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

Article abstract of DOI:10.1007/s11172-011-0253-1

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d] pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1′,2′:4,5]pyrazino[1,2-a] pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a] pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7] triazacycloundecin-8(9H)-one.

Full text of DOI:10.1007/s11172-011-0253-1

Russian Chemical Bulletin, International Edition, Vol. 60, No. 8, pp. 1694—1702, August, 2011
1694
Synthesis and some properties of Nꢀunsubstituted
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 Research 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
Reactions of methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)alkanoates with unsubstituted aliphatic
1,2ꢀ, 1,3ꢀ, and 1,4ꢀdiamines gave Nꢀunsubstituted pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloalkano[1,2ꢀa]ꢀ
pyrazinones. Some of them show ring—chain tautomerism. Transformations of these comꢀ
pounds led to a number of novel heterocyclic systems: 2,10ꢀdihydroꢀ3H,5Hꢀimidazo[1,2ꢀa]ꢀ
pyrrolo[1,2ꢀd]pyrazines, 2,3,4,11ꢀtetrahydroꢀ6Hꢀpyrrolo[1´,2´:4,5]pyrazino[1,2ꢀa]pyrimidines,
1,2,3,5,6,10bꢀhexahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazines, 1,3,4,6,7,11bꢀhexahydroꢀ2Hꢀ
pyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidines, and 2,3,4,5,6,7ꢀhexahydroꢀ1Hꢀpyrrolo[2,1ꢀc]ꢀ
[1,4,7]triazacycloundecinꢀ8(9H)ꢀone.
Key words: aliphatic diamines, formylꢀcontaining acid esters, amino lactams, reduction,
quantum chemical calculations, ketoꢀenol tautomerism, ring—chain tautomerism, pyrroleꢀ
containing heterocyclic systems, Xꢀray diffraction analysis, NMR spectroscopy.
Earlier,1 it has been found that reactions of methyl
Reactions of esters 1 with 1,3ꢀdiaminopropanes under
the same conditions as for the synthesis of compounds 3
gave heterocycles 4 (see Scheme 1). A thorough study of
these pyrrole derivatives revealed that the 1H NMR specꢀ
tra of some of them contain, apart from the main set of
signals corresponding to the tricyclic forms 4a—d, a secꢀ
ond set of signals due to bicyclic imino lactams 5. The
characteristic signal for tricyclic forms 4 is a broadened
singlet or a doublet at δ 5.2—5.3 due to the H(11b) proton.
The characteristic signals for compounds 5 are a singlet at
δ 8.0—8.2 for the imine H(1) proton and a triplet at
2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl) carboxylates (1) with Nꢀsubꢀ
stituted diamines afford novel heterocyclic structures 2a.
The goal of the present work was to obtain their Nꢀunsubꢀ
stituted analogs 2b and examine some of their chemical
properties.
δ 7.5—7.7 (3JH(6),C(5)H = 6.1 Hz) for the amide proton
2
(H(6)). The coexistence of triꢀ and bicyclic forms 4 and 5
in solutions suggests that these compounds undergo
ring—chain tautomerism, which has not been documentꢀ
2: R2 = Alk, CH2Ar (a), H (b)
1
ed hitherto for such systems. According to the H NMR
For the synthesis of heterocycles 2b, we employed
formylꢀcontaining acid esters 1 and unsubstituted aliphatꢀ
ic diamines as the starting materials. Tricyclic structures 3
were obtained from esters 1 and 1,2ꢀdiaminoethane
(Scheme 1). The reaction mixtures containing a 10% moꢀ
lar excess of the diamine were refluxed in ethanol for 1 h.
The products were isolated by crystallization at –4 °C.
The 1H NMR spectra of structures 3 show a characterꢀ
data for some of compounds 4, the ratio of the tautomers
depends on the chemical structures of the compounds,
only slightly varying with the solvent (DMSO and CDCl3
were used) (Table 1). In solutions of compounds 4a and 4b
(with an unsubstituted pyrazine ring, R1 = H) in DMSO
at room temperature, the percentage of the imine form 5 is
somewhat higher (10—13%) than that in solutions of
heterocycles 4c and 4d (R1 = Me). For compound 4d in
DMSO, the imino lactam percentage is ~5%, while a soluꢀ
tion of compound 4c contains the tricyclic form only.
Nearly the same ratios were observed in CDCl3. It should
istic doublet at δ 3.8—5.2 due to the H(10b) (3JH(10b),NH
=
= 11.3—12.4 Hz). Structure 3a was examined by Xꢀray
diffraction (Fig. 1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1669—1677, August, 2011.
1066ꢀ5285/11/6008ꢀ1694 © 2011 Springer Science+Business Media, Inc.

