pubs.acs.
org/OrgLett Letter
Nickel-Catalyzed Cross-Electrophile Ring Opening/gem-
Difluoroallylation of Aziridines
Wei Tang and Pei Fan*
Cite This: Org. Lett. 2023, 25, 5756−5761
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ABSTRACT: Herein we report a nickel-catalyzed regioselective
cross-electrophile ring opening reaction of sulfonyl-protected
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aziridines with trifluoromethyl-substituted alkenes as the gem-
difluoroallylating agents, providing a new and efficient entry to
prepare gem-difluorobishomoallylic sulfonamides. Moreover, the
scaffold of 6-fluoro-1,2,3,4-tetrahydropyridine can be constructed starting from the ring opening products via NaH-mediated
intramolecular defluorinative nucleophilic vinylic substitution.
B y circumventing the pregeneration of sensitive organo-
metallics, transition-metal-catalyzed cross-electrophile
ring opening (XERO) of cyclic compounds represents an
appealing reaction toward C−C bond formation from the
viewpoints of step-economy, functional group compatibility,
and operational simplicity.1,2 To date, suitable heterocyclic
precursors for XERO mainly include epoxides,3 aziridines,4
cyclic anhydrides,5 benzofurans,6 and heteroatom-bridged
bicyclic alkenes.7 Among them, aziridines are versatile building
blocks in organic synthesis,8 and XERO of such a structural
motif with aryl iodides,4ab alkenyl bromides,4c aldehydes,4d
acetals,4e CO2,4f or Michael acceptors4g provides approaches to
a variety of amine derivatives (Scheme 1A).
Scheme 1. Cross-Electrophile Ring Opening of Aziridines
gem-Difluoroalkenes have attracted increased interest from
the organic community in recent years9,10 because such
moieties are not only present as characteristic structural units
in numerous biologically active compounds11 but also serve as
the precursors to reach other fluorine-containing com-
pounds.12 Among many strategies, transition-metal-catalyzed
allylic defluorinative cross-electrophile coupling (XEC) of
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trifluoromethyl-substituted alkenes developed by Wang13−19
and others20 offers a unique reaction pathway to prepare
functional-group-rich gem-difluoroalkenes starting from readily
available organic electrophiles, including alkyl halides,13,20c,d
carbonyl compounds,14,20e acetals,15 epoxides,16 oxime ester-
s,17,20a activated carboxylic esters,20b Katritzky salts,18 cyclo-
alkyl silyl peroxides,19 and alkene-tethered aryl halides.20f
Herein, we envisioned a nickel-catalyzed XERO/gem-
difluoroallylation reaction of N-sulfonyl aziridines with
trifluoromethyl-substituted alkenes under reductive conditions
to provide a series of gem-difluorobishomoallylic sulfonamides
as the products, which can be further transformed into 6-
fluoro-1,2,3,4-tetrahydropyridines via base-mediated intramo-
lecular defluorinative nucleophilic vinylic substitution (Scheme
1B).
For the optimization of the reaction conditions, we used α-
trifluoromethylstyrene 1a and N-tosyl styrenyl aziridine (2a)
(2.0 equiv) as the standard substrates (Table 1). Initially, the
reactions were carried out using Ni(dme)Br2 (10 mol %) as
the precatalyst, L1−7 (15 mol %) as the ligands, and Zn (3
equiv) as the reductant in DMSO (0.2 M) at 40 °C for 24 h.
However, none of these reactions afforded the target product
3aa. In these cases, the full conversion of azitidine 2a was
detected, while α-trifluoromethylstyrene 1a was fully recovered
(entry 1). Considering that halides might facilitate the
anticipated reaction through the in situ generation of a benzyl
halide via ring opening halogenolysis, we carried out the
reactions using ZnI2 (1.0 equiv) as the additive (entries 2−8).
Indeed, in the cases of terpyridine (L1), phenanthrolines L2
Received: June 15, 2023
Published: July 28, 2023
https://doi.org/10.1021/acs.orglett.3c01973
5756 Org. Lett. 2023, 25, 5756−5761
Organic Letters pubs.acs.org/OrgLett Letter

Table 1. Optimization of the Reaction Conditionsa
agent led to a diminished efficiency and poorer selectivity
(entry 17). Increasing the amount of the aziridine 2a to 2 equiv
increased the reaction yield to 86% (entry 18). In addition, no
desired reaction occurred in the absence of the nickel
precatalyst, excluding the zinc-mediated background reaction
(entry 19).
After obtaining the optimized reaction conditions, we started
to evaluate the substrate scope of this nickel-catalyzed XERO/
gem-difluoroallylation reaction (Scheme 2). First, an array of

