Synthesis of fused 1-aminoindole polycycles by a sequence of palladium-catalyzed N-H and C(sp2)-H arylations

Article abstract of DOI:10.1021/jo502137y

An efficient Pd-catalyzed selective intramolecular arylation of functionalized N,N'-substituted 1-aminoindoles has been reported. In all cases, the reactions take place rapidly in DMA and efficiently proceed in the presence of a Pd(OAc)₂/Dpepho

Full text of DOI:10.1021/jo502137y

Subscriber access provided by The University of Montana
Article
Synthesis of Fused 1-aminoindole Polycycles by a Sequence
of Palladium-Catalyzed N-H and C(sp2)-H Arylations
Thi Thanh Huyen Luong, Jean-Daniel Brion, Mouad Alami, and Samir Messaoudi
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Dec 2014
Downloaded from http://pubs.acs.org on December 14, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Fused 1ꢀaminoindole Polycycles by a
Sequence of PalladiumꢀCatalyzed NꢀH and C(sp2)ꢀ
H Arylations
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Thi Thanh Huyen Luong, JeanꢀDaniel Brion, Mouad Alami* and Samir Messaoudi*
1
Univ. ParisꢀSud, CNRS, BioCISꢀUMR 8076, Laboratoire de Chimie Thérapeutique, Equipe
Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 rue J.ꢀB. Clément,
ChâtenayꢀMalabry, Fꢀ92296, France.
samir.messaoudi@uꢀpsud.fr, mouad.alami@uꢀpsud.fr
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
An efficient Pdꢀcatalyzed selective intramolecular arylation of functionalized N,N’ꢀsubstitutedꢀ
1ꢀaminoindoles has been reported. In all cases, the reactions take place rapidly in DMA and
efficiently proceed in the presence of a Pd(OAc)2/Dpephos catalytic system furnishing the fused
indolo[2,1ꢀa]phtalazines in high yields. Additionally, the oneꢀpot double CꢀH arylation at Cꢀ2
and Cꢀ3 positions of N,N’ꢀsubstitutedꢀ1ꢀaminoindoles is effective and lead to unknown
complexes scaffolds of biological interests.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
KEYWORDS. CꢀH arylation, 1ꢀaminindoles, palladium catalysis, indolo[2,1ꢀa]phtalazines.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1. Introduction
1
2
3
4
5
6
7
8
9
The transition metalꢀcatalyzed functionalization of C−H bonds has attracted considerable
attention as a useful alternative to traditional methods in carbonꢀcarbon bond formation.1 This
approach avoids the need of stoichiometric amounts of the organometallic reagent, some of
which are toxic or must be prepared through multistep procedures. Particularly, the
intramolecular version of this approach was used as a powerful tool for the synthesis of fused
heterocycles such as fused indole frameworks which is present in a plethora of biologically
active compounds and are probably the most important nitrogenꢀcontaining heterocyclic of all
structural classes in drug discovery.2 Although, direct C−H arylation of indoles at Cꢀ23 and Cꢀ34
positions has been extensively studied, to the best of our knowledge, there is no previously
reported study involving 1ꢀaminoindoles in direct C−H arylation approach to fused 1ꢀ
aminoindole heterocycles synthesis.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As part of our effort on the development of efficient methods to functionalize heterocycles via
transitionꢀmetal catalysis for generating an original collection of nitrogenꢀcontaining molecules,6
we envisioned that NꢀarylꢀN’ꢀbenzyl 1ꢀaminoindoles of type 2 could be utilized as partners in
intramolecular direct Cꢀ2 arylation approach to fused indolo[2,1ꢀa]phthalazines synthesis
(Scheme 1). This modular strategy is conceptually attractive in terms of diversifying the 1ꢀ
aminoindole frameworks in the aim to identify news scaffolds of biological interest. However, a
number of potential limitations exist: first, the metalꢀmediated N−N bond cleavage7 of the Nꢀ
arylꢀN’ꢀbenzylꢀ1ꢀaminoindoles thus resulting in the formation of undesired indole byꢀproducts.
Secondly, and most importantly, the limitation arise when more than one activated hydrogen is
available (Scheme 1), which can lead to a mixture of byꢀproducts. Therefore, the development of
a selective and general method for the direct arylation of NꢀarylꢀN’ꢀbenzyl 1ꢀaminoindoles is
strongly desirable and presents an interesting challenge. Herein, we report our success on the
development of such protocol.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
SCHEME 1. Potentials Reactive Sites in Direct Arylation of N-aryl-N’-benzyl 1-
Aminoindoles 2
Page 4 of 34
1
2
3
4
5
6
7
8
9
Intramolecular
C-2 arylation
of indole
H
Intermolecular
C-3 arylation
of indole
R2
R1
R2
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
Pd/L. cat.
N
N
R3
N
R2
Br
N-N bond sensitive
Site selective
C-H arylation
H
Intramolecular C-arylation
of N-aryle
2
N-aryl-N'-benzyl-1-aminoindoles
2. Results and Discussion
To achieve successfully our goal, we initially prepared selectively a series of Nꢀmonoarylatedꢀ1ꢀ
aminoindoles 1a-k in good to excellent yields (57ꢀ98%), by coupling of various substituted 1ꢀ
aminindoles with aryl chlorides under our previously reported protocol (Pd2dba3 (2.5 mol%),
Xphos (5 mol%), tꢀBuOK (1.5 equiv), LiCl (2 equiv), toluene, 130°C)8 (Table 1). Following the
selective preparation of Nꢀarylꢀ1ꢀaminoindoles 1a-k, we expected that the remaining N−H bond
can undergo further Nꢀbenzylation with various 1ꢀbromoꢀ2ꢀ(bromomethyl)benzene to lead to
disubstituted 1ꢀaminoindoles 2a-p. To this end, various reactions conditions (base, solvent,
temperature) were screened and the best conditions were found to require Nꢀarylatedꢀ1ꢀ
aminoindoles 1a-k (1 equiv), substituted benzyl bromide derivatives (1.2 equiv), KOH (2 equiv)
in DMSO as the solvent at room temperature for 1ꢀ2 h. In line with these data, compounds 2a-p
bearing various electroꢀwithdrawing or withꢀdonating groups on the indole, the aryl as well as
the benzyl moieties were isolated in excellent yields (89ꢀ99%, Table 1).
4
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
TABLE 1. Synthesis of N,N’-Substituted-1-Aminoindoles 2a-p.
1
2
3
4
5
6
7
8
9
Pd2dba3 (2.5 mol%)
Xphos (5 mol%)
t-BuOK (1.5 equiv)
LiCl (2 equiv)
Toluene, 130 °C, 1-4 h
KOH (2 equiv),
DMSO,
R.T. 1-2 h
R1
R1
R2
R1
R2
H
N
N
N
N
R3
NH2
NH
Br
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
R2
Br
R3
(1.2 equiv)
1a-k
2a-p
(1.2 equiv)
H
H
H
N
N
N
N
N
N
R3
Br
Br
Br
R2
2a
R2
a
2
a
2
3
a
2e
, 92%
2c
2d
, R = OMe, 94%
, R = Me, R = H, 92%
2
a
2
3
a
2b
, R = Cl, 91%
, R = R = OMe, 94%
MeO
Cl
H
N
H
H
N
N
N
N
N
Br
R2
Br
Br
MeO
a
a
2j
2
a
, 80%
2i
, 79%
2f
, R = OMe, 98%
2g, R2 = Me, 99%a
2
a
2h
, R = Cl, 90%
F
O
OMe
O
H
H
H
N
O
O
N
N
N
N
N
Br
Br
R2
MeO
Br
Me
a
2
a
a
2n
, 92%
2l
, R = OMe, 99%
2k
, 89%
2
a
2m
, R = Cl, 91%
H
H
Br
N
N
N
N
S
a
2o
(Z)- , 56% (Z-isomer)
Br
a
a
MeO
2o,
(E)-
MeO
27% (E-isomer)
2p
, 89%
a Yield of isolated products 2a-p related to the Nꢀbenzylation reaction step.
Next, we continued our study by exploration of the second key step concerning the
intramolecular C(sp2)ꢀH arylation. To determinate the feasibility of the Cꢀ2 direct arylation of
the intermediates 2a-p, we examined at first, the arylation of 2a as a model study under various
palladium sources, ligands, bases and solvents. Representative results from this study are
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
summarized in Table 2. The reaction of 2a was first investigated under initially reported
conditions5,9 [Pd(OAc)2, PPh3, K2CO3, TBAB (tetrabutylamonium bromide), DMF at 130 °C].
