The Birch reduction - Baran Lab · OMe1) K, NH 3, tBuOH, THF, -78ºC 2) LiBr 3)MeI Me O Me 33% CO2H...

The Birch ReductionLisa M. BartonBaran Group Meeting

3/10/18

1) Electron-Donating Substituents

Stereochemistry

Re

RROH

RH

He

RH

HROH

RH

H

HH

Re

R ROH

R

H HR

e2

ROHor NH3

e R

H H

H2O or R'X

R'/HR

H H

• In both cases reduction will occur 1,4 across the aromatic ring

• Initial protonation takes place at position with highest electron density andprotonation of the dianion will usually occur at the site that will give the most stable monoanion (exceptions exist)

• Most common side reactions: bond cleavage, dimerization (pyridine), and substituent reduction (esters, amides, ketones)

• Determined by the protonation of the final monoanion• reductive alkylation leads greater selectivity due to increased sterics

R1R2

H

Helpful Resources:

Background

Literature seminar, B. Hafensteiner (2005) [Group Meeting]Organic Reactions, 1992, 42, 1 [review]Nat. Prod. Rep., 1986, 3, 35 [review]Curr. Org. Chem., 2015, 19 , 1491 [review]Targerts in heterocycic systems, 1999, 3, 117 [review - heterocyclic Birch]Recl. Trav. Chim. Pays-Bas., 1995, 114 , 259 [review - electrochemical Birch]

Mechanism

• Originally discovered by Wooster and Godfrey in 1937 in the reduction of toluene in NH3 using either Na or K JACS, 1937, 59, 596

First Publication on: J. Chem. Soc., 1944, 430Complete list of contributions: Tetrahedron, 1988, 44, No. 10, pp. v-xviii

• Extensively developed by Arthur J. Birch and is therefore named after him

OO

HR1

H

• When R1,2 is H no steric preference and protonation occurs equally from either face• When R1,2≠H Cis product predominates

HR

HR

• When there is a π substituent, a boat

conformation is adopted • vinyl hydrogens block

bottom lobe of anion orbital and protonation comes from top face

ProceduresSolvents: Ammonia*

Cosolvents (used to aid in solubility): Diethyl Ether*, Tetrahydrofuran*, Glymes*Proton Sources: Ethanol*, tert-butyl alcohol*, H2O

Metals: Sodium*, Lithium*, Potassium*, Calcium, Magnesium• Li most reactive but can therefore lead to overreduction, in which case Na best

Concentration: Often run under dilute conditions (0.1–0.5 g metal per 100 mL NH3)Temperature: Most commonly ran at –78 ºC, due to low bp of NH3. highest at reflux (–33 ºC)

2) Electron-Withdrawing Substituents

HR

RH

Purity of Reagents: Not necessary but recommendedOrder of Addition: Often very important and empirically determined

• Substrate dissolved in cosolvent with alcohol can be added to NH3 and metal solution• Metal added last to solution containing all other reagents• Alcohol added last to solution containing all other reagents

Quenching Materials: either can use acidic materials (alcohols, water, NH4Cl, FeCl3),electron-transfer reagents (sodium benzoate/dienes then water), or alkyl halides in the case of reductive alkylations

• Most commonly the fast addition of saturated NH4Cl (frothing occurs) is used

Comparison with Other MethodsBenskeser Reduction: reduction of arenes using Li in 1º amines, ethylenediamine, or a mix of 1º and 2º amines; more powerful than Birch conditions and can lead to reduction beyond dihydro stage and mixture of products

Catalytic Hydrogenation: procedes far past Birch reduction

Organic Reactions, 1992, 42, 1

Not Discussed in this group meeting:• Birch reduction of non-aromatic compounds (ie protecting group removal, alkenes, alkynes)• Birch reduction for functionalization of nanotubes

∗ = Most commonly used


3/10/18

OR O O ORR'

OR'

O NEt2

Me

O NEt2

Me

O

MeMe

Me

nBuLi;RBr

J. Chem. Soc., Chem. Commun., 1983, 123

OMeMe

H

H

H

Me

pregn-4-en-20-one(formal of pregesterone)

OMe

C8H17

Na,NH3,

tBuOH

Li,NH3,

tBuOH

OMe

C10H21

1) KNH2,THF, liq. NH3,

–33 ºC; RBr2) HCl

O

C10H21

C5H11 C10H21

O

C5H11

J. Chem. Soc. Perkin Trans. 1. 1983, 7(Z)–henicos-60-en-11-one

Alkylation precursors

Cycloaddition precursors

• Limitations: Partial or complete loss of alkoxy group (usually when para or ortho to EWG)

OMe Li,NH3,

tBuOH

OMe1)

Cl

CN61 ºC, CHCl32)Na2S•9H2O80% (2 Steps)

MeO O

1)BrMg Me

2) 250 ºC3) (CH2OH)2,cat. pTsOH

65% (3 steps)

O

Me

H

H

O

O3:2 α:β

MeN

O

Me

(±)-luciduline

JACS 1972, 94, 4779

O

CO2Et

iPr

1) 50 atm H20.04 mol %

Ir-(R)-SpiroPAP92%, >99% ee

d.r. 95:52) PCC, 92%

O

CO2Et

iPr

OMeI

2 equiv. Cs2CO360 ºC65%

O

iPrCO2Et

OMe

1) MsOH91%

2) H2, Pd/C99%

CO2EtiPr

OMeHNa, NH3

EtOH, THF, -78ºC;

then HCl80%CO2EtiPr

OH

+ 6 other Mulinane Diterpenoids of same scaffold

iPr CO2H

Me

O O

H Me

H

mulinic acid ACIE 2017, 56, 12708

OMe

MeO

Me

Me

1) Birch reduction (not specified)

2) KOtBu, DMSO

OMe

MeO

Me

Me

DMADΔ

OMe

MeO

CO2Me

MeCO2Me

OH

MeOO

O

Me

Me

HO2C

J. Chem. Soc. D, 1969, 788

OMe

MeO

O

O

O Mecurvularin

OMe

MeO

1) Na, NH3, EtOH

2) NaNH2

OMe

MeO+

MeOO

5

RO

OTHP

R:

1) 180 ºC2) H+

38% (2 Steps)OMe

MeO

R

O

OTHP

J. Chem. Soc. Perkin Trans. 1. 1990, 1423

OH

Me

O via TiCl4 acylation

when R=Si(Me)2iPr

JOC 1997, 42, 2032

•β,γ-unsaturated ketones often isomerize into conjugation

HO

Me

OMe

10 Steps

OR

Me

O

O

MeMe

R= Me, 48%

R = TBDMS, 50%

O

Me

OH

OH

R= Me1) Li, NH3, THF,

EtOH,–78 ºC2)Oxalic acid or ZnBr2 or ZnCl277% (2 Steps)

R= TBDMS1) Li, NH3, THF, EtOH, –78 ºC

2)H3BO3, TBAF, 10 ºC

78% (2 Steps) O

Me

O

O

MeMe

Org. Lett. 2006, 8, 2479

Aryl Ethers

OMe

O Me 1) K, NH3, tBuOH, THF,

-78ºC2) LiBr3)MeI

MeO

Me

33%

CO2H

OMe

Li, NH3, THF

CO2H

Tetrahedron 1982, 38, 2831

75%

JOC 1973, 38, 3887Na instead of Li, MeOH as a H+ donor, addition tBuOK prior to reduction, or quenching with

FeCl3 instead of NH4Cl can limit loss of OMe

mycophenolic acid

;

H3O+


3/10/18Aromatic AcidsMO OM

R

R

HO2C R'

•Presence of an alcohol proton donor can sometimes lead to over reduction to dihydrobenzoic acid and/or conjugate product

•If arene is para substituted will often get a mixture of cis and trans isomers largely influenced substituent sterics

•Use of NH4Cl in absence of alcohol can prevent

CO2H1) Li, NH3,

tBuOH; –78 ºC2) MeOH, cat.

