Preparation of substituted hydroquinones and benzofurans from 1,4-quinone monoketals

Article abstract of DOI:10.1055/s-2006-950236

An easy procedure for the preparation of 2-substituted hydroquinones, by addition of organolithium or organomagnesium compounds to 1,4-quinone monoketals followed by acid-catalyzed dienone-phenol type rearrangement, is described. Transformation of the pro

Full text of DOI:10.1055/s-2006-950236

PAPER
3419
Preparation of Substituted Hydroquinones and Benzofurans from
1
,4-Quinone Monoketals
ne Monoketal sJ . Salom-Roig, Philippe Renaud*b
a
Substituted Hydroq
X
a
uinones an
v
d Benzofura
i
ns from
e
1,4-Quino
r
a
LAPP, UMR 5810, Université de Montpellier II, CC 19, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
University of Bern, Department of Chemistry and Biochemistry, Freiestraße 3, 3012 Bern, Switzerland
b
E-mail: philippe.renaud@ioc.unibe.ch
Received 28 March 2006; revised 20 June 2006
OR
RO OR
Abstract: An easy procedure for the preparation of 2-substituted
hydroquinones, by addition of organolithium or organomagnesium
compounds to 1,4-quinone monoketals followed by acid-catalyzed
dienone–phenol type rearrangement, is described. Transformation
of the propargylated derivatives to benzofurans is also reported.
R'
R'
H+
R'-M
,4 addition
Path 1
1
O
OH
OR
RO OR
Key words: phenols, quinones, organometallic reagents, rear-
rangements, heterocycles
RO OR
HO R'
O
H+
2
-Substituted hydroquinones and benzoquinones are com-
R'-M
,2 addition
Path 2
mon subunits in biologically active secondary metabo-
lites. Incorporation of this framework during the synthesis
of natural products remains a challenging problem. In our
1
R'
OH
studies toward the total synthesis of frondosin A and B Scheme 1 Possible strategies for the transformation of 1,4-quinone
1
monoketals into monosubstituted hydroquinones
(
Figure 1), we became interested in developing efficient
procedures to introduce such aromatic moieties.
Commercially available 1,4-quinone monoketal 1 was se-
lected for our initial study (Scheme 2). 1,2-Addition of
5
HO
HO
D
D
organometallics to 1 gave the corresponding p-quinol ket-
al. For instance, addition of lithiated 1-(trimethylsi-
lyl)prop-1-yne afforded derivative 2 in 81% yield
(Scheme 2). Desilylation of 2 with tetrabutylammonium
fluoride gave the terminal alkyne 3 in 65% yield. On the
other hand, addition of benzyllithium to 1 led to p-quinol
ketal 4 in 54% yield. Attempts to run this reaction with
commercially available benzylmagnesium chloride af-
forded the dienol 4 together with the 1,4-addition product.
OH
C O
A
B
A
B
Frondosin A
Frondosin B
Figure 1 Two secondary metabolites with substituted hydroqui-
none (frondosin A) and benzofuran (frondosin B) moieties
Different acidic conditions were then tested for the p-
quinol ketal–phenol rearrangement. The best results were
obtained with protic organic acids such as oxalic acid and
p-toluenesulfonic acid (Scheme 2). Treatment of 2 with a
catalytic amount of oxalic acid (10 mol%) in refluxing tet-
rahydrofuran afforded the rearranged mono-O-alkylated
Readily available 1,4-quinone monoketals are ideal as
starting materials for the preparation of 2-substituted hyd-
roquinones. Two approaches for this conversion are pos-
sible (Scheme 1): the 1,4-addition pathway leading, after
acidic treatment, to a 4-alkoxy-3-alkylphenol (path 1) and
the 1,2-addition process leading, after acid-catalyzed rear-
rangement of the p-quinol ketal intermediate, to a 4-
alkoxy-2-alkylphenol (path 2).2 The acid-catalyzed rear-
rangement of path 2 represents the ketal version of the
1
,4-hydroquinone 6 in 74% yield. Terminal alkyne 3 did
not react under similar conditions and required the use of
p-toluenesulfonic acid (10 mol%) to deliver the rear-
ranged product 7 in 65% yield. Finally, the benzylated de-
rivative 4 afforded product 8 upon treatment with oxalic
acid in 74% yield.
,3
4
known dienone–phenol rearrangement. We report here
the conversion of 1,4-quinone monoketals into 4-alkoxy-
2
-alkylphenols according to path 2. Furthermore, the
In several cases, better overall yields were obtained when
the unstable dienol intermediates were not isolated. Thus,
the crude product of the addition of butyllithium to mono-
protected quinone 1 was directly treated with oxalic acid
to afford the 2-butylhydroquinone 9 in 51% yield
preparation of 4-alkoxybenzofurans from quinone
monoketals is also described.
SYNTHESIS 2006, No. 20, pp 3419–3424
1
7.
1
0
.
2
0
0
6
(
Scheme 2). A similar result was obtained from 1 and al-
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-950236; Art ID: T05306SS
Georg Thieme Verlag Stuttgart · New York
©

3
420
X. J. Salom-Roig, P. Renaud
PAPER
lylmagnesium bromide, leading to 10 in 71% yield over
two steps (Scheme 2).
