okay good morning everybody
uh welcome to the 2021 heterocycles um
so this year we're going to be changing
things up a little bit uh there's no
chalk
there's no board it's all virtual and
we're going to try to maintain the same
level of participation and to do that
we've introduced
a few uh different things so
first if you're a student in the class
you've been sent your assignment
to the new company we have founded
called very therapeutics
and you will either be a medicinal
chemist a process chemist or a
radiochemist within that class which
means you'll have to master
uh the retrosynthetic skills of each of
those types of
chemists and participation is going to
be
encouraged through the mining of a new
crypto
or chemo currency called pyradoge
and um so pure doge is uh a useful
currency to
get points on the exam uh transfer to
current students that your friends or
you can even gift them to future people
who will take the class on their own
um pyradoge can be used in a
myriad of ways including points on the
final exam
if you become a peer doge millionaire
it's conceivable that you wouldn't even
have to take the exam
you could just use all your doge credits
you can also use it for
swag so like yogurt here from spaceballs
you can buy some merchandise that will
be coming soon t-shirts and
unfortunately we're not allowed to sell
flamethrowers or we would do that
but so that's how we're going to try to
get people to to talk
i'll call on people a lot um you're
encouraged to
participate and just come in and unmute
yourself whenever you have a question
for the many people that are taking the
class sort of as outsiders you can also
ask questions through the q a box
which i will not monitor but tucker and
max here are
amazing tas uh we'll be filtering those
questions
answering some of them and then the ones
that are particularly relevant to the
class
uh putting them to my attention and will
address them in front of everybody
now uh some procedural issues regarding
the midterm and the final
that is as usual an open notes exam
it'll be proctored over zoom and you'll
be allowed to use anything you've
written down
yourself along with the essentials
so you've been given these pdfs even if
i think even if you're an outside person
these have been sent to you
so these essentials of heterosexual
chemistry you can print these out and
you can
uh use them on the exams without a
problem
uh and anything you write so if you want
to take the julian mills book and write
it yourself
out all thousand pages of it or take the
portable canvas consultant and write all
thousand pages of that out with
handwriting
you're welcome to use that uh during the
exam
um and let's see is there any other
issue we have to talk about before we
start um
i think that that pretty much covers it
now as far as
the uh textbooks uh julen mills is a
good one
but um the portable chemist consult was
written with the idea that
uh if you really needed a fast way to
grasp the information
you know this would be a way to digest
it very quickly so it's kind of like um
it's written i mean it was written i
don't know how many years ago seven
eight years ago
um yeah it's funny my son actually on
friday he says
daddy you're almost a hundred right and
uh
i was like no and he goes well 40 50 60
70 89 100. so it's basically the same
right
almost you're almost there so yeah
almost 10 years ago we wrote this book
with the idea
of putting me out of business so i
wouldn't need to spend time consulting
anymore
that didn't work but nevertheless the
book is a really fast way of grasping
uh how to make heterocycles and how to
substitute them so you'll notice every
chapter in the book
is written from the standpoint of
how do you substitute a pre-existing
heterocycle
and how do you make it and that really
is a great introduction to the first
three lectures so the first three
lectures are going to be
kind of basic it will be some complex
issues incorporated into there but
these are the things you need to know
before you can make the heterocycles you
got to understand how to functionalize
them so once you make them
or in some cases you'll be able to buy
them
what can you do with them and so each of
these sections is divided between
substitution
which basically is simply a way of
saying reactivity
and then synthesis which is the basic
sort of retrosynthetic
analyses of how you how you go about
putting these things together
and then retrosynthetic analysis for in
this course will be taught from the
vantage point of
three different types of people the
medicinal chemist the process chemist
and the radiochemist and as you'll see
throughout this class the way that they
think
is very very different and hopefully
you'll
understand soon why a processed chemist
route to a molecule
is not necessarily better than a
medicinal chemist route out
and and vice versa so with that
uh let's begin with general reactivity
one
now in general if you want to get into
the world of header cycles you've got to
do something very simple which is you've
got to take an aromatic ring and you've
got to take one of those carbon atoms
and substitute it for nitrogen and if
you do that
you're going to get an electron
deficient heterocycle that has it's like
pyridine type
and it's important to remember that a
pyridine type nitrogen
is very very different than a pyrrole
type nitrogen so a pyridine type
nitrogen
basically is like three different things
in one it's a schizophrenic heterocycle
so within it it reacts like
triethylamine it forms various adducts
obviously
it reacts like nitrobenzene so the if
you look at the electrostatic map
at the last section of the header of the
pcc book you'll see electrostatic maps
of all the heterocycles you'll notice
the effect of pyridine
renders it very sim similar to the
effect of nitrobenzene on the
neighboring carbons in terms of its
ability to do something like
electrophilic aromatic substitution
and then finally the pyridine like
nitrogen
gives that heterocycle an immune like
reactivity
so it's an immune it's triethylamine
it's nitrobenzene all in the same
heterocycle and these effects are
additive so it works on purity and but
it works whenever you see a pyridine
like nitrogen that's embedded
into a heterocycle we're going to get
into some very very complicated
heterocycles by the time we get to
lecture 15
16 whatever we'll look back on lecture
one and laugh
at how simple we were we were looking at
but all the concepts i'll keep bringing
up over and over again
all the problems of the day i'll say
remember lecture one remember lecture
two
they were simple but if you didn't
master it you have sort of no idea about
reactivity
now if we take a carbon atom and we
excise the carbon atom completely
and then we put a nitrogen in there now
what happens is um you get a
pyrrole like hydrogen so if it's an
oxygen
it's obviously a furan sulfur thiophene
and we generally call these types of
nitrogens uh
pi excessive meaning that although
they're still aromatic
they have a strong desire they're not
they're not really happy
you know the pyridines are pretty happy
you know pyridine solvent you know no
problem everybody uses it
it's very happy stable aromatic whereas
pyrol not so happy they're generally
just
uh unhappy with life and they're just
constantly trying to do something
and these pi excessive heterocycles in
the case of something like
like pyrrole have a strong inclination
to
start doing things like that so they
desperately want to attack something
whereas pyridine is pretty content
although it's nitrogen atom can be
somewhat ownery and can stick to silica
gel and it can attack an electrophile
it pretty much stays put and you can
protonate deprotonate it
just fine but a pyrrole is not so happy
now it's really important to understand
aromaticity
and try to categorize in your head a
general
way of thinking about aromaticity so
