Organometallic Compounds

Dr. Ajay Kumar Das Associate Professor Department of Chemistry MLT College Saharsa [email protected] 9431863881 Organometallic Reagents in Synthesis

Organometallic and other C-C bond forming reactions in some representative syntheses: Li = lithium reagent, Mg = Grignard reagent, Cu = organocopper reagent, P = Wittig reagent, Li/P Na/P K/P Horner-Wadsworth-Emmons, Pd/Sn = Stille coupling, Pd/Zn = Negishi coupling, Li/Si = Peterson olefination, Zr/Al = Tebbe reagent, B = organoboron reagent, R = Radical addition/cyclization.

Isoamijiol (14-deoxy) Ruguluvasines A and B Majetich, G.; Song, J. S.; Ringold, C.; Nemeth, G. A. Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F. Tetrahedron Lett. 1990, 31, 2239 J. Am. Chem. Soc 2001, 123, 5918. R OH O H Li Si Pd/Sn Li O NHMe Si Cu R = Radical K

HN Shahamin K Pironetin Lebsack, A. D.; Overman, L. E.; Valentkovitch, R. J. Dias, L. C.; Oliveira, L. G.; Sousa, M. A. J. Am. Chem. Soc. 2001, 123, 4851. O Org. Lett. 2003, 5, 265 AcO O LI H Li Li H O Li OMe OH O Cationic cyclization olefin Li Li P/Na OAc B B B Li Cu H

Penostatin A (Deoxy) Morphine Snider, B. B.; Liu, T. Taber, D. F.; Neubert, T. B.; Rheingold, A. L. J. Org. Chem. 2000, 65, 8490-8498. J. Am. Chem. Soc. 2002, 124, 12416 P/Li H K O Li LI N H Diels Alder (hetero) O O H P K OH Carbene P/Li Li C7H15 OH

Okinellin B Laurenyne Schmitz, W. D.; Messerschmidt, N. B. Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. J. Org. Chem. 1998, 63, 2058 1988, 110, 2248 Li H Cl O O Li/Si Li Li Cr Pd/Zn K/P O Cationic Zr/Al cyclization olefin O K Si Mg OH Hirsutene Dysidiolide D. P. Curran, D. M. Rakiewicz Madnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; J. Am. Chem. Soc., 1985, 107, 1448. Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1615. Cu Li R H Li Pd R R = Radical cyclization • LI Li Li Cu O H H Claisen O OH 53% OH Tedanolide (13-deoxy) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc 2003, 125, 350

Li Li P1 Li1 P1 + S S PPh3 S S Br Br 1 + Li2 Li P1 O PPh3 O OTIPS OH P3 B2 B2 H O OH OMe OPMB L 3 P Li2 + O OMe O Li1 Li 1 PPh3 P2 O P S S Li3 B 1 B3 3 CO2Me Li P2 OH O O

O O iPr B-Enolate O O B-Enolate CO2 O O N O N B CO2iPr O 2 Ph 3 B B1 Ph B Organometallic Reactions in Partial Synthesis of Spongistatin 1

Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675 CO2iPr O B(Ipc)2 (Mg) CO2iPr B(Ipc) B Major disconnections 2 O

OH O O OBn HO Li B HO Li O Li H H H S S Li(Cu) O O H B Li OMe LI Li Li O HO Li O BnO Li OH H S S O Li H O PhSO2 Li O H Li B O OH O H Li Li O TESO Cl B PhSO2 OTES AcO Li Li OAc OTBS OH Spongistatin 1 S S Li t Li Li Li SiMe2 Bu PhSO2 S S S S PhSO2 OTES OTBS OPMB Classes Balancing Assemble Activate Activate C C C C

_ _ _ M M M

M of the the

: + on

N the Nucleophilic

BuLi electrophile: nucleophile:

a H Br Li H SnMe

transition

Weak Weak Strong Weak Reactivity R R R R 3 _ _ _ 2

Cu Si, B, Li, Carbanion, Carbanion, Carbanion,

Carbanion, + + + + +

R R , metal R

_ Pd

Al,

Na,

Sn, Organometallic

° of Me

(mildly Cl O

R R Nucleophile 2

Cl N Zn, M M M X

Hg,

+ + +

O + E

+ O O

O + Non-Lewis Lewis Lewis

Weak R (R

activate R R

various _ AlCl R R _ Ti,

R MgX)

R-SiX

3 Acid Base Lewis

both

ate Reagents and

Pd(0) Acidic 3

, Acid

complexes (R E

Electrophile

and _ MgX)

N):

High N High Unusual Isomerically Regiochemical Cyclic Nucleophilic Stereochemical _

nucleophilicity selectivity O O O O

transition

R R R Reactivity R

stable catalysis

towards + control + +

control states

patterns HCl

HX Me electrophiles 3 SnCl Effect Preparation *** ** * Weak*** Very Strong Very Destabilizing Intermediate Need Alkyl halogen These Type: -OR 5. 4. 3. 2. 1. SR CH=CH -CH

groups

-NO Strong Weak** two Addition Metalation Lithium-metalloid Metalation Reduction O R-M

SO S R-H

types R-X

R O O

R or

3 of - M PR

CH -

2 2

O SR).

these CF

-NR are Substituents

are 2 = + + + N

2 2

Br,

invariably -X not (compared

-C -N R'Li R'Li 2Li of

NHSO 2

(X-CH +

of S

SeR

≡

≡ usually of I, of (Li/H RLi

C-R O OR ° R N-R O N O

- X

SnBu

carbon-X Organolithium N-sulfonylhydrazones 2

-SiR -X') =

to kinetically 2

Ar prepared Cl, exchange) R'Li

-Halogen

for BR C-C exchange

3 3

Se ,

to easy Br, S

+ HgCl, 2

R' R O

R H)*

O NR multiple

deactivating.

bonds I,

2 by metalation on

SPh

n-BuLi 2 metalation,

SePh,

-Ph R PR + (Li/M)

R-Li R-Li R-Li P Carbanion

CN with R O bonds. 3 Li

R with

TePh + + +

but

lithium

LDA. Reagents pKa (Shapiro) R'-H R'M LiX

by R'

other

50-60 20-30 40-50 30-40 10-20

Li metal >60

H-CH

techniques

Stability

2 Ph -X MeLi

(Li/Sn, Li Typical sec

Li n Li/Halg NaOH, PhLi KO- -BuLi, OMe Li LDA, -BuLi, R KH,

RO None

Metalating -Bu, exchange, -BuLi/

sec KO- LiN(TMS) n PhSO

n n -BuLi,

-Bu-Li NaH, -BuLi/TMEDA available -BuLi, t -Bu,

t O BuOK Li

reduction 2

KH LDA

Agents

DBU Li 3 LiTMP

Li t BnO -BuLi

of BnO

O s

Bn S -Bu-Li O O Li H 2 (Me C-CH-CH Brauman O Me Me (CH H MeSCH H Gas CH 2 2 PhCH 3 (Ph) 2 P) ClCH Cl HC C=CH: SiCH 3 PCH

3 R-C ) Li 1995 Phase 2 CH 2 CH 2 CH: CH: CH: ≡ Ph: - 3 H C: C:

2 2 2 2 2 ≡ 3 2 2 J. : : : : : : : : C-Li ,

Acidity Am. 117

-80 -60 -50 -40 -30 -20 -10 -70 10 , 0

Chem. 4908.

(kcal/mol) Me CH Me CH 416.6

NH Soc. HO: HS: H: 3 3 3 3 Sn: Si: O: S: F: 2 : : Effect of Substituents on Carbanion Stability K 1. Hybridization In almost all areas of organometallic chemistry the primary subdivision of reactivity types is by the hybridization of the C-M carbon atom (methyl/alkyl, vinyl/aryl, alkynyl). A key second subdivision is the presence of conjugating substituents (allyl/allenyl/propargyl/benzyl).

The fractional s-character of the C-H bonds has a major effect on the kinetic and thermodynamic acidity of the carbon acid. Only s-orbitals have electron density at the nucleus, and a lone pair with high fractional s character has its electron density closer to the nucleus, and is hence stabilized. This can be easily seen in the gas-phase acidity of the prototypical C-H types, ethane, ethylene and acetylene, as well as for cyclopropane, where the hybridization of the C-H bond is similar to that in ethylene.

CH3-CH3 CH2=CH2 HC≡CH

ΔH°acid (kcal/mol) 420 411 406 375

These effects are also clearly evident in solution, with terminal acetylenes and highly strained hydrocarbons easily metalated by strong bases. Li

n-BuLi

JACS-72-7735

2. Inductive Effects Electron-withdrawing substituents will inductively stabilize negative charge on nearby carbons. These effects are complex, since electronegative substituents interact with carbanions in other ways as well (e.g. O and F substituents have lone pairs, which tend to destabilize adjacent carbanion centers).

