Heck reaction cyclizations

Alkylation. Acetals of enals serve as alkylating agents for t-butyl (3-keto esters using a Pd complex of BINAP. With a cationic Pd complex of (R)-BINAP intramolecular addition of arylboronic acid moiety to a sidechain ketone leads to chiral, tertiary henzylic alcohols. Heck reaction. Cyclization with desymmetrization is shown to proceed in excellent yields and ee by the formation of tetralin derivatives. ... 

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Heck cyclization/anion capture process 576 Heck reaction 566 ff. 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

A novel route to indoles and quinolines has been developed by sequential Wiltig and Heck reactions <96CC2253>. Thus, treatment of o-bromo- or iodo-lV-lrifluoroaceiylanilines (86) with a stabilized phosphorane affords the corresponding enamines 87 as a mixture of isomers. Cyclization to 88 is effected by heating with palladium acetate, tri phenyl phosphine, and bu.se. 

Synthesis of dithieno[2,3-A2,3-,7]thiophene derivatives 122 has been accomplished through the Heck reaction of 3-(4-bromo-2-thienyl)acrylic acid 302 to afford 3-(2,4-thienylene)diacrylic acid 303 which was cyclized with thionyl chloride and a catalytic amount of pyridine to the dichloride 120 in 75% yield (Scheme 56) <2005MOL279>. 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

Overman s group [71,72] enlisted an intramolecular Heck reaction to form a quaternary center in their efforts toward ( )-gelsemine. When the cyclization precursor 70 was submitted to the ligandless conditions [Pd2(dba)3, Et3N] in the weakly coordinating solvent toluene, the quaternary center was formed as a 9 1 ratio of diastereomers (72 71 = 89 11). Addition of a silver salt in polar solvent THF completely reversed the sense of asymmetric induction in the cyclization reaction (72 71 = 3 97). 

Grigg has utilized the Heck reaction in several ways, from the simple cyclization of N-(2-iodobenzoyl)pyrrole (139) to afford tricyclic lactam (140) [100] to the complex cascade... 

Hegedus synthesis of ( )-clavicipitic acid //-acetyl methyl ester culminated in the Pd-induced cyclization of 238 to 239, the latter of which was reduced to the target mixture [251], Substrate 238 was prepared via a Heck reaction with the corresponding 4-bromo compound 223 and 2-methyl-3-buten-2-ol (83%). The cyclization also occurs with tosic acid (97%). 

In a related approach, Murakami synthesized clavicipitic acid and costaclavine [79], and later extended this chemistry to a synthesis of chanoclavine-I featuring the intramolecular Heck vinylation 240 to 241 [266], The corresponding enone failed to cyclize under these conditions. Noteworthy is that radical cyclizations, which often compete successfully with Heck reactions, were poor in this system. 

Several investigators have studied intramolecular Heck reactions on alkene-tethered haloindoles. Black prepared several l-allyl-7-bromoindoles and found that they undergo cyclization in the presence of palladium as shown for 242 to 243 [267]. Although this new synthesis of pyrroloquinolines is reasonably general, some of the products are unstable. Substrate 242 was prepared by bromination of 4,6-dimethoxy-2,3-diphenylindole (92%) and //-alkylation. 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cyclizations of 254 and 255 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 254 and the IV-benzylindole 256 [271,272]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 257, and they prepared a series of peripheral-type benzodiazepine receptors 258 using this chemistry. For example, 258 (n = 3, R = n-Pr) is obtained in 81% yield. 

It has been known for sometime that 2-(2-bromoanilino)enones undergo Heck-type cyclizations to form indoles and carbazoles. Thus, Kibayashi reported the synthesis of 4-keto-l,2,3,4-tetrahydrocarbazoles in this manner [362], and Rapoport employed this reaction (296 to 297) to achieve an improved synthesis of 7-methoxymitosene [363]. A series of related mitosene analogs has been crafted using Pd chemistry by Michael and co-workers [364], They found that P(o-tol)3 was far superior to PPh3 in conjunction with Pd(OAc)2. 

A related Heck reaction of substituted o-bromoacetanilides with styrenes followed by selenium-induced cyclization of the resulting o-styiylacetanilides gives 2-arylindoles [378], Substituted o-bromonitrobenzenes react with ethyl vinyl ether under the influence of Pd(OAc)2 to give the corresponding o-ethoxyethenylnitrobenzenes. Zinc reduction then yields indoles [379]. The one-step Pd-catalyzed conversion of o-bromoanilines to indoles 302 with enamines (or with A/-vinyl-2-pyrrolidone) has been reported [380]. 

Ogasawara employed a Heck reaction of o-iodoaniline derivatives with dihydrodimethoxyfuran and vinylene carbonate to give intermediates that are readily cyclized to indoles with acid [381-383]. An example is shown below [381]. 

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