Iodothiophenes and Related Compounds as Coupling Partners in Copper-Mediated N-Arylation of Anilines

SYNTHESIS

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2020, 52, A–N

paper

A

en

S. Bouarfa et al.

Paper

Synthesis

Iodothiophenes and Related Compounds as Coupling Partners in

Copper-Mediated N-Arylation of Anilines

Salima Bouarfa^a,b

A one-step entry into relevant extended aromatic heterocycles

Ghenia Bentabed-Ababsa*^b

S

Me

William Erb^a

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Laurent Picot*^c

Valérie Thiéry^c

Thierry Roisnel^a

Vincent Dorcet^a

Florence Mongin*^a

O

I

N

NH₂

activated Cu, K₂CO₃

Bu₂O, reflux

98% yield

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^aUniv Rennes, CNRS, ISCR (Institut des Sciences Chimiques de

Rennes) - UMR 6226, F-35000 Rennes, France

^bLaboratoire de Synthèse Organique Appliquée, Faculté des Sci-

ences Exactes et Appliquées, Université d’Oran 1 Ahmed Ben

Bella, BP 1524 El M’Naouer, 31000 Oran, Algeria

bentabedg@gmail.com

^cLa Rochelle Université, Laboratoire Littoral Environnement et

Sociétés, UMRi CNRS 7266, Université de La Rochelle, 17042

La Rochelle, France

laurent.picot@univ-lr.fr

Corresponding Authors

Received: 12.08.2020

Accepted after revision: 18.09.2020

Published online: 26.10.2020

120 °C. The groups of Luker⁷and Kirsch⁸employed biden-

tate BINAP and cesium carbonate in toluene at 110 °C for re-

acting arylamines with bromothiophenes bearing electron-

withdrawing groups; interestingly, while the reactions

worked well with 2,3- and 2,5-isomers, they failed to deliv-

er the products from the 2,4-isomers.^7,8Similarly, the Que-

iroz group documented the coupling of 3-bromoben-

zo[b]thiophene with 2-bromoanilines in moderate yields by

using BINAP and sodium tert-butoxide in toluene at 120

°C;⁹the presence of an (electron-withdrawing) ester func-

tion at the 2-position of the benzothiophene ring proved to

favor the reaction.¹⁰A close protocol was similarly reported

by Buchwald and co-workers for the amination of 3-bromo-

benzo[b]thiophene with aniline, but using a bulky biaryl

electron-rich ligand.¹¹

DOI: 10.1055/s-0040-1706542; Art ID: ss-2020-z0426_op

Abstract N-Arylation of various 2-acylated anilines with different

electron-rich heteroaryl iodides (2- and 3-iodothiophenes, 2- and 3-

iodobenzothiophenes, 2-iodobenzofuran) was achieved by using acti-

vated copper and potassium carbonate in dibutyl ether at reflux. The

reactivity of the different heteroaryl iodides and anilines employed was

discussed and rationalized on the basis of their electronic features. Sub-

sequent cyclization by aromatic electrophilic substitution easily took

place in the case of C2-free (benzo)thienyl or C3-free (benzo)furyl

derivatives, affording original tri- and tetracycles. The antiproliferative

activity of most of them was evaluated in A2058 melanoma cells and

revealed four chlorinated tetracycles as effective growth inhibitors.

Key words, aniline, thiophene, iodine, N-arylation, copper, antiprolifer-

ative activity, melanoma cells

By using reaction conditions close to those of the Wata-

nabe group,⁵the Hartwig group observed that 3-bromo-

thiophene reacts with anilines (diphenylamine < aniline <

N-methylaniline) more rapidly than 2-bromothiophene.¹²

To rationalize the reactivity difference between 2- and 3-

bromothiophenes, the results were compared with those

from 2- and 3-bromofurans: the authors noticed higher

yields from 2-bromofuran than from 2-bromothiophene,

but higher yields from 3-bromothiophene than 3-bromo-

furan. Interestingly, a correlation was found between the

yields recorded (2-furyl > 3-furyl and 3-thienyl > 2-thienyl)

and those of the heteroarylamine reductive elimination

from the corresponding dppf-chelated thienylpalladium

amides [dppf = 1,1′-bis(diphenylphosphino)ferrocene].¹³

The reactivity orders were further found to be related to the

calculated Mulliken charges on carbons of thiophene and

furan, with 2-furyl (C2: +0.16) and 3-thienyl (C3: –0.27)

Thiophenes and their benzo derivatives are aromatic

heterocycles present in numerous bioactive compounds or

in materials endowed with various electronic properties.¹

To access a wide variety of derivatives, functionalization of

thiophenes is usually preferred over cyclization of suitable

substrates.²However, while the introduction of aliphatic

amines into thiophenes has been developed by different

ways,³the use of anilines and derivatives is less developed.

Nucleophilic substitutions by anilines are only possible

with activated thienyl halides under strong reaction condi-

tions.⁴Thus, recourse to transition metal catalysts is man-

datory in the case of unactivated thienyl halides.

Palladium-catalyzed reactions between bromothio-

phenes and diarylamines were documented by the groups

of Watanabe⁵and Rasmussen⁶who used tri-tert-butylphos-

phine (ligand) and sodium tert-butoxide (base) in xylene at

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

S. Bouarfa et al.

Paper

Synthesis

being less electron-rich (i.e. reductive elimination with C–N

bond formation favored) than 3-furyl (C3: –0.34) and 2-

thienyl (C2: –0.43), respectively. Reductive elimination with

C–N bond formation was also reported as being favored in

the case of more electron-donating amido groups.^12,13

However, studies on the corresponding copper-mediat-

ed reactions remain, by far, less documented. In the course

of the synthesis of inhibitors of platelet aggregation,

Elslager and co-workers N-arylated potassium anthranilate

by 3-bromobenzo[b]thiophene in the presence of N-ethyl-

morpholine and catalytic copper(II) bromide, albeit in a

moderate 32% yield after 2 h in refluxing dimethylform-

amide.¹⁴A better result was recorded by Zhu and co-work-

ers who reacted 3-bromothiophene with aniline in water

containing chitosan and copper(I) oxide, both catalytic, po-

tassium hydroxide, and tetrabutylammonium bromide

(80% yield for the monoarylated product after 12 h reaction

at 70 °C).¹⁵In contrast, Lu and Twieg hardly aminated 2-

bromothiophene with N-(2-hydroxyethyl)aniline (em-

ployed as both reagent and solvent) in the presence of cata-

lytic amounts of copper and copper(I) iodide, and potassi-

um phosphate as base (15% yield after 2 days at 85 °C) while

aniline and diphenylamine failed to react in N,N-dimethyl-

ethanolamine used as solvent.¹⁶

Table 1 N-Arylation of Ethyl Anthranilate (1)

O

I-Ar (x equiv)

activated Cu (y equiv)

K₂CO₃(2 equiv)

OEt

NH₂

OEt

NH

Ar

Bu₂O, 140 °C, 24 h

1

2

Entry

I-Ar

x equiv

y equiv

Product 2, yield (%)^a

CO₂Et

1

2

3

1.0

1.5

0.2

2.0

1.0^e

2a, 43^b(20)^c,d

2a, 45^b

I

2a, 52^b(48)^b,f

S

N

S

H

CO₂Et

4

5

6

R = Me

R = COPh

R = Cl

1.5

1.0^e

traces^g

R

I

R

N

S

H

CO₂Et

N

7

1.5

1.0^e

traces^g

S

N

S

H

CO₂Et

8

9

10

1.0

1.5

0.2

2b, 30^b

1.0^e

2b, 34^b

2b, 57^b(53)^h

N

H

S

I

S

CO₂Et

11

12

13

1.5

1.0

1.0^e

<20^g

N

O

I

O

H

CO₂Et

S

2c, 96

2d, 92

N

H

CO₂Et

I

N

H

^aAfter purification (see experimental part).

^bThe rest is mainly recovered ethyl anthranilate and 2-iodothiophene.

^cAfter 57 h reaction time.

^dDegradation was noticed.

^eAdded by portions of 0.2 equiv every 2 h.

^fThe reaction was performed in the presence of CuI (1 equiv).

^gNot possible to isolate the pure product from the reaction mixture.

^hAfter 12 h reaction time.

C

S. Bouarfa et al.

Paper

Synthesis

Within studies dedicated to copper-mediated C–N bond

formation from aryl iodides,^3k,17we successfully reacted 2-

acylated anilines (2-aminoacetophenone and -benzophe-

none, 2-amino-3-benzoylpyridine, and 1-amino-9-thioxan-

thone) with 2-iodothiophene and -benzothiophene.^17g,hIn

order to progress toward a better understanding of this re-

action, here we initially compared the behavior of 2- and 3-

iodothiophene, 2- and 3-iodobenzothiophene, and 2-iodo-

benzofuran in the N-arylation of ethyl anthranilate. Then,

we prepared several thieno-, benzothieno- and benzofura-

no-fused quinolines from 2-aminoacetophenone, 2-amino-

benzophenones, and 2-aminobenzaldehydes by N-arylation

and subsequent cyclization. To highlight the biological in-

terest of these polycyclic heterocycles, they were evaluated

for their antiproliferative activity in A2058 melanoma cells.

