Categories: C=C Bond Formation >
Synthesis of unsaturated esters, amides and carboxylic acids
Allyl-nickel catalysis enables α,β-dehydrogenation of carbonyl compounds. In addition, an oxidative cycloalkenylation reaction provides access to bicycloalkenones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.
D. Huang, S. M. Szewczyk, P. Zhang, T. R. Newhouse, J. Am. Chem. Soc., 2019, 141, 5669-5674.
Activation of the silicon-carbon bond of α-trimethylsilylethylacetate in the presence of P(i-PrNCH2CH2)3N as catalyst allows an efficient synthesis of β-hydroxyesters and α,β-unsaturated esters. Selectivity for either of these two products can be achieved simply by altering the catalyst loading and reaction temperature.
K. Wadhwa, J. G. Verkade, J. Org. Chem., 2009, 74, 4368-4371.
Copper iodide is an effective cocatalyst for the olefin cross-metathesis reaction. It has both a catalyst stabilizing effect due to iodide ion, as well as copper(I)-based phosphine-scavenging properties. A variety of Michael acceptors and olefinic partners can be cross-coupled under mild conditions in diethyl ether and in water using the new surfactant TPGS-750-M.
K. Voigtritter, S. Ghorai, B. H. Lipshutz, J. Org. Chem., 2011, 76, 4697-4702.
A highly practical and general palladium-catalyzed α,β-dehydrogenation of esters and nitriles gives synthetically useful yields of α,β-unsaturated esters, lactones, and nitriles via generation of a zinc enolate or (cyanoalkyl)zinc species followed by the addition of an allyl oxidant and a palladium catalyst. Preliminary mechanistic investigations propose reversible β-hydride elimination and turnover-limiting, propene-forming reductive elimination.
Y. Chen, J. P. Romaire, T. R. Newhouse, J. Am. Chem. Soc., 2015, 137, 5875-5878.
Horner-Emmons Synthesis with Minimal Purification Using ROMPGEL: A Novel High-Loading Matrix for Supported Reagents
A. G. M. Barrett, S. M. Cramp, R. S. Roberts, F. J. Zecri, Org. Lett., 1999, 1, 579-582.
A bifunctional polystyrene bearing both DMAP and piperidine groups is an effective organocatalyst for decarboxylative Doebner-Knoevenagel reactions of arylaldehydes and monoethyl malonate to give E-cinnamates in high yields. A synergistic effect obtained by co-locating the two different catalytic amine groups on the same polymer backbone has been detected.
J. Lu, P. H. Toy, Synlett, 2011, 1723-1726.
The combination of cerium(III) chloride heptahydrate with sodium iodide mediates a useful dehydration of β-hydroxy ketones and β-hydroxy esters to the corresponding α,β-unsaturated derivatives in refluxing acetonitrile. This method, which uses cheap and friendly reagents, provides the corresponding (E)-isomers in good yields as the only isolable products.
G. Bartoli, M. C. Bellucci, M. Petrini, E. Marcantoni, L. Sambri, E. Torregiani, Org. Lett., 2000, 2, 1791-1793.
In an operationally convenient, mechanistically unique protocol, Lewis base activation of silyl acetals generates putative pentacoordinate silicate acetals, which fragment into aldehydes, silanes, and alkoxides in situ. Subsequent deprotonative metalation of phosphonate esters followed by HWE with aldehydes furnishes enoates.
U. S. Dakarapu, A. Bokka, P. Asgari, G. Trog, Y. Hua, H. H. Nguyen, N. Rahman, J. Jeon, Org. Lett., 2015, 17, 5792-5795.
Morpholine efficiently catalyzes Galat reactions between aldehydes and substituted malonic acids half oxyester in refluxing toluene to provide diverse α,β-disubstituted acrylates in to good yields. This method constitutes an attractive alternative to existing methods in terms of scope and eco-compatibility.
T. Xavier, S. Condon, C. Pichon, E. Le Gall, M. Presset, Org. Lett., 2019, 21, 6135-6139.
The Doebner-Knoevenagel condensation enables a selective synthesis of acrylamides under mild conditions at ambient temperatures. The scalable reaction tolerates a wide range of functional groups, and affords the E-isomer with high selectivity. An organocatalytic mechanism has been proposed.