However, this transformation was inefficient and resulted in the formation of the expected
product 3a in only 30% yield (entry 1). A brief survey of other bases was undertaken and
revealed that Cs2CO3 is the most effective with a significant improvement in the performance of
the arylation reaction (65% yield, entry 2). However, using terbutoxide bases such as tꢀBuOLi
and tꢀBuOK failed (entries 4 and 5). The screening reaction was continued with respect to the
solvent. The use of hight polar solvents (DMF or DMA, entries 2 and 5) was found to be the
best choice since reactions with etheral solvents (dioxane and CPME) or nonpolar solvent
(toluene) were much slower (entries 6ꢀ8). DMA was chosen to evaluate the effect of other
parameters reaction, including catalysts, ligands and temperature. The catalytic activity of
Pd(acac)2 proved to be similar to Pd(OAc)2 leading to 3a in a similar yield (64 %, entry 10). The
use of other palladium sources, however, did not promote the C−H arylation reaction or induced
a lowering of the conversion rate (entries 9ꢀ11). With Pd(OAc)2 as the catalyst, the screening
reactions with respect to the ligand (entries 12ꢀ18) revealed that the bidentate phosphine
Dpephos is superior to all other choice, providing 3a in a 80% yield (entry 17). In summary, the
best conditions were found to require Pd(OAc)2 (5 mol %), Dpephos (10 mol %), TBAB (1
equiv), Cs2CO3 (2 equiv) in DMA at 130 °C for 3 h.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Motivated by these results, we next explored the scope of the coupling reaction with previously
synthesized N,N’ꢀsubstitutedꢀ1ꢀaminoindoles 2a-p. Gratifyingly, tetracycles 3 bearing a wide
variety of functional groups could be synthesized in good to excellent yields without any side
product (Table 3). Electronꢀdonating and electroꢀwithdrawing functions on the indole, on the
aryl as well as on the benzyl moieties of 2a-p were well tolerated. It was found that the chloroꢀ
substituted compounds 3b, 3h and 3k survived under the reaction conditions and the presence of
C−Cl bond provided a handle for further diversifications under transition metalꢀcatalysis. It is
noteworthy that the alkenylation reaction of less rigid derivative (Z)ꢀ2o bearing a Zꢀ
6
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
vinylbromide, succeeded and leads to the formation of the tricyclic 3o in a 68% yield, however
all attempts to react its Eꢀisomer (E)ꢀ2o under our optimized conditions have failed.
TABLE 2 Optimization of the Pd-Catalyzed Intramolecular C2-arylation of 2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
solvent
Conv Yield
Entry [Pd]
ligand
base
(%)b
100
100
0
(%)c
30
65
ꢀ
1
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K2CO3
DMF
DMF
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OH)2/
Pd(acac)2
Cs2CO3
3
tꢀBuOLi DMF
tꢀBuOK DMF
4
0
ꢀ
5
Cs2CO3
Cs2CO3
DMA
PhMe
CPME
100
40
65
ꢀ
6
7
Cs2CO3
36
ꢀ
8
Cs2CO3
Dioxane 44
ꢀ
9
Cs2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
10
ꢀ
10
11
12
13
14
15
16
17
18
Cs2CO3
100
63
64
ꢀ
PdCl(C3H5(dppb) PPh3
Cs2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(oꢀtolyl)3
Cs2CO3
100
100
100
100
100
100
100
68
67
66
68
62
80d,e
26
P(cꢀhexyl)3 Cs2CO3
Xantphos
Xphos
Cs2CO3
Cs2CO3
Cs2CO3
Davephos
Dpephos
dppb
Cs2CO3 DMA
Cs2CO3 DMA
a
1a (1 equiv), [Pd] (10 mol %), [L] (20 mol %), base (2 equiv), TBAB (1 equiv), solvent
(0.04M), 3 h at 130 °C. b Ratio was determined by 1H NMR in the crude reaction mixture based
on the chemical shift of the proton signal (ppm) at the 3ꢀposition of the indole nucleus (2a: δ =
6.47, 3a: δ = 6.93). c Yield of isolated product 3a. d Identical yield of 3a was obtained when the
e
reaction was performed with 5 mol % of Pd(OAc)2 and 10 mol% of Dpephos. No reaction
occurred in the absence of Pd(OAc)2 or Dpephos.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Interestingly, the polycyclic heteroaromatic compound 3p bearing the indole and thiophene
rings, which is obtained in good yield, can be used as a platform in further selective C−H
functionalization processes at Cꢀ34 position of the indole or Cꢀ3/Cꢀ4 positions of thiophene
rings.10
Page 8 of 34
1
2
3
4
5
6
7
8
9
TABLE 3 Pd-Catalyzed Intramolecular C2-Arylation of 2a-p.a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R2
Pd(OAc)2 (5 mol%)
R1
R2
H
Dpephos (10 mol%)
Cs2CO3 (2 equiv)
TBAB (1 equiv)
N
N
N
N
R3
R3
R2
DMA, 130 °C, 1-3 h
Br
2a-p
3a-p
N
N
N
N
N
N
R2
R2
3e, 98%b
3a, R2 = OMe, 80%b
3b, R2 = Cl, 91%b
3c, R2 = Me, R3 = H, 71%b
3d, R2 = R3 = OMe, 94%b
R2
Cl
MeO
N
N
N
N
N
N
R2
3i, 94%b
3j, 63%b
3f, R2 = OMe, 98%b
3g, R2 = Me, 73%b
3h, R2 = Cl, 76%b
MeO
F
N
N
O
O
N
N
O
O
N
N
OMe
MeO
3l, R2 = OMe, 74%b
3m, R2 = Cl, 60%b
R2
3k, 75%b
3n, 56%b
Me
S
N
N
N
N
3o, 68%b
3p, 60%b
Z
(from ( )-2o)
MeO
MeO
a
Reactions of 2 (0.122 mmol, 1 equiv) were performed in a sealed tube at 130 °C in DMA
(0.04M) by using Pd(OAc)2 (5 mol %), Dpephos (10 mol %), TBAB (1 equiv) and Cs2CO3 (2
equiv). Yield of isolated product. 75% yield of 3a were obtained when the reaction was
performed in a larger scale (using 0.5 mmol of starting material 2a).
b
c
8
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
Although the exact mechanism of the reaction is still not clear, it is believed that an oxidative
addition of Nꢀbenzyl aminoindole 2a to a zerovalent Pd species is envisioned to take place as an
initial step leading to the arylpalladium complex I. Next, in the presence of Cs2CO3, the complex
I evolves through the C−H functionalization at the Cꢀ2 position of the indole to provide the
intermediate palladocycle II. This later undergoes a reductive elimination to afford the desired
fused tetracycle 3a and the Pd(0) species which back to the catalytic system for the next cycle.
Various scenari may occur at this CꢀH functionalization step including (i) a Heckꢀtype pathway5,
11 involving a carbopalladation followed by an atypical antiꢀβꢀhydride elimination,12 (ii) a direct
Cꢀ2 palladation via a nonelectrophilic pathway,13 and (iii) an electrophilic substitution at the Cꢀ3
position, followed by a Cꢀ3 to Cꢀ2 palladium migration and reductive elimination.14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 2. Proposed mechanism for the Pd- catalyzed intramolecular C-2 arylation of 2a
In the context of the further selective C−H functionalization strategy at of the indole moeity,
preliminary results demonstrate that compound 3a can be selectively arylated at Cꢀ3 position
under the identical conditions used for the Cꢀ2 arylation of 2.Thus the Cꢀ3 arylated 1ꢀ
aminoindoles 4a-d were isolated in yields ranging from 50% and 65% (Scheme 3).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
SCHEME 3 Pd-Catalyzed C-3 Arylation of 3a with Arylbromides
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To prepare the highly functionalized 1ꢀaminoindoles of type 4 avoiding direct manipulation and
purification of 3, we next examined a oneꢀpot Pdꢀcatalyzed Cꢀ2 and Cꢀ3 arylations of derivatives
2 as it would be economically and environmentally advantageous over multistep syntheses
(Scheme 4). In a typical experiment, we achieved this transformation in a single set of
conditions by mixing 2a with 4ꢀbromoanisole as partner under optimal reaction conditions.
Thus, under this protocol, we were pleased to observe that the double C−H arylation worked
well and provided the desired product 4b in a 45% yield.
SCHEME 4 One pot Pd-Catalyzed Double C-2 and C-3 Arylations of 2a
OMe
Pd(OAc)2 (10 mol%)
Dpephos (20 mol%)
Cs2CO3 (2 equiv)
TBAB (1 equiv)
DMA, 130 °C, 12 h
N
N
N
N
Br
OMe
Br
2a
4b, 45% yield
MeO
MeO
One pot!
3. Conclusion
In summary, we have reported a novel palladiumꢀcatalyzed direct arylation process to form a
series of polcyclic 1ꢀaminoindole derivatives in good yields. The protocol is effective with
various Nꢀaryl, N’ꢀbenzylꢀ1ꢀaminoindoles with good functional group tolerance. Moreover,
10
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
double C2/C3ꢀdirect arylations proved to be useful for the rapid construction of disubstituted 1ꢀ
aminoindoles 4.
1
2
3
4
5
6
4. Experimental Section
7
8
9
General. All reactions were conducted under an argon atmosphere. Solvents: cyclohexane, ethyl
acetate (EtOAc) for extraction and chromatography were technical grade. These compounds
were all identified by the usual physical methods, that is 1H NMR, 13C NMR (JꢀMOD), IR, HRꢀ
MS (ESI or APCI). 1H NMR, 13C NMR spectra were measured in CDCl3. 1H chemical shift are
reported in ppm from an internal standard TMS or of residual chloroform (7.27 ppm). The
following abreviations are used: m (multiplet), s (singlet), bs (broad singlet), d (doublet), t
(triplet), dd (doublet of doublet), td (triplet of doublet), q (quadruplet), qui (quintuplet), sex
(sextuplet). 13C chemical shift are reported in ppm from central peak of deuteriochloroform
(77.14). High resolution mass spectra (HRꢀMS) were recorded on a MicroTOF spectrometer,
using ESI or APCI with methanol as the carrier solvent. Nominal and exact m/z values are
reported in Daltons. IR spectra were measured are reported in wave numbers (cmꢀ1). Analytical
TLC was performed on precoated silica gel 60ꢀF254 plates. Silica gel 60 (0.0150 – 0.040 mm)
was used for flash chromatoghraphy. Melting points was recorded on a Bꢀ450 apparatus. Aryl
halides and substituted 2ꢀbromobenzylbromide are commercially available compounds.
a. General procedure for the N-aryation of 1-aminoindoles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 1a-k were synthesized following the procedure of E. Brachet et al.8
1a-c, 1e-k are known compounds and their characterization data was matched with the literature
data.