OH
+
O
+
OH
O
O
O
O
H+
[1,2] shift
2
-Hydroxyethyl ethers such as 6–10 have been reported to
be converted into the free phenol via formation of the cor-
responding iodide followed by reduction with zinc pow-
aromatization
R
HO
R
H
R
OH
6
der. However, a more direct approach to the nonprotected
A
B
C
hydroquinones was developed. Indeed, the rearrangement
of 2 and 3 catalyzed by oxalic acid in the presence of wa-
ter delivered the unprotected 2-propargylhydroquinones
+
H , H2O
H
1
1 and 12 in 58% yield (Scheme 2).
O
OH
O
H+
[1,2] shift
OH
O
aromatization
O
O
O
O
R
RM
(CO2H)2
THF
HO
R
H
O
R
OH
D
E
F
R
HO
R
OH
O
Scheme 3 Assumed reaction mechanism for the conversion of p-
1
2 81%
6 74%
7 65%*
8 74%
quinol monoketals into monosubstituted hydroquinones
Bu4NF
3
4
65% (from 2)
54%
of lithiated 1-(trimethylsilyl)prop-1-yne to the quinone
2
3
4
, 6: R = -CH2-C C SiMe3
, 7: R = -CH2-C C-H
, 8: R = -CH2-Ph
8
monoketals 13 and 14 yielded tertiary dienols that were
* p-TsOH instead of (CO H)
2
2
used without purification for the rearrangement. Treat-
ment of the crude alcohols with oxalic acid (0.1 equiv) in
refluxing tetrahydrofuran afforded 15 and 16 in 54 and
OH
O
O
O
8
4% yield, respectively. Treatment of these two phenols
1
2
) BuLi
with potassium hydroxide in the presence of 18-crown-6
gave benzofurans 17 and 18 in 76 and 71% yield, respec-
tively.
) (CO2H)2, THF
O
OH
(51%)
1
9
MeO OMe
MeO OMe
OH
R
R
R
R
O
(
CO2H)2
O
O
LiCH2-C
C
SiMe3
1
) CH2=CHCH2MgBr
) (CO2H)2, THF
THF, reflux
SiMe3
HO
2
O
1
1
3 R = H
4 R = Me
O
OH
1
10 (71%)
OMe
OH
R
OH
O
O
R
R
MeO
R
(
CO2H)2
KOH, 18-crown-6
THF, reflux
R
THF, H2O
O
HO
R
17 R = H, 76%
8 R = Me, 71%
OH
1
2
3
R = SiMe3
R = H
11 R = SiMe3 (58%)
12 R = H (58%)
SiMe3
1
5 R = H, 54%
Scheme 2 Preparation of monosubstituted hydroquinones from 1,4-
16 R = Me, 84%
quinone monoketals
Scheme 4 Preparation of 5-methoxybenzofurans from 1,4-quinone
monoketals
The assumed mechanism of the rearrangement is depicted
in Scheme 3. Acid-catalyzed opening of the acetal func-
tion in the starting p-quinol monoketal A affords the oxo-
nium ion B that gives, after 1,2-substituent shift and
aromatization, the corresponding monoprotected 2-substi-
tuted-hydroquinone derivative C. In the presence of wa-
ter, the acetal group in A is first hydrolyzed to p-quinol D,
and under acidic conditions the protonated p-quinol E re-
arranges to give the 2-substituted hydroquinone F.
In conclusion, we have demonstrated that addition of or-
ganolithium and organomagnesium reagents to quinone
monoketals, followed by the acid-catalyzed acetal version
of the dienone–phenol rearrangement represents an attrac-
tive procedure for the preparation of 2-subsituted 4-alk-
oxyphenol and 2-substituted hydroquinones. By using a
propargylation process, straightforward access to 4-
alkoxybenzofurans was developed. Application of these
procedures to the preparation of frondosins is currently
being investigated.
Finally, we applied this 1,2-rearrangement to the synthe-
7
sis of 5-methoxybenzofurans (Scheme 4). 1,2-Addition
Synthesis 2006, No. 20, 3419–3424 © Thieme Stuttgart · New York

PAPER
Substituted Hydroquinones and Benzofurans from 1,4-Quinone Monoketals
2-[3-(Trimethylsilyl)prop-2-ynyl]benzene-1,4-diol (11)
3421
THF and CH Cl were dried and purified over activated alumina
2
2
columns prior to use. Other reagents were obtained from commer-
cial sources and used as received. Flash chromatography was car-
ried out over silica gel (0.063–0.200 mm); EtOAc, hexanes, MTBE,
and cyclohexane were used as eluents. TLC detection was either
A soln of 2 (188 mg, 0.71mmol) in THF (5 mL) and H O (2 mL)
was refluxed for 5 h in the presence of oxalic acid (7 mg, 0.07
2
mmol). The mixture was treated with aq sat. NaHCO to reach pH 7.
3
H O (10 mL) was added, the layers were separated, and the aqueous
2
with UV, vanillin, or KMnO and subsequent heating. FT-IR spec-
tra were obtained on a Mattson Unicam 5000 spectrometer. NMR
layer was extracted with MTBE (3 × 25 mL). The combined organic
4
phases were washed with brine (2 × 25 mL), dried (MgSO ), and
4
1
13
spectra were obtained on Bruker AM ( H, 300 MHz; C, 75.5
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, hexanes–EtOAc, 1:1).
1
13
MHz) and Bruker AM ( H, 400 MHz; C, 100.6 MHz) spectrome-
ters; the chemical shifts are expressed in ppm relative to TMS
d = 0) or CHCl (d = 7.26) for H and CDCl (d = 77.0 ppm) for C
NMR. MS was carried out on Vacuum Generators Micromass VG
0/70E and DS 11-250 spectrometers [CI (CH ), EI (70 eV)].
