Scope and mechanism of the (4+3) cycloaddition reaction of furfuryl cations

Article abstract of DOI:10.1002/anie.201104930

It all adds up: Furfuryl alcohols are revealed as direct reaction partners for a wide range of conjugated dienes in a (4+3) cycloaddition motif (see scheme). This novel Lewis acid promoted process gives straightforward access to various polycyclic skeletons containing a seven-membered ring. A plausible cationic stepwise mechanism was confirmed by DFT calculations. Copyright

Full text of DOI:10.1002/anie.201104930

Communications
DOI: 10.1002/anie.201104930
Synthetic Methods
Scope and Mechanism of the (4+3) Cycloaddition Reaction of Furfuryl
Cations**
Johan M. Winne,* Saron Catak, Michel Waroquier, and Veronique Van Speybroeck
The (4+3) cycloaddition reaction between a conjugated diene
and an allylic cation constitutes a convenient and concep-
tually straightforward method to prepare seven-membered
rings.[1,2] In recent years, investigations into this type of
cycloaddition, including a number of elegant applications in
total synthesis,[3] have demonstrated its potential for develop-
ment as a synthetic method that could approach the (4+2)
cycloaddition (Diels–Alder) reactions in terms of selectivity
and efficiency. Of particular interest are allylic cations bearing
a cation-stabilizing substituent (Z group) at the 2-position
[Eq. (1)][4] and stabilized allylic cations such as vinyloxocar-
benium ions [Eq. (2)][5] or, typically, cationic reaction partners
incorporating both of these features [Eq. (2), R = Z].[6]
issues concerning the generation of the allylic cation reaction
partner. The precursors required for allylic cations can be
synthetically challenging, and the carbocationic species them-
selves are generally quite unstable, thus giving rise to various
by-products.
In the course of synthetic studies towards the natural
product rameswaralide,[8] Pattenden and Winne uncovered an
unexpected smooth intramolecular dehydrative reaction
between a diene and a furfuryl alcohol that gave a novel
fused polycycle containing a seven-membered ring [Eq. (3),
TFA = trifluoroacetic acid].
We surmised that the mechanism of this intriguing
cycloaddition reaction involves the initial formation of a
furfuryl cation intermediate,[9] which then undergoes an
intramolecular (4+3)-type cycloaddition with the appended
diene (cf. Scheme 1). The initially formed bicyclic oxocarbe-
nium ion can then be converted into the observed product
through straightforward loss of a proton and regeneration of
the furan ring. The cationic reaction partner in this sequence
can thus be regarded as an allylic cation with a stabilizing
oxygen substituent at the 2-position [cf. Eq. (1)], and more-
over, if the oxonium ion resonance structure is considered
(Scheme 1, bottom), it can be viewed as a vinylogous vinyl-
oxocarbenium ion [cf. Eq. (2)]. If it is concerted, the observed
cycloaddition can then be regarded as a rare example of a
“higher order” pericyclic reaction, that is, a [6p + 4p] cyclo-
addition with an unprecedented 2-oxafulvene-type 6p reac-
tant.[10]
Whereas reactions of vinyloxocarbenium species are
believed to proceed by a concerted (4+2) cycloaddition
followed by a Wagner–Meerwein-type ring expansion,[5]
allylic cations with a Z group at the 2-position have been
suggested to undergo “true” (4+3) cycloaddition reactions,
either through a concerted or a stepwise process.[7] The
synthetic utility of these cycloadditions is limited however by
[*] Dr. J. M. Winne
Department of Organic Chemistry, Ghent University
Krijgslaan 281 S4, 9000 Ghent (Belgium)
E-mail: johan.winne@ugent.be
As the prospect of an efficient (4+3) cycloaddition
method using simple furfuryl alcohol starting materials is
highly attractive from a synthetic point of view, we decided to
investigate the scope and mechanism of this unprecedented
Dr. S. Catak, Prof. Dr. M. Waroquier, Prof. Dr. V. Van Speybroeck
Center for Molecular Modeling, Ghent University
Technologiepark 903, 9052 Zwijnaarde (Belgium)
[**] We thank Prof. Gerry Pattenden of the University of Nottingham,
and Prof. Pierre De Clercq from Ghent University, for their interest
and advice in this study. We also thank undergraduates Maria
Gomez Rodriguez, Nick Van Hulle, and Ilaria Villa for preparing and
performing initial studies with dienes 16, 18, and 21. The Fund for
Scientific Research Flanders (FWO) and the Research Board of
Ghent University are acknowledged for financial support. Compu-
tational resources and services used in this work were provided by
Ghent University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104930.
Scheme 1. Proposed mechanism of cycloaddition via a furfuryl cation
intermediate.
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Angew. Chem. Int. Ed. 2011, 50, 11990 –11993