M. J. Zacuto, J. Org. Chem., 2019, 84, 6465-6474.
A very simple one-pot process involving a cross-metathesis between acryloyl chloride and a terminal olefin followed by the addition of a nucleophile allows the synthesis of various functionalized α,β-unsaturated carbonyl compounds in good yield.
L. Ferrié, S. Bouzbouz, J. Cossy, Org. Lett., 2009, 11, 5446-5448.
Phosphine and amine functionalized polystyrene was used in one-pot Wittig reactions with an aldehyde and either an α-halo-ester, -ketone, or -amide. Due to the heterogeneous nature of the polymer, the desired alkene product of these reactions could be isolated in excellent yield in essentially pure form after only filtration and solvent removal.
P. S.-W. Leung, Y. Teng, P. H. Toy, Org. Lett., 2010, 12, 4996-4999.
A simple protocol for a highly E-selective Wadsworth-Emmons reaction via deprotonation of alkyl diethylphosphonoacetates with MeMgBr allows the conversion of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes.
T. D. W. Claridge, S. G. Davies, J. A. Lee, R. L. Nicholson, P. M. Roberts, A. J. Russel, A. D. Smith, S. M. Toms, Org. Lett., 2008, 10, 5437-5440.
Water is an effective medium for the Wittig reaction over a wide range of stabilized ylides and aldehydes including especially substrates with large hydrophobic entities. Despite sometimes poor solubility of the reactants, good yields and high E-selectivities are achieved, and the rate of the reactions in water is unexpectedly accelerated.
A. El-Batta, C. Jiang, W. Zhao, R. Anness, A. L. Cooksy, M. Bergdahl, J. Org. Chem., 2007, 72, 5244-5259.
A mild and efficient one-pot Wittig reaction performed in both water and sodium dodecyl sulfate (SDS)-water solution in open atmosphere allowed the synthesis of various α,β-unsaturated esters in good yields.
F. Orsini, G. Sello, T. Fumagalli, Synlett, 2006, 1717-1718.
The carbocation Lewis acid tritylium tetrafluoroborate (TrBF4) catalyzes a 1,2-hydride migration of α-alkyldiazoacetates to provide (Z)-α,β-unsaturated esters in good yields and with high regioselectivities. Using the same catalytic system, in situ-generated cross-coupling adducts of aldehydes and α-alkyldiazoacetates give α-branched β-ketocarbonyls.
W. Shang, D. Duan, Y. Liu, J. Lv, Org. Lett., 2019, 21, 8013-8017.
A riboflavin-mediated highly (Z)-selective and operationally simple, catalytic isomerization has been applied to a variety of enone-derived substrates. The reaction can also be used for the synthesis of the medically relevant 4-substituted coumarin scaffold.
J. B. Metternich, R. Gilmour, J. Am. Chem. Soc., 2015, 137, 11254-11257.
Bis(2,2,2-trifluoroethyl)bromophosphonoacetate, a Novel HWE Reagent for the Preparation of (E)-α-Bromoacrylates: A General and Stereoselective Method for the Synthesis of Trisubstituted Alkenes
K. Tago, H. Kogen, Org. Lett., 2000, 2, 1975-1978.
Optimized conditions for the Wittig reaction of aldehydes with ethyl tribromoacetate and triphenylphosphine allowed the synthesis of α-bromoacrylates with high selectivity. A simple and efficient one-pot procedure was developed for the preparation of various conjugated acetylenic carboxylates in good yields.
J.-G. Kim, D. H. Kang, D. O. Jang, Synlett, 2008, 443-447.
Ethyl (benzothiazol-2-ylsulfonyl)acetate engaged in the modified Julia olefination with aldehydes under mild reaction conditions to yield α,β-unsaturated esters. Aryl aldehydes and aliphatic aldehydes possessing significant chain branching elements gave trans alkene products with high stereoselectivity, while straight chain aliphatic aldehydes gave cis products preferentially.
