Formal High-Order Cycloadditions of Donor-Acceptor Cyclopropanes with Cycloheptatrienes.

Design of various cycloaddition / annulation processes is one of the most intriguing challenges during all time in the development of the donor-acceptor (D-A) cyclopropanes chemistry. In this work, a new missing class of formal high-order [6+n]-cycloaddition and annulation processes of D-A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D-A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was study in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates from starting D-A cyclopropanes, when other Lewis acids are ineffective and non-selective. New important examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]- cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself also can successfully act as a hydride anion donor which allows ionic hydrogenation of D-A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered-based carbocycles has been developed.

Coupling of Styrylmalonates with Furan and Benzofuran Carbaldehydes: Synthesis and Chemistry of Substituted (4-Oxocyclopent-2-enyl)malonates.

On the basis of the reaction of ß-styrylmalonates with furfural derivatives in the presence of GaCl3 that occurs with opening of the furan ring, an efficient diastereoselective method for the synthesis of trisubstituted cyclopentenones containing a 1,4-diketone moiety was developed. The regularities of the reaction were studied, and a number of chemical reactions of the resulting substrates were carried out. A mechanism for the formation of substituted (4-oxo-2-arylcyclopent-2-enyl)malonates was suggested.

Reactions of Styrylmalonates with Aromatic Aldehydes: Detailed Synthetic and Mechanistic Studies.

Reactions of styrylmalonates with aromatic aldehydes in the presence of Lewis and Brønsted acids and their regularities have been studied in detail. Approaches to the synthesis of various polysubstituted 5,6-dihydropyran-2-ones, indenes, aryl-containing dienes and trienes, cyclopentadienes, and polycyclic lactones have been developed with chemo-, regio-, stereo-, and diastereoselectivity control. The mechanisms of these reactions were studied in depth using multinuclear NMR experiments, monitoring the reactions in the NMR tube, and 18O isotope labeling.

GaCl3-Mediated Cascade [2 + 4]-Cycloaddition/[4 + 2]-Annulation of Donor-Acceptor Cyclopropanes with Conjugated Dienes: Strategy for the Construction of Benzobicyclo[3.3.1]nonane Skeleton.

Structurally important benzobicyclo[3.3.1]nonane derivatives were synthesized by a gallium trichloride mediated reaction of readily available donor-acceptor cyclopropanes (DACs) with 1,3-dienes as a one-pot cascade ionic [2 + 4]-cycloaddition/Friedel-Crafts-type cyclization process. At the first stage, DACs act as sources of formal gallium 1,2-zwitterionic complexes to give 6-benzylcyclohex-3-ene-1,1-dicarboxylates that are converted under certain conditions in the presence of GaCl3 to give benzobicyclo[3.3.1]nonanes in 30-74% yields. The process is tolerant of varying substituents at different positions of the main framework. Further, potentially useful modifications of benzobicyclo[3.3.1]nonane derivatives are demonstrated. 2-Cyclopropylbutadiene reacts with DAC at higher temperature more deeply with cleavage of three-membered rings in both cyclopropane substrates, and twofold alkylation of the Ph-substituent at ortho- and meta-positions, that leads to a 1,2,7,8,9,10-hexahydro-6H-7,10a-methanocycloocta[cd]indene skeleton. Cyclopropane-1,1-diesters containing a bulky substituent in the ester group react with isoprene in a different way to give bicyclic lactones containing a 2-oxabicyclo[2.2.2]octan-3-one moiety.

Three-Component GaHal3-Promoted Reactions of Substituted Methylidenemalonates and Donor-Acceptor Cyclopropanes with Propargyl Halides: Cascade Diastereoselective Construction of Five-Membered Lactones.

A new cascade three-component process for high trans,trans-diastereoselective assembly of five-membered (1-halovinyl)lactones has been developed. The process is based on reactions of substituted methylidenemalonates and cyclopropanedicarboxylates with 3-haloprop-1-ynes in the presence of GaHal3 and involves the intermediate in situ generation of 1,2-zwitterionic gallium complexes with [Ga(L)3]3+[GaX4-]3 composition. Chloro, bromo, and iodo derivatives can be obtained successfully. Mechanistic and stereochemical aspects of the process we developed have been studied and considered in detail.

Cascade Cleavage of Three-Membered Rings in the Reaction of D-A Cyclopropanes with 4,5-Diazaspiro[2.4]hept-4-enes: A Route to Highly Functionalized Pyrazolines.

