Synthesis of Indolo[2,3- c]quinolin-6(7 H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C-H Arylation

pubs.acs.org/joc

Article

Synthesis of Indolo[2,3‑c]quinolin-6(7H)‑ones and Antimalarial

Isoneocryptolepine. Computational Study on the Pd-Catalyzed

Intramolecular C−H Arylation

́

T í mea Szabo, Marcell Papp, Dora Rita Nemeth, Andras Dancso, Balazs Volk, and Matyas Milen*

Cite This: https://dx.doi.org/10.1021/acs.joc.0c01832

Read Online

sı

*

Metrics & More

Article Recommendations

Supporting Information

ACCESS

ABSTRACT: The synthesis of variously substituted indolo[2,3-

c]quinolin-6(7H)-ones was developed via Pd-catalyzed intra-

molecular C−H arylation. This method highlights a strategy for

preparing indoloquinoline precursors bearing versatile functional

groups and provides a new approach for the synthesis of

antimalarial isoneocryptolepine analogues. The plausible ring

closure mechanism was examined with quantum chemical

calculations, where a trigonal bipyramidal concerted metalation−

deprotonation transition state is presumable.

Because cryptolepines 1−4 and the indoloquinoline skeleton

inherent in them are pharmacologically active compounds,

several precursors and analogues were synthesized. Remarkable

indolo[2,3-c]quinolin-6(7H)-ones as representatives of this

family have been studied nowadays. A member of this group

10-chloro-5-(2-dimethylaminoethyl)-7H-indolo[2,3-c]-

quinolin-6(5H)-one exerts signiﬁcant antitumor activity.¹²

Despite the potential beneﬁts, only a few papers examine

comprehensively their biological properties, along with their

preparation including scope and limitations (Scheme 1).¹³⁻¹⁷Li

and co-workers have developed an eﬃcient method starting

from 3-(2-azidophenyl)-N-phenylacrylamides for the one-pot

synthesis of indolo[2,3-c]quinolin-6(7H)-ones by sequential

photocyclizations in moderate to high yields (Scheme 1a).¹³In

2014, the Pd-catalyzed arylation of Ugi adducts, obtained from

the reaction of indole-2-carboxylic acid, aromatic aldehydes, 2-

bromoanilines, and isocyanides, for the construction of

indoloquinolinone derivatives was developed (Scheme 1b).¹⁴

Using acetyloxy(phenyl)-λ³-iodanyl acetate as a hypervalent

iodine oxidant in C(sp²)−N coupling proved to be an

appropriate method for the synthesis of a series of substituted

indoloquinolinones from indole-2-carboxylic-acid derivatives

with good to excellent yields (Scheme 1c).¹⁵Zhang and co-

workers developed a Cu-mediated intermolecular cascade C−

H/N−H annulation of indolecarboxamides with arynes

prepared in situ from triﬂates for the construction of substituted

INTRODUCTION

■

The indoloquinoline framework is found in a variety of natural

products and biologically active compounds.¹⁻³Cryptolepine

(1, Figure 1) was ﬁrst isolated from Cryptolepis triangularis,⁴and

Figure 1. Selected examples of biologically active indoloquinolines.

2 decades later this alkaloid was also found in the root of the

Cryptolepis sanguinolenta,⁵the extract of which has been

traditionally used in West Africa to treat malaria, diarrhea, and

hypertension.⁶Neocryptolepine (2) and isocryptolepine (3)

were also isolated from the same plant by several independent

research groups.⁷⁻⁹Isoneocryptolepine (4) has not yet been

isolated from natural sources. However, compound 4 was

synthesized by Hostyn et al. in a Belgian−Hungarian

collaboration starting from readily available starting materials.

This research group found that 4 showed signiﬁcant

antiplasmodial activity in the nanomolar range and good

selectivity on L6 cells; therefore, they referred to 4 as a new

lead compound.^1,10,11

Received: July 30, 2020

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

A

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 1. Known Synthesis Methods of Indolo[2,3-c]quinolin-6(7H)-one Derivatives and Our New Preparation Strategy

indoloquinolines (Scheme 1d).¹⁶This straightforward strategy

for the synthesis of indoloquinolines provides the appropriate

products with diverse yields. Recently, microwave-assisted, base-

free, palladium-catalyzed intramolecular cross dehydrogenative

coupling of quinolinones has been accomplished to give

indoloquinolinone derivatives (Scheme 1e).¹⁷

By applying the above methods, a wide range of indolo[2,3-

c]quinolinones can be easily prepared in moderate to high yields.

In addition, the indolo[2,3-c]quinolin-6(7H)-one framework

can also be assembled using other existing strategies including

lactamization catalyzed by platinum,¹⁸combination of acid-

catalyzed rearrangements, the Fischer indol synthesis, and the

enlargement of the lactam ring,¹⁹Pd-catalyzed cross-coupling

reactions,²⁰⁻²⁵and photostimulated S_RN1 reaction.²⁶It is worth

mentioning, that indolo[2,3-c]quinolinones are not the target

molecules of these publications, only presented as unique

examples.

chlorides, which were transformed into amides (8) using

variously substituted anilines. This step was followed by the

alkylation of certain amides at the indole nitrogen atom to give

compounds 8q−ab, while others (8a−p) were used without this

step in the following reactions. Amides (8) were then

transformed into 3-iodo compounds (5) with NIS (N-

iodosuccinimide). In case of congener 5d, the 3-chloro

(5dCl), and 3-bromo (5dBr) analogues have also been prepared

with N-chlorosuccinimide (NCS) and N-bromosuccinimide

(NBS), in 90 and 71% yields, respectively. All compounds (5, 8)

so far were obtained in good yields in a gram-scale procedure

(Table 1).

With the appropriate 3-haloindole derivatives 5 in our hand,

the comprehensive examination of the Pd-catalyzed intra-

molecular construction of the variously substituted indoloqui-

nolinone framework (6) has been accomplished. Our

optimization process was based on the iodinated model

compound 5d and on the known catalytic methods in the

literature.^{14,17,20−25}

First, we started with the reaction conditions described by

Harayama and co-workers for the construction of the lactam

ring: 0.2 equiv Pd(OAc)₂catalyst, 0.4 equiv DPPP [1,3-

bis(diphenylphosphino)propane] as the ligand, 2 equiv Ag₂CO₃

as the base, and dimethylformamide (DMF) (Table 2, entries 1,

4, 5) or MeCN (entries 2, 3) as the solvent.²⁷⁻²⁹Each reaction

was carried out under an Ar atmosphere. We combined the

possible variables mentioned in the references,²⁷⁻²⁹but only a

trace amount of the desired product was formed, even if the

ligand was switched to PPh₃and the temperature was increased

to 80 °C (Table 2, entries 1−4). The reason of the unsuccessful

reaction was the regeneration of amide 8d by iodine loss of 5d,

and other unidentiﬁed byproducts were also observed in the

reaction mixture. Finally, by changing the base to K₂CO₃and by

increasing the temperature to 90 °C, a full conversion was

obtained, and the isolated yield reached 61% in DMF (entry 5).

Under these conditions, we tested several bases with the aim to

RESULTS AND DISCUSSION

■

Encouraged by the previously known methods shown above, we

report here the successful development of a new construction of

the indoloquinolinone skeleton via Pd-catalyzed intramolecular

C−H arylation of 3-halogenated N-phenyl-1H-indole-2-carbox-

amide derivatives 5 (Scheme 1, Table 1). This strategy oﬀers a

method for the synthesis of indoloquinolinones (6) from readily

available starting materials and reactants. To further demon-

strate the utility of this transformation, analogues with various

substituents have been synthesized in order to study the

substrate scope and reaction limitations. Moreover, an

alternative synthesis of antimalarial isoneocryptolepine (4)

was also accomplished.

Aiming at the development of a general method for the

preparation of indolo[2,3-c]quinolin-6(7H)-one derivatives,

commercially available and inexpensive indole-2-carboxylic

acids (7) were chosen as the initial substrates. First, acids 7

were reacted with thionyl chloride in diethyl ether to aﬀord acid

B

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Table 1. Synthesis Route for the Preparation of Compounds 5 and 8 with Isolated Yields

yield [%]

a

b

entry

R¹

R²

R³

R⁴

ID

8

5

1

2

3

4

5

6

7

8

H

4-Me

H

Bn

H

Me

Bn

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

89

100

93

91

72

76

84

90

69

70

71

91

72

67

84

100

76

70

69

75

90

70

75

45

44

86

77

100

89

94

70

89

94

97

94

83

100

94

91

69

81

96

84

96

99

91

74

100

97

91

96

85

84

93

H

OMe

Cl

H

Cl

H

Me

Et

Pr

Bu

Me

Et

Me

Bn

H

2-Me

3-Me

3-OMe

3-Cl

H

4-Me

4-F

4-Cl

H

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

H

2-Me

3-Me

3-OMe

3-Cl

H

4-Me

4-F

4-Cl

H

s

t

u

v

w

x

y

z

H

4-Me

aa

ab

a

b

Yield calculated from 7: 2 steps for 8a−p and 3 steps for 8q−ab. In compounds 5 shown in this table, substituent X stands for iodine (I).

reduce the reaction time (entries 6−10). The only promising

base was KOAc (entry 7), which reduced the reaction time to 3

h, but after the work-up procedure the yield was only 49%.

When applying organic bases such as i-Pr₂EtN or Et₃N in the

ring closure reaction, no product was observed (results not

shown in Table 2). Further investigations were performed to

ﬁnd the suitable solvent, where other solvents [tetrahydrofuran

(THF), toluene, 1,4-dioxane, xylenes] than DMF resulted only

in byproduct 8d (results not shown in Table 2). Next, other Pd

sources were tested, nevertheless the reactions did not seem

eﬀective. The reactions performed in the presence of Pd-

(dppf)₂Cl₂or PdCl₂resulted in many byproducts, and the

increase of reaction time and temperature was not beneﬁcial

either (entries 11, 12). Next, the eﬀect of ligands was tested

(entries 13−15), where only XantPhos [4,5-bis-

(diphenylphosphino)-9,9-dimethylxanthene]³⁰gave tetracycle

6d in acceptable yield but after a longer reaction time (entry 13).

Finally, changing the ligand from PPh₃to the bidental and less

bulky DPPP led to a signiﬁcant reduction of the reaction time to

our pleasant surprise (entries 16, 17). Only 1 h was needed to

reach the full conversion at 90 °C and 6d was obtained in 65%

yield (entry 17), which was found to be the optimum. The

desired product was not formed when the base was changed to

Ag₂CO₃(entry 18). According to our results, decreasing the

amount of either reagent was detrimental (entries 19−22).

Instead of iodo derivative 5d, application of the chlorinated

intermediate (5dCl) did not furnish the desired product, while

the reaction starting from the brominated amide (5dBr)

resulted in a complex mixture containing only a trace amount

of 6d (results not shown in Table 2).

By applying the optimized conditions [Pd(OAc)₂, DPPP,

K₂CO₃, DMF, 90 °C, 1 h, Ar atm], the substrate scope and

limitations of the Pd-catalyzed C−H arylation have been

investigated as the next step. The results are shown in Table 3

with the yield of indoloquinolinone products 6.

The presence of a hydrogen atom on the amide nitrogen was

clearly disadvantageous for the reaction (Table 3, entries 1−3).

In these cases, formation of the desired product was not

C

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Table 2. Optimization of the Reaction Conditions

entry

catalyst

ligand

DPPP

PPh₃

DPPP

PPh₃

base

t [h]

T [°C]

yield [%]

a

1

2

3

4

5

6

7

8

Pd(OAc)₂

Pd(dppf)₂Cl₂

PdCl₂

Pd(OAc)₂

Ag₂CO₃

K₂CO₃

Cs₂CO₃

KOAc

NaOAc

Ag₂CO₃

Na₂CO₃

K₂CO₃

Ag₂CO₃

K₂CO₃

4

5

3

5

80

90

n.a.

bc

,

trace

bc

,

d

b

61

n.a.

a

b

49

8

b

d

9

35

b

10

11

12

13

14

15

16

17

18

19

20

21

22

PPh₃

−

PPh₃

50

b d

,

n.a.

17

3 h at 90 °C, then 3 h at 110 °C

XantPhos

DMAP

( )-BINAP

DPPP

6

2

1

90

80

90

49

n.a.

a

trace

b

65

b

65

ab

,

n.a

18

24

b e

,

b f

,

g

trace

h

K₂CO₃

a

b

c

d

No product observed in the reaction. Formation of the main byproduct (8d). MeCN was used as the solvent, instead of DMF. Formation of

e

f

g

unidentiﬁed byproducts. 0.05 equiv of Pd(OAc)₂and 0.4 equiv of DPPP. 0.1 equiv of Pd(OAc)₂and 0.4 equiv of DPPP. 0.2 equiv of Pd(OAc)₂

and 0.2 equiv of DPPP. 0.2 equiv of Pd(OAc)₂and 0.12 equiv of DPPP.

h

detected, only iodine loss was observed, leading to byproducts 8.

If an alkyl substituent was present on the amide nitrogen atom

(R²= Me, Et, Pr, or Bu), the reaction could be accomplished

with derivatives unsubstituted at the indole nitrogen (R⁴= H,

entries 4−16) but only with a poor yield in many cases (14−

80%), as well as with substituted congeners (R⁴= Me or Bn,

entries 17−28), with signiﬁcantly better yields (up to 99%). The

reaction was tolerant to various substituents at both aromatic

rings. The ring closure starting from meta-substituted

compounds 5f−h and 5s−u resulted in a mixture of two

isomers in the appropriate products 6f−h and 6s−u (see the

Supporting Information for further details).

After successful completion of the C−H arylation on variously

substituted compounds, the question of scalability came into

focus. The scale-up procedure was developed with 5w as the

model compound (for further details see Table S2 in the

Supporting Information). For the 10-fold increase (1.11 g of

5w), some modiﬁcations of the previously optimized reaction

conditions were necessary. The amounts of the catalyst (0.05

equiv), DPPP (0.1 equiv) and the solvent (6 mL) have been

decreased, while the reaction time was increased to 18 h. Every

other condition was unchanged, and compound 6w was

obtained in 81% yield.

accomplished the debenzylation of dibenzyl derivative 6aa at

both the indole and the quinolinone nitrogen atoms to obtain 6a

(Scheme 2).¹⁵

We have developed a method for the selective deprotection of

compound 6aa at the indole structural unit by applying oxidative

debenzylation with KOt-Bu under an air atmosphere, leading to

derivative 6ac (Scheme 2).³³With this selective method, further

transformations become possible at the indole nitrogen atom.

In order to demonstrate the possible application of indolo-

[2,3-c]quinolin-6(7H)-ones prepared, the synthesis of the

antimalarial isoneocryptolepine (4) starting from 6d was carried

out successfully (Scheme 3). First, 6d was reacted with POCl₃to

form chlorinated intermediate 9. This reaction mixture was

carefully poured into CH₃CN−H₂O at 0 °C. Then, Zn dust was

added to the reaction mixture portionwise for the reduction of

the chlorine atom, while the temperature was kept at 0 °C.

Finally, the desired free base (4) could be recovered from 10 via

an acid−base reaction using ammonia in water, followed by

extraction with CH₂Cl₂. This procedure may also be suitable to

transform other indolo[2,3-c]quinolin-6(7H)-ones into ana-

logues of 4.

To gain insight into the intramolecular C−H arylation

mechanism, density functional theory calculations at the

B3LYP-D3(BJ)/def2-TZVP//B3LYP-D3(BJ)/def2-SVP level

were carried out to understand and explain the experimental

ﬁndings (see the Supporting Information for computational

details). The simplest model compound (5d) as well as the

Benzyl groups in the ﬁnal product (6) oﬀer the opportunity of

a deprotection strategy and further transformations. Debenzy-

lation of N-benzylquinolinones can be conveniently performed

with NaH in DMF.^31,32Using this procedure, Li and co-workers

D

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Table 3. Substrate Scope and Isolated Yields of Products 6

entry

R¹

R²

R³

R⁴

ID

yield [%]

1

2

3

4

5

6

7

8

H

2-Me

H

Bn

H

Me

Bn

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

0

65

49

H

OMe

Cl

H

Cl

H

Me

Et

Pr

Bu

Me

Et

Me

Bn

H

4-Me

3-Me

3-OMe

3-Cl

H

2-Me

2-F

2-Cl

H

a

36

a

19

32

a

9

14

21

80

44

52

59

41

49

81

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

H

4-Me

3-Me

3-OMe

3-Cl

H

2-Me

2-F

2-Cl

H

90

a

s

t

99

a

70

89

a

u

v

w

x

y

z

77

99

75

93

94

98

H

2-Me

aa

ab

a

Mixture of two isomers.

Scheme 2. Deprotection of Dibenzyl Derivative 6aa

Scheme 3. Telescoping Synthesis of Isoneocryptolepine (4)

complete DPPP ligand were used for the elucidation the reaction

mechanism. Following the oxidative addition, Pd-catalyzed

direct C−H arylation reactions can proceed via 4 diﬀerent

mechanisms³⁴starting from 5d-II. All mechanisms, where the

base does not participate in the reaction, are either

thermodynamically or kinetically inhibited requiring more

than 31.9 kcal/mol Gibbs free energy (see the Supporting

Information for further details).

deprotonation (CMD) mechanisms (Figure 2). This agrees with

our experiments, suggesting that the presence of CO²₃⁻ions is

necessary for the eﬃcient formation of the product. When using

OAc⁻ions, product formation was also observed (Table 2,

entries 7−8), but the eﬃciency of the reaction decreased

This explains why no product formation was observed with

Et₃N or i-Pr₂EtN base. Hence, the only favorable reaction routes

from 5d-II are the inner- or outer-sphere concerted metalation−

E

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Figure 2. Gibbs free energy proﬁle of the inner- and outer-sphere mechanisms of the intramolecular C−H arylation in the presence of CO²₃⁻.

