An efficient one-pot four-step domino reaction for the synthesis of C2-substituted 3-methylcyclohex-2-enones

Article abstract of DOI:10.1016/j.tet.2010.07.029

An efficient one-pot four-step domino reaction of substituted β-ketoesters has been optimized giving rise to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation of various initiators for cationic or radical cyclizations. The developed methodology is quite general and applicable to a wide range of β-ketoester substrates, allowing the introduction of various functionalities at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.

Full text of DOI:10.1016/j.tet.2010.07.029

Tetrahedron 66 (2010) 7856e7860
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient one-pot four-step domino reaction for the synthesis of C2-substituted
3-methylcyclohex-2-enones
,
Sylvie Goncalves a, Philippe Maillos b, Marc Nicolas b, Alain Wagner a, Rachid Baati a
*
a Université de Strasbourg, Faculté de Pharmacie UMR/CNRS 7199, Laboratoire des Systèmes Chimiques Fonctionnels, 74 route du Rhin, BP 60024, 67 401 Illkirch, France
b Les Laboratoires Pierre Fabre, Centre de Développement Chimique et Industriel, 16 rue Jean Rostand, 81600 Gaillac, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2010
Received in revised form 13 July 2010
Accepted 13 July 2010
Available online 29 July 2010
An efficient one-pot four-step domino reaction of substituted b-ketoesters has been optimized giving rise
to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation
of various initiators for cationic or radical cyclizations. The developed methodology is quite general and
applicable to a wide range of
at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
b-ketoester substrates, allowing the introduction of various functionalities
Keywords:
Domino reaction
Enone
Cyclization
b-Ketoester
1. Introduction
such as keto-epoxide 2,3 allylic alcohol 3,4 dienol acylate 4,5 exo-
cyclic olefin 56 or 2-alkenyl-1,3-dithiolane 6,7 from which in-
teresting polycyclic compounds could be further generated.
Importantly, C2-substituted 3-methylcyclohex-2-enones 1 have
also been used as key synthetic intermediates in numerous total syn-
thesis of natural products, such as (þ/ꢀ)-dichroanal B,8 umbrosone,9
(þ/ꢀ)-isopisiferin10 and more recently (þ/ꢀ)-triptolide7 (Fig. 2).
C2-substituted 3-methylcyclohex-2-enones 1 are known to be
efficient initiators for diastereoselective 6-endo-trig cyclizations1
giving rise to decalin systems stereoselectively (Fig. 1), a scaffold
present in a wide range of natural products, such as di- and tri-
terpenes.2 Moreover, 1 is also a key intermediate in the access to
several other relevant initiators for cationic or radical cyclizations,
O
Me
O
Me
O
OH
Me
O
R1
O
H
R1
R1
R1
2
O
R2
O
Me OH
3
R2
R2
R2
triptolide
ref. 4
ref. 3
ref. 7
R1
Me
Me
Me
R2
6-endo-Trig
OH
HO
Me
ref. 5
Me
O
Me
R1
O
ref. 9
ref. 8
cyclization
O
R2
H
OCOR'
4
1
R
O
ref. 6
Me
OH
CHO
trans-decalin
O
ref. 7
Me Me
umbrosone
1
Me
system
Me Me
dichroanal B
Me
R1, R2= akyl, aryl
ref. 10
OH
R1
Me Me
S
S
R2
5
6
H
Figure 1. Synthetic relevance of C2-substituted 3-methylcyclohex-2-enones.
Me Me
isopisiferin
* Corresponding author. Tel.: þ33 368 854 301; fax: þ33 368 854 306; e-mail
Figure 2. Use of C2-substituted3-methylcyclohex-2-enones 1innatural productssynthesis.
address: baati@bioorga.u-strasbg.fr (R. Baati).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.029

S. Goncalves et al. / Tetrahedron 66 (2010) 7856e7860
7857
Table 1
The important feature of this class of versatile compounds (1) is
Exploring the conditions for the intramolecular aldol reaction
the chemical nature of the nucleophilic functionality introduced at
the C2 position that participates to the cyclization event. To date,
four methods have been reported in literature for the preparation
of C2-susbtituted 3-methylcyclohex-2-enones. The main procedure
consists in the alkylation of Hagemann’s ester, realized under
heating with various bases (sodium or potassium ethoxide, or po-
tassium tert-butoxide), followed by a one-pot saponification and
decarboxylation.11 However, this multistep procedure suffers from
major drawbacks, such as the formation of C4-susbtituted
3-methylcyclohex-2-enone and/or dialkylated by-products, when
highly electrophilic halides are used.12 The second method consists
in the direct alkylation of the C2 position of 3-methylcyclohex-2-
enone via the dienolate with alkyl halides. However, only few ex-
amples have been reported in the literature, due to the limited
scope of application of the methodology.4b,13 The third route to
access C2-substituted 3-methylcyclohex-2-enones is based on
O
aldol
ester hydrolysis
reaction
and
MeO
MeO
Ph
Ph
Ph
decarboxylation
O
O
7
O
O
O
8
9
Entry
Basea
Solvent
DCM
DCM/MeOH
MeOH
DCM
DCM
DCM
DCM
MeCN
MeCN
T
Product
Yieldb
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
rt
rt
rt
d
8
8
d
d
d
9
d
58%
50%
d
L-proline
40 ꢁC
40 ꢁC
rt
TBD
DBU
DBU
DBU
DBU
d
d
40 ꢁC
80 ꢁC
80 ꢁCc
53%
50%
89%
9
9
a
1.1 equiv of base was used.
