Tandem cycloisomerization/Suzuki coupling of arylethynyl MIDA boronates

Article abstract of DOI:10.1016/j.tet.2011.04.011

A tandem gold-catalyzed cycloisomerization/Suzuki cross-coupling sequence involving arylethynyl-N-methyliminodiacetic acid boronates is described. Combining the mildness of homogeneous gold catalysis with the versatility of N-methyliminodiacetic acid (MID

Full text of DOI:10.1016/j.tet.2011.04.011

Tetrahedron 67 (2011) 4306e4312
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem cycloisomerization/Suzuki coupling of arylethynyl MIDA boronates
*
Julian M.W. Chan, Giovanni W. Amarante, F. Dean Toste
Department of Chemistry, University of California, Berkeley, CA 94720, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A
tandem gold-catalyzed cycloisomerization/Suzuki cross-coupling sequence involving arylethynyl-
Received 29 March 2011
Received in revised form 3 April 2011
Accepted 5 April 2011
N-methyliminodiacetic acid boronates is described. Combining the mildness of homogeneous gold
catalysis with the versatility of N-methyliminodiacetic acid (MIDA) boronates, this tandem two-step
method enables the rapid assembly of various aryl-substituted heterocycles without having to isolate or
purify any heterocyclic MIDA boronate intermediates. Another major advantage of this method is that
a wide range of heterocycles bearing different aryl groups may be made from a single MIDA boronate
alkyne precursor.
Available online 15 April 2011
Keywords:
Gold catalysis
Electrophilic cyclization
Suzuki coupling
MIDA boronates
Heterocycles
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
In 2009, the laboratories of Prof. Martin Burke reported the use of
air-stable MIDA boronates to address typical problems associated
Given the biological activity that many benzofuran and indole-
containing molecules possess, it comes as no surprise that these
classes of molecules often represent important targets in the field of
drug discovery and development.1 Accordingly, there exists ongoing
interest in the development of novel synthetic routes toward these
functionalized heterocycles, and in particular, their 2-substituted
derivatives.2 In a bid to construct a range of such heterocycles in an
expeditious fashion, we envisioned a tandem sequence depicted in
Scheme 1 involving two catalytic processes, with the idea of gen-
erating heterocycles with diverse substituents from a single pre-
cursor. For this to work well, the Z moiety should be compatible with
the cyclization event and also serve as a synthetic handle for a cross-
coupling reaction.3 In addition, the first reaction (gold-catalyzed
cycloisomerization) must give reasonably high yields of the in-
termediate, and proceed cleanly enough for next step to continue
without prior intermediate purification and isolation.
with the inherently unstable 2-heterocyclic boronic acids in Suzuki
cross-coupling.4 More recently, the Burke group has also demon-
strated that the highly versatile ethynyl MIDA boronate5 is amenable
to Sonogashira coupling with aryl iodides and that the MIDA boro-
nate functional group is tolerant of a wide variety of reaction con-
ditions. We envisioned that the ethynyl MIDA boronate
methodology could be applied to the synthesis of the aromatic
substrates proposed in Scheme 1, which in turn could be cyclo-
isomerized and coupled with commercial aryl halides to give
substituted heterocycles. No compatibility issues were anticipated
in view of the mildness of gold catalysis6 and the robustness of MIDA
boronates. Additionally, with only the need for catalytic quantities of
gold reagent, we expected that a Suzuki coupling could be carried
out in a tandem fashion, without having to first isolate and purify the
cycloisomerized intermediates. This tandem two-step7 process was
likely to succeed if the 2-heterocyclic MIDA boronate could be
generated cleanly without leaving behind any starting material in
the post-reaction mixture. In addition to benzofurans8 and indo-
les,2e,9 we predicted that the same method could also be used to
regioselectively construct additional heterocycles, such as 1,3-
dihydroisobenzofurans (phthalans)10 and isoindolines11 from ben-
zylic alcohols and N-protected benzylic amines, respectively. This
secondary objective would take advantage of the directing ability of
the electronegative MIDA boronate group to favor 5-exo-dig over 6-
endo-dig products, such as isochromenes12 and isoquinolines.13 Ul-
timately, the goal was to combine the ease of homogeneous gold
catalysis with the versatility of Burke’s MIDA boronate chemistry to
provide facile, quick one-pot access to a range of aryl-substituted
Scheme 1. Tandem process for the rapid construction of 2-substituted heterocycles.
