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A simple and efficient one-pot method is described for the construction of [1,4]thiazepino[5,4-a]isoquinolines containing intramolecular hydrogen bonds by a sequential four-component domino reaction of isoquinoline, a 2-bromoacetophenone, an aryl isothiocyanate, and dimethyl acetylenedicarboxylate.

trans-Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven-membered ring trans-alkenes underwent [4+2] cycloaddition reactions faster than a trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10(9).

The three-component reactions of α,β-unsaturated N-arylaldimines, dimethyl acetylenedicarboxylate (methyl propiolate) and isatylidene malononitriles in dry acetonitrile at room temperature afforded polysubstituted spiro[indoline-3,4′-pyridines] in good yields and with high diastereoselectivity. Under similar reaction conditions, the corresponding functionalized spiro[indene-2,4′-pyridines] were also obtained from the three-component reactions containing 2-(1,3-dioxo-1H-inden-2(3H)-ylidene)malononitrile.

Substituted benzocyclobutenes were isolated from the reaction of substituted oxocycloocta-2,8-diene-1,2-dicarboxylates with DMAD which were themselves formed by the microwave assisted [2+2] cycloaddition of cyclic enaminones to dimethyl acetylenedicarboxylate. The high pressure hydrogenation of (1E,2Z)-dimethyl 3-(dimethylamino)-7-oxocycloocta-2,8-diene-1,2-dicarboxylate gave oxabicyclo[3.3.1]non-3-ene-2,3-dicarboxylates, while use of low pressure hydrogenation resulted in only the carbonyl group being reduced to give the corresponding hydroxyl derivative which was proposed as an intermediate of the oxabicyclo[3.3.1]nonanes formed using high pressure hydrogenation.

Reactions of cyclic enaminones, derived from cyclic five- and six-membered 1,3-diones, and dimethyl acetylenedicarboxylate (DMAD) under microwave irradiation produced a mixture of two products: ring-expansion products as a result of a [2+2] cycloaddition and Michael adducts. Reaction between 4-(dimethylamino)-2H-chromen-2-one and DMAD leads to three products: 2-(4-(dimethylamino)-2-oxo-2H-chromen-3-yl)maleate as a Michael adduct, dimethyl 1-(dimethylamino)naphthalene-2,3-dicarboxylate as the product of the [2+2] cycloaddition followed by 6π disrotatory electrocyclization and elimination of CO2 and 4-(dimethylamino)naphthalene-1,2-dicarboxylate as the product of the [4+2] cycloaddition followed by elimination of CO2.

Reaction of 2-amino-N-substituted benzamides and dimethyl acetylenedicarboxylate (DMAD) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in H2O at room temperature led to the formation of novel 1,2,3,4-tetrahydroquinazolinones.

The domino four-component reaction of hydrated hydrazine, dimethyl acetylenedicarboxylate, isatin and malononitrile or ethyl cycanoacetate in ethanol in the presence of triethylamine afforded the polysubstituted spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives in satisfactory yields. Under similar conditions, the four-component reaction containing acenaphthenequinone also resulted in the spiro[acenaphthyl-3,4′-pyrano[2,3-c]pyrazole] in good yields.

The novel polysubstituted 1,1′-phenylene-bipyrrole compounds were synthesized by the double [3+2] cycloaddition-extrusion reactions of N,N′-phenylene-bimunchnones and dimethyl acetylenedicarboxylate in dry toluene at 80 °C for 24 h. Bimunchnones were prepared successfully by cyclodehydration reactions of N,N′-biacyl-N,N′-(1,4-phenylene)-bis(2-arylglycine) with N,N′-diisopropylcarbodiimide in dry toluene at 0–5 °C for 1.5 h. The structures of the products were characterized on the basis of spectral data.

The green and efficient method succeeds with almost identical yields using diethyl instead of dimethyl acetylenedicarboxylate as the C1-source, but fails with terminal alkynes and 1,2-dialkyl or 1,2-diarylalkynes.

The reaction between enamines and azaenamines containing a thioamide group and dimethyl acetylenedicarboxylate was studied under various conditions. It was shown that exchanging one of the carbon atoms in the structure of the investigated compounds for a nitrogen atom significantly affected the reactivity. Functionalized thiopyrans and thiazolidinones were obtained during this investigation.

The title compounds are efficiently obtained by a simple, regioselective multicomponent reaction of ninhydrin, malononitrile, hydrazine derivatives, and β-ketoesters or dimethyl acetylenedicarboxylate.

