Synthesis of 3-Methylobovatol

Article abstract of DOI:10.1055/s-0035-1560262

Biphenyl lignans are rare compounds that exhibit a broad range of biological activities. The first total synthesis of natural biphenyl ether lignan, 3-methylobovatol, has been achieved in four steps. This synthesis allows for modification of the C-2 phenol and in doing so, will facilitate various structure-activity relationship studies into these bioactive compounds.

Full text of DOI:10.1055/s-0035-1560262

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 2425–2428
2425
letter
Synlett
L. I. Pilkington, D. Barker
Letter
Synthesis of 3-Methylobovatol
Lisa I. Pilkington
OMOM
OH
OH
David Barker*
MeO
Br
via Ullman
condensation
MeO
O
+
School of Chemical Sciences, University of Auckland,
2
7% over 2 steps
23 Symonds St, Auckland 1142, New Zealand
d.barker@auckland.ac.nz
3-methylobovatol
from eugenol
in 2 steps,
including a
1 step from
estragole
regioselective
bromination
Received: 09.07.2015
Accepted after revision: 11.08.2015
Published online: 07.09.2015
OH
OH
OH
RO
3
O
DOI: 10.1055/s-0035-1560262; Art ID: st-2015-d0522-l
Abstract Biphenyl lignans are rare compounds that exhibit a broad
range of biological activities. The first total synthesis of natural biphenyl
ether lignan, 3-methylobovatol, has been achieved in four steps. This
synthesis allows for modification of the C-2 phenol and in doing so, will
facilitate various structure–activity relationship studies into these bio-
active compounds.
R = H, obovatol (3)
R = Me, 3-methylobovatol (6)
magnolol (1)
OH
OH
Key words synthesis, lignin, biphenyl ether, obovatol, Ullmann con-
HO
O
densation
OH
Biphenyl-type lignans are rare compounds from within
the lignan class (Figure 1). These compounds are biosynthe-
sized through the radical coupling of phenolic substrates,
resulting in compounds with either a C–C linkage between
aryl units [as in magnolol (1) and honokiol (2)], or with a
C–O ether linkage [as seen in obovatol (3) and obovatal (4)].
Magnolianin (5) is a novel 1,4-benzodioxane lignan, isolated
from the bark of Magnolia obovata and is a trilignan derived
from two molecules of obovatol (3, red) and one of magno-
CHO
honokiol (2)
obovatal (4)
OH
1
lol (1, blue).
O
O
The most well-known biphenyl ether lignan is obovatol
3), which was first isolated alongside its oxidized deriva-
tive obovatal (4) from the bark of Magnolia obovata, a mate-
O
O
(
O
rial commonly used in Japan and China for the treatment of
gastrointestinal issues and neurosis. Obovatol (3) has
2,3
HO
OH
magnolianin (5)
been reported to have a range of biological activities includ-
ing inhibition of chitin synthase 2, inhibition of NO pro-
4
5
6
duction, displays antiplatelet effects, and also exhibits an-
titumor and anti-inflammatory activities through inhibi-
Figure 1 Naturally occurring biphenyl lignans and magnolianin (5), a
trilignan
7
tion of the transcription factor, NF-κB. Analogues of 3 have
shown activity against colon and prostate cancer whilst 3
8
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L. I. Pilkington, D. Barker
Letter
and closely related compounds 1, 2, and 4 have been
screened for their antibacterial activity against Streptococ-
cus mutans.
likely formed by the addition of HBr to the terminal alkene
in 10.19 Shortening the reaction time to one hour provided
4-allylphenol (10) in 73% yield, with no evidence of bro-
mide 12 being produced.20
2
Kijjoa et al. first isolated 3-methylobovatol (6) from
Magnolia henryi, and it has subsequently been isolated from
Illicium lanceolatum, a plant known for its anti-inflammato-
OH
OH
OMe
9,10
ry activity.
