An expedient synthesis of olfactory lactones by intramolecular hydroacylalkoxylation reactions

Article abstract of DOI:10.1002/ejoc.201001556

A series of 4,5-disubstituted γ-lactones, including whisky and cognac lactones, was synthesised in four steps from a readily available chiral precursor. By using an intramolecular hydroacylalkoxylation reaction in the final step, a correlation between the (E)/(Z) configuration of the precursor and the product distribution has been established, for the first time, in this type of cyclisation reactions. Copyright

Full text of DOI:10.1002/ejoc.201001556

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001556
An Expedient Synthesis of Olfactory Lactones by Intramolecular
Hydroacylalkoxylation Reactions
Luis A. Adrio[a] and King Kuok (Mimi) Hii*[a]
Keywords: Lactones / Copper / Homogeneous catalysis / Hydroacylalkoxylation / O-H addition
A series of 4,5-disubstituted γ-lactones, including whisky and
cognac lactones, was synthesised in four steps from a readily
available chiral precursor. By using an intramolecular hy-
droacylalkoxylation reaction in the final step, a correlation
between the (E)/(Z) configuration of the precursor and the
product distribution has been established, for the first time,
in this type of cyclisation reactions.
Introduction
involves seven steps from commercially available achiral
precursors.[2f]
Lactones are ubiquitous in nature as perfumes and phero-
mones, and are important for the production of flavours,
fragrances and agrochemicals.[1] Olfactory properties of
these compounds are highly dependent upon substituents
present, and their relative and absolute stereochemistries on
the O-heterocycle. This is exemplified by a class of 4,5-di-
substituted γ-lactones, which are key ingredients of whisky,
cognac and brandy (Figure 1). The family of lactones com-
prises four diastereomers, all of which contain a methyl sub-
stituent with the (S) configuration at the β-position. Differ-
ences in their sensory properties are due entirely to substitu-
tion at the α-carbon atom (C-5); whereas the odour of
whisky and oak is associated with an n-butyl substituent,
its n-pentyl homologue evokes the aroma of cognac.
Previously, we have reported the application of Cu-
(OTf)2 for the general addition of an O–H to a C=C
bond,[3] including intramolecular cyclization of 3-alkenoic
acids and 3-alkenols.[4] In this work, we examine whether it
is possible to extend the methodology to an expedient syn-
thesis of 4,5-disubstituted lactones from α-methyl-γ-butyro-
lactone (1), which is readily accessible in both enantiomeric
forms in high optical purity from cheap, achiral precursors
such as 2-methylbutenolide,[5] 2-methylene-γ-lactone[6] or 2-
methylenesuccinate,[7] by well-established bio- and chemo-
catalytic routes (Scheme 1).
Figure 1. cis- and trans-4,5-disubstituted γ-lactones.
Perhaps unsurprisingly, the asymmetric synthesis of these
lactones is an attractive endeavour, for which there has been
a number of reports.[2] By excluding methods that rely on
the kinetic resolution of racemates or a precursor derived
from the chiral pool, the shortest enantioselective route re-
ported for the synthesis of a trans-(whisky) lactone so far
Scheme 1. Stereodivergent synthesis of 3,4-disubstituted γ-lactones.
Results and Discussion
Synthesis of Acyclic Precursors
[a] Department of Chemistry, Imperial College London,
Exhibition Road, South Kensington, London SW7 2AZ, UK
Fax: +44-20-75945804
To demonstrate the feasibility of our proposed route,
commercially available α-methyl-γ-butyrolactone (Ϯ)-1 was
employed as the precursor in this work (Scheme 2). Re-
duction to the lactol 2 was achieved in high yield (92%) by
E-mail: mimi.hii@imperial.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001556.
1852
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1852–1857

Olfactory Lactones by Intramolecular Hydroacylalkoxylation Reactions
using DIBAL-H. Conversion to δ-alkenols 3a–d was then related example of a 3-phenyl-4-pentenoic acid substrate 5,
accomplished selectively by a Wittig reaction between 2 and which cyclised to form the γ-lactone regioselectively in the
an appropriate P-ylide. The (Z) isomer predominated in all presence of either AgOTf or Cu(OTf)2, to give a mixture of
cases, which can be isolated with yields between 71 and cis and trans isomers (Scheme 3).[4,14] Thus, the present
92%.
study will provide an opportunity to assess the selectivity
and general applicability of the hydroacyalkoxylation reac-
tion for the synthesis of 4,5-disubstituted γ-lactones. Par-
ticularly, the (E)/(Z) geometry of the acyclic precursor on
the resultant product distribution will be a point of interest.
Scheme 3. The only previous example of the cyclisation of a 3-
substituted alkenoic acid substrate.
Scheme 2. Three-step synthesis of acyclic precursors.
