Synthesis of Aminoalkyl-Functionalized 4-Arylquinolines from 2-(3,4-Dihydroisoquinolin-1-yl)anilines via the Friedl?nder Reaction

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

©

Georg Thieme Verlag Stuttgart · New York

2020, 52, A–O

paper

A

en

Synthesis

Y. S. Rozhkova et al.

Paper

Synthesis of Aminoalkyl-Functionalized 4-Arylquinolines from 2-

3,4-Dihydroisoquinolin-1-yl)anilines via the Friedländer Reaction

(

Yuliya S. Rozhkova*

Tatyana S. Storozheva

Irina V. Plekhanova

Alexey A. Gorbunov

Andrej A. Smolyak

Yurii V. Shklyaev

0

0-0

0

2-4

0

1

4-3

5

0

3

_R1 _R1

R

R²

R

_R2

R

R²

_R2

O

R²

N

AcOH

60 °C

R⁵

NH2

+

_R4

R¹

and/or

R³

_R1 ^N^H²

_R3

_R5

R1

NH2

5 min to 150 h

_R4

R5

R³

N

26 examples

0–99% yield

N

3

only for unsymmetrical

acyclic aliphatic ketones

R⁵= Me, i-Pr, Allyl, Bn)

Institute of Technical Chemistry UB RAS, 3 Akademika

Korolyeva St., Perm 614013, Russian Federation

rjs@mail.ru

(

R = H, OMe; R¹= H, Me; R²= H, Me; R³= H, OMe, Me, Br, NO2; R⁴= Alk, Ar; R⁵= H, Alk, Allyl, Bn, Ac, COOEt

Received: 12.04.2020

Accepted after revision: 27.07.2020

Published online: 01.09.2020

veloping new synthetic routes to novel, variously

_f_u_n_c_t_i_o_n_a_l_i_z_e_d_,_q_u_i_n_o_l_i_n_e_d_e_r_i_v_a_t_i_v_e_s_.2

DOI: 10.1055/s-0040-1706424; Art ID: ss-2020-t0376-op

One of the oldest methods for the construction of a

quinoline cycle is the Friedländer reaction which in its clas-

Abstract A new approach for the efficient and convenient synthesis of

novel aminoalkyl-functionalized 4-arylquinolines via the Friedländer re-

action of differently substituted 2-(3,4-dihydroisoquinolin-1-yl)anilines

with various -methylene ketones in acetic acid was developed. The re-

action allows easy access to a diversity of 4-arylquinoline derivatives in

moderate to excellent yields under mild conditions.

sical form involves the acid-, base- or heat-promoted con-

densation of aromatic 2-amino carbonyl derivatives with

carbonyl compounds that have an -methylene group, fol-

3

lowed by cyclodehydration (Scheme 1a). The Friedländer

reaction provides a convenient access to a rich diversity of

quinoline derivatives because of the wide substrate scope

of both of its reagents, the applicability of many acid and

base catalysts under various conditions, and the tolerance

of many functional groups.²

Key words Friedländer reaction, Schiff bases, 2-(3,4-dihydroisoquino-

lin-1-yl)anilines, ketones, acetic acid, 4-arylquinolines

,4,5

The quinoline ring system is the core structure of many

natural and synthetic compounds known for exhibiting a

wide variety of biological activities. Many synthetic ap-

proaches to various quinoline derivatives have already been

developed. However, the diversity of pharmacological prop-

erties of these compounds and their exceptional impor-

tance for medicinal chemistry inspire research aimed at im-

proving classical approaches to quinoline synthesis and de-

The Borsche modification is one of the synthetically

useful variations of the Friedländer reaction, where Schiff

bases, usually 2-[(p-tolylimino)methyl]anilines, are used as

substrates instead of the prone to self-condensation o-ami-

1

6

nobenzaldehydes (Scheme 1b). The Borsche modification

allows the effective synthesis of 4-unsubstituted quino-

lines⁶and has been successfully used for the construction

of various quinoline-based polyannelated aza-hetero-

,7

(

a) Classical Friedlander synthesis

(b) Borsche modification (acyclic Schiff bases)

1

^N^H2

R

R¹

N

acid

_R3

p-Tol

O

or

base

R²

R¹

O

acid, base

O

N

R³

or heat

R²

R

+

_R2

R

+

_R1

–

H2O

NH2

– 2 H2O

_R2

NH₂

N

(

c) Borsche modification (cyclic Schiff bases)

NH2

R²

XH

X

N

X

N

X

NH

R²

R¹

O

_R2

N

acid

– H2O

acid

R²

R¹

or

R¹

R

+

R

X = O, NH, etc.

R¹

NH2

_R1

N

spirocyclic

intermediate

Scheme 1 The Friedländer synthesis of quinolines

©

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

B

Synthesis

Y. S. Rozhkova et al.

Paper

cycles,⁷^a^,^d^,⁸including camptothecin and luotonine A⁷^a^,¹⁰

9

quinoline derivatives, and studies directed toward extend-

ing the scope of the Friedländer reaction with respect to the

various cyclic Schiff bases have a great potential for the de-

velopment of new, effective protocols for quinoline synthe-

sis.

In an attempt to contribute toward the development of

new approaches to quinoline synthesis based on

Friedländer annulation, herein, we report for the first time

the use of 2-(3,4-dihydroisoquinolin-1-yl)anilines as new

substrates for the Friedländer reaction and their application

in the synthesis of novel amino-functionalized 4-arylquino-

line derivatives (Scheme 2c).

In order to test that 3,4-dihydroisoquinolines with a 2-

aminophenyl substituent at the C-1 atom could serve as

substrates for the Friedländer reaction, we first examined

the model reaction of 3,4-dihydroisoquinoline 1a with

cyclohexanone (2a) under acidic conditions (Table 1).

alkaloids and related compounds.¹⁰^b^,¹¹

Intriguing synthetic possibilities of the Friedländer re-

action (Borsche modification) appeared with the use of cy-

clic Schiff bases containing a 2-aminophenyl fragment at-

tached to the carbon atom of the imine unit (Scheme 1c).

While the reaction with acyclic imines as substrates releas-

es amine (p-toluidine) to give 4-unsubstituted quinolines,

in the case of cyclic Schiff bases, the amine comes to be

tethered to the C-4 atom of the formed quinoline, and the

type of amino fragment (for example, primary or secondary

amino group) depends on the direction of the spirocyclic

intermediate ring opening which, in turn, is influenced by

the structure of the starting cyclic Schiff base. It should be

noted that, even though the scope of the Friedländer reac-

tion with respect to both reagents has been very well stud-

ied during the 137 years since its discovery, the use of cyclic

Schiff bases as substrates for this reaction remains surpris-

ingly poorly developed, and we found only two reports that

describe the Friedländer synthesis with cyclic Schiff bases

Table 1 Optimization of the Reaction Conditions^a

12

as reagents. In 2006, Luo and co-workers reported the

synthesis of 4-amino-substituted quinolines via the acid-

catalyzed reaction of 2-(4,5-dihydrooxazol-2-yl)anilines

with ketones (Scheme 2a). More recently, the Mamedov

group developed an original approach to 4-(benzimidazol-

OMe

MeO

O

12a

N

+

NH2

2-yl)quinolines which involves the condensation of 3-(2-

NH2

2a

aminophenyl)quinoxalin-2(1Н)-ones with various ketones

via the Friedländer reaction, followed by intramolecular cy-

clization of the intermediate N-(2-aminophenyl)quinoline-

N

3aa

1

a

b

12b

Entry Acid (equiv)

Solvent

Temp (°C) Time

Yield (%) of 3aa

4-carboxamides (Scheme 2b).

The above examples demonstrate that the use of cyclic

Schiff bases as substrates for the Friedländer reaction offers

excellent opportunities to access unique functionalized

1

2

3

4

5

6

7

8

9

–

CH

2

Cl

2

rt

5 d

20 h

40 h

20 h

5 d

trace

65

MsOH (1)

TsOH (1)

TfOH (1)

TFA (1)

rt

61

rt

58

(

a)

_R3

_R2 _R3

R²

rt

63

TsOH

10 mol%)

HN

O

N

₄₀c

(

AcOH (1)

MsOH (1)

MsOH (0.1)

MsOH (5)

MsOH (1)

AcOH^d

CH Cl

rt

OH

Ar

2

+

Ar

NH2

R¹

n-butanol

reflux, 24 h

ref. 12a

DCE

rt

62

N

DCE

rt

22^c

R¹

6

0–89%

₃₀c

rt

4 d

(

b)

1

0

11

12

reflux

rt

1.5 h

54

60

59

51^c

60

80

54

72

HN

NH2

O

MeOH

MeCN

1.5 h

6 h

AcOH

N

HN

N

+

O

R

55 °C

2–5 h

– H2O

NH2

13

14

15

16

toluene

7 h

ref. 12b

1 h

R = Me, Ar

N

R

N

R

6

1–89%

AcOH^d

60

90

60

30 min

15 min

30 min

(

c)

R¹R¹

R

R²

_A_c_O_Hd

R

O

R²

acid

R²

NH2

AcOH^d^,^e

_R5

17

+

N

R⁴

this work

_R1

а

Reaction conditions: 1a (0.35 mmol, 1 equiv), 2a (0.42 mmol, 1.2 equiv),

solvent (0.6 mL).

Isolated yield after recrystallization.

Incomplete conversion was observed.

AcOH (1.5 mL) was used.

2a (1 equiv) was used.

R³

R⁵

NH2

b

c

_R3

_R4

N

d

e

Scheme 2 Cyclic Schiff bases as substrates for the Friedländer reaction

©

C

Synthesis

Y. S. Rozhkova et al.

Paper

Only trace amounts of quinoline 3aa were detected in a

mined as carrying out the reaction in acetic acid at 60 °С

with a 1:1.2 ratio of 1a/2a.

control experiment carried out in CH Cl at room tempera-

2

ture without catalyst (Table 1, entry 1). Performing the re-

action in the presence of 1 equivalent of MsOH in CH Cl at

With the optimized conditions identified, the reaction

of 3,4-dihydroisoquinoline 1a with a range of ketones 2a–n

was further explored (Scheme 3). Reaction of 1a with the

cyclic aliphatic ketones 2-methylcyclohexanone (2b) and

cyclopentanone (2c) occurred smoothly to give the corre-

sponding quinolines 3ab and 3ac in 65% and 73% yield, re-

spectively.

2

room temperature led to the formation of the desired quin-

oline 3aa in 65% yield within 20 hours (entry 2). The struc-

ture of compound 3aa was unambiguously confirmed by X-

ray crystallography (Figure 1; see the Supporting Informa-

13

tion for details). Under the same conditions, TsOH, TfOH

or TFA gave a yield of product 3aa which was comparable

with that obtained with MsOH (entries 3–5), whereas the

use of AcOH resulted in a lower yield of 3aa (40%) with in-

complete conversion even after 40 hours (entry 6). Next, in

order to find the optimal reaction conditions in terms of

improvement of the product yield and shortening of the re-

action time, we tested different reaction parameters using

MsOH (entries 7–13). Although the experiments performed

allowed us to determine the effect of acid loading, tempera-

ture and solvent on the reaction rate and yield of product

The H and ¹³C NMR spectra of compound 3ab revealed

doubling of some of the signals and, in the gas chromato-

gram of the substance (see Figure S74 in the Supporting In-

formation), there were two poorly separated peaks with the

same mass spectrum, which was attributed to the presence

of two atropdiastereomers. In fact, molecule 3ab possesses

two chirality elements including a chirality center at the C-

4′′ atom and a chirality axis lying along the C-2′₍_a_r_y_l₎–C-9′′₍_h_e_t_-

1

bond with restricted rotation around it (the chirality

aryl)

axis is present in all compounds 3, as discussed below). Ac-

1

3aa and significantly reduced the reaction time (entry 2 vs

cording to H NMR spectra, the diastereomeric ratio was de-

entries 10, 11), unfortunately they were not successful in

terms of increasing the yield of quinoline 3aa.

termined to be nearly 52:48, both in CDCl and DMSO-d at

30 °C. Variable temperature H NMR experiments showed

3

6

1

that upon heating 3ab in DMSO-d up to 120 °C broadening

6

of the signals did not occur, which indicates a high rotation-

al barrier for the atropisomers of compound 3ab (see Fig-

ures S71–S73 in the Supporting Information).

Acetone (2d) successfully afforded quinoline 3ad in 97%

yield. The structure of compound 3ad was unambiguously

confirmed by X-ray crystallography (see Figure S76 in the

Supporting Information).¹³Unsymmetrical ketones such as

methyl ethyl ketone (2e), benzylacetone (2f) and allyl-

acetone (2g) gave regioisomeric mixtures of 2,3-disubsti-

tuted/2-monosubstituted quinolines 3ae/3ae′–3ag/3ag′

with predominance of the 2,3-disubstituted products, in

good combined yields. The reaction of 3,4-dihydroisoquino-

line 1a with methyl isobutyl ketone (2h) occurred regiose-

lectively to afford only 2-monosubstituted quinoline 3ah in

61% yield. Regioselectivity of this reaction is caused by ste-

ric hindrance in methyl isobutyl ketone (2h) provided by

the isopropyl group. Sterically hindered pinacolone (2i) re-

quired a considerably longer reaction time relative to the

other aliphatic ketones (150 h vs 30 min to 5 h) to afford

product 3ai in only 30% yield along with amide 4 (12%).

Figure 1 Molecular structure of 3aa according to XRD data with ther-

mal ellipsoids at the 40% probability level [only the (R )-atropisomer is

a

shown]

Further continuing our efforts to improve the yield of

3aa, we examined the reaction in excess acetic acid. These

conditions were chosen because performing the

Friedländer reaction (Borsche modification) in acetic acid

7c,11b,e,12b

proved to be successful in several cases.

According-

ly, condensation of 3,4-dihydroisoquinoline 1a with cyclo-

hexanone (2a) in acetic acid at room temperature gave 3aa

in 60% yield within 1 hour (Table 1, entry 14). To our de-

light, significant improvement was observed when the re-

action was performed at 60 °C (entry 15). In this case, the

reaction was completed within 30 minutes to afford quino-

line 3aa in 80% yield. Further increase of the reaction tem-

perature to 90 °С led to a significant decrease in the product

yield (entry 16). Finally, we found that performing the reac-

tion in acetic acid at 60 °C with 1 equivalent of 2a provided

quinoline 3aa in 72% yield (entry 17). Thus, based on the re-

sults obtained, the optimal reaction conditions were deter-

Compound 4 apparently arises from NH acylation of the

2

starting 2-(3,4-dihydroisoquinolin-1-yl)aniline 1a with

acetic acid in the course of the reaction. As with pinacolone

(2i), acetophenones 2j–l reacted with isoquinoline 1a slug-

gishly and required long reaction times (63–125 h) to give

quinolines 3aj–al in 39–54% yield together with side prod-

uct 4 (5–12%). Performing the reactions of 1a with pina-

colone (2i) or acetophenones 2j–l at 90 °С led to highly

shortened reaction times (15–24 h vs 63–150 h), but did

not have a significant effect on the product yields, with only

a slight increase or decrease in the yield of quinolines 3ai,

©

D

Synthesis

Y. S. Rozhkova et al.

Paper

OMe

MeO

O

AcOH

60 °C

N

+

R²

NH2

R¹

H

R²

R1

NH2

30 min–150 h

N

2a–n

3

aa–an

4

O

1a

N

OMe

MeO

OMe

MeO

NH2

+

NH2

2'

9''

4''

N

3ae

3ae'

3aa: 80% (30 min)

3ab: 65% (2 h)

3ac: 73% (1.5 h)

3ad: 97% (1 h)

3ae + 3ae': 78% (2 h)

a,b

[dr 52:48]

[78:22]

OMe

MeO

OMe

MeO

NH2

+

NH2

+

NH2

Ph

N

af

N

Ph

N

3

3af'

3ag

3ag'

3ah: 61% (3 h)

3

af + 3af': 55% (2.5 h)

3ag + 3ag': 77% (5 h)

a,b

a,c

[67:33]

[69:31]

OMe

MeO

NH2

O

NH2

O

OMe

OEt

N

3an: 50% (2.5 h)

N

Cl

OMe

3

am: 59% (2 h)

_a_i_:₃₀_%₍₁₅₀_h₎_,₁₂_%d

d

3

aj: 54% (125 h), 10%

3ak: 39% (63 h), 5%

3al: 44% (120 h), 12%

e

d

e

d

e

d

e

d

32% (15 h) , 15%

5

2% (22 h) , 6%

40% (20 h) , 10%

40% (24 h) , 23%

Scheme 3 Reaction of 3,4-dihydroisoquinoline 1a with ketones 2a–n. Reagents and conditions: 1a (0.35 mmol), 2a–n (0.42 mmol), AcOH (1.5 mL),

a

1

b

c

6

3

0 °C. Isolated yields are reported. Ratio was determined by H NMR analysis of the crude reaction mixture. Inseparable mixture. Major regioisomer

ag was isolated in 29% yield. ^dAmide 4 was also isolated. Reaction was performed at 90 °C.

e

3

ak and 3aj, 3al, respectively. In these cases, along with

slow the process down. Reaction of acetone (2d) with 3,4-

dihydroisoquinoline 1f unsubstituted on the benzene ring

afforded quinoline 3fd in nearly quantitative yield (99%).