O O O O O O O O O O + S H S CH3 S OMe S F S NMe3 Ph Ph Ph Ph Ph H H H H H

pKa (DMSO) 29.0 31.0 30.7 28.5 19.4

3. Conjugation - π Delocalization Delocalization of negative charge, especially onto electronegative atoms, provides potent stabilizations of carbanionic centers. Since almost all conjugating substituents are also more electronegative than H or CH 3, there is usually a significant inductive contribution to the stabilization. O O N CH4 CH3 H H C H t-BuO

pKa (DMSO) ~55 43 26.5 30.3 31.3

A special case is the aromatic stabilization of cyclopentadienide and related indenide and fluorenide anions (Huckel 4n + 2 π electron rule) .

pKa (DMSO) 18.0 20.1 22.6 30.1

The aromatic anions (6e π system) show a level of stabilization far above that of normal conjugated systems ΔH°acid (kcal/mol) 356.1 373.9

H K 4. Second and Third Row Element Effects ("d-orbital" effects) All measures of acidity show that there is an unusual level of carbanion stabilization for all second row elements (Cl, S, P, Si, as well as higher elements) when these are bonded to a carbanion center.

6 3 10 0.25 300 CH CH3 CH3 CH3 0.013 CH3 S O N

Kinetic acidity 0.25 330 500 14 Isotopic exchange 0.45 24 1 0.2 KNH2/NH3 0.41 6 0.25 0.07

O X Me OMe OPh SPh SePh Bordwell J. Org. Chem. X 1976, 41, 1885 Ph pKa (DMSO) 24.4 22.9 21.1 17.1 18.6

Gas phase acidity FCH3 MeOCH3 Me-CH3 ΔH°acid (kcal/mol) 409 407 420.1

ClCH3 MeSCH3 Me3SiCH3 ΔH°acid (kcal/mol) 395.6 393.2 390.9

ΔΔH°acid 13.4 13.8 19.2

The origin of this stabilization has several components. Classical overlap of the lone pair with the empty d-orbitals is at best a minor contributor, since the d-orbitals are too diffuse and too high in energy. For the electronegative elements (Cl and S) there is an inductive component. For those bearing substituents (SR, PR 2, SiR3) there is a major contribution of σ-hyperconjugation (delocalization of charge into X-R σ* orbitals). n σ* R S

R S C

d-orbital interaction Negative hyperconjugation A factor comparable in size to σ-hyperconjugation is the σ bond strength effect. There is a size difference between the 3p orbitals of the S and 2p orbitals in the C-H compound. In the carbanion the C orbital increases in size, resulting in a stronger sigma bond. In an oxygen-substituted system the orbital mismatch is in the opposite direction (the p orbital at oxygen is smaller than that at carbon, and this size difference is excacerbated in the carbanion). Superimposed on these effects are possible lone pair effects (Cl, S, P).

H R R R H R S C S C O C O C

R H R R H R

σ bond is stronger in S-substituted carbanions because of better orbital size σ bond is weaker in O-substituted carbanion match (negative charge increases size of because of poorer orbital size match C-S orbital)

5. Lone Pair Effects For the first row elements N, O, F, and perhaps also for higher elements, the presence of lone pairs has a strong destabilizing effect on a directly bonded carbanion center. This has several effects on carbanion structure: there are substantial rotational barriers around the C-X bond and the carbanion center is usually more pyramidalized. Gas Phase Acidities

(kcal/mol) δΔH°acid (kcal/mol) 10 ΔH°acid

(420.1)2 CH3-CH3 2 420 Me2CH2 (419.4) 1 CH4 (416.6) 0 2 Me 3CH (413.1) H (408)7 410 3 H FCH3 (409) 7 H2C=CH2 (407) -10 3 CH3OCH3 (407) 7 PhCH2CH2-H (406)

4 1 Ph-H (400.7) 400 H2 (400.4) 1 NH3 (399.6) 3 ClCH3 (395.6) -20

3 MeSCH3 (393.2) 3 7 CH2C(O)-H (387) 1 Me3SiCH3 (390.9) 7 390 HO-H (390.8) F2CH2 (389) 1 H2C=CH-CH3 (387.2) H -30 3 (386.9)4 Me2PCH3 (384) 2 1 F Me3Si-H (383) PhCH3 (379.0) 380 2 3 MeO-H (380.6) F3CH (377) -40 HOO-H (376.5)6 1 HC≡C-H (375.4) 1 MeOO-H (374.6)6 CH3SOCH3 (372.7) 2 3 SiH4 (372.8) 7 Cl2CH2 (374.1) F-H (371.5)1 N≡CCH3 (369) 3 (Me3Si)2CH2 (373) 370 1 1 PH3 (370.4) CH3COCH3 (368.8) 1 3 1 CH3SO2CH3 (366.6) (Me2P)2CH2 (370) -50 PhNH2 (367.1) 1 H 1 Ph2CH2 (364.5) 2 PhCOCH3 (363.2) Me3Ge-H (361.5) (Ph)3C-H N 1 5 1 2 O2NCH3 (358.7) (CH2=CH)2 CH2 (359.7) 360 (360.7) GeH4 (359)

3 Cl3C-H (356.7) -60 (356.1)1 MeS-H (356.9)2 NC-H (353.1)1 PhO-H (351.4)1 350 HS-H (351.2)2 5 Me Sn-H (349)2 CF3COCH3 (347.1) (348.5)5 -70 3

5 EtCO2H (345.2)

5 1 (CH3CO)2CH2 (342.6) 340 PhS-H (338.9) 1 5 HSe-H (338.7) PhCO2H (337.7) -80 5 FCH2CO2H (335.6) 5 ClCH2CO2H (333.6) Cl-H (333.3)1 5 (N≡C)2CH2 (331.7) 330 5 F2CHCO2H (328.4) -90 Br-H (323.6)1 1. Bartmess J. Am. Chem. Soc. 1979, 101, 6046 2. Braumann, J. Am. Chem. Soc. 1995, 117, 4905 320 3. Braumann J. Am. Chem. Soc. 1998, 120, 2919 -100 4. Tetrahedron Lett. 1997, 0, 8519 1 5. Kebarle J. Am. Chem. Soc. 1976, 98, 3399 (add 3-4?) I-H (314.3) 6. Ellison 7. Squires J. Am. Chem. Soc. 1990, 112, 2517 310 Li Reagents by Metalation

Metalations by Organolithium Compounds, Mallan, J. M.; Bebb, R. L. Chem. Rev. 1969, 69, 693. Allylic and Benzylic Carbanions Substituted by Heteroatoms, Biellmann, J. F.; Ducep, J. -B. Org. React . 1982, 27, 1. Polar Allyl Type Organometallics as Key Intermediates in Regio- and Stereocontrolled Reactions: Conformational Mobilities and Preferences, Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49, 10175. Silylallyl Anions in Organic Synthesis: A Study in Regio- and Stereoselectivity, Chan, T.H.; Wang, D. Chem. Rev. 1995, 95, 1279-92. Delocalized Carbanions in Synthesis, Barry, C. E. III, Bates, R. B.; Beavers, W. A.; Camou, F. A.; Gordon, B. III; Hsu, H. F. J.; Mills, N. S. Synlett 1991, 207. Regioselectivity of the Reactions of Heteroatom-Stabilized Allyl Anions with Electrophiles, Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99, 665-722. Heteroatom-Faciliated Lithiations, H. W. Gschwend and H. R. Rodriguez Org. React. 1979, 26, 1. Lateral Lithiation Reactions Promoted by Heteroatomic Substituents, Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1-314. α-Heteroatom Substituted 1-Alkenyllithium Reagents: Carbanions and Carbenoids for C-C Bond Formation, Braun, M. Angew. Chem. Int. Ed. Engl. 1998, 37, 430-51. Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for α-Deprotonation and Stereocontrol, Kessar, S.V.; Singh, P. Chem. Rev. 1997, 97, 721-38. Dipole Stabilized Carbanions, P. Beak Chem. Rev. 1978, 78, 275. Stereo and Regiocontrol by Complex Induced Proximity Effects-Organolithium Compounds, P. Beak, A. I. Meyers Acc. Chem. Res. 1986, 356.

