5- -oxazolidone

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

An alternative route involves the reaction of 1,2-epoxides with isocyanates to yield poly-2-oxazolidones (Figure 27.12). 

These reactions are reversible by changing the system temperature. ME A also reacts with carbonyl sulfide (COS) and carbon disulfide (CSi) to form heat-stable salts that cannot be regenerated. At temperatures above 245°F a side reaction with CO2 exists that produces oxazolidone-2. a heat-stable salt, and consumes MEA from the process. 

The normal regeneration temperature in the still will not regenerate heat-stable salts or oxazolidone-2. Therefore, a reclaimer is usually included to remove these contaminants. A side stream of from 1 to 3% of the MEA circulation is drawn from the bottom of the stripping column, This stream is then heated to boil the water and MEA overhead while the heat-stable salts and oxazolidone-2 are retained in the reclaimer. The reclaimer is periodically shut in and the collected contaminants are cleaned out and removed from the system. However, any MEA bonded to them is also lost. 

A reclaimer is also required to remove oxazolidones produced in a sule reaction of DIPA and CO2. 

Ingham describes two by-products isolated in these reactions, (a) arylene-mandeloamides (8) formed in the presence of water and (b) diazines (11) resulting from dimerization of the chloroimine. Reconsideration by Comforth and Comforth demonstrated that reaction of 5 with water actually produces oxazolidone 9/... 

In 1949, Comforth showed that preparation of 2,5-disubstituted oxazoles was not limited to diaryloxazoles through condensation of aldehydes (benzaldehyde, n-hept-aldehyde) with a-hydroxy-amides (lactamide). The intermediate oxazolidone 13 were converted into oxazoles 14 on warming with phosphoryl chloride. ... 

In a scheme intended to produce a more highly substituted oxazolidone, epichlorohydrin is condensed with morpholine in the presence of strong base to give the aminoepoxide, 27. Ring opening of the oxirane by means of hydrazine gives the hydroxy-hydrazine (28). Ring closure with diethyl carbonate leads to the substituted oxazolidone (29). Condensation with 18 affords furaltadone (30). ... 

The reaction mixture is then warmed on the steam bath for an additional two hours (90°C to 95°C). The excess hydrazine hydrate is removed in vacuo. The residue of viscous 1-hy-drazlno-3-morpholinyl-2-propanol Is not distilled, but is mixed with 10.16 g (0.0B6 mol) diethyl carbonate and a solution of 0.3 g sodium metal in 15 ml methyl alcohol. The mixture is refluxed about 2 hours under a 15 cm Widmer column, the alcohol being removed leaving a thick, green liquid residue, which is cooled and the precipitate which forms is removed by filtration and washed well with ether. Yield B2%, MP114°C to 116°C. Recrystallization from isopropanol gives purified 3-amino-5-(N-morpholinyl)-methyl-2-oxazolidone, MP 120°C as the intermediate. 

N-(Benzvlidene)-3-amino-2-oxazolidone 5-Nitro-2-furaldehyde diacetate... 

In 212 cc of water are mixed 21.2 grams (0.112 mol) of N-(benzylidene)-3-amino-2-oxa-zolidone, 8.93 grams of concentrated sulfuric acid, and 30.1 grams (0.124 mol) of 5-ni-tro-2-furaldehyde diacetate. This mixture is heated to effect the hydrolysis of N-(benzy-lidene)-3-amino-2-oxazolidone, steam distillation of the benzaldehyde and hydrolysis of 5-nitro-2-furaldehyde diacetate. Approximately IV2 hours are required for this reaction to take place. When the bulk of the benzaldehyde has been removed, 50 cc of 99% isopropanol are added, the reaction mixture is refluxed a short time, and the crystals of N-(5-nitro-2-furfurylidene)-3-amino-2-oxazolidone are filtered from the hot suspension. The product is washed with water and isopropanol and dried a yield of 23.3 grams, 92.8% based on N-(benzylidene)-3-amino-2-oxazolidone of MP 254° to 256°C is obtained, according to U.S. Patent 2,759,931. 