Isolated yield.
The reaction was carried out during 3 h.
b
c
a
multistep sequence consisting first in the alkylation of
1,5-dimethoxy-1,4-cyclohexadiene with alkyl halides. This protocol
described initially by Piers et al.14 is then followed by the hydrolysis
of the adduct to 1,3-cyclohexanedione system, which upon ether-
ification affords the corresponding enol, that is, engaged in the
reaction with Grignard reagents giving rise to the C2-substituted
3-methylcyclohex-2-enone.15 Good overall yields are usually
obtained. However, the reaction sequence still remains lengthy
(five steps) and requires the synthesis of the starting diene by Birch
reaction of suitable substituted aromatic substrates. This multistep
protocol has been further optimized by Sutherland et al.12b,16
allowing the synthesis of various C2-substituted 3-methyl-
cylohex-2-enones in two steps with good overall chemical yields.
However, even though the number of steps has been reduced, the
reaction requires tedious preparation of sensitive diene reagents,
limiting the practicability of the reaction. As a consequence, the
development of a straightforward and mild general procedure to
access C2-substituted 3-methylcylohex-2-enones 1 in few steps
remains a challenge of crucial importance due to the versatility of
their chemistry.17 Recently, we described the formal total synthesis
of (þ/ꢀ)-triptolide by using a novel 6-endo-trig cationic cyclization
of 2-alkenyl-1,3-dithiolanes (Fig. 2).7 The synthesis of the key C2-
substituted 3-methylcylohex-2-enone cyclization precursor relied
on an efficient one-pot four-step domino reaction of a substituted
However, performing the aldol reaction in pure methanol with po-
tassium carbonate was less efficient (entry 3). As a consequence,
other bases, such as 1,5,7-triazabicyclo[4.4.0]dec-1-ene (TBD),18
L
-proline and diazabicycloundecene (DBU) were tested in DCM. It
was noticed that no reaction occurred when -proline or TBD were
used as base even under reflux conditions, and the starting
L
b-
ketoester 7 was recovered quantitatively (entries 4 and 5). We next
evaluated the reactivity of DBU, known to promote domino reactions
for the synthesis of 5-trifluoromethylated cyclohexenone in DCM.19
Interestingly, only under reflux conditions, these conditions
allowed the direct formation of 9 in 53% of yield, arising from a one-
pot four-step domino reaction via adduct 8 (entries 6 and 7).
This transformation consisted in the aldol reaction followed by
the in situ saponification of the methyl ester and decarboxylation of
the corresponding 1,3-ketoacid. Since the conversion of 7 was lim-
ited in dichloromethane, a more polar solvent with a higher boiling
point, such as acetonitrile was envisioned. The domino reaction was
thus performed at 80 ꢁC for 16 h in acetonitrile, however, 9 was
isolated in slightly decreased 50% yield (entry 8). It was eventually
found that an extended reaction time (16 h) at 80 ꢁC was responsible
for the partial degradation of the desired reaction product 9.
Therefore, the reaction time of the domino reaction was finally op-
timized at 80 ꢁC for 3 h with 1.1 equiv of DBU, allowing an efficient
access to 9 in 89% of isolated yield (entry 9). Attempts to reduce the
amount of DBU to 0.1 equiv in this reaction failed and only a limited
conversion of 7 resulted, most likely due to the formation of the
stable amidinium salt by abstraction of the most acidic proton of 7,
scavenging the base for further turnover of the catalyst.
b
-ketoester. Herein, we described the optimization of this protocol
and the result of our studies on the scope and application of this
domino process that affords efficiently C2-substituted 3-methyl-
cyclohex-2-enones 1.
