Palladium-catalysed intramolecular enolate O-arylation and thio-enolate S-arylation: synthesis of benzo[b]furans and benzo[b]thiophenes

Article abstract of DOI:10.1016/j.tet.2006.05.004

Enolates derived from α-(ortho-haloaryl)-substituted ketones undergo palladium-catalysed C-O bond formation to deliver benzofuran products in good yield. A catalyst generated from Pd₂(dba)₃ and the ligand DPEphos effects the key bond

Full text of DOI:10.1016/j.tet.2006.05.004

Tetrahedron 62 (2006) 11513–11520
Palladium-catalysed intramolecular enolate O-arylation and
thio-enolate S-arylation: synthesis of benzo[b]furans
and benzo[b]thiophenes
a
b
Michael C. Willis,a, Dawn Taylor and Adam T. Gillmore
*
aDepartment of Chemistry, University of Bath, Bath BA2 7AY, UK
bChemical Research and Development Department, Pfizer Global Research and Development,
Sandwich, Kent CT13 9NJ, UK
Received 3 March 2006; revised 2 May 2006; accepted 4 May 2006
Available online 2 June 2006
Abstract—Enolates derived from a-(ortho-haloaryl)-substituted ketones undergo palladium-catalysed C–O bond formation to deliver benzo-
furan products in good yield. A catalyst generated from Pd2(dba)3 and the ligand DPEphos effects the key bond formation to deliver a variety
of substituted products from both cyclic and acyclic precursors. The analogous thio-ketones undergo C–S bond formation using identical
reaction conditions and are converted to benzothiophene products. A cascade sequence that produces the required a-aryl ketones in situ
has also been developed, although the substrate scope is more restricted.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
would be embedded in an enolate or thio-enolate, generated
from the corresponding ketone or thio-ketone, respectively.
Such a synthesis would open the use of a-(ortho-haloaryl)-
substituted ketones and thio-ketones as new benzofuran
and benzothiophene precursors.7
Benzofurans and benzothiophenes are two of the most
common and consequently most studied classes of aromatic
heterocycle.1 The occurrence of these heterocycles in a sig-
nificant number of medicinal agents, active in a variety of
disease areas, has led to an enduring interest in the develop-
ment of new methods for their synthesis.2 Methods that
utilise new classes of precursor are particularly valuable.
Amongst the many syntheses available, transition metal
catalysed processes3 and palladium-mediated methods in
particular4 feature heavily. Syntheses based on palladium-
catalysed cyclisations of appropriately substituted alkenyl
or alkynyl phenols, or thiophenols, are particularly versatile
and have been used on many occasions.5 Related tandem
processes involving catalysed C–C bond formation, usually
employing Sonogashira type reactions, before construction
of the key C–O or C–S bond have also been developed.6
The crucial bond-forming event in these processes is intra-
molecular attack of a nucleophilic oxygen or sulfur atom
onto a palladium-activated C–C multiple bond, resulting in
formation of the X–C2 bond of the heterocycle. We wished
to develop an alternative synthesis involving formation of
the X–C7a bond and employing the intramolecular attack
of a nucleophilic oxygen or sulfur atom onto a palladium-
activated aryl ring; crucially, the nucleophilic heteroatom
2. Results and discussion
A retrosynthetic scheme representing our proposed route to
benzofurans is shown in Scheme 1. The key palladium-cata-
lysed C–O bond formation is represented by the disconnec-
tion of O–C7a bond of the benzofuran to generate enolate 1.
In turn, the enolate would be generated from a-aryl ketone
2. The use of the thio-ketone corresponding to ketone 2
would allow access to the corresponding thio-enolate and
ultimately to the benzothiophene. Therefore, a-aryl ketones 2
R2
R2
3
R1
Pd(0)
R3
R3
R1
O-
2
O
7a
X
7
1
1
base
R2
Y
R3
R1
Pd(0)
X
R1
R3
4
3
O
X
R2
2
Keywords: Benzofuran; Benzothiophene; Palladium catalysis; Enolate.
* Corresponding author. Tel.: +44 1225 386568; fax: +44 1225 386231;
e-mail: m.c.willis@bath.ac.uk
O
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.004

11514
M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
Table 1. Catalyst optimisationa
become common intermediates for the synthesis of both clas-
ses of heterocycle. Although there are a number of methods
for the synthesis of a-arylated ketones,8 we wished to employ
a second palladium-catalysed transformation involving the
a-arylation of a simple ketone 3 with a 1,2-dihaloarene 4.
Br
Pd2(dba)3, ligand
base
O
O
toluene, temp.
6
8
Over recent years palladium-catalysed intermolecular
C-arylation of enolates9 and similar C-nucleophiles has
been developed as a useful synthetic tool.10 Although the
use of 1,2-dihaloarenes to access the required a-(ortho-halo-
aryl)ketones had not been documented, precedent existed
for the use of o-substituted aryl halides. The preparation of
a-(o-bromophenyl)cyclohexanone 6 is used as an illustrative
example for substrate preparation (Scheme 2). Application
of literature conditions,10a,b involving combining the sub-
strates with Cs2CO3, Pd2(dba)3 and the ligand Xantphos
(5),11 to the coupling of cyclohexanone and 1,2-dibromo-
benzene, resulted in no reaction. However, the use of
1-bromo-2-iodobenzene under identical reaction conditions
delivered the a-arylated ketone 6 in 78% yield. Variations of
this protocol were used to prepare all of the a-arylated
ketones employed in this study.12
Entry
Ligand
Base
T (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
Xantphos
Xantphos
DPEphos
DPEphos
DPEphos
Cs2CO3
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
110
110
110
80
20
20
20
24
30
<5
0
95
52
0
50
a
Conditions: Pd2(dba)3 (2.5 mol %), ligand (6 mol %), base (2.2 equiv).
