C—N bond-forming reactions

The scope of the aromatic C—N bond-forming reaction extends beyond amines. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, amides, carbamates, and sulfonamides... 

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of W-aryl enaminones 97, this reaction could be applied in a tandem... 

Catalytic Asymmetric C-N Bond Forming Reactions in Total Synthesis... 

Also C—N bond forming reactions may be very fast and relatively easy to implement. 

Intramolecular Heck reaction of organomercurial 332 has been used to prepare unsaturated lactone 333 by a non-traditional strategy452. Sequential, regiospecific C—C and C—N bond-forming reactions via a novel Heck-type coupling have been developed453. 

Anions of secondary-sulfonamides, especially N-substituted tosylamidate ions, have emerged as premier partners for C-N bond forming reactions with alkynyliodonium salts. To a much lesser extent secondary-carboxamidate ions have also been used for this purpose. For example, the sequential treatment of -substituted tosylamides with n-butyllithium and phenyl(trimethylsi-lylethynyl)iodonium triflate (26) affords the corresponding N-trimethylsi-lylethynyl-p-toluenesulfonamides, which can be desilylated with tetrabutylam-monium fluoride in wet THF (Scheme 51) [ 151 ]. It is noteworthy that the presence of such groups as n-Bu and CH2 = CH(CH2)2- in the tosylamidate ions did... 

A palladium-catalyzed C-N bond-forming reaction of the azetidin-2-ones 375 formed the carbapenem derivative 376 (Equation 149) <2002TL111>. 

Electrophilic amination is a general entry to chiral a-amino acids or functionalized P-amino and P-hydroxy a-amino acids with an anti stereochemistry. The chiral enolate technology has been applied for the obtaining of C-N bond-forming reactions with stereochemical control. 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

The first intermolecular C-N bond-forming reactions between substituted 2-bromopyrroles 1450 and 1453 with primary (Tpropanamine, 2-methoxy-l-ethanamine, (4-methoxyphenyl)methanamine, cyclopropanamine, cyclobuta-namine), and cyclic secondary amines (pyrrolidine, morpholine, 1-methylpiperazine, ethyl tetrahydro-l(27/)-pyrazi-necarboxylate, 1-phenylpiperazine, l-(3-phenyl-2-propenyl)piperazine) 1451 were performed using Pd2(dba)3 as catalyst with BINAP as the ligand. The aminations proceeded in the presence of Bu ONa at 80-100 °C in 31-93% yields (Equations 301 and 302) <2004TL769>. However, when the above optimized conditions were applied to the coupling reaction of pyrrole 1450 and acyclic secondary amines such as di- -butylamine, diphenylamine and dipropenylamine, no reaction was observed. 

Although the arylation reaction could be effected with (o-tolljP as ligand, Buchwald and co-workers investigated the use of BINAP (1) and other diphosphine ligands in the C-N bond forming reaction. ( )-BINAP often provided better yields of the desired product with both cyclic and acyclic amines, and lower... 

Nishiyama, Yamamoto, and Koie also reported that the (f-Bu)3P/Pd-based catalyst is effective in the C-N bond forming reaction between an aryl iodide as well as an aryl bromide and piperazine [36]. 

The use of aryl chlorides in the palladium catalyzed C-N bond forming reaction is highly desirable since aryl chlorides are often less expensive the analogous bromides and because there are a greater number of aryl chlorides which are commercially available. However, the use of aryl chlorides as reactants in numerous palladium-catalyzed processes has until recently been an elusive goal. 

Dicyclohexyl-o-biphenylphosphine (14) is an excellent supporting ligand for the Pd-catalyzed C-N bond forming reaction, particularly when the coupling involves a functionalized aryl chloride, Eq. (44) [42 a, 44,74]. 