N-(3,5-dimethoxyphenyl)-1H-indol-1-amine (1d). Following the general procedure, a mixture
of Nꢀaminoindole (0.25 mmol, 33 mg) and 1ꢀchloroꢀ3,5ꢀdimethoxybenzene was heated in 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
8/2) to afford the desired product 1d as brown oil. Yield: 62% (0.16 mmol, 42 mg), Rf = 0.47
(cyclohexane/EtOAc 8/2); IR (neat): ν = 1756, 1717, 1609, 1508, 1466, 1437, 1366, 1285, 1245,
1
2
3
4
5
6
1
1223, 1182, 1122, 1035, 912, 829, 758, 743, 618 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm):
7
8
7.63 (dd, J = 6.7, 1.3 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.23 – 7.12 (m, 3H), 6.58 (s, 1H), 6.52
9
13
(dd, J = 3.3, 0.7 Hz, 1H), 6.04 (t, J = 2.2 Hz, 1H), 5.71 (d, J = 2.2 Hz, 2H), 3.67 (s, 6H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (75 MHz, CDCl3, δ, ppm): 162.0 (2C), 149.7 (C), 136.1 (C), 128.8 (CH), 126.9 (C), 122.6
(CH), 121.2 (CH), 120.5 (CH), 109.5 (CH), 101.0 (CH), 93.2 (CH), 91.7 (2CH), 55.4 (2C); HRꢀ
MS (ESI positive, m/z): 269.1292 ([M+H]+), calcd. for C16H17N2O2 (M+H): 269.1290.
b. General procedure for the benzylation of 2a-p
A flash 50 ml was charged with KOH (0.8 mmol, 2 equiv.), compound 1a-k (0.4 mmol, 1
equiv.), substituted benzyl bromide derivatives (0.48 mmol, 1.2 equiv.), capped with a rubber
septum, evacuated and backfilled with argon, then 5 mL of DMSO was added through the
septum. The mixture was stirred at room temperature for 1ꢀ2 hours. The resulting suspension
was added 30 mL of distilled water and the aqueous solution was extracted with 30 mL of
EtOAc (3x 10 mL). The combined organic layer was washed with brine (10 mL), dried over
MgSO4 and evaporated. The crude products obtained were purified by flash chromatography
over silica gel to afford the desired product.
N-(2-bromobenzyl)-N-(4-methoxyphenyl)-1H-indol-1-amine (2a). Following the general
procedure, a mixture of 1a (0.63 mmol, 150 mg) and 2ꢀbromobenzylbromide was stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2a as yellow oil. Yield: 94% (0.59 mmol, 240 mg), Rf = 0.58
(cyclohexane/EtOAc 95/5); IR (neat): ν = 1509, 1440, 1247, 1182, 1130, 822, 742, 618 cmꢀ1; 1H
NMR (300 MHz, CDCl3, δ, ppm): 7.62 – 7.58 (m, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.34 –
7.27 (m, 2H), 7.18 – 7.08 (m, 5H), 6.77 (d, J = 9.2 Hz, 2H), 6.52 (d, J = 9.2 Hz, 2H), 6.46 (dd, J
= 3.4, 0.8 Hz, 1H), 4.97 (s, 2H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 154.3 (C),
12
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
143.1 (C), 136.0 (C), 135.1 (C), 132.9 (CH), 129.9 (CH), 129.3 (CH), 127.6 (CH), 127.2 (C),
126.5 (C), 123.5 (C), 122.5 (CH), 121.2 (CH), 120.4 (CH), 115.2 (2CH), 114.8 (2CH), 110.1
(CH), 101.1 (CH), 58.8 (CH2), 55.7 (CH3); HRꢀMS (ESI positive, m/z): found
407.0759/409.0739 ([M+H]+), calcd. for C22H20N2OBr (M+H): 407.0759.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(2-bromobenzyl)-N-(4-chlorophenyl)-1H-indol-1-amine (2b). Following the general
procedure, a mixture of 1b (0.41 mmol, 100 mg) and 2ꢀbromobenzylbromide was stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2b as beige oil. Yield: 91% (0.37 mmol, 153 mg); Rf = 0.41
(cyclohexane/EtOAc: 95/5); IR (neat): ν = 3473, 3377,3334, 2371, 2235, 2160, 2141, 1509,
1
1440, 1247, 1182, 1130, 822, 742, 418 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.58 – 7.51
(m, 1H), 7.48 (dd, J = 7.5, 1.7 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.16 – 7.02 (m, 7H), 7.01 (d, J
13
= 3.4 Hz, 1H), 6.45 – 6.26 (m, 3H), 4.92 (d, J = 14.1 Hz, 2H); C NMR (75 MHz, CDCl3, δ,
ppm): 147.5 (C), 135.4 (C), 134.6 (C), 133.1 (CH), 129.6 (CH), 129.5 (CH), 129.4 (2CH), 127.7
(CH), 127.3 (CH), 126.7 (C), 125.7 (C), 123.5 (C), 122.8 (CH), 121.5 (CH), 120.7 (CH), 114.6
(2CH), 109.9 (CH), 101.6 (CH), 58.3 (CH2). HRꢀMS (ESI positive, m/z):
411.0263/413.0233 ([M+H]+), caldc. for C21H17N2ClBr (M+H): 411.0264.
found
N-(2-bromobenzyl)-N-(m-tolyl)-1H-indol-1-amine (2c). Following the general procedure, a
mixture of 1c (0.2 mmol, 44 mg) and 2ꢀbromobenzylbromide were stirred for 1 hours. The
residue was filtred through silica gel (EtOAc) to afford the desired product 2c (contaminated by
2ꢀbromobenzylbromide) as a beige oil, yield: 92% (0.184 mmol, 72 mg). Compound 2c is not
1
enough stable for full characterization, it was directly used for the next step. H NMR (300
MHz, CDCl3, δ, ppm): 7.73 – 7.56 (m, 3H), 7.45 – 7.29 (m, 2H), 7.19 (m, 5H), 6.78 (d, J = 7.4
Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.45 (s, 1H), 6.40 (dd, J = 8.3, 1.9 Hz, 1H), 5.07 (d, J = 6.7
Hz, 2H), 2.29 (s, 3H). HRꢀMS (ESI positive, m/z): found 391.0806 ([M+H]+), caldc. for
C22H20N2Br (M+H): 391.0810.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
N-(2-bromobenzyl)-N-(3,5-dimethoxyphenyl)-1H-indol-1-amine (2d). Following the general
procedure, a mixture of 1d (0.23 mmol, 60 mg) and 2ꢀbromobenzylbromide was stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2d as white solid. Yield: 94% (0.22 mmol, 94 mg), m.p.: 85
ꢀ 87oC; Rf = 0.65 (cyclohexane/EtOAc: 9/1); IR (neat): ν = 1681, 1591, 1476, 1453, 1261, 1204,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1153, 1126, 1104, 1068, 1060, 1027, 930, 818, 800, 762, 741, 716, 682, 660 cmꢀ1; H NMR
(300 MHz, CDCl3, δ, ppm): 7.62 – 7.50 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.28 – 7.24 (m, 1H),
7.20 – 7.05 (m, 5H), 6.44 (dd, J = 3.4, 0.8 Hz, 1H), 6.04 (t, J = 2.1 Hz, 1H), 5.71 (d, J = 2.1 Hz,
13
2H), 4.99 (d, J = 17.8 Hz, 2H), 3.63 (s, 6H); C NMR (75 MHz, CDCl3, δ, ppm): 161.8 (2C),
151.1 (C), 135.8 (C), 134.9 (C), 133.0 (CH),129.7 (CH), 129.3 (CH), 127.6 (CH), 126.6 (C),
123.4 (C), 122.6 (CH), 121.3 (CH), 120.5 (CH), 110.0 (CH), 101.3 (CH), 92.7 (2CH), 92.2
(CH), 58.2 (CH2), 55.3 (2CH3); HRꢀMS (ESI possitive, m/z): found 437.0868/439.0862
([M+H]+), calcd. for C23H22N2O2Br (M+H): 437.0865.
N-(2-bromobenzyl)-N-(naphthalen-1-yl)-1H-indol-1-amine (2e). Following the general
procedure, a mixture of 1e (0.2 mmol, 52 mg) and 2ꢀbromobenzylbromide was stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2e as beige oil. Yield: 92% (0.184 mmol, 75 mg); Rf = 0.72
(cyclohexane/EtOAc: 92/8); IR (neat): ν = 1734, 1590, 1509, 1477, 1452, 1247, 1206, 1155,
1126, 1102, 1060, 1028. 892, 869, 822, 742 cmꢀ1; 1H NMR (300 MHz, CDCl3, δ, ppm): 8.25 (d,
J = 8.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.53 – 7.41 (m, 4H), 7.41 –
7.24 (m, 4H), 7.19 – 7.16 (m, 1H), 7.10 – 7.05 (m, 1H), 7.02 – 6.95 (m, 3H), 6.34 (d, J = 3.4 Hz,
1H), 4.94 (s, 2H); 13C NMR (75 MHz, CDCl3, δ, ppm): 144.7 (C), 135.7 (2C), 134.9 (C), 132.8
(CH), 129.5 (CH), 129.2 (CH), 128.8 (C), 128.5 (CH), 127.7 (CH), 126.5 (CH), 126.4 (CH),
126.1 (C), 126.0 (CH), 125.3 (CH), 124.5 (CH), 123.7 (C), 123.0 (CH), 122.5 (CH), 121.1 (CH),
120.2 (CH), 116.6 (CH), 110.0 (CH), 101.2 (CH), 59.9 (CH2); HRꢀMS (ESI positive, m/z):
14
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
found 427.0797/429.0787 ([M+H]+), caldc. for C25H20N2Br (M+H): 427.0804.