Isolated yields.
b
explored the scope of the process (Table 2). All of the exam-
ples shown below employ the standard catalyst: Pd2(dba)3
(2.5 mol %), DPEphos (6 mol %). Entries 1–3 provide
a comparison between the use of bromo- and chloro-substitu-
ents on the aryl ring. With the bromo-substrate, the use of the
base Cs2CO3 was sufficient to achieve an excellent yield of
the benzofuran. Application of these conditions to the
chloro-substrate resulted in only a low conversion to prod-
uct, however, the use of the alternative base NaHMDS
delivered the benzofuran in 94% yield. The ability to employ
Cl-substituted arenes significantly adds to the appeal of the
process given the greater numbers of aryl chlorides that
are commercially available.15 Variation of the base used in
the following cyclisations was important in achieving opti-
mal yields. Although the cycloheptanone-derived substrate
delivered the corresponding benzofuran as expected (entry
4), the cyclopentanone system was unreactive (entry 5).
The use of a variety of base and temperature combinations
also failed to deliver the benzofuran. We were concerned
that competing aldol processes may have been occurring
with the stronger bases, however, the use of the gem-
dimethyl-substituted variant shown in entry 6 was also
unsuccessful. It appears that ring-closure to form a cyclopen-
tane-fused benzofuran is not possible using the current meth-
odology.16 Entries 7–11 demonstrate that benzo- and ketal
substituents are possible on the ketone fragment and that
acyclic as well as cyclic substrates can also be employed.
The remaining examples show that variation of the arene
fragment is also tolerated with F-substituents and a pyridyl
ring all delivering the target benzofurans. While ring-closure
to the corresponding benzofurans was possible without the
use of a palladium catalyst for the pyridyl example, there
was a significant reduction in reaction time if a catalyst
was employed. Although the same catalyst was employed
for all of the examples in Table 2, it can also be seen that
some variation in the choice of base is needed.
Br
X
Br
O
O
Pd2(dba)3 (0.5 mol.%)
Xantphos (1.2 mol.%)
Cs2CO3, PhMe, 80 °C
X = Br, 0%; X = I, 78 %
6
PPh2
PPh2
PPh2
PPh2
O
O
Me Me
Xantphos, 5
DPEphos, 7
Scheme 2.
With a route to the required 2-(haloaryl)-ketones estab-
lished, we turned our attention to the key benzofuran-
forming transformation. Palladium-catalysed aryl C–X bond
formations, and C–N constructions in particular, are now re-
liable and well established methods, with growing numbers
of applications appearing in the literature.13 Intramolecular
versions of these reactions, leading to the formation of a
variety of heterocycles, are also well known.13 Although a
diverse range of nucleophiles have been employed in these
reactions, the use of O- and S-enolates as hetero-nucleo-
philes is rare.14 Substituted cyclohexanone 6 was selected
for initial study (Table 1). Although we had detected trace
amounts of benzofuran 8 during the preparation of arylated
ketone 6, when we resubjected ketone 6 to a Xantphos de-
rived catalyst in combination with Cs2CO3 we could only
isolate small amounts of the benzofuran product (entry 1).
The use of the same catalyst system with a stronger base
was similarly unsuccessful (entry 2). However, the use of
the structurally similar ligand DPEphos11 7 with Cs2CO3
as base at 100 ꢀC provided benzofuran 8 in 95% yield (entry
3). Lowering the reaction temperature simply resulted in
poorer conversions (entries 4 and 5).
Having demonstrated that O-enolates can perform as compe-
tent hetero-nucleophiles with a variety of intramolecular
coupling partners we were interested as to whether the pro-
cess could be extended to S-enolates. Although examples
of palladium-catalysed C–S bond formation are known,17,18
they are much less common than the corresponding C–N
and C–O examples. To test the ability of S-enolates to parti-
cipate in the desired cyclisation reactions we first needed to
convert the a-(ortho-haloaryl)-ketone substrates into the
corresponding thio-ketones. This was achieved in a straight-
forward manner using P2S5.19 Pleasingly, treatment of the
With conditions to effect the key intramolecular O-enolate
aryl-coupling was established using a test system, we next

M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
11515
Table 2. (continued)
Table 2. Scope of benzofuran formationa
Entry
Substrate
Base
Product
Yield (%)b
86c
X
Pd2(dba)3, DPEphos
O
O
N
R3
O
O
base
R1
N
R3
14
NaOtBu
R1
toluene, 100 °C
R2
Cl
R2
a
Conditions: Pd2(dba)3 (2.5 mol %), DPEphos (6 mol %), base (2.2 equiv).
Isolated yields.
In the absence of catalyst a 40% conversion is achieved after 20 h.
