Myers Hydrozirconation and Carbozirconation Chem 115

Reviews: • in regio- and stereoselective synthesis, Vol. 8, Takahashi, T. Ed.; Springer: Berlin; • Hydrozirconation proceeds by a stereospecific, concerted 4-centered process that typically New York, 2005. places on the less-substituted carbon. • Marek, I.; Chechik-Lankin, H.; Functionalized Organozirconium and in Organic • The relative rates of hydrozirconation for different substrates are as follows: Synthesis, in Handbook of Functionalized Organometallics: Applications in Synthesis, Knochel, P Ed.; Wiley-VCH: Weinheim, 2005. R R R2 2 2 > ~ > R2 ~ > R R R1 R3 General Reactivity of Zirconocene Compounds R1 R1 R1

• Selective hydrozirconations have been reported: Y Cl Zr Zr H X Cp2ZrHCl ZrCp2Cl toluene, 23 °C Generalized Zirconocene 81% zirconocene hydrochloride (Schwartz's reagent) Fryzuk, M. D.; Bates, G. S.; Stone, C. J. Org. Chem. 1991, 56, 7201–7211.

0 • Zirconocene complexes of the formula Cp2ZrXY are 16-electron d Zr(IV) complexes with one empty valence shell orbital available for coordination. Consequently, many reactions of these

compounds are initiated by the interaction of an electron donor such as the π-bond of an olefin with Cp2ZrHCl ZrCp2Cl the empty Zr orbital. C H , 23 °C TMS TMS 6 6 Cp Cp Cp Cp Zr Zr >56% H X Crombie, L.; Hobbs, A. J. W.; Horsham, M. A.; Blade, R. J. Tetrahedron Lett. 1987, 28, 4875– C C C C 4878.

bonding backbonding • Neighboring groups can influence the site of zirconation:

Hydrozirconation O Cp2ZrHCl Cp2Zr OK • Treatment of and with zirconocene hydrochloride gives rise to - and THF, 23 °C H3C alkenylzirconium intermediates, respectively.

ZrClCp2 Takaya, H.; Yamakawa, M.; Mashima, K. J. Chem. Soc., Chem. Commun. 1983, 1283–1284. R2 R2 R1 R1 hydrozirconation H H Zr Cl dehydrozirconation ZrClCp R 2 2 H R1 R1 R2 R =alkyl, aryl; R =alkyl, H 1 2 Claudia Kleinlein, Matt Mitcheltree

1 Myers Hydrozirconation and Carbozirconation Chem 115

• CH3Li–ZnCl2 reverses the regioselectivity in hydrozirconation of propargylic . The authors • Isomerization presumably occurs via a dimetalated species: propose that alkoxide generation with CH3Li promotes directed hydrometalation, while ZnCl2 blocks isomerization to the thermodynamically favored linear vinylzirconium species. RL RL ZrCp Cl RS ZrCp2Cl 2 1. Cp2ZrHCl (2 equiv) H H H OH THF, 23 °C OH OH ClCp2Zr ClCp Zr RS H 2 + I R R I R 2. I2, DCM, –78 °C

linear branched • Similarly, internal alkenes undergo rapid isomerization at room temperature to terminal alkenes via β-H-elimination of the initially formed alkyl zirconium intermediate, followed by re-addition. By without additive > 50 1 contrast, considerably higher temperatures are required for isomerization in MeLi (1 equiv), ZnCl2 (6 equiv) 1 > 50 hydroalumination and hydroboration reactions.

Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2007, 129, 12088–12089. CH3 • If the thermodynamic product is desired, however, equilibration can be achieved by treatment with Cp2ZrHCl additional hydrozirconation reagent. Cl Zr CH3 H3C CH3

R Cl Cp2ZrHCl Cl CH H L Zr Zr H C 3 Zr + RS RL 3 quantitative Cl RS C6H6, 23 °C H RL H RS Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115–8116. 1 2 Reactions of organozirconocene compounds Product ratio 1 : 2 Review: Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910. • Due to steric crowding around zirconium, only small react with organozirconocenes. Initially after treatment with RS RL observed Cp2ZrHCl

H n-Bu > 98 : 2 ND R C–C R 2 Cl coupling 2 R Zr R R CH Et 55 : 45 89 : 11 1 H 1 1 H 3 M-X M C CH3 n-Pr 69 : 31 91 : 9 H R2 oxidation or CH3 i-Bu 55 : 45 > 95 : 5 quench with D2O halogenation CH3 i-Pr 84 : 16 > 98 : 2 X C: carbenoid R insertion R CH3 t-Bu > 98 : 2 ND 2 2 R R 1 H 1 H D X

Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679–680. Cl Zr X

H R1 R2 Claudia Kleinlein, Matt Mitcheltree

2 Myers Hydrozirconation and Carbozirconation Chem 115

Oxidation • 1,1-Bimetallic reagents of zirconium and boron can be prepared in situ and converted into • A number of reagents are capable of oxidizing alkylzirconocenes to the corresponding linear valuable building blocks. In the example shown, α-zirconation occured exclusively. alcohols. These methods do not apply to alkenylzirconocenes.

• In the following table, n-octylzirconocene chloride (R = n-Hex) was obtained by hydrozirconation– isomerization of a mixture of linear octenes (vide supra). Cp2ZrHCl ZrCp2Cl NBS Br n-Bu n-Bu B(pin) B(pin) n-Bu DCM, 23 °C B(pin) Conditions Cl Zr HO 98% R R Zheng, B.; Srebnik, M. Tetrahedron Lett. 1994, 35, 1145–1148.

R Conditions Yield • High regioselectivity is observed in the hydrozirconation of alkynyl stannanes as well:

t-Bu O2; H2O 91% SnBu3 isopropenyl O2; H2O 77% Cp2ZrHCl, THF ZrCp Cl I , 0 °C I BnO 2 2 BnO n-Hex H2O2, NaOH 69% 23 °C, 15 min SnBu3 SnBu3 n-Hex t-BuOOH 72% OBn 90% n-Hex m-CPBA 45%

n-Hex CrO2Cl2 52% Lipshutz, B. H.; Keil, R.; Barton, J. C. Tetrahedron Lett. 1992, 33, 5861–5864.

Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115–8116. Carbenoid insertion • Acylzirconocenes are formed by insertion of . Halogenation • Electrophilic halogenation of alkyl- and alkenylzirconocenes is commonly employed for the • These acyl zirconium complexes can be converted into the corresponding aldehydes, carboxylic synthesis of vinyl halides. and by the methods shown: O R Br2, CH3OH Cl X+ 2 n-Bu OCH3 Zr R1 R1 + 51% H X = I2, Br2, PhICl2, NBS, NCS X Cl Cl H R2 Zr CO (1 atm) Zr O NaOH, H2O2 O n-Bu OH • The reaction proceeds with retention of configuration at carbon and affords E-vinyl halides from n-Bu 77% alkynes. n-Bu HCl O H3C H H Cp2ZrHCl; Br OCH3 OCH3 n-Bu H CH 99% NBS 3 OTIPS OTIPS Bertelo, C. A.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 228–230. 86%

Ragan, J. A.; Nakatsuka, M.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Org. Chem. 1989, 54, 4267–4268. Claudia Kleinlein, Matt Mitcheltree

3 Myers Hydrozirconation and Carbozirconation Chem 115

• Homologated aldehydes are obtained by protonation–hydrolysis of isonitrile insertion products. • Halide abstraction can initiate a tandem epoxide rearrangement–carbonyl addition sequence to give allylic alcohols: Cp ZrHCl (1 equiv) 2 OH THF, rt, 1 h; O TBSO CHO TBSO n-Bu n-Bu + n-BuNC, 0 °C to 45 °C, 3 h; Cp2ZrHCl (1 equiv) H C CH3 3 CH Cl , rt, 20 min; 1:1 AcOH–H2O, –78→23 °C 75% 2 2 92%

