okay good morning everyone
today is the very exciting topic of pure
ends and thiophenes not because they in
their parent form make it so much
into actual medicines but rather because
of their
fact that they are often constituents
within
bridged or fused heterocycles so
understanding how to make furan's is key
when we start talking about
things like pyrimidino furans
or perito thiophenes
and so if you don't know the basic ways
of making these you're going to be in
big trouble
now puren is one of the oldest
heterocycles and it was a
first derivative of furan was isolated
by in 1780 by shiel it's furoic acid and
um
ferpheral is probably one of the
cheapest most sustainable starting
materials for
any synthesis and one of the
first drugs to use a furan uh was
renditine and this was one of the i
think the best-selling drug
back in 1988 it's no longer sold for
reasons that will become clear in just a
moment but
anyway we can go through how it's made
so in the first step
you take furforal and um
it is converted to oh yeah you take fir
you have fur for alcohol
and you treat that with a manic
condition where you've got
dimethylamine and formaldehyde
and uh something happens so
we talked before about furan being a pi
excessive heterocycle
it's pretty reactive and so in the
presence of a nice electrophile
what do you think is going to happen
aaron
or uh tiffany
or uh yeah tiffany what do you say
oh i guess it would add into
the two position great
all right now something weird happens
when we treat the uh
manic adduct with this thiol
and hcl and heat some sort of adduct
results and this one is confusing
because we've got
several nucleophiles and several
electrophiles so
we treat this with acid and heat what
might be the first thing that
would happen here debbie
well uh the hcl is gonna protonate
the amine and the alcohol
both maybe
and then sn2 like from the sulfur
that will attack the carbon the carbon
in which the alcohol protonated alcohol
is bounded
you think it's just a straight sm2
maybe it can form a duct with the sulfur
the oxygen
and then maybe
well we could do something like we saw
when we talked about pyrrole
and that is the i think what tim
mentioned back in the
chlorophyll days we talked about that
and i guess lecture number two wherein
these have a strong tendency to make
quinomethide like
oh yeah that's true and then that will
give you the add up you need
phil would you say a methyl or a
methylene at the two position
is a pretty uh good indicator or
something that could be
i guess ionized or lost to form that
quantum method intermediate
would i say that a a methyl or methylene
what do you mean by that
well so like with the the example from
the earlier lecture and then with this
one too you're forming that orthogonal
intermediate
because you have that like ch2 there and
i guess a leaving group
would you say that that is like
ubiquitous for
all heterocycles for a lot of them
there's a nice paper from bms i don't
know it's about a decade ago
uh from a medicinal chemist called mark
saunier
uh really talented medicinal chemist and
um
for example that org that was all about
how these can be used as
these amino thiazoles as linchpin
intermediates to do macrocyclizations
and all sorts of stitching together one
just has to treat it with triplic acid
and a nucleophile and the nucleophile
can be
intramolecular or intermolecular and the
same kind of thing can happen
just like we saw with the other bms
paper uh from jennifer
where they take a trifluoromethyl group
that's anionically activated
this one is um the same situation so you
if you've got a head of a cycle and you
can draw
a resonance form where an electrons can
be moved to kick something out
you can generally invoke this type of
reactivity
a good question no yeah why wouldn't the
um
amine leave instead i mean the nuclear
fugacity is
comparable um well
in general an amine is going to be uh
a less favorable leaving group than uh
water okay so it would be quite
selective in this case yes completely
okay okay great any other questions
so how do you make furons that's a
little bit of substitution
how do you make them not surprisingly
just like pyrroles it's all about one
four dicarbonyl logic
so if you search furan synthesis you'll
find thousands of hits and we could
spend
probably 10 hours talking about all the
papers of how people make furons but at
the end of the day
they're all pretty much conceptually the
same thing you just
look for the 1 4 dicarbonyl and treat it
with
a little bit of acid anhydrous you lose
the water
and out pops the furan so what we're
going to go through
are the strategies and most
valuable ways of making ferands to help
you navigate the thousand papers that
are out there so you don't need to
memorize all of them
and when you do look for a weird furion
synthesis you can immediately recognize
the mechanistic underpinnings
uh and carbon atoms that went into that
furan
so probably one of the most useful and
maybe oldest fearing synthesis is the
feis benari
and it's exemplified with the synthesis
of this small
purine based natural product and it
commences with this
beta keto ester condensing with this
alpha chloroaldehyde
and um so we need some help usually
people use catalytic amounts of
pyridine or triethylamine to get these
types of reactions to go it's always
very high yielding
and i just need someone to help me with
the mechanism to
explain the regiochemistry of the
product and perhaps kelly can start us
off with that
sure so you get deprotonation at the
beta keto ester
and then you get attack of that onto the
carbonyl carbon
of your other reagent
and then and then from here
i think if you draw it like in the enol
form
you can kick out water and cyclize to
get your product
perfect so in essence this chlorohydrin
was basically a 1 4 dicarbonyl masking
because the oxidation state we need
is held there in the form of the water
here even though this carbon is not the
aldehyde oxidation state
the overall carbon count has the
necessary oxidation state you need
it's a theme you see a lot in
heterocyclic chemistry
wherein you don't have to be so dogmatic
about saying i need a 1 4 dicarbonyl for
example or i need a 1
3 or a 1 5 in the case of a purity but
rather
just say you know i need the overall
carbon count
to contain within it this necessary
oxidation state because it will
degenerately go to
the aromatic product there's always that
thermodynamic driving force bringing you
to the heterocycle
now to complete the synthesis all they
need to do is decarboxylate
and um they do that by hydrolyzing to
the acid and then
heating up with copper and quinoline an
ancient way of doing uh decarboxylations
okay let's move on to cycloaddition
which is i think the other main way
that people look at when they think
about making ferams so
how would one conceptualize putting
together uh
a furan containing two ester groups here
and here
and two methyl groups here and here
using a cycloaddition strategy
maybe sunghan can give us an idea
can we do the four plus two
great now in order to do a four plus two
we need some sort of
diene and dienophile what might be
a dienophile uh
the alkyne with two ester group
awesome so now we need
candidates for dienes one of the classic
ways of doing this
is just to take
purine itself with the realization that
the intermediate you get
shown here can do a
retro deals alder to give out let me
draw the methyl groups here
you can get a retro diels alder to
either give back
the starting material or drive off
acetylene to give the desired product
and you can do that at a high
temperature and remove the gas and that
will drive you
to the product there's another way of
doing this this
strategy doesn't always work there's
