Triflic acid mediated dealkylative lactonisation via NMR-observable alkyloxonium intermediates

Article abstract of DOI:10.1002/ejoc.200800970

Trifluoromethanesulfonic acid (TfOH) efficiently induces the dealkylative cyclisation of pent-4-enoates to generate γ-lac-tones with high selectivity. For primary alkyl esters bearing an additional alkene, only monolactonisation occurs, even in the presen

Full text of DOI:10.1002/ejoc.200800970

FULL PAPER
DOI: 10.1002/ejoc.200800970
Triflic Acid Mediated Dealkylative Lactonisation via NMR-Observable
Alkyloxonium Intermediates
M. Paz Muñoz*[a,b] and Guy C. Lloyd-Jones[b]
Keywords: Lactones / Triflic acid / Allylmalonates / Intermediates / Kinetics
Trifluoromethanesulfonic acid (TfOH) efficiently induces the
dealkylative cyclisation of pent-4-enoates to generate γ-lac-
tones with high selectivity. For primary alkyl esters bearing
an additional alkene, only monolactonisation occurs, even in
the presence of excess TfOH. The kinetics of the reaction
have been studied by 1H NMR spectroscopy, which reveal
that the TfOH acid undergoes a self-catalysed reaction with
the pent-4-enoate to generate an oxonium triflate intermedi-
ate (rate ≈ kobsd.[TfOH]2[ester]1), possibly via the dimer
(TfOH)2. The oxonium triflate intermediate then evolves to
the γ-lactone according to unimolecular kinetics, liberating
MeOTf in an SNi reaction. 2H-labelling experiments with
TfOD suggest that the acid protonates the carbonyl moiety
of the ester, with subsequent intramolecular delivery of D+ to
the alkene. The resulting carbocation is transient, being
rapidly captured intramolecularly to generate the oxonium
species. Reversibility in this step mediates equilibration of
diastereomeric oxonium intermediates via the carbocation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Although the reaction of olefinic acids with electrophiles
(E+ or H+) to give cyclic γ- or δ-lactones and ketones has
been known for over half a century,[1] the direct dealkylative
lactonisation of pent-4-enoates by electrophilic addition to
the alkene has been less well studied. This process has re-
cently emerged as a side-reaction occurring under transition
metal catalysed and Lewis acid catalysed cycloisomerisation
of 1,n-dienes (n = 6, 7).[2]
The acid-catalysed lactonisation of pent-4-enoic acids is
generally assumed to involve trans addition to the double
bond in a concerted or near-concerted mechanism. Ring-
closure via a transition state with a greater overlap between
the 2p orbitals of the carbonyl oxygen atom and the vacant
orbital of the γ-carbocation, as compared to the δ-carbo-
cation, can then explain the selective formation of γ-lac-
tones over δ-lactones (Scheme 1).[3]
Scheme 1. Mechanism proposed for the lactonisation of olefinic
acids.[3]
atom, and then dealkylation of the resultant oxonium spe-
cies [– RX, Scheme 2 (a)].[4] Prior ester cleavage and then
capture of the alkene (or carbocation) by the resultant car-
boxylic acid (or acid derivative) has also been proposed
[Scheme 2 (b)].[5] This mechanism is also proposed for the
analogous reaction of olefinic nitriles.[6]
A variety of mechanisms have been proposed for the
Bronsted acid (“HX”) mediated, albeit Lewis acid catalysed,
dealkylative lactonisation of dialkyl allylmalonates.[4–6] All
of the mechanisms invoke the formation of carbocationic
species by addition of a Lewis or Bronsted acid to the al-
kene followed by addition of the alkyl or carbonyl oxygen
[a] Instituto de Química Orgánica General (IQOG),
Juan de la Cierva, 3, 28006 Madrid, Spain
Fax: +34-91-564-48-53
Scheme 2. Mechanisms proposed for the lactonisation of olefinic
esters.[4,5]
[b] School of Chemistry, University of Bristol,
Cantock’s Close, Bristol BS8 1TS, UK
Fax: +44-117-929-8611
E-mail: chmpmh@bristol.ac.uk
trans-Addition has also been proposed for dealkylative
lactonisation of olefinic esters by E+, with formation of cy-
clic oxonium salts stabilised by resonance (Scheme 3). Isola-
guy.lloyd-jones@bristol.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
516
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Triflic Acid Mediated Dealkylative Lactonisation
tion of alkyl bromides in the reaction of bromine with allyl-
The reaction of the (allyl)(crotyl) derivatives 7-cis and 7-
malonates and inversion of configuration of the expelled trans (Scheme 4) with TfOH gave complex mixtures con-
alkyl group (SN2), supported this mechanism.[7]
taining both γ- and δ-lactones.
No lactonisation product was observed in the reaction
of the phenyl-substituted derivative (8, Scheme 5), and only
cyclohexene 9 (tentatively assigned by NMR) could be iso-
lated in a moderate yield.
Scheme 3. Bromolactonisation of diethyl allyl(benzyl)malonate.[7]
As part of an ongoing investigation into acid-catalysed
rearrangements of (alkene)alkylpalladium complexes,[8] we
noted that trifluoromethanesulfonic acid (“triflic acid”,
TfOH) mediates dealkylative lactonisation of dialkyl dial-
lylmalonates.[9] Herein we report a mechanistic study of the
lactonisation reaction, including kinetic measurements, de-
tection of intermediates by NMR spectroscopy, and 2H-
labelling experiments.
Scheme 5. Reaction of allyl(cinnamyl)malonate 8 with TfOH.
Surprisingly, the reaction of di-tert-butyl diallylmalonate
(10, Scheme 6) in the presence of 1 equiv. of TfOH gave the
spirolactone 11 as a 1:1:1 mixture of isomers (symmetrical-
syn, unsymmetrical and symmetrical-anti).[11] This lactone
has been previously reported from the reaction of olefinic
nitriles with sulfuric acid,[6b] and the reaction of diallyl-
malonates with SbF5.[2] The reaction of 10 with 0.5 equiv.
of the acid gave the monolactonisation product 12, in which
the second allyl unit again remained unreacted, and the
second tert-butyl ester was cleaved to the corresponding
carboxylic acid.
Results and Discussion
Dealkylative Lactonisation of Allylmalonates
The reaction of dimethyl diallylmalonate (1, Scheme 4)
with TfOH gives lactone 2 as a mixture of two diastereoiso-
mers (2:1) in good yield. Intriguingly, only monolactonis-
ation was observed, even when 2 equiv. of the acid were
used, leaving one allyl unit unreacted. A similar result was
obtained with the ethyl derivative 3, although in lower
yields.[10] The reaction did not proceed with pTsOH·H2O in
toluene at 40 °C, or HBF4·Et2O in CHCl3 at room tempera-
ture.
Scheme 6. Lactonisation of tert-butyl diallylmalonate (10).
The presence of a second ester is not necessary for the
lactonisation to proceed, as lactones 14 and 16 were ob-
tained in moderate to good yields from pentenoates 13 and
15 (Scheme 7).
Scheme 7. Lactonisation with monoester derivatives 13 and 15.
The monoallylmalonates 17 and 19 also gave lactones (18
and 20, Scheme 8) in good yields, confirming that the reac-
tion only requires the presence of a single alkenyl unit.
