-triazolium-1-
aminides 4. Subsequent photolysis or reduction with car-
SYNLETT 210014, 2517, 2480–2484
Advanced online publication: 08.09.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379010; Art ID: st-2014-d0536-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
N2-Aryl 1,2,3-Triazoles
2481
moiety was protected as an acetamide derivative to afford
triazole 9k in an improved yield of 41%.
R3
R4
Ar1
N
Ar1
Ar1
R3
UV light
270–330 nm
R4
N
N
Table 1 Synthesis of 2,5-Diaryl Tetrazoles
N
N
7
N
N
N
R2
Ar2
Ar2
Ar2
Cu2O (5 mol%)
2 (1 atm)
DMSO, 110 °C
NH
N
N
5
6
8
N
OH
B
O
N
N
N
OH
N
R2
R1
Ar1
Ar2
12
Ar1
11
N
N
not
N
N
N
N
R1
N
Ar2
Ar2
Ar1
Ar2
5
9
10
Entry Compd 5 R1
R2
Yield Time
(%)
Scheme 2 Formation of 2,4,5-triaryl 1,2,3-triazoles as a byproduct
of photochemical pyrazoline synthesis
(h)
1
2
5a
5b
5c
5d
5e
5f28
5g
5h
5i
H
H
86
64
84
85
6
72
24
24
–
With a range of suitably functionalised tetrazole systems
in hand, we conducted a solvent screen; a number of
which were tolerated in the reaction, including: CH2Cl2,
MeCN, TBME, 2-MeTHF, EtOAc, toluene, and DMF.
However, DMSO failed to produce any reaction due to in-
hibition of nitrile imine formation. Further experimenta-
tion revealed that a mixture of 2-MeTHF–isopropyl
alcohol (1:1, v/v) was a suitable environmentally sustain-
able solvent system for the reaction.20
4-Cl
3-Cl
2-Cl
H
3
H
4
H
a
5
4-OMe
H
–
6
H
4-Me
4-OMe
3-OMe
2-OMe
4-NH2
4-NH(CO)Me
4-CO2Et
3-CN
4-NO2
4-OMe
4-OMe
93
6
a
7
H
–
–
8
H
77
49
16
16
–
Tetrazoles 5a–q were irradiated with a UVB lamp (270–
330 nm) in 2-MeTHF–isopropyl alcohol under atmo-
spheric conditions, until all starting material had been
consumed. The triazole products were isolated by chro-
matography, and the results shown in Table 2 provide in-
sight into the effects of substituents on the reaction.
9
H
b
10
11
12
13
14
15
16
17
5j
H
–
c
5k
5l
H
–
–
H
75
60
55
24
6
Tetrazole 5a was chosen as a baseline for comparison of
substituent effects and gave triazole 9a in 19% yield. Ini-
tial substituent effects were investigated with C-aryl sub-
stitution (Table 2, entries 2–5). Electron-donating
substituents appeared to improve yields slightly, relative
to electronically neutral 9a. Substitution in the meta and
para positions were tolerated; however, 2-Cl substitution
failed to yield triazole 9d. It was reasoned that this substi-
tution was not tolerated due to steric effects in the nitrile
imine intermediate.
5m
5n
5o
5p
5q
H
H
24
–
a
4-OMe
4-Cl
–
70
79
22
16
4-SO2NMe2 4-OMe
a Commercially available.
b Synthesised by reduction of tetrazole 5n (86%).
c Synthesised by acetylation of tetrazole 5j (92%).
We then investigated the electronic effect of substituents
on the N-aryl ring (Table 2, entries 6–11)14. In general, ad-
dition of electron-donating groups favoured the formation
of the desired triazoles in significantly improved yields,
particulary in the para position. Interestingly, ortho sub-
stitution is also tolerated, albeit in moderate yield. Substi-
tution with 4-H2N was expected to give excellent
reactivity; however, triazole 9j could only be isolated in
17% yield. Conducting the reaction under more dilute
conditions gave an improved yield of 46% due to reduced
byproduct formation and improved solubility of tetrazole
5j. However, the role of concentration was not explored
further in the current study. Instead, the reactive aniline
As expected, electron-deficient N-aryl substituents were
poorly tolerated. Of these, only 4-CO2Et tetrazole 5l
yielded the desired triazole and in a lower yield than for
electronically neutral tetrazole 5a. Photoactivation of 4-
NO2 tetrazole 5n was inefficient, with starting material
predominating after irradiaton for 100 hours, and no dis-
cernible product evident after this time. Incorporation of a
3-CN in tetrazole 5m did not afford the expected triazole
9m. Instead, isopropyl-N-(3-cyanophenyl) benzohydrazo-
nate 13, formed by trapping of the nitrile imine 6m with
isopropyl alcohol, was isolated as the major product with
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2480–2484

2482
S. Stewart et al.
LETTER
Table 2 Photochemical Synthesis of 2,4,5-Triaryl 1,2,3-Triazoles
CN
CN
CN
R2
R2
hν
(270–330nm)
i-PrOH
N
N
NH
UVB lamp (270–330 nm)
2-PrOH–2-MeTHF (1:1)
r.t.
