okay folks
it's 8 a.m so we can get started uh
welcome to lecture number two
uh where we're going to continue talking
about reactivity of heterocycles and
this is going to aid you
in the process of substitution once you
learn how to make the heterocycle which
we won't cover for another few lectures
so um last time we talked about a number
of
features of how to substitute a
heterocycle and today we're going to
start with
what about electrophilic attack at
carbon
and the canonical representation for
friedel crafts of course with the
regular benzene ring that you learned
back in undergraduate chemistry is shown
here
through the famous sigma complex or
whalen intermediate
and when you get to heterocycles though
things change up a little bit for
example as we talked about
at the beginning of yesterday's class
nitrobenzene
and pyridine can be thought of as
synonymous the only difference is that
when you treat pyridine with an
electrophile of course as we're going to
see today
it goes very quickly at nitrogen as i
think we talked about that last time as
well
so you're not going to get friedel crabs
on a pyridine very easily unless you
start putting
electron donating groups on there such
as an amino pyridine which then
undergoes bromination for example
with pretty good ease and then if you
talk about the pi excessive heterocycles
we talked about that
on monday for instance pyrrole is going
to go at c2
indole is going to go to c3 we talked
about the reason for that
furan a little bit less likely to
undergo frito crafts because you're
um you know there's not that much it's
not as pi excessive
as those nitro pyrol type heterocycles
and then thiophene
sort of a baseline and then we also
talked about how to take a pyrrole
and inverted selectivity by simply
adding a ceracle
sterically blocking group like a tips
group
but it can also be done with things like
a tosal group will also
get you to c3 instead of c2 um so based
on this
and based on the ideas we talked about
on monday where you can take
two types of nitrogens and the
reactivity can be viewed as a
superimposition or combination
of the two reactivities that are
engendered by those two types of
nitrogens
we get the problem of the day number one
and perhaps it's worthwhile to mention
that we have
approximately 145 circulating pure doge
currently a lot of people have um
a good amount of pure doge so i'll let
you volunteer
for this problem of the day or uh
i can call on someone if no one sort of
offers a suggestion for this
i can do it so
you have both uh
pyridine and parole like nitrogen
so you'll end up with bromination at the
c2 position
because of the like control of the
pyridine
like selectivity great so that's exactly
how to rationalize it you don't need to
memorize it you don't need to go into
any fmo theory to do it you just
memorize these simple
understand these simple rules of what a
purity nitrogen does and what a pyro
nitrogen does and
yeah that's exactly what's going to
happen now
a frequent consulting question that i
get
over the years is this one they have a
complicated heterocycle and they wonder
you know where
is electrophilic aromatic substitution
going to go where is bromination going
to go
and um what are some ways that you would
think about
uh rationalizing where these might go it
may be
based on first principles you have any
idea uh to begin with let's
look at this structure what are some
possible sites that you might worry
about
if you're a medicinal chemist looking to
do suzukis or buck walls or whatever
and you're worried about where your
halogen is going to be installed
uh what do you think jin chen
i think it will go one because that's
the
only way you can draw some reasonable
resonance
such structure right okay you're going
to go for one
of uh absolutely valid a good choice
any other any other suggestions do you
agree with that aaron
or perhaps kelly do you agree with uh
jin chen's idea
brominate at c6 because it's kind of
like in the three position of a pyridine
twice
are there people who agree with kelly or
jin chen's location
i agree with kelly agree with kelly
anyone agree with jin
i mean i think um both of those
would be the first i would guess just
because one feels
right for some reason and six i guess
electronically maybe
uh ortho to the uh
uh the um the aniline
yeah nitrogen sorry um but if you look
at the top
heterocycle maybe maybe it's not so
prone to uh
attacking and throwing because of the
this uh cyano group
they're pulling electrons out but i
guess it's tough to say
it's tough to say yeah i'm not going to
give you the answer yet how do you like
that
let me go to the next one brendan since
you're already unmuted uh what do you
think of the next one
i guess i only have three choices there
so i get a 33 chance
maybe maybe see
abc 2.
uh anybody disagree with brennan here do
anybody want to go with c1 or three
um tim or simona or ellie anyone want to
opine on
if they have a differing opinion on this
i would also be kind of split between c2
and c3
um you have like the pearl-like
reactivity with c3 but you also have the
pyridine reactivity with c2 so
it's kind of a toss-up for me kind of a
toss-up yeah
so the the right answer for these is um
c6 uh for the first one and um
for the second one c2 but
the problem is you can rationalize it
along the lines of the ways
you folks rationalize it but it's
ambiguous isn't it
and if you're a medicinal chemist how do
you plan out a route
where at the very end you just have to
sort of hope and pray that
you know you're right and maybe pull the
department and use that as your way of
determining the answer
luckily there is a better way of doing
this and it's a method that i really
really like because it
doesn't require extensive computation
and it comes from this
joc paper from some former students uh
and i've given this out a lot in
consulting sessions it works really well
everybody has chem draw while most
people do and so you can simply use the
proton and carbon prediction software in
the chem draw that is
instantaneous and use that to
justify where the site of halogenation
is going to go
and just by looking at the lowest proton
and carbon shifts
that will basically tell you and they in
this paper they do
a huge study of all these sort of
literature examples they do some of them
in the lab themselves and find that
there's a
a really great correlation and the sort
of take-home message of this is that
for the types of heterocycles you see
here this method works really well
for these ones however there's sometimes
a discrepancy between the prediction
software and chemdraw
and the actual result you get and in
that case it's probably better to use
a homo map if you have a if you're in a
big company you have a computational
department
they can do that for you and that would
be the way of a
medicinal chemist planning out a route
with a late stage halogenation
and a poly substituted heterocycle and
having confidence on the location
of the halogenation
what happens when you take a pi
excessive heterocycle like pyrrole and
you simply submit it to treatment with
acid
yesterday someone already suggested that
this type of thing would happen
but does it stop there has anyone ever
done anything with pyrol in the lab
well it will get polymerization aha
you get polymerization so what must be
happening is that one molecule does
what i show here and another molecule of
pyrrole comes in and says hey i don't
want a proton
i want one of these folks
and uh often when you of course
uh take pyrol and you leave it exposed
to the air or you leave it exposed to
um just let's sit around for a while the
bottle of pyrol you get is usually
very dark color and the reason for that
is it's polymerizing
it's also reaction with oxygen uh
through a single electron transfer
mechanism and so
that's what happens there but there's a
useful way to capitalize on this type of
interesting reactivity so
let me ask you uh nguyen uh does the