(additional computations were performed for explanation, see

Tables S5 and S7).

the best of our knowledge, such a rare CMD transition state,

having a distorted trigonal bipyramidal geometry around the

palladium (see Animation S11 in the Supporting Information),

has only been mentioned in one publication for imidazolium

deprotonation,³⁷but it is unprecedented for Pd-catalyzed C−H

arylation reactions. As opposed to the 5-coordinate transition

states of the imidazolium C−H and the subsequent vinylic

C(sp²)−H activations described in the literature, where the

protonated base remains bound to the palladium, during the

present CMD reaction, the bicarbonate decoordinates simulta-

neously from the metal center.

Inner-Sphere CMD. When K₂CO₃is used, the carbonate

ions can replace the iodide ion bound to the metal, which is a

thermodynamically favorable reaction: 5d-III is by 4.5 kcal/mol

more stable than the iodide-containing structure 5d-II (Figure

2). The activation of the C−H bond may take place in a CMD

step,³⁵which involves a proton abstraction from the carbon

atom in an appropriate position of the aromatic ring by the

carbonate ion coordinated to the Pd, while the corresponding

carbon binds to the palladium. Simultaneously, the bicarbonate

ion leaves the complex resulting in a planar square intermediate

5d-IV. Intriguingly, the inner-sphere reaction may proceed

through a rare 5-coordinate transition state 5d-TS_III−IVwith a

Gibbs free energy barrier of 23.6 kcal/mol.

The C−C bond is formed in the next elimination step³⁸(5d-

TS_IV−V), while recovering the catalyst during the formation of

product 6d. The Gibbs free energy barrier of the elimination

reaction is 11.3 kcal/mol. Overall, the rate-determining step of

the cyclization reaction is the CMD step with a Gibbs free

energy barrier of 23.6 kcal/mol. Our computations suggest that

the carbonate ion has a dual role: it makes the replacement of the

iodide ion thermodynamically favorable, and it is also involved

in the rate-determining CMD step as an inner-sphere base.

Our experiments also showed that no reaction was observed

in the attempted cyclization of derivatives bearing a hydrogen on

the amide moiety. Because of the pseudo-double-bond character

of the amide bond, cis and trans amide species can be formed in

the reaction mixture. The moderately inhibited cis−trans

isomerism may result in the splitting of NMR signals as

observed for some 3-iodo-amide species (5) at room temper-

ature. Nevertheless, the applied reaction conditions (T = 90 °C)

enable the interconversion of the isomers with a rotational Gibbs

free energy barrier of 16−22 kcal/mol.³⁹

For all intermediates, a conformational analysis was carried

out considering the possibility of a rotation around the amide

bond. Following the oxidative addition, the cis structure (shown

in Figure 2) is more stable than the trans conformer in the case of

5d-II, which agrees with the previous ﬁndings for tertiary N-aryl

amides.⁴⁰After the coordination of the carbonate (5d-III), the

cis structure (shown in Figure 2) is destabilized because of

increased repulsion between the phenyl ring and the carbonate

ion. The Gibbs free energy of the trans structure is only 0.5 kcal/

mol lower than that of the cis form; thus, the conformers are in

equilibrium and can be interconverted to each other. The

Outer-Sphere CMD. Via the outer-sphere route, the I⁻

ligand is replaced by the aromatic ring instead of a carbonate ion,

forming 5d-P1. However, this step is thermodynamically

unfavored because it requires 20.4 kcal/mol of Gibbs free

energy. The carbonate ion, acting as an outer-sphere base, may

form an adduct with the η¹-coordinated aryl-Pd moiety (5d-A).

The concerted metalation-deprotonation step has a Gibbs free

energy barrier of less than 1 kcal/mol. However, the overall

barrier with respect to 5d-II becomes by 1.5 kcal/mol higher

than for the inner-sphere mechanism. In addition, the

coordination of the carbonate ion to the palladium (5d-III) is

more favorable than the formation of the adduct 5d-A. Although

these calculated results do not completely exclude the outer-

sphere CMD mechanism because of the small computed free

energy diﬀerence and the lack of detailed microkinetic study,

they suggest that the inner-sphere mechanism may be preferred.

If the reaction proceeds via the outer-sphere route, the rate-

determining step would be the iodide dissociation from the

palladium center, which may be facilitated by using Ag₂CO₃as a

halide scavenger. However, no product formation was observed

when Ag₂CO₃was applied instead of K₂CO₃(Table 2, entries 17

and 18), which indicates that the rate-determining step is not the

iodide dissociation. This experimental ﬁnding also supports the

inner-sphere mechanism instead of the outer-sphere route.

The preference of the 5-coordinate transition state contradicts

the hitherto putative outer-sphere CMD mechanism of C−H

activation reactions in the presence of bidentate ligands.³⁶To

F

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

following CMD step hence can take place with a moderate

barrier.

tested, and the experimental data were supported by quantum

chemical calculations. Based on our computations, the inner-

sphere CMD mechanism through an unexpected 5-coordinate,

trigonal bipyramidal transition state is favorable. Furthermore,

starting from the appropriate precursor obtained using this

procedure, the antimalarial isoneocryptolepine was also

synthesized via a new synthetic route using a telescoping

reaction. In this work, 61 new compounds were synthesized (8n,

r−t, v−ab; 5a−ab; 6c, e−i, k−p, r−y, aa, ab).

Next, derivative 5a bearing a hydrogen atom at the amide

nitrogen was analyzed. Here, the relative stability of the isomers

is diﬀerent. In contrast to tertiary amides, secondary amides may

form a hydrogen bond with a H-acceptor. Secondary anilides

prefer the formation of the trans conformer enabling

conjugation of the aromatic ring with the amide moiety in a

planar arrangement. Accordingly, after the oxidative addition,

the trans conformer of 5a-II is more stable by 8.4 kcal/mol.

Subsequent to the thermodynamically favorable replacement of

the iodide ion by the carbonate on the palladium (5a-III), the

free energy diﬀerence between the conformers is 19.1 kcal/mol

to the advantage of the trans structure (Figure 3). However, the

EXPERIMENTAL SECTION

■

Computational Details. Geometry optimization was performed

with B3LYP functional⁴¹and def2-SVP basis set.⁴²Single-point

energies were calculated with the same functional and def2-TZVP

basis set.⁴²Dispersion interactions were taken into consideration both

for the geometry optimization and energy calculations with Grimme’s

D3 dispersion correction⁴³with the Becke−Johnson damping function

(D3BJ).⁴⁴⁻⁴⁶Local minima found on the potential energy hypersurface

were conﬁrmed by harmonic vibrational frequency calculations at the

level of optimization (no imaginary mode was observed in the

vibrational analysis of initial states). The transition-state structures were

also characterized by harmonic vibration analysis: the presence of one

imaginary frequency belonging to the vibration along the reaction

coordinate was conﬁrmed. Solvent eﬀects were taken into account using

the SMD solvent model⁴⁷with the DMF solvent in single-point

calculations. Thermochemical data were calculated at 363.15 K and 1

atm. To shorten the calculation time, the RIJCOSX approximation⁴⁸

with def2/J auxiliary basis set⁴⁹was used. All calculations were

performed with ORCA 4.1.2 software.⁵⁰

Figure 3. Relative Gibbs free energies (kcal/mol) of cis and trans

isomers of 5a-III.

increased steric and electronic repulsion cannot account for this

signiﬁcant diﬀerence in stability alone. Because of the proximity

of the carbonate ion bound to palladium, an intramolecular

carbonate-amide hydrogen bridge is formed; hence, the trans

conformer is further stabilized (Figure 3). Nonetheless, the

unfavorable rotation to the cis conformation would be essential

for the CMD step because C−H activation can only take place if

the carbonate ion and the phenyl ring are on the same side with

respect to the amide C−N axis. Relative to the more stable trans

isomer, the Gibbs free energy barrier of the CMD step increases

to 36.1 kcal/mol, which explains why the desired cyclized

product is not formed. Thus, protection of the amide nitrogen is

necessary to favor the formation of the cis amide and to avoid

hydrogen bonding interaction between the amide group and the

carbonate ion.

Considering the possibility of the outer-sphere CMD route in

this case, as well, the Gibbs free energy of the iodide-dissociation

step (trans-5a-II to 5a-P1) was calculated (see Figure S7 and

Table S12 in the Supporting Information). The computed

results show an increased reaction free energy of 30.3 kcal/mol.

To examine whether the iodide dissociation may become the

bottleneck, we performed the reaction of 5a using Ag₂CO₃as the

base. While no product 6a was detected, all starting material was

converted into deiodinated analogue 8a. Because the dissocia-

tion of the iodide ligand thus proved to be feasible, the

preference of the highly stable inner-sphere intermediate trans-

5a-III is likely to be responsible for the lack of product

formation. Hence, the dominance of the inner-sphere route over

the outer-sphere mechanism is strongly suggested by these

results.

General Information. All melting points were determined on a

̈

Buchi−Boetius microapparatus and are uncorrected. IR spectra were

1

obtained on a Bruker Alpha FT-IR spectrometer in KBr pellets. H

NMR and ¹³C NMR spectra were recorded in DMSO-d₆or CDCl₃

solution in 5 mm tubes at room temperature on a Bruker AVANCE III

HD 600 (600 and 150 MHz for ¹H and ¹³C NMR spectra, respectively)

spectrometer with the deuterium signal of the solvent as the lock and

tetramethylsilane as the internal standard. Chemical shifts (δ) and

coupling constants (J) are given in parts per million and in hertz,

respectively. The following abbreviations were used to designate

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint =

quintet, m = multiplet, br = broad. Mass spectra were recorded on a

Bruker O-TOF MAXIS Impact mass spectrometer coupled to a Dionex

Ultimate 3000 RS HPLC system with a diode array detector. Reactions

were monitored by thin-layer chromatography (TLC) carried out on

silica gel plates (60 F254) using UV light as the visualizing agent.

Puriﬁcations by ﬂash column chromatography were carried out the

using Merck 107736 silica gel 60 H with a hexane−EtOAc or CH₂Cl₂−

MeOH solvent system. All reagents were purchased from commercial

sources and used without further puriﬁcation. Analytical samples of new

compounds were obtained by recrystallization from the solvents or

solvent mixtures given below in parentheses.

X-ray Crystallographic Analysis of 6q. The crystals were grown

in EtOAc by a 1 week warming at 50 °C in a special apparatus. (For the

apparatus used for crystal growing see Figure S1). Single-crystal X-ray

diﬀraction (XRD) data were collected on a Rigaku R-AXIS RAPID

imaging plate area detector with graphite monochromated Cu K_α

radiation. Indexing was performed from four oscillations that were

exposed for 900 s. The crystal-to-detector distance was 127.40 mm. The

crystal structure was solved by direct methods using SIR92 and

expanded using Fourier techniques performed through the program

and reﬁned by full-matrix least-squares calculations on F. The

nonhydrogen atoms were reﬁned anisotropically. Hydrogen atoms

were reﬁned using the riding model. All calculations were performed

with the Crystal Structure^9,10crystallographic software package. The

crystallographic data of 6q were deposited in the Cambridge

Crystallographic Data Centre with the deposition number CCDC

2013943.

CONCLUSIONS

■

In conclusion, we have developed a novel and highly eﬃcient

synthesis of indolo[2,3-c]quinolin-6(7H)-one derivatives via

Pd-catalyzed intermolecular C−H arylation. The reactions

leading to the corresponding iodine intermediates are opera-

tionally simple, using readily available starting materials and

reagents. The scope and limitations of the ring closure were also

G

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Crystal data for indoloquinolinone 6q: C₁₇H₁₄N₂O, M = 262.31, a =

6.9369(6) Å, b = 11.8229(10) Å, c = 15.7316(12) Å, α = γ = 90° β =

97.628(5)°, V = 1278.80(18) Å³, T = 293(2) K, space group P2₁/a

(#14), Z = 4, μ (Cu Kα) = 6.849 cm⁻¹, 14,686 reﬂections measured,

2391 independent reﬂections (R_int= 0.071). The ﬁnal R values were

0.0516 [(I > 2.00s(I)]. The ﬁnal R_w(F²) values were 0.0481 [I >

2.00s(I)].

(ESI) m/z: [M + H]⁺calcd for C₁₆H₁₅N₂O, 251.1179; found,

251.1174.

N-Methyl-N-(2-methylphenyl)-1H-indole-2-carboxamide (8e).

Yield: 4.720 g (72%). Yellow crystals. mp 209−211 °C (MeCN). IR

(KBr, cm⁻¹): 3421, 3275, 1615, 1521, 1343, 1137, 816, 773, 733. ¹H

NMR (CDCl₃, 600 MHz): δ 9.82 (br s, 1H), 7.44−7.39 (m, 2H), 7.38−

7.31 (m, 3H), 7.29−7.24 (m, 1H), 7.23−7.18 (m, 1H), 7.04−6.96 (m,

1H), 5.17−5.12 (m, 1H), 3.45 (s, 3H), 2.22 (s, 3H) ppm. ¹³C{¹H}

NMR (CDCl₃, 150 MHz): δ 161.9, 142.5, 136.2, 135.3, 131.7, 129.6,

129.0, 128.5, 127.8, 127.7, 124.4, 122.1, 120.1, 111.6, 106.1, 37.6, 17.4

ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₇N₂O, 265.1335;

found, 265.1333.

N-Methyl-N-(3-methylphenyl)-1H-indole-2-carboxamide (8f).

Yield: 4.982 g (76%). Yellow crystals. mp 196−197 °C (MeCN). IR

(KBr, cm⁻¹): 3266, 1622, 1521, 1389, 1342, 1139, 811, 746. ¹H NMR

(CDCl₃, 600 MHz): δ 9.68 (br s, 1H), 7.43−7.34 (m, 3H), 7.30−7.26

(m, 1H), 7.24−7.19 (m, 1H), 7.16−7.10 (m, 2H), 7.05−6.97 (m, 1H),

5.31 (br s, 1H), 3.50 (s, 3H), 2.40 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃,

150 MHz): δ 162.0, 143.9, 140.0, 135.3, 129.64, 129.58, 129.2, 128.5,

127.6, 124.9, 124.3, 122.1, 120.1, 111.6, 107.1, 39.0, 21.3 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₇H₁₇N₂O, 265.1333; found,

265.1333.

N-(3-Methoxyphenyl)-N-methyl-1H-indole-2-carboxamide (8g).

Yield: 5.840 g (84%). Yellow crystals. mp 197−198 °C (MeCN). IR

(KBr, cm⁻¹): 3279, 1614, 1586, 1394, 1233, 1138, 825, 752. ¹H NMR

(CDCl₃, 600 MHz): δ 9.55 (br s, 1H), 7.44−7.34 (m, 3H), 7.24−7.20

(m, 1H), 7.04−6.99 (m, 2H), 6.94−6.91 (m, 1H), 6.89−6.85 (m, 1H),

5.43 (s, 1H), 3.82 (s, 3H), 3.50 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃,

150 MHz): δ 161.9, 160.7, 145.1, 135.3, 130.6, 129.4, 127.7, 124.4,

122.2, 120.2, 120.1, 114.2, 113.4, 111.5, 107.1, 55.5, 39.0 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₇H₁₇N₂O₂, 281.1285; found,

281.1285.

For further details of XRD measurement see the Supporting

Information.

General Procedure for the Preparation of Indole-2-carbonyl

Chlorides. The appropriate indole-2-carboxylic acids (7, 24.8 mmol)

were dissolved in Et₂O (80 mL), the mixture was cooled to 0 °C, and

thionyl chloride (3.84 mL, 6.28 g, 52.8 mmol) was added dropwise

under an Ar atm. After the addition was complete, the mixture was

allowed to warm to room temperature, and it was stirred for 4.5 h. After

the reaction was complete, the solvents were evaporated, and the

residue was dissolved in toluene and evaporated again. The solid

product was stored under Ar atm in a refrigerator and applied in the

next step without further puriﬁcation.

General Procedure for the Preparation of Indole-2-carbox-

amides (8a−p). Anilines (24.8 mmol) and Et₃N (29.8 mmol, 1.2

equiv) were dissolved in THF (40 mL), and the solution of the

appropriate indole-2-carbonyl chloride (24.8 mmol) in THF (40 mL)

was added dropwise under Ar atm at room temperature. After the

addition was complete, the mixture was stirred at room temperature for

2 h. The reaction was followed by TLC. After the reaction was

complete, the solvents were evaporated, and the residue was taken up in

CH₂Cl₂(200 mL, or in the mixture of CH₂Cl₂and MeOH if it was

necessary) and extracted with 1% aqueous HCl solution (2 × 100 mL)

and brine (100 mL). The organic solvents were dried over Na₂SO₄,

ﬁltered, and evaporated. The crude product was recrystallized from

MeCN or EtOH.

N-(3-Chlorophenyl)-N-methyl-1H-indole-2-carboxamide (8h).

Yield: 6.355 g (90%). Yellow crystals. mp 200−202 °C (MeCN). IR

(KBr, cm⁻¹): 3294, 1611, 1491, 1408, 1280, 1156, 747, 540. ¹H NMR

(CDCl₃, 600 MHz): δ 9.73 (br s, 1H), 7.46−7.44 (m, 1H), 7.43−7.39

(m, 3H), 7.37 (t, J = 7.1 Hz, 1H), 7.24−7.20 (m, 2H), 7.05−7.02 (m,

1H), 5.42 (s, 1H), 3.50 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, MHz): δ

162.0, 145.3, 135.4, 135.2, 130.8, 129.1, 128.6, 128.2, 127.5, 126.4,

124.6, 122.2, 120.3, 111.6, 107.3, 39.0 ppm. HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₆H₁₄ClN₂O, 285.0789; found, 285.0786.

5-Methoxy-N-methyl-N-phenyl-1H-indole-2-carboxamide (8i).

