Aryl-bromide bond

Free-radical cyclization on to unsaturated CN bonds and also the cyclization of a range of nitrogen-centred radicals have continued to attract interest and have been reviewed. Aryl radicals, generated from BusSnH- or TTMSS-mediated homolytic cleavage of aryl-bromide bonds, have been shown to cyclize on to the nitrogen atom of imidate esters in the 5-exo mode (Scheme 9). Loss of an ethyl radical leads to the observed A-acylindolines. No cyclization in the 6-endo mode was detected. 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

Compound 71 differs from 70 in that it possesses an acetamide rather than an amine moiety. The Pd/Cu-catalyzed coupling reaction to form 71 proceeded at a faster rate than the coupling to the amine/nitro compound due to the diminished electron donating potential of the acetamide allowing for faster Pd oxidative addition across the aryl bromide bond. The overall net dipole moment of this compound has been calculated to be 2.7 Debye, substantially lower than that for 70. ... 

An interesting free radical carbon-carbon bond formation with concomitant elimination of a /5-thio substituent was achieved during the course of Boger s impressive synthesis of CC-1065.26-27 In the event, treatment of aryl bromide 70 (see Scheme 13) with tri-n-... 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

Nicolaou and coworkers reported efficient enantioselective syntheses of ( )-kinamycin C (3), ( )-kinamycin F (6), and ( )-kinamycin J (10) [39], Nicolaou s retrosyntheses of these targets are shown in Scheme 3.13. The authors envisioned that all three metabolites could be accessed from the common precursor 82. The a-hydroxyketone function of 82 was envisioned to arise from an intramolecular benzoin reaction of the ketoaldehyde 83. This key bond disconnection would serve to forge the cyclopentyl ring of the kinamycin skeleton. The ketoaldehyde 83 was deconstructed by an Ullmann coupling of the aryl bromide 84 and the a-iodoenone 85. The latter were anticipated to arise from the bromojuglone derivative 86 and the enantiomerically enriched enone 87, respectively. 

Palladium-catalyzed reaction of 2-hydroxy-2-methylpropiophenone with aryl bromides shows a unique multiple arylation via successive C-C and C-H bond cleavages, giving tetraarylethanes.96 For example, the reaction of 2-hydroxy-2-methylpropiophenone with bromobenzene in the presence of Pd(OAc)2, P(/-Bu)3, and CS2CO3 gives 1,1,2,2-tetraphenylethane quantitatively, together with l,4,4-triphenyl-7-methylisochroman-3-one (13% yield) (Equation (74)). 

The oxidative addition of palladium(O) to aryl bromide generates the arylpalladium(n) intermediate 126 (Scheme 37). The electrophilic activation of the double bond by palladium facilitates the nucleophilic attack, resulting in cyclization. 

Due to the potential problems associated with f3-H elimination, the first examples that were reported involved the intramolecular formation of G-O bonds between tertiary alcohols and aryl bromides using Pd(OAc)2 with 2,2 -bis(di-/>-tolylphosphino)-l,l -binapthyl (tol-BINAP) or bis(diphenylphosphino)ferrocene (dppf) as the ligands (Equation (12)).91 Although the coupling with primary and secondary alcohols was troublesome with this system, the more recent introduction of ligands 23-28 (Figure 3) has ameliorated many of these difficulties (Equation (13)).92... 

The ring closure to form butenolides by palladium(O) catalysis can be combined with C,C bond linking, as shown by Ma and co-workers. If using tetrakis (triphenyl -phosphane)palladium(O), the products 272 are obtained from 268 (R1 = alkyl, R2 = H) and vinyl iodides or aryl bromides and iodides R3X [304]. The authors assume that... 

The catalytic Pd complex and the aryl bromide together suggest the first step is oxidative addition of Pd(0) to the C5-Br bond. (The reduction of Pd(II) to Pd(0) can occur by coordination to the amine, p-hydride elimination to give a Pd(II)-H complex and an iminium ion, and deprotonation of Pd(IE)-H to give Pd(0).) The C10-C11 k bond can then insert into the C5-Pd bond to give the C5-C10 bond. P-Hydride elimination then gives the Cl 1-C12 n bond and a Pd(II)-H, which is deprotonated by the base to regenerate Pd(0). The overall reaction is a Heck reaction. 

Scheme 69 Palladium(0) catalyzed cathodic cydization of aryl bromides and double bonds.

Reduction of a mixture of two aryl halides is not generally a good route to the mixed biaryl. Either a statistical mixture of the three possible biaryls is formed or, if one aryl halide is more reactive, this forms a single biaryl after which, the second aryl halide reacts with itself. The principal exception to this generalisation involves the reduction of a 1 1 mixture of an aryl bromide and 1-chloropyridine. Oxidative-addition to Ni(o) is faster for the carbon-bromine bond. The second oxidative-addition to ArNi(i) is faster for the 2-chloropyridinc, possibly due to complexation from the pyridine nitrogen. Overall, the 1-aryipyridine is formed in 55-80 % yields [200]. 

A variety of methods exist for the formation of 1,2-thiazines via the construction of an S-N bond by nucleophilic attack of nitrogen onto a sulfur-bearing leaving group. For example, the reaction of aryl bromide 189 with potassium thiocyanate in the presence of copper(l) iodide and triethylamine affords benzothiazine 190, although in low yield and as a mixture with indoline by-product 191 (Equation 28) <2000JOC8152>. 

In aprotic solvents, the radical anion, RX , for aryl halides has been detected as intermediate. In cyclic voltammetry of aryl halides, though an irreversible two-electron reduction occurs at low scan rate, a reversible one-electron reduction occurs at high scan rate. Thus, it is possible to get the values of the standard potential ( °) for the RX/RX couple and the rate constant (k) for RX -> R (therefore, the lifetime of RX ). In Fig. 8.18, the relation between ° and log k for aryl bromides in DMF is linear with a slope of 0.5 [5If], It is apparent that the lifetime of RX , obtained by 1/k, increases with the positive shift of E0. In contrast, the existence of RX for alkyl monohalides has never been confirmed. With these compounds, it is difficult to say whether the two processes, i.e. electron transfer and bond cleavage, are step-wise or concerted (RX+e -> R +X ). According to Sa-veant [5le], the smaller the bond dissociation energy, the larger the tendency for the concerted mechanism to prevail over the step-wise mechanism. 

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