(3 + 3) Cycloaddition of Oxyallyl Cations with Nitrones: Diastereoselective Access to 1,2-Oxazinanes

Article abstract of DOI:10.1021/acs.orglett.8b00617

Oxyallyl cations are prepared in situ from readily available α-tosyloxy ketones and act as transient electrophilic partners in (3 + 3) cycloaddition with nitrones. Under mild conditions, this method provides a chemoselective and diastereoselective route t

Full text of DOI:10.1021/acs.orglett.8b00617

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
(3 + 3) Cycloaddition of Oxyallyl Cations with Nitrones:
Diastereoselective Access to 1,2-Oxazinanes
Marie Cordier† and Alexis Archambeau*,‡
†Laboratoire de Chimie Molec
́
ulaire, UMR 9168, Ecole Polytechnique, CNRS, 91128 Palaiseau Cedex, France
‡Laboratoire de Synthes
̀
e Organique, UMR 7652, Ecole Polytechnique, ENSTA ParisTech, CNRS, 91128 Palaiseau Cedex, France
S
* Supporting Information
ABSTRACT: Oxyallyl cations are prepared in situ from readily available α-tosyloxy ketones and act as transient electrophilic
partners in (3 + 3) cycloaddition with nitrones. Under mild conditions, this method provides a chemoselective and
diastereoselective route to polysubstituted 1,2-oxazinanes. A stepwise process is proposed to rationalize the diastereoselectivity of
this transformation.
xyallyl cations are highly reactive electrophilic 2π systems
that have been successfully engaged as 1,3-dipoles in
numerous cycloaddition reactions. Since the pioneering work of
Fort,1 the (4 + 3) cycloaddition between oxyallyl cations and
dienes or furans has become a dependable tool for the
preparation of seven-membered rings [Scheme 1, eq 1].2,3 This
While the (4 + 2) cycloaddition remains a method of choice
for the preparation of six-membered N-heterocycles,11 the 1,3-
dipolar (3 + 3) cycloaddition between a stable nitrogen-based
dipole and an all-carbon 1,3-dipole is currently growing as a
reliable complementary alternative.12−16 We envisioned that
electrophilic oxyallyl cations could act as a 3C synthon in such
transformations to generate polysubstituted six-membered
heterocycles.
O
Scheme 1. Oxyallyl Cation Reactivity
Only a few studies have been reported for the (3 + 3)
cycloaddition of oxyallyl cations. Schultz17 and West18
demonstrated that the oxyallyl cation intermediate of a Nazarov
cyclization could be trapped by an azide to furnish triazene
compounds [Scheme 1, eq 4]. Inspired by recent findings by Wu
and others on the reactivity of aza-oxyallyl cations,19 this
communication discloses a (3 + 3) cycloaddition between in-
situ-generated oxyallyl cations and stable nitrones. Under mild
conditions, polysubstituted 1,2-oxazinanes (tetrahydro-1,2-
oxazines) are prepared with high diastereocontrol [Scheme 1,
eq 5]. These six-membered heterocycles are found in numerous
biologically active compounds20 and their endocyclic N−O bond
make them attractive synthetic intermediates.21 To the best of
our knowledge, this symmetry-allowed [4π+2π] process
represents the first (3 + 3) cycloaddition between an oxyallyl
cation intermediate and a nitrone.
To conduct our optimization study, we selected α-tosyloxy
ketone 1a and N-methyl-(Z)-aldonitrone 2a as reference
substrates. Gratifyingly, the use of a hydrogen-bond-donor
(HBD) solvent such as 2,2,2-trifluoroethanol (2M)3b under mild
conditions (Et3N, room temperature (rt), 2.5 h) led to a single
diastereomer of oxazinane 3aa in good yield (Table 1, entry 1).
The structure and the relative configuration of the three newly
approach follows a symmetry-allowed [4π+2π] process and has
been envisioned for numerous syntheses of biologically active
natural products.4 Various five-membered ring carbocycles can
also be accessed via a stepwise (3 + 2) cycloaddition with alkenes
or alkynes [Scheme 1, eq 2].5−7 Recently, Chi8 and MacMillan9
reported an elegant application of oxyallyl cation chemistry to
nucleophilic α-substitution of ketones before to develop an
asymmetric version of this reaction [Scheme 1, eq 3].10
Received: February 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of α-OTs Ketone
b
entry
base
Et3N
solvent
TFE
yield (%)
g
1
83, 77
2
Et3N
Et3N
Et3N
HFIP
DCM
THF
62
traces
19
d
3
e
4
e
c
5
TFE
nr
6
7
4-DMAP
imidazole
i-Pr2NEt
Cs2CO3
Et3N
TFE
31
20
a
TFE
Evidence for the formation of an oxyallyl cation.
