Synthesis of benzo[b]furans by palladium-NHC catalyzed ring closure of o-bromobenzyl ketones

Article abstract of DOI:10.1055/s-0028-1083261

The palladium-catalyzed ring closure of aryl o-bromobenzyl ketones, easily accessible from aromatic aldehydes and 2- bromobenzyl bromide, provides a straightforward route to 2-aryl- benzofurans. A study of the ring closure revealed that a heterocyclic car

Full text of DOI:10.1055/s-0028-1083261

PAPER
85
Synthesis of Benzo[b]furans by Palladium–NHC Catalyzed Ring Closure of
o-Bromobenzyl Ketones
Synthesis
á
of Benzo[
b
n
]furans by
R
i
o
ng
C
losure s Faragó,1 András Kotschy*2
Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary
Fax +36(1)8812011; E-mail: andras.kotschy@hu.netgrs.com
Received 20 October 2008
lyzed C–O or C–N coupling (Scheme 1). Copper10
catalysts were successfully applied to the synthesis of
benzofurans in such an approach, and the analogous pal-
ladium-catalyzed ring closure of 1-(o-bromobenzyl)-3,4-
dihydroisoquinolines to form the dibenzopyrrocoline
skeleton has also been published.11 Willis and co-workers
studied the palladium-catalyzed synthesis of benzofurans
and reported12 that the palladium–DPEphos {bis[2-
(diphenylphosphino)phenyl] ether} system in toluene cat-
alyzes the ring closure. Interestingly, the analogous Xant-
phos-based [Xantphos = 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene] system was found to be ineffective.
Abstract: The palladium-catalyzed ring closure of aryl o-bromo-
benzyl ketones, easily accessible from aromatic aldehydes and 2-
bromobenzyl bromide, provides a straightforward route to 2-aryl-
benzofurans. A study of the ring closure revealed that a heterocyclic
carbene based catalyst provides the best results.
Key words: ring closure, palladium, catalysis, benzofurans
In nature’s collection of biologically active heterocycles,
benzo[b]furan derivatives3 constitute a major group. Their
broad range of biological activities and significant phar-
macological potentials have generated extensive and en-
during efforts toward the synthesis of this important
heterocyclic compound class4 and its representatives in
nature.5 It is not surprising therefore that there is an ever
increasing number of synthetic approaches toward the
construction of the benzofuran core. The major synthetic
strategies involve the cyclization of o-ethynylphenols,5c,6
the oxidative cyclization of o-vinylphenols,5a,7 the cy-
clization of phenoxy ketones,8 and cyclizations through
olefin formation.9
Our present work was aimed at establishing if there are
any other palladium-based catalysts that lead to the effi-
cient formation of benzofurans from o-bromobenzyl ke-
tones. From the several routes leading to our key
intermediates (e.g., hydration of alkynes,10c arylation of
ketones12) we envisaged the synthesis of the aryl o-bro-
mobenzyl ketones through a sequence of well-established
transformations utilizing aromatic aldehydes and 2-bro-
mobenzyl bromide as building blocks.
A literature procedure13 was followed to convert a series
of aromatic aldehydes 1a–h into their thioketal deriva-
tives 2a–h by use of propane-1,3-dithiol in the presence of
a catalytic amount of nickel(II) chloride (Scheme 2) in
dichloromethane. As expected, all reactions worked well
and gave the desired 2-aryldithianes 2a–h in excellent
yields (Table 1).
A more recent approach is based on aromatic nucleophilic
substitution as the ring-forming process. d-Halogenated
carbonyl compounds and their imine analogs (e.g., ortho-
halobenzyl ketones and imines) are in equilibrium with
their enol and enamine forms, respectively, which are ide-
ally suited for cyclization through a transition-metal-cata-
We utilized the thus prepared dithianes 2a–h as acyl anion
equivalents (Scheme 2). Their deprotonation with butyl-
lithium proceeded readily and the anions that formed were
quenched by reaction with 2-bromobenzyl bromide (3)
(Scheme 2). After workup, we isolated the desired prod-
ucts 4a–h in good yield (Scheme 2, Table 1). The effi-
ciency of the reactions was in agreement with literature
MLn
Q
QH
Q
X
X
Q = NR, O
Scheme 1 A general strategy for the synthesis of five-membered
heterocycles through tautomeric equilibrium and nucleophilic substi-
tution
SH
Ar
Br
Hg(OAc)2 or
HgCl2/CaCO3
3
Ar
S
Br
n-BuLi
S
S
SH
S
Ar
ArCHO
NiCl2, CH2Cl2
aq MeCN
O
Br
Br
1a–h
2a–h
4a–h
5a–h
Scheme 2 The synthesis of aryl 2-bromobenzyl ketones 5a–h from aromatic aldehydes 1a–h and 2-bromobenzyl bromide (3)
SYNTHESIS 2009, No. 1, pp 0085–0090
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2
.