* Corresponding author. Tel.: þ1 510 642 2850; e-mail address: fdtoste@berke-
ley.edu (F.D. Toste).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.011

J.M.W. Chan et al. / Tetrahedron 67 (2011) 4306e4312
4307
heterocycles while bypassing cumbersome intermediate purifica-
tion. Moreover, as stated earlier, this method would allow each class
of heterocycles to be synthesized from a single arylethynyl MIDA
boronate precursor, without the need to prepare individual alkynes
for Sonogashira coupling. Instead, inexpensive and readily available
aryl halides can simply be fed into the second step of the tandem
sequence to generate a library of substituted heterocycles. Lastly, the
ability of the MIDA boronate moiety to direct 5-exo-dig reactivity
will prove itself a useful complement to the 6-endo-dig regiose-
lectivity of several existing cyclization methods.12,14 The results of
our investigations are described herein.
Further optimization studies were subsequently carried out, and
it was ultimately possible to synthesize the 2-benzofuryl MIDA
boronate in 86% isolated yield after just 5 h of reaction in THF at
65 ꢀC. The same conditions were also found to be effective in
cyclizing tosylated aniline 3 and benzyl alcohol 5, giving the
N-protected indole 4 and phthalan 6 in 89% and 71% isolated yields,
respectively (Scheme 2). The issue of regioselectivity in the
phthalan system will be discussed in Section 2.4.
2. Results and discussion
2.1. Initial catalyst screening and optimization studies
In our initial search for the optimal conditions to bring about the
key 5-endo-dig electrophilic cyclization of phenol 1, a wide variety
of gold catalysts and reaction conditions were screened (Table 1).
The results of these preliminary screens indicated that the more
electrophilic gold catalysts fared better in bringing about the nec-
essary cycloisomerization. This was unsurprising in view of the fact
that the C^C in the substrate is electron-poor due to the inductive
effect of the MIDA boronate moiety. The effect of solvent on the
reaction was also investigated (Table 2) and it was found that the
best yield was obtained when THF was employed. Thus, the use of
3 mol % of [(Ph3PAu)3O]BF4 in THF at 70 ꢀC was established as
a satisfactory set of conditions for achieving yields over 70%.15
Scheme 2. Gold-catalyzed cycloisomerizations of MIDA-alkynylboronates.
Table 1
2.2. Investigation of additional gold oxonium salt catalysts
Results of the initial catalyst screening
MeN
B
Having identified [(Ar3PAu)3O]BF4 as the optimal cyclization
catalyst, further efforts to improve the yields were undertaken, by
screening more reactive gold reagents of the same class. To that
end, two catalysts B, [(Ar3PAu)3O]BF4 (Ar¼p-ClC6H4), and C,
[(Ar03PAu)3O]BF4 (Ar0¼p-CF3C6H4) were investigated. In general,
the electron-withdrawing substituents on the phosphine ligands
render the catalysts more electrophilic, which we hoped would be
more effective in activating the relatively electron-poor C^C of the
MIDA boronates toward intramolecular nucleophilic attack.16 This
indeed proved to be the case with regards to benzofuran and indole
formation, where the heterocycles were obtained in quantitative or
near-quantitative yields. However, these enhanced catalysts were
less successful in making phthalans from benzyl alcohols, with only
65% yield being obtained with catalyst B and complete de-
composition being observed with catalyst C. The results are sum-
marized in Table 3 below, with comparison to the less active but
commercially available catalyst A, [(Ph3PAu)3O]BF4.
O
O
O
MeN
B
O
3 mol% [Au] cat.
Conditions, 12 h
O
O
O
O
O
OH
2
1
Entry
Catalyst
Solvent
Temp (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
Ph3PAuCl, AgSbF6
dppm(AuCl)2, AgSbF6
IMes(AuCl), AgSbF6
DTBM-Segphos(AuCl)2, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
[(Ph3PAu)3O]BF4
(p-CF3C6H4)3PAuCl, AgSbF6
[(Ph3PAu)3O]BF4
DMF
DMF
DMF
DMF
DMF
DMF
MeNO2
MeNO2
70
70
70
70
70
70
55
55
0
0
0
0
50
60
0
0
Table 2
Solvent effects on the isolated yield
2.3. Tandem cycloisomerization/Suzuki cross-coupling
MeN
B
With the cycloisomerization of various substrates having been
accomplished, we set out to develop the tandem two-step cyclo-
isomerization/Suzuki cross-coupling protocol mentioned earlier.
Owing to the mildness of the cyclization step, the complete absence
of any starting material in the post-reaction mixture, there
appeared to be few variables capable of interfering with the sub-
sequent Suzuki coupling step. The only significant issue was the
need for THF as the solvent, which was necessary for achieving high
yields in the gold-catalyzed cyclization, whereas the Suzuki cou-
pling of MIDA boronates as performed by Burke and co-workers
had been optimized with dioxane. It was unfeasible to replace THF
with dioxane in the cyclization step for two reasons: (1) yields were
higher when the reaction was run in THF; (2) significant quantities
of uncyclized alkyne MIDA boronate remain when dioxane is used,
O
O
O
MeN
B
O
3 mol% [Au] cat.
