Cycloaddition of Nitrile Ylides with Diazonium Salts: Copper-Catalyzed One-Pot Synthesis of Fully Substituted 1,2,4-Triazoles

Article abstract of DOI:10.1021/acs.orglett.8b02172

A novel [3 + 2] cycloaddition between nitrile ylides and diazonium salts was well-established. This copper-catalyzed three-component reaction was distinguished by mild conditions, ready availability, and operational simplicity, thus opening access to 1,2,

Full text of DOI:10.1021/acs.orglett.8b02172

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[3 + 2] Cycloaddition of Nitrile Ylides with Diazonium Salts: Copper-
Catalyzed One-Pot Synthesis of Fully Substituted 1,2,4-Triazoles
Huihuang Li, Xueli Wu, Weiwei Hao, Haiyan Li, Yanwei Zhao, Yaxiong Wang, Pengcheng Lian,
Yonggao Zheng, Xiaoguang Bao,* and Xiaobing Wan*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: A novel [3 + 2] cycloaddition between nitrile
ylides and diazonium salts was well-established. This copper-
catalyzed three-component reaction was distinguished by mild
conditions, ready availability, and operational simplicity, thus
opening access to 1,2,4-triazoles with a diverse set of
substitution patterns.
he nitrile ylides are privileged and readily accessible 1,3-
dipoles and have become attractive and powerful
carboxylic acids for the synthesis of unsymmetrical glycine
esters.2c To the best of our knowledge, trapping of nitrile ylide
with a triple bond system to perform intermolecular [3 + 2]
cycloaddition has not yet been reliably implemented. As
illustrated in Scheme 1c, we hypothesized that diazonium salts,
which are a class of readily available and versatile synthetic
precursors,3,4 could undergo [3 + 2] cycloaddition with nitrile
ylides generated in situ from nitriles and diazo compounds to
form the desired 1,2,4-triazoles. Substituted 1,2,4-triazoles and
their derivatives, as privileged nitrogen-containing structural
units, have found wide application in medicines,5 pesticides,6
materials science,7 and organocatalysts,8 and many chemists
have committed to developing practical methods to deliver this
skeleton.9−11
T
synthons for building various heterocyclic compounds.1,2 The
intramolecular cycloaddition of nitrile ylides, which were
generated from the nucleophilic reaction of nitriles and
carbenoids, has evolved into a classic and proverbial reaction
process for synthesis of nitrogen-containing heterocyclic
compounds (see Scheme 1a).1 In sharp contrast, the relevant
Scheme 1. Transformation of Nitrile Ylides
Our initial studies focused on searching for an optimal
catalytic condition to generate 1,2,4-triazole 4a efficiently,
using p-methoxyphenyldiazonium tetrafluoroborate (1a), ethyl
2-diazoacetate (2a), and acetonitrile (3a) as reaction
substrates. Delightfully, an 85% yield of the target product
4a was obtained in the presence of 20 mol % CuBr and 1.0
equiv Li2CO3 at 40 °C for 1 h (see Table S1, entry 1, in the
Supporting Information). Next, we tested other transition-
metal catalysts, such as Cu(OTf)2, CuOTf Pd(OAc)2,
Rh2(OAc)4, AuCl, AgOAc, Mn(OAc)2·4H2O, Co(acac)2,
Fe2(CO)9, leading to significantly decreased yields (see
Table S1, entries 2−10). Not surprisingly, no product 4a
was observed in the absence of the copper catalyst (see Table
S1, entry 11). Replacing Li2CO3 with other inorganic bases
resulted in lower yields (see Table S1, entries 12−17), and the
cascade reaction hardly worked when organic bases, including
4-dimethylaminopyridine (DMAP), triethylenediamine
(DABCO), triethylamine (TEA), were used for this 1,2,4-
triazole formation reaction (see Table S1, entries 18−20).
reports about intermolecular interception of nitrile ylide are
very rare.2 In 2014, Liu and co-workers reported an elegant
gold-catalyzed 1,2-oxoarylation of nitriles through the inter-
molecular nucleophilic attack to nitrile ylides with pyridine-
derived N-oxides (see Scheme 1b).2a Very recently, we
developed an efficient copper-catalyzed three-component
cascade reaction via the interception of nitrile ylide with
Received: July 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02172
Org. Lett. XXXX, XXX, XXX−XXX