Organolithium Reagents Usually Prepared by Metalation R O N O O O O O NC Li Li Li Li S Li S Li (EtO)2P Li LiO R2N Ph Ph

Li Li R Li O Li PhS Li SPh R Li OR R' H

O OtBu Li OCH3 CH2NMe2 CONR2 N Li Li Li N N Li S O Li Li

Li PhSe PhS RO PhS OMe PhS Li S S Li Li Li Li Li Li Selected Metalation Agents A variety of metalation agents are used to deprotonate C-H acidic compounds. For materials with pK values above ca 37 only alkyllithium reagents are effective. For more acidic protons these may also work, but various lithium amides i (especially LiN Pr2) are often faster and give cleaner products. Organolithium Reagents

n-BuLi n-Butyllithium in solvents like ether or THF, sometimes with activating cosolvents like TMEDA, PMDTA, or HMPA is by far the most extensively utilized metalation agent. Alkyllithiums fail to metalate most carbonyl compounds because of competing addition to the carbonyl group, and some heteroatom substituted compounds of the 3rd, 4th and 5th period (e.g, I, Se, Te, Sn) where attack at the heteroatom can interfere (Li/I, Li/Se, Li/Te, Li/Sn exchange). n-BuLi/KO tBu This combination, sometimes referred to as the Schlosser-Lochmann base or LIKOR base, is perhaps the most powerful metalating combination available. The active reagent is believed to be a complex of butylpotassium. Some electrophiles are incompatible with the metalating agent, and conversion of the organometallic to an intermediate Sn compound may be required, for subsequent Li/Sn exchange to prepare the lithium reagent under milder conditions.

s-BuLi sec-Butyllithium is usually more active than n-BuLi and sometimes will successfully perform metalations not possible with the other alkyllithiums. t-BuLi tert-Butyllithium . A more aggressive base than either n-BuLi or s-BuLi, t-BuLi can perform metalations not possible with these. It is more dangerous to handle (e.g., its solutions inflame spontaneously in air) and more expensive. Steric effects may be a problem, but can also result in different selectivity.

Mesityllithium. A special purpose hindered organolithium base with very low propensity to add to Li carbonyl compounds. Used for deprotonations of relatively acidic compunds (pKa < 40) where the presence of amines (if lithium amides would normally be used) is deleterious, where exceptional steric selectivity is desired, or where carbonyl addition or reduction is a problem with alkyllithium bases.

Lithium Amides

Lithium diisopropylamide (LDA, pKa 36). Prepared by reaction of nBuLi with HNiPr2. This is the cheapest and most convenient base for deprotonations of compounds whose pKa is less than 36, including N Li all carbonyl compounds, alkyl sulfoxides, sulfones, and some aromatic compounds. Hindered and certain heterosubstituted ketones are sometimes reduced. [1] In this case use LiTMP or LiN(SiMe 3)2. The amine is volatile and can be removed even from enolate solutions by distillation. LDA can be prepared from Li .

[4] Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP, pK a 37). This is the most potent and least nucleophilic of the amide bases. It is kinetically faster than LDA, and will smoothly do many deprotonations not possible N Li with LDA. Interference by the amine (e.g. in acylations) is minimal because of high steric hindrance. Disadvantage: the amine precursor is expensive. CAUTION: The reaction between n-BuLi and the amine is slow at -78 °C and is best done at 0°C. [5]

[2] Si Lithium Bis(trimethylsilyl)amide (aka Hexamethyldisilazide) (LiN(SiMe3 )2, LiHMDS). A considerably weaker (pKa ca 30) base than the dialkylamides above. Used where a delicate touch is needed (e.g. for N Li [3] enolate alkylation when halide is part of the molecule ) and where hydride reduction occurs with LNiPr2. Si LiN(SiMe3 )2 will give the thermodynamic enolate under appropriate conditions. Several more hindered analogs (such as (PhMe2 Si)2NLi) have found some uses in stereoselective deprotonations

1. a) C. Kowalski, S. Creary, A. J. Rollin and M. C. Burke J. Org. Chem. 1978, 43, 2602. (b) M. T. Reetz Ann. N 1980, 1471. 2. (a) M. W. Rathke J. Am. Chem. Soc. 1970, 92, 3222. (b) "Structure of Lithium Hexamethyldisilazide (LiHMDS): Spectroscopic Study of Ethereal Solvation in the Slow-Exchange Limit," Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 6009-6010. 3. S. Danishefsky, K. Vaughan, R. C. Gadwood, K. Tsuzuki J. Am. Chem. Soc. 1980, 102, 4262; 1981, 103, 4136. 4. M. W. Rathke and R. Kow J. Am. Chem. Soc. 1972, 94, 6854. R. A. Olofson and C. M. Dougherty J. Am. Chem. Soc. 1973, 95, 582. 5. I. E. Kopka, Z. A. Fataftah, M. W. Rathke J. Org. Chem. 1987, 52, 448. DMSO pKa H2O

10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0 32.0 34.0 36.0 38.0 40.0 42.0 44.0 46.0 48.0 50.0 52.0 54.0 56.0 0.0 2.0 4.0 6.0 8.0 H NH NaOAc Na NEt DBU/DBN NaOH NaOMe KO- LiN(SiMe Ph NaNH KH LiN( PhLi MeLi (pKa 2 O 3 2

2 CLi CO 3 (?) Acidity t Ph i -Pr) -Bu

2 of

3 NaOPh 2

Conjugate 3 n Bases

) -BuLi, NaCH 2 N Pyridine

of Li

Conjugate 2

t -BuLi -S-CH N O LiTMP

Acid) DBU N N 3

pKa

Bases 32.0 34.0 36.0 38.0 40.0 42.0 44.0 46.0 48.0 50.0 52.0 54.0 56.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0 0.0 2.0 4.0 6.0 8.0

and RO CH HCPh CH CH CH CH H-S-Ph H-C CH CH CH

Substrates

O O 2 3 2 4 2 3 3 3 O ≡ (SPh) Ph =CH (NO -CO C -SO

C-Ph

≡ 3 N Substrates 2 2 2 O 2 Ph ) Et O 2 2

(pKa) OR CH H-S-CH CH -P Ph 3 2

(C NO + 3 ≡ CH 2 N) 3

2 3 H-O-Ph H-C

≡ N OH Chem Reich

547 Metalated Sulfones Sultone Chemistry D. W. Roberts, D. L. Williams, Tetrahedron 1987, 43, 1027. The Chemistry of Vinyl Sulfones, Simpkins, N. S. Tetrahedron 1990, 46, 6951. The Use of Sulfonyl 1,3-Dienes in Organic Synthesis, Baeckvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 1998, 98, 2291-312. Recent Progress on Rearrangements of Sulfones, Braverman, S.; Cherkinsky, M.; Raj, P. 1999, 22, 49-84. Desulfonylation Reactions: Recent Developments, Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547-658. The Chemistry of Acetylenic and Allenic Sulfones. Back, T. G. Tetrahedron 2001, 57, 5263-301. Stereoselective and Enantioselective Synthesis of Five-Membered Rings via Conjugate Additions of Allylsulfone Carbanions, Hassner, A.; Ghera, E.; Yechezkel, T.; Kleiman, V.; Balasubramanian, T.; Ostercamp, D. Pure. Appl. Chem. 2000, 72, 1671-83.

Preparation. Sulfones are easily prepared by a variety of synthetic procedures: Oxidation of sulfides and sulfoxides Nucleophilic substitution of halides and tosylates by sodium arenesulfinate Conjugate addition of sodium arenesulfinate to α,β-unsaturated carbonyl compounds Alkylation of lithiosulfones Conjugate addition to vinyl and alkynyl sulfones

Cycloaddition of SO2 to dienes

R PhSM R Ph Ph S S 1. base O O PhSM 2. RCH2X Ox SO2 O R S PhSO2M X R Ph O S Ph O O Li S RM BuLi R Ph or O O i S LiN Pr2 O O

Metalation . All types of sulfones (1°, 2°, 3°, allyl, vinyl) which have σ-hydrogens metalate easily with n-BuLi or LiN iPr2, and the anions show good nucleophilicity. Commonly used electrophiles are alkyl halides and tosylates, epoxides, aldehydes, ketones and esters.

