Umpolung: Carbonyl Synthons

Home , Benzoin condensation, Isocyanide, Nef reaction, Umpolung

William D. Shipe

Organic Supergroup Meeting

Princeton University

February 4, 2004 Umpolung - The Carbonyl Group

O O

R R' R R'

normal reactivity inverted reactivity umpolung

O O OH

O O O

odd number of carbons even number of carbons between functional groups between functional groups

Seebach ACIEE 1979 239 Umpolung - Carbonyl Synthons

Polarity inversion is an old concept, but vigorous research in the area is of relatively recent origin.

The concept of synthons, or functional group equivalents, has spurred research.

Synthons: structural units within a molecule which are related to possible synthetic operations

Corey Pure Appl. Chem 1967 19

1. homoenolates O O O 2. α-electrophiles R R 3. acyl anions Umpolung - Carbonyl Synthons

Inversion reactions described as "symmetrization of reactivity"

Corey Pure Appl. Chem 1967 19

"charge affinity inversion"

Evans Acc. Chem. Res. 1974 147

suggested the German word umpolung as a concise expression for the concept Seebach Chem. Ind. 1974 687

umpolung: pole reversal; reversion of polarity; turn-over

(http://dictionaries.travlang.com/GermanEnglish/) Homoenolates

O OMgBr MgBr R3SiO MgBr R''X OSiR3

R' SiR3 R' R' R' R'' SiR3

Kuwajima et al. Chem. Commun. 1979 708

MeOCO2 O Li OTBS Br + TBS Br in THF; –78 °C, 2h; TAS-F, THF-DMF 82% –35 °C to 0 °C, 3h; 90%

4 steps O (±)-δ-araneosene MeOCO2

Corey et al. Org. Lett. 2002 2441 Homoenolates

O Ph + O 2 BuLi N Li E Li PhNH SnBu3 PhNH E O Goswami et al. JACS 1980 5973

RO OTMS TiCl4, CH2Cl2 RO OTMS OR TiCl4 TiCl 4 TMSO

–TMSCl

O O H R' OTiCl R' 3 RO RO OH

Kuwajima et al. JACS 1986 3745 Homoenolates

OR OR OR OR SnCl4 OTMS O Cl Sn 2 O OTMS Cl3Sn O OR

Kuwajima et al. Organometallics 1985 641 mercury, copper, silver, and gold homoenolates have also been synthesized

OR ZnCl2, Et2O 2 O Zn O OTMS RO

Nakamura, Kuwajima et al. JACS 1984 3368 when the zinc reagent contains two Nakamura, Kuwajima et al. JACS 1987 8056 homoenolates bound to each zinc atom, only one of the homoenolates can be transferred; the second is unreactive Homoenolates

OR O O OR ZnCl , Et O Et2O Zn O 2 2 + 2 TMSCl OTMS 2 RO OTMS Cu(I), HMPA, THF

OOR

Kuwajima Pure and Applied Chem. 1988 115

O O H Zn Oi-Pr OR O H OR H HMPA, CuBr•Me2S, BF •Et O H 3 2 80-85% O Oi-Pr

Nakamura, Kuwajima et al. JOC 1986 4323 > 97 : 3 diastereoselectivity cortisone and adrenosterone Nakamura, Kuwajima et al. JACS 1989 6257 intermediate Homoenolates

O O CO2Me MeO2C Zn( OEt) OR 2 OR O O O O HMPA, CuBr•Me2S, H TMSCl H 65%

hν

H O O O O CO2Me O O O O OH C(CH3)3 H OH RO O bilobalide Crimmins et al. JACS 1993 3146 Reviews on Homoenolates: Crimmins, Nantermet Org. Prep. and Proc. Int. 1993 41-81 Werstiuk Tetrahedron 1983 205 α-Electrophiles

O O Nu- R' R' R R X Nu

O + H3O (mild) N O O H N O NH2 O 2 O O N H

HNMe2

AgBF4

O N Cl HO O

Eschenmoser, Woodward et al. in Vitamin B12 synthesis See Classics In Total Synthesis, p. 134 α-Electrophiles

• π-coordination of triple bond to the Pt(III) atom • nucleophilic attack of water • ketonyl–Pt(III) complexes react with amines to give α-amino substituted ketone • with 1° amines, further reaction occurs

2+ ONO2 O H2NOPt H O H NO t-Bu 2 3 + R t-Bu R H2NNPt H H3NNH Pt(III)2 ONO2

NH O 2 O R N R R O Pt(III)2 H O + N H N O R O R Matsumoto et al. JACS ASAP R α-Electrophiles

Anodic Oxidative Cyclization:

