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![Page 1: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/1.jpg)
Ti (II) Mediated Reactions in Organic Chemistry
Chris Tarr
University of North Carolina
February 23, 2007
![Page 2: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/2.jpg)
Outline of Topics Covered
• Background
• Cyclopropanation Reactions
• Olefin/Acetylene Functionalizations
• Reductive Couplings
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Advantages of Titanium
• Titanium (IV) reagents are cheap and readily available
• Low toxicity compared to other transition metal catalysts
• Less reactive than Li or Mg organometallics
• More reactive than corresponding B or Zn organometallics
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Notable Applications Not Covered
• Sharpless Asymmetric Epoxidation (TiIV)
• Lewis Acid Catalysis (TiIV)
• McMurry Coupling (TiIII Ti°)
• Tebbe Reagent (TiIV)
Crimmins M. T.; King, B. W., Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883.
McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708.
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I. Ed; VCH: New York, 1993; p. 103-158.
Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611.
OO
Ti TiORO
E
E
E
EOR
OO
Ti TiORO
E
E
E
E
O
ROR
O O
tBu
O
O
TiCl3
LAH
CH2OH
ORR
CH2OH
(+) DET
4A mol sieves
Ti(OiPr)4
tBuOOH
N O
1 eq. TiCl4amine base
2 eq TiCl4amine base
S
BnRCHO RCHO
O
N O
S
Bn
O
N O
S
Bn
O
R R
OH
Me
OH
Me
Cp2TiCl2 + 2AlMe3 Cp2TiCl
AlMe2
R R'
O R R'
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Generation of Ti(II) from Ti(IV)
• Bercaw accessed and characterized the first Ti(II)-ethylene adduct:
X-ray crystal structure verifies existence as monomer
• Ti(II) was able to dimerize ethylene; however, was not effective as a promoter for further polymerization
Cohen, S. A.; Auburn, P. R.; Bercaw, J. E. J. Am. Chem. Soc. 1983, 105, 1136.
• Two limiting resonance structures: Ti(II) species may react as either a 1,2-dianion or a pi-bound alkene
TiCl
Cl
1. Na/Hg
2. ethylene atmTi
TiCp2 TiCp2
R R2 CO 2 HClCp2Ti(CO)2
Cp2TiCl2
+ +
R R
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TiX2
R
R
TiX
RH
L
R
-RCH2CH3 TiX2
TiX2
R
R
XTiX2
X
2M'(CH2CH2R)
-2M'X
-X
Generation of Ti(II) via Reductive Alkylation
• Ti(IV) converted to Ti(II) via reductive alkylation: an organolithium or organomagnesium compound can be used to generate a dialkyl titanium complex which can lead to a Ti(II) species
X = halide, ORβ-hydride elimination
reductive elimination
Kulinkovich, O. G.; Meijere, A. Chem. Rev. 2000, 100, 2789.
2 M(CH2CH2R)
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Outline of Topics Covered
• Background
• Cyclopropane-forming Reactions
• Olefin/Acetylene Functionalizations
• Reductive Couplings
![Page 8: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/8.jpg)
Kulinkovich Reaction
• Kulinkovich reaction: a facile method for cyclopropanol synthesis from esters
Ti(IV) can also be used catalytically (2 equiv. of Grignard reagent required)
Kulinkovich et al., Zh. Org. Khim. 1989, 25, 2244.Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
R OR'
O
1. EtMgBr (3 equiv)
Ti(OiPr)4
Et2O, -78oC
2. H3O+
OH
R
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Representative Examples
• Kulinkovich cyclopropanation
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
MeOH OH
OHOH OH OH
74%
Et
82%
C5H11
94% 85%
Ph
93% 90%
OH
OHHO
OHOH
Cl
TMS MeO
PhBnN
76%
67% 55% 60%
OH
OH
HO
90%
Ph
PhOH
Me
OH
Me
MeOH
Ph
60% 85%62% 61%
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Mechanism of Kulinkovich Reaction
Kulinkovich et al. Zh. Org. Khim. 1989, 25, 2245.
