Synthesis of Trisubstituted 1,2,4-Triazoles from Azlactones and Aryldiazonium Salts by a Cycloaddition/Decarboxylation Cascade

Article abstract of DOI:10.1002/ejoc.201901467

Azlactones, also known as oxazolones, possess multiple reactive sites, and are thus widely used as versatile class of reagents in organic synthesis, particularly in cycloaddition reactions for heterocycle synthesis. However, the use of azlactones as three

Full text of DOI:10.1002/ejoc.201901467

A Journal of
Accepted Article
Title: Synthesis of Trisubstituted 1,2,4-Triazoles from Azlactones and
Aryldiazounium Salts by Way of Cycloaddition/Decarboxylation
Cascade
Authors: Xiao-Ye Yu, Wen-Jing Xiao, and Jia-Rong Chen
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10.1002/ejoc.201901467
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Trisubstituted 1,2,4-Triazoles from Azlactones and
Aryldiazounium Salts by Way of Cycloaddition/Decarboxylation
Cascade
Xiao-Ye Yu,[a] Wen-Jing Xiao,[a] and Jia-Rong Chen*[a]
Abstract: Azlactones, also known as oxazolones, possess multiple
reactive sites, and are thus widely used as versatile class of
reagents in organic synthesis, particularly in cycloaddition reactions
for heterocycle synthesis. However, the use of azlactones as three-
member fragments in cycloaddition reactions/decarboxylation
mediated dehydrogenative [2+2+1] heteroannulation of N-(o-
alkenylaryl)imines with aryldiazonium salts, wherein the
aryldiazonium salts worked as two-nitrogen unit.[7] To date, few
examples were reported employing these components of
azlactones and aryldiazonium salts to construct heterocycles.
1,2,4-Triazoles are a class of privileged heterocycles, which
not only exhibit broad spectrum of biological activities, but also
exist as core units in many bioactive natural occurring products
(Scheme 1b).[8] For example, both compounds I and II are
pharmaceuticals that are often used as antifungals in clinical
settings.[9a] Bioactive compound III was isolated from the marine
sediment derived fungus Penicillium paneum SD-44.[9b]
Stimulated by the biological significance of the 1,2,4-triazole
scaffolds, a large numbers of practical synthetic methods for
cascade were rarely explored. In this context,
a metal-free
cycloaddition/decarboxylation reaction between azlactones and
aryldiazonium salts has been achieved for the first time, which
provides efficient and facile access to privileged 1,3,5-trisubstituted
1,2,4-triazoles. Notably, aryldiazonium salts serve as two-nitrogen
unit rather than the sources of aryl radicals in this transformation,
which provides an alternative class of reagents for the construction
of N-heterocycles.
their synthesis have thus been developed.[10]
a) Reactive sites of azlactones
Introduction
O
O
R2
R2
electrophile site
nucleophile site
Azlactones, also known as oxazolones, possess multiple
reactive sites; for example, C2 and C5 atoms present
electrophilic nature, while C4 is nucleophilic. Notably, C2
position can be involved in the reaction with electrophiles due to
enol tautomerism (Scheme 1a).[1] These reactivities of azlactone
render them as a type of versatile building blocks for synthesis
of diverse unnatural α-amino acids and privileged heterocyclic
scaffolds. Recently, azlactones have also been widely applied to
1,2 or 1,4-addition reactions that simply occurred at the C4 or
C5 position.[2] Moreover, [4+2] cycloaddition reactions of
azlactones that employed both of the C4 and C5 positions are
also well documented.[3] However, the cycloaddition reactions
which take advantage of nucleophilic C4 and electrophilic C2
atoms of azlactones have been rarely reported.[4] Hence,
exploration of new reaction modes of azlactones to search for
new cycloaddition reactions is still a research topic of great
interest.
