Pd(0)-catalyzed decarboxylative coupling and tandem C-H arylation/decarboxylation for the synthesis of heteroaromatic biaryls

Article abstract of DOI:10.1021/jo3015837

An effective Pd(0) carbene complex was successfully employed in the decarboxylative coupling of the heteroaromatic carboxylic acids (imidazo[1,2-a]pyridine and isoxazole) with aryl halides. For carboxyindoles, either decarboxylative coupling or tandem C-H arylation and decarboxylation occurred, leading to the formation of C2-monoarylated indoles.

Full text of DOI:10.1021/jo3015837

Note
pubs.acs.org/joc
Pd(0)-Catalyzed Decarboxylative Coupling and Tandem C−H
Arylation/Decarboxylation for the Synthesis of Heteroaromatic
Biaryls
Debkumar Nandi, Yang-Ming Jhou, Jhen-Yi Lee, Bing-Chiuan Kuo, Chien-Yu Liu, Pei-Wen Huang,
and Hon Man Lee*
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: An effective Pd(0) carbene complex was
successfully employed in the decarboxylative coupling of the
heteroaromatic carboxylic acids (imidazo[1,2-a]pyridine and
isoxazole) with aryl halides. For carboxyindoles, either
decarboxylative coupling or tandem C−H arylation and
decarboxylation occurred, leading to the formation of C2-
monoarylated indoles.
eteroaromatic biaryls have attracted much attention
because of their significant commercial value. Arylated
imidazo[1,2-a]pyridine and isoxazole, regioselective decarbox-
ylative coupling cleanly occurred to afford the corresponding
biaryls. In cases involving carboxyindoles, 3-carboxyindole can
be utilized to produce C2-monoarylated indoles regioselec-
tively.
H
indoles, for example, exhibit broad pharmacological properties
in numerous therapeutic agents and natural products.1,2 Metal-
catalyzed Suzuki-type cross-coupling reactions have been
widely used in preparing biaryls.2 However, stoichiometric
organometallic substrates are required which give rise to
availability problems, metal waste, and the need for additional
synthetic steps. Recently, C−H arylation3−6 and decarbox-
ylative coupling7−9 have emerged as appealing approaches for
the construction of biaryls. Successive advances in C−H
arylation have allowed a broad range of heteroaromatic biaryls
to be synthesized,10−13 but poor regioselectively is a significant
limitation of these procedures. Decarboxylative coupling is an
equally interesting approach for preparing heteroaromatic
biaryls because the carboxyl group can direct the regioselectivity
and the only waste product from the reaction is CO2. However,
this approach is still largely unexplored,14−23 and reports on
simple monometallic Pd-based systems for the intermolecular
coupling of heteroaromatic carboxylic acids with aryl halides are
scarce.14−17 Forgione pioneered the synthesis of several
heteroaromatic biaryls via decarboxylative couplings with
Pd[P(t-Bu)3]2 as the catalyst.14,16 A number of different
heteroaromatic biaryls can successfully be achieved with the
use of aryl bromides. However, the reaction was found to be
limited by the specificity of the position of the carboxyl group
on the heterocyclic ring. While 2-fuoric acid can be
regioselectively C2-monoarylated, the analogous conversion
of 3-fuoric acid was not able to be observed. Miura’s work on
the 2,3-diarylation of carboxyindole derivatives employing
Pd(OAc)2/PCy3 is a recent example of decarboxylative
coupling involving indole derivatives.15 However, monoarylated
compound is not accessible by the method. Herein, we report
the coupling reactions between heteroaromatic carboxylic acids
and aryl bromides (and in certain cases, chlorides) to produce
decarboxylated biaryls. In cases involving carboxylic acids of
The decarboxylative carbometalation is most often the key
step in decarboxylative couplings.8 However, the difficulty
associated with this process is the general requirement of harsh
conditions for metal carboxylates to extrude CO2. The resulting
organometallic species is therefore unlikely to undergo a C−C
bond formation step but rather, fast protonation by the
surrounding medium. Thus, we developed a new Pd(0)
bis(carbene) complex 1 as a precatalyst for the decarboxylative
coupling of heteroaromatic carboxylic acids with aryl halides
(Chart 1). Facile bond activation via oxidative addition could
be expected from the Pd(0) carbene complex. Another notable
feature is the pendant amide arms of the carbene ligand. We
reasoned that this “biomimetic” functionality may involve in the
molecular recognition of carboxyl group and therefore facilitate
its extrusion. The new complex can be prepared very readily
following the procedure of relevant compounds reported by
us.24 The structure of 1 was established by X-ray crystallo-
graphic analysis (see the Supporting Information). A desirable
characteristic for practical application of 1 is its high stability in
air.
