Quinine-catalysed double Michael addition of malononitrile to 1,5-disubstituted pentadien-3-ones: A stereoselective route to cyclohexanones

Article abstract of DOI:10.1002/ejoc.201100282

The stereoselective synthesis of 4-oxo-2,6-diaryl-cyclohexane-1,1- dicarbonitriles has been developed through double Michael addition of malononitrile to 1,5-disubstituted pentadien-3-ones catalysed by quinine. This simple cascade process affords cyclohex

Full text of DOI:10.1002/ejoc.201100282

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100282
Quinine-Catalysed Double Michael Addition of Malononitrile to
1,5-Disubstituted Pentadien-3-ones: A Stereoselective Route to Cyclohexanones
Claudia De Fusco[a] and Alessandra Lattanzi*[a]
Keywords: Organocatalysis / Alkaloids / Michael addition / Cascade reactions / Diastereoselectivity / Enantioselectivity
The stereoselective synthesis of 4-oxo-2,6-diaryl-cyclohex-
ane-1,1-dicarbonitriles has been developed through double
Michael addition of malononitrile to 1,5-disubstituted pen-
tadien-3-ones catalysed by quinine. This simple cascade pro-
cess affords cyclohexanones in moderate-to-good yields, ex-
cellent diastereoselectivity and up to 86% ee. The isolation
of the monoaddition product helps to shed light on the
stereochemical outcome of the two-step process.
tigated (Scheme 1). We envisaged that quinine could stereo-
selectively promote a double conjugate addition to directly
afford cyclohexanones.
Introduction
The employment of organic promoters in cascade pro-
cesses is a fast growing and highly appealing field in asym-
metric synthesis.[1] Complex molecular structures are selec-
tively constructed in a stereocontrolled fashion by using
simple reagents in a single operation, thus successfully ad-
dressing efficiency and economic concerns.[2] Carbon–car-
bon and carbon–heteroatom bonds are consecutively
formed to afford multifunctionalised cyclic derivatives with
different stereocentres. In the young area of organocascade
processes, covalent catalysis, through iminium–enamine and
enamine–iminium formation, has been the highly preferred
activation strategy that uses secondary and primary amines
as promoters.[3] On the other hand, relatively few examples
of cascade processes have been reported that exploit nonco-
valent catalysis. Successful examples include the use of chi-
ral phosphoric acids[4] or bifunctional promoters, such as
cinchona-based and Takemoto-type thioureas.[5]
Organocatalytic Michael addition reactions that combine
several carbon and heteroatom-based nucleophiles with
common acceptors such as enals, enones and nitro alkenes
have received a lot of attention in the past years.[6] In this
context, malononitrile was scarcely explored as a donor for
this process in comparison to malonate esters, nitro alkanes
and 1,3-dicarbonyl compounds.[7] We recently reported that
quinine promotes the highly enantioselective conjugate ad-
dition of malononitrile to chalcones.[8] On these grounds
and by considering the clear advantages associated with the
development of a process that uses low-cost and easily avail-
able catalysts and reagents, the Michael addition of ma-
lononitrile to 1,5-disubstituted pentadien-3-ones was inves-
Scheme 1. Double Michael addition of malononitrile to 1,5-disub-
stituted pentadien-3-ones catalysed by quinine.
Interestingly, from a literature survey, we disclosed that
cyclic 1,3-dicarbonyl compounds were used as donors by
Wynberg in a pioneering study of double conjugate ad-
dition with compounds 1 catalysed by quinine.[9] The corre-
sponding cyclohexanone spiranes were obtained in moder-
ate yield (Ͻ50%) as a mixture of trans/cis isomers (trans/cis
Ն 2:1), and an optical yield of 30% was determined for the
trans isomer in a specific case.[10] While this manuscript was
in preparation, a similar approach starting from com-
pounds 1 and malononitrile was reported by Yan and co-
authors.[11] Covalent catalysis through iminium ion genera-
tion, provided by 9-amino-9-deoxyepiquinine and trifluoro-
acetic acid as co-catalyst, proved to be a viable route for
the stereoselective synthesis of products 2.
Herein, we illustrate a double Michael addition process
of malononitrile to trans-1,5-disubstituted pentadien-3-ones
promoted by quinine, which proceeds with excellent dia-
stereoselectivity and good enantiocontrol.
Results and Discussion
[a] Dipartimento di Chimica e Biologia, Università di Salerno,
via Ponte don Melillo, 84084 Fisciano, Italy
Fax: +39-089-969603
For the optimisation study, trans,trans-dibenzylidene-
acetone 1a was used as a model compound with toluene as
solvent and cinchona alkaloids or their derivatives as cata-
E-mail: lattanzi@unisa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100282.
3728
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3728–3731

