Mesylate elimination

The Pd-catalyzed elimination of the mesylate 909 at an anomeric center, although it is a saturated pseudo-halide, under mild conditions is explained by the facile oxidative addition to the mesylate C—O bond, followed by elimination of /3-hydrogen to give the enol ether 910[767],... 

Ester eliminations are normally one of two types, base catalyzed or pyrolytic. The usual choice for base catalyzed j5-elimination is a sulfonate ester, generally the tosylate or mesylate. The traditional conditions for elimination are treatment with refluxing collidine or other pyridine base, and rearrangement may occur. Alternative conditions include treatment with variously prepared aluminas, amide-metal halide-carbonate combinations, and recently, the use of DMSO either alone or in the presence of potassium -butoxide. 

The use of mesyl chloride for the dehydration of C-11 alcohols has already been mentioned, and mesylates can certainly be intermediates at least in the a-series. The preference for a coplanar trans arrangement is demonstrated by the well-known elimination reactions of tosylates of epimeric 20-alcohols (ref. 185, p. 616), although this does not restrict the usefulness of the reaction, and in some cases (sulfonates of 1 la-alcohols, for example) cw-elimination occurs (ref. 216, p. 293 ref. 224, 225, 226). 

Dimethyl sulfoxide (DMSO) has been used to effect the elimination of sulfonates at elevated temperatures (see, for example, ref. 237). Benzene-sulfonates are recommended. The elimination of a variety of sulfonates proceeds readily in this medium in the presence of potassium /-butoxide. A -Compounds have been formed at 100°, but heating is not necessary. The effects of temperature change, orientation of the hydroxy group and changes in the sulfonate employed have been examined. The principal side reaction appears to be formation of the original alcohol (uninverted), particularly with equatorial mesylates at low temperatures it is minimized with axial tosylates. 

Disulfonate esters of vicinal diols sometimes undergo reductive elimination on treatment with sodium iodide in acetone at elevated temperature and pressure (usually l(X)-200°). This reaction derived from sugar chemistry has been used occasionally with steroids, principally in the elimination of 2,3-dihy-droxysapogenin mesylates. The stereochemistry of the substituents and ring junction is important, as illustrated in the formation of the A -olefins (133) and (134). 

Mesylates and tosylates may be used as variants of the 0-sulfate ester. For instance, 55% of aziridine 7 was obtained from base-mediated cyclization of amino mesylate 6. In comparison, the classic Wenker protocol only gave 3% of 7. In another instance, A-tosyl amino alcohol 8 was tosylated to give 9, which was transformed to aziridine 10 in 64% yield, along with 29% of the P-elimination product due to the presence of the ester moiety. Likewise, aziridine 12 was assembled from tosylate 11 in two steps and 60% yield. ... 

Dioxepanes 63 were hydrolyzed with aqueous hydrochloric acid to the starting diol. A thionyl chloride promoted ring-opening of dioxepane 63 to intermediate 64 has been reported. When treated with base, compound 64 can be transformed into vinylic ether 65 in 58% yield (81ZOR1047) (Scheme 31). 3-Methylfurazan-4-acetic acid was converted to the vinyl derivative 66 via an esterification, reduction, mesylation, and base elimination sequence (81JHC1247) (Scheme 31). 

O-isopropylidene derivative (57) must exist in pyridine solution in a conformation which favors anhydro-ring formation rather than elimination. Considerable degradation occurred when the 5-iodo derivative (63) was treated with silver fluoride in pyridine (36). The products, which were isolated in small yield, were identified as thymine and l-[2-(5-methylfuryl)]-thymine (65). This same compound (65) was formed in high yield when the 5 -mesylate 64 was treated with potassium tert-hx Xy -ate in dimethyl sulfoxide (16). The formation of 65 from 63 or 64 clearly involves the rearrangement of an intermediate 2, 4 -diene. In a different approach to the problem of introducing terminal unsaturation into pento-furanoid nucleosides, Robins and co-workers (32,37) have employed mild base catalyzed E2 elimination reactions. Thus, treatment of the 5 -tosylate (59) with potassium tert-butylate in tert-butyl alcohol afforded a high yield of the 4 -ene (60) (37). This reaction may proceed via the 2,5 ... 

Dibenz[c,e]azepine (30) is obtained in excellent yield as a stable crystalline solid by base-catalyzed elimination of methylsulfinic acid from 6-mesyl-6,7-dihydro-57/-dibenz[c,e]azepine (29. R = Ms).5 An analogous reaction is noted with 6-nitro-6,7-dihydro-5//-dibenz[c,e,]azepine (29, R = N02). 

Carba-sugars of the a-L-altro and P-D-gluco modifications were prepared from 149 by way of 155. 0-Mesylation of 155 with an excess of mesyl chloride and pyridine resulted in formation of the cyclohexenealdehyde 159, accompanied by y -elimination. Reduction of 159 with sodium borohydride gave the cyclohexenemethanol 160, which is the antipode oP 141. 

