The enantioselective, bronsted acid catalyzed, vinylogous Mannich reaction

Article abstract of DOI:10.1002/anie.200800103

(Chemical Equation Presented) Chiral phosphoric acid 4 catalyzes enantioselectively the highly γ-regioselective addition of a silyl dienolate 2 to imines 1 in good yields and furnishes α,β-unsaturated δ-amino carboxylic esters 3 in one step. The reaction may also be carried out as a direct three-component coupling (PMP = para-methoxyphenyl; TBS = tertbutyldimethylsilyl).

Full text of DOI:10.1002/anie.200800103

Angewandte
Chemie
DOI: 10.1002/anie.200800103
Asymmetric Catalysis
The Enantioselective, Brønsted Acid Catalyzed, Vinylogous Mannich
Reaction**
Marcel Sickert and Christoph Schneider*
Dedicated to Professor Peter Welzel
Asymmetric Mannich reactions are among the most funda-
mental carbon–carbon bond forming reactions in organic
chemistry, and the reaction products are versatile intermedi-
ates in the synthesis of chiral, enantiomerically enriched
amines.[1] Vinylogous Mannich reactions of a,b-unsaturated
carbonyl compounds, furnishing highly functionalized d-
amino a,b-unsaturated carbonyl compounds, have established
themselves in natural product synthesis.[2] However, only very
few catalytic, enantioselective versions have been devised,
and these are limited to very special substrate patterns.
Building on the results of Martin,[3] Hoveyda, Snapper, and
Carswell developed silver-catalyzed, vinylogous Mannich
reactions of 2-silyloxy furans, leading to highly enantiomer-
ically enriched butenolides.[4] Chen and co-workers recently
reported the first direct asymmetric vinylogous Mannich
reaction of a,a-dicyanoalkenes and tert-butyloxycarbonyl
(Boc)-protected imines with a bifunctional thiourea catalyst,
leading to the corresponding products in high yields, excellent
enantioselectivities, and complete g-regioselectivity.[5] Jørgen-
sen and Niess catalyzed the same reaction successfully under
phase-transfer conditions with a chiral pyrrolidinium salt in
up to 95% ee.[6]
highly enantioselective normal Mannich reactions of silylke-
tene acetals with Brønsted acid of this type.[7a,b]
As a model reaction, we chose the reaction of imine 1a
and TBS-substituted dienolate 2,[14] which led to the vinyl-
ogous Mannich product 3a, and investigated various phos-
phoric acids 4a–f (each 30 mol%) in toluene at 08C (Table 1
and Scheme 1). Phosphoric acids with bulky 3,3’-substituents
in the binol backbone led to promising levels of enantiose-
lectivity, with the 3,3’-bismesityl derivative 4e being the most
enantioselective chiral catalyst, and thus it was selected for
further optimization studies (Table 1, entry 5). Coordinating
solvents, such as THF and 1,4-dioxane, exhibited a positive
effect on the enantioselectivity of the reaction and Mannich
product 3a was now obtained with e.r. 91:9 (Table 2, entries 3
and 4). Reaction times, however, remained long under these
conditions and product yields were only moderate. On the
other hand, alcohols as solvent increased the reaction rate to
such an extent that reactions were complete within 1–2h at
08C or room temperature, respectively, with only 5 mol% of
catalyst (Table 2, entries 5 and 6). The decrease in enantio-
selectivity which was initially observed was compensated
Herein we report the first catalytic, enantioselective,
vinylogous Mukaiyama–Mannich reactions of acyclic silyl
dienolates and imines to furnish highly valuable d-amino a,b-
unsaturated carboxylic esters in high yields, complete regio-
selectivity and good to very good enantioselectivities. We
Table 1: Optimization of chiral Brønsted acid 4.[a]
employed
a 2,2’-dihydroxy-1,1’-binaphthyl (binol)-based
Entry
4
t [h]
e.r.[b]
Yield [%][c]
phosphoric acid as chiral catalyst of the same type which
the groups of Akiyama and Terada introduced independently
into asymmetric catalysis.[7] Such chiral Brønsted acids have
proven to be exceptional chiral catalysts for a broad range of
highly enantioselective imine addition reactions which
involve chiral contact ion pairs generated in situ.[8–13] In this
context, Akiyama and co-workers have already developed
1
2
3
4
5
6
4a
4b
4c
4d
4e
4 f
20
52
52
120
68
92
59:41
53:47
53:47
81:19
85:15
70:30
97
70
92
77
52
40
[a] Reaction conditions: 1a (1 equiv), 2 (3 equiv), 4 (30 mol%), 08C,
0.16m in toluene, PMP=para-methoxyphenyl, TBS=tert-butyldimethyl-
silyl. [b] Determined by HPLC on chiral stationary phases (see the
Supporting Information). [c] Yield of isolated product.
