Copper-Catalyzed Ring Expansion of Vinyl Aziridines under Mild Conditions

Article abstract of DOI:10.1055/s-0040-1706007

Vinyl aziridines are versatile starting materials toward ring-expansion transformations. Such processes are widely used to give various medium or larger N-heterocycles of synthetic interest. This letter describes a copper-catalyzed ring expansion of vinyl aziridines to 3-pyrrolines by using a Cu(I) salt [(CuOTf) ₂·toluene or Cu(MeCN) ₄·PF ₆]. In particular, this transformation occurs under mild conditions (THF, rt).

Full text of DOI:10.1055/s-0040-1706007

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, 517–520
cluster
517
The Power of Transition Metals: An Unen-
E. Tosi et al.
Cluster
Synlett
Copper-Catalyzed Ring Expansion of Vinyl Aziridines under Mild
Conditions
Eleonora Tosi
Pyrrolines synthesis
Practical procedure
Mild reaction conditions
Short reaction time
R3
Ts
N
Ts
R3
Kim Spielmann
(CuOTf)2•Toluene
THF, rt
N
R2
R1
Renata Marcia de Figueiredo*
Jean-Marc Campagne*
0
0
0
0
-
0
0
0
1
-
5
3
3
6-6
0
7
1
R1
R2
up to 94% yield
ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
jean-marc.campagne@enscm.fr
renata.marcia_de_figueiredo@enscm.fr
In expression of our respect to Professor Barry M. Trost on the
occasion of his 80th birthday.
Published as part of the Cluster
The Power of Transition Metals: An Unending Well-Spring of New
Reactivity
Corresponding Authors
Received: 29.10.2020
Accepted after revision: 08.12.2020
Published online: 05.01.2021
CO2R4
R1
Ts
R1
OTMS
OR4
LA cat.
N
+
TsN
R2
DOI: 10.1055/s-0040-1706007; Art ID: st-2020-k0569-c
R2
R3
R3
1
2
Abstract Vinyl aziridines are versatile starting materials toward ring-
expansion transformations. Such processes are widely used to give vari-
ous medium or larger N-heterocycles of synthetic interest. This letter
describes a copper-catalyzed ring expansion of vinyl aziridines to 3-pyr-
rolines by using a Cu(I) salt [(CuOTf)2·toluene or Cu(MeCN)4·PF6]. In
particular, this transformation occurs under mild conditions (THF, rt).
R2
O
R1
N
Ts
R3
3
Key words ring expansion, vinyl aziridines, pyrrolines, copper cataly-
sis, heterocycles
Scheme 1 Envisaged reactions of vinyl aziridines 1 with silyl enol
ethers 2
Ring expansion of small-sized carbo- and heterocycles is
among the most widely used transformations toward medi-
um (or larger) carbo- and heterocycles.1 Due to the pres-
ence of both a highly strained three-membered heterocycle
and an activated double bond, vinyl aziridines are an ex-
traordinary source of reactivity, and are therefore valuable
building blocks in organic synthesis.2–4 Consequently, we
have been interested in exploring possibilities for perform-
ing ring-expansion processes with vinyl aziridines under
mild and practical conditions toward novel useful building
blocks. Moreover, N-heterocycles are highly valued and
widely used in medicinal chemistry, revealing much prom-
ise for industrial purposes.5
Ts
N
OTMS
+
OEt
Ph
1a
2a
Cu(OTf)2 (5 mol%)
CH2Cl2, rt
TsN
TsHN
TsN
Ph
Ph
Ph
4a
5a
6a
10–20% yield
O
TsN
3a
not observed !
Ph
Building on our previous work in the area of palladium-
catalyzed [3+2]-cycloadditions of vinyl aziridines 1 with cy-
clic sulfoxyimines,4 we were drawn to the potential use of
silyl enol ethers 2 in the presence of Lewis acids to form the
corresponding five-membered lactams 3 (Scheme 1) bear-
ing a quaternary center.
Scheme 2 Attempted reaction of vinyl aziridine 1a with silyl enol ether
2a under copper catalysis
When the reaction was attempted with model com-
pound 1a and the silyl enol ether 2a in the presence of 5
mol% of Cu(OTf)2 at room temperature in dichloromethane,
the expected compound 3a could not be observed in the
crude material. Instead, along with the rather predictable
elimination compounds 4a and 5a, pyrroline 6a was isolat-
ed from the reaction mixture in low yields (10–20%)
(Scheme 2).