Subsequent Transformations. The products of reaction of metalated sulfones with electrophiles can be used in various ways: Reductive elimination of β-oxy and β-halo sulfones (Julia olefination) Oxidation of β-oxy sulfones to β-keto sulfones and desulfonylation to ketones Reductive desulfonylation with Al/Hg Metalation/oxidation to form ketones If cleavage of the C-S bond gives a stabilized cation, some sulfones can behave as C-electrophiles β-Elimination to give olefins if β-hydrogens are acidic Metalated Sulfone Reactions H R' HO R'

R H R [red] 1. Ac2O Julia [Alkyl anion] 2. Na/Hg Li HO R' O R' O R' [oxid] [red] R Ph R'CHO S R Ph R Ph R S S O O O O O O Heathcock JOC 95-1120 R'X 1. Ac2O 2. base R' R' R' R' [base] R Ph R S R Ph [red] S O O [Alkyl anion] R O O 1. [base] Julia II BuLi; CH2I2, [Alkynyl anion] iPrMgCl 2. [oxid] Otera JACS 84-3670 R' R' R R O [Acyl anion]

Synthetic Uses of Lithiosulfones - Coupling by alkylation of sulfones Coupling using a-Lithio-sulfone Alkylation - alkyl sulfones can be reductively cleaved: Synthesis of Aplyronines: Yamada, et al. J. Org. Chem. 1996, 61, 5326

TBSO OTES OPiv TBSO OTES OPiv I 1. THF/HMPA

+ OBn 2. Na/Hg MeO PhS Li O 2 OBn MeO

Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675

OTBS OTBS OTBS

OBn OBn OBn MeO MeO TBSO MeO TBSO TBSO O O O H H H O O BuLi; CH2I2, iPrMgCl O H H H OBn BuLi, HMPA OBn OBn I OTBS OTBS OTBS PhSO2

O PhSO2 OTBS 1. PhSO2CH2Li OTBS OPMB THF, HMPA OTBS OPMB OPMB Spongistatin 1 2. TBSOTf OPMB Synthetic Uses of Lithiosulfones - The Julia Olefin Synthesis Coupling using Julia Olefination . The original Julia reaction involved a reductive elimination of a β-acetoxy sulfone, formed by addition of a metalated sulfone to an aldehyde or ketone.

PhSO2 PhSO2 H PhSO2 Ac2O Na / Hg + O Li OH OAc

Synthesis of Aplyronine: Yamada, et al. J. Org. Chem. 1996, 61, 5326 OMe

TBSO OR' OPiv PhSO2 OTES OTES OR O 1. Rx LIN + Li 2. Ac2O, DMAP 3. OMe Na/Hg, HaHPO 4 H MeO TBSO OR' OPiv O OMe

R = CH2OCH2-C6H3(OMe)2-3,4 OMe OTES OTES OR O

R' = CH2OCH2-C6H4OMe-4 MeO

Aplyronines O OMe Aplyronine A HO O O

NMe2 O

OMe O OH O OAc Me NMe2 N MeO CHO Acyl Anions A Compilation of References on Formyl and Acyl Anion Synthons, Hase,T.A.; Koskimies, J.K. Aldrichim. Acta 1981, 14, 73; 1982, 15, 35. New Formyl Anion and Cation Equivalents, Dondoni, A.; Colombo, L. Adv. Use of Synthons in Org. Chem. Vol. 1 , Jai Press, 1993. Acylvinyl and Vinylogous Synthons. Chinchilla, R.; Najera, C. Chem. Rev. 2000, 100, 1891-928. The acyl anion equivalents most widely used are:

O O CN O O = S S R Li Li Li R Li Metalated Dithianes: Protected Cyanohydrins Metalated Enol Ethers Seebach, JOC 75-231 Stork, JACS 74-5272 Baldwin, JACS 74-7125

Metalated Dithianes: Synthetic Uses of the 1,3-Dithiane Grouping from 1977-1988, P. C. B. Page, M. B. van Niel, J. C. Prodger Tetrahedron 1989, 45, 7643. Ketene Dithioacetals in Organic Synthesis: Recent Developments, M. Kolb Synthesis 1990, 171. Synthesis of Heterocycles from Ketene Dithioacetals, Yokoyama, M.; Togo, H.; Kondo, S. Sulfur Reports, 1990, 10, 23. New Synthetic Applications of the Dithioacetal Functionality, Luh, T.Y. Acc. Chem. Res. 1991, 24, 257. The Development and Application of 1,3-Dithiane 1-Oxide Derivatives as Chiral Auxiliaries and Asymmetric Building Blocks for Organic Synthesis. A Review, Allin, S. M.; Page, P. C. B. Org. Prep. Proc. Int. 1998, 30, 145-76. The Role of 1,3-Dithianes in Natural Product Synthesis, Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-212. Evolution of Dithiane-Based Strategies for the Construction of Architecturally Complex Natural Products, Smith, A. B. III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365. Metalation of Cyanohydrins: Reactions of Acyl Anion Equivalent Derived from Cyanohydrins, Protected Cyanohydrins, and α-Dialkylamino Nitriles, Albright, J.O. Tetrahedron 1983, 39, 3207. Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications, Gregory, R. J. H. Chem. Rev. 1999, 99, 3649-82.

Metalated Vinyl Ethers Generation and Reactivity of α-Metalated Vinyl Ethers. Friesen, R. W. JCS Perk. I 2001, 1969-2001. Metalated Dithianes

Hispidospermidine: Frontier, A. J.; Raghavan, S.; Danishevsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151. 00-14

SiMe3 S S S S O SiMe3 O H 1, nBuLi L CAN, acetone NaOH H H 2. SiMe3 H S S S S Br O [Dithiane alkylation]

Monicillin I : Garbachio, R. M.; Stachel, S. J.; Baeschln, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903 01-19 O O O O O O O O O

HO HO HO Cl L S S S O

S α/γ 6/1 OTBDMS Li OTBDMS OH Monocillin 1

Silyl Dithiane as a Lynchpin Spongistatin: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675

1. tBuLi n-BuLi; TBS-Cl TBSO TBSO S S OH O Spongistatin 1 S S 2. OTBS O S S O BnO BnO t BuMe2Si 3. O O O HMPA S S HMPA S S Li tBuMe2Si

LiO R tBuMe2SiO R

Mycoticin A: Smith, A. B. et al Org. Lett. 1999, 1, 2001.

O 1. BnO TBSO OH OH OTBS N S S O O S S S S Mycoticin A 2. BnO OBn t BuMe2Si Li HMPA 59% Roflamycoin: Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058 97-07 L BnO O O BnO OH BnO O Bn 1. Li O O O BuLi, DMPU OH S S S S Br 2. Li O O S S S O SnBu S 3 O SnBu3 SnBu3 O Roflamycoin Br Br

Recutive desulfurization of Dithiane Okinellin B : Schmitz, W. D.; Messerschmidt, N. B. J. Org. Chem. 1998, 63, 2058.

t-BuLi S S S S O S S I OBn OBn OBn H O Br W-2 Raney LIN Li Nickel

O OBn O O O

Okinellin B OH Metalation α to Nitrogen Ste Metalation and Electrophilic Substitution of Amine Derivatives Adjacent to Nitrogen: α-Metallo Amine Synthetic G Equivalents, P. Beak, W. J. Zadjel, D. B. Reitz Chem. Rev. 1984, 84, 471. New Metalation and Synthetic Applications of Isonitriles, Ito, Y. Pure & Appl. Chem. 1990, 62, 583. Metalation of Isocyanides, Ito, Y. Synlett 1990, 245. Generation and Reactions of sp2 -Carbanionic Centers in the Vicinity of Heterocyclic Nitrogen Atoms, Rewcatle, G. W.; Katritzky, A. R. Adv. Heterocyclic Chem. 1993, 56, 157. Benzotriazole-stabilized Carbanions: Generation, Reactivity, and Synthetic Utility, Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichimica Acta, 1994, 27, 31-8. The Generation and Reactions of Non-Stabilized α-Aminocarbanions, Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54, 2647-68. Amide Metalations Li O tBu O N Ph N O N-nitroso compounds can tBuO N H N Li Li also be metalated

Beak JOC 93-1109 Meyers TL 84-939 Gawley JOC 89-3002 sBuLi, TMEDA tBuLi, THF nBuLi, THF ether R Synthesis of Solenopsin: Reding, Buchwald J. Org. Chem. 1998, 63, 6344. H tBuO N Li 1. s-BuLi, TMEDA TFA O N C11H23 2. Me 2SO4 Me N C11H23 Me N C11H23 H O OtBu O O tBu R Solenopsin N Li tBuO O

Chiral Organolithium Reagents - Asymmetric Metalation. Hoppe, Hintze, Tebben Angew. Chem. Int Ed. 1990, 29, 1422, 1424.

