Acyl/aroyl Meldrum's acid as an enol surrogate for the direct organocatalytic synthesis of α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2018.12.013

The operationally simple, robust and straightforward organocatalytic protocol is developed for the synthesis of E-selective α,β-unsaturated ketones. The method utilizes simple and easily accessible starting materials such as Meldrum's acid, carboxylic acid, aldehyde and simple bifunctional amine catalyst. The tandem organocatalytic process utilizes acyl/aroyl Meldrum's acid as an enol surrogate for the effective Doebner-Knoevenagel type condensation reactions. A wide variety of aldehydes, carboxylic acids and base sensitive functional groups are well tolerated under the mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2018.12.013

Accepted Manuscript
Acyl/aroyl Meldrum’s acid as an enol surrogate for the direct organocatalytic
synthesis of α,β-unsaturated ketones
Tushar M. Khopade, Prakash K. Warghude, Trimbak B. Mete, Ramakrishna G.
Bhat
PII:
S0040-4039(18)31445-X
https://doi.org/10.1016/j.tetlet.2018.12.013
TETL 50476
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 October 2018
30 November 2018
4 December 2018
Please cite this article as: Khopade, T.M., Warghude, P.K., Mete, T.B., Bhat, R.G., Acyl/aroyl Meldrum’s acid as
an enol surrogate for the direct organocatalytic synthesis of α,β-unsaturated ketones, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.12.013
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2
Graphical Abstract
Acyl/aroyl Meldrum’s acid as an enol
Leave this area blank for abstract info.
surrogate for the direct organocatalytic
synthesis of α,β-unsaturated ketones
Tushar M. Khopade, Prakash K. Warghude, Trimbak B. Mete and Ramakrishna G. Bhat*

1
Tetrahedron Letters
Acyl/aroyl Meldrum’s acid as an enol surrogate for the direct organocatalytic
synthesis of α,β-unsaturated ketones
Tushar M. Khopade, Prakash K. Warghude, Trimbak B. Mete and Ramakrishna G. Bhat*
Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune, 411008, Maharashtra, India, rgb@iiserpune.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Operationally simple, robust and straightforward organocatalytic protocol is developed for the
synthesis of E-selective α,β-unsaturated ketones. The method utilizes simple and easily accessible
starting materials such as Meldrum’s acid, carboxylic acid, aldehyde and simple bifunctional
amine catalyst. The tandem organocatalytic process utilizes acyl/aroyl Meldrum’s acid as an enol
surrogate for the effective Doebner-Knoevenagel type condensation reactions. A wide variety of
aldehydes, carboxylic acids and base sensitive functional groups are well tolerated under the mild
reaction conditions.
Available online
Keywords:
Acyl/aroyl Meldrum’s acid
Doebner-Knoevenagel condensation
Enol surrogate
2009 Elsevier Ltd. All rights reserved.
Organocatalysis
α,β-Unsaturated carbonyl compounds
Introduction
Likewise, carbonyl olefination has been explored for the synthesis
α,β-unsaturated carbonyl compounds are frequently used as
starting materials in various transformations in organic synthesis.