A new cascade process for reactions of donor-acceptor cyclopropanes (DACs) with spiro[cyclopropanepyrazolines] in the presence of EtAlCl2 or Ga halides is reported. The action of a Lewis acid results in DAC activation and addition of the carbocationic intermediate to the azocyclopropane system of the pyrazoline with opening of the second three-membered ring and addition of a halide anion from the Lewis acid. A specific feature of this process is that one activated cyclopropane ring activates another one, and depending on the component ratio, the process can involve two DAC molecules and one pyrazoline molecule or one DAC molecule and two pyrazoline molecules. The process is tolerant to various functional groups and occurs with a wide range of substrates to give polyfunctionalized structures based on a 2-pyrazoline moiety.

Three-Component Gallium(III)-Promoted Addition of Halide Anions and Acetylenes to Donor-Acceptor Cyclopropanes.

A new strategy for the three-component addition of halide anions and acetylenes to donor-acceptor cyclopropanes (DACs) is presented. This reaction, which occurs with high E selectivity, is promoted by gallium(III) salts and based on the 1,2-zwitterionic reactivity of DACs. It opens up a new group of processes involving DACs. The reaction occurs readily with a broad range of substrates and is tolerant of various functional groups. This methodology makes it possible to assemble highly functionalized vinyl halides, which are very convenient building blocks in organic synthesis. A possible mechanism of this reaction and its stereochemical aspects are discussed in detail.

[4 + 2] Annulation of Donor-Acceptor Cyclopropanes with Acetylenes Using 1,2-Zwitterionic Reactivity.

A new process for the [4 + 2] annulation of donor-acceptor cyclopropanes with acetylenes under the effect of anhydrous GaCl3 using 1,2-zwitterion reactivity was elaborated. The reaction opens access to substituted dihydronaphthalenes, naphthalenes, and other fused carbocycles. The direction of the reaction can be efficiently controlled by temperature.

GaCl3 -Mediated Reactions of Donor-Acceptor Cyclopropanes with Aromatic Aldehydes.

A new strategy for cascade assembly of substituted indenes and polycyclic lactones based on reactions of donor-acceptor cyclopropanes and styrylmalonates with aromatic aldehydes in the presence of GaCl3 has been developed. The use of GaCl3 makes it possible to principally change the direction of the reaction known in this series of substrates and to perform the process in a multicomponent version. Generation of formal 1,2-zwitterionic intermediates owing to complexation of dicarboxylate groups with GaCl3 is the driving force of the reactions discovered. This method makes it possible to assemble indenylmalonates or indano[1',2':2,3]indano[2,1-b]furan-2-ones in one synthetic stage from readily available starting compounds with high regio- and diastereoselectivity. A mechanism of the reactions has been suggested using the (18) O label in benzaldehyde.

Three-Component Synthesis of Substituted Perhydropyrans from ß-Styrylmalonates, Aldehydes, and Alkoxyaluminum Dichlorides.

A three-component synthesis of substituted dimethyl dihydro-2H-pyran-3,3(4H)-dicarboxylates in up to 80% yields by the reaction of ß-styrylmalonates with aromatic or aliphatic aldehydes in the presence of ROAlCl2 prepared in advance either by exposure of EtAlCl2 with air access or by mixing equimolar amounts of AlCl3 with a primary or secondary alcohol has been developed. If EtAlCl2, itself, is used, dihydro-2H-pyran-3,3(4H)-diesters are not formed at all, while dimerization of styrylmalonates by (4 + 2)-annulation-type to give substituted tetrahydronaphthalenes is the main process. The possibility of using the CH-O-Al fragment of alkoxyaluminum dichlorides in cycloaddition reactions with α-CH-functionalization has been shown for the first time.

Styrylmalonates as an Alternative to Donor-Acceptor Cyclopropanes in the Reactions with Aldehydes: A Route to 5,6-Dihydropyran-2-ones.

A new strategy for modifying the reactivity of donor-acceptor cyclopropanes (DAC) has been suggested. It involves the use of isomeric styrylmalonates as alternative sources of reactive intermediates. The efficiency of the approach has been demonstrated in reactions with aromatic aldehydes. As a result, a new process for construction of the 5,6-dihydropyran-2-one skeleton has been developed. It efficiently occurs with high diastereoselectivity in the presence of BF3·Et2O; the products can be easily isolated by crystallization. The subsequent use of the resulting dihydropyranones in syntheses providing convenient access to various classes of compounds with broad molecular diversity has been demonstrated.