that when you see a heterocycle you can
recognize
the aromatic parts and the less aromatic
parts and in order to help you with this
we've got in the essentials pdf
a kind of vague overview that shows kind
of some hetero
heterocyclic aromaticity values that are
kind of vague
um but they in general the order here
is accurate showing the most aromatic
something like pyridine going back to
something which is
not very aromatic like isobenzofuran
where you've got
you know something which desperately
wants to react with anything
now it's really important to understand
aromaticity for a variety of reasons
it will guide you in the way you think
about
reactivity so often medicinal chemists
will propose heterocycles in a
consulting session that
simply uh you know would be interesting
ones to think about in theory
but have no basis in reality and you
would never want to give it as an
actual drug because it's inherently not
so stable so knowing what
will make a compound more aromatic helps
you think about
its reactivity and stability
and then there's tatamism which we'll
talk about in a little bit later in
today's lecture which thinks about where
is the proton
that kind of matters where the proton is
if you're a medicinal chemist it matters
because
uh you need to know how it's going to
dock into an enzyme pocket whether it's
going to be a hydrogen bond donor or
hydrogen bond acceptor
if you're a process chemist it kind of
matters because maybe you want to
alkylate one of the nitrogens and you
need to understand
what the dominant tautomeric form where
the hydrogen is going to be
which period which uh nitrogens are
going to be pyridine like
which nitrogen is going to be pyrolike
all of that is determined by tatamism
and all of that can be
traced back to the qualitative guide of
aromaticity
substituent reactivity we're going to
talk about this a lot so the
the effect of the aromatic nature of the
heterocycle controls the reactivity
of neighboring things like methyl groups
or carboxy groups
or hydroxy or amino groups like
how do those comp how do those
functional groups react it all goes back
to aromaticity and then finally as we'll
see when we start thinking about how we
make molecules
it helps you think about retrosynthesis
so when you're talking about
bridged heterocycles that have two
heterocycles uh
within each other how do you know which
ring to break first
something we're going to talk about a
lot in this class and
again aromaticity is a useful way of
thinking about
which one do i buy which one do i make
which one do i emulate
all of that comes back from getting that
sort of intuitive sense
of what is more aromatic than another
one
okay so with that let's go to problem of
the day number one
and in this concept here that the
tendency to give addition rather than
substitution
increases as the aromaticity decreases
is well
illustrated with the classic case of how
you make three bromopyridine
and um so this looks like a good problem
for
a processed chemist and luckily we have
several of them here so maybe
junchen who's a member of the process
team here at
vari therapeutics can help us with
what is going on here what is oleum
what the first step might be
there's no wrong answers whatever you
say i can turn into something useful so
just say something it can be
even how your easter sunday was i'll
turn it into something so
go ahead okay so the first reaction
i can't hear you can you go go ahead say
it again
you can help me yeah i can you know
you're perfect perfect
the paradigm first has a
um long
pair and then reacted with so3
i'll give you a dot
okay now what do i do now then react
with
bromine where
this double bond i would say uh i put
some numbers to help me out
oh two and uh we all react at
uh two three c two n and three three
so um tell me in a compound like this
uh that's a good thought let's look at
two three and let's think that
um you know in in the sort of let's just
draw the resonance form of this one
which one do you think has the highest
electron density
remember over here i said i want you to
think like
pyridine is an immune so that would
suggest to me
jin chen that this two position would be
pretty pretty deactivated don't you
think
yeah i agree you agree good so i would
say
we're not going to touch anything around
two so why don't we move over one
um what do you think you can you can put
the
positive on c3 a c4
and then you will get a something like
inamin
okay so let's do that what we're going
to do here is we're just going to do a
classic
we're just going to pretend it's an
olefin and we're just going to add in
bromine yeah
all right great now i've got to make
some choices
i've got hydrogens there and i need to
somehow
get back to the product of three
bromopyridine so how am i gonna do that
if i eliminate one of these protons i'm
gonna get
three bronchopyridine but if i eliminate
the other one i'm going to get four
bromopyridine which is not the answer
so how do we rationalize there's a
selective deprotonation that takes place
between
one of these hydrogens that leads to the
product and one of these ones that does
not
what do you say junction any ideas
yeah as you mentioned before we can we
can treat
this guy as a immune and if if it's
yeah if this double bond is the part of
immune this
hydrogen is more aesthetic than the
periwin
and this is the more acidic one we're
going to eliminate that
and that's going to give us our product
after work up great
well jin chen the first answer of a
question in heterocycles that's probably
worth the
cool five pure dose do you think yeah
all right great
so he's he's currently the leader um
great now let's take a look in contrast
indole can be brominated this takes
place
probably as low as minus 30 minus 40
and in this case we're actually using
pyridine based brominating agent
so pyridinium trihydrobromide is a nice
popular
happy brominating agent it's stable as
an adduct
with bromine in the form of this
trihydrobromide
and that can be used very easily to
brominate
indole now the site of bromination
is fc3 which follows the rules of
reactivity that you would expect if you
did this on
pyrol what do you think would happen
nathan who is a medicinal chemist at
berry therapeutics
uh i think it would attack as c2
doing an electro electrophilic
parametric substitution
perfect fantastic so this one takes
place at c3
a question i get every year is why is
that um
and the way to think about it is that
because you've got this
benzene here you have effectively
made this compound much more unlikely to
disrupt
that neighboring aromaticity in this
case we have a movement of electrons
that looks like that
to give you higher degree of c2
reactivity
if you were to do the same thing on
indole
it would require that you disrupt the
aromatic core
and that's why that doesn't happen and
that's why all substitution at indole
will in fact take place at c3 not at c2
any questions on that now people yeah go
ahead brennan yeah
so when you brominate the the parole
like that
how how much harder is it to do another
uh electrophilic attack i mean how how
dramatic
hard at all not hard at all okay pyrol
has a lot of juice in it so
if you wanted to do another reaction on
this one you could
and um but you raised a good point there
brennan
so what if i want to get c3 bromination
is there a strategy you might think that
we could use for that
how would you conceptually think about
doing it
um i mean you could do you would have to
put some blocking groups maybe awesome
awesome and the blocking group that
people usually use
is the tips in fact this group is so
popular
that um it actually is a part of the
chapter
on pyro so if you take a look at the
pyro substitution starbursts and
examples
take a look at the right hand side folks
it's all about tips pyrol which was
introduced in the
by a famous medicinal chemist by the
name of joe muhowsky
