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1
Patrick RobichauxTang Group
University of Wisconsin-MadisonDepartment of Chemistry
Literature Seminar04/28/2011
A Recent Inquiryinto the Preparation and Practical Application of
Benzyne
4
Evidence for Benzyne
Cl NEt2
NEt2
no isomerization in NH3 (l)
LiNEt2
NH3 (l), -38 oC
Reaction is fast even at such low temperatures
Br
LiNEt2
NH3 (l), -38 oC
Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290.
5
Neutral Benzyne Intermediate?
Cl= 14C
NH2
NH2KNH2
NH3
1 : 1
Evidence of neutralintermediate
Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290.
6
Singlet or Triplet?O
O
O
O
h
or h
or h
I
HgI
I
Hg
IPhPh
Ph Ph
O
Ph
Ph
Ph
Ph
gasphase
•hν = diradical?•Benzyne actually singlet• singlet-triplet splitting of 37.5 kcal/mol•lifetime at least 20 ms
Wittig, G.; Ebel, H. F. Angew. Chem. 1960, 72, 564.Wentrup, C. Aust. J. Chem. 2010, 63, 979.
8
Traditional Formation of Benzyne
H
X
X1
X2
X
OTf
Strong base: RLi, RMgX, etc.
X=halogen
Fluoride ion: Bu4NF, KF, CsF, etc.
SiMe3
OTf
SiMe3
I(Ph)OTf
Thermolysis
CO2-
N2+
CO2-
IPh
Oxidation: Pb(OAc)4, etc.
NN
NNH2
Kitamura, T. Aust. J. Chem. 2010, 63, 987.Wentrup, C. Aust. J. Chem. 2010, 63, 979.Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.
9
Synthesis of Silyltriflate
HO
i-PrN=C=O
Et3N, CH2Cl2 O ii. TMEDA, n-BuLi
-78 oC
i. TMEDA, TBSOTf
Et2O, 0 to 23 oC
NH
O
N
TBS
LiO
O
NN
TMSCl
acidic workupON
H
OTMS
DBU, Et2NH
CH3CN, 40 oCHO
TMSPhNTf2
23 oC
TMS
TfO66% yieldfrom phenol
OMe
MeO OH
NBS
CH2Cl2-78 oC
OMe
MeO OH
HMDS, THF, 70 oC
n-BuLi, then Tf2O
THF, -100 oC
Br
OMe
MeO OTf
TMS
67%63%
42% overall yield
Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74, 8842-8843.
Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224-1227.
Wu, Q.-c.; Li, B.-s.; Shi, C.-q.; Chen, Y.-x. Hecheng Huaxue 2007, 111.Himeshima, Y.; Sonada, T.; Kobayashi, H. Chem. Lett. 1983, 1211.Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002. 1454.
10
Activation DominoOH
SiMe3
NfF, Cs2CO3, 15-c-6
MeCN
ONf
Si
F
Cycloadditions
Nucleophilic additions
TM catalyzed Reactions
SO O
F F
F F
F FF
FF
Nf=
TBDMSO
OH
TMS
OTBDMSO
O86%
conditions
CsF (1.0 equiv.)
18-c-6 (0.60 equiv.)
MeCN (0.10 M)
50 oC, 2.5 h
OHO
86%
Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S. Org. Lett. 2011, 13, 1730.
•Silyl protecting group tolerant
11
OH
OPdX2, L
HXPd
O
O
L L CO2
PdL2 PdL2
New Method: C-H activation
•highly solvent and concentration dependent•Optimized conditions: Pd(OAc)2 (10 mol %)
Cu(OAc)2 (0.75 equiv.) 1,10-phenanthroline (10 mol %) K2HPO4 (2 equiv.) , TBAB (1 equiv.)
sulfonane, 4 Å MS
Cant, A. A.; Roberts, L.; Greaney, M. F. Chemical Communications 2010, 46, 8671-8673.
