Protocols Hartwig

A synergistic combination of Pd-catalyzed amination and arylation was the central operation of Sakamoto s synthesis of carbolines [147]. Diarylamine 187 was first installed via the Buchwald-Hartwig amination protocol. Subsequent intramolecular Heck-like arylation of 187 provided a novel route to a-carboline 188. 

Ertel, K., Neuman, P., Hartwig, P., Rains, G., and Keswick, B., Leg wash protocol to assess the skin moisturization potential of personal cleansing products. J. Cosmet. Sci. 21 383-397, 1999. 

Hartwig first reported the arylation of diarylamines using both (o-to jP/Pd-and DPPF/Pd-catalysts, Eq. (33) [29,64]. The Yale group utilized the (o-tol jP/Pd-and DPPF/Pd-based protocols for the preparation of triarylamine-containing dendrimers and cyclophanes, respectively. 

Nishiyama, and co-workers first reported that the catalyst derived from Pd(OAc)2 and (f-Bu)3P effects the C-N bond formation to produce triarylamines in excellent yield [65]. This system also is useful in the coupling of diarylamines and aryl chlorides. Hartwig and co-workers found this protocol optimal for the preparation of triarylamines. The (f-Bu)3P/Pd-catalyst was sufficiently active such that the coupfing of diarylamines and aryl bromides can be performed at room temperature,Eq. (34) [50]. The (f-Bu)3P/Pd-system has been used to produce new triarylamine-based polymers [ 64 a - d]. 

Nolan s heterocyclic carbene-based system (7 + KOf-Bu/Pd2(dba)3) was effective in the coupling of secondary amines with aryl chlorides at elevated temperatures, Eq. (47) [52]. This protocol could be used for the room-temperature ami-nation of aryl bromides as well. Hartwig reported that the saturated heterocyclic carbene ligand prepared by deprotonation of 16 forms a catalyst that is considerably more reactive than the system reported by Nolan. The resulting complex formed was capable of coupling aryl chlorides with cyclic amines at room temperature [76]. 

Louie and Hartwig described an application of the DPPF/Pd-catalyst toward the synthesis of oligo(m-anilines). The diarylamine monomer was prepared using this protocol in quantitative yield, Eq. (86) [64b]. Goodson and Hartwig have extended the method to synthesize other monomers for the preparation of poly(N-arylanilines) [54 c]. 

Concurrently with the report by Buchwald, Hartwig described a similar reaction using the DPPF/Pd-based protocol [122]. The C-N bond coupling proceeded in good to excellent yield with 1 mol% Pd, Eq. (148). 

Despite the success of the original Hartwig-Buchwald protocol, this procedure was not without its drawbacks. The scope was limited to aryl bromide substrates and secondary amine coupling partners, and the requirement of a strong rert-butoxide or amide base meant that substrates with base-sensitive fimctional groups would not be compatible. While this latter constraint has since been obviated by the discovery that weaker bases such as CS2CO3 can promote the reaction, the extension of the scope has required some sophisticated catalyst development (vide infra). 

In 2007, Fujii, Ohno and their coworkers developed an efficient one-pot Buch-wald-Hartwig /V-arylation and oxidative coupling reaction to synthesize carbazoles (Scheme 27) [95]. Typically, Pd-catalyzed N-arylation of anilines with aryl triflates was conducted in toluene under the standard conditions. After completion of the N-ary I at ion as determined by TLC, acetic acid was added and an oxygen balloon was connected to the reaction flask (oxygen conditions) or it was subjected to air by an open system (air conditions). The protocol afforded various types of functionalized carbazoles in good to excellent yields (46->99%). 

NaaCOs, affords high yields in the reaction of 4-chloroanisole (71) with -butyl acrylate (38) in DMA at 140 °C. This is likely to be the highest temperature that has appeared in literature for hgand-accelerated Mizoroki-Heck reactions of unreactive aryl chlorides. In the same protocol, several bulky secondary phosphines, namely bis(adamantyl)phosphine, bis(norbomyl)phosphine and f-BuaPH, were also operative yet inferior to f-BusP [133]. Unlike the Hartwig-Fu protocol, this method has found no application so far, which is why its scope cannot be reliably assessed. 

Figure 2.9 Compounds made using the Hartwig-Fu protocol.

Despite electron-rich bulky side-arms as in phosphine pincers 190,191 [245] or 192 [246] (Figure 2.24), these complexes behave strikingly different from their respective dialkyl or trialkylphosphine palladium complexes the latter complexes show t)q)e3 activtity (cf. Hartwig-Fu protocol see above). PCP-pincer complexes 190-192, however, are typical SRPCs exclusively suitable for type 1 reactions of aryl iodides and activated aryl bromides (Table 2.9, entries 1-6). Ligand-acceleration effects are not observed, which unequivocally underlines that the cleavage of these pincer complexes under the reacation conditions occurs to release nonphosphine palladium complexes with indeterminate coordination shell. 

Recently, the arylation of ammonia as the simplest amine was accompHshed by Hartwig [169] (Scheme 3.4). In the same pubhcation, the use of lithium amide for the synthesis of anilines under similar reaction conditions was described this constitutes a user-friendly protocol for small-scale settings, whereas the direct use of ammonia is attractive within an industrial environment Subsequently, Buch-wald also reported the arylation of ammonia using biphenyl-based ligands [170]. 

More recently, Hartwig reported on the use of a zinc variant of LHM DS, namely Zn(HMDS)2, as a mild ammonia equivalent in combination with LiCl or R,NX as additives and P(t-Bu)3 as ligand [173]. This protocol has the advantage of extended functional group tolerance, allowing the use of substrates with, for example, eno-Hzable groups. Hence, when (S)-naproxen methyl ester was deliberately added to the amination reactions no racemization occurred, yet addition of the stronger base LHMDS led to almost complete racemization. 

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