Recent Advancements In The [2+2+2] Cycloaddition
Brandon DutcherJanuary 17, 2007
Michigan State University
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
General Information
[2+2+2] cycloaddition first reported by Bertholet in 1866First transition metal catalyzed [2+2+2] cycloaddition by Reppe et. al. in 1948.A multitude of metals have been employed on the catalysis of the [2+2+2]
Ni, Co, Pd, Cr, Rh, Zr, Nb, Ir, Ta, and Ti
The [2+2+2] cycloaddition has been found to have a wide range in synthesis
Important [2+2+2] Cycloadditions
Used the Nickel complex Ni(PPh3)2(CO)2Between 25°C and 80°C
2CO2R (PPh3)2Ni(CO)2
benzene
R=Bu
CO2R
HO3
(PPh3)2Ni(CO)2
HO
OHOH
OH
HO
OHbenzene65%
Reppe
BertholetFirst [2+2+2] cycloadditionThermally induced reaction
∆
Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767Reppe, V.W.; Schweckendeik, W.J. Justus Leibigs Ann. Chem. 1948, 560, 104-116
General [2+2+2] Cycloaddition
Tolerant of many functional groupsApplicable to many π-bond containing systemsExcellent for building aromatic systems –benzene and pyridine moietiesSymmetry favored – exothermic (∆H= -594 kJ/mol)High temperature or catalyst required due to entropic factors
X∆
X
R
RR
RR
RR
RR
RR
Ror
catalyst
Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
π-bond System Approach To The MetalThree possibilities for alignmentTwo possibilities give the 1,2,4 trisubstituted ringOne gives 1,3,5 trisubstituted ringStatistically slightly greater than a 2 to 1 mixture of
1,2,4- to 1,3,5-trisubstituted rings
MR
RM
R
R R
R
R
MM
R
R
R
R RR
R
M
R
R MR
RR R
R
R
RR
Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767
Metal-Carbon Insertion Mechanism
M
R
R
M
R
RM
RR
R
RR
R
RR -M
MR
R
R
MR
R
MR
R
M
RR
R
M
R
R
R R
R R
R
R RR
R
-M
-M
Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767
Diels-Alder Type Mechanism
M
RR
RR
R
R
M-M
R
RM MR
RRR
R
R
R R
R
M
R
-M
R
R
R
M MR
R R
Kotha, S.; Brachmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivitySubstrate controlReagent control
ChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
Statistical Regioselectivity of [2+2+2] cycloaddition
MR
RM
R
R R
R
R
MM
R
R
R
R RR
R
M
R
R MR
RR R
R
R
RR
Statistically a slightly greater than a 2 to 1 1,2,4- to 1,3,5-trisubstitution ratio
1,2,4 tri-substituted only
1,2,4 tri-substituted only
Mixture of Both
“Tethered” Alkynes
Force regiochemistry of alkyne reactionSpeed up reaction – intramolecular reactionIncrease yield
XR1
R2
X= O, S, C(CO2Me)2 etc.
XR3R3
R3
R3
R1
R2
Macrocycles by [2+2+2] Cycloaddition
1:755
3:449
1:157
1:142
Meta:ParaYield %α,ω-diynes
OO
(CH2)6
(CH2)7EtO2CEtO2C
N
pTol
N
pTol
15 mol% CpCo(CO)2
o-xylene140 oC, 100 h
meta para
N
pTol
O
OOO
Maryanoff, B.E.; et. al. J. Am. Chem. Soc. 2006, 128, 3473-3485
Macrocycle Regioselectivity
N
MO
OOO
N
p-Tol
Tol-
OO
OO
N
p-Tol
O
O
O
O
MN
p-TolO
O
O
O
N
p-Tol
XMO
O O
O
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivitySubstrate controlReagent control
ChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
Ortho/meta Selectivity Of “Tethered”Alkynes
MeMe
Me
RMe Me2 mol%
[Ir(cod)Cl]2
4 mole % ligandargon
Me
Me
Me
MeR
RO M