O
O
N
N
2
R1
R1
azlactones
enol tautomerism
b) Selected biologically active compounds with a 1,2,4-triazole core
N
N
CO2H
N
N
N
F
N
N
N
N
N
N
OH
OH
N
N
N
Me
F
F
F
F
OH
I
II
III
c) Our method: cycloaddition/decarboxylation cascade
O
O
N
Ar
O
H
This work
N
R
R
N2BF4
Ar1
+
O
R
N
Ar
N
N
N
N
Ar1
Ar1
Ar
Scheme 1. Context of azlactones and 1,2,4-triazoles as well as object of this
Aryldiazonium salts are usually employed as the source of aryl
radicals in diverse arylation reactions such as the classic name
reaction-Meerwein arylation.[5] Furthermore, the aryldiazonium
salts could also trap the C-centered radical intermediates with
incorporation of N-N double bond into the final products.[6] It is of
particular note that these salts could successfully participate in
cycloaddition reactions. For example, in 2016, Li, Song, and
work.
The 1,2,4-triazole scaffolds can typically be assembled
through the three categories of methods: condensation reaction
of amides or thioamides with hydrazides,[11] condensation
reaction between in situ-generated primary acylamidines via
primary amidines with activated carboxylic acids, and alkyl
hydrazine, as well as oxidative cyclization in the presence of
copper salt and oxidant.[12] However, the relatively high reaction
temperature and multiple-step operation limit their broad
application in synthetic chemistry to somewhat extent, whereas
the third method usually leads to low yield of the corresponding
1H-3,5-disubstitued products. Hence, development of general
and efficient methods for synthesis of 1,3-disubstituted or 1,3,5-
trisubstituted 1,2,4-triazole cores under the mild condition is still
a highly desirable task for chemists.[13] Drawing inspiration from
this work, we hypothesized that a cycloaddition reaction of
aryldiazonium salts and azlactones might occur to provide
their coworkers discloesed
a pioneering molecular sieve-
[a]
Dr. X.-Y. Yu, Prof. Dr. W.-J. Xiao, Prof. Dr. J.-R. Chen
CCNU-uOttawa Joint Research Centre, Hubei International
Scientific and Technological Cooperation Base of Pesticide and
Green Synthesis, Key Laboratory of Pesticides & Chemical Biology
Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430079, China
E-mail: chenjiarong@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn
Homepage: http://www.jrchen-group.com/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901467
European Journal of Organic Chemistry
COMMUNICATION
practical access to 1,3,5-trisubstituted 1,2,4-triazoles (scheme
1c).
reacted well to furnish the corresponding products 3ba-da and
3ee-fe in moderate to good yields. Interestingly, in the cases of
aryldiazonium salts 1c and 1d, the corresponding products were
obtained as mixture of regioisomers with 2.2:1 and 1:1.6 ratios,
respectively. The structure of major isomer of 3da’ had also
been confirmed by X-ray diffraction analysis.[14] The major
isomers should be formed through the addition of the C2
position of azlactone as nucleophilic site. Though the precise
reaction mechanism remains to be elucidated, it seems
reasonable to presume that the electronic property of the phenyl
ring might play an important role in the regioselectivity of the
reaction.[15] The substrates 1e and 1f bearing electron-donating
groups such as OMe, Me at the para-position of the phenyl ring
as well as the neutral substrate 1g all reacted well with
azlactones 2a and 2e, giving the desired products with moderate
yields.
Results and Discussion
To examine the feasibility of our hypothesis, we started our
investigation with 4-nitrobenzenediazonium tetrafluoroborate 1a
and azlactone 2a as model substrates in CH3CN under Ar at
room temperature without any transition metal catalyst (Table 1).
To our delight, the desired cycloaddition/decarboxylation
reaction indeed occurred to give the corresponding product 3aa
with exclusive regioselectivity in 32% yield (Table 1, entry 1).
