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Update to 2011 Bode Research Group http://www.bode.ethz.ch/
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Topic: Catalytic Divergent Synthesis
1 Selectivity definition 1.1 Diastereoselectivity: preferential formation of one diastereomer over another 1.1.1 Type A: simple diastereoselectivity
CO2Me0oC
CH2Cl2CO2Me
H
HCO2Me
endo80%
exo20%
MeO2C H
endo TS
H CO2Me
exo TS Sauer ACIE 1967, 6, 16
1.1.2 Type B: induced diastereoselectivity
Me MeO
Me OCH2OBn
LiAlH4Et2O Me Me
OH
Me OCH2OBn
chelation controlO alkene
Me
O HCH2OBn
Li
H-
Me MeO
Me OSiPh2tBu
LiAlH4THF Me Me
OH
Me OSiPh2tBu
Felkin controlO alkene
OSiR3
H MeH-
Overman Tet. Lett. 1982, 23, 2355 1.2 Enantioselectivity: preferential formation of one enantiomer over another 1.2.1 Type A: generation of new chiral center
Me OMe
O O
Me (R)(R) OMe
OH ORuCI2[(R)-binap]
H2 99% yield99% ee
Noyori JACS 1987, 109, 5856 1.2.2 Type B: enantiodiscrimination
racemic
N N
O O
tBu tBu
Co
OAc
0.55 equiv H2O
2 mol%
tButBuOCl
/ THF
42%99% ee
OCl
52%89% ee
OHCl OH
Jacobsen Science 1997, 277, 936 & JACS 2002, 124, 1307
1.3 Regioselective: A regioselective reaction is one in which one direction of bond making or breaking
occurs preferentially over all other possible directions.
Type A
R
1) Hg(OAc)2
2) NaBH4
1) BH32) H2O2
Me
R
HO
R OH
Me
cat. a
cat. b
MeX
Me
Xcat. c Me
X
Type B Type C
cat. a
cat. bNHBocHN
NO
OtBu
NHBocHN
NO
OtBu
NHBocN
NO
OtBu
Me
Me Trost Science 1983, 219, 245
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1.4 Chemoselectivity is the preferential reaction of a chemical reagent with one of two or more different functional groups.
OCO2Me
Me
MeO
3
4
NaBH4O
CO2Me
Me
MeO
3
4
NaBH4CeCl3
HOCO2Me
Me
MeO
3
4
Luche's reduction
MeH
O
ONaBH4 NaBH4CeCl3Me
OH
O
MeH
O
OH via
MeHO
HO
O
H2O Ce3+ Yudin ACIE 2010, 49, 262
1.5 Product-selectivity is the preferential formation of two (or more) distinct products that are not stereo-
or regioisomers. This area of research is currently gaining interest within the synthetic community.
HNCO2Et
CuBr•SMe2 2,2`-Bipyridine
(1.1 equiv each)
O2 (1 atm)DMSO, 60 °C
N H
CO2Et
HN
CO2Et
CHO
Cu(OAc)2 (20 mol %DABCO (50 mol %)K2CO3 (2.0 equiv)
O2 (1 atm)DMSO, 80 °C
89% yieldcyclopropanation
56 % yieldcarbooxygenation
Chiba JACS 2011, 133, 13942 2 Selective catalysis 2.1 Why selective catalysis?
- Object of selective catalysis is to use fewer protecting groups, cutting synthetic protocols, thereby contributing to atom economy, step economy, reduced time, and increased efficiency. - Biological systems have an amazing combination of stereo-, regio-, and chemoselectivity. - Chemists can use the following metrics to predict selectivity: redox potential, pKa, HSAB, and A (steric) values.
In an ideal case, we would like to have 4 distinct catalysts to perform, in this particular case, both chemo-, and enantioselective catalysis
O
O
O
O
cat a
cat b
cat c
cat d
2.2 The underlying principle The same rationale and physical organic chemistry concepts apply to asymmetric catalysis as well as catalytic divergent synthesis:
E
reaction coordinateproducta
TSa
productb
TSb
intermediate
!!G
!!G
Fig. B) A generic energy diagram for a catalytic diveregent synthesis
E
reaction coordinate
product"R"
TS"R"
product"S"
TS"S"
intermediate
!!G
Fig. A) A generic energy diagram for an enantioselective reaction
Miller ACIE 2006, 45, 5616
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2.3 Energetic factors in the selectivity
- In some cases, a partition experiment can elucidate the energetic factors behind the competing pathways. This may allow for the use of temperature to control a desired pathway by adjusting the relative energy given to the intermediate.
N
N N
O
Mes
O
ArN
N N
O
Mes
OHAr
O
O
O
O
Ar
O
O
O
Ar
O
OO
O
C from a transiton state
involving a sigmatropic rearrangement
R from a transiton state involving
a C-C bond cleavage
a kinetically importanthemiacetal (HA)
kR
kC
OH
OO
10 mol %
NNN
O
MeMe
Me
Ar
O
H
OH
OOAr = p-OMeC6H4
T(oC)2535456070
!!G -0.33-0.59-0.86-1.26-1.53
!!G = !!H - T!!S
!!H = 7.61 kcal/mol!!S = 26.62 cal/K.mol
a catalytically generated reactive intermediate
krel(R/C)1.433.384.295.629.75
E
reaction coordinatePC
TSC
PR
TSR
HA
!!G in kcal/mol
Bode ACIE 2011, 50, 1673 3 Two classes of catalytic divergent synthesis 3.1 We propose two classes of catalytic divergent synthesis; these differ in their mechanistic nuances: Class A: Divergency arising from a common intermediate:
substrate A
[A-Cat]a common intermediate
(same connectivity, but differ in ligand or metal)
pathway 1
pathway 2
product D
product E
For example:
O
OO O
OTBS
O
OO
R1TBSO
R1
N
N N
O
ArO R3
O
R1
HOR2
(R1 = p-ClC6H4)
O
O
OOH
O
OTBS
R1
H
NNNO
MeMe
Me
Cl-
10 mol %
NNNO
F FF
FF
BF4-
10 mol %
cat B
cat C
Bode Chem. Sci. 2012, 3, 192
Class B: Divergency arising from two catalyst-substrate complexes with two available pathways:
substrate A
intermediate D[substrate A + cat B]
intermediate E[substrate A + cat C]
pathway 1
pathway 2
product F
product G
Cat B
Cat C
structurally distinct
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For example:
ONNs
PhH
ClLScCl2+
TiCl410 mol%
10 mol%
N
O
N
OMe Me
Me MeMeMe
L=N
Ph
Ns
O
O PhNNs
Ns = 4-nitrobenzenesulfonyl
Ar
Ar
O NNs
PhAr
N O
PhAr
Ns
69%
80%40oC
23oC
Yoon ACIE 2010, 49, 930
4 Types of selectivity: - Innate selectivity: the selectivity comes from a substrate-controlled process. - Catalyst-controlled selectivity: the catalyst, ligand, or an additive induces the selectivity. Innate selectivity can be viewed as similar as traditional “background rate” in asymmetric catalysis. Catalytic divergent synthesis may involve overcoming this intrinsic barrier in favor of the desired pathway.
