Synthesis of α,β-Disubstituted Acrylates via Galat Reaction

Article abstract of DOI:10.1021/acs.orglett.9b02291

Galat reactions between aldehydes and substituted malonic acids half oxyester were found to be efficiently catalyzed by morpholine in refluxing toluene. This transformation allows the stereoselective synthesis of diverse α,β-disubstituted acrylates in moderate to good yields. This method constitutes an attractive alternative to existing methods in terms of scope and eco-compatibility.

Full text of DOI:10.1021/acs.orglett.9b02291

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α,β-Disubstituted Acrylates via Galat Reaction
Tania Xavier, Sylvie Condon,* Christophe Pichon, Erwan Le Gall, and Marc Presset*
̀
́
Electrochimie et Synthese Organique, Universite Paris Est, ICMPE, (UMR 7182), CNRS, UPEC, 2-8 rue Henri Dunant, F-94320
Thiais, France
S
* Supporting Information
ABSTRACT: Galat reactions between aldehydes and sub-
stituted malonic acids half oxyester were found to be
efficiently catalyzed by morpholine in refluxing toluene. This
transformation allows the stereoselective synthesis of diverse
α,β-disubstituted acrylates in moderate to good yields. This
method constitutes an attractive alternative to existing
methods in terms of scope and eco-compatibility.
he olefination of aldehydes is one of the most
preparation of acrylamides using β-amido acids.17 Despite its
synthetic potential, the Galat reaction has been more scarcely
used in the case of substituted MAHO. They have been mostly
used in conjunction with formaldehyde or Eschenmoser’s salt
for the synthesis of gem-disubstituted acrylates.18−20 Examples
of trisubstituted olefins obtained through this strategy are even
more rare, as only isolated examples have been reported,21−25
and the only general procedure has been described in the
particular case of 2-amido MAHO and aromatic aldehydes by
Rouden.26,27 Therefore, a general method for the preparation
of trisubstituted acrylates remains highly desirable. Within the
framework of a project pertaining to biomass valorization,28 we
went in search of a useful method for preparing trisubstituted
acrylates. Therefore, we herein report a general procedure for
the olefination of aldehydes by substituted MAHO by means
of a Galat reaction (Scheme 1). This transformation, using
morpholine as a cheap catalyst, is easy to set up and tolerates a
broad range of substrates.
1
Tfundamental reactions in organic synthesis. Indeed, it
allows the preparation of a substituted carbon−carbon double
bond, which is an important motif found in various natural
products and building blocks. While many methods have been
elaborated for the stereoselective synthesis of disubstituted
olefins, the preparation of trisubstituted carbon−carbon
double bonds remains more challenging.2,3 The most common
strategies rely on the use of the Wittig reaction4 or its
derivatives and, to a lesser extent, the Julia reaction.5 Despite
their efficiencies, all of these reactions lead to the formation of
stoichiometric amounts of useless byproducts. Potential
improvements include the development of catalytic Wittig
reactions,6,7 which are based on an in situ reduction of the
phosphane oxide byproduct by stoichiometric amounts of
silane. On the other hand, the use of Knoevenagel-type
reactions is a powerful method for the two-step construction of
substituted acrylate derivatives. Whereas the original Knoeve-
nagel condensation of malonates and aldehydes leads to the
formation of alkylidene malonates under mild conditions,8
acrylate derivatives can be obtained by two means: either by
using the Doebner modification that leads to the synthesis of
acrylic acids through a decarboxylative Knoevenagel reaction9
or by performing a Krapcho reaction that allows a single
decarboxyalkylation but usually under harsh reaction con-
ditions.10 In 1946, Galat reported a useful variation of the
Doebner modification through direct synthesis of substituted
acrylates by piperidine-catalyzed condensation of aldehydes
and malonic acids half oxyester (MAHO) in refluxing
pyridine.11 This reaction constitutes an attractive alternative
to the classical Wittig reaction in terms of eco-compatibility, as
the sole generated byproducts are H2O and CO2. It can also be
considered as an early example of a decarboxylative coupling
reaction.12,13 Improvements of the Galat reaction were
subsequently reported. Rodriguez and Waegell reported its
use in the preparation of 2,4-pentadienoic esters.14 List et al.