another way of doing this that uses
oxazoles
so for example
this oxazole shown here contains the top
half
of the furan that we need to access
in the cycloaddition and the product we
get
results
after a loss of benzonitrol
do people use oxidizals and are those
like
easy to make
oxidizals are pretty easy to make uh
and i haven't seen anybody use an
oxodiazole in a cycloaddition
however to make a
um furan although it's probably known if
we search it
maybe it's a good enough question tim
that the ta should probably take a look
at that
i haven't seen oxidization but it seems
logical that you could do that to get a
lose nitrogen it seems like a good idea
so the tas will check into that and
we'll get back to you if that is a known
reaction but yeah it's a good idea
certainly something you could propose
and oxidize those are very easy to make
we will get into how you make those
after the midterm in the second half of
the class
okay so keep that thought tim sorry i
have a question sure what do you say
somehow
so follow dearest older class we can
lose the
gaslin as a driving force but i think
the
field cyanide is not a gas
so what would be the driving force here
driving force just there is a strong uh
cyano
triple bond okay thank you
and and we will see this again and uh
tim
your idea is known so yeah we'll send
you some nice pure doge for that great
idea that you invented that
has some precedent but yes uh using that
logic you can invent your own reactions
and
often you'll find that they're known all
right so problem of the day number one
is uh taking what we've learned and
seeing if you can put it together
to derive synthesis of all of these
compounds so the first one is
something reminiscent to what we just
talked about and
maybe simona can help us with what would
be a logical disconnection
uh yeah could you do a four plus two
with
tms acetylene and an oxazole
that sounds great
why uh you know what do you think of
the reaction with um why why do you
prefer that
over let's just say taking furion with
the same
uh dienophile simona which why do you
think oxazol is better than just taking
furion and heating it up
i don't think you'd have a kinetic
driving force uh driving the reaction
forward
great exactly they're not really very
well matched so you're probably not
going to get that first adduct to take
place so yeah the oxazole is the great
way to
make this and you can see here with the
dotted lines how that would work
excising benzonitrile
question from the outside what do you
say uh
uh that i oh i have always seen the
fennel there just because people don't
like to liberate hcn
um but we can look into that um i've
never seen the
the corresponding hydrogen one but you
know almost everything is known
so but there's a reason people use the
phenyl because the benzonitrile is not
toxic whereas the hcn is a problem
um so yeah uh but we'll get back to you
uh thanks for the question um so let's
go to the next one
b and uh for this one luckily nathan has
volunteered to help us with b
is it going to be a cycloaddition or you
can start with
like a 1 3 cyclohexane ion
and the other partner could be in
like an alpha bromide cyclohexanone
perfect brilliant let's go on to the
next one how about
c what are the logical disconnections
here are we going to do suzuki city
where we've got multiple different
halogens and we try to stitch it
together
what do you think is a good strategy
here uh carter
um could we use again a 1 4
dicarbonyl and do stetter
awesome and how about d
d what do we think your stone
cycle addition ring synthesis
some sort of substitution strategy
uh cycloaddition i think cycloaddition
and so what would you do there what
would be the order of events
um
[Music]
take promo settling
and uh the
boxes always in party
like that that's the idea
yeah maybe um you know the issue there
is
probably to simona's point before
i'm not sure if you want to use bromo
acetylene if it's going to be a very
good
dienophile in a reaction like this so
but i like cycloaddition
the sneaky way people do this
is by taking advantage of a really good
dienophile
maleic anhydride and once you have malay
anhydride
adduct with furan you can take this and
you can add bromine across the olefin
with the r2 followed by base
gives you this which when heated up
does a retro disalter to give you
the product and that's the sneaky way
that they make this in
on large scale 3-bromo furion
substitution wouldn't be a good idea
because it's gonna be a mess
you're not gonna be able to control it
um cycloaddition
with a bromo acetylene while good on
paper is just gonna be
stymied by the fact that it's not a very
good cycloaddition but maleic and
hydride and furyn that's a really good
one
and then we know we can brominate that
really well and we know we can eliminate
it really well
we can telescope all those steps and
then just heat up the product to get out
three bromofuran let's take a look at
this example which introduces
us to benzofurans benzofurions
are uh not that popular in
medicinal chemistry usually if you make
a benzofuran it's going to be enroute to
something which is much more
metabolically stable and the way to make
it more metabolically stable is almost
always by making it a pareto benzofuran
by starting to add nitrogens
all around the ring and we have an
entire section of the book
that deals with those types of
heterocycles if you're interested
but for now let's just get to this
intermediate here need some logical ways
of deriving what would might be the best
way of making this type of compound
with access to a large family of analogs
so for this hopefully we can lean on
nur to help us with it
uh yeah i think i guess one
disconnection
i would make is to um
um use a little rock type so having a
line
that's a good idea i guess i'm not sure
if i would
add the amine substituent before
or after yeah
up to you good idea so the r group can
either be like you know tbs here where
then you make a library of a million
different amines if you're doing medcam
or perhaps your library is only on the
aryan side and this part always stays
constant
and you keep the immediate it really is
something that's a judgment call the
medicinal chemist would make
depending on which part they're trying
to get analogs up
but yes uh lorac castro those types of
uh
synthesis are almost always i would say
like uh eighty percent of the time are
going to be the go-to ways that a
medicinal chemist is going to want to
make benzopyrenes and even the
heterocyclic ones too
that's a really good way to put them
together so great phil i have a question
what's the what's the
um common metabolite for those
benzofurans and
um what do they normally
uh do well once you epoxidize them it's
game over
oh okay right there's you know bye-bye
okay this this one
you know you can do this type of thing
and um
actually the same chemistry happens with
indoles and once you have this
this is a bad actor this could be an
electrophilic uh intermediate that
you know starts uh uh or my art
it doesn't matter where your r group is
here this can be
attacked by a nucleophile biological one
that's a bad thing
it can be attacked by water giving a
species like this
which then undergo further oxidation
giving you species like this
and then this obviously hydrolyzes and
now you've got
you know it could be if there's if the r
is equal to h you've got a
salicaldehyde which you know could be a
problem so
in general these things are so messy
people want to avoid them
um in the case of
thiophenes or benzothiophines
you often get these types of things
thiophenes can also we'll talk about in
a moment give you these types
and the cell phone indoles can give you
what's known as a
formal kyneronine
that you know keep that one in mind this
