A practical and convenient protocol for the synthesis of (E)-α,β-unsaturated acids

Article abstract of DOI:10.1021/ol402130t

α,β-Unsaturated acids are very useful and versatile reagents in organic synthesis. A novel, practical, and convenient catalytic protocol comprising FeCl₃·6H₂O (0.5 mol %) and H ₂O (1 equiv) in CH₃NO₂ is described for the rapid synthesis of α,β-unsaturated acids with high E-stereoselectivity under both microwave and conventional heating conditions with high TON and TOF values. This powerful approach efficiently demonstrated the utility of biomass derived aldehydes to build chemical agents used as fuel additives. The method proved to be scalable to gram scale synthesis.

Full text of DOI:10.1021/ol402130t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Practical and Convenient Protocol for
the Synthesis of (E)‑r,β-Unsaturated Acids†
Amar R. Mohite and Ramakrishna G. Bhat*
Mendeleev Block, Department of Chemistry, Indian Institute of Science Education &
Research (IISER), Pune, 411008, Maharashtra, India
rgb@iiserpune.ac.in
Received July 27, 2013
ABSTRACT
r,β-Unsaturated acids are very useful and versatile reagents in organic synthesis. A novel, practical, and convenient catalytic protocol com-
prising FeCl3 6H2O (0.5 mol %) and H2O (1 equiv) in CH3NO2 is described for the rapid synthesis of R,β-unsaturated acids with high E-stereoselectivity
under both microwave and conventional heating conditions with high TON and TOF values. This powerful approach efficiently demonstrated the utility of
biomass derived aldehydes to build chemical agents used as fuel additives. The method proved to be scalable to gram scale synthesis.
3
The R,β-unsaturated acids are very important and useful
reagents in organic synthesis. These are significant struc-
tural motifs in many natural products (viz. the secretion of
the queen honey bee,1a,b caffeic acid1c), pheromones,2 and
bioactive compounds.3 Owing to their wide ranging appli-
cations, R,β-unsaturated carboxylic acids are synthesized
on a commercial scale.
preparation of R,β-unsaturated carboxylic acids, but most
often they need severe refluxing conditions and use of
excess base.4 The R,β-unsaturated acids have also been
prepared from dibromoacetic acid and aldehydes with the
aid of an excess amount of SmI2.5 The construction of
carbonÀcarbon double bonds starting from aldehydes
has been achieved via Wittig and HornerÀWadsworthÀ
Emmons reactions.6 However, in both reactions use of a
strong base and the formation of a considerable amount of
organophosphorous byproducts are unavoidable. Most of
these reactions are noncatalytic and less stereoselective. In
some cases eventually esters have been hydrolyzed to
prepare the unsaturated acids.
Indisputably, the DoebnerÀKnoevenagel reaction has
been one of the most extensively used protocols for the
† Dedicated to Prof. K. N. Ganesh on the occasion of his 60th birthday.
(1) (a) Callow, R. K.; Johnston, N. C. Bee World 1960, 41, 152–153.
(b) Brockmann, A.; Dietz, D.; Spaethe, J.; Tautz, J. J. Chem. Ecol. 2006,
32, 657–667. (c) Cho, H.; Ueda, M.; Tamaoka, M.; Hamaguchi, M.;
Aisaka, K.; Kiso, Y.; Inoue, T.; Ogino, R.; Tatsuoka, T.; Ishihara, T.;
Noguchi, T.; Morita, I.; Murota, S. J. Med. Chem. 1991, 34, 1503–1505.
(2) Schilz, S. The Chemistry of Pheromones and other Semiochem-
icals. Topics in Current Chemistry; Springer Verlag: Heidelberg, Berlin,
2004; p 154.
To the best of our knowledge, there is no efficient
catalytic method for the preparation of R,β-unsaturated
acids other than the catalytic method reported by Breit and
(3) (a) Marquardt, U.; Schmid, D.; Jung, G. Synlett 2000, 1131–1132.
(b) Song, J.; Hesse, M. Tetrahedron 1993, 49, 6797–6804. (c) Vanderwal,
C. D.; Jacobsen, E. N. Science of Synthesis;Thieme:Stuttgart, 2006, Vol. 20;
pp 551À565.
ꢀ
ꢀ
(5) Concellon, J. M.; Concellon, C. J. Org. Chem. 2006, 71, 1728–
1731.
(6) For some examples of the Wittig and HWE reaction, see: (a)
Coutrot, P.; Snoussi, M.; Savignac, P. Synthesis 1978, 133–134. (b)
Britelli, D. R. J. Org. Chem. 1981, 46, 2514–2520. (c) Bestmann, H. J.;
Dostalek, R.; Zimmermann, R. Chem. Ber. 1992, 125, 2081–2084. (d)
Sano, S.; Takemoto, Y.; Nagao, Y. ARKIVOC 2003, No. viii, 93–101.
