Copper-catalyzed dehydrogenative C(sp2)-N bond formation via direct oxidative activation of an anilidic N-H bond: Synthesis of benzoimidazo[1,2-a]indoles

Article abstract of DOI:10.1021/acs.joc.7b01617

A dehydrogenative C(sp²)-N bond-forming strategy via copper-catalyzed intramolecular C-H/N-H coupling has been developed, which systematically unraveled the feasibility and practicality for benzoimdazo[1,2-a]indole formations through oxidative anilidic N-H activation. The merit of this strategy is illustrated by the broad tolerance of functionalities, as well as the utilization of extremely cheap copper catalysis to realize potentially useful indole-fused tetracycles in a step- and atom-economical manner.

Full text of DOI:10.1021/acs.joc.7b01617

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Article
Copper-Catalyzed Dehydrogenative C(sp2)–N Bond
Formation via Direct Oxidative Activation of Anilidic
N–H Bond: Synthesis of Benzoimidazo[1,2-a]indoles
Xiaoxia Wang, Na Li, Zhongfeng Li, and Honghua Rao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01617 • Publication Date (Web): 05 Sep 2017
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Copper-Catalyzed Dehydrogenative C(sp2)–N Bond Formation via Di-
rect Oxidative Activation of Anilidic N–H Bond: Synthesis of Benzo-
imidazo[1,2-a]indoles
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Xiaoxia Wang,†,ǁNa Li,†,ǁ Zhongfeng Li† and Honghua Rao*,†,‡
†Department of Chemistry, Capital Normal University, Beijing, 100048, P. R. China
‡Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, P. R. China
Supporting Information Placeholder
ABSTRACT: A dehydrogenative C(sp2)–N bond-forming strategy via copper-catalyzed intramolecular C–H/N–H coupling
has been developed, which systematically unravel the feasibility and practicality for benzoimdazo[1,2-a]indole formations
through oxidative anilidic N-H activation. The merit of this strategy is illustrated by the broad tolerance of functionalities,
as well as the utilization of extremely cheap copper-catalysis to realize this potentially useful indole fused tetracycles in a
step- and atom-economical manner.
Transition metal-catalyzed C–N bond formations
through the coupling of N–H bonds with (pseu-
do)halocarbon or organometallic reagents are fundamen-
tal but powerful tools to access amines and N-
heterocycles, common structural features in material- and
biology-oriented functional molecules.1-2 These classic C–
N bond-forming procedures need pre-installation of reac-
tive groups onto substrates (Figure 1a), which may face
great challenges on account of their low atom-economy
and generation of unavoidable by-products, thus leaving
ample opportunities to develop more economical C–N
bond-forming protocols.3
catalysis” has been well-developed because it can enable
direct metalation of sp,5 sp2,6 or sp3 C–H bonds7 to puta-
tively generate the corresponding organometallic inter-
mediates that easily engage various N–H bonds to even-
tually forge C–N bonds (Figure 1b). Recently, the other
mechanistic manifold involving “N–H activation catalysis”
began to draw increasing attentions in synthetic commu-
nity, of which the key working mode is the generation of
N-centered radicals (NCRs) directly from NH groups and
the ensuing coupling reactions with C–H bonds to form
C–N bonds (Figure 1c).8 Several catalytic systems such as
CuI/DTBP,9
CuII/MnO2,10
CuII/Na2S2O8,11
and
Ni(acac)2/DTBP12 were thus applied to produce NCRs di-
rectly from sulfonamides or N-alkloxyamides, which can
cross-couple with olefinic and aliphatic C–H bonds effi-
ciently. Besides, hypervalent iodine13 and photocatalysis14-
15 capacitate the generation of NCRs and the reaction with
C(aryl)–H bonds by using phosphamides, sulfoamide and
phthalimides as the NH-sources as well. These strategies
offer a great potential in C–N bond formations to access
amines and N-heterocycles, wherein the utilization of
sulfonamidyl and benzamidyl radicals has been the major
focuses; in contrast, generation and utilization of other
NCRs, such as the much less reactive anilidyl radicals,
have been remaining poorly developed because of their
intrinsically lower reactivities.16 Therefore, it is desirable
but challenging to develop such reactivities of anilidyl
Figure 1. Strategies for C–N bond formations
In this context, a more direct approach of using C–H
bonds instead of (pseudo)halocarbon and organometallic
substrates would be an ideal alternative to react with N–H
bonds, which can be classified into two mechanistic
manifolds according to the proposed intermediates on the
reaction pathway.4 The one denoted as “C–H activation
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radicals that can enable C-N bond formations and assem- yield (entries 21-22). Other endeavors to increase the yield
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2
3
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8
ble N-heterocycles (particularly the fused N-heterocycles)
through C–H/N–H coupling pathway eventually.
of 2a, such as adjusting the catalyst loading by 5 mol %
(entry 23), conducting the reaction under argon or oxygen
atmosphere (entries 24 and 25), or performing the reac-
tion at a higher temperature (entry 26), were attempted,
but none of them afforded superior result. Finally, control
experiments run in the absence of oxidant or copper cata-
lyst provided completely none or only 16% of the desired
product, respectively (entries 27 and 28), thus indicating
that the combination of Cu2O catalyst and (tBuO)2 oxi-
dant is crucial for the proposed C–H/N–H coupling reac-
tion as well. However, the above reaction conditions
should be futher optimized when reacting of substrates
bearing electron-donating groups such as 5-methoxy on
indole ring, which should employ Cu2O (10 mol %) as the
catalyst, (tBuO)2 (2.25 equiv) as the oxidant, L1 (20 mol %)
as the ligand and DCE/p-dioxane (7:1 v/v ratio) as the sol-
vent to produce the desired products in the highest effi-
ciency (entry 29). Likewise, superior results for substrates
bearing electron-withdrawing groups such as 5-bromo on
indole ring can be obtained in the catalytic system con-
sisting of 12.5 mol % of Cu2O, 2.5 equiv of (tBuO)2, 25 mol %
of L1 and 1.6 mL of DCE/p-dioxane (6:2 v/v ratio) (entry
30).
As is well-known, indole fused heterocycles, such as
benzoimdazo[1,2-a]indole scaffold, are privileged struc-
tural constituents of numerous natural products and
pharmacological entities.17 In 2016, Sekar group developed
an intramolecular nucleophilic addition reaction of sul-
fonamides to cyclic iodonium ion and subsequent HI-
elimination to afford the benzoimidazo[1,2-a]indoles.18
Alternatively, as indicated above, the dehydrogenative C–
H/N–H coupling protocol would provide a distinct but
still appealing pathway in atom- and step-economy fash-
ion when applied to N-heterocycle constructions.
Ir(ppy)2(dtbbpy)PF6 photocatalysis was thereby employed
to prove this feasibility of assembling benzoimdazo[1,2-
a]indoles, although only one such case via reactive sul-
foamidyl radical was given.14 Following this tendency, we
herein introduce a cheaper copper catalysis to systemati-
cally recognize an intramolecular dehydrogenative C–
H/N–H coupling, forming a practical strategy for benzo-
imidazo[1,2-a]indole installations via direct oxidative acti-
vation of anilidic N–H bonds (Scheme 1).
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Scheme 1. Copper-catalyzed dehydrogenative C–H/N–
H coupling toward benzoimidazo[1,2-a]indoles
Table 1. Screening of the reaction conditionsa
entry cat.
[O] (equiv)
ligand solvent
yield (%)b
Using 1a as the model substrate,19 Cu2O (10 mol %) as
the catalyst and (tBuO)2 (4.0 equiv) as the oxidant,20 we
began our investigations into the proposed intramolecu-
lar dehydrogenative coupling between anilidic N–H
bonds and indolyl C–H bonds in DCE. Initial results re-
vealed that the utilization of ligands such as dppp is es-
sential to affect this C–H/N–H coupling reaction (Table 1,
entries 1 and 2; for the optimization results of other lig-
ands, please refer to section 1 in supporting information).
Seeking to improve on this result, a series of copper(I)
and copper(II) catalysts, frequently applied in N–H activa-
tion strategies,9-11 were evaluated in this reaction, among
which Cu2O was more effective to generate the desired
product 2a (confirmed by X-ray diffraction; for detailed
crystallographic data, please refer to section 4 in support-
ing information) in 30% yield (entries 2-8). Subsequently,
other phosphine ligands such as dppe, dppb, PCy3, Xphos
and tris(2-methoxyphenyl)phosphine (L1) were examined,
and L1 exhibited higher catalytic reactivity to produce 2a
in 37% yield (entries 2 and 9-13). Additionally, loading 2.5
equiv of (tBuO)2 slightly increased the coupling efficiency,
furnishing 2a in 43% yield (entries 13-17). Remarkably, the
reaction efficiency showed a strong dependency on sol-
vent: p-dioxane, TCE or DCE/TCE (7:1 v/v ratio) as solvent
nearly inhibited the reaction completely, while DCE in
combination with p-dioxane as co-solvent showed
marked increase in efficiency (entries 18-21); notably, the
largest improvement in reaction efficiency was observed
when the model reaction was performed in DCE/p-
dioxane (7:1 v/v ratio), affording 2a in the highest 85%
1
Cu2O
(tBuO)2 (4.0)
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
trace
30
2
Cu2O
CuOAc
CuCl
CuBr
CuI
(tBuO)2 (4.0) dppp
(tBuO)2 (4.0) dppp
(tBuO)2 (4.0) dppp
(tBuO)2 (4.0) dppp
(tBuO)2 (4.0) dppp
(tBuO)2 (4.0) dppp
3
28
4
trace
29
5
6
26
7
CuCl2
23
8
Cu(OAc)2 (tBuO)2 (4.0) dppp
27
9
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
-
(tBuO)2 (4.0) dppe
(tBuO)2 (4.0) dppb
(tBuO)2 (4.0) PCy3
14
10
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12
13
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19
20
21
22
23c
24d
25e
26f
27
28
29g
22
12
(tBuO)2 (4.0) Xphos DCE
trace
37
(tBuO)2 (4.0) L1
(tBuO)2 (3.5) L1
(tBuO)2 (3.0) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.0) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
(tBuO)2 (2.5) L1
DCE
DCE
42
DCE
43
DCE
43
DCE
40
p-dioxane
TCE
-
trace
trace
DCE/TCE (7:1)
DCE/p-dioxane (7:1) 85
DCE/ p-dioxane (6:2) 68
DCE/ p-dioxane (7:1) 51
DCE/p-dioxane (7:1) 73
DCE/p-dioxane (7:1) 61
DCE/p-dioxane (7:1) 70
-
L1
DCE/p-dioxane (7:1)
-
(tBuO)2 (2.5) L1
(tBuO)2 (2.25) L1
(tBuO)2 (2.5) L1
DCE/p-dioxane (7:1) 16
DCE/p-dioxane (7:1) 72
DCE/p-dioxane (6:2) 53
Cu2O
30h,i Cu2O
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aReaction conditions: 1a (0.40 mmol), [O] (x equiv), ligand
H
H
Ac
N
cat. Cu2O, L1
(tBuO)2, solvent
90 oC, 24 h, air
Ac
N
o
N
Ar1
1
2
3
4
5
6
7
8
(20 mol%), solvent (1.6 mL), 90 C, under air for 24 h unless
N
Ar1
Ar2
Ar2
otherwise noted. bDetermined by 1H NMR with mesitylene as
1
2
c
Mono-substituted on indole unit
the internal standard. Cu2O (15 mol%) or Cu2O (5 mol%)
d
e
Ac
N
Ac
N
Ac
N
Me
was used. Reaction was conducted under argon. Reaction
was conducted under oxygen. fReaction was conducted at 100
oC. gWith N-(2-(5-methoxy-1H-indol-1-yl)phenyl)acetamide
N
N
N
Me
2a, 84% (A)
2b, 69% (B)
2c, 61% (B)
hWith
N-(2-(5-bromo-1H-indol-1-
Ac
Ac
Ac
Ac
N
as
the
substrate.
