Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

Background -CpCo moiety (14 e species) highly dienophilic. -Cobalt-59 – 1st row Group IX TM -Cobalt dyes used for centuries – glass, pottery and glazes. -Originally confused with Cu – both form blue compounds. -German name "Kobald" – "evil spirits" – describing a mineral that is both hard to mine and O detrimental to health (when heated emits As4O6). -1 of the 3 naturally occuring magnetic metals (Ni/Fe/Co) Co Co -10 to 30 ppm on earth – cobalite/smaltite/chloranthite. -Cobalt-60 – radioactive isotope used to find and treat diseases. Organometallics. VCH:Weinham, 1989, pp 277, 348 Schilling Test - determines if a person is making and using Vit. B12 properly. Treat for cancer. -can form 19, 20 and 21 e sandwich complexes + eg. CpCoC6Me6, [(C6Me6)2Co] , [(C6Me6)2Co].

-Cobaltcarbonyls exist as clusters: Co2(CO)8, Co4(CO)12, Co6(CO)16...

Cobalt in Nature

Vitamin B12 -first compound with a M–C bond in natural product -soluble in water. Comic book -suffix: cobalamin; prefix: depends on upper axial ligand. -cyano (CN), hydroxo (OH), methyl and adenosyl. Oxidation State - Common OS of Co is I, II, III

Co(II) -d7 complex. -forms both Td and Oh complexes –depends on ligand strength. -small Δoct and Δtet difference. Outline Co(III) Characteristic Organic Reactions of Cobalt -d6 complex. -almost exclusively Oh complexes. 1. Pauson-Khand Reaction 2. Nicholas Reaction 3+ - Co2+ E = +1.82 eV Co + e 3. Cyclotrimerization 4. Carbonylation Some Organocobalt compounds -high affinity to π bonds of carbon-carbon, carbon-oxygen and carbon-nitrogen. Other Reactions of Cobalt -forms mutually bridged bond between 2 π bonds of acetylene and Co–Co bond. 5. Radical Chemistry of Cobalt R R' 6. Vit. B12-type Co Reactions 7. Mention of Mukaiyama Co Chemistry (OC)3Co Co(CO)3

Page 1 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

1. Pauson–Khand Reaction 1.5 Modifications to Pauson-Khand

1.5.1 'Interrupted' Intramolecular PK – 'insertion of O2' instead of CO 1.1 Mechanistic Outline O L not R O O Co2(CO)8 R R R R C RL R heat, air (OC)6Co2 [2+2+1] O S R RS R = CN, (CH2)2OTBS, Et, CH2Ph Krafft, JACS 1996, 118, 6080 S S RL R R L S L S 1.5.2 Formal [5+1]/[2+2+1] vs. [5+1]/[2+2]-cycloaddition – epoxyalkyne + olefin +CO R R R R R (OC)5Co2 L H R R R O H O R O O O O (OC) Co (CO) Co (OC) Co (CO) Co 3 2 3 2 (OC)3Co (CO)2Co O Co (CO) R 2 8 R or R heat R' R' 1.2 Pauson–Khand in Total Synthesis CO or N2 H H R' O Me H R = H, Me OH [5+1]/[2+2+1] [5+1]/[2+2] H H H Me O Liu, JOC 2006, 72, 567 N Me OH -If R = Me, heating under CO gives the [5+1]/[2+2+1] adduct; H H H H heating under N2 gives [5+1]/[2+2] adduct. If R = H, only [5+1]/[2+2+1] adduct in CO O or N2. H H N O O - reason unclear - speculated to be due to avoidance of quaternary center generation. O O OH (+)-Epoxydictymene (±)-13-Deoxyserratine (-)-Dendrobine Paecilomycine A 1.5.3 Sequential Staudinger/PK – Fused Tricyclic β-Lactam Schreiber Cassayre Cassayre Danishefsky R JACS 1994, 116, 5505 ACIE 2002, 41, 1783 JACS 1999, 121, 6072 ACIE 2007, 46, 2199 1.TMSOTf, Co2(CO)6 ArNH2 Ar Co (CO) R CH(OEt)2 2. DIPEA N 2 6 1.3 Pauson–Khand Readings Ts ClOC N R = H, Me, SiMe3, Ph n O N n -S. Gibson, N. Mainolfi, ACIE 2005, 44, 3022 Ts -O. Geis, H. Schmalz, ACIE 1998, 37, 911 n = 1, 2 -Nakamura, Chem. Rev. 2004, 104, 2127 –TM catalyzed heterocycle syntheses -Buchwald, JACS 1999, 121, 7026 –Ti (in place of Co) Assymmetric PK