(7) Kemme, S. T.; Smejkal, T.; Breit, B. Adv. Synth. Catal. 2008, 350,
989–994.
(4) (a) Knoevenagel, E. Chem. Ber. 1894, 27, 2345. (b) Doebner, O.
Chem. Ber. 1900, 33, 2140. (c) Kingsbury, C. A.; Max, G. J. Org. Chem.
1978, 43, 3131–3139. (d) Wiley, R. H.; Smith, N. R. Org. Synth. 1953, 33,
62. (e) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Synth.
1979, 59, 1. (f) Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa,
N.; Praveen, V. B. J. Org. Chem. 2007, 72, 9854–9856.
r
10.1021/ol402130t
XXXX American Chemical Society

co-workers.7 Hence there is a demand for an efficient and
rapid catalytic protocol for the stereoselctive synthesis of
R,β-unsaturated acids. Environmentally benign and sus-
tainable catalytic protocols with milder conditions which
can tolerate a wide variety of functionality are highly
desirable. Carrying out the transformations through un-
conventional reagents and catalysts provide a useful and
wider space for selectivity.
Table 1. Reactivity of Catalyst on Decarboxylation
Herein, we report a protocol catalyzed by FeCl3 6H2O
3
T (°C)/
t (h)
Yb MWc
(%) (%)
with the aid of H2O (1 equiv) in CH3NO2 for the synthesis
of R,β-unsaturated acids from the derivatives of cyclic 1,3-
diesters. Moreover this catalytic protocol is very selective
for cyclic 1, 3-diesters over acyclic 1,3-diesters. To the best
of our knowledge methylene tethered Meldrum’s acid
derivatives have not been explored for the synthesis of R,β-
unsaturated carboxylic acids. Earlier literature precedence
reveals that reaction of alkylidene Meldrum’s acids with
phenol derivatives afforded 3-carboxycoumarin deriv-
atives.8,9 Wherein instantaneous decarboxylation was very
tedious due to the presence of a double bond in conjuga-
tion with the carboxylic group. Similarly the reaction of
phloroglucinol with alkylidene Meldrum’s acids under
alkaline conditions gave dihydrocoumarins.10
entry
catalyst (mmol %)
solventa
1
2
CeCl3 7H2O (0.03)
CH3NO2 110/3
CH3NO2 110/3
CH3NO2 110/3
0
0
3
MgSO4 (0.023)
LiBr (0.015)
0
0
5
0
0
6
3
4
FeCl3 6H2O (0.0063) CH3NO2 110/3
3
5
FeCl3 6H2O (0.0063) H2O
100/2
decd decd
3
3
e
6
FeCl3 6H2O (0.0063) CH3NO2 110/45 m 87
86
0
7
FeCl3 6H2O (0.0063) EtOAc
77/2
65/2
82/2
0
0
0
3
8
FeCl3 6H2O (0.0063) MeOH
0
3
3
3
9
FeCl3 6H2O (0.0063) CH3CNe
0
e
10
11
12
FeCl3 6H2O (0.0038) CH3NO2 110/45 m 87
88
39
0
e
B(C6F5)3 (0.0076)
CH3NO2 110/3
39
0
e
CeCl3 7H2O/NaI
CH3NO2 110/3
3
(0.076)
e
13
14
SnCl2 (0.0076)
no catalyst
CH3NO2 110/3
65
0
65
0
These earlier results encouraged us to believe that
alkylidene Meldrum’s acid derivatives would afford the
corresponding R,β-unsaturated carboxylic acids on treat-
ment with an appropriate Lewis acid catalyst and H2O as a
nucleophile.
e
CH3NO2 110/3
a Solvents were used. b Yield of isolated product. c Microwaved for
3À5 min (2.5 GHz, 250 W). d Decomposition. e 1 equiv of H2O used; T,
temperature; t, time in hours (h) or min (m); Y, yield in %; reactions were
carried out using 0.2 g of 1a.
