An access to α, β-unsaturated ketones via dual cooperative catalysis

Article abstract of DOI:10.1016/j.tetlet.2018.11.065

A dual cooperative organocatalytic approach for the synthesis of α, β-unsaturated ketones is described. This one pot transformation is realized via a domino Knoevenagel-Michael-retro Michael reaction sequence. Various aliphatic ketones reacted smoothly with aromatic as well as aliphatic aldehydes in presence catalytic amount of Meldrum's acid and bifunctional amine. The highlights of this protocol are the easy availability of catalysts, high selectivity, and functional group tolerance. The reaction proved to highly E-selective with no side products emanating from self-condensation, unlike the base-mediated reactions.

Full text of DOI:10.1016/j.tetlet.2018.11.065

Accepted Manuscript
An Access to α, β-Unsaturated Ketones via Dual Cooperative Catalysis
Lakshmi V.R. Babu Syamala, Tushar M. Khopade, Prakash K. Warghude,
Ramakrishna G. Bhat
PII:
S0040-4039(18)31412-6
https://doi.org/10.1016/j.tetlet.2018.11.065
TETL 50450
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 October 2018
23 November 2018
24 November 2018
Please cite this article as: Syamala, L.V.R., Khopade, T.M., Warghude, P.K., Bhat, R.G., An Access to α, β-
Unsaturated Ketones via Dual Cooperative Catalysis, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.11.065
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1
Graphical Abstract
An Access to α, β-Unsaturated Ketones via
Dual Cooperative Catalysis
Leave this area blank for abstract info.
Lakshmi V. R. Babu Syamala, Tushar M. Khopade, Prakash K. Warghude and Ramakrishna G. Bhat*
O
O
O
O
(30 mol %)
O
O
N
NH2
R
R
R1
(10 mol %)
R1CHO
EtOAc, 55 °C, 24 h
Dual cooperative catalysis
A domino Knoevenagel-Michael-retro Michael reaction sequence
One pot practical and easy access to -unsaturated ketones
High E-selectivity and regioselectivity
Total of 23 substrates

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An Access to α, β-Unsaturated Ketones via Dual Cooperative Catalysis
Lakshmi V. R. Babu Syamala, Tushar M. Khopade, Prakash K. Warghude and Ramakrishna G. Bhat*
Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, Maharashtra,
India; E-mail: rgb@iiserpune.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A dual cooperative organocatalytic approach for the synthesis of α, β-unsaturated ketones is
described. This one pot transformation is realized via a domino Knoevenagel-Michael-retro
Michael reaction sequence. Various aliphatic ketones reacted smoothly with aromatic as well as
aliphatic aldehydes in presence catalytic amount of Meldrum’s acid and bifunctional amine. The
highlights of this protocol are the easy availability of catalysts, high selectivity, and functional
group tolerance. The reaction proved to highly E-selective with no side products emanating from
self condensation unlike the base mediated reactions.
Available online
Keywords:
