Synthesis and selected properties of N-substituted pyrrolo[2,1-c]-1,3- diazacycloalkano[1,2-a]pyrazinones

Article abstract of DOI:10.1007/s11172-010-0230-0

The reactions of methyl α-(2-formyl-1H-pyrrol-1-yl)carboxylates with N-substituted aliphatic 1,2-, 1,3-, and 1,4-diamines afford new pyrrole-containing heterocyclic systems: 1,2,3,10b-tetrahydroimidazo[1,2-a] pyrrolo[2,1-c]pyrazin-5(6H)-ones, 1,3,4,11b-tetrahydro-2H-pyrrolo[2′, 1′:3,4]pyrazino[1,2-a]pyrimidin-6(7H)-ones, and 1,2,3,4,5,12b-hexahydro- pyrrolo[2′,1′:3,4]pyrazino[1,2-a][1,3]diazepin-7(8H)-ones. The reduction of these compounds with different reagents was studied.

Full text of DOI:10.1007/s11172-010-0230-0

Russian Chemical Bulletin, International Edition, Vol. 59, No. 6, pp. 1254—1266, June, 2010
1254
Synthesis and selected properties of Nꢀsubstituted
pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloalkano[1,2ꢀa]pyrazinones
G. V. Mokrov,a A. M. Likhosherstov,a V. P. Lezina,a T. A. Gudasheva,a I. S. Bushmarinov,b and M. Yu. Antipinb
aV. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences,
8 ul. Baltiiskaya, 125315 Moscow, Russian Federation.
Fax: +7 (495) 151 1261. Eꢀmail: g.mokrov@gmail.com
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6549
The reactions of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylates with Nꢀsubstituted
aliphatic 1,2ꢀ, 1,3ꢀ, and 1,4ꢀdiamines afford new pyrroleꢀcontaining heterocyclic systems:
1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀones, 1,3,4,11bꢀtetrahydroꢀ
2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀones, and 1,2,3,4,5,12bꢀhexahydroꢀ
pyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa][1,3]diazepinꢀ7(8H)ꢀones. The reduction of these compounds
with different reagents was studied.
Key words: aliphatic diamines, aldehyde esters, aminals, pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloꢀ
alkano[1,2ꢀa]pyrazinones, heterocyclization, hydrogenolysis, Xꢀray diffraction study, NMR
spectroscopy.
The reactions of aldehyde acids, keto acids, and their
esters with amino alcohols, amino thiols, and diamines
provide a convenient route to bicyclic saturated and parꢀ
tially unsaturated heterocyclic systems.1—5 These reacꢀ
tions are used for the synthesis of biologically active comꢀ
pounds2,3 and alkaloids4,6 and are employed in the highly
stereoselective synthesis of drugs of natural origin.7,8 These
reactions lied at the basis of the present study. The followꢀ
ing derivatives of the previously unknown heterocyclic sysꢀ
tems were synthesized: 1,2,3,10bꢀtetrahydroimidazoꢀ
[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazines (1), 1,3,4,11bꢀtetrahydroꢀ
2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidines (2),
and 1,2,3,4,5,12bꢀhexahydropyrrolo[2´,1´:3,4]pyrazinoꢀ
[1,2ꢀa][1,3]diazepines (3). These compounds are strucꢀ
turally similar to a series of compounds with a broad specꢀ
trum of biological activities (antiviral, nootropic, spasꢀ
molytic antitussive, anxiolytic, etc.).2,9,10 Hence, these
compounds are of interest as potential new drugs. In addiꢀ
tion, due to the presence of the aminal moiety, heterocyꢀ
cles 1—3 are of interest in terms of chemical transformaꢀ
tions, primarily, under reduction conditions.
n = 1 (1), 2 (2), 3 (3)
in an acidic medium the hydrolysis of the starting acetal 5
containing three reaction centers initially occurs at the
least stable endocyclic ketal group. The resulting carbocaꢀ
tion reacts with the amino group of ester 6 followed by the
closure of the fiveꢀmembered ring, which is transformed
into pyrrole.12,13
The developed method for the synthesis of esters 4 has
an advantage over the procedures described previously14—16
because it has a general character and allows the oneꢀpot
synthesis of these compounds in good yield.
NꢀSubstituted diamines 7—9 served as the second comꢀ
ponents for the synthesis of heterocycles 1, 2, and 3, reꢀ
spectively.
Nꢀ(Arylmethyl)substituted diamines 7—9 were syntheꢀ
sized by the reduction of the condensation products of the
corresponding aromatic aldehydes 10 with unsubstituted
diamines 11 (Scheme 2).17,18 The reactions involved the
hydrogenation of a mixture of the starting compounds in
methanol in the presence of a palladium catalyst under
atmospheric pressure. To reduce the formation of byꢀprodꢀ
Heterocycles 1—3 were synthesized starting from meꢀ
thyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylates (4). We deꢀ
veloped a new procedure for the synthesis of these comꢀ
pounds based on the condensation of 2,5ꢀdimethoxyꢀ2ꢀ
dimethoxymethyltetrahydrofuran (acetal 5)11 with amino
acid methyl ester hydrochlorides 6 in an aqueous phosꢀ
phate buffer (pH 4.7) (Scheme 1). The fiveꢀmembered
heterocycle in this reaction is formed due to the fact that
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1228—1239, June, 2010.
1066ꢀ5285/10/5906ꢀ1254 © 2010 Springer Science+Business Media, Inc.

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1255
Scheme 1
4: R = H (a), Me (b), CH2Ph (c)
(Scheme 3). Previously, such reactions have been perꢀ
formed by prolonged boiling of a mixture of the starting
oxo acids or their esters and diamines1,5,19 in aromatic
solvents. We also showed that heterocyclic compounds 1
and 2 can be prepared in high yields simply by refluxing
esters 4 with diamines 7 and 8 in a ratio of 1 : 1.1 in ethanꢀ
olic solutions for 1 h.
The synthesis of compounds 3 required more drastic
conditions. Thus, these compounds were synthesized by
refluxing esters 4 with diamines 9 in xylene for 7 h.
We suggest that the reaction giving rise to tricyclic
systems 1, 2, and 3 occurs by the mechanism presented in
Scheme 4. Initially, aldehyde ester 4 reacts with diamines
7—9 to give hemiaminal 12 at the primary amino group.
Compound 12 exists in the equilibrium with imine form
13. The second amino group adds at the imine bond to
form cyclic aminal 14, which is acylated by the ester group.
ucts, the threefold molar excess of diamines 11 was used.
Target compounds 7—9 were prepared in 65—80% yields.
Tricyclic fused systems 1, 2, and 3 were accessed by
the reactions of aldehyde esters 4 with diamines 7—9
Scheme 2
Comꢀ
Ar
n
R
Comꢀ
Ar
n
R
pound
pound
7a
7b
7c
7d
Ph
0
0
0
0
H
H
H
H
8a
8b
9a
9b
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
Ph
1
1
2
2
H
Me
H
3,4ꢀ(MeO)2C6H3
3,4,5ꢀ(MeO)3C6H2
2ꢀFuryl
3,4ꢀ(MeO)2C6H3
H

1256
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
Scheme 3
Tricyclic structures 1c and 2d crystallized as racemates
in the centrosymmetric space group P1 (Fig. 1). Comꢀ
–
pound 1c crystallized with one water molecule per formula
unit. The asymmetric unit of compound 2d contains two
independent molecules (hereinafter, 2dA and 2dB).
In the crystal structure of 1c, the water molecule forms
strong hydrogen bonds with the N(1) (O...N, 3.0618(13) Å;
O—H...N, 167.0(18)°) and O(13) (O...O, 2.8457(12) Å;
O—H...O 173.5(19)°) atoms, resulting in the formation of
hydrogenꢀbonded centrosymmetric dimers of 1c, which
are, in turn, linked together by weak van der Waals interꢀ
actions.
Compound 2d crystallized as the trans diastereomer.
The conformations of independent molecules 2dA and 2dB
in the crystal structure of 2d are very similar and differ
only in the C(6)—C(7)—C(14)—C(15) torsion angle
(60.08(11)° and 63.84(12)° for molecules 2dA and 2dB,
respectively). This leads to the difference in the atomic
coordinates of the phenyl moieties after the superposition
of the molecules (0.4 Å for the carbon atoms of the phenyl
ring and no larger than 0.1 Å for the other nonhydrogen
atoms of the molecules). The systems of contacts formed
by 2dA and 2dB in the crystal structure are also similar.
The crystals of 2d are stabilized primarily by van der Waals
Scheme 4
Comꢀ
puound
1a
1b
1c
R
R´
H
H
H
Ph
3,4ꢀ(MeO)2C6H3
3,4,5ꢀ(MeO)3C6H2
2ꢀFuryl
1d
H
1e
H
Me
1f
H
CH2OH
1g
H
CH2NH2
1h
1i
1j
Me
Me
CH2Ph
Ph
3,4,5ꢀ(MeO)3C6H2
3,4ꢀ(MeO)2C6H3
Comꢀ
pound
2a
2b
2c
R
R´
R″
H
H
H
H
H
H
H
Me
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
3,4ꢀ(MeO)2C6H3
Me
CH2Ph
H
2d
2e
Comꢀ
pound
3a
3b
3c
R
R´
H
H
Ме
Ph
3,4ꢀ(MeO)2C6H3
Ph
The structures of compounds 1—3 were confirmed by
1H NMR spectroscopy, elemental analysis, and (for some
compounds) mass spectrometry. The structures of comꢀ
pounds 1c and 2d were determined by Xꢀray diffraction
(see the Experimental section).
n = 1 (1), 2 (2), 3 (3)