Yield: 4.797 g (69%). Yellow crystals. mp 199−200 °C (MeCN). IR

(KBr, cm⁻¹): 3270, 1617, 1589, 1523, 1393, 1168, 1026, 695. ¹H NMR

(CDCl₃, 600 MHz): δ 9.70 (br s, 1H), 7.53−7.44 (m, 3H), 7.36−7.31

(m, 2H), 7.29 (d, J = 8.9 Hz, 1H), 7.28 (dd, J₁= 2.5 Hz, J₂= 8.9 Hz,

1H), 6.74 (d, J = 2.4 Hz, 1H), 5.19 (br s, 1H), 3.74 (s, 3H), 3.51 (s, 3H)

ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.0, 154.2, 144.1, 130.7

(2C), 129.9 (2C), 128.4, 128.0 (2C), 127.8, 116.0, 112.5, 106.8, 102.1,

55.5, 39.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₇N₂O₂[M

+ H]⁺, 281.1285; found, 281.1289.

5-Chloro-N-methyl-N-phenyl-1H-indole-2-carboxamide (8j).

Yield: 4.983 g (70%). Yellow crystals. mp 244−246 °C (MeCN). IR

(KBr, cm⁻¹): 3275, 1615, 1591, 1494, 1392, 1147, 763, 696. ¹H NMR

(CDCl₃, 600 MHz): δ 9.70 (br s, 1H), 7.52−7.47 (m, 3H), 7.35−7.29

(m, 4H), 7.16 (dd, J₁= 2.0 Hz, J₂= 8.8 Hz, 1H), 5.16 (br s, 1H), 3.51 (s,

3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 161.6, 143.8, 133.5,

130.7, 130.0 (2C), 128.6, 128.5, 127.9 (2C), 125.7, 124.9, 121.3, 112.7,

106.4, 39.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₆H₁₄ClN₂O,

285.0789; found, 285.0787.

N-Ethyl-N-phenyl-1H-indole-2-carboxamide (8k). Yield: 4.654 g

(71%). Yellow crystals. mp 301−303 °C (MeCN). IR (KBr, cm⁻¹):

3280, 1609, 1517, 1405, 1278, 1141, 747, 699. ¹H NMR (CDCl₃, 600

MHz): δ 9.83 (br s, 1H), 7.52−7.47 (m, 3H), 7.40 (d, J = 8.3 Hz, 1H),

7.36−7.33 (m, 1H), 7.32−7.28 (m, 2H), 7.23−7.18 (m, 1H), 7.02−

6.97 (m, 1H), 5.19 (br s, 1H), 3.99 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1

Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 161.5, 142.3,

135.3, 129.79 (2C), 129.75, 129.0 (2C), 128.5, 127.6, 124.3, 122.1,

120.0, 111.6, 106.9, 45.8, 12.9 ppm. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₇H₁₇N₂O, 265.1335; found, 265.1332.

N-Phenyl-1H-indole-2-carboxamide (8a). Yield: 5.215 g (89%).

Colorless crystals. mp 200−202 °C (EtOH) (lit.⁵¹190−192 °C,

EtOH). IR (KBr, cm⁻¹): 3423, 3341, 1645, 1596, 1547, 1446, 1245,

746. ¹H NMR (CDCl₃, 600 MHz): δ 9.47 (br s, 1H), 7.88 (br s, 1H),

7.75−7.64 (m, 3H), 7.43 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H),

7.30 (t, J = 7.4 Hz, 1H), 7.22−7.13 (m, 2H), 7.02 (s, 1H) ppm. ¹³C{¹H}

NMR (CDCl₃, 150 MHz): δ 159.5, 137.4, 136.6, 130.7, 129.2 (2C),

127.6, 125.0, 124.7, 122.1, 120.9, 120.1 (2C), 112.0, 102.6 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₅H₁₃N₂O, 237.1022; found,

237.1019.

N-(4-Methylphenyl)-1H-indole-2-carboxamide (8b). Yield: 6.207 g

(100%). Colorless crystals. mp 250 °C (MeCN). IR (KBr, cm⁻¹): 3418,

3332, 1644, 1530, 1234, 813, 746, 505. ¹H NMR (CDCl₃, 600 MHz): δ

9.25 (br s, 1H), 7.84 (br s, 1H), 7.72−7.68 (m, 1H), 7.56−7.52 (m,

2H), 7.48−7.45 (m, 1H), 7.35−7.31 (m, 1H), 7.22−7.16 (m, 3H), 6.99

(br s, 1H), 2.36 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ

159.3, 136.4, 134.8, 134.4, 130.8, 129.7 (2C), 127.7, 124.9, 122.1,

120.9, 120.1 (2C), 111.9, 102.3, 20.9 ppm. HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₆H₁₅N₂O, 251.1179; found, 251.1179.

1-Benzyl-N-phenyl-1H-indole-2-carboxamide (8c). Yield: 7.528 g

(93%). Colorless crystals. mp 198−200 °C (MeCN). IR (KBr, cm⁻¹):

1

3329, 1647, 1496, 1439, 1315, 749, 729, 692. H NMR (CDCl₃, 600

MHz): δ 7.58 (br s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.62−7.54 (m, 2H),

7.39−7.31 (m, 3H), 7.30−7.26 (m, 1H), 7.25−7.20 (m, 2H), 7.19−

7.15 (m, 2H), 7.14−7.08 (m, 3H), 7.05 (s, 1H), 5.83 (s, 2H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 160.3, 139.0, 138.1, 137.6, 131.8,

129.1 (2C), 128.6 (2C), 127.2, 126.5 (2C), 126.2, 124.7, 124.5, 122.0,

120.9, 120.0 (2C), 110.9, 105.2, 47.9 ppm. HRMS (ESI) m/z: [M +

H]⁺calcd for C₂₂H₁₉N₂O, 327.1492; found, 327.1494.

N-Methyl-N-phenyl-1H-indole-2-carboxamide (8d). Yield: 5.649 g

(91%). Yellow crystals. mp 198−200 °C (MeCN) (lit.⁵¹175−177 °C,

EtOH). IR (KBr, cm⁻¹): 3284, 1610, 1589, 1518, 1406, 1117, 746, 698.

¹H NMR (CDCl₃, 600 MHz): δ 9.75 (br s, 1H), 7.51−7.46 (m, 3H),

7.40 (d, J = 8.3 Hz, 1H), 7.36−7.31 (m, 3H), 7.23−7.19 (m, 1H),

7.02−6.98 (m, 1H), 5.27 (br s, 1H), 3.52 (s, 3H) ppm. ¹³C NMR

(CDCl₃, 150 MHz): δ 162.1, 144.1, 135.3, 129.9 (2C), 129.5, 128.4,

128.0, 127.6 (2C), 124.4, 122.1, 120.1, 111.6, 107.1, 39.0 ppm. HRMS

H

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

N-Ethyl-N-(4-methylphenyl)-1H-indole-2-carboxamide (8l).

Yield: 6.282 g (91%). Colorless crystals. mp 193−195 °C (MeCN).

8.0 Hz, 1H), 7.31−7.25 (m, 3H), 7.24−7.20 (m, 1H), 7.19−7.14 (m,

1H), 7.12 (d, J = 7.4 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H), 6.00 (s, 1H), 3.94

(s, 3H), 3.51 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.6,

144.8, 137.7, 131.9, 129.3 (2C), 126.8, 126.6 (2C), 126.1, 123.4, 121.8,

119.8, 109.7, 107.3, 38.1, 31.5 ppm. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₇H₁₇N₂O, 265.1335; found, 265.1335.

N,1-Dimethyl-N-(2-methylphenyl)-1H-indole-2-carboxamide

(8r). Yield: 3.883 g (93%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

1627, 1514, 1463, 1337, 1280, 1147, 752, 735. ¹H NMR (CDCl₃, 600

MHz): δ 7.35 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.24 (t, J =

7.7 Hz, 1H), 7.20−7.13 (m, 4H), 7.00 (t, J = 7.6 Hz, 1H), 5.87 (s, 1H),

3.99 (s, 3H), 3.41 (s, 3H), 2.18 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃,

150 MHz): δ 163.6, 143.6, 137.8, 134.7, 131.5, 131.4, 127.94, 127.89,

127.2, 126.0, 123.5, 121.9, 119.8, 109.7, 107.1, 37.3, 31.7, 17.6 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₉N₂O, 279.1492; found,

279.1491.

N,1-Dimethyl-N-(3-methylphenyl)-1H-indole-2-carboxamide

(8s). Yield: 3.799 g (91%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (ﬁlm, cm⁻¹):

1640, 1605, 1518, 1464, 1335, 1144, 749, 703. ¹H NMR (CDCl₃, 600

MHz): δ 7.40 (d, J = 8.0 Hz, 1H), 7.30 (dd, J₁= 0.8 Hz, J₂= 8.3 Hz, 1H),

7.25−7.20 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.06−6.99 (m, 2H), 6.98

(s, 1H), 6.94−6.88 (m, 1H), 6.04 (s, 1H), 3.95 (s, 3H), 3.49 (s, 3H),

2.29 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz)): δ 163.6, 144.8,

139.3, 137.8, 132.0, 129.1, 127.8, 127.1, 126.1, 123.9, 123.4, 121.8,

119.8, 109.7, 107.2, 38.3, 31.5, 21.3 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₈H₁₉N₂O, 279.1492; found, 279.1491. At room temper-

ature, the compound consists of a 90:10 mixture of two rotamers. Only

the signals of the major species were given.

N-(3-Methoxyphenyl)-N,1-dimethyl-1H-indole-2-carboxamide

(8t). Yield: 3.930 g (89%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (ﬁlm, cm⁻¹):

2941, 1640, 1602, 1465, 1317, 1232, 1144, 1045, 910, 733. ¹H NMR

(CDCl₃, 600 MHz): δ 7.40 (d, J = 7.9 Hz, 1H), 7.32−7.27 (m, 1H),

7.26−7.19 (m, 1H), 7.18−7.12 (m, 1H), 7.06−6.99 (m, 1H), 6.75−

6.72 (m, 1H), 6.71−6.68 (m, 2H), 6.12 (s, 1H), 3.94 (s, 3H), 3.71 (s,

3H), 3.49 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, MHz): δ 163.6, 160.1,

146.0, 137.8, 132.0, 129.9, 126.1, 123.4, 121.8, 119.8, 119.1, 112.7,

112.0, 109.7, 107.1, 55.3, 38.2, 31.5 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₈H₁₉N₂O₂, 295.1441; found, 295.1441.

1

IR (KBr, cm⁻¹): 3277, 1618, 1521, 1390, 1311, 1158, 745, 696. H

NMR (CDCl₃, 600 MHz): δ 9.67 (br s, 1H), 7.40−7.35 (m, 2H), 7.28

(d, J = 7.9 Hz, 2H), 7.22−7.16 (m, 3H), 7.02−6.97 (m, 1H), 5.24 (br s,

1H), 3.95 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 161.5, 139.6, 138.5, 135.2, 130.4

(2C), 129.9, 128.7 (2C), 127.7, 124.2, 122.1, 120.0, 111.5, 106.8, 45.8,

21.3, 12.8 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₉N₂O,

279.1492; found, 279.1491.

N-Ethyl-N-(4-ﬂuorophenyl)-1H-indole-2-carboxamide (8n). Yield:

5.041 g (72%). Pale yellow crystals. mp 181−183 °C (MeCN). IR

(KBr, cm⁻¹): 3288, 1610, 1505, 1406, 1313, 1277, 1219, 1140, 856,

746. ¹H NMR (CDCl₃, 600 MHz): δ 9.68 (br s, 1H), 7.42−7.37 (m,

2H), 7.31−7.26 (m, 2H), 7.24−7.21 (m, 1H), 7.20−7.16 (m, 2H),

7.04−7.00 (m, 1H), 5.22 (br s, 1H), 3.96 (q, J = 7.2 Hz, 2H), 1.26 (t, J =

7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 162.3 (d, J =

249.3 Hz), 161.5, 138.3 (d, J = 3.3 Hz), 135.3, 130.7 (d, J = 8.6 Hz, 2C),

129.5, 127.6, 124.5, 122.2, 120.2, 116.8, (d, J = 22.8 Hz, 2C), 111.6,

106.8, 45.9, 12.8 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₆FN₂O, 283.1241; found, 283.1243.

N-(4-Chlorophenyl)-N-ethyl-1H-indole-2-carboxamide (8m).

Yield: 4.964 g (67%). Yellow crystals. mp 197−199 °C (MeCN). IR

(KBr, cm⁻¹): 3294, 1611, 1491, 1408, 1280, 1156, 747, 540. ¹H NMR

(CDCl₃, 600 MHz): δ 9.67 (br s, 1H), 7.48−7.44 (m, 2H), 7.42−7.37

(m, 2H), 7.27−7.20 (m, 3H), 7.04−7.01 (m, 1H), 5.32 (br s, 1H), 3.95

(q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 161.4, 140.9, 135.3, 134.3, 130.3 (2C), 130.1

(2C), 129.4, 127.6, 124.6, 122.2, 120.3, 111.6, 107.0, 45.9, 12.8 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₆ClN₂O, 299.0946; found,

299.0943.

N-Phenyl-N-propyl-1H-indole-2-carboxamide (8o). Yield: 5.799 g

(84%). Yellow crystals. mp 196−197 °C (MeCN). IR (KBr, cm⁻¹):

3294, 1609, 1514, 1404, 1350, 1156, 749, 697. ¹H NMR (CDCl₃, 600

MHz): δ 9.82 (br s, 1H), 7.52−7.46 (m, 3H) 7.43−7.38 (m, 1H),

7.36−7.33 (m, 1H), 7.32−7.28 (m, 2H), 7.23−7.19 (m, 1H), 7.01−

6.97 (m, 1H), 5.16 (br s, 1H), 3.89 (t, J = 7.8 Hz, 2H), 1.72 (q, J = 7.6

Hz, 2H), 0.98 (t, J = 7.44 Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150

MHz): δ 161.5, 142.5, 135.1, 129.59 (2C), 129.56, 128.7 (2C), 128.3,

127.4, 124.1, 121.9, 119.8, 111.4, 106.7, 52.4, 20.6, 11.1 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₈H₁₉N₂O, 279.1492; found,

279.1491.

N-Butyl-N-phenyl-1H-indole-2-carboxamide (8p). Yield: 7.251 g

(100%). Yellow crystals. mp 228−230 °C (MeCN). IR (KBr, cm⁻¹):

3291, 1610, 1591, 1517, 1405, 1277, 747, 698. ¹H NMR (CDCl₃, 600

MHz): δ 9.83 (br s, 1H), 7.52−7.46 (m, 3H), 7.42−7.38 (m, 1H),

7.36−7.32 (m, 1H), 7.31−7.29 (m, 2H), 7.22−7.17 (m, 1H), 7.02−

6.97 (m, 1H), 5.16 (br s, 1H), 3.92 (t, J = 7.7 Hz, 2H), 1.71−1.63 (m,

2H), 1.45−1.36 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 161.6, 142.6, 135.3, 129.78 (2C), 129.76, 128.9

(2C), 128.5, 127.6, 124.3, 122.1, 120.0, 111.6, 106.9, 50.8, 29.7, 20.1,

13.9 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₉H₂₁N₂O,

293.1648; found, 293.1645.

N-(3-Chlorophenyl)-N,1-dimethyl-1H-indole-2-carboxamide

(8u). Yield: 4.482 g (100%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v→4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

3459, 1642, 1591, 1518, 1463, 1332, 765, 696. ¹H NMR (CDCl₃, 600

MHz): δ 7.27 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.28−7.24

(m, 1H), 7.23−7.21 (m, 1H), 7.20−7.16 (m, 2H), 7.07−7.02 (m, 1H),

7.00−6.95 (m, 1H), 6.08 (s, 1H), 3.96 (s, 3H), 3.50 (s, 3H) ppm.

¹³C{¹H} NMR (CDCl₃, MHz): δ 163.5, 146.1, 137.9, 134.7, 131.4,

130.2, 127.1, 126.6, 126.0, 125.2, 123.7, 121.9, 120.1, 109.8, 107.6, 38.2,

31.5 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₆ClN₂O,

299.0946; found, 299.0945.

5-Chloro-N,1-dimethyl-N-phenyl-1H-indole-2-carboxamide (8v).

Yield: 4.482 g (100%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

1630, 1594, 1515, 1462, 1393, 1142, 793, 696. ¹H NMR (CDCl₃, 600

MHz): δ 7.33 (d, J = 1.9 Hz, 1H), 7.30−7.24 (m, 2H), 7.23−7.18 (m,

2H), 7.15 (dd, J₁= 1.9 Hz, J₁= 8.8 Hz, 1H), 7.12 (d, J = 7.44 Hz, 2H),

5.91 (s, 1H), 3.92 (s, 3H), 3.51 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃,

MHz): δ 163.2, 144.6, 136.0, 133.2, 129.4 (2C), 127.1, 126.9, 126.5

(2C), 125.5, 123.7, 120.9, 110.8, 106.3, 38.1, 31.7 ppm. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₇H₁₆ClN₂O, 299.0946; found, 299.0945.

N-Ethyl-1-methyl-N-(4-methylphenyl)-1H-indole-2-carboxamide

(8w). Yield: 3.596 g (82%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

2932, 1641, 1514, 1402, 1279, 1104, 842, 734. ¹H NMR (CDCl₃, 600

MHz): δ 7.39 (d, J = 7.9 Hz, 1H), 7.32−7.27 (m, 1H), 7.24−7.19 (m,

1H), 7.07 (d, J = 8.0 Hz, 2H), 7.04−6.97 (m, 3H), 6.02 (br s, 1H), 3.97

(q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.28 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H)

ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.2, 140.5, 137.7, 136.9,

General Procedure for the Preparation of 1-Alkylated-

indole-2-carboxamides (8q−ab). Carboxamides (15 mmol) were

dissolved in DMF (40 mL), and Cs₂CO₃(19.548 g, 60 mmol, 4 equiv)

was added. The reaction mixture was stirred for 10 min at room

temperature, and the appropriate halide (31.5 mmol, 2.1 equiv) was

added to the reaction mixture in one portion. The mixture was stirred

for 72 h at room temperature. The reaction was followed by TLC. After

the reaction was complete, the solid compounds were ﬁltered oﬀ and

the ﬁltrate was evaporated. The residue was taken up in CH₂Cl₂(50

mL) and evaporated to silica gel. The crude product was puriﬁed by

ﬂash column chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/

v).

