Substrate-directed hydrogenations with cationic complexes

Transcription

1 M.C. White/M.S. Taylor Chem 153 ydrogenation Week of ctober 21, 2002 Substrate-directed hydrogenations with cationic complexes C 3 TBDS C 2 Et 60:40 anti:syn 2 h (I) 2 () n= 3 (BF 4 - ) TBDS C 2 Et 3 h (I) 3 3 Ir (I) Cy 3 (F 6 - ) C 3 TBDS C 2 Et 65:35 syn:anti It was observed experimentally (and may have been predicted) that hydrogenation of the enantiomerically enriched homoallylic alcohol with the neutral catalyst complex ( 3 ) 3 h produced a 1:1 mixture of diastereomeric products. Use of the cationic complex h(cod)(dppb)bf 4 led to a preference, albeit small, for the formation of the anti hydrogenation product. C 3 C 2 Et TBDS 50:50 anti:syn In contrast, hydrogenation with the cationic iridium complex Ir[(cod)(pyr)(Cy 3 )]F 6 favored the formation of the syn isomer. Du Bois JACS 2002, ASA, ct., Br C 3 TBDS C 2 Et C 3 C 2 Et Et Et h Et Tf Tf TBDS C 2 Et Br C 3 TBDS >95:5 anti:syn 75:25 syn:anti Manzacidin C (5 mol%) General conditions: 2 (1000psi), C 2 2, rt The use of chiral bidentate phosphine ligands makes it possible to reinforce or partially override substrate bias. h (5 mol%) Manzacidin A C 2 Et C 3 C 2

2 M.W. Kanan/M.C. White Chem 153 ydrogenation Week of ctober 21, 2002 Asymmetric hydrogenation in the synthesis of unnatural amino acids F 2 Ac - 2 SbF 6 (CD)h S C 3 1 atm. 2, TF, rt 94% ee, 96% yield F 2 Ac reductive elimination Teicoplanin aglycon 2 S h S 2 h h C oxidative addition 2 h insertion C Asymmetric hydrogenation is a very general and reliable route to amino acids, which are key building blocks for the synthesis of many natural products. In this example, the hydrogenation is carried out in the presence of a nitro group. h C Evans JACS 2001 (123) 12411

3 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Asymmetric hydrogenations of trisubstituted unfunctionalized olefins Ir (I) Cy 3 Crabtree's catalyst (F 6 - ) (F - 6 ) Ar 2 Ir faltz hydrogenation catalyst ecall that Crabtree's catalyst is able to effect the efficient hydrogenation of both tri-and tetrasubstituted olefins. eplacement of the monophosphane and pyridine ligands with the bidentate phosphanodihydrooxazole ligand produces a catalyst that is highly effective in promoting the asymmetric hydrogenation of trisubstituted, unfunctionalized olefins. Counterion effects on conversion (and selectivity) can be dramatic o-tol 2 Ir 2, C 2 2, rt X - 97 % e.e, >99 % conv. B B F 6 - F F F F CF 3 counterion catalyst loading conversion F 4 _ hexafluorophosphate _ tetrakis(pentafluorophenyl)- borate tetrakis[3,5-bis(trifluoromethyl)- phenyl]borate (BAF) 4 mol% 57 %.1 mol% 84%.05 mol% >99% CF 3 4 faltz ACIEE

4 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Titanocene hydrogenation of unfunctionalized olefins riginal report of catalytic hydrogenation activity: First asymmetric example: Ti (IV) 25 mol% i-r Ti (IV) i-r 1 mol% "ed-al" (i( 2 Al(C 2 C 2 C 3 ) 2 )] 6 mol% ial() 3 (7.5 eq), 2 (16 psi), heptane/tf, 40 o C quantitative conversion 2 (1 atm), 20 o C (S) 15 % ee First asymmetric example resulting in high ee Stern T 1968 (60) Asymmetric hydrogenation of "unfunctionalized" trisubstituted olefins Kagan ACIEE 1979 (18) 779. Ti (IV) 1 mol% n-bui (1 mol%), 2 (1 atm), -75 o C (S) 95% optical purity E olefins are reduced more rapidly and with higher ee's than Z olefins all substrates reported are alkenes α to an aromatic ring. Ti (IV) 5 mol% mol%. n-bui, 0 o C. 2 (1 atm) mol% Si 3 3. olefin, 2 (136 atm) 65 o C 79% yield 95% ee Vollhardt JACS 1987 (109) Buchwald JACS 1993 (115)

5 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Titanocene hydrogenation of unfunctionalized olefins Synthesis of allyldicyclopentadienyltitanium (III) complexes from dicyclopentadienyltitanium (IV) dichloride: Ti (IV) 2 equ. Mg Ti (III) Ti (III) Ti (III) 2 Mg 2 Martin and Jellinek JMC 1966 (6) 293; JMC 1968 (12) 149. Ti (IV) mol%. n-bui, 0 o C. 2 (1 atm) Ti (III) mol% Si 3 Buchwald argues that the silane does not serve as a source based on the following experiment: when D 2 was used in the hydrogenation of (E)-1,2-diphenylpropene, 1,2-diphenyl propane resulted which was 98% D 2 by GCMS. Buchwald goes on to note that the only purpose of the phenylsilane is to stabilize the catalyst during manipulations prior to starting the rxn. 5 mol% postulated intermediate based on Martin and Jellinek papers σ-bond metathesis olefin insertion Ti (III) note: regioselectivity of insertion not determined Buchwald JACS 1993 (115) 12569