0
1
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0
0
9
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083261; Art ID: C04708SS
© Georg Thieme Verlag Stuttgart · New York

86
J. Faragó, A. Kotschy
PAPER
Table 1 The Yields of Aryl 2-Bromobenzyl Ketones 5a–h and the 2-Aryl-1,3-dithiane Intermediates 2a–h and the 2-Aryl-2-(2-bromoben-
zyl)-1,3-dithiane Intermediates 4a–h
a
b
c
d
e
f
g
h
Ar
2
Ph
PMP
4-ClC6H4
4-FC6H4
3-MeOC6H4
Naph
4-Me2NC6H4 Tol
87%
69%
50%
99%
75%
82%
87%
72%
72%
90%
94%
60%
99%
62%
65%
87%
83%
60%
65%
45%
40%
99%
85%
64%
4
5
precedence.14 Our attempts to improve the yield of the nyl)imidazolium tetrafluoroborate (IPr), which gave
process by utilizing other bases (LDA, LiHMDS) were nearly full conversion in o-xylene (Table 2, entry 8). Par-
unsuccessful.
tial saturation of the ligand led to decreased activity. Inter-
estingly, the change of the solvent to the more polar N,N-
dimethylformamide resulted in a significant drop in the
efficiency of the catalyst (SIPr and IMes giving 5% and
2% conversion in 24 hours, respectively). We also tested
a series of other bases (K2CO3, Et3N, t-BuONa) for the
conditions of entries 4 and 8, but, in general, we did not
observe any conversion except for decomposition.
The concluding step in the preparation of the key interme-
diate aryl o-bromobenzyl ketones 5a–h was the removal
of the dithiane protecting group (Scheme 2). From the se-
ries of deprotection methods (heavy metal salts, oxidative
treatment), only the use of mercury(II) salts gave satisfac-
tory results. Mercury(II) acetate15 or a mixture of mercu-
ry(II) chloride and calcium carbonate16 were equally
effective in removing the propanedithiol moiety and giv- Using the optimized conditions, we were able to convert
ing the aryl o-bromobenzyl ketones 5a–h10a,c,12b,17 in mod- all the aryl o-bromobenzyl ketones 5a–h into the corre-
erate to good yields (Scheme 2, Table 1). For practical sponding 2-arylbenzofuran derivatives 6a–h (Scheme 3).
reasons, we used the former reagent in our case.
The yield of the process varied greatly with the nature of
the aryl group (Table 3), and we were unable to establish
a clear trend in reactivity. In certain cases we obtained
good yields (6a–d), while in other cases (6e–h) the effi-
ciency of the process was only mediocre, e.g., the reaction
With the bromobenzyl ketones in hand, we set out to iden-
tify the optimal conditions for the ring-closure reaction.
The model reaction was the conversion of 5a into 2-phe-
nylbenzofuran (6a; Scheme 3). The screening of a selec-
tion of phosphine ligands (Table 2, entries 1–4) revealed
that under the applied conditions [Pd2(dba)3, Cs2CO3,
DMF, 100 °C, 4 h] significant conversion occurred only
in the presence of Xantphos (entry 4). It is interesting to
note that the change of the solvent to o-xylene diminished
the catalytic activity of the system (Table 2, entry 5), in
line with the report of Willis et al. who described a similar
‘inefficiency’ for Xantphos in toluene.12 The use of palla-
dium(II) acetate as palladium source (Table 2, entry 6)
was equally successful, while other salts [allylpalladi-
um(II) chloride, palladium(II) chloride or Pd(PPh3)2Cl2]
led to a significant drop in conversion. The transformation
is sensitive to the applied temperature too, since at 80 °C
we observed no conversion, while at 120 °C we started to
see decomposition products.
Table 2 The Optimization of the Reaction Conditions for the Ring
Closure of 2-Bromobenzyl Phenyl Ketone (5a)a
Entry Pd source Ligand
Base
Solvent
Conversionb
(%)
1
2
Pd2(dba)3 (o-Tol)3P
Pd2(dba)3 Cy3P
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
o-xylene
DMF
DMF
10
0
3
Pd2(dba)3 t-Bu3P
Pd2(dba)3 Xantphos
Pd2(dba)3 Xantphos
Pd(OAc)2 Xantphos
Pd2(dba)3 IPrd
8c
4
90
5c
5
6
88
18c
7
8
Pd2(dba)3 IPrd
o-xylene 95c
o-xylene 45c
o-xylene 13c
Ar
Pd, ligand
Ar
9
Pd2(dba)3 SIPrd
Pd2(dba)3 IMesd
Pd2(dba)3 SIMesd
base, solvent
O
O
Br
5a–h
6a–h
10
11
o-xylene
0c
Scheme 3 The synthesis of 2-arylbenzofurans 6a–h by the ring clo-
sure of aryl 2-bromobenzyl ketones 5a–h
a Reagents and conditions: 5a, Pd cat. (5 mol%), ligand (10 mol%),
base (2 equiv), solvent (containing tridecane as internal standard),
100 °C, 4 h.
We also tested a series of heterocyclic carbenes as ligands
in the transformation (Table 2, entries 7–11). In the pres-
ence of these ligands the ring closure was slower in gen-
eral, and its efficiency depended greatly both on the
structure of the carbene and the applied solvent. We ob-
tained the best results with 1,3-bis(2,6-diisopropylphe-
b The conversions were determined by GC analysis.
c The reaction was run for 24 h.
d IMes = 1,3-dimesitylimidazolium tetrafluoroborate; SIMes = 1,3-di-
mesitylimidazolinium tetrafluoroborate; IPr = 1,3-bis(2,6-diisopropyl-
phenyl)imidazolium tetrafluoroborate; SIPr = 1,3-bis(2,6-diisoprop-
ylphenyl)imidazolinium tetrafluoroborate.
