Aryl iodides, double carbonylation

Xia and co-workers synthesised a number of Pd-NHC complexes (33, 34, 36) for carbonylative Suzuki reactions (Fig. 9.6) [41], Various aryl iodides were carbonylatively coupled (P = 1 atm) with either phenylboronic acid or sodium tetraphenylborate. All the complexes were highly active, but 33 provided the best results with >76% selectivity for ketone in all the reactions. Xia followed this work with the double carbonylation of various aryl iodides with several secondary amines using the catalysts [CuX(Mes)] (37-X) and [Cu(IPr)X] (38-X) (X = I, Br, Cl) (3 MPa, 100°C, 10 h) (Scheme 9.7) [42],... 

Scheme 9.7 General scheme for double carbonylation of aryl iodides with secondary amines...

Scheme 13 Pd-catalysed double carbonylation of aryl iodides [35]...

In a further variant of this type of carbonylation, aryl, vinyl and heterocyclic bromides and iodides underwent a double carbonylation to give a-ketoamides (equation 119). 

Double Carbonylation of Aryl Halides. (DIOP)PdCl2 catalyzed the double carbonylation of phenyl iodide in the presence... 

In contrast to the substrate-type presented in Scheme 5.6, intramolecular Mizoroki-Heck reactions with cychc alkene moieties are quite common. Negishi and coworkers [21, 29] screened numerous substrates with different substitution patterns, out of which four are shown in Scheme 5.7. Cychzation of aryl iodide 35 proceeded well and furnished tricyclic 36 in good yield, including 10% of a double-bond isomer (not shown) (35 36). Mizoroki-Heck reactions of cyclohexenones 37 and 39 provided 68% and 82% yields respectively and, probably, due to conjugation with the carbonyl group in isomerically pure form (37,39 38,40). The two analogous cyclohexenone derivatives of aryl iodide 35 (not shown) cyclized under identical conditions in 50% and 71% yields respectively. Substrate 41a even allowed for formation of spirocyclic 42a in good yield, yet with poor... 

Additionally, primary amides and ketoamides were synthesized in good yields via a more traditional carbonylation-deprotection sequence in the presence of Pd(OAc)2/2PPh3 (Scheme 2.13) [134]. Initially, aryl iodides were reacted with ferf-butylamine under 1 bar of CO. When the reaction proceeded at 60 °C, ketoamides resulting from double carbonylation were mainly produced, whereas formation of the amides was favored at 100 °C. The desired primary amides were produced after heating the previous isolated products with one equivalent of tert-butyldimethylsilyl triflate (TBDMSOTf) in toluene at 100 °C. 

Copper as cheap metal was also applied in carbonylation reactions. In 2009 Xia and colleagues described a general and efficient copper-catalyzed double amino-carbonylation of aryl iodides (Scheme 2.46) [292], Using an NHC-Cu catalyst, aryl iodides were double carbonylated with amines in good yields (72-93 %). 

The a-keto amides are less susceptible to hydrolysis and preparation of a-keto esters and acids are preferable for synthesizing various derivatives thereof. Various aryl iodides and bromides can be converted into a-keto esters on reactions with alcohols and carbon monoxide in the presence of a base such as tertiary amines or potassium acetate with catalytic amounts of tertiary phosphine-coordinated palladium complexes (Eq. 11).[42]-[46] jjjgjj yields of a-keto esters can be achieved only when iodide substrates are used. Double carbonylation of aryl bromides to a-keto esters can be accomplished with difficulty at much slower rates. Alkyl and benzyl iodides give no double carbonylation products. 

The proposed mechanism of double carbonylation of aryl iodide with alcohol and triethy-lamine to give a-keto ester is shown in Scheme 3. 

In parallel, Xia and coworkers have made an important contribution to the carbonylation area (Scheme 8.17) [46]. The double carbonylation of aryl iodides vyith amines highlighted [Cu(I)(IPr)j as the best choice for this reaction. Nevertheless, the combination of a NHC salt and [Cu(X)(NHC)j is required to reach high conversion. The influence of the halides clearly depicted a trend (I > Cl > Br). The reaction also occurred in the presence of [Cu(IPr)2] [BF4] alone [47]. When Nal is used as cocatalyst, the transformation is almost quantitative. The bis-NHC-copper complex is believed to be the active species. 

In the palladium-catalysed carbonylation of aryl bromides to yield benzaldehyde derivatives, IV-formylsaccharin is used as the source of the acyl function. A double carbonylation has been observed in the reaction of aryl halides with carbon monoxide and terminal alkenes which yields 4-arylfuranones such as (152). The proposed mechanism involves oxidative addition of the aryl halide to palladium and insertion of the carbon monoxide to give an acyl palladium species. This is followed by coordination and insertion of the alkene. A second carbon monoxide insertion is faster than -hydride elimination and, after intramolecular attack, leads to the product. The palladium-catalysed reaction of aryl iodides with simple ketones such as acetone in the presence of carbon monoxide has been shown to yield 1,3-diketones such as... 

Several papers deal with the products of (formally) "double carbonylation" reactions. The carbonylation product of styrene oxide in the presence of a Co2(C0)g/MeI catalyst under phase-transfer conditions contains two CO derived carbons (eqn.17). Two groups report the synthesis of a-keto esters from aryl iodides, CO, alcohols and tertiary amines the selectivity depends on Replacement of alcohol by water leads to a-keto acids. a-Keto-amides are prepared similarly from secondary amines. In this case the mechanism has been studied in detail oxidative addition of the aryl halide is the rate-determining step (Scheme 5). °... 

Miura and coworkers reported the first palladium catalyzed intermolecular carbonylative Heck reaction of aryl iodides and five membered olefins in the presence of carbon monoxide (Scheme 1.28) [99]. The expected 2,5-dihydrofuran product was not observed in the carbonylative coupling of 4-iodoanisole and 2,3-dihydrofuran as depicted in Scheme 1.28. Instead, isomerization of the double bond via reinsertion of the palladium(II) hydride followed by another ]S-hydride elimination formed the vinyl ether exclusively. 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

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