Synthesis of indoles and polycyclic amides via ruthenium(ii)-catalyzed C-H activation and annulation

Article abstract of DOI:10.1039/c5ob01788b

Ruthenium(ii)-catalyzed oxidative coupling of NH protic amides with alkynes has been developed for the synthesis of a diversity of complex structures, such as N-acyl indole and tricyclic amide derivatives.

Full text of DOI:10.1039/c5ob01788b

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DOI: 10.1039/C5OB01788B
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ARTICLE TYPE
Synthesis of indoles and polycyclic amides via ruthenium(II)-catalyzed
CH activation and annulation
Hui Lin,a Shuai-Shuai Li,a Lin Dong*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
ruthenium(II)-catalyzed CH bond activation of NH protic
amides with alkynes which gives N-acyl indole derivatives using
40 O-atom to direct cyclometalation at the ortho C–H activation, and
tricyclic amide derivatives when primary benzamides were used
as substrates (Scheme 1, eq 6).
Ruthenium(II)-catalyzed oxidative coupling of NH protic
amides with alkynes has been developed for the synthesis of
diversity of complex structures, such as N-acyl indole and
tricyclic amide derivatives.
Transition-metal-catalyzed CH activation is an efficient and
straightforward tool for the construction of various heterocyclics
from simple substrates, which is generally difficult to obtain by
using traditional synthetic methods.1 In particular, chelation
10 assisted strategy has emerged as one of the most powerful
methodologies in rhodium or ruthenium catalyzed CH
activation.2 Among them, NH protic amides as important
directing groups have been successfully utilized in catalytic CH
activation to synthesize complex products, probably due to either
15 the C-aryl or N-aryl ring can potentially undergo CH activation.3
For example, N-substituted isoquinolones or 2-pyridones were
efficiently synthesized from oxidative coupling of N-substituted
benzamides or acrylamides (both N-aryl and N-alkyl) and alkynes
at the ortho position of the C-ring using rhodium or ruthenium
20 catalysts (Scheme 1, eq 1).4,5 In addition, carbonyl group of
amides can facilitate activation of the ortho CH bond to afford
N-acyl indole derivatives with alkynes by rhodium catalyst and
N-acyl pyrrole by ruthenium catalyst, when C-alkyl was
employed (Scheme 1, eqs 2 and 3).6,7 Satoh and Miura and Li
25 have independently developed a rhodium(III)-catalyzed facile
synthesis of tricyclic amides by double CH activation of primary
benzamides with alkynes (Scheme 1, eq 4).4b,4c,8
Despite the significant developments, the substrate scope is
still limited, and rhodium catalysts are most used, while
30 ruthenium catalysts have been less exploited.9 Therefore,
revealing new reactions under less-expensive ruthenium catalysis
is highly desirable. Very recently, Ackermann reported
ruthenium(II) complexes enabled oxidative CH bond
functionalizations with anilines to provide various indoles
35 (Scheme 1, eq 5).9d Our continuous interest is in metal-catalyzed
diverse reactivity CH bond activation process of amides as
45
Scheme 1 Selective CH bond activation of NH protic amides.
chelation-assisted groups. Herein, we describe
a
novel
aH. Lin, S.-S. Li, Prof. Dr. L. Dong
Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
E-mail: dongl@scu.edu.cn
†Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
Results and Discussion
We set out our studies with the screening of reaction conditions
50 between N-phenylacetamide (1a) and diphenylacetylene (2a)
(Table 1). We initially chosen copper salts as an additive under
the catalyst of [RuCl2(p-cymene)]2, while Cu(OAc)2·H2O just
gave the desired product 3aa in 8% yield (entries 1 and 2).
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |1

Organic & Biomolecular Chemistry
Page 2 of 6
Table 1 Optimization of the reaction conditionsa
20 addition, the reaction can be carried out with good efficiency
when 0.6 equiv of Cu(OAc)2·H2O and 0.3 equiv of CH3SO2OAg
View Article Online
were used (entries 7-10). Among the test of the solvents, DCE
DOI: 10.1039/C5OB01788B
gave the same activity as toluene (entries 11-15). To our delight,
the yield was raised to 87% when excess amide 1a was used
25 (entry 16). The reaction temperature was very essential in the
catalyst system (entries 17 and 18). The yield was significantly
diminished when the catalyst loading of [RuCl2(p-cymene)]2was
reduced (entry19). In addition, we also tried the reaction
conditions (KPF6 as the additive) which was reported by
30 Ackermann, but only got 3aa in 10% yield.9d
With the optimal conditions in hand, we began to explore the
scope and limitation of substituted amides (Table 2). Methyl
substituent at the ortho-, meta- and para-positions of the phenyl
ring reacted smoothly providing corresponding products in good
35 to moderate yields (3ba-3da). In addition, 1e proceeded smoothly,
proving the product 3ea in 70% yield. Substrates bearing
electron-rich or electron-poor groups at the para-position (1f-1i)
gave good reactivity. Although N-alkyl groups are generally
tolerated, steric effects of the N-alkyl group seems to play an
40 important role. N-isopropyl substrate 1k is much less efficient
under the same conditions, leading to 3ka in only 40% yield.
Entry Oxidant/[equiv]
Additive/[equiv]
Solvent
Yieldb
[%]
8
N.R.
N.R.
Trace
17
31
29
36
57
37
57
Trace
47
N.R.