1.4 Scope and Limitations Bertrand, JOC 2008, 73, 8469

-Excellent method for 5-membered ring synthesis – atom economical and has potential flexibility - Pioneered by Alcaide et. al. -Long reaction time - addressed by use of tertiary amine N-oxides (xs) to generate free coordination - [4.6.5] and [4.7.5] tricyclic lactam sites at Co by removal of CO ligand. Recent eg. OL 2009, 11, 3104. available -Stoichiometric use of Co - addressed with development of catalytic systems, eg. Co2(CO)8/P(OPh)3; indenylCo(cod); Co(acac)2/NaBH4. eg. Photoactivation of Co2(CO)8: JACS 1996, 118, 2285. -Use of other metals - Ru/Ni/Ti - not covered here. -Existing problems: Assymmetric Pauson–Khand, Limited choice of alkyne substrate (terminal).

Page 2 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

1.5.4 Asymmetric Pauson-Khand Reaction - PNSO ligand works as it is bridging; olefin inserts to Co where S* is bound. - Sterics and higher ! -acidity of sulfinyl ligand favor olefin coordination. Sulfur chirality - 3 approaches: chiral substrates (most common), chiral ligand or chiral amine-oxide promoter. directs olefin insertion into 1 of 2 Co–C bonds. 1.5.4.1 Chirally-modified substrates in Total Synthesis 2. Nicholas Reaction H H 2.1 Mechanistic Outline O O H OR' X Nu H H H OR' 1. Nu- (+)-Hirsutene R' = chiral auxiliary (OC)6Co2 2. [O] Greene, JACS 1990, 112, 9388 R1 R1 For similar total syntheses see JOC 1995, 60, 6670 and JOC 1996, 61, 9016. [O]

Using chiral substrates - in this case a chiral ynamine R1 X R1 R1 Nu LA Nu- O Toluene, -30 oC H NR2* (OC) Co Co(CO) (OC) Co Co(CO) *R2N 3 3 3 3 (OC)3Co Co(CO)3

JOC 2000, 65, 7291 2.2 Scope 1.5.4.2 Chiral amine-oxide promoter - Reactions of propargyl halides with ! -systems required >1 alkyl or Ph substitutents EDGs ==> limited use of propargyl cation as synthons. - Dicobalt hexacarbonyl group efficiently stabilizes the cation. (also used as alkyne PG) - SN1 type reaction - Thermodynamic control (Lewis acid catalyzed).

Kerr, Synlett 1995, 1085 2.3 Readings on Nicholas Reaction

- Although modest ee 44%, first innovative use of chiral amine N-oxide. - Named reaction in Organic Synthesis - for a brief introduction. - can use achiral reagents - JACS 1998, 120, 900 - for Phys Org study on electrophilicity of propargylium ions and compatible nucleophiles. 1.5.4.3 Chiral Ligands - Large number of studies in this field: one major challenge remains – use of symmetrical 2.4 Nicholas Reaction in Total Syntheses alkynes. OR O - Symmetrical alkynes less reactive; chiral phosphine ligand too far away to direct olefin OBn H H insertion, thus end up with an almost racemic product. H H O H i–Bu Me(H2C)4 O O O H NH O Ar N O H H Ar P S O O Tol HO R ß-Lactam Precursor OC Co Co CO (+)-Secosyrin 1 (+)-Epoxydictymene OC CO NMO, rt, CH2Cl2 to thienamycin Mukai Schreiber H ee >90% Jacobi JACS 1994, 116, 5505 R R R JOC 1996, 61, 2413 JOC 1997, 62, 8095 Riera, OL 2009, 11, 4346