N
N
N
N
N
N
Oi-Pr
N
N
N
N
N
N
5m
6m
13
R1
R1
R1
Scheme 3 Trapping of nitrile imine 13 by isopropyl alcohol
5a–q
9a–q
Entry Compd 9 R1
R2
Yield (%) Time (h)
Previously, photochemical formation of this intermediate
had only been observed spectroscopically.17 Further expo-
sure to UV light yielded the desired product by rearrange-
ment to 1,2,3-triazolium-1-aminide 16 and N–N bond
cleavage.
1
2
9a
9b
9c
9d
9e
9f
H
H
19
24
16
31
26
30
19
10
35
40
48 (7)a
6
4-Cl
3-Cl
2-Cl
4-OMe
H
H
27
3
H
28
4
H
0
Ar1
Ar1
Ar1
N
5
H
38
N
N
N
N
N
N
6
4-Me
4-OMe
3-OMe
2-OMe
4-NH2
47
N
Ar2
Ar2
Ar2
7
9g
9h
9i
H
62
5p
6p
14
8
H
25
Ar1 = C6H4(4-OMe)
Ar2 = C6H4(4-Cl)
9
H
33
10
11
12
13
14
15
16
17
9j
H
17 (46)a
Ar1
Ar1
N
Ar1
Ar1
N
Ar1
9k
9l
H
4-NH(CO)Me 41
N
N
N
N
N
N
N
N
N
H
4-CO2Et
3-CN
14
0
23
24
Ar2
Ar2
Ar2
Ar2
Ar2
Ar2
9m
9n
9o
9p
9q
H
15
16
9p
H
4-NO2
4-OMe
4-OMe
0
>100
Scheme 4 Mechanism of N2-aryl 1,2,3-triazole formation
4-OMe
4-Cl
90
67
0
7
16
6
We suggest that formation of this Wanzlick dimer may
occur through the carbenic resonance form 14 of the ni-
trile imine; which explains the tolerance of ortho substit-
uents on the N-aryl ring, but not the C-aryl ring.23 Based
on these observations, we also suggest that the tetrazine
byproducts previously reported during pyrazoline synthe-
ses15,16 may have been Wanzlick dimers, as their NMR
profile would appear similar. Furthermore, we did not ob-
serve tetrazine byproducts during our syntheses of pyra-
zoline adducts.
4-SO2NMe2 4-OMe
a Isopropyl alcohol–2-methyltetrahydrofuran solvent (5× volume).
a yield of 54% (Scheme 3). Such nucleophilic quenching
reactions have been reported previously.21,22 Repeating
the reaction in ethyl acetate also failed to yield the desired
product, presumably due to poor reactivity resulting from
the electron-withdrawing CN substituent. It should be not-
ed that trapping of the nitrile imine was not observed with
the more reactive tetrazole substrates.
Having investigated the synthesis of 2,4,5-triaryl 1,2,3-
triazoles, we then sought to determine if C-heterocyclic or
C-alkyl groups could be tolerated (Scheme 5).
Finally, the observed trends in reactivity were combined
when studying triazoles 9o–q (entries 15–17). As predict-
ed, combining an electron-rich N-aryl ring with electron-
donating groups on the C-aryl ring gave significant im-
provements in yields. However, the electron-withdrawing
effects of a sulfonamide moiety could not be surmounted.
Commercially available 4-(5-ethyl-2H-tetrazol-2-yl)ani-
line (17) was irradiated to give triazole 19 in a modest
23% yield. In this case, masking the aniline with an acet-
amide moiety failed to improve the yield, indicating that
C-alkyl groups are unfavourable. This could be attributed
to a less stable carbocation in the nitrile imine intermedi-
ate, compared to C-aryl systems, resulting in a complex
mixture of products. When irradiating C-morpholine
tetrazole 21 we were surprised to observe efficient con-
Interestingly, during the synthesis of triazole 9p a precip-
itate was formed and, when isolated, Wanzlick dimer 15
was obtained instead of the expected triazole (Scheme 4).
Synlett 2014, 25, 2480–2484
© Georg Thieme Verlag Stuttgart · New York

LETTER
N2-Aryl 1,2,3-Triazoles
2483
confirmed by comparison to the previously obtained prod-
uct (Scheme 6).
.
