Cobalt-catalyzed preparation of arylindium reagents from aryl and heteroaryl bromides

Article abstract of DOI:10.1021/jo201174r

A cobalt-bathophenanthroline catalyst has been developed for the direct preparation of a variety of arylindium reagents from the corresponding aryl and heteroaryl bromides in the presence of indium metal and lithium chloride. The thus-formed arylindium reagents undergo efficient palladium-catalyzed cross-coupling reactions with aryl iodides, tolerating various functional groups including hydroxy and free amino groups.

Full text of DOI:10.1021/jo201174r

NOTE
pubs.acs.org/joc
Cobalt-Catalyzed Preparation of Arylindium Reagents from Aryl and
Heteroaryl Bromides
Laksmikanta Adak and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S Supporting Information
b
ABSTRACT: A cobaltꢀbathophenanthroline catalyst has been devel-
oped for the direct preparation of a variety of arylindium reagents from
the corresponding aryl and heteroaryl bromides in the presence of
indium metal and lithium chloride. The thus-formed arylindium reagents
undergo efficient palladium-catalyzed cross-coupling reactions with aryl
iodides, tolerating various functional groups including hydroxy and free
amino groups.
Scheme 1. CobaltꢀBathophenanthroline-Catalyzed Indium
rganoindium reagents occupy a unique position in the syn-
thetic chemistry of nucleophilic organometallics; they exhi-
O
Insertion into Aryl Bromide
bit sufficient reactivity toward a variety of CꢀC bond-forming
reactions yet tolerate air, moisture, and sensitive functional
groups, including hydroxy and amino groups.1 While allyl- and
propargylindium reagents are easily accessible from the corre-
sponding halides and indium metal,1 the preparation of other classes
of organoindium reagents, aryl- and alkylindiums in particular,
used to be less straightforward. Thus, their preparation has com-
monly resorted to transmetalation of the corresponding organo-
lithium and magnesium reagents with indium trichloride,2
which is less attractive in terms of operational simplicity, atom
efficiency, and functional group compatibility. With this back-
ground, the recent developments of LiCl-assisted indium
insertion into aryl halides by Knochel3 and Minehan4 and
CuCl-assisted indium insertion into alkyl halides by Loh5
represent breakthroughs in the preparative methods for organo-
indium reagents.6
The direct preparation of arylindiums by Knochel and Mine-
han is particularly attractive in the context of biaryl synthesis.7
Nevertheless, their methods have been mostly limited to aryl
iodides, in particular to those bearing activating functional
groups (e.g., ester, ketone, aldehyde, cyano), while the use of
aryl bromides is more desirable in terms of cost and availability.
Encouraged by our recent development of a cobaltꢀXantphos
catalyst for the preparation of arylzinc reagents from aryl
iodides, bromides, and chlorides via zinc insertion,8ꢀ10 we be-
came interested in the ability of cobalt complexes to catalyze
indium insertion into aryl halides. We report here that a cobaltꢀ
bathophenanthroline catalyst promotes indium insertion into a wide
range of aryl and heteroaryl bromides, thereby offering a con-
venient method for the preparation of arylindium reagents
(Scheme 1). The thus-formed reagents participate in palladium-
catalyzed cross-couplings with tolerance to various functional
groups.
Screening of cobalt catalysts was performed on the reaction of
1-bromo-3,5-dichlorobenzene 1 with indium (2 equiv; preacti-
vated with a catalytic amount of allyl chloride) and LiCl (1 equiv)
in THF at 80 °C for 20 h. The degree of indium insertion was
measured by iodolysis of the reaction mixture followed by GC
analysis (Table 1). The cobaltꢀXantphos catalyst,8 which was
the optimum catalyst for the zinc insertion, produced the iodina-
tion product 2 in moderate yield (49%, entry 1). The reaction
was accompanied by a considerable amount (36%) of the reduc-
tion product 3, which is considered to form via hydrogen abstrac-
tion of an arylcobalt species and not via protonation of an
arylindium species (vide infra).8 Other diphosphine ligands such
Received: June 7, 2011
Published: August 12, 2011
r
2011 American Chemical Society
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|

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NOTE
Table 1. Indium Insertion into 1-Bromo-3,5-
dichlorobenzenea
yieldb (%)
entry
ligand
x
y
2
3
1
2
Xantphos
DPEphos
dppp
2
1
1
1
1
1
1
1
1
1
1
0
2
1
49
30
48
31
83
33
12
16
0
36
20
33
13
6
2
3
2
4
dppf
2
5
bathophen
bpy
2
6
2
17
7
Figure 1. Arylindium reagents prepared from aryl bromides with the
cobaltꢀbathophenanthroline catalyst (Table 1, entry 5). Yields were
determined by GC after iodolysis.