O
O
O
O
70 ºC, solvent,
12 h
O
OH
2
1
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
(p-CF3C6H4)3PAuCl, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
(p-CF3C6H4)3PAuCl, AgSbF6
[(Ph3PAu)3O]BF4
MeNO2
1,4-Dioxane
Xylenes
PhF
40
56
15
20
18
0
1,2-Dichloroethane
i-PrNH2
MeNO2
THF
55
75
[(Ph3PAu)3O]BF4

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J.M.W. Chan et al. / Tetrahedron 67 (2011) 4306e4312
Table 3
partner. Lastly, the MIDA boronate is also capable of directing gold-
catalyzed 5-exo-dig reactivity, complementing the 6-endo-dig regio-
selectivity of many existing methods.
Comparison of three gold oxonium salt-based catalysts for cycloisomerization
MeN
MeN
B
B
O
O
X
O
O
4. Experimental
4.1. Materials
O
O
O
3 mol% [(Ar3PAu)3O]BF4
65 ºC, THF, 5-6 h
O
or
MeN
B
XH
O
O
O
O
X = O, NTs, CH2O
O
Unless otherwise noted, all commercial reagents were purchased
from SigmaeAldrich, Alfa Aesar, Fisher Scientific, and TCI America
and used without further purification. Palladium(II) acetate, trans-
dichlorobis(triphenylphosphine)palladium(II), copper(I) iodide,
and tris[triphenylphosphinegold(I)] oxonium tetrafluoroborate
were purchased from Strem Chemicals Inc. and used without further
purification. Tris[triphenylphosphinegold(I)] oxonium tetra-
fluoroborate synthesized using published procedures17 was also
used. Anhydrous organic solvents were purified and obtained via
passage through packed columns as described by Pangborn and co-
workers.18 Deionized water employed as a reagent in the Suzuki
cross-coupling reactions was obtained from the College of Chemis-
try, University of California, Berkeley house deionized water supply.
Solvents used for chromatographic purification procedures (HPLC
grade hexane and ethyl acetate, ACS grade dichloromethane, chlo-
roform, and ethanol) were obtained from Fisher Scientific.
Entry
X
Catalyst
Isolated yield (%)
1
2
3
4
5
6
7
8
9
OH
OH
OH
NHTs
NHTs
NHTs
CH2OH
CH2OH
CH2OH
A
B
C
A
B
C
A
B
C
86
100
100
89
94
98
71
65
0
which would lead to undesired Suzuki coupling products in the
final mixture. Consequently, the tandem two-step sequence in-
volved performing the first reaction exactly as before, but instead of
the usual workup and purification, the reaction vessel was opened
up under positive pressure of nitrogen, into which the reagents for
the Suzuki cross-coupling step were introduced. The second stage
of the tandem process was then initiated immediately thereafter.
Results of the cycloisomerization/cross-coupling sequence leading
to benzofurans and N-protected indoles were encouraging and are
summarized in Table 4. Isolated yields (over two steps) of 2-aryl-
heterocycles were typically 50% or greater.
4.2. General experimental procedures
Unless otherwise stated, all reactions were performed in oven-
dried glassware under an inert atmosphere of nitrogen gas using
standard Schlenk techniques. Thin-layer chromatography (TLC)
analysis of reaction mixtures was performed on E. Merck silica gel
60 F254 TLC plates, with UV light (
l
¼254 nm), potassium perman-
ganate stain, and/or elemental iodine to visualize the post-reaction
components. Flash chromatography was performed on ICN SiliTech
ꢀ
32e63 D 60 A silica gel according to standard procedures. The MIDA
boronates are compatible with standard silica gel column chro-
matography, including the standard loading techniques.
2.4. Regioselectivity
The regioselectivity observed in the cyclization of benzyl alcohol
5 is particularly interesting in that 5-exo-dig reactivity is favored
over 6-endo-dig, exclusively resulting in phthalan 6 and none of the
six-membered isochromene MIDA boronate (Scheme 2). In con-
trast, when a 4-methoxyphenyl substituent was used in place of the
sterically demanding MIDA boronate group, a gold-catalyzed
6-endo-dig cyclization occurred exclusively to afford a known iso-
chromene (Scheme 3), the NMR data of which agreed with pub-
lished literature results. The tandem cyclization/Suzuki coupling
sequence of benzyl alcohol 5, involving 4-bromoanisole in the
Suzuki step, afford phthalan 9 in 53% yield (over two steps). Thus,
with the 5-exo-dig regioselectively conferred by the MIDA boronate
provides complementary reactivity to various electrophilic cycli-
zations of boron-free substrates.