during the synthesis of ketirolac which
we'll talk about i guess next week
but a very useful way of changing the
site of reactivity on a pyrrole
just by blocking that group wonderful
thanks brennan
you purido is coming your way check your
account all right
so uh generally people are not going to
want to put an
indole into their into their medicinally
important compound i rarely see people
just take a
regular indole and you may say hey what
about tryptophan that's in our body
everything you know but
rarely are small molecules uh with an
indole
progress to the clinic without doing
something to them
to attenuate the reactivity of the c2
c23 pi bond so generally there's an
electron withdrawing group
or they make an endosol instead of
indole
or they make a benzamidazole they do
something
or they even take this and turn it into
an as indole as we'll talk about later
so the reason for that is of course you
wanna tone down this reactivity take
electrons out and uh turn it into
something which is actually gonna be
stable in the body
all right so more on how aromaticity
will dictate
how things react cyclic transition state
reactions specifically
paracyclic reactions they increase as
aromaticity
decreases and this makes intuitive sense
it should make intuitive sense to you
right
i mean you can't do diels-alder with
pyridine just like you can't do deals
alder with
benzene very easily unless you have some
sort of
excited form of it it's pretty rare to
do something like that
so uh whereas things like pyrrole if you
take a pyrrole for instance and you
throw a
bach on it that will then do a deals
alder
with that no problem same thing with
furion furion you just heat up that with
with uh acetylene dicarboxylate and
you'll
you'll get out your your product uh with
loss of ethylene
and the product of that reaction will be
that i'm always going to abbreviate in
this class esters with e that's what
that means so if you take fear in you
heat it up
with this compound you get the initial
adduct and then minus ethylene gas
and you get out that product so it's not
very aromatic and it has no problem
acting like it's not
but it is aromatic it's just not very
aromatic
okay uh probably the most important
well one of the most important things
when you think about aromaticity
is thinking about how aromaticity will
affect
your tautomeric state that is
where is the proton and so
in the case of something let's go
through each one of them
if we have for instance uh pyridone
oh sorry so pyridone could be thought of
as a few different forms
we can have this form
you can imagine that the proton is
here
and we can imagine it's like that so
which form is the most important form
here maybe uh
a radiochemist like tim can help us out
i think that the first structure you
drew would be
the dominant automatic form is it
aromatic
uh yes okay great so all of those are
sp2
there it is aromatic it has great
stabilization because of the co double
bond that's a huge stabilization
there's probably also some hydrogen bond
action going on
so in solution it's going to be 99
that only a little bit of this one here
but it helps you to understand what the
different automatic forms are because
when you treat a compound like this with
a halogenating agent it's very easy to
rationalize the halogenation selectivity
by imagining this tautomeric form
now let's take a look at the case of
aminopyridine
so tim using your logic uh i'm going to
predict
that uh this one
is the dominar dominant uh dominant
autonomic form is that right
um i don't think so i think you don't
think so one yes
which one do you think it is the right
one the right one
exactly so in the case of amino purity
it's
it's uh the dominant tautomeric form 99
is going to be the amino pyridine and
just a little bit
is going to be that immunopyridone
so understanding all the tautomeric
structures that you have
in a heterocycle is key and it can play
an important role
even in how you design a medicine so for
example
in this problem that was
pretty much when this class first
started back in the early 2000s this was
a
topic of uh great interest which was the
upheaval of the pharmaceutical industry
by the
removal of merck from the market of this
very efficacious
2 inhibitor vioxx you may have
grandparents that took this compound it
was a really good pain reliever for
arthritis and people shifted now
everything to celebrex from vioxx but it
was a very low dose compound
and merck got in trouble when they
started increasing the dose tremendously
and then there were some real big tox
problems
now as a medicinal chemist in the modern
era when you look
at a compound like this and maybe we'll
pick on brennan again just because he's
worked on compounds like this in the lab
what do you think might be a potential
problem
with employing a butenolide like this
in a medicinal chemistry context you can
tell us whatever you're thinking
yeah no um i'm aware of this because i
remember looking at this when i was
working on uh
the butanolite stuff so yeah that that
ch2 is really hot
um yeah under biological conditions it's
probably gonna get deprotonated and then
oxygen around it's gonna get
oxidized and then now you have a super
hyper electrophile
that can be a nice alkylating agent
so if you just understood the possible
tautomeric form of a two hydroxy theorem
and the real realization that that is a
potential
intermediate one can get that renders
that ch2
kind of acidic and then thinking about
what this compound would do as a very
very
pi excessive heterocycle you could
rationalize as brennan says
that reaction with triplet oxygen would
give you this
hydroperoxy intermediate and that
hydroproxy intermediate has two choices
it can either disproportionate
uh to give the hydroxy compound shown
here or the malachi anhydride compound
shown here through a russell type
mechanism
and and the problem with this one is
you've got a latent aldehyde
and the problem with this one is now you
have a male anhydride which is a
phenomenal uh covalent reactive group
so the jury is out as to whether this is
the reason
high doses of vioxx are toxic but from a
heterocyclic chemistry lesson
it's probably a butanolite is something
you'd want to really carefully de-risk
as a lead candidate before putting that
into the clinic
is there a really fast way that anyone
can think of
of putting this thing together maybe
um we need a maybe a good process
chemist like carter could help us out
in terms of how you would think about
just putting this together really
quickly
is there a bond that you could
potentially break that would make it
really really fast to put it together
um three and four oh yeah brilliant so
breaking that thing up our first ring
synthesis example
so just mixing those in together you'll
get a alkylation and then intramuscular
aldol to do exactly what uh carter told
us so thank you
all right um i see this problem come up
sometimes
in medicinal chemistry consulting
sessions people will ask for things like
that
so the two amito furan um
what do you say tiffany can you give us
some thoughts on this problem of the day
how would you put it together and what
would you tell the medicinal chemist
um
can you just [ __ ] protect the uh of you
i i'm so happy that you said
you made this lecture so much better
awesome that's great so we're just going
to take two immunofuran
and block protected everybody good with
that
everyone's good with that uh
[Music]
i can barely hear you who who is it um
what are you saying what's the problem
with this no um just like
that compound is too electron reason why
i'm not sure if
you can't i mean you can just isolate it
for the reaction
yeah that's right so this compound
please don't ever propose compounds like
this
with this group being x here and
anything here
doesn't matter what you've got here
pretty much the only way this compound
would ever be stable