described general conditions using DMAP as a catalyst in
DMF for the reaction of unsubstituted MAHO with aliphatic
or aromatic aldehydes.15,16 Very recently, Zacuto described the
We began our study by optimizing the Galat reaction
between p-anisaldehyde 1a and MAHO 2a (Table 1). The use
of classical Knoevenagel conditions (10 mol % piperidine and
10 mol % AcOH) in refluxing toluene for 16 h afforded the
expected olefin 3aa in an encouraging 50% yield (entry 1). The
reaction is very stereoselective (16:1, E:Z) ,and the E isomer
Scheme 1. Knoevenagel-Derived Olefinations of Aldehydes
Received: July 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02291
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Substituted MAHO
a
entry
catalyst
co-catalyst
solvent
time (h) yield (%)
1
2
3
4
5
6
7
8
piperidine
piperidine
piperidine
−
AcOH
AcOH
−
AcOH
−
−
−
−
−
−
−
−
bulk toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
16
16
4
16
16
16
16
16
16
4
50
60
47
0
0
47
0
71
26
24
35
80 (75)
−
pyrrolidine
DMAP
morpholine
morpholine
morpholine
morpholine
b
9
10
11
12
1,4-dioxane
p-xylene
toluene
4
4
c
morpholine
a
b
c
GC yield. Reaction performed at 100 °C. Isolated yield.
was identified as the major isomer by NMR analyses. It should
be noted that the reaction needs to be performed in an open
vessel, presumably to ensure CO2 extrusion, as the reaction
performed in a sealed tube led to only 25% of 3aa. As the
presence of water could also be detrimental to the reaction, the
use of a Dean−Stark apparatus was reported in some cases.24
In the study presented here, the addition of molecular sieves (3
or 4 Å, 0.5 g/mmol) was indeed beneficial but we quickly
found that the simple use of toluene, dried over activated 3 Å
sieves,29 was able to provide the same improvement (entry 2).
We next turned our attention to the catalytic system and more
particularly to the amine catalyst as the use of AcOH as a co-
catalyst was not necessary for the reaction to proceed (entries
3−5). Among the different organocatalysts tested (entries 6−
8), morpholine was revealed to be the most efficient as it
afforded an improved conversion after 16 h (entry 8). It could
be noted that DMAP was unable to promote the reaction
under such conditions. The influence of the solvent and the
temperature was finally evaluated (entries 9−11). A screening
of temperatures revealed that a minimum of 100 °C (entry 9)
was necessary for the reaction to proceed (no reaction
occurred at ≤80 °C), and the change in solvent to 1,4-dioxane
or p-xylene (bp of 101 or 138 °C, respectively) did not show
any improvement in the fate of the reaction (entry 10 or 11,
respectively). However, an improved yield was obtained by
decreasing the reaction time to 4 h in refluxing toluene (entry
12). The scope of the reaction was thus explored under such
optimized conditions.
The influence of the substitution of the MAHO partner in
reaction with p-anisaldehyde was first studied (Scheme 2). In
most cases, the reaction proved to be very stereoselective and
afforded predominantly the (E)-acrylate derivative. The
introduction of primary alkyl chains into the α-position of
MAHO 2 was well-tolerated, leading to products 3aa and 3ab
in good yields (75% and 81%, respectively). However, a more
hindered i-Pr group required an extended reaction time and
led to only 3ac in decreased yield (36%) and stereoselectivity.
