the birch reduction - baran lab · ome1) k, nh 3, tbuoh, thf, -78ºc 2) libr 3)mei me o me 33% co2h...
TRANSCRIPT
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
The Birch ReductionLisa M. BartonBaran Group Meeting
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+
The Birch ReductionLisa M. BartonBaran Group Meeting
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
The Birch ReductionLisa M. BartonBaran Group Meeting
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
Tetrahedron Lett. 2003, 44, 3105
The Birch ReductionLisa M. BartonBaran Group Meeting
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
K, NH3, tBuOH, THF, –78 ºC;RX, –78 ºC
O
NOMe
O M
Me
kineticenolate
K, NH3, tBuOH, THF, –78 ºC;RX, –78 ºC
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
The Birch ReductionLisa M. BartonBaran Group Meeting
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
Tetrahedron Lett. 1998, 39, 3075
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
*
The Birch ReductionLisa M. BartonBaran Group Meeting
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
The Birch ReductionLisa M. BartonBaran Group Meeting
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
The Birch ReductionLisa M. BartonBaran Group Meeting
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