A novel proline-catalyzed three-component reaction of ketones, aldehydes, and Meldrum's acid

Article abstract of DOI:10.1055/s-2001-18095

We describe a novel proline-catalyzed three-component domino reaction between ketones, aldehydes and Meldrum's acid. Two new carbon-carbon σ-bonds from three different components are formed in this efficient transformation.

Full text of DOI:10.1055/s-2001-18095

LETTER
1687
A Novel Proline-Catalyzed Three-Component Reaction of Ketones,
Aldehydes, and Meldrum’s Acid
A
N
ovel Proline-
e
C
atalyzed T
n
hree-Com
p
j
onent
R
a
eaction min List,* Chris Castello
Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037, USA
Fax +1(858) 784 7028; E-mail: blist@scripps.edu
Received 29 May 2001
cient and highly diastereoselective process a tertiary ste-
reogenic center is created under concomitant formation of
two new carbon–carbon -bonds.
Abstract: We describe a novel proline-catalyzed three-component
domino reaction between ketones, aldehydes and Meldrum’s acid.
Two new carbon–carbon -bonds from three different components
are formed in this efficient transformation.
Our reaction design was inspired by elegant three-compo-
Key words: multicomponent reactions, organocatalysis, C–C cou- nent reactions introduced by Tietze et al. and Oikawa and
pling, combinatorial chemistry, domino reactions
Yonemitsu et al. that utilize aldehydes, Meldrum’s acid
(1), and enol ethers or indoles to furnish products of
type C and D, respectively (Scheme 2).1,7,8 These trans-
formations are catalyzed by ammonium salts or proline
and follow a domino Knoevenagel–hetero-Diels–Alder
mechanism via intermediate alkylidene Meldrum’s acids
2. Furthermore, silyl enol ethers and enamines are known
to react with activated olefins (e.g. 2), to give Michael-
products (e.g. 3).9,10 We reasoned that alkylidene deriva-
tives 2 and enamines could be generated in situ from ke-
tones, aldehydes and Meldrum’s acid (1) by using a
catalytic amount of proline. Consequently, this reaction
mixture would directly furnish keto esters 3.
The diversity generating potential of multicomponent re-
actions (MCR’s) has been recognized and their utility in
preparing libraries to screen for functional molecules is
well appreciated. Consequently, the design of novel
MCR’s is an important field of research.1–3 We have re-
cently developed an asymmetric aminocatalytic variant of
the three-component Mannich reaction.4 Based on our ex-
perience with this efficient transformation, we decided to
explore a related MCR, in which two C–H-bond-contain-
ing compounds condense with an aldehyde as shown in
Scheme 1.5
It was gratifying to find that mixing p-nitrobenzaldehyde
(1 equiv), Meldrum’s acid (1 equiv) and acetone (excess)
with a catalytic amount of L-proline in chloroform at room
temperature readily furnished crystalline keto ester 3a in
78% yield (Table 1, entry 1).
O
CR'3
CR''3
- H2O
R'3C
H
H CR''3
R
H
R
Scheme 1
Moreover we found that other aldehydes including
-
branched (entry 4) and unbranched (entries 2,3) and cyclic
aldehydes (entry 5) can readily be used to give the expect-
ed products in good yields (Table 1).
Symmetrical variants of this process include reactions of
either two molecules of Knoevenagel nucleophiles or are-
nes with one molecule of aldehyde to furnish products of
type A or B, respectively (Figure 1).6
O
O
R
O
R
R
EWG
EWG
O
OR
Ar
Ar
EWG EWG
Tietze
OR
C
A
B
R
O
O
R
Figure 1
O
O
RCHO
O
O
Indole
O
NH
O
O
Unsymmetrical variants, in which two different C–H-
bond containing compounds combine with an aldehyde
are much less studied but useful for the creation of tertiary
stereogenic centers.1,7,8 Herein we describe a novel pro-
line-catalyzed three-component reaction of unmodified
ketones with aldehydes and Meldrum’s acid. In this effi-
Oikawa-
Yonemitsu
O
O
O
D
1
O
2
O
R
O
O
R
R
R
R
This
Work
O
O
3
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1687,1689,ftx,en;S04901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 2 Three component reactions involving aldehydes and
Meldrum’s acid