Synthesis 2009, No. 1, 85–90 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzo[b]furans by Ring Closure
87
2-Aryl-2-(2-bromobenzyl)-1,3-dithianes 4a–h; General Proce-
dure
Table 3 The Yields of 2-Arylbenzofurans 6a–h Prepared by the
Ring Closure of Aryl o-Bromobenzyl Ketones 5a–h
The appropriate 2-aryl-1,3-dithiane 2 (10 mmol) was dissolved in
freshly distilled THF (40 mL) under argon. After the mixture had
been cooled to –50 °C, 1.6 M n-BuLi in hexane (6.9 mL, 11 mmol)
was added dropwise to the stirring soln. After the mixture had
stirred for 90 min, a soln of 2-bromobenzyl bromide (3; 2.749 g, 11
mmol) in absolute THF (20 mL) was added dropwise, and after stir-
ring for 1 h, the mixture was left to warm to r.t. Following the care-
ful quenching of the reaction by H2O, the THF was removed under
reduced pressure and the remaining aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic phase was dried
(MgSO4). After evaporation of the solvent under reduced pressure,
the residue was purified by column chromatography.
Compound 6
Ar
Yield (%)
6a
6b
6c
6d
6e
6f
Ph
94
82
72
76
36
40
20
38
PMP
4-ClC6H4
4-FC6H4
3-MeOC6H4
Naph
2-(2-Bromobenzyl)-2-phenyl-1,3-dithiane (4a)
Obtained from 2-phenyl-1,3-dithiane (2a); white crystals; yield:
2.52 g (69%); mp 128–130 °C.
6g
6h
4-Me2NC6H4
Tol
1H NMR (250 MHz, CDCl3): d = 7.73–7.68 (m, 2 H), 7.37–7.33 (m,
1 H), 7.24–7.18 (m, 3 H), 7.03–6.91 (m, 2 H), 6.83–6.80 (m, 1 H),
3.43 (s, 2 H), 2.62–2.52 (m, 4 H), 1.89–1.79 (m, 2 H).
of the dimethylaminophenyl derivative 6g giving only
very poor results. In comparison with the analogous cop-
per-catalyzed10 ring-closure reactions, the ring closure
catalyzed by palladium–N-heterocyclic carbene complex-
es might serve only as a second choice for systems where
the copper-catalyzed processes fail.
13C NMR (62.5 MHz, CDCl3): d = 140.2, 134.5, 133.0, 132.5,
129.6, 128.5, 128.4, 127.1, 126.6, 126.2, 60.4, 49.5, 27.6, 24.7.
HRMS (EI): m/z calcd for C17H17BrS2: 363.9955; found: 363.9949.
2-Anisyl-2-(2-bromobenzyl)-1,3-dithiane (4b)
Obtained from 2-anisyl-1,3-dithiane (2b); white crystals; yield:
2.97 g (75%); mp 72–73 °C.
In summary, we have developed a synthetic approach to
benzofuran derivatives starting from aromatic aldehydes
and 2-bromobenzyl bromide. The key step of the process
is the palladium-catalyzed ring closure of aryl o-bro-
mobenzyl ketones. Studying this transformation, we es-
tablished and demonstrated that the heterocyclic carbene
ligand derived from 1,3-bis(2,6-diisopropylphenyl)imida-
zolium tetrafluoroborate (IPr) gives an efficient catalyst.
We also established that the transformation is very sensi-
tive to the applied solvent, and in polar solvents a Xant-
phos-based catalyst is also able to initiate ring closure.
1H NMR (250 MHz, CDCl3): d = 7.61–7.55 (m, 2 H), 7.36–7.32 (m,
1 H), 7.02–6.89 (m, 2 H), 6.82–6.79 (m, 1 H), 6.77–6.71 (m, 2 H),
3.73 (s, 3 H), 3.41 (s, 2 H), 2.67–2.48 (m, 4 H), 1.87–1.77 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 158.5, 134.5, 132.9, 132.5,
132.0, 130.9, 128.3, 126.5, 126.1, 113.4, 59.9, 55.2, 49.5, 27.5,
24.8.
HRMS (EI): m/z calcd for C18H19BrOS2: 394.0061; found:
394.0054.
2-(2-Bromobenzyl)-2-(4-chlorophenyl)-1,3-dithiane (4c)
Obtained from 2-(4-chlorophenyl)-1,3-dithiane (2c); white crystals;
yield: 2.88 g (72%); mp 113–114 °C.
1H NMR (250 MHz, CDCl3): d = 7.74–7.68 (m, 2 H), 7.43 (d, J =
8.3 Hz, 1 H), 7.29–7.23 (m, 2 H), 7.15–7.00 (m, 3 H), 3.50 (s, 2 H),
2.67–2.63 (m, 4 H), 1.98–1.88 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 138.9, 134.1, 133.2, 133.0,
132.7, 131.3, 128.6, 128.4, 126.6, 126.3, 59.7, 49.4, 27.6, 24.7.
Unless otherwise indicated, all starting materials were obtained
from commercial suppliers (Aldrich, Fisher, Merck) and were used
without further purification. Analytical TLC was performed on
Polygram SIL G/ UV 254 precoated plastic TLC plates with 0.25
mm silica gel (Macherey-Nagel Co.). Silica gel column chromatog-
raphy was carried out with flash silica gel (0.040–0.063 mm) from
Merck. When a hexane–EtOAc mixture was used as chromatogra-
phy eluent, the column was prepared with hexane and the EtOAc
content of the eluent was increased gradually during chromatogra-
phy. Melting points were determined on a Büchi B-540 melting
point apparatus. The 1H and 13C NMR spectra of samples in CDCl3
or DMSO-d6 were recorded on a Bruker DRX-250 spectrometer.