In light of literature precedence, catalytic performances
of a strong Brønsted and a Lewis acid were compared in
this work: Hence, solutions of δ-alkenoic acids (Z)-4a–c
were refluxed in dichloroethane in the presence of either
TfOH (10 mol-%) or Cu(OTf)2 (5 mol-%) (Scheme 4 and
Table 1). In all cases, reactions proceeded with complete
conversion, to furnish mixtures of γ- and δ-lactone prod-
ucts, 7 and 8, respectively, in an approximately 2:1 ratio. In
contrast, the cyclisation of 4d (which would have afforded
the insect pheromone eldanolide[15]) gave an intractable
mixture of products under these conditions.
Oxidation of the primary alcohols 3 to their correspond-
ing carboxylic acids 4 proved to be problematic: stoichio-
metric oxidants (Jones reagent, PDC, KMnO4) delivered
capricious reaction mixtures. On the other hand, the
alcohol is remarkably inert towards IBX, Dess–Martin, and
Parikh–Doering oxidations, where no oxidation was ob-
served, even to the aldehyde. (Oxido)ruthenium catalysts
2–
{[RuO3(OH)2]2–/S2O8 and RuCl3/NaIO4} also failed to
give clean conversions; under these conditions, the dihy-
droxylation of the C=C bond was competitive. Eventually,
some success was achieved by using TEMPO and a buffered
solution of NaClO2,[8] but the reaction terminated at 50%
conversion, even by using excess reagents. The problem was
finally solved by replacing the inorganic oxidant by
PhI(OAc)2,[9] whereby full clean conversion to δ-alkenoic
acids 4a–d can be achieved, with isolated yields of ca. 80%.
Scheme 4. Catalysed cyclization of γ-alkenoic acids.
Table 1. Catalyased cyclization of γ-alkenoic acids.[a]
Intramolecular Hydroacyalkoxylation Reactions
Simple Brønsted acids (such as H2SO4) and superacids
(e.g. TfOH[10]) can be effective for certain intramolecular
cyclizations of alkenoic acids, and have been used for the
synthesis of olfactory γ-lactones.[11] However, applications
are limited by their corrosive nature, which is aggravated by
high temperatures needed for these reactions. The low ther-
mal stability of H2SO4 can impart an unpleasant odour to
the final product by its decomposition to SO2. In recent
years, there is growing interest in the use of “Lewis super
acids” for the synthesis of fragrance materials.[12] For exam-
ple, Al(OTf)3 has been shown to be an effective catalyst for
the cyclisation of unsaturated carboxylic acids to lactones
at a temperature of Ͼ 100 °C,[13] whereas we and others re-
Entry
R1
[cat]
t
Ratio 5-exo[b] (7) 6-endo[c] (8)
[h]
7/8
cis/trans
(mixture)
1
2
3
4
5
6
7
nPr (4a)
TfOH
18
63:37
65:35
64:36
57:43
65:35
61:39
8:92
11:89
9:91
12:88
19:81
11:89
10:90
40:60
45:55
50:50
50:50
36:64
46:54
40:60
nPr (4a) Cu(OTf)2 90
nBu (4b) TfOH 18
nBu (4b) Cu(OTf)2 42
nPent (4c) TfOH 18
nPent (4c) Cu(OTf)2 24
nBu (4b) TfOH
1.2 58:42
[a] See Exp. Sect. for typical reaction conditions. Reactions of En-
tries 1–6 were performed with conventional heating (83 °C),
whereas reaction of Entry 7 was performed under microwave irradi-
ation. Reactions proceeded with complete conversion to products
7 and 8 in all cases (no side product was observed). Product distri-
bution calculated by integration of 1H NMR spectrum (see Sup-
porting Information). [b] Calculated by 1H NMR integration. [c]
Relative stereochemistry of cis/trans isomers of 8 cannot be as-
[4]
ported the use of Cu(OTf)2 and AgOTf[14] under milder
conditions (83 °C).
Rather interestingly, the cyclisation of 3,5-disubstituted
alkenoic acids, such as 4, was never examined in any of
these reports. In terms of “prior art”, there was only one signed as they were inseparable.
Eur. J. Org. Chem. 2011, 1852–1857
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1853

L. A. Adrio, K. K. Hii
SHORT COMMUNICATION
The major isomer of the γ-lactone 7 can be isolated chemistry result from kinetic control during the cyclisation
cleanly by column chromatography. The structure of 7c was process.
confirmed by comparison of its NMR spectrum with that
Consequently, cyclisation of different samples of 4c con-
reported previously,[16] whereas the stereochemical assign- taining varying mixtures of (E) and (Z) isomers were car-
ment of 7a and 7b was established by NOE experiments ried out, and the resultant product distributions analysed
(see Supporting Information). In all cases, the selectivity for (Table 2). As was observed before, the formation of trans-
the trans isomer is higher than that previously observed for 7c was favoured when Z-4c was used as the precursor,
the cyclisation of 5 (Scheme 3), with ratios ranging from whereas the formation of 8c was unselective (Entries 1 and
1:4.3 (Table 1, Entry 5), up to 1:11.5 (Entry 1). In compari- 2). In contrast, when (E) isomers were present in the start-
son, δ-lactones 8a–c, also known to have unique olfactory ing material, regio- and stereoselectivity for 7c were eroded,
properties,[17] were obtained as an inseparable mixture of whereas the isomeric distribution of the six-membered ring
cis and trans isomers with ratios between 1:1 and 1:2. Their 8c becomes more selective (Entries 3 and 4). Again, the out-
identity was established by LC-MS and comparison with come is little affected by the choice of catalyst; thus, they
literature data.
are likely to involve similar intermediates.