A mixture of 24.1 g (0.10 mol) of 3-o-methoxyphenoxy-2-hydroxy-1 -propyl carbamate and 6.0 g (0.10 mol) of urea was heated rapidly to the temperature range of 180°C to 200°C, and maintained there for five hours. The reaction melt was poured into 50% ethyl alcohol, from which the product crystallized as a white solid. The crude yield was 18.3 g (82%) melting point 131.5°C to 137 t. Crystallization from water and 95% alcohol gave 9.0 g (40.3%) of pure 5-o-methoxyphenoxymethyl-2-oxazolidone melting point 141°Cto 143. This melting point was not depressed when the material was mixed with an authentic sample. In additional runs acetone was used Instead of ethyl alcohol with equivalent results. 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

One of the first reports involving vinyl diazonium ions and possible vinyl cations is the work of Newman and co-workers (107) on the alkaline decomposition of 3-nitroso-2-oxazolidones, 132. When an aqueous suspension or... 

Scheme VIII. Alkaline Decomposition of 3-Nitroso-2-oxazolidones.

More recently, such vinyl cations generated by the alkaline decomposition of 3-nitroso-2-oxazolidones have been trapped by halogens to give vinyl halides as products (108). It has been suggested that unsaturated carbenes, RjC=C , may be the intermediates in the basic decomposition of 132 (109). Indeed, when 132 (Ri=R2=CH3, R3=H) was treated with lithium ethoxide in the... 

An alternative sequence utilized 2-oxazolidone, which was readily synthesized from urea and ethanolamine, as the glycine equivalent. Subsequent treatment with phosphorous acid and formaldehyde produced iV-phosphonomethyl-2-oxazolidone 12 (16). Upon hydrolysis, and loss of CO2,12 provided the related derivative, iV-phosphonomethylethanolamine 13, which was oxidized at high temperature with a variety of metal catalysts including cadmium oxide (16) or Raney copper (17) to give GLYH3, after acidification. A similar oxidation route has also been reported starting from iV-phosphonomethy 1-morpholine (18). 

For carboxyl terminal determination of peptides by means of CDI the terminal carboxylic acid group of the peptide is selectively reduced with sodium dihydrobis(2-methoxy-ethoxy)aluminate to an alcohol. Subsequent conversion of the amino alcohol moiety with CDI yields an 7V-acyl-2-oxazolidone derivative, from which the oxazolidone unit can be easily removed and characterized.[56]... 

Optical induction emanating from a chiral diazoacetamide is apparently not much higher. The 2-phenylcyclopropanecarboxylates cis-222 and trans-222, obtained in low yield from (N-diazoacetyl)oxazolidones 220,221 and styrene in the presence of Rh2(OAe)4 followed by ethanolysis, showed only small enantiomeric excesses 215). Starting with either diazo compound, the (1/ ) enantiomer was predominant in both cis- and trans-222. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Oxazolidones as Chiral Auxiliaries Chiral Auxiliary-Mediated Aldol-Type Reactions... 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

Usually, (Z)-boron enolates can be prepared by treating /V-acyl oxazolidones with di-K-butylboron triflate and triethylamine in CH2CI2 at 78°C, and the enolate then prepared can easily undergo aldol reaction at this temperature to give a, vy -aldol product with more than 99% diastereoselectivity (Scheme 3-4). In this example, the boron counterion plays an important role in the stereoselective aldol reaction. Triethylamine is more effective than di-wo-propylethyl amine in the enolization step. Changing boron to lithium leads to a drop in stereoselectivity. 

The stereoselectivity probably results from bidentate chelation of the metal (such as boron) with the oxazolidone carbonyl and the enolate oxygen via a chair-type transition state 9 (Scheme 3-4).la 9... 

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