Benzoisothiazolone organo/copper-cocatalyzed redox dehydrative construction of amides and peptides from carboxylic acids using (EtO)3P as the reductant and O2 in air as the terminal oxidant

Article abstract of DOI:10.1021/jacs.6b03168

Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5-36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic "oxidation-reduction condensation" reactions are carried out open to dry air using O₂ as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C-N bonds.

Full text of DOI:10.1021/jacs.6b03168

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Communication
Benzoisothiazolone (BIT) Organo-/Copper Cocatalyzed Redox
Dehydrative Construction of Amides and Peptides from Carboxylic
3
2
Acids using (EtO)P as Reductant and O in Air as the Terminal Oxidant
Lanny S. Liebeskind, Pavankumar Gangireddy, and Matthew G. Lindale
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03168 • Publication Date (Web): 13 May 2016
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Benzoisothiazolone (BIT) Organo-/Copper Cocatalyzed Redox Dehy-
drative Construction of Amides and Peptides from Carboxylic Acids
using (EtO)3P as Reductant and O2 in Air as the Terminal Oxidant.
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Scheme 1. Dehydrative Bond Construction
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Scheme 3. BIT Catalyzed Amidation Exploratory Study
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Scheme 2. An Aerobic, Benzoisothiazolone-Catalyzed Amidation
Scheme 4. Organocatalyst Aerobic Recycle vs Degradation
Figure 1. Benzoisothiazolone Screeninga
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Table 1. BIT Catalyzed Aerobic Amidationsa,b
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product
L-Cbz-L-Trp-Phe-OMe
L-Cbz-Phe-NHcyclopropyl
68 (18)
71 (36)d
72 (18)c
83 (18)
78 (36)e
82 (36)
78 (24)
77 (24)e
79 (24)
61 (36)
ASSOCIATED CONTENT
Supporting Information
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rapid hydrolysis of the effective reducing agent (EtO)3P
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For the preparation of CuI 3-methylsalicylate (CuMeSal),
see the Supporting Information to Savarin, C.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2001, 3, 91-93.
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AUTHOR INFORMATION
Corresponding Author
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Notes
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ACKNOWLEDGMENT
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REFERENCES
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A dependence of the reaction pathway on the nature of
the BIT and the reaction solvent was noticed. Thus, N-
alkyl substituted BITs rapidly produce the anticipated S-
acylthiosalicylamide thioesters, while N-aryl substituted
BITs were problematic, particularly in polar solvents like
DMF. 31P NMR spectroscopy traced the difference to a
very rapid, direct deoxygenation of the N-aryl BITs by
triethylphosphite, particularly in polar solvents. Full
details of the direct deoxygenation of BITs by
triethylphosphite will be disclosed separately.
Denton and Lambert describe the catalytic nucleophilic
substitution of alcohols in reference #2.
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Scheme 1
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TOC graphic
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Structures for Table 1
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