Formal [4 + 1] cycloaddition of o-quinone methides: Facile synthesis of dihydrobenzofurans

Article abstract of DOI:10.1039/c4ra17003b

An efficient and straightforward method for the rapid synthesis of 2-substituted dihydrobenzofurans has been developed via reaction of sulfur ylides with o-quinone methides (o-QMs), which were generated under mild conditions. The products could be obtaine

Full text of DOI:10.1039/c4ra17003b

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Article
Formal [4+1] Cycloaddition of oꢀQuinone Methides: Facile Synthesis of
Dihydrobenzofurans
Xiantao Lei,a,b ChunꢀHuan Jiang,a Xiaoan Wen,a QingꢀLong Xu*a and Hongbin Sun*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
1). When the equivalent of sulfur ylide 2a was raised to 1.5
equiv., the product yield increased to 89% (entry 3, Table 1).
Considering the crucial role of the fluoride source in triggering
the generation of oꢀQMs intermediates, other fluorides such as
50 CsF were examined. We found that CsF displayed the same
reactivity with that of TBAF (entry 4, Table 1). Subsequently, the
equivalent of fluoride and different temperature were examined,
and it was found that the best result could be obtained at room
temperature with 2.5 equiv. of TBAF (entry 8, Table 1). Finally,
55 the influence of solvents was examined. In all solvents tested,
including CH2Cl2, CHCl3, THF, Et2O, toluene, DMF, MeCN, and
MeOH, the desired product was obtained in satisfactory yields
(entries 8ꢀ16, Table 1), indicating a good solvent tolerance of this
reaction. In terms of the product yields and operation
60 convenience, CH2Cl2 was chosen as the best solvent.
An efficient and straightforward method for the rapid
synthesis of 2ꢀsubstituted dihydrobenzofurans has been
developed via reaction of sulfur ylides with oꢀquinone
methides (oꢀQMs), which were generated under mild
10 conditions. The products could be obtained in excellent yields
with various kinds of sulfur ylides.
Introduction
Orthoꢀquinone methides (oꢀQMs) have been of great interest to
the chemical and biological community due to their distinctive
15 properties as Michael acceptors.[1,2] Until now, various
methodologies for generation of oꢀQMs in situ have been
developed, including tautomerization, oxidation, acid or base
catalysis, thermolysis, photolysis and olefination of oꢀ
quinones.[3,4] Moreover, Rokita group reported that Oꢀsilylated
20 phenols exposed to fluoride could also produce oꢀQMs under
mild reaction condition.[5] In contrast to Rokita's method for
generating oꢀQMs, other methods have several disadvantages,
such as harsh reaction conditions (e.g. photolysis, high reaction
temperature), long reaction time, or using transition metals as
25 oxidants.
Table 1. Optimization for the reaction of Oꢀsilylated phenol 1a
with sulfur ylide 2a.a
O
O
OTBS
O
F- source (Y equiv)
solvent, temp. 4 h
S
+
Br
2a (X equiv)
3a
1a
oꢀQMs undergo rapid rearomatization through either Michael
addition with nucleophiles, or [4+2] cycloaddition with
dienophiles, or oxaꢀ6πꢀelectrocyclisation to give benzopyrans.[3,6]
Recently, the Scheidt and Ye groups reported NHCꢀcatalyzed
30 enantioselective formal [4+3] cycloaddition of α,βꢀunsaturated
aldehydes with reactive oꢀQMs to give 2ꢀbenzoxopinones,
providing a new reaction mode for oꢀQMs.[7] On the other hand,
the Zhou and Osyanin groups disclosed that oꢀQMs, which were
generated from inaccessible substrates or in the presence of an
35 oxidant, underwent formal [4+1] cycloaddition with sulfur ylides
Fꢀ
source
temp.
(oC)
yield
(%)b
entry
X
Y
solvent
1
2
TBAF
1.0
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.5
1.5
1.0
2.5
2.5
2.5
2.5
2.5
2.5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
THF
0
0
81
85
89
85
88
82
36
89
86
88
86
74
TBAF
TBAF
CsF
3
0
4
0
5
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
0
or
pyridinium
methylides
to
afford
transꢀ2,3ꢀ
dihydrobenzofurans.[8] Herein, we report an efficient and
straightforward method for the rapid synthesis of 2ꢀsubstituted
dihydrobenzofurans, which widely exist in natural products,[9] via
40 reaction of sulfur ylides with oꢀQMs.