is a formal kynerny we'll talk about
that i think next week
um there's actually an enzyme in your
body that makes formal kineranine from
indole
there's actually a company that made out
pretty well with that enzymatic pathway
for
combination with checkpoint inhibitors
so
yeah understanding this metabolism is
kind of important in the case of
thiophenes
in some cases we're not going to cover
it but um
plavix is a great example of where this
type of oxidation takes place
on a thiophene and it actually forms you
know this type of oxidation
which then ends up leading to a cleavage
to give you this type of thing with the
sulfur here
and so plavix is an example of a drug
that was actually approved without fully
understanding what the
downstream metabolites were
and we actually worked with on that
project with bms about a decade ago it's
an interesting little story but
you know these days medicinal chemists
are far more sophisticated
and the fda is far more discerning about
understanding
every possible metabolite and so in
general what i've observed these days in
the industry is that
to the extent possible medicinal
chemists want to avoid
problematic metabolites and if there are
any they want to make sure there's one
or two
they're totally structurally understood
and that's why you need
radio labeling to find out where they
how they're excreted and what they are
um so they're they're far more
discerning because that's a big issue if
you go all the way to phase three
and there's a metabolite you haven't
explained to the fda you are in deep
doodoo
and it could cost the company i've seen
it it could cost the company billions of
dollars it happened
actually pretty recently so yeah
good question brendan sorry for the long
answer
i appreciate it thanks a lot all right
so let's talk about f
what would be a good and maybe brennan
since you volunteered before you can
just uh help us out with uh what might
be your ruminations on making apps can
we just use one for dicarbonyl
ah definitely definitely not as it
sounds
i don't understand well i guess i guess
if you draw that back you solve the
if you want to bring in that aldehyde
and not deal with that later you're
going to have
two different options for a one-four die
carbonyl yeah that's bad
okay thanks um
but i guess i guess if you wanted to not
oxidize the aldehyde after you could
or the alcohol but um in this case it
seems more likely that we want to just
uh exercise the
uh the fennel nitrile through the
cycloaddition strategy
so brennan looks like this and he says
ah
that is my alkyne and
this part here
is my oxazole is that what you what you
just thought
yep yeah that's that's the idea
great oxazol's easy to make we'll talk
about that
um in the second half of heterocycles so
just for now trust me oxidols are pretty
straightforward to make
he feel quick quick question can we say
something like um
the the vice pinari thing here except
instead of an
ester use an aldehyde or is that um i
mean i could see that you could get
regiochemical
regio isomers but could you use an
aldehyde instead of an ester
generally not so what you're saying is
why don't we make
the ester
um or make the ester then reduce it to
the aldehyde
you want that disconnection right i put
one extra
carbon between the chlorine and ketones
oh sorry that was a uh
ipad drawing mistake there there was
supposed to be an extra carbon thank you
that's what you want yeah uh i
don't see an issue aside from the fact
that what we didn't talk about in vice
pinari
that if anyone is interested in
depending on the conditions and the
structure of your alpha halo ketone
sometimes you can get the wrong
regiochemistry
but it is tunable so as you can imagine
there is a problem where you want the
canopenogl to happen
but it's also possible you can get the
alpha alkylation
now for the purposes of this class uh
you can assume feispinari is going to go
at the ketone to give you the kenobonago
product
and we'll talk about this actually again
uh maybe i can recruit you
in problem of the day g here tim because
it sort of addresses this question but
for a test putting this uh
suggestion tim i see no problem with it
there's no issue
it's fine
so what do you say there tim based on
that logic how are we going to make g
oh question for the outsiders
um so for the four plus two we just need
to look at what where does our delta
plus and delta minus so that
is clearly the case with uh that one
and then we need to identify you know
where
if we look here's our
our group and our aldehyde
are here so
our delta minus
is
here and here does that make sense
that's how you can assign the polarity
of the oxosol
great question
other questions and that's probably
another reason why people use the fennel
because it accentuates and helps with
that polarity assignment
other questions okay uh so tim
what's our answer for the uh for g
yeah sure so you can do um an
alpha halo ketone with uh
and beta-keto ester yeah yeah with that
and then doing the same mechanism that
kelly mentioned earlier
catalytic pyridine or triethylamine
should do it for you
wherein you need this to attack here
followed by a cyclization there
and that will give you the proper
regiochemistry okay so the
mistake people often make when they
think about five spinari is they say oh
this is going to attack at the alpha
chlor position and as i said before
there is a paper which studies this
phenomenon where you can
by changing conditions get that to
happen
but the canonical fights benari involves
canovanago first followed by cyclization
on the chlorine
okay do you know of any conditions that
would favor oh
alkylation he
um if you wanted alkylation specifically
probably
a a hard deprotonation with
um something like uh a potassium
with a potassium counter ion or a cesium
counter ion might give you more oxygen
alkylation
uh okay great so now we have radio
chemical
chemistry problems and we've got some
people in radio chemistry that we
haven't heard from
so maybe camille
who is our resident uh radiochemist can
help us out with this one
can you do five spinari again
well i need my other i don't have a keto
ester so
i see are you suggesting that um
oh i see you're saying you're adding a
group
aren't you
is that what you're saying camille yeah
and then decarboxylation
now how do you get the label in
uh yeah i'm not sure not so easy huh
and that's why we do radio chemistry
because
it forces us not to use the same
disconnections over and over again
so what if instead camille we brainstorm
on
just one four-dicarbonyl logic
how about that yeah it looks good if we
could make this and
incubate it with uh o18 water for a
while
an acid we would probably get some
enrichment there
it's unfortunately not good enough and
so for their purpose they used
a 1 4 dicarbonyl equivalent
which is this one
and when you treat this compound with
hcl
or h2so4 dry it it gives you
a highly enriched furan with o18 label
there
keep it dry and this is derived from the
corresponding
uh o16 compound
just by treating it with o 18 water
and acid and then strong dry acid
gives you the desired product you see
how that works
yes yeah so for radio chemistry you're
you're
you're very myopically obsessed with one
atom
and the synthesis is based upon that one
atom
it's such a weird way of thinking
how about b well if we use the same
logic with b it would require something
like that
correct yes
i've got too many carbons no one's
calling me out on it
there we go that's better
so for this one the conceptual
equivalent that they use
is making this
they take this compound and they treat
it for 30 minutes with
o-18 water to get enrichment here then
they directly
treat that with the coriolis
and when this compound is treated with
dry h2so4
you get the product
