meta-selective aromatic borylation as key step in the synthesis of poipuol

Article abstract of DOI:10.1055/s-2008-1078449

A synthesis of the marine natural product poipuol is reported. The key reaction sequence consists of an iridium-catalyzed meta-selective CH-borylation followed by the conversion of the resulting arylboronic ester into an aryl chloride. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078449

PAPER
2217
meta-Selective Aromatic Borylation as Key Step in the Synthesis of Poipuol
m
eta-Sele
e
ctive
A
rom
n
atic
B
orylati
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on in the Synthe
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Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
Received 2 May 2008
Dedicated to Prof. R. W. Hoffmann on the occasion of his 75th birthday
reaction. Here, we present first results addressing the
Abstract: A synthesis of the marine natural product poipuol is re-
ported. The key reaction sequence consists of an iridium-catalyzed
meta-selective CH-borylation followed by the conversion of the re-
sulting arylboronic ester into an aryl chloride.
point of functional tolerance in the context of a synthesis
of the natural product poipuol (3) (Scheme 1). Poipuol (3)
was isolated by Sitachitta et al. from the marine sponge
Hyrtios sp., collected at a depth of 18 meters near Kauai
Island, Hawaii.2
Key words: meta-selective aromatic substitution, boron, iridium,
natural products, total synthesis
The starting point for the synthesis of the borylation pre-
cursor was the aromatic aldehyde 4 (Scheme 2). A Kno-
evenagel–Doebner reaction3 of 4 with ethyl butyracetate
led to condensation product 5 in nearly quantitative yield.
The hydrogenation of 5 gave b-keto ester 6. Treatment of
the latter with potassium hydroxide in aqueous ethanol re-
sulted in the formation of ketone 7 (Scheme 2).4
For a long time the direct meta-selective functionalization
of benzene derivatives had been restricted to systems car-
rying electron-withdrawing groups and had been impossi-
ble for electron-rich systems. The situation changed with
the discovery of iridium-catalyzed CH-borylation of are-
nes.1 Miyaura et al. introduced the catalyst system
[Ir(cod)Cl]2 (cod = cyclooctadiene) in combination with
4,4¢-di-tert-butyl-2,2¢-bipyridine (dtbpy) and bis(pinaco-
lato)diboron [(Bpin)2] as borylating reagent.1a The use of
[Ir(cod)(OMe)]2 allowed an aromatic CH-borylation at
room temperature.1b The regioselectivity of the borylation
is directed by steric factors, which lead in the case of a
1,3-disubstituted benzene derivative 1 to the predominant
formation of the meta-substitution product 2 (Scheme 1).
The synthetic potential of the CH-borylation of arenes
was expanded by Maleczka and Smith with the introduc-
tion of a C–H activation/borylation/oxidation protocol to
produce meta-substituted phenols.1d
OMe
OMe
O
CHO
OMe
a
b
CO2Et
~100%
96%
OMe
4
5
OMe
O
OMe
O
c
CO2Et
OMe
96%
OMe
6
7
Scheme 2 Reagents and conditions: (a) PrCOCH2CO2Et, AcOH,
piperidine, toluene, reflux; (b) NaOAc, Pd(OH)2/C, H2, EtOAc;
(c) KOH, H2O, EtOH, reflux.
To use this meta-selective aromatic borylation in the com-
plex functional environment of a natural product synthe-
sis, we were interested in the functional tolerance of this
The CH-borylation of arene 7 in the presence of the cata-
lyst system consisting of 0.75% [Ir(cod)(OMe)]2/1.5%
dtbpy/(Bpin)2 (1 equiv) gave arylboronic ester 8 with
complete meta selectivity and in very good yield
(Scheme 3). In contrast to the low-temperature conditions
reported by Miyaura,1b harsher conditions (microwave,
150 °C, 3 h) were necessary for the conversion of 7 into 8.
Notable is the compatibility of the ketone function with
the borylation conditions.
R1
R1
Ir catalyst
(BPin)2
R2
PinB
R2
1
2
Cl
Cl
OH
Cl
OH
The conversion of 8 into poipuol (3) would require the
generation of aryl chloride 9 from the arylboronic ester
(Scheme 3). Attempts to use copper(II) chloride5 for this
purpose failed due to side reactions with the ketone. An
inseparable mixture of a-chloro ketones was obtained.
