Transition-Metal-Free Synthesis of Pyrrolo[1,2- a ]pyrazines via Intramolecular Cyclization of N -Propargyl(pyrrolyl)enaminones

SYNTHESIS

0

3

9

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7

8

1

4

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7

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2017, 49, A–Q

paper

A

en

L. N. Sobenina et al.

Paper

Synthesis

Transition-Metal-Free Synthesis of Pyrrolo[1,2-a]pyrazines via

Intramolecular Cyclization of N-Propargyl(pyrrolyl)enaminones

R²

Lyubov’ N. Sobenina

Elena F. Sagitova

Igor’ A. Ushakov

Boris A. Trofimov*

R³

R¹

N

R²

O

NH

R³

H₂N

11 examples

up to 96% yield

Cs₂CO₃, DMSO

60 °C, 15–30 min

R²

R¹

+

O

N

H

N

H

Unsaturated Heteroatomic Compounds Laboratory,

A. E. Favorsky Irkutsk Institute of Chemistry, Siberian

Branch, Russian Academy of Sciences, 1 Favorsky Str.,

664033 Irkutsk, Russian Federation

O

MeOH, reflux, 5 h

NH

R³

R¹

N

O

NH

boris_trofimov@irioch.irk.ru

Me

Received: 07.04.2017

Accepted after revision: 12.05.2017

Published online: 11.07.2017

proliferative,¹¹antimalarial,¹²and antibacterial proper-

ties.¹³Compounds containing the pyrrolo[1,2-a]pyrazine

core are known to act as inhibitors of HIV-1 integrase,¹⁴ki-

nase¹⁵and ERK2,¹⁶5-HT_2C¹⁷and 5-HT3¹⁸agonists, antago-

nists of vasopressin_1b,¹⁹selective noncompetitive mGluR5,²⁰

and cb1-modulators.²¹Over the past decades, many syn-

thetic methodologies to prepare pyrrolo[1,2-a]pyrazines

have been reported. For example, Pd-catalyzed intramolec-

ular cyclization of pyrrole-2-carboxamides,²²TiCl₄-cata-

lyzed cyclization of 2-acetyl-N-propargylpyrrole,²³reaction

of pyrrole-2-carbaldehydes and vinyl azides,²⁴Curtis reac-

tion in Morita–Baylis–Hillman derivatives,²⁵AuCl₃-cata-

lyzed intermolecular addition of pyrazoles to N-propar-

gylpyrrole,²⁶and reaction of propargylamines with pyra-

zine with subsequent Pd-catalyzed intramolecular

cyclization of intermediate propargylpyrazines¹⁰have been

documented. However, most of them require transition

metals or are limited by substrate unavailability or com-

plexity.

Herein we describe a concise transition-metal-free

strategy for the synthesis of pyrrolo[1,2-a]pyrazines start-

ing from available N-propargyl(pyrrolyl)enaminones

(Scheme 1). The strategy includes the following three steps:

(a) the non-catalyzed cross-coupling of pyrroles 1a–i with

acyl(bromo)acetylenes 2a–c in a solid Al₂O₃medium ac-

cording to a known methodology²⁷adapted to the starting

pyrroles 1a–i to give 2-(acylethynyl)pyrroles 3a–n; (b) the

non-catalyzed chemo- and regioselective nucleophilic addi-

tion of propargylamine to the triple bond of 2-(acyl-

ethynyl)pyrroles 3a–n to afford N-propargyl(pyr-

rolyl)enaminones 4a–n; and (c) base-catalyzed intramolec-

ular cyclization of N-propargyl(pyrrolyl)enaminones 4a–k

to pyrrolo[1,2-a]pyrazines 5c–k and 6a–k.

DOI: 10.1055/s-0036-1588454; Art ID: ss-2017-z0230-op

Abstract A concise transition-metal-free strategy for the synthesis of

pyrrolo[1,2-a]pyrazines with enone substituents has been developed. It

includes the following key steps: (a) cross-coupling of pyrroles with

acyl(bromo)acetylenes in solid alumina at room temperature to give 2-

(acylethynyl)pyrroles; (b) addition of propargylamine to the above acet-

ylenes to form the corresponding N-propargylenaminones; and (c) che-

mo- and stereoselective base-catalyzed (Cs₂CO₃/DMSO) intramolecular

cyclization of the synthesized propargylic derivatives to form (acylmeth-

ylidene)pyrrolo[1,2-a]pyrazines of Z-configuration.

Key words pyrroles, acylacetylenes, enaminones, intramolecular cy-

clization, pyrrolo[1,2-a]pyrazines

Condensed nitrogen-containing heterocycles are of

great interest because of their unique properties, in partic-

ular the wide spectrum of pharmacological activities.

Versatile starting materials for the design of heterocy-

clic compounds, including condensed ones, are enami-

nones, due to the ambident electrophilicity of the enone

and the nucleophilicity of the enamine moieties.¹A variety

of intramolecular reactions of enaminones leading to pyrro-

lines,²pyrroles,³indoles,⁴pyrazoles,⁵dihydropyridines,⁶

pyridines,^3cpyrimidines,⁷and isoxazoles⁸have been imple-

mented. Among the great diversity of enaminones, pyr-

rolylenaminones have, until now, remained insufficiently

known, despite their great synthetic potential. These com-

pounds combine practically inexhaustible synthetic poten-

tial due to the pyrrole nucleus, the functional aminoethene,

and the carbonyl group, making them outstanding flexible

starting materials for the design of azaheterocycles, in par-

ticular pyrrolo[1,2-a]pyrazines.

Pyrrolo[1,2-a]pyrazines are important templates from a

medicinal perspective, with excellent pharmacological ac-

tivities including anticancer,⁹anti-inflammatory,^10,11anti-

B

L. N. Sobenina et al.

Paper

Synthesis

O

the E-isomers is due to the intramolecular H-bonding with

the participation of the pyrrole NH function.

R³

Br

H₂N

R⁴

2a–c

R²

O

R²

N

R¹

The electronic nature of the substituents attached to the

pyrrole ring determines the isomeric ratio. Thus, for enami-

none 4a with an unsubstituted pyrrole ring, the Z/E ratio is

~9:1. When the donor cyclohexane moiety is attached to

the pyrrole ring (enaminone 4b), this ratio becomes 15:1,

probably owing to a lower NH acidity of the pyrrole coun-

terpart and hence a weaker stabilization of isomer E by in-

tramolecular H-bonding. Consequently, for pyrroles with

electron-withdrawing aryl substituents (compounds 4c,g–

k), resulting in a more acidic pyrrole NH proton, the con-

tent of isomer E increases, with a Z/E ratio of ~4:1. Note-

worthy is that in the case of 2-FC₆H₄-substituents (com-

pounds 4d–f), the content of isomer E drops dramatically

(Z/E ratio ~8:1 to 10:1); this can be explained by the com-

peting intramolecular F···NH bonding resulting in destabili-

zation of the E-isomer (Figure 1).

Al₂O₃

R¹

R⁴

1a–i

3a–n

R³

R⁴

Cs₂CO₃, DMSO

R⁴

R²

N

R²

N

O

+

O

NH

O

NH

6a–k

NH

5c–k

H

Me

4a–n

Scheme 1 Synthesis of pyrrolo[1,2-a]pyrazines from N-propargyl(pyr-

rolyl)enaminones

Most 2-(acylethynyl)pyrroles are unknown compounds,

e.g. 3a,d–m (Scheme 2); their synthesis demonstrates once

again the wide substrate scope and generality of the

straightforward alkynylation of the pyrrole ring with halo-

acetylenes in solid metal oxides or salts as reaction media²⁷

(an essential complement to Sonogashira coupling).

H

Nucleophilic addition of propargylamine to the triple

bond of 2-(acylethynyl)pyrroles 3a–n was carried out un-

der reflux (ratio 3/propargylamine = 1:2) in methanol for

five hours to deliver N-propargyl(pyrrolyl)enaminones 4a–

n in yields of up to 85% (Scheme 3). Enaminones 4a–k are

formed as mixtures of E/Z isomers stabilized by intramolec-

ular H-bonds between the carbonyl group and the NH func-

tion of the amino moiety (Z-isomer) or the NH function of

the pyrrole ring (E-isomer) with a predominance of the Z-

isomer (Scheme 3). In the case of N-propargyl(pyr-

rolyl)enaminones 4l–n, having no pyrrole NH function, only

Z-isomers are formed. This confirms that the appearance of

N

...

F

H

O

R

Figure 1 Intramolecular H-bonding in compounds 4d–f

The reaction of 2-(acylethynyl)pyrroles 3 with propar-

gylamine leading to enaminones 4 is accompanied by the

formation of 2-acetylpyrroles 7 (mainly 15–17%) (Scheme

4). These probably result from nucleophilic addition of wa-

ter to adducts 4 and subsequent decomposition of interme-

R³

O

Al₂O₃

+

R²

Br

R²

O

r.t., 1 h

N

R¹

3a–n

N

R¹

1a–i

R⁴

2a–c

R⁴

F

O

N

H

O

N

H

N

H

N

H

N

H

O

3a, 55%

3d, 62%

3e, 59%

3b, 54%

3c, 50%

F

O

N

O

N

H

N

H

3f, 57%

3g, 68%

3h, 63%

3i, 76%

O

S

F

O

N

O

N

H

Me

F

H

F

Me

3n, 68%

S

3j, 59%

3k, 64%

3l, 50%

3m, 71%

Scheme 2 The synthesis of 2-(acylethynyl)pyrroles 3a–n by cross-coupling of pyrroles 1a-I with acyl(bromo)acetylenes 2a–c (ratio 1/2 = 1:1; Al₂O₃

used in 10-fold mass excess).Compounds 3b,c^27aand 3n^27cwere prepared according to literature procedures.

C

L. N. Sobenina et al.

Paper

Synthesis

R³

H₂N

N

H

R²

N

H

R²

N

O

.

+

.

N

R¹

H

O

MeOH, reflux, 5 h

.

R¹

O

R⁴

3a–n

R⁴

(Z)-4a–n

(E)-4a–k

F

N

H

N

H

N

H

N

H

N

H

N

H

O

N

H

O

H

4a, 50%

Z/E, 9:1

4b, 66%

Z/E, 15:1

4c, 50%

Z/E, 4.6:1

4d, 49%

Z/E, 10:1

4e, 65%

Z/E, 8:1

O

F

N

H

N

H

N

H

N

H

N

H

N

H

O

F

O

H

4g, 43%

Z/E, 4:1

4j, 46%

Z/E, 3.7:1

4f, 49%

Z/E, 10:1

4h, 44%

Z/E, 4:1

4i, 46%

Z/E, 4:1

S

O

S

F

N

H

N

H

O

H

O

H

O

N

H

O

F

Me

4l, 85%

4k, 42%

Z/E, 4:1

4m, 75%

4n, 64%

S

Scheme 3 Synthesis of 3-(prop-2-ynylamino)-3-(pyrrol-2-yl)propenones 4a–n

diates 8 to give diketones 9, which add a second molecule of

water; the intermediates 10 thus formed decompose to 2-

acetylpyrroles 7 and the corresponding acid (Scheme 4).

Such a reaction mechanism has been proved previously.²⁸

The direct nucleophilic addition of water to the triple bond

of 2-(acylethynyl)pyrroles 3 to generate diketones 9 is also a

possibility (Scheme 5).

R³

O

R²

H₂O

O

N

R¹

N

R¹

O

R⁴

9

3

R⁴

Scheme 5 The formation of diketones 9 from 2-(acylethynyl)pyrroles 3

R³

tions analogous to those in Schemes 4 and 5. In some cases

(e.g., with ethynylpyrroles 3i,k), these adducts (compounds

11a,b) have been isolated and characterized.

R³

OH

HO

R²

N

R¹

H₂O

H

R²

O

R²

N

R¹

N

R¹

O

H N

2

–

R⁴

R³

4

8

R⁴

R³

OMe

R²

N

R³

O

R³

O

R¹

R²

N

R¹

O

R⁴

H₂O

Me

R²

7

N

R¹

N

R¹

10

O

OH

R⁴

Figure 2 Side products 11a,b formed from ethynylpyrroles 3i,k

+

R⁴

O

R⁴

HO

9

OH

Interestingly, the formation of the target pyrrolo[1,2-

a]pyrazines 5 in small amounts (2–5%) was observable (¹H

NMR) already during the addition of propargylamine to 2-

(acylethynyl)pyrroles 3 (Scheme 6). In this connection, it

might be expected that in the presence of a strong base

(KOH in DMSO, Cs₂CO₃in DMSO), this intramolecular cy-

clization would proceed to a greater extent. We started to

Scheme 4 The formation of 2-acetylpyrroles 7 from enaminones

Other side products, present in the reaction mixtures in

minor quantities (~10%), are 3-methoxy-3-(pyrrol-2-

yl)propenones 11 (Figure 2). They can be formed by reac-

D

L. N. Sobenina et al.

Paper

Synthesis

study this cyclization from enaminone 4b by using the

KOH/DMSO system (Scheme 7). As the experiments

showed, the expected cyclization occurs smoothly even at

room temperature (1.5 h) to form pyrrolopyrazine 6b al-

O

N

. O

.

NH

5e

O

F

KOH, DMSO

60 °C, 20 min

N

H

1

O

most quantitatively (98%, H NMR). The process is strictly

NH

+

F

stereoselective: only the Z-isomer is formed, apparently

due to a strong intramolecular H-bonding between the pyr-

azine NH and the carbonyl group and because of the steric

repulsion between the benzoyl methylene substituent and

the β-pyrrole hydrogen in the adverse isomer (Scheme 7).

O

4e

N

. O

.

NH

F

Me

6e

Scheme 8 Cyclization of enaminone 4e in the KOH/DMSO system

R³

R⁴

H₂N

erizes to the corresponding endocyclic form. Next, by using

the catalytic system Cs₂CO₃/DMSO we explored the scope

and generality of the cyclization. The temperature of the re-

action was always 60 °C, and the duration of the process,

determined by the disappearance of the starting enami-

none 4 (TLC control), was in the range of 15–30 minutes

(Scheme 9).

R⁴

R²

N

H

N

H

O

NH

MeOH, reflux, 5 h

O

3a–k

4a–k

R³

R⁴

MeOH

reflux

R²

N

O

NH

The initial 5/6 isomer ratio seems to be kinetically de-

termined, since further heating under the reaction condi-

tions results in predominance of the thermodynamically

more stable isomer 6 with the endocyclic double bonds (Table

1). The kinetic preference for isomer 5 can be explained by

the smaller steric repulsion between the hydrogen of the

methylene group and the ortho hydrogen of the aryl sub-

stituents when compared to that which might take place in

isomers 6. According to this, it is no surprise that isomers 5

further shift their double bond inside the pyrazine cycle to

gain better conjugation, i.e. to reach more thermodynamic

stability.

5a–k

Scheme 6 The formation of pyrrolo[1,2-a]pyrazines 5 from (acyl-

ethynyl)pyrroles 3 and propargylamine in methanol

Ph

N

KOH, DMSO

N

H

. O

.

NH

5b

O

NH

4b

Ph

N

Table 1 Isomer Ratio Shift upon Heating of Enaminones 4c,e,h in the

System K₂CO₃/DMSO

. O

.

NH

6b

Me

Scheme 7 The formation of pyrrolo[1,2-a]pyrazine 6b by cyclization of

enaminone 4b in the KOH/DMSO system

Heating time

Isomer ratios 5/6

5c/6c^a

5e/6e^b

5h/6h^b

20 min

0:1

4:1

2:3

1:9

4:1

c

120 min

240 min

360 min

–

As follows from the structure of the pyrrolopyrazine ob-

tained (Scheme 7), the initially formed pyrazine 5b with

the exocyclic double bond, in this case, completely isomeri-

zes to the endocyclic isomer 6b, obviously thermodynami-

cally more stable. At 60 °C the cyclization process is com-

pleted within 20 minutes, the yield remaining the same.

However, enaminone 4e appears to be more reluctant to-

wards cyclization: at 20 °C for 3.5 hours it cyclizes to form

pyrrolopyrazine 5e in only 38% yield, while the endocyclic

isomer 6e is undetectable. However, at 60 °C for just 20

minutes, the total yield of the mixture (1:2 ratio) of exo-

(5e) and endocyclic (6e) tautomers reaches 95% (Scheme 8).

When the above mixture of isomers is heated at 60 °C in

the presence of Cs₂CO₃for 15 minutes, only isomer 6e is ob-

tained (¹H NMR), i.e. the exocyclic isomer completely isom-

c

–

1:4

c

–

^aReaction temperature was 80 °C.

^bReaction temperature was 60 °C.

^cNot determined.

The cyclization might be preceded by propargyl-to-

allenyl prototropic isomerization followed by nucleophilic

attack of the pyrrole NH function at the central carbon

atom of the allenyl moiety, as is common for allenes,²⁹to

produce 6-exo-dig cyclization products 5 (Scheme 10).

