Hydrophosphonylation

More than two decades after Wynberg s pioneering work, in 2006, Pettersen and Fini found that aromatic N-Boc-imines such as 168 also react with diethylphosphonate in the presence of catalytic quantities of quinine (10mol%) to produce the a-aminophosphonates 169 in moderate to good yields and with up to 

This chapter presented the current state of the art on the applications of cinchona alkaloids and their derivatives as chiral catalysts in the asymmetric nucleophilic addition of prochiral C=0 and C=N bonds. As shown in many of the examples discussed above, the vast synthetic potential of cinchona alkaloids and their derivatives in these reactions has been well demonstrated over the past few years. Cinchona-based organocatalysts possess diverse chiral skeletons and are easily tunable for diverse catalytic reactions through different mechanisms. Therefore, there is no doubt that the further development of cinchona-based organocatalysts for this major reaction type will continue to provide exciting results in the near future. 

This work was supported by grants KRF-2008-005-J00701 (M EST) and Rll-2005-008-00000-0 (SRC program of MEST/KOSEF). 

5 Horikawa, M., Busch-Petersen, J., and Corey, E.J. (1999) Tetrahedron Lett., 40, 3843-3846. 

Bandini, M., Sinisi, R., and Umani-Ronchi, A. (2008) Chem. Commun., 4360-4362. 

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The 4-thiazolidinyl phosphonates 143 (Scheme 44) are known for their therapeutical properties, in particular as anti-inflammatory agents [5,89]. Their asymmetric synthesis by hydrophosphonylation of 3-thiazolines has been described using various chiral auxiliaries chiral phosphites such as (2S,4i )-2H-2-oxo-5,5-dimethyl-4-phenyl-l,3,2-dioxaphosphorinane (de = 2-8%) [90] or BINOL-phos-phite (de = 65-90%) [91] and also chiral catalyst such as titanium or lanthanide chiral complexes (ee = 29-98%) [92]. Hydrophosphonylation of C2-chiral3-thi-azolines has also been performed (de = 32-38%) [93]. 

Because organophosphorus compounds are important in the chemical industry and in biology, many methods have been developed for their synthesis [1]. This chapter reviews the formation of phosphorus-carbon (P-C) bonds by the metal-catalyzed addition of phosphorus-hydrogen (P-H) bonds to unsaturated substrates, such as alkenes, alkynes, aldehydes, and imines. Section 5.2 covers reactions of P(lll) substrates (hydrophosphination), and Section 5.3 describes P(V) chemistry (hydrophosphorylation, hydrophosphinylation, hydrophosphonylation). Scheme 5-1 shows some examples of these catalytic reactions. 

Scheme 5-18 Stoichiometric reactions relevant to the proposed mechanism for palladium-catalyzed hydrophosphonylation of alkynes...

Scheme 5-25 Titanium-promoted hydrophosphonylation of an a-amino aldehyde...

Scheme 5-26 Titanium alkoxide-catalyzed asymmetric hydrophosphonylation of arylaldehydes...

Scheme 5-28 Asymmetric hydrophosphonylation of arylaldehy-des catalyzed by a heterobimetallic La/Li/BINOL catalyst (LLB)...

Scheme 5-29 LLB-catalyzed asymmetric hydrophosphonylation of cinnamaldehyde LLB = La/Li/BINOL...

An improved preparation of Shibasaki s LLB catalyst allowed higher asymmetric induction in the chemistry shown in Scheme 5-28. The new recipe involved mixing LaCl3 7H20 (1 equiv.), BINOL-dilithium salt (2.7 equiv.) and NaOt-Bu (0.3 equiv.) in THF at 50°C. This catalyst allowed asymmetric hydrophosphonylation of aldehydes in high yields and up to 95% ee (Scheme 5-33, Eq. 1), and gave better results for aliphatic aldehydes than a related aluminum catalyst (ALB, see Scheme 5-37 below). 

Heteroaromatic aldehydes undergo similar enantioselective hydrophosphonylation reactions (Scheme 5-34). 

Scheme 5-36 La/Li/(diphenylBINOL)-catalyzed asymmetric hydrophosphonylation of aldehydes...

Scheme 5-42 Zinc-catalyzed asymmetric hydrophosphonylation of benzaldehyde...

Shibasaki reported the first catalytic asymmetric hydrophosphonylation of imines in 1995 (Scheme 5-45) using heterobimetallic LLB-type catalysts. 

Scheme 5-46 Proposed mechanism for LPB-catalyzed asymmetric hydrophosphonylation ofimines...

Scheme 5-47 Asymmetric hydrophosphonylation of a cyclic imine catalyzed by heterobimetallic rare earth/alkali metal/BI-NOL complexes or by chiral titanium alkoxide complexes...

In comparison to related P(III) chemistry, metal-catalyzed additions of P-H bonds in P(V) compounds to unsaturated substrates have been studied in more detail, and several synthetically useful processes have been developed. In particular, the use of heterobimetallic BINOL-based catalysts allows asymmetric hydrophosphonylation of aldehydes and imines in high yield and enantiomeric excess. 

Groeger, H., Saida, Y., Arai, S., Martens, J., Sasai, H., and Shibasaki, M., First catalytic asymmetric hydrophosphonylation of cyclic imines highly efficient enantioselective approach to a 4-thiazolidinylphosphonate via chiral titanium and lanthanoid catalysts,Tetrahedron Lett., 37, 9291, 1996. 

LLB, a so-called heterobimetallic catalyst, is believed to activate both nucleophiles and electrophiles.162 For the hydrophosphonylation of comparatively unreactive aldehydes, the activated phosphite can react with only the molecules precoordinated to lanthanum (route A). The less favored route (B) is a competing reaction between Li-activated phosphite and unactivated aldehyde, and this unfavored reaction can be minimized if aldehydes are introduced slowly to the reaction mixture, thus maximizing the ratio of activated to inactivated aldehyde present in solution. Route A regenerates the catalyst and completes the catalysis cycle (Fig. 2-9). 

Moreover, ALB was found to be also useful for the hydrophosphonylation of aldehydes. ALB and LLB can thus be used in a complementary manner for the hydrophosphonylation of aldehydes. 

Meanwhile, chiral (thio)urea catalysts have been employed for a variety of imine addition reactions consisting of Mannich, aza-Henry, Pictet-Spengler, and hydrophosphonylation reactions. ... 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

Jacobsen et al. found that cyclohexane-diamine bifunctional catalyst 216 promoted the enantioselective hydrophosphonylation of A-benzyl imines [110]. Using a modified... 

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