Entry
Substrate
Base
Product
Yield (%)b
b
c
O
O
1
Cs2CO3
95
cyclohexanone-derived thio-ketone with the standard benzo-
furan-forming reaction conditions delivered benzothiophene
in 74% yield (Table 3, entry 1). The aryl chloride variant also
underwent cyclisation, although similar to the corresponding
ketone example when using Cs2CO3, in a reduced yield
(entry 2). In contrast to the equivalent ketone, reaction of
the cyclopentanethione derived substrate delivered the ex-
pected benzothiophene (entry 3). This difference in reactivity
between ketone and thio-ketone may be due to the increased
nucleophilicity of the S-atom or the longer C–S bond. In line
with the ketone examples, entries 4 and 5 demonstrate that
further variation in both the ketone and aryl fragments are
possible. One class of substrate not amenable to the catalysed
Br
O
O
O
2
3
54
94
Cs2CO3
NaHMDS
Cl
O
4
NaHMDS
Cs2CO3
Cs2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
95
0
Br
O
O
5
Br
Table 3. Benzothiophene formationa
O
O
O
Me
Me
X
Pd2(dba)3, DPEphos
S
Me
Me
6
0
R3
S
Cs2CO3
R1
R3
R1
Cl
Br
toluene, 100 °C
R2
R2
Yield (%)b
O
O
Entry
Thio-ketone
Yield (%)
S-ketone
Product
7
81
73
50
80
68
81
S
S
O
1
2
3
4
5
71
40
38
40
74
8
Br
Br
O
O
O
O
O
S
S
44
52
57
57
O
9
Cl
Ph
Ph
Br
S
S
O
O
Ph
Ar
10
11
12
13
Br
Ph
Ar
Me
O
Br Me
S
S
O
Br
Br Me
Ar = 4-F-C6H4
Me
F
S
S
F
53
F
O
O
F
NaOtBu
Br
Br
S
N
S
F
N
F
6c
0
67
O
O
NaOtBu
74
Cl
Br
a
Conditions: Pd2(dba)3 (2.5 mol %), DPEphos (6 mol %), Cs2CO3
(2.2 equiv), toluene, 100 ꢀC.
Isolated yields.
(continued)
b
c
Attempted formation of thio-ketone lead directly to cyclised product.

11516
M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
Table 4. Development of a single-ligand cascade reactiona
S-enolate reaction are the pyridyl-substituted variants; at-
tempted conversion of the ketone to the thio-ketone lead
directly to the benzothiophene product (entry 6).
I
O
Br
O
O
Pd2(dba)3 (2.5 mol.%)
The benzofuran and benzothiophene syntheses as presented
consist of two independent palladium-catalysed reactions
leading to the efficient preparation of the individual hetero-
cycles. The similarity of the reaction conditions, particularly
the ligand choice, for the two independent reactions sug-
gested that a one-pot cascade process might be achievable.
Unfortunately, even though there is significant structural ho-
mology between the two optimal ligands for each separate
reaction (Xantphos for the C-arylation, DPEphos for benzo-
furan/benzothiophene formation), neither ligand would
effect the alternate reaction. One solution to this was to com-
bine both ligands in a single reaction:20 Scheme 3 illustrates
the process for the direct preparation of the cyclohexane-
fused benzofuran from cyclohexanone and 1-bromo-2-iodo-
benzene.
ligand (6 mol.%)
Cs2CO3, toluene
Br
6
8
Entry
Ligand
Aryl ketone
conv. (%)b
Benzofuran
conv. (%)b
1
2
3
4
5
6
7
8
Xantphos
DPEphos
BINAP
9
10
11
12
13
13
14
15
16
16
78c
0
0
0
9
0
0
9
25
0
0
9
0
<5
0
0
0
0
0
0
7
25
9
9d
10
11
12
13d
14e
0
20
91
100
Pd2(dba)3 (5 mol.%)
16
0
DPEphos (6 mol.%)
Xantphos (6 mol.%)
O
O
I
a
Conditions: 1-bromo-2-iodobenzene (1.0 equiv), cyclohexanone
(1.2 equiv), toluene, 80 ꢀC, 24 h.
Cs2CO3
toluene, 100 °C, 48 h
Br
Determined by 1H NMR.
Isolated yield.
b
c
d
e
51%
Pd2(dba)3 (5 mol %), ligand (6 mol %), 100 ꢀC.
Pd2(dba)3 (5 mol %), ligand (12 mol %), 100 ꢀC.
Scheme 3.
Although a 51% yield of benzofuran could be obtained from
the mixed-ligand reaction we sought a single ligand system
capable of achieving the desired cascade sequence. The
number of ligands reported to facilitate palladium-catalysed
coupling processes is ever increasing and this combined with
the number of additional variables (base, Pd source, solvent,
temperature) makes a complete evaluation of reaction condi-
tions a prohibitively complex exercise. As a compromise we
elected to simply vary the ligand choice while keeping all
other variables constant. The coupling of cyclohexanone
and 1-bromo-2-iodobenzene was again selected as an appro-
priate test system. Table 4 documents these studies: as al-
ready stated, the ligands Xantphos and DPEphos were not
effective for the desired cascade transformation, neither
was (rac)-BINAP (entries 1–3). The biphenyl-based phos-
phine ligands developed by Buchwald have been shown to
be effective for a number of palladium-mediated transforma-
tions, however, the use of ligands 9 or 10 were similarly
ineffective (entries 4 and 5).21 Recently, ferrocene-based
ligands have appeared in the literature with more frequency
and have shown success in a number of palladium-catalysed
C–O bond-forming reactions.22 Unfortunately, application
of the bis-chelating isopropyl 11 and phenylphosphino vari-
ants 12 gave none of the desired products (entries 6 and 7).
However, the tert-butyl analogue 13 promoted both steps in
the sequence producing 9% of the arylated ketone and 7% of
the benzofuran (entry 8). The respective conversions both
increased to 25% when the catalyst loading was increased
to 5 mol % Pd and 6 mol % ligand (entry 9). Although
the bulky tri-isopropyl-substituted dicyclohexylphosphine
ligand 1423 gave poor conversion to the benzofuran product
it gave complete cyclisation of the arylated ketone (entry
10). The tert-butyl analogue 15 showed decreased activity
(entry 11). Use of the dimethoxy-substituted dicyclohexyl-
phosphine ligand 1624 provided the arylated ketone in 9%
with 20% conversion to the benzofuran product (entry 12).
