Domino rhodium(I)-catalysed reactions for the efficient synthesis of substituted benzofurans and indoles

Article abstract of DOI:10.1016/j.tet.2010.05.106

Rhodium(I) catalysts promote the transformation of o-alkynyl phenols and anilines to the corresponding benzo[b]furans and indoles. The reaction is postulated to proceed via a transient 3-rhodium heterocycle intermediate, which can be trapped with suitable electrophiles to give poly-substituted heterocycles. In the case of mono-substituted electron-withdrawn electrophiles, excellent yield and selectivity for conjugate addition versus Heck-Mizoroki reaction can be achieved. In the case of 2-alkynyl pyridine electrophiles, novel 2-(benzofuran-3-yl)vinylpyridines are formed.

Full text of DOI:10.1016/j.tet.2010.05.106

Tetrahedron 66 (2010) 6468e6482
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Domino rhodium(I)-catalysed reactions for the efficient synthesis of substituted
benzofurans and indoles
*
Alistair Boyer, Naohiro Isono, Sebastian Lackner, Mark Lautens
Department of Chemistry, Davenport Chemical Laboratories, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Rhodium(I) catalysts promote the transformation of o-alkynyl phenols and anilines to the corresponding
benzo[b]furans and indoles. The reaction is postulated to proceed via a transient 3-rhodium heterocycle
intermediate, which can be trapped with suitable electrophiles to give poly-substituted heterocycles. In
the case of mono-substituted electron-withdrawn electrophiles, excellent yield and selectivity for con-
jugate addition versus HeckeMizoroki reaction can be achieved. In the case of 2-alkynyl pyridine elec-
trophiles, novel 2-(benzofuran-3-yl)vinylpyridines are formed.
Received 15 March 2010
Received in revised form 25 May 2010
Accepted 28 May 2010
Available online 8 June 2010
Dedicated with congratulations and respect
to Professor Steven V. Ley, the 2009
recipient of the Tetrahedron Prize
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Rhodium
Benzofuran
Indole
Catalysis
1. Introduction
OH
I
We have a long-standing interest in developing new routes to
synthesise aromatic heterocyclic scaffolds. Herein, we report
O
OH
Et2N
I
a
novel rhodium-catalysed domino process to make poly-
HO
O
O
substituted benzo[b]furans and indoles.
O
Substituted benzofuran skeletons are found in a wide array of
natural substances and are a recurring motif in active pharma-
ceutical ingredients (Fig. 1).1 Indoles, their nitrogen analogue, are
the key motif in tryptophan and as such have an even greater
prevalencedthey can be found in molecules ranging from natural
products to blockbuster drugs.2
As a testament to their importance, there exist many diverse
methods for the synthesis of benzofurans and indoles, which have
been discussed at length in several comprehensive reviews.3 One of
the most commonly employed syntheses of these important het-
erocycles is the cycloisomerisation of the corresponding o-alkynyl
phenol or aniline compound.4
OH
O
OH
O
HO
1
amiodarone
anti-angina
2 daphnodorin A
from Daphne odora
N
N
O
H
N
NMe2
S
O
O
N
H
N
3 Ondansetron
4 Sumatriptan
antiemetic
anti-migraine
OMe
H
N
OMe
Indeed, this has been achieved using a diverse array of reagents,
which are generally proposed to activate the alkyne to intra-
molecular nucleophilic attack (Scheme 1a). Rhodium has featured
O
N
H
OMe
MeO
H
H
O
OMe
MeO2C
5
reserpine
from Rauwolf ia serpentina
* Corresponding author. E-mail address: mlautens@alchemy.chem.utoronto.ca
(M. Lautens).
Figure 1. Benzofurans and indoles as motifs in natural products and drugs.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.106

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6469
Table 1
(a)
M
Optimisation of the cycloisomerisation of o-alkynyl phenols to benzofurans
R
R
Fe, Cu,
Rh, Pd,
R
cyclisation,
10 mol% [Rh(CO) acac]
2
R
11 mol% ligand
proto-
Ir, Pt,
R
X
XH
demetallation
XH
Au, Hg
solvent, H O (15:2, 0.12 M)
O
17
2
OH
16
6
7
8
Ligand Solventa Temp (ꢀC) Time (h) Yieldb (%)
(b)
Entry Phenol
H
H
carbenoid
formation
1
2
3
4
5
6
16a R¼nBu BINAP
16a R¼nBu BINAP
16a R¼nBu BINAP
16a R¼nBu dppp
PhMe
PhMe
PhMe
PhMe
PhMe
Dioxane
100
50
rt
100
100
100
1
1
16
1
1
88
77
62
33
95
92
R
R
[Rh]
XH
R
X
XH
9
10
11
16b R¼Ph
16b R¼Ph
BINAP
BINAP
1
Scheme 1. Cycloisomerisation of o-alkynyl phenols and anilines.
a
Solvent used as a 15:2 mixture with water.
Isolated yield following chromatography.
b
relatively few times as a catalyst for such transformations,5e7 but of
these examples, Trost’s catalytic is noteworthy (Scheme 1b).6 Under
the reaction conditions the terminal alkyne substrate 9 is postulated
to form a rhodium-carbenoid species 10,8 which then undergoes
nucleophilic attack from the nitrogen atom and protodemetallation
to generate the 2,3-unsubstituted aniline product 11. The principal
advantages of using cycloisomerisation to synthesise benzofurans
and indoles are that the starting materials are readily prepared and
there are no by-products from the reaction.9 Further efficiency can
be obtained by the design of processes in which several sequential
transformations occur: a domino reaction.10 The ability of transition
metal complexes both to promote cycloisomerisation and coupling
between an alkyne and aryl halide has been exploited using copper,11
palladium12 gold13 and iron14 to create a double domino reaction,
forming benzofurans and indoles in a single operation from hal-
ophenols or haloanilines and alkynes (Scheme 2a).
be used in place of toluene to give similar yields. Further experiments
were undertaken to explore the generality of this process. A range of
o-alkynyl phenols was readily prepared by Sonogashira reaction20
between MOM protected o-iodophenol 1921 and the appropriate
alkyne followed by acid-mediated deprotection (e.g., Scheme 3).
F
I
b
93%
OR
OR
20 R = MOM
99%
16d
18 R = H
a
99%
c
19
R = MOM
R = H
Scheme 3. Representative synthesis of o-alkynylphenol substrates. Reagents and
i
conditions: (a) MOMCl, Pr2NEt, CH2Cl2, rt, 99%; (b) 2 mol % PdCl2(PPh3)2, 2 mol % CuI,
NEt3, 50 ꢀC, 93%; (c) HCl, MeOH, rt, 99%.
(a)
R
R
The cycloisomerisation proved to be general and an array of
benzofuran products were synthesised using this process (Table 2).
Electron-rich and poor aromatic alkyne substituents were tolerated
as well as alkyl groups. The presence of an ester group did not
impede the process but for bulky groups, such as triisopropylsilane,
the conversion was reduced. Using this method 2,5-disubstituted
benzofurans could also be formed from the appropriate phenols,
but in the case of a tert-butyl substituent harsher reaction condi-
tions were required.
Y
Cu, Pd
Fe, Au
13
R
R
X
XH
XH
12
6
8
(b)
R
M
E
M-Y
E
R
X
X
XH
6
14
15
Table 2
Scheme 2. Domino sequences including cycloisomerisation.
Scope of the cycloisomerisation of o-alkynyl phenols to benzofurans
R1
Systems have also been developed in which cycloisomerisation is
R2
R2
5 mol% [Rh(CO)2acac]
5.5 mol% BINAP
the first step in the domino sequence (Scheme 2b). In these instances,
a metal catalyst promotes the cyclisation by activating the alkyne
group and the result is a 3-metallo-benzofuran/indole 14, which can
be trapped using suitable electrophiles.15e18 Lu et al. have combined
both of these strategies into a palladium-catalysed one-pot three-
component coupling reaction.19 In this manuscript, we describe an
approach based on the strategy outlined in Scheme 2b using alkynes
and electron-poor alkenes as electrophiles under rhodium(I) catalysis.
R1
O
PhMe, H2O (15:2, 0.12 M)
100 °C, 1 h
OH
16
17
Entry
Phenol
R1
R2
Product
Yielda (%)
1
2
3
4
5
8
9
16c
16d
16e
16f
16g
16h
16i
16j
16k
16k
4-MeOeC6H4
3-FeC6H4
2-BreC6H4
3-BreC6H4
BzOCH2CH2
Si(iPr)3
Ph
H
H
H
H
H
H
Cl
17c
17d
17e
17f
17g
17h
17i
92
90
8
72
97
30
84
83
2. Results and discussion
2.1. 2-Mono-substituted benzofurans and indoles
10
11
12b
Ph
Ph
Ph
CO2Me
tBu
tBu
17j
No reaction
17k 44
Our research in this area began with the observation that when
o-alkynyl phenols 16 are treated with a rhodium(I) catalyst and
BINAP ligand in a mixture of toluene and water (15:2) at 100 ꢀC for
1 h, they are transformed to the corresponding 2-substituted ben-
zofuran products 17 in good yield (Table 1).7
An initial screen of conditions demonstrated the transformation
to be quite robust, although at temperatures lower than 90 ꢀC or
when dppp was used as ligand the yield diminished. Dioxane could
a
Isolated yield following chromatography.
Cs2CO3 (1.0 equiv) added; 4 h reaction time.
b
In many cases, the stoichiometric cyclisation of o-alkynyl phenols
proceeds with the phenolic alcohol protected,22 however in this case
when the phenol was protected as its methyl, methoxymethyl or
tert-butyldimethylsilyl ether no reaction was observed.23

6470
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
CN
Ph
When the reaction conditions were applied to o-alkynylanilines
Ph
21 the analogous transformation occurred to give 2-substituted in-
dole products 22 (Table 3). Again, the reaction proceeded with both
alkyl and phenyl alkynes (21a/e) but was somewhat more sensitive
to the nitrogen substituent. The reaction did not occur in the case of
unprotected or N-benzyl anilines (21d/c), but proceeded in excellent
yield for N-mesyl anilines (21a/e). A N-tosyl substrate 21b was
tolerated by the catalytic system but the reaction was slower.
5 mol% [Rh(cod)OH]2
10 mol% BINAP
CN
dioxane, 50 °C, 20 h
O
OH
16b
24
25b
(10 equiv.)
91%
Scheme 5. Domino cycloisomerisation conjugate-addition to 24.
In order to study the scope of reaction the catalyst loading was
lowered to 3 mol % (6 mol % Rh) and an interesting change in reaction
outcome was observed. In all cases the expected product 25 was
isolated as a mixture with the HeckeMizoroki addition compound 26
(Table 4).27 It has been demonstrated that the HeckeMizoroki
product26canbeformedunderpalladiumcatalysis,17 sostudieswere
focussed on maximising the amount of conjugate-addition product
25. Indeed, the Miyaura-type addition product could be selectively
obtained, simply by the addition of BINAP as ligand. The reaction
proved successful with a variety of phenol substrates and the trend
was conserved throughout the series.
Table 3
Cycloisomerisation of o-alkynylanilines to indoles
R
5 mol% [Rh(CO)2acac]
5.5 mol% BINAP
R
PhMe, H2O (15:2, 0.12 M)
100 °C, 3 h
N
P
NHP
21
22
Entry
Aniline
Indole
Time (h)
Yielda (%)
1
2
3
21a P¼Ms, R¼Ph
21b P¼Ts, R¼Ph
21c P¼Bn, R¼Ph
21d P¼H, R¼Ph
21e P¼Ms, R¼nBu
22a
22b
22c
22d
22e
3
91
75
3b
3
No reaction
No reaction
93
Table 4
4
3
1
Substrate scope and effect of ligand in the conjugate addition to 24
5c
CN
CN
R
CN
24
a
Isolated yield following chromatography.
Incomplete conversion of starting material.
[Rh(CO)2acac] (10%), 11% BINAP.
(10 equiv.)
R
b
c
3 mol% [Rh(cod)OH]2
R
dioxane, H2O (20:1)
90 °C, 6 h
O
O
OH
16
25
26
A key observation was that the use of deuterium oxide as
reaction co-solvent led to complete deuterium incorporation at the
3-position of the benzofuran and indole products (Scheme 4). This
suggested that the reaction proceeded by the protodemetallation of
a 2-rhodium benzofuran/indole species 23 and we felt that this
intermediate could be exploited.
Entry
Phenol
Ligand
None
None
None
6.6 mol % BINAP
6.6 mol % BINAP
6.6 mol % BINAP
6.6 mol % BINAP
25a (%)
26a (%)
Ratio
1
2
3
4
5
6
7
16b R¼Ph
67
66
83
78
92
91
91
19
26
10
5
4
5
3.5:1
2.5:1
8.3:1
15:1
23:1
18:1
65:1
16c R¼4-OMeeC6H4
16d R¼3-FeC6H4
16a R¼nBu
16b R¼Ph
16c R¼4-OMe-C6H4
16d R¼3-F-C6H4
1
R
[Rh]
X
D
a
Isolated yield following chromatography.
a
R
R
X
XH
When ethyl vinyl ketone 27 was used as electrophile, no such
behaviour was observed and only the saturated compound 28 was
formed (Table 5).
16b
21e
23
88% d-17b (93% D)
90% d-22e (95% D)
Scheme 4. Site of deuterium incorporation with D2O solvent. Reagents and conditions:
(a) 5 mol % [Rh(CO)2acac], 5.5 mol % BINAP, PhMe, D2O (15:2, 0.12 M), 100 ꢀC, 1 h.
Table 5
Scope of the domino conjugate addition with ethyl vinyl ketone 27
COEt
R
2.2. Extension to a domino process: 2,3-disubstituted
benzofurans and indoles
COEt
3 mol% [Rh(cod)OH]2
R
dioxane, H2O (20:1)
90 °C, 6 h
O
OH
The implication of the existence of an intermediate rhodium-
heterocycle species 23 was that by judicious selection of reaction
conditions, a domino process could be developed for the synthesis
of 2,3-disubstituted benzofurans and indoles. Since the pioneering
work of Miyaura et al.24 and Hayashi et al.25 there have been many
examples of rhodium-catalysed conjugate addition.26 We first
investigated a domino reaction with mono-substituted electron-
poor alkenes.
Initial studies employed 10 mol % Rh(CO)2acac as catalyst with
10 equiv of acrylonitrile in dioxane at 50 ꢀC for 20 h. These were
selected as they had been shown to promote cycloisomerisation (cf.
Table 1, entries 2 and 6) and were more in line with the published
conditions for conjugate addition.24 Quickly, it became apparent
that Rh(CO)2acac was unsuitable for this transformation (<2%
desired product formed) and that [Rh(cod)OH]2 was optimal,
forming the product 25b in excellent yield (Scheme 5). When [Rh
(cod)Cl]2 was used as rhodium-source, the desired product was
isolated in only 40% yield.
16
27
28
(10 equiv.)
Entry
Phenol
Product
Yielda (%)
1
2
3
4
5
6
7
16a R¼nBu
28a
28b
28c
28d
28e
28f
28l
70
94
91
86
d
16b R¼Ph
16c R¼4-OMeeC6H4
16d R¼3-FeC6H4
16e R¼2-BreC6H4
16f R¼3-BreC6H4
16l R¼CH]CH2
80
75
a
Isolated yield following chromatography.
Again, the reaction proved to be general and good to excellent
yields were achieved for a range of phenol substrates including
electron-rich aromatic, electron-poor aromatic, vinyl and alkyl
substituents. As before, the 2-bromo substituted substrate 16e
failed to react (cf. Table 2, entry 3), presumably as it does not
complete the first of the domino steps.

