First I’d like to express my deep appreciation to this organising committee of this meeting
which kindly invited me to attend this meeting to discuss our chemistry especially with young people.
Today I want to discuss a little bit about the cross coupling reaction of organoboron compound,
the ways various organics electrify.
Such a reaction provided us very easy way for carbon-carbon bonding.
I think of course as you know the carbon-carbon bond formation reaction is a very important reaction in the organic synthesis.
For such a carbon-carbon bond formation reaction usually we use the various organometal compounds with various organic halides.
In the presence of transition metal the complex reaction ought to yield the expected cross-coupled product.
In this type of cross coupling reaction we can use many different kinds of organometal compounds
such as organolithium compound, magnesium compound.
This is of course as you know guanylyl ligand.
Other organometal compounds react with organic halide under such reaction condition
to give this kind of carbon-carbon bond formation reaction.
However, in the case of this type of reaction...
As I told you we use many different kind of organometal compound but such a compound is usually very reactable.
Therefore if you try such a reaction in the solvent and if in the solvent you had many smaller amount of the water as impurity,
water immediately reacts with active organometal compound to decompose.
Consequently in such a case we have to remove completely such, even small amount of the water in the solvent.
That is a very troublesome job.
On the other hand if we can use organoboron compound, carbon-boron compound,
if such organoboron compound reacts this type of cross coupling reaction,
that should be very good because organoboron compound is very stable towards water.
So we don’t care anything about the presence of water in such solvent.
But unfortunately usual organoboron compound is very inert.
So this type of cross coupling reaction with organic halide
in the presence of transitional metal catalyst such as palladium compound we never then expected cross coupled product.
But as I told you later we found such a reaction proceed very nicely under such a condition in the presence of base.
So today I’d like to tell you a little bit about this chemistry.
Initially I think that is just middle of 1970 I was thinking
to find nice general synthetic method of all kind of the conjugated alkadienes
because of course as you know in nature we had so many, they are biologically active intermediates.
Such a compound they have this kind of conjugated alkadiene.
But at that time we couldn’t find any successful synthetic method of this kind of cross coupling reaction.
But fortunately we found we can obtain such a compound
by using cross coupling reaction between the binary boron compound and the binary halide.
So not only that, we found many different kinds of organoboron compounds react with a number of organic halide
under such a condition in the presence of palladium catalysed base to give all expected cross coupling product.
By such a reaction we can obtain these expected cross coupled product very nicely.
But today I don’t think we had...
I cannot tell you all of this coupling reactions because we don’t have enough time.
So today I briefly tell you about three reactions.
The first one is the cross coupling reaction between binary boron compound and binary halide
to give expected conjugated alkadiene.
The second one is the cystic reaction of B saturated alkyl-1 compound with alkenyl-halide to give this type of compound.
Finally, I like to tell you this aromatic cross-coupling reaction to give expected all kinds of biphenyl compound very nicely.
So first I tell you the cross-coupling reaction of alkenylborane compound, alkenyl halide,
because in this type of reaction I can point out one of the big advantages.
That is of course as you know we can easily synthesise E-1 or Z-1-alkenylborane compound as indicated here.
This compound we can easily obtain.
For example, when you hydroborate terminal alkyne with diorganoborane
such as disiamylborane, catecholborane to give this type of E-1-alkenylborane compound.
In almost quantitatively leads to high isometric purity.
Similarly we can obtain this Z-1-alkenylborane compound by this reaction by using the disiamylborane or dicyclohexylborane.
By such a hydroboration reaction we can obtain this one.
This one reacts with ... (inaudible 06:35) to give this Z-1-alkenylborane compound,
again in almost quantitatively high isometric purity.
Consequently if we can synthesise we can try such a stereo defined by binary boron compound
with stereo defining binary halide the presence of palladium catalyst.
If the reaction proceeds nicely, then we may obtain all kinds of conjugated alkadiene.
But at that time so many chemists did it to find such a reaction by using this type of cross-coupling reaction
but unfortunately we couldn't find any successful record in those days.
That is the end of 1970s.
But fortunately we found such a reaction goes on very nicely in the presence of base.
So today I first discussed this type of cross-coupling reaction.
