okay to star max
okay good morning everyone uh this is
the final installment of general
reactivity
and um probably the most important from
the standpoint of substitution
in the class of heterocycle that you
will most often be substituting
that is pyridine so we talked a little
bit about electrophilic aromatic
substitution on a purity and in general
that requires some sort of electron
donating substituent obviously
to quell the nitrobenzene-like
activity of pyridine and make it more
sort of active towards that kind of
attack but in general
pyridines are going to be less electron
rich
you're usually not going to have amines
on them or hydroxyls on them
and often you're going to have nothing
at all
and in those cases you're going to need
to think about
things like deprotonation so
nucleophilic attack
on hydrogen and so most of this lecture
is going to cover
a lot of the dazzling things that can
happen when one starts to try
to deprotonate ch atoms on
a pyridine okay so let's talk about this
thrombin inhibitor
reported in this murk paper back in 2004
and to start us off uh sunghan will give
us the three building blocks or the
three
general disconnections that might be
applicable to make a compound like this
so there's three things hiding in here
sunghan can you give us a couple of the
building blocks
i think first i will cut the mi bomb
that the amide bond is a phenomenal idea
um
and that's going to give us um a
fragment here with a
let's say an acid or an ester what's
another bond that might be strategic in
order to break
the other i guess i will cut the
sp3 carbon nitrogen bond
yeah you can imagine cutting either here
or you could also imagine cutting here
these folks chose the latter because
it's easier to do
a snar reaction into an intermediate
like that
so first let's get our amine fragment
and then let's take a look at our
prazonone fragment
and you can imagine when you treat this
with poco3
or you could even use something like
eyebrow you can imagine it's easy then
to do a selective displacement on that
halide or activated oxygen atom
because this one is next to a kind of
pyrrole like nitrogen and this one is
next to a pyridine like nitrogen and so
you should get
nice snar selectivity as we talked about
last time
so now you'll notice and recall that
this class is divided into
medicinal process and radiochemists
we'll get to the radiochemists a lot
eventually but for now
we'll start off with a cage match
between ellie and carter
so ellie is a medicinal chemist and
carter is a process chemist and
um if we need to make a what might be
a good precursor to a
uh either ellie or carter can start us
off in thinking about
oh sorry the n oxide oh
ellie is a real medicinal chemist
and what else do i put on the ring
um well you still have your your
flooring from before
and then uh you could add like
um
oh uh you could add some like maybe tns
tms cyanide and then do like a nitrile
reduction
that sounds brilliant mini doge coming
your way
ellie thank you so carter uh
you're a process chemist so ellie has
now given you this uh background that
she's used to make a million analogs
um but you notice there's something
wrong with that sequence what what are
the
some of the things as a process chemist
you may say not really liking that route
that you use in medcamp
um i suppose you could have some
minor regio selectivity issues
so for a medicinal chemist remember the
only the only
yield that matters is enough for
biological testing
okay it's like get that in your mindset
and the realization that um
yields and mixtures as long as they can
be separated
not a problem you just want to get to
your biological question
as fast as you can it's not about
elegance it's about modularity and about
getting the product quickly
that's what will get you promoted in the
medicinal chemistry department
but in the process chemistry department
you have to pay attention to the weeds
and the little needle in the haystack
here is that three percent regio isomer
and that's a big
problem so we can't do that
anything else carter that you don't like
about that route
uh i guess maybe large-scale cyanide
yeah big problem on large scale we want
to probably avoid that
and every time you make an n oxide
you're going to want to evaluate it by
uh
dsc to make sure it's not an energetic
and it doesn't have a
you know some sort of explosive event at
a certain temperature and so you'll need
to pay attention to it and oxides are
used all the time in process chemistry
it's not like you need to avoid them
you just need to be cognizant of the
fact that there may be an issue you need
to evaluate
so pretty much all three of these things
make it a non-starter
so carter any ideas of where we're going
to start
to make this compound let's assume we
can still
commit ourselves to the fluorocyanide as
a good precursor
but from a process standpoint what might
be a better way to do this that avoids
an oxide
and avoids tms cyanide or any cyanide
source whatsoever
um i suppose we could leverage the
fluorine as a
directing group and deprotonate alpha to
the purity nitrogen
and then quench it with
um i suppose you could do
with co2 and then reductive uh emanation
brilliant carter that was excellent so
we're going to take advantage of the
fact that we can do a chc protonation
we can accomplish that with high
regiochemistry
we'll explain why in just a moment we
can quench that with co2 and then
although it's more steps in the
medicinal chemistry route they're all
crystalline waypoints they're all safe
it's all dump and stir chemistry and it
can all be telescoped
and so that's what makes this a great
process route but from the standpoint
of a medicinal chemist obviously this is
not as good of a route
i will get there quicker with ellie's
route than i will with carter
but when i need to make metric tons i
definitely am not going to do what ellie
did
but both are great ellie gets a
promotion in medcam and carter gets a
promotion in process but if the two
switch roles
they both get demoted
okay how do you know when things are
going to deprotonate and where
well carter pointed out that he could
get deprotonation
and put a lithium here but you could
also argue well why didn't he get
deprotonation here
or why didn't he get deprotonation there
it certainly could be a confusing topic
well in general if there's a pyridine
that has no substitution whatsoever
all of them are just protons for now you
can imagine
that you could get deprotonation here or
here so what guides a selectivity
well what guide to selectivity is a
kinetic or thermodynamic preference
in general the thermodynamic outcome
is going to be c4 deprotonation and the
kinetic
is going to be c2 and the reason for
this
is because of the lone pair you've got
on the nitrogen which serves as a way of
docking the metal it kind of attracts
the metal
brings it there into proximity and then
a deprotonation happens but if you give
it a chance to think about it
obviously there's going to be a lone
pair repulsion you've got that lone pair
and you've got that anion right there
and if it has time to think about things
he's going to say wait a minute
i don't that was a mistake to do that
i'm really not happy with the situation
let's move it to something further away
from that lone pair and so the
thermodynamic outcome
that results from let's say a higher
temperature or letting it equilibrate
for longer
uh will give you uh more of the
thermodynamic outcome versus the kinetic
now how do you control
one versus the other well you can
control this just by changing your base
uh for instance if you use like dually
julie might give you more
lower temperatures of the kinetic
product whereas if you use something
like lda
you might get more of the thermodynamic
product
so what happens when you start adding
directing groups so let's take for
example the case of
that compound
or that compound in the case of
4-fluoropyridine where is the
metallation going to go well
the fluorine is a great directing group
and so it will direct
adjacent to it in the case of the one
that carter just went through
you can imagine conditions to give you
either one here based on kinetic or
thermodynamic preferences
in general though you'll almost always
get the c2
deprotonation of the 3-fluoropyridine
and what about the case of this one
not surprisingly that's your exclusive
lithiation product
let's take a look at the book on page
20.
