Ready; Catalysis
Conjugate Addition
Topics covered
1. 1,4 addition involving copper
a. stoichiometric reactions
b. catalytic reactions
c. allylic substitution
2. Conjugate addition without copper
a. Ni-based systems
b. Rh-based systems
3. Catalytic addition of heteroatoms
Topics not covered: enolate conjugate additions, Friedel-Crafts-type conjugate additions
Ready; Catalysis
Conjugate Addition: origin
1,4 addition reactions involving copper
Review: Org. Rxns, 1992, 41, 135-631
1st report:
Kharasch, JACS, 1941, 2308 "Factors Determining the Course and Mechanisms of Grignard Reactions"
O
O
CH3
HO CH3
CH3MgBr
additive
H3C
CH3
H3C
H3C
H3C
CH3
CH3 H3C
CH3
CH3
H3C
H3C
H3C
additive
none
43
48
0
0
7
83
CuCl (1 mol%)
an unusual example of the catalytic reaction predating the stoichiometric one
classes of copper reagents:
nRM + CuX
n = 1,2
X = halide, CN
RCu
organocopper
R2CuM
M = MgX, Li
R(CN)CuM
M = MgX, Li
R2(CN)CuM2
M = MgX, Li
organocuprate
(Gilman reagent)
lower order cuprate
higher order cuprate
Ready; Catalysis
Conjugate Addition: general
R2CuM (M = MgX, Li)
Most common for simple conjugate additions
Soluble in Et2O, THF
Thermally unstable (usually keep temp < o0 for R = aryl, vinyl; -78 oC for R = alkyl)
R
Cu
R
I
R
R
+
+
General reactivity trends
O
+
Cu(0)
H
Et2O or THF
R2CuLi
α or β sub. OK
α,β sub usually OK
β,β ususally difficult, but possible
X
ketones>esters>amides
R
aldehydes: 1,2 addition competes
O
O
CH3
98%
CH3
CH3
H
CH3
CH3
CH3
OAc
Me2CuLi
55%
Ph
O
Ph2CuLi
Me2CuLi
O
+
R = 1o~2o>3o>Ar>>alkynyl
O
X
R
H3CN
75%
H
O
O
OAc
LiCu
O
2
66%
H
H3CN
O
Ready; Catalysis
Conjugate Addition: mechanism
mechanism
Recall: εC - εCu = 0.6 (polarization: C-Sn > C-Si ~ C-Cu > C-B)
R
Li
CuX
Li
Li
R2CuLi LiX
O
a Cu-enone intermediate has been observed
spectoscopically and implicated kinetically. For lead
references, see Krause, ACIEE, 1999, 1644
O
set
Li
OLi
OLi
R2CuII
III
O
CuR2
Cu R2
OLi
predictions:
some R-R formation (observed, usually use >1 equiv cuprate)
Lewis Acids may help
Can use enolate for further reaction
R
Ready; Catalysis
Conjugate Addition: TMSCl
Added TMSCl+HMPA
very common method
MgBr
O
Ar
5 mol% CuBr-Me2S
additive
+
Nakamura, Tet, 1989, 349
HO
O
additive
none
TMSCl (2.4 equiv)
TMSCl + HMPA (2.4 equiv)
Ar
2
31
99
11
4
<1
enals usually very difficult b/c 1,2 addition competes
using RMgBr + 5 mol% CuBr-Me2S with added TMSCl/HMPA:
OTMS
OTMS
OTMS
H3 C
R
hex
Ph
R
%Y
83
90
E/Z
94:6
91:9
R
hex
Ph
R
%Y
89
91
E/Z
96:4
96:4
R
R
Bu
Ph
CH3
%Y
E/Z
89
87:13
55
92:8
Ready; Catalysis
Conjugate Addition-10
O
Problem with R2CuLi: Waste 1 equiv R
Solution: nontransferable ligand
t-Bu
H
1. MeLi
2. CuI
3. MeLi
O
t-Bu
Cu CH3 Li
O
O
n-C3H7
76%
Whitesides, JACS, 1973, 3893
Corey, JACS, 1972, 7210
CuR Li +
R
R = Ar, tBu, vinyl
Y > 90%
Reagents of the form RR'Cu have reactivity intermediate between R2Cu and R'2Cu
O
O
n-Bu Cu PPh2 Li
+
more reactive than Bu2CuLi
Stable at 0 - 25 oC
Especially good for alkylations with alkyl halides
n-Bu
88%
Bertz, JACS, 1982, 5825
similar: tBuCu(SPh)Li Posner, JACS, 1973, 7788
Origin of selectivity with mixed cuprates: Nakamra, JACS, 2005, 4697
Ready; Catalysis
Conjugate Addition-11
alkyl-cyano-cuprates review: Tet, 1984, 5005
RCu(CN)Li - lower order cuprates
R2Cu(CN)Li2 - Higher order cuprates
Lower order cuprates have reactivity intermediate between RCu and R2CuLi
i.e. CN similar to alkyne (non-transferable ligand)
usually moderate reactivity for 1,4 addns, but OK for SN2'
O
O
+
Li(NC)Cu
HO2C
'single product' 95% yield
Trost, JOC, 1980, 4256
Ready; Catalysis
Conjugate Addition-12
alkyl-cyano-cuprates review: Tet, 1984, 5005
RCu(CN)Li - lower order cuprates
R2Cu(CN)Li2 - Higher order cuprates
experimental observation that higher order cuprates display improved reactivity relative to Gilman reagents.
