Cyclization disubstituted acetylenes

Castro and Stephens16 developed a method for the preparation of unsymmetrical disubstituted acetylenes, which involves the reaction of copper(I) acetylides with aromatic iodo compounds. Bond and Hooper7 extended this route to the preparation of 2-arylisatogens (22). 2-Nitro-phenylpropiolic acid (19a) is readily decarboxylated to the acetylene (19b), which on treatment with copper(I) chloride gives 19c. The reaction of 19c with substituted aromatic iodo compounds (20) gives the corresponding acetylenes (21), which subsequently cyclize to the isatogens (22). The alternative route (23 + 24 - 21) has been little used.17... 

The trimerization reaction with benzene derivatives could sometimes follow a similar path but, since it also occurs with disubstituted acetylenes such as HOCH2C = CCH2OH, some other mechanism must also be operating. Schrauzer explained the cyclization of tolane with a catalyst based on bisacrylonitrilenickel and triphenylphosphine by the so-called V-complex, multicenter processes. With this process, three alkyne molecules would successively coordinate with nickel and then the ring closure would take place (See Figure 6). 

Butenolides.—Interest continues in the carbonylation reaction catalysed by transition metals as a route to butenolides. The catalyst RluCCO) is used in the carbonylation of acetylenes in the presence of olefins yields of 5-alkyl-2(5H)-furanones are good, but mixtures of products are obtained in unsymmetrical cases. The reaction between trichloroacetic acid and olefins is mediated by RuCl2(PPh3)3, and gives initially 2,2-dichloro-4-alkylbutanolides which undergo dehydrochlorination to 4-alkylidenebut-2-enolides. These compounds are also obtained by the cyclization of acetylenic acids (126) (127). ° A general synthesis of disubstituted butenolides (128) has been published, which is simple and effective (Scheme 12) ... 

Armstrong and coworkers capitalized the 1.3-dipole intermediate 122 to synthesize polysubstituted pyrroles via a [3% + 231] cycloaddition reaction with mono and disubstituted acetylenes in the presence of an acid. As previously mentioned, protonation of the enamide followed by cyclization and loss of cyclohexanimine forms the active intermediate 119, which loses a proton to form the 1,3-dipole 122. A [3tt + 2%] cycloaddition reaction of 122 with acetylene 124 forms intermediate 125, which rapidly loses CO2 to provide the aromatized product pyrrole 126 (Scheme 7.37). Some of the key features of this reaction are ... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

In particular, the copper-promoted cycloisomerization of unsaturated alkynes bearing a stabilized nucleophile was found to be a general method that allows the cyclization of a variety of 5-acetylenic-stabilized carbanions by using catalytic amounts of base and copper [52]. This copper-catalyzed reaction was applied to disubstituted alkynes such as 43 and converted to the (Z)-isomer 44 as a single product (Scheme 18). This result further supports... 

Although less common than conversions of a,3-, and of p,Y-acetylenic ketones, Y,5-alkynones can also lead to formation of furans. The Y,8-acetylenic ketone 227 undergoes a Pd-catalyzed cyclization to furnish 2,5-disubstituted furan 228 (no yield provided) [180]. 

A one-pot Trofimov reaction (type Ilac cyclization) has been developed <05ARK(vii)ll>. Treatment of ketoximes with acetylene in the presence of superbase (KOH/DMSO) gave 2-substituted and 2,3-disubstituted p)Troles. 

Aldol condensation of acetone with formaldehyde gives methyl vinyl ketone. This can undergo the ene reaction with isobutylene to give an isomer of methylheptenone, 2-methylhept-l-en-6-one. Isomerization to methylheptenone is easy using an acidic catalyst, and acetylene can be added to either isomer. From methylheptenone, the process leading to linalool is the same as in the examples above. If the acetylene is added to 2-methylhept-l-en-6-one, then isodehydrolinalool results. This is actually advantageous when the monoterpene unit is to be used as a precursor for ionones and vitamins, since the 1,1-disubstituted double bond is more reactive in the cyclization reaction than is the normal 1,1,2-trisubstituted bond. (The cyclization reaction is described in detail below.) The preparation of these two acetylenic ketones is shown in Scheme 4.9 and is the basis of a process commercialized by BASF. 

With mono(trimethylsilyl)acetylene the carbocation has the structure 10 which is stabilized by interaction between and SiMes (cf. structure 4). If the reaction starts from a 2,2-disubstituted-3-unsaturated acid chloride, cyclopentenones are obtained". (equation 13). In this case the intermediate carbocation is believed to cyclize to a cyclohexene (15). A 1,2-acyl shift leads to cation 16, which is stabilized either by addition of a chloride to give 12 or by loss of a proton to give 13 (equation 14). Similarly, compound 14 is formed. 

Various other acetylenic substrates can also be used for the synthesis of furans by intramolecular gold-catalyzed C-O bond formation. Thus, acetylenic diols gave a variety of monosubstituted, disubstituted, or trisubstituted fiirans by dehydrative cyclization in the presence of 2 mol% Au[P(r-Bu)2(o-biphenyl)]Cl/AgOTf or AuCl at 0 °C (Scheme 4-8In the latter case, the catalyst loading can be decreased to 0.05 mol% by scavenging water with activated molecular sieves and conducting the reaction in refluxing THF. 

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