Reactions can be further accelerated by the application
of microwave irradiation, with a small effect on the selectiv-
ity (Table 1, Entry 7 vs. Entry 3). Interestingly, for Cu-
(OTf)2-catalysed reactions, faster conversion was observed
with increasing chain length – reaching 54, 83 and 96% in
18 h, for the cyclisation of 4a, 4b and 4c, respectively.
The cyclisation of these (Z)-alkenoic acids is consider-
ably slower and less regioselective than terminal or (E)-alk-
enoic acids studied in our earlier work [where 5-exo prod-
ucts were obtained exclusively by using 2 mol-% of Cu-
(OTf)2 as catalyst[4]]. Also in contrast to the earlier study,
triflic acid is a more effective catalyst than Cu(OTf)2
(Table 1, Entries 1, 3 and 5 vs. Entries 2, 4 and 6). It is inter-
esting to note that very similar product distributions were
obtained, supporting our earlier idea that TfOH may very
well be the active catalyst in both cases.[4]
From a synthetic point of view, the intramolecular hy-
droacylalkoxylation reaction affords trans-7 with 50–55%
isolated yield. Although this may seem modest, the high
yields of the preceding steps, and the short synthetic se-
quence delivered these olfactory lactones with overall yields
between 34 and 38% from 1. This is a very productive route
for accessing the homologous series of trans-4,5-disubsti-
tuted lactones.
Table 2. Product distribution study.[a]
Entry
4c
(E)/(Z)
[cat]
7c
8c
Yield [%] (cis/trans) Yield [%] (mixture[b]
)
1
2
3
4
0:100
TfOH
65 (18:82)
62 (15:85)
48 (38:62)
44 (40:60)
35 (50:50)
38 (50:50)
52 (33:67)
56 (33:67)
0:100 Cu(OTf)2
60:40 TfOH
60:40 Cu(OTf)2
[a] All reactions were complete within 24 h. Reactions proceeded
with complete conversion to products 7 and 8 in all cases (no side
product was observed). Product distribution calculated by integra-
1
tion of H NMR spectrum. [b] Stereochemistry unassigned.
It is interesting to note that the selectivity of the δ-lac-
tone product was enhanced by the presence of the (E) iso-
mer. However, this aspect of the reaction was not pursued
further at this juncture, as all our attempts to separate and
identify the isomers had been unsuccessful.
Conclusions
During this work, the intramolecular cyclisation of 3,5-
disubstituted δ-alkenoic acids by a hydroacylalkoxylation
reaction was examined for the first time. By means of this
reaction, an expedient synthesis of 4,5-trans-disubstituted
olfactory lactones has been developed. By starting from the
readily available lactone 1, the desired products were pre-
pared in four steps with an overall yield between 34 and
38%. Given that both optical isomers of 1 are accessible
from achiral precursors (Scheme 1), the process offers struc-
tural and stereo-diversity for the synthesis of this particular
class of disubstituted lactones, which will enable further ex-
ploration of their properties.
Mechanistic Insights to the Cyclisation Reaction
Complementary studies were performed in an attempt to
improve the selectivity of the process, which provided some
interesting insights into the nature of these reactions. First,
the reversibility of the process was examined to determine
whether the product distribution is the result of a thermo-
dynamic equilibrium. Previously, cis/trans isomers of the
whisky (oak) lactone have been reported to be stable at
55 °C at pH = 1 for 53 d.[18] In the present work, isolated
samples of pure trans-7b, as well as a mixture of products
depleted of this isomer (trans-7b/cis-7b/cis-8b/trans-8b, in a Experimental Section
ratio of 6:38:38:18), were subjected to microwave irradiation
General: Unless specified, all reagents and catalysts were procured
in the presence of 10 mol-% TfOH, at 150 °C in DCE for
30 min. As it was previously observed, the lactones are
stable even under these harsh conditions; compositions of
both solutions, including the isomeric distribution, re-
commercially and used as received without purification. Anhydrous
solvents were dried by passing through columns of molecular sieves
in a solvent purification system. Chemical shifts of NMR spectra
are reported in δ (ppm), referenced to TMS, and J values are given
mained unaffected. Thus, the observed regio- and stereo- in Hz. Multiplicities are abbreviated as s (singlet), d (doublet), t
1854
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1852–1857

Olfactory Lactones by Intramolecular Hydroacylalkoxylation Reactions
(triplet), q (quartet) and m (multiplet). Infrared spectra were re-
corded with an FT-IR spectrometer equipped with an ATR access-
ory.
NMR (101 MHz, CDCl3): δ = 135.5, 129.3, 61.7, 40.2, 32.1, 28.8,
27.1, 22.4, 21.6, 14.0 ppm. MS (CI, NH3): m/z = 174 [MNH4]+.
