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Home , Martin Heinrich Klaproth, Titanium tetrachloride, Titanocene dichloride

Baran Group Meeting Rohan Merchant Organotitanium 08/04/2017

Ziegler Natta Catalysts

First row transition metal Electron Configuration: [Ar]3d24s2 Common Oxidation States: +2, +3, +4 Highly oxophilic Highly resistant to corrosion Originally Ti-based catalysts used to prepare stereoregular from propylene Highest strength-to-weight ratio of any metal One of the most important use of organotitanium complexes In unalloyed condition, is as strong as Karl Ziegler and Giulio Natta awarded the Nobel Prize in chemistry in 1963 some steels Today, this class of catalysts has been expanded to include: 1. Solid supported Ti-based catalysts, often used in conjunction with organoaluminum cocatalysts () 2. catalysts, often of Ti, Zr, or Hf, and typically in conjuntion with MAO 250,000 tons per year of titanium made from TiCl4 3. Post-metallocene catalysts, various transition metals used with multidentate N and O based , often use MAO Fun Facts about Titanium Worldwide production of polymers using these catalysts in 2010 >100 million tons British pastor discovered titanium in 1791 This topic has not been covered in the interest of time. Named by German chemistry Martin Heinrich Klaproth after Titans of Greek mythology in 1795 See: " Chemistry" GM by D. Holte (2011) 9th most abundant element in the Earth's crust (0.63% of Earth's crust) 7th most abundant metal Common titanium complexes used in synthesis Pure sample isolated in 1910 by Matthew A. Hunter (Hunter Process) i 250,000 tons of titanium produced per year using Kroll process (William J. Kroll ca.1950s) Cl O Pr Ti Cl Ti Ti i 6700,000 tons of rutile and (primary ores) produced per year Cl Cl iPrO O Pr Cl Top producer: Australia, South Africa, Canada, India, Mozambique Cl OiPr i Cost: $1/100g (TiCl4) titanium tetraisopropoxide(Ti(OPr)4) (Cp TiCl ) Boeing 737 Dreamliner is made of 15% titanium colorless liquid colorless liquid 2 2 Aldrich (1.0 M DCM soln): $0.7/mL Aldrich: $0.09/mL bright red solid Most common use at TiO2 in paints and sunscreen Aldrich: $2.6/g Used to make surgical implants Outline of the group meeting: Phase II trial for human Titanium oxidises immediately on exposure to air forming passive oxide coating Pages 2–6 – transformations enabled by Ti(II)/Ti(IV) chemistry breast cancer Pages 6–10 – transformations enabled by Ti(III)/Ti(IV) chemistry Pages 10–12 – titanium carbene complexes Page 12 – organotitaniums in Ni– and Pd– cross–coupling Page 12 – miscellaneous Disclaimer: The primary focus of this group meeting is on the use of organotitanium complexes in chemical synthesis. In the interest of time, transformations such as Sharpless Asymetric Epoxidation, Diels–Alder, Mukaiyama Aldol and others where titanamium complexes behave primarily as Lewis acids have not been included. Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

2 i Generation of divalent titanium complexes First isolated organotitanium(II) Generation of (η -alkyne)Ti(O Pr)2 complex and its reactions TMS H TMS H Cp2TiCl2 + Na or Mg "TiCp2" PhCHO (1.1 eq.) I2 (2 eq.) Cp2TiCl2 + CO + reductant Cp2Ti(CO)2 (C5Me5)2Ti JACS 1999, 121, 2931 C6H13 C6H13 I Cp TiCl + PMe + Mg Cp Ti(PMe ) OH 74% [97:3] 2 2 3 2 3 2 First isolable alkenetitanium "hydrotitanation" complex 84% [98:2] (ArO)2TiCl2 + Na(Hg) "Ti(OAr)2"

