Two-step electrochemical annulation for the assembly of polycyclic systems

Article abstract of DOI:10.1021/ol026771k

(graph presented) A two-step electrochemical annulation has been developed for the preparation of fused furans. The process involves an initial conjugate addition of a furyethyl cuprate and trapping of the enolate as the corresponding silyl enolether. The

Full text of DOI:10.1021/ol026771k

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3763-3765
Two-Step Electrochemical Annulation for
the Assembly of Polycyclic Systems
Christopher R. Whitehead, E. Hampton Sessions, Ion Ghiviriga, and
Dennis L. Wright*
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611-7200
dwright@chem.ufl.edu
Received August 22, 2002
ABSTRACT
A two-step electrochemical annulation has been developed for the preparation of fused furans. The process involves an initial conjugate
addition of a furyethyl cuprate and trapping of the enolate as the corresponding silyl enolether. The second step of the annulation involves
the anodic coupling of the furan and the silyl enol ether to form a six-membered ring.
The construction of a carbocyclic framework, especially one
with a quaternary center, is key to the rapid and efficient
synthesis of many natural products.1 We have developed a
method for constructing functionalized ring systems through
a two-step oxidative annulation process as illustrated in
Scheme 1.
Furan was a particularly attractive system since Moeller
and co-workers3 had shown that furan could be oxidatively
coupled to various nucleophiles using electrochemical oxida-
tion. From a strategic perspective, the furan nucleus would
offer the greatest synthetic flexibility since it can be easily
converted to six- and seven-membered carbocycles through
cycloadditions4 or γ-lactones through oxidation.5 To examine
the proposed annulation,6 we chose to form six-membered
rings by electrochemical cyclizations (Scheme 2).
Scheme 1
Conjugate addition of 3-furylethylmagnesium bromide 6
to cyclohexenone in the presence of trimethylsilyl chloride
and TMEDA7 led to the formation of the sensitive silyl
(2) For other oxidative reactions of silylenol ethers see: (a) Snider, B.
B.; Shi, B.; Quickley, C. A. Tetrahedron 2000, 56, 10127. (b) Ryter, K.;
Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 2658. (c) Snider, B. B.; Lin,
H. Synth. Commun. 1998, 28, 1913. (d) Hintz, S.; Mattay, J.; van Eldik,
R.; Wu W.-F. Eur. J. Org. Chem. 1998, 1583. (e) Hintz, S.; Frohlich, R.;
Mattay, J. Tetrahedron Lett. 1996, 37, 7349. (f) Paolobelli, A. B.;
Ceccherelli, P.; Pizzo, F.; Ruzziconi, R. J. Org. Chem. 1995, 60, 4954.
(3) (a) Moeller, K. D.; New, D. G. Tetrahedron Lett. 1994, 35, 2857.
(b) New, D. G.; Tesfai, Z.; Moeller, K. D. J. Org. Chem. 1996, 61, 1578.
For an excellent review, see: Moeller, K. D. Tetrahedron 2000, 56, 9527.
(4) Reviews: (a) Rigby, J. H.; Pigge, F. C. In Organic Reactions;
Paquette, L. A., Ed.; Wiley and Sons: New York, 1997; Vol. 51, p 351.
(b) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179-
14233.
This annulation strategy involves an initial conjugate
addition of a fragment 2 containing a nucleophilic alkene to
an R,â-unsaturated carbonyl derivative, trapping the resultant
enolate to give 3. The second step of the process, ring-
closure, involves coupling of the two nucleophilic olefins
triggered by oxidation2 of one alkene to an electrophilic
radical cation. In principle, either of the alkenes could
undergo oxidation with the other serving as the nucleophilic
terminator in the cyclization to produce 4.
(5) Kuwajima, I.; Urabe, H. Tetrahedron Lett. 1981, 22, 5191.
(6) Synthesis of annulated furans: Padwa, A.; Murphree, S. S. Org. Prep.
Proc. Int. 1991, 23, 545.
(7) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019. (b)
Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron
Lett. 1986, 27, 4025.
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Fuji, K. Chem. ReV. 1993, 93, 2037.
10.1021/ol026771k CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002

