Experimental and theoretical studies on the bismuth-triflate-catalysed cycloisomerisation of 1,6,10-trienes and aryl polyenes

Article abstract of DOI:10.1002/chem.201202263

Cycloisomerisation of polyenes such as diethyl geranylprenylmalonate [(E)-1 a], diethyl geranylphenylmalonate [(E)-2 a] and diethyl cinnamylgeranylmalonate [(E,E)-3 a] catalysed by bismuth triflate was studied from experimental and theoretical viewpoints. Several intermediates were isolated and characterised, and calculated transition-state structures are proposed for the three reactions. The diastereoselectivity observed during the reaction of (E)- or (Z)-2 a in favour of the formation of trans-fused bicyclic products is discussed in detail. The nature of the active catalytic species derived from bismuth triflate was also investigated, and the formation of a hybrid Lewis acid/Br?nsted acid catalyst with water molecules is proposed, supported by experimental and theoretical data. Round and round: Cycloisomerisation reaction mechanisms involving polyenes and aryl trienes catalysed by bismuth triflate were studied experimentally and theoretically. The diastereoselectivity observed during the reaction of E or Z olefins in favour of trans-fused bicyclic products is discussed. The nature of the active catalytic species derived from bismuth triflate was also investigated, and formation of a hybrid Lewis acid/Br?nsted acid catalyst with water molecules is proposed (see figure). Copyright

Full text of DOI:10.1002/chem.201202263

FULL PAPER
DOI: 10.1002/chem.201202263
Experimental and Theoretical Studies on the Bismuth-Triflate-Catalysed
Cycloisomerisation of 1,6,10-Trienes and Aryl Polyenes
Julien Godeau, Fabien Fontaine-Vive, Sylvain Antoniotti,* and Elisabet DuÇach*[a]
Abstract: Cycloisomerisation of poly-
enes such as diethyl geranylprenylmal-
onate [(E)-1a], diethyl geranylphenyl-
malonate [(E)-2a] and diethyl cinna-
mylgeranylmalonate [(E,E)-3a] cata-
lysed by bismuth triflate was studied
from experimental and theoretical
viewpoints. Several intermediates were
isolated and characterised, and calcu-
lated transition-state structures are pro-
posed for the three reactions. The dia-
stereoselectivity observed during the
reaction of (E)- or (Z)-2a in favour of
the formation of trans-fused bicyclic
products is discussed in detail. The
nature of the active catalytic species
derived from bismuth triflate was also
investigated, and the formation of a
hybrid Lewis acid/Brønsted acid cata-
lyst with water molecules is proposed,
supported by experimental and theo-
retical data.
Keywords: cyclisation
·
density
functional theory · domino reac-
tions · Lewis acids · reaction mech-
anisms
Introduction
Lewis superacids such as metal triflates and triflimidates ex-
hibit strong Lewis acid character and have been used as cat-
ꢀ
alysts in many types of organic transformations based on C
C or carbon–heteroatom bond formation.[1,2] In previous
studies on cycloisomerisation of 1,6-dienes, we found Sn-
Scheme 1. Bi
bicyclic compound 1b.
ACHTUNGRTEN(NNUG OTf)3-catalysed cycloisomerisation of substrate (E)-1a to
ACHTUNGTRENNUNG(NTf2)4 as a very efficient catalyst of 6-enexo-endo-trig ring
closure to form six-membered rings,[3] in contrast with tran-
sition metal catalysed versions, which in most instances de-
liver cyclopentene derivatives.[4] The opportunity of six-
membered ring formation with unactivated and highly sub-
stituted dienes guided us towards the study of polyene cycli-
sation mimicking biosynthetic reactions.[5] We thus recently
ACTHNGUTERNNUG
sources,[10–12] Hg(OTf)2–dimethylaniline complex[13] or a di-
cationic platinum complex of a tridentate phosphine;[14] the
last two examples leading to metallated products.
The remarkable catalytic activity and overall efficiency of
BiACTHNUTRGNEUNG
(OTf)3 in general,[2] used here at 5 mol% catalyst loading
on unactivated substrates such as substituted polyenes,
prompted us to examine the mechanism of the reaction ex-
perimentally and theoretically. We studied reaction rates
and the influence of the temperature, isolated reaction inter-
mediates and prepared independently specific substrates
used as probes and compared their energies obtained by
DFT calculations. Transition-state geometries were deter-
mined for these intermediates. We also studied the nature of
the active catalytic species, taking into account the role of
water in a context of Lewis acid chemistry, whereby the gen-
eration of strong Brønsted acids is of concern.