Scheme 4. Dealkylative monolactonisation of diallylmalonates.
When the 1,5-diene 5 (Scheme 4) was submitted to the
reaction conditions, lactone 6 was obtained, where the
cyclisation occurs only with the allyl unit in a 5-exo manner. Scheme 8. Reaction of monoallylmalonates 17 and 19 with TfOH.
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M. Paz Muñoz, G. C. Lloyd-Jones
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Scheme 9. Reaction of crotyl derivatives 21 and 24 with TfOH.
Crotyl derivatives 21 and 24 reacted with 1 equiv. of
TfOH to give a mixture of the γ- (22 and 25) and δ-lactones
(23 and 26, separable by column chromatography,
Scheme 9), each one being a mixture of two diastereoiso-
mers. In all the cases, isomerisation of the crotyl to the trans
isomer was observed, and similar ratios of γ- and δ-lactones
were obtained from either isomer.
Reaction of the cyclohexyl derivatives 27 and 29 with
TfOH gave the bicyclic γ-lactones with moderate (30) to
high (28) diastereoselectivity (Scheme 10). In these reac-
tions small quantities of the products from the isomeri-
sation of the double bond in the starting material were also
obtained.
Scheme 10. Reaction of cyclic derivatives 27 and 29 with TfOH.
Figure 1. 1H NMR spectra of the reaction of 19 with TfOH in
CDCl3.
Mechanistic Studies: NMR Spectroscopy, Kinetics,
2
Simulations and H-Labelling Experiments
The growth and decay of the signal at δ ≈ 4.5 ppm was
Although the lactonisation reaction might be envisaged observed in all of the reactions monitored, as was the signal
as a simple process involving olefin protonation with subse- at δ = 4.2 ppm, which was assigned as MeOTf, a by-product
quent attack of the ester on the carbocation (see Scheme 2), of the reaction. The signal at δ = 4.5 ppm is tentatively as-
the fact that only one of the two allyl units of the diallyl- signed to the methyl group of an oxonium intermediate (31,
malonates reacts (except for 10), even with excess of acid, Figure 1).[12]
suggested that the mechanism of reaction is more complex.
Figures 2 and 3 show the reaction profiles comparing the
This conclusion was supported by the study of intermedi- experimentally determined temporal concentrations (in
1
2
ates detected by H NMR spectroscopy and also by H- black) of the reactions of 1 and 19, respectively, with TfOH.
labelling experiments. Both cases show the decay of the allylmalonate, the growth
The reactions of di- and monoallylmalonates (1, 17, 19 and decay of an intermediate and the growth of the lactone.
and 29) were monitored by 1H NMR spectroscopy in
A good fit was obtained (grey lines, Figures 2 and 3) in
CDCl3, and the same behaviour was observed in all cases all cases for a two-step mechanism, in which an oxonium
(see Supporting Information). As an example, Figure 1 intermediate is formed first and then evolves to the lactone,
shows the 1H NMR spectra of the reaction of 19 with liberating the MeOTf (δ = 4.2 ppm) in an SN2-type reac-
TfOH recorded at different times. Key results included the tion.[13] However, the decay of the starting material in the
appearance of a singlet at δ = 4.5 ppm (᭿, Figure 1), that first step was found to be faster than that expected for a
started to decay as another singlet at δ = 4.2 ppm (᭹, Fig- bimolecular reaction of 1 and 19 with TfOH, and the simu-
ure 1), as well as the signals of the lactone (᭡, Figure 1), lation was better when 2 equiv. of TfOH were used to give
started growing.
a third-order rate equation for the first step of the type: rate
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Triflic Acid Mediated Dealkylative Lactonisation
The lactonisation can also be performed by using the hy-
drate (TfO–·H3O+), generated by stoichiometric reaction of
TfOH with H2O. However, the reaction is slower due to
the low solubility of the hydrate in chloroform. Moreover,
attempts to lactonise allylmalonates 1, 17, and 19, by using
a catalytic amount of TfOH (10 mol-%) in the presence of
1 equiv. of water or by adding the water slowly during the
reaction, failed, again probably due to the low solubility of
the hydrate in chloroform.
2H-labelling experiments by using TfOD were carried out
in order to confirm the transfer of the proton from the
triflic acid. Thus, reaction of di- (1) and monoallylmalon-
ates (d1-17 and 19) with TfOD gave the deuterated mono-
lactones d1-2, d1-18 and d1-20 (Scheme 12).[16] As expected,
the deuterium atom was incorporated into the exo-methyl
group, and whilst the isotopic purity was high, as evidenced
by 13C NMR and MS analysis (73–86% d1; 1–4% d2),[17]
we did not observe deuterium in the unreacted allyl unit of
d1-2, ruling out the hypothesis that the reaction proceeds
by initial protonation of the alkene, and suggesting an
intramolecular transfer of the proton, probably from a
carbonyl-protonated ester.[18,19]
Figure 2. Graph of the reaction of 1 with TfOH. Experimental val-
ues: o = diallylmalonate (1); ᭿ = intermediate; ᭡ = lactone (2).
Calculated values: grey lines, see Scheme 11 for details.
Figure 3. Graph of the reaction of 19 with TfOH. Experimental
values: o = diallylmalonate (19); ᭿ = intermediate (31); ᭡ = lac-
tone (20). Calculated values: grey lines, see Scheme 11 for details.
Scheme 12. Deuteration experiments with TfOD.
Reaction of the cyclohexyl derivatives (27 and 29,
Scheme 13) with TfOD also gave the d1-lactones (d1-28, d1-
30a, and d1-30b)[20,21] with relatively high deuterium incor-
≈ kobsd.·[TfOH]2·[allylmalonate]1 (see Scheme 11 for rate poration [MS analysis also revealed some d0 and d2 prod-
constants).
ucts (46–50%, d1; 24–36%, d2)[22] as in the case of the allyl
The second-order kinetic dependency on TfOH may derivatives].[17] Although analysis of lactone d1-28 was diffi-
1
arise from a monomer/dimer equilibrium of the triflic cult due to overlap of the key H NMR signals, analysis of
acid,[14] with the monomer as the prevalent species in chlo- d1-30 revealed partial deuteration in both positions, cis and
roform. The dimer is then the active species in the lactoni- trans to the oxygen atom in both isomers.
sation, with the net effect of one TfOH acting as a catalyst
As lactones 30a and 30b did not isomerise, even in the
and the second as the reagent.[15]
presence of excess TfOH,[24] the generation of both dia-
Scheme 11. Simplified two-step mechanism for the kinetics of lactonisation of di- and monoallylmalonates.
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519

M. Paz Muñoz, G. C. Lloyd-Jones
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Thus, the formation of the oxonium intermediates can oc-
cur by intramolecular transfer of the proton from the ester
(involving a seven-membered cyclic transition state) to gen-
erate the carbocationic species, which also mediate the iso-
merisation of the oxonium intermediates (Scheme 14).[27]
The formation of one product or the other would depend
on the rate of the attack of the triflate to liberate the lactone
vs. equilibration of the oxonium intermediates, these being
influenced by the substituents on the alkene and the chain,
and the rigidity of the system.
