Jan Arild Hustad

1
The Evolution of PEPPSI Design, Preparation,
Catalytic Reactivity, and Applications to
Synthesis.
Jan Arild Hustad SAFC Supply Solution Presented
at NTNU Desember 8th, 2006
2
Seminar Outline
Discuss our interests in sp3 - sp3 coupling
reactions
Talk about ligand properties and design and how
that impacts on catalyst reactivity
Demonstrate the use of in-situ-derived
N-heterocyclic carbene (NHC)-based Pd catalysts
in alkyl Negishi couplings
Mechanistic considerations
Introduce the PEPPSI family of Pd-ligand
complexes
Compare in-situ derived NHC-Pd catalysts with
the analogous precatalyst
Demonstrate the general utility of new
catalysts in a spectrum of coupling reactions
3
Designing a New Catalyst For Alkyl-Alkyl Coupling
sp3 - sp3 are considered a Holy Grail of
coupling reaction
Alkyl-alkyl coupling catalysts are plagued by a
number of issues
Lack of a docking site on the halide or
pseudohalide for the metal as we see in allylic
and sp2 system, which means oxidative addition
is tougher The presence of b -hydrogens can
allow b-hydride elimination as a serious
competing side reaction Reductive elimination
of the two alkyl pieces is difficult
In short, they are tough which makes trying to
find the solution to reactions both
challenging and intriguing (and fun!)
4
Consider the Mechanism
enhance basicity of catalyst
increase steric environment around metal
coordinatively saturate the metal
What can be done to overcome the aforementioned
pitfalls?
5
To Begin, The Rational Approach
Is there one ligand system that is capable of
probing all of these mechanistic aspects?
Yes, N-heterocyclic carbene (NHC) ligands
It has been proposed that the carbene, a
phosphine mimic, is a stronger s-donor than a
phosphine perhaps making the metal more
basic/nucleophilic
At the same time, the carbene is less stable
than the corresponding phosphine making it less
likely to dissociate from the metal, which
could suppress b-hydride elimination. This raises
the question of how many carbenes are on a
catalytically-active catalyst?
The carbon-based framework of the NHC allows
for it to serve as a readily modified, modular
scaffold to allow for a very gradual and
systematic evaluation of a variety of parameters.
Consider
6
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Pd Ipr carbene catalyst system Important
catalyst is generated in situ
First examples of metal-catalyzed Negishi
sp3-sp3 coupling using carbene-based ligands
(NHCs)
First report of a RT Pd-catalyzed Negishi
sp3-sp3 coupling reaction
Hadei, N. Kantchev, E. A. B. OBrien, C. J.
Organ, M. G. Org.Lett. 2005, 7, 3805-3807
7
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Optimizing the catalyst
Increasing the amount of ligand from 1 1 to 3
1 has a small impact N-substituent is best
when aromatic Increased bulk at the ortho
position as possible enhances catalyst activity
8
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Finely tuning sterics and its effect on
catalyst activity
Ipr substituent is essential, yield varies
directly with steric bulk
Hadei, N. Kantchev, E. A. B. OBrien, C. J.
Organ, M. G. J. Org. Chem. 2005, 70, 8503-8507.
9
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Sterics vs electronics what is responsible for
reactivity?
How can we evaluate the electronic density of
metal centre?
NMR Spectroscopy
Problem Pd is quadrupolar Question Can we
use Ag as a model for Pd?
How do 13C and 15N chemical shifts compare in
the two systems?
While Ag exerts a greater deshielding effect
on the carbene ring than Pd, the shifts are
close enough together to allow Ag approximate e-
density on Pd
10
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Sterics vs electronics what is responsible for
reactivity
Ag-109 Shifts
The electron density about the silver centre
inversely correlates with apparent reactivity
(thermodynamic)
The rate-determining step is not effected by
basicity of Pd
11
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Some representative examples demonstrating
broad FG compatibility using the Pd IPr
catalyst at RT in THF/NMP
Entry 5 demonstrates useful properties for
potential queued chemical transformations or
multi-component reaction MCR coupling procedures
12
Moving Toward a Viable and Reliable sp3 - sp3
Coupling Catalyst
Do we know the active catalysts structure?
The active catalyst has been proposed to be
composed of two carbenes and one Pd atom - in
fact we deemed it necessary to suppress agostic
interactions and b-hydride elimination
Equivalent studies (from the earlier slide)
showed that increasing the ligand Pd ratio
from 1 1 to 3 1 resulted in a marginal
increase in yield
Perhaps the active catalyst is not dicarbene
species?
Complex shows no catalytic activity
what-so-ever!
13
Understanding the Catalyst
Question With the intense interest in NHCs,
why have only limited successes been reported
so far and why are they not in mainstream use
in the wider synthetic community?
While we can now get reliable catalyst
performance when generated in situ, this was
not always the case..