[*] M. Sickert, Prof. Dr. C. Schneider
Institut für Organische Chemie
Universität Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
Fax: (+ 49)341-973-6599
E-mail: schneider@chemie.uni-leipzig.de
[**] We are grateful to Dr. Claudia Birkemeyer (Universität Leipzig) for
the mass spectrometry experiments and Wacker AG for the
donation of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. 3,3’-Substituted phosphoric acids 4a–f based on binol that
were investigated.
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Table 2: Optimization of reaction conditions.[a]
Table 3: Brønsted acid (4e)-catalyzed vinylogous Mannich reactions.[a]
Entry Solvent
4e
[mol%]
t [h][b] e.r.[c] Yield [%][d]
Entry
R
3
t [h][b]
e.r.[c]
Yield [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3k
3l
3m
3n
3o
8
4
3
6
72
5
1
2
6
9
94:6
95:5
96:4
95:5
91:9
91:9
91:9
91:9
90:10
90:10
92:8
92:8
95:5
91:9
87
89
88
92
66
93
94
94
90
87
90
92
88
83
1
2
3
4
5
6
7
8
toluene
CH2Cl2
30
30
30
30
5
5
5
5
68
68
68
68
1
85:15 52
75:25 56
91:9 65
91:9 68
72:28 91
84:16 75
90:10 81
94:6 87
4-MeC6H4
4-EtC6H4
4-PentC6H4
4-MeOC6H4
4-FC6H4
4-CNC6H4
3-ClC6H4
3-MeC6H4
2-Me-Ph
2-naphthyl
3-thiophenyl
3-furyl
THF
1,4-dioxane[e]
nBuOH
tBuOH[e]
1
2
8
tBuOH/1,4-dioxane 5:1
THF/tBuOH/2-Me-2-
BuOH 1:1:1[f]
8
6
7
48
[a] Reaction conditions: 1a (1 equiv), 2 (3 equiv), 4e (5–30 mol%),
0.16m. [b] Entries 1–4 were stopped after 68 h, entries 5–8 proceeded to
>99% conversion (HPLC). [c] Determined by HPLC on chiral stationary
phases (see the Supporting Information). [d] Yield of isolated product.
[e] RT. [f] À308C, H2O (1.0 equiv).
tBu
[a] Reaction conditions: 1 (1 equiv), 2 (3 equiv), 4e (5 mol%), À308C,
0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O (1.0 equiv), TBS=
tert-butyldimethysilyl. [b] Conversion >99% (HPLC). [c] Determined by
HPLC on chiral stationary phases (see the Supporting Information).
[d] Yield of isolated product.
through the use of a solvent mixture of tBuOH/1,4-dioxane
(5:1) (Table 2, entry 7). Optimal results were eventually
obtained in a solvent mixture containing equal amounts of
THF, tBuOH, and 2-Me-2-BuOH with 1 equiv of water, which
allowed the reaction to proceed quantitatively within 8 h at
À308C with only 5 mol% of catalyst. Under these conditions,
the vinylogous Mannich product 3a was obtained in 87%
yield, complete g-regioselectivity, and an enantiomeric ratio
of 94:6 (Table 2, entry 8).
The optimized procedure is broadly applicable to reac-
tions with aromatic and heteroaromatic aldimines, which
were converted into the corresponding vinylogous Mannich
products 3a–o in good to very good enantioselectivities (up to
e.r. 96:4), and typically high yields (Table 3). The products
contained exclusively E double bonds, and accordingly no
cyclization to the corresponding 5,6-dihydro-2-pyridones was
observed. Electron-rich aldimines required longer reaction
times and afforded lower yields than electron-poor aldimines
(see Table 3, entries 5 and 7). Para-substituted aldimines
showed higher enantioselectivities than ortho- and meta-
substituted aldimines. Also, an aliphatic, nonenolizable
aldimine, such as pivalimine, afforded the corresponding
vinylogous Mannich product 3o in good yield and enantio-
selectivity (Table 3,entry 14).
To demonstrate the practicality of the process, the
reaction of imine 1c was performed with just 1.2equiv of
the silyl dienolate 2 and 5 mol% of phosphoric acid 4e on a
gram scale under otherwise identical conditions. Vinylogous
Mannich product 3c was obtained in 92% yield and e.r. 95:5
after 12h at À308C (Scheme 2). The reaction may also be
performed as a three-component Mannich reaction with
aldehyde, amine, and silyl dienolate as starting materials, as
was demonstrated for the same reaction (Scheme 2). Mannich
product 3c was isolated in 93% yield and e.r. 96:4; thus, even
slightly better results were obtained than with the preformed
imine.