1
2
3
4
5
6
7
8
9
N-(2-bromobenzyl)-N-(2-methoxyphenyl)-1H-indol-1-amine (2f). Following the general
procedure, a mixture of 1f (0.25 mmol, 60 mg) and 2ꢀbromobenzylbromide was stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2f as beige solid. Yield: 98% (0.245 mmol, 99 mg); m.p.: 103
ꢀ 105oC; Rf = 0.59 (cyclohexane/ EtOAc: 9/1); IR (neat): ν = 1593, 1496, 1452, 1260, 1240,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1212, 1177, 1127, 1093, 1026, 1009, 794, 738, 707, 662 cmꢀ1; H NMR (300 MHz, CDCl3, δ,
ppm): 7.56 – 7.43 (m, 4H), 7.38 (d, J = 3.4 Hz, 1H), 7.14 – 6.99 (m, 5H), 6.91 (d, J = 8.0 Hz,
13
1H), 6.86 – 6.77 (m, 2H), 6.40 (d, J = 3.3 Hz, 1H), 5.05 (s, 2H), 3.77 (s, 3H); C NMR (75
MHz, CDCl3, δ, ppm): 152.3 (C), 138.4 (C), 136.7 (C), 135.7 (C), 132.6 (CH), 130.4 (CH),
128.9 (CH), 127.3 (CH), 126.5 (CH), 126.0 (C), 125.0 (CH), 123.9 (C), 122.0 (CH), 121.0 (CH),
120.8 (CH), 120.6 (CH), 119.9 (CH), 112.4 (CH), 110.4 (CH), 100.3 (CH), 58.8 (CH2), 55.8
(CH3); HRꢀMS (ESI positive, m/z): found 407.0761/409.0737 ([M+H]+), caldc. for
C22H20N2OBr (M+H): 407.0759.
N-(2-bromobenzyl)-N-(o-tolyl)-1H-indol-1-amine (2g). Following the general procedure, a
mixture of 1g (0.2 mmol, 44 mg) and 2ꢀbromobenzylbromide was stirred for 1 hours. The
residue was filtred through silica gel (EtOAc) to afford the desired product 2g (contaminated by
2ꢀbromobenzylbromide) as beige oil, yield: 99% (0.198 mmol, 77 mg). Compound 2g is not
1
enough stable for full characterization, it was directly used for the next step. H NMR (300
MHz, CDCl3, δ, ppm): 7.57 – 7.52 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.26 –
7.17 (m, 3H), 7.15 (d, J = 3.4 Hz, 1H), 7.06 (m, 5H), 6.40 (dd, J = 3.4, 0.7 Hz, 1H), 4.88 (s, 2H),
2.07 (s, 3H).
N-(2-bromobenzyl)-N-(2-chlorophenyl)-1H-indol-1-amine (2h). Following the general
procedure 2, a mixture of 1h (0.41 mmol, 100 mg) and 2ꢀbromobenzylbromide were stirred for 1
hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
95/5) to afford the desired product 2h as beige solid. Yield: 90% (0.37 mmol, 140 mg); m.p.:
118 ꢀ 120oC; Rf = 0.55 (cyclohexane/EtOAc: 95/5); IR (neat): ν = 1734, 1587, 1477, 1452, 1440,
1364, 1327, 1214, 1123, 1092, 1027, 985, 759. 739, 705, 665 cmꢀ1; 1H NMR (300 MHz, CDCl3,
δ, ppm): 7.60 (dd, J = 7.6, 1.7 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.47 (dd, J = 2.4, 1.2 Hz, 1H), 7.40
(dd, J = 7.8, 1.4 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H), 7.18 – 7.08 (m, 4H), 7.08 – 7.01 (m, 3H),
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
6.44 (dd, J = 3.4, 0.8 Hz, 1H), 4.99 (s, 2H); C NMR (75 MHz, CDCl3, δ, ppm): 145.9 (C),
135.7 (C), 135.4 (C), 132.7 (CH), 131.3 (CH), 130.0 (CH), 129.2 (CH), 128.5 (C), 127.6 (CH),
127.6 (C), 126.0 (CH), 125.9 (CH), 125.3 (C), 123.6 (CH), 122.4 (CH), 121.7 (CH), 121.0 (CH),
120.3 (CH), 110.4 (CH), 101.1 (CH), 58.8 (CH2); HRꢀMS (ESI positive, m/z): found
411.0255/413.0234 ([M+H]+), caldc. For C21H17N2ClBr (M+H): 413.0237.
N-(2-bromobenzyl)-5-methoxy-N-(4-methoxyphenyl)-1H-indol-1-amine (2i). Following the
general procedure 2, a mixture of 1i (0.4 mmol, 107 mg) and 2ꢀbromobenzylbromide was stirred
for 2 hours. The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product 2i as brown oil. Yield: 79% (0.32
mmol, 140 mg); Rf = 0.5 (cyclohexane/ EtOAc: 9/1); IR (neat): ν = 1735, 1621, 1583, 1506,
1
1471, 1439, 1278, 1237, 1181, 1027, 938, 821, 799. 748, 716, 662, 624 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.30 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 – 7.07
(m, 4H), 7.06 (d, J = 2.3 Hz, 1H), 6.83 – 6.72 (m, 3H), 6.52 (d, J = 9.1 Hz, 2H), 6.36 (d, J = 3.3
Hz, 1H), 4.95 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 154.7 (C),
154.3 (C), 143.2 (C), 136.0 (C), 132.9 (CH), 130.2 (C), 129.9 (CH), 129.3 (CH), 127.8 (CH),
127.6 (CH), 1267.0 (C), 123.5 (C), 115.2 (2CH), 114.8 (2CH), 112.7 (CH), 110.9 (CH), 103.0
(CH), 100.6 (CH), 58.7 (CH2), 55.9 (CH3), 55.7 (CH3); HRꢀMS (ESI positive, m/z): found
437.0862/439.0830 ([M+H]+), caldc. For C23H22N2O2Br (M+H): 437.0865.
N-(2-bromobenzyl)-5-chloro-N-(naphthalen-1-yl)-1H-indol-1-amine (2j). Following the
general procedure, a mixture of 1j (0.4 mmol, 116 mg) and 2ꢀbromobenzylbromide was stirred
16
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
for 2 hours. The residue was filtred through silica gel (EtOAc) to afford the desired product 2j
(contaminated by 2ꢀbromobenzylbromide) as brown oil, yield: 80% (0.32 mmol, 147 mg).
Compound 2j is not enough stable for full characterization, it was directly used for the next step.
1H NMR was provided: 1H NMR (300 MHz, CDCl3, δ, ppm): 8.28 (d, J = 8.5 Hz, 1H), 7.84 (d,
J = 7.6 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 – 7.51 (m, 3H), 7.50ꢀ7.29 (m, 5H), 7.17 (td, J =
7.9, 1.7 Hz, 1H), 7.08 (m, 3H), 6.36 (dd, J = 3.4, 0.7 Hz, 1H), 5.01 (s, 2H). HRꢀMS (ESI
positive, m/z): found 461.0418/463.0393 ([M+H]+), caldc. for C25H19N2ClBr (M+H): 461.0420.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-5-fluoro-N-(o-tolyl)-1H-indol-1-amine (2k).
Following the general procedure, a mixture of 1k (0.33 mmol, 80 mg) and 2ꢀ
bromobenzylbromide was stirred for 2 hours. The residue was purified by flash chromatography
over silica gel (cyclohexane/EtOAc: 98/2) to afford the desired product 2k as beige oil. Yield:
89% (0.27 mmol, 130 mg); Rf = 0.45 (cyclohexane/ EtOAc: 98/2); IR (neat): ν = 1624, 1503,
1
1479, 1442, 1262, 1242, 1115, 1038, 967, 932, 859, 798, 749, 613 cmꢀ1; H NMR (300 MHz,
CDCl3, δ, ppm): 7.29 – 7.20 (m, 3H), 7.18 – 7.11 (m, 3H), 7.06 (t, J = 7.1 Hz, 1H), 6.95 (s, 1H),
6.83 (td, J = 9.1, 2.4 Hz, 1H), 6.60 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 5.83 (s, 2H), 4.70 (s, 2H),
13
2.03 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 159.64 ꢀ 156.54 (d, J = 234.4 Hz, C), 148.1
(C), 147.4 (C), 146.8 (C), 133.4 (C), 132.3 (C), 132.1 (CH), 128.7 (C), 126.9 (C), 126.6 (CH),
126.00 ꢀ 125.87 (d, J = 10.1 Hz, C), 125.2 (CH), 119.4 (CH), 114.8 (C), 112.8 (CH), 110.90 –
110.34 (m, 2CH), 109.9 (CH), 105.96 ꢀ 105.65 (d, J = 23.5 Hz, CH), 101.8 (CH2), 100.9 ꢀ 100.8
(d, J = 4.4 Hz, CH), 59.2 (CH2), 19.4 (CH3); HRꢀMS (ESI possitive, m/z): found
453.0612/455.0607 ([M+H]+), calcd. for C23H19N2O2BrF (M+H): 453.0614.
N-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-methoxyphenyl)-1H-indol-1-amine (2l).
