Catalytic asymmetric inverse-electron-demand diels-alder reaction of N-sulfonyl-1-aza-1,3-dienes

Article abstract of DOI:10.1021/ja0658766

An efficient chiral Lewis acid-catalyzed inverse-electron-demand Diels-Alder reaction of 1-azadienes is described. This procedure is based on the combination of Ni^II-DBFOX complex as catalyst and the use of a metal-coordinating (8-quinolyl)sulfonyl moiety at the iminic nitrogen of the N-sulfonyl 1-aza-1,3-diene, providing highly functionalized piperidine derivatives in good yields with excellent endo-selectivity, and enantioselectivities typically in the range of 77-92% ee. Copyright

Full text of DOI:10.1021/ja0658766

Published on Web 01/19/2007
Catalytic Asymmetric Inverse-Electron-Demand Diels-Alder Reaction of
N-Sulfonyl-1-Aza-1,3-Dienes
Jorge Esquivias, Ramo´n Go´mez Arraya´s,* and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
Received August 13, 2006; E-mail: ramon.gomez@uam.es; juancarlos.carretero@uam.es
Table 1. Effect of the Sulfonyl Group in the Ni-Catalyzed ADAR
The aza Diels-Alder reaction (ADAR) is among the most
powerful and convergent strategies for the stereoselective construc-
tion of piperidine derivatives.1 Although in recent years very
important progress has been achieved in the catalytic asymmetric
ADAR of dienes with imines,2 the complementary alternative
involving the asymmetric cylcloaddition between azadienes and
alkenes has been hardly studied. Ghosez et al.3 described the
Cu(OTf)2/BOX-catalyzed ADAR of electron-rich 2-azadienes with
N-acyl oxazolidinones, and Bode et al.4 have very recently reported
highly asymmetric ADAR of aldimine-derived N-sulfonyl-1-aza-
dienes with â-activated enals catalyzed by chiral N-heterocyclic
carbenes. Surprisingly, the development of chiral Lewis acid
catalysts for the ADAR of 1-azadienes5 with electron-rich olefins
remains undocumented, likely owing to the low reactivity of
1-azadienes (even lower than that of 2-azadienes) and the high
propensity of both azadienes and electron-rich dienophiles to
decompose in the presence of Lewis acids.5d,6
entry
R
azadiene
endo/exoa
product
yield (%)b
1
2
3
4
5
p-Tol
NMe2
2-thienyl
2-pyridyl
8-quinolyl
1a
1b
1c
1d
1e
c
c
c
84:16
70:30
2d
2e
73
62
a By HPLC. b Of isolated endo adduct. c Starting material recovered.
Table 2. Ni-Catalyzed Asymmetric ADAR with DBFOX-Ph Ligand
N-sulfonyl-1-aza-1,3-dienes were found by Boger et al. to
participate as a 4π component in thermal ADAR with electron-
rich dienophiles under high pressure or high temperature, exhibiting
very high endo-selectivity.6 This low reactivity has been greatly
enhanced with azadienes bearing an electron-withdrawing ester
group, paving the way for the development of the first asymmetric
variant of this reaction using vinyl ethers bearing chiral auxiliaries.5d
We7 and others8 have recently demonstrated that the use of
N-(heteroaryl)sulfonyl groups can dramatically affect the reactivity
of N-sulfonyl imines, allowing reactions that are not feasible with
the traditional N-tosyl imines. In this context we describe herein a
Ni-catalyzed highly enantioselective ADAR of N-sulfonyl 1-aza-
dienes with vinyl ethers under mild reaction conditions. The success
of this reaction relies on the use of the Kanemasa’s chiral ligand9
DBFOX-Ph and the choice of the N-(8-quinolinesulfonyl) group
at the iminic nitrogen.