Cp2TiCl2 + 2 EtMgBr TiCp2 C–C bond length [X-ray]: 1.438(5) A Ti(OiPr)4 (1.25 eq.), s-BuOH TMS Ethylene C–C bond length: 1.337(2) A iPrMgCl (2.5 eq.), TMS (1.1 eq.), TMS H TMS TMS –50 ºC, 2h i –50 ºC, 1h JACS 1983, 105, 1136 Ti(O Pr)2 Cp TiCl + + Mg TiCp 2 2 2 C6H13 C6H13 TiX3 For all references: C6H13 inverse selectivity [97:3 - 98:2] TMS TMS Sato, F. and Urabe, H. (2002) (1 eq.) observed Me Titanium(II) in Organic i i Synthesis, in Titanium and in other proton sources TMS H Ti(OPr)4 + 2 PrMgCl Ti(OiPr) afforded less TMS H cat. Cu 2 Organic Synthesis (ed I.Marek) O Tet. Lett. 1995, 36, 3203 Chem. Rev. 2000, 100, 2835 satisfactory results Br C6H13 82% C6H13 tBu O R R [>99:1] O H R R O +L O LnTi Ln–1Ti Ln–1Ti LnTi – R Me O tBu (1.1 eq.) 53% –L β–H elimination R R R [98:2] reductive elimination thermally unstable dialkyltitanium Cyclotrimerization t t Ti(OiPr)4 (1.25 eq.), CO2 Bu CO2 Bu metallocyclopropane more accurate presentation compared to alkene π-complex R iPrMgCl (2.5 eq.), tBuO2C C6H13 C6H13 –50 ºC, 5h i (2nd) JACS 1985, 107, 5027 LnTi Ti(O Pr)2 Ti(OiPr)2 Et2O, C H C6H13 –50 ºC, 3 h General entry into preparation and reactions of Ti(II) complexes (Tet. Lett. 1995, 36, 3203) 6 13 C6H13 (1st) Me SO2Tol iPrMgCl, 1. El1 rt, 3 h i R1 R1 El1 "Metalative Reppe Reaction" (3rd) 2 1 Ti(O Pr)2 2. El2 t R R i CO2 Bu t Ti(OiPr) Ti(O Pr)2 JACS 2001, 123, 7925 CO2 Bu 4 Et O, Me C H I 2 R2 [one-pot] R2 El2 6 13 C H TiX –78 ºC, 2.5 h i I2 6 13 3 Ti(O Pr)2 Me highly chemo– and (Practical method) 1,2-bisdianion di–, tri–, or tetra 56% equivalents regioselective substituted alkenes cyclotrimerization Reactions often more sluggish with the Cp Ti(alkyne) complex C6H13 2 C6H13 single compound Regioselectivity Chart <2 7 86 90 98 49% PhCHO TMS Bu3Sn Ph TMS tBuO C tBuO C Tet. Lett. 1995, 36, 3203 2 2 Synlett 1997, 821 Ti(OiPr) Ti(OiPr) Ti(OiPr) Ti(OiPr) i i C H 2 2 2 2 Ti(O Pr)2 Ti(O Pr)2 Tet. Lett. 1996, 37, 7275 6 13 O C H Me C H 6 13 6 13 C6H13 TMS Tet. Lett. 1997, 38, 4619 93 exclusive 14 >98 ACIE 2000, 39, 3290 O EtO OEt 10 2 C H + + + + + + 6 13 E = PhCHO E = PhCHO E = c-C6H11CHO E = PhCHO E = EtCHO E = PhCHO Ph Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Reactions with Imines TMS complete γ-selectivity n Ti(OiPr) , Pr R 4 (PrO)2Ti R C6H13 TMS I 2 iPrMgCl R X E+ NHBn (PrO)2Ti R Tet. Lett. 1995, 36, 5913 nPr X X (0.7 eq.) E + C6H13 (1.0 eq.) H 83% I2 β–elimination + NBn NHBn X = Cl, Br, OAc, OCO2Et, E = , ketones, 76% OP(O)(OEt)2, OTs, OPh JACS 1995, 117 , 3881 imines, NCS, I2 R (0.8 eq.) TMS Ti(OiPr) TMS 2 Application to an "allyl protecting group" i –50 ºC, 1 h NBn Ti(O Pr)2 Ti(OiPr)2 R = Et or nPr C6H13 Ti(OiPr)4, C6H13 CO2Et R CO2Et complete R 2 iPrMgCl O OEt H2O CO2 (1 atm), R regioselectivity CO Et >90% CO Et CO (1 atm), 74% rt, 24 h O 2 2 67% rt, 24 h TMS R = Bn, C H , I-(CH ) -, R CO2Et addition into aldehydes or mechanism? 