S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium Hexafluorophosphate (HOTT)
(reagent used to convert carboxylic acids into Barton esters and for peptide coupling/amidation)
Physical Data: mp 115-116°C.
Solubility: acetonitrile, CH2Cl2, THF (moderate solubility).
Form Supplied in: white solid.
Purification: recrystallized from CH2Cl2.
Handling, Storage, and Precautions: it is advised to protect the solid from prolonged exposure to light since 2-mercaptopyridine N-oxide and related compounds can be light-sensitive.
Preparative Methods: the title reagent can be prepared by slowly adding Et3N to a dry CH2Cl2 solution of 2-mercaptopyridine-N-oxide and tetramethylchloroformamidinium hexafluorophosphate.1 After removal of CH2Cl2 from the reaction mixture, the resulting solid mass is pulverized, washed with CHCl3, and then filtered to give a white solid of sufficient purity to be used in subsequent reactions.2
Barton Esterification: Reductive Decarboxylation
O-Acyl thiohydroxamates or Barton esters are useful precursors of carbon-centered radicals via thermolysis or photolysis.3 Several different methods are available for converting carboxylic acids into Barton esters (eq 1).4 These reactions generally proceed via the attack of a 2-mercaptopyridine-N-oxide salt on an activated carboxylic acid that has either been preformed (acid chloride, mixed anhydride) or generated in situ (with 1,3-dicyclohexylcarbodiimide or tri-n-butylphosphine +2,2´-dithiodipyridine-1,1´-dioxide). However, HOTT has the distinct advantages of (1) being easy to prepare and handle without the need for any special precautions, (2) facilitates efficient Barton esterification of carboxylic acids, and (3) simplifies subsequent work-up and purifications by avoiding the need to remove by-products like 1,3-dicyclohexylurea.
The HOTT reagent has been shown to significantly improve the yields of reductive decarboxylations of 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid (eq 2) and peracetylated N-acetylneuraminic acid (eq 3).2 In both cases, the yield of reduced product nearly doubled when HOTT was used to esterify these hindered carboxylic acids.
Barton Esterification: Oxidative Decarboxylation
HOTT-mediated Barton esterification was coupled to oxidative decarboxylation in a synthesis of the sesquiterpene (+)-culmorin (eq 4).5 Use of the HOTT reagent was clearly superior with this hindered substrate when compared with the acid chloride method.
Barton Esterification: Radical Addition
One of the best examples illustrating the benefits of HOTT for this transformation is shown in eq 5. The Barton esterification of this very hindered acid was followed by IR spectroscopy by monitoring the disappearance of the carbonyl stretch of the acid (1740 cm-1) and the appearance of the carbonyl stretch of the Barton ester (1810 cm-1). Barton esterification using HOTT was complete within 20 min, whereas over 4 h was required when using the combination of DCC and 2-mercaptopyridine-N-oxide.
HOTT was used to effect Barton esterification in a novel approach to 1, 3, 5,…(2n+1) polyols based on iterative stereocontrolled homologation of chiral hydroxyalkyl radicals (eq 6).6
General notes: As with most Barton esterifications, the reaction should be performed in the dark and under anhydrous conditions.
The HOTT reagent, as well as the corresponding tetrafluoroborate salt (TOTT), have also been reported to be inexpensive alternatives to uronium- and phosphonium-based peptide coupling reagents (eq 7).7 Yields were generally on the same order as those observed with standard peptide coupling reagents. An advantage of these reagents -at least in some instances -may be a reduced propensity of the N-protected amino acid component to racemize during the coupling reaction.
Synthesis of Primary Amides
Carboxylic acids can be converted to their primary amides using HOTT (or TOTT) as the coupling agent (eq 8 and 9).8 The reaction conditions are very mild and do not adversely affect other functionality prone to nucleophilic attack by ammonia. A simple extractive work-up is sufficient to obtain the primary amides in pure form.
- 1. Dourtoglou, V.; Gross, B.; Lambropoulou, V.; Zioudrou, C., Synthesis 1984, 572.
- 2. Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.; Galat, K., J. Org. Chem. 1998, 63, 5732.
- 3. Crich, D., Aldrichimica Acta 1987, 20, 35.
- 4. Barton, D. H. R.; Samadi, M., Tetrahedron 1992, 48, 7083.
- 5. Takasu, K.; Mizutani, S.; Noguchi, M.; Ihara, M., J. Org. Chem. 2000, 65, 4112.
- 6. Garner, P.; Anderson, J. A., Org. Lett. 1999, 1, 1057.
- 7. Bailén, M. A.; Chinchilla, R.; Dodsworth, D. J.; Nájera, C., J. Org. Chem. 1999, 64, 8936.
- 8. Bailén, M. A.; Chinchilla, R.; Dodsworth, D. J.; Nájera, C., Tetrahedron Lett. 2000, 41, 9809.
James T. Anderson, Subhakar Dey & Philip Garner
Case Western Reserve University, Cleveland, OH, USA
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