ORGLIST: S-alkylation of 2 thiouracils- Summary

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From: by way of Joao Aires de Sousa (r.ragno$##$caspur.it)
Date: Thu Mar 27 1997 - 02:42:03 EST


Some times ago, I posted the following question to the list:

>Dear colleagues,
>I've synthesized many 6-substituted-2-alkylthio-4-oxo-pyrimidines by
>S-alkylation of 2-thiouracils with alkyl halides and potassium carbonate
>in DMF, but when I tried to introduce the cyclopropyl group in the same
>way (i.e. with cyclopropyl iodide) I failed. Do you have any suggestion?
>I'll summarize to the list the answers I'll get.
>Thank you in advance,
>
>Gianluca " Blue Merlin" Sbardella

Many thanks to Eric Lucas, Mark Rosen and Gabriel Lemcoff for their
answers.
Here is the summary of their answers:

--------------------------------------------------
Date: Tue, 18 Mar 1997
16:26:56 -0500
From: Eric Lucas <AEALBB1$##$peabody.sct.ucarb.com>
To: 'Gianluca Sbardella' <r.ragno$##$caspur.it>
Subject: RE: S-alkylation of 2-thiouracil

Hi, Gianluca,

Gee, that's a tough one! As I'm sure you know, cyclopropyl halides are
generally very poor electrophiles because of the hybridization of the
carbon. Have you thought about a Cu thiouracil reagent (sort of like a
cuprate), reacted with cyclopropyl iodide? I know Cu-S bonds are awfully
strong, but maybe it would work. (Or perhaps Ag). Cu reagents generally
work by electron transfer (I believe), and the cyclopropyl iodide should
react well with radicals.

On the other hand, maybe it's easier to assemble the cyclopropane ring
once it's already on the thiouracil. Perhaps, for example, you could make
S-vinyl thiouracil, then cyclopropanate it with CH2N2/Pd catalyst, or with
ICH2ZnI.
Finally, could you use cyclopropane thiol as the nucleophile, and
2-iodouracil
as the electrophile?

These are just some random thoughts. Sorry that I can't offer a much
better response.

        Good luck,
                Eric Lucas

-----------------------------------


>>From AEALBB1$##$peabody.sct.ucarb.com Thu Mar 27 08:34:02 1997
Date: Wed, 19 Mar 1997 11:49:15 -0500
From: Eric Lucas <AEALBB1$##$peabody.sct.ucarb.com>
To: Eric Lucas <AEALBB1$##$peabody.sct.ucarb.com>,
    'Gianluca Sbardella' <r.ragno$##$caspur.it>
Cc: Multiple recipients of OrgChem <orgchem$##$gwup.org>,
    Multiple recipients of OrgList <orglist$##$dq.fct.unl.pt>
Subject: RE: S-alkylation of 2-thiouracil

March has some good references on cyclopropanation with carbenes. I don't
know how selective the reaction will be, but it's worth a try.
Cyclopropanation using diazomethane is often catalyzed by transition metal
catalysts. Collman and Hegedus has sever al leading references on this.
In addition, you might try the Simmons-Smith reagent (ICH2ZnI), but,
again, since it is pretty nucleophilic, it might not tolerate other
functionalities in the molecule very well. March has references on both
carbene decom position and on the Simmons-Smith reaction.

        Good luck,
                Eric

----------
From: Gianluca Sbardella[SMTP:r.ragno$##$caspur.it]
Sent: Wednesday, March 19, 1997 4:29 AM
To: Eric Lucas
Cc: Multiple recipients of OrgChem; Multiple recipients of OrgList
Subject: RE: S-alkylation of 2-thiouracil


Dear Eric,
Thank you for your answer. I'd already thought to a radical reaction but
I was afraid that the alkylation of the position 5 of the pyrimidine ring
(its behaviour is quite aromatic...) could also occur. Anyway, I'll
try...
Do you have any reference about the use of the catalysts you says?
Thank you again,

