Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0781 842

Reagents:(i) 59, KOH, PriOH

SCHEME 52

Hydrosilylation of CDO achieves the same objective as hydrogenation, following workup by treatment with aqueous acid. Some very interesting new methods have been reported in recent years. Oxazoline ligands in combination with rhodium(I)241 have given some excellent results, and in particular the ‘pybox’ ligand 60 has been used to good effect. Using this ligand e.e.s of up to 76% have been achieved in the reduction of simple ketones241a and e.e.s of ca 90% for reduction of cyclic ketones (Scheme 53)241b. Titanium-centred C2 symmetric bis cyclo-pentadienyl catalysts have also given some excellent results in reductions of simple ketones, although they may lack the versatility and substrate scope of other methods242. Some excellent e.e.s have been obtained using phosphonites derived from ‘TADDOL’ diols as ligands in asymmetric hydrosilylation243. Asymmetric hydrosilylations of symmetrical diols have been achieved with very high e.e.s and diastereoselectivity using a combination of the diphosphine RR-SS-EtTRAP (P34) with rhodium(I)244.

Reagents:(i) 1% [60.RuCl3 ], 2% AgBF4 , Ph2 SiH2 , 0 °C, (ii) H+/H2 O

SCHEME 53

B. Heterogeneous Methods

1. General comments

Heterogeneous hydrogenations of CDO bonds have been described in detail in other places192,245 and will not be covered in detail here. Many of the same comments as were made for the CDC reduction also apply here. Most common hydrogenation metals may be employed (Ni, Ru, Rh, Ir, Pt etc.) and the scope of the process is very broad. In the case of enones, a careful choice of catalyst must be made so that CDC reduction does not compete.

2. Diastereoselective reductions

As was the case with heterogeneous reduction of CDC bonds, the sense of diastereoselective reduction of CDO bonds is often very difficult to predict. A number of methods have been reported in which carbonyl groups attached to chiral auxiliary groups have been reduced by heterogeneous catalysts, however few give high d.e.s (Scheme 54)245. This is again mainly due to the lack of order and poor definition of the catalyst surface. The effects of small changes to the exact nature of the catalyst, to the solvent etc., can all have a dramatic effect on the sense and level of selectivity. Most of the dramatic and valuable developments in heterogeneous hydrogenation have been in the area of direct asymmetric hydrogenation using a chiral catalyst, and will be described in the next section.

Reagents:(i) H2 , Pd/C

SCHEME 54

3. Enantioselective reductions

Two major areas of research have emerged from studies into asymmetric hydrogenations of carbonyl groups using modified heterogeneous catalysts. The first involves the

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 823

reductions of ˇ-keto esters, a process for which Raney nickel modified by the incorporation of tartaric acid has emerged as the leading method192,246. The modified catalysts appear to be capable of giving reproducible sets of results for a range of substrates (Scheme 55). Although various metals have been examined, few are as successful as the Raney nickel reagent. In some cases, additives such as sodium salts and carboxylic acids may be incorporated into the catalysts and may result in higher e.e.s in some cases. The mechanism and kinetics of this reduction have been studied in considerable detail, and several recent reports have been published247. The process has been refined to a high degree and, using ultrasonicated Raney nickel and sodium chloride together with tartaric acid, leads to a catalyst which is capable of generating e.e.s of up to 94% (Scheme 56)248. Diastereoselective and enantioselective reductions using this class of catalyst are less satisfactory249 Modified catalysts containing nickel supported on alumina also give inferior results250, ˇ-Diketones may be employed in this reaction to good effect, in which case reduction of both ketones is observed to give the anti product248,251. Using the ultrasonicated Raney nickel as described above some very highly selective reductions may be achieved (Scheme 57)251a. Asymmetric reduction of isolated ketones are less selective, although enantiomeric excesses of up to 80% have been reported247c. In one case the addition of pivalic acid was reported to improve the enantiomeric excess252.

Reagents:(i) (RR)-Tartaric acid modified RaNi, NaBr, ultrasound, 100 atm H2

SCHEME 57

The second, large area of research concerning asymmetric heterogeneous catalysis is the reductions of ˛-ketoesters such as methyl lactate. In contrast to the ˇ-ketoester reductions, modified Raney Nickel catalysts, although effective, have proved not to be the best systems253. In contrast, the modification of platinum, on an inorganic support such as silica, with amino alcohols, have emerged as the most promising reagents. Of the many chiral groups examined, the alkaloid cinchonidine has given some of the best results, and

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 825

IV. HYDROGENATION OF C=N BONDS

A. Homogeneous Methods

1. General comments

Many of the comments related to CDO reduction in this section also apply to the homogeneous reductions of CDN bonds, a process for which heterogeneous methods predominate192. This section will therefore concentrate on recent developments and, in particular, on asymmetric transformations. Transfer hydrogenations of CDN bonds by homogeneous catalysts have been reported264.

