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Nickel-Catalyzed Multicomponent Coupling of Alkynes
-Recent development in methodologies and applications
Zhenjie Lu
Department of Chemistry, MSU
January 28, 2004
Ni28 58.69
Nickel
Background Introduction
Conjugate addition using cuprates - well established reactions
Conjugate addition using nickel-catalyzed transmetallation process
1. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry. Part B, 2001, 477.2. Schwartz, J.; Loots, M. J.; Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333.
Stoichiometric copper complex must be used. Alkenylcuprate are thermally unstable. The loss of double bond stereochemistry may occur.
R4R3ZrCp2(H)Cl
R3
ClCp2Zr H
R4
1)R1 R4
O
R3
H
2)H3O+
, Ni(0)
O
R1
R2R2
up to 84% yield
O
R1
R2
O
R1R3Li
CuCNR3Cu(CN)Li
R3
R2
LiR3
Cu(CN)LiR3
O
R1
R2
R3
O
R1
R2
CuCN
Discovery of Nickel-catalyzed Coupling Reaction with Alkynes
1. Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975.2. Ikeda, S.; Yamamoto, H.; Kondo, K; Sato, Y. Organometallics. 1995, 14, 5015.
Conjugate addition
Tandemcoupling
cat. NiR'2Zn
cat. NiMe2Zn, TMSCl
R'R''
hydrolysis hydrolysis
R'ZnO R2
R1 R'
O R2
R1
O R2
R1 R'
TMSO R2
R1 MeR'
R"
O R2
R1 MeR'
R"
1. Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975.2. Ikeda, S.; Yamamoto, H.; Kondo, K; Sato, Y. Organometallics. 1995, 14, 5015.
Nickel Catalyzed Multi-Component Coupling of Alkynes - A General Scheme
R"R' Ni(0)"E", "Nu"
R"
"E"
R'
"E" = enone, enal, aldehyde, imine, CO2, epoxide
"Nu"
"Nu" = R(M)
cat. NiR'R''
O R2
R1
O R2
R1 MeR'
R"
Me2ZnTMSCl
+ +
"Nu""E"
Professor Timothy F. JamisonMassachusetts Institute of Technology
Professor John MontgomeryWayne State University
Professor Miwako MoriHokkaido University
Professor Shin-ichi IkedaNagoya City University
Major Contributors in the Field
Intramolecular coupling of enones orenals with alkynes
Asymmetric coupling of aldehydes, iminesand epoxides with alkynes
Coupling of CO2 with alkynes, andaldehydes with dienes
Intermolecular coupling of enones orenals with alkynes
Ni28 58.69
Nickel
Outline
R1R2+
intra
inter
RR1
R4
O
O R1
R4
R2
R
n
Ni(0), R(M)
R3 R1
OH
R2
intra
inter
HO
RR1
n
R1CO2H
R
NR4
H R3
R1 R3
R HN
R2
R4
O
R1 R3
R2 OH
O
R4
R3CO2
RR2
R3
HO
R
R3
R3
Intramolecular Coupling of Alkynes and Enones
R1R2+
RR1
R4
O
O R1
R4
R2
R
nNi(0), R(M)
O
R4
R3
R3
intramolecular
intermolecular
Intramolecular Cyclization of Enones with Alkynes
Intramolecular Coupling of Enones or Enals and Alkynes
OR2
R1
R2
H
E
HO R1
[3+2]
[2+2+2]H
R2
OMe
R1
O
singlecyclization
R3
R2
R1
O
R3(M)
OMe
E+
3
without R3(M)
Single Cyclization of Enone and Alkyne
Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099.
Intramolecular Coupling of Enones or Enals with Alkynes
entry ligand R1 R2 a yield, % b yield, %
1 - H Me 82 0
2 - H Bu 51 11
3 PPh3 H Bu 0 92
4 - Ph Bu 68 8
5 PPh3 Ph Bu 19 47
R1
O
Bu2Zn or BuZnClNi(COD)2 (5 mol%)
BuR2
R1
O
Bu2Zn or BuZnCl
HR2
R1
O
R2
Ni(COD)2 (5 mol%) PPh3 (25 mol%)
Alkylative coupling
Reductive coupling
a
b
Proposed Mechanism
β-H elimination
1. Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099.2. Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911.3. Montgomery, J. Acc. Chem. Res. 2000, 33, 467.
