En route to metal-mediated and metal-catalysed reactions in water

This perspective report presents the key approaches for the development of various organometallic reactions in aqueous media.


Introduction
Carbon-carbon bond formation plays the central role in synthetic organic chemistry. For polar routes, such transformations necessarily involve carbon nucleophiles and electrophiles. 1 One class of the most commonly used nucleophiles is organometallic compounds. Since the discovery of alkylzinc compounds by Frankland from the reaction of iodoalkanes with metallic zinc, 2 organometallic reagents serving as nucleophiles for organic syntheses have been rapidly evolved both in scope and application. [3][4][5][6][7] The early discoveries of Reformatsky, 8 Barbier, 9 Grignard, 10 and Gilman 11 are among the important milestones in the development of classical organometallic reactions. Subsequently, there have been great progresses in the use of alkali 12 and other metals since the 1930s. Recently, organometallic reactions catalysed by transition metals have become increasingly important in the synthesis of organic molecules, 13 underscored by three Nobel Prizes: for palladiumcatalysed cross-coupling in 2010, [14][15][16] olen metathesis in 2005 [17][18][19] and asymmetric catalysis in 2001 [20][21][22] within the last decade.
In spite of the enormous progress being made, there are obvious shortcomings for classical organometallic reactions in terms of chemical sustainability, such as the extensive use of organic solvents, stoichiometric metals, moisture and functional group intolerances, which are partially ascribed to the limitation of the historical development of classical reactions from fossil based feedstocks 23 bearing no functional groups and being insoluble in water. Accordingly, classical organic reactions were intuitively developed in fossil originated organic solvents. With the increasing concerns of the depletion of nonrenewable fossil resources and the environmental deterioration, 24 developing products from renewable resources and improving resources/energy utilization efficiency are the key measures towards future chemical sustainability. 25 Biomass, as a sustainable and renewable feedstock provided by nature could be a practical alternative towards future chemicals. [26][27][28] In contrast to the fossil-based feedstocks, biomass-based ones are generally over-functionalized and oen soluble or soluble aer depolymerisation in water. As a result, further processing is required to adapt them to the reaction conditions that were initially developed for fossil-based classical organometallic reactions in organic solvents. One of the most common strategies for such purposes is the exhaustive protecting group manipulations, which in turn limiting the possibility of using water as solvent and leading to extra steps and waste etc. Conversely, exploration of organometallic reactions directly in water could be a possible solution in terms of various functional groups tolerance and direct chemical modi-cation of biomolecules. Hence, exploring such fundamentally novel chemistry would potentially simplify chemical synthesis signicantly, improve synthetic efficiency, provide valuable tools for chemical biology, and contribute to the future chemical sustainability 29 with respect to atom-economy, 30 the Efactor 31 and step-economy. 32

General design concept
Most classical organometallic compounds are highly polarized as carbanions, which are also strong bases. Consequently, they are unstable towards active protons (moisture or functional groups) and must be synthesized/used under strictly anhydrous/aprotic conditions. Conceptually, the key to developing successful organometallic reactions in water (aqueous media) is to attenuate or prevent the protonation of carbonmetal bond once the organometallic species is generated (eqn (1)).
There are several conceivable approaches to achieve this objective. The most straightforward approach is to tune the relative electronegativity 33 between carbon and metal atoms to form the more covalent C-M bond. A second approach is to design radical pathways, as the strong O-H bond (enthalpy 436 kJ mol À1 ) is very difficult to break homolytically. The third approach is to mimic nature's lipid bilayer membrane 34 by physically segregating and temporarily stabilizing the organometallic species from water via micelle formation using surfactants 35 or on water strategy. [36][37][38] The fourth approach is to bypass the stoichiometric organometallic reagents by transition-metal-catalysed organic transformations in water, such as via C-H bond activation and hydrazone umpolung. 39,40 This perspective article will illustrate these aspects using the classical nucleophilic additions as examples.