Therefore, the transformation of ketone 7 into dichlo-
roolefin 10 before the borylation–chlorination sequence
was examined next (Scheme 4).
poipuol (3)
Scheme 1 meta-Selective arene borylation of 1,3-disubstituted ben-
zene derivative 1 to produce 1,3,5-trisubstituted benzene 2; structure
of poipuol (3)
SYNTHESIS 2008, No. 14, pp 2217–2220
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078449; Art ID: C01908SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

2218
J. Cordes et al.
PAPER
OMe
O
OMe
O
a
82%
(94% conv.)
PinB
OMe
OMe
8
7
OMe
O
Cl
OMe
9
Figure 1 X-ray crystal structure of compound 117
Scheme 3 Reagents and conditions: (a) [Ir(cod)(OMe)]2, dtbpy,
(Bpin)2, hexane, microwave, 150 °C, 3 h.
tion conditions. The reaction sequence of meta-selective
CH-borylation and chlorination is an efficient way to pre-
pare meta-disubstituted aryl chlorides. The marine natural
product poipuol (3) was synthesized in seven steps in 58%
overall yield when meta-selective CH-borylation–chlori-
nation was applied as the key sequence. Other uses of iri-
dium-mediated CH-borylation in a complex functional
environment of a natural products synthesis are conceiv-
able.
Cl
Cl
OMe
OMe
O
a
79%
OMe
OMe
10
7
Cl
Cl
OMe
b
All nonaqueous reactions were carried out in flame-dried glassware
under argon atmosphere. All solvents were distilled by rotary evap-
oration. Solvents for nonaqueous reactions were dried as follows
prior to use: THF was dried with KOH and subsequently distilled
from sodium/benzophenone, and Et2O from a K/Na (4:1) alloy. All
commercially available reagents and reactants were used without
purification unless otherwise noted. 2,6-Dimethoxybenzaldehyde
(4) was prepared according to a literature procedure.8 Reactions
were monitored by TLC on Merck silica gel 60 F245 plates, which
were visualized by fluorescence quenching under UV light. In addi-
tion, TLC plates were stained with a KMnO4 stain. Chromatograph-
ic purification of products was performed on Merck silica gel 60
(230–400 mesh) with a forced flow of eluents. Concentration under
reduced pressure was performed by rotary evaporation at 40 °C and
appropriate pressure. Reactions under microwave conditions were
performed with a CEM Discover LabMate. Yields refer to purified
and spectroscopically pure products unless otherwise noted. IR
spectra were recorded on a Bruker IFS 200 or a Nicolet Magna-IR
750 spectrometer. NMR spectra were recorded on a Bruker
ARX300, DRX400, or DRX500 spectrometer at r.t. Chemical shifts
are reported relative to the solvent resonance as internal standard.
Mass spectra were recorded on a Finnigan MAT TSQ 700 or MAT
95S spectrometer.
81%
(99% conv.)
PinB
OMe
OMe
11
Cl
Cl
d
c
3
83%
97%
Cl
OMe
12
Scheme 4 Reagents and conditions: (a) (EtO)2P(O)CCl3, n-BuLi,
THF, Et2O, –115 °C to reflux; (b) [Ir(cod)(OMe)]2, dtbpy, (Bpin)2,
hexane, microwave, 150 °C; (c) CuCl2·2H2O, H2O, i-PrOH, micro-
wave, 150 °C; (d) BBr3, CH2Cl2.
The reaction of ketone 7 with diethyl (trichlorometh-
yl)phosphonate and n-butyllithium delivered the desired
dichloroolefin 10 (Scheme 4).6 The following CH-boryla-
tion with catalyst system [Ir(cod)(OMe)]2/dtbpy/(Bpin)2
gave arylboronic ester 11 with complete meta-selectivity
in very good yield (Scheme 4). An X-ray crystal structure
of the product (Figure 1) allowed an unambiguous struc-
tural assignment of the borylation product.7 Treatment of
arylboronic ester 11 with ten equivalents copper(II) chlo-
ride dihydrate5 in isopropyl alcohol–water at 150 °C (mi-
crowave) led to the formation of aryl chloride 12 in nearly
quantitative yield. The synthesis of poipuol (3) was suc-
cessfully completed by the final methyl ether cleavage of
12 mediated by boron tribromide (Scheme 4). The analyt-
ical data of synthetic poipuol (3) were identical to those
previously reported.2
Ethyl 2-(2,6-Dimethoxybenzylidene)-3-oxohexanoate (5)
2,6-Dimethoxybenzaldehyde (4; 10.0 g, 60.2 mmol) was dissolved
in toluene (300 mL). Ethyl butyracetate (9.52 g, 60.2 mmol), gla-
cial AcOH (1.5 mL), and piperidine (1.2 mL) were added and the
mixture was heated in a Dean–Stark apparatus until the generation
of H2O ceased. After the mixture had cooled to r.t., EtOAc
(250 mL) was added. The soln was washed with 1 M HCl (3 ×
200 mL), brine (3 × 200 mL), sat. NaHCO3 (3 × 200 mL), and H2O
(3 × 200 mL) and dried (MgSO4). Removal of the solvents gave 5
as an E/Z mixture (1.0:1.5, according to NOESY).
