Novel and convenient synthesis of substituted quinolines by copper- or palladium-catalyzed cyclodehydration of 1-(2-aminoaryl)-2-yn-1-ols

A general and convenient synthesis of substituted quinolines by regioselective copper- or palladium-catalyzed 6-endo-dig cyclization-dehydration of 1-(2-aminoaryl)-2-yn-1-ols is reported. The crude substrates were easily obtained by the Grignard reaction between the appropriate alkynylmagnesium bromide and 2-aminoaryl ketones and could be used without further purification for the subsequent cyclization step. Heteroannulation reactions were carried out in MeOH or DME as the solvent at 60 or 100 degrees C in the presence of CuCl(2) or PdX(2) (in conjunction with 10 equiv of KX, X = Cl, I) as the catalyst to afford the quinoline derivatives in good to excellent isolated yields based on starting 1-(2-aminoaryl)-2-yn-1-ols (66-90%).     

Versatile synthesis of quinoline-3-carboxylic esters and indol-2-acetic esters by palladium-catalyzed carbonylation of 1-(2-aminoaryl)-2-yn-1-ols

1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI2-KI catalytic system, in the presence and in the absence of an external oxidant. Under oxidative conditions (80 atm of a 4:1 mixture of CO-air, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), 1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group were selectively converted into quinoline-3-carboxylic esters in fair to good yields [45-70%, based on starting 1-(2-aminoaryl)ketones], ensuing from 6-endo-dig cyclization followed by dehydration and oxidative methoxycarbonylation. On the other hand, indol-2-acetic esters, deriving from 5-exo-dig cyclization followed by dehydrating methoxycarbonylation, were selectively obtained in moderate to good yields [42-88%, based on starting 1-(2-aminoaryl)ketones] under nonoxidative conditions (90 atm of CO, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), in the case of 1-(2-aminoaryl)-2-yn-1-ols bearing either a primary or secondary amino group and substituted with a bulky group on the triple bond.     

Cascade reactions: a new synthesis of 2-benzofuran-2-ylacetamides by sequential Pd(0)-catalyzed deallylation-Pd(II)-catalyzed aminocarbonylative heterocyclization of 1-(2-allyloxyaryl)-2-yn-1-ols

A general and efficient synthesis of 2-benzofuran-2-ylacetamides 5 starting from 1-(2-allyloxyaryl)-2-yn-1-ols 1, amines 4, and CO, in the presence of catalytic amounts of PdI2 in conjunction with PPh3 and KI, has been developed based on the "sequential homobimetallic catalysis" concept, that is, a process in which two different complexes of the same metal, but in two different oxidation states, promote two catalytic cycles in sequence. The first cycle corresponds to a Pd(0)-catalyzed aminodeallylation of 1 with formation of the free phenol 2, which then undergoes Pd(II)-catalyzed aminocarbonylative heterocyclization to give the final product 5.     

Gold-catalyzed cyclization of (Z)-2-en-4-yn-1-ols: highly efficient synthesis of fully substituted dihydrofurans and furans

[reaction: see text] The gold-catalyzed cyclization of (Z)-enynols offers an efficient and straightforward route to stereodefined (Z)-5-ylidene-2,5-dihydrofurans and fully substituted furans under extremely mild reaction conditions. Importantly, the results indicated that both the oxyauration and the proto-demetalation steps are highly stereoselective.     

Alk-2-yn-1-amines in the synthesis of substituted quinolines in the presence of palladium complexes

An effective one-step procedure has been developed for the synthesis of 4- and 2,3,4-substituted quinolines via reaction of o-iodoaniline with alk-2-yn-1-amines in the presence of Pd(OAc)₂ as catalyst.     

Silver Acetate Catalyzed Hydroamination of 1-(2-(Sulfonylamino)phenyl)prop-2-yn-1-ols to (Z)-2-Methylene-1-sulfonylindolin-3-ols

A method to prepare (Z)-2-methylene-1-sulfonylindolin-3-ols efficiently that relies on silver acetate catalyzed hydroamination of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols is reported. The reactions proceed rapidly at room temperature with catalyst loadings as low as 1 mol % under conditions that did not require the exclusion of air or moisture. The utility of this N-heterocyclic ring-forming strategy as a synthetic tool that makes use of unsaturated alcohols was exemplified by the conversion of the (Z)-2-methylene-1-sulfonylindolin-3-ol to examples of other members of the indole family of compounds.     

Gold-catalyzed cycloisomerizations of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols to 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols

A method to prepare 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols by gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols with N-iodosuccinimide (NIS) is reported. The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in good to excellent yields (70-99%). The mechanism is suggested to involve activation of the alkyne moiety of the substrate by the gold(I) catalyst. This triggers intramolecular addition of the tethered aniline moiety to give a vinyl gold intermediate, which undergoes iododeauration with NIS to give the (E)-2-(iodomethylene)indolin-3-ol adduct. Subsequent 1,3-allylic alcohol isomerization (1,3-AAI) followed by formylation of this vinyl iodide intermediate then gives the 1H-indole-2-carbaldehyde.     