Conclusions
Scheme 13. Lactonisation of cyclohexylmalonates with TfOD.[23]
We have described the triflic acid mediated dealkylative
lactonisation of mono- and diallylmalonates. A mechanistic
study, including kinetics, simulations, NMR spectroscopy
and 2H-labelling experiments, suggests that the reaction
proceeds according to a three-step mechanism, probably in-
volving an intramolecular transfer of the proton from the
protonated ester to the alkene to form, via a carbocation,
an oxonium intermediate, as identified by H NMR spec-
troscopy, which evolves to the final lactone by SN2 attack
of the triflate to form MeOTf as by-product.
stereoisotopomers suggests that the interconversion of the
oxonium intermediates is relatively facile. In the case of the
cyclohexyl derivative 29, the oxonium intermediates are ste-
rically congested due to the presence of the methyl group,
and their equilibration via a carbocation, which mediates
the isomerisation, would explain the moderate diastereo-
selectivity obtained in this reaction compared with the com-
plete diastereoselectivity in the reaction of 27 where the
substituent is H. The partial deuteration cis and trans to
the oxygen atom and the d0 and d2 products can be ex-
plained by reversible intramolecular protonation to gener-
ate a carbocation in equilibrium with the alkene, during
which H/D exchange can occur with the TfOD/TfOH
(Scheme 14).
1
The intramolecular addition of H+ from the ester to the
alkene[28] is supported by the monolactonisation of diallyl-
malonates, even with excess TfOH, and the lack of deu-
teration in the unreacted allyl unit. Isomerisation of the ox-
onium intermediates via carbocationic species, would ex-
plain the mixture of d1 products obtained in the reaction
with the cyclohexyl derivatives.
Further investigations to unambiguously assign the rela-
tive configuration of the deuterated new stereocenters of
more rigid cyclohexyl derivatives, and therefore confidently
distinguish syn or anti addition of the H and O atoms to
the alkene are in progress. The syn-intramolecular addition
mechanism offers the potential for an asymmetric version
of this reaction by way of a chiral strong sulfonic acid.
Experimental Section
General: See Supporting Information for details of general methods
and analytical techniques.
General Procedure for the Reaction of Allylmalonates with Triflic
Acid: TfOH (0.15–0.40 mmol) was added to a solution of the allyl-
malonate (0.07–0.20 mmol) in chloroform/CDCl3 (0.7–2 mL) at
room temperature. The mixture was stirred for 24 h and then fil-
tered through a pad of silica (washing with hexane/EtOAc, 10:1)
to obtain the pure compounds as colourless oils. In the case of
reaction with TfOD, the starting materials were pre-deuterated
(MeOD, Nacat, room temp., 3 h) if needed, and all the glass mate-
rial washed with D2O/dry THF/dry CDCl3, and dried in the oven
overnight.
Scheme 14. Proposed isomerisation of oxonium intermediates to
explain deuteration experiments. Lactone 30 is used as model.
Although intramolecular proton transfers are character-
ised by small effective molarities (EM ≈ 1–10 ),[25] there
are examples of efficient intramolecular proton transfer be-
tween carbon and oxygen atoms in which seven-membered
cyclic transition states (including the proton) are involved,
1
Lactone 2:[29] 12 mg, 0.06 mmol, 79%. 2 isomers, 1.7:1. H NMR
(400 MHz, CDCl3, 25 °C): δ = 5.77–5.61 (m, 2ϫ1 H, 7-H), 5.24–
5.14 (m, 2ϫ2 H, 8-H), 4.72–4.54 (m, 2ϫ1 H, 4-H), 3.78 (s, 3 H,
minor), 3.76 (s, 3 H, major), 2.84–2.56 (m, 2ϫ2 H, 3 H + 1 H, 4-
H, minor), 2.41 (d, JH,H = 7.3 Hz, 1 H, 4-H, major), 1.82 (dd, JH,H
giving effective molarities up to 50  in rigid systems.[26] = 13.1, 10.2 Hz, 1 H, 4-H, major), 1.52 (d, JH,H = 10 Hz, 1 H, 4-
520
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Triflic Acid Mediated Dealkylative Lactonisation
H minor), 1.42 (d, JH,H = 6.6 Hz, 3 H, 5-H, minor), 1.40 (d, JH,H
Spiro-Lactone 11:[2,6a,31] 35 mg, 0.19 mmol, 76%. 3 isomers, 1:1:1.
= 6.2 Hz, 3 H, 5-H, major) ppm. 13C NMR (100 MHz, CDCl3, 1st isomer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 5.02 (m, 2 H),
25 °C): δ = 173.71 (CO), 169.87 (CO), 131.91 (CH, C-7, major), 2.80 (ddd, JH,H = 12.9, 6.0, 2.6 Hz, 2 H), 1.88 (ddd, JH,H = 12.3,
131.71 (CH, C-7, minor), 120.51 (CH2, C-8, minor), 120.21 (CH2,
C-8, major), 75.28 (CH, C-4), 75.19 (CH, C-4), 56.17 (C-2), 55.44
9.6, 2.7 Hz, 2 H), 1.44 (dd, JH,H = 6.2, 2.6 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 173.55 (CO), 75.97 (CH), 54.02 (C),
(C-2), 53.21 (CH3, ester), 53.17 (CH3, ester), 38.96 (CH2), 38.91 40.48 (CH2), 20.96 (CH3) ppm. 2nd and 3rd isomers: 1H NMR
(CH2), 38.46 (CH2), 38.39 (CH2), 20.78 (CH3, C-5), 20.76 (CH3,
C-5) ppm. HMRS (CI): calcd. for C10H15O4 [MH+] 199.097034;
found 199.096274.
(400 MHz, CDCl3, 25 °C): δ = 4.97 (m, 2 H), 4.69 (m, 2 H), 2.79
(dd, JH,H = 12.9, 5.6 Hz, 2 H), 2.58 (dd, JH,H = 13.5, 8.3 Hz, 2 H),
2.31 (dd, JH,H = 13.2, 6.6 Hz, 2 H), 1.89 (dd, JH,H = 13.2, 9.9 Hz,
2 H), 1.52 (d, JH,H = 6.3 Hz, 6 H), 1.45 (d, JH,H = 6.3 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.82 (CO), 173.58
(CO), 76.04 (CH), 75.11 (CH), 53.99 (C), 41.71 (CH2), 39.69 (CH2),
21.19 (CH3), 20.96 (CH3) ppm. HMRS (CI): calcd. for C9H13O4
[MH+] 185.0814; found 185.0808.
Lactone d-2: 7 mg, 0.034 mmol, 34%. 2 isomers, 2:1. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 5.77–5.61 (m, 2ϫ1 H, 7-H), 5.24–
5.14 (m, 2ϫ2 H, 8-H), 4.72–4.54 (m, 2ϫ1 H, 4-H), 3.78 (s, 3 H,
minor), 3.76 (s, 3 H, major), 2.84–2.56 (m, 2ϫ2 H, 3 H + 1 H, 4-
H, minor), 2.40 (d, JH,H = 7.3 Hz, 1 H, 4-H, major), 1.82 (dd, JH,H
= 13.1, 10.2 Hz, 1 H, 4-H, major), 1.52 (d, JH,H = 10 Hz, 1 H, 4-
H minor), 1.46–1.40 (m, 2ϫCH2D) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 174.32 (CO, minor), 173.1 (CO, major), 170.38
(CO, minor), 169.88 (CO, major), 131.93 (CH, C-7, major), 131.73
(CH, C-7, minor), 120.51 (CH2, C-8, minor), 120.20 (CH2, C-8,
major), 75.24 (CH, C-4, major), 74.60 (CH, C-4, minor), 56.18 (C-
2, major), 55.45 (C-2, minor), 53.17 (CH3, ester), 53.17 (CH3, es-
ter), 38.98 (CH2), 38.47 (CH2), 38.41 (CH2), 37.78 (CH2), 21.34
(s,CH3, C-5), 20.81 (t, JC-D = 19.58 Hz, CH2D), 20.78 (s, CH3, C-
5), 20.51 (t, JC-D = 19.58 Hz, CH2D) ppm. MS (CI): m/z (%) = 199
(15) [d0-M+ + 1], 200 (100) [d1-M+ + 1], 201 (2) [d2-M+ + 1].