Page 3 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

- Tricyclic ethers: [5.6.5] and [5.9.5] poor yield; [5.7.5] and [5.8.5] trans favored; [5.10.5] 2.4.1 Total synthesis of Velloziolide not isolable - dimerizes to give 20-membered-ring. - Benzo-fused ε−lactone unit - 1st synthesis. - Tricyclic amines: [5.7.5] gives excellent cis selectivity; [5.8.5] cis favored; others not - Derived propargyldicobalt cation stable despite the EWG (CO2Me). favored. - Use of 2 Nicholas reactions. - Tricyclic lactones: not successful; also dimerizes to give diolides (ThD controlled). Also featured in JOC 2005, 70, 9088.

CO2Me O MeO O Co2(CO)6 O 2.6 Using ThD to advantage O 1. Rh/C, MeOH O 1. Bu2BOTf O R 2. MeLi HO MeO2C 1. Co2(CO)8 2. [O] BnO 2. cat. TfOH BnO HO BnO O OH Li R 3. Et3N, I2 OH R O Nicholas OBn OBn CO2Me OBn O MeO O Co (CO) 1. Me CuLi R = SiMe3: β/α > 99 BF –OEt O 2 6 O 2 3 2 1. Bu BOTf 2. DIBAL-H 2 CO2Me Inouye, OL 2003, 5, 625 2. [O] - Mitsunobu conditions not α/β selective. - Nicholas gives high β−selectivity since ThD conditions cause epimerization of α anomer Nicholas to β counterpart.

O OR O O O 3. [2+2+2] Cyclotrimerization with Co O MeC(OEt)3 1. BCl3 O EtCO2H 2. AgNO3 3.1 Mechanistic Outline

R R CO2Me R = CH2Cl2 L R OH velloziolide -L -L R R R = H L M L M L M ML n n n LnM n Green, JOC 2009, 74, 7411 L L LnM "template" R coordination to 2.5 Tandem Intramolecular Nicholas/PK for Synthesis of Tricycles R - R satisfy 18 e rule R - Endocyclic cyclization is one of the least studied. Endocyclic cyclization using R +2 LnM alcohol, amine and carboxylic acid as nucleophiles are studied here, where the latter LnM two are unprecedented.

H 3.2 Scope and Limitations Z d.r. dependent on - Catalytic Co (usually CpCo(CO) ). H reaction conditions 2 n O - Other metal alternatives such as Rh, Ru, Ir and Pd. n = 1 – 10 H Z - Used widely to create complicated polycycles. OMe n Co (CO) 2 8 PK 3.3 [2+2+2] Cyclotrimerization with Co in Total Syntheses (OC) Co O N N.B. Bond angle 6 2 (OC)6Co2 reduced to 138º Nicholas H H Z OMe Z H n n H H Oestrone N H (±)-Strychnine Shea, JOC 2008, 74, 3680 Vollhardt O Vollhardt HO H JACS 1979, 101, 215 O OL 2000, 2, 2479

Page 4 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

SiMe3 Other Total Syntheses: SiMe 3 - Diterpene: Illudol – JACS 1991, 113, 381. - Commercial production of butyraldehyde from propylene. Butyraldehyde used to make Stemodin – JACS 1991, 113, 4006. butanol (2.1 × 106 ton/yr), 2-ethylhexanol (3 × 106 ton/yr), etc. - Fullerodendrimers – ACIE 2007, 46, 951. - Rh catalyst has replaced Co (higher selectivity and stability). Me3Si - Helicenes – ACIE 2008, 47, 3188. JOC 1998, 63, 4046. Me3Si 4.2 Hydrocarboxylation JOC 2007, 73, 2074. cat. - A DFT Study – JACS 2006, 128, 8509. RCH=CH + CO + HX RCH CH COX 2 heat 2 2

SiMe3 SiMe3 X = OH, OR, SR, NHR, etc ACIE 1995, 34, 1478 4.3 Amidocarbonylation 3.4 Cobalt (I)-mediated [2+2+2] of Allenediynes NHCOR' RCH=CH2 + R'CONH2 + 2CO + H2 RCH2CH2CHCOOH Ph O 1. CpCo(CO)2 O - Via aldehyde intermediate. ACIE 2000, 39,1011 xylene, 300W Ph heat - Used in the synthesis of aspartame, sarcosinates, etc.

