Catalytic asymmetric michael reactions of acetaldehyde

Article abstract of DOI:10.1002/anie.200800847

(Chemical Equation Presented) Acetaldehyde, now a big contender: A silyl prolinol derivative was found to catalyze the first Michael addition of acetaldehyde with both aromatic and aliphatic nitroolefins in excellent enantioselectivities (see scheme, TMS = trimethylsilyl). The utility of the reaction is illustrated in the synthesis of three current pharmaceuticals and in the synthesis of an enantiopure 3-monosubstituted pyrrolidine.

Full text of DOI:10.1002/anie.200800847

Angewandte
Chemie
DOI: 10.1002/anie.200800847
Organocatalysis
Catalytic Asymmetric Michael Reactions of Acetaldehyde**
Patricia García-García, Arnaud LadØpÞche, Rajkumar Halder, and Benjamin List*
Enamine catalysis recently emerged as a powerful method for
the direct use of ketones and aldehydes as nucleophiles in
asymmetric catalysis.[1] The scope of this chemistry is growing
and a large number of electrophiles, including carbonyl
compounds, imines, Michael acceptors, and many other useful
reagents, have been employed. Even reactions that had been
considered impossible, such as aldehyde cross aldolizations[2]
and a-alkylations,[3] became a reality by using this approach.
Whereas all types of ketones and aldehydes, including
branched, unbranched, cyclic and acyclic, as well as aliphatic
and aromatic ones, have found utility as nucleophiles,
acetaldehyde, the “simplest” of all enolizable carbonyl
compounds, was only very recently added to this list
(Scheme 1).[4,5]
the corresponding Michael reactions are, at least to our
knowledge, completely unknown, even in a nonenantioselec-
tive fashion. Herein we report a practical solution to this
problem; we found that acetaldehyde reacts with both
aromatic and aliphatic nitroolefins in the presence of a silyl
prolinol catalyst to give the corresponding Michael products
in good yields and excellent enantioselectivities.[6]
The Michael addition of acetaldehyde to b-nitrostyrene
(2a) was selected as a model reaction. Preliminary experi-
ments identified prolinol silyl ethers such as 1b, first used by
Jørgensen and co-workers and by Hayashi and co-work-
ers,[6d,7] as suitable catalysts. In contrast, proline and prolinol
1a gave the product in low yields (as expected) and lead to the
formation of significant amounts of byproducts (Table 1,
entries 1–3). We found that the byproduct formation was
significantly suppressed and that good conversions into
Michael adduct 3a were realized by slow addition of a
solution of acetaldehyde, in acetonitrile, to the reaction
mixture. Conditions involving addition of an acetaldehyde
Table 1: Catalyst screening for the Michael addition of acetaldehyde to b-
nitrostyrene.
Scheme 1. Acetaldehyde as a nucleophile in enamine catalysis.
TMS=trimethylsilyl.
We have developed proline-catalyzed Mannich reactions
of acetaldehyde with N-Boc imines that furnish the corre-
sponding b-amino aldehydes with exceptionally high enan-
tioselectivities.[4a] Independently, Hayashi et al. reported
analogous aldol reactions of acetaldehyde with aromatic
aldehydes as electrophiles.[4b] Despite the significant progress,
[b,c]
Entry
Catalyst
Yield [%][a]
e.r.
1
2
3
(S)-proline
10
no conv.
65:35
–
1a
1b
1b
1c
1d
1e
1 f
1g
1h
1i
55
51
46
44
23
25
44
27
5
94:6
96:4
94:6
95:5
94:6
95:5
90:10
92:8
92:8
94:6
96:4
53:47
4[d]
5
[*] Dr. P. García-García, Dr. A. LadØpÞche, Dr. R. Halder, Prof. Dr. B. List
Max-Planck-Institut fürKohlenforschung
6
7
8
9
10
11
12
13
14
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
[**] We thank Jutta Rosentreter for technical assistance. Generous
support by the Max-Planck-Society, the DFG (SPP 1179, Organo-
katalyse), Novartis (Young Investigator Award to B.L.), AstraZeneca
(Award in Organic Chemistry to B.L.), Secretaría de Estado de
Universidades e Investigación del Ministerio de Educación y Ciencia
(Fellowship to P.G.G.), and the Fonds derChemischen Industrie is
gratefully acknowledged.
1j
1k
1l
41
38
6
1
[a] Yields from H NMR analysis of the crude reaction mixture by using
1,3,5-trimethoxybenzene as an internal standard. [b] Determined from
chiral GC analysis. [c] Absolute configuration determined from known
optical rotation.[8b] [d] Reaction performed at 08C for64 h.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Catalytic asymmetric Michael reaction of acetaldehyde with
nitroalkenes.
solution, by syringe pump, to a solution of b-nitrostyrene (2a)
and the catalyst were used to screen prolinol ethers 1b–1l
(Table 1). Catalyst 1b gave product 3a in reasonable yield
(51%) and high enantioselectivity (96:4 e.r.) when the
reaction was conducted at 08C (Table 1, entry 4). Changing
the trimethylsilyl group into either a triphenylsilyl group (1c,
Table 1, entry 5) or a methyl group (1d, Table 1, entry 6) did
not significantly influence the outcome of the reaction.