KO(t)Bu-promoted three-component coupling of aldehydes and alkynes: highly efficient synthesis of 1-en-4-yn-3-ols and 2-en-4-yn-1-ols

A KO(t)Bu-promoted three-component coupling reaction of aldehydes and alkynes without a transition-metal catalyst was developed in which the sequential addition/isomerization/addition processes take place in one pot. This reaction could be developed into a straightforward and effective method for rapid access to stereodefined (E)-1-en-4-yn-3-ol and (Z)-2-en-4-yn-1-ol compounds.     

A general and efficient synthesis of substituted furans and dihydrofurans via gold-catalyzed cyclization of (Z)-2-en-4-yn-1-ols

A highly efficient Au-catalyzed cyclization of (Z)-enynols that proceeds under mild reaction conditions has been developed. This methodology provides rapid access to substituted furans and stereodefined (Z)-5-ylidene-2,5-dihydrofurans in a regioselective manner from suitably substituted (Z)-2-en-4-yn-1-ols.     

Synthesis of benzothiophene derivatives by Pd-catalyzed or radical-promoted heterocyclodehydration of 1-(2-mercaptophenyl)-2-yn-1-ols

Novel and convenient approaches to benzothiophene derivatives 3 and 5 have been developed, based on heterocyclization reactions of 1-(2-mercaptophenyl)-2-yn-1-ols 2 or 4, respectively, readily available from alkynylation of 2-mercaptobenzaldehydes or 1-(2-mercaptophenyl) ketones 1. In particular, 1-(2-mercaptophenyl)-2-yn-1-ols 2, bearing a CH(2)R substituent on the triple bond (R = alkyl, aryl), were conveniently converted in fair to good yields (55-82%) into (E)-2-(1-alkenyl)benzothiophenes 3 when allowed to react in the presence of catalytic amounts (2 mol %) of PdI(2) in conjunction with KI (KI:PdI(2) molar ratio =10) at 80-100 °C in MeCN as the solvent, through a heterocyclodehydration process. On the other hand, 2-alkoxymethylbenzothiophenes 5 were selectively obtained in fair to excellent yields (49-98%) via a radical-promoted substitutive heterocyclodehydration process, by reacting 1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an alkyl or aryl substituent on the triple bond) in alcoholic media at 80-100 °C in the presence of a radical initiator, such as AIBN.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

Syntheses of substituted 2-(l-methyl-2-imidazolyl)quinolines

Reaction of methyllithium with 1-methy1-2-imidazolecarboxaldehyde afforded the corresponding alcohol 2. Oxidation of compound 2 with manganese dioxide gave 2-acety1-1-methylimidazole ( 3 ). Using compound 3 and substituted isatins 4 , the corresponding quinoline-4-carboxylic acids ( 5 ) were prepared. The reaction of acid imidazolides of 5 with appropriate amines yielded the amides 6 . Carbamic acid esters 10 were prepared by the Curtius rearrangement in good yield. Substituted quinolin-4-amines 13 were obtained by the acid hydrolysis of compound 10 (R₁ = t-Bu). Alkylation of amines 13 with diakylaminoalkyl chlorides gave compounds 14 .     

Palladium-catalyzed one-pot synthesis of polysubstituted furans from alkynoates and 2-yn-1-ols

Easily accessible propargyl vinyl ethers are found to be acyclic precursors to construct furan derivatives. According to the reactive behavior of the substrates and the regulation of reaction conditions, three synthetic routes to polysubstituted furans via palladium-catalyzed reactions of propargyl vinyl ethers in situ-prepared from alkynoates and 2-yn-1-ols are presented herein. These methods could have potential application in synthetic and pharmaceutical chemistry for its facilitation and accessible starting materials.     

Synthesis and fungicidal activity of substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols

A series of new substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols has been obtained by the interaction of substituted 3-(oxiranyl)pyridines with 4-chlorophenol or sodium 4-chlorophenoxide for pharmacological and agrochemical screening. Fungicidal activity has been shown for the obtained compounds.     

A novel rearrangement of 1-(2-aminoaryl)imidazoles

6-Ethyl-2,4-bis(1H-imidazol-1-yl)pyrimidin-5-amine was found to undergo a novel rearrangement in the presence of acetic anhydride. The structure of the rearrangement product was deduced using a combination of one- and two-dimensional nmr methods. Confirmation of the structure was obtained by unambiguous synthesis of a reduced analog and establishment of the identity of this material with material prepared by reduction of the rearrangement product. Examination of three related cases indicated that the rearrangement process is significant only when both positions adjacent to the aryl amino group are substituted.     

Nitroimidazoles X . Syntheses of substituted 2-(1-methyl-5-nitro-2-imidazolyl)quinolines

Reduction of substituted-2-nitrobenzaldehyde (1) afforded substituted-2-aminobenzaldehyde (2) . Reaction of compound 2 with 2-acetyl-1-methyl-5-nitroimidazole (3) under basic conditions afforded substituted 2-(1-methyl-5-nitro-2-imidazolyl)quinolines 4 . Reaction of compound 4 (R = X) with hydrogen peroxide in acetic acid afforded compound 5 which was transformed to compound 6 with phosphorus oxychloride.