Like obovatol (3), 6 was found to inhibit NO
BBr3, CH2Cl2
°C to r.t.
production, in a dose-dependent manner, with an IC50 of
+
0
2
6.59 μg/mL; this inhibitory effect was determined to not
10
Br
be attributable to its nonspecific cell toxicity.
In our continuing work on O-aryl-linked lignans,1
1–14
we
sought to prepare 3-methylobovatol (6) using methods that
could later allow for the preparation of obovatol analogues
for further study into the broad range of activities that are
displayed by 3 or could be used to prepare magnolianin (5)
using our previously reported methods for 1,4-benzodiox-
1
2
10
11
1
1
5 min then 3.5 h
5 min then 1 h
31%
–
49%
73%
Scheme 2 Synthesis of 4-allylphenol (10)
11–13
ane lignan construction.
The synthesis began with the selective bromination of
The Ullmann condensation between bromide 9 and
phenol 10 was attempted using conditions reported by
Kwak et al., which used a combination of CuI and Cs CO
eugenol (7), using i-PrMgCl and dibromodimethylhydantoin
15
(
DBDMH). i-PrMgCl is used to form the corresponding
2
3
phenoxide, increasing the nucleophilicity at the carbon
ortho to the phenol for bromination (Scheme 1). Using this
method after three hours, bromide 8 was produced in 31%
yield. If the reaction was left for longer in an effort to in-
crease the yield of 8, polybrominated compounds were ob-
tained which were inseparable from desired 8. Following
this, phenol 8 was protected in 73% yield, to provide MOM
ether 9 for the required Ullmann condensation reaction.17
with N,N-dimethylglycine used as the ligand. However, us-
ing the reported time of two days gave the desired diaryl
ether 13 in a poor yield of 16% (Scheme 3).21 Increasing the
reaction time from two to four days improved the yield of
13 to 36% (with 52% of 9 returned unreacted), and no ob-
16
served isomerization of the terminal alkene, an effect com-
monly observed.2
1,22
It has previously been reported that
MOM groups are unstable in the basic Ullmann condensa-
tion conditions.23 Our result demonstrates that the above
conditions for Ullmann condensations are compatible with
MOM groups.
OH
OH
i-PrMgCl,
DBDMH
MeO
MeO
Br
OMOM
Br
OH
THF,
–
78 °C to r.t., 3 h
MeO
31%
+
7
8
OMOM
Br
MOMCl,
DIPEA
MeO
9
10
CuI, Cs2CO3,
CH2Cl2, r.t., 22 h,
3%
7
N,N-dimethylglycine,
dioxane, 90 °C, 4 d,
36%
9
Scheme 1 Synthesis of bromide 9
OR
MeO
O
The second coupling partner for the Ullmann condensa-
tion was 4-allylphenol (10) which was thought to be easily
produced through the previously reported demethylation of
18
estragole (11). The reaction was first attempted by adding
a solution of BBr at 0 °C, and then allowing the reaction to
3
1
3 R = MOM
2
M HCl, MeOH
warm to room temperature and stir for 3.5 hours, a shorter
time than has been previously reported (Scheme 2).18 Un-
fortunately, it was found that a mixture of desired product
r.t., 18 h, 74%
6 R = H
Scheme 3 Synthesis of 3-methylobovatol (6)
10 (49%) and bromide 12 (31%) was produced, with 12 most
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L. I. Pilkington, D. Barker
Letter
Unreacted starting material 9 and the desired diaryl
ether 13 were inseparable using standard flash chromatog-
(9) Kijjoa, A.; Pinto, M. M. M.; Tantisewie, B.; Herz, W. Phytochemis-
try 1989, 28, 1284.
10) Gui, X.; Wang, G.; Zhang, N.; Huang, B. Fitoterapia 2014, 95, 51.
(11) Pilkington, L. I.; Barker, D. J. Org. Chem. 2012, 77, 8156.
12) Pilkington, L. I.; Barker, D. Eur. J. Org. Chem. 2014, 1037.
