Palladium reductive debenzylation with

The synthesis pathway started with the lithiation of ethylbenzene 121 at the benzylic position, followed by acylation of the toluate anirni intermediate at low temperature. It is noteworthy that a potentially competing orf/io-lithiati(Mi of the type championed by Snieckus 85) i.e. between the two stabilizing methoxyl radicals) was not reported under these conditions. Subsequent reduction of benzyUcetone 122 provided smooth access to the t/irco-dimethyl-substituted bicy-clic intermediate 123 via lactonization. DIBAL reduction (—> 124) and reductive debenzylation with palladium on charcoal gave the ring-opened alcohol 125, which was further demethylated to provide a 1,3-diphenol, and then carboxylated under buffered conditions to yield acid 117, also known as phenol B . This compound was formylated with trimethyl orthoformate and acid, then cyclized to give the quinone structure and natural product, 116 (Scheme 3.1). 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

The reductive debenzylation of N-benzyldialkylamines with hydrogen in the presence of a platinum or palladium catalyst affords an excellent synthesis for symmetrical and unsymmetrical secondary amines. ... 

Debenzylation by reductive cleavage over palladium metal catalysts with molecular hydrogen has been widely utilized for many decades. A comprehensive review of the early literature on hydrogenolysis of benzyl groups emphasized the main applications and described a number of preparative procedures which are still frequently used, along with a wider range of newer chemical and catalytic methods. 

For synthesis decumbenine B, compound 2-14 was condensed with 2-7 in THF with LDA (lithium diisopropylamide) at -70°C followed by deprotonation with dilute hydrochloric acid. The desired intermediate 2-15 was obtained successfully in 49% yield. Lithium aluminum hydride reduction of 2-15 afforded the amine 2-16, which was converted to 2-17 by debenzylation with palladium on charcoal in acetic acid. The final step was dehydrogenation, after comparison with several reagents including palladium on charcoal in acetic acid and DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone)/l,4-dioxane, the best results were obtained by using DDQ/benzene. The yield of decumbenine B was 41% (Scheme 3). 

The piperidine was prepared from 2-(2-cyanoethyl)-butryraldehyde (470) via ketal 471, which was reduced with lithium aluminum hydride and reductively alkylated with benzaldehyde over 10% palladium on charcoal to 472. Acid hydrolysis led to spontaneous cyclization and formation of enamine 473. Treatment of this enamine with methyl bromoacetate and reduction of the iminium species with sodium borohydride gave the 1-benzyl-3,3-disubstituted piperidine 474 which was debenzylated with palladium charcoal under acidic conditions to give the desired piperidine, 466 (216). 

Chromatographic separation of this mixture provides the two diastereomers 401 and 402 in 46% yield and in gram quantities. The highly selective catalytic hydrogenation of 401 in the presence of platinum on charcoal followed by reductive debenzylation in the presence of palladium on charcoal provides a mixture of L-nZ o-403 (3,5-trans) and L-xy/o-404 (3,5-cw) in a diastereomeric ratio of 93 7. Similarly, 402 in two steps affords L-lyxo-405 (3,5-trans) and L-arabino-406 (3,5-cis) in a diastereomeric ratio of 80 20. With the ready availability of (R)-390, the corresponding D-series compounds can be prepared with similar diastereochemical results [136] (Scheme 90). 

A cold soln. of 2-oxobutyric acid in ethanol treated with L-(—)-a-methylhenzyl-amine in the same solvent, 10%-Pd-on-charcoal added, hydrogenated 10 hrs. at 30 /50 p.s.i. until 1 mole of has been absorbed, the catalyst removed by filtration, the filtrate coned., aq. 30%-alcohol and palladium hydroxide-on-charcoal added, then hydrogenated at 25 /50 p.s.i. until Hg-uptake ceases L-butyrine. Y 75.9-84.9% excess of enantiomorph 81.4%.— Debenzylation with other catalysts was not successful. Asym. induction occurs during reduction of the azomethine and debenzylation can be performed with little or no loss of configurational integrity. The configuration of the amino acids is the same as that of the a-methylbenzylamine from which it is derived. The magnitude of the induced asymmetry depends on the substrate and the catalyst. F. e. s. R. G. Hiskey and R. G. Northrop, Am. Soc. 83 4798 (1961) asym. synthesis of amino acids s. a. J. G. Sheehan and R. E. Chandler, Am. Soc. 83, 4795 (1961). 

