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Synthesis 2023; 55(21): 3487-3501
DOI: 10.1055/a-2155-3423
special topic
C–H Bond Functionalization of Heterocycles

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

Daria K. Wanic
a   Institute of Chemical Sciences, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, UK
,
Rebecca Melvin
a   Institute of Chemical Sciences, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, UK
,
Graeme Barker  ∗
a   Institute of Chemical Sciences, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, UK
b   Continuum Flow Lab, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, UK
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Abstract

C–H Deprotometalations have long occupied a key role in modern organic synthesis in both the research laboratory and pharmaceutical and fine chemical manufacture, thanks to readily accessible reagents and well-established procedures. Typically, organolithiums are the reagent of choice thanks to high reactivity and ease of use but these are incompatible with base- and nucleophile-sensitive functional groups. In comparison, organozinc base complexes offer a milder approach to deprotonative C–H functionalisations, and compatibility with a wide range of functionalities which would be problematic when using the alternative organolithium or organomagnesium reagents has now been demonstrated. Here, we review the current state of the art in zinc-mediated C–H metalations at substituted arenes, heteroarenes, and Csp3–H sites.

1 Introduction

2 Csp2–H Functionalisation Using Zinc Bases

2.1 Functionalised Arenes

2.2 Heterocycles

3 Csp3–H Functionalisation Using Zinc Bases

3.1 Zinc Enolate Formation: Traditional Approach

3.2 Zinc Enolate Formation via Zinc Bases

3.3 Non-Enolic Csp3–H Zincations

4 Conclusion


#

Key words

metalation - organozinc - C–H functionalisation - deprotonation
1

Introduction

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Dr Graeme Barker (left) obtained his MChem (Hons.) in 2007 from the University of St Andrews before moving to University of York for a Ph.D. under the supervision of Prof. Peter O’Brien. In 2011 he moved to University of Sheffield as a PDRA with Prof. Iain Coldham, and in 2013 to Heriot-Watt University as a PDRA with Dr Ai-Lan Lee. He was appointed to an assistant professorship at Heriot-Watt in 2016, where his research interests include synthetic methodology, flow chemistry, and medicinal chemistry for therapeutic intervention in cell signalling cascades. Daria Wanic (right) and Rebecca Melvin (centre) were Heriot-Watt undergraduate students in chemistry and graduated with MChem degrees in 2023, both with first class honours.

Organozinc chemistry reaches far back, nearly to the dawn of organometallic chemistry with the first organozinc compound reported in 1849 by Frankland, who discovered that elemental zinc heated with ethyl iodide yields diethylzinc, a highly pyrophoric liquid.[1] Since this discovery, organozinc reagents have been screened in diverse reactions with a range of electrophiles, however they initially exhibited low reactivity and moderate yields in comparison to organolithiums and organomagnesiums, leading to organozincs being largely overlooked for many years.[1]

The first milestone for organozinc chemistry came in 1887, when Reformatsky discovered an aldol-like reaction using zinc enolates derived from α-halo esters.[2] The Reformatsky reaction exploits what had previously been though of as a disadvantage, low reactivity, and allows cross aldol chemistry without a risk of self-reaction, as zinc enolates are unable to react with esters. In 1899, Barbier reported another use for organozinc reagents generated in situ from the reaction of an alkyl iodide and zinc powder with a carbonyl compound. It later became known as the Barbier reaction, which resembles and was subsequently largely replaced by the Grignard reaction.[3] The Simmons–Smith reaction reported in the 20th century was another breakthrough in organozinc chemistry; this involves an organozinc carbenoid reacting with an alkene, resulting in the formation of a highly desired structure: a cyclopropane ring.[4] Another well-known named reaction in the field is the Negishi Pd(0)-catalysed cross-coupling of organozinc compounds with unsaturated organic halides/triflates; a useful and important method of creating C–C bonds for which the Nobel prize for chemistry was awarded in 2010.[5]

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Figure 1Zn-TMP complexes: selected examples

The popularity of zinc organometallics stems from their ease of preparation, predictable reactivity, and high functional group compatibility in comparison to the more commonly used organolithiums.[1] [6] A breakthrough in the zinc metalation field happened in 1999 when Kondo and co-workers used lithium di-tert-butyltetramethylpiperidinozincate (TMPZntBu2Li; 1) (Figure [1]) as a base for directed ortho-metalation (Scheme [1]); the first example of a C–H zincation reaction.[7] The group metalated various alkyl benzoates and benzonitriles as well as N,N-diisopropylbenzamide, obtaining products of type 7 in good yields (73–99%) and demonstrating a high functional group tolerance, even in the presence of the nucleophile-sensitive nitrile group. The same approach was applied to heterocycle metalation with various, but still satisfactory, results with yields ranging between 62% and 89% for 5-membered rings. Notably, the metalation and subsequent iodine trapping of isoquinoline was excellent (93% yield); this reaction had never been successfully achieved with directed α-lithiation which results in dimer formation due to high organolithium reactivity.[7] [8] Although TMPZntBu2Li 1 has a higher functional group tolerance than organolithiums, it is an anionic base: an ‘ate’ complex in which zinc gains a negative formal charge that can be too reactive to be successfully used in the presence of nitro or aldehyde groups.[9] It is also difficult to prepare as it requires isolation of pyrophoric Zn(tBu)2.[10] The alternative neutral bases, however, can be less effective as they react slowly and only sufficiently acidic protons can be removed.[11]

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Scheme 1Directed ortho-metalation using TMPZntBu2Li

