Lecture 16
November 10, 2011
Metal-catalyzed cross-coupling reactions:
Let’s move on now to talk about other metal-catalyzed cross-coupling reactions. All of these reactions
involve the formation of a new carbon-carbon bond between unsaturated carbon atoms (either sp or
sp2-hybridized).
Sonogashira reaction:
The mechanism here (briefly) – is oxidative addition of the aryl iodide to the palladium (0), the alkyne
and copper generate an organocuprate, this organocuprate undergoes transmetallation with palladium,
and then reductive elimination gives the product.
Heck reaction:
This is also called the Mizoroki-Heck reaction. The general reaction scheme is shown below:
and it proceeds via the following mechanism:
Iodides are more reactive than bromides and chlorides (which is the typical order of reactivity, based on
the strength of the carbon-halogen bond), which means that it is possible to convert an aryl iodide
selectively and leave the aryl bromide untouched:
The olefin is almost always electron-deficient. This is b/c the electron-deficient substituents increase the
rate of oxidative addition to palladium. People have done Heck reactions with electron-rich vinyl ethers,
but these usually require modification. For example, the reaction below works well:
but they needed to use the weird phosphine oxide ligand to get good results.
Another interesting aspect of the Heck reaction is its stereoselectivity, which produces trans-alkene
products predominantly. This is because the insertion reaction is stereospecific and syn – meaning that
the R group and the PdX group add to the same side of the double bond. B-hydride elimination also
reinforces the formation of the trans alkene. Let’s do a few Heck reaction examples:
Here you can use the triflate as a halide-like substituent. The vinyl triflate can be formed in one step
from the corresponding ketone by treating it with triflic anhydride and triethylamine:
And the mechanism for this conversion is shown below:
Another Heck example:
And a Heck retrosynthesis example:
Here, you look at a regular trans alkene, and are asked to do a retrosynthesis using a Heck reaction.
There are two things that are missing from your molecule – you really need a diene that is conjugated as
the product of the Heck reaction. You also generally want an electron deficient moiety attached to your
alkene to help it react faster. So you can put those back retrosynthetically. The extra double bond could
have been removed by hydrogenation, and the electron withdrawing ester could have been removed by
hydrolyzing it to a carboxylic acid and then decarboxylating it. This brings you back to intermediate A
that is an excellent candidate for Heck retrosynthesis.
You should also note here that your products are often dienes. These are perfectly poised to react
further in a Diels-Alder reaction with a dienophile (keep this in mind when you have to do multi-step
synthesis!).
Heck reactions can be used to make polyphenylenevinylenes (PPVs), via the general reaction shown
below:
R in this case is generally a long alkyl or alkoxy chain.
Suzuki reaction: General reaction scheme:
Here either the halide or the boronate can be aryl or vinyl (just has to be sp2 hybridized).
The mechanism of the Suzuki reaction has a lot of similarities to the Heck reaction mechanism and is
shown below:
The first step is oxidative addition to a palladium, followed by transmetallation with boronic acid.
Reductive elimination then gives the desired product. One downside to the Suzuki reaction is that you
have to pre-form both a boronic acid and a halide before they can be coupled. It would be more efficient
if you could directly couple compounds with C-H bonds. This is a whole other topic called “C-H
activation” which we are not going to cover today, but it is a highly active field for those who are
interested.
Traditional Suzuki reactions required that both partners had to be sp2 hybridized in order for the
reactions to take place. However, recent advances by people like Greg Fu have demonstrated that you
can do Suzuki reactions with sp3 carbon centers as well, but you need a different catalyst system.
Here is an example from a recent Greg Fu paper:
This is particularly interesting because he uses nickel (instead of the traditional palladium) and he also
uses a chiral ligand (shown below) to get enantioselectivity in the product. The new chiral center has
enantioselectivities up to 90%.
Chiral ligand:
Let’s do some Suzuki reaction examples:
Example 1: Here you can see that the free amino group does not interfere with the Suzuki reaciton
Example 2: Two things to note here – first of all, that the aryl triflate works well as a halide surrogate,
and secondly that this is actually reacting a protected amino acid to generate a biphenyl analogue,
which could be useful synthetically.
Example 3: I think the interesting thing here is that the methoxy group on the ketone alpha carbon
remains totally untouched by this reaction.
There are many examples where the Suzuki reaction is used in a polymerization. To do a polymerization
with a metal-catalyzed cross coupling, you need to have two bifunctional monomers (like we talked
about last time). A polymerization example:
Here they use a boronate ester to couple with the aryl bromide and for the new aryl-aryl bond in the
polymer product.
You can also make PPP (poly-para-phenylenes) by a Suzuki polymerization:
And also polyfluorenes can be made this way:
Glaser coupling reaction: This is between two terminal alkynes, and requires the presence of the copper
and oxygen to generate a dialkyne product. The general reaction scheme is shown below:
This is a big problem as a side product in Sonogashira reactions. You may have noticed that Sonogashira
also has terminal alkynes and also requires a copper catalyst. So you need to be really careful to exclude
oxygen in Sonogashira reactions, since that is the key difference between the Glaser coupling and the
Sonogashira reaction. A lot of times with Sonogashira reactions you will get defects from the homohomo
coupling of two alkyne groups.
People have used the Glaser reaction for polymerization as well. Here is one example:
To do this, they basically used a bis--terminal
terminal alkyne and that allowed them to form the desired polymer
with di-alkyne linkages.
polymer example of a Glaser coupling:
Here is a non-polymer
O 2, CuCl
TMS
H
TMS
N
TMS
N
Glaser products are easy to identify because they will all have the bis
bis-alkyne linkage.
Retrosynthetic toolbox: These metal
metal-catalyzed cross-coupling
coupling reactions open up huge new opportunities
in retrosynthesis (and in synthesis in general). Now an
anyy time you have a target molecule with
unsaturation (alkene, benzene ring, etc) – you can retrosynthetically disconnect that compound and
decide that the key bond-forming
forming reaction was a metal
metal-catalyzed cross coupling.
Here is an example: In this compound yyou
ou have a double bond in conjugation with an arene, that you
can disconnect retrosynthetically and say that it came from a Heck reaction.
HO
CO2Me
HO
CO2Me
e
+
I
And even if you didn’t have a double bond there, you can retrosynthetically decide tthat
hat there used to be
a double bond there that got hydrogenated:
HO
CO2Me
HO
CO2M
Me
HO
CO2Me
+
I
and this gives you the option of disconnecting lots of bonds that may not have been possible otherwise.
There are a number of other cross-coupling
coupling reactions tthat
hat we are not going to talk about, including the
Negishi coupling, and the Stille coupling. Next time we will continue our discussion of conjugated
polymers by talking about select applications of these polymers, predominantly in sensing schemes.