same thing happen
uh with the bromo pyrol here what do you
think might happen with
weekly acidic conditions um you will get
a
rearrangement from the prominent atom to
the three position
brilliant so this is our first exposure
to halogen dancing
and it can be rationalized
i mean usually you will need up some
some substitution on the
nitration of the peril to make the
thermodynamic
equilibrium favor this reposition right
um
it actually works with nh but usually
yes you'll have
an alkyl group but um the important
thing to remember is that these dancings
do work really well
there are some dramatic examples of the
dance for example
you can take this compound
treat it with acid and you can actually
get
that compound to arise as a result it's
not limited to bromine
so there's other types of header atoms
that will do the same dance
most popular is sulfur so a sulfur adam
will also do the same type of dance
we will talk about halogen dancing quite
a bit
in this class particularly on monday but
it's going to be in the context of a
different type of dancing that involves
anions rather than cations
but this is a useful one to keep in your
back pocket to remember
of course conditions here are carefully
controlled so that you don't get
uh black tarry mixture of products but
it is a useful
tactic that has been seen quite a bit so
we're going to cover some total
synthesis
and um you know i don't want the sort of
medicinal and process and industry folks
that are on the line today
to be too bored by this uh but there are
some really important take-home lessons
from looking at these
natural products that can translate into
your own
programs so let's take a look at the
example of prodigiosin
it's a pretty famous little alkaloid it
dates back to biblical times it was
produced by
bacteria and actually alexander the
great's most difficult conquest
apparently
came as a consequence of this alkaloid
because there was a piece of
bread that was apparently bleeding and
that was a
message to the macedonian troops that
victory was
theirs if they just went out and fought
and so alexander the great then went out
and did what he did and i guess
western civilization history followed
after that um so there's been victories
associated but also mass
casualties so the the famous mass of uh
balsana
if you're catholic where some bread was
again found bleeding
uh was named a miracle and started the
festive
festival of corpus christi but it also
led to a lot of um
mass executions of uh jewish people
because they
viewed uh the bread bleeding as a sign
that there was something
the matter with them so uh all of this
because of a little red alkaloid
now how do you make this compound are
there disconnections that you can think
of for
a convergent retrosynthesis of this that
would simplify the picture taking
advantage of innate reactivity
of a pyrrole i'll make it easy for
participation by
maybe labeling some carbon atoms
maybe sunghan over in florida can help
us out what bond do you think might be
an interesting bond to break
i guess seven and eight maybe you can
use
the similar condition you mentioned
above seven and eight that sounds
pretty good um we're gonna use the
conditions we talked about so that's
that's great that's a great idea
are there other bonds that we can break
two and three oh that's awesome a lot of
dogecoin coming your way my friend
all right so that gives us two
intermediates one of them
is the rather electron rich
i roll here and the other one
when we cut that bond what is left in
its wake
is going to be an aldehyde
that will be compound b so let's go
forward with the
root and as somehow
mentioned we can use the same chemistry
we just talked about
and these two will condense together
very easily
to give us the this pyrrole adduct shown
here
just going to label the e is ester
and when we take this compound and treat
it with palladium on carbon and heat
what do you suppose is going to happen
we need a nice processed chemist for
this one how about daniel
um
here's your hint the carbon skeleton is
still there
i'll even throw the ester on there and
i'll i'll give you the methoxy how's
that
yeah um
what's going through your mind are you
thinking like uh where's the hydrogen
gas
yeah that that definitely passed my mind
but i don't i
um i would think
hey daniel i'm going to do you a favor
i'm going to give you hydrogen i'm going
to give you some hydrogen gas watch what
i do
all right now how about that there's
your hydrogen i'm not adding it
taking it away i'm thinking away so
where can i take it from
um
molecule can i take hydrogen gas from
where am i going to get it
um on the to to form the
uh from the new heterocycle that you
added
[Music]
um
at the
i don't i don't know what position
that's called
uh so i'm i was thinking
uh from the two the one and two
well if nitrogen is one and then two
next to it
yes that's exactly right and you'll do
that not once but twice
and that will give you your fully
aromatized pyrrole so dehydrogenation is
like this
are very common in heterocyclic
chemistry uh
the the parolidine is a fantastic
hydrogen donor so you can do a
easy hydride transfer by pushing
electrons in here
kicking out a hydrogen and do that not
once
but twice and then three times and then
four times and then
you've got a uh you've got a fully
aromatic
eye roll okay so this is going to see
you're going to see this quite a bit
this is a good way to remember that
heterocycles unsaturated uh their
saturated header cycles love to be
fully unsaturated and you can do that
with things like ddq
sometimes oxygen will do it various
metals will do it
and will extract hydrogen from these
compounds
so yeah you're just removing hydrogen
great
now in the next step we're going to
treat this compound with hydrazine then
toss a chloride pyridine and then we're
going to heat it up with
sodium carbonate so um in the first
step all we're going to do here is make
the corresponding
semicarbazide there's nothing else to do
than to simply add in there
and um now we treat that with tons of
chloride
and hopefully camille can help us out
with what happens there
uh do you toss late
um the terminal nitrogen
awesome and why don't you take us home
um and then in the presence of base
you eliminate
um and then there's
loss of n2
awesome this is the famous mcfadden
stevens reduction and that gets us to
the corresponding aldehyde
which is super convenient because if we
go back here
wow that's compound b that's what we
needed
so that gives us compound b
and b can be combined with a to give you
the product
now we need to figure out a way to uh
make
the uh oh
yes we need to figure out a way to
access
uh oh it looks like i gave the mechanism
already probably the damage
so great wonderful so camille you got
full credit for that
problem the day number two we just
covered well we covered the second part
here
uh great okay so let's move on to
problem of the day number three which is
the famous synthesis of caterlac
which is a non-steroidal
anti-inflammatory agent that is still
prescribed today
and involves some very interesting
reactivity lessons
uh that start with problem today number
three so how about nathan
in california can help us out with this
one we treat this
so the um dimethyl sulfide will be
activated uh with the ncs reagent
by getting chlorinated
okay and then
um the plural can do
like uh sn2 type reaction
at the two position to kick out the
chloride
and then the counter anion is going to
pick on the methyl group
fantastic now when you take this pyrrole
and you expose it to plco3 and this
benzamide
you make an intermediate villsmeier
reagent that is
highly activated towards frito crafts
and that gives rise to
simply the benzoylated product with the
regiochemistry
you would predict and now when you treat
this with a
meldrum's acid-derived cyclopropane
and base something interesting happens
so hopefully
ellie perhaps or
taiway can help us with what's going on
here sodium hydride does what