Yield: 91 mg (58%); white solid; mp 106–107 °C.
1
13
(
3
3
IR (KBr): 3430, 3560, 3040, 2960, 2890, 2190, 1624, 1610, 1520,
–
1
1
450, 1370, 1250, 1225, 1200, 1030, 850, 800 cm .
7
4
HRMS determinations were recorded on a FTICR mass spectrome-
ter, Bruker 4.7 BioApex II.
1
H NMR (400 MHz, CDCl ): d = 6.72 (d, J = 2.8 Hz, 1 H, COHCH-
3
CC), 6.70 (d, J = 8.5 Hz, 1 H, COHCHCHCOHCC), 6.62 (dd,
J = 8.5 Hz, J = 3.0 Hz, 1 H, COHCHCHCOHCC), 5.41 (s, 1 H,
OH), 4.82 (s, 1 H, OH), 3.56 (s, 2 H, CH ), 0.19 (s, 9 H, CH ).
1
2
8
-[3-(Trimethylsilyl)prop-2-ynyl]-1,4-dioxaspiro[4.5]deca-6,9-
2
3
dien-8-ol (2)
1
3
C NMR (100.6 MHz, CDCl ): d = 149.3, 147.8, 123.4, 117.0,
3
A 1.4 M soln of n-BuLi in hexanes (4.7 mL, 6.57 mmol) was added
dropwise to a soln of 1-(trimethylsilyl)prop-1-yne (0.97 mL, 6.57
mmol) in THF (200 mL) cooled to –78 °C. The mixture was stirred
for 1.5 h at –78 °C, after which a soln of 1 (1.00 g, 6.57 mmol) in
THF (10 mL) was added via cannula. After stirring overnight at r.t.,
1
16.2, 114.7, 102.8, 88.6, 21.7, –0.1.
+
MS (EI, 70 eV): m/z (%) = 220 (40) [M ], 205 (50), 177 (100), 131
(19), 73 (60).
+
HRMS (CI): m/z calcd for C H O Si: 220.09195 [M + 1]; found:
1
2
16
2
the mixture was treated with aq sat. NH Cl (150 mL). The soln was
4
2
20.09193.
extracted with MTBE (3 × 200 mL), dried (MgSO ), and concen-
4
trated in vacuo; this afforded a crude yellow oil that was purified by
flash chromatography (silica gel, cyclohexane–MTBE, 2:1).
8
-(Prop-2-ynyl)-1,4-dioxaspiro[4.5]deca-6,9-dien-8-ol (3)
A 2.4 M soln of n-BuLi in hexanes (4.6 mL, 0.011 mol) was added
Yield: 1.40 g (81%); white solid; mp 85–87 °C.
dropwise to a stirred soln of 1-(trimethylsilyl)prop-1-yne (1.52 mL,
1
0.3 mmol) in THF (100 mL) cooled to –78 °C. After the addition,
the mixture was stirred for 1.5 h at this temperature. A soln of 1
1.30 g, 8.54 mmol) in THF (100 mL) was added via cannula and
IR (KBr): 3472, 2958, 2891, 2178, 1672, 1616, 1509, 1440, 1417,
–
1
1
249, 1204, 1116, 1026, 963, 843, 760 cm .
(
1
H NMR (400 MHz, CDCl ): d = 6.11 (d, J = 12.5 Hz, 2 H, CH),
3
the reaction mixture was stirred overnight at r.t. Sat. NH Cl (150
mL) was added and the soln was extracted with Et O (3 × 200 mL)
and dried (MgSO ). Concentration in vacuo afforded a yellow oil.
4
5
.80 (d, J = 12.5 Hz, 2 H, CH), 4.03 (s, 4 H, OCH CH O), 2.52 (s,
2 2
2
2
H, CCH C), 2.32 (br s, 1 H, OH), 0.15 (s, 9 H, CH ).
2 3
4
1
3
C NMR (100.6 MHz, CDCl ): d = 135.2, 127.6, 101.0, 99.0, 88.7,
3
A 1 M soln of TBAF in THF (11 mL, 11 mmol) was added dropwise
to the resulting crude product in THF (20 mL). After stirring for
2.5 h at r.t., the mixture was treated with an aq sat. NH Cl soln (100
6
6.3, 65.3, 65.0, 33.1, 0.0.
+
HRMS (CI): m/z calcd for C H O Si: 264.11817 [M + 1]; found:
4
14
20
3
mL), and the aqueous phase was extracted with Et O (3 × 200 mL).
2
64.11819.
2
The combined organic phases were washed with brine (2 × 100
mL), dried (MgSO ), and concentrated in vacuo to afford a crude
4
-(2-Hydroxyethoxy)-2-[3-(trimethylsilyl)prop-2-ynyl]phenol
4
yellow oil. Purification by flash chromatography (silica gel, hex-
anes–EtOAc, 5:1) gave 3 as a white solid.