reported a BiACHTUNGTRENNUNG(OTf)3-catalysed cascade cyclisation reaction
of 1,6,10-trienes and aryl polyenes initiated by the electro-
philic catalyst that could be terminated by a Wagner–Meer-
wein rearrangement and proton elimination (Scheme 1).[6]
Polyene cyclisation reactions reported so far were typically
promoted by an excess of Brønsted or Lewis acids such as
H2SO4, p-TsOH, ClSO3H,[7] MeAlCl2,[8] SnCl4,[9] halonium
[a] Dr. J. Godeau, Dr. F. Fontaine-Vive, Dr. S. Antoniotti,
Dr. E. DuÇach
Institut de Chimie de Nice, UMR 7272
Universitꢀ de Nice Sophia Antipolis—CNRS
Parc Valrose, 06108 Nice cedex 2 (France)
Fax : (+33)492076151
Results and Discussion
E-mail: dunach@unice.fr
Kinetics and temperature effect: The BiACTHNUTRGENUG(N OTf)3-catalysed cy-
sylvain.antoniotti@unice.fr
cloisomerisation of model substrate (E)-1a in refluxing ni-
tromethane required 0.4 h for complete conversion to afford
78% yield of bicyclic product 1b. At room temperature,
total conversion of (E)-1a took 4 h and led to a mixture of
1b, its isomer 1c, and 1d, which is a mixture of unsaturated
monocyclised intermediates (Scheme 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202263. It contains detailed
1
synthetic procedures, spectral data, and H and 13C NMR spectra of
starting materials (E)-1a, (E)-2a and (E,E)-3a, products 1b–3b and
intermediates 1c, 1d and 2c; DFT calculated z-matrices of ax-2B
and eq-2B and snapshots of transition states TS1–TS14 and bismuth
triflate hydrates of Table 2.
Chem. Eur. J. 2012, 18, 16815 – 16822
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
16815

Scheme 2. BiACHTUNGTRENNUNG(OTf)3-catalysed cycloisomerisation of model substrate (E)-
1a at room temperature.
Interestingly, at room temperature, the initial rate of con-
version of (E)-1a remained rather fast with kobsd =0.4 mmsꢀ1
for a zero-order reaction (kobsd >100 mmsꢀ1 in refluxing ni-
tromethane), and 50% conversion was reached within a few
minutes. While 1d was initially formed and rapidly convert-
ed to 1c, the latter was slowly consumed with concomitant
formation of 1b (Figure 1).
Scheme 3. i) BiACHTNUTRGNEUNG(OTf)3 (5 mol%), MeNO2, reflux, 5 min (83%); ii) NaH
(1.1 equiv), THF, RT (90%); iii) Same as i) (86%).
from the bridgehead carbon atom to the vicinal tertiary
carbon atom along the ring, together with a hydrogen shift
and H+ elimination, a sequence known to occur for certain
structures in terpenoid chemistry.[16]
Intermediates and transition states: We performed DFT cal-
culations to confirm the energetic validity of the reaction se-
quence 1a!1d!1c!1b. Calculated energies for these
neutral molecules were in full agreement with experimental
data (Figure 2). Taking 1a as reference (0 kJmolꢀ1), we
found close energies for 1d’, 1d’’ and 1d’’’ (ꢀ31.23, ꢀ26.96
and ꢀ28.60 kJmolꢀ1 respectively), ꢀ67.95 kJmolꢀ1 for inter-
mediate 1c and ꢀ92.40 kJmolꢀ1 for the final product 1b,
the most thermodynamically stable of the series.
~
^
Figure 1. Normalised concentration of (E)-1a ( ), 1b (*), 1c ( ) and 1d
(ꢂ) in the reaction medium at room temperature versus time (determined
by GC-FID with internal calibration). Reaction conditions of Scheme 2.
Monocyclic 1d could be isolated after 10 min of reaction
at room temperature and afforded 1b in 84% yield after
10 min in the conditions of Scheme 1. Compound 1c was
isolated too, and subjected to the reaction conditions of
Scheme 1 (5 mol% BiACTHNUTRGNEUNG(OTf)3 in refluxing nitromethane at
0.2m). After 5 min, compound 1b was obtained in 95%
yield.
Similarly, subjecting diethyl geranylmalonate [(E)-1e] to
the conditions of Scheme 1 gave a mixture of three mono-
cyclised products 1 f in 83% yield after only 5 min. Alkyla-
tion of 1 f with prenyl bromide afforded the mixture of
three isomers 1d in 90% yield. Dienes 1d were further
transformed after 5 min in refluxing nitromethane in the
presence of 5 mol% BiACHTUNTRGNEUNG(OTf)3 into the single compound 1b
in 86% yield (Scheme 3). This set of experiments indicated
intermediacy of 1c and 1d in the cyclisation of (E)-1a and
that the cyclization was initiated by ring closure of the ger-
anyl side chain, in good agreement with previous related
studies.[15] The cyclization 1d!1b features a methyl shift
Figure 2. Energies of compounds 1a–d from DFT calculations at the
B3LYP 6-31+GACTHNUTRGNEU(GN d,p) level of theory.