Various approaches
Moving towards more covalent C-M bond The main reason for the necessary anhydrous conditions in classical organometallic reactions was due to the highly polarized and reactive C-M bonds towards water, 3 especially the organometallic compounds of s-block elements. As C-M bonds become more covalent, such as the organometallic compounds of group 14 and group 15, they have less carbanion character and thus are less prone to acidic proton and relatively more stable in aqueous media. Different from s-block and late pblock organometallic compounds, the ones from group 13 elements take up a special position within the main group due to their moderate reactivity towards water. 41 Furthermore, certain classes of organometallics remain viable in the presence of water. For example, the preparation of arylmercuric chlorides in aqueous media has been known since 1905. 42 In the 1960's, tribenzylstannyl halide was prepared in large scale in water (Scheme 1). [43][44][45] The Wurtz-type reductive coupling of allyl halides proceeded in aqueous alcohol. 46 These reports opened up new perspectives regarding the metal-mediated organic reactions and it has been increasingly realized that these kinds of reactions can be conducted in water under special circumstances. Indeed, there has been great progress in this research area over the past decades, such as allylation, 47-49 allenylation, 50,51 propargylation, 52,53 benzylation, 54 phenylation 55,56 etc.
The most explored reaction is the allylation of carbonyls and other electrophiles with allyl halides mediated by various metals (Scheme 2), 57 among which the use of indium to mediate the Barbier-Grignard-type reactions in water reported by Li and Chan received particular attention (Scheme 3). 48 This was attributed to the fact that on one hand, indium possesses the lowest rst ionization potential among the metallic elements near it in the periodic table; and on the other hand, it does not form oxides readily in air and is not sensitive to boiling water or alkali. Consequently, indium was shown to be the most effective for such transformations in water, proceeding smoothly at room temperature without any promoter. This methodology has found wide applications in aqueous synthetic chemistry, [58][59][60][61] particularly important in carbohydrate chemistry.
For example, Chan and Li 62 reported a concise and stereoselective synthesis of (+)-3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) from D-mannose (Scheme 4) and a formal synthesis 63 of KDO (Scheme 5), whereas Whitesides reported the synthesis of N-acetyl-neuraminic acid (Scheme 6) 64 and other sialic acid derivatives by the method. 65,66 This chemistry has also been extended to six-carbon sialic acid derivatives by Chappell and Halcomb 67 and the protocol has been further improved by Warwel and Fessner. 68 Besides being used successfully in carbohydrates chemistry, the metal-mediated allylation has also been applied to the synthesis of other scaffolds such as 1,3-butadienes, 69 Scheme 1 Direct synthesis of tribenzylstannyl halide in water.  vinyloxiranes, 2-methylenetetrahydrofurans, 70 trimethylenemethane equivalent, 71 cyclopentane derivatives. 72 A carbocyclic ring enlargement methodology was also developed (Scheme 7), 73,74 by using the indium-mediated Barbier-type reaction in water, in which 5-, 6-, 7-, 8-, and 12-membered rings are expanded by two carbon atoms into 7-, 8-, 9-, 10-, and 14-membered ring derivatives respectively. The use of water as a solvent was found to be critical for the success of the reaction and similar ring enlargement in organic solvents was not successful. Such a ring expansion strategy can also be applied to heterocyclic medium ring and 75 one carbon-ring expansion. 76 The diastereoselectivity of such reaction was studied in detail by Parquette and co-workers, and found that the free hydroxyl derivatives react with excellent diastereofacial control to give signicantly heightened levels of syn-1,2-diols and antidiols (Scheme 8). 77 Relative reactivities were determined in the a-series and the hydroxyl aldehyde proved to be the most reactive substrate. This reactivity ordering suggests that the selectivity stems from chelated intermediates. The rate acceleration observed in water can be heightened by initial acidication. Then they reported a variety of diastereoselective allylations in aqueous conditions and their synthetic applications such as a practical alternative to the Knoevenagel reaction of aliphatic aldehydes, the formation of a-methylene-g-lactones fused to medium and large rings and the intercalation of multiple carbon atoms between the carbonyls of a-diketones. 78 In 2002, Delgado and co-workers reported a Barbier-type diastereoselective allylation of a-amino aldehydes with an enantiopure 2-sulnylallyl building block in aqueous media mediated by zinc (Scheme 9). 79 High levels of diastereoinduction can be achieved from a-amino aldehydes congurationally related to natural a-amino acids.
The enantioselectivity of such reactions in water was also possible. In 1999, an enantioselective allylation reaction of aldehydes in an aqueous media using chiral pyridine bis(oxazoline) ligand was reported by Loh and co-workers (Scheme 10a). 80 Subsequently, a AgNO 3 /(S)-Tol-BINAPcatalysed enantioselective allylation of aldehydes using allyltributylstannane was achieved by the same group (Scheme 10b). 81 Later, they reported an enantioselective allylation of aldehyde catalysed by a moisture-tolerant chiral (S)-BINOL-In(III) complex. The allylation of a variety of aromatic, a,bunsaturated and aliphatic aldehydes resulted in both moderate to good yields and high enantioselectivities (Scheme 10c). 82 In 2003, Kobayashi and co-workers reported a catalytic asymmetric allylation of aldehydes using allyltributyltin in aqueous media via the combination of cadmium bromide and chiral diamine ligands. Interestingly, these ligands were found to accelerate the reactions signicantly (Scheme 11). 83 Later, they reported an In-catalysed allylation of ketone with allyl Scheme 6 Synthesis of (+)-N-acetyl neuraminic acid.

