P-Alkylation of Secondary Alcohols

A possible mechanism for the P-alkylation of secondary alcohols with primary alcohols catalyzed by a 1/base system is illustrated in Scheme 5.28. The first step of the reaction involves oxidation of the primary and secondary alcohols to aldehydes and ketones, accompanied by the transitory generation of a hydrido iridium species. A base-mediated cross-aldol condensation then occurs to give an a,P-unsaturated ketone. Finally, successive transfer hydrogenation of the C=C and C=0 double bonds of the a,P-unsaturated ketone by the hydrido iridium species occurs to give the product. 

Table 5.12 P-Alkylation of secondary alcohols with primary alcohols catalyzed by [Cp lrCl2]2 (1) ...

P-Alkylation of secondary alcohols with primary alcohols... 

The Peris group has looked at the influence of lmidazol-2-ylidene, imidazol-4 ylidene, and pyrazol-3-ylidene ligands on the P-alkylation of secondary alcohols... 

Due to the microscopic reversibility of transfer hydrogenation, this reaction was particularly suitable for cascade processes. For example, p-alkylation of secondary alcohols with primary alcohols was demonstrated (Scheme 5.12), including the dehydrogenation of the alcohols followed by aldol condensation, which was catalysed by the base typically used in transfer hydrogenations. Subsequent re-hydrogenation of the aldol condensation product provided the p-alkylated alcohol. The normal and abnormal imidazolylidene and the non-classical, normal pyrazol-2-ylidene ruthenium complexes 53-56 were investigated as catalysts in such p-alkylations (Scheme 5.12). ° In line with the... 

Since the iridium(III) complex [(Cp )IrCl2]2 (Cp = pentamethylcyclo-pentadienyl) is an active catalyst for the p-alkylation of secondary alcohols with primary alcohols, a series of iridium(III) complexes 26-28 bearing a Cp unit tethered to an imidazolyhdene was synthesized (Equation (8.15)). These complexes displayed similar activities in the p-alkylation of secondary alcohols with primary alcohols as electrophiles (Equation (8.15)), and surpassed the performance of their parent compound [(Cp )IrQ2]2. Control of the reaction time was found to be crucial to avoid the undesirable dehydrogenation of the product (see Section 8.4.2 for further details). The sequence of catalytic reaction steps was thought to involve the oxidation of both alcohols and the formation of an iridium hydride species. Base-promoted cross-aldolization and elimination to form the ot-enone and hydrogenation of the C=C and C=0 bonds to regenerate an iridium-alkoxide species would complete the cycle. 

NHC)Ru(p-cymene)] complexes (NHC = imidazol-2-ylidene, imidazolin-4-ylidene or pyrazolin-2-ylidene) were also used as catalysts for the p-alkylation of secondary alcohols in the presence of KOH, in refluxing toluene. Notably, abnormal NHC complexes were better performing than normal [(IMe)Ru-Cl2(p-cymene)] 75. For further details the reader is referred to Chapter 5. 

Binuclear complexes with bridging trimethyltriazoldiylidene ligands were also used in TH and p-alkylation reactions. Thus, complexes 76 and 77 were applied for TH of ketones and imines in i-PrOH/KOH (Figure 13.11). The reductions of ketones and A -benzylidene anilines were complete within 1 h. Related 78 and 79 ruthenium complexes were investigated as catalysts in the p-alkylation of secondary alcohols with primary alcohols. Such catalytic systems were very selective and more active than the previously reported catalysts. ... 

Given that previous studies had shown that the iridium(iii) complex [IrCl2Cp ]2 (Cp = pentamethylcyclopentadienyl) is an active catalyst for the p-alkylation of secondary alcohols with primary alcohols, a series of iridi-um(iii) complexes 35-36 bearing a Cp unit tethered to an imidazolylidene, as well as complex 37 containing a chelating NHC-pyrimidine ligand, were synthesised (Figure 8.3). ... 

The alkyl halides used in the Michaelis-Becker reaction (cf. page 728) may be replaced by other alkylating agents such as dialkyl sulfates326 or alkyl sulfonates 295,327 even the use of carboxylic esters for alkylation of sodium dialkyl phosphites is the subject of a patent.328 It is noteworthy that p-toluene-sulfonates often have advantages over alkyl halides in that alcohols are readily converted into these esters and, further, that the p-toluenesulfonate ion liberated, being a weak nucleophile, causes fewer side reactions. Alkyl p-toluene-sulfonates rank between alkyl chlorides and bromides in their reactivity towards sodium dialkyl phosphites.286 p-Toluenesulfonates of secondary alcohols give poor yields of phosphonate. 

