Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from Cyclic Imines and Vinyl Aziridines

Article abstract of DOI:10.1021/acs.orglett.8b00228

The synthesis of cyclic imidazolidines via two N-C bond-forming sequences has been developed. The transformation goes through a (3 + 2)-cycloaddition reaction in the presence of catalytic amounts of palladium by combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly, the use of LiCl as additive allowed the improvement of diastereoselectivities when less encumbered substrates were used. The imidazolidine derivatives that bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and diastereoselectivities (up to >20:1).

Full text of DOI:10.1021/acs.orglett.8b00228

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from
Cyclic Imines and Vinyl Aziridines
Kim Spielmann, Arie van der Lee, Renata Marcia de Figueiredo,* and Jean-Marc Campagne†
†
§
,†
†
Institut Charles Gerhardt Montpellier (ICGM), UMR 5253, Univ Montpellier, CNRS, ENSCM - Ecole Nationale Super
́
ieure de
Chimie, 8 Rue de l’Ecole Normale, Montpellier 34296 Cedex 5, France
§
X-ray structures analysis, Institut Europee
Montpellier 34095 Cedex 5, France
́
n des Membranes (IEM), UMR 5632, Univ Montpellier, CNRS - Place Eugen
̀
e Bataillon,
*
S Supporting Information
ABSTRACT: The synthesis of cyclic imidazolidines via two N−C bond-
forming sequences has been developed. The transformation goes through a (3
+
2)-cycloaddition reaction in the presence of catalytic amounts of palladium by
combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly,
the use of LiCl as additive allowed the improvement of diastereoselectivities
when less encumbered substrates were used. The imidazolidine derivatives that
bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and
diastereoselectivities (up to >20:1).
ollowing the seminal work of Oshima et al. on palladium-
catalyzed rearrangement of vinyl aziridines, their reactivity
Scheme 2. Vinyl Oxiranes and Aziridines on Pd-Catalyzed (3
+ 2)-Cycloaddition Reactions with Cyclic N-Sulfonyl Imines
1
F
as precursors of zwitterionic π-allyl palladium intermediates in
3 + 2)-cycloadditions has emerged as a powerful cycloaddition
strategy, as illustrated early on by Alper using isocyanates,
(
2
−4
carbodiimides, and isothiocyanates.
Thanks to straighfor-
ward access to racemic (or enantioenriched) vinyl aziridines in
two steps from α-branched enals using an organocatalyzed
5
aziridination, followed by a Wittig reaction (Scheme 1), we
became interested in the use of vinyl aziridines in Pd-catalyzed
(
3 + 2)-cycloadditions with cyclic N-sulfonyl imines.
Scheme 1. Targeted Chiral Vinyl Aziridines from α-
Substituted α,β-Unsaturated Enals
temperature, the expected imidazolidine 3aa was obtained in
9
2% yield and 14:1 diastereoselectivity (Scheme 3). The
stereochemistry of the major diastereomer could be ascertained
by X-ray analysis showing a cis relationship between the proton
at the aminal position and the benzyl group (Scheme 3).
The scope of the reaction has then been surveyed using
variously substituted cyclic N-sulfonyl imines 1a−d and vinyl
aziridines 2a−d. The results obtained in these reactions are
summarized in Scheme 4. Starting from vinyl aziridine 2a,
several ortho-, meta-, and para-substituted cyclic N-sulfonyl
imines 1b−d were first tested. In all cases, the imidazolides
4
f
A recent paper by Guo describing the reactivity of cyclic N-
sulfonyl imines with vinyl oxiranes (Scheme 2, eq 1) prompted
us to disclose our work using vinyl aziridines. We report herein
a straightforward way to access cyclic aminal cores through the
synthesis of several imidazolidines by combining cyclic N-
sulfonyl imines 1 and vinyl aziridines 2 in the presence of a Pd
catalyst (Scheme 2, eq 2).