it deprotonates the nitrogen of your
chiral now what do i do um then
i think you can attack the cyclopropane
like the um yeah exactly
and then that will open up
okay now we're gonna treat this with uh
an oxidant and um and then some sort of
base
so what's going on here
what is there to oxidize
you can oxidize the sulfur to the cell
phone
and then kelly and then you can
deprotonate
with base um like alpha to the meldrum's
acid moiety
yes and from there
you can kind of do like an snar
at the carbon where the sulfur is
fantastic and after
uh hydrolysis of the meldrum's acid
derivative treatment with base you get a
decarboxylation that gives you
tiralax let me ask you a question kelly
why can't i
make the anion here and just do a
snar straight on that um
i don't think that's a good enough
leaving group with sulfur in that
oxidation state
no that's correct and it can sometimes
be good enough if you've got pyridine
like nitrogens but in general
to activate those thiomethyls you're
always going to want to oxidize them to
the sulfide
and then you can do your addition
elimination but this is an exception to
the rule that we talked about before
where
addition elimination snar reactions
don't work well on pi excessive
heterocycles the only reason this one is
working
is because we've got this electron
withdrawing group at a position which
can be in resonance with
uh in conjugation with that leaving
group
all right fantastic so there's some
interesting reactivity lessons that
go back to the history of organic
chemistry starting with uh
woodward's famous synthesis of
chlorophyll and um
in order to go through this one we'll go
through it kind of rapidly um
we'll start on the left hand side here
this pyrol bearing an amino group is
treated with hpr
along with this aldehyde and what this
accomplishes
is just a protonation
of this amine first and then a friedel
crafts of the type that we saw with
prodigios and
after reduction with four hydride giving
us the intermediate here
now let's take a look at the right hand
side one i need help with this one
so when this chloropyrol is treated with
the other pyrrole shown here let's call
this
a and b treated with compound b in the
presence of hcl
somehow this adduct is formed it looks
like some sort of sn2 reaction but i
need help to understand
what might be going on here maybe tim
can help us understand
what what's going on
yeah sure so i don't think this is sn2
but i think if you push arrows from the
parole you can actually kick out that
chlorine
to make a pretty hot electrophile
that exocyclic olefin can then be
the electrophile for nucleophilic
addition
at c2 of the parole you're adding in
and this type of thing
is a type of quinoa methide
and um quinomethides are super
duper important in medicinal chemistry
and a lot of drug discovery they bare
their head
in many different ways they're used as
constructs for bioconjugation many of
the
analogs out there for antibody drug
conjugates use quinomethide chemistry in
order to release
cargo through a self-emulation mechanism
but there's a lot of mechanistic
problems and consulting problems that
come
from a understanding of when you can
make quinomethides they're found
all over the place so this is a key
concept and we'll form the basis of the
first consulting question that we'll get
to in just a moment
so thanks tim that's exactly right
following that
what is done is a simple friedel crafts
and then treating this compound that
results from the
fredo craft sodium hydroxide liberates
this milano dinitrile adduct by simply
it's a protecting group for an aldehyde
so all one does there is a michael
addition retro
aldol you liberate uh melanodinitrile
and that gives your aldehyde
and then they found that when they tried
to take this compound and this compound
and put them together
directly it was unfortunately kind of
messy so what
woodward did was a workaround where he
formed
first the thioaldehyde here
and he found he could do that using
ethylamine acetic acid
and then treatment with h2s that form
selectively
although you can get imagine amines
forming here and here
it formed with h2s selectively the
bioaldehyde
yeah there's a bit more nuance to this
but the bottom line is the thioaldehyde
is formed and that gives way to the
selective condensation between
these two units here after uh
union give out the precursor to
chlorophyll
well so where does this play into the
real world
well uh we a few days ago got a nice
consulting question from a big company
that will remain unnamed
and a person that will remain unnamed
but because they submitted the
consulting problem they are going to get
100
doge point so thank you very much for
that maybe you can buy a t-shirt later
on in the course
or something with that currency so the
consulting question was as shown here
they needed a modular synthesis of a
benzamidazole that we haven't talked
about how to make yet
and the substituents can't tolerate
highly acidic conditions
and when they tried this literature
condition where they were condensing
this
diamino trifluoromethyl benzenoid
with this ester what they were getting
instead of the desired product
was this ester type or acid type product
so based on what we just talked about
from this ancient um
chlorophyll example maybe tim can
continue to tell us
what happens based on his answer before
okay sorry i had a separate idea for for
how we could make this um so were you
referencing making the uh quinone
methide
yeah so cf3 groups that are
a para or ortho to an anionically
activated center
will form quinomethides and so you can
imagine the stepwise
expulsion of hfs not once but not twice
but
three times and then each time water
adds in
and finally that hydrolyzes to an acid
so what can we tell these folks uh to do
instead well before we get to those
suggestions
i want to mention that the concept of an
anonymically
activated cf3 group is actually
generalizable
so there's this ol paper from bms
10 years ago now it feels like yesterday
where the workers there found
a medicinal chemistry team
led by jennifer chow as i remember but
the famous
medicinal chemist ruth wexler was also
on that paper
found that when they take anionically
activated cf3 groups and treat them with
one normal
naoh in the presence of
you know this nucleophile let's say like
this amino
phenol the product that results from
that
condensation is the same as if this cf3
were an acid chloride
and although we haven't learned yet how
to make
benzoxazoles uh there's your first
exposure to it
so what do we do to help these folks
make the compound well there are a few
things we can try
first instead of using these highly
basic conditions
we could simply take the same starting
material that they currently have
and we could simply under more mild
conditions
like a simple peptide coupling agent
let's say a2
and apparently according to the
literature there's a patent on the topic
a compound like this should
spontaneously cyclize to give the
product with gentle heating
we won't need the acetic acid to do that
that's one idea
there's another idea you could use so
you could take
this compound which is readily available
and use ch functionalization logic
we're allowed to start with the
aerobromide according to the question
and there's a ton of papers we've we're
going to send everything to this person
there's a ton of papers to get this with
using
palladium rhodium uh you know there's a
thousand papers for doing this hazel's
are really easy to do
direct hex onto it's ch
you know ch activation if you want to
think of that way i just think of it as
a heck reaction
there's another way to do this is just
think about incorporating the cf3 at a
late stage so you can just use radical
chemistry to do that
and the site that you would expect that
the radical would go it's likely going
to give you a mixture but the major
product is most likely going to be here
you could use the diverse nates you
