Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
Stereochemistry
Helpful Resources:
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]
• Determined by the protonation of the final monoanion
• reductive alkylation leads greater selectivity due to increased sterics
HR
R1
HR
Background
• Originally discovered by Wooster and Godfrey in 1937 in the
reduction of toluene in NH 3 using either Na or K JACS, 1937, 59, 596
• When R1,2 is H no steric
O
2
O
R preference and protonation
occurs equally from either face
H • When R1,2 ≠H Cis product
RH H
predominates
HR
Procedures
Solvents: Ammonia*
• Extensively developed by Arthur J. Birch and is therefore named after him
• When there is a π
substituent, a boat
R1 conformation is adopted
• vinyl hydrogens block
H
bottom lobe of anion
orbital and protonation
comes from top face
∗ = Most commonly used
Metals: Sodium*, Lithium*, Potassium*, Calcium, Magnesium
• Li most reactive but can therefore lead to overreduction, in which case Na best
First Publication on: J. Chem. Soc., 1944, 430
Complete list of contributions: Tetrahedron, 1988, 44, No. 10, pp. v-xviii
Cosolvents (used to aid in solubility): Diethyl Ether*, Tetrahydrofuran*, Glymes*
Mechanism
Proton Sources: Ethanol*, tert-butyl alcohol*, H 2O
1) Electron-Donating Substituents
R
R
e
ROH
H
H
R
R
H
H
e
ROH
H
H
Concentration: Often run under dilute conditions (0.1–0.5 g metal per 100 mL NH 3)
R
Temperature: Most commonly ran at –78 ºC, due to low bp of NH 3. highest at reflux (–33 ºC)
Purity of Reagents: Not necessary but recommended
H
H
2) Electron-Withdrawing Substituents
R
R
R
ROH
e
R
e
H H
R
e
2
ROH
or NH 3
H H
H 2O
or R'X
R R'/H
Order of Addition: Often very important and empirically determined
• Substrate dissolved in cosolvent with alcohol can be added to NH 3 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, NH 4Cl,
FeCl 3),electron-transfer reagents (sodium benzoate/dienes then water), or alkyl halides in
the case of reductive alkylations
• Most commonly the fast addition of saturated NH 4Cl (frothing occurs) is used
Organic Reactions, 1992, 42, 1
H H
Comparison with Other Methods
Benskeser 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
• 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)
Not Discussed in this group meeting:
• Birch reduction of non-aromatic compounds (ie protecting group removal, alkenes, alkynes)
• Birch reduction for functionalization of nanotubes
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
Aryl Ethers
OR
OMe
O
O
OR
O
OH O
R'
R'
via TiCl4
acylation
Me
when
R=Si(Me) 2iPr
JOC 1997, 42, 2032
• Limitations: Partial or complete loss of alkoxy group (usually when para or ortho to EWG)
O
Me 1) K, NH ,
CO2H
O
CO2H
3
Me
tBuOH, THF,
Li, NH 3,
-78ºC
Me
THF
2) LiBr
75%
3)MeI
33%
OMe
OMe
JOC 1973, 38, 3887
