Wednesday, January 17, 2007

The Misbehaving Isonitrile

For some time now we have been keen on using 2-morpholinoethyl isonitrile in our Ugi reaction attempts. The main advantage is that it does not stink, as do most isonitriles. We were encouraged by the report of its successful use (over 60% yield) in at least one Ugi reaction (Harriman 1997).

In the process of trying to debug our reactions we mixed it only with boc-glycine and found that it was consumed within minutes. (EXP049) The isonitrile functionality is particularly convenient to track by NMR because the two bond H-N and one bond C-N couplings provide characteristic triplets with peaks of equal height. In the case of the methylene group next to the isonitrile, this shows up as a pretty triplet of triplets (see below).

Unfortunately the reaction seems essentially intractable but the NMRs are available if anyone has a hypothesis to test. The tertiary amine has been reported (Polyakov 1983) to cyclize to a spiro structure by attacking the carbon end of the isonitrile in the presence of tosic or hydrochloric acid. But I would not think that a carboxylic acid like boc-glycine is strong enough for that and, even if it did, the NMRs would be much simpler if that were the dominant process.

This behavior does seem limited to this particular isonitrile, since Khalid just showed that benzyl isonitrile is stable in the presence of boc-glycine in methanol (EXP050) for at least a day.

I guess that means back to the stink...

2-morpholinoethyl isonitrile


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