Such a suggestion is based on the fact that propargylic

heteroatomic compounds, e.g. propargylic ethers, in super-

basic systems such as KOH/DMSO isomerize to the corre-

sponding allenes almost instantly at room temperature.³⁰

E

L. N. Sobenina et al.

Paper

Synthesis

R³

R⁴

R²

N

R²

N

Cs₂CO₃, DMSO

N

O

+

O

NH

O

NH

6a–k

NH

5c–k

H

60 °C, 15–30 min

Me

4a–k

O

N

O

NH

6c

NH

O

NH

Me

5c

6a, 92%^a

6b, 90%^a

93%, 5c:6c, 4:1^b

F

O

N

O

NH

6e

O

NH

6d

Me

5d

5e

91%, 5e:6e, 4:1^b

95%, 5d:6d,8.5:1.5^b,c

F

S

N

O

NH

6f

O

NH

6g

Me

5f

5g

95%, 5f:6f, 4:1^b

95%, 5g:6g, 4:1^b

F

S

O

N

O

NH

O

NH

6h

NH

Me

5h

5i

6i

95%, 5i:6i, 7:3^b,c

96%, 5h:6h, 4:1^b

S

N

F

N

F

O

F

NH

6j

O

F

O

NH

6k

NH

O

NH

Me

5j

5k

95%, 5k:6k, 3:1^b

95%, 5j:6j, 9:1^b

Scheme 9 Cyclization of enaminones 4 in the Cs₂CO₃/DMSO system. Reagents and conditions: enaminone 4 (1 equiv), Cs₂CO₃(1 equiv), DMSO, 60 °C,

under argon. ^aReaction time 15 min. ^bReaction time 30 min. ^cTautomers not separated.

However, N-substituted propargylic enaminones 4l–n,

which are unable to cyclize into pyrrolopyrazines, have

been isolated intact from the reaction mixture under the

same conditions. It follows that the pyrrole NH function is

added to the propargylic group without its preliminary

prototropic isomerization. For N-substituted derivatives

4l–n, another type of ring-closing reaction can be anticipat-

ed (Scheme 11) in view of the known cyclization of N-pro-

pargyl-β-enaminones with alkyl and aryl substituents to

pyrroles in the presence of the same superbasic system

Cs₂CO₃/DMSO.^3cBut, as shown in Scheme 11, such a cycliza-

tion is not realized in this case at all.

R³

R⁴

R²

Cs₂CO₃, DMSO

N

H

O

N

H

O

NH

.

4

R³

R⁴

H

R²

Cs₂CO₃, DMSO

N

H

N

R²

N

O

N

R¹

NH

O

R¹

O

Me

5

R⁴

4l–n

Scheme 10 Cyclization of enaminones 4 into pyrrole[1,2-a]pyrazines 5

through propargyl-to-allenyl prototropic isomerization

Scheme 11 The probable formation of pyrroles from N-substituted

enaminones 4l–n

F

L. N. Sobenina et al.

Paper

Synthesis

As the experiments show, the isomeric mixtures are

separable, and each of the two components can be isolated

by column chromatography (alumina). However, with the

possibility to completely shift the isomer ratio from 5 to 6,

the selective synthesis of both sets of pyrrolopyrazines may

be considered as secured.

¹³C NMR (101 MHz, CDCl₃): δ = 164.9 (C=O), 153.1 (C-2 furan), 147.9

(C-5 furan), 124.0 (C-5 pyrrole), 120.9 (C-3 pyrrole), 120.4 (C-3 furan),

112.7 (C-4 furan), 110.7 (C-4 pyrrole), 109.9 (C-2 pyrrole), 91.2 (≡C),

87.9 (C≡).

Anal. Calcd for C₁₁H₇NO₂: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.03;

H, 3.77; N, 7.64.

We have developed an efficient approach providing pyr-

rolo[1,2-a]pyrazines with enone substituents in good to

high yields. This approach is based on the cross-coupling of

pyrroles with acyl(bromo)acetylenes in solid alumina as

medium, the addition of propargylamine to the formed 2-

(acylethynyl)pyrroles, and chemo- and stereoselective

base-catalyzed (Cs₂CO₃/DMSO) intramolecular cyclization

of the synthesized propargylic derivatives. The synthesized

pyrrolopyrazines consist of highly reactive enone structural

units with aromatic, furyl, and thienyl substituents that es-

sentially strengthen their synthetic potential and consider-

ably extend their application scope as building blocks for

organic synthesis and drug precursors.

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenylprop-2-yn-1-one

(3d)

Yield: 179 mg (62%); yellow crystals; mp 141–142 °C.

IR (KBr): 3382, 3131, 3062, 2171, 1619, 1597, 1574, 1556, 1496, 1467,

1446, 1407, 1332, 1315, 1244, 1218, 1175, 1113, 1044, 1021, 965,

940, 844, 808, 780, 753, 695, 663, 645, 618, 586, 530, 497 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.46 (br s, 1 H, NH), 8.20–8.19 (m, 2 H,

H-2,6 COPh), 7.68–7.61 (m, 2 H, H-6 C₆H₄F, H-4 COPh), 7.55–7.51 (m,

2 H, H-3,5 COPh), 7.30–7.15 (m, 3 H, H-3,4,5 C₆H₄F), 6.95 (dd, J = 3.9,

2.2 Hz, 1 H, H-3 pyrrole), 6.71 (dd, J = 3.9, 2.5 Hz, 1 H, H-4 pyrrole).

¹³C NMR (101 MHz, CDCl₃): δ = 177.6 (C=O), 159.1 (d, ¹J_CF= 246.5 Hz,

C-2 C₆H₄F), 136.9 (C-1 COPh), 133.9 (C-4 COPh), 131.9 (C-5 pyrrole),

3

129.4 (C-3,5 COPh), 129.0 (d, J_CF= 8.6 Hz, C-4 C₆H₄F), 128.6 (C-2,6

3

4

COPh), 127.3 (d, J_CF= 3.5 Hz, C-6 C₆H₄F), 124.9 (d, J_CF= 2.6 Hz, C-5

C₆H₄F), 121.8 (C-3 pyrrole), 118.7 (d, ²J_CF= 10.8 Hz, C-1 C₆H₄F), 116.6

(d, ²J_CF= 22.8 Hz, C-3 C₆H₄F), 111.2 (C-2 pyrrole), 109.9 (C-4 pyrrole),

93.0 (≡C), 88.4 (C≡).

IR spectra were obtained on a Bruker IFS-25 spectrophotometer (KBr

pellets or films, 400–4000 cm^–1region). ¹H (400 MHz) and ¹³C (101

MHz) NMR spectra were recorded on a Bruker Avance 400 instru-

ment; samples were dissolved in CDCl₃or acetone-d₆. Signals in the

¹H NMR spectra were assigned with the aid of COSY and NOESY ex-

periments. Resonance signals of carbon atoms were assigned on the

basis of ¹H–¹³C HSQC and ¹H–¹³C HMBC experiments. The ¹H chemical

shifts (δ) were referenced to HMDS (δ = 0.05) in CDCl₃and the residu-

al deuterated solvent (δ = 2.05 for acetone-d₆); the ¹³C chemical shifts

were referenced against the deuterated solvent (δ = 77.10, CDCl₃; δ =

29.84, acetone-d₆). The ¹⁹F chemical shifts were referenced to CFCl₃

(δ = 0.0). Coupling constants (Hz) were determined from one-dimen-

sional spectra. The (C, H, N, S) microanalyses were performed on a

Flash EA 1112 CHNS-O/MAS (CHN Analyzer) instrument. Fluorine

content was determined on a SPECOL 11 (Carl Zeiss Jena, Germany)

spectrophotometer. Melting points (uncorrected) were determined

with the melting point instrument SMP3 (Stuart Scientific).

Anal. Calcd for C₁₉H₁₂FNO: C, 78.88; H, 4.18; F, 6.57; N, 4.84. Found: C,

78.61; H, 3.87; F, 6.94; N, 4.98.

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-furyl)prop-2-yn-1-

one (3e)

Yield: 165 mg (59%); yellow crystals; mp 128–129 °C.

IR (KBr): 3312, 3147, 2181, 1632, 1584, 1557, 1510, 1459, 1394, 1314,

1261, 1214, 1162, 1079, 1049, 1016, 975, 912, 882, 812, 781, 750,

730, 690, 650, 596 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.42 (br s, 1 H, NH), 7.70–7.69 (dd, J =

1.7, 0.7 Hz, 1 H, H-5 furan), 7.67–7.63 (m, 1 H, H-6 C₆H₄F), 7.39 (dd, J =

3.5, 0.7 Hz, 1 H, H-3 furan), 7.30–7.15 (m, 3 H, H-3,4,5 C₆H₄F), 6.91–

6.90 (m, 1 H, H-3 pyrrole), 6.70–6.69 (m, 1 H, H-4 pyrrole), 6.61 (dd,

J = 3.5, 1.7 Hz, 1 H, H-4 furan).

¹³C NMR (101 MHz, acetone-d₆): δ = 164.3 (C=O), 160.0 (d, ¹J_CF= 247.9

Hz, C-2 C₆H₄F), 154.0 (C-2 furan), 149.2 (C-5 furan), 132.2 (d, ³J_CF= 3.0

Hz, C-5 pyrrole), 130.1 (d, ³J_CF= 8.7 Hz, C-4 C₆H₄F), 128.3 (d, ³J_CF= 3.3

Hz, C-6 C₆H₄F), 125.8 (d, ⁴J_CF= 3.3 Hz, C-5 C₆H₄F), 122.6 (C-3 pyrrole),

2-(Acylethynyl)pyrroles 3a–n; General Procedure

Pyrrole 1a–i (1 mmol) and acyl(bromo)acetylene 2a–c (1 mmol) were

carefully ground in a porcelain mortar with alumina [10-fold amount

by weight of combined mass of pyrrole and acyl(bromo)acetylene] at

r.t. for 5 min. The reaction mixture was left for 1 h. Then the mixture

was subjected to column chromatography (alumina, hexane, then

hexane–Et₂O, 1:1); this afforded pure 2-(acylethynyl)pyrroles 3a–n.

The spectral characteristics of 2-(acylethynyl)pyrroles 3b,c^27aand

3n^27cwere previously reported.

2

121.2 (C-3 furan), 120.1 (d, J_CF= 12.2 Hz, C-1 C₆H₄F), 117.2 (d, J_CF

=

22.4 Hz, C-3 C₆H₄F), 113.5 (C-4 furan), 112.0 (d, ⁴J_CF= 2.1 Hz, C-4 pyr-

role), 111.8 (C-2 pyrrole), 92.0 (≡C), 86.8 (C≡).

¹⁹F NMR (377 MHz, acetone-d₆): δ = –116.0.

Anal. Calcd for C₁₇H₁₀FNO₂: C, 73.11; H, 3.61; F, 6.80; N, 5.02. Found:

C, 72.71; H, 3.86; F, 6.94; N, 4.98.

1-(2-Furyl)-3-(1H-pyrrol-2-yl)prop-2-yn-1-one (3a)

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-thienyl)prop-2-yn-1-

Yield: 102 mg (55%); yellow crystals; mp 108–110 °C.

one (3f)

Yield: 168 mg (57%); yellow crystals; mp 154–155 °C.

IR (KBr): 3211, 3118, 3090, 2182, 1605, 1568, 1461, 1428, 1390, 1320,

1271, 1234, 1162, 1134, 1109, 1022, 961, 907, 881, 822, 743, 594, 514

IR (KBr): 3320, 3082, 2178, 1603, 1579, 1511, 1468, 1454, 1408, 1383,

1354, 1316, 1249, 1218, 1190, 1112, 1080, 1061, 1046, 1025, 940,

cm^–1

.

854, 812, 782, 756, 719, 680, 664, 644, 630, 560, 448 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 8.80 (br s, 1 H, NH), 7.68–7.67 (m, 1 H,

H-5 furan), 7.38–7.37 (m, 1 H, H-3 furan), 6.99–6.98 (m, 1 H, H-5 pyr-

role), 6.86–6.85 (m, 1 H, H-3 pyrrole), 6.59 (dd, J = 3.2, 1.6 Hz, 1 H, H-4

furan), 6.31 (m, 1 H, H-4 pyrrole).

G

L. N. Sobenina et al.

Paper

Synthesis

¹H NMR (400 MHz, acetone-d₆): δ = 11.52 (br s, 1 H, NH), 8.09 (dd, J =

3.9, 1.0 Hz, 1 H, H-3 thiophene), 7.99 (dd, J = 4.9, 1.0 Hz, 1 H, H-5 thio-

phene), 7.86–7.82 (m, 1 H, H-6 C₆H₄F), 7.40–7.35 (m, 1 H, H-4 C₆H₄F),

7.30–7.24 (m, 3 H, H-4 thiophene, H-3,5 C₆H₄F), 7.02 (dd, J = 4.1, 2.2

Hz, 1 H, H-3 pyrrole), 6.78 (dd, J = 4.1, 2.5 Hz, 1 H, H-4 pyrrole).

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-thienyl)prop-2-yn-1-

one (3i)

Yield: 224 mg (76%); yellow crystals; mp 176–178 °C.

IR (KBr): 3283, 3151, 3110, 3065, 2172, 1601, 1563, 1509, 1470, 1450,

1407, 1357, 1312, 1249, 1235, 1187, 1083, 1046, 1023, 957, 936, 863,

¹³C NMR (101 MHz, acetone-d₆): δ = 169.4 (C=O), 160.0 (d, ¹J_CF= 248.0

844, 781, 722, 683, 637, 551, 519 cm^–1

.

Hz, C-2 C₆H₄F), 145.8 (C-2 thiophene), 136.0 (C-5 thiophene), 135.8

¹H NMR (400 MHz, acetone-d₆): δ = 11.55 (br s, 1 H, NH), 8.06 (dd, J =

3.9, 1.0 Hz, 1 H, H-3 thiophene), 7.99 (dd, J = 4.9, 1.0 Hz, 1 H, H-5 thio-

phene), 7.63–7.61 (m, 1 H, H-6 C₆H₄F), 7.57–7.54 (m, 1 H, H-2 C₆H₄F),

7.50–7.45 (m, 1 H, H-5 C₆H₄F), 7.30 (dd, J = 4.9, 3.9 Hz, 1 H, H-4 thio-

phene), 7.10–7.05 (m, 1 H, H-4 C₆H₄F), 6.99 (dd, J = 3.9, 2.2 Hz, 1 H, H-

3 pyrrole), 6.82 (dd, J = 3.9, 2.5 Hz, 1 H, H-4 pyrrole).

3

(C-3 thiophene), 132.3 (C-5 pyrrole), 130.1 (d, J_CF= 8.5 Hz, C-4

C₆H₄F), 129.4 (C-4 thiophene), 128.3 (d, ³J_CF= 3.1 Hz, C-6 C₆H₄F), 125.8

4

2

(d, J_CF= 3.3 Hz, C-5 C₆H₄F), 122.7 (C-3 pyrrole), 120.1 (d, J_CF= 12.2

Hz, C-1 C₆H₄F), 117.2 (d, ²J_CF= 22.2 Hz, C-3 C₆H₄F), 112.0 (d, ⁴J_CF= 2.5

Hz, C-4 pyrrole), 111.8 (C-2 pyrrole), 91.9 (≡C), 87.2 (C≡).

Anal. Calcd for C₁₇H₁₀FNOS: C, 69.14; H, 3.41; F, 6.43; N, 4.74; S, 10.86.

Found: C, 68.85; H, 3.54; F, 6.81; N, 5.08; S, 10.48.

¹³C NMR (101 MHz, acetone-d₆): δ = 169.4 (C=O), 164.2 (d, ¹J_CF= 243.5

Hz, C-3 C₆H₄F), 145.9 (C-2 thiophene), 137.0 (d, ⁴J_CF= 2.5 Hz, C-5 pyr-

role), 136.0 (C-5 thiophene), 135.6 (C-3 thiophene), 134.6 (d, ³J_CF= 8.6

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenylprop-2-yn-1-one

(3g)

3

Hz, C-1 C₆H₄F), 131.9 (d, J_CF= 8.6 Hz, C-5 C₆H₄F), 129.4 (C-4 thio-

4

phene), 123.0 (C-3 pyrrole), 121.5 (d, J_CF= 2.6 Hz, C-6 C₆H₄F), 114.9

(d, ²J_CF= 21.6 Hz, C-4 C₆H₄F), 112.2 (d, ²J_CF= 23.7 Hz, C-2 C₆H₄F), 112.1

(C-2 pyrrole), 109.9 (C-4 pyrrole), 92.0 (≡C), 87.2 (C≡).

Yield: 197 mg (68%); yellow crystals; mp 184–185 °C.

IR (KBr): 3305, 3129, 3062, 2165, 1629, 1612, 1595, 1564, 1503, 1469,

1446, 1375, 1318, 1247, 1225, 1190, 1168, 1071, 1042, 1020, 958,

¹⁹F NMR (377 MHz, acetone-d₆): δ = –114.4.

875, 843, 779, 700, 685, 648, 583, 539, 516 cm^–1

.

Anal. Calcd for C₁₇H₁₀FNOS: C, 69.14; H, 3.41; F, 6.43; N, 4.74; S, 10.86.

Found: C, 69.53; H, 3.41; F, 6.83; N, 4.98; S, 10.65.

¹H NMR (400 MHz, CDCl₃): δ = 9.07 (br s, 1 H, NH), 8.21–8.19 (m, 2 H,

H-2,6 COPh), 7.65–7.61 (m, 1 H, H-4 COPh), 7.54–7.50 (m, 2 H, H-3,5

COPh), 7.43–7.37 (m, 1 H, H-6 C₆H₄F), 7.33–7.31 (m, 1 H, H-2 C₆H₄F),

7.23–7.19 (m, 1 H, H-5 C₆H₄F), 7.04–7.00 (m, 1 H, H-4 C₆H₄F), 6.94

(dd, J = 3.9, 2.2 Hz, 1 H, H-3 pyrrole), 6.61 (dd, J = 3.9, 2.5 Hz, 1 H, H-4

pyrrole).