Catalysts 1e and 1 f, bearing bulky aryl groups, led to lower
conversions and lower yields, whereas the enantioselectivity
remained similar to that observed with catalyst 1b (Table 1,
entries 7 and 8). A significant decrease in the conversion was
observed with a less flexible catalyst (1i, Table 1, entry 11).
Dialkylprolinol silyl ethers, both with linear (1g, Table 1,
entry 9) and branched alkyl groups (1h, Table 1, entry 10)
provided lower enantioselectivities. We continued the screen-
ing by testing diphenylprolinol silyl ethers bearing an OTBS
(TBS = tert-butyldimethylsilyl) group at different positions of
the pyrrolidine ring. The results show that neither cis (1j,
Table 1, entry 12) nor trans substitution (1k, Table 1,
entry 13) at the 4-position significantly affects the enantiose-
lectivity of the reaction. However, the e.r. value was poor with
trans 3-OTBS-substituted catalyst 1l (Table 1, entry 14).
On the basis of these studies the scope of the reaction was
evaluated by using catalyst 1b (Table 2). Indeed, several
nitrostyrenes and related compounds underwent the Michael
reaction with acetaldehyde in reasonable yields and excellent
enantioselectivities (Table 2, entries 1–8). Nitrostyrenes sub-
stituted with both electron-poor and electron-rich arenes, and
one heteroarene, gave products in good yields and high
enantioselectivities (Table 2, entries 1–8). In addition, all
possible monosubstituted substrates (o, m, or p) are well
tolerated. Gratifyingly, after significantly varying the reaction
conditions we were able to use aliphatic nitroolefins in the
reaction (Table 2, entries 9–13). Unbranched (Table 2,
entries 9–11), branched (Table 2, entry 12), and tertiary
(Table 2, entry 13) alkyl substituents on the nitroolefin were
well tolerated, and gave the corresponding products in very
good enantioselectivities and in reasonable yields.
Nitroaldehydes 3 are versatile synthetic intermediates as
demonstrated previously (Scheme 2);[8] for example, the
corresponding g-amino acids can be synthesized in a simple
two-step procedure. Accordingly, compounds 3c and 3j have
been converted into baclofen, a GABAB receptor antagonist,
and into pregabalin, an anticonvulsant drug, respectively.[8b]
Additionally, nitroaldehyde 3g has recently been used by
Palomo et al. in the synthesis of the antidepressant roli-
pram.[8a] We reasoned that aldehydes 3 should be readily
converted into the corresponding 3-monosubstituted pyrroli-
dines, although this has not previously been demonstrated.[9]
Indeed, hydrogenation of aldehyde 3a in the presence of
Pd(OH)2 furnished the desired pyrrolidine in good yield. The
combination of an amine catalyzed Michael reaction of
acetaldehyde with a nitroolefin and subsequent reductive
amination should be a highly attractive approach to other 3-
monosubstituted pyrrolidines.
[b]
Entry Product
3
Conditions Yield [%][a] e.r.
1
2
3
4
5
6
R=H
3a
3b
3c
3d
3e
3 f
A
A
A
A
A
A
51
53
58
51
57
44
96:4
95:5
96:4
96:4
95:5
96:4
R=p-Br
R=p-Cl
R=m-Cl
R=o-Cl
R=p-OMe
7[c,d]
3g
A
50
94:6
8
9
3h
3i
A
B
B
49
38
52
95:5
94:6
97:3
10
3j
11
3k
B
56
96:4
12
13
3l
B
B
61
41
96:4
97:3
3m
[a] Conditions A: MeCN, 08C, 62–93 h; Conditions B: DMF, 10 equiv
iPrOH, RT, 24–40 h. [b] Determined by chiral GC analysis. [c] Reaction
performed at RT for 23 h. [d] The e.r. values were determined by chiral
HPLC after conversion of the aldehyde into the corresponding methyl
ester.
In summary, we have developed a highly enantioselective
Michael reaction of acetaldehyde with nitroolefins. Whereas
the yields are typically around 50%, the enantioselectivities
Scheme 2. Synthetic applications of g-nitroaldehydes.
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Chemie
are excellent in almost all cases studied, including those with
aromatic and aliphatic nitroolefins. The utility of the reaction
is illustrated in the formal synthesis of three pharmaceuticals
and in the synthesis of an enantiopure 3-monosubstituted
pyrrolidine. Our reaction nicely complements a related
approach to the same products that has recently been
reported, involving the Michael addition of nitromethane to
a,b-unsaturated aldehydes.[8] The synthetic utility of acetal-
dehyde as a nucleophile in organic synthesis is additionally
expanded with this work, and more applications will be
forthcoming.
Keywords: asymmetric catalysis · Michael addition ·
nitroolefins · organocatalysis · synthetic methods
.