P. R. Blakemore, D. K. H. Ho, W. M. Nap, Org. Biomol. Chem., 2005, 3, 1365-1368.
gem-Dibromomethylarenes: A Convenient Substitute for Noncommercial Aldehydes in the Knoevenagel−Doebner Reaction for the Synthesis of α,β-Unsaturated Carboxylic Acids
J. K. Augustine, Y. A. Naik, A. B. Mandal, N. Chowdappa, V. B. Praveen, J. Org. Chem., 2007, 72, 9854-9856.
P(NMe2)3 mediates umpolung alkylation of methyl aroylformates with benzylic and allylic bromides via a two-electron redox addition of the tricoordinate phosphorus reagent to the α-keto ester compound (Kukhtin-Ramirez addition). Depending on the work-up conditions, either Barbier-type addition or ylide-free olefination products can be isolated.
S. R. Wang, A. T. Radosevich, Org. Lett., 2015, 17, 3810-3813.
A complete E-selective synthesis of α,β-unsaturated amides through a sequential reaction of a range of dichloroamides with a variety of aldehydes is promoted by Rieke manganese (Mn*). The unsaturated amides obtained are readily and efficiently transformed into α,β-unsaturated ketones, aldehydes, or carboxylic acids.
J. M. Concellón, H. Rodríquez-Solla, P. Díaz, J. Org. Chem., 2007, 72, 7974-7979.
A generally applicable, sequential reaction of dichloroesters with various aldehydes is promoted by active manganese to give α,β-unsaturated esters with complete control of stereoselectivity. The C-C double bond can be di- or trisubstituted. A mechanism based on a successive aldol-type reaction/-elimination is proposed.
J. M. Concellón, H. Rodríquez-Solla, P. Díaz, R. Llaona, J. Org. Chem., 2007, 72, 4396-4400.
The stereoselective reaction of different aldehydes and ethyl dibromoacetate promoted by SmI2 or CrCl2 gives (E)-α,β-unsaturated esters by an an aldol-type reaction and a subsequent β-elimination reaction.
J. M. Concellon, C. Concellon, C. Mejica, J. Org. Chem., 2005, 70, 6111-6113.
A mild protocol for the Horner-Wadsworth-Emmons reaction of diprotic phosphonates makes use of a zinc triflate promoter in the presence of mild tertiary amine bases to produce α,β-unsaturated carboxylic acids and amides.
D. J. Schauer, P. Helquist, Synthesis, 2006, 3654-3660.
The stereoselective reaction of different aldehydes and dibromoacetic acid promoted by SmI2 gives (E)-α,β-unsaturated carboxylic acids. The mechanism is discussed.
J. M. Concellon, C. Concellon, J. Org. Chem., 2006, 71, 1728-1731.
A Cs2CO3-promoted carboxylation of N-tosylhydrazones and CO2 proceeded efficiently at 80°C under atmospheric CO2 and gave the corresponding α-arylacrylic acids in good yields.
S. Sun, J.-T. Yu, Y. Jiang, J. Cheng, J. Org. Chem., 2015, 80, 2855-2860.
The reaction of alkyl-substituted sec-ethoxyalkynyl acetates with water catalyzed by Hg(OTf)2 afforded α,β-unsaturated esters in excellent yield with high catalytic turnover under very mild reaction conditions with virtually complete E-selectivity.
M. Nishizawa, H. Hirakawa, Y. Nakagawa, H. Yamamoto, K. Namba, H. Imagawa, Org. Lett., 2007, 9, 5577-5580.
N-Sulfonyl ketenimine formation followed by a probable 1,3-OAc migration ([3,3]-sigmatropic rearrangement) enables a synthesis of trans-α,β-unsaturated N-tosylamides from readily accessible propargyl acetates and sulfonyl azides in the presence of CuI as catalyst. The reaction is very general and affords products at ambient temperature with excellent diastereoselectivity in good yields.
Y. K. Kumar, G. R. Kumar, M. S. Reddy, J. Org. Chem., 2014, 79, 823-828.
A transition metal-free radical α,β-dehydrogenation of saturated amides under mild conditions even provides α,β-unsaturated Weinreb amides and acrylamides. Mechanistic studies confirm the radical nature of this transformation.
M.-M. Wang, G.-H. Sui, X.-C. Cui, H. Wang, J.-P. Qu, Y.-B. Kang, J. Org. Chem., 2019, 84, 8267-8274.
