Catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes [3]

Full text of DOI:10.1021/ja992314w

J. Am. Chem. Soc. 1999, 121, 10215-10216
10215
Catalytic Enantioselective Conjugate Addition of
,3-Dicarbonyl Compounds to Nitroalkenes
N-methylmorpholine (NMM) was added as cocatalyst, the reaction
proceeded to completion in 3 h, with a selectivity of 91%.
1
2
1
Jianguo Ji,* David M. Barnes,* Ji Zhang, Steven A. King,
Steven J. Wittenberger, and Howard E. Morton
Process Chemistry Research, Pharmaceutical Products
DiVision
Abbott Laboratories, Bldg. R8/1, 1401 Sheridan Road
North Chicago, Illinois 60064
ReceiVed July 6, 1999
In recent years, catalytic enolate bond constructions have
1
,2
emerged as powerful methods for asymmetric synthesis.
However, with few exceptions, it has not been possible to
accomplish these bond constructions in a manner in which
enolization is incorporated into the catalytic cycle. In general,
catalytic enolate bond constructions have required the formation
of a stable activated enolate surrogate, most generally a silyl
ketene acetal or silyl enol ether, which reacts with an electrophile
The effect of ligand structure on the course of the reaction
was investigated (Table 1, eq 2). The unsubstituted aminoindanol-
derived ligand 1b resulted in low conversion, with low selectivity
2
mediated by a Lewis acid catalyst. Notable exceptions include
1
the gold-catalyzed aldol reactions of Ito and Hayashi, the
3
proline-rubidium catalyst system of Yamaguchi, the magnesium
1
3
(entry 2), as did dimethyl-substituted derivative 1c (entry 3).
4
sulfonamide-catalyzed amination of Evans and Nelson, and
Ligands derived from other amino alcohols were also investigated.
While phenyl- and tert-butyl ligands 2c and 3c provided generally
low selectivities (entries 4 and 5), cyclopropyl-bridged diphenyl
bis(oxazoline) 4a did provide excellent reactivity, though only
particularly the mixed-metal systems of Shibasaki.5
The conjugate addition of enolates to activated olefins remains
an active field of research. Indeed, substantial effort has gone
into the investigations of enantioselective versions of this reac-
82% selectivity. Notably, in the absence of ligand, the reaction
6
5c,d
tion, though highly selective variants are rare.
Nitroolefins
did not proceed.
have shown limited success in enantioselective Michael additions.
Due to their multiple reactivities, nitro compounds remain
Magnesium salts with more coordinating counterions (I, Br,
Cl) gave uniformly lower rates and selectivities. Calcium triflate
and samarium triflate both provided fair reaction rates but very
low selectivities. Copper triflate and zinc triflate were unable to
promote the reaction at reasonable rates. The structure of the
amine was relatively unimportant, as others also provided good
selectivity (morpholine, 86%; N-ethylpiperidine, 86%; 5,6-dim-
ethylbenzimidazole, 87%). However, stronger bases, such as tri-
ethylamine and Hunig’s base, gave somewhat inferior results,
presumably due to background reaction. Other solvents have been
7
important intermediates in organic synthesis. Here, we report
the first highly enantioselective catalytic asymmetric conjugate
8
addition of ketoesters and malonates to nitroolefins. This reaction
is catalytic in ligand-metal complex and employs an amine
cocatalyst. It is particularly interesting because it controls absolute
stereochemistry at the â-carbon of the conjugate acceptor.
When ethyl acetoacetate and nitrostyrene were combined in
3
hydrocarbon-stabilized CHCl in the presence of 5 mol % of the
preformed complex of magnesium triflate and bis(oxazoline)
ligand 1a,9 the Michael addition proceeded to 51% conversion
after 15 h; the phenyl-bearing stereocenter of nitroketone 5a was
formed with 59% selectivity (eq 1), indicating enantioselective
attack on nitrostyrene.11 When a small amount (6 mol %) of
,10
(9) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1997, 38, 1145. For
2
a review of the use of C -symmetric bis(oxazoline) ligands in asymmetric
catalysis, see: Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45.
(10) For examples of the use of bis(oxazoline)magnesium complexes in
(1) Sauamura, M.; Ito, Y. Asymmetric Aldol Reactions. In Catalytic
catalysis, see the following. Conjugate additions of O-benzylhydroxylamine
to unsaturated amides: (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J.
Am. Chem. Soc. 1998, 120, 6615-6616. Radical additions to R,â-unsaturated
imides: (b) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800. Diels-Alder
reaction: (c) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.;
Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074-
3088. (d) Carbone, P.; Desimoni, G.; Faita, G.; Filippone, S.; Righetti, P.