Later that year, the Ahman and Buchwald reported an improved procedure for the reaction of triflates and cyclic secondary amines [82]. The use of CS2CO3 as base allowed numerous electron-deficient aryl triflates to be coupled in high yield. The reaction between the 4-cyano-substituted aryl triflate and morpholine in the presence of ( )-BINAP/Pd provided the desired arylamine in 28% yield, Eq. (57). However, when the triflate was added over the course of 30 minutes, the desired product was isolated in 60% yield. The use of CS2CO3 as base improved the yield of arylamine to 84 %. The use of a mild base also allowed for the use of functionalized aryl triflates in the C-N bond forming reaction. 

The BINAP/Pd- and DPPF/Pd-catalyst systems have been used by numerous groups to react aryl bromides with arylamines. Ward and Farina as well as Willoughby and Chapman performed the arylation reaction with arylamines and resin-bound aryl bromides [31,32]. Snieckus reported the use of the Pd-cat-alyzed C-N bond forming reaction to prepare several acridone derivatives, Eq. (81) [92]. Kamikawa et al. prepared phenazine derivatives via an initial C-N bond coupling and subsequent cyclization, Eq. (82) [93]. 

Kagechika et al. reported the preparation of a retinoic nuclear receptor ligand utilizing the BINAP/Pd-catalyzed C-N bond forming reaction [103]. The aniline derivative below was coupled with 4-iodoethylbenzoate in 48% yield, Eq.(lOl). 

The catalyst formed from 6 and palladium acetate mediates the reaction between a large number primary amines and aryl chlorides as room temperature, Eq. (105) [42a, 48]. This catalyst enjoys an even wider substrate scope, however, when the transformation is performed at elevated temperatures. Additionally, elevated temperatures allow for the use of mild bases in the C-N bond forming reaction. 

Several aryl bromides were coupled with the vinylogous amide below in moderate to excellent yields by Edmonson et al., Eq. (154) [126]. The Merck investigators also reported that this C-N bond forming reaction could be exploited to prepare quinoline and indole derivatives. 

Luker et al. subsequently investigated the use of electron-deficient thiophenes in the C-N bond forming reaction [132]. Using a BINAP/Pd-catalyst, the Nottingham group reported that the desired transformations proceed in good to excellent yield with several primary and secondary amines, Eq. (165). 

The intramolecular C-N bond forming reactions proved to be more straightforward than their intermolecular counterparts [138]. The desired couplings often could be achieved using (Ph3P)4Pd as catalyst to form 5-, 6-, and 7-mem-bered nitrogen heterocycles, Eq. (171). 

Kamikawa used two different Pd-catalyzed C-N bond-forming reactions for the convergent preparation of several phenazines [93]. After intermolecular coupling was achieved, the nitro group was reduced. Subsequent Pd-catalyzed cyclization afforded the desired product in 80% yield over three steps, Eq. (175). 

Appukkuttan P, Van der Eycken E (2008) Recent developments in microwave-assisted, transition-metal-catalysed C-C and C-N bond-forming reactions. Eur J Org Chem 7 1133-1155 and references therein... 

C-N bond-forming reaction is promoted by Zr(Ot-Bu)4 in the presence of trimethylsilyl triffuoroacetate and a chiral amine triol (equation 73). This tightly bound multidentate... 

Although the reaction of a carbon nucleophile with an azodicarboxylate ester to a derivative of a hydrazine acid was first reported in 192414a, it wasn t until 1986 that this reaction was used in stereoselective C —N bond-forming reactions and, as often happens in science, simultaneously by several groups15-18. 

Since the catalytic C—N bond-forming reactions discussed in Section 7.4.1. do not take place under the specified conditions in the absence of palladium, these processes are in principle amenable to enantioselective catalysis using enantiomerically pure phosphine ligands (A-J) on the metal58-68 75 76. 

Resin-bound bismuthanes (81a-c) have also been prepared and used as a multidirectional linker for these C—N bond-forming reactions (Figure 20)337. The yields were approximately 30% lower than those reported for similar reactions in solution phase. 

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