7
phen
2
8
neocup
bathophen
2
9
9c
10
11
12
13
2
0
2
0
7
particularly sluggish with 4-Me2N and 2-MeO substituents (4e
and 4f). Polycyclic aromatic indium reagents 4j and 4k could be
prepared in ca. 80% yield. The presence of an olefinic moiety,
which could potentially coordinate to the cobalt catalyst, was
tolerated (4l). Carbonyl and related functional groups (i.e.,
aldehyde, ketone, cyano, ester) were tolerated, as exemplified
by the preparation of the indium reagents 4mꢀq in 75ꢀ81%
yield. Heteroaryl bromides such as 3-quinolyl bromide and 2-
and 3-bromothiophene could be efficiently converted to the
corresponding indium reagents 4sꢀu in >80% yield.
bathophen
bathophen
bathophen
2
0
0
2
42
73
37
8
1.5
a Reaction was performed on a 1 mmol scale. b Determined by GC using
n-tridecane as an internal standard. c CoBr2 was omitted from the
reaction.
as DPEphos, dppp, and dppf also gave unsatisfactory results in
terms of conversion and selectivity (entries 2ꢀ4). Upon further
ligand screening, bathophenanthroline emerged as an effective
ligand, affording 2 in 83% yield together with a small amount
(6%) of 3 (entry 5).
The performance of other bidentate nitrogen ligands, such as
2,2-bipyridine, 1,10-phenanthroline, and neocuproine, was much
poorer (entries 6ꢀ8). Control experiments demonstrated that
CoBr2, bathophenanthroline, and LiCl are all essential compo-
nents of the catalytic system (entries 9ꢀ11). The amount of LiCl
was crucial because the use of 2 equiv of LiCl led to a significant
increase in the reduction product 3 (entry 12). A decrease in the
amount of indium to 1.5 equiv resulted in a slightly lower yield of
2 (entry 13). Note that, unlike the zinc insertion reaction,8 no
biaryl homocoupling product was observed.
The cobaltꢀbathophenanthroline system (Table 1, entry 5)
was applicable to a variety of electron-neutral, -rich, and -poor
aryl/heteroaryl bromides, affording the corresponding indium
reagents 4aꢀu in moderate to excellent yields as indicated by GC
analysis after iodolysis (Figure 1). Some of the arylindium
reagents (4aꢀh,n,p) were prepared at 100 °C, while most of
these reactions could be performed at 80 °C with a slight
decrease in the yield by 5ꢀ10%. The reaction became
Note that the formula “ArInX2” used here is a formal repre-
sentation of the arylindium reagent. 1H and 13C NMR analysis of
the phenylindium reagent 4a indicated that it mainly consists of
two species in an approximate ratio of 2:1 (see Figure S1a in the
Supporting Information). The chemical shifts of the major
species were close to that of a phenylindium reagent prepared
by transmetalation between InCl3 and one equivalent of PhMgBr
(Figure S1b, Supporting Information), while the minor one
showed similar chemical shifts as a reagent prepared from InCl3
and 2 equiv of PhMgBr (Figure S1c, Supporting Information).
Thus, we presume that the reagent 4a exists as a mixture of
phenylindium(III) dihalide (PhInX2) and diphenylindium(III)
halide (Ph2InX) and/or their aggregate species including
phenylindium(III) sesquihalide (Ph3In2X3).1,11,12
The indium insertion into aryl chlorides was also briefly
studied (Scheme 2). In general, aryl chlorides were very reluctant
to participate in the reaction. Even activated substrates such as
4-chlorobenzonitrile and 4-chlorobenzotrifluoride afforded only
a small amount or none of the product (Scheme 2a). Never-
theless, 2-chlorothiophenes could be converted to the corre-
sponding indium reagents in moderate yield (Scheme 2b).
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NOTE
The arylindium reagents prepared by the presentmethod readily
participate in palladium-catalyzed cross-coupling reactions,2cꢀm,3ꢀ5
without apparentinterference fromthe cobaltcatalyst (Scheme 3).
