Tailor made mixed-metal reagents for metalation/C-C bond forming processes

The thesis focusses on advancing the understanding on cooperative effects heterobimetallic compounds which combine an alkali-metal with a divalent metal such as magnesium, zinc and manganese. Through rational design, several alkali-metal ates have been prepared and structurally authenticated. Their applications towards two fundamental organic transformations, namely, deprotonative metallation and metal-halogen exchange have been investigated. Chapter 2 discloses a new family of sodium zincates containing the bulky chelating silyl(bis) amide {Ph2Si(NAr*)2}2¯ (Ar*= 2,6-diisopropylphenyl). Illustrating the enhanced kinetic basicity of Zn-N bonds versus Zn-C bonds, reacting Ph2Si(NHAr*)2 (1) with an equimolar mixture of NaCH2SiMe3 and Zn(HMDS)2 (HMDS= N(SiMe3)2) furnished alkyl sodium zincate [{(Ph2Si(NAr*)2)Zn(CH2SiMe3)}¯{Na(THF)6}+] (3). Contrastingly using a stepwise approach, by treating 1 first with NaCH2SiMe3 afforded sodium amide [{Ph2Si(NHAr*)(NAr*)Na}2] (5), which can subsequently undergo co-complexation with Zn(HMDS)2, favouring the metallation of the remaining NHAr* group to give heteroleptic tris(amido) zincate [{(Ph2Si(NAr*)2)Zn(HMDS)}¯{Na(THF)6}+] (6). The reactivity of sodium zincates 6, 3 and [NaZn(CH2SiMe3)3] (4) towards 2,4,6-trimethylacetophenone led to the isolation of enolate complexes [{(THF)NaZn(OC(=CH2)Mes)3}2] (9), [{(THF)NaZn(CH2SiMe3)(OC(=CH2)Mes)2}2] (8), and [{(THF)Na(OC(=CH2)Mes)}4] (10) (Mes= 2,4,6 trimethylphenyl), respectively. These studies revealed that the chelating silyl(bis)amide {Ph2Si(NAr*)2}2− far from being an innocent spectator is an effective base for the deprotonation of this ketone, showing an unexpected superior kinetic basicity than the CH2SiMe3 alkyl group when part of sodium heteroleptic zincate 3. The bimetallic constitution of enolates 9 and 8 contrasts with that of all-sodium 10, which is formed with concomitant elimination of Zn(CH2SiMe3)2. Revealing the divergent behaviour of Mg versus Zn in these bimetallic systems, reaction of 2,4,6-trimethylacetophenone with the magnesium analogue of 3, [{Ph2Si(NAr*)2Mg(CH2SiMe3)}−{Na(THF)6}+] (11), produces magnesiate enolate [{Ph2Si(NAr*)2Mg(O(=CH2)Mes)(THF)}−{Na(THF)5}+] (12), where the chelating silyl(bis)amide ligand is retained and metalation of the ketone is actioned by the alkyl group. Chapter 3 exploits the sequential deprotonative co-complexation approach developed in Chapter 2 to access novel potassium metal(ates). Thus, monometallation of 1 is accomplished using potassium alkyl KCH2SiMe3 yielding [{Ph2Si(NHAr*)(NAr*)K}∞] (13), which, in turn, undergoes co-complexation with the relevant M(CH2SiMe3)2 (M=Mg, Zn, Mn) enabling metallation of the remaining NHAr* group to furnish silylbis(amido) alkyl potassium metal(ates) [{Ph2Si(NAr*)2M(THF)x(CH2SiMe3)}−{K(THF)y}+] (M=Zn, x=0, y=4, 14; M=Mg, x=1, y=3, 15; and M=Mn, x=0, y=4, 16). Reactivity studies of potassium manganate 16 with the amine HMDS(H) revealed the kinetic activation of the remaining alkyl group on Mn furnishing [K(THF)2{Ph2Si(NAr*)2}Mn(HMDS)] (18). Similarly 16 reacts with phenyl acetylene to give [{Ph2Si(NAr*)2Mn(THF)(C≡CPh)}¯{K(THF)3}+] (17). The structures of these bimetallic complexes along with that of the potassium precursor 13 have been established by X-ray crystallographic studies. Chapter 4 introduces a new type of heterobimetallic base, the specially designed potassium zincate [{Ph2Si(NAr*)2Zn(TMP)}¯{K(THF)6+] (19) which combines a sterically demanding silyl(bis)amide ligand with a kinetically activated terminal TMP amide group (TMP= 2,2,6,6-tetramethylpiperidide). Circumventing common limitations of conventional s-block metallating bases, 19 enables efficient and regioselective zincation of a broad range of substituted fluoroarenes including hypersensitive fluoronitrobenzene derivatives. Trapping and characterization of the organometallic species involved in these reactions [{Ph2Si(NAr*)2Zn(ArF)}¯{K(THF)x+] (ArF =C6H2F3, C6H3F2, C6H2Cl3, C6H2F2NO2, C6H3FNO2, C11H6F2N, C5H3FN, C6F5, C6HF4 and C6F4; x= 3-6) has provided informative mechanistic insights on how these direct zincation reactions may occur as well as shed light on the key role of the supporting silyl(bis)amido ligand. The first examples of directly metalated nitroarenes to be structurally characterised have been presented as well as the ability of this approach to promote polyzincations of fluoroarenes has been disclosed. Expanding the synthetic potential of this heterobimetallic approach it has been shown that these organometallic compounds can engage in onward C-C bond forming processes. Chapter 5 explores the synthesis and reactivity of higher order manganates [(TMEDA)2AM2Mn(CH2SiMe3)4] (AM= Li, 37; Na, 43; K; TMEDA= N,N,N’,N’-tetramethylethylenediamine) to promote Mn-I exchange /alkyne metallation reactions in tandem with oxidative homocoupling reactions. Lithium manganate 37 enables the efficient direct Mn–I exchange of aryliodides, affording transient (aryl)lithium manganate intermediates which in turn undergo spontaneous C−C homocoupling at room temperature to furnish symmetrical (bis)aryls in good yields under mild reaction conditions. The combination of EPR with X-ray crystallographic studies has revealed the mixed Li/Mn constitution of the organometallic intermediates involved in these reactions, including the homocoupling step which had previously been thought to occur via a single-metal Mn aryl species. These studies show Li and Mn working together in a synergistic manner to facilitate both the Mn–I exchange and the C−C bond-forming steps. Both steps are carefully synchronized, with the concomitant generation of the alkyliodide ICH2SiMe3 during the Mn–I exchange being essential to the aryl homocoupling process, wherein it serves as an in situ generated oxidant. Sodium manganate 43 reacts with 4 equivalents of phenylacetylene to give [(THF)4Na4Mn2(C≡CPh)8] (45) which when exposed to dry air furnishes the relevant 1,3 enyne in a 97% yield

