Synthesis of (1-Allylcyclohexa-2,5-dienyl)arenes

Article abstract of DOI:10.1055/s-0029-1218604

(1-Allylcyclohexa-2,5-dienyl)arenes are useful building blocks for the synthesis of natural products including amaryllidaceae, strychnos and morphinan alkaloids. Their synthesis was carried out in a straightforward manner starting from readily available c

Full text of DOI:10.1055/s-0029-1218604

PRACTICAL SYNTHETIC PROCEDURES
1223
Synthesis of (1-Allylcyclohexa-2,5-dienyl)arenes
S
ynthesis of (1-A
l
é
lylcyclohex
r
a-2,5-die
a
nyl)arenesldine Rousseau, Frédéric Robert, Yannick Landais*
Université de Bordeaux, UMR-CNRS 5255, 351, cours de la libération, 33405 Talence Cedex, France
Fax +33(5)40006286; E-mail: y.landais@ism.u-bordeaux1.fr
Received 20 October 2009; revised 27 October 2009
PSP
No181
Abstract: (1-Allylcyclohexa-2,5-dienyl)arenes are useful building blocks for the synthesis of natural products including amaryllidaceae,
strychnos and morphinan alkaloids. Their synthesis was carried out in a straightforward manner starting from readily available cyclohexane-
1,3-dione, through a palladium-mediated arylation–allylation sequence, which was used to install the quaternary center, followed by a trans-
formation of the resulting 1,3-dione into the required diene through generation of a bis-silyl enol ether. After conversion of the latter into
the corresponding bis-enol triflate, it was finally hydrogenated using palladium catalysis to give the title compounds.
Key words: palladium, allylation, arylation, enols, arenes, cyclohexadienes
Procedure 1
1. Pd(OAc)2, ArPR2
K3PO4, ArBr
1. LDA, TMSCl
O
O
O
O
2. CsF, PhN(Tf)2
3. Pd(OAc)2, PPh3
HCO2H, i-Pr2NEt
2. Pd/C, AllylOAc
PPh3
83% (2 steps)
75% (3 steps)
Scheme 1
In the course of our studies on desymmetrization process- methods are available for the synthesis of 2-aryl-1,3-cy-
es, we have developed several methodologies based on clohexadienones. Amongst those that were reported, pho-
symmetry-breaking of cyclohexa-1,4-dienes using vari- tolysis of cyclic 2-diazo-1,3-diketones in aromatic
ous asymmetric approaches.1 The diene precursors II solvents provided low yield of the desired dione.5 Aro-
were generally accessible using Birch reduction of simple matic nucleophilic substitution has been described by
arenes I (Scheme 2).2 More recently, we have developed Bonjoch et al., but this approach is restricted to activated
a new strategy called Birch reductive alkylation desym- arenes such as nitrobenzenes.6 Radical substitution also
metrization (BRAD), in which arylcyclohexadienes such allows access to 2-aryl-1,3-diketones, but the scope is also
as III could be used as simple precursors en route to the rather limited.7 Finally, hypervalent iodine-mediated
synthesis of alkaloids belonging to the Amaryllidaceae, arene-substitution by 1,3-diketones, developed by Kita et
Strychnos and also Morphinan families.3 Such cyclohexa- al. led to the desired product, but with somewhat modest
dienes possess a useful quaternary center flanked by an efficiency.8 A more general route to these symmetrical di-
aryl group and an ethylamino chain, which is found in ones was envisioned that exploited the strategy devised
most of the alkaloids mentioned above.4
Whereas Birch reductive alkylation provides a rapid route
R1
R1
to substituted cyclohexadienes II, lithium reduction of
arenes to access unsubstituted cyclohexadienes III is not
so convenient. We thus wanted to develop a short, general
and alternative methodology to access to arylcyclohexa-
dienes of type III, which would complement the Birch re-
ductive alkylation reported previously. It was envisioned
that III could be assembled instead, through arylation of
cyclohexane-1,3-dione (1) followed by C-allylation, start-
ing from readily available starting materials (Scheme 2).
The 1,3-diketone function of IV would then be converted
into the 1,4-diene moiety of III through a straightforward
three-step sequence involving enol-type chemistry. Few
R2
Li, NH3
R2X
MeO
OMe
MeO
OMe
I
II
R1
R1
NR3
2
O
O
O
O
1. R1PhX, Pd0
2. AllylOAc, Pd0
III
IV
1
Scheme 2 General accesses to 1-substituted (cyclohexa-2,5-di-
enyl)arenes
SYNTHESIS 2010, No. 7, pp 1223–1228
Advanced online publication: 11.12.2009
x
x
.