Thus, cross-coupling with a variety of aryl/heteroaryl iodides
took place smoothly with the PdꢀSPhos catalyst13 in THF
or THF/NMP (NMP = N-methylpyrrolidinone),3 affording a
diverse array of biaryl products 5aꢀq in moderate to excellent
yield. Tolerable functional groups on the aryl iodides include
electrophilic groups such as cyano (5a,n), ester (5b,g,o), alde-
hyde (5c,k), ketone (5d,f), and nitro (5i) groups and protic OH
and NH groups of alcohol (5e), phenol (5k), aniline (5h), indole
(5l), and acetanilide (5p). Heterocyclic iodides such as 3-iodo-
pyridine and 4-iodoantipyrine are also excellent coupling part-
ners (5j,q).
Scheme 2. Indium Insertion into Some Aryl Chlorides
At this stage, we speculate that the present catalytic system for
the indium insertion and the CoꢀXantphos system for the zinc
insertion share a similar catalytic cycle involving redox processes
between Co(I), Co(II), and Co(III) species.8,9 However, given
that common oxidation states of indium are 0, I, and III and that
In(I) can disproportionate to In(0) and In(III),1 we consider
that the redox processes in the present system may be more
complicated than the case of the zinc insertion (Scheme 4). The
reaction would be initiated by reduction of the cobalt(II) pre-
catalyst to a cobalt(I) species by the indium metal. The catalytic
cycle may involve (1) oxidative addition of an aryl halide to
cobalt(I) to give an arylcobalt(III) species, (2) reduction of the
arylcobalt(III) to an arylcobalt(II) species by In or InX, (3) trans-
metalation of the arylcobalt(II) species with InX3 (or ArInX2),
which would be generated through the preceding reduction steps
or disproportionation of InX, to afford ArInX2 (or Ar2InX) and
cobalt(II) halide, and (4) reduction of cobalt(II) halide by In or
InX to regenerate the cobalt(I) species. The reduction product
may form via hydrogen abstraction of THF by the arylcobalt(II)
species, as suggested for the zinc insertion reaction.8
Scheme 3. Palladium-Catalyzed Cross-Coupling of Arylin-
dium Reagentsa
In summary, we have developed a cobaltꢀbathophenanthro-
line catalyst for the efficient insertion of indium into a variety of
aryl and heteroaryl bromides. The resulting arylindium reagents
can be cross-coupled with aryl iodides under palladium catalysis
with a high level of functional group compatibility. Because of the
wider availability and lower cost of aryl bromides than of iodides,
as well as the operational simplicity, the present preparative
method has significantly expanded the accessibility to arylin-
diums as nucleophilic aryl donors. Further efforts will focus on
Scheme 4. Proposed Catalytic Cycle
a Reaction was performed using 1 mmol of the starting aryl bromide and
0.75ꢀ0.46 mmol of the aryl iodide. Yields refer to isolated yields based
on the aryl iodides. See the Experimental Section for details of the
reaction conditions for each case. b 2-Chloro-5-acetylthiophene was
used as the starting halide.
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NOTE
expansion of the substrate scope, applications of the arylindium
reagents, and investigation into the reaction mechanism.
30,50-Dichloro(1,10-biphenyl)-3-carbonitrile (5a). The reaction of
3,5-dichlorophenylindium reagent (Table 1, entry 5) was performed
accordingto procedure A using 3-iodobenzonitrile (151.2 mg, 0.66 mmol)
with a reaction time of 21 h. Silica gel chromatography (eluent: hexane/
EtOAc = 9/1) of the crude product afforded the title compound as a
white solid (134.5 mg, 82%): mp = 252ꢀ253 °C; Rf 0.51 (hexane/
EtOAc = 9/1); 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J = 1.8 Hz,
1H), 7.68 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 1.8 Hz, 2H), 7.89ꢀ7.90 (m,
1H), 8.09ꢀ8.11 (m, 1H), 8.28ꢀ8.29 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 112.2, 118.5, 125.7 (2C), 127.7, 130.1, 130.8, 131.8,
132.1, 134.8 (2C), 138.2, 141.4; HRMS (ESI+) calcd for C13H7Cl2NNa
[M + Na]+ 269.9853, found 269.9852.
’ EXPERIMENTAL SECTION
General Methods. All reactions were performed by standard
Schlenck techniques in oven-dried reaction vessels under nitrogen
atmosphere. Unless otherwise noted, chemicals were purchased from
commercial suppliers and were used as received. Indium powder of
99.99% purity (trace metals basis, excluding ∼1% Mg as an anticaking
agent) was used.14 THF was distilled over Na/benzophenone before
use. Flash chromatography was performed using 40ꢀ63 μm silica gel.