In a one-pot synthesis, 1′-methyl-2,3″-dioxo-5″-aryl-1,2,5a″,7″,8″,9a″-hexahydro-5″H,6″H-dispiro[indole-3,2′-pyrrolidine-3′,2″-pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine]-4′-carboxylic acid methyl ester was prepared via the sequential reaction of 4-aryl-octahydro-pyrano[2,3-d]pyrimidine-2-thione, dimethyl acetylenedicarboxylate (DMAD), and a mixture of isatin and sarcosine. All the novel spiro compounds, in moderate yields, were characterized thoroughly by infrared, NMR, mass spectromentry, and elemental analysis together with x-ray crystallographic analysis.

Oxidation of N-aminophthalimide in the presence of 2-arylideneinden-1,3-diones with electron-withdrawing substituents gives the corresponding 3-aryl-1-phthalimidospiro[aziridine-2,2′-indene]-1′,3′-diones in good yields. Heating these aziridines with standard dipolarophiles (N-phenylmaleimide, dimethyl acetylenedicarboxylate, maleate, and fumarate) leads, in most cases, to spiro[inden-2,2′-pyrrole] derivatives as products of 1,3-dipolar cycloaddition of the intermediate azomethine ylides with up to 70–95% yields in the case of N-phenylmaleimide. As is typical for 2-acylaziridines, the competing rearrangement into 2-aryl-4H-indeno[2,1-d][1,3]oxazol-4-ones prevails for less active dipolarophiles. Increasing the electron-releasing properties of the 3-aryl ring allows the observation of the push–pull effect of electron-donating and electron-withdrawing substituents on the ease of the three-membered ring-opening.

We have developed a method for the synthesis of dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2-(R-imino)-9-oxo-1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylates, based on a three-component reaction of 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones, 1-adamantylisocyanide or о-methylphenylisocyanide, and dimethyl acetylenedicarboxylate.

This is the first report on the synthesis of dihydropyridines using dimethyl acetylenedicarboxylate, primary amines, and in situ generated Knoevenagel condensation products.

Application of diethyl instead of dimethyl acetylenedicarboxylate furnishes the corresponding products in comparable yields.

The one-pot three-component reaction proceeds with comparable yields with diethyl instead of dimethyl acetylenedicarboxylate.

This review presents the recent progress in the chemistry of dimethyl acetylenedicarboxylate (DMAD). The interest in and applications of this powerful reagent with more than 135 years of history have greatly increased in the last 10 years, further proving its versatility. Undoubtedly, DMAD can be a multi-tool in the quest of molecular complexity and diversity. The extreme structural diversity of the products described in this review illustrates the powerful potential of DMAD as a building block in organic synthesis. 1 Introduction 2 Michael Reactions 2.1 Sulfur as Nucleophile 2.2 Nitrogen as Nucleophile 2.3 Oxygen as Nucleophile 2.4 Addition to Carbon–Carbon Double Bonds 3 Cycloaddition Reactions 3.1 Diels–Alder Reactions ([4+2] Cycloadditions) 3.2 1,3-Dipolar Reactions ([3+2] Cycloadditions) 3.3 [2+2] Cycloadditions 3.4 [8+2] Cycloadditions 4 DMAD and the Generation of Zwitterions; Multicomponent Reactions (MCRs) 4.1 Phosphines and Derivatives 4.2 Amines 4.3 Isocyanides 4.4 Carbenes 4.5 Miscellaneous Reactions 5 Conclusion

Oligofurans linked by a rigid tether undergo tandem cycloaddition reactions with high stereoselectivity. The reaction of bisfurans with dimethyl acetylenedicarboxylate (DMAD) involves tandem [4 + 2]/[4 + 2] cycloadditions in a pincer mode. The reaction of oligofurans with arynes involves stereoselective tandem [4 + 2]/[4 + 2] cycloaddition reactions in a domino mode. The corresponding aryne adducts have been transformed into extended perylene derivatives by deoxygenation and aromatization with HCl/EtOH.

Blocked hydrazines were prepared by the reaction of diethyl hydrazinophosphate with fluorinated aldehydes applying Zwierzak’s method and then introduced into the reaction with 3-substituted homoallenyl aldehydes. The resulting non-symmetrical fluorine containing azines reacted in combined intra-intermolecular criss-cross cycloaddition with phenyl isocyanate, phenyl isothiocyanate and dimethyl acetylenedicarboxylate producing fused tricyclic heterocycles. Besides, an interesting cyclization of fluorinated non-symmetrical azines without any dipolarophile initiated by heating was carried out providing fused bicyclic systems.