41
87
73
80
42
T[C]
1
2
Cu(OAc)2·H2O/1.0
Cu(OTf)2 /1.0
-
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
110
110
110
110
110
110
110
110
110
110
110
3
4
5
6
7
8
9
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/1.0
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.3
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
Cu(OAc)2·H2O/0.6
AgSbF6/0.6
AgBF4/0.6
AgPF6/0.6
CH3SO2OAg/0.6
CH3SO2OAg/1.0
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
CH3SO2OAg/0.3
10
11
12
13
14
15
16[c]
17[c]
18[c]
19[c,d]
tAmOH 110
dioxane
DMF
110
110
110
110
100
120
110
THF
toluene
toluene
toluene
toluene
a Reaction conditions unless otherwise specified: 0.05 mmol of 1a, 0.055
mmol of 2a, 5 mol % of [RuCl2(p-cymene)]2, 0.6 mL of solvent, 12 h,
5 under Ar atmosphere. b Isolated yield. c 0.10 mmol of 1a, 0.05 mmol of 2a.
d 2.5 mol % of [RuCl2(p-cymene)]2.
Table 3 The scope of substituted alkynesa
Various kinds of silver salts were added in the presence of
Cu(OAc)2·H2O in the reaction, in which CH3SO2OAg exhibited
10 good reactivity and improve the yield to 31% (entries 3-6). In
Table 2 The scope of substituted amidesa
R1
O
H
N
[RuCl2(p-cymene)]2 (5 mmol %)
Cu(OAc)2 H2O (0.6 equiv)
Ph
R1
N
R2
Ph
R2
+
O
CH3SO2OAg (0.3 equiv)
Ph
toluene, Ar, 110
C
Ph
1
2a
3
O
O
Ph
O
O
N
Cl
N
N
N
Ph
Ph
Ph
Ph
Ph
3ba, 76%
Ph
Ph
3da, 50%b
3ca
, 64%
3ea, 70%
O
O
O
O
Ph
N
N
N
N
Ph
O2N
Ph
Ph
I
Cl
MeO
Ph
Ph
Ph
Ph
3fa, 59%
3ha, 83%
3ia, 34%
3ga, 77%
O
O
O
N
N
N
Ph
Ph
Ph
45 a Reaction conditions unless otherwise specified: 0.10 mmol of 1a, 0.05
mmol of 2, 5 mol % of [RuCl2(p-cymene)]2, 0.6 equiv of Cu(OAc)2·H2O,
0.3 equiv of CH3SO2OAg, 0.6 mL of toluene, 110 C, 12 h, under Ar
Ph
3ja, 50%b
Ph
3ka, 40%
Ph
3la, 75%
b
atmosphere. Yields are reported for the isolated products. 0.3 equiv of
15 a Reaction conditions unless otherwise specified: 0.10 mmol of 1a, 0.05
mmol of 2, 5 mol % of [RuCl2(p-cymene)]2, 0.6 equiv of Cu(OAc)2·H2O,
0.3 equiv of CH3SO2OAg, 0.6 mL of toluene, 110 C, 12 h, under Ar
Cu(OAc)2·H2O.
50
b
atmosphere. Yields are reported for the isolated products. 0.3 equiv of
The scope of the alkynes reactant was subsequently
investigated in Table 3. N-phenylacetamide 1a reacted with
Cu(OAc)2·H2O.
2
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Page 3 of 6
Organic & Biomolecular Chemistry
various alkynes, with either electron-donating or –with drawing
diaryl groups, to form expected products in good yields (3ab-3af).
The reaction was successfully expanded to dialkyl acetylene 2g,
but generating the product in 33% yield. A single isomer 3ah was
isolated by using 2h as a coupling partner. In addition,
unsymmetrically disubstituted alkyne 2i gave products in good
yield albeit with excellent regioselectivity. However, terminal
alkynes couldn’t react in the standard reaction.
View Article Online
DOI: 10.1039/C5OB01788B
5
10 Table 4 Reactions between primary benzamides and diphenyl acetylenesa
O
Ph
O
Ph
[RuCl2(p-cymene)]2 (7.5 mmol %)
Ph
N
NH2
R1
Cu(OAc)2 H2O (2.2 equiv)
R1
+
Na2CO3 (2.0 equiv)
Ph
PhCl, Ar,110
C
Ph
Scheme 2 Proposed catalytic cycle
4
2a
5
O
Ph
O
Ph
O
Ph
Conclusion
Ph
Ph
Ph
N
N
N
In summary, NH protic amides coupled with alkynes
40 provided N-acyl indole derivatives and tricyclic amide derivatives
in high selectivity, indicating that the selectivity of the coupling
of amides with alkynes is substrate-dependent. In particular, the
method in the context broadens the scope of metal-catalyst to
cost-effective ruthenium. Given the wide products in this
45 versatility reaction system, this approach is also likely to find
utility in the synthesis of diversity of complex structures.
MeO
Cl
Ph
5aa, 43%
Ph
Ph
5ca, 40%
5ba, 56%
O
Ph
O
N
Ph
Ph
Ph
N
O2N
F
Ph
Ph
5da, 35%
5ea, 42%
Acknowledgments
Cl
O
Ph
O
Ph
Ph
H3C
Ph
N
N
We are grateful for the financial support from the NSFC
(21202106), Sichuan University “985 project-Science and
50 technology innovation platform for novel drug development”.
Ph
Ph
5fa, 36%
5ga, 18%
a Reaction conditions unless otherwise specified: 0.05 mmol of 4, 0.175
mmol of 2a, 7.5 mol of [RuCl2(p-cymene)]2, 2.2 equiv of
Experimental
%
Cu(OAc)2·H2O, 2.0 equiv of Na2CO3, 0.5 mL of PhCl, 110 C, 16 h,
15 under Ar atmosphere. Yields are reported for the isolated products.
