Twofold Ferrocene C–H Lithiations for One-Step Difunctionaliza- Tions

SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2019, 51, 146–160 short review 146 en

Syn thesis W. Erb, F. Mongin Short Review

Twofold Ferrocene C–H Lithiations For One-Step Difunctionaliza- tions

William Erb* 0000-0002-2906-2091 R(*)

Florence Mongin* 0000-0003-3693-8861 E E R E Fe Fe E Fe Fe Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - E E E UMR 6226, 35000 Rennes, France (*)R [email protected] E [email protected] (*)R E R E Fe Fe Fe Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue E E E R(*) R(*) R

Received: 29.10.2018 Accepted: 05.11.2018 Published online: 05.12.2018 DOI: 10.1055/s-0037-1610396; Art ID: ss-2018-z0724-sr License terms:

Abstract For some aromatics, a twofold C–H deprotolithiation can be achieved, allowing these compounds to be subsequently difunctionalized in one step. This short review brings together examples in which ferrocenes are converted in this way. 1 Introduction 2 Bare Ferrocene 3 Ferrocenes Substituted by Alkyl or Silyl Groups William Erb obtained his Ph.D. in organic chemistry in 2010 under the 4 Ferrocenes Substituted by Aminoalkyls supervision of Prof. Jieping Zhu on the total synthesis of natural prod- 5 Ferrocenes Substituted by Halogens or Oxygen-Based Groups ucts and palladium-catalyzed reactions. During the next four years of 6 Ferrocenes Substituted by Alkoxyalkyls or Acetals postdoctoral studies he worked in various laboratories on different re- 7 Ferrocenes Substituted by Sulfoxides search projects from organocatalysis to supramolecular chemistry with 8 Ferrocenes Substituted by Oxazolines an emphasis on the development of new methodologies (University of 9 Ferrocenes Substituted by Carboxamides Bristol, Prof. Varinder Aggarwal, UK - ESPCI, Prof. Janine Cossy, Paris - 10 Conclusion LCMT, Prof. Jacques Rouden, Caen - COBRA, Prof. Géraldine Gouhier, Rouen). He was appointed assistant professor at the University of Key words ferrocene, deprotolithiation, dilithio compounds, electro- Rennes (France) in 2015 where he is mainly working on the develop- philic trapping, planar chirality, chiral directing group, chiral ligand, fer- ment of original ferrocene functionalizations. rocenophane Florence Mongin obtained her Ph.D. in chemistry in 1994 from the University of Rouen (France) under the supervision of Prof. Guy Que- 1 Introduction guiner. After a two-year stay at the Institute of Organic Chemistry of Lausanne (Switzerland) as a postdoctoral fellow with Prof. Manfred Schlosser, she returned to the University of Rouen as an Assistant Pro- Aromatic organolithiums can be prepared by different fessor in 1997 (HDR in 2003). She took up her present position in 2005 as Professor at the University of Rennes (France) and was appointed Ju- methodologies including halogen/metal exchange, C–H nior Member of the Institut Universitaire de France in 2009. Her present lithiation, transmetalation, and C–heteroatom bond cleav- scientific interests include the functionalization of aromatic compounds age.1 Twofold C–H deprotonation followed by electrophilic including heterocycles with recourse to bimetallic bases or combina- trapping has attracted numerous synthetic organic chem- tions. ists because the approach allows two functionalizations to be achieved at once in a one-pot process. Substrates bene- fiting from relatively acidic hydrogens, either because the cenes, benzenes, and benzo-fused derivatives, for which the corresponding carbanions are stabilized by electron delo- pKa values are ~30–35 or above, presents an important syn- calization or inductively owing to the presence of electron- thetic challenge. Indeed, because of the highly ionic charac- withdrawing groups, can be readily dideprotonated. In con- ter of their C–Li bonds, the corresponding dilithio com- trast, twofold sp2-C–H lithiation of substrates such as ferro- pounds are very reactive.

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Since the discovery and structural elucidation of ferro- Table 1 Dideprotolithiation of Ferrocene in Hexane Followed by Differ- cene in 1951,2 the first sandwich compound rapidly be- ent Electrophilic Trappings came a key player in chemistry due to unequalled redox 1) BuLi–TMEDA H E properties, three-dimensional structure, and air and ther- (n equiv) 3 mal stability. It has since been incorporated into various li- Fe hexane, r.t., t (h) Fe gands (in particular chiral ones) for homogeneous cataly- H 2) Electrophile E sis,4 in materials endowed with various (e.g., optical, elec- tronic, and magnetic) properties,3,5 and in biologically n equiv, t (h) Electrophile (E) Yielda (%) active compounds.6 2.5, 6 CO then H+ (CO H) 9415 Among the methods used to functionalize ferrocenes, 2 2 2.5, 6 Ph C=O [C(OH)Ph ]8015 deprotometalation is probably the most convenient strate- 2 2 gy, allowing various derivatives to be prepared regioselec- 2.5, 6 pyridine (2-pyridyl) 3015 tively.4b,d,h,7 In this short review, our goal is to update the 2.2, overnight DMF (CHO) 8516a

b 16b approaches to dideprotolithiate and subsequently difunc- 2.1, 22 H2C=NMe2I (CH2NMe2)57 tionalize ferrocene and its derivatives. 16c 2.2, overnight ClCO2i-Pr (CO2i-Pr) 58 (18) 2.2, overnight ClCOPh (COPh) 65 (16)16c 2 Bare Ferrocene 2.2, overnight ClTs (Cl) 64 (15)16c

16d 16e 2.2-2.5, 6 to overnight (CCl3)2 (Cl) 60, 75

8 16d The dideprotolithiation of ferrocene being more likely 2.5, 6 Br2 (Br) 23

9 16c than that of benzene, it quickly established itself as a reac- 2.2, overnight (CBrCl2)2 (Br) 89 10 tion competitive to monolithiation. Dismutation of lithio- 16f 2.1, overnight (CHBr2)2 (Br) 67 ferrocene to afford 1,1′-dilithioferrocene and ferrocene is at 2.2 to 2.5, 6 to 16 I (I) 55,16d 60,16c 7216g the origin of this issue.11 In spite of thorough studies in or- 2 c 16e 16h der to get clean ferrocene monolithiation,12 competitive for- 2.2, overnight NFSI (F) 2, 9

16i mation of 1,1′-dilithioferrocene could only be avoided in 2.5, 6 (ClBNMe2)2 [(BNMe2)2]58 13 16j the presence of catalytic potassium tert-butoxide. What 2.5, 6 ClSiMe3 (SiMe3) n.r. was initially a problem, competitive dideprotolithiation, 16k 2.5, 6 ClSi(OMe)3 [Si(OMe)3]52 turned out to be an opportunity, with numerous studies 16l 16m 2.3 to 2.5, 6 to 16 ClSi(OEt)3 [Si(OEt)3] 64, 50 dedicated to the synthesis of 1,1′-difunctionalized ferro- 2.0, 18 ClPt-Bu (Pt-Bu ) n.r.16n cenes using this possibility. 2 2 16o Tetrahydrofuran (THF) is not a solvent in which alkyl- 2.0, 18 ClP(Ph)t-Bu [P(Ph)t-Bu] 60 16c lithium-mediated dimetalation of ferrocene can be carried 2.2, overnight ClPPh2 (PPh2)73 16p out efficiently. Indeed, subsequent electrophilic trapping 2.2, 12 ClP(NEt2)2 [P(NEt2)2]80 shows that, in addition to remaining starting material, mix- 16c 2.2, overnight ClPO(OEt)2 [PO(OEt)2] 60 (22) tures of monolithio- and 1,1′-dilithioferrocenes are, in gen- 2.4, 24 ClPO(Oi-Pr) [PO(Oi-Pr) ]8216q eral, formed.13 2 2 2.1, 3 (SMe) (SMe) 7016r In 1964, Eberhardt and Butte discovered the impact of 2 16r ligands, TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenedi- 2.1, 3 (Si-Pr)2 (Si-Pr) 73 16c amine) and sparteine, in enhancing the reactivity of the al- 2.0, overnight (SPh)2 (SPh) 70

