One-pot and regiospecific synthesis of 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed sonogashira coupling, amidopalladation, and reductive elimination

Article abstract of DOI:10.1021/jo302679f

A practical one-pot and regiospecific three-component process for the synthesis of 2,3-disubstituted indoles from 2-bromoanilides was developed via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.

Full text of DOI:10.1021/jo302679f

Note
pubs.acs.org/joc
One-Pot and Regiospecific Synthesis of 2,3-Disubstituted Indoles
from 2‑Bromoanilides via Consecutive Palladium-Catalyzed
Sonogashira Coupling, Amidopalladation, and Reductive Elimination
Bruce Z. Lu,* Han-Xun Wei, Yongda Zhang, Wenyi Zhao, Marine Dufour, Guisheng Li, Vittorio Farina,†
and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United
States
S
* Supporting Information
ABSTRACT: A practical one-pot and regiospecific three-component
process for the synthesis of 2,3-disubstituted indoles from 2-
bromoanilides was developed via consecutive palladium-catalyzed
Sonogashira coupling, amidopalladation, and reductive elimination.
he indole motif is a ubiquitous feature of alkaloid natural
products and represents a privileged structural element for
which would result in the undesired intramolecular hydro-
amidation of the primary product, o-alkynylanilides 4 (Scheme
2).7 In fact, efficient Sonogashira couplings of unreactive aryl
T
pharmaceutically active compounds.1 Despite the plethora of
methodologies developed for synthesis of this heterocyclic
system,2 efficient general methods for regioselective preparation
of highly substituted indoles are limited.3 As a program of
developing practical and economical processes, we have
reported several efficient methods for the regioselective
synthesis of a variety of indole skeletons,4 including the
recently communicated one-pot regiospecific synthesis of 2,3-
disubstituted indoles from 2-iodoanilides, terminal alkynes, and
aryl bromides via the domino Sonogashira5−Cacchi reactions6
(Scheme 1). Although this three-component cascade reaction
Scheme 2. One-Pot Domino Process for Preparation of 2,3-
Disubstituted Indoles from 2-Bromo- or Chloroanilides,
Terminal Alkynes, and Aryl Bromides or Chlorides
Scheme 1. One-Pot Process for Preparation of 2,3-
Disubstituted Indoles from 2-Iodoanilides via Domino
Sonogashira and Cacchi Reactions
halides bearing ortho substituents such as 2-bromo- or 2-
chloroanilides are rarely reported,8 despite the remarkable
progress in the utilization of unreactive aryl chlorides in Pd-
catalyzed C−C bond formations.9 In addition, in order to
minimize the hydroamidation of intermediate 2, use of copper
salts as cocatalyst, strong base, or high temperature in the
Sonogashira coupling must be avoided.10 Herein we report the
development of this new one-pot approach to 2,3-disubstituted
indoles from 2-bromoanilides, terminal alkynes, and aryl
bromides or chlorides.
allows access to a variety of multisubstituted indoles under mild
conditions, the use of 2-iodoanilides as the starting material is
not ideal from a production perspective because of throughput
consideration and the currently prohibitive iodine cost. We
sought therefore to modify our initial strategy accordingly.
