Reformatsky reaction intermediates

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

The synthesis of (3S,4R)-4-(l-aminocycloprop-l-yl)-3-fluoropyrrolidine (28) is illustrated in Schemes 9 and 10. Namely, Reformatsky reaction of 1-acetylcyclopropanecarboxylate (32) [28] with ethyl bromoacetate yields the hydroxyester intermediate (33). Chlorination of this intermediate with... 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

Reformatsky reactions between allyl chloride and carbonyl cortqiounds are also effected in protic solvents using aluminium and a catalytic amount of tin chloride. Finely divided tin is formed and organotin reagents are involved as intermediates. These react with the carbonyl compound releasing tin ions, which are recycled by the dissolving aluminium [189],... 

The Reformatsky reaction uses an organozinc intermediate to form (3-hydoxy esters (see Figure 12-47). The general Reformatsky reaction is in Figure 12-48 and the mechanism is in Figure 12-49. 

Reformatsky Reaction A reaction leading to formation of 3-hydoxy esters, using an organozinc intermediate. 

The Reformatsky reactions of ethyl a-bromopropionate and related esters with N-substituted 6-bromo-2-oxochromene-3-carboxamides in a mixed diethyl ether-benzene-HMPA-THF solvent system give substituted 9-bromo-2,3,4,4a,5,10b-hexahydro-l//-chromeno[3,4-f]pyridine-2,4,5-triones (HMPA = hexamethylphosphoramide Scheme 45) <2004RJ0892>. Without the THF present in the mixed-solvent system, the reaction stops at the intermediate Wbenzyl-6-bromo-4-(l-alkoxycarbonylalkyl)-2-oxochroman-3-carboxamide stage. 

In the example given in Scheme 3j18 the primary step in the Reformatsky reaction is the addition of the halide reagent and zinc to the protected peptide 12 in THF hydrolysis of the intermediate formed results in the corresponding difluoroalkyl alcohol 13. Since compound... 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

Another intermediate for which Die Is-Alder trapping provided convincing evidence is the oxy-allyl cation. This compound can be made from a,oc -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

Two new cephalotaxine esters having significant antileukemic activity, neoharringtonine (11) and anhydroharringtonine (12), were isolated in 1992 by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1) produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. 

Fe2(CO)g and CeClj—SnClj the latter present some advantages like lower toxicity, lower temperature and homogeneous reaction conditions. The first step in the reaction ofa,a -dibromoketone 56 with CeClj—SnClj (equation 10) involves a single debromina-tion in analogy with a Reformatsky reaction to afford a cerium a-bromo enolate 57, This intermediate suffers from further elimination of bromide via ionization to oxyallyl cation 58 which undergoes the [3 + 2] cycloaddition to the enamine. The aminocyclo-pentanonc 59 obtained was easily deaminated to cyclopentenone 60. 

The synthesis of blastmycinone begins with a Reformatsky reaction. Although the resulting allylic alcohol 192 is a required intermediate, it is formed in this reaction without any stereocontrol. The alcohol 192 is oxidised in a Swern reaction to the enone 193 only to be resurrected in the next reaction but this time with stereocontrol. 

The synthesis of the fluoroketone that combines the retroamide type bond (76) is shown in Scheme 5. The 2,2-difluoro-3-hydroxyester 11 from a Reformatsky reaction was converted to the primary amide 12 by treatment with ammonia in diethyl ether. Reduction of the amide with borane dimethyl sulfide and protection of the resulting amine gave the protected intermediate 13. For the preparation of peptides XIV and XV, the hydroxy function was oxidized to the corresponding ketone using pyridinium dichromate. 

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