Although intrinsically unstable, aminals (N,N-acetals) can be
stabilized by the presence of electron-withdrawing groups and/
or when embedded in a ring. Indeed, the aminal moiety is
prevalent and can be found in a wide range of natural products,
drugs, and ligands (Figure 1).
Starting from racemic vinyl aziridine 2a (R = Bn) and cyclic
3
aa−d were obtained in very good yields (89−92%) and
diastereoselectivities (from 11:1 to 14:1). Notably, the use of
2
sterically more demanding substrates 2b (R = iPr) was not
6
deleterious to the reaction outcome as imidazolidines 3ba−d
Received: January 22, 2018
2
N-sulfonyl imine 1a, the reaction was first investigated in the
presence of Pd(Ph P) in THF. Gratifyingly, at room
3
4
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Scope of the (3 + 2)-Cycloaddition Reaction
Figure 1. Selected examples of natural and biologically relevant
compounds bearing aminal moieties.
Scheme 3. First Trial toward Imidazolidine 3aa via (3 + 2)-
Cycloaddition Reaction between 1a and 2a
a
Reaction conditions: 1 (0.16 mmol), 2 (0.13 mmol), Pd(PPh ) (10
3
4
b
mol %), THF (1.5 mL) at rt for 12 h. Isolated yields of the mixture of
diastereomers. Diastereomeric ratios (dr) were determined on the
basis of H NMR analysis of crude reaction mixture.
c
1
were isolated in good yields (88−92%) and diastereoselectiv-
ities (from 13:1 to >20:1). Therefore, the creation of a
particularly hindered tetra-substituted carbon in the α-position
of the nitrogen from the cyclic N-sulfonyl imine group was
successfully accomplished. Limitations were, however, observed
Table 1. Optimization of Reaction Conditions for Less
Encumbered Substrates
a
2
2
with vinyl aziridines 2c (R = Me) and 2d (R = H) for which a
lower diastereoselectivity was observed (i.e., 2:1 for compounds
3
ca−d and 4:1 for compound 3da), whereas similar good
isolated yields were attained. This result prompted us to
reinvestigate the reaction conditions.
b
c
entry
additive
T (°C)
dr
yield (%)
1
2
3
4
5
rt
rt
2:1
5:1
81
81
83
85
82
The diastereoselectivity issue (see mechanistic discussion
below) appears to be governed by the attack of the transient
amide anion to the less hindered face of the π-allyl palladium as
illustrated in the cis benzylic H−R group relationship observed
in Scheme 3 (X-ray structure of 3aa) .
LiCl
LiCl
LiCl
0
8:1
2
−30
−30
>20:1
2:1
a
Anticipating that a rapid π−σ−π interconversion of the π-
Reaction conditions: 1a (0.16 mmol), 2c (0.13 mmol), Pd(PPh )
3 4
10 mol %), LiCl (2.0 equiv), THF (1.5 mL) at T for 12 h.
Determined on the basis of H NMR analysis of crude reaction
mixture. Isolated yields of the mixture of diastereomers.
(
allyl palladium intermediate could improve the diastereoselec-
b
1
7
tivity, the reaction between 1a and 2c was carried out in the
c
presence of 2 equiv of LiCl (Table 1, entry 2). By doing so, we
were able to improve the diastereomeric ratio to 5:1
maintaining a similar yield of 81%. Gratifyingly, when the
temperature was decreased to −30 °C, imidazolide 3ca was
imidazolides 3ca−d were isolated in good yields and excellent
diastereoselectivities (from 13:1 to >20:1). The reactivity of
monosubstituted vinyl aziridine 2d was also reconsidered.
Imidazolide 3da was obtained in 88% yield and improved
diatereoselectivity (>20:1 vs 4:1 without LiCl) (Scheme 5).
Nonetheless, it might be mentioned that no significant
obtained with high diastereoselectivity (>20:1) and 85% yield
8
(Table 1, entry 4).