Tetrahedron 1998, 54, 6099-6110. (e) Desimoni, G.; Faita, G.; Invernizzi,
A. G.; Righetti, P. P. Tetrahedron 1997, 53, 7671-7688. (f) Takacs, J. M.;
Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R., III. Tetrahedron:
Asymmetry 1997, 8, 3079-3087. (g) Corey, E. J.; Ishihara, K. Tetrahedron
Lett. 1992, 33, 6807-6810. Nitrone 1,3-dipolar cycloadditions: (h) Gothelf,
K. V.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998, 53, 5483-5488.
(11) The adducts of â-ketoesters with nitrostyrenes are formed as 1:1
mixtures of compounds diastereomeric at the product ketoester R-position due
to rapid equilibration under the reaction conditions. By NMR, the enol tautomer
is also observed sometimes. See Supporting Information.
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 7.2,
pp 367-388.
(
2) For a review of Lewis acid-catalyzed additions of enolate surrogates
to electrophiles, see: Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-
3
89. See also: Mahrwald, R. Chem. ReV. 1999, 99, 1095-1120.
3) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61,
(
3
520-3530 and references therein.
(
4) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452-6453.
(
5) (a) Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure Appl. Chem. 1998,
7
0, 1027-1034 and references therein. (b) Yoshikawa, N.; Yamada, Y. M.
A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-
4
178. For leading references on Michael additions catalyzed by heterobime-
tallic complexes, see: (c) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date,
T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104-106. (d)
Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 7557-7558.
(
6) For an early example of a highly selective catalyzed reaction, see: (a)
(12) In a typical experiment, Mg(OTf)
equiv) and ligand 1c (20.1 mg, 0.055 mmol, 0.055 equiv) are combined in
the reaction vessel. One milliliter of CHCl is added, and the mixture is stirred
for 1 h. Four milliliters of CHCl is added, followed by 200 mg of 4-Å
2
2
‚4H O (19.6 mg, 0.05 mmol, 0.05
Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625-
6
28. For a recent example of a highly selective Mukaiyama Michael reaction,
3
see: (b) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994-1995. For a review of catalyzed conjugate
addition reactions, see: (c) Ferigna, B. I.; de Vries, A. H. M. AdVances in
Catalytic Processes; JAI Press: London, 1995; pp 151-192.
3
molecular sieves, and the resulting mixture is stirred for an additional 90 min.
Following this, nitrostyrene (149 mg, 1 mmol, 1 equiv) is added, followed by
ethyl acetoacetate (0.15 mL, 1.2 mmol, 1.2 equiv) and N-methylmorpholine
(6.6 µL, 0.06 mmol, 0.06 equiv). Conversion and selectivity are determined
by HPLC analysis. See the Supporting Information for details.
(13) For a computational study of the effect of the bridge substituents on
the Diels-Alder reaction catalyzed by bis(oxazoline)copper complexes, see:
Davies, I. W.; Deeth, R. J.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett.
1999, 40, 1233-1236. See also ref 9.
(
7) For recent reviews, see: (a) Tamura, R.; Kamimura, A.; Ono, N.
Synthesis 1991, 423-434. (b) Fuji, K.; Node, M. Synlett 1991, 603. (c) Rosini,
G.; Ballini, R. Synthesis 1988, 833-847.
(
8) The addition of 1,3-dicarbonyl compounds to nitrostyrene has been
reported to be promoted by chiral alkaloid catalysts in up to 43% ee. Brunner,
H.; Kimel, B. Monatsh. Chem. 1996, 127, 1063-1072.
1
0.1021/ja992314w CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/13/1999

10216 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Communications to the Editor
Table 1. Effect of Ligand in the Michael Addition
Table 3. Scope of the Asymmetric Addition of 1,3-Dicarbonyl
Compounds to Nitroalkenes
entry
ligand
selectivity11 (%)
conversion (%)
select-
1
2
3
4
5
6
7
1a
1b
1c
2c
3c
4c
4a
91
65
77
58
0
76
82
96
33
44
9
7
15
99
11
ivity
yield
(%)
entry
R1
R2
OEt
R3
adduct
(%)
1
2
3
4
5
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
90
95
Oi-Bu
Ot-Bu
OEt
88
29
94
92
92
94
90
95
CHMe2
OEt
6
OEt
3-MeO-4,5-
OCH2O-Ph
Ph
5f
88a
93
89a,b
96
Table 2. Effect of Water on the Michael Addition
7
8
9
OMe
OEt
OMe
OEt
5g
5h
5i
5j
5k
5l
c
c
c
Ph
95 (93) 92 (93)
OCHMe2 OCHMe2 Ph
94
33
90
92
88
90
1
1
1
0
1
2
OCMe3
OEt
OEt
OCMe3
OEt
OEt
Ph
p-F-Ph
2,6-(MeO)2-
Ph
c
97 (97) 93 (95)
conversion (%)
(2 h)
entry na added water sievesb selectivity11 (%)
13 OEt
OEt
OEt
n-C5H11
Me2CHCH2
5m
5n
89
90
93
88
14
OEt
1
2
3
4
4
0
yes
no
yes
yes
90
73
90
91
91
60
64
91
4
0
a
Reaction run at 35 °C.
b
HPLC yield. Numbers in parentheses refer
c
0.25
0.25
0
to reactions in toluene.
c
4 equiv
a
The extent of salt hydration was determined by KF coulometry.
