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Expedient iron-catalyzed stereospecific synthesis

of triazines via cycloaddition of aziridines with
Cite this: Chem. Commun., 2020,
56, 3381 diaziridines†
Received 31st December 2019,
Accepted 14th February 2020 Tanumay Sarkar, Kangkan Talukdar, Subhasish Roy and
Tharmalingam Punniyamurthy *
DOI: 10.1039/c9cc10089j

rsc.li/chemcomm

Iron-catalyzed stereospecific [3+3]-annulation of aziridines with

diaziridines is described to furnish [1,2,4]-triazines in high yield at
room temperature. The use of an inexpensive iron salt catalyst,
substrate scope and enantiomeric purity are the important practical
features.

Aza-heterocycles are ubiquitous in bioactive natural products,

pharmaceuticals and functional materials.1 In this array, 1,2,4-
triazine and its synthetic congeners are among the most pre-
valent class of heterocycles that display a broad bio-active
spectrum (Fig. 1).2 Development of effective synthetic strategies
for their stereoselective synthesis using readily available simple
building blocks with atom and step economy would thus be
valuable.3 [3+n]-Annulation reactions involving 1,3-dipoles have
emerged as a powerful synthetic tool for the assembly of
heterocyclic scaffolds.4 In this realm, three-membered rings
have witnessed impeccable growth due to their apparent simplicity
and staple architectures.5 The innate ring strain associated with
these saturated heterocycles leads to facile ring-opening in
the presence of Lewis acids and renders them susceptible to
1,3-dipolar cycloaddition. Contextually, diaziridines represent
an imperative class of two nitrogen containing aza-heterocycles
and can be cleaved heterolytically using Lewis acids to serve as
a versatile precursor of azomethine imines in a range of
cycloaddition reactions.6 Notably, bicyclic diaziridines with
two nitrogen atoms at the ring junction are preferentially useful
to accumulate fused polyheterocyclic and spirocyclic frameworks.6
Similarly, aziridines are recognized as a classical 1,3-zwitterionic
component in Lewis acid catalyzed tandem ring-opening and
cyclisation processes to access nitrogen-bearing heterocycles.7,8
Consequently, 1,3-dipolar cycloadditions engaging these two
saturated building blocks can provide a straightforward strategy
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati
781039, India. E-mail: tpunni@iitg.ac.in
† Electronic supplementary information (ESI) available: Optimization table,
experimental procedure, characterization data, HPLC chromatogram, and NMR
(1H, 19F, 13C) spectra. CCDC 1972128 and 1972182. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c9cc10089j
Fig. 1 Selected examples of bio-active triazine derivatives.
to deliver a synthetic rationale for heterocycle synthesis. In
contrast, iron catalysts, being a minimally toxic, eco-benign,
and cost-effective transition metal, have been the interest of
recent sustainable cycloaddition reactions.9 Herein, we report
an iron-catalyzed [3+3]-annulation of N-alkyl aziridines with
bicyclic diaziridines to furnish [1,2,4]-triazines as a single
diastereoisomer. This protocol provides a potential route for
the annulation of two varied three-membered rings to deliver a new
class of fused heterocycles. The use of less expensive iron(III) salt as
the catalyst, substrate scope, functional group diversity and coupling
of optically active aziridine are the important practical features.
We began our optimization studies employing diaziridine 1a
and 1-(4-chlorobenzyl)-2-(p-tolyl)aziridine 2a as the test substrates
using a series of iron catalysts and solvents (Table S1, ESI†).
Gratifyingly, cycloadduct 3aa was formed as a single diastereoi-
somer in 95% yield, when the reaction was performed using 10
mol% FeCl3 in CH2Cl2 at room temperature for 5 minutes. In a
set of iron salts screened, FeCl3, FeCl36H2O, FeCl24H2O,
Fe(NO3)39H2O and Fe(acac)3, the former yielded the best results.
Dichloromethane was found to be the solvent of choice with 95%
yield. The reaction of (CH2Cl)2 and toluene afforded 86% and
81% yields, respectively, whereas MeOH, DMSO, THF and H2O
exhibited inferior results, which might be due to the coordination