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6471
CN
In the case of ethyl acrylate 29, once again a mixture of products
30/31 was formed. However, the addition of BINAP in this case
failed to influence the selectivity of the reaction (Scheme 6). It was
CN
CN
24
(2 equiv.)
nBu
3 mol% [Rh(cod)OH]2
ligand-free
nBu
nBu
dioxane, H2O (20:1)
90 °C, 4 h
N
N
NHMs
CO2Et
Ph
CO2Et
Ph
Ms
Ms
CO2Et
29
(10 equiv.)
21e
Ph
88% 35e
3% 36e
3 mol% [Rh(cod)OH]2
COEt
COEt
nBu
27
(2 equiv.)
dioxane, H2O (20:1)
90 °C, 6 h
O
O
nBu
nBu
OH
3 mol% [Rh(cod)OH]2
ligand-free
16b
30b
31b
dioxane, H2O (20:1)
90 °C, 4 h
N
2.4
3.0
:
:
1
1
92%
93%
ligand-free
6.6 mol% BINAP
NHMs
NHMs
Ms
21e
94% 37e
Scheme 6. Effect of ligand in the conjugate addition to ethyl acrylate 29.
CO2Et
CO2Et
nBu
CO2Et
nBu
29 (2 equiv.)
postulated that the use of a bulkier group might improve the se-
lectivity in the process so tert-butyl acrylate 32 was investigated. In
the studies thus far a large excess (10.0 equiv) of electrophile was
employed, and it was considered that this was unnecessary. Sur-
prisingly, when the amount of electrophile was reduced by half
(5.0 equiv) a dramatic effect in selectivity was observed (Table 6).
This selectivity for the conjugate-addition product was even
greater when the number of equivalents was lowered to 2.0 and
1,2-dimethoxyethane (DME) was used as solvent.
3 mol% [Rh(cod)OH]2
ligand-free
dioxane, H2O (20:1)
90 °C, 4 h
N
N
Ms
Ms
21e
38e
39e
<20:1
89%
Scheme 7. Synthesis of 2,3-disubstituted indoles.
The same reaction conditions could be applied to generate 2,3-
disubstituted indoles in excellent yields and selectivity for conju-
gate-addition versus HeckeMizoroki product.
Table 6
Effect of solvent and stoichiometry in the conjugate addition to 32
CO2tBu
CO2tBu
CO2tBu
(10 equiv.)
Ph
32
2.3. Disubstituted electrophiles
5 mol% [Rh(cod)OH]2
Ph
Ph
With an efficient process developed for the domino synthesis of
2,3-disubstituted benzofurans and indoles using mono-substituted
electrophiles, attention was turned to the use of disubstituted elec-
trophiles (i.e., 2-cyclohexenone). After a great deal of investigation,
including studying the effect of varying conditions, ligand, metal
catalyst and additive; it was found that the conjugate-addition
product 40a was formed typically in only 5e15% yield (Scheme 8).
solvent
O
O
OH
16b
90 °C, 3 h
33b
34b
Entry
Equiv 32
Solvent
(%)a
(%)a
Ratio
1
10.0
10.0
5.0
2.0
2.0
Dioxane
DME
Dioxane
Dioxane
DME
76
82
87
90
89
19
15
9
5.5
4.5
3.9:1
5.3:1
9.2:1
16:1
20:1
2b
3
4
5b
O
a
Isolated yield following chromatography.
Reaction performed at 85 ꢀC.
nBu
OH
b
3 mol%
[Rh(cod)OH]2,
6 mol% BINAP,
5 equiv.
This effect proved general and also provided excellent selectivity
for the domino reaction with ethyl acrylate and acrylonitrile under
ligand-free conditions (Table 7).
Using the knowledge gained from these studies, we turned our
attention to the synthesis of indoles (Scheme 7).
nBu
nBu
O
O
nBu
40a
41a
9%
47%
2-cyclohexenone
5 equiv. LiCl
dioxane : H2O
(20:1, 0.1 M)
90 °C, 24 h
OH
OH
nBu
16a
Table 7
nBu
Effect of reaction stoichiometry
O
EWG
Ph
EWG
Ph
nBu
14% 17a
Ph
O
3 mol% [Rh(cod)OH]2
ligand-free
2% 42a
solvent
90 °C, 6 h
O
,
O
Scheme 8. Typical product distribution for domino reaction with 2-cyclohexenone.
OH
24
25b
26b
,
,
16b
29,
30b,
33b
31b,
34b
32
Despite the low selectivity for the desired conjugate-addition
product, the mass balance of this process was quantitative, with the
remainder comprising unsubstituted benzofuran 17a and dimeric
products 41a/42a.28,29 From these results it was concluded that the
increase in substitution meant that cyclohexenone was no longer
a competitive electrophile as compared to the alkynylphenol starting
material.30 In order to favour the desired addition to an enone over
dimerisation, a system was designed in which the second of the
domino steps would be an intramolecular reaction. The starting
material for this reaction was readily accessed by the Sonogashira
Entry
Electrophile
Solvent
T (ꢀC)
Ratio
Yielda (%)
1
2
3
4
5
6
10 equiv 24
2 equiv 24
10 equiv 29
2 equiv 29
10 equiv 32
2 equiv 32
Dioxane, H2O (20:1)
DME, H2O (10:1)
Dioxane, H2O (20:1)
DME, H2O (10:1)
Dioxane, H2O (20:1)
DME, H2O (10:1)
90
85
90
85
90
85
3.5:1
20:1
2.4:1
>20:1
2.2:1
>20:1
86
86
92
85
88
77
a
Isolated yield of mixture of conjugate-addition and HeckeMizoroki products
following chromatography.

6472
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
reaction20 of aryl iodide 19 with 5-hexyn-1-ol, followed by a one-pot
Ley oxidationdstabilised Wittig reaction (43/44)31 and finally
deprotection to form the phenol 16m (Scheme 9). Ley’s one-pot se-
OH
nBu
3 mol% [Rh(cod)OH]2
6 mol% TDMPP
5 equiv. LiCl
nBu
nBu
OH
quence provided much improved access to the desired
a,b-un-
saturated compound 44 (65% over two steps) compared to isolation
of the intermediate aldehyde, which was prone to decomposition.
nBu
nBu
dioxane : H2O
(20:1, 0.14 M)
90 °C, 24 h
OH
16a
O
O
42a
41a
80%
12%
HO
7% 17a
MeO2C
Scheme 10. Dimerisation of the phenol 16a. TDMPP¼tris(2,6-dimethoxyphenyl)
I
phosphine.
a
b
67%
65%
resulted in the greatest amount of dimer reaction in studies of the
conjugate addition to cyclohexenone (see Section 2.3).
A series of experiments was performed in order to determine
the characteristics of alkyne group, which would either promote or
hinder the addition of the benzofuryl-rhodium species (Table 9). An
OMOM
OMOM
OR
44
R = MOM
19
43
c
93%
16m R = H
Scheme 9. Synthesis of a substrate bearing a tethered electrophile. Reagents and
conditions: (a) 5-hexyn-1-ol, 2 mol % PdCl2(PPh3)2, 4 mol % CuI, NEt3, THF, 50 ꢀC, 67%;
n
ꢀ
(b) 5 mol % Pr4NRuO4, NMO, 4 A sieves, CH2Cl2, rt; then Ph3PCHCO2Me, rt, 65%; (c)
HCl, MeOH, rt, 93%.
Table 9
Effect of coordinating groups for the dimerisation verus cross-addition ratio
With the substrate in hand, optimisation studies revealed that the
reaction resulted in a very good yield of conjugate-addition product
40m when DME was used as a co-solvent with water (Table 8).
1
R
R2
1.0 equiv. alkyne
nBu 3 mol% [Rh(cod)OH]2
17a
6 mol% TDMPP
Table 8
5 equiv. LiCl
41a
nBu
+
Domino intramolecular cyclisation
O
dioxane : H2O
(20:1, 0.14 M)
90 °C, 24 h
42a
OH
16a
MeO2C
MeO2C
cross-
addition
product
MeO2C
O
O
Entry
1
Alkyne
Cross-addition product
Yielda (%)
Selectivityb
40m
17m
[Rh(cod)OH]2
N
nBu
solvent
additive
90 °C
OH
75
>19:1
MeO2C
N
OH
CO2Me
3
16m
nBu
45
nBu
O
46a
3
O
41m
nBu
OMEM
2
34
1:1
Entry
Solvent
mol % Catalyst
and additive
40ma
(%)
17ma
(%)
41ma
(%)
nBu
O
47
nBu
48a
O
O
1b
2
Dioxane
3.5% catalyst
3.5% catalyst
3.0% catalyst
3.0% catalyst,
1.6 equiv LiCl
3.0% catalyst
3.0% catalyst
11
66
48
51
10
9
11
2
d
d
9
O
Dioxane, H2O (20:1)
Dioxane, H2O (20:1)
Dioxane, H2O (20:1)
3
4b
14
3
4
43
24
1:1
5b
6
PhMe, H2O (20:1)
DME, H2O (20:1)
15
70
36
8
d
12
a
Isolated yield following chromatography.
Incomplete conversion of 16m.
b
It is important to note that the addition of lithium chloride18,32
nBu
OMe
1:1.3
to the reaction mixture generally shifted the distribution of prod-
ucts away from the 3-unsubstituted benzofuran 17m.33 Control
experiments demonstrated that when the substrate 16a is heated
to 90 ꢀC for 24 h in dioxane and water (10:1) there is a significant
background reaction to form the 3-unsubstituted benzofuran 17a
(ca. 15% conversion by 1H NMR). The addition of lithium chloride or
bromide (5 equiv) completely inhibited this process.23
nBu
O
51
nBu
52
O
nBu
OAc
5
n.d.
1:1.7
1:2.7
nBu
OAc
53
nBu
54
O
2.4. Investigation of the side-reaction
The formation of the dimer species 41/42 represented a signifi-
cant pathway within our domino process and warranted further
investigation.
When the external electrophile was absent from the reaction
mixture, the o-alkynyl phenol 16a was transformed to the major
dimer 41a in 80% yield (Scheme 10). The conditions were selected
for these experiments on the basis that they were those, which
Et
H
6
14
Et
H
55
nBu
56
O
a
Isolated yield following chromatography.
Selectivity¼relative integration of cross-addition product:41a in the crude 1H
b
NMR spectrum. n.d.¼not determined.

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6473
equimolar mixture of o-1-hexynylphenol 16a and alkyne partner
was treated with a catalytic amount of rhodium(I) complex and
TDMPP at 90 ꢀC for 24 h.
When a pyridyl alkyne 45 was investigated, only a trace amount
of the dimeric product 41/42 could be observed and the major
product was the vinyl pyridine 46a (Table 9, entry 1).
In the case of phenol-derived substrates, there was a general trend
that the ratio of dimer 41 to cross-reaction product generally favoured
the latter as the ‘coordinating ability’ of the substituent increased
(Table 9, entries 2e5).29,34 In the case of unsubstituted 1-buty-
nylbenzene 55, the cross-addition reaction still occurred but signifi-
cantly less than dimerisation. For terminal alkynes (phenyl acetylene),
or alkynes conjugated to ester groups (dimethyl but-2-ynedioate or
ethyl but-2-ynoate) there was no cross-addition reaction and only
compounds related to the phenol were observed (i.e., 17, 41 and 42).
the formation of the 3-unsubstituted benzofuran product, however
in this case lithium bromide was found to be even better. The re-
action also proceeded to give a higher yield of product at higher
concentration. We settled upon the use of 5 equiv of lithium bro-
mide with 12 mol % TDMPP ligand and 6 mol % [Rh(cod)OH]2 in
dioxane and water (10:1) at 90 ꢀC for 24 h as optimal and pro-
ceeded to test the scope of the reaction.
The reaction proved to be quite general and a range of o-alkynyl
phenols, including both alkyl- and aryl-substituted alkynes un-
derwent domino reaction in good to very good yield, even when the
catalyst loading was reduced to half (Table 11). Surprisingly, the
Table 11
Scope of the domino reaction with pyridyl alkyne 45
Entry
Substrate
Product
Yielda (%)
2.5. Application to the synthesis of poly-heteroaromatics
N
nBu
N
nBu
1c
16a
46a
46b
83c
The selective formation of the cross-addition product 46a was
encouraging and we were keen to further optimise this reaction. The
rhodium-catalysed addition of boronic acids to alkynes with nitro-
gen containing heterocycles as directing groups has been reported
previously by our group29 and we investigated this in the context of
a domino process. It was found that [Rh(cod)OH]2 was an excellent
catalyst for promoting this transformation and although at high
loadings the analogous chloride catalyst performed comparably, at
lower loading a significant drop in performance was seen (Table 10).
O
nBu
2b
16b
16b
77
83
Ph
O
N
Table 10
nBu
3c
46b
Screening the domino reaction with pyridyl alkyne 45
Ph
O
N
nBu
nBu
nBu
catalyst
TDMPP
N
nBu
4c
16c
16d
46c
46d
85
76
nBu
N
5 equiv. LiCl
dioxane, H2O (10:1, 0.12 M)
90 °C, 1 h
O
OH
OMe
46a
16a
45
(1.0 equiv.)
O
Entry
mol % Catalyst
Conversiona
46a/17a/41a
Yieldb (%)
N
nBu
5c
1
1.5 [Rh(cod)OH]2
1.5 [Rh(cod)OH]2
3 [Rh(cod)OH]2
3 [Rh(cod)OH]2
6 [Rh(cod)OH]2
6 [Rh(cod)OH]2
6 Rh(cod)2OTf
1.5 [Rh(cod)Cl]2
6 [Rh(cod)Cl]2
6 [Ir(cod)Cl]2
93%
>98%
>98%
1:0.6:0.1
1:0.2:d
1:0.2:d
48
62
62
F
2c
3
4d
5
No reaction
1:0.1:0.2
1:0.1:0.2
1:0.1:d
1:0.7:0.1
1:0.1:0.2
1:25:d
O
>98%
>98%
>98%
72%
>98%
32%
80
80
67
31
74
Trace
2
6c
7e
8
N
nBu
37
(51% 17e)
6b
16e
46e
9
10
11
O
12 PdCl2
55%
1:8.3:8.0
Br
a
Consumption of 16a by 1H NMR.
Isolated yield.
Ligand-free conditions.
BINAP used in place of TDMPP.
No ligand, LiCl, or H2O.
b
c
N
nBu
d
e
7b
8b
9c
16f
16g
16i
46f
46g
46i
55
87
75
Br
O
Electron-rich ligands, such as TDMPP and TFP gave the most amount
of product, in the case of the bidentate BINAP ligand, there was no
formation of the vinyl pyridine product (only 17, 41 and 42 were
observed). As before, the best results were obtained with a dioxane/
water solvent system. Increasing the amount of pyridyl alkyne rel-
ative to phenol seemed to have little effect on the outcome and the
reaction worked well using only 1.0 equiv.
In general, conversion at 24 h was low (<20%) at temperatures
below 80 ꢀC. The optimum conversion and selectivity for the de-
sired product were observed when the reaction was performed at
90 ꢀC. As observed previously, the addition of lithium chloride
seemed to favour the formation of the desired product, suppressing
N
nBu
OBz
O
N
nBu
Cl
Ph
O
(continued on next page)