could use tony's reagent
whatever your favorite radical forming
conditions are to get that product
um this will be sent out to the person
who asked it with all the literature
references
in uh exactly the same way as i would
provide in a consulting session so all
of that is actually
free and in fact you're getting paid to
send such
questions to the class so for those of
you from industry that are listening in
today
you can see no ip was really given we
don't know the company we don't know the
disease area
your lawyers should have no problem with
submitting simple questions like this to
enrich the class so thank you to the
person who sent this out
any questions yeah phil i have a quick
question
um so in using that first example
uh instead of starting with the um
dinitrogen can you start with the two
trifluoromethyl
aniline and then i guess benzoylate that
and then do a condensation um would that
spontaneously cyclized uh
or would you also need strong acid or
base are you saying without the other
amino group
yeah and condense that onto the ketone
or the
yeah the ketone of the amide that you're
forming
are you saying make this compound
yes and then condense with ammonia or
something like that how do we get the
amine here
well i guess uh my thought was that
because it's meta to the cf3 that would
be
electron withdrawn enough for
nucleophilic addition
no no these are um not pi withdrawing
they're sigma withdrawing so cf3s are
terrible activating groups for any kind
of direct
snar you need the oxidation state here
to be something like
even if this was an x it still wouldn't
work
in fact even if this was a nitro it's
meta so it's not going to
work out for you uh so no you can't
unfortunately you're not going to be
able to add ammonia into a triple methyl
aryan it's a good idea but
that's not going to work we also
consider other ways like from nitrogens
the problem is we don't know the
identity of this arrow group so i
have to assume that there could be other
reducible
things on the arrow group so these
suggestions are given
with the greatest likelihood of success
with the greatest variability of the ar
group
but it's a good this is a really good
thing tim because we see this kind of
thing on the test every year
don't do that okay thanks
i'm very happy you you you mentioned
that
awesome okay let's then go on to the
question of how do you do
nucleophilic addition to uh various
ring carbons uh of a of a
oh we're going to get to that in a
minute but before we get to that let's
talk about electrophilic aromatic
substitution on azoles themselves and i
think a good
descriptor explanation for how this
works
is the classic case of taking nmi
and treating with benzoyl chloride
however if you take
just imidazole and treat with benzoyl
chloride a completely different adduct
results
so the chemistry here is kind of similar
to what we talked about with the dondoni
aldehyde synthesis and i remember
alex had helped us out with that and
she's welcome to
uh jump in here unless someone else is
itching to
help us with this problem i can go for
it
um so you'll put
the benzoyl group first on
the pyridine like nitrogen yes
um but if you have enough benzoyl
chloride around then you'll get
functionalization how
you'll have
so you'll deprotonate
and then that anion will be able to add
in
and then will that benzoyl group come
off just in like a
aqueous workup exactly
that's not stable at all so water is
just gonna
voraciously attack into there without
any problem at all but conversely
something different happens when there's
no methyl group
can you tell us what goes on here
so the first step will be the same
um but then i guess it looks like it's
adding into another equivalent
i don't understand how it does that um
what kind of nitrogens are available in
this molecule
yeah i've got a purity nitrogen so why
don't you just keep going like you did
in the previous problem so then that'll
just add into
like you'll have deprotonation again and
then that'll add in
perfect now this is a really
key point that when you form these
azoliums it's really easy to make the
corresponding illet
and those illids will add into
electrophiles very
easily in the case of this one this is a
in the protonated form is a really
powerful
electrophile so you can imagine that is
dimerizing
you lose one of the benzoyl groups that
results before workup
that one and that gives you out the
product now this is a very very
convenient
almost macgyver-like solution to
generate
this compound and i believe there are
some companies which still
make
the aldehyde at the c2 position of the
midazole this way
but as you can imagine all you need to
do is hydrolyze this and you get out the
aldehyde
no need for bromination formulation
conditions so a very very inexpensive
process friendly way to make
the aldehyde of imidazole which i
believe all rich
did this for many years they may still
do it but i just don't know
now continuing with that theme we talked
about this a lot with the dundoni
alex brought us through all of these uh
roots here with the
azoleum and building upon that knowledge
maybe
we can ask nick or debbie
whoever wants to volunteer how does the
uh the famous reaction shown here which
has a name
work so you would do uh schecter
and what do what i do um well i guess
again deprotonation
of the um diazole and then
and then you add in to the aldehyde
[Music]
which yeah which condenses
through the um the breast immediate
and that gives your product steadier
super useful way to do these types of
additions to make one for dicarbonyls
which as we will learn
i think next wednesday we start talking
about how to make heterocycles
one for dicarbonyls are phenomenal
precursors to pyrroles they form the
bedrock
of how we think about making a pyrrole
and this is the famous palnor
synthesis of pyrroles that we'll cover
in a week
let's talk about nitration tendencies as
we learn from problems of the day number
one
we're going to get nitration here these
two are going to be
very easy to nitrate these two are going
to be very very difficult to nitrate
they're
in general quite challenging this one in
fact there's no reaction
so you can't really get nitration on an
oxal it's very very difficult
these other heterocycles are less
reactive but you can probably predict
where they're going to go
just by thinking about pyridine like
nitrogen thiophene like heterocycle
urine like heterocycle pyridine like
nitrogen
same logic pyridine like nitrogen and so
you can imagine that the result of a
nitration event on these is going to be
here
here and here
now finally let's talk about what
happens when you start adding
nucleophiles onto
the heteroaromatic rings and we can
again
go back to the classic example of a
nitro benzene and these
intermediates are known as meisenheimer
complexes
shown here and it shouldn't be greater
than it's roughly the same
as a perillium or
a pyridinium salt and so it's very easy
to
add in nucleophiles to these species
these add in really really quickly here
here triazines can be added in directly
as well
usually people will add it in and then
upon air oxidation they will
re-aromatize to the triazine
and of course these you can get
nucleophiles to add into these
thiazoliums as well
now strong nucleophiles will even attack
the
more electron deficient heterocycles
such as pyrimidines
so pyrimidines are open for direct
attack
uh usually you need a pretty strong
nucleophile like a grignard will do it
it's not a technique which is often used
simply because of the
harsh conditions and functional group
into
intercompatibility and pyridine you can
in fact add to that as well
it's kind of difficult to do it directly
you can add
lithium reagents to them it's known as a
ziegler reaction you can reduce them
directly with borohydra with the lithium
lithium aluminum hydride and um and
there's a sort of dramatic example that
everybody knows
hopefully a famous uh name reaction um
anybody know it chichi bobbin