Intramolecular Coupling of Enones or Enals with Alkynes
Ni R1R2
O LL
R2
O R1
ZnBu2
LnNiR1
R2
reductiveelimination
BuR1
R2
O
alkylative coupling
with PPh3
BuZnO
R2
BuZnO
R1LnNi
H
reductiveeliminationb
reductive couplinga
Ni(COD)2
(transmetallation)
HR1
R2
O
A
B
R1
R2
ONi
LL
C
3
HH
without PPh3
X-ray Structures of Nickel-metallocycles
Amarasinghe, K. K. D.; Chowdhury, S. K.; Heeg, M. J.; Montgomery, J. Organometallics. 2001, 20, 370.
NiO
Ph
HN
N
B
✯ X-ray structures of the nickel-metallocycles supported the proposed mechanism.
NiO
N
N
Ph
HNiN
Ph
NO
H
A
Intramolecular Coupling of Enones or Enals with Alkynes
Total Synthesis of Isogeissoschizoid Skeleton
Fornicola, R. S.; Subburaj, K.; Montgomery, J. Org. Lett. 2002, 4, 615.
Intramolecular Coupling of Enones or Enals with Alkynes
ON
OHTIPSO
N
TIPSO
N H
MeTIPSO
84%(95:5dr)
NOP(OEt2)
O O O
toluene/CH3CN
EtO O
N
O
O
O
HN
OO
O
Me2ZnNi(COD)2 (10 mol%)
1
1
N
N
H
OMeO
HH
H
Me
( )-isogeissoschizoid+_
NH3Cl
NH
NH2
Alkylative Coupling - Vinyl Zr as Coupling Partner
Ni, Y.; Amarasighe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743.
entry R1 R2 R3 yield, %
1 Me Ph C6H13 74
2 Ph H C6H13 80
3 Ph Me (CH2)4OTBS 75
4 H Ph C6H13 68
5 H Me Ph 66
R1
O R2
Cp2ClZrR3
R3
R1O
R2
+ Ni(COD)2 (10 mol%)ZnCl2 (20 mol%)
2.5 equiv.
Intramolecular Coupling of Enones or Enals with Alkynes
Total Synthesis of Isodomoic Acid G
Ni, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J. Org. Lett. 2003, 5, 3771.
Intramolecular Coupling of Enones or Enals with Alkynes
N
O
O
O
Cp2ClZr
OTIPS
Me1
HO
O
NH2
OMe1
MeO
O
NMeO
Me
O
HO
Ni(COD)2 (10 mol%)ZnCl2 (20 mol%), 0oC
70%
N
O
ON
O
Me
Ph
O
O
TIPSO
Me
HO
Me
ON
O
MeON
OO
Ph
NHO2C
HO2C
H
Me
Isodomoic acid G
HO2C
Me
Discovery of [2+2+2] Cyclization
Seo, J.; Chui, H. M. P.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 476.
Intramolecular Coupling of Enones or Enals with Alkynes
R2Zn yield of a yield of b yield of c
(n-Bu)2Zn 19 47 trace
(t-Bu)2Zn 0 10 71
none 0 0 99
Proposed mechanism
NiPh
LL
Ph
O Ni(COD)2(20 mol%) Ni
H Ph
H LL
O
Ni
Ph
LL
HH
Ph O
11
cO
Ph
Ph
PPh3
Ni(COD)2 (20 mol%)PPh3 (40 mol%), R2Zn THF, 25oC H
Ph
OPhPh
+Ph
O Ph
a bc
O
Ph
alkylative coupling
reductive coupling
dimerization
1
RPh
+
OPh HPh
OPh
[2+2+2] Cyclization
Seo, J.; Chui, H. M. P.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 476.
Intramolecular Coupling of Enones or Enals with Alkynes
entry R1 R2 2 product Yield (%)
1 Ph Ph OMe
HPh
OMe
Ph
O75
2 Me H OMe
HH
OMe
Me
O68, 4:1dr
3 Me H O
Me
Me
HH
O
Me
O MeMe
36
Ni(COD)2 (20 mol%)
PPh3, THF, 25oCO
R4
HR2
OR4
R1
O
R1
O R2
+
R3
R3
1 2
[3+2] Cyclization
1. Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6775.2. Mahandru, G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J; Montgomery, J. J. Am. Chem. Soc. 2003,
125, 13481.
