Anodic olefin coupling reactions involving ketene dithioacetals: Evidence for a 'radical-type' cyclization

Article abstract of DOI:10.1016/S0040-4039(02)01663-5

A series of anodic coupling reactions between ketene dithioacetal groups and enol ethers have been studied in order to probe why some of the cyclizations are successful while other closely related attempts fail. It has been found that the success of the cyclization reactions strongly depends on the location of substituents on the olefins. The reactions are highly sensitive to substituents on the terminating olefin but not to substituents on the initial radical cation. This behavior is consistent with what has been observed previously with radical cyclization reactions.

Full text of DOI:10.1016/S0040-4039(02)01663-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7159–7161
Anodic olefin coupling reactions involving ketene dithioacetals:
evidence for a ‘radical-type’ cyclization
Yongmao Sun and Kevin D. Moeller*
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Received 30 July 2002; accepted 9 August 2002
Abstract—A series of anodic coupling reactions between ketene dithioacetal groups and enol ethers have been studied in order to
probe why some of the cyclizations are successful while other closely related attempts fail. It has been found that the success of
the cyclization reactions strongly depends on the location of substituents on the olefins. The reactions are highly sensitive to
substituents on the terminating olefin but not to substituents on the initial radical cation. This behavior is consistent with what
has been observed previously with radical cyclization reactions. © 2002 Elsevier Science Ltd. All rights reserved.
The anodic coupling of electron rich olefins can provide
a powerful means for constructing carbonꢀcarbon
bonds.1 Recently, we have shown that these reactions
are compatible with the synthesis of bicy-
clo[3.2.1]octane ring skeletons.2 The cyclizations
appeared to be particularly useful when a ketene acetal
equivalent was used as one of the olefin participants
(Scheme 1).3 In this way, the reaction led to a product
having the ends of the cyclization already differentiated
for further development.
formation of a quaternary carbon (the oxidation of a
directly analogous bis enol ether substrate lacking the
silyl group led to an 82% yield of the bicy-
clo[3.2.1]octane product).2 Second, it was possible that
the difference between the cyclizations reflected the
location of the ketene acetal in the substrate. This
second possibility was particularly intriguing because
previous studies had shown that olefin coupling reac-
tions involving enol ether derived radical cations pro-
Yet while the example illustrated in Scheme 1 pro-
ceeded very nicely, other apparently related cyclizations
involving ketene acetal equivalents did not. For exam-
ple, model studies had shown that silyl substituted enol
ethers could serve as effective ketene acetal equivalents
for anodic cyclization reactions (Scheme 2, substrates
3a and 3b).2 However, the use of a silyl substituted enol
ether as a participant in the formation of a bicy-
clo[3.2.1]octane ring skeleton (substrate 6) led to none
of the desired product. But why did this reaction fail?
Scheme 1.
There were two possible answers to this question. First,
it was possible that the difference in the reactions
resulting from the oxidation of 1 and 6 reflected an
inherent difference in reactivity between the radical
cation generated from oxidation of the ketene dithioac-
etal and the radical cation generated from oxidation of
the silylated enol ether. Perhaps the presence of the silyl
substituent lowered the reactivity of the radical cation
to a point where it was no longer compatible with the
* Corresponding author. Tel.: 01-314-935-4270; fax: 01-314-935-4481;
e-mail: moeller@wuchem.wustl.edu
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01663-5

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Y. Sun, K. D. Moeller / Tetrahedron Letters 43 (2002) 7159–7161
ceeded in a ‘radical-like’ fashion.5,6 This meant that the
radical cation attacked the trapping olefin in such a
way as to form a radical intermediate at the terminating
end of the cyclization. If the difference between the
cyclizations originating from 1 and 6 did result from
the location of the ketene acetal equivalent in the
substrate, then the observations made would suggest
that the same mechanism operated in the current reac-
tions as well. The cyclization originating from substrate
1 would involve formation of a radical cation from the
ketene acetal on the ring followed by a 6-exo-trig type
cyclization onto a disubstituted enol ether (Scheme 3,
Eq. (1)). The cyclization originating from substrate 6
would involve formation of a radical cation from the
ketene acetal on the side chain followed by 6-exo-trig
type cyclization onto a trisubstituted enol ether. In this
case, the extra substituent would be on the internal
carbon of the enol ether being attacked (Scheme 3, Eq.
(2)). For radical cyclization reactions, such differences
are significant. Radical reactions are generally not sen-
sitive to the presence of substituents on the carbon
bearing the initial radical (R1 in Fig. 1). However,
substituents on the internal carbon of the olefin being
attacked (R2 in Fig. 1) dramatically slow down the
cyclizations.7 Hence, if the radical cation reactions orig-
inating from the oxidation of 1 and 6 were ‘radical-
like’, then the cyclization originating from 1 would be
expected to proceed much better than the cyclization
originating from 6.
Scheme 4.
using the known Horner–Emmons–Wadsworth based
procedure.8
The oxidation of 10 was attempted using the same
electrolysis conditions that had been used to success-
fully trigger the cyclization reaction from substrate 1.
In this case, the reaction led to a complex mixture of
products. None of the desired cyclized product was
1
obtained (Scheme 5). The 300 MHz H NMR spectrum
of the crude material did show that the enol ether
group was intact in the product. Clearly, the ketene
dithioacetal was oxidized but the cyclization did not
occur. Based on this observation, it was apparent that
the difficulties associated with the previous cyclization
of 6 were not simply due to the use of the silylated enol
ether ketene acetal equivalent, but rather resulted from
the location of the ketene acetal initiating group.
With this in mind, we set out to determine if the
difference between the reactions originating from 1 and
6 was the result of either the location of the ketene
acetal or the nature of the initiating group used. Since
a substrate having a silylated enol ether on the ring
proved difficult to synthesize, this effort focused on the
synthesis and oxidation of a substrate having a ketene
dithioacetal group on the sidechain (Scheme 4). In this
sequence, the ketene dithioacetal group was introduced
This observation was not restricted to cyclizations lead-
ing to bicyclo[3.2.1]octane ring skeletons. A pair of
substrates that would afford fused bicyclo[3.3.0]octane
ring skeletons upon cyclization were also studied. First,
a substrate having the ketene acetal moiety on the ring
(13) was synthesized and oxidized (Scheme 6). In this
example, the oxidation led to a 76% isolated yield of
cyclized product. The product had cis bridgehead stereo-
chemistry and was obtained as a 5:1 ratio of stereoiso-
mers about the newly formed bond. For comparison, a
directly analogous substrate having the ketene dithioac-
etal on the side chain (16) was synthesized and oxidized
(Scheme 7). As in the case of the oxidations leading to
bridged bicyclic products, moving the ketene dithioac-
etal to the sidechain stopped the cyclization reaction
from occurring.
Scheme 3.
Figure 1.
Scheme 5.