Yield: 18.4 g (ca. 100%); yellow oil; Rf = 0.30 (hexane–MTBE,
1:1).
In conclusion, it was shown that ketone and dichloroolefin
functionalities can tolerate iridium-mediated CH-boryla-
IR (film): 2964 (m), 2840 (w), 1721 (s), 1597 (s), 1474 (s),
1434 (m), 1377 (m), 1307 (w), 1260 (s), 1147 (w), 1114 (s),
1030 (m), 779 (m), 759 (w), 732 (w) cm–1.
Synthesis 2008, No. 14, 2217–2220 © Thieme Stuttgart · New York

PAPER
meta-Selective Aromatic Borylation in the Synthesis of Poipuol
2219
1H NMR (300 MHz, CDCl3): d (E-isomer) = 7.80 (s, 1 H), 7.26 (t,
J = 8.4 Hz, 1 H), 6.50 (d, J = 8.3 Hz, 2 H), 4.25 (q, J = 7.1 Hz, 2 H),
3.75 (s, 6 H), 2.52 (t, J = 7.5 Hz, 2 H), 1.58 (pseudo sext,
J = 7.4 Hz, 2 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.87 (t, J = 7.5 Hz, 3 H);
d (Z-isomer) = 7.80 (s, 1 H), 7.27 (t, J = 8.4 Hz, 1 H), 6.50 (d,
J = 8.3 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 3.77 (s, 6 H), 2.72 (t,
J = 7.5 Hz, 2 H), 1.68 (pseudo sext, J = 7.3 Hz, 2 H), 1.13 (t,
J = 7.2 Hz, 3 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d (E-isomer) = 198.2, 167.4, 158.6 (2
C), 135.5, 135.1, 131.7, 112.5, 103.5 (2 C), 60.6, 55.6 (2 C), 41.9,
17.7, 13.9, 13.8; d (Z-isomer) = 202.4, 166.0, 158.2 (2 C), 134.5,
134.3, 131.7, 112.1, 103.7 (2 C), 61.2, 55.4 (2 C), 44.0, 17.1, 14.3,
13.8.
solved in hexane (6.0 mL). After the mixture had stirred at r.t. for
15 min, ketone 7 (709 mg, 3.0 mmol) was added. The tube was
sealed with a Teflon cap and heated by microwave for 3 h to 150 °C.
After cooling to r.t., the mixture was poured into MTBE (60 mL)
and washed with H2O (2 × 45 mL). The organic layer was dried
(MgSO4) and concentrated. The crude product was purified by flash
chromatography (silica gel, pentane–Et2O, 9:1).
Yield: 887 mg (82%; or 94% on the basis of 92 mg recovered start-
ing material 7); colorless solid; Rf = 0.50 (hexane–MTBE, 1:1); mp
98 °C.
IR (KBr): 2982 (s), 2939 (m), 1708 (s), 1572 (s), 1451 (m),
1406 (s), 1365 (s), 1245 (w), 1164 (s), 1144 (m), 1124 (s), 967 (w),
852 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.97 (s, 2 H), 3.84 (s, 6 H), 2.95–
2.89 (m, 2 H), 2.57–2.51 (m, 2 H), 2.39 (t, J = 7.4 Hz, 2 H), 1.52
(pseudo sext, J = 7.4 Hz, 2 H), 1.34 (s, 12 H), 0.91 (t, J = 7.4 Hz, 3
H).
13C NMR (125 MHz, CDCl3): d = 211.5, 157.9 (2 C), 127.8, 121.3,
109.6 (2 C), 83.9 (2 C), 55.9 (2 C), 44.6, 42.0, 25.0 (4 C), 18.1, 17.5,
13.9.
11B NMR (160 MHz, CDCl3): d = 30.5.