O O Li CO2H CO sBuLi, Sparteine 2 O N O R O N O R HO R 5h, -78 °C >95% ee

The carbamate group is strongly activating - good coordination to Li The organolithium reagents are configurationally stable at -78 °C Derivatizations occur with retention of configuration, unless R = Ph. Kerrick, Beak J. Am. Chem. Soc. 1991, 113, 9708. H H sBuLi, Sparteine N Li CH3I N N N CH3 Et 2O, -78 °C N O O tBu O O tBu O O tBu H H 76% yield, 95%ee Sparteine This is an asymmetric deprotonation. Aromatic ortho Metalations Directed Lithiation of Aromatic Tertiary Amides: An Evolving Synthetic Methodology for Polysubstituted Aromatics, P. Beak and V. Snieckus Acc. Chem. Res. 1982, 15, 306. Heteroatom Directed Aromatic Lithiation, N. S. Narasimhan, R. S. Mali Top. Curr. Chem. 1987, 138, 63. The Directed Ortho Metalation Reaction. Methodology, Applications, Synthetic Links, and a Non-aromatic Ramification, V. Snieckus, Pure Appl. Chem. 1990, 62, 2047. Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics, Snieckus, V. Chem. Rev. 1990, 90, 879. Combined Directed Ortho Metalation-Cross Coupling Stategies. Design for Natural Product Synthesis, Snieckus, V. Pure App. Chem. 1994, 66, 2155-8. Chelation Control in Metalation Reactions Slocum, D. W.; Jennings, C. A. J. Org. Chem., 1976, 41, 3653.

N N N

Li n-BuLi n-BuLi Et2O TMEDA Et2O Li

OCH3 OCH3 OCH3

ortho-Metalation of Aromatic Amides - Synthesis of ERYTHROLACCIN Mills, R. J.; Snieckus, V. Tetrahedron Lett. 1984, 25, 479, 483. 84-2

NEt2 NEt2 Me NEt2

O 1. s-BuLi, TMEDA O 1. n-BuLi O

2. Me3SiCl 2. MeI MeO MeO SiMe3 MeO SiMe3 OMe OMe OMe

CsF Br2 RCHO

Me OMe Me OMe Me NEt2 O O 1. Zn, NaOH 1. n-BuLi O 2. TFAA O 2. OMe MeO OMe 3. CrO3 MeO OMe MeO Br

OMe O OMe H C OMe OMe O ERYTHROLACCIN Note the use of N,N-diethyl amide, N,N-dimethyl amide is too reactive

Cl Ortho-Metalation Directed by α-Amino Alkoxide Comins D. L.; Brown, J. D. J. Org. Chem., 1984, 49, 1078. (CHO) N O H O- N O H Li N D. L. Comins N TL., 1989, 30, 4337. 1. Li N Li CH3 1. CH3I Li Cl 2. n-BuLi, -78°C Cl 2. H2O Cl MeO N (CHO) JOC, 1990, 55, 69 Ortho Metalation of Heterocycles

Heteroatom Directed Aromatic Lithiation. Reactions for the Synthesis of Condensed Heterocyclic Compounds, N.S. Narasimhan, R.S. Mali, Top, Curr. Chem. 1987, 138, 63. Directed ortho-Metalation of Pyridines, Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, L. Adv. Heterocycl. Chem. 1991, 52, 187. Metalation and Metal-Assisted Bond Formation in π-Electron Deficient Heterocycles, Undheim, K.; Benneche, T. Act. Chem. Scand. 1993, 47, 102. Syntheses of Heterocyclic Compounds Involving Aromatic Lithiation Reactions in the Key Step, Narasimhan,N. S.; Mali, R. S. Synthesis 1983, 957. Synthesis and reactions of lithiated Isoxazoles, Iddon, B. Heterocycles 1994, 37, 1263. Synthesis and reactions of lithiated Oxazoles, Iddon, B. Heterocycles 1994 37, 1321. Synthesis and Reactions of Lithiated Pyrazoles, Grimmett, M. R.; Iddon, B. Heterocycles, 1994, 37, 2087. Synthesis and Reactions of Lithiated Imidazoles, Iddon, B.; Ngochindo, R. I. Heterocycles, 1994, 38, 2487. Synthesis and Reactions of Lithiated Isothiazoles and Thiazoles, Iddon, B. Heterocycles 1995, 41, 533. Metalation of Diazines, Turck, A.; Plé, N.; Quéguiner, G. Heterocycles, 1994, 37, 2149. Synthesis and Reactions of Lithiated Triazoles, Tetrazoles, Oxadiazoles, and Thiadiazoles, Grimmett, M. R.; Iddon, B. Heterocycles, 1995, 41, 1525-74. The Directed Ortho Metalation Cross-Coupling Symbiosis in Heteroaromatic Synthesis, Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999, 36, 1453-68. Synthesis of Substituted Quinazolin-4(3H)-ones and Quinazolines via Directed Lithiation. El-Hiti, G. A. Heterocycles 2000, 53, 1839-68. Metallation of Pyridines, Quinolines and Carbolines. Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059-90. Metalation of Pyrimidines, Pyrazines, Pyridazines and Benzodiazines. Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489-505.

Metalation of Pyridines - Synthesis of Camptothecin Comins, Baevsky, Hong J. Am. Chem. Soc. 1992, 114, 10971; Fand, Xie, Lowery J. Org. Chem. 1994, 59, 6142; Curran, Ko, Josien Angew. Chem., Int. Ed. Engl. 1995, 34, 2683. O OMe 1. tBuLi O OMe O N O 2. Me2N N H C D E N N H B O 3. n-BuLi Me Si Me3Si I A N Et OH 3 4. I2 49% Camptothecin

O MeO MeO MeO N Li 2. Me2N N H NMe N 1. tBuLi N N OLi 3. n-BuLi

Me3Si Me3Si Me3Si

OMe O MeO N MeO N N H NMe NMe H2O N OLi 4. I2 N OLi

Me3Si I Me Si Li Me Si I 3 3 49%

1. LDA Br OH PBr3

2. CH2O N Cl N Cl N Br The Polyfluorovinyl Nucleophilic Preparation Selenium-Stabilized Selenium The Synthetic Aromatic The 83). to The row A BuLi

Uno, Barluenga, Ponthieux, H. Bailey, A. Parham,

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Am.

J. CH ,

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+ The Li/I Exchange Pro Con Fastest of all Li/M exchanges Products are reactive alkylating Works with primary iodide agents Expensive, usually have to Exchange can be made irreversible (t-BuLi) prepare Usually fails with 2° or 3° Often tBuLi is best transmetalating reagent halides

Synthesis of Bafilomycin: K. Toshima Tetrahedron Lett. 1996, 37, 1069. OMe OMe OMe

n-BuLi Bu3SnCl I Li Bu3Sn O O O O O O

The Li/I exchange is several orders of magnitude faster than the Li/Br exchange, and so ist much less susceptible to side reactions. Selective reactions to be performed (Evans J. Am. Chem. Soc. 2000, 122, 10035). I Li t 2 BuLi, Et2O >20/1 selectivity in -105 °C Br Br favor of Li/I exchange OMe OMe Primary allkyl iodides usually work, but primary bromides rarely do. McGarvey J. Org. Chem. 1995, 60, 778. 1. 2 tBuLi OH

O t 2. BuLi with RBr or RI is BnO O O I essentially irreversible - H BnO O O O O tBuX is destroyed by O O excess tBuLi Several coupling methods were tried, including Li-sulfone and Li-dithiane. This one worked best.

The Li/Br Exchange Pro Con Cheapest Fairly slow Often commercially available Side reactions such as α- and β- Stable enough to survive metalation Products may be reactive reactions Best for vinyl and aryl alkylating agents Doesn't work with most bromides alkyl bromides The Li/Br exchange is slow enough that side reactions such as α- and β-metalation can compete (Meyers, J. Org. Chem. 1985, 50, 4872). This is generally not a problem with the Li/I, Li/Sn and Li/Te exchanges.

Br OEt Li OEt Br OEt n-BuLi 1. PhCHO 1. MeI 2. tBuLi THF OEt + Li OEt 2. H Ph O OEt Li/H Li/Br Ph OLi

Amide bases such as LDA or LiTMP are poor transmetalating reagents, and will often perform deprotonations even when a halide is present (Schlosser Helv. Chim. Acta 1977, 60, 2085). In both cases below, the Li/Br exchange is fast enough that BuLi does not perform a Li/H exchange to make the more stable lithium reagent. Br Br Li

LiN(iPr)2 n-BuLi Li O O O Takano Tetrahedron Lett. 1985, 26, 1659

S S S O O O S LiN(iPr)2 S n-BuLi S Li O O Br O Br Li The Li/Sn Exchange Pro Con Modestly stable compounds Neurotoxins Reasonable methods for preparation Expensive - must prepare Not a leaving group - can have in β- Contamination of products with position Not much likelihood of α and β- R4Sn Cannot be made irreversible metalation Especially widely used for Sensitive to steric effects vinyllithiums R4Sn compounds relatively inert NMR active nucleus D. Seyferth, S. C. Vick, J.Organomet. Chem. 1978, 144, 1. This reagent is the synthetic n-BuLi " Li " equivalent of Li Bu3Sn Bu3Sn SnBu3 Li 1,2-dilithioethylene. α-Aminoalkyllithium reagents cannot usually be prepared by the metal-halogen exchange, and the Li/Sn exchange is the best method. D. J. Peterson, J. Am. Chem. Soc. 1971, 93, 4027. Ph Ph n-BuLi 2 3 2-Li N-CH -SnBu o N-CH Me 0 C Me α-Alkoxy lithium reagents are also very commonly prepared by Li/Sn exchange. The α-alkoxy tin compounds are easily prepared by reaction of R3SnLi with aldehydes or ketones, or with α-haloethers. N. Meyer, D. Seebach, Chem. Ber. 1980, 113, 1290. OH 2n-BuLi PhCHO Bu3Sn-CH2-OH Li-CH2-OLi Ph hexane OH