N,1-Dimethyl-N-phenyl-1H-indole-2-carboxamide (8q). Yield:

3.291 g (83%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow crystals. mp 98−99 °C

(MeCN) (lit.⁵¹80−82 °C, EtOH). IR (KBr, cm⁻¹): 1636, 1517, 1462,

1337, 1278, 1144, 798, 680. ¹H NMR (CDCl₃, 600 MHz): δ 7.28 (d, J =

I

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

132.6, 129.9 (2C), 127.4 (2C), 126.2, 123.2, 121.7, 119.7, 109.7, 106.7,

45.2, 31.5, 21.0, 13.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₂₁N₂O, 293.1648; found, 293.1648.

dropwise under Ar atm at room temperature. After the addition was

complete, the mixture was stirred at room temperature for 1 h. The

reaction was followed by TLC. After the reaction was complete, the

solvents were evaporated, and the residue was taken up in CH₂Cl₂(100

mL) and evaporated to silica gel. Puriﬁcation was carried out by ﬂash

column chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v).

The product was further puriﬁed by recrystallization from i-Pr₂O or

MeCN.

3-Iodo-N-phenyl-1H-indole-2-carboxamide (5a). Yield: 3.868 g

(89%). Puriﬁcation: ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 222−224 °C

(MeCN). IR (KBr, cm⁻¹): 3359, 1652, 1600, 1548, 1494, 1315, 1247,

742. ¹H NMR (CDCl₃, 600 MHz): δ 9.96 (br s, 1H), 9.07 (br s, 1H),

7.74 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.44−7.40 (m, 3H),

7.37 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H)

ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 158.3, 137.2, 135.7, 131.0,

130.2, 129.2 (2C), 126.1, 125.0, 122.8, 121.8, 120.3 (2C), 112.3, 59.5

ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₅H₁₂IN₂O, 362.9989;

found, 362.9987.

N-Ethyl-N-(4-ﬂuorophenyl)-1-methyl-1H-indole-2-carboxamide

(8x). Yield: 2.800 g (63%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (ﬁlm, cm⁻¹):

2975, 1640, 1507, 1402, 1274, 1220, 1146, 839, 750. ¹H NMR (CDCl₃,

600 MHz): δ 7.40 (d, J = 7.9 Hz, 1H), 7.32−7.29 (m, 1H), 7.26−7.21

(m, 1H), 7.12−7.06 (m, 2H), 7.05−7.01 (m, 1H), 7.00−6.95 (m, 2H),

5.99 s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.24 (t, J = 7.1 Hz,

3H) ppm. ¹³C{¹H} NMR (CDCl₃, MHz): δ 163.1, 161.2 (d, J = 247.1

Hz), 139.1, 137.7, 132.0, 129.2 (d, J = 8.7 Hz), 126.0, 123.5, 121.7,

119.9, 116.2 (d, J = 23.0 Hz), 109.7, 106.9, 45.3, 31.5, 12.9 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₈H₁₈FN₂O, 297.1398; found,

297.1396.

N-(4-Chlorophenyl)-N-ethyl-1-methyl-1H-indole-2-carboxamide

(8y). Yield: 3.097 g (66%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (ﬁlm, cm⁻¹):

2974, 1639, 1490, 1464, 1411, 1282, 1094, 737. ¹H NMR (CDCl₃, 600

MHz): δ 7.36 (d, J = 8.0 Hz, 1H), 7.44−7.39 (m, 1H), 7.27−7.22 (m,

3H), 7.07−7.01 (m, 3H), 6.03 (s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.93 (s,

3H), 1.24 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz):

δ 163.1, 141.8, 137.8, 132.6, 132.0, 129.5 (2C), 128.8 (2C), 126.0,

123.6, 121.9, 120.0, 109.7, 107.2, 45.3, 31.5, 13.0 ppm. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₈H₁₈ClN₂O, 313.1102; found, 313.1102.

1-Benzyl-N-methyl-N-phenyl-1H-indole-2-carboxamide (8z).

Yield: 4.756 g (94%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

3051, 1633, 1592, 1527, 1452, 1384, 1144, 751. ¹H NMR (CDCl₃, 600

MHz): δ 7.39 (d, J = 8.2 Hz, 1H), 7.36−7.33 (m, 1H), 7.31−7.28 (m,

1H), 7.27−7.26 (m, 1H), 7.25−7.22 (m, 1H), 7.21−7.18 (m, 1H),

7.17−7.13 (m, 3H), 7.12−7.08 (m, 2H), 7.05−7.00 (m, 1H), 6.71 (d, J

= 6.0 Hz, 2H), 6.05 (s, 1H), 5.71 (s, 2H), 3.39 (s, 3H) ppm. ¹³C{¹H}

NMR (CDCl₃, 150 MHz): δ 163.7, 144.8, 138.6, 137.6, 131.6, 129.2

(2C), 128.5 (2C), 127.4, 127.1 (2C), 126.9, 126.7 (2C), 126.2, 123.7,

121.9, 120.1, 110.1, 108.4, 47.4, 38.1 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₂₃H₂₁N₂O, 341.1648; found, 341.1648.

N,1-Dibenzyl-N-phenyl-1H-indole-2-carboxamide (8aa). Yield:

5.435 g (87%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless oil. IR (ﬁlm, cm⁻¹):

3031, 1637, 1595, 1494, 1454, 1270, 959, 730, 698. ¹H NMR (CDCl₃,

600 MHz): δ 7.37 (t, J = 8.1 Hz, 2H), 7.23−7.20 (m, 3H), 7.18−7.17

(m, 3H), 7.14−7.10 (m, 3H), 7.09−7.05 (m, 2H), 7.04−6.97 (m, 4H),

6.49 (d, J = 8.2 Hz, 2H), 6.05 (s, 1H), 5.73 (s, 2H), 5.02 (s, 2H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.4, 143.1, 138.6, 137.7, 136.9,

131.4, 128.9 (2C), 128.6, 128.42 (2C), 128.36 (2C), 128.2 (2C), 128.1,

127.5, 127.4, 127.3, 127.2, 126.9, 126.1, 123.8, 121.9, 120.0, 109.9,

108.8, 53.4, 47.2 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₉H₂₅N₂O, 417.1916; found, 417.1964. At room temperature, the

compound consists of an 81:19 mixture of two rotamers. Only the

signals of the major species were given.

3-Iodo-N-(4-methylphenyl)-1H-indole-2-carboxamide (5b).

Yield: 4.243 g (94%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). mp 246−247 °C (MeCN).

1

IR (KBr, cm⁻¹): 3321, 1655, 1603, 1546, 1302, 1225, 811, 739. H

NMR (CDCl₃, 600 MHz): δ 9.76 (br s, 1H), 9.00 (br s, 1H), 7.61 (d, J

= 8.2 Hz, 2H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.38 (t,

J = 7.6 Hz, 1H), 7.28−7.24 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 2.37 (s,

3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 158.1, 135.6, 134.7,

134.6, 131.1, 130.4, 129.7 (2C), 126.1, 122.8, 121.8, 120.3 (2C), 112.2,

59.2, 21.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₆H₁₄IN₂O,

377.0145; found, 377.0146.

N-Benzyl-3-iodo-N-phenyl-1H-indole-2-carboxamide (5c). Yield:

3.799 g (70%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 180−181

°C (MeCN). IR (KBr, cm⁻¹): 3259, 1647, 1595, 1450, 1441, 1309, 743,

724, 686. ¹H NMR (CDCl₃, 600 MHz): δ 8.09 (br s, 1H), 7.54 (d, J =

7.8 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.42−7.36 (m, 2H), 7.35−7.30

(m, 2H), 7.29−7.22 (m, 3H), 7.21−7.15 (m, 2H), 7.14−7.11 (m, 2H),

5.77 (s, 2H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 159.2, 138.2,

137.6, 137.2, 133.3, 129.7 (2C), 129.1 (2C), 128.7, 127.5, 126.7 (2C),

125.7, 125.0, 123.1, 121.8, 120.0 (2C), 111.0, 61.3, 48.7 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₂₂H₁₈IN₂O, 453.0458; found,

453.0460.

3-Iodo-N-methyl-N-phenyl-1H-indole-2-carboxamide (5d). Yield:

4.018 g (89%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Pale yellow crystals. mp 171−172

°C (i-Pr₂O). IR (KBr, cm⁻¹): 3261, 1630, 1593, 1530, 1492, 1343, 743,

697. ¹H NMR (CDCl₃, 600 MHz): δ 9.29 (br s, 1H), 7.35 (d, J = 8.0

Hz, 1H), 7.27−7.22 (m, 2H), 7.21−7.14 (m, 5H), 7.13−7.09 (m, 1H),

3.52 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.9, 143.2,

135.8, 132.5, 130.1, 129.2 (2C), 127.0, 126.2 (2C), 124.7, 122.0, 121.0,

111.8, 62.1, 38.5 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₆H₁₄IN₂O, 377.0145; found, 377.0146.

3-Chloro-N-methyl-N-phenyl-1H-indole-2-carboxamide (5dCl).

Yield: 3.075 g (90%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow crystals. mp 142−

143 °C (i-Pr₂O). IR (KBr, cm⁻¹): 3237, 1630, 1595, 1541, 1494, 1421,

1382, 744, 699. ¹H NMR (CDCl₃, 600 MHz): δ 9.46 (br s, 1H), 7.43

(d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.28−7.21 (m, 3H), 7.20−

7.15 (m, 3H), 7.12−7.06 (m, 1H), 3.58 (s, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 163.4, 143.5, 134.9, 129.0 (2C), 126.9, 126.7,

126.0 (2C), 125.2, 124.8, 120.6, 119.1, 112.0, 106.9, 38.6 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₆H₁₄ClN₂O, 285.0789; found,

285.0793.

N,1-Dibenzyl-N-(4-methylphenyl)-1H-indole-2-carboxamide

(8ab). Yield: 6.458 g (100%). Puriﬁcation: ﬂash column chromatog-

raphy (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless oil. IR

(KBr, cm⁻¹): 1635, 1512, 1453, 1267, 1194, 1163, 743, 697. ¹H NMR

(CDCl₃, 600 MHz): δ 7.40 (d, J = 8.0 Hz, 2H), 7.24−7.23 (m, 2H),

7.22−7.21 (m, 4H), 7.21−7.20 (m, 1H), 7.15−7.13 (m, 2H), 7.08−

7.06 (m, 2H), 7.04−7.02 (m, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.38 (d, J =

8.1 Hz, 2H), 6.07 (s, 1H), 5.73 (s, 2H), 5.00 (s, 2H), 2.19 (s, 3H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.5, 140.5, 140.1, 138.7, 138.0,

137.7, 137.0, 136.8, 131.6, 131.2, 129.6, 128.6, 128.5 (2C), 128.29,

128.26, 127.4, 127.3, 127.2, 126.2, 125.6, 123.7, 121.9, 120.8, 120.0,

110.0, 108.7, 53.5, 47.2, 20.9 ppm. HRMS (ESI) m/z: [M + H]⁺calcd

for C₃₀H₂₇N₂O, 431.2118; found, 431.2127. At room temperature, the

compound consists of a 85:15 mixture of two rotamers. Only the signals

of the major species were given.

3-Bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (5dBr).

Yield: 2.797 g (71%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow crystals. mp 154−

155 °C (i-Pr₂O). IR (KBr, cm⁻¹): 3249, 1632, 1591, 1539, 1493, 1379,

742, 698. ¹H NMR (CDCl₃, 600 MHz): δ 9.75 (br s, 1H), 7.43 (d, J =

8.0 Hz, 1H), 7.27−7.22 (m, 3H), 7.21−7.14 (m, 4H), 7.12−7.07 (m,

1H), 3.54 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.8,

General Procedure for the Preparation of 3-Iodo-indole-2-

carboxamides (5). Carboxamides (8, 12 mmol) were dissolved in

acetone (170 mL), and the solution of the halogen source (N-

iodosuccinimide, NBS or NCS, 12 mmol) in THF (70 mL) was added

J

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

143.3, 135.3, 129.0 (2C), 128.9, 126.77, 126.76, 126.1 (2C), 124.7,

120.8, 120.0, 112.0, 93.2, 38.5 ppm. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₆H₁₄BrN₂O, 329.0284; found, 329.0289.

175 °C (MeCN). IR (KBr, cm⁻¹): 3261, 1633, 1590, 1491, 1378, 1124,

802, 693. ¹H NMR (CDCl₃, 600 MHz): δ 9.88 (br s, 1H), 7.29 (d, J =

1.6 Hz, 1H), 7.25−7.20 (m, 2H), 7.19−7.14 (m, 3H), 7.10 (dd, J₁= 2.0

Hz, J₂= 8.7 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 3.48 (s, 3H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 164.0, 142.7, 134.2, 134.1, 131.0,

129.2 (2C), 127.2, 126.8, 126.2 (2C), 125.0, 121.2, 113.1, 60.1, 38.4

ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₆H₁₃ClIN₂O, 410.9756;

found, 410.9758.

3-Iodo-N-methyl-N-(2-methylphenyl)-1H-indole-2-carboxamide

(5e). Yield: 4.402 g (94%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). mp 185−186 °C (MeCN).

IR (KBr, cm⁻¹): 3167, 1626, 1584, 1392, 1121, 756, 742, 698. ¹H NMR

(CDCl₃, 600 MHz): δ 8.06 (br s, 1H), 7.44−7.37 (m, 1H), 7.25−7.23

(m, 1H), 7.22−7.20 (m, 2H), 7.19−7.18 (m, 2H), 7.17−7.13 (m, 1H),

7.12−7.08 (m, 1H), 3.40 (s, 3H), 2.24 (s, 3H), ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 162.4, 142.0, 135.5 (2C), 132.0, 130.1, 128.5,

127.8, 127.5, 125.5, 122.5, 121.1 (2C), 111.5, 64.7, 37.7, 18.0 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₆IN₂O, 391.0302; found,

391.0311. At room temperature, the compound consists of a 69:31

mixture of two rotamers. Only the signals of the major species were

given.

3-Iodo-N-methyl-N-(3-methylphenyl)-1H-indole-2-carboxamide

(5f). Yield: 4.542 g (97%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp

174−176 °C (MeCN). IR (KBr, cm⁻¹): 3167, 1626, 1584, 1392, 1121,

756, 742, 698. ¹H NMR (CDCl₃, 600 MHz): δ 9.35 (br s, 1H), 7.36 (d,

J = 8.3 Hz, 1H), 7.21−7.16 (m, 1H), 7.15−7.13 (m, 1H), 7.14−7.08

(m, 2H), 7.06 (s, 1H), 7.01−6.98 (m, 1H), 6.97−6.93 (m, 1H), 3.49 (s,

3H), 2.26 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.9,

143.0, 139.2, 135.7, 132.6, 130.0, 129.0, 127.9, 126.8, 124.6, 123.4,

121.9, 121.0, 111.8, 61.8, 38.6, 21.3 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₇H₁₆IN₂O, 391.0302; found, 391.0310.

N-Ethyl-3-iodo-N-phenyl-1H-indole-2-carboxamide (5k). Yield:

4.402 g (94%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 201−202

°C (MeCN, decomp.). IR (KBr, cm⁻¹): 3253, 1630, 1593, 1529, 1493,

1301, 742, 698. ¹H NMR (CDCl₃, 600 MHz): δ 9.07 (br s, 1H), 7.35

(d, J = 8.1 Hz, 1H), 7.27−7.21 (m, 2H), 7.20−7.14 (m, 5H), 7.13−7.08

(m, 1H), 4.01 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H}

NMR (CDCl₃, 150 MHz): δ 163.2, 141.6, 135.7, 132.7, 130.1, 129.2

(2C), 127.1 (3C), 124.7, 122.0, 121.0, 111.7, 62.1, 45.7, 13.1 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₆IN₂O, 391.0302; found,

391.0306.

N-Ethyl-3-iodo-N-(4-methylphenyl)-1H-indole-2-carboxamide

(5l). Yield: 4.414 g (91%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp

170−172 °C (MeCN). IR (KBr, cm⁻¹): 3277, 1631, 1529, 1511, 1395,

1300, 819, 742. ¹H NMR (CDCl₃, 600 MHz): δ 9.14 (br s, 1H), 7.35

(d, J = 7.9 Hz, 1H), 7.20−7.15 (m, 1H), 7.14−7.12 (m, 1H), 7.11−7.08

(m, 1H), 7.07−7.04 (m, 2H), 7.03−6.99 (m, 2H), 3.95 (q, J = 7.1 Hz,

2H), 2.26 (s, 3H), 1.22 (t, J = 6.9 Hz, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 163.0, 138.7, 136.9, 135.4, 132.7, 129.8, 129.6

(2C), 126.7 (2C), 124.3, 121.7, 120.7, 111.5, 61.6, 45.5, 20.8, 12.8 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₈IN₂O, 405.0458; found,

405.0461.

N-Ethyl-N-(4-ﬂuorophenyl)-3-iodo-1H-indole-2-carboxamide

(5m). Yield: 3.380 g (69%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 73−

74 °C (MeCN). IR (KBr, cm⁻¹): 3441, 3249, 1629, 1508, 1426, 1221,

837, 744. ¹H NMR (CDCl₃, 600 MHz): δ 9.44 (br s, 1H), 7.34 (d, J =

8.0 Hz, 1H), 7.22−7.09 (m, 5H), 6.94−6.87 (m, 2H), 3.92 (q, J = 7.1

Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150

MHz): δ 163.7, 161.1 (d, J = 248.0 Hz), 160.3, 137.4, 135.7, 132.9,

130.0, 128.9, 128.8, 124.7, 121.9, 121.1, 116.0 (d, J = 22.4 Hz), 111.8,

61.4, 45.8, 13.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₅FIN₂O, 409.0208; found, 409.0216.

