Facile Palladium-Mediated Conversion of Ethanethiol Esters to Aldehydes and Ketones

O tratamento de ésteres etanotiólicos com trietilsilano e paládio sobre carbono, a temperatura ambiente, fornece aldeídos. Adicionalmente, uma variedade de cetonas foram preparadas por reações de ésteres etanotiólicos com reagentes organozinco catalisados por paládio. Vários grupos funcionais, incluindo ésteres, cetonas, haletos aromáticos e aldeídos são tolarados em ambas as tarnsformações. Essas novas reações podem também ser aplicadas na síntese de derivados α-amino aldeídicos e α-amino cetônicos utilizando os correspondentes ésteres. (L)-α-amino tióis sem causar racemização.


Introduction
Transformations of carboxylic acids to aldehydes have been the subject of intensive investigation among synthetic organic chemists.With a few exceptions 1 , derivatives of acid chlorides, amides, and esters are usually converted to aldehydes by selective reduction.Although a number of synthetic methods have been reported to date, none seems to be generally applicable to multifunctional compounds.In this paper we describe a highly efficient reduction of ethanethiol esters to aldehydes with triethylsilane and a catalytic amount of palladium on carbon (Scheme 1).During the course of this investigation, it occurred to us that the combination of thiol esters, transition metal catalysts, and appropriate organometallic reagents could be used for the synthesis of ketones 2 .The novel ketone-forming reaction we could successfully developed is exceptionally mild and can be applied to the synthesis of ketones bearing aldehyde, ester, ketone, and arylbromide functionarities (Scheme 1) 3 .
Thiol ester reduction was performed at room temperature in acetone or CH2Cl2 under argon using 10% Pd on carbon and two to three equivalents of triethylsilane.As shown in Table 1, a variety of functional groups survive the essentially neutral reduction conditions.Our method is particularly suited for the conversion of optically active amino acids to amino aldehyde derivatives that are known to racemize even under mild conditions 5 .For example, the optically pure thiol ester 1 derived from L-glutamic acid 5-methyl ester was converted to the dimethyl acetal 2 in 95% yield in a 40 g-scale experiment (Eq 1).The optical purity of 2 was virtually 100% based on the 1 H-NMR studies of the corresponding (R)-(+)-α-methylbenzylamide derivative 3.While the 1 H-NMR spectrum of the racemic amides 3 exhibited two signals at 3.33 and 3.41 ppm for the dimethyl acetal, the amide 3 derived from L-glutamic acid 5-methyl ester showed only a singlet at 3.33 ppm, and no trace of a peak at 3.41 ppm was observed.
The usefulness of our procedure was demonstrated in our total syntheses of neothramycins 3a and leinamycin 6 as well as in other recent reports on synthesis of complex natural products 7 .
Since the combination of thiol ester and palladium catalyst works quite well for the mild reduction system, we envisioned that replacement of triethylsilane with organometallic reagents would lead to the formation of the corresponding ketones.Thus, we then focused our efforts on a transition metal-catalyzed synthesis of ketones.
In order to explore catalytic system for a novel ketone formation, we initially screened various combinations of transition metal catalysts and organometallic reagents using ethanethiol ester 4 as a test substrate.While Sonogashira coupling conditions gave acetylenic ketone 5 in 68% yield (Eq. 2), Suzuki-coupling conditions afforded aryl ketone 6 in low yield (Eq. 3).Finally, we have found that treatment of thiol ester 4 with a catalytic amount of PdCl2(PPh3)2 (5 mol%) and EtZnI (1.5 eq) in toluene at room temperature for 5 min furnished the corresponding ethyl ketone 7 in 91% isolated yield (Eq. 4).When commercially available THF solution of Et2Zn was used instead of EtZnI, the corresponding aldehyde was isolated in moderate yield.Mechanistic details of this unexpected reduction are still not clear.The rate of the reaction was dependent upon the choice of the solvent.While the rate a Isolated yields after chromatographic purification.Pd/C (2 mol%) and Et3SiH (3 eq) in acetone were used unless noted otherwise.b Et3SiH (2 eq) was used.c Isolated as tosylhydrazone.d 5.8-g-scale reaction.Pd/C (0.5 mol%) and Et3SiH (1.5 eq) were used.CH2Cl2 was used as solvent.e 4 mol% of Pd/C was used.f Formation of the cis isomer was not observed.