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a
With the optimized reaction conditions being identified, the
scope of aryldiazonium tetrafluoroborate was investigated as
shown in Scheme 2. The benzene ring of diazonium salt with
Scheme 3. Scope of Diazo Compounds
a
Scheme 2. Scope of Diazonium Salts
a
Conditions: 1a (0.2 mmol), 2 (0.6 mmol), 3a (0.5 mL), CuBr (20
mol %), and Li2CO3 (1.0 equiv) in a test tube was stirred at 40 °C for
a
Conditions: 1 (0.2 mmol), 2a (0.6 mmol), 3a (0.5 mL), CuBr (20
b
1 h under air. The isolated yield for a reaction performed on a 1.0
mol %), and Li2CO3 (1.0 equiv) in a test tube was stirred at 40 °C for
1 h under air. The isolated yield for a reaction performed on a 1.0
mmol scale is shown in parentheses.
b
mmol scale is shown in parentheses.
a
Scheme 4. Scope of Nitriles
electron-donating groups at the para-, meta-, and ortho-
position proceeded well, affording the corresponding 1,2,4-
triazole in moderate to good yields (4a−4f, 4k, 4o). Notably,
substrates containing halogen groups were also tolerated well
and delivered the desired products in satisfactory yields under
the standard reaction conditions (4g−4i, 4l, 4m). The reaction
efficiency was relatively low when aryldiazonium-bearing
electron-withdrawing groups, such as trifluoromethoxy (4j),
trifluoromethyl (4n), nitro (4q), and ester (4r), were used as
reaction partners. Finally, both multisubstituted phenyl
diazoniums (4p−4r) and naphthyl diazonium (4s) worked
well for this 1,2,4-triazole formation reaction. Unfortunately, 4-
nitrophenyl diazonium salt was not a suitable substrate for this
transformation.
We next tested the scope with respect to the diazo
compounds, as shown in Scheme 3. Various diazo acetates
were successfully employed as reaction partners in this reaction
(5a−5f), and the decrease of yield was detected due to the
steric hindrance (5b). A wide range of functional groups, such
as trimethylsilyl (5g), ether (5h), trifluoromethyl (5i), bromo
(5j), thienyl (5k), were well-tolerated in this transformation,
leading to the desired products in satisfactory yields. Note that
both terminal and internal vinyl did not interfere with this
process, which provided an opportunity for further synthetic
manipulation (5l, 5m).
As illustrated by the examples shown in Scheme 4, nitriles
bearing various alkyl groups participated well in this trans-
formation. Primary, secondary, and tertiary nitriles smoothly
underwent cyclization to give the corresponding products in
good yields (6a−6c). Incorporation of different functional
groups into the nitriles, including benzyl (6d), chloro (6e), or
ether group (6f), exhibited inconspicuous effects on product
formation. More attractively, the reactions were also suitable
for vinyl nitriles to deliver the desired products (6g−6i), which
were hardly achieved using previous methods. In addition, the
exact structure of product 6i was expressly determined by X-
ray crystallography.
a
Conditions: 1a (0.2 mmol), 2a (0.6 mmol), 3 (0.5 mL), CuBr (20
mol %), and Li2CO3 (1.0 equiv) in a test tube was stirred at 40 °C for
1 h under air. The isolated yield for a reaction performed on a 1.0
mmol scale is shown in parentheses.
b
A battery of preliminary studies was performed to gain
mechanistic insight into this 1,2,4-triazole formation reaction.
Isotope tracer technique showed that the two N atoms of the
target 1,2,4-triazole molecules originated from aromatic
diazonium salt (Scheme 5a). When 4-tert-butylstyrene was
added to our model reaction, the cyclopropanation product 7
was detected by GC-MS, which implied that a carbene
intermediate was involved in this process (Scheme 5b).12
Notably, analysis of the reaction mixture of nitrile 3i indicated
that the amidated compound 8 was generated in 13% yield
(Scheme 5c), suggesting that the in situ generation of nitrile
ylide intermediate and subsequent interception by water were
involved in this transformation.1
Computational studies were performed to provide a
mechanistic insight into this 1,2,4-triazole formation reaction
(see Figure 1). First, the Cu-catalzyed N2 elimination from
both 2a and 1a cation were evaluated. Computational results
show that the free-energy barrier of extrusion of N2 from diazo
compound 2a is 14.3 kcal/mol, which is 15.9 kcal/mol lower
B
DOI: 10.1021/acs.orglett.8b02172
Org. Lett. XXXX, XXX, XXX−XXX