Single diastereomer obtained in entry 1~4.
entry electrophile product (yield,%) entry electrophile product (yield,%)
1 H3O+
OH
H
PhH
82%4
Ph Cl
OOH
H
Ph
72%
Ph
O
2 I
OH
H
Ph
72%
3Ph H
OOH
H
Ph
82%
Ph
OHH
5 OO
H
Ph
72%
OH
Intramolecular Coupling of Enones or Enals with Alkynes
H
O OH
H
PhE+ E
PhNi
ON
N
Ph
H
H
HPh
H
O
A
TMEDA
Ni(COD)2(100 mol%)
not observed
Proposed Mechanism of [3+2] Cyclization
Mahandru, G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J; Montgomery, J. J. Am. Chem. Soc. 2003,125, 13481.
Intramolecular Coupling of Enones or Enals with Alkynes
NiPh
NN
H
O
PhE
HHO
TMEDAH
O Ph Ni(COD)2(100 mol%) Ni
H H
H NN
O
E+
Ni
H H
H NN
OE
O
HNi
N
NH
HE
H
A
B
1
2
C
A'
Cascade Cyclization
Mahandru, G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J; Montgomery, J. J. Am. Chem. Soc.2003, 125, 13481.
Cyclization of β- substituted enal
Intramolecular Coupling of Enones or Enals with Alkynes
Cyclization of α- substituted enal
TMEDA
Ni(COD)2(100 mol%)
6
6
66H
H
O
O
Ni
O
Ph N
N
O
H
Ph
ONiO
NN
HH
Ph
OH
61%
HOH
Ph
1 1
1
122
2
23
3
33
4
4
4
4
5
5
5
5
A B single diastereomer
H
O
Ni
OH
O
Ph N
N
Ph
ONiO
NN
H
Ph
OH OH
H
49%
PhTMEDA
Ni(COD)2(100 mol%)
OH
123
45
1
1
12
2
23
334
4
45
5
5
6
6
66
C D single diastereomer
Proposed Mechanism of Two Cyclizations
1. Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6775.2. Montgomery, J.; Amarasinghe, K. K. D.; Chowdhury, S. K.; Oblinger, E.; Seo, J.; Savchenko, A. V. Pure. Appl. Chem. 2002, 74, 129.
Intramolecular Coupling of Enones or Enals with Alkynes
NiR2
L
R1
O
R2E
R1HO
R1
O R2
Ni
H R1
H LL
O
Ni
H R1
H NN
OE
O
R1Ni
N
NH
HE
H
OMe
Ni
R2
LL
HH
R1
O
Me O
H
R2
OMe
R1
O
H
[2+2+2][3+2]
E+
R2
R2
R2
Ni(COD)2/LL
Summary of Intramolecular Coupling
Intramolecular Coupling of Enones or Enals with Alkynes
Ni R2
LL
R1
O
R2
O
Me
R2
H
MeO
R2
OH
H
E
R1
Ni(0)
L = PPh3
R2
NiO L
L
R2
R1R3(H)O
R1
O
R1
[2+2+2][3+2]
R1
O
E+
L = TMEDA
R32Zn/L
Intermolecular Coupling of Enones and Alkynes
R1R2+
RR1
R4
O
O R1
R4
R2
R
nNi(0), R(M)
O
R4
R3
R3
intramolecular
intermolecular
Catalytic Enantiomeric Intermolecular Coupling
Ikeda, S. I.; Cui, D. M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712.