Next, we found that 3,3,4,4-tetramethyl-3,4-dihydroiso-

quinoline 1g readily underwent condensation with cyclo-

hexanone (2a) or acetone (2d) to give quinolines 3ga and

3gd in 64% and 87% yield, respectively. 3,4-Unsubstituted

3,4-dihydroisoquinoline 1h is also a suitable substrate for

the Friedländer reaction with ketones 2a, 2d to afford prod-

ucts 3ha and 3hd, respectively, in good yields (Scheme 4).

products 3ai–al, amide 4 was also isolated in 6–23% yield.

Further, the reaction was shown to be also applicable to

acetylacetone (2m) and ethyl acetoacetate (2n), providing

quinolines 3am and 3an in 59% and 50% yield, respectively.

To further demonstrate the substrate scope of the reac-

tion, we explored the condensation of differently substitut-

ed 2-(3,4-dihydroisoquinolin-1-yl)anilines 1b–h with cy-

clohexanone (2a) or acetone (2d) (Scheme 4).

Condensation of ketones 2a, 2d with isoquinolines 1b–e

containing an electron-donating (OMe, 1b; Me, 1c) or elec-

1

The H NMR spectra of almost all compounds 3 demon-

tron-withdrawing substituent (Br, 1d; NO , 1e) in the 2-

aminophenyl moiety provided the expected quinolines

strated nonequivalency of some groups. For example, the

CH protons and/or Me groups in the CH C(Me )NH frag-

2

3ba–da, 3bd–ed in good to excellent yields (61–95%), but

ment of quinolines 3aa, 3ac–an, 3ba–ed appear as two

the reaction times differed significantly. Electron-donating

substituents in the 2-aminophenyl moiety of isoquinolines

doublets (AB system) and as two singlets, respectively. Also,

H NMR spectra clearly indicated the nonequivalency of

1

1b–e, especially the OMe group, strongly increase the rate

protons of both methylene groups in the CH CH NH frag-

2

of the reaction whereas electron-withdrawing substituents

ment of compound 3hd and methyl groups in the

©

E

Synthesis

Y. S. Rozhkova et al.

Paper

R

N

R¹R¹

R²

R

R2

R1

O

AcOH

R²

R⁵

+

N

_R4

NH₂

60 °C

5 min to 100 h

R

R1

2a,d

_R3

_R5

NH2

R⁴

_R3

1

b–h

3

OMe

MeO

NH2

R³

_R3

N

3

3fd: 99% (1 h)

_b_a_:_R3 = OMe, 75% (5 min)

_c_a_:_R3 = Me, 78% (15 min)

_d_a_:_R3 = Br, 84% (2.5 h)

3bd: R = OMe, 95% (10 min)

3

3cd: R = Me, 94% (1 h)

3

3dd: R = Br, 92% (18 h)

3

ed: R = NO2, 61% (100 h)

OMe

MeO

OMe

MeO

NH2 •HBr

NH2•HBr

NH2

N

HBr

N

HBr

N

3ga: 64% (1 h)

3gd: 87% (1.5 h)

3ha•2HBr: 62% (2.5 h)

3hd•2HBr: 66% (72 h)

Scheme 4 Reaction of 3,4-dihydroisoquinolines 1b–h with ketones 2a, 2d. Reagents and conditions: 1b–h (0.35 mmol), 2a, 2d (0.42 mmol), AcOH (1.5

mL), 60 °C.

C(Me )C(Me )NH fragment of quinolines 3ga, 3gd. The

2

only explanation for this is hindered rotation around the

bond connecting the aryl and quinoline moieties of the

molecules, also in the case of quinoline 3ab, the stereoiso-

merism of which is discussed above.

R¹R¹

R²

_R2

R²

R

O

_H+

N

+

R5

_R4

– H2O

H

The proposed reaction mechanism is described in

Scheme 5. The reaction begins with the formation of imini-

um ion A, which tautomerizes to enamine B. Next, intramo-

lecular nucleophilic attack of the enamine fragment on the

electron-deficient azomethine carbon (C-1) of the isoquin-

oline cycle results in the formation of spiro intermediate C.

Finally, acid-promoted isoquinoline ring opening with

cleavage of the C1–N bond affords quinoline 3. This mecha-

nism corresponds well to the observed influence of substit-

NH2

N

2

_R5

R⁴

_R3

R³

1

A

R¹R¹

R²

R

NH

1

H

N

3

uent R on the reaction rate: electron-donating substituents

_R5

at the para position to the amino group in the 2-aminophe-

nyl moiety should increase the electron density on the ami-

no group of starting isoquinolines and on the -carbon of

the enamine fragment of intermediate B and promote the

nucleophilic attack on carbonyl and intramolecular cycliza-

tion of intermediate B, respectively; electron-withdrawing

groups should act in the opposite direction.

In summary, for the first time we have successfully em-

ployed 2-(3,4-dihydroisoquinolin-1-yl)anilines as sub-

strates for the Friedländer reaction. Condensation of differ-

ently substituted 2-(3,4-dihydroisoquinolin-1-yl)anilines

with various -methylene ketones in acetic acid afforded

R4

3

R³

B

– H⁺

R¹R¹

R²

R

R²

NH R⁵

NH

1

H

R

1

5

_R4

R

_R3

_R4

+

N

H

D

C

Scheme 5 Proposed reaction mechanism

©

F

Synthesis

Y. S. Rozhkova et al.

Paper

1

novel aminoalkyl-functionalized 4-arylquinolines in mod-

erate to excellent yields. We demonstrated that this proto-

col is very attractive for the construction of unique amino-

functionalized quinoline derivatives which are of signifi-

cant interest for medicinal chemistry. Further studies to ex-

tend the scope of the reaction to various 3,4-dihydroiso-

quinolines and related compounds, and investigation of

both synthetic transformations and atropisomerism of the

quinolines obtained, are in progress in our laboratory.

H NMR (400 MHz, CDCl ):  = 7.98 (d, J = 8.0 Hz, 1 H), 7.56 (ddd, J =

3

8

6

3

2

.3, 6.7, 1.5 Hz, 1 Н), 7.34 (dd, J = 8.4, 1.0 Hz, 1 Н), 7.29 (ddd, J = 8.2,

.7, 1.2 Hz, 1 Н), 7.09 (s, 1 Н), 6.58 (s, 1 Н), 3.94 (s, 3 Н), 3.78 (s, 3 Н),

.17 (t, J = 6.7 Hz, 2 Н), 2.64–2.46 (m, 2 Н), 2.38 (d, J = 13.7 Hz, 1 Н),

.29 (d, J = 13.7 Hz, 1 Н), 2.01–1.89 (m, 2 Н), 1.83–1.68 (m, 2 Н), 1.28

(br s, 2 Н), 0.85 (s, 3 Н), 0.81 (s, 3 Н).

13

C NMR (100 MHz, CDCl ):  = 159.2 (C), 148.1 (C), 147.6 (C), 146.5

3

(C), 145.8 (C), 129.6 (C), 129.2 (C), 129.1 (C), 128.6 (CH), 128.3 (CH),

1

26.7 (C), 126.0 (CH), 125.4 (CH), 114.4 (CH), 112.8 (CH), 55.9 (2

OСН ), 51.00 (C), 46.7 (СН ), 34.1 (СН ), 30.8 (СН ), 30.7 (СН ), 28.0

3

2

3

(

СН ), 22.9 (СН ), 22.8 (СН ).

2 2 2

+

MS (EI, 70 eV): m/z (%) = 390.1 (0.1) [M] , 389.1 (0.2) [M – H] , 375.2

+

TLC was performed on commercially available Sorbfil silica gel plates,

which were visualized under UV light (254 nm). Column chromatog-

raphy was performed on silica gel 60 (0.063–0.200 mm, Macherey-

Nagel); flash chromatography was performed on silica gel 60 (0.040–

(2) [M – CH

3

] , 333.2 (72) [M – (CH

3

)

2

C=NH] , 332.2 (55) [M –

+

(CH

)

CNH

] , 318.2 (100) [M – СН

C(CH

)

NH

] , 316.1 (10) [M –

3

2

3

2

+

CHNH

– CH

] , 302.1 (6) [M – (CH

)

C=NH – OCH

] , 58.1 (37)

3

2

3

2

3

+

[(CH

)

C=NH

] .

3

2

1

13

0

.063 mm, Merck). H and C NMR spectra were recorded on a Bruker

Anal. Calcd for C₂₅H₃₀N O : С, 76.89; Н, 7.74; N, 7.17. Found: С, 77.21;

Н, 7.96; N, 7.12.

2

Avance III HD 400 spectrometer using CDCl , DMSO-d or D O as sol-

vent. H chemical shifts were measured relative to internal HMDS (_H

.055 ppm) for CDCl and DMSO-d , or residual HDO (_H4.79 ppm)

for D O. C chemical shifts were measured relative to the solvent sig-

nal (_C77.00 ppm for CDCl , _C39.50 ppm for DMSO-d ), or internal

dioxane (_C67.19 ppm) for D O. The assignment of primary (CH ),

secondary (CH ), tertiary (CH) and quaternary (C) carbon nuclei was

made by using DEPT-135 spectra. The signals in the H and C NMR

spectra of compound 3ab were assigned on the basis of 2D H– H

COSY, H– H NOESY, H– C HSQC and H– C HMBC experiments.

Chromatograms and low-resolution mass spectra were obtained with

an Agilent 6890N/5975B GC-MS system [HP-5ms column (30 m ×

.25 mm, 0.25 m), helium as carrier gas, 1 mL/min, electron impact

ionization mode (230 °С, 70 eV)]. To improve the GC separation or to

3

6

2

1

0

3

6

1-(4,5-Dimethoxy-2-(4-methyl-1,2,3,4-tetrahydroacridin-9-

13

2

yl)phenyl)-2-methylpropan-2-amine (3ab) (Mixture of Atropdia-

stereomers)

3

6

2

3

Prepared using 1a (109 mg, 0.35 mmol) and 2-methylcyclohexanone

2

1

13

(2b; 0.051 mL, 0.42 mmol); reaction time: 2 h. H NMR analysis of the

1

crude product in CDCl or DMSO-d indicated the ratio of atropdiaste-

3

6

1

13

1

13

reomers A/B to be ~52:48. The crude product was purified by tritura-

tion with hexane to give pure 3ab as a mixture of atropdiastereomers

1

A/B in a ratio of ~52:48, according to H NMR analysis. The chromato-

gram of a solution of substance 3ab in CH Cl displayed two poorly

2

0

resolved peaks with retention times t_R₁≈13.86 and t_R₂= 13.91 min,

while the mass spectrum from the beginning of the 1st peak to the

end of the 2nd apparently did not change [temperature program:

+

obtain a mass spectrum with an intensive M peak, some substances

were derivatized by adding a slight excess of (CF CO) O to the solution

3

2

1

3

00 °С, rate 30 °С/min, 260 °С, rate 5 °С/min, 300 °С (2 min); inlet:

00 °С]. Under the same temperature program, the trifluoroacetyl de-

before injection. High-resolution mass spectra were recorded with a

Bruker maXis HD UHR-QTOF mass spectrometer equipped with an

electrospray ionization ion source. IR spectra were recorded on a

Bruker IFS 66 FT-IR spectrometer. Elemental analysis was carried out

on a Vario EL Cube analyzer. Melting points were determined using a

PTP apparatus and are uncorrected. For the synthesis of 2-(3,4-dihy-

droisoquinolin-1-yl)anilines 1, see the Supporting Information.

rivatives of the stereoisomers showed a better separation, with peak

resolution R = 1.2 (ratio of peak areas approx. 1:1); retention times

s

were 13.96 and 14.07 min. Mass spectra of the trifluoroacetyl deriva-

tives differed significantly only in intensity of the signal at m/z 332

(the spectra below were averaged across 6 scans).

Yield: 92 mg (65%); white solid.

Quinolines 3; General Procedure

Data refer to the inseparable mixture of atropdiastereomers.

IR (thin film): 3359, 3060, 2956, 2934, 2865, 1605, 1570, 1515, 1492,

A mixture of 2-(3,4-dihydroisoquinolin-1-yl)aniline 1 (0.35 mmol, 1

equiv) and ketone 2 (0.42 mmol, 1.2 equiv) in AcOH (1.5 mL) was

heated with stirring at 60 °C until the starting aniline 1 disappeared

1464, 1454, 1372, 1356, 1249, 1215, 1189, 1100, 1021, 757 cm–1

.

1

H NMR (400 MHz, CDCl ):  = 8.01 (d, J = 8.4 Hz, 1 Н, 5′′-H, both),

3

(

5 min to 150 h, monitored by TLC). Then, the reaction mixture was

cooled to room temperature, poured into a mixture of crushed ice (5–

g) and 25% aq NH (2.6 mL), and extracted with CH Cl (3 × 10 mL).

7.56 (br t, J = 7.6 Hz, 1 H, 6′′-H, both), 7.37 (br d, J = 8.0 Hz, 1 Н, 8′′-H,

both), 7.33–7.27 (m, 1 Н, 7′′-H, both), 7.09 (s, 1 Н, 6′-H, A), 7.08 (s, 1 Н,

7

3

2

6

′-H, В), 6.60 (s, 1 Н, 3′-H, A), 6.58 (s, 1 Н, 3′-H, В), 3.96 (s, 3 Н, 5′-

The combined organic layers were washed with water, dried over an-

OCH , both), 3.80 (s, 3 Н, 4′-OCH , A), 3.79 (s, 3 Н, 4′-OCH , B), 3.30–

3

hydrous Na SO , filtered and concentrated in vacuo. The resulting

2

4

a

b

3

2

(

2

.20 (m, 1 Н, 4′′-H, both), 2.64–2.47 (m, 2 Н, 1′′-H and 1′′-H , both),

.38 (d, J = 13.6 Hz, 1 Н, 1-H , В), 2.36 (d, J = 13.6 Hz, 1 Н, 1-H , A), 2.31

d, J = 13.6 Hz, 1 Н, 1-H , В), 2.26 (d, J = 13.6 Hz, 1 Н, 1-H , A), 2.17–

.05 (m, 1 Н, 3′′-H , both), 1.83–1.78 (m, 1 Н, 2′′-H , both), 1.76–1.64

1

crude product was analyzed by H NMR spectroscopy and purified

further if necessary.

b

a

b

1-(4,5-Dimethoxy-2-(1,2,3,4-tetrahydroacridin-9-yl)phenyl)-2-

a

(

m, 2 Н, 2′′-H and 3′′-H , both), 1.53 (d, J = 7.2 Hz, 3 Н, 4′′-CH , A),

3

methylpropan-2-amine (3aa)

1

.51 (d, J = 7.2 Hz, 3 Н, 4′′-CH , В), 1.08 (br s, 2 Н, NH , both), 0.87 (s, 3

3

2

Prepared using 1a (109 mg, 0.35 mmol) and cyclohexanone (2a; 0.044

mL, 0.42 mmol); reaction time: 30 min. The crude product was puri-

fied by recrystallization from acetone/hexane to give pure 3aa.

Н, C(CH ) , B), 0.85 (s, 3 Н, C(CH ) , A), 0.82 (s, 3 Н, C(CH ) , B), 0.81 (s,

3 2 3 2 3 2

3 Н, C(CH ) , A).

3

2

13

C NMR (100 MHz, CDCl ):  = 163.1 and 163.0 (C4a′′), 148.1 (C5′),

3

Yield: 109 mg (80%); white solid; mp 150–164 °C.