6474
Table 11 (continued)
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
Table 12
Scope of alkyne partner
Entry
Substrate
Product
Yielda (%)
Entry
Alkyne
Cross-addition product
Yielda (%)
10b
16j
46j
71
41
1b
2c
3d
58
58
58
59a
59a
59a
42
52
68
N
nBu
11b
16k
21e
46k
tBu
Ph
N
O
nBu
Only 22e
formed
12c
57e
4b
5c
6b
7c
8d
9b
60 (n¼3)
60 (n¼3)
62 (n¼2)
62 (n¼2)
62 (n¼2)
64 (n¼1)
61a (n¼3)
61a (n¼3)
63a (n¼2)
63a (n¼2)
63a (n¼2)
No reaction
49
73
27
46
57
nBu
N
Ms
a
Isolated yield following column chromatography.
b
Compound 16 (1.0 equiv), 45 (1.0 equiv), 3 mol % [Rh(cod)OH]2, 6 mol % TDMPP,
5 equiv LiBr, dioxane, H2O (10:1, 0.24 M), 90 ꢀC, 24 h.
c
Compound 16 or 21 (1.0 equiv), 45 (1.0 equiv), 6 mol % [Rh(cod)OH]2, 12 mol %,
TDMPP, 5 equiv LiBr, dioxane, H2O (10:1, 0.24 M), 90 ꢀC, 24 h.
cross-addition product could be isolated even for the substrates,
which displayed poor reactivity in the previous domino reactions
(16e, 16k). Unfortunately, when the reactions conditions were ap-
plied to the o-alkynyl aniline substrate 21a the domino process did
not occur and only the 3-unsubstituted indole 22e was formed.
A range of alkynes was alsoconsidered (Table12). It wasfound that,
although in many cases 2-hexynylpyridine gave good yields at 3 mol %
catalyst loading, in general 6 mol % was required to obtain an ac-
ceptable yield. Further improvement could be achieved by using a 1.5
times excess of phenol, compared to the alkynyl pyridine substrate.
We were particularly pleased to find that the 2-alkynyl-3-
chloro-5-(trifluoromethyl)-2-pyridine (58) was a competent part-
ner in the reaction, owing to its prevalence in bioactive
compounds.35
In accordance with the findings for the rhodium-catalysed ad-
dition of boronic acids to alkynylpyridines,29 there was no cross-
addition reaction in the case of a substrate bearing a propargylic
alcohol (64) or for 3- or 4- alkynylpyridines (67, 68). However, we
were able to generate 30% of the addition product 66 with 2-phenyl-
ethynyl-pyridine (65) despite this being unsuccessful previously.
10b
30
11b
No reaction
No reaction
12b
a
Isolated yield following column chromatography.
Compound 16a (1.0 equiv), alkyne (1.0 equiv), 3 mol % [Rh(cod)OH]2, 6 mol %
b
TDMPP, LiBr (5.0 equiv), dioxane, H2O (10:1, 0.24 M), 90 ꢀC, 24 h.
c
Compound 16a (1.0 equiv), alkyne (1.0 equiv), 6 mol % [Rh(cod)OH]2, 12 mol %
TDMPP, LiBr (5.0 equiv),dioxane, H2O (10:1, 0.24 M), 90 ꢀC, 24 h.
d
Compound 16a (1.5 equiv), alkyne (1.0 equiv), 9 mol % [Rh(cod)OH]2, 18 mol %
TDMPP, LiBr (5.0 equiv),dioxane, H2O (10:1, 0.24 M), 90 ꢀC, 24 h.
2.6. Mechanism
In the case of mono-substituted electron-poor alkenes (29) the
3-rhodium heterocycles adds in a conjugate fashion to form a rho-
A series of deuterium labelling and control experiments were
performed in order to gain insight to the mechanism of this process
(Scheme 11). First of all, it is important to note that the substrates
used in these studies contain an internal alkyne. Thus we propose
that initial step in the mechanism is the activation of the alkyne to
intramolecular nucleophilic attack (II), forming a 3-rhodium het-
erocycle (III). This is complimentary to the report of Trost, whose
catalyst did not promote reaction with internal alkynes and was
postulated to proceed through a rhodium carbenoid species.6
When Rh(CO)2acac is used as the catalyst, the major pathway is
protodemetallation to generate the corresponding heterocyclic
product (17). When [Rh(cod)OH]2 is used as the catalyst, a domino
reaction is more likely to occur; either addition to an external
electrophile component (29 or 45) or to another molecule of
starting material (16). Control experiments demonstrated that
FriedeleCrafts type reaction of the 3-unsubstituted benzofuran was
not in operation.36
dium p
-oxo allyl species (V).37 Depending on the nature of the
electrophile and the exact reaction conditions, this intermediate
can undergo protodemetallation to give the saturated product (i.e.,
30) and regenerate the rhodium catalyst; or b-hydride elimination
to give the unsaturated product 31 and a rhodium/hydride species
(VI).27,38 When hexyl acrylate was used as electrophile (10 equiv,
1 equiv 16a, 3 mol % [Rh(cod)OH]2, ligand-free, 90 ꢀC, 6 h) we were
able to detect hexyl propionate (1H NMR
crude reaction mixture suggesting that the active rhodium catalyst
is regenerated from the hydride following reduction of the
electrophile.
d
¼2.32, q, J¼7.6 Hz) in the
The increase in steric crowding in the case of more substituted
electron-poor alkenes, such as 2-cyclohexene means that the al-
kyne motif within the starting material (16) presents a reactive site
and the dimer (41) is formed at a competitive rate. The judicious
choice of alkyne can lead to the generation of interesting cross-
addition products, following addition of the 3-rhodium-heterocycle

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6475
CO2Et
EtO
N
O
nBu
CO2Et
D
Rh
H
nBu
OH
nBu
46a
Ph
VI
O
O
31a
nBu
Rh
X
I
O
41a
EtO
R
O
N
Rh
EtO
nBu
nBu
OH
O
OH
Rh
R
Rh
Ph
16
O
nBu
IX
X
O
Ph
O
V
O
30a
Rh
R
OH
II
OEt
nBu
O
Rh
N
nBu
O
Rh
Rh
H
EtO
VII
Ph
VIII
N
O
nBu
O
nBu
nBu
O
29
45
O
Rh
IV
R
D
O
III
Ph
17b
Scheme 11. Mechanistic hypothesis for domino reaction of o-alkynyl phenols and anilines. D indicates the site of deuterium incorporation when the reaction is performed in D2O.
nBu
OH
O
16a
to the alkyne and protodemetallation. Under the conditions used,
the reaction fails with electron-poor alkynes with no coordinating
groups (e.g., dimethyl but-2-ynedioate, ethyl but-2-ynoate, 67 or
68), supporting our belief that it is coordination of the alkyne
substrate to rhodium and not the inherent electronics of the sys-
tem, which controls the process.
4.2. Cycloisomerisation (general procedure A)
A solution of [Rh(CO)2acac] (5 mol %) and rac-BINAP (5.5 mol %)
in toluene (0.7 cm3) and water (0.15 cm3) was stirred at room tem-
perature for 15 min. The substrate (1 equiv) was added as a solution
in toluene (0.8 cm3) and the reaction mixture was stirred at 100 ꢀC
for the stated time. The reaction was cooled to room temperature
and filtered through a short pad of silica gel, washing with Et2O
(5ꢁ5 cm3). The filtrate was concentrated under reduced pressure
and purified by flash column chromatography to yield the product.
3. Conclusions
We have demonstrated that rhodium can catalyse the cyclo-
isomerisation of o-alkynyl phenols and anilines to the corre-
sponding benzofurans and indoles. The process, which we have
developed is complimentary to the previous example of Trost and
proceeds via a transient 3-rhodium-heterocycle species. This in-
termediate has been exploited in the development of a domino
carbonecarbon bond-forming process. The conjugate addition to
alkenes can be performed with excellent selectivity for the conju-
gate-addition product versus the HeckeMizoroki product in the
case of mono-substituted electron-poor alkenes, however more
substituted systems represent a current limitation of the method.
We have also applied this to a chelation-controlled domino addi-
tion to alkynes, resulting in the rapid synthesis of several novel
poly-heteroaromatic molecules.
4.2.1. 2-n-Butyl-1-benzofuran (17a). Subjecting phenol 16a (43 mg,
0.25 mmol) to general procedure A (with 10 mol % catalyst loading)
followed by purification (gradient from 5 to 9% Et2O in hexane) gave
thetitlecompoundasacolourlessoil(38 mg,88%). Theanalyticaldata
were in agreement with literature values.42 dH (400 MHz; CDCl3):
7.49e7.45 (m, 1H), 7.42e7.39 (m, 1H), 7.22e7.14 (m, 2H), 6.37 (s, 1H),
2.77 (t, J¼7.5 Hz, 2H), 1.73 (app. quintet, J¼7.5 Hz, 2H), 1.43 (app.
sextet, J¼7.5 Hz, 2H), 0.96 (t, J¼7.5 Hz, 3H); dC (100 MHz; CDCl3):
159.7,154.6,129.0,123.0,122.3,120.1,110.7,101.7, 29.8, 28.1, 22.3,13.8.
4.2.2. 2-Phenyl-1-benzofuran (17b). Subjecting phenol 16b (50 mg,
0.26 mmol) to general procedure A (with 10 mol % catalyst loading)
followed by purification (gradient from 5 to 9% Et2O in hexane)
gave the title compound as a white solid (47 mg, 95%). The ana-
lytical data were in agreement with literature values.43
Mp¼118e119 ꢀC; dH (400 MHz; CDCl3): 7.87 (d, J¼8.4 Hz, 2H), 7.59
(d, J¼7.6 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.45 (dd, J¼8.4, 7.4 Hz, 2H),
7.36 (t, J¼7.4 Hz, 1H), 7.29 (dd, J¼8.0, 7.3 Hz, 1H), 7.23 (dd, J¼7.6,
7.3 Hz, 1H), 7.03 (s, 1H); dC (100 MHz; CDCl3): 155.9, 154.9, 130.5,
129.2, 128.8, 128.5, 124.9, 124.2, 122.9, 120.9, 111.1, 101.3.
4. Experimental procedures
4.1. General
The preparation of compounds 16a,15a 16b,38 16c,4c 16h,39 16i,15b
16k,40 19,21 21,15e 5141 and (45, 60, 62, 64, 65, 67, 68)29b have been
reported previously. The synthesis of other starting materials and
general experimental information is listed in the Supplementary
data, which is available free of charge from the Tetrahedron
website.
4.2.3. 3-Duetero-2-phenyl-1-benzofuran (d-17b). Subjecting phe-
nol 16b (50 mg, 0.26 mmol) to general procedure A (using D2O in