(
raphy. However, using the classical, but infrequently ap-
plied method of employing silver impregnated silica,24,25
(
(
the dialkene-containing product 13 was able to be easily
separated from monoalkene aryl bromide 9. Finally, depro-
tection of the MOM ether using 2 M HCl in methanol pro-
13) Pilkington, L. I.; Wagoner, J.; Polyak, S. J.; Barker, D. Org. Lett.
2015, 17, 1046.
(14) Rye, C. E.; Barker, D. Eur. J. Med. Chem. 2013, 60, 240.
(15) Alam, A. Synlett 2005, 2403.
2
6
vided the natural product 6 in 74% yield.
28
1
(16) 4-Bromoeugenol (8)
The H NMR spectra for synthetic 6 was in close agree-
ment with the literature values reported for the natural
product, with slight differences in values for H-7, H-7′, and
To a solution of eugenol (7, 1.00 g, 6.09 mmol) in dry THF (20
mL) at –78 °C was added i-PrMgCl (2.0 M in THF, 3.05 mL, 6.09
mmol), and the mixture was stirred for 30 min at –78 °C. A solu-
tion of DBDMH (1.39 g, 4.87 mmol) in dry THF (10 mL) was then
9
OMe groups. This led us to speculate that the isolated natu-
ral compound could be an alternate methylated derivative
of obovatol, that being 2-methylobovatol. That compound
has been prepared by others via methylation of obovatol
added, and the mixture stirred at –78 °C for 3 h. Sat. aq NH Cl
4
(25 mL) was then added along with EtOAc (20 mL) and the two
layers separated. The aqueous layer was further extracted with
EtOAc (2 × 20 mL), and the combined organic extracts were
27
(
3), and its NMR data show significant differences in the
washed with brine (20 mL), dried (MgSO ), and the solvent
4
aromatic proton signals when compared to reported data
for isolated 6 and our prepared synthetic sample. This indi-
cates that the natural product is not 2-methylobovatol and
most likely is the 3-methyl isomer 6. Unfortunately, no
removed in vacuo. The crude product was purified by flash
chromatography (n-hexanes–EtOAc, 9:1) to yield the title
product 8 (0.360 g, 31%) as a yellow oil. R = 0.42 (n-hexanes–
f
1
EtOAc, 4:1).
H NMR (400 MHz, CDCl , Me Si): δ = 3.29 (2 H, d,
3 4
13
C NMR data were reported when 6 was isolated.
J = 6.4 Hz, H-7), 3.87 (3 H, s, OMe), 5.07–5.10 (2 H, m, H-9), 5.80
(
(
(
(
1 H, br s, OH), 5.86–5.97 (1 H, m, H-8), 6.63 (1 H, s, H-5), 6.92
In conclusion the synthesis of 3-methylobovatol (6) in
13
1 H, s, H-3). C NMR (100 MHz, CDCl ): δ = 39.5 (C-7), 56.2
four steps has been achieved. This synthesis demonstrates
the compatibility of MOM ether protecting groups for alco-
hols in Ullmann condensation reactions, as well as the ef-
fective usage of silver-impregnated silica to separate mono-
and dialkene-containing products that would otherwise be
inseparable. This synthesis also allows for further modifica-
tion of the C-2 phenol for further study into the effect of
this group and other functionalities that could be added
there, on the activities of these compounds.
3
OMe), 109.8 (C-2), 110.4 (C-5), 116.2 (C-9), 124.3 (C-3), 132.7
1
C-4), 136.9 (C-8), 141.3 (C-1), 147.1 (C-6). The H NMR and
13
C NMR data were in agreement with the literature values.
