Ring systems Heck reaction

Domino or cascade reactions are particularly valuable for the construction of various carbo- and heterooligocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades. In this section, such processes with a termination by attack of various nucleophiles will be described. 

Domino or cascade reactions provide valuable approaches, especially to various carbo- and heterocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades, hi this section, the termination of these processes by alkenes, arenes, and related ir-bond systems such as alkynes and allenes will be described. A cascade Heck reaction is considered to consist of an oxidative addition of a heteroatom-carbon bond to palladium (starter), carbopalladation of a nonaromatic carbon-carbon double or triple bond without immediate dehydropalladation (relay), one, two, or more fimher car-bopalladation(s) of a carbon-carbon double or triple bond, and eventually ensuing dehydropalladation. Crucial for a cascade reaction of this kind to occur is the blockage or retardation of a dehydropalladation at one of the intermediate stages by using 1,1-disubsti-tuted alkenes and appropriately substimted cycloalkenes, bicycloalkenes, or alkynes as relays since they give kinetically stable alkyl- or alkenylpalladium intermediates, respectively. 

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]. 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

Thiemann and coworkers [68] sought novel types of steroids with different biological activity, and in doing so prepared areno-annulated compounds such as 6/1-133 (Scheme 6/1.35). This is achieved with a Heck reaction of 6/1-132 with an acrylate, followed by an electrocydic ring closure of the formed hexatriene. The reaction is then terminated by removal of the nitro group, with formation of the aromatic ring system. 

The selectivity in the Heck reaction of allylic alcohol 111 is interesting, and the factors that lead to the observed preference for (3-hydride elimination toward nitrogen in this system are unclear, although a combination of steric effects and stereoelectronic factors (i.e., alignment of C-H and C-Pd bonds, nN a c H interactions) is likely involved. Examination of related examples from the literature (Scheme 4.20) reveals no clear trend. Rawal and Michoud examined substrate 115, which lacks the influence of both the amine and hydroxyl substituents and also seems to favor (3-hydride elimination within the six-membered ring over formation of the exocyclic olefin under standard Heck conditions [18a]. However, under... 

Some interesting fused 1,2,3-triazole ring systems have been reported. A series of 5-piperidyl-substituted 7-hydroxy-3f/-l,2,3-triazolo[4,5-d]pyrimidines 143 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide <06CHE246>. 4-Alkylidene-5,6-dihydro-4//-pyrrolo-[l,2-c][l,2,3]triazoles 144 were prepared from alkylidenecyclopropanes via diiodogenation/Cu(I)-catalyzed 1,3-dipolar cycloaddition/intra-molecular Heck reaction sequence <06SL1446>. 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-27/-benzotriazol-4-one 145 were prepared from A-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine and... 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

Gilchrist examined the cyclization of Af-alkenyl-2-iodoindoles with palladium [268, 269], For example, reaction of A-pentenylindole 244 under Heck conditions affords a mixture of 245 and 246 in very good yield. In the absence of TIOAc, 246 is the major product. Further exposure of 245 to Pd(OAc)2 gives 246. Reaction of l-(4-butenyl)-2-iodoindole under similar conditions affords the pyrrolo[l,2-a]indole ring system in modest yield (35%). 

Grigg s group synthesized a unique bicyclic P-lactam 108 via an intramolecular Heck reaction from 107 [87, 88]. The 7-membered ring was formed via an unusual insertion at C(3) of furan, an aromatic rc-system. 

Heck reactions, the hydroarylation methodology, has been a key tool in the synthesis of varions epibatidine analogues, due to the ability of this approach to address regio- and stereochemistry in substituted azabicyclo ring systems [6],... 

TV-substituted methylenephthalimide derivatives served as the starting material for the preparation of a series of tetracyclic systems. The intramolecular Heck reaction of these compounds (4.10.) led in each case to the formation of a carbon-carbon bond between the exocyclic carbon atom of the olefin bond and the aryl moiety. The formation of five, six and seven membered rings was achieved with near equal efficiency, enabling the preparation of some isoindolobenzazepine alkaloids.11... 

Transition metal catalyzed insertion reactions offer a variety of alternate approaches for the preparation of heterocyclic rings, of which Heck reactions were utilised extensively to prepare rings with more than 6 atoms. At the end of this Chapter some examples of the use of insertion reactions in the formation of the carbacyclic part of condensed heterocyclic systems will also be presented. 

The palladium catalysed sequential alkylation-alkenylation of 5-iodoquinoline leads to the formation of the quinolooxepin ring system (5.20.), The process, closely related to the Catellani reaction,19 runs through an ort/zo-alkylation - Heck reaction sequence. The preparation of a series of benzoxepines has also been achieved in this manner, starting from such iodobenzene derivatives, where one of the or/7 o-positions was blocked by substitution.20... 

In an oxidative addition, Pd(0) complex 22 with BINAP as a ligand accepts alkenyl triflate It. The resulting Pd complex 23 is cationic, since the triflate anion is bound only loosely to the palladium and dissociates from the complex.1 Syn insertion of one of the two enantiotopic double bonds of the cyclopentadienc into the alkenyl-Pd bond of complex 23 leads firs to q -allyl-Pd complex 24. This is in rapid equilibrium with t 3-allyl-Pd complex 25. Neither 24 nor 25 contains a p-H atom in a yn relationship to palladium. Moreover, internal rotation is impossible in the con form a-tionaily fixed ring system. For this reason there is no possibility of a subsequent p-hydride elimination that would once again release the palladium catalyst. In a normal Heck reaction (see discussion) the catalytic cycle would be broken at this point. 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

Another method for activating the versatile alkenyl halide moiety was the oxidative addition of a late transition metal species, which would then facilitate insertion of the C13-C14 double bond. The Rawal,7h Bonjosch,7e and Mori7b syntheses of 1 all employed a Pd-mediated intramolecular Heck reaction to build the F ring of the molecule.71 Our system, in as much as it contained additional unsaturation, was somewhat different from those in the literature and thus had the potential for displaying new chemistry. For example, in Rawal s approach (Scheme... 

Further application of the powerful intramolecular reductive Heck reaction has been realized in the efficient microwave-assisted synthesis (Pd(PPh3)4, 3 mol%, HCOONa, 1.5 equiv, DMF HzO 3 1, 110 °G) of the important 3-benzazepine system. The precursors were A-ethynoyl derivatives of N-substituted n-bromophenethylamines, which afforded, via a type c ring construction, 3-benzazepin-2-ones with a substituted exocyclic methylene group at the Cl position <20070L3017>. 

A broad variety of special aldehydes and ketones are easily accessible by Heck-type reactions with allylic alcohols and their homologs [3]. The potential for the synthesis of carbocydic structures is illustrated by the macrocyde 11 [4] which obviously is the product of a fourfold Heck reaction (Scheme 3). A domino process consisting of a double Heck reaction followed by an intramolecular Aldol condensation leads to the annulated ring system 15 [5]. 

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