3
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carboxamidines 4a-h, were all rapidly formed at room
temperature and in good yields (Table 1). The reaction worked
equally well for aromatic (4d-g) as well as aliphatic amines (4a-
c, 4h). It is noteworthy that sensitive peptide amines could also
be used in this reaction - forming peptide-conjugated thiophene-
2-carboxamidines (4h). When desired, free amidines of 4 could
be quickly made by its Boc-deprotection with TFA in DCM (see
SI 28-45).
2.
3.
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4082.
In summary, we have developed a hassle-free and high-
yielding methodology for the preparation of thiophene-2-
carboxamidines which are a privileged class of potent NOS
inhibitors. This new methodology avoids the release of foul-
smelling thiols and renders purification of the amidines easy,
owing to their non-polar nature. Imidazole, which is the sole side
product formed during the coupling reaction, could be readily
washed away with water, rendering easy isolation of the target
molecules in good yield. Notably, thiophene-2-carboxamidines
conjugated with sensitive peptide fragments / protected amino
acids could also be synthesized efficiently by this method.
4.
Overall, this new methodology represents
improvement to the existing route for the synthesis of
pharmacologically important thiophene-2-carboxamidines.
a substantial
5.
6.
Currently, we are exploring the synthetic potential of this
methodology for developing dual acting NOS inhibitors featuring
thiophene-2- carboxamidine , and the results will be published in
due course.
Acknowledgments
PPR is thankful to CSIR, New Delhi for research fellowships.
GJS thanks SSB-000726 for funding.
7.
Shinji Aki, Takafumi Fujioka, Masashi Ishigami and Jun-ichi
Minamikawa. Bioorganic & Medicinal Chemistry Letters. 2002;
12: 2317-2320.
References and notes
Supplementary Material
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Full experimental procedures, characterization data, HR-MS,
1H and 13C NMR spectra for all compounds. Supplementary data
associated with this article can be found, in the online version.
Click here to remove instruction text...
Mild and efficient reaction condition.
Hassle-free purification.
Good funtional group tolerence
(including peptides).
Avoids liberation of obnoxius thiols.
Water soluble by-product (imidazole)