The Knochel group addressed this problem by developing a neutral version of Kondo’s base for ortho-metalations.[9] (TMP)2Zn·2MgCl2·2LiCl 2, while still highly yielding (67–91%) is compatible with nitro and aldehyde groups as well as heterocycles prone to ring opening in the presence of more reactive bases such as 1,3- and 1,2-oxazoles and 1,2,5- and 1,3,4-oxadiazoles.[12] [13] The enhanced reactivity of this base has been proposed to result from the presence of Lewis acids rather than the ‘ate’ nature of the complex; it is possible, however, that ‘ate’ complexes may exist in equilibria for 2 and 3 in solution, analogous to those observed for turbo-Grignard complexes RMgX·LiCl.[14] Nevertheless, further research in by the Knochel group revealed drawbacks such as low yields for reactions with electron-poor functionalised arenes and heterocycles, and temperatures below –50 °C being required for metalation of pyridazines or compounds containing nitro groups, which make scale up challenging.[15] Thus, the Knochel group developed an improved version of the zinc complex: TMPZnCl·LiCl 3.[15] This new base proved to be highly chemoselective for zincations at 25 °C of sensitive arenes and heterocycles including pyridazines, pyrimidines, pyrazines, purines, and electron-poor nitropyridines. It is also compatible with nitro and aldehyde groups in reactions proceeding at room temperature with good yields ranging between 63% and 92%. Moreover, the group has developed a computational model to predict site-selective deprotonation reactions using 3.[16] The model was based on the assumption that for the neutral base, thermodynamic effects outweigh the kinetic effects, therefore the metalation will happen at the most acidic site and not at the site that would result from coordination of the base counterion to a Lewis basic direct metalation group in order to form an adduct. Calculations of pK a values of various functionalised aromatic and aliphatic compounds were carried out and, as predicted, in over 80% cases, the experimental data matched the model.

An alternative to the anionic base was also introduced by Hlavinka and Hagadorn who suggested use of Zn amido complexes not containing Li or Mg.[11] [17] Their first attempt involved use of EtZnNiPr2 and EtZnNPh2 to obtain functionalised enolates, but the results were not satisfactory. Two of the investigated substrates, 2-methylpentan-3-one and dimethyl methylphosphonate, resulted in yields close to 100% but the rest of the scope was unsuccessful with enolates either not formed at all or in very low yields. Further research led to two new bases: Zn(TMP)2 4 and Zn[N(SiMe3)2]2. The latter displayed poor reactivity, only being able to successfully remove very acidic protons. In contrast, the results obtained with Zn(TMP)2 4 were good to high yields in short periods of time at ambient temperature. The drawback of this methodology is the challenging and time-consuming synthesis and purification (by sublimation) of the Zn(TMP)2 4 base itself, which discourages use by synthetic organic researchers not expert in the inorganic synthesis field.[18] Thus for most purposes, TMPZnCl·LiCl 3 remains the most convenient and widely applicable zinc base, and has come to be termed a ‘turbo-zinc’ reagent.[19]

The discovery of mild organozinc compounds allowed for the functionalisation of moieties containing highly sensitive groups incompatible with traditional organolithium reagents such as ester, azide, nitro, and isothiocyanate groups without the need of incorporating extra synthetic steps to protect them.[6] It also ensured higher selectivity and alleviated the risk of unwanted nucleophilicity or ring fragmentation of heterocycles.[11] [12] This review will focus on Csp2–H and Csp3–H functionalisation using zinc bases and showcase their broad application. We note that the use of (hetero)bimetallic zinc complexes for C–H zincation can give rise to exquisite selectivities and access to organozinc species otherwise out of reach;[19] [20] many such examples report crystallographic characterisation of such organozincs or electrophilic trapping with I2 only. We note that synergistic effects in organometallic chemistry have recently been reviewed,[21] and have herein focussed on examples used in total synthesis or C–C bond forming reactions.


# 2

Csp2–H Functionalisation Using Zinc Bases

The majority of extant C–H functionalisations take place at Csp2–H positions, and a variety of functionalised arenes bearing directing group as well as aromatic and unsaturated heterocycles have been explored as substrates.

2.1

Functionalised Arenes

The generality of C–H zincation and good functional group tolerance of mildly reactive arylzinc intermediates was exploited by the Wang group for the site-selective copper-catalysed amination of unactivated arenes.[10] Their approach presented an alternative to commonly used C–H amination by ortho-lithiation with limited utility due to the instability and sensitive functional group incompatibility of lithiated intermediates.[6] The base used in the study was anionic with a substoichiometric amount of LiTMP to increase the yield, LiTMP0.1Li[ZnEt2(TMP)]; the neutral base TMPZnCl·LiCl 3 was found to be ineffective. The zincation was followed by copper-catalysed amination using copper(II) 2-ethylhexanoate [Cu(eh)2] which was found to be the most effective catalyst under the reaction conditions. Various substrates were tested including both monofunctionalised and multiply functionalised arenes to determine their influence on the regioselectivity (Scheme [2]). For the arenes of type 8 with one functional group, the reaction conditions were proven compatible with N,N-diisopropylcarboxamide, nitrile, methoxy, and halogen groups selectively yielding ortho-aminated product 9. (Trifluoromethyl)benzene, however, was found problematic as besides the major ortho-zincated product, the formation of meta- and para-isomers was observed. Arenes bearing multiple functionalities (e.g., 10) showed regioselective preference for zincation ortho- to the inductively activating group such as fluoride. In the absence of a strongly electron-withdrawing group, functionalisation happens ortho- to the strongest coordinating group instead. The yields for the ortho-aminated products ranged between 39% and 75% for arenes with one direct metalation group, and between 33% and 83% for arenes with multiple functionalities. It was noted that diversely functionalised aminoarenes would be difficult to synthesise using conventional methods. The procedure, however, was found to be incompatible with nitro, aldehyde, and ketone highly electrophilic moieties due to the use of an anionic base.[9]