When any catalyst is made in situ, there are a
number of concerns
What is the structure of the active species?
How quickly does the catalyst form?
How much of the catalyst gets formed?
These questions and our own issues with
inconsistency point toward the need for a
preformed Pd-NHC complex
14
Understanding the Catalysis We Must Have a
Precatalyst
Introducing
Pyridine, Enhanced, Precatalyst, Preparation,
Stabilization and Initiation
or PEPPSI
Synthesis base, PdCl2, imidizolium salt,
3-chloropyridine, heat
NB No glove box, no inert atmosphere, no
special handling, no solvent,
3-chloropyridine is distilled off and recycled
OBrien, C. J. Kantchev, E. A. B. Hadei, N.
Valente, C. Chass, G. A. Nasielski, J. C.
Lough, A. Hopkinson, A. C. Organ, M. G. Chem.
Eur. J., 2006, 12, 4743-4748.
15
PEPPSI-Ipr Does it work?
Precatalyst has many desirable traits
Complex is air and moisture stable
Easily activated in situ in a wide variety of
transformations
Can be VERY easily prepared on large scale (g
to kg)
Activated catalyst is in fact VERY active!
Comparative study with in situ generated
catalyst and PEPPSI All reactions from here
out are conducted with IPr NHC (or PEPPSI-IPr)
16
PEPPSI-Ipr What are the Kinetics?
Comparing kinetic of in-situ catalyst vs. PEPPSI
After 1 h
After 1 day
(4 catalyst)
PEPPSI is much more active than in
situ-generated catalyst
Assuming that the same active catalyst forms,
how can this be?
It is most likely that with all of the basic
species in the in situ preparations that the
carbene may not be getting on the metal at all
leading to inactive Pd byproducts
17
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
First of all..what is in the pot?
Where is the Cl coming from?
Commercial organozinc seems to be only possible
source
What if the Zn salt is the chloride salt?
The byproduct of the reaction would be LiCl
We carefully prepared halide-free Rieke zinc
centrifuged the Zn and decanted off the
THF-soluble LiX supernatant and reconstituted the
Zn
Good News! Halogen exchange stopped!
Bad News! So did the coupling!
18
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
What is the role of LiX in these couplings?
Other salts examined LiCl similar to LiBr
NaBr lt 15 KBr lt 2 NaI 0 LiI lt 6
BuNBr lt 38
The effect of LiX is not catalytic, i.e., less
than 1.0 equiv., reaction fails
Other cations are not as effective as lithium
19
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
What is the role of LiX in these couplings?
ZnX2, a natural byproduct of the Negishi
reaction, inhibits the reaction
20
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
LiX must be involved in the coupling process
we presume that it activates the organozinc in
an analogous way that base activates boronic
acids (Suzuki)
What is the structure of the zinc species that
are possible in solution?
So why does the coupling not proceed with less
than one equivalent of LiX?
Inorganic zinc is more electrophilic than
alkylzinc and could serve as a halide
scavenger, out competing the alkylzinc for the
activator that is necessary to activate it for
the coupling
One eq of LiX is required to form any higher
order zincate thermodynamically
As ZnX2 is forms, it competes for LiCl which is
why gt 1.5 eq gives best result
21
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
How important is the solvent in these couplings?
While the more reactive bromide and iodide
worked suitably with low levels of DMI
solvent, the chloride is optimal around 1 1,
THF DMI
22
What Else Effects the Alkyl-Alkyl Negishi
Reaction?
Comparing Cl, Br, I reactivity as a function of
solvent polarity
Differential reactivity of halides creates a
solvent window for selective couplings and
allows for queued couplings with poly halogen
substrates
23
Is PEPPSI Versatile? One catalyst fits all?
Negishi couplings of various flavours
sp3 - sp3, either way around
Organ, M. G. Avola, S. Dubovyk, I. Hadei, N.
Kantchev, E. A. B. OBrien, C. J. Valente, C.
Chem. Eur. J., 2006, 12, 4749-4755
24
Is PEPPSI Versatile? One catalyst fits all?
Negishi couplings of various flavours
sp2 - sp3
sp3 - sp2
Organ, M. G. Avola, S. Dubovyk, I. Hadei, N.
Kantchev, E. A. B. OBrien, C. J. Valente, C.
Chem. Eur. J., 2006, 12, 4749-4755
25
Is PEPPSI Versatile? One catalyst fits all?
Negishi couplings of various flavours
sp2 - sp2
Organ, M. G. Avola, S. Dubovyk, I. Hadei, N.
Kantchev, E. A. B. OBrien, C. J. Valente, C.
Chem. Eur. J., 2006, 12, 4749-4755
26
Is PEPPSI Versatile? One catalyst fits all?