6476
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
place of H2O) followed by purification (gradient from 5 to 9% Et2O in
1722, 1601, 1586, 1454, 1316, 1275, 1175, 1115, 1071, 1026 cmꢂ1; m/z
hexane) gave the title compound as a white solid (44 mg, 88%, 93%
(EI) 266.0930 (Mþ: C17H14O3 requires 266.0943).
1
D by H NMR). Mp¼118e119 ꢀC; dH (400 MHz; CDCl3): 7.87 (d,
J¼7.4 Hz, 2H), 7.58 (d, J¼7.6 Hz, 1H), 7.53 (d, J¼8.2 Hz, 1H), 7.45 (dd,
J¼7.7, 7.4 Hz, 2H), 7.35 (t, J¼7.7 Hz, 1H), 7.28 (dd, J¼7.8, 7.4 Hz, 1H),
7.23 (dd, J¼7.6, 7.4 Hz, 1H); dC (100 MHz; CDCl3): 155.8, 154.9, 130.4,
129.1, 128.7, 128.5, 124.9, 124.2, 122.9, 120.8, 111.1, 101.1 (J¼26.7 Hz);
nmax 3066, 1553, 1470, 1454, 1269, 1207, 1069 cmꢂ1; m/z (EI)
195.0785 (Mþ: C14H9DO requires 195.0794).
4.2.9. 2-Tri-iso-propylsilylbenzofuran (17h). Subjecting phenol 16h
(50 mg, 0.18 mmol) to general procedure A followed by purification
(hexane) gave the title compound as a colourless oil (15 mg, 30%).
dH (400 MHz; CDCl3): 7.59 (ddd, J¼7.6, 1.4, 0.7 Hz, 1H), 7.51 (ddd,
J¼8.2, 1.7, 0.9 Hz, 1H), 7.27 (ddd, J¼8.2, 7.1, 1.4 Hz, 1H), 7.20 (ddd,
J¼8.2, 7.1, 1.0 Hz, 1H), 7.01 (d, J¼1.0 Hz, 1H), 1.44e1.34 (m, 3H), 1.15
(d, J¼7.6 Hz, 18H); dC (100 MHz; CDCl3): 160.52, 157.94, 127.92,
123.99, 122.12, 120.77, 118.03, 111.25, 18.57, 11.04; nmax 2944, 2890,
2866, 1467, 1441, 1253, 1223, 1111, 1057 cmꢂ1; m/z (EI) 274.1759
(Mþ: C17H26OSi requires 274.1753).
4.2.4. 2-(4-Methoxyphenyl)-1-benzofuran (17c). Subjecting phenol
16c (45 mg, 0.20 mmol) to general procedure A followed by puri-
fication (10:1:1 hexane/CH2Cl2/Et2O in hexane) gave the title
compound as a white solid (41 mg, 92%). The analytical data were in
agreement with literature values.43 Mp¼148e150 ꢀC; dH (400 MHz;
CDCl3): 7.80 (d, J¼8.9 Hz, 2H), 7.56 (dd, J¼7.2, 1.0 Hz, 1H), 7.50 (dd,
J¼7.0, 1.2 Hz, 1H), 7.28e7.18 (m, 2H), 6.98 (d, J¼8.9 Hz, 2H), 6.89 (s,
1H), 3.87 (s, 3H); dC (100 MHz; CDCl3): 160.0, 156.0, 154.7, 129.5,
126.4, 123.7, 133.3, 122.8, 120.5, 114.2, 111.0, 99.6, 55.3.
4.2.10. 5-Chloro-2-phenylbenzofuran (17i). Subjecting phenol 16i
(46 mg, 0.20 mmol) to general procedure A followed by purification
(gradient from 5 to 10% Et2O in hexane) gave the title compound as
a white solid (38 mg, 84%). The analytical data were in agreement
with literature values.11b Mp¼146e148 ꢀC (sublimed); dH (400 MHz;
CDCl3): 7.85e7.81 (m, 2H), 7.52 (d, J¼2.2 Hz, 1H), 7.47e7.34 (m, 4H),
7.22 (dd, J¼8.7, 2.2 Hz, 1H), 6.93 (s, 1H); dC (100 MHz; CDCl3): 157.4,
153.2, 130.5, 129.9, 129.0, 128.8, 128.5, 125.0, 124.4, 120.4, 112.1, 100.8.
4.2.5. 2-(3-Fluorophenyl)-1-benzofuran (17d). Subjecting phenol
16d (46 mg, 0.22 mmol) to general procedure A followed by puri-
fication (9% Et2O in hexane) gave the title compound as a white
solid (41 mg, 90%). The analytical data were in agreement with
literature values.12c Mp¼77e78 ꢀC; dH (400 MHz; CDCl3): 7.64 (ddd,
J¼7.8, 1.8, 1.0 Hz, 1H), 7.60 (dd, J¼7.8, 1.3 Hz, 1H), 7.56 (ddd, J¼10.0,
2.3, 1.8 Hz, 1H), 7.53 (dd, J¼8.2, 1.0 Hz, 1H), 7.41, (ddd, J¼7.8, 7.8,
6.0 Hz, 1H), 7.31 (ddd, J¼8.2, 7.3, 1.3 Hz, 1H), 7.23 (ddd, J¼7.8, 7.3,
1.0 Hz, 1H), 7.08e7.02 (m, 1H), 7.05 (s, 1H); dC (100 MHz; CDCl3):
163.1 (d, J¼245.8 Hz), 154.9, 154.5 (d, J¼3.2 Hz), 132.5 (d, J¼8.6 Hz),
130.4 (d, J¼8.6 Hz), 128.9, 124.7, 123.1, 121.1, 120.5 (d, J¼3.0 Hz),
115.3 (d, J¼21.4 Hz), 111.8 (d, J¼23.7 Hz), 111.2, 102.3.
4.2.11. Methyl 2-phenylbenzofuran-5-carboxylate (17j). Subjecting
phenol 16j (50 mg, 0.20 mmol) to general procedure A followed by
purification (hexane: CH2Cl2/EtOAc, 10:1:1) gave the title compound
as a white solid (41 mg, 83%). The analytical data were in agreement
with literature values.46 Mp¼155e157 ꢀC; dH (400 MHz; CDCl3): 8.30
(d, J¼1.8 Hz,1H),8.00(dd, J¼8.6,1.8 Hz,1H),7.85(dd,J¼8.2,1.3 Hz, 2H),
7.52 (d, J¼8.6 Hz,1H), 7.45 (dd, J¼8.2, 7.4 Hz, 2H), 7.37 (tt, J¼7.4, 1.3 Hz,
1H), 7.04 (s,1H), 3.93 (s, 3H); dC (100 MHz; CDCl3): 167.2, 157.4, 157.3,
129.8, 129.2, 129.0, 128.8, 126.0, 125.3, 125.0, 123.2, 110.9, 101.4, 52.1.
4.2.6. 2-(2-Bromophenyl)benzofuran (17e). Subjecting phenol 16e
(40 mg, 0.15 mmol) to general procedure A followed by purification
(gradient from 5 to 15% Et2O in hexane) gave the title compound as
a yellow oil (3 mg, 8%). The analytical data were in agreement with
literature values.43 dH (400 MHz; CDCl3): 7.97 (dd, J¼7.9, 1.7 Hz, 1H),
7.71 (dd, J¼8.0, 1.2 Hz, 1H), 7.65 (dd, J¼7.7, 1.3 Hz, 1H), 7.54 (s, 1H),
7.53 (dd, J¼8.3, 1.0 Hz, 1H), 7.43 (ddd, J¼7.9, 7.4, 1.2 Hz, 1H), 7.33
(ddd, J¼8.3, 7.3, 1.3 Hz, 1H), 7.26 (ddd, J¼7.7, 7.3, 1.0 Hz, 1H), 7.21
(ddd, J¼8.0, 7.4, 1.7 Hz, 1H); dC (100 MHz; CDCl3): 154.3, 153.1, 134.3,
131.0, 129.8, 129.4, 128.8, 127.5, 124.8, 123.0, 121.5, 120.8, 111.1, 107.0.
4.2.12. 5-tert-Butyl-2-phenylbenzofuran (17k). Subjecting phenol
16k (41 mg, 0.16 mmol) to general procedure A with the addition of
Cs2CO3 for 4 h followed by purification (hexane/CH2Cl2/EtOAc,
10:1:1) gave the title compound as a white solid (18 mg, 44%). The
analytical data were in agreement with literature values.11b
Mp¼100e102 ꢀC; dH (400 MHz; CDCl3): 7.85 (dd, J¼8.5, 1.3 Hz,
2H), 7.58 (d, J¼2.0 Hz, 1H), 7.46e7.41 (m, 2H), 7.44 (d, J¼8.6 Hz, 1H),
7.35 (dd, J¼8.6, 2.0 Hz, 1H), 7.35e7.31 (m, 1H), 6.97 (s, 1H), 1.39 (s,
9H); dC (100 MHz; CDCl3): 156.0, 153.1, 146.0, 130.7, 128.9, 128.7,
128.3, 124.8, 122.2, 117.1, 110.4, 101.5, 34.7, 31.8.
4.2.7. 2-(3-Bromophenyl)benzofuran (17f). Subjecting phenol 16f
(55 mg, 0.20 mmol) to general procedure A followed by chroma-
tography (gradient from 5 to 15% Et2O in hexane) gave the title
compound as a white solid (40 mg, 72%). The analytical data were in
agreement with literature values.44 Mp¼84e85 ꢀC; dH (400 MHz;
CDCl3): 8.02 (dd, J¼2.0, 1.6 Hz, 1H), 7.78 (ddd, J¼7.8, 1.6, 1.0 Hz, 1H),
7.59 (dd, J¼7.6, 1.4 Hz, 1H), 7.52 (dd, J¼8.1, 1.0 Hz, 1H), 7.47 (ddd,
J¼8.0, 2.0, 1.0 Hz, 1H), 7.31 (dd, J¼8.0, 7.8 Hz, 1H), 7.31 (ddd, J¼8.1,
7.3, 1.4 Hz, 1H), 7.24 (ddd, J¼7.6, 7.3, 1.0 Hz, 1H), 7.03 (s, 1H); dC
(100 MHz; CDCl3): 154.9, 154.2, 132.4, 131.3, 130.3, 128.9, 127.8,
124.8, 123.4, 123.1, 123.0, 121.1, 111.2, 102.4.
4.2.13. 1-Methanesulfonyl-2-phenylindole (22a). Subjecting aniline
21a (58 mg, 0.22 mmol) to general procedure A followed by purifica-
tion (gradient from 5 to 10% EtOAC in hexane) gave the title compound
as a white solid (53 mg, 91%). The analytical data were in agreement
with literature values.15e Mp¼103e105 ꢀC; dH (400 MHz; CDCl3): 8.14
(d, J¼8.0 Hz, 1H), 7.64e7.55 (m, 3H), 7.47e7.32 (m, 5H), 6.73 (s, 1H),
2.74 (s, 3H); dC (100 MHz; CDCl3):141.93,137.95,131.93,130.26,130.08,
128.83, 127.67, 125.07, 124.50, 120.98, 115.78, 113.01, 39.42.
4.2.14. 1-(4-Toluene)-sulfonyl-2-phenylindole (22b). Subjecting an-
iline 21b (80 mg, 0.22 mmol) to general procedure A followed by
purification (gradient from 5 to 10% EtOAC in hexane) gave the title
compound as a white solid (60 mg, 75%). The analytical data were in
agreement with literature values.15e Mp¼145e147 ꢀC; dH
(400 MHz; CDCl3): 8.31 (d, J¼8.4 Hz, 1H), 7.53e7.46 (m, 2H),
7.46e7.38 (m, 4H), 7.34 (t, J¼7.6 Hz, 1H), 7.29e7.21 (m, 3H), 7.02 (d,
J¼8.1 Hz, 2H), 6.53 (s, 1H), 2.26 (s, 3H); dC (100 MHz; CDCl3): 144.47,
142.08, 138.23, 134.60, 132.37, 130.50, 130.28, 129.14, 128.59, 127.44,
126.73, 124.72, 124.26, 120.64, 116.60, 113.57, 21.47.
4.2.8. Benzoic acid 2-benzo[b]furan-2-ylethyl ester (17g). Subjecting
phenol 16g (44 mg, 0.16 mmol) to general procedure A followed by
purification (gradient from 5 to 12% EtOAc in hexane) gave the title
compound as a white solid (42 mg, 97%). Mp¼43e44 ꢀC; dH
(400 MHz; CDCl3): 8.03 (d, J¼7.8 Hz, 2H), 7.58e7.53 (m, 1H), 7.50
(dd, J¼7.4, 1.5 Hz, 1H), 7.44 (dd, J¼7.8, 1.4 Hz, 1H), 7.43 (dd, J¼7.8,
7.4 Hz, 2H), 7.24 (ddd, J¼7.8, 7.2, 1.5 Hz, 1H), 7.19 (ddd, J¼7.4, 7.2,
1.4 Hz, 1H), 6.54 (s, 1H), 4.68 (t, J¼6.6 Hz, 2H), 3.27 (t, J¼6.6 Hz, 2H);
dC (100 MHz; CDCl3): 166.4, 155.0, 154.8, 133.0, 130.0, 129.6, 128.7,
128.3, 123.6, 122.6, 120.5, 110.8, 103.5, 62.3, 28.3; nmax 3061, 2962,
4.2.15. 2-n-Butyl-1-methanesulfonylindole (22e). Subjecting aniline
21e (54 mg, 0.22 mmol) to general procedure A followed by