But before discussing this chemistry I'd like to tell you
why we considered to try such a reaction in the presence of base.
Here I tell you the reaction mechanism,
the cross-coupling reaction between the organic halide and organometalic compound in the presence of transition metal catalyst.
Such reaction considered to proceed to the reaction pathway indicated in this slide, which involves the system.
First of all oxidated variation or organic halide to this transition metal complex to give this intermediate.
Next transmetalation of this compound with organometal compound.
And Step B to give this diorganometal intermediate.
Finally elimination of this compound may occur to give expected cross-coupling product.
On the other hand as I told you organoboron compound is very inert in this type of reaction.
Why in the case of organoboron compounds so inert?
Initially I considered such a reason should be located at this Step B, transmetalation stage,
because in the organoboron compound this CB bond is considered almost stable covering.
Therefore such a covering should be difficult to contribute at this Step B transmetalation stage.
If such a speculation is correct, I think we may overcome the difficulty in the clearance of ways in such a reaction.
I think 1973 Haaland in Norway reported an interesting paper.
According to their paper this methyl group in trimethylborane has a -4 atomic charge in 0.01 electron unit.
On the other hand this tetramethylborate, this methyl group has a -22.
That means these methyl group has almost 5.5 times more electron negative than this methyl group.
And also we can consider this type of tetra-coordinate organoboron compound.
With this compound we can obtain their complex very easily from this triorganoborane in the presence of base.
Under such a speculation we tried cross-coupling reaction
between the alkenylboron compound and alkenyl halide in the presence of a tetrakis(triphenylphosphine)palladium as a catalyst.
In this reaction without any base in THF, in benzene solution after 6 hours we never obtained any expected cross-coupled products.
However if we added base for example look at this last reaction condition.
In this case we use 1% of tetrakis(triphenylphosphine)palladium
and that two equivalent double sodium ethoxide and ethanol in benzene solution.
In this case only after two hours we found we can obtain the expected product in 86% of product yield.
In this slide I forgot to show you the isometric purity of this product.
But such isometric purity is very high, usually more than 97 or about 99.
That means essentially we can obtain this cross-coupled product in this reaction.
Next slide shows you the representative of such a cross-coupling reaction
between the alkenylborane compound and the alkenyl halide.
Under these conditions we found we can obtain all expected conjugated alkadienes in high isometric purity
which will be shown in parenthesis.
And also we found in some case we can obtain the expected conjugated alkadienes in high product yield.
For example in this reaction we can obtain this in 86% yield.
This we can obtain this compound 88%, in this compound we can obtain 89%.
However, when we use the Z-1-alkenylborane compound
in this case, this case, this case, of course we can obtain the expected conjugated alkadiene in this compound,
this compound, this compound in high isometric purity which will be shown in parenthesis.
However, it is not so excellent in this case only 49%, in this case 42%, in this case 49%.
So today I don’t think we have enough time to discuss the reason why.
But I’ll tell you why in this type of reaction if we use the cis-Z-1-alkenyldialkoxyborane compound
like here we can obtain the result.
For example in this reaction when we use cis-alkenyl-disiamylborane compound by this reaction under these conditions,
we can obtain the expected product in high isometric purity.
But even though it’s only 49 however in this reaction if we use Z-1-alkenyl-diisopropoxyborane compound,
we can obtain this compound in high isometric purity.
And it is also very high, 87%.
Now, we can synthesise all kinds of the conjugated alkadiene by using these types of cross-coupling reactions.
After many chemists all over the world applied this reaction for the synthesis of their target products.
I will show you one example.
This is reported by Professor Coleman in the United States.
They use this cross-coupling reaction for the synthesis of their target product, this compound.
First they tried the coupling reaction of this alkenyl bromide with alkenylborane compound under these conditions
then they can obtain this cross-coupled purine derivative in high product yield.
Followed by the reaction of this compound under these conditions they can obtain target product.
Today I cannot tell you much of this kind.
Many people apply this reaction but I like to tell you one wonderful example
that is reported by Professor Kishi in Harvard University in the United States.
They reported this reaction in I think 1989.
I think 4 or 5 years before they reported this paper I was invited to give a lecture at Harvard University.
At that time Professor Kishi told me they are planning to synthesise this palytoxin.
