2-Substituted oxetane-3-ones

A practical and efficient asymmetric synthesis of 2-substituted oxetane-3-ones 46 has been developed by Shipman and co-workers by lithiation of SAMP/RAMP hydrazones of oxetane-3-one 45, followed by interception of the putative azaenolate lithiated intermediate with a range of electrophiles that include alkyl, aUyl and benzyl halides, and an aldehyde (Scheme 13) (2013JOC12243). As for the bases, w-BuLi and <-BuLi were found to be the most suitable for the metalation step providing adducts 46 in good yields and enantioselectivities (up to 84% ee), whereas LDA was less effective. Conversion of hydrazones 46 to the enantiomerically enriched 2-substituted oxetane-3-ones 47 can be achieved without detectable racemization using aqueous oxaHc acid at room temperature. 

Commercially available lipase PS has been used to obtain kinetic resolution of racemic 4-substituted oxetan-2-ones and 3- and 3,4-disubstituted oxetan-2-ones in organic solvents <00JCS(P1)71>. The enzyme appears to be relatively insensitive to the substituents on the lactone or to the nature of the ring opened products. 

A rapid one-pot method for converting 1,3-diols into oxetanes by the intramolecular Williamson reaction has recently been described. The monolithium salt is generated by treatment of the diol with one equivalent of butyllithium in cold THF, followed by addition of one equivalent of tosyl chloride to give a monotosylate, which is cyclized by addition of a second equivalent of butyllithium (equation 83). Yields of 70-90% are reported for a variety of alkyl- and aryl-substituted oxetanes (81S550). Another simple method for converting 1,3-diols into oxetanes consists of converting them to cyclic carbonate esters by ester... 

In the present review the ring systems containing one heteroatom are considered first, except for P-lactams which are given a special section at the end. Interest in azetidines continues to be stimulated by the discovery of the potentially useful trinitro derivative. The requirements for the stereoselective synthesis of substituted oxetane are being explored and derivatives of aluminium are useful in the stereoselective routes to oxetanones. The preparation and subsequent pyrolysis of oxetanones is suggested as an alternative to the Wittig route to olefins. Stereoselective routes to thietanes and thietane 1 -oxides are mentioned. 

The chemistry of methylene-substituted 2-oxetanones, and in particular diketene, has attracted a vast amount of research over the years, so other alkylene-substituted oxetanes and oxetan-2-ones, including methylene oxetanes, are discussed separately in Section 2.05.7.4. Diketene is also known as 4-methylene-2-oxetanone and a notable difference between this and other 2-oxetanones is that it undergoes thermal decomposition by a cycloreversion reaction to give ketene, rather than forming allene and C02. CHEC-II(1996) refers to a series of comprehensive reviews of the chemistry of this compound <1996CHEC-II(1)721>. 

Hydrazone anion 957 induced ring opening of the enantiopure 4-substituted oxetan-2-ones 958 followed by cycliza-tion/dehydroamination of the resulting P-ketohydrazones 959 affords dihydropyran-4-ones 960 in good to excellent yield and enantioselectivity (Scheme 256, Table 46) <20020L1823>. 

In contrast to the 1,3-epoxides where a whole variety of substituted oxetanes have been polymerized, there is only one 1,4-epoxide of major importance. This monomer is commonly called tetrahydrofuran, but it has the systematic name 1,4-epoxybutane or tetramethylene oxide. The polymer derived from it is as often called polytetramethylene oxide as poly tetrahydrofuran. We have chosen to use the names tetrahydrofuran (THF) and polytetrahydrofuran (PTHF). An alternate abbreviation for THF that is found in some recent literature is H4furan . 

A C2-symmetric N,W-di-3,5-bis(trifluoromethyl)benzenesulfonyl-(ll ,21 )-l,2-diphenylethylenediamine 20-Et3Al complex promotes the [2-1-2] cycloaddition reaction between ketene and aldehydes to afford optically active 4-substituted oxetan-2-ones 21 (Scheme 20) [50]. The catalyst is prepared by mixing the bis-sulfonamide 20 and EtjAl, and the reaction proceeds by the coordination of the aldehyde to the chiral Lewis acid. 