H3O+R
HO
EtMgBr
OTi(OiPr)2R
OR'
BrMg+
-
R'OMgBr
Ti(OiPr)2
O
R
R
O(PrOi)2TiEtMgBr
(iPrO)2Ti(C2H5)2
R
BrMgO
Kulinkovich, O. Pure Appl. Chem. 2000, 72, 1715.
Ti(OiPr)2
2EtMgBrTi(OiPr)2
HC2H6
Ti(OiPr)2
OTi(OiPr)2MeO
R
R OMe
O
O R
Ti(O iPr)2MeOH3O
+R
OH
Ti(OiPr)4
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Mechanism of Kulinkovich Reaction
Kulinkovich et al. Zh. Org. Khim. 1989, 25, 2245.
Kulinkovich, O. Pure Appl. Chem. 2000, 72, 1715.
Ti(OiPr)2
2 EtMgBrTi(OiPr)2
HC2H6
Ti(OiPr)2
OTi(OiPr)2MeO
R
R OMe
O
Ti(OiPr)4
H3O+R
HO
EtMgBr
OTi(OiPr)2R
OR'
BrMg+
-
R'OMgBr
Ti(OiPr)2
O
R
R
O(iPrO)2Ti
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de Meijere Mechanism
• Key mechanistic difference
Chaplinski, V.; de Meijere, A. Angew. Chem. Int. Ed. 1996, 35, 413.
• de Meijere modification: access to cyclopropylamines
R NR'2
O
1. EtMgBr (2 equiv.) Ti(OiPr)4
Et2O
2. H3O+
NR'2
R
R NR'2
O
EtMgBr (2 equiv.)Ti(OiPr)4
Ti(OiPr)2
OR
R'2NTi(OiPr)2
R'2N
-O
+
NR'2
R
R
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Substrate Scope
• de Meijere modification
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
NBn2
NBn2
NBn2
iPr2N
NMe2
NBn2
NBn2
95% 77% 86%
Ph
47% 42% 50%
Ph2P O
80%
NMe2 NBn2
NMe2
TrO
NMe2
BnO
O NH2
74%54% 72% 89% 53%
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Computational Study on Selectivity of Kulinkovich Reaction
• Computed with B3LYP/HW3 method• Cyclopropane forming step, determines stereochemistry and is the
rate determining step• T.S. cis is 2.5 kcal/mol more favored because of agostic interaction
between ester R group and Ti
Wu, Y. D.; Yu, Z. H. J. Am. Chem. Soc. 2001, 123, 5777.
Ti-H 2.44 Å Ti-H 2.96 Å
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Ligand Exchange in Kulinkovich Reaction
• Allows for a wider range of substitution in cyclopropanols
• Substrates with which alkene exchange has been successful
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
Ti(OiPr)2
R
Ti(OiPr)2R
R' OR"
O
RR'
OH
Ph TMS
Bu3SnP(OEt)2HO RO
O
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Intramolecular Nucleophilic Acyl Substitution
• Typically difficult to balance the necessary reactivity and functional group tolerance
• Exchange of the initial alkene with a second alkene tethered to an ester leads to new products with trans alkyl/(aryl) groups
Generation of1,4 diols
Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 34, 6079.
O Ph
OTi(OiPr)2
O Ph
O(OiPr)2Ti
O
O-
Ph
Ph
OHOH
Ph
(iPrO)2Ti
Ph
O
O-
Ti(OiPr)2
O
Ti(OiPr)2O
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Additional INAS reactions
• Generation of fused bicyclic cyclopropanols
• Use of an alkyne versus an alkene leads to methylene-lactone or α,β-unsaturated carbonyl
Okamoto, S.; Kasatkin, A.; Zubaidha, P.; Sato, F. J. Am. Chem. Soc. 1996, 118, 2208.