In order to verify this we prepared various methylene
tethered Meldrum’s acid derivatives by condensing differ-
ent aldehydes with Meldrum’s acid (2,2-dimethyl-1,3-
dioxane-4,6-dione) in water following the reported pro-
cedure.11 Having obtained the alkylidene derivatives, we
selected a p-methoxybenzylidene derivative of Meldrum’s
acid (1a) as a model substrate and screened various Lewis
acids as catalysts in order to achieve the efficient catalytic
decarboxylation for a one-pot synthesis of R,β-unsatu-
rated carboxylic acids (Table 1). The reactions were
screened under both conventional heating conditions and
microwave irradiation (2.5 GHz). We observed that under
irradiation (entry 6). Different solvents were also screened
asdescribed in Table 1, and we observed that nitromethane
and water(1 equiv) proved tobeverycrucial tobringabout
the desired transformation.12 Interestingly, when water
alonewasused assolvent the reaction led todecomposition
(entry 5). It is very significant to mention that the reaction
worked very efficiently with 0.0038 mmol (0.005 equiv,
0.5 mol %) of FeCl3 6H2O as the catalyst, under both
3
microwave and heating conditions to afford 2a (TON
17660, TOF 44/min, microwave and TON 17459, TOF
3.9/min, heating) (entry 10).
both conditions FeCl3 6H2O (0.8 mol %) and H2O
3
(1 equiv) in the CH3NO2 catalyst system worked efficiently
in a relatively short time. Heating conditions afforded2a in
87% yield in 45 min (entry 6); however, 2a was obtained in
86% yield in a very short time (4 min) under microwave
Encouraged by this initial success we explored this
catalytic protocol using the FeCl3 6H2O (0.005 equiv)À
3
H2O (1 equiv) in CH3NO2 for synthesizing various R,β-
unsaturated carboxylic acids (2aÀ2k) in good yields
(66À91%) (Scheme 1).
(8) (a) Bandgar, B. P.; Uppalla, L. S.; Kurule, D. S. Green Chem.
1999, 1, 243–245. (b) Song, A.; Wang, W.; Lam, K. S. Tetrahedron Lett.
2003, 44, 1755–1758.
(9) Armstrong, V.; Soto, O.; Valderrama, J. A.; Tapia, R. Synth.
Commun. 1988, 18, 717–725.
(10) (a) Nair, V. Synth. Commun. 1987, 17, 723–727. For an
application of this methodology, see: (b) Kumar, A.; Singh, B. K.;
Tyagi, R.; Jain, S. K.; Sharma, S. K.; Prasad, A. K.; Raj, H. G.; Rastogi,
R. C.; Watterson, A. C.; Parmar, V. S. Bioorg. Med. Chem. 2005, 13,
4300–4305.
(11) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.;
Sartori, G. Tetrahedron Lett. 2001, 42, 5203–5205.
(12) It is very interesting to note that the reactivity of alkylidene
derivatives of Meldrum acid with Lewis acid in CH3NO2 is significantly
different from the result that we observed with a Lewis acid and H2O in
CH3NO2. An excess amount of water leads to a mixture of products.
Please see: Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43, 440–454.
Notably, we observed that (E)-stereoisomers were formed
as major products (>99%) using this protocol; however,
compound 2h was obtained in an E/Z = 87:13 ratio. E-
Stereochemistry of the CdC double bond of R,β-unsatu-
1
rated carboxylic acids was assigned on the basis of H
NMR coupling constants. Moreover, to study the reactiv-
ity of the ketone derived cyclic 1,3-diester toward the cata-
lyst system we prepared the alkylidene derivative (1i) from
the corresponding acetophenone. When subjected to the
optimized reaction conditions using FeCl3 6H2O (0.005
equiv)ÀH2O (1 equiv) in CH3NO2 under microwave
irradiation, the alkylidine Meldrum’s acid derivative (1i)
3
B
Org. Lett., Vol. XX, No. XX, XXXX

There is a huge demand to develop methods that can be
utilized for the conversion of biomass derived molecules
into more useful and renewable products. A practical CÀC
bonding approach to make mildly oxygenated hydrocar-
bons (C8ÀC15) from biomass derived molecules would be
very useful in generating gasoline and diesel fuels.13 Bio-
mass derived molecules such as furfural and 5-hydroxy-
methylfurfural (HMF) have been converted into useful
molecules such as R,β-unsaturated carboxylic acids for
potential use in fuels.14
Scheme 1. Decarboxylation of Methylene Tethered Cyclic 1,3-
Diesters with FeCl3 6H2O and H2O (1 equiv) in CH3NO2
3
To date, there is an emphasis on converting biomass into
useful chemical building blocks that may also be pivotal
to chemical manufacturing. It is known that some of R,
β-unsaturated carboxylic acid derivatives obtained from
biomass derived aldehydes are subsequently converted
into fuel additives in the gasoline range C8ÀC9. Owing to
this importance, we demonstrated the utility of biomass
derived aldehydes such as furfural and 5-methylfurfural
for the efficient preparation of corresponding R,β-unsatu-
rated acids (2j, 2k) in good yields (81À82%, TON 16400,
TOF 40.5/min; 66À76% TON 13200, TOF 26.4/min)
using the optimized protocol under both microwave and
conventional heating. Owing to the industrial importance
of such molecules, the utility of the method is further
demonstrated by synthesizing 2j in gram scale (1.5 g)
starting from 1j using a catalytic protocol under refluxing
conditions (110 °C, 3 h) in a round bottomed flask at
ambient pressure resulting in 2j in 85% yield (TON 85000;
Scheme 2. Chemoselective Decarboxylation of Cyclic
1,3-Diesters with Other Substratesa,b
b
c
a 1 equiv of H2O. CH3NO2 as solvent. Microwave irradiation
(2.5 GHz, 250 W). d We observed more than 99% E-selectivity in (2aÀ2g,
2iÀ2k); however 2h gave an E/Z = 87:13 ratio. e 1i was synthesized using
TiCl4 THF complex, pyridine.
