Domino Heck cyclization

Hu et al. [104] disclosed that the spiro phosphine oxide ligand (/ )-30a is highly efficient for the Pd-catalyzed Heck reaction of cyclic and heterocyclic olefins with aryl triflates. An asymmetric domino Heck cyclization was established using catalyst Pd/(/ )-30a to form fused carbo- and heterocycles with excellent stereoselectivity (Scheme 42) [105]. This method was used in a short synthesis of (-)-martinellic acid, a primary ingredient in traditional eye medicine in South America. 

The transition metal-catalyzed domino reactions will undoubtedly have a splendid future which is underlined by the increasing number of publications in this area Steglich et al. presented an approach to arcyriacyanin A via a domino Heck reaction between a bromo(indolyl)maleiimide and 4-bromoindole.1811 The synthesis of 33 -bifurans by Ling et al. was achieved using a novel palladium-catalyzed domino dimerization and subsequent cyclization of acetylenic ketones.1821 Other applications of a combination of Heck reactions for domino processes are the syntheses of aza-heterocydes developed by our group.1831... 

The Ni-catalysed Heck reaction is rather rare. Although the attempted Ni(0)-catalysed cyclization of iodide 107 gave a mixture of many products, the pentacyclic nitrone 108 was isolated in 40% yield by the domino Heck-type reaction, reductive... 

A domino Heck carbopalladation/cyclization reaction of (Z)-3-(2-(but-2-ynyloxy)phenyl)prop-2-en-l-ol 453 with aryl iodides furnishes chroman derivatives 454 in good yield (Equation 185) <2004AGE5997>. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

Cyclopropanes and cyclobutanes were only accessible via xo-type cyclizations, the former only within domino/cascade reactions (see Chapter 8) and the latter being realized by Erase [5a] in desymmetrizing Mizoroki-Heck cyclizations (see Chapter 13) and by Mulzer et al. [5b] five-membered and larger rings are formed in both modes. 

Tetrasubstituted alkenes 118, which contain two ring systems, can be efficiently synthesized by the domino-Heck double cyclization of aryl bromide 117, appended with an allylsilane and alkyne (Scheme 58) (108). As a result of their remarkable switching properties under UV light, these products are crucial elements for the development of reversible optical data storage. 

In a similar manner, the domino-Heck-type double cyclization of (Z,Z)-1,6-diaryl-l,5-hexadien3-ynes 119 yields ( )-l,l -bi-indenylidene derivatives 120 (Scheme 59) (109). 

Fagnou and co-workers succeeded to combine Heck cyclization with direct arylation in 2009. This interesting domino palladium-catalyzed Heck-intermolecular direct arylation reaction gave new access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene could be employed as the direct arylation coupling partner as well and resulted in yields up to 99% (Scheme 2.35). As the authors demonstrated, in addition to... 

In 2012, an intramolecular version was developed by Zhu s group. In the presence of a catalytic amount of palladium acetate and XPhos with potassium carbonate as a base at 100 °C in DMAc, the desired dihydroquinolin-2-ones spiro-fused to dihydrofuranyl, indolinyl, and indanyl were formed in good to excellent yields (Scheme 2.36). The reaction went through a domino sequence involving a 5-exo-trig Heck cyclization followed by an... 

Tobe reported that palladium-catalyzed ring-closure reaction of 200 provides l,l -biindenylidene 201 by a domino-Heck-type double cyclization in moderate yields (Scheme 6.53) [124]. The reaction is appHcable to the synthesis of fulvalene derivatives involving thiophene ring(s) 202 and 203 [125]. The (Z)-isomers of the... 

Toyota, Ihara and coworkers [178] used a combination of a Wacker- and a Heck-type transformation to construct the cedrane skeleton. Thus, reaction of 6/1-374 using 10mol% Pd(OAc)2 under an atmosphere of 02 led to the domino product 6/1-375 in 30% yield. In addition, 58% of the mono-cyclized compound 6/1-376 was obtained (Scheme 6/1.94). 

As an extension of the Heck reaction, Pd-catalyzed hydroarylation of alkynes and alkenes continnes to attract high level of research interest in simple couphng processes and in cyclization reactions. The use of this type of transformation as part of a domino reaction will be of increasing interest. The research in the field of domino reactions is attracting considerable attention in synthetic organic chemistry since it enables the rapid assembly of complex molecirles in one-pot processes. Very elegant examples of palladium-catalyzed cascade processes where a single catalytic cycle entails several sequential bond transformations have been recently reported [la, b, 2a, b, c]. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

A recent paper explored the 1,2-functionalization of the allene moiety in monocyclic P-lactam allenynol derivatives under palladium-catalyzed reaction conditions <02CEJ1719>. Remarkably, a novel domino process, namely allene cyclization/intramolecular Heck reaction... 

Substituted azaazulene 479 was prepared from cycloheptatrienylmethyl ketone O-pentafluorobenzyloxime 478 by Pd-P(r-Bu)3-catalyzed cyclization, followed by treatment with Mn02 [180]. As observed in the Heck reaction, the domino insertion of olefins occurred to produce the polycyclic imine 481 when the trienyloxime 480 was subjected to the Pd-catalyzed reaction [181]. 

The cycloisomerization of 1,6-enynes proceeds smoothly in the presence of AcOH or HCO2H and the reaction is explained by the following mechanism (hydridopalladium acetate mechanism) [45]. Most importantly, oxidative addition of AcOH to Pd(0) generates H-Pd-OAc 143, and the cyclization of 1,6-enynes starts by insertion of the triple bond to 143 to afford the alkenylpalladium 144. Subsequent intramolecular insertion of the double bond gives the alkylpalladium 145. The termination step is (i-R elimination and either the diene 136 or 138 is formed with regeneration of H-Pd-OAc. It should be noted that the alkenylpalladium 144 is a similar species formed in a Heck reaction by oxidative addition of alkenyl halide to Pd(0). Based on this reaction, alkyne is a useful starter in domino cyclization of polyenynes. 

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