¹³C NMR (101 MHz, acetone-d₆): δ = 177.2 (C=O), 164.2 (d, ¹J_CF= 243.5

Hz, C-3 C₆H₄F), 138.0 (C-1 COPh), 137.0 (d, ⁴J_CF= 2.6 Hz, C-5 pyrrole),

134.8 (C-4 COPh), 134.6 (d, ³J_CF= 8.2 Hz, C-1 C₆H₄F), 131.9 (d, ³J_CF= 8.6

Hz, C-5 C₆H₄F), 129.8 (C-2,6 COPh), 129.7 (C-3,5 COPh), 123.1 (C-3

pyrrole), 121.5 (d, ⁴J_CF= 3.0 Hz, C-6 C₆H₄F), 115.0 (d, ²J_CF= 21.1 Hz, C-4

C₆H₄F), 112.2 (d, ²J_CF= 23.3 Hz, C-2 C₆H₄F), 112.2 (C-2 pyrrole), 109.9

(C-4 pyrrole), 92.9 (≡C), 88.7 (C≡).

3-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenylprop-2-yn-1-one

(3j)

Yield: 171 mg (59%); yellow crystals; mp 179–180 °C.

IR (KBr): 3285, 3143, 3068, 2184, 1617, 1597, 1570, 1516, 1467, 1324,

1308, 1234, 1220, 1161, 1045, 1021, 968, 833, 810, 779, 696, 656,

610, 575, 534, 511 cm^–1

.

¹H NMR (400 MHz, acetone-d₆): δ = 11.53 (br s, 1 H, NH), 8.20–8.19

(m, 2 H, H-2,6 COPh), 7.84–7.80 (m, 2 H, H-2,6 C₆H₄F), 7.71–7.67 (m, 1

H, H-4 COPh), 7.59–7.56 (m, 2 H, H-3,5 COPh), 7.23–7.19 (m, 2 H, H-

3,5 C₆H₄F), 6.99 (dd, J = 3.9, 2.2 Hz, 1 H, H-3 pyrrole), 6.70 (dd, J = 3.9,

2.5 Hz, 1 H, H-4 pyrrole).

¹⁹F NMR (377 MHz, acetone-d₆): δ = –114.4.

¹³C NMR (101 MHz, acetone-d₆): δ = 177.1 (C=O), 163.0 (d, ¹J_CF= 246.0

Hz, C-4 C₆H₄F), 137.9 (C-1 COPh), 137.5 (C-5 pyrrole), 134.7 (C-4

COPh), 129.7 (C-3,5 COPh), 129.6 (C-2,6 COPh), 128.8 (C-1 C₆H₄F),

Anal. Calcd for C₁₉H₁₂FNO: C, 78.88; H, 4.18; F, 6.57; N, 4.84. Found: C,

78.61; H, 3.87; F, 6.26; N, 4.95.

127.6 (d, ³J_CF= 8.2 Hz, C-2,6 C₆H₄F), 123.3 (C-3 pyrrole), 116.7 (d, ²J_CF

=

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-furyl)prop-2-yn-1-

one (3h)

22.0 Hz, C-3,5 C₆H₄F), 111.5 (C-2 pyrrole) 109.0 (C-4 pyrrole), 93.1

(≡C), 89.2 (C≡).

Yield: 176 mg (63%); yellow crystals; mp 169–170 °C.

Anal. Calcd for C₁₉H₁₂FNO: C, 78.88; H, 4.18; F, 6.57; N, 4.84. Found: C,

78.61; H, 3.87; F, 6.94; N, 4.98.

IR (KBr): 3320, 3117, 3082, 2178, 1603, 1579, 1511, 1468, 1453, 1408,

1383, 1353, 1316, 1249, 1218, 1190, 1112, 1080, 1061, 1046, 1025,

940, 854, 812, 782, 756, 719, 680, 664, 645, 630, 560, 448 cm^–1

.

3-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-thienyl)prop-2-yn-1-

¹H NMR (400 MHz, acetone-d₆): δ = 11.53 (br s, 1 H, NH), 7.93 (dd, J =

1.7, 0.7 Hz, 1 H, H-5 furan), 7.63–7.61 (m, 1 H, H-6 C₆H₄F), 7.58–7.54

(m, 1 H, H-2 C₆H₄F), 7.51 (dd, J = 3.5, 0.7 Hz, 1 H, H-3 furan), 7.49–7.45

(m, 1 H, H-5 C₆H₄F), 7.10–7.05 (m, 1 H, H-4 C₆H₄F), 6.96 (dd, J = 3.9,

2.0 Hz, 1 H, H-3 pyrrole), 6.81 (dd, J = 3.9, 2.5 Hz, 1 H, H-4 pyrrole),

6.75 (dd, J = 3.5, 1.7 Hz, 1 H, H-4 furan).

one (3k)

Yield: 189 mg (64%); yellow crystals; mp 222–223 °C.

IR (KBr): 3294, 3112, 3081, 2168, 1592, 1565, 1516, 1467, 1407, 1354,

1304, 1244, 1230, 1163, 1104, 1080, 1044, 1021, 942, 920, 861, 833,

780, 721, 691, 656, 604, 530, 511 cm^–1

.

¹H NMR (400 MHz, acetone-d₆): δ = 11.52 (br s, 1 H, NH), 8.06 (dd, J =

3.8, 1.2 Hz, 1 H, H-3 thiophene), 8.00 (dd, J = 4.8, 1.2 Hz, 1 H, H-5 thio-

phene), 7.84–7.81 (m, 2 H, H-2,6 C₆H₄F), 7.29 (dd, J = 4.8, 3.8 Hz, 1 H,

H-4 thiophene), 7.25–7.20 (m, 2 H, H-3,5 C₆H₄F), 6.98 (dd, J = 3.7, 2.2

Hz, 1 H, H-3 pyrrole), 6.71 (dd, J = 3.7, 2.5 Hz, 1 H, H-4 pyrrole).

¹³C NMR (101 MHz, acetone-d₆): δ = 169.4 (C=O), 163.1 (d, ¹J_CF= 245.9

Hz, C-4 C₆H₄F), 145.9 (C-2 thiophene), 137.5 (C-5 pyrrole), 136.0 (C-5

thiophene), 135.6 (C-3 thiophene), 129.4 (C-4 thiophene), 128.9 (d,

¹³C NMR (101 MHz, acetone-d₆): δ = 164.3 (C=O), 164.2 (d, ¹J_CF= 243.6

Hz, C-3 C₆H₄F), 154.1 (C-2 furan), 149.2 (C-5 furan), 137.0 (d, ⁴J_CF= 2.7

Hz, C-5 pyrrole), 134.6 (d, ³J_CF= 8.3 Hz, C-1 C₆H₄F), 131.9 (d, ³J_CF= 8.7

Hz, C-5 C₆H₄F), 122.9 (C-3 pyrrole), 121.5 (d, ⁴J_CF= 2.5 Hz, C-6 C₆H₄F),

2

121.0 (C-3 furan), 114.9 (d, J_CF= 21.4 Hz, C-4 C₆H₄F), 113.5 (C-4 fu-

ran), 112.2 (d, ²J_CF= 23.0 Hz, C-2 C₆H₄F), 112.1 (C-2 pyrrole), 109.8 (C-

4 pyrrole), 92.1 (≡C), 86.8 (C≡).

Anal. Calcd for C₁₇H₁₀FNO₂: C, 73.11; H, 3.61; F, 6.80; N, 5.02. Found:

C, 72.93; H, 3.49; F, 7.19; N, 5.21.

H

L. N. Sobenina et al.

Paper

Synthesis

⁴J_CF= 3.3 Hz, C-1 C₆H₄F), 127.7 (d, ³J_CF= 8.2 Hz, C-2,6 C₆H₄F), 123.2 (C-

3 pyrrole), 116.7 (d, J_CF= 22.0 Hz, C-3,5 C₆H₄F), 111.4 (C-2 pyrrole),

1-(2-Furyl)-3-(prop-2-ynylamino)-3-(1H-pyrrol-2-yl)prop-2-en-1-

one (4a)

2

109.0 (C-4 pyrrole), 92.2 (≡C), 87.7 (C≡).

Yield: 120 mg (50%); Z/E 9:1; yellow solid; mp 106–107 °C.

Anal. Calcd for C₁₇H₁₀FNOS: C, 69.14; H, 3.41; F, 6.43; N, 4.74; S, 10.86.

Found: C, 69.53; H, 3.48; F, 6.31; N, 4.98; S, 10.65.

IR (KBr): 3293, 3251, 2120, 1594, 1533, 1504, 1467, 1431, 1330, 1261,

1156, 1121, 1075, 1042, 934, 881, 781, 739, 676, 604 cm^–1

.

3-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-1-phenylprop-2-

yn-1-one (3l)

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.21 (br t, J = 6.3 Hz, 1 H, NH-CH₂),

9.23 (br s, 1 H, NH pyrrole), 7.44 (m, 1 H, H-5 furan), 7.00–6.99 (m, 2

H, H-3 furan, H-5 pyrrole), 6.77 (m, 1 H, H-3 pyrrole), 6.45 (dd, J = 3.4,

1.8 Hz, 1 H, H-4 furan), 6.34–6.33 (m, 1 H, H-4 pyrrole), 5.90 (s, 1 H,

HC=), 4.20 (dd, J = 6.3, 2.4 Hz, 2 H, CH₂), 2.40 (t, J = 2.4 Hz, 1 H, ≡CH).

Yield: 158 mg (50%); yellow crystals; mp 67–68 °C.

IR (KBr): 3115, 3064, 2174, 1631, 1598, 1577, 1544, 1503, 1466, 1449,

1411, 1396, 1313, 1258, 1231, 1215, 1173, 1095, 1034, 995, 961, 933,

897, 817, 782, 760, 700, 662, 639, 541, 468 cm^–1

.

¹³C NMR (101 MHz, CDCl₃): δ = 177.9 (C=O), 157.3 (C-2 furan), 154.6

(=C-N), 144.3 (C-5 furan), 124.5 (C-2 pyrrole), 121.9 (C-5 pyrrole),

113.7 (C-3 furan), 112.9 (C-4 furan), 112.1 (C-4 pyrrole), 110.6 (C-3

pyrrole), 91.0 (HC=), 80.5 (C≡), 73.0 (≡CH), 34.7 (CH₂).

¹H NMR (400 MHz, CDCl₃): δ = 8.19–8.17 (m, 2 H, H-2,6 COPh), 7.63–

7.60 (m, 1 H, H-4 COPh), 7.53–7.49 (m, 2 H, H-3,5 COPh), 7.41–7.38

(m, 2 H, H-4,6 C₆H₄F), 7.24–7.14 (m, 2 H, H-3,5 C₆H₄F), 7.02 (d, J = 3.8

Hz, 1 H, H-3 pyrrole), 6.90 (dd, J = 15.8, 8.9 Hz, 1 H, H_X), 6.38 (d, J = 3.8

Hz, 1 H, H-4 pyrrole), 5.51 (dd, J = 8.9, 0.7 Hz, 1 H, H_A), 5.14 (dd, J =

15.8, 0.7 Hz, 1 H, H_B).

E-Isomer

¹³C NMR (101 MHz, CDCl₃): δ = 177.4 (C=O), 159.9 (d, ¹J_CF= 249.5 Hz,

C-2 C₆H₄F), 137.2 (C-1 COPh), 133.8 (C-4 COPh), 132.7 (C-5 pyrrole),

131.9 (HC=), 130.7 (d, ³J_CF= 2.2 Hz, C-6 C₆H₄F), 130.7 (d, ³J_CF= 6.9 Hz,

C-4 C₆H₄F), 129.4 (C-3,5 COPh), 128.7 (C-2,6 COPh), 124.4 (d, ⁴J_CF= 3.9

Hz, C-5 C₆H₄F), 123.0 (C-3 pyrrole), 119.9 (d, ²J_CF= 14.7 Hz, C-1 C₆H₄F),

¹H NMR (400 MHz, CDCl₃): δ = 14.89 (br s, 1 H, NH pyrrole), 7.53–7.52

(m, 1 H, H-5 furan), 7.14–7.13 (m, 1 H, H-3 furan), 7.04–7.03 (m, 1 H,

H-5 pyrrole), 6.65–6.64 (m, 1 H, H-3 pyrrole), 6.51–6.50 (m, 1 H, H-4

furan), 6.34–6.33 (m, 1 H, H-4 pyrrole), 5.96 (s, 1 H, HC=), 5.54 (br s, 1

H, NH-CH₂), 4.17–4.16 (m, 2 H, CH₂), 2.40–2.39 (m, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 177.9 (C=O), 157.3 (C-2 furan), 154.6

(=C-N), 144.7 (C-5 furan), 121.9 (C-5 pyrrole), 124.5 (C-2 pyrrole),

114.2 (C-3 pyrrole), 112.4 (C-3 furan), 111.6 (C-4 furan), 109.4 (C-4

pyrrole), 91.0 (HC=), 80.5 (C≡), 73.2 (≡CH), 33.6 (CH₂).

2

116.2 (d, J_CF= 22.0 Hz, C-3 C₆H₄F), 113.5 (C-2 pyrrole), 113.1 (C-4

pyrrole), 108.8 (=CH₂), 95.2 (≡C), 87.5 (C≡).

Anal. Calcd for C₂₁H₁₄FNO: C, 79.99; H, 4.48; F, 6.02; N, 4.44. Found: C,

79.61; H, 4.23; F, 5.76; N, 4.58.

Anal. Calcd for C₁₄H₁₂N₂O₂: C, 69.99; H, 5.03; N, 11.66. Found: C,

69.67; H, 4.97; N, 11.31.

3-[5-(4-Fluorophenyl)-1-methyl-1H-pyrrol-2-yl]-1-phenylprop-2-

yn-1-one (3m)

Yield: 215 mg (71%); yellow crystals; mp 104–106 °C.

1-Phenyl-3-(prop-2-ynylamino)-3-(4,5,6,7-tetrahydro-1H-indol-

2-yl)prop-2-en-1-one (4b)

IR (KBr): 3064, 2167, 1628, 1598, 1576, 1542, 1512, 1470, 1447, 1385,

1341, 1311, 1265, 1222, 1193, 1172, 1159, 1045, 1021, 968, 833, 810,

Yield: 201 mg (66%); Z/E ~15:1; yellow solid; mp 149–150 °C.

779, 696, 656, 610, 575, 534, 511 cm^–1

.

IR (KBr): 3424, 3261, 3137, 3097, 2939, 2921, 2849, 2120, 1599, 1569,

1519, 1459, 1432, 1397, 1358, 1331, 1262, 1233, 1138, 1126, 1065,

¹H NMR (400 MHz, CDCl₃): δ = 8.20–8.18 (m, 2 H, H-2,6 COPh), 7.64–

7.60 (m, 1 H, H-4 COPh), 7.54–7.50 (m, 2 H, H-2,6 C₆H₄F), 7.42–7.38

(m, 2 H, H-3,5 CОPh), 7.18–7.13 (m, 2 H, H-3,5 C₆H₄F), 6.92 (d, J = 4.0

Hz, 1 H, H-3 pyrrole), 6.26 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 3.80 (s, 3 H,

NMe).

867, 839, 815, 770, 753, 694, 649, 632 cm^–1

.

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.60 (br s, 1 H, NH-CH₂), 8.39 (br s, 1

H, NH pyrrole), 7.90–7.88 (m, 2 H, H-2,6 COPh), 7.44–7.38 (m, 3 H, H-

3,4,5 COPh), 6.56 (d, J = 1.8 Hz, 1 H, H-3 pyrrole), 5.90 (s, 1 H, HC=),

4.27 (dd, J = 6.4, 2.2 Hz, 2 H, CH₂), 2.66–2.63 (m, 2 H, CH₂-4), 2.56–

2.53 (m, 2 H, CH₂-7), 2.43 (t, J = 2.2 Hz, 1 H, ≡CH), 1.88–1.83 (m, 2 H,

CH₂-5), 1.80–1.77 (m, 2 H, CH₂-6).

¹³C NMR (101 MHz, CDCl₃): δ = 187.7 (C=O), 157.5 (=C-N), 140.6 (C-1

COPh), 132.6 (C-7a), 130.5 (C-4 COPh), 128.1 (C-3,5 COPh), 127.0 (C-

2,6 COPh), 122.3 (C-2 pyrrole), 119.9 (C-3a), 113.3 (C-3 pyrrole), 90.5

(HC=), 80.6 (C≡), 72.7 (≡CH), 34.7 (CH₂), 23.5, 23.0, 22.9, 22.8 (CH₂-

4,5,6,7).

¹³C NMR (101 MHz, CDCl₃): δ = 177.3 (C=O), 162.7 (d, ¹J_CF= 261.8 Hz,

C-4 C₆H₄F), 139.2 (C-1 COPh), 137.2 (C-5 pyrrole), 133.7 (C-4 COPh),

3

130.7 (d, J_CF= 7.8 Hz, C-2,6 C₆H₄F), 129.2 (C-3,5 CОPh), 128.6 (C-2,6

CОPh), 128.1 (d, ⁴J_CF= 3.0 Hz, C-1 C₆H₄F), 121.0 (C-3 pyrrole), 115.8 (d,

²J_CF= 22.0 Hz, C-3,5 C₆H₄F), 114.4 (C-2 pyrrole), 110.4 (C-4 pyrrole),

95.9 (≡C), 88.1 (C≡), 33.4 (NMe).

