Acid-catalysed or radical-promoted allylic substitution of 2-methylene-2, 3dihydrobenzofuran-3-ols with thiol derivatives: A novel and expedient synthesis of 2-(thiomethyl)benzofurans

Article abstract of DOI:10.1002/ejoc.201000289

The 2-thiomethylbenzofuran derivatives 3 are conveniently prepared in good yields through the reactions between the readily available 2-methylene-2, 3-dihydrobenzofuran-3-ols 1 and the thiol derivatives 2 (including alkyl thiols, thiophenol, and thioacetic acid). The allylic substitution process may be either acid-catalysed or promoted by radical initiators. In the first case, the reactions are carried out at 90 °C in 1, 2-dimethoxyethane (DME) as the solvent in the presence of H₂SO₄ as the proton source. The radical-promoted reactions take place in DME at: 90 °C in the presence of azobis(isobutyronitrile) (AIBN) or benzoyl peroxide (BP) as the radical initiator.

Full text of DOI:10.1002/ejoc.201000289

FULL PAPER
DOI: 10.1002/ejoc.201000289
Acid-Catalysed or Radical-Promoted Allylic Substitution of 2-Methylene-2,3-
dihydrobenzofuran-3-ols with Thiol Derivatives: a Novel and Expedient
Synthesis of 2-(Thiomethyl)benzofurans
Bartolo Gabriele,*[a] Raffaella Mancuso,[b] and Giuseppe Salerno[b]
Keywords: Allylic substitution / Benzofurans / Thioethers / Oxygen heterocycles / Nucleophilic substitution / Radical
reactions
The 2-thiomethylbenzofuran derivatives 3 are conveniently
prepared in good yields through the reactions between the
readily available 2-methylene-2,3-dihydrobenzofuran-3-ols 1
and the thiol derivatives 2 (including alkyl thiols, thiophenol,
and thioacetic acid). The allylic substitution process may be
either acid-catalysed or promoted by radical initiators. In the
first case, the reactions are carried out at 90 °C in 1,2-di-
methoxyethane (DME) as the solvent in the presence of
H2SO4 as the proton source. The radical-promoted reactions
take place in DME at 90 °C in the presence of azobis(iso-
butyronitrile) (AIBN) or benzoyl peroxide (BP) as the radical
initiator.
Introduction
Results and Discussion
Benzofurans are a very important class of heterocyclic
The reaction between 3-methyl-2-methylene-2,3-dihydro-
compounds. A variety of molecules containing the benzo- benzofuran-3-ol (1a, R1 = Me, R2 = R3 = H) and thio-
furan ring system display a wide range of biological activi- phenol (2a, R = Ph) was first investigated under acidic con-
ties, including anti-HIV, anticancer and antimicrobial ditions, with H2SO4 as the proton source, in 1,2-dimethoxy-
activities.[1] The preparation of functionalized benzofurans ethane (DME) as the solvent, at 70 °C and with a 2a/1a
with high efficiency and selectivity from readily available molar ratio of 2. Under these conditions, the degree of con-
starting materials is therefore of particular interest in cur- version of 1a was 70% after 5 h, with selective formation
rent synthesis.[2,3]
of 3-methyl-2-[(phenylsulfanyl)methyl]benzofuran (3aa) in
We have recently reported a novel method for the synthe- 61% isolated yield (Table 1, Entry 1). Substrate conversion
sis of the 2-methylene-2,3-dihydrobenzofuran-3-ols 1, based reached 100% after 15 h, with a yield of 3aa as high as
on palladium-catalysed cycloisomerization of readily avail- 81% (Table 1, Entry 2). The yield of 3aa was lower at lower
able 2-(1-hydroxyprop-2-ynyl)phenols, and have shown that temperatures (Entries 3–4), whereas at 100 °C it remained
these derivatives can be conveniently converted into 2-(hy- practically unchanged (Entry 5). A less satisfactory yield
droxymethyl)benzofurans and 2-(alkoxymethyl)benzofurans was also obtained at 90 °C with an equimolar amount of
by acid-catalysed allylic isomerization or allylic nucleophilic 2a with respect to 1a (Entry 6), or with use of more concen-
substitution.[3d] We have now found that the dihydrobenzo- trated acidic conditions (Entry 7). On the other hand, no
furans 1 are also excellent starting materials for a novel ap- formation of 3aa occurred in the absence of H2SO4 (only
proach to the 2-thiomethylbenzofurans 3,[4] through their partial decomposition of 1a was observed under these con-
reactions with the thiol derivatives 2 under either acidic or ditions; Entry 8).
radical conditions, see Equation (1).
These results show that thiophenol (2a) can be success-
fully employed as a nucleophile in the acid-catalysed allylic
nucleophilic substitution of 1a to afford 3aa by the general
mechanism shown in Scheme 1. The key intermediate of the
process is the allyl cation I formed by protonation of the
substrate followed by loss of water. Regiospecific nucleo-
philic attack by the thiol on I then leads to the final product
with regeneration of the proton.