The Li/Se Exchange Pro Con Easy to prepare Not commercially available Special purpose - α-lithioSe, S Too slow for general aplication Toxic

Tetrahedron Lett. 1987, 28, 1337. J. Lucchetti, A. Krief, Tetrahedron Lett. 1981, 22, 1623. SeMe SeMe

SeMe

TBSO TBSO n-BuLi

H H Br TBSO TBSO

The Li/Te Exchange Pro Con Very fast Difficult to prepare Perhaps most general of all Not commercially available metalloids Even secondary systems Somewhat air and light work sensitive Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am. Chem. Soc. 1992, 114, 11003-11004. TePh Li H H s-BuLi, -78° s-BuLi, -78° Ph Ph Ph Ph H H Li TePh Ph Ph Ph Ph Me Me2S2 2S2 SMe H Ph Ph H SMe Ph Ph Functionalized Organolithium Reagents Prepared by Li/M Exchange M. P. Cooke, Jr. J. Org Chem. 1993, 58, 2910; 1984, 49, 1144. O I O

MeO MeO n-BuLi -78°C 95% I H Flann, Overman J. Am. Chem. Soc. 1987, 109, 6115. O Br CO2Et s-BuLi OH OMe THF, -78°C N N OMe H H N EtO C OMe H OMe O 2 EtO2C O Streptazolin Taxol Synthesis: G. Stork et al J. Am. Chem. Soc. 1998, 120, 1337

O TBSO BuLi, -100 °C Me Sn Li H TBSO 3 TBSO O OH O O O O O TBSO Taxol (partial)

In situ Trapping of an Isocyanate B. M. Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117, 10143 (Pancristitatin synthesis) OTES OTES TESO TESO O O Use of 2 equiv. of t-BuLi in the metal-halogen exchange results in O t O O O 2 BuLi, Et2O, an essentially irreversible process N -78 °C N (t-BuLi + t-BuBr → t-BuH + O O H Br C Me2C=CH2) O MeO MeO O

In Situ trapping of ArLi Reagents - Mesityllithium as Transmetallating agent Kondo Org. Lett. 2001, 3, 13 O

I O Li HO O

O O N OMe N OMe Chem 547 Reich The Bamford-Stevens and Shapiro Reactions Lithioalkenes from Arylsulphonylhydrazones, Chamberlin, A. R.; Bloom, S. H. Org. React . 1990, 39, 1. Recent Applications of the Shapiro Reaction, A. G. M. Barrett, Acc. Chem. Res. 1983, 16, 55. Na H N NaH N Ar Δ Carbene N Ar N S N + : N S products Bamford-Stevens -ArSO2Na O O O O -N2

2 BuLi Li Li + H Shapiro Li N Ar Δ N Li [H ] N S N O O

Vinyllithium Reagents from Tosylhydrazones Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. JOC, 1979, 43, 147. This is a modification of the Shapiro olefin synthesis to allow efficient trapping of the organolithium intermediates. Tosylhydrazones and their decomposition products (p-toluenesulfinates) can behave as proton sources. The solution is to use 2,4,6-triisopropylphenylsulfonylhydrazones (trisyl hydrazones). H Li Li LiO Ar N 2 n-BuLi Li N Δ S N S N S + + N2 O O O O O Stable at -65 °C O Li O Li

C6H13 C6H13

O Li Li O Li +

9:1

Vinyllithium Reagents from Tosylhydrazones Barrett, A. G. M.; Adlington, R. M. Chem. Comm., 1979, 1122; Acc. Chem. Res. 1983, 16, 55 Li 1. n-BuLi, -3 C Li N ° Δ O 2. CO2 N SO2Ar + 550° OLi 3. H3O O -65 °C N SO2Ar O N O 61% O 83% Li

LiO Li Martin, S. F. J. Org. Chem., 1992, 57, 2523.

NHSO2Ar N OTBS 1. 2 n-BuLi Ar = 2. OTBS H OH

O "Softer" Organometallic Reagents

Pros and cons of Using non-Alkali Metal Organometallic Reagents Advantages Disadvantages Prepare and use functionalized reagents Usually much more expensive (R-Li → R-M) Less basic reaction conditions Some elements are quite toxic, disposal problems Wider range of solvents may be used (even protic) Separation from the M-debris can be problematic Presence of β-leaving groups may be tolerated Usually much less reactive than RLi or RMgX Better stereochemical and regiochemical control Narrower range of R groups are nucleophilic Different reactivity patterns

Chiral reagents easier to work with Compatibilty with electrophilic catalysts In situ reactions (Barbier processes) Wider range of synthetic methods to prepare R-M

Some Things We Would Like to be Able to do with Carbon Nucleophiles 1. Functionalized Reagents: E O O M M ( ) n M M X Intramolecular β-Leaving Acyl Anion Homoenolate groups 2. Control Allylic and Propargylic Regioselectivity in Donor and Acceptor. E + E - or + M E R O R O R -M + OH or

3. Control Diastereoselectivity in Donor and Acceptor. OH R O R -M + R or OH O OH OH + M R H R or R

4. Control Enantioselectivity in Donor and Acceptor.

O HO R NR RHN R R -M + R OH R -M + R NHR or or Ph Ph Ph Ph Ph Ph O HO HO M R + * R or R X X X 5. Control Side Reactions.

• Enolization vs. nucleophilic addition.

• Substitution vs. elimination. • Selectivity among functional groups. Chem Reic Boron in Organic Synthesis

Essential Chemical Properties of Organoboron Compounds

1. Lewis Acidic Oxophilic Metal. Many boron reagents provide for simultaneous activation of acceptor and donor portions of substrate, e.g., in conjugate addition reactions: OH O OH O O 1. PhSe B R H2O 2 R 2. RCHO PhSe

2. Boron hydrides can serve as both electrophilic and nucleophilic H- donor. Borohydrides have powerful nucleophilic properties, boranes are weak electrophiles. R R B H -B H R RR 3. Carbanion donor: Enol, allyl and propargyl boranes will transfer the group on boron to suitable electrophiles. Other types show little tendency to behave as carbanion sources.

O O B B B O B O O O 4. Transmetalation of organoboron compounds to organocopper and organopalladium (Suzuki coupling) provides a powerful method for C-C bond formation (Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457). OR' OR'

Br R2B C5H11 C5H11

Pd(PPh3)4 R'O R'O

5. Organic groups on anionic boron readily migrate to electrophilic sites on adjacent atoms:

R - R Y-X Y = O, N, S, C, etc. - B Y B R B Y X = leaving group X R - B R B Y+ Y

R R - + R E - B B B + + + + + E = H , PhSe , R3Sn , epoxide, carbonyl E E E Organoboron Reviews

Organoborates in New Synthetic Reactions, Suzuki, A. Acc. Chem. Res. 1982, 15, 178; Top. in Current Chem. 1983, 112. Carbon-Carbon Formation Involving Boron Reagents, A. Pelter Chem. Soc. Rev. 1982, 11, 191. Formation of Carbon-Carbon and Carbon-Heteroatom Bonds via Organoboranes and Organoborates, E.-I. Negishi, M. J. Idacavage Org. React. 1985, 33, 1. Organoboron Compounds in Organic Synthesis, R. M. Mikhailov, Harwood Academic, 1984. Reactions of Group 13 Alkyls with Dioxygen and Elemental Chalcogens: from Carelessness to Chemistry, Barron, A. R. Chem. Soc. Rev. 1993, 22, 93. Stereodirected Synthesis with Organoboranes, Trost, B.M. Ed., Springer: Berlin, Germany, 1995. Contemporary Boron Chemistry, Davidson, M.; Hughes, A. K.; Marder, T. B.; Wade, K. Royal Society of Chemistry: Cambridge, U.K., 2000. Rhodium- Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids and Their Derivatives to Electron Deficient Olefins. Hayashi, T. Synlett 2001, 879-87. "Organoboranes as a Source of Radicals." Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415-34.

