Regioselective preferential C[sbnd]H activation of sterically hindered 1,3-dienes over [4+2] cycloaddition

Article abstract of DOI:10.1016/j.tet.2017.03.028

The study of Pd-catalyzed preferential C[sbnd]H activation of sterically hindered α, β-olefinic indoles onto alkenes beyond [4?+?2] cycloaddition has been described. The carbazole derivatives were readily synthesized via activation of vinylic C[sbnd]H bonds with excellent regioselectivity. Further, the one-pot strategy has been employed for the synthesis of tricyclic carbazoles. The double and triple C[sbnd]H activation followed by concomitant Michael addition provides an economical approach for the synthesis of N-protected carbazole. A wide range of alkenes at the α- and β-position are compatible with this reaction. The mechanistic and X-ray crystallographic studies supported the designed chemistry of C[sbnd]H activation.

Full text of DOI:10.1016/j.tet.2017.03.028

Accepted Manuscript
Regioselective preferential C-H activation of sterically hindered 1,3-dienes over [4+2]
cycloaddition
Rakesh K. Saunthwal, Kapil Mohan Saini, Monika Patel, Akhilesh K. Verma
PII:
S0040-4020(17)30266-1
10.1016/j.tet.2017.03.028
TET 28534
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 December 2016
Revised Date: 9 March 2017
Accepted Date: 10 March 2017
Please cite this article as: Saunthwal RK, Saini KM, Patel M, Verma AK, Regioselective preferential C-
H activation of sterically hindered 1,3-dienes over [4+2] cycloaddition, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.03.028.
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Regioselective Preferential C-H Activation of
Sterically Hindered 1,3-Dienes over [4+2]
cycloaddition
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Rakesh K. Saunthwal, Kapil Mohan Saini, Monika Patel, Akhilesh K. Verma*
Department of Chemistry, University of Delhi, Delhi-110007

1
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Tetrahedron
journal homepage: www.elsevier.com
Regioselective Preferential C-H Activation of Sterically Hindered 1,3-Dienes over
[4+2] cycloaddition
Rakesh K. Saunthwal, Kapil Mohan Saini, Monika Patel and Akhilesh K. Verma*
a Department of Chemistry, University of Delhi, Delhi-110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The study of Pd-catalyzed preferential C-H activation of sterically hindered α, β-olefinic indoles
onto alkenes beyond [4+2] cycloaddition has been described. The carbazole derivatives were
readily synthesized via activation of vinylic C−H bonds with excellent regioselectivity. Further,
the one-pot strategy has been employed for the synthesis of tricyclic carbazoles. The double and
triple C-H activation followed by concomitant Michael addition provides an economical
approach for the synthesis of N-protected carbazole. A wide range of alkenes at the α- and β-
position are compatible with this reaction. The mechanistic and X-ray crystallographic studies
supported the designed chemistry of C-H activation.
Available online
Keywords:
Pd (II)-catalyzed
C-H activation
regioselective
indoles
2009 Elsevier Ltd. All rights reserved
.
carbazoles
1. Introduction
In recent years significant progress in metal-catalyzed C-H
activation has been The regioselective
observed.1
functionalization of sterically hindered arenes at different sites of
organic molecules provides an opportunity for the introduction of
structural modifications and in the development of fused
carbazoles. However, the extensive application of C–H
functionalization in organic synthesis is inferior due to lack of
methodologies that enable the site-selective activation of C–H
bonds, which often have subtle distinction in the intrinsic
reactivity. For instance, Pd(II)-catalyzed C-H bond metalation
resulted in the general application as robust catalysts for the
direct synthesis of (hetero)arenes.2 Owing to geometric strain, we
mainly focused on the development of metal-catalyzed C–H
activation reactions that are directed by sterically hindered
functional groups. It is believed that the proximity-driven
metalation type of tactic enables the selective functionalization of
C–H bonds that are few bonds away from the directing atom via
cyclometalation.
The carbazole core moiety is present in various natural
products which show enormous pharmaceutical significance.3,4
The Ellipticine exhibit Topoisomerase II inhibitor, Glycoborine
act as anti-HIV agent, Phosphorescence OLEDs, Epocarbazolin
A is an inhibitor of 5-lipoxygenase enzyme, sPLA2 inhibitor, and
Hepatitis C virus replication inhibitor are few remarkable
applications of carbazole derivatives (Figure 1).5
Figure 1. Biologically active carbazole derivatives.
The C-H activation directed through Pd-catalyst, perhaps the
most common method used for the alkenylation6 of the indole-
containing directing group (DG) with an alkene. The C−H
functionalization involving the syntheses of N-protected
carbazoles has been extensively exploited; for example, Itami7
and Yu8 reported the synthesis of carbazole from N-methylindole
using Pd–Cu–Ag and Pd-Cu metallic system respectively;
however C-H activation of indoles with sterically hindered
crotonate has not been much explored. Recently, Pelkey, Kartika,
Argade, Chang, Zhao and Tang co-workers9,10 have contributed
significantly in the field of carbazole synthesis using protected
amine.
*Corresponding author
E-mail address: averma@acbr.du.ac.in

2
Tetrahedron
Table 1. Optimization of reaction conditions a
Previous work
ACCEPTED MANUSCRIPT
R
Pd
i)
Gaunt, Carretero and
Wang groups
R
N
H
R
N
H
R2
R3
R1
R1
R2
R3
Ni/
Au
Ogoshi and Barluenga
groups
ii)
N
Catalyst
Entry
T oC/
time (h)
Yield (%)b
R4
Solvent
R4
N
(mol%)
3a
DMF/DMSO
(9:1)
DMF/DMSO
(9:1)
DMF/DMSO
(7:1)
DMF/DMSO
(6:1)
DMF/DMSO
(5:1)
DMF/DMSO
(4:1)
DMF/DMSO
(5:1)
111a
2
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
70/18
100/18
70/18
70/18
70/18
70/18
70/24
70/18
65
55
70
76
80
78
80
30
R2
R1
Pd
Our Previous work
iii)
R1
R2
N
H
N
H
R2
3
Regioselective
C-3 C-H activation
This work
R3
4
H
R2
R2
R1
iv)
sterically hindered
C-3 alkylation
R1
H
Pd
R3
H
5
N
N
H
H
sterically hindered -C-H
activation
6
7
[4+2] cycloaddition vs C-H functionalization
R2
R2
R3
R2
R3
R1
PdCl2(PPh3)2/
10
DMF/DMSO
(5:1)
R1
R3
R1
8
N
Pd
v)
N
N
a
N
H
H
H
N
Reactions were performed using 4.0 mmol (E)-ethyl but-2-
enoate 1a, indole 2a (2.0 mmol), catalyst, Cu(OAc)2 (2.0 equiv)
in 2.0 mL of solvent.
N
b Isolated yield.
Scheme 1. Regioselective C-H activation
In past few years, Gaunt,11 Carretero,12 Wang13 and co-
After optimizing the reaction condition for the oxidative Heck,
we explore the generality and scope of hindered C-H activation
of crotonate derivative (Scheme 2). A variety of crotonates (1)
and indoles (2), bearing electron-neutral and electron-deficient
substituents were reacted with each other to provide
functionalized vinyl indoles 3a–i in 72–84% yield with excellent
functional group tolerance. The reaction of ethyl (E)-but-2-enoate
1a with a variety of C-5 substituted indoles containing R = H,
OMe, Cl, Br and F (2a-e) successfully provided the coupled
products 3a-e in good yields.
workers demonstrated selective C-2 and C-3 functionalization of
indoles by using Pd-catalyst (Scheme 1, i). In literature, [4+2]
cycloaddition chemistry of 1,3-dienes with nitriles has been
reported by Ogoshi and Barluenga group using nickel and gold
catalyst respectively for the synthesis of pyridine (Scheme 1,
ii).14 Recently, our group have also explored the double C-H
activation chemistry via oxidative Heck palladation from indole
acrylates (Scheme 1, iii).15a-b Inspired by our previous work and
in contradict to the [4+2] cycloaddition reaction herein we report
a novel Pd-Cu bimetallic system catalyzed regioselective C-3
functionalization of indoles with β-steric hindered crotonates
(Scheme 1, iv). The literature survey depicted the formation of
[4+2] cycloaddition product. However the experimental analysis
illustrated the synthesis of carbazoles via C-H functionalization.
2. Results and Discussion
Initially, we optimized the reaction condition for C-C coupling
of β-steric hindered alkenes with C-3 indoles (for detail see
supporting information). A variety of Pd-catalysts, along with
various combinations of organic solvents were examined in the
reaction of ethyl (E)-but-2-enoate 1a with indole 2a (Table 1).
Using Gaunt conditions11a of 10 mol % Pd(OAc)2 with 1.8 equiv
of Cu(OAc)2 as an oxidant in DMF/DMSO (9:1) at 70oC for 18
h, the desired product 3a was obtained in 65% yield (Table 1,
entry 1). Elevating the reaction temperature from 70 °C to 100 °C
declined the yield of product 3a (Table 1, entry 2). It is
interesting to note that use of DMF/DMSO in different ratios, for
instance, 7:1, 6:1, 5:1, 4:1 influenced the yield of product 3a
(Table 1, entries 3–6). The reaction of 1a with indole using 10
mol% of catalyst, 2.0 equiv of oxidant in DMF/DMSO (5:1) at
o
70 C for 18 h was found to the suitable reaction condition for
oxidative Heck coupling reaction (Table 1, entry 5). On running
the reaction for 24 h have not affected the yield of the coupled
product 3a (Table 1, entry 7). Use of PdCl2(PPh3)2 provided the
product 3a in deteriorate yield (Table 1, entry 8).
Scheme 2. Pd (II) catalyzed regioselective β-sterically hindered
C-H activation of crotonate derivative.

3
When methyl-group was used as R2, the reactions were well
ACCEPTED MANUSCRIPT
implemented to form the intriguing coupled products 3f-i in 77-
84% yields. However, on performing the reaction of β-
substituted alkene using R3 as –CH2Br and –Ph with indole 2a,
failed to provide the alkenyleted products 3j-k (Scheme 2).
Table 2. Optimization for Carbazole Synthesisa
T oC/
time (h)
Yield (%)b
Entry
Catalyst
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(OAc)2
Solvent
5a
DMF/DMSO
(5:1)
DMF/DMSO
(5:1)
DMF/DMSO
(5:1)
DMF/DMSO
(5:1)
1c
2
100/18
80/18
40
35
30
30
75
3
120/18
100/24
100/18
4
Scheme 3. Preferential C-H activation over [4+2] cycloaddition
of hindered vinyl indole
DMF/DMSO
(5:1)
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Toluene
DMF
NMP
DMA
DMSO
100/18
100/40
100/40
100/40
100/40
78
23
00
15
trace
Encouraged by above results, we performed the reaction of
alkylindoloacrylate 3l−o with electron-deficient alkene 4a
provided the bi-substituted carbazoles 6a−d in 77-88% yields;
however the reaction of the (Z)-3-(1H-indol-3-yl)-N,N-dimethyl
acrylamide 3p provided the desired products 6e in lower yield.
C-5 (R1 = OMe) and C-2 (R1 = OCH2Ph) substituted vinyl
indoles 3q−s were capable in providing the cyclized product 6f-
h in 73-83% yields. It was interesting to note that the substrate
3t-v; bearing strong electron-withdrawing R1 = CN, NO2, Cl
groups (3t-3v), provided the corresponding carbazoles 6i-k in
profitable yields. The reaction of electron-rich vinyl indole (R2 =
Ph) 3w with electron-deficient alkene fruitfully afforded the
fused product 6l in 68% yield (Scheme 4).
a Reactions were performed using 0.5 mmol of ethyl-(E)-3-(1H-
indol-3-yl)but-2-enoate 3a, acrylonitrile 4a (1.0 mmol), catalyst
(10 mol %), Cu(OAc)2 (1.5 equiv) in 2.0 mL of solvent.
b Isolated yield.
c Cu(OAc)2 (1.8 equiv)
After synthesizing starting compound, we next examine the
optimal conditions for carbazole synthesis, by choosing ethyl
(E)-3-(1H-indol-3-yl)but-2-enoate 3a and acrylonitrile 4a as
model compounds (Table 2). Using our previously optimized
reaction condition of 10 mol % PdCl2(PPh3)2 with 1.8 equiv of
oxidant in DMF/DMSO (5:1) at 100oC for 18 h, the desired
product 5a was obtained in 40% yield (Table 2, entry 1). Altering
the reaction temperature from 80 °C to 120 °C was incapable of
providing the desired product 5a in moderate yields (Table 2,
entries 2–3). No significant change was observed on increasing
the reaction time (Table 2, entry 4). When 10 mol % of Pd(OAc)2
was used in DMF/DMSO (5:1), product 5a was obtained in 75%
yield (Table 2, entry 5). When toluene was used as a solvent, the
desired product 5a was obtained in 78% yield (Table 2, entry 6).
Inferior results were obtained when DMF, NMP, DMA, and
DMSO have been used as solvents (Table 2, entries 7–10).
It is interesting to note that C-H activation is preferred
over [4+2] cycloaddition product; therefore we explore the
concept to examine the scope of hindered vinyl indoles with
acrylonitrile 4a (Scheme 3). When ethyl (E)-3-(1H-indol-3-
yl)but-2-enoate 3a and its derivative 3b (R1 = OMe) were reacted
with acrylonitrile 4a the desired carbazole products 5a-b were
obtained in 78% and 76% yields respectively. Vinylindole
bearing electron-neutral (R1 = H) and electron-releasing (R1 =
OMe) substituents 3f–g were successful in providing the
functionalized carbazoles 5c–d in 81–79% yields. The reaction of
halogen substituted alkyl (E)-3-(5-halo-1H-indol-3-yl) but-2-
enoate (R1 = Cl, Br, F) 3h, 3c-e with vinyl cyanide 4a afforded
the tri-substituted carbazoles 5e–h in good yields.
Scheme 4. Synthesis of disubstituted carbazoles