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Scheme 2Amination of functionalised arenes using an anionic base

In an attempt to obtain functionalised benzynes, Kondo and co-workers tested ‘ate’ bases of the R2Zn(TMP)Li type and discovered significant differences in reaction modes depending on the alkyl ligation environment.[22] In the reaction of 3-bromobenzonitrile (12) with Me2Zn(TMP)Li, bromine is eliminated and benzyne intermediate 13 is formed, which in the presence of a diene undergoes a Diels–Alder reaction with, for example, isobenzofuran 14 to form fused rings system 15. The same conditions, but with tBu2Zn(TMP)Li 1 as a base, lead to a different reaction mechanism; ortho-deprotonation occurs instead of the elimination and the resulting arylzincate 16 can be trapped with an electrophile to give a multifunctionalised arene 17 (Scheme [3]). Since both Me2Zn(TMP)Li and 1 are anionic, they face limitations for use on arenes with highly electrophilic substituents. Nevertheless, the switch in reactivity associated with two different alkyl ligands was considered to be synthetically useful.

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Scheme 3Zinc ‘ate’ bases for arene functionalisation: reaction proceeds via two different intermediates depending on zinc alkyl ligands

The exceptional tolerance of sensitive functional groups while using neutral zinc bases has been demonstrated by a successful zincation of aryl nonaflates with TMPZnCl·LiCl 3.[23] A nonaflate (nonafluorobutanesulfonate) moiety is an excellent, electron-rich leaving group, which poses a risk of elimination during metalation reactions. Magnesiations with TMPMgCl·LiCl followed by electrophilic trapping proceed smoothly in high yields meta to the nonaflate group. Attempts to obtain a C–Mg bond in the ortho position resulted in an elimination reaction to give a benzyne intermediate.[24] With TMPZnCl·LiCl 3, however, it was possible to install both ortho and meta substituents without any side reactions taking place. The meta-substituted derivative 20a was obtained in 89% yield after trapping with 1-iodo-4-(trifluoromethyl)benzene and the yields for ortho substitution ranged between 65% and 85% after quenching with various electrophiles such as ethyl (2-bromomethyl)acrylate to yield 20b or pivaloyl chloride to give 20c (Scheme [4]).

In another study, the scope of functionalities compatible with 3 was extended even further to include difluoronitrobenzene 21, which was fully metalated at 25 °C in 1 h and subsequently acylated with ethyl chloroformate in the presence of Pd(PPh3)4 as a catalyst to give tetrasubstituted nitrobenzene 22 in 63% yield (Scheme [5a]).[25] Quenching without a Pd catalyst was not attempted.

If a more powerful zinc base than TMPZnCl·LiCl 3 is required, TMP2Zn·2MgCl2·2LiCl 2 is an attractive alternative. Although it has been proven to be less compatible with sensitive functional groups and milder reaction conditions,[15] [26] it is useful for the zincation of relatively inactive unsaturated compounds, particularly heterocycles prone to undergoing fragmentation.[27] The base has been shown to successfully facilitate large-scale (100 mmol) C–H activation of ethyl 4-cyanobenzoate (23) ortho to the ester substituent.[28] The resulting organozinc underwent Pd-catalysed Negishi coupling with iodobenzene giving the final diaryl product 24 in 84% yield (Scheme [5b]). Despite the impressive yield, the entire transformation took over 50 h at room temperature making it impractical for industrial synthesis and leaving scope for further research. Possible solutions to this problem would be the application of microwave irradiation and/or flow chemistry.

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Scheme 4Zincations of aryl nonaflates with TMPZnCl·LiCl followed by electrophilic trapping
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Scheme 5Further reactions with zinc bases showing high functional group tolerance: (a) direct zincation of difluoronitrobenzene and subsequent electrophilic trapping; (b) large-scale direct zincation of 4-cyanobenzoate followed by Negishi coupling with PhI
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Scheme 6Zincation of functionalised arenes with and without microwave irradiation

Given that organozincs of the RZnX type are thermally stable and remain functional group tolerant even at elevated temperatures,[29] the use of microwave irradiation to accelerate the reaction in the functionalisation of arenes with (TMP)2Zn·2MgCl2·2LiCl 2 [30] and TMPZnCl·LiCl 3 [31] has been investigated. The reaction time of the direct zincation of ethyl 4-chlorobenzoate (25) was successfully shortened from 110 h at 25 °C to 2 h at 80 °C in a microwave reactor, maintaining the yield over 90% (Scheme [6a]).[30] Additionally, ethyl benzoate (27a) and N,N-diethylbenzamide (27b), which could not be metalated using the (TMP)2Zn·2MgCl2·2LiCl 2 base at 25 °C, yielded the desired reaction product of type 28 in >90% yields when heated in a microwave at 120 °C for 5 h (Scheme [6b]). This method was also proven beneficial with weakly activated arenes such as 1-fluoro-3-methoxybenzene (29b) or aromatics with sensitive functional groups like ethyl 3-fluorobenzoate (29a), which could not be zincated at room temperature.[31] Microwave irradiation at 160 °C for 2 h yielded the desired metalated species 30 in high (>90%) yields (Scheme [6c]). Importantly, the microwave irradiation could not be replaced with conventional heating for either of the bases or substrates as the yields at the same temperatures were not satisfactory (10–20%).[30] [31] Heating in an oil bath at 65 °C, however, was effective for the metalation of 2-bromo-4-fluorobenzonitrile (31) with TMPZnCl·LiCl 3, a substrate which is not metalated at room temperature.[25] After 30 min of heating, the zincated species was shown to readily undergo a Pd-catalysed Negishi coupling with 1-iodo-4-(trifluoromethyl)benzene to form 32a in 89% yield[25] or an electrophilic trapping reaction with benzoyl chloride in the presence of CuCN·2LiCl to obtain 32b in 90% yield on a 50-mmol scale (Scheme [7]).[26]