In view of the tendency of thiols and thiophenols to form
thiyl radicals,[5] we also tested the reactivity of 1a with 2a
in the presence of radical initiators, such as azobis(iso-
butyronitrile) (AIBN) or benzoyl peroxide (BP). The results
obtained under different experimental conditions are shown
[a] Dipartimento di Scienze Farmaceutiche, Università della Calabria,
87036 Arcavacata di Rende (CS), Italy
Fax: +39-0984-492044
E-mail: b.gabriele@unical.it
[b] Dipartimento di Chimica, Università della Calabria,
87036 Arcavacata di Rende (CS), Italy
Eur. J. Org. Chem. 2010, 3459–3464
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Gabriele, R. Mancuso, G. Salerno
Table 1. Synthesis of 3-methyl-2-[(phenylsulfanyl)methyl]benzo- Table 2. Synthesis of 3-methyl-2-[(phenylsulfanyl)methyl]benzo-
FULL PAPER
furan (3aa) through acid-catalysed allylic nucleophilic substitution
of 3-methyl-2-methylene-2,3-dihydrobenzofuran-3-ol (1)a with thio-
phenol (2a).[a]
furan (3aa) through allylic substitution of 3-methyl-2-methylene-
2,3-dihydrobenzofuran-3-ol (1a) with thiophenol (2a) under radical
conditions.[a]
Entry 2a/1a molar
Temp.
[°C]
Time
[h]
Conv. of 1a Yield of 3aa
Entry
2a/1a
Radical Solvent Temp. Time Conv. of Yield of
[°C] [h] 1a [%][b] 3aa [%][c]
ratio
[%][b]
[%][c]
molar ratio initiator
1
2
3
4
5
6
2
2
2
2
2
1
2
2
90
90
80
70
100
90
90
90
5
70
61
81
72
53
82
45
52
0
1
2
3
4
5
6
7
8
2
2
2
5
1
2
2
2
2
2
2
2
2
1
AIBN
AIBN
AIBN
AIBN
AIBN
DME
DME
DME
DME
DME
70
80
90
90
90
2
2
2
2
15
2
2
2
2
2
60
85
100
100
100
83
72
67
80
90
31
65
74
69
27
44
32
33
53
59
36
21
80
34
15
15
15
15
15
15
15
100
100
100
100
100
100
31
AIBN dioxane 90
AIBN MeCN
7[d]
8[e]
90
70
80
90
BP
BP
BP
BP
BP
BP
BP
DME
DME
DME
9
[a] Unless otherwise noted, all reactions were carried out in 9:1
mixtures of DME/H2SO4 (3.74ϫ10–2  in DME; substrate concen-
tration: 0.22 mmol of 1a per mL of solvent, 1.2 mmol scale based
on 1a). Formation of heavy products (chromatographically immo-
bile materials) accounted for the difference between the conversion
of 1a and the yield of 3a in each case. [b] Based on starting 1a, by
GLC. [c] Isolated yield based on starting 1a. [d] The reaction was
carried out in a 9:1 mixture of DME/H2SO4 (0.37  in DME). [e]
The reaction was carried out in pure DME in the absence of
H2SO4.
10
11
12
13
14
dioxane 90
2
2
15
15
72
69
100
100
MeCN
DME
DME
90
90
90
[a] Unless otherwise noted, all reactions were carried out in DME
(substrate concentration: 0.22 mmol of 1a per mL of solvent,
1.2 mmol scale based on 1a) in the presence of radical initiator
(10 mol-% with respect to 1a). Formation of heavy products (chro-
matographically immobile materials) accounted for the difference
between the conversion of 1a and the yield of 3a in each case.
[b] Based on starting 1a, by GLC. [c] Isolated yield based on start-
ing 1a.
A plausible mechanism for the formation of compounds
3 under free-radical conditions is shown in Scheme 2. Re-
giospecific addition of RS· (formed by the reaction between
2 and In·) to the exocyclic carbon of the double bond of 1
may afford the radical intermediate II. Direct fragmentation
of II to give 3 and the hydroxyl radical HO· appears un-
likely in view of the high instability of the latter species.[6]
Alternatively, intermediate II can undergo ionic fragmenta-
tion with elimination of HO– and formation of a radical
cation species III.[7,8] Deprotonation of the latter by HO–
can then afford the stabilized radical species IV. Reaction
of the latter with RSH leads to the formation of 3 with
regeneration of RS·.