Unsaturated or functionalized substituents could also be used
in the reaction. Benzyl-, allyl-, and propargyl-substituted
MAHO 2d−f afforded expected olefins 3ad, 3ae, and 3af in
71%, 65%, and 72%, respectively. Importantly, no isomer-
a
Yields of isolated products; E:Z ratio determined by GC analysis of
the crude reaction mixture. Reaction conditions: 1 (0.5 mmol), 2 (1.0
equiv), morpholine (10 mol %), toluene (0.3 M), reflux, 4 h.
Reactions performed on a 1 mmol scale. Reaction time of 24 h.
Reaction time of 8 h.
b
c
d
ization of the unsaturated system was observed under these
conditions. Halogenated products could also be reached
through this methodology. While the introduction of a
chlorine atom on the side chain of the MAHO has only
limited influence (3ag, 59%), the use of α-halogenated MAHO
led to only limited yields (15% for 3ah and 18% for 3ai),
which are somewhat offset by the possibilities of post-
condensation reactions they afford. The nature of the EWG
of the MAHO was also studied. The nature of the alkyl chain
of the ester has an only limited influence on the fate of the
reaction as methyl (2j), isopropyl (2k), and benzyl esters (2l)
worked well, affording the corresponding trisubstituted olefins
3aj, 3ak, and 3al, respectively, in good yields (58−76%) and
selectivities.
We next turned our attention to the scope of aldehydes
(Scheme 3). A variety of aromatic aldehydes could be used in
reaction with the methyl-substituted MAHO 2b, affording the
expected trisubstituted olefins 3bb−3jf in moderate to
excellent yields. Whereas the use of simple benzaldehyde 1b
led to 3bb in an 83% yield, the introduction of EDG in the
ortho (3cb, 71%) or meta position (3db, 80%) revealed an only
slight influence, even though the reaction was slower in this
last case. Yields were slightly lower when EWG such as -CF3 or
-CN were introduced in the para position (3eb and 3fb, 65%
and 57%, respectively). We were pleased to find that
heteroaromatic aldehydes are very efficient substrates for the
reaction, as the reaction performed with 2-pyridinecarbox-
aldehyde 1g or furfural 1h delivered good to excellent yields of
B
DOI: 10.1021/acs.orglett.9b02291
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
functionalized aldehydes such as hydroxycitronellal 1l or
cyclopropane derivative 1m worked also very well to afford
acrylates 3lb and 3mb. Surprisingly, the use of simpler
aldehydes was trickier. Whereas the use of substrates more
volatile than toluene was not possible, a competitive aldol
dimerization reaction occurred in the case of linear aldehydes
such as octanal 1n. Nevertheless, this side reaction could be
suppressed by the addition of DMAP16 and AcOH, affording
the expected acrylate 3nb in a correct 50% yield. The same
modification was used to convert 3-phenyl propanal 1o or the
secondary cyclohexyl carboxaldehyde 1p with similar efficien-
cies.
Scheme 3. Scope of Aromatic Aldehydes
The reactivity of MAHO toward specific reagents was also
investigated (Scheme 5). When salicylaldehyde 1q was used
Scheme 5. Extension of the Reaction Protocol
a
Yields of isolated products; E:Z ratio determined by GC analysis of
the crude reaction mixture. Reaction conditions: 1 (0.5 mmol), 2 (1.0
equiv), morpholine (10 mol %), toluene (0.3 M), reflux, 4 h.
b
c
Reaction time of 24 h. Reaction time of 17 h.
products 3gb (84%) and 3hb (97%). This last result is
particularly interesting as it constitutes an efficient valorization
of a biomass-derived substrate.30 Moreover, the Galat reaction
could also be applied to other aldehydes to prepare more
original structures. The reaction performed with ethyl
glyoxylate 1i afforded access to substituted fumarate derivatives
such as 3ib with a moderate yield (31%) but excellent
stereoselectivity. When cinnamaldehyde 1j was used, the
expected α,β,γ,δ-unsaturated ester 3jb was obtained in a good
yield (61%) and stereoselectivity (2:1, E:Z) of the newly
formed carbon−carbon double bond, the initial carbon−
carbon double bond of cinnamaldehyde remaining trans.