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1257
C(22)
O(29)
C(30)
O(31)
C(32)
C(21)
C(24)
C(17)
C(25)
C(26)
C(24)
C(23)
C(22)
C(21)
C(2)
C(13)
C(16)
C(15)
C(23)
C(18)
C(27)
C(19)
C(25)
C(14)
N(1)
C(20)
N(1)
C(26)
C(11)
C(3)
C(4)
C(10)
C(11)
C(12)
N(5)
C(2)
C(3)
C(12)
C(10)
C(9)
C(8)
C(28)
C(9) C(8)
C(6)
C(14)
C(20)
C(19)
N(7)
C(6)
C(7)
N(4)
C(5)
C(15)
O(13)
C(16)
C(17)
O(1W)
C(18)
1c
2d
Fig. 1. Molecular structures of 1c and 2d in the crystals. The atoms are represented by thermal ellipsoids (p = 50%). Some hydrogen
atoms of molecule 2d are not shown.
C—H...O and H...H interactions, but there are also weak
stacking interactions between the phenyl and 3,4ꢀdiꢀ
methoxyphenyl moieties of the crystallographically indeꢀ
pendent molecules. The shortest C...C distances for these
interactions are 3.429(2) Å and 3.535(2) Å for two symꢀ
metrically nonequivalent interactions 2dA...2dB; the disꢀ
tances between the centers of the rings are 3.723 and 3.764 Å,
respectively; the angle between the planes involved in the
stacking of the rings is at most 9°.
Like in compound 1c, the N(1) atom in 2d is highly
pyramidalized (the deviations of the substituents from the
plane are larger than 0.4 Å). It should be noted that
the substituent at the N(1) atom in compound 1c is in
a pseudoequatorial position, whereas the corresponding
atom in 2d is in a pseudoaxial position. The pseudoaxial
orientation of the substituent in compound 2d results in
the appearance of the generalized anomeric effect in the
lpꢀN(1)—C(13)—N(5) system, which leads to an elongaꢀ
tion of the C(13)—N(5) bond in 2d compared to the equivꢀ
alent C(12)—N(4) bond in 1c by 0.024(5) Å and a shortꢀ
ening of the N(1)—C(13) bond compared to the equivaꢀ
lent N(1)—C(12) bond by 0.022(2) Å. As a result, the
N(1)—C(12) and C(12)—N(4) bonds in 1c are virtually
equalized (1.473(2) Å), whereas the difference in the bond
lengths in 2d are 0.04 and 0.05 Å for molecules 2dA and
2dB, respectively. These values are typical of the generalꢀ
ized anomeric effect.20
1
In the H NMR spectra of compounds 1, the signals
for the protons of the ethylene chain deserve considerꢀ
ation. Due to the rigidity of the heterocycle, these signals
form an ABCD system, resulting in a considerable differꢀ
ence in their chemical shifts. As an example, Fig. 2 shows
1
a fragment of the H NMR spectrum of 1g containing
signals of this system, which do not overlap with other
signals.
To assign these signals, we used the Xꢀray diffraction
data for the structure of compound 1c (Fig. 3), which
gives the similar spectrum of the ethylene chain, and the
Karplus—Conroy curve,21 which shows the dependence
3
of the vicinal spinꢀspin coupling constants JH,H on the
corresponding dihedral angles.
The signals for all protons are observed as doublets of
doublets of doublets. The signals at δ 2.72 and 3.76 belong
to the protons H(2a) and H(3b), respectively (see Fig. 3).
The dihedral angles corresponding to the vicinal constants
of these protons are about 30° and 150°, with the result
that the geminal coupling constants are similar to the vicꢀ
inal constants (8—11 Hz). The dihedral angle between the
bonds formed by the protons H(2b) (δ 3.45) and H(3a)
(δ 3.58) with the corresponding carbon atoms is close to

1258
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
H(2a)
H(3a)
H(2b)
H(3b)
3.85 3.80 3.75 3.70 3.65 3.60 3.55
3.50 3.45 3.40
2.80 2.75 2.70
δ
Fig. 2. Fragments of the 1H NMR spectrum of compound 1g showing signals for the protons of the ethylene chain.
90°, resulting in the spinꢀspin coupling between H(2b)
and H(3a) as small as 2.0 Hz. It should be noted that there
is a strong difference in the chemical shifts of the protons
H(2a) and H(2b) (0.73 ppm for 1g and 0.4—0.7 ppm for
other compounds 1).
This situation is apparently attributed to the pseuꢀ
doequatorial position of the substituent at the amine
nitrogen atom (Fig. 4), due to which the lone electron
pair of the nitrogen atom shields the nearby protons
in a different fashion. Based on the published data,22
the pseudoaxial lone pair of the nitrogen atom shields
the vicinal axial proton (in the structure under consiꢀ
deration, the proton H(2a)) by up to 1 ppm due to the
nꢀσ* interaction, with no effect on the equatorial proꢀ
ton (H(2b)).
In compound 2, the protons of the propylene chain
form an ABCDEF system. To interpret the 1H NMR specꢀ
trum of this moiety of 2 (Fig. 5), the dihedral angles
between the C—H bonds of this system were deterꢀ
mined from the Xꢀray diffraction data for 2d. The angles
corresponding to pairs of the axial protons H(2a)—H(3b)
and H(3b)—H(4a) are about 165°; the angles correꢀ
sponding to pairs of the equatorial protons H(2b)—H(3a)
and H(3a)—H(4b) and to pairs of the axial and equatoꢀ
rial protons vary from 45 to 70° (Fig. 6). Based on
the data from the Karplus—Conroy curve, the vicinal
spinꢀspin coupling between the axial protons should be
9.5—14 Hz, and the coupling between the equatorial proꢀ
tons and between the axial and equatorial protons should
be 1—5 Hz.
The terminal axial protons H(2a) (δ 2.68) and H(4a)
(δ 2.43) have two large spinꢀspin coupling constants (gemꢀ
inal and vicinal). The central axial proton H(3b) (δ 2.04)
has three constants (one geminal and two vicinal), due to
which it appears as a broad multiplet. The equatorial proꢀ
tons H(2b) (δ 2.82), H(3a) (δ 1.18), and H(4b) (δ 4.71)
have one (geminal) constant each. The geminal spinꢀspin
coupling constants and the vicinal spinꢀspin coupling
constants between the axial protons are approximately
equal (13 Hz).
It should be noted that there is a very large difference
in the chemical shifts of the protons of the C(4)H2 group
(Δδ = 2.3 ppm). This can be attributed to the fact that the
proton H(4b) is almost in one plane with the carbonyl
bond of the amide group (the Xꢀray diffraction data). It is
known5 that in this case the proton is most efficiently
deshielded by this group, resulting in a considerable downꢀ
field shift of this signal. At the same time, the spatial
position of the proton H(4a) is such that the deshielding
effect of the amide group is reduced. As a result, the signal
for H(4a) is observed at even higher field compared to the
signals for the protons of the C(2)H2 group. The chemical
shifts of the protons of the C(3)H2 group are also substanꢀ
tially different. This fact can be attributed to the stronger
deshielding effect of the nitrogen atoms on the proton
Fig. 3. Dihedral angles between the C—H bonds in the ethylene
chain of compound 1c determined by Xꢀray diffraction.
Fig. 4. Stereostructure of the tetrahydroimidazole moiety in comꢀ
pounds 1 according to the 1H NMR spectroscopic data.

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1259
H(4a)
H(3a)
H(2b)
H(2a)
H(4b)
H(3b)
4.8
4.7
2.9 2.8
2.7 2.6
2.5
2.4
2.3
2.2
2.1
2.0
1.9
1.2
δ
Fig. 5. Fragments of the 1H NMR spectrum of compound 2d showing signals for the protons of the propylene chain.
H(3b), which is spatially closer to the nitrogen atoms
than H(3a).
DMSOꢀd6 recorded immediately* after the dissolution of
crystalline samples and after the storage of the solutions
for one day and one week. The largest difference in the
chemical shifts of the corresponding protons in pairs of
diastereomers, which were used for the determination of
their ratios, was observed for the protons of the methyl
(Δδ up to 0.2 ppm) or methylene groups (Δδ up to 0.3 ppm)
in the pyrazine ring and for the protons bound to the chiral
C atoms (Δδ up to 0.15 ppm for the proton in the pyrazine
ring; Δδ up to 1.5 ppm for the proton bound to the aminal
C atom). The observed interconversion of the diastereꢀ
omers can be attributed to the possibility of enolization of
the amide carbonyl (see Scheme 5), which is facilitated
due to the conjugation of the enol that formed with the
aromatic pyrrole ring. Apparently, this transformation reꢀ
In the spectra of 3, the protons of the butylene chain
form a complex system of multiplets, among which only
signals for the protons of the methylene group bound to
the amide nitrogen atom (H(5a) and H(5b)) are clearly
distinguished; the other signals overlap with each other
and are unresolved. The protons H(5a) and H(5b), like
those in compounds 2, essentially differ in the chemical
shifts (Δδ = 0.6—0.8 ppm), which indicates that the lowꢀ
erꢀfield proton (H(5b)) is approximately in the plane of
the amide group.
There are two chiral centers in tricyclic compounds
1—3 containing substituents in the pyrazine ring. Hence,
the synthesis of these compounds can afford two diastereꢀ
omers (A and B, see Scheme 5). The Xꢀray diffraction
study of one of these compounds (2d) showed that in the
crystalline state it exists as the pure diastereomer A (see
Fig. 1). However, according to the 1H NMR spectroscopꢀ
ic data, some of these structures showed that most of these
compounds exist in solution as mixtures of diastereomers
A and B. It appeared that their ratio depends on the nature
of the solvent and, for some compounds, on the time of
the storage of their solutions. Table 1 gives the ratios of the
pairs of diastereomers for heterocycles 1—3 containing
substituents in the pyrazine ring, which were determined
Scheme 5
1
from the H NMR spectra of solutions in CDCl3 and
n = 1—3
1
Fig. 6. Stereostructure of the hexahydropyrimidine moiety in
compounds 2 according to the 1H NMR spectroscopic data.
* The H NMR spectra were recorded within 120—150 s after
the dissolution of the samples.