reaction by a joint experimental and theoretical approach.
Although the efficiency of the cycloaddition reaction in
[Eq. 3] is impressive (the polycycle is obtained as a single
diastereomer in quantitative yield), it is definitely helped by
the intramolecular nature of the reaction and possibly by the
quite specific substitution patterns of the reactants. Thus, we
have examined corresponding intermolecular cycloadditions
of some simple furfuryl cations with 1,3-cyclohexadiene
(CHD) as a model substrate. Our initial results are summar-
ized in Table 1.
Using a number of cation-generating conditions (TFA,
TiCl4, or TMSOTf), we were not able to achieve a cyclo-
addition reaction with furfuryl alcohol itself (Table 1;
entry 1). Instead, we invariably observed a swift polymeri-
zation reaction to give a black tar. However, when the
homologue 1, in which the highly nucleophilic 5-position of
the furan is blocked by a methyl substituent, was used
(entry 2) we could isolate the expected adduct 2, albeit in
poor yield. Best results were obtained using a stoichiometric
amount of TiCl4, as a Lewis acid. However, poly- and
oligomerization reactions still seemed to be the prevalent
reaction pathways for compound 1. By employing an excess of
CHD (2 equiv) and by increasing substitution at the carbinol
position (entries 3–5), we were able to suppress furfuryl
oligomerization and obtained good to excellent yields of
cycloadducts 4, 6, and 8. Moreover, these reactions showed
moderate to good selectivity for the diastereomer that
corresponds to an exo (or “extended”) mode of addition of
the diene to the furfuryl cation (i.e. with the furan oxygen and
the diene are at opposite sides of the plane of the forming
bonds). Finally, almost quantitative yields of cycloadducts
were achieved using the tertiary furfuryl alcohols 9 and 11,
even without resorting to using an excess of diene (entries 6
and 7).
Given the general efficiency of the formation of cyclo-
adducts with CHD, we next examined alternative diene
substrates (Scheme 2). The reaction between furfuryl alcohol
Table 1: Reactions of 1,3-cyclohexadiene (CHD) with various furfuryl
alcohols.
Entry[a]
1
Starting material
Product
Yield [%][b]
–
polymers
2[c]
3[c]
4[c]
17
82 (4:1)[d]
89 (4:1)[d]
5[c]
72 (10:1)[d]
6
96
97
7
[a] Typical procedure: a solution of the furfuryl alcohol (1.0 equiv) and
CHD (1.2 equiv) in CH2Cl2 (0.1–0.25m) was cooled to À788C and treated
with TiCl4 (1.5 equiv), then warmed to À108C over 2 h. [b] Average yield
of the isolated product after multiple runs. [c] 2.0 equiv of CHD used.
[d] Diastereomer ratio between parentheses in favor of the shown isomer
(relative configuration).
Scheme 2. Cycloaddition reactions with alternative dienes.
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Communications
9 and cyclopentadiene smoothly gave the expected cyclo-
either a 6-exo-trig or a 4-exo-trig cyclization process—lead to
six- and four-membered ring intermediates III and IV,
respectively. These intermediates are unable to undergo a
proton elimination to regain a stable furan ring. Moreover,
transition states for low-barrier ring expansions of these
intermediates to seven- or five-membered ring intermediates
(V and VI, respectively) could not be located, instead
intermediates III and IV were found to be more likely to
re-form intermediate II. Low-barrier reactions at the 3-
position of the furan lead either to intermediates V or VI
(formation of a seven- or five-membered ring, respectively).
The 7-endo-trig cyclization was shown to be favored over the
5-endo-trig cyclization (see the Supporting Information,
Table 1–3), in accordance with Baldwinꢀs rules. Simple
deprotonation of this cation (V) then leads to the final
product 8. The observed isomers, exo-8 and endo-8, are
derived from the diastereomeric allylic cation intermediates
exo-II and endo-II (Figure 1). The calculated energy profiles
for the formation of the allylic cation (exo-II/endo-II) and the
subsequent ring closure favor the formation of the exper-
imentally verified major adduct, exo-V (see Figure 2 and the
Supporting Information).
In the pericyclic pathway, the seven-membered-ring
