Cycloaddition of Isocyanides with Aryl Diazonium Salts: Catalyst-Dependent Regioselective Synthesis of 1,3- and 1,5-Disubstituted 1,2,4-Triazoles

Article abstract of DOI:10.1021/acs.orglett.8b03069

An unprecedented catalyst-dependent regioselective [3 + 2] cycloaddition of isocyanides with aryl diazonium salts is reported. 1,3-Disubstituted 1,2,4-triazoles were selectively obtained in high yield under Ag(I) catalysis, whereas 1,5-disubstituted 1,2,4-triazoles were formed by Cu(II) catalysis. These catalytic methodologies provide a controlled, modular, and facile access to 1,2,4-triazole scaffolds with high efficiency, broad substrate scope, and excellent functional group compatibility.

Full text of DOI:10.1021/acs.orglett.8b03069

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[3 + 2] Cycloaddition of Isocyanides with Aryl Diazonium Salts:
Catalyst-Dependent Regioselective Synthesis of 1,3- and 1,5-
Disubstituted 1,2,4-Triazoles
Jian-Quan Liu,† Xuanyu Shen,† Yihan Wang,‡ Xiang-Shan Wang,*,† and Xihe Bi*,‡,§
†School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for Functional Materials Jiangsu Normal
University, Xuzhou, Jiangsu 221116, China
‡Department of Chemistry, Northeast Normal University, Changchun 130024, China
§State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An unprecedented catalyst-dependent regioselective [3 + 2] cycloaddition of isocyanides with aryl diazonium
salts is reported. 1,3-Disubstituted 1,2,4-triazoles were selectively obtained in high yield under Ag(I) catalysis, whereas 1,5-
disubstituted 1,2,4-triazoles were formed by Cu(II) catalysis. These catalytic methodologies provide a controlled, modular, and
facile access to 1,2,4-triazole scaffolds with high efficiency, broad substrate scope, and excellent functional group compatibility.
of isocyanides, which is a challenging issue to be explored in
socyanides are extraordinarily versatile building blocks in
Iorganic synthesis, widely applied in the formation of N- isocyanide chemistry.
heterocycles.1 To date, the significant advances have been
achieved.2 Among these reported protocols, the [3 + 2] dipolar
addition pathway is the most powerful and representative route
to construct five-membered nitrogen heterocyclic compounds,
which have been well developed.3 However, all of them only
afford the unitary products, owing to the carbene-like reactivity
of isocyanide divalent carbon atoms or the activity of α-H.
(Figure 1a). Thus, utilizing the competitive group properties
and altering reaction conditions could control the selectivity of a
reaction to diversified products from the same starting material
1,2,4-Triazole is a class of important heterocyclic frameworks
with multiple impressive applications in biological and
pharmacological arenas as well as in materials science.4 In this
context, we envisioned isocyano groups acting both as a
polarized triple bond and as a carbine and a regioselective [3 + 2]
cycloaddition of isocyanides with diazonium salts giving access
to 1,2,4-triazoles in a one-step straightforward synthesis, which
would benefit from the ready availability of the starting
materials.5 To the best of our knowledge, so far only two
reaction modes of isocyanides with diazonium salts have been
described (Figure 1b).6 The pioneering work by the Matsumoto
group disclosed the significant impact of the electronic effect of
diazonium salts on the reaction outcome.6a Specifically, the
diazonium salts with an electron-donating group readily
underwent a [3 + 2] cycloaddition with isocyanides to give
1,3-disubstituted 1,2,4-triazoles, whereas diazonium salts with
an electron-withdrawing group afforded arylcarboxyamides via
the nucleophilic displacement of nitrogen, followed by
hydration of the nitrilium ion intermediate species. The
broadening of the reaction scope and an improvement of the
regioselectivity for these cycloaddition reactions remain
challenging. In recent years, transition-metal catalysts, such as
copper and silver salts, have proven effective in the exploration of
the chemistry of isocyanides,7 particularly for its cycloaddition
reactions.8,9 In alignment with our continuing interest in copper-
and silver-catalyzed organic transformations,10 we herein report
the first regioselective cycloaddition of isocyanides to diazonium
Figure 1. State of the art for the reaction of isocyanides with diazonium
salts.
Received: September 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
salts (Figure 1c), thereby providing in good yield and functional
group compatibility either 1,3- or 1,5-disubstituted 1,2,4-
triazoles, depending on the catalyst (i.e., silver(I) or copper(II)
salts).
