Heck reaction annulation

Dominguez and coworkers [41] used a twofold Heck reaction for the construction of annulated N-heterocycles such as 6/l-64a-c, starting from the enamides 6/1-63 which can be easily obtained from the corresponding amines 6/l-62a-c and o-iodo-benzoic acid chloride (Scheme 6/1.15). 

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. 

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>. 

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. 

Benzo-annulated pyrrolizin-3-ones 129 were synthesized in good yields from A-o-benzoylated pyrroles 128 by an intramolecular Heck reaction (Scheme 22) <2001JME4615>. 

Conversion of 172 to the tetracyclic benzo-annulated pyrrolizinone 173 was achieved by using the Heck reaction in DMF/H20 (Scheme 38) the best conversion and yield (80%) were observed in the absence of phosphine ligands <2005JOC268>. 

Transition metal catalyzed insertion reactions offer a variety of alternate approaches for the preparation of six membered heterocyclic rings. Besides intramolecular Heck-couplings, annulation reactions involving the insertion of an acetylene derivative, in most cases accompanied by the incorporation of carbon monoxide constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here, while the similar annulation reactions not involving CO insertion are mentioned in Chapter 4.4. 

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]. 

A palladium-mediated annulation of Y-( o-bromoary l)pyrroles across strained alkenes led to the formation of pyrrolo[l,2-a]quinolines <07OL1761>. An intramolecular Heck reaction involving tethered iodoarenes produced an entry to pyrrolo[2,3-t/][2]benzazepin-7-ones, analogues of the pyrrole natural product latonduines <07T867>. A Heck reaction of a 3-iodopyrrole with a 2,3-dihydrofuran provided pyrrole deoxyribonucleosides <07T12747>. 

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.- ... 

Heck reaction/Robinson annulation. The tactical combination of the two reactions... 

Substituted 2-bromo-l,6-heptadienes with one double bond as part of the methylenecy-clopropane system were shown to undergo cyclization in an intramolecular Heck reaction followed by a Diels-Alder reaction when a dienophile was present. In the presence of pal-ladium(II) acetate, triphenylphosphane and silver carbonate 2-spirocyclopropane-annulated bicyclo[4.3.0]non-l(6)-enes were obtained in high yields. 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success with the nickel-catalyzed synthesis of indole from 2-chloro-A -allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [111]. Compound 117, easily prepared from 2-bromo-A-acetylaniline and methyl bromocrotonate, was adopted as a cyclization precursor. Treatment of 117 with PdiOAc), (2 mol%), PhjP (4 mol%), and NaHCOj in DMF provided indole 118 via an intramolecular Heck reaction followed by olefin isomerization to afford the fully aromatic product. Although yields fr om the initial report were moderate, they have been greatly improved over the last two decades [112]. 

The second type of intramolecular Heck reactions involves conversion of an aryl halide into a furan. Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 161 furnishes benzofuran 162 [140], Such an approach has become a popular means of synthesizing fused furans. 

Heck reactions. The o-oxazolinylphenyl(diphenyl)phosphine ligand 11 is an xcellent ligand to direct enantioselective Heck reactions. On the other hand, the iioxazolinylmethane derivative 12 has been used for the annulation of allenes by means of jnctionalized aryl iodides. ... 

The Merck Process Group has developed a new method for indole synthesis involving a Pd-catalyzed annulation between o-iodoanilines 55 and ketones 56 <97JOC2676>. The reaction presumably involves formation of the enamine 57 followed by an intramolecular Heck reaction in the presence of a non-oxidizable amine base such as DABCO. The reaction is especially effective for cyclic ketones and tolerates a variety of functional groups in the product indole 58. 

Unexpected annulation occurred in an attempted Heck reaction of the a,f-unsaturated sulfone 157 with an excess of iodobenzene to give 158 in high yield. The use of Ag2C03 as a base is important [39]. The expected Heck product 159... 

Heck Annulation. Intramolecular Heck reactions are useful for annulation in heterocychc structures. A-(2-Iodobenzoyl)indoles or -pyrrole undergo Pd-catalyzed annulation to furnish... 