4
Tetrahedron
ACCEPTED MANUSCRIPT
The X-ray crystallographic studies of 5c and 6b further
supported in elucidating the cyclized products (Figure 2).16
O1
C11
C12
C9
C8
C11
C5
C1
C5
C6
O1
C10
C12
C4
C4
C7
N1
C10
C8
O2
C6
C9
C7
C13
O2
C3
C3
C13
C14
C16
C15
C1
C2
C2
C16
N1
C14
C15
N2
N2
Figure 2. X-ray crystallographic structure of 5c and 6b with
thermal ellipsoid 50% probability level
Inspired by the former results, we aimed to further explore the
C-H activation chemistry with a variety of indole acrylates 3 and
electron-deficient alkenes 1 for the synthesis of functionalized
carbazoles 7a–k (Scheme 5). Alkyl (E)-3-(1H-indol-3-yl)but-2-
enoate bearing electron-neutral, (R1 = H) electron-releasing (R1 =
OMe) and electron-deficient (R1 = Cl, Br) substituents at C-5
position when reacted with methyl- and ethyl acrylate 1e–f
afforded the fused carbazoles 7a–h in 81–71% yields with
excellent regioselectivity. When ethyl group was used as R2, the
reaction underwent smoothly to give the expected cyclized
products 7i-k in good yields.
Scheme 6. Scope of C-H activation with vinyl ketones
After attaining successful results with vinyl indoles, we
endeavor to attain the one pot synthesis of carbazole using
substituted indoles 2 with acrylonitrile 4a and methyl acrylate 1e
(Scheme 7). It was worthy to note that the one pot carbazole
synthesis occurred in DMF:DMSO (5:1) indeed it is necessary
due to the first-Heck coupling reaction. Indole 2a and its C-5 and
C-2 methyl derivatives 2f-g underwent triple successive Heck
coupling to give the expected carbazole products 9a-c in good
yields. The reaction of 5-chlorolindole 2c with methyl acrylate
1e using Pd-Cu bimetallic system afforded the dimethyl 6-chloro-
9H-carbazole-1,3-dicarboxylate 9d in 65% yield (Scheme 7).
Scheme 7. One pot carbazoles synthesis
In addition to the carbazole synthesis through C-H activation
using vinyl indoles with acrylonitrile 4a in one pot, we observed
a unique finding of N-protected indoles via Michael addition
(Scheme 8). When we performed the reaction of (E)-ethyl 3-(5-
methoxy-1H-indol-3-yl)but-2-enoate 3b and 5-nitroindole 2h
with 4a an unusual carbazole synthesis followed by concomitant
Michael addition products 10a-b were observed in 73 and 45%
yields, respectively.
Scheme 5. Scope of C-H activation with acrylates
Further, we employed vinyl ketones 4b instead of acrylates 1
for the construction of carbazole derivatives (Scheme 6). The
reaction of ethyl/methyl (E)-3-(1H-indol-3-yl)acrylate 3m/3l with
ethyl vinyl ketone 4b provided the desired products 8a-b in 80%
and 78% yields respectively. Sterically hindered vinyl indoles C-
5 (R1 = OMe, Cl) 3b-c were also competent in providing the tri-
substituted carbazoles 8c-d in good yields. Electronically biased
vinyl indoles such as methyl (E)-3-(7-(phenoxymethyl)-1H-
indol-3-yl)acrylate 3s and (E)-3-styryl-1H-indole 3w fruitfully
provided the carbazole derivatives 8e-f in satisfactory yields.
Scheme 8. Carbazole synthesis followed by concomitant
Michael addition
After attaining successful results with free (NH) –indole we
endeavor to perform the reaction with N-protected indole. We

5
performed the reaction of N-methyl indole 3v with acrylonitrile
4a. However we failed to obtained the desired carbazole 11. The
studies revealed that the free -NH group in indole ring is crucial
for the synthesis of carbazole (Scheme 9).
dependable with an attack on the carbon next to R2 palladium
ACCEPTED MANUSCRIPT
and loss of -NH proton leads to the construction of palladium
allyl system (ii). This curial step of the mechanism has been
designed on the basis of the control experiment performed in
scheme 9 which clearly reveals the significance of free –NH
group over –NMe group.The sterically hindered olefin insertion
at the α-position of R2 generate species (iii). The newly produced
Pd-C bond would next attack the imine (C=N) to establish the
tricyclic core skeleton (iv). The di-Heck intermediate v would be
formed via β-hydride elimination followed by N-protonation/C-H
deprotonation at C-H bond next to R2. The intermediate v would
undergo the same C-Pd bond forming process as mentioned
above with proton loss of the -NH bond and nucleophilic attack
of the terminal carbon carrying R3 to palladium to form skeleton
vii which will then undergo intramolecular carbopalladation of
the C=N bond (viii) leading to the formation of carbazoles via β-
hydride elimination followed by C-H deprotonation/N-
protonation (ix). The palladium(II)–hydrido complex reduces
into a Pd(0) complex, which is oxidized by Cu(OAc)2 to
regenerate Pd(II) species (Scheme 11).
Scheme 9. Control experiment
Based on our report and literature survey,11a we proposed a
possible mechanistic pathway in Scheme 10. The mechanism
begins with the C-3 functionalization of indoles 2 generating C3-
palladated species (A) which coordinates with alkenes (1). Due to
steric hindrance, cis-trans isomerization (C) occurs followed by
β-hydride and reductive elimination (E) which leads to the Heck-
type reaction forming C3-functionalized indole 3 (Scheme 10).
3. Conclusion
In summary, we have developed a regioselective synthesis of
highly functionalized carbazoles by using Pd(II)-Cu bimetallic
system. The results of the designed protocol suggested that the C-
H activation is preferred over [4+2] cycloaddition. The sterically
hindered substrate is bearing electron-rich and electron-deficient
vinyl indoles with alkenes were examined for the synthesis of the
tri- and di-substituted carbazoles. The designed one-pot strategy
was also successful in providing the tricyclic N-heterocycle.
Further N-protected carbazoles were prepared by double and
triple C-H activation followed by concomitant Michael addition.
The C-H activation strategy for the synthesis of carbazole has
been well supported by the proposed mechanistic pathway via a
di-Heck intermediate.
Scheme 10. Plausible reaction mechanism of sterically hindered
C-H activation
4. Experimental section
General Experimental
1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded with Jeol (JNM-ECX400P) spectrometers and Delta
4.3.6 version in CDCl3 and DMSO-d6 at r.t., referenced to TMS
as internal standards. FTIR spectra were measured Zn−Se ATR,
cm−1 on a Bruker Alpha infrared spectrophotometer. The mass
spectra (EI, 74 eV; gas-reactant nitrogen) were obtained with a
Agilent 6530 Accurate Mass Q-TOF LC/MS instrument. The
analyses of compounds were conducted in USIC, Univesity of
Delhi analytical laboratory. Full spectral data for all novel
compounds are given below, few previously characterized
compounds gave spectra consistent with the literature. All
solvents were purified according to standard procedures. All the
reactions were performed in an oven-dried Schlenk flask.
Column chromatography was performed using silica gel (100-
200 mesh). All melting points are uncorrected.
Pd (II) Catalyzed regioselective β-sterically hindered C-H
activation of crotonate derivative: In an oven-dried round
bottom flask, a solution of (E)-alkyl but-2-enoate 1 (4.0 mmol),
indole 2 (2.0 mmol), 10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0
equiv) in 2.0 mL of DMF:DMSO (5:1). The resulting reaction
mixture was heated at 70 °C for 18-24 h. Progression of the
reaction was monitored by TLC analysis; after complete
consumption of starting material, the reaction was cooled to room
temperature. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL). The layers were separated, and the
organic layer was washed with aqueous saturated brine solution
Scheme 11. Plausible reaction mechanism of carbazole synthesis
The next phase of the mechanism is based on the formation of
an enamine like motif (i), the electron current would be

6
Tetrahedron
ACCEPTED MANUSCRIPT
and dried over Na2SO4. The organic layer was concentrated
heated at 70 °C for 24 h. Progression of the reaction was
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (100−200
mesh) (hexane:ethyl acetate; 90/10). The structure and purity of
known starting materials (3l-r and 3w)11, 13, 15a-b were confirmed
by comparison of their physical and spectral data (1H NMR, 13C
NMR, and HRMS) with literature data.
monitored by TLC analysis; after complete consumption of
starting material, the reaction was cooled to room temperature.
The reaction mixture was diluted with ethyl acetate (10 mL) and
water (15 mL). The layers were separated, and the organic layer
was washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3c (394.5 mg, 75%); as a
(E)-Ethyl 3-(1H-indol-3-yl)but-2-enoate (3a).
In an oven-dried round bottom flask, a solution of (E)-ethyl
but-2-enoate 1a (4.0 mmol), indole 2a (234.0 mg, 2.0 mmol), 10
mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 18 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200 mesh) (hexane:ethyl
acetate; 90/10) to give the title compound 3a (366.4 mg, 80%);
o
yellow needles, mp: 158–160 C; FTIR (Zn−Se ATR, cm−1 )
3242, 2977, 2924, 2897, 1670, 1600, 1518, 1427, 1373, 1283,
1194, 1138, 752; 1H NMR (400 MHz, DMSO–d6) δ 11.86 (1H,
br s, NH), 7.93 (1H, d, J = 2.2 Hz, CH), 7.55 (1H, d, J = 1.5 Hz,
CH), 4.46 (1H, d, J = 8.4 Hz, CH), 7.18 (1H, dd, J = 8.4 and 1.5
Hz, CH), 6.17 (1H, s, CH), 7.13 (2H, q, J = 6.8 Hz, OCH2), 2.58
(3H, s, CH3), 1.23 (3H, t, J = 6.9 Hz, CH3); 13C NMR (100 MHz,
DMSO–d6) δ 166.6, 150.3, 135.8, 129.8, 125.24, 125.21, 122.0,
119.1, 116.4, 113.9, 110.9, 59.0, 17.7, 14.3. HRMS (ESI)
[M+H]+ Calcd for [C14H15ClNO2] 264.0791, found 264.0784.
(E)-Ethyl 3-(5-bromo-1H-indol-3-yl)but-2-enoate (3d).
In an oven-dried round bottom flask, a solution of (E)-ethyl
but-2-enoate 1a (4.0 mmol), 5-bromo-1H-indole 2d (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 24 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3d (468.1 mg, 76%); as a
brown needles, mp: 154–156oC (468.1 mg, 76%); FTIR (Zn−Se
ATR, cm−1 ) 3249, 2967, 2870, 1679, 1567, 1437, 1376, 1273,
1184, 1132, 756; 1H NMR (400 MHz, DMSO-d6) δ 11.87 (1H,
br s, NH), 7.92–7.89 (2H, m, 2CH), 7.42 (1H, d, J = 9.2 Hz, CH),
7.28 (1H, dd, J = 8.4 and 1.5 Hz, CH), 6.16 (1H, s,CH), 4.11
(2H, q, J = 6.9 Hz, OCH2) 2. 58 (3H, s, CH3), 1.23 (3H, t, J = 7.6
Hz, CH3); 13C NMR (100 MHz, DMSO–d6) δ 166.6, 150.3,
136.0, 129.6, 125.9, 124.6, 122.0, 116.4, 114.3, 113.3, 110.9,
59.0, 17.7, 14.3. HRMS (ESI) [M+H]+ Calcd for [C14H15BrNO2]
308.0286, found 308.0266.
o
as a pale yellow needles, mp: 119–121 C, FTIR (Zn−Se ATR,
cm−1 ) 3277, 2982, 2926, 2902, 1693, 1677, 1599, 1572, 1523,
1461, 1430, 1364, 1327, 1305, 1263, 1188, 1132, 1050, 1019,
910, 857, 828, 738; 1H NMR (400 MHz, DMSO-d6) δ 11.56 (1H,
br s, NH), 7.74–7.68 (2H, m, 2CH), 7.33 (1H, d, J = 8.4 Hz, CH),
7.07–6.99 (2H, m,2CH), 6.17 (1H, s, CH), 3.99 (2H, q, J = 8.4
Hz, OCH2), 2.49 (3H, s, CH3), 1.11 (3H, t, J = 6.87, CH3); 13C
NMR 13C (100 MHz, DMSO–d6) δ 166.8, 161.0, 137.4, 128.4,
124.2, 122.0, 120.7, 120.0, 116.7, 112.4, 110.3, 58.9, 17.7, 14.4.
HRMS (ESI) [M+H]+ Calcd for [C14H16NO2] 230.1181, found
230.1176.
(E)-Ethyl 3-(5-methoxy-1H-indol-3-yl)but-2-enoate (3b).
In an oven-dried round bottom flask, a solution of (E)-ethyl
but-2-enoate 1a (4.0 mmol), 5-methoxy-1H-indole 2b (294.0 mg,
2.0 mmol), 10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0
mL of DMF:DMSO (5:1). The resulting reaction mixture was
heated at 70 °C for 18 h. Progression of the reaction was
monitored by TLC analysis; after complete consumption of
starting material, the reaction was cooled to room temperature.
The reaction mixture was diluted with ethyl acetate (10 mL) and
water (15 mL). The layers were separated, and the organic layer
was washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3b (424.7 mg, 82%); as a pale
(E)-Ethyl 3-(5-fluoro-1H-indol-3-yl)but-2-enoate (3e).
In an oven-dried round bottom flask, a solution of (E)-ethyl
but-2-enoate 1a (4.0 mmol), 5-fluoro-1H-indole 2e (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 22 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3e (355.6 mg, 72%); as a dark
yellow needles, mp: 130–133oC; FTIR (Zn−Se ATR, cm−1 )
3232, 2944, 2887, 1678, 1598, 1523, 1442, 1376, 1263, 1167,
1122, 751; 1H NMR (400 MHz, DMSO–d6) δ 11.80 (1H, br s,
NH), 7.95 (1H, d, J = 3.0 Hz, CH), 7.51 (1H, dd, J = 10.7 and 2.3
o
brown needles, mp: 140–142 C, FTIR (Zn−Se ATR, cm−1 )
3268, 2980, 2912, 1698, 1667, 1579, 1533, 1450, 1370, 1315,
1268, 1122, 1060, 915, 860, 748; 1H NMR (400 MHz, CDCl3) δ
8.63 (1H, br s, NH), 7.39 (2H, s, 2CH), 7.25(1H, d, J = 9.2 Hz,
CH), 6.89–6.86 (1H, m, CH), 6.33 (1H, s, CH), 4.21 (2H, q, J =
7.6 Hz, OCH2), 3.85 (3H, s, OCH3), 2.62 (3H, s, CH3), 1.32–1.29
(3H, m, CH3); 13C NMR (100 MHz, CDCl3) δ 168.0, 155.0,
150.6, 132.1, 126.4, 125.2, 118.8, 112.34, 112.29, 103.6, 59.5,
56.0, 18.3, 14.4. HRMS (ESI) [M+H]+ Calcd for [C15H18NO3]
260.1287, found 260.1281.
(E)-Ethyl 3-(5-chloro-1H-indol-3-yl)but-2-enoate (3c)
In an oven-dried round bottom flask, a solution of (E)-ethyl
but-2-enoate 1a (4.0 mmol), 5-chloro-1H-indole 2c (302.0 mg,
2.0 mmol), 10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0
mL of DMF:DMSO (5:1). The resulting reaction mixture was