The vinylogy due to the vinylogous carbonyl functional group
makes them chemically different from their constituent analogues
such as simple carbonyl compounds and olefins. Many of the
stereoselective chemical transformations make use of α,β-
unsaturated carbonyl scaffolds to construct a diverse array of
organic compounds.1
of α,β-unsaturated ketones in presence of catalytic amount of AgI,7
8
and BF3. The basic anion-exchange resins were employed to
catalyze aldol condensations to afford α,β-unsaturated ketones
starting from ketones and aldehydes.9 Many other approaches
utilized metal reagents and catalysts to access α,β-unsaturated
carbonyl compounds.10
Evidently, a plenty of methods are available in the literature for
the synthesis of α,β-unsaturated carbonyl compounds owing to
their importance. Most frequently used methods include Wittig
reaction2 and Horner–Wadsworth–Emmons reaction.3 Even
though, these methods are routinely used, however, they produce
a
stoichiometric amount of by-products such as
triphenylphosphine oxide and other phosphine salts, and generate
a lot of waste during the process. Notably, α,β-unsaturated
carbonyl compounds have also been synthesized starting from
active methylene compounds such as malonic acid half ester,4a β-
keto acid4d and trifluoroacetate derivatives4b via Doebner-
Knoevenagel type reactions, and organocatalytic aldol
condensation4c (Scheme 1).4 Although, various methods are
available in the literature, some of these methods either suffer due
to limited substrate scope or use of a stoichiometric amount of
base. Other synthetic protocols include synthesis of chalcones by
various approaches. Some of the methods utilize strong base,
Lewis acid such as TiCl4 to promote aldol condensation of
ketones5 and IBX oxidation of ketones to afford α,β-unsaturated
ketones.6
 Dr. Ramakrishna G. Bhat; Tel.: +91-20-25908092; fax: + 91-20-
25898022; e-mail: rgb@iiserpune.ac.in
Scheme 1 Methods for the synthesis of α,β-unsaturated ketones

2
Nevertheless, operationally simple, practical and straightforward
organocatalytic strategy which is devoid of transition metals and
that utilizes easily available or less expensive substrates and
organocatalyst for the synthesis of α,β-unsaturated compounds is
highly desirable.
and benzoyl Meldrum’s acid 4a (1.5 equiv.) in the presence of β-
alanine as a catalyst (20 mol%) in toluene-water (5:1) biphasic
solvent system at room temperature (water was added to hydrolyze
4a). However, under this reaction condition a trace amount of
product 5a was formed (Table 1, entry 5). We also observed that
the compound 4a slowly underwent hydrolysis followed by
decarboxylation to afford acetophenone 4a’ in almost quantitative
yields under the reaction conditions.
Earlier, we have explored the reactivity of alkylidene Meldrum’s
acid4g in the synthesis α,β-unsaturated carboxylic acids, esters and
thioesters.4e,4f As an ongoing research programme, we have been
focusing on the novel use of Meldrum’s acid in organocatalytic
synthesis. It is known that acyl/aroyl Meldrum’s acids 4 undergo
a slow hydrolysis to afford relatively less stable and reactive β-
keto acids 6 (Fig 1). This intrinsic reactivity of acyl/aroyl
Meldrum’s acid 4 has a great potential to be explored in organic
synthesis for the construction of useful compounds. We presumed
that acyl/aroyl Meldrum’s acids 4 can potentially act as a key
reagent or as an enol 7 for the novel synthesis of α,β-unsaturated
carbonyl compounds. The tendency of acyl/aroyl Meldrum’s
acids 4 to deliver a reactive enol 7 in situ via slow and controlled
sequential hydrolysis followed by decarboxylation can be
utilized in constructing α,β-unsaturated carbonyl scaffold. This
reactivity of 4 as an enol surrogate can be successfully explored
to avoid the use of relatively less stable beta-keto acids and half
esters as precursors for generating enol in a stepwise manner
(Fig. 1).4a,4d
Table 1 Optimization of reaction conditionsa-d
5a
Yieldc
Temp
Entry
4a
Catalystb
Solvente
E:Zd
(C)
(%)
4a’
4a’
4a’
4a’
4a’
1
2
β-alanine
Pyrrolidine
DMEDA
DMEDA
β-alanine
β-alanine
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
β-alanine
Toluene
Toluene
Toluene
Toluene
Toluene-H2O
Toluene-H2O
Toluene
CH2Cl2
rt
-
-
-
rt
-
3
rt
Trace
Trace
Trace
52
-
4
60
rt
-
5
-
6
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
60
60
60
60
60
60
60
60
60
60
55
55
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
7
55
8
53
9
CHCl3
52
Fig. 1 Acyl/aroyl Meldrum’s acid as an enol surrogate
10
11
12
13
14
15
16
17
ACN
62
We believed that acyl/aroyl Meldrum’s acids 4 can act as