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Scheme 7Direct zincation of 2-bromo-4-fluorobenzonitrile at elevated temperatures

The Knochel group have also developed a continuous flow protocol for selective zincation of arenes bearing sensitive functional groups (nitro, nitrile, fluoro, and bromo) using an underexplored neutral zinc base, (Cy2N)2Zn·2LiCl.[32] Deprotonation was followed by a Pd-catalysed batch cross coupling with an aryl iodide. The obtained yields were very good, ranging between 71% and 96%. Furthermore, the most efficient zincation reaction of 2,4-difluoro-1-nitrobenzene (21) was scaled-up in flow from a 1.3- to a 15-mmol scale maintaining an excellent yield of 34, 98% (Scheme [8]). The zinc base was obtained by transmetalation from Cy2NLi. It could be stored for several weeks at room temperature under argon without any decomposition and was found to show the highest reactivity in the binary co-solvent system THF/DMPU (10:1).

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Scheme 8Continuous flow zincation of 2,4-difluoro-1-nitrobenzene with subsequent Pd-catalysed Negishi cross coupling

# 2.2

Heterocycles

Following their work on direct ortho-metalation of functionalised arenes, Kondo and co-workers conducted further research using TMPZntBu2Li 1 and lithium di-tert-butyldiisopropylaminozincate (iPr2NZntBu2Li) on the selective zincation of bromopyridines.[33] They found that the deprotonation of 2-bromopyridine (35) with 1 at room temperature followed by electrophilic trapping with iodine resulted in functionalisation at the C6-position. The same reaction carried out with iPr2NZntBu2Li at –20 °C yielded the C3-functionalised product instead, identical regioselectivity to that observed with LDA,[34] but without the need for cryogenic temperatures or the risk of side reactions such as lithium–halogen exchange or pyridyne formation, even at room temperature (Figure [2]).[35] The metalation of 3-bromopyridine (36) also showed different preferential sites for both bases: C2-position with 1 and C4-position with iPr2NZntBu2Li at room temperature (Figure [2]). Since the pyridine ring is a very common motif in pharmaceutical chemistry, its selective functionalisation is of considerable value to medicinal chemists.[36]

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Figure 2Regioselectivity during the metalation of bromopyridines with TMPZntBu2Li and iPr2NZntBu2Li

A similar switch in metalation regioselectivity was observed for the continuous flow zincation of 2,5-dihalopyridine 37. The use of LiCl-activated TMP bases such as TMPZnCl·LiCl 3 results in the formation of a kinetic product and metalation α to the heteroatom. In contrast, under thermodynamically controlled reaction conditions (60 °C, 10 min) in a flow reactor with (Cy2N)2Zn·2LiCl, zincation proceeds preferentially at the C4-position (Scheme [9]).[32]

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Scheme 9Regioselective continuous flow zincation-arylation of 2,5-dichloropyridine

Halopyridines bearing other substituents are also compatible with neutral zinc bases. In 2007, the Knochel group demonstrated metalation of a 2-chloro-3-nitropyridine (40) with (TMP)2Zn·2MgCl2·2LiCl 2 at –40 °C in 1.5 h followed by a subsequent copper-catalysed allylation with 3-bromocyclohexane (Scheme [10]); the final product 42 was obtained in 80% yield.[9] In 2010, the Knochel group suggested an alternative procedure with TMPZnCl·LiCl 3 under milder conditions: 25 °C for 5 h. The deprotozincation was conducted on a large scale (50 mmol) and the intermediate 43 was acylated using an acid chloride and CuCN to give 44 in 77% yield (Scheme [10]).[26]

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Scheme 10Zincation of 2-chloro-3-nitropyridine with (TMP)2Zn·2MgCl2·2LiCl and TMPZnCl·LiCl

The exceptional selectivity of base TMPZnCl·LiCl 3 was also used for the regioselective zincation of diazines among which pyrimidines are of the highest importance as a prevalent scaffold in the FDA-approved drugs list.[36] [37] However, functionalisation of pyrimidine (45) at the C2-position poses a challenge as this position has the highest calculated pK a value (Figure [3]).[38] This is especially problematic for unsubstituted pyrimidine which lacks directing group effects that aid regioselective control. Deprotonation with lithium bases often leads to formation of pyrimidine dimers, as well as byproducts from nucleophilic side-reactions.[39] The use of a milder neutral zinc base instead allowed for successful metalations and subsequent electrophilic quenching at the C2-position, generating C2-substituted pyrimidines of type 46 in good yields (70–95%) at room temperature (Scheme [11]). The same approach was tested for 5-methylpyrimidine (47a), 5-p-tolylpyrimidine (47b), ethyl pyrimidine-5-carboxylate (47c), silyl-protected fenarimol derivative 47d, and 5-(1,3-dioxolan-2-yl)pyrimidine (47e). The metalations proceeded smoothly, although, 47e, 47b, and 47c required heating at 50 °C (2 h), 50 °C (3 h), and 60 °C (1 h), respectively, to react. Then, the zincated functionalised pyrimidines of type 48 underwent iodine trapping (68–93% yield), palladium-catalysed cross-couplings with functionalised aryl iodides (64–83% yield), or cobalt-catalysed amination (54–61% yield) (Scheme [12]). Use of zinc base allowed for a regioselective, previously unachievable transformation.