2. SiO2, CH2Cl2 4.4 Hydrosilylcarbonylation OSiEt Me 48% 2

Available in 6 steps HSiEt2Me + CO 11 β-aryl steroid Aubert, OL 2004, 6, 3937 - ABC ring system generated in 1 step. However stoichiometric Co needed. 4.5 Carbonylation of halides CH2Cl CH2COOMe 3.5 [6+2] Co(I)-mediated Cycloaddition MeOH CO

CoI2(dppe)/Zn/ZnI2 R 43–96% 4.6 Hydroaminomethylation CO/H , Co cat. R 2 NH3 HN Buono, OL 2005, 7, 2353 H2N - A wide range of R groups applicable. Catalytic Chem. Rev. 1999, 99, 3346 system tolerates ketone, sulfone, ester, ketal, - Over alkylation over. Co phased out due to large amounts of byproducts such as ether, alcohol, imide and nitrile. formamides, hydrogenation products and alcohols. - Rh used widely for hydroaminomethylation of olefins, diolefins...

4. Carbonylation 4.7 Hydroazidation - the new hydroamination? - Hydroamination – La and early TM catalysts effect intramolecular hydroaminations. Late - Organocobalt used as catalyst in these reactions. TM prefer Michael acceptors as substrates or activated olefins for intermolecular 4.1 Hydroformylation hydroamination. Lack of general hydroamination procedure. - Azide a good nitrogen sources, as it can be converted to amines easily. Co2(CO)8 + H2 2HCo(CO)4 HCo(CO)3 active species -2CO - Traditional methods require SN of 1º or 2º halides with azides/ or alkenes (those able stabilize carbocation) with TMSN or NaN cat. 3 3. RCH=CH2 + CO + H2 RCH2CH2CHO - Hydroazidation is a catalytic process which enables functionalization of unactivated 100 ºC Omae, AOC 2007, 21, 318 100 atm olefins with high Markovnikov selectivity.

Page 5 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

Ph Ph t–Bu t–Bu - Limitations include the use of expensive GR in excess. Use of GR also limits N CO K substrate functionalities. 2 O L Co n t–Bu N OH R3 O R Ph R1 6 mol % 1 R t–Bu R3 5.1.1 Intramolecular Heck-type Reaction of 6-Halo-1-hexene 3 TsN3 H Ph O 6 mol %Co(BF4)2•6H2O R2 30 mol % t–BuOOH, silane N3 R X R cat. CoCl2(dppb) X generated in-situ 1 2 R1 EtOH, 23 ºC Me3SiCH2MgCl (1.5 eq) R2 JACS 2001, 123, 5374 Careira, JACS 2005, 127, 8294 OL 2002, 4, 2257 I R3 R3 JACS 2006, 128, 8068 - No precedence observed with Pd catalysts. Prior studies required stoichiometric cobaloximes and irradiation. - Radical generation; 5-exo-trig; Co-trap; ß-H elimination.

5.2 Cross-Coupling of Aryl GR with 1º and 2º Alkyl Bromides

CoCl2 R–I ArMgBr (1.2 eq) R–Ar NMe2

NMe2 JACS 2006, 128, 1886 - Applied in the total synthesis of AH13205 - Recently, another group published the chemoselective alkylation of Aryl GR using alkyl bromides/iodides and Co(acac)3/TMEDA as catalysts. TMEDA cheaper than N,N,N',N'-tetramethyl-1,2-cyclohexanediamine – Cahiez, OL 2009, 11, 277. - Also see hydrohydrazination: JACS 2004, 126, 5676 and OL 2005, 7, 4249. - Great review on both processes: JACS 2006, 128, 11693. 5.3 Radical Dimerization - Next question to ask: Asymmetric hydroazidation? 5. Radical Chemistry of Cobalt - Radical dimerization has been used in a number of total syntheses.

