Conversion of substituted benzyl ethers to diarylmethanes. A direct synthesis of diarylbenzofurans

Article abstract of DOI:10.1016/j.tetlet.2012.10.058

The Lewis acid catalyzed rearrangement of substituted benzyl ethers affords diarylmethanes in good yields. One of the products was converted into a diarylbenzofuran using a benzoylation/P4-tBu cyclization protocol.

Full text of DOI:10.1016/j.tetlet.2012.10.058

Tetrahedron Letters 53 (2012) 7072–7074
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Tetrahedron Letters
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Conversion of substituted benzyl ethers to diarylmethanes. A direct synthesis
of diarylbenzofurans
⇑
George A. Kraus , Divya Chaudhary
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Lewis acid catalyzed rearrangement of substituted benzyl ethers affords diarylmethanes in good
yields. One of the products was converted into a diarylbenzofuran using a benzoylation/P4-tBu cycliza-
tion protocol.
Received 24 September 2012
Revised 9 October 2012
Accepted 15 October 2012
Available online 22 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Rearrangement
Benzyl ethers
Diarylbenzofuran
Lewis acid
The diarylmethane subunit is contained in a variety of natural
products. Representative members are shown in Figure 1 and in-
clude procyanidin B2 (1),1 diarylbenzofuran (2),2 and justicidin H
(3).3 Because many of these compounds exhibit useful biological
activity, a number of synthetic approaches to the diarylmethane
subunit have been reported. Organometallic-based approaches4
and Friedel–Crafts-based approaches5 are the most commonly re-
ported strategies. In some cases the former approach is limited
by the requirement for regioselective metallation. The latter ap-
proach has the disadvantage that after the acylation, a one- to
two-step conversion of the benzophenone to the diarylmethane
still needs to be accomplished. We describe herein the Lewis acid
mediated rearrangement of a substituted benzyl aryl ether that is
strategically different from the commonly reported strategies and
is flexible with regard to substituent patterns.
The rearrangement shown below in Scheme 1 was originally
discovered when purification of 4 by silica gel chromatography
produced phenol 5 in 72% yield. This selective reaction was medi-
ated by the acidic surface of the silica gel and occurred at ambient
temperature. To the best of our knowledge, reports of rearrange-
ments of functionalized aryl benzyl ethers are limited.6 A recent re-
port by Luzzio and Chen described a clever camphorsulfonic acid
mediated rearrangement of 2-nitroresorcinol ethers.7
methylene group of the diarylmethane unit could be efficiently
deprotonated, a flexible route to these phenols could lead to a di-
rect synthesis of substituted diarylbenzofurans by an acylation/
rearrangement/cyclization protocol.
We evaluated the ethers shown in Scheme 2 and found
that ethers bearing only one electron-donating substituent re-
quired a Lewis acid such as boron trifluoride etherate for rear-
rangement. Interestingly, a benzyl ether (X = H) did not react
under our conditions. This selectivity may be useful in complex
systems.
Benzyl ethers of sesamol were synthesized and subjected to the
rearrangement conditions as shown in Scheme 3. Although two
isomeric phenols could have been produced, the rearrangement
was regioselective in generating phenols 8 and 9. These regioselec-
tivities parallel the results observed in Friedel–Crafts acylation of
sesamol.9
Substituted benzyl ethers of 2,6-dimethoxyphenol were pre-
pared and were reacted with boron trifluoride etherate as shown
in Scheme 4. In these cases the rearrangement produced the
4-benzyl phenols in good yields.
In an approach to the synthesis of benzofuran, the ether was
regioselectively rearranged in 70% yield as shown in Scheme 5.
Benzoylation of the resulting phenol 13 followed by reaction with
P4-tBu in benzene at 80 °C afforded benzofuran 14 in 47% yield
after chromatography.
Compounds such as 5 were of interest because we had previ-
ously demonstrated that even weakly acidic subunits such as ben-
zyl ethers could be deprotonated by the strong base P4-tBu.8 If the
The Lewis acid mediated rearrangement10 of benzyl ethers into
diarylmethanes provides a facile entry into this subunit. One of the
rearrangement products was converted into a 2,3-diaryl-benzofu-
ran by benzoylation followed by cyclization with P4-tBu.
⇑
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0105.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.058