1260
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
Table 1. Ratio of diastereomers of heterocycles 1—3 containing
substituents in the pyrazine ring depending on the time of the
storage (t1, t2, t3)* of their solutions in CDCl3 and DMSOꢀd6
tion 1 is accompanied by the elimination of these substituꢀ
ents as a result of the hydrogenolysis to give Nꢀunsubstiꢀ
tuted 2ꢀaminoalkylꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ
3(4H)ꢀones 16.
Comꢀ
pound
CDCl3
DMSOꢀd6
Then we investigated the reactions of compounds 1
and 2 with lithium aluminum hydride. These reactions
were found to lead only to the reduction of the carbonꢀ
yl group, whereas the bicyclic aminal system of comꢀ
t1
t2
t3
t1
t2
t3
1h
1i
1j
2c
2d
3c
1 : 2.5
1 : 2.4
1 : 3
1 : 5.5
**
1 : 2.5
1 : 2.4
10 : 1
1 : 1.7
**
1 : 2.5
1 : 2.4
14 : 1
2 : 1
**
1 : 1.5
1 : 10 1 : 9
3 : 7 3.5 : 7
1 : 3
1 : 1
1 : 4
1 : 5.5
**
1 : 1.6
1
pounds 17 remains intact. According to the H NMR
**
1 : 6
**
1 : 8
1 : 6
**
spectroscopic data, heterocycles 17 are hydrolyzed in an
acidic medium to form, most likely, acyclic amino aldeꢀ
hydes 18 (Scheme 6).
1 : 1.5
1 : 1.5
1 : 1.7 1 : 1.7
Tricyclic aminals 17 readily undergo hydrogenation
on the palladium catalyst to form 1,2,3,4ꢀtetrahydropyrꢀ
rolo[1,2ꢀa]pyrazine derivatives 19.
* t1, 120—150 s; t2, 1 day; t3, 1 week.
** One isomer.
The structures of the reduction products of heterocyꢀ
cles 1 and 2 were confirmed by 1H NMR spectroscopy and
elemental analysis.
sults in the thermodynamically most favorable ratio of the
diastereomers for each structure in a particular solvent.
It should be noted that in the present study we did not
determine the relative configurations of the observed diaꢀ
stereomers.
In the present study, we investigated the reduction of
selected representatives of heterocyclic compounds 1 and
2 (Scheme 6). It was shown that the catalytic hydrogenaꢀ
tion of these compounds on 10% Pd/C under atmospheric
pressure affords 1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀ
one derivatives 15, i.e., the aminal moiety of the moleꢀ
cules is subjected to hydrogenolysis. The hydrogenation of
compounds containing arylmethyl substituents in posiꢀ
To sum up, we synthesized the previously unknown
heterocyclic compounds 1—3. The interconversion of the
diastereomers of the derivatives containing two chiral cenꢀ
ters in solution was observed. The hydrogenation of such
compounds on the palladium catalyst leads to the hydroꢀ
genolysis of the aminal moiety and the opening of one
diazacycloalkane moiety, whereas the treatment of these
compounds with lithium aluminum hydride results in the
reduction of the carbonyl group, the aminal function beꢀ
ing intact. The results of the present study are promising
for preparative organic and medical chemistry.
Scheme 6
R´ = Me, n = 1 (a); R´ = H, n = 2 (b)

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1261
78%, colorless oil, b.p. 100—102°C (1.5 Torr) (see lit. data17:
Experimental
20
b.p. 100 °C (0.1 Torr)), nD20= 1.5386 (see lit. data17: nD
=
= 1.5417).
1
The H NMR spectra were recorded on a Bruker ACꢀ250
Nꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,2ꢀethanediamine (7b) was synꢀ
thesized by the reaction of 3,4ꢀdimethoxybenzaldehyde with
1,2ꢀethanediamine. The yield was 75%, colorless oil, b.p.
157—159 °C (1.5 Torr) (see lit. data18: 168—170 °C (4 Torr)),
spectrometer in DMSOꢀd6 and CDCl3 with the use of signals of
the residual protons of the solvents (δ 2.50 and 7.24, respectiveꢀ
ly) as the internal standard. The melting points were determined
on a Kofler hotꢀstage apparatus and are uncorrected. The mass
spectra were measured on a Kratos MSꢀ300 instrument (EI,
70 eV). The course of the reactions and the purity of the reaction
products were monitored by TLC using a toluene—acetone—hepꢀ
tane—triethylamine system (14 : 9 : 3 : 1) on Kieselgel 60 F254
plates with detection by UV light. Starting 2,5ꢀdimethoxyꢀ2ꢀ
dimethoxymethyltetrahydrofuran (5) was synthesized according
to a known procedure.11
Synthesis of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylates
(4) (general procedure). 2,5ꢀDimethoxyꢀ2ꢀdimethoxymethyltetꢀ
rahydrofuran (5) (51.56 g, 0.25 mol) was added to a solution of
NaOH (11.0 g, 0.275 mol), H3PO4 (16 mL, 0.275 mol), and
amino acid methyl ester hydrochloride 6 (0.275 mol) in water
(150 mL). The reaction mixture was refluxed for 25 min. The
product was extracted with toluene, the extract was washed with
a solution of K2CO3 (12.5 g, 90 mmol) in water (60 mL) and
then with water (50 mL), filtered through a paper filter, and
concentrated to dryness. The residue was distilled off.
20
nD = 1.5480.
Nꢀ(3,4,5ꢀTrimethoxybenzyl)ꢀ1,2ꢀethanediamine (7c) was synꢀ
thesized by the reaction of 3,4,5ꢀtrimethoxybenzaldehyde with
1,2ꢀethanediamine. The yield was 65%, colorless oil, b.p.
20
171—173 °C (1.5 Torr), nD = 1.5422. Found (%): C, 59.70;
H, 8.42; N, 11.47. C12H20N2O3. Calculated (%): C, 59.98;
H, 8.39; N, 11.66. 1H NMR (CDCl3), δ: 1.47 (s, 3 H, NH2, NH);
