One-pot assembly of tricyclo[6.2.1.01,6]undecan-4-one and related polycyclic compounds by tandem electroreductive cyclization

Article abstract of DOI:10.1021/ol0484660

(Chemical Equation Presented) Electroreductive tandem cyclization of 4-allyl-4-(2-bromoprop-2-en-1-yl)cyclohex-2-en-1-one to tricyclo[6.2.1.0 ^1,6]undecan-4-one has been demonstrated. This protocol represents an attractive alternative to convent

Full text of DOI:10.1021/ol0484660

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3629-3632
One-Pot Assembly of
Tricyclo[6.2.1.01,6]undecan-4-one and
Related Polycyclic Compounds by
Tandem Electroreductive Cyclization
Masahiro Toyota,* Andivelu Ilangovan, Yoshitomo Kashiwagi, and
Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received August 3, 2004
ABSTRACT
Electroreductive tandem cyclization of 4-allyl-4-(2-bromoprop-2-en-1-yl)cyclohex-2-en-1-one to tricyclo[6.2.1.01,6]undecan-4-one has been
demonstrated. This protocol represents an attractive alternative to conventional tandem radical cyclization.
The assembly of polycyclic molecules through carbon-
carbon bond-forming processes in a single operation is a
significant direction for organic synthesis. Therefore, various
types of tandem reactions have been actively developed in
recent years. In fact, this field is mostly dominated by the
employment of transition-metal chemistry and radical pro-
cesses.1 The advantage of these methods over conventional
reactions is that they proceed under mild conditions and
involve simple manipulation. However, they suffer from
drawbacks resulting from the high cost of the transition
metals and from concerns about toxicity of tin species. In
view of increasing strict environmental legislation, the
creation of toxicologically benign and environmentally
friendly methodologies has become attractive.2
trochemical processes only use electrons as a reagent, they
have received increasing attention in recent years.4
The sequence of electroreductive cyclizations outlined in
Scheme 1 provides a route to tricyclo[6.2.1.01,6]undecane-
Scheme 1. Synthetic Plan
As part of our studies on the discovery and development
of new tandem reactions,3 we herein report a strategy based
on intramolecular electroreductive cyclization. Since elec-
4-one and related polycyclic compounds. Vinyl radical 1,
resulting from the corresponding bromide by means of
cathodic reduction, could consecutively cyclize onto the
appropriate unsaturated side chain and enone to form a
bridged tricyclic ring system 2.5
(1) For recent reviews, see: (a) McCarroll, A. J.; Walton, J. C. Angew.
Chem., Int. Ed. 2001, 40, 2224. (b) Poly, G.; Giambastiani.; Heumann, A.
Tetrahedron 2000, 56, 5959. (c) Malacria, M. Chem. ReV. 1996, 96, 289.
(d) Little, R. D. Chem. ReV. 1996, 96, 93.
(2) Tundo, P.; Anastas, P.; Black, D. StC.; Breen, J.; Collins, T.; Memoli,
S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000, 72,
1207.
(3) (a) Toyota, M.; Yokota.; Ihara, M. J. Am. Chem. Soc. 2001, 123,
1856. (b) Toyota, M.; Yokota, M.; Ihara, M. Org. Lett. 1999, 1, 1627. (c)
Toyota, M.; Yokota, M.; Ihara, M. Tetrahedron Lett. 1999, 40, 1551.
10.1021/ol0484660 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/03/2004