(
6)
Compound 2 (151 mg, 0.57 mmol) was stirred for 4 h at reflux in
THF (5 mL) in the presence of a catalytic amount of oxalic acid (12
Yield: 1.074 g (65%); mp 81–82 °C.
mg, 0.011 mmol). An aq sat. soln of NaHCO was added until pH 7
3
IR (KBr): 3468, 3277, 3037, 2935, 2894, 2361, 2334, 2116, 1674,
was reached, and H O (10 mL) was added. The layers were separat-
2
–1
1
623, 1507, 1446, 1412, 1201, 1115, 1010, 948, 792, 656 cm .
ed and the aqueous phase was extracted with Et O (3 × 25 mL). The
2
1H NMR (300 MHz, CDCl
5.82 (m, 2 H, CHCH), 4.05 (s, 4 H, CH
): d = 6.16–6.11 (m, 2 H, CHCH), 5.88–
CH ), 2.50 (d, J = 2.6 Hz, 2
H, CCCH ), 2.26 (br s, 1 H, OH), 2.11 (t, J = 2.6 Hz, 1 H, CCH).
2
combined organic phases were washed with brine (2 × 25 mL),
3
dried (MgSO ), and concentrated in vacuo. The crude product was
2
2
4
purified by flash chromatography (silica gel, cyclohexane–MTBE,
3
:1).
13
C NMR (75.5 MHz, CDCl ): d = 135.1, 127.6, 98.8, 79.0, 71.3,
3
Yield: 111 mg (74%); yellow oil.
66.3, 65.1, 65.0, 31.3.
IR (film): 3382, 2959, 2248, 2175, 1610, 1508, 1440, 1250, 1206,
MS (EI, 70 eV): m/z (%) = 192 (11), 153 (100), 109 (65), 81 (65),
65 (50), 39 (45).
–1
1
075, 1028, 910, 845, 734 cm .
1
+
H NMR (300 MHz, CDCl ): d = 6.89 (d, J = 2.9 Hz, 1 H,
HRMS (CI): m/z calcd for C11
192.07855.
H
12
O
3
: 192.07864 [M + 1]; found:
3
CHCCH ), 6.71 (d, J = 8.8 Hz, 1 H, COHCHCHCOHCC), 6.60 (dd,
J = 8.8 Hz, J = 2.9 Hz, 1 H, COHCHCHCOHCC), 6.52 (br s, 1 H,
OH), 4.08–3.91 (m, 4 H, CH CH ), 3.54 (s, 2 H, CCCH ), 3.02 (br
2
1
2
4-(2-Hydroxyethoxy)-2-(prop-2-ynyl)phenol (7)
2
2
2
s, 1 H, CH OH), 0.19 (s, 9 H, CH ).
Using the procedure described for 6, starting from 3 (172 mg, 0.89
2
3
1
3
mmol) in CH
2 2
Cl (4 mL) and a catalytic amount of p-TsOH (15 mg,
C NMR (75.5 MHz, CDCl ): d = 151.2, 147.0, 122.5, 115.2,
3
0
.089 mmol), product 17 was obtained as a beige solid.
1
14.5, 112.9, 102.5, 86.9, 68.6, 60.4, 20.2, –1.1.
Yield: 111 mg (65%); mp 86–88 °C.
MS (EI, 70 eV): m/z (%) = 264 (39), 249 (31), 221 (37), 177 (42),
4 (100), 47 (25).
8
IR (KBr): 3364, 3289, 3094, 2969, 2932, 2874, 2116, 1619, 1602,
1514, 1448, 1306, 1255, 1230, 1075, 1058, 898, 869, 817 cm .
–
1
+
HRMS (CI): m/z calcd for C H O Si: 264.11817 [M + 1]; found:
14
20
3
2
64.11819.
Synthesis 2006, No. 20, 3419–3424 © Thieme Stuttgart · New York

3
422
X. J. Salom-Roig, P. Renaud
PAPER
1
H NMR (400 MHz, acetone-d ): d = 8.11 (br s, 1 H, OH), 7.09 (d,
tion, 10-benzyl-1,4-dioxaspiro[4.5]dec-6-en-8-one was also ob-
tained as a white solid; yield: 0.93 g (30%).
6
J = 2.8 Hz, 1 H, COCHCCH ), 6.80 (d, J = 8.5 Hz, 1 H, COCHCH-
2
1
2
COH), 6.71 (dd, J = 8.5 HZ, J = 2.8 Hz, 1 H, COCHCHCOH),
.03–4.00 (m, 2 H, OCH ), 3.89–3.85 (m, 2 H, OCH ), 3.57–3.56
1
H NMR (400 MHz, CDCl ): d = 7.34–7.20 (m, 5 H, CH), 6.72 (d,
3
4
(
2
2
J = 8.5 Hz, 1 H, CHCHCOHC), 6.70 (s, 1 H, COCHCHC), 6.66 (dd,
J = 8.5 Hz, J = 3 Hz, 1 H, CH CH ), 5.16 (s, 1 H, OH), 4.12–3.88
m, 2 H, CCH C), 3.11 (s, 1 H, CH OH), 2.62 (t, J = 2.8 Hz, 1 H,
1
2
2
2
2
2
CCH).
1
(
m, 6 H, OCH CH O and PhCH ), 2.38 (br s, 1 H, OH).
2 2 2
3
C NMR (75.5 MHz, acetone-d ): d = 152.9, 148.7, 124.0, 116.0,
13
6
C NMR (75 MHz, CDCl ): d = 152.6, 148.1, 139.8, 128.7, 128.6,
3
1
15.5, 113.4, 81.9, 71.4, 70.5, 61.0, 19.0.
1
28.5, 126.3, 117.4, 116.3, 113.2, 69.7, 61.5, 36.4.
+
MS (EI, 70 eV): m/z (%) = 192 (26) [M ], 147 (100), 91 (32).