MeO
N
N
i
yl)phenyl)acetamide as the substrate. Cu2O (12.5 mol %), L1
N
N
N
MeO
Br
(25 mol %). cat. = catalyst, [O] = oxidant, dppp = 1,3-
9
2d, 64% (B)
2e, 69% (B)
2f, 72% (B)
Me
bis(diphenylphosphino)propane,
bis(diphenylphosphino)ethane,
dppe
dppb
=
=
1,2-
1,4-
Ac
Ac
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N
N
N
N
N
N
Cl
bis(diphenylphosphino)-butane, Cy = cyclohexyl, Xphos = 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, L1
2g
B)
C)
2h
, 59% (
C)
2i
C)
MeO , 71% (
, 45% (
=
Ac
Ac
N
Ac
F
tris(2-methoxyphenyl)phosphine, DCE = 1,2-dichloroethane,
TCE = 1,1,2-trichloroethane
N
N
N
N
N
Br
F
2j
2k
, 63% (
C)
2l
, 60% (
Me
C)
Ac
, 52% (
With optimal reaction conditions in hand, we first
probed the generality of this dehydrogenative C–H/N–H
coupling reaction with respect to the substrates bearing a
mono-substituent on indole unit. As shown in Scheme 2,
unfunctionalized substrate 1a underwent the titled reac-
tion efficiently (2a, 84% yield), while functionalized ones
exhibited variant reactivities. For example, substrates
bearing electron-donating groups (eg. Me, OMe) per-
formed smoothly to deliver the desired products in good
yields (2b-g, 61-72% yield), while electron-withdrawing
groups such as catalytically reactive halide functionalities
(eg. Cl, Br, F) displayed slightly lower efficiency (2h-l, 45-
63% yield). The ester group was tolerated as well, provid-
ing an encouraging quantity of product 2m in 57% yield.
Notably, substrates containing strong electron-
withdrawing groups such as cyano functionality showed
marked dropoff in efficiency, furnishing the desired prod-
uct in the poorest yield (2n, 20% yield). The steric limit of
substituent on indole ring was also investigated, and a
detrimental effect to coupling efficiency was observed
when using 3-methylated substrate 1o as the coupling
partner (43% yield; cf. 2o and 2a-d); however, it is note-
worthy that substituents at different positions on phenyl
ring of the indole unit do not seem to affect the reaction
efficiency obviously (cf. 2b-d, 2e-g, 2i-j or 2k-l).
Ac
Ac
N
NC
N
N
N
N
N
2m
C)
2n
, 20% (
C)
2o
C)
MeO2C
, 57% (
, 43% (
Mono-substituted on anilide unit
Poly-substituted on both units
Ac
N
Ac
N
Ac
N
N
N
MeO
N
CH3
Me
2q, 67% (B)
2u, 70% (B)
Me
2p
B)
Ac
, 60% (
Ac
Ac
N
N
N
N
N
N
MeO
F
2s, 56% (C)
2v, 55% (B)
2r, 66% (C)
F
F
Ac
Ac
N
Ac
N
N
N
N
N
Me
Br
Br
Br
2w, 65% (B)
2x, 70% (C)
2t, 58% (C)
Me
aGeneral reaction conditions: 1 (0.40 mmol), solvent (1.6 mL),
90 °C, 24 h, under air. Conditions A: Cu2O (10 mol %),
(tBuO)2 (2.5 equiv), L1 (20 mol%), DCE/p-dioxane (7:1 v/v
ratio). Condtions B: Cu2O (10 mol %), (tBuO)2 (2.25 equiv),
L1 (20 mol%), DCE/p-dioxane (7:1 v/v ratio). Conditions C:
Cu2O (12.5 mol %), (tBuO)2 (2.5 equiv), L1 (25 mol%), DCE/p-
dioxane (6:2 v/v ratio). Isolated yields were given. Reaction
conditions are shown in parentheses.
Subsequently, a range of substituents on anilide unit
were examined under the optimal reaction conditions.
And it was found that all of them were viable for this
transformation, affording the desired products in moder-
ate to good yields with no significant differences in effi-
ciency when varying their electronic-effects (2p-t, 56-67%
yield).
Finally, substrates bearing multiple substituents were
evaluated to further exemplify the generality of this C–
H/N–H coupling paradigm. For instance, indole/anilide
Scheme 2. Substrate scopea
units bearing electron-donating/-donating (2u),
-
donating/-withdrawing (2v-w), -withdrawing/-donating
groups (2x) were successfully reacted to deliver the target
products in moderate to good yields (55-70% yield).
Moreover, the tolerance of various functionalities
highlights the potential for downstream modifications of
the indole fused benzoimidazole scaffolds via either
transition-metal-catalyzed cross-coupling reactions or
traditional functional group transformations.
Scheme 3. Investigation into the reaction mechanism
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In summary, we have established an intramolecular de-
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hydrogenative coupling between anilidic N–H and indolyl
sp2 C–H bonds, which systematically unravel the feasibil-
ity and practicality towards benzoimidazo [1,2-a]indole
formations in a step- and atom-economical fashion. The
successful implementation of this C(sp2)–N bond-forming
strategy relies on the direct oxidative activation of anilidic
N–H bonds to anilidyl radicals by using the extremely
cheap and easy-handling copper-catalysis. Moreover, the
power of this C–H/N–H coupling paradigm has been fully
exemplified by the tolerance of various functionalities
that can serve as useful synthetic handles for subsequent
chemical manipulation. We believe that this strategy will
generate broad applications among practitioners of syn-
thetic and pharmaceutical chemistry. Exploring the utility
of anilidyl radicals to construct other fused heterocycles is
currently underway in our laboratory.
Further investigations were performed to gain some in-
sights into the reaction mechanism (Scheme 3). As either
the indolyl sp2 C–H or anilidic N-H activation is the
mechanistic consideration, 1a was thereby exposed to
Conditions A for 12 h, which, after being stirred with 2.0
equiv of D2O for additional 10 minutes, was transformed
into no deuterated products 3 and 4 (by GC-MS) (with
compound 39% of 2a as the expected product) (Scheme
3a), thus suggesting that the proposed reaction may not
involve the indolyl sp2 C–H activation pathway. Mean-
while, a radical-trapping experiment was carried out by
introducing TEMPO into Conditions A, whereas no de-
sired product 2a but a full recovery of starting material 1a
was observed (Scheme 3b); additionally, the coupling re-
action did not occur in the absence of DTBP (Table 1, en-
try 26). Remarkably, an anilidic N-methylated by-product
5 from 1l (a moderated reactive substrate) was detected by
GC-MS (m/z 283 was found for [M+H]+) (Scheme 3c),
which might be formed through radical cross-coupling
between anilidyl radical and methyl radical.21 Finally, the
slightly negative Hammett slope observed (ρ = -0.1627) for
the titled reaction is consistent with a radical-involved
mechanism, which favors electron-rich substrates but is
not markedly influenced by the electronic effects of sub-
stituents on indoly ring (For more information, please
refer to section 5 in supporting information). These results
imply that the titled reaction most probably proceed
through N–H activation, specifically the anilidyl radical-
induced dehydragenative C–N bond formations.
On the basis of the above investigations, a plausible
mechanism for this reaction is proposed in Scheme 4.
Initiation occurs by reducing DTBP with Cu(I) to generate
Cu(II)(OBut) complex and tert-butoxyl radical. Upon re-
action of anilidic N-H bond with tert-butoxyl radical or
Cu(II)(OBut) complex, anilidyl radical A (can be oxidized
to intermediate B with Cu(I) catalyst)9a,20 or Cu(II)-
complex B (may undergo homolysis to generate radical A
and Cu(I) catalyst)12 can be generated, respectively. The
ensuing intramolecular radical addition of radical A to the
very electron-rich indolyl C=C bond would produce a car-
bon-centered radical C, which is believed to undergo di-
rect oxidation by either Cu(II)(OBut) complex or tert-
butoxyl radical and deprotonation to release the final
product 2a. Meanwhile, the low valent Cu(I) species was
regenerated to continue the catalytic cycle.
EXPERIMENTAL SECTION
General Methods. All reactions were carried out un-
der an argon atmosphere unless otherwise stated. All
work-up and purification procedures were carried out
with reagent-grade solvents. Flash column chromatog-
raphy was performed on silica gel (300-400 mesh) with an
appropriate solvent system (see details below). Melting
1
point was recorded on SGW X-4B. H and 13C-NMR spec-
tra were recorded on Varian 600 MHz and Bruker 400
MHz spectrometers in CDCl3 or d6-DMSO solutions and
chemical shifts (δ, ppm) were determined with internal
1
solvent signal as reference (CDCl3: 7.26 for H-NMR and
77.0 for 13C-NMR; d6-DMSO: 2.50 for 1H -NMR and 39.5 for
13C-NMR). NMR data are reported as following: chemical
shift, multiplicity (s = singlet, d = doublet, dd = doublet of
doublets, t = triplet, td = doublet of triplets, q = quartet,
m = multiplet, br = broad signal), coupling constant (Hz),
and integration. High-resolution mass spectra were rec-
orded on Thermo Scientific LTQ Orbitrap Discovery
(Bremen, Germany) (mass analyzer type: linear ion trap).