Aliphatic aldehydes were also suitable substrates in the
transformation (Scheme 4). Thus, the use of our standard
conditions allowed the olefination of citronellal in 3kb with a
very good yield (88%) and a good selectivity (5:1, E:Z). More
with MAHO 2b, the expected substituted coumarin 4, arising
from a domino Galat transesterification reaction,31 was isolated
as a sole product in a 30% yield. This could be attributed to the
degradation of the major (E)-acrylate 3qb upon purification on
silica gel, as NMR analysis of the crude material revealed a
3qb:4 ratio of 2:1 for a conversion of 95%. To prepare gem-
disubstituted olefin 6, MAHO 2d was treated with a
stoichiometric amount of Eschenmoser’s salt 5 and the desired
product was isolated in a fair 55% yield, demonstrating the
generality of this protocol.
We finally explored a potential development of the present
transformation. Indeed, whereas MAHO could be easily
obtained by hydrolysis of the corresponding malonates, Scott
described the preparation of MAHO from Meldrum acids and
alcohols in refluxing toluene.32 As these conditions were
similar to those required for the Galat reaction, we envisioned
to merge these reactions to set up an original multicomponent
reaction. As a proof of concept, the reaction between p-
anisaldehyde 1a, benzyl-substituted Meldrum acid 7, and
benzyl alcohol 8 catalyzed by morpholine (20 mol %)
delivered the desired disubstituted acrylate 3al in an
encouraging 40% yield (Scheme 6).
a
Scheme 4. Scope of Aliphatic Aldehydes
In conclusion, we have developed general conditions for the
olefination of aldehydes via Galat reaction. This trans-
Scheme 6. Multicomponent Approach
a
Yields of isolated products; E:Z ratio determined by GC analysis of
the crude reaction mixture. Reaction conditions: 1 (0.5 mmol), 2 (1.0
equiv), morpholine (10 mol %), toluene (0.3 M), reflux, 4 h.
b
Reaction performed with morpholine (50 mol %), DMAP (10 mol
c
%), and AcOH (1.0 equiv). Sixteen hours.
C
DOI: 10.1021/acs.orglett.9b02291
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. The
decarbethoxylation of geminal dicarbethoxy compounds. Tetrahedron
Lett. 1967, 8, 215−217.
formation, based on the use of morpholine as an organo-
catalyst, is very stereoselective and displays a broad scope,
affording eco-compatible access to α,β-disubstituted acrylates.
Various substituents, including simple halides, could be directly
introduced on the newly formed carbon−carbon double bond
thanks to the use of MAHO. The reaction tolerates a broad
range of aldehydes, making the Galat reaction an important
alternative to the classical Wittig reaction.
(11) Galat, A. A. Synthesis of α,β-Unsaturated Esters. J. Am. Chem.
Soc. 1946, 68, 376−377.
(12) (a) Rodríguez, N.; Goossen, L. J. Decarboxylative coupling
reactions: a modern strategy for C−C-bond formation. Chem. Soc.
Rev. 2011, 40, 5030−5048. (b) Patra, T.; Maiti, D. Decarboxylation as
the Key Step in C−C Bond-Forming Reactions. Chem. - Eur. J. 2017,
23, 7382−7401.
(13) Liu, P.; Zhang, G.-H.; Sun, P.-P. Transition metal-free
decarboxylative alkylation reactions. Org. Biomol. Chem. 2016, 14,
10763−10777.
(14) Rodriguez, J.; Waegell, B. An Efficient One-Pot Preparation of
2,4-Pentadienoic Esters from α,β-Unsaturated Aldehydes. Synthesis
1988, 1988, 534−535.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02291.
(15) List, B.; Doehring, A.; Fonseca, M. T. H.; Wobser, K.; van
Thienen, H.; Torres, R. R.; Galilea, P. L. Practical Synthesis of (E)-
α,β-Unsaturated Esters from Aldehydes. Adv. Synth. Catal. 2005, 347,
1558−1560.
