Zinc reagent

The Reformatsky reaction is the zinc-mediated condensation of an a-haloester, usually the bromoester, with an aldehyde or ketone, to give a 3-hydroxyester, dehydration of which affords an a,P-unsaturated ester as a mixture of (E)- and fZ isomers [24]. It should be noted that a-halonitriles [25] and a-halosulphones [26] also participate in the Reformatsky reaction. The condensation is usually effected by adding a solution of the bromoester and the aldehyde or ketone to a suspension of zinc in a suitable solvent. The Reformatsky reaction has been conducted under sonication conditions [27] and by a continuous flow method [28]. 

For transition metal-catalyzed cross-coupling of organozinc compounds, see the appropriate transition metal (Ni page 382, Section 20 Pd page 386, Section 21 Cu page 392, Section 22). 

E + = Pd catalyst plus ArBr, vinylic Br, RCOC1 or C1C02R 

R1CH=CHLi + R2CH =CHCH2MgX + ZnBr2 Hz° H2C=CHCHR2CHR1CH3 

Larock, Organomercury Compounds in Organic Synthesis, Springer Verlag, New York (1985), Chpt7 (review) 

Olefin Metathesis, Academic Press, London (1983) 

R1CH=CHLi + R2CH=CHCH2MgX + ZnBr2 - 2— H2C= CHCHR2CHR1CH3 

Gajewski has examined the secondary deuterium isotope effects in the addition of allyllithium and allyl Grignard additions to benzaldehyde [157]. With allyl-lithium and allylmagnesium halides a normal secondary deuterium isotope effect was observed. The results indicate that rate-determining single-electron transfer occurs with the allyl reagents. 

The allylic zinc reagents are generally prepared by mixing zinc metal with the requisite allyl halide using either sonication or a saturated aqueous solution of 

A range of aldehydes were treated with the homoallylic alcohol 260 and ZnCla to afford the desired homoallylic alcohols in high yield and excellent diastereo-selectivity (Fig. 10-9). 

All of the reactions proceed in high yield and diastereoselectivity except for the reaction of acetophenone. None of the undesired y-substituted isomer is detected. The high diastereoselectivity observed in these reactions is especially surprising, as the addition of 2-butenylzinc to an aldehyde has already been observed to proceed with almost no diastereoselectivity [166]. 

Step provides the homoallylic alcohol, predominantly as the anti isomer. The high diastereoselectivity is attributed to the generation of pure ( )-2-butenylzinc in the presence of the electrophile. These reactions can proceed in high yield even with only a catalytic (10 mol%) amount of zinc. 

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Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

REFORMATSKY BLAISE Zincahyiallon Synthesis of -hydrexyesters from cartxinyl derivatives arxl a-haloesters via a zmc reagent (Reformatsky). Synthesis ol eloesleis from nitriles and a-haloesters via a zinc reagent (QIaise). 

In addition to the perfluoroalkylzinc compounds, the zinc reagent formed from 1,1,1-trifluorotrichloroethane has received considerable attention. This zinc compound was first reported as a stable ether complex [56]. Later, the DMF complex was isolated and the structure was determined by X-ray diffraction and shown to be monomeric [57] (equation 50). This zinc reagent undergoes a variety of functionalization reactions, and some typical examples are illustrated in Table 2 [47, 58, 59, 60, 61] The alcohol products (Table 2) can be converted to AiCF=CXCF3 (X = Cl, F) by further reaction with diethylaminosulfur trifluoride (DAST) and l,8-diazabicyclo[5 4.0]undec-7-ene (DBU) [60]... 

Vinyl fluorinated zinc reagents can be prepared by two different methods (1) capture of the corresponding vinyllithium reagent at low temperatures with a zinc salt and (2) direct insertion of zinc into a carbon-halogen bond. 

The first method involves generation of an unstable vinyllithium denvative at low temperatures from the corresponding vinyl halide or 1-hydroalkene Addition of zinc chloride and warming to room temperature gives the stable vinyl zinc reagent [100, lOI, 102, 103] (equations 69-72)... 