Materials were purchased from Alfa-Aesar, Acros, Aldrich,
Aladdin, Energy-Chemical, Bide Pharmatech. Ltd., and
Ouhe-Chemicals. Unless otherwise noted, commercial
reagents were used without further purifications. All
1
13
compounds and their H and C NMR spectra are provid-
ed in Supporting Information.
General Procedures for the Synthesis of Substrate 1.
To a well-stirred DMSO solution containing indoles (10.0
mmol, 1.0 equiv) and NaOH (1.0 equiv) was added 1-
fluoro-2-nitrobenzenes (10.0 mmol, 1.0 equiv) slowly. The
reaction mixture was stirred vigorously at room tempera-
ture for 12 hours. After completion of the reaction, the
Scheme 4. Plausible mechanism
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The Journal of Organic Chemistry
7.45 (td, J = 7.92, 1.20 Hz, 1 H), 7.29 (d, J = 7.80, 1.62 Hz, 1
resulting mixture was diluted with water (15 mL) and ex-
1
2
3
4
5
6
7
tracted with ethyl acetate (3 × 40 mL). The combined or-
ganic layer was washed with brine (25 mL), dried with
anhydrous Na2SO4, concentrated under vacuum to give
the crude product, which was purified by silica gel col-
umn with petroleum ether/ethyl acetate (20:1 to 10:1) as
the eluent to give the analytical pure 1-(2-nitro-phenyl)-
1H-indole I-1.22
H), 7.22 (t, J = 7.95 Hz, 1 H), 7.14 (d, J = 3.12 Hz, 1 H), 7.05
(dd, J = 8.34, 1.62 Hz, 1 H), 6.98 (d, J = 8.34 Hz, 1 H), 6.87
(br, s, 1 H), 6.68 (d, J = 2.28 Hz, 1H), 2.48 (s, 3 H), 1.90 (s,
3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.5, 135.0, 134.4,
130.1, 129.0, 128.9, 128.5, 127.9, 124.5, 122.0, 120.9, 110.0,
104.0, 24.7, 21.4. HR-ESI-MS [M+H]+ m/z Calcd for
C17H17N2O 265.1335; Found 265.1331.
8
9
I-1 (9.93 mmol) was then dissolved in EtOH (30 mL)
and water (7.5 mL). After adding concentrated HCl (43 uL)
and iron powder (5.5 g) to the above solution, the result-
N-(2-(6-Methyl-1H-indol-1-yl)phenyl)acetamide (1d). El-
uent: petroleum ether/ethyl acetate 15:1. H NMR (600
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3, ppm) δ 8.44 (d, J = 8.10 Hz, 1 H), 7.61 (d, J =
8.10 Hz, 1 H), 7.47 (td, J = 7.86, 1.62 Hz, 1 H), 7.31 (d, J =
7.50 Hz, 1 H), 7.24 (t, J = 7.59 Hz, 1 H), 7.12 (d, J = 3.18 Hz, 1
H), 7.05 (d, J = 8.10 Hz, 1 H), 6.94 (br, s, 1 H), 6.90 (s, 1 H),
6.72 (d, J = 3.18 Hz, 1 H), 2.43 (s, 3 H), 1.90 (s, 3 H). 13C
NMR (150 MHz, CDCl3, ppm) δ 168.5, 137.1, 134.5, 132.9,
129.0, 128.6, 128.0, 127.8, 126.5, 124.5, 122.5, 122.1, 120.9, 110.2,
104.3, 24.6, 21.7. HR-ESI-MS [M+H]+ m/z Calcd for
C17H17N2O 265.1335; Found 265.1330.
o
ing mixture was stirred vigorously at 100 C for 3 hours
(monitored by TLC). Upon completion of the reaction,
the reaction mixture was cooled to room temperature,
diluted with water (20 mL), extracted with ethyl acetate
(3 × 40 mL ). The combined organic layer was washed
with brine (25 mL), dried with anhydrous Na2SO4, con-
centrated under vacuum to give the crude product, which
was purified by silica gel column with petroleum
ether/ethyl acetate (10:1) as the eluent to give the analyti-
cal pure 2-(1H-indol-1-yl)aniline I-2.23
A CH2Cl2 (58 mL) solution of I-2 (5.76 mmol, 1.20 g)
was placed into an ice bath, added with Et3N (5.7 mmol,
0.8 mL) and acetyl chloride (8.6 mmol, 0.61 mL; in 30 min)
under argon sequentially. The resulting mixture was
warmed to room temperature and stirred for additional 8
h, which, after diluted with water (10 mL), was washed
with HCl (1 M aqueous solution, 2 × 60 mL), saturated
aqueous solution of NaHCO3 (2 × 60 mL) and brine (60
mL). The organic layer was dried with anhydrous Na2SO4,
concentrated under vacuum to give the crude product,
which was purified by silica gel column with petroleum
ether/ethyl acetate (20:1 to 10:1) as the eluent to give the
analytical pure N-(2-(1H-Indol-1-yl)phenyl)acetamide de-
rivatives (substrates 1).24
N-(2-(1H-Indol-1-yl)phenyl)acetamide (1a). Eluent: pe-
troleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.43 (d, J = 8.34 Hz, 1 H), 7.73 (dd, J = 6.39,
3.12 Hz, 1 H), 7.47 (td, J = 7.88, 1.62 Hz, 1 H), 7.31 (d, J =
7.68, 1 H), 7.25-7.21 (m, 3 H), 7.19 (d, J = 3.24, 1 H), 7.109
(dd, J = 8.82, 2.10 Hz, 1 H), 6.84 (s, 1 H), 6.77 (d, J = 3.18 Hz,
1 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.5,
136.6, 134.4, 129.0, 128.7, 128.5, 128.0, 124.6, 122.9, 122.2, 121.3,
120.8, 110.3, 104.5, 104.4, 24.6. HR-ESI-MS [M+H]+ m/z
Calcd for C16H15N2O 251.1184; Found 251.1176.
N-(2-(4-Methoxy-1H-indol-1-yl)phenyl)acetamide
(1e).
1
Eluent: petroleum ether/ethyl acetate 10:1. H NMR (600
MHz, CDCl3, ppm) δ 8.42 (d, J = 8.34 Hz, 1 H), 7.46 (td, J =
7.91,1.50 Hz, 1 H), 7.30 (dd, J = 7.83, 1.56 Hz, 1 H), 7.22 (td, J
= 7.61, 1.44 Hz, 1 H), 7.14 (t, J = 8.01 Hz, 1 H), 7.09 (d, J =
3.18 Hz, 1 H), 6.875 (br, s, 1 H), 6.865 (dd, J = 3.18, 0.90 Hz,
1 H), 6.70 (d, J = 8.28 Hz, 1 H), 6.61 (d, J = 7.98 Hz, 1 H),
4.00 (s, 3 H), 1.88 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm)
δ 168.5, 153.5, 138.0, 134.4, 129.0, 128.5, 128.0, 126.9, 124.5,
123.9, 122.1, 119.3, 103.6, 101.7, 100.6, 55.4, 24.7. HR-ESI-MS
[M+H]+ m/z Calcd for C17H17N2O2 281.1285; Found 281.1280.
N-(2-(5-Methoxy-1H-indol-1-yl)phenyl)acetamide
(1f).
1
Eluent: petroleum ether/ethyl acetate 10:1. H NMR (600
MHz, CDCl3, ppm) δ 8.42 (d, J = 8.28 Hz, 1 H), 7.45 (td, J =
7.86, 1.56 Hz, 1 H), 7.29 (dd, J = 7.80, 1.50 Hz, 1 H), 7.22 (td,
J = 7.56, 1.32 Hz, 1 H), 7.17 (dd, J = 2.49, 0.60 Hz, 1 H), 7.15
(dd, J = 3.12, 0.48 Hz, 1 H), 6.97 (d, J = 8.82 Hz, 1 H), 6.87
(dd, J = 8.70, 2.46 Hz, 1 H), 6.85 (br, s, 1 H), 6.68 (dd, J =
3.15, 0.66 Hz, 1 H), 3.88 (s, 3 H), 1.91 (s, 3 H). 13C NMR (150
MHz, CDCl3, ppm) δ 168.4, 154.9, 134.3, 131.8, 129.2, 129.0,
128.9, 128.6, 127.9, 124.5, 122.1, 113.0, 111.1, 104.1, 102.9, 55.8,
24.7. HR-ESI-MS [M+H]+ m/z Calcd for C17H17N2O2
281.1285; Found 281.1280.
N-(2-(6-Methoxy-1H-indol-1-yl)phenyl)acetamide
(1g).
1
Eluent: petroleum ether/ethyl acetate 10:1. H NMR (600
MHz, CDCl3, ppm) δ 8.41 (d, J = 8.16 Hz, 1 H), 7.57 (d, J =
8.64 Hz, 1 H), 7.47 (td, J = 7.86, 1.56 Hz, 1 H), 7.31 (dd, J =
7.80, 1.44 Hz, 1 H), 7.24 (td, J = 7.64, 1.20 Hz, 1 H), 7.07 (d,
J = 3.18 Hz, 1 H), 6.86 (dd, J = 8.67, 2.28 Hz, 1 H), 6.84 (br,
s, 1 H), 6.68 (dd, J = 3.24, 0.84 Hz, 1 H), 6.52 (d, J = 2.22 Hz,
1 H), 3.75 (s, 3 H), 1.91 (s, 3 H). 13C NMR (150 MHz, CDCl3,
ppm) δ 168.5, 157.2, 137.4, 134.3, 129.0, 128.7, 127.9, 127.2,
124.7, 122.6, 122.4, 121.8, 111.1, 104.4, 93.4, 55.6, 24.7. HR-ESI-
MS [M+H]+ m/z Calcd for C17H17N2O2 281.1285; Found
281.1280.