Y. Sun, K. D. Moeller / Tetrahedron Letters 43 (2002) 7159–7161
7161
the nature of the trapping group. Both cyclization
reactions originating from the oxidation of a ketene
dithioacetal and cyclization reactions originating from
the oxidation of an alkyl enol ether show ‘cation-like’
behaviour when an alcohol nucleophile is employed as
the trapping group.9
Acknowledgements
We thank the National Science Foundation (CHE-
9023698) for their generous support of this work. We
also gratefully acknowledge the Washington University
High Resolution NMR facility, partially supported by
NIH grants RR02004, RR05018, and RR07155, and
the Washington University Mass Spectrometry
Resource Center, partially supported by NIHRR00954,
for their assistance.
Scheme 6.
References
1. For a review see: Moeller, K. D. Tetrahedron 2000, 56,
9527.
2. Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D.
Tetrahedron 2001, 57, 5183.
3. For additional examples, see: Sun, Y.; Liu, B.; Kao, J.;
d’Avignon, D. A.; Moeller, K. D. Org. Lett. 2001, 3, 1729.
4. RVC=reticulated vitreous carbon (100 PPI from the Elec-
trosynthesis Co, Inc.). Preparative electrolyses were con-
ducted utilizing a Model 630 coulometer, a Model 410
potentiostatic controller, and a Model 420A power supply
purchased from The Electrosynthesis Co., Inc.
5. For anodic olefin coupling reactions that lead to ‘radical-
like’ cyclizations involving enol ether radical cation reac-
tions see: Hudson, C. M.; Moeller, K. D. J. Am. Chem.
Soc. 1994, 116, 3347.
6. For detailed mechanistic studies involving enol ether radi-
cal cations, see: (a) Horner, J. H.; Taxil, E.; Newcomb, M.
J. Am. Chem. Soc. 1992, 124, 5402; (b) Horner, J. H.;
Newcomb, M. J. Am. Chem. Soc. 2001, 123, 4364; (c)
Newcomb, M.; Miranda, N.; Sannigrahi, M.; Huang, X.;
Crich, D. J. Am. Chem. Soc. 2001, 123, 6445.
7. (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J.
Chem. Soc., Chem. Commun. 1980, 482; (b) Beckwith, A.
L. J.; Lawrence, T.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 484.
Scheme 7.
In conclusion, it appears that anodic olefin coupling
reactions that are triggered by the oxidation of a ketene
dithioacetal functional group proceed in a ‘radical-like’
fashion. Like radical reactions, they are sensitive to
steric hindrance on the internal carbon of olefin being
attacked but not sensitive to steric groups on the car-
bon bearing the radical. This ‘radical-like’ behaviour is
directly parallel to what has been observed for anodic
cyclizations that are triggered by the oxidation of an
alkyl enol ether, an observation that is critical for the
design of future cyclization and tandem cyclization
reactions that take advantage of ketene dithioacetals as
initiating groups and olefins as trapping groups. It is
important to note that this observation is dependent on
8. Iorga, B.; Mourie`s, V.; Savignac, P. Bull. Soc. Chim. Fr.
1997, 134, 891.
9. For examples using enol ethers, see: (a) Sutterer, A.;
Moeller, K. D. J. Am. Chem. Soc. 2000, 122, 5636; (b)
Duan, S.; Moeller, K. D. Org. Lett. 2001, 3, 2685. For
examples using ketene dithioacetals, see Ref. 3 in addition
to (c) Liu, B.; Moeller, K. D. Tetrahedron Lett. 2001, 42,
7163.