x
x
.2
0
1
0
DOI: 10.1055/s-0029-1218604; Art ID: Z22409SS
© Georg Thieme Verlag Stuttgart · New York

1224
G. Rousseau et al.
PRACTICAL SYNTHETIC PROCEDURES
concomitantly by Hartwig9 and Buchwald,10 based on pal- nylphosphine in toluene (Scheme 3).15 The choice of the
ladium-mediated arylation of ketones. Such arylations of solvent proved crucial because O- and C-alkylation prod-
1,3-cyclohexadienone were therefore investigated using ucts were obtained in a 2:1 mixture of water and 1,2-
Pd(OAc)2 as a catalyst and an electron-rich phosphine as dimethoxyethane (DME). Overall yields over the two
a ligand.11 This approach was previously tested with sim- steps are summarized in Table 1.
ple alkyl arenes and has not yet been extended to more
electron-rich arenes possessing methoxy or methylene-
Allylated products 2a–e were then converted into the cor-
responding 1,4-dienes. A two-step sequence was envi-
dioxy groups, which are ubiquitous aryl substituents in
sioned that involved the transformation of the dione into a
natural products.4 Our preliminary studies showed that
bis-vinyl triflate, using a method developed by Willis,16
Buchwald–Hartwig conditions efficiently provided the re-
followed by conversion into the expected 1,4-diene
quired 2-aryl-1,3-cyclohexadiones 2a–e (Scheme 3). The
through palladium-mediated hydrogenation.
alternative Ullmann-type procedure,12 which uses less
costly CuI and L-proline, also afforded the expected aryl-
cyclohexadienones but led to contrasting result depending
on the nature of the starting arene (see below). The gener-
ality of the approach was illustrated with a range of sub-
stituted arenes (Table 1). However, all our efforts to apply
this procedure to arenes having an ortho substituent unfor-
tunately failed, probably for steric reasons. We also no-
Table 1 Arylation–Allylation of Cyclohexane-1,3-dione (1)
Entry
R1
H
R2
R3
H
Product Yield (%)a
1
2
3
4
5
6
7
H
2a
2b
2c
2d
2e
2a
2c
83
96
71
82
81
80b
67b
Me
H
H
Me
H
OMe
OMe
OCH2O
H
1
ticed that whereas crude yields, estimated through H
OMe
H
H
NMR, were generally high, loss of material occurred upon
purification of these intermediates by silica gel chroma-
tography. Therefore, because the easily enolizable crude
diketones13 were sufficiently pure, they were finally used
directly in the subsequent allylation step without further
purification. Several conditions were thus tested to intro-
H
H
H
H
OMe
duce the allyl group a to both carbonyl groups. Allylation a Isolated overall yield over two steps.
b The arylation step was carried out using CuI (5 mol%), L-proline (10
mol%), ArI, K2CO3, DMSO, 90 °C, 48 h.
of the 2-aryl-1,3-dione under Fuji’s conditions14 (DBU,
THF, allylX) led to a mixture of O- and C-alkylation de-
pending on the nature of the additive salt (LiBr, NaBr or
KI), the solvent (THF, MeCN or toluene) and the electro-
phile. We observed little regioselectivity in tetrahydrofu-
ran or acetonitrile, either in the presence or absence of
added salts. In contrast, higher selectivities were obtained
in apolar solvents such as toluene. Overall, the base-cata-
lyzed allylation was not found to be suitable for our pur-
pose because it led to mixtures that required lengthy
purifications.
In contrast to related examples from the literature, the for-
mation of the bis-vinyl triflate through the formation of
the corresponding bis-lithium or potassium enolate and
reaction with Comins reagent17 [3-Cl-PyrN(Tf)2] proved
difficult. For instance, the reaction of 2a with potassium
hexamethyldisilazide (KHMDS) in a N,N,N¢,N¢-tetra-
methylethylenediamine–tetrahydrofuran (TMEDA–THF)
mixture at –78 °C, followed by addition of the bis-triflic
amide reagent, led to the monotriflate 4 in low yield
(13%), along with the expected bis-triflate 3a (26%) and
considerable amounts (42%) of starting material
(Scheme 4). Similarly, treatment of 4 under the same con-
ditions led to 3a in only 21% yield.