CHEAP!
<47% yield+ side products
13
Regioselectivity: StericsMe
>
Me
ArLiArLi
84%
16%
R
>>
R
ArLiArLi
100%
0% R = TMS, Ph,
MeO
MeOTMS
>>
TMS
ArLiArLi
100%
0%
Me Me
Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.
14
Regioselectivity: Sterics vs. Electronics
OMe
>>
OMe
ArLiArLi
addition favoured bysteric hinderance ofmethoxy group
100% 0%
OMe OMe2-biaryllithium intermediate stablized by methoxy group in ortho position
Ar
Li
Li
Ar
Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.
15
Regioselectivity: Electronics
OMe
>>
OMe
ArLiArLiaddition disfavoured by
steric hinderance ofmethyl group
100% 0%
OMe OMe2-biaryllithium intermediate stablized by methoxy group in ortho position
Ar
Li
Li
Ar
Me Me
MeMe
Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.
16
Distortion/Interaction Model
Cheong, P. H. Y.; Paton, R. S.; Bronner, S. M.; Im, G. Y. J.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267.Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.
127o127o
110o
122o122o
110o
internal bond angle NH2
119o
121o121o
110o
113o136o
H2N
NH
=
54
NR
125o
129o5
6NR
127o
129o6
7NR
135o
116o
17
Reactivity of Indolyne Systems
NH2
54
NR
5
6 NR
6
7NR
5
4
NR
54
NR
NHPhPhHN
R = MeH
Boc
12.56.48.3
:::
111
5
6NR
5
6 NR
+
+PhHN
PhHN
R = MeH
Boc
3.02.91.5
:::
111
91%93%84%
73%91%83%
6
7NR
67 N
R
+PhHN
PhHN
R = MeH
Boc
only13.8only
:::
-1-
91%79%66%
Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.
20
Acyl-Alkylation of Arynes
TMS
OTf OMe
OO CsF (2.5 equiv.)
MeCN (0.2 M)
80 oC, 45-60 minCO2Me
O
OMe
OO
CO2Me
O O
O
OMe
H+
90%
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
21
Acyl-Alkylation of Arynes
O
O
OTf
TMS
OMe
OMe
EtO2C
O
O
O
OMe
OMe
EtO2C
+Cs-O
O
O
OMe
OMeEtO2C
+Cs-O
CsF (2.5 equiv.)
MeCN (0.2 M)
80 oC
O
O
OMe
OMe
EtO2C
O 57%
O
O
OMe
OMe
N Me
(+)-Amurensinine
Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752.
22
Indolines and Isoquinolines
O
NH
CO2Me
N
Boc
CO2Me
N
CO2Me
O
NCO2Me
Boc
Indolines
N
CO2Me
isoquinolines
BocHN CO2Me
87%
61%
Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558.
23
Indolyne: Regioselectivity Reversal
Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832.
NH
TMS
TfO
Br
NH
HN
OMe
OOH
O
CsF, CH3CN, 0 oC to rt NHBr
N
HN
OMeO
OH
O
62%
N
HN
O
NH
OH
indolactam V
NHBr
130o
124o
24Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chemistry-a European Journal 2002, 8, 2034.
E+ E Yield (%)
H2O H 75
Bu3SnCl SnBu3 67
PhCHO PhC(H)OH 69
Me2CO Me2COH 73
ClCO2Et CO2Et 73
PhCH-NPh PhCHNHPh 59
BrCH2CH2Br Br 61
Indole Synthesis
F
N BrMe
1. 3.3 equiv. t-BuLi, -78 to 20 oC
2. E+, -78 to 20 oC
3. H2O
F
N LiMe
F
N LiMe
N LiMe
Li
N
Li
MeNMe
Li
N
Me
E
25
Biaryl Synthesis
Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
n-BuLi
Br
Cl
i-PrO Oi-PrBr
Oi-Pri-PrO
PCy2
Oi-Pri-PrO
n-BuLi
Cy2PCl
i-PrO Oi-Pr
Li Br
Cl
Li
Cl
i-PrO Oi-Pr
Li
Li
Oi-Pri-PrO
Br
Cl
Br
Oi-Pri-PrO
Negishi Coupling ligand
27
OTf
TMS
CsF (4.0 equiv.)