H2SO43) LDA,

BrCH2CO2tBu96% (3 steps)

MeO2C CO2tBu 7 Steps52% overall

10 mol% CuOTf

15 mol%

N N

O O

iPriPr

MeMe

OTBDPS

HPhO2S HO

Or

OR Me OR Me

(–)-platencin(–)-platensimycin

HO2C

HO OHHN O

R:

OTBDPS

SO2PhN2O

Me CO2Me

1) 1,4-addition2) Friedel-Craft Acylation

3) Luche reduction4) ortho directed

carboxylationHO

Me

CO2HMe

1) Na, NH32) CH2N2

HO

Me

CO2MeMe60%

42% (4 Steps)

Note: susceptible to re-aromatization

under any basic conditionCH3C(OMe)2NMe2

xylene, reflux

Me

CO2MeMe

NMe2

O

50%

Me O

O

Me

OOOHHOHO

deoxyanisatin

Rxn with alkyl halides

(most common)

R

HO2C OH

Rxn with H2CO

R

HO2CCO2R'

Rxn with α,β-unsaturated

esters

O O

R

over reduction

CO2H

R

CO2H

RReduction

Reductive Alkylation

Isomerization

R

HO2C

Rxn with epoxide

OH

R'

ORCO2H

Li, NH3, THF;then RCl

OR

O

O OR

RCO2 aq. HCl,

reflux

OR

Tetrahedron 2011, 67, 518

Org. Lett., 2001, 3, 279

JOC 1976, 41, 2649

OMeCO2H

iPr

Li, NH3, THF;then

Br(CH2)2OPh;then aq. HCl

O

iPr

OPh

OH

OHMeH

iPr(±)-oplopanone

O

iPr

OPhBrMgDMS•CuBr

JOC 1978, 43, 4925

Re-aromatization

Annulation

Synthesis Cyclohexenones

Me

OMe

OMe

HO2C

Me

OMe

OMe

O

OLi, NH3,

THF

I

CO2MeOMe Me

OMe

OMe

HO2C

MeOCO2Me

84%

Pb(OAc)4Cu(OAc)2pyridine

88%

Me

OMe

OMe

MeO

MeO2C1) KOH2) TFAA:TFA 1:1

Me

OMe

OMeMeO2CMeO

OH79% (2 Steps)

Aust. J. Chem., 1981, 34, 2249Electrophilic Addition To

CO2H Birch reduction

(not specified)

CO2H1) Br2;

recrystallization62%

CO2HBr

Br

aq. NaHCO365% O

O

Br H

1) NBS2) NaOAc,

HMPA86%O

O

Br H

OAc

CO2H

OHO CO2H

(±)-chorismic acidJACS 1982, 104 , 6787

Nucleophilic Addition ToCO2H

OMe

1)Na, NH3, EtOH;45 minutes stirring;

NH4Cl2) CH2N2

82%

CO2Me

OMe

1) 1.5 eq PhMgBr, –20 ºC;then 15 eq HMPA,

2.6 eq alkylBr2) 2M HCl

O

CO2MeRPh R=

Br 75%

81%Tetrahedron Lett., 1982, 23, 3287

72%95% ee


3/10/18Aromatic Esters

O OR

R R

CO2RR

• Limitations include competitive carbonyl reduction•1-2 equiv. H2O or tBuOH added before Na in NH3 can prevent (doesn't work for methyl esters or those with 4-alkyl substituents)• tBuOH with Li/K in NH3 work with methyl esters and some 4-alkyl substituted

• Unlike aromatic acids, for reductive alkylation esters are usually more soluble, resistant to isomerization, rearomatization and decarboxylation

OMeCO2Me

MeMe

OMe

OMe

I

KOtBu, tBuOH, THF, NH3, –70 ºC;

then K;

MeOCO2Me

98%

N-bromoacetamide, MeOH, 95%

RCO2MeBr

OMeMeO

N

Nreflux;silica, 85%

Me

MeMe

(±)-longifolene

1)

2) Acetone, pTsOH

3

Me Me OMe

OMe

OCO2Me

CHO3

Me Me

2) xylene, reflux40%

CO2Me

O

MeMe

JOC 1985, 50, 915

NNH2

PhPh

1)

Aromatic KetonesO R

R1 R1

R2O

RHO R

R1

R1

R1

MeHO

Me OH

•Over-reduction and Pinacol Coupling major

side products when use metals other than

K or if no H+ source/too strong of a H+ source

(H2O/AcOH)

Me

O

RMe

O1) K, tBuOH,NH3, THF, –78 ºC

Alkyl Group: I 59%

85%

83% (mix ester and acid)