Following the general procedure, a mixture of 1a (0.41 mmol, 100 mg) and 5ꢀbromoꢀ6ꢀ
(bromomethyl)benzo[d][1,3]dioxole was stirred for 1 hours. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc: 95/5) to afford the desired product 2l as
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
beige oil. Yield: 99% (0.406 mmol, 182 mg); Rf = 0.41 (cyclohexane/ EtOAc: 98/2); IR (neat): ν
= 2234, 2050, 1712, 1504, 1477, 1452, 1412, 1360, 1246, 1182, 1111, 1036, 963. 931, 862, 821,
1
2
3
4
5
6
1
791, 764, 742. 719, 673 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.52 (dd, J = 6.7, 1.6 Hz,
7
8
9
1H), 7.21 – 7.17 (m, 1H), 7.10 – 6.99 (m, 3H), 6.91 (s, 1H), 6.75 (s, 1H), 6.67 (d, J = 9.1 Hz,
2H), 6.42 (d, J = 9.1 Hz, 2H), 6.39 (d, J = 3.3 Hz, 1H), 5.81 (s, 2H), 4.77 (s, 2H), 3.64 (s, 3H);
13C NMR (75 MHz, CDCl3, δ, ppm): 154.4 (C), 147.9 (C), 147.6 (C), 143.0 (C), 135.2 (C),
129.2 (C), 127.2 (CH), 126.5 (C), 122.5 (CH), 121.3 (CH), 120.4 (CH), 115.3 (2CH), 114.8
(2CH), 113.8 (C), 112.9 (CH), 110.1 (CH), 109.6 (CH), 101.8 (CH2), 101.2 (CH), 58.7 (CH2),
55.7 (CH3); HRꢀMS (ESI positive, m/z): found 451.0657 ([M+H]+), caldc. for C23H20N2O3Br
(M+H): 451.0657.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-N-(4-chlorophenyl)-1H-indol-1-amine (2m).
Following the general procedure, a mixture of 1b (0.41 mmol, 100 mg) and 5ꢀbromoꢀ6ꢀ
(bromomethyl)benzo[d][1,3]dioxole was stirred for 1 hours. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc: 95/5) to afford the desired product 2m as
beige solid. Yield: 91% (0.37 mmol, 170 mg); m.p.: 126 ꢀ 128oC; Rf = 0.74
(cyclohexane/EtOAc: 95/5); IR (neat): ν = 1594, 1492, 1477, 1452, 1413, 1251, 1251, 1237,
1
1132, 1096, 1037, 1006, 962, 906, 865, 817, 729, 649 cmꢀ1; H NMR (300 MHz, CDCl3, δ,
ppm): 7.67 – 7.58 (m, 1H), 7.23 – 7.11 (m, 5H), 7.10 (d, J = 3.4 Hz, 1H), 7.01 (s, 1H), 6.77 (s,
1H), 6.50 (dd, J = 3.4, 0.7 Hz, 1H), 6.44 (d, J = 9.2 Hz, 2H), 5.92 (s, 2H), 4.89 (d, J = 12.5 Hz,
13
2H); C NMR (75 MHz, CDCl3, δ, ppm): 148.1 (C), 147.7 (C), 147.5 (C), 134.7 (C), 129.4
(2CH), 128.5 (C), 127.2 (CH), 126.7 (C), 125.8 (C), 122.8 (CH), 121.5 (CH), 120.7 (CH), 114.7
(2CH), 113.9 (C), 113.0 (CH), 109.8 (CH), 109.4 (CH), 101.9 (CH2), 101.7 (CH), 58.1 (CH2);
HRꢀMS (ESI positive, m/z): found 455.0166/457.0131 ([M+H]+), caldc. for C22H17N2O2BrCl
(M+H): 455.0166.
N-(2-bromo-5-methoxybenzyl)-N-(4-methoxyphenyl)-1H-indol-1-amine (2n). Following the
18
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
general procedure, a mixture of 1a (0.41 mmol, 100 mg) and 2ꢀbromoꢀ5ꢀmethoxybenzylbromide
was stirred for 1 hours. The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product 2n as beige solid. Yield: 92% (0.38
mmol, 165 mg); m.p.: 87 ꢀ 89oC; Rf = 0.47 (cyclohexane/EtOAc: 92/8); IR (neat): ν = 1734,
1590, 1509, 1477, 1452, 1247, 1206, 1155, 1126, 1102, 1060, 1028. 892, 869, 822, 742 cmꢀ1; 1H
NMR (300 MHz, CDCl3, δ, ppm): 7.62 (dd, J = 6.5, 1.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.31
(d, J = 7.8 Hz, 1H), 7.20 – 7.11 (m, 3H), 6.88 (d, J = 3.0 Hz, 1H), 6.78 (d, J = 9.1 Hz, 2H), 6.67
(dd, J = 8.7, 3.1 Hz, 1H), 6.56 (d, J = 9.1 Hz, 2H), 6.48 (dd, J = 3.4, 0.6 Hz, 1H), 4.95 (s, 2H),
3.75 (s, 3H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 159.1 (C), 154.3 (C), 143.1 (C),
136.9 (C), 135.1 (C), 133.4 (CH), 127.3 (CH), 126.5 (C), 122.5 (CH), 121.3 (CH), 120.4 (CH),
115.4 (CH), 115.2 (2CH), 115.1 (CH), 114.7 (2CH), 113.6 (C), 110.1 (CH), 101.1 (CH), 58.9
(CH2), 55.7 (CH3), 55.5 (CH3); HRꢀMS (ESI positive, m/z): found 437.0857/439.0849
([M+H]+), caldc. for C23H22N2O2Br (M+H): 437.0865.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
E,Z-N-(3-bromoallyl)-N-(4-methoxyphenyl)-1H-indol-1-amine (2o). Following the general
procedure, a mixture of 1a (0.41 mmol, 100 mg) and E,Z ꢀ1,3ꢀdibromopropꢀ1ꢀene was stirred for
1 hours. The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product 2o as pale brown oil. Mixture of E/Z isomers (ratio E/Z = 1/2,
identified by chemical shift of the proton signal (ppm) at the CH2 position of the ally group: for
Zꢀ isomer: 4.50 ppm, for Eꢀisomer: 4.29 ppm).
(Z)-2o: yield = 56% (0.22 mmol, 82 mg); Rf = 0.67 (cyclohexane/EtOAc: 9/1); IR (neat): ν =
1590, 1509, 1477, 1452, 1247, 1206, 1155, 1126, 1102, 1060, 1028. 892, 869, 822, 742 cmꢀ1; 1H
NMR (300 MHz, CDCl3, δ, ppm): 7.64 (dd, J = 7.2, 1.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.23 –
7.11 (m, 3H), 6.78 (d, J = 9.2 Hz, 2H), 6.57 – 6.49 (m, 3H), 6.34 – 6.26 (m, 2H), 4.50 (dd, J =
13
5.1, 1.1 Hz, 2H), 3.74 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 154.4(C), 142.8 (C), 135.6
(C), 130.3 (CH), 126.5 (CH), 126.2 (C), 122.7 (CH), 121.2 (CH), 120.5 (CH), 115.4 (2CH),
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
114.8 (2CH), 110.8 (CH), 109.8 (CH), 101.7 (CH), 55.7 (CH3), 53.6 (CH2). HRꢀMS (ESI
positive, m/z): found 357.0592 ([M+H]+), caldc. for C18H18N2OBr (M+H): 357.0597.
1
2
3
4
5
6
7
8
(E)-2o, yield = 27% (0.11 mmol, 39 mg), Rf = 0.53 (cyclohexane/EtOAc: 9/1); IR (neat): ν =
1590, 1509, 1477, 1452, 1247, 1206, 1155, 1126, 1102, 1060, 1028. 892, 869, 822, 742 cmꢀ1; 1H
NMR (300 MHz, CDCl3, δ, ppm): 7.64 (dd, J = 7.0, 2.0 Hz, 1H), 7.31 – 7.24 (m, 1H), 7.23 –
7.11 (m, 3H), 6.77 (d, J = 9.2 Hz, 2H), 6.54 (dd, J = 3.4, 0.8 Hz, 1H), 6.49 (d, J = 9.2 Hz, 2H),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
6.37 (dt, J = 13.6, 6.3 Hz, 1H), 6.25 (dt, J = 13.6, 1.0 Hz, 1H), 4.29 (s, 2H), 3.74 (s, 3H); C
NMR (75 MHz, CDCl3, δ, ppm): 154.3 (C), 142.4 (C), 135.2 (C), 132.4 (CH), 127.3 (CH),
126.4 (C), 122.6 (CH), 121.3 (CH), 120.6 (CH), 115.0 (2CH), 114.8 (2CH), 109.9 (CH), 109.8
(CH), 101.4 (CH), 55.7 (CH3), 55.3 (CH2). HRꢀMS (ESI positive, m/z): found 357.0594
([M+H]+), caldc. for C18H18N2OBr (M+H): 357.0597.
