Denis N. Tomilin

Direct synthesis of butadiynyl-substituted pyrroles under solvent- and transition metal-free conditions

The work describes a convenient and highly efficient C–H butadiynylation of substituted pyrroles with the use of 1-halobutadiynes. The method requires only a simple grinding of substrates in a mortar under mild, solvent- and transition metal-free conditions and constitutes the first example of pyrrole butadiynylation via cross-coupling reaction with the use of 1-halobutadiynes. The scope of this mechanochemical approach covers 4,5,6,7-tetrahydro-1H-indole, its N-substituted derivatives and 2-phenylpyrrole and on the other hand ester and phenyl end-capped 1-halobutadiynes including chlorides, bromides and iodides. Interestingly, the method has proven effective also for weak electron withdrawing aryl substituted 1-halobutadiynes what has not been yet achieved for 1-haloacetylenes. Such reactivity was unexpected in the view of the literature data and opened a gate to the plethora of substrates for organic synthesis including syntheses of pharmaceuticals. An X-ray analysis of two coupling products is also presented.

Synthesis of secondary propargyl alcohols from aromatic and heteroaromatic aldehydes and acetylene in the system KOH-H2O-DMSO

Ethynylation of aromatic and heteroaromatic aldehydes with acetylene under atmospheric pressure in the catalytic system KOH-H2O-DMSO (aldehyde-KOH molar ratio 1 : 2, −5 to −7°C, 3 h) gave secondary propargyl alcohols in 46–67% yield.

Cross-coupling of 4,5,6,7-tetrahydroindole with functionalized haloacetylenes on active surfaces of metal oxides and salts

Screening was performed of metal oxides (MgO, CaO, ZnO, BaO, Al2O3, TiO2, ZrO2) and salts (CaCO3, K2CO3, ZrSiO4) as active surfaces for the reaction of ethynylation of 4,5,6,7-tetrahydroindole with ethyl bromopropynoate and bromobenzoylacetylene. It was established that Ca, Mg, Zn, and Ba oxides assist the ethynylation of 4,5,6,7-tetrahydroindole, and their activity in the reaction with ethyl bromopropynoate considerably exceeds that of aluminum oxide. The ethynylation is accompanied with the formation of intermediate E-2-(1-bromoethenyl)-4,5,6,7-tetrahydroindole and side 1,1-di(4,5,6,7-tetrahydroindol-2-yl)ethenes and 1,1-di(4,5,6,7-tetrahydroindol-2-yl)bromoethanes.

First example of the synthesis of pyrrolecarbaldehyde with electron-deficient acetylene substituents

Pyrrolecarbaldehydes with acetylene substituents are widely applied to organic syntesis although the systematic research in this fi eld has been started only a little earlier than a decade ago. Now the ethynyl pyrrolecarbaldehydes are used for the preparation of polyfunctional derivatives of pyrrole and indole of defi nite structure and properties [1–6]. They also play a key role in designing macrocycles whose natural analogs possess special kinds of biological action [7–12]. Now the ethynylpyrrolecarbaldehydes are obtained as a rule by criss-coupling of diffi cultly available and unstable halopyrrolecarbaldehydes with terminal acetylenes [4–12] or their organometallic derivatives [13] in the presence of palladium catalysts (Sonogashira reaction). However the ethynylpyrrolecarbaldehydes containing in the acetylene substituent electron-acceptor functions are not known up till now since the Sonogashira reaction is of low effi ciency with activated acetylenes [14]. Yet such ethynylpyrrolecarbaldehydes would provide new opportunities to the targeted organic synthesis, in particular, for the preparation of polyfunctional stable organic radicals and polyradicals [15–17]. In this communication we describe for the fi rst time a simple convenient protocol of the synthesis of such compounds by an example of the preparation of the fi rst specimen of pyrrolecarbaldehydes with the electron-defi cient acetylene substituent. It includes the acetal protection of the aldehyde group of the pyrrole-2-carbaldehyde by the reaction with 2,2-dimethylpropanediol in the presence of p-toluenesulfonic acid, introducing benzoylethynyl group into the pyrrole ring of acetal I by “palladiumless” cross-coupling with 3-bromo-1-phenyl-2-propyn-1-one on alumina, and the removal of the acetal protection in ethynylpyrrole II by the mild acid-catalyzed hydrolysis

Expedient Strategy for the Synthesis of 5-Acylethynylpyrrole-2-carbaldehydes

Abstract 5-Acylethynylpyrrole-2-carbaldehydes have been synthesized from the protected pyrrole-2-carbaldehydes by their transition-metal-free topochemical mechanoactivated ethynylation with acylbromoacetylenes in a solid Al2O3 medium (room temperature, 6 h, 41–54% yields). GRAPHICAL ABSTRACT

Transition metal-free cross-coupling of furan ring with haloacetylenes

Abstract On the example of menthofuran, a naturally abundant compound, it has been shown for the first time that the furan ring can be readily cross-coupled with acylhaloacetylenes in the solid Al2O3 powder at room temperature to afford the corresponding 2-ethynyl derivatives in up to 88% yield. The reaction represents a ring closing/ring opening process that includes reversible formation of the intermediate cycloadducts further producing acetylene derivatives with elimination of HHal.

Transition-Metal-Free, Atom- and Step-Economic Synthesis of Aminoketopyrrolizines from Benzylamine, Acylethynylpyrroles, and Acylacetylenes

A concise, atom-economic strategy for the synthesis of pyrrolizines with amino and keto substituents has been developed. It includes the following key steps: (i) the base-catalyzed (K3PO4/DMSO) addition of a benzylamine to 2-acylethynylpyrroles and (ii) noncatalyzed addition of enaminones obtained to the triple bond of acylacetylenes followed by intramolecular cyclization of the intermediate pentadiendiones thus formed to the target 1-(benzylamino)-2-acyl-3-methylenoacylpyrrolizines.

First example of favorskii ethynylation of pyrrolecarbaldehydes: Synthesis of 1-(1-methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol

Abstract1-(1-Methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol has been synthesized for the first time by ethynylation of 1-methyl-1H-pyrrole-2-carbaldehyde with acetylene in the superbasic system KOH-DMSO-H2O under atmospheric pressure.

Hydroamination of 2-Ethynyl-4,5,6,7-tetrahydroindoles: Toward2-Substituted Amino Derivatives of Indole

Hydroamination of 1-phenyl-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-yn-1-ones with secondary dialkylamines proceeds under mild conditions (room temperature, aqueous ethanol, 1 h) to afford the corresponding (2E)-3-dialkylamino-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-en-1-ones in 72-92% stereoselectivity and 64-88% yield. Under the same conditions, ethyl 3-(4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-ynoates react with dimethylamine and diethylamine in different ways; dimethylamine converts the ester function into an amide, giving the corresponding N,N-dimethyl-3-(4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-ynamides in 70-86% yield, whereas diethylamine adds to the triple bond to give the corresponding ethyl 3-(diethylamino)-3-(4,5,6,7-tetrahydro-1H indol-2-yl)prop-2-enoates with ∼100% stereoselectivity and up to 85% yield. The difference in the reactivity of the two amines can be rationalized in terms of steric hindrance.