ESI-HRMS: m/z calcd for C17H22O5Na [M + Na]+: 329.1359; found:
329.1358.
Ethyl 2-(2,6-Dimethoxybenzyl)-3-oxohexanoate (6)
Olefin 5 (18.4 g, 60.1 mmol) was dissolved in EtOAc (400 mL).
NaOAc (7.94 g, 120 mmol) and Pd(OH)2 (20% wet on C; 900 mg)
were added and the mixture was stirred under a H2 atmosphere at r.t.
overnight. The suspension was filtered through Celite and the fil-
trate was washed with brine (150 mL). The organic layer was dried
(MgSO4) and concentrated.
ESI-HRMS: m/z calcd for C20H31BO5Na [M + Na]+: 385.2157;
found: 385.2147.
Yield: 17.8 g (96%); yellow oil; Rf = 0.42 (hexane–MTBE, 1:1).
IR (film): 2962 (s), 2838 (m), 1713 (s), 1637 (m), 1596 (s),
1475 (s), 1368 (m), 1330 (m), 1258 (s), 1200 (s), 1113 (s),
1038 (m), 776 (m), 728 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (t, J = 8.4 Hz, 1 H), 6.50 (d,
J = 8.3 Hz, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.84–3.76 (m, 7 H), 3.21
(d, J = 8.4 Hz, 2 H), 2.49 (dt, J = 17.4, 7.2 Hz, 1 H), 2.29 (dt,
J = 17.4, 7.2 Hz, 1 H), 1.53 (pseudo sext, J = 7.4 Hz, 2 H), 1.19 (t,
J = 7.1 Hz, 3 H), 0.84 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 205.6, 170.2, 158.4 (2 C), 127.8,
114.7, 103.6 (2 C), 60.9, 57.9, 55.6 (2 C), 43.7, 22.1, 16.9, 14.0,
13.6.
ESI-HRMS: m/z calcd for C17H24O5Na [M + Na]+: 331.1516; found:
331.1523.
2-[3-(Dichloromethylene)hexyl]-1,3-dimethoxybenzene (10)
(EtO)2P(O)CCl3 (1.42 mL, 7.62 mmol) was dissolved in a mixture
of THF (4.0 mL) and Et2O (4.0 mL). The soln was cooled to –
115 °C (EtOH/liquid N2), and 2.5 M n-BuLi in hexane (3.1 mL,
7.6 mmol) was added dropwise. The mixture was stirred for 30 min,
and then a soln of ketone 7 (600 mg, 2.54 mmol) in Et2O (2.0 mL)
was added. After stirring for 1 h at –115 °C, the soln was warmed
to r.t. and then heated to reflux for 18 h. After the mixture had
cooled to 0 °C, sat. aq NH4Cl (15 mL) and Et2O (15 mL) were add-
ed. The aqueous layer was extracted with Et2O (3 × 15 mL) and the
combined organic extracts were dried (MgSO4). The crude product
was purified by flash chromatography (silica gel, pentane–Et2O,
19:1 to 9:1).
Yield: 607 mg (79%); colorless oil; Rf = 0.48 (hexane–MTBE, 9:1).
1-(2,6-Dimethoxyphenyl)hexan-3-one (7)
IR (film): 2960 (s), 2871 (m), 2835 (m), 1596 (s), 1474 (s),
1435 (m), 1280 (w), 1257 (s), 1188 (m), 1164 (m), 1117 (s),
1086 (m), 904 (m), 775 (m), 725 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (t, J = 8.3 Hz, 1 H), 6.53 (d,
J = 8.3 Hz, 2 H), 3.82 (s, 6 H), 2.82–2.76 (m, 2 H), 2.42–2.37 (m, 2
H), 2.31–2.26 (m, 2 H), 1.52 (pseudo sext, J = 7.5 Hz, 2 H), 0.95 (t,
J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.6 (2 C), 139.8, 127.2, 117.9,
115.0, 103.8 (2 C), 55.8 (2 C), 35.6, 32.8, 20.7, 20.6, 14.1.
HRMS (EI): m/z calcd for C15H20O2 [M]+: 302.0840; found:
302.0851.
Keto ester 6 (17.8 g, 57.7 mmol) was dissolved in EtOH (290 mL).
