Literature Seminar (M1 part)

June 4, 2012
Seiko KITAHARA (M1)

Nickel(0)-Catalyzed Alkene-Aldehyde
Non-Reductive Couping Reaction-Byproduct-Free Processes-

Contents
0. Introduction -From Reductive to Non-Reductive1. Alkyne-Aldehyde Reductive Coupling Reaction
2. Alkene-Aldehyde Non-Reductive Coupling Reaction
3. Summary

0. Introductionref) my lit. seminar (B4)reactions picked out for today
A+

B

Byproduct-free = ideally atom economy+Cproduct

Alkene-Aldehyde Non-Reductive CouplingO
R1+

R2

H+

R3SiOTfR1R2

1. Alkene-Aldehyde Reductive Coupling Reaction
two pioneers in this area
John Montgomery

Timothy F. Jamison

Late-transition metal catalysis has potentical advantages:(1)simpler preparation and handling of the catalysts(2)better combatibility with Lewis basic functionality(3)weaker M-O bond ( more efficient catalytic turnovers of R-O-M intermediates)(4)access to reductive elimination chemistry
Nickel has additinonal properties:-chaep-air-stable (unless powdered Ni(0))-stable in the presence of hard organometallics
Ni(0)-catalyzed alkyne-aldehyde reductive coupling to form allylic alcohols

Montgomery's work

NHC ligand 1

Jamison's work(first report)

OSiR3

OSiR3

Ni(0) cat.

&R1

R2

background & challenges
first reports of Ni(0)-catalyzed multi- -component coupling reactions
via nickelacycle

Reppe: 1948
Ni(CN)2 or Ni(CO)4++60-70 C, 15-20 atm
W. Reppe et al. Justus Liebigs Ann. Chem., 1948, 560, 104.
Wilke: 1963
Ni(0)2++G. Wilke et al. ACIE, 1963, 2, 105.
"modern" biomolecular C-C bond formation

basic challenges

Micalizio, G. C. et al. EJOC, 2010, 391.
Regioselectivity

Stereoselectivity

Chemoselectivity
reduction

reduction

reduction

Trans? Or cis?
W hich site?

Reductantoligomerization

reductive dimerization(pinacol formation)

1-1. Some System for Alkyne-Aldehyde Coupling Reactions
Montgomery's first system: Ni(COD)2/PBu3 systema conceptual framework

Is it possible to develop a new catalytic processes via analogous oxametallacycles ??
a discovery leading to develop alkyne-aldehyde reductive couplingin the absence of phosphine ligands
in the presence of phosphine ligands
alkylative cyclization

alkylative
reductivecis

ynal reductive cyclization (the first report)
transsubstrate scope

substrate scope

Montgomery, J. et al. JACS, 1997, 119, 9065.
alkylative couplinghigh chemo-, regio-, stereoselectivity (only E isomers)
no direct addition (intramolecular)
no competitive -H eliminnation (intramolecular)
broad scope of organozincs (intramolecular)
direct addition (intermolecular)
cometitive -H elimination (intermolecular)
limited scope of organozincs (intermolecular,3
only sp-hybridized)
reductive couplinghigh stereoselectivity (only Z isomers)
limited to intramolecularW hat is the role of a phosphine ligand in promoting reduction instead of alkylation?
(W hy pretreatment of Ni(COD)2 with a basic phosphine resulted in reduction?)
proposed mechanism for reductive/alkylative couplings

a common intermediate
for both pathways:

in the presence of phosphine ligands
much more electron-rich at the metal center

the electron-deficient
Ni(II)- complex-Helim.
RE

in the absence of phosphine ligands
electron-poor at at the metal center(by -acceptor properties of the spectator ligand)in light of the previous Montgomery's work (Ni(0)-catalyzed cyclizations of alkynyl enones)

deuterium labeling studies

conclusion (mechanism)

From these results, at least two pathways are operative:
1. -H elimination (major)
2. protonation on workup,
most likely of an alkenylzinc spicies (minor)
Montgomery, J. et al. JACS, 1996, 118, 1996.