this is summarized really well the ways
of getting
c2 parietal anion versus c4 prudel anion
through this chapter there is a
discussion of
how you can use the innate preference of
a pyridine
to give you selectivity in the
lithiation or chd protonation step
and there's also a discussion of halogen
metal exchange
so let's say you've got a poly
halogenated compound
how do you know which is going to
undergo this the
halogen metal exchange and we'll talk
about that um
in just a moment that's really important
and then what about the effect of the
directing group
the important thing to remember in this
page is the
relative sense of directing group
capability
even halogens can act as weak directing
groups not fluorine but things like
iodine bromine and chlorine
and then there are some very strong i
call them sneakers-like
directing groups that are really really
good for instance the
nh bach on a pyridine is a great
directing group for lithiation
and in terms of selectivity that is a
result of these the directing groups
always win over the nitrogen so the
nitrogen in a pyridine
is not a great directing group you can
use it to control
relative kinetic or thermodynamic
deprotonation
but if you've got a directing group
that's where your eyes should go
focus on that when you think about the
selectivity
okay so let's think about how
these ideas can contribute to the way
you do retrosynthetic analysis when you
use substitution
as your primary vehicle to make a purity
let's take a look at the bottom example
and perhaps uh
can explain to us why this is strategic
but this is not strategic
yeah the the left-wing is strategic
because it's
reasonable you can use the directing
you can use the fluorescent group and
the iodine alignation institute together
c3 iodized compound okay
great and why is the one on the right
just not feel right to you
uh that's
really uh i don't know how to put a
fluoride on parroting so it might be
uh you could use you could deprotonate
and use nfsi
for example nfsi would do it okay
so but why why i'm trying to yeah i'm
trying to understand
how your intuition guides you to that
one
on the left rather than one on the right
as a viable disconnection
um it's a chemo selectivity
thought i think yeah you know that's a
good point so
if you take three iota purity and you
treat it with a let's say a base
like bully you have to worry about
halogen metal exchange taking place
before
you know any kind of direction takes
place if you do lda
lda now is just one where it's like okay
you've got the choice between
this position and this position it's not
a fantastic directing group iodine
and so the one that feels right is the
one that gives you
no ambiguity as to what is going to
happen
the best consulting suggestions you can
give to a person
are ones where it's unassailable there's
no ambiguity
and so if you tell someone to make this
compound via three iota pyridine
there's a lot of hand waving and on um
and a lot of reference is needed
if i give you the one on the left though
there's no ambiguity nobody argues with
you you know there's only one result and
that's why that's strategic
now you can take this concept even
further and think about
functional group retrosynthetic priority
which is
something we came up with many years ago
seeing this over and over and over again
and this is the retrosynthetic priority
that
guides you to which disconnection should
be made early on
that is which ones should be installed
and which one should be
installed late meaning normally which
ones are you going to buy
so you're normally going to buy
pyridines it correlates really well
with that have these groups already
installed and normally these
as you get to the middle and towards the
end these are things you're generally
going to install
late in the synthesis and so that's why
they're disconnected retrosynthetically
at an early stage let's take a look at
how this can work in the context of
problem of the day number one
there's a question from the outside so
let's hear it from max i just want to
clarify that
when you have c3
if you have a seat the question from
outside is if you have a c3 directing
group how to get control and so
the strategy one would use is trying to
it's really hard to overcome
the c2 in the case of c3 fluoropyridine
but what you would try to do is use
equilibrating
conditions higher temperature and
that would usually guide it away or at
least give you mixtures guided away
towards more of c4 versus c2 but those
are the kind of strategies one will
employ
the directing group lithiation
literature is replete
we've tried to summarize a lot of this
in the
um in the book here but as you can see
those are the strategies on in table one
that you would normally want to try to
uh use to get uh that kind of
situation so as you can imagine the c4
parity antithermodynamic
you want longer reaction times a little
bit higher temperature
a solvent like thf maybe people use
additives as well whereas the c2 parity
land ion
you'd want to use maybe a base like
bully uh
and a non-co less coordinating solvent
and you know much lower temperature
short reaction time so it doesn't have
time to think about
the situation so that table is a good
guidance to give you
the idea of what conditions you should
start off with and trying to control it
so yeah great question from the outside
so for problem today number one we need
somebody to identify
a unified starting material that can
give us every isomer
of that acid i mean think about how
powerful
that is to be able to start with one
starting material and access
all four isomers of this compound
let's see if there's any volunteers to
take this one if not i'll just call on
someone
i'll jump in here all right what do you
say alex what's my starting material
first off
um a two fluoro pyridine i think could
get to all of these
all right so how do i take two floor
pyridine and go
from here to here so that one's simple
because you can just do
uh a directed lithiation and then throw
in
carbon dioxide yeah all right good good
now well now what do i do about this
next one
so that one i guess
like if you can block the three position
so throw uh throw like a chlorine on
there
and then you can do your directed
lithiation and then
you can get rid of that chlorine
and you already taught us how to make
the chloro
it comes back from there brilliant now
what
how do i make this one so
you could do the same sort of thing and
you can chlorinate
in the three and four position and then
that'll
let you put the exactly where you want
um if you put a larger
um like kind of
blocking group so if you put tms
yeah that would be better normally
people use silanes here as
great blocking groups and then when you
do the lithiation
um you can get selectivity for here but
the problem is you're also going to get
a lot of competitive
uh deprotonation there so
in this particular case one would
choose the route you've shown to avoid
any ambiguity at all
okay uh and
so how would you make that last one and
then kind of the same sort of idea
you can i guess put the chloro group
first and then put a tms group
they'd like the tms ending up in the
four position
or you can do it opposite tms first and
then the chloro and i guess that would
be
better
why might this be a less desirable
strategy
um well you have the tms blocking the
four position but i'm
i mean you also have the chlorine
directing so i don't know
yeah there could be some there could be
some ambiguity there at the end of the
day
it might just be you might find that
this approach works just fine to make a
compound like that
but um you know i think this approach
that you've outlined with the tms
blocking there gives you no ambiguity
whatsoever
you're pretty much guaranteed to get the
right product with that one
fantastic uh how would you do the uh
dechlorination
just palladium on carbon because there's
no other offensive group there
inflating on carbon hydrogen or formic
acid and you'll get rid of those
chlorines right away
great great question nick let's take a
look at
a vivid display of this in action with
uh a case study two
from the pcc book
so case study two is
how to make this interesting little
natural product
from a substitution series of events
uh now retrosynthetically we can
obviously bring the auxin back
to the corresponding aldehyde we then
have two choices
we can imagine that aldehyde comes from
a halogen metal exchange quenching with
dmf
followed by a suzuki coupling or suzuki
coupling
followed by halogen metal exchange and
dms either one
leads you back to the dihalo
intermediate where we have to recall
our lecture number two on halo
selectivity
and hopefully we'll have a good halo
selective way of
accessing one or two of those isomers
but retrosynthetically it makes sense to
take that risk