7
Hz, CH), 7.48–7.45 (1H, m, CH), 7.07–7.02 (1H, m, CH), 6.17
(1H, s, CH), 4.13 (2H, q, J = 6.9 Hz, OCH2), 2.60 (3H, s, CH3),
1.25 (3H, t, J = 7.2 Hz, CH3); 13C NMR (100 MHz, DMSO–d6) δ
166.7, 157.8 (d, J = 231.9 Hz, 1C), 150.6, 134.0, 130.1, 124.4 (d,
J = 11.5 Hz, 1C), 116.8 (d, J = 4.5 Hz, 1C), 113.5 (d, J = 10.5
Hz, 1C), 110.4, 110.2 (d, J = 25.9 Hz, 1C), 105.0 (d, J = 24.9 Hz,
1C), 59.0, 17.7, 14.4. HRMS (ESI) [M+H]+ Calcd for
[C14H15FNO2] 248.1087, found 248.1081.
the reaction was cooled to room temperature. The reaction
ACCEPTED MANUSCRIPT
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. Organic layer was concentrated under reduced pressure.
The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3h (383.4 mg, 77%) as a
yellow needles, mp: 184–186oC; FTIR (Zn−Se ATR, cm−1 )
3300, 2926, 2855, 1688, 1600, 1517, 1460, 1425, 1334, 1282,
1190, 1136, 1028, 784; 1H NMR (400 MHz, DMSO–d6) δ 11.86
(1H, br s, NH), 7.94 (1H, d, J = 3.0 Hz, CH), 7.76 (1H, d, J = 1.5
Hz, CH), 7.46 (1H, d, J = 8.4 Hz, CH), 7.18 (1H, dd, J = 8.3 and
2.3 Hz, CH), 6.19 (1H, s, CH), 3.56 (3H, s, OCH3), 2.58 (3H, s,
CH3); 13C NMR (100 MHz, DMSO–d6) δ 167.0, 150.6, 135.8,
129.9, 125.3, 125.2, 122.1, 119.1, 116.4, 113.9, 110.5, 50.6, 17.7.
HRMS (ESI) [M+H]+ Calcd for [C13H13ClNO2] 250.0635, found
250.0644.
(E)-Methyl 3-(1H-indol-3-yl)but-2-enoate (3f).
In an oven-dried round bottom flask, a solution of (E)-methyl
but-2-enoate 1b (4.0 mmol), indole 2a (2.0 mmol), 10 mol %
Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of DMF:DMSO
(5:1). The resulting reaction mixture was heated at 70 °C for 18
h. Progression of the reaction was monitored by TLC analysis;
after complete consumption of starting material, the reaction was
cooled to room temperature. The reaction mixture was diluted
with ethyl acetate (10 mL) and water (15 mL). The layers were
separated, and the organic layer was washed with aqueous
saturated brine solution and dried over Na2SO4. The organic layer
was concentrated under reduced pressure. The crude material so
obtained was purified by column chromatography on silica gel
(100−200) (hexane:ethyl acetate; 90/10) to give the title
compound 3f (352.6 mg, 82%) as a brown needles, mp: 110–112
oC; FTIR (Zn−Se ATR, cm−1 ) 3266, 3026, 2924, 2855, 1683,
1599, 1519, 1494, 1429, 1202, 1136, 826; 1H NMR (400 MHz,
CDCl3) δ 8.60 (1H, br s, NH), 7.97 (1H, d, J = 6.9 Hz, CH), 7.45
(1H, d, J = 2.3 Hz, CH), 7.40 (1H, dd, J = 6.9 and 1.5 Hz, CH),
7.27–7.20 (2H, m, CH), 6.40 (1H, s, CH), 3.78 (3H, s, OCH3),
2.67 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ 168.3, 150.8,
137.0, 128.1, 127.6, 125.8, 122.8, 121.1, 120.8, 112.3, 111.7,
50.9, 18.2. HRMS (ESI) [M+H]+ Calcd for [C13H14NO2]
216.1025, found 216.1020.
(E)-methyl 3-(5-bromo-1H-indol-3-yl)but-2-enoate (3i).
In an oven-dried round bottom flask, a solution of (E)-methyl
but-2-enoate 1b (4.0 mmol), 5-bromo-1H-indole 2d (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 24 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3i (458.6 mg, 78%) as a off-
(E)-Methyl 3-(5-methoxy-1H-indol-3-yl)but-2-enoate (3g).
o
white needles, mp: 187–188 C; FTIR (Zn−Se ATR, cm−1 )
3320, 2927, 2863, 1692, 1604, 1518, 1428, 1337, 1285, 1029,
762; 1H NMR (400 MHz, DMSO–d6) δ 11.88 (1H, br s, NH),
7.89 (1H, d, J = 1.5 Hz, CH), 7.41 (1H, d, J = 9.2 Hz, CH), 7.29
(1H, dd, J = 8.4 and 1.5 Hz, CH), 7.22 (1H, t, J = 6.9 Hz, CH),
6.19 (1H, s, CH), 3.64 (3H, s, OCH3), 2.57 (3H, s, CH3); 13C
NMR (100 MHz, DMSO–d6) δ 167.0, 150.5, 136.0, 129.8, 128.1,
125.9, 124.6, 122.0, 114.4, 113.3, 110.5, 50.6, 17.7. HRMS (ESI)
[M+H]+ Calcd for [C13H13BrNO2] 294.0130, found 294.0123.
In an oven-dried round bottom flask, a solution of (E)-methyl
but-2-enoate 1b (4.0 mmol), 5-methoxy-1H-indole 2b (2.0
mmol), 10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL
of DMF:DMSO (5:1). The resulting reaction mixture was heated
at 70 °C for 18 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3g (411.6 mg, 84%) as a
(E)-Methyl 3-(7-(benzyloxy)-1H-indol-3-yl)acrylate (3s).
In an oven-dried round bottom flask, a solution of methyl
acrylate 1e (4.0 mmol), 7-(benzyloxy)-1H-indole 2 (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 20 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3q (429.8 mg, 70%) as a off-
o
brown needles, mp: 147–150 C; FTIR (Zn−Se ATR, cm−1 )
1
3255, 2934, 2865, 1680, 1600, 1523, 1480, 1212, 1126; H NMR
(400 MHz, CDCl3) δ 8.75 (1H, br s, NH), 7.39–7.37 (2H, m,
2CH), 7.25 (1H, d, J = 8.4 Hz, CH), 6.88 (1H, dd, J = 9.2 and 2.3
Hz, CH), 6.35 (1H, s, CH), 3.84 (3H, s, OCH3), 3.74 (3H, s,
OCH3), 2.62 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ 168.4,
155.0, 151.1, 132.1, 126.5, 125.1, 118.6, 112.5, 112.4, 111.7,
103.3, 56.0, 50.8, 18.3. HRMS (ESI) [M+H]+ Calcd for
[C14H16NO3] 246.1130, found 246.1120.
(E)-Methyl 3-(5-chloro-1H-indol-3-yl)but-2-enoate (3h).
o
white needles, mp: 146–148 C; FTIR (Zn−Se ATR, cm−1 )
1
3250, 2939, 2870, 1665, 1589, 1517, 1485, 1209, 1118; H NMR
In an oven-dried round bottom flask, a solution of (E)-methyl
but-2-enoate 1b (4.0 mmol), 5-chloro-1H-indole 2c (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 24 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
(400 MHz, CDCl3) δ 8.75 (1H, br s, NH), 7.91 (1H, d, J = 16.0
Hz, CH), 7.51 (1H, d, J = 7.6 Hz, CH), 7.47–7.36 (6H, m, 6CH),
7.15 (1H, t, J = 8.4 Hz, CH), 6.80 (1H, d, J = 7.6 Hz, CH), 6.44
(1H, d, J = 16.0 Hz, CH), 5.20 (2H, s, CH2), 3.80 (3H, s, OCH3);
13C NMR (100 MHz, CDCl3) δ 145.4, 138.5, 136.6, 128.7, 128.3,

8
Tetrahedron
128.1, 127.9, 127.7, 122.0, 114.1, 113.3, 113.1, 104.5, 70.4,
pressure. The crude material so obtained was purified by column
ACCEPTED MANUSCRIPT
51.4 HRMS (ESI) [M+H]+ Calcd for [C19H18NO3] 308.1287,
found 308.1281.
chromatography on silica gel (100−200) (hexane:ethyl acetate;
85/15) to give the title compound 3t (319.6 mg, 68%); as a
yellow needles, mp: 136–138 C; FTIR (Zn−Se ATR, cm−1 )
3233, 2935, 2836, 1695, 1579, 1537, 1449, 1237, 1212; H NMR
o
(E)-Methyl 3-(5-cyano-1H-indol-3-yl)acrylate (3t).
1
(400 MHz, CDCl3) δ 8.91 (1H, br s, NH), 7.85−7.81 (2H, m,
2CH), 7.45 (1H, d, J = 3.0 Hz, CH), 7.31 (1H, d, J = 9.1 Hz,
CH), 7.19 (1H, dd, J = 8.4 and 1.5 Hz, CH), 6.37 (1H, d, J = 16.0
Hz, CH), 3.80 (3H, s, OCH3); 13C NMR (100 MHz, CDCl3) δ
168.7, 137.9, 130.4, 129.9, 127.3, 126.2, 123.6, 119.9, 113.3,
113.0, 112.8, 51.6; HRMS (ESI) [M+H]+ Calcd for
[C12H11ClNO2] 236.0478, found 236.0480.
In an oven-dried round bottom flask, a solution of methyl
acrylate 1e (4.0 mmol), 1H-indole-5-carbonitrile 2 (2.0 mmol),
10 mol % Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 24 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
90/10) to give the title compound 3r (271.2 mg, 60%); as a
General procedure and analytical data for [4+2]
cycloaddition vs C-H activation:
Ethyl 1-cyano-4-methyl-9H-carbazole-3-carboxylate (5a).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(1H-indol-3-yl)but-2-enoate 3a (114.5 mg, 0.5 mmol) in toluene;
2 mL), Pd(OAc)2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC, while noticing complete
consumption of (E)-ethyl 3-(1H-indol-3-yl)but-2-enoate, reaction
was brought to room temperature. The additional amount of
acrylate also added if required for complete conversion. The
reaction mixture was diluted with ethyl acetate (10 mL) and
water (15 mL) and then filtered through a plug of celite. The
layers were separated, and the organic layer was washed with
aqueous saturated brine solution, dried over Na2SO4. Organic
layer was concentrated under reduced pressure. The crude
material so obtained was purified by column chromatography on
silica gel (hexane: ethylacetate; 95/05) to give the title compound
3a (108.3 mg, 78%) as a off white crystal, mp 137−139 °C;
FTIR (Zn−Se ATR, cm−1 ) 3282, 2978, 2852, 2227, 1712, 1589,
1240, 1024, 748; 1H NMR (400 MHz, DMSO–d6) δ 12.52 (br s,
1H), 8.25 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.53 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 6.9 Hz, 1H), 4.31 (q, J
= 6.9 Hz, 2H), 3.08 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, DMSO–d6) δ 166.2, 141.4, 141.0, 140.6, 131.9,
126.9, 123.1, 122.4, 121.2, 120.8, 116.7, 112.0, 90.6, 60.8, 17.9,
14.1 ; HRMS (ESI) [M+H]+ Calcd for [C17H15N2O2] 279.1134
found 279.1128.
o
yellow needles, mp: 146–148 C; FTIR (Zn−Se ATR, cm−1 )
3233, 2919, 2850, 2231, 1678, 1579, 1514, 1489, 1219, 1128;
1H NMR (400 MHz, CDCl3) δ 12.21 (1H, br s, NH), 8.48 (1H, s,
CH), 8.13 (1H, d, J = 2.3 Hz, CH), 7.87 (1H, d, J = 16.0 Hz,
CH), 7.60 (1H, d, J = 8.4 Hz, CH), 7.53 (1H, dd, J = 8.4 and 1.5
Hz, CH), 6.53 (1H, d, J = 16.7 Hz, CH), 3.69 (3H, s, OCH3); 13
C
NMR (100 MHz, CDCl3) δ 167.5, 139.0, 137.5, 133.3, 125.4,
125.3, 124.7, 120.3, 113.5, 112.9, 112.3, 103.0, 51.1. HRMS
(ESI) [M+H]+ Calcd for [C13H11N2O2] 227.0821, found
227.0823.
(E)-Methyl 3-(5-nitro-1H-indol-3-yl)acrylate (3u)
In an oven-dried round bottom flask, a solution of methyl
acrylate 1e (4.0 mmol), 5-nitro-1H-indole 2 (2.0 mmol), 10 mol
%
Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 24 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (100−200) (hexane:ethyl acetate;
85/15) to give the title compound 3s (319.8 mg, 65%); as a
Ethyl
1-cyano-6-methoxy-4-methyl-9H-carbazole-3-
carboxylate (5b)
o
yellow needles, mp: 136–138 C; FTIR (Zn−Se ATR, cm−1 )
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-methoxy-1H-indol-3-yl)but-2-enoate 3b (129.5 mg, 0.5 mmol)
in toluene; 2 mL), Pd(OAc)2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-ethyl 3-(5-methoxy-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 3a (117.0 mg, 76%) as a pale yellow
1
3245, 2929, 2836, 1690, 1569, 1544, 1441, 1230, 1216; H NMR
(400 MHz, DMSO-d6) δ 12.36 (1H, br s, NH), 8.71 (1H, s, CH),
8.19 (s, 1H), 8.07–8.04 (m, 1H), 7.90 (d, J = 16.02 Hz, 1H), 7.61
(d, J = 8.4 Hz, 1H) 6.45 (d, J = 16.02 Hz, 1H), 3.71 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 167.3, 141.9, 140.3, 137.2, 134.2,
13.1, 124.4, 117.8, 116.4, 116.3, 113.5, 51.3 HRMS (ESI)
[M+H]+ Calcd for [C12H11N2O4] 247.0719, found 247.0720.
(E)-methyl 3-(5-chloro-1H-indol-3-yl)acrylate (3v)
In an oven-dried round bottom flask, a solution of methyl
acrylate 1e (4.0 mmol), 5-chloro-1H-indole 2 (2.0 mmol), 10 mol
%
Pd(OAc)2 and Cu(OAc)2 (2.0 equiv) in 2.0 mL of
DMF:DMSO (5:1). The resulting reaction mixture was heated at
70 °C for 22 h. Progression of the reaction was monitored by
TLC analysis; after complete consumption of starting material,
the reaction was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL). The layers were separated, and the organic layer was
washed with aqueous saturated brine solution and dried over
Na2SO4. The organic layer was concentrated under reduced
o
needles, mp: 136–139 C; FTIR (Zn−Se ATR, cm−1 ) 3287,
2922, 2852, 2222, 1711, 1466, 1194, 767; 1H NMR (400 MHz,
CDCl3) δ 8.78 (1H, br s, NH), 8.29 (1H, s, CH), 7.76 (1H, s, CH),

