Arylation of anilines

The access to substituted diphenylamines has been significantly improved through the development of the Pd-catalyzed iV-arylation of anilines by Buch-wald and Hartwig. The cyclization of the substituted diphenylamines to give the corresponding phenazines may then be conducted according to standard methods [78]. 

Guram s phosphine 5 and Pd2(dba)3 efficiently mediate the arylation of aniline derivatives at elevated temperatures as well, Eq. (90) [47]. 

Hartwig reported that ferrocene-based diphosphine 13 catalyzes the arylation of aniline at room temperature, Eq. (91) [72]. Additionally, the (f-BuljP/Pd-based system effects the room-temperatuxe condensation of anilines and aryl bromides. However, the (f-BuljP/Pd-catalyst is considerably more active [50]. While the reaction with 4-bromotoluene and anihne proceeded in 20 h using 5 mol% 15/Pd(dba)2, the reaction between bromoben-zene and aniline was complete in 1 h using only 1 mol% of the (f-BuljP-derived catalyst. 

The arylation of aniline derivatives can be executed such that triarylamine products can be obtained from a one-pot procedure. Marder and co-workers coupled aniline with the first equivalent of aryl bromide using the DPPF/ Pd-based catalyst at 90 °C, Eq. (94) [100]. After the reaction was judged complete by TEC, the second aryl bromide was added to the reaction, along with an addition amount of base and catalyst. The resulting mixture was heated to 90 °C. After chromatography, the unsymmetrical triarylamine was obtained in 72 % yield. 

Hartwig reported the arylation of anilines with aryl iodides using a DPPF/ Pd-catalyst,Eq. (98) [29]. This system provided the desired diarylamines in good to excellent yield. 

The catalyst derived from 13 and Pd(dba)2 is effective in the arylation of primary amines with aryl iodides as well [72]. The 13/Pd-system is sufficiently reactive to accomplish this transformation at room temperature, Eq. (99). While aliphatic amines are coupled in moderate yield, the arylation of aniline derivatives proceeds quite efficiently. 

Hartwig reported the first arylation of aniline using an aryl tosylate. The reaction was catalyzed by a 13/Pd-catalyst, Eq. (126). Using a bulky base and elevated temperatures, the desired product was obtained in 78% yield [72]. 

The above proposal is supported by the lack of reaction of electron-deficient arylamines, such as p-N02-aniline and p-Et02C-aniline, in the copper-mediated reactions with lead acetates because of the inability of the amines to reduce Cu(II) to Cu(I). This lack of reduction is indicated by the lack of a color change upon addition of Cu(OAc)2 to a solution of either of the amines. Further, the presence of Cu(III) species may be responsible for the formation of arenes and polymeric species during the A-arylation of anilines that are easily oxidized (Scheme 11). 

SCHEME 11. Potential mechanism for the formation of arenes and polymeric species during copper-catalyzed JV-arylation of anilines... 

Sadighi, J. P Harris, M. C. Buchwald, S. L., A Highly Active Palladium Catalyst System for the Arylation of Anilines. Tetrahedron Lett. 1998, 39, 5327. 

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%). 

Buchwald has also shown that the easily synthesized DPEphos ligand is an ideal catalyst for the arylation of anilines with aryl bromides.24 Even di-ortho substituted aniline and aryl bromide can be efficiently coupled. Furthermore, Buchwald has reported that readily available, and cheaper, PdCl2 may serve as the Pd source rather than Pd(OAc)2. 

A useful advance in ligand design was made by van Leeuwen who reports that Xantphos serves as an excellent ligand for the arylation of anilines.27 Sterically encumbered aryl bromide 3 cross-couple quite easily with 4 giving aniline 5 using Xantphos as a ligand. 

Additional examples include the electrophilic arylations of sodium arenesulflnates [866], potassium car-bonotrithioates [867] and benzazoles [868] using diaryliodonium salts in ionic liquids and the arylations of anilines [869], sodium tetraphenylborate [870] and vinyUndiums [871]. Particularly important are the reactions of diaryliodonium salts with fluoride anion as nucleophile. This reaction is widely applied for introduction of the radioactive F isotope into different organic substrates to obtain labeled agents for positron emission tomography. This topic is covered separately in Chapter 7 due to its importance and wide usage. 

