Iodo cyclizations

Diaryl-5,6-dihydro-4//-l, 3-thiazines have been obtained by iodo-cyclization of /V-homoallyl thioamides (Scheme 28).55... 

Reactions of Allylation and Propargylation Allylation of prochiral and chiral nitrones (292) with allylmagnesium chloride leads to homoallylic hydroxylamines (416), which via an iodo cyclization step are converted to 5-(iodomethyl)isoxazolidines (417) (Scheme 2.186) (202, 213, 666-668). 

Addition of allylic zinc bromides to nitrones, generated in situ from allylbro-mides and zinc powder in THF (670), allyltributylstannane (671) and lithiated allyl ferf-butyldimethylsilyl ether (672), proceeds regioselectively in good yields and is used to synthesize homoallyl hydroxylamines (Scheme 2.189). The latter were subjected to an iodo cyclization reaction (see Scheme 2.186). 

An organophosphine-mediated cyclization of alkyl 3-aroyloxy-2-butynoates gives rise to the formation of 2,3- and 2,4-disubstituted as well as 2,3,5-trisubstituted furans (Equation 25) <2004JA4118>. 3-Alkyne-l,2-diols undergo iodo-cyclization to give 3-iodofurans after subsequent dehydration <2001TL5945>. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

Finally, examples of highly diastereoselective hydroxy enoate iodo-cyclizations will be mentioned. In the first case, the homoallylic asymmetric induction in the formation of 2,4-disubsti-tuted tetrahydrofurans was investigated41. When the ( )-substrates 3 were iodo-cyclized, the diastereomeric products 4 were formed in ca. 86% yield their relative abundance depended both on the nature of R and the solvent. The effect of the substituent R was interpreted by means of AM 1 calculations41. 

In this connection, intramolecular Michael addition of 0-carbamates to a,3-unsaturated esters (Scheme 60)," iodo cyclization of allylic and homoallylic trichloroacetamidates" or aminomercuration of alkenic carbamates" has been used for the preparation of amino alcohols. 

S Synthesis from n-ribonolactone D-Ribonolactone has been converted to tre-hazolamine derivatives via the allylic alcohol 99, whose condensation with p-methoxybenzylisothiocyanate followed by anti-Markovnikov iodo cyclization with iodine afforded the iodo oxazolidinone 100 (82%) (Scheme 14). The latter was treated with a mixture of acetic anhydride and snlfnric acid followed by activated zinc to furnish the allylic acetate 101 (90%), which nnderwent inversion at C-2 nnder Mitsnnobu conditions and the resnlting alcohol was epoxidized to produce 102. Hydrolysis of the epoxide 102 followed by acetylation of the resulting triol 103 afforded 104, which was treated with CAN to furnish the triacetate 105. Finally, 105 was converted into hexaacetate 86 in three steps. 

Benzothiophenes may be accessed by a variety of methods including variations of the Fiesselmann and Gewald thiophenes synthesis. In addition, acid-catalyzed and electrophilic (iodo) cyclizations have been used to create valuable synthetic thiophene and benzothiophene intermediates with varied substitution patterns. 

Methods to synthesize benzothiophenes via electrophilic (iodo) cyclization were separately published by Flynn and Larock in 2001. " The reaction typically involves electrophilic addition to an alkynyl substituent of a phenyl sulfide or thiophenol in the presence of iodine. Subsequent nucleophilic attack of the sulfur establishes the 5-membered ring system.Loss of a proton produces the corresponding benzothiophene functionalized at the C3 position with iodine. The resulting 3-iodothiophene can then undergo further transformation as described in previous sections. 

A facile route for the synthesis of novel benzo[ ]furanyl benzimidazole derivatives was reported involving iodo-cyclization of 3-(benzimidazol-2-yl)phenyl alkynes (14JHC1491). 

Kang SH, Lee SB, Park CM. Catalytic enantioselective iodo-cyclization of y-hydroxy-cw-alkenes. J. Am. Chem. Soc. 2003 125(51) 15748-15479. 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

The electrochemical reduction of 3-nitrophthalic acid at controlled potentials gave 2,1-benzisoxazole-3-carboxylic acid. Cyclization is presumed to proceed via an intermediate oxime (67AHC(8)277). Treating 5-iodoanthranilic acid with acetic anhydride gave 3-acetoxy-5-iodo-2,l-benzisoxazole (596) (65JMC550). 

The first example of a cyclization of fluorine-containing 5-hexenyl radicals was the study of the radical-iniOated cyclodimenzation reaction of 3,3,4,4-tetra-fluoro-4-iodo-1-butene. In this reaction, the intermediate free radical adds either to more of the butene or to an added unsaturated species [54, 55] (equation 56). Electron-deficient alkenes are not as effective trapping agents as electron-nch alkenes and alkynes [55]. 

To verify the generality of the cyclization of iodopyrazolecarboxylic acids, copper p-phenylbenzoylacetylide was used in the reaction with 3-iodo-l-methylpyra-zole-4-carboxylic acid. The assumed intermediate, alkynylpyrazolylcarboxylic acid, has a distribution of the electron density which is the most favorable for closure of the five-membered cyclic ether. However, the reaction leads only to the 5-lactone (Scheme 120). 

The cyclocondensation of 4-iodo-l-methylpyrazole-5-carboxylic acid with PhC=CCu under similar conditions is over in 1.5 h. Thus, the cyclization of the... 

Whereas the condensation of o-iodonitrobenzene with copper acetylides is accompanied by cyclization into isatogens, neither 4-iodo-3-nitro- nor 5-iodo-4-nitro-l,3-dimethylpyrazole gives cyclized products in conditions of acetylide synthesis. Moreover, nitropyrazolylphenylacetylene, as compared with o-nitrotolane, does not undergo thermal, catalytic, or photochemical isomerization to give the fused five-membered rings. 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

Nucleoside N -oxides have proved useful in preventing intramolecular cyclizations during manipulation of the sugar moiety. A key step is the reductive removal of the oxide when needed. In the presence of Raney nickel, the oxide can be reduced selectively even when such easily reduced substituents as iodo are present. Azides, however, are reduced concomitantly with the oxide 105). 

Benzene- 1,2-diacetonitriles e.g. 19, in the presence of hydrogen bromide in acetic acid, or in diethyl ether, cyclize to 4-bromo-l //-3-benzazepin-2-amines, e.g. 20a.41,42 l//-Naphtho[2,3-t/]azepines, e.g. 22a, are prepared in a similar manner from naphthalene-2,3-diacetonitriles, e.g. 21.41 Replacement of hydrogen bromide by hydrogen iodide yields the corresponding 4-iodo derivatives, e.g. 20b and 22b. 

Iodination of 4 with molecular iodine in the presence of mercuric oxide formed the 3-iodo derivative (52JA4951 66CJC2283). Iodine in tetrahydro-furan oxidatively cyclized /3-(3-benzo[b]thienyl)-a-mercaptoacrylic acids rather than iodinating the thiophene ring [70JCS(C)2431]. 

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

A novel route to indoles and quinolines has been developed by sequential Wiltig and Heck reactions <96CC2253>. Thus, treatment of o-bromo- or iodo-lV-lrifluoroaceiylanilines (86) with a stabilized phosphorane affords the corresponding enamines 87 as a mixture of isomers. Cyclization to 88 is effected by heating with palladium acetate, tri phenyl phosphine, and bu.se. 

---