9
7.48 (1H, d, J = 9.2 Hz, CH), 7.19 (1H, d, J = 9.2 Hz, CH), 4.41
Methyl
carboxylate (5e).
6-chloro-1-cyano-4-methyl-9H-carbazole-3-
ACCEPTED MANUSCRIPT
(2H, d, J = 6.9 Hz, OCH2), 3.95 (3H, s, OCH3), 3.20 (3H s, CH3),
1.46–1.41 (3H, m, CH3); 13C NMR (100 MHz, , CDCl3) δ 166.8,
154.8, 150.1, 142.8, 141.8, 134.3, 132.3, 124.2, 122.0, 116.7,
115.6, 111.8, 107.2, 91.1, 61.2, 56.2, 18.4, 14.4. HRMS (ESI)
[M+H]+ Calcd for [C18H17N2O3] 309.1239, found 309.1234.
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-chloro-1H-indol-3-yl)but-2-enoate 3h (124.5 mg, 0.5 mmol)
in toluene; 2 mL), Pd(OAc)2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 24 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-chloro-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 3a (122.2 mg, 80%) as a pale yellow
Methyl 1-cyano-4-methyl-9H-carbazole-3-carboxylate (5c).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(1H-indol-3-yl)but-2-enoate 3f (107.5 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-methyl 3-(1H-indol-3-yl)but-2-enoate, the
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 3a (106.8 mg, 81%) as a colourless
o
needles, mp: 291–293 C; FTIR (Zn−Se ATR, cm−1 ) 3310,
2955, 2853, 1653, 1452, 1202, 1050, 1000, 760; H NMR (400
1
MHz, DMSO–d6) δ 12.67 (1H, br s, NH), 8.24 (1H, s, CH), 8.20
(1H, d, J = 2.3 Hz, CH), 7.62 (1H, d, J = 9.2 Hz, CH), 7.55 (1H,
dd, J = 8.4 and 2.5 Hz, CH), 3.87 (3H, s, OCH3), 3.04 (3H, s,
CH3); 13C NMR (100 MHz, DMSO–d6) δ 166.4, 141.4, 139.0,
132.7, 128.2, 127.5, 127.3, 125.0, 123.6, 122.4, 122.2, 121.2,
116.4, 91.1, 52.3, 17.8. HRMS (ESI) [M-H]+ Calcd for
[C16H10ClN2O2] 297.0431, found 297.0425.
o
needles, mp: 255–257 C; FTIR (Zn−Se ATR, cm−1 ) 3295,
1
2958, 2926, 2229, 1723, 1332, 1245, 1211, 1029, 826, 759; H
NMR (400 MHz, DMSO–d6) δ 12.53 (1H, br s, NH), 8.25 (1H, d,
J = 7.6 Hz, CH), 8.21 (1H, s, CH), 7.62 (1H, d, J = 8.4 Hz, CH),
7.52 (1H, d, J = 8.4 Hz, CH), 7.31 (1H, t, J = 8.4 Hz, CH), 3.85
(3H, s, OCH3), 3.07 (3H, s, CH3); 13C NMR (100 MHz, DMSO–
d6) δ 166.6, 141.5, 131.9, 128.1, 127.4, 126.9, 125.7, 123.1,
122.5, 120.9, 120.7, 116.6, 112.0, 90.6, 52.1, 17.9. HRMS (ESI)
[M+H]+ Calcd for [C16H13N2O2] 265.0977, found 265.0989.
Ethyl 6-chloro-1-cyano-4-methyl-9H-carbazole-3-carboxylate
(5f).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-chloro-1H-indol-3-yl)but-2-enoate 3c (131.5 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc)2 (12.4 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 22 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-ethyl 3-(5-chloro-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 3a (116.9 mg, 75%) as a off white
Methyl
1-cyano-6-methoxy-4-methyl-9H-carbazole-3-
carboxylate (5d).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-methoxy-1H-indol-3-yl)but-2-enoate 3g (122.5 mg, 0.5
mmol) in toluene; 2 mL), Pd(OAc)2 (11.20 mg, 10 mol %),
Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a (1.0 mmol) were
added. The resulting reaction mixture was heated at 100 °C for
20 h. Progression of the reaction was monitored by TLC, while
noticing complete consumption of (E)-methyl 3-(5-methoxy-1H-
indol-3-yl)but-2-enoate, the reaction was brought to room
temperature. The additional amount of acrylate also added if
required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel
(hexane:ethylacetate; 95/05) to give the title compound 3a (116.1
o
needles, mp: 288–290 C; FTIR (Zn−Se ATR, cm−1 ) 3291,
2920, 2852, 2228, 1714, 1593, 1446, 1285, 1242, 800; 1H NMR
(400 MHz, DMSO–d6) δ 12.62 (1H, br s, NH), 8. 20 (1H, s, CH),
8.16 (1H, d, J = 1.5 Hz, CH), 7.59 (1H, d, J = 8.4 Hz, CH), 7.53
(1H, dd, J = 9.1 and 2.3 Hz, CH), 4.33 (2H, q, J = 6.9 Hz,
OCH2), 3.32 (3H, s, CH3), 1.36 (3H, t, J = 6.8 Hz, CH3); 13C
NMR (100 MHz, DMSO–d6) δ 166.0, 141.9, 141.3, 139.0, 132.5,
126.8, 125.0, 123.5, 122.3, 122.2, 121.4, 116.4, 113.4, 91.0, 60.9,
17.8, 14.1. HRMS (ESI) [M+H]+ Calcd for [C17H14ClN2O2]
313.0744, found 313.0738.
o
mg, 79%) as a yellow needles, mp: 164.3–165 C (116.1 mg,
79%); FTIR (Zn−Se ATR, cm−1 ) 3287, 2956, 2926, 2228, 1718,
1
1608, 1460, 762, 701; H NMR (400 MHz, DMSO–d6) δ 12.35
(1H, br s, NH), 8.18 (1H, s, CH), 7.68 (1H, d, J = 2.3 Hz, CH),
7.52 (1H, d, J = 8.7 Hz, CH), 7.18 (1H, dd, J = 9.2 and 2.3 Hz,
CH), 3.86 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.06 (3H, s, CH3);
13C NMR (100 MHz, DMSO–d6) δ 166.5, 154.0, 141.7, 141.2,
131.8, 128.1, 127.3, 122.8, 120.0, 116.6, 115.6, 112.6, 106.1,
90.5, 55.6, 52.0, 17.8. HRMS (ESI) [M+H]+ Calcd for
[C17H15N2O3] 295.1083, found 295.1078.
Ethyl 6-bromo-1-cyano-4-methyl-9H-carbazole-3-carboxylate
(5g).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-bromo-1H-indol-3-yl)but-2-enoate 3d (153.5 mg, 0.5 mmol)
in toluene; 2 mL), Pd(OAc))2 (11.20 mg, 10 mol %), Cu(OAc)2
(2.0 equiv) and acrylonitrile 4a (1.0 mmol) were added. The

10
Tetrahedron
ACCEPTED MANUSCRIPT
resulting reaction mixture was heated at 100 °C for 24 h.
celite. The layers were separated, and the organic layer was
Progression of the reaction was monitored by TLC while noticing
complete consumption of (E)-ethyl 3-(5-bromo-1H-indol-3-
yl)but-2-enoate, the reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 3a (137.8 mg, 77%) as pale yellow
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6a (103.6 mg, 83%) as a off-white
o
needles, mp: 256–258 C (103.6 mg, 83%); FTIR (Zn−Se ATR,
cm−1 ) 3294, 2923, 2852, 2231, 1725, 1579, 1512, 1458, 1429,
1333, 1262, 1098, 989, 762, 736; H NMR (400 MHz, DMSO–
1
d6) δ 12.61 (1H, br s, NH), 9.03 (1H, d, J = 1.1 Hz, CH), 8.36–
8.33 (2H, m, 2CH), 7.61 (1H, d, J = 8.4 Hz, CH), 7.54 (1H, t, J =
8.4 Hz, CH), 7.31 (1H, t, J = 7.6 Hz, CH), 3.90 (3H, s, OMe); 13
C
NMR (100 MHz, DMSO–d6) δ 165.5, 142.3, 140.8, 130.7, 127.7,
126.6, 123.9, 121.9, 121.4, 120.9, 120.3, 116.5, 112.1, 93.2, 52.2.
HRMS (ESI) [M+H]+ Calcd for [C15H11N2O2] 251.0821, found
251.0790.
o
needles, mp: 272–275 C; FTIR (Zn−Se ATR, cm−1 ) 3281,
2925, 2857, 2238, 1723, 1578, 1465, 1287, 1245, 789; 1H NMR
(400 MHz, DMSO–d6) δ 12.44 (1H, br s, NH), 8.11–8.06 (1H, m,
CH), 8.03 (1H, s, CH), 7.55–7.53 (1H, m, CH), 7.42 (1H, d, J =
8.4 Hz, CH), 4.29 (2H, q, J = 6.9 Hz, OCH2), 2.84 (3H, s, CH3),
1.36–1.33 (3H, m, CH3); 13C NMR (100 MHz, DMSO–d6) δ
165.7, 141.7, 140.9, 139.1, 132.3, 129.1, 124.9, 123.8, 121.8,
120.9, 116.3, 113.6, 112.7, 90.7, 60.8, 17.6, 14.1. HRMS (ESI)
[M]+ Calcd for [C17H13BrN2O2] 356.0160, found 356.0155.
Ethyl 1-cyano-9H-carbazole-3-carboxylate (6b).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(1H-indol-3-yl)acrylate 3m (134.0 mg, 0.5 mmol) in toluene; 2
mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC, while noticing complete
consumption of (E)-ethyl 3-(1H-indol-3-yl)acrylate, reaction was
brought to room temperature. The additional amount of acrylate
also added if required for complete conversion. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL) and then filtered through a plug of celite. The layers were
separated, and the organic layer was washed with aqueous
saturated brine solution, dried over Na2SO4. The organic layer
was concentrated under reduced pressure. The crude material so
obtained was purified by column chromatography on silica gel
(hexane: ethylacetate; 95/05) to give the title compound 6b
(108.1 mg, 82%) as a colourless needles, mp: 210–213 oC; FTIR
(Zn−Se ATR, cm−1 ) 3284, 2920, 2859, 2233, 1720, 1570, 1517,
1453, 1433, 1356, 1234, 1055, 990, 782, 732;; 1H NMR (400
MHz, DMSO-d6) δ 12.62 (1H, br s, NH), 9.03 (1H, s, CH), 8.37–
8.34 (2H, m, 2CH), 7.61 (1H, d, J = 7.6 Hz, CH), 7.54 (1H, t, J =
6.8 Hz, CH), 7.31 (1H, t, J = 7.6 Hz, CH), 4.39 (2H, q, J = 6.8
Hz, OCH2), 1.36 (3H, t, J = 7.6 Hz, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 165.0, 142.3, 140.8, 130.7, 127.8, 126.7, 124.0,
121.9, 121.4, 120.9, 120.6, 116.5, 112.1, 93.1, 61.0, 14.3 HRMS
(ESI) [M+H]+ Calcd for [C16H13N2O2] 265.0977, found
265.0958.
Ethyl 1-cyano-6-fluoro-4-methyl-9H-carbazole-3-carboxylate
(5h).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-fluoro-1H-indol-3-yl)but-2-enoate 3e (123.6 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc)2 (11.20 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 24 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-ethyl 3-(5-fluoro-1H-indol-3-yl)but-2-enoate,
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 5h(108.0 mg, 73%) as a yellow needles,
o
mp: 141–143 C; FTIR (Zn−Se ATR, cm−1 ) 3300, 2984, 2926,
2866, 2231, 1706, 1604, 1464, 1371, 1247, 760; 1H NMR (400
MHz, DMSO–d6) δ 12.51 (1H, br s, NH), 8.17 (1H, s, CH), 7.93
(1H, dd, J = 10.1 and 2.7 Hz,CH), 7.59–7.56 (1H, m, CH), 7.40–
7.34 (1H, m, CH), 4.31 (2H, q, J = 7.3 Hz, OCH2), 2.99 (3H, s,
CH3), 1.34 (3H, t, J = 6.9 Hz, CH3); 13C NMR (100 MHz,
DMSO–d6) δ 165.9, 157.2 (d, J = 236.7 Hz, 1C), 141.9, 141.6,
137.0, 132.4, 128.2, 127.3, 122.6 (d, J = 9.6 Hz, 1C), 120.9,
114.6 (d, J = 24.0 Hz, 1C), 112.9 (d, J = 10.5 Hz, 1C), 108.8 (d, J
= 25.9 Hz, 1C), 90.8, 60.8, 17.7, 14.1. HRMS (ESI) [M-H]+
Calcd for [C17H12FN2O2] 295.0883, found 295.0877.
Butyl 1-cyano-9H-carbazole-3-carboxylate (6c).
In a oven-dried round bottom flask, a solution of (E)-butyl 3-
(1H-indol-3-yl)acrylate 3n (121.5 mg, 0.5 mmol) in toluene; 2
mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC, while noticing complete
consumption of (E)-butyl 3-(1H-indol-3-yl)acrylate, reaction was
brought to room temperature. The additional amount of acrylate
also added if required for complete conversion. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL) and then filtered through a plug of celite. The layers were
separated, and the organic layer was washed with aqueous
saturated brine solution, dried over Na2SO4. Organic layer was
concentrated under reduced pressure. The crude material so
obtained was purified by column chromatography on silica gel
(hexane: ethylacetate; 95/05) to give the title compound 6c
Methyl 1-cyano-9H-carbazole-3-carboxylate (6a).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(1H-indol-3-yl)acrylate 3l (100.6 mg, 0.5 mmol) in toluene; 2
mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(1H-indol-3-yl)acrylate, the
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
o
(116.7 mg, 80%) as a brown needles, mp: 192–194 C; FTIR
(Zn−Se ATR, cm−1 ) 3264, 2912, 2833, 2237, 1715, 1578, 1509,
1456, 1467, 1313, 1243, 1089, 978, 764, 744; 1H NMR (400