Scheme 7
In-mediated carbocyclic ring expansion in water.

Scheme 8
In-mediated diastereoselective allylation of a-oxy aldehydes in water.
boronates in water (Scheme 12). 84 Preliminary asymmetric study using chiral bis-oxazoline ligand showed that a moderate enantioselectivity can be obtained.
In addition to allyl halides, structurally related propargyl halides are also effective for such type of reactions. In 1995, Issac and Chan reported their studies of the propargylation of aldehydes in aqueous medium mediated by indium (Scheme 13). 52 They found that simple prop-2-yn-1-yl bromide reacted with both aliphatic and aromatic aldehydes in water to afford mainly the homopropargyl alcohols. In contrast, when propargyl bromide was g-substituted, the coupling products were predominantly, or exclusively, the allenylic alcohols. Such couplings also proceed with a-chloropropargyl phenyl sulde. 85 The indium-mediated coupling of propargyl bromide with a variety of imines and imine oxides afforded homopropargylamine derivatives in aqueous media under mild conditions (Scheme 14). 86 Propargylation of glyoxylic oxime ether in the presence of a catalytic amount of palladium(0) complex and indium(I) iodide in aqueous media was also studied. 87 The indium-mediated highly diastereoselective allenylation in aqueous medium was also highly successfully applied to the total synthesis of (+)-goniofufurone (Scheme 15). 50,51 Benzyl halides and allyl(propargyl) halides are structurally similar but have distinctively different chemical reactivities in the aqueous Barbier-Grignard-type reactions. Although tribenzyl and dibenzyltin derivatives have been prepared in aqueous conditions since the 1960s, they do not add onto carbonyls, most likely because it is not possible to form a six-membered cyclic transition state with the carbonyl group in a 'twocomponent' fashion. Still, a zinc-mediated benzylation of carbonyl compounds in aqueous media was reported by Wang and co-workers in 2005 (Scheme 16). 88 Compared with allyl and propargyl metal species, p-block aryl-metal (and metalloids) (aryl-tin, aryl-boron, aryl-bismuth, aryl-lead, and aryl-silicon) and vinyl-metal species are highly covalent and very unreactive by themselves. However, by utilizing a transition-metal catalyst, such aryl (and vinyl) derivatives become highly reactive, yet stable towards water and protonic functional groups. This strategy has been widely applied for their various cross-coupling reactions with organic halides. 89 By using a similar strategy, rhodium 90-93 and palladium 94,95 catalysed arylation of carbonyls and (asymmetric) conjugate additions 96-101 with aryl-metal reagents in water and under an air atmosphere are successful (Scheme 17a). 55 A strong electronic effect on Rh-catalysed carbonyl additions and conjugated additions with various arylmetallic reagents was observed (Scheme 17b). 56 Moving towards more radical character Radicals are neutral species with one unpaired valence electron, which, in contrast to organic anions and cations, make them chemically "stable" towards water. Indeed, the aqueous radical Scheme 11 Cd-catalysed asymmetric allylation of aldehyde using allyltributylstannane in an aqueous media.

Scheme 12
In-catalysed asymmetric allylation of ketone using allyl boronate in water.