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1,2,4-triazole is illustrated in Figure 2. The transformation
begins with the formation of carbenoid A from the copper
Scheme 5. Mechanistic Studies
Figure 2. Proposed mechanism.
catalyst coordinated with diazo compounds. Subsequently, the
nitrile performs as a nucleophile to attack A to generate
intermediate B.1,2 The resulting intermediates B subsequently
undergo [3 + 2] cycloaddition with diazonium salt to afford
the five-membered ring intermediate C, which strips a proton
and isomerizes to access the target 1,2,4-triazole in the
presence of base. On the other hand, a small amount of nitrile
ylide intermediate B can be trapped by water to generate
undesired amides as byproducts.
In summary, we have demonstrated a copper-catalyzed
intermolecular [3 + 2] cycloaddition reaction to afford 1,2,4-
triazoles in moderate to high yields, which proceeds via the
trapping of an intermediary nitriles ylides species by diazonium
salt. This methodology offers a simple and efficient strategy to
construct structurally diverse 1,2,4-triazos from readily
available starting materials in a one-step fashion under mild
condition. The preliminary experimental results show that
diazonium salts served as the two N atoms resource for the
target 1,2,4-triazoles skeletons. Further investigations on the
interception of nitriles ylides with other reagents are ongoing
in our laboratory.
Figure 1. Energy profiles (in kcal/mol) for the formation of the Cu-
carbenoid INT1 and the subsequent nucleophilic attacks of 1a+/3a.
Bond lengths are shown in Ångstroms.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02172.
■
S
than that obtained from the 1a cation. Thus, the formation of
the Cu-carbenoid intermediate INT1 is more likely to occur.
Subsequently, the substrate acetonitrile (3a) may undergo a
nucleophilic attack to the carbenoid site of INT1 to afford the
nitrile ylide intermediate INT2. The predicted free-energy
barrier is 13.6 kcal/mol, relative to separated INT1 and 3a and
the generated INT2 is thermodynamically stable. One may
propose that the nucleophilic attack of the diazonium salt 1a to
the carbenoid of INT1 might also be possible. Computational
results suggest that a much higher energy barrier (39.5 kcal/
mol) is required to undergo such a reaction route, which is
unlikely to occur, compared with the nucleophilic attack of 3a.
Afterward, a [3 + 2] cycloaddition reaction between the
generated INT2 and 1a cation could occur, yielding the
intermediate INT3. The predicted free-energy barrier for this
process is 25.5 kcal/mol. Finally, a deprotonation step assisted
by Li2CO3 occurs to furnish the final product 1,2,4-triazole
(4a).
Experimental procedures and full spectroscopic data for
all new compounds, computational method, Figure S1,
and Cartesian coordinates and energies (PDF)
Accession Codes
CCDC 1827426 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xgbao@suda.edu.cn (X. Bao).
*E-mail: wanxb@suda.edu.cn (X. Wan).
ORCID
Based on the above experimental results and DFT
calculations, a plausible mechanism for the construction of
Xiaoguang Bao: 0000-0001-7190-8866
C
DOI: 10.1021/acs.orglett.8b02172
Org. Lett. XXXX, XXX, XXX−XXX

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Meanwell, N. A. Tetrahedron Lett. 2005, 46, 3429. (f) Wang, Y.; Xu,
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S.; Rodriguez, E.; Charette, A. B. Org. Lett. 2015, 17, 1184.
Xiaobing Wan: 0000-0001-9007-2128
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This project was funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions
(PAPD) and NSFC (Nos. 21572148 and 21272165).
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