The initial investigation was aimed at revealing the
effectiveness of 1 in the decarboxylation activity of a range of
heteroaromatic carboxylic acids. As shown in Table 1, 1 was
capable of mediating the decarboxylation of carboxylic acids of
imidazo[1,2-a]pyridine and isoxazole smoothly at 160 °C with
a modest 2.5 mol % of Pd loading (entries 1 and 2). In sharp
contrast, the catalyst system was unable to convert both 2- and
Received: July 31, 2012
Published: September 24, 2012
© 2012 American Chemical Society
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Note
Chart 1. Synthesis of the Pd(0) Precatalyst
Table 1. Study of Decarboxylation Reaction for Various
Heteroaromatic Systems
Table 2. Decarboxylative Arylation of Imidazo[1,2-
a]pyridine-3-carboxylic Acid with Aryl Halides
a
a
entry
X
R1
product
yield (%)
1
2
3
4
5
6
Br
Cl
Br
Br
Br
Br
4-COMe
4-COMe
4-CN
6
74
65
88
73
74
79
6
7
H
8
4-Me
9
3-OMe
10
a
Reaction conditions: 1.3 mmol of imdazol[1,2-a]pyridine-3-carbox-
ylic acid, 1.3 mmol of ArX, 2.6 mmol of KOAc, 2 mL of dry DMA, 2.5
mol % of cat., 160 °C, 24 h.
a
Reaction conditions: 1 mmol of heteroaromatic carboxylic acid, 2
Table 3. Decarboxylative Arylation of 3-(4-Fluorophenyl)-5-
methylisoxazole-4-carboxylic Acid with Aryl Halides
mmol of KOAc, 3 mL of dry DMA, 2.5 mol % of 1, 24 h.
a
3-carboxyindoles into the corresponding decarboxylated
products (entries 3−5). Even under the harsh condition of
200 °C, the decarboxylation of 5′ was still very sluggish
affording only a 10% yield of the decarboxylative product (entry
6).
Since 1 can effectively mediate the decarboxylation of 2′ and
3′, it is expected that the aryl Pd species involved should be
able to cross-couple with aryl halides. Indeed, under similar
decarboxylation conditions and in the presence of aryl halides,
1 successfully catalyzed the decarboxylative couplings of these
substrates leading to the formation of the desirable biaryls.
Using aryl bromides as coupling partners, imidazoles 6−10
were obtained with yields in the range of 73−88% (Table 2,
entries 1, 3−6). Notably, the decarboxylative couplings were
highly regioselective, with the C−C bonds formed only at the
C5 position of the imidazole rings, following the same reactivity
trend of C−H arylation when preparing similar imidazole
compounds.25 In addition to aryl bromides, the catalyst system
was also able to utilize less reactive aryl chloride as substrates.
Thus, 6 could also be obtained from 4-chloroacetophenone
albeit in a slightly lower yield than that from the bromide
analog (65% vs 74%; entries 1 and 2). Similarly, the isoxazole 3′
was also successfully applied in decarboxylative couplings with a
range of aryl halides to afford various novel heteroaromatic
biaryls in a range of 65−90% yields (Table 3). The X-ray
structure of 6 was obtained (see the Supporting Information).
Interestingly, even though the catalyst system was unable to
affect the decarboxylation of 2- or 3-carboxyindoles, these
substrates could still be employed successfully in the coupling
reactions with aryl halides to produce decarboxylated biaryls. In
the case of 3-carboxyindoles, intriguingly, a tandem C−H
entry
X
R1
product
yield (%)
1
2
3
4
5
Br
Cl
Br
Br
Br
COMe
CN
11
12
12
13
14
81
65
90
67
71
CN
OMe
H
a
Reaction conditions: 0.5 mmol of 3′, 0.5 mmol of ArX, 1.0 mmol of
KOAc, 2 mL of dry DMA, 2.5 mol % of 1, 160 °C, 24 h.
arylation/decarboxylation reaction occurred, leading to the
exclusive formation of C2-arylated product despite the acid
group at the C3 position (Table 4). The C3-arylated or 2,3-
diarylated products were not observed, and only unreacted
starting materials remained in the reaction mixture. Thus, C2-
arylated products were obtained in decent yields (45−63%)
from a range of aryl bromides having electron-donating or
-withdrawing groups. In Miura’ work, the same reaction
between 4′ and PhBr did not yield the monoarylated product
19A but a mixture of 1-methyl-2-phenyl-1H-indole-3-carboxylic
acid and 2,3-diphenylated product.15 In contrast, a decent 62%
yield of 19A was obtained in this work (entry 6). The X-ray
structures of 17A, 21A, and 23A were obtained (see the
Supporting Information).
The analogous conversion of the C2 substrate (4″) was
subsequently investigated in order to establish whether it was
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Note
the arylation reaction using 4 as substrate led to a mixture of
C2- and C3-arylated compounds with 41 and 20% yields
respectively (Scheme 1). In contrast, employing 4′ as substrate,
15A can be obtained in 60% yield as a single product (Table 4,
entry 1).