(
17) 5-Allyl-1-bromo-3-methoxy-2-(methoxymethoxy)benzene
(9)
To phenol 8 (0.200 g, 0.82 mmol) in CH Cl (5 mL) at r.t., under
2 2
an atmosphere of nitrogen, was added DIPEA (0.18 mL, 1.03
mmol) followed by MOMCl (0.18 mL, 1.65 mmol), and the
mixture was stirred at r.t. for 22 h. Sat. aq NH Cl (5 mL) was
4
added and the organic layer separated. The aqueous layer was
further extracted with CH Cl (3 × 5 mL), and the combined
2
2
organic extracts were dried (MgSO ) and the solvent removed
in vacuo. The crude product was purified by flash chromatogra-
4
Acknowledgment
phy (n-hexanes–EtOAc, 9:1) to yield the title product 9 (0.176 g,
We thank the University of Auckland for funding this project and a
doctoral scholarship to L.I.P.
7
3%) as a pale yellow oil. R = 0.61 (n-hexanes–EtOAc, 4:1). IR
f
(
1
film): νmax = 3078, 2939, 2842, 1596, 1567, 1487, 1464, 1414,
269, 1159, 1078, 1046, 959, 843, 815, 684 cm . H NMR (400
–1 1
MHz, CDCl , Me Si): δ = 3.30 (2 H, d, J = 6.4 Hz, H-7), 3.65 (3 H, s,
References and Notes
3
4
OCH OCH ), 3.83 (3 H, s, OMe), 5.08–5.13 (2 H, m, H-9), 5.14
2
3
(
(
(
(
1) Fukuyama, Y.; Otoshi, Y.; Miyoshi, K.; Hasegawa, N.; Kan, Y.;
(2 H, s, OCH
6.98 (1 H, s, H-6). C NMR (100 MHz, CDCl
56.0 (OCH OCH ), 57.9 (OMe), 98.6 (OCH OCH
3
2 3
OCH ), 5.86–5.96 (1 H, m, H-8), 6.67 (1 H, s, H-4),
13
Kodama, M. Tetrahedron Lett. 1993, 34, 1051.
2) Ito, K.; Iida, T.; Ichino, K.; Tsunezuka, M.; Hattori, M.; Namba, T.
Chem. Pharm. Bull. (Tokyo) 1982, 30, 3347.
3) Fukuyama, Y.; Otoshi, Y.; Kodama, M.; Hasegawa, T.; Okazaki,
H.; Nagasawa, M. Tetrahedron Lett. 1989, 30, 5907.
4) Hwang, E.-I.; Kwon, B.-M.; Lee, S.-H.; Kim, N.-R.; Kang, T.-H.;
Kim, Y.-T.; Park, B.-K.; Kim, S.-E. J. Antimicrob. Chemother. 2002,
3
): δ = 39.6 (C-7),
), 112.1 (C-4),
2
3
2
116.5 (C-9), 117.6 (C-1), 124.8 (C-6), 136.5 (C-8), 137.4 (C-5),
+
153.0 (C-2), 162.3 (C-3). MS (ESI ): m/z (%) = 311 (100)
8
1
+
79
+
[
BrMNa ], 309 (98) [ BrMNa ], 233 (10) and 199 (5). HRMS
+
81
+
(ESI ): m/z calcd for C12
311.0076; m/z calcd for
[MNa ]: 309.0094.
H
15 BrNaO
: 311.0077; found [MNa ]:
3
9
7
C H15 BrNaO : 309.0097; found
12 3
+
49, 95.
(
(
(
(
5) Matsuda, H.; Kageura, T.; Oda, M.; Morikawa, T.; Sakamoto, Y.;
Yoshikawa, M. Chem. Pharm. Bull. (Tokyo) 2001, 49, 716.
6) Pyo, M. K.; Lee, Y.; Yun-Choi, H. S. Arch. Pharm. Res. 2002, 25,
(18) Lin, J. M.; Prakasha Gowda, A. S.; Sharma, A. K.; Amin, S. Bioorg.
Med. Chem. 2012, 20, 3202.
(19) 4-(2-Bromopropyl)phenol (12)
325.
