Molybdenum-catalyzed allylic alkylations

Scheme 7.15 Solid-phase molybdenum-catalyzed allylic alkylation.

It was found by Trost that the low reactivity could be circumvented by the employment of labile ligands, such as the propionitrile in the Mo(CO)3(EtCN)3 precatalyst [57]. Instead of directly transferring this procedure to microwave heating applications, a useful and easily handled microwave procedure was developed for rapid and selective molybdenum-catalyzed allylic alkylations under noninert conditions (Eq. 11.39) [12]. The former, more sensitive, two-step reaction was fine-tuned into a robust one-step procedure employing the inexpensive and stable precatalyst Mo(CO)6, used in low concentrations. The alkylations were conducted in air and resulted in complete conversions, high yields, and an impressive enantiomeric excess (98%) in only 5-6 min. Despite the daunting temperatures, up to 250°C with THF... 

Equation 11.40 Asymmetric molybdenum-catalyzed allylic alkylation with an optimized ligand. 

Molybdenum-catalyzed allylic alkylation has been used as a complementary synthetic procedure to the palladium-catalyzed process/ because allylic alkylation of unsymmetrical substrates takes place mostly at the more substituted carbon atom, in contrast to the palladium case. 

Hallberg and his co-workers reported in 1999 the first microwave-promoted asymmetric palladium-catalyzed allylic alkylation of acyclic and cyclic allylic esters with dimethyl malonate, using some chiral ligands 57 and 118 (Equations (65) and (55))3 s,l6Sa,i6Sb both cases, microwave irradiation reduces reaction time without any loss of enantio-selectivity. The same group successfully applied this reaction system to the molybdenum-catalyzed allylic alkylation (Equation ((,7)) 60.160 -l60. 

Larhed [34] described the molybdenum-catalyzed allylic alkylation of ( )-3-phenyl-2-propenyl acetate. The reaction occurs with good reproducibility complete conversion, high yields, and excellent enantiomer excess (ee) in only a few minutes (Scheme 5.3). In the standard solvent (THF), and with an irradiation power of 250 W, a yield of 87% was obtained and high regioselectivity and ee (98%) were achieved. Regioselectivity was somewhat lower (17-19 1) than in the previously re-... 

Scheme 12.4 Solid-phase molybdenum(0)-catalyzed allylic alkylation.

As described in many reviews, Trost and his co-workers have carried out a pioneering work on the molybdenum-and tungsten-catalyzed allylic alkylation of allylic esters regioselectivity of the reaction is often complementary to the palladium-catalyzed allylic alkylation. The first asymmetric version was disclosed by Pfaltz and Lloyd-Jones in 1995 (Equation (63)). They used a catalytic amount of a novel tungsten complex, prepared from [W(CO)3(MeCN)3] or [W(cycloheptatriene) (COIs] and optically active (diphenylphosphino)phenyloxazolines 57, for the allylic alkylation of 3-aryl-2-propenyl phosphate with dimethyl sodiomalonate to isolate the corresponding branched alkylated compounds as a major isomer with an excellent enantioselectivity (96% ee). Unexpectedly, 3-aryl-2-propenyl carbonates are shown to be unreactive. It is worth noting that an isostructural molybdenum complex does not promote the catalytic alkylation under the same reaction conditions. In contrast, Lloyd-Jones and Lehmann reported the stereocontrolled... 

The simple metal hexacarbonyls of molybdenum and tungsten will catalyze allylic alkylation, with dramatic effects on the regioselectivity. The comparison of Mo(CO)6 with Pd° shows a remarkable contrast in regioselectivity (equation 67). The basis for the selectivities is somewhat mysterious, especially considering another dramatic reversal of selectivity with change in anion, from malonate, using Mo(CO)6 and the same conditions. This regioselectivity of Mo carbonyl catalysts has been used to synthesize (7 )-baclofen, as shown in equation (68). 

Several other metal catalysts have been shown to mediate the Tsuji-Trost reaction, with molybdenum being the most developed. Trost first reported the use of molybdenum for allylic alkylation in 1982. The most important aspect of the use of this metal is its regiocomplimentary with the palladium-catalyzed process. While palladium preferentially gives linear adducts (in the absence of electronic bias), molybdenum gives preferentially branched adducts. ... 