+
MS (EI, 70 eV): m/z (%) = 244 (100) [M ], 200 (85), 181 (36), 122
HRMS (ESI-MS) calcd for C H O : 193.0873; found: 193.0864.
(100), 115 (37), 94 (52), 91 (56), 65 (34).
11
13
3
+
HRMS (CI): m/z calcd for C H O : 244.10994 [M + 1]; found:
1
5
16
3
2
-(Prop-2-ynyl)benzene-1,4-diol (12)
2
44.10992.
Using the procedure described for 11, starting from 3 (80 mg, 0.42
mmol) in THF (4 mL), H O (1 mL), and a catalytic amount of oxalic
acid (4 mg, 0.042 mmol), product 12 was obtained as a pale color-
less oil.
2
1
0-Benzyl-1,4-dioxaspiro[4.5]dec-6-en-8-one
Mp 64–65 °C.
IR (KBr): 3030, 2973, 2898, 1678, 1492, 1456, 1380, 1286, 1228,
1
Yield: 35 mg (58%).
–1
150, 1081, 1011, 948, 916, 758, 709 cm .
1
H NMR (300 MHz, CDCl ): d = 7.91 (br s, 1 H, OH), 7.78 (br s, 1
1
3
H NMR (400 MHz, CDCl ): d = 7.31–7.12 (m, 5 H, CH arom),
3
H, OH), 7.01 (d, J = 2.9 Hz, 1 H, CHCCH ), 6.71 (d, J = 8.5 Hz, 1
H, COHCHCHCOHCC), 6.59 (dd, J = 8.8 Hz, J = 2.9 Hz, 1 H,
2
6
.67 (d, J = 10 Hz, 1 H, CH), 6.0 (d, J = 10 Hz, 1 H, CH), 4.21 (m,
1
2
1
2
4
2
H, OCH ), 3.15 (dd, J = 13.3 Hz, J = 3.2 Hz, 1 H, CCHCH ),
2
2
COHCHCHCOHCC), 3.54 (d, J = 2.6 Hz, 2 H, CH ), 2.60 (t,
2
.66–2.38 (m, 4 H, COCH , CHCH ).
2
2
J = 2.6 Hz, 1 H, HCC).
1
3
C NMR (100.6 MHz, CDCl ): d = 198.6, 146.3, 138.9, 129.8,
1
3
3
C NMR (75.5 MHz, CDCl ): d = 152.1, 148.9, 125.1, 117.2,
3
1
29.1, 128.5, 126.3, 105.7, 65.7, 65.3, 44.7, 39.6, 34.4.
1
16.9, 115.4, 83.4, 72.5, 20.2.
+
MS (EI, 70 eV): m/z (%) = 244 (36) [M ], 216 (20), 202 (21), 126
MS (EI, 70 eV): m/z (%) = 147 (100), 91 (43), 65 (29).
(
100), 117 (26), 104 (27), 98 (82), 91 (77), 65 (36).
+
HRMS (CI): m/z calcd for C H O : 244.10994 [M + 1]; found:
8
-Benzyl-1,4-dioxaspiro[4,5]deca-6,9-dien-8-ol (4)
15 16
3
2
44.10994.
A 1.4 M soln of n-BuLi in hexanes (3.7 mL, 5.19 mmol) was added
rapidly to a soln of TMEDA (0.78 mL, 5.19 mmol) in toluene (7
2
-Allyl-4-(2-hydroxyethoxy)phenol (10)
mL) under a N atmosphere. The resulting yellow soln was heated
2
A 1.0 M soln of allylmagnesium bromide in Et O (3.3 mL, 3.3
mmol) in THF (30 mL) was cooled to –78 °C and a soln of 1 (0.5 g,
at 80 °C with stirring for 0.5 h. A soln of 1 (0.789 g, 5.19 mmol) in
toluene (7 mL) was added via cannula to the reaction mixture
2
3
.3 mmol) in THF (10 mL) was added dropwise. The reaction mix-
ture was stirred overnight (–78 °C to r.t.). The reaction was treated
with aq sat. NH Cl (150 mL) and the mixture was extracted with
cooled at 0 °C, and then the mixture was stirred overnight at r.t. H O
2
(
10 mL) was added and the soln was extracted with CH Cl (3 × 20
2
2
mL). After concentration in vacuo, the crude beige solid was
4
MTBE (3 × 200 mL) and dried (MgSO ). After concentration in
washed with Et O (3 × 100 mL).
4
2
vacuo, THF (2 mL) and oxalic acid (34 mg, 0.33 mmol) were added
to the resulting yellow oil and the soln was refluxed for 4.5 h. The
mixture was treated with H O (25 mL) and extracted with Et O (3 ×
Yield: 687 mg (54%); white solid; mp 143–145 °C.
IR (KBr): 3430, 3030, 2920, 2890, 2350, 1675, 1600, 1410, 1370,
2
2
–1
1
110, 1035, 960, 700 cm .
25 mL) to afford, after drying (MgSO ) and concentration, a crude
4
1
yellow oil. Purification by flash chromatography (silica gel, cyclo-
hexane–MTBE, 4:1–2:1) furnished 10 as a yellow oil.
H NMR (300 MHz, CDCl ): d = 7.39–7.22 (m, 5 H, CH arom),
3
6
.02 (d, 2 H, CH), 7.70 (d, 2 H, CH), 4.08 (s, 4 H, CH ), 2.91 (s, 2
2
H, CCH C), 2.22 (br s, 1 H, OH).