16816
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16815 – 16822

Cycloisomerisation of 1,6,10-Trienes and Aryl Polyenes
FULL PAPER
Cyclization of polyenes involves cation–p interactions
both in biochemical reactions such as squalene cyclisation to
hopene catalysed by squalene cyclase[17] and in catalytic cyc-
lisation in the reaction flask.[10,18] To determine the reaction
pathway and transition states involved, as well as to avoid
time-consuming calculations with explicit representation of
studies, divergent conclusions were reported on the concert-
ed or stepwise nature of the mechanism of biomimetic poly-
ene cyclisations.[20] In concerted processes, a charge-delocal-
ised transition state is involved and accounts for the diaster-
eospecificity of the reaction, while in processes involving
one or more discrete carbocations, diastereoselective reac-
tions could occur. These reactions were most often studied
at low temperature, typically ꢀ788C, to afford stereoselec-
tively trans- or cis-decalines. In our reactions, the tempera-
ture is higher (0–1018C), and a single concerted mechanism
through kinetic control could be challenged by other path-
ways.
With substrate (E)-2a, bicyclic trans-2b was formed with
total diastereoselectivity, regardless of temperature. With
(Z)-2a however, the expected product cis-2b was formed
with only 16–30% selectivity, depending on the temperature
(Table 1). The Z isomer required longer reaction times than
the BiACHTUNGTRENNUNG(OTf)3 catalyst, a proton was added to (E)-1a to simu-
late the reaction system. Cationic intermediates 1A, 1B,
1C, 1D and 1E were thus considered, with the starting
point at 1A, the carbocation directly obtained by the proto-
nation of (E)-1a at the terminal position. The energy scale
was normalised accordingly to consider the subsequent
mono-charged species formed. We thus identified four tran-
sition states TS1–TS4 with activation energies varying from
13.06 to 58.28 kJmolꢀ1, and the largest energy barrier was
from 1B to bicyclic 1C (Figure 3). The first, with the lower
Table 1. Cyclisation of (E)-2a and (Z)-2a in the presence of 5 mol%
BiACHTNURTGNE(UNG OTf)3 in nitromethane.
Entry
Substrate
T [8C]
t [min]
Selectivity [%]
trans-2b cis-2b
1
2
3
4
5
6
(E)-2a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
(Z)-2a
101
25
0
101
25
0
5
10
300
5
120
1740
100
100
100
84
76
70
0
0
0
16
24
30
the E isomer to reach total conversion. Intermediates
formed on cyclisation of (Z)-2a were isolated and character-
ised from the reaction of Table 1 (entry 6) after 4.5 h and
showed that the cyclisation process started with ring closure
of the neryl side chain to form 2c’ and 2c’’ and proceeded
with further Friedel–Crafts-type cyclisation to trans- and cis-
Figure 3. Reaction pathway from 1A to 1E from DFT calculations at the
B3LYP 6-31+GACHTUNGTRENNUNG(d,p) level of theory.
energy cyclisation (13.06 kJmolꢀ1), involves 1,5-diene ring
closure by a 6-endo-trig process on the geranyl side chain.
The most energetically expensive molecular event of the
process is thus the second ring closure 1B!1C, in which
several atom displacements are involved.
Stereoselectivity of the reaction: Compound (E)-1a was
converted to 1b within 0.4 h in the presence of 5 mol%
BiACHTUNGTRENNUNG(OTf)3 in refluxing nitromethane. When the same reaction
conditions were applied to (Z)-1a, cyclised product 1b was
similarly obtained in 75% yield. We thus became interested
in other starting materials such as (E)-2a and (Z)-2a leading
to diastereoisomers trans-2b and cis-2b, which would allow
us to assess the stereochemical outcome of the reaction and
whether it obeys the Stork–Eschenmoser rule.[19] In recent
Scheme 4. Intermediates and reaction products in the cyclisation of (Z)-
2a.
Chem. Eur. J. 2012, 18, 16815 – 16822
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16817

S. Antoniotti, E. DuÇach et al.
2b (Scheme 4), similarly to the
results obtained in a iodinium-
promoted cyclisation.[11] This
was not the case for (E)-2a
under the same conditions.
The concerted mechanism for
(Z)-2a was therefore question-
able, although for (E)-2a the
fast, clean and fully diastereo-
selective cyclization to trans-
2b suggested
a
concerted
mechanism with formation of
a delocalised transition state.
Intermediates 2c’ and 2c’’
could be isolated as a 1:1 mix-
ture. Subjecting these inter-
mediates to the reaction condi-
tions of entry 6 in Table 1 gave
2b in with 100% yield with a
trans/cis ratio of 7/3. Such a
ratio rules out the idea of a
different reaction outcome de-
pending on the position of the
double bond in the monocycl-
ised intermediate.
Figure 4. Energies of compounds 2a–c from DFT calculations at the B3LYP 6-31+GACTHNUTRGNE(UNG d,p) level of theory.