Anal. Calcd for C₂₀H₁₄FNO: C, 79.19; H, 4.65; F, 6.26; N, 4.62. Found: C,

78.86; H, 4.47; F, 6.01; N, 5.02.

Reactions of 2-(Acylethynyl)pyrroles 3a–n with Propargylamine;

General Procedure

Anal. Calcd for C₂₀H₂₀N₂O: C, 78.92; H, 6.62; N, 9.20. Found: C, 78.54;

H, 6.47; N, 8.98.

A solution of 2-(acylethynyl)pyrrole 3a–n (1 mmol) and propargyl-

amine (2 mmol) in MeOH (7–10 mL) was refluxed for 5 h. The residue

after removing the MeOH was fractioned by column chromatography

(alumina, n-hexane–Et₂O, 3:1). This afforded the desired enaminones

4, 2-acetylpyrroles 7 (7a–c could be isolated after reactions of 3d,f,g,j

with propargylamine), and prop-2-en-1-ones 11 (11a,b were isolated

from reactions of 3i,k with propargylamine).

1-Phenyl-3-(5-phenyl-1H-pyrrol-2-yl)-3-(prop-2-ynylamino)prop-

2-en-1-one (4c)

Yield: 163 mg (50%); Z/E ~ 4.6:1; yellow crystals; mp 129–130 °C.

IR (KBr): 3432, 3281, 3207, 3062, 1592, 1580, 1557, 1534, 1501, 1484,

1457, 1385, 1359, 1333, 1305, 1265, 1254, 1230, 1166, 1062, 806,

759, 692, 661, 635 cm^–1

.

I

L. N. Sobenina et al.

Paper

Synthesis

Z-Isomer

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-furyl)-3-(prop-2-ynyl-

¹H NMR (400 MHz, CDCl₃): δ = 11.56 (br t, J = 6.9 Hz, 1 H, NH-CH₂),

9.21 (br s, 1 H, NH pyrrole), 7.92–7.90 (m, 2 H, H-2,6 COPh), 7.59–7.57

(m, 2 H, H-2,6 Ph), 7.47–7.41 (m, 6 H, H-3,4,5 Ph, H-3,4,5 COPh), 6.84

(dd, J = 3.7, 2.7 Hz, 1 H, H-3 pyrrole), 6.64 (dd, J = 3.7, 2.7 Hz, 1 H, H-4

pyrrole), 6.05 (s, 1 H, HC=), 4.26 (dd, J = 6.9, 2.2 Hz, CH₂), 2.55 (t, J = 2.2

Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 188.7 (C=O), 156.9 (=C-N), 140.4 (C-1

COPh), 136.0 (C-5 pyrrole), 131.6 (C-1 Ph), 130.8 (C-4 COPh), 129.1 (C-

3,5 COPh), 128.3 (C-3,5 Ph), 127.5 (C-4 Ph), 127.1 (C-2,6 COPh), 125.7

(C-2 pyrrole), 124.5 (C-2,6 Ph), 115.2 (C-3 pyrrole), 108.0 (C-4 pyr-

role), 92.1 (HC=), 81.1 (C≡), 73.2 (≡CH), 34.7 (CH₂).

amino)prop-2-en-1-one (4e)

Yield: 217 mg (65%); Z/E ~8:1; yellow solid; mp 138–139 °C.

IR (KBr): 3296, 3145, 2120, 1574, 1489, 1474, 1385, 1252, 1219, 1156,

1077, 1013, 934, 838, 754, 703, 679, 550 cm^–1

.

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.19 (br s, 1 H, NH-CH₂), 9.59 (br s, 1

H, NH pyrrole), 7.67–7.64 (m, 1 H, H-5 furan), 7.46–7.45 (m, 1 H, H-6

C₆H₄F), 7.22–7.12 (m, 3 H, H-3,4,5 C₆H₄F), 7.02–7.01 (m, 1 H, H-3 fu-

ran), 6.82–6.81 (m, 1 H, H-3 pyrrole), 6.73–6.72 (m, 1 H, H-4 pyrrole),

6.46–6.45 (m, 1 H, H-4 furan), 5.95 (s, 1 H, HC=), 4.22–4.21 (m, 2 H,

CH₂), 2.44 (m, 1 H, ≡CH).

E-Isomer

¹³C NMR (101 MHz, CDCl₃): δ = 178.0 (C=O), 159.0 (d, ¹J_CF= 246.2 Hz,

C-2 C₆H₄F), 156.7 (=C-N), 154.6 (C-2 furan), 144.3 (C-5 furan), 130.5

(C-5 pyrrole), 128.6 (d, ³J_CF= 8.5 Hz, C-4 C₆H₄F), 127.2 (d, ³J_CF= 3.6 Hz,

C-6 C₆H₄F), 125.7 (d, J = 1.8 Hz, C-2 pyrrole), 125.0 (d, ⁴J_CF= 2.9 Hz, C-5

C₆H₄F), 119.2 (d, ²J_CF= 11.3 Hz, C-1 C₆H₄F), 116.5 (d, ²J_CF= 22.7 Hz, C-3

C₆H₄F), 114.6 (C-3 pyrrole), 113.0 (C-3 furan), 112.0 (C-4 furan), 109.9

¹H NMR (400 MHz, CDCl₃): δ = 15.77 (br s, 1 H, NH pyrrole), 8.00–7.97

(m, 2 H, H-2,6 COPh), 7.82–7.80 (m, 2 H, H-2,6 Ph), 7.32–7.29 (m, 6 H,

H-3,4,5 Ph, H-3,4,5 COPh), 6.71–6.70 (m, 2 H, H-3,4 pyrrole), 5.95 (s, 1

H, HC=), 5.40 (br s, 1 H, NH-CH₂), 4.18 (dd, J = 5.9, 2.6 Hz, CH₂), 2.43 (t,

J = 2.6 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 187.3 (C=O), 151.3 (=C-N), 140.4 (C-1

COPh), 136.0 (C-5 pyrrole), 131.6 (C-1 Ph), 130.8 (C-4 COPh), 129.0 (C-

3,5 COPh), 128.4 (C-3,5 Ph), 127.7 (C-2,6 COPh), 127.2 (C-4 Ph), 127.0

(C-2 pyrrole), 124.5 (C-2,6 Ph), 111.1 (C-3 pyrrole), 108.2 (C-4 pyr-

role), 90.4 (HC=), 78.4 (C≡), 73.2 (≡CH), 34.5 (CH₂).

4

(d, J_CF= 1.6 Hz, C-4 pyrrole), 91.3 (HC=), 80.5 (C≡), 73.2 (≡CH), 34.7

(CH₂).

E-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 15.56 (br s, 1 H, NH pyrrole), 7.82–7.81

(m, 1 H, H-5 furan), 7.53–7.52 (m, 1 H, H-6 C₆H₄F), 7.22–7.12 (m, 4 H,

H-3,4,5 C₆H₄F, H-3 furan), 6.82–6.81 (m, 1 H, H-3 pyrrole), 6.73–6.72

(m, 1 H, H-4 pyrrole), 6.51–6.50 (m, 1 H, H-4 furan), 5.98 (s, 1 H, HC=),

5.62 (br s, 1 H, NH-CH₂), 4.18 (m, 2 H, CH₂), 2.38 (m, 1 H, ≡CH).

Anal. Calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.65;

H, 5.87; N, 8.98.

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenyl-3-(prop-2-ynyl-

¹³C NMR (101 MHz, CDCl₃): δ = 175.2 (C=O), 159.5 (d, ¹J_CF= 249.7 Hz,

C-2 C₆H₄F), 155.6 (C-2 furan), 151.4 (=C-N), 144.9 (C-5 furan), 130.3

(C-5 pyrrole), 128.2 (d, ³J_CF= 8.0 Hz, C-4 C₆H₄F), 126.9 (d, J_CF= 3.9 Hz,

C-6 C₆H₄F), 125.7 (d, J = 1.9 Hz, C-2 pyrrole), 124.7 (d, ⁴J_CF= 3.0 Hz, C-5

C₆H₄F), 120.2 (d, ²J_CF= 11.8 Hz, C-1 C₆H₄F), 116.4 (d, ²J_CF= 21.8 Hz, C-3

C₆H₄F), 114.4 (C-3 pyrrole), 112.3 (C-4 furan), 111.7 (d, ⁴J_CF= 7.7 Hz, C-

4 pyrrole), 111.0 (C-3 furan), 88.8 (HC=), 78.4 (C≡), 73.2 (≡CH), 33.6

(CH₂).

amino)prop-2-en-1-one (4d)

Yield: 169 mg (49%); Z/E ~10:1; yellow solid; mp 131–132 °C.

IR (KBr): 3430, 3291, 2121, 1593, 1535, 1416, 1309, 1234, 1161, 1109,

1057, 908, 810, 754, 729, 695, 549 cm^–1

.

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.52 (br t, 1 H, J = 6.4 Hz, NH-CH₂),

9.65 (br s, 1 H, NH pyrrole), 7.88–7.87 (m, 2 H, H-2,6 COPh), 7.66–7.63

(m, 1 H, H-6 C₆H₄F), 7.43–7.35 (m, 3 H, H-3,4,5 COPh,), 7.22–7.10 (m,

3 H, H-3,4,5 C₆H₄F), 6.80–6.79 (m, 1 H, H-3 pyrrole), 6.71–6.70 (m, 1

H, H-4 pyrrole), 6.00 (s, 1 H, HC=), 4.20 (dd, J = 6.4, 2.2 Hz, 2 H, CH₂),

2.44 (t, J = 2.2 Hz, 1 H, ≡CH).

Anal. Calcd for C₂₀H₁₅FN₂O₂: C, 71.85; H, 4.52; F, 5.68; N, 8.38. Found:

C, 71.65; H, 4.21; F, 5.39; N, 8.51.

3-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]-3-(prop-2-ynylamino)-1-

(2-thienyl)prop-2-en-1-one (4f)

¹³C NMR (101 MHz, CDCl₃): δ = 188.9 (C=O), 159.0 (d, ¹J_CF= 245.9 Hz,

C-2 C₆H₄F), 156.8 (=C-N), 140.4 (C-1 COPh), 131.0 (C-4 COPh), 130.5

(d, ³J_CF= 1.5 Hz, C-5 pyrrole), 128.7 (d, ³J_CF= 9.2 Hz, C-4 C₆H₄F), 128.4

Yield: 172 mg (49%); Z/E ~10:1; yellow solid; mp 71–72 °C.

IR (KBr): 3286, 2115, 1596, 1487, 1419, 1274, 1237, 1180, 1113, 1079,

3

(C-3,5 COPh), 127.3 (d, J_CF= 3.5 Hz, C-6 C₆H₄F), 127.2 (C-2,6 COPh),

1059, 901, 845, 756, 718, 679 cm^–1

.

4

126.0 (d, J = 2.7 Hz, C-2 pyrrole), 125.0 (d, J_CF= 3.3 Hz, C-5 C₆H₄F),

119.2 (d, ²J_CF= 11.4 Hz, C-1 C₆H₄F), 116.6 (d, ²J_CF= 22.7 Hz, C-3 C₆H₄F),

Z-Isomer

4

114.5 (C-3 pyrrole), 109.8 (d, J_CF= 2.3 Hz, C-4 pyrrole), 92.0 (HC=),

80.6 (C≡), 73.3 (≡CH), 34.7 (CH₂).

¹H NMR (400 MHz, CDCl₃): δ = 11.14 (br t, 1 H, J = 6.5 Hz, NH-CH₂),

9.53 (br s, 1 H, NH pyrrole), 7.68–7.63 (m, 1 H, H-6 C₆H₄F), 7.60–7.59

(m, 1 H, H-3 thiophene), 7.48–7.46 (m, 1 H, H-5 thiophene), 7.23–

7.06 (m, 4 H, H-3,4,5 C₆H₄F, H-4 thiophene), 6.82–6.81 (m, 1 H, H-3

pyrrole), 6.73–6.72 (m, 1 H, H-4 pyrrole), 5.90 (s, 1 H, HC=), 4.22 (dd,

J = 6.5, 2.4 Hz, 2 H, CH₂), 2.46 (t, J = 2.4 Hz, 1 H, ≡CH).

E-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 15.69 (br s, 1 H, NH pyrrole), 7.96–7.95

(m, 2 H, H-2,6 COPh), 7.66–7.63 (m, 1 H, H-6 C₆H₄F), 7.43–7.35 (m, 3

H, H-3,4,5 COPh,), 7.22–7.10 (m, 3 H, H-3,4,5 C₆H₄F), 6.91–6.90 (m, 1

H, H-3 pyrrole), 6.71–6.70 (m, 1 H, H-4 pyrrole), 5.93 (s, 1 H, HC=),

5.64 (br t, J = 4.9 Hz, 1 H, NH-CH₂), 4.10–4.09 (m, 2 H, CH₂), 2.38 (t, J =

2.5 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 181.7 (C=O), 159.0 (d, ¹J_CF= 246.2 Hz,

C-2 C₆H₄F), 156.4 (=C-N), 147.2 (C-2 thiophene), 130.5 (C-5 pyrrole),

3

130.4 (C-5 thiophene), 128.7 (d, J_CF= 8.8 Hz, C-4 C₆H₄F), 128.0 (C-3

thiophene), 127.9 (C-4 thiophene), 127.2 (d, ³J_CF= 3.9 Hz, C-6 C₆H₄F),

4

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.52; H, 4.66; F, 5.61; N, 8.02.

125.8 (d, J_CF= 1.9 Hz, C-5 C₆H₄F), 125.0 (d, J = 2.9 Hz, C-2 pyrrole),

J

L. N. Sobenina et al.

Paper

Synthesis

119.2 (d, ²J_CF= 11.3 Hz, C-1 C₆H₄F), 116.6 (d, ²J_CF= 22.7 Hz, C-3 C₆H₄F),

114.5 (C-3 pyrrole), 109.9 (d, J_CF= 2.7 Hz, C-4 pyrrole), 91.8 (HC=),

Z-Isomer

4

¹H NMR (400 MHz, CDCl₃): δ = 11.13 (br t, 1 H, J = 6.5 Hz, NH-CH₂),

9.40 (br s, 1 H, NH pyrrole), 7.54–7.53 (m, 1 H, H-5 furan), 7.45–7.44

(m, 1 H, H-6 C₆H₄F), 7.39–7.34 (m, 2 H, H-2,5 C₆H₄F), 7.01–7.00 (m, 1

H, H-3 furan), 6.95–6.91 (m, 1 H, H-4 C₆H₄F), 6.79–6.78 (m, 1 H, H-3

pyrrole), 6.62–6.61 (m, 1 H, H-4 pyrrole), 6.45 (dd, J = 3.4, 1.6 Hz, 1 H,

H-4 furan), 5.94 (s, 1 H, HC=), 4.18 (dd, J = 6.5, 2.4 Hz, 2 H, CH₂), 2.49

(t, J = 2.4 Hz, 1 H, ≡CH).

80.5 (C≡), 73.2 (≡CH), 34.7 (CH₂).

E-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 15.36 (br s, 1 H, NH pyrrole), 7.74–7.73

(m, 1 H, H-6 C₆H₄F), 7.60–7.59 (m, 1 H, H-3 thiophene), 7.51–7.50 (m,

1 H, H-5 thiophene), 7.23–7.06 (m, 4 H, H-3,4,5 C₆H₄F, H-4 thio-

phene), 6.82–6.81 (m, 1 H, H-3 pyrrole), 6.69–6.68 (m, 1 H, H-4 pyr-

role), 5.98 (s, 1 H, HC=), 5.35 (br s, 1 H, NH-CH₂), 4.18–4.17 (m, 2 H,

CH₂), 2.41 (t, J = 2.5 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 177.9 (C=O), 163.4 (d, ¹J_CF= 245.7 Hz,

C-3 C₆H₄F), 156.9 (=C-N), 154.4 (C-2 furan), 144.4 (C-5 furan), 134.9

(d, ⁴J_CF= 2.4 Hz, C-5 pyrrole), 133.8 (d, ³J_CF= 8.0 Hz, C-1 C₆H₄F), 130.7

(d, ³J_CF= 8.8 Hz, C-5 C₆H₄F), 125.9 (C-2 pyrrole), 120.2 (d, ⁴J_CF= 2.6 Hz,

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.62; H, 4.25; F, 5.49; N, 7.70; S, 8.81.

2

C-6 C₆H₄F), 115.2 (C-3 pyrrole), 114.2 (d, J_CF= 21.4 Hz, C-4 C₆H₄F),

2

113.1 (C-3 furan), 112.1 (C-4 furan), 111.5 (d, J_CF= 22.9 Hz, C-2

C₆H₄F), 108.7 (C-4 pyrrole), 91.8 (HC=), 80.8 (C≡), 73.2 (≡CH), 34.8

(CH₂).

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenyl-3-(prop-2-ynyl-

amino)prop-2-en-1-one (4g)

Yield: 148 mg (43%); Z/E ~4:1; yellow solid; mp 62–64 °C.