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of the polar solvents with the iron salts that can suppress their
catalytic activity. A control experiment confirmed that the presence
of FeCl3 was crucial to deliver the target heterocycle. In addition,
under these conditions, fused diaziridines such as 1-benzyl-1,2-
diazaspiro[2.5]octane 1b and 1-benzyl-3-phenyl-diaziridine 1c
and aziridines such as 2-phenylaziridine 2b, N-tosylaziridine
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2b 0 and donor–acceptor aziridine 2c are found to be unsuccessful
substrates.
With the optimized reaction conditions in hand, the scope
of the protocol was examined using a series of diaziridines 1a–s
with 1-(4-chlorobenzyl)-2-(p-tolyl)aziridine 2a as a standard
substrate (Scheme 1). Diaziridines having substituents at the
3-position with nitro 1d and trifluoromethyl 1e groups under-
went cycloaddition to furnish the target products 3da and 3ea
in 83% and 85% yields, respectively. Similarly, diaziridines
bearing both electron-rich and electron-deficient substituents
at the 4-position of the aryl ring such as bromo 1f, cyano 1g,
methoxycarbonyl 1h, methoxy 1i, nitro 1j and phenyl 1k groups
efficiently participated in the reaction to deliver cycloadducts
3fa–ka in 77–94% yields. Moreover, the reaction of heteroaryl
diaziridines 1l and 1m proceeded smoothly to afford 3la and 3ma
in 91% and 93% yields, respectively. Furthermore, polycyclic-
aromatic diaziridines bearing 2-fluorene 1n, 2-naphthyl 1o and
trimethoxyphenyl 1p functionalities were found to be amenable,
delivering 3na–pa in 88–92% yields. Intriguingly, 1-naphthyl 1q
and 1-pyrene 1r substituted diaziridines afforded 3qa and 3ra as a
mixture of isomers. In addition, 3,3-disubstituted diaziridine 1s
Scheme 1 Substrate scope of diaziridines.a,b aReaction conditions: 1a–s
(0.2 mmol), 2a (0.2 mmol), FeCl3 (10 mol%), CH2Cl2 (2 mL), 5 minutes,
room temperature. bIsolated yield.
3382 | Chem. Commun., 2020, 56, 3381--3384
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participated in the reaction to give 3sa in 92% yield. These results
suggest that diaziridines with varied substitution patterns can
be reacted.
Next, the scope of the method was expanded for a series of
N-substituted aziridines 2d–o with 6-phenyl-1,5-diazabicyclo-
[3.1.0]hexane 1a as a representative substrate (Scheme 2). Aziridines
bearing allyl 2d, n-butyl 2e, isobutyl 2f, cyclohexyl 2g, cyclopropyl 2h
and isopropyl 2i groups on nitrogen successfully participated to
produce 3ad–ai in 73–92% yields. The structure of 3ai was deter-
mined by single-crystal X-ray analysis (CCDC = 1972128, see ESI†).
Similar results were observed when aziridines having benzyl 2j and
4-methoxybenzyl 2k groups at the nitrogen atom reacted with 1a
affording 3aj and 3ak in 91% and 93% yields, respectively. More-
over, N-isobutyl aziridines with substituents at the aryl ring, such as
3-nitro 2l, 4-chloro 2m, 4-fluoro 2n and 4-methoxy 2o functionalities,
efficiently participated to furnish 3al–ao in 87–94% yields.
The use of the protocol was then extended to the coupling of
the cyclodimer of 6-(4-methoxyphenyl)-1,5-diazabicyclo-[3.1.0]hexane
1i0 with N-alkyl aziridines 2a and 2j–k as the representative sub-
strates (Scheme 3). The reaction of aziridines having substituents at
the N-benzyl ring with 4-chloro 2a, 4-hydrogen 2j and 4-methoxy 2k
groups afforded 3ia–ik as a single diastereoisomer in 89–93% yields.
The stereochemistry of 3ik was determined by single-crystal X-ray
analysis (CCDC = 1972182, see ESI†). The diastereoselectivity of
the product was primarily governed by the formation of the same
azomethine imine A from cyclodimer 1i 0 in the presence of Lewis
acid.6 Finally, to reveal the stereoselectivity, the reaction of a set
of diaziridines was tested using optically active aziridine (S)-2p
(Scheme 4). Diaziridine with a 4-cyano group 1g underwent
Scheme 2 Substrate scope of N-substituted aziridines.a,b aReaction con-