Our goal became to extend the scope of this one-pot, three-
component protocol to aryl bromides or chlorides, which are
significantly less expensive and more throughput efficient than
the corresponding iodides. However, the major anticipated
hurdle of using the rather unreactive and stereohindered 2-
bromo- or chloroanilides as the starting material would be the
harsh reaction conditions needed for the Sonogashira coupling,
Received: December 24, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302679f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Reaction Conditions for the One-Pot, Three-Component Reaction of 2-Bromoanilide 1a, Phenylacetylene, and
a
Bromobenzene
b
entry
catalyst/ligand
Pd(OAc)2/Cy3P
base/solvent
T1/t1 (°C/h) T2/t2 (°C/h)
2/3/4
1
K2CO3/DMF
K2CO3/DMF
K2CO3/DMF
K2CO3/DMF
Cs2CO3/DMF
K2CO3/DMF
Cs2CO3/DMF
KOAc/DMF
80/1.2;
trace of 2
10/11/79
58% 2
2
Pd(tBu3P)2 (3 mol %)
Pd(OAc)2 (3 mol %)/6 (6 mol %)
Pd(OAc)2 (3 mol %)/7 (6 mol %)
Pd(PhCN)2Cl2/8
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(OCOCF3)2/9
Pd(OAc)2/9
60/1.5; 60/23
80/23
3
4
80
trace of 2
82/0/18
5
100/1
c
6
80/1; 80/1
80/1.2; 80/2
80/1.2
0/86/14 (68%)
0/94/6
7
8
10% 2; 48% 4
33% 2; 32% 4
27/70/3
9
n-Bu4NOAc/DMF
Cs2CO3/DMF
Cs2CO3/DMF
Cs2CO3/DMF
Cs2CO3/DMF
Cs2CO3/MeCN
Cs2CO3/NMP
Cs2CO3/toluene
Cs2CO3 /DMF
80/1.2
10
11
12
80/1.2; 80/1.2
80/1.5; 80/2
80/1.5; 80/2
80/5; 80/8
80/1.2; 80/2
80/1.2; 80/2
80/1.2;
19/77/4
PdCl2/9
39/58/3
d
13
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
Pd(PhCN)2Cl2/9
20/55/25
88/4/8
14
15
16
79/13/8
trace 2
e
17
80/1.2; 80/5
20/75/5
a
Unless otherwise noted, all reactions were run by using 3 mol % of palladium precatalyst, 12 mol % of ligand, 1.2 equiv of phenylacetylene, 1.0 equiv
of 1a, and 3.0 equiv of base in the specified solvent (c = 0.2 M). 1.2 equiv of bromobenzene was added once the bromoanilide 1a was consumed
b
c
d
completely. Measured by HPLC at wavelength of 248 μm. Solution yield of 3 (measured by quantitative HPLC). The reaction was run under
otherwise identical conditions except using 1 mol % of Pd(PhCN)2Cl2 and 4 mol % of 9. The reaction was run under otherwise identical conditions
e
except using 2.2 equiv of Cs2CO3.
Our investigation started with the Sonogashira coupling of 2-
bromo-N-trifluoroacetylanilide (1a) with phenylacetylene,
followed by addition of bromobenzene for the Cacchi
cyclization (R = Ph). Important parameters including base,
solvent, temperature, and ligand were examined. No copper
salts were used. The results are summarized in Table 1.
4 were observed during the Sonogashira coupling when KOAc
or n-Bu4NOAc was used as base (entries 8 and 9, Table 1).
Next, several Pd precatalysts, such as Pd(OAc)2, PdCl2, and
Pd(OCOCF3)2, were evaluated in comparison with Pd-
(PhCN)2Cl2 (entries 10−12, Table 1). Although the major
side product 4 was still under control in these cases, the Cacchi
cyclization was slower, suggesting a shorter lifetime of the catalyst
formed from these Pd species. The deactivation of the catalyst was
further evidenced when the reaction was performed under
reduced catalyst loading. With 1 mol % of Pd(PhCN)2Cl2 and 4
mol % of X-Phos (9) in DMF, the Sonogashira coupling took 5
h to reach completion, whereas the subsequent Cacchi
cyclization did not reach completion after 8 h, resulting in
the significant formation of byproduct 4 (entry 13, Table 1).
We speculated that the deactivation of the catalyst might be
attributed to the low solubility of the ligand X-Phos in DMF,
resulting in the formation of palladium black. Other solvents
were examined (entries 14−16, Table 1). While the
Sonogashira coupling proceeded smoothly in both acetonitrile
and NMP, the Cacchi cyclization was significantly retarded in
both solvents. No reaction occurred in toluene, probably due to
poor solubility of the base. It is worthy of notice that a total of 3
equiv of Cs2CO3 is required to complete the reaction, as
evidenced by the incomplete Cacchi cyclization when 2.2 equiv
of the base was used (entry 17, Table 1). Attempt to extend the
reaction to 2-chloroanilide 1b using 3 mol % of PdCl2(PhCN)2,
12 mol % of X-Phos 9, 1.2 equiv of phenylacetylene, and 3.0
equiv of Cs2CO3 in DMF (c = 0.2 M) at 80 °C met with no
success.