14 16s kyllithium reagents through the formation of chelates. 2.0, 18 IAsMe2 (AsMe2)54

Unlike butyllithium, the butyllithium–TMEDA chelate (2.0 16s 2.0, 18 ClAsPh2 (AsPh2)57 to 2.5 equiv; formed from the components after stirring for a Yield in parenthesis is of the competitively formed 1-substituted ferro- a few minutes at 25 °C) can easily 1,1′-dimetalate ferrocene cene; n.r. = yield not reported. in hexane at 25 °C, a result first evidenced by Rausch and b Eschenmoser’s salt. c N-Fluorobenzenesulfonimide. Ciappenelli in 1967.15 Subsequent quenching using various electrophiles allowed many 1,1′-disubstituted ferrocenes to be obtained (Table 1).15,16 has been illustrated here (not exhaustively) to highlight the As exemplified in Table 2, ferrocenophanes can be simi- variety of electrophiles that can be employed to intercept larly obtained from 1,1′-dilithioferrocene, but by trapping 1,1′-dilithioferrocene. with bis-electrophiles such as dichlorides.16m,p,17 Ferroceno- Using diethyl ether as hexane cosolvent still proved con- phanes (or ansa-bridged systems) are a widely developed venient to access 1,1′-disubstituted ferrocenes (Table 3).20 field18 on which there is much to be said, even including ex- Solid-state structures were recorded for chelates of 1,1′- amples with nickel, palladium, and platinum bridges.19 It dilithioferrocene with PMDTA (PMDTA = N,N,N′,N′′,N′′-pen-

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Table 2 Dideprotolithiation of Ferrocene in Hexane Followed by Con- Table 3 Dideprotolithiation of Ferrocene in Diethyl Ether/Hexane Fol- versions into Ferrocenophanes lowed by Different Electrophilic Trappings

1) BuLi–TMEDA H 1) BuLi–TMEDA (n equiv) (n equiv) H E Fe hexane, r.t., t (h) Fe E or Fe E Fe Et2O–hexane r.t., t (h) Fe Fe or Fe E H 2) Electrophile H 2) Electrophile E

n equiv, t (h)Electrophile (E) Yielda (%) n equiv, t (h) Electrophile (E) Yielda (%) 2.3, 16 Cl SiCl (SiCl ) 50,16m 80–9017a 2 2 2 2.5, 24 DMF (CHO) 8520a,b 2.5, 18 Cl SiPh (SiPh )3217b,c 2 2 2 2.5, 24 PhCHO [CH(OH)Ph] 9120a 17d 2.3, 16 Cl2SiMe2 (SiMe2)60 20a 2.5, 24 (CH2O)n [CH2OH] 43 17b 16p 17e 2.3, 16 Cl2SiCl2 (Si) 17, 56, 70 20c 2.7, 24 Ph2CO [C(OH)Ph] 93 16p 17e 2.3, 16 Cl2Si(CH2)3 [Si(CH2)3] 71, 79 20a 2.5, 24 ClCH2OMe (CH2OMe) 33 17f 2.3, 16 Cl2SiMe(5-norbornyl) [SiMe(5-norbornyl)] 50 20d 2.2, 19.5 ClC(=S)NMe2 [C(=S)NMe2]54 17f 2.3, 16 Cl2SiMe(CH=CH2) [SiMe(CH=CH2)] 60 20e 2.1, 18 2,4,6-i-Pr3C6H2SO2N3 (N3)62 17f 2.3, 16 Cl2SiHMe (SiHMe) 80 20f 2.2, 14 (CBrF2)2 (Br) 60 17g 2.5, 18 Cl2SiH2 (SiH2)38 20g 2.2, 6 B(OBu)3 then hydrolysis [B(OH)2]60 17b 2.5, 18 Cl2PPh (PPh) 51 20h 2.0, 18 Cl2AlC(SiMe3)2SiMe2(2-pyridyl) 31 17h [AlC(SiMe ) SiMe (2-pyridyl)] 2.0, 18 Cl2PMe (PMe) 19 3 2 2 17i 2.0, 18 Cl Al[C(SiMe ) SiMe NMe ] 9720i 2.0, 18 Cl2Pt-Bu (Pt-Bu) 46 2 3 2 2 2 {Al[C(SiMe3)2SiMe2NMe2]} 17j 2.0, 18 Cl2P(menthyl) [P(menthyl)] 35 20a 2.5, 24 ClSiMe3 (SiMe3)80 17k 2.5, 6 Cl2PNi-Pr2 (PNi-Pr2)42 20j 2.1, 3 (SMe)2 (SMe) 51 (10) 17l,m 2.5, 18 S(O2SPh)2 (S) 28 20j 2.1, 3 (SPh)2 (SPh) 80 17b,n 2.5, 18 Cl2GePh2 (GePh2)19 20k 2.0, 18 Cl2GaC(SiMe3)2SiMe2(2-pyridyl) 59 17b,n 2.3, 16 Cl2GeMe2 (GeMe2) 30–35 [GaC(SiMe3)2SiMe2(2-pyridyl)]

17b,n 20i 2.3, 16 Cl2GeEt2 (GeEt2) 30–35 2.0, 18 Cl2GaC(SiMe3)2SiMe2NMe2) 68 17o [GaC(SiMe3)2SiMe2NMe2)] 2.5, 6 Cl2GeCl2 (Ge) n.r. 20k 17h 2.0, 18 [Cl2InC(SiMe3)2SiMe2(2-pyridyl)]2 57 2.0, 18 Cl2AsPh (AsPh) 34 [InClC(SiMe3)2SiMe2(2-pyridyl)] 17l 2.5, 18 Se(S2CNEt2)2 (Se) 23 20l 2.5, 6 ClSnBu3 (SnBu3)68 17p 2.5, 18 Se8 (SeSeSe) 31 20m,n 2.2, 17 Cl2Snt-Bu2 (Snt-Bu2)65 17q,r 2.0, 18 Cl2B=N(SiMe3)2 [B=N(SiMe3)2]35 b 20m 2.2, 17 Cl2Sn(Mes)2 [Sn(Mes)2] 85 17q,r 2.0, 18 Cl2B=N(SiMe3)t-Bu [B=N(SiMe3)t-Bu] 44 a Yield in parenthesis is of the competitively formed 1-substituted ferrocene. 17q b Mes = 2,4,6-trimethylphenyl. 2.0, 18 Cl2B=Ni-Pr2 (B=Ni-Pr2)38 a n.r. = yield not reported. tamethyldiethylenetriamine; more soluble)21 and TMEDA.22 3 Ferrocenes Substituted by Alkyl or Silyl The latter can be displaced by THF upon recrystallization.18b Groups That 1,1′-dilithioferrocene is favored under these conditions was attributed to its insolubility in hexane16c and di- In 1964, Benkeser and Bach reported a study in which ethyl ether.20a In order to avoid the presence of the more alkylated ferrocenes were treated by butyllithium in diethyl soluble monosubstituted product, Jahn and co-workers re- ether at room temperature for long reaction times before moved the hexane supernatant by filtration and washed interception with chlorotrimethylsilane. Mixtures resulting the bright orange precipitate of 1,1′-dilithioferrocene be- from non-regioselective mono- and dideprotonation (posi- fore adding THF in order to make it react with electro- tions 3 or/and 1′) were produced.24 A similar result was no- philes.16c Removing the solvent is also useful when it is nec- ticed in 1995 by Manners, O’Hare, and co-workers on 1,1′- essary to know exactly the quantity of formed 1,1′-dilithio- dimethylferrocene by using butyllithium–TMEDA in hex- ferrocene, for instance in order to add the appropriate ane.25 While dideprotonation is favored over monometala- amount of bis-electrophile for a more controlled synthesis tion when bis(tetrahydroindenyl)iron is treated by the che- of ansa-bridged derivatives.23 late butyllithium–TMEDA at 60 °C in hexane, mixtures of