with our label here
so these strategies are used in order to
maximize
o18 labeling because it's really hard to
get the option to sit there
and stay put how about this last one
uh tiffany tim stone our remaining aaron
our remaining
uh we three our remaining radio chemists
anyone want to opine on how you could
make this one
just methylate b
and bulimia methyl
awesome brilliant all right let's move
on
to benzo furan's we talked a little bit
about benzopherians
and uh neuro helped us out with the most
popular benzofuran
synthesis out there and uh here we need
three different ways of thinking about
how to put together a benzofuran
and as we do this exercise we will
basically summarize
the three most useful conceptual ways of
putting these things together
so give me three different
disconnections what what do you think we
could do here
what bonds can we break in particular
uh i want you to remember that that
carbon is going to be
c14 labeled aha so we make it even
harder
can you break the bond well i would
hypothesize to break the bond between
the c
labeled carbon so two and three
essentially ah
brilliant so by looking at that and
saying oh well
i need to be myopically focused on that
one
carbon atom it requires us to break the
c23 bond
and that then leads us back to an
intermediate like this
and uh just treating this with base will
give you the product
i was actually thinking of um having the
ketone on the other side
so on the labeled carbon and then
you'd have like a doubly benzylic
position which you can alkylate
and then you can get the labeled carbon
from something like axial chloride
oh wow okay that's really good
so you want to take
that and simply use a strong base to
protonate here
and get it to close is that right yeah
you'll need a pretty strong base
but i think it probably would work in
this case um just keep it really dry
because that's going to be very
hydrolytically labile
uh it has a good shot of working um you
know
it might be best
to uh perhaps use
a temporary atom here like a sulfur to
help in the formation of that anion but
um that's a really hard anion to make
just keep that in mind so in practice
it's probably not the first thing i
would suggest to someone
just because of the strength of the base
needed to deprotonate that and the
anhydrous conditions that would be
needed
so you don't immediately obliterate that
sensitive phenol ester
okay but it's a good idea other
suggestions for how we would in general
put this together
what if we just go back to your original
uh
suggestion norm
so we could imagine doing a bromination
followed by a suzuki
and then this might come back from
do you like that
normally you'd like it but i've got the
radio label there right
yeah so not not really feeling that one
so much
is there another bond we could break we
have already broken
um 2-3 we've broken one
two via the lorac type is there another
bond we
can perhaps break
four three or three could possibly work
and uh in practice how we would do that
would be in a stepwise way where first
we would disconnect
one five and that would lead us back to
an intermediate like this
and then that comes back from something
like this
so perhaps this could be br i
or brcl or they're differentiated or
even brb army might be fine and do the
whole thing in one pot
wherein you treat this with palladium or
copper you get the first coupling to go
and then via the enol form of this
uh keto ester it then cyclizes to give
you the
one five bond
how would you do um o 18 labels for
benzopherians
uh that's a really good question likely
the first thing i would
think of in doing that would be to
start from a halo compound
and use the litany of ways that are out
there
for doing almond and palladium coupling
to
install rigidly that phenol
because that can't exchange anymore once
we've got that phenol there
it's over o 18 is staying put and then
we would do lorac or whatever we need to
do after that so you could take your
phenol you could halogenate it north of
position
and then go on your way with lorac or
whatever
you want to functionalize the friedel
crafts for example whatever you want
there's another way to make these radio
label compounds and i think it's best
exemplified
uh using this little consulting corner
here so
uh nora what's the problem of using your
favorite lorac disconnection
on this compound
well
i think one problem would be that uh
you'd have
an abromo ariel on the alkyne and
another problem
read your chemistry yeah brilliant great
so we need another way to do this um
and we think about breaking that bond
there that's not really good either
because i don't really have anything
that can make an enolate very well
that's not going to be it doesn't feel
very good
i'm running out of ways of doing this
so that's why you need to know 100 ways
of making these heterocycles because
often medicinal chemists will ask you
these questions which are really really
frustrating for the consultant
which is to have a polyhalogenated
species for which they
later on want to do a bunch of suzukis
and buck walls for their modular
synthesis but by doing so
they they lorac block you in essence
they don't let you make these
heterocycles through any kind of
palladium coupling because
they want to retain the different
halogens on these rings for their later
on couple
so you are relegated then to old style
condensation chemistry as a result so
for a system like this
the best suggestion would likely be
that we're in the intermediate auxin
that you make
analyzes 3-3 happens and then
cyclization to give you your product
after
uh loss of ammonia i feel
what about iodification if you have a
double bond
there like um if you
break the bond between the double bond
and the aromatic ring and you like
have an olefin let's say i don't know if
i can explain
um like if you break the bond between
the oxygen
and the double bond and you do
like order a terrification
yeah and then re-aromatize
because you eliminate hi
for example that yeah well again i'm
lorac
blocked so what about some kind of
metadata this is if you start from a
styrene
and uh the inode
well then you're with two two olefins
that are relatively similar
electronically
so we've got this styrene plus that's
styrene
i i the reason i would never suggest
this to a medicinal chemist is because i
cannot
it's not an organ bedding level
suggestion
as we talked about before would you bet
your kidney that it's going to give you
high yield of the
of the cross product and not just
dimerizing or this thing time rising and
they only get ten percent of their
desired olefin at the end
so it's a good idea
but i can't propose it in a consulting
session and therefore it's not something
you should do
okay thank you yeah great suggestion
though these are all the
kind of things you want to think about
but this one
yes i'm betting a liver
it's gonna work all right
thiophenes biofins are awesome
heterocycles
because they are found on mars so one
day
when we're all on mars we will have a
lot of thiophenes and you'll remember
this class
and it'll help you derivatize them for
sustenance
or maybe a flavoring ingredient for your
food who knows what we'll do over there
so thiophenes again 1 4 dicarbonyl logic
is the way to go
you have some special features though of
a
thiophene that allow for unique
disconnections that are not possible
with furions and
that's because of the great reactivity
of the sulfur atom which is a lot
different
than oxygen most notably
sulfur can be an electrophile allowing
for disconnections that would never be
possible
with um an oxygen so you can use
uh 1-4 dicarbonyl logic of course if you
have a 1 4
carbonyl and you treat it with some
sulfur source you can get it to cyclize
if you've got a diacetylene like this