I
Bu
'RCu'
'RCu'
Bu2CuLi LiI
Bu2Cu(CN)Li2
none
90%
only
'PhCu'
CO2Et
CO2Et
Ph
O
O
Et
O
81%
'PhCu'
Ph2CuLi
Ph2Cu(CN)Li2
n-C3H7
85%
88%
yield
38
75
Ready; Catalysis
Conjugate Addition-13
The structure of higher-order cuprates has been debated:
From Chem Comm. 1996
Ready; Catalysis
Conjugate Addition-14
Brief review: Krause, ACIEE, 1999, 79
So why are higher order cuprates more effective?? Not clear
Ready; Catalysis
Conjugate Addition-15
Copper-mediated addition of alkylzinc reagents
Often characterized by complicated reaction mixtures:
OMs
CH3
CO2Me
O
'MeCu'
CO2Me
O
NBoc
CO2Me
O
NBoc
NBoc
'MeCu'
MeCu(CN)MgBr
Me2Cu(CN)(ZnCl)2 2Mg(Br)Cl 3LiCl
0
100
95
0
TL 1992, 3783
MeMgBr + ZnCl2 --> white suspension
MeMgBr + ZnCl2 + LiCl --> solution
for conjugate addtions:
review: Chem Rev. 1993, 2117
O
RCu(CN)ZnX 2LiX
RZnX + CuCN 2LiCl
soluble in THF
O
65%
NC
O
Ph
PivO
59%
95%
i-PrO2C
OTMS
93%
O
PO
good thermal stability (reflux THF)
Less reactive than RMgBr or RLi-derived
no rxn with epoxides
only 1o iodides
Allows functional groups not compatible
with RMgBr or RLi
CO2Me
n-C5H11
83%
P'O
Ready; Catalysis
Conjugate Addition-16
Ready; Catalysis
Conjugate Addition-17
Problem: often hard to alkylate intermediate Li enolate
Solution: transmetalate to Sn
O
1 (Bu3P)Cu
O
C5H11
(CH2)3CO2Me
OTBS
TBSO
Ph3SnCl
2
3
TBSO
78%, d.r.
Noyori, JACS, 1988, 4718
TBSO
(CH2)3CO2Me
I
C5H11
w/o Sn, get complex mixture resulting from enolate equilibration.
OLi
OLi
OLi
OLi
R
TBSO
TBSO
R
Propose
TBSO
R
OSn(Cl)Ph3 Li
R
less basic
TBSO
R
R
Ready; Catalysis
Conjugate Addition-19
1,4 additions to alkynones
O
O
R2CuLi
R'
CuR2
Li
R'
O
OCuR
CuR
CuR
R'
R
R'
R
R
O
+
R'
O
H
H
R'
R
cis-addn
R
R'
trans-addn
Br
Note: R-Cu can add to unactivated alkynes:
EtCu(Me2S) MgBr2
O
C2H5
Cu
C2H5
C6H13
H
C6H13
C6H13
'carbocupration'
get less-hindered organocopper
so 1,4 addn mechanistically between 1,4 addn and carbocupration
H
85%
Org. Syn. 1985, 64, 1
Ready; Catalysis
Conjugate Addition-20
alkynones and alkynoates are more reactive than enones, so RCu is enough
CO2Me
MeO2C
R
RMgBr/CuBr
MeO2C
CO2Me
EtO
O
TMS Chem Lett, 1981,
905 and 1363
R = alkyl, vinyl, phenyl,
OEt
THPO
CuLi
O
2
THPO
OEt
81%2:1 E:Z
TL 1976, 3245
EtO
somtimes isomerization is good:
O
CO2Me
+
CO2Me
CO2Me
Cu
Crimmins, JOC, 1984, 3033
48%
Ready; Catalysis
Conjugate Addition-22
more examples of enoate addn
OH
CO2Et
CO2Et
O
1. Me2CuLi
2. allyl-Br
3. H+
O
syn comm. 1980, 751
(TMS)2Cu(CN)Li2
Me3Si
H
CO2Et
Mg(0)
65 oC
Cl
Marshall, Syn. Comm.