6
0
7
ꢀ30
rt
rt
rt
rt
rt
8
9
Results and discussion
10
12
13
Our initial investigation was focused on the model reaction of Oꢀ
silylated phenol 1a with sulfur ylide 2a. The reaction proceeded
Et2O
o
smoothly to provide the desired product 3a in 81% yield at 0 C
toluene
45 when TBAF was employed as the fluoride source (entry 1, Table
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1a with chiral sulfonium salt 4a (R’ = H), [10] affording optically
active amide 3p' in only 25% yield. When using the chiral
sulfonium salt 4b (R’ = Me),[11] the yield of the desired product
30 could be increased to 69%, but with the similar enantioselectivity
(60% ee).
14
15
16
TBAF
TBAF
TBAF
1.5
1.5
1.5
2.5
2.5
2.5
DMF
MeCN
MeOH
rt
rt
rt
70
77
71
a
1a (0.5 mmol), 2a, solvent (5 mL), room temperature, 12 h.
[TBAF (1 M in THF solution)]. b Isolated yields.
With the optimized reaction conditions in hand, we explored
the reaction scope with using a variety of Oꢀsilylated phenols 1
and sulfur ylides 2 (Table 2). Sulfur ylide derivatives bearing
electronꢀdonating and withdrawing groups on the phenyl group
were wellꢀtolerated (3a−j), affording the corresponding products
in 83ꢀ92% yields. In general, other aromatic substitutes (2ꢀnathyl,
2ꢀfuryl, 2ꢀthiazolyl, 2ꢀpyridyl) derived sulfur ylides had little
10 influence on the yields (77ꢀ89% yields, entries 12ꢀ15, Table 2).
Interestingly, ester and amide derived sulfur ylides could be
obtained in situ, affording the desired products in 42% and 85%
yields, respectively (entries 16, 17, Table 2). Furthermore, the 4ꢀ
Br substituted Oꢀsilylated phenols 1b reacted well with 2a to
15 afford 2ꢀsubstituted dihydrobenzofuran (3q) in 90% yield (entry
18, Table 2).
5
Scheme 1. Reaction of 1a with chiral sulfonium salt 4.
2ꢀSubstituted dihydrobenzofurans could be further converted
35 into the corresponding aromatic benzofurans with using DDQ as
the oxidizing agent. Thus, 2ꢀbenzoyl dihydrobenzofuran 3a was
transformed smoothly to benzofuran 5a in 81% yield according to
the known literature method.[12] When using 2ꢀfuroyl
dihydrobenzofuran 3l and 2ꢀpicolinyl dihydrobenzofuran 3n
40 under the same conditions, the desired products 5l and 5n were
obtained in moderate yields (53ꢀ56% yields), Notably, 2ꢀthiazole
formyl dihydrobenzofuran 3m was employed in the reaction,
affording the product 5m with 81% yield When the 2ꢀsubstituted
dihydrobenzofuran 3o and 3p was employed, the corresponding
45 benzofuran 5o and 5p could be obtained in 75% and 69% yield,
respectively (Scheme 2).
Table 2. Substrate scopes for the reaction of Oꢀsilylated phenols
1 and sulfur ylides 2.a
entry
1
2
3
4
5
6
7
8
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
X
R2
Ph
yield (%)b
89 (3a)
92 (3a)
81 (3b)
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Ph
4ꢀMeC6H4
4ꢀMeOC6H4 80 (3c)
3ꢀMeOC6H4 91(3d)
Scheme 2. Synthesis of benzofuran 5.