N-(4-Chlorophenyl)-N-ethyl-3-iodo-1H-indole-2-carboxamide

(5n). Yield: 4.128 g (81%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp

171−172 °C (MeCN). IR (KBr, cm⁻¹): 3255, 1631, 1530, 1489, 1413,

1092, 874, 745. ¹H NMR (CDCl₃, 600 MHz): δ 9.56 (br s, 1H), 7.34

(d, J = 8.0 Hz, 1H), 7.22−7.15 (m, 4H), 7.14−7.10 (m, 1H), 7.09−7.06

(m, 2H), 3.93 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H}

NMR (CDCl₃, 150 MHz): δ 163.8, 140.0, 135.8, 132.8, 132.7, 130.0,

129.2 (2C), 128.3 (2C), 124.8, 121.9, 121.2, 111.9, 61.5, 45.7, 13.0

ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅ClIN₂O, 424.9912;

found, 424.9920.

3-Iodo-N-(3-methoxyphenyl)-N-methyl-1H-indole-2-carboxa-

mide (5g). Yield: 4.582 g (94%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Pale

brown crystals. mp 138−140 °C (MeCN). IR (KBr, cm⁻¹): 3279, 1613,

1

1586, 1519, 1393, 1232, 1115, 825, 752, 699. H NMR (CDCl₃, 600

MHz): δ 9.57 (br s, 1H), 7.40−7.38 (m, 1H), 7.37−7.36 (m, 1H),

7.20−7.19 (m, 1H), 7.16−7.11 (m, 1H), 7.03−7.01 (m, 1H), 6.93−

6.90 (m, 1H), 6.88−6.85 (m, 1H), 6.78−6.76 (m, 1H), 3.82 (s, 3H),

3.50 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 160.7, 145.1,

135.3, 129.9, 124.8, 124.4, 122.1, 121.1, 120.2, 118.5, 114.2, 113.4,

111.5, 107.2, 55.5, 39.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₆IN₂O₂, 407.0253; found, 407.0253. At room temperature, the

compound consists of a 60:40 mixture of two rotamers. Only the signals

of the major species were given.

N-(3-Chlorophenyl)-3-iodo-N-methyl-1H-indole-2-carboxamide

(5h). Yield: 4.090 g (83%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Pale yellow crystals. mp

173−174 °C (MeCN). IR (KBr, cm⁻¹): 1650, 1590, 1480, 1463, 1388,

1308, 745, 694. ¹H NMR (CDCl₃, 600 MHz): δ 9.50 (br s, 1H), 7.35

(d, J = 8.5 Hz, 1H), 7.32−7.30 (m, 1H), 7.24−7.21 (m, 2H), 7.17−7.09

(m, 3H), 7.00−6.95 (m, 1H), 3.51 (s, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 164.3, 144.3, 135.9, 134.4, 132.3, 130.1, 130.0,

127.0, 126.3, 125.0, 124.4, 122.1, 121.2, 111.9, 62.0, 38.5 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₆H₁₃ClIN₂O, 410.9756; found,

410.9755. At room temperature, the compound consists of a 97:3

mixture of two rotamers. Only the signals of the major species were

given.

3-Iodo-5-methoxy-N-methyl-N-phenyl-1H-indole-2-carboxa-

mide (5i). Yield: 4.874 g (100%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Brown

crystals. mp 118−119 °C (MeCN). IR (KBr, cm⁻¹): 3271, 1630, 1590,

1528, 1379, 1203, 1121, 698. ¹H NMR (CDCl₃, 600 MHz): δ 8.99 (br

s, 1H), 7.31−7.22 (m, 3H), 7.21−7.14 (m, 3H), 7.08−7.02 (m, 1H),

6.77−6.70 (m, 1H), 3.82, (s, 3H), 3.53 (s, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 163.8, 155.2, 143.3, 132.6, 130.7, 130.6, 129.2

(2C), 126.9, 126.2 (2C), 116.1, 112.8, 102.5, 61.9, 55.7, 38.5 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₆IN₂O₂, 407.0251; found,

407.0254. At room temperature, the compound consists of a 90:10

mixture of two rotamers. Only the signals of the major species were

given.

3-Iodo-N-phenyl-N-propyl-1H-indole-2-carboxamide (5o). Yield:

4.657 g (96%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 203−205

°C MeCN). IR (KBr, cm⁻¹): 3258, 1628, 1593, 1530, 1494, 1402, 739,

697. ¹H NMR (CDCl₃, 600 MHz): δ 8.94 (br s, 1H), 7.35 (d, J = 8.0

Hz, 1H), 7.28−7.22 (m, 2H), 7.20−7.15 (m, 4H), 7.14−7.08 (m, 2H),

3.89 (quint, J = 6.0 Hz, 2H), 1.68 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.4 Hz,

3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.3, 141.9, 135.6,

132.7, 130.1, 129.2 (2C), 127.1, 127.0 (2C), 124.7, 122.0, 121.0, 111.6,

62.2, 52.3, 21.0, 11.3 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₈H₁₈IN₂O, 405.0458; found, 405.0466.

N-Butyl-3-iodo-N-phenyl-1H-indole-2-carboxamide (5p). Yield:

4.216 g (84%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp 177−179

°C (MeCN). IR (KBr, cm⁻¹): 3276, 1630, 1594, 1526, 1494, 1392, 739,

695. ¹H NMR (CDCl₃, 600 MHz): δ 9.30 (br s, 1H), 7.33 (d, J = 8.0

Hz, 1H), 7.24−7.20 (m, 2H), 7.19−7.11 (m, 5H), 7.10−7.06 (m, 1H),

5-Chloro-3-iodo-N-methyl-N-phenyl-1H-indole-2-carboxamide

(5j). Yield: 4.928 g (100%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow crystals. mp 174−

K

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

3.88 (t, J = 7.8 Hz, 2H), 1.63 (quint, J = 7.6 Hz, 2H), 1.39−1.30 (m,

2H), 0.88 (t, J = 7.4 Hz, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz):

δ 163.5, 141.8, 135.7, 133.0, 130.0, 129.1 (2C), 127.1, 127.0 (2C),

124.5, 121.9, 120.9, 111.8, 61.8, 50.6, 29.8, 20.1, 13.8 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₉H₂₀IN₂O, 419.0615; found,

419.0613.

N,1-Dimethyl-3-iodo-N-phenyl-1H-indole-2-carboxamide (5q).

Yield: 4.495 g (96%). Puriﬁcation ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

1639, 1591, 1493, 1389, 1276, 1101, 763, 696. ¹H NMR (CDCl₃, 600

MHz): δ 7.50−7.31 (m, 1H), 7.30−6.91 (m, 8H), 3.79 (s, 3H), 3.56 (s,

3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.5, 142.5, 136.9,

136.1, 129.6, 128.9 (2C), 127.0, 125.7 (2C), 123.7, 121.7, 120.8, 109.7,

58.4, 31.8, 31.6 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₆IN₂O, 391.0302; found, 391.0309. At room temperature, the

compound consists of a 87:13 mixture of two rotamers. Only the signals

of the major species were given.

5-Chloro-3-iodo-N,1-dimethyl-N-phenyl-1H-indole-2-carboxa-

mide (5v). Yield: 5.096 g (100%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (KBr, cm⁻¹): 1640, 1594, 1494, 1640, 1278, 1101, 827, 698. ¹H

NMR (CDCl₃, 600 MHz): δ 7.33−7.26 (m, 1H), 7.24−7.17 (m, 3H),

7.17−7.15 (m, 1H), 7.13−7.05 (m, 3H), 3.78 (s, 3H), 3.57 (s, 3H)

ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.0, 142.4, 135.3, 130.6,

129.4, 128.9, 127.2, 126.6, 125.7, 124.2, 123.8, 121.2, 110.9, 106.4, 57.3,

37.4, 32.1 ppm. HRMS calcd for C₁₇H₁₅ClIN₂O [M + H]⁺, 424.9912;

found, 424.9912. At room temperature, the compound consists of a

92:8 mixture of two rotamers. Only the signals of the major species were

given.

N-Ethyl-3-iodo-N-(4-methylphenyl)-1-methyl-1H-indole-2-car-

boxamide (5w). Yield: 5.071 g (97%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (KBr, cm⁻¹): 2932, 1642, 1511, 1461, 1397, 1310, 819, 741. ¹H

NMR (CDCl₃, 600 MHz): δ 7.30 (d, J = 6.5 Hz, 1H), 7.25−7.16 (m,

2H), 7.16−7.10 (m, 1H), 7.09−7.01 (m, 2H), 6.99−7.89 (m, 2H),

4.13−3.92 (m, 2H), 3.78 (br s, 3H), 2.19 (br s, 3H), 1.30 (br s, 3H)

ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 162.9, 138.5, 137.2, 136.9,

136.7, 129.6, 129.5, 126.6, 123.5, 121.7, 120.6, 109.7, 57.4, 45.0, 31.8,

20.99, 20.93, 13.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₂₀IN₂O, 419.0615; found, 419.0617.

N-Ethyl-N-(4-ﬂuorophenyl)-3-iodo-1-methyl-1H-indole-2-car-

boxamide (5x). Yield: 4.611 g (91%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (ﬁlm, cm⁻¹): 2974, 2936, 1647, 1507, 1462, 1274, 838, 744. ¹H

NMR (CDCl₃, 600 MHz): δ 7.37−7.28 (m, 1H), 7.27−7.22 (m, 1H),

7.21−7.18 (m, 3H), 7.17−7.06 (m, 2H), 6.85 (br s, 1H), 4.12−3.95 (m,

2H), 3.80 (br s, 3H), 1.42−1.17 (m, 3H) ppm. ¹³C{¹H} NMR (CDCl₃,

150 MHz): δ 162.9, 161.2 (d, J = 248.5 Hz), 137.1, 136.8, 136.3, 129.5,

129.3, 128.5, 123.8, 121.7, 120.8, 116.2, 115.8 (d, J = 22.4 Hz), 109.7,

58.2, 45.0, 31.8, 13.0 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₈H₁₇FIN₂O, 423.0364; found, 423.0362.

N-(4-Chlorophenyl)-N-ethyl-3-iodo-1-methyl-1H-indole-2-car-

boxamide (5y). Yield: 5.054 g (96%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (ﬁlm, cm⁻¹): 3056, 2793, 1645, 1461, 1283, 1093, 743. ¹H NMR

(CDCl₃, 600 MHz): δ 7.34−7.25 (m, 1H), 7.20−7.15 (m, 1H), 7.14−

7.10 (m, 1H), 7.09−6.93 (m, 5H), 4.01−3.85 (m, 2H), 3.71 (s, 3H),

1.13−1.12 (m, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 162.5,

139.4, 136.6, 136.0, 132.3, 129.3, 129.2, 128.8, 128.6, 127.8, 123.8,

121.5, 120.8, 109.7, 58.2, 45.0, 31.7, 12.9 ppm HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₈H₁₇ClIN₂O, 439.0069; found, 439.0068. At room

temperature, the compound consists of a 88:12 mixture of two

rotamers. Only the signals of the major species were given.

1-Benzyl-N-ethyl-3-iodo-N-phenyl-1H-indole-2-carboxamide

(5z). Yield: 4.756 g (85%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

3059, 1645, 1594, 1494, 1454, 1393, 1160, 743, 699. ¹H NMR (CDCl₃,

600 MHz): δ 7.41−7.37 (m, 1H), 7.36−7.32 (m, 1H), 7.33−7.25 (m,

7H), 7.22−7.18 (m, 2H), 7.17−7.13 (m, 1H), 7.13−7.08 (m, 1H),

7.04−7.00 (m, 1H), 5.59−5.39 (m, 2H), 3.78−3.62 (m, 3H) ppm.

¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.5, 142.5, 136.9, 129.6, 129.1,

128.7 (2C), 128.5, 127.9 (2C), 127.4 (2C), 126.9, 125.9 (2C), 124.2,

122.0, 121.0, 120.0, 110.3, 53.4, 48.5, 30.9 ppm. HRMS (ESI) m/z: [M

+ H]⁺calcd for C₂₃H₂₀IN₂O, 467.0615; found, 467.0621. At room

temperature, the compound consists of a mixture of two rotamers. Only

the signals of the major species were given.

N,1-Dibenzyl-3-iodo-N-phenyl-1H-indole-2-carboxamide (5aa).

Yield: 5.468 g (84%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow oil. IR (KBr, cm⁻¹):

3029, 1636, 1494, 1453, 1345, 1266, 740, 697. ¹H NMR (CDCl₃, 600

MHz): 7.33−7.29 (m, 2H), 7.24−7.19 (m, 7H), 7.18−7.07 (m, 7H),

6.96−6.87 (m, 2H), 6.64 (br s, 1H), 5.58−5.42 (m, 2H), 5.21−4.87 (m,

2H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 164.5, 140.2, 136.9,

131.0, 129.8, 129.1, 128.7, 128.6, 128.4 (2C), 128.3, 127.9, 127.67,

127.65, 127.5, 127.1, 126.7, 126.5, 123.3, 122.1, 120.7, 120.1, 114.2,

111.0, 110.4, 110.0, 53.6, 48.6, 31.0 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₂₉H₂₄IN₂O, 543.0928; found, 543.0928. At room temper-

3-Iodo-N,1-dimethyl-N-(2-methylphenyl)-1H-indole-2-carboxa-

mide (5r). Yield: 4.803 g (99%). Puriﬁcation ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless

crystals. mp 142.0−142.5 °C (MeCN). IR (KBr, cm⁻¹): 1652, 1491,

1

1463, 1391, 1338, 1172, 1057, 738. H NMR (CDCl₃, 600 MHz): δ

7.50 (d, J = 8.4 Hz, 2H), 7.36−7.35 (m, 1H), 7.34−7.32 (m, 2H),

7.27−7.26 (m, 1H), 7.24−7.21 (m, 1H), 7.06−7.02 (m, 1H), 3.89 (s,

3H), 3.47 (s, 3H), 2.38 (s, 3H), ppm. ¹³C{¹H} NMR (CDCl₃, 150

MHz): δ 164.0, 137.2, 131.5, 131.2, 129.8, 128.4, 128.2, 127.6, 127.24,

127.20, 126.6, 124.0, 121.8, 121.1, 109.9, 39.7, 31.7, 18.9 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₈H₁₈IN₂O, 405.0458; found,

405.0461. At room temperature, the compound consists of a 60:40

mixture of two rotamers. Only the signals of the major species were

given.

3-Iodo-N,1-dimethyl-N-(3-methylphenyl)-1H-indole-2-carboxa-

mide (5s). Yield: 4.414 g (91%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (KBr, cm⁻¹): 1640, 1528, 1463, 1387, 1292, 1129, 753, 700. ¹H

NMR (CDCl₃, 600 MHz): δ 7.38−7.29 (m, 1H), 7.23−7.18 (m, 2H),

7.17−7.10 (m, 1H), 7.10−6.97 (m, 2H), 6.97−6.80 (m, 2H), 3.80 (s,

3H), 3.57 (s, 3H), 2.23 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150

MHz): δ 163.5, 142.5, 138.8, 136.9, 136.4, 129.6, 128.7, 127.9, 126.5,

123.7, 122.8, 121.7, 120.7, 109.7, 58.2, 31.5, 31.8, 21.2 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₈H₁₈IN₂O, 405.0458; found,

405.0466. At room temperature, the compound consists of a 87:13

mixture of two rotamers. Only the signals of the major species were

given.

3-Iodo-N-(3-methoxyphenyl)-N,1-dimethyl-1H-indole-2-carbox-

amide (5t). Yield: 3.732 g (74%). Puriﬁcation ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Brown

oil. IR (KBr, cm⁻¹): 2939, 1646, 1602, 1464, 1232, 1044, 747, 699. ¹H

NMR (CDCl₃, 600 MHz): δ 7.41 (d, J = 7.9 Hz, 1H), 7.32−7.29 (m,

1H), 7.24−7.21 (m, 1H), 7.15−7.14 (m, 1H), 7.04−7.00 (m, 1H),

6.76−6.72 (m, 2H), 6.71−6.70 (m, 1H), 3.94 (s, 3H), 3.73 (s, 3H),

3.50 (s, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 163.7, 146.0,

137.8, 132.0, 130.0, 123.8, 123.4, 121.7, 120.8, 119.8, 117.8, 112.9,

111.8, 109.7, 107.1, 55.3, 38.2, 31.8 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₈H₁₈IN₂O₂, 421.0407; found, 421.0416. At room

temperature, the compound consists of a 60:40 mixture of two

rotamers. Only the signals of the major species were given.

N-(3-Chlorophenyl)-3-iodo-N,1-dimethyl-1H-indole-2-carboxa-

mide (5u). Yield: 5.096 g (100%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (KBr, cm⁻¹): 3451, 1646, 1589, 1461, 1461, 1332, 1090, 743. ¹H

NMR (CDCl₃, 600 MHz): δ 7.35 (d, J = 7.8 Hz, 1H), 7.32−7.28 (m,

2H), 7.27−7.24 (m, 1H), 7.19−7.14 (m, 1H), 7.13−7.06 (m, 2H),

7.05−6.90 (m, 1H), 3.84 (s, 3H), 3.54 (s, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 163.5, 143.7, 137.1, 135.6, 134.3, 129.8, 129.5,

127.2, 126.1, 124.1, 124.0, 121.1, 121.0, 109.8, 58.6, 37.8, 31.8 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅ClIN₂O, 424.9912;

found, 424.9922. At room temperature, the compound consists of a

96:4 mixture of two rotamers. Only the signals of the major species were

given.