and just treat it with hts it will
turn itself into a thiophene
and again you can do cycloadditions
however thiazoles are a lot harder to do
cycle addition than oxazoles and so i
would never recommend this
because the temperature involved to make
that kind of compound but i guess if you
needed that particular thiophene
that might be something interesting for
you to look at
so let's derive what is one of the two
most useful ways of making
thiophenes the first one is the
feisalman
feisalman comes in many different
varieties
and the one we'll discuss right here is
uh
this one which is problem of the day
number three so if we have a volunteer
for some puridoge that would be good
or randomly call on someone i'll do it
what do you say there alex um so the
sulfur will add into
the alkyne um and i guess actually
you'll have like double
addition two of clones of sulfur adding
then
okay you save some steps so i'll just
draw the
adduct directly
okay now what and then
get there and now we do something else
under basic conditions
you'll have deprotonation uh alpha to
the sulfur
and that will add into uh yeah one of
your
carbon yeah the furthest one
um and that will get your five-membered
ring
and then a couple of eliminations will
get you
over to your product
perfect so this is in the right
oxidation state here
and all we need to do is lose
one of these equivalents and we get to
the nice thiopian product
so there are a lot of feisalman
equivalents as you can imagine
all right can i ask a quick question of
course why do both sulfurs add in at the
same
carbon is that hysterically favorable
or is it just electronics driving the
whole thing
well um once you have the first sulfur
add in that deactivates in a strong way
the other position so of the of the
delta positive positions that you've got
there's much more delta positive at the
one with the sulfur
rather the one that is beta to it
because you got those electrons
pushing in like crazy yeah that makes
sense to me but why
like what's the driving force for the
second one to go just the formation of
the thiophene is so favorable
uh well because you usually uh the
driving force is that
it's still a great michael acceptor and
you've still got the
uh a thioate there okay iolates just
love michael acceptors um i mean to
bring it back to pharmaceutical
companies in the past five years we've
seen an explosion
of medicines that have covalent reactive
groups based on
microacceptors so at the outset 10 years
ago
or maybe a little bit more you propose
an acrylate
or an acrylamide in your drug people
would look at you like you've completely
lost your mind
but now they're actually pretty hot and
they work
and they're not toxic and they can be
selective and uh but
yeah so cysteine and dilates active site
cysteines they
actually have a voracious appetite for
michael acceptors of all types so
this is a small microcosm of that it
okay thanks
viceland these are some equivalents of
feisalmin and so to
exemplify uh one of my favorite types of
manifestations of feisselmann
let's talk about how you would
disconnect that based upon fyselman
logic
maybe jun chen can help us out here
yeah we can use the same logic as
uh as a pheisman phasma logic and
we can break the
economic we can break the alpha position
of the carbonyl
the cs bond brilliant
is always looking for that fragment
always look for that fragment how do we
make this thing
um anybody know just just just from the
uh treated with
[Music]
alpha beta and saturated aldehyde
treated with chloride
and chlorine and pyridine
anybody want to do that
yes do you want to do that if i make you
go to the lab right now and do that
reaction is that something you want to
do no
so are you going to suggest let's let's
try the carbonyl chlorination maybe
is that possible i do not know
make that compound untreated with hcl
yeah still not good why is it not good
i guess you will get a couple of mixture
yeah all right so we need a good way of
making that
and it we have a nice introduction here
to
probably my favorite reagent for
heterocyclic chemistry
and that is uh bills meyer
many years ago when dinosaurs still roam
the earth and i would consult at
companies before people had chem draw
and things like that
i brought a suitcase of books with me to
each consulting
session and one of those books was just
about bills meyer
dillsmeyer is one of the most versatile
types of reagents that
exists out there for forging key
functionalities we're going to see this
over and over again through this class
many heterocycles can be made using
vilsmeier's reagent
and it allows you to just take the
corresponding ketone
plco3 and dmf
what in the world is going on there well
that's your first adduct
that's your next adduct
and then your poco3 will handle your
final
now you can work it up but you can also
do other things with that intermediate
too
stay tuned for that
that's a very very nice way of making
you're turning your ketone into a
perfect heterocyclic precursor
you can condense a lot of different
reagents into a species like this
bills meyer is a uh probably one of
medicinal chemists
one of the most useful condensation
reagents out there question from the
outside
um someone asked their friendly
alternative to h2s
friendly alternatives to h2s you can use
i believe thio urea
i believe that works as well that's
that's often a
nice reagent alternative yeah
good question all right let's get to uh
now our case studies and thiophene
synthesis so putting it all together
everything you've learned so far
uh in furan's and thiophenes we should
be able to
put together a coherent analysis of oh
before we get to that we don't want to
skip
zyprexa um olanzapine
probably you know someone or maybe
someone
uh even here today has taken it it's
useful
antidepressant a useful psychoactive
compound made by lily and so we need to
identify
a good disconnection within here we've
got three different rings
we will talk about azepenes in a
separate class in the second half of the
class
but we need a good way to disconnect
this into something that might make
sense based on what we've learned
so yeah what do you say alex you have
your
like uh hidden cyano group there in the
bottom of ring bay
so i guess oh a hidden cyano
you think there's a hidden cyano group
here
and any other hidden cyano groups
perhaps
um
once you disconnect so if you think
about disconnecting the
nitrogen between a and b on the top half
of the ring then you'll also
have like the same motif
there yeah that is really nice
so if we disconnect into those two
fragments it's going to require these
two building blocks
so the order of events to put these
together would first be
to do your snar here
and then reduce this nitro and then the
corresponding amine that results the one
you get here
can be exchanged with the
uh pyrazine uh pipirazine
just by heating it up uh at about 150
degrees 120 degrees sorry
and that will lose ammonia to give you
your desired product so now we have to
think about a way to make that
and luckily you've already told us
how we can put together
this carbon because you identified that
there is a
nitrile hiding so
how do we put that together
what are what are the ways we can think
about maybe we can derive another
reaction
another popular one to make thiophenes
if we bring it back to a nitrile and
just cut it based on first principles
it leads us to what milano nitrile
aha yes
let's draw the milano nitrile
that thing comes from where
aldehyde um sulfur and
the just the milano nitro
okay so what we're going to do is we're
going to take monolithic like simona
says we're going to condense it
we're going to do our canova nozzle and
then with in the same pot with base
we're going to add sulfur to sulfur 8.