A plausible mechanism for this formal [4+2] cycloaddition
50 reaction is depicted in Scheme 3. We proposed that the highly
reactive oꢀQMs A generated through desilylation/elimination
reaction. Then sulfur ylides as nucleophiles attacked at the
external carbon of oꢀQMs, affording the phenoxide B. Finally, the
intermediate B lost one molecular dimethyl sulfide through
4ꢀFC6H4
2ꢀFC6H4
4ꢀClC6H4
3ꢀClC6H4
4ꢀBrC6H4
3ꢀBrC6H4
2ꢀnaphthyl
2ꢀfuryl
86 (3e)
85 (3f)
92 (3g)
90 (3h)
83 (3i)
84 (3j)
84 (3k)
81 (3l)
95 (3m)
77 (3n)
42 (3o)
85 (3p)
90 (3q)
9
10
11
12
13
14
15
16c
17c
18
55 nucleophilic
attack,
providing
the
2ꢀsubstituted
dihydrobenzofuran.
2ꢀthiazolyl
2ꢀpyridyl
OEt
H
H
4ꢀBr
NEt2
Ph
20 a 1 (0.5 mmol), 2 (0.75 mmol), TBAF (2.5 equiv., 1 M in THF
b
solution), CH2Cl2 (5 mL), room temperature, 12 h. Isolated
yields. c Sulfonium salts was used instead of sulfur ylides, using
Cs2CO3 (1.5 equiv.) as a base.
Scheme 3. Proposed mechanism.
We further turned our attention to the reaction with chiral
25 sulfonium salts derived from camphor. As shown in Scheme 1,
moderate enantioselectivity (63% ee) was observed in reaction of
60 Experimental section
2
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General Procedure for the Reaction of Oꢀsilylated Phenols
and Sulfur Ylides: To a solution of sulfur ylides 2 (0.75 mmol,
1.5 equiv.) in dry CH2Cl2 (4 mL), a solution of Oꢀsilylated phenol
1 (0.5 mmol, 1.0 equiv.) in dry CH2Cl2 (1 mL) was added at room
temperature under N2. Then TBAF (1.0 M in THF, 1.25 mL, 2.5
Exact mass calcd. for C15H11O2FNa [M+Na]+ 265.0641, found:
265.0634.
1
3g, White solid, 92% yield, m.p. 113.8ꢀ115.6 °C. H NMR (300
5
MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H),
equiv.) was added dropwise. After the addition, the mixture was 55 7.24ꢀ7.06 (m, 2H), 6.91 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.7 Hz,
stirred at room temperature for
concentrated under reduced pressure and purified by flash
chromatography on silica gel (petroleum ether : ethyl acetate =
4
h. The reaction was
1H), 5.86 (dd, J = 10.3, 7.3 Hz, 1H), 3.64 (dd, J = 15.8, 7.2 Hz,
1H), 3.53 (dd, J = 15.8, 10.4 Hz, 1H). 13C NMR (75 MHz, CDCl3)
δ 194.0, 158.3, 139.7, 132.4, 130.2, 128.6, 127.9, 124.6, 124.5,
120.8, 109.3, 82.3, 31.8. HRMS (ESI): Exact mass calcd. for
60 C15H11O2ClNa [M+Na]+ 281.0345, found: 281.0338.
10 20:1).
3a,[13] White solid, 89% yield, m.p. 93ꢀ95 °C. 1H NMR (300
MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H),
7.53 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8
Hz, 1H), 6.91 (dd, J = 7.4, 4.3 Hz, 2H), 6.02ꢀ5.86 (m, 1H), 3.91ꢀ
3h, Yellow oil, 90% yield. 1H NMR (300 MHz, CDCl3) δ 8.05 (s,
1H), 7.95 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 4.9, 4.0 Hz, 1H), 7.47
(t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.5 Hz,
1H), 6.96ꢀ6.87 (m, 2H), 5.88 (dd, J = 10.2, 7.3 Hz, 1H), 3.65 (dd,
65 J = 16.2, 7.7 Hz, 1H), 3.61ꢀ3.50 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ 193.9, 158.3, 135.6, 134.6, 133.1, 129.6, 128.7, 127.9,
126.8, 124.5, 124.4, 120.8, 109.3, 82.1, 31.8. HRMS (ESI): Exact
mass calcd. for C15H11O2ClNa [M+Na]+ 281.0345, found:
281.0351.
15 3.23 (m, 2H).
