Cyclopropanation of alkynes

The intermolecular reaction of alkynes with acylcarbene complexes normally yields cyclopropenes [587,1022,1060-1062]. Because of the high reactivity of cyclopropenes, however, in some of these reactions unexpected products can result. In particular intramolecular cyclopropanations of alkynes, which would lead to highly strained bicyclic cyclopropenes, often yield rearrangement products of the latter. In many instances these products result from a transient vinylcarbene complex, which can be formed by two different mechanisms (Figure 4.3). 

Rhodium complexes generated from A-functionalized (S)-proline 3.60 [933, 934, 935] or from methyl 2-pyrrolidone-5-carboxylates 3.61 [936, 937, 938] catalyze the cyclopropanation of alkenes by diazoesters or -ketones. Diastereoisomeric mixtures of Z- and E-cydopropylesters or -ketones are usually formed, but only the Z-esters exhibit an interesting enantioselectivity. However, if intramolecular cyclopropanation of allyl diazoacetates is performed with ligand 3.61, a single isomer is formed with an excellent enantiomeric excess [936,937], The same catalyst also provides satisfactory results in the cyclopropanation of alkynes by menthyl diazoacetate [937, 939] or in the intramolecular insertion of diazoesters into C-H bonds [940]. 

As mentioned before, enantioselective cyclopropanation has been known for a long time and there are other efficient catalysts for this reaction apart from dimeric rhodium(II) complexes. This is different to the cyclopropanation of alkynes with diazo compounds. Copper catalysts do not only result in lower enantiomeric excesses but also poor yields, since the high temperatures required for the reaction favor side and consecutive reactions such as the ring opening of the primary products. The improvements brought about by the use of [Rh2(55-mepy)4] (with regard to yield... 

Recently, as a continuing interest in the synthetic application of a-alkyl-a-diazo ester 28, Hashimoto and co-workers reported the first Rh-catalyzed intermolecular asymmetric C—H bond insertion reaction of a-alkyl-a-diazo ester (Scheme l.S). " Despite only moderate yields and ee obtained by employing Rh2(S-TFPTTL)4 or Rh2(iS -TCPTTL)4, excellent results were obtained in a previous report on the asymmetric cyclopropanation of alkyne. ... 

In contrast to the direct photolytic cyclopropanation of alkynes with dimethyl diazomalonate, benzophenone-sensitized photolysis in the presence of alkynes affords furans as the major products in moderate yields (eq 5). ... 

Tertiary bismuthines appear to have a number of uses in synthetic organic chemistry (32), eg, they promote the formation of 1,1,2-trisubstituted cyclopropanes by the iateraction of electron-deficient olefins and dialkyl dibromomalonates (100). They have also been employed for the preparation of thin films (qv) of superconducting bismuth strontium calcium copper oxide (101), as cocatalysts for the polymerization of alkynes (102), as inhibitors of the flammabihty of epoxy resins (103), and for a number of other industrial purposes. 

Some years ago we began a program to explore the scope of the palladium-catalyzed annulation of alkenes, dienes and alkynes by functionally-substituted aryl and vinylic halides or triflates as a convenient approach to a wide variety of heterocycles and carbocycles. We subsequently reported annulations involving 1,2-, 1,3- and 1,4-dienes unsaturated cyclopropanes and cyclobutanes cyclic and bicyclic alkenes and alkynes, much of which was reviewed in 1999 (Scheme l).1 In recent days our work has concentrated on the annulation of alkynes. Recent developments in this area will be reviewed and some novel palladium migration processes that have been discovered during the course of this work will be discussed. 

As has already been mentioned for cyclopropanation of olefins, the diazoester should be added slowly to the mixture of alkyne and Rh2(OAc)4, in order to minimize formation of carbene dimers. The reaction works well with mono- and... 

Recently, Ohe and IJemura reported a novel approach to the catalytic cyclopropanation of alkenes via 2-furyl178 179 or 2-pyrrolyl carbenoids180 that originate from the intramolecular nucleophilic attack of a carbonyl oxygen or an imine nitrogen (ene-yne-ketone and ene-yne-imine precursor, respectively) on a 7t-alkyne complex or a cationic cr-vinyl complex. Initially, the group 6 complexes like Cr(CO)s were used. Soon it was found that a series of late transition... 

Non-heteroatom-substituted vinylcarbene complexes are readily available from alkynes and Fischer-type carbene complexes. These intermediates can undergo the inter- or intramolecular cyclopropanation reactions of non-activated alkenes. Cyclopropanation of 1,3-butadienes with these intermediates also leads to the formation of cycloheptadienes (Entry 4, Table 2.24). 

In the example shown in Figure 4.4 either of these mechanisms leads to insertion of the alkyne into the C-Rh double bond of the initially formed acylcarbene rhodium complex. The resulting vinylcarbene complex undergoes intramolecular cyclopropanation of the 1-cyclohexenyl group to yield a highly reactive cyclopropene, which is trapped by diphenylisobenzofuran. 

In the previous section, the cyclopropanation of a glycal to form a bicyclic intermediate was followed by a ring-expansion reaction en route to each oxepine. Presented here are routes that afford oxepines either by ring-closing metathesis (RCM) reactions or by cycloisomerization of terminal alkynes. 

The cyclopropanation of alkenes using zinc carbenoids displays excellent chemoselec-tivities. A large number of functional groups are compatible with these reagents, such as alkynes, silanes, stannanes, germanes, alcohols, ethers, sulfonate esters, aldehydes. 

Further cycloadditions used to prepare cycloalkenes on insoluble supports include the cyclopropanation of resin-bound alkynes and of polystyrene [165] (Figure 5.18). The latter reaction has been used to introduce tags onto polystyrene beads, which enable the recognition of a certain bead in compound libraries produced using the mix-and-split method (Section 1.2 [165-167]). The structure of polystyrene tagged in this way has not, however, been rigorously determined. 