operationally robust and synthetically simple starting materials
and they could be effectively employed in the synthesis of α,β-
unsaturated carbonyl compounds. In order to validate our
hypothesis, initially we planned to study the reactivity of
acetophenone 4a’ as a reactive equivalent of benzoyl Meldrum’s
acid 4a towards organocatalytic aldol condensation. As
acetophenone 4a’ is a simple, commercially available ketone, we
planned to utilize it in order to compare the reactivity with that
of benzoyl Meldrum’s acid 4a (see, Table 1). To begin with, we
EtOAc
66
THF
62
DMF
15
DMSO
15
H2O
34
THF-H2O
THF-H2O
82
73
performed
a
reaction between acetophenone 4a’ and
synthetically useful aldehyde such as N-Boc β-alaninal 2a11 in the
presence of catalytic amount of β-alanine (20 mol%) in toluene at
room temperature (Table 1). As anticipated, the reaction did not
afford the desired α,β-unsaturated ketone 5a even after stirring the
reaction mixture for a prolonged reaction time (48 h, see Table 1,
entry 1). Similarly, pyrrolidine and bifunctional catalyst such as
N,N-dimethylethylenediamine (DMEDA) and β-alanine proved to
be not beneficial (Table 1, entries 2-5). These results clearly
indicated that probably aromatic ketones are less reactive towards
the amine catalysts for the desired transformation. After initial
experiments, we turned our attention towards the active methine
species such as benzoyl Meldrum’s acid 4a for the desired
transformation. In order to execute the proposed reaction, the
benzoyl Meldrum’s acid 4a was freshly prepared by coupling
Meldrum’s acid 1 with benzoic acid 3a in the presence of coupling
reagent DCC (1.4 equiv.) and DMAP (2.0 equiv.) as a base in
DCM (see ESI). As benzoyl Meldrum’s acid 4a is known to
decompose slowly over a period of time, it was utilized for the
subsequent reaction without any purification. Initially, a model
reaction was carried out between aldehyde 2a (N-Boc β-alaninal)
a
Reaction conditions: Benzoyl Meldrum’s acid 4a was freshly prepared by
coupling Meldrum’s acid 1 (1.0 equiv.) with benzoic acid 3a (1.0 equiv.) by
using coupling reagent DCC (1.4 equiv.) and DMAP (2.0 equiv.) as a base.
Freshly prepared 4a was used immediately without any purification as it is
known to hydrolyze with the time. Aldehyde 2a (1 equiv.), acetophenone/acyl
Meldrum’s acid 4 (1.5 equiv.), were treated in the presence of 20 mol% of
catalyst for 24 h, breactions were stirred for 48 h, cisolated yield after
purification by column chromatography, dE/Z ratio determined by H NMR
spectroscopy.e 5:1 ratio was used for the THF-Water and Toluene-Water
1
solvent system.
Gratifyingly, a moderate amount of desired product 5a was
isolated with an excellent E-selectivity (E/Z >99:1) when the
reaction was carried out at 60 oC for 24 h (Table 1, entry 6). Later,
we switched towards basic bifunctional diamine catalyst DMEDA.
The reaction in the presence of DMEDA afforded the desired
product 5a with a marginal increase in the yield with an excellent
E-selectivity (E/Z >99:1, Table 1, entry 7). From the initial
experiments, N,N-dimethylethylenediamine (DMEDA) found to

3
be a suitable catalyst. Further, various solvents were screened for
the optimization of reaction conditions in terms of improving the
yield of product 5a (Table 1, entries 8-15). It was observed that the
solvents such as CH2Cl2, CHCl3, acetonitrile, ethyl acetate and
THF did not enhance the yield of product 5a (Table 1, entries 8-
12). While, the polar solvents such as DMSO, DMF and H2O
found to be disadvantageous for the desired transformation (Table
1, entries 13-15). Interestingly, THF-water (5:1) solvent system
emerged as most useful for the optimum results by providing the
desired product 5a in 85% yield with an excellent E-selectivity
(E/Z >99:1) at 55 oC (Table 1, entry 16). Further the reaction of 4a
and 2a in presence of β-alanine as a catalyst afforded the desired
product in relatively lower yield than DMEDA as a catalyst (Table
1, entry 17). After exhaustive screening benzoyl Meldrum’s acid
4a (1.5 equiv.) and DMEDA (20 mol%) in THF-water (5:1)
reaction conditions well and we did not observe any premature
deprotection. Further, the reactivity of benzoyl Meldrum’s acid 4a
with various aromatic and heteroaromatic aldehydes (2g-2k) was
explored under the optimized reaction conditions to afford the
corresponding α,β-unsaturated ketones (5g-5k) in good yields with
excellent E-selectivity (65-69% yields, E/Z >99:1). The
substituents containing both electron-withdrawing and -donating
groups tolerated the reaction conditions and did not have any
significant effect on the yields and rate of the reaction.