11
MHz, DMSO–d6) δ 12.59 (1H, br s, NH), 8.99 (1H, s, CH), 8.33
Methyl
1-cyano-6-methoxy-9H-carbazole-3-carboxylate
ACCEPTED MANUSCRIPT
(2H, t, J = 8.4 Hz, 2CH), 7.60 (1H, d, J = 7.6 Hz, CH), 7.53 (1H,
t, J = 7.6 Hz, CH), 7.30 (1H, t, J = 7.6 Hz, CH), 4.30 (2H, t, J =
6.9 Hz, OCH2), 1.75–1.68 (2H, m, CH2), 1.47–1.41 (2H, m,
CH2), 0.94 (3H, t, J = 7.2 Hz, CH3); 13C NMR (100 MHz,
DMSO–d6) δ 165.0, 142.3, 140.8, 130.6, 127.7, 126.6, 123.9,
121.9, 121.3, 120.8, 120.6, 116.5, 112.1, 93.0, 64.6, 30.3, 18.8,
13.7 HRMS (ESI) [M+H]+ Calcd for [C18H17N2O2] 293.1290,
found 293.1285.
(6f). In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-methoxy-1H-indol-3-yl)acrylate 3q (115.5 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-methyl 3-(5-methoxy-1H-indol-3-yl)acrylate,
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6f (116.2 mg, 83%) as a off-white
needles, mp: 155–157 oC; FTIR (Zn−Se ATR, cm−1 ) FTIR
(Zn−Se ATR, cm−1 ) 3214, 2933, 2845, 2257, 1713, 1665, 1436,
tert-Butyl 1-cyano-9H-carbazole-3-carboxylate (6d)
In a oven-dried round bottom flask, a solution of (E)-tert-butyl
3-(1H-indol-3-yl)acrylate 3o (121.5 mg, 0.5 mmol) in toluene; 2
mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC, while noticing complete
consumption of (E)-tert-butyl 3-(1H-indol-3-yl)acrylate, reaction
was brought to room temperature. The additional amount of
acrylate also added if required for complete conversion. The
reaction mixture was diluted with ethyl acetate (10 mL) and
water (15 mL) and then filtered through a plug of celite. The
layers were separated, and the organic layer was washed with
aqueous saturated brine solution, dried over Na2SO4. Organic
layer was concentrated under reduced pressure. The crude
material so obtained was purified by column chromatography on
silica gel (hexane: ethylacetate; 95/05) to give the title compound
1
1347, 1233, 1166, 1037, 955, 815, 758; H NMR (400 MHz,
DMSO–d6) δ 12.41 (1H, br s, NH), 9.01 (1H, s, CH), 8.27 (1H, d,
J = 1.52 Hz, CH), 7.94 (1H, d, J = 2.3 Hz, CH) 7.47 (1H, d, J =
9.2 Hz, CH), 7.13 (1H, dd, J = 8.4 and 2.3 Hz, CH), 3.88 (3H, s,
OCH3), 3.84 (3H, s, OCH3); 13C NMR (100 MHz, DMSO–d6) δ
165,6, 154.5, 142.5, 135.3, 130.5, 126.9, 124.0, 122.6, 119.7,
117.3 116.6, 112.8, 103.7, 93.0, 55.6, 52.2 HRMS (ESI) [M+H]+
Calcd for [C16H13N2O3] 281.0926, found 281.0946.
o
6d (112.3 mg, 77%) as a brown needles, mp: 228–230 C; FTIR
(Zn−Se ATR, cm−1 ) 3396, 2978, 2925, 2850, 2224, 1705, 1578,
1500, 1474, 1455, 1392, 1367, 1329, 1309, 1249, 1221, 1161,
1129,, 1024, 999, 825; 1H NMR (400 MHz, DMSO–d6) δ 12.55
(1H, br s, NH), 8.93 (1H, d, J = 1.5 Hz, CH), 8.30 (1H, d, J = 7.6
Hz, CH), 8.26 (1H, d, J = 1.5 Hz, CH), 7.59 (1H, d, J = 8.0 Hz,
CH), 7.52 (1H, t, J = 6.9 Hz, CH), 7.30 (1H, t, J = 6.9 Hz, CH),
1.58 (9H, s, tBu); 13C NMR (100 MHz, DMSO–d6) δ 164.2,
142.1, 140.8, 130.6, 127.6, 126.4, 123.8, 122.1, 121.9, 121.2,
120.8, 116.6, 112.1, 92.8, 81.0, 27.8. HRMS (ESI) [M+H]+ Calcd
for [C18H17N2O2] 293.1290, found 293.1297.
Butyl 1-cyano-6-methoxy-9H-carbazole-3-carboxylate (6g).
In a oven-dried round bottom flask, a solution of (E)-butyl 3-
(5-methoxy-1H-indol-3-yl)acrylate 3r (136.5 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-butyl 3-(5-methoxy-1H-indol-3-yl)acrylate,
the reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6g (130.3 mg, 81%) as a off-white
1-Cyano-N,N-dimethyl-9H-carbazole-3-carboxamide (6e).
In a oven-dried round bottom flask, a solution of (E)-3-(1H-
indol-3-yl)-N,N-dimethyl acrylamide 3p (107.0 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-3-(1H-indol-3-yl)-N,N-dimethyl acrylamide,
the reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6e (95.9 mg, 73%) as a dark brown
o
needles, mp: 205–208 C; FTIR (Zn−Se ATR, cm−1 ) 3318,
2913, 2850, 2230, 1720, 1656, 1475, 1332, 1241, 1143, 988, 835,
1
755; H NMR (400 MHz, DMSO–d6) δ 12.39 (1H, br s, NH),
8.97 (1H, d, J = 1.5 Hz, CH), 8.25 (1H, d, J = 1.5 Hz, CH), 7.92
(1H, d, J = 2.2 Hz, CH), 7.47 (1H, d, J = 8.4 Hz, CH), 7.13 (1H,
dd, J = 9.2 and 3.0 Hz, CH), 4.28 (2H, q, J = 6.9 Hz, OCH2), 3.85
(3H, s, OCH3), 1.75–1.68 (2H, m, CH2), 1.48–1.39 (2H, m, CH2),
0.93(3H, t, J = 7.6 Hz, CH3); 13C NMR (100 MHz, DMSO–d6) δ
165.1, 154.5, 142.5, 135.3, 130.4, 126.8, 123.9, 122.5, 119.9,
117.2, 116.6, 112.8, 103.6, 92.9, 64.5, 55.6, 30.4, 18.8, 13.7.
HRMS (ESI) [M+H]+ Calcd for [C19H19N2O3] 323.1396, found
323.1416.
o
needles, mp: 199–201 C; FTIR (Zn−Se ATR, cm−1 ) 3232,
2955, 2852, 2225, 1606, 1496, 1396, 1090, 749; 1H NMR (400
MHz, CDCl3) δ 10.10 (1H, br s, NH), 8.32 (1H, s, CH), 7.96 (1H,
d, J = 7.6 Hz, CH), 7.74 (1H, s, CH), 7.53–7.44 (2H, m, 2CH),
7.25 (1H, t, J = 7.6 Hz, CH), 3.14 (6H, s, 2CH3); 13C NMR (100
MHz, CDCl3) δ 170.8, 141.0, 140.3, 128.3, 127.6, 126.7, 124.4,
124.2, 122.1, 120.8, 120.6, 116.7, 111.7, 93.1, 42.6. HRMS (ESI)
[M+H]+ Calcd for [C16H14N3O] 264.1137, found 264.1131.
Methyl
(6h).
8-(benzyloxy)-1-cyano-9H-carbazole-3-carboxylate
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(7-(benzyloxy)-1H-indol-3-yl)acrylate 3s (153.5 mg, 0.5
mmol) in toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %),
Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a (1.0 mmol) were

12
Tetrahedron
ACCEPTED MANUSCRIPT
added. The resulting reaction mixture was heated at 100 °C
washed with aqueous saturated brine solution, dried over Na2SO4.
for 20 h. Progression of the reaction was monitored by TLC,
while noticing complete consumption of (E)-methyl 3-(7-
(benzyloxy)-1H-indol-3-yl)acrylate, reaction was brought to
room temperature. The additional amount of acrylate also added
if required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. Organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 95/05) to give the title compound 6h (129.9 mg,
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6j (107.6 mg, 73%) as a yellow needles,
mp: 231–233 oC; FTIR (Zn−Se ATR, cm−1 ) FTIR (Zn−Se ATR,
cm−1 ) 3378, 2913, 2825, 2230, 1719, 1664, 1469, 1368, 1253,
1
1190, 1031, 969, 845, 778; H NMR (400 MHz, DMSO–d6) δ
13.17 (1H, br s, NH), 9.37 (1H, s, CH), 9.25 (1H, s, CH), 8.38–
8.35 (2H, m, 2CH), 7.68 (1H, d, J = 9.2 Hz, CH), 3.91 (3H, s,
OCH3); 13C NMR (100 MHz, DMSO–d6) δ 165.2, 153.3, 144.3,
143.6, 132.2, 128.3, 123.9, 123.1, 123.0, 121.9, 118.8, 112.5,
94.4, 52.4 HRMS (ESI) [M+Na]+ Calcd for [C15H9N3O4Na]
318.0491, found 318.0485.
o
73%) as a brown needles, mp: 152–154 C; FTIR (Zn−Se ATR,
cm−1 ) FTIR (Zn−Se ATR, cm−1 ) 3228, 2938, 2845, 2268,
1717, 1634, 1456, 1356, 1146, 1057, 959, 845, 758; 1H NMR
(400 MHz, DMSO–d6) δ 12.74 (1H, br s, NH), 9.03–9.02 (1H, m,
CH), 8.33 (1H, t, J = 1.5 Hz, CH), 7.94–7.92 (1H, m,CH), 7.61
(2H, d, J = 7.6 Hz, 2CH), 7.41 (2H, t, J = 2.6 Hz, 2CH), 7.35–
7.31 (1H, m, CH), 7.22–7.21 (2H, m, 2CH), 5.36 (2H,m,CH2),
3.90 (3H, s, OCH3); 13C NMR (100 MHz, DMSO–d6) δ 165.5,
145.1, 141.6, 137.0, 131.5, 131.0, 128.4, 127.8, 126.8, 124.6,
123.6, 120.5, 116.5, 113.5, 110.0, 93.9, 69.6, 54.7. HRMS (ESI)
[M+H]+ Calcd for [C22H17N2O3] 357.1239, found 357.1240.
Methyl 6-chloro-1-cyano-9H-carbazole-3-carboxylate (6k).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-chloro-1H-indol-3-yl)acrylate 3v (117.5 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 21 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-chloro-1H-indol-3-yl)acrylate,
the reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6k (80.1 mg, 77%) as a off-white
Methyl 1,6-dicyano-9H-carbazole-3-carboxylate (6i).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-cyano-1H-indol-3-yl)acrylate 3t (113.0 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 24 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-cyano-1H-indol-3-yl)acrylate,
the reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 95/05) to
give the title compound 6i (98.9 mg, 72%) as a off-white needles,
o
needles, mp: 297–299 C; FTIR (Zn−Se ATR, cm−1 ) 3285,
2917, 2854, 2228, 1717, 1247, 1032, 765; 1H NMR (400 MHz,
DMSO–d6) δ 12.69 (1H, br s, NH), 9.03 (1H, d, J = 1.5 Hz, CH),
8.44 (1H, d, J = 1.5 Hz, CH), 8.30 (1H, d, J = 2.2 Hz, CH), 7.57–
7.49 (2H, m, 2CH), 3.89 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO–d6) δ 165.3, 142.6, 139.2, 131.3, 127.6, 127.4, 125.3,
123.3, 123.0, 121.1, 120.6, 116.3, 113.6, 93.4, 52.3. HRMS (ESI)
[M+H]+ Calcd for [C15H10ClN2O2] 285.0431, found 285.0425.
3-phenyl-9H-carbazole-1-carbonitrile (6l).
o
mp: 298–300 C; FTIR (Zn−Se ATR, cm−1 ) 3418, 2923, 2855,
In a oven-dried round bottom flask, a solution of (E)-3-styryl-
1H-indole 3w (109.5 mg, 0.5 mmol) in toluene; 2 mL),
Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-3-styryl-1H-indole, the reaction was brought
to room temperature. The additional amount of acrylate also
added if required for complete conversion. The reaction mixture
was diluted with ethyl acetate (10 mL) and water (15 mL) and
then filtered through a plug of celite. The layers were separated,
and the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 95/05) to give the title compound 6l (91.1 mg, 68%)
2250, 1709, 1644, 1462, 1366, 1254, 1186, 1027, 999, 825, 768;
1H NMR (400 MHz, DMSO–d6) δ 12.22 (1H, br s, NH), 9.15
(1H, d, J = 1.6 Hz, CH), 8.94 (1H, s, CH), 8.63 (1H, d, J = 16.0
Hz, CH), 7.87 (2H, s, 2CH), 4.01 (3H, s, OCH3); 13C NMR (100
MHz, DMSO–d6) δ 165.9, 147.1, 130.2, 129.4, 127.6, 126.5,
124.3, 124.2, 123.1, 120.9, 118.4, 115.5, 113.7, 112.4, 102.4,
52.4. HRMS (ESI) [M]+ Calcd for [C16H9N3O2] 275.0695, found
275.0689.
Methyl 1-Cyano-6-nitro-9H-carbazole-3-carboxylate (6j).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-nitro-1H-indol-3-yl)acrylate 3u (123.1 mg, 0.5 mmol) in
toluene; 2 mL), Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv) and
acrylonitrile 4a (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 24 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-nitro-1H-indol-3-yl)acrylate, the
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
o
as a brown, mp: 138–140 C; FTIR (Zn−Se ATR, cm−1 ) 3219,
2958, 2828, 2233, 1715, 1642, 1434, 1332, 1267, 1144, 1022,
945, 856, 754;1H NMR (400 MHz, DMSO–d6) δ 12.20 (1H, br s,
NH), 8.82 (1H, d, J = 1.5 Hz, CH), 8.30 (1H, d, J = 7.6 Hz, CH),
8.15 (1H, d, J = 2.3 Hz, CH), 7.82 (2H. d, J = 7.6 Hz, 2CH), 7.57
(1H, d, J = 7.6 Hz, CH), 7.49 (3H, t, J = 6.9 Hz, 3CH), 7.35 (1H,
t, J = 8.4 Hz, CH), 7.27 (1H, t, J = 7.6 Hz, CH); 13C NMR (100

