A versatile and concise route to carbocycles using a 1,6-electrocyclic reaction

Article abstract of DOI:10.1039/b311815k

The viability of the 1,6-electrocyclic route to 1,3-cyclohexadienes has been significantly increased by using a phenyl-sulfonyl substituent in a multi-purpose (≥3) role.

Full text of DOI:10.1039/b311815k

A versatile and concise route to carbocycles using a 1,6-electrocyclic
reaction†
Svante Brandänge* and Hans Leijonmarck
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden. E-mail: svante@organ.su.se; Fax: +46 8 15 49 08; Tel: +46 8 16 24 84
Received (in Cambridge, UK) 26th September 2003, Accepted 21st November 2003
First published as an Advance Article on the web 18th December 2003
The viability of the 1,6-electrocyclic route to 1,3-cyclohex-
adienes has been significantly increased by using a phenyl-
sulfonyl substituent in a multi-purpose (43) role.
using KOBut, NaOH, LDA or DBU.13 We found that Na2CO3(s) in
hot toluene directly converted 1a–c to 2-phenylsulfonyl-1,3-cyclo-
hexadienes 2a–c (Scheme 2). The carbocyclic products 2a–c
were thus formed in two steps starting from allyl phenyl sulfone.
They were indistinguishable from those prepared by other
methods.14a,14d,15 Fortunately, products 2a–c proved relatively
stable during the heating process. In contrast, 2-phenylsulfonyl-
1,3-dienes unsubstituted in the 1-position undergo Diels–Alder
dimerisation even at room temperature.14a
The synthetic construction of aliphatic carbocyclic six-membered
rings in suitably substituted or functionalised forms is an important
part of preparative organic chemistry. Reactions driven by anions,1
cations2 or radicals3 as well as Diels–Alder reactions4 have proven
useful as have various cyclisations of alkenes/alkynes mediated by
transition metal compounds.5
Another route to six-membered ring carbocycles is the electro-
cyclic ring-closure of 1,3,5-trienes to form 1,3-cyclohexadienes.6
This reaction typically proceeds at convenient rates at 100–150 °C
and gives high yields. It can also be carried out photochemically.7
Despite extensive phenomenological studies, mainly in the 1970’s,
the thermal 1,6-electrocyclic reaction of trienes has been little used
in synthesis.8 Two main reasons for this can be seen.
Firstly, the preparation of trienes with the required cis configura-
tion of the central double bond has not been straightforward.9
Reduction of acyclic dienynes has met with only moderate
success,8s,9 and Wittig reactions involving triphenylphosphoranes
show low Z-selectivities.10,11 In many of the previous cyclisations
the configuration problem was solved or avoided by the central
double bond being part of a ring.6,12
Secondly, and perhaps even more limiting, when a subsequent
transformation of the diene moiety of the cyclisation product is
required, regioselectivity problems can be foreseen since re-
activities of the two double bonds may be too similar.
Scheme 2 Reagents and conditions: [a] allyl phenyl sulfone + BuLi, then
Ac2O; [b] Na2CO3, refluxing toluene.
These problems have now been simultaneously eliminated by the
Allylic sulfones and a,b-unsaturated aldehydes are available by
a number of synthetic methods. The example shown in Scheme 3 is
a slight modification of a literature procedure.16 Since it was also of
interest to study the formation of sulfonyltrienes and their ring-
closure separately, the allylic sulfone 3 was converted to the
bicyclic dienyl sulfone 7 in a stepwise fashion (Scheme 4). In the
condensation of 3 with methacrolein ca. 18% of 3 was recovered in
two slightly different runs; this suggested a somewhat unfavourable
condensation equilibrium due to the highly branched nature of the
lithium salt of 4. Similarly to other 1-alken-3-ols,17 4 reacted with
SOCl2–pyridine to exclusively give a rearranged, primary chloride
(5). Elimination of HCl at 67 °C afforded triene 6 in high isomeric
purity ( > 95%). On heating at 110 °C 6 underwent ring-closure to
7 (97%).
Scheme 1
introduction of a suitably placed phenylsulfonyl group (Scheme 1).
This strategy enables facile convergent C3 + C3 synthesis of the C6
skeleton by the condensation of an allylic sulfone and an a,b-
unsaturated aldehyde. In the subsequent elimination to form a triene
the sulfone group governs the configuration of the central double
bond in the triene.13 It also creates a difference in the reactivity of
the two double bonds in the cyclisation product due to its electron-
attracting character.14