The N-tosylimine of chalcone (1a) was recovered unaltered after
treatment with ethyl vinyl ether (5 equiv) in the presence of a variety
of Lewis acids, such as Cu(OTf)2, Ni(ClO4)2‚6H2O, Mg(ClO4)2‚
6H2O, or Zn(ClO4)2‚6H2O in CH2Cl2 at room temperature (Table
1, entry 1). In the hope that the reluctance of N-sulfonyl R,â-
unsaturated ketimines to undergo Lewis acid-catalyzed ADAR could
be overcome by combining the high electrophilic character of the
sulfonyl group with the use of an appropriate metal-coordinating
functionality, substrates 1b-e, of varied electronic and coordinating
nature, were evaluated in the model reaction using Ni(ClO4)2‚6H2O
as catalyst.10 Interestingly, while azadienes 1b and 1c led to the
recovery of the starting material after 5 days (entries 2 and 3), the
N-(2-pyridyl)sulfonyl and N-(8-quinolyl)sulfonyl derivatives 1d7a
and 1e, respectively, provided the corresponding cycloadduct (2d
and 2e, respectively) in good yield with moderate endo-selectivity
(entries 4 and 5).
entry
azadiene
R
endo/exoa
product
yield (%)b
ee (%)a,b
1
2
3
4
5
1d
1e
1e
1e
1e
Et
Et
n-Pr
Cy
t-Bu
98:2
97:3
98:2
98:2
80:20
2d
2e
3e
4e
5e
80
73
66
70
35
42
88
91
88
68
a Determined by HPLC. b Of the endo adduct after chromatograpy.
the presence of Binap, BOX, and PyBOX chiral ligands led to very
low enantioselectivities (typically 0-20% ee). A maximum of 66%
ee was achieved in the case of 2d using the Bn-BOX ligand,
whereas 2e was obtained racemic in all cases. To generate a more
efficient face shielding around nickel, the NiII aqua complex11,12
of the trans-chelating DBFOX-Ph ligand was tested (Table 2).
Fortunately, this ligand proved to be highly efficient for the N-(8-
quinolyl)sulfonyl imine 1e, leading to the cycloaddition product
2e in good yield, excellent endo-selectivity (endo/exo ) >30:1)
and high enantiocontrol (88% ee; entry 2). In contrast, the
2-pyridylsulfonyl azadiene 1d provided much lower asymmetric
induction under identical conditions (42% ee, entry 1). Good results
were also obtained in the reaction of 1e with propyl vinyl ether
(91% ee, entry 3) and cyclohexyl vinyl ether (88% ee, entry 4) as
dienophiles, while the more sterically demanding tert-butyl vinyl
ether led to poorer results (entry 5). Cyclic dienophiles such as
dihydrofuran did also participate in the ADAR with 1e to afford
the endo-adduct in 83% yield, albeit moderate asymmetric induction
(58% ee at 0 °C).13
To evaluate the scope of this cycloaddition protocol with regard
to the 1-azadiene counterpart, ketimines 6e-16e were surveyed
under the optimal experimental conditions (Table 3). Good yields
(61-75%) and high levels of endo-selectivity and enantioselectivity
Encouraged by these results, we next turned our attention to
asymmetric catalysis. Unfortunately, the reaction of 1d and 1e in
9
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J. AM. CHEM. SOC. 2007, 129, 1480-1481
10.1021/ja0658766 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Structural Variations at the 1-Azadiene
established by NMR experiments, and unequivocally confirmed by
X-ray crystallographic analysis of enantiopure 32b,13 otherwise
allowing the assignment of the absolute configuration of the ADAR
endo cycloadducts. It is worthy of mention that products 30-32
can be considered as chiral nonracemic [1,2,4]benzothiadiazine-
5,5-dioxide derivatives, which have proven to be potential drugs
for memory and learning disorders and neurodegenerative disease.14
In summary, the combination of the (8-quinolyl)sulfonyl moiety
at the iminic nitrogen and NiII-DBFOX as catalyst has led to the
development of an efficient chiral Lewis acid-mediated inverse-
electron-demand Diels-Alder reaction of 1-azadienes, providing
highly functionalized piperidine derivatives in good yields with
excellent endo-selectivity and enantioselectivities typically in the
range of 77-92% ee. Initial experiments that highlight the synthetic
potential of these cycloadducts have also been presented.