1983, 531
CO2Me
MgCl
CO2Me
CuI, TMEDA
H
Oppolzer, TL, 1986, 5471
H
Ready; Catalysis
Conjugate Addition-21
Asymmetric 1,4 addn
Breakthrough came with observation that R2Zn are effective alkyl sources
-functionalized Nu's
-can do catalytically without competing rxns of nucleophile
OZnR
Cu(II)
details of mechanism not known
stereoselectivity not understood
L*, R2Zn
R
R2Zn
Proposals
Concerted transfer (ie no Cu(III) intermediate:
Noyori, Bull. Chem. Soc. 2000, 999; Kitamura,
Chem Lett. 2003, 224.
L*2Cu(I)R
O
M = Cu, Zn
OM
R2Zn
RCuL*2
R
a poorly-defiined complex
Rate limiting OA: Gennari, JOMC, 2005, 689,
2169
Rate limiting RE: Schrader, Chem-E.J. 2004,
6049.
Ready; Catalysis
Conjugate Addition-23
two best systems:
O
O
Cu(OTf)2 (2 mol%)
+
R2Zn
n
n
O
R
n
Ph
P
N
1
2
3
4
2
Ph
O
R
Et
Et
Et
Et
iPr
4 mol%
Feringa, Accts, 2000, 346
AcO
2
O
95
O
+
n
ee
10
98
98
97
94
R2Zn
[Cu(OTf)]2 (1 mol%)
i-Pr
N
H
N
O
NHBn
n
R
O
Bn
PPh2 2.4 mol%
overall best ligand,
can optimize for individual substrates
n
R
ee
1
1
2
2
3
3
Et
iPr
Et
iPr
Et
iPr
97
79
98
72
98
62
Hoveyda, JACS, 2001, 755
Ready; Catalysis
Asymmetric addition of Grignards
Chemo- and stereoselectivity
Feringa: PNAS, 2004, 5834
JACS, 2004, 12784
ACIEE, 2005, 2752
Conjugate Addition
Ready; Catalysis
Conjugate Addition-24
SN2' additions
β
Nu-
LG
γ
α
β
γ
Nu
α
SN2
β
Nu
γ
SN2'
α
issues:
regioselectivity (α vs γ) (usually SN2')
SN2' favored: RCu-BF3; R2CuLi-ZnCl2; RCu; R2Cu(Cl or Br)(MgBr)2, THF
SN2 favored: R2CuI(MgBr)2; Et2O
stereoselectivity (syn vs anti) (usually anti)
substrates
X
X
X = halide, OAc, OCO2R, OP(O)(OR)2, OS(O)R
O
Ready; Catalysis
Conjugate Addition-25
Ready; Catalysis
Conjugate Addition-26
SN2' addns: examples
R'
O
R
O
R'
R''
R''MgBr/CuBr DMS
R
regio 98:2
70-90%
R-R'' = alkyl
CO2H JOC, 1986, 1612
H
Me2CuLi
OAc
+
cis
trans
1
98
99
2
OMs
OTBS
MeCu(CN)Li BF3 LiBr
OMs
R
O
O
H
OTBS
H
E
minimize
A1,3
CO2Me
OCO2Me
N3
H
CO2Me
JACS, 1986, 7420
MgBr
O
O
O
O
OMe
CuCN
O
N3
O
OMe
Trost, JACS, 1995, 10143
Ready; Catalysis
Conjugate Addition-27
SN2' addns involving alkynes
n-C8H17MgBr
10% CuBr
OMe
n-C8H17
Bu
BuCu
TMS
OS(O)CH3
TMS
91%
sulfinate
NR2
Et
OH
EtCu
O
NR2
60%
Ready; Catalysis
Conjugate Addition-28
best systems to date:
t-BuO2C
H
N
N
R
OP(O)(OEt)2
+ R2Zn or
R-AliBu2 or
R-B(Pin)
R'
note: similar but different than
ligand for 1,4 addn
O
NHBn
O
OH
Ar
Cu(OTf)2
R
R = Et
Ar = e poor, neutral