3
furnished the corresponding R,β-unsaturated acid (2i) in
just 3 min in very good yield (91%). To our knowledge this
is the first protocol which effectively demonstrated the
synthesis of R,β-unsaturated carboxylic acids from the
correspondingketones. Furtherwedemonstratedthegram
scale synthesis of 2a (80% yield) starting from 1a (53 g)
using this catalytic protocol under refluxing conditions
(110 °C, 6.5 h) in a round bottomed flask at ambient
pressure.
b
a Substrates were treated in equimolar ratio (1:1). Reactions were
The catalyst system showed good functional group
compatibility, as many functional moieties were tolerated
under these reaction conditions.
carried out using FeCl3 6H2O (0.005 equiv)ÀH2O (1 equiv) in CH3NO2
3
under microwave condition (2.5 GHz) for 3À5 min.
Org. Lett., Vol. XX, No. XX, XXXX
C

TOF 283/h). It is important to note that the catalyst
(FeCl3 6H2O) loading was reduced to 0.1 mol % in this
reaction
Unlike previously reported protocols this one-pot cata-
lytic approach is certainly very convenient, practical, cost-
effective, and environmentally friendly. Moreover, this
method proved to be reproducible on gram scale (1.5À53 g),
as exemplified by the synthesis of compounds (2j, 2a) of
industrial importance.15
In summary, a methodology to achieve R,β-unsaturated
carboxylic acids from derivatives of cyclic 1,3-diesters
(Meldrum’sester) usingahighly efficient catalyticprotocol
3
In order to verify the efficiency of this protocol, we further
embarked on the study of selective decarboxylation of
various substituted cyclic 1,3-diesters with varied substrates.
Competitive experiments were carried out with alkyli-
dine acyclic 1,3-diesters (eq 1), substituted acyclic 1,3-
diesters (eqs 2À4), and an ester (eq 5) under optimized
reaction conditions to demonstrate the selectivity of the
catalyst system for cyclic 1,3-diesters (Scheme 2).
Initially for the competitive experiments we subjected
derivatives of acyclic 1,3-diesters (3a, 3c) and cyclic 1,3-
diesters (1a, 3b) using the optimized catalytic protocol
containing an inexpensive FeCl3 6H2O has been de-
3
scribed. The methodology reported herein is very rapid,
with volatile byproduct formation, and is reliably selective.
This selective decarboxylation route enables a gram-scale
synthesis, using a very low catalyst loading (0.001 equiv).
This simple approach gives easy access to a variety of R,β-
unsaturatedacids ingood toexcellent yields. The approach
opens an avenue for a whole range of new chemical entities
and molecules of high industrial value. It effectively aug-
ments the biomass derived aldehydes into precursors for
fuel additives.
FeCl3 6H2O (0.005 equiv, 0.5 mol %)ÀH2O (1 equiv) in
3
CH3NO2 under microwave irradiation for 3À5 min. It is
quite remarkable that a catalyst system reacted exclusively
with substituted cyclic 1,3-diesters (1a, 3b) and competitive
substrates were significantly unreactive. Unreacted sub-
strates were recovered in almost quantitative yields
(eqs 1À3). Also when compound 3d containing both cyclic
and acyclic 1,3-diester moieties (eq 4) was treated with the
catalyst system, the cyclic 1,3-diester underwent selective
decarboxylation to afford compound 4b in 98% yield
(Scheme 2).
Supporting Information Available. Experimental pro-
cedures and 1H, 13C NMR. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. A.R.M. thanks IISER-Pune for the
fellowship. Financial support from IISER-Pune is grate-
fully acknowledged by authors to carry out this research
work.
(13) (a) Subrahmanyam, A. V.; Thayumanavan, S.; Huber, G. W.
ChemSusChem 2010, 3, 1158–1161. (b) Huang, Y.-B.;Yang, Z.;Dai, J.-J.;
Guo, Q.-X.; Fu, Y. RSC Adv. 2012, 2, 11211–11214.
(14) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411–
2502 and references cited therein.
(15) Provisional Patent filed in India, App No.: 2437/MUM/2013.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX