Stoichiometric Enamine Chemistry

Jonathan LocknerBaran Group Meeting Stoichiometric Enamine Chemistry

But no one seized the opportunity for nearly two decades ! until Stork...

NR2

Stork, Terrell, Szmuszkovicz, J. Am. Chem. Soc. 1954, 76, 2029Stork, Landesman, J. Am. Chem. Soc. 1956, 78, 5128Stork, Landesman, J. Am. Chem. Soc. 1956, 78, 5129Stork, Brizzolara, Landesman, Szmuszkovicz, Terrell, J. Am. Chem. Soc. 1963, 85, 207

Collie, Liebigs Ann. Chem. 1884, 226, 294-322Benary, Ber. Dtsch. Chem. Ges. 1909, 42, 3912-3925Robinson, J. Chem. Soc. 1916, 109, 1038-1046

Vinylamine reactivity known since 1884...

Page 1November 3, 2007

Wittig coined "enamine" as nitrogen analog of enol...

Wittig, Ber. Dtsch. Chem. Ges. 1927, 60, 1085-1094

Enamine preparation was first made practical by Mannich...

Mannich, Ber. Dtsch. Chem. Ges. 1936, 69, 2106-2112

OH

Until silyl enol ethers emerged in the early 1970s, enamines enjoyed a unique status as noncharged enolate equivalents...

Today, enamine chemistry remains a powerful tool in the synthetic chemist's armamentarium...

Silyl enol ethers: superior stability

Enamines: neutral conditions mitigate self-condensation side reactions

Enolates: quick/easy generation; predictable regioselectivity

Metalloenamines: low levels of proton transfer; hence little polyalkylation

N

Asymmetric induction ! as early as 1969 with (S)-proline...

www.colby.edu/chemistry/CH432/Lecture8.pdfalso Evan's Chem 206 (Harvard)

Reviews:

Szmuszkovicz, Adv. Org. Chem. 1963, 4, 86Kuehne, Synthesis 1970, 510Valentine, Synthesis 1978, 329Hickmott, Tetrahedron 1982, 38, 1975 & 3363Whitesell, Synthesis 1983, 517

Books:

Enamines: Synthesis, Structure, and Reactions; Cook, A.G., Ed.; Marcel Dekker: New York, 1988

The Chemistry of Enamines; Rappoport, Z., Ed.; John Wiley & Sons: New York, 1994

Yamada, Tet. Lett. 1969, 10, 4233 & 4237



O

Me

N

Me

MVK

acid or base

MVK

neutral cond.

Me

O

Me

O

(Robinson)

(Stork)

tBu

O LDA

MeI tBu

O

tBu

O

55 : 45

tBu

N

tBu

NNMe2

MeI

H3O+90 : 10

1. LDA2. MeI

3. CuCl2H2O, pH=7

97 : 3

Stork enamine

Coreydimethylhydrazone

ONH2

BnOMe

N

Bn

OMe

LDA

!30°C

N

Bn

OMeLi

OEtI

H3O+

Et

Enamines are ambident nucleophiles: nitrogen and "-carbon(s)

NR2

R

NR2

R

R

NR2

H

R

NR2

H

R

R> > >

Ketone enamines are more reactive than aldehyde enamines:

opportunity for selectivity;e.g. "-tetralones...

tend to react preferentially at N;therefore try metalloenamine chemistry...

Cyclic ketone enamines ! general reactivity order:

NR2

>

NR2 NR2NR2

> >

"Structure!Nucleophilicity Relationships for Enamines" H. Mayr, Chem. Eur. J. 2003, 9, 2209

Enamine chemistry complements other methods, e.g.:

Enamine chemistry offers significant enhancements in selectivity, e.g.:

Me

Me

Enamine chemistry has been exploited in asymmetric methods, e.g.:

1970s: A.I. Meyers (e.g. above, later chiral oxazolines), see also D. Enders (SAMP/RAMP)





Reactivity/Outcome depends on many parameters:

