PIDA-mediated oxidative aromatic C[sbnd]N bond cleavage: Efficient methodology for the synthesis of 1,2-diaza-1,3-dienes under ambient conditions

Article abstract of DOI:10.1016/j.tetlet.2021.153252

A series of functionalized 1,2-diaza-1,3-diene derivatives were synthesized from 5–aminopyrazoles via oxidative cleavage of the aromatic C[sbnd]N bond under transition metal-free conditions. A control experiment revealed that the presence of a free NH

Full text of DOI:10.1016/j.tetlet.2021.153252

Tetrahedron Letters 77 (2021) 153252
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PIDA-mediated oxidative aromatic CAN bond cleavage: Efficient
methodology for the synthesis of 1,2-diaza-1,3-dienes under ambient
conditions
Abhishek Kumar a, Sarita Katiyar a,d,1, Arvind Kumar Jaiswal a,1, Ruchir Kant b,d, Koneni V. Sashidhara a,c,d,
⇑
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
b Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
c Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
d Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of functionalized 1,2-diaza-1,3-diene derivatives were synthesized from 5–aminopyrazoles via
oxidative cleavage of the aromatic CAN bond under transition metal-free conditions. A control experi-
ment revealed that the presence of a free NH2 group on the 5–aminopyrazole is important for the reac-
tion. The utility of this valuable synthon for building diverse heterocyclic structures is also presented,
which otherwise would be difficult to access using conventional methods.
Received 25 May 2021
Revised 10 June 2021
Accepted 17 June 2021
Available online 1 July 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Metal-free
Hypervalent iodine
Selective CAN bond cleavage
Ambient temperature
Azo compounds are ubiquitous in both medicinal and synthetic
chemistry (Fig. 1) [1]. More specifically, 1,2-diaza-1,3-dienes are
versatile synthetic intermediates with numerous applications for
the assembly of heterocyclic compounds and in the target-oriented
synthesis of bioactive compounds [2,3].
In the last few decades, 1,2-diaza-1,3-dienes have gained signif-
icant attention due to their versatile reactivity and applications in
various synthetic transformations [4]. However, only a few strate-
gies have been developed to prepare these valuable intermediates.
Traditionally, 1,2-diaza-1,3-dienes are generated in situ from
and (vi) poor atom economy. Thus, an efficient one-step method
to access these valuable 1,2–diaza-1,3-dienes is highly desirable.
Pyrazoles are heterocycles characterized by a five-membered
ring containing three carbon atoms and two adjacent nitrogen
atoms [8]. Pyrazoles are known to require high dissociation energy
for ring-opening of the seemingly unreactive CAN bond [9,10].
Interestingly, Smith and co-workers have demonstrated the first
N2 dissociation of azide from pyrazoles to produce hetero-
aromatic nitrene intermediates, which were further converted into
1,2-diaza-1,3-dienes (Scheme 1b) [11]. Recently, Bao and co-work-
ers reported the oxidative ring-opening of 5–aminopyrazoles to
produce the corresponding 1,2-diaza-1,3-dienes as well as their
applications in constructing diverse heterocyclic scaffolds via dom-
ino cyclization (Scheme 1c) [12].
a-halohydrazones using commercially available bases [5,6].
Nenajdenko and co-workers have developed a one-pot copper-
catalyzed coupling of N-substituted hydrazones with polyhalo-
genated compound to synthesize various polyhalogenated
1,2-diaza-1,3-dienes (Scheme 1a) [7].
Despite the utility of the reported methods, these reactions
often suffer from disadvantages such as (i) the requirement for pre-
functionalized starting materials, (ii) multiple reaction steps, (iii)
harsh reaction conditions, (iv) use of bases (v) low selectivity,
In this context, we report the regioselective ring-opening of 5-
aminopyrazoles in the presence of hypervalent iodine (PIDA),
affording 1,2-diaza-1,3-dienes (Scheme 1d). The utility of this
strategy to build diverse, complex structures from simple starting
materials is also demonstrated.
Results and discussion
⇑
Corresponding author at: Medicinal and Process Chemistry Division, CSIR-
Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road,
Lucknow 226031, UP, India.
We started our investigation using commercially available 5-
amino-3-methyl-1-phenylpyrazole 1a as a model substrate. Ini-
tially, we explored the reaction in DCE at 25 °C for 30 min, in the
E-mail address: kv_sashidhara@cdri.res.in (K.V. Sashidhara).
These co-authors have contributed equally.
1
https://doi.org/10.1016/j.tetlet.2021.153252
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