E-Isomer

IR (KBr): 3298, 3231, 2121, 1589, 1540, 1416, 1301, 1236, 1160, 1080,

¹H NMR (400 MHz, CDCl₃): δ = 15.71 (br s, 1 H, NH pyrrole), 7.56–7.55

(m, 1 H, H-5 furan), 7.42–7.41 (m, 1 H, H-6 C₆H₄F), 7.31–7.30 (m, 1 H,

H-2 C₆H₄F), 7.29–7.28 (m, 1 H, H-5 C₆H₄F), 7.19–7.18 (m, 1 H, H-3 fu-

ran), 6.98–6.97 (m, 1 H, H-4 C₆H₄F), 6.68–6.65 (m, 2 H, H-3,4 pyrrole),

6.52 (dd, J = 3.4, 1.7 Hz, 1 H, H-4 furan), 5.98 (s, 1 H, HC=), 5.43 (br t,

J = 4.4 Hz, 1 H, NH-CH₂), 4.19 (dd, J = 4.4, 2.4 Hz, 2 H, CH₂), 2.40 (t, J =

2.4 Hz, 1 H, ≡CH).

1060, 908, 836, 773, 730, 646, 518 cm^–1

.

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.50 (br t, 1 H, J = 6.6 Hz, NH-CH₂),

9.29 (br s, 1 H, NH pyrrole), 7.90–7.87 (m, 2 H, H-2,6 COPh), 7.48–7.27

(m, 6 H, H-3,4,5 COPh, H-2,5,6 C₆H₄F), 6.98–6.92 (m, 1 H, H-4 C₆H₄F),

6.80 (dd, J = 3.8, 2.0 Hz, 1 H, H-3 pyrrole), 6.62 (dd, J = 3.8, 1.9 Hz, 1 H,

H-4 pyrrole), 6.02 (s, 1 H, HC=), 4.22 (dd, J = 6.6, 2.4 Hz, 2 H, CH₂), 2.55

(t, J = 2.4 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 188.2 (C=O), 163.4 (d, ¹J_CF= 245.9 Hz,

C-3 C₆H₄F), 156.9 (=C-N), 140.2 (C-1 COPh), 134.8 (d, ⁴J_CF= 2.0 Hz, C-5

pyrrole), 133.8 (d, ³J_CF= 8.3 Hz, C-1 C₆H₄F), 131.0 (C-4 COPh), 130.7 (d,

³J_CF= 8.7 Hz, C-5 C₆H₄F), 128.3 (C-3,5 COPh), 127.2 (C-2,6 COPh), 126.2

¹³C NMR (101 MHz, CDCl₃): δ = 174.9 (C=O), 163.4 (d, ¹J_CF= 245.2 Hz,

C-3 C₆H₄F), 155.5 (C-2 furan), 151.5 (=C-N), 145.0 (C-5 furan), 134.8

(d, ⁴J_CF= 2.4 Hz, C-5 pyrrole), 134.2 (d, ³J_CF= 8.0 Hz, C-1 C₆H₄F), 130.6

(d, ³J_CF= 8.8 Hz, C-5 C₆H₄F), 127.3 (C-2 pyrrole), 120.2 (d, ⁴J_CF= 2.6 Hz,

2

C-6 C₆H₄F), 114.5 (C-3 furan), 114.0 (d, J_CF= 21.4 Hz, C-4 C₆H₄F),

112.4 (C-4 furan), 111.4 (d, ²J_CF= 22.9 Hz, C-2 C₆H₄F), 111.1 (C-3 pyr-

role), 108.8 (C-4 pyrrole), 88.6 (HC=), 78.3 (C≡), 73.3 (≡CH), 33.5 (CH₂).

4

(C-2 pyrrole), 120.1 (d, J_CF= 1.9 Hz, C-6 C₆H₄F), 115.1 (C-3 pyrrole),

Anal. Calcd for C₂₀H₁₅FN₂O₂: C, 71.85; H, 4.52; F, 5.68; N, 8.38. Found:

C, 71.84; H, 4.90; F, 5.93; N, 8.27.

114.2 (d, ²J_CF= 21.2 Hz, C-4 C₆H₄F), 111.5 (d, ²J_CF= 23.0 Hz, C-2 C₆H₄F),

108.7 (C-4 pyrrole), 92.5 (HC=), 81.0 (C≡), 73.3 (≡CH), 34.7 (CH₂).

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-3-(prop-2-ynylamino)-1-

(2-thienyl)prop-2-en-1-one (4i)

E-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 15.88 (br s, 1 H, NH pyrrole), 7.98–7.96

(m, 2 H, H-2,6 COPh), 7.59–7.57 (m, 1 H, H-6 C₆H₄F), 7.48–7.27 (m, 5

H, H-3,4,5 COPh, H-2,5 C₆H₄F), 7.00–6.99 (m, 1 H, H-4 C₆H₄F), 6.69–

6.68 (m, 2 H, H-3,4 pyrrole), 5.95 (s, 1 H, HC=), 5.41 (br t, J = 5.2 Hz, 1

H, NH-CH₂), 4.16 (dd, J = 5.2, 2.4 Hz, 2 H, CH₂), 2.42 (t, J = 2.4 Hz, 1 H,

≡CH).

Yield: 161 mg (46%); Z/E ~4:1; yellow solid; mp 66–67 °C.

IR (KBr): 3296, 3238, 2121, 1586, 1486, 1416, 1259, 1197, 1163, 1082,

1063, 908, 846, 774, 715, 645, 524 cm^–1

.

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.04 (br t, 1 H, J = 5.9 Hz, NH-CH₂),

9.54 (br s, 1 H, NH pyrrole), 7.48–7.47 (m, 1 H, H-3 thiophene), 7.43–

7.42 (m, 1 H, H-5 thiophene), 7.40–7.39 (m, 1 H, H-6 C₆H₄F), 7.37–

7.31 (m, 2 H, H-2,5 C₆H₄F), 7.01–6.95 (m, 2 H, H-4 C₆H₄F, H-4 thio-

phene), 6.73–6.72 (m, 1 H, H-3 pyrrole), 6.61–6.60 (m, 1 H, H-4 pyr-

role), 5.86 (s, 1 H, HC=), 4.15–4.14 (m, 2 H, CH₂), 2.45 (t, J = 2.0 Hz, 1 H,

≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 187.4 (C=O), 163.3 (d, ¹J_CF= 246.7 Hz,

C-3 C₆H₄F), 151.4 (=C-N), 142.5 (C-1 COPh), 134.6 (d, ⁴J_CF= 2.0 Hz, C-5

pyrrole), 134.3 (d, ³J_CF= 8.5 Hz, C-1 C₆H₄F), 131.1 (C-4 COPh), 130.6 (d,

³J_CF= 8.5 Hz, C-5 C₆H₄F), 128.4 (C-3,5 COPh), 127.8 (C-2,6 COPh), 127.5

(C-2 pyrrole), 120.7 (d, J_CF= 2.5 Hz, C-6 C₆H₄F), 113.9 (d, J_CF= 21.2

Hz, C-4 C₆H₄F), 111.2 (d, ²J_CF= 22.6 Hz, C-2 C₆H₄F), 109.0 (C-3 pyrrole),

108.8 (C-4 pyrrole), 90.6 (HC=), 78.3 (C≡), 73.3 (≡CH), 33.5 (CH₂).

4

2

¹³C NMR (101 MHz, CDCl₃): δ = 181.9 (C=O), 163.5 (d, ¹J_CF= 245.4 Hz,

C-3 C₆H₄F), 156.6 (=C-N), 147.1 (C-2 thiophene), 134.9 (C-5 pyrrole),

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.51; H, 4.74; F, 5.33; N, 8.26.

3

133.8 (d, J_CF= 8.3 Hz, C-1 C₆H₄F), 130.8 (d, J_CF= 8.7 Hz, C-5 C₆H₄F),

130.5 (C-5 thiophene), 128.1 (C-3 thiophene), 128.0 (C-4 thiophene),

126.0 (C-2 pyrrole), 120.1 (d, ⁴J_CF= 2.0 Hz, C-6 C₆H₄F), 115.0 (C-3 pyr-

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1-(2-furyl)-3-(prop-2-ynyl-

amino)prop-2-en-1-one (4h)

2

role), 114.3 (d, J_CF= 21.2 Hz, C-4 C₆H₄F), 111.5 (d, J_CF= 22.9 Hz, C-2

C₆H₄F), 108.6 (C-4 pyrrole), 92.4 (HC=), 80.9 (C≡), 73.3 (≡CH), 34.7

(CH₂).

Yield: 147 mg (44%); Z/E ~4:1; yellow solid; mp 153–154 °C.

IR (KBr): 3301, 3187, 2126, 1613, 1538, 1473, 1383, 1253, 1207, 1182,

1083, 1016, 927, 840, 756, 701, 692, 526 cm^–1

.

K

L. N. Sobenina et al.

Paper

Synthesis

E-Isomer

IR (KBr): 3298, 3231, 2121, 1589, 1540, 1416, 1301, 1236, 1160, 1080,

1060, 908, 836, 773, 730, 646, 518 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 15.52 (br s, 1 H, NH pyrrole), 7.72–7.71

(m, 1 H, H-3 thiophene), 7.52–7.50 (m, 2 H, H-6 C₆H₄F, H-5 thio-

phene), 7.37–7.31 (m, 2 H, H-2,5 C₆H₄F), 7.09–7.08 (m, 1 H, H-4 thio-

phene), 6.92–6.90 (m, 1 H, H-4 C₆H₄F), 6.65–6.64 (m, 2 H, H-3,4 pyr-

role), 5.96 (s, 1 H, HC=), 5.41 (br t, J = 4.8 Hz, 1 H, NH-CH₂), 4.14–4.13

(m, 2 H, CH₂), 2.40 (t, J = 2.4 Hz, 1 H, ≡CH).

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.14 (br t, J = 6.6 Hz, 1 H, NH-CH₂),

9.18 (br s, 1 H, NH pyrrole), 7.73–7.70 (m, 1 H, H-3 thiophene), 7.57–

7.51 (m, 3 H, H-2,6 C₆H₄F, H-5 thiophene), 7.14–7.09 (m, 3 H, H-3,5

C₆H₄F, H-4 thiophene), 6.79 (dd, J = 3.7, 2.0 Hz, 1 H, H-3 pyrrole), 6.55

(dd, J = 3.7, 2.6 Hz, 1 H, H-4 pyrrole), 5.89 (s, 1 H, HC=), 4.20 (dd, J =

6.6, 2.3 Hz, 2 H, CH₂), 2.51 (t, J = 2.3 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 179.3 (C=O), 163.4 (d, ¹J_CF= 245.0 Hz,

C-3 C₆H₄F), 150.9 (=C-N), 148.6 (C-2 thiophene), 134.9 (C-5 pyrrole),

3

134.2 (d, J_CF= 8.3 Hz, C-1 C₆H₄F), 131.2 (C-5 thiophene), 130.7 (d,

³J_CF= 8.7 Hz, C-5 C₆H₄F), 129.4 (C-4 thiophene), 128.1 (C-3 thio-

¹³C NMR (101 MHz, CDCl₃): δ = 181.7 (C=O), 162.3 (d, ¹J_CF= 247.4 Hz,

C-4 C₆H₄F), 156.7 (=C-N), 147.2 (C-2 thiophene), 135.3 (C-5 pyrrole),

130.4 (C-5 thiophene), 129.2 (C-1 C₆H₄F), 128.0 (C-3 thiophene),

127.9 (C-4 thiophene), 126.4 (d, ³J_CF= 8.0 Hz, C-2,6 C₆H₄F), 125.5 (C-2

4

phene), 127.4 (C-2 pyrrole), 120.2 (d, J_CF= 2.0 Hz, C-6 C₆H₄F), 114.0

(d, ²J_CF= 21.5 Hz, C-4 C₆H₄F), 111.5 (d, ²J_CF= 22.9 Hz, C-2 C₆H₄F), 111.0

(C-3 pyrrole), 108.8 (C-4 pyrrole), 89.8 (HC=), 78.4 (C≡), 73.4 (≡CH),

33.6 (CH₂).

2

pyrrole), 116.2 (d, J_CF= 21.8 Hz, C-3,5 C₆H₄F), 115.2 (C-3 pyrrole),

107.9 (C-4 pyrrole), 92.1 (HC=), 80.9 (C≡), 73.2 (≡CH), 34.7 (CH₂).

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.37; H, 4.34; F, 5.51; N, 7.64; S, 9.11.

E-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 15.48 (br s, 1 H, NH pyrrole), 7.70–7.69

(m, 1 H, H-3 thiophene), 7.47–7.46 (m, 3 H, H-2,6 C₆H₄F, H-5 thio-

phene), 7.07–7.05 (m, 3 H, H-3,5 C₆H₄F, H-4 thiophene), 6.66 (dd, J =

3.8, 2.0 Hz, 1 H, H-3 pyrrole), 6.60 (dd, J = 3.8, 2.6 Hz, 1 H, H-4 pyr-

role), 5.97 (s, 1 H, HC=), 5.34 (br t, J = 4.7 Hz, 1 H, NH-CH₂), 4.17–4.16

(m, 2 H, CH₂), 2.42 (t, J = 2.4 Hz, 1 H, ≡CH).

3-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-1-phenyl-3-(prop-2-ynyl-

amino)prop-2-en-1-one (4j)

Yield: 158 mg (46%); Z/E ~3.7:1; yellow crystals; mp 123–124 °C.

IR (KBr): 3436, 3298, 3227, 3061, 1643, 1586, 1564, 1545, 1503, 1486,

1467, 1380, 1360, 1332, 1302, 1259, 1234, 1160, 1060, 1025, 909,

836, 810, 788, 758, 732, 695, 640 cm^–1

.

¹³C NMR (101 MHz, CDCl₃): δ = 179.2 (C=O), 162.2 (d, ¹J_CF= 247.5 Hz,

C-4 C₆H₄F), 151.0 (=C-N), 148.7 (C-2 thiophene), 135.3 (C-5 pyrrole),

131.1 (C-5 thiophene), 128.4 (C-1 C₆H₄F), 128.1 (C-3 thiophene),

Z-Isomer

¹H NMR (400 MHz, CDCl₃): δ = 11.55 (br t, J = 6.6 Hz, 1 H, NH-CH₂),

9.14 (br s, 1 H, NH pyrrole), 7.92–7.90 (m, 2 H, H-2,6 COPh), 7.56–7.52

(m, 2 H, H-2,6 C₆H₄F), 7.48–7.40 (m, 3 H, H-3,4,5 COPh), 7.15–7.10 (m,

2 H, H-3,5 C₆H₄F), 6.83 (dd, J = 3.5, 2.6 Hz, 1 H, H-3 pyrrole), 6.56 (dd,

J = 3.5, 2.8 Hz, 1 H, H-4 pyrrole), 6.04 (s, 1 H, HC=), 4.25 (dd, J = 6.6, 2.4

Hz, 2 H, CH₂), 2.55 (t, J = 2.4 Hz, 1 H, ≡CH).

3

128.0 (C-4 thiophene), 126.9 (C-2 pyrrole), 126.3 (d, J_CF= 8.1 Hz, C-

2

2,6 C₆H₄F), 116.0 (d, J_CF= 20.7 Hz, C-3,5 C₆H₄F), 111.2 (C-3 pyrrole),

108.0 (C-4 pyrrole), 89.5 (HC=), 78.4 (C≡), 73.3 (≡CH), 33.6 (CH₂).

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.40; H, 4.15; F, 5.38; N, 7.61; S, 9.02.

¹³C NMR (101 MHz, CDCl₃): δ = 188.8 (C=O), 162.3 (d, ¹J_CF= 247.6 Hz,

3-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-1-phenyl-3-(prop-

2-ynylamino)prop-2-en-1-one (4l)

C-4 C₆H₄F), 156.8 (=C-N), 140.3 (C-1 COPh), 135.1 (C-5 pyrrole), 130.9

4

(C-4 COPh), 128.3 (C-3,5 COPh), 128.0 (d, J_CF= 3.1 Hz, C-1 C₆H₄F),

3

Yield: 315 mg (85%); yellow oil.

127.1 (C-2,6 COPh), 126.3 (d, J_CF= 8.0 Hz, C-2,6 C₆H₄F), 125.8 (C-2

2

pyrrole), 116.2 (d, J_CF= 21.7 Hz, C-3,5 C₆H₄F), 115.2 (C-3 pyrrole),

IR (film): 3300, 3110, 3062, 2922, 2845, 2246, 2122, 1918, 1644,

1582, 1554, 1528, 1497, 1480, 1463, 1396, 1358, 1323, 1279, 1234,

1156, 1098, 1078, 1057, 1026, 961, 910, 815, 760, 732, 689, 653, 619,

107.9 (C-4 pyrrole), 92.1 (HC=), 81.2 (C≡), 73.2 (≡CH), 34.7 (CH₂).

E-Isomer

544 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 15.81 (br s, 1 H, NH pyrrole), 7.99–7.96

(m, 2 H, H-2,6 COPh), 7.78–7.75 (m, 2 H, H-2,6 C₆H₄F), 7.48–7.40 (m, 3

H, H-3,4,5 COPh), 7.15–7.10 (m, 2 H, H-3,5 C₆H₄F), 6.70 (dd, J = 3.5, 2.5

Hz, 1 H, H-3 pyrrole), 6.64 (dd, J = 3.5, 2.6 Hz, 1 H, H-4 pyrrole), 5.95

(s, 1 H, HC=), 5.40 (br t, J = 5.5 Hz, 1 H, NH-CH₂), 4.18 (dd, J = 5.5, 2.3

Hz, 2 H, CH₂), 2.43 (t, J = 2.3 Hz, 1 H, ≡CH).

