Diazo Activation with Diazonium Salts: Synthesis of Indazole and 1,2,4-Triazole

Article abstract of DOI:10.1021/acs.orglett.0c01232

A donor/acceptor diazo activation strategy, processing via condensation using diazonium salts without the addition of any other catalysts or reagents, is reported. The diazenium intermediate was found to undergo cyclization to give indazoles in excellent yields. Alternatively, in the presence of nitriles, substituted 1,2,4-triazoles were obtained in good to excellent yields. This interesting diazenium route provides a new approach to achieve complex heterocycle synthesis under mild conditions.

Full text of DOI:10.1021/acs.orglett.0c01232

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Letter
Diazo Activation with Diazonium Salts: Synthesis of Indazole and
1,2,4-Triazole
Xuming Li, Xiaohan Ye, Chiyu Wei, Chuan Shan, Lukasz Wojtas, Qilin Wang,* and Xiaodong Shi*
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ABSTRACT: A donor/acceptor diazo activation strategy, process-
ing via condensation using diazonium salts without the addition of
any other catalysts or reagents, is reported. The diazenium
intermediate was found to undergo cyclization to give indazoles
in excellent yields. Alternatively, in the presence of nitriles,
substituted 1,2,4-triazoles were obtained in good to excellent
yields. This interesting diazenium route provides a new approach
to achieve complex heterocycle synthesis under mild conditions.
iazo compounds have been of great interest over the past
application of an in situ formed diiodide ester to the
Dseveral decades as excellent carbene precursors. Tran- preparation of cyclopropane under mild conditions (Scheme
1B).3 Herein, we report the formation of diazenium A as a key
sition metal catalyzed carbene transfer from diazo compounds
intermediate through diazo activation by diazonium salt.
Sequential cyclization/condensation (with nitriles) of this
intermediate offers an alternative route to achieve the synthesis
of substituted indazoles and 1,2,4-triazoles with high efficiency
under mild conditions (Scheme 1C).
is considered to be a typical reaction pathway, providing a
powerful strategy for the construction of carbon−carbon or
carbon−heteroatom bonds (Scheme 1A).1 Furthermore, diazo
carbon can serve as a nucleophile to react with Lewis acid
activated aldehydes (Roskamp reaction), giving the corre-
sponding C−C bonded product.2 Inspired by these ideas, our
group recently reported diazo activation by iodide and the
In the past decade, our group has focused on developing
new chemical transformations using homogeneous gold
catalysts.4 These efforts have led to discoveries of gold(I)-
catalyzed diazo activation5 and gold(I)/(III) redox catalysis
with base-assisted diazonium salt activation as the oxidants.6
According to the literature, the coupling of diazo compounds
with aryl diazonium salts has received extensive attention. As
shown in Figure 1A, pioneering work by Huisgen and Koch
demonstrated the possibility of electrophilic attack of
Scheme 1. Diazo as Important Synthon for Efficient
Transformations
diazonium salts by diazo carbon. When ArN2 Cl− salt was
+
applied, a fast sequential denitrogenation was caused by
chloride anion addition, producing chlorohydrazones.7 Wan
and Shao extended this strategy to generate nitrilimines in situ,
leading to pyrroles by coupling with 1,3-dicarbonyl com-
pounds.8 Under copper-catalyzed conditions, the three-
component coupling of ethyl diazoacetate, aryl diazonium
salts, and nitriles resulted in 1,2,4-triazoles through a metal
carbene intermediate.9 Similarly, a silver-catalyzed [3 + 2]
Received: April 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01232
© XXXX American Chemical Society
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A