147.6 (C4′), 146.7 and 146.6 (C10a′′), 145.6 and 145.5 (C9′′), 129.8 and

29.7 (C1′), 129.4 (C2′), 129.0 and 128.89 (C5′′), 128.93 and 128.8

(C9a′′), 128.14 and 128.12 (C6′′), 126.6 (C8a′′), 126.0 (C8′′), 125.44 and

1

IR (thin film): 3356, 3286, 3062, 2936, 2863, 1605, 1571, 1516, 1493,

₄₆₄_,₁₃₉₅_,₁₃₇₁_,₁₃₅₄_,₁₃₃₆_,₁₂₉₀_,₁₂₄₉_,₁₂₁₅_,₁₁₆₆_,₁₀₉₅_,₇₅₈_c_m_–1

1

.

©

G

Synthesis

Y. S. Rozhkova et al.

Paper

1

125.41 (C7′′), 114.5 and 114.4 (C6′), 113.0 and 112.9 (C3′), 56.00 (2

H NMR (400 MHz, DMSO-d ):  = 7.96 (br d, J = 8.4 Hz, 1 Н), 7.70–

6

OСН ), 55.98 (2 OСН ), 50.9 (C2), 46.93 and 46.86 (С1), 37.2 and 37.1

7.65 (m, 1 Н), 7.46–7.40 (m, 2 Н), 7.29 (s, 1 Н), 7.14 (s, 1 Н), 6.75 (s, 1

Н), 3.84 (s, 3 Н), 3.70 (s, 3 Н), 2.68 (s, 3 Н), 2.54 (d, J = 13.3 Hz, 1 Н),

2.21 (d, J = 13.3 Hz, 1 Н), 1.12 (br s, 2 Н), 0.70 (s, 3 Н), 0.67 (s, 3 Н).

13

3

(

C4′′), 31.2 and 31.0 (C3′′), 31.03, 31.01, 30.86 and 30.84 [C(CH ) ],

3 2

2

8.6 and 28.4 (C1′′), 21.9 and 21.4 (4′′-CH ), 20.4 and 20.0 (C2′′).

3

+

MS (EI, 70 eV): m/z (%) = 404.1 (0.1) [M] , 403.1 (0.2) [M – H] , 389.1

C NMR (100 MHz, DMSO-d ):  = 158.0 (C), 148.0 (C), 147.8 (C),

6

+

(

[

1) [M – CH ] , 347.1 (63) [M – (CH ) C=NH] , 346.1 (42) [M –

147.5 (C), 146.8 (C), 129.7 (C), 129.4 (C), 129.0 (CH), 128.6 (CH), 125.6

(CH), 125.6 (CH), 125.5 (C), 123.6 (CH), 114.9 (CH), 113.5 (CH), 55.52

(OСН ), 55.48 (OСН ), 50.3 (C), 46.3 (СН ), 30.7 (СН ), 30.4 (СН ), 24.8

3

3 2

+

CH ) CNH ] , 332.1 (100) [M – CH C(CH ) NH ] , 330.1 (11) [M –

3

2

3

2

+

CH ) CHNH – CH ] , 316.1 (7) [M – (CH ) C=NH – OCH ] , 58.1 (46)

3

2

3

2

3

2

3

+

(CH ) C=NH ] .

(СН₃).

3

2

+

MS of trifluoroacetyl derivative with t 13.96 min (EI, 70 eV): m/z (%)

MS (EI, 70 eV): m/z (%) = 350.1 (0.03) [M] , 349.1 (0.08) [M – H] ,

R

+

=

500.1 (25) [M] , 387.1 (10) [M – CF CONH ] , 347.0 (46) [M –

335.1 (1) [M – CH ] , 293.1 (52) [M – (CH ) C=NH] , 292.1 (100) [M –

3 3 2

3

2

+

CH =C(CH )NHCOCF ] , 346.0 (100) [M – (CH ) CNHCOCF ] , 332.0

(CH ) CNH ] , 278.0 (9) [M – СН C(CH ) NH ] , 276.0 (8) [M –

2

3

2

3

3 2 2 2 3 2 2

+

(52) [M

–

CH C(CH ) NHCOCF ] , 330.0 (19), 153.9 (13)

(CH ) CHNH – CH ] , 58.1 (30) [(CH ) C=NH ] .

3 2 2 3 3 2 2

HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₇N O : 351.2067; found:

2

3

2

3

+

[

(CH ) C=NHCOCF ] .

3

2

3

2 2

MS of trifluoroacetyl derivative with t 14.07 min (EI, 70 eV): m/z (%) =

351.2072.

R

+

5

00.1 (26) [M] , 387.1 (10) [M – CF CONH ] , 347.0 (47) M –

3 2

+

CH =C(CH )NHCOCF ] , 346.0 (100) [M – (CH ) CNHCOCF ] , 332.0

2

3

2

3

1-(2-(2,3-Dimethylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-meth-

ylpropan-2-amine (3ae) and 1-(2-(2-Ethylquinolin-4-yl)-4,5-dime-

thoxyphenyl)-2-methylpropan-2-amine (3ae′)

+

(47) [M

–

CH C(CH ) NHCOCF ] , 330.0 (20), 153.9 (12)

2 3 2 3

+

[

(CH ) C=NHCOCF ] .

3

2

3

Anal. Calcd for C₂₆H₃₂N O : C, 77.19; H, 7.97; N, 6.92. Found: С, 77.10;

Н, 8.38; N, 6.82.

Prepared using 1a (109 mg, 0.35 mmol) and methyl ethyl ketone (2e;

0.038 mL, 0.42 mmol); reaction time 2 h. H NMR analysis of the

2

1

crude product indicated the ratio of regioisomers 3ae/3ae′ to be

1-(2-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)-4,5-dimethoxy-

78:22; no further purification was required.

phenyl)-2-methylpropan-2-amine (3ac)

Combined yield of both regioisomers 3ae and 3ae′: 100 mg (78%);

Prepared using 1a (109 mg, 0.35 mmol) and cyclopentanone (2c;

white solid.

0

.037 mL, 0.42 mmol); reaction time: 1.5 h. The crude product was

Data refer to the inseparable mixture of regioisomers 3ae and 3ae′.

purified by recrystallization from acetone to give pure 3ac.

IR (thin film): 3361, 2998, 2960, 2932, 2861, 2837, 1603, 1586, 1515,

Yield: 96 mg (73%); white solid; mp 215–224 °C.

1

494, 1455, 1397, 1368, 1327, 1290, 1263, 1244, 1215, 1102, 1074,

–1

IR (thin film): 3366, 3294, 3061, 2999, 2956, 2932, 2846, 2834, 1605,

1026, 996, 897, 863, 839, 777 cm .

1

573, 1517, 1500, 1461, 1441, 1407, 1380, 1352, 1331, 1294, 1268,

1

H NMR (400 MHz, DMSO-d ):  (3ae) = 7.91 (dd, J = 8.4, 0.8 Hz, 1 Н),

6

–1

245, 1211, 1152, 1104, 1071, 1001, 781, 767 cm

.

7

.59 (ddd, J = 8.4, 6.8, 1.6 Hz, 1 Н), 7.37 (ddd, J = 8.4, 6.8, 1.2 Hz, 1 Н),

7.27–7.25 (m, 1 H), 7.26 (s, 1 Н), 6.61 (s, 1 Н), 3.844 (s, 3 Н), 3.68 (s, 3

Н), 2.67 (s, 3 H), 2.25 (d, J = 13.6 Hz, 1 Н), 2.20 (d, J = 13.6 Hz, 1 Н),

2.14 (s, 3 H), 1.15 (br s, 2 Н), 0.71 (s, 3 Н), 0.67 (s, 3 Н);  (3ae′) = 7.98

(dt, J = 8.4, 0.8 Hz, 1 Н), 7.70–7.65 (m, 1 H), 7.44–7.43 (m, 2 H), 7.30 (s,

1 Н), 7.13 (s, 1 Н), 6.76 (s, 1 Н), 3.840 (s, 3 Н), 3.71 (s, 3 Н), 2.96 (qd, J =

7.6, 2.0 Hz, 2 H), 2.54 (d, J = 13.2 Hz, 1 Н), 2.20 (d, J = 13.6 Hz, 1 Н),

H NMR (400 MHz, CDCl ):  = 8.04 (br d, J = 8.4 Hz, 1 Н), 7.61–7.55

3

(m, 1 H), 7.50 (br d, J = 8.4 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.03 (s, 1 Н),

6

(

.65 (s, 1 Н), 3.95 (s, 3 Н), 3.80 (s, 3 Н), 3.28–3.14 (m, 2 Н), 2.90–2.72

m, 2 Н), 2.41 (s, 2 Н), 2.20–2.06 (m, 2 Н), 0.88 (br s, 2 Н), 0.82 (s, 3 Н),

0.80 (s, 3 Н).

13

C NMR (100 MHz, CDCl ):  = 167.4 (C), 148.2 (C), 148.0 (C), 147.5

3

1

.33 (t, J = 7.8 Hz, 3 Н), 0.70 (s, 3 Н), 0.67 (s, 3 Н).

(C), 142.7 (C), 134.5 (C), 129.6 (C), 129.0 (C), 128.9 (CH), 128.2 (CH),

13

126.5 (C), 125.8 (CH), 125.5 (CH), 114.5 (CH), 112.9 (CH), 56.0 (2

C NMR (100 MHz, DMSO-d ):  (3ae) = 158.7 (C), 147.6 (C), 147.0

6

OСН ), 50.7 (C), 47.1 (СН ), 35.2 (СН ), 30.8 (СН ), 30.7 (СН ), 30.6

(C), 145.6 (C), 145.1 (C), 130.1 (C), 128.6 (C), 128.3 (CН), 128.1 (C),

3

2

3

2

(

СН ), 23.4 (СН ).

127.8 (CH), 126.5 (C), 126.0 (CH), 125.4 (CH), 114.7 (CH), 113.1 (CH),

3

2

+

55.50 (OСН

(СН ), 16.9 (СН

146.9 (C), 129.8 (C), 129.4 (C), 129.0 (CН), 128.8 (CН), 125.8 (C), 125.7

3

), 55.4 (OСН

3

), 50.4 (C), 46.2 (СН ), 30.70 (2 СН ), 24.2

2

3

MS (EI, 70 eV): m/z (%) = 376.1 (0.02) [M] , 375.2 (0.08) [M – H] ,

+

3

);  (3ae′) = 162.7 (C), 148.1 (C), 147.8 (C), 147.5 (C),

3

61.2 (1) [M – CH ] , 319.1 (61) [M – (CH ) C=NH] , 318.1 (100) [M –

3

3 2

+

(CH ) CNH ] , 302.1 (8) [M

–

(CH ) CHNH

–

CH ] , 58.1 (28)

3

2

3

2

3

+

(CН), 125.5 (CН), 122.7 (CН), 115.0 (CН), 113.5 (CН), 55.53 (OСН

3

),

[

(CH ) C=NH ] .

3

2

5

0.3 (C), 46.3 (СН ), 31.3 (СН ), 30.66 (СН ), 30.3 (CH ), 13.5 (СН );

2 2 3 3 3

Anal. Calcd for C₂₄H₂₈N O : С, 76.56; Н, 7.50; N, 7.44. Found: С, 76.34;

2

the missing signal for one of the OCH groups is overlapped.

3

Н, 7.76; N, 7.09.

+

MS (EI, 70 eV): 3ae m/z (%) = 364.3 (0.05) [M] , 363.1 (0.2) [M – H] ,

+

3

(

[

49.2 (2) [M – CH ] , 307.1 (71) [M – (CH ) C=NH] , 306.1 (67) [M –

3

2

1

-(4,5-Dimethoxy-2-(2-methylquinolin-4-yl)phenyl)-2-methyl-

+

CH ) CNH ] , 292.1 (100) [M – СН C(CH ) NH ] , 290.1 (6) [M –

3 2 2 2 3 2 2

propan-2-amine (3ad)

+

CH ) CНNH – CH ] , 276.1 (9) [M – (CH ) C=NH – OCH ] , 58.1 (34)

3 2 2 3 3 2 3

Prepared using 1a (109 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

.42 mmol); reaction time: 1 h. H NMR analysis of the crude product

revealed that no further purification was required.

+

(CH ) C=NH ] ; MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) =

3 2 2

1

0

+

4

60.2 (25) [M] , 347.1 (21) [M – CF CONH ] , 307.1 (52) [M –

3 2

+

CF CONC(CH ) ] , 306.1 (100) [M – CF CONHC(CH ) ] , 292.1 (67) [M

– CF CONHC(CH ) CH ] , 291.1 (23), 290.1 (16), 276.1 (12), 260.0 (19),

54.0 (16) [CF CONHC(CH ) ] ; 3ae′ m/z (%) = [M] not detected, 363.1

0.1) [M – H] , 349.2 (1) [M – CH ] , 307.1 (51) [M – (CH ) C=NH] ,

] , 290.1 (7) [M – (CH

78.1 (7) [M – (CH ) C=NH – C H ] , 58.1 (31) [(CH ) C=NH ] ; MS of

3

2

3

3 2

+

Yield: 119 mg (97%); white solid; mp 142–158 °C.

3 3 2 2

+

1

(

IR (thin film): 3357, 3288, 3060, 2959, 2935, 2866, 2845, 1598, 1560,

517, 1504, 1464, 1410, 1391, 1355, 1256, 1231, 1215, 1192, 1178,

3 3 2

+

1

3

2

+

–1

306.1 (100) [M – (CH

2

3

)

2

CNH

2

3

)

2

CНNH – CH ] ,

2 3

1149, 1096, 763, 754 cm

.

+

3

2

5

3

2

©

H

Synthesis

Y. S. Rozhkova et al.

Paper

+

trifluoroacetyl derivative: m/z (%) = 460.2 (25) [M] , 306.1 (100) [M –

product indicated the ratio of regioisomers 3ag/3ag′ to be 69:31. The

crude residue was purified by silica gel flash chromatography

(EtOAc/MeOH, 4:1 → 1:1) to afford (in order of elution) 3ag (40 mg,

+

CF CONHC(CH ) ] , 292.1 (67) [M – CF CONHC(CH ) CH ] , 290.1 (17),

3

2

3

2

+

1

54.0 (16) [CF CONHC(CH ) ] .

3 3 2

2

9%), a mixture of 3ag and 3ag′ (46 mg, 3ag/3ag′ = 78:22) and a mix-

Anal. Calcd for C₂₃H₂₈N O : С, 75.79; Н, 7.74; N, 7.69. Found: С, 76.02;

Н, 7.88; N, 7.27.

2

ture of 3ag and 3ag′ (20 mg, 3ag/3ag′ = 13:87).

Combined yield of both regioisomers 3ag and 3ag′: 106 mg (77%).

1

2

-(2-(3-Benzyl-2-methylquinolin-4-yl)-4,5-dimethoxyphenyl)-

-methylpropan-2-amine (3af) and 1-(4,5-Dimethoxy-2-(2-

3ag: white solid; mp 130–134 °C (acetone/hexane); R = 0.10 (EtOAc/

MeOH, 4:1).

f

phenethylquinolin-4-yl)phenyl)-2-methylpropan-2-amine (3af′)

IR (thin film): 3359, 3290, 3077, 3061, 2999, 2958, 2934, 2846, 1636,

Prepared using 1a (109 mg, 0.35 mmol) and benzylacetone (2f; 0.063

1

606, 1581, 1516, 1493, 1465, 1445, 1393, 1372, 1351, 1252, 1215,

1

mL, 0.42 mmol); reaction time: 2.5 h. H NMR analysis of the crude

–1

190, 1160, 1106, 1089, 1014, 999, 916, 870, 772, 761 cm

.

product indicated the ratio of regioisomers 3af/3af′ to be 67:33. The

H NMR (400 MHz, CDCl ):  = 8.03 (br d, J = 8.4 Hz, 1 Н), 7.64–7.57

3

crude product was recrystallized from acetone/hexane to give a pure

(m, 1 H), 7.34–7.32 (m, 2 Н), 7.10 (s, 1 Н), 6.65 (s, 1 Н), 5.91–5.81 (m,

1

regioisomeric mixture of 3af/3af′ in a ratio of 79:21, according to H

1

(

H), 5.03 (dq, J = 10.2, 1.7 Hz, 1 H), 4.78 (dq, J = 17.1, 1.9 Hz, 1 H), 3.96

s, 3 Н), 3.77 (s, 3 Н), 3.37–3.34 (m, 2 H), 2.77 (s, 3 H), 2.33 (d, J = 13.6

Hz, 1 Н), 2.27 (d, J = 13.6 Hz, 1 Н), 1.22 (br s, 2 Н), 0.85 (s, 3 Н), 0.82 (s,

NMR analysis.

