Amination aryl bromides

Verkade was able to aminate aryl bromides and chlorides where R1 contains an acidic proton (phenol, amide, or ketone) by simply using 2.4 equiv of LiHMDS rather than the usual 1.4 equiv. NaO/-Bu.46a This procedure works well for cyclic secondary amines and anilines of all types, but gives poor yields for primary aliphatic and secondary acyclic amines. 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

A Pd-cataly2ed reaction of amines with halides is expected, but actually little is known about the reaction. The CDE ring system of lavendamycin (805) has been constructed by the intramolecular reaction of aryl bromide with aniline derivative in 804, but 1.2 equiv, of Pd(Ph3P)4 is required[679]. 

Although It IS possible to prepare aryl chlorides and aryl bromides by electrophilic aromatic substitution it is often necessary to prepare these compounds from an aromatic amine The amine is converted to the corresponding diazonmm salt and then treated with copper(I) chloride or copper(I) bromide as appropriate... 

For the in situ preparation of the required arenediazonium salt from an aryl amine by application of the diazotization reaction, an acid HX is used, that corresponds to the halo substituent X to be introduced onto the aromatic ring. Otherwise—e.g. when using HCl/CuBr—a mixture of aryl chloride and aryl bromide will be obtained. The copper-(l) salt 2 (chloride or bromide) is usually prepared by dissolving the appropriate sodium halide in an aqueous solution of copper-(ll) sulfate and then adding sodium hydrogensulfite to reduce copper-(ll) to copper-(1). Copper-(l) cyanide CuCN can be obtained by treatment of copper-(l) chloride with sodium cyanide. 

Independently, Antane reported that arylisonipecotic acids were obtained from aryl bromides in a two-step process involving microwave-assisted palladium-catalyzed amination with ethyl isonipecotate followed by ester hydrolysis with KOH (Scheme 91) [96]. Interestingly, toluene, which is the standard solvent for Buchwald-Hartwig aminations under conventional heating, was used as the sole reaction medium, although it is a very weak... 

But in the presence simultaneously of a nickel catalyst and of a tertiary amine, the aryl bromide is activated and the bromhydric acid fixed, in such a way to give a very good yield (80 %) in aryl ether in regard to the moderate temperature... 

Grubbs reported the synthesis of several N, N -aryl substituted imidazolinium salts 35 from chiral Ar,AT -aryl diamines obtained by palladium-catalyzed amination of the appropriate aryl bromide with (li, 2i )-diaminocyclohexane... 

Regarding bis-NHC chelating ligands, several structures that differ in the motifs used for the enlargement of the tether have been proposed as catalysts for the Mizoroki-Heck reaction. They range from non-functionalised aliphatic chains [23-25] to phenyl [26], biphenyl [27], binaphthyls [28] and to chains containing additional coordination positions like ethers [29], amines [30], and pyridines in an evolution towards pincer complexes [31-35], In most cases, the activity of aryl bromides in Mizoroki-Heck transformations was demonstrated to be from moderate to high, while the activation of chlorides was non-existent or poor (Scheme 6.7). 

The original conditions used amines as solvents or cosolvents. Several other bases can replace the amine. Tetrabutylammonium hydroxide or fluoride can be used in THF (see Entry 1 in Scheme 8.11).163 Tetrabutylammonium acetate is also effective with aryl iodides and EWG-substituted aryl bromides (Entry 2).164 Use of alkenyl halides in this reaction has proven to be an effective method for the synthesis of enynes165 (see also Entries 5 and 6 in Scheme 8.11). 

The N,N-diethylamide of salicylic acid is a useful ligand in conjunction with Cul and permits amination of aryl bromides by primary alkylamines.151... 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

With the exception of intramolecular amination reactions, all of the early aryl halide aminations were catalyzed by palladium complexes containing the sterically hindered P(o-tol)3. In papers published back-to-back in 1996, amination chemistry catalyzed by palladium complexes of DPPF and BINAP was reported.36,37 These catalysts allowed for the coupling of aryl bromides and iodides with primary alkyl amines, cyclic secondary amines, and anilines. 

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. 

In 1978 and 1980 the coupling of aryl bromides and iodides with both aliphatic and aromatic thiols was first reported in the presence of NaO-t-Bu and Pd(PPh3)4 (Equation (35)).118,119 In contrast to aryl halide aminations and etherifications, the thiation reactions did not require unusual catalysts. Yet, reactions that form aryl alkyl sulfides from alkyl thiols occurred in modest yields in many cases ... 

Scheme 6.59 Inter- and intramolecular palladium-catalyzed amination reactions of aryl bromides and triflates.

A variety of amides has been formed in moderate to high yields with aryl bromides or iodides as aryl precursors and single-mode microwave heating for 15 min at 150 °C (Eq. 11.15) [29]. Under these conditions, aliphatic, unhindered primary, and secondary amines reacted readily, whereas sterically hindered amines or amines of low nucleophilicity, e.g. anilines, afforded low yields and incomplete conversions. Among the homogeneous catalytic systems tested the most suitable for the use with aryl bromides was a 2 1 mixture of BINAP and Herrmann s palladacycle. 

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 . A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 200 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 201, with sodium azide afforded aryl tetrazoles 202 . 

The selectivity in favor of the desired monobenzylated product was found to be >99% and the immobilized Pt02 was found to be 4-5 times more active than the commercial Adams catalysts. In solution or in immobilized form, the PtOz colloid is effective in the hydrogenation of carbonyl compounds or of olefins. Recently, the heterogeneous catalytic amination of aryl bromides by immobilized Pd(0) particles has been reported [163], Secondary amines such as piperidine and diethyl amine are used in the amination of aryl bromides and the reaction proceeds with good turnover numbers and regio-control. The catalysts can be reused repeatedly without loss of activity or selectivity after filtration from the reaction mixture. 

The silylated tin compound 199, obtained from tributyltin hydride and N-bis(trimethylsilyl)propargylamine (198) in the presence of a trace of AIBN (2,2/-azobisisobutyronitrile), is a versatile reagent for the preparation of allylic amines. Treatment with aryl bromides ArBr (Ar = Ph, 4-MeOCgH4, 4-O2NC6H4 etc.) under Pd(PPh3)4 catalysis yields the silylated amines 200, which are hydrolysed by acids to the free amines 201. 199 is converted into the lithium compound 202, which is transformed into 203 by aqueous ammonium chloride and into 204 by the action of alkyl halides RX (R = Me, Et or allyl) (equation 76)204. 

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. 

Singh, U., Strieter, E., Blackmond, D., and Buchwald, S. Mechanistic insights into the Pd(BINAP)-catalyzed amination of aryl bromides kinetic studies under synthetically relevant conditions. J. Am. Chem. Soc. 2002, 724, 14104-14114. 

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