endo/
exoa
yield
(%)b
ee
entry
R1
R2
imine
product
(%)a
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1e
98:2
98:2
97:3
98:2
97:3
98:2
97:3
97:3
98:2
98:2
98:2
90:10
3e
66
75
69
65
52
61
73
69
67
63
70
68
91
92
90
80
77
84
90
91
6
p-FC6H4
2-Naph
p-MeOC6H4
2-Furyl
t-Bu
6e
17e
18e
19e
20e
21e
22e
23e
24e
25e
26e
27e
7e
8e
9e
10e
11e
12e
13e
p-ClC6H4
Ph
p-CF3C6H4 Ph
2-Naph
Ph
10 p-ClC6H4
11 p-CNC6H4
12 CHdCHPh Ph
CHdCH-Ph 14e
92
92
20
Acknowledgment. Financial support by the Ministerio de
Educacio´n y Ciencia (MEC, BQU2003-0508) and the UAM/
Consejer´ıa de Educacio´n de la Comunidad Auto´noma de Madrid
(08/PPQ/001) is gratefully acknowledged. J.E. thanks the MEC for
a predoctoral fellowship. We also thank Jordi Benet-Buchholz
(ICIQ) for the X-ray structure of 32b.
CHdCH-Ph 15e
16e
a Determined by HPLC. b Of the endo adduct after chromatography.
Scheme 1. Stereoselective Transformations of the Cycloadducts
Supporting Information Available: Experimental procedures and
characterization data of new compounds (CIF), copies of NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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(10) Ni(ClO4)2‚6H2O showed the highest reactivity among all Lewis acids
tested. CH2Cl2 proved to be the optimal solvent (DCE led to poorer endo-
selectivity while no reaction was observed in toluene, Et2O, or THF).
(11) The nickel catalyst was generated in situ by stirring equimolar amounts
of Ni(ClO4)2‚6H2O and DBFOX-Ph in CH2Cl2 at room temperature for
4-5 h. Lower catalyst-aging time resulted in a significant loss of
enantioselectivity.
1
a From the crude H NMR spectra.
(77-92% ee) were achieved in most cases. Aryl substituents of
varied electronic and steric nature at the â-position (R2) are well
tolerated (entries 1-5), although electron-rich groups lead to a slight
decrease in enantioselectivity (entries 4 and 5). Even the substrate
10e, with a tert-butyl group as R2 proved to be suitable (entry 6,
84% ee). In contrast, substitution compatibility at the iminic carbon
proved to be more limited. While p-substituted aryl groups were
compatible, a dramatic drop in the enantioselectivity was observed
with the more sterically demanding 2-naphthyl group (6% ee, entry
9). Particular attention is given to the results obtained in the reaction
of azatrienes 14e and 15e (entries 10 and 11), affording with
complete chemocontrol the corresponding 4-alkenyl-substituted
piperidines 25e and 26e in 92% ee in both cases. In contrast, the
cycloaddition of the N-sulfonyl imine of dba (16e) took place with
low enantiocontrol (entry 12), highlighting again the sensitivity of
this protocol to substitution at the iminic carbon.
Some interesting results have been obtained in the Lewis acid-
promoted nucleophilic displacement of the alkoxy group, which is
known to proceed with inversion of configuration5d (Scheme 1).
Transformation of 3e into the 2-hydroxy derivative 2913 was readily
performed in 88% yield with complete stereoselectivity by treatment
with BF3‚Et2O in CH2Cl2 and further hydrolysis of the resulting
intermediate quinolinium salt 28. Alternatively, trapping of inter-
mediate 28 with hard nucleophiles such as hydride (NaCNBH3) or
Grignard reagents resulted, unexpectedly, in the selective attack to
the R-position of the bicyclic quinoline ring system, affording the
tetracyclic compounds 30-32 in good yields. High stereoselec-
tivities were obtained in the cases in which two new stereogenic
centers are generated (products 31 and 32), the major isomers 31a
and 32a being isolated pure in 71% and 60% yield, respectively.
The stereochemistry of the diastereomers 32a and 32b was
(12) The reaction of 1e with ethyl vinyl ether catalyzed by Ni(ClO4)2‚6H2O-
DBFOX (10 mol %) in the presence of molecular sieves led to racemic
2e in 68% yield (endo/exo ) 90:10).
(13) See Supporting Information for details.
(14) For an example on the preparation of a chiral [1,2,4]benzothiadiazine-
5,5-dioxide with activity as AMPA receptor modulator, see: Cobley, C.
J.; Foucher, E.; Lecouve, J.-P.; Lennon, I. C.; Ramsdem, J. A.; Thominot,
G. Tetrahedron: Asymmetry 2003, 14, 3431.
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