Chemical shifts (d) are expressed relative to residual solvent pro-
tons as internal standards (CDCl3: d = 7.26 for 1H, d = 77 for 13C;
DMSO-d6: d = 2.50 for 1H, d = 39.43 for 13C). The following com-
pounds were prepared according to literature procedures: 2-phenyl-
1,3-dithiane (2a),13 2-anisyl-1,3-dithiane (2b),13 2-(4-chlorophe-
nyl)-1,3-dithiane (2c), 2-(4-fluorophenyl)-1,3-dithiane (2d), 2-(3-
methoxyphenyl)-1,3-dithiane (2e), 2-(2-naphthyl)-1,3-dithiane
(2f),13 2-[4-(dimethylamino)phenyl]-1,3-dithiane (2g), 2-(p-tolyl)-
1,3-dithiane (2h).13
HRMS (EI): m/z calcd for C17H16BrClS2: 397.9565; found:
397.9556.
2-(2-Bromobenzyl)-2-(4-fluorophenyl)-1,3-dithiane (4d)
Obtained from 2-(4-fluorophenyl)-1,3-dithiane (2d); white crystals;
yield: 3.60 g (94%); mp 103–104 °C.
1H NMR (250 MHz, CDCl3): d = 7.76–7.68 (m, 2 H), 7.40 (dd, J =
7.7, 1.4 Hz, 1 H), 7.13–6.91 (m, 5 H), 3.48 (s, 2 H), 2.68–2.59 (m,
4 H), 1.99–1.86 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 161.8 (d, J = 247.3 Hz), 135.6 (d,
J = 3.3 Hz), 134.1, 132.9, 132.5, 131.5 (d, J = 7.8 Hz), 128.5, 126.5,
126.1, 114.9 (d, J = 21.2 Hz), 59.5, 49.4, 27.4, 24.6.
HRMS (EI): m/z calcd for C17H16BrFS2: 381.9861; found:
381.9857.
2-(2-Bromobenzyl)-2-(3-methoxyphenyl)-1,3-dithiane (4e)
Obtained from 2-(3-methoxyphenyl)-1,3-dithiane (2e); white crys-
tals; yield: 2.45 g (62%); mp 85–86 °C.
Synthesis 2009, No. 1, 85–90 © Thieme Stuttgart · New York

88
J. Faragó, A. Kotschy
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1H NMR (250 MHz, CDCl3): d = 7.36–7.32 (m, 2 H), 7.28 (m, 1 H),
7.09 (t, J = 7.7 Hz, 1 H), 6.98–6.95 (m, 2 H), 6.90–6.84 (m, 2 H),
3.70 (s, 3 H), 3.40 (s, 2 H), 2.66–2.46 (m, 4 H), 1.86–1.75 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 154.8, 137.0, 135.3, 133.4,
133.1, 131.0, 128.5, 126.5, 126.1, 120.5, 119.5, 112.2, 61.1, 55.0,
49.9, 27.5, 24.8.
13C NMR (62.5 MHz, CDCl3): d = 195.6, 136.1, 134.7, 132.8,
132.2, 131.4, 128.3, 128.2, 127.8, 127.1, 124.7, 45.3.
HRMS (EI): m/z calcd for C14H11BrO: 273.9993; found: 273.9990.
Anisyl 2-Bromobenzyl Ketone (5b)
Obtained from 2-anisyl-2-(2-bromobenzyl)-1,3-dithiane (4b);
white crystals; yield: 0.50 g (82%); mp 51–53 °C.
1H NMR (250 MHz, CDCl3): d = 7.89–7.83 (m, 2 H), 7.41 (d, J =
7.8 Hz, 1 H), 7.10–7.06 (m, 2 H), 6.99–6.92 (m, 1 H), 6.81–6.75 (m,
2 H), 4.22 (s, 2 H), 3.66 (s, 3 H).
HRMS (EI): m/z calcd for C18H19BrOS2: 394.0061; found:
394.0051.
2-(2-Bromobenzyl)-2-(2-naphthyl)-1,3-dithiane (4f)
Obtained from 2-(2-naphthyl)-1,3-dithiane (2f); white crystals;
yield: 3.45 g (83%); mp 116–117 °C.
1H NMR (250 MHz, CDCl3): d = 8.15 (d, J = 1.7 Hz, 1 H), 7.83 (dd,
J = 8.8, 2.0 Hz, 1 H), 7.75–7.66 (m, 3 H), 7.39–7.35 (m, 2 H), 7.33–
7.26 (m, 1 H), 6.92–6.85 (m, 2 H), 6.78–6.72 (m, 1 H), 3.49 (s, 2 H),
2.60–2.53 (m, 4 H), 1.86–1.70 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 137.7, 134.3, 133.1, 132.8,
132.5, 132.2, 129.4, 128.5, 128.3, 128.1, 127.2, 126.9, 126.4, 126.2,
126.1, 125.9, 60.3, 49.2, 27.6, 24.6.
13C NMR (62.5 MHz, CDCl3): d = 194.5, 163.3, 135.1, 132.4,
131.5, 130.3, 129.3, 128.3, 127.2, 124.8, 113.6, 55.2, 45.1.
HRMS (EI): m/z calcd for C15H13BrO2: 304.0099; found: 304.0095.
2-Bromobenzyl 4-Chlorophenyl Ketone (5c)
Obtained from 2-(2-bromobenzyl)-2-(4-chlorophenyl)-1,3-dithiane
(4c); white crystals; yield: 0.45 g (72%); mp 76–77 °C.
1H NMR (250 MHz, CDCl3): d = 7.98 (d, J = 8.5 Hz, 2 H), 7.59 (d,
J = 7.9 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.32–7.12 (m, 3 H), 4.41
(s, 2 H).
HRMS (EI): m/z calcd for C21H19BrS2: 414.0112; found: 414.0109.