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6477
purification (gradient from 10 to 17% EtOAc in hexane) gave the title
compound as a white solid (50 mg, 93%). The analytical data were in
agreement with literature values.15d Mp¼79e80 ꢀC; dH (400 MHz;
CDCl3): 8.02e7.98 (m, 1H), 7.51e7.47 (m, 1H), 7.30e7.23 (m, 2H),
6.46 (s, 1H), 3.00 (s, 3H), 2.96 (t, J¼7.6 Hz, 2H), 1.75 (app. quintet,
J¼7.6 Hz, 2H), 1.46 (app. sextet, J¼7.6 Hz, 2H), 0.98 (t, J¼7.6 Hz, 3H);
dC (100 MHz; CDCl3): 142.5, 136.8, 129.8, 123.9, 123.6, 120.2, 114.1,
108.4, 40.3, 31.0, 28.6, 22.4, 13.9.
152.1, 130.3, 129.0, 128.9, 128.9, 127.1, 124.9, 122.9, 119.0, 118.9, 112.1,
111.4, 20.8, 17.3; nmax cmꢂ1; 3061, 2930, 2247, 1456, 1443, 1260,
1215, 1177, 1119, 1065, 1007 cmꢂ1; m/z (EI) 247.0991 (Mþ: C17H13NO
requires 247.0997). 26b: mp¼126e128 ꢀC; dH (400 MHz; CDCl3):
7.76e7.71 (m, 3H), 7.69 (d, J¼16.6 Hz, 1H), 7.60e7.52 (m, 4H), 7.42
(ddd, J¼7.7, 7.3, 1.5 Hz, 1H), 7.37 (ddd, J¼7.7, 7.3, 1.3 Hz, 1H), 6.08 (d,
J¼16.6 Hz, 1H); dC (100 MHz; CDCl3): 158.0, 154.5, 142.0, 130.3,
129.1, 129.1, 128.6, 125.9, 125.8, 124.2, 120.4, 118.7, 112.3, 111.9, 96.7;
nmax 3067, 2216, 1620, 1555, 1456, 1441, 1252, 1206, 1136, 1072,
961 cmꢂ1; m/z (EI) 245.0830 (Mþ: C17H11NO requires 245.0841).
4.2.16. 2-n-Butyl-3-deutero-1-methanesulfonylindole (d-22e). Sub-
jecting aniline 21e (55 mg, 0.22 mmol) to general procedure A with
D2O in place of H2O (purification using gradient from 10 to 17%
EtOAc in hexane) gave the title compound as a white solid (50 mg,
4.3.3. 3-[2-(4-Methoxyphenyl)benzofuran-3-yl]propionitrile (25c) and
3-[2-(4-methoxyphenyl)benzofuran- 3-yl]acrylonitrile (26c). Subject-
ing phenol 16c (42 mg, 0.19 mmol) with acrylonitrile (0.13 ml,
1.9 mmol) to general procedure B followed by chromatography
(gradient from 10 to 25% EtOAc in hexane) gave 25c (48 mg, 91%) as
a white solid and 26c (3 mg, 5%) as a white solid. 25c: mp¼96e97 ꢀC;
dH (400 MHz; CDCl3): 7.68 (d, J¼9.0 Hz, 2H), 7.53 (dd, J¼7.5, 1.5 Hz,
1H), 7.50 (dd, J¼7.6, 1.3 Hz, 1H), 7.32 (ddd, J¼7.6, 7.2, 1.5 Hz, 1H), 7.27
(ddd, J¼7.5, 7.2,1.3 Hz,1H), 7.04 (d, J¼9.0 Hz, 2H), 3.88 (s, 3H), 3.29 (t,
J¼7.7 Hz, 2H), 2.73 (J¼7.7 Hz, 2H); dC (100 MHz; CDCl3): 160.1, 153.8,
152.3, 129.2, 128.5, 124.4, 122.9, 122.8, 119.1, 118.6, 114.4, 111.2, 110.8,
55.4, 20.8, 17.3; nmax 2957, 2934, 2837, 2247, 1611, 1508, 1454, 1298,
1252, 1177, 1098, 1032, 833 cmꢂ1; m/z (EI) 277.1105 (Mþ: C18H15NO2
requires 277.1103). 35ca: mp¼122e124 ꢀC; dH (400 MHz; CDCl3):
7.72 (dd, J¼7.0, 1.6 Hz, 1H), 7.67 (d, J¼8.9 Hz, 2H), 7.66 (d, J¼16.6 Hz,
1H), 7.55 (dd, J¼7.8, 1.4 Hz, 1H), 7.39 (ddd, J¼7.8, 7.3, 1.6 Hz, 1H), 7.36
(ddd, J¼7.3, 7.0, 1.4 Hz, 1H), 7.07 (d, J¼8.9 Hz, 2H), 6.04 (d, J¼16.6 Hz,
1H), 3.91 (s, 3H); dC (100 MHz; CDCl3): 161.3, 158.4, 154.3, 142.2,
130.2, 126.1, 125.4, 124.1, 121.5, 120.2, 119.0, 114.6, 111.7, 111.3, 95.8,
55.5; nmax 2934, 2839, 2214, 1607, 1505, 1452, 1422, 1387, 1346, 1304,
1261,1209,1179,1078,1028 cmꢂ1; m/z (EI) 275.0942 (Mþ: C18H13NO2
requires 275.0946).
1
90%, 95% D by H NMR). Mp¼80e81 ꢀC; dH (300 MHz; CDCl3):
8.02e7.97 (m, 1H), 7.52e7.46 (m, 1H), 7.30e7.22 (m, 2H), 3.00 (s,
3H), 2.95 (t, J¼7.6 Hz, 2H), 1.75 (app. quintet, J¼7.6 Hz, 2H), 1.46
(app. sextet, J¼7.6 Hz, 2H), 0.98 (t, J¼7.6 Hz, 3H); dC (100 MHz;
CDCl3): 142.4, 136.8, 129.8, 123.9, 123.6, 120.2, 114.1, 108.2
(J¼26.4 Hz), 40.3, 31.0, 28.5, 22.4, 13.9; nmax 2959, 2932, 2872, 1559,
1452, 1366, 1327, 1223, 1169, 1150, 1047, 1024 cmꢂ1; m/z (EI)
252.1037 (Mþ: C13H16DNO2S requires 252.1043).
4.3. Domino reaction with mono-substituted electron-
withdrawn electrophiles using rac-BINAP (general procedure B)
A solution of [Rh(cod)OH]2 (3 mol %), rac-BINAP (6.6 mol %) in
dioxane (1.0 cm3) and water (0.1 cm3) was flushed with argon and
stirred at room temperature for 15 min. The electrophile was added
followed by a solution of the phenol in dioxane (1.0 cm3) and the
reaction mixture was stirred at 90 ꢀC for 6 h. Et2O (5 cm3) was
added to the reaction mixture and it was filtered (short silica pad)
washing with Et2O (4ꢁ5 cm3). The filtrate was concentrated under
reduced pressure then purified by flash column chromatography to
yield the product.
4.4. 3-[2-(3-Fluorophenyl)benzofuran-3-yl]propionitrile (25d)
4.3.1. 3-(2-n-Butylbenzofuran-3-yl)propionitrile (25a) and 3-(2-n-
butylbenzofuran-3-yl)acrylonitrile (26a). Subjecting phenol 16a
(42 mg, 0.24 mmol) and acrylonitrile (0.16 cm3, 2.4 mmol) to gen-
eral procedure B followed by purification (gradient from 5 to 11%
Et2O in hexane) gave 25a (43 mg, 78%) as a colourless oil and 26a
(3 mg, 5%) as a yellow oil. 25a: dH (400 MHz; CDCl3): 7.43e7.40 (m,
2H), 7.25e7.20 (m, 2H), 3.01 (t, J¼7.3 Hz, 2H), 2.78 (t, J¼7.5 Hz, 2H),
2.64 (t, J¼7.5 Hz, 2H), 1.74 (app. quintet, J¼7.5 Hz, 2H), 1.40 (app.
sextet, J¼7.5 Hz, 2H), 0.96 (t, J¼7.5 Hz, 3H); dC (100 MHz; CDCl3):
156.1, 154.0, 128.2, 123.6, 122.4, 119.1, 118.1, 111.0, 110.7, 30.4, 26.1,
22.4, 20.2, 17.9, 13.8; IR (neat): 2957, 2932, 2862, 2247, 1626, 1456,
1424, 1379, 1325, 1279, 1256, 1211, 1171, 1103, 1065, 1030 cmꢂ1; m/z
(EI) 227.1309 (Mþ: C15H17NO requires 227.1310). Compound 26a: dH
(400 MHz; CDCl3): 7.66e7.62 (m, 1H), 7.49e7.46 (m, 1H), 7.47 (d,
J¼16.5 Hz, 1H), 7.36e7.31 (m, 2H), 5.90 (d, J¼16.5 Hz, 1H), 2.87 (t,
J¼7.5 Hz, 2H), 1.75 (app. quintet, J¼7.5 Hz, 2H), 1.41 (app. sextet,
J¼7.5 Hz, 2H), 0.96 (t, J¼7.5 Hz, 3H); dC (100 MHz; CDCl3): 163.1,
154.3, 141.0, 125.2, 124.8, 123.8, 119.9, 118.9, 112.3, 111.5, 94.3, 30.3,
26.6, 22.3, 13.7; IR (neat): 2959, 2932, 2872, 2216, 1626, 1564, 1478,
1454, 1389, 1209, 1182, 1103, 957 cmꢂ1; m/z (EI) 225.1162 (Mþ:
C15H15NO requires 225.1154).
and 3-[2-(3-fluorophenyl)benzofuran-3-yl] acrylonitrile (26d)
Subjecting phenol 16d (48 mg, 0.22 mmol) with acrylonitrile
(0.15 ml, 2.2 mmol) to general procedure B followed by chroma-
tography (gradient from 10 to 17% EtOAc in hexane) gave 25d
(54 mg, 91%) as a white solid and 26d (1 mg, 1%) as a yellow solid.
25d: mp¼80e81 ꢀC; dH (400 MHz; CDCl3): 7.57e7.49 (m, 3H),
7.49e7.42 (m, 2H), 7.35 (ddd, J¼8.2, 7.6, 1.4 Hz, 1H), 7.29 (ddd, J¼7.6,
7.2, 1.0 Hz, 1H), 7.10 (dddd, J¼8.4, 8.2, 2.5, 1.0 Hz, 1H), 3.29 (t,
J¼7.6 Hz, 2H), 2.73 (t, J¼7.6 Hz, 2H); dC (100 MHz; CDCl3): 162.9 (d,
J¼246.7 Hz), 153.9, 150.6 (d, J¼2.7 Hz), 132.3 (d, J¼8.4 Hz), 130.5 (d,
J¼8.4 Hz), 128.8, 125.3, 123.0, 122.5 (d, J¼3.2 Hz), 119.1, 118.8, 115.7
(d, J¼21.2 Hz), 114.0 (d, J¼23.3 Hz), 113.0, 111.5, 20.7, 17.3; nmax 3073,
2924, 2249, 1614, 1582, 1489, 1456, 1424, 1223, 878 cmꢂ1; m/z (EI)
265.0910 (Mþ: C17H12FNO requires 265.0903). Compound 26d: dH
(400 MHz; CDCl3): 7.75 (dd, J¼7.4, 1.1 Hz, 1H), 7.67 (d, J¼16.6 Hz,
1H), 7.59 (dd, J¼7.3, 1.2 Hz, 1H), 7.54 (ddd, J¼8.0, 7.6, 5.5 Hz, 1H),
7.51e7.42 (m, 3H), 7.39 (ddd, J¼7.6, 7.4, 1.2 Hz, 1H), 7.23 (dddd,
J¼8.4, 8.1, 2.6, 1.3 Hz, 1H), 6.11 (d, J¼16.6 Hz, 1H).
4.5. Ligand-free domino reaction with mono-substituted
electron-withdrawn electrophiles (general procedure C)
4.3.2. 3-(2-Phenylbenzofuran-3-yl)propionitrile (25b) and 3-(2-
phenylbenzofuran-3-yl)acrylonitrile (26b). Subjecting phenol 16b
(43 mg, 0.22 mmol) with acrylonitrile (0.15 ml, 2.2 mmol) to gen-
eral procedure B followed by chromatography (gradient from 5 to
25% Et2O in hexane) gave 25b (51 mg, 92%) as a white solid and 26b
(2 mg, 4%) as a white solid. Compound 25b: Mp¼59e60 ꢀC; dH
(400 MHz; CDCl3): 7.75 (d, J¼7.3 Hz, 2H), 7.58e7.41 (m, 5H), 7.34
(ddd, J¼8.2, 7.2, 1.4 Hz, 1H), 7.29 (ddd, J¼7.6, 7.2, 1.4 Hz, 1H), 3.33 (t,
J¼7.8 Hz, 2H), 2.75 (t, J¼7.8 Hz, 2H); dC (100 MHz; CDCl3): 153.9,
A solution of [Rh(cod)OH]2 (3 mol %), in dioxane (1.0 cm3) and
water (0.1 cm3) was flushed with argon. The electrophile was added
followed by a solution of the phenol/aniline in dioxane (1.0 cm3)
and the reaction mixture was stirred at 90 ꢀC for 6 h. Et2O (5 cm3)
was added to the reaction mixture and it was filtered (short silica
pad) washing with Et2O (4ꢁ5 cm3). The filtrate was concentrated
under reduced pressure then purified by flash column chroma-
tography to yield the product.

6478
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
4.5.1. 1-(2-n-Butylbenzofuran-3-yl)pentan-3-one (28a). Subjecting
phenol 16a (45 mg, 0.26 mmol) with ethyl vinyl ketone (0.25 ml,
2.5 mmol) to general procedure C followed by chromatography
(gradient from 5 to 10% Et2O in hexane) gave the title compound
(46 mg, 70%) as a colourless oil. dH (400 MHz; CDCl3): 7.44e7.36
(m, 2H), 7.23e7.15 (m, 2H), 2.90 (t, J¼7.6 Hz, 2H), 2.76e2.71 (m,
4H), 2.34 (q, J¼7.3 Hz, 2H), 1.68 (app. quintet, J¼7.5 Hz, 2H), 1.38
(app. sextet, J¼7.5 Hz, 2H), 1.04 (t, J¼7.5 Hz, 3H), 0.94 (t, J¼7.3 Hz,
3H); dC (100 MHz; CDCl3): 210.6, 155.0, 153.9, 129.2, 123.1, 122.0,
118.6, 112.9, 110.7, 42.0, 36.2, 30.5, 26.0, 22.4, 17.7, 13.8, 7.7; nmax
2957, 2934, 2872, 1717, 1628, 1456, 1377, 1360, 1256, 1211, 1169,
1113, 1055, 1013 cmꢂ1; m/z (EI) 258.1623 (Mþ: C17H22O2 requires
258.1620).
1.0 Hz,1H), 7.56 (dd, J¼7.7, 1.4 Hz, 1H), 7.49 (ddd, J¼8.0, 2.0,1.0 Hz,1H),
7.49 (dd, J¼8.1, 1.0 Hz, 1H), 7.34 (dd, J¼8.0, 7.8 Hz, 1H), 7.32 (ddd, J¼8.1,
7.3, 1.4 Hz, 1H), 7.26 (ddd, J¼7.7, 7.3, 1.0 Hz, 1H), 3.22 (t, J¼7.8 Hz, 2H),
2.83 (t, J¼7.8 Hz, 2H), 2.43 (q, J¼7.3 Hz, 2H), 1.06 (t, J¼7.3 Hz, 3H); dC
(100 MHz; CDCl3): 210.2, 153.9, 149.1, 133.0, 131.1, 130.3, 129.7, 129.6,
125.1, 125.0, 122.9, 122.7, 119.6, 116.0, 111.2, 41.5, 36.2, 18.3, 7.8; nmax
2974, 2938, 1717, 1586, 1476, 1452, 1408, 1358, 1273, 1211, 1111,
;
1074, 1051 cmꢂ1 m/z (EI) 356.0407 (Mþ: C19H17BrO2 requires
356.0412).
4.5.6. 1-(2-Vinylbenzofuran-3-yl)pentan-3-one
(28l). Subjecting
phenol 16g (45 mg, 0.31 mmol) with ethyl vinyl ketone (0.31 ml,
3.1 mmol) to general procedure C followed by chromatography
(gradient from 5 to 11% Et2O in hexane) gave the title compound
(53 mg, 75%) as a colourless oil. dH (400 MHz; CDCl3): 7.47 (dd,
J¼7.6, 1.3 Hz, 1H), 7.41 (dd, J¼8.2, 1.0 Hz, 1H), 7.26 (ddd, J¼8.2, 7.2,
1.3 Hz, 1H), 7.19 (ddd, J¼7.6, 7.2, 1.0 Hz, 1H), 6.75 (dd, J¼17.3,
11.2 Hz, 1H), 5.92 (dd, J¼17.3, 1.5 Hz, 1H), 5.37 (dd, J¼11.2, 1.5 Hz,
1H), 2.99 (t, J¼7.7 Hz, 2H), 2.74 (t, J¼7.7 Hz, 2H), 2.37 (q, J¼7.3 Hz,
2H), 1.02 (t, J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 210.2, 154.1,
150.4, 129.1, 124.8, 123.1, 122.4, 119.3, 116.4, 114.9, 111.0, 41.8, 36.2,
17.4, 7.7; nmax 2974, 2938, 1715, 1614, 1456, 1414, 1360, 1258, 1115,
4.5.2. 1-(2-Phenylbenzofuran-3-yl)pentan-3-one (28b). Subjecting
phenol 16b (42 mg, 0.22 mmol) with ethyl vinyl ketone (0.21 ml,
2.1 mmol) to general procedure C followed by chromatography
(gradient from 5 to 15% Et2O in hexane) gave the title compound
(56 mg, 94%) as a white solid. mp¼52e53 ꢀC; dH (400 MHz; CDCl3):
7.78 (d, J¼7.2 Hz, 2H), 7.55 (dd, J¼7.9, 1.2 Hz, 1H), 7.52e7.46 (m, 3H),
7.40e7.35 (m, 1H), 7.31 (ddd, J¼7.9, 7.2, 1.4 Hz, 1H), 7.25 (ddd, J¼7.4,
7.2, 1.2 Hz, 1H), 3.23 (t, J¼8.0 Hz, 2H), 2.84 (t, J¼8.0 Hz, 2H), 2.43 (q,
J¼7.3 Hz, 2H), 1.06 (t, J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 210.4,
153.9, 150.8, 131.0, 130.0, 128.7, 128.2, 126.7, 124.4, 122.5, 119.3,
114.8, 111.1, 41.6, 36.1, 18.3, 7.7; nmax 2976, 2937, 1713, 1456, 1443,
1358, 1260, 1213, 1113, 1069, 1026 cmꢂ1; m/z (EI) 278.1307 (Mþ:
C19H18O2 requires 278.1307).
1013, 878 cmꢂ1
228.1150).
;
m/z (EI) 228.1151 (Mþ: C15H16O2 requires
4.5.7. 3-(2-Phenylbenzofuran-3-yl)propionic acid ethyl ester (30b)
and 3-(2-phenylbenzofuran-3-yl)acrylic acid ethyl ester (31b). Ethyl
acrylate (0.04 ml, 0.41 mmol) was added to a solution of phenol
16b (39 mg, 0.20 mmol) in DME (2.0 cm3) and water (0.2 cm3).
The mixture was flushed with argon then [Rh(cod)OH]2 (3 mol %)
was added and the resulting mixture was stirred at 90 ꢀC for 6 h.
The reaction mixture was cooled, Et2O (5 cm3) was added and it
was filtered through a short silica pad, washing with Et2O
(4ꢁ5 cm3). The filtrate was concentrated under reduced pressure,
then purified by column chromatography (gradient from 5 to 11%
Et2O in hexane) to give a mixture of 30b and 31b (51 mg, 85%,
>20:1 30b/31b by 1H NMR) as a colourless oil. Compound 30b: dH
(400 MHz; CDCl3): 7.79 (d, J¼7.2 Hz, 2H), 7.58 (dd, J¼7.6, 1.3 Hz,
1H), 7.51e7.46 (m, 3H), 7.41e7.35 (m, 1H), 7.30 (ddd, J¼7.8, 7.4,
1.3 Hz, 1H), 7.25 (ddd, J¼7.6, 7.4, 1.2 Hz, 1H), 4.12 (q, J¼7.2 Hz, 2H),
3.28 (t, J¼8.2 Hz, 2H), 2.73 (t, J¼8.2 Hz, 2H), 1.21 (t, J¼7.2 Hz, 3H);
dC (100 MHz; CDCl3): 172.7, 153.9, 151.1, 131.0, 129.9, 128.8, 128.3,
126.9, 124.5, 122.5, 119.4, 114.3, 111.1, 60.6, 34.1, 19.8, 14.1. Com-
pound 31b: dH (400 MHz; CDCl3): 8.02 (d, J¼16.0 Hz, 1H), 7.87 (dd,
J¼7.1, 1.7 Hz, 1H), 7.76 (dd, J¼8.1, 1.3 Hz, 2H), 7.54e7.46 (m, 4H),
7.38e7.31 (m, 2H), 6.67 (d, J¼16.0 Hz, 1H), 4.30 (q, J¼7.1 Hz, 2H),
1.36 (t, J¼7.1 Hz, 3H); dC (100 MHz; CDCl3): 167.2, 157.5, 154.4,
135.8, 129.7, 129.7, 128.9, 128.5, 126.7, 125.2, 123.7, 121.0, 119.2,
112.6, 111.5, 60.4, 14.3.
4.5.3. 1-[2-(4-Methoxyphenyl)benzofuran-3-yl]pentan-3-one
(28c). Subjecting phenol 16c (43 mg, 0.19 mmol) with ethyl vinyl
ketone (0.19 ml, 1.9 mmol) to general procedure C followed by
chromatography (gradient from 5 to 15% Et2O in hexane) gave
compound the title compound (54 mg, 91%) as a white solid.
mp¼67e68 ꢀC; dH (400 MHz; CDCl3): 7.71 (d, J¼8.9 Hz, 2H), 7.52
(dd, J¼7.2, 1.5 Hz, 1H), 7.47 (dd, J¼7.4, 1.3 Hz, 1H), 7.28 (ddd, J¼7.4,
7.3, 1.5 Hz, 1H), 7.24 (ddd, J¼7.3, 7.2, 1.3 Hz, 1H), 7.01 (d, J¼8.9 Hz,
2H), 3.87 (s, 3H), 3.19 (t, J¼7.9 Hz, 2H), 2.82 (t, J¼7.9 Hz, 2H), 2.43
(q, J¼7.4 Hz, 2H), 1.05 (t, J¼7.4 Hz, 3H); dC (100 MHz; CDCl3): 210.5,
159.6, 153.7, 151.0, 130.1, 128.2, 124.0, 123.6, 122.4, 119.1, 114.2,
113.2, 110.9, 55.3, 41.6, 36.1, 18.3, 7.7; nmax 2974, 2935, 2837, 1715,
1613, 1510, 1456, 1298, 1252, 1179, 1113, 1094, 1030, 833 cmꢂ1; m/z
(EI) 308.1417 (Mþ: C20H20O3 requires 308.1412).
4.5.4. 1-[2-(3-Fluorophenyl)benzofuran-3-yl]pentan-3-one (28d).
Subjecting phenol 16d (45 mg, 0.22 mmol) with ethyl vinyl ketone
(0.21 ml, 2.1 mmol) to general procedure C followed by chroma-
tography (gradient from 5 to 11% Et2O in hexane) gave the title
compound (54 mg, 86%) as a white solid. mp¼72e73 ꢀC; dH
(400 MHz; CDCl3): 7.58e7.54 (m, 2H), 7.51 (ddd, J¼9.9, 2.5, 1.8 Hz,
1H), 7.49 (dd, J¼8.0, 1.2 Hz, 1H), 7.44 (ddd, J¼8.2, 7.8, 6.0 Hz, 1H),
7.33 (ddd, J¼8.0, 7.4, 1.4 Hz, 1H), 7.26 (ddd, J¼7.4, 7.0, 1.2 Hz, 1H),
7.07 (dddd, J¼8.4, 8.2, 2.5, 1.0 Hz, 1H), 3.23 (t, J¼7.8 Hz, 2H), 2.84 (t,
J¼7.8 Hz, 2H), 2.43 (q, J¼7.3 Hz, 2H), 1.06 (t, J¼7.3 Hz, 3H); dC
(100 MHz; CDCl3): 210.1, 162.9 (d, J¼246.1 Hz), 153.8, 149.4 (d,
J¼2.6 Hz),133.0 (d, J¼8.5 Hz),130.3 (d, J¼8.5 Hz),129.8,124.9,122.7,
122.2 (d, J¼3.0 Hz), 119.6, 115.8, 115.1 (d, J¼21.3 Hz), 113.6 (d,
J¼23.4 Hz), 111.2, 41.4, 36.1, 18.3, 7.7; nmax 2976, 2938, 1715, 1614,
1582, 1491, 1456, 1360, 1229, 1223, 1184, 1115, 880 cmꢂ1; m/z (EI)
296.1213 (Mþ: C19H17FO2 requires 296.1213).
4.5.8. tert-Butyl 3-(2-phenylbenzofuran-3-yl)propanoate (33b) and
(E)-tert-butyl 3-(2-phenylbenzofuran-3-yl)acrylate (34b). Subject-
ing phenol 16b (40 mg, 0.20 mmol) with tert-butyl acrylate
(0.06 ml, 0.41 mmol) to general procedure C followed by chro-
matography (gradient from 5 to 11% Et2O in hexane) gave a mix-
ture of 33b and 34b (51 mg, 77%, >20:1 33b/34b by 1H NMR) as
a colourless oil. Compound 33b: dH (400 MHz; CDCl3): 7.80 (dd,
J¼8.4, 1.3 Hz, 2H), 7.60 (dd, J¼7.4, 1.6 Hz, 1H), 7.52e7.46 (m, 3H),
7.38 (tt, J¼7.4, 1.3 Hz, 1H), 7.30 (ddd, J¼7.9, 7.2, 1.6 Hz, 1H), 7.25
(ddd, J¼7.4, 7.2, 1.1 Hz, 1H), 3.24 (t, J¼8.2 Hz, 2H), 2.65 (t, J¼8.2 Hz,
2H), 1.42 (s, 9H); dC (100 MHz; CDCl3): 172.1, 153.1, 151.0, 131.0,
130.0, 128.7, 128.3, 126.9, 124.4, 122.5, 119.6, 114.5, 111.1, 80.6, 35.3,
28.1, 20.0; nmax 2978, 1732, 1589, 1476, 1456, 1443, 1393, 1368,
4.5.5. 1-(2-(3-Bromophenyl)benzofuran-3-yl)pentan-3-one (28f). Sub-
jecting phenol 16f (43 mg, 0.16 mmol) with ethyl vinyl ketone
(0.16 cm3, 1.6 mmol) to general procedure C followed by chromatog-
raphy (gradient from 5 to 11% Et2O in hexane) gave the title
1258, 1211, 1146, 1065, 1009 cmꢂ1
;
m/z (EI) 322.1568 (Mþ:
compound (45 mg, 80%) as
(400 MHz; CDCl3): 7.95 (dd, J¼2.0, 1.6 Hz, 1H), 7.70 (ddd, J¼7.8, 1.6,
a
white solid. mp¼72e73 ꢀC; dH
C21H22O3 requires 322.1569). Compound 34b: dH (400 MHz;
CDCl3): 7.97 (d, J¼16.0 Hz, 1H), 7.90 (dd, J¼6.9, 1.7 Hz, 1H), 7.79