R2
R3
R1
1. Pd(OAc)2, K3PO4, L
O
O
ArBr, THF, 80 °C, 12–24h
O
O
2. Pd/C, PPh3, AllylOAc
toluene, 70 °C, 12 h
1
P(t-Bu)2
2a–e
TfO
OTf
L:
KHMDS (2 equiv)
TMEDA, THF
–78 °C to r.t., 1 h
KHMDS, THF
–78 °C, 12 h
Scheme 3 Arylation–allylation of cyclohexa-1,3-dienone (1)
3a (26%)
O
O
then r.t., 3 h
Cl
Cl
More satisfying results were observed using palladium-
catalyzed allylation. Various palladium catalysts were
tested with 2-phenyl-1,3-diketone in the presence of allyl
acetate. Whereas [Pd(allyl)Cl2]2 and dppe ligand led to al-
lylated product 2a in only 17% yield, more satisfying
yields of the C-alkylation products were obtained under
heterogeneous conditions, for example, Pd/C and triphe-
N
N(Tf)2
N
N(Tf)2
2a
O
OTf
(21%)
4 (13%)
Scheme 4 Attempted synthesis of bis-enol triflate 3a from 2a
Synthesis 2010, No. 7, 1223–1228 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (1-Allylcyclohexa-2,5-dienyl)arenes
1225
A more satisfying answer to this problem was found, by oxidation (OsO4, NaIO4).20 Such aldehydes can then be
preparing the bis-enol triflates from the corresponding si- converted through reductive amination into chiral amines
lyl enol ethers.18 Accordingly, when diketones 2a–e were that can be used in a diastereoselective protonation–
treated with two equivalents of lithium diisopropylamide hydroamination tandem process, which is a key step in the
(LDA), and the resulting lithium enolate was quenched synthesis of crinine-type alkaloids.3a
with trimethylsilyl chloride (TMSCl), the desired bis-silyl
enol ethers were obtained in high yield (Scheme 5). These
All reactions were carried out in dry glassware under a nitrogen at-
moisture-sensitive intermediates were then directly con-
verted, without further purification, into the expected bis-
vinyltriflates 3a–e using PhN(Tf)2 in the presence of
CsF.18 Palladium-catalyzed conversion of the triflate into
the corresponding olefin19 was finally carried out using
formic acid as a hydrogen source, which led to formation
of the desired trienes 5a–e in good to excellent overall
yields over the three steps (Table 2).
mosphere with anhydrous solvents under anhydrous conditions.
Yields refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous materials, unless otherwise stated. Com-
mercial reagents were used without further purification, unless oth-
erwise stated. THF was distilled from sodium and benzophenone.
CH2Cl2, DME and DMF were distilled from CaH2. Toluene was dis-
tilled from sodium. Petroleum ether (PE) had a boiling range 40–
60 °C. Phosphate buffer (pH 7) was prepared by mixing KH2PO4
(34 g, 0.25 mol) and NaOH (5.8 g, 0.15 mol) in H2O (500 mL).
1H NMR and 13C NMR were recorded on Brüker AC-250 FT (1H:
250 MHz, 13C: 62.5 MHz) and Brüker Avance-300 FT (1H: 300
MHz, 13C: 75.4 MHz) NMR spectrometers. Mass spectra were re-
corded on a Nermag R10-10C. High-resolution mass spectra were
recorded on a Brüker 4.7T BioApex II FT-ICR mass spectrometer.
Melting points were determined by using a Stuart Scientific appara-
tus (SMP3) and are not corrected.
R2
R3
R2
R3
R1
R1
1. LDA, TMSCl
THF, –40 °C, 5 min
O
O
TfO
OTf
2. CsF, PhN(Tf)2
DME, r.t., 12 h
Pd-Catalyzed Arylation–Allylation of Cyclohexane-1,3-dione
(1); General Procedure
2a–e
3a–e
R2
R3
Preparation of 2-Allyl-2-arylcyclohexane-1,3-diones 2a–e
Into a dry flask equipped with a screw-cap (or a three-necked round-
bottom flask for larger quantities), was placed Pd(OAc)2 (2–5
mol%), 2-di-tert-butylphosphino-2¢-methylbiphenyl (4–11 mol%),
cyclohexane-1,3-dione (1; 1.2 equiv), and K3PO4 (2.3 equiv) under
an N2 atmosphere. The flask was flushed several times with N2 then
THF (0.3 M) and aryl bromide (1 equiv) were added. The reaction
mixture was stirred at 80 °C until TLC indicated complete con-
sumption of the starting material. MeOH (5 mL/mmol) was added
and the reaction mixture was stirred for 15 min, filtered and concen-
trated in vacuo. The crude mixture was used without further purifi-
cation in the next step.
Pd(OAc)2, Ph3P
i-PrNEt2, HCO2H
DMF, 60 °C, 1 h
R1
5a–e
Scheme 5 Three-step access to (1-allylcyclohexa-2,5-dienyl)arenes
5a–e from 2-allyl-2-arylcyclohexa-1,3-diones 2a–e
Table 2 Three-Step Access to (1-Allylcyclohexa-2,5-dienyl)arenes
5a–e from 2-Allyl-2-arylcyclohexa-1,3-diones 2a–e
Pd/C (5 mol%), Ph3P (20 mol%) followed by allyl acetate (1 equiv)
were added to a suspension of the preceding crude diketone in tolu-
ene (0.1 M, 1 equiv). The reaction mixture was stirred at 70 °C
overnight, then filtered and concentrated in vacuo. Purification by
flash chromatography (silica gel; PE–EtOAc) yielded the desired
diketones.