13C NMR (62.5 MHz, CDCl3): d = 195.1, 139.7, 134.8, 134.6,
2-(2-Bromobenzyl)-2-[4-(dimethylamino)phenyl]-1,3-dithiane
(4g)
Obtained from 2-[4-(dimethylamino)phenyl]-1,3-dithiane (2g);
132.8, 131.6, 129.7, 129.0, 128.8, 127.5, 125.0, 45.7.
HRMS (EI): m/z calcd for C14H10BrClO: 307.9604; found:
307.9598.
white crystals; yield: 1.82 g (45%); mp 128–130 °C.
1H NMR (250 MHz, CDCl3): d = 7.60–7.53 (m, 2 H), 7.35–7.30 (m,
1 H), 7.00–6.90 (m, 3 H), 3. 6.56–6.52 (m, 2 H), 3.44 (s, 2 H), 2.86
(s, 6 H), 2.72–2.51 (m, 4 H), 1.88–1.77 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 150.1, 132.1, 130.4, 130.0,
129.5, 128.1, 126.6, 124.0, 123.4, 112.0, 59.7, 49.4, 40.3, 27.5,
24.8.
2-Bromobenzyl 4-Fluorophenyl Ketone (5d)
Obtained from 2-(2-bromobenzyl)-2-(4-fluorophenyl)-1,3-dithiane
(4d); white crystals; yield: 0.35 g (60%); mp 65.5–66 °C.
1H NMR (250 MHz, CDCl3): d = 8.11–8.03 (m, 2 H), 7.59 (dd, J =
7.9, 0.9 Hz, 1 H), 7.32–7.21 (m, 2 H), 7.19–7.11 (m, 3 H), 4.42 (s,
2 H).
HRMS (EI): m/z calcd for C19H22BrNS2: 407.0377; found:
407.0371.
13C NMR (62.5 MHz, CDCl3): d = 194.7, 165.8 (d, J = 255.1 Hz),
134.7, 132.9 (d, J = 3.2 Hz), 132.8, 131.6, 131.0 (d, J = 9.4 Hz),
128.8, 127.5, 125.0, 115.8 (d, J = 22.1 Hz), 45.6.
2-(2-Bromobenzyl)-2-(p-tolyl)-1,3-dithiane (4h)
Obtained from 2-(p-tolyl)-1,3-dithiane (2h); white crystals; yield:
3.22 g (85%); mp 70–71 °C.
1H NMR (250 MHz, CDCl3): d = 7.59–7.54 (m, 2 H), 7.49–7.46 (m,
1 H), 7.19–7.15 (m, 2 H), 7.14–7.12 (m, 1 H), 7.10 (d, J = 2.0 Hz, 1
H), 6.90 (dd, J = 7.4, 2.0 Hz, 1 H), 3.45 (s, 2 H), 2.73–2.53 (m, 4 H),
2.30 (s, 3 H), 1.86–1.74 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 137.5, 136.3, 134.4, 132.8,
132.3, 129.0, 128.8, 128.0, 126.5, 125.9, 59.3, 48.6, 27.0, 24.2,
20.5.
HRMS (EI): m/z calcd for C14H10BrFO: 291.9899; found: 291.9891.
2-Bromobenzyl 3-Methoxyphenyl Ketone (5e)
Obtained from 2-(2-bromobenzyl)-2-(3-methoxyphenyl)-1,3-
dithiane (4e); white crystals; yield: 0.40 g (65%); mp 67–68 °C.
1H NMR (250 MHz, CDCl3): d = 7.46 (d, J = 7.8 Hz, 1 H), 7.41–
7.38 (m, 2 H), 7.19 (t, J = 7.7 Hz, 1 H), 7.11–7.03 (m, 2 H), 6.97–
6.91 (m, 2 H), 4.24 (s, 2 H), 3.62 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 196.4, 160.3, 138.4, 135.5,
133.1, 132.2, 130.1, 129.2, 128.0, 125.6, 121.3, 120.1, 113.1, 55.8,
46.3.
HRMS (EI): m/z calcd for C18H19BrS2: 378.0112; found: 378.0105.
HRMS (EI): m/z calcd for C15H13BrO2: 304.0099; found: 304.0090.
Aryl 2-Bromobenzyl Ketones 5a–h; General Procedure
Hg(OAc)2 (1.59 g, 5 mmol) was added to a slurry of the appropriate
2-aryl-2-(2-bromobenzyl)-1,3-dithiane 4 (2 mmol) in a mixture of
MeCN (4.4 mL) and H2O (1.1 mL), and the resulting slurry was
stirred at r.t. for 25 min. The reaction mixture was filtered through
Celite and the Celite was washed with EtOAc. The combined organ-
ic phase was dried (MgSO4). After evaporation of the solvent under
reduced pressure, the residue was purified by column chromatogra-
phy.
2-Bromobenzyl 2-Naphthyl Ketone (5f)
Obtained from 2-(2-bromobenzyl)-2-(2-naphthyl)-1,3-dithiane
(4f); white crystals; yield: 0.39 g (60%); mp 121–122 °C.
1H NMR (250 MHz, CDCl3): d = 8.58 (s, 1 H), 8.08 (dd, J = 8.6, 1.8
Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H), 7.91–7.84 (m, 2 H), 7.63–7.51
(m, 3 H), 7.32–7.23 (m, 2 H), 7.19–7.09 (m, 1 H), 4.57 (s, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 196.2, 135.6, 135.0, 133.8,
132.8, 132.4, 131.7, 130.0, 129.6, 128.7, 128.5, 128.5, 127.7, 127.5,
126.8, 125.1, 124.0, 45.8.