Suzuki-Miyaura couplings with K2CO3 and KOH in
dioxane
sp2 - sp2
Base is very important KOH works best, all F-
sources fail completely
OBrien, C. J. Kantchev, E. A. B. Hadei, N.
Valente, C. Chass, G. A. Nasielski, J. C.
Lough, A. Hopkinson, A. C. Organ, M. G. Chem.
Eur. J., 2006, 12, 4743-4748.
27
Is PEPPSI Versatile? One catalyst fits all?
Amination reactions
All chlorides
All done at room temperature, but not yet
general for anilines or amides
28
Is PEPPSI Versatile? One catalyst fits all?
Kumada-Tamao-Corriu couplings
sp3-sp3
First alkyl-alkyl coupling using the Pd-NHC
system
sp3-sp2
29
Is PEPPSI Versatile? One catalyst fits all?
Kumada-Tamao-Corriu couplings
sp2-sp2
Can we simplify the process?
Coupling works well at room temperature
Does not require high dielectric constant
solvent
Abdel-Hadi, M. Avola, S. Hadei, N. Nasielski,
J. OBrien, C. J. Valente, C. Organ, M. G.
Chem. Eur. J., 2006, 12, (in press).
30
Kinetics Unsatuarted (IPr) vs. Saturated (SIPr)
version of PEPPSI
Time study (50 C)
Temperature study (24 h)
The saturated NHC catalyst (SIPr (2)) is more
reactive than the unsaturated (IPr (1)) and
either activates or turns over better at a lower
temperature
Abdel-Hadi, M. Avola, S. Hadei, N. Nasielski,
J. OBrien, C. J. Valente, C. Organ, M. G.
Chem. Eur. J., 2006, 12, (in press).
31
Some More Interesting Kumada-Tamao-Corriu
Results/Applications
First RT tetra ortho substituted cross coupling
reported of any kind
Sequential coupling chemistry
Can we go even lower? Are sub zero couplings
attainable?
32
Is PEPPSI Versatile? One catalyst fits all?
Enolate Arylation
sp3-sp2
33
Is PEPPSI Versatile? One catalyst fits all?
Boron Coupling (the Miyaura Reaction)
sp3- B
Hindered aryl bromides have not been generally
successful as yet
34
Is PEPPSI Versatile? One catalyst fits all?
Sonagashira couplings
Primary alkyl centres
Secondary alkyl centres
35
Is PEPPSI Versatile? One catalyst fits all?
Amination-Heck Sequence Queued transformations
Have prepared a small library of 20 indole
analogues, all yields gt 75
Flowed reactions, if heating is necessary, must
be complete in lt 1 minute!
36
What About Scale-UP??
Pd-catalyzed reactions can sometimes be
precarious on scale up?
Buchwald-Hartwig Scale Up
Work Up i. filter thru Celite, ii.
extract into acid, iii. titrate until basic
iv. back extract into ether, v. dry and
remove solvent
Suzuki Scale Up
26.5 G!
10 G!
Kumada Scale Up
10 G!
37
Summary
Pd-NHC complexes are indeed active catalysts
for a variety of Pd-mediated coupling reactions
It is highly likely that such catalysts formed
in situ are variable in term of their
composition and amount, and therefore their
reactivity
We have created a precatalyst family PEPPSI
that activates smoothly under a wide variety
of reaction conditions - but they must be reduced!
Our data to date suggest that PEPPSI is a very
active and widely applicable catalyst Zn, B,
Mg, Sn, Si, amination, Kumada, Heck,
Sonagashira, enolate arylation, aryl boration
sp2-sp2, sp2-sp3, sp3-sp2, sp3-sp3
In NHC catalyst design, sterics are most
important, supporting the notion that reductive
elimination is rate limiting in many cross
coupling procedures
Preliminary data also suggests that PEPPSI is
effective in couplings that historically prove
challenging for Pd catalysis, i.e., the coupling
of nitrogen and sulfur-containing compounds
A few examples demonstrated that
PEPPSI-catalyzed reactions scale well
It is possible that PEPPSI could replace
(PPh3)4Pd as the first go-to catalyst system
38
New Information Concerning PEPPSI
Precatalyst is now commercially-available
through Aldrich
In situ catalysts invariably lead to
disappointing results, must use precatalyst
Until now, NHC-Pd catalysts have been expensive
curiosities
Because of the process developed to make
PEPPSI, it is now one of the affordable Pd
catalysts available
less than (PPh3)4Pd on Pd basis!
Now available in 1G and 5G sizes,
Bulk quantities are available by quote
PEPPSI behaves well in microwave conditions,
many Pd catalysts do not
Details of this talk covered in
PEPPSI Webpage ChemFiles, Aldrichimica
Acta (just out), Angewandte Chemie Review
(Dec.), Activation Guide www.sigma-aldrich.com/p
eppsi
Back-to-back articles in Chemistry A
European Journal (with more to come!)