To a solution of methyl ether 11 (100 mg, 0.674 mmol) in CH
(5 mL) under an atmosphere of nitrogen and cooled to 0 °C was
added dropwise a solution of BBr (0.190 mL, 2.0 mmol) in
CH Cl (1 mL). The resulting solution was stirred at 0 °C for 15
min and then let warm to r.t. and stirred for 3.5 h. The mixture
was then cooled to 0 °C and quenched with H O (10 mL). The
2 2
Cl
7) Lee, S. Y.; Yuk, D. Y.; Song, H. S.; Yoon, D. Y.; Jung, J. K.; Moon, D.
C.; Lee, B. S.; Hong, J. T. Eur. J. Pharmacol. 2008, 582, 17.
8) Lee, M. S.; Yang, J. E.; Choi, E. H.; In, J. K.; Lee, S. Y.; Lee, H. S.;
Hong, J. T.; Lee, H. W.; Suh, Y. G.; Jung, J. K. Bull. Korean Chem.
Soc. 2007, 28, 1601.
3
2
2
2
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Synlett
L. I. Pilkington, D. Barker
Letter
aqueous mixture was extracted with CH Cl2 (10 mL), and then
(n-hexanes–EtOAc, 9:1) with silver impregnated silica to yield
2
the combined organic extracts were washed with brine (10 mL),
the title product 13 (80.0 mg, 36%) as a pale yellow oil. R = 0.61
f
dried (MgSO ), and the solvent removed in vacuo. The crude
(n-hexanes–EtOAc, 4:1) 0.61. IR (film): νmax = 2967, 2839, 1565,
4
product was purified by flash chromatography (n-hexanes–
EtOAc, 9:1) to yield the title product 12 (44.4 mg, 31%) as a col-
1504, 1487, 1463, 1269, 1216, 1156, 1078, 1045, 952, 815, 774
–1 1
682 cm . H NMR (400 MHz, CDCl , Me Si): δ = 3.26 (2 H, d, J =
3
4
orless oil. R = 0.39 (n-hexanes–EtOAc, 4:1). IR (film): ν
=
6.8 Hz, H-7), 3.34 (2 H, d, J = 6.8 Hz, H-7′), 3.51 (3 H,
s, OCH OCH ), 3.86 (3 H, s, OMe), 5.03–5.08 (4 H, m, H-9 and
f
max
3
316, 2969, 2921, 1612, 1598, 1512, 1443, 1377, 1223, 1171,
2
3
–1 1
1
057, 999, 847, 820, 772 cm . H NMR (400 MHz, CDCl , Me Si):
H-9′), 5.09 (2 H, s, OCH OCH ), 5.86–5.99 (2 H, m, H-8 and H-8′),
3
4
2 3
δ = 1.67 (3 H, d, J = 6.4 Hz, CH ), 2.97 (1 H, q, J = 3.2 Hz, ArCH H ),
6.41 (1 H, d, J = 2.0 Hz, H-6), 6.54 (1 H, d, J = 2.0 Hz, H-4), 6.88
(2 H, d, J = 8.0 Hz, H-2′ and H-6′), 7.09 (2 H, d, J = 8.0 Hz, H-3′
3
a
b
3
.12 (1 H, q, J = 3.2 Hz, ArCH H ), 4.21 (1 H, sext, J = 6.4 Hz,
a b
13
CHBr), 5.40 (1 H, br s, OH), 6.78 (2 H, d, J = 8.4 Hz, H-2), 7.06
and H-5′). C NMR (100 MHz, CDCl ): δ = 39.4 (C-7′), 40.0 (C-7),
3
13
(
2 H, d, J = 8.4 Hz, H-3). C NMR (100 MHz, CDCl ): δ = 25.5
55.9 (OMe), 56.9 (OCH OCH ), 98.2 (OCH OCH ), 108.0 (C-4),
3
2
3
2
3
(
(
2
CH ), 46.6 (CH ), 51.1 (CHBr), 115.3 (C-2), 130.4 (C-3), 130.8
113.1 (C-6), 115.6 (C-9′), 116.0 (C-9), 117.4 (C-2′ and C-6′),
129.5 (C-3′ and C-5′), 134.2 (C-4′), 135.6 (C-2), 136.4 (C-5),
136.8 (C-8), 137.5 (C-8′), 149.8 (C-1), 153.7 (C-3) and 155.9 (C-1′).
