Enantioselective Michael additions of nitromethane by a catalytic double activation method using chiral Lewis acid and achiral amine catalysts

Article abstract of DOI:10.1021/ja027313+

Reactions of nitromethane with 1-(2-alkenoyl)-3,5-dimethylpyrazoles can be effectively catalyzed by R,R-DBFOX/Ph·Ni(ClO₄)₂·3H₂O and achiral amine bases, each in a catalytic loading of 10 mol %, to give 1-(3-substituted 4-n

Full text of DOI:10.1021/ja027313+

Published on Web 10/17/2002
Enantioselective Michael Additions of Nitromethane by a Catalytic Double
Activation Method Using Chiral Lewis Acid and Achiral Amine Catalysts
Kennosuke Itoh† and Shuji Kanemasa*
Institute of AdVanced Material Study, CREST of JST (Japan Science and Technology), Kyushu UniVersity,
6-1 Kasugakoen, Kasuga 816-8580, Japan, and Department of Molecular and Material Sciences, Graduate School
of Engineering Sciences, Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan
Received June 17, 2002
Scheme 1 a
Chiral Lewis acid-catalyzed enantioselective reactions provide
one of the most powerful and economical synthetic approaches
leading to a variety of enantiomers. Generally, electrophiles are
activated by coordination to a chiral Lewis acid catalyst, and
nucleophiles react preferentially with the resulting enantiopure
electrophile/catalyst complexes to give enantiomerically enriched
products. When reactivity of nucleophiles is not sufficiently high
enough to react smoothly with the electrophiles activated by
coordination to the catalyst, effective enantiomer formation becomes
difficult. Although additional activation of the nucleophiles by use
of a base catalyst would be a possible solution, such combined use
of two catalysts should cause a serious problem such that acid and
base catalysts strongly bind each other, resulting in the disappear-
ance of catalytic capability. Success would be realized only when
both the catalysts show separate catalytic activities when they are
used together in one flask.1
a a: In the presence of A and TMP (10 mol % each), rt.
We have effective chiral Lewis acid catalysts in hand, which
are the cationic aqua complexes derived from (R,R)-4,6-dibenzo-
furandiyl-2,2′-bis(4-phenyloxazoline) (R,R-DBFOX/Ph hereafter)2
and transition metal salt hydrates having noncoordinating anionic
counterions. One of the most important features of these aqua R,R-
DBFOX/Ph complexes is high tolerance toward strongly nucleo-
philic substrates. Although highly coordinating nucleophiles do bind
with the metallic center of the catalyst, the binding should be
relatively weak to undergo rapid ligand exchange between such
strong nucleophiles and electrophilic substrates.3 Thus, the transition
metal aqua complexes of R,R-DBFOX/Ph show highly effective
chirality control in cyclopentadiene Diels-Alder reactions even in
the presence of a variety of amine additives.4 Accordingly, the R,R-
DBFOX/Ph aqua complexes would be the chiral Lewis acid
catalysts of our choice for the double activation method by use of
both Lewis acid and base catalysts.5
In this communication, we report a new synthetic methodology
for catalytic enantioselective Michael addition reactions of nitro-
methane.6 Therein, both R,â-unsaturated carbonyl acceptors as
electrophiles and nitromethane as nucleophile can be activated by
catalytic amounts of chiral Lewis acid and amine catalysts,
respectively. We propose this new catalytic method leading to
enantiomers of products to be named “catalytic double actiVation
method (CDAM)”.1,5
give 3-methyl-4-nitrobutanoyl-3,5-dimethylpyrazole (2a) as Michael
adduct in 95% yield (77% ee) after 5 h at room temperature
(Scheme 1). Although TMP as amine catalyst catalyzes the above
reaction by itself (10 mol %, rt, 72 h, 89%),7 A as Lewis acid shows
no catalytic activity. An even more obvious example for the high
activation of the nitromethane conjugate addition under CDAM
conditions is the reaction with â-phenyl-substituted pyrazole 1k as
acceptor: The adduct 2k was obtained in only 5% yield after 168
h at room temperature when the reaction was catalyzed only by
TMP (10 mol %), while the same reaction under CDAM conditions,
even at -20 °C, gave adduct 2k in 90% yield (93% ee). Thus, the
combined use of Lewis acid and amine catalysts works in a highly
effectiVe manner to accelerate Michael addition reactions with
nitromethane.
Under the optimized conditions, the reaction of nitromethane with
1a was performed in a 1:1 vol/vol mixture of nitromethane and
THF at room temperature (5 h) in the presence of 10 mol % each
of A and TMP to give 2a in 97% yield with an enantioselectivity
of 84% ee (Scheme 1).8,9 As the Lewis acids, the R,R-DBFOX/Ph
complex derived from Ni(ClO4)2‚6H2O was the most effective
catalyst,10,11 and the aqua complex A showed both a much higher
reactivity and greater selectivity than the anhydrous complex
