Iodophenols

A spore-forming strain of Desulfitobacterium chlororespirans was able to couple the dechlorination of 3-chloro-4-hydroxybenzoate to the oxidation of lactate to acetate, pyruvate, or formate (Sanford et al. 1996). Whereas 2,4,6-trichlorophenol and 2,4,6-tribro-mophenol supported growth with the production of 4-chlorophenol and 4-bromophenol, neither 2-bromophenol nor 2-iodophenol was able to do so. The membrane-bound dehalogenase contains cobalamin, iron, and acid-labile sulfur, and is apparently specific for ortho-substituted phenols (Krasotkina et al. 2001). 

Pal et al. explored an efficient Pd/C-catalyzed reaction of 2-iodophenols with terminal alkynes in water without the use of any organic cosolvents in the presence of PPh3, Cul, and prolinol to give the expected benzofuran products (Eqs. 4.42, 4.43).78 The hydroxyl group was well tolerated during reactions. When used as a base, prolinol afforded better yields of products than triethylamine, a common organic base, possibly due to its better miscibility with water. 

Lamaty and coworkers described a straightforward combination of three Pd-cata-lyzed transformations first, an intermolecular nucleophilic substitution of an al-lylic bromide to form an aryl ether second, an intramolecular Heck-type transformation in which as the third reaction the intermediate palladium species is intercepted by a phenylboronic acid [124]. Thus, the reaction of a mixture of 2-iodophenol (6/1-253), methyl 2-bromomethylacrylate 6/1-254 and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-di-hydrobenzofuran 6/1-255 (Scheme 6/1.66). In addition to phenylboronic acid, several substituted boronic acids have also been used in this process. 

Substituting the benzene ring with a double bond, Pd-catalyzed intramolecular alkoxylation of alkyne 122 also proceeded via an alkenyl palladium complex to form furan 123 instead of a benzofurans [99, 100]. In addition, 3-hydroxyalkylbenzo[fc]furans was prepared by Bishop et al via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis, [101]. 

First, oxidative addition of 2-iodophenol to a Pd(0) species gives rise to an arylpal-ladium complex, which in turn undergoes carbonylation followed by insertion of allene to generate a 2-acyl-jt-allylpalladium complex. Attack by an internal hydroxyl group gives an a-exo-methylene ketone (Scheme 16.11). 

The Pd-catalyzed electro-cleavage of the C—O bond of allyl aryl ether proceeds smoothly in a DMF-Bu4NBp4-(Mg)-(Stainless Steel) system, giving depro-tected products in 73 99% yield [437]. The sp-sp intermolecular coupling reaction with the Pd water-soluble catalyst prepared in situ from Pd(II) acetate and sul-fonated triphenylphosphine in an MeCN-H2O system yields diynes in 45 65% yields [438]. Similarly, the sp -sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indol and furan... 

A formal [4-1-3] cycloaddition leading to products with a core structure similar to that of 220 was found when 2-iodophenols and furan are treated with a mixture of BusSnH, 2,2 -azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70), and a catalytic amount of diphenyl diselenide, albeit moderate yields have been achieved (Equation 86) <2005OL3625>. 

O-propargyl-2-iodophenol in the presence of a palladium catalyst and phenylzinc chloride (3.30.) led to the formation of the 3-alkylidenedihydrobenzofurane in good yield (c.f 3.26.),37 The use of norbomene as capture reagent under similar conditions led to the formation of benzofurane bearing a tetracyclic hydrocarbon substituent.38... 

The addition of allene and a secondary amine to O-propargyl-2-iodophenol led to the sequential intramolecular insertion of the acetylene bond, followed by the intermolecular insertion of allene and finally the capture of the formed allylpalladium complex by the secondary amine to give benzofurane analogues bearing an exocyclic diene system (3.31.). 

The same reaction, the conversion of 2-iodophenol to 2-arylbenzofuranes was also accomplished in the presence of a copper-phenantroline catalyst and caesium carbonate. Different arylacetylenes and iodophenols were coupled to give the corresponding benzofurane derivatives in good to excellent yield (3.55.)71... 