Scheme 1. Plausible mechanism for the acid-catalysed conversion
of the dihydrobenzofurans 1 into the 2-thiomethylbenzofurans 3
with the thiol derivatives 2 as nucleophiles.
in Table 2. As can be seen, formation of 3aa was observed
with both AIBN and BP. In DME at 70 or 80 °C for 2 h in
the presence of AIBN (10 mol-%) and a twofold excess of
2a with respect to 1a, substrate conversion was not quanti-
tative, and 3aa was formed in 31% and 65% yields, respec-
tively (Table 2, Entries 1 and 2). Under similar conditions,
but at 90 °C, substrate conversion was 100% and the yield
of 3aa reached 74% (Entry 3). This yield did not improve
with a higher 2a/1a molar ratio (Table 2, Entry 4), whereas
the use of equimolar amounts of 1a and 2a led to a signifi-
cantly lower yield of the product, due to the formation of
a complex mixture of heavy, chromatographically immobile
products (Table 2, Entry 5). Lower yields of 3aa were also
observed in dioxane (Table 2, Entry 6) or acetonitrile
(Table 2, Entry 7) as solvents. With BP, the best yield of 3aa
(80%) was observed under conditions similar to those of
Entry 3, but after a reaction time of 15 h rather than 2 h
(Table 2, Entry 13).
Scheme 2. Plausible mechanism for the radical-promoted conver-
sions of the dihydrobenzofurans 1 into the 2-thiomethylbenzo-
furans 3 by treatment with the thiol derivatives 2.
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Eur. J. Org. Chem. 2010, 3459–3464

Radical-Promoted Allylic Substitution Reaction
Table 3. Synthesis of the 2-thiomethylbenzofurans 3 by allylic sub-
stitution of the 2-methylene-2,3-dihydrobenzofuran-3-ols 1 with the
thiol derivatives 2 under acidic or radical conditions.[a]
With the goal of expanding the scope of the reaction, we
then tested the reactivity of 1a and the other differently
substituted 2-methylene-2,3-dihydrobenzofuran-3-ols 1b–d
(bearing a secondary alcoholic group together with an elec-
tron-withdrawing or a π-donating group on the aromatic
ring) with several thiol derivatives 2a–d (including thio-
phenol, alkyl thiols, thioacetic acid) under the conditions
(both acidic and radical) already optimized for the reaction
between 1a and thiophenol (2a; summarized in Table 3, En-
tries 1–3). The results obtained are shown in Table 3. As
can be seen, fair to high yields of the corresponding 2-thio-
methylbenzofurans 3 were obtained in most cases (Table 3,
Entries 1–9, 11–13, 18–19, 21–29, 33–37, and 39–40), al-
though some combinations of dihydrobenzofurans 1 and
thiol derivatives 2 gave lower yields under particular condi-
tions. More specifically, the radical process did not work
well in the case of the reaction of substrates bearing a sec-
ondary alcoholic group (R1 = H) with thiophenol 2a (R
= Ph, Table 3, Entries 14–16 and 30–31), probably due to
competitive attack of PhS· on the hydrogen at C-3. On the
other hand, the use of thioacetic acid 2d (R = Ac) led in
some cases to less satisfactory results under acidic condi-
tions (Table 3, Entries 10, 20, and 38), whereas the radical
process proceeded well (Table 3, Entries 11–12, 21–22, and
39–40).
Entry
1
R1 R2
2
R
Condi-
tions[a]
3
Yield of
3 [%][b]
1
2
3
4
5
6
7
8
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2b
2b
2b
Ph
Ph
Ph
Bn
Bn
Bn
A
B
C
A
B
C
A
B
C
A
B
3aa
3aa
3aa
3ab
3ab
3ab
3ac
3ac
3ac
3ad
3ad
3ad
3ba
81
74
80
67
60
67
51
56
60
36
78
60
47
2c Ph(CH2)2
2c Ph(CH2)2
2c Ph(CH2)2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
2d
2d
2d
2a
2a
2a
2a
2b
2b
2b
2d
2d
2d
2b
2b
2b
2d
2d
2d
Ac
Ac
Ac
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Ac
Ac
Ac
Bn
Bn
Bn
Ac
Ac
Ac
Ph
Ph
Ph
Bn
Bn
Bn
C
A
B
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
H
H
H
H
H
H
H
H
H
H
3ba traces[c]
B[d]
C
A
B
3ba
3ba
3bb
3bb
3bb
3bd
3bd
3bd
3cb
3cb
3cb
3cd
3cd
3cd
3da
3da
3da
3db
3db
3db
3dc
3dc
3dc
3dd
3dd
3dd
5[e]
3[f]
30
55
66
26
77
74
63
61
60
47
86
71
45
12[g]
8[h]
23
55
47
64
45
42
38
71
80
C
A
B
C
A
B
C
A
B
C
A
B[d]
C
A
B
C
A
B
C
A
B
Conclusions
1c Me Cl
1c Me Cl
1c Me Cl
1c Me Cl
1c Me Cl
1c Me Cl
In conclusion, we have shown that the 2-methylene-2,3-
dihydrobenzofuran-3-ols can easily be converted in a one-
step fashion and under mild conditions into 2-thiomethyl-
benzofurans by treatment with thiols (including thiophenol,
alkyl thiols, and thioacetic acid) under either acidic or radi-
cal conditions. The methodology reported here thus allows
an innovative and convenient route to the sulfur-function-
alized benzofuran derivatives from readily available starting
materials.