PR2
PR2
PR2
iPr
PCy2
OMe
X
iPr
MeO
Fe
PR2
iPr
9, R = tBu, X = H
14, R = tBu
15, R = Cy
11, R = Ph
16
10, R = Cy, X = NMe2 12, R = iPr
13, R = tBu
Increasing the palladium loading to 5 mol % significantly in-
creased the conversion to benzofuran (entry 13), and finally,
simultaneously increasing the ligand loading to 12 mol %
resulted in complete conversion to benzofuran (entry 14).
A preparative scale reaction using these optimised conditions
delivered benzofuran 8 in 91% yield (Scheme 4). Unfortu-
nately, these conditions were not transferable to alternative
substrates, with only low yields of mixtures of arylated
ketone and benzofuran being obtained in almost all cases.
For example, reactions involving the coupling of 2-bromo-
iodobenzene with either cycloheptanone or a-tetralone were
unsuccessful. It appears that it would be necessary to develop
an optimised catalyst system for individual substrates. The ef-
fort needed to optimise for individual substrates in cascade
processes suggests that the use of multi-ligand systems may
offer advantages, in that it is often more convenient to
optimise for a single one-step transformation using a single li-
gand and then apply this information to the cascade sequence.
Pd2(dba)3 (5 mol.%)
ligand 16 (12 mol.%)
O
O
I
Cs2CO3, toluene
Br
8, 91%
100 °C, 24 h
Scheme 4.

M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
11517
3. Conclusion
diethyl ether/petrol) to yield the ketone (90 mg, 50%) as a
creamy/white solid: mp 63–64 ꢀC. nmax (KBr)/cmꢁ1 2961,
2867, 1736, 1478, 1460, 1437, 1381, 1360, 1329, 1258,
1190, 1128, 1089, 1062, 1031, 767, 753; dH (300 MHz,
CDCl3) 1.15 (3H, s, C(CH3)2), 1.20 (3H, s, C(CH3)2),
1.81–2.07 (3H, m, CH2 and ArCHCH2), 2.42–2.53 (1H, m,
ArCHCH2), 3.85–3.97 (1H, m, Ar–CH), 7.03 (1H, dd,
J 7.5 and 2.1, Ar–H), 7.18 (1H, td, J 7.5 and 1.9, Ar–H),
7.23 (1H, td, J 7.5 and 1.9, Ar–H), 7.38 (1H, dd, J 7.5 and
2.1, Ar–H); dC (75 MHz, CDCl3) 24.2, 25.5, 28.1, 37.0,
45.8, 53.1, 127.5, 128.6, 129.6, 130.0, 135.0, 137.9, 221.5;
m/z LRMS (CI+, NH3) 242 [M:37Cl]+, 240 [M:35Cl]+, 206
We have demonstrated that a simple catalyst comprising
Pd2(dba)3 and the ligand DPEphos effects the cyclisation
of a-(ortho-haloaryl)-substituted ketones and thio-ketones
to benzofurans and benzothiophenes, respectively. The pro-
cess tolerates variations in both the ketone and aryl frag-
ments to deliver the heterocyclic products in good yields.
The key cyclisation reaction involves the coupling of enolate
and thio-enolate heteroatoms to palladium-activated aryl ha-
lides. Although it is possible to construct a cascade reaction
sequence, involving the in situ preparation of the arylated
ketones, the process is less general and requires optimsation
for individual substrates. Applications of similar enolate-
heteroatom cyclisations to the synthesis of alternative het-
erocycles are underway.
35
37
[Mꢁ Cl]+, 204 [Mꢁ Cl]+; HRMS (ES+) calcd for
C13H19ClNO: 240.1150 [M+NH4]+, found: 240.1153
[M+NH4]+. C13H15ClO requires C 70.11, H 6.79%, found C
69.80, H 6.78%.
4.1.1.2. Preparation of 2-(2-bromophenyl)-1-phenyl-
ethanone (Table 2, entry 9 substrate).25 General proce-
dure A was followed employing 1-bromo-2-iodobenzene
(2.000 g, 7.070 mmol, 0.91 mL) and acetophenone
(1.020 g, 8.480 mmol, 0.99 mL) using HPtBu3BF4 (90 mg,
0.320 mmol) as the ligand and sodium tert-butoxide
(1.600 g, 16.560 mmol) as the base, heating at 60 ꢀC for
9 h. The product was purified via flash column chromato-
graphy (5% diethyl ether/petrol) to yield the ketone
(1.19 g, 51%) as a white crystalline solid: mp 66–67 ꢀC.
nmax (NujolÔ)/cmꢁ1 3057, 1691, 1585, 1581, 1567, 1470,
1447, 1427, 1407, 1331, 1277, 1219, 1202, 1174, 1156,
1025, 990, 756, 690, 666, 650, 575; dH (300 MHz, CDCl3)
4.46 (2H, s, Ar–CH2CO), 7.15 (1H, ddd, J 7.9, 6.8 and 2.3,
Ar–H), 7.22–7.32 (2H, m, Ar–H), 7.47 (2H, tt, J 8.1 and
1.5, Ar–H), 7.55–7.62 (2H, m, Ar–H), 8.05 (2H, d, J 7.2,
Ar–H); dC (75 MHz, CDCl3) 45.8, 125.1, 127.5, 128.3,
128.7, 131.7, 132.8, 133.3, 133.8, 134.9, 136.6, 196.3;
m/z LRMS (CI+, NH3) 294 [M+NH4:81Br]+, 292
[M+NH4:79Br]+, 277 [M+NH3:81Br]+, 275 [M+NH3:79Br]+;
HRMS (ES+) calcd for C14H15BrNO: 292.0332
[M+NH4:79Br]+, found: 292.0331 [M+NH4:79Br]+;
C14H11OBr requires C 61.11, H 4.03%, found C 61.10, H
4.01%.