26%

Br

Br OEt

OCl CN

JOC 1973, 38, 3887

2) LiBr, –78 ºC3) RI, 0 to 10 ºC

O OMe1) tBuOH, K, NH3,

THF, –78 ºC2) LiBr, MeI,

–78 ºC 53%

OMeO

Me

MeO2C

O3, MeOH; Zn, AcOH, then

Jones' reagent

MeOMeO

MeO

J. Chem. Soc., Perkin Trans. I. 1985, 383

Tetrahedron Lett. 1986, 27, 5253

1) LDA; PhSeCl2) H2O2

Arylsilanes • Most commoly used to control regiochemistry of reduction as give allylic silanes• Many times C–Si bond cleaved directly using standard conditions

SiMe3

R

Side Products:

R R

SiMe3

R

SiMe3Li, NH3, EtOH

R

Product(major)

SiMe3

Yield 76%

SiMe3

Me

SiMe3

Me

SiMe3

Me

Me

SiMe3

Me

Me

SiMe3

Me

SiMe3

Me

60% 70% 70%

SiMe3

SiMe3

SiMe3

96%

J. Chem. Soc., Perkin Trans. I. 1975, 470

Polyaromatic• more reactive than simple benzenes• site of reduction controled by distribution of e- density in anionic intermediates• mixture products common

Na, NH3, EtOH, Et2O; H2O62%

Li, NH3, THF 30 min, –33 ºC; NH4Cl

98%Li, NH3,THF, –78 ºC

15 min; NH4Cl

Li, NH3,THF, –78 ºC, 30 min; FeCl3, 45 min, –33 ºC; NH4Cl

JOC 1983, 48, 4266J. Chem. Soc., 1951, 1945

1 mol% OsO4, NMMO

60%OH

OH

+OH

OH1:8

1) Ac2O, Pyridine2) mCPBA

3) 10% AcOH85%

OAc

OAc

OH

OH

OH

OH

OH

OH

HOHO

HOHO

OH

OH

OH

OH

HOHO

HOHO

neo-inositolORchiro-inositol



3/10/18

Asymmetric Methods: Amides

JACS 1988, 110 , 7828

N

O OMe

R NH

NO

OH

RO

NO

HR

• Most methods use L-proline derivatives as a chiral auxiliary for diastereoselective reductive alkylation• Procedures use K instead of Li to prevent F.G. reduction

N

O OMe

O

NO

H

OMe

N

O OMe

OMe

R

O

NO

H

R

R= Me, d.r. 85:15R= Et, d.r. ≥99:1

R= Me, d.r. 260:1R= Et, d.r. >99:1

• Opposite selectivity arises though chelation enolate to OMe

as well as NH3•Selectivity reversed by allowing equilibration to thermodynamic

enolate before addition RX

N

O OMe

Me

N

O OMe

Me

R

R= Me, d.r. >99:1

K, NH3, tBuOH, THF, –78 ºC;RX, –78 ºC


O

NOMe

O M

Me

kineticenolate


O

NMO

HDrawbacks: •dificulty in remove aux.•Need o–substituent to promote good selectivity

Me

MeMe

(–)-longifolene

JOC 1985, 50, 915

MeMe

OMe

OMe

I

KOtBu, tBuOH, THF, NH3, –70 ºC;

then K;

96%O

NO

Hsingle diastereomer

MeMe

OMeMeO

75%

RCO2Me

OMe

Same as prior sequence

NH

OH

NH

OH

MeN

OH

(–)-isonitramine (+)-nitramine

(+)-sibirineN

O OMe

OMe

N

O OMe

OMe

K, NH3, tBuOH;

ClBr

K, NH3, tBuOH;

N

O OMe

OMe

OAc

Br OAc

single diastereomer

Heterocycles 1987, 25, 437N

O

O

OHHO

H

H

(+)-lycorine

JACS 1996, 118 , 6210

O

NO

H

K, NH3, tBuOH;

ClBrO

NO

H

Cl

Or

N

O OMe

R2

R1

4 Steps

K, NH3, tBuOH, THF, –78 ºC;R3X, –78 ºC

N

O OMe

R2

R1 R3

Opposite Diastereomer: • at R3 if R2=OMe• at R2 and R1 if use different catalysts like Rh or Al