¹H NMR (400 MHz, CDCl₃): δ = 11.16 (br t, 1 H, J = 5.9 Hz, NH-CH₂),

7.93–7.91 (m, 2 H, H-2,6 COPh), 7.48–7.36 (m, 5 H, H-4,6 C₆H₄F, H-

3,4,5 COPh), 7.23–7.13 (m, 2 H, H-3,5 C₆H₄F), 6.79 (dd, J = 15.8, 8.9 Hz,

1 H, H_X), 6.56 (d, J = 3.6 Hz, 1 H, H-3 pyrrole), 6.35 (d, J = 3.6 Hz, 1 H,

H-4 pyrrole), 6.03 (s, 1 H, HC=), 4.98 (dd, J = 15.8, 1.0 Hz, 1 H, H_A), 4.84

(dd, J = 8.9, 1.0 Hz, 1 H, H_B), 3.98 (dd, J = 5.9, 2.6 Hz, 2 H, CH₂), 2.29 (t,

J = 2.6 Hz, 1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 187.4 (C=O), 162.2 (d, ¹J_CF= 246.0 Hz,

¹³C NMR (101 MHz, CDCl₃): δ = 189.2 (C=O), 159.8 (d, ¹J_CF= 248.2 Hz,

C-2 C₆H₄F), 156.9 (=C-N), 139.9 (C-1 COPh), 132.1 (d, ³J_CF= 1.8 Hz, C-5

pyrrole), 131.2 (HC=CH₂), 130.6 (C-2 pyrrole), 130.4 (C-4 COPh), 130.3

(d, ³J_CF= 8.0 Hz, C-4 C₆H₄F), 128.6 (d, ³J_CF= 3.6 Hz, C-6 C₆H₄F), 128.4 (C-

3,5 COPh), 127.3 (C-2,6 COPh), 124.3 (d, ⁴J_CF= 3.8 Hz, C-5 C₆H₄F), 120.5

(d, ²J_CF= 14.9 Hz, C-1 C₆H₄F), 116.0 (d, ²J_CF= 22.0 Hz, C-3 C₆H₄F), 113.9

(C-3 pyrrole), 112.0 (C-4 pyrrole), 107.4 (=CH₂), 95.7 (HC=), 79.4 (C≡),

72.6 (≡CH), 34.2 (CH₂).

C-4 C₆H₄F), 151.3 (=C-N), 142.6 (C-1 COPh), 135.1 (C-5 pyrrole), 131.0

4

(C-4 COPh), 128.4 (C-3,5 COPh), 128.0 (d, J_CF= 3.1 Hz, C-1 C₆H₄F),

3

127.8 (C-2 pyrrole), 127.0 (C-2,6 COPh), 126.3 (d, J_CF= 8.0 Hz, C-2,6

C₆H₄F), 116.0 (d, ²J_CF= 20.1 Hz, C-3,5 C₆H₄F), 111.0 (C-3 pyrrole), 108.0

(C-4 pyrrole), 90.4 (HC=), 78.3 (C≡), 73.3 (≡CH), 33.6 (CH₂).

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.81; H, 4.66; F, 5.19; N, 7.87.

Anal. Calcd for C₂₄H₁₉FN₂O: C, 77.82; H, 5.17; F, 5.13; N, 7.56. Found:

C, 77.45; H, 4.97; F, 5.20; N, 7.91.

3-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-3-(prop-2-ynylamino)-1-

(2-thienyl)prop-2-en-1-one (4k)

Yield: 147 mg (42%); Z/E ~4:1; yellow solid; mp 66–67 °C.

L

L. N. Sobenina et al.

Paper

Synthesis

3-[5-(4-Fluorophenyl)-1-methyl-1H-pyrrol-2-yl]-1-phenyl-3-

1-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]ethan-1-one (7b)

(prop-2-ynylamino)prop-2-en-1-one (4m)

Yield: 35 mg (17%); light pink crystals; mp 154–155 °C.

Yield: 269 mg (75%); yellow oil.

IR (KBr): 3300, 1638, 1421, 1290, 1061, 780, 660 cm^–1

.

IR (film): 3414, 3299, 3103, 3061, 2923, 2854, 2145, 2120, 1898,

1596, 1586, 1552, 1527, 1500, 1484, 1458, 1382, 1332, 1285, 1227,

1177, 1159, 1136, 1079, 1056, 1024, 910, 840, 813, 764, 734, 692,

¹H NMR (400 MHz, CDCl₃): δ = 9.79 (br s, 1 H, NH), 7.38–7.33 (m, 3 H,

H-2,5,6 C₆H₄F), 7.02–6.97 (m, 1 H, H-4 C₆H₄F), 6.95–6.94 (m, 1 H, H-3

pyrrole), 6.57–6.56 (m, 1 H, H-4 pyrrole), 2.46 (s, 3 H, Me).

634, 538 cm^–1

.

¹³C NMR (101 MHz, CDCl₃): δ = 188.3 (C=O), 163.3 (d, ¹J_CF= 245.7 Hz,

¹H NMR (400 MHz, CDCl₃): δ = 11.23 (br t, J = 6.0 Hz, 1 H, NH-CH₂),

7.93–7.90 (m, 2 H, H-2,6 COPh), 7.47–7.40 (m, 5 H, H-2,6 C₆H₄F, H-

3,4,5 COPh), 7.16–7.12 (m, 2 H, H-3,5 C₆H₄F), 6.50 (d, J = 3.3 Hz, 1 H,

H-3 pyrrole), 6.28 (d, J = 3.3 Hz, 1 H, H-4 pyrrole), 5.95 (s, 1 H, HC=),

4.08 (dd, J = 6.0, 2.2 Hz, 2 H, CH₂), 3.62 (s, 3 H, NMe), 2.33 (t, J = 2.2 Hz,

1 H, ≡CH).

¹³C NMR (101 MHz, CDCl₃): δ = 188.8 (C=O), 162.2 (d, ¹J_CF= 247.6 Hz,

C-4 C₆H₄F), 156.8 (=C-N), 139.9 (C-1 COPh), 137.4 (C-5 pyrrole), 131.0

(C-4 COPh), 130.6 (d, ³J_CF= 8.0 Hz, C-2,6 C₆H₄F), 128.6 (d, ⁴J_CF= 3.1 Hz,

C-1 C₆H₄F), 128.2 (C-3,5 COPh), 128.1 (C-2 pyrrole), 127.1 (C-2,6

COPh), 115.5 (d, ²J_CF= 21.6 Hz, C-3,5 C₆H₄F), 111.9 (C-3 pyrrole), 109.0

(C-4 pyrrole), 95.6 (HC=), 79.8 (C≡), 72.4 (≡CH), 34.2 (NMe), 33.7

(CH₂).

3

C-3 C₆H₄F), 137.7 (C-5 pyrrole), 133.4 (d, J_CF= 8.3 Hz, C-1 C₆H₄F),

3

133.1 (C-2 pyrrole), 130.4 (d, J_CF= 8.4 Hz, C-5 C₆H₄F), 121.0 (C-6

C₆H₄F), 118.7 (C-3 pyrrole), 114.8 (d, ²J_CF= 21.3 Hz, C-4 C₆H₄F), 112.4

(d, ²J_CF= 23.2 Hz, C-2 C₆H₄F), 108.9 (C-4 pyrrole), 25.3 (Me).

Anal. Calcd for C₁₂H₁₀FNO: C, 70.93; H, 4.96; F, 9.35; N, 6.89. Found: C,

71.04; H, 4.75; F, 9.21; N, 7.12.

1-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]ethan-1-one (7c)

Yield: 30 mg (15%); light pink crystals; mp 154–155 °C.

IR (KBr): 3300, 1638, 1421, 1290, 1061, 780, 660 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.79 (br s, 1 H, NH), 7.63–7.59 (m, 2 H,

H-2,6 C₆H₄F), 7.13–7.09 (m, 2 H, H-3,5 C₆H₄F), 6.96 (dd, J = 3.60, 2.00

Hz, 1 H, H-3 pyrrole), 6.51–6.50 (m, 1 H, H-4 pyrrole), 2.46 (s, 3 H,

Me).

Anal. Calcd for C₂₃H₁₉FN₂O: C, 77.08; H, 5.34; F, 5.30; N, 7.82. Found:

C, 76.76; H, 4.99; F, 5.15; N, 7.98.

¹³C NMR (101 MHz, CDCl₃): δ = 187.8 (C=O), 163.3 (d, ¹J_CF= 248.3 Hz,

C-4 C₆H₄F), 137.9 (C-5 pyrrole), 132.8 (C-2 pyrrole), 127.5 (d, ⁴J_CF= 3.3

3-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-1-phenyl-3-(prop-

2-ynylamino)prop-2-en-1-one (4n)

3

Hz, C-1 C₆H₄F), 127.1 (d, J_CF= 8.0 Hz, C-2,6 C₆H₄F), 118.6 (C-3 pyr-

2

role), 116.1 (d, J_CF= 21.8 Hz, C-3,5 C₆H₄F), 108.3 (C-4 pyrrole), 25.4

Yield: 204 mg (64%); yellow solid; mp 86–87 °C.

(Me).

IR (KBr): 3294, 3087, 3060, 2931, 2850, 2240, 2153, 1592, 1569, 1516,

1458, 1427, 1389, 1353, 1316, 1284, 1239, 1185, 1127, 1079, 1057,

Anal. Calcd for C₁₂H₁₀FNO: C, 70.93; H, 4.96; F, 9.35; N, 6.89. Found: C,

71.04; H, 4.75; F, 9.21; N, 7.12.

1025, 910, 873, 808, 762, 732, 696, 664, 645, 614, 596, 548 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 11.34 (br t, J = 6.1 Hz, 1 H, NH-CH₂),

7.92–7.90 (m, 2 H, H-2,6 COPh), 7.44–7.38 (m, 3 H, H-3,4,5 COPh),

6.25 (s, 1 H, H-3 pyrrole), 5.85 (s, 1 H, HC=), 4.08 (dd, J = 6.1, 2.4 Hz,

CH₂), 3.51 (s, 3 H, NMe), 2.58–2.52 (m, 4 H, CH₂-4,7), 2.32 (t, J = 2.4 Hz,

1 H, ≡CH), 1.87–1.85 (m, 2 H, CH₂-5), 1.78–1.75 (m, 2 H, CH₂-6).

¹³C NMR (101 MHz, CDCl₃): δ = 188.0 (C=O), 157.4 (=C-N), 140.1 (C-1

COPh), 132.8 (C-7a pyrrole), 130.6 (C-4 COPh), 128.0 (C-3,5 COPh),

126.9 (C-2,6 COPh), 124.3 (C-2 pyrrole), 117.9 (C-3a pyrrole), 110.8

(C-3 pyrrole), 94.8 (HC=), 79.9 (C≡), 72.2 (≡CH), 34.2 (CH₂), 31.3

(NMe), 23.3, 22.9, 22.8, 22.1 (CH₂-4,5,6,7).

3-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-3-methoxy-1-(2-thie-

nyl)prop-2-en-1-one (11a)

Yield: 33 mg (10%); orange crystals; mp 166–167 °C.

IR (KBr): 3074, 2927, 1616, 1586, 1511, 1410, 1323, 1266, 1192, 1158,

1065, 842, 800, 721, 685 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 14.70 (br s, 1 H, NH), 7.78–7.77 (m, 1

H, H-3 thiophene), 7.59–7.58 (m, 1 H, H-5 thiophene), 7.54–7.52 (m,

1 H, H-6 C₆H₄F), 7.42–7.36 (m, 2 H, H-4,5 C₆H₄F), 7.15–7.12 (m, 1 H,

H-2 C₆H₄F), 6.98–6.93 (m, 2 H, H-4 thiophene, H-3 pyrrole), 6.67 (dd,

J = 3.60, 2.00 Hz, 1 H, H-4 pyrrole), 6.21 (s, 1 H, HC=), 3.98 (s, 3 H, Me).

Anal. Calcd for C₂₁H₂₂N₂O: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.55;

H, 6.71; N, 8.96.

¹³C NMR (101 MHz, CDCl₃): δ = 180.8 (C=O), 163.7 (=C-OMe), 163.4 (d,

¹J_CF= 245.5 Hz, C-3 C₆H₄F), 147.6 (C-2 thiophene), 135.0 (C-5 pyrrole),

3

1-[5-(2-Fluorophenyl)-1H-pyrrol-2-yl]ethan-1-one (7a)

134.2 (d, J_CF= 8.4 Hz, C-1 C₆H₄F), 132.4 (C-2 pyrrole), 130.6 (d, J_CF

=

8.6 Hz, C-5 C₆H₄F), 130.2 (C-5 thiophene), 128.4 (C-3 thiophene),

Yield: 35 mg (17%); light pink crystals; mp 125–126 °C.

4

128.2 (C-4 thiophene), 120.3 (d, J_CF= 2.6 Hz, C-6 C₆H₄F), 116.1 (C-3

IR (KBr): 3319, 1636, 1465, 1259, 1058, 757, 654 cm^–1

.

pyrrole), 114.1 (d, ²J_CF= 21.5 Hz, C-2 C₆H₄F), 111.5 (d, ²J_CF= 22.8 Hz, C-

¹H NMR (400 MHz, CDCl₃): δ = 9.97 (br s, 1 H, NH), 7.69–7.65 (m, 1 H,

H-6 C₆H₄F), 7.29–7.24 (m, 1 H, H-5 C₆H₄F), 7.20–7.12 (m, 2 H, H-3,4

C₆H₄F), 6.96–6.95 (m, 1 H, H-3 pyrrole), 6.68–6.67 (m, 1 H, H-4 pyr-

role), 2.46 (s, 3 H, Me).

4 C₆H₄F), 109.0 (C-4 pyrrole), 92.3 (HC=), 55.9 (Me).

Anal. Calcd for C₁₈H₁₄FNO₂S: C, 66.04; H, 4.31; F, 5.80; N, 4.28; S, 9.79.

Found: C, 65.67; H, 4.14; F, 6.08; N, 4.46; S, 9.40.

¹³C NMR (101 MHz, CDCl₃): δ = 187.6 (C=O), 159.3 (d, ¹J_CF= 248.2 Hz,

3-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-3-methoxy-1-(2-thie-

nyl)prop-2-en-1-one (11b)

C-2 C₆H₄F), 132.7 (C-2 pyrrole), 130.3 (C-5 pyrrole), 129.3 (d, ³J_CF= 8.8

3

4

Hz, C-4 C₆H₄F), 127.6 (d, J_CF= 2.5 Hz, C-6 C₆H₄F), 124.7 (d, J_CF= 2.5

Hz, C-5 C₆H₄F), 118.8 (d, ²J_CF= 11.4 Hz, C-1 C₆H₄F), 117.4 (C-3 pyrrole),

116.5 (d, ²J_CF= 22.5 Hz, C-3 C₆H₄F), 110.1 (d, ⁵J_CF= 3.2 Hz, C-4 pyrrole),

25.3 (Me).

Yield: 33 mg (10%); orange crystals; mp 129–130 °C.

IR (KBr): 3438, 2923, 1619, 1517, 1410, 1320, 1262, 1124, 1158, 1061,

836, 799, 713, 685 cm^–1

.

Anal. Calcd for C₁₂H₁₀FNO: C, 70.93; H, 4.96; F, 9.35; N, 6.89. Found: C,

70.88; H, 4.57; F, 9.42; N, 6.96.

M

L. N. Sobenina et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃): δ = 14.68 (br s, 1 H, NH), 7.76–7.71 (m, 3

H, H-3 thiophene, H-2,6 C₆H₄F), 7.59–7.58 (m, 1 H, H-5 thiophene),

7.16–7.12 (m, 3 H, H-4 thiophene, H-3,5 C₆H₄F), 6.98–6.97 (m, 1 H, H-

3 pyrrole), 6.63–6.62 (m, 1 H, H-4 pyrrole), 6.19 (s, 1 H, HC=), 3.96 (s,

3 H, Me).

¹³C NMR (101 MHz, CDCl₃): δ = 184.1 (C=O), 147.2 (C=CH), 140.9 (C-1

COPh), 129.9 (C-4 COPh), 129.2 (C-6a pyrrole), 128.2 (C-3,5 COPh),

126.6 (C-2,6 COPh), 125.3 (C-3a pyrrole), 122.9 (C-2 pyrrole), 120.4

(C-Me), 111.5 (=CH-NH), 106.6 (C-3 pyrrole), 83.3 (C=CH), 25.7 (CH₂-

6), 23.9 (CH₂-9), 23.7 (CH₂-7), 22.6 (CH₂-8), 18.2 (Me).

¹³C NMR (101 MHz, CDCl₃): δ = 180.6 (C=O), 163.7 (=C-OMe), 162.2 (d,

¹J_CF= 247.0 Hz, C-4 C₆H₄F), 147.7 (C-2 thiophene), 135.4 (C-5 pyrrole),

Anal. Calcd for C₂₀H₂₀N₂O: C, 78.92; H, 6.62; N, 9.20. Found: C, 78.63;

H, 6.35; N, 9.01.