We began by using benzenediazonium tetrafluoroborate (1a)
and ethyl 2-isocyanoacetate (2a) as model substrates for our
investigation into this reaction. In the presence of Ag2CO3 (10
mol %), the reaction in N,N-dimethylformamide (DMF)
exclusively afforded after 6 h at room temperature the 1,3-
disubstituted 1,2,4-triazole (4a) in 65% isolated yield (Table 1,
yields of 3a (entry 15), clearly suggesting that copper salts may
control the product selectivity for 3a, while AgOAc serves as a
base. When LiOAc was used as a base, the yield of the target
product 3a increased (entry 16). Replacement of DCE with
THF resulted in maximization of the product 3a yield (entry
17). A comparative experiment between 1g (4-(trifluoro-
methyl)phenyldiazonium tetrafluoroborate) and 2a under
Matsumoto’s conditions6a failed to produce the expected
products 3g or 4d.
Under the optimized reaction conditions, we explored the
versatility of the [3 + 2] cycloaddition to 1,5-disubstituted 1,2,4-
triazoles in the presence of catalytic amounts of Cu(OAc)2
(Scheme 1). A range of variously functionalized diazonium salts
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of 1,5-Disubstituted 1,2,4-Triazoles
b
yield (%)
entry
[M]
additive
solvent
DMF
T (°C) 3a
4a
1
2
3
4
5
6
7
8
Ag2CO3
AgOAc
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0
0
0
0
0
0
0
0
0
65
61
58
0
0
23
0
74
26
76
79
85
49
41
38
17
15
DMF
DMF
DMF
DMF
DMF
DMF
1,4-dioxane
MeOH
THF
toluene
DCE
DCE
DCE
DCE
AgF
Ag3PO4
CuI
Pd(OAc)2
AuCl(PPh3)2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
9
10
11
12
0
0
0
c
13
CuI
0
0
0
0
33
37
46
52
72
c
14
Cu(OAc)2
Cu(OAc)2
LiOAc
c
15
d
16
Cu(OAc)2
Cu(OAc)2
DCE
THF
d
17
LiOAc
0
a
Standard reaction conditions: all reactions were carried out with 1a
(0.5 mmol), 2a (0.6 mmol), and catalyst (10 mol %) in solvent (2.0
b
c
mL) under Ar atmosphere for 6 h. Yield of isolated product. The
d
amount of additive is 10 mol %. The amount of additive is 2.0 equiv.
reacted with isocyanides to afford the corresponding products 3
in good yields. Both electron-donating and electron-with-
drawing substituents on the benzenediazonium tetrafluorobo-
rate reactants were tolerated in the reaction with isocyanide 2a,
leading to the desired products (3a−h) in moderate to good
yields. Disubstituted benzenediazonium tetrafluoroborates were
also compatible with the cycloaddition reaction conditions,
affording the corresponding products (3i−k) in high yields.
Treatment of fused aromatic (1l and 1m) diazonium salts with
2a also efficiently afforded the expected products 3l and 3m.
Substrates with potentially reactive functional groups, such as
keto and alkynyl groups, were productive under the optimized
conditions, giving compounds 3n−p in 43−71% yield.1,11
Methyl isocyanoacetate (2b) and toluenesulfonylmethyl iso-
cyanide (2c) also smoothly reacted with diazonium salt 1j,
producing 1,5-disubstituted cycloadducts 3q and 3r in 74% and
57% yield, respectively. The structure of product 3r was
conclusively assigned by single-crystal X-ray analysis.
entry 1). Upon screening a range of silver salts, we observed that
both AgOAc and AgF were efficient catalysts, while Ag3PO4 was
unreactive under the same conditions (entries 2−4). In contrast,
other known metal catalysts, such as CuI, Pd(OAc)2, and
AuCl(PPh3)2, were not reactive or gave 4a in poor yield (entries
5−7). Solvent effects were also investigated (entries 8−12).
Although 1,4-dioxane, THF, and toluene (entries 8, 10, and 11)
also allowed for a satisfactory reaction outcome, 1,2-dichloro-
ethane (DCE) proved the most suitable, giving the highest yield
even when the reaction was run at 0 °C (entry 12). Conversely,
methanol produced 4a in poor yield.