Meldrum’s acid
Knoevenagel condensation
Retro-Michael reaction
Unsaturated ketones
Dual cooperative catalysis
2009 Elsevier Ltd. All rights reserved.
α, β-Unsaturated carbonyl compounds and their derivatives
are very important building blocks in organic synthesis.1,2 These
α, β-unsaturated ketone derivatives are key intermediates in
several fields of organic synthesis,1 biochemistry,3 food
chemistry and in agrochemicals.4 However, these are widely used
especially as the starting materials in synthetic transformations
such as conjugate addition,1,6 oxidation,7 epoxidation,8
peroxidation,9 hydrogenation,10,11 cycloaddition,2 Morita-Baylis-
Hillman reaction,12 Diels-Alder Reaction,13 cyclopropanation.14
Traditionally, these compounds are synthesized by Claisen-
Schmidt condensation15 using aldehydes and ketones catalyzed
by strong bases such as NaOH, KOH and Ca(OH)2 frequently
used in stoichiometric amounts. However, the use of strong bases
limits the scope of the reaction, as they produce a complex
mixture of self-condensed side products and formation of large
amounts of corrosive solid waste during work-up, and these
methods have severe drawbacks with especially base-sensitive
functional groups. In spite of these drawbacks, Claisen-Schmidt
condensation is one of most common methods to prepare α, β-
unsaturated ketone derivatives. The other widely used methods
such as Wittig, Horner-Wadsworth-Emmons,16 Peterson
olefination,17 require strong bases to initiate the reaction and also
they generate a stoichiometric amount of phosphorous and
silicon containing by-products. Owing to the importance α, β-
unsaturated ketone derivatives several other methods including
organometallic transformations have been developed.18-26
We commenced our study by choosing acetone 1a and
benzaldehyde 2a as model substrates to optimize the reaction
conditions. Initially we screened different catalysts and co-
catalysts to optimize the reaction conditions. Catalysts such as L-
proline, pyrrolidine, N,N-dimethylethylene diamine (DMEDA)
were screened at room temperature with and without the presence
of any co-catalyst. However, the reactions in presence of
catalysts such as L-proline, pyrrolidine, N,N-dimethylethylene
diamine (DMEDA) did not work even after prolonged reaction
time (48 h, Table 1, entries 1-3). Interestingly, the addition of
Meldrum’s Acid (MA) 4 as a co-catalyst (10 mol %, 48 h)
facilitated the formation of desired unsaturated ketone 3a in
modest yields (Table 1, entries 4-6). The attempt to increase the
yield of 3a by elevating the reaction temperature led to the
decomposition of Meldrum’s acid 4 (Table 1, entry 7). Later,
Meldrum’s acid 4 (30 mol %) was added in two portions under
refluxing condition to afford the desired product 3a in 55% yield.
In order to minimize the decomposition of the Meldrum’s acid
and to increase the yield of the desired product 3a, we planned to
optimize the reaction temperature.
To our delight, when the reaction was carried out at 55 °C for
24 h, we observed the formation of benzylidene acetone 3a in
80% yield (Table 1, entry 8). We also observed that co-catalyst
alone could not catalyze the desired reaction independently even
after prolonged reaction time (Table 1, entry 9). The reaction in
the presence of DMEDA as a catalyst and N, N-1,3-dimethyl
barbituric acid 6 (DMBA, 10 mol % co-catalyst) at 55 °C
afforded the desired product 3a in 70% yield (Table 1, entry 10).
We observed that prolonging the reaction time (36 h) and
increase in the catalyst loading (DMBA, 30 mol %) did not have
any significant effect on the yield and rate of the reaction (Table
1, entry 11).
In spite of many methods available in the literature, it is very
desirable and challenging to develop more efficient practical
protocol which affords the desired unsaturated ketones in good
yields without forming any competing side products. Herein, we
wish to report a dual cooperative organocatalytic approach for the
synthesis of α, β-unsaturated ketones via aldol condensation of
acetone with various aromatic and aliphatic aldehydes.
TfouhstrMiaphcoeuidfrnsyashvterolpidthapr6mycaheBdopmieohebrtwu-oaitslabohfctriaeabitneyolgenl-/4.ndreuMdao

2
the neat reaction condition, however, it afforded the product 3a in
moderate yield (52% yield, Table 2, entry 10). Considering the
environmental impact, we preferred the use of EtOAc over
CHCl3 for evaluating the substrate scope. Based on the
exhaustive screening DMEDA 5 (10 mol %) and Meldrum’s acid
Table 1: Screening of catalysts and co-catalysts for optimizing
the reaction conditionsa
CHO
O
Catalyst (10 mol %)
O
co-catalyst (10-30 mol %)
o
4 (30 mol%) in ethyl acetate at 55 C proved to be the optimum
reaction condition.
+
EtOAc, temp (°C), time (h)
1a
2a
3a
(5 equiv.)
(1 equiv.)
