Formation via Heck reaction

Methyl-l,2,3,9-tetrahydro-4H-carbazol-4-one, the key building block of the neuroactive compound alosetron, was easily obtained from 3-[(2-halophenyl)(methyl)amino]cyclohex-2-en-l-one by pyrrole ring formation via Heck reaction under microwave irradiation [94], While the iodo substrate gave an excellent yield in only 30 min at 100 °C the corresponding bromo derivative converted only poorly under the same reaction conditions (Scheme 88). 

Intramolecular formation of large rings can be carried out efficiently on solid support, which may help to suppress competitive intermolecular reactions, as illustrated by some recent examples Macrocyclisation of the acrylamido peptide-3-iodobenzylamide 13 via Heck reaction on solid support proceeds more rapidly than the corresponding solution phase reaction22 (Scheme 1.6.5). 

The coupling reaction of zinc(II) (3- or)8-monobromodeuteroporphyrin dimethyl ester (ID with 1,4-divinylbenzene under the typical conditions of the Heck reaction results in the formation of dimeric porphyrin 12 linked via a divinylbenzene moiety. Use of 1,3,5-trivinyl-benzene in the same reaction makes the trisadduct available."5... 

Polystyrene-bound secondary aliphatic amines and /V-alkyl amino acids can be ally-lated by treatment with a diene and an aryl iodide or bromide in the presence of palla-dium(II) acetate (Entry 14, Table 10.3). As the diene, 1,3-, 1,4-, and 1,5-dienes can be used, and, besides aryl halides, heteroaryl bromides have also been successfully used [63], This remarkable reaction is likely to proceed via the formation of an aryl palladium complex, with subsequent insertion of an alkene into the C-Pd bond. The resulting organopalladium compound does not undergo ( -elimination (as in the Heck reaction), but isomerizes to an allyl palladium complex, which reacts with the amine to give the observed allyl amines. 

The Heck reaction has now been reviewed448,449. Evidence for the formation of zerova-lent palladium from (AcO Pd and Ph3P via a redox process has been provided450. This explains the origin of Pd(0) required for certain palladium-catalysed reactions in cases where Pd(II) is added to the reaction as the primary form of the Pd-catalyst. Thallium has been found to accelerate the Heck-type cyclization-carbonylation451. 

One significant consequence of the formation of allylpalladium derivatives is that it represents an escape from the Heck reaction manifold permitting a wide variety of non-Heck processes via carbopalladation, which is the focal point of the rest of this chapter. 

The Murai reaction (Scheme 4), the replacement of an ortho-CH on an aromatic ketone by an alkyl group derived from a substrate olefin, is catalyzed by a variety of Ru complexes. This C bond formation occurs via chelate directed C-H bond activation (cyclometalation) in the first step, followed by alkene insertion into RuH and reductive elimination of the alkylated ketone. In a recent example of the use of a related cyclometalation in complex organic synthesis, Samos reports catalytic arylation (Suzuki reaction) and alkenylation (Heck reaction) of alkyl segments of a synthetic intermediate mediated by Pd(II). 

Scheme 1 shows the desired Heck reaction of alkoxy-DSB 1 with 2. The formation of 3 is accompanied by two destructive pathways the reductive debromination of 1 to 4 as a side reaction and the protodesilylation to 5 as a subsequent reaction. Particularly the latter limits the reaction conditions in terms of time and temperature. The phosphine is a decisive factor in this system consisting of three reactions a fine-tuning of the reaction conditions is possible via electronic and steric effects of the substituents in the phosphine electron-rich trialkylphosphines 6 and 7 strongly favor the reduction. Fast coupling reactions were observed with tris-o-tolylphosphine 8, the chelating diphosphine dppe 9 being even more efficient in terms of turnover, yield, and suppression of side reactions. Compared with Heck reactions of polycyclic or electron-deficient arenes with 2 [21, 22], the yield of 3 is only moderate. The reactivity of bromo-distyrylbenzenes 1 and 12 -14 in the coupling reaction is controlled by the substituents on the opposite side of the n-system (Fig. 1, Table 2) a compensation for the electron-donating alkoxy groups by a cyanide (13) or exchange of donors with electronically neutral alkyl side chains strongly improves the yields.

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

Ley, S. V., Marsden, S. P. Diastereoselective and enantioseiective formation of quaternary carbon centers via the intramolecular Heck reaction the influence of the coordination state of the palladium catalyst. Chemtracts Org. Chem. 1993, 6, 23-26. 

Another important reaction, the Heck reaction catalyzed by palladium salts and complexes, has been studied as well via EXAFS [191]. The authors of the study highlight the importance of correlating structural data with reaction kinetics. Among others the authors showed that in chloride-based ionic liquids the Heck reaction shows poor reactivity until, at some point during the reaction, Pd nanoparticles form, which initiates the reaction. They pointed out that the correlation between the induction period and the nanoparticle formation was strong, and although the metal may not be the active site for the catalysis [91], the presence of Pd(0) is clearly important. 

The same reaction sequence as employed for the conversion of 101 to 103 was applied to ent-101 to give tetracycle ent-103 in 18% yield (two steps) (Scheme 22). Alternatively, Wittig reaction of ent-101 with Ph3P=CHI afforded vinyl iodide 108 in better yield (72%, E Z = 1 2). The Heck reaction of 108, however, resulted in the formation of ent-103 with lower yield (31%) than that of ent-102. The attempted new procedure via vinyl iodide 108 slightly improved the overall yield of ent-103 from ent-101 (22% for two steps). Inversion of the C-6 hydroxy group and deprotection of IV-Boc group gave methylamine 81. Aminomercuration/ demercuration of 81 provided (-)-codeine in 24% yield. 

Another scenario for AHRs is the formation of quaternary chirality centers. Here, (3-elimination via path b is impossible (when Hb is replaced by a hydrocar-byl group). The downside, however, is that construction of such centers is difficult because it requires the insertion of trisubstituted C=C bonds, which normally react sluggishly in Heck reactions. Some of this lack of reactivity, however, can... 

Cyclopropane formation via homoallylpalladium intermediates is also observed in numerous other examples of modified Heck-type reactions - which involve additional insertion steps... 

Muller and coworkers have recently developed a coupling-isomerization reaction, initially identified as a side reaction which occurred under standard Sonogashira conditions [79]. As demonstrated below, the coupling reaction is followed by a shuffling of oxidation states via an alkyne-allene isomerization [80]. The product, a,P-unsaturated ketone 146, is reminiscent of a product which would be obtained from a Heck reaction. The utility of this reaction was further demonstrated when diamine 147 was added to the reaction pot. Following a conjugate addition reaction and imine formation, compound 148 resulted from the three-component, one-pot reaction sequence enabled by the coupling-isomerization reaction. 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

---