A Stereoselective Route to Cyclohexanones
lysts (Table 1). When quinine was used, the trans isomer quinine-derived and quinidine-derived thioureas (eQNT
2[12] was formed in 44% yield, with a good diastereoselec- and eQDT, respectively) were also screened as promoters
tive ratio and 65% ee (Entry 1). The reaction carried out for this process (Entries 8 and 9). They proved to be less
by using stoichiometric amounts of quinine under more di- effective than natural cinchona alkaloids QN and QD, al-
luted conditions afforded compound 2a in 43% yield and though a good level of stereoselectivity was observed. The
72% ee (Entry 2).
monoaddition product 4a was isolated as the prevalent
compound, whereas trans-cyclohexanone 2a was obtained
in low amounts. The poor activity shown by cinchona-de-
rived thioureas was found to be in agreement with findings
previously reported in the enantioselective Michael addition
of malononitrile to trans-chalcones promoted by these cata-
lysts.[7b]
Table 1. Double conjugate addition of malononitrile to compound
1a with cinchona-based catalysts (R1 = R2 = Ph).[a]
By taking into account the results illustrated in Table 1,
quinine was chosen as the most effective catalyst for further
studies of the cascade process; the solvent effect was briefly
investigated (Table 2). Although in chlorobenzene a faster
conversion to the product was observt lower temperatures
(Entries 1 and 2). m-Xylene gave a comparable result to
toluene (Entry 3), whereas halogenated and ethereal sol-
vents afforded inferior results (Entries 4 and 5). Toluene
was confirmed to be the best medium in which to perform
the reaction. Pleasingly, working at higher dilution gave es-
sentially the exclusive formation of the trans isomer 2a in
satisfactory yield and with 86% ee (Entry 6). Slightly in-
ferior results were achieved when working under more con-
centrated conditions at lower temperature and when using
20 mol-% of catalyst loading (Entries 7 and 8).
Entry Catalyst
C
[m]
t
[h]
2a/3a[b] Yield 2a (4a) ee 2a (4a)
[%][c]
[%][d]
1
2[e]
3[f]
QN
QN
QN
0.2
0.1
0.1
0.04
0.04
0.04
0.04
0.04
0.04
87
42
48
66
52
54
71
66
66
9:1
2:1
5:1
44
43
48
65
72
77
4[g]
5[g,h]
6[g]
7[g]
8[g]
9[g]
QN
10:1
24:1
30:1
–
70
61
17 (46)
– (37)
Ͻ5 (76)
15 (57)
79
–51
80 (52)
– (45)
n.d.[i] (86)
–86 (–76)
QD
CD
Table 2. Optimisation study for the double conjugate addition of
CPD
eQNT
eQDT
malononitrile to compound 1a with quinine at room temperature.[a]
n.d.[i]
Ͼ30:1
Entry
Solvent
t [h] 2a/3a[b] Yield 2a [%][c]
ee 2a [%][d]
[a] Reaction conditions: 1a (0.1 mmol), malononitrile (0.12 mmol),
quinine (0.03 mmol). [b] Determined by 1H NMR analysis. [c]
Yield of isolated product; yield of 4a in parenthesis. [d] Determined
by chiral HPLC analysis; ee of 4a in parenthesis. [e] 1 equiv. quinine
was used. [f] 0.05 mmol malononitrile was used. [g] 0.1 mmol ma-
lononitrile was used. [h] Negative ee indicates the formation of the
opposite enantiomer. [i] Not determined.
1
2[e]
3
ClC6H5
ClC6H5
m-xylene
CHCl3
THF
toluene
toluene
toluene
36
47
70
67
67
103
91
74
14:1
Ͼ30:1
20:1
18:1
n.d.
Ͼ50:1
Ͼ30:1
Ͼ30:1
66
61
66
50
Ͻ5
55
54
56
72
76
80
62
n.d.
86
4
5
6[f]
7[g]
8[h]
83
80
In both cases the starting material was almost consumed,
and the formation of a coloured solid was also observed.
The unidentified mixture of side products could derive from
intermolecular Michael addition reactions to afford oligo-
mers. Indeed, when 0.5 equiv. malononitrile was used the
yield and the enantioselectivity of compound 2a signifi-
cantly improved (Entry 3). In order to favour the cyclisation
of the firstly formed Michael adduct, the reaction mixture
was further diluted with 1a/malononitrile in a 1:1 ratio (En-
try 4). We were pleased to observe the formation of trans-
cyclohexanone 2a in 70% yield and 79% ee. Under these
conditions, quinidine afforded the opposite enantiomer of
trans-2a in higher diastereocontrol, although a significantly
lower ee was observed (Entry 5). As expected, cinchonidine
proved to be a less active, although selective, catalyst for
the reaction, as trans-cyclohexanone 2a was obtained in
17% yield and 80% ee (Entry 6). Moreover, the monoaddi-
tion adduct 4a was isolated in 46% yield. In the presence
of cupreidine (CPD), the adduct 4a was exclusively formed
[a] Reaction conditions: 1a (0.1 mmol), malononitrile (0.1 mmol),
quinine (0.03 mmol) in 2.5 mL solvent. [b] Determined by 1H
NMR analysis. [c] Yield of isolated product. [d] Determined by
chiral HPLC analysis. [e] Reaction performed at –18 °C. [f] C =
0.02 m. [g] Reaction performed at 4 °C. [h] 20 mol-% of catalyst was
used.
In order to shed some light on the stereochemical out-
come of the entire process, the reaction performed under
conditions reported in Entry 4 of Table 1 was quenched af-
ter 20 h. In addition to compound trans-2a, the adduct 4a
was isolated in 69% ee (Scheme 2).
in modest yield and enantioselectivity (Entry 7). Finally, Scheme 2. Monitoring of the double Michael addition over time.
Eur. J. Org. Chem. 2011, 3728–3731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3729

