Three-component coupling reactions of isoquinolines, dimethyl acetylenedicarboxylate and indoles: a facile synthesis of 3-indolyl-1,2-dihydro-2-isoquinolinyl-2-butenedioate

A three-component coupling of isoquinolines, dimethyl acetylenedicarboxylate (DMAD) and indoles is achieved for the first time to produce dimethyl (E)-2-[1-(1H-3-indolyl)-1,2-dihydro-2-isoquinolinyl]-2-butenedioates in excellent yields and with high selectivity. The reaction proceeds smoothly at room temperature without a catalyst. Quinoline, DMAD and indole also undergo smooth coupling to furnish dimethyl (E)-2-[2-(1H-3-indolyl)-1,2-dihydro-1-quinolinyl]-2-butenedioate under similar conditions. This method is very useful to functionalize both indoles and aza-aromatic compounds in a one-pot operation.     

Reaction between naphthols and dimethyl acetylenedicarboxylate in the presence of phosphites. Synthesis of stable oxa-2 lambda 5-phosphaphenanthrenes,and benzochromene derivatives

The reaction of dimethyl acetylenedicarboxylate (DMAD) with 2-naphthol in the presence of trimethyl or triphenyl phosphite leads to stable dimethyl oxa-2 lambda 5-phosphaphenanthrene derivatives in good yields. The reaction of DMAD and trimethyl phosphite in the presence of 1-naphthol or 8-hydroxyquinoline leads to dimethyl 2-(dimethoxyphosphoryl)-3-(1-hydroxy-2-naphthyl)succinate or dimethyl 2-(dimethoxyphosphoryl)-3-(8-hydroxyquinolin-7-yl)-succinate in excellent yields. Using triethyl phosphite and DMAD in the presence of 2-naphthol or 1-naphthol produces methyl 3-oxo-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate or methyl 2-oxo-3,4-dihydro-2H-benzo[h]-chromene-4-carboxylate in excellent yields.     

Further study on 1,3-dialkylaminouracil with dimethyl acetylenedicarboxylate

On the treatment of 1,3-dialkyl-6-alkylaminouracil (1) with dimethyl acetylenedicarboxylate (DMAD), we were able to develop a new synthesis of deazapurine (pyrrolo[2,3-d]pyrimidine, 4) , and proposed the plausible mechanism for the formation of 3 and 4 from the adduct [dimethyl 2-(1,3-dialkyl-6-alkylamino-2,4-dioxopyrimidin-5-yl)fumarate, 2] of 1 with DMAD.     

Synthesis of dimethyl heterocyclic‐o‐dicarboxylates using dimethyl acetylenedicarboxylate

Dimethyl acetylenedicarboxylate (DMAD) is a very important and useful reagent for the preparation of dimethyl heterocyclic‐o‐dicarboxylates, which are key intermediates in the synthesis of fused pyridazine derivatives. The synthesis of thiopyranes by the Diels‐Alder reaction of dithiocarboxylate derivatives, synthesis of various cyclazines by [2 + 8] cycloaddition reactions, and synthesis of dimethyl pyrazolo[3,4‐b]pyridine‐5,6‐dicarboxylates and polycyclic heterocycles containing the 1,6‐naphthyridine ring system by the reaction of o‐aminonitrile compounds with DMAD are described here.     

One-pot three-component synthesis of functionalized spirolactones by means of reaction between aromatic ketones, dimethyl acetylenedicarboxylate, and N-heterocycles

A simple and convenient one-pot multi-component reaction has been described for the synthesis of functionalized spirolactones. This strategy demonstrated three-component reaction between aromatic ketones (11H-indeno[1,2-b]quinoxalin-11-one) and dimethyl acetylenedicarboxylate (DMAD) in the presence of N-heterocycles, such as pyridine, quinoline, and isoquinoline in CH₂Cl₂ at ambient temperature without use of any catalyst or activator.     

Novel 1,2,3,4‐Tetrahydroquinazolinones via Reaction of 2‐Amino‐N‐substituted Benzamides and Dimethyl Acetylenedicarboxylate

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.     