is if there's a electron withdrawing
group here then you sometimes you could
probe you can propose that sometimes but
in general
amido furan's mido and indoles
uh amino amino indoles aminocurins
aminopyrols
don't ever propose them um they're gonna
be
instantaneously react with oxygen they
won't last for more than a minute
and this thing will likely just lose
ammonia and give you butanolite if
you're lucky
but probably just give a polymeric mess
but your job as a consultant
is never to question what the medicinal
or processed chemist or processed
chemist wouldn't ask this question but a
medicinal chemist would
uh ask something like this you never
question what compound they want to make
or you'll never be hired again so i need
to make this compound how am i going to
do it
can we stop from acid or aldehyde
so if i start from an acid what reaction
do you want to do
yeah i i don't remember many name
reactions
it's a courteous reaction or
brilliant so we just take the
commercially available
and available from ferphorel you know
two feroic acid is one of the cheapest
commodity chemicals you can find
and uh that's how you're going to get
your nh box there just through a
courteous and that's one of the tricks i
often use for these
rare occasions where someone will ask
for a heterocycle that i know will never
be part of their drug
but they still insist on getting a root
to it
okay great so understanding tonomeric
forms leads us into one of the most
popular
consulting questions that arises which
is
regioselective alkylation and isolation
this is a problem which comes out
a lot it's probably like eight or ten
percent of the problems i've seen
is people struggling with the issue of
how to get an r
group on a heterocycle in their proper
orientation
so for uh
exhibiting this aspect of tautomerism
let's take a look at the iso
auxes alone shown here and perhaps stone
uh can help us out and thinking about
first what are the two taught american
forms
and then after we talk about the taught
american forms
which one potentially plays a role
in getting either of these two adducts
so
i'll make it easy for you to participate
by labeling these so you can talk to us
about
what the tautomeric forms might be so
stone what are you thinking
um so um
uh i summarize uh three
four and a carbonyl to the enol
nice okay that's one and how about
another one
um and
i guess you could um
uh have those vither island
well uh i'm gonna give you a little clue
here you've got these two hydrogens here
i mean you could in fact think about it
you're not you're not wrong
you certainly could keep doing that yeah
but there's something else
oh sorry i have the um
the two three double bond really
okay now uh
so stone let's keep going on this one
we're gonna label them
a b and c
um and d uh which of these is not
aromatic
uh the the one we started from
brilliant so not aromatic so
we we should still remember it as a
potential
tautomer but recognize it's likely not
going to be a
dominant tautomer when we think about
reactivity
so that gets us to problem of the day
number three
which uh stone you can continue on or
you can recruit help from your
neighboring um radiochemist camille who
i know
also wants to help here uh and so
we're gonna take that ox ice oxazolone
and we're going to either treat it with
base and benzoyl chloride or we're going
to treat it with acetic anhydride and
heat
and so need to have some way to
rationalize
what's going on here which product do
you think we might get
we can get if you think about it we can
get alkylation or isolation
here here or here
maybe even one could propose here so
where is it going to go
how about let's tackle the first one
benzoyl chloride
and sodium hydroxide save time i'll draw
the five member ring
i i think first you're going to
depregnate all right so we're going to
deprotonate
resulting in what kind of adduct it's
going to go with oxygen
carbon carbon or nitrogen do you think
uh
resulting in an adduct oxygen brilliant
awesome and now if we take that compound
and we treat with acetic anhydride
and just heat it up neutral conditions
what is going to be the product do you
think
um the nitrogen is going to react first
why did you say that what made you say
that
um it's uh it's appearing like not sure
oh that's so great every year the
students get better better
so quickly they pick up on it awesome
yeah
that's exactly right so when you're
thinking about these conditions of
how do you control regiochemistry you're
always going to be looking for
the pyridine atom and you're going to be
looking for the pyrrole atom
and that's going to result in some
puridoge coming your way for sure
five more for you great let's talk about
the typo on the
example there's a typo in the bio sample
sorry what is the type of uh so your
retro you have uh
oh oh yeah yeah sorry sorry oh thanks
thanks
there you go sorry about that thank you
um phil yeah
if you do uh venezulation on one of
those
uh tautomeric uh forms would you see a
mixture
if you do benzyl chloride for instance
right yeah
uh yes you would it would depend on and
we're going to talk about this a lot in
a moment
but in general you're you're going to
have a few options for
making selectively let's say if you
wanted to
to address your question
make that compound versus that compound
and the things you would do
would you have a few strategies that
we'll talk about later but so let's
revisit this question it's a good one is
that nick
yeah yeah it's me nick we're going to
get into that in just a moment
of the strategies one will use when
you're confronted with this problem
so stay tuned i'm gonna return to your
question
very sure yeah thanks okay uh yeah i i
had another quick one
that's okay um when we compare the puri
uh the pyrodone
with um the other form um so what about
a
thiotyridon would look well it would be
like a
period of thion is there a way to shift
the equilibrium into the um the scion
form
well for all intents and purposes uh
and when you see this this is commonly
the probably most
uh common uh
application of this is when you see it
in the case of the barton type
uh decaboxylations usually there's an n
hydroxy here
of this type um for all intents and
purposes the reactivity of this
is going to be always at sulfur
so whether it's reacting in this form or
in this form electrophiles
are always going to react here and i
guess your question is how do i get
n n reactivity instead of sulfur is that
right yeah right you'd say i wanted to
ventilate at
n or if i wanted to if i wanted the m to
be deprotonated
oh that's a great question i'm so happy
you asked that question so let's take
this and
uh the first thing i would do if this
was a consulting question i would say
hey
what you'll need to do is convert that
to s methyl turn it into a pyridine
now i've got a pyridine right watch what
happens watch what happens i'm going to
treat this with benzyl bromide or benzyl
chloride
and it's going to do this
how do you like that right so it's
basically you protect first and then you
do
like an sm2 uh that that
d protects it correct you've got to
shield it
and then you can uh get the reactivity
you want because
it's unfortunately not that easy and
there may be some random paper you can
find out there but not i don't know it
off the top of my head a way to
uh stop sulfur from reacting with an
electrophile
you've got to protect it and then make
the pyridinium
and then that should spontaneously
demethylate giving you methyl bromide
and
your desired product right all right i
see you thank you great great question
that's awesome
um just a big question regarding that so
like can you like selectively methylate
the sulfur over the nitrogen
that's what's going to happen
automatically automatically
okay that's the first thing that's going
to happen so when i treat this with
methyl iodide or whatever methyltriplate
whatever your favorite methylating agent