2. Results and discussion
Finally, with the optimized conditions in hand for the prepara-
tion of the C2-substituted 3-methylcyclohex-2-enone 9, we next
Our strategy for the preparation of C2-substituted 3-methyl-
cyclohex-2-enones consisted in the regioselective intramolecular
aldol reaction of the substituted b-ketoester 7 leading to the elimi-
nation product 8, which would give the desired compound 9 after
a second decarboxylation step (Table 1). Firstly, the intramolecular
aldol reaction was studied with 7 as the model substrate, in order to
find suitable conditions for the preparation of 8. The substituted
applied this reaction to a large panel of functionalized
b-ketoesters
in order to study the scope and limitations of the domino process
(Table 2). Accordingly, substituted
thesized from the corresponding
b
b
-ketoesters 10e22 were syn-
-ketoesters by an improved
Michael addition with MVK (see Supplementary data). All the
substrates shown in Table 2 were reacted with 1.1 equiv of DBU in
acetonitrile at 80 ꢁC for 3 h. The majority of the domino reactions
proceeded well, affording the corresponding C2-substituted
3-methylcyclohex-2-enones 11e23, in good to excellent yields.
b-ketoester 7 of interest was synthesized from the corresponding
b-ketoester by a Michael addition onto methylvinylketone (MVK)
(see Supplementary data). The intramolecular aldol reaction of 7 was
first tried in dichloromethane as solvent in the presence of potas-
sium carbonate as base and at room temperature for 16 h. Un-
fortunately, in these conditions, the aldol reaction was inefficient and
7 was recovered unchanged (Table 1, entry 1). The addition of
methanol to better dissolve K2CO3 permitted the aldol reaction to
proceed and adduct 8 was formed in a reasonable yield of 58% (entry
2). This result might be ascribed to the in situ formation of potassium
methoxide and/or to the polarity increase of the reaction medium.
b-ketoester 10 and 12 bearing di- and trisubstituted arene behaved
similarly to 7 and gave the expected C2-substituted 3-methyl-
cyclohex-2-enones 11 and 13 with excellent yields of 85% and 90%,
respectively (entries 2 and 3). The reactivity of substrates function-
alized with unsaturated functions in their side chain was next ex-
amined. Substituted
b-ketoesters carrying terminal alkene 14,
disubstituted (E)-alkene 16 or cyclohexene moiety 18 reacted

7858
S. Goncalves et al. / Tetrahedron 66 (2010) 7856e7860
Table 2
and then to the dehydration product 25. In situ ester hydrolysis
followed by decarboxylation deliver the desired C2-substituted
3-methylcyclohex-2-enone 9.
One-pot four-step domino reaction of a panel of
b
-ketoesters
Product
Entry
Starting
b
-ketoester
Yield (%)
89
O
O
OH
1
MeO
Me
O
DBU
MeO
9
O
O
7
MeCN
Ph
Ph
MeO
HO
O
Ph
Ph
O
O
O
O
24
7
O
OH
2
3
85
90
MeO
-H2O
11
O
10
O
O
H2O
O
OMe
MeO
OMe
-MeOH
MeO
O
13
O
O
O
O
26
25
12
O
-CO2
4
78
9
MeO
O
15
O
Figure 3. Rational mechanism of the one-pot four-step domino reaction.
O
O
O
14
3. Conclusion
5
6
86
73
We have developed a new protocol for the straightforward
preparation of C2-substituted 3-methylcyclohex-2-enones, an im-
portant scaffold in organic chemistry. The reaction consists in
a one-pot four-step domino reaction using DBU in acetonitrile
under reflux conditions. Several C2-substituted 3-methylcyclohex-
2-enones were successfully synthesized with good to excellent
yields, ranging from 69% to 90%. The optimized conditions are
compatible with various functionalities on the side chain of the
MeO
O
17
O
16
O
MeO
19
O
O
O
18
O
starting substituted
protected alcohols.
b-ketoester, such as alkene, alkyne and TBDPS
7
8
84
69
MeO
21
O
O
O
4. Experimental section
4.1. General methods
20
O
OTBDPS
MeO
OTBDPS
O
23
All reagents were purchased from SigmaeAldrich, ABCR, Alfa-
O
O
22
Aesar and Acros and were used as received. NMR spectra were
recorded on a Brücker Advance 400 (300 MHz 1H NMR, 75 MHz 13
C
NMR) in CDCl3. Chemical shift values (d) are reported in parts per
satisfactorily under the optimal conditions of the domino reaction,
and permitted access to the expected C2-substituted 3-methyl-
cyclohex-2-enones 15, 17 and 19, in good yields ranging from 73% to
86% (entries 4, 5 and 6). Moreover, C2-substituted 3-methylcyclohex-
2-enone 21, having a terminal alkyne in the side chain, was efficiently
million (residual chloroform
d
¼7.26 ppm for 1H; residual chloro-
form
d
¼77.16 ppm for 13C). Infra-red spectra were recorded with
a Nicolet 380 FT-IR apparatus. High resolution mass spectra were
recorded with an Agilent Q-Tof 6520 apparatus equipped with
a
b
positive ESI source. Syntheses and analysis of starting
-ketoesters are reported in Supplementary data.