1) PDC, tBuOOH, Celite2) H2,

[Ir(cod)py(Pcy3)]PF6

N

O OMe

R2

R1 R3

OR2O

O

R1 R3O

N

OMe

1) NaOMe2) H+ mCPBA

O

R1

OR2

CO2MeR3

Tet. Lett. 1992, 33, 6614

N

O OMe

OMe

MeK, NH3, tBuOH,

THF, –78 ºC;EtI, –78 ºC N

O OMe

OMe

Me EtO

Me

O

OMe

CO2MeEt NN

MeO2C Et

H

JOC 1997, 62, 1223 (+)-apovincamine

Me

NH

NO

HO

4 equiv. K, NH3, 2 equiv.

tBuOH;NH4Cl

Me

NH

NO

HOH

H H2, [Ir(cod)py(Pcy3)]PF6

Me

NH

NO

HOH

H

CHOH

NHCO2tBuH

MeH

H

Me

NH

Pr

(+)-pumiliotoxin C JACS 1987, 109 , 6493

K, NH3, tBuOH;

MeI

N

O OMe

OMe

Me6M HCl N

O OMe

O

Me I2, H2O81%

O

OI

MeH

O

OMe

HO2C

O

HO

O Me

40%

41%

Cl

OO

MeN

SPh

O 4 Steps52%

LiOH+

ONO

H

HH

O

Me

1) nBu3SnH, AIBN

2) K2CO374%

JOC 2004, 69, 7734

(–)-9,10-epi-stemoamide


3/10/18

JOC 1996, 61, 7664

Heterocycles• Just as with carbocycles, co-solvents can be used to increase solubility (Dioxane, THF, Et2O, DME) and order of addition can impact yield and product• Alcohol addition depends on substrate (i.e. moderately activated usch as e--deficient pyrroles and furans don't need)

Pyrroles Unactivated or with only Electron Donating substituents: No desired products

NO

R2Na, NH3,

THF, tBuOH; MeI N

MeR

O

R1 = Me,N 25-30%

OiPr 20%

NMe O

H

Major Byproduct

R1 R1

R1 = Boc,N

85% (tBuOH

excluded)

Yield

∗ = Optimized conditions; can also be used with EtI, BuI, iBuI, BnBr and AllylBr

R2 =

R2 =

–78 ºC

NR1

2-substituted

3-substituted

R2O

Na, NH3, THF; RX

–78 ºC


NR1

R3R2O

10 eq. (MeOCH2CH2)2NH needed to prevent loss of R1 group when = Adoc

R1 R2 R3 Yield

Boc

Boc

Adoc

Adoc

OCy

OCy

R1 = Me,R2 =

N

N

Me

Me

70%

Bn

H

69%

74%

72%

3,4-disubstituted

NBoc

CO2EtEtO2C Li, NH3, THF;

then RXNBoc

CO2EtRR

EtO2C

Li, NH3, THF;

then R1X;then R2X

NBoc

CO2EtR2R1

EtO2C

Rcis:trans

Yield

Me Et Allyl iBu>20:1 >10:1 >10:1 >10:177% 82% 70% 79%

R1 cis:trans YieldMeBn 77%

82%only cisonly cis

R2

iBuiBu

J. Chem. Soc. Chem. Commun. 1999, 141

Pyridines Very sensitive to rxn conditions

N Me RN MeMeNMe

NMeMe

Li, NH; MeI

3 eq. Li, NH3, 2 eq. EtOH;RX or NH4Cl

R=Me or H80-93%

93%

JOC, 1975, 40, 3606N NH

EtLi, NH3,

EtOH, Et2OEtOH, NaOH

OMe

J. Chem. Soc. Chem. Commun. 1975, 480

63% (2 Steps)

Indoles

NMe

RNMe

R

Reduction carbocyclic ring

NMe

R

Reduction heterocyclic ring

Li, NH3; NH4Cl

Li, NH3; MeOH

(excess)

JOC, 1971, 36, 279

•It is thought that MeOH is acidic enough to rapidly protonate the radical anion as it forms in equilibrium with the N-alkylindole but NH3 is not acidic enough and can only protonate the dianion