4.3. Structural analysis
All 1H and 13C NMR spectra were recorded at ambient temper-
ature on the Bruker AVB-400 and AVQ-400 NMR spectrometers.
Chemical shifts (d) are reported in parts per million (ppm) and
referenced to residual proton and carbon resonances in the NMR
solvent (1H: CDCl3,
d
d
¼7.26; CD2Cl2,
d
¼5.32, center line; acetone-d6,
¼2.04, center line; 13C: CDCl3,
d
¼77.2, center line; CD2Cl2, ¼54.0,
d
center line; acetone-d6,
d
¼29.8, center line). Data are reported as
follows: chemical shift, integration, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, quint¼quintet, sext¼sextet,
sept¼septet, m¼multiplet, b¼broad, app¼apparent), and coupling
constant (J) in Hertz (Hz). Carbons attached to boron substituents
were typically not observed due to quadrupolar relaxation. High
resolution mass spectra (HRMS) and analytical data were obtained
via the QB3/Chemistry Mass Spectrometry Facility operated by the
QB3 Institute and the College of Chemistry, University of California,
Berkeley.
3. Summary and conclusions
The ubiquity of heterocycles in fields as diverse as drug discovery,
total synthesis, agricultural chemistry, and materials science high-
lights the need for more efficient synthetic methods for their con-
struction. The results revealed herein show that by combining the
advantages of modern gold catalysis, MIDA boronate chemistry, and
palladium-catalyzed cross couplings, awide range of aryl-substituted
heterocycles can be rapidlyand easilyassembled in a tandem fashion,
bypassing the need to isolate and purify any intermediates. Further-
more, using this method, each class of heterocycles may be made
starting from a single arylethynyl MIDA boronate precursor, without
having to individually synthesize every unique Sonogashira coupling
4.4. General procedure A: Sonogashira coupling
A 50-mL round-bottom flask equipped with a magnetic stir bar
was charged with an aryl iodide (3.57 mmol, 1.1 equiv), ethynyl
MIDA boronate (3.24 mmol, 1.0 equiv), CuI (9 mol %), PdCl2(PPh3)2
(5 mol %), and placed under nitrogen atmosphere. Then, anhydrous
DMF (15 mL) and Et3N (1.4 mL) were introduced via syringe, and
the reaction mixture was allowed to stir for 6e7 h at room tem-
perature, after which the mixture was poured into a separatory

J.M.W. Chan et al. / Tetrahedron 67 (2011) 4306e4312
4309
Table 4
Tandem cycloisomerization/Suzuki coupling leading to 2-arylheterocycles
MeN
B
3 mol% [(Ph3PAu)3O]BF4
65 ºC, THF, 5 to 6 h
1.
2.
O
O
O
O
Ar
Y
ArX,
YH
Pd(OAc)2, SPhos,
3M K3PO4, THF
60 ºC, 6 -12 h
Y = O, NTs
Entry
1
Y
ArX
Product
% Isolated yield (over two steps)
OH
64
69
48
38
58
2
OH
3
OH
4a
OH
5
NHTs
6
NHTs
NHTs
70
56
7
a
Catalyst C (instead of A) was employed in this example.
Scheme 3. Regioselective formation of phthalan and isochromene using complementary methods.

4310
J.M.W. Chan et al. / Tetrahedron 67 (2011) 4306e4312
funnel containing deionized water. Extraction with ethyl acetate
(3ꢁ25 mL) was carried out, and the combined organic extracts
were concentrated in vacuo to give a crude residue. The crude
product was subsequently loaded onto a silica gel column and
purified by flash column chromatography (on this scale, 2e3
rounds of column chromatography was typically required for
complete purification) to afford the desired compound.
(1H, t, J¼7.2 Hz), 6.83 (1H, t, J¼7.2 Hz), 6.72 (1H, s), 4.06 (2H, d,
J¼17.2 Hz), 3.85 (2H, d, J¼16.8 Hz), 2.56 (3H, s). 13C NMR (400 MHz,
acetone-d6,
d ppm): 169.4, 158.7, 129.6, 125.8, 123.8, 122.6, 115.9,
112.5, 63.0, 48.4. HRMS: calcd: 273.0809 (M)þ, found: 273.0811.