9 19 2 4 JOC 1996, 61, 2266 ketones gives oxatitanacycles NBn CH2=C(Me)CH2CH2- TMS C H Tet. Lett. 1996, 37, 7787 NBn 6 13 Et R1 1 1 C6H13 Tet. Lett. 1997, 38, 6849 R Ti(OiPr)4, (PrO) Ti (PrO)2Ti R 2 2 + Et R2 2 iPrMgCl R X E R2 Reactions with Nitriles 1 R X 2 1 1 R1 X R E R Ti(OiPr) , R H R3 4 2 X = Cl, Br, OAc, OCO Et, + R SO Tol R2 2 E = aldehydes, ketones, iPrMgBr (2 eq.) 2 OP(O)(OEt) , OMs + 2 imines, NCS, I2 Ti(OiPr)2 (0.8 eq.) Ti Tet. Lett. 1995, 36, 3207 N 2 N R3 R3 N SO Tol Stereospecific preparation of allenyl alcohols R (0.8 eq.) 2 Me JACS 2000, 122, 7138 Me JACS 2005, 127, 7474 N N Ph 4 TMS MeO R CHO 1 i R Ti(OiPr)4, Ti(O Pr)2 HN * P 2 iPrMgCl Et h H+(D+) R2 * TMS * * Et TMS Et2O:THF E+ Me (1:1) Me R R1 R1 3 El 2 R R1 R N SO2Tol Me R2 2 TiX3 E or Z enynes react selectively with aldeydes, ketones or E+ = H+; 67%, 95:5 dr H(D) + 3 imines in regioselective and stereospecific way E = Me2CO; 45%, 93:7 dr R N CHO R3 R4 R3 O O H R1 Reaction of haloalkyne R CHO Constructing cyclobutenes R2 Synthesis 2000, 917 HO nBu nBuTi(OiPr) , Me Me R = I 85% 4 nBu OCO Et 2 iPrMgCl 2 nBu 3 i Ti(OiPr) R N TiX3 Me Me OCO Et 87% Ti(O Pr)2 3 2 –50 ºC Cl Ti(OiPr) , nBu El+ 4 Ti(OiPr) nBu 2 iPrMgCl 2 Cl(PrOi)2Ti R JACS 2001, 123, 7937 –50 ºC to rt –78 ºC Cl R –50 ºC, R1 R 2h i E Yield n nBu Ti(O Pr) + D D nBu Bu nBu R2 2 D H 47 E+ E Ti(OR)3 Ti(OiPr) , D 46 (97%D) Synlett 1999, 1939 4 Cl(PrO)2Ti R D R PhCH(OH) 51 (1.5:1 dr) R3 N El 2 iPrMgCl R = C8H17, 93% (>95% d3) Baran Group Meeting Rohan Merchant Organotitaniums in synthesis 08/04/2017

Kulinkovich Reaction Asymmetric Kulinkovich (JACS 1994, 116 , 9345) Ar Ar H 1. EtMgBr (2 equiv.), O PhCH2CH2MgBr (2 equiv.), Me OH Me O Ti(OiPr)4 (5-10 mol%), O Ti* (0.3-1 equiv.), rt, 3 h Ti* = Ti O Et O, –78 ºC R1 OH Me O 2 64%, 78% ee O + Me OEt H R1 OR2 2. H2O/H Ph Ar Ar R1 = , aryl, alkenyl "completely diastereoselective for 2 R2 = Me, Et, iPr cis-1,2-dialkyated cyclopropanol" Ar = 3,5-bis(trifluoromethyl) phenyl References: Vinylogous Kulinkovich O EtMgBr, HO Zh. Org. Khim. 1989, 25, 2244 or CO2Et J. Org. Chem. USSR (Engl. Transl.) Ti(OiPr) BF3•Et2O 4 OH 1989, 25, 2027 OMe R 90% Chem. Rev. 2000, 100, 2789 OMe R EtO2C CO2Et The Kulinkovich cyclopropanation of MgX OH THF carboxylic acid derivatives Organic Ti(OiPr) (Lewis basic O Russ. J. Org. Chem. (Engl. Transl.) 1997, 33, 830 Reactions, 2012, 77 4 R O O ) Ti(OiPr)2 O Proposed Mechanism: Org. Lett. 2004, 6, 2365 C2H6 R R1 OR2 (R'O)2Ti de Meijere Modification (Access to cyclopropylamines) 1,2-bisdianion 2 EtMgBr 2 iPrOMgBr 1. EtMgBr (2 equiv.), Me Ti(OiPr)4 (1 equiv.), Similar exchange with OR2 O 2 1 i Et O, rt R 2N R alkenes can be utilised Ti(OPr)4 (R'O)2Ti (R'O)2Ti 2 1 Me O R 1 2 + R NR 2 2. H OR2 Me Me H O, 1 2 R1 OMgBr ACIE 1996, 35, 413 Me Me R OH H+ (R'O)2Ti O (PrO)2Ti –[TiO(OiPr)2] Me N Me (R'O) Ti R1 2 EtMgBr R1 2 2 R2O O + R OMgBr O 2 key mechanistic difference 1 R 2N R Ti(OiPr)2 (20% yield) Ligand exchange of titanacyclopropanes with other added alkenes O R1 "most highly congested EtMgBr (2 equiv.), Ti(OiPr)2 R2 N O Me OH 2 tertiary " + Ti(OiPr)4 (0.05 equiv.), reflux primarily limited to Me OEt 42%, 98:2 cis:trans terminal alkenes Route to primary cyclopropylamines – Addition into nitriles Ph (2 equiv.) Mendeleev Comm. 1993, 230 BF OEt BF (PrO) Ti 3. 