3
2.66 (t, 2 H, CH2NH2, J = 5.8 Hz); 2.79 (s, 2 H, CH2NH,
3J = 5.8 Hz); 3.70 (s, 2 H, CH2Ar); 3.78 (s, 3 H, 4ꢀOMe); 3.82
(s, 6 H, 3ꢀOMe, 5ꢀOMe); 6.53 (s, 2 H, Ar).
Nꢀ(2ꢀFurylmethyl)ꢀ1,2ꢀethanediamine (7d) was synthesized
by the reaction of 2ꢀfurylaldehyde with 1,2ꢀethanediamine. The
yield was 81%, colorless oil, b.p. 70 °C (1 Torr) (see lit. data23:
68—70 °C (2 Torr)), nD20 = 1.5021 (see lit. data23: nD20 = 1.5029).
Nꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,3ꢀpropanediamine (8a) was synꢀ
thesized by the reaction of 3,4ꢀdimethoxybenzaldehyde with
1,3ꢀpropanediamine. The yield was 74%, colorless oil, b.p.
20
173—175 °C (2.5 Torr), nD = 1.5418. Found (%): C, 64.53;
Methyl (2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)acetate (4a) was syntheꢀ
sized by the reaction of acetal 5 with glycine methyl ester hydroꢀ
chloride (6a). The yield was 70%, paleꢀpink oil, b.p. 98—101 °C
(1.5 Torr), nD20 = 1.5421. Found (%): C, 57.53; H, 5.28; N, 8.37.
C8H9NO3. Calculated (%): C, 57.48; H, 5.43; N, 8.38. 1H NMR
(CDCl3), δ: 3.73 (s, 3 H, OMe); 5.02 (s, 2 H, CH2); 6.24
(m, 1 H, H(4)); 6.90 (m, 1 H, H(3)); 6.95 (m, 1 H, H(5)); 9.48
(s, 1 H, CHO).
H, 8.96; N, 12.37. C12H20N2O2. Calculated (%): C, 64.26;
H, 8.99; N, 12.49. 1H NMR (CDCl3), δ: 1.52—1.69 (m, 5 H, NH2,
NH, NH2CH2CH2); 2.64 and 2.72 (both t, 2 H each, CH2NH2,
CH2NH, 3J = 6.8 Hz, 3J = 6.9 Hz); 3.68 (s, 2 H, CH2Ar); 3.81
and 3.83 (both s, 3 H each, 2 OMe); 6.73—6.85 (m, 3 H, Ar).
Nꢀ(3,4ꢀDimethoxybenzyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediamine
(8b) was synthesized by the reaction of 3,4ꢀdimethoxybenzaldeꢀ
hyde with 2,2ꢀdimethylꢀ1,3ꢀpropanediamine. The yield was 72%,
20
Methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)propionate (4b) was synꢀ
thesized by the reaction of acetal 5 with alanine methyl ester
hydrochloride (6b). The yield was 75%, paleꢀyellow oil, b.p.
colorless oil, b.p. 175—177 °C (2.5 Torr), nD = 1.5300.
Found (%): C, 66.71; H, 9.39; N, 11.07. C14H24N2O2. Calculatꢀ
ed (%): C, 66.63; H, 9.59; N, 11.10. 1H NMR (CDCl3), δ: 0.85
(s, 6 H, 2 Me); 1.67 (s, 3 H, NH2, NH); 2.38 (s, 2 H, CH2NH);
2.53 (s, 2 H, CH2NH2); 3.71 (s, 2 H, CH2Ar); 3.85 and 3.87
(both s, 3 H each, 2 OMe); 6.76—6.91 (m, 3 H, Ar).
20
105—107 °C (1.5 Torr), nD = 1.5323. Found (%): C, 59.59;
H, 6.22; N, 7.89. C9H11NO3. Calculated (%): C, 59.66; H, 6.12;
1
3
N, 7.73. H NMR (CDCl3), δ: 1.74 (d, 3 H, Me, J = 7.2 Hz);
3.74 (s, 3 H, OMe); 5.88 (q, 1 H, CH, 3J = 7.2 Hz); 6.30
(m, 1 H, H(4)); 6.98 (m, 1 H, H(3)); 7.17 (m, 1 H, H(5)); 9.50
(s, 1 H, CHO).
NꢀBenzylꢀ1,4ꢀbutanediamine (9a) was synthesized by the reꢀ
action of benzaldehyde with 1,4ꢀbutanediamine. The yield was
20
73%, colorless oil, b.p. 131—133 °C (2 Torr), nD = 1.5260.
Methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ3ꢀphenylpropionate (4c)
was synthesized by the reaction of acetal 5 with phenylalꢀ
anine methyl ester hydrochloride (6c). The yield was 67%, paleꢀ
yellow crystals, m.p. 38—40 °C. Found (%): C, 69.70; H, 5.96;
N, 5.30. C15H15NO3. Calculated (%): C, 70.02; H, 5.88; N, 5.44.
1H NMR (CDCl3), δ: 3.29 (dd, 1 H, Ha(CHb)Ph, 2J = 13.6 Hz,
3J = 9.6 Hz); 3.53 (dd, 1 H, Hb(CHa)Ph, 2J = 13.6 Hz, 3J = 5.0 Hz);
3.74 (s, 3 H, OMe); 6.07 (m, 1 H, CHCO2Me); 6.21 (m, 1 H,
H(4)); 6.98—7.27 (m, 7 H, H(3), H(5), Ph); 9.43 (s, 1 H, CHO).
Synthesis of Nꢀ(arylmethyl)ꢀsubstituted 1,2ꢀ, 1,3ꢀ, and 1,4ꢀ
diamines 7—9 (general procedure). The palladium on carbon catꢀ
alyst (0.3 g, 10% Pd) was added to a solution of aromatic aldeꢀ
hyde (0.1 mol) and diamine (0.3 mol) in methanol (100 mL).
The reaction mixture was hydrogenated until the theoretical
amount of hydrogen was consumed. The catalyst was filtered off,
and the filtrate was concentrated to dryness. The residue was
distilled.
Found (%): C, 73.99; H, 10.32; N, 15.65. C11H18N2. Calculatꢀ
ed (%): C, 74.11; H, 10.18; N, 15.71. 1H NMR (CDCl3), δ: 1.21
(s, 3 H, NH2, NH); 1.46 (m, 4 H, CH2CH2CH2NH2); 2.61
(m, 4 H, CH2NH, CH2NH2); 3.71 (s, 2 H, CH2Ph); 7.12—7.33
(m, 5 H, Ph).
Nꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,4ꢀbutanediamine (9b) was synꢀ
thesized by the reaction of 3,4ꢀdimethoxybenzaldehyde with
1,4ꢀbutanediamine. The yield was 77%, colorless oil, b.p.
20
184—186 °C (2 Torr), nD = 1.5378. Found (%): C, 65.36;
H, 9.39; N, 11.80. C13H22N2O2. Calculated (%): C, 65.52;
H, 9.30; N, 11.75. 1H NMR (CDCl3), δ: 1.35—1.54 (m, 7 H, NH2,
NH, CH2CH2CH2NH2); 2.59 and 2.65 (both t, 2 H each,
3
3
CH2NH2, CH2NH, J = 6.9 Hz, J = 6.6 Hz); 3.69 (s, 2 H,
CH2Ar); 3.81 and 3.83 (both s, 3 H each, 2 OMe); 6.74—6.85
(m, 3 H, Ar).
Reaction of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylates
(4) with 1,2ꢀ and 1,3ꢀdiamines 7 and 8 (general procedure).
A solution of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylate (4)
(20 mmol) and diamine 7 or 8 (22 mmol) in ethanol (30 mL) was
NꢀBenzylꢀ1,2ꢀethanediamine (7a) was synthesized by the reꢀ
action of benzaldehyde with 1,2ꢀethanediamine. The yield was