O
R= Me,
48%
O R = TBDMS,
50%
OR
O
Me
Me
2)H3BO 3, TBAF,
10 ºC
78% (2 Steps)
R= Me
1) Li, NH 3, THF,
EtOH,–78 ºC
Org. Lett. 2006, 8, 2479
Alkylation precursors
Me
Na,
NH 3,
tBuOH
O
O
NEt 2
2)Oxalic acid or
ZnBr2 or ZnCl2
77% (2 Steps)
nBuLi;
RBr
H 3O+
Me
NEt 2
C8H17
O
Me
OMe
O
OH
Me
Me
H
J. Chem. Soc. Perkin Trans. 1. 1983, 7
1) MsOH
91%
2) H 2, Pd/C
99%
OMe
iPr
Na, NH 3
EtOH, THF,
-78ºC;
then HCl
80%
H
CO2Et
iPr
CN
61 ºC, CHCl 3 MeO
2)Na2S•9H 2O
80% (2 Steps)
OH
C5H11
(Z)–henicos-60-en-11-one
O
OMe
H
3:2 α:β
Me
MeO
Me
1) Na, NH 3,
EtOH
2) NaNH 2
R
+
J. Chem. Soc. Perkin Trans. 1. 1990, 1423
1) 180 ºC
2) H +
38% (2 Steps)
R:
MeO
OTHP
(±)-luciduline
CO2Me
Me
OMe O
Me
OMe O
O
J. Chem. Soc. D, 1969, 788
MeO
O
MeO
Me
OMe
C10H 21
O
O
Me
N
CO2Me
MeO
mycophenolic acid
H
H
Me DMAD
Δ
O
HO 2C
H
1)
BrMg
Me
2) 250 ºC
O 3) (CH 2OH)2,
cat. pTsOH
65% (3 steps)
OMe
Me
O
C10H 21
Cl
1)
Me
O
pregn-4-en-20-one
(formal of pregesterone)
C5H11
CO2Et
CO2Et
ACIE 2017, 56, 12708
Me 1) Birch reduction
(not specified)
2) KOtBu, DMSO
MeO
O
O
iPr
OMe
Me
1) KNH 2,THF,
liq. NH 3,
–33 ºC; RBr
2) HCl
C10H 21
OMe
JACS 1972, 94, 4779
;
Li,
NH 3,
tBuOH
Li,
NH 3,
tBuOH
OH
Me
Me
Me
Me
O
2 equiv. Cs2CO 3
60 ºC
65%
O
Cycloaddition precursors
O
O
OMe
H
iPr CO2H
mulinic acid
OMe
Me
Me
J. Chem. Soc., Chem. Commun., 1983, 123
OMe
iPr
O O
H
R= TBDMS
1) Li, NH 3, THF, Me
EtOH, –78 ºC
10 Steps Me
Me
CO2Et
Tetrahedron 1982, 38, 2831
Me
I
O
Me
+ 6 other Mulinane
Diterpenoids of
H
same scaffold
Na instead of Li, MeOH as a H + donor, addition tBuOK prior to reduction, or quenching with
FeCl 3 instead of NH 4Cl can limit loss of OMe
•β,γ-unsaturated ketones often isomerize into conjugation
HO
1) 50 atm H 2
0.04 mol %
CO2Et Ir-(R)-SpiroPAP
92%, >99% ee
d.r. 95:5
iPr
2) PCC, 92%
O
MeO
curvularin
O
OMe O
O MeO
O
5
Me
O
R
OTHP
Me
Aromatic Acids
MO
OM
O
CO2H
Reduction
O
Isomerization
Synthesis Cyclohexenones
OR
Li, NH 3, THF;
CO2H
then RCl
CO2H
over
reduction
R
R
R
R
HO 2C
OH
HO 2C
HO 2C
CO2R'
Reductive
Alkylation
R
R
OH
R
Annulation
1) Li, NH 3,
CO2H tBuOH; –78 ºC
2) MeOH, cat. MeO 2C
H 2SO 4
3) LDA,
BrCH 2CO2tBu
96% (3 steps)
HO 2C
OTBDPS
10 mol%
CuOTf
15 mol%
CO2tBu
7 Steps
52% overall
O
R
O
N
SO2Ph
(–)-platencin
Me
HO HO
deoxyanisatin O
Me
O
Me
OH
O
JOC 1978, 43, 4925
Re-aromatization
OMe
HO 2C
Li, NH 3,
THF
O
I
OMe
HO 2C
CO2Me MeO
OMe
84%
O
Me
OMe
OMe
CO2Me
Me
OMe
MeO
MeO 2C
Pb(OAc) 4
Cu(OAc)2
pyridine
88%
72%
95% ee
Me
CO2Me
MeO
MeO 2C
Me
79% (2 Steps)
OH OMe
Me
OMe
Aust. J. Chem., 1981, 34, 2249
Electrophilic Addition To
CO2H
Birch
reduction
(not specified)
CO2H
1) Br 2;
recrystallization
62%
CO2H
CO2H
Br aq. NaHCO 3
65%
JACS 1982, 104 , 6787
Tetrahedron Lett., 1982, 23, 3287
O
Br
O
CO2H
OH
Br
H
O
O
Br
(±)-chorismic acid
Note: susceptible
to re-aromatization Nucleophilic Addition To