yes thank you simona so chichi bobbin
reaction since you volunteered the name
can you help us understand how this
thing works
yeah so you get a nucleophilic addition
of the
nh2 minus at the c2
and then this anion can be stabilized by
na plus and then you get loss of sodium
hydride
to get your product so the world's worst
synthesis of sodium hydride
chichi bobbin reaction not used very
often but it is an inspirational
reaction that led other people to
develop useful types of reactions such
as a
famous example that i can think of at
least of heart wigs
silver fluoride method for taking
pyridines
and going directly to the two floor
pyridine
which was directly inspired by the
chichi bobbin reaction
now there's another very useful way of
adding to
heteromatic rings this works on nitro
pyridines it works on nitro aryans of
all type
and this is a famous example from the
bristol-myers square process team when
they went about to make gram quantities
of the
famous alkaloid that we'll talk about
lotness class called duracomycin
do we have any boger students in this
class
uh okay maybe they're not raising their
hand
how about um maybe
fang fang over in florida can you maybe
guide us through what might be happening
here
um yeah so first
the potential tribute oxide will
uh deprotonate the chloride so uh
so yeah yeah yeah and now we will
directly attack the uh
yet disposition by a
snr snar type
now what do i do and you will be finally
deprotonated by uh
to build oxide and form the final
product
and upon workup as thing said
we get out the desired product brilliant
now
there's something very interesting about
this uh chemistry they call it vicarious
nucleophilic substitution
you see it quite a bit it's a really
useful tactic to achieve
a formal ch functionalization and um it
takes advantage of the fact that
the oxidation state that you need is
built into the reagent itself a concept
we will see over and over and over again
we talk about ring synthesis so overall
the if you didn't have that chlorine you
would need some sort of oxidant but
because the chlorine is there the
oxidant is built into the reagent
thereby eliminating and re-establishing
the aromatic compound
so a really probably the best example
i'm aware of out there currently
of a dns reaction from the bristol-myers
square process team mike schmidt
great so let's talk more about
pyridiniums because they are super
useful ways
of making saturated heterocycles
and a classic example of this comes from
dan komen's classic use of pyridinium
salts to generate
alkaloids and this sort of set the stage
for
dozens if not hundreds of different
papers around the world where they use
this type of chemistry to
start with simple pyridines and turn
them into highly decorated
pipyridines so when you treat this
compound with cbz chloride
what do you think happened stone
uh you um cbz
uh you formed the cbc adduct with the
nation
and then um and then add into the two
position of
the pyridinium sole
and then and then
we're gonna work it up right
yep
and now comes your puritone for
um pyridone product now when you treat
this with a grignard reagent it has two
choices
this arrow group can adopt the axial
configuration or it can adopt the
equatorial
when it adopts the equatorial
configuration
ar here that's maybe a bad color choice
there's a strong steric repulsion with
that cbz group so it prefers to adopt
the axial
and because of a stereo electronic
requirement
when the nucleophile comes in it can't
approach here
it must approach from the axial side and
so that gives rise to
the what you might think is
counter-intuitive
the assist product
and in order to complete the synthesis
all they need to do is
some simple functional group
manipulations that involve removal of
the cbz
lithium carbonate then cyclizes at that
position and then l-selectride does
a selective stereoselective reduction
of that ketone to give the desired
product
now there is a really nice guy that came
out from a former student joel smith
at the university of florida where he
outlines
a innate reactivity guide to anal
pyridiniums and the sort of previously
unrecognized
phenomena that sometimes these additions
can be
highly regioselective in a simple case
like 3-bromopyridine
when you methylate it you see the
selectivity is not very good
but when you start putting various
substituents for reasons that are sort
of at this moment not quite explainable
you start getting useful levels of
selectivity so
not sure how to rationalize this at the
moment but the interesting thing is that
in the cases where you do get high
selectivity these can be used to
very rapidly generate high complexity as
you can see here
in their synthesis of this interesting
insecticide now one of the
maybe the most dramatic example that i'm
aware of
of taking this commons type chemistry
towards complex molecule synthesis
emerges from snider synthesis of
cylindrospermopsin
this is a beautiful synthesis and um in
order to keep the industry folks uh
happy that are here today
i'm not going to talk too much about the
details of of the retrosynthetic
analysis i do want to just focus on
how they were able to make this compound
from the most innocent of starting
materials three piccolin
that's pretty crazy if you think about
it so we take three piccolin
and after a few steps we're going to be
able to convert this
all the way to a that certainly should
be
of some entertainment value to those
listening today so what happens when we
take
three piccolin and treat this with uh
h3o2 and acetic anhydride
what do you say tiffany
um i guess you might oxidize
awesome and now when we take the n oxide
and we treat this with
nitric acid and h2so4
perhaps carter can tell us what happens
oh sorry was muted uh now you can
nitrate
at the two position so we have a choice
of nitrating either here here
or here and you're saying let's just
call this two
four six i would i would say six
that's a great a great uh point
and i think what helps us to think about
the resonance structure of this compound
so that is a a dominant resonance form
in terms of the way you can
rationalize selectivity so when people
make an oxides of
pyridines and then they do this
nitration which you can find this
example if you check scifinder you will
find 20 000 hits for it
it's one of the most popular ways of
achieving
c4 selective functionalization
and almost always people are doing
nitration so
there's your surprise answer
now when you take this compound and you
treat it with potassium carbonate and
methanol
something can happen to that nitro group
any suggestions
on what that might be maybe they all
come from
brendan
um
oh um
can you can you add in methanol to
uh
i'm going to say the sixth position
awesome basically just an smar well
never mind that's not what i said the
wrong thing but oh you said six fishes
sorry
yes sorry but but yeah oh that's great
i'm glad you said six right you thought
the nitro group was
very stable and couldn't be moved right
i mean it is a toss-up
as hard to say well i'm glad you didn't
get it right
because then there's a reason to be here
so um
so yeah when you have an oxide that
nitro group is your gateway
you can add any nucleophile to that and
the nitro nitro will gracefully depart
and uh now with the only reason that
chemistry was enabled was because of
that and oxide
now we need to get rid of the inoxide
and that can be accomplished using
h2 and palladium there's a number of
ways of deoxygenating in oxides but
that's one of them
and then with that compound in hand
we're simply going to treat that with
the
chemistry we know well that we just
learned the commons chemistry
and that will give rise to this compound
with this compound in hand we're going
to treat this with the vinyl grignard
and exactly what we talked about with
the commons chemistry
will happen again
hey phil from a practical standpoint is
there a reason why
they use truck instead of cbz
because they have olefins and they want