1,4-dioxane
N
Ts
[2+2]
110 oC
N
Ts
ring-opening: amide in an outward rotation
NTs
NTs18 h
95% yield
NTs
H
H
Enamide Cascade
Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666.
28
OH
Cl
Cl
NaH
DMF
(-)-mentholR O
OR*
R*O =O
F
F
F
F
F
BuLi, heptane
0 oC to rt, 12 h
F
F
F
F
R O OR**
F
F
F
F
OR* *R O(R,R) (S,S)
*
Chiral Ligands = L*
[4+2] Cycloaddition on Arene System
O
PhB(OH)2
[RhCl(L*)]2
(3 mol % Rh)
KOH (50 mol %)
1,4-dioxane/H2O
(10/1), 30 oC, 1 h
O
Ph
[RhCl(R,R)]2 97%, 99% ee (R)[RhCl(S,S)]2 94%, 99% ee (S)
Nishimura, T.; Nagaosa, M.; Hayashi, T. Chem.Lett.2008, 37, 860.
29
Metal Free Click Chemistry
SiO
Si SiO
Si PhI(OAc)2, TfOH
CH2Cl2, 0 oC to rt
SiO
Si
Si(OH)Me2
I(Ph)OTfi-Pr2NH, rt
CsF SiO
Si
N3Si
OSi N
NN
SiO
Si NN
N SiO
Si NN
N SiO
Si NN
N
SiO
Si NN
N
OMe Me Cl
NO2
56% 63% 80%
87%67%
Lin, Y.; Chen, Y.; Ma, X.; Xu, D.; Cao, W.; Chen, J. Tetrahedron 2011, 67, 856.
30Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784.
N
Ph HPh N
H
Ph
Ph
HN
NN
Ph
Ph
Ph
Ph H
Ph
Ph
Ph
Indole Synthesis
32
3-Component Benzyne Coupling
O
O OO
OO
O
O
OMe
OMe
M
H
OOSiPh2t-Bu
O
OMe
OMe
OH
OH
OMe
OMe
O
SharplessEpoxidation
Three-ComponentBenzyne Coupling
OxidativeLactonization
RCM
O
O OO
O
Clavilactone B
Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.
33
3-Component Benzyne Coupling
O
O OO
O
Clavilactone B
Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.
OMe
OMe
F 1) n-BuLi, THF, -78oC
2)
-78 to 25 oC
MgCl
MeO
OMe
MgCl
OH
OSiPh2t-Bu
OMe
OMe
O
H
OOSiPh2t-Bu
O
-78 to -35 oC
65% total yield 2:1 d.r.
34
Catalytic Carbonylation
cat [(p-C3H5)PdCl]2
dppe, CsFCO, OAc
CH3CN
1 atm, 80 oC, 4 h
TMS
OTf
O
80%
Pd(OAc)Ln Pd(OAc)LnCO
Pd(OAc)Ln
O
OPd(OAc)Ln
PdLn + HOAc
Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2001, 123, 12686.
35
Pd-catalyzed
Heck:
Suzuki:
Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2005, 7, 2921.Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9, 5589.
I OTf
TMS
CO2t-BuCO2t-Bu
CsF (6 equiv.)Pd(OAc)2 (5 mol %)P(o-tol)3 (10 mol %)
MeCN, 45 oC, 4 h
63%
Br
Br
OTf
TMS
Cl
(HO)2B
Ph
CsF, MeCN, rt, 8 h
Pd(dba)2 / dppb
Ph88%