O
OMe
Ti(OiPr)2
O
OMe
Ti(O iPr)2
O
Ti(OR)3
OH
Ti(OiPr)2
R
O OEt
O
n
(iPrO)2Ti
R
O
OOEt
nO
OR
(iPrO)2Ti
R
CO2Et
O-
(iPrO)2Ti
n
n
+
OEt
nO
OR
R
CO2Et
OHn
+
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Enantioselective Catalytic Kulinkovich Reaction
• Corey demonstrated limited success in achieving an asymmetric reaction based on catalyst control
• Very limited catalyst screen and substrate scope• Only moderate yields and enantiomeric induction are achieved
TADDOL-based pre-catalystAr = 3,5-bis(trifluoromethyl)phenyl
With ethyl acetatesubstrate:65% yield70-80% ee
Corey, E. J.; Rao, S. A.; Noe, M. S. J. Am. Chem. Soc. 1994, 116, 9345.
OTi
OO
OO
O
O
OArAr
Ar ArAr
Ar
Ar Ar
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Substrate controlled INAS Reaction
• Stereoselectivity can be transferred from starting material to the final products
Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1799.
Quan, L. G.; Kim, S. H.; Lee, J. C.; Cha, J. K. Angew. Chem. Int. Ed. 2002, 41, 2160.
3 : 1
Mizojiri, R.; Urabe, H.; Sato, F. Angew. Chem. Int. Ed. 1998, 71, 1673.
Ar
NMe2
O
NBn
MgBr
ArCO2H
NH2
3 steps
N N
Me2N
Bn
Ar Ar
Bn
Me2N
+
Ti(O iPr)4
SO2
N
O
C5H11
Ti(O iPr)2 C5H11OH
R
OH
R
OTi(OiPr)3
RMgCl Ti OO iPr
RR' OR"
O
OH
R
R'
HO
Ti(OiPr)4
![Page 20: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/20.jpg)
Cyclopropylamines from Nitriles
• Initial adduct can lead to tertiary amines and ketones
• Addition of a BF3 Lewis acid results in the formation of cyclopropylamines
Bertus, P.; Szymoniak, J. Chem. Comm. 2001, 1792.Laroche, C.; Behr, J. B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org. Chem. 2005, 5084.
Ph CN Ti(OiPr)2+Ti(OiPr)2
NPh
BF3OEt2 H2O
EtMgBr EtEt
Ph
NH2
EtPh
O
Ti(O iPr)2N
PhBF3
H2NPh
![Page 21: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/21.jpg)
Cyclopropylamines from Nitriles
• Nitriles can easily be installed in carbohydrate backbones; this strategy allows the synthesis of cyclopropylamine substituted sugars
Laroche, C.; Behr, J. B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org. Chem. 2005, 5084.
OO
OO
BnO
CN O
O
O OCN
OBn
OPiv
OBn
NC
BnO
CN
BzOOBz
OBz
OO
OO
OBn
O
O
O O
OBn
OPiv
BnOBnO BzO OBz
BzONH2
NH2 H2N
57% 62% 54% 55%
NH2
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First Access to Spirocyclopropyl Iminosugar
• Iminosugars are potent glycosidase inhibitors and have been identified as possible anti-diabetes, anti-retroviral, and anti-tumor targets
• High cytotoxicities preclude their use• Cyclopropane ring is a key pharmacophore that induces
binding in other bioactive molecules
6 steps13% overall yield
Laroche, C.; Plantier-Royon, R.; Szymoniak, J.; Bertus, P.; Behr, J.-B. Synlett 2006, 2, 223.
O
OBn
OH
BnO
BnO NH2OH HCl
NaHCO3
OBn
OH
NOHOBn
BnO
OBn
OPiv
N
OBn
BnO
PivCl
OBn
OPiv
NH2
OBn
BnO
Ti(OiPr)2HN
HO OH
HO
![Page 23: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/23.jpg)
Vinylogous Kulinkovich Reaction
• Cha has recently developed a procedure for a vinylogous Kulinkovich reaction
• When toluene and a Lewis acid are employed, a vinyl cyclopropane is formed
• Reaction produces a spirocyclic cyclopropane ring with no directly bound heteroatom
Masalov, N.; Wei, F.; Cha, J. K. Org. Lett. 2004, 6, 2365.
O
O
R MgX
O
O Ti
Rtoluene
LA
THF
O
OH
R
O OR'R'
LA
O
R
TiOR'O
+
O
R
Ti(OiPr)4
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Ring Expansions to Cyclobutanones
• Acid mediated ring expansion/cyclization of Kulinkovich reaction products
• Pinacol-type rearrangement to access chiral α-substituted cyclobutanones
Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337.
