BIPHEPHOS

Much progress has been made on regioselective hydroformylation of terminal alkenes in favor of the linear product. In particular bidentate phosphine or phosphite ligands, which have a natural bite angle 9 of about 110°, will favor the linear product. The most successful ligand types are BISBI [49, 50], BIPHEPHOS [51,52], and XANTPHOS systems (Scheme 8) [53]. 

As demonstrated by Hoffmann and coworkers, hydroformylation can also be combined with an allylboration and a second hydroformylation, which allows the formation of carbocycles and also heterocycles [213]. A good regioselectivity in favor of the linear aldehyde was obtained by use of the biphephos ligand [214]. Reaction of the allylboronate 6/2-76 having an B-configuration with CO/H2 in the presence of catalytic amounts of Rh(CO)2(acac) and biphephos led to the lactol 6/2-80 via 6/2-77-79 (Scheme 6/2.17). In a separate operation, 6/2-80 was oxidized to give the lactone 6/2-81 using tetrabutyl ammonium perruthenate/N-methylmorpholine N-oxide. 

The unsubstituted quinazolidine system 5 was constructed from mesylate 173. The key feature in this synthesis is based on a cyclohydrocarbonylation of the protected 4-amino-l,6-heptadiene 169 catalyzed by Rh(acac)(CO)2-BIPHEPHOS. Formation of the hemiamidal-aldehyde 171 took place by hydroformylation of the two olefin moieties and cyclization. Elimination of water gave 172, which, after treatment with NaBFE, subsequent mesylation to 173, and catalytic hydrogenation, afforded 5 (Scheme 29) <1998TL4599>. 

General Procedure for the Hydroformylation/N,N-acetal Formation. Synthesis of Biaza-cycloalkanes. The unsaturated diamine (leq), [Rh(OAc)2h (0.5 mol % Rh atoms) and BIPHEPHOS (2 mol %) were placed in an autoclave under N2 followed by deoxygenated benzene The vessel was flushed and evacuated three times with CO/H2 (1 1,13 bar) and then pressurized to 28 bar. The reaction was kept at 40-80 °C for 20h. The autoclave was cooled and the gases were released followed by selective extraction of the total product with light petroleum. Concentration of the solvent gave in most cases NMR pure material of the title compounds. 

Recently, we reported that the rhodium/BIPHEPHOS-catalyzed hydroformylation of trans-4-octene (Scheme 6) provides an interesting approach for the synthesis of n-nonanal [23]. In this context trans-4-octene can also be seen as a model substance for hydroformylation of internally unsaturated fatty acid esters. This could open up access to the use of renewable resources for the synthesis of valuable n-aldehydes. 

Propylene carbonate is a good solvent of the rhodium precursor [Rh(acac) (00)2] and the phosphite ligand BIPHEPHOS and can thus be used as the catalyst phase in the investigation of the isomerizing hydroformylation of trans-4-octene to n-nonanal in a biphasic system [24]. As already mentioned, the reaction products can be extracted with the hydrocarbon dodecane. Instead of an additional extraction after the catalytic reaction, we carried out in-situ extraction experiments, where the products are separated from the catalytic propylene carbonate phase while the reaction is still in progress. Conversion of 96% and selectivity of 72% was achieved under comparably mild conditions (p(CO/H2) = 10 bar, T = 125 °C, 4 h, substrate/Rh = 200 1). 

Table Influence of the addition of methylated /3-cyclodextrin in the two-phase system propylene carbonate/dodecane. Reaction conditions 0.1 mmol [Rh(acac)(CO)2], 0.5 mmol BIPHEPHOS, 19.4 mmol trans-4-octene, 20 ml propylene carbonate, 20 ml do-decane, p(CO/H2 = 1/1) = 10bar, T = 125 °C, t = 4h, stirring velocity 500 rpm...

Table 10 Hydroformylation of trans-4-octene in cyclic carbonate/N-octyl-2-pyrrolidone/ extraction agent, T = 125 °C, p(syngas, 1 1) = 10bar, t(reaction) = 4h, m(solvents) = 30 g, n([Rh(acac)(CO)2]) = lO- mol, n(BIPHEPHOS) = 5 x mol...

The combination of rhodium dicarbonyl acetylacetonate complex (Rh(acac)(CO)2) and a diphosphite ligand, (2,2 -bis[(biphenyl-2,2 -dioxy)phosphinoxy]-3,3 -di-/i t/-butyl-5,5 -dimethoxy-l,T-biphenyl (BIPHEPHOS), is an excellent catalyst system for the linear-selective hydroformylation of a wide range of alkenes. This catalyst system has been successfully applied to the cyclohydrocarbonylation reactions of alkenamides and alkenylamines, which are employed as key steps for the syntheses of piperidine,indolizidine, and pyrrolizidine alkaloids. ... 

Cyclohydrocarbonylation of unsymmetrical amidodiene 29 catalyzed by Rh-BIPHEPHOS complex yielded dehydropiperidine aldehyde 31 as the sole product (Scheme S). The fact that no pyrroline was formed indicates that this reaction was extremely chemo- and regioselective so that the hydroformylation took place at the homoallylic olefin moiety exclusively, yielding the linear aldehyde intermediate 30. 

A short total synthesis of (-l-)-prosopinine 36 from (R)-serine was achieved via cyclohydrocarbonylation catalyzed by Rh-BIPHEPHOS complex for the construction of the key piperidine ring (2R,33 )-33 (Scheme 6). Compound 33 was converted to (-l-)-prosopinine 36 via the nucleophilic displacement of the ethoxy group with organocopper reagent 34 forming 35, followed by deprotection. A similar procedure has been used for the total synthesis of (—)-deoxoprosophylline 37. 

The Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation has also been successfully applied to the rapid synthesis of a variety of l-azabicyclo[X.Y.O]alkane amino acids, which serve as conformationally restricted dipeptide surrogates for enzyme inhibitors and receptor antagonists, directly from dehydrodipeptide substrates (Scheme Reaction... 

The cascade hydroformylation-allylboration-hydroformylation of ( )-aminoallylborate 85 catalyzed by Rh(acac)(CO)2-BIPHEPHOS afforded oxazabicyclic lactol 87 via linear aldehyde 86 in 83% yield (Scheme 14)." The regioselective hydroformylation of 7-amidoallylboronate 88 gave linear aldehyde 89 which was in equilibrium with lactol 90. Removal of the benzyloxycarbonyl (Cbz) group by hydrogenolysis initiated another cascade process, that is, amination-hydro-genation, affording indolizidine 91 in 60% overall yield." ... 

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