1
3b, Colorless oil, 81% yield. H NMR (300 MHz, CDCl3) δ 7.95
(d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.4 Hz,
1H), 7.13 (d, J = 7.8 Hz, 1H), 6.94ꢀ6.82 (m, 2H), 5.90 (m, 1H),
3.60ꢀ3.52 (m, 2H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
20 194.6, 158.6, 144.2, 131.5, 129.0, 128.8, 127.8, 124.8, 124.4,
1
120.6, 109.3, 82.1, 32.3, 21.3. HRMS (ESI): Exact mass calcd. 70 3i, Yellow solid, 90% yield, m.p. 119.5ꢀ120.0 °C. H NMR (300
for C16H14O2Na [M+Na]+ 261.0891, found: 261.0883.
MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H),
7.26ꢀ7.11 (m, 2H), 6.93 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.7 Hz,
1H), 5.87 (dd, J = 9.9, 7.7 Hz, 1H), 3.65 (dd, J = 15.8, 7.2 Hz,
1H), 3.54 (dd, J = 15.8, 10.4 Hz, 1H). 13C NMR (75 MHz, CDCl3)
1
3c,[14] White solid, 80% yield, m.p. 108.5ꢀ110 °C. H NMR (300
MHz, CDCl3) δ 8.04 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 7.4 Hz, 1H),
25 7.13 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.88 (dd, J = 75 δ 194.7, 158.8, 133.3, 132.0, 130.7, 128.9, 128.4, 125.0, 124.9,
7.5, 5.6 Hz, 2H), 5.89 (dd, J = 10.2, 7.6 Hz, 1H), 3.89 (s, 3H),
3.61 (dd, J = 15.8, 7.7 Hz, 1H), 3.52 (dd, J = 15.8, 10.4 Hz, 1H).
121.3, 109.8, 82.7, 32.2. HRMS (ESI):Exact mass calcd. for
C15H11O2BrNa [M+Na]+ 324.9840, found: 324.9851.
3d, White solid, 91% yield, m.p. 94ꢀ95.8 °C. 1H NMR (300 MHz,
CDCl3) δ 7.67ꢀ7.54 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.20 (d, J =
3j, Yellow oil, 84% yield. 1H NMR (300 MHz, CDCl3) δ 8.20 (s,
1H), 7.99 (d, J = 7.5 Hz, 1H), 7.76 (dd, J = 8.0, 0.9 Hz, 1H), 7.40
30 7.3 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.97ꢀ6.84 (m, 2H), 5.95 (t, 80 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 7.9 Hz,
J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.59 (d, J = 8.9 Hz, 2H). 13C NMR
(75 MHz, CDCl3) δ 195.3, 159.9, 159.0, 135.7, 129.7, 128.3,
125.1, 124.8, 121.6, 121.1, 120.2, 113.3, 109.8, 82.6, 55.4, 32.8.
HRMS (ESI): Exact mass calcd. for C16H14O3Na [M+Na]+
35 277.0841, found: 277.0851.
1H), 6.96ꢀ6.86 (m, 2H), 5.88 (dd, J = 10.2, 7.3 Hz, 1H), 3.64 (dd,
J = 16.6, 8.0 Hz, 1H), 3.55 (dd, J = 16.0, 10.6 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 193.8, 158.3, 136.0, 135.8, 131.6, 129.8,
127.9, 127.2, 124.5, 124.5, 122.6, 120.9, 109.3, 82.1, 31.8.
85 HRMS (ESI): Exact mass calcd. for C15H11O2BrNa [M+Na]+
324.9840, found: 324.9848.