N
Me
OCH3
5 mol% Pd(OAc)21.05 equiv NCS
CH3CN or AcOH100 oC, 12 h
1.1 equiv NCS
CH3CN or AcOH100 oC, 12 h
N
Me
OCH3
N
Me
OCH3
Cl
Cl95 %
76 %catalyst-directed
chlorination
Innate selectivity:Electrophilic aromatic
substitution
N
Me
OCH3
PdAcO OAc
Sanford Org. Lett. 2006, 8, 2523
- Innate selectivity may be absolute Chemospecificity arises when a pair of functional groups react preferentially only with one another (i.e. below the ketoacid couples only with the hydroxylamine, even in the presence of 2 other amines).
H2NHN N
HOH
O
O
O
OH2N
Me
Ph
HOHN N
H
HN OH
O
O
O
Me Ph
COOH
+ H2NHN N
H
HN
O
O
O
H2N
Me
Ph
NH
HN OH
O
O
O
Me Ph
COOHaq. DMF40 oC-CO2-H2O
Bode ACIE 2006, 45, 1248 5 Methods to achieve selectivity (either regio-, chemo-, or product-selectivity) 5.1 Change of substrate (substrate control selectivity) - Circumvent the intrinsic preference of functional groups by modifying the substrate
OHO
MeH+H+
HO O
Me
favored
OO
Me
H
Hstrained
HO
OMeO
OMe
H
H
introduce structural bias
OHO
MeH+H+
HO O
Me
favored
OO
Me
H
Hstrained
HO
OMe
OH
H
OOH
H
O
H
HO
OMe
H
HO
Jamison Science 2007, 317, 1189 5.2 Change of the reaction condition such as solvent, pH, or temperature
N DMSO:H2O
46-60 %(~2.5:1)
R NaSO2CF3tBuOOH
N
R
DCM:H2O
NaSO2CF3tBuOOH
52-67 %(~2.5:1)
N
R
CF3
CF3
R = Ac or CN
Baran PNAS 2011, 108, 14411
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- Depending on the excitation energy given to the diester, chemoselective cleavage is possible.
O
O
O O
O OMe
OmeO2NOMe
MeOn
hv, 254 nmMeCN, 5 min
hv, 420 nmMeCN, 24 h
O
O
O O
OH
OMe
MeOn
HO
O O
O OMe
OMeO2Nn 78-96%
yield
70-87% yield
Bochet JOC 2002, 67, 5567 5.3 Introduction of a directing group (substrate control selectivity - Circumvent the intrinsic preference of functional groups by modifying the substrate or adding a catalyst
20% Pd(TFA)2
R= Ac
2 equiv CsOAc
61%
NR
H
H
Me NAc
H
Me 75%
NPiv
H
R = Piv
5% Pd(TFA)23 equiv AgOAc
Me
Me
Me
Me
PivOH (no oxidant)
Fagnou JACS 2007, 129, 12072 5.4 Innate vs. reagent-controlled selectivity
OAcBr
NaCH(CHO2Me)2
no catSN2
OAc(MeO2HC)2HC
Pd(PPh3)4 Br
75 %
CH(CHO2Me)2 77 %
!-allylationvia
Br[Pd]
"inniate"
reagent-controlled
Trost Science 1983, 219, 245 5.5 Reagent vs. catalyst-controlled selectivity
Me OH
Me Me
Me OH
Me Me
Me OH
Me Mereagent
A B
mCPBA A:B = 2:1VO(acac)2 + tBuO2H A:B = 0:1
O O
reagent-controlledcatalyst-controlled
Trost Science 1983, 219, 245 6 Regioselective Catalysis 6.1 Definitions and Key Principles Regioisomer: The positional isomers formed from the different directions of bond formation/cleavage Note: The term “regiospecific” to refer to a reaction that is 100% regioselective is discouraged, and has no correlation to the difference between “stereoselective” and “stereospecific”
R1R2
H X
HX
R1R2
X
HR1
R2H
X
Regioisomers IUPAC Gold Book (http://goldbook.iupac.org/)
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Controlling regioselectivity in reactions of non-aromatic pi-systems is dependent on electronic and steric factors- charged intermediates and polarized transition states dictate relative position of nucleophile and electrophile
OHH
H+
H
more stable benzylic cation
H2O HOH H
H+, H2O
-H+
M+, NuH
MNu M
Nu!+
developing+ve charge
benzylic
MNu
HNu
more stericallyhindered
exposed
Clayden, et al. Organic Chemistry, Oxford Uni. Press. 2011
The regioselectivity of aromatic substitution reactions is heavily influenced by the inherent electron distribution of the conjugated pi-system. The canonical example is the regioselectivity of the Friedel-Crafts reaction:
OMeE E
OMe OMe
E
+
+ charge most stabilized
OMeE
OMe
E
+
ortho/para selective
H
H
- H+
OMeO
E
EH
OMeO
+ charge least destabilized
- H+
OMeO
E
Electron-Donating Groups
Electron-Withdrawring Groups
meta selective
Clayden, et al. Organic Chemistry, Oxford Uni. Press. 2011
It is worth mentioning that issues of regioselectivity are normally encountered in reactions of functional groups with relatively weak dipoles. In the example below, the red attack would lead to a regioisomeric product, but this product is not formed due to the required inversion of polarity this implies.