R
R
N
In conclusion, we have demonstrated the photochemical
synthesis of a number of 2,4,5-triaryl 1,2,3-triazoles in
two steps under mild conditions. Although the reaction
shows strong dependence on substituent effects, with
electron-donating groups giving the best reactivity, we be-
lieve the current approach offers efficient access to this
useful heterocyclic scaffold. This reaction is therefore
complementary to other synthetic routes and alternative
sources of nitrile imines can also be adopted. The synthe-
sis of N2-aryl 4,5-dialkyl 1,2,3-triazole and 3-substituted
indazole systems was also shown to be possible using this
methodology.
UVB lamp (270–330 nm)
2-PrOH–2-MeTHF (1:1)
r.t., 20 h
N
N
N
N
N
N
19 R = NH2 (23%)
20 R = NH(CO)Me (21%)
17 R = NH2
18 R = NH(CO)Me
98%
OMe
H
N
UVB lamp (270–330 nm)
2-PrOH–MeTHF (1:1)
r.t., 7 h
N
N
Acknowledgment
N
N
N
N
We would like to thank The University of Strathclyde and GlaxoS-
mithKline for the financial support of this project.
OMe
N
O
22 (79%)
O
21
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
Scheme 5 Synthesis of a N2-aryl 4,5-dialky 1,2,3-triazole and unex-
pected formation of substituted indazoles
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
version into 3-morpholine indazole 22. Such transforma-
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Finally, we wished to investigate if other sources of nitrile
imine intermediates could also yield 2,4,5-trisubtituted
1,2,3-triazoles. Interestingly, formation of tetrazine prod-
ucts via nitrile imine intermediates had been reported by
Molteni et al. from C-acyl and N-aryl hydrazonyl chlo-
rides.24 To determine if C-aryl substitution would instead
yield triazole products we synthesised hydrazonoyl chlo-
ride 2327 and generated nitrile imine 6f using sodium hy-
droxide. Gratifyingly, the main product of the reaction
was triazole 9f28 (29% yield, unoptimised conditions) as
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UVB lamp (270–330 nm)
Ar1
2-PrOH–2-MeTHF (1:1)
N
r.t.
N
N
N
Ar2
5f
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N
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N
N
N
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Ar2
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6f
9f
Ar1
NH
Ar1 = C6H4(4-Me)
Ar2 = Ph
N
NaOH (10 equiv)
THF, r.t., 30 min
Ar2
Cl
23
Scheme 6 Synthesis of triazole 9f from 2,5-diaryl tetrazoles or
hydrazonyl chlorides
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2480–2484

2484
S. Stewart et al.
LETTER
O2 (1 atm) at 110 °C for 6 h. The reaction mixture was
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chromatography (Si, 50 g, 0–10% EtOAc–cyclohexane, 60
min) gave 5-phenyl-2-(p-tolyl)-2H-tetrazole 5f (1.51 g,
93%) as a white solid; mp 103–104 °C. IR: 1507, 1448,
1212, 1012 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.26 (dd,
J = 2.0, 8.1 Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 7.57–7.47 (m,
3 H), 7.38 (d, J = 8.6 Hz, 2 H), 2.46 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.1, 139.9, 134.8, 130.5, 130.2,
128.9, 127.3, 127.0, 120.0, 119.8, 77.3, 77.2, 77.0, 76.7, 21.2
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Representative Example for the Preparation of 2,4,5-
Trisubstituted 1,2,3-Triazoles: 4,5-Diphenyl-2-(p-tolyl)-
2H-1,2,3-triazole (9f)
A solution of 5-phenyl-2-(p-tolyl)-2H-tetrazole 5f (200 mg,
0.85 mmol) in 2-PrOH–2-MeTHF (1:1, 10 mL) was stirred
under irradiation with a UVB lamp (270–330 nm) for 19 h.
The reaction mixture was concentrated in vacuo and the
residue purified by reverse-phase chromatography (Si C18,
50–95% MeCN–H2O, HCO2H modifier, 30 min) to give 4,5-
diphenyl-2-(p-tolyl)-2H-1,2,3-triazole 9f (62 mg, 47%) as a
brown gum. IR: 1510, 1441, 1268 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.10 (d, J = 8.6 Hz, 2 H), 7.72–7.65 (m, 4 H),
7.43 (dd, J = 1.9, 4.9 Hz, 6 H), 7.33 (d, J = 8.6 Hz, 2 H), 2.45
(s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 145.7, 137.6,
137.3, 130.9, 129.8, 128.6, 128.6, 128.5, 127.1, 118.7, 21.1.
HRMS (ESI+): m/z calcd for C21H18N3: 312.1495; found:
312.1496.
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Diaryl Tetrazoles: 5-Phenyl-2-(p-tolyl)-2H-tetrazole (5f)
A solution of p-tolyl boronic acid (1.86 g, 13.7 mmol), 5-
phenyl tetrazole (1.00 g, 6.84 mmol), and Cu2O (5 mol%,
0.049 g, 0.342 mmol) in DMSO (30 mL) was stirred under
Synlett 2014, 25, 2480–2484
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