The few studies dedicated to the copper-catalyzed reac-

tions of halogenated thiophenes with anilines suggest a re-

activity order between 2- and 3-bromothiophenes similar

to the one observed in palladium-catalyzed reactions; how-

ever, it is difficult to come to a clear conclusion due to the

different reaction conditions employed. Thus, by starting

from ethyl anthranilate (ethyl 2-aminobenzoate; 1), we de-

cided to compare the reactivities of different thienyl and

benzothienyl iodides (Table 1).

tion of thiophene similarly led to traces of the N-thienylat-

ed products (entries 5 and 6). In these cases, an intramolec-

ular electron transfer from the nitrogen lone pair to the

thienyl ring, facilitated by the presence of an electron-with-

drawing group,^3kcould explain the low stability of the

formed 2-(arylamino)thiophenes during both synthesis and

purification. Note that using 2-iodothiazole as aryl iodide

also led to a similar result, with traces of the expected prod-

uct only detected in the crude (entry 7).

We next turned our attention to the reaction between 1

and 2-iodobenzothiophene. After optimization of the con-

ditions (entries 8–10), the expected N-heteroarylated prod-

uct 2b was produced in a slightly higher 57% yield (entry

10; Figure 1). As far as 2-iodobenzofuran is concerned, the

reaction worked to some extent, but it proved impossible to

isolate the pure product from the reaction mixture due to

its low stability (entry 11).¹⁹

Inspired by the conditions previously found to couple 2-

acylated anilines with (benzo)thienyl iodides,^17g,hwe first

attempted the reaction between 1 and 2-iodothiophene in

the presence of a catalytic amount of activated copper and

2 equivalents of potassium carbonate. The expected N-thie-

nylated product 2a was isolated in 43% yield after 24 h reac-

tion time at 140 °C in dibutyl ether while lower yields were

noticed after extended contact times due to increased un-

known byproducts formation (entry 1). By increasing the

amount of copper to 2 equivalents, 2a was obtained in a

similar 45% yield (entry 2). However, by using 1 equivalent

of copper, added in fractions of 0.2 equivalent every two

hours, 2a was isolated in a slightly improved 52% yield. Be-

cause copper(I) iodide is sometimes recommended as an

additive in such N-arylations,¹⁶it was added with copper by

fractions of 0.2 equivalent every two hours; however, no

improvement was noticed (entry 3). It is worth noting that

in the other conditions tested [either (i) copper(I) iodide

(0.05 equiv), N,N′-dimethylethylenediamine (0.1 equiv), po-

tassium phosphate (2 equiv) in dioxane at 90 °C for 15 h,¹⁸

or (ii) copper(I) iodide (0.05 equiv), potassium phosphate (2

equiv) in dimethyl sulfoxide at 90 °C for 15 h^17d] no reaction

took place.

Figure 1 ORTEP diagram (50% probability) of the compound 2b

When compared with its 2-iodinated isomer, 3-iodo-

benzothiophene proved much more reactive, affording the

N-arylated derivative 2c in a nearly quantitative yield upon

treatment by 1 as before (entry 12). A reactivity higher than

that of the 2-iodinated isomer was also recorded in the case

of 3-iodothiophene, which was converted into the deriva-

tive 2d in high yield (entry 13).

For palladium-catalyzed coupling reactions in which

oxidative addition is rate determining, the literature pro-

vides approaches to predict the regioselectivity in the case

of polyhalogenated substrates. In the case of two identical

halogens, the reaction is generally favored at the most elec-

tron-deficient carbon.²⁰In this vein, Fairlamb and co-work-

ers proposed to employ the ¹³C NMR chemical shifts as a

measure of their electrophilicities, with the most deshield-

ed carbon corresponding to the preferred coupling site.²¹

We thus compared the ¹³C NMR spectra of 2-iodothiophene

(C2 at  = 72.8) and 3-iodothiophene (C3 at  = 76.8),²²as

well as those of 2-iodobenzothiophene (C2 at  = 78.5) and

its 3-iodo isomer (C3 at  = 78.4).²³All these C–I chemical

shifts are below that of iodobenzene ( = 94.4), in line with

the lower reactivities noticed. The values are in accordance

with an easier oxidative addition at C3 in the iodothio-

phene series. However, they alone cannot explain the dis-

crepancy observed in the iodobenzothiophene series;

In the reaction of 1 with 2-iodo-5-methylthiophene un-

der the conditions optimized for 2-iodothiophene, only

traces of the expected product were detected (entry 4).

Since it is known from the literature that such methyl-sub-

stituted products can be more prone to decomposition than

their methyl-free analogues,¹²this result cannot be used to

better understand the reaction. Introducing an electron-

withdrawing ketone function or chloro group at the 5-posi-

D

S. Bouarfa et al.

Paper

Synthesis

therefore, inspired by the studies performed under palladi-

um catalysis, we also looked at the reductive elimination

step.

(5-methyl-2-thienyl)acetophenone (8c′) were, for example,

isolated in 50% and 13% yields, respectively (entries 6 and

9). By using 2-iodo-5-methylthiophene, the cyclized prod-

ucts were obtained in slightly higher yields than from 2-iodo-

thiophene (entries 9–11); in contrast, 2-iodothiophenes

bearing electron-withdrawing groups at C5 gave only traces

of products (entries 12–15), a result probably due to the in-

stability issue already observed with 5-substituted iodo-

thiophenes (Table 1, entries 4–6).

On the basis of the carbons’ Mulliken charges (see Fig-

ure 2), the obtained results show that the reactions are fa-

vored for less electron-rich 3-thienyl and 3-benzothienyl,

when compared with 2-thienyl and 2-benzothienyl. Be-

tween thiophene and benzothiophene, charges for the car-

bons at C2 are close with a slightly less negative value for

the latter. Less electron-rich aryl groups (that facilitate re-

ductive elimination) seem to also favor this copper-mediat-

ed N-arylation, as proposed by the Hartwig group for relat-

ed palladium-catalyzed reactions in the thiophene and

furan series.^12,13

–0.18

+0.06

–0.28

–0.45

–0.14

–0.38

–0.28

–0.45

–0.18

–0.17

S

_–0.19S

+0.455

+0.695

–0.18

–0.20

+0.02

–0.335

+0.09

–0.235

+0.07

–0.335

+0.09

–0.18

–0.19

O

_+0.29O

–0.44

–0.20

–0.47

Figure 2 Mulliken charges on atoms calculated (MP2/6-31G(d)) by

Belen’kii, Suslov, and Chuvylkin for thiophene, benzo[b]thiophene,

benzo[b]furan, and furan²⁴

Due to the instability of some of the N-arylated ethyl

anthranilates, it proved difficult to compare the reactivities

of all the thienyl iodides and related compounds. We

thought an alternative way could consist of trapping the

formed N-thienyl derivatives as soon as they are formed by

cyclization, as documented in a previous study (Scheme

1).^17g

To this purpose, we replaced the ester 1 by more reac-

tive aldehydes and ketones, and chose a wider range of re-

agents [2-aminoacetophenone (3), 2-aminobenzophenone

(4), 2-aminobenzaldehyde (5), 2-amino-5-chlorobenzophe-

none (6), and 2-amino-5-chlorobenzaldehyde (7)] in order

(i) to study the impact of the aniline on the course of the

reaction, and (ii) to prepare a larger range of molecules for

biological evaluation. Reactions were performed with 2-io-

dothiophene and related compounds (Table 2), as well as

with 3-iodothiophene and its benzo analogue (Table 3) un-

der the optimized reaction conditions. Even though the re-

actions were carried out using only 0.2 equivalent of acti-

vated copper,^17gwe have included previously published re-

sults shown in Scheme 1 in these tables in order to give a

comprehensive view.

First of all, N-arylation was readily followed by in situ

cyclization in the case of 2-iodobenzothiophene (Table 2,

entries 1–5; Figure 3), 2-iodobenzofuran (entries 16–20),

and 2-iodofuran (entry 21), but cyclization was delayed for

other 2-iodothiophenes. Indeed, after 24 h reaction time,

the intermediate N-(2-thienyl)benzophenone (9b′) and N-

Figure 3 ORTEP diagrams (50% probability) of the compounds 10a,

12d, 11g, and 12g

E

S. Bouarfa et al.

Paper

Synthesis

Table 2 N-Arylation-Cyclization between 3–7 and 2-Iodo(benzo)thiophenes/furans To Afford Tri- and Tetracycles

R

N

R'

I

R'

O

R'

O

X

NH

NH₂

X

cat. activated Cu (1 equiv;

0.2 equiv every 2 h)

X

3: R = Me, R' = H

4: R = Ph, R' = H

5: R = R' = H

8: R = Me, R' = H

9: R = Ph, R' = H

10: R = R' = H

K₂CO₃(2 equiv)

Bu₂O, reflux, 24 h

6: R = Ph, R' = Cl

7: R = H, R' = Cl

11: R = Ph, R' = Cl

12: R = H, R' = Cl

Entry

Aniline

Iodide

Equiv

Product, yield (%)^a

1^17g

3

4

5

6

7

1.5

1

8a (R = Me, R′ = H), 46

9a (R = Ph, R′ = H), 64

10a (R = R′ = H), 78

11a (R = Ph, R′ = Cl), 59

12a (R = H, R′ = Cl), 42

R

2^17g

3

R'

I

4

5

S

N

1

R

6^17g

7

8

4

6

7

1.5

1

9b (R = Ph, R′ = H), 10^b

11b (R = Ph, R′ = Cl), 4

12b (R = H, R′ = Cl), 5

R'

I

S

N

R

9

10

11

3

4

5

1.5

8c (R = Me), 22^c

9c (R = Ph), 14

10c (R = H), 17

Me

S

N

R

12

13

3

4

1.5

R = Me: traces

R = Ph: traces

I

COPh

S

COPh

S

N

R

14

15

3

4

1.5

R = Me: traces

R = Ph: traces

Cl

S

N

16

17

18

19

20

3

4

5

6

7

1.5

–

1

8d (R = Me, R′ = H), 94, 57^17g

9d (R = Ph, R′ = H), 79, 85^17g

10d (R = R′ = H), 82

11d (R = Ph, R′ = Cl), 85

12d (R = H, R′ = Cl), 59

R

R'

d

I

O

N

Ph

21^17g

5

1.5

9e, 61

O

N

^aAfter purification (see experimental part).

