A one-pot preparation of aryl- and heteroarylcycloalkenes: Application to the total synthesis of (±)-laurokamurene B

Article abstract of DOI:10.1055/s-0029-1217964

A general one-pot method has been developed for the preparation of various aryl- and heteroarylcycloalkenes. After lithiation of aryl and heteroaryl bromides followed by transmetalation with CeCl3, the organocerium addition to cycloalkanones proceeds clea

Full text of DOI:10.1055/s-0029-1217964

LETTER
2761
A One-Pot Preparation of Aryl- and Heteroarylcycloalkenes: Application to
the Total Synthesis of ( )-Laurokamurene B
A
pplicatio
e
n to the To
a
tal Synthes
n
is of
(
)-Laurokam
T
urene
B
allineau, Georges Bashiardes, Jean-Marie Coustard, Frédéric Lecornué*
Laboratoire Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, UMR-CNRS 6514,
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
Fax +33(5)49453965; E-mail: frederic.lecornue@univ-poitiers.fr
Received 26 May 2009
ester, and an E2 elimination. We report herein that this
method is indeed a practical one-pot and synthetically
useful preparation of cycloalkenyl arenes.
Abstract: A general one-pot method has been developed for the
preparation of various aryl- and heteroarylcycloalkenes. After lithi-
ation of aryl and heteroaryl bromides followed by transmetalation
with CeCl3, the organocerium addition to cycloalkanones proceeds
cleanly to provide the intermediate alkoxide. Addition of MsCl or
SOCl2 with DBU gave aryl-substituted cycloalkenes in good yields.
A short total synthesis of ( )-laurokamurene B making use of this
reaction is described.
Initial experiments involved lithiation of 4-bromoanisole
(1a) with n-BuLi, transmetalation with CeCl3, and addi-
tion to cyclohexanone providing the intermediate alkox-
ide which was not quenched (Table 1).
Key words: organocerium reagents, addition reactions, elimina-
tions, arylcycloalkenes, laurokamurene B
Table 1 Optimization of Reaction Conditions for the One-Pot Prep-
aration of 2a from 4-Bromoanisole and Cyclohexanone
OMe
OMe
Preparation of aryl-substituted cycloalkenes can be car-
ried out most commonly through two approaches. Firstly,
amongst the transition-metal-catalyzed reactions, the
Heck reaction appears to be the most straightforward
method.1a However, the coupling of cyclic olefins gener-
ates a mixture of double-bond regioisomers.1b,c Cross-
coupling reactions of cycloalkenyl phosphates,2 triflates,3
and halides4 have been reported with aryl Grignard re-
agents,5 arylboronic acids,6 arylstannanes,7 and orga-
nozinc reagents8 under Ni(0) and Pd(0) catalysis. Other
methods have been developed using iron,9 cobalt,10 and
copper11 complexes. While these reactions lead to aryl-
substituted cycloalkenes in good yields, each requires the
functionalization of ketones into their corresponding vi-
nyl derivatives, and the isolation of an intermediate. The
second approach involves classically addition of aryllith-
ium or aryl Grignard reagents to the cyclic ketones,12 fol-
lowed by dehydratation of the resulting tertiary alcohols
or elimination of the corresponding sulfonate esters.13
Nevertheless, with this two-step method, addition to ke-
tones with these strongly basic organometallic com-