4. Experimental
4.1. General
The preparation of several of the a-arylated ketones and
the corresponding benzofuran products has been previously
described.7,12
4.1.1. General procedure (A) for the preparation of
a-arylated ketones. Exemplified by the preparation of
2-(2-bromophenyl)-cyclohexanone 6. Caesium carbonate
(4.570 g, 14.00 mmol) was added to a flask charged with
Pd2(dba)3 (0.030 g, 0.033 mmol) and Xantphos (0.040 g,
0.080 mmol) under nitrogen. The reagents were suspended
in anhydrous dioxane (6.4 mL) and 1-bromo-2-iodobenzene
(1.80 g, 6.370 mmol, 0.82 mL) and cyclohexanone (1.25 g,
12.74 mmol, 1.3 mL) were added under nitrogen and the
reaction was heated to 80 ꢀC for 24 h. After cooling, the
reaction mixture was diluted with diethyl ether (ca. 10 mL),
filtered through Celite and reduced in vacuo. The residue
was purified via flash column chromatography (5–10%
diethyl ether/petrol) to yield ketone 6 (1.26 g, 78%) as
a white solid: mp 57–58 ꢀC (MeOH) (lit. 58–59 ꢀC).1 nmax
(NujolÔ)/cmꢁ1 2920, 2855, 1709, 1566 (w), 1462, 1377,
1281, 1196, 1121, 1070, 1027, 977, 940, 769, 746, 722,
674; dH (300 MHz, CDCl3) 1.71–2.10 (4H, m, CH2), 2.15–
2.35 (2H, m, ArCHCH2), 2.51–2.89 (2H, m, CH2CO), 4.11
(1H, app. dd, J 12.4 and 5.3, Ar–CH), 7.12 (1H, ddd, J
7.9, 7.2 and 1.9, Ar–H), 7.21 (1H, dd, J 7.9 and 1.9,
Ar–H), 7.31 (1H, td, J 7.9 and 1.1, Ar–H), 7.56 (1H, td,
J 7.9 and 1.5, Ar–H); dC (75 MHz, CDCl3) 25.1, 27.1,
33.6, 41.8, 56.0, 124.6, 126.8, 127.8, 128.9, 132.1, 137.8,
208.3; m/z LRMS (CI+, NH3) 270 [M+NH4]+, 253
4.1.2. General procedure (B) for the preparationof benzo-
furans from a-arylated ketones. Exemplified by the
preparation of 1,2,3,4-tetrahydro-dibenzofuran (Table
2, entry 1). Caesium carbonate (180 mg, 0.560 mmol)
was added to a flask charged with Pd2(dba)3 (9 mg,
0.009 mmol) and DPEphos (13 mg, 0.022 mmol) under
nitrogen. The reagents were suspended in anhydrous toluene
(1 mL) prior to the addition of ketone 6 (100 mg,
0.40 mmol) and the reaction heated to 100 ꢀC for 20 h. After
cooling the reaction mixture was filtered through a plug of
Celite and the filtrate reduced in vacuo. The residue was
purified via flash column chromatography (petrol) to yield
the benzofuran (64 mg, 95%) as a colourless oil. Data con-
sistent with that reported in the literature.26
79
79
[M+H:79Br]+, 173 [Mꢁ Br]+, 145 [Mꢁ BrꢁCO]+, 115
[Mꢁ BrꢁCOꢁC2H4]+; HRMS (ES+) calcd for
79
C12H14BrO: 253.0223 [M+H]+, found: 253.0225 [M+H]+.
4.1.1.1. Preparation of 5-(2-chlorophenyl)-2,2-di-
methylcyclopentanone (Table 2, entry 6 substrate). General
procedure A was followed employing 1-bromo-2-chloro-
benzene (159 mg, 0.830 mmol, 0.10 mL), 2,2-dimethyl-
cyclopentanone (112 mg, 0.997 mmol, 0.13 mL) and
2-dicyclohexylphosphino-20-methylbiphenyl (18 mg, 0.049
mmol) as the ligand, heating at 110 ꢀC for 17 h. The product
was purified via flash column chromatography (5–10%
4.1.3. General procedure (C) for the preparation of thio-
ketones. Exemplified by the preparation of 2-(2-bromo-
phenyl)-cyclohexanethione (Table 3, entry 1 substrate).
2-(2-Bromophenyl)-cyclohexanone (500 mg, 1.981 mmol)
was added to a flask charged with phosphorus pentasulfide
(220 mg, 0.489 mmol) under nitrogen and the reaction

11518
M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
mixture suspended in anhydrous toluene (2.50 mL). The
mixture was stirred at room temperature for 10 min prior to
the addition of hexamethyldisiloxane (550 mg, 3.360 mmol,
0.71 mL) and heated to 90 ꢀC for 21 h. After cooling, the re-
action mixture was filtered through a plug of silica and the
filtrate reduced in vacuo to yield the thio-ketone (375 mg,
71%) as a colourless oil. The product was used without fur-
ther purification. nmax (NaCl)/cmꢁ1 3050, 2924, 2855, 1642,
1587, 1559, 1466, 1435, 1334, 1258, 1243, 1136, 1115,
1078, 1050, 1027, 1014, 821, 799, 751, 724, 688; dH
(300 MHz, CDCl3) 1.63–1.80 (4H, m, CH2), 1.95–2.12
(1H, m, ArCHCH2), 2.24–2.38 (3H, m, ArCHCH2 and
CH2CS), 2.39 (1H, br s, Ar–CH), 7.03–7.10 (2H, m,
Ar–H), 7.24 (1H, td, J 7.9 and 1.4, Ar–H), 7.53 (1H, dd,
J 7.9 and 1.4, Ar–H); dC (75 MHz, CDCl3) 23.2, 24.0,
32.0, 34.1, 123.4, 125.9, 128.2, 129.0, 130.6, 133.4,
133.7, 143.8; m/z LRMS (EI+) 271 [M:81Br]+ (53%), 270
[MꢁH:81Br]+ (52%), 269 [M:79Br]+ (100%), 268
[MꢁH:79Br]+ (48%), 189 [MꢁBr]+ (40%); (CI+, NH3) 288
[M+NH3:81Br]+, 286 [M+NH3:79Br]+, 272 [M+H:81Br]+,
271 [M:81Br]+, 270 [M+H:79Br]+, 269 [M:79Br]+; HRMS
(EI) calcd for C12H13BrS: 267.9916 [M]+, found: 267.9917
[M]+.
