in in situ cuprate syntheses a Li salt by‐product is often formed and is rarely separated prior to application of the cuprate. Whilst the influence upon and/or inclusion of LiX (X = an inorganic anion, often a halide) in cuprate structures has been subject to several investigations (most recently by in‐depth NMR spectroscopy), solid‐state evidence for association remains rare (X = CN constitutes a special class of cuprate, which is discussed separately). However, the reaction of ortho diamine‐chelated aryllithium reagents with CuBr has given cuprates of formula Ar2Cu(Br)Li2 (Ar = C6H4{CH2N(Me)CH2CH2NMe2}‐2 112 and 1‐C10H6{CH2N(Me)CH2CH2NMe2}‐2 113, Figure 1.15) [148]. Interestingly, it was noted that the benzylic nitrogen centres became stereogenic upon coordination to Li, though only R,R and S,S pairs were observed in the solid‐state, implying selectivity during assembly.
As mentioned above, cyanocuprates are often considered as a distinct class of cuprates. They have been recognized as highly reactive and robust reagents that offer advantages over traditional Gilman reagents in substitution [149] and addition [150] reactions. However, the structures of cyanocuprates proved controversial for many years. Unlike halides, the ability of cyanide to act as a strongly coordinating ligand raised the possibility that it might remain bonded to Cu during cuprate formation. This behaviour has been plainly evidenced over a number of years in a range of lower‐order cyanocuprates (obtained from the stoichiometric reaction of CuCN and RLi) both in the solid state [151–153] and in solution [154]. However, upon adding two equivalents of RLi to CuCN (to give a Lipshutz cuprate, a species of the type R2Cu(CN)Li2), the outcome became less straightforward to predict. Two possibilities arose: (i) expulsion of cyanide as LiCN (or else retention by the cuprate but without a direct Cu–CN interaction) or (ii) retention of a Cu–CN bond to form a higher‐order cuprate. Although 13C NMR spectroscopy initially suggested CN− to be bound to copper [155], subsequent work demonstrated that the 13C NMR chemical shift of CN was indifferent to the organic R groups, arguing against a direct Cu–CN bond [156]. This latter scenario was subsequently supported by extended X‐ray absorption fine structure (EXAFS) measurements [157, 158], IR spectroscopy [159], and calculations [160, 161]. However, the most conclusive evidence disfavouring higher‐order structures arrived with the crystal structures of (DMBA)2Cu(CN)Li2(THF)4114 [162] and [t‐Bu2Cu][CN{Li(THF)(PMDETA)}2] 115 [163]. These structures contrasted; displaying CIP and SIP structures, respectively. However, the lack of Cu–CN bonding in either case was obvious. This was particularly noteworthy in 115, where the absence of a Cu–CN bond contrasted with its presence in the product of the 1 : 1 reaction of t‐BuLi with CuCN; t‐BuCu(CN)Li2(Et2O)2116 (Figure 1.16).
Figure 1.15 Molecular structure of [C6H4{CH2N(Me)CH2CH2NMe2}‐2]2Cu(Br)Li2112.
Source: Adapted from Kronenburg et al. [148].
Figure 1.16 Molecular structures of (a) polymeric (DMBA)2Cu(CN)Li2(THF)4114, (b) [t‐Bu2Cu][CN{Li(THF)(PMDETA)}2] 115 and (c) a cuprophilic aggregate of t‐BuCu(CN)Li2(Et2O)2116.
Sources: Adapted from Kronenburg et al. [162]; Boche et al. [163].
Several explanations have been posited for the apparently higher reactivity of Lipshutz cuprates, though the idea has also been contested [164]. Indeed, it has been suggested that the differing solubility of organic groups may be a contributory factor to observed variations in reactivity. For example, NMR spectroscopy uncovered the possibility that unreactive Cu‐rich cuprates may form in the presence of LiI when the organic groups were solubilizing [165], whereas lower‐order cyanocuprates (which did not interfere with unconsumed reactant) were the preferred sink for organocopper by‐product in the presence of cyanide. Differences in reactivity could then be understood in terms of the ability of the organocopper by‐product to sequester otherwise reactive cuprate. However, while these ideas have been considered in the context of applied conjugate addition, they have yet to be applied in detail to directed deprotonation or to copper‐halogen exchange reactions.
1.3.4 Solid‐phase Synthesis
Solid‐phase synthesis has become a recognized and attractive methodology for constructing libraries of biologically active small molecules in connection with combinatorial chemistry and automated synthesis oriented towards drug discovery research [166]. Various synthetic methodologies have been applied to solid‐phase synthesis [167]; however, organometallic chemistry has not yet been well explored in this area due to the lack of effective preparative methods of immobilized organometallic compounds for reaction with electrophilic linkages such as esters. That said, organometallic compounds have played an important role in solution‐phase chemistry for selective carbon–carbon bond forming reactions directed toward construction of complex molecules. This has led to the development of new solid phase carbon–carbon bond forming processes, with the halogen–metal exchange reaction of organic halides supported on polymer with an electrophilic linkage being the target of investigation [168]. The ate complexes t‐Bu3ZnLi 65 and (Me3SiCH2)2Cu(CN)Li2117 turned out to be very effective as the solid phase metalating agents in this context (Scheme 1.25). Various modes of carbon–carbon bond formation were achieved using immobilized arylmetal ate complexes, including 1,2‐addition to benzaldehyde, 1,4‐addition to 2‐cyclohexenone, and alkylations with methyl iodide and allyl iodide (118–120). Meanwhile, the metalation of insoluble polymers such as cross‐linked polystyrene has been investigated in connection with the preparation of materials for polymer‐assisted chemistry, with lithiation routinely being used for the functionalization of polystyrene resin. However, this approach has typically been restricted to examples where electrophilic functional groups are not present, and only a few reports of the solid phase lithiation of immobilized small molecules bearing electrophilic functional groups have appeared in the literature. In spite of these limitations, solid‐state synthesis has retained its appeal where functional groups not compatible with solution derivatization are concerned. For example, organometallic compounds containing an alkoxycarbonyl group are typically unstable at elevated temperatures due to self‐condensation or homocoupling. Immobilized organometallic compounds, on the other hand, have a track record of demonstrating enhanced stability, even when they bear highly reactive electrophilic groups, because of the diminished chance of self‐condensation and homocoupling by pseudo‐dilution effects. In the face, however, of the intrinsic limitations of traditional monometallic reagents, there has been great interest in developing new ways for the chemoselective metalation of small molecules on polystyrene, and this has focused on the use of metalating agents capable of being used in tandem with the presence of electrophilic functional groups. It is in this context that chemoselective solid‐phase halogen–metal exchange reactions, focusing principally on the preparation and transformation of immobilized intermediary organozincate and organocuprate species, have