Phenyl 2-Bromobenzyl Ketone (5a)
Obtained from 2-(2-bromobenzyl)-2-phenyl-1,3-dithiane (4a);
white crystals; yield: 0.28 g (50%); mp 71–72 °C.
HRMS (EI): m/z calcd for C18H13BrO: 324.0150; found: 324.0139.
1H NMR (250 MHz, CDCl3): d = 7.97 (d, J = 7.4 Hz, 2 H), 7.50–
7.43 (m, 2 H), 7.35 (t, J = 7.7 Hz, 2 H), 7.16–7.12 (m, 2 H), 7.05–
6.98 (m, 1 H), 4.34 (s, 2 H).
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Synthesis of Benzo[b]furans by Ring Closure
89
2-Bromobenzyl 4-(Dimethylamino)phenyl Ketone (5g)
Obtained from 2-(2-bromobenzyl)-2-(4-dimethylaminophenyl)-
1,3-dithiane (4g); white crystals; yield: 0.26 g (40%); mp 113–
114 °C.
HRMS (EI): m/z calcd for C14H9ClO: 228.0342; found: 228.0336.
2-(4-Fluorophenyl)benzofuran (6d)18
Obtained from 2-bromobenzyl 4-fluorophenyl ketone (5d); white
crystals; yield: 0.242 g (76%).
1H NMR (250 MHz, CDCl3): d = 7.87–7.79 (m, 2 H), 7.59–7.49 (m,
2 H), 7.32–7.20 (m, 2 H), 7.18–7.09 (m, 2 H), 6.95 (s, 1 H).
1H NMR (250 MHz, CDCl3): d = 7.97–7.91 (m, 2 H), 7.56 (d, J =
7.8 Hz, 1 H), 7.25–7.23 (m, 2 H), 7.14–7.06 (m, 1 H), 6.67–6.61 (m,
2 H), 4.34 (s, 2 H), 3.03 (s, 6 H).
13C NMR (62.5 MHz, CDCl3): d = 194.3, 153.4, 135.9, 132.6,
13C NMR (62.5 MHz, CDCl3): d = 162.8 (d, J = 248.6 Hz), 155.0,
154.8, 129.1, 126.7, 126.7 (d, J = 8.3 Hz), 124.2, 123.0, 120.9,
115.9 (d, J = 22.0 Hz), 111.1, 101.0 (d, J = 1.8 Hz).
131.5, 130.5, 128.2, 127.3, 125.0, 124.5, 110.6, 44.9, 39.9.
HRMS (EI): m/z calcd for C16H16BrNO: 317.0415; found:
317.0407.
HRMS (EI): m/z calcd for C14H9FO: 212.0637; found: 212.0630.
2-Bromobenzyl p-Tolyl Ketone (5h)
Obtained from 2-(2-bromobenzyl)-2-(p-tolyl)-1,3-dithiane (4h);
white crystals; yield: 0.37 g (64%); mp 48–49 °C.
2-(3-Methoxyphenyl)benzofuran (6e)19
Obtained from 2-bromobenzyl 3-methoxyphenyl ketone (5e); white
crystals; yield: 0.121 g (36%).
1H NMR (250 MHz, CDCl3): d = 7.93 (d, J = 8.2 Hz, 2 H), 7.55 (d,
J = 8.2 Hz, 1 H), 7.28–7.19 (m, 4 H), 7.13–7.06 (m, 1 H), 4.39 (s, 2
H), 2.38 (s, 3 H).
1H NMR (250 MHz, CDCl3): d = 8.73 (d, J = 8.7 Hz, 1 H), 7.70–
7.59 (m, 2 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.31 (s, 1 H), 7.21–7.11 (m,
3 H), 7.00 (dt, J = 7.7, 1.6 Hz, 1 H), 3.69 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 195.7, 143.9, 135.0, 134.0,
13C NMR (62.5 MHz, CDCl3): d = 198.0, 159.7, 138.9, 135.3,
130.5, 129.5, 128.5, 128.0, 127.4, 127.3, 123.9, 122.98, 120.8,
113.0, 55.4.
132.5, 131.5, 129.2, 128.4, 128.3, 127.3, 124.9, 45.4, 21.5.
HRMS (EI): m/z calcd for C15H13BrO: 288.0150; found: 288.0148.
HRMS (EI): m/z calcd for C15H12O2: 224.0837; found: 224.0832.
2-Arylbenzofurans 6a–h; General Procedure
A flame-dried vial was charged with the appropriate aryl 2-bro-
mobenzyl ketone 5 (1.5 mmol), Pd2(dba)3 (69 mg, 0.075 mmol),
1,3-bis(diisopropylphenyl)imidazolinium tetrafluoroborate (IPr;
71.6 mg, 0.15 mmol), Cs2CO3 (980 mg, 3 mmol), and anhyd xylene
(5 mL). After the vial had been purged with argon, it was closed and
heated under argon in a 110 °C oil bath for 24 h. After cooling to r.t.
and evaporation of the volatiles, the residue was purified by column
chromatography [alumina (neutral, Brockmann II grade), hexane–
EtOAc, 10:0 to 10:2].
2-(2-Naphthyl)benzofuran (6f)20
Obtained from 2-bromobenzyl b-naphthyl ketone (5f); white crys-
tals; yield: 0.147 g (40%).
1H NMR (250 MHz, CDCl3): d = 8.30 (s, 1 H), 7.86–7.74 (m, 4 H),
7.55–7.37 (m, 4 H), 7.27–7.14 (m, 2 H), 7.06 (d, J = 0.6 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 155.9, 155.0, 133.4, 133.3,
129.3, 128.5, 128.4, 127.8, 127.7, 126.6, 126.5, 124.4, 123.8, 123.0,
122.8, 120.9, 111.2, 101.9.
