Back to natural cinchona alkaloids: Highly enantioselective Michael addition of malononitrile to enones

Article abstract of DOI:10.1002/adsc.200900712

An efficient and convenient highly enantioselective Michael addition of malononitrile to enones has been developed by using quinine as the organocatalyst. The adducts were isolated in excellent yield and high asymmetric induction (up to 95% ee). An easy r

Full text of DOI:10.1002/adsc.200900712

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DOI: 10.1002/adsc.200900712
Back to Natural Cinchona Alkaloids: Highly Enantioselective
Michael Addition of Malononitrile to Enones
Alessio Russo,a Alessandra Perfetto,a and Alessandra Lattanzia,*
a
Dipartimento di Chimica, Universitꢀ di Salerno, Via Ponte don Melilllo, 84084 Fisciano, Italy
Fax : (+39)-089-969-603; e-mail: lattanzi@unisa.it
Received: October 14, 2009; Published online: December 8, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900712.
Abstract: An efficient and convenient highly enan-
tioselective Michael addition of malononitrile to
enones has been developed by using quinine as the
organocatalyst. The adducts were isolated in excel-
lent yield and high asymmetric induction (up to
95% ee). An easy route to difficultly accessible
ester derivatives has been also disclosed.
a,b-unsaturated imides.[7d,e] Modified Cinchona alka-
loids, such as the primary amines 9-amino-9-deoxyepi-
quinidine and 9-amino-9-deoxyepicinchonine, were
recently employed in the presence of acids as co-cata-
lysts in Michael additions of malononitrile to a,b-un-
saturated ketones[9] or aromatic ketones to alkylidene-
malononitriles, respectively.[10] These two complemen-
tary approaches are based on covalent activation of
the carbonyl compounds by the primary amine of the
catalyst to generate chiral iminium ions and enamines
as the reactive intermediates, respectively. The prod-
ucts were obtained in good to high yield and moder-
ate to high enantioselectivity. Cinchona alkaloids are
privileged catalysts, which are highly effective and
Keywords: Cinchona alkaloids; enones; malononi-
trile; Michael addition; organocatalysis
The high demand for enantiopure compounds as versatile in asymmetric catalysis.[11] The seminal work
building blocks in organic synthesis and in the phar- of Wynberg and Hiemstra[12] and more recent find-
maceutical industry requires the development of ings[13] showed that natural and modified Cinchona al-
highly efficient and enantioselective methodologies. kaloids are able to provide non-covalent activation of
In the last years, organocatalysis has increasingly the reacting partners in several asymmetric transfor-
gained importance as a tool for the synthesis of chiral mations. The basic tertiary nitrogen was suggested to
targets with respect to classical approaches based on deprotonate the pro-nucleophiles, whereas the secon-
chiral metal complexes and biocatalyses.[1] In the area dary hydroxy group would serve as hydrogen-bonding
of organocatalysed Michael additions, several exam- donor in the activation of a variety of electrophiles
ples of stereoselective carbon-carbon and carbon-het- such as a,b-unsaturated carbonyl compounds or nitro-
eroatom bond forming reactions have been successful- alkenes. The proximity and cooperative action of
ly reported.[2] Nucleophiles such as malonate esters,[3] these groups in the chiral environment of the catalyst
diketones,[4] keto esters[4c,e,5] and nitroalkanes[6] have would lead to a preferential approach of the reagents
been extensively used for carbon-carbon bond form- leading to the generally observed high stereocontrol.
ing reactions mainly with nitroolefins and a,b-unsatu- Indeed, only one example of non-covalent catalysis
rated carbonyl compounds as the acceptors. Widening promoted by a Cinchona-derived thiourea was report-
the scope of either the acceptors or the donors em- ed by Wang in the addition of malononitrile to trans-
ployable in the asymmetric Michael addition is an im- chalcone which furnished the product in 77% yield
portant advance in order to have access to diversely and 88% ee.[14]
functionalised and synthetically useful chiral adducts.
On the basis of our interest in organocatalysed Mi-
The use of malononitrile as donor in conjugate addi- chael addition reactions exploiting the non-covalent
tions has received much less attention,[7] although the type of activation,[15] we undertook an investigation
nitrile group can undergo further transformations to on the conjugate addition of malononitrile to a,b-
1,3-dicarbonyl derivatives[7a,8] or amines.[7c] Chiral thi- enones mediated by easily accessible Cinchona alka-
oureas proved to be efficient promoters in the enan- loids. A convenient process has been developed by
tioselective conjugate additions of malononitrile to using quinine as the organocatalyst.