Structural and synthetic insights on oxidative homocouplings of alkynes mediated by alkali-metal manganates

Exploiting bimetallic cooperation alkali-metal manganate (II) complexes can efficiently promote oxidative homocoupling of terminal alkynes furnishing an array of conjugated 1,3-diynes. The influence of the alkali-metal on these C−C bond forming processes has been studied by preparing and structurally characterizing the alkali-metal tetra(alkyl) manganates [(TMEDA)2Na2Mn(CH2SiMe3)4] and [(PMDETA)2K2Mn(CH2SiMe3)4]. Reactivity studies using phenylacetylene as a model substrate have revealed that for the homocoupling to take place initial metalation of the alkyne is required. In this regard, the lack of basicity of neutral Mn(CH2SiMe3)2 precludes the formation of the diyne. Contrastingly, the tetra(alkyl) alkali-metal manganates behave as polybasic reagents, being able to easily deprotonate phenylacetylene yielding [{(THF)4Na2Mn(C≡CPh)4}∞] and [(THF)4Li2Mn(C≡CPh)4]. Controlled exposure of [{(THF)4Na2Mn(C≡CPh)4}∞] and [(THF)4Li2Mn(C≡CPh)4] to dry air confirmed their intermediary in formation of 1,4-diphenyl-1,3-butadiyne in excellent yields. While the Na/Mn(II) partnership proved to be the most efficient in stoichiometric transformations, under catalytic regimes, the combination of MC≡CAr (M= Li, Na) and MnCl2 (6 mol %) only works for lithium, most likely due to the degradation of alkynylsodiums under the aerobic reaction conditions.</p

Metallation of sensitive fluoroarenes using a potassium TMP-zincate supported by a silyl(bis)amido ligand

Combining a bulky bis(amide) and a reactive one-coordinate TMP (2,2,6,6-tetramethylpiperidide) ligand, a new mixed K/Zn heteroleptic base has been developed for regioselective zincation of fluoroarenes. This special ligand set allows for trapping and structural authentication of the first intermediates of direct Zn-H exchange of fluoroarenes obtained via deprotonative metallation, providing mechanistic insights of the processes involved

Tandem Mn-I Exchange and Homocoupling Processes Mediated by a Synergistically Operative Lithium Manganate

Pairing lithium and manganese(II) to form lithium manganate [Li2Mn(CH2SiMe3)4] enables the efficient direct Mn-I exchange of aryliodides, affording transient (aryl)lithium manganate intermediates which in turn undergo spontaneous C@C homocoupling at room temperature to furnish symmetrical (bis)aryls in good yields under mild reaction conditions. The combination of EPR with X-ray crystallographic studies has revealed the mixed Li/Mn constitution of the organometallic intermediates involved in these reactions, including the homocoupling step which had previously been thought to occur via a single-metal Mn aryl species. These studies show Li and Mn working together in a synergistic manner to facilitate both the Mn-I exchange and the C@C bond-forming steps. Both steps are carefully synchronized, with the concomitant generation of the alkyliodide ICH2SiMe3 during the Mn-I exchange being essential to the aryl homocoupling process, wherein it serves as an in situ generated oxidant