HRMS (EI): m/z calcd for C18H12O: 244.0888; found: 244.0886.
2-Phenylbenzofuran (6a)17a
2-[4-(Dimethylamino)phenyl]benzofuran (6g)21
Obtained from 2-bromobenzyl 4-(dimethylamino)phenyl ketone
(5g); white crystals; yield: 0.071 g (20%).
1H NMR (250 MHz, CDCl3): d = 7.66 (dt, J = 9.0, 2.1 Hz, 2 H),
7.47–7.37 (m, 2 H), 7.17–7.10 (m, 2 H), 6.72 (d, J = 0.8 Hz, 1 H),
6.69 (dt, J = 9.0, 2.1 Hz, 2 H), 2.94 (s, 6 H).
Obtained from 2-bromobenzyl phenyl ketone (5a); white crystals;
yield: 0.274 g (94%).
1H NMR (250 MHz, CDCl3): d = 7.92 (d, J = 7.4 Hz, 2 H), 7.59 (d,
J = 7.6 Hz, 1 H), 7.52 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 2 H),
7.38 (t, J = 7.2 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.25 (t, J = 7.2
Hz, 1 H), 7.03 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 155.9, 154.9, 130.5, 129.2,
128.8, 128.5, 124.9, 124.2, 122.9, 120.9, 111.2, 101.3.
13C NMR (62.5 MHz, CDCl3): d = 157.0, 154.5, 150.6, 129.9,
126.1, 123.1, 122.6, 120.1, 118.6, 112.1, 110.8, 98.1, 40.3.
HRMS (EI): m/z calcd for C14H10O: 194.0732; found: 194.0728.
HRMS (EI): m/z calcd for C16H15NO: 237.1154; found: 237.1149.
2-Anisylbenzofuran (6b)10a
Obtained from anisyl 2-bromobenzyl ketone (5b); white crystals;
yield: 0.276 g (82%).
2-(p-Tolyl)benzofuran (6h)10a
Obtained from 2-bromobenzyl p-tolyl ketone (5h); white crystals;
yield: 0.119 g (38%).
1H NMR (250 MHz, CDCl3): d = 7.81 (dt, J = 9.0, 2.2 Hz, 2 H),
7.57–7.47 (m, 3 H), 7.22 (dt, J = 6.7, 2.2 Hz, 2 H), 7.00–6.97 (m, 2
H), 3.87 (s, 3 H).
1H NMR (250 MHz, CDCl3): d = 7.76 (dt, J = 8.5, 1.9 Hz, 2 H),
7.59–7.55 (m, 1 H), 7.54–7.49 (m, 1 H), 7.31–7.18 (m, 4 H), 6.97
(d, J = 1.0 Hz, 1 H), 2.40 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 156.0, 154.7, 128.0, 126.4,
123.7, 123.3, 122.8, 120.5, 116.0, 114.2, 111.0, 99.7, 55.4.
13C NMR (62.5 MHz, CDCl3): d = 156.2, 151.3, 138.6, 135.7,
129.5, 129.3, 124.9, 124.0, 122.8, 120.7, 111.1, 100.5, 21.4.
HRMS (EI): m/z calcd for C15H12O2: 224.0837; found: 224.0834.
HRMS (EI): m/z calcd for C15H12O: 208.0888; found: 208.0885.
2-(4-Chlorophenyl)benzofuran (6c)7
Obtained from 2-bromobenzyl 4-chlorophenyl ketone (5c); white Acknowledgment
crystals; yield: 0.247 g (72%).
1H NMR (250 MHz, CDCl3): d = 7.83–7.77 (m, 2 H), 7.61–7.50 (m,
2 H), 7.45–7.40 (m, 2 H), 7.34–7.23 (m, 2 H), 7.02 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 133.1, 132.4, 132.1, 130.9,
128.8, 127.6, 127.4, 126.8, 125.2, 124.7, 124.7, 120.5.
The financial support of the Hungarian Scientific Research Fund
(OTKA F047125/2004), the Gedeon Richter Chemical Works (a
fellowship to J.F.), and KPI (GVOP-3.2.1.-0358/2004) is gratefully
acknowledged.
Synthesis 2009, No. 1, 85–90 © Thieme Stuttgart · New York

90
J. Faragó, A. Kotschy
PAPER
(8) (a) Shen, Q.; Peng, Q.; Shao, J.-L.; Liu, X.-L.; Huang, Z.-H.;
Pu, X.-Z.; Ma, L.; Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Eur.
J. Med. Chem. 2005, 40, 1307. (b) Mashraqui, S. H.; Patil,
M. B.; Sangvikar, Y.; Ashraf, M.; Mistry, H. D.; Daub, E. T.
H.; Meetsma, A. J. Heterocycl. Chem. 2005, 42, 947.
(c) Santini, C.; Berger, G. D.; Han, W.; Mosley, R.;
MacNaul, K.; Berger, J.; Doebber, T.; Wu, M.; Moller, D.
E.; Tolman, R. L.; Sahoo, S. P. Bioorg. Med. Chem. Lett.
2003, 13, 1277. (d) Jorgensen, M.; Krebs, F. C.; Bechgaard,
K. J. Org. Chem. 2000, 65, 8783.
(9) (a) Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org.
Chem. 2007, 72, 10283. (b) Yuan, Y.; Men, H.-B.; Lee, C.