In preparation for scale-up of the strigol synthesis described by Sih (8), efforts were made to improve the yield of some of the seven steps involved in the scheme. Of these steps, nine are satisfactory from the standpoint of yield and experimental conditions. For three of the steps, we have improved the yield and/or experimental conditions such that the yield of (+ )-strigol would be raised to 2.85% overall from citral rather than 1.53% based on Sih s procedure and reported yields. Improvements were developed preparation of a-cyclocitral (III), the oxidation of the hydroxyaldehyde (V) to the ketoacid (VII), and for the preparation of the hydroxybutenolide (XVII). For the remaining five steps, our attempts to change experimental conditions have failed to improve, and in most cases to even obtain, the yields reported in the literature (8). We have considered the preparation of strigol analogs and determined the conditions and limitations for the preparation of a series of alkoxybutenolides (XVI) and a butenolide dimer (XVIII). Modification of the literature procedure (11) to eliminate the use of the mesylate (XX) and the use of polar aprotic solvents gave better yields of the 2-RAS (XXI). 

With a common intermediate from the Medicinal Chemistry synthesis now in hand in enantiomerically upgraded form, optimization of the conversion to the amine was addressed, with particular emphasis on safety evaluation of the azide displacement step (Scheme 9.7). Hence, alcohol 6 was reacted with methanesul-fonyl chloride in the presence of triethylamine to afford a 95% yield of the desired mesylate as an oil. Displacement of the mesylate using sodium azide in DMF afforded azide 7 in around 85% assay yield. However, a major by-product of the reaction was found to be alkene 17, formed from an elimination pathway with concomitant formation of the hazardous hydrazoic acid. To evaluate this potential safety hazard for process scale-up, online FTIR was used to monitor the presence of hydrazoic acid in the head-space, confirming that this was indeed formed during the reaction [7]. It was also observed that the amount of hydrazoic acid in the headspace could be completely suppressed by the addition of an organic base such as diisopropylethylamine to the reaction, with the use of inorganic bases such as... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

Reaction of 3-ketoester 2-97 and acrolein 2-98 in presence of stoichiometric amounts of 2-103 led to the desired product 2-100 in 45 % yield. A transition-state model 2-99 may be postulated assuming an ion-pairing mechanism as reported for similar asymmetric transformations [37]. The diastereomeric mixture of 2-100 was transformed into 2-101 by mesylation and subsequent elimination. Despite the moderate 64% ee determined for 2-101, it was possible to obtain optically pure 2-101 by recrystallization from hexane. 

The unsubstituted quinazolidine system 5 was constructed from mesylate 173. The key feature in this synthesis is based on a cyclohydrocarbonylation of the protected 4-amino-l,6-heptadiene 169 catalyzed by Rh(acac)(CO)2-BIPHEPHOS. Formation of the hemiamidal-aldehyde 171 took place by hydroformylation of the two olefin moieties and cyclization. Elimination of water gave 172, which, after treatment with NaBFE, subsequent mesylation to 173, and catalytic hydrogenation, afforded 5 (Scheme 29) <1998TL4599>. 

Similarly, proximate-parallel bishydrazine 442 can be transferred to 443 by direct acylation with maleic anhydride. Analogous derivative 445 can be obtained from the same starting compound by treatment with methyl 3,4-epoxy-butanoate to provide 444, followed by mesylation and elimination of the intermediate mesylate (Scheme 73) <2005EJ01311>. 

Pyridopyrrolopyrimidine 156 was obtained from compound 155 by removal of the protecting group followed by elimination of the mesylate anion (Equation 8) <2001TL315, 2003JOC10020, 2003TL6191, 2004ARK74, 2004M615>. 

Methanesulfonates 844, obtained by addition of diphenyl phosphite to aldehydes At1 Cl IO and mesylation of the hydroxyl group of the adducts, react with benzotriazole to give diphenyl a-(benzotriazol-l-yl)benzylphosphonates 845. Lithiation and treatment with aldehydes Ar2CHO converts phosphonates 845 into stilbenes 846, which can eliminate benzotriazole to give diarylacetylenes 847 (Scheme 135) <2002ARK(xiii)17>. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

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]. 

A nucleophilic attack at an allene system of the type of 417 was described for the first time by Cainelli et al. [172], namely at 444 with the chloride ion as the nucleophile (Scheme 6.91). After the treatment of the mesylate 443 with triethylamine in the presence of lithium, sodium or tetrabutylammonium chloride, mixtures of the vinyl chlorides 445 and 447 were isolated in high yields. Since the reaction did not proceed in the absence of triethylamine, the first step should be a /3-elimination of methanesulfonic acid from 443 to generate 444, which would accept a chloride ion at the central allene carbon atom. A proton transfer to either allyl terminus of the anion thus formed (446) would lead to the products 445 and 447. 

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

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