BocHN
was comparable in CH2Cl2 and CH3CN, the reaction proceeded considerably more slowly in THF and benzene.The reaction in DMF did not proceed at all.In the absence of the catalyst, however, only a minute amount of 7 was formed (7%) with recovery of 83% of 4 even after 15 h of stirring at room temperature (Eq.5).
As shown in Table 2, ethylzinc iodide as well as i-butyl-, benzyl-, phenyl-, β-phenethyl-, and vinylzinc halides reacted smoothly to afford the corresponding ketones 8 .Ester-and protected amine-containing zinc reagents could also be used 9,10 .On the other hand, a range of ethanethiol esters such as alkyl, aryl, and α,β-unsaturated thiol esters could be converted into the corresponding ethyl ketones in good to excellent yields (Table 3).It should be noted that a variety of sensitive functional groups including ketone, α-acetate, sulfide, aromatic bromide, chloride and even aldehyde are compatible with this protocol.This remarkable chemoselectivity indicates that the ketone formation is much faster than oxidative addition of palladium to aromatic bromide or nucleophilic addition of zinc reagents to aldehydes.
We next examined a conversion of thiol ester derivatives of N-protected L-α-amino acids into the corresponding amino ketone derivatives.The ketone formation proceeded smoothly to give the desired α-amino ketones in good to high isolated yields from the optically pure N-Cbz-L-α-phenylalanine thiol esters without appreciable racemization (Table 4, entries 1 and 2).Combinations of functionalized organozinc reagents and L-glutamic acid or L-proline derivatives afforded structurally intriguing amino ketones in good yields.

Experimental
Typical procedure for the conversion of carboxylic acids into ethanethiol esters using mixed anhydride method.

Dimethyl acetal (2). A large scale procedure for the reduction of ethanethiol ester
To a stirred mixture of 40 g of N-Boc-1-ethylthio-5methyl-L-glutamate (1) and 2.78 g (2 mol%) of 10% palladium on carbon in 250 mL of acetone under argon atmosphere at room temperature was slowly added 31.3 mL (197 mmol, 1.5 eq) of triethylsilane over a period of 1 h.Upon completion of the reaction, the catalyst was filtered off through a Celite column.The solvent was carefully evaporated under reduced pressure.The residue was dissolved in 500 mL of methanol, and to this solution was added 43.0 mL (393 mmol, 3 eq) of trimethyl orthoformate and 1.52 g (6.56 mmol, 0.5 eq) of camphorsulfonic acid.The reaction went to completion in 6 h at room temperature.Solid sodium carbonate was added to neutralize the acid.The reaction mixture was evaporated under reduced pressure to a smaller volume, and partitioned between CH2Cl2 and water.The organic phase was dried over MgSO4, filtered, concentrated and chromatographed on a silica gel column (80% ether in hexane) to yield 36.

Diastereomeric acetal amides (3)
To a solution of 500 mg of (±) 2 in 5 mL of methanol and water (4:1) was added 0.5 mL of 3N NaOH.After 30 min, this mixture was acidified with 3N HCl to pH ~5, and evaporated to dryness under reduced pressure.The resulting acid was taken up in CH2Cl2, dried through Na2SO4 column, and evaporated.To a stirred solution of the acid and 345 mg (1.72 mmol, 1 eq) of DCC in CH2Cl2 was added 332 µL (2.58 mmol, 1.5 eq) of (+)-α-methylbenzylamine at 0 °C.After 20 min, the reaction mixture was partitioned between CH2Cl2 and diluted HCl.The organic layer was washed with a saturated aqueous NaHCO3, dried through a Na2SO4 column and evaporated.Purification on a silica gel column with ether as an eluant gave a 1:1 mixture of 3a and 3b.The optically active (-)-2 (250 mg) prepared from 1 was converted to the corresponding amide following the procedure described above.A single compound 3 was obtained, which was also purified on a silica gel column; 3a, IR (CHCl3, cm -1 ) 3310, 3060, 2930, 1690, 1645; 1

Conclusion
In summary, we have demonstrated efficient methodologies for the synthesis of aldehydes and ketones from thiol esters.Since acids can be readily converted to ethanethiol esters under mild conditions and our procedures possess unusually high chemoselectivity, these protocols provide powerful alternatives to the arsenal of synthetic chemists for transformation of acids to aldehydes and ketones, and may find widespread use in organic synthesis.