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regioisomers (1,1′-, 1,2′-, and 2,2′-disubstituted) are again t-Bu 1) BuLi–TMEDA t-Bu obtained, a result evidenced by using chlorodiphenylphos- Fe H (2 equiv) Fe Li·TMEDA 26 phine as electrophile. H t-Bu Et2O–hexane TMEDA·Li t-Bu 24 h According to Aratani, Gonda, and Nozaki, hexane is a (42%) more suitable solvent than diethyl ether to dilithiate iso- Cl2SiPh2, Et2O 1) DMF, Et2O –78 °C to r.t., 3 h propylferrocene. In 1969, the efficient formation of 1′,3- –78 °C, 2 h (36%) 2) Hydrolysis disubstituted derivatives was reported by using butyllithi- (75%) um and (–)-sparteine at –70 °C for 10 hours before trapping t-Bu t-Bu CHO (Scheme 1). A marginal enantiomeric excess was recorded, Fe t-Bu Fe SiPh2 probably due to the lack of coordinating atom in this ferro- OHC t-Bu cene substituent.27 Scheme 3 Double deprotolithiation of 1,1′-di-tert-butylferrocene using butyllithium–TMEDA

1) BuLi–(–)-sparteine (2.5 equiv) i-Pr hexane i-Pr During the synthesis of a stable ferrocene-based N-het- –70 °C, 10 h a H Fe Me3Si Fe 80% erocyclic carbene, Siemeling and co-workers prepared the

H 2) ClSiMe3 SiMe3 same 1,1′-di-tert-butyl-3,3′-dilithioferrocene, and convert- or + or (i) CO2 (ii) H ed it into the corresponding dibromo, bis(trimethylsilyl), (iii) CH2N2 i-Pr and diazido derivatives.33 Lentz and co-workers employed MeO2C Fe 58% both the 1,1′-di-tert-butyl- and the 1,1′-bis(1-ethyl-1- CO2Me methylpropyl)ferrocene to generate the 3,3′-dilithio deriva- Scheme 1 Double deprotolithiation of isopropylferrocene using butyllithi- tives and make them react with chlorotributylstannane a 34 um–(–)-sparteine in hexane at –70 °C. 12% yield using Et2O as solvent. (Scheme 4).

Replacing isopropyl by tert-butyl similarly leads to 1′,3- R 1) BuLi–TMEDA (2 equiv) R hexane, r.t., 24 h disubstituted derivatives upon treatment by butyllithium– Fe H Fe SnBu3

TMEDA in hexane. As already shown from bare ferrocene,28 H R 2) ClSnBu3 Bu3Sn R (62–69%) interception of the 1′,3-dilithio compound with sulfur here produces the corresponding 1,2,3-trithia[3]ferrocenophane (Scheme 2).29 By starting from ferrocenophanes in which R = t-Bu or the cyclopentadienyl groups are connected through a te- tramethyldimethylene or a trimethylene bridge, the corre- Scheme 4 Double deprotolithiation of hindered 1,1′-dialkylferrocenes sponding 1,2,3-trithia[3]ferrocenophanes are still generat- followed by trapping with chlorotributylstannane ed, but in very low yields.30

1) BuLi–TMEDA When compared with an alkyl group, a diphenylphos- (2 equiv) H hexane S phino behaves differently since it is electron-accepting. As a t-Bu Fe r.t., 20 h t-Bu Fe S consequence, when present on ferrocene adjacent depro- S H 2) S8 tonation is observed. But, probably due to steric hindrance (58%) and low ability to coordinate lithium, deprotonation re- Scheme 2 Double deprotolithiation of tert-butylferrocene using butyl- mote from the phosphine is favored. Thus, the 1′,3-dilithiat- lithium–TMEDA in hexane ed product predominates after a long contact between (diphenylphosphino)ferrocene and 2:1 butyllithium–TMEDA When submitted to the butyllithium–TMEDA chelate in diethyl ether at room temperature.35 (2.4 equiv) in hexane at r.t. for 20 hours, 1,1′-trimethylene- When (electron-withdrawing) silylated substituents are ferrocene mainly leads to mixtures.31 In the case of 1,1′-di- present on ferrocene substrates, the dilithiation takes place tert-butylferrocene, the reaction rather takes place regio- at a remote position, but preferably on the same ring. Thus, and stereoselectively (C2-symmetry) by using butyllithium– in 1992 Roberts, Silver, and co-workers reported that upon TMEDA in diethyl ether, as shown by interception with addition of excess butyllithium–TMEDA chelate to 1,1′- DMF32 or dichlorodiphenylsilane23 to respectively produce bis(trimethylsilyl)ferrocene, the reaction occurs at the 3,3′- the expected dicarbaldehyde or ferrocenophane. In the for- positions to furnish, after quenching, tetrasubstituted de- mer case, it is important to isolate and analyze the interme- rivatives (Scheme 5, top). Trapping the 3,3′-dilithio deriva- diate 3,3′-dilithio product (which contains two molecules tive with chlorodiphenylphosphine selectively leads to C2- of TMEDA) before quenching it in order to calculate the re- symmetric diastereomers, i.e. to the smallest steric interac- quired amount of electrophile (Scheme 3).23 tions between the silyl groups in the lithio intermediate. Further metalation of the tetrasubstituted ferrocenes

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Syn thesis W. Erb, F. Mongin Short Review proves difficult, probably due to important steric hin- 1) BuLi (4 equiv) 16j drance. In 1995, this 1,1′-bis(trimethylsilyl)-3,3′-dilithio- H Fe CH2NMe2 THF, reflux, 1.5 h Ph2(HO)C Fe CH2NMe2 45% ferrocene was converted into silicon-bridged [1]- and H 2) Ph2CO C(OH)Ph2 [2]ferrocenophanes upon addition of dichlorodimethylsi- 3) H2O lane and 1,2-dichloro-1,1,2,2-tetramethylsilane, respective- Ph2(HO)C Fe CH2NMe2 13% ly (Scheme 5, bottom).36

SiMe3 Fe CH2NMe2 10% 1) BuLi–TMEDA Me3Si Fe 49% (5 equiv) C(OH)Ph2 Me3Si SiMe3 petroleum ether SiMe3 H Fe r.t., 6 h Scheme 7 Double deprotolithiation of [(dimethylamino)methyl]ferro- SiMe Me Si 3 cene using butyllithium in refluxing THF 3 H 2) ClSiMe 3 Ph2P Fe 35%a or ClPPh2 Me3Si PPh2 yl]ferrocene (Scheme 8, bottom, left).41 Under these condi- SiMe SiMe3 3 tions, one can assume a first stereoselective lithiation next