R O H H H N H N 5.1 "Heck"-like coupling with Cobalt Me Me N S N O O 5.1.1 Strylation of alkyl halides N S Me O Me S N cat. [CoCl (dpph)] N O 2 O N S Me O Me3SiCH2MgCl (2.5 eq) R Me R–X N H N H Ar Ar R O H H R – normally long alkyl R = H; (+)-chimonanthine X – usually Br Oshima, JACS 2002, 124, 6514 (+)-11,11'-Dideoxyverticillin A (+)-Biatractylolide JACS 2006, 128, 8068 R = Me; (+)-folicanthine Movassaghi Baldwin - Pd catalyzed Heck coupling experience ß-H elimination when Movassaghi Science 2009, 324, 238 JOC 2004, 69, 9100 alkyl halides are used as substrates. Alkyl halides also have slower oxidative addition rates. ACIE 2007, 46, 3725 - Ni catalyzed versions afford moderate yields. Not as eco-friendly as Co. - This Co reaction involves SET resulting in alkyl radical generation which adds to styrene, - Reductive dimerization employed in all syntheses using ClCo(PPh3)2 as stoichiometric propagating a new stabilized radical. This radical is then trapped by Co and subsequent reagent. ß-H elimination yields product.

Page 6 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

- Wide range of terminal epoxides can undergo HKR followed by 1,2-diol ring opening - ClCo(PPh3)3 was actually used in preceding literature for dimerization of allylic halides. - Typical reaction coonditions are mild and non-basic. Reaction proceeds with preservation with water as stiochiometric nucleophile. Complements OsO4 dihydroxylation. of stereochemistry. - Double resolution performed if high ee are needed. - >99 % ee and >40% yield. - Relatively cheap catalyst and recyclable with low-boiling substrates. Solid residue from distillation can be reoxidized to Co(III) with no loss of reactivity or selectivity up to 6 cycles.

Cl Cl - It was found that oligomers of Co cat. O O gave higher ee. - Eg. asymmetric hydroxylation of O O cyclohexene oxide difficult with monomeric (salen)Co(OAc) but effective with oligomeric H t–Bu H (salen)Co(OTs) (>94% ee) using water as N O t–Bu O N nucleophile. Co Co N O O N - Alcohols can also be used as nucleophiles Yamada, TL 1983, 24, 921 t–Bu t–Bu H H in this protocol. OH - Coupling of benzylic halides was also reported – CL 1981, 1277. (R,R)-cat. O HO O LPTS R1 O R1 OH R2 Why ClCo(PPh ) ? R2 3 3 O O Cl Cl JACS 2001, 123, 2687 n = 1-5 ACIE 2002, 41, 1374 6. Vitamin B12-like compounds - Both monomeric or oligomeric (salen)CoOTf successful in intramolecular oxetane 6.1 Some Co compounds with vitamin B12 character ring opening. achiral reagents to optically active products. H - depending on the tether, quaternary stereocenters can be formed. Me CN O H R O O O H H Me N N Me Me Me N N R Co Co N N O O Co OH OH Me N N Me t–Bu O O O OH t–Bu H t–Bu t–Bu Me Me JACS 2009, 131, 2786 N (Salen)Co(II) Bis(acetylacetone)ethylenediamine - For a detailed mechanistic study on HKR of epoxides, see JACS 2004, 126, 1360. "Jacobsen" (BAE)-type cobalt Square planar "Yamada" CN 4 coordinate -Used widely in enantioselective 6.3 AKR of Terminal Epoxides Bis(dimethylgloximato)cobalt(III) Forms an axial borohydride reduction, cyclopropanation, Co–C bond. hetero Diels-Alder, Henry reaction... - Useful tool for preparation of optically active N-protected1,2-amino alcohols. - Use of carbamates as nucleophiles. rt in air. OH 6.2 HKR of Terminal Epoxides with (salen)Co(III) complexes NH2R (1 eq) (R,R)-cat. NHR (S,S) (R,R) R O OH O p-nitrobenzoic acid 1 Cl (salen)Co(III).OAc O (salen)Co(III).OAc (2.2 eq) Cl TBME (5M) >99% ee Cl OH ± >99% ee >99% ee R1 Bartoli, OL 2004, 6, 3973 Science 1997, 129, 1105; JACS 2002, 124, 1307