(1) solvent (hexanes vs. THF vs. HMPA)(2) temperature (equilibration...)(3) amine moiety (steric/electronic issues)(4) amount of base used(5) proportion of reagents, and order of addition(6) number and type (e.g. acyl vs. alkyl) of substituents present on the enamine(7) type of electrophile

Case in point:Hickmott, J. Chem. Soc. Perkin Trans. I 1975, 1885; ibid 1974, 2544; ibid 1973, 2063; ibid 1973, 1514; Tetrahedron 1967, 3151

NR2

ZZ

O O

OZ

R

O

O

R

OH O

R

OH OR'

O

Z

R

O

RO O

OH O R O

Z Z Z Z20°C

80°C

80°C crotonyl chloridemethacryloyl chloride

acryloyl chloride

(Z = CO2Et, CN, H)

Cl

O

R

Pyramidalization, induction, pπ-conjugation:

Degree of pyramidalization influences extent to which N lone pair can donate electron density into the π orbital of the alkene (pπ-conjugation). Better orbital alignment means greater pπ-conjugation, and hence greater nucleophilicity at β-carbon of the alkene...

Nature of substituents on amine influences same (e.g. inductive withdrawal by oxygen)...

N N N

O

N

OO

(A1,3- and A1,2-strain vs. pπ-conjugation)

NO

Nature of substituents on amine can also "tune" E/Z ratio:

Nature of substituents on amine influences isomer distribution:(∝ of less-substituted isomer increases with increasing pπ-conjugation)

OMe

NR2Me

NR2Me+

pyrrolidine (90% A)dimethylamine (60% A)morpholine (52% A)piperidine (46% A)diethylamine (25% A)2,5-dimethylpyrrolidine (10% A)N-methylaniline (0% A)A B

NR2Me

EtNR2

Et

Me(E) (Z)

pyrrolidine (98:2)dimethylamine (97:3)piperidine (90:10)morpholine (88:12)diethylamine (86:14)diisopropylamine (55:45)

pπ- vs. ππ-conjugation:

C6H11(Me)N (83:17)Ph(Me)N (20:80)o-MeC6H4(Me)N (83:17)

inc.pπ-conj

← a really bad situation (see 19c above); N lone pair orthogonal, ∴ zero pπ-conjugation

decreasing pyramidalizationincreasing p-character

increasing pπ-conjugation



Ground states vs. transition states in enamine chemistry...(gs enamine isomer distribution, governed by factors described on the previous pages, is not necessarily a reliable predictor of product distribution)

Curtin−Hammett: product distribution reflects ts energies rather than gs populations

Valentin, Tetrahedron, 1974, 30, 2741



Enamine preparation:

via condensation of carbonyl with amine, aided by a dehydrating agent/mechanism

chemically inert dehydrating agents: MS, K2CO3, MgSO4, Na2SO4

aldehydes: Mannich & Davidsen 1936 (2 eq amine to generate aminal, which yields enamine upon destructive distillation)

enamines of aldehydes are often unstable, being readily hydrolyzed, oxidized, polymerized"new" method for aldehydes: JOC 2006 7481 (cf. White, JACS 1981 1813)

via terminal epoxides:JACS 2004 6870

no N-alkylation; provides !-substituted aldehydes (including nBu and iPr); cf. JOC 1975 607

N

O

N

O

N

O+

KOtBu

DMSO"

89 : 11

cat. PhCO2H

quant.

via allyl amines:Chem. Ber. 1969 1917

Other methods of enamine preparation:

As a function of amine nucleophilicity:

• if strong (pKa of conj. acid 6-10), then addition may proceed without acid catalysis, and dehydration is rate-determining

• if weak (pKa of conj. acid 3-5), then addition and dehydration both require acid catalysis

ON

NH

(pKa 11.26)

PhH, reflux94%

ACIE 2006 5194

JOC 1990 2317

or K-10 Mont. clay, 56% yield:J. Chem. Res. Synopses 1995, 1, 21

O NMePh

PhNH

Me

(pKa 4.70)

cat. PTSAor cat. ZnCl2PhMe or neat

reflux

A process paper on optimization of morpholine enamine preparation: Carlson, OPRD 2005 321