(Z)-3-Methyldec-4-en-1-ol (3c): Prepared according to a procedure
similar to that described for 3a, from n-C6H13PPh3Br[22] (11.62 g,
24.5 mmol, 2.5 equiv.) and 2 (1 g, 9.73 mmol, 1 equiv.). The crude
product was purified by column chromatography to yield 3c
Tetrahydro-3-methylfuran-2-ol (2):[19] A solution of 3-methyldihy-
drofuran-2(3H)-one (1) (5.0 g, 50 mmol, 1 equiv.) in dry CH2Cl2
(150 mL) was cooled to –78 °C under N2. Diisobutylaluminum hy-
dride (1.0 m in hexanes, 70.3 mL, 70.3 mmol, 1.4 equiv.) was added
dropwise to the stirred solution, and the resultant solution was
stirred at –78 °C for an additional 5 h. Thereafter, the reaction was
quenched by the addition of methanol (48 mL) before the mixture
was warmed up to room temperature. The cloudy suspension was
then filtered through a pad of Celite, and the residue washed with
methanol (30 mL). The combined filtrates were concentrated in
vacuo to afford 2 as a colourless oil (4.69 g, 92%). Containing a
mixture of cis and trans isomers, this was used in the next step
(1.53 g, 92%) as a colourless oil. Rf (CH2Cl2) = 0.45. IR (liquid
1
film): ν
= 3332 (br.), 2956, 2925, 1457, 1051, 999, 742 cm–1. H
˜
max
NMR (400 MHz, CDCl3): δ = 5.34 (dt, J = 11.0, 7.3 Hz, 1 H,
CH=), 5.16 (tt, J = 11.0, 1.5 Hz, 1 H, =CH), 3.71–3.55 (m, 2 H,
CH2OH), 2.69–2.53 (m, 1 H, CHMe), 2.18–1.93 (m, 2 H, CH2),
1.68–1.18 (m, 9 H, 4 CH2, OH), 0.98 (d, J = 6.8 Hz, 3 H, CHMe),
0.89 (t, J = 6.8 Hz, 3 H, CH2Me) ppm. 13C NMR (101 MHz,
CDCl3): δ = 135.5, 129.4, 61.7, 40.3, 31.5, 29.6, 28.8, 27.4, 22.6,
21.6, 14.1 ppm. HRMS (CI, NH3): calcd. for C11H26NO 188.2014,
found 188.2010 [MNH4]+.
without further purification. IR (liquid film): ν
= 3390 (OH),
˜
max
1002 (C–O) cm–1. 1H NMR (400 MHz, CDCl3): cis isomer: δ =
5.25 (d, J = 4.5 Hz, 1 H), 3.76–3.85 (m, 2 H), 2.06–2.16 (m, 1 H),
2.72 (br. s, 1 H), 1.91–2.04 (m, 1 H), 1.66–1.80 (m, 1 H), 1.09 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 99.1,
67.1, 38.5, 30.6,12.8; trans isomer: δ = 5.10 (s, 1 H), 4.00–4.14 (m,
2 H), 3.90–3.99 (m, 1 H), 2.90 (br. s, 1 H), 2.15–2.28 (m, 1 H),
1.46–1.58 (m, 1 H), 1.02 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 104.2, 66.8, 40.3, 31.6,17.1 ppm. EIMS:
m/z (%) = 102 (1) [M+], 85 (100), 56 (50), 43 (43).
3,7-Dimethylocta-4,6-dien-1-ol (3d): Prepared according to a pro-
cedure similar to that described for 3a, from (3-methylbut-2-en-1-
yl)triphenylphosphonium bromide[23] (8 g, 19.47 mmol, 2.5 equiv.)
and 2 (0.8 g, 7.78 mmol, 1 equiv.). The crude yellow residue was
purified by column chromatography using CH2Cl2 to yield an in-
separable mixture of (Z) and (E) isomers (ratio 46:54) as a trans-
parent oil (0.85 g, 71%). IR (liquid film): ν
= 3378 (br.), 2970,
˜
max
2932, 2876, 1695, 1457, 1377, 1150, 1052, 970 cm–1. 1H NMR
(400 MHz, CDCl3): (Z) isomer: δ = 6.15 (t, 1 H, J = 11.0 Hz,
CH=), 6.07 (d, 1 H, J = 11.0 Hz, =CH), 5.11 (t, 1 H, J = 11.0 Hz,
=CH), 3.74–3.57 (m, 2 H, CH2OH), 2.90–2.74 (m, 1 H, CHMe),
1.82 (s, 3 H, Me), 1.78 (s, 3 H, Me), 1.72–1.38 (m, 2 H, CH2), 1.03
(d, 3 H, J = 6.7 Hz, CHMe); (Z) isomer: δ = 6.22 (dd, 1 H, J =
15.1, 10.8 Hz, CH=), 5.77 (d, 1 H, J = 10.8 Hz, =CH) 5.42 (dd, 1
H, J = 15.1, 8.3 Hz, CH=), 3.73–3.55 (2 H, m CH2OH), 2.45–2.28
(m, 1 H, CH2), 1.82 (s, 3 H, Me), 1.78 (s, 3 H, Me), 1.72–1.38 (m,
2 H, CH2), 1.06 (d, 3 H, J = 6.8 Hz, CHMe). 13C NMR (101 MHz,
CDCl3, mixture of isomers): δ =137.0, 135.9, 134.9, 133.6, 125.5,
124.9, 124.0, 120.1, 61.5, 61.4, 40.2, 39.9, 34.1, 28.9, 26.4, 25.9,
21.5, 21.1, 18.3, 18.1 ppm. HRMS (CI, NH3): calcd. for C10H22NO
172.1701, found 172.1698 [MNH4]+.