84/1668Benzene reflux 2 hDPPF(CH2)3OH686/1483Benzene reflux 1 hDPPFn-Oct588/1284Benzene reflux 1 hDPPFn-Bu418/8275Benzene r.t 12 hDPPE(CH2)3OH319/8180Benzene r.t 1 hDPPEn-Oct220/8092Benzene r.t 0.5 hDPPEn-Bu1
Ratio O/M Yield%ConditionsLigandREntry
Ph2PPPh2
DPPE
Fe
Ph2P
PPh2
DPPF
Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552
Regioselective Pathways
Me
MeIr
Me
PP
Cl
R
Ir
Me
Me
R
PP Me
Me
Me
R
Me
MeIr
Me
PB
PA
Cl Me
MeIr
Me
PBCl PA
R
Ir
Me
Me
Me R
ClPA
PB
Me
Me
MeR
Meta Pathway
Ortho Pathway
Takeuchi, R.; et. al. J. Org. Chem. 2006, 71, 543-552
Substrate Directed Regioselectivity
C2H2 (1atm)THF
-40oC to rt, 4 h
B
R
OO
(Pin)B RB(Pin)R
CoCpR R
B(Pin)(Pin)B
CoCp
A B
CpCo
-tBu1
4A/4B 1:9 (84)CH2OMe45A/5B 1:20 (92)Ph5
3A/3B 1.5:1 (93)C6H1332A/2B 1:0 (18)iPr2
A/B (yield%)REntry
R B(Pin)
R(Pin)BCoCp
R=tBu 59%
Aubert, C.; Vollhardt, K.P.C.; Malacria, M.; et. al. Angew. Chem. Int. Ed. 2005, 44, 7114-7118
1,2,4 –Trisubstitution Using Titanium-Calixarene Complexes
RCatalyst
Na, toluene
R
RR R
RR
A B
O
O
Ti
ClCl But
But
ButBut
O
O
SiMeMe
>97<3Ph3
100--N,N’-dimethylamine4
973p-Tol2
982TMS1
B(Yield%)A(Yield%)REntry
Lapido, F.T.; Ozerov, O.V.; Patrick, B.O. J. Am. Chem. Soc. 1999, 121, 7941-7942
1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes
S SSO OO
O
ButBut
ButBut
S
Ti
ClCl
Ti
ClCl
1: 65% yield� ratio A:B 77:23
OS
SSS
O
Ti
ClCl But
But
ButBut
O
O
TiClCl
2: 95% yield� ratio A:B 85:15
PhCatalyst
Na, toluener.t., 20 h
Ph
PhPh Ph
PhPh
A B
Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161
1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes (continued)
XX
XHO OO
OH
ButBut
ButBut
SiSi Pri
Pri
Pri
PriO
X
3: X=S: 93% yield � ratio A:B 83:174: X=CH2: 94% yield ratio A:B 1:99
XOHOH
ButBut
5: X=S: 95% yield� ratio A:B 32:686: X=CH2: 85% yield � ratio A:B 33:67
PhCatalyst
Na, toluener.t., 20 h
Ph
PhPh Ph
PhPh
A B
Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161
1,3,5 –Trisubstitution Using Titanium-Calixarene Complexes (continued)
R2.5 mol% 2
Na, toluene
R
RR R
RR
A B
100:0141550TMS595:5711523Oct4
75:25731523Pr3~100:0303.5234-CF3C6H42
95:5953.5234-Tol1
Ratio A:BYield%Time (h)Temp (oC)REntry
OS
SSS
O
Ti
ClCl But
But
ButBut
O
O
TiClCl
2
Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161
OS
SSS
O
Ti
ClCl But
But
ButBut
O
O
TiClCl
O
O
Ti
ClCl But
But
ButBut
O
O
SiMeMe
Lapido catalyst vs. Morohashi catalyst
Lapido catalyst vs. Morohashi catalyst
OS
SSS
O
Ti
ClCl But
But
ButBut
O
O
TiClCl
O
O
Ti
ClCl But
But
ButBut
O
O
SiMeMe
1,2,4 regioselectivity
Morohashi, N.;Yokomakura, K., Hattori, T, Miyanao, S. Tet. Lett. 2006, 47, 1157-1161
O
O
TiClCl But
But
ButBut
O
O
SiMeMe
ButBut
O O
Si
MeMeButBut
O O
Ti
R RButBut
O O
Si
MeMeButBut
O O
Ti RR
1,2,4 regioselectivity (continued)
ButBut
O O
Si
MeMeButBut
O O
TiButBut
O O
Si
MeMeButBut
O O
Ti
R
RR
R
R
R R
R
1,3,5 Regioselectivity
O
But
O
But
O
Ti
O
But But
RR
S
O
But
O
But
O
Ti
O
But But
S
R
R
O
But
O
But
O
Ti
O
But But
S
RR
O
But
O
But
O
Ti
OS
But But
R
R
1,3,5 Regioselectivity (continued)
O
But
O
But
O
Ti
O
But But
S
O
But
O
But
O
Ti
O
But But
S
R
R
O
But
O
But
O
Ti
O
But But
S
RR
O
But
O
But
O
Ti
OS
But But
R
R
RR
Explanation of Regioselectivity
O
But
O
But
O
Ti
OS
But But
R
R
R
O
But
O
But
O
