original synth (click for references, extra articles, and even contact info, although the contacts are probably outdated) written by dm_telvis and fiaof93
Thiomuscimol:
GABA-A receptor agonist
5-(aminomethyl)-3-(2H)-isothiazolone
Mol. Wt. 130.10; C4H13N3O2S; [62020-54-6]; White solid; mp 140°C
Soluble in water, slightly soluble in ethanol. Solutions may be stored
tightly sealed for several days at 4°C
O
\\
C---C
| \\
| C-CH2-NH2
| /
HN---S
Br. J. Pharmacol., 87, 677 (1986); Eur. J. Med. Chem., 20, 447 (1985);
J. Neurochem., 32, 1717 (1979).
Research Biochemicals International (RBI), 1998
Pricing: 5mg $64, 25mg $208.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
Yesterday during my exam I finally had time to read through the papers more
thoroughly, and to look at a synthesis of the chain compound. I agree with
you that that is the tricky part. I would be tempted to try a quick and
easy synthesis just to see if it works, namely start with malonitrile
(NC-CH2-CN) add H2S (probably H2S/pyridine would be fine, and use two moles
H2S), then you get
HN NH
\\ //
C--CH2--C
/ \
HS SH
which should react with one mole of persulfate to give dithiamuscimol:
HS
\
C---CH
// \\
N C--NH2
\ /
S
Sorry, I didn't mean dithiamuscimol, I meant the amine precursor to that.
To get this compound would be very easy, and the reactions fairly likely to
work. You could then try hydrolyzing the compound with OH-, and hope that
the SH will hydrolyze and that the NH2 will stay intact. The 3- and 5-
positions are vulnerable to nucleophilic attack (unlike many aromatics),
because of the nitrogen. This hydrolysis would be a bit more of a gamble,
though I would say the odds are in favor of it working (at least if you can
get the conditions right).
If this fails, you might want to take malonitrile and then form an
imidate using PhCH2O-, to give a benzyl monoimidate, then doing the py/H2S
reaction with the other nitrile. The thing is this gets tricky because you
have to selectively produce the monoimidate, and there is no difference in
reactivity between the two cyano groups in malonitrile. Also, I don't know
whether an imidate would react with py/H2S, complicating the issue still
further. You could solve the first problem by making the benzyl imidate
from the corresponding monoamide, 2-cyanoacetamide (which I see is cheaply
available). However if the second problem is real, then you still have to
face that. If the imidate survives, then you get the following route to
your amine:
NH2-CO-CH2-CN + PhCH2OTf ===> PhCH2O-C(=NH)-CH2-CN ===>
HN NH
\\ //
C--CH2--C
/ \
Ph-CH2-O SH
and this should cyclize to give the desired isothiazole with persulfate.
After the Sandmeyer rxn etc, you should end up with the cyano compound, and
if you choose the reducing agent well you can probably both reduce off the
benzyl to leave OH and also reduce -CN to CH2NH2 in one step.
You are quite right about the stability of the isothiazole system.
once I thought about it some more I realized that the lone pair on the ring
N is tied up at 90 degrees to the pi system of the ring (as it is in
pyridine). This bends it out of the way of conflicting with the sulfur
lone pair which is used to provide 4 of the 6 pi electrons for aromaticity,
and which is clearly vertical (if the ring is defined as horizontal). The
second S lone pair is pointing away from the ring also. So whereas a system
R-CH=N-S-R would be too unstable to even exist (I would guess) in an open
chain, when in this ring it is in fact very stable. Since the same
arguments also apply to muscimol itself, I can see why it has unusual
stability for an N-O compound.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
[...] as well as a couple [of papers] that was cited in J. Chem. Soc.,
3061 (1959), which look relevant. You should be aware that there is
probably a much simpler way of making your target compound, but it is
also true that the kind of chemistry from that time is pretty reliable
and easy to run, even if it is a lot of work. I was thinking along the
lines of:
O CH3O
// \
CN--CH2--C ==Me2SO4 or Me3BF4O==> C--CH2--CN ==H2S/Pyridine==>
\ //
NH2 HN
CH3O SH CH3O
\ / \
C--CH2--C ==K2S2O8==> C---CH
// \\ // \\
HN NH N C--NH2
\ /
S
OR:
(Simpler, but may not work - worth a try definitely)
CN-CH2-CONH2 ==H2S/Pyridine==> H2N-CO-CH2-CS-NH2 ==K2S2O8==>
HO
\
C---CH
// \\
N C-NH2
\ /
S
There is a good chance it would work, and would save trying to go R-OCH3 to
R-OH later on. However it may that it *could* mess up the diazotization step.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
I have recently synthesized a sulfur for oxygen (thio) homolog of muscimol.