NMe 2
CO2H
under any basic
1)Na, NH 3, EtOH;
CH 3C(OMe)2NMe 2
condition
45 minutes stirring;
xylene, reflux
NH 4Cl
Me
50%
2) CH2N 2
OMe
CO2Me
82%
Org. Lett., 2001, 3, 279
OMe
1) KOH
2) TFAA:TFA 1:1
N
Me
HO
H
O
iPr
(±)-oplopanone
iPr
iPr
iPr
OMe
OTBDPS
O
H
PhO 2S
H
R
Me OH
H
OPh
BrMg
DMS•CuBr
OPh
Me
Tetrahedron 2011, 67, 518
1) 1,4-addition
Me
2) Friedel-Craft Acylation
1) Na, NH 3
3) Luche reduction
2) CH2N 2
4) ortho directed
CO2Me
carboxylation
Me 60%
42% (4 Steps)
HO
CO2H
O
O
O
OMe
iPr
MeO
Or
(–)-platensimycin
Li, NH 3, THF;
then
CO2H
Br(CH 2)2OPh;
then aq. HCl
O
O
iPr
R
OMe
Me Me
O
N2
MeO
R
OH
O
R:
Me
O
aq. HCl,
reflux
CO2
JOC 1976, 41, 2649
R
Rxn with
Rxn with
Rxn with
Rxn with
alkyl halides
α,β-unsaturated
epoxide
H 2CO
esters
(most common)
•Presence of an alcohol proton donor can sometimes lead to over reduction to
dihydrobenzoic acid and/or conjugate product
•Use of NH 4Cl in absence of alcohol can prevent
•If arene is para substituted will often get a mixture of cis and trans isomers largely
influenced substituent sterics
HN
OR
OR O
R'
HO 2C R'
HO
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
1) NBS
2) NaOAc,
HMPA
86%
H
OAc
O
CO2Me
OMe
1) 1.5 eq
PhMgBr, –20 ºC; Ph
then 15 eq HMPA,
2.6 eq alkylBr
2) 2M HCl
R CO2Me
R=
Br 75%
O
81%
Aromatic Esters
O
• Limitations include competitive carbonyl reduction
•1-2 equiv. H 2O or tBuOH added before Na in NH 3 can
prevent (doesn't work for methyl esters or those with 4R CO2R
alkyl substituents)
• tBuOH with Li/K in NH 3 work with methyl esters and
R
some 4-alkyl substituted
• Unlike aromatic acids, for reductive alkylation esters are
usually more soluble, resistant to isomerization,
rearomatization and decarboxylation
OR
R
KOtBu, tBuOH,
THF, NH 3, –70 ºC;
OMe
then K;
CO2Me
Me Me
OMe
I
CO2Me
N-bromoacetamide, MeO OMe
3 OMe MeOH, 95%
CO2Me
Br
R
Me Me OMe
1)
Side Products:
HO
R
O
R2
R
R1
O
R
85%
Br
Br
O
Cl
JOC 1973, 38, 3887
OEt
83%
(mix ester and acid)
CN
26%
Me OH
CO2Me
3
CHO
Me Me
N
reflux;
silica, 85%
2) Acetone,
pTsOH
• Most commoly used to
control regiochemistry of
SiMe 3
reduction as give allylic silanes
Li, NH 3,
•
Many
times
C–Si
bond
R
EtOH
R
cleaved directly using
standard conditions
SiMe 3
R
R
Me
SiMe 3
76%
60%
SiMe 3
SiMe 3
SiMe 3
SiMe 3
Me
Yield
Me
Me
Me
Product
(major)
SiMe 3
SiMe 3
SiMe 3
R
SiMe 3
Me
70%
70%
96%
Polyaromatic
• more reactive than simple benzenes
• site of reduction controled by distribution of e- density in anionic intermediates
• mixture products common
Li, NH 3,THF, –78 ºC, 30 min;
Na, NH 3, EtOH, Et 2O; H 2O
FeCl 3, 45 min, –33 ºC; NH 4Cl
62%
Li, NH 3, THF 30
min, –33 ºC; NH 4Cl
98%
Li, NH 3,THF, –78 ºC
15 min; NH 4Cl
Me O
JOC 1983, 48, 4266
J. Chem. Soc., 1951, 1945
1) LDA;
PhSeCl
2) H 2O2
1 mol% OsO4,
NMMO
60%
Me O
MeO 2C
Tetrahedron Lett.