SiMe2 to the chiral directing group followed by a second depro- Fe SiMe2 Fe SiMe2 tonation at the remote cyclopentadienyl ring. With the aim Me3Si Me3Si of obtaining chiral ferrocenylphosphine–transition metal 56% 47% complexes for asymmetric catalysis, the study was extend- Scheme 5 Double deprotolithiation of 1,1′-bis(trimethylsilyl)ferrocene ed by Hayashi and Yamazaki to the synthesis of different a using butyllithium–TMEDA. Only one diastereomer isolated. bis(diarylphosphino) derivatives starting from (R)-[1-(dimethylamino)ethyl]ferrocene (Scheme 8, bottom, right). As To our knowledge, dilithiation of phenylferrocenes has shown in Scheme 8, a sufficiently long reaction time for the never been described. Nevertheless, albeit in a low yield, (5- dilithiation step is crucial for the success of the reaction.42 methyl-2-thienyl)ferrocene was converted into a diphosphine by consecutive treatment with butyllithium–TMEDA 1) BuLi (1 equiv) Et O–hexane, r.t., 1 h 37 2 and chlorodiphenylphosphine, as shown in Scheme 6. 2) BuLi–TMEDA (1 equiv) Me2N Me2N Fe H Et2O–hexane, r.t., 5 h Fe PR2 (S) H Ph2P H 3) ClPPh2 or ClPMe2 PR2 (58 or 12%) S 1) BuLi–TMEDA S (RP) (2.2 equiv) Et O, r.t., 4 h Fe 2 Fe H Me PPh2 Me 1) BuLi (1 equiv) 2) ClPPh2, r.t. NMe2 Et2O–hexane, r.t., 1 h NMe2 (22%) H Fe Ar2P Fe (R) 2) BuLi–TMEDA H Ar2P Scheme 6 Double deprotolithiation of (5-methyl-2-thienyl)ferrocene (1 equiv) 1) BuLi–TMEDA Et2O–hexane (SP) followed by phosphination (2 equiv) r.t., 5 h (40%) hexane, 3) ClPAr 2 R = Ph: 70% r.t., 18 h a 2) SiCl , Et O R = 4-F3CC6H4: 63% (18%) 4 2 a 4 Ferrocenes Substituted by Aminoalkyls R = 3-F3CC6H4: 62% (18%) R = 4-FC H : 80% (7%)a NMe2 6 4 Fe R = 4-MeOC H : 30% (20%)a Cl2Si 6 4 a R = 3,5-Me2-4-MeOC6H2: 27% (4%) In 1965, Slocum, Rockett, and Hauser documented the formation of a mixture of 1′,2-dilithiated, 2-lithiated, and Scheme 8 Dideprotolithiation of [1-(dimethylamino)ethyl]ferrocenes a 1′-lithiated products upon treatment of [(dimethylami- followed by phosphination or silylation. Yield for the monophosphine competitively formed. no)methyl]ferrocene by butyllithium in THF at reflux. After interception with benzophenone, the corresponding alco- hols were obtained in 45%, 13%, and 10% yields, respectively In 1983, Cullen and co-workers reported the synthesis (Scheme 7).9 An improved procedure was later developed38 of [1]ferrocenophanes from [1-(dimethylamino)alkyl]ferro- in order to convert it into the 1′,2-diphosphine.39 cenes. The latter can be similarly attacked by butyllithium Thus, in 1980, Kumada and co-workers difunctionalized then butyllithium–TMEDA in diethyl ether/hexane to afford (S)-[1-(dimethylamino)ethyl]ferrocene in diethyl ether by the 1′,2-dilithio derivatives, which are next trapped with stepwise treatment with butyllithium and butyllithium– dichlorophosphines and diiodophenylarsine (Scheme 9, 17i,43 TMEDA, e.g. to provide the (S,RP)-1,1′-diphosphines shown top). Probably inspired by the enantioselective func- in Scheme 8 (top).38,40 In 1987, it was shown that it is simi- tionalizations described above (Scheme 8), Fukuzawa and larly possible to enantioselectively obtain ferrocenophanes Wachi extended the protocol to the synthesis of 1,1′- by starting from an enantiopure [1-(dimethylamino)eth- trichalcogena[3]ferrocenophanes (Scheme 9, bottom).44

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1) BuLi (1 equiv) 1) BuLi (1 equiv) H Ph2P Et O–hexane Et2O–hexane, r.t., 1 h Me2N 2 Me2N R 2) BuLi–TMEDA (1 equiv) R Fe SiMe3 30–32 °C, 2 h Fe SiMe3 r.t., 10 h Fe H Fe PPh or Pt-Bu or AsPh H 2) BuLi–TMEDA (1.3 equiv) PPh2 2) Cl PPh or Cl Pt-Bu 32–34 °C, 5 h H 2 2 (S) or I AsPh 2) ClPPh2, reflux, 18 h 2 t-BuOK (40–65%) (75%) 38% DMSO

R = CH(Me)NMe2 or CH(i-Pr)NMe2

Ph2P Me2N (S ) 1) base (1 equiv) NMe2 P NMe2 Fe Et2O–hexane, r.t., 1 h 2) BuLi–TMEDA (1 equiv) PPh2 R R r.t., 5 h Fe E Fe H E Scheme 11 Dideprotolithiation of trimethylsilyl-protected (S)-[1-(di- 2) S or Se E H 8 8 methylamino)ethyl]ferrocene followed by phosphination and deprotec- (30–52%) E = S or Se tion (R) R = Me: base = BuLi R = Ph: base = t-BuLi (SP) Scheme 9 Dideprotolithiation of substituted ferrocenes followed by were produced, the major one being isolated in 44% yield. conversions into [1]- and [3]ferrocenophanes The first lithiation occurs at the 2-position closest to nitrogen (albeit with a stereoselectivity different from that ob- In 1986, Cullen and co-workers showed that 1′,2-dilithi- served for the nonbridged substrate) while the second one ation of (R)-[1-(dimethylamino)ethyl]ferrocenes can be (mediated by butyllithium–TMEDA) takes place at the op- performed by using the chelate butyllithium–TMEDA at posite 2′-position on the other cyclopentadienyl ring.49 once, as evidenced by subsequent reaction with chlorotrimethylsilane (Scheme 10).45 Replacing chlorotrimethylsi- NMe2 1) BuLi (1 equiv) NMe2 Et2O–hexane lane by elemental sulfur45 or 1,2-dibromo-1,1,2,2-tetra- r.t., 3 h 46 Fe H Fe PPh2 chloroethane led to the corresponding 1,2,3-trithia[3]fer- 2) BuLi–TMEDA (3 equiv) rocenophane or 1′,2-dibromide, respectively. Even if r.t., 20 h 2) ClPPh2, reflux, 1 h H PPh mixtures are formed, the silanes produced according to (S)( (44%) 2 SP,RP) Scheme 10 can undergo dilithiation under similar condi- Scheme 12 Dideprotolithiation of a bridged aminoferrocene followed tions.45 by phosphination

1) BuLi–TMEDA R Me3Si Although dilithiation generally occurs on each cyclo- (2 equiv) R = H: Me2N Me2N Fe H hexane, r.t., 18 h Fe 80% pentadienyl of a substituted ferrocene, Kim, Jeong, and co- (SP) workers documented an example in which a (R,R)-diferro- H 2) ClSiMe3 SiMe3 (R) cenyl diamine is attacked at both ferrocenes to stereoselec- Me3Si 50 tively afford a C2-symmetric diphosphine (Scheme 13). Me2N Fe SiMe 3 R = SiMe3

SiMe3 1) BuLi (2.4 equiv) Me Me THF–hexane Me Me N N H N N PPh Scheme 10 Dideprotolithiation of (R)-[1-(dimethylamino)ethyl]ferro- –78 °C to rt 2 Me Me Me Me cenes followed by silylation Fe Fe 2) ClPPh2, rt Fe Fe H (60%) PPh2

Scheme 13 Dideprotolithiation of a diferrocenyl diamine followed by (S)-[1-(Dimethylamino)ethyl]ferrocene can be convert- phosphination ed into (S,RP)-1,1′-diphosphines. The second reaction depicted in Scheme 10 (bottom) shows that a trimethylsilyl As exemplified by Fukuzawa and co-workers in 2007, if group can protect the position usually deprotonated next to a phenyl group is connected at the α-position of an (amino- the 1-(dimethylamino)ethyl group and reroute the reaction methyl)ferrocene, it can be attacked by the base at the same to the other adjacent position. Such a possibility was em- time as the ferrocene ring to provide a difunctionalized ployed in 1989 by Pastor and Togni to access, after depro- product after electrophilic trapping (Scheme 14).51 47 tection, (S,SP)-1,1′-diphosphines (Scheme 11). H I From [1-(dimethylamino)ethyl]ferrocene, 1′,2-dilithia- Me N Me N H 2 I 2 tion was evidenced together with 2-lithiation upon reaction 1) t-BuLi (2.4 equiv) Et2O, 0 °C, 2 h with butyllithium (1.5 equiv) in diethyl ether–hexane for Fe SiMe Fe SiMe 48 3 2) I2 3 long lithiation periods. In the case of the bridged amino- (80%) ferrocene shown in Scheme 12, four isomeric diphosphines Scheme 14 Dideprotolithiation of an α-(dimethylamino)benzylferro- cene followed by iodolysis