synthesized starting from substituted
isolated yield of 84% (entry 7). The reaction conditions also tolerated
functionalized -ketoester 22 bearing a primary tert-butyldiphe-
b-ketoester 20, with a good
b
nylsilyl (TBDPS) protected alcohol, yielding the corresponding
3-methylcyclohex-2-enone 23 in a good chemical isolated yield 69%
(entry 8). As a general trend, it is important to note that this one-pot
four-step domino reaction allows the introduction of a wide variety of
functionalities on the side chain of the C2-substituted 3-methyl-
cyclohex-2-enone, useful for further functionalizations, cyclizations,
or functional group transformations.
4.2. General procedure for the synthesis of substituted
ketoesters used in this study
b-
Potassium carbonate (4.00 mmol, 1.0 equiv) followed by a solu-
tion of methylvinylketone (MVK) (4.00 mmol, 1.0 equiv) in
dichloromethane (2 mL) was added to a solution of the starting
b-ketoester (4.00 mmol, 1.0 equiv) in dichloromethane (11 mL). The
The mechanism of this one-pot four-step domino reaction is sim-
ilar to the one described for the preparation of 5-trifluoromethylated
cyclohexenones.19 However, in contrary to precedent report this re-
action does not proceed if a catalytic amount of DBU is used. The first
step of the domino process consists in the regioselective intra-
molecular aldol reaction, leading to the addition product 24 (Fig. 3),
reaction mixture was stirred for 16 h. After quenching by addition
of water (25 mL), the aqueous phase was extracted by diethyl ether
(3ꢂ20 mL). The combined organic extracts were washed with
brine, dried over sodium sulfate and evaporated to dryness. The
residue was purified by flash chromatography on a silica gel column
(eluent: chloroform) to give the desired substituted b-ketoesters.

S. Goncalves et al. / Tetrahedron 66 (2010) 7856e7860
7859
4.2.1. Methyl-3-oxo-2-(3-oxobutyl)-6-phenylhexanoate (7). Obtained
as a colourless oil (981 mg, 74%). Rf (98/2 CHCl3/MeOH)¼0.61. IR
1242, 1160, 1110, 1078, 1066, 823, 743, 703, 314, 505 cmꢀ1. 1H NMR:
¼7.64 (m, 4H), 7.36 (m, 6H), 3.70 (s, 3H), 3.64 (t, J¼6.4 Hz, 2H), 3.50
(t, J¼6.8 Hz, 1H), 2.45 (m, 4H), 2.04 (m, 5H), 1.64 (m, 2H), 1.51 (m,
2H), 1.05 (s, 9H) ppm. 13C NMR:
129.7, 127.8, 63.6, 57.3, 52.5, 41.9, 40.6, 31.9, 30.0, 27.0, 21.9, 20.1,
19.3 ppm. HRMS (ESI, m/z): calcd for C28H38O5Si [MþH]þ: 483.2567,
found: 483.2562.
d
(neat):
NMR:
n
¼2950, 1742, 1711, 1497, 1367, 1201, 1159, 748, 701 cmꢀ1. 1H
d
¼7.14 (m, 6H), 3.70 (s, 3H), 3.48 (t, J¼7.2 Hz,1H), 2.44 (m, 6H),
d
¼207.5, 204.9, 170.1, 135.6, 134.0,
2.02 (m, 5H), 1.84 (quint., J¼7.4 Hz, 2H) ppm. 13C NMR:
d¼207.6,
204.8, 170.1, 141.5, 128.6, 128.5, 126.1, 57.3, 52.5, 41.3, 40.6, 34.9, 30.0,
24.9, 21.9 ppm. HRMS (ESI, m/z): calcd for C17H22O4 [MþH]þ:
291.1596, found: 291.1591.
4.3. General procedure for the synthesis of C2-substituted
3-methylcyclohex-2-enones
4.2.2. Methyl 2-[3-(3-methylphenyl)propanoyl]-5-oxohexanoate (10).
Obtained as a yellow oil (3.48 g, 90%). Rf (95/5 CHCl3/MeOH)¼0.87. IR
(neat):
NMR:
n
¼2952, 1743, 1712, 1489,1435,1360, 1205, 1161, 782 cmꢀ1. 1H
DBU (0.243 mmol, 1.1 equiv) was added to a solution of
substituted the b-ketoester (0.221 mmol, 1.0 equiv) in acetonitrile
d
¼7.14 (t, J¼7.6 Hz, 1H), 6.96 (m, 3H), 3.67 (s, 3H), 3.49 (t,
J¼6.8 Hz, 1H), 2.78 (m, 4H), 2.39 (t, J¼6.8 Hz, 2H), 2.32 (s, 3H), 2.09 (s,
(5 mL, extra dry, water<10 ppm, AcroSealÒ) and the reaction
mixture was stirred under reflux for 3 h until completion. After
cooling the reaction media to room temperature and addition of
water (20 mL), the aqueous phase was extracted with diethyl ether
(3ꢂ10 mL). The combined organic extracts were dried over sodium
sulfate and evaporated in vacuo. The residue was purified by flash
chromatography on a silica gel column to give the desired
C2-susbtituted 3-methylcyclohex-2-enone.
