Oxetanes preparing methods

This is one of the few methods available for the direct and efficient conversion of an acid, via the acid chloride, to an ortho ester. The preparation of the oxetane is straightforward, and a large number of oxetanes have been prepared [triol, (EtO)2CO, KOH]." In addition, the -butyl analogue has been used for the protection of acids. During the course of a borane reduction, the ortho ester was reduced to form a ketal. This was attributed to an intramolecular delivery of the hydride. ... 

Photocycloaddition of Alkenes and Dienes. Photochemical cycloadditions provide a method that is often complementary to thermal cycloadditions with regard to the types of compounds that can be prepared. The theoretical basis for this complementary relationship between thermal and photochemical modes of reaction lies in orbital symmetry relationships, as discussed in Chapter 10 of Part A. The reaction types permitted by photochemical excitation that are particularly useful for synthesis are [2 + 2] additions between two carbon-carbon double bonds and [2+2] additions of alkenes and carbonyl groups to form oxetanes. Photochemical cycloadditions are often not concerted processes because in many cases the reactive excited state is a triplet. The initial adduct is a triplet 1,4-diradical that must undergo spin inversion before product formation is complete. Stereospecificity is lost if the intermediate 1,4-diradical undergoes bond rotation faster than ring closure. 

Photocycloaddition of thiones to alkenes is the most popular and fruitful method for the preparation of the thietane system. In analogy to the formation of the oxetanes by cycloaddition of the electronic excited ( ,tc ) carbonyls, thietanes can be expected to arise photochemically from aromatic thioketones and substituted olefins as well as 1,2- and 1,3-dienes. ° Thiobenzophenone serves as a source of a sulfur atom and, because of its blue color, which disappears on photocycloaddition, permits exact control over the reaction time. A mixture of thiobenzophenone and a-phellandrene must be irradiated for 70 hr before the blue color disappears (Eq. 2) and... 

In the years since these reviews were written the usefulness of the photocycloaddition reaction for the preparation of oxetanes has certainly been demonstrated. The yields can be high, sometimes nearly quantitative, and the starting materials are readily available. Photocycloaddition is frequently the method of choice for the preparation of oxetanes since they can be difficult to prepare by more classical methods. 

The conditions for the photocycloaddition (discussed in detail in a later section of this review) can be relatively mild. There is usually a small probability of the oxetane being destroyed in dark reactions which would probably preclude isolation after preparation by any method. One mode of decomposition of oxetanes is fragmentation, either back to the starting materials or to the other possible carbonyl compound and olefin. For example, the oxetane from 4,4 -dimethoxybenzophenone and isobutylene forms readily and is easily detected and characterized by infrared and NMR spectroscopy. All efforts to purify it, however, have led to its decomposition into formaldehyde and the diarylethy-lene.17 37 In some cases, as with fluorenone and isobutylene37 or 2-methyl-2-butene,25b the oxetane is apparently too unstable for detection, but the presence of the olefin 96 attests to its formation. 

There are a wide variety of other synthetic methods for the preparation of oxetanes however, most of these are not very general. They frequently require starting materials which are difficult to prepare, and rarely give high yields (never as high as the better photochemical preparations). It is clear then that in comparison with the alternative methods of oxetane synthesis, the photocycloaddition reaction is more generally useful and convenient. This synthetic utility justifies a brief description of experimental conditions. 

Previous general reviews of oxetanes and of 2-oxetanones were published in 1964 (64HC(19-2)983, 64HC( 19-2)729), covering the literature to about 1962. Additional surveys of methods of preparation and reactions of these classes of compounds were published in 1963 and 1965 <63HOU(6/2)511, 65HOU(6/3)489>. 

In a new method of ring enlargement of oxiranes to oxetanes, the intramolecular Williamson reaction is the essential last step. Reaction of an oxirane with selenomethyl-lithium reagents, followed by bromination, gives y-bromo alcohols, which can be cyclized by base to oxetanes. Since the oxiranes can be prepared readily from ketones and the selenomethyllithium reagent, this is also a synthesis of oxetanes from ketones (80TL585). 

