Intramolecular anodic olefin coupling reactions: The use of a nitrogen trapping group

Article abstract of DOI:10.1021/ja806259z

Anodic olefin coupling reactions using a tosylamine trapping group have been studied. The cyclizations are favored by the use of a less-polar radical cation and more basic reaction conditions. The most significant factor for obtaining good yields of cyclic product is the use of the more basic reaction conditions. The cyclizations allow for the rapid synthesis of substituted proline derivatives. Copyright

Full text of DOI:10.1021/ja806259z

Published on Web 09/23/2008
Intramolecular Anodic Olefin Coupling Reactions: The Use of a Nitrogen
Trapping Group
Hai-Chao Xu and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130
Received August 8, 2008; E-mail: moeller@wuchem.wustl.edu
Scheme 1
Scheme 2
Anodic oxidation reactions can be used to generate reactive
radical cation intermediates and trigger interesting new umpolung
reactions.1 For example, we have found that the oxidation of
electron-rich enol ethers and ketene acetals can lead to a variety of
cyclization reactions involving the formation of either carbon-
carbon2 or carbon-oxygen bonds.3 In each case, the oxidation
reaction resulted in the coupling of two groups normally thought
to be nucleophiles. With this in mind, we hoped to build cyclic
amino acid derivatives by oxidatively coupling an enol ether or
ketene acetal derivative to a nitrogen-based nucleophile (Scheme
1). Initial attempts to accomplish such a transformation failed.
When an oxidation of an amine or methoxy amine was performed
in hopes of adding a nitrogen-based radical or radical cation to an
enol ether,4-6 decomposition of the enol ether dominated the
reaction. When the nitrogen was substituted with an electron-
withdrawing group and the oxidation channeled toward the enol
ether, decomposition of the enol ether derived radical cation prior
to nitrogen trapping dominated the reaction. In both cases, a poor
yield of cyclized product was obtained. We report here that these
problems can be solved with the use of more basic electrolysis
conditions and that anodic cyclization reactions can be used to build
proline derivatives by generating new carbon-nitrogen bonds.
Initial efforts to improve the cyclization reactions varied the
substituents on the double bond in 1. We have found that the nature
of the substituents on a radical cation can dramatically alter its
reactivity.2b,c,e,g The study was started by examining substrates
3a-d (Scheme 2). An enol ether, a vinylsulfide, and a ketene
dithioacetal were chosen as the olefin coupling partners for the
reaction. A tosylated amine was used as the nucleophile because
of its known effectiveness for trapping electrophiles.7 As in earlier
studies, the oxidation of the enol ether substrate 3a using a
reticulated vitreous carbon anode, a platinum cathode, tetraethy-
lammonium tosylate as electrolyte, 2,6-lutidine as an proton
scavenger, and 30% methanol/THF solvent led to a mixture of
products out of which only a 20% isolated yield of the desired
cyclization product 4a was obtained. The reaction was conducted
at a constant current of 6 mA until 2.2 F/mol of current had been
passed. The yield of the reaction could be improved to 26% by
using methanol as the reaction solvent; however, a much more
significant improvement in the yield of the cyclization was obtained
when thioenol ether substrate 3b was oxidized. Using the same
conditions as those for the initial oxidation of 3a, a 54% isolated
yield of product 4b was obtained. This result was consistent with
earlier observations that more polarized radical cation intermediates
tend to favor carbon-carbon bond formation while less polarized
radical cations tend to favor carbon-heteroatom bond formation.2b
To complete the initial study, the anodic oxidation of dithioketene
acetal substrate 3c was examined. In this case, only a 14% yield of
the desired product was obtained. In addition, 4% of a dimethoxy-
lated product (4 where R ) OMe) was formed.8 This product
resulted from the elimination of methanol from 4c followed by a
Scheme 3
second oxidation. To avoid the elimination of methanol from 4c,
substrate 3d was synthesized and oxidized. The reaction led to a
43% yield of an ∼1/1.3 mixture of cyclized products 4d and 5d.
Six-membered ring product 5d resulted from methanol trapping
of the radical cation competing with trapping by the tosylamine.
This observation suggested that the reactions might benefit from
conditions that increased the nucleophilicity of the nitrogen trapping
group. With this in mind, the reaction conditions were made more
basic by replacing the 2,6-lutidine acid scavenger with LiOMe. The
LiOMe was generated in situ by adding 0.5 equiv of n-BuLi to the
reaction mixture. LiOMe was selected as the base because it would
not be consumed in the reaction. During the electrolysis, methanol
is reduced at the cathode. Hence, for every proton scavenged at