Page 7 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

6.4 Enantioselective Nitro-Aldo (Henry Reaction) using self-assembled (salen)Co(II) - The resultant O-benzyloxime or oximonitrile can be converted into the corresponding aldehyde by hydrolysis with formaldehyde and cat. HCl. - Self assembly of novel dinuclear (salen)Co(II) catalyst using non-covalent H-bonds (proved by X-ray structure). 7. A Mention of Mukaiyama Co Chemistry - Applied system to Henry reaction in anhydrous solvent CH2Cl2 (essential). - monomeric species gave modest %ee and yields. 7.1 Mukaiyama 'Oxidation-Reduction' Hydration OOSiEt3 Et SiH cat. 3 H O DIPEA OH R CH Cl O2, Co(acac)2 CH NO (10 eq) 2 2 R 3 2 NO2 Ar H Ar PhSiH3 OH 82–96 % ee H R CL 1989, 1071 Hong, JACS 2008, 130, 16484 7.2 Preparation of α,β-nitriles, amides and esters

HO X X 1. cat. CoL2, PhSiH3 RCHO + 2. H3O R

X = CN, CONR2, COOR CL 1989, 2005 6.5 Salen-type Co hydrochlorination

R3 7.3 Oxidative Cyclization of 5-hydroxy-1-alkenes with O2 R1 Co cat., PhSiH3, EtOH R R TsCl 1 3 + R2 OH or Co(BF4)2.6H2O H R 2 ligand, t–BuOOH, O , Co(modp) Cl 2 2 O PhSiH3, EtOH t–BuOOH, i–PrOH OH Ph Ph t–Bu O trans N N N Co OK O O O O O OH modp = N t–Bu t–Bu t–Bu CL 1990, 67 t–But–Bu Careira, ACIE 2008, 47, 5758 O - Used TsCl as a Cl source. 7.3.1 Total Synthesis of (–)-mucocin - First protocol optimal for 1,1-disubstituted olefins or electron poor olefins. Second protocol optimal for monosubstituted olefin. Mechanism analogous to hydroazidation (see before). - Similar hydrocyanation see ACIE 2007, 46, 4519. (Avoids use of HCN). HO OH O

6.6 Salen-type Co Reductive C–C Bond Forming Reactions O O 9 (–)-Mucocin O OH OH X P. Evans 1 OBn N N OBn JACS 2003, 125, 14702 same cat. Ph TBSO Ph Ph S X PhSiH3 O EtOH, RT 5 O O OHC O Careira, JACS 2009, 131, 13214 9 O X = H, CN 2 OH OPMP 3 4 O

Page 8 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo

TBSO

5 O OHC O 9 O 2 OH OPMP 3 4 O

O O

OH 6 5

O OH 1. Mitsunobu Co(modp)2 HO inversion O2, t–BuOOH OH O 2. AllylMgBr 5 OPMP OPMP

8. What I could not cover

- Cyclization with Co – [2+2]; [3+2]; [5+2] cyclizations - Oxidation with Co - 1,4-Reduction with Co - Radical Chemistry of Co - Use of Co in Living Radical Polymerization of Vinyl Acetate/Isoprene - Yamada Co Chemistry - - -

9. Conclusion

- Observation: most seminal studies began with Co as choice of metal. However, Co is replaced by other metal alternatives, mainly Rh and Ru. - Room for development: Instead of working on reactions which currently use Co, such as PK or Nicholas reaction, maybe the focus should be on replacing other metals with Co.

Respect the Co!!!