Reactions of arylaldehydes and N-sulfonated imines with dimethyl acetylenedicarboxylate catalyzed by nitrogen and phosphine lewis bases

[reaction: see text] In the reaction of arylaldehydes or N-sulfonated imines (0.5 mmol) with dimethyl acetylenedicarboxylate (DMAD) (0.6 mmol) catalyzed by pyridine or DMAP (20 mol %), we found that (E)-2-aryl-but-2-enedioic acid dimethyl ester 1 or (E)-2-[aryl-(toluene-4-sulfonylimino)methyl]-but-2-enedioic acid dimethyl ester 2 was formed in good yields at 60 degrees C in THF. A plausible mechanism has been proposed.     

Copper(II) in organic synthesis. IV Reaction of the copper(II) acetate complex of isatin-3-arylhydrazones with dimethyl acety-lenedicarboxylate.

The copper(II) acetate complex of isatin-3-phenylhy-drazone (2a) reacted with dimethyl acetylenedicarboxylate (DMAD) by two competitive pathways: a Cu⁺⁺ oxidation of the ligand and a [2+2] cycloaddition. The former reaction gave 3-car- benindolin-2-one (13) which reacted with DMAD in a l,3-dipolar cycloaddition, to give 3a. This was synthesized by an independent route. The phenyl radical, generated in the same process, was trapped by three DMAD and gave $\text{4a}$. The [2+2] cycloaddition gave a spiro adduct 10 which, by electrocyclic ring opening and intramolecular cyclization, allowed isolation of a pyridazino [3,4-b] indole (|5a). The reaction was performed on $\text{p}$-chlorophe-nylhydrazone 1b and the structure of 5b was demonstrated by X-ray analysis. A rationalization of the reactivity was attempted in terms of MO interactions of the reactants.     

The reaction of methyl 3-amino-4-cyano-5-methylthiothiophene-2-carboxylate with dmad. A new synthesis of polyfunctionalized quinolines

The Reaction of Methyl 3-Amino-4-cyano-5-methylthiothiophene-2-carboxylate ( 2 ), which was prepared by the reaction of bis(methylthio)methylenepropanedinitrile ( 1 ) with methyl thioglycolate followed by dimethyl acetylenedicarboxylate (DMAD) in the presence of potassium carbonate in dimethyl sulfoxide gave the polyfunctionalized quinoline, pentamethyl 4-amino-5-mercaptoquinoline-2,3,6,7,8-pentacarbox-ylate ( 3 ). The oxidation of 3 with iodine in DMSO provided the novel ring system in the form of the derivative, pentamethyl 2H-isothiazolo[3,4,5-de]quinoline-3,4,6,7,8-pentacarboxylate ( 4 ).     

An experimental and theoretical reinvestigation of the Michael addition of primary and secondary amines to dimethyl acetylenedicarboxylate

Theoretical calculations of the Michael addition of diethylamine, pyrrolidine, and benzylamine to DMAD at the DFT (B3LYP/6-31+G^∗) level indicate that the reaction follows a stepwise mechanism via a zwitterionic intermediate. The reactions have low activation barriers, 13–15 kcal mol⁻¹ and are exothermic, ΔH° = −29 to −44 kcal mol⁻¹. The detailed investigation of the reaction of benzylamine with DMAD reveals participation of the reactant-, transition structure-, and the product-complexes and that the 1,3-prototropic shift occurs through the benzylamine molecule. It also predicts formation of dimethyl 2-(N-benzylimino)butane-1,4-dicarboxylate as one of the products, which has been duly isolated and characterized experimentally.     

Synthesis of pyrrolizines by intramolecular capture of 1,4-dipolar intermediates in reactions of enamines with dimethyl acetylenedicarboxylate

Solvent polarity and reaction temperature strongly influence the reactions of dimethyl acetylenedicar-boxylate (DMAD) with 1-pyrrolidinyl enamines of acyclic and cyclic ketones. Whereas DMAD and 1-[1-phenyl-2-(phenylthio)ethenyl]pyrrolidine (3) give only a mixture of the isomeric 1,3-butadienes (5) in apolar solvents, in methanol the main product is the pyrrolizine 7, together with 5. Again in methanol, DMAD reacts at 0-5° with 8, 9 and 10 to give exclusively 1:1 adducts, the pyrrolizines 11,12 and 13, respectively, whereas at ?50° 8 and 9 give 1:2 (enamine : DMAD) adducts, the pyrrolizines 14 and 15, respectively; a single crystal X-ray analysis of 14 gave the structure of the 1:2 adducts. In the same solvent methyl propiolate and 8 give only the linear Michael adduct 17. The enamine-ketone 18 reacts with DMAD in propylene carbonate at 0–5° to give, via (2 + 2)-cycloaddition and ring expansion, 19, and the linear Michael adduct 20. The mechanism of (2 + 2)-cycloaddition and pyrrolizine formation is discussed in terms of a common tied-ion pair intermediate formed in the first, rate-determining step, followed by a second solvent-dependent step.     

