Asymmetric organocatalytic decarboxylative Mannich reaction using β-keto acids: A new protocol for the synthesis of chiral a-amino ketones

Article abstract of DOI:10.3762/bjoc.8.144

The first decarboxylative Mannich reaction employing β-keto acids, catalyzed by cinchonine-derived bifunctional thiourea catalyst has been described. The desired a-amino ketones were obtained in excellent yields and with moderate to good enantioselectivities.

Full text of DOI:10.3762/bjoc.8.144

Asymmetric organocatalytic decarboxylative
Mannich reaction using β-keto acids: A new protocol
for the synthesis of chiral β-amino ketones
Chunhui Jiang, Fangrui Zhong and Yixin Lu*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1279–1283.
Department of Chemistry & Medicinal Chemistry Program, Life
Sciences Institute, National University of Singapore, 3 Science
Drive 3, Republic of Singapore, 117543
doi:10.3762/bjoc.8.144
Received: 23 May 2012
Accepted: 16 July 2012
Published: 13 August 2012
Email:
Yixin Lu* - chmlyx@nus.edu.sg
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
* Corresponding author
Keywords:
decarboxylative addition; β-keto acid; Mannich reaction;
© 2012 Jiang et al; licensee Beilstein-Institut.
License and terms: see end of document.
organocatalysis
Abstract
The first decarboxylative Mannich reaction employing β-keto acids, catalyzed by cinchonine-derived bifunctional thiourea catalyst
has been described. The desired β-amino ketones were obtained in excellent yields and with moderate to good enantioselectivities.
Introduction
Chiral β-amino ketones are an important class of building to only acetone and cyclic alkyl ketones. Application of aryl
blocks for the synthesis of 1,3-amino alcohols [1,2], 1,3-amino methyl ketones in the asymmetric Mannich reaction by enamine
acids [3] and other bioactive nature products [4-6]. Given their catalysis remains elusive. On the other hand, the only chiral
synthetic significance, methods for the asymmetric synthesis of Brønsted acid catalytic system based on BINOL-phosphates
β-amino ketones have been extensively investigated over the was reported by Rueping et al. Unfortunately, the yields of the
past few decades [7]. Among them, the Mukaiyama–Mannich reported reactions were unsatisfactory and the enantio-
reaction performed with silyl enol ethers and sulfonyl selectivities were modest [20].
aldimines, catalyzed by a chiral Lewis acid complex, is one of
the most important synthetic methods [8-13]. Apparently, direct In recent years, inspired by the enzymatic synthesis of polyke-
use of inactivated ketones as a donor would be of great prac- tides and fatty acids in biological systems, the enantioselective
tical value. Indeed, direct approaches such as asymmetric decarboxylative reactions of malonic acid half thioesters
enamine catalysis [14-17] and Brønsted acid catalysis [18] have (MAHTs) have received much attention. In this regard, various
been reported, through the activation of ketones or aryl imines electrophiles, including aldehydes, ketones, imines, activated
[19]. However, substrates for the enamine activation are limited alkenes and azodicarboxylates, have been employed as elec-
1279

Beilstein J. Org. Chem. 2012, 8, 1279–1283.
Scheme 1: Working hypothesis: Decarboxylative Mannich reaction.
trophiles in the presence of metal [21-25] or organocatalysts (Table 1, entries 8–10). The influence of different imines
[26-36].
on the reaction was subsequently explored, and it was found
that the electronic nature of the sulfonyl protective groups
To provide a practical solution to the low reactivity associated affected the enantioselectivity. While the employment of
with aryl methyl ketones, we wondered whether β-keto nosylimine 1b led to decreased enantioselectivity (Table 1,
acids could serve as an enolate equivalent to aryl methyl entry 11), replacement of tosylimine 1a with N-(p-methoxy-
ketones upon decarboxylation (Scheme 1). The proposed benzenesulfonyl)imine 1c resulted in further improvement,
addition–decarboxylation sequence is consistent with current and the product was obtained in 65% ee (Table 1, entry 12).
mechanistic understanding [31,35,37,38]. However, we cannot However, when ethoxycarbonylimine 1d was used, nearly
exclude an alternative decarboxylation–addition pathway at this racemic products were obtained, suggesting the importance of
stage. In fact, in sharp contrast to the popular use of malonic the sulfonyl group in the asymmetric induction (Table 1, entry
acid half thioesters (MAHTs) as an ester enolate equivalent in 13). Less reactive imines, such as diphenylphosphinoylimine 1e
enantioselective decarboxylative additions [39], the employ- and Cbz-imine 1f, proved to be unsuitable for the reaction
ment of β-keto acids as a reaction partner in decarboxylative (Table 1, entries 14 and 15).
processes has rarely been explored [37]. Herein, we reported the
first decarboxylative Mannich reaction between the β-keto acids A screening of the solvent effect was then followed, and the
and sulfonylimines, affording chiral β-amino ketones in excel- results are summarized in Table 2. In general, the reaction
lent yields and good enantioselectivities.
proceeded very well in common aprotic solvents, and excellent
yields were consistently obtained (Table 2, entries 1–9).
Enantioselectivity of the reaction varied, and diethyl ether was
Findings
In our initial screening, we examined the model reaction found to be the best solvent, furnishing the desired product with
between tosylimine 1a and β-keto acid 2a in the presence of a 72% ee. Employment of other etheric solvents, including
range of bifunctional catalysts (Table 1). We first evaluated the methyl tert-butyl ether and dioxane, and lowering reaction
catalytic effects of several cinchona alkaloid derivatives. temperature did not offer further improvement (Table 2, entries
Commercially available cinchonidine (CD-1) led to the forma- 10–12).
tion of the product with disappointing enantioselectivity
(Table 1, entry 1). Quinine-derived sulfonamide [40], To establish the substrate scope, a number of sulfonylimines
β-isocupreidine (β-ICD) [41,42] and biscinchona alkaloid derived from aromatic aldehydes were employed as acceptors,
(DHQ)2AQN were all found to be poor catalysts (Table 1, and the results are summarized in Table 3. In general, the reac-
entries 2–4). On the other hand, cinchona alkaloid derived tion worked well for imines with various substituents at
bifunctional thiourea tertiary amine catalysts afforded much different positions of the phenyl ring, including electron-with-
improved results (Table 1, entries 5–7). Among them, the drawing groups, electron-donating groups and halogen atoms,
cinchonine based thiourea C-1 turned out to be the best catalyst, and excellent yields and moderate ee values were obtained
and the Mannich product was isolated with 58% ee (Table 1, (Table 3, entries 1–10). Heterocycles were well-tolerated, and
entry 7). In addition, we also examined several other bifunc- good enantioselectivities were obtained with 2-furyl and thio-
tional catalysts based on amino acids [43,44], including threo- phen-2-yl containing substrates (Table 3, entries 11 and 12).
nine derived Thr-1 [45], and tryptophan based Trp-1 [46], as The aryl groups of β-keto acids could also be varied, and the
well as threonine incorporated multifunctional catalyst CD-3 reaction was applicable to β-keto acids with different aromatic
[47]. However, no further improvement could be achieved substituents (Table 3, entries 13–17). Furthermore, the reaction
1280