G. A. Kraus, D. Chaudhary / Tetrahedron Letters 53 (2012) 7072–7074
OH
7073
OMe
O
HO
O
OH
OH
O
MeO
OH
O
HO
OMe
OMe
O
O
O
OH
OMe
3
2
1
Figure 1. Compounds containing the diarylmethane subunit.
Acknowledgment
OMe
O
OH
We thank Iowa State University for partial support of DC.
silica gel
OMe
OMe
OMe
References and notes
MeO
OMe
MeO
OMe
4
1. Chamorro, S.; Viveros, A.; Alvarez, I.; Vega, E.; Brenes, A. Food Chem. 2012, 133,
308–314.
5
2. Durani, N.; Jain, R.; Saeed, A.; Dikshit, D. K.; Durani, S.; Kapil, R. S. J. Med. Chem.
1989, 32, 1700–1707.
Scheme 1. Rearrangement during column chromatography.
3. Yang, M.; Wu, J.; Cheng, F.; Zhou, Y. Magn. Reson. Chem. 2006, 44, 727–730.
4. (a) Lee, D.-H.; Kwon, K.-H.; Yi, Chae S. J. Am. Chem. Soc. 2012, 134, 7325–7328;
(b) Bruno, J. G.; Chang, M. N.; Choi-Sledeski, Y. M.; Green, D. M.; Regan, J. R.;
McGarry, ; Volz, F. A. J. Org. Chem. 1997, 62, 5174–5190; (c) Wilkinson, J. A.;
Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron 2006, 62, 1833–
1844; (d) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915–1920; (e) DeLang,
R.-J.; van Hooijdonk, M. J. C. M.; Brandsma, L.; Kramer, H.; Seinen, H.
Tetrahedron 1998, 54, 2953–2966.
5. (a) Zhang, C.; Gao, X.; Zhang, J.; Peng, X. Synlett 2010, 261–265; (b) Sagrera, G.;
Seoane, G. Synthesis 2009, 4190–4202; (c) Sun, H. B.; Li, B.; Chen, S.; Hua, R.
Tetrahedron 2007, 63, 10185–10188; (d) Cetinkaya, Y.; Gocer, H.; Menzek, A.;
Gulcin, I. Arch. Pharm. 2012, 345, 323–334; (e) Kamada, A.; Sasaki, A.; Kitazawa,
N.; Okabe, T.; Nara, K.; Hamaoka, S.; Araki, S.; Hagiwara, H. Chem. Pharm. Bull.
2004, 52, 79–88.
X
OH
O
X
BF3 Et2O
MeO
OMe
MeO
OMe
6: X = OMe 77%
7: X = H 0%
Scheme 2. Rearrangement of phloroglucinol ethers
6. Leonard Jurd; Richard L Fye; John Morgan, Jr. J. Agric. Food Chem. 1979, 27, 1007.
7. Luzzio, F. A.; Chen, J. J. Org. Chem. 2009, 74, 5629–5632.
8. Kraus, G. A.; Zhang, N.; Verkade, J. G.; Nagarajan, M.; Kisanga, P. B. Org. Lett.
2000, 2409.
9. Musso, L.; Dallavalle, S.; Merlini, L.; Farina, G. Chem. Biodivers. 2010, 7, 887–
897.
OMe
OH
O
BF3 Et2O
OMe
X
10. General Procedure for the rearrangement
X
To a solution of aryl ether (1.43 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added
BF3.Et2O (0.13 mL, 1.0 equiv) dropwise at 0 °C under argon. Reaction mixture
was allowed to stir at rt overnight. After the completion of the reaction, water
was added. The aqueous layer was extracted with CH2Cl2 (3Â). The combined
organic layers were washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude product was purified on silica gel by column chromatography
using EtOAc–hexanes as the eluent.
O
O
O
8
: X = OMe 78%
9: X = H 80%
O
Scheme 3. Rearrangement of sesamol ethers.
The reactions were typically run on a 1.0–1.5 mmol scale.
(5) 2-(3,4-dimethoxybenzyl)-3,5-dimethoxyphenol
1H NMR (400 MHz, CDCl3): d 6.82 (s, 1H), 6.75–6.76 (m, 2H), 6.12 (d, J = 2.0 Hz,
1H), 6.03 (d, J = 2.0 Hz, 1H), 5.50 (s, 1H of OH), 3.91 (s, 2H), 3.81 (s, 6H), 3.79 (s,
3H), 3.71 (s, 3H).
OMe
MeO
OMe
O
BF3 Et2O
13C NMR (100 MHz, CDCl3): d 159.7, 159.3, 155.6, 149.0, 147.3, 133.9, 120.2,
112.1, 111.4, 108.4, 94.0, 91.6, 56.1, 56.0, 55.5, 28.2.
MeO
OMe
X
X
HO
HRMS (ESI) m/z exact mass calculated for C17H21O5 [M+H]+ 305.1384. Found
305.1388.
OMe
10
: X = OMe 68%
11: X = H 62%
(6) 3,5-dimethoxy-2-(4-methoxybenzyl)phenol
1H NMR (400 MHz, CDCl3): d 7.14 (d, J = 9 Hz, 2H), 6.78 (d, J = 9 Hz, 2H), 6.13 (d,
J = 2.4 Hz, 1H), 6.01 (dd, J = 7.8, 2.4 Hz, 1H), 4.81 (s, 1H of OH), 3.90 (s, 2H), 3.79
(s, 3H), 3.76 (s, 6H).
Scheme 4. Rearrangement of 2,6-disubstituted phenol ethers.
13C NMR (100 MHz, CDCl3): d 159.7, 159.3, 157.9, 155.6, 133.2, 129.4, 114.0,
OMe
OMe
OH
O
OMe 1. PhCOCl
2. P4-tBu
47%
MeO
MeO
13
O
OMe
12
14
Scheme 5. Synthesis of a diarylbenzofuran.