(Z)-3-Methyloct-4-en-1-ol (3a): A round-bottom flask was charged
with n-C4H9PPh3Br[20] (9.71 g, 24.47 mmol, 2.5 equiv.) and dry
THF (80 mL) under N2. The suspension was cooled to –42 °C (by
using an acetonitrile/dry ice bath), and a solution of nBuLi (1.6 m
in hexane, 15.33 mL, 2.5 equiv.) was added dropwise. Stirring was
maintained at –42 °C until a red solution was generated. Com-
pound 2 (1.0 g, 9.73 mmol, 1 equiv.) was then added slowly by
using a syringe pump over 1 h, after which the mixture was warmed
up room temperature and stirred overnight. The reaction was
quenched by the addition of water (25 mL) and the mixture diluted
with EtOAc (25 mL). The aqueous layer was separated and ex-
tracted with EtOAc (3ϫ50 mL). The combined organic layers were
washed with brine, dried (MgSO4) and concentrated. The crude
yellow residue was purified by column chromatography[21] to give
Z-3a (1.08 g, 78%) as a transparent oil. Rf (25% EtOAc/hexane) =
Typical Procedure for the Oxidation of Alcohols 3 to Acids 4: A
mixture of diacetoxyiodobenzene (1.0 g, 3.1 mmol) and the alcohol
(1.4 mmol) was suspended in acetonitrile/water (1:1, 6.6 mL). This
mixture was sonicated for 3 min until the reagents were completely
dissolved. TEMPO (0.044 g, 0.2814 mmol), was then added to the
reaction vessel and the reaction mixture was stirred at room tem-
perature for 7 h. After this time, the aqueous layer was extracted
with Et2O (3ϫ15 mL). The combined organic layers were washed
with brine, dried (MgSO4) and concentrated. The residue was puri-
fied by column chromatography.
0.5. IR (liquid film): ν
= 3312 (br.), 2957, 2929, 2871, 1456,
˜
max
1376, 1050, 1000, 734 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.35
(dt, J = 11.0, 7.3 Hz, 1 H, =CH), 5.18 (tt, J = 11.0, 1.5 Hz, 1 H,
CH=), 3.75–3.55 (m, 2 H, CH2O), 2.73–2.56 (m, 1 H, CHMe),
2.13–1.99 (m, 2 H, CH2), 1.72–1.57 (m, 2 H, CH2), 1.57–1.35 (m,
3 H, CH2 and OH), 1.00 (d, J = 6.7 Hz, 3 H, CHMe), 0.93 (t, J =
7.4 Hz, 3 H, CH2Me) ppm. 13C NMR (101 MHz, CDCl3): δ =
135.7, 129.1, 61.7, 40.2, 29.5, 28.9, 23.0, 21.5, 13.8 ppm. HRMS
(CI, NH3): calcd. for C9H22NO 160.1701; found 160.1702
[MNH4]+.
(Z)-3-Methyloct-4-enoic Acid (4a): Obtained from 3a (0.20 g,
1.4 mmol). Purified by column chromatography using 10% EtOAc/
hexane, the product was obtained as a transparent oil (180 mg,
82%). IR (liquid film): ν
= 2961, 2929, 1706, 1411, 1291, 1193,
˜
max
(Z)-3-Methylnon-4-en-1-ol (3b): Prepared according to a procedure
similar to that described for 3a, from n-C5H11PPh3Br[20] (9.99 g,
24.2 mmol, 2.5 equiv.) and 2 (0.99 g, 9.67 mmol, 1 equiv.) The
product was purified by column chromatography to yield Z-3b
(1.24 g, 82%) as a transparent oil. Rf (20% EtOAc/hexane) = 0.45.
937, 738 cm–1. H NMR (400 MHz, CDCl3): δ = 11.0 (br. s, 1 H,
OH), 5.34 (dt, J = 11.0, 7.4 Hz, 1 H, CH=), 5.21 (tt, J = 11.0,
1.5 Hz, 1 H, =CH), 3.09–2.89 (m, 1 H, CHMe), 2.40–2.19 (m, 2
H, CH2), 2.12–1.94 (m, 2 H, CH2), 1.48–1.23 (m, 2 H, CH2), 1.04
(d, J = 6.7 Hz, 3 H, CHMe), 0.89 (t, J = 7.4 Hz, 3 H, CH2Me)
ppm. 13C NMR (101 MHz, CDCl3): δ = 179.3, 133.5, 129.8, 42.0,
29.4, 28.9, 22.8, 20.9, 13.7 ppm. HRMS (CI, NH3): [MNH4]+,
found 174.1495. C9H20NO2 requires 174.1494.