(16) List, B.; Doehring, A.; Hechavarria Fonseca, M. T.; Job, A.;
Rios Torres, R. A Practical, efficient, and atom economic alternative
to the Wittig and Horner−Wadsworth−Emmons reactions for the
synthesis of (E)-α,β-unsaturated esters from aldehydes. Tetrahedron
2006, 62, 476−482.
(17) Zacuto, M. J. Synthesis of Acrylamides via the Doebner−
Knoevenagel Condensation. J. Org. Chem. 2019, 84, 6465−6474.
(18) Ando, M.; Kataoka, N.; Yasunami, M.; Takase, K.; Hirata, N.;
Yanagi, Y. Tropolone derivatives as synthetic intermediates. 1. A novel
synthetic method of the octahydro-2H-cyclohepta[b]furan-2-one
derivatives. J. Org. Chem. 1987, 52, 1429−1437.
(19) Vassiliou, S.; Weglarz-Tomczak, E.; Berlicki, L.; Pawelczak, M.;
Nocek, B.; Mulligan, R.; Joachimiak, A.; Mucha, A. Structure-Guided,
Single-Point Modifications in the Phosphinic Dipeptide Structure
Yield Highly Potent and Selective Inhibitors of Neutral Amino-
peptidases. J. Med. Chem. 2014, 57, 8140−8451.
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: condon@icmpe.cnrs.fr.
*E-mail: presset@icmpe.cnrs.fr.
ORCID
Erwan Le Gall: 0000-0002-8972-3971
Marc Presset: 0000-0003-0994-5572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The financial support of this work by the CNRS, the University
■
́
Paris-Est Creteil, and the University Paris-Est (Ph.D. grant to
(20) For a general method involving 5-monosubstituted Meldrum’s
acids: Hin, B.; Majer, P.; Tsukamoto, T. Facile Synthesis of α-
Substituted Acrylate Esters. J. Org. Chem. 2002, 67, 7365−7368.
(21) Leeper, F. J.; Rock, M.; Appleton, D. Synthesis of analogues of
porphobilinogen. J. Chem. Soc., Perkin Trans. 1 1996, 2633−2642.
(22) Dell’Orco, P.; Brum, J.; Matsuoka, R.; Badlani, M.; Muske, K.
Monitoring Process-Scale Reactions Using API Mass Spectrometry.
Anal. Chem. 1999, 71, 5165−5170.
T.X.) is gratefully acknowledged.
DEDICATION
Dedicated to Pr. Jean Rodriguez.
■
REFERENCES
■
(1) Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH:
Weinheim, Germany, 2004.
(2) Faulkner, D. J. Stereoselective Synthesis of Trisubstituted
̈
(23) Åberg, O.; Lindhe, O.; Hall, H.; Hellman, P.; Kihlberg, T.;
̈
Långstrom, B. Synthesis and biological evaluation of [carboxyl -
11C]eprosartan. J. Labelled Compd. Radiopharm. 2009, 52, 295−303.
(24) Staples, M. K.; Grange, R. L.; Angus, J. A.; Ziogas, J.; Tan, N. P.
H.; Taylor, M. K.; Schiesser, C. H. Tandem free-radical addition/
substitution chemistry and its application to the preparation of novel
AT1 receptor antagonists. Org. Biomol. Chem. 2011, 9, 473−479.
(25) Qiu, G.; Mamboury, M.; Wang, Q.; Zhu, J. Ketenimines from
Isocyanides and Allyl Carbonates: Palladium-Catalyzed Synthesis of
β,γ-Unsaturated Amides and Tetrazoles. Angew. Chem., Int. Ed. 2016,
55, 15377−15381.
Olefins. Synthesis 1971, 1971, 175−189.
(3) Chatterjee, A. K.; Grubbs, R. H. Synthesis of Trisubstituted
Alkenes via Olefin Cross-Metathesis. Org. Lett. 1999, 1, 1751−1753.