Jamison's system
the first report of catalytic intermolecular reductive coupling

optimization of reaction conditions

substrate scopetrialkylphosphines's effectsmaller: yield regioselectivity
larger:yield regioselectivity
Bu3P gave the best combinationhigh regioselectivity (except internal aliphatic alkynes)
compelete stereoselectivity (exclusive cis-addition)broad substrate scope (both intra- and inter-molecular)commercially available catalyst and reagentsa 1:1 ratio of alkyne to aldehyde
no reductive coupling of ketones (e.g. acetophenone)
competitive [2+2+2] cyclization of alkynes
applicapable to site-selective f ragment coupling reactions
at rate stage in complex molecule snthesis ??
Hypothesis
High regioselectivity observed with aryl-substitued alkynes is likely
due to an electronic differentiation between alkyl- and aryl- substituents.
(This is found not to be compelely correct later.)Jamison, T. F. et al. OL, 2000, 2, 4221.

Jamison's system -Asymmetric inductionthe first report of catalytic asymmetric reductive coupling

Substrate Scope

the higest
up to that pointof this particular
reactionin all cases exclusive cis-addition (>98:2)

Jamison, T. F. et al. JOC, 2003, 68, 156.
the model for these resultsLS

syn to a small Me(away from a much larger Fc)

1a hasthe greatest difference
in steric demand
between Fc vs. R(Me)low to moderate regio- and enantioselectivity
limited to only a few cases(alkyl-C C-alkyl)the complementary systemsustrate scope

X-ray diffraction study of NMDPP

R=R=Jamison, T. F. et al. JACS, 2003, 125, 3442.
Hackless, D. C. R. et al. J.Organomet. Chem., 1997, 544, 189.
the model for these results
Both the ax placement and the orientationof a M-PPh2 group over the Cy ring of NMDPP
have been observed in the solid state.
(See above)a cooperative effect-steric properties of the ligand-electronic differences of the alkyne substituents

From this f ramework...
Can more steric dif f erentiationof the two aldehyde coordination sites
enhance enantioselectivity ??

Montgomery's second sytem: Ni(COD)2/NHC systemhigh regioselectivity (except internal aliphatic alkynes)
compelete stereoselectivity (exclusive cis-addition)broad substrate scope
stable & easilyhandled reducing agent
unprotected alcohol tolerance entry 10

Montgomery, J. et al. JACS, 2004, 126, 3698.
Why is there a significant difference of substrate scopes between two systems ??
crossover deutrium-labeling experiments

plausible mechanisms from crosspver experiments

1-2. Mechanistic Analyses
assumption 1: formation of oxanickelacycle
Although no metallacycles derived from OA of one alkyne and one adehyde
have been isolated, ...
confirmed oxonickelacycle fomation by X-ray anaysis(coupling of alkynes and carbon dioxide)

Tsay, Y.-C. et al. J. Organomet. Chem. 1984, 266, 203.

assumption 2: -hydride elimination vs. reductive elimination
Some phosphine ligands prompt -hydride elimination.
the first example of the transition metal complex-catalyzed alkyl group isomerization(The product is in general a mixture.)
products using various phosphinesplausible mechanismconversion

Kumada, M. et al. JACS, 1972, 94, 9628.
The extent is dependent strongly upon electronic natureof the phosphine ligand.
-electron donating
n-propylbenzene
isopropylbenzene-electron accepting
Benzene is formed only in the cases
where n-propylproduct is formed pregerentially.
(with a few exception)

information which serves as evidence for scheme 1(+)-(S)-2-methylbutyl chloride

Ni(dpp)Cl2" -effect"
Electron-donating ligands
increase electron density on the metal center
lower the activation energy for the - conversion
facilitate the -hydride elimination[ ]18D +1.68 (neat)
98% optical purity(+)-(S)-2-methylbutylbenzene[ ]25D +10.54 (neat)
n25D 1.4869 (lit. n25D 1.4862)
with a little loss of optical purity

Ni(dmpe)Cl2(+)-(S)-2-methylbutylbenzene[ ]25D +9.56 (neat)
relatively low optical purity

mechanistic study 1: producted-oriented mechanistic analyses<1,3-enynes (Jamison's system)>High regioselectivity isjust due to an electronic distinction
between two alkyne substituents, or... ??

due to neither the nature or size of the other alkyne substituent
nor the dgree of alkene substitution

Some unique effects(1)compelete reversal regioselectivity
In the previous result,C-C bond formation favored
distal to the allyl substituent.

substrate scope(written again)

In the previous result,C-C bond formation favored
proximal to the allyl substituent.
(See entry 1)
A vinyl group is a significantly
more potent DG than a phenyl ring ??
(2)a remarkable increase in reactivity
t-BuC C-C-alkyl and t-BuC C-C-aryl don't react.

t-BuC C-CH=CH2 underwent reaction,
and with excellent regioselectivity to favor C-C bond formation
at the more hindered alkyne carbon!
(See entry 2)
Jamison, T. F. et al. JACS, 2004, 126, 4130.