Intermolecular Coupling of Enones or Enals and Alkynes
N
O
t-Bu
Me
L*
O
+ R1 R2
Ni(acac)2 (5 mol%) L*(10 mol%)
Me2Zn, TMSCl
OTMS
Me
R2R1
H3O+
O
Me
R2R1triglymen n nR1 < R2
entry n alkyne product yield, % ee, %
1 1 Et Et
O
Me
EtEt
61 76
2 2 Et Et
Et
Me
Et
O
39 38
3 1 H SiMe3
O
Me
SiMe3H
60(100%regio-selectivity)
63
Cyclic Cotrimerization
1. Ikeda, S. I.; Mori, N.; Sato, Y. J. Am. Chem. Soc. 1997, 119, 4779. 2. Ikeda, S. I. Acc. Chem. Res. 2000, 33, 511.
Proposed mechanism
Intermolecular Coupling of Enones or Enals and Alkynes
OAl
Ni
NiO
O
Ni
AlNi
O
trimerizationproduct
A
B
C
Regioselectivity is highly substrate dependent.
O
R2R1
OR 2,R 1
R1 ,R2
Ni(acac)2 (5 mol%)PPh3 (10 mol%)
Me3Al/PhOH+
Ni(0) (10mol%) TMSCl
R(M)
OTMS
R1
R2R
Control of Regioselectivityin Trimerization with the Same Alkyne
1. Mori, N.; Ikeda, S. I.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 2722.2. Ikeda, S. I.; Kondo, H.; Mori, N. Chem. Commun. 2000, 815.
entry ligand n R yield, %(a + b)
ratio(a : b)
1 PPh3 2 Bu 83 92:8
2 A 2 Bu 81 100:0
3 PPh3 1 TMS 33 0:100
4 A 1 TMS 69 96:4
5 PPh3 1 t-Bu 45 11:89
6 A 1 t-Bu 67 100:0
Intermolecular Coupling of Enones or Enals and Alkynes
O
n
+ R2 equiv.
1)Ni(acac)2 (10 mol%) L /Me3Al/PhOH2)DBU, in air
R
R
O
n
RO
n
O
nR R
R
a b c
+ +
N
O
Me
Ph
A
Ikeda, S. I.; Kondo, H.; Arii, T.; Odashima, K. Chem. Commun. 2002, 2422.
Regioselectivity > 95:5 in every example.
Control of Enantioselectivityin Trimerization with the Same Alkyne
N
O
Ph
PhN
O
Ph
Ph
PhPhor
higher yieldlower ee
lower yieldhigher ee
A B
Intermolecular Coupling of Enones or Enals and Alkynes
entry X R ligand product yield, % ee, %
1 A 93 25
2CH2 n-Bu
B
O BuH
BuH
H
H 66 48
3 A 93 22
4CH2 t-Bu
B
OtBu
H
tBuH
H
H 72 58
5 A 95 10
6CMe2 t-Bu
B
OtBu
H
tBuH
H
H 25 40
X
O
+ R
Ni(acac)2(5 mol%)L* (10 mol%)
Me3Al/PhOH (40 mol%) THF, rt X
O R
R
H
H
Summary of Intermolecular Coupling
Intermolecular Coupling of Enones or Enals and Alkynes
Ni R2
O R2Ni
R1
R1
Ni(0)R3
R2R1
∗
OL*,TMSCl, ZnR3
2
trimerization
R1 R2
Me3Al/PhOH, L*
O
∗
∗
R2
R2
R1
R1
O
Coupling of Aldehydes and Alkynes
R2R1+
Ni(0), R(M)
R3 R2
OH
R1
HO
RR2
n
R
R3 H
O
intramolecular
intermolecular
Introduction to The Coupling of Aldehydes and Alkynes
Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 35, 2554.
Coupling of Aldehydes and Alkynes
Ni
LLNi
O R2
LL
OR2
H
B
HO R2R
? R(M)
Ni R2LL
O
R1
R2Ni
LL O
R1
A
R2RO
R1R(M)
Catalytic Reductive Coupling of Aldehydes
Huang, W. S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221.
Coupling of Aldehydes and Alkynes
entry R3 R1 R2 product yield, %(regioselectivity)
1 Ph H n-Hex Hex Ph
OH
76% (96:4)
2 o-tolyl Me Ph Ph
OH
Me
Me
83% (93:7)
3 n-Pr Me Ph Ph Pr
OH
Me
85% (92:8)
4 n-Hept SiMe3 Ph Ph Hept
OH
SiMe3
89% (>98:2)
R1 R2R3 H
O
+Ni(COD)2 (10 mol%) Bu3P (20 mol%)
Et3B (200 mol%) toluene, rt
R2 R3
OH
R1
H
R1 < R2 2 equiv.