1
IR (liquid film): ν
= 3335 (br.), 2957, 2926, 2873, 1456, 1372,
˜
max
1
1050, 999, 734 cm–1. H NMR (400 MHz, CDCl3): δ = 5.34 (dt, J
= 11.0, 7.3 Hz, 1 H, CH=), 5.15 (tt, J = 11.0, 1.5 Hz, 1 H, =CH),
3.75–3.50 (m, 2 H, CH2OH), 2.73–2.53 (m, 1 H, CHMe), 2.17–1.94
(m, 2 H, CH2), 1.61 (dtd, J = 11.9, 6.8, 5.1 Hz, 1 H, CHaHb), 1.52–
1.41 (m, 1 H, CHaHb), 1.37–1.26 (m, 4 H, 2 CH2), 0.97 (d, J =
(Z)-3-Methylnon-4-enoic Acid (4b): Prepared by using 3b (100 mg,
0.64 mmol). Purified by column chromatography using 25%
6.7 Hz, 3 H, CHMe), 0.90 (t, J = 7.0 Hz, 3 H, CH2Me) ppm. 13C EtOAc/hexane; the product was obtained as a transparent oil
Eur. J. Org. Chem. 2011, 1852–1857
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1855

L. A. Adrio, K. K. Hii
SHORT COMMUNICATION
(92 mg, 85%). IR (liquid film): νmax = 2959, 2928, 1706, 1412, 1290,
(dt, J = 7.8, 4.0 Hz, 1 H, CHO), 2.77–2.62 (m, 1 H, CHMe), 2.33–
2.13 (m, 2 H, CH2), 1.77–1.24 (m, 8 H, 4 CH2), 1.12 (d, J = 6.4 Hz,
3 H, CHMe), 0.89 (t, J = 6.8 Hz, 3 H, CH2Me) ppm. 13C NMR
˜
1
929, 747 cm–1. H NMR: (400 MHz, CDCl3): δ = 11.4 (br. s, 1 H,
OH), 5.34 (dt, J = 11.0, 7.4 Hz, 1 H, CH=), 5.19 (tt, J = 11.0,
1.5 Hz, 1 H, =CH), 3.13–2.93 (m, 1 H, CHMe), 2.43–2.22 (m, 2 (101 MHz, CDCl3): δ = 176.7, 87.5, 37.1, 36.1, 33.99, 31.6, 25.4,
H, CH2), 2.43–2.02 (m, 2 H, CH2), 1.41–1.28 (m, 4 H, 2 CH2), 1.07
(d, J = 6.8 Hz, 3 H, CHMe), 0.92 (t, J = 6.8 Hz, 3 H, CH2Me)
ppm. 13C NMR (101 MHz, CDCl3): δ = 179.0, 133.3, 130.1, 41.9,
31.9, 28.9, 27.1, 22.3, 21.0, 14.0 ppm. HRMS (CI, NH3): calcd. for
C10H22NO2 188.1651, found 188.1653[MNH4]+.
22.5, 17.5, 14.0 ppm. MS (CI, NH3): m/z = 188 [MNH4]+.
(؎)-trans-5-Hexyl-4-methyldihydrofuran-2(3H)-one (7c):[16] Colour-
1
less oil. H NMR (400 MHz, CDCl3): δ = 4.04 (dt, 1 H, J = 7.8,
3.9 Hz, CHO), 2.79–2.62 (m, 1 H, CHMe), 2.34–2.13 (m, 2 H,
CH2), 1.77–1.22 (m, 10 H, 5 CH2), 1.13 (d, 3 H, J = 6.4 Hz,
CHMe), 0.91 (t, 3 H, J = 6.8 Hz, CH2Me) ppm. 13C NMR
(101 MHz, CDCl3): δ = 176.6, 87.5, 37.1, 36.1, 34.0, 31.6, 29.5,
25.7, 22.5, 17.5, 14.0 ppm.
(Z)-3-Methyldec-4-enoic Acid (4c): Prepared from 3c (100 mg,
0.54 mmol). Purified by column chromatography using 25%
EtOAc/hexane, which afforded the product as a transparent oil
(93 mg, 86%). IR (liquid film): νmax = 2958, 2926, 1706, 1410, 1292,
˜
Supporting Information (see footnote on the first page of this arti-
cle): IR and NMR (1H and 13C) spectra of all intermediates and
products, an example of how product distribution is determined by
1H NMR integration, and NOE experiments with trans-7a and 7b.
