Appel bromination reaction

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

Construction of the 2,5-disubstituted pyrrole 79 commenced with a one-pot acylation amidation protocol, whereby a Vilsmeier-Hack formylation furnished 74 in two steps in moderate yields. Assembly of the more complicated a-bromoketone was achieved by the use of 81, which was synthesized from the L-diethyl tartrate in four steps using a known procedure. The halide 82 was obtained through a one-pot Appel bromination/DlBAlH reduction of the ester. Protection of the primary alcohol followed by reaction with dithiane 83 led to 84. The yields of this reactimi were highly dependent upon the use of 2.0 equiv. of NaH, 2.0 equiv. of 83, and a catalytic amount of tBuOH. Any divergence from these conditions resulted in decreased yields. Subsequent reduction and removal of the dithiane provided 85 which was crai-verted to the desired a-bromoketone 78 (Scheme 28). 

For the synthesis of alkyl bromides and chlorides, the Appel reaction remains one of the most widely adopted and successful approaches [7]. The classic reaction uses PPhj and carbon tetrachloride to convert alcohols into alkyl chlorides. The reaction is operationally trivial, often high yielding, and has been extended to bromination reactions using CBr. Furthermore, an extension of this classic reaction enabled the conversion of alcohols into alkyl iodides (Scheme 7.24 and Example 7.11) [38, 39]. In related work, visible light catalysis has been used to convert alcohols into alkyl halides [40]. The following examples will highlight additional advancements that have been made to this classic reaction. 

The catch and release monolithic phosphine can be employed in a flow Appel reaction [53]. The monolith (9) was treated with carbon tetrabromide to give the active bromophosphonium (10), with which alcohols were transformed into alkyl bromides. As a result, the functional group on the monolith changed into phosphine oxide. Although complete bromination of reactive benzyl alcohols... 

S,6S)-isomer (9%). Reaction of 571 with lithium aluminum hydride effected reduction of both the lactone and the N-methoxylactam, leading to the diol (—)-572. The primary alcohol was brominated by Appel reaction with carbon tetrabromide and triphenylphosphine, the bromide then cycliz-ing spontaneously to give the oft-synthesized swainsonine acetonide (-)-488 in 88% yield. Finally, hydrolysis with aqueous hydrochloric acid followed by purification by ion-exchange chromatography provided the target alkaloid, (—)-378. 

Phospholane- and 1,2,3,4,5,6-hexahydrophosphinine derivatives, tetra-hydro- and hexahydrophosphepines, as well as a dibenzophosphole were applied as the P(III)-reactant. The corresponding phosphine oxides formed were reduced by Ph2SiH2 in the course of the reaction. A typical realization using 1-phenyl-dibenzophosphole as the catalyst in the bromination of 2-phenylethanol is shown in Scheme 64. Another group dealing with the catalytic Appel reaction utilized the reagents triphenylphosphine oxide and oxalyl chloride in the chlorination of alcohols (Scheme 65). ... 

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