[1] a) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem.Rev.
2007, 107, 5471 – 5569.
[2] A. B. Northrup, D. W. C. MacMillan, J.Am.Chem.Soc. 2002, 124,
6798 – 6799.
[3] N. Vignola, B. List, J.Am.Chem.Soc. 2004, 126, 450 – 451.
[4] a) J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B. List, Nature
2008, 452, 453 – 455; b) Y. Hayashi, T. Itoh, S. Aratake, H.
Ishikawa, Angew.Chem. 2008, 120, 2112 – 2114; Angew.Chem.
Int.Ed. 2008, 47, 2082 – 2084.
[5] For previous attempts of using acetaldehyde as a nucleophile in
aldolizations giving either low yield or enantioselectivity, see:
a) A. Córdova, W. Notz, C. F. Barbas III, J.Org.Chem. 2002, 67,
301 – 303; b) A. Bogevig, N. Kumaragurubaran, K. A. Jorgensen,
Chem.Commun. 2002, 620 – 621.
[6] Asymmetric Michael additions of other aldehydes and ketones to
nitroolefins: a) B. List, P. Pojarliev, H. J. Martin, Org.Lett. 2001, 3,
2423 – 2425; b) J. M. Betancort, C. F. Barbas III, Org.Lett. 2001, 3,
3737 – 3740; c) W. Wang, J. Wang, H. Li, Angew.Chem. 2005, 117,
Experimental Section
Typical procedure, conditions A (Table 2, entry 1): 250 mL of a 0.8m
solution of catalyst 1b in dry MeCN was added to nitroolefin 2a
(149 mg, 1 mmol) in a vial under argon at 08C. Then 1 mL of a 5m
solution of acetaldehyde in anhydrous MeCN, prepared at 08C from
freshly distilled acetaldehyde, was added at 12 mLminÀ1 (tad =
83.3 min). After stirring for 64 h, the reaction mixture was treated
with 1N HCl and extracted twice with ethyl acetate. The organic
extracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. Purification by flash column chromatography
(hexane/ethyl acetate = 3:1) gave nitroaldehyde 3a (99 mg,
0.51 mmol) in 51% yield and with an e.r. value of 96:4.
1393 – 1395; Angew.Chem.Int.Ed.
Hayashi, H. Gotoh, T. Hayasi, M. Shoji, Angew.Chem. 2005, 117,
4284 – 4287; Angew.Chem.Int.Ed. 2005, 44, 4212 – 4215; e) S.
Luo, X. Mi, L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew.Chem.
2006, 118, 3165 – 3169; Angew.Chem.Int.Ed. 2006, 45, 3093 –
3097; f) M. Wiesner, J. D. Revell, H. Wennemers, Angew.Chem.
2008, 120, 1897 – 1900; Angew.Chem.Int.Ed. 2008, 47, 1871 –
2005, 44, 1369 – 1371; d) Y.
Typical procedure, conditions B (Table 2, entry 11): 500 mL of
DMF, 760 mL of 2-propanol and 250 mL of a 0.8m solution of catalyst
1b in dry DMF were successively added to nitroolefin 2l (155 mg,
1 mmol) contained in a vial under argon at room temperature. Then
500 mL of a 10m solution of acetaldehyde in anhydrous DMF,
prepared at 08C from freshly distilled acetaldehyde, was added at
12 mLminÀ1 (tad = 41.6 min). After stirring for 23 h, the reaction
mixture was quenched with 1n HCl and extracted twice with ethyl
acetate. The organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification by flash column
chromatography (pentane/diethyl ether= 9:1) gave nitroaldehyde 3l
(122 mg, 0.61 mmol) in 61% yield and with an e.r. value of 96:4.
1874. A review on asymmetric organocatalytic 1,4-additions:
g) S. B. Tsogoeva, Eur.J.Org.Chem. 2007, 1701 – 1716.
[7] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jorgensen,
Angew.Chem. 2005, 117, 804 – 807; Angew.Chem.Int.Ed. 2005,
44, 794 – 797; b) C. Palomo, A. Mielgo, Angew.Chem. 2006, 118,
8042– 8046; Angew.Chem.Int.Ed. 2006, 45, 7876 – 7880.
[8] a) C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S.
Vera, Angew.Chem. 2007, 119, 8583 – 8587; Angew.Chem.Int.
Ed. 2007, 46, 8431 – 8435; b) H. Gotoh, H. Ishikawa, Y. Hayashi,
Org.Lett. 2007, 9, 5307 – 5309; c) L. Zu, H. Xie, H. Li, J. Wang, W.
Wang, Adv.Synth.Catal. 2007, 349, 2660 – 2664; d) Y. Wang, P. Li,
X. Liang, T. Y. Zhang, J. Ye, Chem.Commun. 2008, 1232 – 1234.
[9] For the synthesis of disubstituted pyrrolidines by using a similar
approach see references [6a and b].
Received: February 20, 2008
Published online: April 28, 2008
Angew. Chem. Int. Ed. 2008, 47, 4719 –4721
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