Table 2: Screening of solventsa
O
O
O
N
N
N
NH2
O
O
O
O
O
O
4
5
6
O
O
Meldrum's Acid
(MA)
N,N-dimethylethylene diamine N, N-1,3-dimethyl barbituric acid
4
(30 mol %)
N
(DMEDA)
(DMBA)
CHO
O
NH2
O
5
(10 mol %)
Temp
Time
Yield
(%)c
solvent, 55 °C, 24 h
1a
2a
3a
Entry
Catalyst
Co-catalyst
(°C)
(h)
1
2
L-Proline
-
-
rt
rt
48
NR
Entry
Solvent
Time (h)
48
Yield (%)b
Pyrrolidine
48
48
48
48
Trace
1
2
3
4
5
6
7
8
9
10
DCM
CHCl3
Toluene
EtOAc
ACN
72
82
48
3
4
5
DMEDA
Pyrrolidine
L-Proline
-
rt
rt
rt
Trace
15
48
75
MA (0.1)
MA (0.1)
24
80
10
48
73
6
7
DMEDA
DMEDA
DMEDA
-
MA (0.1)
MA (0.3)b
MA (0.3)b
MA (0.3)b
DMBA (0.1)
rt
Reflux
55
48
48
24
48
24
20
55
THF
48
78
MeOH
DMF
48
45
8
80
48
Trace
Trace
52
9
55
NR
70
DMSO
Neat
48
10
DMEDA
55
48
11
12
13
DMEDA
L-Proline
Pyrrolidine
DMBA (0.3)b
MA (0.3)b
55
55
55
36
36
36
76
37
42
aReaction of aldehyde 2a (4 mmol, 1equiv.), acetone 1a (20 mmol, 5 equiv.),
catalyst 5 (DMEDA) (10 mol %) and co-catalyst 4 (MA) (30 mol %, added in
two portions-15 mol% initially at rt and the remaining 15 mol% after 12 h,) in
various solvents. bIsolated yield of the product, purified by column
chromatography, reaction progress was monitored by TLC.
MA (0.3)b
aReaction of aldehyde 2a (4 mmol, 1 equiv.), acetone 1a (20 mmol, 5 equiv.),
catalysts (10 mol %) and co-catalysts (10-30 mol %) in ethyl acetate as
solvent. b30 mol% of Meldrum’s acid was added in two portions-15 mol%
Having the optimized reaction condition in hand, we decided
to explore the scope of the reaction using different aromatic and
aliphatic aldehydes as substrates under the optimized reaction
conditions (Table 3). It was observed that the aromatic aldehydes
with electronically activated as well deactivated groups reacted
satisfactorily under the reaction conditions to afford the
corresponding desired products (3b-3n) in good to very good
yields with excellent E-selectivity (Table 3).
c
initially at rt and the remaining 15 mol% after 12 h, Isolated yield of the
product, purified by column chromatography, reaction progress was
monitored by TLC.
Further, the reaction in presence of L-proline/pyrrolidine as a
catalyst along with Meldrum’s acid 4 (30 mol % as co-catalyst)
at 55 °C afforded the desired product 3a in moderate yields
(Table 1, entries 12, 13).
In order to evaluate the effect of solvents on the outcome of the
reaction, further we carried out a series of reactions in presence
of optimized catalyst 5 (DMEDA, 10 mol %) and co-catalyst 4
(MA, 10-30 mol %) in different solvents at 55 °C. The reactions
in DCM and CHCl3 afforded the corresponding desired product
3a in 72% and 82% yields respectively (Table 2, entries 1-2).
The reaction in toluene afforded the desired product 3a in 75%
yield (Table 2, entry 3). Among the polar solvents EtOAc proved
to be the optimum solvent by affording 3a in 80% yield (Table 2,
entries 4-7). While the solvents such as DMF and DMSO proved
to be disadvantageous by affording a trace amount of product
(Table 2, entries 8-9). Even though, the reaction worked under
Further, in order to widen the substrate scope, we explored the
reaction of heteroaromatic aldehyde:furfural and aliphatic
aldehydes under the reaction conditions to afford the
corresponding α, β-unsaturated ketones (3o, 3p-3r) respectively
in moderate to good yields (Table 3). Later, we explored the
protocol using few unsymmetrical and cyclic ketones with
different aromatic aldehydes. Ethyl methyl ketone 1b and 2-
octanone 1c reacted with p-anisaldehyde under the optimized
reaction conditions to afford the corresponding α, β-unsaturated
ketones 3s and 3t in good yields (see Table 3). It is very
important to note that the reaction occurred at the less substituted
side of the ketones 1b, 1c (via unhindered less substituted

3
enamine) to furnish the corresponding α, β-unsaturated ketones
3s and 3t exclusively. Even the cyclic ketone such
cylcohexanone 1d reacted sluggishly with benzaldehyde to afford
the corresponding product 3u in modest yield. Further, we
extended the scope of the protocol by treating the active
methylene compound such as methyl acetoacetate 1e with p-
tolualdehyde and p-anisaldehyde to give the corresponding
desired products 3v and 3w respectively in good yields (see
Table 3). However, the attempted reaction of acetophenone with
benzaldehyde under the optimum reaction condition was
unsuccessful.