ditions: 1a (0.2 mmol), 2d–o (0.2 mmol), FeCl3 (10 mol%), CH2Cl2 (2 mL),
5 minutes, room temperature. bIsolated yield.
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Scheme 3 Substrate scope of cyclodimers.a,b aReaction conditions: 1i 0
(0.1 mmol), 2a,j–k (0.2 mmol), FeCl3 (10 mol%), CH2Cl2 (2 mL), 5 minutes,
room temperature. bIsolated yield.
Scheme 4 Enantiospecific synthesis.a,b aReaction conditions: 1g–h and 1j
(0.2 mmol), (S)-2p (0.2 mmol), FeCl3 (10 mol%), CH2Cl2 (2 mL), 5 minutes,
room temperature. bIsolated yield.
reaction to afford 3gp in 497% ee. The reaction of 4-methoxy-
carbonyl 1h and 4-nitro 1j substituted diaziridines gave 3hp and
3jp in 499% ee. These outcomes suggest that the protocol is
stereospecific to furnish [1,2,4]-triazines with high optical purities.
However, our attempts toward enantioselective syntheses using
chiral ligands L1–3 employing ()-2p and 1h as the representative
examples were unsuccessful, which might be due to an involve-
ment of the SN2 type reaction (Table S2, ESI†).
To get insight into the reaction pathway, control experiments
were performed (Scheme 5). Diaziridine bearing an electron
Scheme 5 Control experiments.
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Scheme 6 Plausible mechanism.
donating 4-methoxy 1i group exhibited a greater reactivity com-
pared to that with an electron withdrawing 4-nitro 1j group
(Scheme 5a). Similarly, aziridine having an electron-withdrawing
4-fluoro 2n group showed a superior reactivity compared to that
having an electron-donating 4-methoxy 2o group (Scheme 5b). In
addition, 3aa exhibited no epimerization in the presence of
AcOH (Scheme 5c).10 These results suggest that chelation of the
unactivated aziridines 2 with FeCl3 can lead to the formation of a,
which can lead to stereospecific ring opening using the azo-
methine imine intermediate A to furnish b (Scheme 6). The latter
can lead to an intramolecular cyclisation to deliver the target
heterocycles 3. The obtained diastereoselectivity is primarily gov-
erned by the steric factors during the approaches of aziridine with
the azomethine imine A. Thus, the sterically less hindered
approach (path I) favoured the formation of cycloadduct 3 with
exclusive trans-selectivity.6,11 In contrast, path II that can lead to
cis-selectivity is unfavored due to the steric hindrance.
To present the synthetic uses, post synthetic transformations
were performed (Scheme 7A). A bromo-containing cycloadduct
3fa could be transformed to borylated 4 in 75% yield. Suzuki
coupling of 4 furnished 5 in 82% yield. Furthermore, the
Scheme 7 Synthetic use of the cycloadduct.
Chem. Commun., 2020, 56, 3381--3384 | 3383

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reaction of 3fa with trimethylsilylacetylene afforded 6 in 71%
yield. Intriguingly, in the acid catalyzed debenzylation using
trifluoroacetic acid, the benzyl group residing in between two
nitrogen centres can be removed selectively to give dihydro-
pyrazoles 7 in 63% yield, which are versatile building blocks and
are found in a broad spectrum of bioactive pharmaceuticals as a
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core unit.12 In addition, the scale up of the protocol was investi-
gated using 1a and 2a as the representative examples (Scheme 7B).
The reaction occurred to furnish 3aa in 86% yield (see ESI†).
In conclusion, we have presented an iron-catalyzed [3+3]-
annulation of unactivated azirdines with diaziridines to produce
functionalized [1,2,4]-triazines in high yields. The substrate
scope, use of iron-catalysis and synthetic applications are the
important practical features.
We thank Council of Scientific and Industrial Research
(02(0255)/16/EMR-II) for the financial support. We also thank
Department of Chemistry, Indian Institute of Technology Guwahati
for DST-FIST and COE-FAST for HRMS and NMR facilities.
Conflicts of interest
There are no conflicts to declare.
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