4.6.3. 2-(N-Tosylamino)phenylethynyl MIDA boronate (3). Prepared
according to General procedure A using N-tosyl-2-iodoaniline
(0.666 g, 1.79 mmol), ethynyl MIDA boronate (0.294 g, 1.62 mmol),
CuI (0.027 g, 0.11 mmol), PdCl2(PPh3)2 (0.057 g, 0.081 mmol), DMF
(8 mL), and Et3N (0.66 mL). The reaction mixture was allowed to stir
for 6 h. The crude product was purified by flash column chroma-
tography (SiO2; gradient: 1:9/1:1/3:2 ethyl acetate/dichloro-
methane) to afford 3 as an off-white solid (0.311 g, 45%). 1H NMR
4.5. General procedure B: gold-catalyzed cycloisomerization
A 25-mL two-neck round-bottom flask equipped with a mag-
netic stir bar was charged with the arylethynyl-2-MIDA boronate
(0.090 mmol, 1.0 equiv), [(Ph3PAu)3O]BF4 (0.0027 mmol, 3 mol %),
and THF (2.5 mL). The solution was stirred at 65 ꢀC for 5e7 h under
nitrogen, after which the mixture was cooled down to room tem-
perature, diluted with ethyl acetate, and poured into a separatory
funnel containing aqueous NaCl solution. Extraction with ethyl
acetate (3ꢁ20 mL) was carried out, and the combined organic ex-
tracts were concentrated in vacuo to give a crude product that was
subsequently loaded onto a silica gel column and purified by flash
chromatography to afford the target heterocycle as a white solid.
(Note: post-reaction workup and purification were only done in
cases where the heterocyclic MIDA boronate was to be isolated and
characterized.)
(400 MHz, CDCl3,
d
ppm): 7.75 (1H, s), 7.68 (2H, d, J¼8.4 Hz), 7.39
(1H, d, J¼8.0 Hz), 7.1e7.3 (4H, m), 6.97 (1H, t, J¼7.6 Hz), 4.23 (2H, d,
J¼17.2 Hz), 4.00 (2H, d, J¼16.8 Hz), 3.14 (3H, s), 2.28 (3H, s). 13C NMR
(400 MHz, CDCl3,
d ppm): 168.6, 144.3, 138.3, 136.3, 133.0, 130.1,
129.9, 127.5, 124.8, 121.0, 115.0, 62.2, 60.6, 48.5, 21.7. HRMS: calcd:
426.1057 (M)þ, found: 449.0948 (MþNa)þ.
4.6.4. 1-Tosyl-2-indole MIDA boronate (4). Prepared according to
General procedure B using compound 3 (38.4 mg, 0.09 mmol),
([Ph3PAu)3O]BF4 (4 mg, 0.00269 mmol), and anhydrous THF
(2.5 mL). The reaction was stirred at 65 ꢀC for 6 h. The crude product
was purified by flash column chromatography (SiO2; gradient:
3:7/2:3 ethyl acetate/dichloromethane) to afford 4 as a white
4.6. General procedure C: tandem two-step preparation of
aryl-substituted heterocycles
solid (42.7 mg, 89%). 1H NMR (400 MHz, acetone-d6,
d ppm): 8.26
(1H, d, J¼8.4 Hz), 8.03 (2H, d, J¼8.4 Hz), 7.62 (1H, d, J¼7.6 Hz), 7.40
(1H, t, J¼7.2 Hz), 7.35 (2H, d, J¼8.4 Hz), 7.27 (1H, t, J¼7.6 Hz), 7.14
(1H, s), 4.52 (2H, d, J¼17.2 Hz), 4.36 (2H, d, J¼17.2 Hz), 3.22 (3H, s),
The first step was carried out exactly as detailed in General
procedure B, except that the no workup/purification/isolation of
the intermediate heterocyclic MIDA boronate was carried out. In-
stead, following the completion of the first reaction, the reaction
vessel was simply opened up briefly under positive nitrogen pres-
sure, whereupon Pd(OAc)2 (0.9 mg, 0.0045 mmol, 5 mol %), SPhos
(3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M aqueous K3PO4 (0.23 mL,
7.5 equiv of base), and the aryl halide (0.090 mmol, 1 equiv) were
introduced. The mixture was then stirred under nitrogen at 60 ꢀC
for 6e15 h depending on the specific substrate, before being poured
into a separatory funnel containing aqueous NaCl solution. Ex-
traction with ethyl acetate (3ꢁ20 mL) was carried out, and the
combined organic extracts were concentrated in vacuo to give
a crude product that was subsequently loaded onto a silica gel
column and purified by flash chromatography to afford the
2-arylheterocycle.
2.35 (3H, s). 13C NMR (400 MHz, acetone-d6,
d ppm): 169.3, 146.1,
140.0, 136.6, 131.1, 130.6, 128.0, 126.0, 124.2, 122.9, 122.2, 115.5, 65.7,
55.0, 50.4, 32.3, 23.3, 21.5, 14.4. HRMS: calcd: 426.1057 (M)þ, found:
449.0948 (MþNa)þ.