1262
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
2
refluxed for 1 h. The reaction mixture was kept at –10 °C for
2 days. The precipitate that formed was filtered off, washed with
cold ethanol, and recrystallized if necessary.
2J = 14.4 Hz); 3.90 (d, 1 H, Hb(CHa)Fur, J = 14.4 Hz); 4.56
and 4.63 (both d, 1 H each, HaC(6) and HbC(6), 2J = 17.2 Hz);
5.13 (s, 1 H, H(10b)); 6.20 (m, 1 H, HFur(3)); 6.30 (m, 1 H,
HFur(4)); 6.32 (m, 1 H, H(9)); 6.36 (m, 1 H, H(10)); 6.67 (m, 1 H,
H(8)); 7.39 (m, 1 H, HFur(5)).
1ꢀBenzylꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]ꢀ
pyrazinꢀ5(6H)ꢀone (1a) was synthesized by the reaction of aldeꢀ
hyde ester 4a with diamine 7a. The yield was 69%, white crysꢀ
tals, m.p. 106—108 °C. Found (%): C, 71.60; H, 6.50; N, 15.57.
C16H17N3O. Calculated (%): C, 71.89; H, 6.41; N, 15.72.
1H NMR (CDCl3), δ: 2.73 (ddd, 1 H, HaC(2), 2J2a,2b = 10.5 Hz,
1ꢀEthylꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]ꢀ
pyrazinꢀ5(6H)ꢀone (1e) was synthesized by the reaction of aldeꢀ
hyde ester 4a with Nꢀethylꢀ1,2ꢀethanediamine. The yield was
86%, white crystals, m.p. 123—124 °C (recrystallization from
toluene). Found (%): C, 63.77; H, 7.61; N, 20.80. C11H15N3O.
Calculated (%): C, 64.37; H, 7.37; N, 20.47. 1H NMR (CDCl3),
3
3J2a,3b = 11.2 Hz, J2a,3a = 8.5 Hz); 3.23 (ddd, 1 H, HbC(2),
3
2J2b,2a = 10.5 Hz, J2b,3b = 7.5 Hz, 3J2b,3a = 1.8 Hz); 3.56 (ddd,
1 H, HaC(3), 2J3a,3b = 11.3 Hz, 3J3a,2a = 8.5 Hz, 3J3a,2b = 1.8 Hz);
3.60 (d, 1 H, Ha(CHb)Ph, 2J = 13.2 Hz); 3.74 (ddd, 1 H, HbC(3),
δ: 1.20 (t, 3 H, Me, J = 7.2 Hz); 2.45 (dq, 1 H, Ha(CHb)Me,
3
2J = 11.9 Hz, J = 7.2 Hz); 2.62 (ddd, 1 H, HaC(2), J2a,2b
=
3
2
3
3
3
3
2J3b,3a = 11.3 Hz, J3b,2a = 11.2 Hz, J3b,2b = 7.5 Hz); 3.99
(d, 1 H, Hb(CHa)Ph, 2J = 13.2 Hz); 4.58 and 4.65 (both d,
1 H each, HaC(6) and HbC(6), 2J = 17.7 Hz); 5.12 (s, 1 H,
H(10b)); 6.24 (m, 1 H, H(9)); 6.28 (m, 1 H, H(10)); 6.67 (m, 1 H,
H(8)); 7.22—7.38 (m, 5 H, Ph).
= 10.0 Hz, J2a,3b = 9.8 Hz, J2a,3a = 8.4 Hz); 3.07 (dq, 1 H,
Hb(CHa)Me, 2J = 11.9 Hz, 3J = 7.2 Hz); 3.49 (ddd, 1 H, HbC(2),
2J2b,2a = 10.0 Hz, 3J2b,3b = 7.7 Hz, 3J2b,3a = 1.9 Hz); 3.60 (ddd, 1 H,
HaC(3), J3a,3b = 11.0 Hz, J3a,2a = 8.4 Hz, J3a,2b = 1.9 Hz);
3.77 (ddd, 1 H, HbC(3), J3b,3a = 11.0 Hz, J3b,2a = 9.8 Hz,
3J3b,2b = 7.7 Hz); 4.53 and 4.61 (both d, 1 H each, HaC(6)
2
3
3
2
3
1ꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]ꢀ
pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1b) was synthesized by the reꢀ
action of aldehyde ester 4a with diamine 7b. The yield was 80%,
white crystals, m.p. 99—101 °C. Found (%): C, 66.33; H, 6.64;
N, 13.03. C18H21N3O3. Calculated (%): C, 66.04; H, 6.47;
N, 12.84. 1H NMR (CDCl3), δ: 2.72 (ddd, 1 H, HaC(2),
2J2a,2b = 10.9 Hz, 3J2a,3b = 11.3 Hz, 3J2a,3a = 8.4 Hz); 3.22 (ddd,
1 H, HbC(2), 2J2b,2a = 10.9 Hz, 3J2b,3b =7.5 Hz, 3J2b,3a = 1.6 Hz);
3.52 (d, 1 H, Ha(CHb)Ar, 2J = 12.3 Hz); 3.59 (ddd, 1 H, HaC(3),
2J3a,3b = 11.6 Hz, 3J3a,2a = 8.4 Hz, 3J3a,2b = 1.6 Hz); 3.76 (ddd, 1 H,
2
and HbC(6), J = 17.6 Hz); 4.86 (s, 1 H, H(10b)); 6.20—6.26
(m, 2 H, H(9), H(10)); 6.62 (m, 1 H, H(8)).
1ꢀ(2ꢀHydroxyethyl)ꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]ꢀ
pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1f) was synthesized by the reꢀ
action of aldehyde ester 4a with Nꢀ(2ꢀhydroxyethyl)ꢀ1,2ꢀethaneꢀ
diamine. The yield was 73%, white crystals, m.p. 82—84 °C. MS,
m/z: 221 [M]+, 190 [M – CH2OH]+, 176 [M – CH2CH2OH]+.
Found (%): C, 59.76; H, 6.76; N, 19.09. C11H15N3O2. Calculatꢀ
ed (%): C, 59.71; H, 6.83; N, 18.99. 1H NMR (CDCl3), δ: 2.47
(s, 1 H, OH); 2.64 (m, 1 H, Ha(CHb)CH2OH); 2.81 (ddd, 1 H,
2
3
3
HbC(3), J3b,3a = 11.6 Hz, J3b,2a = 11.3 Hz, J3b,2b = 7.5 Hz);
2
3
3
3.88 and 3.89 (both s, 3 H each, 2 OMe); 3.97 (d, 1 H,
HaC(2), J2a,2b = 10.5 Hz, J2a,3b = 11.2 Hz, J2a,3a = 8.5 Hz);
3.02 (m, 1 H, Hb(CHa)CH2OH); 3.51 (ddd, 1 H, HbC(2),
2J2b,2a = 10.5 Hz, 3J2b,3b = 7.7 Hz, J2b,3a = 1.8 Hz); 3.61 (ddd,
2
Hb(CHa)Ar, J = 12.3 Hz); 4.61 and 4.68 (both d, 1 H each,
2
3
HaC(6) and HbC(6), J = 17.8 Hz); 5.12 (s, 1 H, H(10b)); 6.30
(m, 1 H, H(9)); 6.34 (m, 1 H, H(10)); 6.70 (m, 1 H, H(8)); 6.82
and 6.88 (both d, 1 H each, HAr(5) and HAr(6), J = 8.1 Hz);
6.92 (s, 1 H, HAr(2)).
1 H, HaC(3), 2J3a,3b = 11.4 Hz, 3J3a,2a = 8.5 Hz, 3J3a,2b = 1.8 Hz);
3.69—3.82 (m, 3 H, HbC(3), CH2OH); 4.54 and 4.61 (both d,
1 H each, HaC(6) and HbC(6), 2J = 17.5 Hz); 5.07 (s, 1 H, H(10b));
6.25 (m, 2 H, H(9), H(10)); 6.64 (m, 1 H, H(8)).
3
1ꢀ(3,4,5ꢀTrimethoxybenzyl)ꢀ1,2,3,10bꢀtetrahydroimidazoꢀ
[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1c) was synthesized by
the reaction of aldehyde ester 4a with diamine 7c. The yield was
86%, white crystals, m.p. 129—131 °C. Found (%): C, 60.93;
H, 6.46; N, 11.08. C19H23N3O4•H2O. Calculated (%): C, 60.79;
H, 6.71; N, 11.19. 1H NMR (CDCl3), δ: 2.72 (ddd, 1 H, HaC(2),
2J2a,2b = 10.9 Hz, 3J2a,3b = 11.3 Hz, 3J2a,3a = 8.7 Hz); 3.24 (ddd,
1 H, HbC(2), 2J2b,2a = 10.9 Hz, 3J2b,3b =7.5 Hz, 3J2b,3a = 1.7 Hz);
3.49 (d, 1 H, Ha(CHb)Ar, 2J = 13.3 Hz); 3.56 (ddd, 1 H, HaC(3),
2J3a,3b = 11.6 Hz, 3J3a,2a = 8.7 Hz, 3J3a,2b = 1.7 Hz); 3.75 (ddd, 1 H,
1ꢀ(2ꢀAminoethyl)ꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrꢀ
rolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1g) was synthesized by the reacꢀ
tion of aldehyde ester 4a with Nꢀ(2ꢀaminoethyl)ꢀ1,2ꢀethanediꢀ
amine. The yield was 76%, white crystals, m.p. 67—69 °C. MS,
m/z: 220 [M]+, 190 [M – CH2NH2]+, 176 [M – CH2CH2NH2]+.
Found (%): C, 59.89; H, 7.31; N, 25.59. C11H16N4O. Calculatꢀ
ed (%): C, 59.98; H, 7.32; N, 25.44. 1H NMR (CDCl3), δ: 1.70
(s, 2 H, NH2); 2.50 (m, 1 H, Ha(CHb)CH2NH2); 2.72 (ddd,
2
3
3
1 H, HaC(2), J2a,2b = 10.4 Hz, J2a,3b = 10.9 Hz, J2a,3a
=
2
3
3
HbC(3), J3b,3a = 11.6 Hz, J3b,2a = 11.3 Hz, J3b,2b = 7.5 Hz);
= 8.3 Hz); 2.84—2.98 (m, 3 H, Hb(CHa) CH2NH2, CH2NH2);
2
3
3.82 (s, 3 H, 4ꢀOMe); 3.84 (s, 6 H, 3ꢀOMe, 5ꢀOMe); 3.92 (d, 1 H,
3.45 (ddd, 1 H, HbC(2), J2b,2a = 10.4 Hz, J2b,3b = 7.7 Hz,
2
2
Hb(CHa)Ar, J = 13.3 Hz); 4.58 and 4.66 (both d, 1 H each,
3J2b,3a = 2.0 Hz); 3.58 (ddd, 1 H, HaC(3), J3a,3b = 11.4 Hz,
2
3
HaC(6) and HbC(6), J = 17.5 Hz); 5.11 (s, 1 H, H(10b)); 6.27
3J3a,2a = 8.3 Hz, J3a,2b = 2.0 Hz); 3.76 (ddd, 1 H, HbC(3),
3
3
(m, 2 H, H(9), H(10)); 6.58 (s, 2 H, Ar); 6.67 (m, 1 H, H(8)).
1ꢀ(2ꢀFurylmethyl)ꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrꢀ
rolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1d) was synthesized by the reacꢀ
tion of aldehyde ester 4a with diamine 7d. The yield was 76%,
paleꢀyellow crystals, m.p. 100—102 °C. Found (%): C, 65.46;
H, 5.96; N, 16.02. C14H15N3O2. Calculated (%): C, 65.36; H,
2J3b,3a = 11.4 Hz, J3b,2a = 10.9 Hz, J3b,2b = 7.7 Hz);
2
4.54 and 4.61 (both d, 1 H each, HaC(6) and HbC(6), J = 17.5
Hz); 4.98 (s, 1 H, H(10b)); 6.25 (m, 2 H, H(9), H(10)); 6.63
(m, 1 H, H(8)).
1ꢀBenzylꢀ6ꢀmethylꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrꢀ
rolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1h). The reaction of aldehyde esꢀ
ter 4b with diamine 7a afforded compound 1h as a mixture of
diastereomers (see Table 1). The yield was 75%, white powder,
m.p. 93—95 °C. Found (%): C, 72.27; H, 6.73; N, 14.96.
C17H19N3O. Calculated (%): C, 72.57; H, 6.81; N, 14.93.
1H NMR (CDCl3), δ (the signals of the minor diastereomer are
given in italic type): 1.63, 1.82 (d, 3 H, Me, 3J = 7.1 Hz);
1
5.88; N, 16.33. H NMR (CDCl3), δ: 2.94 (ddd, 1 H, HaC(2),
2J2a,2b = 11.0 Hz, 3J2a,3b = 11.2 Hz, 3J2a,3a = 8.5 Hz); 3.35 (ddd,
1 H, HbC(2), 2J2b,2a = 11.0 Hz, 3J2b,3b =7.8 Hz, 3J2b,3a = 2.0 Hz);
2
3
3.52 (ddd, 1 H, HaC(3), J3a,3b = 11.4 Hz, J3a,2a = 8.5 Hz,
3J3a,2b = 2.0 Hz); 3.77 (ddd, 1 H, HbC(3), J3b,3a = 11.4 Hz,
3J3b,2a = 11.2 Hz, J3b,2b =7.8 Hz); 3.81 (d, 1 H, Ha(CHb)Fur,
2
3