ee's >90
Hoveyda, JACS, 2004, 10676
NHC-based ligands
Mes
N
N
solid state:
N
N
Cu O
O Cu
HO
or
Ph
Me Et
R
R = Me, 74% ee 91% ee
R = Et, 86% ee
N N
Hoveyda, JACS, 2004, 11130
JACS, 2014, 2149
c-C6H11
c-C6H12
Me Et
93% ee
Et
94% ee
N
N
O
O
Me R
R = Me
ee's ~ 90
Ph
Ph
O S
Ph
Ar
or
Ar
Cu
O
Boc
N
Ar
H3C
Ar
CH3
Ar
>80%ee
>80% ee
Ar
R
>80% ee
Ready; Catalysis
Conjugate Addition-31
Rh-catalyzed 1,4 addns of boronic acids - a remarkable rxn
review: Hayashi Chem Rev. 2003, 2829
original report: Miyaura OM, 1997, 4229
Rh(acac)(CO)2
dppb
H2O/MeOH
O
Ar
B(OH)2
+
R
R
O
R
R
enantioselective version
O
Ar
B(OH)2
+
R
R
O
R
n
R
o
35 C
R
1
2
2
2
2
3
R
Ph
Ph
4OMe-Ph
4-F-Ph
Hexenyl
Ph
Ar
ee
98
99
99
99
94
96
R
O
[Rh(OH)(BINAP)]2
H2O/dioxane
R
n
moderate yields
high temp
long times
R
O
Ar
Ph
98% ee
R
O
Ph
92% ee
n-C5H11
Ready; Catalysis
Conjugate Addition-32
Mechanism of Rh-catalyzed 1,4 addn
P2 = BINAP
P2Rh
HO
O
R
P2Rh
OH
No Oxidation state change on Rh!
RhP2
OH
R
B(OH)2
B(OH)3
H2O
O
RhP2
P2Rh
R
hydrolysis faster than
β-hydride elimination
P2Rh
O
R
O
R
Ready; Catalysis
Conjugate Addition-33
Rh-catalyzed 1,4 addn: other substrates
Esters and amides:
O
Ph
Ph
Ph
O
CO2Me
CO2Me
89% ee
NHBn
Ph
98% ee
98% ee
98% ee
(requires K2CO3)
Ph
Phosphonates
Ph
O
P
96% ee
nitro olefins
OEt
uses
2
Ph
Ph
O
B
B
O
O
B
Ph
Ph
NO2
NaHCO3
98% ee
9:1 dr
initial product
O
NO2
98% ee
Ready; Catalysis
Conjugate Addition-34
O
How to do 3 component coupling?
O
+ Ph
cat.
[Rh(OMe)(cod)]2
BINAP
toluene
B
OBR2
BuLi, allyl-Br
n
O
n
only for n = 1,2
D
D2O
Ph
n
98% ee
RCHO
Ph
n
O
H
Ph
OH
R
O
OTMS
OTi(OiPr)3
cat. [Rh(OH)(BINAP)]2
R
1. LiOiPr
2. TMSCl
R
n
R
ArTi(Oi-Pr)3
R
R
OTMS
n
Ar
R
n
1
2
2
2
3
Ar
Ph
Ph
4F-Ph
4MeOPh
Ph
Ar
R
R
Ar
R
ee(%)
99
99
99
99
98
Ph
OTMS
99% ee
Ph
Pd-Catalyzed addition of aryl boronic acids: formation of quaternary stereocenters
Stoltz, JACS, 2011, 6902
ArB(OH)2
O
Pd(OCOCF3)2
ClCH2CH2Cl, 40-80 oC
R
Ar
O
LnPd
+
N
N
B(OH)2
OB(OH)2
OPdLn
O
R Ar
R Ar
Ar R
O
R Ar
Heck-type addition
No possibility of !-hydride elimination
tBu
yields mostly >80%, ee's mostly >90%
O
O
Me
Me
O
Me
O
O
Me
Me
CO2Me
OMe
O
CF3
O
Cl
O
BnO
Me Ph
Br
O
O
Me
Ph
(no 2-substituted)
Ready; Catalysis
Conjugate Addition-35
1,4-addn of O nucleophiles
Bergman and Toste, JACS, 2003, 8696
EWG
EWG
PMe3 (5 mol%)
R'OH
R
R
OR'
EWG
R
R’OH
Y (%)
COMe
H
MeOH
56
COEt
Me
H2O
77
CO2Me
Me
MeOH
71
CN
H
MeOH
79
COMe
Ph
MeOH
0