Youn, J. H.; Lee, J.; Cha, J. K. Org. Lett. 2001, 3, 2935.
>90% chirality transfer
HO
CHO
H+
OH
O
R CO2Et
OH
EtMgBrR
OH
OH
MsCl
pyridine O
RClTi(O iPr)3
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Outline of Topics Covered
• Background
• Cyclopropane-forming Reactions
• Olefin/Acetylene Functionalizations
• Reductive Couplings
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Olefin-imide Coupling• Ti (II) can react with imides,
however only poor regioselectivity is obtained
Kim, S.; Park, Y.; Choo, H.; Cha, J. K. Tetrahedron Lett. 2002, 43, 6657.
• Intramolecular trapping provides poor diastereoselectivity; however, reduction with H2/PtO2 leads to the same product arising from both diastereomers
NH
O
OEtMgBr
NH
O
O Ti(O iPr)2
NH
O
O
(iPrO)2Ti
+ H2O NH
O
OH
NH
O
HO
2 : 1
+ClTi(OiPr)3
NH
O
OEtMgBr
NH
O
O Ti(O iPr)2
NH
O
O
Ti(OiPr)2
+ H2O NH
O
OH
NH
O
HO
2 : 1
BnOBnO
BnO
BnO BnO
+ClTi(OiPr)3
N
O
O
EtMgBrNN
O O
OHOH
+
1 : 1
H2PtO2
N
O
H
90% yield
ClTi(OiPr)3
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• Cha also developed a diastereoselective cyclization between imides and substituted tethered olefins
• When R = H, poor diastereoselectivities are achieved; however, larger R groups such as Me or Ph higher diastereoselectivities were obtained
Olefin-imide Coupling
Santra, S.; Masalov, N.; Epstein, O. L.; Cha, J. K. Org. Lett. 2005, 7, 5901.
N
O
O
R
N
O
R
OH
m
n nm
m,n = 1,2R = Me, Ph
Ti(OiPr)4nBuLi
![Page 28: Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23, 2007.](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649e115503460f94afcf40/html5/thumbnails/28.jpg)
Olefin-imide Coupling
Santra, S.; Masalov, N.; Epstein, O. L.; Cha, J. K. Org. Lett. 2005, 7, 5901.
N
O
O
R
N
O
R
OH
m
n nm
m,n = 1,2R = Me, Ph
Ti(OiPr)4nBuLi
N
O
H
OH
N
OH
Ph
O
67% yield12:1 d.r.
N
OH
H
O
77% yield2 : 1 d.r.
N
O
Me
OH
N
O
Ph
OH
87% yield3:1 d.r.
70% yield5:1 d.r.
65% yield9:1 d.r.
N
OH
O
60% yield21:1 d.r.
Ph
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Addition of Imine-Based Titanocyclopropanes
• Addition to an imine followed by trapping with acetylene leads to allyl and alkynyl amines, as well as pyrroles
• Asymmetric induction from chiral R group
• Stereochemical model for observed products
Ohkubo, M.; Hayashi, D.; Oikawa, D.; Fukuhara, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2006, 47, 6209.Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
Ar
NR
Ti(OiPr)2N
Ti(O iPr)2
Ar
R
R'
X
Ti(O iPr)2
N
Ti(O iPr)2
N
R
R
X
R'
Ar
Ar+
H+
H+
Ar R'
NHR
Ar
NHR
X
X
N R
R'
Ar
X
-HX
HN
Ar
Ti ONAr
H H
Ph
MeiPrO
OiPr
H
N Ti(OiPr)2
OMeN Ti(OiPr)2
HAr
Ph
R
X
Ph
Ar
H
RX
Ti(O iPr)2
Ar
N Ph
OMe
R
X
HN
R
Ph
OMe
HAr
HN
C
Ph
OMe
HAr
R'R
R'
R
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Diastereoselectivity of Allyl Amine Formation
R d.r. Yield (%)
TMS 97:3 81
Hexyl 98:2 82
Ph 98:2 84
CO2Et 96:4 63
SO2Tol 94:6 28