and believe that you could differentiate
those two groups
that comes back to the dihalo
intermediate you see here
and leading us back to finally three
hydroxy pyridine
in the forward sense let's go through it
so you take that three hydroxy pyridine
you
per iodinate it it goes to the para and
ortho positions
in high yield you then protect that
phenol with a mom
with mom chloride and that is a
phenomenal directing group
so that mom group then can be used to
do with just with lda or latmp a
hindered amide base
give you the anion which can be quenched
with trimethyl borate and then oxidized
upon work up with per acetic acid to
give the hydroxyl compound that can be
subsequently methylated
and now take a look at what they do
they use the directing a group ability
of the mom
to get exclusive lithiation
at c2 they then take that c2 lithiated
species transmetallate to the zinc
and then do a negishi reaction and after
acidic workup
the mom group gracefully departs
following a
quick uh halogen metal exchange in the
presence of that acidic proton we'll see
that again later
halogen metal exchanges take place near
diffusion control and can be done
in the presence of acidic functionality
quenching with dmf gives the aldehyde
and then finally condensation with
hydroxylamine gives your natural product
any questions on this route
okay let's move on to another case study
where we have to think about this
interesting uh
three heterocycles linked to one uh
intermediate shown from this pfizer
paper in oprd
so we need help with uh
interrupt before you start um how
can you make the determination between
um
halogen metal exchange versus getting
directed lithiation
my rule of thumb is like this if you
want to get halogen metal exchange
put secularly or bully over the arrow
if you want to get if you want instead
to the halogen to just be a bystander
and act as a directing group
use lda as over the arrow now the actual
conditions when you go to sci finder
might be oh it's better to use litmp
or whatever but it'll be a hindered
amide base that's how you ensure
that you get no halogen metal exchange
okay
okay thank you good question all right
so we need some building blocks we need
uh to think about how to put this
together
in a modular fashion uh what might be
some good disconnections we can make
camille any initial ideas or thoughts on
disconnections for a compound like this
um you could
disconnect um between the pyridine
and the aniline love it
so that's a great disconnection and
as a result we can put down
that indole as our donor
it means that something will be left in
its wake uh
what do you think that will be left in
its wake
what is a good group here that would be
activated towards some sort of addition
um
you could have an electrophile
great so let's just put x here it could
be chlorine for example
great okay another bond which might be
worth
considering the disconnection of anyone
have an idea of how to simplify this
the error bomb the aerobond brilliant
okay so that gets us back to a couple of
simple intermediates
and um
that's that one and we will use
that's the name in a silly coupling so
the sequence of events will be
silly coupling here and snar reaction
there
great let's take a look at how they made
compound b
so compound b is subjected to triethyl
orthoformate and meldrum's acid
which gives us an initial adduct that
looks something like what
brendan any ideas
um so i guess the uh the amine and the
melodramp acid can be
merged together through uh to the
enamine um
well what happens with meldrum's acid
and triethyl orthoformate
uh those are gonna condense
and then i guess the amine can can
attack
yep and then the amine just comes in
from the enamine
and then we're going to heat that thing
up to 240 degrees and the resulting
product might be what
we'll retain our thiophene um
so i guess it's going to decarboxylate
and then the thiopin can
can attack from its c2 position
to form the what will be the
uh intermediate the core of intermediate
b
after we treat it with uh poco3 and then
yeah do the
so plco3 is going to take this and turn
it into the chloropyridine
yep and then buly is going to
deprotonate right here and quench iodine
and we get out
our desired iodo product brilliant
why did the lithiation go there stay
tuned we'll talk about in just a minute
right here is where we're going to talk
about it so in general you might be
wondering
what is the hierarchy of chc protonation
within heterocycles
and if you have a pyrrole-like that is
a very acidic position but z
cannot be a free nh because you get that
so if you try to take pyrol and treat it
with bully
and expect to get c2 lithiation we've
seen that in past
years and tests you're not going to get
any product you're just going to get
deprotonation
it makes it impossible to deprotonate
that
so so please don't do that z can be an
oxygen maybe a sulfur we just saw
benzothiophen a second ago
those are really fast these ones we
covered i think alex
covered these problems already when we
talked about stetter we talked about
dondoni
that ch bond becomes really really
acidic
okay and then finally you've got the
pyridine case
now you have two possible scenarios in
the case of purity
you've got the case of regular pyridine
and let's say you've got the case of
an imidazole where you can recognize
that is a purine like nitrogen however
that pyridine like nitrogen with respect
to deprotonation
is a bit different than the one in the
six-membered array so
the six-membered ring is slower because
of a lone pair repulsion
you can imagine geometrically that lone
pair
is closer to that hydrogen whereas in
the five-membered ring for geometry
reasons
it's splayed out and so there's actually
lone pairs are actually helping to
acidify
that position and there is not that kind
of steric clash
between the lone pair and the metal
because it's kind of tied inward
so a five-membered pyridine nitrogen is
going to be faster
than a six-membered pyridine nitrogen
and that explains the selectivity
we just saw right here does everybody
get that
fantastic well let's take a look we're
not done with that compound we still
need to figure out how to make compound
a
so how might we do this based on what we
just talked about
we need to put a tin needs to go there
so any suggestions
um you could deprotonate the pyridine
like nitrogen
uh the pyridine-like proton and um
essentially block it and then
deprotonate the parole type position
and then put a quantity tributal think
chloride
okay nora that's a really good
suggestion and the question i have for
you is based on the rules we just saw up
here why would you say that one's going
to be
faster than this one i would assume it's
more acidic
uh because it's a in an election more
electron-deficient system
well as it turns out it can't be
controlled and so when you treat this
with buly and t-meter and hexane you
actually get the dilithio species
we're going to be stuck with that nor so
stick with me we're then going to do
what you just suggested which is use
tin chloride we're going to quench it
and we make this compound and i want you
to tell me
based on the exact logic you just used
and what we talked about in lecture one
and two
how might we convert that to a
i guess you can um
i'm thinking something along the lines
of
snar type yeah you got it so you know
what
how about just add water and you get a
uh proto-d
and that brings us to a little
interesting topic that is seen often in
the
modern uh medicinal chemistry era
which is the curious case of
these types of suzuki reactions
which one do you think is going to be
easier and why kelly
um i
think the top one is going to be easier
because
i guess based on the fact that
when you consider a puritan like
nitrogen that's the
most reactive site
so this one looks a lot more like
phenylboronic acid in a sense right
and what might be the problematic part
of using that
with the suzuki conditions which usually
involve some hydroxide presence
uh
can you get reaction at the three
position
on that one well in this case when you
treat this with the conditions of suzuki
that are hydroxide like
we're going to see the same thing that
nora just suggested a moment ago with
the c2
proto-d-stenolation the main often the
main product that
beleaguer's medicinal chemist is
proto-deborah lation
and so a whole cottage industry of 100
different papers have come out to try to
solve this problem
there are many different solutions to it
for instance one
is to use a protecting group for the
bronic acid like a mida or dam group
another some people have shown that a
trifluoroborate can be more robust
another is to use copper chloride as an
additive
there are a lot of different papers out
there my favorite is the copper chloride
condition
of merck if you're in industry now and