Table 4. Tandem C−H Arylation and Decarboxylation of 1-
a
Alkylindole-3-carboxylic Acid and Aryl Halides
To evaluate the effectiveness of our monometallic Pd catalyst
system, the same reaction between 3′ and 4-bromobenzonitrile
was repeated with Becht’s bimetallic Pd/Ag catalytic con-
ditions.27 The high Pd loading of 30 mol % afforded a yield of
68% (Scheme 2). The use of 1 (2.5 mol %) in Becht conditions
entry
R1
X
R2
product
yield (%)
1
2
Me (4′)
Bn (5′)
Me
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
4-COMe
4-COMe
4-CN
15A
16A
17A
17A
18A
19A
20A
21A
22A
23A
60
58
53
35
63
62
45
50
48
45
3
Scheme 2. Decarboxylative Coupling under Becht
Conditions
4
Me
4-CN
5
Bn
4-CN
6
Me
H
7
Me
3,4,5-OMe
Ph
8
Me
9
Me
3-OMe
4-Me
10
Me
a
Reaction conditions: 3.0 mmol of 4′ or 5′, 3.0 mmol of aryl halide,
6.0 mmol of KOAc, 4 mL of dry DMA, 2.5 mol % of 1, 160 °C, 24 h.
gave a yield of 72%. In both cases, the yields were inferior to
the 90% yield obtained by our conditions (see entry 3, Table
3). We also compared the efficiency of our catalyst system with
that reported by Forgione,16 the reaction between 4′ and 4-
bromobenzonitrile was repeated under his conditions employ-
ing MW heating (Scheme 3). A 55% yield was obtained,
also possible. In this case, ipso decarboxylative coupling
occurred more favorably, leading to the formation of C2-
arylated indole as the major compound (Table 5). Similar to
Table 5. Decarboxylative Coupling of 1-Methylindole-2-
a
carboxylic Acid with Aryl Halides
Scheme 3. Tandem C−H Arylation/Decarboxylation under
Forgione Conditions
entry
X
R1
product
yield (%)
selectivity
1
2
3
4
5
Br
Br
Cl
Br
Br
4-COMe
4-CN
4-CN
H
15A,B
17A,B
17A,B
19A
58
61
41
52
46
3:1
3:1
3:1
3-OMe
22A
whereas the replacement of Pd(P(t-Bu)3)2 with 1 under
Forgione conditions gave a yield of 50%. These yields were
comparable to the 53% yield obtained by our conditions (see
entry 4, Table 3). Finally, we compared the catalytic activities of
1 with other catalyst systems (see Table S3, Supporting
Information). In general, the Pd(0) carbene catalyst out-
performed those based on Pd/PR3 in regard to both yield and
the selectivity of the product.
The catalyst system based on 1 exhibits remarkable
chemoselectivity. In the case of substrates 2′ and 3′,
decarboxylation was possible, but decarboxylative couplings
occur preferentially leading to the desired biaryl products. For
3-carboxyindole (4′ and 5′), no decarboxylation was possible,
whereas coupling reaction occurred leading to the 2-arylated
a
Reaction conditions: 3.0 mmol of 4″, 3.0 mmol of aryl halide, 6.0
mmol of KOAc, 4 mL of dry DMA, 2.5 mol % of cat., 160 °C, 24 h.
the C3 substrates, various aryl halides were successfully
employed. Interestingly, a certain amount of C3-arylated
products were also observed in several cases (entries 1−3).
The structure of 17B was also established by X-ray structural
study (see the Supporting Information).
Since 1 is also capable of mediating the C−H arylation, it
would be of interest to compare its effectiveness in catalyzing
C−H arylation and decarboxylative transformation to obtain
the monarylated indole. Following our previously established
conditions of C−H arylation using a Pd(II) carbene complex,26
Scheme 1. C−H Arylation Catalyzed by 1
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Note
Scheme 4. Proposed Catalytic Cycles for the Coupling Reaction with (a) 3-Carboxyindole and (b) 2-Carboxyindole
recorded at 300.13 and 75.48 MHz, respectively. ESI-MS was carried
out on a sector field mass spectrometer.
indole. In the case of the 2-carboxyindole (4″), its
decarboxylation was also not possible, and ipso decarboxylative
coupling occurred favorably. For the decarboxylation reactions
in Table 1, a Pd(0) species is probably involved in the oxidative
addition of the O−H bonds. The decarboxylated product was
obtained after the extrusion of CO2 and reductive elimination
(see Scheme S1, Supporting Information). The results in Table
1 also implied that the decarboxylative couplings with 2′ and 3′
(see Table 2 and 3) share a similar catalytic cycle, whereas the
reactions with 4′, 4″, and 5′ involve alternative mechanisms
(see Tables 4 and 5). Liu reported the monometallic Pd-
catalyzed decarboxylative coupling of potassium polyfluoro-
benzoates with aryl halides and triflates and the computational
analysis of the mechanism.17 A similar mechanism could be
constructed for the decarboxylative couplings with 2′ and 3′
(see Scheme S2, Supporting Information). For the coupling
reactions with 4′, 4″, and 5′ as substrates, unlike the
mechanistic pathways for 2′ and 3′, electrophilic palladations
as reported by Forgione were involved.14,16 For 3-carbox-
yindoles, both C2 and C3 electrophilic palladations were
possible, forming species A and B, respectively (Scheme 4a).