First, several bulky and electron-rich phosphines as ligand
were evaluated using K2CO3 as base in DMF. Preliminary
results showed that besides the expected non-Pd-catalyzed side
product 4, a new impurity, identified as 5, was observed; its
formation could be explained assuming some 1,3-diyne, formed
by homocoupling of the alkyne, may undergo a Larock-like
insertion with the bromoanilide.11 With Pd(OAc)2 and Cy3P as
the catalyst,12 the Sonogashira coupling of phenylacetylene with
1a did not occur at 80 °C (entry 1, Table 1). Using Pd(t-
Bu3P)2 as the catalyst,13 the Sonogashira coupling reaction was
completed in 1.5 h at 60 °C; however, the subsequent Cacchi
cyclization was extremely slow, resulting in the formation of 2-
phenyl indole 4 as the major product after prolonged reaction
time (entry 2, Table 1). When DiPPF 6 was used as ligand, the
Sonogashira coupling was incomplete even after 23 h at 80 °C,
while no reaction occurred by using DtBPF 7 as the ligand,
probably due to the steric hindrance of the bulky ligand (entries
3 and 4, Table 1). With biarylphosphine 8 as ligand and
Cs2CO3 as base, the Sonogashira coupling did not proceed until
the temperature was elevated to 100 °C. The coupling reaction
was completed in 1 h at this temperature, giving the desired
product 2 and the byproduct 4 in a ratio of 82/18 (entry 5,
Table 1). Finally, using X-Phos 9 as ligand,14 the Sonogashira
coupling in DMF was completed in 1.5 h at 80 °C, affording 2
as the only product. After addition of bromobenzene, the
Cacchi cyclization proceeded smoothly, affording the desired
product 3 and byproduct 4 in a ratio of 86/14 (entry 6, Table
1). The ratio of 3 to 4 was further improved to 94/6 by using
Cs2CO3 as base under otherwise identical conditions (entry 7,
Table 1). On the other hand, noticeable amounts of byproduct
The deactivation of the Pd catalyst became more severe
when alkylalkyne 10 was used under the same conditions,
resulting in incomplete Sonogashira coupling reaction (Scheme
3). With 3 mol % of Pd catalyst, the Sonogashira coupling
proceeded very rapidly at the beginning, with about 50%
conversion in just 10 min at 80 °C. However, the reaction rate
slowed afterward. Addition of an extra equivalent of the alkyne
B
dx.doi.org/10.1021/jo302679f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. Domino Sonogashira Coupling,
Amidopalladation, and Cyclization Using Alkylalkyne
Table 2. Synthesis of 2,3-Disubstituted Indoles via the One-
Pot Three-Component Sonogashira−Cacchi Domino
a
Reaction
did not enhance the reaction rate, indicating that the
sluggishness was not due to potential consumption of the
alkyne 10 via homocoupling but rather to catalyst instability.
The Sonogashira coupling took over 12 h to complete, but
subsequent addition of bromobenzene did not lead to
cyclization, showing that no active catalyst was available at
this stage. However, to our delight, addition of 1 equiv of n-
Bu4NBr (TBAB) significantly stabilized the catalyst, producing
the desired product 12 in good yield. The rate of the cyclization
depended on the concentration of chlorobenzene. With 1.5
equiv of chlorobenzene, the reaction took 10 h to complete,
giving 12 and 13 in a ratio of 76: 24. With 3 equiv of
chlorobenzene, the reaction took only 1 h to complete,
affording 12 and 13 in a ratio of 78:22. Employment of more
chlorobenzene did not further improve the ratio. We speculated
that the effect of TBAB on stabilizing the active palladium
catalyst might be related to formation of colloidal palladium
nanoparticles under the current reaction conditions.15 The
same effect was achieved by using n-Bu4NCl as additive.