1986, 27, 5253
Me
Me
SiMe 3
J. Chem. Soc., Perkin Trans. I. 1975, 470
•Over-reduction and
Pinacol Coupling major
1
R
side products when
use metals other than
K or if no H + source/too
strong of a H + source
(H 2O/AcOH)
O 1) tBuOH,
K, NH 3, MeO
THF, –78 ºC
2) LiBr, MeI,
–78 ºC
53%
O3, MeOH; Zn,
AcOH, then
Jones' reagent
O
Me
MeO
Me MeO
59%
I
HO Me
R1 R1
R1
1) K, tBuOH,NH 3,
THF, –78 ºC
Me 2) LiBr, –78 ºC
3) RI, 0 to 10 ºC
Alkyl Group:
O
N
JOC 1985, 50, 915
R
O
1)
CO2Me
Aromatic Ketones
O
NH 2
N
Ph
Ph
2) xylene, reflux
40%
O
Me
(±)-longifolene
Arylsilanes
SiMe 3
MeO
OMe
98%
Me Me
Me Me
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
J. Chem. Soc., Perkin
Trans. I. 1985, 383
HO
HO
chiro-inositol
HO
HO
OH
OH
OH
OH
OH
1) Ac2O, Pyridine
OAc
2) mCPBA
3) 10% AcOH
+
85%
OAc
OH
OH
1:8
HO
OH
HO
OH
OH
OR neo-inositol
HO
OH
OH
OH
HO
Tetrahedron Lett. 2003, 44, 3105
OH
Asymmetric Methods: Amides
OMe
O
O
O
N
N
R
R
N
R
N
H
H
O
K, NH 3, tBuOH,
THF, –78 ºC;
RX, –78 ºC
N
OMe
OMe
K, NH 3, tBuOH,
THF, –78 ºC;
RX, –78 ºC
O
N
Me
O
K, NH 3, tBuOH,
THF, –78 ºC;
RX, –78 ºC
N
R
O
N
R2
Me
N
OMe
JOC 1997, 62, 1223
kinetic
O enolate
M
K, NH 3, tBuOH,
THF, –78 ºC; Me
EtI, –78 ºC
R3
O
N
N
R1
mCPBA
N
R2
OMe
O
Me O
N
N
R2
O
Tet. Lett. 1992, 33, 6614
Et
O
OMe
O
O
N
OMe
Me
Et
75%
OMe
Me
(–)-longifolene
O
Cl
N
Cl
NH
Or
OH
(+)-nitramine
OH
(–)-isonitramine
H
O
K, NH 3,
tBuOH;
NH
Me
N
OMe
O
N
Cl
(+)-sibirine
OH
OMe
OMe
OAc
OH
K, NH 3,
HO
OMe
O
tBuOH;
H
JOC 1985, 50, 915
OAc
O
Br
JACS 1996, 118 , 6210
N
Heterocycles 1987, 25,
H
K, NH 3,
N
43769, 7734
JOC 2004,
O
OMe
tBuOH;
(+)-lycorine
single
diastereomer
MeI
Me
OMe
OMe
O
I
O
O
Me
Me
O
O
I 2, H 2O
N
N
6M HCl
81% H
Me LiOH
40%
HO
+
OMe
O
O
O
H
O
1) nBu 3SnH, O
Me
O
O
4 Steps
O
AIBN
N
O
52%
41%
N
O 2) K 2CO 3
Me
HH
74%
HO 2C
Me
SPh
(–)-9,10-epi-stemoamide
JACS 1988, 110 , 7828
R3
4 Steps
N
Br
H
OMe
O
O
Cl
OMe
O
R2
R3
Br
H
O
OMe 1) PDC, tBuOOH,
Celite
2) H 2,
[Ir(cod)py(Pcy 3)]PF6
O
K, NH 3,
tBuOH;
N
N
Me Me
Same
as
prior
R
sequence
CO2Me
OMe
H
O
single diastereomer
OMe
96%
O
OMe
H
O
R= Me, d.r. 85:15
R= Et, d.r. ≥99:1
OMe
K, NH 3, tBuOH, 1
R
THF, –78 ºC;
R 3X, –78 ºC
OMe
I
OMe
O
R= Me, d.r. 260:1
R= Et, d.r. >99:1
Me
OMe • Opposite selectivity arises
O
R
though chelation enolate to OMe
N
as well as NH 3
•Selectivity reversed by allowing
Me
equilibration to thermodynamic
R= Me, d.r. >99:1
enolate before addition RX
O
MO
R
N
N
Opposite
CO2Me
Diastereomer:
O
3
R
• at R 3 if R 2=OMe
R1
R2
• at R 2 and R1 if O
1) NaOMe
use different
2) H + O
catalysts like Rh
1
R
O
or Al
O
OMe
O
KOtBu, tBuOH, MeO
THF, NH 3, –70 ºC;
Me
then K;
Me
Me Me
OMe
• Most methods use Lproline derivatives as a
chiral auxiliary for
diastereoselective
reductive alkylation
• Procedures use K
instead of Li to prevent
F.G. reduction
N
H
O
Drawbacks: •dificulty in remove aux.