The latter species can transform rapidly into the former species
via facile C3 to C2 migration. The species A can then generate
the C2-arylated product via 1,2-H shift and decarboxylation.
For 2-carboxyindole as substrate (Scheme 4b), the species B
from C3 palladation can also undergo facile C3 to C2
migration, leading subsequently to the same C2-arylated
product. Notably, this species can also proceed via 1,2-H shift
and then decarboxylation, leading to the eventual formation of
the C3-arylated compound as the minor product.
Synthesis of [LH]+Cl−. To a 100 mL Schlenk flask were added 1-
(2,4,6-trimethylphenyl)-1H-imidazole (2.87 g, 15.4 mmol), 2-chloro-
N-methyl-N-phenylacetamide (1.94 g, 15.4 mmol), and dry DMF. The
mixture was allowed to stir at 100 °C for 2 days. After the mixture was
cooled to room temperature, the solvent was removed completely
under vacuum. The residue was washed thoroughly with THF. The
white solid formed was then filtered on a frit and dried under vacuum.
1
Yield: 3.98 g, 70%. Mp = 237.4−238.7 °C dec. H NMR (CDCl3): δ
2.03 (s, 6H), 2.29 (s, 3H), 3.29 (s, 3H), 5.53 (s, 2H), 6.95 (s, 2H),
7.05−7.56 (m, 7H), 10.49 (s, 1H). 13C{1H} NMR (CDCl3): δ 17.4,
17.4, 21.0, 37.8, 51.7, 122.1, 124.5, 127.6, 128.8, 129.6, 130.3, 130.7,
134.3, 134.3, 139.8, 140.8, 141.0, 164.3. Anal. Calcd for C21H24ClN3O:
C, 68.19; H, 6.54; N, 11.36. Found: C, 68.33; H, 6.61; N, 11.36.
Synthesis of 1. To a 50 mL Schlenk flask containing the Pd(0)
precursor28 (0.41 g, 1.10 mmol), [LH]+Cl− (0.81 g, 2.20 mmol), and
K2CO3 (0.31 g, 2.20 mmol) was added dry DMF (10 mL). The
mixture was allowed to stir for 5 h at ambient temperature. The
solvent was completely removed under vacuum. The residue was
dissolved in CH2Cl2. The organic layer was then washed twice with
water. After drying with anhydrous MgSO4, the solvent was completely
removed under vacuum. The residue was washed with diethyl ether.
The pale yellow solid was then filtered on a frit and dried under
vacuum. Crystals suitable for X-ray diffraction studies were obtained by
vapor diffusion of Et2O into a CH2Cl2 solution containing 1. Yield:
0.62 g, 65%. Mp = 231.2−232.9 °C dec. 1H NMR (CDCl3): δ 1.43 (s,
3H), 1.67 (s, 3H), 1.77 (s, 3H), 2.03 (s, 3H), 2.07 (s, 3H), 2.23 (s,
2
3H), 2.33 (s, 1H), 3.02 (d, JHH = 18 Hz, 1H), 3.20 (s, 3H), 3.25 (s,
1H), 3.31 (s, 3H), 4.06 (d, 2JHH = 18 Hz, 1H), 4.40 (d, 2JHH = 18 Hz,
2
1H), 5.15 (d, JHH = 18 Hz, 1H), 6.08 (s, 1H), 6.56 (s, 1H), 6.61 (s,
2H), 6.71 (s, 1H), 6.88 (s, 2H), 6.97 (s, 1H), 7.26−7.29 (m, 4H),
7.41−7.57 (m, 6H). 13C{1H} NMR (CDCl3): δ 17.3, 17.4, 18.0, 18.5,
21.1, 21.2, 37.2, 38.7, 38.9, 39.3, 51.2, 53.3, 122.0, 122.3, 122.6, 123.2,
127.0, 127.9, 128.1, 128.7, 128.9, 129.0, 129.9, 130.5, 134.5, 135.2,
135.8, 136.8, 137.0, 137.8, 138.0, 138.1, 141.7, 142.6, 166.2, 166.5,
173.9, 174.1, 188.7, 193.1. Anal. Calcd for C46H48N6O5Pd: C, 63.40;
H, 5.55; N, 9.64. Found: C, 62.97; H, 5.70; N, 9.43.