8
TFE
66
9
TFE
traces
42
10
TFE (0.1 M)
TFE
3af−3aj bearing various substituents in the meta or ortho position
can also be accessed from the corresponding nitrones in excellent
yields (70%−85%). The presence of an allyl group did not affect
the outcome of the transformation and nitrone 2k yielded isomer
3ak as the sole product of the transformation (70%). We next
tackled a more challenging chemoselectivity issue by investigat-
ing the reactivity of heteroaromatic nitrones 2l and 2m bearing a
furan and a free indole group, respectively. We were delighted to
observe the exclusive formation of oxazinanes 3al and 3am, with
no traces of (4 + 3)2 or (3 + 2)5 cycloaddition adduct. Styryl and
alkyl groups were also well-tolerated and oxazines 3an−3ap were
prepared in high yields and diastereoselectivity. Interestingly, the
in situ formation of the N-benzyl nitrone 2q derived from
formaldehyde yielded disubstituted heterocycle 3aq bearing a
methylene moiety. This oxazinanone was isolated in excellent
yield (93%) as a mixture of diasteroisomers (diastereomeric ratio
(dr) = 80:20). Finally, oxazinanes 3ar and 3as in which the
nitrogen atom is protected by a benzyl group and a para-
methoxybenzyl group, respectively, were obtained from their
nitrone precursors with complete diastereoselectivity (see
Scheme 3).
f
11
Et3N
59
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), base (0.625
mmol) in solvent (0.25 mL) for 2.5 h at room temperature. Isolated
yields. nr = no reaction. LiClO4 (1.5 equiv), solvent (0.75 mL).
Reaction time = 24 h. 2a (1 equiv). 1a (6 mmol), 2a (12 mmol),
b
c
d
e
f
g
Et3N (7.5 mmol) in TFE (3 mL) for 2.5 h at room temperature.
formed stereocenters were confirmed by single-crystal X-ray
analysis of the related compound 3af bearing a m-OMe phenyl
group (see Scheme 3, presented later in this work). The three
substituents of this heterocycle are located on the same face of
the ring. HFIP gave slightly deteriorated yield (Table 1, entry 2),
and our investigations revealed the essential role of a strong HBD
solvent as only a small amount of oxazinanone 3aa was formed in
the presence of LiClO4 as a Lewis acid (1.5 equiv) and
triethylamine in DCM or THF (Table 1, entries 3 and 4). While
triethylamine appeared to be needed for the (3 + 3)
cycloaddition to occur (Table 1, entry 5), a rapid survey of
bases (4-DMAP, imidazole, i-Pr2NEt and Cs2CO3) failed to
improve the efficiency of the reaction (Table 1, entries 6−9).
Finally, a 2:1 nitrone/ketone ratio along with a high
concentration of the reaction mixture (2M) were necessary to
isolate 3aa in a good yield (Table 1, entries 10 and 11). To
evaluate the robustness of our process, we conducted a gram-
scale preparation of 3aa in a similar good yield (77%), starting
from 6 mmol of ketone.
With these optimized conditions in hand, we turned our
attention to the scope of different ketones with N-methyl nitrone
2a. Acyclic α-OTs ketones 1b (R1 = Et) and 1c (R1 = n-Pr)
bearing aliphatic substituents were successfully converted into
the corresponding oxazinanones 3ba (78%) and 3ca (80%) with
complete diastereoselectivity [Scheme 2, eq 1]. The conversion
of α-tosyloxy ketone 1d afforded a 1.3/1 mixture of isomers 3da
and 3′da and supported the formation of the putative
unsymmetrical oxyallyl cation A as a transient intermediate
[Scheme 2, eq 2].
Because of their peculiar geometry, spiro compounds have
recently emerged as valuable scaffolds for drug discovery.22 We
recognized that our strategy could provide a straightforward
access to these structures and symmetrical ketonitrones 2t and
2u derived from cyclopentanone and cyclohexanone, respec-
tively, delivered spiro oxazinanes 3at (81%) and 3au (89%) as
single cis-diastereomers.
To shed light on the mechanism of this cycloaddition, we next
turned our attention to the reactivity of cyclic (E)-nitrones.
Gratifyingly, isoquinoline N-oxide 2v underwent a stereo-
controlled transformation leading to tricyclic oxazinane 3av, in
which the aromatic substituent is now located on the opposite
side of the two methyl groups. The relative configuration of the
three newly created stereocenters was ascertained by single-
crystal X-ray analysis. Cycloadditions involving quinoline N-
oxide 2w and pyrroline tetrahydroisoquinoline N-oxide 2x
proceeded smoothly to yield the expected polycyclic hetero-
cycles 3aw and 3ax (dr = 92:8), respectively (see Scheme 4).