13
MHz, DMSO–d6) δ 140.7, 139.6, 139.3, 131.4, 129.0, 128.1,
Dimethyl
dicarboxylate (7c).
6-methoxy-4-methyl-9H-carbazole-1,3-
ACCEPTED MANUSCRIPT
127.2, 126.8, 124.7, 123.8, 122.1, 121.1, 120.0, 117.4, 111.8,
93.4. HRMS (APCI) [M+H]+ Calcd for [C19H13N2] 269.1079,
found 269.1073.
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-methoxy-1H-indol-3-yl)but-2-enoate 3g (122.5 mg, 0.5
mmol) in toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %),
Cu(OAc)2 (2.0 equiv) and methyl acrylate 1e (1.0 mmol) were
added. The resulting reaction mixture was heated at 100 °C for
18 h. Progression of the reaction was monitored by TLC, while
noticing complete consumption of (E)-methyl 3-(5-methoxy-1H-
indol-3-yl)but-2-enoate, the reaction was brought to room
temperature. The additional amount of acrylate also added if
required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 90/10) to give the title compound 7c (125.9 mg,
77%) as a yellow needles, mp: 123–125 C; FTIR (Zn−Se ATR,
cm−1 ) 3402, 2954, 2853, 1698, 1594, 1309, 1200, 1098, 1026,
755; H NMR (400 MHz, DMSO–d6) δ 11.54 (1H, br s, NH),
8.45 (1H, s, CH), 7.69 (1H, d, J = 9.2 Hz, CH), 7.66 (1H, d, J =
1.1 Hz, CH), 7.24 (1H, t, J = 6.9 Hz, CH), 3.96 (3H, s, OCH3),
3.85 (6H, s, 2OCH3), 3.07 (3H, s, CH3); 13C NMR (100 MHz,
DMSO–d6) δ 167.2, 165.8, 153.9, 141.8, 140.3, 129.8, 128.1,
127.4, 125.7, 123.6, 122.7, 119.2, 114.9, 113.0, 106.1, 55.6, 52.0,
51.8, 17.8. HRMS (ESI) [M+H]+ Calcd for [C18H18NO5]
328.1185, found 328.1177.
General Procedure analytical data for the of C-H
activation:
Dimethyl 4-methyl-9H-carbazole-1,3-dicarboxylate (7a).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(1H-indol-3-yl)but-2-enoate 3f (107.5 mg, 0.5 mmol) in
toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and methyl acrylate 1e (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 18 h.
Progression of the reaction was monitored by TLC while noticing
complete consumption of (E)-methyl 3-(1H-indol-3-yl)but-2-
enoate, reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 3a (120.2 mg, 81%) as a pale yellow
o
1
o
needles, mp: 226–228 C; FTIR (Zn−Se ATR, cm−1 ) 3377,
2955, 2924, 2855, 1694, 1595, 1443, 1371, 1325, 1245, 1099,
1029, 825, 758; 1H NMR (400 MHz, DMSO–d6) δ 11.72 (1H, br
s, NH), 8.50 (1H, s, CH), 8.25 (1H, d, J = 8.4 Hz, CH), 7.81 (1H,
d, J = 8.4 Hz, CH), 7.49 (1H, t, J = 8.4 Hz, CH), 7.28 (1H, t, J =
7.6 Hz, CH), 3.97 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.11 (3H,
s, CH3); 13C NMR (100 MHz, DMSO–d6) δ 167.2, 165.8, 141.5,
139.9, 129.7, 128.1, 127.3, 126.3, 125.6, 122.7, 120.3, 119.8,
112.5, 108.9, 52.0, 51.9, 17.9. HRMS (ESI) [M+H]+ Calcd for
[C17H16NO4] 298.1079, found 298.1079.
1-Ethyl 3-methyl 6-methoxy-4-methyl-9H-carbazole-1,3-
dicarboxylate (7d).
In an oven-dried round bottom flask, a solution of (E)-methyl
3-(5-methoxy-1H-indol-3-yl)but-2-enoate 3g (122.5 mg, 0.5
mmol) in toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %),
Cu(OAc)2 (2.0 equiv) and ethyl acrylate 1f (1.0 mmol) were
added. The resulting reaction mixture was heated at 100 °C for
18 h. Progression of the reaction was monitored by TLC while
noticing complete consumption of (E)-methyl 3-(5-methoxy-1H-
indol-3-yl)but-2-enoate, the reaction was brought to room
temperature. The additional amount of acrylate also added if
required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 90/10) to give the title compound 7d (126.1 mg,
1-Ethyl 3-methyl 4-methyl-9H-carbazole-1,3-dicarboxylate
(7b).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(1H-indol-3-yl)but-2-enoate 3f (107.5 mg, 0.5 mmol) in
toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and ethyl acrylate 1f (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 18 h.
Progression of the reaction was monitored by TLC while noticing
complete consumption of (E)-methyl 3-(1H-indol-3-yl)but-2-
enoate, reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7b (122.8 mg, 79%) as a yellow needles,
o
74%) as a yellow needles, mp: 110–113 C; FTIR (Zn−Se ATR,
cm−1 ) 3301, 2988, 2939, 2831, 1684, 1597, 1515, 1485, 1437,
1330, 1284, 1218, 1039, 764; 1H NMR (400 MHz, DMSO–d6) δ
11.60 (1H, br s, NH), 8.48 (1H, s, CH), 7.72 (1H, d, J = 3.8 Hz,
CH), 7.24 (1H, d, J = 2.3 Hz, CH), 7.17 (1H, dd, J = 8.4 and 2.3
Hz, CH), 4.47 (2H, q, J = 6.9 Hz, OCH2), 3.88 (6H, s, 2OCH3)
3.12 (3H, s, CH3), 1.41 (3H, t, J = 6.9 Hz, CH3); 13C NMR (100
MHz, DMSO–d6) δ 167.3, 166.7, 156.1, 141.7, 140.4, 123.7,
122.7, 122.3, 115.0, 114.1, 113.2, 113.0, 102.4, 60.8, 55.6, 55.5,
17.9, 14.4. HRMS (ESI) [M+H]+ Calcd for [C19H20NO5]
342.1341, found 342.1332.
o
mp: 238–240 C; FTIR (Zn−Se ATR, cm−1 ) 3384, 2955, 2950,
1691, 1596, 1325, 1248, 1069, 761; 1H NMR (400 MHz,
DMSO–d6) δ 11.74 (1H, br s, NH), 8.49 (1H, s, CH), 8.24 (1H,
d, J = 7.6 Hz, CH), 7.82 (1H, d, J = 8.4 Hz, CH), 7.49 (1H, t, J =
7.6 Hz, CH), 7.28 (1H, t, J = 7.6 Hz, CH), 4.46 (2H, q, J = 7.6
Hz, OCH2), 3.86 (3H, s, OCH3), 3.10 (3H, s, CH3), 1.40 (3H, t, J
= 6.9 Hz, CH3); 13C NMR (100 MHz, DMSO–d6) δ 167.4, 165.5,
140.8, 140.1, 129.6, 128.2, 127.5, 126.4, 122.9, 122.3, 120.5,
120.0, 112.6, 109.2, 60.9, 52.0, 18.1, 14.4. HRMS (ESI) [M+H]+
Calcd for [C18H18NO4] 312.1236, found 312.1228.
Dimethyl 6-chloro-4-methyl-9H-carbazole-1,3-dicarboxylate
(7e).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-chloro-1H-indol-3-yl)but-2-enoate 3h (0.5 mmol) in toluene

14
Tetrahedron
ACCEPTED MANUSCRIPT
2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv) and
conversion. The reaction mixture was diluted with ethyl acetate
methyl acrylate 1e (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 22 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-chloro-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7e (120.8 mg, 73%) as a off-white
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7g (137.2 mg, 73%) as a pale yellow
o
needles, mp: 190–192 C; FTIR (Zn−Se ATR, cm−1 ) 3422,
2956, 2854, 2253, 1697, 1605, 1137, 1024, 760; H NMR (400
1
MHz, DMSO–d6) δ 11.90 (1H, br s, NH), 8.52 (1H, s, CH), 8.35
(1H, d, J = 1.3 Hz, CH), 7.76 (1H, d, J = 9.2 Hz, CH), 7.65–7.62
(1H, m, CH), 3.97 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.09 (3H,
s, CH3); 13C NMR (100 MHz, DMSO–d6) δ 167.1, 164.5, 147.3,
145.7, 140.1, 139.5, 133.4, 131.0, 130.3, 128.9, 124.9, 124.1,
114.4, 109.3, 52.8, 52.2, 17.9. HRMS (ESI) [M+H]+ Calcd for
[C17H15BrNO4] 376.0184, found 376.0184.
o
needles, mp: 282–284 C; FTIR (Zn−Se ATR, cm−1 ) 3412,
2923, 2854, 1710, 1639, 1217, 950, 838, 794, 756; 1H NMR
(400 MHz, DMSO–d6) δ 11.84 (1H, br s, NH), 8.30 (1H, s, CH),
8.23 (1H, s, CH), 8.19 (1H, d, J = 1.3 Hz, CH), 7.52 (1H, dd, J =
2.3 and 1.5 Hz, CH), 3.97 (3H, s, OCH3), 3.86 (3H, s, OCH3),
3.06 (3H, s, CH3); 13C NMR (100 MHz, DMSO–d6) δ 167.0,
165.7, 145.9, 136.9, 136.5, 135.4, 134.3, 128.4, 127.6, 126.9,
123.8, 121.1, 118.3, 102.3, 51.6, 51.1. HRMS (ESI) [M+H]+
Calcd for [C17H15ClNO4] 332.0690, found 332.0694.
1-Ethyl
dicarboxylate (7h)
3-methyl
6-bromo-4-methyl-9H-carbazole-1,3-
In a oven-dried round bottom flask, a solution of E)-methyl 3-
(5-bromo-1H-indol-3-yl)but-2-enoate 3i (146.5 mg, 0.5 mmol) in
toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and ethyl acrylate 1f (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 24 h.
Progression of the reaction was monitored by TLC while noticing
complete consumption of E)-methyl 3-(5-bromo-1H-indol-3-
yl)but-2-enoate, the reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7h (140.4 mg, 72%) as a pale yellow
1-Ethyl
dicarboxylate (7f).
3-methyl
6-chloro-4-methyl-9H-carbazole-1,3-
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-chloro-1H-indol-3-yl)but-2-enoate 3h (124.5 mg, 0.5 mmol)
in toluene 2 mL, Pd(OAc))2 (11.2 mg, 10 mol %), Cu(OAc)2 (2.0
equiv) and ethyl acrylate 1f (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 22 h.
Progression of the reaction was monitored by TLC while noticing
complete consumption of (E)-methyl 3-(5-chloro-1H-indol-3-
yl)but-2-enoate, the reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7f (122.4 mg, 71%) as a pale yellow
o
needles, mp: 167–169 C; FTIR (Zn−Se ATR, cm−1 ) 3240,
2955, 2853, 1718, 1683, 1493, 1453, 1216, 756; 1H NMR (400
MHz, DMSO–d6) δ 11.92 (1H, br s, NH), 8.61 (1H, s, CH), 8.50
(1H, s, CH), 7.77 (1H, d, J = 9.2 Hz, CH), 7.64 (1H, dd, J = 8.4
and 2.3 Hz, CH), 4.37 (2H, q, J = 7.6 Hz, OCH2), 3.87 (3H, s,
OCH3), 3.08 (3H, s, CH3), 1.39–1.34 (3H, m, CH3); 13C NMR
(100 MHz, DMSO–d6) δ 165.2, 164.1, 145.7, 139.6, 133.3,
130.1, 128.2, 127.4, 126.8, 124.9, 124.1, 122.8, 114.5, 109.4,
60.9, 52.0, 17.9, 14.4. HRMS (ESI) [M+H]+ Calcd for
[C18H17BrNO4] 390.0341, found 390.0344.
o
needles, mp: 273–275 C; FTIR (Zn−Se ATR, cm−1 ) 3367,
2956, 2870, 1688, 1508, 1305, 1246, 1025, 760; H NMR (400
1
MHz, DMSO–d6) δ 11.86 (1H, br s, NH), 8.47 (1H, s, CH), 8.18
(1H, d, J = 1.3 Hz, CH), 7.79 (1H, d, J = 9.2 Hz, CH), 7.51 (1H,
dd, J = 8.4 and 1.5 Hz, CH), 4.45 (2H, q, J = 6.9 Hz, CH2), 3.86
(3H, s, OCH3), 3.05 (3H, s, CH3), 1.39 (3H, t, J = 6.8 Hz, CH3);
13C NMR (100 MHz, DMSO–d6) δ 167.1, 165.2, 141.9, 139.2,
130.1, 128.2, 127.4, 125.7, 124.6, 122.8, 122.0, 120.2, 114.0,
109.4, 60.9, 52.0, 17.9, 14.3. HRMS (ESI) [M+H]+ Calcd for
[C18H17ClNO4] 346.0846, found 346.0841.
3-Ethyl 1-methyl 4-methyl-9H-carbazole-1,3-dicarboxylate
(7i)
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(1H-indol-3-yl)but-2-enoate 3a (114.5 mg, 0.5 mmol) in toluene
2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv) and methyl
acrylate 1e (1.0 mmol) were added. The resulting reaction
mixture was heated at 100 °C for 18 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-ethyl 3-(1H-indol-3-yl)but-2-enoate, the
reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
Dimethyl 6-bromo-4-methyl-9H-carbazole-1,3-dicarboxylate
(7g)
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(5-bromo-1H-indol-3-yl)but-2-enoate 3i (146.5 mg, 0.5 mmol)
in toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv)
and methyl acrylate 1e (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 24 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-methyl 3-(5-bromo-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete

15
give the title compound 7i (124.4 mg, 80%) as a yellow needles,
mp: 143–145 C; FTIR (Zn−Se ATR, cm−1 ) 3394, 2985, 2952,
Hz, CH2), 4.35 (2H, q, J = 7.6 Hz, OCH2), 3.05 (3H, s, CH3),
ACCEPTED MANUSCRIPT
1.40 (3H, t, J = 7.6 Hz, CH3), 1.36 (3H, t, J = 6.9 Hz, CH3); 13C
NMR (100 MHz, DMSO–d6) δ 166.7, 165.2, 141.7, 140.2, 139.5,
130.0, 128.8, 124.9, 124.0, 122.7, 120.7, 114.4, 112.5, 109.4,
60.9, 60.6, 17.9, 14.3, 14.2. HRMS (ESI) [M+H]+ Calcd for
[C19H19BrNO4] 404.0497, found 404.0492.
o
2839, 1700, 1596, 1485, 1309, 1223, 1167, 1037, 763; 1H NMR
(400 MHz, CDCl3) δ 10.15 (1H, br s, NH), 8.60 (1H, s, CH),
8.25–8.23 (1H, m, CH), 7.57–7.53 (1H, m, CH), 7.50–7.48 (1H,
m, CH), 7.33–7.29 (1H, m, CH), 4.42 (2H, q, J = 6.9 Hz, OCH2),
4.01 (3H, s, OCH3), 3.16 (3H, s, CH3), 1.45 (3H, t, J = 6.9 Hz,
CH3); 13C NMR (100 MHz, CDCl3) δ 167.8, 167.4, 142.5, 136.3,
130.2, 126.3, 124.6, 124.0, 123.1, 121.4, 121.3, 120.6, 116.3,
60.8, 52.0, 18.3, 14.4. HRMS (ESI) [M+H]+ Calcd for
[C18H18NO4] 312.1236, found 312.1232.
Ethyl 1-propionyl-9H-carbazole-3-carboxylate (8a).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(1H-indol-3-yl)acrylate 3m (107.5 mg, 0.5 mmol) in toluene 2
mL, Pd(OAc)2 (10 mol %), Cu(OAc)2 (2.0 equiv) and pent-1-en-
3-one 4b (1.0 mmol) were added. The resulting reaction mixture
was heated at 100 °C for 18 h. Progression of the reaction was
monitored by TLC while noticing complete consumption of (E)-
ethyl 3-(1H-indol-3-yl)acrylate, the reaction was brought to room
temperature. The additional amount of acrylate also added if
required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 90/10) to give the title compound 8a (118.0 mg,
3-Ethyl 1-methyl 6-methoxy-4-methyl-9H-carbazole-1,3-
dicarboxylate (7j)
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-methoxy-1H-indol-3-yl)but-2-enoate 3b (129.5 mg, 0.5 mmol)
in toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv)
and methyl acrylate 1e (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 18 h. Progression of
the reaction was monitored by TLC while noticing complete
consumption of (E)-ethyl 3-(5-methoxy-1H-indol-3-yl)but-2-
enoate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7j (131.2 mg, 77%) as a yellow needles,
o
80%) as a off-white needles, mp: 168–170 C ; FTIR (Zn−Se
ATR, cm−1 ) 3410, 2969, 1715, 1635, 1532, 1445, 1387, 1167,
1088, 1045, 1012, 933, 812, 758; 1H NMR (400 MHz, DMSO–
d6) δ 12.12 (1H, br s, NH), 9.00 (1H, s, CH), 8.64 (1H, d, J = 1.5
Hz, CH), 8.30 (1H, d, J = 8.4 Hz, CH), 7.78 (1H, d, J = 7.6 Hz,
CH), 7.47 (1H, t, J = 6.9 Hz, CH), 7.29–7.24 (1H, m, CH),
4.40(2H, q, J = 7.6 Hz, OCH2), 3.25 (2H, q, J = 6.9 Hz, CH2),
1.39 (6H, t, J = 6.9 Hz, 3CH3); 13C NMR (100 MHz, DMSO–d6)
δ 201.0, 165.9, 140.1, 128.2, 127.0, 126.6, 124.6, 121.5, 120.7,
120.5, 119.6, 118.7, 112.8, 60.7, 31.5, 14.4, 8.1. HRMS (ESI)
[M+H]+ Calcd for [C18H18NO3] 296.1287, found 296.1281.
o
mp: 151–153 C; FTIR (Zn−Se ATR, cm−1 ) 3246, 2984, 2830,
1
1674, 1592, 1478, 1284, 1134, 853, 786; H NMR (400 MHz,
CDCl3) δ 10.05 (1H, br s, NH), 8.62 (1H, s, CH), 7.77 (1H, d, J =
2.3 Hz, CH), 7.44 (1H, d, J = 8.7 Hz, CH), 7.15 (1H, dd, J = 9.2
and 2.7 Hz,CH), 4.42 (2H, q, J = 7.3 Hz, OCH2), 4.02 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 3.19 (3H, s, CH3), 1.45 (3H, t, J =
7.3 Hz, CH3); 13C NMR (100 MHz, , CDCl3) δ 167.8, 167.4,
154.4, 142.6, 141.8, 134.8, 130.4, 124.0, 123.9, 120.9, 114.6,
111.7, 108.6, 107.2, 60.9, 56.2, 52.0, 18.3, 14.4. HRMS (ESI)
[M+H]+ Calcd for [C19H20NO5] 342.1341, found 342.1336.
Methyl 1-propionyl-9H-carbazole-3-carboxylate (8b).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(1H-indol-3-yl)acrylate 3l (100.5 mg, 0.5 mmol) in toluene 2
mL, Pd(OAc)2 (10 mol %), Cu(OAc)2 (2.0 equiv) and pent-1-en-
3-one 4b (1.0 mmol) were added. The resulting reaction mixture
was heated at 100 °C for 18 h. Progression of the reaction was
monitored by TLC while noticing complete consumption of (E)-
methyl 3-(1H-indol-3-yl)acrylate, the reaction was brought to
room temperature. The additional amount of acrylate also added
if required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. The organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 90/10) to give the title compound 8b (109.5 mg,
78%) as a off-white needles, mp: 196–198 C; FTIR (Zn−Se
ATR, cm−1 ) 3390, 2985, 1715, 1650, 1544, 1444, 1367, 1185,
1090, 1045, 1012, 956, 812, 758; H NMR (400 MHz, CDCl3) δ
10.79 (1H, br s, NH), 8.95 (1H, s, CH), 8.72 (1H, d, J = 1.5 Hz,
CH), 8.13 (1H, d, J = 7.6 Hz, CH), 7.54–7.48 (2H, m, 2CH),
7.35–7.29 (1H, m, CH), 4.01 (3H, s, OCH3), 3.24 (2H, q, J = 7.6
Hz, CH2), 1.34–1.30 (3H, m, CH3); 13C NMR (100 MHz, CDCl3)
δ 202.8, 167.2, 140.4, 128.7, 127.2, 127.18, 125.0, 122.2, 121.0,
120.6, 120.2, 118.2, 111.6, 52.2, 31.7, 8.3. HRMS (ESI) [M+H]+
Calcd for [C17H16NO3] 282.1130, found 282.1125.
Diethyl
(7k).
6-bromo-4-methyl-9H-carbazole-1,3-dicarboxylate
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-bromo-1H-indol-3-yl)but-2-enoate 3d (153.5 mg, 0.5 mmol)
in toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv)
and ethyl acrylate 1e (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 24 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-ethyl 3-(5-bromo-1H-indol-3-yl)but-2-
enoate, reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 7k (141.4 mg, 70%) as a yellow needles,
o
1
o
mp: 258–260 C; FTIR (Zn−Se ATR, cm−1 ) 3420, 2979, 1709,
1640, 1540, 1463, 1381, 1178, 1094, 1039, 1002, 955, 834, 768;
1H NMR (400 MHz, DMSO–d6) δ 11.84 (1H, br s,NH), 8.46 (1H,
s, CH) 8.31 (1H, d, J = 2.3 Hz, CH), 7.75 (1H, d, J = 8.4 Hz,
CH), 7.61 (1H, dd, J = 8.4 and 1.5 Hz, CH), 4.46 (2H, q, J = 6.9
Ethyl
6-methoxy-4-methyl-1-propionyl-9H-carbazole-3-
carboxylate (8c).

16
Tetrahedron
ACCEPTED MANUSCRIPT
In a oven-dried round bottom flask, a solution of (E)-ethyl
Progression of the reaction was monitored by TLC while noticing
3-(5-methoxy-1H-indol-3-yl)but-2-enoate 3b (129.5 mg, 0.5
mmol) in toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0
equiv) and pent-1-en-3-one 4b (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 16 h.
Progression of the reaction was monitored by TLC, while
noticing complete consumption of (E)-ethyl 3-(5-methoxy-1H-
indol-3-yl)but-2-enoate, reaction was brought to room
temperature. The additional amount of acrylate also added if
required for complete conversion. The reaction mixture was
diluted with ethyl acetate (10 mL) and water (15 mL) and then
filtered through a plug of celite. The layers were separated, and
the organic layer was washed with aqueous saturated brine
solution, dried over Na2SO4. Organic layer was concentrated
under reduced pressure. The crude material so obtained was
purified by column chromatography on silica gel (hexane:
ethylacetate; 90/10) to give the title compound 8c (132.2 mg,
complete consumption of (E)-methyl 3-(7-(benzyloxy)-1H-indol-
3-yl)acrylate, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 8e (139.3 mg, 72%) as a pale brown
o
needles, mp: 155–157 C; FTIR (Zn−Se ATR, cm−1 ) 3442,
2924, 2855, 1710, 1461, 1323, 1249, 1121, 992, 762; 1H NMR
(400 MHz, CDCl3) δ 10.79 (1H, br s, NH), 8.91 (1H, s, CH), 8.69
(1H, s, CH), 7.70 (1H, d, J = 7.6 Hz, CH), 7.48 (2H, d, J = 7.6
Hz, 2CH), 7.42–7.38 (2H, m, 2CH), 7.36–7.32 (1H, m, CH), 7.19
(1H, t, J = 7.6 Hz, CH), 7.00 (1H, d, J = 7.6 Hz CH,), 5.26 (2H,
s, OCH2), 3.98 (3H, s, OCH3), 3.21 (2H, q, J = 7.6 Hz, CH2),
1.31–1.27 (3H, m, CH3); 13C NMR (100 MHz, CDCl3) δ 202.5,
167.1, 145.2, 140.9, 136.5, 131.0, 128.7, 128.6, 113.1, 108.7,
70.5, 52.2, 31.6, 8.2. HRMS (ESI) [M+H]+ Calcd for
[C24H22NO4] 388.1549, found 388.1543.
o
78%) as a yellow needles, mp: 168–170 C; FTIR (Zn−Se ATR,
cm−1 ) 3412, 2915, 2865, 1712, 1613, 1416, 1290, 1232, 1099,
750, 660; 1H NMR (400 MHz, DMSO–d6) δ 11.92 (br s, 1H), 8.
47 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H),
7.13 (dd, J = 9.2 and 2.3 Hz, 1H), 4.34 (q, J = 6.9 Hz, 2H), 3.85
(s, 3H), 3.33 (s, 3H), 3.16 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz,
3H), 1.19–1.15 (m, 3H); 13C NMR (100 MHz, DMSO–d6) δ
200.6, 167.1, 153.9, 141.5, 139.4, 135.6, 129.6, 123.6, 122.4,
119.6, 116.2, 114.8, 113.3, 105.9, 60.5, 55.6, 30.8, 18.0, 14.2,
8.2. HRMS (ESI) [M+H]+ Calcd for [C20H22NO4] 340.1549,
found 340.1543.
1-(3-Phenyl-9H-carbazol-1-yl)propan-1-one (8f).
In a oven-dried round bottom flask, a solution of (E)-3-styryl-
1H-indole 3w (109.5 mg, 0.5 mmol) in toluene 2 mL, Pd(OAc)2
(10 mol %), Cu(OAc)2 (2.0 equiv) and pent-1-en-3-one 4b (1.0
mmol) were added. The resulting reaction mixture was heated at
100 °C for 24 h. Progression of the reaction was monitored by
TLC while noticing complete consumption of (E)-3-styryl-1H-
indole, the reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 8f (104.6 mg, 70%) as a yellow needles,
Ethyl
6-chloro-4-methyl-1-propionyl-9H-carbazole-3-
carboxylate (8d).
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-
(5-chloro-1H-indol-3-yl)but-2-enoate 3c (131.5 mg, 0.5 mmol) in
toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0 equiv) and
pent-1-en-3-one 4b (1.0 mmol) were added. The resulting
reaction mixture was heated at 100 °C for 24 h. Progression of
the reaction was monitored by TLC, while noticing complete
consumption of (E)-ethyl 3-(5-chloro-1H-indol-3-yl)but-2-
enoate, reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 8d (130.4 mg, 76%) as a pale yellow
o
mp: 145–147 C; FTIR (Zn−Se ATR, cm−1 ) 3431, 2926, 2856,
1710, 1658, 1481, 1206, 1023, 759 1H NMR (400 MHz, CDCl3)
δ 10.58 (1H, br s, NH), 8.48 (1H, s, CH), 8.21 (1H, s, CH), 8.13
(1H, d, J = 7.6 Hz, CH), 7.71 (2H, d, J = 7.6 Hz, CH), 7.54–7.46
(4H, m, 4CH), 7.40–7.37 (1H, m, CH), 7.29 (1H, t, J = 7.6 Hz,
CH), 3.24 (2H, q, J = 6.1 Hz, CH2), 1.36–1.32 (3H, m, CH3); 13
C
NMR (100 MHz, DMSO–d6) δ 201.7, 141.0, 140.5, 137.3, 130.5,
130.0, 129.0, 127.0, 126.8, 126.4, 126.1, 125.2, 123.9, 121.6,
120.5, 119.6, 119.4, 112.5, 31.2, 8.3. HRMS (ESI) [M+H]+ Calcd
for [C21H18NO] 300.1388, found 300.1385.
o
needles, mp: 194–196 C; FTIR (Zn−Se ATR, cm−1 ) 3420,
2925, 2855, 1702, 1691, 1452, 1289, 1212, 1092, 759, 668; 1H
NMR (400 MHz, CDCl3) δ 10.88 (1H, br s, NH), 8.58 (1H, s,
CH), 8.20 (1H, s, CH), 7.45 (2H, d, J = 1.4 Hz, 2CH), 4.45 (2H,
q, J = 7.3 Hz, OCH2), 3.22–3.18 (2H, m, CH2), 3.16 (3H, s, CH3),
1.47 (3H, t, J = 6.4 Hz, CH3), 1.31 (3H, t, J = 7.3 Hz, CH3); 13C
NMR (100 MHz, CDCl3) δ 202.4, 167.7, 143.2, 140.9, 138.5,
130.6, 126.4, 126.2, 124.0, 123.6, 122.8, 121.4, 116.5, 112.4,
61.1, 31.5, 18.5, 14.5, 8.3 HRMS (APCI) [M+H]+ Calcd for
[C19H19ClNO3] 344.1053, found 344.1048.
General Procedure and analytical data for the one pot
carbazoles synthesis:
9H-Carbazole-1,3-dicarbonitrile (9a).
In a oven-dried round bottom flask, a solution of 1H-indole 2a
(58.5 mg, 0.5 mmol) in DMF/DMSO (5:1; 2 mL), Pd(OAc)2 (15
mol %), Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a (2.0 mmol)
were added. The resulting reaction mixture was heated at 70 °C
for 24 h. Progression of the reaction was monitored by TLC
while noticing complete consumption of indole, the reaction was
brought to room temperature. The additional amount of acrylate
also added if required for complete conversion. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15
mL) and then filtered through a plug of celite. The layers were
Methyl
8-(benzyloxy)-1-propionyl-9H-carbazole-3-
carboxylate (8e).
In a oven-dried round bottom flask, a solution of (E)-methyl
3-(7-(benzyloxy)-1H-indol-3-yl)acrylate 3s (153.5 mg, 0.5
mmol) in toluene 2 mL, Pd(OAc))2 (10 mol %), Cu(OAc)2 (2.0
equiv) and pent-1-en-3-one 4b (1.0 mmol) were added. The
resulting reaction mixture was heated at 100 °C for 24 h.