Asymmetric cyclopropanations of alkenes and alkynes with a-diazocarbonyl compounds have been extensively explored in recent years and a number of very effective chiral catalysts have been developed2. Copper complexes modified with such chiral ligands as salicy-laldimines 38202,203, semicorrins 39204 208, bis(oxazolines) 40209-2" and bipyridines 41212 have... 

A recent modification of these reactions that appears to have significant potential in oiganic synthesis is a tandem sequence of alkyne insertion and cyclopropanation (Scheme 2).11S One particularly impressive, fully intramolecular case is shown in Table 7 (ref. 115). 

The cyclopropanation of alkenes, alkynes, and aromatic compounds by carbenoids generated in the metal-catalyzed decomposition of diazo ketones has found widespread use as a method for carbon-carbon bond construction for many years, and intramolecular applications of these reactions have provided a useful cyclization strategy. Historically, copper metal, cuprous chloride, cupric sulfate, and other copper salts were used most commonly as catalysts for such reactions however, the superior catalytic activity of rhodium(ll) acetate dimer has recently become well-established.3 This commercially available rhodium salt exhibits high catalytic activity for the decomposition of diazo ketones even at very low catalyst substrate ratios (< 1%) and is less capricious than the old copper catalysts. We recommend the use of rhodium(ll) acetate dimer in preference to copper catalysts in all diazo ketone decomposition reactions. The present synthesis describes a typical cyclization procedure. 

The oxidative ring opening of 3-oxabicyclo[4.1.0]hept-4-enes, formed by the intramolecular Pt(ll)-catalyzed cyclopropanation of enol ethers by alkynes, gives oxepane derivatives. Alternatively, the acid-catalyzed opening of the cyclopropane ring leads to dihydrobenzofurans or 3,4-dihydro-2//-chrorncncs <20040L3191>. 

The carbene complex 253 reacts with alkyne to give vinylcarbene complex 255 via the metallacyclobutene 254. The triple bond in allylpropargylamine 256 reacts at first to form vinylcarbene 257, and cyclopropanation of the double bond gives 258 [82],... 

Carbene complexes of Fe and Co carbonyls are also prepared. Unlike the Cr carbene complexes, no cyclopropanation of alkenes occurs with these carbene complexes. Furans are formed by the reaction of alkynes involving rearrangement of methoxy group. The 2-aminofuran 323 is formed by the reaction of the dimethylaminocarbene complex 319 of Fe carbonyl, via rearrangement of the amino group. Under CO pressure, pyrone 324 is the main product [97]. In these reactions, the... 

Furthermore, the successful [3+2+1] cycloaddition of alkynes bearing a cyclopropane ring and a carbene complex unit has been reported. These benzannulations result in the formation of bimetallic naphthohydroquinone chromium tricarbonyl complexes [48]. Additionally, (non-strained) cyclic alkynes are potent reaction partners in the cycloaddition of chromium carbene complexes [49]. 

Recently, cyclopropane derivatives were produced by a ruthenium-catalyzed cyclopropanation of alkenes using propargylic carboxylates as precursors of vinylcarbenoids [51] (Eq. 38). The key intermediate of this reaction is a vinylcarbene complex generated by nucleophilic attack of the carboxylate to an internal carbon of alkyne activated by the ruthenium complex. Then, a [2+1] cycloaddition between alkenes and carbenoid species affords vinylcyclo-propanes. 

When the double bond of the enyne possesses a cyclopropyl substituent, an intramolecular [5+2] cycloaddition of alkyne and vinylcyclopropane takes place [75, 76]. The ruthenacycle does not undergo /l-hydride elimination but a rearrangement of the cyclopropane to produce a ruthenacyclooctadiene. Thus, a variety of bicyclic and tricyclic cycloheptadienes were obtained in good yields [75] (Eq. 55). 

The battle is not yet won, of course, but the HIV protease inhibitors are being followed by a new generation of nonnucleoside reverse transcriptase inhibitors, which promise to be less toxic to humans. An example is the DuPont-Merck compound DMP-266, made as a single enantiomer and now under clinical trials. This compound, though it contains a most unusual cyclopropane and alkyne combination, is nevertheless a much simpler compound than Crixivan. We shall devote most of this final chapter to the synthesis of the established and chemically more interesting drug Crixivan. 

As demonstrated below, a Lewis acid-mediated reaction was utilized in the synthesis of dihydro[b furan-based chromen-2-one derivatives from l-cyclopropyl-2-arylethanones and allenic esters <070L4017>. The TiCh-catalyzed anti-Markovnikov hydration of alkynes, followed by a copper-catalyzed O-arylation was applied to the synthesis of 2-substituted benzo[6]furan <07JOC6149>. In addition, benzo[6]furan-based heterocycles could be made from chloromethylcoumarins <07SL1951>, substituted cyclopropanes <07AGE1726>, as well as benzyne and styrene oxide <07SL1308>. On the other hand, DBU-mediated dehydroiodination of 2-iodomethyl-2,3-dihydrobenzo[6]furans was also useful in the synthesis of 2-methylbenzo[Z>]furans <07TL6628>. 

Treatment of j]2-iminosilaacyl complex 6c with LiEt3BH gave azazircona-cyclopropane 10, which was hydrolyzed to give (silylmethyl)aniline in 82% yield (Scheme 5). Treatment of 10 with 4-octyne gave alkene 12 in 73% yield after hydrolysis. Presumably, the insertion of alkyne into the carbon-zirconium bond of 10 gives silazirconacyclopentene 11. When CuCl and allyl chloride were added to a THF solution of silazirconacyclopentene 11, tetrasubstituted alkene... 

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