In order to make this protocol more practical and general, we
planned to explore various tricarbonyl derivatives of Meldrum’s
acid including ester and formyl analogues (4b-4j) for the synthesis
of different α,β-unsaturated compounds (see Table 3). Various
acyl/aroyl Meldrum acids (4b-4i) were synthesized (see ESI) and
were treated with the different aldehydes under optimum reaction
conditions. The corresponding α,β-unsaturated ketones (5k-5v)
were isolated in moderate to good yields with exclusive E-
selectivity (52-84%, E/Z >99:1, Table 3).
o
solvent system at 55 C emerged as optimum reaction conditions
(Table 1, entry 16).
Having obtained the optimum reaction conditions in hand,
further, we planned to investigate the substrate scope for the
synthesis of different α,β-unsaturated ketones 5 by using different
aldehydes 2 and benzoyl Meldrum’s acid 4a. The reactions of
simple aliphatic aldehydes (2b-2d) under optimum reactions
afforded the corresponding α,β-unsaturated ketones (5b-5d) as
single E-isomers exclusively in moderate to good yields (58-64%,
see Table 2). Probably, lower boiling points of aliphatic aldehydes
(2b, 2c) might have resulted in the corresponding desired products
(5b and 5c) in moderate yields. Similarly, the aliphatic aldehyde
such as glycinal 2e derived from glycine was successfully utilized
in the synthesis of the corresponding E-isomer of α,β-unsaturated
ketone 5e in good yield (69%). The reaction of Fmoc-protected
aldehyde 2f derived from β-alanine under optimum reaction
conditions afforded the corresponding α,β-unsaturated ketone 5f
in good yield with an excellent E-selectivity (75%, E/Z >99:1,
Table 2).
Having synthesized α,β-unsaturated ketones, we turned our
attention to synthesize α,β-unsaturated aldehydes and esters by
using this protocol. Under optimized reaction conditions the
aldehyde analogue of Meldrum’s acid 4j12 afforded the
corresponding α,β-unsaturated aldehydes (5w-5x) in poor yields,
however, with excellent E-selectivity (8-10% yield, E/Z >99:1).
On the other hand, the corresponding ester analogue of Meldrum’s
acid 4k upon treatment with benzaldehyde 2a gave only a trace
amount of corresponding α,β-unsaturated ester.
Table 3 Substrate scopea-d
Table 2 Substrate scopea,b
Reaction conditions: Unless otherwise noted, acyl/aroyl Meldrum’s acid (4b-
4i) were freshly prepared by coupling reaction of Meldrum’s acid 1 (1 equiv.)
with corresponding carboxylic acids 3, DCC (1.4 equiv.) as coupling reagent,
DMAP (2 equiv.) as a base in DCM at room temperature for 12 h followed by
workup with 1 M HCl. aAldehyde analogue 4j was prepared by the reaction of
triethyl formate and Meldrum’s acid 1 followed by treatment with 1 M HCl,
bester analogue 4k was prepared by the treatment of benzyl chloroformate with
Meldrum’s acid 1 in DCM at rt. Then aldehyde 2 (1 equiv.), 4 (1.5 equiv.),
Reaction conditions: Unless otherwise noted, benzoyl Meldrum’s acid 4a
was freshly prepared by coupling reaction of Meldrum’s (1 equiv.) acid with
benzoic acid 3a, DCC (1.4 equiv.) as coupling reagent, DMAP (2 equiv.) as a
base in DCM at room temperature for 12 h followed by workup with 1 M HCl.