17
separated, and the organic layer was washed with aqueous
HRMS (ESI) [M+H]+ Calcd for [C15H10N3] 232.0875, found
232.0875.
ACCEPTED MANUSCRIPT
saturated brine solution, dried over Na2SO4. The organic layer
was concentrated under reduced pressure. The crude material so
obtained was purified by column chromatography on silica gel
(hexane: ethylacetate, 90/10) to give the title compound 9a (65.1
Dimethyl 6-chloro-9H-carbazole-1,3-dicarboxylate (9d).
In a oven-dried round bottom flask, a solution of 5-chloro-1H-
indole 2c (75.5 mg, 0.5 mmol) in DMF/DMSO (5:1; 2 mL),
Pd(OAc)2 (15 mol %), Cu(OAc)2 (2.0 equiv) and methyl acrylate
1e (2.0 mmol) were added. The resulting reaction mixture was
heated at 70 °C for 24 h. Progression of the reaction was
monitored by TLC while noticing complete consumption of 5-
chloro-1H-indole, reaction was brought to room temperature. The
additional amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate ; 90/10) to
give the title compound 9d (103.0 mg, 65%) as a yellow needles,
o
mg, 60%) as a off-white needles, mp: 119–121 C (65.1 mg,
60%); FTIR (Zn−Se ATR, cm−1) 3281, 2921, 2853, 2238, 2231,
1570, 1460, 1283, 1242; 1H NMR (400 MHz, DMSO–d6) δ
12.97 (1H, br s, NH), 9.02 (1H, s, CH), 8.40 (1H, d, J = 1.5 Hz,
CH), 8.29 (1H, d, J = 7.6 Hz, CH), 7.67–7.62 (1H, m, CH), 7.57
(1H, t, J = 7.6 Hz, CH), 7.38–7.33 (1H, m, CH); 13C NMR (100
MHz, DMSO–d6) δ 141.0, 129.8, 128.3, 124.3, 122.6, 121.4,
121.2, 120.6, 118.3, 115.8, 112.3, 100.9, 94.2, 87.1. HRMS (ESI)
[M+H]+ Calcd for [C14H8N3] 218.0718, found 218.0720.
6-Methyl-9H-carbazole-1,3-dicarbonitrile (9b).
In a oven-dried round bottom flask, a solution of 5-methyl-
1H-indole 2f (65.5 mg, 0.5 mmol) in DMF/DMSO (5:1; 2 mL),
Pd(OAc)2 (15 mol %), Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a
(2.0 mmol) were added. The resulting reaction mixture was
heated at 70 °C for 24 h. Progression of the reaction was
monitored by TLC while noticing complete consumption of 5-
methyl-1H-indole, the reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 9b (66.9 mg, 58%) as a yellow needles,
o
mp: 240–242 C; FTIR (Zn−Se ATR, cm−1 ) 3381, 2922, 2856,
1713, 1572, 1461, 1282, 1242, 773; 1H NMR (400 MHz, CDCl3)
δ 10.11 (1H, br s, NH), 8.87 (1H, d, J = 1.4 Hz, CH), 8.76 (1H, d,
J = 1.8 Hz, CH), 8.07 (1H, s, CH), 7.45 (2H, d, J = 1.4 Hz, 2CH),
4.04 (3H, s, OCH3), 3.99 (3H, s, OCH3); 13C NMR (100 MHz, ,
CDCl3) δ 167.1, 166.8, 142.7, 138.4, 129.6, 127.4, 127.17, 126.5,
123.8, 123.7, 121.1, 120.5, 112.4, 111.6, 52.3, 52.2. HRMS (ESI)
[M+H]+ Calcd for [C16H13ClNO4] 318.0533, found 318.0528.
Ethyl
1-cyano-9-(2-cyanoethyl)-6-methoxy-4-methyl-9H-
carbazole-3-carboxylate (10a)
In a oven-dried round bottom flask, a solution of (E)-ethyl 3-(5-
methoxy-1H-indol-3-yl)but-2-enoate 3b (129.5 mg, 0.5 mmol) in
DMF/DMSO (5:1; 2 mL), Pd(OAc)2 (15 mol %), Cu(OAc)2 (2.0
equiv) and acrylonitrile 4a (2.0 mmol) were added. The resulting
reaction mixture was heated at 70 °C for 24 h. Progression of the
reaction was monitored by TLC while noticing complete
consumption of (E)-ethyl 3-(5-methoxy-1H-indol-3-yl)but-2-
enoate, reaction was brought to room temperature. The additional
amount of acrylate also added if required for complete
conversion. The reaction mixture was diluted with ethyl acetate
(10 mL) and water (15 mL) and then filtered through a plug of
celite. The layers were separated, and the organic layer was
washed with aqueous saturated brine solution, dried over Na2SO4.
The organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 10a (131.7 mg, 73%) as a pale yellow
o
mp: 215–217 C (66.9 mg, 58%); FTIR (Zn−Se ATR, cm−1 )
1
3271, 2901, 2833, 2232, 2214, 1560, 1434, 1242; H NMR (400
MHz, DMSO-d6) δ 12.65 (1H, br s, NH), 8.92 (1H, s, CH), 8.34
(1H, s, CH), 8.07 (1H, s, CH), 7.51 (1H, d, J = 8.4Hz, CH), 7.39
(1H, d, J = 8.4 Hz, CH), 2.47 (3H, s, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 141.7, 139.0, 133.0, 130.3, 129.6, 129.5, 124.1,
121.4, 121.0, 118.9, 115.8, 112.0, 100.7, 94.1, 21.1 HRMS (ESI)
[M+Na]+ Calcd for [C15H9N3Na] 254.0694, found 254.0689.
8-Methyl-9H-carbazole-1,3-dicarbonitrile (9c).
In a oven-dried round bottom flask, a solution of 7-methyl-1H-
indole 2g (65.5 mg, 0.5 mmol) in DMF/DMSO (5:1; 2 mL),
Pd(OAc)2 (15 mol %), Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a
(2.0 mmol) were added. The resulting reaction mixture was
heated at 70 °C for 24 h. Progression of the reaction was
monitored by TLC, while noticing complete consumption of 7-
methyl-1H-indole, reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 9c (63.5 mg, 55%) as a brown needles,
o
needles, mp: 183–185 C; FTIR (Zn−Se ATR, cm−1 ) 2924,
2850, 2232, 2228, 1465, 1268, 1226, 751; 1H NMR (400 MHz,
CDCl3) δ 8.31(1H, d, J = 2.3 Hz, CH), 7.75 (1H, d, J = 2.3 Hz,
CH), 7.51–7.49 (1H, m, CH), 7.28–7.23 (1H, m, CH), 4.99 (2H
,q, J = 6.1 Hz, OCH3), 4.44–4.39 (2H, m, NCH2), 3.94 (3H, s,
OCH3), 3.15 (3H, s, CH3), 3.03–2.99 (2H, m, CH2), 1.47–1.43
(3H, m, CH3); 13C NMR (100 MHz, CDCl3) δ 166.4, 155.3,
142.9, 139.6, 135.3, 134.5, 124.5, 123.7, 122.4, 117.9, 116.8,
115.3, 109.6, 107.8, 89.8, 61.3, 56.1, 39.3, 18.8, 18.2, 14.3.
HRMS (ESI) [M+H]+ Calcd for [C21H20N3O3] 362.1505, found
362.1499.
o
mp: 221–223 C (63.5 mg, 55%); FTIR (Zn−Se ATR, cm−1 )
3271, 2924, 2843, 2228, 2212, 1460, 1283, 1232, 778; 1H NMR
(400 MHz, DMSO–d6) δ 12.57 (1H, br s, NH), 8.99 (1H, s, CH),
8.37 (1H, s, CH), 8.15–8.10 (1H, m, CH), 7.36 (1H, d, J = 7.6
Hz, CH), 7.24 (1H, d J = 7.6 Hz, CH), 2.61 (3H, s, CH3); 13C
NMR (100 MHz, DMSO–d6) δ 141.4, 133.6, 129.6, 129.0, 126.4,
124.9, 123.2, 122.5, 121.4, 121.2, 120.7, 118.6, 101.0, 94.4, 17.3.
9-(2-Cyanoetshyl)-6-nitro-9H-carbazole-1,3-dicarbonitrile
(10b). In a oven-dried round bottom flask, a solution of 5-nitro-
1H-indole 2h (131.0 mg, 0.5 mmol) in DMF/DMSO (5:1; 2 mL),
Pd(OAc)2 (15 mol %), Cu(OAc)2 (2.0 equiv) and acrylonitrile 4a
(2.0 mmol) were added. The resulting reaction mixture was
heated at 70 °C for 24 h. Progression of the reaction was

18
Tetrahedron
ACCEPTED MANUSCRIPT
monitored by TLC while noticing complete consumption of 5-
(6) (a) García-Rubia, A.; Laga, E.; Cativiela, C.; Urriolabeitia, E. P.;
nitro-1H-indole, the reaction was brought to room temperature.
The additional amount of acrylate also added if required for
complete conversion. The reaction mixture was diluted with ethyl
acetate (10 mL) and water (15 mL) and then filtered through a
plug of celite. The layers were separated, and the organic layer
was washed with aqueous saturated brine solution, dried over
Na2SO4. The organic layer was concentrated under reduced
pressure. The crude material so obtained was purified by column
chromatography on silica gel (hexane: ethylacetate; 90/10) to
give the title compound 10b (70.8 mg, 45%) as a brown crystal,
mp 106−108 °C; (70.8 mg, 45%), FTIR (Zn−Se ATR, cm−1 )
2914, 2847, 2223, 2223, 1456, 1245, 1223, 764; 1H NMR (400
MHz, CDCl3) δ 8.60 (1H, s, CH), 8.16 (1H, d, J = 9.2 Hz, CH),
7.38−7.33(2H, m, CH), 6.76 (1H, s, CH), 4.53−4.50 (2H, m,
NCH2), 2.90−2.87 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) δ
142.1, 138.2, 130.6, 130.4, 128.2, 118.6, 118.5, 117.9, 117.8,
116.7, 108.7, 108.6, 105.5, 105.4, 42.4, 19.3; HRMS (ESI) Calcd
for [C17H9N5O2] requires [M]+ 315.0756 found 315.0787.
Gómez-Arrayás, R.; Carretero, J. C. J. Org. Chem.
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The work was supported by SERB. R.K.S., K.M.S. and M.P. are
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ACCEPTED MANUSCRIPT
Highlights
1. A regioselective synthesis of highly functionalized carbazoles by using Pd(II)-Cu bimetallic
system. The sterically hindered substrate bearing electron-rich and electron-deficient
styrylindoles with alkenes, were examined for the synthesises of the tri- and di-substituted
carbazoles.
2. The results of the designed protocol suggested that the C-H activation is preferred over [4+2]
cycloaddition.
3. The designed one-pot strategy was also successful in providing the tricyclic N-heterocycle.
4. N-Protected carbazoles were prepared by double and triple C-H activation followed by
concomitant Michael addition.
5. The C-H activation strategy for the synthesis of carbazole has been well supported by the
proposed mechanistic pathway via di-Heck intermediate.