6 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Stereochemical model ydride transfer via a four-centered transition state. leads to the formation of a new stereogenic center at the disubstituted carbon of the olefin. In this model, the olefin approaches from the "front" of the complex with hydrometallation resulting in formation of the less sterically hindered Ti alkyl bond. Ti () major product, >99% e.e. Ti transition state A vs. The olefin arrangement shown in transition state A minimizes the steric interactions between the large substituents on the olefin and the cyclohexyl portion of the tetrahydroindenyl ligand.the rate of reduction for Z olefins is slower than the rate of reduction for E olefins. Can this result be rationalized based on this model for the transition state? Ti transition state B (S)

7 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Asymmetric hydrogenation of cyclic imines Ti Ti 2 82 % yield, 98 % e.e % yield, 98 % e.e. ' ' '' Ti '' e.g. Kinetic studies suggest that the hydrogenolysis of the Ti- bond may be the rate-determining step in this catalytic cycle '' ' Ti Ti ' '' Ti the ethylene bridge is omitted for clarity Buchwald JACS 1994 (116) Ti ' ''

8 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Asymmetric hydrogenation of acyclic imines Acyclic imines exist as mixtures of anti and syn isomers. This property proves relevant in the asymmetric hydrogenation of these substrates. Ti 2 anti/syn : 11/1 93 % yield, 76 % e.e. Ti c-hex favored () Ti c-hex disfavored anti Ti syn Ti (S) c-hex c-hex disfavored favored Buchwald JACS 1994 (116) 8952 the ethylene bridge is omitted for clarity

9 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Substrate-Directed Ketone ydrogenations Et 2 2 u (II) (S) 41% yield 4% ee u(ii)-bia dicarboxylate catalysts were found to be ineffective for ketone hydrogenations mediated via α or β-oxygenated functionality. These hydrogenations could be effected in high yields and ee's with poorly defined halogen-containing u complexes. The dicarboxylate catalysts were effective for ketone hydrogenations mediated via highly basic α (or β) amino functionality. binap May pre-coordinate to the u center via a 5-membered ring chelate X ()-1(0.1 mol%), 2 (100 atm), 23 o C, 48h ()-1(0.1 mol%) Et, 2 (50 atm), 23 o C, 12h ux 2 [()-binap] 0.1 mol% Et, 2 ( atm), rt () u hydride must have some hydridic character. X () 72% yield 96% ee Et () black box chemistry 2 2 u (II) 2 equ. X (X=, Br, I) ux 2 [()-binap] molecular weight unknown ote: opposite sense of stereoinduction Br Br ewis basic functionality X May pre-coordinate to the u center via a 6-membered ring chelate ux 2 [()-binap] 0.1 mol% Et, 2 ( atm), rt oyori JACS 1987 (109) 5856 oyori JACS 1988 (110) 629. ydrogenation of ketones performed under forcing conditions (recall that olefin hydrogenations were performed at 4 atm with this catalyst). () X quantitative yield 92% ee quantitative yield 98% ee 97% yield 92% ee Et quantitative yield >99% ee (best substrates) <1% yield 74% ee ux 2 [(S)-binap] gives the (S) enantiomer <1% yield 30% ee quantitative yield >96% ee () 2

10 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 oyori substrate-directed ketone hydrogenation: mechanism X ux 2 [()-binap] 0.1 mol% Et, 2 ( atm), rt () X May pre-coordinate to the u center via a 6-membered ring chelate 2 2 u (II) 2 eq X (X=, Br, I) ux 2 [()-binap] molecular weight unknown 2 X () ux[()-binap] 2 u(ii) monohydride X u X u X u

11 M.W. Kanan/M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Dynamic Kinetic esolution of 2-substituted-ß-keto esters Ac ubr 2 [()-BIA] 2 (100 atm) C C, 50h Ac 99:1 syn:anti, 98% ee, 100% conversion oyori JACS1989 (111), 9134 Scenario 1: There are at least two possibilities for the mechanism of stereoselectivity. ne is that the β-keto-ester enantiomers can interconvert under the reaction conditions and the catalyst reacts with one isomer much more rapidly than the other and with high stereoselectivity to produce a single product. Scenario 2: Both starting enantiomers are converted to a single intermediate species (a prochiral enol formed via deprotonation of the α-proton) and the catalyst reacts stereoselectively with this species to produce a single stereoisomer. ubr 2 [()-BIA], 2 k 1 Ac Ac major product Ac Ac Ac Ac k 2 k 1 >k 2 Ac Ac Ac ubr 2 [()-BIA], 2 major product The following observations support the interconversion mechanism: reacts to give β-hydroxy ester in 88-96% ee depending on the solvent [u(c 6 6 )(()-BIA)] 2 (100 atm) C C, 70h 1:99 syn: anti, 93% ee Question: why does the result with the cyclic substrate support the interconversion mechanism?

12 M.C. White/M.W. Kanan Chem 153 ydrogenation Week of ctober 21, 2002 Diastereoselectivity in the oyori dynamic kinetic resolution ubr 2 [()-BIA] 2, C 2 2 () (S) () syn:anti 99:1 in C 2 2 () syn:anti 71:29 in Ac Ac Ac Excellent enantioselectivity and syn diastereoselectivity is seen in the dynamic kinetic resolution of racemic α-acetamido-ß-keto-esters when the reaction is carried out in C 2 2. The observed syn selectivity with these substrates can be rationalized by considering the Felkin-Anh model for the transition state of hydride addition in which the small substituent () is adjacent to the Burgi- Dunitz trajectory of the incoming hydride and the best acceptor (acetamido group) is preferentially oriented anti to the incoming hydride. ( - ) Ac Ac C 2 interconversion under reaction conditions C 2 Ac ( - ) Ac C 2 C 2 ote that ester position is fixed b/c of chelate formation w/the catalyst Ac C 2 = (S) Ac Ac C 2 = () Ac ecall that in this system hydrogenation is thought to proceed through a u-monohydride species, capable of coordinating the adjacent ester moiety. The transition state with the acetamido group anti to the incoming hydride may additionally be stabilized via hydrogen bonding between the of the acetamido group and the of the ester. Interruption of this hydrogen bonding interaction via competetive binding to solvent may account for the diminished syn selectivity seen in. X u vs. (S) favored syn X u () Ac anti