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In studies published at the end of the 1990s, Schwink Br MeO 1) RLi (2.5 equiv) and Knochel studied the behavior of ferrocenes 1,1′-disub- H solvent N Fe Br stituted by identical 1-(dimethylamino)alkyl groups N Fe H –78 to 0 °C, 1 h N (Scheme 15). By using an excess of butyllithium or tert-bu- N OMe 2) (BrCl C) OMe 2 2 MeO tyllithium in diethyl ether, the 2,2′-dilithio products are or I2 a (S,S) BuLi in Et2O: 47:50:3 formed. The stereoselectively proves to be in favor of the C2- 1) s-BuLi (2.5 equiv) s-BuLi in Et O: 0:95:5a Et O, –78 to –20 °C, 1 h 2 symmetric isomers, as demonstrated by interception with 2 s-BuLi in THF: 57:40:3a 2) ClSiR3, –78 °C to r.t. a chlorodiphenylphosphine or 1,2-dibromo-1,1,2,2-tetra- t-BuLi in Et2O: 0:25:75 52 chloroethane. In 2006, 2,2′-disubstituted 1,1′-trichalco- R Si 3 or gena[3]ferrocenophanes were synthesized by employing N Fe SiR3 I 44 N this protocol. (SP,SP) N Fe I OMe N 1) AlkLi (n equiv) MeO H Ph2P OMe Et2O, r.t., time Me2N Me2N SiR = SiMe : 66% MeO Fe H 2) ClPPh2, r.t. Fe PPh2 3 3 SiR3 = SiEt3: 73% s-BuLi in Et2O: 0:>95:5 R NMe2 (>98% ee) R NMe2 SiR3 = SiMe2Ph: 54% 80% SiR3 = SiMe2H: 53% (R,R) R (SP,SP) R R = Me, Ph, 2-naphthyl; Alk = Bu (n = 4; 6 h): 29–57% Scheme 17 Dideprotolithiation of (S,S)-1,1′-bis[2-(methoxymeth- R = Pent; Alk = t-Bu (n = 6; 18 h): 39% a R = Et: Alk = t-Bu (n = 3; 0.5 h): 40% yl)pyrrolidino]ferrocene by using different alkyllithiums. The (SP)- monobromo/dl-dibromo/meso-dibromo ratios are given. 1) t-BuLi (excess) H Br Et2O, 0 °C, 0.5 h Me2N Me2N Fe H 2) (CCl2Br)2 Fe Br In order to reach tetradentate ligands bearing phosphi-

Ar NMe2 Ar NMe2 (>98% ee) no, aminomethyl, and tert-butyl groups, in 2015 Pirio, Hier- (R,R) Ar (SP,SP) Ar so and co-workers compared two strategies, (i) the assem- Ar = Ph: 80%; Ar = 2-tolyl: 52%; Ar = 2-naphthyl: 43% bly of ferrocene from the appropriate cyclopentadienyl Scheme 15 Dideprotolithiation of (R,R)-1,1′-disubstituted ferrocene rings and (ii) the successive functionalization of 1,1′-di-tert- diamines followed by phosphination or bromolysis butylferrocene. While the former furnishes a 1:1 mixture of meso and rac stereoisomers, the latter proved to be diaste- In 1998, the scope of the reaction was enlarged to the 1- reoselective. Thus, dl-2,2′-di-tert-butylferrocene-1,1′-dicar- (dimethylamino)propyl group by Kang and co-workers.53 baldehyde (prepared according to Scheme 3) was submitted The corresponding 2,2′-diiodo derivative is generated in to reductive amination, and the aminomethyl-substituted high yield and stereoselectivity (Scheme 16).54 ferrocenes regioselectively dilithiated to introduce the required phosphino groups (Scheme 18). It is worth noting H 1) BuLi (3 equiv) I that dilithiation of 1,1′-bis[(diethylamino)methyl]ferrocene Me2N Me2N Fe H Et2O, r.t., 12 h Fe I is not stereoselective.59 Et NMe2 Et NMe2 2) I2 Et (67%) Et (R,R)(SP,SP) 1) BuLi–TMEDA (2 equiv) H Et O–hexane PR' Scheme 16 Dideprotolithiation of (R,R)-1,1′-disubstituted ferrocene t-Bu 2 t-Bu 2 NR2 r.t., overnight NR2 diamines followed by iodolysis H Fe R'2P Fe R N 2 2) ClPR' R2N t-Bu 2 t-Bu With the aim of building 2-phospha[3]ferrocenophanes NR2 = NEt2: 78% (R' = Ph), 67% (R' = i-Pr), 48% (R' = 5-methyl-2-furyl) with planar chirality, Marinetti and co-workers studied the NR2 = pyrrolidino: 62% (R' = Ph) behavior of different alkyllithiums toward the ferrocene di- Scheme 18 Double deprotolithiation of dl-1,1′-bis[(dialkylami- amine (derived from ferrocene-1,1′-dicarbaldehyde) de- no)methyl]-3,3′-di-tert-butylferrocene followed by phosphination picted in Scheme 17.55 The choice of the base proves to be crucial. By using sec-butyllithium in diethyl ether, the reac- 5 Ferrocenes Substituted by Halogens or tion takes place in good yield and excellent diastereoselec- tivity, as demonstrated by quenching the dilithio product Oxygen-Based Groups with 1,2-dibromo-1,1,2,2-tetrachloroethane,55 chlorosila- nes,55,56 and iodine.57 It could be deduced from the configu- 1,1′-Dichloroferrocene can be 2,2′-dilithiated under ration displayed by the major stereoisomer that a chiral in- conditions employed for ferrocene. Thus, Osborne, Rossein- duction similar to that exhibited by the pyrrolidine group sky and co-workers obtained various tetrasubstituted de- during the monofunctionalization of (S)-[2-(methoxymeth- rivatives upon treatment by butyllithium–TMEDA in hex- yl)pyrrolidino]ferrocene using butyllithium takes place.58 ane and subsequent electrophilic interception, (Scheme 19).17o

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1) BuLi–TMEDA (2.5 equiv) hexane, r.t., 1.5 h OHC E H Fe Cl E Fe Cl OHC Fe Fe H 2) Electrophile E Cl Cl E Cl Cl Cl Cl 1) BuLi (2 equiv) Fe HO C Cl THF, r.t., 4 h SiPh2 2 Fe Fe Fe Si Fe SiCl2 O 2) Electrophile O Fe H Fe E CO2H Cl O E = Me: 65% O Cl Cl Cl Cl H E = SiMe3: 60% E Scheme 19 Dideprotolithiation of 1,1′-dichloroferrocene followed by E = Br: 35% electrophilic trapping (yields not reported) Scheme 22 Twofold 1′,2-functionalization of ferrocenecarbaldehyde acetal The stereoselectivity issue of the reaction was later studied by Sünkel and co-workers. After trapping the From 1,1′-bis(methoxymethyl)ferrocene, a large excess dilithio compound with dimethyl disulfide, they obtained of butyllithium is required in diethyl ether to achieve di- both the dl and the meso compound in an approximate 2:1 metalation, a reaction that favors the stereoisomers of C2- ratio (Scheme 20).60 Dideprotonation of 1,1′-bis(meth- symmetry (Scheme 23).20a,65 tert-Butyllithium is less suit- ylthio)ferrocene was attempted, but only mixtures were able, leading to a complex mixture.66 obtained.60–62 1) BuLi (6 equiv) Et2O–hexane H Fe CH OMe reflux, 14 h Ph P Fe CH OMe 1) BuLi–TMEDA 2 2 2 (2 equiv) H PPh 2) ClPPh2 2 hexane, r.t., 12 h a H Fe O Ph2P Fe O CH2OMe (63%) CH2OMe