N-(2-(4-Methyl-1H-indol-1-yl)phenyl)acetamide (1b). El-
1
uent: petroleum ether/ethyl acetate 15:1. H NMR (600
MHz, CDCl3, ppm) δ 8.44 (d, J = 8.28 Hz, 1 H), 7.46 (td, J =
7.86, 1.56 Hz, 1 H), 7.30 (dd, J = 7.83, 1.50 Hz, 1 H), 7.23 (td,
J = 7.62, 1.38 Hz, 1 H), 7.18 (d, J = 3.24 Hz, 1 H), 7.13 (td, J =
7.68, 1.08 Hz, 1 H), 7.01 (d, J = 7.20 Hz, 1 H), 6.93 (d, J =
8.22, 1.08 Hz, 1 H), 6.88 (br, s, 1 H), 6.78 (dd, J = 3.30, 0.84
Hz, 1 H), 2.63 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz,
CDCl3, ppm) δ 168.4, 136.9, 134.4, 129.3, 128.7, 128.6, 127.9,
126.0, 124.4, 122.9, 121.9, 120.1, 119.3, 113.8, 110.3, 24.7, 9.7.
HR-ESI-MS [M+H]+ m/z Calcd for C17H17N2O 265.1335;
Found 265.1331.
N-(2-(5-Chloro-1H-indol-1-yl)phenyl)acetamide (1h). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.40 (d, J = 8.34 Hz, 1 H), 7.68 (d, J = 1.74
Hz, 1 H), 7.48 (td, J = 7.85, 1.62 Hz, 1 H), 7.29 (dd, J = 7.74,
1.62 Hz, 1 H), 7.24 (td, J = 7.70, 1.26 Hz, 1 H), 7.21 (d, J =
3.24 Hz, 1 H), 7.16 (dd, J = 8.76, 2.04 Hz, 1 H), 6.99 (d, J =
N-(2-(5-Methyl-1H-indol-1-yl)phenyl)acetamide (1c). Elu-
1
ent: petroleum ether/ethyl acetate 15:1). H NMR (600
MHz, CDCl3, ppm) δ 8.44 (d, J = 8.28 Hz, 1 H), 7.50 (s, 1 H),
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8.70 Hz, 1 H), 6.74 (br, s, 1 H), 6.70 (dd, J = 3.21, 0.90 Hz, 1 167.6, 136.2, 134.5, 132.2, 131.7, 129.5, 128.1, 128.0, 124.8, 124.7,
H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.4,
135.0, 134.3, 129.8, 129.7, 129.3, 128.2, 127.9, 126.5, 124.8, 123.2,
122.5, 120.7, 111.4, 104.0, 24.6. HR-ESI-MS [M+H]+ m/z
Calcd for C16H14ClN2O 285.0789; Found 285.0784.
122.6, 121.8, 120.9, 112.4, 104.5, 52.0, 24.5. HR-ESI-MS
[M+K]+ m/z Calcd for C18H16KN2O3 347.0793; Found
347.0786.
1
2
3
4
5
6
7
8
N-(2-(4-Cyano-1H-indol-1-yl)phenyl)acetamide (1n). Elu-
ent: petroleum ether/ethyl acetate 2:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.36 (d, J = 8.34 Hz, 1 H), 7.53 (dd, J = 7.32,
1.02 Hz, 1 H), 7.51 (td, J = 7.56, 2.04 Hz, 1 H), 7.38 (d, J =
3.24 Hz, 1 H), 7.32-7.24 (m, 4 H), 6.95 (dd, J = 3.24, 0.90
Hz, 1 H), 6.77 (br, s, 1 H), 1.92 (s, 3 H). 13C NMR (150 MHz,
CDCl3, ppm) δ 168.7, 136.4, 134.2, 131.2, 129.9, 129.7, 127.9,
126.0, 125.1, 123.4, 122.5, 118.0, 115.3, 103.6, 103.1, 24.4. HR-
ESI-MS [M-H]- m/z Calcd for C17H12N3O 274.0980; Found
274.0987.
N-(2-(4-Bromo-1H-indol-1-yl)phenyl)acetamide (1i). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.37 (d, J = 8.10 Hz, 1 H), 7.47 (td, J = 7.83,
1.68 Hz, 1 H), 7.37 (d, J = 7.44 Hz, 1 H), 7.29 (d, J = 1.62 Hz,
1 H), 7.25-7.22 (m, 2 H), 7.07 (t, J = 7.83 Hz, 1 H), 7.02 (d, J
= 8.22 Hz, 1 H), 6.83 (br, s, 1 H), 6.81 (dd, J = 3.21, 0.84 Hz,
1 H), 1.88 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.5,
136.9, 134.3, 129.42, 129.38, 129.0, 128.2, 128.0, 124.8, 123.8,
123.7, 122.6, 115.1, 109.6, 104.6, 24.6. HR-ESI-MS [M-H]- m/z
Calcd for C16H12BrN2O 327.0133, 329.0113; Found 327.0138,
329.0117.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(2-(3-Methyl-1H-indol-1-yl)phenyl)acetamide (1o). El-
1
uent: petroleum ether/ethyl acetate 15:1. H NMR (600
N-(2-(5-Bromo-1H-indol-1-yl)phenyl)acetamide (1j). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.40 (d, J = 7.74 Hz, 1 H), 7.85 (s, 1 H), 7.48
(t, J = 7.83 Hz, 1 H), 7.29 (t, J = 7.59 Hz, 2 H), 7.24 (t, J =
7.56 Hz, 1 H), 7.19 (d, J = 2.94 Hz, 1 H), 6.95 (d, J = 8.70 Hz,
1 H), 6.73 (br, s, 1 H), 6.70 (dd, J = 2.34, 0.78 Hz, 1 H), 1.91
(s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.4, 135.3,
134.3, 130.3, 129.6, 129.4, 128.1, 127.9, 125.8, 124.8, 123.8, 122.5,
114.1, 111.8, 103.9, 24.6. HR-ESI-MS [M+H]+ m/z Calcd for
C16H14BrN2O 329.0284, 331.0262; Found 329.0279, 331.0257.
N-(2-(4-Fluoro-1H-indol-1-yl)phenyl)acetamide (1k). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.41 (d, J = 8.40 Hz, 1 H), 7.48 (td, J = 7.88,
1.50 Hz, 1 H), 7.31 (dd, J = 7.77, 1.20 Hz, 1 H), 7.24 (t, J =
7.44 Hz, 1 H), 7.16 (d, J = 3.18 Hz, 1 H), 7.13 (td, J = 8.04,
5.16 Hz, 1 H), 6.87 (dd, J = 7.62, 10.2 Hz, 1 H), 6.850 (d, J =
11.58 Hz, 1 H), 6.847 (s, 1 H), 6.75 (br, s, 1 H), 1.90 (s, 3 H).
MHz, CDCl3, ppm) δ 8.43 (d, J = 8.28 Hz, 1 H), 7.68-7.65
(m, 1 H), 7.43 (td, J = 7.85, 1.56 Hz, 1 H), 7.26 (dd, J = 7.77,
1.62 Hz, 1 H), 7.23-7.19 (m, 3 H), 7.06-7.04 (m, 1 H), 6.96 (d,
J = 1.20 Hz, 1 H), 6.92 (br, s, 1 H), 2.41 (d, J = 1.14, 3 H), 1.90
(s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.5, 136.4,
134.4, 130.8, 129.0, 128.62, 128.57, 128.0, 127.8, 124.5, 123.0,
122.1, 121.0, 107.9, 102.9, 24.7, 18.7. HR-ESI-MS [M+H]+ m/z
Calcd for C17H17N2O 265.1335; Found 265.1329.
N-(2-(1H-Indol-1-yl)-5-methylphenyl)acetamide (1p). El-
1
uent: petroleum ether/ethyl acetate 15:1. H NMR (600
MHz, CDCl3, ppm) δ 8.26 (s, 1 H), 7.72-7.71 (m, 1 H), 7.23-
7.18 (m, 3 H), 7.16 (d, J = 3.24 Hz, 1 H), 7.09-7.07 (m, 1 H),
7.04 (d, J = 7.26 Hz, 1 H), 6.76 (s, 1 H), 6.74 (dd, J = 3.21,
0.84 Hz, 1 H), 2.46 (s, 3 H), 1.88 (s, 3 H). 13C NMR (150
MHz, CDCl3, ppm) δ 168.4, 139.3, 136.8, 134.0, 128.65, 128.61,
127.7, 126.0, 125.3, 122.8, 122.6, 121.2, 120.6, 110.3, 104.2, 24.7,
21.6. HR-ESI-MS [M+H]+ m/z Calcd for C17H17N2O 265.1335;
Found 265.1331.
13C NMR (150 MHz, CDCl3, ppm) δ 168.4, 156.4 (d, JC-F
=
247.0 Hz), 139.1 (d, JC-F = 10.8 Hz), 134.3, 129.4, 128.4, 128.2,
127.9, 124.7, 123.5 (d, JC-F = 7.9 Hz), 122.5, 117.8 (d, JC-F = 22.5
Hz), 106.4 (d, JC-F = 3.7 Hz), 105.6 (d, JC-F = 18.9 Hz), 100.4,
24.6. HR-ESI-MS [M+H]+ m/z Calcd for C16H14FN2O
269.1085; Found 269.1078.
N-(2-(1H-Indol-1-yl)-4-methylphenyl)acetamide (1q). El-
uent: petroleum ether/ethyl acetate 15:1. H NMR (600
1
MHz, CDCl3, ppm) δ 8.26 (d, J = 8.40 Hz, 1 H), 7.72 (dd, J
= 6.60, 2.16 Hz, 1 H), 7.27 (dd, J = 8.22, 1.80 Hz, 1 H), 7.23-
7.18 (m, 2 H), 7.18 (d, J = 3.18 Hz, 1 H), 7.12 (s, 1 H), 7.09
(dd, J = 7.68, 1.26 Hz, 1 H), 6.76 (br, s, 1 H), 6.74 (d, J = 3.12
Hz, 1 H), 2.37 (s, 3 H), 1.88 (s, 3 H).13C NMR (150 MHz,
CDCl3, ppm) δ 168.4, 136.6, 134.7, 131.7, 129.6, 128.7, 128.6,
128.5, 128.3, 122.8, 122.4, 121.2, 120.7, 110.4, 104.2, 24.5, 20.7.
HR-ESI-MS [M+H]+ m/z Calcd for C17H17N2O 265.1335;
Found 265.1331.