to remove the truck without touching all
of them
great question so the truck can be
easily reductively
excised whereas the cbz will require
something like palladium on carbon
and you've got that annoying alkyne and
the
annoying olefin that is going to be a
problem with the cbz
so redrawn
you've got this compound which when you
treat this
compound with zinc and acetic acid it's
going to epimerize
this position
that is going to give you the after
l-selectride
compound a that you need so
i think it's a absolutely extraordinary
way
to think about taking a feedstock
material like
piccolin and converting it to something
super useful
so i have proof that this chemistry is
useful for the people on the
call that maybe are not able to speak
and they're from industry and they're
saying why is he teaching this useless
stuff
here's a consulting question straight
out of industry so
using the logic we just talked about now
how do we make that compound
anybody want to offer a suggestion
we maybe can let's see
uh who have we not called on how about
debbie any thoughts
any thoughts at all
um well we we can start from the period
as we we saw right now
we can form the anoxide
then uh treat with uh um
like you know from the nitro in the same
condition we saw before and then reduced
the nitro
after not now
oh i see i see what you're saying um so
you want to go
to a count you want to install that
nitrogen from the beginning
yeah is that what you're saying yeah
that is an interesting idea
now if we just go sort of we take a
a step backwards and just
retrosynthetically think about
how we can simplify this molecule what
is the first thing you would want to
look at and say i want to get rid of
that as fast as possible to make my life
easy
i mean the tetris of urine i want to get
rid of that but at a late stage
i do need to worry about this amino
group and i need to worry about that
stereochemistry
these are things i need to worry about
yeah so basically we have to use exactly
the same type of sequence we saw before
and in order to use that sequence i'm
going to require
that this becomes a carbonyl group right
yeah that's right okay
because i know there's a hundred ways of
doing reductive emanation to give me the
right stereochemistry
at that position i can use kinetic
thermodynamic conditions whatever bulky
reducing agent and i'm confident that i
can get that
so now i need to be able to put this
together and
uh it's probably going to come from a
compound like this
wherein
yeah copper yes and then
uh we attack there
this oxidant can be moof it can be
davis-oxaziridine
and that would give you
so the trans delivery when you do a
vicinal by functionalization
and all we need to do to finish is what
well
we can like
i've got to install a hydroxy here don't
i yeah
so i can do a hydroboration and then
just
sn2 yeah
selective tosolation of the primary
alcohol and then treat with base and it
should
slam shot to the thf frame
great so when you're making one of the
ways of thinking about we have a whole
class of zero unsaturated heterocycles
um and one of the the common tactics of
making more complicated saturated
heterocycles is going to be thinking
about
how you can get back to it from a
puridine
so that's a key lesson there all right
let's talk about
halo selectivity and a good way to start
off with halo selectivity
again this encompasses a ton
of um of of different
uh consulting questions i've gotten over
the years
is how do you think about putting the
molecule like this together
anybody have uh some suggestions on some
thoughts
what they might do here maybe some
building blocks
we need a good medicinal chemist maybe
ellie
yeah so um
i think that you have to
or i was thinking of starting with um
like where you see all of the added on
amines
uh have chlorines there
and then maybe doing some sort of
like fuckball tart wig nice
um that's wonderful idea ellie
that is exactly the way a medicinal
chemist would think now i have a
question for you though that might be a
little difficult
um i need to add those amines in you
said buckwall heart wig but
i'm going to counter with how about just
snar
yeah yeah because you know you use
you can use uh transition metal
catalyzed
amination when it strategically makes
sense
we'll talk about that when but when the
compound is innately primed
to do the chemistry already for you
there's no need
to break out your bottle of palladium
yet or copper
so in this problem we have a
trichloropyrimidine ellie
and obviously if you're a medicinal
chemist doing this stuff
you're going to have a challenge with
regards to the regiochemistry
so is that going to be on your mind as a
problem or do you think that this is
going to be okay and if it's okay what
order do i add the things in
yeah i think it's gonna be okay
okay tell me how um i'm gonna label it
for you so let's label yeah yeah thanks
so i think six and four have similar
reactivity for snar and they would react
first
oh that's really nice so i'm to
abbreviate this by
saying a i'm going to call this one
b i'm going to call this one c as our
three
amino components and what you're telling
me to do
is add in a first
i'm understanding you correctly yeah
yeah and then
b and then c i think
so you're telling me in the next step
maybe we need somebody to maybe we need
some audience participation
there is a two position and a four
position
and you're telling me it's going at four
next
yeah i thought so because it's like also
to one pyridine and then para to the
other pyridine
nitrogen but certainly sounds reasonable
anyone have a does anyone think c2 might
be the right answer
yeah i think it's c2 because suddenly
you have an electron donating group
um at your a position
well shouldn't c2 it's a one
will be the one that reacts first uh
when you come by with
a oh wow there's even some debate
as to whether where our first one is
right so we may be in a
a a lot of trouble so
um some people think c2 is going to be
the first
some people think that's either okay
with c4 being or c6 being
uh first but then there's this sort of
debate as to whether c2 or 4 are going
to be next
you can imagine if you're going to be
interviewed at a company one day
you probably should know exactly what's
going to happen
and luckily the rules are available for
you so
the first step is correct ellie is 100
right when you have a two four six uh
pyrimidine
chloride the trichloride the four and
the six
react really quickly first the second
one to react
is going to be c2
for roughly the reason that simona
outlined
and then finally
that's your product now uh halo
selectivity
is a really important concept in
uh heterocyclic chemistry and um
trying to rationalize what halogen will
get attacked first
often encompasses the way you will
design your
entire medicinal chemistry program
medicinal chemists
love poly halogenated aryans
processed chemists hate them so
poly halogenated aryans for uh processed
chemists
is bad for a number of reasons you'll
sometimes see that be done we'll talk
about examples where it's done
but in general they want to avoid the
halide waste and it also is a different
type of thinking
so medicinal chemistry all they care
about is getting to diversity
as fast as possible where each step is
modular so as you can imagine if we were
going to make a
tri-substituted pyrimidine a modular
casset-like approach where you've got
three halogens and you dump one thing
dump another thing and a third thing
is going to be pretty much 100 ideality
from the standpoint
of a medicinal chemistry program and
exploring diversity around a ring
a processed chemist though may look at
such a problem and say
you know what we need to start with
building blocks that don't have this
chloride
and simply build the exact target we
want such an approach might be beautiful
to a process chemist but an approach
like that would be
a horrific nightmare for medicinal
chemists
so halo selectivity is probably