RVC anode O TBSO H carbon cathode 0.4 M LiClO4 TBSO TBSO MeOH/CH2Cl2 (1:4) O O 2,6-lutidine, RT 15–20 mA, 2.2 F/mole MeO

RVC = reticulated vitreous carbon TsOH, RT

O O H

O OH HO O O alliacol A Moeller et al. JACS 2003 36 Acyl Anions

1a. Benzoin condensation: Cyanide ion catalyzed addition • cyanide ion catalyzed dimerization of aromatic and heterocyclic aldehydes to form α-ketols • nitrile-stabilized anions can also add to α,β-unsaturated ketones, esters, and nitriles • the reaction requires aprotic solvents (most preferably DMF) • cyanide ion catalysis fails with aliphatic aldehydes because they undergo aldol condensations under the strongly basic conditions

O CN O OH O

Ar H Ar CN Ar CN Ar H

Ar H

O O OH OH OH O Ar Ar Ar CN H CN H Ar Ar Ar a benzoin

Lapworth J. Chem. Soc. 1903 995 Acyl Anions

1b. Protected cyanohydrins • can serve as reagents for annulation

Stork et al. JACS 1974 5272 Kraus et al. Tet. Lett. 2000 21

H O H THF O HN N –78 to rt O O + O OMe OMe 85% OMe Li OMe OH NC OH O OH O

A. G. Myers et al. JACS 1997 6072 a dynemicin A intermediate Acyl Anions

2. Thiazolium salt catalyzed addition

N NH2 N Br N N I N Cl N Cl S HO HO S S HO S HO

vitamin B1 (thiamine) • in the presence of base, quaternary thiazolium salts are converted to the ylide, which acts as catalyst (5-10 mol %) • aliphatic, aromatic, and heterocyclic aldehydes add to α,β-unsaturated ketones, esters, and nitriles • Et3N or NaOAc are preferred bases • DMF, dioxane, or even alcohols can function as solvent cat. thiazolium salt, O O O Et3N, DMF + X R H X R O Acyl Anions

2. Thiazolium salt catalyzed addition (mechanism) O Bn Bn Bn Cl R H N O N base N H S HO S H R HO HO S

O X X X Bn Bn OH Bn O N OH N N

R S R S R HO HO O HO S OH Breslow Chemistry and Industry 1956 R.28 Bn Breslow Chemistry and Industry 1957 893 O Breslow JACS 1957 1762 N Breslow JACS 1958 3719 X R + Breslow JACS 1959 3080 S Stetter ACIEE 1976 639 O HO Acyl Anions

2. Thiazolium salt catalyzed addition (example) Bn O N O

BzO BzO O HO S

O 2 equiv. H

cat. Et3N, dioxane 60% 3 steps

formal total synthesis O of roseophilin

Tius Org. Lett. 1999 649 Acyl Anions

3. Dithianes

n-BuLi, THF E+ SS SS SS

R H R R E • usually formed from corresponding aldehydes by thioacetalization • R = primary, secondary, and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups

• with alkyl halides: 70-90% yield from protected formaldehyde, two alkylations can be done in a single reaction mixture without isolation of intermediates • with epoxides: 70% yield to give mercaptals of β-hydroxy ketones or aldehydes • with ketones and aldehydes: 70-90% yield to give mercaptals of α-hydroxy ketones or aldehydes • with imines: 70% yield to give mercaptals of α-amino ketones or aldehydes • with CO2: 70-75% yield to give mercaptals of α-keto carboxylic acids

• biggest drawback: removal of dithiane 1. hydrolysis 2. alkylative or oxidative hydrolysis 3. reductive desulfurization (Raney Ni) Corey, Seebach ACIEE 1965 1075 Corey, Seebach ACIEE 1965 1077 Seebach, Groebel Synthesis 1977 357 Page, Van Niel, Prodger Tetrahedron 1989 7643 Acyl Anions

3. Dithianes

n-BuLi, THF SS SS

R H R The 1,3-dithiane grouping was carefully chosen:

SS + S S R R 1,2-dithianes undergo a fragmentation reaction.

MeS SMe MeS + SMe R R Dimethyl thioacetals are susceptible to carbene formation. Acyl Anions

3. Dithianes (example)

HO CO2Bn TMSO CO2Bn OTMS BnO2C BnO2C OH BnO2C SS OH CO2Bn CHO H O + O O SS SS n-BuLi, THF, –40 °C; then O O O O O O aldehyde, –78 °C, 5 min O O O 30% 34%