Yield: 453 mg (71%).
2
1
3
C NMR (75.5 MHz, CDCl ): d = 136.4, 135.8, 130.7, 128.0,
IR (film): 3360, 3080, 2930, 2870, 2370, 1640, 1610, 1510, 1440,
1210, 1070, 1050, 910, 810 cm .
3
–
1
1
26.7, 126.6, 99.1, 67.5, 65.1, 47.1.
+
1
MS (EI, 70 eV): m/z (%) = 244 (30) [M ], 153 (100), 109 (21), 91
H NMR (400 MHz, CDCl ): d = 6.72–6.60 (m, 3 H, CH), 6.04–
3
(
47), 81 (19), 65 (21).
5.83 (m, 1 H, CH), 5.74 (br s, 1 H, OH), 5.14 (m, 2 H, CCH ), 4.01–
2
+
3.92 (m, 4 H, CH
2
CH ), 3.34 (d, 2 H, J = 8.5 Hz, CCH ), 2.80 (br s,
2
2
HRMS (CI): m/z calcd for C H O : 244.10994 [M + 1]; found:
1
5
16
3
1
H, OH).
2
44.11009.
1
3
C NMR (75 MHz, CDCl ): d = 152.4, 150.0, 148.3, 136.1, 127.0,
3
2
-Benzyl-4-(2-hydroxyethoxy)phenol (8)
116.7, 116.2, 113.3, 69.7, 61.4, 34.8.
MS (EI, 70 eV): m/z (%) = 194 (77) [M ], 150 (100), 135 (40), 107
27), 84 (42), 77 (24).
HRMS (CI): m/z calcd for C H O : 194.09429 [M + 1]; found:
Using the procedure described for 6, starting from 4 (23 mg, 0.094
mmol) in THF (1 mL) and a catalytic amount of oxalic acid (1 mg,
.009 mmol), product 8 was obtained as a yellow oil; yield: 17 mg
+
(
0
+
(
74%).
11 14
3
1
94.09421.
Compound 8 was also obtained as follows: A 20 wt% soln of Bn-
MgCl in THF (10.5 mL, 0.014 mol) in THF (40 mL) was cooled to
2
-Butyl-4-(2-hydroxyethoxy)phenol (9)
–
78 °C, and a soln of 1 (1.90 g, 0.012 mol) in THF (10 mL) was add-
A 1.4 M soln of n-BuLi in hexanes (3.3 mL, 4.6 mmol) in THF (30
mL) was cooled to –78 °C and a soln of 1 (0.70 g, 4.6 mmol) in THF
ed via cannula. After 6 h at –78 °C, the reaction mixture was treated
with sat. aq NH Cl (100 mL) and extracted with Et O (3 × 15 mL).
4
2
(
10 mL) was added dropwise. The mixture was stirred overnight
Concentration in vacuo afforded a yellow oil that was purified by
flash chromatography (silica gel, hexanes–EtOAc, 4:1) giving 8;
yield: 1.11 g (40%). During this reaction, the product of 1,4-addi-
(
–78 °C to r.t.), then treated with aq sat. NH Cl (150 mL), and ex-
4
tracted with MTBE (3 × 200 mL). After the soln had been dried
(
MgSO ), the solvents were evaporated in vacuo. THF (8 mL), fol-
4
Synthesis 2006, No. 20, 3419–3424 © Thieme Stuttgart · New York

PAPER
Substituted Hydroquinones and Benzofurans from 1,4-Quinone Monoketals
3423
1
lowed by oxalic acid (48 mg, 0.46 mmol), was added to the resulting
H NMR (300 MHz, CDCl ): d = 7.31 (d, J = 8.8 Hz, 1 H, CHCH-
1
3
yellow oil, and the soln was refluxed for 4.5 h. H O (10 mL) was
CO), 6.97 (d, J = 2.4 Hz, 1 H, COMeCHCC), 6.83 (dd, J = 8.8 Hz,
J = 2.4 Hz, 1 H, COMeCHCHCO), 6.33 (s, 1 H, CCHC), 3.84 (s, 3
H, OCH ), 2.46 (s, 3 H, CH ).
2
2
added and the mixture was extracted with Et O (3 × 55 mL). Drying
2
(
MgSO ) and concentration in vacuo afforded an orange oil that was
4
3
3
purified by flash chromatography (silica gel, cyclohexane–MTBE,
:1).
13
C NMR (75.5 MHz, CDCl ): d = 155.2, 154.7, 148.7, 128.7,
3
4
1
10.2, 109.9, 102.0, 101.7, 54.8, 13.0.
Yield: 492 mg (51%); white solid.
+
MS (EI, 70 eV): m/z (%) = 162 (100) [M ], 147 (84), 119 (52), 91
IR (KBr): 3321, 2956, 2928, 2863, 1706, 1612, 1595, 1506, 1443,
(26).
–1
1
277, 1264, 1208, 1190, 1074, 980, 812, 799 cm .
+
HRMS (CI): m/z calcd for C H O : 162.06808 [M + 1]; found:
1
0
10
2
1
H NMR (400 MHz, CDCl ): d = 6.70 (d, J = 3 Hz, 1 H, COCHCH-
162.06807.
3
COHC), 6.66 (d, J = 8.5 Hz, 1 H, COCHCHCOH), 6.57 (dd,
J = 8.5 Hz, J = 3 Hz, 1 H, COCHCC), 5.56 (s, 1 H, COH), 4.02–
3
2
J = 7.3 Hz, 2 H, CH CH ), 0.93 (t, J = 7.3 Hz, 3 H, CH ).
