Aryl halides cleavage

The value of alkyl halides as starting materials for the preparation of a variety of organic functional groups has been stressed many times In our earlier discussions we noted that aryl halides are normally much less reactive than alkyl halides m reactions that involve carbon-halogen bond cleavage In the present chapter you will see that aryl halides can exhibit their own patterns of chemical reactivity and that these reac tions are novel useful and mechanistically interesting... 

The strength of their carbon-halogen bonds causes aryl halides to react very slowly in reactions in which carbon-halogen bond cleavage is rate determining as m nude ophilic substitution for example Later m this chapter we will see examples of such reactions that do take place at reasonable rates but proceed by mechanisms distinctly dif ferent from the classical S l and 8 2 pathways... 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

The catalytic process is also achieved in the Pd(0)/Cr(II)-mediated coupling of organic halides with aldehydes (Scheme 33) [74], Oxidative addition of a vinyl or aryl halide to a Pd(0) species, followed by transmetallation with a chromium salt and subsequent addition of the resulting organo chromate to an aldehyde, leads to the alcohol 54. The presence of an oxophile [Li(I) salts or MesSiCl] allows the cleavage of the Cr(III) - 0 bond to liberate Cr(III), which is reduced to active Cr(II) on the electrode surface. 

Another sequence involving an anionic and a Pd-catalyzed step was described by the groups of Rossi and Arcadi [477]. These authors prepared substituted tetrahy-dro-2H-pyrrolo[3,2-c]pyrazolones 2-934 starting from hydrazones 2-932 and aryl-halides or alkenyl triflates 2-933 (Scheme 2.208). The first step is the formation of a pyrazolone. There follows cleavage of the urea moiety with piperidine and an inter-as well as an intramolecular Heck-type reaction with 2-933. 

Reaction of allyl nalides with the iron powders is rapid and exothermic and leads to near quantitative yields of the self-coupled product 1,5-hexadiene. Similarly, reaction of benzyl chloride with the iron powders at room temperature yields bibenzyl in 60-70% yields along with 20-25% of toluene. In contrast, reaction of aryl halides with the iron powders leads to reductive cleavage rather than self-coupling. Similarly, reaction of 1-bromoheptane with the iron powder in THF for three hours at room... 

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

An alternative approach to developing new reagents for DNA cleavage was founded in the conversion of aryl diazonium salts to aryl halides by the well-known Sandmeyer reaction. The reaction (Eq. 1) is thought to proceed via aryl radicals [7]. These reactions are high yielding and catalytic with respect... 

While C-C bond formation via metallation and alkyl or aryl halides is well known (COMC (1982) 5.4.2.7.5), the C-C bond formation with TBAF and aldehyde, enones, or enals is new (Figure 9).318 Carboranyl groups can actually be used as protecting groups for aldehydes and ketones due to the facile cleavage of the cage C-C(OH) bond with... 

In the absence of nucleophile, the aryl halide undergoes a two-electron reductive cleavage according to an ECE-DISP mechanism (Scheme 2.21). The two-electron stoichiometry occurs because the aryl radical produced on the one-electron reductive cleavage is easier to reduce than the substrate. The competition between the ECE and DISP pathways is governed by the parameter... 

The proposed mechanism involves the usual oxidative addition of the aryl halide to the Pd(0) complex affording a Pd(II) intermediate (Ar-Pd-Hal), subsequent coordination of allene 8 and migratory insertion of the allene into the Pd-C bond to form the jt-allylpalladium(II) species 123. A remarkable C-C bond cleavage of 123 leads by decarbopalladation to 1,3-diene 120 and a-hydroxyalkylpalladium species 124. /8-H elimination of 124 affords aldehyde 121 and the H-Pd-Hal species, which delivers Pd(0) again by reaction with base (Scheme 14.29). The originally expected cyclization of intermediate 123 by employment of the internal nucleophilic hydroxyl group to form a pyran derivative 122 was observed in a single case only (Scheme 14.29). 

Fig. 9 Electrochemical reductive cleavage of aryl halides in a poor H-atom donor solvent. Cyclic voltammetry as a function of the scan rate, v. E, Electrode potential i, current. Reduction (cathodic) currents are represented as being upwards.

As represented in Fig. 9, the irreversible reduction of aryl halides at low scan rate is a two electron per molecule process, at least in poor H-atom donor solvents such as liquid ammonia (Amatore et al., 919 Saveant and Thiebault, 1978). This is due to the fact that aryl radicals, produced upon cleavage of RX-, are very easy to reduce, around —0.3 V vs SCE (Jaun et al., 1980), much more than the starting aryl halides (from about — 1 to — 2.8V vs SCE). It follows that R-, as soon as produced in (47), is immediately reduced into the corresponding carbanion, R" (71 and/or 72), which is eventually protonated (73) by the strongest acid present in the... 

All the evidence gathered so far points to the conclusion that the RX radicals are intermediates in the reductive cleavage of aryl halides by outer sphere electron donors in polar solvents. This was an already established conclusion for the reduction of several aryl halides in the gas phase (Steelhammer and Wentworth, 1969 Wentworth et al., 1967), and for iodobenzene in apolar or weakly polar matrixes from y-irradiation studies with esr detection at low temperatures (Symons, 1981). It might, however, not have been true in the polar media used in direct and indirect electro-... 

The addition of the nucleophile to the aryl radical is the reverse of the cleavage of substituted aromatic anion radicals that we have discussed in Section 2 in terms of an intramolecular concerted electron-transfer-bondbreaking process and illustrated with the example of aryl halides. The present reaction may thus be viewed conversely as an intramolecular concerted electron-transfer-bond-forming process. The driving force of the reaction can be divided into three terms as in (131). The first of these, the... 

Intramolecular dissociative electron transfer in aryl halide radical-anions involves an interaction between the n-aroinatic orbital and the o-type carbon-halogen bond. These orbitals are orthogonal, but bending of the carbon-halogen bond allows the necessary interaction. Qualitatively, the influence of several factors on the bond cleavage rate can be discerned [18],... 

Moreover, reaction time was reduced from hours to minutes or even seconds. Indeed, the carbonylation of aryl halides 335 was completed in 10 s to give symmetrical diaryl ketones 336 in excellent yields (Equation (31)). The process optimization to reduce the amount of catalyst disclosed the fact that this carbonylation reaction followed a radical pathway, initiated by the homolytic cleavage of Co2(CO)8 into -00(00)4. It also appeared that the amount of the Oo catalyst had a direct correlation with the internal temperature reached during the reaction. These findings are critical for the development of extremely fast synthesis using carbonylations. 

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