1. 2% HCl in MeOH, CH2Cl2 (76%) 2. Hg(ClO4)2, CaCO3, THF-H2O (72%) facile hyrolysis is perhaps assisted by nearby -OH group BnO2C CO2Bn O OH O OH O Nicolaou et al. in zaragozic acid A synthesis O O See Classics In Total Synthesis, p. 701 Acyl Anions 4. t-Butyl hydrazones • formed by condensation of t-butyl hydrazine with aldehydes or ketones • with methyl hydrazones, N-alkylation can be a problem; t-butyl group directs reaction along desired C-alkylation pathway • can add to: aldehydes/ketones (40-95%) alkyl halides (15-83%) Michael acceptors (methyl crotonate, methyl acrylate, acrylonitrile) • acidic hydrolysis (oxalic acid) gives ketones

n-BuLi HN N N N N N

HR HR HR O

HR'

O HN H O+ H O, taut. R' 3 N 2 N R H N R' H OH R R' H OH R O Baldwin et al. 1983 JCSCC 1040 Baldwin et al. 1984 JCSCC 1095 Acyl Anions

5. Oximes • formed by condensation of aldehydes or ketones with hydroxylamine • base causes an inversion of polarity by deprotonation of the N-hydroxyl • can be cleaved by oxidation, reduction, or hydrolysis Cl Cl Cl Cl Cl 1 N NaOH 100 °C

N N OH N O O

N N OH O Eschenmoser et al. Helv. Chim. Acta 1958 2103 Acyl Anions

5. Oximes (example)

OH O N N NaOH

a β-ionone derivative intense blue color

OH N

Eschenmoser et al. Chimia 1965 538 Acyl Anions

6. Nitronate anions (Henry reaction)

NO2 O NO2 base Nef R' R' R R R O O O R'

(Henry) O O O O N N

R R

Henry reaction: Nef reaction: Henry Compt. Rend. 1895 1265 Nef Liebigs Ann. Chem. 1894 263 Rosini Comp. Org. Synth. 1991 321 Petrini Tetrahedron 2004 1017 Acyl Anions

6. Nitronate anions (example)

O CO2Et O O

EtO EtO OEt BnMe3NOH NO2 79% NO2

1. NaOEt 2. O3 67% 3. aq. HCl

O O

EtO OEt O

Cappon et al. Recl. Trav. Chim. Pays-Bas 1991 158 Acyl Anions

7. Metalated enol derivatives • metalation of a protected enol, followed by reaction with an electrophile • after hydrolysis, a net nucleophilic acylation has occurred

OLi OH BuLi Li H+ O O O O O R R

R O R Li RLO i O

• big advantage: enol ether products are hydrolyzed under very mildly acidic conditions

• in addition to reactivity with ketones and aldehydes, lithio vinyl ethers are alkylated by primary iodides or allylic halides; acylated by aromatic acids (0.5 equiv.) or nitriles; silylated to give acylsilanes Acyl Anions

7. Metalated enol derivatives • aliphatic or aromatic esters add 2 equiv. of reagent to give bis-adducts • such products are difficult to access without nucleophilic acylation

ROH ROH RO OR

Review: Lever Tetrahedron 1976 1943

Li OH OH O + O OEt H3O O –78 °C

Funk, Shipe unpublished results Acyl Anions

7. Metalated enol derivatives (example) Li O O OEt

HO O OEt

–H2O

O O hydrolysis

O OEt

In total synthesis of nicandrenones: Corey, Stoltz, Kano JACS 2000 9044 Umpolung - Carbonyl Synthons

O O

R R' R R'

normal reactivity inverted reactivity umpolung

O O O O O O

R R R R

Umpolung provides flexibility in synthetic planning: • Michael acceptors vs. homoenolates • enolates vs. α-electrophiles • carbonyls vs. acyl anions Umpolung - Carbonyl Synthons

An interesting ring expansion was observed when a cyclopropyllithium reagent was treated with an isocyanide. Provide a plausible mechanism for the formation of the two products.

1. 0 °C, 10 min Ph Ph N + Ph O O 2. H3O Ph + Ph Ph Li +

46% 4%

Walborsky JOC 1974 608 Acyl Anions

8. Metallo aldimines

Li E+ E RLi + N N N R' R' R R' R

+ H3O

R'NH2 + O • can be regarded as masked acyl anion equivalents R • less efficient with Grignard reagents and aryllithiums • fails with less basic anions like acetylides • vinyl and propenyllithium undergo complicated side reactions

Walborsky et al. JOC 1974 600 Walborsky et al. JACS 1969 7778 Walborsky et al. JACS 1970 6675 Mechanism Problem

An interesting ring expansion was observed when a cyclopropyllithium reagent was treated with an isocyanide. Provide a plausible mechanism for the formation of the two products.

1. 0 °C, 10 min Ph Ph N + Ph O O 2. H3O Ph + Ph Ph Li +

+ 46% 4% H3O

Ph Ph N R N R Ph Ph Li Li

+ H3O Ph Ph HO OH Ph Ph H Walborsky JOC 1974 608