7
130
J . Org. Chem. 1998, 63, 7130-7131
High ly Efficien t Gen er a tion of Ra d ica ls fr om
Ester En ola tes by th e F er r ocen iu m Ion .
Ap p lica tion to Selective r-Oxygen a tion a n d
Dim er iza tion Rea ction s of Ester s†
Sch em e 1
Ullrich J ahn*
Institut f u¨ r Organische Chemie, Technische Universit a¨ t
Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany
Received J une 23, 1998
The challenge of synthetic efficiency calls for the design
of transformations that allow the flexible combination of
different intermediates in reaction sequences. In contrast
to well documented “homointermediate reaction sequences”1
that involve a single type of intermediate (eq 1), much less
is known about “heterointermediate reaction sequences”,2
where different intermediates are selectively generated and
reacted along a carbon chain (eq 2).
1
2
3
n
M f R* f R * f R * f R * f f R * f P
ment for the design of oxidative heterointermediate reaction
sequences. As a prelude, we report about the efficient SET
oxidation of simple ester enolates 3 with 1 and the applica-
tion of the so generated R-carbonyl radicals in efficient
oxygenation by TEMPO9 2 according to Scheme 1, and
dimerization reactions.
+
•
-
*
)
or or
(eq 1)
M f R f R f R2• f R3• f R4+ f R5+ f P
-
1-
(eq 2)
Deprotonation of 3a , oxidation to radical 4a , and trapping
by 2 at -78 °C at a [75 mM] enolate concentration provided
TEMPO adduct 5a in 42 % yield (Table 1, entry 1). Other
This strategy requires efficient electron transfer steps
between reaction steps and selective SET reagents. Tradi-
3
tionally, SET oxidations of alkali enolates are mediated by
10
products isolated were the meso- and d/ l-dimers 6 and 7
4
5
4cf,6
7
Cu(II) or Fe(III) salts, I2,
or anodic oxidation, as studied
11
in a 1:1 ratio, small amounts of the â-keto ester 8, and a
mainly in oxidative dimerizations. For reaction sequences
mixture of trimers 9 (not shown) (entry 1). Increasing either
the concentration of 3a to 0.2 M or of TEMPO to 2.5 equiv
to facilitate trapping provided compounds 5-9 in comparable
amounts, indicating a negligible influence of the reactant
concentrations (entries 2, 3). Remarkably, however, upon
addition of 6 equiv (relative to LDA) of HMPA prior to
enolate formation, the yields of 5a and d/ l-dimer 7a
increased to 67% and 25%, respectively, with concomittant
decrease in the yields of meso-dimer 6a , 8, and 9 (entry 4).
The structure of esters 3b-f significantly influenced the
results of the R-oxygenation by LDA/1/2/(HMPA). γ-Branched
ethyl isocaproate 3b gave a similar result as the straight
chain ester 3a (entry 5). Again, the addition of HMPA
facilitated the formation of 5b at the expense of dimerization
products 6-8 (entry 6). If branching occurs closer to the
reaction center, selectivity improved considerably. Ester
enolates 3c-f gave uniformly high yields of oxygenated
products 5c-f (entries 7-14). Dimer and oligomer forma-
tion played essentially no role, except for 3c, where small
amounts of dimers 6c/7c were detected (entry 7). The
reaction can be scaled up without influence on the yield, as
exemplified for the oxygenation of 3c (entry 8). The applied
solvent system has only a minor influence on yield and
stereoselectivity, so that THF is the solvent of choice with
R- or â-branched esters (entries 7, 8, 9, 11, 13). Methyl
(
eq 2), however, problems may arise with these reagents,
4
g,6b
since varying yields depending on the ester structure
and
ligand transfer4
d,f,g
were observed.
Recently, we introduced ferrocenium hexafluorophosphate
as a mild, stable and recyclable SET oxidant for malonate
1
enolates and certain nucleophilic radicals in “heterointer-
mediate tandem reactions” (eq 2).8 The predictable general
applicability of 1 in enolate oxidations is a crucial require-
*
Corresponding author. Tel.: +49-531-391-7371, FAX: +49-531-391-
5
388, e-mail: u.jahn@tu-bs.de.
†
Dedicated to Prof. Dr. W. Schroth on the occasion of his 70th birthday.
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(
2) Dalko, P. I. Tetrahedron 1995, 51, 7579-7653.
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Organischen Chemie; 4th ed.; Regitz, M., Giese, B., Eds.; Thieme: Stuttgart,
1
989; Vol. E19a, pp 717-747.
4) (a) Chakraborty, T. K.; Dutta, S. Synth. Commun. 1997, 27, 4163-
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(
4
Mahal, L. K. Macromolecules 1997, 30, 6445-6450 and refs therein. (c)
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therein. (d) Quermann, R.; Maletz, R.; Sch a¨ fer, H. J . Liebig's Ann. Chem.
3
-methylvalerate 3d provided adduct 5d in ca. 90% yield as
a diastereomeric mixture in a 2:1 ratio (entries 9, 10). The
configuration of the adducts could not be assigned at this
1
993, 1219-1223 and refs therein. (e) Porter, N. A.; Rosenstein, I. J .
Tetrahedron Lett 1993, 34, 7865-7868. (f) Porter, N. A.; Su, Q.; Harp, J .
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(g) Rathke, M. W.; Lindert, A. J . Am. Chem. Soc. 1971, 93, 4605-4606.
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Shigei, T.; Itoh, M. Chem. Lett. 1975, 621-624.
(8) J ahn, U.; Hartmann, P. Chem. Commun. 1998, 209-210.
(9) While this work was in progress, an example of Cu(II)-promoted
oxygenation appeared.4b
J ., J r.; Dong, Y. Tetrahedron 1993, 49, 7931-7942 and refs therein. (b)
Chung, S. K.; Dunn, L. B., J r. J . Org. Chem. 1983, 48, 1125-1127. (c)
Frazier, R. H., J r.; Harlow, R. L. J . Org. Chem. 1980, 45, 5408-5411.
(6) (a) Alvarez-Ibarra, C.; Csaky, A. G.; Colmenero, B.; Quiroga, M. L.
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Petragnani, N.; Rodrigues, R.; La Scala Texeira, H. Synthesis 1975, 396-
(10) For configuration assignment see ref 4d.
(11) 8 was probably formed during enolate generation.
3
97.
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Published on Web 09/30/1998