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
H
H
H
H
H
H
H
H
H
H
H
H
OMe 2a
OMe 2a
OMe 2a
OMe 2b
OMe 2b
OMe 2b
OMe 2c Ph(CH2)2
OMe 2c Ph(CH2)2
OMe 2c Ph(CH2)2
Experimental Section
OMe 2d
OMe 2d
OMe 2d
Ac
Ac
Ac
General: The starting 2-methylene-2,3-dihydrobenzofuran-3-ols 1
were prepared as described previously.[3d] The thiol derivatives 2
and DME were commercially available (Aldrich, Fluka) and were
used as received. H2SO4 (96% w/w) was purchased from Carlo–
Erba Reagenti (Milan, Italy) and was used as received. The solu-
tion of H2SO4 in DME (3.74ϫ10–2 ) was prepared as follows:
H2SO4 (96% w/w, d = 1.835 g mL–1, 1.0 mL) was diluted with
DME in a volumetric flask (10 mL) to a total volume of 10 mL,
and a portion of this solution (200 µL) was then transferred into
another volumetric flask (10 mL) and diluted with DME up to a
total volume of 10 mL.
C
[a] Unless otherwise noted, reaction conditions were the following.
Conditions A: reactions were carried out at 90 °C for 15 h in a 9:1
mixture of DME/H2SO4 (3.74ϫ10–2 in DME) (substrate concen-
tration: 0.22 mmol of 1 per mL of solvent, 1.2 mmol scale based
on 1), with a 2/1 molar ratio of 2. Conditions B: reactions were
carried out at 90 °C for 2 h in DME (substrate concentration:
0.22 mmol of 1 per mL of solvent, 1.3 mmol scale based on 1), with
a 2/1/AIBN molar ratio of 20:10:1. Conditions C: reactions were
carried out at 90 °C for 15 h in DME (substrate concentration:
0.22 mmol of 1 per mL of solvent, 1.3 mmol scale based on 1), with
a 2/1/BP molar ratio of 20:10:1. Unless otherwise noted, substrate
conversion was quantitative in all cases, and the formation of heavy
products (chromatographically immobile materials) accounted for
the difference between the conversion of 1 and the yield of 3 in all
cases. [b] Isolated yield based on starting 1. [c] Substrate conversion
was ca. 10%. [d] Reaction time was 15 h. [e] Substrate conversion
was ca. 30%. [f] Substrate conversion was ca. 40%. [g] Substrate
conversion was ca. 50%. [h] Substrate conversion was ca. 55%.
All reaction mixtures were analysed by TLC on silica gel (60 F254
,
Merck) and by GLC with a Shimadzu GC-2010 gas chromatograph
and capillary columns with polymethylsilicone + 5% phenylsilicone
as the stationary phase (HP-5). Column chromatography was per-
formed with silica gel 60 (Merck, 70–230 mesh). Evaporation refers
to the removal of solvent under reduced pressure. 1H NMR and
13C NMR spectra were recorded at 25 °C with a Bruker DPX
Eur. J. Org. Chem. 2010, 3459–3464
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3461

B. Gabriele, R. Mancuso, G. Salerno
FULL PAPER
Avance 300 spectrometer in CDCl3 solutions at 300 MHz and
75 MHz, respectively, with Me4Si as internal standard. Chemical
shifts (δ) and coupling constants (J) are given in ppm and in Hz,
respectively. IR spectra were taken with a Jasco FT-IR 4200 spec-
trometer. Mass spectra were obtained with a Shimadzu QP-2010
GC–MS apparatus at 70 eV ionization voltage. Microanalyses were
carried out with a Carlo–Erba Elemental Analyzer Mod. 1106.
Entry 12); 3bb is a pale yellow oil (223 mg, 66%; Table 3, Entry 19);
3bd is a pale yellow oil (201 mg, 74%; Table 3, Entry 22); 3cb is a
pale yellow oil (240 mg, 60%; Table 3, Entry 25); 3cd is a pale yel-
low oil (240 mg, 71%; Table 3, Entry 28); 3db is a pale yellow oil
(175 mg, 47%; Table 3, Entry 34); 3dc is a pale yellow oil (167 mg,
42%; Table 3, Entry 37); 3dd is a pale yellow oil (250 mg, 80%;
Table 3, Entry 40).
