Lithium Naphthalenide Induced Reductive Selenenylation of α-Cyano Ketones: A Regiocontrolled Process for α-Phenylseleno Ketones and One-Pot Conversion into Enone System

Abstract

An efficient procedure for the regiocontrolled synthesis of a-phenylseleno ketones has been developed, making use of the lithium naphthalenide induced reductive selenenylation of the a-cyano ketone system as a key operation. Moreover, seleno ketones thus generated in situ, upon subsequent treatment with hydrogen peroxide and acetic acid, could be further converted into the corresponding enones with a high degree of regioselectivity, presumably due to the lithium salt mediated selenoxide syn-elimination process.a-Phenylseleno ketones are of great importance in synthetic chemistry where they are commonly used as the substrates for preparation of a,b-unsaturated ketones 1 or the intermediates for synthesizing polycyclic compounds via a free-radical cyclization process. 2 In addition to their synthetic versatility, a specific series of a-phenylseleno ketones as reported by Cotgreave et al. 3 has been shown to possess glutathione peroxidase-like biological properties, indicating that a-phenylseleno ketones might have potential to serve as anticancer, antiviral and anti-inflammatory agents, 4 and/or as the selenium source of selenoproteins, which are essential for human immune system and known to play a critical role in reducing the incidence of a wide variety of cancers, particularly that of the prostate. 5,6 While a number of procedures are accessible to provide aphenylseleno ketones, an efficient control over the regioselectivity remains problematic for unsymmetrical ketones with the a and a¢ carbons to a ketone carbonyl equally susceptible to selenenylation. 7-11 Herein, we wish to report that a convenient synthetic method, making use of the lithium naphthalenide (LN) 12 induced reductive selenenylation of a-cyano ketones as a key operation, has been developed to facilitate the formation of the corresponding a-phenylseleno ketones with complete regioselectivity. It was found that a-cyano ketones could be readily reduced with LN under mild conditions (-40°C) to give the corresponding ketone enolates. 13 When the reduction was followed by the addition of a phenylselenenylating agent, a-selenenylation was effected, resulting in the specific replacement of the cyano group with a phenylseleno group. A typical experiment is depicted in Scheme 1. 14 However, it is noteworthy that among several phenylselenenylating agents investigated, phenylselenyl bromide is superior to its counterparts such as phenylselenyl chloride (65% yield) and diphenyl diselenide (52% yield) in offering compound 2. Scheme 1This reductive selenenylation process proved to be general as outlined in Table 1. In all cases examined, the reactions proceeded smoothly and the desired products were obtained in synthetically useful yields (75-92%). Substrates 1 and 3-9 are prepared by alkylation of the corresponding a-cyano ketones using an appropriate alkylating agent and lithium hydride (LiH) in THF at room temperature for 24 hours, which are readily accessible via the Thorpe-Ziegler reaction, 15 the base-induced rearrangement of isoxazoles 16 or the a-cya...

Lithium Naphthalenide

“…Moreover, a-phenylseleno thus formed without isolation upon subsequent treatment with hydrogen peroxide and acetic acid, could be further converted into the corresponding a,b-unsaturated ketones with high regioselectivity. 13 (D) Reductive Cleavage of a,b-Epoxy Ketones: LN is also used as a mild and efficient reagent for the reductive of a,b-epoxy ketones to give the corresponding b-hydroxy ketones. 14 (E) Reductive Elimination of Epoxy Mesylates: Wu et al have found that LN can serve as a mild reducing agent for reductive elimination of epoxy mesylates into the transpositioned allylic alcohol.…”

α-Activated Cross Conjugated Cycloalkenone Systems in Organic Synthesis

“…In principle, the corresponding -phenylseleno alkenones could also serve as effective dienophiles for Diels-Alder reaction [24], providing facile access to -phenylseleno ketones, which might be useful in the preparation of various , -unsaturated cyclic ketones or have potential to serve as anti-cancer and anti-inflammatory agents [25]. Initial attempts to carry out Diels-Alder reactions with these dienophiles under thermal conditions were fruitless.…”

Efficient Preparation of α,α-Dialkyl-α-(phenylselanyl)acetates and α,β-Unsaturated Esters from the Corresponding α,α-Dialkyl-α-cyanoacetates by a Lithium Naphthalenide Induced Reductive Selenenylation Process

“…7 We have been working on devising more powerful and versatile methods for the preparation of a-(phenylselanyl) carbonyl compounds, and have recently reported a highly efficient procedure for the preparation of a-(phenylselanyl) ketones from the corresponding a-cyano ketones. 8 Our approach is based on the reductive decyanation of acyano ketones: reduction with lithium naphthalenide (LN) is followed by the rapid one-pot selenenylation of the resulting enolates with phenylselenenyl bromide (PhSeBr); this gives the corresponding a-(phenylselanyl) ketones with the overall replacement of the cyano group by a phenylselanyl group. Through this protocol, a great variety of a-cyano ketones have been efficiently converted into the corresponding a-(phenylselanyl) ketones with complete control over the regiochemistry.…”

“…Our recent studies on some addition and cyclization reactions involving carbon-centered radicals resulting from C-Se bond cleavage required the efficient generation of highly substituted a-(phenylselanyl)acetates with a broad structural diversity. On the basis of our previous experiences, 8 we envisaged that a process involving the reductive selenenylation of a-cyano esters might lead to an attractive method. Our strategy consisted of first introducing the selected alkyl groups to the a-position of cyanoacetate 6, to provide a,a-dialkyl-a-cyanoacetates 7 (Scheme 2), which would then be subjected to reductive selenenylation, thus giving the desired products 1 by intentional control of the substitutions at the quaternary carbon center (Scheme 2).…”