132.2 (C-2 pyrrole), 130.0 (C-5 thiophene), 128.3 (d, ⁴J_CF= 2.6 Hz, C-1

3

C₆H₄F), 128.2 (C-3 thiophene), 128.0 (C-4 thiophene), 126.3 (d, J_CF

=

(Z)-2-(4-Methylene-6-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-

1(2H)-ylidene)-1-phenylethan-1-one (5c) and (Z)-2-(4-Methyl-6-

phenylpyrrolo[1,2-a]pyrazin-1(2H)-ylidene)-1-phenylethan-1-one

(6c)

7.8 Hz, C-2,6 C₆H₄F), 116.3 (C-3 pyrrole), 116.0 (d, ²J_CF= 21.6 Hz, C-3,5

C₆H₄F), 108.3 (C-4 pyrrole), 91.9 (HC=), 55.8 (Me).

Anal. Calcd for C₁₈H₁₄FNO₂S: C, 66.04; H, 4.31; F, 5.80; N, 4.28; S, 9.79.

Found: C, 66.17; H, 4.02; F, 5.78; N, 4.32; S, 9.91.

Method A: After heating at 60 °C for 30 min, a mixture of isomers 5c

and 6c was obtained; yield: 304 mg (93%); ratio 4:1. It was fractionat-

ed by column chromatography (alumina, n-hexane–Et₂O, 2:1) to give

5c.

Cyclization of Enaminones 4a–k in the Presence of Cs₂CO₃/DMSO;

General Procedure

A mixture of enaminone 4a–k (1.0 mmol) and Cs₂CO₃(1.0 mmol) in

DMSO (5 mL) was heated under argon. After cooling to r.t., the reac-

tion mixture was diluted with brine (1:10) and the obtained precipi-

tate was filtered off, washed with H₂O (5 × 15 mL), and dried to afford

individual compounds 6a,b (for enaminones 4a,b) or mixture of iso-

mers 5c–k and 6c–k (for enaminones 4c–k). The mixtures were sepa-

rated by column chromatography (alumina) to give the individual iso-

mers.

Yield: 176 mg (54%); yellow crystals; mp 197–198 °C.

IR (KBr): 3060, 1658, 1577, 1481, 1418, 1388, 1341, 1229, 1053, 878,

739, 694, 604, 548 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 11.63 (br s, 1 H, NH), 7.92–7.91 (m, 2

H, H-2,6 COPh), 7.43–7.35 (m, 8 H, H-3,4,5 COPh, Ph), 6.95–6.94 (m, 1

H, H-3 pyrrole), 6.42–6.41 (m, 1 H, H-4 pyrrole), 6.25 (s, 1 H, =CH),

4.84 (s, 1 H, =CH₂), 4.42 (s, 1 H, =CH₂), 4.26 (s, 2 H, CH₂-NH).

¹³C NMR (101 MHz, CDCl₃): δ = 187.4 (C=O), 150.9 (C=CH), 139.9 (C-1

COPh), 135.9 (C-1 Ph), 134.0 (C=CH₂), 130.9 (C-4 COPh), 129.6 (C-4

Ph), 127.7 (C-3,5 COPh), 127.6 (C-3,5 Ph), 127.3 (C-2,6 COPh), 127.1

(C-5 pyrrole), 126.0 (C-2,6 Ph), 125.6 (C-2 pyrrole), 113.3 (C-4 pyr-

role), 110.9 (C-3 pyrrole), 104.4 (=CH₂), 85.3 (C=CH), 44.8 (CH₂).

(Z)-1-(2-Furyl)-2-(4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene)ethan-1-one (6a)

After heating at 60 °C for 15 min, isomer 6a was obtained.

Yield: 221 mg (92%); yellow crystals; mp 182–183 °C.

Anal. Calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.64;

H, 5.18; N, 8.73.

IR (KBr): 3437, 1738, 1583, 1541, 1491, 1350, 1275, 1217, 1181, 1110,

1012, 830, 725, 653, 593 cm^–1

.

Method B: After heating at 80 °C for 10 min, 6c was obtained.

Yield: 268 mg (82%); yellow crystals; mp 171–172 °C.

¹H NMR (400 MHz, CDCl₃): δ = 14.36 (br s, 1 H, NH), 7.48–7.47 (m, 1

H, H-5 furan), 7.22–7.21 (m, 1 H, H-3 furan), 7.05–7.04 (m, 1 H, H-5

pyrrole), 7.01–7.00 (m, 1 H, H-3 pyrrole), 6.73–6.72 (m, 1 H, H-4 fu-

ran), 6.48–6.47 (m, 2 H, H-4 pyrrole, HC-NH), 6.24 (s, 1 H, =CH), 2.34

(s, 3 H, Me).

¹³C NMR (101 MHz, CDCl₃): δ = 175.3 (C=O), 154.8 (C-2 furan), 147.4

(C=CH), 143.6 (C-5 furan), 123.1 (C-2 pyrrole), 118.9 (C-5 pyrrole),

116.3 (C-Me), 113.7 (C-4 furan), 111.9 (C-3 furan), 111.4 (C-3 pyr-

role), 111.1 (=CH-NH), 108.1 (C-4 pyrrole), 83.4 (C=CH), 15.4 (Me).

IR (KBr): 2923, 1578, 1475, 1384, 1261, 1175, 1067, 909, 743, 702,

563 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 14.87 (br s, 1 H, NH), 8.00–7.97 (m, 2

H, H-2,6 COPh), 7.46–7.38 (m, 8 H, H-3,4,5 COPh, Ph), 7.13 (d, J = 4.0

Hz, 1 H, H-3 pyrrole), 6.65 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.42 (s, 1 H,

HC-NH), 6.39 (s, 1 H, =CH), 1.89 (s, 3 H, Me).

¹³C NMR (101 MHz, CDCl₃): δ = 184.5 (C=O), 148.2 (C=CH), 140.6 (C-1

COPh), 133.9 (C-1 Ph), 133.4 (C-5 pyrrole), 131.0 (C-3,5 COPh), 130.2

(C-4 COPh), 128.7 (C-4 Ph), 128.3 (C-3,5 Ph), 127.6 (C-2,6 COPh), 126.7

(C-2,6 Ph), 124.5 (C-2 pyrrole), 120.7 (C-Me), 116.5 (C-4 pyrrole),

113.1 (=CH-NH), 107.2 (C-3 pyrrole), 83.9 (C=CH), 19.2 (Me).

Anal. Calcd for C₁₄H₁₂N₂O₂: C, 69.99; H, 5.03; N, 11.66. Found: C,

69.63; H, 4.75; N, 11.31.

(Z)-2-(4-Methyl-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-

Anal. Calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.84;

H, 5.63; N, 8.31.

ylidene)-1-phenylethan-1-one (6b)

After heating at 60 °C for 15 min, isomer 6b was obtained.

Yield: 274 mg (90%); yellow crystals; mp 221–223 °C.

(Z)-2-[6-(2-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-phenylethan-1-one (5d) and (Z)-2-[6-

(2-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-ylidene]-

1-phenylethan-1-one (6d)

IR (KBr): 3435, 1580, 1521, 1405, 1358, 1268, 1172, 1132, 1035, 832,

740, 698, 599 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 14.76 (br s, 1 H, NH), 7.94–7.93 (m, 2

H, H-2,6 COPh), 7.42–7.41 (m, 3 H, H-3,4,5 COPh), 6.84 (s, 1 H, H-3

pyrrole), 6.33 (s, 1 H, HC-NH), 6.23 (s, 1 H, =CH), 3.22–3.19 (m, 2 H,

CH₂-6), 2.75–2.71 (m, 2 H, CH₂-9), 2.57 (s, 3 H, Me), 1.91–1.87 (m, 2 H,

CH₂-7), 1.80–1.77 (m, 2 H, CH₂-8).

After heating at 60 °C for 30 min, a mixture of isomers 5d and 6d was

obtained; yield: 327 mg (95%); ratio ~8.5:1.5; yellow solid. Then this

mixture was heated at 80 °C for 4.5 h to give, after treatment, 6d.

Yield: 310 mg (90%); yellow crystals; mp 143–144 °C.

IR (KBr): 3440, 1656, 1578, 1525, 1468, 1382, 1263, 1221, 1167, 1095,

1032, 820, 741, 696, 603 cm^–1

.

N

L. N. Sobenina et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃): δ = 14.90 (br s, 1 H, NH), 7.99–7.96 (m, 2

H, H-2,6 COPh), 7.45–7.41 (m, 5 H, H-4,6 C₆H₄F, H-3,4,5 COPh), 7.23–

7.20 (m, 1 H, H-5 C₆H₄F), 7.16–7.12 (m, 2 H, H-3 C₆H₄F, H-3 pyrrole),

6.68 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.45 (m, 1 H, =CH), 6.39 (s, 1 H,

HC-NH), 1.96 (s, 3 H, Me).

7.07 (m, 2 H, H-4 thiophene, H-3 C₆H₄F), 6.94 (d, J = 4.0 Hz, 1 H, H-3

pyrrole), 6.44 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.13 (s, 1 H, =CH), 4.75

(s, 1 H, =CH₂), 4.39 (s, 1 H, =CH₂), 4.22 (s, 2 H, CH₂-NH).

¹³C NMR (101 MHz, CDCl₃): δ = 181.3 (C=O), 159.5 (d, ¹J_CF= 249.4 Hz,

C-2 C₆H₄F), 151.5 (C=CH), 147.6 (C-2 thiophene), 135.4 (C=CH₂), 130.9

(d, ³J_CF= 2.6 Hz, C-6 C₆H₄F), 130.4 (d, ³J_CF= 8.0 Hz, C-4 C₆H₄F), 130.3 (C-

5 pyrrole), 129.7 (C-5 thiophene), 127.8 (C-3 thiophene), 127.3 (C-4

¹³C NMR (101 MHz, CDCl₃): δ = 184.5 (C=O), 160.8 (d, ¹J_CF= 246.5 Hz,

C-2 C₆H₄F), 148.0 (C=CH), 140.5 (C-1 COPh), 132.9 (C-5 pyrrole), 131.1

3

4

(d, J_CF= 8.0 Hz, C-4 C₆H₄F), 130.2 (C-4 COPh), 128.2 (C-3,5 COPh),

thiophene), 126.3 (C-2 pyrrole), 124.6 (d, J_CF= 3.6 Hz, C-5 C₆H₄F),

126.7 (C-2,6 COPh), 126.1 (C-6 C₆H₄F), 125.0 (C-2 pyrrole), 123.7 (d,

120.2 (d, ²J_CF= 14.7 Hz, C-1 C₆H₄F), 116.2 (d, ²J_CF= 21.7 Hz, C-3 C₆H₄F),

114.8 (C-4 pyrrole), 111.6 (C-3 pyrrole), 103.1 (=CH₂), 86.1 (C=CH),

45.5 (CH₂).

⁴J_CF= 3.2 Hz, C-5 C₆H₄F), 121.9 (d, ²J_CF= 16.1 Hz, C-1 C₆H₄F), 120.5 (C-

2

Me), 117.0 (C-4 pyrrole), 115.2 (d, J_CF= 21.5 Hz, C-3 C₆H₄F), 113.1

(=CH-NH), 107.4 (C-3 pyrrole), 84.0 (C=CH), 17.4 (Me).

¹⁹F NMR (377 MHz, CDCl₃): δ = –113.4.

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.81; H, 4.88; F, 5.47; N, 8.15.

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.21; H, 4.12; F, 5.48; N, 8.00; S, 9.04.

(Z)-2-[6-(2-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-(2-furyl)ethan-1-one (5e) and (Z)-2-

[6-(2-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene]-1-(2-furyl)ethan-1-one (6e)

(Z)-2-[6-(3-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-phenylethan-1-one (5g) and (Z)-2-[6-

(3-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-ylidene]-

1-phenylethan-1-one (6g)

After heating at 60 °C for 30 min, a mixture of isomers 5e and 6e was

obtained; yield: 304 mg (91% yield); ratio ~4:1; yellow solid. After

heating of enaminone 4e at 60 °C for 120 min, a mixture of isomers 5e

and 6e (1:20) was obtained. It was fractionated by column chroma-

tography (silica gel, n-hexane–Et₂O, 1:4) to give pyrrolopyrazine 6e.

After heating at 60 °C for 30 min, a mixture of isomers 5g and 6g was

obtained; yield: 327 mg (95%); ratio ~4:1; yellow crystals; mp 192–

193 °C. Then this mixture was heated at 80 °C for 2 h to give, after

treatment, isomer 6g.

Yield: 320 mg (93%); yellow crystals; mp 150–151 °C.

Yield: 234 mg (70%); yellow crystals; mp 185–187 °C.

IR (KBr): 3057, 1584, 1538, 1468, 1380, 1346, 1271, 1227, 1169, 1093,

IR (KBr): 3437, 1664, 1575, 1545, 1484, 1372, 1261, 1236, 1168, 1093,

880, 845, 777, 742, 698, 660, 514 cm^–1

.

1055, 1012, 935, 846, 815, 760, 687, 650, 593, 525 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 14.87 (br s, 1 H, NH), 7.99–7.97 (m, 2

H, H-2,6 COPh), 7.46–7.44 (m, 3 H, H-3,4,5 COPh), 7.40–7.35 (m, 1 H,

H-6 C₆H₄F), 7.22–7.21 (m, 1 H, H-2 C₆H₄F), 7.17–7.11 (m, 3 H, H-4,5

C₆H₄F, H-3 pyrrole), 6.66 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.45 (s, 1 H,

HC-NH), 6.39 (s, 1 H, =CH), 1.94 (s, 3 H, Me).

¹H NMR (400 MHz, CDCl₃): δ = 14.39 (br s, 1 H, NH), 7.51–7.50 (m, 1

H, H-5 furan), 7.46–7.40 (m, 2 H, H-4,6 C₆H₄F), 7.23–7.19 (m, 1 H, H-3

furan), 7.17–7.16 (m, 1 H, H-5 C₆H₄F), 7.14–7.12 (m, 1 H, H-3 C₆H₄F),

7.03 (d, J = 3.6 Hz, 1 H, H-3 pyrrole), 6.67 (d, J = 3.6 Hz, 1 H, H-4 pyr-

role), 6.50 (dd, J = 3.2, 1.6 Hz, 1 H, H-4 furan), 6.40 (s, 1 H, HC-NH),

6.32 (s, 1 H, =CH), 1.94 (s, 3 H, Me).

¹³C NMR (101 MHz, CDCl₃): δ = 184.7 (C=O), 161.8 (d, ¹J_CF= 246.5 Hz,

C-3 C₆H₄F), 148.0 (C=CH), 140.4 (C-1 COPh), 135.8 (d, ³J_CF= 8.4 Hz, C-1

C₆H₄F), 131.8 (d, ⁴J_CF= 2.1 Hz, C-5 pyrrole), 130.3 (C-4 COPh), 129.1 (d,

³J_CF= 8.8 Hz, C-5 C₆H₄F), 128.3 (C-3,5 COPh), 126.9 (d, ⁴J_CF= 2.9 Hz, C-6

C₆H₄F), 126.7 (C-2,6 COPh), 124.7 (C-2 pyrrole), 120.4 (C-Me), 118.0

¹³C NMR (101 MHz, CDCl₃): δ = 175.3 (C=O), 161.0 (d, ¹J_CF= 247.7 Hz,

C-2 C₆H₄F), 154.9 (C-2 furan), 147.9 (C=CH), 143.6 (C-5 furan), 133.0

(C-5 pyrrole), 131.2 (d, ³J_CF= 7.9 Hz, C-4 C₆H₄F), 126.4 (d, ³J_CF= 3.9 Hz,

4

C-6 C₆H₄F), 125.0 (C-2 pyrrole), 123.8 (d, J_CF= 3.1 Hz, C-5 C₆H₄F),

2

(d, J_CF= 21.5 Hz, C-4 C₆H₄F), 116.6 (C-4 pyrrole), 115.7 (d, J_CF= 21.5

Hz, C-2 C₆H₄F), 113.3 (=CH-NH), 107.4 (C-3 pyrrole), 84.1 (C=CH), 19.2

(Me).

120.3 (C-Me), 120.0 (d, ²J_CF= 14.7 Hz, C-1 C₆H₄F), 117.1 (C-4 pyrrole),

115.4 (d, ²J_CF= 21.5 Hz, C-3 C₆H₄F), 112.7 (C-3 furan), 111.9 (=CH-NH),

111.5 (C-4 furan), 107.9 (C-3 pyrrole), 83.2 (C=CH), 17.5 (Me).

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.81; H, 4.98; F, 5.63; N, 7.94.

Anal. Calcd for C₂₀H₁₅FN₂O₂: C, 71.85; H, 4.52; F, 5.68; N, 8.38. Found:

C, 71.53; H, 4.13; F, 5.57; N, 8.40.

(Z)-2-[6-(3-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-(2-furyl)ethan-1-one (5h) and (Z)-2-

[6-(3-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene]-1-(2-furyl)ethan-1-one (6h)

(Z)-2-[6-(2-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-(2-thienyl)ethan-1-one (5f) and (Z)-2-

[6-(2-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene]-1-(2-thienyl)ethan-1-one (6f)

A mixture of enaminone 4h (0.15 mmol) and Cs₂CO₃(0.15 mmol) in

DMSO (5 mL) was stirred at 60 °C under argon for 30 min. After cool-

ing to r.t., the reaction mixture was diluted with brine (1:10) and the

obtained precipitate was filtered off, washed with H₂O (5 × 15 mL)

and dried to afford pyrrolopyrazines 5h and 6h; yield: 48 mg (96%);

ratio ~4:1. This mixture was fractionated by column chromatography

(alumina, n-hexane–Et₂O, 1:4) to give pyrrolopyrazine 5h.

