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Redox-neutral zinc-catalyzed cascade

[1,4]-H shift/annulation of diaziridines
Cite this: Chem. Commun., 2024,
60, 3441 with donor–acceptor aziridines†
Received 16th January 2024,
Accepted 23rd February 2024 Swati Samantaray, Prabhat Kumar Maharana, Subhradeep Kar, Sharajit Saha and
Tharmalingam Punniyamurthy *
DOI: 10.1039/d4cc00226a

rsc.li/chemcomm

The coupling of diaziridines with donor–acceptor aziridines (DAAs) diaziridines as 1,2-dipolar systems in achieving unprecedented
has been achieved using Zn-catalysis to furnish imidazopyrazole- (2+n) reactivity has yet to be explored. Moreover, the cascade
4,4-dicarboxylates via [1,4]-hydride shift. The use of Zn-catalysis, [1,4]-hydride shift9 triggered C(sp3)–H bond functionalization
[1,4]-hydride shift, natural product modification and a late-stage and cyclization of diaziridine has emerged as a new avenue for
molecular docking study are important practical features. the construction of valuable aza-heterocycles (Scheme 1). In
addition, N-heterobicyclic derivatives are privileged structural
Recent advances in cycloaddition reactions permitting the con- motifs, owing to their profound relevance in a wide range of
struction of a broad range of cyclic compounds via carbon–carbon biological, medicinal, and pharmaceutical properties, such as
and carbon–heteroatom bonds, have established them among the anticancer, anti-inflammatory and antiviral activities.10 Herein,
most robust and synthetically useful transformations.1 Conse- we report a Zn-catalyzed annulation of diaziridines with donor–
quently, crafting elegant strategies for their valuable construction acceptor aziridines (DAAs) to furnish structurally diverse
from readily accessible elementary building blocks2 has emerged imidazo[1,5-b]pyrazole-4,4-dicarboxylates. The (2+n) reactivity
as a fledging research area. In this context, cycloaddition involving with a pyrazoline intermediate and late-stage diversified 4 in
three-membered congeners, masked as 1,3-dipoles, stands as a exhibiting in silico antifungal activity are significant features.
powerful synthetic tool for the assembly of diverse structural We initiated optimization employing diaziridine 1a and 2,
frameworks.3 Their innate ring strain, staple architecture and 2 0 -diester aziridine 2a as model substrates (Table 1 and
apparent simplicity command their incessant utilization in Table S1, ESI†). To our delight, the reaction occurred to
cycloaddition as well as ring-opening and cyclization via Lewis
acid catalysis.4 Depending on the reaction conditions and electro-
nic nature of the strained aza-ring, aziridines are infamously
known to generate 1,3-dipoles via either C–C or C–N bond
cleavage.5 In this vein, 2,2 0 -diester aziridines, a class of donor–
acceptor (DA) variants, undergo heterolytic C–C bond cleavage to
form the transient azomethine ylide and take part in cycloaddi-
tion with dipolarophiles.6 Conversely, diaziridines are character-
ized as two-nitrogen-containing bicyclic ring systems that serve as
versatile building blocks in fabricating nitrogenous cycloadducts
via an in situ generated azomethine imine.7 Considerable
efforts have thus been made towards developing strategies for
the cycloaddition of diaziridines with dipolarophiles to acquire
N-heterocycles.8 Unlike conventional reactivity, the use of

Department of Chemistry, Indian Institute of Technology Guwahati,

Guwahati-781039, India. E-mail: [email protected]
† Electronic supplementary information (ESI) available. CCDC 2293903. For ESI
and crystallographic data in CIF or other electronic format see DOI: https://doi. Scheme 1 Reactivity of diaziridines and DA aziridines via [1,4]-hydride
org/10.1039/d4cc00226a shift.

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Table 1 Optimization of reaction conditionsa

Published on 23 February 2024. Downloaded by Indian Institute of Technology Kanpur on 3/29/2024 2:36:11 PM.

Entry Catalyst Solvent Yieldb (%)

1 Sc(OTf)3 Toluene 51
2 Zn(OTf)2 Toluene 80
3 Ni(OTf)2 Toluene 38
4 Yb(OTf)3 Toluene 25
5 Mg(OTf)2 Toluene 20
6 Ni(ClO4)26H2O Toluene 35
7 Zn(OAc)2 Toluene 42
8 ZnBr2 Toluene 21
9 ZnCl2 Toluene 30
10 Zn(OTf)2 THF Trace
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), catalyst (10 mol%),
solvent (1 mL), rt, 4 Å MS, 10 h. b Isolated yield.