O
Me
N
R1
O
Me
NH
O
O
A
B
Catalyst
5
O
-H2O
-H2O
1a
O
O
H
N
Me
O
O
N
O
Me
O
+
Catalyst
Me
N
R1
H
R1
5
2
O
H2N
(Catalyst
Me
+H2O
5
)
O
O
4
O
H
O
O
O
O
R1
R1
desired product
The protocol proved to be practical as different aromatic and
aliphatic aldehydes reacted smoothly with symmetrical as well as
unsymmetrical ketones to furnish the desired products. The
electron rich aldehydes proved to be more efficient than the
electron deficient aldehydes by affording the desired products in
relatively higher yields. It is also significant to note that we did
not observe any side product emanating from the self
condensation of aliphatic aldehyde unlike the base mediated
condensation.
3
O
C
retro-Michael
reaction
Scheme 1: Plausible mechanism for organocatalytic domino
reaction sequence
In summary, we have developed a practical dual cooperative
organocatalytic approach for the synthesis of α, β-unsaturated
ketones via
a domino Knoevenagel-Michael-retro Michael
Table 3: Substrate scope of the reactiona
reaction sequence. The easily and commercially available less
expensive catalysts, high selectivity, and functional group
tolerance are the highlights of this methodology.
O
O
O
O
4 (30 mol %)
Acknowledgments
O
O
N
NH2
R
R
R1
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for the generous research grant. Authors also thank Indian
Institute of Science Education and Research (IISER), Pune for
the financial support. L.V. R. B. S. and P. K. W. thank UGC,
New Delhi and T. M. K. thanks CSIR-New Delhi for the
fellowship.
5 (10 mol %)
R1CHO
EtOAc, 55 °C, 24 h
3
2
1
1a = R = H
1b = R = Me
1c = R = Pentyl
1d = Cyclohexanone, R = H
1e = R = CO2Me
O
O
O
O
O
F
Cl
Br
Supplementary Material
3e
(82%, E/Z >99:1)
3d
3a
3b
3c
(77%, E/Z >99:1)
(80%, E/Z >99:1)
(82%, E/Z >99:1)
(80%, E/Z >99:1)
Experimental details, 1H, 13C NMR spectra of compounds 3a-3w
O
O
O
O
O
are available in the supporting information.
MeO
NO2
Cl
Br
F
3j
3i
3f
3g
3h
References and notes
(80%, E/Z >99:1)
(65%, E/Z >99:1)
(72%, E/Z 94:6)
(73%, E/Z 93:7)
(77%, E/Z 93:7)
O
O
O
O
MeO
O
O
2N
1.
2.
3.
4.
5.
Perlmutter P. Conjugate addition reactions in organic synthesis;
Elsevier, 2013; Vol. 9.
Carruthers W. Cycloaddition reactions in organic synthesis;
Elsevier, 2013; Vol. 8.
Hadi T, Dahl U, Mayer C, Tanner ME. Biochemistry-US
2008;47:11547.
Ogawa M, Ishii Y, Nakano T, Irifune S. Jpn. Kohai Tokkyo JP
1988;6323 A2.
O
NC
OMe
3k
3l
3n
3o
3m
(69%, E/Z >99:1)
(84%, E/Z 95:5)
(68%, E/Z >99:1)
(69%, E/Z >99:1)
(62%, E/Z >99:1)
O
O
O
O
O
C5H11
BocHN
MeO
OMe
MeO
3t
3p
3q
3r
3s
(60%, E/Z >99:1)
(52%, E/Z >99:1)
(60%, E/Z >99:1)
(58%, E/Z >99:1)
(62%, E/Z 93:7)
O
O
O
O
Taylor MS, Zalatan, DN, Lerchner AM, Jacobsen EN. J Am Chem
Soc. 2005;127:1313.
O
OMe
Ph
6.
7.
Gandelman M, Jacobsen EN. Angew Chem Int Ed. 2005;44:2393.
Yu L, Wu YL, Cao HE, Zhang X, Shi XK, Luan J, Chen T, Pan Y,
Xu Q. Green Chem. 2014;16:287.
MeO
3u
3v
3w
(77%, E/Z 55:45)
(46%, E/Z >99:1)
(75%, E/Z 53:47)
8.
9.
Xia QH,Ge HQ, Ye CP, Liu ZM, Su KX. Chem Rev.
2005;105:1603.
Lu XJ, Liu Y, Sun BF, Cindric B, Deng L. J Am Chem Soc.