L

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

ature, the compound consists of a 80:20 mixture of two rotamers. Only

the signals of the major species were given.

6fG2 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v), followed by recrystallization from 1,4-

dioxane−EtOAc.

N,1-Dibenzyl-3-iodo-N-(4-methylphenyl)-1H-indole-2-carboxa-

mide (5ab). Yield: 6.210 g (93%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Yellow

oil. IR (ﬁlm, cm⁻¹): 3030, 1639, 1511, 1479, 1346, 1268, 1157, 740,

699. ¹H NMR (CDCl₃, 600 MHz): δ 7.33−7.30 (m, 2H), 7.29−7.26

(m, 2H), 7.23−7.20 (m, 3H), 7.19−7.16 (m, 3H), 7.15−7.12 (m, 2H),

7.11−7.06 (m, 2H), 6.74−6.65 (m, 2H), 6.62−6.47 (m, 2H), 5.52−

5.39 (m, 2H), 5.22−5.03 (m, 2H), 2.11 (s, 3H) ppm. ¹³C{¹H} NMR

(CDCl₃, 150 MHz): δ 163.4, 140.1, 138.4, 138.0, 137.6, 136.9, 136.0,

129.8, 129.3, 129.1, 128.9, 128.7, 128.6, 128.32, 128.28, 127.8, 127.6,

127.5, 127.4, 127.3, 126.9, 124.0, 122.0, 113.9, 110.5, 110.0, 60.0, 53.6,

48.7, 20.9 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₃₀H₂₆IN₂O,

557.1084; found, 557.1089. At room temperature, the compound

consists of a 75:25 mixture of two rotamers. Only the signals of the

major species were given.

General Procedure for the Preparation of indolo[2,3-

c]quinolin-6-ones (6). 3-Iodo-indolecarboxamides (5, 0.266

mmol), K₂CO₃(73 mg, 0.53 mmol, 2 equiv), and DPPP (44 mg,

0.053 mmol, 0.4 equiv) were put in a sealed ﬂask and dissolved in dry

DMF (3 mL). An inert gas (Ar) was bubbled trough the mixture for 15

min, and Pd(OAc)₂(12 mg, 0.053 mmol, 0.2 equiv) was put in the ﬂask.

The reaction mixture was stirred under Ar atm at 90 °C for 1 h in a

metal block. The reaction was followed by TLC. After the reaction was

complete, the solvents were evaporated, and the residue was taken up in

CH₂Cl₂(20 mL) and evaporated to silica gel. The crude product was

puriﬁed by ﬂash column chromatography in hexane−EtOAc. The

product was further puriﬁed by recrystallization from EtOAc or

EtOAc−1,4-dioxane.

5-Methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6d). Yield:

43 mg (65%). Puriﬁcation ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 301−303

°C (1,4-dioxane−EtOAc) (lit.²⁰> 300 °C, 1,4-dioxane−EtOAc). IR

(KBr, cm⁻¹): 3174, 1639, 1563, 1382, 1332, 1253, 1132, 763. ¹H NMR

(DMSO-d₆, 600 MHz): δ 12.41 (br s, 1H), 8.54 (dd, J₁= 1.3 Hz, J₂= 7.8

Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.66 (d, J =

8.3 Hz, 1H), 7.57−7.52 (m, 1H), 7.51−7.47 (m, 1H), 7.46−7.42 (m,

1H), 7.35−7.31 (m, 1H), 3.84 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-

d₆, 150 MHz): δ 155.6, 139.2, 136.1, 127.2, 126.6, 126.0, 123.7, 122.9,

122.7, 122.3, 121.0, 119.1, 117.2, 116.0, 113.3, 29.5 ppm. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₆H₁₃N₂O, 249.1022; found, 249.1020.

4,5-Dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6e).

Yield: 34 mg (49%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Pale yellow crystals. mp

308−309 °C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3193, 1644,

1579, 1380, 1323, 1279, 770, 734. ¹H NMR (DMSO-d₆, 600 MHz): δ

12.36 (br s, 1H), 8.46 (d, J = 1.1 Hz, 1H), 8.37 (dd, J₁= 2.4 Hz, J₂= 6.9

Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.37−7.29

(m, 3H), 3.87 (s, 3H), 2.75 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆,

150 MHz): δ 157.7, 139.3, 137.5, 131.1, 127.0, 126.4, 125.9, 123.3,

122.7, 122.3, 121.8, 121.0, 120.9, 117.6, 113.3, 37.2, 24.0 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅N₂O, 263.1179; found,

263.1178.

3,5-Dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6fG2). Colorless crystals. mp 265−267 °C (1,4-dioxane−EtOAc). IR

(KBr, cm⁻¹): 3196, 1636, 1582, 1383, 1316, 1281, 766, 745. ¹H NMR

(DMSO-d₆, 600 MHz): δ 12.51 (br s, 1H), 8.37 (d, J = 8.5 Hz, 1H),

7.64 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.2 Hz,

1H), 7.48−7.38 (m, 1H), 7.35−7.28 (m, 2H), 3.82 (s, 3H), 3.03 (s,

3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.3, 139.4, 137.0,

136.1, 133.4, 128.5, 126.2, 125.9, 125.4, 123.9, 123.0, 120.8, 117.0,

113.6, 113.2, 30.0, 25.2 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₅N₂O, 263.1179; found, 263.1179.

3-Methoxy-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6gG1) and 1-Methoxy-5-methyl-5,7-dihydro-6H-indolo[2,3-

c]quinolin-6-one (6gG2). Yield: 14 mg (19%). Mixture of two isomers.

Crude product.

IR (KBr, cm⁻¹): 3179, 2925, 1643, 1562, 1381, 1316, 1047, 741. ¹H

NMR (DMSO-d₆, 600 MHz): δ 12.41 (br s, 1H), 12.23 (br s, 1H), 8.64

(d, J = 8.4 Hz, 1H), 8.45 (dd, J₁= 2.8 Hz, J₂= 8.2 Hz, 2H), 7.63−7.58

(m, 2H), 7.50−7.43 (m, 2H), 7.43−7.38 (m, 1H), 7.32−7.27 (m, 2H),

7.24−7.20 (m, 1H), 7.15−7.13 (m, 1H), 7.09−7.05 (m, 2H), 4.12 (s,

3H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) ppm. 13C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 158.3, 155.8, 139.6, 139.2, 137.6, 137.5,

129.8, 128.8, 127.3, 127.1, 127.0, 126.0, 125.7, 125.6, 124.9, 123.4,

122.6, 122.0, 120.7, 120.1, 117.7, 115.9, 114.9, 113.2, 112.8, 112.7,

110.1, 108.9, 104.9, 100.9, 55.7, 55.4, 30.2, 29.6 ppm.

6gG1 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v), followed by recrystallization from 1,4-

dioxane−EtOAc.

3-Methoxy-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6gG1). Colorless crystals. mp 310−311 °C (1,4-dioxane−

EtOAc). IR (KBr, cm⁻¹): 3179, 1641, 1619, 1564, 1382, 1298, 1049,

742. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.23 (br s, 1H), 8.45 (d, J =

8.2 Hz, 2H), 7.61 (dd, J₁= 2.4 Hz, J₂= 6.9 Hz, 1H), 7.47 (t, J = 7.6 Hz,

1H), 7.37−7.28 (m, 3H), 3.92 (s, 3H), 3.82 (s, 3H) ppm. ¹³C{¹H}

NMR (DMSO-d₆, 150 MHz): δ 158.3, 155.8, 139.2, 137.7, 126.0,

125.7, 124.9, 122.6, 122.0, 120.7, 117.7, 113.2, 112.8, 110.0, 100.9, 55.7,

29.6 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅N₂O₂,

279.1128; found, 279.1134.

3-Chloro-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6hG1) and 1-Chloro-5-methyl-5,7-dihydro-6H-indolo[2,3-c]-

quinolin-6-one (6hG2). Yield: 24 mg (32%). Mixture of two isomers.

Crude product.

IR (KBr, cm⁻¹): 3223, 2924, 1634, 1589, 1381, 1334, 1129, 742. ¹H

NMR (DMSO-d₆, 600 MHz): δ 12.73 (br s, 1H), 12.49 (br s, 1H), 8.73

(d, J = 8.5 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H),

7.75−7.71 (m, 1H), 7.66−7.65 (m, 1H), 7.64−7.62 (m, 1H), 7.61−

7.58 (m, 1H), 7.53−7.51 (m, 1H), 7.50−7.42 (m, 1H), 7.47−7.43 (m,

2H), 7.35−7.32 (m, 1H), 7.28−7.25 (m, 2H), 3.84 (s, 3H), 3.82 (s,

3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.5, 155.2, 139.9,

139.2, 138.0, 137.2, 136.2, 130.9, 129.3, 127.2, 127.1, 127.0, 126.2,

125.6, 125.2, 125.1, 122.7, 122.6, 122.4, 122.0, 121.2, 120.1, 118.3,

118.0, 116.7, 115.7, 115.3, 115.0, 113.4, 113.2, 30.4, 29.6 ppm.

6hG1 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v), followed by recrystallization from 1,4-

dioxane−EtOAc.

3,5-Dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6fG1)

and 1,5-Dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6fG2). Yield: 25 mg (36%). Mixture of two isomers. Crude product.

IR (KBr, cm⁻¹): 3189, 2923, 1637, 1381, 1315, 1283, 1118, 735. ¹H

NMR (DMSO-d₆, 600 MHz): δ 12.53 (br s, 1H), 12.31 (br s, 1H), 8.47

(d, J = 8.4 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H),

7.65 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.53−7.50 (m, 1H),

7.49−7.46 (m, 1H), 7.45−7.40 (m, 1H), 7.34−7.29 (m, 2H), 7.28−

7.26 (m, 2H), 7.25−7.22 (m, 2H), 3.821 (s, 3H), 3.815 (s, 3H), 3.36 (s,

3H), 3.03 (s, 3H) ppm. 13C{¹H} NMR (DMSO-d₆, 150 MHz): δ

155.6, 155.4, 139.5, 139.2, 137.0, 136.22, 136.16, 133.5, 128.5, 126.7,

126.2, 125.9, 125.8, 125.5, 125.3, 124.0, 123.6, 123.0, 122.7, 122.2,

120.81, 120.78, 120.1, 119.1, 117.4, 116.7, 116.1, 113.7, 113.2, 58.8,

30.1, 29.5, 25.2, 21.7 ppm.

3-Chloro-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6hG1). Grey crystals. mp 334−335 °C (1,4-dioxane−EtOAc). IR

(KBr, cm⁻¹): 3206, 1629, 1557, 1376, 1331, 1101, 773, 761. ¹H NMR

(DMSO-d₆, 600 MHz): δ 12.48 (br s, 1H), 8.53 (d, J = 8.4 Hz, 1H),

8.48 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.3 Hz,

1H), 7.52−7.47 (m, 1H), 7.46−7.44 (m, 1H), 7.36−7.31 (m, 1H), 3.82

(s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.5, 139.2,

137.2, 130.9, 127.1, 126.2, 125.2, 122.7, 122.5, 122.0, 121.2, 117.9,

116.7, 115.7, 113.4, 29.7 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₆H₁₂ClN₂O, 283.0633; found, 283.0635.

10-Methoxy-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6i). Yield: 10 mg (14%). Puriﬁcation: ﬂash column chromatog-

raphy (SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Pale yellow crystals.

mp 313−314 °C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3176, 1636,

M

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

1475, 1383, 1260, 1227, 1110, 839, 730. H NMR (DMSO-d₆, 600

MHz): δ 12.27 (br s, 1H), 8.53 (dd, J₁= 1.1 Hz, J₂= 7.9 Hz, 1H), 7.86

(d, J = 2.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.57−7.51 (m, 2H), 7.45

(t, J = 7.2 Hz, 1H), 7.14 (dd, J₁= 2.4 Hz, J₂= 8.9 Hz, 1H), 3.94 (s, 3H),

3.83 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.6,

154.7, 135.9, 134.3, 127.6, 126.3, 123.8, 122.8, 122.4, 119.3, 116.82,

116.79, 115.8, 114.1, 103.6, 55.9, 29.5 ppm. HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₇H₁₅N₂O₂, 279.1128; found, 279.1128.

5-Propyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6o). Yield:

30 mg (41%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 252−254

°C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3188, 1635, 1564, 1441,

1377, 1311, 763, 741. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.38 (br s,

1H), 8.55 (dd, J₁= 1.4 Hz, J₂= 7.9 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H),

7.72 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.56−7.51 (m, 1H),

7.50−7.46 (m, 1H), 7.49−7.39 (m, 1H), 7.34−7.31 (m, 1H), 4.44 (t, J

= 7.2 Hz, 2H), 1.58−1.52 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H) ppm.

¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.4, 139.2, 135.0, 127.1,

10-Chloro-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6j). Yield: 26 mg (21%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp >

335 °C (lit.⁵²> 360 °C, DMF). IR (KBr, cm⁻¹): 3165, 1635, 1579,

1382, 1269, 1118, 757, 689. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.59

(br s, 1H), 8.66−8.41 (m, 2H), 7.77−7.61 (m, 2H), 7.60−7.31 (m, 3H)

3.82 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.4,

137.6, 136.1, 128.3, 126.9, 126.1, 125.5, 123.1, 123.0, 121.8, 118.6,

116.7, 115.9, 114.8, 66.5, 29.6 ppm. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₆H₁₂ClN₂O, 283.0633; found, 283.0633.

5-Ethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6k). Yield:

56 mg (80%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 230−232

°C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3212, 1646, 1563, 1297,

1267, 1162, 762, 739. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.40 (br s,

1H), 8.56 (dd, J₁= 1.3 Hz, J₂= 7.9 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H),

7.74 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.58−7.52 (m, 1H),

7.51−7.46 (m, 1H), 7.45−7.42 (m, 1H), 7.37−7.31 (m, 1H), 4.52 (q, J

= 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆,

150 MHz): δ 155.1, 139.2, 134.8, 127.2, 126.7, 126.0, 124.1, 122.72,

122.68, 122.2, 121.0, 119.4, 117.3, 115.7, 113.3, 36.8, 13.3 ppm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅N₂O [M + H]⁺, 263.1179; found,

263.1177.

5-Ethyl-2-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6l). Yield: 32 mg (44%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp

312−314 °C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3179, 1633,

1563, 1392, 1294, 1238, 796, 738. ¹H NMR (DMSO-d₆, 600 MHz): δ

12.34 (br s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.34 (s, 1H), 7.67−7.59 (m,

2H), 7.51−7.44 (m, 1H), 7.39−7.29 (m, 2H), 4.49 (q, J = 8.3 Hz, 2H),

2.51 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆,

150 MHz): δ 155.0, 139.2, 132.8, 131.9, 127.7, 127.3, 125.9, 123.8,

122.8, 122.3, 120.9, 119.4, 117.1, 115.6, 113.2, 36.7, 20.7, 13.4 ppm.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₇N₂O, 277.1335; found,

277.1333.

5-Ethyl-2-ﬂuoro-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6m). Yield: 39 mg (52%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 315

°C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3181, 1636, 1585, 1568,

1468, 1434, 1285, 742. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.50 (br s,

1H), 8.52 (d, J = 8.3 Hz, 1H), 8.26 (dd, J₁= 2.9 Hz, J₂= 9.5 Hz, 1H),

7.76 (dd, J₁= 4.8 Hz, J₂= 9.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52−

7.47 (m, 1H), 7.42−7.36 (m, 1H), 7.35−7.31 (m, 1H), 4.51 (q, J = 7.1

Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150

MHz): δ 158.0 (d, J = 238.8 Hz), 154.8, 139.1, 131.4, 127.8, 126.1,

122.6, 122.1, 121.2, 120.5 (d, J = 8.8 Hz), 117.6 (d, J = 8.9 Hz), 116.4

(d, J = 3.3 Hz), 113.8 (d, J = 23.4 Hz), 113.3, 109.4 (d, J = 23.4 Hz),

37.1, 13.3 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₄FN₂O,

281.1085; found, 281.1088.

126.6, 126.0, 124.0, 122.72, 122.68, 121.0, 119.4, 117.3, 115.9, 113.3,

66.6, 43.1, 21.0, 11.4 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₈H₁₇N₂O, 277.1335; found, 277.1335.

5-Butyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6p). Yield:

38 mg (49%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 264−265

°C (EtOAc). IR (KBr, cm⁻¹): 3185, 1634, 1564, 1440, 1331, 1298, 763,

740. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.36 (br s, 1H), 8.55 (dd, J₁=

1.4 Hz, J₂= 7.9 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.3 Hz,

1H), 7.65 (d, J = 8.3 Hz, 1H), 7.58−7.52 (m, 1H), 7.51−7.45 (m, 1H),

7.44−7.40 (m, 1H), 7.35−7.30 (m, 1H), 4.47 (t, J = 7.6 Hz, 2H), 1.71

(quint, J = 7.7 Hz, 2H), 1.49−1.41 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H)

ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.4, 139.2, 135.0,

127.1, 126.6, 126.0, 124.0, 122.71, 122.68, 122.2, 121.0, 119.2, 117.3,

115.8, 113.3, 41.3, 29.9, 19.9, 14.0 ppm. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₉H₁₉N₂O, 291.1492; found, 291.1491.

5,7-Dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6q).

Yield: 57 mg (81%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp

250.0−250.5 °C (EtOAc). IR (KBr, cm⁻¹): 3193, 1644, 1579, 1552,

1323, 770, 734, 715. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.56 (s, 2H),

7.78 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.63−7.49 (m, 2H),

7.48−7.30 (m, 2H), 4.34 (s, 3H), 3.80 (s, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 157.7, 139.3, 137.5, 131.1, 127.0, 126.4,

125.9, 123.3, 122.7, 122.3, 121.8, 121.0, 120.9, 117.6, 113.3, 37.2, 24.0

ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₅N₂O, 263.1179;

found, 263.1180.