General remarks
NMR data were obtained for 1H at 400 MHz or 600 MHz, and for
55 13C at 100 MHz or 151 MHz. Chemical shifts were reported in
ppm from tetramethylsilane with the solvent resonance as the
internal standard in CDCl3 solution. ESI HRMS was recorded on
a Waters SYNAPT G2 and Water XEVO G2 Q-ToF. UV
detection was monitored at 220 nm. TLC was performed on
60 glass-backed silica plates. Column chromatography was
performed on silica gel (200-300 mesh), eluting with ethyl acetate
and petroleum ether. N-phenylacetamide, benzamide and alkynes
were commercially available.
Next, various substituted primary benzamides were tested in
the catalyst system (Table 4).10 Primary benzamide 4a react
differently between N-substituted secondary benzamides due to
20 two alkyne units are oxidatively incorporated to give tricyclic
products 5aa. The electronic effects of diverse para-substituted
groups slightly impacted the reaction efficiency (5ba-5ea), while
5da was obtained in 35% yield. Substituent in the meta-position
of the phenyl ring (4f) was a suitable coupling partner for the
25 coupling reaction. In contrast, substrate 4g furnished the
corresponding product in only 18% yield, probably owing to
strong steric effects.
A plausible catalytic cyclewas posposed (Scheme 2). CH
first undergoes insertion by ruthenium(II) complex to form six-
30 membered ruthenacycle I. Subsequently, alkyne coordinates to a
ruthenium species to give intermediate II, which undergo
migratory insertion with alkyne to provide ruthenacycle III.
Finally, reductive elimination generates the product 3aa, and
General procedure for synthesis of indoles, polycyclic amides
65 and Characterization data
N-phenylacetamide 1a (13.5 mg, 0.1 mmol), diphenylacetylene
2a (8.9 mg, 0.05 mmol), [RuCl2(p-cymene)]2 (1.5 mg, 5 mmol %),
Cu(OAc)2·H2O (6.0 mg, 0.6 equiv) and CH3SO2OAg (3.0 mg, 0.3
equiv) were stirred in toluene (0.6 mL) at 110 C for 12 h. After
70 completion, the reaction mixture was purified by flash
chromatography eluting with ethyl acetate and petroleum ether
(1:20) to give the product 3aa as a white solid (13.5 mg, 87%).6a
Benzamides 4a (6.1 mg, 0.05 mmol), diphenylacetylene 2a (31.2
mg, 0.175 mmol), [RuCl2(p-cymene)]2 (2.3 mg, 7.5 mmol %),
75 Cu(OAc)2·H2O (22.0 mg, 2.2 equiv) and Na2CO3 (10.6 mg, 2.0
equiv) were stirred in chlorobenzene (0.5 mL) at 110 C for 16 h.
reoxidation regenerates the ruthenium(II) complex.
35
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After completion, the reaction mixture was purified by flash
113.9, 102.2, 55.8, 27.8 ppm. ESI HRMS: calcd. for
chromatography eluting with ethyl acetate and petroleum ether 60 C23H19NO2+H 342.1494, found 342.1511.
View Article Online
DOI: 10.1039/C5OB01788B
(1:30) to give the product 5aa as a yellow solid (10.2 mg, 43%).10
1-(2,3-diphenyl-1H-indol-1-yl)ethanone (3aa). 12 h, 87% yield,
white solid; m.p. 148.7-150.2 C; IR (KBr): υ = 3053, 2922, 2851,
1694, 1612, 1512, 1448, 1307 cm-1. 1H NMR (400 MHz, CDCl3)
1-(5-chloro-2,3-diphenyl-1H-indol-1-yl)ethanone (3ga). 12 h,
77% yield, pale yellow solid; m.p. 208.9-210.6 C; IR (KBr): υ =
1
5
3059, 2927, 2855, 1700, 1597, 1513, 1445, 1305 cm-1. H NMR
(400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H),
δ 8.46 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 65 7.38~7.34 (m, 6H), 7.30~7.26 (m, 3H), 7.18 (d, J = 6.4 Hz, 2H),
7.6 Hz, 1H), 7.37~7.32 (m, 5H), 7.30~7.25 (m, 4H), 7.24~7.21
1.98 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.4, 136.2,
135.1, 132.5, 132.4, 130.7, 130.6, 129.9, 129.4, 128.9, 128.7,
128.4, 127.2, 125.6, 122.7, 119.1, 117.4, 27.8 ppm. ESI HRMS:
calcd. for C22H16ClNO+Na 368.0818, found 368.0821, 370.0804.
70 1-(5-iodo-2,3-diphenyl-1H-indol-1-yl)ethanone (3ha). 12 h, 83%
yield, pale yellow solid; m.p. 223.9-225.4 C; IR (KBr): υ = 3055,
(m, 2H), 2.00 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.6,
10 136.8, 135.0, 133.1, 132.9, 130.8, 130.1, 129.3, 128.6, 128.2,
126.9, 125.5, 123.8, 123.4, 119.6, 116.2, 27.9 ppm. ESI HRMS:
calcd. for C22H17NO+H 312.1388, found 312.1384.
