2-Oxazolines 3-hydroxy amides

Oxazolines Hydroxy amides, prepared from p-hydroxy amines and acid chlorides, are converted into 2-oxazolines with the Mitsunobu reagent at 0 25° (equation I). 

TABLE 8.3. OXAZOLINES EROM PRIMARY 3-HYDROXY AMIDES AND SOCI2... 

For secondary (3-hydroxy amides, the ring closure occurs via an Sn2 mechanism with complete inversion at carbon bearing the hydroxyl group. Thus, both cis- and trans-4,5-disubstituted oxazolines can usually be obtained reliably. Representative examples are shown in Table... 

TABLE 8.4. OXAZOLINES FROM SECONDARY AND TERTIARY p-HYDROXY AMIDES AND SOCI,... 

The reaction of the p-hydroxy amides with SOCI2 can be solvent sensitive. For example, during the semisynthesis of pachtaxel from baccatin 111, the reaction of hydroxybenzamide 16 with SOCI2 in benzene gave a mixture of isomeric 2-oxo-1,2,3-oxathiazohdines 17a and 17b together with a small amount of the trans-oxazoline 18a. If a polar solvent is used, 18a is formed as the exclusive product. ... 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

Phosphorous oxychloride (POCI3) can also be used without further activation. For the synthesis of the antidepressant (/ )-(—)-rolipram 24, cyclization of the (3-hydroxy amide 21 with POCI3 gave the oxazoline intermediate 22. Diastereo-selective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (/ )-( )-rolipram (Scheme 8.11). 

Secondary and tertiary (3-hydroxy amides can be cyclized to oxazolines in the presence of strong acids such as methanesulfonic acid or p-toluenesulfonic acid. For tertiary (3-hydroxy amides, elimination to the enamide can often be a competing... 

TABLE 8.5. OXAZOLINES FROM P-HYDROXY AMIDES USING VILSMEIER REAGENT"... 

Deprotection of urethane-protected tertiary (3-hydroxy amides 37 with trifluoro-acetic acid followed by spontaneous cyclization of the liberated hydroxy amide affords oxazolines 38. The rate of deprotection is further accelerated by the addition of CaCl2. Examples are shown in Table 8.6 (Fig. 8.4 Scheme 8.15). 

TABLE 8.6. OXAZOLINES FROM URETHANE-PROTECTED TERTIARY P-HYDROXY AMIDES"... 

Conversion of the hydroxyl group of a p-hydroxy amide to a mesylate, triilate, ° ° or an acetate ° ° followed by intramolecular displacement of the leaving group is a commonly employed strategy for oxazoline formation. Some examples from the recent literature are hsted in Table Oxazolines... 

Burgess reagent has also been used to effect cyclodehydration of p-hydroxy amides to oxazolines. Representative examples are shown in Table The advantage of this reagent is that the cyclodehydration is performed under essentially neutral and mild conditions, typically in THF at room temperamre or reflux. 

The Mitsunobu reaction has also been applied successfully for the preparation of oxazolines from p-hydroxy amides. This method provides an alternative to the Burgess reagent. Some recent examples are listed in Table... 

TABLE 8.10. OXAZOLINES VIA THE MITSUNOBU REACTION OF P-HYDROXY AMIDES... 

TABLE 8.12. OXAZOLINES EROM P-HYDROXY AMIDES USING DAST... 

Hydroxy amides undergo cyclodehydration to oxazolines under very mUd conditions with triphenylphosphine and carbon tetrachloride. Carbon tetrabromide can also be used. The formation of the corresponding p-chloro amide is generally not a significant problem. The major disadvantage is that removal of the byproduct triphenylphosphine oxide may be difficult at times. Representative examples are shown in Table 8.14 (Fig. 8.5).n4,i4o,i73-i8i... 

TABLE 8.14. OXAZOLINES EROM HYDROXY AMIDES USING TRIPHENYLPHOSPHINE AND CARBON TETRACHLORIDE... 

The preparation of oxazolines from p-hydroxy amides and SOCI2 via the corresponding p-chloro amides under basic conditions is well known and has been discussed earlier. Potassium fluoride on alumina has been reported as a mild alternative to the aqueous or alcoholic bases that are commonly used. The reaction is typically carried out in acetonitrile or tetramethylene sulfone and moderate to good yields of oxazolines and oxazines can be obtained as shown in Scheme 8.29. 

Hydrolysis is undoubtedly the most common nucleophilic reaction at the 2-position. It is generally used to unmask the hydroxy amide or amino alcohol after synthetic manipulations on the oxazoline ring are completed. Hydrolysis under... 

Strongly acidic conditions gives the amino alcohol. However, the reaction can be stopped at an intermediate stage if it is carried out under mild conditions. For example, the initially formed amino ester can be isolated or trapped in certain cases although it is more commonly rearranged to the hydroxy amide, typically under mildly basic conditions (Schemes 8.88 and 8.89). The configuration of the oxazoline at the 4 and 5-positions is normally retained under the hydrolysis... 

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24 Scheme It is noteworthy that a solution of the amino... 

TABLE 8.2 OXAZOLINES FROM CARBOXYLIC ESTERS AND AMINO ALCOHOLS, 337 TABLE 8.3 OXAZOLINES FROM PRIMARY p-HYDROXY AMIDES AND SOCI2, 340-344... 

TABLE 8.5 OXAZOLINES FROM p-HYDROXY AMIDES USING VILSMEIER REAGENT, 348... 

N-(/3-hydroxy)amides are cyclized with DIPCD in the presence of a catalytic amount of Cu(OTf)2 to give 2-oxazolines. Similarly, N-(2-hydroxyethyl)thioamides and N-(2-hydroxyethyl)thioureas are converted with DCC in refluxing acetonitrile to give 2-oxazolines in 88-94% yield." Benzo-fused heterocycles 465 ( = 0,1,2) are obtained from the thiourea derivatives 464 and DCC (Yields 81-92%)... 

Crosignani et al. [16] synthesized the 2-oxazolines (ix) in high yields from the cyclization of N-(/i-hydroxy)amides (viii) by diisopropylcarbodiimide (DIC) under microwave irradiation. 

Addition of diethyl aluminum chloride at — 78 °C to a,/ -unsaturated oxazolidinone (154) affords an aluminum enolate that, on hydroxylation with (63a), gives the / -ethyl-a-hydroxy amide (155) with high anti selectivity (Equation (38)) <91AG(E)694>. Formation of the enolate of oxazoline thiol ester (156) under chelation (NaHMDS) and stereoelectronic (NaHMDS/HMPA) control gives the syn and anti alcohols (157), respectively, on hydroxylation with (63a) in good to excellent yield and better than 95% diastereoselectivity (Scheme 28) <93JOC6180>. A counterion dependent reversal in stereochemistry has also been reported for the hydroxylation of chiral amide enolates where the auxiliary was 2-pyrrolidinemethanol <85TL3539>. 

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