Dyker, G., Grundt, R, Markwitz, H. and Henkel, G. (1998) Heck reaction and Robinson-type annulation a versatile combination. J. Org. Chem., 63, 6043-7. 

Of course, syntheses of annulated aromatic compounds via classic Mizoroki-Heck reaction of aryl (pseudo)halides are prevalent a selection of substrates with open-chain allyl moieties is depicted in Scheme 5.4. Simple aryl iodide 19a was cyclized in high yield (90%), but in a 60 40 mixture of exocyclic and endocyclic double-bond isomers (19a -> 20a) [21]. A structural modification, conjugation with an ester group, a recurrent motif in Mizoroki-Heck chemistry, allowed for preparation of isomerically pure 20b in 74% yield (19b 20b) [22]. In the second example, reaction of pyridine 21 leads to an intermediate... 

The first example in Scheme 5.23 stems from the ( )-duocarmycin S A (127) synthesis by Natsume and coworkers [59] cyclization of 125 provided the expected product 126 in 82% yield along with 11% the isomeric enamine (not shown) (125 126, Scheme 5.23). In the Mizoroki-Heck reaction of 128, an eight-membered ring was exclusively tra 5-annulated in 64% yield, resembling a steroid-like polycyclic structure (128 129) [45, 60]. 

Apte, S., Radetich, B., Shin, S. et al. (2004) Silylstannylationof highly functionalized acetylenes. Synthesis of precursors for annulations via radical or Heck reactions. Org. Lett., 6, 4053-6. 

Dominguez and coworkers [47] used a twofold Mizoroki-Heck reaction for the con-straction of annulated A-heterocycles such as 80a-c starting from the enamides 78, which can easily be obtained from the corresponding amines and o-iodobenzoic acid chloride (Scheme 8.19). 

Thiemann et al. [92] prepared steroid analogues containing an areno-annulation as in 169 (Scheme 8.44). They also used a combination of a Mizoroki-Heck reaction and an electrocyclic ring closure of an intermediately formed 1,3,5-hexatriene. Thus, reaction of... 

In 2003, Ferreira and Stoltz [48] described an aerobic palladium(II)-catalysed intramolecular oxidative Heck reaction to form annulated indoles. The core annulated indole smicture is prevalent in a number of biologically active natural products, including pax-illine, penitrem A, and yuehchukene (Figure 9.5). Because indoles are susceptible to oxidative decomposition, carefully optimized conditions had to be developed that were compatible with the substrate and product indole species. 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

As in the palladium(II)-catalysed indole annulation, a diastereomerically pure substrate was designed to help elucidate the mechanism of the benzofuran and dihydrobenzo-furan syntheses (Scheme 9.21). When aryl allyl ether 163 was treated with the palladium oxidation catalyst, dihydrobenzofuran 164 was produced as an exclusive di-astereomer in 60% yield. This observation confirmed that an oxidative Heck reaction pathway, featuring arene palladation, alkene insertion and /3-hydride elimination, was operative. 

In 2006, Lu and coworkers [53] described a method for the synthesis of carbazoles using the palladium(ll)-catalysed oxidative Heck reaction (Scheme 9.25). Indole 177 was subjected to catalytic Pd(OAc)2 and 2.1equiv of benzoquinone to afford carbazole 178 in 88% yield. Because the alkene is 1,1-disubstituted, a 5-exo cyclization mode (as seen in Ferreira and Stoltz s [48] indole annulation) is unproductive, and a 6-endo cyclization ultimately occurs. The putative intermediate is then believed to be oxidized to the aromatic carbazole by the excess benzoquinone. When indole 179, featuring a terminal alkene, was treated with these oxidative conditions, a mixture of products from 6-endo cyclization (180) and 5-exo cyclization (and subsequent isomerization and [3+2] cycloaddition, 181) was observed. A variety of substituted carbazoles were obtained by this palladium(n)-catalysed oxidative cyclization. 

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