1-(5-methyl-2,3-diphenyl-1H-indol-1-yl)ethanone (3ba). 12 h,
76% yield, pale yellow solid; m.p. 182.0-183.8 C; IR (KBr): υ =
1
2930, 1698, 1603, 1578, 1515, 1441, 1301 cm-1. H NMR (400
1
15 3057, 2921, 2856, 1693, 1608, 1512, 1462, 1311 cm-1. H NMR
MHz, CDCl3) δ 8.23 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.68~7.66
(400 MHz, CDCl3) δ 8.34 (d, J = 8.4 Hz, 1H), 7.34~7.39 (m, 6H),
(m, 1H), 7.38~7.37 (m, 3H), 7.34~7.31 (m, 3H), 7.29~7.25 (m,
7.27~7.20 (m, 6H), 2.43 (s, 3H), 1.99 (s, 3H) ppm. 13C NMR 75 2H), 7.19~7.17 (m, 2H), 1.98 (s, 3H) ppm. 13C NMR (100 MHz,
(100 MHz, CDCl3) δ 171.4, 135.1, 135.1, 133.4, 133.2, 133.1,
130.8, 130.1, 129.5, 128.6, 128.2, 126.9, 126.8, 123.3, 119.4,
20 116.0, 27.9, 21.4 ppm. ESI HRMS: calcd. for C23H19NO+H
326.1545, found 326.1547.
CDCl3) δ 171.5, 136.1, 135.7, 133.9, 132.4, 132.4, 131.6, 130.7,
130.0, 128.9, 128.7, 128.4, 128.3, 127.2, 122.3, 118.2, 87.8, 27.9
ppm. ESI HRMS: calcd. for C22H16INO+Na 460.0174, found
460.0177.
1-(6-methyl-2,3-diphenyl-1H-indol-1-yl)ethanone (3ca). 12 h, 80 1-(5-nitro-2,3-diphenyl-1H-indol-1-yl)ethanone (3ia). 12 h, 34%
64% yield, pale yellow solid; m.p. 129.1-130.5 C; IR (KBr): υ =
yield, yellow solid; m.p. 152.9-154.6 C; IR(KBr): υ = 3061,
1
1
3059, 2920, 2854, 1693, 1614, 1512, 1480, 1311 cm-1. H NMR
2922, 2851, 1715, 1611, 1575, 1519, 1445, 1336, 1295 cm-1. H
25 (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34
(s, 5H), 7.30~7.25 (m, 3H), 7.23~7.20 (m, 2H), 7.13 (d, J = 8.0
NMR (400 MHz, CDCl3) δ 8.52 (d, J = 9.2 Hz, 1H), 8.45 (s, 1H),
8.29~8.26 (m, 1H), 7.42~7.39 (m, 3H), 7.38~7.36 (m, 2H),
Hz, 1H), 2.53 (s, 3H), 1.98 (s, 3H) ppm. 13C NMR (151 MHz, 85 7.35~7.31 (m, 3H), 7.22~7.20 (m, 2H), 2.03 (s, 3H) ppm. 13C
CDCl3) δ 171.4, 136.9, 135.4, 134.1, 133.0, 132.8, 130.5, 129.7,
128.3, 128.2, 127.9, 126.8, 126.6, 124.9, 123.0, 118.9, 116.0,
30 27.7, 21.8 ppm. ESI HRMS: calcd. for C23H19NO+Na 348.1364,
found 348.1362.
NMR (100MHz, CDCl3) δ 171.6, 144.4, 139.6, 137.7, 131.8,
131.6, 130.6, 129.9, 129.4, 129.3, 128.9, 128.7, 127.7, 123.5,
120.6, 116.3, 116.0, 27.9 ppm. ESI HRMS: calcd. for
C22H16N2O3+Na 379.1059, found 379.1053.
1-(7-methyl-2,3-diphenyl-1H-indol-1-yl)ethanone (3da). 12 h, 90 1-(2,3-diphenyl-1H-indol-1-yl)propan-1-one (3ja). 12 h, 50%
50% yield, pale yellow solid; m.p. 130.1-132.9 C; IR (KBr): υ =
yield, pale yellow solid; m.p. 145.4-147.5 C; IR (KBr): υ = 3063,
1
1
3044, 2925, 2853, 1707, 1617, 1542, 1512, 1446, 1283 cm-1. H
2984, 2937, 2875, 1696, 1609, 1565, 1485, 1447, 1274 cm-1. H
35 NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 1H), 7.35 (s, 5H),
NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.4 Hz, 1H), 7.56 (d, J =
7.6 Hz, 1H), 7.42~7.39 (m, 1H), 7.36~7.32 (m, 5H), 7.29~7.25
7.30~7.16 (m, 7H), 2.44 (s, 3H), 2.06 (s, 3H) ppm. 13C NMR
(151 MHz, CDCl3) δ 172.9, 135.2, 134.8, 133.2, 132.1, 130.6, 95 (m, 4H), 7.22~7.20 (m, 2H), 2.20 (q, J = 7.2 Hz, 2H), 1.02 (t, J =
129.8, 129.8, 128.4, 128.3, 127.9, 127.3, 126.4, 124.3, 123.0,
121.0, 117.3, 28.4, 21.1 ppm. ESI HRMS: calcd. for
40 C23H19NO+H 326.1545, found 326.1554.
7.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 175.8, 136.8,
134.8, 133.2, 133.1, 130.6, 130.1, 129.2, 128.6, 128.5, 128.2,
126.9, 125.4, 123.6, 123.1, 119.6, 115.8, 33.2, 9.4 ppm. ESI
HRMS: calcd. for C23H19NO+Na 348.1364, found 348.1373.
1-(6-chloro-2,3-diphenyl-1H-indol-1-yl)ethanone (3ea). 12 h,
70% yield, yellow solid; m.p. 139.2-141.3 C; IR (KBr): υ = 3024, 100 1-(2,3-diphenyl-1H-indol-1-yl)-2-methylpropan-1-one (3ka).