•Need o–substituent to
promote good selectivity
R1
H
O
OMe
O
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
N
H
H
O
4 equiv. K,
NH 3, 2 equiv.
tBuOH;
NH 4Cl
CO2Me
H
N
OMe
MeO 2C
Me O
H
N
H H
H 2,
[Ir(cod)py(Pcy 3)]PF6
N
H
O
Me
H
N
Et
(+)-apovincamine
Me O
H
N
Pr
H H
(+)-pumiliotoxin C
N
H H
Me
H
H
N
H
O
CHO
NHCO 2tBu
JACS 1987, 109 , 6493
Heterocycles
Indoles
• Just as with carbocycles, co-solvents can be used to increase solubility (Dioxane, THF,
Et 2O, 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)
R
Pyrroles
Unactivated or with only Electron Donating substituents: No desired products
Yield
2-substituted
R1 = Me,
Na, NH 3,
25-30%
H
N
Me
R2 =
R 2 THF,
N
R
tBuOH; MeI
N
N
Me O
R1 = Me,
O
–78 ºC
R1 O
20%
R1
R 2 = OiPr
Major
Byproduct
*
∗ = Optimized conditions; can also be
1
85%
R = Boc,
used with EtI, BuI, iBuI, BnBr and AllylBr
(tBuOH
R2 =
N
JOC 1996, 61, 7664
excluded)
3-substituted
R1
R2
R3
Yield
O
O
R2
2
70%
R
Boc
Me
N
R3
Na, NH , THF;
3
RX
–78 ºC
N
N
R1
R1
10 eq. (MeOCH 2CH2)2NH needed to prevent
loss of R1 group when = Adoc
Boc
N
Adoc
OCy
Adoc
OCy
R
CO2Et Li, NH ,
3 EtO 2C
THF;
then RX
N
Boc
R
CO2Et
N
Boc
R1 R 2
Li, NH 3, EtO 2C
CO2Et
THF;
then R1 X;
N
then R 2X
Boc
Pyridines
NMe
Me
Li, NH; MeI
93%
Li, NH 3,
EtOH, Et 2O
N
69%
Me
72%
H
74%
R
Me
Et
Allyl
iBu
cis:trans
Yield
>20:1
77%
>10:1
82%
>10:1
70%
>10:1
79%
R1
R2
cis:trans
Yield
iBu
iBu
Me
Bn
only cis
only cis
82%
77%
N
H
N
Me
Reduction
carbocyclic ring
N
Me
3 eq. Li, NH 3,
2 eq. EtOH;
RX or NH 4Cl
RN
J. Chem. Soc. Chem. Commun. 1975, 480
Et
EtOH,
NaOH
R1
JOC, 1971, 36, 279
+R
5 eq. Li, NH 3;
MeOH
R1
1
N
N
H R1 = 7–OMe or H
JOC, 1975, 40, 3606
N
JOC, 1971, 36, 279
N
R2
J. Chem. Soc., Perkin
Trans. 1, 1973, 2754
J. Heterocycl. Chem., 1 992, 29, 1025
Theorized ring opening
do to the instability of
carbanion intermediate:
O
O
R
N
R
O
Most stable
O
O
R
O
NiPr 2
O
O
O
O
O
NiPr 2 Li, NH 3;
RX, –78 ºC
iPr allyl
Bn
Yield 92% 90% 98% 98% 85% 92%
R
H
Me
Et
Note: can be done asymmetrically using same
L-proline derived amides as previously shown
J. Heterocycl. Chem., 1 996, 33, 1313
2,5-disubstituted
R
O
2 eq. Li, NH 3;
1
NH 4Cl or R 2X R
When R1 =H
As with pyrroles unactivated or furans with
Furans
R 2 Me iPr Bn CH2OMe CO2Me
electron donating substituents cannot be
reduced under Birch conditions
78%