intermediate cation V is formed directly through a concerted
[6p+4p] cycloaddition. The calculated energies for the
pericyclic TSꢀs were found to be at least 3.0 kcalmolÀ1
higher than for the corresponding stepwise pathways and
favor the formation of the exo-adduct (Figure 3 and the
Supporting Information). The evolution of furanyl bond
distances throughout the reaction suggests that all 6p-
electrons of the furfuryl cation are involved in the process
(see the Supporting Information).
adduct 13. The corresponding reaction with the acyclic diene
isoprene proved somewhat less efficient. However, the cyclo-
hepta[b]furan 14 was obtained as a single regioisomer in
reasonable yield when an excess of isoprene was used.
Surprisingly, reactions with furan, which is one of the most
widely used dienes in (4+3) cycloadditions, were quite
problematic. The only observed cycloaddition product was
the unusual bisadduct 15, which was isolated as a single
diastereomer. To further explore the scope and synthetic
potential of this reaction, cycloadditions with some the more
challenging dienes 16, 18, and 21 were tested. Thus, the
tricyclic furan 17, which incorporates the widdrane sesquiter-
pene carbon skeleton,[11] was obtained in a single step from
the commercially available diene 16. Reactions with the
bicyclic diene 18 gave access to C-homo-d-oxasteroids 19 and
20,[12] with interesting substrate-dependant regioselectivities.
Finally, the novel terpene-like homochiral polycyclic com-
pound 22 was efficiently obtained from a reaction with
(+)-nopadiene 21.
These intriguing cycloaddition reactions almost certainly
take place by the formation of a furfuryl cation, and we have
modelled their reactions with CHD at the DFT level of
theory.[13] The phenyl-substituted furfuryl alcohol 7 (see
Table 1, entry 5) was chosen for this purpose, as this substrate
gives mostly exo-selective cycloaddition. Several competing
pathways have been investigated in an effort to deduce a
plausible mechanism (Scheme 3). Both a stepwise and a
concerted process were identified as viable routes for the
formation of the observed reaction products, although
calculated energies were shown to consistently favor the
stepwise pathway at different levels of theory (See the
Supporting Information, Tables 1–3).
In conclusion, the reactions reported here uncover a
readily available and versatile class of starting materials for
the (4+3) cycloaddition reaction between a diene and an
allylic cation. The synthetic usefulness of the novel cyclo-
addition has been shown by a number of illustrative examples
and its mechanism has been investigated at the DFT level of
In the stepwise pathway, a highly reactive allylic cation
intermediate II is formed, and this intermediate can undergo
several very low barrier intramolecular electrophilic additions
(Scheme 3). Reactions at the 2-position of the furan—by
Scheme 3. Possible pathways for the reaction of CHD and furfuryl
cation by either a stepwise electrophilic addition (AdE) pathway or a
concerted (conc.) pathway.
Figure 1. Observed diastereomers for 8 and optimized geometries
(BMK/6-311+G(d,p)//B3LYP/6-31+G(d,p)) for the corresponding
diastereomeric intermediate allylic cations II.
11992 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 11990 –11993

reaction mechanism are now under way and will be reported
in due course.
Received: July 14, 2011
Published online: September 9, 2011
Keywords: DFT calculations · carbocations · cycloaddition ·
.
furans · fused-ring systems
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Figure 2. Free-energy profile for the stepwise (4+3) cycloaddition
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Figure 3. Transition-state geometries and Gibb’s free energies of
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theory. The theoretical results point to an efficient and
stereoselective two-step cationic cyclization process and are
in good qualitative agreement with the experimental results.
Further investigations into substrate tolerance and applica-
tions in total synthesis, as well as further refinement of the
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