2 3 2 Ph N or N Ph Me OH Ph CN Ph MeCO2Et Ti(OiPr)2 Ti(OiPr) 2 EtMgBr (PrO)2Ti TiCl4 2 Ti(OiPr)4 (PrO)2Ti Ph Ph Doesn't work with aromatic nitriles 67% EtMgBr 70% For other alkyl olefins, ligand exhange not fast enough de Meijere modification for aromatic nitriles (excess) Better results with stoich. Ti and iPrMgX, nBuMgX, cylopentylMgX, cyclohexylMgCl Et2Zn (1.25 equiv.) H O 2 NH MgCl MeTi(OiPr)3 (1.25 equiv.) 70% 2 H2N Ph Me LiOiPr (2.5 equiv.), Ph O (4.5 equiv.) OH CN LiI (2.5 equiv.) Et H N R1 Et + R THF, 20ºC, 8 h 2 O OTIPS Me OEt Ti(OiPr) ( 1 equiv.) 4 OTIPS Ph Chem. Comm. 2001, 1792 42% Org. Lett. 2003, 5, 753 Et JACS 1996, 118 , 4198 Eur. J. Org. Chem. 2005, 5084 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Intramolecular Nucleophilic Acyl Substitution (INAS) O TMS Ti(OiPr) , (PrO)2XTi Ph 4 O OBn TMS H OBn O 2 iPrMgCl (PrO)2Ti TMS OBn O Ti(OiPr)4, OH O Ph 2 iPrMgCl O Ph Ti(OiPr) O 2 75% Tet. Lett. 1995, 36, 6079 (exclusive E) OBn OBn OBn 85:15 dr OH O Ti(OiPr)2 OTiX(OiPr)2 E/Z = 93:7 Ph Ph Tet. Lett. 1996, 37, 1253 H+ O For 1,2-dien-7-ynes and 1,2-dien-6-ynes; JACS 1997, 119 , 11295 OH O 85%, >97:3 dr Ph Using a chiral auxilliary (Reversible dissociation resulting in the more stable chelated product) Me O TMS Ti(OiPr)4, R* O C6H13 Total Synthesis of Allopumiliotoxin 267A (JACS 1997, 119 , 6984) Me Ph 2 iPrMgCl I2 O O C8H17 TMS nBu nBu Me Me C H CHO 8 17 H OH Ti(OiPr)4, I NBoc 5 steps Me4N(OAc)3BH N Me 2 iPrMgCl C6H13 JACS 2003, 125, 6074 CO Me N H 48%, 95:5 dr CO H 2 67% 2 OH H H O Me H Ti(OiPr)4, and/or MeOH 2 iPrMgCl Ti(OiPr)2 0 ºC Ti(OiPr) Ti(OiPr)2 NHR1 –50 ºC 2 R2 nBu Me CO2Et CO2Et EtO C EtO 2 OH Ar R2 –50 ºC E+ R1 Ti(OiPr) , JACS 1997, 119 , 10014 E+ Et CO 4 R1 X 1 N H 2 N 2 iPrMgCl N NHR Ti(OiPr)2 OH E Ar –40 ºC X = Br, OAc, Ar H Ar OP(O)(OEt) MeOH only with 2 E E R1 allopumiliotoxin 267A α,β–acetylenic esters CO2Et N E Tet. Lett. 2006, 47, 6209 Et EtO2C EtO Org. Lett. 2003, 5, 2145 OEt O Et Ar E+ = H 91% E+ = H 74% OEt = 99% d2 = D 78%, 99% d2 Tet. Lett. 1995, 36, 4261 TMS Total Synthesis of α-Kainic acid OBn 1,6–, 1,6– TMS Me Me Me I JOC 1996, 61, 6756 enyne, 1,7–enyne OBn Ti(OiPr)2 H H+ PhO Ti(OiPr) , JACS 1999, 121, 1245 and 1,6–diyne I 4 I 2 iPrMgCl PhO 2 BnO 97% suitable substrates OMe Me BnO I OMe OMe N N TMS N Bn OMe OBn Ti(OiPr) , OBn Bn OMe Bn OMe TMS 4 87% I 2 iPrMgCl 2 (6 steps from Ti(OiPr)2 (S)-Garner ) Me 66%, 96:4 dr PhCHO 4 steps CO2H OBn (1,6-enyne) OBn TMS TMS titanabicycle OBn H Asymmetric Ti PK: OBn Chem. Commun. 1999, 245 N CO2H JACS 1999, 121, 7026 56% CO J. Chem. Soc., Perkin Trans.1 2000, 3194 O (1 atm) BnO OH Ph H BnO Me α-Kainic acid Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Total Synthesis of Carbacyclin (JACS 2000, 122, 11244) Reductive Coupling by Micalizio

TMS CO2Et For more details see: "Reductive Coupling" GM by I. S. Young I TMS Acc. Chem. Res. 2015, 48, 663 Ti(OiPr)4, OH Me Me Me 2 iPrMgCl; Tetrahedron 2016, 7093 O I 4 steps The Development of -Directed Metallacycle- Me Br 2 Mediated Annulative Cross-Coupling Chemistry + Ti(OiPr) , 73% –50 ºC 4 Isr. J. Chem. ASAP (–)-phorbasin C 2 iPrMgCl OAc (3 steps from OH OTBS Ti(OiPr)4, TMS 2-buten-1,4-diol) OTBS EtO2C Me TMS c-C5H9MgCl, Et2O, Ln CO Et CO Et CO Et –78 ºC to 0 ºC, 1h Ti Me 2 2 2 Me –78 ºC to 0 ºC, 3h O Me O Me O nBuLi, CHO O 20 min, –78 ºC O O C5H11 M+ Me H H H C5H11 H H H H HO (RO)(PrOi)2Ti CO Et (iPrO) Ti 2 OH EtO2C H (PrOi)2Ti 2 (4 steps) Me Me OH O OEt Me Me O Me O Me 10 steps H+ (–)-phorbasin C O TMS O TMS CO Et CO Et CO H 47%, 2 2 2 + H > 20:1 dr M Ti(L) JACS 2009, 131, 1392 HO –O O n-1 NaBH4, MeOH, 0 ºC 3 steps Enantioselective Allylation H H 55% H H H H C5H11 C5H11 C5H11 (over 2 steps) Ph Ph Ti O MgCl Ti O PhCHO, OH Cl –74 ºC OH O Ph O Ph OH OH O OH 84:16 dr OH Ph carbacyclin Ph O Ph O Ph Ph 93%, 95% ee O Me O Me (Siloxy)enyne cyclization JACS 1992, 114 , 2321 TiCl(OiPr)3, Me Me 2 iPrMgCl, iPr iPr iPr –40 ºC, 6 h; iPr TBAF, OH Ti(III)/Ti(IV) Chemistry Si H+ O Si 2 THF O R R2 1 Proposed mechanism for hydrotitanation of 1,3- 1 R R2 single diastereomer R RMgX RMgX H R1 Me Cp TiCl Cp TiCl 1 Cp2Ti–H anti methyl group to hydroxy Me 2 2 2 R α Tet. Lett. 2004, 45, 4253 Me Cp2Ti R2 Me HWE; [H–] 0.5 R–R R1 OPMB OH OH 2 R TiCp2 syn/anti = 5/95 THF (siloxy)enyne HO (chair TS) Et HO cyclisation Me R2 (siloxy)enyne Me Me Me O Me Me (MeO)2P R2 EtCHO cyclisation O O Me Me Me Me O OH metathesis Me HMPA/THF syn/anti = 88/12 (3:1) TiCp2 HWE Me Me Cp2Ti Me (open TS) Et CO2H Tet. Lett. 1981, 22, 243 OH OH not produced Me dictyostatin TBSO OTBS OPMB J. Chem. Soc., Chem. Commun. 1981, 342 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Catalytic Modification O Me O O (Gansauer): 1/2 MCl MeCN complete γ-regioselectivity PhCOCl 2 R1 Me observed Ph III 2 60% 81% Cp2Ti Cl R Me Me 2 1/2 M O R2 R PhN=C=O CO2 CO H Me 2 5 mol% Ti R1 NHPh 60% R = H: 85% Cp TiIVCl 2 2 IV R = Me: 83% Me 1 OTi Cp2(Cl) Me TiCp2 R OH R2 NHPh Me nBu SnCl Ph NPh R1 OTiIVCp (Cl) 3 R2 H 2 Bu Sn Me Ph 1/2 3 70% Organometallics 1988, 7, 2289 70% Me R2 H base base•HCl 1/2 "Nugent-Rajanbabu" reagent Cat. Conditions Reduction: Cp TiCl (5 mol%), collidine HCl (1.25 equiv.), THF 2 2 • Mn (1.1 equiv.), 1,4-cyclohexadiene (4.5 mmol), THF, 16 h M Cl (lewis basic solvent) Cl IV III 1,4-addition: Acceptor (6 equiv.), collidine•HCl (6 equiv.), 2 Cp2Ti Cl2 Cp2Ti TiCp2 Cp2Ti –MCl2 Cl S = solvent S Zn (4 equiv.), ZnCl (2 equiv.), THF, 16 h n Cyclization: Cp TiCl (5 mol%), collidine•HCl (2.5 equiv.), red sol 15 min M =Mn, Zn lime green 2 2 Mn (1.5 equiv.), THF, 30 h ACIE 1998, 37,101; JACS 1998,120, 12849 Original Prep (1972): TiCl + 2CpTl Cp TiCl + 2TlCl 3 2 Total Synthesis of Ceratopicanol J. Chem. Soc., Dalton Trans. 1972, 1000 H OH H Me OH O H Me 4 steps Cp2TiCl, THF Radical from epoxides Me 82% Seminal transformation Follow up transformations with stoichiometric Ti(III) H H Me O H Me H ceratopicanol R OH First report of Cp2TiCl in synthesis Tet. Lett. 1995, 36, 15 Radical Polyene Cyclisations in Synthesis 4 steps EtO2C CO2Et Cp2TiCl (1.05 equiv.), Me reduction 1,4-cyclohexadiene (10 equiv.) Cp2TiCl (2 equiv.), 68% THF, rt, 50 min Cp2TiCl2 (85:15 cis:trans) Me Me Me Me Me Me O THF, rt, 5 min OAc (20 mol%), Mn, OAc collidineTMSCl Cp2TiCl (2.3 equiv.), O Me Me OTi(Cp) Cl THF, rt, 20 min R 36% 2 R Me HO O deoxygenation O H H Me RSC Adv., 2012, 2, 12922 Me Me Me Me furanoditerpenoid EWG 1,4-addition Cp TiCl (2 equiv.), 1. Cp2TiCl2, O EtO2C CO2Et 2 Me Zn, THF, THF, rt Me Me Me radical 60 ºC, 30 min 9 steps CN 2. TBSCl, im, cyclization Me JACS 1989, 111 , 4525 Me Me Me Me HO Me Me DMF, rt, 16 h O R JACS 1990, 112 , 6408 O EWG JACS 1994, 116 , 986 42% (2 steps) H Me H OMe TBSO TBSO O O Me H H EtO2C CO2Et Reviews: Eur. J. Org. Chem. 2015, 4567 Me Me Me Me Me (2 steps from berkeleyone A JACS 1988, 110 , 8562 Org. Chem. Front. 