We then turned our attention to the synthesis of 1,5-
disubstituted 1,2,4-triazoles by varying the catalyst while
maintaining a reaction temperature of 0 °C. Intriguingly, when
CuI (10 mol %) was introduced as an additive in the Ag2CO3-
catalyzed reaction, regioisomeric 1,5-disubstituted 1,2,4-triazole
(3a) was formed instead in 33% yield, along with 4a in 49% yield
(entry 13). In an attempt to boost efficiency and selectivity, a
range of binary metal catalysts incorporating silver were
employed, such as Cu/Ag, Rh/Ag, and Pd/Ag (entry 14; see
the Supporting Information for more details). We found that the
combination of AgOAc with Cu(OAc)2 provided increased
The scope and limitations of the silver-catalyzed cyclo-
addition of isocyanides to diazonium salts to give 1,3-
disubstituted 1,2,4-triazoles were subsequently investigated. As
shown in Scheme 2, benzenediazonium tetrafluoroborates
bearing electron-withdrawing groups (Br, I, Cl, CF3, and
B
DOI: 10.1021/acs.orglett.8b03069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of 1,3-Disubstituted 1,2,4-Triazoles
Scheme 3. Gram-Scale Synthesis and Application to the
Synthesis of ABEE Derivatives
Scheme 4. Mechanistic Investigations
CO2Me) were well tolerated in the reaction with 2a, delivering
the corresponding cycloadducts 4b−k in up to 82% yield. Under
the conditions described by Matsumoto, the same reactants
failed to give the same products.6 Diazonium tetrafluoroborates
featuring fused aromatics, such as the 2-naphthyl and 2-fluorenyl
groups, or electron-donating (Me, OMe) substituents provided
the corresponding products (4l−o) in yields comparable to or
higher than that recorded for substrates with electron-with-
drawing substituents. The structure of 4o (CCDC 1816490)
was unequivocally confirmed by X-ray diffraction analysis.
Similar to the copper-catalyzed cycloaddition, the silver-
catalyzed protocol could also be applied to a variety of
disubstituted diazonium salts (4s−y), including those with a
keto or alkynyl functionality, from which the target products
4aa−ac were obtained in good yields. Methyl 2-isocyanoacetate
(2b) and toluenesulfonylmethyl isocyanide (2c) also proved
reactive and gave the corresponding products 4ad and 4ae in
high yields.
To determine the robustness of this method, two reactions
between benzenediazonium tetrafluoroborate 1a and ethyl 2-
isocyanoacetate 2a were conducted on a 10 mmol scale (1.92 g
of 1a) under both catalytic optimized conditions. The two
desired products 3a and 4a were obtained in moderate to good
yield (Scheme 3, eq 1). When the optimized cycloaddition
reaction conditions were applied to commercially available
benzocaine (ABEE) as starting material,12 1,2,4-triazole
derivatives 5a and 5b were obtianed in good yield (eq 2).
A series of control experiments was executed to investigate the
reaction mechanism (Scheme 4). Under the optimized
conditions, the addition of 2 equiv of radical scavengers such
as TEMPO or BHT to the reaction mixture (Scheme 4, eq 3) did
not affect the reaction rate, with the desired cycloadducts 3a and
4a being produced in 67% and 79% yield, respectively. This
result indicates that the reaction did not likely proceed via a
radical process.13
The addition of 2 equiv of D2O to the reaction mixture
resulted in the formation of deuterated 1,2,4-triazoles [D]-3a
and [D]-4a in comparable yield. However, deuterium was
incorporated in [D]-3a to a lesser extent (35%) than in [D]-4a
(90%) (Scheme 4, eq 4). Based on these experimental
observations, we surmised that the two regioisomeric 1,2,4-
triazoles were formed via two different mechanistic routes, with
water playing the role as a proton source in one of them.
Moreover, when the reaction of 1j and 2d′ was carried out under
the optimized conditions, the desired methyl group fragmented
products 3r and 4y′ were obtained in 43% and 67% yields
(Scheme 4, eq 5).
The described experiments and literature precedents14 led us
to propose the plausible mechanism shown in Scheme 5,
whereby the nature of the interaction between the metal catalyst
and the isocyanide determines the formation of either 3a or 4a.
In the case of the copper-catalyzed reaction, isocyanide 2a
coordinates with Cu(OAc)2 to generated the copper complex
A.1a,15 In the presence of base, cross-coupling between A and
diazonium salt 1a gives intermediate B, which undergoes an
intramolecular nucleophilic addition to form cyclized cationic
C
DOI: 10.1021/acs.orglett.8b03069
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Organic Letters
Letter
ORCID
Scheme 5. Proposed Reaction Mechanism
Xiang-Shan Wang: 0000-0002-0077-7819
Xihe Bi: 0000-0002-6694-6742
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by NSFC of China
(21702078, 21871043) and NSF of Jiangsu Province
(BK20170231).
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03069.
Experimental procedures and spectra (PDF)
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Accession Codes
CCDC 1816490 and 1817318 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
(18) Liao, J.-Y.; Shao, P.-L.; Zhao, Y. J. Am. Chem. Soc. 2015, 137, 628.
(19) Ma, Y.; Yan, Z.; Bian, C.; Li, K.; Zhang, X.; Wang, M.; Gao, X.;
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*E-mail: bixh507@nenu.edu.cn.
*E-mail: xswang1974@yahoo.com.
D
DOI: 10.1021/acs.orglett.8b03069
Org. Lett. XXXX, XXX, XXX−XXX