Amino alcohols hydrogenolysis

An unusual by-product was obtained in small yield in palladium-catalyzed reduction of 2-amino-4,5-dimethoxyindanone hydrochloride, The reduction was done in two stages first, a rapid absorption of 1 mol of hydrogen at 38 C to give the amino alcohol, and then a much slower reduction in the presence of HCIO4 at 70 "C. The rearranged by-product was shown to arise from attack of acid on the amino alcohol (50), Resistance to hydrogenolysis is characteristic of / -amino aromatic alcohols (56), a fact that makes reduction of aromatic oximino ketones to amino benzyl alcohols a useful synthetic reaction. 

In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of the isoxazole of the intermediate... 

Oxazines are prone to hydrogenolysis since the relatively weak N-O bond is easily cleaved. This reaction has often been employed for the transformation of this cycle (generally obtained from nitrones) into amino alcohols in a stereocontrolled manner. For example, reaction of 57 with hydrogen and palladium on charcoal as catalyst (Equation 1) furnished the expected substituted pyrrolidine 58 in moderate yields <2003EJ01153>. 

These amino alcohols can be prepared by disubstitution of the benzylamine with a suitable halogenated or sulfonated derivative of the alcohol, followed by debenzylation (hydrogenolysis) using H2. 

Another possible route to thienamycin (487) has utilized the dipolar cycloaddition of 1-pyrroline 1-oxide (482) with methyl crotonate (79TL4359). The reaction is highly stereoselective due to the operation of secondary orbital effects. The isoxazolidine (483), produced in 90% yield, was subjected to hydrogenolysis, and the resulting amino alcohol (484) was selectively blocked with hexamethyldisilazane to give (485). Treatment with ethylmagnesium bromide then gave /3-lactam (486 Scheme 107). 

A very high degree of stereoselectivity was observed when certain chiral amino alcohols were used as the amine component (Scheme 7.9) [34]. For example, either enantiomer of homo-phenylalanine (61 and 64) could be efficiently prepared beginning with one of the two enantiomers of 2-phenylglycinol (59 and 62), followed by hydrogenolysis of the corresponding intermediate (60 and 63). 

The N—O bond of isoxazolines can easily be cleaved via reduction. It is for this reason that isoxazolines are interesting synthetic intermediates. y-Amino alcohols are formed by reduction with LiAlH4 (for an example, see Figure 15.46, left). Hydrogenolysis of isoxazolines catalyzed by Raney nickel yields /j-hydroxy imines, which undergo hydrolysis to / -hydroxy-carbonyl compounds in the presence of boric acid (Figure 15.46, right). 

Kindler et al. hydrogenated a-hydroxyiminoacetophenone and a-hydroxyimino-propiophenone (eq. 8.26) to the corresponding phenylalkylamines over a palladium black in acetic acid in the presence of sulfuric acid.51 The hydrogenolysis of the intermediate amino alcohols proceeded not at all in alcohol and acetic acid, and only rather slowly in acetic acid-sulfuric acid. In contrast, 3 -hydroxy-3 -phenylpropylamine, with one more carbon atom between the hydroxyl and amino groups, was hydrogenolyzed much faster under these conditions. Perchloric acid may also be used instead of sulfuric acid, but some hydrogenation of the aromatic ring occurred even when the hydro-... 

Touster and Carter hydrogenolyzed an isoxazole to a P-amino alcohol over Raney Ni.315 By hydrogenation of 3,5-diethoxycarbonyl-4-hydroxyisoxazole (105) over Raney Ni in ethanol at room temperature under high pressure, followed by hydrolysis, P,y-dihydroxyglutamic acid was obtained (eq. 13.167).315 The high activity of Raney Ni for the hydrogenolysis of fully substituted isoxazoles has also been noted by Stork et al.316... 

Suitably protected spiro isoxazoline 129 afforded the amino alcohol 130 with concomitant hydrogenolysis of benzyl ethers and reductive cleavage of the N-O bond by hydrogenation over Pd(OH)2/C (Equation 14) <2006TL6143>. 

The hydrogenolysis/decarboxylation/asymmetric protonation reaction cascade of acyclic benzyl P-oxo-esters such as 47 catalyzed by Pd/C with H2 in the presence of a catalytic amount of cinchonine 43 afforded the (S)-ketone 48 with enantioselec-tivities up to 75% ee, similar to previous results obtained with other P-amino alcohols. The reaction was carried out at room temperature in a short reaction time [28]. The best solvent for both yield and ee was ethyl acetate, compared with acetonitrile and THF. Comparative performances of cinchona alkaloids with other commonly used P-aminoalcohols are displayed on Scheme 7.22. 

Photochemical conversion of an amino(cyclopropyl)carbene (obtained from cyclopro-pyl(methoxy)carbene with optically pure D,i.-erythro amino alcohols) gave a cyclopropyl-substituted lactone, e.g. formation of 13, which upon hydrogenolysis gave a chiral cyclopropyl-glycine system.The reaction proceeds via a ketene complex. 

In the following case, no hydrogenolysis of the benzyl groups occurs because the amino alcohol poisons the Pd-C or Pd(OH)2. ... 

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