N-(2-(5-Fluoro-1H-indol-1-yl)phenyl)acetamide (1l). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.41 (d, J = 7.98 Hz, 1 H), 7.47 (td, J = 7.89,
1.38 Hz, 1 H), 7.36 (dd, J = 9.33, 2.28 Hz, 1 H), 7.30 (d, J =
7.62 Hz, 1 H), 7.24 (d, J = 7.98 Hz, 1 H), 7.22 (d, J = 3.06 Hz,
1 H), 6.99 (dd, J = 8.94, 4.62 Hz, 1 H), 6.96 (td, J = 8.88,
2.40 Hz, 1 H), 6.75 (br, s, 1 H), 6.72 (d, J = 3.18 Hz, 1 H), 1.91
(s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.5, 158.4 (d,
JC-F = 234.9 Hz), 134.3, 133.2, 130.0, 129.2, 129.1 (d, JC-F = 10.1
Hz), 128.4, 127.9, 124.7, 122.4, 111.3 (d, JC-F = 26.0 Hz), 111.1 (d,
JC-F = 9.6 Hz), 106.1 (d, JC-F = 23.5 Hz), 104.3 (d, JC-F = 4.6 Hz),
24.6. HR-ESI-MS [M+H]+ m/z Calcd for C16H14FN2O
269.1085; Found 269.1078.
N-(5-Fluoro-2-(1H-indol-1-yl)phenyl)acetamide (1r). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.34 (dd, J = 9.24, 1.20 Hz, 1 H), 7.73 (dd, J =
6.45, 1.98 Hz, 1 H), 7.27-7.20 (m, 3 H), 7.15 (d, J = 3.18 Hz, 1
H), 7.05 (d, J = 7.74 Hz, 1 H), 6.92 (td, J = 8.13, 2.88 Hz, 1
H), 6.86 (br, s, 1 H), 6.77 (d, J = 3.18 Hz, 1 H), 1.89 (s, 3 H).
13C NMR (150 MHz, CDCl3, ppm) δ 168.5, 162.3 (d, JC-F
=
Methyl 1-(2-acetamidophenyl)-1H-indole-6-carboxylate
(1m). Eluent: petroleum ether/ethyl acetate 3:1. H NMR
245.4 Hz), 136.8, 136.0 (d, JC-F = 12.2 Hz), 129.2 (d, JC-F = 9.8
Hz), 128.7, 128.5, 123.8, 123.1, 121.3, 120.9, 111.0 (d, JC-F = 23.0
Hz), 110.1, 108.9 (d, JC-F = 28.9 Hz), 104.7, 24.7. HR-ESI-MS
[M-H]- m/z Calcd for C16H12FN2O 267.0934; Found
267.0939.
N-(4-Fluoro-2-(1H-indol-1-yl)phenyl)acetamide (1s). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.36 (dd, J = 9.06, 5.70 Hz, 1 H), 7.72 (dd, J
1
(600 MHz, CDCl3, ppm) δ 8.43 (d, J = 8.94 Hz, 1 H), 7.89
(dd, J = 8.37, 1.44 Hz, 1 H), 7.79 (t, J = 1.26 Hz, 1 H), 7.74 (d,
J = 8.34 Hz, 1 H), 7.51 (td, J = 7.85, 1.56 Hz, 1 H), 7.34 (d, J =
3.12 Hz, 1 H), 7.31 (d, J = 6.78 Hz, 1 H), 7.26 (t, J = 7.98 Hz, 1
H), 6.80 (dd, J = 3.15, 0.78 Hz, 1 H), 6.76 (br, s, 1 H), 3.88 (s,
3 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.4,
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H). 13C NMR (150 MHz, CDCl3, ppm) δ 168.4, 135.3, 134.9,
= 7.41, 1.32 Hz, 1 H), 7.26-7.20 (m, 3 H), 7.17 (d, J = 3.24 Hz,
1
2
3
4
5
6
7
8
1 H), 7.10 (d, J = 8.10 Hz, 1 H), 7.06 (dd, J = 8.49, 3.00 Hz, 1
H), 6.772 (dd, J = 2.97, 0.84 Hz, 1 H), 6.769 (br, s, 1 H), 1.89
(s, 3 H).13C NMR (150 MHz, CDCl3, ppm) δ 168.5, 158.8 (d,
131.5, 130.3, 129.9, 129.7, 128.3, 128.2, 125.6, 123.7, 122.7, 114.0,
111.9, 103.7, 24.5, 20.7. HR-ESI-MS [M+H]+ m/z Calcd for
C17H16BrN2O 343.0441, 345.0418; Found 343.0435, 345.0412.
Typical procedures for dehydrogenative C–H/N–H
coupling. Procedure A: An oven-dried round bottom re-
action vessel was charged with Cu2O (5.76 mg, 0. 04
mmol, 10.0 mol %), substrate 1a (0.40 mmol), L1 (28.2 mg,
0.08 mmol, 20 mol %) and (tBu2O) (146.1 mg, 1.0 mmol,
2.5 equiv). DCE/p-dioxane (1.6 mL, 7:1 v/v ratio) was add-
ed by syringe and the reaction mixture was stirred at
room temperature for 5 min. Then the vessel was sealed,
placed into an oil bath and heated to 90 oC for 24 h. Upon
completion of the reaction, the resulting mixture was
cooled to room temperature, filtered through a short sili-
ca gel pad and washed with chloroform. The above solu-
tion was evaporated under vacuum, and the residue was
purified by silica gel column with petroleum ether/ethyl
acetate (10:1) as the eluent to give the analytically pure
product 2a.
JC-F = 245.0 Hz), 136.3, 130.5 (d, JC-F = 3.4 Hz), 130.0 (d, JC-F
=
9.5 Hz), 128.8, 128.1, 124.1 (d, JC-F = 8.6 Hz), 123.2, 121.4, 121.0,
115.7 (d, JC-F = 21.6 Hz), 114.9 (d, JC-F = 23.7 Hz), 110.2, 105.0,
24.4. HR-ESI-MS [M+H]+ m/z Calcd for C16H14FN2O
269.1085; Found 269.1078.
9
N-(5-Bromo-2-(1H-indol-1-yl)phenyl)acetamide (1t). Elu-
ent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz,
CDCl3, ppm) δ 8.71 (s, 1 H), 7.73-7.71 (m, 1 H), 7.35 (dd, J =
8.31, 2.22 Hz, 1 H), 7.25-7.20 (m, 2 H), 7.16 (d, J = 8.34 Hz, 1
H), 7.14 (d, J = 3.24 Hz, 1 H), 7.07-7.05 (m, 1 H), 6.82 (br, s,
1 H), 6.77 (dd, J = 3.21, 0.90 Hz, 1 H), 1.90 (s, 3 H).13C NMR
(150 MHz, CDCl3, ppm) δ 168.3, 136.5, 135.5, 129.2, 128.8,
128.2, 127.5, 127.1, 124.7, 123.2, 122.6, 121.4, 121.0, 110.2, 105.0,
24.7. HR-ESI-MS [M-H]- m/z Calcd for C16H12BrN2O
327.0133, 329.0113; Found 327.0138, 329.0117.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(2-(5-Methoxy-1H-indol-1-yl)-5-
methylphenyl)acetamide
(1u).
Eluent:
petroleum
Procedure B: An oven-dried round bottom reaction ves-
sel was charged with Cu2O (5.76 mg, 0. 04 mmol, 10.0
mol %), substrate 1 (0.40 mmol), L1 (28.2 mg, 0.08 mmol,
20 mol %) and (tBu2O) (131.6 mg, 0.9 mmol, 2.25 equiv).
DCE/p-dioxane (1.6 mL, 7:1 v/v ratio) was added by sy-
ringe and the reaction mixture was stirred at room tem-
perature for 5 min. Then the vessel was sealed, placed
1
ether/ethyl acetate 10:1. H NMR (600 MHz, CDCl3, ppm)
δ 8.24 (s, 1 H), 7.17-7.16 (m, 2 H), 7.12 (d, J = 3.12 Hz, 1 H),
7.02 (d, J = 7.38 Hz, 1 H), 6.96 (d, J = 8.94 Hz, 1 H), 6.86
(dd, J = 8.88, 2.46 Hz, 1 H), 6.79 (br, s, 1 H), 6.66 (dd, J =
3.15, 0.72 Hz, 1 H), 3.87 (s, 3 H), 2.45 (s, 3 H), 1.89 (s, 3 H).
13C NMR (150 MHz, CDCl3, ppm) δ 168.4, 154.8, 139.19,
139.17, 134.0, 132.0, 129.1, 127.6, 126.1, 125.3, 122.5, 112.9, 111.1,
103.8, 102.8, 55.8, 24.7, 21.6. HR-ESI-MS [M+H]+ m/z Calcd
for C18H19N2O2 295.1441; Found 295.1436.
o
into an oil bath and heated to 90 C for 24 h. Upon com-
pletion of the reaction, the resulting mixture was cooled
to room temperature, filtered through a short silica gel
pad and washed with chloroform. The above solution was
evaporated under vacuum, and the residue was purified
by silica gel column with petroleum ether/ethyl acetate
(10:1 to 9:1) as the eluent to give the analytically pure
products 2b-g, 2q-s, and 2u-w.
N-(4-Fluoro-2-(5-methoxy-1H-indol-1-
yl)phenyl)acetamide (1v). Eluent: petroleum ether/ethyl
acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm) δ 8.35 (dd, J
= 9.18, 5.70 Hz, 1 H), 7.18-7.15 (m, 2 H), 7.14 (d, J = 3.18 Hz,
1 H), 7.04 (dd, J = 8.52, 2.94 Hz, 1 H), 6.98 (d, J = 8.82 Hz, 1
H), 6.89 (dd, J = 8.88, 2.40 Hz, 1 H), 6.79 (br, s, 1 H), 6.68
(dd, J = 3.15, 0.84 Hz, 1 H), 3.87 (s, 3 H), 1.90 (s, 3 H). 13C
NMR (150 MHz, CDCl3, ppm) δ 168.4, 158.8 (d, JC-F = 245.0
Hz), 155.0, 131.5, 130.4 (d, JC-F = 3.1 Hz), 130.1 (d, JC-F = 9.5
Hz), 129.3, 128.6, 124.0 (d, JC-F = 8.6 Hz), 115.5 (d, JC-F = 21.7
Hz), 114.8 (d, JC-F = 23.6 Hz), 113.2, 111.0 , 104.7, 103.0, 55.8,
24.4. HR-ESI-MS [M+H]+ m/z Calcd for C17H16FN2O2
299.1190; Found 299.1186.