4.6.5. 2-(Hydroxymethyl)phenylethynyl MIDA boronate (5). Prepared
according to General procedure A using 2-iodobenzyl alcohol
(0.834 g, 3.56 mmol), ethynyl MIDA boronate (0.588 g, 3.24 mmol),
CuI (0.054 g, 0.28 mmol), PdCl2(PPh3)2 (0.114 g, 0.162 mmol), DMF
(15 mL), and Et3N (1.32 mL). The reaction mixture was allowed to stir
for 6 h. The crude product was purified by flash column chroma-
tography (SiO2; gradient: ethyl acetate/9:1 ethyl acetate/ethanol)
to afford 5 as an off-white solid (0.277 g, 27%). 1H NMR (400 MHz,
acetone-d6,
d
ppm): 7.57 (1H, d, J¼7.6 Hz), 7.46 (1H, d, J¼8.0 Hz), 7.39
(1H, t, J¼7.2 Hz), 7.25 (1H, t, J¼7.6 Hz), 4.80 (2H, s), 4.34 (2H, d,
4.6.1. 2-Hydroxyphenylethynyl MIDA boronate (1). Prepared accord-
ing to General procedure A using 2-iodophenol (0.393 g, 1.79 mmol),
ethynyl MIDA boronate (0.294 g, 1.62 mmol), CuI (0.027 g,
0.142 mmol), PdCl2(PPh3)2 (0.057 g, 0.081 mmol), DMF (6 mL), and
Et3N (1.5 mL). The reaction was stirred for 6 h. The crude product,
a reddish-brown oil, was purified by flash column chromatography
(SiO2; ethyl acetate) to afford the 1 as an off-white crystalline solid
J¼16.8 Hz), 4.18 (2H, d, J¼16.8 Hz), 3.34 (3H, s), 2.88 (1H, s). 13C NMR
(400 MHz, acetone-d6, d ppm): 168.6, 145.2, 132.9, 129.6, 127.5, 127.3,
121.4, 63.0, 62.4, 48.6. HRMS: calcd: 287.0965 (M)þ, found: 310.0859
(MþNa)þ.
4.6.6. Isobenzofuran-1(3H)-ylidenemethyl MIDA boronate (6).
Prepared according to General procedure B using compound 5
(25.8 mg, 0.09 mmol), ([Ph3PAu)3O]BF4 (4 mg, 0.00269 mmol), and
anhydrous THF (2.5 mL). The reaction was stirred at 65 ꢀC for 7 h. The
crude product was purified by flash column chromatography (SiO2;
gradient: 49:1/19:1/9:1 ethyl acetate/ethanol) to afford 6 as an
off-white solid (18.3 mg, 71%). 1H NMR (400 MHz, acetone-d6,
(0.221 g, 50%). 1H NMR (400 MHz, acetone-d6,
d ppm): 7.36 (1H, d,
J¼7.6 Hz), 7.22 (1H, t, J¼8.4 Hz), 6.91 (1H, d, J¼8.4 Hz), 6.83 (1H, t,
J¼7.6 Hz), 4.32 (2H, d, J¼17.2 Hz), 4.16 (2H, d, J¼16.8 Hz), 3.32 (3H, s).
13C NMR (400 MHz, acetone-d6,
d ppm): 169.0, 159.6, 134.3, 131.4,
120.8, 116.7, 111.5, 62.7, 49.0. HRMS: calcd: 273.0809 (M)þ, found:
296.0701 (MþNa)þ.
d
ppm): 7.58 (1H, d, J¼6.4 Hz), 7.31e7.41 (3H), 5.33 (2H, s), 4.81 (1H,
s), 3.91 (2H, d, J¼16.4 Hz), 3.84 (2H, d, J¼16.0 Hz), 2.86 (3H, s). 13C
4.6.2. 2-Benzofuryl MIDA boronate (2). Prepared according to
General procedure B using compound 1 (24.5 mg, 0.09 mmol),
[(Ph3PAu)3O]BF4 (4 mg, 0.00269 mmol), and anhydrous THF
(2.5 mL). The reaction was stirred at 65 ꢀC for 5 h. The crude product
was purified by flash column chromatography (SiO2; ethyl acetate)
to afford 2 as a white solid (21 mg, 86%). 1H NMR (400 MHz, ace-
NMR (400 MHz, acetone-d6, d ppm): 168.3, 166.8, 140.7, 134.1, 130.1,
128.6, 121.9, 121.6, 74.7, 62.9, 47.3. HRMS: calcd: 287.0965 (M)þ,
found: 288.1038 (MþH)þ.