H2O (16 mL) and KOH (16.2 g, 289 mmol) were added and the soln
was heated for 4 h under reflux. After the mixture had cooled to r.t.,
the EtOH was removed in vacuo. The residue was taken up in
CH2Cl2 (300 mL), washed with H2O (3 × 250 mL), and dried
(MgSO4). The crude product was purified by flash chromatography
(silica gel, pentane–Et2O, 9:1).
Yield: 13.1 g (96%); colorless solid; Rf = 0.56 (hexane–MTBE,
1:1); mp 35 °C.
IR (KBr): 2960 (m), 2837 (w), 1711 (s), 1595 (s), 1474 (s),
1436 (m), 1367 (w), 1256 (s), 1189 (w), 1160 (m), 1115 (s),
1068 (w), 1040 (w), 777 (m), 727 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.13 (t, J = 8.3 Hz, 1 H), 6.52 (d,
J = 8.3 Hz, 2 H), 3.79 (s, 6 H), 2.93–2.88 (m, 2 H), 2.58–2.53 (m, 2
H), 2.39 (t, J = 7.5 Hz, 2 H), 1.61 (pseudo sext, J = 7.4 Hz, 2 H),
0.92 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 211.6, 158.2 (2 C), 127.8, 117.5,
103.6 (2 C), 55.6 (2 C), 44.5, 42.1, 17.8, 17.3, 13.8.
ESI-HRMS: m/z calcd for C14H21O3 [M + H]+: 237.1485; found:
237.1488.
{4-[3-(Dichloromethylene)hexyl]-3,5-dimethoxyphenyl}(pina-
colato)borane (11)
In a glass tube, (Bpin)2 (254 mg, 1.0 mmol), dtbpy (4.0 mg,
15 mmol), and [Ir(cod)(OMe)]2 (5.0 mg, 7.5 mmol) were dissolved
in hexane (2.0 mL). After the mixture had stirred at r.t. for 15 min,
dichloromethylene 10 (303 mg, 1.0 mmol) was added. The tube
was sealed with a Teflon cap and heated by microwave for 3 h to
150 °C. After cooling to r.t., the mixture was poured into MTBE
(20 mL) and washed with H2O (2 × 15 mL). The organic layer was
dried (MgSO4) and concentrated. The crude product was purified by
flash chromatography (silica gel, pentane–Et2O, 9:1).
1-[2,6-Dimethoxy-4-(pinacolatoboryl)phenyl]hexan-3-one (8)
In a glass tube, (Bpin)2 (762 mg, 3.0 mmol), dtbpy (12.1 mg,
45.0 mmol), and [Ir(cod)(OMe)]2 (14.9 mg, 22.5 mmol) were dis-
Synthesis 2008, No. 14, 2217–2220 © Thieme Stuttgart · New York

2220
J. Cordes et al.
PAPER
Yield: 346 mg (81%; or 99% on the basis of 55 mg recovered start-
ing material 10); colorless solid; Rf = 0.20 (hexane–MTBE, 9:1);
mp 81 °C.
IR (film): 3420 (br s), 2963 (s), 2934 (m), 2872 (w), 1611 (s),
1597 (s), 1510 (w), 1422 (s), 1340 (w), 1160 (s), 1096 (m),
1050 (s), 969 (w), 902 (s), 822 (m) cm–1.
IR (KBr): 2971 (s), 1575 (s), 1446 (m), 1404 (s), 1371 (s),
1305 (m), 1262 (w), 1238 (w), 1209 (w), 1178 (m), 1164 (s),
1145 (m), 1125 (s), 1087 (w), 693 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.41 (s, 2 H), 4.99 (br s, 2 H),
2.76–2.71 (m, 2 H), 2.44–2.40 (m, 2 H), 2.30–2.25 (m, 2 H), 1.51
(pseudo sext, J = 7.6 Hz, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 6.97 (s, 2 H), 3.86 (s, 6 H), 2.82–
2.78 (m, 2 H), 2.41–2.35 (m, 2 H), 2.30–2.24 (m, 2 H), 1.52 (pseudo
sext, J = 7.5 Hz, 2 H), 1.35 (s, 12 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.0 (2 C), 139.7, 127.8, 121.6,
115.0, 109.7 (2 C), 83.9 (2 C), 56.0 (2 C), 35.6, 32.7, 25.0 (4 C),
21.0, 20.6, 14.1.
13C NMR (100 MHz, CDCl3): d = 155.2 (2 C), 139.1, 132.2, 115.8,
113.0, 108.8 (2 C), 35.8, 32.6, 20.7, 20.6, 14.0.