Procedure C: An oven-dried round bottom reaction ves-
sel was charged with Cu2O (7.10 mg, 0. 05 mmol, 12.5
mol %), substrate 1 (0.40 mmol), L1 (35.3 mg, 0.10 mmol,
25 mol %) and (tBu2O) (146.1 mg, 1.0 mmol, 2.5 equiv).
DCE/p-dioxane (1.6 mL, 6:2 v/v ratio) was added by sy-
ringe and the reaction mixture was stirred at room tem-
perature for 5 min. Then the vessel was sealed, placed
o
into an oil bath and heated to 90 C for 24 h. Upon com-
N-(5-Bromo-2-(5-methoxy-1H-indol-1-
pletion of the reaction, the resulting mixture was cooled
to room temperature, filtered through a short silica gel
pad and washed with chloroform. The above solution was
evaporated under vacuum, and the residue was purified
by silica gel column with petroleum ether/ethyl acetate
(10:1 to 3:1) as the eluent to give the analytically pure
product 2h-n, 2r-t and 2x.
yl)phenyl)acetamide (1w). Eluent: petroleum ether/ethyl
1
acetate 10:1. H NMR (600 MHz, CDCl3, ppm) δ 8.71 (s, 1
H), 7.50 (s, 1 H), 7.34 (dd, J = 8.34, 2.28 Hz, 1 H), 7.14 (d, J =
8.34 Hz, 1 H), 7.10 (d, J = 3.24 Hz, 1 H), 7.06 (dd, J = 8.34,
1.80 Hz, 1 H), 6.95 (d, J = 8.28 Hz, 1 H), 6.85 (br, s, 1 H),
6.68 (dd, J = 3.21, 0.96 Hz, 1 H), 2.47 (s, 3 H), 1.90 (s, 3 H).
13C NMR (150 MHz, CDCl3, ppm) δ 168.4, 135.5, 134.9, 130.4,
129.09, 129.05, 128.2, 127.4, 127.2, 124.7, 124.5, 122.5, 121.0,
109.8, 104.5, 24.7, 21.4. HR-ESI-MS [M+H]+ m/z Calcd for
C17H16BrN2O 343.0441, 345.0418; Found 343.0435, 345.0412.
N-(2-(5-Bromo-1H-indol-1-yl)-4-methylphenyl)acetamide
1-(10H-Benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone
(2a). Prepared according to Procedure A. Eluent: petrole-
um ether/ethyl acetate 10:1. Yellow solid, m.p. 201.1-201.7
1
oC. Isolated yield 84% (80.4 mg from 100.2 mg of 1a). H
NMR (600 MHz, CDCl3, ppm) δ 8.43 (s, 1 H), 7.72 (dd, J =
6.72, 1.62 Hz, 1 H), 7.65 (dd, J = 6.09, 2.88 Hz, 1 H), 7.61 (d,
J = 7.80 Hz, 1 H), 7.33 (t, J = 7.71 Hz, 1 H), 7.29-7.26 (m, 2
H), 7.23 (t, J = 7.83 Hz, 1 H), 6.04 (s, 1 H), 2.66 (s, 3 H).13C
NMR (100 MHz, CDCl3, ppm) δ 167.7, 138.5, 133.7, 132.1,
128.9, 126.8, 124.8, 123.1, 121.7, 120.9, 120.8, 117.4, 110.6, 109.8,
1
(1x). Eluent: petroleum ether/ethyl acetate 15:1. H NMR
(600 MHz, CDCl3, ppm) δ 8.22 (d, J = 8.34 Hz, 1 H), 7.83 (d,
J = 1.74 Hz, 1 H), 7.30-7.27 (m, 2 H), 7.17 (d, J = 3.18 Hz, 1
H), 7.09 (s, 1 H), 6.95 (d, J = 8.64 Hz, 1 H), 6.67 (dd, J =
3.24, 0.84 Hz, 1 H), 6.65 (br, s, 1 H), 2.37 (s, 3 H), 1.89 (s, 3
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Page 8 of 11
82.2, 25.5. HR-ESI-MS [M+H]+ m/z Calcd for C16H13N2O 111.1, 109.9, 109.2, 103.2, 82.1, 55.7, 25.3. HR-ESI-MS [M+H]+
1
249.1028; Found 249.1022.
m/z Calcd for C17H15N2O2 279.1134; Found 279.1128.
2
3
4
5
6
7
8
9
1-(1-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2b). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. White solid, m.p.
1-(3-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanon-e (2g). Prepared according to Procedure B.
Eluent: petroleum ether/ethyl acetate 9:1. Reddish brown
solid, m.p. 162.7-163.5 oC. Isolated yield 71% (77.3 mg from
112.0 mg of 1g). 1H NMR (600 MHz, CDCl3, ppm) δ 8.43 (s,
1 H), 7.63 (d, J = 8.76 Hz, 1 H), 7.59 (d, J = 7.80 Hz, 1 H),
7.34 (td, J = 7.71, 1.14 Hz, 1 H), 7.22 (td, J = 7.86, 1.14 Hz, 1
H), 7.13 (d, J = 2.46 Hz, 1 H), 6.91 (dd, J = 8.76, 2.46 Hz, 1
H), 6.01 (s, 1 H), 3.89 (s, 3 H), 2.68 (s, 3 H). 13C NMR (100
MHz, CDCl3, ppm) δ 167.5, 155.4, 137.7, 133.8, 128.8, 127.2,
126.0, 124.6, 123.0, 121.2, 117.4, 110.5, 109.6, 95.3, 81.8, 55.9,
25.4. HR-ESI-MS [M+H]+ m/z Calcd for C17H15N2O2
279.1134; Found 279.1127.
o
144.8-145.6 C. Isolated yield 69% (70.3 mg from 105.7 mg
1
of 1b). H NMR (600 MHz, CDCl3, ppm) δ 8.37 (s, 1 H),
7.48 (t, J = 8.70 Hz, 2 H), 7.28 (t, J = 7.68 Hz, 1 H), 7.18 (t, J
= 8.79 Hz, 1 H), 7.16 (t, J = 7.80 Hz, 1 H), 7.04 (d, J = 7.20
Hz, 1 H), 5.83 (s, 1 H), 2.58 (s, 3 H), 2.54 (s, 3 H). 13C NMR
(100 MHz, CDCl3, ppm) δ 167.7, 138.0, 133.6, 131.6, 130.1,
128.9, 126.4, 124.7, 123.0, 122.0, 120.9, 117.3, 109.7, 108.2, 80.6,
25.5, 18.8. HR-ESI-MS [M+H]+ m/z Calcd for C17H15N2O
263.1184; Found 263.1177.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(2-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2c). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. Deep orange solid,
m.p. 172.4-173.2 oC. Isolated yield 61% (62.5 mg from 105.8
mg of 1c). 1H NMR (600 MHz, CDCl3, ppm) δ 8.38 (s, 1 H),
7.51 (d, J = 8.16 Hz, 1 H), 7.48 (dd, J = 7.74, 1.08 Hz, 1 H),
7.37 (s, 1 H), 7.28 (td, J = 7.70, 1.14 Hz, 1 H), 7.18 (td, J =
7.83, 1.14 Hz, 1 H), 7.05 (d, J = 8.16 Hz, 1 H), 5.84 (s, 1 H),
2.57 (s, 3 H), 2.49 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.6, 138.4, 133.5, 132.2, 131.0, 128.8, 124.9, 124.6, 122.7,
122.2, 120.5, 117.2, 110.1, 109.4, 81.7, 25.3, 21.6. HR-ESI-MS
[M+H]+ m/z Calcd for C17H15N2O 263.1184; Found 263.1179.
1-(3-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
1-(2-Chloro-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2h). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Orange solid, m.p.
191.2-191.9 oC. Isolated yield 59% (65.7 mg from 113.8 mg of
1
1h). H NMR (600 MHz, CDCl3, ppm) δ 8.37 (s, 1 H), 7.53
(d, J = 1.92 Hz, 1 H), 7.50 (d, J = 8.52 Hz, 1 H), 7.47 (d, J =
7.86 Hz, 1 H), 7.30 (t, J = 7.62 Hz, 1 H), 7.22 (t, J = 7.86 Hz,
1 H), 7.15 (dd, J = 8.52, 2.04 Hz, 1 H), 5.89 (s, 1 H), 2.60 (s, 3
H).13C NMR (100 MHz, CDCl3, ppm) δ 167.6, 139.3, 133.5,
133.1, 128.4, 127.2, 125.0, 124.8, 123.4, 121.0, 120.2, 117.4, 111.3,
109.7, 81.8, 25.4. HR-ESI-MS [M+H]+ m/z Calcd for
C16H12ClN2O 283.0638; Found 283.0634.
yl)ethanone (2d). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. Reddish brown
solid, m.p. 162.7-163.5 oC. Isolated yield 64% (65.2 mg
1-(1-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2i). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light yellow solid,
m.p. 199.2-199.5 oC. Isolated yield 45% (58.0 mg from 131.5
mg of 1i). 1H NMR (600 MHz, CDCl3, ppm) δ 8.46 (s, 1 H),
7.77 (d, J = 7.14 Hz, 1 H), 7.67 (dd, J = 7.32, 1.92 Hz, 1 H),
7.37 (td, J = 7.74, 1.08 Hz, 1 H), 7.31-7.24 (m, 3 H), 6.10 (s, 1
H), 2.70 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm) δ 167.7,
138.5, 133.8, 132.1, 129.0, 126.8, 124.8, 123.1, 121.7, 120.9, 120.8,
117.5, 110.6, 109.8, 82.2, 25.5. HR-ESI-MS [M+H]+ m/z Calcd
for C16H12BrN2O 327.0133; Found 327.0128.