3H), 2.03 (m, 2H) ppm. 13C NMR:
d¼207.5, 204.2, 169.9, 140.6, 138.1,
129.2, 128.5, 127.0, 125.4, 57.5, 52.5, 43.6, 40.4, 30.0, 29.5, 21.8,
21.4 ppm. HRMS (ESI, m/z): calcd for C17H22O4 [MþH]þ: 291.1596,
found: 291.1600.
4.2.3. Methyl 6-(3-isopropyl-2-methoxyphenyl)-3-oxo-2-(3oxo-bu-
tyl) hexanoate (12). Obtained as a yellow oil (1.42 g, 96%). Rf (95/5
CHCl3/MeOH)¼0.55. Data analysis of compound 12 can be found in
Ref. 7.
4.3.1. 3-Methyl-2-(2-phenylethyl)cyclohex-2-enone (9). Obtained from
7 (73 mg, 0.25 mmol) as a yellow oil (48 mg, 89%). Rf (70/30 cyclo-
4.2.4. Methyl-3-oxo-2-(3-oxobutyl)oct-7-enoate (14). Obtained as
a yellow oil (1.31 g, 66%). Rf (95/5 CHCl3/MeOH)¼0.76. IR (neat):
hexane/EtOAc)¼0.61. IR (neat):
1180,1138, 1033, 754, 702 cmꢀ1.1H NMR:
2.37 (t, J¼6.0 Hz, 2H), 2.28 (t, J¼6.0 Hz, 2H), 1.89 (quint., J¼6.0 Hz, 2H),
1.74 (s, 3H) ppm. 13C NMR:
n
¼2930, 1664, 1628, 1496, 1454, 1380,
d
¼7.15 (m, 5H), 2.55 (m, 4H),
n
¼2952, 1743, 1712, 1641, 1436, 1367, 1206, 1159, 998, 914 cmꢀ1. 1H
NMR:
d
¼5.69 (m, 1H), 4.95 (m, 2H), 3.70 (s, 3H), 3.50 (t, J¼7.2 Hz,
d
¼198.8, 156.2, 142.4, 134.8, 128.8, 128.3,
1H), 2.44 (m, 4H), 2.11 (s, 3H), 2.03 (m, 4H), 1.63 (quint., J¼7.2 Hz,
125.9, 38.1, 35.2, 32.9, 27.7, 22.4, 21.2 ppm. HRMS (ESI, m/z): calcd for
2H) ppm. 13C NMR:
d
¼207.5, 204.9, 170.1, 137.8, 115.4, 57.3, 52.5,
C15H18O [MþH]þ: 215.1436, found: 215.1432.
41.2, 40.6, 32.9, 30.0, 22.5, 21.9 ppm. HRMS (ESI, m/z): calcd for
C13H20O4 [MþH]þ: 258.1705, found: 258.1708.
4.3.2. 3-Methyl-2-(3-methylbenzyl)cyclohex-2-enone (11). Obtained
from 10 (3.44 g, 11.85 mmol) as a yellow oil (2.15 g, 85%). Rf (80/20
4.2.5. Methyl
Obtained as a yellow oil (2.18 g, 65%). Rf (95/5 CHCl3/MeOH)¼0.79.
IR (neat):
¼2955, 2929, 1744, 1713, 1435, 1409, 1367, 1204, 1159,
1066, 720 cmꢀ1. 1H NMR:
(7E)-3-oxo-2-(3-oxobutyl)dodec-7-enoate
(16).
cyclohexane/EtOAc)¼0.59. IR (neat):
n
¼2921, 2866, 1659, 1625, 1605,
1429, 1377, 1181, 1136, 958, 749, 693 cmꢀ1
.