1
Lactone 12:[32] 12 mg, 0.07 mmol, 58%. 2 isomers, 19:1. H NMR
(270 MHz, CDCl3, 25 °C): δ = 9.84 (br. s, 2 H, acid), 5.79–5.61 (m,
2ϫ1 H, 7-H), 5.25–5.13 (m, 2ϫ2 H, 8-H), 4.79–4.67 (m, 2ϫ1 H,
4-H), 2.85–2.57 (m, 3 H, 6-H + 1 H, 3-H), 2.47–2.42 (m, 3 H,
minor), 1.88 (dd, JH,H = 13.5, 9.9 Hz, 1 H, 3-H), 1.45 (d, JH,H
=
6.2 Hz, 3 H, 5-H, minor), 1.42 (d, JH,H = 6.3 Hz, 3 H, 5-H, major)
ppm. 13C NMR (67.5 MHz, CDCl3, 25 °C): δ = 176.06, 174.95,
173.59, 131.65, 131.41, 120.74, 120.18, 75.63, 57.86, 56.28, 38.66,
38.35, 37.72, 20.90 ppm. HMRS (CI): calcd. for C9H12O4 [MH+]
185.081384; found 185.081275.
1
Lactone 14:[33] 7 mg, 0.05 mmol, 55%. 2 isomers, 1:2.3. H NMR
(400 MHz, CDCl3, 25 °C): δ = 5.82–5.71 (m, 2ϫ1 H), 5.14–5.06
(m, 2ϫ2 H), 4.64 (sext, JH,H = 6.4, 1.2 Hz, 1 H, minor), 4.49 (ddt,
JH,H = 11.09, 10.4, 6.1 Hz, 1 H, major), 2.79–2.68 (m, 2ϫ1 H),
2.66–2.52 (m, 2ϫ1 H), 2.43 (ddd, JH,H = 12.6, 8.5, 5.5 Hz, 1 H,
major), 2.31–2.19 (m, 2ϫ1 H), 2.13 (dt, JH,H = 12.9, 7.4 Hz, 1 H,
minor), 1.98 (ddd, JH,H = 13, 9.2, 5.5 Hz, 1 H, minor), 1.53 (dt,
JH,H = 12.3, 10.3 Hz, 1 H, major), 1.41 (d, JH,H = 6.2 Hz, 3 H,
major), 1.37 (d, JH,H = 6.5 Hz, 3 H, minor) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 178.34 (CO), 134.72 (CH, major),
134.54 (CH, minor), 117.93 (CH2, minor), 117.60 (CH2, major),
75.33 (CH, major), 75.17 (CH, minor), 41.15 (CH, major), 39.10
(CH, minor), 36.34 (CH2, major), 34.82 (CH2, minor), 34.41 (CH2,
major), 34.41 (CH2, major), 34.30 (CH2, minor), 21.39 (CH3,
minor), 21.06 (CH3, major) ppm. HMRS (CI): calcd. for C8H13O2
[MH+] 141.0916; found 141.0919.
Lactone 4:[30] 6 mg, 0.025 mmol, 30%.
(270 MHz, CDCl3, 25 °C): δ = 5.80–5.59 (m, 2ϫ1 H, 7-H), 5.21–
5.13 (m, 2ϫ2 H, 8-H), 4.73–4.54 (m, 2ϫ2 H, ester), 2.80–2.53 (m,
2
isomers.1H NMR
2ϫ2 H, 6-H), 2.40 (d, JH,H = 8.0 Hz, 1 H, 3-H), 1.83 (dd, JH,H
=
13.2, 10.1 Hz, 1 H, 3-H), 1.42 (d, JH,H = 6.8 Hz, 3 H, 5-H), 1.40
(d, JH,H = 6.3 Hz, 3 H, 5-H), 1.26 (m, 2ϫ3 H, ester) ppm. 13C
NMR (67.5 MHz, CDCl3, 25 °C): δ = 173.71 (CO), 169.97 (CO),
132.10, 131.91, 120.51, 120.21, 75.30, 74.66, 62.37, 56.83, 55.48,
39.13, 38.48, 37.87, 31.01, 21.49, 20.91, 14.08 ppm. HMRS (CI):
calcd. for C11H17O4 [MH+] 213.112684; found 213.111977.
Lactone 6: 15 mg, 0.08 mmol, 76%. 2 isomers, 1:1.1. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 5.84 (q, JH,H = 1.48 Hz, 1 H, 6-H,
minor), 5.80 (q, JH,H = 1.96 Hz, 1 H, 6-H, major), 5.71–5.58 (m,
2ϫ2 H, 7-H), 4.60–4.52 (m, 1 H, 4-H), 4.52–4.47 (m, 1 H, 7-H),
3.73 (s, 3 H, ester), 3.71 (s, 3 H, ester), 2.88 (dd, JH,H = 12.92,
5.84 Hz, 1 H, 3-H, major), 2.45 (dd, JH,H = 12.44, 8.8 Hz, 1 H, 3-
H, minor), 2.39 (dd, JH,H = 13.44, 7.32 Hz, 1 H, 3-H, minor), 1.92
(dd, JH,H = 12.72, 9.52 Hz, 1 H, 3-H, major), 1.71–1.68 (m, 6 H,
2ϫ8-H), 1.38 (d, JH,H = 6.36 Hz, 3 H, 5-H, minor), 1.36 (d, JH,H
= 6.12 Hz, 3 H, 5-H, major) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 173.18 (CO), 172.89 (CO), 169.67 (CO), 169.28 (CO),
129.02 (CH, C-6), 128.88 (CH, C-6), 126.60 (CH, C-7), 125.10
(CH, C-7), 75.11 (CH, C-4), 74.57 (CH, C-4), 58.39 (C-2), 58.20
(C-2), 53.41 (CH3, ester), 53.25 (CH3, ester), 40.57 (CH2, C-3),
40.34 (CH2, C-3), 20.63 (CH3, C-5), 20.33 (CH3, C-5), 17.99
(2ϫCH3, C-8) ppm. HMRS (CI): calcd. for C10H15O4 [MH+]
199.0970; found 199.0963.