Here is an outline of the reaction. I am not including stoichiometry; the
knowledgeable can figure that out for themselves. Also, I assume no
responsibility for anyone's assay of this new compound, which may be toxic,
and whose dosage level is unknown. It is highly likely, though, that this is
a new psychedelic of high potency and powerful effect, as simple thio
substitutions have been highly successful, ala Shulgin and phenethylamine
homologs. I use literal IUPAC style nomenclature here, and it is not totally
compatible with separate heterocyclic nomenclature -- but does give more
detail for the layman. Here are the structures.
Start with or make the chain 3-amino-1-imino-1-propanol (tautomer of
3-amino-propionamide).
HO
\
C-CH2-CH2-NH2
//
HN
Bubble this with H2S for some time with a pyridine catalyst (pyridine and
hydrogen sulphide is perhaps the smelliest mixture in all chemistry so use
a hood). This produces 1-imino-3-thioamido-1-propanol.
HO NH2
\ /
C--CH2--CH
// \
HN SH
React this with ammonium persulphate/NaOH for the cyclization to
HO HO
\ \
C---CH C---CH2
// \\ // \
N C-NH2 <----> N C=NH
\ / \ /
S S
(Two isomeric resonance structures)
5-amino-2-aza-3-hydroxy-1-thio-cyclopentadiene, or "5-amino-isothiazole"
React with cuprous bromide to 2-aza-5-bromo-3-hydroxy-1-thio-cyclopentadiene.
React with cuprous cyanide to 2-aza-5-cyano-3-hydroxy-1-thio-cyclopentadiene.
React with HCl in stannous chloride to give the final product.
HO
\
C---CH
// \\
N C-CH2-NH2
\ /
S
2-aza-3-hydroxy-5-methylamino-1-thio-cyclopentadiene (which could also be
called "5-aminomethyl-isothiazole" or "thiomuscimol"). It is a tautomer of
the structure 5-(aminomethyl)-3-(2H)-isothiazolone, seen at the top of this
file.
This is just the outline. Details can be found in published journal
articles. If anyone qualified is interested, I will send a bibliography and
more details to them. Again, I assume no responsibility for the misuse of
this unknown, untasted compound. It is currently legal to make and possess,
but I also assume no legal responsibility for misuse of it.
10/31/97
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
6/15/98 Update:
It has now been tasted up to 500 mcg, with distinct psychedelic threshold
effects. This makes sense, as animal studies give it a GABA-A binding affinity
strength an order of magnitude greater than that of muscimol.
[fidelis note: if anyone has pics of the reactions/chemicals in the ascii art, pls post! its hard 2 read bc the text editor ignores extra spaces :c but if u need 2 c the reactions/chemicals better rn, just click the link at the beginning]
Thiomuscimol:
GABA-A receptor agonist
5-(aminomethyl)-3-(2H)-isothiazolone
Mol. Wt. 130.10; C4H13N3O2S; [62020-54-6]; White solid; mp 140°C
Soluble in water, slightly soluble in ethanol. Solutions may be stored
tightly sealed for several days at 4°C
O
\\
C---C
| \\
| C-CH2-NH2
| /
HN---S
Br. J. Pharmacol., 87, 677 (1986); Eur. J. Med. Chem., 20, 447 (1985);
J. Neurochem., 32, 1717 (1979).
Research Biochemicals International (RBI), 1998
Pricing: 5mg $64, 25mg $208.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
Yesterday during my exam I finally had time to read through the papers more
thoroughly, and to look at a synthesis of the chain compound. I agree with
you that that is the tricky part. I would be tempted to try a quick and
easy synthesis just to see if it works, namely start with malonitrile
(NC-CH2-CN) add H2S (probably H2S/pyridine would be fine, and use two moles
H2S), then you get
HN NH
\\ //
C--CH2--C
/ \
HS SH
which should react with one mole of persulfate to give dithiamuscimol:
HS
\
C---CH
// \\
N C--NH2
\ /
S
Sorry, I didn't mean dithiamuscimol, I meant the amine precursor to that.
To get this compound would be very easy, and the reactions fairly likely to
work. You could then try hydrolyzing the compound with OH-, and hope that
the SH will hydrolyze and that the NH2 will stay intact. The 3- and 5-
positions are vulnerable to nucleophilic attack (unlike many aromatics),
because of the nitrogen. This hydrolysis would be a bit more of a gamble,
though I would say the odds are in favor of it working (at least if you can
get the conditions right).
If this fails, you might want to take malonitrile and then form an
imidate using PhCH2O-, to give a benzyl monoimidate, then doing the py/H2S
reaction with the other nitrile. The thing is this gets tricky because you
have to selectively produce the monoimidate, and there is no difference in
reactivity between the two cyano groups in malonitrile. Also, I don't know
whether an imidate would react with py/H2S, complicating the issue still
further. You could solve the first problem by making the benzyl imidate
from the corresponding monoamide, 2-cyanoacetamide (which I see is cheaply
available). However if the second problem is real, then you still have to
face that. If the imidate survives, then you get the following route to
your amine:
NH2-CO-CH2-CN + PhCH2OTf ===> PhCH2O-C(=NH)-CH2-CN ===>
HN NH
\\ //
C--CH2--C
/ \
Ph-CH2-O SH
and this should cyclize to give the desired isothiazole with persulfate.