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Alessio Russo et al.
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Figure 1. Cinchona alkaloids checked in the Michael addition.
The adducts were obtained in excellent yield while played by the promoters used at 20 mol% in terms of
achieving high enantiocontrol (up to 95% ee). conversion and asymmetric induction (entries 1–6).
At the outset, trans-chalcone 1a and malononitrile Quinine proved to be the most efficient compound af-
2 were reacted with natural alkaloids (Figure 1) at fording product 3a in 98% yield and 82% ee. Further
room temperature (Table 1). Toluene was initially solvent screening confirmed toluene as the best
chosen as solvent since most of the reactions mediat- choice among the apolar solvents tested (entries 7–9).
ed by Cinchona alkaloids proceeded best in this As expected polar and polar protic media were detri-
medium. Significantly different reactivities were dis- mental for the asymmetric induction (entries 10 and
11). Quinine could be conveniently employed at
10 mol% loading at higher dilution (entry 12). In-
creasing the dilution further and working at À188C
enabled the formation of the product in good yield
and 92% ee (entry 13).
Table 1. Michael addition of malononitrile to trans-chalcone
promoted by Cinchona alkaloids under different
conditions.[a]
With the optimized conditions in hands we ex-
plored the scope and limitations of the quinine-cata-
lysed Michael addition of malononitrile to a variety
of enones (Table 2).
trans-Chalcones bearing electron-donating or elec-
tron-withdrowing groups at both the aromatic rings
and sterically more demanding naphthyl or heteroaro-
matic groups were well tolerated (entries 1–13) They
were smoothy transformend into the final adducts in
excellent yield and high enantioselectivity ( ꢀ 90%
ee). Interestingly, trans,trans-1,5-diphenylpentane-2,4-
dien-1-one 2o regioselectively afforded the 1,4-addi-
tion product in 89% ee (entry 14).
Enones bearing b-alkyl substituents proved to be
slightly less reactive and the level of enantioselectivity
was influenced by the steric hindrance of the R
moiety (entries 15–17). The most sterically demanding
cyclohexyl derivative was obtained in 95% ee
(entry 17). Finally, trans-4-phenyl-3-butenone reacted
sluggishly affording a racemic product (entry 18). This
methodology can be considered complementary to
the employment of 9-amino-9-deoxyepiquinidine/TFA
system,[9] since enones bearing R1 as an alkyl group
led to the products with up to 97% ee, whereas chal-
cones gave inferior results likely ascribed to their
poor reactivity toward the generation of iminium ion
intermediates.[16]
Entry
Catalyst
[mol%]
Solvent
t
Yield
[%][b]
ee
G
[h]
[%][c]
1
2
3
4
5
6
7
8
CD [20]
CN [20]
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
m-xylene
CH2Cl2
CH3CN
CH3OH
toluene
toluene
16
20
16
16
20
18
18
19
18
21
19
20
18
80
40
97
98
80
80
98
98
94
90
98
98
74
44 (S)
43 (R)
63 (R)
82 (S)
60 (R)
79 (S)
81 (S)
81 (S)
62 (S)
15 (S)
rac
QD [20]
QN [20]
DHQD [20]
DHQN [20]
QN [20]
QN [20]
QN [20]
QN [20]
QN [20]
QN [10]
QN [10]
9
10
11
12[d]
13[e]
86
92
[a]
Reaction conditions: 1a (0.2 mmol)/2 (0.24 mmol)/catalyst
(0.04 mmol) in 0.4 mL of solvent.
Isolated yields after flash chromatography.
Determined by chiral HPLC. Absolute configuration de-
termined by comparison with optical rotation in the liter-
ature.[7a]
Reaction performed at c=0.2M with respect to 1a.
Reaction performed at À188C and at c=0.1M with re-
spect to 1a.