XY
R RNu
XY
R R
Nu H+XY
R R
Nu
H
R XNu
YR
H+R X
NuR
Y Hregioisomers
Example:
O
R2R1
ONAr
NHO
R
For example, see MacMillan JACS 2003, 125, 10808 & Maruoka JACS 2006, 128, 6046
6.2 Regioselective Functionalization of Alkenes and Alkynes The design of catalytic regioselective reactions can overcome poor selectivity inherent to the substrate. For example, Tsuji-Wacker oxidation of allylic carbamates gives a nearly 1:1 ratio of aldehyde and ketone products. This is likely because the electronic bias of the bond formation is counteracted by the sterics of the neighbouring group, leading to poor selectivity in the intermolecular attack of water on the Pd-activated alkene:
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56% (6:4)NCbz
O
MeMe
Me
O
NCbzO
MeMe
O
NCbzO
MeMe
H2O, O2
10% Pd(OAc)2CuCl
NCbzO
MeMe
PdX2
OH
HElectronically favouredSterically disfavoured
Sterically favouredElectronically disfavoured
NCbzO
MeMe
OHPdX
NCbzO
MeMe
PdXOH
H2O
PdX2
+
+
!-hydride elim.then tautomerization
- Sigman has designed a new ligand/oxidant combination that renders this reaction remarkably selective and illustrates some design elements that could have general implications for Pd-catalyzed activation of alkenes. - Key elements include the use of electronically asymmetric ligands to pre-organize both reactants, a complexed nucleophile to make the addition intramolecular (migratory insertion) and a cationic metal for high reactivity and maximum electronic bias in the transition state. These factors combine to precisely control the site of attack.
N N
O
electon-poordonor
electon-richdonor
PdOO
t-Bu R
defined, pre-coordinatedNu-Pd-alkene complex
electron-richnucleophile
electron-pooralkene
coordinatively saturatedPd centre (prevents extra
substrate ligation)
single isomer
NN
O
PdCl Cl
18% AgSbF6TBHP (aq)
69%
NCbzO
MeMe NCbzO
MeMe
Me
O
(5 mol %)
2
via
Sigman, Acc. Chem. Res. 2011, doi: 10.1021/ar200236v
This catalyst system can even completely reverse the inherent selectivity of the substrate:
Me
NO O
PdCl2 (10 mol %)CuCl (1.0 equiv)
DMF/H2O (7:1)O2, 3 dMe
NO O
O
94% yield>99:1 aldehyde
NN
O
PdCl Cl
AgSbF6 (18 mol%)TBHP (aq)
CH2Cl2, 17 h
(5 mol %)
Me
NMe
O O
O91% yield
ketone only Aldehyde selective: Feringa, JACS, 2009, 131, 9473 & Ketone selective: Sigman, JACS, 2011, 133, 8317.
Regioselectivity can be altered by the appropriate choice of catalyst- Pd vs Cu-catalyzed diamination of dienes proceeds with reversal of internal/terminal selectivity based on a change in the mechanism.
R N N
O+
Pd(PPh3)4(10 mol %)
C6D6, 65 °CNN
R
OCuCl•P(OPh)3(6 mol %)
RN
NO
Reaction atterminal alkene Reaction at
internal alkene
C6D6, rt
via
N N
O
Cu(II)R+
R N
N OCu
Cu: Radical Mechanism
more stable radical
Pd: Polar Mechanism via
NPd
N
O
R+
insertion into mostelectron-rich alkene
NPd N
R
O
Pd-Catalyzed: Shi, JACS, 2007, 129, 762; Shi, JACS, 2010, 132, 3523
Cu-Catalzyed: Shi, OL, 2007, 9, 2589.
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The ligand environment around the same metal can also play an important role: Fe-catalyzed hydroboration of dienes with reversal of regioselectivity.
While the change in regioselectivity is difficult to rationalize, it should be pointed out that the reaction is chemoselective as well- only the conjugated diene reacts. This can be explained by stronger, two-point chelation to the low-valent iron catalyst.
myrcene
Me
Me
10% Mg
N FeCl2
N3,5-diMePh
3,5-diMePh
N FeCl2
N
iPr
iPr
HBPin
10% Mg
Me
Me
Me
Me
BPin
PinB
80%
78%
viaMe
Me
[Fe](4 mol %)
(5 mol %)
H
pinB
Me
Me
[Fe]Bpin
H
via
H
H
Ritter JACS 2009, 131, 12915
This kind of ligand-dependant regioselectivity has also been demonstrated in catalytic conjugate additions. In this case, the right choice of ligand can lead to preferential nucleophilic attack on the more hindered and less electropositive carbon atom of the maleimide.
N
O
OEt
Bn
[RhCl(C2H4)]2(2.5 mol %)
Ligand (2.75 mol %)N
O
O
BnEt
Ph
PhB(OH)2 (3.0 equiv)
KOH (0.5 equiv)Dioxane/H2O (10:1)
50 °C, 3h
N
O
O
BnEt
Ph+
(R)-H8-binap
C1
C2
C2 attacked C1 attacked
Ph
Ph
87 13
15 85
Hayashi JACS 2006, 128, 5628
Hydrometallation of alkynes is a very important synthetic transformation since it provides vinyl organometallics that are very useful in cross-coupling reactions. Control of regioselectivity is essential as the often-sensitive regioisomeric products can be difficult to seperate.
The regioselective hydrostannation of alkynes can be affected by Pd catalysts. Here, the selectivity between internal and terminal stannation is determined by the ligand (larger ligands lead to better terminal selectivity).
OH
Me
L2PdCl2(1 mol %)
PhCH3, rt
OH
MeBu3SnH
OH
MeHSnBu3
+
terminal internalL
PPh3
P(o-tol)3
P(Cy)3
68 32 (57% yield)
80 20 (60% yield)
95 5 (84% yield)
increasingsize
Pd HBu3Sn L
OH
MeviaBu3SnH +
Chong OL 2008, 5, 861
Selective synthesis of the internal stannane can be achieved using Mo catalysts. In this case, the presence of the bulky CNt-Bu ligands is proposed to favour placing the Mo center at the less hindered terminal position (note that this also implies that Mo-Sn migratory insertion preceeds Mo-H reductive elimination).
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OAcBu3SnH +
Mo(CO)3(CNt-Bu)3(2 mol %)
THF, 55 °C HSnBu3
OAc OH
MeBu3SnH
+
96 4 (91% yield)internal terminal
with P(Cy)3PdCl2 33 67 (61% yield)
SnBu3
[Mo]
OH
Hvia
Kazmaier OL 1999, 1, 1017; Kazmeier EJOC, 2000, 2761
Similar control of selectivity can be achieved in hydroalumination of arylalkynes- in this case the catalyst controls both the regio and chemo selectivity, as it directs the hydrometalation and suppresses competitive deprotonation of the acidic terminal proton.