Then aldehyde 2 (1 equiv.), benzoyl Meldrum’s acid 5a (1.5 equiv.), DMEDA
DMEDA (20 mol%) in THF/H2O (5:1) at 55 C
for 12 h, cisolated yield after
(20 mol%) in THF/H2O (5:1) at 55 C
for 12 h, aisolated yield after purification
purification by column chromatography, dE/Z ratio are >99:1 for all the
by column chromatography, bE/Z ratio are >99:1 for all the products, cβ-alanine
products.
(20 mo%) was used as a catalyst.
The method proved to be very simple and practical and afforded
the corresponding α,β-unsaturated ketones/aldehydes in very high
selectivity. We explored the novel utility of acyl/aroyl Meldrum’s
It is very important to note that highly base sensitive protecting
group such as Fmoc (Fluorenylmethyloxycarbonyl) tolerated the

4
acid as enol equivalents for the construction of α,β-unsaturated
carbonyl scaffold. Unlike the previous procedures, this protocol
proved to catalytic13 and practical.14 It is very interesting to note
that acetone generated in situ as a by-product did not compete with
4 to generate the corresponding aldol condensation products. We
believe that this is probably due to the high reactivity of enol
generating from enol surrogate 4.
Similarly, mild reaction conditions tolerated acid and base
sensitive protecting groups.
Acknowledgments
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for the generous research grant. T. M. K. and T. B. M. thank CSIR,
New Delhi for the fellowship. P. K. W. thanks UGC, New Delhi
for the fellowship. Authors also thank IISER Pune for the
financial assistance.
In order to have a wider and novel application of the protocol,
further, benzoyl Meldrum’s acid 4a was treated with 2-hydroxy
pyrrolidine 2y (eq. 1, Scheme 2) under optimum reaction
conditions. The reaction worked satisfactorily and afforded the
corresponding heterocyclic compound 5y, an important precursor
of many indolizidine alkaloids in modest yield (45%, eq. 1,
Scheme 2).15 It is interesting to note that the tandem aldol
condensation/intra-aza-Michael addition happened in one pot to
give the corresponding heterocyclic derivative 5y. Later, the
compound 5a was synthesized on a gram scale and method proved
to be practical and scalable (eq. 2, Scheme 2). We observed that
the selectivity remained excellent (E/Z >99:1) even on a larger
scale.
Supplementary data
Supplementary data (experimental details and 1H, 13C NMR
spectra of compounds 5a–5y) associated with this article can be
found, in the online version.
References and notes
1. (a) X. Jiang, R. Wang Chem. Rev. 113 (2013) 5515; (b) P.
Melchiorre Angew. Chem., Int. Ed. 51 (2012) 9748; (c) K.C.
Nicolaou, S.A. Snyder, T. Montagnon, G. Vassilikogiannakis
Angew. Chem., Int. Ed. 41 (2002) 1668; (d) H. Pellissier Adv.
Synth. Catal. 354 (2012) 237; (e) L.F. Tietze, G. Brasche, K.
Gericke Domino reactions in organic synthesis; John Wiley &
Sons, 2006.
Scheme 2 Application and gram scale synthesis
Based on the earlier literature findings,4d we propose the
2. (a) G. Wittig, W. Haag Chem. Ber. 88 (1955) 1654; (b) G. Wittig,
U. Schöllkopf Chem. Ber. 87 (1954) 1318.
3. W.S. Wadsworth Jr Organic reactions 25 (2004) 73.
4. (a) B. List, A. Doehring, M.T.H. Fonseca, K. Wobser, H. van
Thienen, R.R. Torres, P.L. Galilea Adv. Synth. Catal. 347 (2005)
1558; (b) B. China Raju, P. Suman Chem. Eur. J. 16 (2010)
11840; (c) K. Zumbansen, A. Döhring, B. List Adv. Synth. Catal.
352 (2010) 1135; (d) E. Balducci, E. Attolino, M. Taddei Eur. J.