4.6.7. 2-(40-tert-Butylphenyl)benzofuran (7a). Prepared according
to General procedure C using Pd(OAc)2 (0.9 mg, 0.0045 mmol,
5 mol %), SPhos (3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M aqueous
tone-d6,
d
ppm): 7.26 (1H, d, J¼7.6 Hz), 7.11 (1H, d, J¼8.4 Hz), 6.91

J.M.W. Chan et al. / Tetrahedron 67 (2011) 4306e4312
4311
K3PO4 (0.23 mL, 7.5 equiv of base), and 1-bromo-4-tert-butylben-
zene (0.014 mL, 0.090 mmol, 1 equiv). The mixture was stirred
under nitrogen at 60 ꢀC for 4 h. The crude product was purified by
flash column chromatography (SiO2; hexanes) to afford 7a as an off-
white solid (14.4 mg, 64% over two steps). 1H NMR (400 MHz,
a white tacky solid (21.9 mg, 70% over two steps). 1H NMR
(400 MHz, CD2Cl2,
ppm): 7.97 (1H, d, J¼8.4 Hz), 7.76 (2H, d,
J¼8.4 Hz), 7.50e7.60 (3H, m), 7.20e7.32 (7H, m), 6.69 (1H, s), 2.33
(3H, s). 13C NMR (400 MHz, CD2Cl2,
ppm): 145.9, 135.6, 135.3,
131.3, 130.4, 127.3, 126.9, 125.0, 123.8, 121.9, 113.9, 109.6, 21.8.
HRMS: calcd: 347.0980 (M)þ, found: 347.0986.
d
d
CDCl3,
(1H, d, J¼8.4 Hz), 7.53 (2H, d, J¼6.4 Hz), 7.30 (2H, m), 7.03 (1H, s),
1.42 (9H, s). 13C NMR (400 MHz, CDCl3,
ppm): 156.3, 155.0, 152.0,
d
ppm): 7.86 (2H, d, J¼6.4 Hz), 7.63 (1H, d, J¼6.8 Hz), 7.57
d
4.6.13. 1-Tosyl-2-(40-trifluoromethylphenyl)indole
according to General procedure using Pd(OAc)2 (0.9 mg,
(8c). Prepared
129.5, 127.9, 125.9, 124.9, 124.2, 123.0, 120.9, 111.3, 100.9, 35.0, 31.4.
HRMS: calcd: 250.1358 (M)þ, found: 250.1362.
C
0.0045 mmol, 5 mol %), SPhos (3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M
aqueous K3PO4 (0.23 mL, 7.5 equiv of base), and 4-chlorobenzotri-
fluoride (0.012 mL, 0.090 mmol, 1 equiv). The mixture was stirred
under nitrogen at 60 ꢀC for 15 h. The crude product was purified by
flash column chromatography (SiO2; gradient: 1:3/3:7/2:3
dichloromethane/hexanes) to afford 8c as a white solid (21 mg, 56%
4.6.8. 2-Phenylbenzofuran (7b). Prepared according to General
procedure C using Pd(OAc)2 (0.9 mg, 0.0045 mmol, 5 mol %), SPhos
(3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M aqueous K3PO4 (0.23 mL,
7.5 equiv of base), and chlorobenzene (9 mL, 0.090 mmol, 1 equiv).
The mixture was stirred under nitrogen at 60 ꢀC for 4.5 h. The crude
product was purified by flash column chromatography (SiO2;
hexanes) to afford 7b as a white solid (12 mg, 69% over two steps).
over two steps). 1H NMR (400 MHz, acetone-d6,
d ppm): 8.02 (1H, d,
J¼7.6 Hz), 7.87 (2H, d, J¼8.4 Hz), 7.71 (1H, s), 7.58 (2H, d, J¼8.0 Hz),
7.35 (5H, m), 7.23 (1H, t, J¼7.2 Hz), 6.79 (1H, s), 2.33 (3H, s). 13C NMR
1H NMR (400 MHz, CDCl3,
d
ppm): 7.89 (2H, d, J¼7.0 Hz), 7.61 (1H, d,
(400 MHz, acetone-d6, d ppm): 146.9, 136.5, 136.2, 132.4, 132.1, 131.4,
J¼7.8 Hz), 7.55 (1H, d, J¼8.2 Hz), 7.48 (2H, t, J¼7.3 Hz), 7.38 (1H, t,
129.1,128.3,128.0,127.5,125.9,125.6,124.7,124.6,110.6,101.4, 21.9. 19F
J¼7.5 Hz), 7.23e7.33 (2H, m), 7.06 (1H, s). 13C NMR (400 MHz, CDCl3,
NMR (400 MHz, acetone-d6,
d
ppm): ꢂ62.16. HRMS: calcd: 415.0854
d
ppm): 156.1, 155.1, 147.9, 130.6, 129.4, 129.0, 128.7, 125.3, 124.4,
(M)þ, found: 415.0855.