Ni complex (3 mol%)
THF, 22 °C, 2 h
Al(i-Bu)2
HH
Al(i-Bu)2
Ni(PPh3)2Cl2Ni(dppb)Cl2
93 7
< 2 > 98
+
(i-Bu)2AlH (1.3 equiv) Al(i-Bu)2
+
none
0
0
25050 (+ 25% styrene)
terminal internal deprotonation
Hoveyda JACS 2010, 132, 10961
Catalytic hydration of alkynes is typically under Markovnikov control as the transition states are highly polarized and use hard nucleophiles. Recently, gold-catalysts have emerged as highly reactive catalysts for this process, however the influence of the inherent selectivity is obvious from the examples below:
NN
Au+SbF6-
Ar Ar
(50-100 ppm)
Dioxane/H2O (2:1)100 °C
R1 R2 R1R2
O
R1R2
O
+
A B
H
85% yieldonly A
81% yield4.4 A: 1 B
Me
74% yield2.1 A: 1 B
Decreasing bias, decreasing selectivityAr = 2,6-i-PrC6H3
Nolan JACS 2009, 131, 448
In order to reverse the selectivity, a new mechanism is required. Hydration of terminal alkynes catalyzed by Ru complexes leads very selectively to anti-Markovnikov products (aldehydes), especially under the influence of new ligands developed by Hintermann:
R
H CpRuCl(PPh3)2 (2-10 mol %)ISIPHOS (2-10 mol %)
acetone/H2O (4:1), 60-70 °CR
O
Haldehyde only
NPh3P
i-Pr
i-Pr i-Pr
ISIPHOSR
[Ru]
HH •
R
[Ru]
H2O
terminal carbonnow electrophilic
H[Ru]
ROH
H
tautemerization/reductive elim.
Catalyst: Hintermann JACS, 2011, 133, 8138 Mechanism: Wakatsuki ACIE 1998, 37, 2867
6.3 Regioselective Functionalization of Arenes There are three main methods for the regioselective functionalization of arenes- 1) Reagent-controlled reactions 2) Chelation-assisted directing-group controlled reactions 3) Catalyst-controlled reactions
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While by modern methods nearly any substitution pattern can be achieved on nearly any arene, these are typically achieved by applying a variety of different chemistries to the starting material at hand, exploiting the inherent reactivity of the specific arene involved. General regiocontrol in arene substitution remains an area of intense investigation. 6.3.1 Reagent-Controlled Reactions
Reactions of monosubstituted alkylbenzenes (o/p directing group) typically favour formation of the para isomer because of the steric hindrance around the ortho position. However, judicious choice of reagents can lead to reversal of regioselectivity- in this case the “naked” iodonium provided by Barluenga’s reagent is guided to the ortho position by pre-complexation with the trifluoroacetamide
HN
O
CF3
I2
H2O, AcOH, HClO4 50 to 70 °C
CH2Cl2, TFART
Barluenga'sReagent
HN
O
CF3
I
para 51% yield
single isomer
HN
O
CF3
I
ortho85% yieldo/p 25:1
IPy2BF4•2 HBF4Barluenga'sReagent
N
O
CF3
I
H
via
Ortho-selective: Barluenga ACIE 2007, 46, 1281
Para-selective: US2003/225266 A1, 2003
Especially interesting are examples where the expected regioselectivity can be overridden. Cu-catalyzed reactions of pivanilides with diaryliodonium salts are highly meta-selective, despite the nitrogen group being a strong o/p director. Note that Cu(OTf)2 is required to activate the electrophile but plays no role in the selectivity- reactions without copper at higher temperature give the same meta regioisomer
HN OI OTf
+Me
Cu(OTf)2 (10 mol %)
DCE, 70 °C
HN OMe
strong o/pdirector O
HN
EH
Mevia
Gaunt Science 2009, 323, 1593
Discussion on role of Cu(OTf)2, see footnote 14 in Gaunt ACIE 2011, 50, 463 For the mechanism, see Wu JACS, 2011, 133, 7668
6.3.2 Chelation-Assisted Directing Group-Controlled Reactions
Many reactions take advantage of the coordinating ability of the functional groups on the arene to direct functionalization of adjacent positions.
This is especially common for Pd-catalyzed reactions, where the directing group also helps stabilize high oxidation state intermediates. In the example below, the pivanilide group directs ortho-palladation of the aromatic ring. Note that consecutive alkylations/arylations are hallmarks of electrophilic substitutions where the product is more nucleophilic than the starting material. Also, contrast this example with the copper-catalyzed reation just above- this will reinforce the importance of directing groups and changes in mechanism.
HN
Me O
I PF6+
Pd(OAc)2(5 mol %)
AcOH 70 °C
HN
Me O
Ph
Ph79% yieldortho only
PdONH
OAcvia
Daugulis ACIE 2005, 44, 4046
The main drawback of using directing groups is that their presence in the molecule is often permanent, limiting the overall generality of the process. A new trend is the use of directing groups that can be converted into a range of new products:
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SiNi-Pri-Pr
Pd(OAc)2 (10 mol%)NIS (2 equiv)PhI(OAc)2 1.5 equiv
DCE, 60 °C
SiNi-Pri-Pr
I
93% yieldonly 1 ortho
isomer formed
BCl3 thenH2O2
Me Me
I
Me
OH
I
Me
BPin
80% yield
BCl3 thenpinacol
80% yield
chelatinggroup
removaltether
Gevorgyan ACIE 2010, 49, 8729
Different types of regioselectivity can work together to make for very highly selective reactions. In the example below, a chelating group puts the Pd catalyst ortho to the amide. The resulting Pd(IV) intermediate is attacked by the toluene solvent in a reagent controlled fashion- this is an electrophilic palladation that favours the para position of the nucleophile for steric reasons.
Me ONHAr
+
Me
H
H
Pd(OAc)2 (10 mol%)F+ source (1.5 equiv)DMF (2 equiv)
toluene, 100 °C
ONHAr
Me
Me
Directing groupcontrolled
Reagentcontrolled(F+ source)
NPd
OAr
AcO
F-X NPd
OAr
AcOF
X
Me
N
OAr
AcO
- HX
Me
red. elim.ONHAr
Me
Me
Me Me
MeNN
Cl
F
2BF4
p/m 8:118% yield
p/m 10:111% yield
N F BF4 N F BF4
Me
Me
Me
p/m 13:170% yield
PhO2S N SO2Ph
Fp/m 13:181% yield
Yu JACS 2011, 133, 13864
6.3.3 Catalyst-Controlled Reactions
This is an emerging area which is being hotly pursued and is a step toward ideal regioselectivity in the functionalization of arenes.
A Pd-catalyzed reaction of thiophenes with aryl iodides can be tuned to give either regioisomer simply by changing the ligand. This has been calculated to be a result of a change in mechanism- electron-rich phosphines favour CMD-based direct arylation, while electron-poor phosphites allow a Heck-type carbopalladation.
