HASPO

The use of aryl tosylates as electrophiles is attractive, since they can be synthesized from readily available phenols with less expensive reagents than those required for the preparation of the corresponding triflates. More importantly, tosylates are more stable towards hydrolysis than are triflates. However, this greater stability renders tosylates less reactive in transition metal-catalyzed coupling reactions. As a result, protocols for traditional cross-coupling reactions of these electrophiles were only recently developed [1], In contrast, catalytic direct arylations with aryl tosylates were not reported previously. However, a ruthenium complex derived from heteroatom substituted secondary phosphine oxide (HASPO) preligand 72 [81] allowed for direct arylations with both electron-deficient, as well... 

Efficient direct arylations of 2-aryloxazolines with aryl tosylates as electrophiles were further accomplished with HASPO preligand 72 (Scheme 9.27) [60]. 

Following Zhang and He s work, Ackermann and Barfuesser developed a protocol using a Pd-complex derived from air-stable heteroatom-substituted secondary phosphine oxides (HASPO) for the selective C3-arylation of a variety of functionalized NH-free indoles with bromoarenes (09SL808). Optimized conditions gave good-to-high yields and allowed the use of sterically hindered substrates (Scheme 32). 

Scheme 32 Pd-catalyzed direct C3-arylation of NH-free indoles with an air-stable HASPO.

Heteroatom-substituted secondary phosphine oxide (HASPO) preligands, such as H-phosphonates and their derivatives, display significantly different steric and electronic properties. These preligands (e.g. compound 12), as well as the corresponding phosphine chlorides, were found to be highly effective for Suzuki reactions of aryl chlorides (Equation 2.31) [53]. 

Ackermann HASPO Ligands Ackermann presented two new ligand families, named heteroatom-substituted secondary phosphine oxides (HASPO) and the corresponding phosphine chlorides. The development of the former ligand class is related to studies of Li (DuPont), who described the use of dialfeylphosphine oxides with electronically distinct properties as active and easily accessible ligands for palladium-catalyzed aminations (Figure 3.10) [107]. 

Air-stable sterically congested phosphine oxides such as 48 are also excellent Ug-ands for the nickel-catalyzed cross-coupling of aryl fluorides [43] (Scheme 5.8). The association of nickel salts with these so-caUed heteroatom-substituted secondary phosphine oxide (HASPO) ligands leads to species reactive enough to activate the generally inert arene-fluorine bond (BDE Ph-F = 126kcalmol ). This improved reactivity has been explained by the formation of a bimetallic species 52 (Scheme 5.8), which facilitates the oxidative insertion step that proceeds via transition state TSl (Figure 5.1) [44]. 

Scheme 5.8 Ni-catalyzed cross-coupling reaction of arylmagnesium reagents with aryl fluorides in the presence of HASPO ligands [43],...

Figure 5.1 Proposed transition state for the insertion of Ni(0) into the carbon-fluorine bond in the presence of HASPO ligands [44].

Well-defined homobimetallic catalysts such as 86 prepared from palladium(II) salts and air-stable HASPOs of type 48 can catalyze the coupling of aryl Grignard reagents and aryl, heteroaryl, or alkenyl tosylates [57] (Scheme 5.15). Likewise, palladium complexes of bulky, electron-rich ligands of the JosiPhos family such as 92 catalyze the coupHng of aromatic tosylates at room temperature with both aryl and alkenyl Grignard reagents [58] (Scheme 5.15). 

In later work, it was discovered that the use of heteroatom-substituted phosphine oxide (HASPO) combined with [RuCl2(p-cymene)]2 was even more competent than R2P(0)H. The direct o/t/jo-arylation was achieved with the less reactive aryl tosylates and aryl chlorides using substrates such as oxazolines, phenylpyridine and phenylpyrazole in the presence of K2CO3 in NMP at 120 °C. Interestingly, the selectivity of the product was tuned by changing the electrophile. Aryl chlorides produced the diatylated products while aryl tosylates generated monoaiylated products (Scheme 4). 

SPO = secondary phosphine oxide HASPO = heteroatom substituted phosphine oxide... 

Replacement of one C-substituent in phosphines by an alkoxy or aryloxy group produces esters of phosphinous acid (phosphinites). Further substitution of alkyl or aryl by oxy groups gives first the diesters of phosphonous acid (phosphonites) and finally triesters of phosphorous acid (phosphites). Secondary phosphine oxides (SPOs) or heteroatom-substituted phosphine oxides (HASPOs), which are derived from the corresponding free acids by tautomerism, have been only occasionally investigated as ligands. However, they play a pivotal role as hydrolysis products of esters. In this role, they may exert an impact on the catalytic reaction. 

As shown with phosphines (see Section 2.1.6), decomposition of phosphites can occur via an orthometallation process in the presence of Co, Rh, or Ru and subsequent hydrolysis to produce HASPOs (Scheme 2.117) [150]. 

The hydrolysis is autocatalytic because of the acidic properties of the diorganohydrogenphosphites (HASPOs), organodihydrogenphosphites, and H3PO3 formed (Scheme 2.120) [157]. This cascading effect was evidenced by the addition of diethyl hydrogen phosphite to a trimethylphosphite/water system or by addition of basic compounds, such as hydrotalcite, as an acid scavenger [158]. 

After hydrolysis of the P-O bond and formation of the pentavalent phosphorus species, the ligating properties are not completely lost. HASPOs form an equilibrium consisting of a pentavalent and a trivalent species (Scheme 2.121). The... 

Moreover, HASPOs may add to aldehydes in a temperature-dependent equilibrium [160]. a-Hydroxy phosphonates are acids and thus accelerate the decomposition of the original ligand with water by autocatalysis [153,162]. Probably, the well-known stabihzing effect of added epoxides can counterbalance this effect. It was shown that such a-hydroxy phosphonates can also serve as ligands in Rh-catalyzed hydroformylation [163]. 

HASPOs formed as products of the hydrolysis are in equilibrium with the corresponding trivalent species, the latter being acids. In turn, they may contribute to the hydrolysis of the starting amidite and an autocatalytic process is initiated, similar to that seen with phosphites (Scheme 2.133). 

Scheme 2.134 Serendipitous formation of HASPOs by the hydrolysis of phosphoramidites as the precondition for the formation of an active catalyst.

Ackermann previously showed that a ruthenium(II) catalyst, associated with the secondary phosphine oxide (HASPO), promoted the arylation of 2-aryloxazolines with aryl tosylates containing a large variety of functional groups, although they are not as reactive as the arylchlorides under the same conditions [(Eq. 29)] [45]. 

A more direct approach involves now the arylation with in situ generated tosylate from the reaction of phenol in the presence of p-tolylsulfonylchloride. The reaction is performed with [RuCl2(/ -cymene)]2 and 10 mol% of HASPO ligand [(Eq. 30)] [102]. The catalytic system tolerates other heterocycle directing groups such as pyridine and pyrazole. 

---