Methoxytropolones are useful scaffolds for therapeutic development because of their known biological activity and established value in the synthesis of α-hydroxytropolones. Upon treatment with triflic acid, a series of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones rearrange rapidly and cleanly to form methoxytropolones. Interestingly, bicycles that are derived from dimethyl acetylenedicarboxylate (R2 = R3 = CO2Me) instead form furans as the major product.

A simple one-step method for efficient synthesis of pyrrole-2,3,4,5-tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine using ceric (IV) ammonium nitrate as one electron oxidant is described.

The synthesis of the title compounds (VII) is based on the condensation of 1-aminopyridinium salt (I) with dimethyl acetylenedicarboxylate followed by regioselective saponification to give the key intermediate (IV) which can be converted to the useful tricyclic derivatives.

Title compounds of type (I) react with dimethyl acetylenedicarboxylate (II) and triphenyl phosphine to give cyclobutenes of type (III).

The outcome of the reaction of thioacetamides with dimethyl acetylenedicarboxylate depends on the structure of thioacetamide substrates.

An efficient procedure is elaborated for the synthesis of tetrasubstituted pyrazoles (IV) by cyclization—aromatization of aryl hydrazones (I) with aldehydes (II) and DMAD (III).

The reaction of 2-[1-(naphthalen-2-yl)ethylidene]hydrazinecarbothioamide with hydrazonoyl halides afforded new thiazole derivatives, whilst reaction with compounds containing an activated double bond such as ethoxymethylene-malononitrile and benzylidenemalononitrile yielded the respective pyrimidine derivatives. A 4-thiazolidin-4-one was obtained by reaction of the hydrazinecarbothioamide with ethyl bromoacetate. Subsequent condensation of the thia-zolidinone with aromatic aldehydes afforded the corresponding arylidene derivatives. Treatment of the hydrazinecarbothioamide with dimethyl acetylenedicarboxylate resulted in the formation of a (methoxycarbonylmethylidene) thiazolinone. Reaction of the hydrazinecarbothioamide with 2-chloro-1,3-dicarbonyl compounds gave the respective thiazole derivatives. The structures of the newly synthesised compounds were confirmed by their elemental analysis and spectral data.

Ring opening in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes gives cyclic azomethine imines which are prone to exchange of arylidene moiety with (het)arylidenemalononitriles to form the metathesis products being new azomethine imines. These species were fixed as pyrazolines due to the 1,4-H shift or trapped by dimethyl acetylenedicarboxylate or CS2.

Diethyl acetylenedicarboxylate can be used as starting material giving similar results as dimethyl acetylenedicarboxylate.

The title compounds (III) are obtained via microwave-accelerated reaction of thioureas (I) with dimethyl acetylenedicarboxylate (II).

A simple and efficient one-pot three-component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH-acids, such as acetylacetone, 1,3-indandione, dibenzoylmethane, anthrone, and N,N-dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N-dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4-diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21067

HClO4–SiO2 has been found to be a highly efficient catalyst for the synthesis of substituted tetrahydropyrimidine and bis-tertahydropyrimidine derivatives in good to excellent yields involving the reaction of dimethyl acetylenedicarboxylate, amines/diamines, and formaldehyde. One-pot, atom economy, high-bond forming efficiency, environmentally benign, good yields, and mild reaction conditions are some of the salient features of this multicomponent reaction.

(Z)-Methyl 2-[3-(arylideneamino)-2-(arylidenehydrazono)-4-oxothiazolidin-5-ylidene]acetate prepared during the reaction between thiocarbonohydrazides and dimethyl acetylene dicarboxylate. Rational for there conversations involving the nucleophilic addition on C/C triple bond of dimethyl acetylenedicarboxylate are presented.

In some cases the reaction stops upon the addition of the imide or dimethyl acetylenedicarboxylate at the nitrogen of the imidazoline system.

The multicomponent assembly of dimethyl acetylenedicarboxylate, electron-deficient aldehydes, and triaryl- or trialkylphosphanes in a molar ratio of 3:1:6 gives γ-lactones bearing an α-phosphorus ylide moiety in moderate to good yields.

2,3-Bis(5-tert-butyl-2-methoxyphenyl)buta-1,3-diene was prepared by bromination of (Z)- and (E)-2,3-bis(5-tert-butyl-2-methoxyphenyl)-2-butene followed by treatment with zinc powder in a mixture of CH2Cl2 and acetic acid, which was converted to the corresponding o-terphenyl skeleton by the condensation with dimethyl acetylenedicarboxylate followed by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone.

The synthesis of polyfunctionalized pyrroles by reaction of a ketoxime with dimethyl acetylenedicarboxylate using europium(III) triflate as the catalyst is described.

Alternatively to dimethyl acetylenedicarboxylate (II), the corresponding diethyl esters can be used as well.