00 mg of powdered 4-Å sieves/mmol of nitrostyrene was employed.
Water was added to the dry Mg(OTf) before complexation.
Adduct 5h can be recrystallized to 99% ee (88% recovery).
This has been converted in three steps (85% yield) to (R)-4-
phenyl-2-pyrrolidinone (6), establishing the sense of induction
of these reactions and demonstrating the utility of the adducts in
forming substituted pyrrolidinones (eq 5).15
b
c
2
2
2 2
investigated, including toluene (86% selectivity), CH Cl (81%
selectivity), THF (58% selectivity), and DMF (0% selectivity);
chloroform and toluene have proven to be optimal for this
reaction. In particular, coordinating solvents lower selectivity and
reactivity.
The effect of water on the reaction is illustrated in Table 2 (eq
3
(
4
). The data indicate that it is necessary to have hydrated Mg-
OTf) present during ligand-metal complexation (entries 3 and
); however, the catalytic Michael addition proceeds more
2
12
The experimental results to date, including a kinetic analysis
which will be reported later, support a mechanism in which the
amine deprotonates the catalyst-bound dicarbonyl compound. The
resulting chiral enolate complex, which is a long-lived intermedi-
effectively in an anhydrous reaction mixture. Practically, the
catalyst formation is conducted with Mg(OTf) ‚4H O, and then
molecular sieves are added, and the mixture is stirred for 90 min
prior to addition of the reactants. The presence of sieves during
the catalytic reaction increases both the rate and selectivity of
the reaction (entries 1 vs 2).14
The rate and selectivity of the Michael addition are influenced
by the size of the ester group (Table 3, eq 4). iso-Butyl
acetoacetate reacts with nitrostyrene with 88% selectivity (entry
2
2
16
ate, adds diastereoselectively to the nitroalkene.
In summary, we have developed a catalyst system for the
conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes.
These reactions proceed with low catalyst loading and excellent
facial selectivities at the conjugate acceptor. The products of these
reactions are important intermediates for the syntheses of
2), but the larger tert-butyl ester reacts slowly and with only 29%
4-substituted pyrrolidines. Further investigations, including mecha-
selectivity (entry 3). However, substitution on the ketone moiety
is accommodated, as in the cases of ethyl isobutyryl acetate (94%
selectivity, entry 4) and the still bulkier 2,2-dimethylpentyl
derivative (g88% selectivity, entries 5 and 6). 2-Alkylated keto-
esters were unreactive under the reaction conditions.
nistic studies, will be reported shortly.
Acknowledgment. We gratefully acknowledge Michael Fitzgerald
for assistance in the development of many of the chiral assays for this
project.
The reaction has been further extended to the addition of
malonates to nitroalkenes. These reactions are generally faster
and less sensitive to reaction conditions. In particular, reactions
in toluene provide excellent levels of selectivity (entries 8 and
Supporting Information Available: General experimental and
characterization details of Michael adducts 5a-n and proofs of induction
of adducts 5f and 5m and possible transition states. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
2). The steric bulk of the ester affects rates and selectivities in
a manner similar to that observed in ketoester reactions (entries
-10). A number of nitroalkenes have been found to undergo
the reaction with high yields and selectivities. Electron-poor (entry
1) and -rich (entry 12) nitrostyrenes react with equal facility.
7
JA992314W
1
(15) Raney nickel hydrogenation was followed by saponification and
decarboxylation, see: Petzoldt, K.; Schmiechen, R.; Hamp, K.; Gottwald, M.
U.S. Patent 553911, 1996. Mulzer, J. Prakt. Chem. 1994, 336, 287. (R)-4-
Additionally, alkyl-substituted nitroolefins (entries 13 and 14)
undergo clean and selective reaction.
25
Phenylpyrrolidinone (6) thus obtained had a rotation of [R]
D
) +35.2 (c
25
1
.02 MeOH) (lit. [R]
D
) -33.8 (c 0.89 MeOH) for the (S)-isomer: Meyers,
A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36-42).
(16) See Supporting Information for a description of possible transition
states.
(14) The effect of water on magnesium bis(oxazoline)-catalyzed reactions
has been documented in other cases (refs 10d,e,h). See the Supporting
Information for an investigation of this effect.