Olefins have the ability to form a favorable bonding interaction with Ni
in a high-energy intermediate 1 serving to lower the TS energy

conclusion
The alkene substituents appears to strongly direct regioselectivity and also significantly increase reactivity.
complexation of the alkene to the metal center during the regioselectivity-determining step?
How about a remote alkene ??

<1,6-enynes (Jamison's system)>
A remote, unconjugated alkene dictates regioselectivity??

override the steric demand

Only one tether length provided the marked difference
in reactivity and selectivity.
with little difference in the steric and electronic propertiesof the alkyne substituents
A tethered alkene is sufficient to reinforce"inherent" regioselectivities.
Jamison, T. F. et al. JACS, 2004, 126, 15342.
Tethered alkenes is affected by ligand-switchable directing effect.

plausible mechanism

type I
Aldehyde
displaces L,
cis to C(A) andthe bound olefin.

type II
Aldehydedisplaces olefin
stereospecifically.

Jamison, T. F. et al. OL, 2006, 8, 7598.

Don't atom at propargyl position play a key rolein the mode of diastereoinduction??

typeIII
2 eq. of phosphines
are bound to Ni,
and aldehyde
displaces one of them.

olefin=the most weakbound ligand

PCy3=more strong
bound ligand

O and C at propargyl position have similar effect.

One possible explanation
Oxygen in the etheral tether was binding
to the aldehyde via the boron??
directing the aldehyde to the top face
due to the conformation of the ring chelate... But the effect is measurable different.
Jamison, T. F. et al. tetrahedron, 2006, 62, 7598.
The influence of the chiral center in the tether is minimal.
nearly equimolar amounts of regioisomers
via a type III mechanistic pathway
modest diastereoinduction
in both the R and S phosphine ligands cases
no influence of the enyne stereocenterson the diastereoselectivity
conclusion
Phosphine is bound to Ni
during the C-C bond-forming stepmechanistic study 2: kinetic
analysisVia which pathway the reductive coupling proceed ??

Montgomery, J. et al. JACS, 2011, 133, 5728.

a rate study of the cyclization of a ynal by in situ IR monitoringynal:
first-order dependence
Ni(COD)2: first-order dependence
Et3SiH:zeroth-order dependence
a kinetic isotope effect study & a crossover-labeling study

c.f. PBu3-promoted process originally reporeted
See Montgomery's second system

These seem to be inconsistent with rate-determining oxidative addition of Ni(0) to the Si-H bond (Scheme 2).
For a mechanism involving the production of nickel hydride 4 to be consistent with the kinetic order studies...
a fast reaction between a PCy3 adduct of Ni(COD)2 with Et3SiH
a slow subsequent insertion step
Is it possible??
in situ IR monitoringa solution of Et3SiH

Ni(COD)2/PCy3

no consumption or change of the Si-H stretch
This is inconsistent with formation of 4(Scheme 2),
but consitent with formation of 5 or 6 (Scheme 2).
a solution of Et3SiH+aldehyde

Ni(COD)2/PCy3

a solution of Et3SiH+alkyne

Ni(COD)2/PCy3

no consumption or change of the Si-H stretch
These are inconsistent with formation of 5 or 6 (Scheme 2).
Scheme 2 is ruled out! How about Scheme 1?
in situ IR monitoringa solution of Et3SiH+enal

Ni(COD)2/PCy3

steady depletion of SiConclusion
All experiments support the nickelacycle mechanism (Scheme1).

mechanistic study 3: a detailed computational study

stabilization by back-donation

T.F.Jamison et al. JACS, 2009, 131, 6654.

appendix: free-energy for the full catalytic cycle

2. Akene-Aldehyde Non-Reductive Coupling Reaction
from alkyne to alkene
non-reductive

reductive
more easily preparedalkynealkene(numoreous olefins commerically avilable &abound synthetic methods for them)
have potential to eliminate compatibility issues

with reducing agents

without reducing agentsNon-reductive have some merits, but both aldehydes and alkenes are intrinsically unreactive toward each other.
How can these components are activated?