3-Methyl-2-[(phenylsulfanyl)methyl]benzofuran (3aa): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.46–7.32 (m, 4 H, aromatic),
7.28–7.15 (m, 5 H, aromatic), 4.16 (s, 2 H, CH2), 1.91 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.3, 149.0, 135.3,
132.2, 129.1, 128.9, 127.4, 124.1, 122.3, 119.1, 112.9, 111.0, 31.3,
General Procedure for the Synthesis of the 2-(Thiomethyl)benzo-
furans 3 by Reactions between 2-Methylene-2,3-dihydrobenzofuran-
3-ols 1 and Thiols 2 under Acidic Conditions (Table 3, Conditions A):
In a typical experiment, a mixture of the 2-methylene-2,3-dihydro-
benzofuran-3-ol 1 (1.23 mmol), the thiol derivative 2 (2.46 mmol)
and H2SO4 (3.74ϫ10–2  in DME, 560 µL) in DME (5.0 mL) was
stirred under nitrogen at 90 °C for 15 h. After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel with hexane/AcOEt 99:1 as eluent to give the pure thio-
methylbenzofurans 3. 3aa is a pale yellow oil (254 mg, 81%;
Table 3, Entry 1); 3ab is a pale yellow oil (220 mg, 67%; Table 3
Entry 4); 3ac is a pale yellow oil (178 mg, 51%; Table 3, Entry 7);
3ad is a pale yellow oil (98 mg, 36%; Table 3, Entry 10); 3ba is a
pale yellow oil (140 mg, 47%; Table 3, Entry 13); 3bb is a pale yel-
low oil (94 mg, 30%; Table 3, Entry 17); 3bd is a pale yellow oil
(65 mg, 26%; Table 3, Entry 20); 3cb is a pale yellow oil (236 mg,
63%; Table 3, Entry 23); 3cd is a pale yellow oil (148 mg, 47%;
Table 3, Entry 26); 3da is a pale yellow solid, m.p. 69–71 °C
(150 mg, 45%, Table 3, Entry 29); 3db is a pale yellow oil (80 mg,
23%; Table 3, Entry 32); 3dc is a pale yellow oil (235 mg, 64%;
Table 3, Entry 35); 3dd is a pale yellow oil (111 mg, 38%; Table 3,
Entry 38).
7.6 ppm. IR (film): ν = 1582 (m), 1477 (m), 1439 (s), 1262 (m),
˜
1198 (w), 1079 (m), 743 (s), 690 (m) cm–1. GC–MS (EI, 70 eV): m/z
(%) = 254 (35) [M]+, 147 (8), 146 (50), 145 (100), 127 (30), 117 (12),
116 (24), 115 (51), 109 (31), 102 (8), 91 (32), 89 (11), 77 (25), 75
(10). C16H14OS (254.35): calcd. C 75.55, H 5.55, S 12.61; found C
75.63, H 5.54, S 12.59.
2-[(Benzylsulfanyl)methyl]-3-methylbenzofuran (3ab): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.46–7.40 (m, 2 H, aromatic),
7.38–7.17 (m, 7 H, aromatic), 3.74 (s, 2 H, CH2), 3.72 (s, 2 H, CH2),
2.10 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.1,
149.7, 137.8, 129.9, 129.0, 128.5, 127.1, 124.0, 122.3, 119.1, 112.2,
111.0, 36.1, 26.0, 8.1 ppm. IR (film): ν = 1494 (m), 1453 (s), 1262
˜
(w), 1198 (w), 1079 (s), 849 (w), 747 (m), 699 (s) cm–1. GC–MS (EI,
70 eV): m/z (%) = 268 (20) [M]+, 146 (12), 145 (100), 115 (13), 91
(14). C17H16OS (268.37): calcd. C 76.08, H 6.01, S 11.95; found C
76.15, H 6.04, S 12.01.
3-Methyl-2-[(phenethylsulfanyl)methyl]benzofuran (3ac): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.48–7.39 (m, 2 H, aromatic),
7.33–7.12 (m, 7 H, aromatic), 3.84 (s, 2 H, CH2SCH2CH2), 2.92–
2.72 (m, 4 H, CH2SCH2CH2), 2.21 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 154.1, 154.0, 149.8, 140.3, 129.9, 128.5,
126.4, 124.0, 122.3, 119.1, 112.1, 111.0, 36.1, 33.3, 26.8, 8.1 ppm.
General Procedure for the Synthesis of the 2-(Thiomethyl)benzo-
furans 3 by Reactions between 2-Methylene-2,3-dihydrobenzofuran-
3-ols 1 and Thiols 2 under Radical Conditions with AIBN as Initiator
(Table 3, Conditions B): In a typical experiment, a mixture of the
2-methylene-2,3-dihydrobenzofuran-3-ol 1 (1.28 mmol), the thiol
derivative 2 (2.56 mmol) and AIBN (21 mg, 0.13 mmol) in DME
(5.8 mL) was stirred under nitrogen at 90 °C for 2 h. After evapora-
tion of the solvent, the residue was purified by column chromatog-
raphy on silica gel with hexane/AcOEt 99:1 as eluent to give the
pure thiomethylbenzofurans 3. 3aa is a pale yellow oil (240 mg,
74%; Table 3, Entry 2); 3ab is a pale yellow oil (205 mg, 60%;
Table 3 Entry 5); 3ac is a pale yellow oil (202 mg, 56%; Table 3,
Entry 8); 3ad is a pale yellow oil (221 mg, 78%; Table 3, Entry 11);
3bb is a pale yellow oil (180 mg, 55%; Table 3, Entry 18); 3bd is a
pale yellow oil (204 mg, 77%; Table 3, Entry 21); 3cb is a pale yel-
low oil (235 mg, 61%; Table 3, Entry 24); 3cd is a pale yellow oil
(280 mg, 86%; Table 3, Entry 27); 3db is a pale yellow oil (200 mg,
55%; Table 3, Entry 33); 3dc is a pale yellow oil (171 mg, 45%;
Table 3, Entry 36); 3dd is a pale yellow oil (216 mg, 71%; Table 3,
Entry 39).