and as i mentioned before sulfur
is unlike oxygen that it can be a great
electrophile
so that anion that is uh viniligously
activated
namely that one that's a super acidic
position will attack
s8 leading you to this compound which
will
spontaneously cyclize to give you that
and you folks have derived
one of my favorite thiophene synthesis
known as gewald
phenomenal questions
great let's make sure we're not skipping
anything
okay that gets a sound now to the case
studies problem of the day number five
so how do we put these things together
so let's see who have we not heard from
today maybe
i'm not sure if we called on daniel
already
but maybe daniel can help us with
this one
sorry um
i suppose you couldn't do the the 1 4
dicarbonyl condensation
um almost never fails right yeah
fantastic is there another way we could
do this to
make sure what if you know it could be
the medicinal chemist says hey
i don't want to deal with sulfur i don't
want to have any smelly compounds i
don't want to have that aldehyde is
there another way we could make this
what if we had to insert a group what if
we need to insert a group to make
everything easy
the uh um
could really yeah
then just go through the decarboxylation
and you know how to make this right
uh yeah uh with the uh
um phil
filsmeyer yep now for the bills meyer
for that mechanism to work
does my ketone go here or does my ketone
go here
i think it was the first position
brilliant awesome job
so we took a simple ketone we treated
vilsmeyer and we get out this adduct
which then can
go and fight some in its way to victory
in a nice medicine
fantastic how about problem of the day
be
this one is probably signaling for some
sort of immediate disconnection
in order to simplify our life and um so
what would that
disconnection look like
still me yo go ahead keep going daniel
yeah oh
um great
hmm
as a medicinal chemist what bond do you
think you'd want to break first just get
rid of something
maybe the and four and six
lovely
and now what can we do
be
remember this one daniel
what is that your signaling element for
oh
the uh fuzzy men
yes every time you see that it's
screaming out
feisalman that means this compound is
needed
this can be o triflate and then we can
do
uh suzuki coupling to put in that
biphenyl
and this just comes back from
that with dry hcl or poco3 or oxalyl
chloride whatever
and then that can become back to the
corresponding ketone
great how about c
um
i'm just going to be a pure doge
trillionaire
my knee jerk reaction would be the
double 1 4
carbonyl condensation but that would
get you selectivity issues with the
different
isomers that could be formed so
maybe you could just do one with the
love it yeah
perfect
all right how about um
you know i i mean daniel is going to be
crowned
sort of uh king thiophy and if he keeps
going this way so i'm happy for you to
keep going or if anyone else wants to
jump in
um no by all means
keep going yes kelly um
so i think that you could disconnect the
thiophene and make it through
first thing you're a medicinal chemist
so the fir oh compound so
is there something we need to get rid of
right away oh i don't want the piece on
the right
okay we got to get rid of that urea and
it's probably something that they're
going to want to make a million analogs
of
yeah so i guess amino thiophene
and your favorite way of making urea uh
with an isocyanate
awesome great so now we've got that
compound now how are we gonna put this
together
is there something is something hiding
in there um
i think there's a hidden nitrile
oh that's too big
yeah i'll need to practice the
highlighting step later but yeah
there you go there's your hidden nitrile
so if you start from the papyridone
and the i guess
i don't know how to abbreviate this but
it's like a nitrile pendant to an amide
then you can do the walled
brilliant see how cool gewald is
how nice and modular it's fantastic
all right well sometimes
the nitrogen is not always next to the
higher atom we had a question last class
where somebody asked that
it's not always there so in this case
maybe
it's a nitration of some sort a
reduction or maybe there's a nitrile i
don't know
can someone help us out here
uh i can give a shot okay let me uh
label some carbons to help you out here
all right go ahead uh so
i guess the first one i would probably
disconnect
would be are we so breaking through the
the
you're thyrophene the show yeah go ahead
okay uh
i would try to disconnect that amide
bond there
um get rid of that okay let's get rid of
that right away
that's certainly you can do that or you
can leave it on whatever you want yeah
so i would i would have the an arrow
ketone
um from the i think it's the three or
two
fluoro um and make that
five and four carbons the carbonyl
sorry i'm jumping all over the place a
little bit
and then and then from here
could you make that
into um like a vilsmeyer reagent
and then you have your
fuselman type
sulfur with an electron withdrawing
group
so canonical bills meyer just give this
and then
adding in to that
so could you could you turn that um like
instead of doing
getting the aldehyde like keep it at the
uh
the amine you can go even a step further
than that
um and so what we can do with the bills
meyer
is as we talked about before the
intermediate before you work it up
is that this intermediate can be taken
without any workup
and add an equivalent of hydroxylamine
and then dehydration
gives you that which upon attack with
this
gives you that directly how do you like
them apples
and all along here was a little rat
hiding
okay so it's always worthwhile to it
doesn't always work
but if it's next to a header atom it
works 99 of the time if it's just in a
random carbon
um it doesn't always work but just
conceptually thinking about where the
hidden nitrile might be
can often lead you to extremely
simplified ways of making
molecules so let's take a look at
this interesting fungicide called
silphiopham now still thiopham
is an interesting i think it's used as
an
agrochemical and it's an interesting
compound because it has a
silo group in it in the final product
and the discovery route uses a standard
type of gewald
and the gowall leads to a mixture of
something so simona what is the problem
with this
um you can get the style either at
um either at the
at yeah bottom position or at the
like adjacent to the metal
um probably the second one
brilliant yes i need that and um
so that's the main problem so after the
gewald happens
uh i can do a sandmeyer reaction to give
where the broom where the
nh2 used to be a bromine in its wake
is it easy to control that tautomer
nope no okay not for
methyl versus ethyl that's a challenge
and that's why but for men chemists they
don't care
probably they wanted both isomers at the
beginning anyway so
you know mixture is fine
and then to finish the synthesis what