Proposed Mechanism
Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065.
Coupling of Aldehydes and Alkynes
β-H elimination
R1 R2
R3 H
OO
HR3
R2
R1
Ni
L L large substituent
small substituent(or tether chain)
NiO
LL
R2
R1HR3
(M)O
R3H
R1
R2LnNiR4
R4
R2R1
OH
R3
H
(M)O
R3H
R1
R2LnNiH
H
R2
OH
R3
H
LnNi(0)+
R4(M)
L = THF
L = PBu3
reductive coupling alkylative coupling
(transmetallation)
CD
R1
Catalytic Asymmetric Coupling of Aliphatic Alkynes
Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156.
R1 R2
R3 H
O+
Ni(COD)2 (10 mol%) L* (10 mol%)
Et3B (200 mol%) EtOAc, rt
R2 R3
R1
OH
R1 R3
R2
OH
+
a b
H H
R1 < R2 2 equiv.Fe
P PhMe
A
β-H elimn. reductive elimn.
Coupling of Aldehydes and Alkynes
Proposed mechanism
Fe
PNiMe
PhCy
MeOBEt3
i-Pr
H
ONi
Cy
Me PR3
BEt3Hi-Pr
Cy i-PrMe
OHH
Cy i-PrMe
OBEt2NiPR3
H
entry ligand R3 R1 R2 product yield,%(a : b)
ee, a(%)
ee, b(%)
1 A i-Pr Me Cy
OH
65 (2.2:1) 46 45
2 A n-Pr Me CyOH
30 (2.2:1) 67 68
3 A Ph n-Pr n-PrOH
85 49 N/A
Miller, K. M.; Huang, W. S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
Me
PPh2
Me
Me(+)-NMDPP
Catalytic Asymmetric Coupling of Aromatic AlkynesCoupling of Aldehydes and Alkynes
entry R3 alkyne yield,%(a : b) ee of a (%)
1 i-PrMe
95 (>95:5) 90
2 i-PrCH2NHBoc
60 (>95:5) 96
3 n-PrMe
82 (>95:5) 65
4 PhMe
79 (91:9) 73
5 i-Pr 35 42
NN MeMe
O
DMI
R1 R2R3 H
O+
Ni(COD)2 (10 mol%) L* (20 mol%)
Et3B (200 mol%)EtOAc:DMI(1:1)
R2 R3
R1
OH
R1 R3
R2
OH
+
a b
H H
R1 < R2 2 equiv.
Proposed Model for Enantio- and Regioselectivity
1. Miller, K. M.; Huang, W. S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.2. Whittall, I. R.; Humphrey, M. G.; Samoc, M.; Luther-Davies, B.; Hockless, D. C. R. J. Organomet. Chem. 1997, 544, 189.
NiO
PR3
Ph
MeR
R PhMe
H
D
major
Et3BOH
Coupling of Aldehydes and Alkynes
P
Me
Ni
MeMe
O
RHMe
Ph
P
Me
Ni
MeMe
Me
PhH
OR
P
Me
Ni
MeMe
Ph
MeH
OR
sterically disfavored,electronically favored
sterically and electronicallydisfavored
sterically favoredelectronically disfavored sterically and
electronically favored
A B
C D
P
Me
Ni
MeMe
O
RHPh
Me
Total Synthesis of (-)-Terpestacin
Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 11514.
Coupling of Aldehydes and Alkynes
OOSiMe3H
HMeMe1
TIPSO
MeCo(CO)3
Co(CO)3Me3Si
H
+
I
OAcMe
Me Me 2HO
HO
HOTBS
Me 2
O
OH
H
HMe
Me3SiO
Me
Fe
P MePh
(R)-A
Ni(COD)2 (10 mol%)(R)-A (10 mol%), Et3B
1
Me
TBSO
2
70% combined(dr 3:1; regio: 2:1)
HHO
HO
Me
Me
O
OH
Me
Me
Me
(-)- Terpestacin
H
Tang, X.Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950.