The analogous palladium catalyzed reaction of internal acetylenes, 2-iodophenol and carbon monoxide leads to the selective formation of coumarins. The heterocyclic analogues of o-iodophenol are also effective. The o-iodopyridone shown in 4.16. for example gave rise to the formation of azacoumarin in 70% yield.18 In these processes the insertion of the acetylene derivative occurs in advance of the insertion of CO. Interestingly, the change of the acetylene to an alkene reverses the insertion order and leads to flavone formation.19... 

Pd/tppts-catalysed intermolecular sp-sp couplings to afford diynes and sp2-sp coupling of 2-iodophenols or iodoanilines with alkynes followed by intramolecular cyclization to benzofurans and indoles, respectively, with moderate to good yields in H20/CH3CN solvent mixtures have also been described.517 8... 

Benzofurans and dihydrobenzofurans have been prepared on polymeric supports by the palladium-mediated reaction of 2-iodophenols with dienes or alkynes (Entries 1 and 2, Table 15.9). This reaction is closely related to the synthesis of indoles from 2-iodoanilines, and probably proceeds via an intermediate palladacycle (Figure 15.3). Benzofuran and isobenzofuran derivatives have also been prepared on cross-linked polystyrene by intramolecular addition of aryl radicals to C=C double bonds and by intramolecular Heck reaction. 

Iodophenyl acetates undergo palladium-catalyzed carbonylation in the presence of aryl alkynes to yield flavones (Equation 309) <20000L1765>. 2-Iodophenols can similarly undergo a palladium-catalyzed carbonylation in the presence of terminal alkynes to afford chromones (Equation 310) <2005JOC6097>. 

A one-pot chroman-4-one synthesis-azomethine ylide cycloaddition can be performed using 2-iodophenol, carbon monoxide, allene and imine 1099 to furnish a mixture of exo- and OTr/o-cycloadducts 1100 (Equation 431) <2000TL7129>. Other nucleophiles are viable alternatives for this process <2000TL7125>. Synthesis of chroman-4-one 1101 is possible using a palladium catalyzed carbonylative cyclization of o-allyloxyliodobenzene (Equation 432) <2001JOC2175>. 

Iodophenol has been carbonylated in the presence of norbornadiene to give a reasonable yield of coumarin, which is formed by a spontaneous retro Diels-Alder reaction from the initially formed product (equation 158)891. 

The photochemistry of aqueous 2-iodophenol was the subject of a subsequent study [19]. Although ring contraction, carbene formation and photohydrolysis took place in this case too, they all were minor pathways (

comparison with homolytic C -1 cleavage forming phenyl radicals and I" atoms (

radical anions. It was concluded that the heterolytic dehalogenation mechanism observed for aqueous 2-chloro- and 2-bromophenol is overruled in the case of 2-iodophenol by a homolytic one promoted by the comparatively weaker carbon-halogen bond [19]. 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Nitroxynil is obtained either by iodination of 4-cyano-2-nitrophenol (47) [47,48] or by nitration of 4-cyano-2-iodophenol (48) [49] (Scheme 3). 

Coupling 2-iodophenols and 2-iodoanilines and terminal alkynes in water in the presence of Pd(OAc)2/tppts gave the corresponding indoles and benzofurans in good yields lEq. (21)] [112]. 

The palladium-catalyzed arylation of cyclic enamide 160 with 2-iodophenol furnished a ca. 2 1 mixture of 161 and pyrido[l,2-c][l,3] benzoxazin-6-one (162) (90JOC2464). 

Palladium-catalyzed carbonylative addition reactions of 2-iodophenols 3 to norbornadiene lead to coumarin systems 4 via stereoselective cis-exo addition and retro-Diels-Alder elimination of cyclopentadiene12, l3. Intramolecular versions of this reaction type have been reported34 35, which include the use of nickel36-42-4 3 and rhodium3 catalysts. 

Similarly, reaction with, V-acetyI-2-bromoaniline gives quinolones after retro-Diels-Alder cleavage13. With 2-bromophenol and norbornadiene under similar conditions, a competitive pathway results in simple hydrocarboxylation without cleavage of the C-Br bond13. The reaction of 2-iodophenol with ethynylbenzene leads to an alkylidenebenzofuranone,3. 

Fluoromethylated benzo[i) furans were made by palladium-catalyzed coupling of fluorine-containing internal alkynes with various 2-iodophenols in the presence of P( Bu>3 as an essential ligand <04T11695>. 

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