Ohkubo, M.; Hayashi, D.; Oikawa, D.; Fukuhara, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2006, 47, 6209.Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
Ar
NTi(O iPr)2
Ar R
HN
RH+
Ph
OMe
Ph
OMe
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Diastereoselectivity of Allenyl Amine Formation
Ar R/R’/X d.r. Yield
Ph H/H/Br 98:2 74
o-iodophenyl H/H/Br 98:2 61
1-naphthyl H/H/Br 98:2 59
p-OTBS-phenyl H/H/Br 98:2 62
Ph Hexyl/H/OP(O)(OEt)2 98:2 49
Ph Ph/H/OP(O)(OEt)2 98:2 62
Ar
NTi(O iPr)2
Ar
HN
H+
Ph
OMe
Ph
OMe
R'X
R R'
RC
Ohkubo, M.; Hayashi, D.; Oikawa, D.; Fukuhara, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2006, 47, 6209.Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
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Diene Functionalization
• Titanium can add into a diene to form a cyclopentenyltitanium species which can add to an aldehyde with good regio- and diastereoselectivity
• The resulting species can be opened via protonolysis
• Good asymmetric induction was achieved by tethering a chiral 8-phenylmenthol ester to the diene backbone
Urabe, H.; Mitsui, K.; Ohta, S.; Sato, F. J. Am. Chem. Soc. 2003, 125, 6074.
SiR3
tBuO2C
C6H13
Ti(O iPr)2
tBuO2C
C6H13
SiR3
R'CHO
O Ti(O iPr)2
SiR3
tBuO2C
H
R' C6H13H+(iPrO)2Ti R SiR3
H OH
tBuO2CC6H13
1. Ti(OiPr)4iPrMgBr (2 equiv.)O
O SiR3
C6H13
O
SiR3R'
O C6H13
HH OH
69% yield88% ee
2. R'CHO
3. H+
DIBALR'
OH
HO C6H13
Ph Ph
KOtBu
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Addition to Acetylenes
• Reaction of alkynes with Ti(II) allows for trapping with two subsequent electrophiles
• Reaction with dichlorophosphites leads to cyclic phosphites
• Reaction with sec-BuOH followed by a second electrophile leads to one C-C or C-X and one C-H bond
Urabe, H.; Hamada, T.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931.
Ti(OiPr)4
R
R
RPCl2 PR
R
R
R
R'iPrMgBr
Ti(O iPr)2
R
R
1. E1+
2. E2+
R
R'
E1
E2
Ti(OiPr)4
TMS
R
H
I
Ti(OiPr)2
TMS
R
sBuOHTMS
R TiX3
H
I2
PhCHO
O
O
O
Br
TMS
R
H O
O
TMS
R
H
OTMS
R
H
OH
Li2Cu(CN)Cl2 (cat)
Li2Cu(CN)Cl2 (cat)
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Regioselectivity of Titanacyclopropene Opening
• When unsymmetrical acetylenes are used to form the titanacyclopropene, electrophilic ring opening can occur with a high degree of regioselectivity
Urabe, H.; Hamada, F.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931.
Ti(O iPr)2
Ti(OiPr)2
Ti(O iPr)2 Ti(OiPr)2
Ti(OiPr)2 Ti(O iPr)2
TMS
tBuO2C
TMS
tBuO2C
C6H13
Ph
Me
Bu3Sn
TMS
C6H13
EtO OEt
OTHP
7
93 14
86 2
98
98
2
90
10
0
100
El = PhCHO El = c-C6H11CHO El = PhCHO
El = PhCHOEl = EtCHOEl = PhCHO
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Cross Coupling Reactions
• Recently, the Ti(II)-cyclopropene complex has been found to undergo a newly developed cross coupling reaction
• Treatment with aryl iodide and a Ni(COD)2 complex leads to a mixture of mono- and di-arylated products with mono-coupled products predominating
Obora, Y.; Moriya, H.; Tokunaga, M.; Tsuji, Y. Chem. Comm. 2003, 2820.