969 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.35 (dt, J = 11.0,
7.6 Hz, 1 H, CH=), 5.20 (tt, J = 11.0, 1.5 Hz, 1 H, =CH), 3.12–
2.94 (m, 1 H, CHMe), 2.41–2.23 (m, 2 H, CH2), 2.14–2.03 (m, 2
H, CH2), 1.48–1.12 (m, 6 H, 3 CH2), 1.12–0.96 (d, J = 6.8 Hz, 3
H, CHMe), 0.92 (t, J = 6.8 Hz, 3 H, CH2Me) ppm. 13C NMR
(101 MHz, CDCl3): δ = 179.0, 133.3, 130.2, 126.9, 41.9, 31.5, 29.4,
27.3, 22.6, 21.0, 14.1 ppm. HRMS (CI, NH3): calcd. for
C11H24NO2 202.1807, found 202.1804 [MNH4]+.
Acknowledgments
We thank the Xunta Galicia (Angeles Alvariño program) for a
postdoctoral fellowship to L. A. A. We are also grateful to Dr.
Martin Heeney (Imperial College London) for providing access to
his microwave equipment.
(Z)- and (E)-3,7-Dimethylocta-4,6-dienoic Acid (4d): Obtained from
3d (0.22 g, 1.43 mmol). Purified by column chromatography using
25% EtOAc/hexane to yield a inseparable mixture of (Z) and (E)
isomers as a transparent oil (175 mg, 73%). IR (liquid film): ν
˜
max
= 2966, 2927, 1705, 1410, 1291, 1208, 957, 757 cm–1. 1H NMR
(400 MHz, CDCl3): (Z) isomer: δ = 6.05–6.19 (m, 2 H, CH=), 5.13
(t, J = 10.0 Hz, 1 H, =CH), 3.24–3.06 (m, 1 H, CHMe), 2.43–2.27
(m, 2 H, CH2), 1.79 (s, 3 H, Me), 1.75 (s, 3 H, Me), 1.06 (d, J =
6.7 Hz, 3 H, CHMe); (E) isomer: δ = 6.26 (dd, J = 15.1, 10.0 Hz,
1 H, =CH), 5.78 (d, J = 10.0 Hz, 1 H, CH=), 5.48 (dd, J = 15.1,
7.5 Hz, 1 H, =CH), 2.81–2.63 (m, 1 H, CHMe), 2.47–2.24 (m, 2
H, CH2), 1.74 (s, 6 H, 2 Me), 1.09 (d, J = 6.7 Hz, 3 H, CHMe)
ppm. 13C NMR (101 MHz, CDCl3, mixture of isomers): δ = 178.8,
136.3, 134.8, 134.3, 132.5, 125.8, 124.7, 124.4, 120.0, 41.8, 41.65,
33.6, 29.0, 26.3, 25.9, 20.85, 20.3, 18.25, 18.1 ppm. MS (TOF, ES):
m/z = 167 [M – H]–.
[1] The Chemistry of Fragrances (Eds.: D. H. Pybus, C. S. Sell),
The Royal Society of Chemistry, U.K., 1999.
[2] For selected examples (synthesis of trans-lactones), see: a) X.
Jiang, C. Fu, S. Ma, Eur. J. Org. Chem. 2010, 687–693; b) M.
Ozeki, D. Hashimoto, K. Nishide, T. Kajimoto, M. Node, Tet-
rahedron: Asymmetry 2005, 16, 1663–1671; c) F. Schleth, T.
Vogler, K. Harms, A. Studer, Chem. Eur. J. 2004, 10, 4171–
4185; d) K. Suzuki, M. Shoji, E. Kobayashi, K. Inomata, Tet-
rahedron: Asymmetry 2001, 12, 2789–2792; e) F. Benedetti, C.
Forzato, P. Nitti, G. Pitacco, E. Valentin, M. Vicario, Tetrahe-
dron: Asymmetry 2001, 12, 505–511; f) H. Nishikori, K. Ito, T.
Katsuki, Tetrahedron: Asymmetry 1998, 9, 1165–1170.
[3] a) L. A. Adrio, K. K. Hii, Chem. Commun. 2008, 2325–2327;
b) J. G. Taylor, N. Whittall, K. K. Hii, Chem. Commun. 2005,
5103–5105.
[4] L. A. Adrio, L. S. Quek, J. G. Taylor, K. K. Hii, Tetrahedron
2009, 65, 10334–10338.
[5] K. Shimoda, N. Kubota, T. Hirata, Y. Kondo, H. Hamada,
Tetrahedron Lett. 2007, 48, 1345–1347.
[6] T. Ohta, T. Miyake, N. Seido, H. Kumobayashi, H. Takaya, J.
Org. Chem. 1995, 60, 357–363.
[7] M. Ostermeier, B. Brunner, C. Korff, G. Helmchen, Eur. J. Org.
Chem. 2003, 3453–3459.
[8] M. Shibuya, T. Sato, M. Tomizawa, Y. Iwabuchi, Chem. Com-
mun. 2009, 1739–1741.
[9] a) A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Pian-
catelli, J. Org. Chem. 1997, 62, 6974–6977; b) J. B. Epp, T. S.
Widlanski, J. Org. Chem. 1999, 64, 293–295.
[10] L. Coulombel, E. Duñach, Synth. Commun. 2005, 35, 135–160.