Gianluca "Blue Merlin" Sbardella

----------------------------------------


>>From mrosen$##$ucsd.edu Thu Mar 27 08:33:47 1997
Date: Tue, 18 Mar 1997 23:01:02 -0800 (PST)
From: Mark Rosen <mrosen$##$ucsd.edu>
To: Gianluca Sbardella <r.ragno$##$caspur.it>
Subject: Re: S-alkylation of 2-thiouracil

At 08:50 AM 3/18/97 +0100, you wrote:
>Dear colleagues,
>I've synthesized many 6-substituted-2-alkylthio-4-oxo-pyrimidines by
>S-alkylation of 2-thiouracils with alkyl halides and potassium carbonate
>in DMF, but when I tried to introduce the cyclopropyl group in the same
>way (i.e. with cyclopropyl iodide) I failed. Do you have any suggestion?
>I'll summarize to the list the answers I'll get.
>Thank you in advance,
>
>Gianluca " Blue Merlin" Sbardella
>

I would imagine this is due to the fact that the sulfur nucleophile
displaces the halogen in an SN2 type mechanism. Thus the sulfur
approaches the from the opposite side of the halide. This is precluded
in the cyclopropyl system. Furthermore, SN2 type reactions occur with
inversion of stereochemistry (if relevent), showing that the relative
position of the substituants at the carbon in question must invert. This
again cannot occur in a cyclic system.

--------------------------------------------


>>From lemcoff$##$post.tau.ac.il Thu Mar 27 08:34:20 1997
Date: Thu, 20 Mar 1997 08:26:14 +0200 (IST)
From: Lemcoff Gabriel <lemcoff$##$post.tau.ac.il>
To: Multiple recipients of list orglist <orglist$##$dq.fct.unl.pt>
Subject: Re: ORGLIST: S-alkylation of 2-thiouracil

One possibility is the formation of an allyl cation by electrocyclic ring
opening of the cyclopropyl cation then you would get an allyl derivative
instead of the cyclopropyl derivative you were looking for. The
cyclopropyl cation is not formed readily but with a good leaving group
such as iodide and depending on reaction conditions it might be formed,
the rearrangement to allyl cation is then very fast. Hope it might help
you, Gabriel

  ______________________________________
/ \
I Gabriel Lemcoff I
I Chemist I
I tel.: 03-6408436 (University) I
I 09-9524377 (Home) I
I Tel-Aviv University I
I I
I Home Address: Kibbutz Yakum (60972)I
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I e-mail: lemcoff$##$ccsg.tau.ac.il I
\ /
 ---------------------------------------




On Wed, 19 Mar 1997, Gianluca Sbardella wrote:

> On Tue, 18 Mar 1997 alihoyer$##$inet.uni-c.dk wrote:
>
> > Dear Gianluca,
> >
> > What was the product of the reaction?
> >
>
> As I wrote in the original message, using many different alkyl- and
> cycloalkylhalides the product was a 2-alkyl- or
> 2-cycloalkylthio-4-oxopirimidine (that's to say the tautomer of
> 2-thiouracil in which the hydrogen on the sulfur atom is substituted by an
> alkyl or cycloalkyl group).
> With cyclopropyl iodide the reation doesn't occur...
>
> Gianluca "Blue Merlin" Sbardella
>
> >
> > Dear colleagues,
> > > I've synthesized many 6-substituted-2-alkylthio-4-oxo-pyrimidines by
> > > S-alkylation of 2-thiouracils with alkyl halides and potassium carbonate
> > > in DMF, but when I tried to introduce the cyclopropyl group in the same
> > > way(i.e. with cyclopropyl iodide) I failed. Do you have any suggestion?
> > > I'll summarize to the list the answers I'll get.
> > > Thank you in advance,
> > >
> > > Gianluca " Blue Merlin" Sbardella
> > __________________

-------------------------------------------



If anybody has something more to say on this topic, please send a message
to the list. Of course I'll summarize again...
Thank you all,

Gianluca "Blue Merlin" Sbardella

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