pounds often leads to unwanted reactions such as
enolization, reduction, and pinacol coupling. Recently al-
so, a sequential semipinacol rearrangement–Grob frag-
mentation of allylic alcohols leading to alkenes was
reported.14
1) n-BuLi (1.2 equiv), THF, –78 °C
2) CeCl3 (1.3 equiv), THF, –78 °C
3) cyclohexanone (1 equiv), THF
–78 °C to r.t.
4) base (3 equiv), sulfonyl agent
(3 equiv), THF, –30 °C to r.t.
Br
1a
(1.1 equiv)
2a
Entry
Base
Sulfonyl agent
MsCl
Yield (%)a
1
2
3
4
5
6
7
Et3N
73
70
73
87
22
15
28
Et3N
(F3CSO2)2O
(F3CSO2)2O
MsCl
DBU
DBU
DABCO
pyridine
DIPEA
MsCl
MsCl
MsCl
a Isolated yield.
Addition of Et3N and MsCl led to the desired cycloalkene
2a in 73% yield (entry 1). We then investigated the influ-
ence of different bases and sulfonyl agents. The use of
Et3N or DBU with (F3CSO2)2O (entries 2 and 3) did not
increase the yield whereas DABCO, pyridine, and DIPEA
with MsCl (entries 5–7) led to lower yields. Finally, the
best result was obtained using DBU and MsCl, thus pro-
viding the product 2a in an improved 87% yield (entry 4).
Under these conditions but without addition of cerium(III)
chloride, cyclohexene 2a was isolated in 53% yield.
While investigating a straightforward route to arylcy-
cloalkenes, we reasoned that in order to avoid operating in
strongly basic conditions, it might be possible to add neu-
tral organocerium reagents15 to cycloalkanones, followed
by conversion of the intermediate alkoxide to a sulfonate
With these optimized conditions in hand, the scope of this
reaction was explored utilizing various aryl- and heteroar-
yl bromides 1a–d with cycloalkanones. The desired cy-
cloalkenyl arenes 2a–k were formed generally in 51–93%
SYNLETT 2009, No. 17, pp 2761–2764
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217964; Art ID: D13109ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2762
J. Tallineau et al.
LETTER
yield (Table 2). Reactions with five-, six- and seven- methoxybenzene 2d was obtained in 17% yield (entry 4).
membered cycloalkanones (entries 1–3) gave the expect- This yield was not improved using procedure B or C. With
ed cycloalkenes 2a–c while only the 1-cyclobutenyl-4-
Table 2 Synthesis of Aryl- and Heteroarylcycloalkenes
R1
R1
Procedure
A, B or C
R2
Br
1a–d
Entry
1
2a–k
n = 1–4
n
Aryl bromide
Cycloalkanone
Product
Yield (%)a
87
Procedureb
A
Br
1a
1a
OMe
OMe
O
2a
2b
OMe
2
3
4
93
73
17
A
A
A
O
O
O
OMe
1a
1a
2c
OMe
2d
OMe
5
6
1a
86
70
A
A
O
O
2e
S
Br
S
1b
2f
MeO
72
7
8
A
2g/2h = 70:30c
O
Br
OMe
OMe
1c
2g 2h
O
1a
1a
65
Ad
OMe
2i
O
O
O
51
68
A
B
OMe
9
O
O
2j
0
75
Ae
Ce
NC
Br
NC
10
O
2k
1d
a Isolated yield.
b Procedure A: 1) n-BuLi, 1a–d, -78 °C, 1 h; 2) CeCl3, THF, –78 °C, 90 min; 3) cycloalkanone, THF, –78 ° to r.t., 3 h; 4) DBU, MsCl, –30 °C
to r.t., overnight. Procedure B: see procedure A except that before step 4 THF was evaporated, and toluene was added; then DBU, MsCl at –30
°C and reflux overnight. Procedure C: see procedure A except for step 4: DBU, SOCl2 (3 equiv), –30 °C to r.t., overnight.
c Ratio determined by 1H NMR of the crude mixture.
d After addition of DBU and MsCl at –30 °C, the mixture was heated at reflux overnight.
e Addition of n-BuLi was carried out at –100 °C.
Synlett 2009, No. 17, 2761–2764 © Thieme Stuttgart · New York

