2.1 Insertion reactions to organic halides

Whereas the insertion of zinc dust to aryl iodides can be accomplished only by using highly reactive zinc powder (Rieke zinc) [5] or polar solvents, the reaction of commercial zinc dust with ethyl 4-iodobenzoate (3) in THF is very sluggish and provides the desired zinc reagent 4 in less than 5% after 24 h at 70 °C. However, in the presence of LiCl (0.3–2 equiv) a fast reaction takes place at 25 °C and leads to the desired zinc reagent 4 in ca. 98% yield. The role of LiCl is to solubilize the aryl zinc halide (ArZnX) produced on the zinc surface (Scheme 2) [6].

This reaction is very versatile and allows the synthesis of various aromatic and heterocyclic zinc reagents bearing sensitive functional groups like an ester, an aldehyde, or a ketone (Scheme 3).

This LiCl-activation of the zinc surface is quite general and a number of metals like Al, In, or Mg can be efficiently activated by addition of LiCl in THF. Thus, the treatment of the mixed carbonate 4 with Mg powder in the presence of LiCl provides the expected Grignard reagent 5 in 91% yield. The insertion reaction is complete at −20 °C within 1 h. Quenching with an aldehyde provides the expected alcohol 6 in 90% yield [7]. In the presence of more sensitive functional groups such as a methyl ester (7), the Mg-insertion is performed in the presence of ZnCl₂, so that the intermediate Mg-reagent (8) is converted in situ into the corresponding zinc reagent (9). Copper-catalyzed allylation affords the diester 10 in 83% yield (Scheme 4).

Benzylic chlorides are excellent substrates for preparing the corresponding Zn-reagent, either by a direct reaction with Zn dust in the presence of LiCl or by using Mg-powder in the presence of ZnCl₂ and LiCl-. This second method allows an expeditive synthesis of the zinc reagent 11 (45 min us. 24 h using only Zn and LiCl) [8]. The presence of MgCl₂ generated during the formation of a benzylic zinc reagent using Mg/ZnCl₂/LiCl has an additional beneficial effect. It enhances greatly the reactivity of the zinc species. Thus, whereas the zinc compound 12 does not react with the aldehyde 13 in the absence of MgCl₂, in its presence a fast reaction occurs producing the alcohol 14 in 80% isolated yield [9] (Scheme 5).

The presence of MgCl₂ facilitates the addition CO₂ to the zinc reagent, a reaction which otherwise proceeds only in polar solvents [10]. This allowed us to prepare ibuprofen (15) in 89% yield in a one-pot procedure starting from the benzylic chloride (16) [11]. The rate acceleration due to MgCl₂ is best explained by assuming that the usual transition state A for the addition of a zinc organometallic to a carbonyl compound is now rather of the type B where the carbonyl group is coordinated to MgCl₂ which is a much stronger Lewis-acid than R’ZnCl (Scheme 6) [9].

2.2 Directed deprotonation using LiCl-solubilized TMP-bases

The use of sterically hindered 2,2,6,6-tetramethylpiperidyl (TMP)-metal amides solubilized by LiCl allows the direct magnesiation or zincation of a range of polyfunctional aromatics and heterocycles. Thus, TMPMgCl·LiCl (17) which is readily prepared by the reacting of 2,2,6,6-tetramethylpiperidine with iPrMgCl·LiCl has a monomeric structure in solution as shown by García-Álvarez et al. [11]. It has excellent solubility in THF (1.2 M) and deprotonates positions in heterocycles otherwise difficult to metalate. Thus, the furan (18) reacts readily at −78 °C with TMPMgCl·LiCl (17) producing the magnesium reagent 19 which after transmetalation with ZnCl₂ undergoes a smooth cross-coupling with an aryl iodide providing the cross-coupling product 20 in 79% yield (Scheme 7) [12].

The corresponding zinc base TMPZnCl·LiCl (21) is prepared in a similar way starting from TMP-H using BuLi and a subsequent transmetalation with ZnCl₂. The base (21) has also an excellent solubility in THF (ca. 1.3 M) and shows a unique chemoselectivity in deprotonation reactions. Thus, the heterocycles 22 and 23 which bear respectively an aldehyde and an nitro group are readily zincated at 25 °C with TMPZnCl·LiCl (21) within a few minutes (Scheme 8) [13].

Also, a sensitive heterocycles such as the purine (24) are zincated at 25 °C with TMPZnCl·LiCl (21) leading to a selective zincation at the imidazole ring of the purine skeleton. Very sensitive substrates like the furan (25) which bears both a nitro group and an ester function is smoothly zincated with TMPZnCl·LiCl (21) at the α-position to the methyl ester group. After allylation with 3-bromocyclohexene the expected furan 26 is obtained in 76% yield (Scheme 9) [13].