1
from 105.8 mg of 1d). H NMR (600 MHz, CDCl3, ppm) δ
8.43 (s, 1 H), 7.61 (d, J = 7.74 Hz, 1 H), 7.52 (d, J = 7.98 Hz, 1
H), 7.51 (s, 1 H), 7.33 (td, J = 7.71, 1.14 Hz, 1 H), 7.23 (td, J =
7.95, 1.14 Hz, 1 H), 7.09 (d, J = 7.86 Hz, 1 H), 5.96 (s, 1 H),
2.64 (s, 3 H), 2.55 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.7, 138.0, 133.8, 130.8, 129.8, 129.0, 127.2, 124.7, 123.2,
122.9, 120.4, 117.4, 110.8, 109.7, 82.0, 25.4, 21.9. HR-ESI-MS
[M+H]+ m/z Calcd for C17H15N2O 263.1184; Found 263.1178.
1-(1-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanon-e (2e). Prepared according to Procedure B. El-
uent: petroleum ether/ethyl acetate 9:1. Purple gray solid,
m.p. 198.2-198.6 oC. Isolated yield 69% (74.8 mg from 112.3
mg of 1e). 1H NMR (600 MHz, CDCl3, ppm) δ 8.44 (s, 1 H),
7.62 (d, J = 7.80 Hz, 1 H), 7.37 (d, J = 8.10 Hz, 1 H), 7.34 (td,
J = 7.74, 1.14 Hz, 1 H), 7.24 (td, J = 7.80, 1.14 Hz, 1 H), 7.20
(t, J = 7.98 Hz, 1 H), 6.70 (d, J = 7.80 Hz, 1 H), 6.14 (s, 1 H),
4.00 (s, 3 H), 2.68 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.7, 152.9, 137.1, 133.7, 128.8, 127.6, 124.6, 123.1, 121.9, 121.7,
117.4, 109.7, 103.9, 101.7, 79.2, 55.3, 25.3. HR-ESI-MS [M+H]+
m/z Calcd for C17H15N2O2 279.1134; Found 279.1128.
1-(2-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2j). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Dark brown solid,
o
m.p.189.8-190.2 C. Isolated yield 52% (65.6 mg from 131.7
mg of 1j). 1H NMR (600 MHz, CDCl3, ppm) δ 8.37 (s, 1 H),
7.68 (s, 1 H), 7.44 (t, J = 8.31 Hz, 2 H), 7.30 (t, J = 7.08 Hz, 1
H), 7.27 (t, J = 6.72 Hz, 1 H), 7.22 (t, J=7.80 Hz, 1 H), 5.87 (s,
13
1 H), 2.59 (s, 3 H). C NMR (100 MHz, CDCl3, ppm) δ 167.5,
139.1, 133.6, 133.5, 128.4, 125.2, 124.8, 123.6, 123.5, 123.2, 117.4,
114.8, 111.7, 109.8, 81.7, 25.4. HR-ESI-MS [M+H]+ m/z Calcd
for C16H12BrN2O 327.0133, 329.0113; Found 327.0131,
329.0104.
1-(2-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-
1-(1-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2k). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. White solid, m.p.
yl)ethanon-e (2f). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 9:1. Brown solid, m.p.
o
o
162.7-163.2 C. Isolated yield 72% (78.4 mg from 112.2 mg
155.1-156.3 C. Isolated yield 63% (65.6 mg from 107.2 mg
of 1f). 1H NMR (600 MHz, CDCl3, ppm) δ 8.33 (s, 1 H), 7.45
(d, J=8.70 Hz, 1 H), 7.38 (d, J = 8.16 Hz, 1 H), 7.24 (td, J =
7.68, 1.14 Hz, 1 H), 7.14 (t, J = 7.56 Hz, 1 H), 7.03 (d, J = 2.52
Hz, 1 H), 6.83 (dd, J = 8.73, 2.46 Hz, 1 H), 5.80 (s, 1 H), 3.87
(s, 3 H), 2.53 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm) δ
167.6, 155.2, 138.8, 133.3, 132.8, 128.7, 124.6, 122.6, 121.7, 117.2,
of 1k). H NMR (600 MHz, CDCl3, ppm) δ 8.40 (s, 1 H),
1
7.55 (d, J = 7.86 Hz, 1 H), 7.44 (d, J = 8.10 Hz, 1 H), 7.32 (td,
J = 7.70, 1.14 Hz, 1 H), 7.24 (td, J = 7.88, 1.38 Hz, 1 H), 7.16
(td, J = 7.98, 4.98 Hz, 1 H), 6.94 (dd, J = 10.26, 7.98 Hz, 1
13
H), 6.07 (s, 1 H), 2.65 (s, 3 H). C NMR (100 MHz, CDCl3,
ppm) δ 167.5, 155.9 (d, JC-F = 245.0 Hz), 138.1, 133.6, 128.7 (d,
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The Journal of Organic Chemistry
mg of 1p). 1H NMR (600 MHz, CDCl3, ppm) δ 8.26 (s, 1 H),
JC-F = 11.4 Hz), 128.4, 124.8, 123.5, 121.3 (d, JC-F = 7.6 Hz),
1
2
3
4
5
6
7
8
120.6 (d, JC-F = 21.8 Hz), 117.4, 109.8, 106.8 (d, JC-F = 25.8 Hz),
106.7 (d, JC-F = 3.4 Hz), 77.9, 25.4. HR-ESI-MS [M+H]+ m/z
Calcd for C16H12FN2O 267.0934; Found 267.0926.
7.71 (d, J = 8.10 Hz, 1 H), 7.65 (dd, J = 7.74, 1.32 Hz, 1 H),
7.49 (d, J = 7.92 Hz, 1 H), 7.29-7.24 (m, 2 H), 7.13 (d, J =
7.92 Hz, 1 H), 6.04 (s, 1 H), 2.66 (s, 3 H), 2.46 (s, 3 H). 13C
NMR (100 MHz, CDCl3, ppm) δ 167.7, 138.5, 133.7, 133.0,
131.9, 126.7, 126.6, 125.1, 121.4, 120.72, 120.68, 117.9, 110.5,
109.2, 82.0, 25.4, 21.7. HR-ESI-MS [M+H]+ m/z Calcd for
C17H15N2O 263.1184 ; Found 263.1178.
1-(2-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2l). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light orange solid,
m.p. 186.4-187.0 oC. Isolated yield 60% (62.4 mg from
107.3 mg of 1l). 1H NMR (600 MHz, CDCl3, ppm) δ 8.42 (s,
1 H), 7.63 (dd, J = 8.82, 4.32 Hz, 1 H), 7.59 (d, J = 7.68 Hz, 1
H), 7.35 (td, J = 7.88, 1.14 Hz, 1 H), 7.30 (dd, J = 9.48, 2.48
Hz, 1 H), 7.25 (td, J = 7.86, 1.20 Hz, 1 H), 7.00 (td, J = 9.02,
2.52 Hz, 1 H), 6.04 (s, 1 H), 2.67 (s, 3 H). 13C NMR (100
MHz, CDCl3, ppm) δ 167.6, 158.8 (d, JC-F = 235.5 Hz), 139.6,
133.4, 132.8 (d, JC-F = 10.3 Hz), 128.6, 124.8, 123.3, 123.2, 117.4,
111.1 (d, JC-F = 9.9 Hz), 109.4, 108.8 (d, JC-F = 26.1 Hz), 106.1
(d, JC-F = 24.3 Hz), 82.4, 25.4. HR-ESI-MS [M+H]+ m/z
Calcd for C16H12FN2O 267.0934; Found 267.0927.
Methyl 10-acetyl-10H-benzo[4,5]imidazo[1,2-a]indole-3-
carboxylate (2m). Prepared according to Procedure C. El-
uent: petroleum ether/ethyl acetate 5:1. Light pink solid,
m.p. 214.5-215.2 oC. Isolated yield 57% (68.8 mg from 123.2
mg of 1m). 1H NMR (600 MHz, CDCl3, ppm) δ 8.37 (s, 1 H),
8.32 (s, 1 H), 7.89 (dd, J = 8.40, 1.44 Hz, 1 H), 7.68 (d, J =
7.74 Hz, 1 H), 7.57 (dd, J = 8.31, 0.66 Hz, 1 H), 7.36 (td, J =
7.71, 1.14 Hz, 1 H), 7.26 (td, J = 7.86, 1.20 Hz, 1 H), 6.06 (s, 1
H), 3.98 (s, 3 H), 2.66 (s, 3 H). 13C NMR (100 MHz, CDCl3,
ppm) δ 167.6, 167.5, 140.7, 135.8, 133.4, 128.4, 125.9, 125.0,
123.7, 122.8, 122.2, 120.0, 117.3, 112.5, 110.2, 82.8, 52.0, 25.5.
HR-ESI-MS [M+H]+ m/z Calcd for C18H15N2O3 307.1083;
Found 307.1075.
1-(7-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
9
yl)ethanone (2q). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. Pink solid, m.p.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
165.7-166.2 C. Isolated yield 67% (67.9 mg from 105.7 mg
1
of 1q). H NMR (600 MHz, CDCl3, ppm) δ 8.29 (s, 1 H),
7.74 (dd, J = 7.74, 1.92 Hz, 1 H), 7.66 (dd, J = 6.45, 2.58 Hz,
1 H), 7.43 (s, 1 H), 7.29-7.25 (m, 2 H), 7.03 (dd, J = 8.19,
13
0.90 Hz, 1 H), 6.03 (s, 1 H), 2.65 (s, 3 H), 2.50 (s, 3 H). C
NMR (100 MHz, CDCl3, ppm) δ 167.5, 138.6, 134.8, 132.0,
131.5, 128.9, 126.7, 123.5, 121.5, 120.74, 120.67, 116.9, 110.6,
110.3, 82.0, 25.3, 21.6. HR-ESI-MS [M+H]+ m/z Calcd for
C17H15N2O 263.1184 ; Found 263.1179.
1-(8-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2r). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light pink solid,
m.p. 209.2-210.1 oC. Isolated yield 66% (68.2 mg from 107.3
mg of 1r). 1H NMR (600 MHz, CDCl3, ppm) δ 8.21 (s, 1 H),
7.68 (dd, J = 7.62, 1.68 Hz, 1 H), 7.66 (dd, J = 7.77, 1.86 Hz,
1 H), 7.50 (dd, J = 8.58, 4.50 Hz, 1 H), 7.31-7.26 (m, 2 H),
7.05 (td, J = 8.75, 2.58 Hz, 1 H), 6.06 (s, 1 H), 2.65 (s, 3 H).
