Palladium based reductive amination

Scheme 4.10 General strategy for the chemoenzymatic synthesis of iminocyclitols based in the use of aldolases and palladium-mediated reductive amination.

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or S isomer of DOM preferentially. Also, the above-mentioned l-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The mp of either of the optical isomers, as the hydrochloride salts, was 204-205 °C. 

The application of resin 13 to the sohd-phase synthesis of other useful target compounds was also explored and an example of this is the multistep synthesis of Meclizine (Fig. 10).26 The starting material, 3-methyl-4-hydro-xybenzaldehyde, is attached to the PFS hnker, and a polymer-bound amine intermediate is prepared by a reductive amination of resin 23 with amine 24. The resulting resin 25 is subjected to a palladium-mediated reductive cleavage to give Meclizine 26 in 80% yield, based on the original resin loading. 

Commonly used metal salts and palladium precursors include Pd(OAc)2, Pd (acac)2 (acac = acetylacetonato) and Pd2(dba)3 or Pd(dba)2 (dba = dibenzylide-neacetone). If a Pd(II) salt is used as pre-catalyst, reduction by base or by excess phosphine ligand is required. The exact nature of the reducing agent is somewhat contended, but it is often assumed that the phosphine takes up this role, for which evidence has been reported [26]. A typical catalytic system consists of a palladium source and an aryl- or alkylphosphine (typically PPh3), in at least 2 eq., as ligand. The addition of bases, typically amines and alkoxides, is often found to be beneficial for activity, which is also reflected in the patent literature [27-29]. The bases are thought to facilitate in the attack of the nucleophile in the rate-determining step and, in the case of the amines, in the reduction of Pd(II) to Pd(0). 

BusP as ligand.Poor yields in the reductive cyclization method—when competitive cyclization is possible—and also the need for milder reaction conditions in the cyclization step urged Emoto et al. to report an alternative method based on sequential palladium-catalyzed aryl amination (Scheme 10). The substrate for the cyclization was 2-amino-2 -bromo-diphenylamine, obtained by selective bromination and reduction of the well-known 2-nitrodiphenyl-amines or by coupling of 2-bromoaniline with a l-bromo-2-nitrobenzene and subsequent reduction. Treatment of 2-bromo-2 -nitrodiphenylamine with catalytic amounts of palladium(II) and BINAP as ligand afforded the desired phenazines in good yields. ... 

The resulting intermediate (—)-107 underwent cyclization to the piperidine (—)-108 after mesylation and base treatment. Acidic hydrolysis of the acetal and reduction of the resulting cycHc hemiacetal with sodium borohydride produced the triol (—)-109, the vicinal diol component of which was cleaved with periodate before reductive amination with hydrogen and palladium on carbon completed the synthesis of (+)-88. 

The addition of N-bromosuccinimide (1.1equiv) to a dichlo-romethane solution containing the alkene (1 equiv) and cyana-mide (4 equiv). The solution was maintained at room temperature (3 days) and then washed with water, dried, and concentrated in vacuo. Treatment of the bromocyanamide [intermediate] with 1% palladium on charcoal in methanol (1h) led to reduction of the for-madine. Addition of base to the reaction mixture (50% aqueous KOH, reflux 6h) followed by extraction with ether gave monoamine. (Yield is 48-64% final amine from alkenes analogous to safrole)... 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

For more selective hydrogenations, supported 5—10 wt % palladium on activated carbon is preferred for reductions in which ring hydrogenation is not wanted. Mild conditions, a neutral solvent, and a stoichiometric amount of hydrogen are used to avoid ring hydrogenation. There are also appHcations for 35—40 wt % cobalt on kieselguhr, copper chromite (nonpromoted or promoted with barium), 5—10 wt % platinum on activated carbon, platinum (IV) oxide (Adams catalyst), and rhenium heptasulfide. Alcohol yields can sometimes be increased by the use of nonpolar (nonacidic) solvents and small amounts of bases, such as tertiary amines, which act as catalyst inhibitors. 

The mechanism involves a Pd(0) monocoordinate complex as the active species that undergoes oxidative addition to the aryl halide [141]. Thereafter, coordination of the amine to the palladium centre and deprotonation by the external base results in halide abstraction. After reductive elimination, the coupling product is obtained and the catalytic active species regenerated (Scheme 6.45). 

PVP, a water soluble amine-based pol5mer, was found to be an optimum protective agent because the reduction of noble metal salts by polyols in the presence of other surfactants often resulted in non-homogenous colloidal dispersions. PVP was the first material to be used for generating silver and silver-palladium stabilized particles by the polyol method [231-233]. By reducing the precur-sor/PVP ratio, it is even possible to reduce the size of the metal particles to few nanometers. These colloidal particles are isolable but surface contaminations are easily recognized because samples washed with the solvent and dried in the air are subsquently not any more pyrophoric [231,234 236]. 

The Pd-catalyzed amination of / -rm-butylphenyl bromide with pyrrole in the presence of Pd(OAc)2, dppf and one equivalent of NaOr-Bu led to the Af-arylation product 88. A simplified version of the mechanism commences with the oxidative addition of p-te/t-butylphenyl bromide to Pd(0), giving rise to the palladium complex 89. Ligand exchange with pyrrole followed by deprotonation by the base (NaOr-Bu) results in amido complex 90. Reductive elimination of 90 then gives the amination product 88 with concomitant regeneration of Pd(0) catalyst. If the amine had a (3-hydride in amido complex 90, a (3-hydride elimination would be a competing pathway, although reductive elimination is faster than P-hydride elimination in most cases. 

The fate of the acyl palladium complex depends on the circumstances. In the presence of a suitable nucleophile (alcohol, amine) it is converted into the corresponding carboxylic acid derivative. The side product, a palladium hydride is converted to the active form of the catalyst in a reductive elimination step, resulting in the formation of an equimolar amount of acid, which is quenched by an added base (in most cases the excess of the nucleophile). 

Platinum sulfide appeared superior to palladium for the reductive alkylation of piperidine with acetone. A more carefully controlled comparison of platinum sulfide with palladium and with platinum is shown in Table 2 for the reaction of N-ethylcyclohexylamine with cyclohexanone. Platinum gave a very poor conversion of the starting secondary amine (27%) and a correspondingly low yield of the tertiary amine product (22%), although the yield based on conversion was good (81%). The... 

Since the substitution reaction succeeded so well with olefins, the obvious extension to acetylenes was tried. Of course, only terminal acetylenes could be used if an acetylenic product was to be formed. This reaction has been found to occur but probably not by a mechanism analogous to the reaction of olefins (43,44). It was found that the more acidic acetylene phenylacetylene reacted with bromobenzene in the presence of triethylamine and a bisphos-phine-palladium complex to form diphenylacetylene, while the less acidic acetylene, 1-hexyne did not react appreciably under the same conditions. The reaction did occur when the more basic amine piperidine was used instead of triethylamine, however (43). Both reactions occur with sodium methoxide as the base (44). It therefore appears that the acetylide anion is reacting with the catalyst and that a reductive elimination of the disubstituted acetylene is... 

---