A more detailed analysis of
this process was obtained from
DFT calculations, which con-
firmed that the pathways lead-
ing from (E)-2a to trans-2b
and from (Z)-2a to cis-2b via
intermediates 2c’ and 2c’’ are
thermodynamically favoured
(Figure 4). However, the main
question regarded the results
observed with (Z)-2a: how
could the formation of trans-
2b be favoured, while with
(E)-2a no cis-2b was observed
in the temperature range ex-
amined. We thus focused on
the cyclization mechanism of
(Z)-2a. Density functional cal-
culations indicated that the bi-
cyclic products trans-2b and
cis-2b are more stable than
substrates (E)-2a and (Z)-2a
by 96.98 and 82.05 kJmolꢀ1, re-
spectively. The optimised geo-
metries and energies of the
transition states involved in
the sequence starting with pro-
Figure 5. Reaction pathway from (E)-2 A and (Z)-2A to trans-2C and cis-2C from DFT calculations at the
B3LYP 6-31+G
(d,p) level of theory. (Z)-2A is taken as reference (0 kJmolꢀ1) and (E)-2 A is located at
0.35 kJmolꢀ1
AHCTUNGTRENNUNG
.
tonated (Z)-2A, derived from (Z)-2a, were determined
(Figure 5).
An interesting finding of these calculations is the identifi-
cation of conformers ax-2B and eq-2B with a Gibbs free
energy difference of 17.13 kJmolꢀ1. In the reaction leading
from (Z)-2A to cis-2C, a first high energy barrier of
91.47 kJmolꢀ1 leads to TS5 and further to ax-2B. We pro-
pose that, along the (Z)-2A!cis-2C reaction path, ax-2B is
predominantly converted to the more stable eq-2B, pre-or-
ganised in a chair–chair conformation. The reaction of (Z)-
16818
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16815 – 16822

Cycloisomerisation of 1,6,10-Trienes and Aryl Polyenes
FULL PAPER
2A thus leaves the cis pathway to join a trans pathway, and
this explains the trans/cis ratio observed experimentally
(Table 1). Transition structures from ax-2B to trans-2C and
from eq-2B to cis-2C were determined. It costs
85.89 kJmolꢀ1 to go from eq-2B to cis-2C via TS7’ and
128.30 kJmolꢀ1 to go from ax-2B to trans-2C via TS8’, indi-
cating that these pathways should not be operative (not
shown, see Supporting Information).
The stereospecificity of polyene cyclisation reactions (E!
trans, Z!cis) obeying the Stork–Eschenmoser rule is due to
conformational inversion of the six-membered intermediate
being slower than the cyclisation occurring in a concerted
mechanism. Axial side chains therefore lead to cis-fused
rings, and equatorial side chains to trans-fused rings. Our
data support a different process: the reaction of (Z)-2a is
stepwise and features a conformational inversion ax-2B/eq-
2B, thermodynamically favoured, leading to trans-2b. Note-
worthily, almost the same energy demand was calculated to
attain TS6 and TS7 (31.58 and 31.89 kJmolꢀ1, respectively).
The Curtin–Hammett principle tells us that in such a case, if
interconversion of conformers ax-2B/eq-2B is fast, then the
final cis-2b/trans-2b ratio should reflect the energy differ-
ence of transition states TS6 and TS7. Conversely, if the in-
terconversion is the rate-limiting step, then the final diaster-
eomeric ratio should reflect the energy barrier between ax-
2B and eq-2B. In our case, the experimental diastereomeric
ratio ranges from 3:7 to 0:10 as a function of temperature
and is never 5:5, while the energies of TS6 and TS7 are
almost equal. We could thus conclude that interconversion
of the two conformers is the rate-limiting step and controls
the stereoselectivity. Final cations cis-2C and trans-2C have
high energies but lead to stable cis-2b and trans-2b after
proton elimination and recovery of the aromaticity of the
phenyl group.
Figure 6. Energetics of compounds (E,E)-3a, 3b and neutral intermedi-
ates from DFT calculations at the B3LYP 6-31+GACTHNUTRGNE(NUG d,p) level of theory.
This mechanism features several molecular events includ-
ing a methyl shift as encountered in the cyclization of
(E)-1a and an additional hydrogen shift necessary to form
carbocation 3F, leading to 3b through a Friedel–Crafts-type
reaction involving the ortho position of the phenyl substitu-
ent via TS13 and leading to 3G, located about 105 kJmolꢀ1
lower than starting cation 3A. Although proton migration
from 3E to 3F seems not to be thermodynamically fav-
oured, one must consider the final stabilisation when 3F is
converted to 3G by ring closure with an energy barrier of
39.71 kJmolꢀ1, easily attained under our experimental condi-
tions (refluxing nitromethane).
Tandem triene cycloisomerisation/Friedel–Crafts reaction:
We investigated the mechanism of cyclisation of substrate
(E,E)-3a, leading efficiently to tetracyclic compound 3b as
a single diastereomer featuring a trans,trans-fused ring
Again, the process starts with the activation of the geranyl
side chain. The pathway 3B!3C is barrierless, since TS9 is
lower in energy than 3B, and several experimental attempts
to isolate intermediates 3c and 3d were unsuccessful. It is
thus reasonable to consider the transition 3A!3C as a fast
process with energy barriers within the relative error of
B3LYP energy calculations.