4,5,7-Trimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6r).

Yield: 66 mg (90%). Puriﬁcation: ﬂash column chromatography (SiO₂,

hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp 200−202

°C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3421, 1646, 1476, 1311,

1283, 1024, 1000, 733. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.46 (d, J =

7.4 Hz, 1H), 8.38 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.48−

7.17 (m, 3H), 4.31 (s, 3H), 3.80 (s, 3H), 2.71 (s, 3H) ppm. ¹³C{¹H}

NMR (DMSO-d₆, 150 MHz): δ 158.2, 140.6, 137.6, 131.1, 126.23,

126.18, 125.7, 123.3, 122.9, 121.7, 121.4, 121.2, 120.7, 118.1, 111.4,

37.4, 31.6, 23.9 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₈H₁₇N₂O, 277.1335; found, 277.1335.

3,5,7-Trimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6sG1) and 1,5,7-Trimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-

6-one (6sG2). Yield: 73 mg (99%). Mixture of two isomers. Crude

product.

IR (KBr, cm⁻¹): 2854, 1646, 1580, 1477, 1046, 1311, 1249, 729. ¹H

NMR (DMSO-d₆, 600 MHz): δ 8.44 (d, J = 8.1 Hz, 1H), 8.33 (d, J = 8.2

Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 8.7 Hz, 2H), 7.55−7.51

(m, 1H), 7.50−7.48 (m, 1H), 7.40 (s, 3H), 7.36−7.31 (m, 1H), 7.29−

7.25 (m, 1H), 7.20−7.18 (m, 2H), 4.32 (s, 3H), 4.25 (s, 3H), 3.71 (s,

3H), 3.70 (s, 3H), 3.39 (s, 3H), 3.38 (s, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 156.0, 155.8, 140, 44, 140.36, 136.9, 136.2,

136.1, 133.3, 127.0, 126.3, 126.1, 125.8, 125.6, 125.33, 125.25, 123.8,

123.4, 122.8, 121.1, 121.0, 120.2, 120.0, 118.2, 117.92, 117.85, 116.3,

115.8, 113.1, 111.2, 111.1, 31.8, 31.5, 29.9, 29.2, 24.6, 21.7 ppm.

6sG1 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v), followed by recrystallization from EtOAc.

3,5,7-Trimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6sG1). Colorless crystals. mp 191−193 °C (EtOAc). IR (KBr, cm⁻¹):

3049, 1644, 1614, 1476, 1405, 1310, 1276, 807, 729. ¹H NMR (DMSO-

d₆, 600 MHz): δ 8.47 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.72

(d, J = 8.3 Hz, 1H), 7.66−7.48 (m, 1H), 7.41 (s, 1H), 7.35 (t, J = 7.0 Hz,

1H), 7.22 (d, J = 7.7 Hz, 1H), 4.28 (s, 3H), 3.73 (s, 3H), 2.49 (s, 3H)

2-Chloro-5-ethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6n). Yield: 47 mg (59%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals. mp >

335 °C (1,4-dioxane−EtOAc). IR (KBr, cm⁻¹): 3183, 1634, 1558,

1390, 1282, 813, 740, 559. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.38

(br s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 7.60−7.52

(m, 1H), 7.53 (t, J = 7.1 Hz, 1H), 7.45 (t, J = 7.0 Hz, 2H), 7.34 (d, J =

6.8 Hz, 1H), 4.65−4.39 (m, 2H), 1.55−1.08 (m, 3H) ppm. ¹³C{¹H}

NMR (DMSO-d₆, 150 MHz): δ 154.9, 139.2, 133.6, 127.7, 127.1,

126.3, 126.2, 122.7, 122.6, 121.9, 121.4, 120.8, 117.7, 113.4, 66.6, 37.1,

13.3 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₇H₁₄ClN₂O,

297.0789; found, 297.0790.

N

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 156.1, 140.4, 136.3,

136.1, 126.1, 125.3, 123.9, 123.5, 122.8, 121.15, 121.06, 117.9, 116.3,

115.3, 111.3, 31.7, 29.3, 21.7 ppm. HRMS calcd for C₁₈H₁₇N₂O [M +

H]⁺, 277.1335; found, 277.1336.

3-Methoxy-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-

6-one (6tG1) and 1-methoxy-5,7-dimethyl-5,7-dihydro-6H-indolo-

[2,3-c]quinolin-6-one (6tG2). Yield: 54 mg (70%). Mixture of two

isomers. Crude product.

5-Ethyl-2,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6w). Yield: 77 mg (99%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless

crystals. mp 166−167 °C (EtOAc). IR (KBr, cm⁻¹): 1641, 1291, 1274,

1235, 1088, 793, 732. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.57 (d, J =

7.8 Hz, 1H), 8.32 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.0 Hz,

2H), 7.45−7.36 (m, 1H), 7.35−7.21 (m, 1H), 4.58−4.39 (m, 2H), 4.32

(s, 3H), 2.51 (s, 3H), 1.29 (t, J = 6.7 Hz, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 155.5, 140.5, 132.8, 131.9, 127.9, 126.2,

125.8, 123.7, 123.0, 121.3, 121.1, 119.0, 117.6, 115.6, 111.3, 36.7, 31.6,

20.7, 13.3 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₉H₁₉N₂O,

291.1492; found, 291.1491.

2-Fluoro-5-ethyl-7-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-

6-one (6x). Yield: 26 mg (75%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless

crystals. mp 190−191 °C (EtOAc). IR (KBr, cm⁻¹): 1639, 1585, 1463,

1422, 1283, 1275, 737, 594. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.50 (s,

1H), 8.19 (s, 1H), 7.94−7.63 (m, 2H), 7.62−7.46 (m, 1H), 7.45−6.96

(m, 2H), 4.42 (br s, 2H), 4.30 (br s, 3H), 1.28 (br s, 3H) ppm. ¹³C{¹H}

NMR (DMSO-d₆, 150 MHz): δ 158.0 (d, J = 238.8 Hz), 155.3, 140.4,

131.4, 126.3, 126.2, 122.6, 121.6, 120.9, 120.5 (d, J = 8.7 Hz), 117.4 (d,

J = 7.7 Hz), 116.9, 113.9 (d, J = 23.1 Hz), 111.4, 109.2 (d, J = 23.3 Hz),

37.1, 31.6, 13.2 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₈H₁₆FN₂O, 295.1241; found, 295.1248.

IR (KBr, cm⁻¹): 2925, 1639, 1463, 1281, 1221, 1082, 1023, 729. ¹H

NMR (DMSO-d₆, 600 MHz): δ 8.65 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.2

Hz, 1H), 8.36−8.32 (m, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.3

Hz, 1H), 7.54−7.50 (m, 1H), 7.49−7.46 (m, 2H), 7.34−7.30 (m, 1H),

7.28−7.24 (m, 2H), 7.20−7.15 (m, 3H), 4.30 (s, 3H), 4.22 (s, 3H),

3.89 (s, 3H), 3.86 (s, 3H) 3.68 (s, 3H), 3.66 (s, 3H) ppm. ¹³C{¹H}

NMR (DMSO-d₆, 150 MHz): δ 158.2, 156.2, 140.8, 140.4, 137.5,

137.4, 137.3, 126.1, 125.84, 125.80, 124.7, 124.3, 123.2, 122.7, 122.2,

121.5, 120.9, 120.8, 120.3, 120.0, 119.3, 116.9, 112.7, 112.5, 112.4,

111.1, 110.6, 110.4, 109.9, 100.4, 55.6, 55.4, 31.4, 31.3, 30.0, 29.3 ppm.

6tG1 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v), followed by recrystallization from 1,4-

dioxane−EtOAc.

3-Methoxy-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-

6-one (6tG1). Colorless crystals. mp 199−200 °C (1,4-dioxane−

EtOAc). IR (KBr, cm⁻¹): 3179, 1641, 1564, 1382, 1298, 1049, 833, 742.

¹H NMR (DMSO-d₆, 600 MHz): δ 8.50 (d, J = 8.1 Hz, 1H), 8.46 (d, J =

8.7 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.35 (t, J

= 7.8 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.05 (dd, J₁= 2.3 Hz, J₂= 8.7

Hz, 1H), 4.30 (s, 3H), 3.92 (s, 3H), 3.77 (s, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 158.4, 156.3, 140.5, 137.6, 126.2, 124.9,

124.4, 122.8, 121.1, 120.9, 118.3, 112.4, 111.3, 110.1, 100.6, 55.7, 31.7,

29.4 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₇N₂O₂,

293.1285; found, 293.1289.

2-Chloro-5-ethyl-7-methyl-5,7-dihydro-6H-indolo[2,3-c]-

quinolin-6-one (6y). Yield: 62 mg (75%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless

crystals. mp 217−218 °C (EtOAc). IR (KBr, cm⁻¹): 2975, 1638, 1560,

1

1411, 1279, 1232, 1102, 809, 738, 556. H NMR (DMSO-d₆, 600

MHz): δ 8.51 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.79 (d, J =

8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.62−7.56 (m, 1H), 7.54 (dd, J₁=

2.4 Hz, J₂= 8.1 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 4.45 (q, J = 7.0 Hz,

2H), 4.33 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 155.4, 140.4, 133.5, 127.1, 126.44, 126.38,

126.2, 122.62, 122.56, 121.8, 120.8, 120.5, 117.5, 116.5, 111.5, 37.0,

31.6, 13.1 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₁₆ClN₂O,

311.0946; found, 311.0948.

7-Benzyl-5-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one

(6z). Yield: 84 mg (93%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp

178−180 °C (EtOAc). IR (KBr, cm⁻¹): 1640, 1463, 1323, 1296, 1275,

1157, 1120, 744, 699. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.59 (t, J =

8.1 Hz, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.59−

7.54 (m, 1H), 7.53−7.49 (m, 1H), 7.48−7.43 (m, 1H), 7.39−7.35 (m,

1H), 7.28−7.22 (m, 2H), 7.21−7.15 (m, 3H), 6.20 (s, 2H), 3.80 (s,

3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.9, 139.9, 138.8,

136.1, 128.7 (2C), 127.3, 127.0, 126.9 (2C), 126.5, 125.4, 123.8, 123.0,

123.0, 121.7, 121.5, 118.7, 118.4, 115.8, 112.0, 47.2, 29.5 pm. HRMS

(ESI) m/z: [M + H]⁺calcd for C₂₃H₁₉N₂O, 339.1492; found,

339.1491.

5,7-Dibenzyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one (6aa).

Yield: 104 mg (94%). Puriﬁcation: ﬂash column chromatography

(SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless crystals. mp

222−225 °C (EtOAc). IR (KBr, cm⁻¹): 1637, 1463, 1453, 1295, 1271,

747, 738, 699. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.74−8.55 (m, 2H),

7.82 (d, J = 8.2 Hz, 1H), 7.61−7.50 (m, 2H), 7.49−7.29 (m, 6H),

7.28−7.18 (m, 7H), 6.27 (s, 2H), 5.75 (s, 2H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 156.3, 140.2, 138.8, 137.3, 135.3, 128.9 (2C),

128.7 (2C), 127.3, 127.2, 127.0, 126.9 (2C), 126.9, 126.7 (2C), 125.2,

124.1, 123.2 (2C), 121.9, 121.6, 119.04, 119.00, 116.4, 112.1, 47.3, 44.9

pm. HRMS (ESI) m/z: [M + H]⁺calcd for C₂₉H₂₃N₂O, 415.1805;

found, 415.1813.

5,7-Dibenzyl-2-methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6ab). Yield: 112 mg (98%). Puriﬁcation: ﬂash column

chromatography (SiO₂, hexane−EtOAc 1:0, v/v → 4:1, v/v). Colorless

crystals. mp 211−213 °C (EtOAc). IR (KBr, cm⁻¹): 1630, 1573, 1454,

1419, 1273, 1205, 736, 700. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.66 (d,

J = 8.2 Hz, 1H), 8.40 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 8.4

Hz, 1H), 7.46−7.38 (m, 2H), 7.37−7.16 (m, 11H), 6.25 (s, 2H), 5.72

(br s, 2H), 2.49 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ

3-Chloro-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6uG1) and 1-Chloro-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-

c]quinolin-6-one (6uG2). Yield: 70 mg (89%). Mixture of two isomers.

Crude product.

IR (KBr, cm⁻¹): 2923, 1655, 1637, 1467, 1273, 1073, 766, 738. ¹H

NMR (DMSO-d₆, 600 MHz): δ 8.57 (d, J = 8.4 Hz, 1H), 8.39 (dd, J₁=

8.2 Hz, J₂= 8.2 Hz, 2H), 7.88−7.70 (m, 1H), 7.63−7.56 (m, 2H),

7.54−7.44 (m, 4H), 7.40−7.26 (m, 2H), 7.34−7.30 (m, 2H), 4.34 (s,

3H), 4.25 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H) ppm. ¹³C{¹H} NMR

(DMSO-d₆, 150 MHz): δ 155.8, 155.7, 140.6, 140.4, 137.9, 137.0,

133.4, 132.5, 131.0, 128.7, 128.0, 127.7, 127.4, 127.1, 127.0, 126.8,

126.3, 126.0, 125.7, 125.6, 125.0, 122.6, 121.5, 121.1, 120.2, 117.4,

115.8, 115.3, 114.8, 111.1, 31.9, 31.6, 30.2, 29.5 ppm.

6uG2 was isolated by ﬂash column chromatography (SiO₂, hexane−

EtOAc 1:0, v/v → 1:1, v/v) followed by recrystallization from EtOAc.

3-Chloro-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6uG2). Colorless crystals. mp 126−127 °C (EtOAc). IR (KBr,

cm⁻¹): 3206, 1629, 1557, 1376, 1331, 1101, 773, 761. ¹H NMR

(DMSO-d₆, 600 MHz): δ 8.58 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz,

1H), 7.60 (dd, J₁= 2.1 Hz, J₂= 7.4 Hz, 1H), 7.54−7.50 (m, 1H), 7.49−

7.47 (m, 2H), 7.32−7.27 (m, 1H), 4.35 (s, 3H), 3.75 (s, 3H) ppm.

¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 155.7, 140.6, 137.9, 128.1,

127.7, 127.1, 127.0, 125.8, 125.0, 121.1, 120.2, 117.4, 115.8, 114.8,

111.1, 31.9, 30.2 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₄ClN₂O, 297.0789; found, 297.0798.

10-Chloro-5,7-dimethyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6v). Yield: 61 mg (77%). Puriﬁcation: ﬂash column chromatog-

raphy (SiO₂, hexane−EtOAc 1:0, v/v → 1:1, v/v). Colorless crystals.

mp 298−300 °C (EtOAc). IR (KBr, cm⁻¹): 1638, 1474, 1420, 1268,

1246, 1105, 809, 740, 709. ¹H NMR (DMSO-d₆, 600 MHz): δ 8.66 (s,

1H), 8.57 (dd, J₁= 1.3 Hz, J₂= 7.6 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H),

7.67 (d, J = 7.7 Hz, 1H), 7.59 (dd, J₁= 2.0 Hz, J₂= 8.9 Hz, 1H), 7.58−

7.53 (m, 1H), 7.46−7.42 (m, 1H), 4.34 (s, 3H), 3.80 (s, 3H) ppm.

¹³C{¹H} NMR (DMSO-d₆, 150 MHz): δ 156.0, 138.9, 136.1, 127.1,

126.8, 126.3, 126.0, 124.0, 123.7, 123.1, 122.0, 121.9, 118.3, 115.8,

113.2, 31.9, 29.5 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₇H₁₄ClN₂O, 297.0789; found, 297.0793.

O

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

156.1, 140.1, 138.8, 137.4, 133.2, 132.4, 128.8 (2C), 128.7 (2C), 128.1,

127.3, 127.2, 126.9 (2C), 126.6 (3C), 125.3, 123.8, 123.3, 121.7, 121.6,

119.0, 118.8, 116.3, 112.0, 47.2, 44.8, 20.7 ppm. HRMS (ESI) m/z: [M

+ H]⁺calcd for C₃₀H₂₅N₂O, 429.1961; found, 429.1974.

Crystallographic Data Centre, 12 Union Road, Cambridge

CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

Corresponding Author

■

Preparation of 5-Benzyl-5,7-dihydro-6H-indolo[2,3-c]-

quinolin-6-one (6ac). Compound 6aa (55 mg, 0.133 mmol) was

dissolved in DMSO (2 mL), and KOt-Bu (104 mg, 0.927 mmol) was

added in one portion. Air as oxygen source was bubbled through the

reaction mixture while it was vigorously stirred overnight at room

temperature. The reaction was followed by TLC. After the reaction was

complete, concentrated NaHCO₃solution (10 mL) was added to the

reaction mixture. After dilution with water, the mixture was extracted

EtOAc (3 × 10 mL). The combined organic layers were extracted with

brine, dried over Na₂SO₄, ﬁltered, and evaporated. The crude product

was puriﬁed by recrystallization from the EtOAc−1,4-dioxane solvent

mixture.

