Reduction

As already shown in paragraph Section 6.2.2, the multiphasic conditions for hydrodechlorination, are also active for hydrogenation reactions, such as was the case of haloaromatic ketones, which could selectively be reduced to the alcohol.44-47,49,50 This reaction was investigated from the kinetic standpoint, using kinetic models that allowed an accurate analysis of the reaction selectivity.51 In particular, it was shown that halogen removal was accelerated with respect to carbonyl reduction in the presence of A336.

The multiphasic system was also used for the enantioselective hydrogenation of acetophenone—a model carbonyl compound—using chiral modifiers in place of A336.53 The idea was to employ chiral phase-transfer agents derived from chincona alkaloids in place of A336, coupled with Pt/C as catalyst. A rapid screening, however, demonstrated that the pure alkaloids chincona and chinco-nidine were more active than the corresponding ammonium salt in promoting a degree of enantioselectivity in the reduction of acetophenone (Figure 6.26). The amount of chincona modifier was correlated with the degree of conversion and ee, demonstrating that it covered the heterogeneous catalyst and formed chiral pockets able to stereo-recognize the substrate (Figure 6.27). This reaction was the first example of heterogeneous chiral catalysis on nonactivated ketones.

The use of Raney-Ni in place of more expensive Pd and Pt catalysts was considered from the beginning, and it showed potential for the hydrodechlorination reaction, as already discussed. It proved to be a less active catalyst—not surpris-ingly—but it also showed high potential in the multiphasic system, since its activity was always strongly enhanced by the presence of A336.55 A striking example of this difference was shown in the case of the hydrogenolysis of benzylmethyl ether, where only Raney-Ni proved active enough to promote the C-O bond-breaking reaction under the multiphasic conditions (Table 6.2). The potential of this reaction was investigated over a series of different ethers, including BOC-protected O-benzyl-serine (Figure 6.28), where only the benzyl group was selectively removed under the multiphasic conditions.

>90% selectivity toward 1 -phenylethanol up to 20% ee

Figure 6.26 Acetophenone enantioselective reduction.

Figure 6.27 Effect of varying amounts of CD on conversion and ee for the enantioselec-tive multiphasic reduction of acetophenone.

CDIN:Pt/C (weight ratio)

Figure 6.27 Effect of varying amounts of CD on conversion and ee for the enantioselec-tive multiphasic reduction of acetophenone.

TABLE 6.2 Hydrogenolysis of Benzyl Methyl Ether

Catalyst

Solvent System

PT Agent

Time (min)

Conversion (%)

Pd/C

Ethanol

None

30

100

Multiphasic

A336

310

3

None

330

85

Pt/C

Ethanol

None

240

33a

Multiphasic

A336

360

0

None

300

5a

Ra-Ni

Ethanol

None

230

37

Multiphasic

A336

150

100

None

420

85

SDS

435

98

"Toluene was further reduced to methylcyclohexane.

"Toluene was further reduced to methylcyclohexane.

HOOC H2, Raney-Ni HOOC

BOCNH OBn multiphasic BOCNH OH Figure 6.28 Selective debenzylation of BOC-protected serine.

Et3N

X=l,Br multiphasic

Figure 6.29 Heck reaction.

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