1
3e, White solid, 86% yield, m.p. 118.0ꢀ120.2 °C. H NMR (300
1
MHz, CDCl3) δ 8.12 (dd, J = 8.6, 5.5 Hz, 2H), 7.21 (dd, J = 6.0,
2.7 Hz, 3H), 7.15 (d, J = 8.1 Hz, 1H), 6.98ꢀ6.84 (m, 2H), 5.89 (dd,
J = 10.3, 7.3 Hz, 1H), 3.66 (dd, J = 15.8, 7.2 Hz, 1H), 3.55 (dd, J
40 = 15.8, 10.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 194.0, 167.7, 90 7.7 Hz, 1H), 6.92 (dd, J = 7.2, 5.7 Hz, 2H), 6.11 (dd, J = 10.0, 7.7
3k, White solid, 84% yield. m.p. 141.5ꢀ143.7 °C. H NMR (300
MHz, CDCl3) δ 8.62 (s, 1H), 8.10 (dd, J = 8.6, 1.5 Hz, 1H), 8.05ꢀ
7.89 (m, 3H), 7.63 (m, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.17 (d, J =
164.3, 158.8, 132.0, 131.9, 128.3, 125.1, 124.9, 121.3, 116.0,
115.7, 82.7, 32.2. HRMS (ESI): Exact mass calcd. for
C15H11O2FNa [M+Na]+ 265.0641, found: 265.0634.
Hz, 1H), 3.71 (dd, J = 14.3, 6.1 Hz, 1H), 3.63 (dd, J = 14.3, 8.8
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 195.4, 159.0, 135.8, 132.5,
131.8, 131.1, 129.7, 128.8, 128.6, 128.3, 127.8, 126.9, 125.2,
124.9, 124.4, 121.2, 109.8, 82.6, 32.6. HRMS (ESI): Exact mass
1
3f, Yellow oil, 85% yield. H NMR (300 MHz, CDCl3) δ 7.94 (t, 95 calcd. for C19H14O2Na [M+Na]+ 297.0891, found: 297.0896.
45 J = 7.4 Hz, 1H), 7.60 (m, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.25ꢀ7.12
1
(m, 3H), 6.92 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H)., 5.99ꢀ
5.82 (m, 1H), 3.69 (dd, J = 15.8, 10.9 Hz, 1H), 3.43 (dd, J = 15.9,
5.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 194.7, 163.3, 160.0,
159.3, 135.3, 135.2, 131.3, 131.3, 128.3, 124.8, 124.8, 124.7,
3l, Yellow oil, 81% yield. H NMR (300 MHz, CDCl3) δ 7.68 (s,
1H), 7.47 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 6.6 Hz, 1H), 7.16 (d, J
= 7.8 Hz, 1H), 6.99ꢀ6.85 (m, 2H), 6.60 (dd, J = 3.5, 1.6 Hz, 1H),
5.69 (dd, J = 10.3, 7.5 Hz, 1H), 3.63 (dd, J = 15.9, 10.4 Hz, 1H),
50 121.0, 116.7, 116.3, 109.6, 85.0, 84.9, 32.5, 32.5. HRMS (ESI): 100 3.53 (dd, J = 16.0, 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
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50 of sulfur ylides with oꢀquinone methides that could be generated
under mild conditions. In addition, chiral sulfonium salts could
also be employed in this reaction, affording the desired product
with moderate enantioselectivity. The products 2ꢀsubstitiuted
dihydrobenzofurans could be conveniently converted to 2ꢀ
55 substituted benzofurans with using DDQ as the oxidant.
Applications of this [4+1] cycloaddition reaction to other
substrates and to the construction of biologically relevant
compounds are ongoing in our laboratory.
184.9, 158.5, 149.9, 146.9, 127.9, 124.6, 124.4, 120.8, 119.8,
112.0, 109.2, 82.4, 32.6. HRMS (ESI): Exact mass calcd. for
C13H10O3Na [M+Na]+ 237.0528, found: 237.0519.
3m, Yellow oil, 95% yield. 1H NMR (300 MHz, CDCl3) δ 8.01 (d,
J = 3.8 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.25ꢀ7.15 (m, 3H), 6.92
(t, J = 7.2 Hz, 2H), 5.68 (t, J = 8.5 Hz, 1H), 3.61 (d, J = 8.8 Hz,
2H). 13C NMR (75 MHz, CDCl3) δ 189.7, 158.4, 140.0, 134.5,
133.7, 127.9, 127.8, 124.6, 124.5, 120.9, 109.3, 83.5, 32.9.
HRMS (ESI): Exact mass calcd. for C13H10O2SNa [M+Na]+
5
Acknowledgement
10 253.0299, found: 253.0305.
60 Financial support from National Natural Science Foundation of
China (grants 81373303 and 81473080) and State Key
Laboratory of Durg Research (SIMM1403KFꢀ13) is gratefully
acknowledged.