Thus, the reactivity of the vinyl aziridine 2c, (i.e., reluctant
substrate concerning diastereoselectivity issues) was reinvesti-
gated in the presence of LiCl (Scheme 5). Pleasingly, now
B
DOI: 10.1021/acs.orglett.8b00228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Influence of LiCl in (3 + 2)-Cycloaddition
Reaction between 1a−d and Vinyl Aziridines 2d and 2c
reach suitable reaction rates. The isomerization of the double
bond (2f → 3fa) further confirms a π−σ−π interconversion of
the transient π-allyl palladium intermediate (Scheme 6, eq 2).
Mechanistically, the first step of the reaction can be seen as
the behavior of the Pd(0) source in the presence of vinyl
aziridine 2 to form the zwitterionic π-allyl palladium species I
(
Scheme 7). The anion part of the complex I could then react
Scheme 7. Proposed Mechanism
improvement of the diastereomeric outcome was observed in
with cyclic N-sulfonyl imine 1a to give intermediate II that
could further intramolecularly react with the π-allyl palladium
to give imidazolide 3. As highlighted by the isomerization of the
Z double bond in 2f → 3fa (see Scheme 6, eq 2), and the need
of LiCl to ensure high diastereoselectivities through the release
the model reaction 1a + 2a (Scheme 3) in the presence of LiCl.
2
Anticipating that using a vinyl aziridine with less bulky R =
H group might have a strong impact on the diastereoselectivity
of the reaction, efforts have been undertaken to obtain an X-ray
structure of 3da. Indeed, as illustrated in Scheme 5 (X-ray
structure of compound 3da), the aminal H group and the vinyl
moiety have in this case a cis relationship. An X-ray structure for
8
of the amide anion from the positive Pd sphere, one can
assume a rapid π−σ−π interconversion of the π-allyl palladium
(
II → III). The second N−C bond formation, which affords
3
ba was also obtained (see Supporting Information),
the tetra-substituted carbon, proceeds in high diastereoselectiv-
ities and is dependent on the first N−C bond formation (see
intermediate II) through an intramolecular allylic amination
were the amide anion attacks the π-allyl palladium on its less
encumbered face, as previously mentioned.
confirming the relative stereochemistry observed for 3aa.
Accordingly, the relative stereochemistry for compounds
3
ab−d, 3bb−d, and 3ca−d was tentatively assigned by analogy
to 3aa and 3ba.
Thanks to the straightforward access to vinyl aziridines
Scheme 6), substituted double bonds can also be easily
This assumption was confirmed when enantioenriched 2a
80% ee) was reacted in the presence of 1a leading to 3aa in an
(
(
almost racemic form (19% ee, Scheme 8). Interestingly, the
Scheme 6. (3 + 2)-Cycloaddition Reaction with Vinyl-
Substituted Aziridines 2e and 2f
Scheme 8. Insights toward an Asymmetric (3 + 2)-
Cycloaddition Reaction in the Presence of a Chiral Ligand
obtained using either Wittig or Horner−Wadsworth−Emmons
(
HWE) reactions. From 2e, obtained by a HWE reaction with
rapid π−σ−π interconversion paves the way to the develop-
ment a dynamic kinetic asymmetric transformation (DYKAT).
Indeed, in a preliminary experiment in the presence of a chiral
ligand [i.e., (R)-Taniaphos], imidazolide 3aa was obtained in
triethyl phosphonoacetate, the imidazolide 3ea was isolated in
80% yield and a diastereomeric ratio of 10:1 (Scheme 6, eq 1).
Z-Vinyl aziridine 2f, prepared via a Wittig reaction with
ethyltriphenylphosphonium bromide, gave in the presence of
cyclic N-sulfonyl imine 1a the expected imidazolide 3fa in 80%
yield and excellent diastereoselectivity (>20:1) as the single E
stereoisomer. In these cases, room temperature was required to
9
17% ee (dr = 3:1 and 60% yield).