[11] D. D. Zope, S. G. Patnekar, V. R. Kanetkar, Flavour Fragrance
J. 2006, 21, 395–399.
[12] L. Coulombel, F. Grau, M. Weïwer, I. Favier, X. Chaminade,
A. Heumann, J. C. Bayón, P. A. Aguirre, E. Duñach, Chem.
Biodiversity 2008, 5, 1070–1082.
[13] L. Coulombel, M. Rajzmann, J.-M. Pons, S. Olivero, E. Duñ-
ach, Chem. Eur. J. 2006, 12, 6356–6365.
[14] C. G. Yang, N. W. Reich, Z. Shi, C. He, Org. Lett. 2005, 7,
4553–4556.
[15] G. Kunesch, P. Zagatti, J. Y. Lallemand, A. Debal, J. P. Vig-
neron, Tetrahedron Lett. 1981, 22, 5271–5274.
[16] A. J. Pratt, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1989,
1521–1527.
General Procedure for Cyclization Reactions: A Radley’s reaction
tube was charged with a magnetic stir bar, and a mixture of the
requisite (Z)-alkenoic acid (1 mmol), copper(II) triflate
(0.05 mmol, 5 mol-%) or triflic acid (8.8 μL, 0.1 mmol, 10 mol-%)
and 1,2-dichloroethane (2 mL) was added. The vessel was fitted
with a Teflon screwcap, placed in the reaction carousel and heated
at reflux for the required length of time. After cooling, the solvent
was removed under reduced pressure to furnish a residue, which
was purified by column chromatography (EtOAc/hexane, 1:4). The
trans-7 isomer always eluted first, followed by cis-7[24–25] (insuf-
ficient quantity for characterisation), and finally a mixture of the
cis/trans-6 products. Alternatively, these reactions were performed
under microwave radiation in DCE at 150 °C by using a Biotage
Initiator 2.5 instrument.
(؎)-trans-3-Methyl-4-octanolide, trans-Whisky Lactone (7a):[26]
Colourless oil. IR (liquid film): ν
= 2960, 2935, 1773, 1459,
˜
max
1210, 1171, 983, 926 cm–1. H NMR (400 MHz, CDCl3): δ = 4.01
(dt, J = 7.8, 4.0 Hz, 1 H, CHO), 2.75–2.57 (m, 1 H, CHMe), 2.30–
2.13 (m, 2 H, CH2), 1.74–1.26 (m, 6 H, 3 CH2), 1.13 (d, J = 6.4 Hz,
3 H, CHMe), 0.90 (t, J = 6.7 Hz, 3 H, CH2Me) ppm. 13C NMR
(101 MHz, CDCl3): δ = 176.7, 87.5, 37.2, 36.1, 33.7, 27.9, 22.5,
17.5, 13.9 ppm. m/z (CI, NH3) 174 [MNH4]+.
1
(؎)-trans-3-Methyl-4-nonanolide, trans-Cognac Lactone (7b):[27]
Colourless oil. IR (liquid film): ν
= 2958, 2932, 1778, 1459,
˜
max
1207, 1169, 1001, 937 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.03
1856
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1852–1857

Olfactory Lactones by Intramolecular Hydroacylalkoxylation Reactions
[17] A. O. Pittet, E. M. Klaiber, J. Agric. Food Chem. 1975, 23,
1189–1195.
[23] Synthesized according to a published procedure: T. Haag, B.
Luu, C. Hetru, J. Chem. Soc. Perkin Trans. 1 1988, 2353–2363.
[24] Y. Zhang, Y. Wang, W.-M. Dai, J. Org. Chem. 2006, 71, 2445–
2455.
[18] A. P. Pollnitz, G. P. Jones, M. A. Sefton, J. Chromatogr. A 1999,
857, 239–246.
[19] D. J. Collins, A. M. James, Aust. J. Chem. 1989, 42, 223–228.
[25] Y. Wu, X. Shen, C.-J. Tang, Z.-L. Chen, Q. Hu, W. Shi, J. Org.
Chem. 2002, 67, 3802–3810.
[20] Synthesized according to
a
published procedure: A.
da Silva Magaton, M. M. M. Rubinger, F. C. de Macedo Jr, L.
Zambolim, J. Braz. Chem. Soc. 2007, 18, 284–290.
[21] In a previous synthesis, the crude product was subjected to
distillation to yield (E)/(Z) isomers in a ratio of 1:4: K. Mori,
Tetrahedron: Asymmetry 2008, 19, 857–861.
[22] Procured commercially from Sigma–Aldrich and used as re-
ceived without purification.
[26] H.-U. Reissig, H. Angert, T. Kunz, A. Janowitz, G. Handke,
E. Bruce-Adjei, J. Org. Chem. 1993, 58, 6280–6285.
[27] Y. Ohta, T. Okamoto, M. Tamura, M. Doe, Y. Morimoto, T.
Kinoshita, K. Yoshihara, J. Heterocycl. Chem. 1998, 35, 485–
487.
Received: November 17, 2010
Published Online: February 17, 2011
Eur. J. Org. Chem. 2011, 1852–1857
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1857