13 M.W. Kanan/M.C.White Chem 153 ydrogenation Week of ctober 21, 2002 Stereoselective synthesis of iso-dolaproine: the power and limitations of DK with α-substituted-β-keto esters 3 4S 2 Dolaproine As part of an effort to develop a stereocontrolled synthesis of dolaproine, Genet and coworkers carried out the oyori DK shown below. Based on the literature precedents for DK with α-methyl-substituted ß-keto esters. the authors were expecting a syn relationship between C2 and C3. Instead that observed very good diastereoselectivity in the formation of the undesired anti isomer. This example highlights a lilmitation of the oyori methodology. In DK of α-substituted-β-keto esters, the ligand on u controls the stereochemistry of the ketone being reduced, but the diastereoselectivity is controlled by the substrate. This means that only one of the syn or anti relationships between the two stereocenters can be accessed reliably and, in this case, prevents access to the desired product. This particular substrate has a γ-stereocenter which may be exerting an influence on the selectivity. ; 10 bar 2, Et, 50 C Et 1 mol% u[(s)--bie]br Et 4S 2S 4S 3 2S Boc ; Boc-(2S)-iso-dolaproine quant. yield (2S,3):(2,3S) 92.5:7.5 (S)--BIE ; Et u[(s)--bie]br 2, 2 k slow ; 4S 3S 2 Et Genet rg. ett. 2001, (3) ; Et u[(s)--bie]br 2, 2 k fast ; 4S 3 2S Et

14 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 The riginal eport: on-directed carbonyl hydrogenations: a reversal in chemoselectivity u 2 ( 3 ) mol% 2 (10 atm), benzene, 70 o C 83% yield under these conditions, ketones are not hydrogenated. Suzuki Chem. ett u 2 ( 3 ) mol% 2 (29 atm), ethanol/benzene, rt 93% yield strong preference for hydrogenation of sterically unhindered olefins. Suzuki Chem. ett Selective hydrogenation of carbonyl vs. olefinic functionality using hydrogenation conditions B: 250 x faster ydrogenation conditions A: u 2 ( 3 ) 2,0.2 mol% 2 (4 atm), 2-propanol/toluene, rt Bases have been used in conjunction with u(ii) catalysts to effect olefin hydrogenations. ecall that base is thought to promote heterolytic cleavage of 2 to form the catalytically active u monohydride species. Therefore, the observed reversal in chemoselectivity must be primarily due to the added 1,2 diamine x faster ydrogenation conditions B: u 2 ( 3 ) 2,0.2 mol% 2 (C 2 ) 2 2 (0.5 mol%), K (1.0 mol%) 2 (4 atm), 2-propanol/toluene, rt oyori JACS 1995 (117) % isolated yield 98.6:1.4 (unsat. alcohol: sat. alcohol) n-c % isolated yield 97% isolated yield 100:0 (unsat. alcohol: sat. alcohol) 98.2:1.8 (unsat. alcohol: sat. alcohol) 98% isolated yield 100:0 (unsat. alcohol: sat. alcohol) 90% isolated yield 99.6:0.4 (unsat. alcohol: sat. alcohol) quantitative isolated yield 70:30 (unsat. alcohol: sat. alcohol)

15 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 on-directed carbonyl hydrogenations u- formed acts as a "bulky hydride" eactive u- species generated acts as a bulky source of hydride displaying similar diastereoselectivities observed with other stoichoimetric large hydride reagents such as KB(s-Bu) 3. t-bu M- b. torsionally favored axial trajectory generally observed for non-bulky hydride sources (recall: avoids formation of eclipsing interactions in TS) b a M- a. sterically favored equatorial trajectory generally observed for bulky hydride reagents (recall: avoids unfavorable steric interactions with diaxial 's during approach). 1,2-Diamine is a ligand for the u Both the chiralityof the diphosphine(binap) and the 1,2-diamineaffect the stereochemical outcome of the carbonyl hydrogenation. Therefore, the diamine ligand is attached to the u center during the catalytic cycle. u 2 [(S)-binap](dmf) n,0.2 mol% Diamine 0.5 mol%, K 1.0 mol% 2 (4 atm), 28 o C, 6h a b osphine Diamine % ee t-bu cis t-bu trans (S)-Binap (S,S)-Diamine 2 2 (,)-Diamine 97% 14% ydride source ratio (cis: trans) % i in 3 (non-bulky) KB(s-Bu) 3 (bulky) u 2 ( 3 ) 3 / 2 (C 2 ) 2 2 /K 1:99 97:3 98.4:1.6 3 (in u 2 ( 3 ) 3 ) 2 2 (S,S)-Diamine 75% oyori JC 1996 (61) D.A. Evans. Chem 206 otes. ctober 2000 oyori JACS 1995 (117) 2675.