So big their natural product, very toxic natural product.
According to his explanation, he’s just planning to synthesise this compound by using our cross-coupling reaction.
According to his explanation they intended to synthesise two necessary compounds,
this red upper component and this black lower component independently.
Finally, they cross-coupled such two compound at this position using our cross-coupling reaction.
Fortunately they found this compound very nicely by using our cross-coupling reaction.
Here, in this slide I like to tell you a little bit about reaction mechanism of the selective synthesis by using such reaction.
As I told you in the introduction initially I considered this type of alkenyl tetracoorrdinate borane compound
react with alkenyl halide in the presence of palladium catalyst to give expected cross-coupled product.
In order to make sure such a speculation is correct or not we tried actually this reaction.
And we found we can obtain the expected conjugated alkyne but only 9%.
However, when we tried same reaction using alkenyl disiamylborane compound without this methyl group.
Whereas alkenyl halide in the presence of palladium catalyst and base such as sodium methoxide or sodium ethoxide,
then we can obtain this expected product, very high product yield, 85% yield or 87% yield.
So high product we obtained.
Consequently in order to obtain some evidence of this mechanism we tried some experiment indicated under this slide.
First we tried the reaction of this chloride with tetrakis(triphenylphosphine)palladium, then we can obtain this compound.
Fortunately we can obtain this compound as a pure solid.
We can then purify this compound by the crystallisation.
Next we tried the reaction of this with sodium methoxide by Otsuka procedure
and then we can obtain this alkenyl-palladium-methoxide.
Again we can obtain this compound as a pure compound.
Next we tried the reaction of this compound with alkenylborane compound.
In this reaction without any base at room temperature even after 17 hours, we never obtained expected cross-coupling product.
However, in this reaction when we added base sodium methoxide at room temperature only after hours
in this case after 7 hours we never obtained the expected product.
But this case only after 2 hours we can obtain expected cross-coupled product in 89% of product yield.
Next we tried such a cross-coupling reaction using this compound
instead of that with alkenylborane compound in this case without any base at room temperature.
Only after 15 minutes we found we can obtain this expected cross-coupled product in 6% yield.
If we try same reaction for one hour, this is 50 minutes...
We try this reaction one hour we can obtain this expected product in almost...
Consecutively, we considered in this type of cross-coupling reaction of alkenylborane compound
as you can see here alkenyl palladium alkoxide this compound should be very important intermediate in this type of reaction.
Consequently we considered such a reaction may proceed through reaction pathway indicated in this four step reaction.
After that I proposed this mechanism in I think 1981 or ’82 for our full paper reported in GHGS.
After we reported this paper two research groups, one in Spain and one in Brazil they reported interesting paper
which supported this mechanism.
According to their paper alkenylboron compound react with metal compound like sodium compound, potassium compound
react with the alkenyl alkoxyboron derivatives.
This compound is very big reaction with this to give this compound.
So this is very important intermediate in such a cross-coupling reaction.
The two research different groups support this reaction may proceed as indicated in this slide.
I think I told you previously various alkenylboron compounds
react with a number of organic halides in the presence of palladium catalyst base to give this compound,
obtain this compound in high product yield.
So next we tried the same reaction using B saturated alkylborane compound
instead of B Alkenylborane compound under similar condition.
But we never obtained this expected product.
Why in this case we never obtained this expected product?
Today I cannot tell you precisely about this reason.
But I can only tell you in such a case of reaction using B saturated alkylborane compound
if we use palladium catalyst, this palladium dichloride (dppf),(dppf) means (diphenylphosphino)ferrocen.
If we use this compound as catalyst, coupling very nicely occurred.
For example in this reaction, reaction of iodobenzene with b-oxyl-(9-BBN)
under these conditions we can obtain this expected coupled product oxylbenzene in almost quantitative yield.
However, if we try this reaction by using usual palladium catalyst such as tetrakis(triphenylphosphine)palladium,
we never obtained any expected product.
That is very important to use this palladium compound in this reaction.
And also we found alpha-bromonaphthalene...
react with this compound under these conditions to give the expected product.
And also we found not only aromatic halide, alkenyl halide singly
react with this expected alkenylborane compound under similar reaction condition to give expected product.