the theoretical 2 Faraday/mol. With sufficiently low current
densities (0.5-1 mA/cm2) the amount of charge required to
completely consume the starting enolether was nearly the
theoretical amount. Surprisingly, electrodes that have a high
surface area and thus a low current density such as reticulated
vitreous carbon8 (RVC) were far inferior to typical graphite
electrodes. High current densities may favor the formation
of oligomers9 by producing high concentrations of electro-
active species at the electrode.
Scheme 2
With an optimized method in place, a series of annulations
were examined to establish the scope of the method (Table
2).
enolether 7 that was used without the benefit of further
purification. Initial attempts to effect electrooxidative ring
closure using methanol as a cation terminator were frustrated
by competitive methanolysis of the silyl enolether. This
unwanted reaction could be eliminated by the use of less
reactive 2-propanol. Under these conditions, the annulated
furan 9 was formed after a mildly acidic workup. Although
initial electrolyses were conducted at a 0.4 M concentration
of the electrolyte, it was determined that concentrations as
low as 0.1 M provided successful cyclizations. The addition
of 2,6-lutidine as an acid scavenger was also beneficial.
Although additives were an important parameter, the nature
of the electrode system was the most critical factor in the
cyclization (Table 1).
Table 2. Electrochemical Annulation Reactions
Table 1. Electrode Optimization for the Synthesis of 9
current
anode
cathode
densityb
(mA/cm2)
entrya
material
material
yield %c
1
2
3
4
5
6
7
8
9
carbon
carbon
carbon
carbon
carbon
platinum
platinum
RVC
steel
steel
steel
steel
carbon
carbon
carbon
carbon
carbon
0.5
1.0
5.0
10.0
0.5
0.5
0.1
N/A
N/A
68
66
35d
10d
67
27d
54
30d
35
a Reaction conditions: 0.02 M substrate, 0.1 M LiClO4, 0.04 M lutidine
in a 4:1 acetonitrile/2-propanol solution. All reactions were run under
constant current conditions in an undivided cell. b Yield is reported for two
steps based on the enone.
RVC
a Reaction conditions: 0.02 M substrate, 0.4 M LiClO4, 0.1 M lutidine
in a 4:1 acetonitrile/2-propanol solution. All reactions were run under
constant current conditions in an undivided cell. b Current density was
approximated by dividing the applied current by the surface area of the
electrode. c Yield is reported for two steps based on the starting enone.d The
amount of charge consumed was 2-3 times the theoretical amount (2
F/mol).
The electrochemical annulation was highly effective with
five- and six-membered enones delivering the corresponding
indanones and decalones in very good yield (64-78% over
two steps). The process was compatible with the creation of
quaternary centers either at the cuprate addition step (e.g.,
11) or during the electrocyclization (e.g., 12). Additionally,
it was determined that these reactions were extremely
stereoselective, delivering the cis-fused products exclusively.
This high degree of stereocontrol eroded completely in the
Current density proved to be the most important charac-
teristic of the electrode. This refers to the amount of current
applied per unit area of electrode surface. As the current
density increased for a given electrode (entries 1-4), the
yield of the cyclized product dropped significantly and high
molecular weight products were formed. Moreover, when
the reaction was conducted at a high current density, the
amount of charge consumed was many times greater than
(8) Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996, 37,
8317.
(9) For example, Kolbe dimerization is enhanced at high current
densities: Coleman, J. P.; Lines, R.; Utley, J. H. P. J. Chem. Soc., Perkin
Trans. 2 1973, 1064.
3764
Org. Lett., Vol. 4, No. 21, 2002

closure onto a cycloheptyl system (entry 16) where the
stereoselectivity reversed, giving the trans-fused system in
a 4:1 predominance over the cis isomer. This change may
reflect the increased flexibility of the seven-membered ring
that allows alternative stereochemical paths to occur.
During the course of these studies we gained insight into
the nature of the reaction through structural characterization
of the initial reaction product. Although the furan 9 is the
typical product isolated, the moderately unstable dihydrofuran
8 could be isolated if the acidic workup was eliminated. The
structure of the intermediate, including relative stereochem-
istry, was determined by NMR and shown to exist as a 1:1
mixture of two isomeric acetals. The three contiguous centers
at the ring junctions were formed in a single configuration
indicating that the cyclization occurred in a cis fashion with
the furan approaching the enolether through an exo orienta-
tion. The initial formation of a nonfuran intermediate may
be important in that it protects the ring from over-oxidation.
We have also examined the ability of an electron-rich
benzenoid ring to function as the cyclization terminator
(Scheme 3).
suggesting that trapping of the radical cation by the anisyl
group is somewhat slower than furan. This elimination
product could be suppressed by employing 3-methyl-
cyclohexenone in the annulation reaction. Electrochemical
cyclization of 18b was somewhat better, although still giving
only a 47% yield. Although the arenes can function in the
cyclization, it is clear that furan is far superior in this
annulation process.
The flexibility of the annulation could be extended by
reversing the order in which groups are added to the enone
prior to the electrochemical cyclization (Scheme 4).
Scheme 4
1,2-Addition of the Grignard reagent 6 to cyclohexenone
followed by oxidative rearrangement delivered the furyl-
appended enone 22. Addition of groups such as vinyl and
phenyl was easily accomplished, and electrolysis of the
resulting enolethers led to smooth cyclization to give
decalins 23a and 23b in very good yield.
Scheme 3
The development of this two-step annulation protocol
provides direct access to polycyclic systems containing
annulated furans. We are currently employing cyclization
product 11 in combination with an oxyallyl cation cyclo-
addition to gain entry into the cyathane natural products.10
Studies on the closure of different ring sizes and the use of
other terminator groups will be reported in due course.
To examine this closure, the Grignard reagent 17 was
added in conjugate fashion to cyclohexenone to generate the
corresponding enolether 18a in high yield. Electrolysis of
the silyl enolether under the conditions optimized previously
failed to generate any ring-closed products and resulted
primarily in the formation of polymeric materials. However,
increasing the electrolyte concentration to 1 M resulted in a
moderate yield of the ring-cyclized product as a 4:1 mixture
of regioisomers. Interestingly, enone 21 was isolated as a
significant byproduct. This compound probably arises by
proton loss from the initially generated radical cation,
Acknowledgment. We are grateful to the National
Science Foundation for support of this research.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL026771K
(10) Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Frey,
D. A. Org. Lett. 1999, 1, 1535.
Org. Lett., Vol. 4, No. 21, 2002
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