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 517–520
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

518
E. Tosi et al.
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The copper-catalyzed ring expansion of vinyl aziridines
to 3-pyrrolines is a known reaction, originally described by
Njardarson and co-workers in 2008 (Scheme 3).6 However
these reactions required the presence of an unusual copper
complex, bis(hexafluoroacetylacetonato)copper [Cu(hfa-
cac)2], under relatively harsh conditions (toluene, 150 °C).7
As shown in Scheme 3, various substituted 3-pyrrolines
could be efficiently obtained under these reaction condi-
tions; the reaction mechanism was also unveiled.6c
Table 1 Pyrroline 6a Synthesis from Vinyl Aziridine 1a: Optimization
Studya
Entry
Solvent
Cat. (5 mol%)
(4a + 5a)/6ab Yield (%) of 6a
1c
2
3
4
5
6
7
CH2Cl2
CH2Cl2
THF
Cu(OTf)2
70:30
100:0
NRe
10
–
d
Cu(OTf)2
[(i-Pr)CuCl]
[(Ph3P)3CuF]
CuTCf
–
THF
NR
–
THF
NR
–
Ts
N
Ts
R1
THF
(CuOTf)2·toluene
TFA
<5: >95
NR
60
–
R2
Cu(hfacac)2 (5 mol%)
toluene, 150 °C
N
R3
THF
R1
a Reactions conditions: 1a (0.05 mmol), catalyst (5 mol%), solvent (0.5
mL), rt, argon atmosphere, 12 h.
b Determined by 1H NMR of the crude product.
c With silyl enolate 2a (1.5 equiv).
d Or THF.
R3
Me
R2
Me
Me
Me
N
N
Ts
99%
N
Ts
Ts
e NR = no reaction.
f TC = thiophene-2-carboxylate.
80%
Ph
98%
Ph
this purpose, a small collection of vinyl aziridines 1 were
prepared by following a sequence involving an organocata-
lyzed aziridination/Wittig reaction (Scheme 4).6,10 The ex-
pected substrates needed for the ring-expansion transfor-
mation were obtained in moderate-to-good yields.
CO2Me
N
Ts
N
Ts
98%
60%
Scheme 3 Some examples of vinyl aziridine rearrangements under
Njardarson’s conditions6a
As shown in Scheme 5, various mono- and disubstituted
pyrrolines 6 were isolated in good yields. In the presence of
both R1 and R2 groups in the starting vinyl aziridine, pyrro-
lines 6a and 6b were obtained in yields of 60 and 33%, re-
spectively. Notably, no reaction was observed when an elec-
tron-withdrawing group (R2 = CO2Et; compound 6c) was
present, and for which Njardarson’s conditions are effi-
cient.6 From monosubstituted aziridines 1d–g, the corre-
sponding pyrrolines 6d–g were obtained in yields of 60–
94%. Of note, the presence of functionalized side-chains
was well tolerated (6g and 6j). The rearrangement of vinyl
aziridine 1d was also performed at a 1 mmol scale (as op-
posed to 0.14 mmol) to give the expected pyrroline 6d in a
comparable isolated yield of 83%. The ring expansion of vi-
nyl aziridines 1h–j with substituents at the R3 position was
next investigated. In this case, pyrrolines 6h–j were formed
in moderate to good yields of 40–57%. From these results,
we can deduce that hindrance around the NTs functional
group (the R2 and R3 groups) has a deleterious effect on the
ring-expansion process, as the expected compounds were
isolated in lowers yields (<60%). In these cases, the reac-
tions were complete according to TLC monitoring, but were
accompanied by the formation of unidentified byproducts.
This trend was reinforced when substrate 1k was submit-
ted to the ring-expansion conditions, as none of the trisub-
stituted pyrroline 6k was formed. In contrast, pyrrolines
monosubstituted at R1 were obtained in excellent yields
(≤94%). Interestingly, Cu(MeCN)4·PF6 could also be used as
catalyst for the synthesis of 6b, 6d, and 6i, affording similar
yields (32, 90, and 40%, respectively).
The very mild conditions (Scheme 2) in which 6a was
formed in our reaction prompted us to reinvestigate the re-
action conditions (Table 1) towards the exclusive, or at least,
main formation of pyrroline 6a. Interestingly, in the ab-
sence of silyl enolate 2a, the pyrroline 6a was not observed
(Table 1, entry 2). Suspecting an in situ Cu(II) → Cu(I) re-
duction in the reaction process,8 we investigated the use of
Cu(I) salts in the absence of silyl enolate 2a. Whereas vari-
ous Cu(I) salts proved unsuccessful in catalyzing the reac-
tion (entries 3–5), we were delighted to observe the clean
formation of 6a in the presence of 10 mol% of (CuOTf)2·tolu-
ene (entry 6) at room temperature in THF.9 To exclude the
possibility of an organic acid-catalyzed transformation, we
ran a trial in the presence of 5 mol% of TFA; in this case, no
reaction was observed (entry 7).