These zinc reagents are useful precursors for stereocontrolled palladium-catalyzed cross-coupling reactions, as illustrated in equations 73-80 [100, 101, 102, 103, 104, 105, 106, 107, 108] This methodology has been used to prepare new fluorinated analogues of codlemone [I09. ... 

Vinyl Halide Solvent Zinc Reagent Yield (%]... 

As noted, these zinc reagents find extensive application in the preparation of fluorinated styrenes [113, 114], aryl-substituted fluorinated propenes [114],fluor-inateddienes [115,116], and tnfluorovinyl ketones [117], as illustrated in equations 83-88... 

Fluorinated acetylenic zinc reagents have received only limited attention. The trifluoromethyl analogue can be generated via the reaction of zinc with... 

Because the vinylzinc and vinylcadmium reagents can be prepared directly from the vinyl halides (I, Br) with zinc or cadmium metal, this route avoids cross coupling processes and provides a one-pot in situ preparation of perfluo-rovinylcopper compounds Table 7 shows examples of this method of preparation of vinylcopper reagents from the indicated cadmium or zinc reagent [145]... 

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

Each oxygen atom in the dioxolane has two lone pairs available for coordination to the zinc reagent. In each case, one is proximal to the double bond and one is distal, the latter being too far away to be involved in any kind of productive interaction. The proximal lone pair of the equatorial oxygen substituent is referred to as the topographically preferred site" (Fig. 3.7). 

Substitution Reactions with Copper-Zinc Reagents... 

Scb ir 7.11. Copper-catalyzed enantlocelectlve 1-addition of a functionalized zinc reagent. 

Tlie constrLiction of carbocydic cotnpoutidi by ring-annulation procedures frequently plays a prominent role in total syntliesis. Tlie tolerance of various functional groups in tlie zinc reagents employed in copper-catalyzed asymmetric 1,4-additions fornis tlie basis for tliree novd catalytic enantioselective annulation metliods discussed bete. 

The preparation of cyclopropane derivatives has been greatly facilitated by the development of carbene-type intermediates (see Chapter 13) and their ready reaction with olefins. The preparation of phenylcyclopropane from styrene and the methylene iodide-zinc reagent proceeds in only modest yield, however, and the classical preparation of cyclopropane derivatives by the decomposition of pyrazolines (first employed by Buchner in 1890) is therefore presented in the procedure as a convenient alternative. 

The Michael addition of the copper-zinc reagent derived from ethyl 4-bromobntyrate to the plperonal-derived nitroalkene proceeds cleaniy to give the nitre ester, which is an intermediate for the synthesis of lycoricidine alkaloids fEq. 4.85. ... 

Phenylcyclopropane has been prepared by the base catalyzed decomposition of 5-phenylpyrazoline (33 %),2 by the reaction of 1,3-dibromo-l phenylpropane with magnesium (68%),3 and by the reaction of 3-phenylpropyltrimethylammomum iodide with sodium amide in liquid ammonia (80%)4 However, the method frequently used at present is the reaction of styrene with the methylene iodide-zinc reagent (32%)5... 

Addition of alkynes to a-alkoxy aldehydes is most favorably performed with the corresponding zinc reagents (Table 12)46. As with Grignard reagents, the chelation-controlled addition of zinc alkynes proceeds with higher diastereoselectivity when diethyl ether rather than tetrahydrofuran is used as reaction solvent. 

However, addition of (+ )-(7 )-l-methyl-4-(mcthylsulfinyl)benzene, to aldehydes and ketones proceeds with low stereoselectivity. An improvement of the 3-syn diaslereoselectivity was found with the zinc reagent obtained by transmetalation of the lithiated sulfoxide with anhydrous zinc chloride38. An improvement of the stereoselectivity was also attained by exchange of the 4-methylphenyl substituent for a 2-methoxyphenyl or 2-pyridinyl substituent. Thus, the introduction of an additional complexing site into the aromatic part of the sulfoxide reagent enhances the stereoselectivity35. 

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