[b]
[c]
[d]
[e]
The quinine-catalysed Michael addition of malono-
nitrile could be successfully scaled up to 5 mmol of
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Table 2. Asymmetric Michael addition of malononitrile to
enones promoted by quinine.[a]
Entry R1
R
3
t
Yield ee
[h] [%][b] [%][c]
1
2
3
4
5
5
6
Ph
3-MeC6H4
4-MeOC6H4 Ph
4-BrC6H4
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
Ph
Ph
Ph
Ph
Ph
Ph
3a 60 99
3b 68 99
3c 111 87
3d 90 90
3e 92 93
3f 90 95
3g 86 98
3h 68 99
92
91
90
94
90
91
92
94
90
91
91
91
90
90
89
74
88
95
rac
Ph
Ph
4-MeC6H4
4-ClC6H4
2-ClC6H4
2-naphthyl
4-MeOC6H4 3j 136 95
4-CNC6H4
4-CF3C6H4
4-MeOC6H4 3m 140 96
3-furyl 3n 139 89
CH=CHPh 3o 186 74
Me
ACHTUNGTRENNUNG
cyclohexyl
Ph
7
8[d]
9
3i
134 88
10
11
12[d]
13
14[d]
15
16
17[d]
3k 64 98
3l 70 88
3p 90 71
3q 130 96
3r 115 98
3s 120 28
Figure 2. Postulated transition state for the quinine-cata-
lysed Michael addition of malononiltrile to trans-chalcone
1a.
Ph
18[d,e] Me
[a]
Reaction conditions: 1a (0.2 mmol)/2 (0.24 mmol)/QN
(0.02 mmol) in 2 mL of solvent.
Isolated yields after flash chromatography.
Determined by chiral HPLC.
Using 20 mol% of QN.
Reaction performed at c=0.5M with respect to 1s.
adduct. This might also justify the drop in the stereo-
control observed in the case of an alkyl ketone,
namely enone 1s, where a less favourable steric inter-
action would arise.
As a synthetic modification of the 1,4-addition
products, we envisioned their transformation to the
corresponding synthetically more versatile esters, via
[b]
[c]
[d]
[e]
compound 1a giving adduct 3a in 98% yield and 93% Baeyer–Villiger oxidation (Scheme 1).
ee. Indeed, the direct conjugate addition of malononi-
A plausible transition state is illustrated in Figure 2. trile to a,b-unsaturated esters is very difficult to
Malononitrile would be deprotonated by the tertiary achieve, given their low reactivity as acceptors. Jacob-
nitrogen of the catalyst and orientated via hydrogen- sen[7b] and Takemoto[7e] reported the transesterifica-
bonding, while the hydroxy group would be engaged tion of enantioenriched Michael adducts of malononi-
in hydrogen-bonding interaction with the oxygen of trile with a,b-unsaturated imides to obtain the corre-
the carbonyl moiety of trans-chalcone 1a.[17] The pref- sponding esters.
erential attack of malononitrile toward the re-face of
Compound 3a was selectively oxidated with
the enone might likely be assisted by a favourable p- mCPBA in ClCH2CH2Cl at 608C to the phenyl ester
1
p stacking interaction between the quinoline residue 4a in 70% conversion as judged by H NMR analy-
of the catalyst and the aromatic moiety linked to car- sis.[18] Transesterification of crude 4a under basic or
bonyl group, which would lead to the S-configured acidic conditions furnished complex mixtures. How-
Scheme 1. Baeyer–Villiger oxidation of ketone 3a.
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ACHTUNGTRENNUNG
In conclusion, we have developed an efficient and
highly enantioselective Michael addition of malononi-
trile to enones catalysed by commercially available
and low cost quinine. The adducts were obtained in
excellent yields and high enantioselectivity. An origi-
nal approach based on the selective oxidation of the
1,4-addition products, under Baeyer–Villiger condi-
tions, enabled the formation of ester derivatives.
Experimental Section
General Procedure for the Michael Addition of
Malononitrile to Enones
Enone 1 (0.2 mmol) and quinine (0.02 mmol, 6.5 mg) were
dissolved in anhydrous toluene (2 mL). Malononitrile 2
(0.24 mmol, 16 mg) was added and the reaction mixture was
stirred at À188C until completion as monitored by TLC.
The mixture was directly purified by flash chromatography
(petroleum ether/ethyl ether, 90/10 to pure chloroform) to
give the adducts.[20]
Acknowledgements
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MIUR and University of Salerno are acknowledged for finan-
cial support. Dr. P. Iannece is thanked for mass spectra anal-
yses.
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the product in 20% yield and 21% ee. This experiment
clearly shows the relevant role of the secondary OH
group in the catalysis.
[18] Compound 4a proved to be difficult to isolate by classi-
cal chromatographic methods as it showed similar TLC
mobility with respect to unreacted 3a.
[19] The transesterification process was not optimised.
[20] Characterisation data of all new compounds 3 are re-
ported in the Supporting Information.
[17] The reaction of 1a and 2 at room temperature in the
presence of O-acetylquinine (20 mol%) gave after 24 h
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