A heterogeneous source of copper, the well-characterized, strongly basic, copper-exchanged fluorapatite (CuFAP), is formed as the (mainly) Cu(II) species from Caio(P04)6(F)2 upon treatment with Cu(OAc)2. CuFAP mediates displacement of all aryl halides (F, Cl, Br, I) in DMF (X = F, Cl) or DMSO (X = Br, I), as shown below (Eqn. 1-6). Less basic CHAP [from Caio(P04 (OH)2 + Cu(OAc)2], Cu(OAc)2, CuI alone, or Cu powder are inactive. Interestingly, in 3-chloro-4-fluoronitrobenzene, the C-F bond reacts selectively with imidazole in high yield (85%, isolated). Polymer-supported copper (1) and copper (II) on polystyrene have both been shown usefUl for arylations of anilines and heteroaromatics with boronic acids. 

Aniline and N-methylaniUne derivatives are the most reliable substrates for the Hartwig-Buchwald coupling, and they experience a high level of functional group tolerance. Similar to the coupling of primary amines, the double arylation of aniline can be a competing side reaction. A slight excess of the amine relative to the aryl component usually diminishes this side reaction. 

Scheme 13.60 Arylation of aniline derivatives employing DPPF (9) as supporting ligand [39].

Despite the great success of the BINAP (1) ligand in the arylation of anilines, the amination of aryl chlorides required high reaction temperatures and high catalyst loadings. In contrast, the Q-Phos ligand (24) in combination with [Pd(dba)2] was capable of promoting the amination of aryl bromides and chlorides at room temperature or at 100°C, respectively (Scheme 13.64) [95]. 

Scheme 13.64 Q-Phos-supported arylation of aniline derivatives [95].

Scheme 13.65 Arylation of aniline with aryl chlorides [85].

Scheme 13.66 Arylation of anilines by aryl chlorides at room temperature [44].

Scheme 13.67 Arylation of anilines with aryl tosylates [94].

Generally, the arylation of diarylamines is considerably slower than the arylation of anilines hence, selective monoarylation of anilines can easily be achieved. This is due to the lower nucleophilicity of the diarylamines. Mostly the same catalyst systems can be applied for the coupling of diarylamines with aryl halides. Therefore, only selected examples will be discussed in the following section. 

Although Beringer s arylations of aniline and piperidine resulted in poor yields, reactions with sulfonamides dehvered the N-arylated products in 50% yield under basic conditions [87]. McEwen found that arylation of sodium azide was facile at 80 °C in dioxane/water, delivering arylazides in excellent yields [88]. The chemoselective arylation of azides has been demonstrated with an luisymmetric polyfluorinated salt [90], and a computational study supports the ligand coupling pathway [32, 33]. 

Gaunt and coworkers discovered that anilides were selectively wcta-arylated in the presence of Cu(OTf)2 in DCE at 70 °C (Scheme 16b) [80]. In a similar fashion, the group achieved the para-arylation of anilines and phenol ethers, and the meta-arylation of a-arylacetamides and a-arylketones [217, 218]. Unsymmetric salts with mesityl or TRIP dummy substituents could be chemoselectively employed, and the reactions also proceeded in the absence of copper at slightly higher temperature, which makes mechanistic interpretations difficult [43]. 

Arylation of Anilines. It was demonstrated that la, as well as other diphenyliodonium salts with other non-nucleophiUc counterions, can efficiently arylate aniline to AliV-diphenylamine (2) (eq 1). Salts Ig-i bearing halide counterions were found to be completely ineffective. A similar copper-catalyzed Buchwald-Hartwig-type phenylation of both alkyl and aryl amines using [Ph2l]BF4 (If) and its analogs has been reported. ... 

After achieving excellent results with imidazoles, we further applied this catalytic system for the A-arylation of aromatic amines and aliphatic amines. The results are shown in Table 32 and Table 33. Table 32 shows the results of A-arylation of aniline with several arylboronic acids. 

Table 32 W-Arylation of aniline with various arylboronic acids...

---