Entry Dione
R1
H
R2
R3
H
Diene Yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
H
5a
5b
5c
5d
5e
75
70
87
34
75
Me
H
H
Me
H
OMe
OMe
OCH2O
2-Allyl-2-(3,5-dimethylphenyl)cyclohexane-1,3-dione (2b)
Synthesized according to the general procedure described above
from cyclohexane-1,3-dione (1; 246 mg, 2.2 mmol, 1.1 equiv),
Pd(OAc)2 (18 mg, 0.08 mmol, 4 mol%), 2-di-tert-butylphosphino-
2¢-methylbiphenyl (48 mg, 0.16 mmol, 8 mol%), K3PO4 (976 mg,
4.6 mmol, 2.3 equiv) and 1-bromo-3,5-dimethylbenzene (0.28 mL,
2 mmol, 1 equiv) in THF (6 mL) for the first step. Pd/C 10% (106
mg, 0.1 mmol, 5 mol%), Ph3P (105 mg, 0.4 mmol, 20 mol%), and
allyl acetate (0.24 mL, 2 mmol, 1 equiv) in toluene (14 mL) were
used for the second step. Purification by flash chromatography
(silica gel; PE–EtOAc, 9:1) afforded diketone 2b.
OMe
H
H
a Isolated overall yield over three steps.
In summary, dienes 5a–e were prepared in five steps from
readily available cyclohexane-1,3-dione (1) in good over-
all yield (Scheme 1). The whole sequence requires a sin-
gle purification (chromatography over silica gel) of one of
the intermediates (diketones 2a–e) and is based on simple
and reproducible steps that can be easily extended to
gram-scale syntheses. It is also worth noting that three of
the steps rely on catalytic processes. These dienes are
valuable intermediates for organic synthesis; for instance,
they can be further elaborated through transformation of
the allyl group into an aldehyde using Lemieux–Johnson
Yield: 494 mg (96%); pale-yellow oil.
IR (neat, NaCl): 2919, 1728, 1696, 1597, 1048 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.91 (s, 1 H), 6.61 (s, 2 H), 5.71–
5.55 (m, 1 H), 5.01–4.91 (m, 2 H), 2.81–2.46 (m, 6 H), 2.27 (s,
6 H), 1.95–1.84 (m, 1 H), 1.77–1.63 (m, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 207.4, 139.0, 137.4, 134.5,
129.5, 124.2, 118.1, 75.4, 39.34, 39.29, 21.4, 17.3.
Synthesis 2010, No. 7, 1223–1228 © Thieme Stuttgart · New York

1226
G. Rousseau et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (EI): m/z [M]+ calcd for C17H20O2: 256.14633; found:
256.1469.
1H NMR (300 MHz, CDCl3): d = 6.72 (d, J = 8.3 Hz, 1 H), 6.50–
6.40 (m, 2 H), 5.93 (s, 2 H), 5.67–5.53 (m, 1 H), 4.95–4.86 (m,
2 H), 2.77–2.43 (m, 6 H), 1.92–1.81 (m, 1 H), 1.76–1.63 (m, 1 H).
2-Allyl-2-(4-methoxyphenyl)cyclohexane-1,3-dione (2c)
Synthesized according to the general procedure from cyclohexane-
1,3-dione (1; 246 mg, 2.2 mmol, 1.1 equiv), Pd(OAc)2 (18 mg, 0.08
mmol, 4 mol%), 2-di-tert-butylphosphino-2′-methylbiphenyl (48
mg, 0.16 mmol, 8 mol%), K3PO4 (976 mg, 4.6 mmol, 2.3 equiv) and
1-bromo-4-methoxybenzene (0.25 mL, 2 mmol, 1 equiv) in THF (6
mL) for the first step. Pd/C 10% (106 mg, 0.1 mmol, 5 mol%), Ph3P
(105 mg, 0.4 mmol, 20 mol%), and allyl acetate (0.24 mL, 2 mmol,
1 equiv) in toluene (14 mL) were used for the second step. Purifica-
tion by flash chromatography (silica gel; PE–EtOAc, 7:3) afforded
diketone 2c.
13C NMR (75.4 MHz, CDCl3): d = 207.0, 148.5, 147.2, 134.2,
130.9, 120.1, 118.2, 108.8, 107.0, 101.4, 74.7, 39.10, 39.06, 17.1.
HRMS (EI): m/z [M]+· calcd for C16H16O4: 272.10486; found:
272.1063.
Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found: C, 70.80; H,
5.96.
2-Allyl-2-phenylcyclohexane-1,3-dione (2a)
PhI (0.13 mL, 0.5 mmol, 1 equiv) was added to a solution of CuI
(9.5 mg, 0.025 mmol, 5 mol%), L-proline (11.5 mg, 0.05 mmol, 10
mol%), K2CO3 (276 mg, 2 mmol, 4 equiv) and diketone 1 (168 mg,
1.5 mmol, 3 equiv) in DMSO (2 mL). The reaction mixture was then
stirred at 90 °C for 48 h. The cooled solution was poured into aq
HCl (1M, 15 mL) and the organic layer was extracted with EtOAc
(3 × 10 mL). The combined organic extracts were washed with
brine (25 mL) and dried over MgSO4, filtered and concentrated in
vacuo. Purification of the crude residue by flash chromatography
(silica gel; PE–EtOAc, 2:8) afforded the arylated diketone (92 mg,
98% yield) as a colorless oil.
Yield: 366 mg (71%); colorless oil.