16 M.C. White Chem 153 ydrogenation Week of ctober 21, 2002 Asymmetric, non-directed ketone hydrogenations In situ method using binap oyori JACS 1995 (117) u 2 [(S)-binap](dmf) n,0.5 mol% (S)-Diamine, 0.5 mol%, K 1.0 mol% 2 (8 atm), 28 o C, 3h >99 % yield >99 % chemoselectivity 70 % ee 2 2 (S)-Diamine DAIE = 1,1-dianisyl-2 -isopropyl- 1,2-ethylenediamine reformed catalyst using xylbinap α,β-unsaturated ketones: base-sensitive n-c 5 11 (S,S)-1 (0.001 mol%) K 2 C 3 (0.04 mol%) 2-propanol, 2 (80 atm), rt, 43 h (S,S)-1 (0.2 mol%) K 2 C 3 (0.04 mol%) 2-propanol, 2 (8 atm), rt, 43 h () >99% yield >99% chemoselectivity 97% ee n-c 5 11 () 98% yield >99% chemoselectivity 97% ee Ar = Ar 2 Ar 2 u (II) (S,S) aryl ketones: heteroaromatic ketones = F,, Br, I, CF 3, C(), 2, 2 in m, p, o positions for: = p- (S,S)-1 (0.002 mol%) Kt-Bu (0.08 mol%) 2-propanol, 2 (8 atm), rt, 16 h 99.9% yield 99% ee oyori JACS 1998 (120) also effective for furyl and thiazolyl ketones (S,S)-1 (0.2 mol%) Kt-Bu (0.08 mol%) 2-propanol, 2 (50 atm), rt, 24 h 99.9% yield 96% ee oyori 2000 (2) 1749.

17 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Catalyst Synthesis Catalyst is 2 sensitive: does not store well [u 2 (benzene)] 2 (S)-XylBIA XylBIA rep: 1. DMF (degassed), Ar, 100 o C,10 min 2. (S)-DAIE, 25 o C 6h Chiral elements are not commercially available Ar 2 Ar 2 u (II) (S,S) Ar = Workup done under strictly anhydrous conditions under an Ar atomosphere emove DMF (pump) Dissolve in Et 2 (degassed, dried) Filter through Si pad Concentrate Add hexanes (degassed, dried) Cannula filtration Concentrate and store under Ar oyori, JACS, 1998, 120, Br Br 1. Mg 2. Ar 2 ~ 89% optical resolution using chiral organic acid ()Ar 2 1.dibenzoy-- tartaric acid Ar 2 ()Ar 2 2. Si 3, Et 3, 92% Ar 2 Ar = (±) (S)-XylBIA Takaya, JC, 1994, 59, 3064 DAIE rep: 3 C 2 p-c 6 5 MgBr 67% 2 1. Cbz, 60% 2. a 3, 95% BzC 3 2 (50 psi) 10% d/c 85% 2 2 -alanine methyl ester hydrochloride (S)-DAIE Burrows, T, 1993, 34, 1905

18 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 on-assical Bifunctional Catalyst 2 2 u (II) 2 2 2, K K, u (II) 2 2 trans effect results in weakening of the u- bond and may increase it's hydridic behavor towards ketones u (II) 2 note: 1 is generated from the u()(-binap)(tmen) precursor rather than the dichloro precursor typically used in ketone hydrogenations 2 2 δ- u (II) δ 2 Morris JACS 2001 (123) hydridoamido intermediate:observed by M when dihydride is treated with ketone in the absence of 2. When the hydridoamido complex is placed under 2, the dihydride is regenerated. The proposed mechanism for ketone hydrogenation involves a concerted transfer of the hydridic u- and protic - to the ketone via a 6-membered pericyclic TS. The ketone substrate cannot interact directly with the 18 e-, coordinatively saturated u- catalyst without disrupting one of it's chelate rings or displacing a hydride, both energetically unfavorable processes. This may account for the observation that 1,2-diamines are effective at shutting down the olefin hydrogenation pathway, known to proceed through olefin coordination to the metal followed by hydride migratory insertion.

19 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 Transfer hydrogenations: organic hydride donors The catalysts: u u Ts 2 Ts u II 2 n Ts u II n Aryl ketones [u 2 (mesitylene)] 2 (S,S)-TsDE (S,S)-1 (S,S)-2 is the active transfer hydrogenation catalyst and can be formed in situ from pre-catalyst (S,S)-1 in the presence of K or from [u 2 (aryl)] 2 /ligand/k. For base sensitive substrates, (S,S)-2 can be prepared and isolated separately. α,β-acetylenic ketones (S,S)-2 = [u 2 (mesitylene)] mol% (S,S)-TsDE 1 mol%, K 2.5 mol% i-r (0.1M in ketone) (S) = : 95% yield, 97% ee : 95% yield, 93% ee : 53% yield, 72% ee (S,S) mol% C 3 K 0.6 mol% C 4 i-r (0.1M) 9 C 4 9 Both aryl and alkylethynyl ketones serve a good substrates. 70% yield 98% ee C 3 oyori JACS 1995 (117) oyori JACS 1997 (119) verriding substrate bias: (S) (,)-2 1 mol% i-r, rt (S) (S) CBz 98% ee 97% yield CBz 98% ee (S,S)-2 2 mol% i-r, rt (S) (S) CBz >99% ee >97% yield

20 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 roposed mechanism of oyori transfer hydrogenations Both the hydroamido ("true catalyst") and dihydride ("loaded catalyst") u complexes have been isolated and characterized by x-ray crystallography. Both compounds are capable of effecting transfer hydrogenations to aryl ketones at comparable rates to the pre-catalyst without the presence of base. u II Ts pre-catalyst base base The reversability of the hydrogenation step may lead to an erosion in ee's and incomplete conversions for substrates with low oxidation potentials. To minimize interaction of the product with the catalyst, the reactions are often run at substrate concentrations of 0.1M. u II X true catalyst 2-propanol hydrogen transfer The presence of or 2 on the chelating ligand is critical for catalytic activity. The dialkylamino analogues are ineffective. X u ± X = Ts, X u ± 3 C C 3 u II X loaded catalyst oyori Acc. Chem. es (30) 97. oyori JACS 2000 (122) 1466 oyori JC 2001 (66) 7931.