Scheme 13
In-mediated propargylation of aldehydes in water.
Scheme 15 Indium-mediated allenylation in aqueous media and its application to the synthesis of (+)-goniofufurone.
Scheme 16 Zn-mediated benzylation of carbonyl compounds in aqueous media in the presence of CdCl 2 and InCl 3 . chemistry predominates in biological processes. 102,103 As radicals are nonpolar, their additions to C]C bonds were rst realized in water. In 1998, Oshima and co-workers reported that the Et 3 B-induced atom transfer radical cyclization of allyl iodoacetate proceeded much more smoothly in water at ambient temperature than in benzene or hexane (Scheme 18a). 104 Treatment of the allylic iodoacetate in water with Et 3 B (metalloid) at room temperature for 3 h provided b-iodomethyl-g-butyrolactone in 67% yield. In contrast, in benzene the desired product was not obtained at all and oligomeric by-products were formed.
The remarkable solvent effect of water was also observed in the case of medium and large ring construction. For example, Oshima and co-workers reported an intramolecular cyclization mediated by Et 3 B in water provided the 9-membered lactone in 69% yield (Scheme 18b). The same reaction carried out in benzene afforded much inferior yield. 105 Although the exact role of water was not clear at that stage, a hydrogen bonding between water and the carbonyl oxygen could be formed to facilitate the abstraction of iodine, generating the (alkoxycarbonyl)methyl radical. Hydrophobic interaction may also accelerate the cyclization.
With regard to metal-mediated conjugate additions involving alkyl groups, Luche and coworkers reported that alkyl halides in the presence of zinc-copper couple reacted smoothly with conjugated carbonyl compounds and nitriles to give 1,4addition products in good yields under sonication conditions in aqueous conditions (Scheme 19a). 106-108 A moderate diastereoselectivity was obtained in those reactions where a mixture of diastereomers could be generated. 109,110 The reactivity of the halides followed the order of tertiary > secondary J primary, and iodide > bromide (chlorides did not react). The preferred solvent system was aqueous ethanol. The reaction was proposed to undergo a free radical mechanism occurring on the metal surface under sonochemical conditions (Scheme 19b). Efforts to trap the intermediate intramolecularly only gave a very low yield of the cyclization product. 111 Similar additions also occurred on vinylphosphine oxides. When optically active vinylphosphine oxide was used, P-chiral alkylphosphine oxide was obtained with retention of conguration (Scheme 20). 112 Giese and co-workers studied the diastereoselectivity associated with a related addition in water 113 and found that the anti-isomer was the main product if the attacking radical is bulky (Scheme 21).
The authors rationalized the high diastereoselectivity by proposing that the more stable 'A-strain' conformer of the alkene reacts much slower with bulky alkyl radical than the less stable 'Felkin-Anh' conformer.
The diastereoselective ultrasonically induced 1,4-addition of alkyl iodides in the presence of zinc-copper couple to chiral a,bunsaturated systems in aqueous media was studied by Suarez and co-workers (Scheme 22). They observed that good diastereoselectivities were obtained with the Z-isomer while the reactions with the E-isomer were non-stereoselective. 114,115 For the more challenging nucleophilic addition of radicalbased alkyl-metal species to polar C]X bonds, the key is to

Scheme 19
Zinc-copper couple-mediated conjugate additions of alkyl halides to carbonyl compounds in aqueous media and the proposed radical mechanism.
Scheme 20 Zinc-copper couple-mediated conjugate addition of alkyl halides to vinylphosphine oxides in aqueous media.

