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org/OrgLett Letter

Sc(OTf)3‑Catalyzed Domino C−C/C−N Bond Formation of Aziridines

with Quinones via Radical Pathway
Kshitiz Verma, Manmath Mishra, Prabhat Kumar Maharana, Hemanga Bhattacharyya, Sharajit Saha,
and Tharmalingam Punniyamurthy*
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ABSTRACT: Sc(III)-catalyzed domino C−C and C−N bond formation of N-

sulfonyl aziridines with quinones has been accomplished to furnish function-
alized indolines at a moderate temperature. The umpolung reactivity of
aziridines, radical pathway, mild reaction conditions, substrate scope, and
coupling of drug molecules in a postsynthetic application are the important
practical features.

I n the past decades, the scientific community has been keen

to develop synthetic methodologies for the construction of
biologically important heterocyclic scaffolds.1 In particular, N-
Scheme 1. . Approaches for the Annulation of Quinone
Esters with Aziridines

heterocyclic moieties are rife for investigation due to their

important biological aspects.2 In this regard, indolines3 are
ubiquitous moieties with multiple pharmacological activities
(Figure S3 in the SI).4 Notably, conventional approaches to
constructing these privileged structural scaffolds often required
multistep procedures and harsh reaction conditions.5 Hence,
the development of methodologies for synthesizing multi-
substituted indolines in a single step is highly desirable. In this
regard, the innate ring strain in aziridines directs their facile
ring opening in the presence of Lewis acids and marks them as
prominent precursors for constructing N-containing hetero-
cycles.6 Hitherto, most annulations of aziridines involve a
zwitterionic species as the reactive partner, although very few
involve this staple structure as a radical precursor.7 On the
other hand, quinones have emerged as some of the most
lucrative precursors, acting as three-component synthons in
multiple chemical transformations. The versatility of the
privileged scaffold is also observed in various functionalization
reactions such as in cycloaddition,8 C−H activation,9 and the
synthesis of natural products.10 In general, there has been (Scheme 1b).8a Thus, we envisaged that monitoring the
extensive study on the reactivity of quinone esters with 2π- reactivity of quinone esters with a stable three-membered-ring
components of unsaturated systems, while the use of N- system would be fascinating. Herein, we present an effective
Sc(III)-catalyzed unprecedented [3 + 2]-annulation between
containing strained ring systems as versatile coupling partners
is still a fledging topic. The activation of quinone esters to their
enol forms is achieved upon exploiting Lewis acids, and further Received: October 10, 2023
cycloaddition delivers the rearomatized fused heterocycles. Revised: October 20, 2023
However, an efficient annulation pathway involving a phenyl Accepted: October 23, 2023
radical intermediate has not yet been documented (Scheme Published: October 24, 2023
1a). Recently, a Sc(OTf)3-catalyzed annulation of quinone
esters with diaziridines to give 1,3,4-oxadiazinanes has emerged

© 2023 American Chemical Society https://doi.org/10.1021/acs.orglett.3c03318

7933 Org. Lett. 2023, 25, 7933−7938
Organic Letters pubs.acs.org/OrgLett Letter

quinone esters and aziridines to furnish substituted indoline Scheme 2. . Scope of Aziridinesa,b
moieties.
First, we initiated our optimization studies using 2-phenyl-1-
tosylaziridine 1a and methyl 3,6-dioxocyclohexa-1,4-diene-1-
carboxylate 2a as the model substrates, employing various
Lewis acids, solvents, and temperatures (Table 1 and Table S1