The first allylic C-H olefination with α-diazo esters synergistically catalyzed by a palladium(II) complex and (salen)CrCl directly generates conjugated polyene derivatives in good yields and with excellent stereoselectivities.
P.-S. Wang, H.-C. Lin, X.-L. Zhou, L.-Z. Gong, Org. Lett., 2014, 16, 3332-3335.
A simple iridium/copper relay catalysis system enables a direct aerobic α,β-dehydrogenation of γ,δ-unsaturated amides and carboxylic acids to provide conjugated dienamides and dienoic acids in excellent yield. Instead of α-C-H metalation, this reaction proceeds by β-C-H activation, which results in enhanced α-acidity.
Z. Whang, Z. He, L. Zhang, Y. Huang, J. Am. Chem. Soc., 2018, 140, 735-740.
A sequence of three reactions enables the synthesis of trisubstituted (E)-α,β-unsaturated esters: an aldol reaction, acetylation of the hydroxy group at the β-position, and an E1cB reaction induced by DBU. The E1cB reaction works with a diastereoisomeric mixture of β-hydroxy ester intermediates. The whole sequence is usable for gram-scale syntheses of trisubstituted (E)-α,β-unsaturated esters.
M. Ozeki, H. Egawa, A. Kuse, T. Takano, N. Yasuda, H. Mizutani, S. Izumiya, D. Nakashima, K. Arimitsu, T. Miura, T. Kajimoto, S. Hosoi, H. Iwasaki, N. Kojima, M. Node, M. Yamashita, Synthesis, 2015, 47, 3392-3402.
A Ba/Pd cooperative catalysis system enables a dehydrative cross-coupling of allylic alcohols with P-ylides followed by a Wittig reaction in one pot. Various multisubstituted 1,4-dienes were isolated in very good yields with a broad range of P-ylides and aldehydes with excellent E selectivity.
P. Xie, W. Fu, X. Cai, Z. Sun, Y. Wu, S. Li, C. Gao, X. Yang, T.-P. Loh, Org. Lett., 2019, 21, 7055-7059.
The use of FeCl3 as catalyst enables a rapid decarboxylation of methylene tethered cyclic 1,3-diesters in the presence of water to yield α,β-unsaturated acids with high E-stereoselectivity under both microwave and conventional heating conditions. This powerful approach proved to be scalable to gram scale synthesis.
A. R. Mohite, R. G. Bhat, Org. Lett., 2013, 15, 4564-4567.
Efficient and stereoselective rearrangement catalyzed by only one mole-percent gold(I) chloride/silver(I) trifluoromethanesulfonate of Baylis-Hillman acetates afforded 2-(acetoxymethyl)alk-2-enoates under mild reaction conditions in very good yields with 100% E-selectivity.Cyclohex-2-enone derived Baylis-Hillman acetates gave 2-alkylidenecyclohex-3-enones by elimination of acetic acid.
Y. Liu, D. Mao, J. Qian, S. Lou, Z. Xu, Y. Zhang, Synthesis, 2009, 1170-1174.
Zinc-promoted reduction of 2-(bromomethyl)alkenoates derived from Baylis-Hillman adducts gave (E)-2-methylacrylates in good yield and high stereoselectivity. Synthesis of the male ant pheromone (E)-2,4-dimethyl-2-hexenoic acid was performed using this simple methodology.
L. Fernandes, A. J. Bortoluzzi, M. M. Sa, Tetrahedron, 2004, 60, 9983-9989.
Stereoselective β-elimination of diastereomeric mixtures of 2-bromo-3-hydroxyesters is achieved by using unactivated manganese and trimethylsilyl chloride, to yield (E)-α,β-unsaturated esters with total diastereoselectivity.
J. M. Concellón, H. Rodríguez-Solla, V. del Amo, Synlett, 2006, 315-317.
Dimethyl sulfoxide efficiently causes the reductive elimination of 3-aryl 2,3-dibromopropanoates to cinnamates with good yield. For most substrates debromination is the major pathway, whereas dehydrobromination is a competing pathway with thiophene derivatives. 1H NMR, 81Br NMR, and MS indicated the formation of brominated-DMSO, MeBr, and HBr as byproducts.