To evaluate the scope of this one-pot process, a variety of
indoles were synthesized from 2-bromoanilides. Two proce-
dures were used: in the cases when there is competing oxidative
insertion of LPd(0) to both the 2-bromoanilides and the aryl
halides (reactive ones like bromobenzene), the aryl halides
were added after the Sonogashira coupling was complete
(Method A); in the cases when there are no competing
oxidative insertion of LPd(0), the aryl halides were added in
one-pot at the beginning, thus eliminating the need to monitor
the progress of the Sonogashira coupling before proceeding to
the next step (Method B). The results are summarized in Table
2. Since the problem related to the Sonogashira coupling with
alkylalkynes is uniquely demanding, all the 2,3-diarylindoles
were prepared under the normal conditions, without addition
of n-Bu4NBr. Even without this beneficial additive, good to
excellent yields were achieved in all cases examined. 2-
Bromoanilides bearing a carboxylate at the C6 position gave
only moderate yield, mainly due to the hydroamidation side
reaction (entries 5 and 6, Table 2). Also, with substrates
bearing a nitrile group at the C5 position, the Sonogashira
coupling was significantly slower. Nevertheless, the overall
yields for the two steps are not compromised in these cases
(entries 7 and , Table 2).
a
Method A: The reactions were run by mixing 3 mol % of
PdCl2(PhCN)2, 12 mol % of X-Phos 9, 1.2 equiv of alkyne, and 1.0
equiv of the anilide and 3.0 equiv of Cs2CO3 in DMF (c = 0.2 M) at 80
°C. After the bromoanilide was consumed completely, 1.2 equiv of aryl
bromide or chloride was added at 80 °C. Method B: The reactions
were run by mixing 3 mol % of PdCl2(PhCN)2, 12 mol % of X-Phos 9,
1.2 equiv of alkyne, 1.2 equiv of the aryl chloride, and 1.0 equiv of the
anilide and 3.0 equiv of Cs2CO3 in DMF (c = 0.2 M) at 80 °C.
b
c
Isolated yield. 3.0 equiv of PhCl, 2.0 equiv of acetylene, and 1.0
equiv of n-Bu4NBr were used under otherwise identical conditions.
In summary, we have developed a regiospecific one-pot
process for rapid access to a variety of 2,3-disubstituted indoles
from aryl bromides via consecutive palladium-catalyzed
Sonogashira coupling, amidopalladation, and reductive elimi-
nation This mild method provides a complementary tool for
the regiospecific synthesis of highly substituted indoles.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in oven-dried
glassware sealed with rubber septa under an inert atmosphere of argon.
All commercial materials were used without further purification.
HPLC conditions for reaction monitoring and quantitation: column
C
dx.doi.org/10.1021/jo302679f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Zorbax Eclipse XDB-C8, 4.6 × 150 mm, 5 μm particle size, column
temperature at 40 °C, mobile phase A (0.1% trifluoroacetic acid in
water), mobile phase B (0.1% trifluoroacetic acid in acetonitrile), flow
rate: 2.0 mL min−1, gradient program 30% B to 95% B in 10 min, to
100% B in 3 min, hold at 100% B for 3 min, λ = 248 nm. The samples
for HPLC were diluted with CH3CN. Chemical shifts are reported in δ
(ppm) relative to TMS in CDCl3 as internal standard (1H NMR) or
the residual CHCl3 signal (13C NMR).
8.03 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.53−7.21 (m,
10H), 3.93 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 167.3, 140.3,
136.0, 135.1, 132.3, 129.9, 128.9, 128.4, 128.3, 128.1, 127.7, 126.9,
123.0, 120.9, 119.5, 114.0, 111.1, 52.0; LC-MSD (API-ES, positive) m/
z = 328 (M + H+).
General Procedure for One-Pot Reaction Conditions
(Method B). The reaction was performed under the same conditions
as described above in method A, except that bromobenzene (1.2 equiv)
was replaced with chlorobenzene (3 equiv) and added at the beginning.
There is no need to monitor the Sonogashira coupling reaction. After
the reaction went to completion with the time indicated in the text, the
product was purified by column chromatography on silica gel to afford
the desired product.
General Procedure for Sequential Addition Reaction Con-
ditions (Method A). 2,3-Diphenyl-1H-indole (3).16 A 10 mL, three-
neck flask, equipped with a magnetic-stirring bar, thermocouple, and
argon inlet, was charged 2-bromo-N-trifluoroacetylanilide 1 (209 mg,
0.78 mmol, 1.0 equiv), PdCl2(PhCN)2 (8.9 mg, 0.02 mmol, 3 mol %),
X-Phos 9 (44 mg, 0.09 mmol, 12 mol %), and cesium carbonate (753
mg, 2.31 mmol, 3 equiv), followed by addition of 3 mL of anhydrous
DMF. The reaction mixture was stirred at room temperature for 10
min and added with phenylacetylene (95 mg, 0.93 mmol, 1.2 equiv).