Yield 88% 78% 45% 79%
2-substituted
2.5 eq. Li,
• Note if too large an
R 2 Me iPr Bn H
NH 3, –78 ºC;
excess of metal isused
R
Yield 75% 95% 75% 80% dimeric and ring openned
then RX
CO2H
O CO2H
O
or NH 4Cl
side products predominate
• Amides as EWG also work
Tetrahedron Lett., 1 975, 9, 627
3-substituted
HO autoregulator
CO2H1) Na, NH ,
CO2Me
Me
Li, NH 3;
3
(±)-A-factor
NH 4Cl
8 eq. iPrOH;
Me
NH 4Cl
O
HO
O (no added
O
O
proton source) O
2) CH2N 2
85%
Me
3
Aust. J. Chem., 976, 29, 2553
O
O
63% (2 Steps)
Me
N
Me
O
R=Me or H
80-93%
Me
•It is thought that MeOH is
acidic enough to rapidly
protonate the radical anion
as it forms in equilibrium with
N
Me the N-alkylindole but NH 3 is
not acidic enough and can
Reduction
heterocyclic ring only protonate the dianion
Li, NH 3;
NH 4Cl R
Li, NH 3;
MeOH R
(excess)
Quinolines
J. Chem. Soc. Chem. Commun. 1999, 141
Very sensitive to rxn conditions
Me
MeN
Bn
Tetrahedron Lett. 1998, 39, 3075
3,4-disubstituted
EtO 2C
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
O
3 eq. Li, NH 3,
1.6 eq.MeOH
–78 ºC;
CO2H then
R
NH 4Cl
R
O
CO2H
Me
Et
nPr
tBu Bn (p-MeO)Bn
Yield 83% 85% 64% 71% 40%
cis:
trans (1:1) (1:1) (1:1) (1:1) (3:2)
40%
(3:2)
Bull. Chem. Soc. Jpn., 1 975, 48, 491
Benzofurans
Application to Methodology
Very sensitive to reaction conditions.
R=H
Li, NH 3, MeO
no proton
source
OH
50%
R=Me
Li, NH 3, tBuOH
Me
MeO
Synthesis chiral cyclohexanes
R=H
Li, NH 3, MeO
15% EtOH
R
88%
Et
MeO
O
O
R3
MeO
R=Me
Li, NH 3,15% EtOH
Me
S
O
NH 3, Li,
MeOH; H 2O
+
S
30%
Me
S
NH 3, Li,
MeOH; H 2O
S
NH 3, Li,
Me MeOH; H 2O
2-substituted
HS
CO2Me
R2
S
12%
Me
S
26%
Me
+
Me
S
7%
+
Me
S
Li, NH 3,
MeOH; R 2
NH 4Cl
R1 =H
S
32%
+
Me
S
OR1
Li, NH 3,
MeOH; R 2
NH 4Cl
R1
O
Chem. Lett., 1981, 1341
H
Cy
nPr nC7H15
H nBu
Me
3
Bn
allyl
R
Bn
Bn
Me
Yield 82% 68% 80% 76% 44%
No comment on cis:trans selectivity
H
O
OH 3:2 mix product to starting
material; low yielding
OH
+
S
S
nPr nPr
R1
R2
O
S
(slight ring
opening only
OH
observed
when R 2=H)
O
J. Chem. Soc., 1951, 3411
R3
3-substituted - almost no examples
O
2.5 eq. Na,
OH
NH 3,iPrOH;
H 3O+
S
Tetrahedron Lett., 1985, 26, 1791
S
S
78%
Targets in heterocyc. sys., 1999, 3, 117
Et
SH
iPr
Me
MeO
Me
trans:cis
>99:1
ee >99%
iPr
CF 3
NH 2 OMe MeO H 2N
N
NH
O
O
*
*
N
QA
N
Or
QDA
CO2H
PhCH 3
-25ºC
*
Cl
Or
Me
O
N
HN
N
R2
*
Me
Me
QA= 75%, QA= 84%,