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Scheme 11Zincation of pyrimidine
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Scheme 12Zincation of substituted pyrimidines

Pyrimidine zincation has found additional roles in pharmaceutical synthesis. Pilli and co-workers have recently reported the use of TMP2Zn·2MgCl2·2LiCl 2 in the synthesis of antimalarial P218 (52) via zincation of a dichloroalkoxypyrimidine precursor 50 in the only remaining heteroaryl C–H position before trapping with iodine (Scheme [13]).[40] Notably, a high yield of 88% was obtained without reaction at the chloroaryl, enone, or ester moieties after a short optimisation.

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Scheme 13Pyrimidine zincation in antimalarial synthesis

The high selectivity and sensitive functional group tolerance of zinc bases have been used for a large-scale (90 kg) synthesis of an antitumour drug intermediate, ARS-1620.[41] Sales et al. tested both MgTMP and ZnTMP bases and found that the use of TMP2Zn·2MgCl2·2LiCl 2 not only results in higher yields than with TMPMgCl·LiCl (93% vs. 65%), but also the reaction proceeds at room temperature rather than at –30 °C. Thus, they incorporated the zincation step into their scaled-up reaction sequence and obtained key synthetic intermediate 59 in 85% yield with 99% purity (Scheme [14]).

The Knochel group have also employed TMPZnCl·LiCl 3 as a zincation reagent for tert-butyl ester substituted naphthyridine ring 60 using very mild conditions. Substitution at the C4-position precludes the complexation of zinc to the neighbouring N5 position and instead favours complexation at N1 where directed zincation happens at the C8-position (Scheme [15]). Following zincation, electrophilic trapping using I2, copper-catalysed allylation, or Negishi cross coupling were utilised giving products 62, 63, 64a, and 64b in yields of up to 98%.[42]

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Figure 3Pyrimidine pK a values
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Scheme 14Multikilogram synthesis of antitumour agent via zincation
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Scheme 15 Zincation of tert-butyl naphthyridine-4-carboxylate

Metalations of pyridazines 65 are challenging, however the Knochel group achieved this by performing boron Lewis acid catalysed regioselective zincations using TMPZnCl·LiCl 3. ortho- and meta-Zincations have been reported using Lewis acids BF3·OEt2 and 5,10-dichloro-5,10-dihydroboranthrene, respectively (Scheme [16]).[43]

The addition of BF3·OEt2 was shown to decrease the pK a of the proton at C3 on the pyridazine ring from 36.9 to 24.9 which enables the zinc bases to readily remove the proton at this position. The boranthrene was shown to decrease the pK a of the proton at C4 from 34.8 to 25.8 and the proton at C3 down to 23.2.[43] The increased acidity of the proton at C3 however did not lead to deprotonation here due to steric effects from the bulky Lewis acid. Instead, the ring was deprotonated at C4 and was trapped with iodine to give the 4-substituted product 70 in 63% yield. Following this development, the Knochel group developed a protocol for directed ortho-zincations of pyridazines without the use of Lewis acids (Scheme [17]). They employed the use of TMPZnCl·LiCl 3 at 70 °C for 2 h followed by iodination, copper-catalysed allylation, or palladium-catalysed arylation.[37]

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Scheme 16Zincation of pyridazines
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Scheme 17Lewis acid free zincation-arylation of pyridazines

The Knochel group reported using the same chemistry on 2-pyridones 72 (Scheme [18]) and 2,7-naphthyridone 76 (Scheme [19]) using the zincating reagent TMP2Zn·2MgCl2·2LiCl 2. A 2-methoxyethoxymethyl (MEM) protecting group was installed on 72 and 76 prior to zincation, which was found to be incompatible with lithiation and magnesiation. Trapping of zincated intermediate 73a and 73b with I2 gave the corresponding iodinated products 74a and 74b in yields of 93% and 80%, respectively. Negishi cross-coupling reactions were also investigated, yielding arylated products in up to 92%. The same iodine trapping procedure was used on naphthyridone 76 and gave the trapped product 78 in 90% yield, similar to the yields for 2-pyridones. Negishi cross coupling was achieved using 3 different palladium-catalysed protocols (dependant on the aryl halide coupling partner) and gave the products 79 in good yields of 52–86%.[44]

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Scheme 18Zincation of 2-pyridones
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Scheme 19Zincation of naphthyridone
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Scheme 20Zincation-arylation of pyrazolo[1,5-a]pyridine

The Knochel group have also reported the first direct zincation of pyrazolo[1,5-a]pyridine (80) using TMPZnCl·LiCl 3. The group successfully performed a Negishi cross coupling with the zincated intermediate to give the p-(ethoxycarbonyl)phenyl- and m-methoxyphenyl-substituted products 81a and 81b in 97% and 74% yield, respectively (Scheme [20]).[45]

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Scheme 21 Zinc-mediated functionalisation of 1,3,4-oxadiazoles
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Scheme 22Functionalisation of 1,2,4-triazoles using TMPZnCl·LiCl
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Scheme 23Cu-catalysed cyclisation of an N-iodobenzyltriazole following C–H zincation with TMPZnCl·LiCl