Beilstein J. Org. Chem. 2012, 8, 1279–1283.
Table 1: Exploration of the decarboxylative addition of β-ketoacids to imines.
Entrya
1
cat
Yield (%)b
ee (%)c
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
CD-1
Q-1
86
17
13
2
2
54
3
(DHQ)2AQN
β-ICD
CD-2
QD-1
C-1
90
4
93
27
44
54
58
12
21
13
49
65
5
5
97
6
93
7
95
8
Thr-1
Trp-1
CD-3
C-1
88
9
95
10
11
12
13
14
15
92
95
C-1
96
C-1
91
C-1
trace
trace
–
C-1
–
aReactions were performed with 1 (0.05 mmol), 2a (0.075 mmol) and the catalyst (0.005 mmol) in CHCl3 (0.5 mL). bIsolated yield. cDetermined by
HPLC analysis on a chiral stationary phase.
was also applicable to alkyl β-keto acids, and comparable chem- In conclusion, we have developed the first organocatalytic de-
ical yields and enantioselectivities were attainable (Table 3, carboxylative Mannich reaction employing β-keto acids as the
entries 18–19). The absolute configurations of the products donor. The reaction was effectively catalyzed by cinchonine-
were assigned by comparing the optical rotation of 3a with the based bifunctional catalyst C-1, and the synthetically useful
value reported in the literature [48] (see the Supporting Infor- β-amino ketones were prepared in excellent yields and with
mation File 1 for details).
moderate to good enantioselectivities. The method reported
1281

Beilstein J. Org. Chem. 2012, 8, 1279–1283.
Table 2: Solvent screening.
Table 3: Substrate scope. (continued)
18
19
Ph
Ph
n-Pr
t-Bu
3w 92
3x 75
54
73
aReactions were performed with 1 (0.05 mmol), 2 (0.075 mmol) and
C-1 (0.005 mmol) in Et2O (0.5 mL). bIsolated yield. cDetermined by
HPLC analysis on a chiral stationary phase. dThe catalyst loading was
20 mol %.
Entrya
Solvent
Yield (%)b
ee (%)c
1
CHCl3
96
93
92
90
93
92
90
91
92
65
64
66
63
72
66
67
66
52
62
65
65
represents a new protocol for the asymmetric construction of
2
THF
β-amino ketones.
3
DCM
4
toluene
diethyl ether
ethyl acetate
benzene
DCE
Experimental
General procedure for the decarboxylative
Mannich reaction of β-keto acids and
aldimines
To a solution of imine 1c (13.8 mg, 0.05 mmol) and C-1
(2.8 mg, 0.005 mmol) in ether (0.5 mL) at room temperature,
was added β-keto acid 2a (12.3 mg, 0.075 mmol). The reaction
mixture was stirred for 12 h. The solvent was then removed
under reduced pressure, and the residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate 5:1 to 3:1)
to afford 3c as a white solid (18.4 mg, 93% yield).
5
6
7
8
9
acetone
10
11
12d
methyl tert-butyl ether 92
dioxane
94
67
diethyl ether
aReactions were performed with 1c (0.05 mmol), 2a (0.075 mmol) and
C-1 (0.005 mmol) in the solvent specified (0.5 mL). bIsolated yield.
cDetermined by HPLC analysis on a chiral stationary phase. dReaction
was performed at 0 °C.
Table 3: Substrate scope.
Supporting Information
Supporting Information File 1
Characterization data and spectra of synthesized
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-144-S1.pdf]
Entrya
Ar
R
3
Yield ee
(%)b (%)c
Acknowledgements
We are grateful for generous financial support from the
National University of Singapore (R-143-000-469-112) and
GSK–EDB (R-143-000-491-592).
1
Ph
Ph
3c 93
3g 90
3h 88
72
64
61
55
62
65
65
59
65
61
83
77
64
70
69
67
60
2
4-Me-C6H4
4-Br-C6H4
4-CF3-C6H4
4-OMe-C6H4
2-F-C6H4
2-Me-C6H4
2-Br-C6H4
3-Me-C6H4
3-Br-C6H4
2-furyl
Ph
3
Ph
4
Ph
3i
3j
85
97
5
Ph
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