1H NMR:
d
¼7.10 (t,
n
J¼7.6 Hz,1H), 6.93 (m, 3H), 3.65 (s, 2H), 2.42 (t, J¼5.6 Hz, 2H), 2.38 (t,
d
¼5.35 (m, 1H), 5.24 (m, 1H), 3.70 (s, 3H),
J¼6.0 Hz, 2H), 2.30 (s, 3H), 1.97 (s, 3H), 1.94 (m, 2H) ppm. 13C NMR:
3.50 (t, J¼7.2 Hz, 1H), 2.46 (m, 4H), 2.11 (s, 3H), 1.98 (m, 6H), 1.58
d
¼198.6, 157.0, 140.6, 137.8, 134.9, 129.2, 128.2, 126.5, 125.3, 37.9, 33.1,
(quint., J¼7.2 Hz, 2H), 1.28 (m, 4H), 0.86 (m, 3H) ppm. 13C NMR:
30.6, 22.3, 21.9, 21.5 ppm. HRMS (ESI, m/z): calcd for C15H18
O
d
¼207.5, 205.1, 170.1, 131.2, 128.5, 57.3, 52.5, 41.5, 40.6, 31.9, 30.0,
[MþH]þ, 215.1436, found: 215.1439.
27.1, 26.5, 23.5, 22.4, 21.9, 14.0 ppm. HRMS (ESI, m/z): calcd for
C17H28O4 [MþH]þ: 297.2066, found: 297.2062.
4.3.3. 2-[2-(3-Isopropyl-2-methoxyphenyl)ethyl]-3-methylcyclohex-
2-enone (13). Obtained from 12 (1.42 g, 3.92 mmol) as a yellow oil
(1.02 g, 90%). Rf (80/20 cyclohexane/EtOAc)¼0.59. Data analysis of
compound 13 can be found in Ref. 7.
4.2.6. Methyl 6-cyclohex-1-en-1-yl-3-oxo-2-(3-oxobutyl)hexanoate
(18). Obtained as a yellow oil (2.15 g, 85%). Rf (95/5 CHCl3/MeOH)¼
0.83. IR (neat):
n
¼2926, 2836, 1743, 1713, 1436, 1366, 1204, 1159,
1108, 1008, 918 cmꢀ1. 1H NMR:
J¼7.2 Hz, 1H), 2.40 (m, 4H), 2.12 (s, 3H), 2.04 (m, 2H), 1.87 (m, 7H),
1.49 (m, 7H) ppm. 13C NMR:
d
¼5.35 (m, 1H), 3.71 (s, 3H), 3.50 (t,
4.3.4. 2-But-3-enyl-3-methylcyclohex-2-enone (15). Obtained from
14 (1.28 g, 5.34 mmol) as a yellow oil (685 mg, 78%). Rf (70/30 cy-
clohexane/EtOAc)¼0.64. Data analysis of compound 15 can be
found in Ref. 4a.
d¼207.5, 205.1, 170.1, 136.8, 121.9, 57.4,
52.4, 41.5, 40.6, 37.4, 30.0, 28.1, 25.3, 23.0, 22.6, 21.9, 21.4 ppm.
HRMS (ESI, m/z): calcd for C17H26O4 [MþH]þ: 295.1909, found:
295.1912.
4.3.5. 3-Methyl-2-[(3E)-oct-3-en-1-yl]cyclohex-2-enone(17). Obtained
from 16 (2.15 g, 7.25 mmol) as a colourless oil (1.37 g, 86%). Rf (80/20
4.2.7. Methyl-3-oxo-2-(3-oxobutyl)oct-7-ynoate (20). Obtained as
a colourless oil (736 mg, 86%). Rf (95/5 CHCl3/MeOH)¼0.82. IR
cyclohexane/EtOAc)¼0.66. IR (neat):
1430, 1378, 1325, 1179, 1138, 1118, 1051, 725 cmꢀ1. 1H NMR:
2H), 2.30 (m, 6H), 1.96 (m, 4H), 1.88 (m, 5H), 1.27 (m, 4H), 0.86 (m,
3H) ppm. 13C NMR:
n
¼2926, 2860, 1662, 1628, 1455,
d
¼5.30 (m,
(neat):
n
¼3281, 2954, 1741, 1710, 1435, 1369, 1207, 1161, 1108,
649 cmꢀ1. 1H NMR:
d
¼3.71 (s, 3H), 3.52 (t, J¼7.2 Hz, 1H), 2.59 (m,
d
¼198.8, 155.4, 135.4, 130.4, 129.2, 38.0, 33.0, 32.1,
2H), 2.46 (t, J¼7.2 Hz, 2H), 2.19 (m, 2H), 2.11 (s, 3H), 2.05 (m, 2H),
27.0, 26.8, 25.4, 22.5, 22.4, 21.4, 14.1 ppm. HRMS (ESI, m/z): calcd for
1.94 (t, J¼2.8 Hz, 1H), 1.75 (quint., J¼7.2 Hz, 2H) ppm. 13C NMR:
C15H24O [MþH]þ: 221.1905, found: 221.1902.
d
¼207.5, 204.5, 170.0, 83.4, 69.3, 57.4, 52.5, 40.5, 40.4, 30.0, 22.0,
21.9, 17.6 ppm. HRMS (ESI, m/z): calcd for C13H18O4 [MþH]þ:
4.3.6. 2-(2-Cyclohex-1-enylethyl)-3-methylcyclohex-2-enone
(19). Obtained from 18 (2.07 g, 7.04 mmol) as a yellow liquid
(1.12 g, 73%). Rf (80/20 cyclohexane/EtOAc)¼0.68. IR (neat):
239.1283, found: 239.1280.