was followed employing relevant ketone (430 mg, 1.619
mmol) to yield the thio-ketone (181 mg, 40%) as a colourless
oil. nmax (NaCl)/cmꢁ1 3049, 2923, 2848, 2569, 1630, 1587,
1558, 1466, 1446, 1432, 1356, 1343, 1269, 1148, 1026,
979, 750, 726, 685; dH (300 MHz, CDCl3) 1.61–1.90 (5H, m,
CH2), 2.27–2.69 (5H, m, ArCHCH2, CH2CS and CH2),
2.70 (1H, br s, Ar–CH), 7.08–7.17 (2H, m, Ar–H), 7.30
(1H, app. td, J 7.2 and 1.5, Ar–H), 7.61 (1H, app. dd,
J 7.9 and 1.5, Ar–H); dC (75 MHz, CDCl3) 26.6, 26.8, 32.1,
35.9, 38.5, 122.9, 128.3, 128.7, 130.4, 131.0, 133.5,
137.3, 146.3; m/z LRMS (EI+) 284 [M:81Br]+ (12%),
81
282 [M:79Br]+ (12%), 203 [MꢁBr]+ (52%), 202 [Mꢁ Br]+
(54%), 201, 173, 160, 147; (CI+, NH3) 300 [M+NH3]+,
286 [M+H2:81Br]+, 285 [M+H:81Br]+, 284 [M:81Br]+, 283
79
81
[M+H:79Br]+, 204 [Mꢁ Br]+, 203 [M+Hꢁ Br]+, 202
[Mꢁ Br]+, 201 [MꢁHꢁ Br]+; HRMS (EI) calcd
for C13H15BrS: 282.0072 [M:79Br]+, found: 282.0072
[M:79Br]+.
81
81
4.1.3.4. Preparation of 2-(4-fluoro-2-bromophenyl)-
cyclohexanethione, (Table 3, entry 5 substrate). General
procedure C was followed employing relevant ketone
(200 mg, 0.738 mmol) to yield the thio-ketone (113 mg,
53%) as a colourless oil. nmax (NaCl)/cmꢁ1 2962, 2932,
2858, 2833, 1715, 1644, 1596, 1577, 1483, 1446, 1384,
1336, 1260, 1198, 1016, 872, 815, 666; dH (300 MHz,
CDCl3) 1.70–1.88 (4H, m, CH2), 2.00–2.14 (1H, m,
ArCHCH2), 2.41–2.27 (3H, m, ArCHCH2 and CH2CS),
2.43 (1H, s, Ar–CH), 7.03 (1H, td, J 8.4 and 2.5, Ar–H),
7.11 (1H, dd, J 8.4 and 6.2, Ar–H), 7.35 (1H, dd, J 8.4 and
2.5, Ar–H); dC (75 MHz, CDCl3) 23.2, 24.0, 32.1, 34.2,
115.4 (d, JCF 24.2), 126.9, 120.5 (d, JCF 21.1), 131.5 (d,
JCF 8.1), 132.8, 139.8 (d, JCF 3.7), 160.1, 163.5; m/z
LRMS (EI+) 288 [M:81Br] (87%), 286 [M:79Br] (100%);
4.1.3.1. Preparationof2-(2-chlorophenyl)-cyclohexane-
thione, (Table 3, entry 2 substrate). General procedure C
was followed employing the relevant ketone (180 mg,
1.318 mmol) to yield the thio-ketone (119 mg, 40%) as a col-
ourless oil. nmax (NaCl)/cmꢁ1 3645, 3055, 2925, 2857, 2833,
2661, 2571, 2318, 1799, 1722, 1643, 1590, 1564, 1470,
1428, 1335, 1260, 1174, 1121, 1078, 1059, 1034, 1016,
941, 862, 801, 753, 728, 709, 650; dH (300 MHz, CDCl3)
1.69–1.86 (4H, m, CH2), 2.02–2.19 (2H, m, ArCHCH2),
2.31–2.44 (2H, m, CH2CS), 2.46 (1H, br s, Ar–CH), 7.15
(1H, dd, J 7.2 and 2.3, Ar–H), 7.24 (1H, app. qd, J 7.2 and
2.3, Ar–H), 7.41 (1H, dd, J 7.2 and 2.3, Ar–H); dC
(75 MHz, CDCl3) 23.2, 24.1, 31.9, 34.2, 126.0, 127.5,
128.9, 130.2, 130.6, 132.2, 133.2, 141.8; m/z LRMS (EI+)
79
79
(CI+, NH3) 208 [Mꢁ Br]+, 207 [M+Hꢁ Br]+, 206
[Mꢁ Br]+, 205 [MꢁHꢁ Br]+; HRMS (EI) calcd for
C12H12BrFS: 285.9822 [M:79Br]+, found: 285.9826
[M:79Br]+.
81
81
35
224 [M:35Cl]+ (34%), 189 [Mꢁ Cl]+ (100%), 188
35
37
[MꢁHꢁ Cl]+ (62%), 187 [Mꢁ Cl] (33%); HRMS (ES+)
calcd for C12H14ClS: 225.0499 [M+H]+, found: 225.0498
[M+H]+.
