Lit. Seminar. 2010. 6.16 Shinsuke Mouri (D3)Regioselective Reductive Cross-Coupling Reaction
Glenn C. Micalizio obtained a Ph.D. at the University ofMichigan in 2001 under the supervision of Professor William
R. Roush. After postdoctoral study as a Fellow of the Helen
Hay Whitney Foundation at Harvard University in thelaboratory of Professor Stuart L. Schreiber, he moved to Yale
University as an Assistant Professor in the Department ofChemistry (2003). In 2008, he moved to the Department ofChemistry at The Scripps Research Institute as an Associate
Professor. His research is focused on the development ofnew synthetic methods and application of these methods tocomplex molecule synthesis.

recent review : G. C. Micalizio et.al. Eur. J. Org. Chem. 2010, 391.
Contents
0. Introduction (P. 1)
1. Micalizio work : Reductive Cross Coupling Reaction (P. 3)
1.1. Alkyne with Alkyne (P. 3)
1.2. Alkyne wtih Alkene (P. 5)
1.3 Allene (P.7)
1.4. Imine (P.9)
1.5. Toward complex molecule (P. 10)
2. Mecahism of Ni-caltalyzed reductive cross coupling reaction (P.13)
3. Summary and perspective (P.15)
4. Appendix (P.16)

0. Introductiondifficulty in control of reactivity and regioselectivity

Micalizio's strategy
Ti-mediated alkoxide directed reductive cross coupling

O OiPrTiRRR[Ar]3d24s2•oxidation states : +4, +3 or +2•coordiantion : 4-coordinated complex, 5 and 6•bond energy : Ti-F > Ti-O > Ti-Cl > Ti-N > Ti-C (Ti-C <Zr-C)•polarized Ti-C, cationic Ti•reactivity of RTiLn is affected by the ligand at Ti
Yukikinzokuhannouzai -handbook , Kagakudouzin (P. 93)

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Why did Micalizio focus attention on Ti-mediated strategy?
1. The ability of Ti alkoxide to undergo rapid and reversible ligand exchange.

pastemechanism of katsuki sharpless epoxidation in
Strategic Applications of Named Reactions in Organic Chemistry (Kagakudouzin)

Sharpless et. al. J. Am. Chem. Soc. 1991, 113, 106.
Katuski T. et. al. Org. React. 1996 ,48, 1.
2. Cp2Ti-π complex are known to participate reductive cross coupling.

Bercaw et. al. J. Am. Chem. Soc. 1983, 105, 1136.
Sato. et. al Chem. Rev. 2000, 100, 2835
3. Ti alkoxide could be employed to acess similar reactivity seen with Cp2Ti-π comples (Kulinkovich, Sato)

Kulinkovich et. al. Zh. Org. Khim. 1989, 25, 2244.

the cost of stoichiometric Ti(OiPr)4 is significantly less than known catalytic systems based on Ni, Rh, Ir or Ru.
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Alkyne + Alkyne

Micalizio et. al. J. Org. Chem. 2009, 74, 7211.
Class I

262827•O-protected alkyne gave products with moderate rr.
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Class II
Micalizio et. al. J.Am. Chem. Soc .2006 128, 2764.

Substrate scope is limited based onfactors influencing reactivity and resioselectivity.

Ti(OiPr)2Ti(OiPr)4

iPrMgClTi(OiPr)2
R1

R2-78 ºC to -50 ºC
2hR1

D2OTi(OiPr)2R2

Sato, F. et. al.
Tetrahedron Lett. 1995, 36, 3203.

the tetherd alkoxide plays a central rolein determing regio selection.

R1

DR2

Dup to 100%
Z :E = >99: 1

Jin Kun Cha et. al. J. Am. Chem. Soc. 1996, 118, 4198.

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1.2 Alkyne with Alkene

Micalizio et. al. Angew Chem. 2007. 119, 1462.

Micalizio et. al. J. Am. Chem. Soc. 2007, 129, 15112.
allylic alcohol case
OPMB

OH+

65%
PMBO

PMBO

OPMB

alkyne (1.0 equiv), ClTi(Oi-Pr)3, PhMe, C5H9MgCl, -78 to -35 ºC,then recool to -78 ºC add Li-alkoxide of allylic alcohol (1.0 equiv)(-78 to 0 ºC).

• via formal [3,3]-rearrangement route

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<Blank Space>

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1.3 Allen
1.3.1 allene+ alkyne
Micalizio et. al. Chem. Commun. 2007, 4531.

OPMB

OH
•

OH

OPMB
OPMB+MeMe

PMBO

74%

alkyne (1.4 eq.), Ti(Oi-Pr)4 (2.1 eq.), c-C5H9MgCl (4.2 eq.),PhMe (-78 ºC to -30 ºC), cool to -78 ºC then add allenylalkoxide (1 eq.), (-78 ºC to 0 ºC).

1.3.2 allene+ imineNiPr

OH+ Cl•Micalizio et. al. Synlett, 2008, 735.
nPrnPr

NHCl
iPr
63%, E/Z = >20:1

Typical reaction conditions: imine (1.0 equiv), ClTi(Oi-Pr)3(1.25 equiv), c-C5H9MgCl (2.5 equiv), Et2O (-78 ºC to -40ºC), then add allenyl alkoxide (3-4 equiv, -40 ºC to 0 ºC).
Micalizio et. al. Tetrahedron 2008, 68, 3437.

