Aryl halides with heterocyclic amines

Copper-Catalyzed Reactions of Aryl Halides with Heterocyclic Amines... 

In 1995, Buchwald and Hartwig independently discovered the direct Pd-catalyzed C—N bond formation of aryl halides with amines in the presence of stoichiometric amount of base [93, 94], This field is becoming rapidly mature and many reviews covering the scope and limitations of this animation have been published since 1995 [95-102]. In the context of heteroaryl synthesis, one example is given to showcase the utility and mechanism of this reaction. Applications to individual heterocycles may be found in their respective chapters. 

Recently, Buchwald and Hartwig have developed the palladium-catalyzed coupling reaction of aryl halides with amines (Scheme 165), and they have extended this reaction to the intramolecular version to give a variety of the aza-heterocyclic compounds 547 (Scheme 166).231 This methodology has provided a wide variety of alkaloids, such as indoles,232 inda-zoles,233 benzimidazoles,234 benazepines,235 phena-zines,236 carbapenems,237 the mitomycin ring system,238 a-carbolines,239 and polyheterocycles.240 Pharmacologically active natural products, such as (—)-asperlicin (550) (Scheme 167),241 dehydrobufotenine (553) (Scheme 168),242 and makaluvamine C... 

Consecutive palladiumotalyzed carbon-nitrogen bond forming reactions can also be employed to access aromatic heterocycles. Nozaki has demonstrated this approach in the double N-arylation of 20 as a route to efficiently generate carbazoles (Scheme 6.40) [52]. This reaction can proceed with a range of alkyl and aryl amines, replacement of the aryl halides with sulfonates, and can even be performed consecutively to construct extended heteroacenes. 

Over a century ago, Ullmann reported coupling reactions catalysed by metallic copper. ° ° The harsh conditions typically involved limited its applicability, but Ullmann s work ultimately stimulated the search for milder conditions using copper catalysis. Both copper(I) and copper(II) salts can catalyse the coupling of aryl halides with a range of heteroatom nucleophiles, including phenols (Scheme 2.168, 2.169), ° alcohols (Scheme 2.170),thiols (Scheme 2.171, 2.172), amines (Scheme 2.173), anilines (Scheme 2.174)2" and A/ -heterocycles (Scheme 2.175,2.176).2i2.2i3... 

The following discussion focuses on the synthesis of aromatic heterocycles where a key palladium- or copper-catalyzed aryl halide (or equivalent) amination, etherification or thioetherification process is employed. Annulative routes utilizing anilines and related compounds with alkynes (Larock type) are also considered. Routes that do not lead to aromatic products or that rely on the functionalization of preexisting heterocycles have been discounted. Similarly, the synthesis of heterocycles via TT-allylpalladium chemistry or intramolecular cyclization of palladium Tr-olefin and TT-alkyne complexes is not featured. The discussion is structured predominantly around the type of bond being formed (C—N, C—O, or C—S) and is classified further by heterocycle type. Intramolecular and intermolecular C—X bond formations as well as tandem catalytic processes leading to aromatic heterocycle products are all discussed. 

Table 27 Coupling of aryl halides with N(H) heterocyclic amines catalyzed by Cu/Al-HTB...

This chapter covers more specifically the copper-catalyzed C(aryl)-N bond formation via the coupling of aryl halides with nitrogen nucleophiles such as N-heterocycles, amines, anilines, amides, ammonia, azides, hydroxylamines, nitrite salts or phosphonic amides. The C(aryl)-N bond formation as a result of the coupling between these nucleophiles and arylboronic acids (the Chan-Lam reaction) will be also presented. It is worth noting that this chapter mainly focuses on the most significant results and important breakthroughs in this field. 

Harrwig and Bnchwidd have developed a new methodology for aryladon of amines or phenols with aryl halides and palladium catiilysts This reacdon provides a very useful strategy for the preparadon of various heterocyclic compounds such as phenazines, as shown in Scheme... 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

Recently, Taillefer et al. reported an Fe/Cu cooperative catalysis in the assembly of N-aryl heterocycles by C—N bond formation [90]. Similarly, Wakharkar and coworkers described the N-arylation of various amines with aryl halides in the presence of Cu—Fe hydrotalcite [91]. Interestingly, Correa and Bolm developed a novel and promising ligand-assisted iron-catalyzed N-arylation of nitrogen nucleophiles without any Cu co-catalysts (Scheme 6.19) [92]. Differently substituted aryl iodides and bromides react with various amides and N-heterocycles. The new catalyst system consists of a mixture of inexpensive FeCl3 and N,N -dimethylethylenediamine (dmeda). Clearly, this research established a useful starting point for numerous future applications of iron-catalyzed arylation reactions. 