The mixture was heated at 80 °C until the Sonogashira reaction was
complete, judged by the disappearance of the bromoanilide 1, followed
by addition of bromobenzene (146 mg, 0.93 mmol, 1.2 equiv). The
reaction mixture was stirred at 80 °C until the o-alkynylanilide
intermediate was completely consumed. The mixture was quenched
with water and diluted with EtOAc. The organic phase was separated
and the aqueous layer was extracted with EtOAc two times. The
combined organic layers were washed with brine and dried over
Na2SO4. After removal of solvents, the crude product was purified by
column chromatography on silica gel to afford the desired product 3 as
2-Cyclohexyl-3-phenyl-1H-indole (12). The reaction was per-
formed under the same conditions as described above, using 2-
bromo-N-trifluoroacetylanilide 1 (206 mg, 0.77 mmol, 1.0 equiv),
PdCl2(PhCN)2 (8.7 mg, 0.02 mmol, 3 mol %), X-Phos 9 (44 mg, 0.09
mmol, 12 mol %), Cs2CO3 (753 mg, 2.31 mmol, 3 equiv),
cyclohexylacetylene (166 mg, 1.5 mmol, 2.0 equiv), chlorobenzene
(260 mg, 2.3 mmol, 3 equiv), and n-Bu4NBr (248 mg, 0.77 mmol, 1.0
equiv). The desired compound 12 was obtained as an off-white solid
1
(152 mg, 72% yield): H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H),
7.62 (bs, 1H), 7.47−7.40 (m, 4H), 7.34−7.26 (m, 2H), 7.21−7.07 (m,
2H), 3.03 (t, 1H, J = 12 Hz), 1.97−1.81 (m, 2H), 1.76−1.62 (m, 2H),
1.54−1.20 (m, 5H); 13C NMR (400 MHz, CDCl3) δ 140.7, 135.6,
135.0, 129.8, 128.5, 128.0, 125.9, 121.6, 119.9, 119.0, 113.2, 110.5,
35.5, 33.8, 26.5, 22.8; HRMS m/z (M + H+) calcd for C20H22N
276.1747, found 276.1748.
Methyl 6-(2,3-Diphenylindolyl)carboxylate (17).19 The reaction
was performed under the same conditions as described above, using
methyl 4-bromo-3-(trifluoroacetylamino)benzoate (326 mg, 1.0 mmol,
1.0 equiv), PdCl2(PhCN)2 (12 mg, 0.03 mmol, 3 mol %), X-Phos 9
(57 mg, 0.12 mmol, 12 mol %), Cs2CO3 (977 mg, 3.0 mmol, 3 equiv),
phenylacetylene (122 mg, 1.2 mmol, 1.2 equiv), and chlorobenzene
(338 mg, 3.0 mmol, 3 equiv). The desired compound 17 was obtained
1
an off-white solid (174 mg, 83% yield): mp 108−110 °C; H NMR
(400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.46−6.90 (m, 14H); 13C
NMR (400 MHz, CDCl3) δ 135.9, 135.1, 134.1, 132.7, 130.2, 128.8,
128.7, 128.5, 128.2, 127.7, 126.2, 122.7, 120.4, 119.7, 115.1, 110.9; LC-
MSD (API-ES, positive) m/z = 270 (M + H+).
1
as pale brown solid (216 mg, 66% yield): mp 234−236 °C; H NMR
(400 MHz, CDCl3) δ 8.59 (bs, 1H), 8.20 (s, 1H), 7.84−7.68 (m, 2H),
7.47−7.34 (m, 10H), 3.95 (s, 3H); 13C NMR (400 MHz, CDCl3) δ
168.1, 137.5, 135.1, 134.4, 132.3, 132.1, 130.1, 128.2, 128.9, 128.7,
128.3, 126.6, 124.2, 121.5 119.2, 115.4, 113.3, 52.0; LC-MSD (API-ES,
positive) m/z = 328 (M + H+).