1,3,4-Oxadiazoles and 1,2,4-triazoles are difficult to functionalise heterocycles that were found to be compatible with mild zinc base conditions;[9] [46] metalations with magnesium and lithium bases do not work well leading to the fragmentation of the heterocycles.[12] [13] For 1,3,4-oxadiazole (82), the Knochel group demonstrated a selective double functionalisation in multiple steps using TMP2Zn·2LiCl at rt for 5 min, which was found to be the most efficient for the first zincation-arylation, and TMP2Zn·2MgCl2·2LiCl 2 at rt for 20 min for the second deprotonation (Scheme [21]).[46] A wide scope of 1,3,4-oxadiazoles of type 84 bearing two functional groups, one arene and one amine, were obtained in high yields. The scope of the hydroxylaminobenzoate derivatives included reagents derived from morpholine, diallylamine, azepane, and piperazine, while a variety of amines bearing functional groups such as ester, protected ketone, and an amide could be prepared.

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Scheme 24Large-scale zincation-electrophilic trapping of 4H-chromen-4-one

An N-protected 1,2,4-triazole 85 was metalated using TMPZnCl·LiCl 3 for 30 min at 0 °C in two sequential deprotonation–trappings to give first 5-substituted product 1,2,4-triazole 86 and then the 3,5-disubstituted 1,2,4-triazole 87 (Scheme [22]). The scope of fully functionalised triazoles 87 via the use of zinc bases is limited to this one example and leaves the topic underexplored. Interestingly, TMPZnCl·LiCl 3 was also used to perform a copper-catalysed cyclisation of N-2-iodobenzyl-protected 1,2,4-triazole 88 in 94% yield (Scheme [23]).[46]

Another pharmaceutically useful heterocycle functionalisation was achieved using TMPZnCl·LiCl 3 for selective zincation of 4H-chromen-4-one (90).[47] It was found that the use of the zinc base alone induces metalation at the C3-position, analogous to ortho-metalation this is triggered by carbonyl coordination to the metal base, whereas in the presence of MgCl2, zincation happens preferentially at C2-position as a result of the stronger Lewis acid coordinating to the carbonyl and preventing the base from doing so (Scheme [24]). The same reaction was successfully carried out on a multigram scale (50 mmol) maintaining both the high yields and an exceptional regioselectivity. A structural isomer of 4H-chromen-4-one, 2H-chromen-2-one (coumarin; 97), also reacts smoothly at 25 °C with TMP2Zn·2MgCl2·2LiCl 2 and after subsequent electrophilic trapping, gives the final product 99 in 71% yield on a large (100 mmol) scale.[28] With milder base TMPZnCl·LiCl 3, the metalation of 97 takes a week to proceed at rt, however, if heated in a microwave reactor at 80 °C, 1 h is enough to achieve a full conversion (Scheme [25]).[31]

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Scheme 25Zincation of 2H-chromen-2-one with TMP2Zn·2MgCl2·2LiCl and TMPZnCl·LiCl

Non-aromatic heterocycles can also be metalated at Csp2–H positions easily with zinc bases. Oxazolines benefit from mild reaction conditions as their deprotonation at the C2-position with traditional organolithiums and organomagnesiums leads to ring fragmentation.[48] In contrast, direct C–H functionalisation of 4,4-dimethyloxazoline (102) using TMPZnCl·LiCl 3 (0 °C, 1 h) results in a formation of 4,4-dimethyloxazolinylzinc intermediate 103 in 94% yield (Scheme [26]);[49] 103 is stable at room temperature and does not undergo fragmentation. It can subsequently be trapped with an electrophile either through cross-coupling reaction or copper-catalysed acylation to yield 2-substituted oxazolines of type 104 in high yields ranging between 64% and 92%. It is a synthetically valuable transformation since oxazolines are commonly used as ortho-directing groups.[50]

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Scheme 26 C2-Zincation of 4,4-dimethyloxazoline with TMPZnCl·LiCl

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# 3

Csp3–H Functionalisation Using Zinc Bases

As discussed in Section 2, zinc bases have been extensively used for Csp2–H functionalisations, and hence the substrate scope is broad and includes numerous arenes and heterocycles bearing various functional groups. Zincation of Csp3 sites, however, is less frequently reported in the literature and is mostly dominated by deprotonations in the α-position to a carbonyl moiety, leading to zinc enolate formation. Herein we compare traditional methods of zinc enolate preparation with modern zinc base approaches as well as isolated examples of other types of Csp3–H zincations.

3.1

Zinc Enolate Formation: Traditional Approach

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Scheme 27The Reformatsky reaction

There are three general approaches to the synthesis of zinc enolates: insertion of Zn(0) into the carbon–halogen bond of an α-halo ester (Reformatsky’s enolate), transmetalation of a lithium enolate with Zn(II) salts, and catalytic addition of dialkylzinc to Michael acceptors.[51] The classical Reformatsky reaction involves the formation of β-hydroxy esters via addition of an aldehyde or a ketone to an α-halo ester of type 105 in the presence of zinc powder.[2] [51] [52] In 1943, Gilman and Speeter reported the first use of imine derivatives (i.e., Y = NR) in place of a carbonyl compound to yield β-amino esters in a modified version of the Reformatsky reaction (Scheme [27]).[53] This straightforward procedure for obtaining zinc enolates has its limitations; the surface of zinc powder has been shown to be covered with a thin layer of passive zinc oxide, which decreases the available reactive surface area.[54] Zinc reactivation can be achieved by treatment with trimethylsilyl chloride (TMSCl),[54] trifluoroacetic acid (TFA),[55] addition of diethylaluminium chloride (DEAC) in THF,[56] or addition of Lewis acidic BF3·Et2O,[57] which adds extra steps to the synthesis and can pose safety issues. Additionally, in comparison to direct deprotozincation, pre-functionalised, halogenated substrates are required adding to cost and producing an equivalent of HX waste.