21 M.C. White, Chem 153 ydrogenation Week of ctober 21, 2002 rigin of asymmetric induction: C-/π attraction DFT calculations indicate that the sterically more congested Si-TS for the hydrogenation of benzaldehyde is 8.6 kcal/mol more stable than its relatively uncrowded diastereomeric e-ts. The rationale given is that Si-TS is stabilized by the C-/π attractive interaction between a C(sp2) substituent on the benzene ligand of the u complex and the π system of the aryl group on the substrate. (S) u "loaded catalytic intermediate" The partial positive charge on the C(sp 2 ) of the benzene is enhanced by binding to the metal (recall: benzene is a good π-donor) resulting in its increased ability to act as a C donor to the electron rich π-system of the aryl group on the substrate. Ar u ± u ± Si-TS e-ts Ar () Ar (S) major enantiomer observed in aryl ketone and benzaldehyde-1-d transfer hydrogenations oyori ACIEE 2001 (40) 2818.

22 M.C. White/M.S. Taylor Chem 153 ydrogenation Week of ctober 21, 2002 Synthetic application of oyori transfer hydrogenation Ts u II MB TES TMS i-r i-r MB TES TMS Fostriecin 93% yield >95:5 d.r. It was possible to control the relative stereochemistry of the 1,3 diol unit by selection of the appropriate enantiomer of oyori's transfer hydrogenation catalyst. TMS TMS Ts u II Ts u II 2 i-r i-r u(ii) u(ii) d 6, 18e - d 6, 16e - Jacobsen ACIEE 2001 (113) 3779.

23 M.C. White, Chem 153 ydrosilyation Week of ctober 21, 2002 Wilkinson s catalyst: not just for hydrogenations Generally, the rate of olefin isomerization for terminal olefins is much slower than the rate of isomerization. owever, the yields are seldom quantitative because of this side reaction. Internal olefins are not hydrosilylated. owever the catalyst isomerizes them to terminal olefins which then undergo hydrosilylation: h( 3 ) 3 2 Si- Si 2 80% trans-2-pentene cis-2-pentene h( 3 ) 3 2 Si- 75% Si 2 Chalk JMC 1970 (21) 207. eductive elimination from the branched metal alkyl is not observed. nce formed, this intermediate can undergo β-hydride elimination to form an internal olefin or a terminal olefin. The terminal olefin will re-enters the catalytic cycle at a faster rate than the internal olefin (recall high sensitivity to sterics of the Wilkinson catalyst towards alkene hydrogenations. Si h (I) 3 reductive elimination Si 3 Si h (I) 3 Si- oxidative addition Si 3 h (III) 3 branched metal alkyl 3 h (III) 3 linear metal alkyl 3 Si 3 h (III) 3 3 β-hydride elimination cis-migratory insertion (hydrometallation) 3 h (III) 3 olefin isomerization biproduct Jardine rog. Inorg. Chem (28) 63.

24 M.C. White, Chem 153 ydrosilylation Week of ctober 21, 2002 ydrosilylation of alkynes h( 3 ) mol% Et 3 Si-, rt 1h C 4 9 C 4 9 SiEt 3 SiEt 3 trans product 65% cis product 20% arish JMC 1978 (161) 91 Stereospecific cis hydrometallation of the coordinated alkyne followed stereospecific reductive elimination of the alkenyl silane should result exclusively in trans product. The experimental observation that cis product formed was accounted for by envoking addition of a second round of hydrometallation on the alkene followed by β-hydride elimination. This hypothesis is supported by the observation that pure trans product partially isomerizes to the cis upon treatment with the catalyst and silane (note: no isomeriztion occurs in the absence of silane) Si 3 Si 3 C 4 9 Si 3 stereospecific reductive elimination 3 3 h (I) 3 Si- C 4 9 SiEt 3 C 4 9 β-hydride elimination h (III) 3 3 Si 3 Si 3 h (III) 3 3 h (III) 3 3 Si 3 Si 3 cis-migratory insertion (hydrometallation) 3 h (III) 3 C 4 9 C 4 9 Si 3 3 Si 3 h (III) C 4 9 3

25 M.C. White/Q. Chen Chem 153 ydrosilylation Week of ctober 21, 2002 Application of trans hydrosilylation to the synthesis of Brefeldin A TBS C 2 Et 1) [Cpu(C 3 C) 3 ][F 6 ] 1 mol% (Et) 3 Si, C 2 2 2) CsF, Et TBS C 2 Et ()-Brefeldin A Trost JACS 2002 (124) 9328 Cp u = C 3 C Cp 3 Si u - 3 Si - oxidative addition C 2 Et 3 Si Cp u C 2 Et cis migratory insertion Cp u Si 3 C 2 Et? Cp u Si 3 C 2 Et CsF, Et C 2 Et Trost JACS 2002 (124) 9328 ote that this substrate contains a free hydroxyl and an epimerizable stereogenic center α to the Weinreb amide; both of these functionalities are well tolerated in this reaction which proceeds with very high trans selectivity.