2) ClPPh2 Scheme 23 Dideprotolithiation of 1,1′-di(methoxymethyl)ferrocene –78 °C to r.t., 1.5 h H PPh2 a (67%) followed by conversion into a diphosphine. Together with 3% of the meso compound. Scheme 20 Dideprotolithiation of 1,1′-dichloroferrocene followed by reaction with dimethyl disulfide After addition of the lithium salt of (+)-(S)-1-(pyrroli- din-2-ylmethyl)pyrrolidine to ferrocene-1,1′-dicarbalde- In 2010, Schaarschmidt and Lang reported the synthesis hyde in order to form the diaminal dianion, 2,2′-dilithiation of a 1′,2-diphosphine by starting from an aryl ferrocenyl becomes possible by using tert-butyllithium in excess. By ether and using butyllithium–TMEDA in hexane (Scheme this way, in 1998 Manoury, Balavoine, and co-workers

21). The phenyl group was only attacked in the presence of achieved the enantioselective synthesis of a C2-symmetric a larger amount of base, to form tri- or tetrafunctionalized tetrasubstituted ferrocene (Scheme 24, top).67 In turn, the derivatives.63 meso product was generated stereoselectively by starting from the chiral 1,1′-diacetal shown in Scheme 24 (bottom), but in a very low yield explained by important monofunc- 1) BuLi–TMEDA tionalization.68 (2 equiv) hexane, r.t., 12 h H Fe O Ph2P Fe O 1) N 2) ClPPh2 N –78 °C to r.t., 1.5 h Li H PPh2 (67%) (2.4 equiv) Et2O, r.t., 0.5 h 2) t-BuLi (3 equiv) Scheme 21 Twofold 1′,2-functionalization of an aryl ferrocenyl ether OHC Fe H OHC Fe SiMe3 –78 °C, 1 h H Me3Si CHO 3) ClSiMe3 CHO 6 Ferrocenes Substituted by Alkoxyalkyls or (28%, >99% ee) (RP,RP)

Acetals O O 1) MeLi (2 equiv) CHO Et2O, –78 °C to r.t. The acetal of ferrocenecarbaldehyde with propane-1,3- Fe H MeO Fe SiMe3 O diol can be readily turned into different 1′,2-disubstituted O 2) ClSiMe3 CHO 3) Hydrolysis H SiMe3 derivatives in the presence of butyllithium (2 equiv) in THF, MeO (5%) (SP,RP) as reported by Loh and co-workers in 2007 (Scheme 22).64 Scheme 24 Enantioselective dideprotolithiation of a diaminal dianion of ferrocene-1,1′-dicarbaldehyde followed by silylation

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The behavior of the acetal of ferrocene-1,1′-dicarbalde- 1) BuLi (2 equiv) t-Bu H THF, 0 °C, r.t. t-Bu hyde and propane-1,3-diol was documented by Connell and O Fe S O E Fe S O O co-workers in 2009. The C2-symmetric 2,2′-disubstituted S 2) ClPPh2 S products were isolated in good yields after deprotonation t-Bu H or (CHBr2)2 t-Bu E using tert-butyllithium in diethyl ether followed by trap- (R,R) (RP,RP) ping with electrophiles (Scheme 25, left and middle).69 In E = PPh2: 71% E = Br: 30% order to access ferrocene-1,1′,2,2′-tetracarbaldehyde, DMF was also employed as the electrophile by Hildebrandt and Scheme 27 Dideprotolithiation of (R,R)-1,1′-bis(tert-butylsulfinyl)ferrocene followed by electrophilic trapping co-workers in 2016 (Scheme 25, right).70

1) t-BuLi (2 equiv) 8 Ferrocenes Substituted by Oxazolines O Et2O O Fe H –78 °C to r.t., 2 h Fe E O O O O Oxazolylferrocenes have attracted scientific interest be- 2) Electrophile 73 H O 3) Hydrolysis E O cause of applications in asymmetric catalysis. The ligands developed in this part have notably found applications in

O asymmetric allylic substitution and hydrogenation reac- O O CHO Fe PPh2 Fe SiMe2 Fe 74 O O O tions. O O O O Whereas (S,S)-1,1′-bis(4-alkyloxazolin-2-yl)ferrocenes O CHO O PPh2 O Me2Si are mainly monofunctionalized using butyllithium, 2,2,′-

62% (using ClPPh2) 61% (using ClSiMe2NMe2) 83% (using DMF) dilithiation occurs with tert-butyllithium and sec-butyllithium. In 1995, Park and co-workers trapped the dilithio Scheme 25 Twofold 2,2′-functionalization of the diacetal of ferrocene- product, obtained by using tert-butyllithium at –78 °C in di- 1,1′-dicarbaldehyde ethyl ether, with chlorodiphenylphosphine to obtain meso diphosphines (Scheme 28).75 7 Ferrocenes Substituted by Sulfoxides

O O In the course of the development of diastereoselective Fe H 1) t-BuLi (2.2 equiv) Fe PPh2 N Et2O, –78 °C N syntheses on ferrocene derivatives, Kagan and co-workers H PPh2 R 2) ClPPh2 R showed that tert-butyl sulfoxide is a powerful substituent ON ON to induce 1′,2-deprotolithiation. Thus, upon consecutive R = i-Pr: 60% (S,S)(RP,SP) treatment with butyllithium (2 equiv, THF, 0 °C to r.t.) and R R = t-Bu: 43% R chlorodiphenylphosphine, (S)-(tert-butylsulfinyl)ferrocene Scheme 28 Dideprotolithiation of (S,S)-1,1′-bis(4-alkyloxazolin-2- was diastereoselectively converted into the corresponding yl)ferrocene followed by conversion into diphosphines

(S,SP)-1′,2-diphosphine, isolated in 80% yield (Scheme 26). Note that the oxygen present in the directing group faces In 1996, Ikeda and co-workers ensured the 2,2′-didepro- the pro-S ferrocene position, a result coming from the anti tolithiation of 1,1′-bis(4-alkyloxazolin-2-yl)ferrocene by orientation of the tert-butyl with respect to the iron atom.71 using sec-butyllithium in THF, this time preferentially af-

fording, and in high yield, C2-symmetric ferrocene phos- H PPh 1) BuLi (2 equiv) 2 phines (Scheme 29, top).76 Kang and co-workers also used t-Bu Fe S THF, 0 °C to r.t. Fe S t-Bu sec-butyllithium in THF to prepare the corresponding diio- O O 54 2) ClPPh2 dide (Scheme 29, bottom). (80%) H (S) PPh2 In fact, the outcome of the reaction heavily depends on (SP) the reaction parameters (temperature, solvent, base), as Scheme 26 Dideprotolithiation of (S)-(tert-butylsulfinyl)ferrocene fol- documented by Park, Ahn, and co-workers in 1996. By us- lowed by conversion into a diphosphine ing alkyllithiums (s-BuLi or t-BuLi; 1 equiv) to monolithiate, and then chlorodiphenylphosphine, opposite stereoselec-

