Synthesis of α,β-Disubstituted Acrylates via Galat Reaction | Organic

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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 Synthèse Organique, Université Paris Est, ICMPE, (UMR 7182), CNRS, UPEC, 2-8 rue Henri Dunant, F-94320 Thiais, France

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ABSTRACT: 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. 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. 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

T

he olefination of aldehydes is one of the most fundamental reactions in organic synthesis.1 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 Knoevenagel 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 conditions.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 © XXXX American Chemical Society

Scheme 1. Knoevenagel-Derived Olefinations of Aldehydes

Received: July 3, 2019

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DOI: 10.1021/acs.orglett.9b02291 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Substituted MAHOa

Table 1. Optimization of the Reaction Conditions

entry

catalyst

co-catalyst

solvent

time (h)

yielda (%)

1 2 3 4 5 6 7 8 9b 10 11 12

piperidine piperidine piperidine − − pyrrolidine DMAP morpholine morpholine morpholine morpholine morpholine

AcOH AcOH − AcOH − − − − − − − −

bulk toluene toluene toluene toluene toluene toluene toluene toluene toluene 1,4-dioxane p-xylene toluene

16 16 4 16 16 16 16 16 16 4 4 4

50 60 47 0 0 47 0 71 26 24 35 80 (75)c

GC yield. bReaction performed at 100 °C. cIsolated yield.

a

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 cocatalyst 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. b Reactions performed on a 1 mmol scale. cReaction time of 24 h. d Reaction time of 8 h.

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 postcondensation 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-pyridinecarboxaldehyde 1g or furfural 1h delivered good to excellent yields of B

DOI: 10.1021/acs.orglett.9b02291 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of Aromatic Aldehydesa

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 efficiencies. 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 Reaction time of 24 h. cReaction 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 gemdisubstituted 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 panisaldehyde 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). In conclusion, we have developed general conditions for the olefination of aldehydes via Galat reaction. This trans-

Scheme 4. Scope of Aliphatic Aldehydesa

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 %), and AcOH (1.0 equiv). cSixteen hours. C

DOI: 10.1021/acs.orglett.9b02291 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(10) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. The decarbethoxylation of geminal dicarbethoxy compounds. Tetrahedron Lett. 1967, 8, 215−217. (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. (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 Aminopeptidases. J. Med. Chem. 2014, 57, 8140−8451. (20) For a general method involving 5-monosubstituted Meldrum’s acids: Hin, B.; Majer, P.; Tsukamoto, T. Facile Synthesis of αSubstituted 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. (23) Åberg, O.; Lindhe, Ö .; Hall, H.; Hellman, P.; Kihlberg, T.; Långström, B. Synthesis and biological evaluation of [carboxyl 11 C]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. (26) Previous isolated examples involving 2-amido MAHO: (a) Velázquez, 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. (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.

formation, based on the use of morpholine as an organocatalyst, 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.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02291. Experimental procedures, compound characterization data, and NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Erwan Le Gall: 0000-0002-8972-3971 Marc Presset: 0000-0003-0994-5572 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The financial support of this work by the CNRS, the University Paris-Est Créteil, and the University Paris-Est (Ph.D. grant to T.X.) is gratefully acknowledged.

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DEDICATION Dedicated to Pr. Jean Rodriguez. REFERENCES

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DOI: 10.1021/acs.orglett.9b02291 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b02291 Org. Lett. XXXX, XXX, XXX−XXX