123.5, 121.6, 121.1, 111.5, 103.9, 101.5. HRMS: calcd: 194.0732 (M)þ,
found: 194.0731.
4.6.14. 1-(40-Methoxybenzylidene)-1,3-dihydroisobenzofuran
(9). Prepared according to General procedure C using Pd(OAc)2
(1.8 mg, 0.009 mmol, 5 mol %), SPhos (6.2 mg, 0.018 mmol,
10 mol %), 3.0 M aqueous K3PO4 (0.46 mL, 7.5 equiv of base), and 4-
bromoanisole (0.023 mL, 0.090 mmol, 1 equiv). The mixture was
stirred under nitrogen at 60 ꢀC for 15 h. The crude product was
purified by flash column chromatography (SiO2; gradient:
hexanes/1:4/3:7/2:3 dichloromethane/hexanes) to afford 9a
as a white solid (11.3 mg, 53% over two steps). 1H NMR (400 MHz,
4.6.9. 2-(40-Trifluoromethylphenyl)benzofuran (7c). Prepared accord-
ing to General procedure C using Pd(OAc)2 (0.9 mg, 0.0045 mmol,
5 mol %), SPhos (3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M aqueous
K3PO4 (0.23 mL, 7.5 equiv of base), and 4-chlorobenzotrifluoride
(0.012 mL, 0.090 mmol, 1 equiv). The mixture was stirred under
nitrogen at 60 ꢀC for 5 h. The crude product was purified by flash
column chromatography (SiO2; hexanes) to afford 7c as a white solid
(11.3 mg, 48% over two steps). 1H NMR (400 MHz, CDCl3,
d
ppm):
CD2Cl2,
(3H, m), 6.88 (2H, d, J¼6.8 Hz), 5.92 (1H, s), 5.51 (2H, s), 3.81 (3H, s).
13C NMR (400 MHz, CD2Cl2,
ppm): 157.2, 154.5, 138.8, 134.5, 128.9,
d
ppm): 7.67 (2H, d, J¼8.8 Hz), 7.56 (1H, d, J¼6.8 Hz), 7.36
8.00 (2H, d, J¼8.4 Hz), 7.72 (2H, d, J¼8.0 Hz), 7.64 (1H, d, J¼7.2 Hz),
7.56 (1H, d, J¼8.0 Hz), 7.27 (1H, t, J¼7.6 Hz), 7.20 (1H, s). 13C NMR
d
(400 MHz, CDCl3,
d
ppm): 129.4, 128.9, 126.3, 125.7, 125.5, 124.0,
128.5, 128.1, 127.7, 127.2, 120.9, 119.2, 113.8, 113.4, 95.2, 74.5, 54.8.
HRMS: calcd: 238.0994 (M)þ, found: 238.0993.
123.8, 122.1, 121.9, 121.1, 111.8, 103.9. HRMS: calcd: 262.0605 (M)þ,
found: 262.0607.
Acknowledgements
4.6.10. 2-(40-tert-Butylphenyl)benzofuran (7d). Prepared in the
same way as 7a starting with 39.5 mg of the precursor phenol, but
Catalyst C was used instead of Catalyst A. Upon purification, 7d was
afforded as a white solid (13.7 mg, 38% over two steps). Charac-
terization data was identical to 7a (i.e., same compound).
We gratefully acknowledge NIHGMS (RO1 GM073932) and
Amgen for financial support. G.W.A. thanks the National Council
for Scientific and Technological Development (CNPq)-Brazil for
a postdoctoral fellowship. We also thank Professor Martin D.
Burke and his group at the University of Illinois, Urbana-
Champaign for their generous gift of ethynyl MIDA boronate
and Johnson Matthey for a donation of AuCl3. Gold catalysts B and
C were provided by Dr. William E. Brenzovich.
4.6.11. 1-Tosyl-2-(40-tert-butylphenyl)indole (8a). Prepared accord-
ing to General procedure C using Pd(OAc)2 (0.9 mg, 0.0045 mmol,
5 mol %), SPhos (3.1 mg, 0.0090 mmol, 10 mol %), 3.0 M aqueous
K3PO4 (0.23 mL, 7.5 equiv of base), and 1-bromo-4-tert-butylben-
zene (0.014 mL, 0.090 mmol, 1 equiv). The mixture was stirred
under nitrogen at 60 ꢀC for 5 h. The crude product was purified by
flash column chromatography (SiO2; gradient: 1:3/2:3/1:1
dichloromethane/hexanes) to afford 8a as a white solid (19.3 mg,
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4312
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