Prior to testing the feasibility of the envisaged protocol,
the requisite substrates were prepared as depicted in Scheme
2. Namely, E-olefin 5 and Z-olefin 6 were synthesized from
nickel(II) perchlorate complex) was chosen as the catalyst
for the present cyclization. Results of the cyclization are
summarized in Table 1. First, the formation of the bicyclo-
[2.2.0]heptane ring system was investigated. Electrolysis of
E-olefin 5 provided endo-product 16 in 58% yield (entry 1).
When the reaction was performed on Z-olefin 6, exo-product
17 was obtained in 73% (entry 2).
Scheme 2. Preparation of Key Substrates
Although there was question of stereoselectivity in the
cyclization of 5, the stereochemical outcome of electrore-
ductive tandem cyclization of 6 could be rationalized as
follows: the radical intermediate resulting from substrate 6
might react through either of the two conformers A and B.
The allylic-type 1,3-strain interaction8 in B between pseudo
axial hydrogen and ester moiety causes the reaction to
proceed predominantly via conformer A (Figure 1).
Figure 1. Conformations for electroreductive tandem cyclization.
Analyses of the 1H-1H COSY experiments of 16 and 17
enabled the assignment of all protons of each compounds.
In addition, the relative stereochemistries were established
on the basis of NOESY correlations as described in Figure
2.
Figure 2. Significant NOESY correlations.
Encouraged by these results, we explored the construction
of bridged tricyclic systems. The electroreductive tandem
cyclization of 4-allyl-4-(2-bromoprop-2-en-1-yl)cyclohex-2-
en-1-one (9) was conducted to lead to tricyclo[6.2.1.01,6]-
undecan-4-one derivative 18, in 50% yield, as well as
spiro[4.5]decane 19 (3%) and spiro[5.5]undecane 20 (33%),
produced through ring expansion.9 The structures and relative
stereochemistry of 18 and 19 were established by various
spectral analyses.
ethyl 4-pentenoate (3) by alkylation followed by DIBAL-H
reduction and Wadsworth-Emmons olefination. Silica gel
chromatography achieved the separation of 5 and 6. Enone
9 was next prepared from compound 7 using Stork-
Danheiser’s protocol.6 After alkylation of 7, the resulting
vinyl bromide was subjected to DIBAL-H reduction followed
by acidic treatment to give rise to 9. Compounds 11, 12,
and 15 were synthesized by the same method described
above.
When the reaction was run at 60 °C, it was complete in
20 h and gave 18 in 40% yield. By employing 20 mol % of
After extensive investigation,7 [Ni(tet a)](ClO4)2 (5,5,7,-
12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane-
(7) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto, K. J.
Org. Chem. 1996, 61, 677.
(4) Grimshaw, J. Electrochemical Reactions and Mechanisms in Organic
Chemistry; Elsevier: Amsterdam, 2000.
(5) Ozaki, S.; Matsui, E.; Waku, J.; Ohmori, H. Tetrahedron Lett. 1997,
38, 2705.
(8) For reviews, see: (a) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(b) Johnson, F. Chem. ReV. 1968, 68, 375
(9) (a) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27,
4525. (b) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529.
(6) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
3630
Org. Lett., Vol. 6, No. 20, 2004

Table 1. Tandem Electroreductive Cyclizationa
a All reactions were carried out using [Ni(tet a)](ClO4)2 (10% mol) in DMF at rt. b 60 °C. c 60 °C, [Ni(tet a)](ClO4)2 (20% mol). d Based on recovered
starting material.
[Ni(tet a)](ClO4)2 at 60 °C, the reaction was complete in 9
h and a 50% yield of 18 was isolated (entry 3). On the basis
of this observation, the substituent effect on the enone moiety
was next investigated. As a result, the reaction of 12
displayed completely different reactivity. Compound 12 did
not provide any of the desired tricyclic compound, but instead
a significant amount of 21 was generated along with 22 (entry
4). The formation of 21 is believed to proceed as outlined
in Scheme 3. Homoallyl radical E arising from 5-exo-trig
dodecane ring system 23 (57%). Interestingly, the reaction
of iodide 11 afforded cis-hydrindan 25, in 90% yield, in
which 5-exo-trig cyclization predominated.11
In conclusion, tandem electroreductive cyclization has been
successfully applied to the construction of tricyclo[6.2.1.01,6]-
undecan-4-one and related polycyclic compounds. The
favorable profile of this novel protocol is increased by the
(10) A recent review: Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc.
ReV. 2001, 30, 94.
(11) Typical Procedure for Electroreduction. Compound 6 (163 mg,
0.597 mmol), [Ni(tet a)](ClO4)2 (32 mg, 59.4 µmol), NH4ClO4 (141 mg,
1.20 mmol), and Et4NClO4 (35.4 mg, 0.154 mmol) were dissolved in 12
mL of dimethylformamide. This clear solution was transferred to one
compartment of a separable H-type cell, divided by a Nafion 117
ion-exchange membrane. This compartment was then equipped with a
graphite felt cathode and Ag/AgCl reference electrode. The electrolyte was
degassed by bubbling nitrogen through it for 45 min. The platinum counter
electrode was equipped with the other compartment and filled with 12 mL
of dimethylformamide containing Et4NClO4 (35.4 mg, 0.154 mmol).
Electroreduction was carried out potentiostatically at -1.32 V under nitrogen
gas at room temperature. After 14 h, the reaction mixture was diluted with
30 mL of Et2O and separated. The ethereal layer was washed three times
with water, dried over Na2SO4, and evaporated. The residue was purified
by column chromatography on silica gel using 97:3 hexane/EtOAc to
provide 17 (89 mg, 73%) as an oil.
Scheme 3. 1,6-Hydrogen Transfer
cyclization undergoes 1,6-hydrogen atom transfer10 to give
the more stable radical F. As shown in entry 5, the present
protocol is effective for the construction of tricyclo[7.2.1.01,7]-
Org. Lett., Vol. 6, No. 20, 2004
3631

low cost as well as the toxicologically and environmentally
benign character of electrochemistry.
Supporting Information Available: Experimental and
spectral data along with 1H and 13C NMR spectra for various
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work is supported by a Grant-
in-Aid (No. 14571994) from the Ministry of Education,
Science, Sports and Culture, Japan.
OL0484660
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Org. Lett., Vol. 6, No. 20, 2004