One-pot synthesis of novel 3,10-dihydro-2H-1,3-oxazepino[7,6-b]indoles via 1,4-dipolar cycloaddition reaction

3,10-Dihydro-2H-1,3-oxazepino[7,6-b]indoles are synthesized via a convenient one-pot three-component 1,4-dipolar cycloaddition reaction, involving 3-alkyl(aryl)imidazo[1,5-a]pyridines, dimethyl acetylenedicarboxylate (DMAD) and N-alkylisatins. Structures of the newly synthesized heterocycles are evidenced from spectral data and further confirmed by single crystal X-ray diffraction. A plausible reaction mechanism is advanced, whereby the intermediate 1,4-dipole, generated in situ from imidazo[1,5-a]pyridine and DMAD, initially adds to the keto group of N-alkylisatins to form the corresponding 1,3-oxazin-spiro-oxindole cycloadduct. The latter undergoes subsequent unprecedented skeletal rearrangement through a cascade of bond breaking and bond making processes, eventually leading to ring enlargement, furnishing the tricyclic oxazepino[7,6-b]indole ring system as the end product.     

Some aspects of the chemistry of pyrimido[1,2-B]pyridazinones

On reacting the 3-aminopyridazines 1a,d,e with dimethyl acetylenedicarboxylate (DMAD), the pyrimido[1,2-b]pyridazin-2-(2H)-ones 2e-g , whereas starting from 1f , the 4(4H)-ones 5a and 3b,d were prepared. In the 2(2H)-one series, the reactions of 2b with various amino compounds resulted in various types of products. The reaction of N-methylaminopyridazines 1g,h with DMAD led to the endo-N-substituted derivatives 8a,b , whereas 1h with diethyl ethoxymethylenemalonate (DEM) gave the exo-N-substituted compound 1k. The constitution of the compounds was proved by spectroscopic and chemical evidences.     

Duplicated ring enlargement of 4,9-methanothia[11]annulene to 6,11-methanothia[15]annulene

3,10-Dipyrrolidinyl-4,9-methanothia[11]annulene reacts with excess dimethyl acetylenedicarboxylate (DMAD) in refluxing toluene to give ring-enlarged 6,11-methanothia[15]annulene. X-ray crystallographic analysis of the product shows two different cis,trans-dienyl parts in the ring system. Product formation possibly involves π-facial selective addition of the enamine with DMAD and torque-selective ring opening of the intermediate cyclobutenes.     

Microwave-induced generation and reactions of nitrile sulfides: an improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles

The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation of 1,3,4-oxathiazol-2-ones, have been investigated. By this approach ethyl 1,2,4-thiadiazole-5-carboxylates 3 were prepared in good yield by cycloaddition of the nitrile sulfides to ethyl cyanoformate. Similarly, reaction of benzonitrile sulfide with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 3-phenylisothiazole-4,5-dicarboxylate (5). In contrast, o-hydroxybenzonitrile sulfide, generated from the corresponding oxathiazolone 2d, reacted with DMAD to give methyl 4-oxo-4H-[1]benzopyrano[4,3-c]isothiazole-3-carboxylate (8) in high yield. A ca. 1:1 mixture of ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7) was formed from benzonitrile sulfide and ethyl propiolate. The corresponding reaction with diethyl fumarate gave diethyl trans-4,5-dihydro-3-phenylisothiazole-4,5-dicarboylate (10). 3-Arylisothiazoles, unsubstituted at both the 4- and 5-positions, were prepared from the reaction of 5-aryl-1,3,4-oxathiazolones with norbornadiene by a pathway involving cycloaddition of the nitrile sulfide to the norbornadiene, followed by retro-Diels-Alder extrusion of cyclopentadiene from the resulting isothiazoline cycloadduct 12. In summary, the use of microwave irradiation, rather than conventional heating methods, allows nitrile sulfide generation and reactions to be carried out in shorter times, with easier work-up and, in some cases, in higher yields.     

Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate and subsequent site-selective Suzuki-Miyaura reactions

The [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 4-chloro-3,5-dihydroxyphthalate. Site-selective Suzuki-Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-chlorophthalates containing two different aryl groups.     

Heterocyclisation of substituted ylidenethiocarbonohydrazides using dimethyl acetylenedicarboxylate

A facile and rapid procedure for the synthesis of dimethyl-2-[3-amino-5-(2-methoxy-2-oxoethylidene)-4-oxothiazolidin-2-ylidenehydrazono]succinate, dimethyl {[2-alkylidenehydrazono)-5-(2-methoxy-2-oxoethylidene)-4-oxothiazolidin-3-yl)amino]succinate and methyl (4-amino-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-yl)acetate affording yields of 61–54 %, 22–18 % and 14–11 %, respectively, via a condensation reaction of dimethyl acetylenedicarboxylate (DMAD) with (substituted ylidene)thiocarbonohydrazides. One of the products was conclusively confirmed by single-crystal X-ray analysis. A mechanism for the formation of the products is presented.     

Highly regioselective synthesis of 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylate derivatives under mild conditions

7-Oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylate derivatives are biologically and pharmacologically useful heterocycles. An efficient synthetic methodology for this class of compounds was developed through catalyst-free, one-pot reactions between 2-aminothiadiazoles and dimethyl acetylenedicarboxylate (DMAD) in THF with the aid of ultrasound irradiation. The reactions show applicability to a wide range of substrates and high regioselectivity for the “7-one” products over their “5-one” isomers. Detailed reaction mechanisms were mapped out by theoretical modeling analysis based on density functional theory (DFT) calculations. Mechanistic studies indicate that the favored reaction pathway involves a sequence of hydrogen-bond directed Michael addition, synergistic proton transfer/five-membered ring opening, and intramolecular cyano hetero-Diels-Alder reactions.     

New Cycloadditon Reaction of 2-Chloroprop-2-enethioamides with Dialkyl Acetylenedicarboxylates: Synthesis of Dialkyl 2-[4,5-bis(alkoxycarbonyl)-2-(aryl{alkyl}imino)-3(2H)-thienylidene]-1,3-dithiole-4,5-dicarboxylates

The 1,3-dipolar cycloaddition of 1,2-dithiole-3-thiones with alkynes to form 1,3-dithioles is one of the most studied reactions in this class of polysulfur-containing heterocycles. Nucleophilic substitution of chlorine atoms in dimethyl 2-(1,2-dichloro-2-thioxoethylidene)-1,3-dithiole-4,5-dicarboxylate, which was obtained by addition one molecules of DMAD to 4,5-dichloro-3H-1,2-dithiole-3-thione, led to a series of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides. Cycloaddition reaction of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides with activated alkynes led to the unexpected formation of 2-(thiophen-3(2H)-ylidene)-1,3-dithioles via new intermediate, 1-(1,3-dithiol-2-ylidene)-N-phenylethan-1-yliumimidothioate. Structure of dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate was finally proven by single crystal X-ray diffraction study. Optimized reaction conditions and a mechanistic rationale for the 1,3-dipolar cycloaddition of novel intermediate are presented.     

Cyclocondensation of 3-amino-2-hydrazino-4(3H)-pyrimidinones with dimethyl acetylenedicarboxylate. Formation of 1-amino-2,6-dihydro-2,6-dioxo-1H-pyrimido[1,2-b][1,2,4]triazine-3-acetic acid esters

[(1-Amino-6-hydroxy-2(1H)-pyrimidinylidene)hydrazone]butanedioic acid dimethyl esters 3 , formed from 3-amino-2-hydrazino-4(3H)-pyrimidinones and dimethyl acetylenedicarboxylate in acetic acid at room temperature, underwent a facile, thermal rearrangement to 1-amino-2,6-dihydro-2,6-dioxo-1H-pyrimido-[1,2-b]-[1,2,4]triazine-3-acetic acid methyl esters 6 in hot acetic acid.