2014, 1, 15 (natural products) farnesyl bromide) JACS 2016, 138, 14868 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Asymmetric Reduction Radical from Ozonides R O R R Me Me OEt 10 mol% Ti*, O OTiCp (Cl) Zn, 1,4-C6H8, OH Cl Cl O 2 H O collidine•HCl O Cp2TiCl R O EtO Ti R EWG OEt R O O OTiCp2(Cl) 76%, 94% ee Me Me weak O–O bond R O R O OEt ACIE 1999, 38, 2909 Me Me Ti* R H (Cl)Cp2TiO O (Cl)Cp2TiO H2CO HCO2TiCp2(Cl) Hydrogen atom transfer from water JOC 2012, 77, 4171 OH O OH Me Radical from Enone Me Cp TiCl (3.3 equiv.), 2 O O Me THF Cp2TiCl2 (10 mol%), Me Me CN Me H Zn (2 equiv.) TBAF Me O H Me O + TMSCl (1.5 equiv.), JOC 2002, 67, 2566 O or HCl OTMS O O Me (5 equiv.) HCl/Et3N (1.3 equiv.); O NC Me A B HCl or TBAF CN [TiIV] Cp TiCl Chem. Eur. J. 2011, 17, 5507 O 2 Condtions A B Me Me anhydrous 97 3 OTiCp Cl CN OTiCp2Cl OTiCp2Cl 2 Et3N•HCl 0.5 Zn, +H2O (28 eq.) 15 85 Cp TiCl Me CN 2 CN TMSCl +D O (28 eq.) 25 75 (70% D) H 2 Me O O Me Et N 0.5 ZnCl , See: Hydrogen-Atom Transfer GM (Lo, 2014) Me 3 Me 2 Cp2TiCl2 Cp2TiCl

Radical from Oxetanes Me reduction of ketones: Tet. Lett. 2003, 44, 1079 R O reduction of alkenes, alkynes (metal hydrides): Org. Lett. 2007, 9, 2195 HO R H Cp TiCl (20 mol%), Me 2 2 IV Mn (2.5 equiv.), OTi Cp2(Cl) Cp Cl OH Cp Cl calcd. BDE = 49.4 kcal/mol O collidineHCl EWG Ti + H BDE decrease = 58.7 kcal/mol EWG Ti Cp OH R Cp OH2 R Me Me R Me Tetrahedron 2008, 64, 11839 R OH HO H HO + H calcd. BDE = 108.1 kcal/mol H Me Reformatsky Reaction 1 O 1 5 –1 –1 H R Cp TiCl O Cp TiCl OTiCp Cl 3 Cp Cl R K = 1.0 x 10 M s Cp Cl + 2 2 2 R CHO O OH Ti + Ti X Cp OH Cp OH 2 R1O R1O 1 2 R2 R R O R1O R3 ACIE 2006, 45, 5522 R2 R2 2 Cp2TiCl(X) R R2 JOC 2008, 73, 7901 X= Cl, Br Stoich Ti (in situ prep from Mn+Cp2TiCl2): Org. Lett. 2003, 5, 3615 Cat Ti (with collidine.TMSCl): JOC 2008, 73, 1616 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Barbier–Type Reaction Deoxygenation of benzylic and allylic alcohols (JACS 2010, 132, 254)

O Cp TiCl (0.2 equiv.), OH + X 2 2 Cl Cl Mn (8 equiv.), THF, rt TiCp2 Δ Cp TiCl 2 1 Cp2TiCl TiCp 2 R R R1 2 R R TiCp2Cl Me 2 R OH aldehydes, X = Cl, Br R R O O H+ ketones H R H Cl Cp2TiClOH R H Me N Me Chem. Eur. J. 2009, 15, 2774 Require toluene reflux for alkyl alcohols TMS (4 equiv.) Me Me Cp2TiCl2 (0.3 equiv.), Oltra's catalytic procedure: Me TMSCl (4 equiv.), Mn (8 equiv.), Me Me O O + OH THF, reflux, 4 h OTMS H3O Me Me 85% R1 R1 Me 2 R2 Me formation of hydroxy–Ti(III) complex Me Me N Me R significantly decreases the energy of Mn HO H Cl IV activation for C–O bond homolysis 2 x Cp2Ti Cl2 MnCl McMurry Coupling Me N Me 2 TiCl or TiCl , 1 3 3 4 R1 R3 TMS R R reducing agent O + O IV reducing agent: Li, Na, 2 4 OTi ClCp2 R2 R4 R R III Mg, Zn, LiAlH4, Zn-Cu 2 x Cp2Ti Cl R1 R2 Original references: Chem. Lett. 1973, 1041 preference for trans olefins Bull. Soc. Chim. Fr. 1973, 2147 IV O JACS 1974, 96, 4708 mainly used for homocoupling of Cp2Ti Cl2 aldehydes or ketones 1 2 TiIIIClCp R R In natural product synthesis (review): O 2 ACIE 1996, 35, 2442 mixed coupling feasible if one X component used R1 R2 Other References: in excess or a diaryl ketone Takeda, T. and Tsubouchi, A. 2013. The McMurry Multimetallic Barbier–Type Reactions (with allylic carbonates) Coupling and Related Reactions. Organic Reactions Traditionally Ti(0) or Ti(II) Chem. Commun. 