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1695
Scheme 1
1, 3: R1 = H (a), Me (b), CH2Ph (c)
4, 5: R1 = R2 = H (a); R1 = H, R2 = Me (b); R1 = Me, R2 = H (c); R1 = R2 = Me (d)
Reagents and conditions: i. EtOH, reflux, 1 h.
also be noted that the ratio of tautomers 4 and 5 is indeꢀ
pendent of the exposure time of the solutions (i.e., an
equilibrium ratio of these forms is reached immediately
upon the dissolution of the corresponding solids).
responding solutions only in the presence of a protic
(CF3COOH) or Lewis acid (AlCl3). The interconversions
of the diastereomers can be explained by two types of tautoꢀ
merism (Scheme 2): ketoꢀenol (pathway a) and ring—chain
Although compounds 4a,b,d in solutions are actually
mixtures of tautomers 4 and 5, there is convincing eviꢀ
dence that their crystals contain tricyclic forms only. For
compound 4b, this was unambiguously confirmed by Xꢀray
diffraction (Fig. 2). For the other compounds 4, the presꢀ
ence of pure tricyclic forms in the crystals is suggested by
their definite melting points. In addition, the IR spectra of
crystalline compounds 4 in KBr pellets are very similar to
the IR spectra of compounds 3 and 4c, which show no
tautomerism in solutions.
N(1)
C(10)
C(2)
C(10B)
C(9)
C(10A)
N(7)
C(3)
C(8)
N(4)
C(5)
C(6)
According to 1H NMR data, heterocyclic compounds
3 and 4 with R1 ≠ H are formed as pure diastereomers.
Interconversions of the diastereomers, which have been
observed1 for substituted heterocycles 2a, occurred under
neutral conditions only for structure 4c in CDCl3. For
compounds 3b and 4d, they were detected in the corꢀ
Fig. 1. General view of structure 3a in the crystal with atomic
thermal displacement ellipsoids (p = 50%).
C(2)
C(11)
C(10)
N(1)
N(5)
C(11A)
C(11B)
C(15)
C(3)
Table 1. Ratio of tautomers 4 and 5 (4 : 5) from the 1H NMR
spectra of their solutions in DMSOꢀd6 and CDCl3 4, 5
C(9)
C(4)
4, 5
4 : 5
DMSOꢀd6
4, 5
4 : 5
DMSOꢀd6
N(8)
C(14)
C(6)
O(1)
CDCl3
CDCl3
C(7)
a
b
9 : 1
7 : 1
10 : 1
8 : 1
c
d
*
*
18 : 1
18 : 1
Fig. 2. General view of structure 4b in the crystal with atomic
thermal displacement ellipsoids (p = 50%).
* Only tricyclic tautomer 4.

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Mokrov et al.
Scheme 2
volves cleavage of the interior aminal bond with presumꢀ
able formation of zwitterionic intermediate I2; a change in
the configuration occurs at the center bound to the pyrrole
C atom. The final ratios of the diastereomers in solutions
kept for two weeks were always about 1 : 1. Compound 3c
containing a bulky benzyl substituent undergoes no such
interconversions, probably because of the relatively larger
energy difference between its diastereomers compared to
compounds 3b and 4c,d with R1 = Me. Note that determiꢀ
nation of the relative configurations of the diastereomers
in question was beyond the scope of this study.
Reactions of esters 1 with 1,4ꢀdiaminobutane in ethaꢀ
nol followed a pathway that is substantially different from
that observed in the reactions with 1,2ꢀ and 1,3ꢀdiamines.
We found that the reaction mixtures should be refluxed for
4—6 h for completion of the reaction. The major products
from 1,4ꢀdiaminobutane were bicyclic (6) rather than triꢀ
cyclic structures (7) (Scheme 3). For instance, a reaction
of ester 1a with 1,4ꢀdiaminobutane yielded bicyclic prodꢀ
uct 6a only, tricyclic compound 7a being detected only in
trace amounts. Compound 6a was isolated in the individꢀ
ual state. Its 1H NMR spectrum show the following charꢀ
acteristic signals: a singlet at δ 8.10 for the imine proton
and a triplet at δ 7.61 for the amide proton. The IR specꢀ
trum of this compound in the carbonyl absorption range
contains two bands at 1657 (C=O) and 1640 cm–1 (C=N),
while the spectra of heterocyclic products 3 and 4 each
exhibit only one band (C=O).
(pathway b). In the case of ketoꢀenol tautomerization,
which is facilitated by possible conjugation of the enol
with the aromatic pyrrole ring (intermediate I1), a change
in the configuration occurs at the asymmetric center bound
to the pyrrole N atom. Ring—chain tautomerization inꢀ
The structure of bicyclic compound 6a was also conꢀ
firmed chemically: its palladiumꢀcatalyzed hydrogenation at
an atmospheric pressure gave 2,3,4,5,6,7ꢀhexahydroꢀ1Hꢀ
pyrrolo[2,1ꢀc][1,4,7]triazacycloundecinꢀ8(9H)ꢀone (8).
Scheme 3
6, 7: R1 = H (a), Me (b)
Reagents and conditions: i. EtOH, reflux, 4—6 h; ii. H2, 10% Pd/C, EtOH; iii. CHCl3 (or DMSO), 25 °C, one month.