ꢀ
system through formation of three new C C bonds
(Scheme 5).[6] Density functional calculations on neutral in-
Active species: The role of protons in Lewis acid catalysed
reactions is pivotal, and recent studies have been designed
to explain their participation in catalytic cycles involving
metal triflates.[21] In particular, the role of an active proton
in the presence of metal triflates in hydroalkoxylation reac-
tions was proposed, in the specific case where the substrate
bears a hydroxyl functional group.[22] A striking example of
Scheme 5. BiACHTUNGTRENNUNG(OTf)3-catalysed cyclization of (E,E)-3a.
TfOH generation from CuACTHNUTRGNE(NUG OTf)2 was given, but involved a
termediates were performed and showed a huge Gibbs free-
energy difference of 151.33 kJmolꢀ1 between (E,E)-3a and
3b (Figure 6). Cationic intermediates and transition states
3A–3G were theoretically characterised, and the reaction
coordinate starting from protonated species 3A derived
from (E,E)-3a is presented in Figure 7.
redox process of copper(II) with unavoidable liberation of
the acid.[23]
A common argument is that metal triflates could be parti-
ally hydrolysed by traces of water and maintain a low con-
centration of TfOH in the reaction medium.[24] This hypoth-
esis was examined by a series of DFT calculations (B3LYP
Chem. Eur. J. 2012, 18, 16815 – 16822
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16819

S. Antoniotti, E. DuÇach et al.
Figure 7. Reaction pathway from (E,E)-3A to 3G from DFT calculations at the B3LYP 6-31+GACTHNUTRGNEUGN(d,p) level of theory.
LANL2DZ with the polarisable continuum model for nitro-
methane) aimed at comparing the energy of hydration and
hydrolysis of complexes derived from BiACHTUNTGRNEUNG(OTf)3·nH2O with
n=0–3 (Table 2). In all cases, hydration is strongly favoured
over hydrolysis (95.3–144.5 kJmolꢀ1 energy difference).
These results do not support the hydrolysis hypothesis, but
Mulliken charges of the hydrogen atoms of this transition
state, we found a partial positive charge of 0.59 for the
transferred hydrogen atom, while other water molecules had
hydrogen atoms with lower charges (0.44–0.46). In the
BiOH moiety, a positive charge of 1.81 was found on the
bismuth atom, a negative charge of ꢀ0.92 on the oxygen
atom and a positive charge of 0.41 on the hydrogen atom.
For comparison, the Mulliken charge on the hydrogen atom
of TfOH was found to be +0.453 with the same calculation
formation of hydrated forms of BiACTHNUTRGNENUG(OTf)3. Such hydrated
metal triflates could act as active catalysts in a Lewis acid
assisted Brønsted acid (LBA) type of activation.[25] For ex-
ꢀ
ample, the geometry analysis of complex Bi
(OTf)3·4H2O
method. In the transition state, the Bi O bond lengths were
ꢀ
ꢀ
ꢀ
ꢀ
gave average bond lengths of 2.42 ꢃ for Bi OTf, and 2.34 ꢃ
2.06 ꢃ for Bi OH, 2.37 ꢃ for Bi OH2 and 2.49 ꢃ for Bi
ꢀ
for Bi OH2, showing that both triflate anions and water
OH3+. From a theoretical viewpoint, Bi
ACHTUNGTRENNU(G OTf)3·4H2O exhib-
its a strongly acidic hydrogen atom, and an incoming
Brønsted base such as a water molecule could therefore
easily abstract a proton.
molecules are located roughly at the same distance from the
metal centre. Bismuth triflate seemed to be saturated with
five water molecules, since when we modelled the optimised
geometry of Bi
mained outside of the coordination sphere. For Bi-
(OTf)3·6H2O, the sixth water molecule re-
Experimentally, the presence of water has been shown to
strongly influence the activity of metal triflates such as Al-
(OTf)3·5H2O, a transition-state structure could be localised
(OTf)3.[26] To probe this possibility, the catalytic activities of
ACHTUNGTRENNUNG
at +17.6 kJmolꢀ1 with a negative imaginary frequency fea-
commercial Bi
(OTf)3, supposedly a hydrated form,[27] and of
ACHTUNGTRENNUNG
turing a hydrogen transfer between water molecules of the
Bi
ACHTUNGTRENNUNG
inner sphere forming H3O+ and a Bi OH bond (TS14, see
as well as that of TfOH and other metal triflates were tested
in the cyclization of
ꢀ
Supporting Information). By considering the variation in
(E)-1a (Scheme 2). The results
are summarised in Table 3.
The hydrated form of com-
Table 2. Calculated energies of hydration and hydrolysis of BiACTHNUTRGNEUNG
(OTf)3·nH2O (n=0–4).[a]
Entry
Substrate
Hydrolysis
Hydration
mercially available bismuth tri-
Product
DG
+7.0
+43.3
+62.0
+36.4
Product
DG
DDG[b]
flate was clearly superior to
the anhydrous DMSO-solvated
salt (Table 3, entries 1 and 2).