7074
G. A. Kraus, D. Chaudhary / Tetrahedron Letters 53 (2012) 7072–7074
108.5, 94.4, 91.5, 60.8, 55.9, 55.5, 27.6.
13C NMR (100 MHz, CDCl3): d 158.0, 146.5, 145.5, 138.8, 133.7, 129.9, 128.0,
120.3, 113.9, 106.5, 60.7, 56.4, 55.5, 35.0.
HRMS (ESI) m/z exact mass calculated for C16H19O4 [M+H]+ 275.1278. Found
275.1268.
HRMS (ESI) m/z exact mass calculated for C16H17O4 [MÀH]À 273.1132. Found
(8) 6-(3,4-dimethoxybenzyl)benzo[d][1,3]dioxol-5-ol
273.1135.
1H NMR (400 MHz, CDCl3): d 6.73–6.80 (m, 3H), 6.58 (s, 1H), 6.41 (s, 1H), 5.87
(s, 2H), 4.79 (s, 1H of OH), 3.84 (s, 3H), 3.83 (s, 2H), 3.82 (s, 3H).
13C NMR (100 MHz, CDCl3): d 149.3, 148.5, 147.8, 146.8, 141.6, 132.6, 120.6,
119.2, 112.0, 111.6, 110.1, 101.2, 98.9, 56.1, 56.0, 36.1.
HRMS (ESI) m/z exact mass calculated for C16H15O5 [MÀH]À 287.0925. Found
287.0923.
(13) 5-methoxy-2-(4-methoxybenzyl)phenol
1H NMR (400 MHz, CDCl3): d 7.13 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.83
(d, J = 8.0 Hz, 2H), 6.46 (dd, J = 8.4,2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz,1H), 4.95 (s, 1H
of OH), 3.88 (s, 2H), 3.79 (s, 3H), 3.76 (s,3H).
13C NMR (100 MHz, CDCl3): d 159.7, 158.3, 154.9, 132.3, 131.5, 129.7, 119.7,
114.3, 106.3, 102.3, 55.6, 55.5, 35.2.
+
(9) 6-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-ol
HRMS (ESI) m/z exact mass calculated for C15H17O3 [M+H] 245.1172. Found
1H NMR (400 MHz, CDCl3): d 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H),
6.59 (s, 1H), 6.40 (s, 1H), 5.88 (s, 2H), 4.61 (s, 1H of OH), 3.83 (s, 2H), 3.78 (s,
3H).
245.1174.
Procedure for the preparation of 6-methoxy-3-(4-methoxyphenyl)-2-
phenylbenzofuran (14)
13C NMR (100 MHz, CDCl3): d 158.4, 148.4, 146.8, 141.7, 132.1, 129.7, 119.4,
114.3, 110.2, 101.2, 98.9, 55.5, 35.6.
To a solution of the benzoyl derivative of phenol 13 (0.76 mmol, 1 equiv.) in
dry benzene (10 mL) was added 1 M solution of P4-tBu in hexane (0.84 mL,
1.1 equiv). The reaction mixture was refluxed for 3 h. After the completion of
the reaction the benzene was evaporated in vacuo. The resulting liquid was
purified on silica gel by column chromatography using 5% EtOAc–hexanes as
eluent to get a pure compound in 47% yield.
HRMS (ESI) m/z exact mass calculated for C15H13O4 [MÀH]À 257.0808. Found
257.0797.
(10) 4-(3,4-dimethoxybenzyl)-2,6-dimethoxyphenol
1H NMR (400 MHz, CDCl3): d 6.74–6.79 (m, 3H), 6.58 (s, 2H), 5.56 (s, 1H of OH),
3.89 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H).
13C NMR (100 MHz, CDCl3): d 149.0, 147.4, 146.5, 145.5, 138.8, 134.1, 127.8,
120.9, 120.2, 112.4, 111.3, 106.5, 60.7, 56.4, 56.1, 56.0, 35.4.
HRMS (ESI) m/z exact mass calculated for C17H19O5 [M-H]- 303.1227. Found
303.1232.
(14) 6-methoxy-3-(4-methoxyphenyl)-2-phenylbenzofuran
1H NMR (300 MHz, CDCl3): d 7.63 (d, J = 6.6 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),
7.29 -7.37 (m, 4H), 7.09 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 6.87 (dd,
J = 8.7, 2.1 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H)
13C NMR (75 MHz, CDCl3): d 159.3, 158.6, 155.1, 149.6, 131.1, 131.0, 128.6,
128.0, 126.7, 125.3, 124.2, 120.4, 117.3, 114.6, 112.1, 95.9, 56.0, 55.5
(11) 2,6-dimethoxy-4-(4-methoxybenzyl)phenol
1H NMR (400 MHz, CDCl3): d 7.10 (d, J = 8.4 Hz, 2H), 6.8 (d, J = 8.8 Hz, 2H), 6.58
(s, 2H), 5.53 (s, 1H of OH), 3.88 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H).
HRMS (ESI) m/z exact mass calculated for C22H19O3 [M+H] 331.1334. Found
+
331.1187.