^bN-(2-Thienyl)benzophenone (9b′) was also isolated in 50% yield.

^cN-(5-Methyl-2-thienyl)acetophenone (8c′) was also isolated in 13% yield.

^dTo improve the yield, 1.5 equiv of 2-aminobenzaldehyde and 1 equiv of 2-iodobenzofuran were used.

I

R

N

R

N

X

O

(1.5 equiv)

or

NH₂

X

cat. activated Cu (0.2 equiv)

K₂CO₃(2 equiv)

3: R = Me

4: R = Ph

Bu₂O, reflux, 24 h

8a: X = S; R = Me: 46%

8d: X = O; R = Me: 57%

9a: X = S; R = Ph: 64%

9d: X = O; R = Ph: 85%

9b: X = S; R = Ph: 10%

9e: X = O; R = Ph: 61%

Scheme 1 Results obtained in the frame of a previous study^17g

F

S. Bouarfa et al.

Paper

Synthesis

Table 3 N-Arylation-Cyclization between 3–7 and 3-Iodo(benzo)thiophenes To Afford Tri- and Tetracycles

R

N

S

R

R'

S

R'

O

I

NH₂

NH

cat. activated Cu (1 equiv;

0.2 equiv every 2 h)

K₂CO₃(2 equiv)

8: R = Me, R' = H

9: R = Ph, R' = H

10: R = R' = H

11: R = Ph, R' = Cl

12: R = H, R' = Cl

3: R = Me, R' = H

4: R = Ph, R' = H

5: R = R' = H

6: R = Ph, R' = Cl

7: R = H, R' = Cl

Bu₂O, reflux, 24 h

S

Entry

1

Aniline

Iodide

Equiv

1.5

Product, yield (%)^a

Me

S

3

8f, 98

N

I

2

3

4

5

6

3

4

5

6

7

1.5

1

8g (R = Me, R′ = H), 98

9g (R = Ph, R′ = H), 96

10g (R = R′ = H), 40

11g (R = Ph, R′ = Cl), 89

12g (R = H, R′ = Cl), 63

R

S

R'

S

I

N

1

^aAfter purification (see experimental part).

When compared with 2-iodobenzothiophene, 2-iodo-

benzofuran gave the tetracycles in higher yields, irrespec-

tive of the aniline employed (entries 16–20). These results

could be rationalized by a less electron-donating 2-benzo-

furyl, when compared with 2-benzothienyl, thus favoring

reductive elimination. If such was the case, 3-iodobenzo-

thiophene should be more reactive than its 2-isomer on the

basis of the Mulliken charges of carbons (see Figure 2).

Indeed, 3-iodobenzothiophene reacted with 2-amino-

acetophenone (3) in a quantitative yield (Table 3, entry 1).

Concerning 3-iodothiophene, its reactivity toward the test-

ed anilines proved, in general, to be very high, superior to

that of its 2-isomer, a result still in good agreement with

the reactivity predicted by the Mulliken charges. Moreover,

cyclization by attack of the C2 carbon of thiophene is much

more efficient than by attack of its less electron-rich C3

carbon (entries 2–6).

In spite of renewed interest in the synthesis of thieno-

[2,3-b]quinolines,²⁵benzothieno[2,3-b]quinolines,²⁶benzo-

furo[2,3-b]quinolines,^25d,27thieno[3,2-b]quinolines,²⁸and

benzothieno[3,2-b]quinolines,²⁹biological activities of

these compounds have been reported unevenly. While nu-

merous studies have concerned bioactive thieno[2,3-

b]quinolines³⁰and furo[2,3-b]quinolines,³¹fewer works

have been dedicated to the benzo-fused analogues, and spe-

cifically to benzothieno[2,3-b]quinolines³²and benzofuro-

[2,3-b]quinolines.^32,33The biological properties of thieno-

[3,2-b]quinolines³⁴and benzothieno[3,2-b]quinolines³⁵

have not yet been extensively studied either.

In the course of our previous study,^17gcompounds 8a

and 8d were tested against A2058 melanoma cells, and

showed a significant antiproliferative activity (60–70%

growth inhibition of 2000 cells at 10^–5M after 72 h); albeit

less efficient, 9a and 9d also proved promising (45–55% at

The use of different anilines shows that their nature has

an impact on the efficiency of the reaction. For example,

under the optimized conditions, no reaction was observed

between 2-iodothiophene and anilines such as 3,5-di-

methoxyaniline and 4-fluoroaniline while degradation was

noticed with 4-nitroaniline. Even the more reactive 3-iodo-

thiophene did not react at all with 3,5-dimethoxyaniline

and 4-fluoroaniline. The presence of the C=O group next to

amino is required since 4-acetylaniline also failed to react

with 3-iodothiophene. However, for a currently unex-

plained reason, 2-amino-3-formylpyridine did not react.

Aldehyde functions gave generally lower yields than ke-

tones, in particular when chlorine is present at the para po-

sition relative to the aniline. Thus, it seems that reactions

are less favored in the presence of electron-withdrawing

groups, as previously observed under palladium catalysis.⁸

N

O

S

R

8d: R = Me

9d: R = Ph

8a: R = Me

9a: R = Ph

R

Me

N

S

N

Me

R = H: cryptolepine

R = Me: 11-methylcryptolepine

8f

Figure 4 Compounds previously shown to inhibit melanoma cells

growth (top); similarity between 8f and cryptolepines (bottom)

G

S. Bouarfa et al.

Paper

Synthesis

Figure 5 Antiproliferative activity of four compounds previously evaluated (top, colored) and of 16 of the compounds here synthesized (bottom, grey)

at 10^–5M after 72 h in A2058 human melanoma cells

10^–5M after 72 h) (Figure 4, top; Figure 5, top). Tsuchimoto

and co-workers reported in 2018 an efficient approach to

access such compounds in a similar scope by indium-

catalyzed annulation of 2-acylanilines with suitably meth-

oxy-substituted (benzo)furans or (benzo)thiophenes.²⁸In

the same paper, they also highlighted the similarity be-

tween 11-methylbenzothieno[3,2-b]quinoline (8f) and 11-

methylcryptolepine (Figure 4, bottom), which is a submicro-

molar cytotoxic agent against KB cancer cells.³⁶Further-

more, Bonjean, Bailly, and co-workers showed in 1998 that

cryptolepine selectively binds to DNA and acts both as a po-

tent topoisomerase II inhibitor and a promising antitumor

agent in melanoma cells.³⁷

Consequently, some of the tri- and tetracycles obtained

in the frame of this study were tested for their antiprolifer-

ative activity against melanoma cells (Figure 5, bottom).

Most of the tested compounds showed an activity against

A2058 cell lines, selected because of their natural and ac-

quired resistance to chemotherapy and radiotherapy. How-

ever, while 8f only exerted a moderate antiproliferative ac-

tivity, other compounds proved more promising. In particu-

lar, the tetracyclic compounds 12a and 12d possessing no

methyl group but a chlorine atom at the 9-position showed

stronger activity as antiproliferative drugs in human inva-

sive melanoma cells. Compounds 11a and 11d which are

the 9-chloro analogues of 9a and 9d, respectively, also ex-

hibited activities superior to their non-chlorinated ana-

logues.

Through this copper-mediated N-arylation of anilines

using five-membered heteroaromatic iodides such as 2-

and 3-iodothiophenes and their benzo-fused analogues, we

could evidence the impact of the electronic features of both

the heteroaryl group of the iodide and the aryl group of the

aniline.

When N-arylation is in situ followed by aromatic elec-

trophilic substitution [a combination that easily takes place

from 3-iodo(benzo)thiophene or 2-iodo(benzo)furan], this

reaction offers a general one-step entry into relevant ex-

tended aromatic heterocycles. On the model of the previ-

ously tested compounds 8a and 8d, the molecules 12a and

12d showed promising activity as antiproliferative drugs in

human invasive melanoma cells. It would be of interest to

evaluate the 9-chloro analogues of 8a and 8d for their anti-

proliferative activity against such cells. In addition, due to

their structural analogy with cryptolepines, this original

family of compounds could be subjected to further biologi-

cal activity studies in search of valuable antibacterial and

antimalarial properties.