2-Phenyl-3-(p-methoxyphenyl)-1H-indole (14).17 The experiment
was performed in the same way as described above, using 2-bromo-N-
trifluoroacetylanilide 1 (209 mg, 0.78 mmol, 1.0 equiv),
PdCl2(PhCN)2 (8.9 mg, 0.02 mmol, 3 mol %), X-Phos (9) (44 mg,
0.09 mmol, 12 mol %), Cs2CO3 (753 mg, 2.31 mmol, 3 equiv),
phenylacetylene (95 mg, 0.93 mmol, 1.2 equiv), and p-bromoanisole
(174 mg, 0.93 mmol, 1.2 equiv). The desired compound 14 was
obtained as a pale brown solid (173 mg, 74% yield): mp 185−187.5
°C; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.65 (d, J = 8.0 Hz,
1H), 7.44−6.92 (m, 12 H), 3.85 (s, 3H); 13C NMR (400 MHz,
CDCl3) δ 158.2, 135.9, 133.7, 132.8, 131.2, 129.0, 128.7, 128.0, 127.6,
127.3, 122.6, 121.0, 119.7, 114.73, 114.1, 110.8, 55.2.
Methyl 6-[2-(p-Methylphenyl)-3-phenylindolyl]carboxylate
(18).4c The reaction was performed under the same conditions as
described above, using methyl 4-bromo-3-(trifluoroacetylamino)-
benzoate (326 mg, 1.0 mmol, 1.0 equiv), PdCl2(PhCN)2 (12 mg,
0.03 mmol, 3 mol %), X-Phos 9 (57 mg, 0.12 mmol, 12 mol %),
Cs2CO3 (977 mg, 3.0 mmol, 3 equiv), p-methylphenylacetylene (139
mg, 1.2 mmol, 1.2 equiv), and chlorobenzene (338 mg, 3.0 mmol, 3
equiv). The desired compound 18 was obtained as a pale brown solid
(205 mg, 60% yield): mp 227−229 °C; 1H NMR (400 MHz, CDCl3)
δ 8.45 (s, 1H), 8.18 (bs, 1H), 7.83−7.81 (m, 1H), 7.66 (d, J = 8.4 Hz,
1H), 7.43−7.28 (m, 7H), 7.15 (d, J = 8.0 Hz, 2H), 3.93 (s, 3H), 2.36
(s, 3H); 13C NMR (400 MHz, CDCl3) δ 168.3, 138.3, 137.7, 135.1,
134.6, 132.4, 130.1, 129.5, 129.1, 128.7, 128.2, 126.5, 123.9, 121.4,
119.1, 115.0, 113.2, 52.0, 21.3; LC-MSD (API-ES, positive) m/z = 342
(M + H+).
2-Phenyl-3-(p-methylphenyl)-1H-indole (15).17 The experiment
was performed in the same way as described above, using 2-bromo-N-
trifluoroacetylanilide 1 (209 mg, 0.78 mmol, 1.0 equiv),
PdCl2(PhCN)2 (8.9 mg, 0.02 mmol, 3 mol %), X-Phos (9) (44 mg,
0.09 mmol, 12 mol %), Cs2CO3 (753 mg, 2.31 mmol, 3 equiv),
phenylacetylene (95 mg, 0.93 mmol, 1.2 equiv), and p-bromotoluene
(159 mg, 0.93 mmol, 1.2 equiv). The desired compound 15 was
obtained as an off-white solid (179 mg, 81% yield).