you want that paper
max can send it out to your tucker later
on but that's usually the way that
people solve this problem
of the c2 c3 dichotomy
in suzuki couplings now let's move on to
this interesting example of a
free nh imidazole so when we take this
and we treat it with
bully what do you think happens based on
what we just saw
in the previous example nathan any
suggestions
uh would you alleviate the position
between the two nitrogen
and then you add into the carbonyl
anybody disagree with that
shouldn't it just deprotonate the
nitrogen and then it's
dead to lithiation
uh any other suggestions lithium halogen
exchange
that's rather daring to suggest
so you want us to believe we're going to
do a lithium-halogen exchange
in the presence of that nh
anybody agree with that one
it's all about the hierarchy of rates
so when we treat with something like t
bully
t bully is going to have a voracious
appetite for halogens
halogen metal exchange with something
like tbuli or sexually or even bully in
a case like this is going to take place
as i mentioned before
with diffusion control we saw this in
the case of cyrillomycin case study
number two that we just covered in the
pcc book
we had a free phenol and we were able to
do a lithiation uh halogen metal change
of a c2 bromo purity in the presence of
that free hydroxy
same thing goes here just what uh i
don't i don't know who said it but
um whoever that was get some dosh going
this is going to happen first very very
quickly and then quench it
before even deprotonation can happen in
fact you can get halogen metal to
exchange
to happen even in something like
methanol
before deprotonating the methanol it's
that quick and
one of the slowest processes is going to
happen is is the c2
lithiation definitely deprotonation
would happen
before that would happen and i don't
know how you would actually get that to
work without using some sort of
protecting group on that nitrogen
because if you use something like lda
all that would happen is you deprotonate
the imidazole questions
hey phil yeah how does this change if
the bromide was instead
a chloride oh that's a good question in
that case
because the rate of chloro in a case
like this
i believe that you would just get
deprotonation could be wrong we can look
it up
it's a good question there carter but
things change quite a bit when you go to
chlorine
definitely not a good halogen for a
halogen metal exchange you usually need
very specialized conditions to get
the chloro to react with like a bromo or
iota but that's a great point
please don't put on the test chlorine
atoms that are then treated with julie
and convert it to lithium
and if you have uh oh yes right go ahead
yeah so would that mean
in the case of if you had an iota group
would it didn't have the theme palace
exchange if you had in bully in that
case
or deprotonation aaron you said what if
we had iota instead of a bromo
yeah would you have would you extend
deprotonate within building or would you
still have lithium pilots in exchange
exactly what you just said you'd still
have lithium halogen exchange and even
faster
yes iodine even faster bromine super
quick
chlorine fluorine dead
so can you distinguish if you have both
iodine and bromine can you distinguish
between them
yeah yes i've seen people do that you
can
okay yes okay so based on what we just
saw then the obvious product when we
treat this oxazole
with uh beuley is going to be
what
lithiation between the nitrogen and the
oxygen
what if i told you that none of this
product was formed
you'll have fragmentation in fact
yes the product that you form
is this scary creature
that goes by way of this intermediate
which is then quenched with tms chloride
so in order to avoid ring opening uh
the late ed veris invented a really
brilliant method that allows you to
overcome this problem by adding an
equivalent of boring
this is a phenomenal trick to use now
this ring opening process is
stopped and so if you first add boring
and then you deprotonate
you can get the exact product that you
said initially
questions on that great
let's get the problem of the day number
two which sets the stage for
perhaps the most confusing part of
lectures one through three
so problem of the day number two takes
intermediate interesting
iodinated aryan treats it with lda the
iodine has somehow
moved around and somehow that carbamate
has now made a carbon-carbon bond
so some weird stuff is going on here
something mystical perhaps
we need a very deep thinker to try to
guide us through this
maybe maybe taway
and if taway is not on the line you know
okay what do you say that way
uh
first tell me uh what do you think this
is good at doing
uh i think it's a protecting group of
a high gossip group okay but it's a
weird one isn't it
yeah and what do you think it likes to
do when it sees a metal
i think it would coordinate with lithium
and it helps
the iodide to eliminate
okay so one possibility is that it
accentuates the ability
of halogen metal of change to happen
what's another conceivable outcome
oh it would
any any thoughts on what might happen
uh
the nitrogen would coordinate with
lithium and the lda would
deprotonate the alpha proton
brilliant so we're going to get a
lithium here
chlorine and now we've got that
now you need to fight try to guide
everyone here to how we're going to get
this strange
product at the end where the iodine has
somehow magically moved over
maybe the the lithium
iodide exchange product is more stable
thermodynamically
i like your background music by the way
oh
nice we should have you leave that on
all the time
you know in past years we used to teach
this class with the music behind
and that really helped me my train of
thought but i don't know if that's gonna
work over zoom anymore
okay so you're suggesting that the
lithium goes here
and you're absolutely right but the
mechanism by which it does this
is really really interesting so the
first thing you said when we started off
was
you said this is going to do lithium
halogen exchange correct
yeah lda is a really bad way of doing
that but guess what is a good reagent
for that
something like phenylithium so we'll
label this compound as
a and i'm going to react it with
compound a and i'm going to make
this compound which i guess is the same
as that one along with
a small amount of this compound
you see how that happens uh is the
is the left one
is the iodine should be lithium
uh oh sorry yeah you're right thank you
oh
great that's right so when you treat
this with a
you're going to get exactly what you
first this was your initial suggestion
fantastic and that's going to give you a
little bit of
of this compound plus this compound now
i have a choice when i'm taking this
compound that's been generated a little
bit of this guy and a little bit of this
guy are together in a room
it's going to say well which iodine is
going to be the better one to do
the halogen metal exchange and the rules
you use for chc protonation are the same
rules you use for halogen metal exchange
in a poly halogenated species there's a
directing group here
there's a directing group here that's
the one that goes well this one's more
active
yes and then finally the sequence ends
with an anionic freeze rearrangement to
give you the product
yeah and this is known
as a halogen dance so
the apparent product is a halogen
migration
but how it happened is via the
intermediates you see here
we're going to spend a lot of time in
halogen dance so if this is confusing to
you don't worry it should be it's
supposed to be confusing
but hopefully by the end of this little
20 minute diatribe
it no longer is confusing if i've done
my job properly
okay let's dance so if we take
uh a 3-iodo 2-fluoropyridine and we
treat it with something like
ah we can just use n-buly that's fine
and we treat it with n-bully what are
some of the things that might happen
um how about daniel anything you say
could be right here
um i would think
lithium halogen exchange uh but
uh no but why are you butting given
given the halogen dance i would think
deprotonation would happen at the fourth
position as well
or is likely to occur
lovely
now uh what can happen next by analogy
to
problem of the day number two we just
talked about what could happen
this now takes the role of
a strong metallated lithium species that
can do
another halogen metal exchange can't it
uh so you would react it with the
starting material to form the
diiodo species
as well as
the uh lithiated
product at the at the three position
exactly so yeah yeah b um
[Music]
and now we have b floating around don't
we the compound you initially suggested
what is b going to do to a species like
that
uh halogenating at the three position
of the dye iodo yes yes yes
why did you choose to go there
um