AgClO (5 mol%) Negishi, E.-i.; Swanson, D. R.; Miller, S. R. Tetrahedron Lett. 1988, 29, 1631–1634. 4 10 min OH OTBDPS n-Bu + OTBDPS • Similarly, Buchwald and LaMaire report the preparation of homologated by treatment of an O n-Bu organozirconocene with cyanotrimethylsilane and iodine. 56%

Cp2ZrHCl (1 equiv) C H , 23 °C, 13 h; CH3 BnO CH3 6 6 CH3 BnO CH3 • The reaction with epoxides is proposed to be initiated by [Zr]+-induced epoxide opening, followed H3C TMSCN, 55 °C, 24 h; H3C CN 59% by [1,2]-hydride shift and nucleophilic attack on the resulting aldehyde. I2, 5 °C, 20 min

TMS CH3 I TMS + Cl Cl 2 Cl N N I- H Zr R Zr Zr + H R R I R I OZrR''Cp N 2 [1,2]-H-shift R R' TMS CH3 C N TMS N TMS Cp2ZrHCl O R Buchwald, S. L.; LaMaire, S. J. Tetrahedron Lett. 1987, 28, 295–298. AgClO4 H + Cp2R''ZrCl Cp2R''Zr H R Silver-catalyzed Addition to Aldehydes and Epoxides CH3 O • Silver-promoted chloride abstraction from organozirconocenes relieves steric congestion and forms R ZrR''Cp2 a Lewis-acidic cationic complex that activates aldehydes for 1,2-addition. R'' CH3 OZrCp2Cl R Cp2ZrHCl (1 equiv) AgClO4 time yield [%] R'' migratory CH2Cl2, 23 °C, 10 min; OH CH3 none 2 h 17 insertion n-Bu Cp R''ZrCl O Ph(CH2)2CHO, n-Bu Ph 5 mol% 10 min 90 2 ZrCp2 AgClO4 (5 mol%) 90% R R'' CH3 Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron Lett. 1992, 33, 5965–5968. OH

Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825–826. Claudia Kleinlein, Matt Mitcheltree

4 Myers Hydrozirconation and Carbozirconation Chem 115

Transmetalation • Special procedures have been developed to enable asymmetric vinyl additions. • While steric bulk limits the scope of electrophiles that organozirconocenes may engage directly, transmetalation enables a broad variety of transformations involving organometallic intermediates. 1. Cp2ZrHCl (1 equiv) CH Cl , 23 °C • of organozirconocenes to aluminum, boron, , mercury, nickel, palladium, 2 2 CH tin, and zinc have been reported. Zn 3 2. (CH3)2Zn (1 equiv) Transmetalation to Zinc toluene, –78 °C 3. Ti(Oi-Pr)4 (0.5 equiv) Review: Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778–1784. (5 mol%) PhCH , –78 °C • Transmetalation to zinc combines the facile formation of organozirconium compounds with the broad 3 synthetic utility of organozincs. Ligand: 4. PhCOCH3, 0→23 °C O Cp2ZrHCl (1 equiv) CH O CH CHO OH 3 O O 3 CH2Cl2, 23 °C, 1.5 h; Ph S NH HN S Ph ZnMe n-Bu n-Bu Ph n-Bu HO CH3 (CH3)2Zn, –65 °C 0 °C 94% CH3 OH HO CH3 90%, 95% ee Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197–5200.

Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355–8361. • Addition of substoichiometric dramatically enhances the rate of palladium-catalyzed cross-coupling of organozirconocenes. It is believed that direct Zr→Pd transmetalation is prohibitively slow due the steric demands of the zirconocene. • A drawback of in situ organozinc generation is that residual zirconocene complexes can complicate further reactions. For example, zirconocene complexes can catalyze racemic Et CO CH Pd(PPh ) (5 mol%) Et CH carbonyl additions, resulting in low enantioselectivities for otherwise robust asymmetric Br 2 3 3 4 3 Et + Et organozinc additions. ZrCp2Cl CH3 CO2CH3 > 97% E,E Cp2ZrHCl (CH3)2Zn n-Bu ZrCp2Cl ZnCH3 0.5 equiv ZnCl2, 1 h 82% n-Bu n-Bu CH Cl , 22 °C toluene 0.2 equiv ZnCl , 2 h 72% 2 2 2 –65 °C no ZnCl2, 6 h < 2% Ligand (10 mol%) O –30 °C Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, Ligand yield ee Ph H 100, 2254–2256. H C CH3 3 OH • However, less bulky, electron-rich organozirconocenes undergo transmetalation to Pd or Ni N(CH3)2 77% 3% rapidly enough such that no organozinc intermediate is necessary. OH n-Bu Ph