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Letter
Clearly, both indazole14 and 1,2,4-triazole15 are valuable
heterocyclic structures. Their derivatives are a versatile class of
compounds found in numerous natural products and bio-
logically active compounds. Therefore, new methodology to
facilitate the synthesis of these compounds is highly desired.
One general concern is how to achieve the overall selectivity
for the formation of indazole vs triazole. Based on the
proposed reaction mechanism, it is reasonable to rationalize
that the formation of 1,2,4-triazole can be avoided if non-nitrile
solvents are applied. After exploring various other solvents,
DMF was identified as the optimal solvent. The reaction was
conducted at 80 °C under Ar, giving the desired indazole 3b in
78% yield. Some alternative conditions examined in the
reaction are summarized in Table 1, and detailed screening
conditions are included in the Supporting Information (SI).
a
Table 1. Screening Conditions for Indazole Syntheisis
Entry
Variation from “standard conditions”
3 (%)
5 (%)
1
2
3
4
5
6
7
8
9
none
78
0
<5
82
<5
<5
<5
10
8
DCE as Solvent
NMP as solvent
DMSO as solvent
1.0 equiv of 2b
1.5 equiv of 1a
50 °C
Figure 1. Diazo activation by diazonium: formation of diazenium.
<5
37
68
55
62
77
41
cycloaddition of diazo compounds (CF3CHN2) with aryl
diazonium salts has been reported for the synthesis of
tetrazoles.10 Surprisingly, the scope of the diazo component
has largely been limited to ethyl diazoacetate (acceptor diazo),
while aryl diazoesters (acceptor/donor diazo) have received
less attention. Since gold(I) complexes can react with both
diazo and diazonium salts, we considered exploring gold-
catalyzed C−C bond coupling by combining these two
reagents and the resulting potential new chemical trans-
formations.11
With this idea in mind, we explored the reaction between
diazo compound 1a and diazonium salt 2a under various
conditions. However, heating the mixture of 1a and 2a at 50
°C in MeCN, two new compounds were isolated. Their
structures were determined as indazole 3a (14%; CCDC
1989187) and 1,2,4-triazole 4a (39%; CCDC 1989189) by X-
ray crystallography analysis (Figure 1). Notably, this trans-
formation occurred without the presence of gold catalysts.
Based on this result, an interesting reaction pathway between
the diazonium salt and diazo compound was proposed via
nucleophilic addition of a diazo compound to the diazonium
salts, followed by denitrogenation to form diazenium
intermediate A. Intramolecular electrophilic cyclization (path-
way a) then gives indazole 3a. In addition, the addition of
nitrile to diazenium A, with sequential cyclization and
decarboxylation, yields 1,2,4-triazole 4a. Diazenium salts are
known to be generated by Lewis acid (MCln) promoted
elimination from 1-chloroalkyl-azo compounds (R2ClC−N
N−Ar). It requires multiple steps, and the resulting alkyl
substituted diazenium species is highly reactive and allows less
controllable product formation.12 To the best of our
knowledge, this is the first example of aryl diazonium salts
condensation with donor/acceptor diazo compounds for the
formation of a diazenium intermediate compound reported
and applied in chemical synthesis.13
0.05 M
0.5 M
<5
20
a
Conditions: 1a (0.2 mmol, 1.0 equiv) and 2b (0.6 mmol, 3.0 equiv)
were added to DMF (2 mL, 0.1 M) at 80 °C. Yield was determined by
1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
To facilitate nucleophilic addition of the diazo compound to
diazonium salts, we initiated the screening of polar aprotic
solvents. First, DCE failed to promote the desired reaction
owing to the poor solubility of the diazonium salts. Instead,
dimeric azine compound 5 (CCDC 2000393, structure
confirmed by X-ray analysis; see Table S5 in Supporting
Information) was observed as the major product (entry 2).
Polar solvents, such as NMP and DMSO, gave poor yields of
the desired products, which is likely due to the decomposition
of the diazonium salt at high temperature (entries 3−4).
Finally, DMF was found to be the optimal solvent. Notably,
formation of the dimeric azine compound 5 is a major
competitive reaction pathway, as reported previously.16
Accordingly, 3 equiv of diazonium salt, a reasonable
concentration (0.1 M), and a high temperature were necessary
to suppress the self-dimerization of the diazo compound,
ensuring a good yield and selectivity (entries 6−9). With
optimal conditions in hand, we then explored the indazole
substrate scope (Scheme 2).
As shown in Scheme 2, most aryl diazonium salts containing
electron-withdrawing substituents were suitable for this
transformation, giving good to excellent yields (3a−3f). Aryl
diazonium salts with electron-donating substituents failed to
produce any desired product. para-Methyl substituted aryl
diazoesters reacted smoothly to afford the cyclized products
(3g−3k). As expected, two regioisomers (3o and 3p) were
B
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Letter
a b
,
a b
,
Scheme 2. Substrate Scope of Indazole
Scheme 3. Substrate Scope of 1,2,4-Triazole
a
Conditions: 1 (1.5 mmol, 1.5 equiv) and 2 (1.0 mmol, 1.0 equiv)
were added to RCN (10 mL), and the mixture was stirred at 25 °C for
b
48 h under argon. Isolated yield.
ring did not promote the reaction due to rapid decomposition.
The presence of both electron-withdrawing/-donating groups
on the aromatic ring of the aryl diazo esters did not influence
