Large scale synthesis of N-benzyl-4-formylpiperidine through partial reduction of esters using aluminum hydride reagents modified with pyrrolidine

Abe, Tokiya; Haga, Toyokazu; Negi, Shigeto; Morita, Yukio; Takayanagi, Keizou; Hamamura, Kimio

doi:10.1016/s0040-4020(01)00143-0

Cited by 39 publications

(21 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 The structures of aldehydes 2a,b were confirmed by data from IR and 1 H NMR spectroscopy and mass spec trometry. Such a difference in the properties of the reducing agents used is due to the relative stabilities of aldehydes in the presence of BMAP under the aforemen tioned conditions.…”

Section: Resultsmentioning

confidence: 89%

Synthesis of 2-alkylthio-6-methylpyridine-3-carbaldehydes

2005

View full text Add to dashboard Cite

The action of sodium bis(2 methoxyethoxy)aluminum hydride and its complex with pip eridine on 2 alkylthio 3 cyano 6 methylpyridines and on their esters in anhydrous ether yielded 2 alkylthio 3 formyl 6 methylpyridines. The aldehydes obtained undergo condensation with malononitrile and methyl cyanoacetate to give the corresponding hetarylidene derivatives.Key words: 2 alkylthio 3 cyano 6 methylpyridines, 2 alkylthio 3 formyl 6 methyl pyridines, aldehydes, sodium bis(2 methoxyethoxy)aluminum hydride, reduction, malono nitrile, methyl cyanoacetate, condensation.Earlier, 1 we demonstrated that the action of lithium aluminum hydride on substituted 3 cyanopyridine 2(1H ) thiones and 2 (alkylthio) 3 cyanopyridines in boiling anhydrous ether affords the corresponding 3 aminomethyl derivatives. The use of sodium bis(2 methoxyethoxy)aluminum hydride (BMA) under analogous conditions leads to various products, depend ing on the structure of the starting reagent. For instance, pyridine 2(1H ) thiones yield aminomethyl derivatives, 3 cyano 6 methyl 2 methylthiopyridine yields azo methine, and 3 cyano 4,6 dimethyl 2 methylthiopyri dine yields a mixture of an amine, azomethine, and dipyridylmethane. 2 Apart from amines, aldehydes of the pyridine 2(1H ) thione and 2 alkylthiopyridine series are of considerable interest as building blocks in heterocyclic synthesis.BMA is known 3-7 to be used for the synthesis of not only amines but also aldehydes from both nitriles 3 and esters; 4,7 BMA is employed alone or together with sec ondary amines such as pyrrolidine, morpholine, and pip eridine. 5, 6 The goal of the present study was to develop methods of preparing aldehydes of the 2 (alkylthio)pyridine series with BMA and its complex with piperidine (BMAP) as reducing agents. Results and DiscussionWe found that the action of BMA on 3 cyano 6 me thyl 2 methylthiopyridine (1) in ether at 0 °C gives alde hyde 2a (as a mixture with the starting nitrile 1). The aldehyde content of the mixture is 50% at a nitrile : BMA ratio of 1 : 2 ( 1 H NMR data); use of more BMA leads to by products. With a milder reducing agent, BMAP, pre pared from BMA by the reaction with piperidine, 5 the yield of the target product was not increased significantly. According to the 1 H NMR data, the content of aldehyde 2a (in the mixture with the starting nitrile 1) in this case is 60% at a nitrile : BMAP ratio of 1 : 3 (Scheme 1). An increase in the amount of BMAP causes side processes to occur.With the aim of increasing the yield of the aldehyde and avoiding side processes, we used esters 3a,b (synthe sized according to known procedures 8,9 ) in the reduction instead of the corresponding nitriles.In contrast to nitrile, the reduction of ester 3a with BMA in ether at 0 °C led to 3 hydroxymethyl 6 methyl 2 methylthiopyridine (4) in 99% yield (see Scheme 1).The structure of compound 4 was confirmed by data from IR and 1 H NMR spectroscopy and mass spectro metry. Its IR spectrum contains no absorption band of the CO 2 Me group but shows a wide band of the hydroxyl group ...

show abstract

Section: Resultsmentioning

confidence: 89%

Synthesis of 2-alkylthio-6-methylpyridine-3-carbaldehydes

2005

View full text Add to dashboard Cite

show abstract

“…Although AH m has been thought to be a key intermedi- ate, 31 this result is in contrast to the prior synthesis and isolation of AH m (Figure 12), in which formation of salt waste could not be avoided. …”

Section: α Alkylation Of Ketones Initiated By Dehydrogenation Of 1 Anmentioning

confidence: 80%

“…Donepezil was obtained in 90% yield (by NMR). In the reported synthesis (Figure 12), 31,33 donepezil was available from ES m in four steps 33b using four reaction vessels and giving non negligible amounts of different salt wastes. On the other hand, we succeeded in synthesizing donepezil from ES m via multistep HT processes in a one pot operation.…”

Section: α Alkylation Of Ketones Initiated By Hydrogenation Ofmentioning

confidence: 99%

See 1 more Smart Citation

Versatile Ruthenium Complex “RuPCY” for Directed Catalytic Hydrogen Management in Organic Synthesis

Takada¹,

Iida²,

Iida³

et al. 2016

J. Synth. Org. Chem. Jpn.

View full text Add to dashboard Cite

Abstract:The ruthenium (Ru) precatalyst complex dichlorobis[2 [(dicyclohexylphosphino κ P)methyl]pyridine κ N]ruthenium(II) (RuPCY), rst developed by us, was shown to be useful not only for the catalytic hydrogenation of inert carboxylic acid derivatives including amides and esters, but also for the catalytic dehydrogenation of primary (1 ) and secondary (2 ) alcohols and subsequent reactions. RuPCY is versatile, and different Ru catalysts derived therefrom are quite useful for realizing a variety of indiscrete/discrete catalytic hydrogen management (HyMA) reactions. The sequential use of different starting materials and different catalysts (all derived from RuPCY) permits otherwise challenging orthogonal HyMA processes. This accommodates, for example, a salt free access and/or shortcut to synthetic intermediates of pharmaceutically important substances such as donepezil (Aricept ® ) and atorvastatin (Lipitor ® ).

show abstract

“…Some types of modified Red‐Al reducing agents bearing secondary amines such as morpholine, N ‐methylpiperazine, and pyrrolidine have been used for the partial reduction of esters or diesters. Among these, pyrrolidine‐modified Red‐Al was the most effective partial reducing agent for monoesters when used with potassium t ‐butoxide as an additive, which suppressed the formation of by‐products . Recently, we synthesized a new modified Red‐Al reducing agent by treating Red‐Al with cis ‐2,6‐dimethylmorpholine in the absence of any additive at room temperature, with very good‐to‐excellent yield …”

Section: Methodsmentioning

confidence: 99%