1H and 13C NMR spectra are reported in ppm downfield from an
internal standard, tetramethylsilane (0 ppm) and CHCl3 (77.0 ppm),
respectively. Gas chromatographic (GC) analysis was performed on a
GC system equipped with an FID detector and a (5% phenyl)-
methylpolysiloxane capillary column (0.25 mm i.d. ꢁ 30 m, 0.25 μm
film thickness). The melting points of solid materials were determined
by a capillary melting point apparatus and are uncorrected. Mass
spectrometry data were recorded on a high-resolution mass spectro-
meter with the ESI (positive) method.
General Procedure for Cobalt-Catalyzed Preparation of
Arylindium Reagents. Anhydrous LiCl (42.4 mg, 1 mmol) was
placed in a 10 mL Schlenk tube, dried under vacuum (1 mbar) at 150 °C
for 1 h, and cooled to room temperature (20 °C) under N2. To the
Schlenk tube was added indium powder (230 mg, 2 mmol), and the tube
was evacuated and backfilled with N2 three times. The In/LiCl mixture
was suspended with THF (1 mL), followed by the activation of In with
allyl chloride (25 μL, 0.31 mmol) and stirring for 10 min. Then bath-
ophenanthroline (16.8 mg, 0.05 mmol) and CoBr2 (10.9 mg, 0.05 mmol)
were added sequentially. After the solution was stirred for an additional
10 min, an aryl halide (1 mmol) was added in one portion. The reaction
was stirred at 80 or 100 °C and monitored by GC analysis. After
complete conversion of the starting material, the reaction was cooled to
0 °C, quenched by the addition of I2 (0.38 g, 1.5 mmol), and then stirred
at room temperature for 1 h. The resulting mixture was analyzed by GC
using n-tridecane as an internal standard to determine the yield of the
arylindium reagent. Note that, for some cases (4m and Scheme 2b, R = Ac),
indium was activated by BrCH2CH2Br (5 μL, 0.05 mmol) and Me3SiCl
(3 μL, 0.02 mmol) instead of allyl chloride.
Palladium-Catalyzed Cross-Coupling of Arylindium Re-
agents. Procedure A. An as-prepared arylindium reagent was diluted
by the addition of THF (0.8 mL) at room temperature, followed by
stirring for 15 min. The mixture was allowed to stand for 10 min, and the
supernatant solution was carefully transferred via syringe to another
Schlenk tube, which had been charged with an aryl iodide, Pd(OAc)2
(4 mol %), S-Phos (8 mol %), and THF (0.5 mL). The resulting mixture
was heated to 80 °C and stirred for 12ꢀ22 h. The reaction was allowed
to cool to room temperature, diluted with EtOAc (5 mL), and quenched
by the addition of saturated aqueous solution of NH4Cl (1 mL). The
aqueous layer was extracted with ethyl acetate (3 ꢁ 10 mL). The
combined organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel chroma-
tography to afford a cross-coupling product.
Palladium-Catalyzed Cross-Coupling of Arylindium Re-
agents. Procedure B. An as-prepared arylindium reagent was diluted
by the addition of THF (1.0 mL) at room temperature, followed by
stirring for 15 min. The mixture was allowed to stand for 10 min, and the
supernatant solution was carefully transferred via syringe to another
Schlenk tube, which had been charged with an aryl iodide, Pd(OAc)2
(4 mol %), S-Phos (8 mol %), and NMP (0.8 mL). The resulting mixture
was heated to 80 °C and stirred for 12ꢀ20 h. Workup and purification
were performed similarly as described for procedure A.
Ethyl (1,10-Biphenyl)-4-carboxylate (5b). The reaction of phenylin-
dium reagent (Figure 1, 4a) was performed according to the procedure
A using ethyl 4-iodobenzoate (126 μL, 0.75 mmol) with a reaction time
of 21 h. Silica gel chromatography (eluent: hexane/EtOAc = 19/1) of
the crude product afforded the title compound as a colorless solid (161.2 mg,
95%). The 1H and 13C NMR spectra showed good agreement with the
literature data (see the Supporting Information).15
5,6-Dimethoxy(1,10:40,100-terphenyl)-3-carbaldehyde (5c). The reac-
tion of 4-biphenylindium reagent (Figure 1, 4c) was performed accord-
ing to procedure A using 3-iodo-4,5-dimethoxybenzaldehyde (219 mg,
0.75 mmol) with a reaction time of 19 h. Silica gel chromatography
(eluent: hexane/EtOAc = 4/1) of the crude product afforded the title
compound as a brown solid (215.0 mg, 90%): mp = 97ꢀ98 °C; Rf 0.30
(hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H),
3.99 (s, 3H), 7.36ꢀ7.40 (m, 1H), 7.45ꢀ7.49 (m, 3H), 7.54 (d, J = 1.8
Hz, 1H), 7.63ꢀ7.70 (m, 6H), 9.95 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 56.2, 61.0, 109.7, 127.1 (2C), 127.2 (2C), 127.4, 127.6,
128.9 (2C), 129.7 (2C), 132.6, 135.8, 136.1, 140.6, 140.7, 152.2, 153.9,
191.3; HRMS (ESI+) calcd for C21H19O3 [M + H]+ 319.1334, found
319.1336.