Typical Procedure for Decarboxylation Reaction. To a 50 mL
flask fitted with a magnetic stirrer were added imidazo[1,2-a]pyridine-
3-carboxylic acid (0.162 g, 1.00 mmol), KOAc (0.196 g, 2.00 mmol),
and 1 (0.022 g, 0.025 mmol) (2.5 mol %) under N2. Dry DMA (2 mL)
was added to it. The reaction mixture was stirred at 160 °C for 24 h
and then was allowed to cool at room temperature. After dilution with
distilled water (15 mL), the solution was extracted with EtOAc (3 ×
15 mL). The organic layer was separated and dried over anhydrous
MgSO4. Removal of the solvent resulted in a brownish gummy mass
which was subjected to column chromatography over silica gel using n-
hexane and an increasing proportion of EtOAc as eluent.
In summary, we have identified a new, effective monometallic
Pd catalyst for the regioselective syntheses of decarboxylated
biaryls from heteroaromatic carboxylic acids. To our knowl-
edge, this is the first example of preformed Pd(0) carbene
complex employed in such reactions. The high chemoselectivity
exhibited by 1 ensured the success of these processes. Such
methodology for obtaining heteroaromatic biaryls is an
attractive alternative complementary to the C−H arylations
previously reported in the literature.
EXPERIMENTAL SECTION
■
All manipulations were performed under a dry nitrogen atmosphere
using standard Schlenk techniques. Solvents were dried with standard
procedures. Starting chemicals were purchased from commercial
1
sources and used as received. H and 13C{1H} NMR spectra were
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Note
Imidazo[1,2-a]pyridine (2).29 Brownish liquid. Yield: 0.08 g,
99%. 1H NMR (300 MHz, CDCl3): δ 6.49 (td, J = 6.9 Hz, J = 1.2 Hz,
1H), 6.88 (ddd, J = 9.3 Hz, J = 6.7 Hz, J = 1.2 Hz, 1H), 7.33−7.41 (m,
3H), 7.87 (dt, J = 6.9 Hz, J = 1.2 Hz, 1H).
(300 MHz, CDCl3): δ 2.43 (s, 3H), 6.98 (t, J = 8.7 Hz, 2H), 7.23−
7.33 (m, 4H), 7.63 (d, J = 8.1 Hz, 2H). 13C{1H} NMR (75 MHz,
CDCl3): δ 11.8, 111.7, 114.4, 116.0 (d, JCF = 22.6 Hz), 118.4, 124.5 (d,
JCF = 3.0 Hz), 128.0, 130.3, 130.4 (d, JCF = 9.1 Hz), 132.6, 132.9,
135.2, 163.6 (d, JCF = 249.1 Hz), 167.5.
3-(4-Fluorophenyl)-5-methylisoxazole (3).30 Colorless viscous
compound. Yield: 0.078 g, 98%. 1H NMR (300 MHz, CDCl3): δ 2.44
(s, 3H), 6.22 (s, 1H), 7.10 (t, J = 9.0 Hz, 2H), 7.71−7.76 (m, 2H).
1-Benzylindole (5).31 Yellowish liquid. Yield: 0.01 g, 10% yield.
1H NMR (300 MHz, CDCl3): δ 5.32 (s, 2H), 6.55 (d, J = 1.5 Hz, 1H),
3-(4-Fuorophenyl)-4-(4-methoxyphenyl)-5-methyl-1,2-oxa-
zole (13). Yellow solid. Yield: 0.095 g, 67%. Mp = 92.3−92.7 °C.
1
HRMS (EI): calcd C17H14FNO2 283.1005, found 283.1002. H NMR
(300 MHz, CDCl3): δ 2.27 (s, 3H), 3.68 (s, 3H), 6.76 (d, J = 9.0 Hz,
2H), 6.85 (t, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 7.25−7.30 (m,
2H). 13C{1H} NMR (75 MHz, CDCl3): δ 29.7, 55.3, 114.3, 115.3,
115.6 (d, JCF = 21.9 Hz), 122.2, 125.4, 130.3 (d, JCF = 8.3 Hz), 131.0,
159.2, 160.3, 163.4 (d, JCF = 249.1 Hz), 166.6.
7.09−7.31 (m, 9H), 7.65 (d, J = 3.8 Hz, 1H).