If a second tert-butylsulfinyl group is present at the 1′- tivities are noticed in diethyl ether (RP) and THF (SP) for the position, ferrocene is logically 2,2′-dilithiated. Thus, Zhang obtained phosphines. With an excess of base (s-BuLi or t- and co-workers succeeded in obtaining the tetrasubstituted BuLi; 2 equiv) to ensure 2,2′-dilithiation, the meso product ferrocenes stereoselectively with butyllithium in THF is observed as major product in diethyl ether (s-BuLi or t- 72 77 (Scheme 27). BuLi) or THF using t-BuLi, while the (SP,SP)-phosphine only forms as major product using s-BuLi in THF, in accordance with the previous studies.77,78

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1) s-BuLi Ph2P 1) s-BuLi (4 equiv) (2.6 equiv) O O O O Ph P Fe Fe Et O, –78 °C, 2 h Fe PPh H Fe THF 2 2 2 O O then r.t., 0.5 h O –78 to 0 °C N N N PPh N + meso i-Pr 2 Ph2P N PPh R i-Pr N 2) ClPPh N H R 2) ClPPh 2 2 NO 2 R (SP,RP) (24%) R i-Pr 0 °C (SP,SP) (S,S) i-Pr R = i-Pr: 78 (66%) : 22 R = t-Bu: 85 : 15 Scheme 31 Tetrafold deprotolithiation of (S,S)-1,1′-bis(4-isopropyloxazolin-2-yl)ferrocene ferrocene followed by phosphination

O O H Fe 1) s-BuLi (3 equiv) I Fe O O N THF, –78 °C, 3 h N served using sec-butyllithium in THF; Scheme 29), higher N i-Pr H 2) ICH2CH2I N I i-Pr yields were obtained after interception with benzophenone i-Pr –78 °C to r.t. i-Pr 81 (S ,S ) (Scheme 32). (S,S) (55%) P P

Scheme 29 Dideprotolithiation of (S,S)-1,1′-bis(4-alkyloxazolin-2- 1) s-BuLi–TMEDA O yl)ferrocenes followed by phosphination or iodolysis O (2.6 equiv) Ph (HO)C H 2 Fe Fe THF O O N N –78 to 0 °C + meso R N C(OH)Ph As for mono-4-alkyloxazolin-2-yl-substituted ferro- N H R 2 2) Ph2CO R R cenes, the first lithiation is controlled by coordination of the 3) H2O (RP,RP) (S,S) oxazoline nitrogen to the base. The stereoselectivity no- R = i-Pr: 62% + 17% R = t-Bu: 69% + 15% ticed can be rationalized by the steric hindrance existing between the oxazoline alkyl group and the aggregated base, Scheme 32 Dideprotolithiation of (S,S)-1,1′-bis(4-alkyloxazolin-2- leading to an alkyl substituent toward the other cyclopen- yl)ferrocene followed by electrophilic trapping using benzophenone tadienyl ring in THF. In less coordinating diethyl ether, the nitrogens of both oxazolines would participate in the first Interestingly, in diethyl ether, a selectivity improvement lithiation, and the second lithiation ring would be directed was observed by replacing sec-butyllithium with sec-butyl- by the remote oxazoline oxygen.75–77,79 With oxazolines, the lithium–TMEDA (see Table 4), whereas tert-butyllithium chelation is different from what happens with ferrocene and butyllithium proved inappropriate. Methyl iodide was sulfoxides and amines, for which the bulky groups are ori- employed by Richards and co-workers as an electrophile in entated anti to the iron atom. this study. Using instead hexachloroethane or 1,2-dibromo-

Further dilithiation of a C2-symmetric 1,1′-bis(4-alkyl- 1,1,2,2-tetrachloroethane also gives the expected halides; oxazolin-2-yl)-2,2′-bis(diphenylphosphino)ferrocene is still nevertheless, due to instability, their purification is pre- possible next to the oxazoline ring, as demonstrated by Park cluded and yields of 39% (chloro) and 70% (bromo) were re- and co-workers in the course of the synthesis of corded for the whole process leading to the corresponding 1,1′,2,2′,3,3′-hexasubstituted ferrocenes (Scheme 30).80 methyl halogeno esters.82

Me3Si O O Fe PPh2 1) s-BuLi (2 equiv) Fe PPh2 Table 4 Dideprotolithiation of (S,S)-1,1′-Bis(4-isopropyloxazolin-2- N O Et2O, –78 to r.t., 3.5 h N yl)ferrocene under Different Reaction Conditions Followed by Electro- i-Pr SiMe3 Ph2P philic Trapping82 i-Pr PPh2 N 2) ClSiMe3 NO i-Pr (51%) (RP,RP) (S,S) i-Pr O O H Fe 1) see Table Me Fe O O Scheme 30 Dideprotolithiation of a C2-symmetric 1,1′-bis(4-alkyloxaz- N –78 °C, 5 h N + meso olin-2-yl)-2,2′-bis(diphenylphosphino)ferrocene followed by silylation i-Pr N H i-Pr 2) MeI N Me i-Pr i-Pr (S,S) (RP,RP) With oxazolines as directing group, even tetralithiation becomes possible. By starting from the valine-derived 1,1′- Base (2.6 equiv), solvent TMEDA (2.6 equiv) Ratio C2-symmetric/meso bis(4-alkyloxazolin-2-yl)ferrocene shown in Scheme 31, it s-BuLi, THF no 3.8:1 was achieved (albeit in moderate yield) in order to prepare s-BuLi, THF yes 4:1 a tetrakisphosphine by using an excess of tert-butyllithium s-BuLi, Et O yes 10:1 in diethyl ether.80 2 In 2000, Ikeda and co-workers combined sec-butyllithi- t-BuLi, Et2O yes 2:1 a um with TMEDA in THF to dideprotolithiate (S,S)-1,1′-bis(4- BuLi, Et2O yes 10:1 alkyloxazolin-2-yl)ferrocenes. If no improvement was no- s-BuLi, hexanes yes no lithiationb ticed concerning the stereoselectivity (similar to that ob- a About 50% of monomethylated product also obtained. b Due to poor solubility.

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In 2015, Zhang and co-workers reported their findings Table 6 Dideprotolithiation of (S,S)-1,1′-Bis(4-alkyloxazolin-2-yl)ferro- on the effect of the temperature on the stereoselectivity of cene at Different Reaction Temperatures Followed by Different Electro- 74 the reaction using (S,S)-1,1′-bis(4-alkyloxazolin-2-yl)ferro- philic Trapping cenes (Table 5). When the base is added at –90 °C, the SP,SP C -symmetric is the major product, formed with a small O 2 E Fe O amount of the meso product. In contrast, when the base is N added at a higher temperature, the formation of the S ,S C - 1) s-BuLi–TMEDA t-Bu P P 2 N E (2.6 equiv) symmetric product drastically decreases. In the case of R = O t-Bu Fe THF, T, 3 h a O + meso i-Pr, it is in favor of the meso product at temperatures of 25 N then 0 °C, 10 min O E and 40 °C. With R = t-Bu, the meso product predominated N t-Bu Fe 2) Electrophile O t-Bu N when the base was added at –10 °C but, at 40 °C, the RP,RP (S,S) t-Bu E N C2-symmetric product is obtained instead. To rationalize b t-Bu these results, the authors proposed a SP-lithiation favored under kinetic conditions (steric hindrance between the oxazoline alkyl, toward the other cyclopentadienyl ring, and Electrophile (E) T (°C) Total yield (%) Ratio a/b/meso the base for both deprotonations), and a privileged RP-lithi- MeI (Me) –90 50 84:0:16 ation under thermodynamic conditions. The nature of the –10 60 45:14:41 electrophile also has a considerable impact on the stereose- 40 52 5:43:52 lectivity, as shown in Table 6.74 Another approach was developed by Arthurs and Rich- ClSiMe3 (SiMe3) –90 70 92:0:8 –10 75 26:0:74 ards in order to obtain the most challenging RP,RP C2-symmetric 2,2′-disilylated product. Indeed, they used deuteri- 40 65 0:58:42 um as protecting group in order to abstract the required Ph2CO [C(OH)Ph2] –90 60 86:0:14 83 proton. –10 71 16:0:84 Even if less common, the dimeric ferrocene oxazolines

