Halides, aryl, also with alcohols

The reaction is of the 8 2 type and works best with primary and secondary alkyl halides Elimination is the only reaction observed with tertiary alkyl halides Aryl and vinyl halides do not react Dimethyl sulfoxide is the preferred solvent for this reaction but alcohols and water-alcohol mixtures have also been used... 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

Aryl- and heteroaryl halides can undergo thermal or transition metal catalyzed substitution reactions with amines. These reactions proceed on insoluble supports under conditions similar to those used in solution. Not only halides, but also thiolates [76], nitro groups [76], sulfinates [77,78], and alcoholates [79] can serve as leaving groups for aromatic nucleophilic substitution. 

Similar to the formation of allylmagnesium chloride (25), the oxidative addition of allyl halides to transition metal complexes generates allylmetal complexes 26. However, in the latter case, a 7i-bond is formed by the donation of 7i-electrons of the double bond, and resonance of the n-allvl and 7i-allyl bonds in 26 generates the 7i-allyl complex 27 or (/ -allyl complex. The carbon-carbon bond in the 7i-allyl complexes has the same distance as that in benzene. Allyl Grignard reagent 25 is prepared by the reaction of allyl halide with Mg metal. However, the 7i-allyl complexes of transition metals are prepared by the oxidative addition of not only allylic halides, but also esters of allylic alcohols (carboxylates, carbonates, phosphates), allyl aryl ethers and allyl nitro compounds. Typically, the 7i-allylpalladium complex 28 is formed by the oxidative addition of allyl acetate to Pd(0) complex. 

In the presence of a ruthenium catalyst, 3-diazochroman-2,4-dione 716 undergoes insertion into the O-H bond of alcohols to yield 3-alkyloxy-4-hydroxycoumarins 717 (Equation 285) <2002TL3637>. In the presence of a rhodium catalyst, 3-diazochroman-2,4-dione 716 can undergo insertion into the C-H bond of arenes to yield 3-aryl-4-hydroxy-coumarins (Equation 286) <2005SL927>. In the presence of [Rh(OAc)2]2, 3-diazochroman-2,4-dione 716 can react with acyl or benzyl halides to afford to 3-halo-4-substituted coumarins (Equation 287) <2003T9333> and also with terminal alkynes to give a mixture of 477-furo[3,2-f]chromen-4-ones and 4/7-furo[2,3-3]chromen-4-ones (Equation 288) <2001S735>. 

After obtaining this encouraging result, the Rh2(OAc)4 catalyst was evaluated with several other alcohols using diisopropylsilane (Scheme 24). The reaction works with primary, secondary and tertiary alcohols (Table 5). Alcohols with aryl halide functionality also work, however the reaction failed with alcohols containing double and triple bonds because hydrosilylation and/or hydrogenation of double and triple bonds is believed to be a major side reaction as judged by NMR analysis of crude mixture. 

Disulfides are also formed in good yield when alkyl or aryl halides react with sodium disulfide. According to Blanksma,280 who prepared many aliphatic and aromatic disulfides by this method, the halide is heated with an equivalent amount of sodium disulfide in alcoholic solution. In this way have been prepared, inter alia, bis-(o-nitrophenyl) disulfide (62%),281 dithiodi-(malonic acid),250 and 2,2 -diphenyl-2,2 -dithiodi(acetic acid).251... 

Sulfonic acids can also be obtained by the Strecker synthesis from sodium sulfite and aryl halides that contain reactive halogen. Thus o-formylbenzene-sulfonic acid is formed in very good yield when o-chlorobenzaldehyde is heated under pressure with sodium sulfite,354 2-formyl-4-nitrobenzenesulfonic acid is formed on merely boiling 2-chloro-5-nitrobenzaldehyde with alcoholic sodium sulfite solution.355 The nitro group of nitroaryl halides may also be reduced to an amino group (cf. page 626) using polyhalo compounds leads to poly sulfonic acids.356... 

Nucleophilic azide ion displacements are enhanced by polar, aprotic solvents (e.g. DMSO) with which high yield, aryl halide displacement to form even mononitrophenyl azides can occur. Phase-transfer catalysis (permitting the use of less polar solvents) or ultrasonication (for activated primary halides) has also been used. Under such conditions, 8 2 inversion of configuration occurs and this has been observed also for alcohols under Mit-sunobu conditions (Triphenylphosphine, Diethyl Azodicarboxy-late, HN3). Retention is possible where a neighboring group is present. ... 

Interestingly, in the presence of KOH and aliquat 336, the Pd-catalyzed hydrogenolysis of (4 -chlorophenyl)-l-propanol in hydrocarbon solvents gave propylbenzene in 96% yield along with 4% of 1-phenyl-1-propanol (Scheme 87). With nonhalogenated aryl alcohols, such as 1-phenyl-1-propanol, the hydrogenolysis did not proceed unless an aryl halide was also added. Thus, in the presence of o-dichlorobenzene even t-benzylic alcohol 278 was hydrogenolyzed quite rapidly. The reason for this selectivity is unknown at this time. 

There has been a review of palladium-catalysed carbonylative coupling reactions of aryl halides with carbon nucleophiles in the presence of carbon monoxide. It has been shown that rhodium is an efficient catalyst for the homocoupling reaction of arylzinc compounds in the presence of 1 atm of carbon monoxide to give diaryl ketones. Under similar conditions, palladium and nickel catalysts yield biaryls. The beneficial catalysis by rhodium is likely to derive from the ease of migration of the aryl ligand to carbon monoxide in the rhodium(III) intermediate. A rhodium catalyst has also been used in the formation of indole-3-carboxylates by reaction of indoles with alcohols in the presence of carbon monoxide. The catalytic cycle. Scheme 5, is likely to involve metallation of the indole at the 3-position, followed... 

The first palladium-catalyzed carbonylations of aryl halides were published in 1974 and 1975 (Equation 17.59). ° Heck first reported the synthesis of benzoates by the reaction of an aryl iodide, carbon monoxide, and an alcohol in the presence of a tertiary amine and catalytic amoimts of the combination of palladium acetate and triphenylphosphine. Concurrently, he reported the synthesis of benzamides from an aryl iodide, carbon monoxide, a primary amine, and a tertiary amine as base catalyzed by the same type of palladium complex. The related reactions of vinyl halides were also reported, and these reactions occurred with retention of the olefin geometry. ... 

The combination of N,N-dimethylglycine and Cul also catalyzes the coupling of aryl halides with alcohols. The scope of the reaction of aryl iodides with primary aliphatic alcohols in the presence of this catalyst was similar to that of the reaction catalyzed by copper complexes of 1,10-phenanthroline derivatives, but the scope of the reactions catalyzed by the complexes of tetrametlnylphenanthroline was somewhat broader. 

Mitsunobu and Wada first reported the use of the Mitsunobu reaction in the preparation of ethers in 1972. Since then, the Mitsunobu reaction has become a useful alternative to the reaction of phenols with alkyl halides. Other sufficiently acidic alcohols with a p a of less than 13 may also react under the Mitsunobu reaction conditions. Interestingly, unactivated, less acidic alcohols will form ethers when reacting in an intramolecular manner. The figures below show a number of applications of the Mitsunobu reaction in the preparation of alkyl and aryl ethers. 

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