N-((2-bromothiophen-3-yl)methyl)-N-(4-methoxyphenyl)-1H-indol-1-amine (2p). Following
the general procedure, a mixture of 1a (0.21 mmol, 50 mg) and 2ꢀbromoꢀ3ꢀ
(bromomethyl)thiophene was stirred for 1 hours. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc: 95/5) to afford the desired product 2p as
brown oil. Yield: 89% (0.18 mmol, 73 mg); Rf = 0.57 (cyclohexane/EtOAc: 9/1); IR (neat): ν =
1734, 1590, 1509, 1477, 1452, 1247, 1206, 1155, 1126, 1102, 1060, 1028. 892, 869, 822, 742
1
cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.59 (dd, J = 6.4, 1.9 Hz, 1H), 7.25 (d, J = 8.1 Hz,
1H), 7.18 – 7.04 (m, 4H), 6.81 – 6.72 (m, 3H), 6.59 (d, J = 9.1 Hz, 2H), 6.46 (d, J = 3.4 Hz, 1H),
4.81 (s, 2H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 143.1 (C), 136.6 (C), 135.3 (C),
128.4 (CH), 127.0 (CH), 126.4 (C), 126.0 (CH), 122.4 (CH), 121.2 (CH), 120.3 (CH), 115.5
(2CH), 114.8 (2CH), 111.5 (C), 110.0 (CH), 101.2 (CH), 55.7 (CH3), 52.3 (CH2); HRꢀMS (ESI
positive, m/z): found 413.0322/415.0302 ([M+H]+), caldc. for C2oH18N2OBrS (M+H):
413.0323.
20
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
c. General procedure for Palladium catalyzed Intramolecular C2 –arylation of 2a-p
1
2
3
4
5
6
7
8
9
A flameꢀ dried resealable tube was charged with Pd(OAc)2 (5 mol%), DPEphos (10 mol%),
TBAB (0.12 mmol, 1 equiv.), Cs2CO3 (0.24 mmol, 2 equiv.), compound 2a-p (0.12 mmol, 1
equiv.). The tube was capped with a rubber septum, evacuated and backfilled under argon, then
DMA (3 mL, 0.04M) was added through the septum under argon. The septum was replaced with
a Teflon screw cap. The tube was sealed and the mixture was stirred at 130oC for 1ꢀ3 hours. The
resulting suspension was cooled at room temperature and filtered through a pad of celite eluting
with ethyl acetate and the organic salts were removed. The filtrate was transferred to a
separating funnel and was extracted with aqueous NH4Cl (30 mL, twice) and with distilled water
(30 mL). The combined organic phases was dried with MgSO4, evaporated to dry and purified
by flash chromatography over silica gel to afford the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(4-methoxyphenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3a). The compound 3a was
prepared by using 2a (0.12 mmol, 50 mg), following the general procedure (reaction time: 3
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
98/2) to afford the desired product as yellow solid. Yield: 80% (0.096 mmol, 31 mg); Rf = 0.37
(cyclohexane/EtOAc: 95/5), m.p.: 139 ꢀ 141°C; IR (neat): ν = 2266, 2241, 2200, 2172, 2139,
1
2099, 2069, 1995, 1972, 1711, 1506, 1462, 1247, 1182, 1034, 823, 760, 742 cmꢀ1; H NMR
(300 MHz, CDCl3, δ, ppm): 7.77 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 6.9, 2.1 Hz, 1H), 7.37 – 7.29
(m, 2H), 7.23 – 7.09 (m, 4H), 6.93 (s, 1H), 6.61 (d, J = 9.1 Hz, 2H), 6.38 (d, J = 9.1 Hz, 2H),
4.88 (s, 2H), 3.63 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 155.5 (C), 143.0 (C), 134.4 (C),
132.5 (C), 129.3 (C), 128.2 (CH), 128.0 (CH), 127.8 (C), 126.9 (CH), 123.8 (CH), 122.7 (CH),
120.9 (CH), 120.7 (CH), 119.2 (2CH), 114.4 (2CH), 110.0 (CH), 95.3 (CH), 58.1 (CH2), 55.4
(OMe); HRꢀMS (APCI possitive, m/z): found 327.1493 ([M+H]+), calcd. for C22H19N2O
(M+H): 327.1493.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
6-(4-chlorophenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3b). The compound 3b was
prepared by using 2b (0.24 mmol, 100 mg), following the general procedure (reaction time: 1
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
98/2) to afford the desired product as yellow solid. Yield: 91% (0.22 mmol, 73 mg); Rf = 0.46
(cyclohexane/EtOAc: 95/5), m.p.: 105 ꢀ 107°C; IR (neat): ν = 2063, 2031, 1728, 1488, 1462,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1339, 1260, 1193, 1178, 1116, 1097, 1006, 907, 841, 760, 743, 648, 628 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 7.77 (d, J = 7.7 Hz, 1H), 7.70 (dd, J = 7.1, 2.6 Hz, 1H), 7.37 – 7.30 (m,
2H), 7.27 – 7.13 (m, 4H), 7.03 (d, J = 9.0 Hz, 2H), 6.95 (s, 1H), 6.35 (d, J = 9.0 Hz, 2H), 4.92 (s,
13
2H); C NMR (75 MHz, CDCl3, δ, ppm): 148.2 (C), 134.3 (C), 132.3 (C), 129.2 (3C : 2CH,
1C), 128.4 (CH), 128.1 (CH), 128.0 (C), 127.6 (C), 126.8 (CH), 125.9 (C), 123.9 (CH), 123.0
(CH), 121.1 (CH), 120.9 (CH), 119.0 (CH), 109.8 (2CH), 95.8 (CH), 57.6 (CH2); HRꢀMS
(APCI positive, m/z): found 331.100 ([M+H]+), caldc. for C21H16N2Cl (M+H): 331.0997.
6-(m-tolyl)-5,6-dihydroindolo[2,1-a]phthalazine (3c). The compound 3c was prepared by
using 2c (0.13 mmol, 50 mg), following the general procedure (reaction time: 3 hours). The
residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc: 95/5) to
afford the desired product as beige solid. Yield: 71% (0.17 mmol, 53 mg); Rf = 0.71
(cyclohexane/EtOAc: 9/1), m.p.: 62 ꢀ 65°C; IR (neat): ν = 1605, 1585, 1488, 1462, 1378, 1339,
1262, 1155, 1028, 759, 741, 701 cmꢀ1; 1H NMR (300 MHz, CDCl3, δ, ppm): 7.76 (d, J = 7.5 Hz,
1H), 7.71 – 7.65 (m, 1H), 7.35 – 7.28 (m, 2H), 7.23 – 7.11 (m, 4H), 6.95 – 6.89 (m, 2H), 6.66
13
(d, J = 7.5 Hz, 1H), 6.38 (s, 1H), 6.10 (dd, J = 8.1, 2.3 Hz, 1H), 4.94 (s, 2H), 2.16 (s, 3H); C
NMR (75 MHz, CDCl3, δ, ppm): 149.6 (C), 138.9 (2C), 129.6 (C), 129.0 (CH), 128.2 (CH),
127.9 (CH), 127.8 (C), 126.8 (CH), 125.8 (C), 123.8 (CH), 123.7 (CH), 122.7 (CH), 120.9 (CH),
120.6 (CH), 118.4 (CH), 114.7 (CH), 110.0 (CH), 95.5 (CH), 57.5 (CH2), 21.7 (CH3); HRꢀMS
(APCI positive, m/z): found 311.1551 ([M+H]+), caldc. for C22H19N2 (M+H): 311.1543.
6-(3,5-dimethoxyphenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3d). The compound 3d was
22
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
prepared by using 2d (0.15 mmol, 65 mg), following the general procedure (reaction time: 2
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as yellow solid. Yield: 94% (0.14 mmol, 50 mg); Rf = 0.35
(cyclohexane/EtOAc: 9/1), m.p.: 145 ꢀ 148°C; IR (neat): ν = 1595, 1461, 1426, 1339, 1261,
1204, 1155, 1059, 797, 761, 745 cmꢀ1; 1H NMR (300 MHz, CDCl3, δ, ppm): 7.74 (d, J = 7.5 Hz,
1H), 7.65 (dd, J = 7.8, 1.1 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.24 – 7.09 (m, 4H), 6.90 (s, 1H), 5.97
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(t, J = 2.1 Hz, 1H), 5.61 (d, J = 2.1 Hz, 2H), 4.91 (s, 2H), 3.57 (s, 6H); C NMR (75 MHz,
CDCl3, δ, ppm): 161.3 (2C), 151.8(C), 134.6 (C), 132.5 (C), 128.3 (C), 127.9 (CH), 127.8 (CH),
126.8 (C), 125.8 (CH), 123.9 (C), 122.8 (CH), 121.0 (CH), 120.6 (CH), 109.9 (CH), 96.9 (2CH),
95.6 (CH), 94.2 (CH), 57.4 (CH2), 55.2 (2CH3); HRꢀMS (ESI possitive, m/z): found 357.1598
([M+H]+), calcd. for C23H21N2O2 (M+H): 357.1598.