Table 1. Optimization of the Reaction Conditionsa

yield (%)b
entry catalyst solvent 3aa 2aa
1 Sc(OTf)3 CH2Cl2 47 30
2 Cu(OTf)2 CH2Cl2 41 22
3 Ni(OTf)2 CH2Cl2 25 40
4 Mg(OTf)2 CH2Cl2 trace 55
5 Sc(OTf)3 (CH2Cl)2 35 25
6 Sc(OTf)3 toluene 42 38
7 Sc(OTf)3 CH3CN n.d. n.d
8 Sc(OTf)3 EtOH n.d. n.d. a
Reaction conditions: 1b−u (0.2 mmol), 2a (0.2 mmol), Sc(OTf)3
9 TfOH CH2Cl2 15 12 (10 mol %), TfOH (50 mol %), CH2Cl2 (2 mL), 60 °C, 1 h. bIsolated
10c Sc(OTf)3 CH2Cl2 68 15 yield. n.d. = not detected.
11d Sc(OTf)3 CH2Cl2 60 23
12e Sc(OTf)3 CH2Cl2 81 trace
13f Sc(OTf)3 CH2Cl2 67 12 substituted 1c) aziridines in the aryl ring provided 3ba and 3ca
14g - CH2Cl2 n.d. n.d. in 75% and 80% yields, respectively. The structure of 3ca was
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (10 confirmed by X-ray analysis (CCDC 2287180, see the SI).
mol %), solvent (2 mL), 5 h, rt. n.d. = not detected. TfOH = Similarly, 3-methyl- (1d), 3-chloro- (1e), 3-bromo- (1f), and
trifluoromethanesulfonic acid. bIsolated yield. cAt 60 °C, 1 h. dAt 80 3-nitro-substituted (1g) aziridines furnished 3da−ga, respec-
°C, 1 h. eWith TfOH (50 mol %) at 60 °C, 1 h. fWith Yb(OTf)3 (5 tively, in 77−82% yields. In contrast, aziridine 1h bearing an
mol %) at 60 °C, 1 h. gIn the absence of catalyst and additive. electron donating 3-methoxy group failed to undergo the
annulation, whereas aziridines having methyl (1i), bromo (1j),
in the SI). To our delight, the reaction occurred to deliver trifluoromethyl (1k), phenyl (1l), and acetoxy (1m)
annulated product 3aa in a 47% yield along with rearomatized functionalities at the 4-position of the aryl ring afforded
quinone 2aa and the decomposition of aziridine when the heterocycles 3ia−ma, respectively, in 72−80% yields. These
reaction was carried out employing 10 mol % Sc(OTf)3 in results show that the substrates with electron-withdrawing
CH2Cl2 for 5 h at room temperature (Table S1 in the SI).11a,b substituents exhibited greater reactivity compared to those
The structure of 3aa was confirmed by X-ray analysis (CCDC containing electron-donating substituents, which may be due
2286918, see the SI). In a set of Lewis acids screened, viz., to the facile cleavage of the C−N bond of azirdines. Further,
Sc(OTf)3, Cu(OTf)2, Ni(OTf)2 and Mg(OTf)2, the former the reaction of trisubstituted aziridine 1n failed to produce
gave the superior result (entries 1−4, respectively). CH2Cl2 3na, while polyaromatic 2-naphthyl 1o delivered a trace
was found to be the solvent of choice, while (CH2Cl)2, amount of 3oa, which may be attributed to the sterically
toluene, acetonitrile, and EtOH produced inferior outcomes hindered reacting site. Similar results observed with alkyl-
(entries 5−8). TfOH was able to furnish 3aa in a 15% yield, substituted aziridine 1p, whereas 2-methyl-3-phenyl-1-tosyla-
whereas other protic acids failed to produce the desired ziridine 1q underwent the reaction to give a 2.2:1 regio-
product (entry 9 and Table S1 in the SI). To our delight, isomeric mixture of 3qa in a 79% yield. The methodology was
increasing the reaction temperature to 60 °C improved the further extended by varying the N-sulfonyl substituents. The
yield to 68% (entry 10). Further increasing the temperature to aziridines bearing N-sulfonyl methyl (1r), N-sulfonyl phenyl
80 °C led to a slight decrement of yield (entry 11). (1s), and N-nosyl (1t) were able to give the target products
Gratifyingly, using Sc(OTf)3 with TfOH as an additive at 60 3ra−ta, respectively, in 66−80% yields. Similarly, aziridine
°C increased the yield to 81% (entry 12).11c However, having a 4-tert-Bu (1u) substitution at the 4-position of the N-
Sc(OTf)3 doped with Yb(OTf)3 gave a 67% yield (entry sulfonyl phenyl ring gave the cycloadduct 3ua in a 75% yield.
13).11d A control experiment confirmed that 1a and 2a were The scope of the procedure was extended to a series of
unable to furnish 3aa in the absence of a catalyst and additive quinone esters 2b−j with aziridine 1a as the representative
(entry 14). substrate (Scheme 3). Quinone esters with a variety of alkyl
Having the optimized reaction conditions, the scope of the substitutions, like ethyl (2b), propyl (2c) and butyl (2d),
procedure was elaborated by engaging the substituted afforded the annulated products 3ab−ad, respectively, in 72−
aziridines 1b−u with quinone 2a as a standard substrate 78% yields. Similarly, the allyl-tethered quinone ester 2e
(Scheme 2). The reaction of 2-methyl- (1b) and 2-fluoro- furnished 3ae in 65% yield. The substrates having benzyl (2f),
7934 https://doi.org/10.1021/acs.orglett.3c03318
Org. Lett. 2023, 25, 7933−7938
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 3. . Scope of Quinonesa,b ester 2a afforded 3aa in a 75% yield in racemic form, which
suggests that ring opening of aziridine followed the formation
of the zwitterionic intermediate via the SN1 pathway (Scheme
4a). Further, radical scavenger experiments using 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) and 2,6-ditert-butyl-4-
methylphenol (BHT) inhibited the formation of 3aa (Scheme
4b and c, respectively). In addition, the ESI-MS analyses
confirmed the formation of TEMPO adducts A and B or C
(see the SI), suggesting that the reaction involved a radical
pathway. Moreover, the reactions of aziridine 1a with 1,4-
benzoquinone 2k and quinone ketone 2l failed to afford the
desired 3ak and 3al, respectively (Scheme 4d and e), which
suggests that an ester group is crucial for the transformation.
Although 1a and 2a reacted under an oxygen atmosphere,
there was considerable decrease in the yield (Scheme 4f). This
outcome suggest that air might not be involved in the radical
formation.
On the basis of the preliminary mechanistic investigations
a
Reaction conditions: 1a (0.2 mmol), 2a−j (0.2 mmol), Sc(OTf)3 and literature precedents, a plausible reaction pathway is
(10 mol %), TfOH (50 mol %), CH2Cl2 (2 mL), 60 °C, 1 h. bIsolated proposed (Scheme 5). The reaction of aziridine 1a with Lewis
yield. n.d. = not detected.
Scheme 5. . Plausible Mechanism
2-bromobenzyl (2g), 4-bromobenzyl (2h), and 4-fluorobenzyl
(2i) functionalities at ester afforded 3af−ai, respectively, in
70−75% yields, whereas napthoquinone derived ester 2j was
an unsuccessful substrate.
To gain insight into the reaction pathway, control
experiments were performed (Scheme 4). The reaction of
enantiopure (R)-2-phenyl-1-tosylaziridine 1a′ with quinone