Scheme 2. Evaluation of the Substrate Scope of

Trifluoromethyl-Substituted Alkenesa,b,c

entry ligand Ni precat. additive yield (%)b 3aa/3aa′c

1 L1−7 Ni(dme)Br2 0
2 L1 Ni(dme)Br2 ZnI2 28 20:1
3 L2 Ni(dme)Br2 ZnI2 25 4:1
4 L3 Ni(dme)Br2 ZnI2 23 4:1
5 L4 Ni(dme)Br2 ZnI2 15 2:1
6 L5 Ni(dme)Br2 ZnI2 22 4:1
7 L6 Ni(dme)Br2 ZnI2 70 >99:1
8 L7 Ni(dme)Br2 ZnI2 trace n.d.d
9 L6 Ni(dme)Br2 LiI 55 14:1
10 L6 Ni(dme)Br2 NaI 57 14:1
11 L6 Ni(dme)Br2 ZnBr2 32 10:1
12 L6 NiBr2 ZnI2 62 50:1
13 L6 Ni(acac)2 ZnI2 58 30:1
14 L6 Ni(COD)2 ZnI2 61 75:1
15e L6 Ni(dme)Br2 ZnI2 40 7:1
16f L6 Ni(dme)Br2 ZnI2 47 11:1
17g L6 Ni(dme)Br2 ZnI2 57 20:1
18h L6 Ni(dme)Br2 ZnI2 86 >99:1
19 ZnI2 0
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the α-trifluoromethylstyrene 1a using 2.0 equiv of N-tosyl
styrenyl aziridine (2a), 10 mol % Ni-precatalyst, 15 mol % ligand L,
1.0 equiv of additive, and 3.0 equiv of Zn in 1.0 mL of DMSO at 40
°C for 24 h. bCombined yield of the isolated 3aa and 3aa′ after
column chromatography. cDetermined by 19F NMR spectroscopy.
d
Not determined. eThe reaction was performed in DMF. fThe
reaction was performed in DMA. gMn was used as the reductant
instead of Zn. hThe reaction was performed with 2.0 equiv of N-tosyl
styrenyl aziridine (2a). a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the trifluoromethyl-substituted alkenes 1a−v using 2.0 equiv
of N-tosyl styrenyl aziridine (2a), 10 mol % Ni(dme)Br2, 15 mol %
and L3, BiOX L4, PyrOX L5, and 2,2′-biquinoline (L6), ligand L6, 1.0 equiv of ZnI2, and 3.0 equiv of Zn in 1.0 mL of DMSO
desired product 3aa and hydrobenzylation byproduct 3aa′ at 40 °C for 24 h. bYields of the isolated products after column
were obtained as the mixture, and the best result was achieved chromatography. cUnless otherwise specified, the ratio of the
in the case of L6 regarding both efficiency and the ratio of 3aa defluorinative products 3 to the hydrobenzylation product 3′ is
to 3aa′. An exception was observed in the case of bipyridine >99:1. dThe reaction was performed on a 3 mmol scale of 1a.
e
L7, which gave only a trace amount of 3aa (entry 8). Next, Referring to the ratios of the defluorinative products 3 to the
several metal halides, including LiI, NaI, and ZnBr2, were hydrobenzylation product 3′. fDetermined by 19F NMR spectroscopy.
screened for this reaction, providing no improved outcome
(entries 9−11, respectively). Moreover, other nickel precata- substituted α-trifluoromethylstyrenes (1a−q) were reacted
lysts including NiBr2, Ni(acac)2, and Ni(cod)2 could also with the aziridine 2a under the standard conditions, furnishing
promote the target reaction but less efficiently and less the corresponding products 3aa−qa in moderate to high
selectively (entries 12−14, respectively). Performing the yields. It turned out that diverse functional groups including
reaction in other polar aprotic solvents such as DMF and alkoxy (3aa−ea), thioether (3fa), aryl halide (3ia−ma),
DMA resulted in inferior results (entries 15 and 16, alcohol (3na), ester (3oa), nitrile (3pa), and ketone (3qa)
respectively). Replacing zinc with manganese as the reducing were well tolerated in the studied reactions. In general, better
5757 https://doi.org/10.1021/acs.orglett.3c01973
Org. Lett. 2023, 25, 5756−5761
Organic Letters
results were achieved in the cases of electron-donating and
weak electron-withdrawing substituents than those of strong
electron-withdrawing substituents in terms of both yield and
selectivity. Moreover, the trifluoromethyl alkenes containing β-
naphthyl (1r), 3-benzothienyl (1s), 3-indolyl (1t), or 3-
pyridinyl (1u) as the geminal substituent were also competent
precursors for the studied reaction, delivering the products
3ra−ua, respectively, in moderate to high yields. Furthermore,
the trifluoromethyl alkene 1v derived from estrone, respec-
tively, was also successfully employed as the substrate,
affording the coupling products 3va in good efficiency. The
low yields (around or below 50%, for example, 3ma, 3pa, and
3al) are attributed to incomplete conversion of the α-
trifluoromethylstyrenes, while the aziridines have been almost
completely consumed.
Subsequently, we investigated the generality of aziridines in
this nickel-catalyzed reaction (Scheme 3). Gratifyingly, a broad
Scheme 3. Evaluation of the Substrate Scope of
Aziridinesa,b,c
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the trifluoromethyl alkene 1a using 2.0 equiv of the aziridines