1688
B. List, C. Castello
LETTER
Table 1 Proline-Catalyzed Three-Component Reaction of Alde-
hydes with Ketones and Meldrum’s Acid.
highly enantioselective proline-catalyzed aldol- and Man-
nich reactions.12–15,4
O
O
R3
O
O
O
O
We propose that this new three-component reaction in-
volves the domino Knoevenagel–hetero-Diels–Alder se-
quence postulated for the Tietze-three-component
reaction (Scheme 3).1,7 In this sequence, proline utilizes
both iminium- and enamine-catalysis.11 Accordingly, the
initial Knoevenagel condensation (a–c) proceeds via imi-
nium ion 7 and ammonium ion 8 to give olefin 2. The role
of proline in the hetero-Diels–Alder step (d–f) is to gener-
ate the dienophile, enamine 9, which reacts with hetero di-
ene 2 furnishing cyclo-adduct 10 and upon hydrolysis the
final product (5) while regenerating the catalyst.
O
L-Proline
(10-20%)
O
O
O
R3
H
R1
R2
R1
R2
CHCl3
rt, 12-24h
1 eq
O
1 eq
20 vol%
3a-g
Entry Product R1
R2 R3
Yield dra
78%
1
3a
H
H
NO2
2
3
3b
3c
H
H
H
H
83%
79%
Although proline’s -chirality is not utilized for asymmet-
ric induction, the carboxylate functionality seems essen-
tial for catalysis as indicated by the fact that pyrrolidine is
ineffective.
Meldrum’s acid derivatives 3 are valuable precursors of
diversified 1,5-dicarbonyl compounds.8,9 This was dem-
onstrated by methanolysis and in situ decarboxylation of
compound 3b to give keto ester 4b in good yield
(Scheme 4).
4
5
6
3d
3e
3f
H
H
H
H
51%
65%
69% >95%
i. H+, MeOH
ii. Pyridine, ∆
O
O
O
O
O
7
3g
75% >95%
O
OMe
70%
3b
4b
O
a Determined from HPLC and NMR analyses.
Scheme 4
Cyclic ketones may be used as well and the corresponding
products (3f, 3g) are obtained as single diastereomers (en-
tries 6,7). The enantioselectivity of this new reaction is
generally low and keto esters 3 were typically obtained in
ee’s under 5%. This result is consistent with our earlier
experiments on proline-catalyzed Michael additions of
ketones to nitro-olefins, which showed low enantioselec-
tivities.11 Presumably both proline-catalyzed transforma-
tions, Michael reaction and the present three-component
reaction, have similar mechanisms, which differ from the
In summary we have developed a novel proline-catalyzed
three-component reaction of aldehydes, ketones and Mel-
drum’s acid. The reaction allows the rapid construction of
complex carbon-scaffolds with two new C–C -bonds
from three different commercially available components.
From our initial experiments the scope of this new trans-
formation appears to be broad since all aldehydes tested
and various small and inexpensive cyclic and acyclic ke-
tones could be used. Operational simplicity, mild reaction
O
O
O
R
O
O
O
R
O
CO2H
O
O
N
H
O
O
1
N
O
CO2
d
b
8
H
6
O
O
O
R
O
HO2C
O
O
O
R
c
e
R
N
O
O
N
O2C
5
HN
HO2C
a
HN
f
2
7
3
O
O
HO2C
R
H
Scheme 3 Proposed mechanism
Synlett 2001, No. 11, 1687–1689 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Proline-Catalyzed Three-Component Reaction
1689
(8) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron
Lett. 1978, 1759. (b) Oikawa, Y.; Hirasawa, H.; Yonemitsu,
O. Chem. Pharm. Bull. 1982, 30, 3092.
(9) Mizukami, S.; Kihara, N.; Endo, T. Tetrahedron Lett. 1993,
34, 7437.
(10) Penades, S.; Kirsch, H.; Tortschanoff, K.; Margaretha, P.;
Polansky, O. E. Monatsh. Chem. 1973, 104, 447.
(11) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(12) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 496.
conditions, and the inexpensive and non-toxic catalyst
proline all contribute to the overall usefulness of the pro-
cess.
Our new reaction adds to an increasing number of effi-