See reductive couplingof 1,3- and 1,6-enynes

carbonyl-ene reactions catalyzed by transition-metal complexes as Lewis acids

Transition-metal-catalyzed intermolecular coupling reactions of alkenes remained elusive.
Historically, the most direct method for intermolecular couplings of unactivated alkenes and aldehydes iscarbonyl-ene reaction, and late transition-metal complexes (cationic Lewis acid complexes) catalyze it.
a pioneer woek (chiral Pd(II)complexes)a Ni(II) catalyst system showing excellent ee

2b =Feng, X. M. et al. JACS, 2008, 130, 15770.
excellent enantioselectivity
a wide range of "simple" alkenes(1,1-disubstituted and trisubstituted olefins)limited scope of electrophile(few aromatic or sterically demanding aldehyde)

Develop a reaction with f eatures
not amenable to exisiting carbonyl-ene methodorog!
Mikami, K. et al. OL, 2000, 2, 34059.

-the ability to transform less activated alkenes-enhanced and complementary electrophile scope-the option to produce allylic alcohol in addition tohomollylic productJamison's unique system
Jamison, T. F. et al. JACS, 2006, 128, 11513.

Simple aromatic aldehydes
react efficiently.
o-Substitution don't deter
the reaction.
Enolizable aldehydes
generally are not appropriate(but some are tolerated
as in entry 14).
Heteroaromatic aldehyde
are tolerated!
E-rich aromatic aldehydes
are more efficient substrates
than e-poor ones.
Some common silyl triflates
can be used.

Byproducts(resulting from a pinacol coupling)
are observed only in these enetries.

How about regioselectivity, if substituted olef ins are used??

What occured??

T wo distinct types of coupling products are typically observed.
How can the ration of them be controlled?

ligand effect
A higher H:A ratio can be achieved
by decreasing electron-donating abilityof the phosphine ligand.

However, some very electron-deficientphosphines are not effective
due to the larger cone angle??

On the other hand,high A:H ratio can be obtainedby using electron-rich phosphineswith a large cone angle.

two combined effects:-electron-donating ability-the cone angle of the phosphine ligands

base effect

Et3N is the bese probable because of a combinationof low coordination ability and appropriate basicity

substrate scope (H)Highly regioselective & E/Z serective (favoring E)
Aromatic aldehydes, heteroaromatic aldehydes, andstrically demanding aldehydes can be used.
As the case of ethylene, e-rich aldehydes are more efficiency.
Substitution at the homoallylic position (of alkenes) don't affect,
but at the alylic position different ones.

unusual E-1,3-disubstituted allylic alcohol productan important observationin understanding the mechanism

substrate scope (A)Aromatic aldehydes and heteroaromatic aldehydes
can be used.
As cases above, e-rich aldehydes are more efficiency.
Substitution at the homoallylic position (of alkenes)
don't affect, but at the alylic position different ones.
competition study
Trisubstituted alkenes are stable.
See entry 6
In general, 1,1- and acyclic 1,2-disubstituted
alkenes are significantly less reactive, andtrisubstituted alkenes don't react under the
standard reaction conditions.

poposed reaction mechanism based on some observations and in analogy to the Heck reaction
nickel-hydride pathway-Helim.

-Helim.

Ni-H species are suggested by-observation of isomerization & dimerizationof the starting olefins-the requirement of a baseoxanickelacycle model (in more detail)

From the entirely difference of both substrate scopes of alkenes and aldehydes,
the direct precursor to the oxanickelacycle is a Ni(0) species, not a cationic Ni(II) Lewis acid species.

3. SummaryJmaison's non-reductive pocess, different from carbonyl-ene reactions of reductive processes,
conceptually serve alkenes as substituteds for both allylmetal and alkenylmetal reagents.
This system affords two type products with high selcetivity in either direction

1997
Montgomery
intramolecularreductive

2000
Jamisonintermolecularreductive

2004
Montgomery
intermolecularreductive

2006
Jamisonintermolecular
non-reductive