1
2925, 2854, 1702, 1602, 1561, 1513, 1456, 1306 cm-1. H NMR
(400 MHz, CDCl3) δ 8.52 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H),
45 7.39~7.36 (m, 3H), 7.35~7.32 (m, 2H), 7.30~7.26 (m, 4H),
7.20~7.18 (m, 2H), 1.99 (s, 3H) ppm. 13C NMR (100 MHz,
12 h, 40% yield, pale yellow solid; m.p. 123.2-125.0 C; IR
(KBr): υ = 3023, 2966, 2929, 2871, 1697, 1617, 1564, 1511,
1
1447, 1272 cm-1. H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0
Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.40~7.28 (m, 10H), 7.26~7.22
CDCl3) δ 171.5, 137.0, 135.4, 132.6, 132.5, 131.4, 130.7, 129.9, 105 (m, 2H), 2.55~2.48 (m, 1H), 0.97 (d, J = 6.8 Hz, 6H) ppm. 13C
128.9, 128.7, 128.4, 127.8, 127.2, 124.3, 123.0, 120.3, 116.5,
27.8 ppm. ESI HRMS: calcd. for C22H16ClNO+Na 368.0818,
50 found 368.0811, 370.0796.
NMR (100 MHz, CDCl3) δ 180.1, 137.0, 134.5, 133.4, 132.8,
130.2, 130.1, 129.1, 128.6, 128.4, 128.3, 126.9, 125.2, 123.3,
122.3, 119.6, 114.8, 37.2, 19.0 ppm. ESI HRMS: calcd. for
C24H21NO+Na 362.1521, found 362.1524.
1-(5-methoxy-2,3-diphenyl-1H-indol-1-yl)ethanone (3fa). 12 h,
59% yield, pale orange solid; m.p. 186.3-188.5 C; IR (KBr): υ = 110 cyclohexyl(2,3-diphenyl-1H-indol-1-yl)methanone (3la). 12 h,
3005, 2958, 2930, 2832, 1692, 1606, 1544, 1512, 1468, 1370,
75% yield, pale yellow solid; m.p. 142.3-143.9 C; IR (KBr): υ =
1
1
1297 cm-1. H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz,
3053, 2929, 2849, 1699, 1604, 1562, 1507, 1447, 1312 cm-1. H
55 1H), 7.36~7.31 (m, 5H), 7.29~7.24 (m, 3H), 7.22~7.19 (m, 2H),
7.03~6.99 (m, 2H), 3.82 (s, 3H), 1.98 (s, 3H) ppm. 13C NMR
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 7.57 (d, J =
7.6 Hz, 1H), 7.39~7.23 (m, 12H), 2.15 (t, J = 7.2 Hz, 1H),
(100 MHz, CDCl3) δ 171.2, 156.7, 135.7, 133.1, 133.0, 131.6, 115 1.63~1.56 (m, 3H), 1.48~1.34 (m, 4H), 1.08 (q, J = 12.8 Hz, 1H),
130.8, 130.2, 130.0, 128.6, 128.6, 128.3, 126.9, 123.3, 117.3,
0.69 (q, J = 12.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ
4
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Organic & Biomolecular Chemistry
178.7, 136.9, 134.7, 133.3, 133.0, 130.3, 130.1, 129.0, 128.6,
yellow oil; IR (KBr): υ = 3048, 2957, 2930, 2863, 1703, 1602,
128.4, 128.2, 126.8, 125.1, 123.3, 122.3, 119.5, 115.1, 46.7, 29.1, 60 1578, 1518, 1460, 1311 cm-1. 1H NMR (400 MHz, CDCl3) δ
View Article Online
25.5, 25.4 ppm. ESI HRMS: calcd. for C27H25NO+Na 402.1834,
found 402.1834.
1-(2,3-di-p-tolyl-1H-indol-1-yl)ethanone (3ab). 12 h, 71% yield,
7.76~7.74 (m, 1H), 7.49~7.47 (m, 1H), 7D.2O5I~: 710.2.1203(9m/C, 52OHB)0, 127.8988B
(t, J = 7.6 Hz, 2H), 2.76 (s, 3H), 2.64 (t, J = 7.6 Hz, 2H),
1.62~1.52 (m, 4H), 1.44~1.37 (m, 4H), 0.97~0.93 (m, 6H) ppm.
13C NMR (100 MHz, CDCl3) δ 170.0, 138.3, 135.7, 130.9, 123.3,
5
white solid; m.p. 170.0-171.8 C; IR (KBr): υ = 3016, 2939, 2861,
1
1687, 1590, 1504, 1448, 1311 cm-1. H NMR (400 MHz, CDCl3) 65 122.6, 120.1, 118.7, 114.5, 32.5, 32.4, 27.7, 26.8, 23.7, 22.9, 22.8,
δ 8.44 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (t, J =
7.6 Hz, 1H), 7.30~7.25 (m, 1H), 7.23~7.21 (m, 2H), 7.17~7.13
14.0, 13.9 ppm. ESI HRMS: calcd. For C18H25NO+Na 294.1834,
found 294.1840.
10 (m, 2H), 7.11~7.09 (m, 4H), 2.37 (s, 3H), 2.33 (s, 3H), 1.99 (s,
ethyl 1-acetyl-2-phenyl-1H-indole-3-carboxylate (3ah). 12 h,
26% yield, pale yellow solid; m.p. 104.5-106.1 C; IR (KBr): υ =
3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.7, 138.5, 136.8,
136.5, 135.0, 130.6, 130.1, 130.0, 129.9, 129.5, 129.3, 129.0, 70 3057, 2987, 2945, 2897, 1796, 1707, 1608, 1555, 1515, 1446,
1
125.3, 123.7, 123.0, 119.5, 116.2, 28.0, 21.4, 21.2 ppm. ESI
HRMS: calcd. for C24H21NO+H 340.1701, found 340.1700.