1
1
2
4-Methoxy-3,5-dimethyl-2-[3-(trimethylsilyl)prop-2-ynyl]phe-
nol (16)
A 1.4 M soln of n-BuLi in hexanes (1.95 mL, 2.7 mmol) was added
dropwise at –78 °C to a soln of 1-(trimethylsilyl)prop-1-yne (0.41
mL, 2.7 mmol) in THF (50 mL). The mixture was stirred for 1.5 h
at –78 °C and a soln of 14 (0.50 g, 2.7 mmol) in THF (10 mL) was
added via cannula; stirring continued overnight (–78 °C to r.t.). The
.94 (m, 4 H, OCH CH O), 2.67 (br s, 1 H, OH), 2.56 (t, J = 7.5 Hz,
2 2
H, CCH CH ), 1.61–1.53 (m, 2 H, CH CH CH ), 1.37 (sept,
2
2
2
2
2
3
2
3
3
C NMR (100.6 MHz, CDCl ): d = 152.3, 148.0, 130.2, 116.7,
3
1
15.7, 112.4, 69.8, 61.5, 31.8, 29.8, 22.5, 13.9.
+
MS (EI, 70 eV): m/z (%) = 210 (48) [M ], 166 (57), 123 (100).
ESI-HRMS: m/z calcd for C H O : 211.1344; found: 211.1334.
reaction mixture was treated with aq sat. NH Cl (100 mL) and ex-
4
tracted with Et O (3 × 200 mL). The organic phases were dried
2
12
19
3
(
MgSO ) and concentrated in vacuo to afford a yellow oil. THF (20
4
mL) was added to the crude oil followed by oxalic acid (57 mg, 0.55
4
-Methoxy-2-[3-(trimethylsilyl)prop-2-ynyl]phenol (15)
mmol) and the soln was refluxed for 3.5 h. H O (10 mL) was added
A 2.4 M soln of n-BuLi in hexanes (2.8 mL, 6.8 mmol) was added
dropwise at –78 °C to a soln of 1-(trimethylsilyl)prop-1-yne (0.92
mL, 6.2 mmol) in THF (80 mL). The mixture was stirred for 1 h at
2
and the soln was extracted with MTBE (3 × 25 mL). The combined
organic phases were washed with brine (2 × 25 mL), dried
(
MgSO ), and concentrated. The crude product was purified by
4
–
78 °C and a soln of 13 (871 mg, 5.6 mmol) in THF (20 mL) was
added via cannula. The reaction mixture was stirred overnight
–78 °C to r.t.) and treated with an aq sat. NH Cl soln (100 mL). The
flash column chromatography (silica gel, cyclohexane–MTBE,
:1).
4
(
4
soln was extracted with Et O (3 × 200 mL) and dried (MgSO ).
2
4
Yield: 607 mg (84%); beige solid; mp 126–127 °C.
Concentration in vacuo afforded a crude yellow oil. THF (20 mL)
and oxalic acid (57 mg, 0.55 mmol) were added to this oil and the
soln was refluxed for 3.5 h. The reaction mixture was treated with
IR (CDCl ): 3600, 3446, 2960, 2250, 2170, 1615, 1476, 1450, 1410,
3
–
1
1
250, 1230, 1170, 1015 cm .
1
H O (10 mL) and extracted with MTBE (3 × 25 mL). The combined
H NMR (300 MHz, CDCl ): d = 6.54 (s, 1 H, CH), 5.56 (br s, 1 H,
2
3
organic phases were washed with brine (2 × 25 mL), dried
OH), 3.65 (s, 3 H, OCH ), 3.57 (s, 2 H, CH ), 2.27 (s, 3 H, CH ),
3
2
3
(
MgSO ), and concentrated in vacuo. Purification by flash chroma-
2.23 (s, 3 H, CH ), 0.15 (s, 9 H, SiCH ).
4
3
3
tography (silica gel, hexanes–EtOAc, 4:1) afforded 15 as a colorless
oil.
13
C NMR (75.5 MHz, CDCl ): d = 150.8, 150.0, 130.3, 130.0,
3
1
19.7, 116.0, 103.3, 86.6, 60.2, 18.0, 16.0, 12.5, –0.1.
Yield: 710 mg (54%).
+
MS (EI, 70 eV): m/z (%) = 262 (70) [M ], 247 (75), 219 (60), 189
IR (film): 3410, 2958, 2833, 2176, 1669, 1609, 1507, 1465, 1449,
(70), 173 (35), 116 (32), 73 (100).
–1
1
433, 1348, 1250, 1202, 1151, 1041, 935, 844, 760 cm .
+
HRMS (CI): m/z calcd for C H O Si: 262.13890 [M + 1]; found:
1
5
22
2
1
H NMR (400 MHz, CDCl ): d = 6.86 (d, J = 2.9 Hz, 1 H,
262.13892.
3
COMeCHCCH ), 6.75 (d, J = 8.6 Hz, 1 H, COMeCHCHCOH),
6
2
1
2
.69 (dd, J = 8.6 Hz, J = 2.9 Hz, 1 H, COMeCHCHCOH), 5.37 (br
5-Methoxy-2,4,6-trimethylbenzofuran (18)
s, 1 H, OH), 3.77 (s, 3 H, CH ), 3.60 (s, 2 H, CH ), 0.19 (s, 9 H,
CH3).