In the presence of TfOH, the
desired cyclization was ob-
served, albeit with lower over-
1
2
3
4
Bi
Bi
Bi
Bi
N
Bi
Bi
Bi
Bi
G
Bi
Bi
Bi
Bi
A
ꢀ88.3
ꢀ82.5
ꢀ82.5
ꢀ79.9
95.3
125.8
144.5
116.3
E
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
[a] B3LYP LANL2DZ, PCM nitromethane (e=36.562), DG are given in kJmolꢀ1
.
[b] DDG=
DGHydrolysisꢀDGHydration
.
16820
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16815 – 16822

Cycloisomerisation of 1,6,10-Trienes and Aryl Polyenes
FULL PAPER
Table 3. Catalytic activity of triflate-based catalysts in the cyclisation of
minal double bond of the geranyl side chain to yield mono-
cyclic intermediates. A second cyclisation then occurs, in-
volving the prenyl, phenyl or cinnamyl side chain, respec-
tively, to yield bi- or tricyclic intermediates. The proposed
carbocationic intermediates undergo methyl/hydrogen shifts
followed by proton elimination or intramolecular Friedel–
Crafts reaction, in the case of (E,E)-3a, to deliver the final
bi-, tri, or tetracyclic products 1b–3b. The reaction of
(E)-2a was compared with that of (Z)-2a and it was found
that trans-2b was formed exclusively or preferentially, de-
pending on the stereochemistry of the starting material. A
rationale for such selectivity is proposed on the basis of a
stepwise mechanism for (Z)-2a with a conformational inver-
sion leading to trans-fused products. A rather large energy
difference was indeed found between two conformers in the
course of the reaction of (Z)-2a, namely, ax-2B and eq-2B
(17 kJmolꢀ1), in favour of eq-2B leading to trans-fused rings
and explaining our experimental results. Based on theoreti-
cal calculations, the nature of the active species in this Bi-
(E)-1a.[a]
Entry
Catalyst
t [h]
Conversion [%]
Yield [%]
1b
1c
1d
1
2
3
4
5
6
Bi
Bi
U
0.4
3
3
5
3
100
87
100
100
100
80
78
12
48
66
76
22
5
25
10
15
6
–
35
4
–
–
TfOH
TfOH[b]
Al
La
G
N
3
16
19
[a] Reaction conditions: 5 mol% catalyst in refluxing nitromethane
(0.2m). [b] 1 mol% catalyst was used.
all yield and selectivity and much longer reaction times
(Table 3, entries 3 and 4). Interestingly, Al
ACHTUNGRTEN(NGNU OTf)3 efficiently
catalysed the reaction in 3 h, and La(OTf)3 did not allow
AHCTUNGTRENNUNG
completion to be reached and resulted in both poor yield
and selectivity (Table 3, entries 5 and 6). These last results
could be linked to the dissociation constants of inner-sphere
aqua ligands.[29]
AHCTUNGTRENNUNG
The presence of water molecules in the vicinity of the bis-
muth cation could generate a hybrid Lewis/Brønsted acid as
active catalytic species. Since such a phenomenon is depend-
ent on the presence of water, we performed an additional
series of experiments. First, the reaction was performed with
(E)-1a under refluxing conditions in the presence of 2,6-di-
tert-butylpyridine. This base is known to behave as a Brønst-
ed base but not as a Lewis base for reason of steric hin-
drance.[30] The cyclisation reaction was completely inhibited
and no conversion of (E)-1a was observed. The reaction of
(E)-1a was also performed in various grades of nitrome-
thane: dried over CaCl2, 3 ꢃ molecular sieves (MS) or 4 ꢃ
MS and untreated (Table 4). The reaction was strongly de-
ACHTUNGTRENNUNG
exhibiting acidic hydrogen atoms, associated with a delocal-
ised anionic bismuth complex counterion.
Experimental Section
Representative procedure: Substrate (E)-1a (1 mmol) was added to a ni-
tromethane solution (5 mL) of BiACHTNUTRGENNG(U OTf)3 (0.05 mmol) under an nitrogen
atmosphere according to the conditions indicated in Table 1. After com-
plete consumption of the substrate, monitored by GC-FID with internal
calibration, the reaction mixture was filtered over a pad of silica gel and
eluted with diethyl ether. After concentration, the residue was purified
by column chromatography to afford cyclised compound 1b as colourless
oil. 1H NMR (500 MHz, CDCl3): d=4.30–4.00 (4H, m), 2.73 (1H, d, 2J=
16.5 Hz), 1.96 (2H, s), 1.98–1.85 (1H+1H, m), 1.82–1.77 (1H, m), 1.76
(1H, p, 3J=6.8 Hz), 1.60–1.45 (2H+1H, m), 1.38–1.31 (1H, m), 1.28–
1.19 (6H, m), 1.14 (3H, s), 0.97 (3H, s), 0.96 (3H, s), 0.88 (3H, d, 3J=
6.8 Hz), 0.72 ppm (3H, d, 3J=6.8 Hz); 13C NMR (125 MHz, CDCl3): d=
173.3, 172.0, 132.9, 132.7, 61.4, 60.9, 52.3, 40.0, 39.7, 35.8, 34.8, 34.4, 30.9,
29.1, 27.1, 27.0, 24.9, 19.7, 17.2, 16.3, 14.2, 14.1 ppm; MS (70 eV): m/z
Table 4. Effect of solvent drying on the cyclisation reaction of (E)-1a.[a]
Entry
Nitromethane treatment
t [h]
Conversion [%]
Yield [%]
1
2
3
4
3 ꢃ MS
4 ꢃ MS
CaCl2
4
3
0.4
1
0
35
100
100
0
15
78
76
(%): 364 (1) [M] +, 321 (52), 275 (4), 247 (100), 237 (5), 219 (7), 201(11),
C
none
177 (12), 133 (51), 105 (52), 95 (17), 69 (8).