After optimizing of the basic rearrangement reaction
with vinyl aziridine 1a, we examined its general scope. For
R3
Wittig or
HWE
R3
R3
NTs
TsO-NHTs
NTs
R1 CHO
R1
reactions
Pyrrolidine
or diarylprolinol
derivative
R1 CHO
R2
>10 examples
up to 50% yield
(2 steps)
Ref 10
Scheme 4 Synthesis of vinyl aziridines 1. For additional details, see
Supporting Information.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 517–520

519
E. Tosi et al.
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Starting from the enantiomerically enriched vinyl aziridine
(Z)-1a (80% ee),10 the corresponding pyrroline 6a was ob-
tained in 62% yield in a racemic form (Scheme 7).
R3
R1
Ts
N
(CuOTf)2•Toluene
(5 mol%)
Ts
R3
R1
N
R2
THF, rt
R2
1
6
Ts
Ts
N
(CuOTf)2•Toluene
(5 mol%)
Bn
Ts
Ts
N
Ts
N
N
N
Me
THF, rt
62%
Me
Me
CO2Et
Bn
Me
Z-1a
Me
Bn
Bn
6a
6b (from Z-1b)
6a (from Z-1a)
6c (from E-1c)
(80% ee)
(rac)
33%a
60%
NR
Scheme 7 Rearrangement of enantiomerically enriched vinyl aziridine
(Z)-1a
Ts
N
Ts
N
Ts
N
Ts
N
Bn
Me
5
7
These results, including the racemization of enantio-
merically enriched vinyl aziridines, are in full accordance
with Njardarson’s observations. Mechanistic studies per-
formed by Njardarson and co-workers highlighted a cop-
per(I) insertion into the C–N bond to give an allylcopper in-
termediate, ultimately leading, to the pyrroline 6 after re-
ductive elimination (Scheme 8; left-hand pathway).6c An
alternative mechanistic scenario (Scheme 8; right-hand
pathway) involving copper coordination and subsequent
heterolytic rupture of the C–N bond, followed by the attack
of the N-tosyl anion, cannot be totally excluded under our
reaction conditions.
6d
91%
6e
94%
6f
90%
6g
90%
@ 1mmol scale 83%
Ts
Ph
Ts
N
Ts
N
Et
N
TBSO
Me
Me
Ph
6h
57%
6i
40%
6j
40%
Et
(CuOTf)2•Toluene
Ts
N
Ts
Et
(5 mol%)
N
Me
X
Me
Me
THF, rt
Me
Z-1k
6k
Ts
Scheme 5 Scope of the rearrangement of vinyl aziridines 1. Reagents
and conditions: 1 (0.14 mmol), (CuOTf)2·toluene (5 mol%), THF (0.7
mL), rt, 2 h. Isolated yields after purification by silica gel column chro-
matography are reported. NR = no reaction. a Pyrroline 6b was, for an
unknown reason, very difficult to purify.
Ts
N
N
6
Cu(I)
Ts
N
R
6
R
[Cu]
[Cu]
R
R
1
Ts
N
TsN
[Cu]
N
Ts
R
Thanks to an easy access to 2-substituted vinyl cyclo-
propanes,11 a related reaction of the vinylcyclopropane 7
was next attempted under the same reaction conditions,
but with no success (Scheme 6). The rearrangement of vinyl
epoxides had been previously reported by Njardarson
[Cu(hfacac)2 (5 mol%), toluene, 150 °C].6d We therefore at-
tempted a rearrangement of vinyl epoxide 9 in the presence
of (CuOTf)2 at room temperature, but the reaction led to an
intractable mixture of products, and dihydropyran 10 could
not be isolated.
R
Scheme 8 Proposed mechanistic scenarios
These mechanistic insights prompted us to test the use
of palladium salts in these ring-opening aziridine reactions.
In a model reaction with (Z)-1a, we eventually found that,
under aza-Wacker conditions,12 the corresponding pyrrole
11 could be obtained in an unoptimized 50% yield (Scheme
9).13
The mild conditions used in this transformation (THF,
rt) prompted us to check the reaction stereospecificity.
