Heck cyclization, Intramolecular

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). 

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>. 

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... 

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. 

This intramolecular Heck cyclization can be extended to diunsaturated aryl iodides, which can undergo two consecutive cyclizations to form polycyclic systems.7 Examples ... 

The intramolecular Heck cyclization of resin bound A-homoallyl-2-iodobenzamides has been the key step in the preparation of substituted benzazepines (5.6.), The ring closure has also been extended to internal akynes, which gave benzylidene-benzazepines6... 

The construction of enantiomerically-pure carbocycles is a general problem in organic synthesis. Dirk Trauner (UC Berkeley) reports (Organic Lett. 2003, 5,4113-4115) an elegant intramolecular Heck cyclization. The alcohol 7 is readily prepared in enantiomerically-pure form. Conditions can be varied so that either 8 or 9 is the dominant product from the cyclization. 

The N-heterocyclic alkenes derived from ring-closing metathesis are useful substrates for further transformation. In a synthesis directed toward the insecticidal cripowellin 12, Dieter Enders of RWTH Aachen has shown (Angew. Chem. Int. Ed. 2005,44, 3766) that the tertiary amide 8 cyclizes efficiently to the nine-membered alkene 9. The vision was that an intramolecular Heck cyclization could then deliver the cripowellin skeleton. Indeed, the Heck did proceed, and, depending on conditions, could be directed toward either 10 or 11. Unfortunately, the conformation of 9 is such that the cyclization proceeded cleanly across the undesired face. Nevertheless, both 10 and 11 appear to be valuable intermediates for further transformation. 

Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T (2007) Chemoenzymatic Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck Cyclizations via C-B-D Ring Construction. Synlett 2859... 

Omori AT, Finn KJ et al (2007) Chemoenzymatic total synthesis of (+)-codeine by sequential intramolecular Heck cyclizations via C-B-D ring construction. Synlett 2007 2859-2862... 

Intramolecular Heck cyclizations.13 Pd(0)-catalyzed cyclization of substrates containing one alkenyl and one vinyl iodide group is a well-established route to bicyclic products (14, 297-298 15, 301-302). Tandem cyclization to tricyclic products is possible when the substrate contains a triple bond. Thus, in the presence of a Pd(0) catalyst and 2 equiv. of triethylamine, 1 undergoes tricyclization to 2 in high... 

In total syntheses of (+)-codeine and (-)-galanthamine, the bcnzo /> I uran core of both molecules was built up by intramolecular Heck cyclization, as shown below <07SL2859 07OL1867>. The Heck reaction was applied to make several bcnzo b furan-bascd benzazepin cores from their corresponding ap-unsaturated amides <07OBC655>. In addition,... 

Starting from 1-methyl-17/-pyrrole-2-carboxylic acid, the tricyclic fused quinolin-4-one and naphthyridin-4-one derivatives 441 were prepared, in only three steps, by an intramolecular Heck cyclization of derivative 440 (Scheme 94) <2005EJ02091>. This reaction was performed in DMA as solvent, with potassium acetate as base and Pd(PPh3)4 as catalyst. The use of microwave irradiation, in some cases, gives better yields of cyclized products. 

A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <20040L4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of... 

Scheme 6-38 Intramolecular Heck cyclization from an approach to complex cardenolides.

Both S-endo and 8-exo Heck cyclizations have been described. In an early example, Sundberg and Cherney reported an S-endo cyclization of 88 to the homoibogamine analog 89 (Scheme 6-15) [30]. Among the most striking examples of the application of intramolecular Heck cyclizations to assemble complex polycyclic products, Danishefsky, Masters, and co-workers have reported several S-exo cyclizations during investigations that culminated in a total synthesis of baccatin III (96) [32]. In an early example, exposure of... 

The intramolecular Heck cyclizations highlighted in this chapter were typically conducted with 5-20 mol% of a palladium catalyst. In few, if any, of these studies were catalyst loadings and cyclization conditions carefully optimized. As a result, we have not included catalyst loadings in the schemes in this chapter. Only recently has serious attention been directed to optimizing catalyst turnover in Heck reactions and to the development of more robust catalyst systems. It seems likely that in the future many Heck cyclizations will be accomplished with catalyst loads of 1 % or lower [76]. 

B.M. Trost and co-workers conducted studies toward the total synthesis of saponaceolide B, an antitumor agent active against 60 human cancer cell lines. " One of the challenging structural features of this compound was the cis 2,4-disubstituted 1-methylene-3,3-dimethylcyclohexane ring. The key steps to construct this highly substituted cyclohexane ring were a diastereoselective Barbier reaction to install a vinyl bromide moiety followed by an intramolecular Heck cyclization reaction. 

We will encounter more of these fantastic tandem cascade Pd-induced cyclizations in Chapter 3. Using microwave heating, Beccalli and co-workers performed an intramolecular Heck cyclization with pyrrole 211 leading to tricycle 212 in excellent yield [127]. 

An intramolecular variation of the Heck reaction was used in the construction of the monoterpene alkaloid ( )-oxerime 395 [138]. Nucleophilic addition to 392 of an allyl anion equivalent produced 393, a precursor to an intramolecular Heck cyclization. Palladium-catalyzed ring closure afforded 394, an intermediate in the synthesis of the natural product 395. 

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