Combined yield of both regioisomers 3af and 3af′: 85 mg (55%);

white solid.

3

Н).

Data refer to the inseparable mixture of regioisomers 3af and 3af′.

13

C NMR (100 MHz, CDCl ):  = 159.3 (C), 148.3 (C), 147.2 (C), 146.7

3

IR (thin film): 3359, 3291, 3061, 3025, 3000, 2958, 2935, 2845, 1604,

(C), 146.6 (C), 135.9 (СН), 129.6 (C), 129.5 (C), 129.2 (C), 128.7 (СН),

128.6 (СН), 127.0 (C), 126.5 (СН), 125.7 (СН), 116.0 (СН ), 114.2 (СН),

113.3 (СН), 56.0 (OСН ), 55.9 (OСН ), 50.8 (C), 46.9 (СН ), 35.0 (СН ),

31.0 (СН ), 30.9 (СН ), 24.0 (СН ).

1

582, 1516, 1494, 1465, 1452, 1407, 1392, 1372, 1351, 1253, 1215,

2

–1

190, 1159, 1106, 1085, 870, 772, 753, 723, 697 cm

.

3

2

3

H NMR (400 MHz, CDCl ):  (3af) = 8.06 (d, J = 8.4 Hz, 1 Н), 7.65–7.61

3

+

(m, 1 H), 7.40–7.33 (m, 2 Н), 7.20–7.08 (m, 3 H), 7.07 (s, 1 Н), 6.88 (br

MS (EI, 70 eV): m/z (%) = 390.2 (0.04) [M] , 333.1 (35) [M –

+

d, J = 7.1 Hz, 2 H), 6.45 (s, 1 Н), 4.03 (s, 2 H), 3.92 (s, 3 Н), 3.36 (s, 3 Н),

.65 (s, 3 H), 2.39 (d, J = 13.6 Hz, 1 Н), 2.30 (d, J = 13.8 Hz, 1 Н), 1.46

br s, 2 Н), 0.87 (s, 3 Н), 0.85 (s, 3 Н);  (3af′) = 8.11 (d, J = 8.4 Hz, 1 Н),

(CH

СН

[M – (CH

182.1 (34) [C

3

)

2

C=NH] , 332.1 (16) [M – (CH

3

)

2

CNH

2

] , 318.1 (100) [M –

+

2

(

2

C(CH

3

)

2

NH

CNH

2

] , 305.1 (55) [M – (CH

3

)

2

– CH=CH

] , 302.1 (11) [M – (CH

2

] , 304.1 (67)

+

)

– CH

=CH

)

C=NH – OCH

] ,

3

2

3

2

3

+

7

.69–7.64 (m, 1 Н), 7.50 (br d, J = 8.0 Hz, 1 Н), 7.40–7.33 (m, 1 Н),

.27–7.22 (m, 3 Н), 7.20–7.08 (m, 3 H), 6.99 (s, 1 Н), 6.65 (s, 1 Н), 3.95

9

H

4

N(CH )(CH

3

2

CH=CH

2

)] , 58.1 (64) [(CH

3

)

2

C=NH

2

] .

Anal. Calcd for C₂₅H₃₀N O : С, 76.89; Н, 7.74; N, 7.17. Found: С, 77.12;

2

(

1

s, 3 Н), 3.81 (s, 3 Н), 3.36–3.13 (m, 4 H), 2.59 (d, J = 13.6 Hz, 1 Н), 2.31

d, J = 13.6 Hz, 1 Н), 1.46 (br s, 2 Н), 0.81 (br s, 6 Н).

Н, 7.63; N, 7.12.

ag′: R = 0.14 (EtOAc/MeOH, 4:1).

3

f

3

C NMR (100 MHz, CDCl ):  (3af) = 159.6 (C), 148.2 (C), 147.20 (C),

3

Data refer to the inseparable mixture of regioisomers 3ag and 3ag′

1

(

1

47.15 (C), 146.8 (C), 139.8 (C), 130.0 (C), 129.2 (C), 129.1 (C), 128.8

CH), 128.7 (CH), 128.4 (2 СН), 127.9 (2 СН), 126.9 (C), 126.5 (СН),

26.0 (СН), 125.8 (СН), 114.3 (СН), 113.0 (СН), 56.0 (OСН ), 55.4

(

3ag/3ag′ = 13:87).

1

H NMR (400 MHz, CDCl ):  = 8.08 (br d, J = 8.4 Hz, 1 Н), 7.65 (ddd, J =

3

8

1

.4, 6.8, 1.4 Hz, 1 Н), 7.51 (br d, J = 8.2 Hz, 1 Н), 7.37 (ddd, J = 8.2, 6.8,

.2 Hz, 1 Н), 7.20 (s, 1 H), 7.00 (s, 1 Н), 6.72 (s, 1 Н), 5.98–5.87 (m, 1

(

OСН ), 51.4 (C), 46.4 (СН ), 36.5 (СН ), 30.5 (СН ), 30.4 (СН ), 24.4

3 2 2 3 3

(

СН );  (3af′) = 161.1 (C), 148.6 (C), 148.4 (C), 148.3 (C), 147.5 (C),

3

H), 5.07 (dq, J = 17.2, 1.6 Hz, 1 H), 4.99–4.96 (m, 1 Н), 3.96 (s, 3 Н),

.82 (s, 3 Н), 3.12–3.07 (m, 2 H), 2.66 (d, J = 13.6 Hz, 1 Н), 2.64–2.58

m, 2 Н), 2.35 (d, J = 13.6 Hz, 1 Н), 2.00 (br s, 2 Н), 0.84 (s, 3 Н), 0.82 (s,

1

5

41.4 (C), 130.7 (C), 129.31 (СН), 129.27 (СН), 129.0 (C), 128.5 (2 CH),

26.2 (C), 125.9 (CH), 123.3 (СН), 114.5 (СН), 113.7 (СН), 56.1 (OСН₃),

1.2 (C), 40.8 (СН ), 35.8 (СН ), 30.8 (СН ), 30.2 (СН ); the missing sig-

3

(

2

3

Н).

nals for one of the OCH and CH groups, as well as for four aromatic

CH carbons, are overlapped.

3

2

13

C NMR (100 MHz, CDCl ):  = 161.4 (C), 148.6 (C), 148.5 (C), 148.3

3

+

(C), 147.5 (C), 137.7 (CH), 130.7 (C), 129.7 (2 CH), 129.2 (C), 126.2 (C),

125.9 (CH), 125.8 (СН), 123.1 (СН), 115.3 (СН ), 114.5 (СН), 113.7

MS (EI, 70 eV): 3af m/z (%) = 440.2 (0.02) [M] , 439.0 (0.07) [M – H] ,

+

4

(

[

25.1 (0.8) [M – CH ] , 383.2 (18) [M – (CH ) C=NH] , 382.1 (6) [M –

2

3

3 2

+

(СН), 56.1 (OСН ), 56.0 (OСН ), 51.0 (C), 46.6 (СН ), 38.5 (СН ), 33.7

CH ) CNH ] , 368.2 (100) [M – СН C(CH ) NH ] , 352.1 (5) [M –

3 3 2 2

3

2

3

2

+

(СН ), 30.44 (СН ), 30.39 (СН ).

2 3 3

CH ) C=NH – OCH ] , 292.1 (5) [M – (CH ) C=NH – PhCH ] , 91.1 (5)

PhCH ] , 58.1 (23) [(CH ) C=NH ] ; 3af′ m/z (%) = 440.0 (0.05) [M] ,

39.0 (0.1) [M – H] , 425.1 (1) [M – CH ] , 383.1 (62) [M –

3

2

3

2

+

2

3

2

MS (EI, 70 eV): m/z (%) = 390.1 (0.05) [M] , 333.1 (56) [M –

+

4

(CH ) C=NH] , 332.1 (100) [M

–

(CH ) CNH ] , 58.1 (32)

3

2

3 2 2

+

(CH ) C=NH] , 382.1 (100) [M

–

(CH ) CNH ] , 368.1 (5) [M

–

[(CH ) C=NH ] .

3

2

3

2

3 2 2

+

СН C(CH ) NH ] , 366.0 (6) [M – (CH ) CHNH – CH ] , 278 (10) [M –

2

3

2

3

2

3

+

(

CH ) C=NH – CH CH Ph and/or M – (CH ) CNH – CH =CHPh] , 58.1

3 2 2 2 3 2 2 2

1-(2-(2-Isobutylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-methyl-

propan-2-amine (3ah)

+

(31) [(CH ) C=NH ] .

3

2

^Aⁿ^a^l^.^C^a^l^c^d^f^o^r^C²9^H32N O : С, 79.06; Н, 7.32; N, 6.36. Found: С, 79.36;

Н, 7.49; N, 6.07.

2

Prepared using 1a (109 mg, 0.35 mmol) and methyl isobutyl ketone

(

2h; 0.053 mL, 0.42 mmol); reaction time: 3 h. The crude product was

purified by recrystallization from hexane to give pure 3ah.

1

-(2-(3-Allyl-2-methylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-

methylpropan-2-amine (3ag) and 1-(2-(2-(But-3-en-1-yl)quinolin-

-yl)-4,5-dimethoxyphenyl)-2-methylpropan-2-amine (3ag′)

Yield: 84 mg (61%); white solid; mp 113–115 °C.

IR (thin film): 3360, 3060, 2957, 2934, 2868, 2845, 1597, 1556, 1517,

4

1

501, 1465, 1411, 1365, 1255, 1230, 1214, 1178, 1150, 1098, 1085,

Prepared using 1a (109 mg, 0.35 mmol) and allylacetone (2g; 0.049

mL, 0.42 mmol); reaction time 5 h. H NMR analysis of the crude

–1

1009, 756 cm

.

1

©

I

Synthesis

Y. S. Rozhkova et al.

Paper

1

H NMR (400 MHz, CDCl ):  = 8.09 (br d, J = 8.4 Hz, 1 Н), 7.65 (ddd, J =

were further recrystallized from acetone/hexane (for 3aj) or hexane

(for 4) to give pure quinoline 3aj (60 °C: 78 mg, 54%; 90 °C: 75 mg,

52%) and amide 4 (60 °C: 12 mg, 10%; 90 °C: 7 mg, 6%).

3

8

.4, 6.8, 1.4 Hz, 1 Н), 7.52 (dd, J = 8.4, 0.8 Hz, 1 Н), 7.38 (ddd, J = 8.1,

.8, 1.1 Hz, 1 Н), 7.18 (s, 1 Н), 7.01 (s, 1 Н), 6.73 (s, 1 Н), 3.96 (s, 3 Н),

.82 (s, 3 Н), 2.92–2.83 (m, 2 H), 2.66 (d, J = 13.6 Hz, 1 Н), 2.36 (d, J =

3.6 Hz, 1 Н), 2.31–2.17 (m, 1 H), 1.15 (br s, 2 Н), 1.00 (d, J = 6.6 Hz, 6

6

3

1

3

aj: white solid; mp 172–174 °C; R_f= 0.30 (CH Cl /MeOH/TEA,

2 2

98.5:1:0.5).

Н), 0.84 (s, 3 Н), 0.81 (s, 3 Н).

IR (thin film): 3358, 3291, 3060, 3000, 2959, 2934, 2844, 1593, 1546,

13

C NMR (100 MHz, CDCl ):  = 161.6 (C), 148.4 (C), 148.3 (C), 148.3

3

1516, 1504, 1494, 1464, 1445, 1409, 1390, 1361, 1262, 1247, 1231,

(C), 147.4 (C), 130.7 (C), 129.4 (C), 129.3 (CH), 129.1 (CH), 126.2 (C),

–1

1213, 1184, 1096, 773, 753, 696 cm

.

1

25.8 (2 CH), 123.7 (CH), 114.5 (CH), 113.7 (CH), 56.1 (OСН ), 56.0

3

1

H NMR (400 MHz, DMSO-d ):  = 8.31–8.27 (m, 2 Н), 8.13 (br d, J =

6

(OСН ), 50.7 (C), 48.4 (СН ), 46.9 (СН ), 30.7 (СН ), 30.7 (СН ), 29.4

3

2

3

8.4 Hz, 1 Н), 8.00 (s, 1 Н), 7.79–7.73 (m, 1 Н), 7.57–7.48 (m, 5 Н), 7.16

(CH), 22.6 (СН ), 22.5 (СН ).

3

(s, 1 Н), 6.87 (s, 1 Н), 3.86 (s, 3 Н), 3.73 (s, 3 Н), 2.58 (d, J = 13.2 Hz, 1

+

MS (EI, 70 eV): m/z (%) = 392.2 (0.07) [M] , 391.2 (0.3) [M – H] , 377.2

Н), 2.26 (d, J = 13.2 Hz, 1 Н), 1.14 (br s, 2 Н), 0.72 (s, 3 Н), 0.70 (s, 3 Н).

¹³C NMR (100 MHz, DMSO-d

):  = 155.4 (C), 149.2 (C), 148.0 (C),

+

(

[

1) [M – CH ] , 335.2 (54) [M – (CH ) C=NH] , 334.2 (100) [M –

CH ) CNH ] , 318.1 (8) [M – (CH ) CHNH – CH ] , 278.1 (10) [M –

CH ) C=NH – C H and/or M – (CH ) CNH – C H ] , 58.1 (29)

(CH ) C=NH ] .

3

2

+

6

3

2

3

2

3

+

147.8 (C), 147.0 (C), 138.7 (C), 129.9 (C), 129.61 (CH), 129.60 (CH),

129.56 (CH), 129.5 (C), 128.8 (2 CH), 127.2 (2 CH), 126.5 (CH), 126.3

3

2

4

9

3

2

4

8

+

3

2

(

C), 125.7 (CH), 120.4 (CH), 115.0 (CH), 113.7 (CH), 55.6 (OСН ), 55.5

3

^Aⁿ^a^l^.^C^a^l^c^d^f^o^r^C²5^H32N O : С, 76.49; Н, 8.22; N, 7.14. Found: С, 76.90;

Н, 8.34; N, 6.99.

2

(OСН ), 50.4 (C), 46.5 (СН ), 30.7 (СН ), 30.4 (СН ).

3 2 3 3

+

MS (EI, 70 eV): m/z (%) = 412.2 (0.03) [M] , 411.1 (0.08) [M – H] ,

+

3

–

97.1 (0.9) [M – CH ] , 355.1 (58) [M – (CH ) C=NH] , 354.1 (100) [M

3

2

1

-(2-(2-tert-Butylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-methyl-

+

(CH ) CNH ] , 338.1 (10) [M – (CH ) CHNH – CH ] , 278.1 (6) [M –

3

2

3

2

3

propan-2-amine (3ai)

+

(

CH ) C=NH – Ph] , 58.1 (28) [(CH ) C=NH ] .

3

2

3

2

Prepared using 1a (109 mg, 0.35 mmol) and pinacolone (2i; 0.052 mL,

0

due was purified by silica gel column chromatography (CH Cl /

MeOH/TEA, 98.5:1:0.5) to afford crude products 3ai and 4, which

were further recrystallized from hexane to give pure quinoline 3ai

Anal. Calcd for C₂₇H₂₈N O : С, 78.61; Н, 6.84; N, 6.79. Found: С, 78.50;

2

.42 mmol); reaction time: 150 h (60 °C), 15 h (90 °C). The crude resi-

Н, 6.86; N, 6.73.

2

Characterization data for amide 4 are given below.

(

1

60 °C: 41 mg, 30%; 90 °C: 44 mg, 32%) and amide 4 (60 °C: 15 mg,

2%; 90 °C: 18 mg, 15%).

1-(2-(2-(4-Chlorophenyl)quinolin-4-yl)-4,5-dimethoxyphenyl)-2-

methylpropan-2-amine (3ak)

3

ai: white solid; mp 122–126 °C; R_f= 0.35 (CH Cl /MeOH/TEA,

Prepared using 1a (109 mg, 0.35 mmol) and 4′-chloroacetophenone

(2k; 0.054 mL, 0.42 mmol); reaction time: 63 h (60 °C), 20 h (90 °C).

The crude residue was purified by silica gel column chromatography

2

98.5:1:0.5).

IR (thin film): 3361, 3293, 3060, 2959, 2934, 2909, 2866, 1605, 1594,

(

CH Cl /MeOH/TEA, 98.5:1:0.5) to afford crude products 3ak and 4,

2 2

1

555, 1516, 1501, 1465, 1409, 1391, 1357, 1263, 1243, 1233, 1214,

180, 1149, 1092, 1022, 1008, 869, 785, 763 cm

–1

which were further recrystallized from hexane/CH Cl (for 3ak) or

2 2

.

hexane (for 4) to give pure quinoline 3ak (60 °C: 61 mg, 39%; 90 °C:

63 mg, 40%) and amide 4 (60 °C: 6 mg, 5%; 90 °C: 12 mg, 10%).