1-[40-Methoxy(1,10-biphenyl)-4-yl]ethanone (5d). The reaction of
4-methoxyphenylindium reagent (Figure 1, 4d) was performed accord-
ing to procedure A using 4-iodoacetophenone (162.4 mg, 0.66 mmol)
with a reaction time of 17 h. Silica gel chromatography (eluent: hexane/
EtOAc = 4/1) of the crude product afforded the title compound as a
white solid (127.1 mg, 85%). The 1H and 13C NMRspectra showed good
agreement with the literature data (see the Supporting Information).16
1-[40-Fluoro(1,10-biphenyl)-4-yl]ethanol (5e). The reaction of 4-fluo-
rophenylindium reagent (Figure 1, 4g) was performed according to
procedure B using 1-(4-iodophenyl)ethanol (188.5 mg, 0.76 mmol)
with a reaction time of 12 h. Silica gel chromatography (eluent: hexane/
EtOAc = 3/2) of the crude product afforded the title compound as a light
brown solid (156.2 mg, 95%): mp = 100ꢀ102 °C; Rf 0.58 (hexane/
EtOAc = 3/2); 1H NMR (400 MHz, CDCl3) δ 1.54 (d, J = 6.9 Hz, 3H),
2.04 (s, 1H), 4.95 (q, J = 5.9 Hz, 1H), 7.10ꢀ7.16 (m, 2H), 7.44 (d, J =
8.2 Hz, 2H), 7.52ꢀ7.56 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 25.4,
70.3, 115.8 (d, 2JCꢀF = 21.9 Hz, 2C), 126.1 (2C), 127.3 (2C), 128.7 (d,
3JCꢀF = 8.6 Hz, 2C), 137.1 (d, 4JCꢀF = 2.9 Hz), 139.6, 145.0, 162.6 (d,
1JCꢀF = 245.2 Hz); HRMS (ESI+) calcd for C14H13OFNa [M + Na]+
239.0848, found 239.0844.
1-[40-(Trifluoromethyl)(1,10-biphenyl)-4-yl]ethanone (5f). The reac-
tion of 4-trifluoromethylphenylindium reagent (Figure 1, 4h) was per-
formed according to procedure A using 4-iodoacetophenone (172.2 mg,
0.70 mmol) with a reaction time of 18 h. Silica gel chromatography
(eluent: hexane/EtOAc = 19/1) of the crude product afforded the title
1
compound as a white solid (170.2 mg, 92%). The H and 13C NMR
spectra showed good agreement with the literature data (see the Sup-
porting Information).17
Ethyl 4-(Phenanthren-9-yl)benzoate (5g). The reaction of 9-phe-
nanthrenylindium reagent (Figure 1, 4k) was performed according to
procedure A using ethyl-4-iodobenzoate (116 μL, 0.69 mmol) with a
reaction time of 18 h. Silica gel chromatography (eluent: hexane/
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NOTE
EtOAc = 19/1) of the crude product afforded the title compound as a
4.09 (q, J = 7.1 Hz, 2H), 7.35 (dd, J = 7.5, 1.2 Hz, 1H), 7.45ꢀ7.63 (m,
6H), 7.91 (dd, J = 7.8, 0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
13.8, 61.2, 124.1 (q, 3JCꢀF = 3.8 Hz), 124.3 (q, 1JCꢀF = 272 Hz), 125.5
(q, 3JCꢀF = 3.8 Hz), 128.1, 128.6, 130.4, 130.6 (q, 2JCꢀF = 32 Hz), 130.8,
131.2, 131.7, 132.0, 141.2, 142.6, 168.3; HRMS (ESI+) calcd for
C16H14F3O2 [M + H]+ 295.0946, found 295.0940.