After that this reaction using the suggested alkenylborane compound they carried out,
they applied for the synthesis, their target product.
For example Professor Sasaki’s group they applied such a reaction
using b-arkyl-(9-BBN) to synthesise polycyclic ether derivative as you can see here.
First they hydroborate this olefin with (9-BBN) to give this compound.
Without any isolation of purification this compound reacted with alkenyl triphorate
in the presence of palladium catalyst and active base to give this cross-coupling product.
Next they hydroborate this olefin by oxidation with alkenyl hydrogen peroxide they obtained this ketone.
Next they tried the acetyl formation with this compound to give this polycyclic ether compound very easily by using this reaction.
So Sasaki’s group synthesised many very complicated polycyclic ether marine natural products.
I indicated some examples here.
Without such a synthetic method it would be very difficult to synthesise this kind of complex molecule.
Finally, I'd like to tell you aromatic-aromatic cross-coupling reaction.
We first tried this reaction by using benzene boronic acid and this phenyl halide under these conditions.
This reaction is of course as you know heterogeneous conditions.
Even heterogeneous conditions give us expected this compound with high product yield.
So this is synthetic method of biphenyl compound, for the synthesis of biphenyl compound.
Of course as you know we can synthesise such a biphenyl compound by using Ullmann reaction.
Ullmann reaction is a German professor, he discovered this reaction,
Ullmann reaction about a 120 or 130 years, a long time years ago here in Germany.
But by the Ullmann reaction we tried the aromatic halide with kappa powder at relatively very high reacting temperature.
In the organic reaction high temperature is no good to use but in this Ullmann reaction we needed very high temperature,
usually more than 200 sometimes more than 220, so high temperature we need.
But anyway this is only one method of different compound.
Therefore this Ullmann reaction until recently many industry used this reaction for their target product, biphenyl derivative.
However, in the Ullmann reaction there’s another disadvantage
that is by the Ullmann reaction we can synthesise symmetric biphenyl compounds.
Left and right side is the same, this one and this one.
But if we want to synthesise this asymmetric biphenyl compound in such a Ullmann reaction
by using a mixture of two aromatic halides then we may obtain three mixtures of different compounds.
This one, this one, this one.
We never obtained these compounds selectively.
On the other hand, by using our cross-coupling reaction we can,
as you can see here, we can synthesise symmetric purine compound and asymmetric biphenyl compound very nicely.
Therefore... I think I don’t have enough time.
The university’s research group also applies such a reaction for the synthesis of biphenyl derivative.
Not only their chemists are devoted in their academia, mainly chemical industry uses this coupling reaction.
For example recent American Merck company produced this result on this compound, by this coupling reaction.
This is very nice anti-hypertensive.
If you have blood pressure high, we can take this compound, blood pressure comes down.
So that is very important.
Not only about the Novartis company other chemical industry.
For example Novartis Company they also synthesise this Valsartan by using coupling reaction.
Before in Novartis Company they obtained this compound by this way.
This compound as certain material, but in this case they need 5 synthetic steps.
So overall yield from this compound is very small.
Therefore Novartis changed synthetic method.
Instead they use our cross-coupling reaction.
Only one step reaction, they can obtain this compound very high product yield, very high isometric purity.
And also not only the pharmaceutical industry, you know, agro-chemical industry produce the agro-chemical.
For example BASF they produce these Boscalid by this cross-coupling reaction.
And also recently Bayer Company they synthesise this compound using this cross-coupling reaction.
Bayer people say they produce this compound in very high productivity, very high amount.
The multi-100tonne product they produce this cross-coupling reaction.
And not only that recently many chemists use such aromatic-aromatic coupling reaction
for the production of a liquid crystal as indicated here.
Or most recently many of chemical industry applies such a reaction for the production of every day materials as indicated here.
I only show this here but many industries use this cross-coupling reaction.
So finally I don’t have enough time so finally I tell you advantage of acid reaction.
But I never tell you this reaction, our cross-coupling reaction is one of many clean or very green chemical method for synthesis.
If you feel interested in this reaction, in the near future if you try this reaction for the synthesis of your target product.
I'd be very happy.
Thank you very much for you kind attention.