Pure Enantiomers via Chiral Organoboranes, H. C. Brown, B. Singram Accounts Chem. Res. 1988, 21, 287. Boronic Esters in Stereodirected Synthesis, D. S. Matteson Tetrahedron 1989, 45, 1859. Recent Advances in Asymmetric Synthesis with Boronic Esters, Matteson, D. S. Pure & Appl. Chem. 1991, 63, 339. Stereodirected Synthesis with Organoboranes, D. S. Matteson, Springer, 1995. Asymmetric Syntheses via Chiral Organoboranes Based on α-Pinene, by Brown, H.C. Adv. in Asymm. Synth. Vol. 1, Hassner, A., Ed. JAI: Greenwich, CT, 1995. α-Halo Boronic Esters in Asymmetric Synthesis, Matteson, D. S. Tetrahedron 1998, 54, 10555-607. Vinyl Boranes: Synthetic Applications of Vinylic Organoboranes, H. C. Brown and J. B. Campbell, Jr. Aldrichim. Acta 1981, 14, 3. Haloboration of 1-Alkynes and Its Synthetic Application [Vinyl Boranes], Suzuki, A. Rev. Heteroatom Chem. 1997, 17, 271-314.

Recent Developments in the Chemistry of Amine- and Phosphine-Boranes, Carboni, B.; Monnier, L. Tetrahedron 1999, 55, 1197-248. Useful Synthetic Transformations Via Organoboranes. 1. Amination Reactions, Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1995, 132, 1003-8. Migration of Groups from Boron to Carbon - α Leaving Groups

R - R Y-X - Y = O, N, S, C, etc. B Y B R B Y X = leaving group R R X Oxidation of Boranes

R - R O-OH - R R B B O B O R R R R O R H Reaction with α-X Organolithium Reagents . Hoffman, Stiasny Tetrahedron Lett. 1995, 36, 4595. TBSO Br O TBSO Br TBSO Br B n-BuLi O B O - O Br Li -110 °C 3:1 dr

O - O TBSO OH + - TBSO B Me 3N-O

Serricornin - Boronic Ester Homologation Matteson, 98-04 D. S.; Singh, R. P. J. Org. Chem. 1998, 63, 4467

Cy Cl MgBr O LiCH2Cl O LiCHCl2 O Cy B B B Cy O Cy O ZnCl2 O B O O Cy Cy 1. LiCHCl2 Cy Cy 2. MeMgCl Cy O OH O O O 1. H2O2 B 1. LiCHCl2 B Cy O 2. OsO4, NaIO4 2. EtMgCl

Serricornin

Cl Cl Cy Cy O Me O Cy Cl O - Cl H H B B B Me O Me O Cy H O Cy Cy • The process is repeatable, adding one chiral center at a time. • The diastereoselectivity is very high. Allyl-Metal Species

Structure and Dynamics M M Structure Metals E / Z Isomerization rate

Ionic, contact or separated ion pairs: Li, Na, K Slow

M+

Covalent, but rapidly equilibrating: Mg, Al, Zn, Hg, B, Ti, Cr Fast M M ΔG = 10 - 25 kcal/mole

Covalent, slow equilibration: Sn, Ge, Si Slow

M M ΔG > 25 kcal/mole

Transition metal π-complexes Pd, Pt, Ni, Co, Mo Depends on rate of σ-allyl to π-allyl interconversion M M (L)n (L)n Allyl-Metal Species: Reactivity

The reactivity decreases as C M bond becomes more covalent. Lithium reagents are aggressive nucleophiles, react with weak electrophiles such as alkyl halides. Grignard reagents react well with carbonyl compounds. Allyl silanes react only with good electrophiles such as carbonium ions or halogens. Allylic rearrangement also causes cis-trans isomerization of double bonds. If covalently bound, the stable structure has the metal on the less-substituted side of the allyl system. For such systems, reactions usually occur at the site remote from the metal (S E2'). Lewis-Acidic metals (Mg, B) usually react by a cyclic "Zimmerman-Traxler" type of transition state. For extensive comparative studies of crotyl-M species see: Yamamoto, J. Orgmet Chem., 1985, 284, C45. Martin, J. Org. Chem., 1989, 54, 6129. Transition metal allyl π-complexes can show either nucleophilic or electrophilic reactivity, depending on the metal and ligands.

Some Uses of Allyl Adducts OH Functionalized OH sec-alkyl

1. H-BR'2 R 2. [O] R M OH OH H [O] Equivalent of aldol + O condensation

R [H2] R O OH Stereocontrol for net addition of sec-alkyl R Reactivity Reactions

log k Bartl, 10 11 Both Fleming, Me Me 1 2 3 4 5 6 7 8 9 3 3

Si Si starting Steenken.

I.; 10.3

6.1 6.6 7.7 8.3 8.8

of of

Langley,

allyl

π Allylsilanes -Nucleophiles

Mayr, Cl H RS

silanes EtOH SiMe SiMe H - Reactivity

J. 2

X J. O

- A.

Am.

2 2 in give

Ph Ph J.

acetonitrile SiCl OSiMe

OMe

Chem. with h Chem.

the ν towards 3

H with

same

+ Electrophiles 3

Soc. Soc. 6.3 6.8 7.6 8.3

Carbenium (MeC at

product

Perk. 1991 20 3

6 ° Si H + C

, Trans 4

113

) ratio. H 2 C + H ,

7710;

+ OEt OMe 1 ions OEt ,

SnBu 1981 SiMe SiMe SnPh

Mayr. SiMe 3 ,

3 3 3 26 SiMe

, 2 Kempf,

Ph 1421. 3

Ofial

Acc. Me

3 Chem. Si H O Bu SiMe SiMe

OSiMe OSiMe 1 4 SiMe

1 1 Res. 1 2.7 1 1

: 3

: : 7216

0.19

4.8

3 3 37 15 : 2

2003 Ph 1 ,

SiMe 36 OEt O SiMe ,

66 OEt 3 OMe 3 Allyl Silanes Aratani, M. Tetrahedron Lett., 1982, 23, 3921.

OCO2PNB OCO2PNB CO2 PNB Cl SiR3 CO2PNB N AgBF4 N O 69% O

CO2CH3 CH3O2C

G.Majetich, C.Ringold, Heterocycles, 1987, 25, 271.

SiMe3

EtAlCl2

94% O O O

PERFORENONE Overman, L. E. JACS, 1991, 113, 5378.

1. (Siamyl)2BH R2B 1. Me3SiCl 2. LiTMP 2. HOAc Li SiMe3

O H O H O O SiMe3 CHO BF3 OEt2 Cram O H O H OH 73% H H

Epoxide Cyclization of Allyl Silane - Phorbol Synthesis Pettersson, Frejd Chem. Commun. 1993, 1823.

O O Me3SiO O Me3SiO OH

BF3 OEt2 TBSO O TBSO O Phorbol

SiMe3 Akuammicine Synthesis by Propargylsilane Cyclization Bonjoch, Sole, Garcia-Rubio, Bosch J. Am. Chem. Soc. 1997, 119, 7230

N N SiMe3 N Ar 1. LDA; N≡CCO2Me BF3 OEt3

Ar 2. H2, Pd N O O Ar = o-NO2C6H4 H CO2Me Akuammicine

Synthesis of Steroids by Propargylsilane Cationic Cyclization Schmidt, 80-7 R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122.

SiMe3 SiMe3

EtO Li H 1. HCl, H EtO 1. NaNH2 2O EtO EtO Cl 2. Me3SiCH2Cl 2. CH=C(CH3)MgBr EtO EtO HO

SiMe3 O O CH3-C(OEt)3 H PPh3 EtCO2H, 130 °C SiMe3 SiMe3 [Claisen - Johnsom] 1. O O O O 1. LiAlH4

2. CrO 2. PhLi 3 EtO O H O [Wittig - trans] 1. HCl, H2O O O 2. NaOH SiMe3 O 3. MeLi

H H 1. O3; Zn CF3CO2H H H 2. NaOH H H O 58% OH 4-Androstene-3,17-dione

SiMe3 SiMe3 + Efficient termination of cationic cyclization

+ Stereochemistry of Allyl-M Carbonyl Reactions

SnBu3 H Y. Yamamoto, JOMC 1985, 284, C45 Me Martin, JOC, 1989, 54, 6129 B O R H Me R H Roush, JOC, 1990, 55, 4109. H Keck, JOC, 1994, 59, 7889. O Cyclic - Metal is coordinated to carbonyl group.Acyclic - Metal is not coordinated to carbonyl group. Configuration of product is determined by Configuration of product is more or less independent of configuration of double bond. Reaction is double bond configuration. Reaction may be highly Stereospecific. Stereoselective.