Typical Procedure for Decarboxylative Coupling of Imidazo-
[1,2-a]pyridine-3-carboxylic Acid with Aryl Halides. To a 50 mL
flask fitted with magnetic stirrer were added imidazo[1,2-a]pyridine-3-
carboxylic (0.211 g, 1.30 mmol), 4-bromobenzonitrile (0.236 g, 1.30
mmol), KOAc (0.255 g, 2.60 mmol), and 1 (0.028 g, 0.032 mmol)
(2.5 mol %) under nitrogen. Dry DMA (3 mL) was added to it. The
reaction mixture was stirred at 160 °C for 24 h and then was allowed
to cool at room temperature. After dilution with distilled water (15
mL), the solution was extracted with EtOAc (3 × 15 mL). The organic
layer was separated and dried over anhydrous MgSO4. Removal of the
solvent resulted in a brownish gummy mass which was subjected to
column chromatography over silica gel using n-hexane and an
increasing proportion of EtOAc as eluent.
3-(4-Fluorophenyl)-5-methyl-4-phenylisoxazole (14).34 Yel-
low solid. Yield: 0.090 g, 71%. 1H NMR (300 MHz, CDCl3): δ 2.42 (s,
3H), 6.98 (t, J = 8.7 Hz, 2H), 7.13−7.16 (m, 2H), 7.33−7.43 (m, 5H).
Preparation of 12 under Becht Conditions. A degassed DMSO
solution (6 mL) containing a mixture of 4-bromobenzonitrile (0.090 g,
0.50 mmol, 1.0 equiv), 3′ (0.115 g, 0.50 mmol, 1.0 equiv), Ag2CO3
(0.414 g, 1.5 mmol, 3.0 equiv), AsPh3 (0.092 g, 0.30 mmol, 0.6 equiv),
and PdCl2 (0.027 g 0.15 mmol, 30 mol %) or 1 (0.011 g, 2.5 mol %)
was heated under N2 at 150 °C for 6 h. The workup procedure was
that reported in the literature.27 Yields: 0.095 g, 68% from PdCl2; 0.10
g, 72% from 1.
4-Imidazo[1,2-a]pyridin-3-ylacetophenone (6).25 Yellow solid.
Yield: 0.23 g, 74%. 1H NMR (300 MHz, CDCl3): δ 2.62 (s, 3H), 6.84
(t, J = 6.9 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.64−7.76 (m, 3H), 7.77
(s, 1H), 8.07 (d, J = 7.8 Hz, 2H), 8.37 (d, J = 6.9 Hz, 1H).
4-Imidazo[1,2-a]pyridin-3-ylbenzonitrile (7).25 Orange solid.
Typical Procedure for Coupling Reactions of Carboxyin-
doles with Aryl Halides. To a 50 mL flask fitted with magnetic
stirrer were added N-methylindole-3-carboxylic acid (0.526 g, 3.00
mmol), 4-bromobenzonitrile (0.596 g, 3.00 mmol), KOAc (0.588 g,
6.00 mmol), and 1 (0.065 g, 0.075 mmol) (2.5 mol %) under N2. Dry
DMA (4 mL) was added to it. The reaction mixture was stirred at 160
°C for 24 h and then was allowed to cool at room temperature. After
dilution with distilled water (15 mL), the solution was extracted with
EtOAc (3 × 15 mL). The organic layer was separated and dried over
anhydrous MgSO4. Removal of the solvent resulted in a brownish
gummy mass which was subjected to column chromatography over
silica gel using n-hexane and an increasing proportion of EtOAc as
eluent.
1
Yield: 0.25 g, 88%. H NMR (300 MHz, CDCl3): δ 6.85 (td, J = 6.9
Hz, J = 1.2 Hz, 1H), 7.22 (ddd, J = 9.0 Hz, J = 6.9 Hz, J = 1.2 Hz, 1H),
7.62−7.75 (m, 6H), 8.32 (dt, J = 6.9 Hz, J = 0.9 Hz, 1H).
3-Phenylimidazo[1,2-a]pyridine (8).32 Brownish liquid. Yield:
0.18 g, 73%. 1H NMR (300 MHz, CDCl3): δ 6.67 (td, J = 6.9 Hz, J =
1.2 Hz, 1H), 7.06 (ddd, J = 9.0 Hz, J = 6.6 Hz, J = 1.2 Hz, 1H), 7.25−
7.59 (m, 7H), 8.19 (dt, J = 6.9 Hz, J = 1.2 Hz, 1H).
3-(4-Methylphenyl)imidazo[1,2-a]pyridine (9).33 Brownish
1
liquid. Yield: 0.21 g, 75%. H NMR (300 MHz, CDCl3): δ 2.30 (s,
2-(p-Acetylphenyl)-1-methylindole (15A).35 Yellow solid.
3H), 6.64 (td, J = 6.9 Hz, J = 1.2 Hz, 1H), 7.03 (ddd, J = 9.0 Hz, J =
6.6 Hz, J = 1.2 Hz, 1H), 7.16−7.31 (m, 4H), 7.54−7.57 (m, 2H), 8.16
(dt, J = 6.9 Hz, J = 1.2 Hz, 1H).