Scheme 21
Zinc-copper couple-mediated conjugate addition of alkyl halides and electron-deficient alkenes in water.
prevent the more facile reversed reaction to break the C-C bonds of the radical addition intermediate. One approach is via the stabilization of the radical. Thus, in 2002, Li and co-workers reported a zinc-mediated conjugate addition reaction of alkyl halides to a-phthalimidoacylate derivatives and nucleophilic addition to imines for the efficient synthesis of a-amino acid derivatives and amines in the presence of NH 4 Cl in water (Scheme 23). Notably, no reaction was observed in absence of water. 116 It is noteworthy that Li and co-workers also reported a magnesium-mediated Barbier-type allylation of aldehyde using water as a sole solvent, which proceeds most likely via a radical process on the metal surface (Scheme 24). 117 In 2002, Naito and co-workers reported an intermolecular alkyl radical addition to imine derivatives and electron-decient C-C double bond in aqueous media by using indium as a singleelectron-transfer radical initiator (Scheme 25). 118 The one-pot reaction provided a convenient method for preparing a-amino acids.
In 2003, they reported an indium-mediated cascade reaction, in which the addition-cyclization-trapping sequences efficiently generated the cyclized products in aqueous media (Scheme 26). 119 The substrates bearing vinylsulfonamide and hydrazone proceeded smoothly in aqueous media to provide the functionalized cyclic products.
For the even more challenging Barbier-Grignard-type carbonyl alkylation using unactivated alkyl halides in water, in absence of radical stabilization, the "reductive Lewis acid" concept was used by Li and co-workers successfully, in which conceptually the addition is accompanied by reduction and "free radical intermediate" is not "free" during the reaction progress (Scheme 27). 120 In 2008, Loh and co-workers further developed this Barbier-Grignard-type alkylation reaction of aldehydes including aliphatic version using unactivated alkyl halides in water catalysed by In/CuI or In/AgI catalysis (Scheme 28). 121 The reactions proceeded more efficiently in water than in organic solvent.
Another type of reactions is the metal-mediated Reformatsky-type reaction. The reaction of a metal with an ahalogen carbonyl compound would generate an organometallic intermediate that can equilibrate between the carbanion form and the enolate form. Like the case of allyl and propargyl, the enolate form would allow the reaction to proceed through a sixmembered cyclic transition state and thus could be energetically favorable. Indeed, the reaction of an a-halogen carbonyl compound with an aldehyde in the presence of zinc, tin, or indium in water provided a direct cross-aldol reaction product (Scheme 29). 122,123 While a direct Reformatsky-type reaction occurred in low yields in the case of aromatic aldehydes were Scheme 22 Zinc-copper couple-mediated diastereoselective addition of alkyl iodides and a,b-unsaturated compounds in water.

Scheme 23
Zinc-mediated conjugate addition of alkyl halides to aphthalimidoacylate and imine derivatives in aqueous media.

Scheme 24
Barbier-Grignard allylation of aldehydes with magnesium in water.

Scheme 25
In-mediated alkyl radical addition to imine and phenyl vinyl sulfone derivatives in aqueous media.

Scheme 28
In/CuI or In/AgI-mediated alkylation of carbonyls in water. used in water mediated by zinc. 124 Later Lee and co-workers reported that the reactions of aldehydes or ketones with ethyl bromoacetate in the presence of indium promoted by ultrasound afforded b-hydroxyesters in good to excellent yields under mild conditions. 125 Bieber and co-workers found that even catalytic amounts of benzoyl peroxide or peracids can greatly enhance the reactions of bromoacetates and aromatic aldehydes, giving satisfactory yields. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, was proposed (Scheme 30). 126 The indium-mediated aqueous Reformatsky reaction was successfully applied to the synthesis of a,a-diuoro-b-hydroxy ketones by Welch and co-workers in 2001 (Scheme 31). 127

Via temporarily stabilization (surfactant) or on water strategy
One strategy that nature frequently adopts to perform reactions in aqueous media is encapsulation via lipid bilayer membranes. 34 Chemists, in turn, have developed surfactants that can be self-assembled in water to form micelles, 128 which provide the lipophilic interior to serve, in essence, as the solvent for catalysis. Organic solutes interact with micelles according to their polarity: non-polar solutes are encapsulated in the interior of the micelle, while polar solutes locate themselves at the surface of the micelle and moderately polar molecules would be positioned closer to the polar surface. This compartmentalization of solutes lays the foundation and is responsible for many organic reactions in aqueous media, particularly assisting with organometallic processes, as the lipophilic interior of the surfactants provides the hydrophobic area to temporarily stabilize polar carbon-metal bond and facilitate the chemical transformation, such as in oxidation, reduction and C-C coupling reactions. 129 Recently, the application of surfactants for aqueous catalysis has been demonstrated in the development of catalytic organometallic reactions in water. For example, in 2004, Kobayashi and co-workers reported a Zn-mediated enantio and diastereoselective, stereospecic Mannich-type reaction in water, in which the surfactant CTAB (cetyltrimethylammonium bromide) signicantly improved the yield (Scheme 32). 130 In 2012, Lipshutz and co-workers reported a coppercatalysed conjugate addition of alkyl halides to enones mediated by zinc in aqueous media using TPGS-750-M as surfactant (Scheme 33). 131 Various cross-coupling reactions catalysed by transition metals in aqueous media using surfactants were also reported by his group. 132,133 In 2014, Li and co-workers reported the Rh-catalysed and Znmediated Barbier-Grignard-type arylation of aldehydes using unactivated aryl iodides in water, in which the organometallic species could be temporarily stabilized by encapsulation into the lipophilic interior of the surfactant BrijC10 (Scheme 34). 134 In 2018, Lipshutz and co-workers developed an environmentally responsible, mild method for the synthesis of functionalized 1,3-butadienes via Pd-catalyzed cross-coupling of substituted allenic esters in water in the presence of the surfactant TPGS-750-M (Scheme 35). 135 Various sp-sp 2 , sp 2 -sp 2 , and sp 2 -sp 3 coupling reactions were realized and these transformations tolerated broad functional groups.
As for the reactivity of polar organometallic compounds on water, recently Capriati and co-workers reported the nucleophilic addition of Grignard reagents and lithium reagents to g- Scheme 29 Zn, Sn and In-mediated direct cross-aldol reactions of aldehydes and a-halogen carbonyls.