is it more kinetically favored or
it's everything favored because you have
two directing groups here
and here so same rules you use for chd
protonation with regards to directing
group i want you to do the same thing
with regards to halogen metal exchange
okay are there if the fluorine could be
replaced with another
stronger directing group could you get
immediate lithium halogen exchange
from the starting material
or like is this yes yes say yes exactly
we're going to get to that so let's say
i quench this with co2
that's my product just so you have a
real what a real product would look like
from this reaction but what you're
asking
is the next topic which is how do you
control the dance like
it's kind of annoying if this happens
when you didn't want it to happen isn't
it
right so let's talk about that luckily
there's a whole section in the book on
it
so yeah those types of pyridines
eliminate to form
uh pyridines or like a peptide they can
under the right conditions but
what we're going to be talking about now
is how to avoid
and how to propagate a halogen dance
uh reaction so here it is in all the
gory details but we already went through
this
so um there's prototypical examples of
how a halogen dance can work
um we'll go through it again for the
example we just saw
we treat this with some sort of
lithiating agent
i'll get to which one is a good one to
use in a moment
it gives you a directed lithiation at
the adjacent position to the x
it then reacts with another molecule of
starting material to
essentially give a disproportionation
where you now have uh
the dihalo intermediate and the starting
lithiated the apparent product of a
halogen metal exchange
now that compound can act as its own
halogen metal exchange reagent
reacting again with that dihalo
intermediate to give you that product
which after quenching
gives you the appearance that the
halogen
has moved over but
let's look at a case where halogen dance
won't work remember
halogen dance is guided by
thermodynamics it will
only happen if it's going downhill it's
like a radical reaction
a cyclization you only want to go to the
thermodynamically more stable product so
the bottom example is one where
you're likely not going to get a lot of
halogen dams because you do your
directing
your directing group does its halogen uh
its deprotonation chc pronation but
there's really no got there's no driving
force for
the formation of the product uh
that is that is halogen halogen dance
because the product is less stable than
the starting material and instead
the only product that you see is the
product of a simple
chd protonation with no dancing to occur
so the dancings do not go uphill
the dancings go downhill how do you get
a dance to happen
and how do you prevent it from happening
well to promote
halogen dance you want to use something
like low temperature
that makes sense you don't want an
excess of base often to
extend to propel a halogen dance people
will use 0.7 0.8 equivalents of base
you want to add the base to the halide
so you can propagate the cycle to make
that dihalogenated intermediate
you use a solvent like thf and you want
to use a slow reacting electrophile like
co2 or dmf
or tms chloride
whereas hd prevention atmosphere may not
be a good one by the way
stick to co2 and dmf hc prevention would
be higher temperature
excess of base so you can't get the
propagation of the cycle the addition of
the halide to the base so you
never can get that trihalogenate
dihydrogen intermediate
a solvent like thp and a fast reacting
electrophile like maybe
iodine for example
um okay so let's go to more examples so
that
the concept gets driven really really
strong why does
why does lower temperature favor the
current in dancing
at higher temperature this is sort of a
um
because you want the propagation to
happen so this intermediate step that's
going on
right here
the intermediate step of this
propagation happens at low temperature
at higher temperature you're likely just
going to get
an immediate um rather than the
propagation going on in this
in this middle section you'll get an
immediate simple quenching of the
initial
methylated intermediate at higher
temperature it will just sticky so
it will just get trapped yeah right okay
yeah thanks
okay let's take a look at this
difluorinated
pyridine and i want you to try to help
me find conditions to make
all three possible iodinated materials
so i want to put an iodine at all the
arrows provided
so who can help us do this what would
happen if we just started off with
lithiation so uh maybe stone can help us
with this
what's the sort of easiest ionated
product to get
uh c4
all right that one that one's a a
freebie do we get the next one over
could you take uh your product and then
the theater again then you'd have
halogen dance
uh the c5 position
what would be your quenching reagent
uh iot no just a proton
so we do exactly what you said halogen
dense conditions
will give us the product here with a
lithium
and then we just quench with water or
methanol or hcl whatever
so if you quench with iodine you get the
diode product out
and finally how do we get the one at the
para position
we can use a trick perhaps we learned
before
you can use a blocking group so tms
group at the four position
normally people use nis here but i guess
you could use i2 and then finally tb
remove that blocking group fantastic
great how about a question
we have two related two related
questions from the audience basically
about solving effects in favor and
college events why it is
thf for college advanced replication
it has to do with i mean these are uh
phenomenological
sort of aggregate state uh changes that
that just sort of give you one or the
other um in terms of trying to
rationalize
why a solvent might be
better than another this is one of those
factors that's not really
you know there's not really a good
good explanation for why this happens
it's um
yeah unfortunately i don't have a good
explanation we can send out a review
on uh why this might be but nobody
really has a good example
or a good real explanation for why the
solvent
might be you know changing from th to
thf it's just aggregate state
so it's kind of an empirical observation
is the best i can do for you right now
but for an exam all you would need to do
is hd promoted over the arrow
right so you wouldn't need to memorize
conditions from a schlosser paper
that would give you hd you would just
say hd promoted that's enough
it's all basically empirical observation
there is no way to rationalize and
predict for example we solve them for
example
if you use info isn't going to disfavor
the housing school
well you've got trends that you can take
advantage of so
the book and the reviews have trends of
solvents that will be better to use
for promoting hd one thing is clear is
that h
halogen dance is a predictable thing
okay so if you you can predict it you
can rationalize it
and then the little intricacies of how
do you get your yield up and how do you
promote it
there are small empirical things like
solvent choice and sometimes
one base might be better than another in
a particular instance
but it's hard for me to give you a like
you know guaranteed rationale
to explain it yeah good questions
let's take a look at uh the case of this
bromo cf3 now i want you to put a co2 at
each of these positions
so what are we going to do
so i think in using the logic you talked
about with like
nviolian secular versus um perioding
based or
nitrogen bases you can use lda
which would not be as favorable for
lithium halogen exchange
so you can do lda and then
quench with co2 to get
carboxylation at um
if the in this case the bromine is a
directing group so
it would be right yeah right there um
lithiation and then quench
okay a lot of doge coming your way there
tim that's fantastic
what are your thoughts on how we might
uh for even more coins how how might we
get the other isomers using this
technique
yeah sure so here if you do that lba
again to get that lithium there you can
quench with iodine instead
and then do halogen dance to put that at
the four position
and then the same iteration where you
can
use base and make that into the
carboxylic acid
so you could use grignard conditions
let's say
and um the iodide is going to react far
faster than the bromide don't worry
about that and that will give you that
one
how about the final one how do we get it
nearer to the cf3 yeah so
from that first intermediate you drew
after the lda you can
um quench with tms chloride uh
and using the blocking logic
your c4 position is now blocked
and then in the presence of base you
would deprotonate at the other site
um excluding the lithium halogen
exchange bit
and then you would yeah exactly with him
there and then quench with co2
oh then t-bath