white solid (164.4 mg, 73%): mp = 112ꢀ113 °C; Rf 0.35 (hexane/EtOAc =
1
19/1); H NMR (400 MHz, CDCl3) δ 1.46 (t, J = 7.1 Hz, 3H), 4.46
(q, J = 7.1 Hz, 2H), 7.53ꢀ7.57 (m, 1H), 7.62ꢀ7.72 (m, 6H), 7.86 (d, J =
8.2 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.2 Hz, 2H), 8.73 (d, J =
7.8 Hz, 1H), 8.79 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.6, 61.3, 122.8, 123.2, 126.8, 126.9 (2C), 127.1, 127.2, 127.8,
129.0, 129.7, 129.8 (2C), 130.3 (3C), 130.8, 130.9, 131.5, 137.9,
145.7, 166.8; HRMS (ESI+) calcd for C23H19O2 [M + H]+ 327.1385,
found 327.1389.
3-(Quinolin-3-yl)benzonitrile (5n). The reaction of 3-quinolylindium
reagent (Figure 1, 4s) was performed according to procedure A using
3-iodobenzonitrile (155.7 mg, 0.68 mmol) with a reaction time of 17 h.
Silica gel chromatography (eluent: hexane/EtOAc = 3/2) of the crude
product afforded the title compound as a faint yellow solid (147.2 mg,
40-Vinyl(1,10-biphenyl)-3-amine (5h). The reaction of 4-styrylindium
reagent (Figure 1, 4l) was performed according to procedure B using
3-iodoaniline (70 μL, 0.58 mmol) with a reaction time of 20 h. Silica gel
chromatography (eluent: hexane/EtOAc = 3/2) of the crude product
afforded the title compound as a light brown solid (72.5 mg, 64%): mp =
69ꢀ70 °C; Rf 0.56 (hexane/EtOAc = 3/2); 1H NMR (400 MHz,
CDCl3) δ 3.68 (brs, 2H), 5.23 (d, J = 11.0 Hz, 1H), 5.77 (d, J = 17.4 Hz,
1H), 6.63 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 17.6, 11.0 Hz, 1H), 6.87 (s,
1H), 6.97 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.42ꢀ7.46 (m,
2H), 7.48ꢀ7.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 113.8, 113.9,
114.4, 117.6, 126.7 (2C), 127.3 (2C), 129.8, 136.6, 136.7, 140.8, 141.9,
146.8; HRMS (ESI+) calcd for C14H14N [M + H]+ 196.1129, found
196.1135.
1
94%): mp = 141ꢀ142 °C; Rf 0.36 (hexane/EtOAc = 3/2); H NMR
(400 MHz, CDCl3) δ 7.58ꢀ7.64 (m, 2H), 7.69ꢀ7.77 (m, 2H), 7.88 (d,
J = 8.2 Hz, 1H), 7.92 (dt, J = 7.8, 1.6 Hz, 1H), 7.96 (t, J = 1.4 Hz, 1H),
8.14 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 113.6, 118.6, 127.6, 127.8, 128.3, 129.5,
130.2, 130.3, 131.0, 131.6, 131.7, 131.8, 133.9, 139.4, 147.9, 149.2;
HRMS (ESI+) calcd for C16H11N2 [M + H]+ 231.0922, found 231.0927.
Ethyl 4-(Thiophene-2-yl)benzoate (5o). The reaction of 2-thienylin-
dium reagent (Figure 1, 4t) was performed according to procedure A
using ethyl 4-iodobenzoate (124 μL, 0.74 mmol) with a reaction time of
16 h. Silica gel chromatography (eluent: hexane/EtOAc = 19/1) of the
crude product afforded the title compound as a colorless solid (156.4 mg,
91%). The 1H and 13C NMR spectra showed good agreement with the
literature data (see the Supporting Information).21
30-Nitro(1,10-biphenyl)-4-carbaldehyde (5i). The reaction of 4-for-
mylphenylindium reagent (Figure 1, 4m) was performed according to
procedure B using 3-iodonitrobenzene (154.4 mg, 0.62 mmol) with a
reaction time of 16 h. Silica gel chromatography (eluent: hexane/EtOAc =
9/1) of the crude product afforded the title compound as a white solid
N-[3-(5-Acetylthiophene-2-yl)phenyl]acetamide (5p). The reaction
of 2-(5-acetyl)thienylindium reagent (Scheme 2b, R = Ac) was per-
formed according to the procedure A using N-(3-iodophenyl)acetamide
(120.1 mg, 0.46 mmol) with a reaction time of 20 h. Silica gel chromato-
graphy (eluent: hexane/EtOAc = 1/4) of the crude product afforded the
title compound as a yellow solid (94.3 mg, 79%): mp = 173ꢀ174 °C; Rf
0.34 (hexane/EtOAc = 1/4); 1H NMR (400 MHz, DMSO-d6) δ 2.09 (s,
3H), 2.55 (s, 3H), 7.39 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.55
(d, J = 4.1 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 3.7 Hz, 1H), 8.05
(s, 1H), 10.12 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 24.0, 26.3,
116.2, 119.6, 120.5, 124.8, 129.7, 133.0, 135.0, 140.1, 142.7, 151.3, 168.6,
190.5; HRMS (ESI+) calcd for C14H14NO2S [M + H]+ 260.0745, found
260.0742.
