SCHEME 1
When Ethyl Is Infinitely Different from Methyl:
Double Addition of Lithiated Dithianes to
Aromatic Carboxylates Revisited
Roman A. Valiulin, Rudresha Kottani, and
Andrei G. Kutateladze*
Department of Chemistry and Biochemistry,
UniVersity of DenVer, DenVer, Colorado 80208-2436
efficient double addition of lithiodithianes to benzoates is the
case of methyl dithiane.
Previously, we utilized such bisadducts of methyl dithiane
in the development of a new generation of externally sensitized
photocleavable latches possessing high quantum yields of
fragmentation.3
ReceiVed April 12, 2006
Extension of this photochemical project required a series of
different alkyl dithianes as labeling tags for mass-discriminating
GCMS detection; thus, we proceeded with syntheses of nine
bisdithiane adducts, using methyl- through nonyl-substituted
dithianes. The reactions were run according to both the original
Corey-Seebach procedure (i.e., at -20 °C1d) and a simpler
method which we have developed for +20 °C experiments.4 In
subsequent benzophenone-sensitized photochemical experi-
ments, all nine dithianes were released from their respective
adducts, as expected. Similar photochemistry notwithstanding,
the proton NMR spectrum of the methyl dithiane-based bisad-
duct was noticeably different from the ones obtained for the
higher, ethyl through nonyl, homologues.
Addition of lithiated alkyl dithianes to benzoyl chloride or
methyl benzoate does not produce the expected product of
double addition, R,R-bis(alkyldithianyl) benzyl alcohol, for
alkyls larger than methyl. Instead, the first step intermediate,
i.e. 2-benzoylated dithiane, undergoes an electron-transfer
reduction by the second molecule of the dithianyl anion. This
reduction is followed by the ring-opening mesolytic frag-
mentation of the dithiane ring in the ketyl anion radical and
subsequent radical recombination yielding acetophenone-
tethered thioortho esters 4, R-[3-(2-alkyl-1,3-dithiane-2-
ylthio)propylthio]-R-alkyl-acetophenones. It appears that the
Corey-Seebach bisaddition of lithiated dithianes to methyl
benzoate is an exception rather than the rule in the alkyl
dithiane series.
Although the integration ratio of the aromatic protons to the
aliphatic protons indicated that two molecules of dithiane were
indeed added, there was a triplet at approximately 4 ppm, J )
7.3 Hz, which was difficult to assign (Figure 1). Initially, this
spectral inconsistency was attributed to the differences in the
conformational behaviors of methyl vs ethyl dithiane adducts,
which we have previously seen in the methyl/ethyl dithiane
adducts of benzophenone;5 the anisotropy associated with the
aromatic ring and sulfur atoms caused some unusual chemical
shifts. Yet, further spectroscopic investigation of the “anoma-
lous” adducts revealed that they are not the R,R-bis(dithianyl)
benzyl alcohols but rather rearranged products.
1
Figure 1 shows a comparison of aliphatic H NMR signals
for the bisadducts of methyl and ethyl dithianes with benzoyl
chloride. In the bisadduct of methyl dithiane, 3a (top spectrum),
resonances of dithiane’s CH2S protons, both axial and equatorial
pairs, are more compact, appearing in the 2.5-3.0 ppm range.
In the ethyl dithiane bisadduct, 4b (bottom spectrum), the two
axial CH2S protons of dithiane are found 0.7 ppm downfield
The Corey-Seebach umpolung approach, based on reactions
of lithiodithianes with a variety of electrophiles, including
carbonyl compounds, has secured a prominent place among the
classical methodologies of synthetic organic chemistry.1 One
of its flavors, the methyl dithiane addition to alkyl benzoates
or benzoyl chloride, offers access to tertiary alcohols 3 contain-
ing two dithiane moieties, much like the double addition of other
organometallic reagents (Scheme 1). Unsubstituted dithiane was
noted to react less efficiently because of possible deprotonation
of the enolizable intermediate, benzoylated dithiane, by an
excess dithiane anion.2 Thus, it appears that the only known
(2) See ref 1d, although examples of high-yielding double addition of
unsubstituted lithiodithiane to benzoyl chloride are known: Kita, Y.;
Sekihachi, J.-I.; Hayashi, Y.; Da, Y.-Z.; Yamamoto, M.; Akai, S. J. Org.
Chem. 1990, 55, 1108.
(3) Li, Z.; Kutateladze, A. G. J. Org. Chem. 2003, 68 (21), 8236.
(4) We found that at room temperature addition of butyllithium to a THF
solution of dithiane generates >90% anion within 15-20 min after which
it slowly degrades. Most of the reactions with carbonyl compounds occur
at room temperature at much higher rates, within minutes furnishing the
desired adducts in excellent yields, even in the case of less-reactive aromatic
ketones, for which the reaction time at low temperatures can be as long as
12-24 h (ref 1d).
(1) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075. (b) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1077. (c) Corey, E. J.; Seebach, D.; Freedman, R. J. Am. Chem. Soc. 1967,
89, 434. (d) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. (e)
Groebel, B. T.; Seebach, D. Synthesis 1977, 357.
(5) Gustafson, T. P.; Kurchan, A. N.; Kutateladze, A. G. Tetrahedron
2006, 62.
10.1021/jo060780f CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/26/2006
J. Org. Chem. 2006, 71, 5047-5049
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