1998, 2549 expected to be the active species Ni(PPh3)2Cl2 (0.1 equiv.) Cp2TiCl2 (0.4 equiv.), OH Pinacol Coupling O HO OCO Et Mn (8 equiv.), THF, rt O TiCl –Mg(Hg), Me + 2 1 O 4 2 1 R 0 ºC, THF HO Me R R Me R2 + (4 equiv.) aldehydes, Me Me Cl (4 equiv.) ketones JOC 1976, 41, 260 Me N Me Eur. J. Org. Chem. 2012, 1499 K.C. Nicolaou's Taxol synthesis TMS O HO OH OBn O Me Me MeOBn OCO2Et Me Cp2TiCl2 (0.4 equiv.) OH Me [TiCl3(dme)1.5]/ Me O PdCl2 (0.2 equiv.), Me Me Zn(Cu), DME, Δ taxol MeO C PPh (0.4 equiv.) MeO C Me Me + 2 3 2 8 O H 23-25% 8 MeO C Mn (8 equiv.), TMSCl (4 equiv.), MeO2C O H O O 2 O O 2,4,6-collidine (7 equiv.), THF Nature 1994, 367, 630 O Me (4 equiv.) O Me Me 52% Me Me Me ACIE 2008, 47, 7515 Me Me Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Me Me Me Me Me Cross–McMurry Coupling OBn CHO Cp TiCl (3 equiv.), O Me 2 2 Me OHC Me Me Me Me O Mn (8 equiv.), THF, Me Me Me Me O reflux O + O OBn Me Me Me Me Me Me 77% Me Me Me 1. TiCl3–Zn-Cu, DME (66%, E-isomer) JACS 2010, 132, 254 72 membered macrocylic lipids 2. KO2CN=NCO2K (88%) (5 equiv.) 3. H2 Pd(C)/EtOAc (80%) JOC 1998, 63, 2689 Me Me Me Me Me OH Radical Polymerization O Me Me Me Me Cp TiCl + Zn + 0.5 ZnCl Me Me Me Me 2 2 Cp2TiCl 2 O O O OH Cp ClTi–OCH CHR Me Me Me Me Me R 2 2 Cp ClTi–OCHRCH H O 2 2 Me H Me with anhydrides and aldehydes R H TiCl4/Mg(Hg) Cp2ClTi–O–CHR CHO J. Chem. Res. Synop. 1989, 226 O n Ph Me Me O OO Cp2TiCl Pn HO O R X Cp2TiClX + R JACS 2004, 126, 15932 Cp2TiCl2 (0.3 equiv.), Cl Tetrahedron 2008, 11831 Mn (8 equiv.), TMSCl (4 equiv.), O THF, reflux O R R O Cl 95% Cp2ClTiOR + RO Cl O 2 x Cp TiIIICl MnCl2 2 + P –TiCp Cl Pn Cp TiCl n 2 green soln R 2 Mn effectiveness of the initiators: aldehydes>peroxides>epoxides>halides Titanium Carbene Complexes cat. McMurry coupling IV IV 2 x Cp2Ti Cl2 involving Ti(III) pinacolates OTi Cp2Cl Lewis base in the deoxygenation step Cp TiCl + 2 AlMe Cp2Ti AlMe2 Cp Ti red soln R 2 2 3 Cl 2 JACS 2010, 132, 254 R –AlMe2Cl, CH4 –AlMe2Cl Tebbe Reagent OTiIVCp Cl titanocene methylidene 2 x TMS O 2 2 Me Me 13CH Me JACS 1978, 100, 3611 4 x TMSCl 2 IV III Me 2 x Cp2Ti O OTi Cp2 Mn 13 Cp2Ti Cp2Ti C R R MnCl2 Tebbe reported the first olefin R Me metathesis between OTiIIICp 13 2 CH2 CH2 titanocene-methylidene and R cat. Cp TiCl mediated pinacol couplings: Me simple terminal olefins 2 JACS 1979, 101, 5074 Chem. Commun. 1997, 457 13C JOC 1998, 63, 2070 13 Cp Ti Cp2Ti CH2 JOC 2009, 74, 3616 (ketones) 2 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Grubbs Total Synthesis of Δ(9,12)−Capnellene Higher homologues of titanium-methylidene are better 1. CpMgCl, Me Me Cp Ti O Me TiCp Cp2Ti 2 THF,rt 2 + O Me Me Me 3 steps OtBu 2. C6H6, 75 ºC Me Me Me O TsO 67% Me Me (2 steps) Me Me Me tBuO O resulting Ti carbene complex more stable than starting alkylidene n Cp Ti AlMe 20ºC JACS 1986, 108, 855 2 Cl 2 DMAP, C6H6, rt; n Me 90 ºC Me Me Me Me Me Me Me JACS 1986, 108, 733 H H H HO TsOH, H H OtBu 60ºC Cp Ti (CH OH) Cp2Ti 2 9 steps O 2 2 81% Petasis Reagent Me H H H MeLi or Me Δ (9,12) Δ −Capnellene Cp2TiCl2 Cp2Ti Cp2Ti MeMgCl Me titanocene methylidene Tandem carbonyl olefination– JACS 1990, 112 , 6392 Petasis reagent Org. Synth. 