6-(naphthalen-1-yl)-5,6-dihydroindolo[2,1-a]phthalazine (3e). The compound 3e was
prepared by using 2e (0.234 mmol, 100 mg), following the general procedure (reaction time: for
2 hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as white ꢀyellow solid. Yield: 98% (0.23 mmol, 80 mg), Rf =
0.59 (cyclohexane/EtOAc: 9/1), m.p.: 181 ꢀ 183°C; IR (neat): ν = 1575, 1505, 1461, 1449, 1394,
1
1339, 1316, 1261, 1222, 1089, 1019, 988, 801, 775, 760, 743, 734, 692 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 8.68 (d, J = 8.6 Hz, 1H), 7.87 (t, J = 8.4 Hz, 2H), 7.74 – 7.64 (m, 2H),
7.58 (t, J = 8.1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.29 – 7.23 (m, 1H),
13
7.19 – 7.04 (m, 3H), 7.02 – 6.91 (m, 3H), 6.07 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H); C NMR (75
MHz, CDCl3, δ, ppm): 144.7 (C), 134.7 (C), 133.9 (C), 133.5 (C), 128.7 (CH), 128.6 (C), 128.3
(CH), 128.1 (CH), 127.6 (C), 127.4 (C), 127.2 (CH), 126.3 (CH), 126.2 (CH), 125.7 (CH), 125.1
(CH), 123.7 (CH), 123.1 (CH), 122.6 (CH), 120.8 (CH), 120.7 (CH), 116.7 (CH), 109.9 (CH),
94.7 (CH), 57.6 (CH2); HRꢀMS (APCI positive, m/z): found 347.1541 ([M+H]+), caldc. for
C25H19N2 (M+H): 347.1543.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
6-(2-methoxyphenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3f). The compound 3f was
prepared by using 2f (0.22 mmol, 90 mg), following the general procedure (reaction time: 2
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as beige solid. Yield: 98% (0.215 mmol, 70 mg); Rf = 0.44
(cyclohexane/EtOAc: 9/1), m.p.: 171 ꢀ 173°C; IR (neat): ν = 1592, 1494, 1460, 1384, 1339,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1244, 1116, 1026, 793, 759, 744, 613 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.81 (d, J =
7.1 Hz, 1H), 7.70 – 7.63 (m, 1H), 7.37 – 7.28 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.15 – 7.07 (m,
3H), 6.96 (s, 1H), 6.92 – 6.87 (m, 2H), 6.49 – 6.41 (m, 1H), 5.55 (d, J = 7.6 Hz, 1H), 4.97 (s,
13
2H), 4.06 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 150.6 (C), 137.9 (C), 133.9 (C) 133.8
(C), 129.7 (C), 128.2 (CH), 128.1 (CH), 127.7 (C), 127.2 (CH), 126.3 (C), 124.8 (CH), 123.8
(CH), 122.7 (CH), 121.3 (CH), 120.9 (CH), 120.8 (CH), 119.7 (CH), 112.1 (CH), 110.3 (CH),
95.0 (CH), 56.2 (CH3), 55.6 (CH2); HRꢀMS (ESI possitive, m/z): found 327.1504 ([M+H]+),
calcd. for C22H19N2O (M+H): 327.1497.
6-(o-tolyl)-5,6-dihydroindolo[2,1-a]phthalazine (3g). The compound 3g was prepared by
using 2g (0.22 mmol, 90 mg), following the general procedure (reaction time: 2 hours). The
residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc: 95/5) to
afford the desired product as yellow solid. Yield: 73%; Rf = 0.51 (cyclohexane/EtOAc: 95/5),
m.p.: 121 ꢀ 123°C; IR (neat): ν = 2367, 2159, 1488, 1461, 1449, 1379, 1340, 1210, 1176, 1110,
1
908, 759, 742, 712, 684, 647 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.84 (d, J = 7.6 Hz,
1H), 7.67 – 7.60 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.23 – 7.15 (m, 3H), 7.12 – 7.02 (m, 3H),
6.94 (s, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H), 5.93 (d, J = 8.1 Hz, 1H), 4.68 (s,
13
2H), 2.69 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 147.4 (C), 133.9 (C), 133.5 (C), 131.2
(CH), 130.3 (C), 128.5 (C), 128.2 (CH), 128.1 (CH), 127.9 (C), 127.0 (CH), 126.7 (CH), 126.2
(C), 124.8 (CH), 123.6 (CH), 122.5 (CH), 120.7 (CH), 120.6 (CH), 120.2 (CH), 109.8 (CH),
94.5 (CH), 56.4 (CH2), 18.4 (CH3). HRꢀMS (ESI positive, m/z): found 311.1552 ([M+H]+),
24
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
caldc. for C22H19N2 (M+H): 311.1548.
1
2
3
4
5
6
7
8
9
6-(2-chlorophenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3h). The compound 3h was
prepared by using 2h (0.22 mmol, 100 mg), following the general procedure (reaction time: 3
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as white ꢀ yellow solid. Yield: 76% (0.165 mmol, 63 mg); Rf
= 0.76 (cyclohexane/EtOAc: 9/1), m.p.: 55.7 ꢀ 57.5°C; IR (neat): ν = 2294, 1720, 1585, 1474,
1446, 1339, 1261, 1197, 1102, 1057, 1047, 1007, 801, 758, 741, 678 cmꢀ1; 1H NMR (300 MHz,
CDCl3, δ, ppm): 7.84 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 5.9, 2.7 Hz, 1H), 7.41 – 7.34 (m, 2H),
7.30 – 7.19 (m, 2H), 7.16 – 7.08 (m, 3H), 6.95 (s, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.77 (t, J = 7.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 1H), 5.89 (d, J = 8.1 Hz, 1H), 4.92 (s, 2H); C NMR (75 MHz, CDCl3, δ, ppm): 145.6 (C),
133.7 (C), 133.3 (C), 130.6 (CH), 128.6 (C), 128.6 (C), 128.4 (CH), 128.2 (CH), 127.7 (CH),
127.1 (CH), 126.3 (C), 126.2 (C), 125.7 (CH), 123.7 (CH), 122.8 (CH), 121.6 (CH), 120.9
(2CH), 120.8 (CH), 110.0 (CH), 56.1 (CH2); HRꢀMS (APCI possitive. m/z): found 331.0990
([M+H]+), calcd. for C21H16N2Cl (M+H): 331.0997.
10-methoxy-6-(4-methoxyphenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3i). The compound
3i was prepared by using 2i (0.18 mmol, 80 mg), following the general procedure (reaction time:
1 hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as yellow solid. Yield: 94% (0.17 mmol, 60mg); Rf = 0.57
(cyclohexane/EtOAc: 9/1), m.p.: 73 ꢀ 75°C; IR (neat): ν = 1623, 1551, 1505, 1460, 1439, 1378,
1
1294, 1246, 1219, 1181, 1141, 1120, 1032, 941, 875, 826, 800, 757, 735 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 7.74 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.27 – 7.16 (m, 2H),
7.12 (t, J = 4.2 Hz, 2H), 6.85 (dd, J = 8.7, 2.5 Hz, 2H), 6.60 (d, J = 9.0 Hz, 2H), 6.37 (d, J = 9.0
13
Hz, 2H), 4.86 (s, 2H), 3.88 (s, 3H), 3.63 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 155.5
(C), 154.9 (C), 143.0 (C), 133.1 (C), 129.7 (C), 128.9 (C), 128.2 (CH), 127.9 (CH), 127.7 (C),
126.9 (CH), 126.3 (C), 123.6 (CH), 119.2 (2CH), 114.3 (2CH), 113.2 (CH), 110.7 (CH), 102.3
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
(CH), 94.8 (CH), 58.1 (CH2), 55.9 (CH3), 55.4 (CH3); HRꢀMS (APCI positive, m/z): found
357.1604 ([M+H]+), caldc. for C23H21N2O2 (M+H): 357.1598.
1
2
3
4
5
6
7
8
10-chloro-6-(naphthalen-1-yl)-5,6-dihydroindolo[2,1-a]phthalazine (3j). The compound 3j
was prepared by using 2j (0.24 mmol, 110 mg), following the general procedure (reaction time:
3 hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as white ꢀ yellow solid. Yield: 63% (0.15 mmol, 57 mg); Rf =
0.62 (cyclohexane/EtOAc: 95/5), m.p.: 171 ꢀ 173°C; IR (neat): ν = 1531, 1471, 1208, 1150,
1130, 1023, 815, 767, 747, 724, 711 cmꢀ1; 1H NMR (300 MHz, CDCl3, δ, ppm): 8.64 (d, J = 8.4
Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.58 (t, J =
7.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 – 7.13 (m, 2H), 7.01 – 6.88
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m, 4H), 6.01 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H); C NMR (75 MHz, CDCl3, δ, ppm): 144.4 (C),
134.8 (C), 134.7 (C), 132.3 (C), 128.8 (CH), 128.5(CH), 128.5 (C), 128.4 (CH), 127.3 (C),
127.3 (C), 127.2 (CH), 127.1 (C), 126.5 (CH), 126.3 (CH), 126.3 (C), 125.6 (CH), 125.4 (CH),
123.8 (CH), 123.0 (CH), 122.9 (CH), 120.1 (CH), 116.5 (CH), 110.9 (CH) 94.2 (CH), 57.5
(CH2); HRꢀMS (APCI positive, m/z): found 381.1141 ([M+H]+), caldc. for C25H18N2Cl (M+H):
381.1153.
