Benzylic mesylate

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

Even though aliphatic mesylates are difficult to hydrogenolyze, no difficulty was encountered in the cleavage of benzylic mesylate 322 (Scheme 99). " ... 

Here the transition state, for which the degree of charge separation is estimated to be 0.7 [15], is well on the way to the fully ionised species in which the halide ion is strongly stabilised by hydrogen bonding and the cation is stabilised to some extent by coordination to the lone pair of the solvent. More recent studies by Creary [16] emphasise the dramatic effect of solvent on the rates of ionisation processes. He studied the solvolysis of a benzylic mesylate, known to occur via an ionisation mechanism (equation 12.7). 

From these results, it can be inferred that the present conditions tolerate halogen atoms attached to the aryl group of the benzyl mesylates. Of special interest is entry 11 in Table 8.7 clearly this approach tolerates the presence of a trifluoromethyl group. 

In 1992, Yus et al. reported that allylic and benzylic mesylates reacted with lithium naphthalenide to give the corresponding organolithium reagents, giving cross-coupling products upon treatment with electrophiles [35,35a]. 

Functionalized benzylic mesylates containing a halogen atom were also investigated. Reactions of the halogenated benzyl manganese mesylates with acid chlorides, aldehydes, and ketones yielded the corresponding ketone, secondary alcohol, and tertiary alcohol in good to excellent isolated yields as shown in Table 8.11. As mentioned earlier, it is of interest that the mesylates... 

Benzyl mesylate (9 mmol) was added via a syringe to the slurry of active manganese (lOmmol) being stirred in THF (10ml) at rt. The resulting mixture was stirred at rt for 20 min. The reaction was monitored by gas chromatography. 

The following is a representative procedure to a slurry of Rieke manganese (10.0 mmol) in THF (10 ml) under argon was added benzyl mesylate... 

Figure 1.23 Displacement on a benzylic chloride by aniline has a transition state with significant hydrophobic overlap of the phenyls, but there is no overlap in the transition state for displacement by phenoxide ion. Thiophenoxide ion can perform a single-electron-transfer displacement mechanism with a benzylic iodide, but not with a benzylic mesylate.

A one-pot conversion of benzyl alcohols to benzyl fluorides by treatment of the alcohols with a combination of methanesulfonyl fluoride, cesium fluoride and 18-crown 6 ether in tetrahydrofuran has been repotted The reaction involves mesylation of the alcohols followed by cleavage of the resultant mesyl esters with a fluoride ion The reaction has been extended also to certain heterocycles bearing the N hydroxymethyl group [43] (equation 31)... 

Li, catalytic naphthalene, —78°, THE, 68-99% yield. In addition, tosyl, benzyl, and mesyl amides are cleaved with excellent efficiency. 

Alkylation of the monobenzyl ether of hydroquinone 34 with mesylate 35, gives ether 36. Hydrogenolytic removal of the benzyl group gives phenol 37. This affords cicloprolol (38) when subjected to the standard alkylation scheme 17]. In much the same vein, alkylation of g-hydroxy-phenylethanol 39, obtainable from the corresponding phenylacetic acid, with epichlorohydrin... 

Intermediate 10 must now be molded into a form suitable for coupling with the anion derived from dithiane 9. To this end, a che-moselective reduction of the benzyl ester grouping in 10 with excess sodium borohydride in methanol takes place smoothly and provides primary alcohol 14. Treatment of 14 with methanesulfonyl chloride and triethylamine affords a primary mesylate which is subsequently converted into iodide 15 with sodium iodide in acetone. Exposure of 15 to tert-butyldimethylsilyl chloride and triethylamine accomplishes protection of the /Mactam nitrogen and leads to the formation of 8. Starting from L-aspartic acid (12), the overall yield of 8 is approximately 50%, and it is noteworthy that this reaction sequence can be performed on a molar scale. 

Hydrogenolysis of the C-7 benzyl ether, followed sequentially by selective triethylsilylation of the newly liberated C-7 hydroxyl and mesylation of the C-5 secondary hydroxyl, provides compound 34 in 60% overall yield (see 33—>34, Scheme 6). On the basis of Potier s studies,35 it was hoped that the C 20 hydroxyl group,... 

The objective in selecting the reaction conditions for a preparative nucleophilic substitution is to enhance the mutual reactivity of the leaving group and nucleophile so that the desired substitution occurs at a convenient rate and with minimal competition from other possible reactions. The generalized order of leaving-group reactivity RSOj" I- > BF > CF pertains for most Sw2 processes. (See Section 4.2.3 of Part A for more complete data.) Mesylates, tosylates, iodides, and bromides are all widely used in synthesis. Chlorides usually react rather slowly, except in especially reactive systems, such as allyl and benzyl. 

Glycals are also available from 2-deoxy sugars by acid- or base-induced eliminations ofanomeric substituents. These methods are limited by the availability ofthe 2-deoxy sugars, for which the glycals themselves are the most obvious synthetic precursors. However, examples of these methods (Scheme 5.43) are in the direct preparation oftri-O-benzyl-D-glucal (14) from 2-deoxy-tri-O-benzyl-D-glucopyranose (13) via its 1-O-mesylate [117], and di-O-benzyl-D-ribal (16) from the phenylselenide 15 via oxidation to the selenoxide followed by elimination [118]. 

As shown in the last section, the arene-catalyzed lithiation of mesylates has the limitation that it only proceeds for allylic and benzylic substrates. This drawback has been... 

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