1
(109.8 mg, 78%). The H and 13C NMR spectra showed good agree-
ment with the literature data (see the Supporting Information).18
1-[4-(Pyridin-3-yl)phenyl]ethanone (5j). The reaction of 4-acetyl-
phenylindium reagent (Figure 1, 4n) was performed according to the
procedure B using 3-iodopyridine (131.2 mg, 0.64 mmol) with a reac-
tion time of 18 h. Silica gel chromatography (eluent: hexane/EtOAc = 3/2)
of the crude product afforded the title compound as a faint yellow solid
1
(117.4 mg, 93%). The H and 13C NMR spectra showed good agree-
ment with the literature data (see the Supporting Information).19
40-Benzoyl-6-hydroxy-5-methoxy(,10-biphenyl)-3-carbaldehyde (5k).
The reaction of 4-benzoylphenylindium reagent (Figure 1, 4o) was
performed according to procedure B using 5-iodovaniline (187.7 mg,
0.675 mmol) with a reaction time of 18 h. Silica gel chromatography
(eluent: hexane/EtOAc = 3/2) of the crude product afforded the title
compound as a colorless gummy oil (139.1 mg, 62%): Rf 0.33 (hexane/
EtOAc = 3/2); 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 7.02 (s, 1H),
7.43ꢀ7.49 (m, 3H), 7.55ꢀ7.60 (m, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.82
(d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 9.87 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 56.5, 108.2, 126.5, 128.3, 128.4 (2C), 129.1 (2C),
129.4, 130.1 (2C), 130.2 (2C), 132.5, 136.5, 137.6, 140.7, 147.7, 149.1,
190.9, 196.4; HRMS (ESI+) clcd for C21H17O4 [M + H]+ 333.1127,
found 333.1135.
1,5-Dimethyl-2-phenyl-4-(thiophene-3-yl)-1H-pyrazol-3(2H)-one (5q).
The reaction of 3-thienylindium reagent (Figure 1, 4u) was performed
according to procedure A using iodoantipyrine (216.7 mg, 0.69 mmol) with
a reaction time of 22 h. Silica gel chromatography (eluent: hexane/EtOAc =
3/2) of the crude product afforded the title compound as a white solid
(153.0 mg, 82%): mp = 157ꢀ158 °C; Rf 0.19 (hexane/EtOAc = 3/2); 1H
NMR (400 MHz, CDCl3) δ2.42 (s, 3H), 3.11 (s, 3H), 7.26ꢀ7.30 (m, 1H),
7.34ꢀ7.36 (m, 1H), 7.43ꢀ7.48 (m, 5H), 7.66ꢀ7.67 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 12.7, 36.2, 107.1, 122.0, 124.1 (2C), 125.1, 126.6,
127.1, 129.3 (2C), 131.6, 135.4, 151.5, 164.6; HRMS (ESI+) calcd for
C15H15N2OS [M + H]+ 271.0905, found 271.0914.
1H and 13C NMR Analysis of Phenylindium Reagents. Phe-
nylindium Reagent 4a. The reagent 4a was prepared according to the
general procedure, followed by removal of most of the THF solvent
under vacuum. The NMR sample was prepared by dissolving the residue
4-(1H-Indol-5-yl)benzonitrile (5l). The reaction of 4-cyanophenylin-
dium reagent (Figure 1, 4p) was performed according to procedure B
using 5-iodoindole(162.8 mg, 0.67 mmol) with a reaction time of 19 h.
Silica gel chromatography (eluent: hexane/EtOAc = 3/2) of the crude
product afforded the title compound as a white solid (112.6 mg, 77%).