Scheme 30
Zinc-mediated Reformatsky-type reaction of bromoacetates and aromatic aldehydes and the proposed radical chain mechanism.
Scheme 31 In-mediated synthesis of a,a-difluoro-b-hydroxy ketones in water.
Scheme 32 Zinc-mediated asymmetric Mannich-type reactions in water using CTAB as surfactant. chloroketone on water at room temperature and under air for efficient formation of THF derivatives, in which water may play an important role as demonstrated by the solvent isotope effect and the control experiments that indicate the strong intermolecular hydrogen bonds jointly with trans-phase H-bonding with the substrate, thus (a) shielding the organometallic reagent from competitive protonolysis processes and (b) activating the carbonyl derivative towards nucleophilic addition (Scheme 36a). 136 Later, they further developed the nucleophilic additions of organolithium and organomagnesium reagents to imines and nitriles using bulk water as a privileged reaction medium, working under air, at room temperature, with vigorous stirring (Scheme 36b). 137 The signicant solvent D/H isotope effect observed for the on-water nucleophilic additions of organolithium compounds to imines suggests the on-water catalysis arises from proton transfer across the organic-water interface. The strong intermolecular hydrogen bonds between water molecules may play a key role in disfavouring protonolysis, which occurs extensively in other protic media such as methanol. 138,139 Bypass stoichiometric reagents Via C-H bond activation. The rising of green chemistry raises the awareness of atom economic and environmentally friendly method development. 140 In this context, a large number of highly efficient and selective reaction systems have been developed, in which C-H activation catalysed by transition metals is undoubtedly one of the fastest growing areas. [141][142][143] In view of both synthetic efficiency and future chemical sustainability, the development of the organometallic reactions in water via C-H bond activation, generating a transient C-M based intermediate that quickly reacts with electrophiles rather than water in absence of stoichiometric organometallic reagents, becomes attractive. 144 In the past two decades, there have been great advances in aqueous C-H bond activation catalysed by transition metals. Since C(sp)-H bonds are the most acidic, hence the easiest to activate in water. In 2002, Li and co-workers reported that a bimetallic Ru-In catalytic system could catalyse alkynylation of aldehydes in water (Scheme 37). 145 Then, by using Cu/Ru or Cu/pyridine-oxazoline catalyst, they succeeded the addition and asymmetric addition of arylacetylenes to imines to form propargylamines in excellent yields and enantioselectivity in water (Scheme 38). 146,147 Furthermore a series of transition-metal-catalysed C(sp)-H bond activation reactions in water were reported by his group. 148,149 For the less acidic C(sp 2 )-H bonds, one strategy to facilitate their reaction in water is via chelation. In 2010, Dixneuf and coworkers reported a Ru-catalysed and pyridine-directed C(sp 2 )-H bond activation in water for efficient ortho-phenylation (Scheme 39). 150 The selectivity of mono-phenylation and bisphenylations was found to be better in water than in organic solvent.
In 2012, Ackermann and co-workers developed the Rucatalysed tandem cyclization of aniline derivative and alkyne for efficient indole synthesis via C(sp 2 )-H bond activation in water (Scheme 40). 151 In 2014, Loh and co-workers presented the Rh-catalysed and pyrimidine-directed 2-phenylation of indole derivatives via C(sp 2 )-H bond activation in water using trimethoxyphenylsilane as phenylation reagent (Scheme 41). 152 In 2015, Li and co-workers reported the Rh-catalysed homo-coupling of aryl carboxylic acid in water via two-fold C(sp 2 )-H bond activation using MnO 2 as terminal oxidant (Scheme 42). 153 Such a chelation strategy can also be applied towards the least acidic C(sp 3 )-H bonds. For example, in 2014, Chen and coworkers reported a Pd-catalysed N-quinolylcarboxamide directed b-arylation of alanine at room temperature via C(sp 3 )-H bond activation, in which water is used as a co-solvent (Scheme 43). 154 This method provided a convenient approach for the synthesis of both natural and unnatural aromatic aamino acids.
