Palladium-catalyzed amination primary amines

The palladium-catalyzed amination reaction with a monofunctional primary amine 167 effects i / -diarylation to afford the tertiary amine polymers 168. Hence, polycondensation of 167 with bifunctional arylene dihalides leads to 168 (Equation (81)). Polycondensation of a primary amine bearing an azobenzene moiety with dibromides in the presence of Pd2(dba)3 (2.5mol%)- Bu3P (P/Pd = 3 l) and NaO Bu at 100°G for 24h in toluene gives 168 in 81-93% yields, as reported by Kanbara. 

The 2,3-dichloro-4-hydroxyphenyl derivative of aripiprazole was prepared to confirm the structure of a primary metabolite of aripiprazole (Scheme 21). The synthesis began with the protection of 4-bromo-2,3-dichlorophenol as its benzyl ether 71. Palladium-catalyzed amination of 71 with piperazine proceeded regioselectively in excellent yield. Alkylation of the piperazine 72 with 69 in the presence of K2CO3 and... 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

The palladium-catalyzed amination of aryl halides has recently emerged as a powerful alternative to other methods for the synthesis of aryl amines.5 This method allows for the cross-coupling of aryl halides arrd triflates with amines in the presence of a stoichiometric amount of a base and catalytic amounts of palladium complexes bearing tertiary phosphine ligands. As shown in Tables I and II, the Pd/BlNAP catalyst is highly effective for reactions of aryl bromides and triflates with primary and cyclic... 

Hartwig s group has developed chelating ferrocene ligands for this animation.21 They demonstrated that readily available DPPF serves as a competent ligand for the palladium catalyzed amination of primary aliphatic and aromatic amines. The coupling is conducted in THF and works equally well for both aryl iodides and bromides. Secondary amines were not extensively reported. 

Buchwald s XPhos ligand (L7) works well to catalyze the amination of 5-bromopyrimidine with anilines and secondary cyclic amines.67 Buchwald also found that ligands L20 and L21 were the best ligand for the palladium-catalyzed amination of benzothiazoles with secondary amines and anilines. Hartwig reports that (r-Bu)3P was excellent for the catalytic amination of 2-chloroheteroaryl compounds with secondary amines and anilines.35,68 As with other examples using bulky mono-dentate phosphines, primary aliphatic amines were not reported. 

Fort and co-workers first reported that [(IPr)2Ni] (formed in situ from [Ni(acac)2], SIPr-HCl, and base) allowed for the efficient amination of various aryl chlorides under mild conditions (Equation (10.6)). Both electron-poor and electron-rich substituents were supported as well as pyridinic core. A great variety of anilines and secondary amines were easily introduced in good to excellent yields. Primary amines also reacted in moderate yields with activated aryl chlorides. The catalytic cycle was presumably similar to that postulated for the palladium-catalyzed amination of aryl halides using NHC-Pd systems. ... 

Finally, it should be noted that the synthesis of methyl 2,3-butadiene-l-carboxylate can be achieved by the palladium-catalyzed carbonylation of 1-bromoallene with carbon monoxide in methanol [25]. Similarly, 2,3-allenamides are accessible from bromoallenes, carbon monoxide and primary amines or ammonia [26]. 

A palladium-catalyzed amidation of halo(hetero)aromatics substituted in the ortAo-position by a carbonyl function with a primary or secondary amine has been introduced as an alternative to the Friedlander condensation for the synthesis of naphthyridinones (and quinolinones) (Scheme 32) <2004OL2433>. 

Ionic liquids have been used for the selenium- or palladium-catalyzed carbonylation of primary amines to form carbamates or ureas.After completion of the carbonylation, addition of water induced the precipitation of desired products, which were isolated by fdtration and separated from the ionic liquid, containing the catalytic species. Then, the catalyst could be reused after removal of residual methanol and water by distillation. Although the conversion of the reaction slightly decreased after the second run, the catalytic activity was considerably improved (from 70% to 99 %) by the addition of a small amount of the fresh catalyst. " ... 

The last example focuses not on the functionalization of heterocycles by a transition metal mediated carbon-heteroatom bond forming reaction, but the palladium catalyzed conversion of primary amines, including amino-heterocycles, into urea derivatives. A representative example, shown in 8.38., includes the reaction of an amino-carbazole derivative with morpholine, carbon monoxide and oxygen in the presence of catalytic amounts of palladium(II) iodide. The formation of the urea moiety proceeds with great selectivity and in high yield.49 The reaction works equally well for primary aliphatic and aromatic amines. 

Amides are produced from the palladium-catalyzed carbonylation of organic halides if primary or secondary amines are present rather than only an alcohol (/5) ... 

Another variation of the palladium-catalyzed carbonylation reaction occurs when hydrogen is added rather than an alcohol or a primary or secondary amine. This variation leads to aldehyde formation the hydrogen reduces the acylpalladium intermediate to aldehyde and metal hydride (76). A basic tertiary amine is also added as in the ester-forming reaction to neutralize the hydrogen halide formed in the dissociation of the hydride ... 

Ammonia fails to act as an effective nucleophile for 7r-allylpalladium complexes. Some examples of primary amines81-181-183 have been reported, although diallylation is often a problem in these reactions. Secondary amines are, however, excellent substrates for palladium-catalyzed allylation.81-84,181-183-195 Amides,176-196 sulfonamides,196-197 azides198 and magnesium amides199 have also been shown to be effective nucleophiles. 

Fig. 10. Multiple derivatization of purines including palladium-catalyzed reaction at the poorly reactive C2 position, (a) NaBH(OAc)3, 1% HOAc, THF (b) 59 (0.5 equiv.), 2,6-dichloropurine (1 equiv.), DIEA (1.5 equiv.), BuOH 80° (c) R2OH, PPh3, DiAD (1.5 2 1.3) in excess, THF, RT (d) boronic acids (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, Cs2C03 (6 equiv.), 1,4-dioxane, 90°, 12 h (e) anilines (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, KO Bu (6 equiv.), 1,4-dioxane, 90°, 12 h (f) phenols (5 equiv.), 7% Pd2(dba)3, 28% phosphine ligand, K3P04 (7 equiv.), toluene, 90°, 12 h (g) primary or secondary amines (5 equiv.), 90°, 12 h.

Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudohalides (for example triflates) and primary or secondary amines. 

In a radically different approach, Alper has discovered that Me-DuPhos may be used in the synthesis of a-amino acids through a palladium-catalyzed double carbohydroamination whereby aryl iodides 74 can be converted to the corresponding arylglycine amides 75 in the presence of excess primary amine (Scheme 13.27).72... 

In the palladium-catalyzed allylic amination reaction, primary and secondary amines can be used as nucleophiles, whereas ammonia does not react. Therefore, many ammonia synthons have been developed, and a variety of protected primary allyl amines can now be prepared using azide, sulphonamide, phthalimide, di-f-butyl iminocarbonate ((Boc)2NLi), and dialkyl A-(rerr-butoxycarbonyl)phosphoramide anions as the nucleophile [20], An example of the use of ((Boc)2NLi) 30 as the amine nucleophile in the palladium-catalyzed allylic amination reaction is shown in Eq. (9). This reaction also illustrates the problem with the regioselectivity in the reaction as a mixture of the products 31-33 are obtained [21]. 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

---