The 1H and 13C NMR spectra showed good agreement with the
literature data (see the Supporting Information).20
1
with THF-d8 (conc = ca. 0.2 M): H NMR (400 MHz, THF-d8) δ
7.01ꢀ7.03 (m), 7.07ꢀ7.11 (m), 7.14ꢀ7.18 (m), 7.24ꢀ7.25 (m), 7.46ꢀ
7.48 (m, 1H), 7.59ꢀ7.61 (m, 1H); 13C NMR (100 MHz, THF-d8) δ
127.1, 127.5, 128.1, 128.2, 137.5, 138.5. The signal of the ipso carbon was
not detected.
Phenylindium Reagent Prepared from a 1:1 Mixture of InCl3 and
PhMgBr. To a solution of InCl3 (466 mg, 2.1 mmol) in THF (4.6 mL)
was added a THF solution of PhMgBr (1.49 M, 1.4 mL, 2 mmol)
at ꢀ78 °C. The reaction was stirred for 2 h, and then most of the solvent
was removed under vacuum. The NMR sample was prepared by
dissolving the residue with THF-d8 (conc = ca. 0.3 M): 1H NMR
Ethyl 30-(Trifluoromethyl)(1,10-biphenyl)-2-carboxylate (5m). The
reaction of 4-ethoxycarbonylphenylindium reagent (Figure 1, 4q) was
performed according to the procedure A using 3-iodobenzotrifluoride
(92 μL, 0.64 mmol) with a reaction time of 12 h. Silica gel chromatog-
raphy (eluent: hexane/EtOAc = 19/1) of the crude product afforded the
title compound as a colorless oil (171.4 mg, 91%): Rf 0.33 (hexane/
EtOAc = 19/1); 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.1 Hz, 3H),
7567
dx.doi.org/10.1021/jo201174r |J. Org. Chem. 2011, 76, 7563–7568

The Journal of Organic Chemistry
NOTE
(400 MHz, THF-d8) δ 7.12ꢀ7.15 (t, J = 7.9 Hz, 1H), 7.17ꢀ7.21 (t, J =
7.8 Hz, 2H), 7.45ꢀ7.48 (d, J= 7.6 Hz, 2H); 13C NMR (100 MHz, THF-d8)
δ 128.2, 128.4, 137.4. The signal of the ipso carbon was not detected.
Phenylindium Reagent Prepared from a 1:2 Mixture of InCl3 and
PhMgBr. The reagent and the NMR sample were prepared by a similar
procedure as described above: 1H NMR (400 MHz, THF-d8) δ 7.01ꢀ
7.05 (t, J = 7.3 Hz, 1H), 7.08ꢀ7.13 (t, J = 7.3 Hz, 2H), 7.58ꢀ7.61 (d, J =
7.8 Hz, 2H); 13C NMR (100 MHz, THF-d8) δ 127.2, 127.6, 138.4. The
signal of the ipso carbon was not detected.
(d) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(8) Jin, M.-Y.; Yoshikai, N. J. Org. Chem. 2011, 76, 1972.
(9) For Co-catalyzed zinc insertion in acetonitrile, see: (a) Fillon, H.;
Gosmini, C.; Pꢀerichon, J. J. Am. Chem. Soc. 2003, 125, 3867.
(b) Kazmierski, I.; Gosmini, C.; Paris, J.-M.; Pꢀerichon, J. Tetrahedron
Lett. 2003, 44, 6417. (c) Gosmini, C.; Amatore, M.; Claudel, S.; Pꢀerichon,
J. Synlett 2005, 2171. (d) Kazmierski, I.; Gosmini, C.; Paris, J.-M.;
Pꢀerichon, J. Synlett 2006, 881.
(10) For LiCl-assisted zinc insertion in THF, see: (a) Krasovskiy, A.;
Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 6040. (b) Boudet, N.; Sase, S.; Sinha, P.; Liu, C. Y.; Krasovskiy, A.;
Knochel, P. J. Am. Chem. Soc. 2007, 129, 12358.
(11) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(b) Yasuda, M.; Haga, M.; Baba, A. Eur. J. Org. Chem. 2009, 5513.
(12) A possible stoichiometric equation that results in the formation
of PhInX2 and Ph2InX in 2:1 ratio is shown below. Note that InX3 in this
equation may be formed during the preactivation of In metal with allyl
chloride or 1,2-dibromoethane.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
the phenylindium reagents and the compounds 5aꢀq. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
12PhX þ 8In þ InX3 f 6PhInX2 þ 3Ph2InX
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
(13) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Milne, J. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2004, 126, 13028. (c) Martin, R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3844.
’ ACKNOWLEDGMENT
We thank Singapore National Research Foundation (NRF-
RF2009-05 to N.Y.) and Nanyang Technological University for
financial support.
(14) The use of indium powder that does not contain trace Mg often
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