they're going to do is treat this with
sodium hydroxide that's going to
hydrolyze the
uh ester to the acid they're gonna then
do a halogen metal exchange
quench that with tms then make the acid
chloride and then finally the amide bond
and they get latitude
great now the processed chemists don't
have the luxury of being able to
separate
things and having even small amounts of
impurities so the way they
go about fixing this problem is starting
with this compound
pure derived from this ketone which is
apparently
cheap and commercial so by making
this through a
simple sn2 reaction they get
regiochemically controlled formation of
the alpha thiol ketone
which can then be added in in a michael
fashion
it will go in not once but twice
and that will give you
[Music]
after elimination just like we saw in
alex's mechanism earlier
will give you this compound with an h
here
notice they don't do gawal but rather
feisalman
and they do that because they don't need
anything here the medicinal chemist
maybe wanted the bromine there for
you know ease sake or analogs or
whatever but the process chemist
realized
that that position as we learned in
lecture number three
is innately primed for an immediate
chd protonation so you can hydrolyze the
ester
treat that with lda it generates a
carboxylate which is a good directing
group you don't even need the directing
group effect however
and then it deprotonates and then quench
with tms chloride
puts it at the only available position
to give you that which after acid
chloride formation
and my bond formation gives you the
desired product so
the first one was guald stymied by the
fact that gewald had no selectivity
with regards to the regio control and
then in order to control
things properly the process chemists
pivoted to
a fiesta now in the final 15 minutes of
the class we need to talk about
probably uh i would say and there's
probably
a lot of people online that maybe they
disagree with me but i would say it's
probably
the um most useful
type of thiophene in drug discovery and
that is the
benzothiophile a lot of very interesting
medicines based on benzothiophene one of
them
is shown here called evista now
i need some help in putting this thing
together so
what disconnections might we think about
and maybe in your who is so good with
the furan benzofuran can help us out
again
with the benzothiophile
i think one one thing that comes to mind
right away is the
by arrow maybe to disconnect that
through coupling
that sounds really good how we gonna
make that
actually okay so if we sort of follow
through what the
example that we had before you can
disconnect the two and three bond
and have um an ester sort of like a
i don't know if that's a good idea but
having like a
a thiocarbonate if that makes sense
it does make sense but unfortunately
those are not very stable
and um don't really do the desired
um so this type of thing
uh no i'm thinking have an ester at the
arrow
so like sorry you have like an uh like a
ethoxy or something
foxy where can we give me a carbon
number uh so at the arrow so you have
like the
thio ester
carving
like that yep and then if you sort of
alkylate um then you could have
you can install a triflate sort of um
handle and then you could do
the cross coupling hmm
usually maybe that might work
but not by the mechanism you think it
might be first a
formulation and then the sulfur comes
back and attacks so
maybe maybe that might work um
okay yeah that's uh it's certainly
reasonable
so you've disconnected the two seven
bond we're still gonna have to figure
out a way to make this thing
this one is probably straightforward
based on what we learned on benzofuran's
going back to your top approach how do
we conceptualize putting that together
i think maybe you can install the bromo
through like a
deprotonation quench with like nbs sure
so you know nbs by itself is probably
enough
but you could deprotonate as well so we
could do an nbs step to get rid of that
now we've got the corresponding
how do we make that
can you do like a frito crafts type
thing there
okay nobody wants to make a
benzothiophene
except newer's idea here
well could you just oompole that
strategy that she she discussed
ah that's interesting if we unpoll what
she just said
it leads us back to the ar here
we do a frito crafts then
and so how do we put that together can
we just use one for dicarbonyl logic
and imagine that it comes from something
like
that upon treatment with acid
does anybody want to make that
i'm not sure if i want to make that but
you can use an alternative to this
and what about some kind of gold
chemistry if you have the alkyne
and the sulfur and gold one you do the
cyclization
we'll get to that maybe um
but we want to try to keep it simple
but i'll get to the the sort of pi acid
in a second
so this type of thing may would if you
cyclize it
treat it with acid this is called the
biscular cyclization
the product of this reaction
is actually not
that but rather
the intermediate undergoes a fanonium
shift
to actually produce
this as your actual product
and then you can do a frito-craft
cyclization
now there's yet another way to think
conceptually about putting something
like this together
which is to imagine
starting from an
aldehyde
treating that with base and thio dmf
that leads you to this compound
and when you treat this compound with
something like methane sulfonic acid
it leads you to this
and this can undergo frito crafts
very easily and guess what
this compound you can react it with a
grignard
and it does an addition elimination of
dimethylamine
as activated by that electron
withdrawing group
now let's go back to debbie's point can
we think about these things in terms of
alkynes
so i'm glad nobody suggested doing a
lorac
because in general lorac is going to be
stymied by that sulfur
but let's imagine you could find a way
to get the alkyne on there
could you treat it with something i
don't know
uh indium gold silver
a proton saliva i don't know
anything is going to close that that
ring okay you don't need to do anything
fancy for a cyclization this
trivial but the challenge is getting
this compound without the sulfur
muddying up your catalyst that's the
issue that's probably why
it wouldn't be the first thing i would
suggest so a visa was made
through this strange reaction called the
bishler cyclization which in the case of
thiophenes
undergoes the rearrangement followed by
frito crafts
for analogs though this would be
certainly a fine way to go
phil could we think about using alkynes
but doing a 1-4
edition on them with the arrow
sulfur and still have that
halogen ortho to that sulfur present
something like this yeah
uh and then treating that with some sort
of um
silver or proton or something you know
perhaps but then you've got the problem
of regiochemistry you know you better