H3C Cp ZrHCl (1 equiv) PhI, THF, 23 °C, 12 h 2 N(CH3)2 EtO EtO H3C EtO ZrCp2Cl Ph C6H6, rt, 2 h Ni(PPh3)4 (cat.) SH 80% 95% 99%

Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393–2401. Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–6455. Claudia Kleinlein, Matt Mitcheltree Myers 5 Myers Hydrozirconation and Carbozirconation Chem 115

Transmetalation to Copper • can be synthesized from halides and alkenes or alkynes: • Commonly used copper sources for transmetalation include CuBr•S(CH ) and CuCN. 3 2 CuBr•S(CH3)2 O • Reaction of the resulting organocopper intermediate with allyl halides leads to C–C bond formation TMS Cp ZrHCl ZrCp Cl (15 mol%) 2 n-Pr 2 by SN2' addition. n-Pr Ph n-Pr CH2Cl2 TMS 35 °C TMS Cp2ZrHCl (1 equiv) O THF, 23 °C, 1 h; H C CH 81% 3 3 CH3 Cl + Ph Ph CH3 H3C Ph 89 : 11 Sun, A.; Huang, X. Synthesis 2000, 6, 775–777. H3C Br Wipf, P.; Xu, W. Synlett 1992, 9, 718–721. CuCN, 23 °C, 12 h 89%

Other Applications of Organozirconium Intermediates Venanzi, L. M.; Lehmann, R.; Keil, R.; Lipshutz, B. H. Tetrahedron Lett. 1992, 33, 5857–5860. Anti-Markovnikov Hydroamination • Amination of zirconocene alkyl chloride intermediates can be achieved using commercially • Addition of an often accelerates transmetalation to copper. In the following available N-methylhydroxylamine-O-sulfonic acid. example, n-BuLi is added to promote organocuprate formation in a hydrozirconation– transmetalation–conjugate addition sequence en route to a prostaglandin. CH3 HN Cp2ZrHCl OCH3 CH3O O THF, 23 °C, 1 h; Cp2ZrHCl (1 equiv), THF; H3C OTMS CH3 CH NHOSO H, n-BuLi (2 equiv); CuCN (1 equiv); CO CH OBn 3 3 OBn 2 3 50 °C, 0.5 h TESO CH3 CH3Li (1 equiv) H N N O OTMS 92% 71% CH3 CO2CH3 Strom, A. E.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8909–8914. TESO

Babiak, K. A.; Behling, J. R.; Dygos, J. H.; McLaughlin, K. T.; Ng, J. S.; Kalish, V. J.; Kramer, S. Synthesis of Cyclic Silyl Enol Ethers W.; Shone, R. L. J. Am. Chem. Soc. 1990, 112, 7441–7442. • Tandem asymmetric conjugate addition of alkenylzirconocenes to cyclic enones can be catalyzed by Rh(I) to give silyl enol ethers in good yield with high enantioselectivity. • Hydrozirconation of readily available alkynyldioxaborolanes gives access to 1,1-bimetalloalkenes, 1. [Rh(cod)Cl] (2.5 mol%) which can be used to synthesize trisubstituted alkenes. 2 R-segphos (6 mol%)