i have a question about this please ask
so how
how would you i guess both the cf3 group
from the bromo groups are directing
how would you judge which one would be
the stronger all about the hierarchy
so the little bit of memorization is
needed it's in the book
um of the what is a strong what is a
moderate what is a weak
and a bromo is going to be a cf3 is not
a really good directing group it's very
weak
um whereas a bromo is also not a super
one but it's better than cf3 so that's
kind of thing you need to need to commit
to memory
okay thanks yeah uh so in this case
would you still expect small amounts of
retro isomers then
we started with some directing of the
cf3 group now the bromo is
is pretty is is good enough that you're
going to get the major product to be
that lithiation there
all right tucker is something here we
have another outside outside question
about
uh is it used in processing positive
uh i have not seen halogen dance used in
process chemistry
it could be used if there is a
very very strong directing effect the
problem with halogen dances you can
imagine
is concentration effects on scale so
because of
the intricacy of the mechanism i don't i
mean it may be there may be some in the
audience who who is a process chemist at
a big company who is screaming right now
saying yes we use it all the time
i haven't in my personal experience seen
process chemists use it
i don't see a reason why it couldn't be
used if the system is set up properly
but this is used all the time in medcamp
i've seen it
dozens of times over the past 20 years
people in frost and med chem using
halogen dance
or or doing it inadvertently
okay let's take a look i have one
question about
deprotonation in that system um
could you use a bulkier base like p
oh yeah absolutely to just get direct
oh c4 i mean yeah
perhaps um although
in general the directing group as i said
before
for the purposes of having some general
rules in mind
imagine that the directing group is
strong enough that it's going to stop
that from happening so the directing
group will usually
override the innate preference of a
pyridine
yeah so there may be you know there's
thousands of papers out there folks
there may be an exception to what i'm
saying but the general rule is that the
directing group wins
it's strong enough that you can't get it
to move over
okay does that make sense hey phil i
have a quick question just about this
you mentioned um grignard
and i was wondering if you could talk a
little bit about the selectivity of that
for the bromine versus iodine
is it just that iodine is heavier
uh that's correct so you use here no
shells turbo grignard isopropyl
magnesium chloride
in general this sort of effect of
relative rates of halogen reactions
also transcend into the world of
palladium so for instance the rate of a
heck reaction on this compound is about
a thousand times
faster with the iodo than on the bromo
same goes for sangashira same goes for a
lot of things like almond chemistry the
same story
so and indeed also making grignard
reagents so you can use this
orders of magnitude faster reactivity
myoto bromo
to get halo selective reactions question
from the outside
oh halogen dance does not occur on
pseudohalites so
tonsil groups don't migrate uh no
yeah good question you know this is
limited halogen dance is limited to
halogens
at least to my knowledge let's take a
look at the case before we go
back to the book of um when you take
these dibromothiophines
and you treat them with lda and
electrophile so based on
all the dancing we've been doing you
should all be dancing experts and
therefore if i
randomly call on a name they should be
very how about newton
uh in california
so first you for the first example you
have the deprotonations at the
c3 position
uh so for this one you mean see through
let me let me label them
uh yeah that that would be c4 sorry
so that's a great uh example here of
where we should be talking about the
hierarchies of
directing group effects so in the case
of a pyridine
the directing effect is weak so to
daniel's question
earlier about how you could use a very
big base to maybe get the c4 selectivity
is different than a thiophene let's go
back up to the hierarchy that we had
here
these are super favorable deprotonations
in fact so much more favorable even than
a directed group can override
so if we go down here the lithiation
event that takes place first
this is a weak directing group and this
is an innately
very very primed and acidic position so
the initial lithiation product
is that one okay okay
so now what happens after that we quench
this with an electrophile
so is the product just um
quench with an electrophile uh i
there will be the halogen exchange with
the starting material at the
c2 promo i believe aha
so we don't get that and instead we make
a little bit of this thing
and in order to make that
it needed to take it from somewhere it
took it
from here
so in that process of dancing behind the
scenes there was also a little bit of
this one made right
yes we've got this species around we've
got this species around
the two of them need to meet together
and make a decision
now based on what i've told union we've
got this precursor here we've got this
reagent here which of the three bromines
do you think will undergo halogen metal
exchange
we've got a b and c
um the c1 will undergo
the halogen metal exchange because you
have
both directing group pointing towards
the c position
brilliant awesome awesome job
now the same logic can be used in the
diorama thiophene shown here
so when we take this one and we
deprotonate it with lda
what do you think is going to happen so
we start with the um deprotonation
that's c3 and c4 because it's just only
one position
now lovely then
we have the halogen exchange to make the
same compound
and we add up the same product
you got it
brilliant so
let's reflect for a moment i think this
probably would have been confusing
um an hour ago hopefully now it's not
confusing
and rather intuitive but really
beautiful that you can start off with
these two different materials and they
thermodynamically coalesce
into the same uh electrophile
product let's take a look at case study
number one which is kind of the ultimate
manifestation of this type of phenomenon
case study number one that one's a doozy
we've got the dimethoxy the bromo the
amide there
and this may you know this is a good
page of the book to study
because it is exactly what you would do
if you're a medicinal chemist
thinking about the roots that you could
use to put this together
so let's take a look at why the root at
the top here i'm not able to annotate
the screen but
at the top why are these three
retrosynthetic arrows with the x is not
good
well because selective snar reactions
are going to be very difficult on those
types of compounds so you don't want to
propose something like that
so we want to move backwards and
disconnect early
the bromo right if we look at that table
we talked about before the bromo is
probably going to be one we want to
disconnect early
leading us to the intermediate you see
in the dead center of the stream
and then you can imagine that arises
from a selective snar
on the top which is that's a decent
disconnection and then you can imagine
you could put a halogen there
that's decent and that could get us back
finally to the
five halo 2 carboxy pyridine
that is a certainly viable
retrosynthesis you could write that on a
test and you get full credit
in the middle though if we move down and
think about the other methoxy as arising
from a
snar reaction it leads us to the five
halo four methoxy intermediate
which can be brought back through some
sort of hopefully lithiation event as
we'll see in a moment
and that gets all the way back to a
piccolinamide shown there
a halopicolinomide that's what they
actually did let's take a look at the
forward route
so the forward route does a chlorination
and acid chloride formation it then
makes the corresponding
amide by dumping in isopropyl amine we
treat that for chloropyridine with
sodium methoxide it gives us a clean
snar reaction
we then deprotonate it with duly we've
got two fine directing groups there
they help put it at the c3 position
that's where the iota goes
we use a hindered amide base now to
deprotonate the only position left open
you've got a great directing group that
methoxy is great
it directs it towards c5 the lithium
goes there
you get the dihalogenated intermediate
it then does the halogen dance to give
the
switcheroo of the iodine to the opposite
spot
you then add that sodium methoxide with
copper iodide and a kind of
almond type reaction to give the
dimethoxy compound and again you can use
the
lithiation to direct at c3 because
you've got two great directing groups
there it goes straight there