Computational methods: The calculations were performed with Gaussi-
an 03.[32] The structures of molecules were optimised and energies were
calculated by the DFT method with the exchange-correlation functional
[a] Reaction conditions: 5 mol% BiACHTNUGRTENUNG(OTf)3 in refluxing nitromethane
(0.2m).
B3LYP[33] and the 6-31+G
ACHTNUTRGNE(NUG d,p) basis set for calculations with organic in-
termediates and the LANL2DZ basis set for calculations with bismuth
derivatives. The effects of nitromethane as solvent were taken into ac-
count by using the polarisable continuum model (PCM). The intermedi-
ates and transition states (TS) of the proposed mechanism correspond to
stationary points on potential-energy surface and were characterized by
calculating vibrational frequencies.
pendent on the presence of water in the reaction medium.
This water was probably contained in the solvent, since
parts-per-million levels of water may remain in organic sol-
vents even after drying procedures.[31]
Conclusion
Acknowledgements
We have studied the mechanism of the bismuth-triflate-cata-
lysed cycloisomerisation reaction of diethyl geranylprenyl-
malonate [(E)-1a], geranylphenylmalonate [(E)-2a] and cin-
namylgeranylmalonate [(E,E)-3a]. Our results show that
the reaction proceeds through initial cyclisation of the ter-
This work was supported by the French Agence Nationale de la Recher-
che (project ANR07-CP2D, CASAL-04-01), the University of Nice -
Sophia Antipolis and the CNRS. We a grateful to Dr Gilles Lemiꢄre for
a critical reading of the manuscript and scientific discussions. Calcula-
tions were performed using HPC resources from GENCI-CINES.
Chem. Eur. J. 2012, 18, 16815 – 16822
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16821

S. Antoniotti, E. DuÇach et al.
[20] a) S. P. T. Matsuda, W. K. Wilson, Q. Xiong, Org. Biomol. Chem.
2006, 4, 530–543; b) B. A. Hess, L. Smentek, Org. Lett. 2004, 6,
1717–1720; c) R. Rajamani, J. Gao, J. Am. Chem. Soc. 2003, 125,
12768–12781; d) C. Raptis, I. N. Lykakis, C. Tsangarakis, M. Strata-
kis, Chem. Eur. J. 2009, 15, 11918–11927; e) Y. J. Hong, D. J. Tantil-
lo, J. Am. Chem. Soc. 2009, 131, 7999–8015; f) D. J. Tantillo, J. Phys.
Org. Chem. 2008, 21, 561–570.
[21] a) T. T. Dang, F. Boeck, L. Hintermann, J. Org. Chem. 2011, 76,
9353–9361; b) T. C. Wabnitz, J.-Q. Yu, J. B. Spencer, Chem. Eur. J.
2004, 10, 484–493.
[22] a) S. Seo, T. Marks, Chem. Eur. J. 2010, 16, 5148–5162; b) A.
Dzudza, T. J. Marks, Chem. Eur. J. 2010, 16, 3403–3422; c) L. Cou-
lombel, M. Rajzmann, J.-M. Pons, S. Olivero, E. DuÇach, Chem.
Eur. J. 2006, 12, 6356–6365.
[23] M. J. L. Tschan, C. M. Thomas, H. Strub, J.-F. Carpentier, Adv.
Synth. Catal. 2009, 351, 2496–2504.
[24] D. C. Rosenfeld, S. Shekhar, A. Takemiya, M. Utsunomiya, J. F.
Hartwig, Org. Lett. 2006, 8, 4179–4182.
[25] H. Yamamoto, K. Futatsugi, Angew. Chem. 2005, 117, 1958–1977;
Angew. Chem. Int. Ed. 2005, 44, 1924–1942.
[26] D. B. G. Williams, M. Lawton, J. Mol. Catal. A 2010, 317, 68–71.
[27] H. Gaspard-Iloughmane, C. Le Roux, Eur. J. Org. Chem. 2004,
2517–2532.
[28] S. Antoniotti, E. DuÇach, Chem. Commun. 2008, 993–995.