QA= 60%,
QA= 58%,
ee: -87%
ee: -83%
ee: -78%
ee: -80%
QDA= 83%, QDA= 79%, QDA= 67%, QDA= 75%,
ee: 90%
ee: 89%
ee: 85%
ee: 88%
Synthesis of Spiral Lactams Eur. J. Org. Chem. 2017, 6, 1074
NH
CN
CO2H Li, NH 3,
CO2H
O
–78 ºC;
ClCH2CN
H 2, PtO 2
R1
NH
O Me
NH
O
70%
98%
R1
Me
CO2H
PhF
-15ºC
96%
Me
97%
Me
Me
Me
Me
O
2 Steps
H
Me
Me
Me O
O
Me 96%
O
74%
NH
O
R2
R1
Li, NH 3, Et 2O;
(CO 2H) 2
Me
CO2Me
Me
NH
SH
OMe
OMe
*
Na, NH 3
S
MeO
JACS 2012, 134 , 18209
R1
R1
Benzothiophenes and Dibenzothiophenes - very few examples
Na, NH 3
trans:cis
56:44
ee trans: 96%
R1
O
R3
ee: 89%
(conditions not specified)
O
R2
Or
Et
O
R2
R1
Ph
N
OH
1) Birch Reduction
2) Hydrolysis
+ cleaved product
Me (Yields not reported)
R1 =Li salt
O
S
iPr
Synthesis of chiral cyclohex-2-enones
+ 10% cleaved product
N
Ph
H 2 (20 bar)
trans:cis
Me
86:14
ee trans: 94% Me
MeO
Or
N
R2
Ph
Ph
P
Ir
S
OMe
S
R2
J. Chem. Soc., 1951, 3411
OMe
trans:cis
>99:1
ee >99%
+ 17% cleaved product
+
S
27%
Na, NH 3,
R1 Et 2O, EtOH;
NH 4Cl;
O
R 3X
S
+
R2
R3
MeO
Unlike furans and pyrroles, unactivated thiophenes has been reported but
gives a mixtures of over-reduced and ring cleaved products
Ph
Ph
P
Ir
Na, NH 3,
R 2 tBuOH, THF R1
or Et 2O
R1
R1
Chem. Commun. 2011, 47, 3989
JOC, 1967, 32, 2794
O
Thiophenes
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
H
Me
Me
QDA
method
69%
ee: 86%
Me
CHO
140ºC
46%
H
(3 Steps) Me
Me
(–)-isoacanthodoral
Synthesis ortho-alkylated vinylarenes
CO2H
82%
O
P OEt
OEt
ACS Catal. 2018, 8, 1213
R1 CO2H
Li, NH 3; R1 X
(specific conditions
not reported)
Me
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
R2
+
Me
O
R1
5 mol% Pd(TFA) 2
4 eq.TEMPO
EtCO 2H
80 ºC
R2
Me
R=H, 34%
R=Me, 44%
R R=Ph, 83%
R=OMe, 77%
R=NMe 2, 74% Me
iPr
Ph
CO2Me Me
+ BArF -
Me
H
H
NH Me
NH
Chem. Eur. J. 2018, 24, 1681
Ph Ph
O
O
R2
Or
81%
60%
NH
Me
F
MeO 2C 69%
NH
R1
R2
Ar R1
R3
O
O
33%
62%
Me
Synthesis of chiral allylsilanes for Hosomi–Sakurai allylation
γ-Arylation of β,γ-Unsaturated Ketones
ACIE 2008, 47, 177
O
OH
Li, NH 3,
2% Pd(OAc) 2
EtOH,THF;
4% dppe
+ ArBr 1.5 equiv. Cs2CO 3,
H+
100 ºC
R2
R2
1
1
R
R
O
O
O
O
when Ar =
ortho-NH2
H
NH
nPr
61%
Me
80%
O
Me
Me
Me
MeO 66%
O
Me
Ir
N
SiMe 3 Li, NH 3,
SiMe 3
OMe
tBuOH or R1
R1
N
MeO
R2
R2
EtOH, THF;
H2
NH 4Cl
Me
Et
Me
Me
Me
Me
Ph
Cy
iBu
Ph
Me
Me
R1
32% OH
69% OH
42% OH
65% OH
d.r.
24:1
d.r.