A. Kumar, S. Katiyar, A. Kumar Jaiswal et al.
Tetrahedron Letters 77 (2021) 153252
Fig. 1. Representative examples of azo containing compounds.
Scheme 1. Synthesis of 1,2-diaza-1,3-dienes.
presence of inexpensive PIDA (1.5 equiv.) as an oxidant, which
gave 2a in 90% yield.
Inspired by this result, we screened the effect of various aprotic
solvents such as DMF, toluene, THF, CHCl3, and 1,4-dioxane
(Table S1, ESI). 1,4-Dioxane was the best solvent and gave the
desired product in 96% yield after 30 min. Lower yields were
obtained in protic solvents such as ethanol and water. Other oxi-
dants such as PIFA, I2, KI, PhI(OPiv)2, and HTIB were ineffective
and provided low yields (Table S2, ESI). Decreased yields were also
observed with lower equivalents of PIDA. Finally, the reaction was
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A. Kumar, S. Katiyar, A. Kumar Jaiswal et al.
Tetrahedron Letters 77 (2021) 153252
performed without PIDA; in this case, no product was obtained.
The structure of 2a was elucidated based on spectroscopic data
and X-ray crystallographic analysis [13].
desired products in 86–94% yield. Furthermore, substrates with
sterically hindered aliphatic motifs such as tert-butyl or
indolylpyrazole at the third position of the 5-amino-1-phenylpyra-
zole 4j-4k afforded the corresponding azadiene derivatives in
excellent yields. Interestingly, substrates containing aromatic and
aliphatic groups on the third and fourth positions of 5-amino-1-
phenylpyrazoles 4l-4p were also suitable substrates, affording
the desired products in 83–92% yield. Notably, heterocyclic pyra-
zoles with pyridine and thiophene substituents were compatible
with the reaction conditions and gave the corresponding azadienes
4q-4r in 72–74% yield.
Since halogenated compounds are important in the production
of biologically active compounds, the introduction of halogen
atoms was attempted. Thus, 5-amino-1-phenylpyrazoles bearing
halogen substitution at the fourth position were employed under
the optimized reaction conditions (Scheme 3). Fluoro-substituted
5-amino-1-phenylpyrazole 6a afforded the desired product in
excellent yield. The reaction also proceeded well with the other
halogen substituents 6b-6d such as chloro, bromo, and iodo to give
the desired products in good yields.
With the optimized reaction conditions in hand, we systemati-
cally investigated the reaction scope starting with different N-
substituted pyrazole derivatives bearing electron-donating, -neu-
tral, and -withdrawing groups (Scheme 2a). Aromatic rings with
electron-donating groups 2b-2g such as Me, iPr, OMe, NH2, CH2OH,
and electron-withdrawing groups 2h-2p at the para position such
as Cl, Br, CF3, NO2, CN, CO2Me, CO2Et, COOH, SO2NH2, were all tol-
erated and afforded the desired products in 69–97% yield. Substitu-
tion at the ortho and meta positions with electron-donating groups
2q, 2u or electron-withdrawing groups 2r-2w as well as o-m 2x-2z,
m-p 2ab, and p-o 2aa di-substituted arene rings were also tolerated
and gave the desired products in good to excellent yields. Addition-
ally, a substrate bearing pentafluoro substitution on the aromatic
ring afforded the corresponding product 2ac in 86% yield. Notably,
aliphatic 2ad-2ae and heteroarene motifs such as pyridine 2af,
quinoline 2ag, or thiazole 2ah were also suitable substrates, afford-
ing the azadiene derivatives in good to excellent yields.
Next, we examined the substitution pattern on the third and
fourth positions of the 5-amino-1-phenylpyrazoles (Scheme 2b).
A wide variety of substrates possessing electron-donating and elec-
tron-withdrawing groups on the arene rings such as p-Me, p-OMe,
p-F, p-Cl, p-Br, p-CO2Me 4a-4f and m-Me, m-Cl 4h-4i, afforded the
corresponding products in 88–95% yield. The reactions with di-
substituted and meta substituted phenyl rings 4g-4i gave the
A series of control experiments were conducted to gain insight
into the possible mechanism of this formal CAN bond cleavage
(Scheme 4). The use of radical scavengers (TEMPO and BHT, 2.0
equiv.) under the optimized reaction conditions gave the desired
product 2a in 87% and 91% yield, respectively, which indicated