Cp2ClZr O Pd(PPh3)4 O n-Bu OTMS Br n-Bu ZrCp2Cl (0.5 equiv) THF, 23 °C O PPh2 n-Bu n-Bu B(pin) B(pin) O PPh2 CuCN (0.1 equiv) PhI (1.0 equiv) 2. CH3Li (2.6 equiv), -78 °C, 1 h Ph n-Bu THF, 23 °C, 12 h NaOEt, EtOH 3. TMSCl (3 equiv), -78 °C, 1 h H reflux, 3 h O 90% 82% 95%, 96% ee R-segphos

Deloux, L.; Skrzypczak-Jankun, E.; Cheesman, B. V.; Srebnik, M.; Sabat, M. J. Am. Chem. Soc. Westmeier, J.; Pfaff, C.; Siewert, J.; von Zezschwitz, 1994, 116, 10302–10303. P. Adv. Synth. Catal. 2013, 355, 2651–2658. Claudia Kleinlein, Matt Mitcheltree Myers 6 Myers Hydrozirconation and Carbozirconation Chem 115

Hydrozirconation – Compatibility • Triisopropylsilyl, t-butyl, and benzyl esters are tolerated with fast-reacting, unhindered C–C

• Reduction of most epoxides, isonitriles, aldehydes, ketones, nitriles and esters by Cp2ZrHCl is double and triple bonds as substrates. competitive with hydrozirconation of alkenes and alkynes.

Cp2ZrHCl (1 equiv) OTIPS ClCp2Zr OTIPS • Alcohols and acids are deprotonated by Cp2ZrHCl with loss of H2; α,β-unsaturated ketones undergo 1,2-reduction with Cp2ZrHCl. O THF, 23 °C O > 80% • Acetals and THP ethers are inert to Cp2ZrHCl unless they are allylic or vinylic, in which case β- elimination can occur. Allylic or vinylic ethers can be reductively cleaved by Wipf, P.; Xu, W.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1991, 50, 1935– Cp2ZrHCl. 1954.

Cp ZrHCl OTMS 2 OTMS Cp ZrHCl • Schwartz's reagent also reduces Evans' N-acyl oxazolidinones to give aldehydes: 2 80% THF, 23 °C O O OTMS Cp2ClZr OZrCp2Cl O + (CH3)3SiH Cp2ZrHCl (1.5 equiv) H3C CH3 H3C CH3 N O H THF, 23 °C, 15 min 85% H3CO H CO H3C Ph 3 92% Uhlig, E.; Bürglen, B.; Krüger, C.; Betz, P. J. Organomet. Chem. 1990, 382, 77–88. White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, 122, 11995–11996. • Hydrozirconation of vinyloxiranes leads to formation of α-hydroxycyclopropyl derivatives. Ring formation proceeds with inversion of configuration at the allylic carbon.

• In their synthesis of kainic acid, Xia and Ganem successfully reduced a lactam using Schwartz's Cp ZrHCl (1 equiv) O 2 reagent in the presence of an isopropenyl group. CH2Cl2, 23 °C; HO

Ph CH3 NaHCO3 Ph CH3 EtO2C CH3 Cp2ZrHCl (1.5 equiv) EtO2C CH3 H H Harada, S.; Kowase, N.; Tabuchi, N.; Taguchi, T.; Dobashi, Y.; Dobashi, A.; Hanzawa, Y. THF, –30→15 °C, 1 h O N N Tetrahedron 1998, 54, 753–766. H

• Tertiary amides can be reduced to aldehydes in the presence of excess Schwartz's reagent. Note TMSCN (2 equiv) that amides can be selectively reduced in the presence of esters: CH2Cl2, 1 h

O O Cp2ZrHCl (1.5 equiv) NEt H 2 EtO2C CH3 steps EtO2C CH3 THF, 23 °C, 15 min H H OAc OAc HO2C N NC N 99% H H

Spletstoser, J. T.; White, J. M.; Runoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, kainic acid 75% 3408–3419. Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485–487. Claudia Kleinlein, Matt Mitcheltree

7 Myers Hydrozirconation and Carbozirconation Chem 115

• A hydrozirconation–transmetallation–cross-coupling sequence was used in the synthesis of analogues of the natural product FR901464.