In recent years, catalytic applications of half-sandwich metal complexes have been extensively developed. A series of (p-cymene)Ru(II) complexes containing pyrazole-based iV-heterocyclic carbine (pyrazoUn-3-ylidene) ligands (Fig. 21.13a and b) showed excellent catalytic y3-alkylation of secondary alcohols with primary alcohols and the dimerization of phenylacetylene [30]. 

The reaction of secondary alcohols 101 with primary alcohols 99 using [Cp lrCl2]2 and a base such as NaO Bu was reported to afford the corresponding P-alkylation products 102 (Equation 10.23) [46]. 

Alkyl halides or nitriles Alcohols are converted conveniently into alkyl halides or nitriles by consecutive addition of a lithium halide or LiCN and the alcohol to a preformed complex of P(C6H5)3 and DEAD in anhydrous THF at 0° to 25°. Yields range from 60% to 97%. Reaction of secondary alcohols is accompanied by complete inversion. 

Most Williamson reactions proceed by the 8 2 mechanism, but there is evidence (see p. 446) that in some cases the SET mechanism can take place, especially with alkyl iodides. Secondary alcohols have been converted to the corresponding methyl ether by reaction with methanol in the presence of ferric nitrate nonahy-drate. Vinyl ethers have been formed by coupling tetravinyl tin with phenols, in the presence of cupric acetate and oxygen. " The palladium-catalyzed coupling of vinyl triflates and phenols has also been reported. ... 

Furthermore, Jia and co-worker recently reported the Ru-catalyzed Guerbet-type p-alkylation of primary and secondary alcohols [184]. In a representative example of this reaction, 1-phenyl ethanol (1.0 mmol) was reacted with benzyl alcohol (2.0 mmol) in the presence of RuCl2(PPh3)2(2-NH2CH2Py) (2-NH2CH2Py = 2-aminomethyl pyridine) (1 mol%) combined with f-BuOK in toluene at 105 °C to give the corresponding P-alkylated product in quantitative yield (Scheme 34). 

There are also many stable binary complexes with these ligands, their number being sometimes restricted. For instance Zr(0 -Bu)4 and Mo(NMe2)4 are respectively 16-electron and 18-electron complexes (and not 8- and 10-electron complexes, respectively ), which is better in accord with their stability. With this LX mode, the chains M-N-R and M-N-O are linear in monometallic complexes and the bond angle M-O-R tends to open up to 180°. The alkoxy ligands, as the alkyls, undergo P-elimination under the same conditions as the latter (P-H atom and less than 18 valence electrons). Thus, the transition metal is a good oxidant of primary alcohols to aldehydes and of secondary alcohols to ketones, especially in the... 

Tertiary amines may also be synthesised by the alleviation of secondaiy amines with alcohols. Whereas the alkylation of primary amines involves formation of an imine intermediate, the alleviation of secondaiy amines requires the more challenging formation of an iminium ion intermediate prior to the return of hydrogen to the substrate. The pharmaceutical agents piribedil, tripelennamine, and chlorpheniramine were all prepared on milligram scale by [Ru(p-cymene)Cl2]2-catalysed iV-alkylation of secondary amines (Scheme 12.5). ... 

A synthesis of 2-alkyl-2,3-dihydro-y-pyrones (187) from methoxybutenyne and aldehydes has been described (83TL4551). The condensation of lithiomethoxy-butenyne (184) with aldehydes at -78°C leads to the secondary alcohols 185, which form the dihydropyrones 187 via hydration of the acetylenic bond and hydrolysis of the methoxyethenyl group to the ketoenol 186 (0°C, p-TSA, THF, H2O or 30% HCIO4, 20 min) folowed by intramolecular cycloaddition. 

Aldehydes, formates, primary, and secondary alcohols, amines, ethers, alkyl halides, compounds of the type Z—CH2—Z, and a few other compounds add to double bonds in the presence of free-radical initiators/ This is formally the addition of RH to a double bond, but the R is not just any carbon but one connected to an oxygen or a nitrogen, a halogen, or to two Z groups (defined as on p. 548). The addition of aldehydes is illustrated above. Formates and formamides " add similarly ... 

In a corresponding manner, the mono-esters of P(III) systems can be produced by controlled reaction of the P(III) halides with the appropriate hydroxyl compound. Significantly better yields are obtained for the aryl esters (from phenols — Equation 4.3) than for alkyl esters (from alcohol), and primary alcohols provide better yields than do secondary alcohols.5 6... 

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