Yields 40 – 80%Selectivities range from 10:1 to 1:1
R
Rn-BuLi
Ti(OiPr)4
R
R
ArI
Ni(COD)2
50oC
R R
H Ar
R R
Ar Ar+
thermally stable
Ti(OiPr)4
Ni0Ar-I
Ni-Ar
M-R
M-I
Ar-Ni-R
R-Ar
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Enyne Cyclization
• A tethered alkyne and alkene can be used in an annulation reaction
• Depending on the substitution of enyne, 1,2-difuntionalized rings and variously functionalized bicyclic rings can be achieved
Okamoto, S.; Ito, H.; Tanaka, S.; Sato, F. Tetrahedron Lett. 2006, 47, 7537.
A
X
R
Ti(OiPr)2
R
AX
A = H
A = FG
R
TiX3
R
TiX3
A
E+
R
E
A = CO2R
A = CH2X
R
O
R
n n
n
n
n
n
n
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Diversity of Enyne Cyclization Manifold
• 1,2 substituted acrylynes can also undergo titanium mediated cyclization to form exocyclic cyclopentenes, [3.3.0]-bicyclooctanes, and [3.1.0]-bicyclohexanes
Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.
X
R
CO2R'R' = bulky
X
CO2R'
ElH
X
R
CO2R' R' = smallX O
H El
X
CO2R
R
R' = small
X
R
CO2R'El El
R
TMS
H
OH
CO2tBu
62% yield
TMS
H
CO2tBu
TMS
H
OH
CO2tBu
TMS
H
CO2tBu
83% yield 61% yield 52% yield
OCO2Et
CO2EtCO2Et
BnNCO2Et
C5H11
C5H11
53% yield 76% yield 74% yield 51% yield
O
TMS
O
TMS
O
TMS
O
C5 H11
80% yield
C4H9H
89% yield97:3 d.r.
TBSO H
69 % yield9:1 d.r.
73 % yield
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Asymmetric Metallo-ene Reaction
• Metallo-ene reaction, difficult to achieve enantioselectivity
• Ti-mediated cyclization: does allow for asymmetirc induction
• Camphor esters gave poor ee’s; however, chiral acetals gave high ee’s• Acetals offer a convenient synthetic handle for further product
manipulation
Takayama, Y.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1999, 121, 3559.
R
MM
X
M
RO
R
TiTi
RO
Ti
RO
R
TiLn
C5H11
O
O
Ph
Ph
Ti(OiPr)2
C5H11
O
OHPh
H
96 % ee20:1 E/Z87% yield
PPTS
Ph
C5H11
O
O
Ph
Ph H
Ac2OTsOH
C5H11
HMeOOMe
1. (CO2H)2
2. Jones ox.3. (COCl)2
4. SnCl4
O
C5H11
H
Normal Metallo-ene Reaction Titanium (II) Equivalent
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Siloxy-enyne Cyclization
• Phillips and co-workers developed a siloxy-enyne cyclization• Cleavage of the C-Si bond allows for the installation of an anti-methyl
group alpha to a hydroxy group• This strategy has been applied to natural product synthesis
O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253.O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.
R
OSi
R2
R3R4
ClTi(OiPr)3
iPrMgCl
O Si
R
R2
R3 R4O SiR3 R4
R Ti(OiPr)2
R2 H+
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HO
OH OH
OO
OH
Dictyostatin Synthesis
• Dictyostatin, an anti-cancer marine macrocycle synthesized by Phillips
• Two 3° stereocenters set by siloxy-enyne reaction
HO
OPMB
O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.
R
OSi
R2
R3R4
ClTi(OiPr)3
iPrMgCl
O Si
R
R2
R3 R4O SiR3 R4
R Ti(OiPr)2
R2 H+
OPMB
O(MeO)2P
O
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2+2+2 Cyclization• Trapping of cyclopentadienyl-titanium species with another
unsaturated molecule results in a 2+2+2 cyclization
• Rothwell developed a 2+2+2 reaction; however, the product is formed with only poor regioselectivity due to metal-assisted 1,5-hydride shifts under reaction conditions
Johnson, E. S.; Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1997, 119, 7685.