After heating at 60 °C for 30 min, a mixture of isomers 5f and 6f was

obtained; yield: 333 mg (95%); ratio ~4:1; yellow solid. This mixture

was fractionated by column chromatography (alumina, n-hexane–

Et₂O, 1:4) to give pyrrolopyrazine 5f.

Yield: 151 mg (43%); yellow crystals; mp 192–193 °C.

IR (KBr): 3105, 1662, 1586, 1485, 1418, 1388, 1346, 1236, 1157, 1059,

850, 762, 725, 662, 604, 516 cm^–1

.

Yield: 19 mg (38%); yellow crystals; mp 184–185 °C.

¹H NMR (400 MHz, CDCl₃): δ = 11.22 (br s, 1 H, NH), 7.61–7.60 (m, 1

H, H-3 thiophene), 7.45–7.40 (m, 2 H, H-6 C₆H₄F, H-5 thiophene),

7.39–7.33 (m, 1 H, H-4 C₆H₄F), 7.23–7.19 (m, 1 H, H-5 C₆H₄F), 7.12–

IR (KBr): 2923, 1663, 1574, 1464, 1386, 1347, 1265, 1062, 879, 774,

698, 593, 524 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 11.27 (br s, 1 H, NH), 7.50–7.49 (m, 1

H, H-5 furan), 7.45–7.41 (m, 1 H, H-6 C₆H₄F), 7.40–7.35 (m, 1 H, H-2

C₆H₄F), 7.24–7.20 (m, 1 H, H-3 furan), 7.13–7.09 (m, 1 H, H-5 C₆H₄F),

O

L. N. Sobenina et al.

Paper

Synthesis

7.03–7.02 (m, 1 H, H-4 C₆H₄F), 6.97 (d, J = 4.0 Hz, 1 H, H-3 pyrrole),

6.49 (dd, J = 3.2, 1.6 Hz, 1 H, H-4 furan), 6.45 (d, J = 4.0 Hz, 1 H, H-4

pyrrole), 6.21 (s, 1 H, =CH), 4.76 (s, 1 H, =CH₂), 4.40 (s, 1 H, =CH₂), 4.24

(s, 2 H, CH₂-NH).

IR (KBr): 3058, 1664, 1578, 1538, 1421, 1380, 1345, 1260, 1233, 1157,

1057, 876, 838, 783, 746, 696, 637, 542 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 11.62 (br s, 1 H, NH), 7.92–7.89 (m, 2

H, H-2,6 COPh), 7.43–7.37 (m, 5 H, H-3,4,5 COPh, H-2,6 C₆H₄F), 7.11–

7.06 (m, 2 H, H-3,5 C₆H₄F), 6.92 (d, J = 4.0 Hz, 1 H, H-3 pyrrole), 6.37

(d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.24 (s, 1 H, =CH), 4.84 (s, 1 H, =CH₂),

4.40 (s, 1 H, =CH₂), 4.24 (d, J = 1.6 Hz, 2 H, CH₂-NH).

Anal. Calcd for C₂₀H₁₅FN₂O₂: C, 71.85; H, 4.52; F, 5.68; N, 8.38. Found:

C, 71.92; H, 4.33; F, 5.74; N, 8.12.

¹³C NMR (101 MHz, CDCl₃): δ = 188.5 (C=O), 162.6 (d, ¹J_CF= 248.5 Hz,

C-4 C₆H₄F), 151.7 (C=CH), 140.8 (C-1 COPh), 135.7 (C=CH₂), 135.0 (C-4

COPh), 130.6 (C-5 pyrrole), 130.3 (d, ³J_CF= 7.9 Hz, C-2,6 C₆H₄F), 128.3

(Z)-2-[6-(3-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-(2-thienyl)ethan-1-one (5i) and (Z)-2-

[6-(3-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene]-1-(2-thienyl)ethan-1-one (6i)

4

(C-3,5 COPh), 128.0 (d, J_CF= 3.0 Hz, C-1 C₆H₄F), 127.0 (C-2,6 COPh),

2

126.6 (C-2 pyrrole), 115.8 (d, J_CF= 21.7 Hz, C-3,5 C₆H₄F), 114.2 (C-4

After heating at 60 °C for 30 min, a mixture of isomers 5i and 6i was

pyrrole), 111.8 (C-3 pyrrole), 105.3 (=CH₂), 86.4 (C=CH), 45.8 (CH₂).

obtained; yield: 333 mg (95%); ratio ~7:3; yellow solid; mp 192–193

°C.

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.52; H, 4.77; F, 5.63; N, 7.88.

IR (KBr): 3296, 1585, 1536, 1486, 1416, 1380, 1329, 1296, 1243, 1197,

1163, 1082, 1063, 966, 908, 846, 774, 715, 684, 645, 524 cm^–1

.

Method B: After heating at 80 °C for 1.5 h, pyrrolopyrazine 6j was ob-

tained. Its purification (alumina, n-hexane–Et₂O, 1:4) gave isomer 6j.

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.67; H, 3.98; F, 5.13; N, 7.74; S 9.32.

Yield: 193 mg (56%); yellow crystals; mp 175–177 °C.

5i: ¹H NMR (400 MHz, CDCl₃): δ = 11.25 (br s, 1 H, NH), 7.61–7.60 (m,

1 H, H-3 thiophene), 7.45–7.43 (m, 1 H, H-5 thiophene), 7.38–7.33

(m, 1 H, H-6 C₆H₄F), 7.21–7.19 (m, 1 H, H-2 C₆H₄F), 7.15–7.07 (m, 3 H,

H-4 thiophene, H-4,5 C₆H₄F), 6.92 (d, J = 3.8 Hz, 1 H, H-3 pyrrole), 6.43

(d, J = 3.8 Hz, 1 H, H-4 pyrrole), 6.12 (s, 1 H, =CH), 4.88 (s, 1 H, =CH₂),

4.45 (s, 1 H, =CH₂), 4.24 (s, 2 H, CH₂-NH).

IR (KBr): 3094, 1690, 1583, 1537, 1471, 1384, 1348, 1266, 1220, 1171,

1094, 884, 837, 777, 742, 699, 645, 551 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 14.87 (br s, 1 H, NH), 7.98–7.97 (m, 2

H, H-2,6 COPh), 7.45–7.39 (m, 5 H, H-3,4,5 COPh, H-2,6 C₆H₄F), 7.12–

7.08 (m, 3 H, H-3,5 C₆H₄F, H-3 pyrrole), 6.63 (d, J = 4.0 Hz, 1 H, H-4

pyrrole), 6.43 (s, 1 H, HC-NH), 6.38 (s, 1 H, =CH), 1.89 (s, 3 H, Me).

¹³C NMR (101 MHz, CDCl₃): δ = 181.3 (C=O), 162.8 (d, ¹J_CF= 246.6 Hz,

C-3 C₆H₄F), 151.3 (C=CH), 147.5 (C-2 thiophene), 135.3 (C=CH₂), 134.7

(C-5 pyrrole), 133.8 (d, ³J_CF= 8.2 Hz, C-1 C₆H₄F), 130.3 (d, ³J_CF= 8.4 Hz,

C-5 C₆H₄F), 129.7 (C-5 thiophene), 127.8 (C-3 thiophene), 127.3 (C-4

¹³C NMR (101 MHz, CDCl₃): δ = 184.4 (C=O), 163.0 (d, ¹J_CF= 248.9 Hz,

C-4 C₆H₄F), 148.1 (C=CH), 140.5 (C-1 COPh), 132.7 (d, ³J_CF= 8.2 Hz, C-

4

2,6 C₆H₄F), 132.1 (C-4 COPh), 130.2 (C-5 pyrrole), 129.8 (d, J_CF= 3.2

Hz, C-1 C₆H₄F), 128.3 (C-3,5 COPh), 126.7 (C-2,6 COPh), 124.5 (C-2

pyrrole), 120.4 (C-Me), 116.5 (C-4 pyrrole), 114.6 (d, ²J_CF= 21.6 Hz, C-

3,5 C₆H₄F), 113.3 (=CH-NH), 107.1 (C-3 pyrrole), 83.9 (C=CH), 19.2

(Me).

4

thiophene), 126.9 (C-2 pyrrrole), 124.2 (d, J_CF= 2.2 Hz, C-6 C₆H₄F),

115.4 (d, ²J_CF= 22.4 Hz, C-4 C₆H₄F), 115.0 (d, ²J_CF= 21.0 Hz, C-2 C₆H₄F),

114.7 (C-4 pyrrole), 111.9 (C-3 pyrrole), 105.7 (=CH₂), 86.2 (C=CH),

45.7 (CH₂).

Anal. Calcd for C₂₂H₁₇FN₂O: C, 76.73; H, 4.98; F, 5.52; N, 8.13. Found:

C, 76.52; H, 4.77; F, 5.63; N, 7.88.

¹⁹F NMR (377 MHz, CDCl₃): δ = –112.7.

6i: ¹H NMR (400 MHz, CDCl₃): δ = 14.30 (br s, 1 H, NH), 7.64–7.63 (m,

1 H, H-3 thiophene), 7.45–7.43 (m, 1 H, H-5 thiophene), 7.38–7.33

(m, 1 H, H-6 C₆H₄F), 7.21–7.19 (m, 1 H, H-2 C₆H₄F), 7.15–7.07 (m, 2 H,

H-5 C₆H₄F, H-4 thiophene), 7.05–7.01 (m, 2 H, H-4 C₆H₄F, H-3 pyr-

role), 6.63 (d, J = 3.8 Hz, 1 H, H-4 pyrrole), 6.36 (m, 1 H, HC-NH), 6.24

(s, 1 H, =CH), 1.90 (s, 3 H, Me).

(Z)-2-[6-(4-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-(2-thienyl)ethan-1-one (5k) and (Z)-2-

[6-(4-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-

ylidene]-1-(2-thienyl)ethan-1-one (6k)

After heating at 60 °C for 30 min, a mixture of isomers 5k and 6k was

obtained; yield: 333 mg (95%); ratio ~3:1; yellow solid. Then this mix-

ture was heated at 80 °C for 1.5 h to give isomer 6k. Its purification

(alumina, n-hexane–Et₂O, 1:4) gave pyrrolopyrazine 6k.

¹³C NMR (101 MHz, CDCl₃): δ = 179.1 (C=O), 161.9 (d, ¹J_CF= 248.0 Hz,

3

C-3 C₆H₄F), 151.3 (C=CH), 147.5 (C-2 thiophene), 135.8 (d, J_CF= 8.1

Hz, C-1 C₆H₄F), 132.1 (C-5 pyrrole), 129.2 (d, ³J_CF= 7.8 Hz, C-5 C₆H₄F),

129.1 (C-5 thiophene), 126.9 (C-3 thiophene), 126.7 (C-4 thiophene),

Yield: 203 mg (58%); yellow crystals; mp 208–209 °C.

4

2

124.5 (d, J_CF= 2.5 Hz, C-6 C₆H₄F), 120.0 (C-2 pyrrole), 118.1 (d, J_CF

=

21.1 Hz, C-4 C₆H₄F), 116.6 (C-4 pyrrole), 116.6 (C-Me), 115.7 (d, ²J_CF

IR (KBr): 3077, 1656, 1579, 1509, 1414, 1391, 1256, 1224, 1164, 1092,

849, 753, 701, 555 cm^–1

.

21.0 Hz, C-2 C₆H₄F), 112.8 (C-3 pyrrole), 107.7 (=CH-NH), 83.3 (C=CH),

¹H NMR (400 MHz, CDCl₃): δ = 14.30 (br s, 1 H, NH), 7.65–7.64 (m, 1

H, H-3 thiophene), 7.45–7.44 (m, 1 H, H-5 thiophene), 7.42–7.39 (m,

2 H, H-2,6 C₆H₄F), 7.12–7.08 (m, 4 H, H-3,5 C₆H₄F, H-4 thiophene, H-3

pyrrole), 6.62 (d, J = 4.0 Hz, 1 H, H-4 pyrrole), 6.35 (s, 1 H, HC-NH),

6.25 (s, 1 H, =CH), 1.87 (s, 3 H, Me).

19.1 (Me).

¹⁹F NMR (377 MHz, CDCl₃): δ = –113.4.

(Z)-2-[6-(4-Fluorophenyl)-4-methylene-3,4-dihydropyrrolo[1,2-

a]pyrazin-1(2H)-ylidene]-1-phenylethan-1-one (5j) and (Z)-2-[6-

(4-Fluorophenyl)-4-methylpyrrolo[1,2-a]pyrazin-1(2H)-ylidene]-

1-phenylethan-1-one (6j)

¹³C NMR (101 MHz, CDCl₃): δ = 178.0 (C=O), 162.1 (d, ¹J_CF= 249.0 Hz,

3

C-4 C₆H₄F), 146.6 (C-2 thiophene), 146.5 (C=CH), 131.8 (d, J_CF= 8.2

4

Hz, C-2,6 C₆H₄F), 131.4 (C-5 pyrrole), 128.8 (d, J_CF= 3.5 Hz, C-1

Method A: After heating at 60 °C for 30 min, a mixture of isomers 5j

and 6j was obtained; yield: 327 mg (95%); ratio ~9:1. It was fraction-

ated by column chromatography (alumina, n-hexane–Et₂O, 1:4) to

give pyrrolopyrazine 5j.

C₆H₄F), 128.1 (C-5 thiophene), 126.8 (C-3 thiophene), 125.7 (C-4 thio-

phene), 123.2 (C-2 pyrrole), 119.0 (C-Me), 115.6 (C-4 pyrrole), 113.7

2

(d, J_CF= 21.6 Hz, C-3,5 C₆H₄F), 111.6 (=CH-NH), 106.6 (C-3 pyrrole),

82.1 (C=CH), 18.3 (Me).

Yield: 210 mg (61%); yellow crystals; mp 183–184 °C.

P

L. N. Sobenina et al.

Paper

Synthesis

Anal. Calcd for C₂₀H₁₅FN₂OS: C, 68.55; H, 4.31; F, 5.42; N, 7.99; S, 9.15.

Found: C, 68.44; H, 4.25; F, 5.33; N, 7.71; S, 9.32.

(13) Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.; Pathak, A. K.; Dabur,

R.; Chhillar, A. K.; Singh, R.; Sharma, G. L.; Chandra, R.; Verma, A.

K. Bioorg. Med. Chem. Lett. 2006, 16, 413.

(14) Fisher, T. E.; Kim, B.; Staas, D. D.; Lyle, T. A.; Young, S. D.; Vacca, J.

P.; Zrada, M. M.; Hazuda, D. J.; Felock, P. J.; Schleif, W. A.;

Gabryelski, L. J.; Anari, M. R.; Kochanskyd, C. J.; Wai, J. S. Bioorg.

Med. Chem. Lett. 2007, 17, 6511.

Funding Information

This work was supported by the President of the Russian Federation

(programs for the support of leading scientific schools, grant NSh-

(15) (a) Bamberg, J. T.; Joe, Du. B. D.; Elworthy, T. R.; Hendricks, R. T.;

Hermann, J. C.; Jahangir, A.; Kondru, R. K.; Lemoine, R.; Lou, Y.;

Owens, T. D.; Park, J.; Smith, D. B.; Soth, M.; Yang, H. Patent

WO2009106441 A1, 2009. (b) Soth, M.; Hermann, J. C.; Yee, C.;

Alam, M.; Barnett, J. W.; Berry, P.; Browner, M. F.; Frank, K.;

Frauchiger, S.; Harris, S.; He, Y.; Hekmat-Nejad, M.; Hendricks,

T.; Henningsen, R.; Hilgenkamp, R.; Ho, H.; Hoffman, A.; Hsu, P.-

Y.; Hu, D.-Q.; Itano, A.; Jaime-Figueroa, S.; Jahangir, A.; Jin, S.;

Kuglstatter, A.; Kutach, A. K.; Liao, C.; Lynch, S.; Menke, J.; Niu,

L.; Patel, V.; Railkar, A.; Roy, D.; Shao, A.; Shaw, D.; Steiner, S.;

Sun, Y.; Tan, S.-L.; Wang, S.; Vu, M. D. J. Med. Chem. 2013, 56,

345. (c) Padilla, F.; Bhagirath, N.; Chen, S.; Chiao, E.; Goldstein,

D. M.; Hermann, J. C.; Hsu, J.; Kennedy-Smith, J. J.; Kuglstatter,

A.; Liao, C.; Liu, W.; Lowrie, L. E. Jr.; Luk, K. C.; Lynch, S. M.;

Menke, J.; Niu, L.; Owens, T. D.; O-Yang, C.; Railkar, A.;

Schoenfeld, R. C.; Slade, M.; Steiner, S.; Tan, Y.-C.; Villaseñor, A.

G.; Wang, C.; Wanner, J.; Xie, W.; Xu, D.; Zhang, X.; Zhou, M.;

Lucas, M. C. J. Med. Chem. 2013, 56, 1677.

7145.2016.3).

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Acknowledgment

Authors acknowledge Baikal Analytical Center for collective use of the

equipment (SB RAS).

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0036-1588454.

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Article Doi

Transition-Metal-Free Synthesis of Pyrrolo[1,2- a ]pyrazines via Intramolecular Cyclization of N -Propargyl(pyrrolyl)enaminones

DOI: 10.1055/s-0036-1588454

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Article abstract of DOI:10.1055/s-0036-1588454

Full text of DOI:10.1055/s-0036-1588454

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