The stereoselectivity of this cycloaddition prompted us to
examine the behavior of the unsymmetrical ketonitrone 2y
arising from cyclohexenone. Two isomeric mixtures [(E)/(Z) =
13:1 and (E)/(Z) = 1:3] were subjected to the usual conditions,
along with oxyallyl cation precursor 1a. A rapid conversion
generated the expected oxazinanes bearing a quaternary spiro
center as a mixture of two diastereomers 3Eay and 3Zay. In both
cases, an erosion of the diastereoselectivity was observed and
The high diastereoselectivity of this (3 + 3) cycloaddition
motivated us to investigate the reactivity of N-methyl (Z)-
nitrones derived from various aromatic aldehydes in the presence
of ketone 1a. The electronic properties of the phenyl ring seems
to have very little influence on the outcome of the transformation
as aldonitrones 2b−2e bearing either an electron-donating (Me,
OMe) or an electron-withdrawing (F, Br) group in the para
position were converted smoothly to the corresponding
stereodefined oxazinanones 3ab−3ae (73%−87%). Steric
hindrance did not play a crucial role either as heterocycles
B
DOI: 10.1021/acs.orglett.8b00617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab
,
Scheme 3. Scope of Aldonitrones
Scheme 5. Reactivity of an Unsymmetrical Ketonitrone
then yield the observed diastereomer B. However, the
observation of isomer D (in the case of 3ak, 3aq, 3ax, and
3ay) could be better explained by a stepwise pathway (b) where
intermediate C could undergo rapid iminium ion isomerization
to C′ before the ring-closing step. A competitive concerted
pathway (a′) involving a compact (endo) transition state cannot
be ruled out at this stage (see Scheme 6).
Scheme 6. Proposed Mechanism
a
Reaction conditions: ketone (0.5 mmol), nitrone (1 mmol), Et3N
(0.625 mmol) in TFE (0.25 mL) for 1−3 h at room temperature. The
The X-ray structure of 3f (recall Scheme 3) prompted us to
investigate further derivatization of these oxazinanones. Because
of the bulky phenyl ring, one would expect a nucleophile
b
consumption of 1a was monitored by TLC. Isolated yields. cTFE (0.5
mL). dNitrone 2q was prepared in situ. eIsolated as a cis/trans mixture
1
(cis/trans = 80:20) based on H NMR analysis.
following a Burgi-Dunitz trajectory to attack the less-hindered
̈
face of the molecule exclusively. Gratifyingly, the treatment of
oxazinanone 3aa with MeMgBr (3 equiv, Et2O, −10 °C to rt)
afforded a single diastereomer of oxazinane 4 bearing four
contiguous stereocenters, including one quaternary center. Ring-
opening of heterocycle 3ar by N−O bond cleavage could provide
valuable aminoalcohols. After diastereoselective reduction of
oxazinanone 3ar (DIBAL-H, Et2O, −20 to 0 °C), alcohol 5
(62%) underwent SmI2-induced reductive N−O bond cleavage
to afford the linear amine-diol 6 (86%) as a single diastereomer
(see Scheme 7).
ab
,
Scheme 4. Preparation of Spiro and Polycyclic Oxazinanes
Scheme 7. Derivatization of Oxazinanones
a
Reaction conditions: ketone (0.5 mmol), nitrone (1 mmol), Et3N
(0.625 mmol) in TFE (0.25 mL) for 1 h at room temperature. The
b
consumption of 1 was monitored by TLC. Isolated yields. cTFE (0.5
mL).
3Eay/3Zay mixtures were formed in 8:1 and 1:1.5 ratios,
respectively (see Scheme 5).
A mechanistic rationale was proposed to account for the
diastereoselective formation of B. When aldonitrones partic-
ipates in the transformation, this [4π+2π] cycloaddition often
leads to a single isomer and could occur via a concerted pathway
(a) involving an extended (exo) transition state or via a stepwise
pathway (b) where the nucleophilic oxygen of the nitrone first
attacks the electrophilic W-shaped2a oxyallyl cation to afford
intermediate C. A rapid intramolecular Mannich reaction could
To conclude, we have developed a (3 + 3) cycloaddition
involving an oxyallyl cation intermediate. In the presence of a
readily available nitrone as the nucleophilic partner, this
transformation generates stereodefined oxazinanones after
creation of two new σ bonds and three stereocenters. This
strategy provides straightforward access to valuable N−O
C
DOI: 10.1021/acs.orglett.8b00617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00617.
■
S
(10) Liu, C.; Oblak, E. Z.; Vander Wal, M. N.; Dilger, A. K.; Almstead,
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Experimental procedures and NMR spectra for all new
compounds (PDF)
Accession Codes
CCDC 1817917 and 1817918 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, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alexis.archambeau@polytechnique.edu.
ORCID
Alexis Archambeau: 0000-0002-1311-503X
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Junghan Son (Ecole Polytechnique) for technical
assistance.
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