Part I: The Development of the Catalytic Wittig Reaction

Abstract

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96%) by using a precatalyst loading of 4-10 mol%. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74% yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions.

The Deoxygenation of Phosphine Oxides under Green Chemical Conditions

“…Based on the experimental details presented in Table 1 (6). Based on the experimental details presented in Table 3 (entry 1), yield: 91%; colorless oil; 31 Dimethyl-phenylphosphine (8). Based on the experimental details presented in Table 4 General Procedure for the Deoxygenation of 1-Phenyl-3-methyl-3-phospholene 1-Oxide (9), and for the Trapping of the Phosphine (10) so Obtained A mixture of 0.11 g (0.55 mmol) of 1-phenyl-3methyl-3-phospholene 1-oxide (9) and 0.068 mL (0.55 mmol) of PS or 0.19 mL (1.1 mmol) of TMDS or 0.042 mL (1.1 mmol) of PMHS was heated under nitrogen atmosphere at the appropriate temperature in a glass bomb immersed in an oil bath or in a commercial MW vial in the MW oven for the appropriate time.…”

“…It has been a challenge to develop catalytic versions of these reactions involving the recycling of the waste cyclic phosphine oxides in in situ reduction [6]. O wide range of phosphine oxides including mainly phospholene-and phospholane derivatives [7][8][9][10]. In these cases, the phosphoranes were formed in situ by the quaternization of the phosphine by the α-haloacetic ester [7][8][9] or even an unactivated alkyl halide [8], followed by dehydrohalogenation by Na 2 CO 3 [7,9], diisopropylethylamine [8], or in situ generated t BuONa [10].…”

A study on the deoxygenation of trialkyl‐, dialkyl‐phenyl‐ and alkyl‐diphenyl phosphine oxides by hydrosilanes

“…These problems can be eliminated by applying the phosphine in a catalytic amount, and by insuring the in situ reduction of the phosphine oxide formed. This was first elaborated for the Wittig reaction using silanes as the reducing agent by O'Brien . Since then, the catalytic Wittig reaction has become a hot topic and found a number of applications .…”

Catalytic Wittig and aza-Wittig reactions

“…Subsequently they reported that the soluble organic base N , N -diisopropylethylamine was a good replacement for sodium carbonate in such reactions [19], and that the addition of 4-nitrobenzoic acid facilitated the phosphine oxide reduction step using phenylsilane (PhSiH 3 ) instead of diphenylsilane [20]. Using this combination of 4-nitrobenzoic acid and phenylsilane for phosphine oxide reduction allowed reactions starting with phosphine oxide 24 (Fig.…”