In 2015, Rao and coworkers reported the Pd-catalysed b-C(sp 3 )-H bond oxidation of amides using 8-aminoquinoline as directing group in water (Scheme 44). 155 Interestingly, the isotope labelling experiment indicates that the oxygen originates from water.
An alternative strategy for the C(sp 3 )-H bonds activation is via radical process. In 2008, Li and co-workers reported a direct addition of cycloalkanes to imines mediated by peroxide and the reaction tolerates a wide range of functionalities as well as aqueous conditions (Scheme 45). 156 Via hydrazone umpolung. Umpolung is a phenomenon in which the polarity of a functional group is reversed. 157,158 This opens up reactions on a functional group which is otherwise not possible. In nature, numerous enzymes such as acetohydroxy acid pseudoephedrine synthase (AHAS) catalyse both nucleophilic acylation and benzoin condensation reactions in aqueous media via umpolung strategy, in which a cofactor thiamine pyrophosphate (TPP) facilitates the catalytic function of these enzymes (Scheme 46). [159][160][161] Inspired by the biocatalytic methods that use enzymes as catalysts for various C-C bond forming reactions, chemists have successfully developed numerous C-C forming reactions based on umpolung with carbonyls as acyl anion equivalents. Most of those reactions were catalysed by either N-heterocyclic carbene (NHC) or cyanide ion. 162,163 Related to organometallic reactions, one attractive approach is the metal-catalysed umpolung chemistry  via hydrazone intermediate that originates from naturally occurring carbonyls (Scheme 47). This strategy not only improves compatibility towards benign protic solvents and accommodates various functional groups, but also provides an opportunity for enantioselective catalysis when involving chiral ligands.
In 2017, Li and co-workers reported the ruthenium catalysed umpolung strategy for the nucleophilic addition to carbonyl 164 (Scheme 48a) and aryl imine 165 (Scheme 48b) compounds through hydrazone intermediates using aldehydes as carbanion equivalents. The unique chemoselectivity exhibited by carbonylderived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility.
Subsequently, they described a ruthenium catalysed conjugate additions via hydrazone approach, in which water was tolerated in the transformation (Scheme 49). 166 Recently, Li and coworkers reported a nickel-catalysed C(sp 2 )-C(sp 3 ) cross-coupling reaction from two sustainable biomass-based feedstocks: phenol derivatives with umpolung aldehydes through moisture/air-stable hydrazones intermediate generated in situ (Scheme 50). 167 Water tolerance, functional group compatibility and late-stage elaboration of complex biological molecules exemplied its practicability and unique chemoselectivity over stoichiometric organometallic reagents. Further development of such reactions in water is foreseen and being actively pursued in our lab.

Conclusions
The past few decades have witnessed the rapid development of water-based organic synthesis, in which the organometallic reactions in water has also made considerable progress. This article aims to summarize the key approaches for realizing the various organometallic reactions focusing on nucleophilic additions in aqueous media, which provides the readers with perspectives for further developments in this eld. In view of future sustainability, the use of renewable biomass-based feedstocks constitutes an important part for sustainable development of chemical industry. The development of efficient organometallic reactions in water provides important tools for the direct conversion of biomass-derived feedstocks into highvalued chemicals and direct modication of biomolecules under native aqueous environment, and constitutes overall synthetic efficiency.

Conflicts of interest
The authors declare no competing interests.