After the Sandmeyer rxn etc, you should end up with the cyano compound, and
if you choose the reducing agent well you can probably both reduce off the
benzyl to leave OH and also reduce -CN to CH2NH2 in one step.
You are quite right about the stability of the isothiazole system.
once I thought about it some more I realized that the lone pair on the ring
N is tied up at 90 degrees to the pi system of the ring (as it is in
pyridine). This bends it out of the way of conflicting with the sulfur
lone pair which is used to provide 4 of the 6 pi electrons for aromaticity,
and which is clearly vertical (if the ring is defined as horizontal). The
second S lone pair is pointing away from the ring also. So whereas a system
R-CH=N-S-R would be too unstable to even exist (I would guess) in an open
chain, when in this ring it is in fact very stable. Since the same
arguments also apply to muscimol itself, I can see why it has unusual
stability for an N-O compound.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
[...] as well as a couple [of papers] that was cited in J. Chem. Soc.,
3061 (1959), which look relevant. You should be aware that there is
probably a much simpler way of making your target compound, but it is
also true that the kind of chemistry from that time is pretty reliable
and easy to run, even if it is a lot of work. I was thinking along the
lines of:
O CH3O
// \
CN--CH2--C ==Me2SO4 or Me3BF4O==> C--CH2--CN ==H2S/Pyridine==>
\ //
NH2 HN
CH3O SH CH3O
\ / \
C--CH2--C ==K2S2O8==> C---CH
// \\ // \\
HN NH N C--NH2
\ /
S
OR:
(Simpler, but may not work - worth a try definitely)
CN-CH2-CONH2 ==H2S/Pyridine==> H2N-CO-CH2-CS-NH2 ==K2S2O8==>
HO
\
C---CH
// \\
N C-NH2
\ /
S
There is a good chance it would work, and would save trying to go R-OCH3 to
R-OH later on. However it may that it *could* mess up the diazotization step.
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
I have recently synthesized a sulfur for oxygen (thio) homolog of muscimol.
Here is an outline of the reaction. I am not including stoichiometry; the
knowledgeable can figure that out for themselves. Also, I assume no
responsibility for anyone's assay of this new compound, which may be toxic,
and whose dosage level is unknown. It is highly likely, though, that this is
a new psychedelic of high potency and powerful effect, as simple thio
substitutions have been highly successful, ala Shulgin and phenethylamine
homologs. I use literal IUPAC style nomenclature here, and it is not totally
compatible with separate heterocyclic nomenclature -- but does give more
detail for the layman. Here are the structures.
Start with or make the chain 3-amino-1-imino-1-propanol (tautomer of
3-amino-propionamide).
HO
\
C-CH2-CH2-NH2
//
HN
Bubble this with H2S for some time with a pyridine catalyst (pyridine and
hydrogen sulphide is perhaps the smelliest mixture in all chemistry so use
a hood). This produces 1-imino-3-thioamido-1-propanol.
HO NH2
\ /
C--CH2--CH
// \
HN SH
React this with ammonium persulphate/NaOH for the cyclization to
HO HO
\ \
C---CH C---CH2
// \\ // \
N C-NH2 <----> N C=NH
\ / \ /
S S
(Two isomeric resonance structures)
5-amino-2-aza-3-hydroxy-1-thio-cyclopentadiene, or "5-amino-isothiazole"
React with cuprous bromide to 2-aza-5-bromo-3-hydroxy-1-thio-cyclopentadiene.
React with cuprous cyanide to 2-aza-5-cyano-3-hydroxy-1-thio-cyclopentadiene.
React with HCl in stannous chloride to give the final product.
HO
\
C---CH
// \\
N C-CH2-NH2
\ /
S
2-aza-3-hydroxy-5-methylamino-1-thio-cyclopentadiene (which could also be
called "5-aminomethyl-isothiazole" or "thiomuscimol"). It is a tautomer of
the structure 5-(aminomethyl)-3-(2H)-isothiazolone, seen at the top of this
file.
This is just the outline. Details can be found in published journal
articles. If anyone qualified is interested, I will send a bibliography and
more details to them. Again, I assume no responsibility for the misuse of
this unknown, untasted compound. It is currently legal to make and possess,
but I also assume no legal responsibility for misuse of it.
10/31/97
༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚≽ ^ • ⩊ • ^ ≼༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚༝༚
6/15/98 Update:
It has now been tasted up to 500 mcg, with distinct psychedelic threshold
effects. This makes sense, as animal studies give it a GABA-A binding affinity
strength an order of magnitude greater than that of muscimol.
[fidelis note: if anyone has pics of the reactions/chemicals in the ascii art, pls post! its hard 2 read bc the text editor ignores extra spaces :c but if u need 2 c the reactions/chemicals better rn, just click the link at the beginning]