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6479
(dd, J¼7.0, 1.5 Hz, 2H), 7.57e7.44 (m, 4H), 7.38 (ddd, J¼7.8, 7.3,
1.7 Hz, 1H), 7.34 (d, J¼7.3, 6.9, 1.4 Hz, 1H), 6.62 (d, J¼16.0 Hz, 1H),
1.56 (s, 9H); dC (100 MHz; CDCl3): 166.6, 157.3, 154.5, 134.8, 129.8,
129.6, 128.9, 128.5, 126.9, 125.2, 123.6, 121.1, 121.1, 112.7, 111.5,
80.5, 28.3.
1088, 1034, 1011 cmꢂ1; m/z (ESI) 372.1233 (MþþNa: C18H23NO4SNa
requires 372.1240).
4.6. Typical domino reaction with 2-cyclohexene
A solution of [Rh(cod)OH]2 (4 mg, 3 mol %, 6 mol % Rh) and
Tol-BINAP (12 mg, 6 mol %) in dioxaneewater (1 cm3, 10:1) was
stirred at room temperature for 0.5 h. A solution of phenol 16a
(50 mg, 0.29 mmol) and 2-cyclohexenone (0.14 cm3, 1.4 mmol) in
dioxane (1 cm3) was added and the mixture was heated to 90 ꢀC
for 6 h. The reaction was cooled to room temperature, diluted
with Et2O (5 cm3) and filtered through a short pad of silica,
washing with Et2O (4ꢁ5 cm3). The filtrate was concentrated un-
der reduced pressure and purified by column chromatography
(gradient from 0 to 3% Et2O in pentane) to give 17a (7 mg, 14%)
followed by 42a (1 mg, 2%), then 41a (24 mg, 47%) and 40a (3 mg,
9%) all as pale yellow oils.
4.5.9. 3-(2-n-Butyl-1-methanesulfonylindol-3-yl)propionitrile (35e)
and 3-(2-n-butyl-1-methanesulfonylindol-3-yl)acrylonitrile (36e).
Subjecting aniline 67 (50 mg, 0.20 mmol) with acrylonitrile
(0.13 ml, 2.0 mmol) to general procedure B followed by chroma-
tography (gradient from 9 to 25% EtOAc in hexane) gave 35e
(53 mg, 88%) as a white solid and 36e (2 mg, 3%) as a white solid.
Compound 35e: mp¼100e101 ꢀC; dH (400 MHz; CDCl3): 8.08e8.03
(m, 1H), 7.46e7.41 (m, 1H), 7.36e7.29 (m, 2H), 3.07 (t, J¼7.3 Hz, 2H),
2.99 (t, J¼7.6 Hz, 2H), 2.96 (s, 3H), 2.67 (t, J¼7.3 Hz, 2H), 1.72e1.63
(m, 2H), 1.42 (app. sextet, J¼7.4 Hz, 2H), 0.96 (t, J¼7.4 Hz, 3H); dC
(100 MHz; CDCl3): 139.6, 136.4, 129.3, 124.7, 123.9, 118.8, 117.9,
116.7, 114.9, 40.0, 33.1, 26.0, 22.7, 20.4, 17.9, 13.8; nmax 2959, 2932,
2872, 2247, 1607, 1454, 1362, 1329, 1242, 1171, 1082 cmꢂ1; m/z (EI)
304.1251 (Mþ: C16H20N2O2S requires 304.1245). 36e:
mp¼116e118 ꢀC; dH (400 MHz; CDCl3): 8.11e8.06 (m, 1H),
7.74e7.69 (m, 1H), 7.54 (d, J¼16.7 Hz, 1H),7.427.37 (m, 2H), 5.98 (d,
J¼16.7 Hz, 1H), 3.12 (s, 3H), 3.08 (t, J¼7.4 Hz, 2H), 1.72e1.64 (m, 2H),
1.50e1.41 (m, 2H), 0.97 (t, J¼7.4 Hz, 3H); dC (100 MHz; CDCl3):
145.1, 141.4, 136.2, 126.6, 125.4, 124.8, 119.6, 118.8, 115.2, 114.6, 96.4,
41.4, 33.3, 26.0, 22.7, 13.7; nmax 2959, 2932, 2872, 2214, 1616, 1452,
4.6.1. 3-(2-Butylbenzofuran-3-yl)cyclohexanone (40a). The analyti-
cal data were in agreement with literature values.16 dH (400 MHz;
CDCl3): 7.62e7.59 (m, 1H), 7.44e7.40 (m, 1H), 7.26e7.17 (m, 2H),
3.14 (dddd, J¼12.9, 12.9, 3.8, 3.8 Hz, 1H), 2.93 (t, J¼13.7 Hz, 1H), 2.73
(t, J¼7.5 Hz, 2H), 2.57e2.42 (m, 3H), 2.35e2.19 (m, 2H), 2.04e1.97
(m, 1H), 1.88e1.74 (m, 1H), 1.72e1.64 (m, 2H), 1.42e1.32 (m, 2H),
0.94 (t, J¼7.4 Hz, 3H); dC (100 MHz; CDCl3): 210.60, 154.14, 154.12,
127.63, 123.10, 121.94, 119.55, 116.12, 111.15, 47.40, 41.29, 36.44,
31.03, 30.65, 26.26, 25.85, 22.30, 13.78.
1368, 1329, 1175, 1090 cmꢂ1
C16H19N2O2S requires 303.1161).
;
m/z (ESI) 303.1165 (MþþH:
4.6.2. (E)-2-(2-n-Butyl-2-(2-n-butylbenzofuran-3-yl)vinyl)phenol
(41a). dH (400 MHz; CDCl3): 7.54e7.51 (m, 1H), 7.45e7.42 (m, 1H),
7.27e7.19 (m, 4H), 6.99e6.93 (m, 2H), 6.45 (s, 1H), 5.00 (s, 1H), 2.87
(dd, J¼7.5, 7.8 Hz, 2H), 2.54 (dd, J¼7.8, 7.2 Hz, 2H), 1.82e1.74 (m, 2H),
1.44 (ddt, J¼14.7, 7.3, 7.4 Hz, 2H), 1.33e1.16 (m, 4H), 0.96 (t, J¼7.4 Hz,
3H), 0.74 (t, J¼7.2 Hz, 3H); dC (100 MHz;CDCl3): 155.50,153.79,152.96,
139.39, 129.74, 128.78, 128.69, 124.02, 124.00, 123.37, 122.41, 120.33,
119.58, 117.56, 115.18, 110.83, 31.28, 30.63, 30.58, 26.83, 22.56, 22.49,
13.84, 13.72; m/z (EI) 348.2094 (Mþ: C24H28O2 requires 348.2089).
4.5.10. 1-(2-n-Butyl-1-methanesulfonylindol-3-yl)pentan-3-one
(37e). Subjecting aniline 21e (47 mg, 0.19 mmol) with ethyl vinyl
ketone (0.19 ml, 1.9 mmol) to general procedure C followed by
chromatography (gradient from 10 to 17% EtOAc in hexane) gave
the title compound (60 mg, 94%) as a white solid. mp¼58e59 ꢀC; dH
(400 MHz; CDCl3): 8.04e7.99 (m, 1H), 7.47e7.43 (m, 1H), 7.32e7.27
(m, 2H), 2.98e2.93 (m, 4H), 2.92 (s, 3H), 2.71 (t, J¼7.7 Hz, 2H), 2.42
(q, J¼7.3 Hz, 2H), 1.63 (app. quintet, J¼7.5 Hz, 2H), 1.41 (app. sextet,
J¼7.5 Hz, 2H), 1.06 (t, J¼7.3 Hz, 3H), 0.94 (t, J¼7.5 Hz, 3H); dC
(100 MHz; CDCl3): 210.3, 138.1, 136.3, 130.2, 124.2, 123.6, 119.4,
118.4, 114.6, 42.0, 39.8, 36.1, 33.0, 25.8, 22.7, 18.3, 13.8, 7.7; nmax
2959, 2934, 2872, 1713, 1607, 1454, 1412, 1362, 1240, 1171, 1153,
1113, 1067, 964 cmꢂ1; m/z (ESI) 336.1645 (MþþH: C18H26NO3S re-
quires 336.1627).
4.6.3. (E)-2-(1-(2-n-Butyl-benzofuran-3-yl)hex-1-enyl)phenol
(42a). dH (400 MHz; CDCl3): 7.38 (d, J¼8.1 Hz, 1H), 7.28e7.16 (m,
3H), 7.12 (td, J¼7.8, 1.0 Hz, 1H), 7.04 (dd, J¼7.6, 1.7 Hz, 1H), 6.97 (dd,
J¼8.2, 1.1 Hz, 1H), 6.88 (ddd, J¼7.5, 7.5, 1.2 Hz, 1H), 6.18 (t, J¼7.5 Hz,
1H), 5.28 (s, 1H), 2.58 (t, J¼7.6 Hz, 2H), 2.22e2.16 (m, 2H), 1.62e1.24
(m, 8H), 0.91e0.83 (m, 6H).
4.5.11. 3-(2-n-Butyl-1-methanesulfonylindol-3-yl)propionic
acid
ethyl ester (38e) and 3-(2-n-butyl-1-methane sulfonylindol-3-yl)
acrylic acid ethyl ester (39e). Subjecting aniline 21e (48 mg,
0.19 mmol) and ethyl acrylate (0.042 cm3, 0.39 mmol) to general
procedure C followed chromatography (gradient from 9 to 17% Et2O
in hexane) to give 38e and 39e (59.9 mg, 89%, >40:1 37e/39e by 1H
NMR). Compound 38e: colourless oil. dH (400 MHz; CDCl3):
8.04e7.99 (m, 1H), 7.52e7.47 (m, 1H), 7.32e7.27 (m, 2H), 4.13 (q,
J¼7.2 Hz, 2H), 3.01 (t, J¼8.0 Hz, 2H), 2.95 (t, J¼7.8 Hz, 2H), 2.92 (s, 3H),
2.60 (t, J¼8.0 Hz, 2H), 1.67e1.61 (m, 2H), 1.41 (app. sextet, J¼7.4 Hz,
2H),1.24 (t, J¼7.2 Hz, 3H), 0.95 (t, J¼7.4 Hz, 3H); dC (100 MHz; CDCl3):
172.7, 138.4, 136.4, 130.2, 124.3, 123.6, 119.1, 118.5, 114.6, 60.6, 39.8,
34.4, 33.0, 25.9, 22.7,19.7,14.2,13.8; nmax 2959, 2932, 2872,1732,1607,
1454,1362,1242,1171,1119,1080,1047,1020 cmꢂ1; m/z (ESI) 352.1586
(MþþH: C18H26NO4S requires 352.1577). 39e: white solid.
Mp¼132e133 ꢀC; dH (400 MHz; CDCl3): 8.10e8.05 (m,1H), 7.90e7.84
(m,1H), 7.88 (d, J¼16.2 Hz,1H), 7.39e7.34 (m, 2H), 6.58 (d, J¼16.2 Hz,
1H), 4.30 (q, J¼7.2 Hz, 2H), 3.15 (t, J¼7.8 Hz, 2H), 3.09 (s, 3H),
1.74e1.62 (m, 2H), 1.50e1.39 (m, 2H), 1.37 (t, J¼7.2 Hz, 3H), 0.96 (t,
J¼7.4 Hz, 3H); dC (100 MHz; CDCl3): 167.4, 144.8, 136.3, 135.3, 127.5,
125.0, 124.5, 120.2, 118.7, 115.9, 114.4, 60.5, 41.0, 33.2, 25.9, 22.6, 14.4,
13.7; nmax 2959, 2932, 2874, 1705, 1628, 1452, 1366, 1306, 1277, 1169,
4.6.4. (1,2,3,4-Tetrahydrodibenzofuran-1-yl)acetic acid methyl ester
(40m) and 6-benzofuran-2-ylhex-2-enoic acid methyl ester (17m).
Subjecting phenol 16m (42 mg, 0.17 mmol) to general procedure C
(with DME in place of dioxane) followed by chromatography (gra-
dient from 5 to 20% Et2O in hexane) gave 40m (30 mg, 70%) as
a colourless oil, followed by 17m (3 mg, 8%) as a colourless oil. 40m:
dH (400 MHz; CDCl3): 7.45, (dd, J¼7.2, 1.7 Hz, 1H), 7.40, (dd, J¼7.6,
1.6 Hz, 1H), 7.21 (ddd, J¼7.6, 7.4, 1.7 Hz, 1H), 7.18 (ddd, J¼7.4, 7.2,
1.6 Hz, 1H), 3.72 (s, 3H), 3.50e3.42 (m, 1H), 2.94 (dd, J¼15.4, 4.3 Hz,
1H), 2.78e2.68 (m, 2H), 2.42 (dd, J¼15.4, 10.1 Hz, 1H), 2.02e1.85 (m,
3H), 1.76e1.67 (m, 1H); dC (100 MHz; CDCl3): 173.1, 154.4, 154.4,
127.6, 123.1, 122.2, 118.8,114.9, 111.0, 51.6, 38.9, 29.0, 28.3, 23.4, 19.5;
nmax 2945, 1738, 1634, 1476, 1454, 1435, 1360, 1269, 1192, 1167, 1071,
1013 cmꢂ1; m/z (ESI) 267.1004 (MþþNa): C15H16O3Na requires
267.0991. Compound 17m: dH (400 MHz; CDCl3): 7.48 (dd, 7.5,
1.6 Hz, 1H), 7.41 (dd, 7.8, 1.2 Hz, 1H), 7.21 (ddd, J¼7.8, 7.2, 1.6 Hz, 1H),
7.18 (ddd, J¼7.5, 7.2, 1.2 Hz, 1H), 6.98 (dt, J¼15.6, 7.0 Hz, 1H), 6.39 (s,
1H), 5.86 (dt, J¼15.6, 1.5 Hz, 1H), 3.73 (s, 3H), 2.80 (t, J¼7.2 Hz, 2H),
2.31 (ddt, J¼7.6, 7.0, 1.5 Hz, 2H), 1.93 (tt, J¼7.6, 7.2 Hz, 2H); dC
(100 MHz; CDCl3): 167.0, 158.3, 154.7, 148.4, 128.8, 123.2, 122.5,
121.6, 120.2, 110.7, 102.4, 51.4, 31.4, 27.7, 26.0; nmax 2949, 1728, 1659,

