Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

Article abstract of DOI:10.3762/bjoc.8.165

The organocatalytic Michael addition of malonates to symmetric unsaturated 1,4-diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C-C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and calculated VCD spectra of the reaction product 3a.

Full text of DOI:10.3762/bjoc.8.165

Organocatalytic asymmetric addition of malonates
to unsaturated 1,4-diketones
Sergei Žari, Tiiu Kailas, Marina Kudrjashova, Mario Öeren, Ivar Järving,
Toomas Tamm, Margus Lopp and Tõnis Kanger*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1452–1457.
Department of Chemistry, Tallinn University of Technology,
Akadeemia tee 15, 12618 Tallinn, Estonia
doi:10.3762/bjoc.8.165
Received: 24 May 2012
Email:
Accepted: 06 August 2012
Published: 04 September 2012
Tõnis Kanger* - kanger@chemnet.ee
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
Michael addition; non-covalent catalysis; organocatalysis;
squaramide; thiourea
© 2012 Žari et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The organocatalytic Michael addition of malonates to symmetric unsaturated 1,4-diketones catalyzed by thiourea and squaramide
derivatives with Cinchona alkaloids afforded the formation of a new C–C bond in high yields (up to 98%) and enantiomeric puri-
ties (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and calculated
VCD spectra of the reaction product 3a.
Introduction
The asymmetric 1,4-conjugated addition (Michael reaction) of tion of nitroalkanes to 4-oxo-enoates, using chiral urea deriva-
C-nucleophiles to enones is a powerful tool for obtaining a tives [7]. Miura et al. achieved an asymmetric addition of α,α-
significant variety of enantioenriched products through a disubstituted aldehydes to maleimides catalyzed by primary
carbon–carbon bond formation [1-5]. Recently, unsaturated 1,4- amine thiourea organocatalyst [13]. Wang et al. reported the ad-
dicarbonyl compounds, such as 1,4-ketoesters [6-8], 1,4-di- dition of dialkylmalonates and nitromethane to 4-oxo-4-aryl-
ketones [9], 1,4-ketoamides [9,10] and dialkylfumarates [11], butenoates catalyzed by N,N´-dioxide-Sc(OTf)3 complexes [8].
have been the substrates for this reaction. The reaction products Despite these and other successful experimental results, the
can undergo further chemical transformations, allowing the asymmetric addition of malonates to symmetric aromatic unsat-
possibility of cascade reactions, making the method attractive urated 1,4-diketones has not been systematically studied. Prod-
for the synthesis of several valuable compounds, such as drugs ucts of that reaction can be used as precursors of biologically
and natural products. Tan et al. performed the addition of 1,3- active compounds. Padmaja et al. have reported that racemic
alkylthiomalonates to 1,4-dicarbonylbut-2-enes, catalyzed by heterocyclic compounds derived from the Michael addition of
chiral bicyclic guanidines [7,9,12]. Xiao et al. reported the addi- malonates and malononitrile to unsaturated 1,4-diketones pos-
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Beilstein J. Org. Chem. 2012, 8, 1452–1457.
sess antimicrobial and antifungal properties [14,15]. Therefore, were used for this purpose: Cinchona alkaloids (I–V), thiourea
new asymmetric additions of C-nucleophiles to unsaturated 1,4- derivatives (VI, VII) and squaramide derivatives (VIII, IX)
diketones are highly in demand.
(Figure 2). All of these screened catalysts are bifunctional com-
pounds possessing hydrogen-bonding donor and acceptor
The asymmetric desymmetrization of symmetric unsaturated moieties. Catalysts based on thiourea and squaramide differ
1,4-diketones is a very challenging target. si-Attack on one from each other in their possible hydrogen-bond angles, rigidity
carbon atom of the double bond and re-attack on the other leads of conformation, and pKa values [20]. Although the two
to the same enantiomer. From the synthetic point of view, the squaramide based catalysts VIII and IX are structurally similar,
conjugate addition of the nucleophile is, at the same time, a they have quite different properties. Catalyst IX is a self-associ-
formal umpolung reaction with respect to the other carbonyl ation-free compound [21], while catalyst VIII forms associates,
group (Figure 1).
and the stereoselectivity of the reaction in its presence depends
on the catalyst concentration [22].
The catalysts were screened in the reaction of phenyl disubsti-
tuted unsaturated 1,4-diketone 1a with diethyl malonate (2a,
Table 1). The reaction was run in DCE at room temperature in
the presence of 10 mol % of catalyst with a five-fold excess of
malonate. In all cases, the yields of the products were very high.
Cinchona alkaloids (Table 1, entries 1–4) catalyzed the reac-
tion with low stereoselectivity. There was a remarkable differ-
ence in their reaction rates. Quinine (II) and quinidine (IV,
Table 1, entries 2 and 4) were more efficient than cinchonine (I)
and cinchonidine (III, Table 1, entries 1 and 3). The reduction
of the vinyl group in quinine afforded dihydroquinine V. Unfor-
Figure 1: The conjugated addition to unsaturated 1,4-diketone 1.