3
2
+
81
+
C-4), 154.4 (C-1). MS (ESI ): m/z (%) = 215 (50) [ BrM – H] ,
79
+
+
13 (50) [ BrM – H] , 181 (100). HRMS (ESI ): m/z calcd for
81
+
+
+
C9H10 BrO: 214.9900; found [M – H] : 214.9894. m/z calcd for
MS (ESI ): m/z (%) = 363 (100) [MNa ], 265 (5), 207 (5). HRMS
79
+
+
C9H10 BrO: 212.9921; found [M – H] : 212.9922. In a separate
fraction, 4-allylphenol (10, 43.8 mg, 49%) was isolated as a col-
orless oil.
(ESI+): m/z calcd for C21H24NaO : 363.1567; found: [MNa ]:
4
363.1578. In a separate fraction, bromide 9 (98 mg, 0.381
mmol) was isolated as a colorless oil.
(
20) 4-Allylphenol (10)29
(23) Kobayashi, S.; Hirano, T.; Iwakiri, K.; Miyamoto, H.; Nakazaki, A.
Heterocycles 2009, 79, 805.
To a solution of methyl ether 11 (1.00 g, 6.74 mmol) in CH Cl
2
2
(
18 mL) under an atmosphere of nitrogen and cooled to 0 °C was
(24) Li, T.-S.; Li, J.-T.; Li, H.-Z. J. Chromatogr. A 1995, 715, 372.
(25) Williams, C. M.; Mander, L. N. Tetrahedron 2001, 57, 425.
(26) 5-Allyl-1-(4′-allylphenoxy)-3-methoxyphenol (6) or 3-Meth-
ylobovatol (6)
added dropwise a solution of BBr (0.96 mL, 10 mmol) in CH Cl
3
2
2
(18 mL). The resulting solution was stirred at 0 °C for 15 min
and then let warm to r.t. and stirred for 1 h. The mixture was
then cooled to 0 °C and quenched with H O (20 mL). The
To a solution of methoxymethyl ether 13 (50.0 mg, 0.15 mmol)
in MeOH (5 mL) was added 2 M HCl (0.5 mL), and the resultant
mixture was stirred at r.t. for 18 h. 1 M NaOH was added until
the solution was pH 5, and then the solution was extracted with
EtOAc (3 × 5 mL). The combined organic extracts were dried
2
aqueous mixture was extracted with CH Cl (20 mL), and then
2
2
the combined organic extracts were washed with brine (20 mL),
dried (MgSO ), and the solvent removed in vacuo. The crude
4
product was purified by flash chromatography (n-hexanes–
EtOAc, 9:1) to yield the title product 10 (0.66 g, 73%) as a color-
(MgSO ) and the solvent removed in vacuo. The crude product
was purified by flash chromatography (n-hexanes–EtOAc, 9:1)
4
1
less oil. R = 0.45 (n-hexanes–EtOAc, 4:1). H NMR (400 MHz,
f
CDCl , Me Si): δ = 3.33 (2 H, d, J = 6.8 Hz, ArCH ), 5.05–5.10 (2 H,
to give the title product 6 (32.0 mg, 74%) as a yellow oil. R = 0.42
3
4
2
f
m, CH=CH ), 5.53 (1 H, br s, OH), 5.92–6.02 (1 H, m, CH=CH ),
(n-hexanes–EtOAc, 4:1). IR (film): νmax: 3507, 2976, 2915, 2844,
2
2
6
.78 (1 H, dd, J = 2.0, 6.4 Hz, H-2), 7.06 (1 H, dd, J = 2.0, 6.4 Hz,