S
PdCl2 (10 mol %)Ligand (20 mol %)
AgCO3 (1 equiv)m-xylene, 130 °C
!
"
+ Ph-I S
!-product "-productS
PCy3 > 99% < 1% (99% yield)
+
P{OCH(CF3)2}3 14 86 (86% yield)
S
H
Pd OO
O!-product via CMD
"-product via Heck-type
S PdOCO2HH
HPh
Itami ACIE 2010, 49, 8946
Calculation of mechanism: Fu CEJ 2011, 17, 13866
Functionalization of indole has been of long-standing interest in the field of direct arylations. Only very recently have truly catalyst controlled reactions been found that can control the C2/C3 regiochemistry. At present the mechanism and the reason for the switch are unknown, and the selectivities are modest.
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N
O
+
Pd source (5 mol %)Ligand (5 mol %)
PhH/EtCO2H (10:1)1 atm O2, 120 °C
C2
C3
N
O
N
O
+
N N
N N
O
+ Pd(TFA)2
C2 productC3 product
14.4 (52% yield)
+ Pd(OPiv)2 4.81 (66% yield)
Stahl Chem.Commun. 2010, 47, 10257
7 Chemoselective catalysis 7.1 Chemoselective functionalization of nucleophiles 7.1.1 Selective acylation reactions: the issue of innate relative acidity, steric, or nucleophilicity
OH
OHmore acidic
more nucleophilicOH
more nucleophilic
less nucleophilic
NH2
acylate first
OH
more sterricallyhindered
less sterricallyhindered
OH
acylate first
acylate first
Me
Selective acylation strategies is about how to override this inherent preference
Melman OBC 2004, 2, 1563 7.1.2 Reagent-controlled selective acylation of phenolic OH over aliphatic OH group.
HOOH
N S
SO
tBu N S
SO
tBu
Et3N
HOO
OtBu
80%"innate pathway"
OOHO
tBu
98%
via
OOH
Yamada TL 1992, 33, 2171 7.1.3 Overriding steric preference.
O
O
O
MeHO
OH
Me
OHMe
O
O
MeMe
Me Me
O
OMeMe
OHMe
OHO
NMe2
Me
(10 mol%)Ac2O (1 equiv.)
O
O
O
MeHO
OH
Me
OHMe
O
O
MeMe
Me Me
O
OMeMe
OHMe
OHONMe2
Me
MeO C2'-monoacetate
O
O
O
MeHO
O
Me
OHMe
O
O
MeMe
Me Me
O
OMeMe
OHMe
OHONMe2
Me
MeO
C11-monoacetate
N
ON HBoc
N
N
Me HNH
O
NO
MeMe
NHO
H
NBoc
OMeO
Ph
cat
Ac2O (2 equiv.)(2) MeOH quench
N NMe
5 mol% catErythromycin A
Miller ACIE 2006, 45, 5616
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7.1.4 Another challenging issue is chemoselective monoacylation for diols. This is possible, for example, in the presence of a catalytic amount of YbCl3 due to the stability of the bidentate complex.
PhPh
OHHOYbCl3 (10 mol %)Ac2O (10 equiv)
THF PhPh
OAcHO
quantitative
YbCl3Ph Ph
OH
OH+ Ac2O
YbCl3 O
O
Ph
Ph
H
O
OO
Me
Me H
YbO O
O Ph
Ph
Me
OMe
OH
Cl3
Ph PhOH
OAc
+ AcOH
Clarke JOC 2002, 67, 5226 7.1.5 Selective O-acylation in the presence of amine - Catalytically generated acyl azoliums have been long known to prefer to acylate alcohols and water, rather than amines. This chemoselectivity may be used to acylate hydroxyl groups in the presence of amino groups. Catalytic amidation reaction may be achieved when HOAt or imidazole is used.
H
O 2 mol% NHC O
R
OH
NN
NMe
Me
3 mol% DBU100% oxidantPh
OH
H2N Ph O
NH2
R
O
NN
NMe
Me
OH
H2N
oxidation
tBu
tButBu
tBu
OOacyl azolium
Studer JACS 2010, 132, 1190 - Polymeric Zn catalyst selectively allows for acylation of the hydroxyl group and not the amine due to the enhanced oxophilicity of the Zn ions.
Zn4(OCOCF3)6O
iPr2O, reflux, 180hPh
O
OMeNH2
+ O
O PhHO
NH2
99%
Mashima JACS 2008, 130, 2944 - The anionic nature of ligand A attenuates the electrophilicity of Cu(I) and favors coordination of amine. The Cu(I) complex with B is much more electrophilic and favors binding of alcohol.
H2N
HO
IBr+
CuI (5 mol%), A (20 mol%)Cs2CO3 (2 equiv)
CuI (5 mol%), B (20 mol%)Cs2CO3 (2 equiv)
DMF, RT, 7h
toluene, 3A MS90 oC, 16h
BrHN
OH
Br O
NH2
97% yield
86% yield
O O
iPrA =
B =N N
Me
Me
Me
Me
Buchwald JACS 2007, 129, 3490 7.1.6 Selective O- vs. N-alkylation Selective Buchwald-Hartwig amination of 1,2 amino alcohol (simple amines and alcohols do not work). The selectivity arises from the relative tightness of chelation, depending on the reaction condition and additive.
RR
N(H)R1
OH
+ R2
I
CuI (2.5 mol %)K3PO4 (2 equiv)
ethylene glycol (1 equiv)iPrOH, 75oC
CuI (5 mol %)Cs2CO3 (2 equiv)
butyronitrile, 125oC
R2
NR1
RR
OH
RR
N(H)R1
OR2
66-76%47-74% yield
Buchwald OL 2002, 4, 3703
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7.2 Chemoselective oxidation and reduction Depending on the mechanism, selective oxidation reactions may reinforce or override innate steric or nucleophilic preference (similar to the cases above)
- Innate steric preference. The catalyst reinforces innate chemoselectivity to achieve complete oxidation of primary over secondary alcohol.