is
you're only going to get that very
quickly low temperature instant
okay thank you yup okay
super now uh this is an interesting one
to just to mention
um many of you are probably gonna
end up in the pharma sector and you
might want a little bit of history this
was first made in
1884 by uh ludwig noor of the
famous nor reaction that we'll talk
about next week
it's the first synthetic pharmaceutical
agent that i'm aware of and it was
marketed by sandos
uh antipyrene it was to lower fevers if
you had a fever
and this was made by simple methylation
and uh we can probably rationalize how
to make our very first uh
perazolone by using um
simple disconnection logic so how about
um
kelly help us out with how you would
just put this together
in one pot really quickly can you make
it from
phenyl hydrazine and methyl acetoacetate
brilliant so we're just going to take
that
so pure doge has been deposited into
your account
and uh there we go brilliant
okay let's take a look at some other
tautomeric uh
quagmires and think about uh which
tautomeric form
these might reside in and so for this
one maybe daniel
over in florida a process chemist at
very
therapeutics can help us with this first
one based on what we've talked about
already
what do you suspect is a dominant
tautomeric form here a
or b
what do you say dan
and if is that on the line
and if dan is on the line um
luckily taiway is going to help us out
hmm so many chances for pure doge
how about alex
um so your dominant form will be b
because you have
the opportunity for h bonding in that
form
that's strange i mean i also have
opportunity for
hydrogen bonding um in this compound
but yet everybody was adamant that two
amino pyridine is going to be in the
form of the amino autonomy and i believe
that was
tim who insisted upon that so
tim are you in agreement with alex
yes does anybody think a is the right
answer
do you think it could be depending on
the solvent if for example the age
bonding is attenuated
in a way that could become actually a
dominant form
that would be a way of thinking about
how you might be able to control
uh selectivity in terms of alkylation
but
what alex said is actually right in this
case it is very very dominant form
to the extent that it's the major one
you're going to see in terms of
reactivity in solution for precisely the
reasons you mentioned
which is hydrogen bonding effects so in
a case like this
the more nitrogen atoms you add to a
heterocycle the less
aromatic it is and so the penalty you
pay
is actually very low anyway this
compound is still aromatic
and you've got the bonus of hydrogen
bonding effects
but maybe the situation changes here
alex do you still want to do the same
thing and select b
or are you going to finally go with
a um i think b is still more dominant
for the same reason anybody want to
disagree with her
so i will so i will say like when you
first look at look at these two
two forms um the first one
feels more correct just because when you
see the the exocyclic olefin or the
exocyclic immune
like that it just doesn't feel right but
then you
consider yeah the higher level effects
that might be happening in a in a flask
or an
insolvent um and that might push you to
think that maybe
yeah the hydrogen bonding is a little
more of a stronger force here
yes um especially because like if our
i imagine what life would look like if
um
you know uh those automatic forms where
we're in the enol form and not the
the form that can h bond and i wonder
what would happen to
to our dna and things like that so
you'll find out in a minute we're
actually going to cover that brennan but
that's a great
that's a great point and so again in
both cases
b is the right answer so the take-home
lesson here is remember the more
nitrogens you put into a ring
the less aromatic it becomes other
effects become dominant and one of those
is hydrogen bonding that can direct the
tautomeric
equilibrium to the one shown there um
another case of aromaticity driving you
to important directions is thinking
about patent law
so i've seen cases where folks will put
the wrong
pottimer in their patent and their
structure
we probably have people on the line in
the outside room that
you know write patents all day so if you
are putting the wrong form taught
america form you open yourselves
up to potential litigation uh with folks
saying oh
it's not the same compound they didn't
know what they had and um
you know generic cases have been tried
with with with very very similar types
of situations so it might seem frivolous
to you
but it's kind of important to know what
automatic form your api is in
let's take a look at the effect of
hydrogen bonding as alex brought to our
attention here
and how it can impact tautomeric forms
of
substituents on a heterocycle so for
example if we have a
pyrazine or a pyridine such as a
and we've got a ketone that's adjacent
to it
what what do you think is going to be
the effect
of the tautomeric four equilibrium is it
going to reside
as compound b or will it just stay
in the form of compound a uh
maybe million
uh or um carter
whoever wants to jump in first seems
like b
would be the correct one based on what
we've been talking about
yeah b would be the right one but let's
take it a step further
since you you you volunteered what
happens when i now
benz annulate in the case of c so if
i've got a quinoxylane
or aquinolin what happens then
i think still the nitrogen would be
available for hydrogen bonding
uh and even though it wouldn't it
wouldn't disrupt
the aromaticity of the uh appended ring
yeah uh that's true however in the case
of c
the dominant form when you start putting
a benz annulation on there
it is it is in the form of c not in the
form of the enol form
um and so but but your point is a good
one
and this compound is still very acidic
so
this is kind of like a melanate proton
very very acidic because remember as we
talked about before
you got a pyridine like nitrogen that's
like an immune
so this to me looks the same as
dimethylaminate in terms of reactivity
now we get to brendan's question of he
thinks it would you know this type of uh
tautomeric situation has a lot of impact
on
you know potentially our evolution and
it turns out the reason
we're doing this class over zoom and
we're not just
climbing trees and eating small fruits
and
little monkeys is because of this
phenomenon
so tautomerism is the reason you're here
and the reason we're doing this
with an ipad and normally the
dna bases like to sort of get together
atgc we know that
so adenine and thymine have a nice
complementary hydrogen bond or hydrogen
bond acceptor
forms the basis of the dna double strand
keeps it together really nice and tight
however something can go wrong when
cytosine
starts masquerading as thymine because
cytosine can sometimes be
in this tautomeric form
and now you can imagine you can have a
hydrogen bond acceptor
here and a hydrogen bond donor here and
so
c can sometimes couple with a
and such types of mutations are what
happen in
evolution and that's what sort of drives
i guess a lot of evolution is
one of the fastest of it is this
tautomeric form of cytosine
that steps in for thymine on occasion
and that's how you get
random mutations there's a question from
the chat so what is that
let's know how relative
well how relevant is the bond strength
argument when determining tautomeric
form it is very relevant it's kind of
like the same
for the same reason that uh
you can go everything i'm talking to you
about you can go back to frontier
orbitals and
and rationalize it out the point of this
class is so that you don't have to
necessarily
do that rationalization but if you want
to take it back to first principles you
certainly can
so everything i'm saying has a strong
basis in what you learned
in uh phys org i guess
you know the pka of phenol is around
10. pka of aniline is around 35.