and look what happens after that we
treat that with lda
and we dance again so two different
dances to move
bromines and iodines around the ring
this is phenomenal
is anybody confused by this we can go
through questions
yes uh not about the halogen dancing but
with the uh being able to do selective
snir
can't you also do that selectively even
if you have two halogens around
if you have two different halogens on
the ring
and have selectivity between those two
yeah
in this particular case however the
selective s and the r
is difficult because you've got in the
case of the one
on the very left you've got a bromine
and let's say another uh group there
that is you know
c2 versus c4 you could possibly get
selectivity but
it's not a great consulting suggestion
because people are going to be like
the first thing they're going to say is
how do you know you're going to get that
one and you're going to again you're
going to do hand waving
on um maybe conditions blah blah blah
and they never hire you again and the
top one the same thing
the snar is difficult because you've got
a para
electron withdrawing group and you've
got the ortho c2 bromo
again you can wave hands and say here's
some papers i found that c2 goes first
instead of c3
it's just not unassailable right so
we're looking for the suggestion to the
people that there's no you can walk away
and know it's going to work and the only
reason it doesn't work is to say set it
up wrong
your idea was bad yeah okay
so yeah there are some nuances
associated with this and you can make
some
you know suggestions that in certain
cases you may have no choice but to make
such a suggestion
yeah questions
um just a quick question um not related
to the halogen dance but actually the
first step like
uh is it the electrophilic substitution
on the first step to install the
chlorine to the pyridine ring
yeah so there's a docking on of the
nitrogen to the socl2
and then an addition into that
pyridinium
of chloro at the power position
yeah so it's more like you oxidize the
nitrogen to like the ncl plus to make
you make the amplus with the ncl bond
and you have the chloride add into the
full position in nucleophilic manner
rather than just is an electrophilic
substitution right
i don't believe you get n chloro i
believe you're getting an n
s o uh n sulfur adduct that's what
happened
yes okay but it's basically it's and as
we access some kind of living room
correct okay exactly exactly
for the halogen dance um is it normally
is it always possible to drive it to
completion or there is some
sometimes a danger of ending up with the
mixture of you know the glycol compound
and yeah so these are examples where
it is so um it is so
clean because there's multiple directing
groups giving it really no choice but to
go to their desired spot so the yield is
high
but often so these would be good
candidates for processed chemists to
employ
halogen dance like i think these would
work well on a ton scale
where it where it falters is where
there's some nuanced reactivity
and it can go either way or it's very
weakly directing
and in those cases the yields don't
often go above 70
and you do get some byproducts in the
reaction so that is a
caveat of hd for large-scale work
also caveat because it's run at negative
78 which is difficult to do on a really
big scale
that's always a problem i mean you know
it depends what process chemists you
talk to some of them say well we're
using flow these days we can handle
cryogenic but kelly is totally right
cryogenic is usually something that they
desperately want to avoid
they'll do these lithiations and they'll
do halogen metal exchange and they'll
often try to get it as high of a
temperature as they can minus 20
zero degrees and so these higher
temperatures don't favor hd
and that's why maybe is another reason
good point kelly that
hc is not really used very much in
process that i've seen
and if someone in the audience has done
it please email us and we'll include
that example
okay well that concludes chd protonation
um we only have 15 minutes left and we
may not make it to the rest of the
lecture but that's fine because as i
mentioned
this year we don't have to rush because
the remainder of lecture three
is most of it online so if we don't
finish in time
we will simply adjourn it with the exact
time and you can watch the rest of it on
the 2019 edition let's take a look at
how radicals can be used in
functionalizing
various header cycles and one sort of
emblematic example of this
is a synthesis of this ergot alkaloid
precursor shown here so we need a good
disconnection
on this molecule wonder if there's any
suggestions out there
um maybe simona or maybe nathan
or yeah so you can disconnect between
the carbonyl and the pyridine
in a miniski type disconnection
fantastic
and yeah that traces you back to an acl
radical which you can get from
an oxalate
brilliant
so the miniski reaction one of medicinal
chemists
favorite reactions to do has definitely
become more of a popular thing to do
in the past uh 10 years or so
because of the realization of the
remarkable chemoselectivity of the
process
under more modern conditions that don't
normally require
the very harsh old style conditions
which i think
turned off a lot of medicinal chemists
and in the sort of canonical
manifestation one takes a acid
and they treat it with something like
silver nitrate
and something like a persulfate sodium
or ammonium for sulfate
and that gives you your radical so
the silver and the per sulfate get
together
and you get
silver two plus
so4 anion
and then the silver two is the active
species to take this thing down to the
radical
which gives you back silver one
plus co2 plus a proton
so when you have a charge heteroaromatic
those charge headed aromatics which you
generate by
nc2 protonation normally people do this
with an acid like tfa
h2so4 the old conditions are usually
boiling it in the acid
and that gives you uh substitution now
let's take a look at
simona's suggestion and how we make that
oxalate
so the first step is treating this with
kh then
nbuli then trimethylborate and then
finally
the bromo compound and some palladium
and following that all we need to do is
make the corresponding
oxalate with oxal chloride
so who can guide us through um
how this works maybe
maybe tiffany can tell us what is going
on with the kh step
and then the bully and then the
trimethylborate what's going on there
now what um
then
i guess
you
oh
any thoughts on what bully might be
doing here lithium
that sounds great so i'm going to put a
lithium right there then i'm going to
quench it with trimethylborate that'll
give me my bronic acid
and then i do palladium so the key here
is the bully
is a protecting group i'm sorry the kh
is a protecting group for the nh and you
may say hey phil didn't you just tell us
before
that we could do a halogen metal change
even the presence of an nh
sometimes that works but in the case of
a poor electrophile like
trimethyl borate it's not as good of an
electrophile then
you actually in in the case of an indole
you'll usually want to
deprotonate it with something like
sodium hydride or potassium hydride
first and that enables the halogen metal
exchange to take place just in a cleaner
and more reproducible fashion phil
what would it just quench itself and so
you would get
the lithiated
yeah that's that's of course so if you
know you're using a nucleophile which
doesn't react very quick
so you'll get halogen metal exchange and
then it'll just find another endo lying
around and they'll say hey i want that
proton i'm done
and you get just the product is just
bromination and you're over
exactly yep
so miniski can be very useful to achieve
ch functionalization notice we don't say
ch activation
no ch bonds were cleaved during these
processes
but it gives the appearance of a
cleavage event so
it's essentially a siege
functionalization but hey
so is a frito crafts and an aldol
reaction so but
these ones are more of a ch
functionalization field to them
so a compound like this can obviously
just trace back
to pyridine and you can use something
like
um protected
proline this is from a merc process
paper and or glad
this one can come from pyridine
and a variant of the miniski called the
burano meniscus
so you can take aerobronic acids and you
can treat them with miniski conditions
and they give you
uh the product that you would expect in
this case you can use a sneaky little
reagent called
a diversinate or sulfonate
which generates when you heat it up in
the presence of an oxidant
will generate the corresponding radical
usually tbhp
is used but other means of activation
can be used as well
in the case of this one this is just
old-style fenton chemistry so you can
just take
dioxane you can use some iron filings