Org. Chem. 2011 (2011) 311; (e) A.R. Mohite, R.G. Bhat Org.
Lett. 15 (2013) 4564; (f) A.R. Mohite, T.B. Mete, R.G. Bhat
Tetrahedron Lett. 58 (2017) 770; (g) A.M. Dumas, E. Fillion Acc.
Chem. Res.43 (2010) 440.
stepwise reaction sequence for the decarboxylative aldol
condensation reaction (Scheme 3). Initially, acyl/aroyl Meldrum’s
acid 4 undergoes slow hydrolysis and subsequent decarboxylation
to furnish β-keto acid intermediate 6. Further, decarboxylation of
β-keto acid intermediate 6 generates a reactive enol intermediate 7
which further, undergoes primary amine catalyzed aldol
condensation reaction with aldehyde 2 to afford the corresponding
α,β-unsaturated ketones/aldehydes 5.
5. M. Sugiura, Y. Ashikari, M. Nakajima J. Org. Chem. 80 (2015)
8830.
6. M. Shibuya, S. Ito, M. Takahashi, Y. Iwabuchi Org. Lett. 6 (2004)
4303.
7. T. Selvi, K. Srinivasan J. Org. Chem. 79 (2014) 3653.
8. J.U. Rhee, M.J. Krische Org. Lett. 7 (2005) 2493.
9. W. Bonrath, Y. Pressel, J. Schütz, E. Ferfecki, K.-D. Topp
ChemCatChem 8 (2016) 3584.
10. (a) J.K. Augustine, Y.A. Naik, S. Poojari, N. Chowdappa, B.S.
Sherigara, K. Areppa Synthesis 2009 (2009) 2349; (b) T.-L. Choi,
C.W. Lee, A.K. Chatterjee, R.H. Grubbs J. Am. Chem. Soc. 123
(2001) 10417; (c) J.M. Concellón, E. Bardales Org. Lett. 4 (2002)
189; (d) A. Yanagisawa, R. Goudu, T. Arai Org. Lett. 6 (2004)
4281.
11. (a) N.T. Jui, J.A.O. Garber, F.G. Finelli, D.W.C. MacMillan J.
Am. Chem. Soc. 134 (2012) 11400; (b) M. Kitajima, Y. Murakami,
N. Takahashi, Y. Wu, N. Kogure, R.-P. Zhang, H. Takayama Org.
Lett. 16 (2014) 5000; (c) R. van der Westhuyzen, E. Strauss J. Am.
Chem. Soc. 132 (2010) 12853.
Scheme 3 Plausible reaction mechanism
In conclusion, we have developed a facile, practical and mild
protocol for the synthesis of α,β-unsaturated ketones. The process
utilized simple starting materials accessed through one step from
easily and commercially available carboxylic acids and
Meldrum’s acid. This straightforward protocol tolerates a wide
variety of aldehydes and various acyl/aroyl Meldrum’s acid
derivatives. The effective use of acyl/aroyl Meldrum’s acid
derivatives as enol surrogates have been demonstrated
successfully. The method affords α,β-unsaturated ketones in
moderate to good yields with very high E-stereoselectivity.
12. J. Saadi, H. Wennemers Nat. Chem. 8 (2016) 276.
13. In Previous methods reported by China Raju and Taddei groups
relied on the stoichiometric amount of amines (see ref. 4b and 4d)
and proved to be not catalytic.

5
14. In Earlier methods were limited to either only to electron
deactivated (-CF3) active methylene compounds (see ref. 4b) or
aliphatic β-keto acids (see ref. 4d) and β-keto acid had to be
prepared in two steps. While the use of acyl/aroyl Meldrum acid
4, a precursor of β-keto acids in our protocol proved to be practical
as an effective enol surrogate.
15. S. Hanessian, A.K. Chattopadhyay Org. Lett. 16 (2014) 232.
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Highlights
 An easy approach to -unsaturated
ketones
 Acyl/Aroyl Meldrum's acid as enol
surrogate
 Access to precursor of indolizidine alkaloid
 Very high E-selectivity and gram scale
synthesis
 Total of 25 examples