H Cp2ZrHCl Cp2ClZr O CH3 CH3 O CH Cp2ZrHCl H C O 3 H C O THF, 23 °C to 50 °C, 2.5 h; 3 3 I TESO I , THF, 0 °C, 15 min CH TESO THF, 0 °C, 40 min 2 HO CH 3 O CH 3 O HO 3 65%

ZnCl CH 1. ClCH SO Cl, pyr, 2 ClZn O CH3 3 2 2 THF, 0 °C H3C O DMAP, THF, 23→50 °C, 3h + I 10 min TESO 2. LiN3, DMPU, 50 °C, 36 h O N3 CH3 55% (2 steps)

Pd(PPh3)4, THF 0→23 °C, 1 h

O CH3 CH3 CH3 H3C O O CH3 H3C O H3C O O CH3 steps O

N3 CH3 TESO N CH3 HO O H O 84% FR901464 Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974–9983.

• A vinylzirconium compound was successfully coupled with a vinyl iodide en route to lissoclinolide. Schwartz's reagent was generated in situ by β-hydride elimination of i-BuZrCp2Cl (inset).

1. i-BuZrCp Cl 2 HO steps Br TBSO I OH TBSO TBSO 2. I , THF Br 2 89%, 98% E-isomer Pd(PPh3)4 (5 mol%) TBSO pyrrolidine, 23 °C, 0.5 h 92% i-BuZrCp Cl [] 2 TBSO ZrCp2Cl TBSO ZrCp2Cl PdCl2(PPh3)2 90% cat. DIBAL-H

Cp Cl Cp HO Zr OH steps Zr Cl + OTBS Cp TBSO Cp H H3C CH3 O Br H3C CH3 O lissoclinolide 91%, > 98% stereoselectivity

Xu, C.; Negishi, E.-i. Tetrahedron Lett. 1999, 40, 431–434. Claudia Kleinlein, Matt Mitcheltree Myers 8 Myers Hydrozirconation and Carbozirconation Chem 115

Carbozirconation • Diastereoselective addition to a was achieved by hydrozirconation followed by in situ Negishi, E.-i. Arkivoc 2011, 8, 34–53. transmetallation to zinc. General Reaction Scheme

Cp2ZrHCl (1 equiv) CH2Cl2, 23 °C, 10 min; R O Zr BnO O Cl BnO O (CH3)2Zn, –78 °C, 10 min; O H3C OH R H C 3 R R 45% R 2 R 2 O 1 1 R–AlX , cat. Cp ZrCl [M] 4h, 23 °C 2 2 2 R R steps 2 [M] R1 R1 R2 (CH3)3Al OH OH OH Fostriecin (CI-920) R1 = alkyl, aryl; R2 = alkyl, H; [M] = [Al], [Zr] O O H3C OH • is the addition of a carbon–metal bond across a carbon–carbon π-bond. The process is believed to be concerted. Chavez, D. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2001, 40, 3667–3670.

• A stoichiometric amount of trialkylaluminum reagent is needed, but only a catalytic amount of

Cp2ZrCl2 is required.

• Hydrozirconation of nitriles provides metallo-imine complexes that can further react with acyl chlorides. This strategy was used in the synthesis of a spirooxindole library by interception of the • Experimental evidence points toward a bimetallic mechanism: imine intermediate through a Friedel–Crafts cyclization with a pendant indole substituent.

CN Al(CH3)2Cl BnO Cp ZrHCl OBn Cl Cl CH R Cl 2 OBn + Al(CH ) 3 CH Cl , 23 °C; Zr 3 3 Zr Cl Al Zr 2 2 NH Cl CH3 N O CH3 Cl N CH3 R O N Bn Cl Bn O O N Ph Cl Ph Bn 12 h, 23 °C Ph carbometalation 61% dr = 88:12 Al(CH3)2Cl transmetalation Cl Cl H3C Al(CH3)2 Zr + Zr LaPorte, M. G.; Tsegay, S.; Hong, K. B.; Lu, C.; Fang, C.; Wang, L.; Xie, X.-Q.; Floreancig, P. E. Cl R H R ACS Comb. Sci. 2013, 15, 344–349. H3C Claudia Kleinlein, Matt Mitcheltree