H NMR (400 MHz, CDCl ):  = 8.09 (br d, J = 8.4 Hz, 1 Н), 7.63 (ddd, J =

3

8.4, 6.8, 1.6 Hz, 1 Н), 7.48 (dd, J = 8.4, 0.8 Hz, 1 Н), 7.42 (s, 1 Н), 7.36

3

ak: white solid; mp 139–142.5 °C; R_f= 0.35 (CH Cl /MeOH/TEA,

2 2

(ddd, J = 8.0, 6.8, 1.2 Hz, 1 Н), 7.00 (s, 1 Н), 6.74 (s, 1 Н), 3.96 (s, 3 Н),

98.5:1:0.5).

3

9

.83 (s, 3 Н), 2.61 (d, J = 13.6 Hz, 1 Н), 2.33 (d, J = 13.6 Hz, 1 Н), 1.48 (s,

Н), 1.06 (br s, 2 Н), 0.84 (s, 3 Н), 0.82 (s, 3 Н).

IR (thin film): 3360, 3061, 3002, 2959, 2934, 2848, 1593, 1544, 1516,

1504, 1492, 1464, 1417, 1361, 1261, 1247, 1232, 1213, 1182, 1093,

13

C NMR (100 MHz, CDCl ):  = 168.5 (C), 148.3 (C), 148.2 (C), 147.7

3

–1

1

012, 866, 835, 754 cm

¹H NMR (400 MHz, CDCl

):  = 8.19 (br d, J = 8.4 Hz, 1 Н), 8.15–8.12

3

.

(C), 147.4 (C), 131.3 (C), 129.8 (CH), 129.5 (C), 128.9 (CH), 126.0 (C),

125.8 (CH), 125.5 (CH), 120.2 (CH), 114.5 (CH), 113.7 (CH), 56.1

(

OСН ), 56.0 (OСН ), 50.7 (C), 46.9 (СН ), 38.1 (C), 30.8 (СН ), 30.7

(m, 2 H), 7.76 (s, 1 Н), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1 Н), 7.56 (dd, J =

8.4, 0.9 Hz, 1 Н), 7.50–7.46 (m, 2 H), 7.43 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 Н),

7.04 (s, 1 Н), 6.77 (s, 1 Н), 3.97 (s, 3 Н), 3.83 (s, 3 Н), 2.66 (d, J = 13.6

Hz, 1 Н), 2.39 (d, J = 13.6 Hz, 1 Н), 1.32 (br s, 2 Н), 0.86 (s, 3 Н), 0.85 (s,

3 Н).

3

2

3

(СН ), 30.1 (3 СН ).

3

+

MS (EI, 70 eV): m/z (%) = 392.2 (0.05) [M] , 391.2 (0.2) [M – H] , 377.2

+

(

[

1) [M – CH ] , 335.2 (54) [M – (CH ) C=NH] , 334.2 (100) [M –

CH ) CNH ] , 318.1 (8) [M – (CH ) CHNH – CH ] , 278.1 (7) [M –

CH ) C=NH – C H and/or M – (CH ) CNH – C H ] , 58.1 (28)

(CH ) C=NH ] .

3

2

+

3

2

3

2

3

+

¹³C NMR (100 MHz, CDCl

(C), 147.5 (C), 138.0 (C), 135.7 (C), 130.7 (C), 130.1 (CH), 129.7 (CH),

29.5 (C), 129.1 (2 CH), 128.8 (2 CН), 126.8 (C), 126.6 (CH), 125.9

CH), 120.3 (CH), 114.5 (CH), 113.6 (CH), 56.1 (OСН ), 56.0 (OСН ),

):  = 155.3 (C), 149.6 (C), 148.60 (C), 148.55

3

2

4

9

3

2

4

8

+

3

2

1

Anal. Calcd for C₂₅H₃₂N O : С, 76.49; Н, 8.22; N, 7.14. Found: С, 76.54;

Н, 8.59; N, 7.09.

Characterization data for amide 4 are given below.

2

(

3

5

0.8 (C), 46.9 (СН ), 30.9 (СН ), 30.8 (СН ).

2 3 3

+

MS (EI, 70 eV): m/z (%) = 446.1 (0.03) [M] , 445.1 (0.07) [M – H] ,

+

4

–

31.1 (0.9) [M – CH ] , 389.1 (59) [M – (CH ) C=NH] , 388.1 (100) [M

3

2

1

-(4,5-Dimethoxy-2-(2-phenylquinolin-4-yl)phenyl)-2-methyl-

+

(CH ) CNH ] , 372.1 (9) [M – (CH ) CHNH – CH ] , 278.1 (6) [M –

3

2

3

2

3

propan-2-amine (3aj)

+

(

CH ) C=NH – ClC H ] , 58.1 (45) [(CH ) C=NH ] .

3 2 6 4 3 2 2

Prepared using 1a (109 mg, 0.35 mmol) and acetophenone (2j; 0.049

mL, 0.42 mmol); reaction time: 125 h (60 °C), 22 h (90 °C). The crude

residue was purified by silica gel column chromatography (CH Cl /

Anal. Calcd for C₂₇H₂₇ClN O : C, 72.55; H, 6.09; N, 6.27. Found: С,

2

72.17; Н, 6.38; N, 6.11.

2

Characterization data for amide 4 are given below.

MeOH/TEA, 98.5:1:0.5) to afford crude products 3aj and 4, which

©

J

Synthesis

Y. S. Rozhkova et al.

Paper

+

1

-(2-(2-(3,4-Dimethoxyphenyl)quinolin-4-yl)-4,5-dimethoxy-

MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) = 488.2 (12) [M] ,

+

phenyl)-2-methylpropan-2-amine (3al)

375.1 (100) [M – CF CONH ] , 335.1 (100) [M – CF CONC(CH ) ] ,

3 2 3 3 2

+

3

34.1 (55) [M – CF CONHC(CH ) ] , 332.1 (17) 320.1 (100) [M –

CF CONHC(CH ) CH ] , 318.1 (37), 316.1 (11), 292.1 (93), 276.1 (35),

48.1 (11), 218.0 (10), 154.0 (28) [CF CONHC(CH ) ] , 114.0 (10), 59.1

Prepared using 1a (109 mg, 0.35 mmol) and 3′,4′-dimethoxyace-

tophenone (2l; 76 mg, 0.42 mmol); reaction time: 120 h (60 °C), 24 h

3 3 2

+

3

2

+

2

(90 °C). The crude residue was purified by silica gel column chroma-

3 3 2

+

(18), 43.1 (19) [CH CO] .

tography (CH Cl /MeOH/TEA, 98.5:1:0.5) to afford crude products 3al

3

2

and 4, which were further recrystallized from hexane/CH Cl (for 3al)

Anal. Calcd for C₂₄H₂₈N O ·H O: С, 70.22; Н, 7.37; N, 6.82. Found: С,

2 3 2

2

or hexane (for 4) to give pure quinoline 3al (60 °C: 73 mg, 44%; 90 °C:

70.22; Н, 7.62; N, 6.63.

66 mg, 40%) and amide 4 (60 °C: 15 mg, 12%; 90 °C: 25 mg, 23%).

3

al: white solid; mp 112–113.5 °C; R_f= 0.35 (CH Cl /MeOH/TEA,

Ethyl 4-(2-(2-Amino-2-methylpropyl)-4,5-dimethoxyphenyl)-2-

methylquinoline-3-carboxylate (3an)

2

98.5:1:0.5).

IR (thin film): 3359, 3061, 3002, 2959, 2935, 2838, 1673, 1593, 1546,

Prepared using 1a (109 mg, 0.35 mmol) and ethyl acetoacetate (2n;

1

517, 1500, 1464, 1423, 1348, 1263, 1242, 1214, 1172, 1147, 1132,

0.053 mL, 0.42 mmol); reaction time: 2.5 h. The crude product was

–1

096, 1026, 872, 753 cm

.

purified by recrystallization from CH Cl /hexane to give pure 3an.

2 2

H NMR (400 MHz, CDCl ):  = 8.19 (dd, J = 8.4, 0.5 Hz, 1 Н), 7.92 (d, J =

Yield: 74 mg (50%); white solid; mp 101.5–106 °C.

3

2

.0 Hz, 1 Н), 7.77 (s, 1 Н), 7.71–7.65 (m, 2 Н), 7.53 (dd, J = 8.4, 1.0 Hz, 1

IR (thin film): 3361, 3064, 2962, 2936, 2847, 1725, 1606, 1565, 1517,

Н), 7.40 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 Н), 7.04 (s, 1 Н), 6.98 (d, J = 8.4 Hz,

1

cm

494, 1465, 1406, 1371, 1299, 1249, 1218, 1184, 1098, 1063, 777, 765

1

2

Н), 6.79 (s, 1 Н), 4.04 (s, 3 Н), 3.98 (s, 3 Н), 3.95 (s, 3 Н), 3.84 (s, 3 Н),

.67 (d, J = 13.6 Hz, 1 Н), 2.40 (d, J = 13.6 Hz, 1 Н), 1.05 (br s, 2 Н), 0.87

–1

.

1

H NMR (400 MHz, CDCl ):  = 8.05 (d, J = 8.4 Hz, 1 Н), 7.67 (ddd, J =

3

(s, 3 Н), 0.85 (s, 3 Н).

8.4, 6.8, 1.4 Hz, 1 Н), 7.53 (dd, J = 8.4, 0.9 Hz, 1 Н), 7.39 (ddd, J = 8.2,

13

C NMR (100 MHz, CDCl ):  = 156.1 (C), 150.6 (C), 149.6 (C), 149.1

3

6.8, 1.2 Hz, 1 Н), 7.12 (s, 1 Н), 6.74 (s, 1 Н), 4.11 (q, J = 7.1 Hz, 2 H),

(C), 148.6 (C), 148.5 (C), 147.5 (C), 132.5 (C), 130.9 (C), 130.0 (CH),

3.93 (s, 3 Н), 3.80 (s, 3 Н), 2.76 (s, 3 H), 2.46 (d, J = 14.0 Hz, 1 Н), 2.36

1

29.53 (C), 129.49 (CH), 126.6 (C), 126.1 (CH), 125.8 (CH), 120.3 (CH),

20.3 (CH), 114.5 (CH), 113.7 (CH), 111.2 (CH), 110.6 (CH), 56.1 (2

(d, J = 14.0 Hz, 1 Н), 1.08 (t, J = 7.1 Hz, 3 H), 1.02 (br s, 2 Н), 0.88 (s, 3

Н), 0.86 (s, 3 Н).

OСН ), 56.0 (2 OСН ), 50.8 (C), 46.9 (СН ), 30.9 (СН ), 30.8 (СН ).

3

2

3

+

13

C NMR (100 MHz, CDCl ):  = 168.5 (C), 154.9 (C), 148.7 (C), 147.8

3

+

MS (EI, 70 eV): m/z (%) = 472.1 (0.06) [M] , 471.1 (0.1) [M – H] , 457.1

(C), 147.3 (C), 145.9 (C), 130.3 (CH), 130.1 (C), 129.1 (CH), 128.1 (C),

+

(

0.6) [M – CH ] , 415.1 (57) [M – (CH ) C=NH] , 414.1 (100) [M –

CH ) CNH ] , 398.1 (10) [M – (CH ) CHNH – CH ] , 278.1 (5) [M –

CH ) C=NH – Ar] , 58.1 (31) [(CH ) C=NH ] .

3

2

127.9 (C), 126.8 (CH), 126.4 (CH), 125.4 (С), 114.6 (CH), 113.5 (CH),

61.4 (СН ), 56.03 (OСН ), 55.98 (OСН ), 51.0 (С), 47.3 (СН ), 31.1

+

3

2

3

2

3

2

3

2

+

3

2

3

2

(СН ), 30.4 (СН ), 23.9 (СН ), 13.9 (СН ).

3 3 3 3

Anal. Calcd for C₂₉H₃₂N O ·0.75 CH Cl : С, 66.63; Н, 6.30; N, 5.22.

Found: С, 66.78; Н, 6.66; N, 5.07.

Characterization data for amide 4 are given below.

+

2

4

2

MS (EI, 70 eV): m/z (%) = [M] not detected, 421.1 (0.02) [M – Н] ,

+

4

07.1 (0.9) [M – CH ] , 365.2 (81) [M – (CH ) C=NH] , 364.2 (100) [M

] , 336.1 (6) [M – (CH

CH ) CHNH – C H O] , 292.1 (63) [M – (CH ) C=NH – C H OCO] ,

3

3 2

+

– (CH

(

2

)

CNH

)

C=NH – C

H

] , 318.1 (6) [M –

3

2

3

2

5

+

3

2

5

3

2

5

+

76.1 (9) [M – (CH ) CNH – C H OCO] , 58.1 (43) [(CH ) C=NH ] .

1-(4-(2-(2-Amino-2-methylpropyl)-4,5-dimethoxyphenyl)-2-

3 3 2 2 5 3 2 2

+

methylquinolin-3-yl)ethanone (3am)

MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) = 518.2 (12) [M] ,

+

4

05.1 (47) [M – CF CONH ] , 365.1 (100) [M – CF CONC(CH ) ] , 364.1

Prepared using 1a (109 mg, 0.35 mmol) and acetylacetone (2m; 0.043

mL, 0.42 mmol); reaction time: 2 h. The crude product was purified

by recrystallization from MeOH to give pure 3am.

3 2 3 3 2

+

(

58) [M – CF CONHC(CH ) ] , 320.1 (13) [M – CF CONC(CH ) –

3 3 2 3 3 2

+

C H O] , 318.1 (37), 292.1 (40), 291.1 (20), 276.1 (14), 260.0 (15),

54.0 (17) [CF CONHC(CH ) ] , 59.1 (18).

2

5

+

1

3 3 2

Yield: 85 mg (59%); white solid; mp 147–154 °C.

Anal. Calcd for C₂₅H₃₀N O : С, 71.07; Н, 7.16; N, 6.63. Found: С, 71.38;

2

4

IR (thin film): 3360, 3298, 3063, 3001, 2961, 2936, 2848, 1697, 1605,

Н, 7.56; N, 6.59.

1

564, 1545, 1517, 1492, 1465, 1444, 1404, 1393, 1369, 1354, 1252,

–1

220, 1209, 1180, 1150, 1098, 761 cm

.

1

-(4,5-Dimethoxy-2-(7-methoxy-1,2,3,4-tetrahydroacridin-9-

yl)phenyl)-2-methylpropan-2-amine (3ba)

H NMR (400 MHz, DMSO-d ):  = 7.99 (br d, J = 8.4 Hz, 1 Н), 7.75

6

(ddd, J = 8.4, 6.8, 1.5 Hz, 1 Н), 7.60 (dd, J = 8.4, 0.8 Hz, 1 Н), 7.50 (ddd, J

Prepared using 1b (119 mg, 0.35 mmol) and cyclohexanone (2a;

.044 mL, 0.42 mmol); reaction time: 5 min. The crude residue was

purified by silica gel flash chromatography (EtOAc/MeOH, 3:1 → 1:1)

to afford 3ba.

= 8.4, 6.8, 1.2 Hz, 1 Н), 7.31 (s, 1 Н), 6.82 (s, 1 Н), 3.84 (s, 3 Н), 3.72 (s,

3 Н), 2.59 (s, 3 Н), 2.26 (d, J = 14.0 Hz, 1 Н), 2.22 (d, J = 14.0 Hz, 1 Н),

2.01 (s, 3 Н), 1.08 (br s, 2 Н), 0.71 (s, 3 Н), 0.64 (s, 3 Н).

0

13

C NMR (100 MHz, DMSO-d ):  = 204.7 (C), 153.0 (C), 148.4 (C),

6

Yield: 110 mg (75%); white solid; mp 141–143 °C; R = 0.21 (EtOAc/

f

147.0 (C), 146.6 (C), 143.2 (C), 135.0 (C), 130.9 (C), 129.9 (CH), 128.4

MeOH, 3:1).