OHMe
OH
N N
N OO
O
Cl
ClCl
0.01 mol% TEMPO1 equiv
OMe
OH
Giacomelli OL 2001, 3, 3041 - Selective oxidation of secondary alcohol over primary may be achieved by employing Pd & benzoquinone
OHHOOH
OHHOO
N NMe MePd
AcO2
5 mol%3 equiv benzoquinone 92%
N NMe MePd
OH
HO
O
H
!-hydride elim.N N
Me MePdOH
HO
OH
!-hydride elim. N N
Me MePdO
HO
HOH
X
Waymouth ACIE 2010, 49, 9456
Ru-catalyzed chemoselective amide formation over esterification
OHR2 NH2 R1
R2NH
ORu
N P tButBu
NEt Et
COH
1 mol%R1reflux-tol
C6H13BnN
H
O96%
C5H11PhN
H
O58%
NH
O
OMe
99%
RuN P tBu
tBuNEt
EtOC H
O
R1
OR1
RuN P tBu
tBuNEt
EtOC H
H
- H2
RuN P tBu
tBuNEt
EtOC H
OR1
NHR2
+ R2NH2
OH
R1 NHR2
RuN P tBu
tBuN
Et EtCO
H R1R2N
H
O
competing pathwayR1
R1O
O
faster, better Nu+ R1OH slower
Milstein Science 2007, 317, 790 7.2.1 Chemoselective reduction reactions Hantzsch ester for selective reduction of amide in the presence ketone or ester.
Ph
O
N
NH
HH
MeMe
O
OEt
O
EtOHEH =Tf2O
HEH (2.5 equiv)Tf2O (1.1 equiv)
CH2Cl2RT, 1h
Ph N
HH
HEH
Ph
OTf
N
OTfHEH
Ph
H
N
OTf
O O86%
NaBH4Ph
O
N
OH
Charette JACS 2008, 130, 18
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Chemoselective hydrogenation of heteroaromatic systems. A proper choice of ligand (steric and/or electronic) can completely control the chemoselectivity.
N
N Ph
Ph
Me
N NAr Ar(10 mol %)
Ru(cod)(methallyl)2 (5 mol %)
KOt-Bu (15 mol %)H2 (60 bar), PhCH3
80 °C, 18 h
Ar = 2,6-(i-Pr)2C6H3
NH
HN
Ph
PhMe99% yield
N NCy Cy(10 mol %)
Ru(cod)(methallyl)2 (5 mol %)
KOt-Bu (15 mol %)H2 (65 bar), C6H14
60 °C, 18 h
Cl Cl
N
N Ph
Ph
Me99% yield
Glorius ACIE 2011, 50, 3803
8 Chemoselective α ,β-unsaturated carbonyl reactions
1,2- vs 1,4-Addition: α,β-unsaturated carbonyl compounds are ambident electrophiles- nucleophiles can attack either the C=O or C=C bonds
O
X
R
Nu1,2-
addition1,4-
addition
O
X
R NuR
XO Nu
O.59
-.39
-.48.51
O.59
.48
-.3-.58
LUMO
HOMOLUMO coefficients correspond with
increased reactivity of !-carbon
O
Frontier Orbitals: Charge Distribution:
-.41
+.23
-.34
Compare butadiene with acrolein-
-.35
+.48
Oxygen atom makes !-carbon
more positive
Significantly morepositive charge on C=O
carbon
LUMO calculations: Houk, JACS, 1973, 4094. Charges: Tidwell, JOC, 1994, 4506
8.1 Substrate-controlled chemoselective addition to α,β-unsaturated carbonyl reactions
The selectivity is determined by a combination of the nature of the leaving group and nucleophile:
O
Cl + NH3
morereactivecarbonyl
O
NH21,2-addition only
O
OMe + NH3
lessreactivecarbonyl
O
OMe 1,4-addition only
H2N Fleming, Molecular Orbitals and Organic Chemical Reactions, 2010, p 188
8.2 Catalyst-controlled chemoselective reduction or addition to α,β-unsaturated carbonyls - Ligand controlled 1,2 vs. 1,4 reductions as a result of “subtle and complex interactions between the substrate, solvent, and bulky ligands.”
O
MePh
O
Me
Me
Phcat. Cu(OAc)2.H2O
DMES
1,2-reduction 1,4-reduction!,"-unsaturated
ketone
Me cat. Cu(OAc)2.H2O
DMES
O
O
O
O
PAr2PAr2
92 %97 %ee
OH
MePh
Me
90 %99 %ee
PPh2P(tBu)2
MeH
Fe
Lipshutz Tetrahedron 2011, doi:10.1016/j.tet.2011.10.056
For selective non-metal-catalyzed 1,4-reduction, see MacMillan JACS 2005, 7, 32 & List JACS 2006, 128, 13368 - Diene ligands can provide exquisite chemo- and enantioselectivity - additions to unsaturated aldehydes proceed by 1,4-addition, not 1,2. This is in stark contrast to a Rh/phosphine catalyst, which furnishes the 1,2-additon product exclusively.
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Me
MeO Me
i-Bu
Bn
(3.3 mol %)[Rh(C2H4)2Cl]2 (1.5 mol %)
KOH (50 mol %)
Ar2B(OH)2
O
HAr1
+O
H
Ar2
Ar1
R = pOMe-Ph, 80%, 92% eeR = pF-Ph, 90%, 93% eeMeOH, H2O, 50 °C
cat. Rh(acac)(coe)2 / tBu3P
DME / H2O 3:2, rt
OH
Ar2Ar1
1,2-addition 1,4-addition!,"-unsaturated
aldehydephosphine ligand diene ligand
Carreira, JACS 2005, 10851 & Miyaura, JOC 2000, 65, 4450
- Changing counterion can change the preference for selective 1,2- vs 1,4-conjugate addition
Ph
O
CO2Me
+
NMe
OO P
O
OH
Ph
Ph(10 mol )
InX3 (10 mol %)
CH2Cl2, 4Å MS, -80 °CPh
O
CO2Me
NMe
Ph CO2MeHO
NMe
X = Br 31 1X = F 1 30
+
::
Luo ACIE 2011, 50, 6610 9 Chemoselective arene functionalization
Bond Bond Strenth (in kcal/mol)
C-C 90 C-O 92 C-N 85 C-F 115 C-Cl 84 C-Br 72 C-I 58
Blanksby and Ellison Acc. Chem. Res. 2003, 36, 255 9.1 C-X substitution - Chemoselective Suzuki-Miyaura cross-coupling. It was found that monoligated Pd (favored with PtBu) favors C-Cl insertion and bisligated Pd (the active species with PCy3) favors C-OTf insertion.