it's easier to take phenol and do
alkylations the alpha position that's
known
but it's pretty much unheard of to do
that here
and it has to do again with the bond
strength argument that you can make for
the oh bond here and the nh bond here
the same bond strength arguments can be
made
for determining tautomeric equilibrium
but all of that
is directly proportional to uh as well
the relative aromaticity
so these kind of um
uh ways of quickly ascertaining
tautomeric equilibrium are a
substitute for going to your dft
calculations and actually calculating
uh bds but you can do that if you want
to
great question uh so tautomeric
equilibrium can also be used to help you
in terms of
reactivity so when i look at a uh
isoquinolone like this
you can imagine this isoquinolone is
very very
similar to a regular amide and or even
looking at this as a carboxylic acid so
if you wanted to take a carboxylic acid
and convert it into a derivative by loss
of water you could imagine doing that
with a variety of different coupling
peptide coupling reagents and one of the
ones that you can use here is pi brop
this is a very very useful method for
skipping the step that often people do
which is a pocl3 step
to convert that into a chloride instead
you can just do it in one pot
and get your nucleophile added in there
directly as if it was a simple
carboxylic acid
in fact you can take such intermediates
and even use them as
surrogates for a halide in suzuki cross
coupling
so these are this is a really useful set
of conditions to remember
especially when for instance the rest of
your molecule
doesn't tolerate something like pocl3
this is a much more mild way of getting
the job done
okay um yeah uh if i wanted to
um protect this kind of quinolone uh
with this group
and then if i had halogen as well and i
wanted to do a saluki
cross coupling with the halogen go first
or i couldn't use that as a protecting
group
what do you mean you want to sorry i
don't get the question so you want to
convert it to plco3 convert it
uh yes so if i re reacted with the
eyebrow
okay okay i and that had say a bromine
in the throat position
or somewhere and i wanted to do it
you're asking what the relative
reactivity is of that intermediate
add-on
standard bromide it's going to react
kind of like a triflate
and so i would anticipate you could find
conditions that would give you
selectivity
of the pi drop activated in this case
it's usually an oat
hoat type adduct um
that you could get selectivity of for
sure i bet you would get the selectivity
of that coupling
under the right conditions versus a
bromide it might be even easier to use a
chloride but i bet you could even get
a difference between um if you had the
bromo here and you had the o
activated group here is that the
question yes yes so the question is
basically
could i use this fiber as a protecting
group for oxygen or that would go first
well you wouldn't protect it so you'd
make this in c2 nobody makes the adduct
and then
carries it forward in a subsequent step
it's not stable so you activate it in c2
and then you do your suzuki right yeah
yeah what i mean is if
if i wanted to do a suzuki on a just a
three bromo queen alone
uh normally you would have to be
protected somewhere either and
ventilated or it would have to be an
opmb or some other protective group so
that's why i'm asking whether you could
just detect it an oxygen and then do
absolutely on the bromide but you're
saying basically it's gonna
go i think the best way to achieve
that and that's a really good question
so we might as well take a sidebar by
the way this year
i'm not under a time crunch to finish
these lectures because
much of the content we've added a lot of
new content but a lot of it is also on
youtube
so if we don't finish the lecture in
time because there's a lot of good
questions
i'm not going to rush you'll just have
to finish a lecture yourself on youtube
if you're taking the class for a grade
so let's go through next question and he
points out that when you do a standard
suzuki the problem is these suzuki
conditions are rather basic this is a
great i see this consulting problem all
the time this type of thing
you generate this anion and guess what
oxidative addition is shut down
that's next question how do you do
suzuki on that so there's a few
ways of thinking about it one is to try
to
nc2 protect as a tms i've seen people do
that
they use usually this bt
msa this trifluoro sorry
this trimethylsilo acetamide
and that will instantly put a tms group
here
and uh that gives you a better chance of
getting the coupling
another way i've seen people do this is
using anhydrous conditions
that are less basic suzuki conditions
another way i've seen is people
using additives like copper to chelate
that nitrogen
and thereby allowing for less of an
equilibrium that
lies less than the anionic side and more
of an n metal and copper
that gets you oxidative addition here uh
worst case scenario if none of that
works as you said you could throw a
dimethoxy benzyl on there
and then remove it upon workup with tfa
but that's a great
great point and we're also going to talk
a lot about in this class
halo selectivity so when you've got
multiple halogens on a molecule which
ones react first
yeah i'm asking this because the ligands
that make the period on ligands are
always
hard to protect uh the oxygen first
you use a pmb or a tse protection group
and do a suzuki
so normally they work with a it's a much
lower yield if it's an unprotected
very very done and that's the reason why
yeah okay thanks
yup great great question um you know the
facility of
as just as the facility of uh parasitic
reactions
uh increases as aromaticity decreases
the same thing for
strange little rearrangements like this
one that can be quite useful
in this case we take an again we see an
ice oxazolone
we treat this compound with either heat
or light whatever your favorite
conditions are
and out pops an oxazole from this so
can someone rationalize what might be a
step maybe
uh aaron could tell us anything about
this compound
what he suspects happens when you just
heat this thing up
or like it looks like it's a deep
carboxylation
oh brilliant that is great so if we do a
decarboxylation i'm just sort of
abbreviated like that
that's going to give us basically r1
here
[Music]
r2 eraser
with a carbine which you can also if you
don't like to think about carbines in
your mechanism
a little trick to use is a plus minus
there
and then cyclization and tautomerization
and there's your product
just in thinking about this mechanism i
had drawn it where you
like have stepwise cleavage of the no
bond and then decarboxylation
yeah we can certainly do that too if you
like um so if you want to go through
sort of more of a radical like mechanism
you can imagine
that you get an intermediate like that
and then we can do the whole sequence of
events in the same way so
that rate of decarboxylation should be
high
and then that di-radical will then
cyclize via
going here here here is that what you
had alex
yeah essentially yeah that's fine too
either mechanism is fine
but remember the key the key message
from this is that although this ice
azalone is aromatic it's barely aromatic
right it's kind of like yeah i'm
aromatic but i'm not too happy so you
heat me up or you shine light on me
and i'll very happily liberate co2 to
become
something which is more aromatic which
in this case is an oxazole
great let's talk about
the effect of different types of
nitrogens on
attack with electrophiles so
this is really important um and again
these are the sort of constituent parts
of
lar of complicated heavier cycles so
i've seen this in exams
it is maddening just remember this if
you have a pyrole and you deprotonate it
that is wicked reactive it will alkylate
really really well
it will react at nitrogen if you have a
pyrrole that has an r group on it
this lone pair will not attack anything
don't do that in a test don't propose it
please
they don't attack anything they're
always going to attack at carbon
uh nitrogen atoms and pyridines
obviously really really high reactivity
and if you have a perillium or a sorry a
pyridinium
do not try to attack it's all dead it's
pretty much
nothing left there the nitrogen can't do
any more attacking
so with that in mind
when we treat pyridine with
acetylchloride and methanol
two types of esters arise as the product
and luckily we have some volunteers to
help us with this one
they can speak up now or i can call on
them
how about ellie
what is the first elementary step do you
think of treating pyridine with acetyl
chloride
will you um like acetylate the
nitrogen oh that's okay wonderful
great now what do i do
um you can attack with the um
like methoxide or with methanol
all right awesome where do i attack
um at the carbonyl carbon
that cleanly gets me back to my product
uh starting material sorry
great and that gives us
methyl acetate and starting material
which means we need to do something
different
because certainly i wasn't asking you to