(

CH), 126.7 (CH), 126.6 (C), 126.2 (CH), 125.3 (C), 114.9 (CH), 113.4

CH), 55.6 (OСН ), 55.4 (OСН ), 50.2 (C), 46.3 (СН ), 31.6 (СН ), 31.2

IR (thin film): 3356, 3291, 3000, 2937, 2864, 1621, 1516, 1496, 1466,

1353, 1248, 1225, 1169, 1093, 835, 755 cm

3

2

3

–1

СН ), 30.3 (СН ), 23.4 (СН ).

.

3

+

¹H NMR (400 MHz, CDCl

MS (EI, 70 eV): m/z (%) = [M] not detected, 391.1 (0.04) [M – Н] ,

3

):  = 7.91 (d, J = 9.1 Hz, 1 H), 7.25 (dd, J = 9.3,

+

3

(

77.1 (1) [M – CH ] , 335.1 (85) [M – (CH ) C=NH] , 334.1 (82) [M –

2.8 Hz, 1 H), 7.11 (s, 1 H), 6.65 (d, J = 2.8 Hz, 1 H), 6.59 (s, 1 H), 3.96 (s,

3 H), 3.81 (s, 3 H), 3.67 (s, 3 H), 3.15 (t, J = 6.6 Hz, 2 H), 2.59–2.46 (m, 2

H), 2.40 (d, J = 13.6 Hz, 1 H), 2.31 (d, J = 13.7 Hz, 1 H), 1.98–1.92 (m, 2

H), 1.79–1.72 (m, 2 H), 1.34 (br s, 2 H), 0.88 (s, 3 H), 0.85 (s, 3 H).

3

3 2

+

CH ) CNH ] , 320.1 (100) [M – СН C(CH ) NH ] , 318.1 (14) [M –

3 2 2 2 3 2 2

+

CH ) CHNH – CH ] , 304.1 (6) [M – (CH ) C=NH – OCH ], 292.1 (53)

3 2 2 3 3 2 3

+

[

5

M – (CH ) C=NH – CH CO], 276.1 (15) [M – (CH ) CNH – CH CO] ,

3 2 3 3 3 2 3

+

8.1 (82) [(CH ) C=NH ] , 43.0 (5) [CH CO] .

3 2 2 3

©

K

Synthesis

Y. S. Rozhkova et al.

Paper

1

3

+

C NMR (100 MHz, CDCl ):  = 157.0 (С), 156.6 (C), 148.1 (C), 147.7

MS (EI, 70 eV): m/z (%) = 404.1 (0.1) [M] , 403.2 (0.2) [M – H] , 389.2

3

+

(C), 144.7 (C), 142.7 (C), 130.1 (CН), 129.8 (C), 129.5 (С), 129.4 (С),

(1) [M – CH ] , 347.2 (58) [M – (CH ) C=NH] , 346.2 (30) [M –

3

2

+

1

5

2

27.6 (C), 120.7 (CH), 114.4 (CH), 112.8 (CH), 104.3 (СН), 56.0 (OСН₃),

5.9 (OСН ), 55.3 (OСН ), 50.8 (C), 46.8 (СН ), 33.8 (СН ), 31.0 (2 СН ),

8.1 (СН ), 23.0 (СН ), 22.9 (СН ).

(CH ) CNH ] , 332.2 (100) [M – СН C(CH ) NH ] , 58.1 (44)

3 2 2 2 3 2 2

+

[(CH ) C=NH ] .

3

2

3

2

HRMS (ESI): m/z [M + H]⁺calcd for C₂₆H₃₃N O : 405.2537; found:

2 2

+

MS (EI, 70 eV): m/z (%) = 420.2 (0.1) [M] , 419.2 (0.2) [M – H] , 405.1

405.2541.

+

(

[

1) [M – CH ] , 363.2 (54) [M – (CH ) C=NH] , 362.2 (18) [M –

CH ) CNH ] , 348.1 (100) [M

(CH ) C=NH ] .

3

2

+

– СН C(CH ) NH ] , 58.1 (42)

2 3 2 2

3

2

1-(2-(2,6-Dimethylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-meth-

ylpropan-2-amine (3cd)

+

3

2

HRMS (ESI): m/z [M + H]⁺calcd for C₂₆H₃₃N O : 421.2486; found:

4

2

3

Prepared using 1c (113 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

0.42 mmol); reaction time: 1 h. H NMR analysis of the crude product

1

21.2488.

revealed that no further purification was required.

1

2

-(4,5-Dimethoxy-2-(6-methoxy-2-methylquinolin-4-yl)phenyl)-

-methylpropan-2-amine (3bd)

Yield: 120 mg (94%); white solid; mp 208–213 °C.

IR (thin film): 3357, 3291, 2960, 2931, 2851, 1596, 1560, 1516, 1465,

Prepared using 1b (119 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

–1

1441, 1402, 1385, 1355, 1257, 1215, 1154, 1093, 1018, 828, 753 cm

.

1

0.42 mmol); reaction time: 10 min. H NMR analysis of the crude

1

H NMR (400 MHz, CDCl ):  = 7.94 (d, J = 8.6 Hz, 1 H), 7.47 (dd, J = 8.6,

3

product revealed that no further purification was required.

1.9 Hz, 1 Н), 7.22 (br s, 1 H), 7.13 (s, 1 H), 7.00 (s, 1 Н), 6.70 (s, 1 Н),

Yield: 126 mg (95%); white solid; mp 135–137 °C.

3.96 (s, 3 Н), 3.82 (s, 3 Н), 2.72 (s, 3 H), 2.60 (d, J = 13.6 Hz, 1 Н), 2.39

IR (thin film): 3356, 3290, 3001, 2960, 2936, 2845, 1621, 1603, 1561,

(s, 3 H), 2.33 (d, J = 13.6 Hz, 1 Н), 1.10 (br s, 2 Н), 0.84 (s, 3 Н), 0.83 (s,

1

516, 1501, 1465, 1405, 1356, 1267, 1248, 1230, 1215, 1158, 1090,

3 Н).

–1

034, 1017, 834, 753 cm

.

13

C NMR (100 MHz, CDCl ):  = 157.2 (C), 148.3 (C), 148.0 (C), 147.4

3

H NMR (400 MHz, CDCl ):  = 7.95 (d, J = 9.2 Hz, 1 Н), 7.30 (dd, J = 9.2,

(C), 146.8 (C), 135.6 (C), 131.5 (CH), 130.9 (C), 129.4 (C), 128.8 (CH),

125.9 (C), 124.6 (CH), 123.6 (CH), 114.5 (CH), 113.7 (CH), 56.04

(OСН ), 55.99 (OСН ), 50.7 (C), 46.9 (СН ), 30.8 (2 СН ), 25.2 (СН ),

3

2

.8 Hz, 1 Н), 7.14 (s, 1 H), 7.00 (s, 1 Н), 6.76 (d, J = 2.9 Hz, 1 Н), 6.72 (s,

Н), 3.95 (s, 3 Н), 3.82 (s, 3 Н), 3.70 (s, 3 Н), 2.71 (s, 3 H), 2.62 (d, J =

3.6 Hz, 1 Н), 2.35 (d, J = 13.6 Hz, 1 Н), 1.14 (br s, 2 Н), 0.84 (s, 6 Н).

1

3

2

3

21.6 (СН₃).

1

3

+

C NMR (100 MHz, CDCl ):  = 157.4 (C), 155.7 (C), 148.3 (C), 147.51

MS (EI, 70 eV): m/z (%) = 364.1 (0.03) [M] , 307.1 (62) [M –

3

+

(C), 147.45 (C), 144.3 (C), 130.9 (C), 130.5 (CH), 129.4 (C), 126.8 (C),

(CH ) C=NH] , 306.1 (100) [M – (CH ) CNH ] , 292.1 (41) [M –

3

2

3

2

+

1

23.8 (CH), 121.5 (CH), 114.5 (CH), 113.5 (CH), 104.0 (CH), 56.03

СН C(CH ) NH ] , 290.1 (13), 58.1 (54) [(CH ) C=NH ] .

2 3 2 2 3 2 2

(

3

OСН ), 55.99 (OСН ), 55.4 (OСН ), 50.7 (C), 46.9 (СН ), 30.8 (СН ),

HRMS (ESI): m/z [M + H]⁺calcd for C₂₃H₂₉N O : 365.2224; found:

365.2222.

3

2

3

2 2

0.7 (СН ), 25.0 (СН ).

3

+

MS (EI, 70 eV): m/z (%) = 380.2 (0.04) [M] , 365.2 (2) [M – CH ] , 323.1

3

+

(70) [M – (CH ) C=NH] , 322.1 (62) [M – (CH ) CNH ] , 308.1 (100) [M

3

2

3

2

1-(2-(7-Bromo-1,2,3,4-tetrahydroacridin-9-yl)-4,5-dimethoxy-

phenyl)-2-methylpropan-2-amine (3da)

+

–

CH C(CH ) NH ] , 58.1 (69) [(CH ) C=NH ] .

2 3 2 2 3 2 2

HRMS (ESI): m/z [M + H]⁺calcd for C₂₃H₂₉N O : 381.2173; found:

3

2

3

Prepared using 1d (136 mg, 0.35 mmol) and cyclohexanone (2a;

0.044 mL, 0.42 mmol); reaction time: 2.5 h. The crude residue was

purified by silica gel flash chromatography (EtOAc/MeOH, 3:1 → 1:1)

to afford 3da.

81.2177.

1

-(4,5-Dimethoxy-2-(7-methyl-1,2,3,4-tetrahydroacridin-9-

yl)phenyl)-2-methylpropan-2-amine (3ca)

Yield: 138 mg (84%); white solid; mp: 231–234 °C (dec; compound

Prepared using 1c (113 mg, 0.35 mmol) and cyclohexanone (2a; 0.044

mL, 0.42 mmol); reaction time: 15 min. The crude product was puri-

fied by washing with cold acetone to give pure 3ca.

began to darken above 180 °C); R = 0.20 (EtOAc/MeOH, 3:1).

f

IR (thin film): 3357, 3286, 3064, 2938, 2864, 2845, 1603, 1568, 1516,

–1

1481, 1464, 1368, 1355, 1248, 1217, 1180, 1095, 1008, 834, 758 cm

.

Yield: 110 mg (78%); white solid; mp: 210–212 °C (dec; compound

began to darken above 206 °C).

1

H NMR (400 MHz, CDCl ):  = 7.85 (d, J = 8.9 Hz, 1 H), 7.63 (dd, J = 8.9,

3

2

.2 Hz, 1 Н), 7.50 (d, J = 2.2 Hz, 1 Н), 7.13 (s, 1 Н), 6.54 (s, 1 Н), 3.96 (s,

3 H), 3.81 (s, 3 Н), 3.15 (t, J = 6.7 Hz, 2 Н), 2.61–2.48 (m, 2 Н), 2.34 (d,

J = 13.7 Hz, 1 Н), 2.26 (d, J = 13.7 Hz, 1 Н), 1.99–1.92 (m, 2 Н), 1.81–

1.70 (m, 2 Н), 1.27 (br s, 2 Н), 0.86 (s, 3 Н), 0.83 (s, 3 Н).

IR (thin film): 3367, 3021, 2939, 2862, 1566, 1517, 1496, 1465, 1398,

–1

1

253, 1219, 1168, 771, 758 cm .

1

H NMR (400 MHz, CDCl ):  = 7.89 (d, J = 8.6 Hz, 1 H), 7.41 (dd, J = 8.6,

3

13

2.0 Hz, 1 H), 7.11 (m, 2 H), 6.58 (s, 1 H), 3.97 (s, 3 H), 3.81 (s, 3 H), 3.16

C NMR (100 MHz, CDCl ):  = 159.9 (C), 148.5 (C), 147.8 (C), 145.09

3

(

1

0

t, J = 6.6 Hz, 2 H), 2.59–2.46 (m, 2 H), 2.42–2.35 (m, 4 H), 2.28 (d, J =

3.7 Hz, 1 H), 2.01–1.90 (m, 2 H), 1.82–1.69 (m, 2 H), 1.15 (br s, 2 H),

.88 (s, 3 H), 0.83 (s, 3 H).

(C), 145.08 (C), 131.8 (CH), 130.5 (CH), 130.4 (C), 129.8 (C), 128.3 (С),

128.2 (СН), 128.1 (C), 119.4 (C), 114.6 (CH), 112.8 (CH), 56.1 (OСН₃),

56.0 (OСН ), 50.9 (C), 46.7 (СН ), 34.2 (СН ), 31.1 (СН ), 31.0 (СН ),

3

2

3

1

3

28.1 (СН

2

), 22.8 (СН

2

), 22.7 (СН ).

2

C NMR (100 MHz, CDCl ):  = 158.2 (C), 148.1 (C), 147.6 (C), 145.2

3

+

(C), 145.1 (C), 135.1 (C), 130.6 (CH), 129.7 (C), 129.4 (C), 129.2 (С),

MS (EI, 70 eV): m/z (%) = [M] not detected, 453.0 (1) [M – CH ] , 411.0

(20) [M – (CH ) C=NH] , 409.9 (10) [M – (CH ) CNH ] , 396.0 (23) [M

3

+

1

5

2

28.4 (СН), 126.7 (C), 124.8 (CH), 114.5 (CH), 112.9 (CH), 56.0 (OСН₃),

5.9 (OСН ), 50.8 (C), 46.9 (СН ), 34.1 (СН ), 31.0 (СН ), 30.9 (СН ),

8.0 (СН ), 22.94 (СН ), 22.88 (СН ), 21.6 (СН ).

3

2

3

+

2

+

– СН C(CH ) NH ] , 58.0 (100) [(CH ) C=NH ] .

3

2

3

2

3

2

3

2

3

MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) = 564.2 (14) [M] ,

+

451.1 (10) [M – CF CONH ] , 411.1 (44) [M – (CH ) C=NCOCF ] , 410.1

3 2 3 2 3

+

(24) [M – (CH ) CNHCOCF , 396.1 (46) [M – CH C(CH ) NHCOCF ] ,

3 2 3 2 3 2 3

+

331.1 (100) [M – Br – (CH ) CNHCOCF ] , 330.1 (31) [M – HBr –

3 2 3

©

L

Synthesis

Y. S. Rozhkova et al.

Paper

+

(

CH ) CNHCOCF ] , 329.1 (15), 316.1 (14) [M

–

HBr

–

MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) = 491.2 (11) [M] ,

3

2

3

+

CH C(CH ) NHCOCF ] , 300.1 (58) [M – Br – (CH ) CNHCOCF

OCH ] , 154.0 (56) [(CH ) CNHCOCF ] , 114.0 (19), 59.1 (36), 42.1

476.1 (0.4) [M – CH ] , 378.1 (21) [M – CF CONH ] , 338.1 (19) [M –

CF CONC(CH ) ] , 337.1 (9) [M – CF CONHC(CH ) ] , 321.1 (100),

2

3

2

3

2

3

2

+

3

2

3

3 3 2 3 3 2

(

13), 41.1 (20).

320.1 (10), 304.1 (15), 303.1 (14), 291.1 (40), 290.1 (24), 276.1 (11),

+

_H_R_M_S₍_E_S_I₎_:_m_/_z_[_M₊_H_]+ calcd for C₂₅H₃₀BrN O : 469.1485; found:

260.0 (55), 154.0 (59) [CF

3

CONHC(CH

3

)

2

] , 114.0 (10), 59.1 (18).

2

469.1491.

Anal. Calcd for C₂₂H₂₅N O : С, 66.82; Н, 6.37; N, 10.63. Found: С,

3 4

67.03; Н, 6.15; N, 10.21.

1-(2-(6-Bromo-2-methylquinolin-4-yl)-4,5-dimethoxyphenyl)-2-

methylpropan-2-amine (3dd)

2-Methyl-1-(2-(2-methylquinolin-4-yl)phenyl)propan-2-amine

3fd)

(

Prepared using 1d (136 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

1

0.42 mmol); reaction time: 18 h. H NMR analysis of the crude prod-

Prepared using 1f (88 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

1

uct revealed that no further purification was required.

0.42 mmol); reaction time: 1 h. H NMR analysis of the crude product

revealed that no further purification was required.

Yield: 140 mg (92%); white solid; mp 195–196 °C.

Yield: 100 mg (99%); white solid; mp 92–93 °C.

IR (thin film): 3356, 3290, 3065, 2961, 2848, 1599, 1516, 1485, 1464,

1

376, 1262, 1248, 1222, 1214, 1167, 1098, 1017, 830, 754 cm^–¹

.

IR (thin film): 3357, 3278, 3060, 2961, 2922, 2868, 1594, 1559, 1508,

1485, 1466, 1444, 1406, 1381, 1344, 1193, 1150, 870, 844, 769, 743,

1

H NMR (400 MHz, CDCl ):  = 7.91 (d, J = 8.9 Hz, 1 H), 7.70 (dd, J = 8.9,

3

–

1

7

22 cm .