All the reactions were performed under an argon atmosphere. Col-

umn chromatography separations were achieved on silica gel (40–63

m); PE = petroleum ether. Melting points were measured on a Kofler

apparatus. IR spectra were taken on a Perkin-Elmer Spectrum 100

spectrophotometer. ¹H and ¹³C NMR spectra were recorded either on

a Bruker Avance III spectrometer at 300 MHz and 75 MHz respective-

ly, on a Bruker Avance III spectrometer at 400 MHz and 100 MHz re-

spectively, or on a Bruker Avance III HD spectrometer at 500 MHz and

126 MHz respectively. ¹H chemical shifts () are relative to the solvent

H

S. Bouarfa et al.

Paper

Synthesis

residual peak and ¹³C chemical shifts are relative to the central peak

of the solvent signal.³⁸Mass spectra (HRMS) were recorded in ASAP

mode on a Maxis 4G apparatus. Activated copper,³⁹2-iodobenzothio-

phene,^17a,402-iodobenzofuran,^17a,402-iodothiazole,⁴¹3-iodobenzo-

thiophene,²³2-chloro-5-iodothiophene,⁴²2-benzoyl-5-iodothio-

phene,^17e,43and 2-aminobenzaldehyde⁴⁴were prepared as described

previously. Bu₂O was degassed prior to use. All reagents not listed in

the publication were obtained from commercial sources.

N-Arylation of 2-Aminobenzaldehyde (5); General Procedure 4

(GP4)

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), freshly prepared 2-amino-

benzaldehyde (5; 0.12 g, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The

mixture was degassed and refluxed under argon for 24 h. Activated Cu

(4 × 13 mg, 4 × 0.2 mmol) was added after 2, 4, 6, and 8 h of heating.

The mixture was cooled to r.t. and concentrated, then H₂O (25 mL)

was added and the mixture was extracted with EtOAc (3 × 10 mL). The

combined extracts were dried (Na₂SO₄), the solvent was removed, and

the residue was purified by chromatography (silica gel) to give the

product.

Crystallography: The samples were studied with monochromatized

MoK radiation ( = 0.71073 Å, multilayered monochromator). The X-

ray diffraction data of 2b, 10a, 12d, 11g, and 12g (Figures 1 and 3)

were collected at 150 K by using D8 VENTURE Bruker AXS diffractom-

eter equipped with a (CMOS) PHOTON 100 detector. The structures

were solved by dual-space algorithm using the SHELXT program,⁴⁵

and then refined with full-matrix least-square methods based on F²

(SHELXL-2014).⁴⁶All non-hydrogen atoms were refined with aniso-

tropic atomic displacement parameters. In the case of 2b, H1 was in-

troduced in the structural model through Fourier difference maps

analysis, otherwise H atoms were finally included in their calculated

positions and treated as riding on their parent atom with constrained

thermal parameters. The molecular diagrams were generated by

ORTEP-3 (version 2.02).⁴⁷CCDC 2015229 (2b), 2015230 (10a),

2015226 (11g), 2015227 (12d), and 2015228 (12g) contains the sup-

plementary crystallographic data for this paper. The data can be ob-

tained free of charge from The Cambridge Crystallographic Data Cen-

tre via www.ccdc.cam.ac.uk/getstructures.

N-Arylation of 2-Amino-5-chlorobenzophenone (6); General Pro-

cedure 5 (GP5)

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), 2-amino-5-chlorobenzo-

phenone (6; 0.23 g, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The

mixture was degassed and refluxed under argon for 24 h. Activated Cu

(4 × 13 mg, 4 × 0.2 mmol) was added after 2, 4, 6, and 8 h of heating.

The mixture was cooled to r.t. and concentrated, the H₂O (25 mL) was

added and the mixture was extracted with EtOAc (3 × 10 mL). The

combined extracts were dried (Na₂SO₄), the solvent was removed, and

the residue was purified by chromatography (silica gel) to give the

product.

N-Arylation of 2-Amino-5-chlorobenzaldehyde (7); General Proce-

dure 6 (GP6)

N-Arylation of Ethyl Anthranilate (1); General Procedure 1 (GP1)

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), ethyl anthranilate (1; 0.15

mL, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The mixture was de-

gassed and refluxed under argon for 24 h. Activated Cu (4 × 13 mg, 4 ×

0.2 mmol) was added after 2, 4, 6, and 8 h of heating. The mixture was

cooled to r.t. and concentrated, then H₂O (25 mL) was added and the

mixture was extracted with EtOAc (3 × 10 mL). The combined extracts

were dried (Na₂SO₄), the solvent was removed, and the residue was

purified by chromatography (silica gel) to give the product.

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), 2-amino-5-chlorobenzalde-

hyde (7; 0.16 g, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The mixture

was degassed and refluxed under argon for 24 h. Activated Cu (4 × 13

mg, 4 × 0.2 mmol) was added after 2, 4, 6, and 8 h of heating. The mix-

ture was cooled r.t. and concentrated, then H₂O (25 mL) was added

and the mixture was extracted with EtOAc (3 × 10 mL). The combined

extracts were dried (Na₂SO₄), the solvent was removed, and the resi-

due was purified by chromatography (silica gel) to give the product.

N-Arylation of 2-Aminoacetophenone (3); General Procedure 2

(GP2)

Ethyl 2-(2-Thienylamino)benzoate (2a)

Following GP1 using 2-iodothiophene (0.17 mL) with eluent: heptane/

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), 2-aminoacetophenone (3;

0.12 g, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The mixture was de-

gassed and refluxed under argon for 24 h. Activated Cu (4 × 13 mg, 4 ×

0.2 mmol) was added after 2, 4, 6, and 8 h of heating. The mixture was

cooled to r.t. and concentrated, then H₂O (25 mL) was added and the

mixture was extracted with EtOAc (3 × 10 mL). The combined extracts

were dried (Na₂SO₄), the solvent was removed, and the residue was

purified by chromatography (silica gel) to give the product.

EtOAc 95:5 (R_f= 0.45) gave 2a (129 mg, 52%) as a yellow oil.

IR (ATR): 689, 746, 848, 1018, 1045, 1078, 1138, 1160, 1236, 1309,

1368, 1442, 1496, 1543, 1582, 1678, 2981, 3075, 3301 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 1.39 (t, J = 7.1 Hz, 3 H, CH₃), 4.35 (q, J =

7.1 Hz, 2 H, CH₂), 6.73 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H, H₄or H₅), 6.80 (dt,

J = 3.7, 1.2 Hz, 1 H, H_3′), 6.91 (dd, J = 5.7, 3.5 Hz, 1 H, H_4′), 6.99–7.07 (m,

2 H, H₃, H_5′), 7.30 (ddd, J = 8.6, 7.0, 1.7 Hz, 1 H, H₄or H₅), 7.97 (dd, J =

8.0, 1.7 Hz, 1 H, H₆), 9.48 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃):  = 14.3 (CH₃), 60.7 (CH₂), 111.5 (C), 113.7

(CH), 117.2 (CH), 120.9 (CH), 121.5 (CH), 125.9 (CH), 131.2 (CH), 134.3

(CH), 143.7 (C), 149.7 (C), 168.5 (C).

N-Arylation of 2-Aminobenzophenone (4); General Procedure 3

(GP3)

HRMS: m/z [M + H]⁺calcd for C₁₃H₁₄NO₂S: 248.31945; found:

248.3196 (1 ppm).

To the heteroaryl iodide (1.5 mmol) in Bu₂O (1.5 mL) were successive-

ly added activated Cu (13 mg, 0.2 mmol), 2-aminobenzophenone (4;

0.20 g, 1.0 mmol), and K₂CO₃(0.28 g, 2.0 mmol). The mixture was de-

gassed and refluxed under argon for 24 h. Activated Cu (4 × 13 mg, 4 ×

0.2 mmol) was added after 2, 4, 6, and 8 h of heating. The mixture was

cooled to r.t. and concentrated, then H₂O (25 mL) was added, and the

mixture was extracted with EtOAc (3 × 10 mL). The combined extracts

were dried (Na₂SO₄), the solvent was removed, and the residue was

purified by chromatography (silica gel) to give the product.

Ethyl 2-(2-Benzothienylamino)benzoate (2b)

Following GP1 using 2-iodobenzothiophene (0.39 g) with eluent:

heptane/EtOAc 95:5 (R_f= 0.56) gave 2b (170 mg, 57%) as a beige pow-

der; mp 86 °C.

I

S. Bouarfa et al.

Paper

Synthesis

IR (ATR): 707, 725, 750, 860, 1020, 1083, 1139, 1162, 1185, 1237,

1299, 1368, 1438, 1453, 1477, 1494, 1540, 1579, 1682, 2983, 3282

2,4-Dimethylthieno[2,3-b]quinoline (8c)

[CAS Reg. No. 2245159-23-1]

cm^–1

.

Following GP2 using 2-iodo-5-methylthiophene [crude; prepared

from thiophene (0.12 mL, 1.5 mmol) by treatment with BuLi (1.8

mmol) in THF (2 mL) at –20 °C for 30 min, MeI (0.11 mL, 1.8 mmol) at

0 °C for 1 h, BuLi (1.6 mmol) in THF (2 mL) at –20 °C for 30 min, and I₂

(0.41 g, 1.6 mmol) in THF (2 mL)] with eluent: heptane/EtOAc 90:10

(R_f= 0.475) gave 8c (47 mg, 22%) as a beige powder; mp 92 °C (Lit.²⁸

mp 91–92 °C).

¹H NMR (300 MHz, CDCl₃):  = 1.44 (t, J = 7.1 Hz, 3 H, CH₃), 4.40 (q, J =

7.1 Hz, 2 H, CH₂), 6.83 (sept, J = 4.1 Hz, 1 H), 7.02 (s, 1 H, H_3′), 7.27 (td,

J = 7.5, 1.3 Hz, 1 H), 7.34 (td, J = 7.5, 1.3 Hz, 1 H), 7.38–7.41 (m, 2 H),

7.65 (d, J = 7.3 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H,

H₆), 9.85 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃):  = 14.4 (CH₃), 61.0 (CH₂), 112.3 (C), 114.5

(CH), 114.6 (CH), 118.2 (CH), 122.2 (CH), 122.7 (CH), 123.7 (CH), 124.6

(CH), 131.5 (CH), 134.5 (CH), 136.0 (C), 139.1 (C), 144.1 (C), 148.2 (C),

168.6 (C).