4.2.8. Methyl 7-{[tert-butyl(diphenyl)silyl]oxy}-3-oxo-2-(3-oxobutyl)
heptanoate (22). Obtained as a yellow oil (2.36 g, 85%). Rf (95/5
n
¼2926, 2836, 1743, 1713, 1436, 1366, 1204, 1159, 1108, 1008,
918 cmꢀ1. 1H NMR:
d
¼5.35 (m, 1H), 2.29 (m, 6H), 1.80 (m, 12H), 1.55
¼198.7, 155.1, 137.8, 135.6,
CHCl3/MeOH)¼0.57. IR (neat):
n
¼2958, 2901, 1745, 1716, 1428, 1393,
(m, 2H), 1.50 (m, 2H) ppm. 13C NMR:
d

7860
S. Goncalves et al. / Tetrahedron 66 (2010) 7856e7860
Zhang, C.-L.; Peng, X.-J.; Chen, B.; Yang, Y.; Pan, X.-F. Gaodeng Xuexiao Huaxue
Xuebao 2003, 24, 1219e1221; (d) Hauser, F. M.; Caringal, Y. J. Org. Chem. 1990,
55, 555e559.
121.0, 38.0, 37.2, 32.9, 28.4, 25.3, 23.9, 23.1, 22.6, 22.4, 21.2 ppm.
HRMS (ESI, m/z): calcd for C15H22O [MþK]þ: 257.1308, found:
257.1304.
2. (a) Liu, Y.; Wang, L.; Jung, J. H.; Zhang, S. Nat. Prod. Rep. 2007, 24, 1401e1429; (b)
Ghershenzon, J.; Dudareva, N. Nat. Chem. Biol. 2007, 3, 408e414; (c) Salminen,
A.; Lehtonen, M.; Suuronen, T.; Kaarniranta, K.; Huuskonen, J. Cell. Mol. Life Sci.
2008, 65, 2979e2999; (d) Garcia, P. A.; Braga de Oliveira, A.; Batista, R. Mole-
cules 2006, 11, 1e33; (e) Zubia, E.; Ortega, M. J.; Carballo, J. L. J. Nat. Prod. 2008,
71, 2004e2010; (f) Sunazuka, T.; Omura, S. Chem. Rev. 2005, 105, 4559e4580.
3. (a) Marson, C. M. Tetrahedron 2000, 56, 8779e8794; (b) Amupitan, J. A.; Huq, E.;
Mellor, M.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1983,
751e753; (c) Huq, E.; Mellor, M.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc.,
Chem. Commun. 1978, 526e528; (d) Mellor, M.; Santos, A.; Scovell, E. G.;
Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 528e529; (e) Scovell, E. G.;
Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 529e530; (f) Amupitan, J.
A.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 11983, 755e757; (g)
Amupitan, J. A.; Beddoes, R. L.; Mills, O. S.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1983, 759e763.
4.3.7. 2-But-3-ynyl-3-methylcyclohex-2-enone (21). Obtained from
20 (706 mg, 2.96 mmol) as a colourless oil (403 mg, 84%). Rf (80/20
cyclohexane/EtOAc)¼0.39. IR (neat):
n
¼2939, 1656, 1627, 1430,
1380, 1327, 1181, 1138, 1122, 1048, 633 cmꢀ1
.
1H NMR:
d
¼2.51
(t, J¼7.2 Hz, 1H), 2.33 (m, 4H), 2.22 (td, J¼2.8 , 7.2 Hz, 2H), 1.99 (s,
3H), 1.90 (m, 2H), 1.88 (t, J¼2.8 Hz, 1H) ppm. 13C NMR:
¼198.6,
d
157.2, 133.9, 84.4, 68.4, 37.8, 33.0, 24.5, 22.3, 21.7, 18.0 ppm. HRMS
(ESI, m/z): calcd for C11H14O [MþH]þ: 163.1123, found: 163.1121.