Another method, transmetalation, is also common and involves use of reactive bases, usually organolithiums[58] or lithium amides.[59] This straightforward transformation may prove problematic due to unwanted nucleophilicity, rigorous temperature control (cryogenic), and instability in common solvents (e.g., THF) imposed by proceeding via an organolithium intermediate.[60] Nevertheless, it has been used extensively and successfully with less demanding substrates. For example, in 1997, Koizumi and co-workers described an enantioselective protonation of zinc enolates using a chiral γ-hydroxy selenoxide 111 (Scheme [28]).[58] The group demonstrated that switching lithium enolates to zinc enolates of type 110 improves not only the yield, but also the enantioselectivity by zinc coordinating simultaneously to the hydroxyl group and the oxygen bonded to selenium of the γ-hydroxy selenoxide 111 as well as the enolate oxygen, rigidifying the transition state.

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Scheme 28Enantioselective protonation of zinc enolates

# 3.2

Zinc Enolate Formation via Zinc Bases

Traditional approaches for obtaining zinc enolates impose several limitations, therefore, an alternative method that overcomes all the problems outlined in Section 3.1 is necessary and has emerged in the form of a selective C–H metalation in the α-position of carbonyl-bearing substrates using Zn-TMP bases. The first successful direct zincation of a Csp3–H was reported by Hlavinka and Hagadorn, who used Zn(TMP)2 4 on carbonyl substrates 113 (in a 1:2 stoichiometry of 4/113) bearing different functionalities including esters, amides, and ketones.[11] The reported metalations proceeded in high yields (100% by in situ 1H NMR) at room temperature and the zincated intermediates underwent electrophilic quenching in a Pd-catalysed reaction with PhBr to give products 115 in up to 96% yield (Scheme [29]).

McDonald and Wang used TMP2Zn 4 to explore dual reactivity of O-acylhydroxylamines toward zinc enolates.[61] Since O-acylhydroxylamines can be used either as aminating or as acylating agents, they wished to determine reaction conditions that would unlock both reaction modes selectively. It was shown that if a zinc enolate of 116 is treated with an O-acylhydroxylamine, acylation is preferred and a 1,3-dicarbonyl compound 117 is obtained (Scheme [30]). If a copper catalyst is present, the reaction mode switches into amination with α-amino ketones 118 obtained in up to 99% yield (Scheme [31]). To the authors’ best knowledge, it was the first case of an electrophilic, one-step α-amination of zinc enolates. The procedure thus developed also overcomes the limitations that stem from the presence of a sensitive functional group and alleviates the need for subsequent amine modification.

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Scheme 29Direct zinc enolate formation using TMP2Zn followed by Pd-catalysed arylation
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Scheme 30α-Acylation of tert-butyl acetate using TMP2Zn then O-acylhydroxylamines
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Scheme 31Cu-catalysed α-amination of tert-butyl acetate following zincation

# 3.3

Non-Enolic Csp3–H Zincations

Despite the growing popularity of zinc bases and their successful use to obtain zinc enolates, there are few extant examples of unactivated Csp3–H functionalisations. An early example was reported by Hlavinka and Hagadorn, who used their zinc base TMP2Zn 4 to deprotonate 2-methylpyridine (119), dimethyl methylphosphonate (122), trimethylphosphine oxide (125), dimethyl sulfoxide (DMSO; 129), and dimethyl sulfone (127).[11] The reported metalations were high yielding (100% by in situ 1H NMR) at room temperature, except for 2-methylpyridine (119), which required heating at 50 °C. The zincated intermediates of 119 and 122 underwent electrophilic quenching in a Pd-catalysed cross-coupling reaction with PhBr (Scheme [32]). Further reactions of zinc intermediates 125, 127, and 129 were not reported. Interestingly, metalation of 119 leads to the formation of an aza-enolate intermediate. However, to the best of our knowledge, this is the only example of a direct synthesis of zinc aza-enolates reported in the literature, leaving the research area under-investigated. Zinc aza-enolates are predominantly obtained via transmetalation of lithiated species with zinc halides or dialkylzincs, which is a method of limited utility due to poor functional group tolerance.[62] Developing a protocol for a direct and selective synthesis of this moiety under mild conditions would be beneficial and pharmaceutically relevant, especially for functionalisation of common drug scaffolds such as thiadiazoles, pyridines, pyrimidines, triazoles, and tetrazoles.[36]

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Scheme 32Csp3–H zincations using TMP2Zn

Another example of a direct Csp3 zincation was reported by Dalziel, Carrera, and co-workers who worked on a highly diastereoselective α-arylation of 3-methyl-3-(triethylsiloxy)cyclobutanecarbonitrile (131) to form cis and trans diastereomers of type 132.[63] They discovered that for this purpose switching the literature conditions of LiHMDS to TMPZnCl·LiCl 3 significantly increased the diastereoselectivity. Further reaction optimisation to include a precatalyst with a large bite angle improved both the reaction efficiency and diastereoselectivity (Scheme [33]). Additionally, the reaction conditions were tested on different functionalised cyclic nitriles to obtain a scope of compounds for structure-activity relationship (SAR) studies (Scheme [34]).