Lactone 16:[4d] 16 mg, 0.074 mmol, 77%. 2 isomers, 1:3.2. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.53–7.26 (m, 2ϫ5 H, Ph), 5.69–
5.54 (9m, 2ϫ1 H), 5.12–5.06 (m, 2ϫ2 H), 4.65 (sextm, JH,H
=
6.4 Hz, 1 H, minor), 4.35 (septm, JH,H = 4.8 Hz, 1 H, major), 2.72–
2.64 (m, 2ϫ1 H), 2.28 (dd, JH,H = 13, 7.9 Hz, 1 H, minor), 2.07
(dd, JH,H = 12, 8 Hz, 1 H, major), 1.40 (d, JH,H = 8 Hz, 3 H,
major), 1.34 (d, JH,H = 8 Hz, 3 H, minor) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 171.62 (CO), 138.89 (C), 133.31
(CH), 128.96 (CH, major), 128.58 (CH, minor), 127.71 (CH,
major), 127.24 (CH, minor), 126.58 (CH, minor), 126.33 (CH,
major), 119.37 (CH2), 73.94 (CH, major), 73.67 (CH, minor), 53.85
(C), 44.11 (CH2, minor), 43.79 (CH2, minor), 41.31 (CH2, major),
41.18 (CH2, minor), 20.51 (CH3) ppm. HMRS (CI): calcd. for
C14H17O2 [MH+] 217.1229; found 217.1223.
Cyclic Compound 9: 5 mg, 0.017 mmol, 25%. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.29 (tt, JH,H = 7.1, 1.5 Hz, 2 H), 7.20 (tt, JH,H Lactone 18:[34] 21 mg, 0.135 mmol, 78%. 2 isomers, trans/cis, 1:1.4.
1
= 7.3, 1.5 Hz, 1 H), 7.08 (dd, JH,H = 8.3, 1.3 Hz, 2 H), 3.75 (s, 6
H), 2.61 (br. s, 2 H), 2.31 (m, 2 H), 2.26 (m, 2 H), 1.59 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.12, 131.27 (C),
128.43 (2ϫCH), 128.11 (CH), 126.40 (C), 126.36 (C), 53.76 (C),
trans isomer: H NMR (400 MHz, CDCl3, 25 °C): δ = 4.83 (sext,
JH,H = 6.56 Hz, 1 H, 4-H), 3.81 (s, 3 H, ester), 3.64 (t, JH,H
4.5 Hz, 1 H, 2-H), 2.75 (ddd, JH,H = 13.2, 6.84, 4.88 Hz, 1, 3-H),
2.09 (ddd, JH,H = 13.2, 9.52, 7.58 Hz, 1 H, 3-H), 1.43 (d, JH,H
=
=
52.73 (CH3), 36.53 (CH2), 29.03 (CH2), 28.34 (CH2), 20.55 (CH3) 6.84 Hz, 3 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
ppm. HMRS (CI): calcd. for C17H20O4 [MH+] 288.1362; found
288.1360.
171.65 (CO), 168.21 (CO), 76.61 (CH, C-4), 53.08 (CH3, ester),
46.93 (CH, C-2), 33.54 (CH2, C-3), 20.92 (CH3, C-5) ppm. cis iso-
Eur. J. Org. Chem. 2009, 516–524
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
521

M. Paz Muñoz, G. C. Lloyd-Jones
FULL PAPER
mer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.61 (dq, JH,H
=
(dd, JH,H = 9.7, 5 Hz, 1 H, 2-H), 2.70 (ddd, JH,H = 13.3, 6.9, 4.9 Hz,
1 H, 3-H), 2.11 (ddd, JH,H = 13.1, 9.5, 7.4 Hz, 1 H, 3-H), 1.75 [m
9.76, 6.36 Hz, 1 H, 4-H), 3.82 (s, 3 H, ester), 3.67 (dd, JH,H = 11.6,
9.28 Hz, 1 H, 2-H), 2.60 (ddd, JH,H = 13.2, 9.32, 6.12 Hz, 1 H, 3-
H), 2.31 (ddd, JH,H = 13.2, 11.24, 9.28 Hz, 1 H, 3-H), 1.49 (d, JH,H
= 6.8 Hz, 3 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
3
(3JH,H = 7.3 Hz), 1 H, 5-H], 1.67 [m, JH,H = 5.7 Hz, 1 H, 5-H],
1.02 (t, JH,H = 7.4 Hz, 3 H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 171.87, 168.25, 81.47 (CH,4), 53.10 (CH3),
= 171.65 (CO), 168.21 (CO), 75.87 (CH, C-4), 53.00 (CH3, ester), 46.78 (CH, C-2), 31.47 (CH2, C-3), 28.39 (CH2, C-5), 9.37 (CH3,
47.58 (CH, C-2), 33.74 (CH2, C-3), 20.74 (CH3, C-5) ppm. HMRS C-6) ppm. cis isomer: 1H NMR (600 MHz, CDCl3, 25 °C): δ = 4.40
(CI): calcd. for C7H11O4 [MH+] 159.0657; found 159.0653.
(dq, JH,H = 12.9, 5.9 Hz, 1 H, 4-H), 3.81 (s, 3 H, ester), 3.65 (dd,
JH,H = 11.3, 9.3 Hz, 1 H, 2-H), 2.55 (ddd, JH,H = 12.9, 9.1, 5.9 Hz,
1 H, 3-H), 2.34 (ddd, JH,H = 12.9, 11.1, 9.5 Hz, 1 H, 3-H), 1.85
(sept, JH,H = 7.3 Hz, 1 H, 5-H), 1.74 (m, JH,H = 5.7 Hz, 1 H, 5-
H),1.03 (t, JH,H = 7.3 Hz, 3 H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 171.87, 168.25, 80.73 (CH,C-4), 53.02 (CH3),
47.23 (CH, C-2), 31.67 (CH2, C-3), 28.24 (CH2, C-5), 9.37 (CH3,
C-6) ppm. HMRS (CI): calcd. for C8H13O4 [MH+] 173.0814; found
173.0813.
Lactone d-18: 44 mg, 0.28 mmol, 63%. 2 isomers, trans/cis, 1:1.4.
1
trans isomer: H NMR (400 MHz, CDCl3, 25 °C): δ = 4.83 (m, 1
3
3
H, 4-H), 3.81 (s, 3 H, ester), 3.59 (t, JH,H = 4.9 Hz, 1 H, 2-H), 2.71
(ddd, JH,H = 13.2, 6.9, 4.9 Hz, 1, 3-H), 2.05 (ddd, JH,H = 13.2, 9.57,
7.26 Hz, 1 H, 3-H), 1.43 (d, JH,H = 6.84 Hz, 3 H, 5-H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 171.66 (CO), 168.19 (CO),
75.86 (CH, C-4), 53.06 (ester, CH3), 47.57 (CH, C-2), 33.54 (CH2,
C-3) (33.49), 20.89 (s, CH3, C-5), 20.61 (t, JC-D = 19.20 Hz, CH2D)
ppm. cis isomer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.61 (m, Lactone 23: From 21-cis, 5 mg, 0.03 mmol, 11%, 2 isomers, 1:1.