W. Li, J. Li, M. Lin, S. Wacharasindhu, K. Tabei, T. S. Mansour, J. Org. Chem., 2007, 72, 6016-6021.
(E)-α-Ethynyl-α,β-unsaturated esters were prepared in good yields from allenyl acetates by treatment with 10 mol % DABCO in DMF at room temperature.
Y. Choe, P. H. Lee, Org. Lett., 2009, 11, 1445-1448.
α,β-Dihalopropanoate derivatives undergo efficient, selective dehydrohalogenation to form α-haloacrylate analogues in the presence of DMSO. A variety of α-halo Michael acceptors were prepared in dimethyl sulfoxide under mild, base-free conditions, including the preparation of α-bromoacrolein and α-chloro- and bromoacrylonitriles.
W. Li, J. Li, Z.-K. Wan, J. Wu, W. Massefski, Org. Lett., 2007, 9, 4607-4610.
Deprotonation of a 64:36 mixture of ethyl bromo(diphenylphosphono)acetate and ethyl dibromo(diphenylphosphono)acetate using NaH as base at 0 °C and subsequent reaction with various aldehydes provided unsaturated α-bromoesters in good yields and high E-selectivities.
T. Olpp, R. Brückner, Synthesis, 2004, 2135-2152.
A zinc carbenoid-mediated chain extension of β-dicarbonyl compounds provides access to α,β-unsaturated-γ-keto esters and amides with complete E selectivity via an intermediate zinc enolate, which is treated sequentially with iodine and DBU.
M. D. Ronsheim, C. K Zercher, J. Org. Chem., 2003, 68, 4535-4538.
Among the reported examples of new reactivity of the hypervalent iodine reagent DMP (Dess-Martin periodinane) are the one-step oxidation of secondary amides to imides and N-acyl vinylogous carbamates or ureas and the direct oxidation of benzylic and related primary amines to the corresponding nitriles.
K. C. Nicolaou, C. J. N. Mathison, Angew. Chem. Int. Ed., 2005, 44, 5992-5997.
In the presence of ruthenium-based olefin metathesis catalysts and triphenylphosphine, α,β-unsaturated aldehydes can be olefinated with diazoacetates. A tandem transformation of terminal olefins to 1,3-dienoic olefins in a single operation based on olefin cross-metathesis and Wittig olefination has been developed.
R. P. Murelli, M. L. Snapper, Org. Lett., 2007, 9, 1749-1752.
An expeditious synthesis of α-substituted tert-butyl acrylates from commercially available aldehydes and Meldrum's acid includes a telescoped condensation-reduction sequence to afford 5-monosubstituted Meldrum's acid derivatives followed by a Mannich-type reaction triggered by a rapid cycloreversion of the dioxinone ring on heating with tert-butyl alcohol.
C. G. Frost, S. D. Penrose, R. Gleave, Synthesis, 2009, 627-635.
TiCl4/Et3N promotes a condensation of acetate and formate esters to provide (E)-β-alkoxy- and (E)-β-aryloxyacrylate moieties. A plausible mechanism involving a bimetallic titanium intermediate for this type of transformation.
J. M. Álvarez-Calero, Z. D. Jorge, G. M. Massanet, Org. Lett., 2016, 18, 6344-6347.
A copper-amine catalyst system enables a general and facile synthetic method for β-fluoroenones from silyl enol ethers or ketones via tandem process of difluoroalkylation-hydrolysis-dehydrofluorination. This reaction offers high yields, excellent Z/E ratios, a low-cost catalyst, and a broad substrate scope.
Y. Li, J. Liu, S. Zhao, Y. Du, M. Guo, W. Zhao, X. Tang, G. Wang, Org. Lett., 2018, 20, 917-920.
A Pd-catalyzed α,β-desaturation of N-protected lactams provides conjugated unsaturated counterparts under mildly acidic conditions at room temperature. The reaction tolerates a wide range of functional groups and shows reactivity complementary to that of prior desaturation methods. Lactams with various ring sizes and substituents at different positions all reacted smoothly.
M. Chen. G. Dong, J. Am. Chem. Soc., 2017, 139, 7757-7760.