2008;130:8134.
aReaction of aldehyde 2a (4 mmol, 1equiv.), ketone 1 (20 mmol, 5 equiv.),
catalyst 5 (DMEDA) (10 mol %) and co-catalyst 4 (30 mol %, added in two
portions-15 mol% initially at rt and the remaining 15 mol% after 12 h,) in
EtOAc.
10. Martin NJA, List B. J Am Chem Soc. 2006;128:13368.
11. Lu W-J, Chen Y-W, Hou X-L. Angew Chem Int Ed.
2008;47:10133.
12. Basavaiah D, Rao AJ, Satyanarayana T. Chem Rev. 2003;103:811.
13. Boger DL,Weinreb SM. Hetero Diels-Alder methodology in
organic synthesis; Elsevier, 2012; Vol. 47.
14. Aggarwal VK, Smith HW, Hynd G, Jones RVH, Fieldhouse R,
Spey SE. J Chem Soc, Perkin Trans. 1 2000;3267.
15. Qiu RH, Qiu YM, Yin SF, Xu XH, Luo SL, Au CT, Wong WY,
Shimada S. Adv Synth Catal. 2010;352:153.
16. Edmonds M, Abell A. In Modern Carbonyl Olefination; Wiley-
VCH, Weinheim, 2004.
Based on the earlier literature findings,27 we propose that the
catalyst-Meldrum’s acid 4 reacts with benzaldehyde 2a to give
the corresponding Knoevenagel adduct A. Simultaneously,
acetone 1a reacts with catalyst-DMEDA 5 to form enamine B.
Further, enamine B undergoes conjugate addition with the
Knoevenagel adduct A to afford an intermediate C.28 This
intermediate undergoes retro-Michael reaction to afford the
desired benzylidene acetone 3a29 thus regenerating catalyst 4. We
believe that the reaction follows dual cooperative catalysis as two
different catalysts activate the electrophile as well as nucleophile
in the reaction cycle (Scheme 1).
17. Kano N, Kawashima T. Modern Carbonyl Olefination 2004;18.
18. Chatterjee AK, Toste FD, Choi T-L, Grubbs RH. Adv Synth Catal.
2002;344:634.

4
29. General Procedure for the synthesis of unsaturated carbonyl
compounds (3): To a stirred solution of benzaldehyde 2 (4 mmol,
19. Dheur J, Sauthier M, Castanet Y, Mortreux A. Adv Synth Catal.
2007;349:2499.
20. Botella L, Najera C. Tetrahedron Lett. 2004;45:1833.
21. Wang YF, Gao YR, Mao S, Zhang YL, Guo DD, Yan ZL, Guo
SH, Wang YQ. Org Lett. 2014;16:1610.
22. Bethi V, Fernandes RA. J Org Chem. 2016;81:8577.
23. Cordova A. Tetrahedron Lett. 2004;45:3949.
24. Qian H, Liu DB, Lv CX. Ind Eng Chem Res. 2011;50:1146.
25. Mori K, Oshiba M, Hara T, Mizugaki T, Ebitani K, Kaneda K.
New J Chem. 2006;30:44.
1 equiv.), acetone 1 (20 mmol, 5 equiv.) and N, N-
dimethylethylenediamine (DMEDA) 5 (0.4 mmol, 10 mol%) in
EtOAc (5 mL) was added Meldrum’s Acid 4 (1.2 mmol, 30 mol%
in two portions, 15 mol% initially at rt and the remaining 15 mol%
o
after 12 h). Then the reaction mixture was warmed to 55 C and
stirred for 24 h. After completion of reaction (as monitored by
TLC), volatiles were evaporated and the residue was purified by
silica gel column chromatography using EtOAc/petroleum ether
(5-15:95-85) as an eluent to afford the α,β-unsaturated ketones (3).
26. Narender T, Reddy KP. Tetrahedron Lett. 2007;48:3177.
27. Khopade, T. M., Mete, T. B., Arora, J. S., Bhat, R. G. Chem. Eur.
J. 2018; 24: 6036.
28. Based on the time depended 1H-NMR studies we observed that
reaction proceeds via the formation intermediate C (see Appendix-
I, ESI)
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Highlights
.
.
Dual cooperative catalysis
A domino Knoevenagel-Michael-retro Michael
reaction sequence
.
One pot practical and easy access to -
unsaturated ketones
.
.
Very high E-selectivity and regioselectivity
Total of 23 examples