4-H), 3.82 (s, 3 H, ester), 3.64 (dd, JH,H = 11.22, 9.24 Hz, 1 H, 2- From 21-trans, 6 mg, 0.04 mmol, 14%, 2 isomers, 1:1. 1H NMR
H), 2.57 (ddd, JH,H = 14.8, 8.91, 5.94 Hz, 1 H, 3-H), 2.32 (ddd,
JH,H = 12.87, 11.22, 9.57 Hz, 1 H, 3-H), 1.49 (d, JH,H = 6.8 Hz, 3
(400 MHz, CDCl3, 25 °C): δ = 4.51 (m, 2ϫ1 H, 5-H), 3.82 (s, 3 H,
ester), 3.81 (s, 3 H, ester), 3.59 (t, JH,H = 7.6 Hz, 1 H, 2-H), 3.52
H, 5-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.66 (dd, JH,H = 9.3, 7.6 Hz, 1 H, 2-H), 2.33–2.09 (m, 2ϫ3-H + 2ϫ3-
(CO), 168.19 (CO), 75.82 (CH, C-4), 52.97 (CH3, ester), 46.91 (CH, H), 2.07–1.92 (m, 2 H 4-H + 4-H), 1.75 (m, 1 H, 4-H), 1.61 (m, 1
C-2), 33.74 (CH2, C-3), 33.71, 20.71 (s, CH3, C-5), 20.45 (t, JC-D
=
H, 4-H), 1.42 (t, JH,H = 6.5 Hz, 2ϫ3 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.7, 169.0, 77.75 (CH), 76.95
(CH), 53.02 (CH3, ester), 52.95 (CH3, ester), 47.58 (CH), 45.85
(CH), 29.00 (CH2), 27.53 (CH2), 23.08 (CH2), 21.79 (CH), 21.73
(CH2), 21.43 (CH3) ppm. HMRS (CI): calcd. for C8H13O4 [MH+]
173.0814; found 173.0817.
19.72 Hz, CH2D) ppm. MS (CI): m/z (%) = 159 (31) [d0-M+ + 1],
160 (100) [d1-M+ + 1], 161 (6) [d2-M+ + 1].
Lactone 20:[35] 20 mg, 0.12 mmol, 73%. 2 isomers, 1:2.63. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.69 (m, 2ϫ1 H, 4-H), 3.79 (s, 3 H,
ester, minor), 3.77 (s, 3 H, ester, major), 2.81 (dd, JH,H = 13.68,
6.88 Hz, 1 H, 3-H, major), 2.47 (dd, JH,H = 13.2, 8.08 Hz, 1, 3-H,
minor), 2.27 (dd, JH,H = 12.44, 6.08 Hz, 1 H, 3-H, minor), 1.76
(dd, JH,H = 12.96, 9.76 Hz, 1 H, 3-H, major), 1.54 (s, 3 H, 6-H,
minor), 1.54 (s, 3 H, 6-H major), 1.47 (d, JH,H = 6.12 Hz, 3 H, 5-
H, minor), 1.44 (d, JH,H = 6.36 Hz, 3 H, 5-H, major) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 175.46 (CO, minor), 175.10
(CO, major), 171.24 (CO, minor), 170.96 (CO, major), 74.76 (CH,
Lactone 25: From 24-cis, 47 mg, 0.25 mmol, 80%, 2 isomers, 1:1.1.
From 24-trans, 48 mg, 0.25 mmol, 68%, 2 isomers, 1:2.6. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.52–4.36 (m, 2ϫ1 H, 4-H), 3.77
(s, 3 H, minor), 3.76 (s, 3 H, major), 2.75 (dd, JH,H = 13.2, 6.0 Hz,
1 H, 3-H, major), 2.48 (dd, JH,H = 13.2, 8.9 Hz, 1 H, 3-H, minor),
2.20 (dd, JH,H = 12.9, 6.3 Hz, 1 H, 3-H, minor), 1.87–1.85 (m, 1
H, 3-H, major + 2ϫ2 H, 5-H), 1.52 (s, 3 H, minor, 7-H), 1.51 (s,
C-4, major), 74.51 (CH, C-4, minor), 53.11 (CH3, ester, major), 3 H, major, 7-H), 1.00 (t, JH,H = 7.6 Hz, 3 H, 6-H, minor), 1.00 (t,
53.08 (CH3, ester, minor), 52.10 (C-2, major), 51.55 (C-2, minor),
JH,H = 7.6 Hz, 3 H, 6-H, major) ppm. 13C NMR (100 MHz,
43.04 (CH2, C-3, major), 41.75 (CH2, C-3, minor), 20.99 (CH3, C- CDCl3, 25 °C): δ = 175.23, 171.13, 79.70 (CH, C-4, major), 79.55
5, minor), 20.86 (CH3, C-6, major), 20.78 (CH3, C-5, major), 19.95 (CH, C-4, minor), 53.23 (2ϫCH3, ester), 51.81 (C-2, major), 51.34
(CH3, C-6, minor) ppm. HMRS (CI): calcd. for C8H13O4 [MH+] (C-2, minor), 41.09 (CH2, C-3, major), 39.91 (CH2, C-3, minor),
173.0814; found 173.0808.
28.48 (2ϫCH2, C-5), 21.12 (CH3, C-7, major), 20.17 (CH3, C-7
minor), 9.52 (2ϫCH3, C-6) ppm. HMRS (CI): calcd. for C9H15O4
[MH+] 187.0970; found 187.0965.
Lactone d-20: 22 mg, 0.13 mmol, 75%. 2 isomers, 1:2. 1H NMR
(270 MHz, CDCl3, 25 °C): δ = 4.69 (m, 2ϫ1 H, 4-H), 3.79 (s, 3 H,
ester, minor), 3.77 (s, 3 H, ester, major), 2.81 (dd, JH,H = 13.20, Lactone 26: From 24-cis, 2 mg, 0.009 mmol, 4%, 2 isomers, 1.7:1.
5.61 Hz, 1 H, 3-H, major), 2.47 (dd, JH,H = 13.2, 8.58 Hz, 1, 3-H,
From 24-trans, 9 mg, 0.04 mmol, 14%, 2 isomers, 1:4. 1H NMR
minor), 2.27 (dd, JH,H = 12.87, 6.6 Hz, 1 H, 3-H, minor), 1.76 (dd, (400 MHz, CDCl3, 25 °C): δ = 4.57–4.49 (m, 1 H, 5-H, minor),
JH,H = 13.20, 9.90 Hz, 1 H, 3-H, major), 1.54 (s, 3 H, 6-H, minor),
1.54 (s, 3 H, 6-H major), 1.47 (m, 2ϫCH2D) ppm. 13C NMR
(67.9 MHz, CDCl3, 25 °C): δ = 175.47 (CO, minor), 175.10 (CO,
4.46–4.38 (m, 1 H, 5-H, major), 3.79 (s, 3 H, major), 3.78 (s, 3 H,
minor), 2.50 (ddd, JH,H = 13.9, 8.9, 7.4 Hz, 1 H, major), 2.38–2.33
(m, 1 H, minor), 2.03–1.95 (m, 1 H, major), 1.92–1.86 (m, 1 H,
major), 171.23 (CO, minor), 170.96 (CO, major), 74.75 (CH, C-4, minor), 1.83–1.62 (m, 2ϫ2 H), 1.58 (s, 3 H, 7-H, minor), 1.57 (s,
major) (74.71), 74.51 (CH, C-4, minor) (74.46), 53.11 (CH3, ester,
major), 53.08 (CH3, ester, minor), 52.10 (C-2, major), 51.55 (C-2,
3 H, 7-H, major), 1.43 (d, JH,H = 6.4 Hz, 3 H, 6-H, minor), 1.40
(d, JH,H = 6.3 Hz, 3 H, 6-H, major) ppm. 13C NMR (100 MHz,
minor), 43.06 (CH2, C-3, major) (43.03), 41.76 (CH2, C-3, minor) CDCl3, 25 °C): δ = 78.77 (CH, C-5, minor), 75.91 (CH, C-5,
(41.74), 21.01 (s, CH3, C-5, minor), 20.86 (CH3, C-6, major), 20.79
(s, CH3, C-5, major), 20.60 (t, JC-D = 19.72 Hz, CH2D), 20.52 (t,
JC-D = 19.72 Hz, CH2D), 19.95 (CH3, C-6, minor) ppm. MS (CI):
minor), 53.21 (CH3, ester, major), 53.05 (CH3, ester, minor), 49.59
(C-2, major), 48.68 (C-2, minor), 32.45 (CH2, minor), 29.99 (CH2,
major), 28.31 (CH2, minor), 27.58 (CH2, major), 23.44 (CH3,
m/z (%) = 173 (31) [d0-M+ + 1], 174 (100) [d1-M+ + 1], 175 (6) [d2- minor), 23.21 (CH3, major), 22.12 (CH3, minor), 21.63 (CH3,
M+ + 1].