9 Myers Hydrozirconation and Carbozirconation Chem 115

• The reaction of trimethylaluminum with terminal alkynes proceeds with excellent stereo- and • Thus, carboalumination of alkynes is limited to methylation in practice. Together, hydrozirconation regioselectivity. and carboalumination provide reliable access to two classes of trisubstituted olefins commonly encountered in synthesis: (CH3)3Al Pd(PPh3)4 (5 mol%) CH CH Cp2ZrCl2 3 ZnCl2 (1 equiv) 3 n-Bu n-Bu Al(CH3)2 n-Bu DCE, 23 °C Br H CH 73% 3 [M] [M] R R Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, CH H 100, 2254–2256. 3

• Carbometalation is compatible with free hydroxyl groups. In the case of homopropargylic alcohols, Hydrozirconation Carbometalation anti-carbometalation products can be obtained by thermal isomerization of the initial adducts:

(CH ) Al (3 equiv) 3 3 CH Cp ZrCl (25 mol%) 3 2 2 CH3 I2 CH3 R R HO Al(CH3)2 I DCE, 23 °C (H3C)2AlO HO 85% reflux, 3 d >98% E

H3C CH3 I2 Zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA) HO AlCH3 • By contrast, olefins reliably give regiodefined carbometalation products even with higher-order O I such as ethyl and propyl groups. Enantioselective methods employing chiral zirconocene 60% catalysts have been developed. >98% Z Ma, S.; Negishi, E.-i. J. Org. Chem. 1997, 62, 784–785. • Negishi and coworkers have developed a protocol for asymmetric carboalumination of alkenes Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org. Chem. 1981, 46, 4093–4096. giving functionalized products in moderate to high yields with synthetically useful enantiomeric purities. • Carboalumination with Et3Al or Et2AlCl can proceed through a variety of mechanisms and usually results in regioisomeric products. It has therefore found little use in organic synthesis. R3Al R H3C Et2AlCl cat. (–)-(NMI) ZrCl ; 2 2 CH3 Cp ZrCl (10 mol%) OH 2 2 Et AlEtCl R1 R H3C O 1 AlEtCl + Et 2 n-Hex DCE n-Hex n-Hex

(–)-(NMI)2ZrCl2: Cl Zr Cl

DCl–D2O R Yield ee CH –CH3 68–92% 70–90% 3 H3C Et D –CH CH 56–90% 85–95% 2 3 CH3 D + Et n-Hex n-Hex –(CH2)nCH3 74–85% 90–95% commercially available 61% 30% Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1996, 118, 1577–1578. Metallocenes in regio- and stereoselective synthesis, Vol. 8, Takahashi, T. Ed.; Springer: Berlin; Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 10771–10772. New York, 2005; p.155. Claudia Kleinlein, Matt Mitcheltree Myers 10 Myers Hydrozirconation and Carbozirconation Chem 115 • Cyclic olefins are excellent substrates for ZACA. When heteroatoms are positioned β to the newly formed C–M bond, irreversible elimination occurs to give terminal alkenes with good stereoenrichment at the allylic position.

R–MgCl (5 equiv) (R)-[Zr] cat (10 mol%) R Cl (R)-[Zr] Zr n catalyst X THF, 25 °C, 6–12 h X n Cl

Olefin Grignard Product Yield ee

EtMgCl CH3 65% > 97% O HO

EtMgCl CH3 75% > 95% N HN n-nonyl n-nonyl

EtMgCl CH3 73% 95% HO O

CH3 CH n-PrMgCl 3 40% 98% HO O (60% brsm)

CH3

O EtMgCl 75% 92%

OH

• Stereoinduction is determined by the oxidative coupling step, wherein the substrate reacts with a

Zr-olefin complex formed upon β-H elimination of Cp2ClZr–R.

EtMgCl L2ZrCl2 Zr Zr H –MgCl2 –HCl X X

Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6997–6998. Claudia Kleinlein, Matt Mitcheltree

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