Total Synthesis of (+)-Allopumiliotoxin 339ACoupling of Aldehydes and Alkynes
NO
HOSEM
O
Me
Br
Me
Me Me
OO
N
HMe
OOBn
Me Me
OO
Me
H
N
MeMe
HOBnMe
OTES
H
OO
Me
Ni(COD)2 (10 mol%) PBu3, Et3SiH, THF
93%
HN
Me
MeMe
OH
OH
OHMeOH
H
(+)-Allopumiliotoxin-339A
H
+
Two-Step Four-Component Coupling
Lozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124, 2106.
Coupling of Aldehydes and Alkynes
O
R2
H R3
H
R4
Bu3Sn H R3
R4
R2
H
O
RR4
R3
HR2
HO
TMSCl
Ni(acac)2( mol%)DIBAL-H+ +
NiO
LLPh
H
ONi H
H
LL
via via
R2Zn or R3B
R1
R1
R1
1 2
Ni(COD)2/L( mol%)
entry R1 R2 R3 R L % yield of 1 % yield of 2 (dr)
1 H H n-hexyl H(Et3B) PBu3 69 85
2 Me H H Me(Me2Zn) none 63 74(2.7:1)
3 H Me H Me(Me2Zn) none 67 80(5.3:1)
Summary of Coupling Reaction Between Aldehydes and Alkynes
Coupling of Aldehydes and Alkynes
Ni
LLNi
O R1
LL
OR1
HNi(0)
inter/ intra-molecular
reductivecouplingL*,R3B
H ∗ R1
OH
alkylativecoupling
ZnMe2 or BMe3H R1
OH MeH
H
Other Electrophile Equivalents
Coupling of Other Electrophile Equivalents and Alkynes
NiN R2
LLNi
O R2
LL
O
ONi
LLR2
R1
R2R1+
Ni(0), R(M) R2HO
NR4
H R3
O
R3CO2
R
H R3
O
NiO R2
LL
R1R3R1R3
R4
R1R3 R1R3
HO2CR2
R
R1
R3 R2
R1
NHR4
R
R3 R2
OH R1
R
R(M)
R(M) R(M) R(M)
Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345.
Coupling of Alkynes and CO2
R1 = Ph, Bz, Bu, Me, alkylative product; R1 = Et, major product is reductive coupling product. An efficient way to prepare β,β’-disubstituted α,β-unsaturated acid under mild conditions.
Proposed mechanism
Coupling of Other Electrophile Equivalents and Alkynes
R
+
CO2NiO O
RNi
O O
R
ZnR1
X
Ni(0) R1-ZnX
R O
Ni OZnXR1
R O
R1 OZnX
RCO2H
R1
H3O+
R
CO
O
Ni
A
B
R +R
CO2HR1
R1)1 equiv. Ni(COD)2 2 equiv. DBU2)R1
2Zn or R1ZnXCO2R1
53 ~ 81% yield
CO2
Total Synthesis of Erythrocarine
Shimizu, K.; Takimoto, M. Mori, M. Org. Lett. 2003, 5, 2323.
Coupling of Other Electrophile Equivalents and Alkynes
Br
CHOO
O
O
O
1)CO2, 1.1equiv. Ni(COD)2 3.3 equiv. DBU, 0oC
2)CH2N2
ZnClTMSO
O
N
O
O
OAc
69%(2 steps)
SiMe3
CO2Me
TMS
NHBoc NHBoc
N
O
O
HO
( )-Erythrocarine+_
Imine as Electrophile Equivalent
1. Patel, S. J.; Jamison, T. F. Angew.Chem. Int. Ed. 2003, 42, 1364.2. Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymm. 2003, 14, 3619.
Coupling of Other Electrophile Equivalents and Alkynes
R1 R2 NR4
H R3
Ni(COD)2 (5 mol%)Cyp3P (5 mol%)
R2 R3
Et HN
R1
R4
R2 R3
H HN
R1
R4
+ +
a bEt3B (300 mol%) MeOAc/ MeOH
entry product yield (%) a : b regioselectivity
1 Ph o-tol
Et
Me
NHMe
85 94:6 90:10
2 Ph (p-CF3)C6H4
Et
Me
NHMe
98 96:4 89:11
3 Ph Ph
Et
Me
HNCO2Me
75 94:6 91:9
4 Ph
Et NHMe
nPr
nPr
91 94:6 -
5 c-C6H11
Et NHBu
nPrnPr
52 >96:4 -
Imine as Electrophile Equivalent
1. Patel, S. J.; Jamison, T. F. Angew.Chem. Int. Ed. 2003, 42, 1364.2. Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymm. 2003, 14, 3619.