15 1-(2,3-di-m-tolyl-1H-indol-1-yl)ethanone (3ac). 12 h, 77% yield,
1290, 1240, 1178 cm-1. H NMR (400 MHz, CDCl3) δ 8.32 (d, J
= 7.2 Hz, 1H), 8.23~8.20 (m, 1H), 7.51~7.48 (m, 5H), 7.42~7.40
(m, 2H), 4.20 (q, J = 7.6 Hz, 2H), 1.92 (s, 3H), 1.16 (t, J = 7.6 Hz,
3H) ppm. 13C NMR (151 MHz, CDCl3) δ 171.7, 164.2, 143.6,
pale yellow oil; IR (KBr): υ = 3033, 2961, 2860, 1695, 1608,
1515, 1449, 1307 cm-1. H NMR (400 MHz, CDCl3) δ 8.45 (d, J 75 136.2, 132.6, 130.4, 129.5, 128.3, 126.9, 125.7, 124.5, 121.7,
1
= 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz 1H),
7.29 (t, J = 7.2 Hz, 1H), 7.25~7.21 (m, 1H), 7.18~7.12 (m, 4H),
20 7.08~7.04 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 2.32 (s, 3H), 2.29 (s,
3H), 2.00 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 170.7,
115.6, 112.4, 60.1, 27.8, 14.0 ppm. ESI HRMS: calcd. for
C19H17NO3+Na 330.1106, found 330.1102.
1-(2-(tert-butyl)-3-phenyl-1H-indol-1-yl)ethanone (3ai); 1-(3-
(tert-butyl)-2-phenyl-1H-indol-1-yl)ethanone (3ai'); (3ai:3ai'
137.2, 136.6, 135.7, 134.1, 132.0, 131.9, 130.3, 129.7, 128.3, 80 = 17:1). 12h, 45% yield, pale yellow solid; m.p. 86.3-87.9 C; IR
128.3, 127.4, 127.0, 126.9, 126.6, 126.1, 124.3, 122.7, 122.2,
118.6, 115.1, 26.9, 20.4, 20.3 ppm. ESI HRMS: calcd. for
25 C24H21NO+Na 362.1521, found 362.1520.
(KBr): υ = 3060, 2994, 2963, 2918, 2864, 1713, 1584, 1516,
1
1454, 1295 cm-1. H NMR (400 MHz, CDCl3) δ 3ai: 7.48~7.12
(m, 9H), 2.87 (s, 3H), 1.34 (s, 9H) ppm; 3ai': 8.44 (d, J = 8.0 Hz,
1H), 7.86 (d, J = 8.0 Hz, 1H), 7.48~7.12 (m, 7H), 1.50 (s, 3H),
1-(2,3-di-o-tolyl-1H-indol-1-yl)ethanone (3ad). 12 h, 80%
yield.pale yellow solid; m.p. 85.1-86.9 C; IR(KBr): υ = 3034, 85 1.25 (s, 9H) ppm. 13C NMR (151 MHz, CDCl3) δ 174.9, 145.5,
1
2952, 2860, 1695, 1606, 1516, 1448, 1307 cm-1. H NMR (400
MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H),
30 7.42~7.38 (m, 1H), 7.31~7.28 (m, 1H), 7.25~7.21 (m, 1H),
7.18~7.12 (m, 4H), 7.08~7.05 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H),
136.5, 134.8, 131.4, 130.8, 128.2, 127.1, 123.6, 123.0, 121.8,
119.8, 111.4, 35.2, 32.1, 31.1, 29.9, 28.3 ppm.6a
5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-8-one
(5aa). 16 h, 43% yield, yellow solid; m.p. 296.5-297.9 C; IR
2.32 (s, 3H), 2.29 (s, 3H), 2.00 (s, 3H) ppm. 13C NMR (100 MHz, 90 (KBr): υ = 3021, 1673, 1595, 1540, 1477, 1309 cm-1. H NMR
1
CDCl3) δ 171.8, 138.2, 137.7, 136.8, 135.1, 133.0, 132.9, 131.4,
130.7, 129.4, 129.4, 128.4, 128.1, 127.9, 127.7, 127.1, 125.4,
35 123.7, 123.3, 119.6, 116.2, 27.9, 21.5, 21.4 ppm. ESI HRMS:
calcd. for C24H21NO+Na 362.1521, found 362.1521.
(400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 7.62~7.58 (m, 1H),
7.56~7.53 (m, 5H), 7.44 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz,
1H), 7.28~7.20 (m, 3H), 7.18~7.12 (m, 5H), 7.08 (s, 5H), 6.88 (t,
J = 7.6 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 162.2,
1-(2,3-bis(4-methoxyphenyl)-1H-indol-1-yl)ethanone (3ae). 12 95 138.6, 137.1, 137.1, 136.2, 136.1, 133.8, 133.0, 132.3, 132.1,
h, 80% yield, pale yellow solid; m.p. 148.6-150.1 C; IR (KBr): υ
131.4, 129.6, 129.0, 128.8, 128.4, 128.1, 127.9, 127.6, 127.4,
127.1, 126.9, 126.8, 126.6, 126.4, 126.3, 125.8, 125.6, 125.5,
116.9 ppm. ESI HRMS: calcd. for C35H23NO+Na 496.1677,
found 496.1674.