Scheme 2. a) 1c (1.15 g, 1.0 equiv), 2 (1.30 g, 1.2 equiv), 4e (5 mol%),
À308C, 12 h, 30 mL THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O
(1.0 equiv). b) Aldehyde (1.0 equiv), amine (1.0 equiv), 2 (3.0 equiv),
4e (5 mol%), À308C, 3 h, 6 mL THF/tBuOH/2-Me-2-BuOH (1:1:1),
H2O (1.0 equiv), PMP=para-methoxyphenyl, TBS=tert-butyldimethyl-
silyl.
Our optimized reaction conditions are distinctly different
from the procedure which Akiyama et al. developed for the
normal Mannich reaction. In particular, the use of the 2-
hydroxyphenyl group as imine substituent had proven to be
essential for obtaining high enantioselectivities in the normal
Mannich reaction, which was rationalized through a double
coordination of the phosphoric acid to the imine.[7a,b] In the
vinylogous Mannich reaction reported herein, however, such
an imine afforded the product with no enantioselectivity
under our conditions.[15] We assume that in the first step of the
catalytic cycle a chiral contact ion pair 5 is formed through
monocoordination of phosphoric acid 4e to imine
1
(Scheme 3). Subsequently, silyl dienolate 2 adds to contact
ion pair 5 in the carbon–carbon bond-forming process and
generates contact ion pair 6 which is converted into product 3
and silanol 7 through the aqueous solvent, whereupon chiral
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Chemie
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Lett. 2004, 6, 345.
[3] S. F. Martin, O. D. Lopez, Tetrahedron Lett. 1999, 40, 8949.
[4] E. L. Carswell, M. L. Snapper, A. H. Hoveyda, Angew. Chem.
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[6] B. Niess, K. A. Jørgensen, Chem. Commun. 2007, 1620.
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3790.
[8] Reviews: a) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal.
2006, 348, 999; b) S. J. Connon, Angew. Chem. 2006, 118, 4013;
Angew. Chem. Int. Ed. 2006, 45, 3909; c) T. Akiyama, Chem. Rev.
2007, 107, 5744, and references therein.
Scheme 3. Proposed catalytic cycle.
phosphoric acid 4e is regenerated. To shed some light on this
issue, we followed the synthesis of vinylogous Mannich
product 3a (R = Ph) by mass spectrometry. Through
ESI(+)-MS/MS, contact ion pair 6a was clearly detected
and also structurally characterized.[16] In addition, using
online NMR experiments, the quantitative formation of
silanol 7 was observed in the same reaction.
In conclusion, we have described the first catalytic,
enantioselective, vinylogous Mannich reaction of acyclic
silyl dienolates, furnishing valuable d-amino a,b-unsaturated
carboxylic esters in high yields, complete regioselectivity and
good to very good enantioselectivities. Although an excess of
nucleophile has been typically employed for the purpose of
increasing the reaction rate, almost identical results have been
obtained with a nearly stoichiometric ratio of reactants and
longer reaction times. The process is further facilitated by the
discovery that it may be executed successfully as a three-
component Mannich reaction, which avoids the need to
synthesize the imine in a separate step.[18]
[9] Reduction of imines with Hantzsch esters: see, for example,
a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte,
Org. Lett. 2005, 7, 3781; b) S. Hoffmann, A. M. Seayad, B. List,
Angew. Chem. 2005, 117, 7590; Angew. Chem. Int. Ed. 2005, 44,
7424; c) R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J.
Am. Chem. Soc. 2006, 128, 84; d) M. Rueping, A. P. Antonchick,
T. Theissmann, Angew. Chem. 2006, 118, 3765; Angew. Chem.
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Am. Chem. Soc. 2006, 128, 13074; f) G. Li, Y. Liang, J. C. Antilla,
J. Am. Chem. Soc. 2007, 129, 5830; g) M. Rueping, A. P.
Antonchick, Angew. Chem. 2007, 119, 4646; Angew. Chem. Int.
Ed. 2007, 46, 4562.
[10] Aza Diels–Alder reactions with imines: see, for example, a) J.
Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. 2006, 118, 4914;
Angew. Chem. Int. Ed. 2006, 45, 4796; b) T. Akiyama, H. Morita,
K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070; c) T. Akiyama,
Y. Tamura, J. Itoh, H. Morita, K. Fuchibe, Synlett 2006, 141.
[11] Friedel–Crafts reactions with imines: see, for example, a) D.