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1263
2
3
2.72 (ddd, 1 H, HaC(2), J2a,2b = 10.7 Hz, J2a,3b = 11.2 Hz,
Hb(CHa)Ar, 2J = 13.2 Hz); 3.70 (s, 1 H, H(10b)); 3.84 and 3.85
(both s, 3 H each, 2 OMe); 4.95 (t, 1 H, CHCH2Ph, 3J = 4.5 Hz);
6.14 (m, 1 H, H(10)); 6.28 (m, 1 H, H(9)); 6.64 (m, 1 H, H(8));
6.71—6.86 (m, 5 H, Ar, HPh(2), HPh(6)); 7.09—7.26 (m, 3 H,
HPh(3), HPh(4), HPh(5)).
3J2a,3a = 8.5 Hz); 3.23 (ddd, 1 H, HbC(2), J2b,2a = 10.7 Hz,
2
3J2b,3b =7.5 Hz, J2b,3a = 1.7 Hz); 3.56 (ddd, 1 H, HaC(3),
3
2J3a,3b = 11.4 Hz, 3J3a,2a = 8.5 Hz, 3J3a,2b = 1.7 Hz); 3.59 (d, 1 H,
2
2
Ha(CHb)Ph, J = 13.1 Hz); 3.70 (ddd, 1 H, HbC(3), J3b,3a
=
3
3
= 11.4 Hz, J3b,2a = 11.2 Hz, J3b,2b = 7.5 Hz); 4.06 (d, 1 H,
Hb(CHa)Ph, 2J = 13.1 Hz); 4.57, 4.72 (q, 1 H, CHMe, 3J = 7.1 Hz);
5.11, 5.13 (s, 1 H, H(10b)); 6.29 (m, 1 H, H(9)); 6.32 (m, 1 H,
H(10)); 6.69, 6.78 (m, 1 H, H(8)); 7.24—7.42 (m, 5 H, Ph).
6ꢀMethylꢀ1ꢀ(3,4,5ꢀtrimethoxybenzyl)ꢀ1,2,3,10bꢀtetrahydroꢀ
imidazo[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1i). The reacꢀ
tion of aldehyde ester 4b with diamine 7c afforded compound 1i
as a mixture of diastereomers (see Table 1). The yield was 70%,
white powder, m.p. 63—65 °C. Found (%): C, 64.37; H, 6.61;
N, 11.11. C20H25N3O4. Calculated (%): C, 64.67; H, 6.78; N, 11.31.
1H NMR (CDCl3), δ (the signals of the minor diastereomer are
1ꢀMethylꢀ1,3,4,11bꢀtetrahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]pyrꢀ
azino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (2a) was synthesized by the reꢀ
action of aldehyde ester 4a with Nꢀmethylꢀ1,3ꢀpropanediamine.
The yield was 93%, white powder, m.p. 58—60 °C. Found (%):
C, 64.28; H, 7.57; N, 20.65. C11H15N3O. Calculated (%):
C, 64.37; H, 7.37; N, 20.47. 1H NMR (CDCl3), δ: 1.40 (dm, 1 H,
HaC(3), 2J3a,3b = 13.7 Hz); 2.04 (m, 1 H, HbC(3)); 2.10 (s, 3 H,
2
Me); 2.81 (ddd, 1 H, HaC(4), J4a,4b
=
3J4a,3b = 13.1 Hz,
3J4a,3a = 3.3 Hz); 2.93—3.07 (m, 2 H, H2C(2)); 4.57 and 4.65
(both d, 1 H each, HaC(7) and HbC(7), J = 18.1 Hz); 4.78
(ddm, 1 H, HbC(4), J4b,4a = 13.1 Hz, J4b,3b = 4.9 Hz); 5.24
(s, 1 H, H(11b)); 6.10 (m, 1 H, H(11)); 6.22 (m, 1 H, H(10));
6.55 (m, 1 H, H(9)).
2
2
3
3
given in italic type): 1.61, 1.80 (d, 3 H, Me, J = 7.1 Hz); 2.70
(ddd, 1 H, HaC(2), 2J2a,2b = 10.5 Hz, 3J2a,3b = 11.1 Hz, 3J2a,3a
=
8.5 Hz); 3.24 (ddd, 1 H, HbC(2), 2J2b,2a = 10.5 Hz, 3J2b,3b = 7.6
1ꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,3,4,11bꢀtetrahydroꢀ2Hꢀpyrroloꢀ
[2´,1´:3,4]ꢀpyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (2b) was synꢀ
thesized by the reaction of aldehyde ester 4a with diamine 8a.
The yield was 82%, white crystals, m.p. 108—109 °C. Found (%):
C, 66.74; H, 6.80; N, 11.97. C19H23N3O3. Calculated (%): C,
3
2
Hz, J2b,3a = 1.7 Hz); 3.48 (d, 1 H, Ha(CHb)Ph, J = 13.1 Hz);
2
3
3.56 (ddd, 1 H, HaC(3), J3a,3b = 11.4 Hz, J3a,2a = 8.5 Hz,
3J3a,2b = 1.7 Hz); 3.71 (ddd, 1 H, HbC(3), J3b,3a = 11.4 Hz,
2
3J3b,2a = 11.1 Hz, J3b,2b = 7.6 Hz); 3.82 (s, 3 H, 4ꢀOMe); 3.84
3
(s, 6 H, 3ꢀOMe, 5ꢀOMe); 3.97 (d, 1 H, Hb(CHa)Ph, 2J = 13.1 Hz);
66.84; H, 6.79; N, 12.31. H NMR (CDCl3), δ: 1.34 (d, 1 H,
1
3
2
2
4.57, 4.71 (q, 1 H, CHMe, J = 7.1 Hz); 5.07, 5.10 (s, 1 H,
H(10b)); 6.27 (m, 2 H, H(9), H(10)); 6.68 (s, 2 H, Ar); 6.68,
6.76 (m, 1 H, H(8)).
HaC(3), J3a,3b = 13.5 Hz); 2.10 (ddm, 1 H, HbC(3), J3b,3a
=
=
= 13.5 Hz, 3J3b,4a = 13.2 Hz); 2.93 (ddd, 1 H, HaC(4), 2J4a,4b
3
=
3J4a,3b = 13.2 Hz, J4a,3a = 3.3 Hz); 2.95—3.02 (m, 2 H,
6ꢀBenzylꢀ1ꢀ(3,4ꢀdimethoxybenzyl)ꢀ1,2,3,10bꢀtetrahydroimꢀ
idazo[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazinꢀ5(6H)ꢀone (1j). The reaction
of aldehyde ester 4c with diamine 7b afforded compound 1j as
a mixture of diastereomers (see Table 1). The yield was 72%,
white crystals, m.p. 72—74 °C. Found (%): C, 71.95; H, 6.32;
N, 10.15. C25H27N3O3. Calculated (%): C, 71.92; H, 6.52;
N, 10.06. MS, m/z: 417 [M]+, 326 [M – CH2Ph]+, 266 [M –
– CH2Ph(OCH3)2ꢀ3,4]+, 175 [M – CH2Ph – CH2Ph(OCH3)2ꢀ
3,4]+. The H NMR spectrum of the first diastereomer of 1j,
which was obtained by subtraction of the spectrum recorded
within one week after the dissolution of crystalline compound 1j
in CDCl3 from the spectrum recorded immediately after the
H2C(2)); 3.30 (d, 1 H, Ha(CHb)Ar, 2J = 12.7 Hz); 3.47 (d, 1 H,
Hb(CHa)Ar, 2J = 12.7 Hz); 3.83 and 3.84 (both, 3 H each,
2 OMe); 4.65 and 4.74 (both d, 1 H each, HaC(7) and HbC(7),
2J = 18.2 Hz); 4.90 (dd, 1 H, HbC(4), 2J4b,4a = 13.2 Hz, 3J4b,3b
=
= 4.5 Hz); 5.68 (s, 1 H, H(11b)); 6.27 (m, 2 H, H(10), H(11));
6.60 (m, 1 H, H(9)); 6.67—6.79 (m, 3 H, Ar).
1ꢀ(3,4ꢀDimethoxybenzyl)ꢀ7ꢀmethylꢀ1,3,4,11bꢀtetrahydroꢀ
2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (2c).
The reaction of aldehyde ester 4b with diamine 8a afforded comꢀ
pound 2c as a mixture of diastereomers (see Table 1). The yield
was 80%, white crystals, m.p. 71—73 °C. Found (%): C, 67.60;
H, 7.38; N, 11.68. C20H25N3O3. Calculated (%): C, 67.58;
H, 7.09; N, 11.82. MS, m/z: 355 [M]+, 340 [M – Me]+, 204
1
2
dissolution (CDCl3), δ: 1.79 (d, H, Ha(CHb)Ar, J = 13.3 Hz);
2
3
1
2.77 (ddd, 1 H, HaC(2), J2a,2b = 12.0 Hz, J2a,3b = 11.4 Hz,
[M – CH2Ph(OMe)2ꢀ3,4]+. The H NMR spectrum of the first
3J2a,3a = 8.7 Hz); 2.89 (ddd, 1 H, HbC(2), J2b,2a = 12.0 Hz,
diastereomer of 2c, which was obtained by subtraction of the
spectrum recorded within one week after the dissolution of crysꢀ
talline compound 2c in CDCl3 from the spectrum recorded imꢀ
mediately after the dissolution (CDCl3), δ: 1.34 (d, 1 H, HaC(3),
2
3J2b,3b =8.0 Hz, J2b,3a = 2.1 Hz); 2.99 (d, 1 H, Hb(CHa)Ar,
3
2J = 13.3 Hz); 3.33 (ddd, 1 H, HaC(3), J3a,3b = 11.5 Hz,
2
3J3a,2a = 8.7 Hz, J3a,2b = 2.1 Hz); 3.47 (dd, 1 H, Ha(CHb)Ph,
3
2J = 14.0 Hz, J = 4.2 Hz); 3.55 (ddd, 1 H, HbC(3), J3b,3a
=
2J3a,3b = 13.5 Hz); 1.77 (d, 3 H, Me, J = 6.9 Hz); 2.10 (ddm,
3
2
3
3
3
= 11.5 Hz, J3b,2a = 11.4 Hz, J3b,2b = 8.0 Hz); 3.68 (dd,
Hb(CHa)Ph, J = 14.0 Hz, J = 4.2 Hz); 3.84 and 3.86 (both s,
3 H each, 2 OMe); 5.04 (t, 1 H, CHCH2Ph, J = 4.2 Hz); 5.20
(s, 1 H, H(10b)); 6.21 (m, 1 H, H(10)); 6.39 (m, 1 H, H(9)); 6.54
(d, 1 H, HAr(5), 3J = 8.1 Hz); 6.67 (m, 1 H, H(8)); 6.74 (d, 1 H,
HAr(6), 3J = 8.1 Hz); 6.90—7.11 (m, 6 H, Ph, HAr(2)).
1 H, HbC(3), 2J3b,3a = 13.5 Hz, 3J3b,4a = 13.2 Hz); 2.93 (ddd, 1 H,
2
3
2
HaC(4), J4a,4b = 3J4a,3b = 13.2 Hz, 3J4a,3a = 3.5 Hz); 2.96—3.03
3
(m, 2 H, H2C(2)); 3.25 (d, 1 H, Ha(CHb)Ar, 2J = 12.8 Hz); 3.42
2
(d, 1 H, Hb(CHa)Ar, J = 12.8 Hz); 3.83 and 3.84 (both s, 3 H
each, 2 OMe); 4.71 (q, 1 H, CHMe, 3J = 6.9 Hz); 4.87 (dd, 1 H,
2
3
HbC(4), J4b,4a = 13.2 Hz, J4b,3b = 4.4 Hz); 5.70 (s, 1 H,
H(11b)); 6.28 (m, 2 H, H(10), H(11)); 6.69 (m, 1 H, H(9));
6.71—6.78 (m, 3 H, Ar).
1
The H NMR spectrum of the second diastereomer of 1j,
which was obtained by subtraction of the spectrum recorded
immediately after the dissolution of crystalline compound 1j in
CDCl3 from the spectrum recorded within one week after the
dissolution (CDCl3), δ: 2.39 (ddd, 1 H, HaC(2), 2J2a,2b = 10.9 Hz,
1
The H NMR spectrum of the second diastereomer of 2c,
which was obtained by subtraction of the spectrum recorded
immediately after the dissolution of crystalline compound 2c in
CDCl3 from the spectrum recorded within one week after the
dissolution (CDCl3), δ: 1.41 (d, 1 H, HaC(3), 2J3a,3b = 13.3 Hz);
1.79 (d, 3 H, Me, 3J = 6.9 Hz); 2.04 (ddddd, 1 H, HbC(3),
3J2a,3b = 11.1 Hz, J2a,3a = 8.5 Hz); 3.05 (ddd, 1 H, HbC(2),
3
2J2b,2a = 10.9 Hz, J2b,3b =7.6 Hz, J2b,3a = 1.9 Hz); 3.22—3.39
(m, 4 H, CH2Ph, Ha(CHb)Ar, HaC(3)); 3.59 (ddd, 1 H, HbC(3),
2J3b,3a = 11.4 Hz, 3J3b,2a = 11.1 Hz, 3J3b,2b =7.6 Hz); 3.67 (d, 1 H,
3
3
3
3
3
3
2J3b,3a = 13.3 Hz, J3b,4a = J3b,2a = 13.1 Hz, J3b,4b = J3b,2b
=