O

1.2 eq amine4A MS

CHCl30 °C 1 h

NR2R R good yields

"In the original procedure, TiCl4 is added dropwise to a solution of the ketone, and the amine and the mixture are then stirred for several hours. We found that the reaction time could be considerably shortened by a modified procedure: TiCl4 is added at 0 °C to a solution of the amine in petroleum ether to form a solid TiCl4-amine complex. The mixture is then heated to reflux with vigorous stirring, and the ketone is rapidly added. For nonhindered ketones, the reaction is completed within minutes. It was, however, found that the amounts of TiCl4/ketone and amine/ketone to be used for a rapid conversion were dependent on the structure of the ketone. For this reason, the amounts of titanium tetrachloride and amine to be used have to be determined for each ketone."

ketones: Stork 1963 (Dean-Stark azeotropic removal of H2O; w/ Bronsted acids: AcOH, PTSA; in refluxing solvent: PhH, PhMe, xylene)

methyl ketones problematic (self-condensation under these conditions), so TiCl4 as water scavenger is typically employed (White, JOC 1967 213; Carlson, Acta Chem. Scand. 1983, B 37, 7)

C4H9

O LTMP-analog

THF

RX

MeCNC4H9

NtBu

Me tBu

C4H9

O

R



Representative Sampling of Synthetic Uses:

Generating 1,3-dicarbonyl: Acylation

Generating 1,4-dicarbonyl: Alkylation

Generating 1,5-dicarbonyl: Michael Addition

Cascade of bond-forming events is sometimes possible:(β-carbon nucleophilic, then α-carbon electrophilic)

NR2

O O

O

OO

O

Cycloadditions:[2+2] with vinylketenes (HCA 1982 2230)

H

H NR2

Ph

OH

H NR2

O Ph

H2OH

H O

O

Ph

N Cl2

−78 °C

H2ONO

ClCl 65%

R2N

Et

NO2

Ph100%

R2N

Et

NO2

Ph

(EDG) (EWG)

strong preference for axial attack (Tetrahedron 1974 2741

Halogenation:α−chlorination (Chem. Ber. 1979 1670)

Oxygenation:(Chem. Comm. 1969 314)

next page: chemoselective α−bromination enabled by enamine chemistry

N

O2

cat. CuCl OO

[4+2] with pyrones (JOC 1983 4869)

+

[2+2] with nitrostyrenes (JOC 1965 4280)

MeMe O

R'N R"

Me Me

N•O

R' R"+

OMeMe

R"

R'

N

Cyclopropanation:(Org. Lett. 2006 2261

CO2RMe Me

R"R'

CO2RMe Me

R"R'

N

O

O

CO2RMe Me

O

Δ

− CO2

Spiroannulation via homologation-alkylation sequence:(Martin, JOC 1976 3337; ibid 1978 3792)

NCH2Cl2

TiCl4/Mg/THFN

50%

chemoselective

Michael-Stork addition:(Silvestri, JOC 2005 8239)



Enamines in Natural Product Synthesis:

vitamin B12 (Woodward, Classics I)intramolecular imino-ester-enamine condensation mediated by pyrrolidinium acetate

ecteinascidin 743 (Corey, Classics II)Ru-catalyzed asymmetric hydrogenation

vinblastine (Fukuyama, Classics II)intramolecular Diels−Alder

(+)-mesembrine (Yamada, Chem. Pharm. Bull. 1973 2130)asymmetric enamine Michael into MVK; then condensation (cf Woodward above)

Review: Kuehne, Synthesis 1970 510

analog of steganone (Becker, JCS Chem Comm 1974 430)

camptothecin (Kametani, JCS Perkin I 1981 1563)enamine annulation

pyrazine metabolite (Heathcock, JOC 1993 6155)hetero-[4+2]; enamine tactic was vital

diterpene resin acids (Kuehne, JACS 1961 1492)chemoselective bromination of ketone in presence of anisole ring through enamine activation

Stoichiometric Enamine Chemistry

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