salts),8 and tris(trimethylsilyl)methane.9 Each of these
H-donor replacements, however, brings their own lim-
itations, including cost, availability, and toxicity. De-
spite the progress represented by these innovations, the
availability of an H-donor that is effective, readily
available, inexpensive, and easily removed from the
final reaction products and with an acceptable toxicity
profile is still lacking. Indeed, a reagent with these
features would significantly enhance the attractiveness
of the Barton reductive decarboxylation reaction.
Herein we report on the utility of chloroform as such
an H-donor.
and exposed to the sodium salt of 1-hydroxypyridine-
2(1H)-thione (5) to generate the Barton thiohydroxamic
ester 3 (R = n-C15H31). Irradiation of the solution at
reflux, with a tungsten lamp, afforded the reduced material
2 (R = n-C15H31), but only in 32% yield (Table 1, entry 1).
When chloroform was used, instead of nitromethane, a
dramatic increase in yield was observed (i.e., 86% isolated
over two steps) (Table 1, entry 2). Together with this yield
improvement, a practical advantage was also gained in
that palmitoyl chloride could be generated in chloroform
and used without purification in the next step. The Barton
ester 3 (R = n-C15H31) was also obtained directly from the
carboxylic acid using peptide coupling agents as has been
previously reported.3 In this case, the overall hydrocarbon
yield fell to 72% (Table 1, entry 3), which is attributed to
the efficiency of the coupling process rather than the
inefficiency in the reductive decarboxylation step. These
results are comparable, if not improvements, on the results
obtained with classical H-donor sources such as n-Bu3SnH,
t-BuSH, and PhSH (Table 1, entries 4À6). Given the
favorable results obtained using the acid chloride ap-
proach (Table 1, entry 2), this method was applied to a
range of other substrates (Table 1). Both the adamantanyl
and cubyl systems performed well (Table 1, entries 9 and
10), whereas 4-(methoxycarbonyl)cyclohexanecarboxylic
acid afforded the methyl cyclohexanecarboxylate in only
48% yield (Table 1, entry 8). The decreased yield in this
case was most likely a result of isolation difficulties rather
than poor reactivity. Ketone functionality is well tolerated,
and acid 1i proceeds smoothly giving the product in 74%
yield (Table 1, entry 14).12 The two steroidal substrates
(Table 1, entries 11 and 12) gave similar yields of product
(i.e., 65 and 68%, respectively). In the case of entry 11, two
minor byproducts, the alcohol 8 and aldehyde 7, were
isolated. These are presumably the result of extraneous
oxygen acting on the radical intermediate. Slight oxida-
tion was also apparent with diphenylacetic acid
(Table 1, entry 15), which gave dimer 9 as the major
product.
Scheme 1. Barton Reductive Decarboxylation Reaction
Our chance observation that chloroform preferentially
delivered hydrogen to 4-methoxycarbonyl-1-cubyl radical
(Table 1, entry 5) under Barton conditions prompted a
detailed investigation into its potential as a bona fide
H-atom donor. While the original intent was to substitute
the increasingly inaccessible carbon tetrachloride, an ex-
cellent Cl-atom donor under Barton conditions,2e with
chloroform,10 we were surprised to find that the major
component isolated was methyl cubanecarboxylate, with
only a trace of the corresponding chloride (methyl 4-chl-
orocubanecarboxylate) as observed by GPC.
Accordingly, we set out to explore the utility of chloro-
form, and other commonly used solvents, including nitro-
methane, as convenient H-donors for use in Barton reduc-
tive decarboxylation reactions.
While the mainstream free-radical literature has been
somewhatsilent on the synthetic utilityof chloroformasan
H-donor in the reduction of alkyl radicals, its behavior as a
chain-transfer agent in the polymer literature has been well
documented.11
Aromatic carboxylic acids (i.e., Table 1, entry 15) were
found not to undergo reductive decarboxylation under
these conditions, but instead gave anhydrides. This finding
is consistent with Barton’s observations,14 although Bar-
ton has demonstrated aromatic decarboxylative halogena-
tion is possible with activated aromatic substrates.15
Finally, our attempts to use this protocol to reduce
R-amino acids led to complex, intractable, mixtures.
From a mechanistic perspective, the observed results can
berationalized inatleast two ways. The first involvesdirect
H-transfer from chloroform to the alkyl radical (6), thus
furnishing the observed reduction product (2) and the
Using palmitic acid as a test vehicle the corresponding
acid chloride was generated, dissolved in nitromethane,
(9) Perchyonok, V. T. Tetrahedron Lett. 2006, 47, 5163.
(10) Chloroform has previous been observed to act as a hydrogen
donor but not exploited synthetically: (a) Recupero, F.; Bravo, A.;
Bjorsvik, H.-R.; Fontana, F.; Minisci, F. J. Chem. Soc., Perkin Trans. 2
1997, 2399. (b) Bekhazi, M.; Lawrynowicz, W.; Wrakentin, J. Can. J.
Chem. 1991, 69, 1507. (c) Koichi, J. K.; Subramanian, R. V. J. Am.
Chem. Soc. 1965, 87, 4855. (d) Kharasch, M. S.; Jensen, E. V.; Urry,
W. H. J. Am. Chem. Soc. 1947, 69, 1100. (e) Harmon, J.; Ford, T. A.;
Hanford, W. E.; Joyce, R. M. J. Am. Chem. Soc. 1950, 72, 2213.
(11) (a) Furunocuoglu, T.; Uger, I.; Degirmenci, I.; Aviyente, V.
Macromolecules 2010, 43, 1823 and references cited therein. (b) Howard,
G. J.; Lai, S.-H. J. Polym. Sci. Polym. Chem. Ed. 1979, 17, 3273.
(12) Method A resulted in dihydropyrone formation, as previously
reported; see: Shashidhar, M. S.; Bhatt, M. V. J. Chem. Soc., Perkin
Trans. 2 1986, 355.
(13) Dauben, W. G.; Bridon, D. P.; Kowalczyk, B. A. J. Org. Chem.
1990, 55, 376.
(14) Barton, D. H. R.; Lacher, B.; Zard, S. Z. Tetrahedron Lett. 1985,
26, 5939.
(15) Barton, D. H. R.; Lacher, B.; Zard, S. Z. Tetrahedron 1987, 43,
4321.
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