NR1

5 eq. Li, NH3;MeOH

NH

R1 +N

R1

R1 = 7–OMe or HJOC, 1971, 36, 279

2 eq. Li, NH3;NH4Cl or R2X

NR1

R2

Quinolines

J. Chem. Soc., Perkin Trans. 1, 1973, 2754

When R1=HR2

YieldMe iPr Bn CH2OMe CO2Me88% 78% 45% 79% 78%

Furans As with pyrroles unactivated or furans with electron donating substituents cannot be reduced under Birch conditions

• Note if too large an excess of metal isused

dimeric and ring openned side products predominate

• Amides as EWG also work

2-substituted

3-substituted

O CO2H

2.5 eq. Li, NH3, –78 ºC;

then RX or NH4Cl O

RCO2H

R2

YieldMe iPr Bn H75% 95% 75% 80%

Tetrahedron Lett., 1 975, 9, 627

2,5-disubstituted

O CO2H

3 eq. Li, NH3, 1.6 eq.MeOH

–78 ºC;then

NH4ClR O CO2HR

RYield

Me Bn83% 85% 64%

Et nPr tBu (p-MeO)Bn71% 40% 40%

Bull. Chem. Soc. Jpn., 1 975, 48, 491

cis:trans (1:1) (1:1) (1:1) (1:1) (3:2) (3:2)

O

CO2HLi, NH3;NH4Cl

(no added proton source)O

Me

OHO

1) Na, NH3, 8 eq. iPrOH;

O

CO2Me

O

OO

HO

Me

Me

3J. Heterocycl. Chem., 1 992, 29, 1025

NH4Cl

autoregulator (±)-A-factor

2) CH2N2 85%

O

ONiPr2 Li, NH3;

RX, –78 ºC

O

RNiPr2

OR

YieldMe iPr Bn

92% 90% 98% 98% 85%H Et allyl

92%Note: can be done asymmetrically using same L-proline derived amides as previously shownJ. Heterocycl. Chem., 1 996, 33, 1313

Theorized ring opening do to the instability of carbanion intermediate:

Aust. J. Chem., 976, 29, 2553

O

O

OO

O

O

N

O

O

R

RMost stable

*


3/10/18

JOC, 1967, 32, 2794

Benzofurans Very sensitive to reaction conditions.

O

MeOLi, NH3, no proton

source

MeO Et

OH 50%

Li, NH3, 15% EtOH

O

MeO

88%R

R=HR=H

Li, NH3, tBuOH Li, NH3,15% EtOHR=Me R=Me

O

MeOMe

O

MeOMe

Benzothiophenes and Dibenzothiophenes - very few examples

Unlike furans and pyrroles, unactivated thiophenes has been reported but gives a mixtures of over-reduced and ring cleaved products

SNH3, Li,

MeOH; H2O S12%

S26%

S30%

+ 17% cleaved product

SNH3, Li,

MeOH; H2O S7%

S32%

S27%

+ 10% cleaved product

Me Me Me Me

SNH3, Li,

MeOH; H2O S SSMe Me Me Me+ cleaved product

(Yields not reported)

J. Chem. Soc., 1951, 3411

2-substituted

SO

OR1

R1=H

Li, NH3, MeOH;NH4Cl

HS CO2MeR1=Li salt

Li, NH3, MeOH;NH4Cl

SO

OH(slight ring

opening only observed

when R2=H)J. Chem. Soc., 1951, 3411

R2R2

No comment on cis:trans selectivityChem. Lett., 1981, 1341

SO

R1R2

Na, NH3, Et2O, EtOH;

NH4Cl;R3X

SR2 R3R1

O

R1

R2

R3

Yield

nPr nPr nPr nC7H15CyH H H nBu MeBn allyl Bn Bn Me

82% 68% 80% 76% 44%3-substituted - almost no examples

S

OHO

2.5 eq. Na, NH3,iPrOH;

H3O+

S

OHO

S

OHO

+ +

++

+ +

+3:2 mix product to starting

material; low yieldingTetrahedron Lett., 1985, 26, 1791

S SH

Et

SSH

Na, NH378%

Na, NH370%

Targets in heterocyc. sys., 1999, 3, 117

Application to Methodology

Synthesis of chiral cyclohex-2-enonesOMe

R2

R1

1) Birch Reduction2) Hydrolysis

(conditions not specified)