major) ppm. HMRS (CI): calcd. for C9H15O4 [MH+] 187.0970;
found 187.0977.
Lactone 22: From 21-cis, 26 mg, 0.15 mmol, 56%, 2 isomers, 1:1.3
(trans/cis). From 21-trans, 24 mg, 0.14 mmol, 53%, 2 isomers, 1:1.3
Lactone 28:[36] 15 mg, 0.07 mmol, 52%. 1 isomer. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.72 (dt, app. q, JH,H = 5.3, 5.3 Hz,
1 H), 3.78 (s, 3 H), 3.33 (d, JH,H = 5.3 Hz, 1 H), 2.80 (m, 1 H),
1
(trans/cis). trans isomer: H NMR (600 MHz, CDCl3, 25 °C): δ =
4.62 (dt, JH,H = 13.1, 6.9 Hz, 1 H, 4-H), 3.82 (s, 3 H, ester), 3.615
522
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 516–524

Triflic Acid Mediated Dealkylative Lactonisation
Chem. Soc. 1933, 577–580; c) E. J. Boorman, R. P. Linstead,
H. N. Rydon, J. Chem. Soc. 1933, 568–576; d) R. P. Linstead,
H. N. Rydon, J. Chem. Soc. 1933, 580–586; e) R. S. Mali, K. N.
Babu, Helv. Chim. Acta 2002, 85, 3525–3531; f) reaction with
E+: R. T. Arnold, K. L. Lindsay, J. Am. Chem. Soc. 1953, 75,
1048–1049; g) J. Klein, J. Am. Chem. Soc. 1959, 81, 3611–3614;
h) M. Eriksson, A. Hjelmencrantz, M. Nilsson, T. Olsson, Tet-
rahedron 1995, 51, 12631–12644.
a) I. J. S. Fairlamb, S. Grant, S. Tommasi, J. M. Lynam, M.
Bandini, H. Dong, Z. Lin, A. C. Whitwood, Adv. Synth. Catal.
2006, 348, 2515–2530; b) F. Grau, A. Heumann, E. Duñach,
Angew. Chem. Int. Ed. 2006, 45, 7285–7289.
a) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77,
5068–5077; b) M. F. Ansell, M. H. Palmer, J. Chem. Soc. 1963,
2640–2644; c) G. Berti, Tetrahedron 1958, 4, 393–402.
a) R. Verhe, N. de Kimpe, L. de Buyck, N. Schamp, Synth.
Commun. 1981, 11, 35–42; b) J.-F. Roudier, A. Foucaud, Tetra-
hedron Lett. 1984, 25, 4375–4378; c) S. GowriSankar, C. G.
Lee, J. N. Kim, Tetrahedron Lett. 2004, 45, 6949–6953; d) M. F.
Oswald, A. F. Parsons, W. Yang, M. Bowden, Tetrahedron Lett.
2005, 46, 8087–8089.
1.89–1.73 (m, 3 H), 1.59–1.49 (m, 1 H), 1.46–1.34 (m, 4 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 172.16 (CO), 167.89
(CO), 78.45 (CH), 53.28 (CH), 53.07 (CH3), 39.13 (CH), 28.10
(CH2), 26.31 (CH2), 22.11 (CH2), 20.36 (CH2) ppm. HMRS (CI):
calcd. for C10H15O4 [MH+] 199.0970; found 199.0969.
Lactone d-28: 91 mg, 0.46 mmol, 79%. 1 isomer. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.72 (t, JH,H = 5.13 Hz, 1 H), 3.78
(s, 3 H), 3.33 (d, JH,H = 5.38 Hz, 1 H), 2.80 (m, 1 H), 1.85–1.70
(m, 2 H, 1D), 1.59–1.49 (m, 2 H), 1.48–1.35 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 171.96 (CO), (171.71), 167.69
(CO), (166.73), 78.19 (CH), 52.95 (CH3), (52.68), 52.81 (CH),
[2]
[3]
[4]
(52.22), 38.90 (CH), (38.80), 27.87 (s, CH2), 27.51 (t, JC-D
=
19.22 Hz, CHD), 26.05 (CH2), (21.83), 21.79 (CH2), (20.16), 20.07
(CH2) ppm. MS (CI): m/z (%) = 199 (30) [d0-M+ + 1], 200 (100)
[d1-M+ + 1], 201 (82) [d2-M+ + 1].
Lactones 30a and 30b: 20 mg, 0.93 mmol, 84%. 2 isomers, 3.4:1.
1
30a, major isomer: H NMR (400 MHz, CDCl3, 25 °C): δ = 4.56
(dt, app. q, JH,H = 3.4, 3.2 Hz, 1 H, 4-H), 3.79 (s, 3 H), 2.61 (ddd,
JH,H = 12.46, 6.11, 3.91 Hz, 1 H, 3-H), 2.25 (dm, JH,H = 14.66 Hz,
1 H, 5-H), 1.82–1.70 (m, 2 H, 7-H and 8-H), 1.65–1.55 (m, 2 H, 5-
H and 6-H), 1.42 (s, 3 H), 1.40–1.36 (m, 1 H, 6-H), 1.28–1.21 (m,
1 H, 6-H), 1.14–1.04 (m, 1 H, 8-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 175.53 (CO), 171.66 (CO), 76.54 (CH), 57.85
(C), 53.06 (CH3), 42.90 (CH), 27.34 (CH2), 23.43 (CH2), 23.40
(CH2), 19.57 (CH2), 15.15 (CH3) ppm. 30b, minor isomer: 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 4.63 (dt, app. q, JH,H = 4.4,
4.3 Hz, 1 H, 4-H), 3.79 (s, 3 H), 2.61 (ddd, JH,H = 10.0, 6.0, 5.6 Hz,
1 H, 3-H), 2.16 (ddd, JH,H = 13.9, 9.5, 5.8 Hz, 1 H, 5-Heq), 1.73
(m, JH,H = 10, 5.4, 4.7 Hz, 1 H, 5-Hax), 1.59 (s, 3 H), 1.60–1.45 (m,
6 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 175.53 (CO),
170.58 (CO), 75.88 (CH), 55.95 (C), 52.56 (CH3), 45.19 (CH), 27.70
(CH2), 23.95 (CH2), 22.69 (CH2), 19.96 (CH2), 19.73 (CH3) ppm.
