The anionic route to tricyclanes

Article abstract of DOI:10.1016/S0040-4039(99)02270-4

A very mild anion induced intramolecular ring closure route to tricyclanes is reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02270-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1287–1290
The anionic route to tricyclanes
Kamyar Afarinkia ∗ and Farzana Mahmood
Department of Chemistry, King’s College, The Strand, London WC2R 2LS, UK
Received 29 October 1999; accepted 7 December 1999
Abstract
A very mild anion induced intramolecular ring closure route to tricyclanes is reported. © 2000 Elsevier Science
Ltd. All rights reserved.
The extensive development of the chemistry of the tricyclane (tricyclo[2.2.1.02,6]heptane) ring system
over the past three decades owes much to its role in unravelling mechanistic aspects of Wagner–Meerwein
rearrangements and the concept of non-classical carbocations. Interestingly, tricyclanes have even found
a biological role as phenoxytricyclane 1 is reported to have as equal a potency as an insecticide as DDT.1
Carbene insertion in norbornanes,2 and both radical3 and cationic4 ring closures in norbornenes
have been widely employed for the synthesis of tricyclanes. However, there are very few examples of
the analogous anion-induced ring closure in the literature.5 Here, we report a series of observations
which suggest that the anionic route is a significantly more versatile route to tricyclanes than previously
believed.
Compound 2 was prepared by cycloaddition of cis-1,2-phenylsulfonylethene and cyclopentadiene
followed by base-induced elimination of phenylsulfinic acid. Epoxidation (mCPBA/CH2Cl2 or H2O2/t-
BuOK in THF) afforded exo epoxide 3 in quantitative yield under both reaction conditions. Upon
treatment with lithium methoxide in methanol at room temperature, an addition product was obtained
which on the basis of NMR spectra was assigned structure 4. However, when this reaction was carried
out at reflux, compound 4 was not the isolated product. Instead, tricyclane 5 was isolated in 81%
yield (Scheme 1). X-Ray structure determination confirmed the formation of tricyclane and that the
nucleophilic methoxide had attacked from the less hindered exo face.6 Compound 4 could be transformed
∗
Corresponding author. E-mail: kamyar.afarinkia@kcl.ac.uk (K. Afarinkia)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02270-4
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to 5 by treatment with a variety of bases in good yield (Scheme 1). A related observation was recently
made confirming that such anionic ring closure of tricyclanes are facile.5c
Scheme 1. Reagents and conditions: (i) mCPBA, CH2Cl2, 100%; (ii) MeOLi, MeOH, rt, 3 h, 100%; (iii) MeOLi, MeOH, reflux,
5 days, 81%; (iv) t-BuOK, DMSO, 70°C, 5 days, 90%; (v) MeLi, THF, 0°C, 3 h, 100%; (vi) 10% Pd/C, hydrogen, EtOAc, rt,
100%
Further investigation revealed that nucleophilic addition/epoxide ring opening is a general reaction of
compound 3. Additions of a number of other nucleophiles afforded the corresponding tricyclanes in a
similar manner (Scheme 2). Reactions can be carried out under a range of conditions and even treatment
with nucleophiles in organic solvents at room temperature afforded tricyclane, albeit in moderate yields.
Presumably, these reactions proceed in two steps. The first is a slow and reversible conjugate addition
of the nucleophile to the vinylsulfone which is then followed by a fast and irreversible intramolecular
nucleophilic attack of the sulfonyl-stabilised carbanion on the epoxide, leading to ring opening of the
epoxide. However, when we prepared 6 and 8, which lack the methoxy group, and studied the tricyclane
formation under basic conditions we made an unexpected observation. Under conditions previously
employed (MeOLi, MeOH, reflux, 5 days) the rates of cyclisation of compounds 6 and 8 are relatively
slow compared to that observed for 4. Following the progress of the reaction by NMR revealed that
compound 4 was half transformed to compound 5 in 85 h. Under similar conditions, compound 8 was half
transformed to compound 9 in 215 h. Furthermore, compound 6 afforded none or only trace quantities
of cyclised tricyclane upon treatment with reagents that gave near quantitative yields of cyclisation with
3 (e.g. 0.1 M aqueous KOH in THF at room temperature) or 4 (e.g. potassium t-butoxide in DMSO at
70°C). Indeed, good yields of tricyclane 7 could only be obtained when a strong organometallic base
(methyllithium in THF) was used.
Scheme 2. Nuc=OMe (A, 100%, M=Li); OCH2Ph (A, 100%, M=Li); OH (A, 100%, M=K); Me (B, 100%, M=Li); Ph (B, 82%,
M=Li or 100%, M=MgBr); PhS (C, 42%); PhNCH3 (C, 35%); NH2 (C, 28%, dioxane as solvent)
The contrast between the relatively mild basic conditions used for formation of tricyclanes from 4 and
the more strongly basic condition required for formation of tricyclane from 6 and 8 is striking. The only

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feature of compound 4 which distinguishes it from 6 and 8 is the methoxy substituent at the position β to
the sulfonyl rather than hydrogen (for compound 6) or methyl (for compound 8). To gauge if the effect
is related to the stereochemistry of the methoxy substituent in compound 4, we also prepared its epimer
containing the β-methoxy substituent at the endo position (Scheme 3).7 In a competition experiment, the
half life of cyclisation of 10 when treated with lithium methoxide at reflux was 130 h compared to 85 h
for that of 4.
Scheme 3.
The role of the β-methoxy substituent in the more facile cyclisation of 4, compared to that of 6 or 8,
may be attributed to easier deprotonation at the position α to the sulfonyl group. Stirling has previously
reported that loss of an α proton from methoxyethylphenylsulfone 11 is faster than that observed from
propyl- and ethylphenylsulfone 12 and 13.8 Although, as proposed by Stirling, the influence of the
methoxy substituent can be attributed to the polar effect of the methoxy substituent, that will not explain
the slight, though observable, differences in the rates of cyclisation between 4 and its epimer 10.
The anionic cyclisation is a general and high yielding route to tricyclanes and other norbornene and
norbornane epoxides undergo a similar reaction (Scheme 4). There were no observable differences in the
facility of the reaction between the endo and exo isomers. Interestingly, the use of two molar equivalents
of MeLi in the reaction of 17 affords the corresponding acetyl derivative 20, which is obtained via formal
addition of a methyl anion to a nitrile followed by hydrolysis; however, in general, MeLi acts as a base
and not a nucleophile. Our results also showed that the effect of a β-methoxy substituent is significantly
less pronounced, but never-the-less observable, for groups such as carbomethoxy.
Scheme 4.
In conclusion, we have shown a new, facile and general anionic route for synthesis of tricyclanes.
The tricyclanes obtained by this method are functionally rich. We are currently further investigating the
factors that influence the facility of the cyclisation and also the use of these functionalised tricyclane
templates in peptide design.

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Acknowledgements
We would like to thank Prof. W. B. Motherwell for useful discussions, and the Commonwealth
Scholarship Commission for a studentship to F.M. We are indebted to the University of London
Intercollegiate Research Services (ULIRS) at King’s College and EPSRC’s Chemical Database Service
at Daresbury Laboratories for the use of their facilities. This work was made possible by a grant from the
University of London Central Research Fund (Stern Trust).
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