13C NMR (100 MHz, CDCl3, ppm) δ 167.7, 158.9 (d, JC-F
=
239.1 Hz), 138.8, 134.2 (d, JC-F = 13.8 Hz), 131.8, 126.7, 125.4,
121.8, 121.2, 121.0, 111.2 (d, JC-F = 24.4 Hz), 110.3, 109.5 (d, JC-F
= 9.8 Hz), 106.1 (d, JC-F = 30.7 Hz), 82.5, 25.3. HR-ESI-MS
[M+H]+ m/z Calcd for C16H12FN2O 267.0934; Found
267.0927.
10-Acetyl-10H-benzo[4,5]imidazo[1,2-a]indole-1-
carbonitrile (2n). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 3:1. Light orange solid,
m.p. 228.4-229.3 oC. Isolated yield 20% (18.6 mg from 110.0
mg of 1n). 1H NMR (600 MHz, CDCl3, ppm) δ 8.45 (s, 1 H),
7.95 (d, J = 8.22 Hz, 1 H), 7.69 (d, J = 7.98 Hz, 1 H), 7.59
(dd, J = 7.53, 0.84 Hz, 1 H), 7.42 (td, J = 7.73, 1.14 Hz, 1 H),
7.34 (td, J = 7.89, 1.14 Hz, 1 H), 7.30 (t, J = 7.86 Hz, 1 H),
6.34 (s, 1 H), 2.75 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.6, 140.3, 133.8, 133.6, 128.1, 126.5, 126.4, 125.1, 124.3,
120.3, 118.4, 117.7, 114.9, 110.1, 102.8, 81.3, 25.6. HR-ESI-MS
[M+H]+ m/z Calcd for C17H12N3O 274.0980; Found
274.0973.
1-(7-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2s). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Yellow solid, m.p.
o
194.3-195.4 C. Isolated yield 56% (58.0 mg from 107.1 mg
1
of 1s). H NMR (600 MHz, CDCl3, ppm) δ 8.30 (s, 1 H),
7.60-7.59 (m, 1 H), 7.53-7.52 (m, 1 H), 7.27-7.23 (m, 2 H),
7.15 (dd, J = 8.07, 2.52 Hz, 1 H), 6.86 (td, J = 9.05, 2.58 Hz, 1
13
H), 5.90 (s, 1 H), 2.55 (s, 3 H). C NMR (100 MHz, CDCl3,
ppm) δ 167.5, 159.9 (d, JC-F = 242.5 Hz), 138.9 (d, JC-F = 6.2
Hz), 132.1, 129.9, 129.4 (d, JC-F = 9.2 Hz), 126.6 (d, JC-F = 3.0
Hz), 122.1, 121.2, 120.9, 118.1, 110.5, 109.2 (d, JC-F = 23.4 Hz),
98.0 (d, JC-F = 29.5 Hz), 82.5, 25.2. HR-ESI-MS [M+H]+ m/z
Calcd for C16H12FN2O 267.0934; Found 267.0926.
1-(11-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2o). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light pink solid,
m.p. 191.9-192.4 oC. Isolated yield 43% (43.5 mg from 105.7
1-(8-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-
1
mg of 1o), H NMR (600 MHz, CDCl3, ppm) δ 7.90 (d, J =
yl)ethanone (2t). Prepared according to Procedure C. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light red solid,
8.16 Hz, 1 H), 7.74-7.72 (m, 1 H), 7.66-7.65 (m, 1 H), 7.62 (d,
J = 7.98 Hz, 1 H), 7.33-7.28 (m, 3 H), 7.17 (td J = 7.91, 1.14
Hz, 1 H), 2.72 (s, 3 H), 2.58 (s, 3 H). 13C NMR (100 MHz,
CDCl3, ppm) δ 167.4, 136.0, 134.4, 133.8, 129.4, 126.7, 124.6,
122.1, 121.2, 121.1, 119.2, 115.8, 110.3, 109.7, 91.9, 25.9, 10.8. HR-
ESI-MS [M+H]+ m/z Calcd for C17H15N2O 263.1184; Found
263.1179.
1-(8-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-
yl)ethanone (2p). Prepared according to Procedure B. Elu-
ent: petroleum ether/ethyl acetate 10:1. Light pink solid,
m.p. 197.5-198.3 oC. Isolated yield 60% (61.0 mg from 105.7
o
m.p. 178.1-178.7 C. Isolated yield 58% (74.7 mg from 131.6
mg of 1t). 1H NMR (600 MHz, CDCl3, ppm) δ 8.54 (s, 1 H),
7.64-7.62 (m, 1 H), 7.60-7.59 (m, 1 H), 7.38 (dd, J = 8.31,
1.92 Hz, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.28-7.25 (m, 2 H),
5.97 (s, 1 H), 2.57 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.4, 138.1, 134.3, 132.0, 127.6, 127.4, 126.5, 122.0, 121.2,
120.9, 120.3, 115.6, 110.5, 110.2, 82.4, 25.2. HR-ESI-MS
[M+H]+ m/z Calcd for C16H12BrN2O 327.0133; Found
327.0130.
1-(2-Methoxy-8-methyl-10H-benzo[4,5]imidazo[1,2-
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*E-mail: raohonghua@tsinghua.org.cn
a]indol-10-yl)ethanone (2u). Prepared according to Proce-
1
2
3
4
5
6
7
8
dure B. Eluent: petroleum ether/ethyl acetate 9:1. Light
yellow solid, m.p. 171.9-172.4 C. Isolated yield 70% (80.1
Author Contributions
ǁX.W. and N.L. contributed equally to this work.
o
mg from 117.6 mg of 1u). 1H NMR (600 MHz, CDCl3, ppm)
δ 8.12 (s, 1 H), 7.40 (d, J = 8.70 Hz, 1 H), 7.21 (d, J = 7.92 Hz,
1 H), 7.01 (d, J = 2.34 Hz, 1 H), 6.99 (d, J = 7.98 Hz, 1 H),
6.82 (dd, J = 8.76, 2.46 Hz, 1 H), 5.76 (s, 1 H), 3.87 (s, 3 H),
2.49 (s, 3 H), 2.38 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm)
δ 167.7, 155.2, 139.0, 133.5, 132.6, 126.7, 125.1, 121.8, 117.9, 111.1,
109.9, 108.7, 103.2, 82.0, 55.8, 25.4, 21.6. HR-ESI-MS
[M+H]+ m/z Calcd for C18H17N2O2 293.1290; Found
293.1282.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from NSFC (21402128), Beijing Natural Sci-
ence Foundation (2172015, 2144045), Key Laboratory of Bioor-
ganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), and Capital Normal University are greatly
appreciated.
9
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(7-Fluoro-2-methoxy-10H-benzo[4,5]imidazo[1,2-
a]indol-10-yl)ethanone (2v). Prepared according to Proce-
dure B. Eluent: petroleum ether/ethyl acetate 9:1. White
solid, m.p. 167.5-168.2 oC. Isolated yield 55% (63.2 mg from
119.4 mg of 1v). 1H NMR (600 MHz, CDCl3, ppm) δ 8.33 (s,
1 H), 7.48 (d, J = 8.58 Hz, 1 H), 7.20 (dd, J = 8.10, 1.86 Hz, 1
H), 7.08 (d, J = 1.86 Hz, 1 H), 6.90-6.86 (m, 2 H), 5.92 (s, 1
H), 3.88 (s, 3 H), 2.61 (s, 3 H). 13C NMR (100 MHz, CDCl3,
ppm) δ 167.4, 160.0 (d, JC-F = 242.1 Hz), 155.6, 139.4, 133.0,
129.6, 129.4 (d, JC-F = 12.3 Hz), 121.6, 118.0, 111.1, 110.3, 108.8
(d, JC-F = 23.4 Hz), 103.5, 97.6 (d, JC-F = 28.9 Hz), 82.6, 55.7,
25.2. HR-ESI-MS [M+H]+ m/z Calcd for C17H14FN2O2
297.1039; Found 297.1030.
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1-(8-Bromo-2-methyl-10H-benzo[4,5]imidazo[1,2-a]indol-
10-yl)ethanone (2w). Prepared according to Procedure B.
Eluent: petroleum ether/ethyl acetate 10:1. Brick red solid,
m.p. 234.9-235.7 oC. Isolated yield 65% (86.7 mg from 137.3
mg of 1w). 1H NMR (600 MHz, CDCl3, ppm) δ 8.57 (s, 1 H),
7.52 (d, J = 8.22 Hz, 1 H), 7.44-7.41 (m, 2 H), 7.38 (d, J =
8.28 Hz, 1 H), 7.08 (d, J = 8.22 Hz, 1 H), 5.94 (s, 1 H), 2.61 (s,
3 H), 2.49 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm) δ
167.6, 138.5, 134.5, 132.3, 131.5, 128.0, 127.5, 125.0, 122.7, 120.8,
120.5, 115.5, 110.3, 110.2, 82.2, 25.3, 21.7. HR-ESI-MS [M+H]+
m/z Calcd for C17H14BrN2O 341.0290; Found 341.0287.
1-(2-Bromo-7-methyl-10H-benzo[4,5]imidazo[1,2-a]indol-
10-yl)ethanone (2x). Prepared according to Procedure C.
Eluent: petroleum ether/ethyl acetate 10:1. Brick red solid,
m.p. 253.7-254.5 oC. Isolated yield 70% (93.9 mg from 137.2
mg of 1x). 1H NMR (600 MHz, CDCl3, ppm) δ 8.19 (s, 1 H),
7.65 (d, J = 1.80 Hz, 1 H), 7.38 (d, J = 8.52 Hz, 1 H), 7.25 (dd,
J = 8.46, 1.80 Hz, 1 H), 7.17 (s, 1 H), 6.98 (dd, J = 8.28, 0.84
13
Hz, 1 H), 5.77 (s, 1 H), 2.52 (s, 3 H), 2.44 (s, 3 H). C NMR
(100 MHz, CDCl3, ppm) δ 167.4, 139.3, 135.0, 133.6, 131.4,
128.5, 125.2, 124.0, 123.4, 123.1, 117.0, 114.7, 111.8, 110.4, 81.5,
25.3, 21.6. HR-ESI-MS [M+H]+ m/z Calcd for C17H14BrN2O
341.0290; Found 341.0285.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications websites at DOI: 10.1021/acs.joc.xxxxxxxx.
Detailed optimization process and Copies of 1H and
13C NMR spectra for the products (PDF)
AUTHOR INFORMATION
Corresponding Author
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t
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