Ts
Ts
N
Pd(OAc)2 (10 mol%)
Pyridine, Na2CO3
N
Bn
Me
EtO2C
O2, Toluene, 80 °C
50%
(CuOTf)2•Toluene
EtO2C CO2Et
Bn
CO2Et
Bn
(5 mol%)
X
THF, rt
Me
Z-1a
11
Bn
7
8
Scheme 9 Aza-Wacker-type rearrangement of (Z)-1a
(CuOTf)2•Toluene
(5 mol%)
O
O
In conclusion, we have developed a practical protocol14
for the synthesis of 3-substituted pyrrolines from accessible
vinyl aziridines. The ring-expansion process takes place un-
der Cu(I) catalysis. In particular, mild conditions (THF, rt)
are sufficient to accomplish the rearrangements. In the
Bn
<10%
THF, rt
Bn
9
10
Scheme 6 Attempted copper-catalyzed rearrangements of vinylcyclo-
propane 7 and epoxide 9
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 517–520

520
E. Tosi et al.
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presence of R2 and R3 groups (steric hindrance around the
NTs functionality), yields ranged from 33 to 60%, whereas
3-pyrrolines (R2 = R3 = H) were isolated in higher yields
(>90%). Further investigations will be carried in an attempt
to understand the correlation (if any) between conversion
and steric encumbrance, and also to broaden the actual
scope. The present procedure might be an efficient method
for the synthesis of 3-pyrrolines, which are useful building
blocks in both organic and medicinal chemistry. Moreover,
the Wacker-type reactions disclosed are currently under in-
vestigation.
(6) (a) Brichacek, M.; Lee, D.; Njardarson, J. T. Org. Lett. 2008, 10,
5023. (b) Brichacek, M.; Villalobos, M. N.; Plichta, A.;
Njardarson, J. T. Org. Lett. 2011, 13, 1110. (c) Mack, D. J.;
Njardarson, J. T. Chem. Sci. 2012, 3, 3321. (d) Batory, L. A.;
McInnis, C. E.; Njardarson, J. T. J. Am. Chem. Soc. 2006, 128,
16054.
(7) For thermal rearrangements of 2-vinyl aziridines, see:
(a) Mente, P. G.; Heine, H. W. J. Org. Chem. 1971, 36, 3076.
(b) Pommelet, J. C.; Chuche, J. Can. J. Chem. 1976, 54, 1571.
(c) Borel, D.; Gelas-Mialhe, Y.; Vessière, R. Can. J. Chem. 1976, 54,
1590. (d) For a [4+1] access to 3-pyrrolines, see also: Wu, Q.; Hu,
J.; Ren, X.; Zhou, J. Chem. Eur. J. 2011, 17, 11553.
(8) (a) Kobayashi, Y.; Taguchi, T.; Morikawa, T.; Tokuno, E.;
Sekiguchi, S. Chem. Pharm. Bull. 1980, 28, 262. (b) Ferraris, D.;
Young, B.; Cox, C.; Drury, W. J. III.; Dudding, T.; Leckta, T. J. Org.
Chem. 1998, 63, 6090. (c) Pagenkopf, B. L.; Krüger, J.; Stojanovic,
A.; Carreira, E. M. Angew. Chem. Int. Ed. 1998, 37, 3124; See also
the Njardarson mechanistic studies in reference 6 (c).
(9) After a short screening of solvents (e.g., THF, CH2Cl2, toluene,
hexane), THF was chosen to perform the transformation.
(10) Desmarchelier, A.; Pereira de Sant’Ana, D.; Terrasson, V.;
Campagne, J.-M.; Moreau, X.; Greck, C.; de Figueiredo, R. M. Eur.
J. Org. Chem. 2011, 4046.
Funding Information
This work was supported by the Ecole Nationale Supérieure de
Chimie de Montpellier (ENSCM) (K.S.), the ANR (ANR- 18-CE07-0038-
01; E.T.), and the CNRS (Centre National de la Recherche Scientifique).
Brigita Mudráková is kindly thanked for her help with the synthesis of
some aziridines.
A
g
e
n
c
e
N
ati
o
n
a
l
e
d
el
a
Re
c
herc
h
e
(A
N
R-
1
8-C
E
0
7-0
0
3
8-0)
(11) Terrasson, V.; van der Lee, A.; de Figueiredo, R. M.; Campagne, J.-
M. Chem. Eur. J. 2010, 16, 7875.
Supporting Information
(12) Bao, X.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2018, 57, 1995.
(13) For related reactions involving Pt- or Au-catalyzed ring expan-
sions of alkynyl aziridines, see: (a) Yoshida, M.; Easmin, S.; Al-
Amin, M.; Hirai, Y.; Shishido, K. Tetrahedron 2011, 67, 3194.