1600, 1504, 1453, 1433, 1312, 1220, 1168, 1058, 994, 914, 823
13
–1 1
H-3). C NMR (100 MHz, CDCl ): δ = 39.3 (ArCH ), 115.3 (C-2),
cm . H NMR (400 MHz, CDCl , Me Si): δ = 3.25 (2 H, d, J = 6.8
3
2
3 4
1
15.4 (CH=CH ), 129.7 (C-3), 132.2 (C-4), 137.8 (CH=CH ), 153.7
Hz, H-7), 3.34 (2 H, d, J = 6.8 Hz, H-7′), 3.90 (3 H, s, OMe), 5.02–
5.09 (4 H, m, H-9 and H-9′), 5.45 (1 H, br s, OH), 5.81–6.01 (2 H,
m, H-8 and H-8′), 6.43 (1 H, d, J = 2.0 Hz, H-6), 6.53 (1 H, d, J =
2.0 Hz, H-4), 6.90 (2 H, d, J = 8.0 Hz, H-2′ and H-6′), 7.10 (2 H, d,
2
2
1
13
(C-1). The H NMR and C NMR data were in agreement with
the literature values.
(
21) Kwak, J.-H.; In, J.-K.; Lee, M.-S.; Choi, E.-H.; Lee, H.; Hong, J. T.;
Yun, Y.-P.; Lee, S. J.; Seo, S.-Y.; Suh, Y.-G.; Jung, J.-K. Arch. Pharm.
Res. 2008, 31, 1559.
22) 5-Allyl-1-(4′-allylphenoxy)-3-methoxy-2-(methoxyme-
thoxy)benzene (13)
13
J = 8.0 Hz, H-3′ and H-5′). C NMR (100 MHz, CDCl ): δ = 39.4
3
(C-7′), 39.9 (C-7), 56.2 (OMe), 107.3 (C-4), 113.0 (C-6), 115.7
(C-9′), 115.8 (C-9), 117.3 (C-2′ and C-6′), 129.6 (C-3′ and C-5′),
131.4 (C-5), 134.4 (C-4′), 135.6 (C-2), 137.3 (C-8), 137.5 (C-8′),
(
+
A mixture of bromide 9 (189 mg, 0.658 mmol), phenol 10 (132
mg, 0.987 mmol), Cs CO (429 mg, 1.32 mmol), CuI (12.5 mg,
143.0 (C-1), 147.8 (C-3), 155.8 (C-1′). MS (ESI ): m/z (%) = 319
+
+
(100) [MNa ], 227 (80), 158 (20). HRMS (ESI ): m/z calcd for
2
3
+
1
0.066 mmol), and N,N-dimethylglycine hydrochloride (28.0 mg,
C19H20NaO3 [MNa ]: 319.1305; found: 319.1304. The H NMR
data were in agreement with the literature values.
9
0.197 mmol) in dioxane (3 mL) in a sealed tube under an atmo-
sphere of nitrogen was heated at 90 °C for 4 d. The solution was
removed from the heat and allowed to cool to r.t. The cooled
(27) Kwon, B.-M.; Han, D. C.; Lee, S.-K.; Kim, H.-Y.; Han, Y.-M.; Shin,
D.-S. US 20090239955 A1, 2009.
mixture was partitioned between EtOAc (2 mL) and H O (2 mL),
and the organic layer was separated. The aqueous layer was
further extracted with EtOAc (2 × 2 mL). The combined organic
(28) Menini, L.; Parreira, L. A.; Gusevskaya, E. V. Tetrahedron Lett.
2007, 48, 6401.
(29) Denton, R. M.; Scragg, J. T.; Saska, J. Tetrahedron Lett. 2011, 52,
2554.
2
extracts were dried (MgSO ), and the solvent was removed in
4
vacuo. The crude product was purified by flash chromatography
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Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2425–2428