4.1.4. General procedure (D) for the preparation of
benzothiophenes. Exemplified by the preparation of
1,2,3,4-tetrahydro-dibenzothiophene (Table 3, entry 1).
Caesium carbonate (180 mg, 0.557 mmol) was added to
a flask charged with Pd2(dba)3 (9 mg, 0.009 mmol) and
DPEphos (13 mg, 0.022 mmol) under nitrogen. The reagents
were suspended in anhydrous toluene (0.5 mL) prior to the
addition of 2-(2-bromophenyl)-cyclohexanethione (100 mg,
0.372 mmol) and the reaction heated to 100 ꢀC for 20 h.
After cooling, the reaction mixture was filtered through
a plug of Celite and the filtrate reduced in vacuo. The residue
was purified via flash column chromatography (petrol) to
yield the benzothiophene (52 mg, 74%) as a colourless oil.
4.1.3.2. Preparation of 2-(2-bromophenyl)-cyclopen-
tanethione, (Table 3, entry 3 substrate). General proce-
dure C was followed employing relevant ketone (200 mg,
0.837 mmol) to yield the thio-ketone (80 mg, 38%) as a col-
ourless oil. nmax (NaCl)/cmꢁ1 3062, 2923, 2848, 1742 (vs),
1634, 1559, 1467, 1429, 1317, 1262, 1204, 1115, 1057,
1028, 752, 722, 699; dH (300 MHz, CDCl3) 1.93–2.05 (2H,
m, CH2), 2.57–2.71 (5H, m, Ar–CH, ArCHCH2 and
CH2CS), 7.04–7.14 (2H, m, Ar–H), 7.21–7.27 (1H, m,
Ar–H), 7.53 (1H, dd, J 7.9 and 0.8, Ar–H); dC (75 MHz,
CDCl3) 27.4, 29.0, 30.2, 121.8, 123.5, 123.7, 124.2, 135.7,
141.2, 143.4, 145.5; m/z LRMS (EI+) 256 [M+H:79Br]+
(95%), 254 [MꢁH:79Br]+ (100%); (CI+, NH3) 272
[M+NH3:79Br]+, 258 [M+H:81Br]+, 257 [M:81Br]+, 256
[M+H:79Br]+, 255 [M:79Br]+, 254 [MꢁH:79Br]+; HRMS
(EI) calcd for C11H11BrS: 253.9759 [M]+, found: 253.9756
[M]+.
4.1.4.1. Preparation of 2,3-dihydro-1H-benzo(b)cyclo-
penta(d)thiophene (Table 3, entry 3). General procedure D
was followed employing the relevant thio-ketone (50 mg,
0.196 mmol) to yield the benzothiophene (17 mg, 52%) as
a colourless oil. nmax (NaCl)/cmꢁ1 3058, 2923, 2851, 1699,
1571, 1467, 1428, 1378, 1319, 1296, 1258, 1152, 1066,
1017, 800, 750, 728; dH (300 MHz, CDCl3) 2.51–2.62 (2H,
m, CH2), 2.86–2.93 (2H, m, CH2C]CS), 2.98–3.07 (2H,
m, CH2C]CS), 7.24 (1H, td, J 7.5 and 1.3, Ar–H), 7.32
(1H, td, J 7.5 and 1.3, Ar–H), 7.56 (1H, d, J 7.5, Ar–H),
4.1.3.3. Preparation of 2-(2-bromophenyl)-cyclohep-
tanethione, (Table 3, entry 4 substrate). General procedure C

M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
11519
7.76 (1H, dt, J 7.5 and 1.3, Ar–H); dC (75 MHz, CDCl3) 27.4,
29.0, 30.2, 121.8, 123.5, 123.7, 124.2, 135.7, 141.2, 143.4,
145.5; m/z LRMS (EI+) 174 [M]+ (18%), 173 [MꢁH]+
(39%); (CI+, NH3) 173 [M]+; HRMS (EI) calcd for
C11H9S: 173.0419 [MꢁH]+, found: 173.0415 [MꢁH]+.
(75 MHz, CDCl3) 22.6, 23.6, 23.7, 26.1, 30.1, 119.4,
127.7, 128.2, 138.2, 145.6, 161.2; m/z LRMS (EI+) 189
[M]+ (65%), 161 [MꢁC2H4] (100%); (CI+, NH3) 190
[M+H]+; HRMS (ES+) calcd for C11H12NS: 190.0685
[M+H]+, found: 190.0686 [M+H]+.
4.1.4.5. Preparation of 1,2,3,4-tetrahydro-dibenzofu-
ran using a one-pot two-ligand cascade reaction (Scheme
3). Caesium carbonate (1.727 g, 5.301 mmol) was added
to a flask charged with Pd2(dba)3 (81 mg, 0.088 mmol),
Xantphos (61 mg, 0.106 mmol) and DPEphos (57 mg,
0.106 mmol) under nitrogen. The reagents were suspended
in anhydrous toluene (2.00 mL) and 1-bromo-2-iodobenz-
ene (0.500 g, 1.767 mmol, 0.23 mL) and cyclohexanone
(0.260 g, 2.651 mmol, 0.28 mL) were added under nitrogen
and the reaction heated to 100 ꢀC for 48 h. After cooling, the
reaction mixture was diluted with diethyl ether (ca. 10 mL),
filtered through Celite and reduced in vacuo. The residue
was purified via flash column chromatography (petrol) to
yield the benzofuran (0.223 g, 51%) as a colourless oil.