1264
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
2
3
= 4.6 Hz); 2.79 (dd, 1 H, HaC(2), J2a,2b = J2a,3b = 13.1 Hz);
2J = 17.4 Hz); 5.61 (s, 1 H, H(12b)); 6.24 (m, 2 H, H(11),
H(12)); 6.57 (m, 1 H, H(10)); 7.16—7.35 (m, 5 H, Ph).
2.90 (ddd, 1 H, HaC(4), J4a,4b = 3J4a,3b = 13.1 Hz, 3J4a,3a = 2.9 Hz);
2
2
2.96 (d, 1 H, HbC(2), J2b,2a = 13.1 Hz); 3.28 (d, 1 H, Ha(CHb)Ar,
1ꢀ(3,4ꢀDimethoxybenzyl)ꢀ1,2,3,4,5,12bꢀhexahydropyrroloꢀ
[2´,1´:3,4]pyrazino[1,2ꢀa][1,3]diazepinꢀ7(8H)ꢀone (3b) was
synthesized by the reaction of aldehyde ester 4a with diamine 9b.
The yield was 85%, white crystals, m.p. 100—102 °C. Found (%):
C, 64.12; H, 7.27; N, 11.30. C20H25N3O3•H2O. Calculated (%):
2J = 12.7 Hz); 3.61 (d, 1 H, Hb(CHa)Ar, J = 12.7 Hz); 3.84
2
(s, 6 H, 2 OMe); 4.74 (q, 1 H, CHMe, 3J = 6.9 Hz); 4.85
2
3
(dd, 1 H, HbC(4), J4b,4a = 13.1 Hz, J4b,3b = 4.6 Hz); 5.51
(s, 1 H, H(11b)); 6.25 (m, 1 H, H(11)); 6.30 (m, 1 H, H(10));
6.67 (m, 1 H, H(9)); 6.70—6.80 (m, 3 H, Ar).
1
C, 64.32; H, 7.29; N, 11.25. H NMR (CDCl3), δ: 1.63—2.02
7ꢀBenzylꢀ1ꢀ(3,4ꢀdimethoxybenzyl)ꢀ1,3,4,11bꢀtetrahydroꢀ
2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (2d)
was synthesized by the reaction of aldehyde ester 4c with diꢀ
amine 8a. The yield was 87%, white crystals, m.p. 110—112 °C.
Found (%): C, 71.97; H, 6.85; N, 10.03. C26H29N3O3. Calculatꢀ
(m, 4 H, H2C(3), H2C(4)); 2.79—3.07 (m, 2 H, H2C(2)); 3.39
(m, 1 H, HaC(5)); 3.56 and 3.67 (both d, 1 H each, CH2Ar,
2J = 13.4 Hz); 3.83 (s, 6 H, 2 OMe); 4.14 (m, 1 H, HbC(5)); 4.58
and 4.66 (both d, 1 H each, H2C(8), 2J = 17.4 Hz); 5.60 (s, 1 H,
H(12b)); 6.23 (m, 2 H, H(11), H(12)); 6.57 (m, 1 H, H(10));
6.74—6.80 (m, 3 H, Ar).
1ꢀBenzylꢀ8ꢀmethylꢀ1,2,3,4,5,12bꢀhexahydropyrroloꢀ
[2´,1´:3,4]pyrazino[1,2ꢀa][1,3]diazepinꢀ7(8H)ꢀone (3c). The
reaction of aldehyde ester 4b with diamine 9a afforded comꢀ
pound 3c as a mixture of diastereomers (see Table 1). The yield
was 78%, paleꢀyellow crystals, m.p. 91—93 °C. Found (%):
C, 73.88; H, 7.43; N, 13.55. C19H23N3O. Calculated (%):
C, 73.76; H, 7.49; N, 13.58. 1H NMR (CDCl3), δ (the signals of the
minor diastereomer are given in italic type): 1.55—1.92 (m),
1.66, 1.79 (d) (7 H, H2C(3), H2C(4), Me, 3J = 7.0 Hz);
2.79—3.02 (m, 2 H, H2C(2)); 3.38 (m, 1 H, HaC(5)); 3.62 and
3.70, 3.78 and 3.93 (both d, 1 H each, CH2Ph, 2J = 13.5, 13.8 Hz);
4.16 (m, 1 H, HbC(5)); 4.67, 4.71 (q, 1 H, HC(8), 3J = 7.0 Hz);
5.54, 5.56 (s, 1 H, H(12b)); 6.24 (m, 2 H, H(11), H(12)); 6.65
(m, 1 H, H(10)); 7.22—7.34 (m, 5 H, Ph).
Catalytic hydrogenation of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloꢀ
alkano[1,2ꢀa]pyrazinones 1 and 2 (general procedure). The 10%
Pd/C catalyst (0.4 g) was added to a solution of pyrrolo[2,1ꢀc]ꢀ
1,3ꢀdiazacycloalkano[1,2ꢀa]pyrazinone 1 or 2 (10 mmol) in ethꢀ
anol (40 mL). The hydrogenation of the reaction mixture was
performed until the theoretical amount of hydrogen was conꢀ
sumed. Then the catalyst was filtered off, and the filtrate was
concentrated to dryness.
2ꢀ(2ꢀEthylaminoethyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ
3(4H)ꢀone (15a) was synthesized by the catalytic hydrogenation
of compound 1e. The yield was 97%, viscous paleꢀyellow oil. 1H
NMR (CDCl3), δ: 1.08 (t, 3 H, Me, 3J = 7.2 Hz); 1.84 (br.s, 1 H,
NH); 2.66 (q, 2 H, CH2Me; 3J = 7.2 Hz); 2.87 (t, 2 H, CH2NH,
3J = 6.6 Hz); 3.62 (t, 2 H, CH2CH2NH, 3J = 6.6 Hz); 4.59
(s, 4 H, H2C(1), H2C(4)); 5.96 (m, 1 H, H(8)); 6.20 (m, 1 H,
H(7)); 6.58 (m, 1 H, H(6)).
1
ed (%): C, 72.37; H, 6.77; N, 9.74. H NMR (CDCl3), δ: 1.18
2
(d, 1 H, HaC(3), J3a,3b = 13.2); 2.04 (ddddd, 1 H, HbC(3),
3
3
3
3
2J3b,3a = J3b,2a = J3b,4a = 13.2 Hz, J3b,2b = J3b,4b = 4.9 Hz);
2.43 (ddd, 1 H, HaC(4), 2J4a,4b = 3J4a,3b = 13.2 Hz, 3J4a,3a = 3.8 Hz);
2.68 (dd, 1 H, HaC(2), 2J2a,2b = 13.8 Hz, 3J2a,3b = 13.2 Hz); 2.82
2
(d, 1 H, HbC(2), J2b,2a = 13.8 Hz); 3.20 (d, 1 H, Ha(CHb)Ar,
2J = 13.4 Hz); 3.22 (dd, 1 H, Ha(CHb)Ph, 2J = 13.4 Hz, 3J = 3.4 Hz);
3.34 (d, 1 H, Hb(CHa)Ar, 2J = 13.4 Hz); 3.44 (dd, Hb(CHa)Ph,
2J = 13.4 Hz, J = 3.4 Hz); 3.81 and 3.83 (both s, 3 H each,
3
2 OMe); 4.56 (s, 1 H, H(11b)); 4.71 (dd, 1 H, HbC(4), 2J4b,4a
=
3
= 13.2 Hz, J4b,3b = 4.9 Hz); 4.74 (t, 1 H, CHCH2Ph,
3J = 3.4 Hz); 6.06 (m, 1 H, H(11)); 6.32 (m, 1 H, H(10));
6.57—6.76 (m, 6 H, H(9), Ar, HPh(2), HPh(6)); 7.08—7.25
(m, 3 H, HPh(3), HPh(4), HPh(5)).
3,3ꢀDimethylꢀ1ꢀ(3,4ꢀdimethoxybenzyl)ꢀ1,3,4,11bꢀtetrahydroꢀ
2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (2e)
was synthesized by the reaction of aldehyde ester 4a with diꢀ
amine 8b. The yield was 88%, white crystals, m.p. 64—66 °C.
Found (%): C, 66.47; H, 7.32; N, 11.05. C21H27N3O3•1/2H2O.
Calculated (%): C, 66.64; H, 7.46; N, 11.10. 1H NMR (CDCl3),
δ: 0.85 and 1.07 (both s, 3 H each, 2 Me); 2.09 (d, 1 H, HaC(2),
2J2a,2b = 12.0 Hz); 2.61 (d, 1 H, HaC(4), 2J4a,4b = 12.6 Hz); 2.63
2
(d, 1 H, HbC(2), J2b,2a = 12.0 Hz); 3.03 (d, 1 H, Ha(CHb)Ar,
2J = 13.1 Hz); 3.80 and 3.83 (both s, 3 H each, 2 OMe); 4.12
(d, 1 H, Hb(CHa)Ar, 2J = 13.1 Hz); 4.51 (d, 1 H, HbC(4),
2J4b,4a = 12.6 Hz); 4.67 and 4.79 (both d, 1 H each, HaC(7) and
2
HbC(7), J = 17.2 Hz); 4.86 (s, 1 H, H(11b)); 6.19 (m, 2 H,
H(10), H(11)); 6.63 (m, 1 H, H(9)); 6.68—6.77 (m, 3 H, Ar).
Reaction of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylates
(4) with Nꢀsubstituted 1,4ꢀdiamines (9) (general procedure).
A solution of methyl αꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)carboxylate (4)
(10 mmol) and diamine 9 (11 mmol) in xylene (30 mL) was
refluxed for 7 h. The reaction mixture was concentrated to
dryness, and the residue was refluxed with petroleum ether
(b.p. 80—100 °C, 60 mL; 150 mL in the synthesis of 3b). The
hot solution was decanted and kept at room temperature for one
day. The oil that formed was dissolved in propanꢀ2ꢀol (5 mL),
and the solution was kept at –10 °C overnight. The precipitate
that formed was filtered off and recrystallized from propanꢀ2ꢀol.
1ꢀBenzylꢀ1,2,3,4,5,12bꢀhexahydropyrrolo[2´,1´:3,4]pyrꢀ
azino[1,2ꢀa][1,3]diazepinꢀ7(8H)ꢀone (3a) was synthesized by the
reaction of aldehyde ester 4a with diamine 9a. The yield was
83%, white crystals, m.p. 75—77 °C. Found (%): C, 72.97;
H, 7.28; N, 14.03. C18H21N3O. Calculated (%): C, 73.19;
Hydrooxalate, m.p. 139—142 °C. Found (%): C, 49.40;
H, 6.83; N, 13.52. C11H17N3O•C2H2O4•H2O. Calculated (%):
C, 49.52; H, 6.71; N, 13.33.
2ꢀ(3ꢀMethylaminopropyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrꢀ
azinꢀ3(4H)ꢀone (15b) was synthesized by the catalytic hydrogeꢀ
nation of compound 2a. The yield was 96%, viscous yellow oil.
1H NMR (CDCl3), δ: 1.81 (m, 2 H, CH2CH2NH); 2.08 (br.s, 2 H,
NH); 2.41 (s, 3 H, Me); 2.59 (t, 2 H, CH2NH, 3J = 6.8 Hz); 3.58
3
(t, 2 H, CH2CH2CH2NH, J = 7.0 Hz); 4.52 and 4.59 (both s,
2 H each, H2C(1), H2C(4)); 5.96 (m, 1 H, H(8)); 6.20 (m, 1 H,
H(7)); 6.57 (m, 1 H, H(6)).
Hydrooxalate, m.p. 129—131 °C. Found (%): C, 46.98;
H, 6.99; N, 12.59. C11H17N3O•C2H2O4•2H2O. Calculated (%):
C, 46.84; H, 6.95; N, 12.61.
1
H, 7.17; N, 14.23. H NMR (CDCl3), δ: 1.62—1.98 (m, 4 H,
H2C(3), H2C(4)); 2.80—3.04 (m, 2 H, H2C(2)); 3.40 (m, 1 H,
HaC(5)); 3.62 and 3.72 (both d, 1 H each, CH2Ph, 2J = 13.6 Hz);
4.16 (m, 1 H, HbC(5)); 4.59 and 4.68 (both d, 1 H each, H2C(8),
2ꢀ(2ꢀAminoethyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀ
one (16a) was synthesized by the catalytic hydrogenation of comꢀ
pound 1a. The yield was 94%, viscous yellow oil. 1H NMR