26 M.C. White, Chem 153 ydrosilylation Week of ctober 21, 2002 latinum "Speier's Catalyst" / 2 t 6 2 / chloroplatinic acid is an extremely active catalyst for olefin hydrosilylations. It demonstrates the same regioselectivity observed with Wilkinson's catalyst in the hydrosilylation of terminal olefins. It also effects isomerization of internal olefins to terminal olefins prior to hydrosilylation. owever unlike Wilkinson's catalyst, chloroplatinic acid is able to hydrosilylate cyclic internal olefins such as cyclohexene in excellent yields. terminal olefins internal olefins 2-pentene 2 t mol% 2 Si- 100 o C 2 t mol% 2 Si- 100 o C 93% 89% Si 2 Si 2 The widely accepted mechanism of this reaction, advanced by Chalk and arrod, involves reduction of 2 t 6 to a t(ii) species that shuttles between (II) and (IV) oxidation states to effect hydrosilylation in a manner analogous to that proposed for Wilkinson's catalyst. In support of this is the observation of an induction period before hydrosilylations begins and that certain t(ii) complexes can effect hydrosilylation, although the exact reactivity (substrate scope, yields, etc...) has never been reproduced. It has also been suggested that the active catalyst is colloidal platinum metal. Colloidal metals are suspensions of fine particles (~ Å radius) of metal in a liquid. ften the solutions appear homogeneous and are able to pass though micropore filters and surviving centrifugation unaffected. n the basis of known chemistry of d 8 metal complexes, a mechanism is suggested Chalk and arrod JACS 1965 (87) 16. t (II) oxidative addition 3 Si- Si 3 t (IV) cyclic internal olefins Si 3 reductive elimination Si 3 migratory insertion 2 t mol% Si 2 t (IV) 2 Si- 100 o C quantitative Speier JACS 1957 (79) 974. For a lead reference on methods for testing for colloidal metal catalysis see: Crabtree M 1983 (2) 855.

27 M.C. White/Q. Chen Chem 153 ydrosilylation Week of ctober 21, 2002 Application of an intramolecular hydrosilylation in the synthesis of Jatrophatrione Bn Si 10 mol% MDS 2 mol% 2 t ( 3 Si) ( 3 Si) 4 2 Bn Si 2 1) ial 4 Et 2 2) 2 Si Et 3 Bn (t 2 ) ature of active catalyst unclear as platinum colloids have also been implicated as viable catalysts. Bn Si t Bn Si t Trisubstituted olefin and benzylic ether not affected. Directed silyl transfer from convex face of substrate. Alternative iodolactonization from the corresponding carbonate was ineffective. Bn Si t aquette JACS 2002 (124) 6542.

28 M.C. White, Chem 153 ydrosilylation Week of ctober 21, 2002 First report on palladium catalyzed hydrosilylations: alladium Terminal olefins hydrosilylated with anti-markovnikoff selectivities 1,3-dienes afford 2-silylated-3-ene products (π-allyl intermedaite?) d( 3 ) mol% 3 Si-, 110 o C 90% Si 3 d( 3 ) mol% 3 Si-, 110 o C Si 3 80% Internal olefins hydrosilylated at slower rates and lower yields than terminal olefins. 3 Si d( 3 ) mol% 3 Si-, 110 o C 30% o terminally hydrosilylated products from internal olefins were observed. Unlike platinum catalyzed hydrosilylations, simple palladium salts are inactive. It was found that a variety of d(ii) sources can be activated towards effecting hydrosilylation in the presence of phosphine ligands. osphines are thought to reduce d(ii) to catalytically active d(0) (avoids high energy d(iv) intermediates) and to act as ligands to the d(0) preventing its plating out of solution. In support of this, d( 3 ) 4 can be used directly to effect hydrosilylation. The rate of hydrosilylation is affected by the nature of the phosphine used indicating that d-phosphine species are present in the catalytic cycle. This observation suggests that the selectivity of the reaction may be tuned via the phosphine ligand. Triphenylphosphine was found to afford a palladium catalyst with the highest activity. d( 3 ) 4 cat. 3 Si- major product Si 3 3 > Et 3 > Bu 3 > Cy 3 > (C 3 ) 3 Aryl-substituted olefins underwent d catalyzed hydrosilylation with high regioselectivity for the Markovnikoff products. Si 3 roposed intermediate in d catalyzed hydrosilylation: d( 3 ) mol% 3 Si-, 110 o C 95% 3 Si d II 3 Tsuji Tetrahedron 1974 (30) 2143.

29 M.C. White, Chem 153 ydrosilylation Week of ctober 21, 2002 reparation of optically active 2 o alcohols from terminal olefins via asymmetric hydrosilylation/tamao oxidation sequence d d 0.1 mol% Si 3 (1.2 eq) Si 3 minor product Si 3 major product Et Et 3 Si(Et) Stereospecific Tamao xidation 2 "M" mol% The regioselectivities range from ~15:1 (major:minor), and the isolated yields of secondary alcohols ranged from 45-75%. The ee's for this process are generally excellent and range from 94-97%. alladium complexes coordinated with a chelating bis(phosphine) (e.g. dppb, chiraphos, or BIA) did not catalyse the hydrosilation, even at 80 o C. Alternatively, the reaction proceeded in good to excellent yields at 40 o C with monodentate phosphine ligands. Why? ote: nly unfunctionalized, aliphatic terminal olefins were reported. 1. d d M Si 3 (1.2 eq) 2. Et, Et regioselectivity (87:13) 70% yield 94% ee d d 1. M Si 3 (1.2 eq) 2. Et, Et BIA regioselectivity (66:34) 45% yield, 96% ee ayashi JACS d d 0.5 mol% Si 3 (1.2 eq) Si 3 This reaction proceeds in good to excellent yields (74-94%) and with very high ee (95-99%) for a variety of styrene derivatives: =3-2,2or 3-, 2 or 3-CF 3, 2-C 3. Stereospecific Tamao oxidation yields nearly optically pure benzylic alcohols. 2 mol% Johannsen JACS