cient organocatalytic transformations that are catalyzed
by small-molecule amines and amino acids.16 Future stud-
ies include the search for novel enantioselective ami-
nocatalysts for this three-component reaction and the
utilization of resin-bound Meldrum’s acid. We are also
pursuing the question whether additional substrates may
be used to extend this novel MCR17 beyond three compo-
nents.
(13) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc.
2000, 122, 2395.
(14) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(15) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
(16) For other interesting recent examples, see: (a) Ahrendt, K.
A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243. (b) Jen, W. S.; Wiener, J. J. M.;
Acknowledgement
We thank Richard A. Lerner and The Scripps Research Institute, for
encouragement and generous support and Peter Pojarliev for tech-
nical assistance.
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874.
(c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370. (d) Gröger, H.; Wilken, J. Angew. Chem.
Int. Ed. 2001, 40, 529; and references cited therein.
(e) Albus, S. Nachr. Chem. Techn. Lab. 2000, 48, 1459.
(f) Bahmanyar, S.; Houk, K. N. Chemtracts 2000, 13, 904.
(g) Diez, E.; Ley, S. Chemtracts 2000, 13, 592. (h)Doye, S.
Chem. Unserer Zeit 2001, 35, 62.
References
(1) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993,
32, 131.
(17) The synthesis of 3b illustrates the general experimental
procedure: 4-Pentenal (1.66 mL, 17 mmol), Meldrum’s acid
(2.16 g, 15 mmol), acetone (30 mL) and L-proline (3 mmol,
20 mol%) were stirred in CHCl3 (120 mL) at r.t. for 12 h. The
mixture was washed with sat. aq NH4Cl solution and the
aqueous layer was extracted with EtOAc. The combined
organic layers were dried (MgSO4), filtered and
(2) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S.
D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(3) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. Engl. 2000,
39, 3168. (b) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem.–Eur. J. 2000, 6, 3321.
(4) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(5) A transformation of this class formally represents a bis-
alkyl(or aryl)-de-oxo-bisubstitution reaction. As this
reaction has close similarities to the acetalization, which is a
bis-alkoxy-de-oxo-bisubstitution reaction, we refer to this
process as carba-acetalization.
(6) (a) Tietze, L. F. In Comprehensive Organic Synthesis, Vol.
2; Trost, B. M., Ed.; Pergamon: Oxford, 1991, 341–394.
(b) An important industrial application of this reaction is the
synthesis of DDT from trichloro-acetaldehyde and chloro-
benzene, catalyzed by sulfuric acid.
(7) (a) Tietze, L. F. J. Hetereocyclic Chem. 1990, 27, 47.
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115. (c) For a recent
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Chem. Int. Ed. 2001, 40, 903.
concentrated. Chromatography on SiO2 with hexanes–ethyl
acetate (gradient 4:1 1:2) furnished product 3b (3.33 g,
83%). 1HNMR (250 MHz, CHCl3): = 1.50 (m, 2 H), 1.71
(s, 3 H), 1.72 (s, 3 H), 2.05 (m, 2 H), 2.21 (s, 3 H), 2.75 (dd,
1 H, J = 3.3, 12.3 Hz), 2.88, (m, 1 H), 2.97 (dd, 1 H, J = 9.9,
12.3 Hz), 4.12 (d, 1 H, J = 2.2), 4.96 (m, 2 H), 5.72 (m, 1 H).
13CNMR (75 MHz, CHCl3): = 26.7, 28.2, 30.4, 31.5, 32.2,
43.7, 47.7, 104.8, 115.3, 137.5, 165.0, 165.1, 209.0. FT-
IR(neat): 2924, 1746, 1301, 1206. HRMS (MALDI-FTMS):
calcd for [M-H]– 267.1238, found 267.1231.
Synlett 2001, No. 11, 1687–1689 ISSN 0936-5214 © Thieme Stuttgart · New York