Me
(HO)2B
OTf
Cl+
Pd(OAc)2 (3 mol %)PCy3 (6 mol %)
KF (3.0 equiv)THF, RT
Pd2(dba)3 (1.5 mol %)P(t-Bu)3 (3 mol %)
KF (3.0 equiv)THF, RT
Me
Cl
Me
TfO
95% yield 87% yieldBDE = 90.6
kcal/mol
BDE = 101.5kcal/mol
Fu JACS 2000, 122, 4020
For rationale: Houk and Schoenebeck JACS 2010, 132, 2496 & Schoenebeck ACIE 2011, 50, 8192 - Changing the ligand and Pd sources can affect the chemoselectivity of cross-coupling reaction. A working hypothesis postulates that the more bulky ligand directs an oxidative addition at the less hindered para position while oxidative addition is irreversible at the ortho position for a system with less bulky ligand.
COOHBr
Br
B(OH)2 Pd2(dba)3NMP-H2OLiOH
NMP-H2OLiOH
COOHBr
p-MePh
COOHp-MePh
Br
p-MePh
99%92%
OPPh2 PPh2 0.5%Pd(OAc)2
Houpis (Johnson and Johnson) OL 2008, 10, 5601
[M]
Y
X+
Me
XX and Y maybe Cl, Br, I, OTf, etc
Me
vs.
YMe
If oxidative addition is RDS, then selectivity depends on the Lv (i.e. Cl slower than Br)
If reductive elimination or transmetallation is RDS, then selectivity may depend on other factor such as choice of metal, ligand, etc
substrate control
reagent control
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9.2 C-H functionalization Parameter: kinetics (rate) vs.
thermodynamic (bond strength or pKa)
Rates of C-H oxidation normally follow tertiary C-H> ethereal C-H ≈ benzylic C-H > secondary C-H >
primary C-H. These are general rules dependent upon electronic factors and not steric bias.
Bond BDE (kcal/mol) pKa CMethyl-H 105 48
CIsopropyl-H 99 51 Ctertbutyl-H 97 53
Callyl-H 89 43 Cphenyl-H 113 43 Cvinyl-H 111 50
HCC-H (ethyne) 133 25
Blanksby and Ellison Acc. Chem. Res. 2003, 36, 255 & Bordwell Acc. Chem. Res. 1988, 21, 456 9.2.1 Aryl C-H functionalization: depending on the mechanism, formal classification of C-H bond
functionalization may change
[Metal] HSEAr
oxidativeaddition
MH
X-
MX H
ConcertedMetalation
Deprotonation
Heck-typereaction
MX
HB
XMH
chemoselectivereactions
regioselectivereactions
Ackermann ACIE 2009, 48, 9792 - Changing the base, along with the Pd source, may allow for selectively C-H bond activation by selective deprotonation at a different site.
Br
Me
Pd2(dba)3
NaOtBuK2CO3
iPrCy2P
Pd(OAc)2
N+
N
HHO-
HBF4PtBu3
iPriPr
X-PhosN+
N
O-
MeMe
89%sp2 arylation
N+
N
MeO-
Me
Me
79%sp3 arylation
Me
N+
N
HHO-
Mesp2 C-H
LPdAr
X
sp3 C-H
K2CO3
NaOtBu
N+
N
LPdHO-
Me
Ar
N+
N
HPdLO
Me
Ar
PdLO
NN MeMe
HO
MeN+
N
O-
Me Me
N+
N
MeO-
Me
Me
concerted metallation-deprotonation (CMD)
O-
Fagnou JACS 2008, 130, 3266 & Tetrahedron 2009, 65, 3155 & Chem. Lett. 2010, 39, 1118
- Pd catalyst mediates standard cross-coupling reaction. Switching to iron leads to a directed C-H activation/ortho arylation in the presence of a leaving group.
+
10% Fe(acac)3Me
N p-OMePh
XX = Br or TfO
H
ZnCl2-TMEDA
4,4ʼ-di-tert-butyl-2,2'-bipyridine
10% PdCl2(dppf)
0oC60oC
Me
O
X Ph
Me
O
Ph H
C-H activationcross-coupling 83-92%96-97%
PhMgBr
(H+ workup)
(H+ workup)
Nakamura ACIE 2009, 48, 2925 - Ortho iodination can be achieved with an acidic directing group. In order to achieve mono-iodination, it was necessary to use a tetra-alkyl ammonium salt as an additive. Mono-iodination normally occurs on less hindered side.
O
OHX
Pd(OAc)2 (5 mol%)IOAc (2-4 equiv)
R4NICH2ClCH2Cl
O
OHXI
Pd(OAc)2 (5 mol%)IOAc (3equiv)
DMF
O
OHXI
I
65-89% yield 62-75% yield
Yu ACIE 2008, 47, 5215
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9.3 Chemoselective alkane functionalization - Rh-catalyzed C-H acitivation/annulation Du Bois and co-workers observed that product formation could be catalyst dependent slightly in favor of steric factors when comparing a secondary C-H to a benzylic C-H.
Ph
O
nPr
SH2N
OO RhII catalystPhI(OAc)2
MgO, CH2Cl2Ph
O
nPr
SHN
OO
+
Ph
O
nPr
NHSOO
Catalyst = [Rh2(OAc)4] 8 : 1 = [Rh2(O2CCPh3)4] 1 : 1.5
Du Bois ACIE 2004, 43, 4349 - Depending on the choice of ligand, an aziridine or a product obtained from an allylic C-H oxidation can be obtained. Carboxylate ligands tend to give aziridine adducts and carboximidates give the product arising from allylic C-H oxidation.
Et O
OH2N RhII catalystPhIOC6H6
N O
O
EtEt
OHN
O
+
Catalyst = [Rh2(oct)4] 71% 6% = [Rh2(S-meox)4] 1 40%
NHO
O
OMeO
S-meox =
oct = O
OH
Hayes Chem. Comm. 2006, 4501 - N-arylation is favored for Cu due to a large energy difference (14 kcal/mol) between M-C vs M-N complex. - C-arylation is favored for Pd due to the equilibrium between the M-C and M-N complexes. The outcome then follows Curtin-Hammett situation – red. eim. from M-C complex is lower in energy by 2.4 kcal/mol.