the anode a new methoxide ion would be generated at the cathode.
The change had a dramatic impact on the yield of the cyclization
reactions (Scheme 3). For example, the oxidation of 3a led to an
82% isolated yield of the desired cyclized product 4a. Anodic
oxidation of 3b led to a 90% yield of 4b. Once again, the oxidation
of 3c was plagued by the elimination of methanol from the initially
formed product (4c, R ) H). When the conditions for the
experiment shown in Scheme 3 were used, a 22% yield of cyclized
product (4c, R ) H) was obtained along with 8% of the
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13542 J. AM. CHEM. SOC. 2008, 130, 13542–13543
10.1021/ja806259z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 5
in an asymmetric fashion,3a the oxidation of 3g highlights the
opportunity the cyclizations afford for building chiral amino acid
derivatives.
Finally, the oxidation of substrates 9a and 9b (Scheme 5)
demonstrated that the oxidative coupling reactions are compatible
with other electron-rich olefins. In the case of 9a, the anodic
oxidation of an allylsilane led to the cyclization reaction. In 9b,
oxidation of a styrene moiety triggered the cyclization.
In conclusion, we have found that anodic olefin coupling
reactions can take advantage of nitrogen trapping groups and lead
to the formation of proline derivatives. The reactions benefit from
the use of a less polar radical cation intermediate and the use of
more basic reaction conditions. Efforts to extend this work to the
synthesis of six-membered rings and the construction of more
complex natural products and peptidomimetics are underway.
dimethoxylated product (4 where R ) OMe, R2 ) H). The total
yield of cyclized product isolated could be improved by reducing
the concentration of electrolyte in the reaction to 0.03 M Et4NOTs
in methanol. With these conditions, a 50% yield of 4c was obtained
along with 16% of the dimethoxylated product. Clearly, the initial
cyclization proceeded well. Removing the possibility for the
elimination again led to a significant improvement in the reaction.
Anodic oxidation of 3d led to a 73% isolated yield of the five-
membered ring product 4d along with 7% of 5d.
The use of the enol ether and thioenol ether initiating groups
also proved compatible with the formation of a tetrasubstituted
carbon. The anodic oxidation of both substrates 3e and 3f led to
the desired five-membered ring product in high yield. As in the
oxidation of 3a and 3b, the best yield was obtained using the less
polar thioenol ether substrate.
Supporting Information Available: The procedures for synthesizing
substrates 3a-3g and 9a,b, a general procedure for the electrolysis
reaction, and spectral data for all new compounds are included. This
material is available free of charge via the Internet at http://pubs.acs.org.
In line with our rationale for using the more basic reaction
conditions, the use of LiOMe in the reactions is thought to improve
the reactions by deprotonating the sulfonamide thereby increasing
the rate of the cyclization (Scheme 4). The cyclization can be thought
of as occurring by the formation of a olefin radical cation that is then
trapped by the nitrogen anion or by the formation of a nitrogen-based
radical that then adds to the electron-rich olefin. These two alternatives
are resonance forms of each other. The cyclization generates a radical
(7) which is then oxidized to form 8 and then trapped by solvent to
afford the final product.
The oxidation of substrate 3g suggests that an increase in the
trapping of 8 might also play a role in improving the yield of
reactions using LiOMe. The oxidation of 3g in methanol solvent
led to 4g in an 83% isolated yield (Scheme 3). When the solvent
for this transformation was changed to 30% methanol in THF, a
change made to slow down methanol trapping of the intermediates
generated, only a 28% yield of 4g was obtained. Slowing solvent
trapping before the cyclization reaction should not hurt the yield
of cyclic product obtained. However, slowing solvent trapping of
8 could allow more time for its decomposition thereby decreasing
the yield of 4g. Hence, the oxidations of 3g were most consistent
with a cyclization that proceeded quickly (faster than methanol
trapping of the radical cation in methanol solvent) but then required
rapid trapping of the cationic intermediate generated after the
cyclization.
References
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(8) For spectral data, see the Supporting Information.
Product 4g was obtained as a single isomer with the stereo-
chemistry illustrated in Scheme 3. This stereochemistry was
consistent with earlier cyclizations employing alcohol nucleophiles
and ketene dithioacetals.3 Since substrates like 3 can be made nicely
(9) Optimization of the yield in this case required the use of 0.03 M Et4NOTs.
All other conditions were the same.
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