6480
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
1603, 1587, 1456, 1435, 1275, 1198, 1175, 1148, 1084, 1042 cmꢂ1; m/z
1178, 1092, 1031 cmꢂ1; m/z (EI) 383.1892 (Mþ: C26H25NO2 requires
383.1885).
(EI) 244.1096 (Mþ: C15H16O3 requires 244.1099).
4.7. Domino reaction with pyridyl alkynes: general
procedure D
4.7.4. (E)-2-(2-(2-(3-Fluorophenyl)benzofuran-3-yl)hex-1-enyl)pyri-
dine (46d). Subjecting phenol 16d (61 mg, 0.29 mmol) with 2-(1-
hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(6 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave the title compound (81 mg,
76%) as a pale yellow solid. mp¼73e75 ꢀC, dH (400 MHz; CDCl3):
8.70 (d, J¼4.6 Hz, 1H), 7.74 (d, J¼7.9 Hz, 1H), 7.72e7.64 (m, 2H), 7.63
(d, J¼7.8 Hz, 1H,), 7.53 (d, J¼8.2 Hz, 1H), 7.40e7.31 (m, 2H),
7.30e7.24 (m, 2H), 7.17 (dd, J¼7.4, 4.5 Hz,1H), 7.02 (td, J¼8.3, 2.5 Hz,
1H), 6.73 (s, 1H), 3.06e3.00 (m, 2H), 1.49e1.39 (m, 2H), 1.26 (app.
sextet, J¼7.4 Hz, 2H), 0.76 (t, J¼7.2 Hz, 3H); dC (100 MHz; CDCl3):
162.9 (d, J¼251.3 Hz),156.4,153.9,149.5,148.6,139.4, 136.1,132.9 (d,
J¼8.5 Hz), 130.9, 130.4, 130.1 (d, J¼8.4 Hz), 125.0, 124.3, 123.0,
122.45 (d, J¼3.1 Hz), 121.4, 121.0, 120.5, 115.1 (d, J¼21.4 Hz), 113.5 (d,
J¼23.7 Hz), 111.1, 32.0, 30.8, 22.9, 13.8; nmax 2957, 2926, 2855, 1613,
1585, 1454, 1428, 1222, 1180, 1157, 1095 cmꢂ1; m/z (EI) 371.1691
(Mþ: C25H22FNO requires 371.1685).
A solution of [Rh(cod)OH]2 (3 or 6 mol %) and tris(2,5-dime-
thylphenyl)phosphine (1.0 equiv per atom of Rh) in a mixture of
dioxane and water (0.24 M) was stirred at ambient temperature for
30 min. The catalyst solution was added to the phenol/indole and
alkyne. Lithium bromide (5.0 equiv) was added, the reaction vessel
was flushed with argon and the mixture was stirred at 90 ꢀC for
24 h. The reaction mixture was cooled to ambient temperature and
filtered through a short silica pad, washing with ethyl acetate (5ꢁ).
The filtrate was concentrated under vacuum and purified by flash
column chromatography.
4.7.1. (E)-2-(2-(2-n-Butylbenzofuran-3-yl)hex-1-enyl)pyridine
(46a). Subjecting phenol 16a (50 mg, 0.29 mmol) with 2-(1-hex-
ynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D (6 mol %
[Rh(cod)OH]2) followed by chromatography (gradient from 0 to
20% EtOAc in hexane) gave the title compound (85 mg, 83%) as
a yellow oil. dH (400 MHz; CDCl3): 8.66 (ddd, J¼4.8, 1.8, 0.8 Hz, 1H),
7.67 (ddd, J¼7.8, 7.7, 1.8 Hz, 1H), 7.57e7.54 (m, 1H), 7.45e7.42 (m,
1H), 7.28 (br d, J¼7.8 Hz, 1H), 7.26e7.18 (m, 2H), 7.14 (ddd, J¼7.7, 4.8,
1.1 Hz, 1H), 6.56 (s, 1H), 3.05 (t, J¼7.3 Hz, 2H), 2.87 (t, J¼7.5 Hz, 2H),
1.82e1.73 (m, 2H), 1.48e1.36 (m, 4H), 1.36e1.26 (m, 2H), 0.95 (t,
J¼7.4 Hz, 3H), 0.82 (t, J¼7.2 Hz, 3H); dC (100 MHz; CDCl3): 156.77,
155.31, 153.84, 149.31, 139.89, 135.96, 129.42, 128.99, 124.15, 123.23,
122.31, 121.07, 119.83, 118.84, 110.73, 31.29, 30.68, 30.59, 26.81,
22.72, 22.57, 13.88, 13.84; nmax 2957, 2929, 2871, 2860, 1632, 1584,
1559, 1471, 1455, 1427, 1379, 1255, 1175, 1013 cmꢂ1; m/z (EI)
333.2099 (Mþ: C23H27NO requires 333.2093).
4.7.5. (E)-2-(2-(2-(2-Bromophenyl)benzofuran-3-yl)hex-1-enyl)pyr-
idine (46e). Subjecting phenol 16e (79 mg, 0.29 mmol) with 2-(1-
hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(3 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave 17e (40 mg, 51%) followed by
the title compound 46e (46 mg, 37%) as a white solid. 46e:
mp¼48e50 ꢀC, dH (400 MHz; CDCl3): 8.64 (d, J¼4.6 Hz, 1H), 7.81
(dd, J¼7.7, 1.3 Hz, 1H), 7.71 (dd, J¼7.9, 1.3 Hz, 1H), 7.64 (td, J¼7.7,
2.0 Hz, 1H), 7.58e7.52 (m, 2H), 7.37 (tt, J¼7.9, 1.4 Hz, 2H), 7.34e7.27
(m, 2H), 7.22 (d, J¼7.9 Hz, 1H), 7.11 (ddd, J¼7.5, 4.9, 1.0 Hz, 1H), 6.81
(s,1H), 2.77e2.71 (m, 2H),1.42e1.33 (m, 2H),1.21e1.12 (m, 2H), 0.73
(t, J¼7.2 Hz, 3H); dC (100 MHz; CDCl3): 156.7, 154.5, 150.5, 149.3,
138.9,135.9,133.2,132.8,132.6,130.8,130.1,128.7,127.1,124.7,124.3,
124.2, 122.9, 121.3, 121.1, 120.8, 111.4, 30.8, 30.6, 22.7, 13.7; nmax
3056, 3004, 2956, 2928, 2870, 1738, 1629, 1585, 1472, 1448, 1428,
1246, 1200, 1093, 1027 cmꢂ1; m/z (EI) 431.0892 (Mþ: C25H22BrNO
requires 431.0885).
4.7.2. (E)-2-(2-(2-Phenylbenzofuran-3-yl)hex-1-enyl)pyridine
(46b). Subjecting phenol 16b (56 mg, 0.29 mmol) with 2-(1-
hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(6 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave the title compound (85 mg,
83%) as colourless plates. Mp¼64e66 ꢀC, dH (400 MHz; CDCl3):
8.69 (dd, J¼4.8, 0.8 Hz, 1H), 7.94 (d, J¼7.6 Hz, 2H), 7.68 (td, J¼7.6,
2.0 Hz, 1H), 7.63 (dd, J¼7.6, 0.4 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.42
(t, J¼7.6 Hz, 2H), 7.35e7.30 (m, 2H), 7.29e7.23 (m, 2H), 7.16 (ddd,
J¼7.6, 4.8, 0.8 Hz, 1H), 6.75 (s, 1H), 3.03 (dd, J¼9.6, 6.4 Hz, 2H),
1.48e1.37 (m, 2H), 1.25 (app. sextet, J¼7.6 Hz, 2H), 0.75 (t,
J¼7.6 Hz, 3H); dC (100 MHz; CDCl3): 156.7, 153.9, 150.1, 149.4,
139.9, 136.1, 131.0, 130.6, 130.5, 128.5, 128.3, 126.9, 124.5, 124.3,
122.8, 121.3, 120.3, 119.9, 111.0, 31.8, 30.9, 22.9, 13.8; nmax 3006,
3005, 2956, 2928, 2870, 2858, 1635, 1584, 1559, 1472, 1454, 1443,
1427, 1257, 1092, 1064 cmꢂ1; m/z (EI) 353.1775 (Mþ: C25H23NO
requires 353.1780).
4.7.6. (E)-2-(2-(2-(3-Bromophenyl)benzofuran-3-yl)hex-1-enyl)pyr-
idine (46f). Subjecting phenol 16f (20 mg, 0.07 mmol) with 2-(1-
hexynyl)-pyridine (12 mg, 0.07 mmol) to general procedure D (3 mol
% [Rh(cod)OH]2) followed bychromatography (gradient from 0 to 20%
EtOAc inhexane) gavethetitlecompound (21 mg, 55%)asayellowoil.
dH (400 MHz; CDCl3): 8.70 (d, J¼4.4 Hz, 1H), 8.13 (br s, 1H), 7.87 (d,
J¼7.9 Hz,1H), 7.69 (dt, J¼7.6,1.6 Hz,1H), 7.63 (d, J¼7.7 Hz,1H), 7.53 (d,
J¼8.1 Hz, 1H), 7.45 (d, J¼7.7 Hz, 1H), 7.34 (t, J¼7.3 Hz, 1H), 7.30e7.24
(m, 3H), 7.17 (dd, J¼7.1, 5.1 Hz, 1H), 6.74 (s, 1H), 3.05e2.97 (m, 2H),
1.49e1.37 (m, 2H), 1.31e1.21 (m, 2H), 0.76 (t, J¼7.3 Hz, 3H); m/z (EI)
431.0896 (Mþ: C25H22BrNO requires 431.0885).
4.7.7. (E)-2-(3-(1-(Pyridin-2-yl)hex-1-en-2-yl)benzofuran-2-yl)ethyl
benzoate (46g). Subjecting phenol 16g (77 mg, 0.29 mmol) with 2-
(1-hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(3 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave the title compound (107 mg,
87%) as a yellow oil. dH (400 MHz; CDCl3): 8.65 (d, J¼5.5 Hz, 1H),
8.01 (d, J¼8.3 Hz, 2H), 7.64 (t, J¼7.6 Hz, 1H), 7.57 (d, J¼7.6 Hz, 1H),
7.52 (t, J¼7.1 Hz, 1H), 7.45 (d, J¼8.3 Hz, 1H), 7.38 (t, J¼8.3 Hz, 2H),
7.30e7.16 (m, 3H), 7.13 (dd, J¼7.3, 5.1 Hz, 1H), 6.58 (s, 1H), 4.73 (t,
J¼6.8 Hz, 2H), 3.36 (t, J¼5.5 Hz, 2H), 3.10e3.03 (m, 2H), 1.45e1.34
(m, 2H), 1.33e1.21 (m, 2H), 0.78 (t, J¼7.8 Hz, 3H); dC (100 MHz;
CDCl3): 166.4, 156.5, 154.1, 150.5, 149.3, 139.3, 136.0, 132.9, 130.1,
129.8,129.7,128.6,128.3,124.3,123.9,122.6,121.2,121.0,120.1,111.0,
62.7, 31.3, 30.7, 27.0, 22.7, 13.8; nmax 3425, 3062, 3005, 2956, 2930,
2871, 1725, 1715, 1634, 1603, 1583, 1559, 1472, 1454, 1428, 1385,
4.7.3. (E)-2-(2-(2-(4-Methoxyphenyl)benzofuran-3-yl)hex-1-enyl)
pyridine (46c). Subjecting phenol 16c (65 mg, 0.29 mmol) with 2-
(1-hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(6 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave the title compound (94 mg,
85%) as a yellow oil. dH (400 MHz; CDCl3): 8.69 (d, J¼4.4 Hz, 1H),
7.87 (d, J¼8.8 Hz, 2H), 7.68 (td, J¼7.7, 1.7 Hz, 1H), 7.60 (d, J¼7.7 Hz,
1H), 7.50 (d, J¼8.0 Hz, 1H), 7.31e7.21 (m, 3H), 7.15 (dd, J¼7.7, 4.8 Hz,
1H), 6.95 (d, J¼8.8 Hz, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 3.04e2.98 (m,
2H), 1.48e1.38 (m, 2H), 1.24 (app. sextet, J¼7.3 Hz, 2H), 0.75 (t,
J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 159.8, 156.8, 153.7, 150.3, 149.9,
140.1,136.0, 130.7,130.5,128.4,124.3,124.1,123.7,122.7,121.2,120.0,
118.3, 114.0, 110.9, 55.3, 31.8, 30.9, 22.9, 13.8; nmax 3057, 3003, 2956,
2931, 2870, 2837, 1612, 1583, 1559, 1505, 1454, 1427, 1303, 1249,