get turn pyridine
back to pyridine so let's think about
what else
uh this can do
um maybe attack at like the two position
the methoxide
great let's think about that
okay now what what's that gonna do
oh i should draw it like that there you
go
i'll give you a hint
there you go that's the great hint
um okay so you analyze
[Music]
um
now what do i do i have a new there's a
new nucleophile in town
okay so you can attack another acetyl
chloride
okay but product is going to have two
different esters
and i still haven't made even one
so what else can i do i have this is a
you've identified this as an
electrophile
are there any other electrophiles that
you've generated before and previously
drawn on this screen
let me give you a nice hint
oh so the sorry the two position of the
alkylated purity
and then what happens to that all i need
is one more step i need and i can turn
this into an
ester
um methanol attacks at the carbonyl
and i said there are two products you
identified the one
arising from a c2 attack is there
another position that i can attack
yeah the c4
chapter hydrolysis
brilliant tons of pyridox coming your
way that was great
so that's why when people do ricer type
reactions or when they
alkylate at c2 you don't use
you use something like cbz chloride or
benzoyl chloride you don't use acetyl
chloride because then this uh
mischief can go on that makes sense
let's get into the um and maybe for the
we tried to install because we knew we'd
have so many outside folks
that were in companies and lecture one
two and three is often difficult for
these outside folks because
often they they know a lot of this stuff
so we tried in each of these lectures to
put what i call a little consulting
corner
which is to encompass what is uh a large
a very large proportion of the questions
that
i get which is the curious case
of amidazole but furthermore it applies
to a lot of other heterocycles as well
so when you treat a imidazole
with uh an electrophile there's two
different nitrogens that are hiding in
there
obviously we have a pyridine like
nitrogen here
but we also have a pyro like nitrogen
here and so
if there's an electrophile with no base
whatsoever
what do you think their um
debbie is going to happen
well uh it's going to react with the
pyridine type nitrogen
that sounds good to me
um oops following
the loss of a proton
you'll get out your product
now if we treat this compound with base
we will obviously form
that but the problem with this
is it's called a mesomeric
anion and mesomeric anions are
a disaster for medicinal chemists
because they
provide regioselective quagmires
so when you alkylate a system like this
you can't get any control you end up
with a mixture
you often only want one obviously
they're going to represent themselves in
space
very very differently when you have r
groups here
and so that's a big big problem for
amidazole
for pyrazole all sorts of systems so
let's think about ways we can solve this
problem
one way of doing this is through
electronic bias
so if you take an imidazole and you bias
it in such a way
that there is let's say a halogen atom
put an x here where x can you be equal
to chloro
bromo iodo
and we treat this with sodium hydride
and our electrophile which is this
let's say alkyl bromide or alkyl iodide
you get 100
control with only
alkylation taking place here
and then you can do your suzuki
to get your product so electronically
biasing
headrest cycles is one way to do that
there are many many examples of this in
literature
for example if you wanted to take
triazole how would you take triazole
and alkylate it selectively
here
well um the answer is there's no good
way to do that
so the solution to doing that was
introduced by
bi many years ago in an orglad you can
put two bromines here
same concept and now the exclusive
product
is the one you want so
answer number one for how to control
register activity is electronic bias
so let's take a look at another
consulting problem that comes up a lot
which is
how do you alkylate a tetrazole this one
is tough because there's two possible
ones that
that you can get the one here or the one
here
it's one of the unsolved problems of
heterosexual chemistry of
how do you control which one you get so
in general when i'm faced with a
consulting problem like this
there are several things you can tell
the practitioner
one of them is kind of obvious
temperature acid base and electrophile
screen those sometimes you'll find that
there's one idiosyncratic base
and one type of solvent with a certain
electrophile
that just gives you amazing region
selectivity
and that comes from screening it's a
terrible consulting suggestion because
they look at you like uh you don't think
we thought of that
so that's the first thing you just make
sure that they're thinking
about that and they're thinking about uh
modulating the tautomeric forms they get
the next thing you can tell them is to
use a blocking group
such as a trital group so that's where
we get to steric blocking
so if you throw a trill group on that
because of the repulsion between a
triddle and whatever this r group is
here
you can get selective reaction at the
n2 position and so if you have a big
group at r often you'll get alkylation
away from that group
the final thing you can think about
telling people is
using neutral conditions for getting
their alkylation to go or acidic
conditions to get it to go
and if none of those things work you can
tell them to just make the heterocycle
from scratch
and that's why you need the other 19
lectures of the class so we'll get into
how to make all these heterocycles as
regiochemically pure compounds that
don't require
an alkylation step well there's another
very popular trick that people use out
there
called the cemetric eccentric is a
really nice one for basically taking an
imidazole
and making it do what you want because
you now have
discrete control of the type of nitrogen
atom in the ring
when we put a sem group on the midazole
we now have
in this case something which looks like
a ch bond
adjacent to a pyrrole which we'll learn
tomorrow or
on next week when we talk about chd
protonation
makes us quite acidic towards
deprotonation
when we then take this adduct and we
treat it with catalytic sem chloride
something really cool happens and to
help us with that
hopefully alex can
guide us
um so if after alkylation if you add
catalytic stem chloride you'll
protect the other nitrogen
but that will also essentially activate
like make the other stem group more
labile
so that'll be removed and
and then that'll make the other nitrogen
parole-like
so you can alkylate there
why do you think this reaction works
what's driving it
anyone
could be repulsion between the r group
and the sem group yeah
exactly so you're getting a
thermodynamic outcome this way we'll see
this a lot
this is a trick which is used quite a
bit in companies
in different manifestations
and in the in the first step so would
you still get
a bit of the calculation between the
night the
um yeah in the first step with utility
or something okay would you still get uh
an installation of the same group at v2
position
uh no in this case here this ch bond as
we'll talk about in a few days that ch
bond is more acidic than that one
if you did another alkylation you could
deprotonate there and put something else
there
where's the sneakers chemistry are we
getting to that
what's that yes it's what
oh i did on that and that's really good
because
we we skipped over oh yes great i'm so
happy we skipped it over because now is
the right time to talk about it
so let's talk about this case of as
indole
this is a super popular hedera cycle as
i mentioned to you before
indoles are very bad lee they're good
leads but they're terrible
drugs you don't take a regular indole
you usually try to turn into
something like an as indole so what what
based on everything we've been talking
about now
what conditions would you use to get
this product
versus this product and all we need is
sort of the conceptual
thought of what conditions you should be
thinking about maybe
we can either someone can jump in and
just volunteer or we can
go to maybe sunghan in florida
so to generate the top
molecule i would say use a basic
condition
what kind of base
that will give you that very cleanly and
now um
taking it further then what would you do
conceptually what would you do
to get the bottom one
so for the fountain one i think i would
use neutral condition and trade them
with the electrophile
brilliant
now for uh bonus doge coins
song han how do i go from there to there
so
anyone want to jump in for the save
that's worth at least couple of doge
points i would say
you just hit it up
[Music]
well you need something else um
remember the problem we just talked
about with imidazole
and some chloride what do we do there
oh you use the catalytic uh the uh
the separation in catalytic mao and hit
it up brilliant
lovely
so um the reactivity of these two things
is very different and that will come
into play when we talk