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋅LiX (X=Cl, Br)

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles. Contrasting with other s-block metalating systems, which lack selectivity in their reactions even when operating at low temperatures, these mixed Li/Zn bases enabled unprecedented regioselectivities that cannot be replicated by either LiTMP nor Zn(TMP)2 on their own. Spectroscopic and structural interrogations of organometallic intermediates involved in these reactions have shed light on the complex constitution of reaction mixtures and the origins of their special reactivities

Structural and synthetic insights on oxidative homocouplings of alkynes mediated by alkali‐metal manganates

Exploiting bimetallic cooperation alkali-metal manganate(II) complexes can efficiently promote oxidative homocoupling of terminal alkynes furnishing an array of conjugated 1,3-diynes. The influence of the alkali-metal on these C-C bond forming processes has been studied by preparing and structurally characterizing the alkali metal tetra(alkyl) manganates [(TMEDA)2Na2Mn(CH2SiMe3)4] and [(PMDETA)2K2Mn(CH2SiMe3)4]. Reactivity studies using phenylacetylene as a model substrate have revealed that for the homocoupling to take place initial metalation of the alkyne is required. In this regard, the lack of basicity of neutral Mn(CH2SiMe3)2 precludes the formation of the diyne. Contrastingly, the tetra(alkyl) alkali-metal manganates behave as polybasic reagents, being able to easily deprotonate phenylacetylene yielding [{(THF)4Na2Mn(C≡CPh)4}∞] and [(THF)4Li2Mn(C≡CPh)4]. Controlled exposure of [{(THF)4Na2Mn(C≡CPh)4}∞] and [(THF)4Li2Mn(C≡CPh)4] to dry air confirmed their intermediary in formation of 1,4-diphenyl-1,3-butadiyne in excellent yields. While the Na/Mn(II) partnership proved to be the most efficient in stoichiometric transformations, under catalytic regimes, the combination of MC≡CAr (M= Li, Na) and MnCl2 (6 mol%) only works for lithium, most likely due to the degradation of alkynylsodiums under the aerobic reaction conditions

Exploiting Deprotonative Co‐complexation to Access Potassium Metal(ates) Supported by a Bulky Silyl(bis)amide Ligand

Bimetallic complexes combining an alkali‐metal with a lower electropositive metal have demonstrated unique chemical profiles which can be rationalised in terms of chemical cooperativity. Advancing the rational design of these types of complexes, a adaptable method is described to prepare a new family of potassium metal(ates) containing the highly sterically demanding silyl(bis)amide {Ph2Si(NAr*)2}2− (Ar*=2,6‐diisopropylphenyl). Using a sequential deprotonative co‐complexation approach, mono‐metallation of Ph2Si(NHAr*)2 (1) is accomplished using potassium alkyl KCH2SiMe3 yielding [{Ph2Si(NHAr*)(NAr*)K}∞] (2), which, in turn, undergoes co‐complexation with the relevant M(CH2SiMe3)2 (M=Mg, Zn, Mn) enabling metallation of the remaining NHAr* group to furnish silylbis(amido) alkyl potassium metal(ates) [{Ph2Si(NAr*)2M(THF)x(CH2SiMe3)}−{K(THF)y}+] (M=Zn, x=0, y=4, 3; M=Mg, x=1, y=3, 4; and M=Mn, x=0, y=4, 5). Reactivity studies of potassium manganate 5 with the amine HMDS(H) (HMDS=N[SiMe3]2 revealed the kinetic activation of the remaining alkyl group on Mn furnishing [K(THF)2{Ph2Si(NAr*)2}Mn(HMDS)] (6). The structures of these bimetallic complexes along with that of the potassium precursor 2 have been established by X‐ray crystallographic studies

Versatile coordination chemistry of the phosphonoformate anion

Phosphonoformate – the simplest member of the group of phosphono-carboxylic-acids containing a phosphonic as well as a directly bonded carboxylic moiety - can be regarded as a structural mimic of the pyrophosphate anion, a very important building block in biochemistry involved in processes of energy transfer as well as in growth of DNA or RNA strands. This derivative selectively inhibits the pyrophosphate binding side on viral polymerases, which qualifies the title compound as an antiviral medication used in the treatment of herpes viruses including drug-resistant cytomegaloviruses and as part of salvage therapy for highly treatment-experienced patients infected with HIV. Surprisingly only the crystal structure of the widely used trisodium salt is reported in the literature, whereas the coordination behavior towards other (earth) alkaline as well as transition metals is still unexplored. First insights into this field are reported in this work