10-fluoro-6-(o-tolyl)-5,6-dihydro-[1,3]dioxolo[4,5-g]indolo[2,1-a]phthalazine (3k). The
compound 3k was prepared by using 2k (0.18 mmol, 81 mg), following the general procedure
(reaction time: 3 hours). The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product as white ꢀ yellow solid. Yield: 75%
(0.135 mmol, 50 mg); Rf = 0.46 (cyclohexane/EtOAc: 9/1), m.p.: 256 ꢀ 158°C; IR (neat): ν =
1
1502, 1474, 1454, 1383, 1336, 1249, 1198, 1159, 1039, 936, 793, 724 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 7.27 – 7.15 (m, 3H), 7.07 (dd, J = 8.8, 4.6 Hz, 1H), 6.90 (t, J = 7.3 Hz,
1H), 6.85 – 6.65 (m, 3H), 6.52 (s, 1H), 5.95 (s, 2H), 5.87 (d, J = 8.1 Hz, 1H), 4.57 (s, 2H), 2.64
13
(s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 158.93– 156.82 (d, J = 234.8 Hz, C), 148.0 (C),
26
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
147.7 (C), 147.0 (C), 135.2 (C), 131.3 (CH), 130.3 (C), 130.3 (C), 126.7 (CH), 126.46– 126.32
(d, J = 10.3 Hz, C), 125.0 (CH), 122.5 (C), 121.5 (C), 120.1 (CH), 110.78– 110.43 (d, J = 26.5
Hz, CH), 110.33– 110.20 (d, J = 9.7 Hz, CH), 107.6 (CH), 105.43– 105.11 (d, J = 23.9 Hz, CH),
104.1 (CH), 101.4 (CH2), 93.49– 93.43 (d, J = 4.6 Hz, CH), 56.4 (CH2), 18.3 (CH3); HRꢀMS
(APCI positive, m/z): found 373.1353 ([M+H]+), caldc. for C23H18N2O2F (M+H): 373.1347.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(4-methoxyphenyl)-5,6-dihydro-[1,3]dioxolo[4,5-g]indolo[2,1-a]phthalazine (3l). The
compound 3l was prepared by using 2l (0.24 mmol, 110 mg), following the general procedure
(reaction time: 3 hours). The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product as white ꢀ yellow solid. Yield: 74%
(0.178 mmol, 66mg), Rf = 0.44 (cyclohexane/EtOAc: 95/5), m.p.: 203 ꢀ 205°C; IR (neat): ν =
2168, 1504, 1475, 1248, 1180, 1038, 937, 904, 829, 726, 649 cmꢀ1; 1H NMR (300 MHz, CDCl3,
δ, ppm): 7.66 – 7.61 (m, 1H), 7.33 – 7.29 (m, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.16 – 7.10 (m,
2H), 6.78 (bs, 1H), 6.64 – 6.59 (m, 3H), 6.36 (d, J = 9.2 Hz, 2H), 5.93 (s, 2H), 4.77 (s, 2H), 3.64
13
(s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 155.4 (C), 147.6 (C), 142.6 (C), 134.0 (C), 132.7
(C), 125.8 (C), 123.2 (C), 122.3 (CH), 121.6 (C), 120.5 (CH, 1C), 120.5 (CH), 119.0 (2CH),
114.2 (2CH), 109.7 (2CH) 107.3 (CH), 104.1 (CH), 101.2 (CH2), 94.1 (CH), 57.9 (CH2), 55.3
(OMe); HRꢀMS (APCI positive, m/z): found 371.1394 ([M+H]+), caldc. for C23H19N2O3
(M+H): 371.1396.
6-(4-chlorophenyl)-5,6-dihydro-[1,3]dioxolo[4,5-g]indolo[2,1-a]phthalazine
(3m).
The
compound 3m was prepared by using 2m (0.24 mmol, 109 mg), following the general procedure
(reaction time: 3 hours). The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product as beige solid. Yield: 60% (0.144
mmol, 54 mg); Rf = 0.42 (cyclohexane/EtOAc: 9/1), m.p.: 197 ꢀ 199°C; IR (neat): ν = 3460,
2851, 2365, 2187, 2005, 1977, 1488, 1474, 1310, 1250, 1230, 1160, 1094, 936, 865, 828, 781,
746, 729 cmꢀ1; 1H NMR (300 MHz, CDCl3, δ, ppm): 7.65 (dd, J = 6.0, 2.4 Hz, 1H), 7.33 – 7.22
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
(m, 1H), 7.21 – 7.11 (m, 3H), 7.03 (d, J = 9.0 Hz, 2H), 6.79 (s, 1H), 6.62 (s, 1H), 6.32 (d, J = 9.0
1
2
3
13
Hz, 2H), 5.94 (s, 2H), 4.81 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 148.1 (C), 147.9 (C),
4
5
6
7
8
147.8 (C), 134.1 (C), 132.5 (C), 129.2 (2CH), 128.1 (C), 125.9 (C), 123.3 (2C), 122.7 (CH),
121.6 (C), 120.8 (2CH), 119.1 (2CH), 109.7 (CH), 107.4 (CH), 104.4 (CH), 101.4 (CH2), 94.8
(CH), 57.6 (CH2); HRꢀMS (APCI positive, m/z): found 375.0898 ([M+H]+), caldc. for
C22H16N2O2Cl (M+H) : 375.0895.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-methoxy-6-(4-methoxyphenyl)-5,6-dihydroindolo[2,1-a]phthalazine (3n). The compound
3n was prepared by using 2n (0.24 mmol, 105 mg), following the general procedure (reaction
time: 2 hours). The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product as white ꢀ yellow solid. Yield : 56%
(0.134 mmol, 48 mg), Rf = 0.44 (cyclohexane/EtOAc: 95/5), m.p.: 155 ꢀ 157°C; IR (neat): ν =
2357, 2217, 2168, 2023, 1711, 1610, 1507, 1360, 1248, 1221, 1183, 1221, 1183, 1038, 829, 745
1
cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.69 (d, J = 8.5 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.32
(dd, J = 6.2, 2.9 Hz, 1H), 7.18 – 7.09 (m, 2H), 6.87 (dd, J = 8.5, 2.5 Hz, 1H), 6.81 (s, 1H), 6.67
(d, J = 2.5 Hz, 1H), 6.61 (d, J = 9.1 Hz, 2H), 6.37 (d, J = 9.1 Hz, 2H), 4.84 (s, 2H), 3.78 (s, 3H),
13
3.63 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 159.6 (C), 155.5 (C), 143.0 (C), 134.1 (C),
132.8 (C), 130.9 (C), 126.1 (C), 125.2 (CH), 122.2 (CH), 120.7 (C) 120.6 (CH), 120.5 (CH),
119.2 (2CH), 114.4 (2CH), 114.0 (CH), 112.3 (CH), 109.8 (CH), 93.8 (CH), 58.2 (CH2), 55.4 (2
CH3); HRꢀMS (APCI positive, m/z): found 357.1597 ([M+H]+), caldc. for C23H21N2O2 (M+H):
357.1598.
1-(4-methoxyphenyl)-1,2-dihydropyridazino[1,6-a]indole (3o). The compound 3o was
prepared by using 2o (0.25 mmol, 90 mg), following the general procedure (reaction time: 3
hours). The residue was purified by flash chromatography over silica gel (cyclohexane/EtOAc:
95/5) to afford the desired product as beige solid. Yield: 68% (0.17 mmol, 47 mg), m.p.: 58 ꢀ
60oC; Rf = 0.58 (cyclohexane/EtOAc: 9/1); IR (neat): ν = 1512, 1492, 1272, 1230, 1200, 1166,
28
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1020, 993, 846, 814, 789, 755, 724, 707, 687 cmꢀ1; H NMR (300 MHz, CDCl3, δ, ppm): 7.60
1
1
2
3
4
5
(d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.16 – 7.05 (m, 2H), 6.80 (d, J = 9.9 Hz, 1H), 6.67
(d, J = 9.0 Hz, 2H), 6.48 (s, 1H), 6.28 (d, J = 9.0 Hz, 2H), 5.84 (dt, J = 9.9, 3.9 Hz, 1H), 4.38
6
13
7
8
(dd, J = 3.9, 1.1 Hz, 2H), 3.68 (s, 3H); C NMR (75 MHz, CDCl3, δ, ppm): 155.7 (C), 143.4
9
(C), 134.4 (C), 132.1 (C), 125.7 (C), 122.9 (CH), 121.6 (CH), 120.9 (CH), 120.7 (CH), 120.4
(CH), 119.5 (2CH), 114.3 (2CH), 109.8 (CH), 97.8 (CH), 55.5 (CH3), 54.8 (CH2); HRꢀMS
(APCI positive, m/z): found 277.1338 ([M+H]+), caldc. for C18H17N2O (M+H) : 277.1341.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(4-methoxyphenyl)-4,5-dihydrothieno[3',2':4,5]pyridazino[1,6-a]indole
(3p).
The
compound 3p was prepared by using 2p (0.24 mmol, 99 mg), following the general procedure
(reaction time: 3 hours). The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 95/5) to afford the desired product as white solid. Yield: 60% (0.144
mmol, 48 mg); Rf = 0.44 (cyclohexane/EtOAc: 9/1), m.p.: 79 ꢀ 81°C; IR (neat): ν = 1732, 1504,
1
1336, 1307, 1244, 1188, 1178, 1065, 1034, 1009, 836, 771, 734, 698, 663 cmꢀ1; H NMR (300
MHz, CDCl3, δ, ppm): 7.62 (dd, J = 7.3, 2.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 5.0
Hz, 1H), 7.16 – 7.07 (m, 2H), 6.84 (d, J = 5.0 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J = 9.1 Hz, 2H),
6.33 (d, J = 9.1 Hz, 2H), 4.87 (s, 2H), 3.64 (s, 3H); 13C NMR (75 MHz, CDCl3, δ, ppm): 155.7
(C), 143.2 (C), 134.4 (C), 131.1 (C), 130.4 (C), 128.3 (C), 126.1 (C), 125.8 (CH), 124.5 (CH),
122.9 (CH), 120.8 (CH), 120.7 (CH), 119.4 (2CH), 114.4 (2CH), 110.0 (CH), 94.9 (CH), 55.5
(CH2), 55.4; HRꢀMS (APCI positive, m/z): found 333.1055 ([M+H]+), caldc. for C20H17N2OS
(M+H): 333.1056.
d. Generale procedure for palladium-catalyzed C3 –arylation of 3a:
A flameꢀ dried resealable tube was charged with Pd(OAc)2 (5 mol %), DPEphos (10 mol %),
Cs2CO3 (0.16 mmol, 2 equiv.), compound 3a (0.08 mmol, 1 equiv.), arylbromide (0.12 mmol,
29
ACS Paragon Plus Environment