The structure of 3aa was also confirmed by its X-ray
crystallographic analysis.[14] Then, we turned our attention to
˖
screening of additives and found that MgCl2 6H2O can
significantly improve the reaction yield (entry 2). Further
extensive screen of different commonly used salts containing
coordinating chloride anions revealed that addition of Bu4N+Cl−
enhanced the yield of 3aa to 68% (entry 5). In order to confirm
the role of Bu4N+Cl−, we further screened ammonium salts of
different anions and found that Bu4N+Cl− still exhibited the best
result (entries 5-7). These results showed that Bu4N+Cl− might
serve as Cl source to stabilized the intermediate, thus faciliatting
the reaction. Subsequently, a brief evaluation of the reaction
media showed that CH3CN is still the best solvent of choice. A
range of commonly used solvents such as acetone, CH2Cl2 and
DCE displayed inferior results compared to CH3CN (entries 8-
10); while the reactions performed in polar solvents such as
MeOH, DMF or DMSO resulted in no target products (Table 1,
entries 11-13). Next, we attempted to further improve the yield
by adding molecular sieves or some desiccants as co-additives
(entries 14-17). To our delight, upon addition of Na2SO4 as
drying reagent, the reaction proceeded smoothly to afford
product 3aa with 72% yield (entry 17).
Table 1. Condition optimization.[a]
Entry
Additive
-
Solvent
Yield[%][b]
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Acetone
CH2Cl2
DCE
32
˖
2
MgCl2 6H2O
50
3
LiCl
64
4
KCl
64
5
nBu4NCl
nBu4NBr
nBu4NI
68
6
50
7
48
8
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
20
9
48
10
11
12
13
14[c]
15[d]
16[e]
17[f]
44
Having established the optimal reaction conditions, we next
MeOH
DMF
N.D.
Trace
Trace
50
explored
the
substrate
scope
of
the
cycloaddition/decarboxylation (Table 2). Aside from 2a, the
reaction tolerated different substituted functional groups on the
aryl moiety such as Me or F, furnishing the desired products 3ab
and 3ac with good yield in spite of moderate regioselectivity for
product 3ab. In addition, we also examined the generality of the
reaction by using various azlactones. A range of azlactones 2d-
h derived from differently substituted amino acids with R being
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
27
65
72
[a] Unless noted otherwise, reactions were performed with 1a (0.1 mmol), 2a
(0.15 mmol), and additive (20 mol%) in solvent (2 mL) under argon
atmosphere at room temperature for 9 h. DCE = 1, 2-dichloroethane. N.D. =
Not detected. [b] Isolated yield. [c] 25 mg of activated 3Ǻ MS was added. [d]
25 mg (30 wt%) of activated 4Ǻ MS was added. [e] 25 mg (30 wt%) of MgSO4.
[f] 25 mg (30 wt%) of Na2SO4.
various
alkyl
groups
can
react
well
with
4-
nitrobenzenediazonium tetrafluoroborate 1a; and the desired
products 3ad-ah were obtained with 43-72% yields. Furthermore,
N-Boc protected tryptophane derived azlactone 2i also
participated in the desired reaction smoothly to give the
corresponding product 3ai in moderate yield. However, as
shown in the cases of 2j and 2k, no desired products 3aj and
3ak were observed when a phenyl group or hydrogen was
incorporated at C4 position of azlactones.
As demonstrated in the synthesis of 1,2,4-triazoles 3ha and
3ia, variation of the substitution pattern of the phenyl ring has no
obvious deleterious effect on the reaction. In addition, the
reactions
of
2-naphthyldiazonium
salt
1j
and
1-
naphthyldiazonium salt 1k also proceeded smoothly to deliver
the expected products 3ja and 3ka in 47% and 35% yields,
respectively. Notably, heteroaryl group substituted diazonium
salt 1l also proved to be suitable for the reaction, resulting in the
formation of product 3la in 56% yield.