more important for a medicinal chemist
than it is for a processed tennis
now it turns out that when you're
thinking about snar reactions on a
pyrimidine sorry can i see a question
about that problem sure
so you when you're adding a versus b
you add the morpholine last because if
you added it
first does that have the potential to
react in the next couple steps like why
specifically would you add a first
i believe the reason you would add that
one first is because
it is the least reactive of the amines
okay
and so you want your snars to be as
rapid as possible and an aminopyrazole
is like an amino pyridine far less
reactive than a
morpholine so these chemists realize
that
the morpholine can be put in last simply
because it's going to be super reactive
as you add in nitrogen nucleophiles to a
trichloro
pyrimidine it becomes less and less
likely to do
snar the conditions are more and more
forcing so that first set of first
conditions you can imagine the
temperature
is low then a little bit higher and then
a little bit higher
so you'll be one you'll want to plan out
these routes based on the
basicity nucleophilicity of your your
nucleophile
as well as the perceived halo
selectivity in the reaction
now this is snar but the rules often
also work for oxidative addition when
you do
suzuki reactions or buck wall heart
heartwood reactions
it's a fairly complex topic and it can
be
in some cases rather
idiosyncratic with the heterocycle and
the nucleophile you use but there are
some hard and fast rules that you can
use that we'll talk about
let's do this consulting corner where we
talk about halo selectivity in general
so in the case of a 2-6 dichloropyridine
uh let's see how about
maybe shenghan any thoughts on
a 2-6 dichloropyridine
which one goes first
uh i guess two so if i'm doing a suzuki
coupling usually two position goes first
if i do an snr reaction
it's nucleophile dependent i can
sometimes get four or i can
get two but in general the literature
shows that you're going to get
more c2 for uh transition metal
catalyzed
cross coupling what about the case of
three chloro indole we need an indole
expert
and um maybe tanner if he's on the line
can help us
yeah we yeah tell me about the three
chloro
indole can i just add in a nucleophile
to this let's say i want to add in um
this position should be already pretty
electron rich so maybe no
yeah i'm going to be out of luck i see
this a lot
and people are like well my buck walls
are not working and the reason they may
not be working is simply
when you if you're even able to make
that product it's not going to be very
stable
when you generate that product
as you can imagine that's not a very
happy compound we talked about why
already
on monday it's pretty pi excessive
heterocycle and so likely this compound
is simply going to
hydrolyze and deliver to you
that
so don't try to do snar reactions we see
this in a test every year
people try to do snr reactions on
heterocycles just like this
stop doing that if you want to do it
you have to have an ewg then it's okay
okay we already talked about this case
above
in this case this is one of medicinal
chemist's favorite starting materials
because you can dump in the
nucleophiles one at a time um unless you
have a very reactive
system amine for instance you can
sometimes get this edition but usually
it goes cleanly mono
this and tris now this is an interesting
case
can i take two amino pyridine and simply
convert it into
how would you do this let's say i want
to do
a suzuki reaction or
let's say i want to add a nucleophile
into a two amino pyridine is there a way
to do that
what do you say aaron any ideas
or stone uh form the diazonium or
perillium salt
diazonium is a good idea it's a classic
way you could do sand meyer
but the perillium one you mentioned is a
newly emerging
strategy former student
pep cornella has a really powerful way
of taking these perilliums
and adding all sorts of nucleophiles
into them and this is a really powerful
way
of thinking about an amine as a
placeholder for a halide or
a halide surrogate people often don't
like sandmeyer because of the conditions
can be harsh or not functional group
tolerant particularly if you're in a
really complicated heterocycle
so for the medicinal chemist in the line
this is a very useful method for you to
remember
uh there's he pep already published a
paper in aguavante but there's also a
chem archive the
deposition from a couple weeks ago where
he shows that the nucleophile can even
be things like a chloride or bromide
so very simple mild way of taking an
amino
pyridine and converting it into a halide
for subsequent cross coupling or adding
in a sulfur nucleophile or an oxygen
nucleophile or another nitrogen
nucleophile
to replace it let me ask you a question
would this reaction work am i gonna
am i gonna see this on the exam
um simona are you gonna put this on the
exam
no why not
uh because that position is too electron
rich yeah so this technology can only
work
when you've got adjacency to a pyridine
like nitrogen
please don't do this on positions which
are not activated so
the same goes for we talked about on
monday the piper chemistry
same thing goes for that so if i try to
do pipe drop
and some cross coupling on that it's not
going to work
on the 3 hydroxy purity it's only going
to work on the two
and the four great
how do you control it yes uh so
uh with regard to the um
trichlorophyrimidine
yes essentially uh the
the one that adds in first in the snar
is basically the one that
is uh relatively in a four and stupid
position in comparison to the one that
is double two position
whereas for example for um two four
dichlorophyridine
the one in the two position uh
is more active in transition network or
scotland so is that the same
for the current pyramiding or is it
different no in the in case of
like i said before almost always the
rules of snar
track evenly to the rules of
cross-coupling almost always
but there are a couple of cases like a
simple 2-4
dichloropyridine where those rules can
be somewhat nuanced
based upon nucleophile and conditions
and in fact
suzuki's in the case of a pyridine will
usually break that rule
of the snar but certain snars depending
on your nucleophile and your solvent
and your conditions will go at c2
instead of c4
so i'm going to talk more about these
nuances in just a moment but to
sort of get to that point i just want to
point out two things
before i jump in with a question before
you move on yeah please do
um you drew out a pyridinium but you
said perillium would either work
or so what i meant is that this is
derived from
a perillium
sorry about that wait i'm sorry can you
explain what you're saying
so if i take perillium and i treat it
with
a amine i'm going to get an addition
we're going to actually cover this down
below get an addition a loss of water
and it exchanges it to make a pyridinium
okay thank you yup and we're going to
cover that in just a minute great great
point there alex i sort of jumped the
gun
so how about the case of a compound like
that
where is that gonna go well as it turns
out the literature suggests that
soft nucleophiles we'll add here
hard nucleophiles will add here
and cross coupling will take place here
here's another example for you before we
get to a broad
overview
in this case we can do suzuki here
first followed by snar
here and in a case like this one here
if you've got a bromochloropyridine
and you want to control where the
amination is going to go using palladium
the sigmund group found a way to use
ligands to control selectivity so they
showed how they could use
one set of ligands in order to get two
chloro reactivity
and another set of conditions to get
three bromo reactivity or five bromo
reactivity
if you didn't know these conditions
existed i suspect it might be possible
to
to simply take aniline
and base if you show if you put this on
an exam
it would be 100 right
because again for the same reason that