IR (film): ν = 1497 (w), 1475 (w), 1454 (s), 1263 (m), 1199 (w),
˜
1080 (w), 1055 (w), 698 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) =
282 (16) [M]+, 146 (11), 145 (100), 115 (19), 91 (17), 77 (9).
C18H18OS (282.40): calcd. C 76.56, H 6.42, S 11.35; found C 76.27,
H 6.44, S 11.32.
S-(3-Methylbenzofuran-2-yl)methyl Thioacetate (3ad): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.46–7.34 (m, 2 H, aromatic),
7.28–7.15 (m, 2 H, aromatic), 4.26 (s, 2 H, CH2), 2.34 [s, 3 H,
Me(CO)], 2.24 (s, 3 H, Me at C-3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 194.4, 154.1, 148.3, 129.8, 124.2, 122.3, 119.2, 112.7,
110.9, 30.3, 24.5, 7.9 ppm. IR (film): ν = 1496 (w), 1475 (w), 1455
˜
(s), 1263 (m), 1199 (m), 1080 (m), 1055 (w), 747 (s), 698 (m) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 220 (13) [M]+, 146 (11), 145 (100),
115 (19). C12H12O2S (220.29): calcd. C 65.43, H 5.49, S 14.56;
found C 65.51, H 5.51, S 14.51.
General Procedure for the Synthesis of the 2-(Thiomethyl)benzo-
furans 3 by Reactions between 2-Methylene-2,3-dihydrobenzofuran-
3-ols 1 and Thiols 2 under Radical Conditions with BP as Initiator
(Table 3, Conditions C): In a typical experiment, a mixture of the
2-methylene-2,3-dihydrobenzofuran-3-ol 1 (1.32 mmol), the thiol
derivative 2 (2.64 mmol) and BP (32 mg, 0.13 mmol) in DME
(6.0 mL) was stirred under nitrogen at 90 °C for 15 h. After evapo-
ration of the solvent, the residue was purified by column
chromatography on silica gel with hexane/AcOEt 99:1 as eluent to
give the pure thiomethylbenzofurans 3. 3aa is a pale yellow oil
(270 mg, 80%; Table 3, Entry 3); 3ab is a pale yellow oil (236 mg,
67%; Table 3 Entry 6); 3ac is a pale yellow oil (225 mg, 60%;
Table 3, Entry 9); 3ad is a pale yellow oil (175 mg, 60%; Table 3,
2-[(Phenylsulfanyl)methyl]benzofuran (3ba): Pale yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.50–7.41 (m, 2 H, aromatic), 7.41–
7.34 (m, 2 H, aromatic), 7.31–7.15 (m, 5 H, aromatic), 6.47 (s, 1
H, 3-H), 4.21 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ
= 155.2, 154.3, 135.5, 130.9, 129.0, 128.6, 127.1, 124.1, 122.8, 120.8,
111.2, 104.7, 32.4 ppm. IR (film): ν = 1584 (w), 1479 (m), 1454 (s),
˜
1439 (m), 1253 (s), 1087 (w), 1024 (w), 952 (w), 739 (s), 689
(m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 240 (15) [M]+, 132 (11),
131 (100), 77 (22). C15H12OS (240.32): calcd. C 74.97, H 5.03, S
13.34; found C 75.15, H 5.95, S 13.31.
2-[(Benzylsulfanyl)methyl]benzofuran (3bb): Pale yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.54–7.42 (m, 2 H, aromatic), 7.38–
3462
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3459–3464

Radical-Promoted Allylic Substitution Reaction
7.16 (m, 7 H, aromatic), 6.53 (s, 1 H, 3-H), 3.74 (s, 2 H, CH2), 3.69
(s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.2, 154.9,
137.8, 129.4, 129.1, 128.6, 127.2, 124.0, 122.8, 120.7, 111.2, 104.4,
= 284 (23) [M]+, 162 (17), 161 (100), 146 (5), 118 (12), 91 (15).
C17H16O2S (284.37): calcd. C 71.80, H 5.67, S 11.28; found C 71.67,
H 5.69, S 11.31.
36.3, 28.1 ppm. IR (film): ν = 1494 (w), 1454 (s), 1253 (m), 1192
˜
5-Methoxy-2-[(phenethylsulfanyl)methyl]benzofuran (3dc): Pale yel-
low oil. H NMR (300 MHz, CDCl3): δ = 7.38–7.14 (m, 6 H, aro-
(w), 1071 (w), 952 (w), 743 (m), 700 (m) cm–1. GC–MS (EI, 70 eV):
m/z (%) = 254 (18) [M]+, 132 (27), 131 (100), 91 (18), 77 (20).
C16H14OS (254.35): calcd. C 75.55, H 5.55, S 12.61; found C 75.63,
H 5.51, S 12.63.