Ti
OS
But But
R
RR
R
RR
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivity
Nitriles, olefins and alkynesIsocyanates, isothiocyanates and carbondisulfide
Enantioselectivity ConclusionsAcknowledgments
Olefin vs. Nitrile
OCN
2 mol %Wilkinson's
catalyst
tBuOH82oC, 6 h
XCN
59%
Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc. Perkin Trans I, 1988, 1365-1369
X NX
3 mol% [Rh(cod)2]BF4/
BINAP
CH2Cl2, rt-40 oC
X=C(CO2Me)2
CN
59%
Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem., 2006, 3917-3922
PPh2PPh2
BINAP
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivity
Nitriles, olefins and alkynesIsocyanates, isothiocyanates and carbondisulfide
Enantioselectivity ConclusionsAcknowledgments
Alkenyl Isocyanates and Alkynes
Trace56(CH2)2OTBS71270n-Bu6
trace60n-Pr536313-furanyl438342-thiophenyl372--p-OMeC6H4263--p-Tol1
Yield% 4Yield% 3REntry
NC
OR
R
N
OR
R
NR
R
O
[Rh(ethylene)2Cl]2(5 mol%)
P(4-OMe-C6H4)310 mol%
toluene, 110 oC
1 2 3 4
Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783
Mechanistic Pathways
NC
OR
R
NRh
O
Pathway A
NRhO
1 21
Rh NRh
O
R
R
NRhR
R O
Rh
NR
R O
N
OR
R
NR
R
O
Rh
Pathway B
Rh
Rh
3 4
Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783
(+)-Lasubine II
N
OMeMeO
HOH
NC
OR2
R1
N
OR2
R1
NR1
R2
O
[Rh(ethylene)2Cl]2(5 mol%)
P(4-OMe-C6H4)310 mol%
toluene, 110 oC
R1 = H OMe
OMe
R2=
N
OMeMeO
HOH
Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 2782-2783
(+)-Lasubine II
Total Synthesis of (+)-Lasubine II
OMeOMe
O C N
N
OMeMeO
OH
N
OMeMeO
HOH
OP
OO
O
Ph Ph
Ph Ph
N
5 mol% Rh(C2H2)2Cl]210 mol% L
Toluene, 110oC
62% yield98% ee
N
OMeMeO
HOH
Pd/C, H2
80% yieldd.r.>20:1
1) PPh3, DEAD p-nitrobenzoic acid
2) K2CO3, MeOH 64% yield
MeOHL=
Rovis, T.; Yu, R.T. J. Am. Chem. Soc. 2006, 128, 12370-12371
Isocyanate Selectivity
X OCNR
5 mol% Cp*RuCl(cod)
DCE, 90oCArgon
XN
O
R
87654321Entry
SO
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
X
PhPhCyPrBn
2-furyl1-napthyl
PhR
6058858993877987
Yield%
Yamamoto, Y.; Takagishi, H. J. Am. Chem. Soc. 2005, 127, 605-613
Isothiocyanate And Carbon Disulfide Selectivity
54321Entry
SNCOPhNCO2Et
NCyNPh
X
5476715088
Yield%
SCXS
X
MeO2C
MeO2C
MeO2C
MeO2C
10 mol% Cp*RuCl(cod)dichloroethane,
90oC Argon
Yamamoto, Y.; Takagishi, H. J. Am. Chem. Soc. 2005, 127, 605-613
Isothiocyanate And Carbon Disulfide Selectivity (continued)
X CY
S
[Rh(cod)Cl]2/2BINAP(5 mol% Rh)
dichloroethane80 oC, 12-20 h
SX
Y
75SC(CH2OMe)2787NPhC(CH2OMe)2674SC(C=OMe)2581NPhC(C=OMe)2485SC(CO2Me)2389N(4-ClC6H4)C(CO2Me)2288NPhC(CO2Me)21
Yield%YXentry
Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006, 8, 907-909
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
Total Chirality Transfer
PhPPh2
O
Ph
OH
(S) (S)
>95%ee >95%ee
CpCo(CO)2
THF, ∆hν
H
CpCo
P OPh
Ph
Ph
quant.>95%ee
Malacria, M.; Aubert, C.; Buisine, O. Synthesis, 2000, 7, 985-989
Chirality Transfer Mechanism
Ph
PhCo
H
PhP
Co
H
PCp Cp
Co
H
Cp
approachsyn to Ph
approachanti to Ph
H
CpCo
P
Ph
P
P = PO
PhPh
Malacria, M.; Aubert, C.; Buisine, O. Synthesis, 2000, 7, 985-989
Ortho-diarylbenzenesO
O
Ar
ArOO
ArAr10 mol%[IrCl(cod)]2 + 2(S,S)-MeDUPHOS
xylene
90
95
90
87
90
%ee
5
4
3
2
1
Entry
E
D
C
B
A
Ar
60
60
60
r.t.