30 M.C. White, Chem 153 ydrosilylation Week of ctober 21, 2002 reparation of optically active axially chiral allenylsilanes via hydrosilylation of 4-substituted 1-buten-3-ynes d d Fe 1 mol% 3 Si MgBr 3 Si Fe Si 3 (2.2 eq) = t-bu 59% yield, 85% ee = 2,4,6-3 C % yield, 77% ee = Si 2 t-bu 40% yield, 68% ee 2.2 mol% d Si 3 3 Si A bulky group required to get selectivity in the formation of allenylsilane. The authors speculate that this sterically bulky group is important in retarding the competing hydropalladtion of the alkyne moiety. 3 Si d reductive elimination 3 Si d oxidative addition 3 Si d proposed π-propargyl(silyl)- palladium intermediate migratory insertion 3 Si d ayashi JACS

31 M.C. White, Chem 153 ydroformylation Week of ctober 21, 2002 The xo rocess xo rocess: 1938 tto oelen. Co2(C)8 is still the principle catalyst for hydroformaylation of terminal alkenes industrially. More than 4 million tons of aldehydes are made annually this way. inear aldehydes are more desirable than branched aldehydes because they can be converted to linear alcohols used as chemical feedstocks and detergents. Co 2 (C) 8 cat. 2 :C (1:1, atm), o C linear (n) = (70-80% yield) branched (iso) roposed mechanism: Anti-Markovnikov addition of water to a terminal olefin catalyst?? 2 n hydroformalation: n = 1 hydration: n = 0 C (C) 3 Co Co(C) 3 (C) 4 Co Co(C) 4 2 (C) 4 Co Co(C) 4 C σ-bond metathesis σ-bond metathesis? 2 2 Co(C) 4 catalytically active species C C Co(C) 3 Co(C) 3 eck and Breslow JACS 1961 (83) Sommer JACS 1969 (91) C C Co(C) 3 C

32 M.C. White, Chem 153 ydroformylation Week of ctober 21, h(c)( 3 ) 3 Strem ( ) 1g = $75 ates of hydroformylation of terminal vs. internal olefins. asured as rate of uptake of 2 C (1:1) C 5 11 C 2 5 h (I) 3 C 3 rate 3.5 ml/min 0.15 ml/min Wilkinson: hydroformylation Aliphatic terminal olefins h(c)( 3 ) 3 3mol% ~ 4% hydrogenation C 5 11 C 5 11 benzene, 2 :C (1:1, 1 atm), rt C 5 11 and isomerization products linear: branched (6.4:1) note: when excess 3 is added (3 eq w/respect to catalyst) the ratio of linear: branched product increases from 6.4 to 9. The amount of hydrogenated/isomerization product also decreases (<4%). This increase in selectivity is at the expense of reaction rate. Wilkinson notes that one way to increase the regioselectivity to favor linear product is to use a bulky phosphine. Aromatic terminal olefins h(c)( 3 ) mol% benzene, 2 :C (1:1, 1 atm), rt linear:branched (0:11) C 3 h (I) C - 3 C h (I) 3 C 3 C 3 h (I) 3 3 C All steps up to 2 A are reversible Wilkinson J. Chem. Soc. A Wilkinson J.Chem. Soc.A Morokuma M 1997 (16) oxidative addition (DS) 3 2 h (III) 3 3 C h (I) 3 C C migratory insertion reductive elimination C h (I) 3 3 C 3 C h (I) 3 C migratory insertion C h (I) 3 C desired intermediate branched product 3 h (I) C C

33 M.C. White Chem 153 ydroformylation Week of ctober 21, 2002 egioselectivity: bulky phosphine ligand igand h (I) C C 0.54 mol% igand, 2 mol% 2 /C (5 atm), 60 o C, TF 18h n:iso n (linear) iso (branched) Buchwald proposes active hydroformylation catalyst 3 2.4:1 () 3 3:1 t-bu t-bu t-bu t-bu 20:1 (iso was not observed by M C h I 1 This system was reported in the patent literature to give high n:iso ratios under mild conditions: Billig US atent 4,769,498 (1988). Buchwald screens substrate scope. Substrate scope: ketones, acids, esters, amides alcohols, halides, nitiles h(c) 2 (acac) 0.54 mol% 1 2 mol%, n 2 /C (5 atm) 60 o C, TF 18h Buchwald JACS 1993 (115) n = C 3, n= 1, 86%, n= 8, 68%, n= 8, 91% (Et) 2, n= 2, 93% C n h(c) 2 (acac) 0.54 mol% 1 2 mol%, 2 /C (5 atm) 60 o C, TF 18h note: the alkyl halides do not undergo A n C =, n= 10, 53% Br, n= 2, 71% I, n= 2, 64% C, n= 2, 84%

34 M.C. White Chem 153 ydroformylation Week of ctober 21, 2002 Asymmetric hydroformylation 2 h C 3 C 3 (0.5 mol%, 2:1 :h) 2 /C (100 atm), 60 o C, benzene 36 h note: chiral phosphinephosphonate ligand BIAS and h(i)(c) 2 (acac) were mixed in 2:1 ratio in situ. C =, >99% conv.; iso:n (88:12), 94% ee, >99% conv.; iso:n (87:13), 88% ee, >99% conv.; iso:n (87:13), 93% ee A few other substrates were reported: Ac C C C 4 9 C 99% conv. iso:n (86:14) 92% ee 98% conv. iso:n (89:11) 85% ee 90% conv. iso:n (24:76) 75% ee 2 h C 3 C 3 2 /C (1 atm) C 2 h C bserved by M. The rhodium monohydride complex displays the same hydroformylation reactivity and selectivity as observed above, suggesting that it is a valid catalytically active species. Takaya JACS 1993 (115) 7033.