Using the procedure described for 17, starting from 16 (212 mg,
0.81 mmol), KOH (91 mg, 1.6 mmol), and 18-crown-6 (85 mg, 0.32
mmol) in THF (4 mL), product 18 was obtained as a yellow oil.
3
2
1
3
C NMR (100.6 MHz, CDCl ): d = 152.7, 146.8, 122.2, 115.8,
3
1
13.8, 112.3, 101.9, 87.6, 54.7, 20.9, –1.1.
Yield: 129 mg (84%).
+
MS (EI, 70 eV): m/z (%) = 234 (95) [M ], 219 (93), 191 (96), 161
IR (film): 2921, 2827, 1610, 1588, 1449, 1406, 1292, 1222, 1196,
1163, 1102, 1054, 1006, 933, 844, 790 cm .
–
1
(60), 145 (91), 115 (46), 73 (100).
+
1
HRMS (CI): m/z calcd for C H O Si: 234.10760 [M + 1]; found:
H NMR (400 MHz, CDCl ): d = 7.07 (s, 1 H, CH arom), 6.32 (t,
13
18
2
3
2
34.10768.
J = 1.3 Hz, 1 H, CH), 3.75 (s, 3 H, OCH ), 2.44 (s, 3 H, CH COC),
3
3
2
.41 (s, 3 H, CH ), 2.40 (s, 3 H, CH ).
3
3
5
-Methoxy-2-methylbenzofuran (17)
13
C NMR (75 MHz, CDCl ): d = 154.8, 152.2, 150.8, 128.0, 126.4,
3
Compound 15 (180 mg, 0.77 mmol) in THF was stirred under reflux
3 mL) with KOH (81 mg, 1.4 mmol) and 18-crown-6 (81 mg, 0.31
1
21.4, 109.6, 101.5, 60.2, 16.7, 14.0, 12.5.
(
+
MS (EI, 70 eV): m/z (%) = 190 (70) [M ], 175 (100), 119 (15).
mmol) for 2.5 h. Sat. aq NH Cl (5 mL) was added to the reaction
mixture and the soln was extracted with Et O. The combined organ-
ic phases were washed with brine (2 × 25 mL), dried (MgSO ), and
concentrated in vacuo. Purification of the crude oil by flash chroma-
4
+
2
HRMS (CI): m/z calcd for C H O : 190.09938 [M + 1]; found:
190.09943.
1
2
14
2
4
tography (silica gel, hexanes–EtOAc, 60:1) gave 17 as a yellow oil.
Acknowledgment
Yield: 95 mg (76%).
We thank the Swiss National Science Foundation (Project 20-
103627) for supporting this work.
IR (film): 2996, 2952, 2832, 1688, 1617, 1478, 1450, 1308, 1264,
–
1
1
205, 1185, 1165, 1032, 932, 834, 791 cm .
Synthesis 2006, No. 20, 3419–3424 © Thieme Stuttgart · New York

3
424
X. J. Salom-Roig, P. Renaud
PAPER
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(
1
(
(
1) (a) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte,
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Prod. Lett. 1998, 11, 153.
(
4) The dienone–phenol rearrangement of p-quinols has been
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Synthesis 1982, 46. (b) Ward, R. S.; Pelter, A.; Abd-El-
Ghani, A. Tetrahedron 1996, 52, 1303. (c) Ward, R. S.;
Pelter, A.; Abd-El-Ghani, A. J. Chem. Soc., Perkin Trans. 1
2) 1,2-Addition to quinone monoketal has been reported:
(
1
a) Swenton, J. S.; Bradin, D.; Gates, B. D. J. Org. Chem.
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(
1992, 2249. (d) Pelter, A.; Ward, R. S.; Abd-El-Ghani, A. J.
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substituted aromatic ethers. For review articles, see:
Chem. Soc., Perkin Trans. 1 1996, 1353. To the best of our
knowledge, only two examples concerning 1,2-migrations in
p-quinol ketals have been reported. Alkenyl shift:
(
(
d) Swenton, J. S. Acc. Chem. Res. 1983, 16, 74.
e) Swenton, J. S. In The Chemistry of Quinonoid
(e) Parker, K. A.; Coburn, C. A.; Koh, Y. J. Org. Chem.
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Compounds, Vol. 2, Part 2; Patai, S.; Rappoport, Z., Eds.;
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3) (a) Stern, A. J.; Swenton, J. S. J. Org. Chem. 1988, 53, 2465.
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5) See reference 2c for the preparation of 1.
6) Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61,
(
(
(
(b) Stern, A. J.; Rohde, J. J.; Swenton, J. S. J. Org. Chem.
6772.
1989, 54, 4413. (c) Swenton, J. S.; Callinan, A.; Wang, S. J.
(
7) For a review on the preparation of benzofurans, see: Dell, C.
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In Science of Synthesis, Vol. 10; Thomas, J., Ed.; Georg
Thieme Verlag: Stuttgart, 2000, 11.
Org. Chem. 1992, 57, 78. (d) Swenton, J. S.; Carpenter, K.;
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5
8, 3308. (e) Swenton, J. S.; Callinan, A.; Chen, Y.; Rohde,
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Tetrahedron Lett. 1995, 36, 4893. (g) Marks, T. M.;
(
8) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc., Perkin Trans. 1
1
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Synthesis 2006, No. 20, 3419–3424 © Thieme Stuttgart · New York