1
Yield: 0.45 g, 60%. H NMR (300 MHz, CDCl3): δ 2.65 (s, 3H),
3.77 (s, 3H), 6.65 (s, 1H), 7.16 (t, J = 6.9 Hz, 1H), 7.24−7.30 (m,
1H), 7.37 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 6.9 Hz, 3H), 8.04 (d, J = 6.6
Hz, 2H).
3-(3-Methoxyphenyl)imidazo[1,2-a]pyridine (10).33 Brown
1
solid. Yield: 0.23 g, 79%. H NMR (300 MHz, CDCl3): δ 3.71 (s,
3-(p-Acetylphenyl)-1-methylindole (15B).36 Yellow solid.
3H), 6.63 (td, J = 6.9 Hz, J = 0.9 Hz, 1H), 6.78−6.82 (m, 1H), 6.94−
7.05 (m, 3H), 7.27 (t, J = 8.1 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.58
(s, 1H), 8.20 (d, J = 6.9 Hz, 1H).
1
Yield: 0.11 g, 15%. H NMR (300 MHz, CDCl3): δ 2.64 (s, 3H),
4.09 (s, 3H), 7.13−7.18 (m, 1H), 7.34−7.39 (m, 2H), 7.46 (s, 1H),
7.68−7.72 (m, 3H), 8.04 (d, J = 7.8 Hz, 2H).
1,1′-[(1-Methyl-1H-indole-2,3-diyl)dibenzene-4,1-diyl]-
diethanone (15C). Yellow solid. Yield: 0.16 g, 15%. Mp = 189.7−
190.2 °C. HRMS (EI): calcd C25H21NO2 367.1572, found 367.1579.
1H NMR (300 MHz, CDCl3): δ 2.57 (s, 3H), 2.63 (s, 3H), 3.70 (s,
Typical Procedure for Decarboxylative Coupling of 3-(4-
Fluorophenyl)-5-methylisoxazole-4-carboxylic Acid with Aryl
Halides. To a 50 mL flask fitted with magnetic stirrer were added 3-
(4-fluorophenyl)-5-methylisoxazole-4-carboxylic acid (0.110 g, 0.50
mmol), 4-bromobenzonitrile (0.091 g, 0.50 mmol), KOAc (0.098 g,
1.00 mmol), and 1 (0.011 g, 0.0125 mmol) (2.5 mol %) under
nitrogen. Dry DMA (2 mL) was added to it. The reaction mixture was
stirred at 160 °C for 24 h and then was allowed to cool at room
temperature. After dilution with distilled water (15 mL), the solution
was extracted with EtOAc (3 × 15 mL). The organic layer was
separated and dried over anhydrous MgSO4. Removal of the solvent
resulted in a brownish gummy mass which was subjected to column
chromatography over silica gel using n-hexane and an increasing
proportion of EtOAc as eluent.
3H), 7.22−7.25 (m, 1H), 7.32−7.45 (m, 6H), 7.78 (d, J = 6.0 Hz,
1H), 7.86 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 9.0 Hz, 2H). 13C{1H} NMR
(75 MHz, CDCl3): δ 26.6, 26.7, 31.2, 110.0, 115.1, 119.6, 121.0, 123.1,
128.6, 129.7, 131.3, 134.5, 136.4, 136.6, 137.8, 140.3, 197.6, 197.7.
1-[4-(1-Methyl-1H-indol-2-yl)phenyl]ethanone (16A). Yellow
solid. Yield: 0.56 g, 58%. Mp = 129.8−130.2 °C. HRMS (EI): calcd
1
C23H19NO 325.1467, found 325.1468. H NMR (300 MHz, CDCl3):
δ 2.60 (s, 3H), 5.38 (s, 2H), 6.75 (s, 1H), 7.04 (d, J = 8.1 Hz, 2H),
7.17−7.32 (m, 6H), 7.53 (dd, J = 6.6 Hz, J = 1.8 Hz, 2H), 7.68−7.71
(m, 1H), 7.96 (d, J = 6.0 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3):
δ 29.7, 47.9, 103.7, 110.7, 120.5, 120.9, 122.6, 125.8, 127.3, 128.2,
128.6, 128.9, 129.0, 136.2, 137.3, 137.9, 138.6, 140.4, 197.6.
1-Methyl-2-(4′-cyanophenyl)indole (17A).37 Orange-red solid.
Yield: 0.37 g, 53%. 1H NMR (300 MHz, CDCl3): δ 3.76 (s, 3H), 6.65
(s, 1H), 7.17 (td, J = 6.9 Hz, J = 0.9 Hz, 1H), 7.29 (td, J = 6.9 Hz, J =
1.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.60−7.66 (m, 3H), 7.74 (d, J =
9.0 Hz, 2H).
1-[4-[3-(4-Fluorophenyl)-5-methyl-1,2-oxazol-4-yl]phenyl]-
ethanone (11). Yellow solid. Yield: 0.12 g, 81%. Mp = 99.3−99.8 °C.