J. Am. Chem. Soc. 2004, 126, 14720. (c) Rele, S.; Talukdar,
S.; Banerji, A.; Chattopadhyay, S. J. Org. Chem. 2001, 66,
2990. (d) Fürstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995,
117, 4468. (e) Banerji, A.; Nayak, S. K. J. Chem. Soc.,
Chem. Commun. 1990, 150. (f) Jean, G.; Nicole, B.; Pierre,
D. J. Heterocycl. Chem. 1990, 27, 10.
References
(1) New address: J. Faragó, Gedeon Richter Chemical Works,
Gyömröi út 19–21, Budapest, Hungary.
(2) New address: A. Kotschy, Servier Research Institute of
Medicinal Chemistry, Záhony u. 7, 1031 Budapest,
Hungary.
(3) (a) Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, 259. (b) Comprehensive
Heterocyclic Chemistry, Vol. 4; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon: London, 1984, 531. (c) Cagniant, P.;
Cagniant, D. In Advances in Heterocyclic Chemistry, Vol.
18; Katritzky, A. R.; Boulton, A. J., Eds.; Academic Press:
New York, 1975, 337. (d) Schneiders, G. E.; Stevenson, R.
J. Org. Chem. 1979, 44, 4710.
(4) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Curr. Org.
Chem. 2006, 10, 1423. (b) Zeni, G.; Larock, R. C. Chem.
Rev. 2006, 106, 4644. (c) Hou, X.-L.; Yang, Z.; Yeung, K.-
S.; Wong, H. N. C. Prog. Heterocycl. Chem. 2005, 17, 142.
(d) Hou, X.-L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl.
Chem. 2003, 15, 167. (e) Dell, C. P. In Science of Synthesis,
Vol. 10; Thomas, E. J., Ed.; Thieme: Stuttgart, 2001, 11.
(5) (a) Aslam, S. N.; Stevenson, P. C.; Phytian, S. J.; Veitch, N.
C.; Hall, D. R. Tetrahedron 2006, 62, 4214. (b) Novák, Z.;
Timári, G.; Kotschy, A. Tetrahedron 2003, 59, 7509.
(c) Yao, T.-L.; Yue, D.-W.; Larock, R. C. J. Org. Chem.
2005, 70, 9985. (d) Csékei, M.; Novák, Z.; Timári, G.;
Kotschy, A. ARKIVOC 2004, (vii), 285. (e) Jinno, S.; Okita,
T.; Inouye, K. Bioorg. Med. Chem. Lett. 1999, 9, 1029.
(f) Sakai, A.; Aoyama, S.; Shioiri, T. Tetrahedron Lett.
1999, 40, 4211. (g) Beutler, U.; Mazacek, J.; Penn, G.;
Schenkel, B.; Wasmuth, D. Chimia 1996, 50, 154.
(6) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org.
Lett. 2006, 8, 2803. (b) Belting, V.; Krause, N. Org. Lett.
2006, 8, 4489. (c) Yue, D.-W.; Yao, T.-L.; Larock, R. C.
J. Org. Chem. 2005, 70, 10292.
(10) (a) Chen, C.-y.; Dormer, P. G. J. Org. Chem. 2005, 70,
6964. (b) Carril, M.; SanMartin, R.; Tellitu, I.; Dominguez,
E. Org. Lett. 2006, 8, 1467. (c) Ackermann, L.; Kaspar, L.
T. J. Org. Chem. 2007, 72, 6149.
(11) Vincze, Z.; Bíró, A. B.; Csékei, M.; Timári, G.; Kotschy, A.
Synthesis 2006, 1375.
(12) (a) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett.
2004, 6, 4755. (b) Willis, M. C.; Taylor, D.; Gillmore, A. T.
Tetrahedron 2006, 62, 11513.
(13) Khan, A. T.; Mondal, E.; Sahu, P. R.; Islam, S. Tetrahedron
Lett. 2003, 44, 919.
(14) (a) de la Fuente, M. C.; Castedo, L.; Dominguez, D. J. Org.
Chem. 1996, 61, 5818. (b) Garcia, A.; Castedo, L.;
Dominguez, D. Tetrahedron 1995, 51, 8585. (c) Lamas, C.;
Garcia, A.; Castedo, L.; Dominguez, D. Tetrahedron Lett.
1989, 30, 6927.
(15) Wei, W.-G.; Yao, Z.-J. J. Org. Chem. 2005, 70, 4585.
(16) Smith, P. M.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1998, 3541.
(7) (a) Pan, C.-F.; Yu, J.; Zhou, Y.-Q.; Wang, Z.-Y.; Zhou, M.-
M. Synlett 2006, 1657. (b) Fujita, M.; Qi, G.-Z.; Verkerk, U.
H.; Dzwiniel, T. L.; McDonald, R.; Stryker, J. M. Org. Lett.
2004, 6, 2653. (c) Merlini, L.; Cardillo, G.; Cricchio, R.
Tetrahedron 1971, 27, 1875. (d) Lattanzi, A.; Senatore, A.;
Massa, A.; Scettri, A. J. Org. Chem. 2003, 68, 3691.
(17) Baumgartner, M. T.; Jimenez, L. B.; Pierini, A. B.; Rossi, R.
A. J. Chem. Soc., Perkin Trans. 2 2002, 1092.
(18) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.;
Tranmer, G. K. Chem. Eur. J. 2006, 12, 4407.
(19) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761.
(20) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.;
Marinelli, F. J. Org. Chem. 1996, 61, 9280.
(21) Raspanti, G. US 5362481, 1994; Chem. Abstr. 1994, 122,
187375.
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