40 67% 13:42:45 depicted in Scheme 33 were difunctionalized diastereoselectively and in satisfying yields through a dilithio species by using butyllithium in diethyl ether.84 t-Bu t-Bu E 1) BuLi (2.2 equiv) H N Fe N Fe Et2O, rt, 2 h O O O O 2) ClSiR3 or Fe N Fe N Ph2CO E Table 5 Dideprotolithiation of (S,S)-1,1′-Bis(4-alkyloxazolin-2-yl)ferro- H t-Bu E = SiMe3: 58% 74 t-Bu cenes at Different Reaction Temperatures Followed by Phosphination E = SiEt3: 46% E = C(OH)Ph2: 59% Scheme 33 Dideprotolithiation of a di(oxazolylferrocene) followed by O Ph2P Fe electrophilic trapping O N 1) s-BuLi–TMEDA R N PPh (2.6 equiv) 2 O R Fe THF, T, 3 h (SP,SP) 9 Ferrocenes Substituted by Carboxamides O + meso N then 0 °C, 10 min O PPh N R Fe 2 2) ClPPh2 O In 1997, Jendralla and Paulus synthesized either the R N (S,S) meso (Scheme 34, top) or the C -symmetric diphosphine R 2 PPh2 N (bottom) from N,N-diisopropylferrocene-1,1′-dicarboxam- (RP,RP) R ide. As in the case of the 1,1′-bis(4-alkyloxazolin-2-yl)ferrocenes (Section 8) under similar conditions, the second R T (°C) Total yield (%) Ratio SP,SP/RP,RP/meso lithiation of the twofold process occurs with an enantiose- i-Pr –90 55 88:0:12 lectivity opposite to the first one. In contrast, when the mo- 25 47 7:0:93 nophosphine is isolated before submission to a second

40 47 5:3:93 deprotolithiation–phosphination sequence, the C2-sym- 85 t-Bu –90 53 86:0:14 metric diphosphine becomes the main product. Note that the 2,2′-dilithiation-trapping sequence from N,N-diisopro- –10 51 18:0:82 pylferrocene-1,1′-dicarboxamide can be achieved by using 40 50 0:82:18 sec-butyllithium–TMEDA in diethyl ether at –78 °C and then benzophenone to afford the expected ferrocenediol.86

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1) s-BuLi–(–)-sparteine 1) s-BuLi–TMEDA (4.4 equiv) H NEtR* E NEtR* i-Pr NOC H i-Pr NOC PPh Fe (6.4 equiv) Fe 2 Fe Et O, –78 °C, 2 h 2 Fe 2 2 R*EtN O R*EtN O H H PPh2 PhMe 2) ClPPh2 O H O E CONi-Pr CONi-Pr –78 °C, 4 h 2 (85%) 2 2) Electrophile a 1) BuLi–(–)-sparteine (RP,SP) E = Me: 56% (4.4 equiv) E = PPh2: 41% (58%) R* = Et2O, –78 °C, 1 h 2) ClPPh , –78 °C OEt 2 1) BuLi–(–)-sparteine (2.2 equiv) Scheme 36 Diastereoselective deprotolithiation of a chiral ferrocene- i-Pr NOC Fe PPh Et O, –78 °C, 0.5 h i-Pr NOC Fe PPh 2 2 2 2 2 1,1′-dicarboxamide. a Together with the meso product (7%) and the H H Ph2P 2) ClPPh2 (RP)-monofunctionalized product (17%, >99 dr). CONi-Pr2 (55%) CONi-Pr2

(RP,RP)

Scheme 34 Enantioselective deprotolithiation on N,N-diisopropylfer- 10 Conclusion rocene-1,1′-dicarboxamide followed by phosphination As shown in this short review, ferrocene dideprotolithi- In 2006, Snieckus and co-workers, who already experi- ation, which is above all a method to introduce substituents mented the need for isolating the intermediate 1,1′,2-tri- facing each other from their respective cyclopentadienyl substituted ferrocene in the conversion of N,N-diisopropyl- group, has aroused the interest of many chemists taking ferrocene-1,1′-dicarboxamide into the 1,1′,2,2′-tetrasubsti- into account the numerous applications that can have these tuted derivatives,78 disclosed their dilithiation-interception elaborated metallocenes. results (Scheme 35).87 By using butyllithium–TMEDA [or We are confident that the scope of this chemistry is ex- –(–)-sparteine] (>2 equiv) in diethyl ether, and chloro- pected to continue to grow with the development of other trimethylsilane as electrophilic partner, they obtained disi- bases with which polydeprotonation of ferrocenes could be lylated products in good yields, but low levels of diastereo- more easily modulated. For example, Mulvey and co-work- selectivity [and optical purity with (–)-sparteine]. By re- ers already showed the possible polydeprotonation of bare placing butyllithium by sec-butyllithium, quantitative ferrocene by employing mixed alkali metal–magnesium89 yields were obtained, but a stereoselectivity in favor of the or –manganese90 amides.91 Finally, by combining deproto- meso product. These results, similar to those of Jendralla lithiation with in situ trapping using softer metallic species, and Paulus using chlorodiphenylphosphine,85 are depen- dimetallated ferrocenes bearing sensitive directing groups dent on the electrophile used. Indeed, turning to iodometh- can be generated and next difunctionalized.92 ane, iodine, or benzophenone, with butyllithium–(–)- sparteine as base under the same reaction conditions, leads Funding Information to monofunctionalization, suggesting a deprotonation fast- er at this low temperature (maybe due to the presence of Université de Rennes 1. () LiCl) than the reaction between the base and chlorotrimethylsilane.87 Acknowledgment

1) base (4 equiv) We thank Université de Rennes 1. H SiMe3 SiMe3 Et2O Fe CONi-Pr2 –78 °C, 2 h Fe CONi-Pr2 Fe CONi-Pr2

H H Me3Si SiMe3 References 2) ClSiMe3 CONi-Pr2 CONi-Pr2 CONi-Pr2 (1) For access to dilithium compounds using these methodologies, base = BuLi–(–)-sparteine: 87% (37:63) dl meso base = BuLi–TMEDA: 46% (49:51) see: (a) Maercker, A.; Theis, M. Top. Curr. Chem. 1987, 138, 1. base = s-BuLi–(–)-sparteine: 99% (4:96) (b) Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1. (c) Foubelo, base = s-BuLi–TMEDA: 99% (25:75) F.; Yus, M. Curr. Org. Chem. 2005, 9, 459. Scheme 35 Dideprotolithiation of N,N-diisopropylferrocene-1,1′-di- (2) Kealy, T. J.; Pauson, P. L. Nature (London) 1951, 168, 1039. carboxamide followed by silylation (3) (a) Ferrocenes: Homogeneous Catalysis, Organic Synthesis, Mate- rials Science; Togni, A.; Hayashi, T., Ed.; Wiley-VCH: Weinheim, 2007. (b) Ferrocenes: Ligands, Materials and Biomolecules; In order to access ferrocene amido-phosphines, Dimi- Štěpnička, P., Ed.; John Wiley & Sons: Chichester, 2008. trov and co-workers examined the dilithiation of ferrocene- (c) Astruc, D. Eur. J. Inorg. Chem. 2017, 6. 1,1′-dicarboxamides. By using the chiral amido group (4) (a) Ferrocenes; Togni, A.; Hayashi, T., Ed.; VCH: Weinheim, 1995. shown in Scheme 36, they could perform the 2,2′-dilithia- (b) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, tion by using an excess of sec-butyllithium–TMEDA at low 2377. (c) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. temperature.88 Chem. Res. 2003, 36, 659. (d) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc. Rev. 2004, 33, 313. (e) Gómez-Arrayás, R.;

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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 146–160