Scheme 4. . Preliminary Mechanistic Investigations

acid can lead to the formation of the 1,3-dipole D,12a which

can react with 2a to give the short-lived transient species E
(detected by ESI-MS, see the SI).12b In the presence of
Sc(OTf)3, E might generate the intermediate F.13 This can
lead to the formation of G (detected by ESI-MS, see the SI),
which can undergo homolytic N−O bond cleavage to give H
(path I). The latter can undergo homolytic C−O bond
cleavage to give the intermediate I having both the nitrogen
and phenyl radicals, which have been detected by the radical
scavenger experiments (see A and B). The radical I can
undergo annulation to produce the target heterocycle 3aa.
Alternatively, F can transform to J and a superoxide radical
anion,14 which can lead to the formation I by single electron
transfer (SET) to produce the target heterocycle 3aa.
Finally, to showcase the synthetic utility of the procedure,
first we studied the scale-up of the procedure having aziridine
1e with quinone 2a as representative examples to afford 3ea in
a 63% (542 mg) yield (Scheme 6). Further, the indoline 3ea
was subjected to coupling with drug molecules like gemfibrozil,
used for treating high cholesterol, and naproxen, which is an
anti-inflammatory drug. Gratifyingly, both drug molecules
coupled efficiently with 3ea to produce 4 and 5 (dr 1:1) in
7935 https://doi.org/10.1021/acs.orglett.3c03318
Org. Lett. 2023, 25, 7933−7938
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 6. . Scale-Up Synthesis ■ ASSOCIATED CONTENT