Remarkably, TMPZnCl·LiCl is also able to zincate functionalized olefins such as the trifluoromethyl ketone derivative 27 or nitro olefins of type 28. The resulting zinc reagents 29 and 30 can either be acylated or allylated providing polyfunctional compounds like 31 and 32 (Scheme 10) [14].

The metalation of pyridines is an important synthetic challenge and Kessar et al. have shown that BF₃·OEt₂ enables a low temperature lithiation of pyridines with TMPLi [15]. We could show that LiCl-solubilized TMP-bases such as TMPMgCl·LiCl (17) or TMPZnCl·LiCl (21) are compatible with BF₃·OEt₂ at temperature below −20 °C. Thus, 3-fluoropyridine (33) can be readily metalated in position 4 by the reaction with BF₃·OEt₂ followed by the addition of TMPMgCl·LiCl (17) [16]. After a Pd-catalyzed cross-coupling with an aryl iodide the desired 4-substituted pyridine (34) is obtained in 74% yield. In contrast with the absence of BF₃·OEt₂, a selective magnesiation occurs in position 2 providing the 2-arylated pyridine 35 [16]. A similar behaviour is observed for a number of pyridines bearing an electron-withdrawing substituent in position 3. Thus, 3-cyanopyridine (36) can be substituted with complete regioselectivity either in position 2 in the absence of BF₃·OEt₂ or in position 4 in the presence of BF₃·OEt₂ (Scheme 11) [16].

A full functionalization of the pyridine scaffold was performed using LiCl-solubilized TMP-bases of Zn and Mg. Thus, 4-cyanopyridine (37) is successively functionalized in position 3, then position 2, then position 5 and finally in position 6. This demonstrates the versatility of the TMP-bases and although all functionalizations of a given pyridine cannot be achieved in each case, a significant progress has been made with these new TMP-bases in combination with BF₃·OEt₂ (Scheme 12) [17].

Organozincs were used for the synthesis of new types of heterocycles or for improving current heterocycle syntheses. Thus, the Fisher-indole synthesis requires strong acidic conditions, uses non-commercial aryl hydrazines as substrates and provides often a mixture of regioisomeric indoles. These problems can be solved by performing a zinc mediated Fischer-indole synthesis. This one-pot procedure requires readily available aryldiazonium salts and tolerate a range of functional groups. Thus, various zinc reagents such as 38 and 39 add under mild conditions to the aryldiazonium salts 40 and 41 providing after a [3,3]-sigmatropic shift at 125 °C (microwave irradiation) the indoles 42 and 43 in 75–90% yields (Scheme 13) [18].

Secondary cycloalkylzinc reagents can be used as well. These reagents produce annulated indoles such as 44 and 45 in 81–88% yields. This method has also be applied to the synthesis of biologically active indoles such as iprindole 46 which is prepared in a efficient procedure starting from cyclohexylzinc bromide which is obtained by the direct zinc insertion to cyclohexyl bromide using Zn dust and LiCl in THF (50 °C, 1 h); Scheme 14 [18].

2.3 Diastereoselective cross-couplings

The preparation of diastereomerically pure compounds by using cross-coupling reactions is an important synthetic method. Starting from menthyl iodide (47), we have found that the resulting diastereomeric zinc reagent react in a stereoconvergent way with an arylpalladium(II)-halide providing only one Pd(II)-intermediate bearing all the substituents in a equatorial position (48). After reductive elimination, arylated menthyl derivatives of type 49 are obtained with high diastereoselectivity (Scheme 15) [19].

Remarkably, this diastereoselective cross-coupling can be extended to synthesis bearing a substituent in position 2, 3 or 4. Thus, cyclohexylzinc reagent such as 50–52 undergo highly diastereoselective cross-couplings with methyl 4-iodobenzoate leading to the arylated cyclohexane derivatives 53–55 in 72–82% yields and dr > 95:5; Scheme 16 [19].

It was also possible to extend these cross-coupling to the arylation of Boc-protected piperidines of type 56. Their metalation with s-BuLi and transmetalation with ZnCl₂ provides the zinc reagents 57 which after reaction with an aryl iodide (Ar-I) are furnishing the 2,4-disubstituted piperidines 58a–d in diastereoselectivities > 99:1; Scheme 17 [20].

By using 2,6-disubstituted zincated piperidines of type 59, a Pd-catalyzed rearrangement takes place via an elimination and readdition of ArPd-H leading to 2,5-disubstituted piperidines of type 60. Thus, the arylated piperidines 60a–c are obtained with diastereoselectivities better than 88:12 (Scheme 18) [20].

The preparation of alkynylcyclohexane derivatives in a diastereoselective fashion can also be realized via a Pd-catalyzed cross-coupling. Interestingly, although most Pd-catalyses require a phosphine ligand, it was possible to perform Csp³-Csp cross-coupling of cyclohexylzinc reagents with alkynyl bromides using neocuproine (61) as a ligand. The cross-coupling furnish the alkynylated products of type 62 in good yields and high diastereoselectivities (up to 98:2); Scheme 19 [21].