simona mentioned
that bromo is not activated but that
chloro
is like a quasi-acid chloride
so sort of the future i think of this
type of halo selectivity we'll be using
ligands to override innate selectivity
now we did a great group meeting on this
topic 10 years ago
uh by will goodkunst who's now a
professor at
georgia tech and in here is
a lot of a summary by a lot of the work
that a
individual scott handy did many years
ago
where just like the chem draw prediction
software i showed you to predict
electrophilic aromatic substitution
the handy method is actually a truth in
advertising
a handy method for figuring out the site
selectivity
of cross coupling wherein you can use
the proton
uh spectrum to predict based on which
one is higher field
which one will undergo cross-coupling
first second and third
but this group meeting is a great
summary that
max will send to you it's also available
online for the visitors
to that summarizes really in a lot of
gory detail
um the details of halo selectivity which
make up
a large portion of consulting questions
that are out
there what about the case going back to
simona's point of these three bromo or
three activated systems being kind of
dead well what happens if i push it
what happens if i take free bromo purity
and right just push it with sodium amide
any ideas what might happen
sorry i can't hear you what do you say
brendan maybe like a like a benzylics it
won't it won't add in
so maybe it'll just eliminate the hp of
the the bromide
exactly
so pyradine exactly pure pyridine can be
very useful a lot of great work from the
guard group
over the past few years and others on
making and employing pyridine
in their chemistry okay so we have about
10 minutes left and in those 10 minutes
we're going to cover
rather strange additions to um
heterocycles and so nucleophiles adding
in to
not only pyridiniums but other types of
heterocycles that are
not that aromatic or have a an ability
to
undergo ring opening and addition so for
that let's take a look at
problem of the day number seven where we
need someone brave to tell us
what is going on when we treat this with
hydroxide
somehow it morphs itself into a
pyridone that is no longer a pyridinium
so who is going to volunteer for this
one
oh i can go with it all right great
union what do you say
um so you have the hydroxide adding to
the c2 position of the pyridinium
so then that will give you the structure
that is
similar to the hemiacetal
so then it can ring open from
the to form the ketone and the enaming
yeah then you have the the bond rotation
and then the ear the nitrogen just
attack the ester group and you have
the periodontal product
brilliant awesome job does everybody see
that
great what happened
okay what happens when we take oxazole
and we just boil it up with
formamide what might happen there
if we're using the same logic um we're
just going to
go from the oxazole to the imidazole uh
so nucleophilic addition
into that and then you get into c2 so
then
you have your ring opening and then
ring closing and you lose
water to re-amortize
and prior to the close to the workup
there was a
chl group here which just cleans nicely
upon workup same kind of logic again
here in the next one maybe tim you just
want to shout out what is the product of
taking this
ice oxazole and treating with hydrazine
what might emerge from that
your pyrazine just a naming issue
pure result
the isoxazole is simply a one
three dicarbonyl compound that is hiding
it's hiding when we talk about oxazol
synthesis and ice oxidal synthesis we'll
talk all about that but
you can imagine it's easy to exchange
that with hydrazine just by cooking it
up
let's move over to the other side same
exact logic
for this one and
it's actually kind of similar to the
chichi bobbin reaction
so we're going to add koh into this
we're going to continue to heat it for a
while
let's draw the ni in there
loss of hydride
basically hydrogen
after workup we get out that
uh we just talked about this alex uh
do you see how this is working
yeah so kind of the same idea how to add
in and then open up
when we talk about perilliums this will
be kind of important
how about uh taking an oxide and
treating with acetic anhydride
and then water what might be the product
of that
who is that nick nick uh yeah i said the
terror down it's the
bucket idea rearrangement well i'm glad
you said that because it's not the
vocalize
but it's something very very similar to
the buckle height
so this goes via
and then after work up you get that
right so it's not
it's not intramolecular
is intramolecular i mean okay let's
imagine we
you can draw it that way
uh i know that geometry is right for
this so no
usually people invoke the formation of
the c2 adduct followed by loss of acetic
acid
and then upon workup the oac cleaves
give you product
you're thinking of something different
and so i'm thinking that uh
when you said bocal hide what you're
recalling is a reaction that takes the
methyl group here
oh that must be the one yeah okay that
is the alcohol
a very useful way of doing
ch functionalization of alkyl pyridines
right right that one is the
intramolecular one that makes sense
yes exactly it's member yeah okay and
this one is
via
and that's how you get that so this is
the bocal hive
very useful reaction for functionalizing
methyl pyridines now what happens when
you take pie drop and a nucleophile
any kind of coupling reagent dehydrating
your agent tozo chloride will work too
sometimes but in general this is a
really useful way of taking in oxides
and priming them
for attack with loss of the
corresponding
and oxide and this is a very interesting
reaction
called the bamberger reaction
and the bamberger is important because
it's actually used in protein labeling
it forms the basis for why histidines
label really well
under these types of conditions not with
benzoyl chloride a different
electrophile
but can someone sort of shout out what
the product of this bamberger reaction
might be
it goes back to a problem of the day
that alex worked on earlier
she's welcome to opine on this or
someone else can jump in
i'll give you a clue the base is usually
with water present
you can do it in a buffer solution if
you want
do you get the one sorry
amino yes
so the intermediate this benzoylated
compound we shot we saw before
can be attacked and loss of formamide
gives you your cleaved product the
bamberger cleavage extremely important
if you're in chemical biology
that's how they label in a lot of old
cases at least they probably still do it
today
that's how they label histamine and we
have one minute left
and i'm just going to point out that the
zinc a reaction is shown here
a really useful way of excising the
nitrogen on a pyridine and putting
anything in its place that you want
and you can work out the mechanism on
your own it's pretty much identical to
problem of the day number seven that we
already covered so the nitrogen the new
nitrogen nucleophile
will come in ring opening ring closing
loss of dinitrophenyl
amine and you get a sort of metathesis
of one nitrogen
into another and we'll end the lecture
right on time
with the classic reaction known as the
ricert
can someone call out how this works it's
very similar to coman's chemistry that's
your clue
who wants to bring it home you isolate
the nitrogen
and then your cyanide anion attacks at
the two positions
and this type of reaction can even be
done in a an anti-selective fashion
dating all the way back i think 20 years
ago to shibasaki's work so
a lot of applications of the ricer
reaction and synthesis we will see it
again
when we talk about uh isoquinolines
in a few weeks i guess um so with that
folks uh
keep your consulting problems coming we
really enjoy them a lot of dogecoin
given out today
and um have a great weekend and we will
see you on monday for the last
installment of reactivity
before we get into how to make these
ring systems so
talk to you soon folks take care