(4) Maryanoff, B. E.; Reitz, A. B. The Wittig olefination reaction and
modifications involving phosphoryl-stabilized carbanions. Stereo-
chemistry, mechanism, and selected synthetic aspects. Chem. Rev.
1989, 89, 863−927.
(5) Blakemore, P. R. The modified Julia olefination: alkene synthesis
via the condensation of metallated heteroarylalkylsulfones with
carbonyl compounds. J. Chem. Soc., Perkin Trans. 1 2002, 2563−2585.
(6) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A.
L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A. Recycling the Waste:
The Development of a Catalytic Wittig Reaction. Angew. Chem., Int.
Ed. 2009, 48, 6836−6839.
(26) Previous isolated examples involving 2-amido MAHO:
́
(a) Velazquez, F.; Venkatraman, S.; Wu, W.; Blackman, M.;
Prongay, A.; Girijavallabhan, V.; Shih, N.-Y.; Njoroge, F. G.
Application of Ring-Closing Metathesis for the Synthesis of
Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease.
Org. Lett. 2007, 9, 3061−3064. (b) Xu, F.; Zacuto, M.; Yoshikawa, N.;
Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey, G. R.;
Cowden, C.; Strotman, N.; Devine, P. Asymmetric Synthesis of
Telcagepant, a CGRP Receptor Antagonist for the Treatment of
Migraine. J. Org. Chem. 2010, 75, 7829−7841.
(7) O’Brien, C. J.; Nixon, Z. S.; Holohan, A. J.; Kunkel, S. R.; Tellez,
J. L.; Doonan, B. J.; Coyle, E. E.; Lavigne, F.; Kang, L. J.; Przeworski,
K. C. Part I: The Development of the Catalytic Wittig Reaction.
Chem. - Eur. J. 2013, 19, 15281−15289.
̈
(8) Knoevenagel, E. Condensation von Malonsaure mit aromati-
(27) Singjunla, Y.; Colombano, S.; Baudoux, J.; Rouden, J.
Stereoselective synthesis of dehydroamino acids using malonic acid
half oxyester and aromatic aldehydes. Tetrahedron 2016, 72, 2369−
2375.
schen Aldehyden durch Ammoniak und Amine. Ber. Dtsch. Chem. Ges.
1898, 31, 2596−2619.
̈
(9) Doebner, O. Synthese der Sorbinsaure. Ber. Dtsch. Chem. Ges.
1900, 33, 2140−2142.
D
DOI: 10.1021/acs.orglett.9b02291
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(28) Bensemhoun, J.; Condon, S. Valorization of glycerol 1,2-
carbonate as a precursor for the development of new synthons in
organic chemistry. Green Chem. 2012, 14, 2595−2599.
(29) Williams, D. B. G.; Lawton, M. Drying of Organic Solvents:
Quantitative Evaluation of the Efficiency of Several Desiccants. J. Org.
Chem. 2010, 75, 8351−8354.
́
́
́
(30) Mika, L. T.; Csefalvay, E.; Nemeth, A. Catalytic Conversion of
Carbohydrates to Initial Platform Chemicals: Chemistry and
Sustainability. Chem. Rev. 2018, 118, 505−613.
(31) Blaquiere, N.; Shore, D. G.; Rousseaux, S.; Fagnou, K.
Decarboxylative Ketone Aldol Reactions: Development and Mecha-
nistic Evaluation under Metal-Free Conditions. J. Org. Chem. 2009,
74, 6190−6198.
(32) Ryu, Y.; Scott, A. I. Self-condensation of activated malonic acid
half esters: a model for the decarboxylative Claisen condensation in
polyketide biosynthesis. Tetrahedron Lett. 2003, 44, 7499−7502.
E
DOI: 10.1021/acs.orglett.9b02291
Org. Lett. XXXX, XXX, XXX−XXX