O

R2

R1

O

R2

R1

*NN

NH

N

OMeN

NH2

HN

MeON

H2N

CF3

QA QDAOr

Me

Cl

CO2H

OrMe CO2H

PhCH3-25ºC

PhF-15ºC

O

iPrMe

QA= 75%, ee: -87%

QDA= 83%, ee: 90%

*

O

Me

QA= 84%, ee: -83%

QDA= 79%, ee: 89%

*

O

Me

QA= 58%, ee: -80%

QDA= 75%, ee: 88%

*

O

*

QA= 60%, ee: -78%

QDA= 67%, ee: 85%

Me

Me CO2Me

O

MeMe

H

O

MeMe

OMe

MeMe

Li, NH3, Et2O; (CO2H)2

MeMe

H

OMe

MeMe

H

MeCHO

(–)-isoacanthodoral

QDA method

69%ee: 86%2 Steps

140ºC46%

(3 Steps)

74%

JACS 2012, 134 , 18209

Synthesis of Spiral Lactams Eur. J. Org. Chem. 2017, 6, 1074

R1

CO2H Li, NH3, –78 ºC;

ClCH2CN

R1

CO2HCN

R1

NHO

H2, PtO2

NHO

98%

NHO

96%

Me

NHO

97%Me

NHO

96%Me

Chem. Commun. 2011, 47, 3989Synthesis chiral cyclohexanes

R1 R2Na, NH3,

tBuOH, THF or Et2O

R1 R2

R1 R2

S

NPh

P IrPh Ph

N

NPh

P IrPh Ph

Or

H2 (20 bar)

MeO OMe

trans:cis>99:1

ee >99%

Et

trans:cis56:44

ee trans: 96%

OHMe

MeMeO iPr

trans:cis86:14

ee trans: 94%MeO

trans:cis>99:1

ee >99%

OMe

MeO Me

iPr

R3 R3

R1 R2

R3

ee: 89%Thiophenes

Or


3/10/18

Chem. Eur. J. 2018, 24, 1681Synthesis of chiral allylsilanes for Hosomi–Sakurai allylation

SiMe3

R2R1

Li, NH3, tBuOH or

SiMe3

R2R1 SiMe3

R2R1

R2R1

OH

R3

N

NIr

Ph Ph

OMeMeO

+ BArF-

H2 TiCl4,RCHO,-78ºCMe

OH

CyMe65%

d.r. single diastereomer

Me

OH

iBuMe32%

d.r. 24:1

Me

OH

Ph

Et

69%d.r. single

diastereomer

EtOH, THF; NH4Cl

Me

OH

Ph

Me

42%d.r. 31:1

CO2H CO2HR1 R1

R2

ACS Catal. 2018, 8, 1213Synthesis ortho-alkylated vinylarenes

Li, NH3; R1X5 mol% Pd(TFA)2

4 eq.TEMPOEtCO2H

80 ºC

+ R2(specific conditions

not reported)

MePO

OEtOEt

82%

Me R=H, 34%R=Me, 44%R=Ph, 83%

R=OMe, 77%R=NMe2, 74%

R

O Me

MeMe

Ph

62%CO2Me

iPr33%

R2

OR1

OMe

1) Li, NH3, tBuOH, THF, –78 ºC

R2=(S)-2-(methoxymethyl)pyrrolidine

2) RR3

R4

R1

OMeO

R2R4

R3

6M HClR1

OO

R2R4

R3

R2

O

OR1

R4

R3

Δ

R2

O

OPh

32% (3 Steps)d.r. = 35:1

R2

O

O53% (3 Steps)

d.r. = >99:1

MeO

MeO

Enantioselective Birch-Cope Sequence for Quaternary Stereocenters JOC 2007, 72, 930

R2

O

OMe

51% (3 Steps)d.r. = >99:1

(when K instead of Li and AllylCl)

Me

O

R2

OMe61% (3 Steps)

d.r. = 110:1

R2

O

OMeO41% (3 Steps)

d.r. = 50:1

OH Li, NH3, EtOH,THF;