1
matic), 6.97 (d, J = 2.6 Hz, 1 H, 4-H), 6.85 (dd, J = 8.8, 2.6 Hz,
1 H, 6-H), 6.48 (s, 1 H, 3-H), 3.82 (s, 3 H, OMe), 3.79 (s, 2 H,
CH2SCH2CH2), 2.93–2.76 (m, 4 H, CH2SCH2CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 156.2, 155.9, 150.2, 145.4, 140.4,
129.2, 128.6, 126.6, 112.7, 111.6, 104.4, 103.7, 56.1, 36.1, 33.6,
S-(Benzofuran-2-yl)methyl Thioacetate (3bd): Pale yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.52–7.46 (m, 1 H, aromatic), 7.45–
7.39 (m, 1 H, aromatic), 7.28–7.15 (m, 2 H, aromatic), 6.61 (s, 1
H, 3-H), 4.26 (s, 2 H, CH2), 2.37 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 194.2, 154.9, 153.4, 128.4, 124.1, 122.8,
29.2 ppm. IR (film): ν = 1616 (w), 1602 (w), 1496 (w), 1476 (s),
˜
1453 (m), 1206 (s), 1167 (m), 1031 (m), 954 (w), 839 (m), 699
(m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 298 (14) [M]+, 162 (12),
161 (100), 146 (7), 118 (20), 91 (14), 77 (10). C18H18O2S (298.40):
calcd. C 72.45, H 6.08, S 10.75; found C 72.54, H 6.06, S 10.78.
120.8, 111.1, 104.8, 30.3, 26.3 ppm. IR (film): ν = 1695 (s), 1600
˜
(w), 1586 (w), 1454 (m), 1354 (w), 1253 (m), 1131 (m), 954 (m),
743 (m), 697 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 206 (14)
[M]+, 132 (9), 131 (100), 91 (5), 77 (19). C11H10O2S (206.26): calcd.
C 64.05, H 4.89, S 15.55; found C 64.15, H 4.87, S 15.59.
S-(5-Methoxybenzofuran-2-yl)methyl Thioacetate (3dd): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.31 (distorted d, J = 8.8 Hz,
1 H, 7-H), 6.95 (distorted d, J = 2.6 Hz, 1 H, 4-H), 6.85 (distorted
dd, J = 8.8, 2.6 Hz, 1 H, 6-H), 6.55 (s, 1 H, 3-H), 4.24 (s, 2 H,
CH2), 3.82 (s, 3 H, OMe), 2.37 [s, 3 H, Me(CO)] ppm. 13C NMR
(75 MHz, CDCl3): δ = 194.4, 156.0, 154.3, 150.0, 129.0, 112.9,
2-[(Benzylsulfanyl)methyl]-5-chloro-3-methylbenzofuran (3cb): Pale
yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.17 (m, 8 H,
aromatic), 3.74 (s, 2 H, CH2), 3.70 (s, 2 H, CH2), 2.07 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.4, 151.5, 137.6,
131.3, 128.9, 128.5, 127.9, 127.1, 124.1, 118.8, 111.9, 36.2, 26.0,
111.6, 105.0, 103.4, 56.0, 30.4, 26.4 ppm. IR (film): ν = 1694 (s),
˜
1617 (w), 1477 (s), 1448 (m), 1354 (w), 1206 (s), 1168 (m), 1133
(m), 1031 (m), 957 (m), 800 (m), 725 (w), 624 (m) cm–1. GC–MS
(EI, 70 eV): m/z (%) = 236 (22) [M]+, 162 (13), 161 (100), 146 (6),
118 (12), 89 (6). C12H12O3S (236.29): calcd. C 61.00, H 5.12, S
13.57; found C 61.12, H 5.10, S 13.61.
8.0 ppm. IR (film): ν = 1494 (w), 1453 (s), 1267 (m), 1199 (w), 1090
˜
(m), 1058 (w), 803 (w), 758 (w), 701 (m) cm–1. GC–MS (EI, 70 eV):
m/z (%) = 304 (6) [M + 2]+, 302 (16) [M]+, 181 (32), 180 (14), 179
(100), 144 (10), 116 (8), 115 (17), 91 (17). C17H15ClOS (302.82):
calcd. C 67.43, H 4.99, Cl 11.71, S 10.59; found C 67.32, H 5.01,
Cl 11.75, S 10.57.