TiArO
ArO Cl
Cl2 Na/Hg
Ti(OAr)2
PhEtEt+
(ArO)2TiCl2 Et
Et
Ph
Et
Et
Et Et
Et
Ph
Et
Et
Ph
Et
Et
Et
10% 55% 35%Ti Ti
HHTi
H
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2+2+2 Cyclization
Yields ~50-80%
• Cha developed a 2+2+2 coupling reaction with tethered acetylenes β-hydroxy olefins• The reaction proceeds in good to moderate yields• No double bond migration occurs, so initially formed cyclohexadienes can be isolated
Sung, M. J.; Pang, J. H.; Park, S. B.; Cha, J. K. Org. Lett. 2003, 5, 2137.
+OH
R c-C5H9MgCl
TiO R
OiPrOH
R
TMS
TMS
TMS
TMS
ClTi(OiPr)3
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Synthesis of Titanated Benzene Rings
Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925.
CO2tBu
C6H13 C6H13
Ti(OiPr)2
Ti(OiPr)2
CO2tBuC6H13
C6H13
SO2Tol C6H13
CO2tBu
TiX3
C6H13
C6H13
CO2tBu
I
C6H13
C6H13
C6H13
C6H13
CO2tBu
C6H13
I256%
PhCHO
49%
O
Ph
O
H+
57%
Ti(OiPr)2
CO2tBuC6H13
C6H13
SO2Tol
4+2
insertion
X2Ti
TiX2
CO2tBu
C6H13
SO2TolC6H13
CO2tBuC6H13
C6H13SO2Tol
C6H13
CO2tBu
TiX3
C6H13
TiX2SO2Tol
C6H13
C6H13
tBuO2C
Two Mechanisms for Alkyne Addition
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Synthesis of Aromatic Rings
• Sato developed a regioselective coupling between an acetylene and a nitrile, followed by trapping with another unsaturated molecule
• A single intermediate allows access to pyridine, furan, and pyrrole containing molecules
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.
N
R
R'
R"
EtMgBr (2 equiv.) NTi(OiPr)2
R"
R'R
+
SO2Tol
N
OMe
R'''CHO
H(D)+ N
O
NH
R''
R'
R
TiX3
R''
R' R
R'''
R''
R' R
CHO
R'H(D)
R
OR''
Ti(OiPr)4
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Mechanism for Pyridine Formation
• Tosyl acetylenes lead to titanated pyridines, which allow for the regiocontrolled synthesis of tetrasubstituted pyridines
• Reaction conditions also allow for the preparation of chiral pyridine rings starting from the easily accessible optically active propargyl alcohols
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.
NTi(OiPr)2
C4H9
C4H9SO2Tol
NR''
R'
R
TiX3
OMe
N
Ti
C4H9
C4H9
OMe
SO2TolN
C4H9
C4H9
OMe
SO2TolTiX3
N
C4H9
C4H9
H(D) N
C6H13
TMS
H(D)
N
C6H13
TMS
H N
Ph
TMS
H N
C6H13
TMS
H
N
C6H13
TMS
I
OMe
Cl OMe OMe
OMe OMe
C8H17
76% 58%50%
53% 56% 57%
N
C4H9
C4H9
H(D)Me
OTBS
N
C4H9
C4H9
IMe
OTBS
N
Ph
TMS
H(D)Me
OTBS
N
Ph
TMS
IMe
OTBS
73% (99%) 69%(99%)
69%(99%) 58%(99%)
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Furan Formation
• Interception of the cyclopentadienyl intermediate with an aldehyde leads to an insertion, followed by protonolysis, ring closing, and aromatization
• The reaction produces moderate yields of tetrasubstituted furan rings
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.
NTi(OiPr)2
C4H9C4H9
OMe
PhCHO
N TiO
OMe
C4H9
C4H9 Ph
H+
MeONH2
Ph
OH
C4H9
C4H9
H+
OH3NMeO
C4H9 C4H9
Ph
H
O Ph
C4H9C4H9
MeO
O Ph
C4H9C4H9
MeO
O C8H17
C4H9C4H9
MeO
O Ph
C4H9C4H9
MeO
O Ph
TMSC6H13
MeO
O Ph
PhPh
MeO
O C8H17
TMSC6H13
MeO
68% 60% 57%
55% 54% 66%
C8H17
C8H17
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Pyrrole Formation
• Nitrile insertion leads to a di-imine product after hydrolysis, which under acidic conditions cyclizes to the formyl pyrrole
• Trapping by two different nitriles leads to regioselective formation of the aldehyde at the least substituted side chain
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.