In conclusion, a Pd-catalyzed (3 + 2)-cycloaddition reaction
has been developed affording a straightforward route to several
functionalized cyclic imidazolidines in both high yields and
C
DOI: 10.1021/acs.orglett.8b00228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diastereoselectivities. The cycloaddition takes place via the
J.-H; Wang, H.; Yang, Z.-T.; Yang, W.-L.; Tang, W.; Deng, W.-P. Org.
Lett. 2018, 20, 104. (b) Wang, Y.-N.; Yang, L.-C.; Rong, Z.-Q.; Liu, T.-
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formation of two N−C bonds in the presence of vinyl aziridines
1
(
precursors of N -1,3-dipoles in the π-allyl palladium
(
́
c) Laugeois, M.; Ling, J.; Ferard, C.; Michelet, V.; Ratovelomanana-
intermediates) and cyclic N-sulfonyl imine. Interestingly, the
low-to-moderate diastereoselectivities that were first obtained
with less sterically encumbered substrates could be improved
through the addition of LiCl as additive. The extent to which
the last N−C bond formation proceeds in high diastereose-
lectivities is dependent on the rapid π−σ−π interconversion
Vidal, V.; Vitale, M. R. Org. Lett. 2017, 19, 2266. (d) Mei, G.-J.; Bian,
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+
and could be explained by the ability of Li to facilitate the
cyclization step by strongly coordinating to the amide anion.
Further studies on the synthesis of novel compounds through
imidazolidines derivatization and the development of an
asymmetric version are underway in our laboratory.
2
927. (i) Leth, L. A.; Glaus, F.; Meazza, M.; Fu, L.; Thøgersen, M. K.;
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(b) Li, Q.-H.; Wei, L.; Chen, X.; Wang, C.-J. Chem. Commun. 2013,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00228.
4
9, 6277. (c) Ohmatsu, K.; Kawai, S.; Imagawa, N.; Ooi, T. ACS Catal.
2
014, 4, 4304. (d) Armstrong, R. J.; D’Ascenzio, M.; Smith, M. D.
Synlett 2016, 27, 6. (e) Sawatzky, E.; Drakopoulos, A.; Ro
Sotriffer, C.; Engels, B.; Decker, M. Beilstein J. Org. Chem. 2016, 12,
280. (f) Trost, B. M.; Gnanamani, E.; Hung, C.-I. Angew. Chem., Int.
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lz, M.;
Experimental details and spectroscopic data (PDF)
2
Accession Codes
Ed. 2017, 56, 10451. (g) Mukhopadhyay, S.; Pan, S. C. Chem.
CCDC 1589055−1589057 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing 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.
Commun. 2018, 54, 964.
(7) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.
(8) Interestingly, the use of LiBr has been described in (3 + 2)-
cycloadditions with vinyl aziridines, however, with the opposite
consequence as lower diastereoselectivity was observed; see ref 3a.
(9) These trials were done in the absence of LiCl to check a possible
control by the chiral ligand (see ref 3a). The reaction in the presence
of the Trost ligand was also tested, but a very low enantioselectivity
was observed (ee < 10%).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: renata.marcia_de_figueiredo@enscm.fr.
ORCID
Renata Marcia de Figueiredo: 0000-0001-5336-6071
Jean-Marc Campagne: 0000-0002-4943-047X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to ENSCM (Ecole Nationale Super
Chimie de Montpellier) for a grant (K.S.) and to CNRS
■
́
ieure de
(
Centre National de la Recherche Scientifique). Aurel
Lebrun, from the Laboratoire de Mesure Physiques de
l’Universite de Montpellier, is kindly thanked for his help
́
ien
́
with NMR analysis.
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DOI: 10.1021/acs.orglett.8b00228
Org. Lett. XXXX, XXX, XXX−XXX