2a−q, 10 mol % Ni(dme)Br2, 15 mol % ligand L6, 1.0 equiv of ZnI2,
and 3.0 equiv of Zn in 1.0 mL of DMSO at 40 °C for 24 h. bYields of
the isolated products after column chromatography. cThe ratio of the
defluorinative products 3 to the hydroalkylation product 3′ is >99:1
as determined by 19F NMR spectroscopy.
range of 2-aryl-substituted N-tosyl-protected aziridines con-
taining alkyl (2b−d), phenoxy (2e), acyloxy (2f), methoxy
(2g), halide (2h−j), trifluoromethyl (2k), or ester (2l) groups
on different positions of the phenyl ring readily underwent the
cross-coupling reaction with the α-trifluoromethylstyrene 1a,
affording the gem-difluorobishomoallylic sulfonamides 3ab−al,
respectively, in moderate to excellent yields. Furthermore, the
pubs.acs.org/OrgLett Letter
β-naphthyl-substituted aziridine 2m and the unsubstituted
aziridine 2n posed no problem, furnishing ring-opening
products 3am and 3an in moderate yields, respectively.
Moreover, aziridines with sulfonyl substituents other than a
tosyl group were also examined in the studied reaction. It
turned out that both alkyl (2o and 2p) and benzyl (2q)
sulfonamides were suitable substrates, leading to the formation
of the coupling products 3ao−aq with good to high efficiency.
Next, various tosyl-protected 6-fluoro-1,2,3,4-tetrahydropyr-
idines 4 were readily synthesized in moderate to high yields
starting from selected gem-difluorobishomoallylic sulfonamides
3 via NaH-mediated intramolecular defluorinative nucleophilic
vinylic substitution (Scheme 4).
Scheme 4. Derivatization of gem-Difluorobishomoallylic
Sulfonamides to 6-Fluoro-1,2,3,4-tetrahydropyridinesa,b
a
Unless otherwise specified, reactions were performed on a 0.15
mmol scale of the gem-difluorobishomoallylic alcohols 3 using 2.0
equiv of the NaH in 1.0 mL of DMF at room temperature. bYields of
the isolated products.
During the optimization of the reaction conditions, we
noticed that the presence of a metal halide is essential for the
desired reaction, which supports a reaction pathway involving
aziridine iodolysis4a,21 followed by XEC of trifluoromethyl-
substituted alkenes with the iodolysis product.13,20c To confirm
it, we carried out the reaction between alkene 1a and benzyl
iodide 5 (Scheme 5). Indeed, the allylic defluorinative cross-
coupling product 3aa was obtained in a 17% yield with the
hydrobenzylation product 3aa′ as the byproduct.
In conclusion, we have developed a nickel-catalyzed cross-
electrophile ring opening reaction of sulfonyl-activated
aziridines with trifluoromethyl-substituted alkenes. This
reductive cross-coupling reaction features complete regiocon-
5758 https://doi.org/10.1021/acs.orglett.3c01973
Org. Lett. 2023, 25, 5756−5761
Organic Letters pubs.acs.org/OrgLett
Scheme 5. Reaction using the Benzyl Iodide
trol and high functionality tolerance, offering appealing access
to gem-difluorobishomoallylic sulfonamides. Zinc iodide has
been proven to act as a crucial additive that initiates the ring
opening of aziridine via iodolysis, providing the resultant alkyl
iodides for the following allylic defluorinative cross-electrophile
coupling reaction. Notably, the ring opening products can be
further converted into an array of 6-fluoro-1,2,3,4-tetrahy-
dropyridines through a simple NaH-mediated nucleophilic
vinylic substitution reaction.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.3c01973.
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
■ AUTHOR INFORMATION
Corresponding Author
Pei Fan − School of Chemical and Materials Engineering,
Anhui Province Key Laboratory of Low Temperature Co-fired
Materials, Huainan Normal University, Huainan, Anhui
232038, P. R. China; Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China; orcid.org/0000-0002-4394-1017;
Email: fanpei@ustc.edu.cn
Author
Wei Tang − School of Chemical and Materials Engineering,
Anhui Province Key Laboratory of Low Temperature Co-fired
Materials, Huainan Normal University, Huainan, Anhui
232038, P. R. China; Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.3c01973
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work is supported by the Natural Science Foundation of
Anhui Province (2208085QB35), the Natural Science
Foundation of Educational Department of Anhui Province
(2022AH030144), the China Postdoctoral Science Foundation
(2022T150616), and the Anhui Province Postdoctoral Science
Foundation (2021B536).
5759
Letter
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