4.1.4.2. Preparation of 6,7,8,9-tetrahydro-5H-10-oxa-
benzothiazulene (Table 3, entry 4).27 General procedure
D was followed employing the relevant thio-ketone
(100 mg, 0.369 mmol) to yield the benzothiophene (42 mg,
57%) as a yellow solid: mp 65–66 ꢀC. nmax (NaCl)/cmꢁ1
3059, 2921, 2838, 1442, 1435, 1359, 1311, 1262, 1223,
1151, 1090, 1019, 823, 800, 750, 725, 667; dH (300 MHz,
CDCl3) 1.68–1.82 (4H, m, CH2), 1.90–1.99 (2H, m, CH2),
2.87–2.96 (4H, m, CH2C]CS and CH2CS]C), 7.25 (1H,
td, J 7.9 and 1.1, Ar–H), 7.34 (1H, td, J 7.9 and 1.1, Ar–
H), 7.62 (1H, d, J 7.9, Ar–H), 7.75 (1H, dt, J 7.9 and 1.1,
Ar–H); dC (75 MHz, CDCl3) 26.0, 26.8, 28.7, 29.3, 31.3,
119.8, 121.1, 122.1, 122.6, 133.2, 137.0, 139.6, 139.9; m/z
LRMS (EI+) 202 [M]+ (100%), 173 [MꢁC2H5] (90%), 160
[MꢁC3H6] (45%), 147 [MꢁC4H7]+ (58%); (CI+, NH3)
203 [M+H]+, 202 [M]+; HRMS (EI) calcd for C13H14S:
202.0811 [M]+, found: 202.0810 [M]+.
4.1.4.6. Preparation of 1,2,3,4-tetrahydro-dibenzofu-
ran using a one-pot one-ligand cascade reaction (Scheme
4). Caesium carbonate (691 mg, 2.212 mmol) was added to
a flask charged with Pd2(dba)3 (32 mg, 0.035 mmol) and li-
gand 16 (17 mg, 0.042 mmol) under nitrogen. The reagents
were suspended in anhydrous toluene (1.00 mL) and 1-
bromo-2-iodobenzene (200 mg, 0.707 mmol, 0.09 mL) and
cyclohexanone (80 mg, 0.848 mmol, 0.09 mL) were added
under nitrogen and the reaction heated to 100 ꢀC for 48 h.
After cooling, the reaction mixture was diluted with diethyl
ether (ca. 10 mL), filtered through Celite and reduced in
vacuo. The residue was purified via flash column chromato-
graphy (petrol) to yield the benzofuran (0.111 g, 91%) as a
colourless oil.
4.1.4.3. Preparation of 8-fluoro-1,2,3,4-tetrahydro-di-
benzothiophene (Table 3, entry 5). General procedure D
was followed employing the relevant thio-ketone (100 mg,
0.369 mmol) to yield the benzothiophene (43 mg, 57%) as
a colourless oil. nmax (NaCl)/cmꢁ1 3063, 2932, 2857,
2840, 1603, 1556, 1470, 1446, 1401, 1376, 1349, 1338,
1314, 1298, 1250, 1201, 1150, 1136, 1111, 1069, 1050,
1022, 979, 951, 894, 848, 822, 804, 790, 701, 600, 534; dH
(300 MHz, CDCl3) 1.85–1.98 (4H, m, CH2), 2.69–2.77
(2H, m, CH2C]CS), 2.80–2.87 (2H, m, CH2CS]C), 7.07
(1H, td, J 8.9 and 2.4, Ar–H), 7.42–7.51 (2H, m, Ar–H);
dC (75 MHz, CDCl3) 22.6, 23.9, 26.0, 30.1, 108.9 (d, JCF
25.4), 112.8 (d, JCF 23.6), 121.5 (d, JCF 8.7), 129.4, 136.7,
137.0, 159.0, 162.1; m/z LRMS (EI+) 206 [M]+ (73%), 205
[MꢁH]+ (24%), 178 [MꢁC2H4]+ (100%); (CI+, NH3) 207
[M+H]+, 206 [M]+; HRMS (EI) calcd for C12H11FS:
206.0560 [M]+, found: 206.0561 [M]+.
Acknowledgements
This work was supported by the EPSRC and Pfizer. We thank
Mr. Gareth Brace for helpful discussions. The EPSRC Mass
Spectrometry Service at the University of Wales Swansea is
also thanked for their assistance.
4.1.4.4. Preparation of 5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3,b]pyridine (Table 3, entry 6). The starting ke-
tone (Table 3, entry 6 substrate, 200 mg, 0.738 mmol) was
added to a flask charged with phosphorus pentasulfide
(82 mg, 0.184 mmol) under nitrogen and the reaction mix-
ture suspended in anhydrous toluene (0.74 mL). The mixture
was stirred at room temperature for 10 min prior to the
addition of hexamethyldisiloxane (204 mg, 1.250 mmol,
0.27 mL) and heated to 90 ꢀC for 18 h. After cooling the re-
action mixture was filtered through a plug of silica and the
filtrate reduced in vacuo. The residue was purified via flash
column chromatography (petrol) to yield the benzothio-
phene (113 mg, 57%) as a colourless oil. nmax (NaCl)/
cmꢁ1 3047, 2924, 2855, 2359, 1728, 1584, 1537, 1456,
1392, 1368, 1350, 1336, 1304, 1261, 1240, 1218, 1156,
1136, 1122, 1094, 1069, 1023, 972, 950, 848, 791, 748,
733, 672; dH (300 MHz, CDCl3) 1.87–2.01 (4H, m, CH2),
2.69–2.77 (2H, m, CH2C]CS), 2.84–2.93 (2H, m,
CH2CS]C), 7.25 (1H, dd, J 7.9 and 4.9, Ar–H), 7.81 (1H,
dd, J 7.9 and 1.5, Ar–H), 8.46 (1H, d, J 3.8, Ar–H); dC
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M. C. Willis et al. / Tetrahedron 62 (2006) 11513–11520
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