IR (neat, NaCl): 2959, 1723, 1699, 1513 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.95–6.83 (m, 4 H), 5.71–5.57 (m,
1 H), 4.97–4.88 (m, 2 H), 3.78 (s, 3 H), 2.78–2.45 (m, 4 H), 1.92–
1.83 (m, 2 H), 1.77–1.65 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 207.3, 159.1, 134.4, 129.3,
127.8, 118.2, 114.7, 74.6, 55.2, 39.2, 39.1, 17.2.
HRMS (EI): m/z [M]+· calcd for C13H13O3: 258.12559; found:
258.1259.
Pd/C (27 mg, 0.025 mmol, 5 mol%), Ph3P (26 mg, 0.1 mmol, 20
mol%), and allyl acetate (60 mL, 0.5 mmol, 1 equiv) were added to
a suspension of the above diketone (0.5 mmol, 1 equiv) in toluene
(3 mL). The reaction mixture was stirred at 70 °C overnight, filtered
and concentrated in vacuo. Purification by flash chromatography
(silica gel; PE–EtOAc, 8:2) afforded diketone 2a.
2-Allyl-2-(3,4-dimethoxyphenyl)cyclohexane-1,3-dione (2d)
Synthesized according to the general procedure described above
from cyclohexane-1,3-dione (1; 135 mg, 1.2 mmol, 1.2 equiv),
Pd(OAc)2 (11 mg, 0.05 mmol, 5 mol%), 2-di-tert-butylphosphino-
2¢-methylbiphenyl (35 mg, 0.11 mmol, 11 mol%), K3PO4 (488 mg,
2.3 mmol, 2.3 equiv) and 4-bromoveratrole (0.14 mL, 1 mmol, 1
equiv) in THF (3 mL) for the first step. Pd/C (53 mg, 0.05 mmol, 5
mol%), Ph3P (52 mg, 0.2 mmol, 20 mol%), and allyl acetate (0.12
mL, 1 mmol, 1 equiv) in toluene (7 mL) were used for the second
step. Purification by flash chromatography (silica gel; PE–EtOAc,
6:4) afforded diketone 2d.
Yield: 92 mg (80%); clear oil.
1H NMR (300 MHz, CDCl3): d = 7.33–7.24 (m, 3 H), 7.03–6.99 (m,
2 H), 5.73–5.59 (m, 1 H), 4.99–4.89 (m, 2 H), 2.78–2.48 (m, 6 H),
1.96–1.82 (m, 1 H), 1.80–1.65 (m, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 207.1, 137.4, 134.3, 129.3,
127.8, 126.6, 118.2, 75.4, 39.21, 39.15, 17.27.
HRMS (EI): m/z [M]+ calcd for C15H16O2: 228.11503; found:
228.1159.
Yield: 237 mg (82%); colorless oil.
IR (neat, NaCl): 1696, 1516, 1208, 1144, 1024 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.80 (d, J = 8.2 Hz, 1 H), 6.56–
6.51 (m, 2 H), 5.72–5.57 (m, 1 H), 5.00–4.90 (m, 2 H), 3.85 (s,
3 H), 3.83 (s, 3 H), 2.80–2.70 (m, 4 H), 2.54–2.48 (m, 2 H), 1.94–
1.84 (m, 1 H), 1.80–1.63 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 207.3, 149.5, 148.7, 134.4, 129.5,
119.1, 118.2, 74.8, 56.0, 55.9, 39.23, 39.17, 17.2.
MS (EI): m/z = 288 (43) [M]+, 247 (100) [M – CH2-CH=CH2]+, 177
(51).
HRMS (ESI): m/z [M + Na]+ calcd for C17H20O4Na: 311.1253;
found: 311.1255.
2-Allyl-2-phenylcyclohexa-3,6-diene-1,3-diyl Bis(trifluoro-
methanesulfonate) (3a) and 6-Allyl-5-oxo-6-phenylcyclohex-1-
enyl Trifluoromethanesulfonate (4)
Into a three-necked round-bottom flask was placed a solution of
diketone 2a (114 mg, 0.5 mmol, 1 equiv), Comins’ reagent (432 mg,
1.1 mmol, 2.2 equiv) and TMEDA (0.15 mL, 1 mmol, 2 equiv) in
THF (5 mL). KHMDS (0.5 M in toluene, 2.1 mL, 1 mmol, 2 equiv)
was then added dropwise, over 30 min at –78 °C. The reaction mix-
ture was stirred at –78 °C for 1 h and then allowed to warm slowly
to r.t. over 5 h. Hexane (20 mL) was added and the organic layer
was washed with H2O (5 mL), aq NaOH (10%, 5 mL) and brine (5
mL). The organic layer was dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography (silica gel;
pentane–EtOAc, 9:1) gave bis-triflate 3a, mono-triflate 4 and start-
ing material 2a (48 mg).