(b) Yoshida, M.; Maeyama, Y.; Al-Amin, M.; Hirai, Y.; Shishido,
K. J. Org. Chem. 2011, 76, 5813. (c) Davies, P. W.; Martin, N. Org.
Lett. 2009, 11, 2293. (d) Chen, D.-D.; Hou, X.-L.; Dai, L.-X. Tetra-
hedron Lett. 2009, 50, 6944.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706007.
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References and Notes
(1) For selected reviews, see: (a) Donald, J. R.; Unsworth, W. P.
Chem. Eur. J. 2017, 23, 8780. (b) Clarke, A. K.; Unsworth, W. P.
Chem. Sci. 2020, 11, 2876. (c) Mack, D. J.; Njardarson, J. T. ACS
Catal. 2013, 3, 272. (d) Huang, C.-Y.; Doyle, A. G. Chem. Rev.
2014, 114, 8153. (e) Dauban, P.; Malik, G. Angew. Chem. Int. Ed.
2009, 48, 9026.
(2) For a review, see: Ohno, H. Chem. Rev. 2014, 114, 7784.
(3) For some selected recent publications see: (a) Kaldas, S. J.; Kran,
E.; Mück-Lichtenfeld, C.; Yudin, A. K.; Studer, A. Chem. Eur. J.
2020, 26, 1501. (b) Zhao, Q.-Q.; Zhou, X.-S.; Xu, S.-H.; Wu, Y.-L.;
Xiao, W.-J.; Chen, J.-R. Org. Lett. 2020, 22, 2470. (c) Wan, S.-H.;
Liu, S.-T. Tetrahedron 2019, 75, 1166. (d) Singh, D.; Ha, H.-J. Org.
Biomol. Chem. 2019, 17, 3093. (e) Wu, A.; Feng, Q.; Sung, H. H.
Y.; Williams, I. D.; Sun, J. Angew. Chem. Int. Ed. 2019, 58, 6776.
(f) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Chem. Commun. 2018, 54,
2401. (g) Jiang, F.; Yuan, F.-R.; Jin, L.-W.; Mei, G.-J.; Shi, F. ACS
Catal. 2018, 8, 10234; and references cited therein.
(14) 4-Benzyl-2-methyl-1-tosyl-2,5-dihydro-1H-pyrrole
(6a):
Typical Procedure
A flame-dried 10 mL flask equipped with a stirrer bar was
charged with vinyl aziridine 1a (46 mg, 0.14 mmol, 1.00 equiv),
(CuOTf)2·toluene (3.5 mg, 0.007 mmol, 0.05 equiv), and THF (0.7
mL), and the mixture was stirred for 2 h under argon at rt. The
solvent evaporated under reduced pressure, and the crude
product was purified by chromatography [silica gel, pentane–
EtOAc (100:0 to 70:30)] to give a pale-yellow solid; yield: 28 mg
(60%); mp 80–83 °C.
FTIR (neat): 1402, 1355, 1178, 1163, 1090, 993, 945, 858, 840,
765, 664 cm–1 1H NMR (400 MHz, CDCl3):  = 7.65–7.63 (m, 2
.
H), 7.27–7.20 (m, 5 H), 7.01–6.99 (m, 2 H), 5.19–5.17 (m, 1 H),
4.48–4.46 (m, 1 H), 4.04–3.90 (m, 2 H), 3.33–3.23 (m, 2 H), 2.43
(s, 3 H), 1.38 (d, J = 6.40 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  =
143.2, 137.6, 137.1, 134.8, 129.6 (2 C), 128.5 (2 C), 128.5 (2 C),
127.4 (2 C), 126.5, 126.3, 63.4, 56.6, 35.1, 22.9, 21.5. HRMS-
ASAP: m/z [M + H]+ calcd for C19H22NO2S: 328.1371; found:
328.1381.
(4) (a) Spielmann, K.; Tosi, E.; Lebrun, A.; Niel, G.; van der Lee, A.;
de Figueiredo, R. M.; Campagne, J.-M. Tetrahedron 2018, 74,
6497. (b) Spielmann, K.; van der Lee, A.; de Figueiredo, R. M.;
Campagne, J.-M. Org. Lett. 2018, 20, 1444.
(5) (a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. J. J. Med. Chem.
2014, 57, 5845. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T.
J. Med. Chem. 2014, 57, 10257. (c) Aldeghi, M.; Malhotra, S.;
Selwood, D. L.; Chan, A. W. E. Chem. Biol. Drug Des. 2014, 83,
450.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 517–520