60
Temp. (°C)
0.5
0.3
0.3
18
0.5
Time (hours)
95
>99
86
68
82
Yield%
12:1
2:1
14:1
>20:1
5:1
dl:meso
Cl
NO2
Me
OMe
OMe
A
B
C
D
E
Shibata, T.;Tsuchikama, K.; Otsuka, M Tetrahedron: Asym, 2006, 17, 614-619
P
P
Me
Me
Me
Me
(S,S)-MeDUPHOS
dl Ortho-dinaphthylbenzene
Structure: ChemDraw 3D
Chiral Intermediate
IrO P
PMe
O
Me
O
O
Ir
P
PMe
Me
OO
Enantioselective Isothiocyanate Addition
MeO2C
Ph RhS
NPhRh
A
Ph CO2Me
B
Rh
2
2
3
Low%ee
High%ee
Ph
MeO2C
1
Ph
MeO2CCN
S
Ph [Rh(cod)Cl]2/2(R)-BINAP(10 mol% Rh)
dichloroethane60 oC, 12 h
S
NPhPh
MeO2C
21 (R)-(+)-3 98%, 61% ee
Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006, 8, 907-909
Chiral Anilides
9662PhPhEtO49869BnOMeMeNSO2(4-BrC6H4)39779PhPhMeC(CO2Me)229729BnPhMeC(CO2Me)21
%eeYield%R3R2R1Xentry
XR1
R1SiMe3
NR2
O10%
[Rh(cod)2]BF4/(S)-xyl-BINAP
CH2Cl2, rt15-42 h
XR1
R1
NR2
O
SiMe3
R3
R3
Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586-4587
Chiral Anilide - Selectivity
Ar
RhX
R1
R1
P P
Ar
Ar
Ar
Me3Si
N
R3
R2
O
Ar
Rh
X
R1R1
P P ArAr
ArMe3Si N
R3
R2
O
Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586-4587
XR1
R1SiMe3
NR2
O10%
[Rh(cod)2]BF4/(S)-xyl-BINAP
CH2Cl2, rt15-42 h
XR1
R1
NR2
O
SiMe3
R3
R3
Enantioselective 1,4-Diene-Ynes to Bridged Cyclohexenes
X
R2
R1[Rh(cod)2]BF4/
tolBINAP10 mol%
X
R1R2
*
*DCE, 60oC
21
924024PhO4937648HC(CO2Bn)2393836HNTs2
>994648BuNTs1%eeYield%Time (h)R1XEntry
Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767
P(p-Tol)2
P(p-Tol)2
tolBINAP
Enantioselective 1,4-Diene-Ynes to Cyclohexadienes
XR1
DCE, 60oC X
Me
*Me
1 3
[Rh(cod)2]BF4/tolBINAP10 mol%
945548PhO3
90806HC(CO2Bn)22
999112MeNTs1%eeYield%Time (h)R1XEntry
Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767
P(p-Tol)2
P(p-Tol)2
tolBINAP
1,4-diene-yne cyclization mechanism
Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128, 11766-11767
X
R1R2
*
*
2
XR1 M
MX
R2
R1
R2
olefininsertion
MX
R1 R2
*
*
MX
R1 R2
H
-MR2 = H
MX
R1
H
X
Me
*Me
3
Chiral Spyrocycles From Diynes and Exo-Methylene Compounds
X
X=C(CO2Bn)2
Me
Me
[Rh(cod){(S)-xylyl-binap}]BF4(5 mol%)
dichloroethane, 80oC, 30 minX
Y
Me
Me O
n
P(3,5-Xylyl)2
P(3,5-Xylyl)2
(S)-xylyl-binap97883
81624
98932
99941
%eeYield%Exo-methyleneEntry
OO
O
OO
OO
Shibata, T.; Kuwata, Y.; Tsuchikama, K. J. Am. Chem. Soc. 2006, 128, 13686-13687
Chiral Intermediate
RhRhXPH
P
3,5-xylyl
OO
3,5-xylyl3,5-xylyl
3,5-xylyl
X
O
O
PP
lylyx-5,3
lylyx-5,33,5-xylyl
3,5-xylyl
XO
Me
Me OX=C(CO2Bn)2
OutlineOverview of [2+2+2] cycloadditionMechanism of the [2+2+2] cycloadditionIssues with selectivity
RegioselectivityChemoselectivityEnantioselectivity
ConclusionsAcknowledgments
Conclusions
[2+2+2] cycloaddition is a useful synthetic toolWide scope of reaction – highly functional group tolerantExcellent multi-component reactionEnantioselective and regioselective advancements increase synthetic value of [2+2+2] cycloaddition