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1265
20
(CDCl3), δ: 1.54 (br.s, 2 H, NH2); 2.94 (t, 2 H, CH2NH2,
3J = 6.5 Hz); 3.57 (t, 2 H, CH2CH2NH2, 3J = 6.5 Hz); 4.57 and
4.60 (both s, 2 H each, H2C(1), H2C(4)); 5.96 (m, 1 H, H(8));
6.20 (m, 1 H, H(7)); 6.58 (m, 1 H, H(6)).
Hydrooxalate, m.p. 182—184 °C. Found (%): C, 49.00;
H, 5.68; N, 15.69. C9H13N3O•C2H2O4. Calculated (%): C, 49.07;
H, 5.62; N, 15.61.
(1.5 Torr), nD = 1.5242. Found (%): C, 67.88; H, 10.21;
N, 21.55. C11H19N3. Calculated (%): C, 68.35; H, 9.91; N, 21.74.
1H NMR (CDCl3), δ: 1.10 (t, 3 H, Me, 3J = 7.2 Hz); 2.05 (br.s, 1 H,
NH); 2.60—2.79 (m, 6 H, CH2CH2NHCH2); 2.84 (t, 2 H,
H2C(3), 3J = 5.6 Hz); 3.63 (s, 2 H, H2C(1)); 3.98 (t, 2 H,
H2C(4), 3J = 5.6 Hz); 5.83 (m, 1 H, H(8)); 6.13 (m, 1 H, H(7));
6.53 (m, 1 H, H(6)).
2ꢀ(3ꢀAminopropyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀ
one (16b) was synthesized by the catalytic hydrogenation of comꢀ
pound 2b. The yield was 94%, viscous yellow oil. 1H NMR
(CDCl3), δ: 1.73 (m, 2 H, CH2CH2NH2); 1.95 (br.s, 2 H,
NH2); 2.69 (t, 2 H, CH2NH2, 3J = 6.6 Hz); 3.59 (t, 2 H,
CH2CH2CH2NH2, 3J = 6.9 Hz); 4.50 and 4.58 (both s, 2 H each,
H2C(1), H2C(4)); 5.96 (m, 1 H, H(8)); 6.20 (m, 1 H, H(7)); 6.57
(m, 1 H, H(6)).
2ꢀ(3ꢀMethylaminopropyl)ꢀ1,2,3,4ꢀtetrahydropyrrolo[1,2ꢀa]ꢀ
pyrazine (19b) was synthesized by the catalytic hydrogenation of
compound 17b. The yield was 94%, colorless oil, b.p. 135—138 °C
20
(1.5 Torr), nD = 1.5285. Found (%): C, 67.97; H, 10.10;
N, 21.87. C11H19N3. Calculated (%): C, 68.35; H, 9.91; N, 21.74.
1H NMR (DMSO), δ: 1.61 (m, 2 H, CH2CH2NH); 2.25 (s, 3 H,
Me); 2.48 (m, 4 H, CH2CH2CH2NH); 2.72 (t, 2 H, H2C(3),
3J = 5.5 Hz); 3.49 (s, 2 H, H2C(1)); 3.89 (t, 2 H, H2C(4),
3J = 5.5 Hz); 5.69 (m, 1 H, H(8)); 5.96 (m, 1 H, H(7)); 6.57
(m, 1 H, H(6)).
Xꢀray diffraction study. Single crystals of compounds 1c and
2d suitable for Xꢀray diffraction were obtained by recrystallizaꢀ
tion from ethanol. The lowꢀtemperature Xꢀray diffraction studꢀ
ies were carried out on SMART APEX II CCD (1c) and SMART
APEX 1000 CCD (2d) diffractometers (MoꢀKα radiation, graphꢀ
ite monochromator, ωꢀscanning technique). The structures were
Hydrooxalate, m.p. 161—163 °C. Found (%): C, 51.01;
H, 6.08; N, 14.85. C10H15N3O•C2H2O4. Calculated (%): C, 50.88;
H, 6.05; N, 14.83.
Reduction of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloalkano[1,2ꢀa]ꢀ
pyrazinones 1 and 2 with lithium aluminum hydride (general proꢀ
cedure). A solution of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloalkano[1,2ꢀa]ꢀ
pyrazinone 1 or 2 (15 mmol) in toluene (30 mL) was added
dropwise with stirring to a suspension of lithium aluminum hyꢀ
dride (0.95 g, 25 mmol) in anhydrous diethyl ether (40 mL) and
toluene (20 mL) at 25 °C. The reaction mixture was stirred at
40 °C for 4 h, and then a 20% NaOH solution (1 mL) and water
(8 mL) were added. The solution was decanted from the precipꢀ
itate, and the precipitate was washed with toluene and also deꢀ
canted. The combined solutions were concentrated to dryness.
The residue was distilled.
Table 2. Principal crystallographic data and the refinement staꢀ
tistics for compounds 1c and 2d
Parameter
1c
2d
1ꢀEthylꢀ1,2,3,5,6,10bꢀhexahydroimidazo[1,2ꢀa]pyrroloꢀ
[2,1ꢀc]pyrazine (17a) was synthesized by the reduction of comꢀ
pound 1e. The yield was 80%, colorless oil, b.p. 122—124 °C
Empirical formula
Molecular weight
T/K
Crystal system
Space group
Z
a/Å
b/Å
c/Å
α/deg
C19H25N3O5
375.42
100
C26H29N3O3
431.52
120
20
(1.5 Torr), nD = 1.5443. Found (%): C, 68.90; H, 9.26;
Triclinic
Triclinic
P–1
P–1
N, 21.71. C11H17N3. Calculated (%): C, 69.07; H, 8.96; N, 21.97.
1H NMR (DMSO), δ: 1.01 (t, 3 H, Me, 3J = 7.2 Hz); 2.16
(q, 2 H, CH2Me; 3J = 7.2 Hz); 2.70—3.00 and 3.07—3.24
(both m, 3 H each, H2C(2), H2C(3), H2C(5)); 3.73—3.95
(m, 2 H, H2C(6)); 3.98 (s, 1 H, H(10b)); 5.93 (m, 1 H, H(10));
5.99 (m, 1 H, H(9)); 6.67 (m, 1 H, H(8)).
2
4
7.1503(5)
9.1065(7)
14.9297(13)
106.213(2)
102.096(3)
92.722(2)
906.91(12)
1.375
9.4746(9)
13.0247(12)
18.6863(17)
81.435(4)
89.817(3)
78.018(2)
2229.6(4)
1.286
1ꢀMethylꢀ1,3,4,6,7,11bꢀhexahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]ꢀ
pyrazino[1,2ꢀa]pyrimidine (17b) was synthesized by the reducꢀ
tion of compound 2a. The yield was 82%, colorless oil, b.p.
β/deg
γ/deg
V/Å3
20
105—108 °C (1 Torr), nD = 1.5546. Found (%): C, 68.89;
dcalc/g cm–3
μ/cm–1
H, 8.94; N, 21.83. C11H17N3. Calculated (%): C, 69.07; H, 8.96;
N, 21.97. 1H NMR (DMSO), δ: 1.50 (dm, 1 H, HaC(3),
2J3a,3b = 13.2 Hz); 2.34 (m, 1 H, HbC(3)); 2.50 (s, 3 H, Me);
2.63—2.85 and 3.03—3.33 (both m, 2 H and 4 H, H2C(2),
H2C(4), H2C(6)); 4.14 (m, 2 H, H2C(7)); 4.36 (s, 1 H, H(11b));
6.08 (m, 1 H, H(11)); 6.27 (m, 1 H, H(10)); 6.86 (m, 1 H, H(9)).
Catalytic hydrogenation of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloꢀ
alkano[1,2ꢀa]pyrazines 17 (general procedure). The 10% Pd/C
catalyst (0.2 g) was added to a solution of pyrrolo[2,1ꢀc]ꢀ1,3ꢀ
diazacycloalkano[1,2ꢀa]pyrazine 17 (10 mmol) in ethanol
(40 mL). The hydrogenation of the reaction mixture was perꢀ
formed until the theoretical amount of hydrogen was consumed.
Then the catalyst was filtered off, and the filtrate was concenꢀ
trated to dryness. The residue was distilled.
1
400
60
11907
0.85
920
56
28591
F(000)
2θmax/deg
Number of measured
reflections
Number of independent
reflections
Number of reflections
with I > 2σ(I)
Number of refined
parameters
R1
5270
4438
255
10720
4523
581
0.0404
0.1125
1.002
0.0565
0.1172
1.000
wR2
GOOF
Residual electron density
(dmax/dmin)/e•Å–3
2ꢀ(2ꢀEthylaminoethyl)ꢀ1,2,3,4ꢀtetrahydropyrrolo[1,2ꢀa]ꢀ
pyrazine (19a) was synthesized by the catalytic hydrogenation of
compound 17a. The yield was 92%, colorless oil, b.p. 131—134 °C
0.461/–0.250
0.414/–0.252

1266
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Mokrov et al.
solved by direct methods and refined by the fullꢀmatrix leastꢀ
squares method with anisotropic displacement parameters based
on F2hkl. The hydrogen atoms were positioned geometrically
and refined using a riding model, except for the hydrogen atoms
of the water molecule in compound 1c, which were located in
difference Fourier maps and refined isotropically. Principal
crystallographic data and the structure refinement statistics are
given in Table 2. All calculations were carried out using the
SHELXTL PLUS program package.24
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Received December 10, 2009;
in revised form March 3, 2010