β-H elimination
Proposed mechanism
a and b were isolated in identical ee.
Coupling of Other Electrophile Equivalents and Alkynes
Me
PPh2
Me
Me(+)-NMDPP
NiPR3
L H Ar
NMe+
∗
NNi
PR3
BEt2
Ar
Me
Me
∗
Ar
Ni N BEt2
MePR3
H ∗
Ar
Ni N BEt2
MePR3
H
∗
Ar
H NBEt2Me
∗
Ar
Ni N BEt2
MeOHR3PEt
Me
∗
Ar
Et NBEt2Me
Et3B
reductiveelimination
MeOH
a b1
reductive elimination
2
Ph MeN
Me
H Ar
Ni(COD)2 (5 mol%)(+)-NMDPP (20 mol%)
Ph∗
Ar
Et HN
Me
Me
Ph∗
Ar
H HN
Me
Me
+ +
a b
Et3B (300 mol%) MeOAc/ MeOH
Ar ee of a ee of b
Ph 41 42p-ClC6H4 33 33P-CF3C6H4 40 39
Epoxide as Electrophile Equivalent
Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076.
Proposed mechanism
Coupling of Other Electrophile Equivalents and Alkynes
R1 R2O
R3+ R2 R3
R1 OH
Ni(COD)2 (10 mol%) Bu3P (20 mol%)
Et3B (200 mol%)
R1,R3 = aryl, alkylR2 = alkyl
up to 71% yield> 95:5 regioselectivity> 99% ee
H
R1 < R2
Ni O
R3PR2
OBEt2
NiPR3Et
R1 R3
OBEt2
Ni
R2
PR3H
R1 R3
OHH
R2
LnNi-PR3
Et3B
R1
R2O
R3+
R3R1
ONi
R3
PR3R2
R1
R1 R3R2
A B
Summary
R2R1+
intra
inter
RR2
R3
O
O R2
R3
R1
R
n
Ni(0), R(M)R3
∗
R2
OH
R1
intra
inter
HO
RR2
n
R2CO2H
R
NR4
H R3
R2∗
R3
R HN
R1
R4
O
R2 R3
R1 OH
O
R3
R3CO2
RR1
R3
HO
RL*
L*
Multicomponent Coupling of Alkynes
Recent Applications in Total SynthesisMulticomponent Coupling of Alkynes
NiO
R3
NiX
R2
NiO
R3
R1
R2R1R2
R1
NHO2C
HO2C
H
Me
Isodomoic acid G
HO2C
Me
N
Me
MeMe
OH
OH
HOHMe
OH
H
(+)-Allopumiliotoxin-339AN
O
O
HO
( )-Erythrocarine
HO
HO
Me
Me
O
OHH
Me
Me
Me
(-)-Terpestacin
N
N
H
OMeO
HH
H
Me
( )-Isogeissoschizoid Skeleton
+_
+_
H H
Future Development
Alkylative coupling of aldehyde
Coupling of ketone for the generation of tetra-substituted alkene & tertiary allylic alcohol
Multicomponent Coupling of Alkynes
H R3
OR2R1
R3 R2
OH R4
R1Ni(0), R4(M)
(More complicated R4)
R4 R3
OR2R1
R3R2
OH R5
R1Ni(0), R5(M) R4
Future Development
Tandem coupling-aldol condensation
Control of absolute stereochemistry
Multicomponent Coupling of Alkynes
∗
OTMS
Me
R2R1
n∗
∗
O
Me
R2R1
n
∗
Mukaiyama aldolR
OH
R H
O
O
R1
R2Ni(0)
Ni(0), R3(M)
N N
*
∗R2
R2
H
RO
R2
OH
H
E
R1
R3(H)O
R1
O
R1
[2+2+2] [3+2]
chiral L*
or
Acknowledgement
Professor William WulffProfessor Jetze Tepe
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