catalyst R,R-DBFOX/Ph‚Ni(ClO4)2 (rt, 48 h, 2a: 19%, 31% ee).
The same reaction catalyzed by A in the presence of MS 4A gave
2a in 84% yield (67% ee). Although a variety of amine catalysts
could be utilized effectively, 2,2,6,6-tetramethylpiperidine (TMP)
as bulky amine gave the best balance of the catalytic activity and
enantioselectivity.12 The reaction using 3-crotonoyl-2-oxazolidinone
(3) was much less reactive than the pyrazole substrate 1a, indicating
that the pyrazole acceptors 1 derived from 3,5-dimethylpyrazole
were needed (Scheme 1).
The reaction between nitromethane and 1-crotonoyl-3,5-dimethyl-
pyrazole (1a) was successfully induced in the presence of R,R-
DBFOX/Ph‚Ni(ClO4)2‚3H2O (A) and 2,2,6,6-tetramethylpiperidine
(TMP), both in catalytic amonts (10 mol %), in nitromethane to
* To whom correspondence should be addressed. E-mail: kanemesa@
cm.kyushu-u.ac.jp.
† Department of Molecular and Material Sciences, Graduate School of Engineer-
ing Sciences, Kyushu University.
9
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J. AM. CHEM. SOC. 2002, 124, 13394-13395
10.1021/ja027313+ CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
nitromethane under catalytic double activation (CDAM), in which
both R,â-unsaturated carbonyl acceptors and nitromethane can
be effectively activated by catalytic amounts of chiral Lewis acids
and amine catalysts. For this purpose, the high tolerance of the
R,R-DBFOX/Ph aqua complex catalyst derived from nickel(II)
perchlorate hexahydrate toward amine bases as well as an effective
chirality induction was essential. Other related reactions along this
line are in progress in our group.
Supporting Information Available: Experimental procedure and
spectral data of all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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a a: A and TMP (10 mol % each) in MeNO2/THF (1:1 v/v).
Scheme 3 a
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a a: R,R-DBFOX/Ph - Ni(ClO4)2‚6H2O (10/10 mol %), TMP (10 mol
%), MeNO2/THF (1:1 v/v, 0.1 M), -20 °C, 168 h, 91%. b: H2 Raney Ni,
EtOH/CH2Cl2 (3:2 v/v (0.06 M), 1 atm, rt, 96 h. c: (Boc)2O and 4-DMAP
(2 equiv each), Et3N (1 equiv), rt, 12 h.
Finally, Michael additions of nitromethane with 1-(2-alkenoyl)-
3,5-dimethylpyrazoles (1a-n) having a variety of â-substituents
were found to take place smoothly under the standard conditions
at -20 °C to produce the Michael adducts 2a-n (Scheme 2).
Enantioselectivities up to 98% ee were observed. Acceptor sub-
strates 1a-h with methyl and primary to tertiary alkyl substituents
could be applied successfully, although acceptor 1h with a bulky
tert-butyl substituent is much less reactive. Other â-substituents
such as 1-alkenyl, ester, aryl, heteroaryl moieties work effectively.
Synthetic potential of this new methodology of nitromethane
conjugate additions under CDAM conditions could be demonstrated
successfully in the effective and short step synthesis of (R)-(-)-
rolipram (5o)13 known as an antidepressant and phosphodiesterase
inhibitor (Scheme 3). The desired starting substrate 1o was
synthesized by Wittig-Horner olefination of the substituted benz-
aldehyde, followed by transformation to the pyrazole amide in two
steps. The optical yield of the Michael adduct 2o was determined
to be 98% ee after its reductive conversion to (R)-rolipram 5o
followed by acylation to the N-Boc pyrrolidinone derivative 6o.
The absolute configuration of 5o was determined on the basis of
the reported optical rotation,13,14 indicating that the Re-faces of 1o
have been involved in the carbon-carbon bond-formation step.
In conclusion, the authors have presented a new synthetic
methodology for the enantioselective Michael addition reaction of
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(8) The addition reaction in nitromethane/THF (1:1 vol/vol) in the presence
of A and TMP (10 mol % each) is called “standard conditions” hereafter.
(9) One advantage in the use of THF as cosolvent is that the preparation of
catalyst A from the ligand and Ni(ClO4)2‚6H2O can be completed in a
few minutes at room temperature.4a
(10) The R,R-DBFOX/Ph complex derived from Co(ClO4)2‚6H2O showed a
little higher selectivity, but a lower activity (rt, 144 h, 2a: 36%, 86%
ee).
(11) Other R,R-DBFOX/Ph complex catalysts derived from the following salts
did not show any catalytic activity: Zn(ClO4)2‚6H2O, Cu(ClO4)2‚6H2O,
Mg(ClO4)2‚6H2O, Zn(OTf)2, Cu(OTf)2, and Mg(OTf)2.
(12) See Supporting Information.
(13) (a) Mulzer, J.; Zuhse, R.; Schmiechen, R. Angew. Chem., Int. Ed. 1992,
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(14) R)-(-)-Rolipram (5o) was purified by crystallization from AcOEt/hexane
(>99% ee). [R]D -33.9° (c 1.09, MeOH) (Lit.14 [R]D -31.1° (c 1.08,
MeOH)).
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