= 3066, 2955, 2837, 1701, 1610, 1568, 1504, 1451, 1300, 1249
1
40 cm-1. H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.4 Hz, 1H),
7.54 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6
Hz, 1H), 7.27~7.23 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 100 11-chloro-5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-
8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H),
2.01 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.7, 159.8,
45 158.4, 136.7, 134.6, 132.0, 131.1, 129.5, 125.4, 125.3, 125.2,
123.7, 122.7, 119.4, 116.2, 114.1, 113.8, 55.3, 55.2, 27.3 ppm.
8-one (5ba). 16 h, 56% yield, yellow solid; m.p. 334.2-336.1 C;
IR (KBr): υ = 3025, 1667, 1591, 1529, 1449, 1317 cm-1. 1H NMR
(400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.58~7.50 (m, 5H),
7.38 (d, J = 8.4 Hz, 1H), 7.32~7.23 (m, 4H), 7.19~7.11 (m, 5H),
ESI HRMS: calcd. for C24H21NO3+Na 394.1419, found 394.1423. 105 7.08 (s, 5H), 6.89 (t, J = 7.6 Hz, 1H) ppm. 13C NMR (151 MHz,
1-(2,3-bis(4-chlorophenyl)-1H-indol-1-yl)ethanone (3af). 12 h,
59% yield, pale yellow solid; m.p. 204.2-205.8 C; IR (KBr): υ =
CDCl3) δ 161.5, 139.0, 138.4, 137.9, 136.9, 136.0, 135.9, 135.2,
133.1, 132.0, 131.3, 129.9, 129.3, 129.1, 128.8, 128.8, 128.4,
127.9, 127.2,127.2, 127.0, 126.9, 126.9, 126.8, 126.4, 125.7,
1
50 3062, 2957, 2853, 1698, 1598, 1557, 1447, 1301 cm-1. H NMR
(400 MHz, CDCl3) δ 8.41 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.6 Hz,
124.8,
123.9,
115.8
ppm.ESI
HRMS:
calcd.
for
1H), 7.40 (t, J = 7.6 Hz, 1H), 7.38~7.36 (m, 2H), 7.33~7.30 (m, 110 C35H22ClNO+H508.1468, found 508.1468, 510.1452.
2H), 7.28~725 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 2.06 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ 171.0, 136.8, 135.0, 133.9,
55 133.2, 131.9, 131.3, 131.2, 129.1, 128.9, 128.7, 125.9, 124.0,
122.7, 119.4, 116.2, 28.1 ppm. ESI HRMS: calcd. for
C22H15Cl2NO+Na 402.0428, found 402.0443, 404.0373.
11-methoxy-5,6,13-triphenyl-8H-isoquinolino[3,2-a]
isoquinolin-8-one (5ca). 16 h, 40% yield, yellow solid; m.p.
301.6-303.1 C; IR (KBr): υ = 3021, 2938, 2839, 1670, 1604,
1540, 1475, 1279, 1217 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.19
115 (d, J = 8.8 Hz, 1H), 7.54~7.50 (m, 5H), 7.27~7.21 (m, 3H),
7.16~7.09 (m, 5H), 7.06 (s, 5H), 7.03~7.00 (m, 1H), 6.86 (t, J =
1-(2,3-dibutyl-1H-indol-1-yl)ethanone (3ag). 12 h, 33% yield,
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Journal Name, [year], [vol], 00–00 |5

Organic & Biomolecular Chemistry
Page 6 of 6
8.0 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H) ppm. 13C NMR
(151 MHz, CDCl3) δ 162.9, 161.7, 139.2, 138.7, 137.3, 136.3,
136.2, 134.6, 133.2, 132.1, 131.5, 129.7, 129.7, 129.1, 128.8,
128.5, 128.1, 127.9, 127.5, 127.1, 126.9, 126.7, 126.3, 126.2,
125.6, 119.9, 116.6, 115.1, 107.5, 55.3 ppm. ESI HRMS: calcd.
for C36H25NO2+Na 526.1783, found 526.1780.
11-nitro-5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-8-
one (5da). 16 h, 35% yield, red solid; m.p. 348.5-349.7 C; IR
(KBr): υ = 3026, 1666, 1605, 1578, 1519, 1456, 1340, 1293 cm-1.
Rev., 2011, 111, 1315; (c) H. M. Davies, J. Du. Bois, J. -Q. Yu, Chem.
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C. S. Yeung, V. M. Dong, Chem. Rev., 2011, 111, 1215; (i) C. Liu, H.
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X. Li, Chem. Soc. Rev., 2012, 41, 3651; (i) T. Satoh, M. Miura,
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For selected examples of nitrogen as the directing group, see: (a) L.
Li, W. W. Brennessel, W. D. Jones. J. Am. Chem. Soc., 2008, 130,
12414; (b) Y. Hashimoto, K. Hirano, T. Satoh, F. Kakiuchi, M.
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51, 8092; (d) Z.-Z. Shi, C.-H. Tang, N. Jiao, Adv. Synth. Catal., 2012,
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For selected examples of rhodium-catalyzed C-ring activation, see:
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G. Song, D. Chen, C.-L. Pan, R. H. Crabtree, X. Li, J. Org. Chem.,
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For selected examples of ruthenium-catalyzedC-ring activation, see:
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5
2
10 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.4 Hz, 1H), 8.22 (s,
1H), 8.15 (d, J = 8.4 Hz, 1H), 7.61~7.57 (m, 3H), 7.52~7.50 (m,
2H), 7.29~7.20 (m, 4H), 7.17~7.15 (m, 4H), 7.09 (s, 5H), 6.93 (t,
J = 7.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 160.8,
150.3, 137.7, 137.2, 136.4, 136.0, 135.8, 135.6, 133.1, 131.8,
15 131.2, 130.2, 129.4, 129.3, 129.2, 128.9, 128.8, 128.4, 128.0,
127.8, 127.3, 127.2, 127.1, 126.7, 126.6, 125.9, 121.2, 119.7,
116.3 ppm.ESI HRMS: calcd. for C35H22N2O3+H519.1709, found
519.1705.