Aryl chlorides are more reluctant to participate in amination than most other aryl halides/pseudohalides. To tackle this problem, Caddick et al. examined the effect of palladium-N-heterocyclic carbenes as catalysts in rapid microwave-promoted reactions [87]. Para-tolyl and -anisyl chloride were reacted with aromatic and aliphatic amines in mostly good yields within 6 minutes of heating at 160 °C. Reactions using anisyl, tolyl or phenyl chlorides and aliphatic amines have also been reported by Maes et al. using a phosphine ligand and a strong base, which creates the desired products after 10 minutes of heating at 110-200 °C [88]. 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

Aminations of five-membered heterocyclic halides, such as furans and thiophenes, are limited. These substrates are particularly electron-rich. As a result, oxidative addition of the heteroaryl halide and reductive elimination of the amine are slower than for simple aryl halides (see Sections 4.7.1 and 4.7.3). In addition, the amine products can be air-sensitive and require special conditions for their isolation. Nevertheless, Watanabe has reported examples of successful couplings between diarylamines and bromothiophenes [126]. Triaryl-amines are important for materials applications because of their redox properties, and these particular triarylamines should be especially susceptible to electrochemical oxidation. Chart 1 shows the products formed from the amination of bromothiophenes and the associated yields. As can be seen, 3-bromothiophene reacted in higher yields than 2-bromothiophene, but the yields were more variable with substituted bromothiophenes. In some cases, acceptable yields for double additions to dibromothiophenes were achieved. These reactions all employed a third-generation catalyst (vide infra), containing a combination of Pd(OAc)2 and P(tBu)3. The yields for reactions of these substrates were much higher in the presence of this catalyst than they were in the presence of arylphosphine ligands. 

The use of a strong base in the palladium-catalyzed amination of aryl halides precludes the use of many substrates, such as those with aromatic nitro groups or enolizable hydrogens, esters other than tert-butyl esters, and many substrates with base-sensitive stereochemistry such as some protected amino acids and heterocyclic substrates [191]. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those used for reactions conducted with sodium tert-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts. 

Extensive mechanistic studies have been conducted on the oxidative addition of aryl halides to Pd(0) complexes ligated by PPh3 in different media and with different additives175, 176. However, palladium complexes containing these ligands are not active catalysts for amination. Instead, one must consider the addition of aryl halides to palladium complexes bound by ligands relevant to amination. Studies of the mechanism of oxidative addition to palladium(O) complexes of P(tol-o)3, DPPF, BINAP, Q-phos, P(Bu-f)3 and an /V-heterocyclic carbene ligand have been reported. 

Aryl halides which are rather inert in usual organic reactions can undergo reactions by means of palladium catalysts. Thus, styrene and stilbene derivatives are obtained by reaction of olefins with aryl bromides at 125 °C using Pd(0Ac)2 (1 mol%) and tri-(o-tolyl)phosphine (2 mol%)83. The palladium-catalyzed vinylic substitution reaction is applicable to a variety of heterocyclic bromides including pyridine, thiophene, indole, furan, quinoline and isoquinoline84. Thus, reaction of 3-bromopyri-dine with l-(3-butenyl)phthalimide at 100 °C gives l-[4-(3 -pyridyl)-3-butenyl]-phthalimide (yield of mixed amine 57%, selectivity 68%) at 100 °C. This phthalimide is subsequently converted to nornicotine (188) (Scheme 59). The reaction of acrylic... 

Syntheses of derivatives of indole, carbazole, and other TV-heterocycles using Pd-catalyzed C-N coupling of amines with aryl halides 04MI44. 

In a second report, the Bergman and Ellman groups improved on their original procedure for the arylation of heterocycles with aryl halides [103]. The key improvements over the previous method were three-fold (1) the use of the hindered tertiary amine base Pr.NBu in replacement of Et3N (2) microwave irradiation for rapid (<1 h), high temperature (250 °C) reactions in 1,2-dichlorobenzene (3) the use of bulky bicyclic trialkylphosphine ligands of the phobane family in replacement of PCy3 (Scheme 15). Under typical reaction conditions, the heterocycle... 

The palladium-catalyzed amination of heteroaromatic halides, or the arylation of heteroaromatic containing amines, is complicated by the Lewis basicity of the heteroatom. The heterocycle may thus act as a ligand for palladium and cause catalyst inhibition and/or poisoning. R. Dommisse demonstrated that by using excess K2CO3 with the Pd/BINAP or L5 catalyst system, a series of pyridyl chlorides could be efficiently aminated by either anilines or aminopyridines.63... 

Arylation with various heterocyclic compounds can be carried out when their reactive halides are available at proper positions. For example, the antihistamine norastemizole derivative 85 was synthesized by the reaction of the chlorobenzim-idazole 83 with the diamine 84. Selective arylation of the primary amine in the diamine 84 proceeded with high selectivity [58]. BINAP is a good ligand for the amination of 3-bromopyridine (86) [59]. Similarly benzylamine was introduced to the bromopyridine moiety of the 3-carboxy- -carbolines 87 to give 88 [60]. Another example is the C-8 aminated adenosine derivative 90 was obtained in a high yield by the amination of 89 [61]. 

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