ESI-HRMS: m/z calcd for C13H15Cl3O2Na [M + Na]+: 328.9873;
found: 328.9868.
Acknowledgment
11B NMR (160 MHz, CDCl3): d = 31.5.
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
ESI-HRMS: m/z calcd for C21H31BCl2O4Na [M + Na]+: 451.1585;
found: 451.1589.
5-Chloro-2-[3-(dichloromethylene)hexyl]-1,3-dimethoxyben-
zene (12)
References
In a glass tube, CuCl2·2H2O (1.0 g, 6.1 mmol) was suspended in a
mixture of H2O (0.5 mL) and i-PrOH (4.5 mL). Boronate 11
(260 mg, 0.61 mmol) was added and the tube was sealed with a
Teflon cap and heated under microwave for 2 h to 150 °C. After
cooling to r.t., the mixture was poured into MTBE (75 mL) and
washed with H2O (2 × 25 mL). The organic layer was dried
(MgSO4) and concentrated. The crude product was purified by flash
chromatography (silica gel, pentane–Et2O, 9:1).
(1) (a) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N.
Angew. Chem. Int. Ed. 2002, 41, 3056. (b) Ishiyama, T.;
Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
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M. K.; Holmes, D.; Maleczka, R. E. Jr.; Smith, M. R. III.
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7792. (e) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove,
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(2) Sata, N.; Galario, M. A.; Sitachitta, N.; Scheuer, P. J.; Kelly,
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(3) Antonioletti, R.; Bovicelli, P.; Malancona, S. Tetrahedron
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Yield: 199 mg (97%); colorless oil; Rf = 0.57 (hexane–MTBE, 9:1).
IR (KBr): 2961 (s), 1589 (s), 1453 (m), 1409 (m), 1229 (w),
1182 (w), 1167 (m), 1126 (s), 898 (w), 875 (w), 815 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 6.53 (s, 2 H), 3.80 (s, 6 H), 2.75–
2.72 (m, 2 H), 2.38–2.35 (m, 2 H), 2.28–2.25 (m, 2 H), 1.52 (pseudo
sext, J = 7.5 Hz, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.8 (2 C), 139.4, 132.7, 116.3,
115.2, 104.7 (2 C), 56.0 (2 C), 35.6, 32.6, 20.6, 20.5, 14.1.
(4) Briese, R. R.; McElvain, S. M. J. Am. Chem. Soc. 1933,
1697.
(5) Kabalka, G. W.; Akula, M. R.; Huffman, J. W. Synthesis
2005, 547.
HRMS (EI): m/z calcd for C15H19Cl3O2 [M]+: 336.0451; found:
336.0457.
(6) Roedig, A.; Ganns, E. M.; Henrich, C.; Schnutenhaus, H.
Liebigs Ann. Chem. 1981, 1674.
(7) The crystal data of compound 11 have been deposited at the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 686558. Crystal data: C21H31BCl2O4,
M = 429.17, monoclinic, C2/c, a = 16.8261 (9) Å,
b = 13.2384 (7) Å, c = 21.5067 (13) Å, b = 104.026 (4)°,
V = 4647.8 (4) Å3, Z = 8, Dcalcd = 1.227 g/cm3, 20619
collected reflections, 4102 independent (Rint = 0.0775),
R1 = 0.0339, wR2 = 0.0709 (all data).
(8) Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.;
Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.;
Oliver, P. A.; Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger,
M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang, W. Org.
Process Res. Dev. 2004, 8, 897.
5-Chloro-2-[3-(dichloromethylene)hexyl]benzene-1,3-diol
(Poipuol; 3)
Chlorobenzene 12 (70 mg, 0.21 mmol) was dissolved in
CH2Cl2 (4.0 mL). A 1 M soln of BBr3 in CH2Cl2 (0.62 mL,
0.62 mmol) was added, and the resulting soln was stirred at r.t. for
3 d. After dilution of the mixture with CH2Cl2 (50 mL), H2O (1 mL)
was added and the mixture was stirred for 30 min. The soln was
washed with H2O (20 mL) and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were dried
(MgSO4) and concentrated. The crude product was purified by flash
chromatography (silica gel, pentane–Et2O, 19:1 to 9:1).
Yield: 53 mg (83%); colorless solid; Rf = 0.35 (hexane–MTBE,
3:1); mp 54 °C.
Synthesis 2008, No. 14, 2217–2220 © Thieme Stuttgart · New York