IR (ATR): 549, 584, 610, 664, 754, 806, 954, 1090, 1262, 1370, 1435,

1552, 1666, 2956 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 2.63 (s, 3 H), 2.87 (s, 3 H), 7.05 (q, J =

1.3 Hz, 1 H), 7.52 (ddd, J = 8.3, 6.8, 1.2 Hz, 1 H), 7.68 (ddd, J = 8.2, 6.7,

1.4 Hz, 1 H), 8.08 (dd, J = 8.5, 1.4 Hz, 2 H).

HRMS: m/z [M + H]⁺calcd for C₁₇H₁₆NO₂S: 298.08962; found:

298.0897 (0 ppm).

¹³C NMR (75 MHz, CDCl₃):  = 15.3 (CH₃), 17.5 (CH₃), 117.4 (CH), 124.2

(CH), 125.1 (CH), 125.2 (C), 128.5 (CH), 129.0 (CH), 132.4 (C), 136.6

(C), 141.9 (C), 146.0 (C), 163.6 (C).

Crystal data for 2b (CCDC 2015229): C₁₇H₁₅NO₂S, M = 297.36, triclinic,

P1, a = 7.5861(6), b = 10.5280(8), c = 10.7427(8) Å,  = 115.185(2),  =

108.486(3),  = 93.901(3)°, V = 715.47(10) Å³, Z = 2, d = 1.380 g cm^–3, 

= 0.230 mm^–1. A final refinement on F²with 3258 unique intensities

and 201 parameters converged at R(F²) = 0.0839 [R(F) = 0.0333] for

2901 observed reflections with I > 2(I).

The analyses are as described previously.²⁸

Also isolated with eluent: heptane/EtOAc 90:10 (R_f= 0.62) was 2-(5-meth-

yl-2-thienylamino)acetophenone (8c′) (30 mg, 13%) as an orange oil.

IR (ATR): 594, 612, 750, 796, 955, 1019, 1038, 1092, 1151, 1242, 1311,

1357, 1398, 1419, 1450, 1504, 1572, 1604, 1638, 1678, 2914, 2965,

Ethyl 2-(3-Benzothienylamino)benzoate (2c)

Following GP1 using 3-iodobenzothiophene (0.39 g) with eluent:

heptane/EtOAc 95:5 (R_f= 0.65) gave 2c (285 mg, 96%) as a yellow

powder; mp 58 °C.

3236 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 2.45 (s, 3 H), 2.64 (s, 3 H), 6.57–6.61

(m, 2 H), 6.73 (t, J = 7.5 Hz, 1 H), 7.06 (dd, J = 8.6, 1.0 Hz, 1 H), 7.32

(ddd, J = 8.6, 6.9, 1.5 Hz, 1 H), 7.79 (dd, J = 8.0, 1.5 Hz, 1 H), 10.3 (br s, 1

H).

¹³C NMR (75 MHz, CDCl₃):  = 15.3 (CH₃), 28.1 (CH₃), 114.4 (CH), 116.7

(CH), 118.5 (C), 122.6 (CH), 123.7 (CH), 132.3 (CH), 135.0 (CH), 136.2

(C), 140.4 (C), 150.2 (C), 201.3 (C).

IR (ATR): 657, 697, 719, 744, 755, 792, 858, 896, 1024, 1053, 1083,

1106, 1149, 1186, 1186, 1233, 1252, 1308, 1326, 1365, 1434, 1453,

1466, 1520, 1572, 1588, 1676, 2912, 2993, 3064, 3112, 3302 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 1.48 (t, J = 7.1 Hz, 3 H, CH₃), 4.46 (q, J =

7.1 Hz, 2 H, CH₂), 6.79 (t, J = 7.5 Hz, 1 H, H₄or H₅), 7.18 (d, J = 8.5 Hz, 1

H, H₃), 7.22 (s, 1 H, H_2′), 7.35 (ddd, J = 8.4, 7.3, 1.0 Hz, 1 H), 7.40–7.44

(m, 2 H), 7.81 (dd, J = 6.1, 3.2 Hz, 1 H, H_4′or H_7′), 7.88 (dd, J = 6.2, 2.9

Hz, 1 H, H_4′or H_7′), 8.09 (dd, J = 8.0, 1.2 Hz, 1 H, H₆), 9.90 (s, 1 H, NH).

11-Methylbenzofuro[2,3-b]quinoline (8d)

¹³C NMR (75 MHz, CDCl₃):  = 14.4 (CH₃), 60.8 (CH₂), 111.9 (C), 113.0

(CH), 114.3 (CH), 117.1 (CH), 121.2 (CH), 123.1 (CH), 124.2 (CH), 125.0

(CH), 131.6 (CH), 133.3 (C), 134.4 (CH), 135.3 (C), 138.7 (C), 148.7 (C),

168.8 (C).

[CAS Reg. No. 70751-32-5]

Following GP2 using 2-iodobenzofuran (0.37 g) with eluent: hep-

tane/EtOAc 90:10 (R_f= 0.47) gave 8d (219 mg, 94%) as a white pow-

der; mp 194 °C (Lit.⁴⁸189–190.5 °C).

HRMS: m/z [M + H]⁺calcd for C₁₇H₁₆NO₂S: 298.08962; found:

298.0898 (1 ppm).

IR (ATR): 698, 720, 745, 756, 852, 895, 1022, 1039, 1084, 1103, 1149,

1191, 1209, 1253, 1310, 1342, 1365, 1388, 1454, 1513, 1592, 1606,

1676, 2992, 3064, 3302 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 3.15 (s, 3 H), 7.41 (td, J = 7.6, 1.1 Hz, 1

H), 7.55 (td, J = 7.8, 1.3 Hz, 1 H), 7.59 (ddd, J = 8.3, 6.9, 1.3 Hz, 1 H),

7.64 (br d, J = 8.1 Hz, 1 H), 7.76 (ddd, J = 8.3, 6.8, 1.4 Hz, 1 H), 8.12–

8.17 (m, 2 H), 8.21 (dd, J = 8.5, 0.9 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃):  = 15.3 (CH₃), 112.1 (CH), 116.1 (C), 123.3

(CH), 123.4 (C), 123.5 (CH), 124.0 (CH), 124.9 (CH), 126.2 (C), 128.7

(CH), 129.2 (CH), 129.5 (CH), 140.8 (C), 146.0 (C), 155.7 (C), 162.2 (C).

Ethyl 2-(3-Thienylamino)benzoate (2d)

Following GP1 using 3-iodothiophene (0.15 mL) with eluent: hep-

tane/EtOAc 95:5 (R_f= 0.80) gave 2d (228 mg, 92%) as a yellow oil.

IR (ATR): 698, 745, 771, 834, 958, 1018, 1045, 1078, 1140, 1160, 1216,

1236, 1316, 1367, 1454, 1503, 1544, 1583, 1677, 2980, 3108, 3314

cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 1.43 (t, J = 7.1 Hz, 3 H, CH₃), 4.38 (q, J =

7.1 Hz, 2 H, CH₂), 6.74 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H, H₄or H₅), 6.94–

6.97 (m, 1 H, H_2′), 7.03 (dd, J = 5.1, 1.4 Hz, 1 H, H_4′or H_5′), 7.21 (dd, J =

8.5, 0.8 Hz, 1 H, H₃), 7.29 (dd, J = 5.1, 3.1 Hz, 1 H, H_4′or H_5′), 7.34 (ddd,

J = 8.6, 7.0, 1.6 Hz, 1 H, H₄or H₅), 8.02 (dd, J = 8.0, 1.6 Hz, 1 H, H₆), 9.61

(s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃):  = 14.3 (CH₃), 60.5 (CH₂), 111.4 (C), 111.7

(CH), 113.7 (CH), 116.7 (CH), 124.5 (CH), 125.1 (CH), 131.5 (CH), 134.2

(CH), 139.4 (C), 148.6 (C), 168.4 (C).

The analyses are as described previously.^17g

11-Methylbenzothieno[3,2-b]quinoline (8f)

[CAS Reg. No. 2035-00-9]

Following GP2 using 3-iodobenzothiophene (0.39 g) with eluent:

heptane/EtOAc 90:10 (R_f= 0.55) gave 8f (244 mg, 98%) as a yellow

powder; mp 150 °C.

IR (ATR): 709, 736, 752, 766, 789, 854, 1013, 1108, 1167, 1229, 1261,

HRMS: m/z [M + H]⁺calcd for C₁₃H₁₄NO₂S: 248.31945; found:

248.3195 (0 ppm).

1337, 1441, 1455, 1497, 1553, 1590, 1673, 2920 cm^–1

.

J

S. Bouarfa et al.

Paper

Synthesis

¹H NMR (300 MHz, CDCl₃):  = 2.63 (s, 3 H, CH₃), 7.40–7.53 (m, 3 H),

7.62–7.72 (m, 2 H), 7.83 (dd, J = 8.5, 1.4 Hz, 1 H), 8.23 (dd, J = 8.5, 1.2

Hz, 1 H), 8.54–8.59 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃):  = 17.0 (CH₃), 122.6 (CH), 122.8 (CH),

123.9 (CH), 124.8 (CH), 125.6 (CH), 125.8 (C), 128.2 (CH), 129.5 (CH),

129.9 (CH), 131.8 (C), 134.9 (C), 136.7 (C), 140.6 (C), 146.5 (C), 152.9

(C).