2002, 79, 19 H H H No Lewis acid - no epimerization H H H O O Me OPRD 2004, 8, 256 O O Me Cp2Ti AlMe2 BnO Cleaner reaction than Tebbe BnO Cl Can remove Ti impurities by filtration O react with sterically hindered carbonyls BnO O THF, rt BnO O H H H H H H react with esters, thioesters, amides, carbonates and ureas Me 77% Me strong Ti=O driving force JACS 1996, 118 , 1565 Cp2Ti AlMe2 Cp Ti AlMe Review: Tetrahedron 2007, 63, 4825 Cl JACS 1996, 118 , 10335 2 Cl 2 Lombardo Reagent rt, then reflux Construction of polyether THF, reflux 71% frameworks of maitotoxin Zn, CH2Br2, Takai: Tet. Lett. 1978, 2417 H H H H H H O TiCl , THF O O Me O O Me 4 Lombardo: Tet. Lett. 1982, 23, 4293 BnO 65% BnO R1 R2 R1 R2 Using Nysted Reagent: Tetrahedron 1995, 51, 1623 BnO O BnO O H H H H H H Olefination of thioacetals TiCp Mg, 2 P(OEt)3 2 4 A MS, THF, rt Cp2TiCl2 Cp2Ti[P(OEt)3]2 Bulky Cp ligand disfavours the formation of titanocene-alkylidene SPh O 1 eq. R R1 SPh R1 R 2 Cp2Ti[P(OEt)3]2 Cp2Ti R2 X R or R1 TiCp TiCp Cp2Ti 2 2 2 – Cp2Ti(SPh)2 X = H, alkyl, aryl, R X S R R OR3, SR3, NMePh R JACS 1997, 119 , 1127 R1 S Chem. Lett. 1998, 115 olefin metathesis using titanocene-methylidene not necessarily regarded as useful synthetic tool 1.1 eq. Tet. Lett. 2003, 44, 5571 Baran Group Meeting Rohan Merchant Organotitanium Chemistry 08/04/2017

Aryltitanium alkoxides in cross coupling Me Me OBn Me Me OBn iPr iPr H O Ni(acac) (0.5 mol%), O O Cp Ti[P(OEt) ] H O Ti(OEt)3 2 2 3 2 O O Ligand (0.5 mol%), N N N H THF, reflux THF, rt O H + BnO 52-67% O MOMO Me BnO Me Cl N 98% iPr iPr H O H MOMO BnO H Me H Me Cl PhS SPh BnO (1.5 equiv.) Synlett 2007, 2077 Ligand J ring of ciguatoxin With Pd: Synlett 2002, 871 Chem. Commun. 2001, 381 ACIE 2009, 48, 7436 Organotitaniums in Cross–coupling Miscellaneous

Alkyl radical from Ti(III) epoxide opening trapped by Ni CO2Me Titanium homo–enolates O OH O Me H TiCl4, TMSO OMe O TiCl Br NiCl2(dme) (0.1 equiv.), 3.5 hexanes, rt 3 Me O O 2,2'-BiPy (0.1 equiv.), Me + + 83% MeO DCM, rt, 6 h Me Cp TiCl (0.1 + 0.04 equiv.), (10 g) Et 2 2 (deep purple crystals) MeO2C Et N•HCl (1 equiv.), Mn (2 equiv.), 79% 3 CO2Me can be isolated Me DMPU, rt, 12 h OH 62% JACS 1986, 108, 3745 Me 1.0 For more details about the Ni-catalysed reductive cross-couplings: CO2; Hex + Revisting Nickel GM (Edwards, 2016) JACS 2014, 136, 48 MgCl Hex MgCl H Cp2TiCl2 (.12 equiv.), Me Me O (3 equiv.) THF/hexane 72% CO2H NC Me Me Me [Ti] (0.1 equiv.), + –20 ºC, 3h NiCl2(dme) (0.1 equiv.), Hex Br Hex O 2,2'-BiPy (0.1 equiv.), Hex TBDPS OH TiCl2 Et3N•HCl (1 equiv.), Mn (2 equiv.), Me Me Me Me MgCl + Br DMPU, rt, 12 h Me Me 2 Chem. Commun. 2008, 5836 TBDPSCl Cp TiCl 72%, 97:3 E:Z 80%, 94% ee, O Me Me 2 2 NC >20:1 dr [Ti] Hex MgCl Asymmetric variant MgCl JACS 2015, 137, 3237 Me Me

O O Br MgCl Ti Ar Br N NiII [TiIV]O N Ar Cp2 H O N 0 Ni O III N [Ti ] TiCp2 [TiIV]O Alkyl Ti Mn2+ Br N NiIII [NiII] Cp2 Mn0 N Ar Alkyl Br IV I N II O [Ti ] [Ni ] Ni MgCl N Cl [TiIV]O N NiI Br O N TiCp TiCp Ar H+ HO 2 2 [TiIII] [TiIV] Ar MgClX Alkyl–X MgCl