Appropriately substituted diazo ketones have been converted into oxetanes in two instances by Wolf rearrangement processes. The structure of compound (52) was established by X-ray crystallography (69MI51300, 81CSC345). Reaction of 4,4-dibromo-2,2,5,5-tetramethyltetrahydro-3-furanone with aqueous base is a good method of preparation for 3-hydroxy-2,2,4,4-tetramethyloxetane-3-carboxylic acid (equation 90) (66JA1242). 

Diones are normally synthesized from /3-hydroxy acids in two steps first, conversion into carbamates by reaction with sodium cyanate, and then cyclization with thionyl chloride (Scheme 103) (54JCS839). Alternative preparations utilize oxetanes, which may be combined either with isocyanates in the presence of boron trifluoride (68JAP6808278) or with S-alkylthioureas (Scheme 104) (69ZOR1844). In the last example the initial products are imines (224) which may readily be hydrolyzed to the required diones. Similar methods can be applied to the synthesis of tetrahydro-l,3-thiazine-2,4-diones, and, for instance, the 4-oxo-2-thioxo derivative (225) is obtained from /3-propiolactone and dithiocarbamic acid (Scheme 105) (48JA1001). 

Dehydrofluorination using potassium hydroxide is a method for preparing unsaturated heterocyclic compounds. 3,4-Difluoro-2,2-bis(trifluoromcthyl)oxetane (1) with potassium hydroxide gives 3-fluoro-2,2-bis(trifluoromethyl)-2//-oxete (2).144... 

Analogues of 70 have been prepared by various methods including nucleophilic displacement of triflate esters attached directly to the oxetane ring (see Section 2.05.7.2) <2001TL4247>, from xylose, 145, via the benzyl-idene-protected oxetane, 146 (Scheme 24) <2004TA2667>, or from L-rhamnose, 147, via a l,4-lactone-2-O-triflate, 148 (and key oxetane 149 (Scheme 25)) <2004TA2681>. The /3-azidoester monomers formed by these methods were converted to the /3-amino acids and subsequently to /3-peptides by reduction of the azide and ester hydrolysis. 

All of these findings clearly indicate that the demand for synthetic oxetanes is high. There are basically three methods for preparing oxetanes ... 

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. 

The standard method for preparing OBO derivatives was perfected by Corey and Raju.223 Reaction of an acid chloride with 3-methyl-3-oxetanemethanol231 followed by treatment of the resultant oxetane ester with trifluoroborane ethe-rate secures the OBO ester in good yield as illustrated in Scheme 2.110.232... 

A single step method for preparing other Step 4 perfluoroalkoxy-oxetane derivatives is illustrated in Fq. 1 and discussed (1). 

Other methods for preparing perfluoroalkyl- and perfluoroalkoxy oxetanes intermediates and derivatives of the current invention are described (3,4). 

A general method has been elaborated for the synthesis of oxetanes from oxiranes by means of carbene insertion, with an a-selenoalkyllithium reagent that has also been utilized for the regioselective preparation of the oxirane itself from a carbonyl compound (Eq. 185). ... 

A more practical method relies on the preparation of oxetane-3-ol and its subsequent oxidation to give oxetan-3-one (Scheme 13.3). " ° This procedure suffers from the necessity to use Pyridinium chlorochromate (PCC) for oxidation of oxetane-3-ol, because separation of oxetan-3-one from the reaction by-products could only be effected by preparative gas chromatography (GC). It was furthermore reported that other oxidizing conditions failed for this substrate. Having to rely on... 

By far the most important method of preparation of fluorinated oxetanes is [2 + 2] cycloaddition that can either be photoinitiated (Paterno-Buchi reaction) or result from electrophilic condensation. 

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