¹³C NMR (75 MHz, CDCl₃):  = 111.9 (CH), 115.7 (C), 122.5 (C), 123.0

(CH), 123.2 (CH), 125.1 (CH), 125.7 (C), 126.3 (CH), 128.7 (CH), 129.1

(CH), 129.1 (CH), 129.2 (2 CH), 129.4 (2 CH), 129.7 (CH), 135.5 (C),

144.1 (C), 146.3 (C), 156.0 (C), 162.2 (C).

The analyses are as described previously.^17g

9-Phenylthieno[3,2-b]quinoline (9g)

The NMR data are as described previously.²⁸

[CAS Reg. No. 2245159-24-2]

Following GP3 using 3-iodothiophene (0.15 mL) with eluent: hep-

tane/EtOAc 80:20 (R_f= 0.47) gave 9g (251 mg, 96%) as a beige powder;

mp 194 °C.

9-Methylthieno[3,2-b]quinoline (8g)

[CAS Reg. No. 1450739-76-0]

Following GP2 using 3-iodothiophene (0.15 mL) with eluent: PE/EtOAc

IR (ATR): 708, 742, 760, 807, 1074, 1405, 2972 cm^–1

.

80:20 (R_f= 0.32) gave 8g (195 mg, 98%) as a beige powder; mp 84 °C.

¹H NMR (300 MHz, CDCl₃):  = 7.45 (ddd, J = 8.4, 6.8, 1.3 Hz, 1 H),

7.53–7.60 (m, 5 H), 7.66 (d, J = 5.7 Hz, 1 H), 7.73 (ddd, J = 8.5, 6.7, 1.5

Hz, 1 H), 7.84 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 5.9 Hz, 1 H), 8.25 (d, J = 8.6

Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃):  = 123.5 (C), 125.2 (CH), 125.3 (CH), 125.7

(CH), 129.0 (2 CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 129.5 (2 CH),

131.7 (C), 135.2 (CH), 136.6 (C), 142.4 (C), 147.8 (C), 157.2 (C).

IR (ATR): 683, 700, 744, 797, 860, 1014, 1079, 1224, 1259, 1367, 1406,

1439, 1506, 1552, 1579, 2962 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 2.74 (s, 3 H, CH₃), 7.42 (ddd, J = 8.1, 6.6,

1.2 Hz, 1 H), 7.51 (d, J = 5.7 Hz, 1 H), 7.63 (ddd, J = 8.4, 6.6, 1.4 Hz, 1 H),

7.76 (d, J = 5.7 Hz, 1 H), 7.89 (dd, J = 8.5, 1.3 Hz, 1 H), 8.11 (dd, J = 8.6,

1.2 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃):  = 17.1 (CH₃), 122.9 (CH), 124.0 (C), 125.2

(CH), 125.4 (CH), 128.6 (CH), 129.6 (CH), 131.5 (C), 133.7 (CH), 137.7

(C), 147.0 (C), 156.6 (C).

The NMR data are as described previously.²⁸

Benzothieno[2,3-b]quinoline (10a)⁵⁰

The NMR data are as described previously.⁴⁹

[CAS Reg. No. 243-47-0]

Following GP4 using 2-iodobenzothiophene (0.39 g) with eluent:

heptane/EtOAc 95:5 (R_f= 0.75) gave 10a (184 mg, 78%) as a beige

powder; mp 126 °C.

2-Methyl-4-phenylthieno[2,3-b]quinoline (9c)

Following GP3 using 2-iodo-5-methylthiophene [crude; prepared

from thiophene (0.12 mL, 1.5 mmol) by treatment with BuLi (1.8

mmol) in THF (2 mL) at –20 °C for 30 min, MeI (0.11 mL, 1.8 mmol) at

0 °C for 1 h, BuLi (1.6 mmol) in THF (2 mL) at –20 °C for 30 min, and I₂

(0.41 g, 1.6 mmol) in THF (2 mL)] with eluent: PE/EtOAc 90:10 (R_f=

0.57) gave 9c (39 mg, 14%) as a beige powder; mp 174 °C.

IR (ATR): 734, 761, 780, 909, 1066, 1377, 2972 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.42–7.55 (m, 3 H), 7.73 (t, J = 7.7 Hz, 1

H), 7.80 (d, J = 7.9 Hz, 1 H), 7.94 (d, J = 8.1 Hz, 1 H), 8.10–8.14 (m, 2 H),

8.65 (s, 1 H, H₁₁).

¹³C NMR (75 MHz, CDCl₃):  = 122.3 (CH), 123.2 (CH), 125.1 (CH),

125.5 (C), 125.7 (CH), 127.9 (CH), 128.2 (CH), 128.4 (CH), 128.5 (CH),

128.8 (C), 129.8 (CH), 132.5 (C), 138.5 (C), 147.8 (C), 163.3 (C).

IR (ATR): 550, 611, 643, 662, 703, 739, 754, 773, 820, 1059, 1132,

1267, 1440, 1546, 3056 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 2.56 (s, 3 H), 6.73 (d, J = 1.4 Hz, 1 H),

7.40–7.60 (m, 6 H), 7.69 (ddd, J = 8.4, 6.7, 1.4 Hz, 1 H), 7.80 (dd, J = 8.6,

1.3 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃):  = 17.4 (CH₃), 118.4 (CH), 124.4 (C), 125.3

(CH), 126.3 (CH), 128.5 (CH), 128.6 (CH), 128.6 (CH), 128.7 (2 CH),

130.1 (2 CH), 131.9 (C), 136.5 (C), 140.9 (C), 142.7 (C), 146.4 (C), 163.6

(C).

Crystal data for 10a (CCDC 2015230): C₁₅H₉NS, M = 235.29, ortho-

rhombic, Pca2₁, a = 22.6342(15), b = 5.9707(4), c = 16.1450(12) Å, V =

2181.9(3) Å³, Z = 8, d = 1.433 g cm^–3,  = 0.268 mm^–1. A final refine-

ment on F²with 4798 unique intensities and 308 parameters con-

verged at R(F²) = 0.0979 [R(F) = 0.0426] for 4092 observed reflec-

tions with I > 2(I).

HRMS: m/z [M + H]⁺calcd for C₁₈H₁₄NS: 276.08415; found: 276.0845

(1 ppm).

2-Methylthieno[2,3-b]quinoline (10c)

Following GP4 using 2-iodo-5-methylthiophene [crude; prepared

from thiophene (0.12 mL, 1.5 mmol) by treatment with BuLi (1.8

mmol) in THF (2 mL) at –20 °C for 30 min, MeI (0.11 mL, 1.8 mmol) at

0 °C for 1 h, BuLi (1.6 mmol) in THF (2 mL) at –20 °C for 30 min, and I₂

(0.41 g, 1.6 mmol) in THF (2 mL)] with eluent: PE/EtOAc 80:20 (R_f=

0.65) gave 10c (34 mg, 17%) as a beige solid; mp 97 °C.

11-Phenylbenzofuro[2,3-b]quinoline (9d)

[CAS Reg. No. 129190-65-4]

Following GP3 using 2-iodobenzofuran (0.37 g) with eluent: heptane/

EtOAc 90:10 (R_f= 0.70) gave 9d (233 mg, 79%) as a white powder; mp

211 °C (Lit.^17gmp 208 °C).

IR (ATR): 475, 505, 522, 598, 655, 704, 782, 823, 862, 912, 1051, 1136,

1219, 1339, 1392, 1435, 1488, 1597, 2918 cm^–1

.

IR (ATR): 700, 718, 740, 816, 879, 934, 1018, 1100, 1145, 1192, 1219,

1307, 1336, 1349, 1387, 1455, 1591, 2972 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 2.62 (s, 3 H, CH₃), 6.95 (t, J = 1.4 Hz, 1

H, H₃), 7.50 (ddd, J = 8.0, 6.7, 1.2 Hz, 1 H, H₆or H₇), 7.69 (ddd, J = 8.4,

6.7, 1.5 Hz, 1 H, H₆or H₇), 7.89 (dd, J = 8.3, 1.4 Hz, 1 H, H₅or H₈), 8.11

(d, J = 8.6 Hz, 1 H, H₅or H₈), 8.29 (s, 1 H, H₄).

¹³C NMR (75 MHz, CDCl₃):  = 17.4 (CH₃), 118.5 (CH), 125.4 (CH),

126.0 (C), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.8 (CH), 133.2 (C),

143.2 (C), 146.1 (C), 164.0 (C).

¹H NMR (300 MHz, CDCl₃):  = 7.06–7.11 (m, 1 H), 7.12 (td, J = 7.8, 1.0

Hz, 1 H), 7.43–7.50 (m, 2 H), 7.54–7.57 (m, 2 H), 7.61 (d, J = 8.2 Hz, 1

H), 7.63–7.69 (m, 3 H), 7.77 (ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.82 (dd, J =

8.6, 0.8 Hz, 1 H), 8.22 (dd, J = 8.3, 1.2 Hz, 1 H).

K

S. Bouarfa et al.

Paper

Synthesis

HRMS: m/z [M + H]⁺calcd for C₁₂H₁₀NS: 200.05285; found: 200.0528

These data are as reported previously.⁵²

(0 ppm).