C. De Fusco, A. Lattanzi
SHORT COMMUNICATION
According to our previous findings on the quinine-pro- Table 3. Stereoselective double conjugate addition of malononitrile
to compounds 1 catalysed by quinine.[a]
moted Michael addition of malononitrile to trans-chalc-
ones, the first adduct 4a should be S configured.[8] An am-
plification of the enantiomeric excess of compound 2a was
observed, which is expected on the basis of Horeau’s prin-
ciple.[13] After 48 h, trans-2a was isolated in 60% yield and
with 81% ee, whereas adduct 4a was nearly consumed.
Moreover, compound 3a was detected, although in very low
amount. Unreacted 1a was still present in the crude reac-
tion mixture in both experiments. On the basis of the data
illustrated in Scheme 2, it appears that the course of the
second Michael addition reaction, to give the cyclised prod-
uct 2a, is also influenced by the chiral non-racemic adduct
4a. If the opposite were true, according to Horeau’s prin-
ciple, compound 2a would be expected to achieve 92% ee
and cis-3a product would be formed in about a 25% yield
at full conversion. Racemic 4a was then reacted under the
same reaction conditions (Scheme 3). After 15 h, unreacted
4a was isolated in 11% ee and product 2a in 13% ee. A
poorly effective process of kinetic resolution occurs during
cyclisation, which indicates that this step is also subjected
to substrate control, although to a minor extent.[14]
Entry
R1, R2
Donor
Yield 2 ee 2 [%][c]
[%][b]
(2/3[d]
)
1
2
3
4
5
6
7
8[e]
9
Ph, Ph (a)
4-MeC6H4, 4-MeC6H4 (b)
4-CF3C6H4, 4-CF3C6H4 (c)
4-MeC6H4, Ph (d)
4-MeOC6H4, Ph (e)
4-ClC6H4, Ph (f)
2-thienyl, Ph (g)
NCCH2CN
NCCH2CN
NCCH2CN
NCCH2CN
NCCH2CN
NCCH2CN
NCCH2CN
NCCH2CN
CH2(CO2Me)2
CH3NO2
55
54
62
68
48
53
32
47
–
86 (Ͼ50:1)
85 (Ͼ50:1)
83 (19:1)
82 (Ͼ30:1)
85 (Ͼ40:1)
80 (Ͼ40:1)
86 (Ͼ40:1)
80 (16:1)
–
2-thienyl, Ph (g)
Ph, Ph (h)
Ph, Ph (i)
10
–
–
[a] Reaction conditions: 1a (0.1 mmol), malononitrile (0.1 mmol),
quinine (0.03 mmol) in 5 mL solvent. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis. [d] Determined by 1H
NMR analysis. [e] Reaction quenched after a longer reaction time.
Scheme 4. Stereoselective quinine-catalysed double Michael ad-
dition of ethyl cyanoacetate to 1a.
Scheme 3. Kinetic resolution of the monoadduct 4a in the second
conjugate addition.
Cyclic compounds of this type have recently been ob-
tained in high diastereo- and enantioselectivity by Mel-
chiorre and co-authors by using 9-amino(9-deoxy)-epi-hy-
droquinine and 2-fluoro benzoic acid as co-catalyst in a
Michael–Michael cascade process that combines enamine–
iminium activation of enones.[15]
The double Michael addition, illustrated in Scheme 4,
proceeded with an excellent control of the diastereoselectiv-
ity, and trans-cyclohexanone 5a was isolated in high yield
and 60% ee.
The absolute configuration of compound 5a was deter-
mined to be (2R,6R) by comparing HPLC retention times
and optical rotation values with those previously re-
ported.[15] This result confirms that the stereochemical out-
come of the first conjugate addition on compounds 1, to
give adducts 4, is consistent with our previous findings.[8,16]