35 M.C. White/M.S. Taylor Chem 153 ydroformylation Week of ctober 21, 2002 First application of Takaya asymmetric hydroformylation to TS C 3 C / 2 (1:1, 20 atm) C 3 C 3 2 h C 3 C 3 C C 3 C 3 91:9 iso:n 96:4 d.r. (0.5 mol%, 2:1 :h) This is the first application of the Takaya catalytic asymmetric hydroformylation to target-oriented synthesis. ther approaches to such stereocenters have relied upon chirality transfer strategies, requiring several steps. C C 3 C 3 3 () - Ambruticin C 3 C 3 Total synthesis of () - Ambruticin iu,.; Jacobsen, E.; JACS 2001, 123,

36 M.C. White/M.W. Kanan Chem 153 ydroformylation Week of ctober 21, 2002 Substrate conformational bias leads to diastereoselective hydroformylation 0.7 mol% [h(c) 2 acac/4() 3 ] toluene, 70 C, 20 bar ( 2 /C, 1:1) iv DEIS 36 h. 80% I dr 99:1 intermediate in Toshima's bafilomycin A 1 synthesis Catalytic cycle: C C 3 () 3 C 3 C 3 2 C 3 h (I) () 3 reductive elimination h (III) () 3 C Stereoselectivity depends on which face of the olefin is available for coordination to the h(i) species. The strongly preferred conformation of the substrate effectively blocks one face from coordination and allows the hydroformylation to proceed with excellent diastereomeric excess. 3 h (I) C C C 3 C 3 C C C 3 C 3 C 3 C 3 h (I) h (I) () 3 prefered olefin conformation to avoid syn-pentane-like interaction; this dictates diastereoselectivity C stereospecific hydride insertion C () 3 C insertion C () 3 h (I) C () 3 () 3 Breit T 1998, (39) 1901.

37 M.C. White, Chem 153 Q&A Week of ctober 21, 2002 u(c 3 C 2 ) 2 -[(S)-BIA] catalyzes the hydrogenation of α-(acylamino)acrylic esters to give the (S) saturated product in >90% ee's. ropose a mechanism that accounts for the observed mixture of hydrogenation products when the reaction is run in D. ote: your mechanism need not rationalize the absolute stereochemistry obtained. C 3 (S) (1 atm), D (II) u ne mechanistic possibility that accounts for these observations is the following: C 3 u (II) C 3 = C 2 u (II) C 3 the amide carbonyl (more lewis basic than ester carbonyl) preferentially binds to u C 3 C 3 D D A B C 2 u (II) Ac 79:14:2 eterolytic cleavage of 2 C 3 D C 3 oyori JACS 2002 (124) It's interesting to note that the mechanism of a reaction may vary depending on substrate. D u (II) Ac C 3 C 3 D protonolysis D 2 /σ-bond methathesis u (II) C 3 cis-migratory insertion regioselectively forms the 5 membered ring chelate D C 3

38 Q. Chen/M.C. White, Chem 153 Q&A Week of ctober 21, 2002 Question 1 Mild hydrogenation of benzene can be achieved with the cobalt complex below. The rate of cyclohexadiene reduction is similar to the rate of benzene hydrogenation while cyclohexene is reduced at three to four times slower than benzene. ropose 2 mechanisms for the arene hydrogenation. cat. Co () 3 () 3 () 3 < 1 atm 2, 25 C, rt.

39 M.S. Taylor/M.C. White, Chem 153 Q&A Week of ctober 21, 2002 Question 2 alpern's seminal mechanistic studies on the h - DIAM system for asymmetric dehydroamino acid hydrogenation permitted improvement of the reaction conditions to increase enantiomeric excess. rovide a rationalization for the following observations, in light of alpern's results. i) Decreasing the 2 pressure of the reaction increases the enantiomeric excess. ii) Increasing the reaction temperature increases the enantiomeric excess.

40 M.C. White, Chem 153 Q&A Week of ctober 21, 2002 Question 3 ydroformylation proceeds with h( 3 ) 3, however there is an induction period. It was shown that in the presence of a base the induction period is removed. What is the role of the base? Indicate the active catalyst for this process and specify how it is formed under the reaction conditions. 3 3 h (I) 3 cat. C 3 7 C3 7 2 :C (1:1, 100 atm), 70 o C 16 h, >99% conversion C 3 7 linear: branched (2.7:1)

41 M.S. Taylor/M.C. White Chem 153 Q&A Week of ctober 21, 2002 Question 4 rovide a mechanism to account for the following transformation C 6 13 C aac / Ac C 6 13 d 2, Cu 2

42 M.C. White, Chem 153 Q&A Week of ctober 21, 2002 Question 5 A rhodium hydroformylation catalyst was reported that hydroformylates internal alkenes to produce linear aldehydes preferentially. rovide a detailed mechanism for this transformation. ationalize the effect of the bulky phosphine ligand in the observed regioselectivity. h (I) C C 0.1 mol% C 5 11 igand, 1 mol% C /C (20 atm), 80 o C, toluene 18h n mixture of branched aldehydes iso t-bu t-bu igand n:iso % 1-nonanal % 90% 1

43 Q.Chen/M.C. White, Chem 153 Q&A Week of ctober 21, 2002 Question 6 The rhodium complex below catalyzes the isomerization of vinyl silanes to silyl enol ethers. ropose a mechanism for the transformation. h Si(ir) 3 (ri) 3 Si Si(ir) 3 2% Si ir ir