We are excited to announce that
our paper “Alkyl-(Hetero)Aryl Bond
Formation via Decarboxylative Cross-Coupling: A Systematic Analysis” (in
the following referred to as the Guide)
has today been published in AngewandteChemie International Edition!
I joined the Baran lab as a visiting student around six
months ago. When I had my first meeting with Phil, he had two important
messages for me. First of all he introduced me to the project and one of the
things he showed me was the sales statistics of N-hydroxytetrachlorophthalimide (TCNHPI). This reagent was
commercialized as a typical activating agent used in cross-couplings of
redox-active esters. Impressively, all major pharmaceutical companies world-wide
could be found in the list of buyers – RAE cross coupling was already being
applied broadly and its adoption was proceeding at blistering pace less than a
year after the invention of this reaction. At this point four different
reaction types had been published, and we were using several different RAEs and
various procedures for their generation. We had gathered rich in-house
knowledge by that time and after running thousands of reactions my lab mates
and I had developed a "feeling" how to get almost any substrate to
work. As we did not want it to be lost forever, we were asking ourselves how can we pass this valuable information on
to all the chemists out there? The answer was rather simple – we were going
to create the Guide.
Owing to my German origin Phil's second advice was rather
practical: American highways are not the Autobahn,
and if I was speeding I should do it carefully - "there is a science to
speeding!"
Starting to work in the lab I was certainly not lost in time
and space, but still in need for the friendly advice DON’T PANIC. There was a maze of four publications with more than 900 pages of SI and more
unpublished material in front of me. The first challenge was to get an overview
of all the published and unpublished procedures, and to arrange them in a
simple and clear manner. Our team developed a matrix chart, in which four
different catalytic systems are fixed on the x-axis, while four different modes
of activation are fixed on the y-axis giving a total of 16 different procedures
(Figure 1). Combined with a visual identification of the success of the
reactions by a simple color code the Heart of the Guide was born.
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Figure 1. a) Activating
agents, nucleophiles and catalytic systems in RAE cross-coupling. b) Simple
classification combined with visual identification.
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Next, Matt and I selected nine different substrates covering
a broad chemical space. The Guide
offers a selection of variously functionalized primary, secondary and tertiary
carboxylic acids including α-amino
acids, heterocycles and bioisosteres (Figure 2a). Each of these substrates was
subjected to our 16 different reaction conditions and the obtained data was clearly
arranged in a one-page table (Figure 2b). Looking at the number of red squares,
we were definitely exploring the edges of our methodology here…! However, in
each case we found at least one set of conditions to yield the desired product
in more than 60% yield! This underlines how being able to fall back on many
different conditions combined with a Guide
can be a real asset when tackling challenging synthetic problems!
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| Figure 2. a) Selection of substrates for b) the Guide. |
In the second part of my stay, I tried to expand the scope
of the Guide to new areas of RAE cross-coupling. What we were really
excited about was applying more heterocycles in our chemistry. At this point we
had mainly explored the nature of the alkyl carboxylic acid, as previous
investigations suggested that the influence of the aryl nucleophile on the
reaction outcome was rather small, except
for heteroarenes. After some experimentation we discovered that methylpyrazole
magnesium bromide undergoes simple Fe-Kumada coupling in synthetically useful yield!
Encouraged by this result we decided to widen the scope of our Kumada, Negishi
and Suzuki couplings to medicinally relevant heterocyclic nucleophiles (Figure
3).
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Figure 3. Heterocyclic
nucleophiles explored in the Guide.
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Except for furan and thiophene all of the heteroarenes explored
in the Guide contain basic nitrogens
(“real heterocycles”). Searching the literature
for instances where these heteroaryl nucleophiles were used in cross-coupling
reactions revealed what we had already suspected: despite their importance in
medicinal chemistry and other chemical industries cross-coupling of N-heterocycles is severly underdeveloped.
During our investigations we found that the best choice of method for RAE cross
coupling is strongly depending on the electron-density of the metalated carbon
atom. While electron rich heteroarenes easily undergo Fe-Kumada coupling,
Ni-Suzuki is the best choice for electron deficient heterocycles.
Interestingly, we observed 2-pyridyls to be most challenging with our
methodology. While the 2-pyridineboronic acids are known to be unstable, Kumada
coupling turned out not to be feasible either. We think that the homo-coupling
byproduct (bipy) is the culprit and deactivates the Fe catalyst. Fortunately,
we could solve these issues by applying a modified Fe-Negishi protocol.
A good guide should provide you with overview and main
directions at a glance, but also with detailed information where you need it.
That’s why we have put together a Supporting Information which contains clear, exact
and easy-to-follow experimental procedures to make the application as
straightforward as possible. Besides graphical descriptions of the reactions
and detailed characterizations of the products, our Supporting Information includes
an overview of all reaction conditions in one scheme (Figure 4). We were
delighted that this important part of the
Guide was also acknowledged by the referees:
“The supporting information is of high quality […]”
“The Supporting Information, to the best of my ability to determine, is
spectacular, and includes pictures detailing each step. Only a full-length
motion picture could be better. The products are adequately characterized and
look pristine.”
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Figure 4. Overview of all 16
different reaction conditions.
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Unfortunately, Angewandte did not print the words DON’T PANIC in large and friendly letters
on its cover, but I still hope that the Guide will help
many organic chemists to find their way through RAE cross-coupling – in our lab
it already finds regular application.
Fred and the team of the
Guide
We apologize to all
those who expected 42 to be the answer to everything – we could at least
confirm it in three cases.