On the basis of all the experimental findings, the organo-
catalyst seems to predominantly control the stereoselec-
tivity of the cascade process.
The scope of the double Michael addition was next inves-
tigated by reacting symmetrically- and unsymmetrically
substituted dienones 1 with malononitrile (Table 3).
Symmetrically substituted trans products 2 were ob-
tained in high-to-excellent diastereoselectivity and up to
86% ee (Entries 1–3). Unsymmetrically aryl-substituted di-
enones with electron-donating and electron-withdrawing
groups were also suitable substrates for the process and af-
forded the trans isomer 2 in satisfactory yield, with excellent
diastereocontrol and good ee (Entries 4–6). The heteroaro-
matic derivative 1g furnished compound trans-2g in modest
yield, with excellent diastereoselectivity and fairly good en-
antiomeric excess (Entry 7). An improvement in the yield
for trans-2g could be obtained after a prolonged reaction
time, although with a slightly decreased level of diastereo-
and enantiocontrol (Entry 8). Dimethyl malonate and nitro-
methane were also checked as donors, but they did not react
(Entries 9 and 10).
Conclusions
In conclusion, we developed a simple organocatalytic
cascade process to trans-4-oxo-2,6-diaryl-cyclohexane-1,1-
By assuming adducts 4 to be S configured, the absolute dicarbonitriles by double Michael addition of malononitrile
configuration of the major enantiomer of compounds trans- to 1,5-disubstituted pentadien-3-ones by using low-cost and
2 should be 2R,6R. In order to confirm this hypothesis, easily available quinine as the catalyst. The trans-cyclohexa-
model compound 1a was treated with ethyl cyanoacetate in nones have been isolated in moderate-to-good yield, with
the presence of quinine (Scheme 4).
excellent diastereocontrol and good enantioselectivity. In
3730
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3728–3731

A Stereoselective Route to Cyclohexanones
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Experimental Section
General Procedure for the Double Michael Addition of Malononitrile
to Compounds 1: A solution of 1 (0.1 mmol), malononitrile (6.6 mg,
0.1 mmol) and quinine (9.7 mg, 0.03 mmol) in toluene (5 mL) was
stirred at room temperature until the pentadien-3-one was con-
sumed as monitored by TLC (petroleum ether/diethyl ether, 60:40).
The crude reaction mixture was directly purified by flash
chromatography on silica gel eluting with petroleum ether and mix-
tures of petroleum ether/diethyl ether (90:10 to 70:30) to afford
cyclohexanones 2.[17]
Supporting Information (see footnote on the first page of this arti-
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1
acterisation data, HPLC traces, H and 13C NMR spectra for new
compounds are presented.
Acknowledgments
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is thanked for the MS analyses.
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Supporting Information.
Received: February 28, 2011
Published Online: April 26, 2011
Eur. J. Org. Chem. 2011, 3728–3731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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