[29] S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc. 1998,
120, 8287–8288.
[30] H. C. Brown, B. Kanner, J. Am. Chem. Soc. 1966, 88, 986–992.
[31] D. B. G. Williams, M. Lawton, J. Org. Chem. 2010, 75, 8351–8354.
[32] Gaussian03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski,
J. A. J. Montgomery, R. E. Stratmann, J. C. Burant, S. Dapprich,
J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J.
Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli,
C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q.
Cui, K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G. Baboul, B. B. Stefa-
nov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts,
R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, C. Gonzalez, M. Challacombe, P. M. W. Gill, B. John-
son, W. Chen, M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-
Gordon, E. S. Replogle, J. A. Pople, Gaussian, Inc., Wallingford CT,
2004.
[1] a) S. Kobayashi, M. Sugiura, H. Kitagawa, W. W. L. Lam, Chem.
Rev. 2002, 102, 2227–2302; b) R. Ghosh, S. Maiti, J. Mol. Catal. A
2007, 264, 1–8; c) S. Antoniotti, S. Poulain-Martini, E. DuÇach, Syn-
lett 2010, 2973–2988; d) S. Antoniotti, V. Dalla, E. DuÇach, Angew.
Chem. 2010, 122, 8032–8060; Angew. Chem. Int. Ed. 2010, 49, 7860–
7888.
[2] J. M. Bothwell, S. W. Krabbe, R. S. Mohan, Chem. Soc. Rev. 2011,
40, 4649–4707.
[3] F. Grau, A. Heumann, E. DuÇach, Angew. Chem. 2006, 118, 7443–
7447; Angew. Chem. Int. Ed. 2006, 45, 7285–7289.
[4] a) G. C. Lloyd-Jones, Org. Biomol. Chem. 2003, 1, 215–236; b) K. L.
Bray, G. C. Lloyd-Jones, M. P. MuÇoz, P. A. Slatford, E. H. P. Tan,
A. R. Tyler-Mahon, P. A. Worthington, Chem. Eur. J. 2006, 12,
8650–8663.
[5] R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105, 4730–4756.
[6] J. Godeau, S. Olivero, S. Antoniotti, E. DuÇach, Org. Lett. 2011, 13,
3320–3323.
[7] A. F. Barrero, J. Altarejos, E. J. Alvarez-Manzaneda, J. M. Ramos, S.
Salido, J. Org. Chem. 1996, 61, 2215–2218.
[8] a) G. Frꢅter, F. Schrçder, J. Org. Chem. 2007, 72, 1112–1120; b) S.
Hong, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 1346–1352.
[9] K. Ishihara, S. Nakamura, H. Yamamoto, J. Am. Chem. Soc. 1999,
121, 4906–4907.
[10] S. A. Snyder, D. S. Treitler, Angew. Chem. 2009, 121, 8039–8043;
Angew. Chem. Int. Ed. 2009, 48, 7899–7903.
[11] S. A. Snyder, D. S. Treitler, A. P. Brucks, J. Am. Chem. Soc. 2010,
132, 14303–14314.
[12] S. A. Snyder, D. S. Treitler, A. Schall, Tetrahedron 2010, 66, 4796–
4804.
[13] A. S. Gopalan, R. Prieto, B. Mueller, D. Peters, Tetrahedron Lett.
1992, 33, 1679–1682.
[14] J. G. Sokol, C. S. Korapala, P. S. White, J. J. Becker, M. R. Gagnꢀ,
Angew. Chem. 2011, 123, 5776–5779; Angew. Chem. Int. Ed. 2011,
50, 5658–5661.
[15] R. L. Snowden, J. C. Eichenberger, S. M. Linder, P. Sonnay, C. Vial,
K. H. Schulte-Elte, J. Org. Chem. 1992, 57, 955–960.
[16] D. W. Christianson, Chem. Rev. 2006, 106, 3412–3442.
[17] N. Morikubo, Y. Fukuda, K. Ohtake, N. Shinya, D. Kiga, K. Saka-
moto, M. Asanuma, H. Hirota, S. Yokoyama, T. Hoshino, J. Am.
Chem. Soc. 2006, 128, 13184–13194.
[18] J. H. Koh, M. R. Gagne, Angew. Chem. 2004, 116, 4932–4932;
Angew. Chem. Int. Ed. 2004, 43, 4828–4828.
[19] a) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77, 5068–
5077; b) A. Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni, Helv.
Chim. Acta 1955, 38, 1890–1904; c) P. A. Stadler, A. Eschenmoser,
H. Schinz, G. Stork, Helv. Chim. Acta 1957, 40, 2191–2198.
[33] a) A. D. Becke, Phys. Rev. A 1988, 38, 3098–3100; b) A. D. Becke, J.
Chem. Phys. 1993, 98, 5648–5652; c) C. Lee, W. Yang, R. G. Parr,
Phys. Rev. B 1988, 37, 785–789.
Received: June 26, 2012
Revised: October 1, 2012
Published online: November 9, 2012
16822
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16815 – 16822