What is N-(tert-Butoxycarbonyl)-4-piperidone?

What is N-(tert-Butoxycarbonyl)-4-piperidone? 

N-(tert-Butoxycarbonyl)-4-piperidone is also known as N-boc-4-piperidone, where boc is short for t-Butyloxy carbonyl. Also, boc is often adopted as a protecting group in organic synthesis.1 N-boc-4-piperidone is the derivative of 4-piperidone and is an important pharmaceutical intermediate. N-boc-4-piperidone can be used to synthesize angiotensin-converting enzyme inhibitor (ACEI) (Trandolapril), anti-AIDS protease inhibitor indinavir (Indinavir), etc. The drugs synthesized by it can also treat degenerative diseases, certain cancers and diseases caused by viral, fungi, bacterial infections, etc. 2

Fig 1. Chemical structure formula of N-(tert-Butoxycarbonyl)-4-piperidone

N-boc-4-piperidone can be synthesized by various methods, such as:

➀ 4-Piperidone hydrate hydrochloride/H2O solution was added with sodium hydroxide, di-tert-butyl dicarbonate, and THF. After 16 h of stirring at ambient temperature, the reaction mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give N-Boc-4-piperidone as a white solid in quantitative yield (100%).3

➁ Oxidation of 1-Boc-4-hydroxypiperidine under the catalysis of (N‐heterocyclic carbene)–Ni0 system in 2,4-dichlorotoluene at room temperature for 30 min with a yield of 95%.4

N-boc-4-piperidone can be used in many reactions, and some of them are listed as follows5, 6

➀ Synthesis of bispidines through double Mannich reaction then Wolff-Kishner-style reduction.7

➁ Synthesis of human and rat P2X7 activities for amine-substituted adamantylmethylaminebenzamides by a lithiation approach followed by addition to N-boc-4-piperidone, acid-catalyzed dehydration, and selective hydrogenation of the resulting olefin.8

➂ Synthesis of phosphates (as Scheme 1 shown) in good yield from the potassium enolates of N-boc-4-piperidone.9

Scheme 1. Reagents and conditions: (i) 1, ClP(O)(OR)2 (1.2 equiv), HMPA (1.4 equiv), KHMDS (1.3 equiv), THF, -78 oC, 2 h.

➄ The ring expansion of N-Boc-4-piperidone (Scheme 2), which had been reported previously as having shown dangerous accumulation, exothermicity and gas evolution when conducted in diethyl ether or DCM/MTBE. This was followed by a warning that the reaction should not be attempted at a scale of more than 1 kg in batch mode for safety reasons. 

Scheme 2. Ring expansion reaction of N-Boc-4-piperidone