LETTER
Application to the Total Synthesis of ( )-Laurokamurene B
2763
2-methylcyclohexanone (entry 5), the less substituted cy-
OTMS
O
cloalkene 2e was isolated exclusively in 86% yield.
MeMgBr, CuBr⋅SMe2
HMPA, TMSCl, Et3N
100%
A satisfactory yield was observed with 2-bromothiophene
(1b, entry 6). In the case of cyclohexenone (entry 7), 1,2-
addition of the organocerium reagent proceeded exclu-
sively to give, after esterification and E2 elimination, the
2-substituted 1,3-diene 2g and the 1-substituted 1,3-diene
2h in 72% yield as a 70:30 mixture of regioisomers, re-
spectively, which was separated by column chromatogra-
phy. With tetralone (entry 8), it was necessary to heat at
reflux overnight to afford the product 2i in 65% yield.
However, from 1,4-cyclohexanedione monoethylene ket-
al and 1a, using procedure A, the yield dropped to 51%
(entry 9). We assumed that this low yield was due to a
probable difficulty to achieve antiperiplanarity between
the mesyloxy group and the methine proton. A better yield
was achieved by slightly modifying the procedure. As
such, before the esterification–E2 elimination step, THF
was evaporated and toluene was added, followed by DBU
and MsCl. The mixture was refluxed overnight to afford
product 2j in an improved 68% yield. With 4-bromoben-
zonitrile and cyclopentanone (entry 10), only the corre-
sponding tertiary alcohol was isolated in 43% yield. Using
SOCl2 instead of MsCl (procedure C), the desired product
2k was readily obtained in 75% yield.
3
O
OTMS
Et2Zn CH2I2
84%
MeOH
NaOH (2 M)
86%
4a,b
5
1) n-BuLi, THF, –78 °C
2) CeCl3, THF, –78 °C
3) 5, THF, –78 °C to r.t.
4) DBU, SOCl2, –30 °C to r.t.
55%
Br
( )-laurokamurene B
Scheme 1 Total synthesis of ( )-laurokamurene B
stirred at –78 °C for 90 min. Then cyclohexanone (343 mg, 363 mL,
3.5 mmol) dissolved in anhyd THF (5 mL) was added to the corre-
sponding organocerium reagent. The resulting mixture was stirred
at –78 °C for 90 min then at r.t. for 90 min. At –30 °C, after dilution
with anhyd THF (20 mL), DBU (1.57 mL, 10.5 mmol), then MsCl
(815 mL, 10.5 mmol) were added dropwise. The reaction mixture
was then allowed to warm to r.t. and stirred overnight. At 0 °C aq 1 M
HCl (15 mL) was added, and the solution was stirred for 1 h. The
aqueous layer was extracted with Et2O (3 × 30 mL). The resulting
organic layers were washed successively with aq 2 M NaOH (10
mL), H2O (10 mL), brine (10 mL), dried over MgSO4, and the sol-
vent evaporated. The residue was purified by chromatography on
silica gel (pentane–Et2O = 95:5) to provide the product 2a in 87%
yield.
The interest of this one-pot preparation of cycloalkenyl
arenes was exemplified by a short total synthesis of ( )-
laurokamurene B (Scheme 1).16 Copper-catalyzed 1,4-ad-
dition of methylmagnesium bromide to 2-methylcyclo-
pentenone and enolate trapping using trimethylsilyl
chloride gave the silyl enol ether 3 in quantitative yield
without purification. Cyclopropanation of 3 with CH2I2
and Et2Zn17 led to trimethylsilyl ethers 4a and 4b in 84%
yield as a 59:41 mixture of diastereomers, respectively,
1H NMR (300 MHz, CDCl3): d = 7.32 (2 H, d, J = 8.9 Hz), 6.85 (2
H, d, J = 8.9 Hz), 6.01–6.06 (1 H, m), 3.81 (3 H, s), 2.41–2.35 (2 H,
m), 2.22–2.16 (2 H, m), 1.81–1.73 (2 H, m), 1.70–1.61 (2 H, m)
which could not be separated by column chromatography. ppm. 13C NMR (75 MHz, CDCl3): d = 158.4, 135.8, 135.3, 125.9,
123.1, 113.5, 55.2, 27.4, 25.8, 23.1, 22.2 ppm. MS (EI): m/z (%) =
After treatment of 4a,b with sodium hydroxide in hy-
188 (100) [M+], 173 (22), 160 (50), 159 (45), 115 (21), 91 (21).
dromethanolic solution, 2,2,3-trimethylcyclopentanone 5
HRMS (EI): m/z calcd for C13H16O: 188.1201; found: 188.1216.
was isolated in 86% yield and characterized.18 Finally, nu-
cleophilic addition of 4-methylphenylcerium reagent to 5
followed by treatment with DBU and SOCl2 gave ( )-lau-
rokamurene B in four steps and 40% overall yield. For this
last step, using MsCl instead of SOCl2, the yield dropped
to 30%.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
In conclusion, we have developed a general one-pot syn-
thesis of aryl- and heteroarylcycloalkenes. This method
was applied to the total synthesis of ( )-laurokamurene B.
Financial supports from CNRS and the University of Poitiers are
gratefully acknowledged. J.T. thanks the Région Poitou-Charentes
for a doctoral fellowship. We also thank Dr Luis Blanco for helpful
discussions about the total synthesis of ( )-laurokamurene B.
Procedure A for the Preparation of Cyclohexene 2a
References and Notes
Cerium chloride heptahydrate (1.7 g, 4.5 mmol) was quickly ground
to a fine powder in a mortar, placed in a two-necked flask and dried
at 140 °C for 2 h in vacuo. At r.t., nitrogen gas was introduced, and
anhyd THF (25 mL) was added with vigorous stirring. The white
suspension was stirred for 90 min at r.t. To a cold (–78 °C) stirred
solution of 1a (720 mg, 3.85 mmol) in anhyd THF (25 mL) was add-
ed n-BuLi (2.2 M in hexane, 1.9 mL, 4.2 mmol) dropwise. This so-
lution was stirred at –78 °C for 90 min, then added to the cold (–
78 °C) suspension of CeCl3 in THF. The resulting solution was
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2764
J. Tallineau et al.
LETTER
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