In the first version of our route to carbocycles, lithiated allyl
phenyl sulfone was allowed to react with three different a,b-
unsaturated aldehydes; these reactions were quenched by acetic
anhydride to produce b-acetoxy sulfones 1a–c as mixtures of
diastereomers (3–7 : 1, Scheme 2). Such compounds are inter-
mediates in the Julia–Lythgoe olefination.13 Elimination of acetic
acid to produce a vinylic sulfone has previously been carried out
As shown in our last example (Scheme 5), the electrocyclic
reaction is capable of providing six-membered ring carbocycles in
† Electronic Supplementary Information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b3/b311815k/
Scheme 3 Reagents and conditions: [a] PhSCH3 + BuLi + DABCO; [b]
MCPBA; [c] HOTs, D.
292
C h e m . C o m m u n . , 2 0 0 4 , 2 9 2 – 2 9 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 4 Reagents and conditions: [a] BuLi; [b] methacrolein; [c] SOCl2,
pyridine; [d] Cs2CO3, THF, D; [e] toluene, 110 °C, 3 h, argon.
7 R. B. Woodward and R. Hoffmann, The Conservation of Orbital
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give high Z-selectivities, see: Q. Wang, M. El Khoury and M. Schlosser,
Chem. Eur. J., 2000, 6, 420–426.
12 See e.g. P. von Zezschwitz, F. Petry and A. de Meijere, Chem. Eur. J.,
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and M. Julia, Tetrahedron, 1987, 43, 859–872; G. E. Keck, K. A. Savin
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6396–6403; (b) M. F. Hentemann and P. L. Fuchs, Tetrahedron Lett.,
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M. Yus, Chem. Rev., 1998, 98, 2291–2312; (d) D. J. Meyers and P. L.
Fuchs, J. Org. Chem., 2002, 67, 200–204; (e) J. Evarts, E. Torres and P.
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Scheme 5 Reagents and conditions: [a] BuLi, then 2-butenal; [b] SOCl2,
pyridine, 84% from 8; [c] Cs2CO3, THF, D, 1 h, > 80%; [d] toluene, 110 °C,
5 h, argon, > 90%.
which every position in the ring is either substituted or derivatised
to enable subsequent substitution. Alcohol 9, as a ca. 3 : 1 mixture
of diastereomers, was converted (SOCl2–pyridine) to a mixture of
at least four isomeric chlorides; ratio 10 : 11, ca. 10 : 1.
Elimination of HCl gave a mixture of triene isomers which was
unstable in air. Besides the major isomer 12 isomers with Z
configuration either at the central double bond ( < 2%) or at the
methyl-substituted double bond (11%; 1H NMR) were also
produced. The ring-closure of 12 was monitored by 1H NMR
spectroscopy and a half-life t1/2 = 0.9 h was found when the
reaction was run in toluene at 100 °C. The two minor triene isomers
gave no or little ring-closure. The product expected7 from 12 was
the cis-isomer 13. The product obtained showed a 1H NMR signal
at d 0.66 (d, 3H) which seems consistent with a cis configuration
and a shielding effect exerted by the adjacent phenyl group.18
Although 1H NMR analysis indicated high yields in the two steps
from (10 + 11) to 13, only 47% of 13 was isolated after purification
on silica gel. The loss is probably due to the instability of both 12
and 13. No instability in air was noticed for the carbocycles 2a–c
and 7 which lack a phenyl substituent.
In summary, the synthetic utility of the 1,6-electrocyclic reaction
of 1,3,5-trienes, leading to 1,3-cyclohexadienes, has been sig-
nificantly increased by using an auxiliary phenylsulfonyl group.
This group is used a) in the assembly of the carbon skeleton, b) to
obtain the required configuration of the triene, and c) in one or more
regioselective manipulations14 of the 2-phenylsulfonyl-1,3-cyclo-
hexadiene. Finally, the phenylsulfonyl group can be detached either
by substitution, elimination, reduction or oxidation, i.e. also in a
constructive step.19
15 See ESI†.
16 E. J. Corey and D. Seebach, J. Org. Chem., 1966, 31, 4097–4099; P. J.
Kocienski, B. Lythgoe and S. Ruston, J. Chem. Soc., Perkin Trans. 1,
1978, 829–834.
Notes and references
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2 W. S. Johnson, Tetrahedron, 1991, 47, xi–l (issue 41); C. M. Marson,
Tetrahedron, 2000, 56, 8779–8794.
17 W. G. Young, F. F. Caserio, Jr. and D. D. Brandon, Jr., J. Am. Chem.
Soc., 1960, 82, 6163–6168 and later examples.
18 C. S. Wannere and P. von Ragué Schleyer, Org. Lett., 2003, 5, 605–608
and references therein.
19 N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon, Oxford,
1993; C. Nájera and M. Yus, Tetrahedron, 1999, 55, 10547–10658.
C h e m . C o m m u n . , 2 0 0 4 , 2 9 2 – 2 9 3
293