An efficient synthetic procedure for the synthesis of functionalized tetrahydrospiro[indoline-3,2′-quinoline] derivatives was successfully developed and involves the four-component reaction of arylamines, dimethyl acetylenedicarboxylate, isatins, and a cyclohexane-1,3-dione in acetic acid. The advantages of this reaction include the use of common starting materials and mild reaction conditions and it is operationally simple.

New and stable phosphorous ylides are obtained from a simple and efficient one-pot three-component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate in the presence of NH-heterocyclic compounds in excellent yields at an ambient temperature. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of the restricted rotation around the carbon–carbon partial double bond resulting from the conjugation of the ylide moiety with the adjacent carbonyl group. Dynamic effects are observed in the 1H NMR spectra that are attributed to the restricted rotation around the carbon–carbon double bond. The experimental rotational energy barrier (Δ G#) and other activation parameters on the basis of the 1H NMR study for the rotational interchangeable process of major and minor isomers in ylides 4a–dare reported. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:131–137, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20761

Since about the year 2000, the research area of asymmetric organocatalysis has grown rapidly to become one of the most fascinating and current fields in organic chemistry. In the last years, asymmetric domino reactions have widely benefited from this fast-growing field, as exemplified by the development of an explosive number of novel and powerful asymmetric organocatalytic domino processes, which allowed the easy construction of complex chiral molecular architectures from simple materials with high yields and very often remarkable enantioselectivities in a metal-free environment. Indeed, the possibility to join two or more organocatalytic reactions in one asymmetric domino process has become a challenging goal for chemists, due to several advantages from economical and environmental points of view, avoiding costly protecting groups and time-consuming purification procedures after each step, for example. This review aims to update the latest developments of this hot and fascinating field, covering the literature since the beginning of 2009. Abbreviations: Ac: acetyl; Ar: aryl; BDHP: 1,1′-binaphth-2,2′-diyl hydrogen phosphate; BA: Bronsted acid; BINAPO: 2-diphenylphosphino-2′-diphenylphosphinyl-1,1′-binaphthalene; BINOL: 1,1′-bi-2-naphthol; Boc: tert-butoxycarbonyl; Bn: benzyl; Bu: butyl; Bz: benzoyl; CSA: camphorsulfonic acid; Cy: cyclohexyl; Cbz: benzyloxycarbonyl; DABCO: 1,4-diazabicyclo[2.2.2]octane; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE: dichloroethane; de: diastereomeric excess; DFT: density functional theory; DHQ: hydroquinine; DHQD: dihydroquinidine; DIPEA: diisopropylethylamine; DKR: dynamic kinetic resolution; DMAD: dimethyl acetylenedicarboxylate; E: electrophile; ee: enantiomeric excess; ESI: electrospray ionization; Et: ethyl; Fu: furyl; Hept: heptyl; Hex: hexyl; HOMO: highest occupied molecular orbital; IBX: o-iodoxybenzoic acid; LB: Lewis base; LUMO: lowest unoccupied molecular orbital; Me: methyl; MOM: methoxymethyl; Mes: mesyl; MS: mass spectroscopy; MTBE: methyl tert-butyl ether; NADH: nicotinamide adenine dinucleotide; Naph: naphthyl; NHC: N-heterocyclic carbene; NMM: N-methylmorpholine; NMP: N-methylpyrrolidinone; Ns: nosyl; Nu: nucleophile; Oct: octyl; PCC: pyridinium chlorochromate; Pent: pentyl; PFBA: pentafluorobenzoic acid; Ph: phenyl; PMB: para-methoxybenzyl; Pr: propyl; Py: pyridine; r.t.: room temperature; TBA: tribromoacetic acid; TBS: tert-butyldimethylsilyl; TCBA: 2,4,6-trichlorobenzoic acid; TES: triethylsilyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; Thio: thiophene; TMEDA: tetramethylethylenediamine; TMS: trimethylsilyl; Tol: tolyl; Ts: 4-toluenesulfonyl (tosyl).

The C-alkylation of 2-benzyl-1,4,5,6-tetrahydropyrimidines (I) by ethyl benzoylacetate and dimethyl acetylenedicarboxylate, respectively, is studied.

Optimum conditions are examined for the reaction of several nitrogen-containing heterocycles with dimethyl acetylenedicarboxylate.

The present procedure has the advantage that the reactions are performed under neutral conditions and that the substances can be mixed without any activation or modification.

o-Alkynyl substituted N-heterocyclic ketones of type (I) and (V) react with the chromium carbene complex (II) to generate a dienylazaisobenzofuran intermediate which undergoes [8 + 2] cycloaddition with DMAD.