produce 51% cycloadduct 3aa when the substrates were reacted

using 10 mol% Sc(OTf)3 in toluene at room temperature with
4 Å molecular sieves as an additive for 10 h (entry 1). The yield
increased to 80% utilizing Zn(OTf)2 as the Lewis acid, whereas
Ni(OTf)2, Yb(OTf)3, Mg(OTf)2, Ni(ClO4)26H2O, Zn(OAc)2, ZnBr2
and ZnCl2 produced only moderate outcomes (entries 2–9).
Toluene was found to be the solvent of choice, whereas THF,
CH3CN, MeOH, (CH2Cl)2 and DMSO produced inferior results.
However, an increase in reaction temperature did not exhibit
any further enhancement in the reaction yield (see ESI,†
Table S1). Control experiments confirmed that annulation Scheme 2 Scope of diaziridines.a,b a Reaction conditions: 1b–p
was unsuccessful in the absence of a Lewis acid. (0.1 mmol), 2a (0.12 mmol), Zn(OTf)2 (10 mol%), toluene (1 mL), 4 Å MS,
With optimized conditions in hand, we examined the scope rt, 10 h. b Isolated yield.
of the procedure with various diaziridines 1b-p, utilizing 2a as a
standard substrate (Scheme 2). Diaziridine bearing a 3-bromo
substituent reacted to produce 3ba in 63% yield. Likewise, the
substrates bearing substituents at the 4-position of the aryl
ring, such as bromo 1c, chloro 1d, fluoro 1e, phenyl 1f and tert-
butyl 1g, participated, yielding cycloadducts 3ca–ga in 62–74%
yields. However, 4-methoxy substituted 1h produced only a
trace amount of 3ha. Furthermore, heterocyclic thiophene
derived diaziridine 1i underwent reaction to produce imidazo-
pyrazole 3ia in 65% yield. In addition, diaziridines bearing
poly-aromatic moieties, such as 1-naphthyl 1j, 2-naphthyl 1k
and 1-pyrene 1l, successfully reacted to deliver intended hetero-
cycles 3ja–la in 57–75% yields, whereas 2-fluorenyl derived 1m
furnished desired 3ma in 73% yield. Moreover, diaziridine
derived from bioactive monoterpenoids such as ()-borneol
and (L)-menthol proved amenable in delivering target hetero-
cycles 3na and 3pa in 55% and 68% yields, respectively,
whereas diaziridine 1o containing a ()-a-tocopherol unit furn-
ished 3oa in 60% yield.
Next, we set out to evaluate the scope of DAAs 2a–o with 1a
as a standard substrate (Scheme 3). DAAs bearing substituents Scheme 3 Scope of DA aziridines.a,b aReaction conditions: 1a (0.1 mmol),
at the 3-position of the aryl ring with bromo 2b, methyl 2c and 2a–o (0.12 mmol), Zn(OTf)2 (10 mol%), toluene (1 mL), 4 Å MS, rt, 10 h.
b
trifluoromethyl 2d underwent annulation to furnish target Isolated yield. n.d. = not detected.

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bicyclic scaffolds 3ab–ad in 65–72% yields. However, substrate

2e with a nitro group failed to generate the target product,
which may be attributed to the strong electron-withdrawing
nature of the substituent.6e However, the annulation of DAAs
with bromo 2f, chloro 2g, fluoro 2h and ester 2i groups at the
4-position of the aryl ring furnished 3af–ai in 60–76% yields.
Published on 23 February 2024. Downloaded by Indian Institute of Technology Kanpur on 3/29/2024 2:36:11 PM.

Moreover, 2-naphthyl derived aziridine 2j underwent reaction

to deliver cycloadduct 3aj in 58% yield. The generality of the
procedure was then tested by varying the substituents at the N-
sulfonyl aryl ring. For example, N-sulfonylphenyl bearing 2k
and 4-chloro substituted N-sulfonyl aryl aziridine 2l partici-
pated in yielding cycloadducts 3ak and 3al in 68% and 73%
yields, respectively. Moreover, DAA bearing various ester sub-
stituents, such as methyl 2m, iso-propyl 2n and tert-butyl 2o,
proved viable substrates in delivering cycloadducts 3am-ao in
65-85% yield. The structure of 3am was confirmed by single-
crystal X-ray analysis (CCDC 2293903, see ESI†). These results
showcase the versatility of the protocol to synthesize a plethora
of functionalized imidazo[1,5-b]pyrazole derivatives.
To shed light on the underlying reaction pathway, radical
scavenger experiments were conducted in the presence of Scheme 5 Plausible reaction pathway.
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT) (Scheme 4a). In both cases, as
These observed experimental results and the literature6,7,11
above, the reaction occurred to furnish the target heterocycles,
suggest that the coordination of Zn(OTf)2 with dicarboxylates of
which suggests the reaction may not involve a radical pathway.
DAA 2m can generate III, which can undergo C–C bond
In addition, intermediate II was isolated from 1a using
cleavage to form azomethine intermediate IV. Azomethine
Zn(OTf)2, which reacted with 2m to produce 3am under the
imine I formed from diaziridine 1a may react with IV to furnish
optimized conditions. This confirms the involvement of the
V, which upon subsequent [1,4]-H shift and annulation can
pyrazoline intermediate in the reaction pathway (Scheme 4b).7b
afford target bicyclic scaffold 3am (Path A). On the contrary,
In addition, substrate 1a with optically active 2h 0 afforded 3ah 0
imine I generated from 1a may undergo isomerization via [1,4]-
in racemic form, which suggests that the ring opening of DA
H shift to give pyrazoline II that can react with IV to give a
aziridine may be involved in the SN1 pathway (Scheme 4c).
zwitterionic intermediate VI. Finally, intramolecular cyclization
can occur to produce target product 3am (Path B) (Scheme 5).
To reveal the practical utility of the reaction, scale-up
synthesis was carried out using 1a (3 mmol) and 2m (3.6 mmol)
as representative substrates to afford 3am in 65% yield
(Scheme 6). In addition, post-synthetic transformation of the
cycloadduct was studied to obtain functionalized scaffolds
(Scheme 7). For example, base-mediated mono decarboxylation
of 3am afforded 4 in 72% yield. Furthermore, the reduction of
the diester furnished diol 5 in 82% yield. Moreover, cycloadduct
3af was subjected to Pd-catalyzed Suzuki-coupling using phe-
nylboronic acid to furnish 6 in 78% yield. Intriguingly, com-
pound 4, when subjected to an in silico molecular docking
study, exhibited promising bioactivity (Table S2, ESI†).12 This
preliminary outcome may lead to further examination and
development towards its activity as a potential antifungal drug.

Scheme 4 Preliminary mechanistic investigations. Scheme 6 Scale-up synthesis.

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