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

Trost and Hachiya [140] studied asymmetric molybdenum-catalyzed alkylations. Interestingly, they noticed that the regioselectivity of this transformation performed with a non-symmetric allylic substrate varied according to the nature of the metal Pd-catalyzed substitutions on aryl-substituted allyl systems led to attack at the less substituted carbon, whereas molybdenum catalysis afforded the more substituted product. They prepared the bis(pyridylamide) ligand 105 (Scheme 55) and synthesized the corresponding Mo-complex from (C2H5 - CN)3Mo(CO)3. With such a catalyst, the allylic... 

A similar pathway involving a microwave-driven molybdenum-catalyzed asymmetric allylic alkylation as the key step was elaborated by Moberg and coworkers for the preparation of the muscle relaxant (R)-baclofen (Scheme 6.52) [108]. The racemic form of baclofen is used as a muscle relaxant (antispasmodic) lipophilic derivative of y-aminobutyric acid (GABA). Pharmacological studies have shown that the (R)-enantiomer is the therapeutically useful agonist of the GABAb receptor. Asymmetric alkylation of the allylic carbonate precursor with dimethyl malonate afforded... 

Scheme 6.50 Palladium- and molybdenum-catalyzed asymmetric allylic alkylations.

Scheme 6.51 Molybdenum-catalyzed asymmetric allylic alkylation in the synthesis ofTipranavir.

A fast and efficient molybdenum-catalyzed asymmetric allylic alkylation under noninert conditions has been reported using MW-accelerated reaction [178]. Inter-molecular hydroacylation of 1-alkenes with aldehydes has been presented as a greener alternative to classical approach using a homogeneous catalyst in toluene. 

Kaiser, N.-F., Bremberg, U., Larhed, M., Moberg, C. and Hallberg, A. Fast, convenient, and efficient molybdenum-catalyzed asymmetric allylic alkylation under noninert conditions an example of microwave-promoted fast chemistry, Angew. Chem., 2000, 112, 3742-3744. 

In 1965, Tsuji et al. observed that palladium could catalyze the allylic alkylation reaction [18]. This discovery, which is a very attractive way to expand the scope of the allylic amination reactions mentioned above, has stimulated an intense research in this field, and even though complexes of nickel, platinum, rhodium, iron, ruthenium, molybdenum, cobalt, and tungsten have been found also to catalyze the alkylation, palladium complexes have received by far the greatest attention [19]. 

AUylic alkylations. This complex in combination with 2,2 -bipyridyl (bpy) catalyzes nucleophilic alkylation of allylic acetates and carbonates, but is less active than molybdenum or palladium catalysts. The displacement occurs with retention of configuration, as with Mo and Pd catalysts. However, alkylation occurs almost entirely at the more substituted end of the allylic group, regardless of the nucleophile. 

The molybdenum-catalyzed asymmetric allylic alkylation can also be carried out under non-inert conditions with microwave activation (eq 5). In comparison to the thermally promoted reaction, reaction times are shorter (5 min vs 4 h). Nevertheless, high yields (87%) and ee (98%) are obtained, the regioselectivity is lower in the microwave reactions (19 1). This can be improved (41 1) by introducing an electron-donating substituent (4-methoxypyridine derivative) into the title ligand. ... 

Molybdenum-catalyzed alkylation of aryl-substituted allylic carbonates has been directed to give the alkylation at the substituted site affording the branched isomer as the major product with a high enantioselectivity by employing a specially designed diamine type ligand (Eq. 16) [37]. 

Other examples of microwave-assisted catalysis include allylic alkylation, both palladium catalyzed and molybdenum catalyzed. In the latter case, air stable precursor complexes could be used under non-inert conditions. Microwave-enhanced Pauson-Khand reactions have also been reported, as have hydroamination of alkynes, and metathesis of functionalized alkynes. " Recently, microwave enhancement has been applied to C-H activation reactions, for example, for the formation of functionalized heterocycles, allowing the reaction to be performed with no solvent purification and minimal precautions to exclude air. A solvent-free chelation-assisted hydroacylation... 

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