Heterocyclic compounds vinyl substitutions

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

A variety of arenes and heterocyclic compounds will react with alkenes in the presence of palla-dium(II) salts to produce vinyl substitution products (equation 3). 

Several other heterocyclic compounds have been used in the vinyl substitution. Quinones, for example, are readily substituted with a variety of heterocycles as well as with benzene.7 Heterocycles which react include 2-acetylfuran (5-position), furfural (5-position) (equation 5) methyl furoate (5-position), 2-ace-tylthiophene (5-position), N-benzenesulfonylpyirole (2-position), N-benzenesulfonylindole (3-position), 4-pyrone (3-position) and N-methyl-2-pyridone (3- and 5-positions). 

This correlation includes seven methy- and four halo-substituted benzenes, three heterocyclic compounds, and two phenols, along with benzene, naphthalene, and -NH2, -OCH3, -CN, -N02, -CHO, vinyl, and phenyl-substituted benzene. For aromatics, the range of values was only a factor of 5, and all data are within a factor of 1.6 of the correlation line therefore, simple calculations were likely to give data of about the same accuracy as experimental measurements (see Figure 5.31). 

A number of related distonic superelectrophiles have been generated from A-heteroaromatic compounds (Table 2). Vinyl-dications (111-112) have been produced from the ethynyl pyridines,40 while /V-alkenyl A-heterocycles provide dications (113-115).42a Vinyl-substituted A-heterocycles provide access to distonic superelectrophiles such as dication 116.39 Dications 117 and 118 are generated from their precursors, and both intermediates lead to efficient cyclization reactions with the adjacent... 

The work of Nazarov on vinyl ethynyl carbinols involves condensation of vinylacetylene with ketones in the presence of caustic potash and also their conversions, many of which are catalytic in nature. A review of his work involving polymerization, isomerization, hydrogenation, and other conversions was published by him (252). Hydration of divinylacetylenes in methanol solution in the presence of mercuric sulfate and sulfuric acid gave vinyl alkyl ketones. These can be reacted with hydrogen sulfide, amines, etc., to yield heterocyclic compounds. Substituted vinyl alkyl ketones underwent spontaneous cyclization to cyclopentenones. Nazarov summarized a decade of this research in this field in 1951 (253). His general review of organic syntheses based on acetylene is also of interest in this connection (254). 

The reactions of 1-vinyl- (R = H) and Tprop-2-enyl- (R = Me) substituted tetrahydroindoles 690 with tetracyano-ethylene in equimolar amounts in DMSO afforded 3-tricyanovinyl-substituted derivatives 691 as the only products (Equation 166) <2001ARK37>. Hence, the iV-alkenyl substituent in the pyrroles does not react with tetracyanoethy-lene according to the [2-1-2] cycloaddition mechanism typical of other 1-vinyl-substituted heterocyclic compounds. 

Formation of a cation radical of the diene may catalyze Diels-Alder reactions with certain dienophiles thus oxidation of substituted vinylindoles to the cation radical in the presence of a push-pull dienophile may form different heterocyclic compounds by the Diels-Alder reaction, for instance pyrido[l,2i7]indoles from vinylindoles and yS-enamino-esters [33]. Similarly, anodic oxidation in MeCN of certain oxazolidines in presence of vinyl ether leads to derivatives of oxazepines in a catalytic reaction in which the ring-opened radical cation of the oxazolidine adds to the vinyl ether and the radical cation of the resulting oxazepine oxidizes the oxazolidine [34]. 

U.v.-induced addition of secondary phosphines to chlorovinylsilanes and allyl(chloro)silanes leads to the silylphosphines (36). A similar addition to vinyl-substituted heterocyclic silanes has given compounds such as (37). ... 

These alkenylation products are easily utilized for the formation of heterocyclic compounds by cyclization reactions. For example, ethyl A -methyl-lV-(3,4-methylenedioxy)benzylglycinate is cyclopalladated regiospecifically at C(6) when treated with Li2PdCl4. The product, the di-p-chloro-bis(AOV-dialkylbenzylamine-6-C,iV)-dipalladium(II) complex 7.19, undergoes a substitution reaction via the insertion of methyl vinyl ketone between the palladium metal and the phenyl carbon atom. The resultant p-aryl-a,p-unsaturated ketone 7.20 is cyclized using anhydrous potassium carbonate in ethanol to the corresponding ethyl iV-methyl-1,2,3,4-tetrahydroisoquinolinium-3-carboxylate 7.21, as shown in Eq. (7.19) [76, 77]. 