Head-to-head [2+2]photocycloaddition of 1,2-diarylethanediones and 2-aminopropene nitriles (CH2 C(CN)NR2) occurs to yield oxetanes 10 in moderate to good yields. The formation of only one diastereoisomer in each of the cases investigated is rationalized in terms of the most easily accessible and stabilized 1,4-diradical intermediate <95RTC498>. 2,3,4-Trisubstituted oxetanes 11 are obtained in high yield by intramolecular nucleophilic attack of the anion from certain 2-(l-alkoxyethyl)-3-substituted oxiranes <96JOC4466>. 

High facial diastereoselectivity has been reported in the [2+2] photocycloaddition of aromatic aldehydes with a chiral enamide to give the ds-2,3-disubstituted oxetanes 11 and 12 with only minor amounts of the trans-oxetanes <99TL9003>. The same group of workers have investigated the photocycloaddition of m-substituted benzaldehydes to 3,4-dihydro-l.H-pyridin-2-ones to give mainly 13 <99JA10650>. 

FMO calculations using PM3-C1 were used to investigate the regioselectivities obtained by the photochemical reactions between 2-pyridone and pcnta-2,4-dienoate.46 The hard and soft acid-base principle has been successfully used to predict product formation in Patemo-Buchi reactions.47 The 2 + 2-photo-cycloaddition of homobenz-valene with methyl phenylglyoxylate, benzyl, benzophenone, and 1,4-benzoquinone produced the corresponding Patemo-Buchi products.48 The photo-cycloaddition of acrylonitrile to 5-substituted adamantan-2-ones produces anti- and svn-oxetanes in similar ratios irrespective of the nature of the 5-substituent49... 

An attempt to extend this approach to the preparation of the oxetan-3-one system, i.e. use of an aldehyde in place of an epoxide, failed. Instead, a 2-acyl-3-substituted-l,4-dithiepane derivative was obtained. 

The intramolecular nudeophilic substitution reaction - for example, the William-son-type reaction - represents one of the important methods for preparing oxetane ring structures, and have been widely applied to the synthesis of oxetanes (Scheme 7.1) [10]. Unfortunately, side reactions - which indude fragmentation from the intermediary alkoxide anion or elimination from the intermediary carboca-tion - often decrease the chemical yields of oxetane formation. 

There is a striking difference between the photochemical reactivity of oc,(3-unsaturated enones and the corresponding ynones. Whereas many cyclic enones undergo [2+2] cycloaddition to alkenes at the C=C double bond of the enone (probably from the triplet nn state) to yield cyclobutanes, acyclic enones easily deactivate radiationless by rotation about the central C-C single bond. Ynones on the other hand behave much more like alkyl-substituted carbonyl compounds and add to (sterically less encumberd) alkenes to yield oxetanes (Sch. 11) [38,39]. The regioselectivity of the Paterno-Biichi reaction is similar to that of aliphatic or aromatic carbonyl compounds with a preference for primary attack at the less substituted carbon atom (e.g., 41 and 42 from the reaction of but-3-in-2-one 40 with... 

The first examples of exclusive oxetane formation upon olefin photoaddition to the cyclohexen-l,4-dione 4-oxoisophorone 45, leading to two novel 2-substituted l-oxaspiro[3,5]non-5-en-7-ones 46 and 47, respectively, was reported by Catalani and coworkers (Sch. 12) [42]. They demonstrated that the chemoselectivity of the olefin-enone photochemistry... 

The diol is made into an epoxide by an intramolecular substitution reaction that is Sn2 and so goes with inversion. There are two possible rings that could form, depending on which hydroxyl group attacks, but (as you will shortly see) three-membered rings form faster than four-membered ones, and the reaction gives none of the oxetane. The other hydroxyl group can now be protected as a benzyl ether. 

The Paterno-BUchi Reaction. One well-known class of photocycloadditions is the Paterno-Buchi reaction in which aldehydes or ketones combine with alkenes to give oxetanes. The excited state of the ketone is 11-71, and it is the orbitals of this state which interact with the ground-state orbitals of the alkene. The orientation usually observed for C- and X-substituted alkenes is shown for benzophenone 8.15 and 2-methylpropene 8.16. 

---