1
3n, White solid, 77% yield. m.p. 118.5ꢀ120.5 °C. H NMR (300
MHz, CDCl3) δ 8.74 (d, J = 4.1 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H),
7.90 (dt, J = 7.7, 1.6 Hz, 1H), 7.54 (dd, J = 7.0, 5.4 Hz, 1H), 7.17
(t, J = 7.4 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.4 Hz,
15 1H), 6.49 (dd, J = 10.9, 7.6 Hz, 1H), 3.85 (dd, J = 16.0, 10.9 Hz,
1H), 3.31 (dd, J = 16.1, 7.6 Hz, 1H). 13C NMR (75 MHz, CDCl3)
δ 196.3, 159.7, 151.6, 149.1, 137.1, 128.2, 127.6, 125.2, 124.7,
123.0, 120.8, 109.8, 82.3, 34.0. HRMS (ESI): Exact mass calcd.
for C14H11NO2Na [M+Na]+ 248.0687, found: 248.0680.
Notes and references
65 a Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and
State Key Laboratory of Natural Medicines, Center of Drug Discovery,
China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009,
China
Email: qlxu@cpu.edu.cn, hbsun2000@yahoo.com
70 b State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Science, 555 Zuchongzhi Road, Shanghai
201203, China
1
20 3q,[15] White solid, 90% yield, m.p. 138.5ꢀ140 °C. H NMR (300
MHz, CDCl3) δ 8.07ꢀ8.00 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.51
(t, J = 7.5 Hz, 2H), 7.32ꢀ7.20 (m, 2H), 6.76 (t, J = 9.8 Hz, 1H),
5.96 (dd, J = 10.1, 7.4 Hz, 1H), 3.61 (dd, J = 16.1, 7.4 Hz, 1H),
3.57ꢀ3.47 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 194.8, 158.2,
25 134.2, 133.8, 131.1, 129.1, 128.8, 127.8, 127.7, 113.0, 111.2,
82.9, 32.2.
† Electronic Supplementary Information (ESI) available: The prodedure
for synthesis of Oꢀsilylated phenol 1 and the copies of spectra. See
75 DOI: 10.1039/b000000x/
1
For reviews, see: (a) H. Amouri, J. Le Bras, Acc. Chem. Res., 2002,
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80
85
2
General Procedure for Synthesis of 3o, 3p: A mixture of Oꢀ
silylated phenol 1 (0.5 mmol, 1.0 equiv.), sulfonium salt 2 (0.75
mmol, 1.5 equiv.) and Cs2CO3 (0.75 mmol, 1.5 equiv.) in dry
30 CH2Cl2 (5 mL) was stirred at room temperature under N2. Then
TBAF (1.0 M in THF, 1.25 mL, 2.5 equiv.) was added dropwise.
After the addition, the mixture was stirred at room temperature
for 24 h. The reaction was concentrated under reduced pressure
and purified by flash chromatography on silica gel (petroleum
35 ether : ethyl acetate = 10:1ꢀ5:1).
3
4
90
3o,[16] Yellow oil, 42% yield. H NMR (300 MHz, CDCl3) δ 7.17
1
(dd, J = 10.8, 7.8 Hz, 2H), 6.90 (t, J = 7.3 Hz, 2H), 5.20 (dd, J =
10.4, 7.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.58 (dd, J = 15.8,
10.6 Hz, 1H), 3.39 (dd, J = 15.8, 7.0 Hz, 1H), 1.33 (t, J = 7.1 Hz,
40 3H).
95
100
105
110
3p,[17] Colorless oil, 85% yield. H NMR (500 MHz, CDCl3) δ
1
7.19 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.4
Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.36 (dd, J = 9.8, 7.7 Hz, 1H),
3.73 (dd, J = 15.6, 7.6 Hz, 1H), 3.57ꢀ3.39 (m, 4H), 3.32 (dd, J =
45 15.5, 9.9 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz,
3H).
5
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Conclusions
In summary, we have developed a straightforward and efficient
approach to 2ꢀsubstitiuted dihydrobenzofurans through reaction
4
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