Uraguchi, K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2004, 126,
11804; b) M. Terada, K. Sorimachi, J. Am. Chem. Soc. 2007, 129,
292; c) G. B. Rowland, E. B. Rowland, Y. Liang, J. Perman, J. C.
Antilla, Org. Lett. 2007, 9, 2609; d) G. Li, G. B. Rowland, E. B.
Rowland, J. C. Antilla, Org. Lett. 2007, 9, 4065.
[12] For a selection of further applications with imines see: a) M.
Terada, K. Machioka, K. Sorimachi, Angew. Chem. 2006, 118,
2312; Angew. Chem. Int. Ed. 2006, 45, 2254; b) M. Rueping, E.
Sugiono, C. Azap, Angew. Chem. 2006, 118, 2679; Angew. Chem.
Int. Ed. 2006, 45, 2617; c) X.-H. Chen, X.-Y. Xu, H. Liu, L.-F.
Cun, L.-Z. Gong, J. Am. Chem. Soc. 2006, 128, 14802; d) J.
Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128,
1086; e) M. Rueping, A. P. Antonchick, C. Brinkmann, Angew.
Chem. 2007, 119, 7027; Angew. Chem. Int. Ed. 2007, 46, 6903;
f) M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba, J. H.
van Maarseveen, H. Hiemstra, Angew. Chem. 2007, 119, 7629:
Angew. Chem. Int. Ed. 2007, 46, 7485.
Experimental Section
General procedure: Aldimine 1c (96 mg, 0.40 mmol, 1.0 equiv) and
catalyst 4e (12mg, 0.02mmol, 5 mol%) were dissolved in 2.5 mL of a
solvent mixture (THF/tBuOH/2-Me-2-BuOH 1:1:1 and 1.0 equiv
H2O) and cooled to À308C. After 1 min silyl dienolate 2 (274 mg,
1.20 mmol, 3.0 equiv) was added in one portion, whereupon the
reaction mixture was stirred for 3 h at À308C. The solvents were
removed in vacuo and the crude product was purified by flash
chromatography (SiO2, diethyl ether/petroleum ether 1:5) to afford
124 mg (88%, e.r. 96:4) of (2E, 5S)-3c. The enantiomeric ratio was
determined by HPLC on a chiral stationary phase (see the Supporting
Information).[17]
Received: January 9, 2008
Published online: April 2, 2008
À
Keywords: asymmetric catalysis · C C coupling ·
contact ion pairs · organocatalysis · phosphoric acid
[13] For a selection of other applications, see: a) S. Mayer, B. List,
Angew. Chem. 2006, 118, 4299; Angew. Chem. Int. Ed. 2006, 45,
.
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Communications
4193; b) M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J.
[16] Contact ion pair 6a (m/z = 1024) cleanly fragments during
collision experiments in the ion trap into product 3a (m/z = 326)
and the silyl ester of phosphoric acid 4e (m/z = 699).
[17] The absolute configuration of the products was assigned by
conversion of the related ethyl (2E,5S)-5-phenylamino-5-(4-
chlorophenyl)-2-pentenoate (e.r. 92:8) into the saturated acid
followed by comparison of the rotation value with reported data
(see the Supporting Information).
Nachtsheim, Angew. Chem. 2007, 119, 2143; Angew. Chem. Int.
Ed. 2007, 46, 2097; c) E. B. Rowland, G. B. Rowland, E. Rivera-
Otero, J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 12084; d) X.
Wang, B. List, Angew. Chem. 2008, 120, 1135; Angew. Chem. Int.
Ed. 2008, 47, 1119; e) M. Rueping, B. J. Nachtsheim, S. A.
Moreth, M. Bolte, Angew. Chem. 2008, 120, 603; Angew. Chem.
Int. Ed. 2008, 47, 593.
[14] S. E. Denmark, G. L. Beutner, J. Am. Chem. Soc. 2003, 125,
7800.
[15] Imines with different nitrogen substituents afforded the follow-
ing e.r.: 2-HOC6H4 50:50, 2-MeOC6H4 66:34, Ph 95:5, 4-MeC6H4
94:6.
[18] Note added in proof: Akiyama et al. reported on a phosphoric
acid catalyzed, vinylogous Mannich reaction of 2-silyloxyfurans:
T. Akiyama, Y. Honma, J. Itoh, K. Fuchibe, Adv. Synth. Catal.
2008, 350, 399.
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