A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
6481
1267, 1176, 1111, 1071, 1027 cmꢂ1; m/z (ESI) 426.2056 (MþþH:
122.56, 119.83, 118.78, 110.88, 31.38, 30.74, 30.57, 26.94, 22.65,
22.61, 13.89, 13.80; nmax 2959, 2932, 2873, 2863, 1594, 1455, 1320,
1165, 1137, 1090, 1054 cmꢂ1; m/z (EI) 435.1577 (Mþ: C24H25ClF3NO
requires 435.1577).
C28H28NO3 requires 426.2063).
4.7.8. (E)-2-(2-(5-Chloro-2-phenylbenzofuran-3-yl)hex-1-enyl)pyri-
dine (46i). Subjecting phenol 16i (66 mg, 0.29 mmol) with 2-(1-
hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(6 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 20% EtOAc in hexane) gave the title compound (84 mg,
75%) as a white solid. mp 110e112 ꢀC. dH (400 MHz; CDCl3): 8.70
(d, J¼4.5 Hz, 1H), 7.92 (d, J¼7.9 Hz, 2H), 7.69 (td, J¼7.5, 1.3 Hz, 1H),
7.57 (d, J¼1.6 Hz, 1H), 7.46e7.40 (m, 3H), 7.35 (t, J¼7.2 Hz, 1H),
7.30e7.25 (m, 2H), 7.17 (dd, J¼7.5, 4.9 Hz, 1H), 6.72 (s, 1H),
3.03e2.97 (m, 2H), 1.47e1.37 (m, 2H), 1.30e1.19 (m, 2H), 0.76 (t,
J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 156.4, 152.2, 151.5, 149.4,
139.2, 136.1, 132.0, 130.9, 130.4, 128.7, 128.6, 128.5, 126.9, 124.7,
124.4, 121.4, 119.8, 119.4, 112.1, 31.8, 30.9, 22.9, 13.8; nmax 2956,
2926, 2855, 1727, 1631, 1583, 1462, 1452, 1440, 1260, 1204, 1093,
1068, 1027 cmꢂ1; m/z (EI) 387.1391 (Mþ: C25H22NOCl requires
387.1390).
4.7.12. (E)-4-(2-butylbenzofuran-3-yl)-5-(pyridin-2-yl)pent-4-en-1-ol
(61a). Subjecting phenol 16a (50 mg, 0.29 mmol) with 60 (46 mg,
0.29 mmol) to general procedure D (6 mol % [Rh(cod)OH]2) followed
by chromatography (gradient from 30 to 50% EtOAc in pentane) gave
the title compound (70 mg, 73%) as a yellow oil. dH (400 MHz;
CDCl3): 8.59 (d, J¼4.5 Hz, 1H), 7.72 (td, J¼7.7, 1.9, 1H), 7.54 (d,
J¼7.3 Hz, 1H), 7.44 (d, J¼8.0 Hz, 1H), 7.27e7.24 (m, 1H), 7.23e7.17 (m,
3H), 6.63 (s, 1H), 6.61 (br s, 1H), 3.65 (br d, J¼4.6 Hz, 2H), 3.28e3.22
(m, 2H), 2.84 (t, J¼8.4 Hz, 2H), 1.79e1.70 (m, 2H), 1.69e1.62 (m, 2H),
1.46e1.36 (m, 2H), 0.94 (t, J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 156.0,
155.6, 154.0, 148.3, 139.4, 137.2, 129.6, 128.4, 125.5, 123.5, 122.5, 121.8,
119.8, 117.8, 110.9, 59.4, 30.6, 29.8, 27.0, 26.5, 22.6, 13.9; nmax 3287,
3057, 2930, 2860, 1725, 1634, 1588, 1560, 1473, 1454, 1428, 1377,
1255, 1234, 1176, 1155, 1077, 1014 cmꢂ1; m/z (EI) 335.1894 (Mþ:
C22H25NO2 requires 335.1885).
4.7.9. (E)-Methyl 2-phenyl-3-(1-(pyridin-2-yl)hex-1-en-2-yl)benzo-
furan-5-carboxylate (46j). Subjecting phenol 16j (73 mg,
0.29 mmol) with 2-(1-hexynyl)-pyridine (46 mg, 0.29 mmol) to
general procedure D (3 mol % [Rh(cod)OH]2) followed by chroma-
tography (gradient from 0 to 20% EtOAc in hexane) gave the title
compound (84 mg, 71%) as a pale yellow solid. mp¼100e101 ꢀC, dH
(400 MHz; CDCl3): 8.79 (d, J¼4.8 Hz, 1H), 8.32 (s, 1H), 8.05 (dd,
J¼8.5, 1.0 Hz, 1H), 7.95 (d, J¼7.8 Hz, 2H), 7.70 (td, J¼7.5, 1.4 Hz, 1H),
7.55 (d, J¼8.5 Hz, 1H), 7.43 (t, J¼7.6 Hz, 2H), 7.35 (t, J¼7.4 Hz, 1H),
7.29 (d, J¼7.8 Hz, 1H), 7.18 (dd, J¼7.2, 5.0, 1H), 6.74 (s, 1H), 3.93 (s,
3H), 3.05 (dd, J¼9.5, 6.0 Hz, 2H), 1.49e1.40 (m, 2H), 1.32e1.21 (m,
2H), 0.76 (t, J¼7.6 Hz, 3H); dC (100 MHz; CDCl3): 167.3, 156.5, 156.4,
151.4, 149.4, 139.2, 136.1, 130.9, 130.6, 130.4, 128.7, 128.6, 126.9,
126.4, 125.3, 124.5, 122.6, 121.4, 120.2, 111.0, 52.1, 31.9, 30.9, 22.9,
13.8; nmax 3059, 2955, 2929, 2871, 1724, 1584, 1469, 1443, 1435,
1283, 1266, 1238, 1207, 1100, 1058 cmꢂ1; m/z (EI) 411.1840 (Mþ:
C27H25NO3 requires 411.1834).
4.7.13. (E)-3-(2-Butylbenzofuran-3-yl)-4-(pyridin-2-yl)but-3-en-1-ol
(63a). Subjecting phenol 16a (50 mg, 0.29 mmol) with 62 (28 mg,
0.19 mmol) to general procedure D (9 mol % [Rh(cod)OH]2) followed
by chromatography (30% EtOAc in pentane) gave the title compound
(36 mg, 57%) as a yellow oil. dH (400 MHz; CDCl3): 8.57 (d, J¼4.7 Hz,
1H), 7.73 (td, J¼7.7, 1.6 Hz, 1H), 7.48 (d, J¼7.4 Hz, 1H), 7.27e7.21 (m,
3H), 7.19 (t, J¼7.1 Hz, 1H), 6.88 (br s, 1H), 6.73 (s, 1H), 3.81e3.76 (m,
2H), 3.15e3.09 (m, 2H), 2.88 (t, J¼8.1 Hz, 2H), 1.81e1.71 (m, 2H),
1.47e1.36 (m, 2H), 0.93 (t, J¼7.4 Hz, 3H); dC (100 MHz; CDCl3): 156.5,
154.7, 153.9, 147.9, 138.2, 137.2, 130.7, 128.6, 124.7, 123.5, 122.5, 122.2,
119.5, 118.1, 110.9, 61.0, 34.3, 30.7, 26.5, 22.5, 13.9; nmax 3233, 3057,
2956, 2929, 2859, 2684, 1725, 1635, 1588, 1560, 1473, 1454, 1428,
1378, 1281, 1237, 1175, 1151, 1044, 1005 cmꢂ1; m/z (EI) 321.1724 (Mþ:
C21H23NO2 requires 321.1729).
4.7.14. (E)-2-(2-(2-Butylbenzofuran-3-yl)-2-phenylvinyl)pyridine
(66a). Subjecting phenol 16a (50 mg, 0.29 mmol) with 65 (52 mg,
0.29 mmol) to general procedure D (3 mol % [Rh(cod)OH]2) fol-
lowed by chromatography (gradient from 0 to 20% EtOAc in pen-
tane) gave the title compound (31 mg, 30%) as a yellow oil. dH
(400 MHz; CDCl3): 8.56 (ddd, J¼4.9, 1.7, 0.9 Hz, 1H), 7.41 (dt, J¼8.3,
0.7, 1H), 7.35 (dd, J¼7.7, 1.9 Hz, 1H), 7.31 (dd, J¼5.0, 1.5 Hz, 1H),
7.30e7.25 (m, 4H), 7.19 (ddd, J¼8.5, 7.0, 1.5 Hz, 1H), 7.11 (ddd, J¼7.8,
1.5, 0.7 Hz, 1H), 7.08e7.05 (m, 1H), 7.04e7.00 (m, 1H), 6.98 (s, 1H),
6.89 (d, J¼8.1, 1H), 2.65e2.59 (m, 2H), 1.69e1.60 (m, 2H), 1.34e1.23
(m, 2H), 0.85 (t, J¼7.6 Hz, 3H); dC (100 MHz; CDCl3): 157.6, 156.6,
153.9, 149.5, 139.5, 137.6, 135.2, 130.1, 129.9, 128.6, 128.5, 128.0,
124.2, 123.4, 122.4, 121.2, 120.4, 118.4, 110.7, 30.3, 27.0, 22.4, 13.8;
nmax 3055, 2957, 2928, 2871, 2859, 1612, 1597, 1583, 1563, 1493,
1455, 1431,1256,1174,1069 cmꢂ1; m/z (EI) 353.1779 (Mþ: C25H23NO
requires 353.1780).
4.7.10. (E)-2-(2-(5-tert-Butyl-2-phenylbenzofuran-3-yl)hex-1-enyl)
pyridine (46k). Subjecting phenol 16k (72 mg, 0.29 mmol) with 2-
(1-hexynyl)-pyridine (46 mg, 0.29 mmol) to general procedure D
(3 mol % [Rh(cod)OH]2) followed by chromatography (gradient
from 0 to 10% EtOAc in hexane) gave the title compound (49 mg,
41%) as a yellow oil. dH (0 MHz): 8.70 (dd, J¼4.8, 0.9 Hz, 1H),
7.96e7.92 (m, 2H), 7.67 (td, J¼7.7, 1.9 Hz, 1H), 7.58 (d, J¼1.6 Hz, 1H),
7.44 (d, J¼9.6 Hz, 2H), 7.40e7.37 (m, 3H), 7.33e7.23 (m, 1H), 7.15
(ddd, J¼7.5, 4.9, 1.0 Hz, 1H), 6.73 (s, 1H), 3.08 (dd, J¼8.0, 7.8 Hz, 2H),
1.55e1.21 (m, 4H), 1.38 (s, 9H), 0.78 (t, J¼7.3 Hz, 3H); dC (100 MHz;
CDCl3): 156.73, 152.09, 150.22, 149.35, 145.88, 140.18, 136.05, 131.12,
130.44, 130.06, 128.45, 128.06, 126.74, 124.33, 122.47, 121.19, 120.15,
116.31, 110.29, 34.79, 31.88, 31.39, 30.80, 22.90, 13.79; nmax 2957,
2930, 2870, 1584, 1473, 1427, 1266, 1062 cmꢂ1; m/z (EI) 409.2403
(Mþ: C29H31NO requires 409.2406).
Acknowledgements
4.7.11. (E)-2-(2-(2-n-Butylbenzofuran-3-yl)hex-1-enyl)-3-chloro-5-
(trifluoromethyl)pyridine (59a). Subjecting phenol 16a (50 mg,
0.29 mmol) with alkyne 58 (50 mg, 0.19 mmol) to general pro-
cedure D (9 mol % [Rh(cod)OH]2) followed by chromatography
(pentane) gave the title compound (57 mg, 68%) as a pale orange
oil. dH (400 MHz; CDCl3): 8.81 (d, J¼1.0 Hz, 1H), 7.93 (dd, J¼2.1,
0.6 Hz,1H), 7.61e7.57 (m,1H), 7.46e7.43 (m,1H), 7.28e7.20 (m, 2H),
6.85 (s, 1H), 3.09 (dd, J¼7.8, 7.5 Hz, 2H), 2.90 (dd, J¼7.8, 7.5 Hz, 2H),
1.83e1.74 (m, 2H), 1.49e1.22 (m, 6H), 0.95 (t, J¼7.4 Hz, 3H), 0.80 (t,
J¼7.3 Hz, 3H); dC (100 MHz; CDCl3): 157.23 (q, J¼1.4 Hz, 1H), 155.95,
153.86, 145.85, 143.57 (q, J¼4.0 Hz), 133.94 (q, J¼3.7 Hz), 130.95,
128.56, 124.69 (q, J¼33.5 Hz), 123.65, 123.51, 122.89 (q, J¼272.6 Hz),
We gratefully acknowledge NSERC (Canada), Merck-Frosst,
Otsuka Pharmaceutical Co., Ltd. (Tokyo) and the University of Tor-
onto for financial support.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.106. These data include
MOL files and InChIKeys of the most important compounds
described in this article.

6482
A. Boyer et al. / Tetrahedron 66 (2010) 6468e6482
2007, 1775e1779; (j) Kimio, H.; Yusuke, I.; Toshiaki, W.; Shinya, O.; Nobutaka, F.;
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