[1] For recent examples, see: a) O. Saku, M. Saki, M. Kurokawa,
K. Ikeda, T. Takizawa, N. Uesaka, Bioorg. Med. Chem. Lett.
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K. Kawasaki, H. Ebiike, Y. Shiratori, T. A. Fukami, O. Kon-
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ani, Bioorg. Med. Chem. Lett. 2009, 19, 1753–1757; q) Y. Chen,
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S-(5-Chloro-3-methylbenzofuran-2-yl)methyl Thioacetate (3cd): Pale
yellow oil. H NMR (300 MHz, CDCl3): δ = 7.39 (d, J = 2.1 Hz,
1 H, 4-H), 7.28 (distorted d, J = 8.8 Hz, 1 H, 7-H), 7.18 (distorted
dd, J = 8.8, 2.1 Hz, 1 H, 6-H), 4.24 (s, 2 H, CH2), 2.36 [s, 3 H,
Me(CO)], 2.21 (s, 3 H, Me at C-3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 194.0, 152.7, 150.2, 131.4, 128.2, 124.4, 119.1, 112.5,
1
111.9, 30.2, 24.6, 7.8 ppm. IR (film): ν = 1695 (s), 1452 (s), 1354
˜
(w), 1267 (m), 1199 (w), 1130 (m), 1092 (m), 1061 (w), 957 (w), 905
(w), 863 (m), 803 (m), 701 (m), 623 (m) cm–1. GC–MS (EI, 70 eV):
m/z (%) = 256 (6) [M + 2]+, 254 (17) [M]+, 181 (32), 180 (13), 179
(100), 144 (13), 115 (20). C12H11ClO2S (254.73): calcd. C 56.58, H
4.35, Cl 13.92, S 12.59; found C 56.65, H 4.33, Cl 14.01, S 12.52.
5-Methoxy-2-[(phenylsulfanyl)methyl]benzofuran (3da): Pale yellow
1
solid, m.p. 69–71 °C. H NMR (300 MHz, CDCl3): δ = 7.40–7.16
(m, 6 H, aromatic), 6.92 (d, J = 2.6 Hz, 1 H, 4-H), 6.84 (distorted
dd, J = 8.8, 2.6 Hz, 1 H, 6-H), 6.40 (s, 1 H, 3-H), 4.17 (s, 2 H,
CH2), 3.80 (s, 3 H, OMe) ppm. 13C NMR (75 MHz, CDCl3): δ =
156.2, 155.1, 150.3, 135.6, 130.9, 129.2, 129.0, 127.1, 112.7, 111.5,
104.8, 103.8, 56.0, 32.4 ppm. IR (film): ν = 1599 (w), 1476 (s), 1440
˜
(m), 1233 (m), 1210 (s), 1165 (m), 1113 (w), 1031 (m), 954 (m), 843
(m), 735 (s), 710 (w), 689 (m) cm–1. GC–MS (EI, 70 eV): m/z (%)
= 270 (10) [M]+, 162 (11), 161 (100), 146 (7), 118 (19). C16H14O2S
(270.35): calcd. C 71.08, H 5.22, S 11.86; found C 71.16, H 5.21, S
11.91.
2-[(Benzylsulfanyl)methyl]-5-methoxybenzofuran (3db): Pale yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.41–7.19 (m, 6 H, aromatic),
6.92 (d, J = 2.6 Hz, 1 H, 4-H), 6.86 (distorted dd, J = 8.8, 2.6 Hz,
1 H, 6-H), 6.47 (s, 1 H, 3-H), 3.83 (s, 3 H, OMe), 3.74 (s, 2 H,
CH2), 3.67 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
156.3, 155.8, 150.3, 137.8, 130.4, 129.1, 128.6, 127.2, 112.6, 111.5,
104.6, 103.8, 56.1, 36.3, 28.2 ppm. IR (film): ν = 1616 (w), 1601
˜
(w), 1476 (s), 1452 (m), 1206 (s), 1167 (m), 1030 (m), 955 (w), 842
(w), 798 (w), 764 (w), 701 (m) cm–1. GC–MS (EI, 70 eV): m/z (%)
Eur. J. Org. Chem. 2010, 3459–3464
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3463

B. Gabriele, R. Mancuso, G. Salerno
FULL PAPER
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[4]
2-Thiomethylbenzofurans have been shown to possess interest-
ing pharmacological activity; see, for example: a) H. Ebiike,
M. Masubuchi, P. Liu, K. Kawasaki, K. Morikami, S. Sogabe,
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Russ. J. Org. Chem. 2005, 41, 631–648; b) I. V. Koval’, Russ. J.
Org. Chem. 2007, 43, 319–346. For a recent review on thiol-
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A few examples of radical fragmentation to give rather high-
energy radicals are known in the literature, but they involve the
simultaneous formation of stabilized aromatic compounds; see,
for example: a) J. C. Walton, A. Studer, Acc. Chem. Res. 2005,
38, 794–802; b) J. Guin, C. Mück-Lichtenfeld, S. Grimme, A.
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779–782.
We are indebted to a referee for the suggestion of this mecha-
nism. It is worth noting that radical cation formation under
reductive conditions (also induced by an initial thiyl radical
addition) for similar systems has been reported: D. Crich, X.-
S. Mo, J. Am. Chem. Soc. 1997, 119, 249–250.
[5]
[6]
[7]
[8]
For a literature overview on ionic fragmentation of radical in-
termediates to give radical cations, see: D. Crich, M. Shirai, F.
Brebion, S. Rumthao, Tetrahedron 2006, 62, 6501–6518.
Received: March 2, 2010
Published Online: May 4, 2010
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Eur. J. Org. Chem. 2010, 3459–3464