in lecture three for how the differing
ability to get these two
uh outcomes just based on thinking about
tutomerism
can be usually beneficial when you think
about how to functionalize
different parts of this ring system
so very very useful chemistry there that
we will
re-investigate in a future lecture
let's get to a real world problem uh
jmed chem problem here
from pretty recent um you see these
covalent reactor groups emerging as very
popular chemotypes
in medchem these days and because it's a
med chem paper
i'm going to make a disconnection for
you
that uses a simple suzuki and gets us
back to
this compound and then i need someone
from the medicinal chemistry team
to help us with a synthesis of this
compound now notice
we haven't done imidazoles yet so the
answer i'm looking for is not an
imidazole synthesis
answer but rather an imidazole
substitution
answer so where are our medicinal
chemists uh
we've got um let's see how about
uh
fang or britney one of them
i don't know if they're on they're
auditing the class
any thoughts me
yeah anything anything you want to say
now remember the challenge here is i've
got to find a way to put that method
group on selectively
yeah that's that's what i'm thinking
about but
um
[Music]
can you play the sound trick again
that's a great idea let's play the same
trick again
if i played the sim trick again what
would happen to this methyl group
what do i need to do to that methyl
group to play this word in other words
where do i put sem so
before you introduce the uh
the aromatic appendant or
the bromide you have to
um
the whole crux of the problem is how to
get that right regiochemistry of that
methyl group
i need it next to the arrow and this
bromine and this arrow
if i try to let's say let's say your
suggestion was
can i just do this
of course not because ar is
obviously larger than bromine bromide
right so there's going to be an issue
there you're probably going to
definitely get a mixture of these two so
bad disconnection so what am i where am
i going to put the
the sem group so that if i treated it
with a methyl electrophile
like methyltriplate for example it would
end up on the correct nitrogen
three or one uh
which nucleophile are you using sorry so
what my question for you fang is where
do i put my sem group
so that after treatment with an
electrophile my methyl group ends up on
c1
do i put it here or do i put it here
we can do both and see what happens
you'll probably get uh and three
methylated right so
we're going to put the same group here
we're going to put a bromine here
if you treat this with methyltriplate
it's going to dock here
and then the triplet will kick off the
stem where does this thing come from
well that's just a simple bromination
and so your starting material is simply
something like this
where you can take this compound you can
do a suzuki if you want you put the
cement group on first
then do your suzuki and then you
brominate the only available position
and then you switch the methyl group
over to the desired one just by treating
the methyl triplet
so see how this procedure this
understanding of how to dance is so
valuable
and think about it putting together
imidazoles it's kind of complicated
in fact uh we've got a section on that
for all the sort of topics that are
complicated in heterosexual chemistry
we've got a topic in the book on it so
let me let me direct your attention to
uh this one i hope it doesn't scare you
but
this is a cheat sheet for you in the
book that you could study
um you can of course make notes yourself
but here's the way to navigate the
roadmap
of amidozola substitution it's your
cheat sheet
of how to do it various sem tricks can
be used
um it'll teach you about which ones can
be deprotonated which ch bonds can be
protonated and when
all of this is in the book and all well
referenced
and so this is a little introduction to
something which is a little bit more
complicated
and so if you're in a company this could
be a very useful thing for you and if
you're taking it for
a grade it's something you should
probably you don't need to memorize
the great thing about this book is you
don't need to memorize anything you just
need to understand it
once you understand it you can draw this
yourself
so all of this is sort of easy to
rationalize based on first principles as
long as you know the first principles
a cheat sheet like this is not
complicated at all it doesn't require
memorization it just requires that you
understand
okay all right so we're nearing we're
doing great on time we have eight
minutes
and this is all we have to cover left
unless there's any other questions and
one of these is problem today number
five
a classic uh synthesis known as the
dondoni aldehyde synthesis
so it takes together the concept we just
talked about in a slightly new setting
which is a thiazole so we need
someone here this is problem today
number five is probably worth a
hearty amount of pure doge uh we'll let
someone volunteer or if there's no
volunteers
we'll pick on someone
i'll jump in all right what do you say
alex yeah
um so the first step uh the
nitrogen is like pyridine-like so
it will attack the aldehyde
now what do i do um the
negative oxygen can pull off the tms
group
and then that'll give you like a zwitter
ion on the heterocycle
um and that anion can then do that
sorry now what do i do alex
attack a second equivalent of the
aldehyde
at the carbon
and
now what do i do then you can play that
same tms trick
and that'll give you back an equivalent
of
the aldehyde also
awesome this is the dondoni now alex uh
to get even more puridoge
can you tell us what the oxidation state
of this position is
uh acid yes
and you'll notice that the product in
the dondoni aldehyde
this is the canonical one which is shown
down here is an aldehyde
so conceptually what do i need to do to
this thiazole to get me down to the
dondoni aldehyde
reduce it by one oxidation state and how
am i going to do that with these set of
conditions i've got this methyltriplate
and then borohydride and then
this is not an organometallics class i'm
just going to say
oxidant so
what's the for what's the first step
doing let's focus on the heterocycle so
i treat this compound with
methyltriplate
what happens you'll methylate at the
nitrogen
now what and then i guess the cn bond
will be reduced
now what oxidation state is that carbon
the aldehyde
and then a general oxidant in the old
days they use mercury
you can use hypervalent iodine these
folks use copper
and then this is just hydrolyzed to the
corresponding
aldehyde that is dondoni uh
what things did i not mention today um i
didn't mention
pyridine and oxides and in the last
couple of minutes
that's a really important topic for me
to cover very quickly
and luckily we've done the hard work of
covering pyridine and oxide
already in the pyridine chapter so
when you think about substitution on
pyridine we're going to talk a lot about
some of the most popular ways of
substituting pyridine
tomorrow and especially on monday
another class that we don't talk about
so much
when you think about what pyridines do
with electrophiles
with obviously with acids they give
salts with lewis acids they form
coordination complexes they form ligands
as nick
of course is making a bunch of those
ligands in his in his lab
with halides they form reactive uh
complex like pyridinium trio or bromide
um with acid chlorides they give acyl
pyridiniums
we'll talk about the reactivity of those
types of things with uh
emanating agents they give n-amino
derivatives but with oxidizing agents
like mpva for example
you get pyridine and oxide which is one
of the most useful types of ways of
derivatizing a pyridine
because of all the variety of things you
can do which usually involves
as we'll talk about tomorrow ortho types
of reactions where the pyridine and
oxide
is rearranging you're losing the oxygen
re-aromatizing
after nucleophile adds and uh that gives
you out a
sort of substitution adjacent to the
nitrogen
you can do a lot of different types of
reactions i really recommend strongly
recommend you spend
i don't know one minute that's why they
all you need one minute on this chapter
you can look at this page for a minute
you can tap on these different numbers
and it'll show you sort of examples of
all these things
um but a really useful uh broad summary
of the
interesting things you can do with a
purine and oxide which is one thing that
kind of belongs in this lecture
but uh there was no time to talk about
it today so with that
we are done with lecture one of three of
the general reactivity phenomenon of
heterocycles
how do you substitute them to get the
right compound you want of course the
lectures after the third one are going
to be all about the multi-faceted ways
of making them but we have to get
through
even though it is quite tedious we have
to get through the ways of rationalizing
substitution and that's what this
lecture was all about
so we'll see you for the next
installment at
8 am sharp on wednesday have a great day
everybody