H+

OACIE 2008, 47, 177γ-Arylation of β,γ-Unsaturated Ketones

2% Pd(OAc)24% dppe

1.5 equiv. Cs2CO3,100 ºC

O

R2

R1 R1R2

Ar R1R2

O

R1

R2

NH

R3

Or

when Ar = ortho-NH2O

MeO

Me

80%

O

Me O

Me

61%Me

O

Me

MeNH

69%

O

nPr

HNH

66%MeO

+ ArBr

O

Me

HNH

60%

O

Me

HNH

81%F

MeO2C

Org. Lett. 2007, 9, 2677Synthesis of annulated arenes

Li, NH3, tBuOH;

BrBr3,4CO2tBu

CO2tBuBr3,4

1) CrO3, AcOH, Ac2O

2) NaItBuO2C

O

0,1OH

0,1

2)Bu3SnH, AIBN, 85 ºC

2) Saegusa [O]

OH OHOHOH

Me

1) RMgCl2) BiCl3•H2O

CO2tBuI3,4

O

1) NaBH42) BiCl3•H2O

BiCl3•H2O

0,1

0,1

R

Or

Or

Ph


3/10/18

Electrochemical Birch Reduction

JACS 1963, 85, 2858; JACS 1964, 86, 5272;

J. Electrochem. Soc., 1966, 113, 1060

R RRPt, LiCl, MeNH2,

Pt, LiCl, MeNH2,

undivided cell divided cell

H MeEt iPr tBu

R=Divided Undivided

49%64%73%82%85%

49%44%63%75%81%

• methylamide serves as proton source forming LiNHMe

• in undivided cell methylamine HCl can quench LiNHMe; in divided two are seperated so LiNHMe isn't neutralized and isomerizes to conjugated 1,3-diene which can be further reduced

Other reported procedures:• Pt, LiCl, MeNH2 JACS 1963, 85, 2858;• Pt, Graphite or C; LiCl, ethylenediamine: major product cyclohexene J. Electrochem. Soc., 1963, 110, 425•Al, LiCl, EtOH:HMPA 67:33, undivided: major product cyclohexane Bull. Chem. Soc. Jpn., 1982, 55, 347•Hg, (Bu3EtN)OH, H2O, 60ºC, J. Electrochem. Soc., 1981, 128, 322•Hg, (TBA)BF4, THF/H2O, rt JOC., 1985, 50, 556

•First reported by Birch himself:

Nature, 1946, 158, 60

CO2H

NH2

CO2H

NH2

Pt, NH3, LiOAc, H2O, tBuOH

72%C.E. 45%

Me O

MeO

Pt, LiCl, MeNH2

Me OH

MeO

93%C.E. 44%

NH2 NH2Al,HMPA, LiCl,

EtOH44-48%

C.E. 41-46%

O OHMeSn,iPrOH,

Et4NOTs70%

OMe

HO

OMe

HO

Al,HMPA, LiCl,

EtOH34-37%

C.E. 33-35%

OMe OMeAl,HMPA, LiCl,

EtOH46%

Red. Trav. Chim. Pays-Bas. 1995, 114 , 259

Electrochemical Birch reductions

Mechanismecath Solvent eS

•The observed differences in product distribution (cyclohexadiene vs. cyclohexene vs cyclohexane) has been attributed to proton availability

Control by lowering current density, temperature and EtOH concentrationJACS 1969, 91, 4194

eS +

+

+ MeNH2

HH + MeNHLi

eS+H

HH

H

HH

HH

HH+ MeNHLi+ MeNH2

Note that unlike under standard Birch conditions no loss of Si reported

•substratesresulting in vinylic TMS

groups can be overreduced

SiMe3R

SiMe3R

Pt, LiCl, MeNH2,

–5 ºC or –50 ºCundivided

SiMe3 4% regioisomer and

overreduced80%

+SiMe3

53%+

SiMe3SiMe3

SiMe3

17%+ 5% regioisomer

SiMe3Me3Si

68%

6% overreduced

+

SiMe3

Me3Si

93%cis:trans:

78:20 at –5 ºC85:15 at –50 ºC

SiMe3

Me

75%

J. Chem. Soc., Perkin Trans. 1 1974, 2055

The Birch reduction - Baran Lab · OMe1) K, NH 3, tBuOH, THF, -78ºC 2) LiBr 3)MeI Me O Me 33% CO2H...

Documents

Transcript of The Birch reduction - Baran Lab · OMe1) K, NH 3, tBuOH, THF, -78ºC 2) LiBr 3)MeI Me O Me 33% CO2H...