Reaction of 10a and 11a with the aluminum amide prepared from MejAl and the (R)-phenethylamine and subsequent reduction step occurred with the same excellent anti/syn diastereoselection as precedently, leading respectively to anti amino alcohols 8a and 9a. These amino alcohols were obtained in an excellent purity from 10a (8a/9a = 93/7) and from 11a (9a/8a = 90/10). The stereoisomeric excess is the same as the enantiomeric excess of starting epoxy ethers. No racemization occurred in the reaction ring opening does not involve a carbenium ion, and no enolization occurs from intermediate A or B. Both enantiommc amino alcohols 12a and 13a were obtained by debenzylation with palladium hydroxide imfortunately, we have not been able to assign the absolute configuration of the asymmetric carbons of 8a and 9a (Scheme 7). 

Hydrogenation of 2-butoxy-3//-azepine (3) with palladium on charcoal and hydrogen affords 2-butoxy-4,5,6,7-tetrahydro-3f/-azepine (4),79 whereas reduction of the 2-benzyloxy derivative, under the same conditions, is accompanied by debenzylation and formation of hexahydroazepin-2-one (77% mp 67-69 C).79,241... 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

Enders and Hundertmark [9] recently reported that debenzylation of 5 with calcium in liquid ammonia gives the corresponding alcohol 6 in quantitative yield [10]. Similar debenzylation of 7 produces 8 in 83% yield. The use of calcium, in contrast with the more reactive lithium, circumvents reduction of the existing phenyl ring. They also found that the calcium method is far more reliable than palladium-catalyzed hydrogenolysis, which is very sensihve to catalyst poisoning by traces of sulfur and tin by-product. 

Catalytic debenzylation of 2-benzyl-4-methyl-6 -l,2,6-thiadiazin-3(2//)-one 1,1-dioxide (165) is effected in high yield (86%) with palladium-charcoal and hydrogen over a short period (1 h) <84CCC840>. However, on prolonged treatment (12 h) debenzylation is followed by reduction of the C-4—C-5 double bond and formation of 4-methyl-5,6-dihydro-4 -l,2,6-thiadiazin-3(2//)-one 1,1-dioxide (166) (Equation (17)). 

Reactions of this type are confined to debenzylations of A-benzylated derivatives. Catalytic debenzylations of 1-benzyl-6//-l,2,6-thiadiazin-3(2//)-one 1,1-dioxides are readily effected with palladium charcoal and hydrogen <84CCC840>. However, care is needed as prolonged reaction times result in reduction of the thiadiazine ring (Section 6.16.6.7). 

In imidazo[l,2-a]pyridines, reduction of the six-membered ring occurred fairly readily and has been reported, when using palladium on charcoal as the catalyst, to be competitive with reduction of a nitro group or with debenzylation <89CPB2293, 86JCR(S)404>. A similar facile reduction has been reported for imidazo[l,5-a]pyridines <91JMC725>. 

S, 4 S)-1-Benzyl-3,4-dihydroxypyrrolidine (762), prepared in 70% yield by a lithium aluminum hydride reduction of 761, undergoes efficient disilyl protection to afford 770 in 83% yield. Debenzylation of 770 with palladium hydroxide followed by treatment with... 

Preparation of the jcy/o-configurated deoxyimino sugars 805 and 807 from 802 or 806 illustrates the value of tartaric acid in enantiospecific syntheses of valuable target molecules. Ozonolysis of 802 followed by reduction with sodium borohydride in methanol provides 803. Subsequent borane-dimethylsulfide—THF complex reduction, OTBS deprotection with 60% aqueous acetic acid, and purification with Amberite IRA400(OH) resin provides, after acidification, 804 in 75% yield. Catalytic debenzylation in the presence of palladium hydroxide occurs quantitatively to afford (27, 3/ ,4R)-2-(2-hydroxyethyl)-3,4-dihydroxypyrrolidine hydrochloride (805) in an overall yield of 53% (Scheme 176). 

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