31:1
d.r.
single
d.r. single
diastereomer
diastereomer
SiMe 3 Synthesis of annulated arenes
R1
Li, NH 3,
tBuOH;
Br
Br
3,4
CO2tBu
R2
TiCl4,
RCHO,
-78ºC
R2
OH
O
R1
R2
R3
1) Li, NH 3, tBuOH,
THF, –78 ºC
R4
R1
2)R 3
R
R 2 6M HCl
OMe
O
OMe
R1
Ph
O
MeO
O
32% (3 Steps)
d.r. = 35:1
61% (3 Steps) Me
d.r. = 110:1
R2
MeO
R2
O
53% (3 Steps)
d.r. = >99:1
O
O
OH
CO2tBu
OH
Me
BiCl 3•H 2O
Or
Ph
0,1
R
0,1
O
51% (3 Steps)
d.r. = >99:1
(when K instead of
Li and AllylCl)
41% (3 Steps)
d.r. = 50:1 MeO
1) NaBH 4
2) BiCl 3•H 2O
Or
R4
R2
Δ
0,1
O
R4
R3
R2
tBuO 2C
0,1
OH
OH
JOC 2007, 72, 930
O
Me
O
R2
OH
O
2)Bu3SnH,
AIBN, 85 ºC
2) Saegusa [O]
R3
R4
R 2=(S)-2-(methoxymethyl)pyrrolidine
O
3,4
1) CrO 3,
AcOH, Ac2O
2) NaI
I
CO2tBu
3,4
O
R3
Me
Enantioselective Birch-Cope Sequence for Quaternary Stereocenters
Br
Org. Lett. 2007, 9, 2677
O
R2
R1
O
O
R2
O
1) RMgCl
2) BiCl 3•H 2O
Baran Group Meeting
3/10/18
The Birch Reduction
Lisa M. Barton
Electrochemical Birch Reduction
Electrochemical Birch reductions
•First reported by Birch himself:
CO2H
Other reported procedures:
• Pt, LiCl, MeNH 2
NH 2
CO2H
Pt,
NH 3, LiOAc,
H 2O, tBuOH
72%
C.E. 45%
NH 2
JACS 1963, 85, 2858;
• Pt, Graphite or C; LiCl, ethylenediamine:
major product cyclohexene
Me O
J. Electrochem. Soc., 1963, 110, 425
Pt, LiCl,
MeNH 2
•Al, LiCl, EtOH:HMPA 67:33, undivided:
major product cyclohexane
Bull. Chem. Soc. Jpn., 1982, 55, 347
Nature, 1946, 158, 60
•Hg, (Bu 3EtN)OH, H 2O, 60ºC,
MeO
NH 2
J. Electrochem. Soc., 1981, 128, 322
•Hg, (TBA)BF 4, THF/H2O, rt
JOC., 1985, 50, 556
R
Pt, LiCl,
MeNH 2,
undivided cell
R
Pt, LiCl,
MeNH 2,
divided cell
Mechanism
ecath
eS
+
+
+ MeNH 2
H
H
H
H
+
eS
+ MeNH 2
H
H
+ MeNHLi
H
H
H
H
R= H
Me
Et
R iPr
tBu
Divided Undivided
49%
49%
44%
64%
63%
73%
75%
82%
81%
85%
OMe
HO
OMe
• in undivided cell methylamine
HCl can quench LiNHMe; in
divided two are seperated so
LiNHMe isn't neutralized and
isomerizes to conjugated 1,3diene which can be further
reduced
70%
OMe
HO
34-37%
C.E. 33-35%
OMe
Al,
HMPA, LiCl,
EtOH
R
SiMe 3
Me 3Si
JACS 1969, 91, 4194
Al,
HMPA, LiCl,
EtOH
44-48%
C.E. 41-46%
Me OH
Sn,
iPrOH,
Et 4NOTs
SiMe 3
80%
•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 concentration
NH 2
46%
Red. Trav. Chim. Pays-Bas. 1995, 114 , 259
JACS 1963, 85, 2858;
JACS 1964, 86, 5272;
J. Electrochem. Soc., 1966, 113, 1060
+ MeNHLi
H
H
93%
C.E. 44%
MeO
Al,
HMPA, LiCl,
EtOH
O
• methylamide serves as proton
source forming LiNHMe
eS
Solvent
Me OH
4%
+ regioisomer and
overreduced
Pt, LiCl,
MeNH 2,
–5 ºC or –50 ºC
undivided
SiMe 3
SiMe 3
68%
6%
overreduced
SiMe 3
SiMe 3
SiMe 3
+
75%
17%
53%
+ 5% regioisomer
Me
93%
cis:trans:
78:20 at –5 ºC
85:15 at –50 ºC
SiMe 3
SiMe 3
+
SiMe 3
R
Me 3Si
•substrates
resulting in
vinylic TMS
groups can be
overreduced
Note that unlike under standard Birch conditions no loss of Si reported
J. Chem. Soc., Perkin Trans. 1 1974, 2055