TY - JOUR
T1 - Synthesis of N-Substituted 3-Amino-4-halopyridines
T2 - A Sequential Boc-Removal/Reductive Amination Mediated by Brønsted and Lewis Acids
AU - Wilhelmsen, Christopher A.
AU - Dixon, Alexandre D.C.
AU - Chisholm, John D.
AU - Clark, Daniel A
N1 - Funding Information:
Acknowledgement is made to the National Institute of General Medical Sciences (R15-GM116054) for partial financial support. We thank the Chisholm and Totah research groups (Syracuse University) for copious sharing of chemicals, instrumentation, and pertinent discussions. We thank Ijaz Ahmed, Patrick J. Heaphy, Rachel Wilson, and Breanna Tomiczek for preliminary deprotection/reductive amination studies. We thank Tomas Smith for the synthesis of compound 13.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/2/2
Y1 - 2018/2/2
N2 - N-Substituted 3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted 3-amino-4-halopyridines is problematic, as reductive aminations and base-promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted 3-amino-4-halopyridines. This protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.
AB - N-Substituted 3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted 3-amino-4-halopyridines is problematic, as reductive aminations and base-promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted 3-amino-4-halopyridines. This protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.
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U2 - 10.1021/acs.joc.7b02966
DO - 10.1021/acs.joc.7b02966
M3 - Article
C2 - 29308898
AN - SCOPUS:85041567356
SN - 0022-3263
VL - 83
SP - 1634
EP - 1642
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 3
ER -