and tbhp
these are really weak ch bonds and so
they're kind of like cheater substrates
but it's really useful
in the case of the benzofuran shown here
you can use the exact same logic so
you can start off with this
compound because there's no
regiochemistry issues
x can be equal to n2 diazonium
and then it's a so-called short reaction
or it can be equal to a bronic acid
and you can use the same verano miniski
conditions to get the product
and then finally the compound shown here
maybe someone
uh who do we have from shenvi's group i
know simonas in chenby's group there
might be others
what would you say here is a good
disconnection
uh you can disconnect from like a
scleralite derivative
and the chloropyridine so
which you can get from like a suzuki
cross coupling
and then the miniski brilliant so
you could
let's just put it like this you need to
make
that radical right
yes yes so we can get that radical from
the corresponding olefin using
iron ac
and phenyl silane
you could also get it from the
corresponding acid
you could also get it from the
corresponding alcohol by making the
xanthane or making the oxalate
so however way you want to make that
radical that will then cyclize clothes
to give you the product
so we will close with a little
consulting corner here
it's a area of questions that i get
quite often which is uh
exemplified with the two examples i show
here
a typical question i will get
is um hey phil we want to do
a radical addition and we want to
understand
how to control the selectivity one of
the main reasons that people
avoided miniski chemistry for a long
time
was the perception that radicals simply
couldn't be controlled very well
and as a consequence
people viewed them as being somewhat
inferior means of functionalization
but that's because they were not
consulting because when you talk to a
medicinal chemist
they often like to get racemic mixtures
of compounds
they often like to get regio isomeric
mixtures of compounds because guess what
those are bonus analogs for them so
the mixtures are not necessarily a
problem but sometimes they'd like to
find out if there is a way
to controllably get one or the other now
the advantage of doing
miniski chemistry on a pyridine is that
you have the nitrogen
and that nitrogen can be protonated
and once you do that it changes
everything so
protonation of this compound and
submission to a radical would give which
adduct do you think
how about
tanner
so so if you protonate the bottom
pyridine let's go with this one first
and i want to know what do you think
might be the major product
the one next to the
methyl okay great and why do you say
that
um we want us people who agree or
disagree to speak up now
or forever you hold your peace so you're
saying that when i protonate here i make
that position more delta plus is that
what you're saying
uh yes okay anybody disagree or agree
i would say the four position yeah i
agree that it would be four
let me ask you this question
you see the analogy of that oxonium to
that iminium
you wouldn't expect that this would be
delta plus here would you tanner
no but would you like to revise the
answer
um yeah then we should go to the fourth
position
brilliant so when you protonate you'll
get selectivity here however
when you you when you have no proton
source present
the directing group look at the nitrile
hiding here i didn't mention it but it's
a good
pi acceptor and it activates such that
you would expect the major product to be
perhaps here or you could also imagine
potentially there
same thing goes for this one if you
protonate
you're going to get that is the major
product with a proton source and you'll
get this as a major product without
a proton source now uh turns out we we
wrote a paper on this
a long time ago ancient history but um
there is a
really good way we worked on this with
donna blackman's group many many years
ago
and lead author fiona really talented
medicinal chemist at rochester
um worked on the rules and regulations
for radical edition so
this is a very useful guide uh i know a
lot of medicinal chemists have found it
useful
to take you through the first uh
thought of how you would design a route
using selective radical chemistry
nobody does chemistry just on pyridine
often not right you usually have
substituents on it so
you know where your innate reactive
positions are your groups
incur either conjugate reactivity or
donating reactivity
and that then changes the sense of
innate reactivity
then you want to look at the step three
which is the sites that are
activated as a consequence of electron
donating or neutral groups such as a
halide or
a c2 electron withdrawing group a c2
electron donating group or a methyl
group
then you add the effect together and you
decide on your conditions
whether you're going to promote the
innate reactivity by adding acid whether
you're going to
reduce the innate reactivity incurred by
the nitrogen of the
pyridine and promote the conjugate
addition reactivity of the substituent
in something like dmso how does it work
in principle
in action so here's a typical
pyridine those are innately reactive
sites c2 and c4
our conjugate site is going to be at c5
and so step three now we look at the
effect of the methyl the methyl is going
to
be activating ortho and the ester
is going to deactivate at c6 we add the
effects together in a little traffic
light
and we determine which conditions we
want to use
if we want to promote innate reactivity
we're going to go for adding acid and
it's going to probably go adjacent to
the methyl
and if we want to promote conjugate
reactivity
we want to use conditions that get rid
of the acid and indeed
when you treat this with a radical
reaction under acidic conditions
you get r group that is consistent with
the innate reactivity
ortho direction of that methyl group and
when you treat it under dmso no acid
conditions
the selectivity gets dominated by the
effect of the electron withdrawing group
on the c2 position of the pyridine
fantastic any questions
all right so we have uh one minute left
and uh luckily this last uh bit of
material i'm going to skip this bit of
material it's on the
youtube video a great advantage of doing
this over zoom
we don't need to cover any of this we
covered all of this in 2019 so please
look at it
i think something that's interesting to
keep in mind
is the effect of the type of heterocycle
on the substituents which we have talked
about a little bit already
so for example in the bogor synthesis of
fredericomycin
which position when we treat this with
lda do we think we're going to
deprotonate
how about um deb
yeah um i think you have two choices of
course you can deprotonate on the
pyridine
or on the metal but in this case i think
it's going to undergo on the metal
because it looks like a ketone exactly
so if you go to the youtube video you'll
find out what happens next but in fact
that is just like a ketone just as
debbie said
and in the case of singulair same story
we're going to make a disconnection just
like that
because uh quinlan
with a methyl group
it's just like this
so you can do a simple aldol or
canovanagal reaction
and that's how singular was made on
process scale by
merck just a simple aldol reaction by
recognizing that that's just a ketone
and a titin uh in the case of these two
this is kind of
topical one of these is a covalent
reactive group and one of them is not
brendan which one is the covalent
reactive group uh definitely the purity
this one is basically methyl vinyl
ketone hiding
this one is styrene hiding
easy right this is intuitive stuff so we
don't need to spend too much time on it
um and in these last i'm going to skip
probably number five you can check that
out in the youtube video
and in the case of the final example
shown here we kind of already covered
this when we cover chlorophyll
remember that because of the ability of
these things to form quinoa diets
it's easy for these types of groups to
add in
and in fact just um for completion's
sake let's just mention that this famous
intermediate here
is known as a grammy and grammys are
really good at being displaced
because again this quinomathide like
thing that we saw
in lecture number two so uh i'm
sort of ending one minute late sorry to
go over time but
i'm really enjoying the zoom format
because i can skip to the end
you can look at that final 15 minutes on
the 2019 lecture but we did a i think a
much better job
this year than two years ago and going
really really slowly through
halogen dance and lithiation chemistry
which can be very confusing
and so hopefully less of you are
confused in 2021
than were confused in 2019 so with that
we'll see you for the next installment
where we finally cover
how to make heterocycles that's coming
up
on wednesday stay tuned thanks everyone