2,3-Diphenyl-5-cyano-1H-indole (19).4c The reaction was per-
formed under the same conditions as described above, using 3-bromo-
4-(trifluoroacetylamino)benzonitrile (293 mg, 1.0 mmol, 1.0 equiv),
PdCl2(PhCN)2 (12 mg, 0.03 mmol, 3 mol %), X-Phos 9 (57 mg, 0.12
mmol, 12 mol %), Cs2CO3 (977 mg, 3.0 mmol, 3 equiv),
phenylacetylene (122 mg, 1.2 mmol, 1.2 equiv), and chlorobenzene
(338 mg, 3.0 mmol, 3 equiv). The desired compound 19 was obtained
as a pale brown solid (270 mg, 92% yield): decomposed at 157 °C. 1H
NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.89 (s, 1H), 7.62−7.30
(m, 12H); 13C NMR (400 MHz, DMSO-d6) δ (ppm) 137.7, 136.5,
2-Phenyl-3-(p-methoxycarbonylphenyl)-1H-indole (16).18 The
experiment was performed in the same way as described above,
using 2-bromo-N-trifluoroacetylanilide 1 (209 mg, 0.78 mmol, 1.0
equiv), PdCl2(PhCN)2 (8.9 mg, 0.02 mmol, 3 mol %), X-Phos (9) (44
mg, 0.09 mmol, 12 mol %), Cs2CO3 (753 mg, 2.31 mmol, 3 equiv),
phenylacetylene (95 mg, 0.93 mmol, 1.2 equiv), and methyl 4-
chlorobenzoate (159 mg, 0.93 mmol, 1.2 equiv). The desired
compound 16 was obtained as a pale brown solid (245 mg, 96%
yield): mp 155−157 °C; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H),
D
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Note
133.7, 131.3, 129.7, 128.8, 128.6, 128.3, 128.2, 127.6, 126.6, 124.6,
124.0, 120.4, 113.8, 112.7, 101.8.
(6) For the Cacchi reaction, see: (a) Cacchi, S.; Fabrizi, F. Chem. Rev.
2005, 105, 2873. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Adv.
Synth. Catal. 2006, 348, 1301.
2-Phenyl-3-(p-methoxycarbonylphenyl)-5-cyano-1H-indole (20).
The reaction was performed under the same conditions as described
above, using 3-bromo-4-(trifluoroacetylamino)benzonitrile (293 mg,
1.0 mmol, 1.0 equiv), PdCl2(PhCN)2 (12 mg, 0.03 mmol, 3 mol %),
X-Phos 9 (57 mg, 0.12 mmol, 12 mol %), Cs2CO3 (977 mg, 3.0 mmol,
3 equiv), phenylacetylene (122 mg, 1.2 mmol, 1.2 equiv), and methyl
4-chlorobenzoate (512 mg, 3.0 mmol, 3 equiv). The desired
compound 20 was obtained as a pale brown solid (257 mg, 73%
(7) For reviews on hydroamidation, see: (a) Muller, T. E.; Hultzsch,
̈
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
(b) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407. (c) Alonso,
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̈
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(8) For references containing examples of Sonogashira reaction of 2-
bromoanilides or -anilines, see: (a) Federica, P.; Sejberg, J. J. P.; Blain,
C.; Ng, W. H.; Aboagye, E. O.; Spivey, A. C. Synlett 2011, 241.
(b) Jiang, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synthesis 2008, 2417.
1
yield): H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.08−7.97 (m,
3H), 7.63−7.31 (m, 9H), 3.95 (s, 3H). 13C NMR (400 MHz, CDCl3)
δ 167.0, 138.8, 137.6, 137.1, 131.2, 130.2, 129.8, 129.1, 128.9, 128.5,
128.4, 128.3, 125.7, 125.1, 120.5, 114.4, 112.05, 104.0, 52.2; HRMS m/
z (M + H+) calcd for C23H17N2O2 353.1285, found 353.1282.
(c) Lop
2823.
́
ez-Deber, M. P.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3,
(9) For a recent review on Pd-catalyzed reactions of aryl chlorides,
see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(10) For direct cyclization of 2-alkynylanilides, see: (a) Hiroya, K.;
Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (b) Cacchi, S.;
Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (c) Rodriguez, A. L.;
Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39,
2488.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(11) For a review on Pd-catalyzed homocoupling of alkynes, see:
Negishi, E.; Alimardanov, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience:
New York, 2002; Vol. 1, pp 989.
(12) Yi, C.; Hua, R. J. Org. Chem. 2006, 71, 2535.
(13) (a) Huang, H.; Liu, H.; Jiang, H.; Chen, K. J. Org. Chem. 2008,
73, 6037. (b) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G.
C. Org. Lett. 2000, 2, 1729.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bruce.lu@boehringer-ingelheim.com.
Present Address
†Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse,
Belgium.
(14) (a) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed.
2005, 44, 6173. (b) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed.
2003, 42, 5993.
Notes
The authors declare no competing financial interest.
(15) Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed. 2000, 39,
165.
REFERENCES
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