Bromides, preparation from sulfonates

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

Ethers. In the presence of anhydrous agents such as ferric chloride (88), hydrogen bromide, and acid chlorides, ethers react to form esters (see Ethers). Esters can also be prepared from ethers by an oxidative process (89). With mixed sulfonic—carboxyhc anhydrides, ethers are converted to a mixture of the corresponding carboxylate and sulfonate esters (90) ... 

Metal halide salts other than sodium iodide have been used sparsely to prepare halodeoxy sugars from sulfonate esters. Lithium chloride (107) and lithium bromide (33) have found limited application. Potassium fluoride (dihydrate) in absolute methanol has been used (51, 52) to introduce fluorine atoms in terminal positions of various D-glucose derivatives. The reaction is conducted in sealed tube systems and requires... 

The method described here is a modification of that of Schoeller.1 Diphenyl selenide has also been prepared from diazotized aniline and alkali monoselenides 2 by the Friedel-Crafts reaction with benzene and selenium tetrachloride3 or selenium dioxide 4 from diphenyl sulfone and selenium 5 from phenylmagnesium bromide and selenium,6 selenium dichloride,7... 

This reaction, parallel with 10-77, is the standard method for the preparation of sulfonyl halides. Also used are PCI3 and SOCI2, and sulfonic acid salts can also serve as substrates. Sulfonyl bromides and iodides have been prepared from sulfonyl hydrazides (ArS02NHNH2, themselves prepared by 10-126) by treatment with bromine or iodine.Sulfonyl fluorides are generally prepared from the chlorides, by halogen exchange. 

The second cycloaddition substrate took to form of 91 (Scheme 1.9b), incorporating a vinyl sulfone dipolarophile. Beginning with cyano ketone 84, which was readily prepared from 1,5-dicyanopentane via a previously reported three-step sequence [45], condensation with thiophenol produced vinyl sulfide 85 in 84 % yield. Vinyl sulfide 85 underwent bromination in acetonitrile to afford bromo-vinyl sulfide 86 (86 %), which was then treated with isopropylmagnesium chloride [46] to effect metal-halogen exchange affording an intermediate vinyl magnesium bromide species. Subsequent alkylation with Mel in the presence of catalytic CuCN provided the alkylated vinyl sulfide 87 in 93 % yield. The nitrile within vinyl... 

In the original patent published by Merck in 1995, rofecoxib (2) was synthesized in three steps from the known 4-(methylthio)acetophenone (10), prepared from the Friedel-Crafts acylation of thioanisole. As depicted in Scheme 2, oxidation of sulfide 10 using an excess of magnesium monoperoxyphthalate hexahydrate (MMPP, an inexpensive, safe and commercially available surrogate for w-CPBA) gave rise to sulfone 11, which was subsequently brominated with bromine and AICI3 to afford 2-bromo-l-(4-(methylsulfonyl)phenyl)ethanone (12). After recrystallization from 1 1 EtOAc/hexane, the pure phenylacyl bromide 12 was then cyclo-condensed with phenylacetic acid under the influence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to deliver rofecoxib (2) in... 

Halogeno saccharides can be prepared by the displacement of a sulfonate ester with a halogen ion. Primary fluorides, bromides, chlorides and iodides can be prepared from mesylates (R0S02CH3) and tosylates (R0S02PhMe) (Scheme 3.3a).12 The latter derivatives can be obtained cheaply by treatment of alcohols with a sulfonyl chloride in pyridine or triethylamine. 

Instead of the carbanion, stabilized by the sulfone group, a Grignard reagent can be prepared from a side chain bromide. This reacts with the carbonyl group of the lactone in a similar way. The transformation (not transesterification) of IX/67 —> IX/68 is only realized in a yield of 37 %, Scheme IX/12 [31]. Lactone to carbocycle transformations are rare the method presented is a possibility for the realization of such a conversion. 

Acetylenic Grignard reagents are less active than sodium alkydes but are readily alkylated by benzyl halides as well as by alkyl sulfates and sulfonates.. . The Grignard reagents are conveniently prepared from the acetylenes and ethylmagnesium bromide in ether solution. 

The method given here employs the commercially available ammonium (4-)-ff-bromocamphor-7t-sulfonate instead of the more expensive silver salt used by Werner, and it gives higher yields of enantiomers. - The chloride, bromide, and ni trate of the ( + ) series can be prepared from the precipitated (+)(+)-bro-mocamphorsulfonate diastereoisomer by metathesis with the appropriate concentrated acid, whereas the chloride, bromide, and nitrate of the (—)-series can be prepared by treatment with the appropriate concentrated acid of the (—)-dithionate precipitated from the diastereoisomer filtrate. 

The sulfonate is prepared from the silver salt of the sulfonic acid by reaction with the phenacyl bromide in CH3CN at reflux for 48 h (35-39% yield). It is cleaved by photolysis at >280nm in benzene (90-94% yield). The corresponding phosphate ester is cleaved similarly. 

Conversion of D to (+)-testudinariol A (149) is summarized in Figure 6.8. After reduction of D with DIBAL-H, the resulting aldehyde E was treated with dimethylaluminum chloride in dichloromethane to give the cyclized product F after TBS protection. Ketone G, prepared from F, was then treated with a chiral phosphonoacetate H in the presence of NaHMDS to give the desired (Z)-ester as the major product. Reduction of the (Z)-ester with DIBAL-H furnished I. Alcohol I was converted to bromide J and sulfone K, respectively. Alkylation of K with J afforded L. Its reductive desulfonization and silyl deprotection yielded (+)-testudinariol A (149) in 4.4% overall yield based on A (19 steps). The spectroscopic... 

The free base 3a was further converted to the mandelate salt, a white crystalline product. The cyclobutyl analog 3b was similarly prepared from 8 and converted to the crystalline mandelate salt. The (S ) A-tetrahydrofurfuryl derivative 3c was prepared from (S) tetrahydrofurfuryl (1/f) camphor-10-sulfonate (10) as previously reported (Mertz et al., 1997). The 10-keto morphinans were prepared by the oxidation (Michne and Albertson, 1972) of the morphi-nan 7 with Cr03/H2S04 followed by alkylation with cyclopropyl methyl bromide and 0-demethylation to yield 4b (Scheme 1). O-Demethylation of 11 to form 13 followed by alkylation with (S) tetrahydrofurfuryl (I R) camphor-10 sulfonate (10), led to 4a. The assignment of the stereochemistry of 4a was based on the work of Merz and Stockhaus (1979). 

As part of a project to synthesize stable analogs of the indole-2,3-quinodimethane system, the 2,4-di-hydropyrrolo[3,4]indole (251) has been prepared from formylindole (249). Knoevenagel condensation with ethyl malonate followed by bromination and nucleophilic substitution of the bromide with azide yields (250), which immediately undergoes intramolecular 1,3-dipolar cycloaddition to give the triazoline (252). Treatment of (252) with toluene-p-sulfonic acid affords diethyl diazomalonate and (251 ... 

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