the reaction outcome, and the products were formed in good
yields. Notably, alkyl diazoester (4y) also participated in the
reaction affording the product in 37% yield, which was likely
caused by fast decomposition. Employing different nitriles,
such as EtCN (4z), iPrCN (4aa), and TMSCH2CN (4ab),
furnished the substituted 1,2,4-triazoles in moderate yields.
However, less nucleophilic nitriles, such as PhCN (4ad), did
not promote this reaction. Notably, allylic nitrile (4ac)
produced the product in moderate yield, highlighting the
mild conditions and synthetic potential for further modifica-
tion.
To probe the possible reaction pathway, we monitored the
reaction using in-operando infrared spectroscopy analysis. The
mixing of diazo compound 1a and diazonium salt 2b (1:1
ratio) in MeCN at room temperature resulted in the N2 gas
bubbling out of the reaction mixture. As shown in Figure 2A,
the characteristic CO stretch absorption peak of 1a at 1705
cm−1 disappeared, along with the formation of a new
absorption peak at 1751 cm−1. HRMS analysis of the reaction
mixture indicated the formation of 6, which was formed
through simultaneous trapping the diazenium intermediate by
MeCN. This result accounted for the higher selectivity for
1,2,4-triazoles over indazoles at room temperature. To
understand the subsequent decarboxylation step, the reaction
was conducted with a more sterically demanding tert-butyl
ester (Figure 2B). A decreased yield was observed with the tert-
butyl ester, indicating a Krapcho-type decarboxylation process.
This process was unlikely to proceed via the hydrolysis of the
ester to carboxylic acid with subsequent decarboxylation.
In summary, we have disclosed the first example of donor/
acceptor diazo activation by diazonium salts under metal-free
conditions, via the corresponding diazenium intermediate. This
transformation provides a synthetic route for the formation of
either indazole or 1,2,4-triazole derivatives in good to excellent
a
Conditions: 1 (1.0 mmol, 1.0 equiv) and 2 (3.0 mmol, 3.0 equiv)
were added to DMF and stirred at 80 °C for 0.5 h under argon.
b
Isolated yield.
isolated when a meta-methyl substituted aryl diazoester was
employed in the reaction. An electron-donating group
(−OMe) modified aryl diazoester (3l) resulted in a low
yield, and the dimeric compound 5l was obtained as the major
product (55% yield). We next examined the different sizes of
ester groups of the diazo ester component. Thus, changing the
methyl ester to bulkier iPr and tBu esters reduced the yield of
the product indazoles 3m and 3n to 43% and 12%,
respectively. Diazoesters with modified ester chain containing
functional groups, such as alkene (3q), saturated ring system
(3r), benzyl (3s), alkyne (3t), and menthol (3u), were
compatible with this reaction. Furthermore, vinyl diazoester
was also explored, giving the corresponding N-arylpyrazole in
moderate yield under metal-free conditions (3v). When
electron-withdrawing groups were present on the diazo aryl
ring, no product was formed.
Encouraged by the successful synthesis of various indazoles,
we turned our attention to the selective synthesis of 1,2,4-
triazoles. We anticipated that nitrile addition to the diazenium
intermediate would be dominant in acetonitrile solvent, while
the cyclization pathway would be more kinetically favored over
pathway b (Figure 1B). Accordingly, the reaction between 1a
and 2b afforded desired 1,2,4-triazole 4d in 74% yield, and
with indazole obtained in 5% yield (for more details of
conditions optimization, see Table S2 in the SI). The reaction
scope is shown in Scheme 3.
As shown in Scheme 3, aryl diazonium salts containing
electron-withdrawing substituents worked well in this trans-
formation, providing the desired 1,2,4-triazoles in good to
excellent yields (4a−4l). Carbonyl groups (4m) were well
tolerated under this condition. As expected, aryl diazonium
salts containing an electron-donating group on the aromatic
C
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Lukasz Wojtas − The Department of Chemistry, University of
South Florida, Tampa, Florida 33620, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01232
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE-1665122) and NIH
(1R01GM120240-01) for financial support.
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ASSOCIATED CONTENT
* Supporting Information
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Accession Codes
CCDC 1989187, 1989189, and 2000393 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.
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AUTHOR INFORMATION
Corresponding Authors
■
Xiaodong Shi − The Department of Chemistry, University of
South Florida, Tampa, Florida 33620, United States;
orcid.org/0000-0002-3189-1315; Email: xmshi@usf.edu
Qilin Wang − Institute of Functional Organic Molecular
Engineering, College of Chemistry and Chemical Engineering,
Henan University, Kaifeng 475004, China; orcid.org/0000-
0003-4637-0392; Email: wangqilin@henu.edu.cn
Authors
Xuming Li − The Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States
Xiaohan Ye − The Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States
Chiyu Wei − The Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States
Chuan Shan − The Department of Chemistry, University of
South Florida, Tampa, Florida 33620, United States
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