2

1

2

.2 Hz, 1 H), 7.61 (d, J = 2.2 Hz, 1 H), 7.20 (s, 1 H), 7.02 (s, 1 H), 6.67 (s,

H), 3.96 (s, 3 H), 3.82 (s, 3 H), 2.73 (s, 3 H), 2.60 (d, J = 13.6 Hz, 1 H),

.28 (d, J = 13.6 Hz, 1 H), 1.09 (br s, 2 H), 0.84 (s, 6 H).

1

H NMR (400 MHz, CDCl ):  = 8.06 (br d, J = 8.0 Hz, 1 Н), 7.64 (ddd, J =

3

8.4, 6.8, 1.6 Hz, 1 H), 7.49–7.33 (m, 5 H), 7.22–7.20 (m, 1 Н), 7.20 (s, 1

Н), 2.76 (s, 3 Н), 2.69 (d, J = 13.6 Hz, 1 H), 2.42 (d, J = 13.6 Hz, 1 H),

13

C NMR (100 MHz, CDCl ):  = 158.8 (C), 148.6 (C), 148.0 (C), 147.6

3

0.93 (br s, 2 Н), 0.83 (s, 6 Н).

(C), 146.8 (C), 132.8 (CH), 130.8 (CH), 129.8 (C), 129.5 (C), 127.9 (CH),

13

1

5

27.4 (C), 124.4 (CH), 119.8 (C), 114.6 (CH), 113.5 (CH), 56.05 (OСН₃),

6.02 (OСН ), 50.8 (C), 46.8 (СН ), 30.8 (СН ), 30.8 (СН ), 25.3 (СН ).

C NMR (100 MHz, CDCl ):  = 158.2 (C), 148.7 (C), 148.1 (C), 138.4

3

(C), 137.0 (C), 131.4 (CН), 130.6 (CН), 129.3 (CH), 129.0 (CH), 127.8

(CН), 126.4 (CH), 125.77 (CH), 125.76 (CH), 123.4 (CH), 50.7 (C), 47.3

3

2

3

+

MS (EI, 70 eV): m/z (%) = [M] not detected, 413.0 (1) [M – CH ] , 371.0

3

+

(СН

2 3 3 3

), 30.7 (СН ), 30.6 (СН ), 25.4 (СН ); the missing signal for one of

(

33) [M – (CH ) C=NH] , 369.9 (50) [M – (CH ) CNH ] , 260.1 (10),

3

2

3

2

+

the aromatic carbons is overlapped.

5

8.0 (100) [(CH ) C=NH ] .

3 2 2

+

MS (EI, 70 eV): m/z (%) = 290.0 (0.04) [M] , 289.1 (0.2) [M – Н] , 275.1

MS of trifluoroacetyl derivative (EI, 70 eV): m/z (%) = 524.2 (14) [M] ,

+

(4) [M – CH

3

] , 233.1 (52) [M – (CH

3

)

2

C=NH] , 232.1 (100) [M –

4

(

11.2 (10) [M – CF CONH ] , 371.1 (42) [M – (CH ) C=NCOCF ] , 370.1

3 2 3 2 3

+

(CH

CH

3

)

2

CNH

2

] , 231.1 (17) [M – (CH

3

)

2

CHNH

2

] , 218.1 (10) [M –

58) [M – (CH ) CNHCOCF ] , 291.2 (100) [M – Br – (CH ) CN-

3

2

3

2

+

2

C(CH

3

)

2

NH

2

] , 58.1 (28) [(CH

3

)

2

C=NH

2

] .

HCOCF ] , 290.2 (29) [M – HBr – (CH ) CNHCOCF ] , 276.1 (15) [M –

3

2

3

+

HBr – CH C(CH ) NHCOCF ] , 260.1 (79) [M – Br – (CH ) CNHCOCF –

Anal. Calcd for C₂₀H₂₂N : С, 82.72; Н, 7.64; N, 9.65. Found: С, 83.03; Н,

2

3

2

3

2

3

2

+

OCH ] , 246.1 (11) [M – Br – CH C(CH ) NHCOCF – OCH ] , 217.1

12), 154.1 (56) [(CH ) CNHCOCF ] , 114.1 (12), 59.1 (24), 41.1 (11).

8.01; N, 9.32.

3

2

+

3

2

3

(

3

2

3

HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₆BrN O : 429.1172; found:

3-(4,5-Dimethoxy-2-(1,2,3,4-tetrahydroacridin-9-yl)phenyl)-2,3-

dimethylbutan-2-amine (3ga)

2

429.1168.

Prepared using 1g (118 mg, 0.35 mmol) and cyclohexanone (2a;

1-(4,5-Dimethoxy-2-(2-methyl-6-nitroquinolin-4-yl)phenyl)-2-

0.044 mL, 0.42 mmol); reaction time: 1 h. The crude product was pu-

methylpropan-2-amine (3ed)

rified by recrystallization from CH Cl /hexane to give pure 3ga.

2 2

Prepared using 1e (124 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

Yield: 94 mg (64%); white solid; mp 198–200 °C.

0

.42 mmol); reaction time: 100 h. The crude product was purified by

IR (thin film): 3371, 3061, 2982, 2936, 2867, 2839, 1605, 1570, 1517,

recrystallization from hexane/acetone to give pure 3ed.

1

492, 1464, 1399, 1365, 1349, 1311, 1246, 1216, 1169, 1129, 1063,

–1

Yield: 84 mg (61%); yellow solid; mp 200–203.5 °C.

1002, 772, 756 cm

.

1

IR (thin film): 3361, 3083, 3000, 2961, 2936, 2850, 1619, 1601, 1565,

H NMR (400 MHz, CDCl ):  = 7.98 (d, J = 8.4 Hz, 1 H), 7.81 (s, 1 Н),

3

1

532, 1516, 1493, 1465, 1381, 1341, 1262, 1247, 1227, 1215, 1111,

7.56 (ddd, J = 8.3, 6.7, 1.5 Hz, 1 Н), 7.38 (dd, J = 8.4, 1.0 Hz, 1 Н), 7.29

(ddd, J = 8.2, 6.7, 1.2 Hz, 1 Н), 6.26 (s, 1 Н), 3.96 (s, 3 Н), 3.73 (s, 3 Н),

3.16 (t, J = 6.6 Hz, 2 Н), 2.68–2.59 (m, 1 Н), 2.53–2.44 (m, 1 Н), 2.02–

–1

075, 1017, 841, 799, 755 cm

.

H NMR (400 MHz, CDCl ):  = 8.44 (d, J = 2.4 Hz, 1 Н), 8.40 (dd, J = 9.2,

3

1

3

.87 (m, 2 Н), 1.83–1.74 (m, 2 Н), 1.10 (br s, 2 Н), 1.11 (s, 3 Н), 1.01 (s,

Н), 0.96 (s, 3 Н), 0.85 (s, 3 Н).

2

.4 Hz, 1 Н), 8.15 (d, J = 9.2 Hz, 1 Н), 7.35 (s, 1 Н), 7.06 (s, 1 Н), 6.68 (s,

Н), 3.98 (s, 3 Н), 3.83 (s, 3 Н), 2.81 (s, 3 Н), 2.63 (d, J = 13.6 Hz, 1 Н),

.27 (d, J = 13.6 Hz, 1 Н), 0.98 (br s, 2 Н), 0.83 (s, 3 Н), 0.82 (s, 3 Н).

1

2

13

C NMR (100 MHz, CDCl ):  = 159.0 (C), 150.6 (C), 147.0 (C), 146.9

3

1

3

(C), 146.2 (C), 137.8 (C), 129.3 (C), 128.4 (CH, C), 128.2 (CH), 127.6 (C),

C NMR (100 MHz, CDCl ):  = 162.5 (C), 150.8 (C), 150.3 (C), 149.0

3

1

5

2

²⁶^.⁹⁽^C^H⁾^,¹²⁵^.⁰⁽^C^H⁾^,¹¹⁵^.⁸⁽^C^H⁾^,¹¹³^.⁵⁽^C^H⁾^,⁵⁶^.¹⁽^C⁾^,⁵⁵^.⁸⁹⁽^O^С^Н3⁾^,

(C), 147.7 (C), 145.2 (C), 130.8 (CH), 129.5 (C), 128.8 (C), 125.3 (CH),

5.85 (OСН ), 47.1 (C), 34.2 (СН ), 28.9 (СН ), 28.8 (СН ), 28.6 (СН ),

1

25.2 (C), 122.9 (CH), 122.8 (CH), 114.7 (CH), 113.5 (CH), 56.1 (2

3

2

3

2

6.7 (СН ), 25.7 (СН ), 23.0 (СН ), 22.8 (СН ).

OСН ), 50.8 (C), 46.8 (СН ), 30.9 (СН ), 30.8 (СН ), 25.7 (СН ).

3

2

3

2

3

+

MS (EI, 70 eV): m/z (%) = 418.2 (0.12) [M] , 417.2 (0.2) [M – Н] , 403.2

MS (EI, 70 eV): m/z (%) = [M] not detected, 380.0 (0.7) [M – CH ] ,

3

+

(1) [M – CH

(CH CNH

3

+

] , 361.2 (100) [M – СН

2

=C(CH

C=NH – CH

3

)NH

2

] , 360.2 (39) [M –

] , 344.2 (12) [M –

38.0 (14) [M – (CH ) C=NH] , 337.0 (4) [M – (CH ) CNH ] , 321.0 (28)

3

2

3

2

+

3

)

2

] , 346.2 (58) [M – (CH

3

)

2

3

[

M – (CH ) CHNH – CH ] , 260.0 (5), 58.1 (100) [(CH ) C=NH ] .

3 2 2 3 3 2 2

+

(

CH ) CHNH – CH ] , 332.2 (54) [M – (CH ) CNH – C H ] , 330.2 (10)

3

2

3

2

4

©

M

Synthesis

Y. S. Rozhkova et al.

Paper

+

13

[

3

(

M – (CH ) C=NH – OCH ] , 318.2 (89) [M – (CH ) СC(CH ) NH ] ,

C NMR (100 MHz, D O):  = 158.1 (C), 156.0 (C), 149.9 (C), 148.6 (C),

3

2

3

2

3

2

+

02.1 (8) [M – (CH ) СHC(CH ) NH – CH ] , 286.1 (6), 184.1 (5), 58.1

136.9 (C), 134.4 (CH), 133.0 (C), 129.9 (CH), 128.0 (C), 127.5 (C), 127.1

(CH), 127.0 (C), 120.2 (CH), 114.0 (CH), 112.6 (CH), 56.7 (OСН ), 56.6

3

2

3

2

3

+

48) [(CH ) C=NH ] .

3

2

3

(

OСН ), 40.3 (СН ), 30.5 (СН ), 29.5 (СН ), 27.2 (СН ), 21.7 (СН ), 20.9

^С^Н2⁾^.

Anal. Calcd for C₂₇H₃₄N O : С, 77.48; Н, 8.19; N, 6.69. Found: С, 77.38;

Н, 8.57; N, 6.69.

3

2

+

MS (EI, 70 eV): free base m/z (%) = 362.1 (7) [M] , 333.1 (60) [M –

CH NH] , 332.1 (64) [M – CH NH ] , 318.1 (100) [M – СН CH NH ] ,

3

HRMS (ESI): m/z [M – 2 HBr + H]⁺calcd for C23

+

3-(4,5-Dimethoxy-2-(2-methylquinolin-4-yl)phenyl)-2,3-dimeth-

2

+

16.1 (15) [M – CH NH – CH ] , 302.0 (9), 30.1 (5) [CH =NH ] .

ylbutan-2-amine (3gd)

3 2 3 2 2

Prepared using 1g (118 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

H N O : 363.2067;

27 2 2

0.42 mmol); reaction time: 1.5 h. The crude product was purified by

found: 363.2067.

recrystallization from acetone/hexane to give pure 3gd.

Yield: 115 mg (87%); pale yellow solid; mp 161–166 °C.

IR (thin film): 3375, 2967, 2935, 2839, 1596, 1561, 1518, 1503, 1464,

Anal. Calcd for C₂₃H₂₆N O ·2 HBr·0.25 H O: С, 52.24; Н, 5.43; N, 5.30;

Br, 30.22. Found: С, 52.61; Н, 5.31; N, 5.10; Br, 29.77.

2

2-(4,5-Dimethoxy-2-(2-methylquinolin-4-yl)phenyl)ethan-1-

1

7

1

407, 1377, 1346, 1309, 1248, 1229, 1213, 1192, 1177, 1156, 1067,

–1

amine Dihydrobromide (3hd·2 HBr)

82, 754 cm

.

Prepared using 1h (99 mg, 0.35 mmol) and acetone (2d; 0.031 mL,

H NMR (400 MHz, DMSO-d ):  = 7.92 (d, J = 8.4 Hz, 1 Н), 7.63 (t, J =

6

0.42 mmol); reaction time: 72 h. Quinoline 3hd was isolated as the

7.6 Hz, 1 Н), 7.44 (s, 1 Н), 7.40 (t, J = 7.6 Hz, 1 Н), 7.33 (s, 1 Н), 7.30 (d,

dihydrobromide salt, obtained by analogy with a literature proce-

J = 8.3 Hz, 1 Н), 6.38 (s, 1 Н), 3.86 (s, 3 Н), 3.63 (s, 3 Н), 2.66 (s, 3 Н),

14

dure. The crude product was dissolved in MeOH (2 mL) and 33% HBr

in AcOH (0.22 mL) was added. The mixture was stirred at room tem-

perature for 30 min and concentrated in vacuo. The residue was dis-

solved in MeOH (2–3 mL) and concentrated in vacuo; this procedure

was then repeated three times. After, the crude residue was dissolved

1.27 (s, 3 Н), 1.22 (br s, 2 Н), 0.98 (s, 6 Н), 0.64 (s, 3 Н).

13

C NMR (100 MHz, DMSO-d ):  = 157.1 (C), 151.8 (C), 146.9 (C),

6

146.5 (C), 145.9 (C), 137.0 (C), 129.0 (C), 128.4 (CH), 128.1 (CH), 127.2

(

C), 126.1 (CH), 125.1 (CH), 122.6 (CH), 116.0 (CH), 114.9 (CH), 55.6

OСН ), 55.3 (OСН ), 54.4 (C), 46.6 (C), 28.0 (СН ), 27.4 (СН ), 27.4

3

in MeOH (1 mL) and Et O (~1.5–1.7 mL) was added. The mixture was

2

СН ), 24.9 (СН ), 24.5 (СН ).

3

left to stand overnight at room temperature. The precipitated dihyd-

+

MS (EI, 70 eV): m/z (%) = 378.2 (0.3) [M] , 377.2 (0.4) [M – Н] , 363.2

robromide salt was collected by filtration, washed with MeOH/Et O

2

+

(

[

0.8) [M – CH ] , 321.1 (53) [M – (CH ) C=NH] , 320.1 (61) [M –

(~1:2) and dried in a desiccator at room temperature.

3

3 2

+

CH ) CNH ] , 306.1 (100) [M – (CH ) C=NH – CH ] , 305.1 (20) [M –

3

2

3

2

3

Yield: 117 mg (66%); yellow solid; mp: 231–234 °C (dec; compound

began to darken above 180 °C).

+

CH ) CNH – CH ] , 304.1 (20) [M – (CH ) CHNH – CH ] , 290.1 (21)

3

2

3

2

3

+

M – (CH ) C=NH – OCH ] , 58.1 (89) [(CH ) C=NH ] .

3

2

3

2

IR (Vaseline oil): 2724, 2683, 2639, 1643, 1605, 1519, 1494, 1461,

Anal. Calcd for C₂₄H₃₀N O : С, 76.16; Н, 7.99; N, 7.40. Found: С, 75.95;

2

1

414, 1379, 1362, 1358, 1257, 1240, 1219, 1179, 1157, 1142, 1106,

Н, 8.21; N, 7.03.

–1

087, 1020, 1006, 985, 855, 766 cm

.