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Scheme 33Zincation-arylation and zincation-vinylation of a cyclobutanecarbonitrile derivative
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Scheme 34Zincation of functionalised cyclobutanecarbonitriles

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# 4

Conclusion

Zinc bases offer exceptional selectivity and high functional group tolerance for metalation reactions. Their use often alleviates the need for cryogenic temperatures and protecting groups, saving both time and resources, hence making them attractive alternatives to organolithium and organomagnesium reagents. Zinc bases have been successfully applied to Csp2–H functionalisation of a diversity of substituted arenes and heterocycles. Extensive research has been carried out to investigate the regioselectivity of these reagents and numerous strategies have been developed to control it utilising different reaction conditions. Csp3–H functionalisations, however, remain elusive and are limited mostly to enolate formation. Given the drive to diversify pharmaceutical candidates away from heavily Csp2-dominated structures,[64] as well as the compatibility of organozincs with druglike substrates, we propose that the unique advantages of organozinc chemistry may allow powerful new Csp3–H functionalisation protocols to be developed in line with the needs of colleagues active in pharmaceutical research.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Frederick G. Powell for proofreading this manuscript.


Corresponding Author

Graeme Barker
Continuum Flow Lab, Heriot-Watt University
Riccarton, Edinburgh, EH14 4AS
UK   

Publication History

Received: 10 July 2023

Accepted after revision: 16 August 2023

Accepted Manuscript online:
16 August 2023

Article published online:
15 September 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


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Dr Graeme Barker (left) obtained his MChem (Hons.) in 2007 from the University of St Andrews before moving to University of York for a Ph.D. under the supervision of Prof. Peter O’Brien. In 2011 he moved to University of Sheffield as a PDRA with Prof. Iain Coldham, and in 2013 to Heriot-Watt University as a PDRA with Dr Ai-Lan Lee. He was appointed to an assistant professorship at Heriot-Watt in 2016, where his research interests include synthetic methodology, flow chemistry, and medicinal chemistry for therapeutic intervention in cell signalling cascades. Daria Wanic (right) and Rebecca Melvin (centre) were Heriot-Watt undergraduate students in chemistry and graduated with MChem degrees in 2023, both with first class honours.
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Figure 1Zn-TMP complexes: selected examples
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Scheme 1Directed ortho-metalation using TMPZntBu2Li
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Scheme 2Amination of functionalised arenes using an anionic base
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Scheme 3Zinc ‘ate’ bases for arene functionalisation: reaction proceeds via two different intermediates depending on zinc alkyl ligands
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Scheme 4Zincations of aryl nonaflates with TMPZnCl·LiCl followed by electrophilic trapping
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Scheme 5Further reactions with zinc bases showing high functional group tolerance: (a) direct zincation of difluoronitrobenzene and subsequent electrophilic trapping; (b) large-scale direct zincation of 4-cyanobenzoate followed by Negishi coupling with PhI
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Scheme 6Zincation of functionalised arenes with and without microwave irradiation
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Scheme 7Direct zincation of 2-bromo-4-fluorobenzonitrile at elevated temperatures
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Scheme 8Continuous flow zincation of 2,4-difluoro-1-nitrobenzene with subsequent Pd-catalysed Negishi cross coupling
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Figure 2Regioselectivity during the metalation of bromopyridines with TMPZntBu2Li and iPr2NZntBu2Li
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Scheme 9Regioselective continuous flow zincation-arylation of 2,5-dichloropyridine
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Scheme 10Zincation of 2-chloro-3-nitropyridine with (TMP)2Zn·2MgCl2·2LiCl and TMPZnCl·LiCl
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Scheme 11Zincation of pyrimidine
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Scheme 12Zincation of substituted pyrimidines
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Scheme 13Pyrimidine zincation in antimalarial synthesis
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Figure 3Pyrimidine pK a values
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Scheme 14Multikilogram synthesis of antitumour agent via zincation
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Scheme 15 Zincation of tert-butyl naphthyridine-4-carboxylate
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Scheme 16Zincation of pyridazines
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Scheme 17Lewis acid free zincation-arylation of pyridazines
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Scheme 18Zincation of 2-pyridones
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Scheme 19Zincation of naphthyridone
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Scheme 20Zincation-arylation of pyrazolo[1,5-a]pyridine
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Scheme 21 Zinc-mediated functionalisation of 1,3,4-oxadiazoles
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Scheme 22Functionalisation of 1,2,4-triazoles using TMPZnCl·LiCl
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Scheme 23Cu-catalysed cyclisation of an N-iodobenzyltriazole following C–H zincation with TMPZnCl·LiCl
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Scheme 24Large-scale zincation-electrophilic trapping of 4H-chromen-4-one
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Scheme 25Zincation of 2H-chromen-2-one with TMP2Zn·2MgCl2·2LiCl and TMPZnCl·LiCl
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Scheme 26 C2-Zincation of 4,4-dimethyloxazoline with TMPZnCl·LiCl
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Scheme 27The Reformatsky reaction
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Scheme 28Enantioselective protonation of zinc enolates
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Scheme 29Direct zinc enolate formation using TMP2Zn followed by Pd-catalysed arylation
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Scheme 30α-Acylation of tert-butyl acetate using TMP2Zn then O-acylhydroxylamines
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Scheme 31Cu-catalysed α-amination of tert-butyl acetate following zincation
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Scheme 32Csp3–H zincations using TMP2Zn
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Scheme 33Zincation-arylation and zincation-vinylation of a cyclobutanecarbonitrile derivative
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Scheme 34Zincation of functionalised cyclobutanecarbonitriles