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1.4. Imine(Micalizio et.al. Angew. Chem. Int. Ed. 2007, 46, 391.)

aza-Pauson Khand-like annulation reaction for thesynthesis of tetrasubstituted γ-lactams(Micalizio et.al. Chem Commun. 2010, 46, 3336.)

carbometalation process is irreversible.

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Toward complex molecule
Micalizio et. al. J. Am. Chem .Soc. 2008, 130, 16870

ca. 50%a) MeC(MgBr)CH2 , MeC(OMe)3, EtCOOH (cat), reflux•This empirical model does not yet address the number ofligands presenton the metal center in the transition state.
•Others have suggested ate complexes as reactive
intermediates in the Kulinkovich reaction.
OR

OR+ Ti(OiPr)4nPrMgBr

Ti (OiPr)4O

ORR
octahedral ate complex(Micalizio et.al. J. Am. Chem. Soc. 2009, 48, 3648.)

Kulinkovich et. al. Eur. J. Org. Chem. 2007, 2121.

(d) Imine (2.0 equiv), Ti(Oi-Pr)4 (3.0 equiv),
c-C5H9MgCl (6.0 equiv), 8 (1 equiv), Et2O.
(b) HCl(aq), THF.

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Micalizo et. al. Nat. Chem. DOI: 10.1038/NCHEM.665

1)Reaction conditions for cross-coupling: vinylsilane, ClTi(Oi-Pr)3, c-C5H9MgCl, Et2O (-78 to -50 ºC), then add lithium alkoxide ofvinylcyclopropane(–70 ºC to roomtemperature over 3 h). Oxidation conditions: TBHP, H2O, CsOH.H2O, TBAF, DMF, 70 ºC.
2)Oxidation conditions: KF, KHCO3, H2O2, MeOH, THF. CH2Cl2, Sm[Hg], THF, (85%, dr= 20:1). PDC, 4-Å molecular sieves,
CH2Cl2 (91%), then L-Selectride, THF (76% of desired isomer, dr=6:1).

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(a)ClTi(Oi-Pr)3, c-C5H9MgCl, 35 (-78 to 30 ºC), PhMe, then lithium alkoxide of 34 in Et2O (-70 ºC to room
temperature over 3 h)(b)TBAF, THF(c)ClTi(Oi-Pr)3, c-C5H9MgCl, alkyne (-78 to -30 ºC), PhMe, then lithium alkoxide of the vinylcyclopropane in Et2O(-70 ºC to room temperature over 3 h);(d) HF.pyr, CH3CN, CH2Cl2;(e) PDC, DMF, H2O.
Yields reported are over the three-step sequence (c-e) and are adjusted based on the quantity of recovered
starting material (vinylcyclopropane). Isolated yields for each reaction sequence are 38% (equation (2)), 36%(equation (3)) and 23% (equation (4)) over the three-step process (corresponding to average yields of 60-70% perstep).

total synthesis
Micalizio et. al. J. Am. Chem. Soc. 2009, 131, 1392.

Micalizio et. al. Angew. Chem. Int. Ed. 2008, 47, 4005.

NH2OH MeMeO

H
Me

Me
Me

MeO

OAc
OH

Me

Phorbasin CH

OO

MeOMe
Me H
HON
MeH
OOMe
O
Macbecin I12/16

2. Mechanism of Ni-catalyzed reductive cross coupling reaction

J. Montgomery et. al.
J. Am. Chem. Soc. 2007, 129, 9568.

J. Krische et. al.
J. Am. Chem. Soc. 2007, 129, 8432.

F. Jamison, et. al.
J. Am. Chem. Soc. 2004, 126, 15342.

Ni(0) catalyst
H+/H2OOR1R2++H

R3

BEt3OBEt2
R1R3R2Jamison and Houk et. al. J. Am. Chem. Soc. 2009, 131, 6654(a) oxidative cyclization of alkyne and aldehyde to form a metallacycle intermediate, followed bytransmetalation of the reductant and subsequent reductive elimination of the product(b) a similar mechanism but with the metal bonded to the reductant in the oxidative cyclization(c) oxidative addition of the reductant to the metal and subsequent insertion of the two π components(d) oxidative addition to one π component (alkyne or aldehyde) and subsequent insertion of the secondcomponent.

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R1L
NiL

3

R1R2R2H

5R3R36L
Ni O

R1L
Ni

R1O

R2O
4

R1

oxidative
cyclization
TS1-A
Path A

R1BEt3R2 H R3

L
Ni

BEt3

L
Niacetylene

Path Bethylene

R2oxidative
cyclization
TB1-B

O BEt3R38transmetalation(alkyl migration)
TS2L
Ni O BEt3
R2L
R1H R3EtNiR27O BHEt2
R39OBEt2 +R1R3R211R1OR1+ HR2R3210LNiR2β-hydrogenelimination andreductiveelimination
TS3OBEt2
R3114/16

3. Summary and Perspective
Micalizio demonstrated new type of reductive cross coupling based on the Ti mediated alkoxide directedstrategy. This system is applicable to many type of reductive cross coupling and also Micalizio is also
successful in to complex molecule. Further if possible....
1) catalytic2) mechanism - ligand number and effect on Ti (transition state )(Micalizio et.al. Angew. Chem. Int. Ed. 2009, 48, 3648.)

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4. Appendix

Jamison and Houk et. al. J. Am. Chem. Soc. 2010, 132, 2050.

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