Stereochemistry of Crotyl Stannane Addition to Aldehydes Yamamoto, Yatagai, Naruta, Maruyama J. Am. Chem. Soc., 1980, 102, 7109. Keck, Savin, Cressman, Abbott J. Org. Chem. 1994, 59, 7889. OH OH O BF3 OEt2 SnBu3 + R R + R CH2Cl2 H E : Z syn : anti

SnBu3 R = Ph 90 : 10 42.8 : 1 (85%) R = cHex 90 : 10 14.9 : 1 (88%) E SnBu3 R = Ph 12 : 88 4.2 : 1 (80%) Z R = cHex 12 : 88 1.41 : 1 (82%) Yamamoto explanation: antiperiplanar transition state. Keck explanation: Synclinal transition states. Focus on interaction between R and CH3 groups Focus on interactions between the BF3 group and the (place these anti to each other) allyl stannane, as well as on secondary orbital interactions which favor synclinal transition states.

SnBu3 SnBu3

H CH3 H CH3 H CH3 R H R H O R + H CH3 F3B + O O R O H BF3 F3B BF3 syn H syn

Stereochemistry of the Allyl Tin Reaction with Aldehydes - Intramolecular Case. Denmark, S. E.; Weber, E. J. J. Am. Chem. Soc. 1984, 106, 7970.

OHC H OH HO H +

SnBu3

Et2O BF3 87 : 13

CF3CO 2H 99 : 1

SnBu3 O H O H H H SnBu3 Synthesis of Avermectin Danishefsky, S.J.; et. al. J. Am. Chem. Soc., 1989, 111, 2967. O PvO O t-Bu Ph3Si Me

Me2CuLi t-Bu O CH3 Me Me . O BF3 Et2O H H O O PvO H H O PvO H t-Bu O OMe HO Me O O OMe O Me O Me Me H O O Me H O H Me H H SiPh3 Me O H Me O H O O Me H HO cis-silane SiPh3 3/1 to 5/1 trans-silane 1/3 O Reaction is stereospecific, to some extent. Me H OMe

AVERMECTIN A1a Crotyl Borane Addition to Aldehydes - Zimmerman-Traxler Type Transition States Hoffmann, R. W. Ang. Chem. Int. Ed., 1982, 21, 255.

HO O K B(NMe2)2 HO B Cl-B(NMe 2)2 O

Me OH Me H R H O O R O O R B Me B + O H OH O H R Me cis-Olefin syn (erythro) syn (erythro) trans-Olefin anti (threo) syn/anti = 97/3

Allyl Borane Equilibration: The Curtin-Hammett Principle Wang, Gu, Liu J. Am. Chem. Soc. 1990, 112, 4425. Interconversion among the isomers is faster than reaction of the major isomer with the aldehyde.

Me3Si

Me3Si B B B

Me3Si

THF 25% 75% <2% All reactions occur from this isomer. H H H B B R O B R O R O Me Me3Si Me 3Si H Me3Si Me

Me Me Me H Me H A B NaOH Me H2SO4 R R R = n-C5H11 R R A; NaOH 94 1 4 1

A; H2SO4 1 90 3 6

B; NaOH 0 0 98 2

B; H2SO4 0 0 8 92

In the Peterson Olefination, treatment of the β-hydroxy silane with NaOH gives a syn elimination, whereas H2SO4 gives an anti elimination.

Electrophilic Allylboranes will even add to Olefins. Singleton Org. Lett. 1999, 1, 485. Sn BBr3 OH BBr2 ( ) 4 BBr 1. 2

0 °C, hexane To get high yields olefin needs to be somewhat activated - 2. NaOH, H2O2 norbornene, styrene, 1,1-dialkylethylenes, cyclohexadiene and 90% cyclopentadiene all work. 1-Nonene gives only 33% yield. Chiral Allyl and Crotylboronate Reagents Allylborane - stereoselectivity poorer than for crotylboranes: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675 OH

CHO 1. Ipc2B-Allyl 2. BPSO BPSO )2 B NaOH, H2O 2 92/8 er Ipc2B-Allyl Crotylboronates Roush, W. R.; Palkowitz, A. D. J. Am. Chem. Soc., 1987, 109, 953; 1990, 112, 6339. O CO2iPr OH O -78 °C TBDPSO H + RO B CO2iPr O 88% ds mismatched 75% 1. Et3SiCl, Et3N, DMF 2. O3, MeOH; Me2S

CO2iPr Et3SiO OH Et3SiO O O + RO RO H B CO2iPr 98% ds O matched

CO2iPr H O AcO O O OMe R O B CO2iPr O H OMe HO AcO O O OMe O + CO2iPr CO2iPr OMe O 91% ds H O B CO2iPr O B CO2iPr O C-19 to C29 of Rifamycin S R O

Transition state model

Crotylboronates Synthesis of Rutamycin B: White et al. J. Org. Chem. 2001, 66, 5217

CO2iPr OH O O 9 : 1 + RO TBDPSO H B CO2iPr O 80% ds matched

CO2iPr TBSO O TBSO OH O >98 : 2 + RO H B CO2iPr RO O >96% ds matched Allenylboronic Ester: Synthesis of (-)-Ipsenol 86-2 N. Ikeda, A. Arai, H. Yamamoto, J. Am. Chem. Soc., 1986, 108, 483.

B(OH) O CO2R 1. Mg(Hg) 2 B 2. B(OMe) 3 HO CO2R O Br CO2R 3. H2O

HO CO2R CHO

CH2=CHBr 1. 9-BBN-Br

HO Pd(PPh3)4 THPO Br 2. HOAc HO + (-)-Ipsenol H , MeOH 3. H2O2, NaOH 78%, >99% ee 4. DHP,H + Allenyl and Propargyl Boranes Corey, Yu, Lee J. Am. Chem. Soc. 1990, 112, 878. H Ph Ph Ph Ph Ph CHO SnBu Ph 3 N N H N N TolSO SO Tol TolSO 23 °C 2 B 2 -78 °C, 2.5 h 2 B SO2Tol OH Br >99% ee, 74%

Ph Ph SO2Tol Ph N CHO SnPh3 Ph BO N N TolSO 2 B SO2Tol R -78 °C, 2.5 h N 23 °C OH H 98% ee, 79% SO2 H

1. Bu3SnCl Ph Ph H H Ph Ph 2. Reflux, MeOH

BBr3 MgBr 78% TolSO N N SO Tol TolSO N N SO Tol SnBu3 2 2 2 B 2 "propargylmagnesium bromide" H H Br H Ph3SnCl, Et2O SnPh3 MgBr 71%

Allenyl Borane Trost, Doherty J. Am. Chem. Soc. 2000, 122, 3801. HO O H Ph Ph

N N TolSO SO2Tol + 2 B Roseophilin

Allenyl Stannanes Rousch, et al. J. Am. Chem. Soc. 2002, 124, 6981 OMe

TESO OTBS OH SiMe3 TESO OTBS O Bu3Sn Bifilomycin 5 equiv. SiMe H 3

BuSnCl3, -40 °C OMe Kinetic 85% 20:1 ds (4:1 with 1.2 equiv) resolution Chelation and Felkin-Anh Controlled Additions of Allyl Stannanes to Aldehydes Keck, Boden, Tetrahedron Lett. 1984, 25, 265.

OBn OBn OBn SnBu3 H + OH O MgBr2, CH2Cl2 OH -23 °C 85% >250:1

OSiMe2tBu OSiMe2tBu SnBu3 OSiMe2tBu H BF3 should not be able to chelate - + monodentate Lewis O 2 BF3 OEt2 OH OH acid CH2Cl2, -78 °C 83% threo (syn) 5:95 erythro (anti)

MgBr2 + BF3 OOBn O erythro threo OSiMe2tBu H attack attack H H H Chelation control Felkin-Anh control (Cram)

Stereochemistry of the Allyl Fragment Hayashi, Konishi, Ito, Kumada, J. Am. Chem. Soc. 1982, 104, 4662, 4963.

SiMe3 Me3Si MgBr Cat* Pd Ph Br + 85% ee Ph H OH E+ H Ph Me3CCOH, TiCl Ph CH3 Ph 4 H t-Bu CH3 O R SiMe3 H H 99/1 syn SiMe3

CH3 CH3 O CH3 Ph t-Bu Ph Ph HO H 86% ee H 87% ee H 53% ee O O

O O TiCl4 Me3CCl, TiCl4 CH3CCl, AlCl3 Stereochemistry of the Allenyl Fragment Buckle, Fleming, Tetrahedron Lett. 1993, 34, 2383.

H TiCln Me O Me Product of iPr + TiCl4, -78° anti addition Me H Me Me3Si 30% CH3 H 98% ee Cl H Me3Si 99:1 H Me OH Me iPr + H TiCl4, -78° H + Me3Si 89% CH3 O OH OH H 95:5