have an electron withdrawing group here
or you're going to get mixtures
um it's just not very messed it's just
not very clean
well wouldn't wouldn't you have on one
end
in this particular electron yeah the
electron
rich um
what the the lower arrow as well as
and then on the on the top side you'd
have that ketone yes so you don't have
that product
you would get that adduct but then the
question is cyclizing it
and you know uh
i would be reluctant to use palladium
with a system like that
um i wouldn't recommend it maybe we can
find a paper that
demonstrates that that's possible but in
general i would
avoid using palladium with free thiols
or these kind of thial esters
this is a vanilla style ester and it's
known that palladium reacts really well
with thioester thioesters so don't think
of this as a vinyl sulfide it's not
it's a vanilla thioester you know what i
mean
daniel so i wouldn't want to propose it
during a consulting session
because i can't be sure you know i would
furthermore i wouldn't want to do it
myself in the hood
and that's at the end of the day the
ultimate litmus test for is a suggestion
worthwhile or not would you go to the
hood and do it yourself
and this one i would be really really
worried about vanilla
style ester reacting like this
which is known to undergo lots of
palladium chemistry
right so you're asking for an oxidative
addition to happen
insertion to happen at this alkyl halide
aryl halide
versus just this carbon sulfur bond
and i don't i can't tell you what's
going to happen i don't know but these
other suggestions i can guarantee what's
going to happen
let's take a look at this consulting
corner question
that i think will challenge you quite a
bit to think
even more differently about how one puts
a system like this together
so what's a good disconnection that we
can start off with
we've only got five minutes remaining
um so what's a good disconnection that
we could think about who's gonna
maybe sung han
can we call the aerobank on
c1
something like this
yeah i also consider whether can we use
radical reactions to copying
the
you mean basically a direct aeration
either way
yeah okay let's not get into that but
either way it's bromine or a halogen
there
right okay
so how do we make that thing
or can we do the relatiation on that
position
maybe i want to remind you of something
very annoying about this problem as i
mentioned
uh before a little trick that medicinal
chemists like to use
is putting lots of halogen atoms here to
make
life very miserable so if we have a
bromine here and a bromine here
and you want to do halogen metal
exchanges and cross couplings
you cannot bet a kidney that you're
going to get the right regiochemical
outcome
between those two are you you're not
positive
so that makes it really hard to offer
such a suggestion
and furthermore as is clear from this
problem
it's probably going to be something
where we want to install that amine at a
very
late stage so
you're left with this as your only
possible
logical starting material
wherein somehow we have to get a almond
reaction
or something to work there now the
corollary to the consulting problem is
that
trying to do this reaction with
palladium or copper
leads to no good productive product and
the other problem with this is that even
if you tried to do it
remember that the desired amine that
you're adding in
is a far more reactive amine
with itself so polymerization is going
to take over
this is a terrible system
insertion into because you've got the
electron donating product
just like indoles and benzophilurans
whenever you're trying to do cross
couplings at that position it's always
much more difficult
so you've got easy insertion here
difficult there
what do you do and that gets us to a
rare
and beautiful form of heterocyclic
thiopenzothiophene reactivity the fact
that you can take these compounds
and make thiophene
s oxide holy cow
the thiophene s oxide
it's not wizardry you can make this
compound it's a nice crystalline
compound you can run a column on it and
guess what this one
is not at all hassled by the fact that
there is a bromine here because we're
just going to use base
in a simple snar reaction
and then you can reduce that off
with a variety of different conditions
that are halogen sparing
um for example a hydride will do it and
be on your way this was actually used on
a process scale despite the fact that
the process chemists at the time were
really worried that that
oxidation would be problematic and that
the subsequent s oxide would be
difficult to reduce but
it was actually used up until i think a
phase one
kilogram scale batch
so very interesting way to take
advantage of the innate reactivity of a
and
also a metabolic possible liability of a
benzothiophene
to activate it for snar reactions for
analog synthesis and even a process
application
now in the final 10 seconds or so
we just need a quick tim tiffany aaron
camille stone or we
radio chemical solution to this problem
and we'll be on our way
that's going to be c14
i'll save you time the answer has a
benzene ring in it
any of our radiochemists can help us
maybe disconnect to the aldehyde
and
the thigh on it or yeah yeah exactly
and how about an x here or your opposite
disconnection
would be
so we get our we do our label dmf for
this one
same thing labeled label dmf
uh followed by uh this probably needs to
be protected
if it was me i'd prefer the top route
because i could start off with something
like this i could easily
with or without the iodine doesn't even
need to be there you just say
chlorobenzene you could
you could take bromobenzene whatever
just do the ortho orthomethylation
quench with the labeled dmf and then
fiesome in a way
but feiselman in a kind of snar aromatic
version of visceramen
now in the old days when we used to go
much much faster and everybody was
confused
we would spend the next 30 minutes on
biotin a super important natural product
that is found in all your foods and uh
was made commercially for
quite a long time i think there's now a
fermentation method to make it but was
made
synthetically for quite a long time and
biotin is really great because it gives
you
an interesting way of thinking about
making these saturated
thiophene heterocycles from the
unsaturated precursors so
this was discussed on youtube two years
ago so you can go back to the 2019
lecture and look at our discussion of
this one
as well as the references in the handout
there's a great camera view on making
biotin
from scratch so please check that out in
your spare time a lot of really
interesting chemistry that we don't have
time to talk about today but
we added a bunch of new content today
especially bolstering our discussion of
benzofuran
and benzothiophene so with that folks
have a wonderful weekend and we'll see
you on monday for more fun