Data Availability Statement
The data underlying this study are available in the published
article and its online Supporting Information.
*
sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.3c03318.
90% and 82% yields, respectively (Scheme 7a and b). Similarly, General information; crystal data of 3aa and 3ca;
the phenolic OH group of 3ea was coupled with propargyl experimental procedures; characterization data; and
copies of 1H, 13C, and 19F NMR spectra (PDF)
Scheme 7. Post-Synthetic Utilitiesa
Accession Codes
CCDC 2286918 and 2287180 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.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■ AUTHOR INFORMATION
Corresponding Author
Tharmalingam Punniyamurthy − Department of Chemistry,
Indian Institute of Technology Guwahati, Guwahati, Assam
781039, India; orcid.org/0000-0003-4696-8896;
Email: tpunni@iitg.ac.in
Authors
Kshitiz Verma − Department of Chemistry, Indian Institute of
a
Reaction conditions: (a) 3ea (0.1 mmol), gemfibrozil (0.1 mmol), Technology Guwahati, Guwahati, Assam 781039, India;
DCC (0.25 mmol), DMAP (0.05 mmol), CH2Cl2 (2 mL), 0 °C to rt, orcid.org/0000-0001-8496-2829
24 h; (b) 3ea (0.1 mmol), naproxen (0.1 mmol), DCC (0.25 mmol), Manmath Mishra − Department of Chemistry, Indian Institute
DMAP (0.05 mmol), CH2Cl2 (2 mL), 0 °C to rt, 24 h; (c) 3ea (0.1 of Technology Guwahati, Guwahati, Assam 781039, India
mmol), propargyl bromide (0.3 mmol), K2CO3 (0.5 mmol), acetone Prabhat Kumar Maharana − Department of Chemistry,
(1.5 mL), rt, 12 h; (d) 6 (0.05 mmol), TsN3 (0.065 mmol), Cu(I)Tc
(0.005 mmol), toluene (0.5 mL); (e) 3ea (0.1 mmol), MeI (0.15
Indian Institute of Technology Guwahati, Guwahati, Assam
mmol), K2CO3 (0.2 mmol), DMF (2 mL), rt, 4 h; (f) 3ea (0.1 781039, India
mmol), Tf2O (0.15 mmol), Et3N (0.15 mmol), CH2Cl2 (1.5 mL), Hemanga Bhattacharyya − Department of Chemistry, Indian
−78 °C to rt, N2, 4 h. Institute of Technology Guwahati, Guwahati, Assam
781039, India; orcid.org/0009-0005-3357-1138
Sharajit Saha − Department of Chemistry, Indian Institute of
Technology Guwahati, Guwahati, Assam 781039, India
bromide to give 6 in a 75% yield (Scheme 7c), which was then Complete contact information is available at:
subjected to click reaction in the presence of a Cu(I) catalyst https://pubs.acs.org/10.1021/acs.orglett.3c03318
to afford triazole skeleton 7 in an 85% yield (Scheme 7d). In
addition, 3ea was subjected to methylation to afford 8 in a 78% Notes
yield (Scheme 7e), which is an integral part of several natural The authors declare no competing financial interest.
products.4c Moreover, indoline 3ea was converted to triflate 9,
which can act as a potential precursor for coupling reactions
(Scheme 7f).
■ ACKNOWLEDGMENTS
We thank CSIR (02(0458)/21/EMR-II) for the financial
In conclusion, we described domino C−N and C−C bond support and CIF and NECBH (BT/CoE/34/SP28408/2018),
formation of aziridines with quinones using Sc(OTf)3 with and DST-FIST (SR/FST/CS-II/2017/23c) for NMR, mass,
and X-ray analyses. K.V. acknowledges the Ministry of
TfOH to afford functional and biologically active indoline Education for the Prime Minister’s Research Fellowship
moieties. The study indicates that a Lewis acid is essential for (PMRF).
the reaction and reveals an unusual kind of reactivity of
aziridines and quinone esters. Lewis acid-driven aromatization
of E to generate a N-umpolung cation species F via C−N bond
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