Preparation of aliphatic 4-substituted heteroatom-containing aldehydes

Preparation of 1-methyl-4-piperidinecarboxaldehyde

The preparation of 1-methyl-4-piperidinecarboxaldehyde (3) starting from 1-methylpiperidin-4-one (1) was achieved via a new synthetic pathway. Thus, 1-methylpiperidin-4-one (1) underwent a Wittig-reaction with (methoxymethyl)triphenylphosphonium chloride in THF solution at -60 °C to yield 4-(methoxymethylene)-1-methylpiperidine (2), which was hydrolysed in acidic solution to give the aldehyde in an overall high yield (68%).

a: Ph3PCH2OCH3Cl, ButOK/THF, -60 °C; yield: 79%; b: HCl/THF; yield: 87%

This new pathway for the synthesis of 1-methyl-4-piperidinecarboxaldehyde (3) showed several advantages:
1-Methyl-4-piperidinecarboxaldehyde (3) is not too stable a compound once isolated and therefore cannot be stored for long periods of time, but 4-(methoxymethylene)-1-methylpiperidine (2) is sufficiently stable not to decompose upon storage in a freezer for a long time. Furthermore, it was easily possible to produce 4-(methoxymethylene)-1-methylpiperidine (2) on a reasonable scale (20-25 g).

Preparation of 4-Formyl-1-piperidinecarboxylic acid 1,1-dimethylethylester

4-Formyl-1-piperidinecarboxylic acid 1,1-dimethylethylester (7) was prepared via a pathway according to patent literature [1] as outlined below.

a: Di-tert-butyl dicarbonate, 1 M NaOH/THF; yield: quantitative; b: Ph3PCH2OCH3Cl, ButOK/THF, -60 °C; yield: 88%; c: HCl/THF; yield: 77%

Preparation of 2H-Tetrahydrothiopyran-4-carboxaldehyde

For the synthesis of 2H-tetrahydrothiopyran-4-carboxaldehyde (10) two new synthetic methods were developed. Utilizing 4H-tetrahydrothiopyran-4-one (8) as starting product 2H-tetrahydrothiopyran-4-carboxaldehyde (10) was approached by the Lewis acid promoted ring-opening of 1-oxa-6-thiaspiro[2.5]octane (9) [2].

a: (CH3)3SOJ, NaH/DMSO; yield: 77%
b: I. Electrochemical conversion: LiClO4/CH2Cl2, THF, 12 V, 0 °C, Pt-anode, Ni-cathode; yield: 78%;
II. LiJ/THF; yield: 40%

Various commonly used Lewis acids do not yield the desired product, only after detailed experimental studies could appropriate reaction conditions be developed.

I. Electrochemical conversion [3]
Stirring the oxirane in a preelectrolysed solution of lithium perchlorate in a mixture of methylenechloride/THF (5 h electrolysis at 12 V and 0 °C, Pt-anode, Ni-cathode) at room temp. gave the desired product in excellent yield (78%). A major disadvantage of this method is the limiting factor of the apparatus only allowing small-scale experiments.

II. Rearrangement with lithium iodide in THF
Lithium iodide, highly concentrated and used in a large excess in THF, turned out to be the only Lewis type salt to promote the rearrangement of 1-oxa-6-thiaspiro[2.5]octane (9) to 2H-tetrahydrothiopyran-4-carboxaldehyde (10) in reasonable yield (40%).

Preparation of 2H-Tetrahydropyran-4-carboxaldehyde

A different synthetic approach was set towards the preparation of 2H-tetrahydropyran-4-carboxaldehyde (14) [4] as in this case no ketone was used as starting material, but 4H-tetrahydropyran-4,4-dicarboxylic acid diethylester (11), readily available from di(2-chloroethyl) ether and malonic acid diethylester. By saponification and decarboxylation of 4H-tetrahydropyran-4,4-dicarboxylic acid diethylester (11) - without isolation of the intermediate 4H-tetrahydropyran-4,4-dicarboxylic acid - 2H-tetrahydropyran-4-carboxylic acid (12) was prepared, which was then reduced to 2H-tetrahydropyran-4-methanol (13). By subsequent Swern oxidation 2H-tetrahydropyran-4-carboxaldehyde (14) was made available.

a: NaOEt/EtOH; yield: 62%; b: 6 M HCl; yield: 80%; c: LiAlH4/THF; yield: 70%; d: (COCl)2, DMSO, Et3N/CH2Cl2, -60 °C; yield: 70%

Reaction steps a-d were performed by analogy with ref. 4a-d with partial modifications.