Then, we continued to evaluate the substrate scope of
aryldiazonium tetrafluoroborates by reacting them with
azlactones 2a and 2e. It was found that a wide range of
aryldiazonium salts 1b-f bearing electron-withdrawing or
electron-donating group at the para-position of the aromatic ring
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10.1002/ejoc.201901467
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COMMUNICATION
On the basis of related literature,[4,16] a possible mechanism is
then proposed as outlined in Scheme 2. For example,
azlactones 2a first undergoes isomerization to its enol tautomer
2a’, which reacts with aryldiazonium salt 1a in
a
cycloaddition manner to generate uns intermediate A. Then,
intermediate A undergoes facile ring-opening decarboxylation to
[3+2]
Table 2. Substrate scope of aryl diazonium salts and azlactones.[a, b]
[a] Unless otherwise noted, reactions were performed with aryl diazonium salts 1 (0.3 mmol), 2 (0.45 mmol), Bu4N+Cl− (20 mol%) and Na2SO4
(30 wt%, 75 mg) in CH3CN under Ar at room temperature for 24 h. [b] Isolated yield. [c] N.D. = Not detected. [d]r.r. = regioselectivity ratio. [e] The ratio
of 1 and 2 is 1.5 to 1.0.
give the final product 3aa. This process should be driven by its
inherent strong propensity for aromatization. On the other hand,
enol 2a’ could also isomerize to B and its nucleophilic C4
position first undergoes addition to aryldiazonium salt 1c or 1d,
followed by cyclization to give formal [3+2] adduct C. Then,
intermediate C undergoes further ring-opening decarboxylation
to afford the corresponding isomeric products 3ca’ and 3ad’.
The additive could facilitate the enolization of the azlactone 2a to
form 2a’.
Scheme 2. The possible mechanism.
Conclusions
In conclusion, we have developed an efficient and practical
method for synthesis of 1,3,5-trisubstituted 1,2,4-triazoles by a
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10.1002/ejoc.201901467
European Journal of Organic Chemistry
COMMUNICATION
cycloaddition/decarboxylation cascade of aryl diazonium salts
with azlactones. In this process, the aryl diazonium salts serve
as two-nitrogen units rather than sources of aryl radicals.
Considering the operational simplicity and broad substrate
scope, the current protocol provides a complementary approach
to access an library of interesting and biologically important
1,2,4-triazoles.
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Experimental Section
General procedure for the Cycloaddition/Decarbonation of
Azlactones with Aryldiazonium: 1a (67.2 mg, 0.3 mmol), 2a (87.6 mg,
0.45 mmol), nBu4NCl (16.7 mg, 0.06 mmol) and Na2SO4 (75 mg, 25
mg/mmol) were dissolved in CH3CN (6.0 mL) in a Schlenk tube under Ar.
The resulting mixture was stirred continuously until the reaction was
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yield. H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.7 Hz, 2H), 7.54 (d, J =
8.7 Hz, 2H), 7.47 (d, J = 7.2 Hz, 3H), 7.41 (t, J = 7.6 Hz, 2H), 2.53 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 161.3, 154.4, 146.4, 142.5, 130.3, 128.6,
128.6, 127.2, 124.7, 124.5, 13.9. IR (in KBr): 1520, 1380, 1089, 1250,
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Acknowledgments
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We are grateful to the NNSFC (21622201, 21772053,
91856119, 21971081, and 21820102003), the Science and
Technology Department of Hubei Province (2016CFA050 and
2017AHB047), and the Program of Introducing Talents of
Discipline to Universities of China (111 Program, B17019) for
support of this research.
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Keywords: cycloaddition • decarboxylation • azlactones •
aryldiazonium salts • 1,2,4-triazoles
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[14] a) CCDC 1547212 (3aa) and 1547209 (3da') contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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10.1002/ejoc.201901467
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Heterocycle Synthesis
Xiao-Ye Yu, Wen-Jing Xiao, and Jia-
Rong Chen*
Page No. – Page No.
Synthesis of Trisubstituted 1,2,4-
Triazoles from Azlactones and
Aryldiazounium Salts by Way of
Cycloaddition/Decarboxylation
Cascade
A metal-free cycloaddition/decarboxylation reaction between azlactones and
aryldiazonium salts has been achieved for the first time, which provides efficient
and facile access to privileged 1,3,5-trisubstituted 1,2,4-triazoles. Notably,
aryldiazonium salts serve as two-nitrogen unit rather than the sources of aryl
radicals in this transformation, which provides an alternative class of reagents for
the construction of N-heterocycles.
This article is protected by copyright. All rights reserved.