H NMR (400 MHz, D O):  = 8.34 (br d, J = 8.5 Hz, 1 H), 8.28–8.22 (m,

2

2-(4,5-Dimethoxy-2-(1,2,3,4-tetrahydroacridin-9-yl)phenyl)-

1

H), 7.98 (s, 1 H), 7.96–7.89 (m, 2 H), 7.33 (s, 1 H), 7.11 (s, 1 H), 4.13

ethan-1-amine Dihydrobromide (3ha·2 HBr)

(s, 3 H), 3.94 (s, 3 H), 3.16 (s, 3 H), 3.15–3.03 (m, 2 H), 3.02–2.92 (m, 1

Prepared using 1h (99 mg, 0.35 mmol) and cyclohexanone (2a; 0.044

mL, 0.42 mmol); reaction time: 2.5 h. Quinoline 3ha was isolated as

the dihydrobromide salt, obtained by analogy with a literature proce-

H), 2.78–2.70 (m, 1 H).

13

C NMR (100 MHz, D O):  = 157.8 (C), 157.5 (C), 150.2 (C), 148.0 (C),

2

14

138.4 (C), 135.3 (CH), 130.3 (CH), 128.1 (2 C), 127.5 (CH), 127.2 (C),

25.1 (CH), 120.7 (CH), 113.9 (2 CH), 56.7 (OCH ), 56.6 (OCH ), 40.7

dure. The crude product was dissolved in MeOH (2 mL) and 33% HBr

in AcOH (0.22 mL) was added. The mixture was stirred at room tem-

perature for 30 min and concentrated in vacuo. The residue was dis-

solved in MeOH (2–3 mL) and concentrated in vacuo; this procedure

was then repeated three times. After, the crude residue was dissolved

in MeOH (1 mL) and i-PrOH (2.5 mL) was added. The mixture was left

to stand overnight at room temperature. The precipitated dihydro-

bromide salt was collected by filtration, washed with MeOH/i-PrOH

1

3

(

CH ), 30.6 (CH ), 20.8 (CH ).

2 2 3

+

MS (EI, 70 eV): free base m/z (%) = 322.1 (2) [M] , 293.1 (55) [M –

+

CH

276.1 (15) [M – CH

234.1 (5), 218.1 (6), 30.1 [CH

NH] , 292.1 (100) [M – CH

NH

] , 278.1 (10) [M – CH

NH

CH

– OCH

NH

] ,

2

+

NH

– CH

] , 260.1 (5) [M – CH

=NH ] (5).

] ,

3

2

3

2

3

+

2

_H_R_M_S₍_E_S_I₎_:_m_/_z_[_M_–₂_H_B_r₊_H_]+ calcd for C₂₀H₂₃N O : 323.1754;

2

(~1:2.5) and dried in a desiccator at room temperature.

found: 323.1754.

Yield: 114 mg (62%); yellow solid; mp: 265–267 °C (dec; compound

began to darken above 170 °C).

Anal. Calcd for C₂₀H₂₂N O ·2 HBr·0.7 H O·0.15 Et O: С, 48.71; Н, 5.34;

N, 5.51; Br, 31.46. Found: С, 48.62; Н, 5.21; N, 5.32; Br, 31.46.

2

IR (Vaseline oil): 2726, 2641, 1642, 1594, 1519, 1490, 1461, 1408,

1

8

1

379, 1362, 1286, 1256, 1220, 1165, 1154, 1106, 1087, 1019, 1003,

N-(2-(6,7-Dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolin-1-

yl)phenyl)acetamide (4)

–1

51, 761 cm

.

H NMR (400 MHz, D O):  = 8.28 (br d, J = 8.5 Hz, 1 H), 8.18 (ddd, J =

Pale yellow solid; mp 170–172 °C (hexane); R_f= 0.60 (CH Cl /

2

8

.5, 6.9, 1.3 Hz, 1 H), 7.88 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 Н), 7.73 (d, J = 8.1

Hz, 1 H), 7.36 (s, 1 Н), 6.99 (s, 1 Н), 4.13 (s, 3 Н), 3.93 (s, 3 Н), 3.55 (t,

J = 6.5 Hz, 2 Н), 3.14–2.96 (m, 2 Н), 2.92–2.58 (m, 4 Н), 2.26–2.09 (m,

MeOH/TEA, 98.5:1:0.5).

IR (thin film): 3246, 3064, 3007, 2965, 2934, 2833, 1690, 1605, 1581,

1

559, 1515, 1463, 1446, 1349, 1299, 1273, 1229, 1212, 1170, 1130,

2

Н), 2.07–1.94 (m, 2 Н).

–1

1094, 756 cm

.

©

N

Synthesis

Y. S. Rozhkova et al.

Paper

1

H NMR (400 MHz, CDCl ):  = 11.05 (br s, 1 Н), 8.27 (d, J = 8.0 Hz, 1

130, 73. (c) Nainwal, L. M.; Tasneem, S.; Akhtar, W.; Verma, G.;

Khan, M. F.; Parvez, S.; Shaquiquzzaman, M.; Akhter, M.; Alam,

M. M. Eur. J. Med. Chem. 2019, 164, 121. (d) Li, L.-H.; Niu, Z.-J.;

Liang, Y.-M. Chem. Asian J. 2020, 15, 231. (e) Orozco, D.;

Kouznetsov, V. V.; Bermúdez, A.; Vargas Méndez, L. Y.; Mendoza

Salgado, A. R.; Meléndez Gómez, C. M. RSC Adv. 2020, 10, 4876.

3) Pflum, D. A. Friedländer Quinoline Synthesis, In Name Reactions

in Heterocyclic Chemistry; Li, J.-J.; Corey, E. J., Ed.; Wiley-Inter-

science/John Wiley & Sons Inc: Hoboken, 2005, 411–415.

4) For reviews on the Friedländer reaction, see: (a) Cheng, C.-C.;

Yan, S.-I. Org. React. 1982, 28, 37. (b) Marco-Contelles, J.; Pérez-

Mayoral, E.; Samadi, A.; do Carmo Carreiras, M.; Soriano, E.

Chem. Rev. 2009, 109, 2652. (c) Shiria, M.; Zolfigol, M. A.;

Kruger, H. G.; Tanbakouchian, Z. Adv. Heterocycl. Chem. 2011,

3

Н), 7.44–7.38 (m, 1 Н), 7.32 (dd, J = 7.8, 1.5 Hz, 1 H), 7.10 (td, J = 7.7,

1

.1 Hz, 1 Н), 6.76 (s, 1 Н), 6.71 (s, 1 Н), 3.94 (s, 3 Н), 3.70 (s, 3 Н), 2.75

(s, 2 Н), 2.11 (s, 3 Н), 1.33 (s, 6 Н).

13

C NMR (100 MHz, CDCl ):  = 168.5 (C), 165.0 (C), 152.2 (C), 147.3

3

(C), 137.6 (C), 131.7 (C), 130.5 (CH), 130.3 (CH), 125.5 (C), 123.3 (CH),

(

1

22.9 (CH), 120.0 (C), 112.6 (CH), 111.2 (CH), 56.2 (OСН ), 56.1

3

(OСН ), 54.8 (C), 38.4 (СН ), 27.6 (2 СН ), 24.5 (СН ).

3

2

3

+

MS (EI, 70 eV): m/z (%) = 352.2 (27) [M] , 337.2 (100) [M – CH ] , 321.1

3

+

(16), 310.1 (16), 309.1 (42) [M – C(O)CH ] , 295.1 (13), 294.1 (20) [M –

3

+

NHC(O)CH ] , 279.1 (11).

3

Anal. Calcd for C₂₁H₂₄N O : С, 71.57; Н, 6.86; N, 7.95. Found: С, 71.20;

Н, 6.97; N, 7.73.

2

3

102, 139. (d) Fallah-Mehrjardi, M. Mini-Rev. Org. Chem. 2017, 14,

187.

Funding Information

(5) For some recent examples of the Friedländer reaction, see:

a) Chan, C.-K.; Lai, C.-Y.; Wang, C.-C. Synthesis 2020, 52, 1779.

(

This work was financially supported by the Russian Foundation for

Basic Research (grant 16-03-00561) and the Ministry of Science and

Higher Education of the Russian Federation (project АААА-А18-

(b) Shao, Y.-D.; Dong, M.-M.; Wang, Y.-A.; Cheng, P.-M.; Wang,

T.; Cheng, D.-J. Org. Lett. 2019, 21, 4831. (c) Das, A.; Anbu, N.;

Varalakshmi, P.; Dhakshinamoorthy, A.; Biswas, S. New J. Chem.

2020, 44, 10982. (d) Barman, M. K.; Jana, A.; Maji, B. Adv. Synth.

Catal. 2018, 360, 3233. (e) Chan, C.-K.; Lai, C.-Y.; Lo, W.-C.;

Cheng, Y.-T.; Chang, M.-Y.; Wang, C.-C. Org. Biomol. Chem. 2020,

18, 305. (f) Rahul, P.; Nitha, P. R.; Omanakuttan, V. K.; Babu, S.

A.; Sasikumar, P.; Praveen, V. K.; Hopf, H.; John, J. Eur. J. Org.

Chem. 2020, 3081.

118033090090-0).

R

u

si

a

n

F

o

u

n

d

ati

o

n

for

B

asi

c

R

esearc

h

(16-03-0

0

5

6

1)M

i

n

i

stry of

S

c

i

e

n

c

e

a

n

d

H

i

g

h

er

E

d

u

c

ati

o

n

of th

e

R

u

si

a

n

F

e

d

erati

o

n

(А

А

А-А

1

8-1

1

8

0

3

0

9

0

9

0-0)

Acknowledgment

The work was carried out using the equipment of The Core Facilities

Center ‘Research of Materials and Matter’ at the PFRC UB RAS.

(

6) (a) Borsche, W.; Barthenheier, J. Justus Liebigs Ann. Chem. 1941,

5

48, 50. (b) Borsche, W.; Ried, W. Justus Liebigs Ann. Chem. 1943,

54, 269.

Supporting Information

(

7) (a) Sridharan, V.; Ribelles, P.; Ramos, M. T.; Menéndez, J. C.

J. Org. Chem. 2009, 74, 5715. (b) Patteux, C.; Levacher, V.; Dupas,

G. Org. Lett. 2003, 5, 3061. (c) Mezhnev, V. V.; Dutov, M. D.;

Sapozhnikov, O. Y.; Kachala, V. V.; Shevelev, S. A. Mendeleev

Commun. 2007, 17, 234. (d) Leleu, S.; Papamicaël, C.; Marsais, F.;

Dupas, G.; Levacher, V. Tetrahedron: Asymmetry 2004, 15, 3919.

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706424.

S

u

p

orti

n

g Inform ati

o

n

S

u

p

orit

n

g Inform ati

o

n

References

(e) Vicente, J.; Chicote, M. T.; Martínez-Martínez, A. J. Tetrahe-

dron Lett. 2011, 52, 6298. (f) Vitry, C.; Vasse, J.-L.; Dupas, G.;

Levacher, V.; Quéguiner, G.; Bourguignon, J. Tetrahedron 2001,

(

1) For selected reviews on the biological activity of synthetic and

natural quinolines, see: (a) Syed, M. A. H. Expert Opin. Ther. Pat.

016, 26, 1201. (b) Razzaghi-Asl, N.; Sepehri, S.; Ebadi, A.;

Karami, P.; Nejatkhah, N.; Johari-Ahar, M. Mol. Diversity 2020,

4, 525. (c) Musiol, R. Expert Opin. Drug Discovery 2017, 12, 583.

d) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi,

57, 3087. (g) Beale, S. C.; Hsieh, Y.-Z.; Wiesler, D.; Novotny, M.

2

J. Chromatogr., A 1990, 499, 579.

(

8) (a) Vasse, J.-L.; Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahe-

dron 2003, 59, 4911. (b) Baumgarten, H. E.; Barkley, R. P.; Chiu,

S.-H. L.; Thompson, R. D. J. Heterocycl. Chem. 1981, 18, 925.

9) For selected examples, see: (a) Wang, S.; Coburn, C. A.;

Bornmann, W. G.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 611.

2

(

M.; Bawa, S. Eur. J. Med. Chem. 2015, 97, 871. (e) Püsküllü, M. O.;

Tekiner, B.; Suzen, S. Mini-Rev. Med. Chem. 2013, 13, 365.

(

(f) Singh, S.; Kaur, G.; Mangla, V.; Gupta, M. K. J. Enzyme Inhib.

(b) Ejima, A.; Terasawa, H.; Sugimori, M.; Tagawa, H. J. Chem.

Med. Chem. 2015, 30, 492. (g) Kaur, K.; Jain, M.; Reddy, R. P.; Jain,

R. Eur. J. Med. Chem. 2010, 45, 3245. (h) Fan, Y.-L.; Cheng, X.-W.;

Wu, J.-B.; Liu, M.; Zhang, F.-Z.; Xu, Z.; Feng, L.-S. Eur. J. Med.

Chem. 2018, 146, 1. (i) Hu, Y.-Q.; Gao, C.; Zhang, S.; Xu, L.; Xu, Z.;

Feng, L.-S.; Wu, X.; Zhao, F. Eur. J. Med. Chem. 2017, 139, 22.

Soc., Perkin Trans. 1 1990, 27. (c) Shen, W.; Grillet, F.; Sabot, C.;

Anderson, R.; Babjak, M.; Greene, A. E.; Kanazawa, A. Tetrahe-

dron 2011, 67, 2579.

(

10) (a) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1999,

1, 1953. (b) Gavara, L.; Boisse, T.; Hénichart, J.-P.; Daïch, A.;

5

(

j) Chung, P.-Y.; Bian, Z.-X.; Pun, H.-Y.; Chan, D.; Chan, A. S.-C.;

Chui, C.-H.; Tang, J. C.-O.; Lam, K.-H. Future Med. Chem. 2015, 7,

47. (k) Shang, X.-F.; Morris-Natschke, S. L.; Liu, Y.-Q.; Guo, X.;

Xu, X.-S.; Goto, M.; Li, J.-C.; Yang, G.-Z.; Lee, K.-H. Med. Res. Rev.

018, 38, 775. (l) Shang, X.-F.; Morris-Natschke, S. L.; Yang, G.-

Rigo, B.; Gautret, P. Tetrahedron 2010, 66, 7544.

(

11) For selected examples, see: (a) Lerchen, A.; Knecht, T.; Koy, M.;

Daniliuc, C. G.; Glorius, F. Chem. Eur. J. 2017, 23, 12149.

9

(b) Brunin, T.; Hénichart, J.-P.; Rigo, B. Tetrahedron 2005, 61,

2

7916. (c) Yoneda, R.; Kimura, T.; Harusawa, S.; Kurihara, T. Het-

Z.; Liu, Y.-Q.; Guo, X.; Xu, X.-S.; Goto, M.; Li, J.-C.; Zhang, J.-Y.;

Lee, K.-H. Med. Res. Rev. 2018, 38, 1614.

erocycles 1997, 46, 357. (d) Babjak, M.; Kanazawa, A.; Anderson,

R. J.; Greene, A. E. Org. Biomol. Chem. 2006, 4, 407. (e) Boisse, T.;

Gavara, L.; Gautret, P.; Baldeyrou, B.; Lansiaux, A.; Goossens, J.-

F.; Hénichart, J.-P.; Rigo, B. Tetrahedron Lett. 2011, 52, 1592.

(2) For selected reviews on recent advances in the synthesis of

quinolines, see: (a) Ramann, G. A.; Cowen, B. J. Molecules 2016,

21, 986. (b) Sharma, R.; Kour, P.; Kumar, A. J. Chem. Sci. 2018,

©

O

Synthesis

Y. S. Rozhkova et al.

Paper

(

12) (a) Luo, F.-T.; Ravi, V. K.; Xue, C. Tetrahedron 2006, 62, 9365.

b) Mamedov, V. A.; Kadyrova, S. F.; Zhukova, N. A.; Galimullina,

V. R.; Polyancev, F. M.; Latypov, S. K. Tetrahedron 2014, 70, 5934.

(13) CCDC 1945600 (3a) and 1945601 (3ad) contain the supplemen-

tary crystallographic data for this paper. The data can be

obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/getstructures.

(

(14) Slowinski, F.; Ben Ayad, O.; Vache, J.; Saady, M.; Leclerc, O.;

Lochead, A. J. Org. Chem. 2011, 76, 8336.

©

Article Doi

Synthesis of Aminoalkyl-Functionalized 4-Arylquinolines from 2-(3,4-Dihydroisoquinolin-1-yl)anilines via the Friedl?nder Reaction

DOI: 10.1055/s-0040-1706424

Source and publish data:

Authors:

Article abstract of DOI:10.1055/s-0040-1706424

Full text of DOI:10.1055/s-0040-1706424

Products guided by the article

R&D Labs maybe for 22276-64-8

Relevant to this article

Hot Product