HMRS (CI): calcd. for C11H17O4 [MH+] 213.1127; found 213.1121.
[5]
[6]
O. Piva, Tetrahedron 1994, 50, 13687–13696.
a) J. Klein, J. Org. Chem. 1958, 23, 1209–1210; b) other mecha-
nisms have been proposed for these substrates: M. Tiecco, M.
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2817–2824; c) M. Tiecco, L. Testaferri, M. Tingoli, D. Bartoli,
Tetrahedron 1989, 45, 6819–6832; d) M. Tiecco, L. Testaferri,
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R. T. Arnold, M. de Moura Campos, K. L. Lindsay, J. Am.
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N. Fey, J. N. Harvey, G. C. Lloyd-Jones, M. P. Muñoz, P. A.
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boxylic acids, see: L. Coulombe, E. Duñach, Synth. Comunn.
2005, 35, 153–160.
The acetoxylactonisation of alkenoic acids promoted by am-
monium persulfate [(NH4)2S2O8] and triflic acid in acetic acid
has been reported: M. Tiecco, L. Testaferri, M. Tingoli, Tetra-
hedron 1993, 49, 5351–5358. However, the reaction of 1 with
TfOH in the presence of 2 equiv. of AcOH gave the same mix-
ture 2:1 of the lactone 2 in 69%, with no incorporation of the
acetate unit.
[7]
[8]
[9]
[10]
1
Lactones d-30a and d-30b: 2 isomers, 3.4:1. 30a, major isomer: H
NMR (400 MHz, CDCl3, 25 °C): δ = 4.56 (t, JH,H = 2.93 Hz, 1 H,
4-H), 3.79 (s, 3 H), 2.61 (ddd, JH,H = 12.45, 6.11, 4.15 Hz, 1 H, 3-
H), 2.25 [dm, 0.6 H (D), 5-H], 1.82–1.70 (m, 2 H, 7-H and 8-H),
1.60–1.55 [m, 0.5 H (D) + 1 H, 5-H and 6-H], 1.42 (s, 3 H), 1.40–
1.05 (m, 3 H, 6-H, 6-H and 8-H) ppm. MS (CI): m/z (%) = 213
(48) [d0-M+ + 1], 214 (100) [d1-M+ + 1], 215 (53) [d2-M+ + 1]. 30b,
minor isomer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.63 (t,
JH,H = 4.62 Hz, 1 H, 4-H), 3.78 (s, 3 H), 2.61 (m, 1 H, 3-H), 2.25
[dm, 0.6 H (D), 5-Heq], 1.73 [dm, 0.5 H (D), 5-Hax], 1.58 (s, 3 H),
1.55–1.00 (m, 6 H) ppm. MS (CI): m/z (%) = 213 (39) [d0-M+ + 1],
214 (100) [d1-M+ + 1], 215 (77) [d2-M+ + 1].
[11]
[12]
W. E. Fristad, S. S. Hershberger, J. Org. Chem. 1985, 50, 1026–
1031.
A similar intermediate has been proposed in the reaction of
olefinic amides with triflic acid: C. M. Marson, A. Fallah, Tet-
rahedron Lett. 1994, 35, 293–296.
The direct hydrolysis of the oxonium intermediate to produced
the lactone, MeOH and TfOH cannot be ruled out, but seems
less probable due to the fast appearance of the MeOTf ob-
served by 1H NMR spectroscopy: K. B. Hong, M. G. Don-
ahue, J. N. Johnston, J. Am. Chem. Soc. 2008, 130, 2323–2328.
E. S. Stoyanov, K.-C. Kim, C. A. Reed, J. Phys. Chem. A 2004,
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[13]
Supporting Information (see footnote on the first page of this arti-
cle): Details of kinetics, simulations and NMR studies, as well as
NMR spectra of the compounds.
[14]
[15]
TfOH is very hygroscopic, and as it was used without any puri-
fication or drying, it is expected to contain some water in the
form of the hydrate TfO–·H3O+. This residual water can react
with the MeOTf formed in the lactonisation to give MeOH
Acknowledgments
1
(observed by H NMR spectroscopy) and regenerate TfOH.
We would like to thank Dr. M. Crump (University of Bristol) for
access to a 600 MHz NMR instrument and to Dr. C. Butts (Uni-
versity of Bristol) for his assistance with the structural elucidation
(NMR and theoretical calculations) and useful discussions. This
work was supported by a post-doctoral fellowship from the Spanish
Government (Ministerio de Educación y Ciencia, Spain) and the
EPSRC (EP/E061575).
[16]
The unsubstituted malonate 17 had to be pre-deuterated in the
acidic position in order to achieve high incorporation of deute-
rium in the lactonisation, due to H/D exchange of the malonate
C–H proton with the triflic acid. Lactone d-18 was obtained
with H in that position due to D/H exchange during purifica-
tion by column chromatography.
MS analysis also revealed some d0 and d2 products: Lactone 2:
d0, 13%; d1, 86%; d2, 1%. Lactone 18: d0 23%; d1, 73%; d2
4%. Lactone 20: d0 23%; d1, 73%; d2 4%.
[17]
[18]
[1] a) M. F. Ansell, M. H. Palmer, Q. Rev., Chem. Soc. 1964, 211–
225; b) reaction with H+: E. J. Boorman, R. P. Linstead, J.
This mode of addition is also in accordance with the results of
the reaction of (alkene)alkylpalladium complexes with TfOH.[8]
Eur. J. Org. Chem. 2009, 516–524
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
523

M. Paz Muñoz, G. C. Lloyd-Jones
FULL PAPER
In this case, protonation of only one of the diastereotopic esters
is observed in the 1H NMR spectrum (broadening of the signal
at δ = 3.93 ppm), which gives the active species for the re-
arrangement.
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[28]
At this point, the anti addition of H and O (near-concerted or
via carbocation) cannot be ruled out completely, as it would
explain some of the results obtained in the 2H-labelling experi-
ments of the cyclohexyl derivatives. However, the results with
the diallylmalonates, as well as the evidence of protonation of
one ester group in the (alkene)alkylpalladium complexes,[8] sug-
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[19] Protonation of the ester can also explain the easier hydrolysis
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[20] Both isomers were separable by column chromatography and
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[21] The identity of the diastereoisomers was established by NOE
and theoretical calculations of the energy of the possible iso-
mers. For an example of the use of DPFGSE-NOE experi-
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[22] Lactone 28: d0, 15%; d1, 49%; d2, 36%. Lactone 30a: d0 24%;
d1, 50%; d2 26%. Lactone 30b: d0 18%; d1, 46%; d2 36%.
[23] The unsubstituted malonate 27 had to be pre-deuterated in the
acidic position in order to achieve high incorporation of deute-
rium in the lactonisation, due to H/D exchange of the malonate
C–H proton with the triflic acid. Lactone d-28 was obtained
with H in that position due to D/H exchange during purifica-
tion by column chromatography.
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[34] Comercially available.
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Received: October 3, 2008
Published Online: December 15, 2008
524
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 516–524