9-Chloro-11-phenylbenzofuro[2,3-b]quinoline (11d)

Benzofuro[2,3-b]quinoline (10d)

Following GP5 using 2-iodobenzofuran (0.37 g) with eluent: PE/EtOAc

90:10 (R_f= 0.52) gave 11d (280 mg, 85%) as a yellowish powder; mp

260 °C.

[CAS Reg. No. 19960-29-3]

Following GP4 using 2-iodobenzofuran (0.25 g, 1.0 mmol) with elu-

ent: heptane/EtOAc 90:10 (R_f= 0.375) gave 10d (180 mg, 82%) as a

white powder; mp 198 °C (Lit.⁴⁸mp 188–189 °C).

IR (ATR): 658, 700, 719, 749, 808, 869, 894, 949, 1077, 1100, 1148,

1176, 1236, 1318, 1407, 1443, 1490, 1509, 1571, 1611, 2989 cm^–1

.

IR (ATR): 480, 557, 574, 619, 715, 743, 786, 864, 907, 937, 985, 1014,

1100, 1173, 1198, 1261, 1336, 1350, 1389, 1454, 1509, 1596, 2922

¹H NMR (300 MHz, CDCl₃):  = 7.08 (td, J = 7.5, 1.2 Hz, 1 H, H₂), 7.14

(dd, J = 7.8, 0.9 Hz, 1 H, H₁), 7.48 (ddd, J = 8.4, 7.1, 1.6 Hz, 1 H, H₃),

7.52–7.55 (m, 2 H), 7.59 (d, J = 8.2 Hz, 1 H, H₄), 7.65–7.71 (m, 4 H),

7.74 (d, J = 2.2 Hz, 1 H, H₁₀), 8.12 (d, J = 8.9 Hz, 1 H, H₇).

¹³C NMR (75 MHz, CDCl₃):  = 112.0 (CH), 116.6 (C), 122.2 (C), 123.2

(CH), 123.4 (CH), 125.0 (CH), 126.5 (C), 129.3 (2 CH), 129.4 (CH),

129.4 (2 CH), 129.6 (CH), 130.3 (CH), 130.4 (CH), 131.0 (C), 134.8 (C),

143.1 (C), 144.6 (C), 156.2 (C), 162.3 (C).

cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.33 (t, J = 7.4 Hz, 1 H), 7.46–7.58 (m, 3

H), 7.71 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H), 7.92 (dd, J = 7.5, 3.0 Hz, 2 H),

8.11 (d, J = 8.5 Hz, 1 H, H₇), 8.53 (s, 1 H, H₁₁).

¹³C NMR (75 MHz, CDCl₃):  = 112.0 (CH), 117.7 (C), 121.7 (CH), 122.2

(C), 123.5 (CH), 125.1 (CH), 126.1 (C), 128.2 (CH), 128.5 (CH), 129.0

(CH), 129.3 (CH), 129.6 (CH), 146.0 (C), 155.9 (C), 162.6 (C).

HRMS: m/z [M + H]⁺calcd for C₂₁H₁₃³⁵ClNO: 330.06802; found:

330.0679 (0 ppm).

Thieno[3,2-b]quinoline (10g)

7-Chloro-9-phenylthieno[3,2-b]quinoline (11g)

[CAS Reg. No. 269-62-5]

Following GP5 using 3-iodothiophene (0.15 mL) with eluent: PE/EtOAc

80:20 (R_f= 0.35) gave 11g (263 mg, 89%) as a beige powder; mp 140 °C.

Following GP4 using 3-iodothiophene (0.15 mL) with eluent: PE/EtOAc

80:20 (R_f= 0.40) gave 10g (74 mg, 40%) as a beige powder; mp 120 °C.

IR (ATR): 658, 699, 719, 746, 808, 869, 949, 1075, 1148, 1241, 1317,

IR (ATR): 742, 1066, 1225, 1394, 2972 cm^–1

.

1407, 1444, 1490, 1510, 1570, 2902, 2989, 3676 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.49 (ddd, J = 8.0, 6.6, 1.1 Hz, 1 H), 7.60

(d, J = 5.7 Hz, 1 H), 7.71 (ddd, J = 8.5, 6.7, 1.5 Hz, 1 H), 7.84 (dd, J = 8.3,

1.4 Hz, 1 H), 7.88 (d, J = 5.7 Hz, 1 H), 8.18 (d, J = 8.6 Hz, 1 H), 8.58 (s, 1

H, H₉).

¹³C NMR (75 MHz, CDCl₃):  = 124.7 (CH), 125.0 (C), 125.7 (CH), 127.4

(CH), 129.2 (CH), 129.3 (CH), 129.7 (CH), 131.0 (C), 134.7 (CH), 147.0

(C), 157.5 (C).

¹H NMR (300 MHz, CDCl₃):  = 7.52–7.65 (m, 7 H), 7.78 (d, J = 2.2 Hz, 1

H, H₈), 7.87 (d, J = 5.7 Hz, 1 H, H₂or H₃), 8.15 (d, J = 9.1 Hz, 1 H, H₅).

¹³C NMR (75 MHz, CDCl₃):  = 123.8 (CH), 124.0 (C), 125.2 (CH), 129.2

(2 CH), 129.4 (CH), 129.4 (2 CH), 130.0 (CH), 131.1 (CH), 131.5 (C),

132.6 (C), 135.7 (CH), 135.9 (C), 141.5 (C), 146.1 (C), 157.3 (C).

HRMS: m/z [M + H]⁺calcd for C₁₇H₁₁³⁵ClNS: 296.02952; found:

296.0298 (1 ppm).

The NMR data are as described previously.⁴⁹

Crystal data for 11g (CCDC 2015226): C₁₇H₁₀ClNS, M = 295.77, mono-

clinic, P2₁/c, a = 13.8767(8), b = 6.0408(3), c = 32.0906(19) Å,  =

9-Chloro-11-phenylbenzothieno[2,3-b]quinoline (11a)

100.996(2)°, V = 2640.7(3) Å³, Z = 8, d = 1.488 g cm^–3,  = 0.434 mm^–1

.

[CAS Reg. No. 320590-06-5]

A final refinement on F²with 5970 unique intensities and 361 para-

meters converged at R(F²) = 0.0887 [R(F) = 0.0393] for 4588 ob-

served reflections with I > 2(I).

Following GP5 using 2-iodobenzothiophene (0.39 g) with eluent:

PE/EtOAc 90:10 (R_f= 0.53) gave 11a (204 mg, 59%) as a beige powder;

mp 250 °C (Lit.⁵¹239–241 °C).

IR (ATR): 658, 672, 701, 718, 749, 772, 808, 869, 894, 918, 949, 1075,

1103, 1149, 1178, 1236, 1317, 1408, 1445, 1490, 1510, 1570, 1612,

9-Chlorobenzothieno[2,3-b]quinoline (12a)

[CAS Reg. No. 2387308-69-0]

2162, 3058 cm^–1

.

Following GP6 using 2-iodobenzothiophene (0.39 g) with eluent:

heptane/EtOAc 95:5 (R_f= 0.27) gave 12a (113 mg, 42%) as a pale yel-

low powder; mp 230 °C (Lit.^26b230–232 °C).

¹H NMR (300 MHz, CDCl₃):  = 6.77 (d, J = 8.1 Hz, 1 H, H₁), 7.09 (ddd,

J = 8.2, 7.7, 1.0 Hz, 1 H, H₂or H₃), 7.38–7.43 (m, 3 H), 7.56 (d, J = 2.3 Hz,

1 H, H₁₀), 7.64–7.70 (m, 4 H), 7.79 (d, J = 7.9 Hz, 1 H, H₄), 8.10 (d, J = 9.0

Hz, 1 H, H₇).

¹³C NMR (75 MHz, CDCl₃):  = 123.0 (CH), 124.8 (CH), 125.3 (CH),

125.7 (CH), 126.3 (C), 126.7 (C), 128.2 (CH), 129.0 (2 CH), 129.3 (CH),

129.8 (CH), 129.8 (2 CH), 130.5 (CH), 131.4 (C), 132.8 (C), 135.7 (C),

138.8 (C), 142.8 (C), 145.5 (C), 163.5 (C).

IR (ATR): 706, 728, 749, 768, 802, 820, 916, 1021, 1070, 1220, 1260,

1338, 1385, 1452, 1480, 1585, 2961 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.49–7.59 (m, 2 H, H₂, H₃), 7.70 (dd, J =

9.0, 2.1 Hz, 1 H, H₈), 7.86 (dd, J = 6.9, 1.1 Hz, 1 H, H₁or H₄), 7.99 (d, J =

1.9 Hz, 1 H, H₁₀), 8.10 (d, J = 9.0 Hz, 1 H, H₇), 8.20 (d, J = 7.2 Hz, 1 H, H₁

or H₄), 8.67 (s, 1 H, H₁₁).

¹³C NMR (75 MHz, CDCl₃):  = 122.6 (CH), 123.4 (CH), 125.4 (CH),

126.2 (C), 127.0 (CH), 127.0 (CH), 129.1 (CH), 129.7 (C), 129.7 (CH),

130.8 (CH), 131.5 (C), 132.2 (C), 138.8 (C), 145.9 (C), 163.6 (C).