the absence of radical pathways. Furthermore, the reaction did
not take place when N-substituted sulfonyl and acyl substituted
Scheme 2. Substrate scope for the synthesis of azadienes.a,b aReagents and conditions: 1a (0.15 mmol), PIDA (1.5 equiv.), 1,4-dioxane (2.0 mL), 25 °C, 15–30 min. bIsolated
yields.
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A. Kumar, S. Katiyar, A. Kumar Jaiswal et al.
Tetrahedron Letters 77 (2021) 153252
b
Scheme 3. Substrate scope for the synthesis of halo azadienes.a,b aReagents and conditions: 1a (0.15 mmol), PIDA (1.5 equiv.), 1,4-dioxane (2.0 mL), 25 °C, 15–30 min.
Isolated yields.
Scheme 4. Control experiments.
5-amino-3-methyl-1-phenylpyrazoles were utilized, which under-
scores the importance of the free NH2 group for the reaction.
Based on the control experiments and previous literature
dienes in the presence of catalytic diphenyl phosphate (10 mol%)
in good to excellent yields. Furthermore, primary alcohols (D) were
reacted with 1,2-diaza-1,3-dienes in the presence of K3PO4 (0.5
equiv.) in good yields. Also, 1,2-diaza 1,3-dienes were reacted with
trialkyl phosphites (E) and NH2-NH2ÁH2O (F) in ethanol in 90–96%
yield.
[12,14,15],
a plausible reaction mechanism was proposed
(Scheme 5). Initially, PhI(OAc)2 (PIDA) coordinates with 5-
aminopyrazoles to give the electrophilic N-iodo species A. Next,
intermediate A is converted into intermediate B by oxidative
ring-opening of the pyrazole with the elimination of iodobenzene
and an acetate group. Subsequently, proton abstraction from B
leads to rearranged 1,2-diaza-1,3-dienes.
Next, various synthetic manipulations were conducted to
explore the utility and reactivity of these highly versatile 1,2-
diaza-1,3-dienes (Scheme 6).
Accordingly, several nucleophiles were reacted with the olefinic
carbon of selected 1,2-diaza 1,3-dienes. Interestingly, a variety of
nucleophiles including substituted indoles (A), thionaphthols,
heteroaromatic thiols (B), and naphthols (C), underwent 1,4-
Michael addition with the olefinic carbon of the 1,2-diaza-1,3-
Conclusion
We have developed a simple and efficient method for preparing
1,2-diaza-1,3-dienes utilizing an inexpensive hypervalent iodine
(PIDA) catalyst. This reaction represents the first example of the
oxidative ring-opening of CAN bonds under metal-, photocata-
lyst-, and light-free conditions. Control experiments revealed that
the free NH2 group is important for the reaction. The synthetic util-
ity of these 1,2-diaza-1,3-dienes was demonstrated by the reac-
tions with diverse nucleophiles which readily provided access to
a variety of functionalized scaffolds.
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A. Kumar, S. Katiyar, A. Kumar Jaiswal et al.
Tetrahedron Letters 77 (2021) 153252
Scheme 5. Plausible reaction mechanism.
Scheme 6. Synthetic utility of substituted 1,2-diaza-1,3-dienes. Reagents and conditions: (A) 2-substituted indoles, (C6H5)2P(O)OH (10 mol%), CH2Cl2, 25 °C, 2 h; (B) b-
substituted thiols, (C6H5)2P(O)OH (10 mol%), CH2Cl2, 25 °C, 2 h; (C) b-substituted naphthols, (C6H5)2P(O)OH (10 mol%), CH2Cl2, 25 °C, 2–3 h; (D) aliphatic alcohols, K3PO4 (0.5
equiv.), 70 °C, 1–2 h; (E) trialkylphosphites, neat, 25 °C, 5–7 h; (F) NH2-NH2ÁH2O, EtOH, reflux, 1 h.
tural Biology Division, CSIR-CDRI for supervising the X-ray Data
collection and structure determination. The authors also acknowl-
edge the Sophisticated Analytical Instrument Facility and Research
(SAIFR) CDRI, Lucknow, India, for providing spectral analysis data
of chemical compounds and Dr. S. P. Singh for technical support.
AK, SK, and AKJ are thankful to CSIR, New Delhi, for the fellowship.
The CDRI manuscript number is 10262.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
The authors acknowledge the Academy of Scientific & Innovative
Research (AcSIR), Ghaziabad-201002, U. P., India and Director, CSIR-
CDRI, for providing the required infrastructural support. The
authors are grateful to Dr. Tejender S. Thakur, Molecular and Struc-
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153252.
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Tetrahedron Letters 77 (2021) 153252
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