Results and Discussion
Catalyst screening
As a part of our ongoing studies in organocatalysis [16-19] we tunately, no changes in the stereoselectivity of the model reac-
investigated the organocatalytic approach to the asymmetric tion were observed (Table 1, entry 5). Both thiourea catalysts
desymmetrization of the title compounds with malonates. Three derived from Cinchona alkaloids (VI, VII) gave high yields
types of organocatalysts providing noncovalent interactions with good selectivities (Table 1, entries 6 and 7). Squaramide
Figure 2: Organocatalysts screened.
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Beilstein J. Org. Chem. 2012, 8, 1452–1457.
Table 1: Screening of the catalysts for the asymmetric conjugated-addition reaction.
entry
catalyst
time (h)
yielda (%)
eeb (%)
abs. conf.c
1
2
3
4
5
6
7
8
9
I
II
120
28
97
98
13
27
10
19
18
74
74
60
39
R
R
R
S
R
S
R
R
R
III
168
24
88
IV
V
>98
>98
>98
98
20
VI
VII
VIII
IX
24
19
15
96
96
96
aIsolated yield; bdetermined by chiral HPLC; cdetermined by a comparison of the experimental and calculated VCD spectra (see the following).
VIII and C2-symmetric squaramide IX gave good yields but with squaramide catalyst IX. Almost equally high ee values
slightly lower selectivities (Table 1, entries 8 and 9). The cata- were obtained with methyl, phenyl or benzyl malonates
lyst VII was selected for further studies as being the most effi- (Table 2, entries 4, 10 and 12). A possible reason for the high
cient. Also, considering the partially aromatic character of the selectivity with the phenyl-ring-containing esters could be the
cyclobutenedione system, which may possibly allow additional aromatic nature of the squaramide functional group in catalyst
interactions with the aromatic substrates 1, the catalyst IX was IX, allowing additional π–π-interactions.
also chosen.
The properties of the enone double bond of the substrate depend
Scope of the reaction
on the nature of the substituents in the phenyl ring. Therefore,
Next, we studied the effect of the malonate structure on the the electronic effect of the para-substituent of unsaturated 1,4-
stereoselectivity of the reaction (Table 2). Although, the ester diketone 1 on the reaction was investigated (Table 3). Electron-
moiety can be replaced by other functional groups in the course withdrawing groups, such as bromo and nitro, (Table 3, entries
of further synthetic transformations its main role is to provide 10 and 13) as well as the electron-donating methoxy group
the addition products with high ee value. The conditions for the (Table 3, entry 7) led to an increase in stereoselectivity, but the
reaction remained the same as they were in the catalyst reaction time was also increased and the yields were lower with
screening experiments, except that a smaller excess of malonate catalyst VII. A methyl substituent slightly decreased the
(3 equiv, unless stated otherwise) was used. This did not influ- enantioselectivity (Table 3, entry 4). This means that these
ence the reaction time or the enantioselectivity, but afforded dependencies cannot be clearly rationalized by the use of the
easier purification of the crude product.
electronic effects of the substituents in the phenyl ring. In the
case of squaramide catalyst IX, all of the reactions became
1,4-Diketone 1a reacted smoothly with a variety of malonates sluggish at room temperature (Table 3, entries 5, 8, 11 and 14).
2a–2f, affording the products 3a–3f in high yields and with The reaction times were unreasonably long and the yields
moderate to high stereoselectivities. In the case of the catalyst remained low. However, in the case of reactions with electron-
VII, the increase of steric hindrance of the malonate (Table 2, withdrawing groups, the enantiomeric purity of the products
entries 1, 3, 5 and 7) led to a gradual drop in selectivity. Steri- was higher (Table 3, entries 11 and 14).
cally more demanding malonates with branched alkyl or aryl
groups (2c–e) gave products in much lower enantioselectivity Increasing the temperature had a drastic positive effect on the
(ee 37–69%) than the simple alkyl malonates (2a, b) (ee reactions performed in the presence of catalyst IX. It was found
73–74%). There was no clearly observed similar dependence that by raising the temperature to 80 °C it was possible to
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Beilstein J. Org. Chem. 2012, 8, 1452–1457.