Other reactions of synthetic utility can be observed when suitable nucleophiles are added to the reaction system. Typical examples of these nucleophiles are azide, cyanate, thiocyanate, and cyanide anions and thioanisole. Reactions using these nucleophiles provide a reaction path to functionalized vinyl derivatives. The transformations are successfully achieved by using triaryl-substituted alkenyl halides. The reactions with such nucleophiles provide an efficient path to heterocyclic compounds, among others. Some examples, such as the pyrroHnes, isoxazoHnes, isoquinolones, and thio derivatives, are prepared by this method and are shown in Equation 11.11. 

An example of the first type of study is the cationic pol erization of alkenes and heterocyclic monomers in the presence of 2-alWlfurans. As discussed above, electrophilic substitution at C5 is quite facile with these compounds and one can therefore prepare monofunctional oligomers bearing a furanic end-group. By a judicious choice of experimental conditions this transfer reaction will predominate over all other chain-breaking events and virtually all the chains will have the same terminal structure, i.e. a 5-oligomer-2-al lfuran. Structure 32 illustrates this principle with isobutyl vinyl ether oligomers capped by 2-methylfuran ... 

Yu and co-workers have expanded upon Ojima s work through development of an effective Rh-catalyzed protocol for the cyclization/hydrosilylation of allenyl carbonyl compounds to form silylated vinylcycloalkanols and heterocyclic alcohols.For example, reaction of tosylamide 44 (X = NTs, R = H, n= ) and triethylsilane catalyzed by Rh(acac)(GO)2 (1 mol%) under GO (10 atm) at 70 °G for 8h gave the silylated vinyl pyrrolidinol 45 (X = NTs, R = H, n= ) in 74% yield with exclusive formation of the m-diastereomer (Equation (29)). The rhodium-catalyzed reaction was also effective for the cyclization of alleneones and for the formation of carbocycles, oxygen heterocycles, and six-membered cyclic alcohols (Equation (29)). However, Rh-catalyzed cyclization/hydrosilylation of allenyl carbonyl compounds that possessed substitution on an allenyl carbon atom was not established (Equation (29)). The efficiency of the Rh-catalyzed reaction of allenyl carbonyl compounds depended strongly on GO pressure. Reactions run under 10 atm GO were more efficient than were... 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, seienophene[233,234], and cyclobutadiene iron carbonyl complex[235] react with alkenes to give vinyl heterocycles. The ease of the reaction of styrene with substituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

From the synthetic viewpoint, a particularly interesting trifluoroacetylation reaction of simple vinyl ethers was reported first by Hojo et al in 1976 [73] The scope and limitation of this particular reaction were elaborated intensively, the reaction proved to be of general applicability with practically no restrictions on substituents of the vinyl ether moiety 9] (equation 34) This general validity is particularly beneficial because a trifluoroacetylated vinyl ether is the synthetic equivalent of a specifically protected tnfluoromethyl-substituted 1,3-dicarbonyl compound 19], thus the reaction provides access to a broad spectrum of variously substituted synthetic building blocks with selective reactivities on each carbon acceptor (a) and donor (d) center (equation 35) Obviously, such building blocks can react as heterodiene systems m cycloaddition reactions [< 74] or can be treated with a wide variety ot 1,2 or 1 3-dinucleophihc species to give any desired tnfluoromethyl-substituted carbocychc or heterocyclic system [8 75] Treatment of simple vinyl ethers with an excess of trifluoroacetic anhydride at elevated temperature leads to doubly acylated products [76] Comparable acylation reactions occur with vinyl thioethers [73], and the mesoiomc l,3-oxathiol-4-ones show, at least in a formal sense, similar behavior [77] (equation 36)... 

Using this principle, Kibayashi and coworkers [147] have introduced a sequential cyclic carbopalladation-Stille vinylation of enyne compounds. Upon treating the enyne 196 and vinyl tributylstannane with catalytic amounts of Pd2(dba)3 CHCI3 in the presence of AcOH the allyl-substituted methylene cyclopentane 197 was formed in 53% yield (Scheme 80). The subsequent cross-coupling occurs with complete suppression of /M I-climinalion and the Alder-ene product 198 was not detected. Likewise, this sequence was extended to heteroatom-linked enynes and further vinyl tin compounds to provide the heterocyclic analogs 199 in moderate to excellent yields (Scheme 81). 

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