́

Matyas Milen − Directorate of Drug Substance Development,

Egis Pharmaceuticals PLC, H-1475 Budapest, Hungary;

orcid.org/0000-0002-3538-8872; Phone: +36 1

8035874; Email: milen.matyas@egis.hu

Authors

́

Tímea Szabo − Directorate of Drug Substance Development,

Egis Pharmaceuticals PLC, H-1475 Budapest, Hungary;

orcid.org/0000-0003-0700-4680

Marcell Papp − Directorate of Drug Substance Development,

Egis Pharmaceuticals PLC, H-1475 Budapest, Hungary;

Department of Inorganic and Analytical Chemistry, Budapest

University of Technology and Economics, H-1111 Budapest,

Hungary; orcid.org/0000-0002-2464-4818

Yield: 26 mg (61%). Colorless crystals. mp 189−190 °C (1,4-

dioxane−EtOAc). IR (KBr, cm⁻¹): 2924, 1661, 1460, 1309, 1262, 802,

743, 709. ¹H NMR (DMSO-d₆, 600 MHz): δ 11.97 (br s, 1H), 8.57 (d,

J = 8.2 Hz, 1H), 8.52 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.55−

7.48 (m, 1H), 7.47−7.42 (m, 1H), 7.39−7.34 (m, 2H), 7.29−7.23 (m,

2H), 7.22−7.17 (m, 3H), 6.22 (s, 2H) ppm. ¹³C{¹H} NMR (DMSO-

d₆, 150 MHz): δ 156.5, 139.7, 138.7, 135.2, 128.7 (2C), 127.3, 127.0

(2C), 126.6, 126.4, 125.9, 123.3, 123.0, 122.8, 121.9, 121.6, 119.5,

117.9, 116.1. 112.0, 47.1 ppm. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₂H₁₇N₂O, 325.1335; found, 325.1337.

Preparation of Isoneocryptolepine (5-Methyl-5H-indolo[2,3-

c]-quinoline, 4). 5-Methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-6-

one (6d, 83 mg, 0.334 mmol) was suspended in POCl₃(3.1 mL) and

stirred at reﬂux temperature for 1 h in an oil bath. After that, the reaction

was cooled to room temperature and poured slowly into the mixture of

MeCN−H₂O (4:1) at 0 °C. To the mixture, Zn dust (425 mg, 6.500

mmol) was added portionwise and stirred for 2 h at 0 °C. This was

followed by the alkalization of the mixture with 25 mL of 25% NH₃

solution and extraction with CH₂Cl₂(3 × 15 mL). The combined

organic phase was dried over Na₂SO₄, ﬁltered oﬀ, and evaporated,

resulting in isoneocryptolepine as red crystals. The crude product was

puriﬁed by preparative TLC (Al₂O₃, 60 F₂₅₄, 1.5 mm) with the

CH₂Cl₂−MeOH (9:1) eluent in the presence of NH₃solution (2 mL in

200 mL eluent).

́

Dora Rita Nemeth − Directorate of Drug Substance

Development, Egis Pharmaceuticals PLC, H-1475 Budapest,

Hungary

́

Andras Dancso − Directorate of Drug Substance Development,

Egis Pharmaceuticals PLC, H-1475 Budapest, Hungary;

orcid.org/0000-0001-8460-217X

́

Balazs Volk − Directorate of Drug Substance Development, Egis

Pharmaceuticals PLC, H-1475 Budapest, Hungary;

orcid.org/0000-0002-2019-1874

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c01832

Author Contributions

All authors have given approval to the ﬁnal version of the

manuscript.

Notes

Yield: 72 mg (93%). Red crystals. mp 189−191 °C (decomp.) (lit.⁵³

>

The authors declare no competing ﬁnancial interest.

220 °C, decomp.). IR(KBr, cm⁻¹): 3174, 1639, 1563, 1382, 1332, 1253,

1132, 763. ¹H NMR (DMSO-d₆, 600 MHz): δ 9.58 (br s, 1H), 8.92 (d,

J = 7.8 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.89−

7.82 (m, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.20 (t, J

= 7.8 Hz, 1H), 4.58 (s, 3H) ppm. ¹³C{¹H} NMR (DMSO-d₆, 150

MHz): δ 156.8, 141.4, 141.2, 130.5, 127.5, 126.7, 125.4, 125.2, 124.5,

124.1, 123.7, 122.3, 120.4, 118.9, 118.8, 44.3 ppm. HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₆H₁₃N₂, 233.1073; found, 233.1074.

ACKNOWLEDGMENTS

We acknowledge NIIF for awarding us access to super-

computing resources based in Debrecen, Hungary.

■

REFERENCES

■

(1) Lavrado, J.; Moreira, R.; Paulo, A. Indoloquinolines as scaffolds for

drug discovery. Curr. Med. Chem. 2010, 17, 2348−2370.

(2) Nuthakki, V. K.; Mudududdla, R.; Sharma, A.; Kumar, A.; Bharate,

S. B. Synthesis and biological evaluation of indoloquinoline alkaloid

cryptolepine and its bromo-derivative as dual cholinesterase inhibitors.

Bioorg. Chem. 2019, 90, 103062.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c01832.

(3) Nadein, O. N.; Aksenov, D. A.; Abakarov, G. M.; Aksenov, N. A.;

Voskressensky, L. G.; Aksenov, A. V. Methods of synthesis of natural

indoloquinolines isolated from Cryptolepis sanguinolenta. Chem.

Heterocycl. Compd. 2019, 55, 905−932.

X-ray crystallographic data of compound 6q (CCDC

2013943); X-ray crystallographic data; computational

studies; geometries; and further quantum chemical

interpretations (PDF)

(4) Clinquart, E. On the chemical composition of Cryptolepis

triangularis, plant from the (Belgian) Congo. Bull. Acad. R. Med. Belg.

1929, 9, 627−635.

Spectroscopic and analytical data as well as the original

copy of ¹H NMR, ¹³C NMR, IR, and HRMS spectra of all

compounds (PDF)

́

(5) Gellert, E.; Raymond-Hamet, E.; Schlittler, E. Die konstitution des

alkaloids cryptolepin. Helv. Chim. Acta 1951, 34, 642−651.

(6) Osafo, N.; Mensah, K. B.; Yeboah, O. K. Phytochemical and

pharmacological review of Cryptolepis sanguinolenta. Adv. Pharmacol.

Sci. 2017, 2017, 3026370.

Accession Codes

CCDC 2013943 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_

request@ccdc.cam.ac.uk, or by contacting The Cambridge

(7) Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B. Isocryptolepine

from Cryptolepis sanguinolenta. Phytochemistry 1995, 39, 735−736.

(8) Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger, C.

A. In Vitro and in Vivo Antiplasmodial Activity of Cryptolepine and

P

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Related Alkaloids from Cryptolepis sanguinolenta. J. Nat. Prod. 1997,

60, 688−691.

reactions with nitrogen nucleophiles. Tetrahedron Lett. 2009, 50, 3829−

3832.

(27) Harayama, T.; Akiyama, T.; Kawano, K. A convenient synthesis

of benzo[c ]phenanthridine alkaloid, chelerythrine, by the palladium-

assisted internal biaryl coupling reaction. Chem. Pharm. Bull. 1996, 44,

1634−1636.

(28) Harayama, T.; Akiyama, T.; Nakano, Y. Internal aryl-aryl

coupling reaction using a novel and highly active palladium reagent

prepared from Pd(OAc)₂, DPPP, and Bu₃P. Chem. Pharm. Bull. 1997,

45, 1723−1725.

(29) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka, H.; Abe, H.;

Takeuchi, Y. Aryl −aryl coupling reaction using a novel and highly active

palladium reagent prepared from Pd(OAc)₂, 1 ,3-bis-

[diphenylphosphino]propane (DPPP), and Bu₃P. Chem. Pharm. Bull.

2002, 50, 519−522.

(30) Ruiz-Castillo, P.; Buchwald, S. L. Applications of palladium-

catalyzed C −N cross-coupling reactions. Chem. Rev. 2016, 116,

12564−12649.

(31) Zhang, X.; Zhang-Negrerie, D.; Deng, J.; Du, Y.; Zhao, K.

Synthesis of diversely substituted indoloquinolinones via Pd(II)/

Cu(II)-mediated oxidative C −C bond formation and I (III)-mediated

C −N bond formation. J. Org. Chem. 2013, 78, 12750−12759.

(32) Zhong, H.; Yang, D.; Wang, S.; Huang, J. Pd-catalysed synthesis

of isoquinolinones and analogues via C −H and N −H bonds double

activation. Chem. Commun. 2012, 48, 3236−3238.

(9) Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.;

Martin, G. E. Two new indoloquinoline alkaloids from Cryptolepis

sanguinolenta: Cryptosanguinolentine and cryptotackieine. J. Hetero-

cycl. Chem. 1996, 33, 239−243.

́

(10) Van Baelen, G.; Hostyn, S.; Dhooghe, L.; Tapolcsanyi, P.;

́

̀

Matyus, P.; Lemiere, G.; Dommisse, R.; Kaiser, M.; Brun, R.; Cos, P.;

́

Maes, L.; Hajos, G.; Riedl, Z.; Nagy, I.; Maes, B. U. W.; Pieters, L.

Structure-activity relationship of antiparasitic and cytotoxic indoloqui-

noline alkaloids, and their tricyclic and bicyclic analogues. Bioorg. Med.

Chem. 2009, 17, 7209−7217.

(11) Van Miert, S.; Hostyn, S.; Maes, B. U. W.; Cimanga, K.; Brun, R.;

́

̀

Kaiser, M.; Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.;

Pieters, L. Isoneocryptolepine, a synthetic indoloquinoline alkaloid, as

an antiplasmodial lead compound. J. Nat. Prod. 2005, 68, 674−677.

(12) Grunberg, E.; Kramer, M. J.; Buck, M.; Trown, P. W. Activity of

10-chloro-5-(2-dimethylaminoethyl)-7 H -indolo[2,3-c ]-quinolin-

6(5 H )-one hydrochloride against experimental tumors in mice and rats.

Chemotherapy 1978, 24, 77−80.

(13) Zhang, W.; Li, Z.; Wang, W.; Zhang, X.; Hu, C. One-pot

synthesis of indolo[2,3-c ]quinolin-6-ones by sequential photocycliza-

tions of 3-(2-azidophenyl)-N -phenylacrylamides. Synlett 2013, 24, 73−

78.

(14) Rasouli, M. A.; Mahdavi, M.; Firoozpour, L.; Shafiee, A.;

Foroumadi, A. Synthesis of novel indolo[2,3-c ]quinolinones via Ugi-

4CR/palladium-catalyzed arylation. Tetrahedron 2014, 70, 3931−3934.

(15) Li, Y.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. A convenient

synthesis of indoloquinolinones via 3-arylation of indole-2-carbox-

amides and PIDA-mediated C −N bond formation. Tetrahedron 2015,

71, 2927−2935.

(33) Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. An

efficient method for the N -debenzylation of aromatic heterocycles.

Tetrahedron Lett. 2002, 43, 399−402.

(34) Simonetti, M.; Cannas, D. M.; Larrosa, I. Biaryl synthesis via C −

H bond activation: strategies and methods. Adv. Organomet. Chem.

2017, 67, 299−399.

(35) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A.

M. Proton abstraction mechanism for the palladium-catalyzed intra-

molecular arylation. J. Am. Chem. Soc. 2006, 128, 1066−1067.

(36) Chapman, M. R.; Pask, C. M.; Ariafard, A.; Willans, C. E. σ -

Alkenyl endo-palladacycle formation via regiospecific functionalisation

of an unreactive NHC-tethered C(sp²)-H bond. Chem. Commun. 2015,

51, 5513−5515.

(37) Pascual, S.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.;

Echavarren, A. M. Bidentate phosphines as ligands in the palladium-

catalyzed intramolecular arylation: the intermolecular base-assisted

proton abstraction mechanism. Tetrahedron 2008, 64, 6021−6029.

(38) For further mechanisms, see Supporting Information and:

(16) Zhang, T.-Y.; Liu, C.; Chen, C.; Liu, J.-X.; Xiang, H.-Y.; Jiang, W.;

Ding, T.-M.; Zhang, S.-Y. Copper-mediated cascade C −H/N −H

annulation of indolocarboxamides with arynes: construction of

tetracyclic indoloquinoline alkaloids. Org. Lett. 2018, 20, 220−223.

(17) Gu, C.-X.; Chen, W.-W.; Xu, B.; Xu, M.-H. Synthesis of

indolo[2,3-c ]coumarins and indolo[2,3-c ]quinolinones via microwave-

assisted base-free intramolecular cross dehydrogenative coupling.

Tetrahedron 2019, 75, 1605−1611.

(18) Clemo, G. R.; Felton, D. G. I. The influence of structure on the

ultra-violet absorption spectra of hetercyclic systems. J. Chem. Soc.

1951, 671−677.

(19) Tokmakov, G. P.; Zemlyanova, T. G.; Grandberg, I. I. Synthesis

of 5,7-dihydro-6h-indolo[2,3-c ]quinolin6-ones. Chem. Heterocycl.

Compd. 1994, 30, 434−437.

̈

Gensch, T.; Thoran, R.; Richter, N.; Knolker, H.-J. Reductive

Eliminations from Diarylpalladium(II) Complexes: A Combined

Experimental and Computational Investigation. Chem.Eur. J. 2017,

23, 15116−15123.

́

(20) Franck, P.; Hostyn, S.; Dajka-Halasz, B.; Polonka-Balint, A.;

́

Monsieurs, K.; Matyus, P.; Maes, B. U. W. Pd-catalyzed intramolecular

direct arylations at high temperature. Tetrahedron 2008, 64, 6030−

(39) Dugave, C.; Demange, L. Cis −Trans Isomerization of Organic

Molecules and Biomolecules: Implications and Applications. Chem.

Rev. 2003, 103, 2475−2532.

6037.

(21) Peng, X.; Wang, W.; Jiang, C.; Sun, D.; Xu, Z.; Tung, C.-H.

Strain-promoted oxidative annulation of arynes and cyclooctynes with

benzamides: palladium-catalyzed C −H/N −H activation for the

synthesis of N-heterocycles. Org. Lett. 2014, 16, 5354−5357.

(40) Pros, G. J.; Bloomfield, A. J. Why do N-alkylated anilides bend

over? The factors dictating the divergent conformational preferences of

2 ° and 3 ° N-aryl amides. J. Phys. Chem. A 2019, 123, 7609−7618.

(41) Becke, A. D. Density-functional thermochemistry. I. The effect of

the exchange-only gradient correction. J. Chem. Phys. 1992, 96, 2155−

2160.

̈

(22) Ansari, N. H.; Dacko, C. A.; Akhmedov, N. G.; Soderberg, B. C.

G. Double Palladium Catalyzed Reductive Cyclizations. Synthesis of

2,2 ′-, 2,3 ′-, and 3,3 ′-Bi-1 H -indoles, Indolo[3,2-b ]indoles, and Indolo-

[2,3-b ]indoles. J. Org. Chem. 2016, 81, 9337−9349.

(42) Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence,

triple zeta valence and quadruple zeta valence quality for H to Rn:

Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7,

3297−3305.

(43) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and

accurate ab initio parametrization of density functional dispersion

correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010,

132, 154104.

(44) Becke, A. D.; Johnson, E. R. A density-functional model of the

dispersion interaction. J. Chem. Phys. 2005, 123, 154101.

(45) Johnson, E. R.; Becke, A. D. A post-Hartree-Fock model of

intermolecular interactions. J. Chem. Phys. 2005, 123, 024101.

(23) Liu, R.-R.; Xu, Y.; Liang, R.-X.; Xiang, B.; Xie, H.-J.; Gao, J.-R.;

Jia, Y.-X. Spirooxindole synthesis via palladium-catalyzed dearomative

reductive-Heck reaction. Org. Biomol. Chem. 2017, 15, 2711−2715.

(24) Chen, Z.; Wang, X. A Pd-catalyzed, boron ester-mediated,

reductive cross-coupling of two aryl halides to synthesize tricyclic

biaryls. Org. Biomol. Chem. 2017, 15, 5790−5796.

(25) Nealmongkol, P.; Calmes, J.; Ruchirawat, S.; Thasana, N.

Synthesis of phenanthridinones using Cu- or Pd-mediated C −N bond

formation. Tetrahedron 2017, 73, 735−741.

́

(26) Vaillard, V. A.; Buden, M. E.; Martín, S. E.; Rossi, R. A. Synthesis

of novel fused azaheterocycles by photostimulated intramolecular S_RN

1

Q

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(46) Johnson, E. R.; Becke, A. D. A post-Hartree-Fock model of

intermolecular interactions: Inclusion of higher-order corrections. J.

Chem. Phys. 2006, 124, 174104.

(47) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal solvation

model based on solute electron density and on a continuum model of

the solvent defined by the bulk dielectric constant and atomic surface

tensions. J. Phys. Chem. B 2009, 113, 6378−6396.

(48) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient,

approximate and parallel Hartree −Fock and hybrid DFT calculations.

A “chain-of-spheres ” algorithm for the Hartree −Fock exchange. Chem.

Phys. 2009, 356, 98−109.

(49) Weigend, F. Accurate coulomb-fitting basis sets for H to Rn. Phys.

Chem. Chem. Phys. 2006, 8, 1057−1065.

(50) Neese, F. Software update: the ORCA program system, version

4.0. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2018, 8, No. e1327.

(51) La Regina, G.; Silvestri, R.; Gatti, V.; Lavecchia, A.; Novellino, E.;

Befani, O.; Turini, P.; Agostinelli, E. Synthesis, structure-activity

relationships and molecular modeling studies of new indole inhibitors

of monoamine oxidases A and B. Bioorg. Med. Chem. 2008, 16, 9729−

9740.

(52) Walser, A.; Silverman, G.; Flynn, T.; Fryer, R. I. Nucleophilic

displacement of aromatic fluorine, Part III, indoloquinolines and

benzofuranoquinolines. J. Heterocycl. Chem. 1975, 12, 351−358.

̀

́

(53) Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.; Matyus,

́

P.; Hajos, G.; Dommisse, R. A. Synthesis of the benzo-β -carboline

isoneocryptolepine: the missing indoloquinoline isomer in the alkaloid

series cryptolepine, neocryptolepine and isocryptolepine. Tetrahedron

2005, 61, 1571−1577.

R

https://dx.doi.org/10.1021/acs.joc.0c01832

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Synthesis of Indolo[2,3- c]quinolin-6(7 H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C-H Arylation

DOI: 10.1021/acs.joc.0c01832

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.0c01832

Full text of DOI:10.1021/acs.joc.0c01832

Products guided by the article

R&D Labs maybe for 52865-69-7

Relevant to this article

Hot Product