2. Diastereoselective and enantioselective reductions

Asymmetric hydrogenation of CDN bonds has proved more challenging than most other reductions. As in the case of carbonyl reduction, however, some excellent recent results in this area have been achieved. Using simple imines as substrates, some good asymmetric inductions have been achieved using rhodium265 and ruthenium266 catalysts. Of particular note is the use of the partially sulphonated ligands P35, as mediators in complexes with rhodium for asymmetric hydrogenations in aqueous solvents (Scheme 59). In the example shown mixtures of sulphonated ligands were used; a sulphonation extent of 1.41 corresponds to a mixture of 59% monoand 41% di-substituted, for example. Enantiomeric excesses of up to 96% have been recorded in the products of reductions using this ligand system265. The degree of sulphonation, however, is essential, the best results being achieved with monosulphonated ligands. Good enantiomeric excesses can be achieved by matching the directing effect of a chiral group on the nitrogen atom with that of the ligand267. This latter method has actually been employed in a kinetic resolution of racemic amines via a reductive alkylation process.

Reagents (i) 1.41−1.65 eq. SO3 H sulfonated P35. [Rh(COD)Cl2 ], 70 bar H2 , H2 O. AcOEt

SCHEME 59

SO3 H

PAr2 PAr2

(P35) Ar = Ph or 1-4 sulphonated ligands

Iridium complexes appear to be more suited to the control of asymmetric reductions of simple imines than those of rhodium or ruthenium268,269. The use of ligand BDPP (P12)

this class of reduction. Transfer hydrogenation of imines using a complex related to 59 (employed for carbonyl reduction) has very recently been reported to give excellent results when applied to the reduction of imines. Cyclic imines are especially good substrates which give, upon reduction, amines with enantiomeric excesses of up to 97%, depending on the exact catalyst used238b.

B. Heterogeneous Methods

1. General comments

Heterogeneous hydrogenation of the CDN bond is a very widely used synthetic process with application to small and large-scale reactions. Many of the catalysts described in other sections may also be employed, for example those based on supported rhodium, palladium etc, and Raney Nickel. This area has been reviewed extensively recently192. Hydrogenation of oximes and hydrazones results in formation of amines. Milder conditions can be used for oxime reduction if the ethylaminocarbonyl derivative is prepared in situ prior to reduction276.

One of the most valuable and widely used applications of CDN bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from ˛-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277.

MeO

OMe

(66)

This section will deal with some recent developments in this area and concentrate mostly on stereoselective transformations.

2. Diastereoselective and enantioselective reductions

Many stereoselective reductions of CDN bonds have been reported, and in the case where the original chiral group is removable (i.e. a chiral auxiliary) this method may be

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 829

employed for the asymmetric synthesis of amines. The area has been quite extensively reviewed recently278 and will be described only briefly here.

The formation and reduction of Schiff’s bases by heterogeneous catalysts has been extensively used as the favoured method of approaching reductions of this type, for practical reasons. The condensation of ˛-keto acids with simple chiral benzylic amines provides an attractive approach to amino acid synthesis because the auxiliary group can be removed by further hydrogenation after the reduction. However, the e.e.s achieved using this method are rather low, with some notable exceptions278,279. The use of amines with extended -systems gives the best results. In a recent report of the use of Pt-alumina modified by 1-(1-naphthyl)ethylamine for the reduction of ethyl pyruvate, a reductive alkylation of the amine occurred in situ with a selectivity of 97:3, one of the highest levels reported (Scheme 64)260c. This procedure led to a process for the synthesis of amino acids in >95% e.e. after hydrogenation of the chiral directing group. Efforts have been made to correlate the sense of induction with the conformation of the substrate and its interactions with the catalyst surface. However, as has been described in previous sections, the uncertainty of the structure of heterogeneous catalyst surfaces limits the reliability of this. The nature of the solvent and other reaction parameters has also been shown to have a dramatic effect on the selectivity of these reactions. Chiral benzylamines have recently been applied to the enantioand diastereoselective reductions of imines derived from cyclic ketones280.

NH2

97 :3

Reagents:(i) Pt, Al2 O3 , AcOH, 25°C, 25 bar H2

SCHEME 64

The reductive alkylation of methyl pyruvate with and the t-butyl esters of amino acids using Pd/C catalyst leads to the formation of iminodicarboxylic acids such as 67 in selectivities of 29 75% d.e. depending on the amino acid and solvent used (hexane gave the best results). Hydrolysis of the t-butyl ester to the acid 68 followed by hypochloritepromoted decarboxylation and imine hydrolysis leads to the formation of (S)-alanine 69 in correspondingly high e.e.s278,281. The likely decarboxylation mechanism as far as the imine stage is shown in Scheme 65.

SCHEME 65

Although there is evidence to suggest that a chelation mechanism operates in the reductions of chiral imines bearing co-ordinating groups such as acids, esters and alcohols278, excellent selectivities may also be achieved using sterically directed reductions. These processes work especially well in cyclic substrates, where the most reactive (i.e. unhindered) face can generally be predicted with a high degree of accuracy282,283. This has proved to be the basis of an excellent approach to chiral alkaloids282. The reduction of a cyclic nitrone attached to a sultam chiral auxiliary (Scheme 66) serves to illustrate this methodology284.

SCHEME 66

V. CONCLUSIONS

This review has served to illustrate recent developments in the uses of hydrogenation reactions in synthesis. The emphasis on asymmetric applications serves to reflect the great growth in this area over recent years and the central position in asymmetric synthesis which this technique now occupies. New developments and trends have been identified for what is certain to be a continuing period of growth in the synthetic importance of hydrogenation.