NH
O
H
pKa = 18.5
pKa = 18.5
+
Ar-X
[Pd2(dba)3] (1 mol %)XPhos (5 mol %)K2CO3 (2 equiv)
CuI(1-5 mol %)CyDMEDA (4-10 mol %)
K2CO3 (2 equiv)
NH
O
Ar
NO
Ar
55-94% yield
61-94% yield
solvent, 80-100oC, 24 h
dioxane, 40-100oC, 8-24h
iPriPr
iPr
P MNO
iPriPr
iPr
P MNH
O
iPriPr iPr
P M N
OiPriPr iPr
P M NH
O
!!E = 4.8 kcal mol-1 for Pd = 14 kcal mol-1 for Cu
!!E = 2.4 kcal mol-1 for Pd
Buchwald JACS 2008, 130, 9613 10 Chemoselective olefin metathesis reaction
Cross Metathesis (CM)R + R' R
R' RR'
+ +[M]
Ring-Closing Metathesis (RCM)
Ring-Opening Metathesis+
( )nAcyclic DieneMetathesis (ADMET)
Ring-Opening MetathesisPolymerization (ROMP)
Some general metathesis catalysts
PCy3
RuPh
PCy3Cl
Cl
Grubbs I
i-Pr i-PrN
Mo PhOO
F3C
CF3
CF3F3CSchrock
N N
RuPh
N N
Ru
PCy3Cl
Cl
Oi-PrCl
Cl
Grubbs II
Hoveryda-Grubbs
Classes of metathesis reaction
For a general review of olefin metathesis reaction: Hoveyda Nature 2007, 450, 243
Update to 2011 Bode Research Group http://www.bode.ethz.ch/
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- Olefin metathesis reaction has emerged as one of the most powerful synthetic tools. Many class of reactions (CM, RCM, ROMP) have been investigated; several reports have demonstrated that catalyst structure or type can influence the distribution of metathesis products, i.e. the chemoselectivity.
For a review in chemoselective metathesis reaction: Nolan Chem. Soc. Rev. 2010, 39, 3305
10.1 Innate reactivity of olefins in metathesis reactions - Grubbs and co-workers developed an empirical system for categorizing olefins in metathesis. For example, terminal olefins and allylic alcohols fall under the type I. Type IV olefins are spectators (no catalyst deactivation) and are slow cross-metathesis.
OAc
+ Grubbs I (5 mol%)
78%E/Z 4.5:1
Type I olefin
Type I olefin
Type IV olefinPCy3
RuPhCl
PCy3
ClO
OAcMe
O
MeOAc
Grubbs JACS 2003, 125, 11360 10.2 Catalyst controlled chemoselective metathesis reaction - Large phosphine ligand in Grubb I catalyst is too sterically hindered for RCM.
PCy3
RuPhCl
PCy3
ClO
O Me
10 mol%
O
O Me
RuPhCl
PCy3
Cl
10 mol%
O
O
Me
65%RCM favored
2
79%dimerization
favored
NN MesMes
Furstner CEJ 2001, 7, 3236 - NHC ligand prefers the thermodynamic product vs. the phosphine ligand prefers the kinetic (RCM) product
PCy3
RuPhCl
PCy3
Cl
10 mol%
RuPhCl
PCy3
Cl
10 mol%
85% (12:1)Ring-rearrangmentmetathesis favored
75% (5:1)RCM favored
N
O
NN MesMes
N ON
O
Ma CEJ 2004, 10, 3286 11 Product-selective catalysis
This is a recent area of research that deals with catalyst-controlled reactions with the preferential formation of two (or more) unrelated products that are not stereo- or regioisomers. Many of these reactions were discovered serendipitously, and rational design of this kind of selectivity is not easy. However, advances in understanding this type of selectivity and development of this mode of catalysis is especially relevant in modern synthesis, in which increased efficiency and selective functionalization of complex targets is highly desirable. We highlight here some notable examples, whose explanation illustrate the case.
- By adjusting the strength of the base (pKa), selective generation of a reactive species may be achieved.
H
O
Ph
+
EtO2C
10 mol% cat15 mol% NMM
O
O
EtO2C Me MeOH
Me
OH
Me10 mol% cat
25 mol% DBUO
OEtO2C
Me MeOH
Ph
Ph
via
NNN
O
Mes
N
N N Mes
O-
Ph
enolate(DA reaction)
viaN
N N Mes
OH
Ph
homoenolateaddition/cyclization
O
Bode PNAS 2010, 107, 20661
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- Selectivity arises from different affinity of each metal to the alkyne and allene. Pt(II) and Pt(IV) activate the alkyne and Au(I) activates the allene towards nucleophilic attack by the hydroxyl
HOR
MeMe
MeMe
PtCl2 or PtCl4 (5 mol%)toluene, reflux 36 h
[AuCl(PPh3)] (2 mol %)AgSbF6 (2 mol %)
CH2Cl2, reflux, 1h
HOR
MeMe
MeMe
M
MeMe
MeMe
RH
O
MeMe
MeMe
RH
MHO H
H+
HOR
MeMe
MeMe
M
O
R
HMe
Me Me
MeM O
R
Me
Me Me
Me
M
M
R = CH2iPr
85% yield
72% yield-H+
Fensterbank and Malacria CEJ 2008, 14, 1482 - Selectivity arises from tuning of the electronic nature of the ligands for Au catalysis
[(t-Bu)2P(o-biphenyl)P-AuCl] (5 mol %)
AgSbF6 (5 mol %)electron-rich
83% yield(8:1)
TESO Me
[(C6F5)3]PAuCl] (5 mol %)AgSbF6 (5 mol %)electron-poor
H
OTES
Me[Au]
pinacol
[3,3]
H
OTES
Me
H
TESO
Me
[Au]
[Au]
Me
O
81% yield(19:1)
Me
H
O
Duschek and Kirsch OL 2008, 10, 2605 For a brief review on electronic tuning of ligand in Au catalysis, see Kirsch ChemCatChem 2011, 3, 649
- Direct olefination of 1,4-dien-3-ones remains a synthetic challenge. Competing catalytic Meyer−Schuster rearrangement versus Nazarov-type electrocyclization may be selectively promoted by V vs Au catalysts.
5% VO(acac)284%
Meyer-Schusterrearrganement
dehydrativecyclization
93%
Me
Ph
Me
Ph
HOOEt PhMe, 80oC
5% AuCl3THF rt
Ph
Me
Ph
OEt
Me
Ph
Me
Ph
CO2Et
Me
Ph
Me
Ph
OEt
4!-electro-cyclization
hydrationtautomerization
West JOC 2011, 76, 50 - Changing the metal catalyst from Pd to Rh allows for acceleration of decarbonylation over reductive elimination, although only with moderate selectivity. As an improvement to the previous system, changing the metal catalyst from Pd to Cu allows for acceleration of decarboxylation over reductive elimination, with better selectivity.
120oC
O
arylation
esterification
32-98%
46-95%
R
R
R20% Pd(TFA)2O
OH
RRB(OH)2
R
fast red. elim
slow red. elimCu
O
Ar1Ar2-CO2
Ag2CO3
120oC
20% Cu(OTf)2Ag2CO3
O
O
PdO
Ar1Ar2 O
Liu Chem. Comm. 2011, 47, 677