2-Allyl-2-(benzo[d][1,3]dioxol-6-yl)cyclohexane-1,3-dione (2e)
Synthesized according to the general procedure described above
from cyclohexane-1,3-dione (1; 246 mg, 2.2 mmol, 1.2 equiv),
Pd(OAc)2 (9 mg, 0.04 mmol, 2 mol%), 2-di-tert-butylphosphino-2¢-
methylbiphenyl (24 mg, 0.08 mmol, 4 mol%), K3PO4 (976 mg, 4.6
mmol, 2.3 equiv), 4-bromo-1,2-(methylenedioxy)benzene (0.24
mL, 2 mmol, 1 equiv) and THF (6 mL) for the first step. Pd/C 10%
(106 mg, 0.1 mmol, 5 mol%), Ph3P (105 mg, 0.4 mmol, 20 mol%),
allyl acetate (0.24 mL, 2 mmol, 1 equiv) and toluene (14 mL) were
used for the second step. Purification by flash chromatography (sil-
ica gel; PE–EtOAc, 8:2) afforded diketone 2e.
3a
Yield: 64 mg (26%); yellow oil.
IR (neat, NaCl): 2971, 1711, 1598, 1416, 1211 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.34 (m, 5 H), 5.97 (t,
J = 3.6 Hz, 2 H), 5.87–5.73 (m, 1 H), 5.30–5.22 (m, 2 H), 3.18 (dt,
J = 22.9, 3.7 Hz, 2 H), 2.93 (d, J = 7.3 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 147.3, 137.1, 131.3, 128.7,
128.6, 127.7, 120.2, 118.0, 113.0, 51.2, 35.2, 24.6.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14O6F6NaS2: 512.0028;
Yield: 442 mg (81%); yellow solid; mp 73–75 °C.
IR (neat, NaCl): 2985, 1727, 1695, 1494 cm–1.
found: 512.0027.
Synthesis 2010, No. 7, 1223–1228 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (1-Allylcyclohexa-2,5-dienyl)arenes
1227
4
mmol, 3.5 equiv), TMSCl (1.3 mL, 10.62 mmol, 5.5 equiv) and
THF (10 mL) for the first step. PhN(Tf)2 (3.45 g, 9.65 mmol, 5
equiv), CsF (2.35 g, 15.44 mmol, 8 equiv) and DME (8 mL) were
used for the second step. HCO2H (0.58 mL, 15.44 mmol, 8 equiv),
DIPEA (2 mL, 11.58 mmol, 6 equiv), Pd(OAc)2 (43 mg, 0.19 mmol,
10 mol%), Ph3P (101 mg, 0.39 mmol, 20 mol%) and DMF (18 mL)
were used for the third step. Purification by flash chromatography
(silica gel; PE–EtOAc, 99:1) gave triene 5b.
Yield: 23 mg (13%); yellow oil.
IR (neat, NaCl): 1726, 1416, 1209, 1140, 975 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.42–7.29 (m, 5 H), 6.36–6.32 (m,
1 H), 5.74–5.58 (m, 1 H), 5.22–5.11 (m, 2 H), 3.53 (dd, J = 13.4,
6.7 Hz, 1 H), 2.68–2.35 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 204.8, 147.6, 137.6, 132.2,
129.0, 128.1, 126.8, 119.9, 118.1, 117.5, 61.3, 37.3, 35.0, 20.3.
Yield: 302 mg (70% overall yield); colorless oil.
IR (neat, NaCl): 3022, 2916, 1602, 1439 cm–1.
Preparation of (1-Allylcyclohexa-2,5-dienyl)arenes 5a–e from
2-Allyl-2-arylcyclohexane-1,3-dione 2a–e; General Procedure
In a three-necked round-bottom flask, a solution of diketone 2a–e
(1 equiv) in THF (0.13 M) was added dropwise at –40 °C to a mix-
ture of LDA (0.67 M in THF, 3.5 equiv) and TMSCl (5.5 equiv). Af-
ter complete addition and further stirring for 5 min, NH4Cl (10 mL/
mmol) was added followed by pentane (10 mL/mmol). The two lay-
ers were separated and the aqueous layer was extracted with Et2O
(15 mL/mmol) . The combined organic extracts were washed with
brine (5 mL/mmol), dried over MgSO4, filtered and concentrated in
vacuo. The crude mixture was used in the next step without further
purification.
1H NMR (300 MHz, CDCl3): d = 6.99 (s, 2 H), 6.85 (s, 1 H), 5.89–
5.64 (m, 5 H), 5.10–5.00 (m, 2 H), 2.71–2.56 (m, 2 H), 2.60 (td,
J = 7.0, 1.3 Hz, 2 H), 2.32 (s, 6 H).
13C NMR (75.4 MHz, CDCl3): d = 147.5, 137.7, 135.4, 132.6,
132.6, 127.7, 124.4, 124.4, 123.3, 116.7, 44.9, 43.5, 26.0, 21.5.
HRMS (EI): m/z [M]+· calcd for C17H20: 224.1565; found: 224.1556.
