Heck cyclization

To continue with cyclization reactions of olefins we choose the Heck cyclization because it proved to be a powerful tool to construct alicyclic as well as heterocyclic rings, to anellate rings to aromatic systems, and, last not least, to overcome steric hindrance. 

Notwithstanding all these advantages, problems can arise with regioselectivity and also with stereoselectivity. 

As far as regioselectivity goes, one notices that the general mode of cyclizations follows the so called exo route, which generates only exo double bonds as in 427 and 430. 

however, a water-soluble catalyst is applied in an aqueous medium, the 6-endo products 429 and 432 are obtained nearly exclusively [158]. 

Face selective Heck cyclization is of course particularly challenging with a sterically highly congested substrate, such as the gelsemine precursor 433. Interestingly, again catalyst manipulations provided an elegant solution to this problem too [159]. 

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Scheme 4. Overman s sequential Heck cyclization approach to the synthesis of the scopadulcic acids.

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. 

Scheme 8. Rawal s Heck cyclization strategy for the synthesis of ( )-dehydrotubifoline [( )-40].

In an extension of this work, the Shibasaki group developed the novel transformation 48—>51 shown in Scheme 10.25c To rationalize this interesting structural change, it was proposed that oxidative addition of the vinyl triflate moiety in 48 to an asymmetric palladium ) catalyst generated under the indicated conditions affords the 16-electron Pd+ complex 49. Since the weakly bound triflate ligand can easily dissociate from the metal center, a silver salt is not needed. Insertion of the coordinated alkene into the vinyl C-Pd bond then affords a transitory 7t-allylpalladium complex 50 which is captured in a regio- and stereocontrolled fashion by acetate ion to give the optically active bicyclic diene 51 in 80% ee (89% yield). This catalytic asymmetric synthesis by a Heck cyclization/ anion capture process is the first of its kind. 

Scheme 10. Shibasaki s asymmetric Heck cyclization process.

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

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

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>. 

Dai ch and co-workers carried out an intramolecular Heck cyclization on the enamidone 120 to close the dihydropyridine ring and give 121 (Equation 28) <1998SC1839>. 

Subsequent Heck cyclization and trapping of the allylpalladium intermediate by the diketopiperazine nitrogen led to efficient formation of protected spirotryprostatin B 326 (Scheme 24). 

Although bromide 87, could also be suitable, we spent most of our efforts on accessing iodide 88, which would presumably be more reactive in the final Heck cyclization. 

Scheme 4.20 [S-H elimination selectivity in relevant Heck cyclizations by the Rawal group and in the MacMillan strychnine synthesis...

The Heck cyclization of bromopyrrole 77 and the corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied <06SL3081>. While the Heck cyclization of 77 led to a mixture of [3.3.l]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F. 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

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... 

In his synthetic approaches to iboga alkaloids, Sundberg pursued several Heck cyclization strategies but found the best one to be 247 to 248 [257],... 

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. 

Mdrour synthesized a series of indolo[2,l-a]isoquinolines and pyrrolophenanthridines via Heck cyclizations onto the C-2 and C-7 positions of indole, respectively [274], Two examples are shown. 

This indole C-7 Heck cyclization strategy was employed by Shao and Cai in a synthesis of anhydrolycorine-7-one from the requisite N-aroylindoline [275], by Miki in syntheses of pratosine and hippadine from substrates like 262 [276], and by Rigby to synthesize anhydrodehydrolycorine from an N-benzylhydroindolone [277, 278]. Thai and co-workers constructed examples of the new ring systems, pyrido[2 ,3-d ]pyridazino[2,3-a]indole (264) and pyrido[2 ,3 -oxidative-addition with methyl acrylate at the C-3 position. This resulting product (not shown) can also be obtained from 263 in a tandem Heck sequence with methyl acrylate (62% yield). 

Several other Heck cyclizations that do not involve the indole ring directly have been developed. Kelly employed the Heck cyclization of 266 to synthesize (and revise the structure of) maxonine (267) [281], The product resulting from attack at C-8 was also obtained. 

Following the application of a Heck cyclization to a concise synthesis of the Strychnos alkaloid dehydrotubifoline [287, 288], and earlier model studies [289], Rawal employed a similar strategy to achieve a remarkably efficient synthesis of strychnine [290]. Thus, pentacycle 277 is smoothly cyclized and deprotected to isostrychnine (278) in 71% overall yield — an appropriate finale to this section ... 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

This indole synthesis has been extended to P-tetrahydrocarbolines (300) [371], azaketotetrahydrocarbazoles [372], carbolines, carbazoles, and pyrido[l,2-a]benzimidazoles [373]. Examples of the former two reaction types are illustrated. An early Heck cyclization of 2-carboxy-2 -iododiphenylamine to 1-carbazolecarboxylie acid (73% yield) [374] has been generally overlooked by subsequent investigators. 

Spiro-2-oxindoles, such as 331, are readily crafted from the Pd-catalyzed reactions of o-haloanilines with vinyl halides and triflates in the presence of CO [428]. The o-iodo enamide is presumed to form initially, followed by Heck cyclization. 

The intramolecular Heck cyclization of 4-iodopyridine 175 with a pendant crotyl ether led to a mixture of bicyclic ethers 176 and 177 in which the endocyclic isomer 176 was predominant [138],... 

An intramolecular Heck cyclization of substrate 178 was the central feature in Overman s synthesis of pyridinomorphinans [139]. Octahydroisoquinoline 178, derived from an allylsilane-iminium ion cyclization as a single stereoisomer, was cyclized under forcing conditions to afford enantiomerically pure 179, an intermediate for a (-)-morphine (180) analog. 

Pd(Ph3P)4 and Et3N in refluxing acetonitrile to form the intramolecular Heck cyclization product 152 [125]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 24). In another case, the intramolecular Heck cyclization of enamidone 153 with a pendant thienylbromide moiety furnished the 6-trig-endo product, indolizine 154, in 63% yield, along with the debrominated enamidone 155 in 37% yield [126],... 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Benzo-annulated dihydropyrrolizine 155 was quantitatively prepared via the Heck cyclization of 154 (Scheme 31) <2001TL7513>. 

Michael et al. <2001TL7513> described a Heck cyclization of 154 to form functionalized mitosene 155 which was further transformed into tetracyclic compound (route b). Also Lee et al. <1999JOC4224> described a synthesis in... 

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