4.3.8. 2-(3-{[tert-Butyl(diphenyl)silyl]oxy}propyl)-3-methyl-
cyclohex-2-enone (23). Obtained from 22 (2.33 g, 4.83 mmol) as
a yellow oil (1.36 g, 69%). Rf (80/20 cyclohexane/EtOAc)¼0.65. IR
4. (a) Brunke, E.-J.; Hammerschmidt, F.-J.; Struwe, H. Tetrahedron 1981, 37,
€
1033e1038;(b)Vial, C.;Thommen,W.;Naf,F. Helv. Chem. Acta1989, 72,1390e1399.
5. Cooper, J. L.; Harding, K. E. Tetrahedron Lett. 1977, 38, 3321e3324.
6. (a) Ghosh, A. K.; Ghosh, K.; Pal, S.; Chatak, U. R. J. Chem. Soc., Chem. Commun.
1993, 809e811; (b) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Org. Chem.
1994, 59, 2687e2694; (c) Ghosh, A. K.; Mukhopadhyaya, J. K.; Ghatak, U. R.
J. Chem. Soc., Perkin Trans. 1 1997, 2747e2755.
7. Goncalves, S.; Hellier, P.; Nicolas, M.; Wagner, A.; Baati, R. Chem. Commun. 2010,
46, 5778e5780.
8. Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Org. Lett. 2003, 5,
3931e3933.
(neat):
505 cmꢀ1. 1H NMR:
2H), 2.29 (m, 6H), 1.87 (m, 5H), 1.54 (m, 2H), 1.06 (s, 9H) ppm. 13C
NMR:
n
¼2931, 2858,1664,1428,1380,1110,1088, 823, 742, 702, 613,
d
¼7.66 (m, 4H), 7.35 (m, 6H), 3.64 (t, J¼6.4 Hz,
d
¼198.7, 155.3, 135.5, 135.4, 134.1, 129.5, 127.6, 63.8, 37.8, 32.8,
32.0, 26.9, 22.3, 21.6, 21.1, 19.2 ppm. HRMS (ESI, m/z): calcd for
C26H34O2Si [MþH]þ: 407.2406, found: 407.2402.
9. Sengupta, S.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Tetrahedron Lett.
2005, 46, 1515e1519.
Acknowledgements
10. Deb, S.; Bhattacharjee, G.; Ghatak, U. R. J. Chem. Soc., PerkinTrans.11990,1453e1458.
11. (a) Smith, L. I.; Rouault, G. F. J. Am. Chem. Soc. 1943, 65, 631e635; (b) Marshall, J.
A.; Cohen, N.; Hochstetler, A. R. J. Am. Chem. Soc. 1966, 88, 3408e3417; (c)
Johnson, W. S.; Neustaedter, P. J.; Schmiegel, K. K. J. Am. Chem. Soc. 1965, 87,
5148e5157; (d) Ladika, M.; Sunko, D. E. J. Org. Chem. 1985, 50, 4544e4548.
12. (a) Nasipuri, D.; Sarkar, G.; Guha, M.; Roy, R. Tetrahedron Lett. 1966, 9, 927e930;
(b) Amupitan, J. A.; Huq, E.; Mellor, M.; Scovell, E. G.; Sutherland, J. K. J. Chem.
Soc., Perkin Trans. 1 1983, 747e749.
We acknowledge the Laboratoire Pierre Fabre (Plantes et
Industries) and the CNRS for financial support to S.G.
Supplementary data
13. (a) Garro Galvez, J. M.; Angers, P.; Canonne, P. Tetrahedron Lett. 1994, 35,
2849e2852; (b) Sono, M.; Onishi, S.; Tori, M. Tetrahedron 2003, 59, 3385e3395.
14. Piers, E.; Grierson, J. R. J. Org. Chem. 1977, 42, 3755e3757.
15. Gannon, W. F.; House, H. O. Org. Synth. 1960, 40, 41e42.
Supplementary data associated with this article can be found
in online version at, doi:10.1016/j.tet.2010.07.029. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
16. Amupitan, J.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 852e853.
€
17. Vlattas, I. T.; Harrison, I. T.; Tokés, L.; Fried, J. H.; Cross, I. T. J. Org. Chem. 1968, 50,
4544e4548.
References and notes
18. (a) Ghobril, C.; Sabot, C.; Mioskowski, C.; Baati, R. Eur. J. Org. Chem. 2008, 24,
4104e4108; (b) Hammar, P.; Ghobril, C.; Antheaume, C.; Wagner, A.; Baati, R.;
Himo, F. J. Org. Chem. 2010, 75, 4728e4736.
1. (a) Storck, G.; Burgstahler, A. J. Am. Chem. Soc. 1951, 73, 3544e3546; (b) Saha, N.
N.; Bagchi, P. N.; Dutta, P. C. J. Am. Chem. Soc. 1955, 77, 3408e3409; (c) Bie, P.-Y.;
19. Christophe, C.; Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2005, 3745e3748.