1-(1-Allylcyclohexa-2,5-dienyl)-4-methoxybenzene (5c)
Synthesized according to the general procedure described above
from diketone 2c (360 mg, 1.40 mmol, 1 equiv), LDA (7.3 mL, 4.90
mmol, 3.5 equiv), TMSCl (1.0 mL, 7.67 mmol, 5.5 equiv) and THF
(10 mL) for the first step. PhN(Tf)2 (2.5 g, 7.00 mmol, 5 equiv), CsF
(1.7 g, 11.2 mmol, 8 equiv) and DME (6 mL) were used for the sec-
ond step. HCO2H (0.42 mL, 11.20 mmol, 8 equiv), DIPEA (1.46
mL, 8.40 mmol, 6 equiv), Pd(OAc)2 (31 mg, 0.14 mmol, 10 mol%),
Ph3P (73 mg, 0.28 mmol, 20 mol%) and DMF (13 mL) were used
for the third step. Purification by flash chromatography (silica gel;
PE–EtOAc, 96:4) gave triene 5c.
In a flask equipped with a screw-cap, PhN(Tf)2 (5 equiv) and CsF
(8 equiv) were sequentially added to a solution of the preceding bis-
silylenol ether in DME (1.65 M) and the tube was sealed. The reac-
tion mixture was stirred at r.t. for 18 h, then the flask was carefully
opened and Et2O (2.5 mL/mmol) and a pH 7 buffer solution (2.5
mL/mmol) were then added sequentially. The two layers were sep-
arated and the aqueous phase was extracted with Et2O (10 mL/
mmol). The combined organic layers were washed with brine (2.5
mL/mmol), dried over MgSO4, filtered and the solvents concentrat-
ed in vacuo. The crude mixture was used without any purification
in the next step.
Yield: 286 mg (87% overall yield); yellow oil.
IR (neat, NaCl): 3018, 2932, 1608, 1464, 1440, 1248, 1180, 1038,
912, 828 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.31–7.24 (m, 2 H), 6.90–6.84
(2 H), 5.88–5.62 (m, 5 H), 5.11–5.02 (m, 2 H), 3.80 (s, 3 H), 2.69–
2.65 (m, 2 H), 2.59 (d, J = 7.0 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 159.8, 141.9, 137.4, 134.8,
134.8, 129.7, 125.3, 116.3, 57.3, 46.9, 28.1.
HRMS (EI): m/z [M – C3H5]+ calcd for C13H13O: 185.09664; found:
185.0963.
HCO2H (8 equiv) was added to a solution of the preceding bis-tri-
flate (1 equiv), DIPEA (6 equiv), Pd(OAc)2 (10 mol%) and Ph3P (20
mol%) in DMF (0.12 M) and the reaction mixture was stirred at
60 °C for 1 h. EtOAc (10 mL/mmol) was added and the reaction
mixture was washed with H2O (5 mL/mmol) and brine (5 mL/
mmol), dried over MgSO4, filtered and the solvents concentrated in
vacuo. Purification by flash chromatography (silica gel) yielded the
desired dienes 5a–e.
4-(1-Allylcyclohexa-2,5-dienyl)-1,2-dimethoxybenzene (5d)
Synthesized according to the general procedure described above
from diketone 2d (0.3 g, 1.04 mmol, 1 equiv), LDA (1.6 mL, 1.04
mmol, 3.5 equiv), TMSCl (0.72 mL, 5.72 mmol, 5.5 equiv) and
THF (8 mL) for the first step. PhN(Tf)2 (1.86 g, 5.21 mmol, 5
equiv), CsF (1.27 g, 8.33 mmol, 8 equiv) and DME (3.6 mL) were
used for the second step. HCO2H (0.31 mL, 8.32 mmol, 8 equiv),
DIPEA (1.1 mL, 6.24 mmol, 6 equiv), Pd(OAc)2 (23 mg, 0.1 mmol,
10 mol%), Ph3P (54 mg, 0.21 mmol, 20 mol%) and DMF (10 mL)
were used for the third step. Purification by flash chromatography
(silica gel; PE–EtOAc, 95:5) gave triene 5d.
(1-Allylcyclohexa-2,5-dienyl)benzene (5a)
Synthesized according to the general procedure described above
from diketone 2a (792 mg, 3.47 mmol, 1 equiv), LDA (18 mL,
12.16 mmol, 3.5 equiv), TMSCl (2.4 mL, 19.11 mmol, 5.5 equiv)
and THF (20 mL) for the first step. PhN(Tf)2 (6.2 g, 17.4 mmol, 5
equiv), CsF (4.22 g, 27.8 mmol, 8 equiv) and DME (12 mL) were
used for the second step. HCO2H (1.05 mL, 27.79 mmol, 8 equiv),
DIPEA (3.63 mL, 20.84 mmol, 6 equiv), Pd(OAc)2 (78 mg, 0.35
mmol, 10 mol%), Ph3P (182 mg, 0.69 mmol, 20 mol%) and DMF
(20 mL) were used for the third step. Purification by flash chroma-
tography (silica gel; pentane) gave triene 5a.