70
3
4
75
11-fluoro-5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-
20 8-one (5ea). 16 h, 42% yield, yellow solid; m.p. 298.2-300.0 C;
IR(KBr): υ = 3024, 1673, 1614, 1580, 1490, 1399, 1286 cm-1. 1H
NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 6.4, 8.4 Hz, 1H),
7.59~7.53 (m, 3H), 7.51~7.49 (m, 2H), 7.28~7.21 (m, 3H),
7.19~7.12 (m, 6H), 7.08 (s, 5H), 6.98~6.95 (m, 1H), 6.89 (t, J =
80
85
25 7.6 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 165.4(d, JC-F
=
5
252 Hz), 161.4, 139.6 (d, JC-F= 10.0 Hz), 138.2, 137.0, 136.1,
136.0, 135.2, 133.2, 132.0, 131.4, 130.7 (d, JC-F = 10.0 Hz), 129.9,
129.1, 128.8, 128.8, 128.4, 127.9, 127.2, 127.1, 127.0, 126.9,
126.8, 126.4, 125.7, 122.3, 116.2, 115.0 (d, JC-F = 24.0 Hz), 110.6
30 (d, J = 24.0 Hz) ppm. ESI HRMS: calcd. for C35H22FNO+Na
514.1583, found 514.1581.
90
95
10-methyl-5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-
8-one (5fa). 16 h, 36% yield, yellow solid; m.p. 252.1-253.5 C;
IR (KBr): υ = 3025, 2923, 2852, 1669, 1606, 1537, 1467, 1326
1
35 cm-1. H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.57~7.50 (m,
100
5H), 7.46~7.42 (m, 1H), 7.26~7.20 (m, 5H), 7.17~7.11 (m, 4H),
7.07 (s, 5H), 8.87 (t, J = 7.6 Hz, 1H), 2.45 (s, 3H) ppm. 13C NMR
(151 MHz, CDCl3) δ 162.2, 138.7, 137.2, 136.7, 136.2, 136.2,
134.8, 133.8, 132.9, 132.9, 132.1, 131.4, 129.6, 128.9, 128.8,
40 128.2, 128.0, 127.9, 127.8, 127.1, 127.0, 126.9, 126.7, 126.6,
126.2, 125.7, 125.6, 125.6, 117.0, 21.3 ppm.ESI HRMS: calcd.
for C36H25NO+K526.1573, found 526.1573.
6
(a) Y. Hoshino, Y. Shibata, K. Tanaka, Adv. Synth. Catal., 2014, 356,
1577; (b) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K.
Fagnou, J. Am. Chem. Soc., 2008, 130, 16474; (c) D. R. Stuart, P.
Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc., 2010, 132, 18326.
(a) L. Wang, L. Ackermann, Org. Lett., 2013, 15, 176; (b) B. Li, N.
Wang,Y. Liang, S. Xu, B. Wang, Org. Lett., 2013, 15, 136.
S. Mochida, N.Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Lett.,
2010, 39, 744.
105 7
8
9-chloro-5,6,13-triphenyl-8H-isoquinolino[3,2-a]isoquinolin-
8-one (5ga). 16 h, 18% yield, yellow solid; m.p. 229.7-230.6 C;
45 IR (KBr): υ = 3024, 1689. 1581, 1528, 1447, 1294 cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.58~7.52 (m, 3H), 7.46~7.36 (m, 4H),
7.29~7.21 (m, 3H), 7.18~7.09 (m, 10H), 7.04~7.02 (m, 1H), 6.88
(t, J = 7.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3) δ 161.5,
140.3, 138.7, 136.5, 136.4, 136.0, 134.3, 133.8, 133.4, 132.0,
50 131.4, 131.3, 129.8, 129.0, 128.9, 128.7, 128.5, 128.1, 127.9,
127.4, 127.1, 127.0, 126.6, 126.2, 125.8, 125.5, 124.4, 122.2,
114.7 ppm.ESI HRMS: calcd. for C35H22ClNO+Na 530.1288,
found 530.1271, 532.1256.
9
(a) P.-B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev., 2012,
112, 5879; (b) F. Kakiuchi, N. Chatani, Adv. Synth. Catal., 2003, 345,
1077; (c) J. Dupont, C. S. Consorti, J. Spencer, Chem. Rev., 2005,
105, 2527; (d) L. Ackermann, A. V. Lygin, Org. Lett., 2012, 14, 764;
(e) L. Ackermann, Acc. Chem. Res., 2014, 47, 281; (f) S. D. Sarkar,
W. Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal., 2014,
356. 1461; (g) L. Ackermann, L. Wang, R. Wolfram, A. V. Lygin,
Org. Lett., 2012, 14, 728.
110
115
10 B. Li, H.-L. Feng, N.-C. Wang, J.-F. Ma, H.-B. Song, S.-S. Xu, B.-Q.
Wang, Chem.Eur. J., 2012, 18, 12873.
55 Notes and references
1
For selected recent reviews, see: (a) D. A. Colby, R. G. Bergman, J.
A.Ellman, Chem. Rev., 2010, 110, 624; (b) L.Ackermann, Chem.
6
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