NH
R R'
OMeOHC
NH
R'R
MeOCHO +
1 : 1
NH
C4H9
CHO NH3NMeO
C4H9 C4H9
NTi(O iPr)2
C4H9C4H9
OMe
NOMe
NTi(OiPr)2
N
C4H9C4H9
OMeMeO
MeO OMe
H
NH NH
C4H9 C4H9
OMe
OH2
H+
H+
C4H9
MeO
NMeO
Ti(OiPr)2
R
R'
3 equivalents
MeO OMeNH NH
Ha Hb
R R'
NMeO
Ti(OiPr)2
R
R'
1 equivalent
MeO OMeNH NH
Ha Hb
R R'
NH
R R'
OMeOHC
NMeO
1 equivalent
C4H9
C4H9
x
C4H9
exclusively formed
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Outline of Topics Covered
• Background
• Cyclopropane-forming Reactions
• Olefin/Acetylene Functionalizations
• Reductive Couplings
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Pinacol Coupling
• Pinacol reaction: coupling of two carbonyl radicals
• Titanium mediated pinacol couplings lead to high selectivities for the dl isomer over the meso compound via a di-oxo-titanium intermediate
Mukaiyama, T.; Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron 2001, 57, 2499.
R
O2
O- O-
RR
OH
OH
R H
O+ TiX2 + Cu2 O
TiO
H R
R HHO
OHHH
R
Rdl selective
TiI4 TiI2 + 2CuICu
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Pinacol Coupling (cont.)
94% (99:1) 76% (99:1)76% (98:2)98% (85:15)93% (99:1)
80% (81:19) 72% (80:20)92% (85:15)98% (84:16)85% (75:25)
Mukaiyama, T.; Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron 2001, 57, 2499.
H
O
H
O
Cl
H
O
H
O
O
O
H
H OH
O
H
O
H
O
O
H
R
O2 TiI4, 2 Cu
RR
OH
OH
RR
OH
OHdl meso
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Reformatsky Reaction
O
R
X
Me
H
Ti O
R
H
X
Me
Ti
Kagayama, A. et al. Bull. Chem. Soc. Jpn. 2000, 73, 2579.
• Reformatsky Reaction: An aldol surrogate, enolate is formed via insertion into a C-X bond
• Mukaiyama et al. developed a Ti-based Reformatsky-type reaction that displays high diastereoselectivity
E-enolatedisfavored
Z-enolatefavored
R
O
X
Zn
R
O
ZnX R
OZnX
R
O
Br TiCl2Cu R
O TiX3
PhCHOR
O
Ph
OH
RBr
O
X
R
OTi
R
OTi
OTiO
OTiX2O
RR2
R
R2
H
X
R
O OH
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Substrate Scope for Reformatsky Reaction
TiCl2, Cu
aldehyde
96% (96:4) 89% (91:9) 94% (91:9)
84% (84:16) 92% (85:15)
TiCl2, Cu
aldehyde
81% (63:37)74% (64:36)
21% (82:18) 69% (74:26)
Kagayama, A. et al. Bull. Chem. Soc. Jpn. 2000, 73, 2579.
Br
O O
R
OH
EtSBr
O
EtS
O
R
OH
CHO CHOCHO
CHO
CHO
CHO CHO
CHO
CHO
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Summary
• Titanium (II) complexes can easily be generated from readily available and inexpensive starting materials
• The chemistry of Ti (II) complexes allows entry into several intriguing reaction manifolds including:– Cyclopropanation
– Alkene/acetylene/imine functionalization
– Synthesis of novel aromatic rings
– Various reductive coupling reactions
• Titanium (II) chemistry is amenable to the synthesis of interesting natural products
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Acknowledgements
• Dr. Jeffrey Johnson• Johnson Group Members• UNC Chemistry
Department