1
HRMS (EI): calcd C18H14FNO2 295.1009, found 295.0999. H NMR
(300 MHz, CDCl3): δ 2.44 (s, 3H), 2.58 (s, 3H), 6.98 (t, J = 8.7 Hz,
2H), 7.25 (d, J = 1.8 Hz, 2H), 7.33−7.38 (m, 2H), 7.94 (d, J = 6.6 Hz,
2H). 13C{1H} NMR (75 MHz, CDCl3): δ 11.8, 26.7, 114.9, 115.8 (d, J
= 21.9 Hz), 124.8, 127.5, 128.8, 129.9, 130.5 (d, J = 7.5 Hz), 135.2,
136.3, 160.2, 163.5 (d, J = 249.1 Hz), 167.3, 197.6.
1-Methyl-3-(4′-cyanophenyl)indole (17B). Orange-red solid.
4-[3-(4-Fluorophenyl)-5-methyl-4-isoxazolyl]benzonitrile
1
(12). Orange-red solid. Yield: 0.13 g, 90%. Mp = 129.8−130.2 °C.
Yield: 0.11 g, 16%. Mp: = 136.5−137.1 °C. H NMR (300 MHz,
1
HRMS (EI): calcd C17H11FN2O 278.0855, found 278.0848. H NMR
CDCl3): δ 3.85 (s, 3H), 7.20−7.40 (m, 4H), 7.65−7.76 (m, 4H), 7.91
9388
dx.doi.org/10.1021/jo3015837 | J. Org. Chem. 2012, 77, 9384−9390

The Journal of Organic Chemistry
Note
(d, J = 6.0 Hz, 1H). HRMS (EI): calcd C16H12N2 232.1000, found
232.1006. 13C{1H} NMR (75 MHz, CDCl3): δ 32.7, 108.0, 109.5,
114.5, 119.0, 119.1, 120.3, 122.1, 125.1, 126.6, 127.4, 132.2, 137.2,
140.2.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
4-(1-Benzyl-1H-indol-2-yl)benzonitrile (18A). Brown solid.
Yield: 0.58 g, 63% yield. Mp = 183.2−183.8 °C. HRMS (EI): calcd
C22H16N2 308.1313, found 308.1317. 1H NMR (300 MHz, CDCl3): δ
5.35 (s, 2H), 6.74 (s, 1H), 7.00 (d, J = 7.2 Hz, 2H), 7.15−7.29 (m,
6H), 7.51(d, J = 8.1 Hz, 2H), 7.63−7.70 (m, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 48.0, 104.2, 110.7, 111.4, 118.7, 120.7, 121.1, 123.0,
125.8, 127.5, 128.0, 129.0, 129.4, 132.4, 137.2, 137.6, 138.8, 139.6.
2-Phenyl-1-methylindole (19A).38 White solid. Yield: 0.38 g,
62%. 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 3H, CH3), 6.56 (s, 1H),
7.14 (t, J = 9.0 Hz, 1H), 7.24 (td, J = 7.2 Hz, J = 0.9 Hz, 1H), 7.35−
7.53 (m, 6H), 7.64 (d, J = 9.0 Hz, 1H).
We are grateful to the National Science Council of Taiwan for
financial support of this work.
REFERENCES
■
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2-(Naphthalene-1-yl)-N-methylindole (21A).39 Yellow solid.
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(s, 1H), 7.24 (td, J = 5.4 Hz, J = 0.9 Hz, 1H), 7.32 (t, J = 6.0 Hz, 1H),
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1
solid. Yield: 0.34 g, 48%. H NMR (300 MHz, CDCl3): δ 3.77 (s,
3H), 3.87 (s, 3H), 6.59 (s, 1H), 6.97 (dd, J = 8.1 Hz, J = 2.4 Hz, 1H),
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Pd[P(t-Bu)3]2; 0.350 g, 50% from 1.
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mmol) (2.5 mol %) under N2. Dry DMA (4 mL) was added to the
solution. The reaction mixture was allowed to stir at 140 °C for 16 h.
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separated and dried over anhydrous MgSO4. Removal of the solvent
resulted in a brownish gummy mass which was subjected to column
chromatography over silica gel using n-hexane and an increasing
proportion of EtOAc as eluent. Yield: 0.306 g, 41% (15A) and 0.150 g,
20% (15B).
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ASSOCIATED CONTENT
■
S
* Supporting Information
Additional catalytic table, schemes, NMR spectra for all
products, and crystallographic data of 1, 6, 17A, 17B, 21A,
and 23A. This material is available free of cost via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
(37) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250.
(38) Ishikura, M.; Terashima, M. J. Org. Chem. 1994, 59, 2634.
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Corresponding Author
*E-mail: leehm@cc.ncue.edu.tw.
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The Journal of Organic Chemistry
Note
(40) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1473.
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