Table 2: Enantioselective addition of malonates 2a-2f to unsaturated 1,4-diketone 1a.
entry
R
catalyst
time (h)
yieldc (%)
eed (%)
1
2
a: Et
a: Et
VII
IX
19
96
15
30
36
96
75
33
3
99
96
92
95
96
96
70
95
44
41
95
92
74
39
73
87
69
60
59
70
37
81
68
84
3
b: Me
b: Me
c: iPr
c: iPr
d: t-Bu
d: t-Bu
e: Ph
e: Ph
f: Bn
VII
IX
4
5
VII
IX
6
7a
8a
9b
10b
11
12
VII
IX
VII
IX
2
VII
IX
6
f: Bn
6
aReaction at 80 °C, malonate/dione 2:1; bmalonate/dione 1:1; cyields of isolated products; ddetermined by chiral HPLC.
Table 3: Enantioselective addition of diethylmalonate 2a to substituted 1,4-diketones 1a, g–j.
entry
R
catalyst
temp. (°C)
time (h)
yieldb (%)
eec (%)
1
2
a: H
a: H
VII
IX
IX
VII
IX
IX
VII
IX
IX
VII
IX
IX
VII
IX
IX
rt
rt
19
96
10
18
213
22
88
48
22
48
123
6
99
97
97
96
25
76
90
—
74
39
82
69
18
66
79
—
3
a: H
80
rt
4
g: Me
g: Me
g: Me
h: MeO
h: MeO
h: MeO
i: Br
5
rt
6
80
rt
7
8
rt
9
80
rt
90
83
20
86
66
44
98
83
81
93
91
81
89
89
10a
11a
12a
13
14
15
i: Br
rt
i: Br
80
rt
j: NO2
j: NO2
j: NO2
54
94
6
rt
80
aDione/malonate 1.2:1; byields of isolated products; cdetermined by chiral HPLC.
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Beilstein J. Org. Chem. 2012, 8, 1452–1457.
significantly decrease the reaction time and increase yields up to
98% with almost no negative effect on the stereoselectivity (ee
66–89%, Table 3, entries 6, 9, 12 and 15). Moreover, the com-
pounds 3a and 3g were obtained in much higher enantio-
selectivities, and the reaction with the unsaturated 1,4-diketone
containing the electron-donating substituent 1h, which did not
react at room temperature, also afforded the product in good
yield and selectivity (Table 3, entry 9). As the squaramide-type
catalyst IX is known to be self-association-free [21], the
increase in enantioselectivity at higher temperatures can be
attributed to the thermodynamic control of the conjugate addi-
tion. At the same time, the increase in temperature resulted in a
small drop in stereoselectivity for the model reaction with cata-
lyst VII.
Figure 3: Proposed transition state.
conformers to verify their stability. The Boltzmann distribution
of the Gibbs energy showed that one conformation out of six is
The mechanism of the reaction is believed to be similar to that dominant (84%). The experimental and calculated IR spectra
previously reported for 1,3-dicarbonyl compounds and acyl match well in the range 1500–1800 cm−1 (both experimental
phosphonates [23]. Squaramide IX is a bifunctional catalyst that and calculated spectra are normalized to 100% by using the
simultaneously coordinates electrophilic unsaturated 1,4-di- highest peak from that range, Figure 4A).
ketone via hydrogen bonding and activates the nucleophilic
malonate via the tertiary amine of the quinuclidine moiety. Due The most characteristic peaks of VCD spectra are in the same
to the symmetry of the substrate, there is no regioselectivity region (Figure 4B). The good agreement between calculated
problem. A face selection is determined by the different access and experimental spectra directly allows for the assignment of
of the nucleophile to the tertiary amino group between the side the absolute configuration of 3a as the R-enantiomer.
chains of the catalysts. The re-face of the Michael acceptor is
shielded by the flat quinoline unit and the si-attack of the Conclusion
malonate is preferred, affording R-selectivity (Figure 3).
We have developed a highly enantioselective method for the
desymmetrization of aromatic unsaturated 1,4-diketones
through organocatalytic reactions with malonates. The reaction
Determination of the absolute configuration
The absolute configuration of the product 3a was determined by is catalyzed by thiourea and squaramide derivatives with
a comparison of the experimental and calculated vibrational Cinchona alkaloids and affords products in very high yields (up
circular dichroism (VCD) spectra. DFT calculations (method to 99%) and in high enantioselectivities (up to 93%). This
B3PW91/6-311G**) of a series of conformers of compound 3a enantioselective 1,4-addition to unsaturated 1,4-diketones
with R-configuration were performed. Calculations of harmonic affords valuable intermediates for further synthetic transforma-
vibrational frequencies were carried out for all favored tions.
Figure 4: Calculated (red) and experimental (blue) IR (A) and VCD spectrum (B) of compound (R)-3a.
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Beilstein J. Org. Chem. 2012, 8, 1452–1457.
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Acknowledgements
The authors thank the Estonian Science Foundation (Grants No.
8289, 8255), the Ministry of Education and Research (Grant
No. SF0140060s12), and the EU European Regional Develop-
ment Fund (3.2.0101.08-0017) for financial support and COST
Action CM0905 (ORCA, Organocatalysis).
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