6-Chloro-4-phenylthieno[2,3-b]quinoline (11b)

[CAS Reg. No. 62452-41-9]

Following GP5 using 2-iodothiophene (0.17 mL) with eluent: PE/EtOAc

90:10 gave 11b (12 mg, 4%) as an orange oil.

These data are as reported previously.^26b

¹H NMR (300 MHz, CDCl₃):  = 7.11 (d, J = 6.3 Hz, 1 H, H₃), 7.47–7.64

(m, 5 H, Ph), 7.55 (d, J = 6.3 Hz, 1 H, H₂), 7.68 (dd, J = 9.0, 2.3 Hz, 1 H,

H₇), 7.82 (d, J = 2.3 Hz, 1 H, H₅), 8.17 (d, J = 9.1 Hz, 1 H, H₈).

6-Chlorothieno[2,3-b]quinoline (12b)

[CAS Reg. No. 65038-83-7]

L

S. Bouarfa et al.

Paper

Synthesis

Following GP6 using 2-iodothiophene (0.17 mL) with eluent: PE/EtOAc

70:30 (R_f= 0.50) gave 12b (11 mg, 5%) as an orange powder; mp 164

°C (Lit.⁵³167–168 °C).

Antiproliferative Activity

The antiproliferative activity on melanoma cell line A2058 (ATCC®

CRL-11147) was studied as reported previously.^17gA2058 are known

to be highly invasive human epithelial adherent melanoma cells. They

are derived from lymph nodes metastatic cells obtained from a 43-

year-old male patient and are tumorigenic at 100% frequency in nude

mice. They are considered as very resistant to anticancer drugs. All

cell culture experiments were performed at 37 °C. Cells were grown

to confluence in 75 cm² flasks in DMEM supplemented with 10% fetal

calf serum (FCS) and 1% penicillin-streptomycin (Dominique

Dutscher, France) in a 5% CO₂humidified atmosphere. Molecules were

solubilized in DMSO at 10^–3M and diluted in the cell culture medium

to obtain 2.10^–5M solutions. Confluent cells were trypsinized and

centrifuged in FCS at 1500 g for 5 min. The supernatant containing

trypsin was discarded and the cell pellet was suspended in cell cul-

ture medium to obtain a 4.104 cell·mL^–1suspension. At t0, 50 L of

the 2.10^–5M molecules solutions were deposited in a 96-wells flat

bottom microplate, and 50 L of the cell suspension were added. The

2000 cells were then grown for 72 h in the cell culture medium con-

taining 10^–5M molecules. At t72, 20 L of a 5 g·L^–1MTT solution were

added in each well of the microplate, allowing living cells containing a

functional mitochondrial succinate deshydrogenase to metabolize

MTT to the corresponding blue formazan salt for 4 h. The cell culture

medium was removed using an Eppendorf epMotion 5070 pipeting

robot (Eppendorf, France) and formazan crystals were dissolved in

200 L DMSO. Microplates were placed at 37 °C for 5 min to solubilize

formazan crystals and absorbance was read at 550 nm using a VERSA-

max microplate reader (Molecular devices, France). The percentage of

growth inhibition was calculated as GI (%) = 100 – [(A550 nm sample

– A550 nm BG)/(A550 nm control – A550 nm BG)] × 100 with:

IR (ATR): 740, 758, 803, 823, 926, 961, 1045, 1071, 1089, 1133, 1206,

1259, 1283, 1335, 1390, 1474, 1545, 1591, 1670, 2920 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.37 (d, J = 6.2 Hz, 1 H, H₃), 7.64 (d, J =

6.2 Hz, 1 H, H₂), 7.68 (dd, J = 9.2, 2.3 Hz, 1 H, H₇), 7.95 (d, J = 2.1 Hz, 1

H, H₅), 8.12 (d, J = 9.1 Hz, 1 H, H₈), 8.47 (s, 1 H, H₄).

¹³C NMR (75 MHz, CDCl₃):  = 121.2 (CH), 126.2 (C), 126.8 (CH), 129.5

(CH), 129.8 (CH), 129.8 (CH), 130.6 (CH), 131.4 (C), 132.3 (C), 144.7

(C), 163.3 (C).

¹H NMR data are as reported previously.⁵³

9-Chlorobenzofuro[2,3-b]quinoline (12d)

[CAS Reg. No. 124028-51-9]

Following GP6 using 2-iodobenzofuran (0.25 g, 1.0 mmol) with elu-

ent: PE/EtOAc 95:5 (R_f= 0.32) gave 12d (150 mg, 59%) as a yellow

powder; mp 254 °C (Lit.⁵⁴mp 245–247 °C).

IR (ATR): 726, 739, 779, 816, 881, 917, 927, 1075, 1178, 1192, 1258,

1350, 1389, 1462, 1498, 1596, 2961 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.42 (td, J = 7.6, 1.1 Hz, 1 H, H₂or H₃),

7.59 (ddd, J = 8.4, 7.7, 1.2 Hz, 1 H, H₂or H₃), 7.64 (d, J = 8.0 Hz, 1 H, H₁

or H₄), 7.69 (dd, J = 9.0, 2.3 Hz, 1 H, H₈), 7.99 (d, J = 2.3 Hz, 1 H, H₁₀),

8.03 (d, J = 7.7 Hz, 1 H, H₁or H₄), 8.09 (d, J = 9.0 Hz, 1 H, H₇), 8.57 (s, 1

H, H₁₁).

¹³C NMR (75 MHz, CDCl₃):  = 112.3 (CH), 118.8 (C), 122.0 (C), 122.1

(CH), 123.8 (CH), 126.8 (C), 126.8 (CH), 128.1 (CH), 130.0 (CH), 130.1

(CH), 130.5 (CH), 130.9 (C), 144.5 (C), 156.2 (C), 162.8 (C).

A550 nm sample: median absorbance of 8 wells containing cells treat-

ed with 10^–5M molecule.

These data are as reported previously.^27b

Crystal data for 12d (CCDC 2015227): C₁₅H₈ClNO, M = 253.67, mono-

clinic, C c, a = 23.719(4), b = 3.7644(8), c = 12.327(2) Å,  = 94.558(7)°,

V = 1097.2(4) Å³, Z = 4, d = 1.536 g cm^–3,  = 0.331 mm^–1. A final re-

finement on F²with 2305 unique intensities and 163 parameters con-

verged at R(F²) = 0.1096 [R(F) = 0.0402] for 2160 observed reflec-

tions with I > 2(I).

A550 nm BG: median background absorbance of 8 wells containing

control cell culture medium + 1% DMSO.

A550 nm control: median absorbance of 8 wells containing cells

grown in control cell culture medium + 1% DMSO.

Data are expressed as GI (%) + sem (%) from 3 independent assays.

7-Chlorothieno[3,2-b]quinoline (12g)

Funding Information

Following GP6 using 3-iodothiophene (0.15 mL) with eluent: PE/EtOAc

70:30 (R_f= 0.60) gave 12g (138 mg, 63%) as a beige powder; mp 162 °C.

We thank the Université de Rennes 1 and the Centre National de la

Recherche Scientifique (F.M.). We acknowledge the European Region-

al Development Fund (Fonds Européen de Développement Régional,

FEDER; D8 VENTURE Bruker AXS diffractometer). L.P. and V.T. thank

La Ligue contre le Cancer (French Cancer League; Comité 17 and

Comité 86) for financial support and the Cancéropôle Grand Ouest

(axis: Marine Molecules, Metabolism and Cancer 3MC) for scientific

support. This research has been partly performed as part of the CNRS

PICS project ‘Bimetallic synergy for the functionalization of heteroar-

IR (ATR): 748, 784, 816, 831, 901, 927, 1019, 1076, 1172, 1286, 1347,

1387, 1468, 1508, 1545, 1579, 1608, 3039 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 7.61 (d, J = 5.6 Hz, 1 H, H₂or H₃), 7.66

(dd, J = 9.1, 2.1 Hz, 1 H, H₆), 7.87 (d, J = 2.1 Hz, 1 H, H₈), 7.95 (d, J = 5.6

Hz, 1 H, H₂or H₃), 8.12 (d, J = 9.1 Hz, 1 H, H₅), 8.56 (s, 1 H, H₉).

¹³C NMR (75 MHz, CDCl₃):  = 124.8 (CH), 125.5 (C), 125.9 (CH), 128.8

(CH), 130.4 (CH), 130.9 (CH), 131.4 (C), 132.1 (C), 135.2 (CH), 145.3

(C), 157.8 (C).

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HRMS: m/z [M + H]⁺calcd for C₁₁H₇³⁵ClNS: 219.99822; found:

219.9980 (1 ppm).

Crystal data for 12g (CCDC 2015228): C₁₁H₆ClNS, M = 219.68, mono-

clinic, P2₁/n, a = 12.8017(8), b = 5.8980(3), c = 13.1896(8) Å,  =

Acknowledgment

112.039(3)°, V = 923.10(9) Å³, Z = 4, d = 1.581 g cm^–3,  = 0.589 mm^–1

.

We thank Frédéric Lassagne for his help throughout the study.

A final refinement on F²with 2106 unique intensities and 127 para-

meters converged at R(F²) = 0.0883 [R(F) = 0.0342] for 1821 ob-

served reflections with I > 2(I).

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706542. Su

p

ortingInformatio

n

Su

p

ortingInformatio

n

M

S. Bouarfa et al.

Paper

Synthesis

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Article Doi

Iodothiophenes and Related Compounds as Coupling Partners in Copper-Mediated N-Arylation of Anilines

DOI: 10.1055/s-0040-1706542

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