Yield: 90 mg (34% overall yield); colorless viscous oil.
IR (neat, NaCl): 3015, 2933, 2834, 1603, 1255, 1145 cm–1.
Yield: 507 mg (75% overall yield); yellow oil.
IR (neat, NaCl): 3023, 2923, 1638, 1598 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.93–6.81 (m, 3 H), 5.88–5.64 (m,
5 H), 5.09–5.00 (m, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 2.69–2.66 (m,
2 H), 2.59 (d, J = 7.2 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 148.7, 147.2, 140.3, 135.2,
132.6, 123.3, 118.4, 116.8, 110.9, 110.5, 55.8, 44.9, 43.3, 26.0.
1H NMR (300 MHz, CDCl3): d = 7.38–7.19 (m, 5 H), 5.91–5.68 (m,
5 H), 5.12–5.03 (m, 2 H), 2.72–2.68 (m, 2 H), 2.67–2.62 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 147.5, 135.3, 132.5, 128.3,
126.6, 126.0, 123.5, 116.9, 44.8, 43.7, 26.1.
MS (EI): m/z = 155 (100) [M – C3H5]+.
HRMS (EI): m/z [M]+ calcd for C17H20O2: 256.14633; found:
256.1469.
1-(1-Allylcyclohexa-2,5-dienyl)-3,5-dimethylbenzene (5b)
Synthesized according to the general procedure described above
from diketone 2b (494 mg, 1.93 mmol, 1 equiv), LDA (9.8 mL, 6.56
Synthesis 2010, No. 7, 1223–1228 © Thieme Stuttgart · New York

1228
G. Rousseau et al.
PRACTICAL SYNTHETIC PROCEDURES
5-(1-Allylcyclohexa-2,5-dienyl)benzo[d][1,3]dioxole (5e)
Synthesized according to the general procedure described above
from diketone 2e (346 mg, 1.27 mmol, 1 equiv), LDA (7 mL, 4.41
mmol, 3.5 equiv), TMSCl (0.9 mL, 7 mmol, 5.5 equiv) and THF (10
mL) for the first step. PhN(Tf)2 (2.27g, 6.35 mmol, 5 equiv), CsF
(1.54g, 10.16 mmol, 8 equiv) and DME (4.4 mL) were used for the
second step. HCO2H (0.38 mL, 10.16 mmol, 8 equiv), DIPEA (1.33
mL, 7.62 mmol, 6 equiv), Pd(OAc)2 (28 mg, 0.13 mmol, 10 mol%),
Ph3P (67 mg, 0.25 mmol, 20 mol%) and DMF (12 mL) were used
for the third step. Purification by flash chromatography (silica gel;
pentane) gave triene 5e,
(5) Wheeler, T. N. J. Org. Chem. 1979, 44, 4906.
(6) (a) Solé, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996, 52,
4013. (b) Solé, D.; Bonjoch, J. Tetrahedron Lett. 1991, 32,
5183. (c) Solé, D.; Bonjoch, J. Tetrahedron 1996, 52, 4013.
(7) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.; Bellandi, P.
Tetrahedron 1991, 47, 333.
(8) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684.
(9) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382.
(10) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108.
(11) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 1473. (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 1360. (c) Rutherford, J.
L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 15168. (d) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234. (e) Ehrentraut, A.; Zapf, A.; Beller, M.
Adv. Synth. Catal. 2002, 344, 209. (f) Churruca, F.;
SanMartin, R.; Tellitu, I.; Domínguez, E. Tetrahedron Lett.
2006, 47, 3233. (g) Brenstrum, T.; Clattenburg, J.; Britten,
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Yield: 229 mg (75% overall yield); yellow viscous oil.
IR (neat, NaCl): 2881, 1483, 1235, 1039 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.89–6.74 (m, 3 H), 5.93 (s, 2 H),
5.88–5.60 (m, 5 H), 5.10–5.00 (m, 2 H), 2.66 (m, 2 H), 2.56 (td,
J = 7.0, 1.3 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 147.6, 145.6, 141.7, 135.1,
132.4, 123.3, 119.4, 116.9, 107.9, 107.7, 100.9, 44.9, 43.4, 26.0.
HRMS (EI): m/z [M]+ calcd for C16H16O2: 240.11503; found:
240.1153.
Acknowledgment
(12) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731.
(13) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org.
Chem. 1987, 52, 3223.
We gratefully acknowledge the CNRS and MNERT for financial
support.
(14) Bedekar, A.; Watanabe, T.; Tanaka, K.; Fuji, K. Synthesis
1995, 1069.
(15) Felpin, F. X.; Landais, Y. J. Org. Chem. 2005, 70, 6441.
(16) Willis, M. C.; Claverie, C. K. Tetrahedron Lett. 2001, 42,
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6299.
(18) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 11290.
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25, 4821. (b) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato,
Y. J. Am. Chem. Soc. 2003, 125, 9801.
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Synthesis 2010, No. 7, 1223–1228 © Thieme Stuttgart · New York