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1697
Scheme 4
We demonstrated that the pathway of the reaction with
1,4ꢀdiaminobutane strongly depends on the structure of
the starting esters 1. For instance, a reaction with ester 1b
(R1 = Me) gave a 2 : 1 mixture of imino lactam 6b and
tricyclic product 7b, the latter consisting of diastereomers
in a ratio of 1 : 1.5.
The aforesaid different pathways of the reactions of
esters 1 with unsubstituted 1,2ꢀ, 1,3ꢀ, and 1,4ꢀdiamines is
probably due to the different rates of formation of interꢀ
mediate aminals A, B, and D (see Schemes 1 and 3). The
rate of formation of sevenꢀmembered aminal D is much
lower than those for analogous fiveꢀ and sixꢀmembered
aminals A and B.2,3 That is why the preferential pathway
of the reaction with 1,4ꢀdiaminobutane is intramolecular
Nꢀacylation with the ester group in intermediate C (pathꢀ
way c). Apparently, pathway d is followed, to some deꢀ
gree, only in the case of ester 1b: the yield of tricyclic
product 7b is ~33%.
A study of the 1H NMR spectra of the reaction prodꢀ
ucts obtained from esters 1a,b and 1,4ꢀdiaminobutane in
CDCl3 and DMSO revealed that tricyclic forms 7 graduꢀ
ally accumulate in their solutions with time for a period of
about a month (Fig. 3). The percentages of compounds 7a
and 7b increase to 45 and 79%, respectively.
To explain the observed trends associated with the presꢀ
ence or the absence of ring—chain tautomerism in comꢀ
pounds 3—7, as well as with the dependence of the ratio of
the tricyclic and bicyclic structures on the size of the diazaꢀ
cycloalkane fragment and the presence of the substituent
at the pyrazine ring of compounds 3, 4, and 7, we anaꢀ
lyzed Xꢀray diffraction data for compounds 3a and 4b and
performed quantum chemical calculations for six pairs of
tautomers T1 and T2 (Scheme 4).
According to Xꢀray diffraction data, the crystals of
compounds 3a and 4b can show the stereoelectronic interꢀ
actions lp—N—C—N (lp stands for lone electron pair),
which is evident from the pseudotorsion angles lp—N(1)—
C(10B)—N(4) (156°) and lp—N(1)—C(11B)—N(5) (171°)
n = 2—4
corresponding to the antiperiplanar arrangement of the
lone electron pair of the N(1) atom and the polar C—N
bond. Such interactions in the system lp—X—C—Y should
involve electron transfer from the lone pair of the donating
heteroatom X to the antibonding orbital of the polar C—Y
bond, thus strengthening the X—C bond and weakening
the C—Y bond.4 Indeed, in the crystal of compound 3a,
the N(1)—C(10B) bond (1.4460(14) Å) is shorter by
0.022(3) Å than the N(1)—C(2) bond (1.4684(15) Å),
while the N(4)—C(10B) bond (1.4843(13) Å) is longer by
0.023(3) Å than the N(4)—C(3) bond (1.4613(15) Å).
Similar differences in bond lengths are observed for comꢀ
pound 4b: the N(1)—C(11B) bond (1.4477(19) Å) is shortꢀ
er by 0.021(4) Å than the N(1)—C(2) bond (1.4683(18)
Å), while the N(5)—C(11B) bond (1.4807(18) Å) is longꢀ
er by 0.013(4) Å than the N(4)—C(3) bond (1.4677(17)
Å). Thus, the stereoelectronic interactions lp—N—C—N
occur in both structures 3a and 4b and are comparable in
strength. The resultant weakening of the N(4)—C(10B)
and N(5)—C(11B) bonds can facilitate the ring—chain
tautomerization discussed above.
Quantum chemical calculations of structures T1 and
T2 were performed using the B3LYP/6ꢀ311++G(d,p)//
B3LYP/6ꢀ311++G(d,p) method. The geometrical paraꢀ
meters calculated for the tricyclic forms with n = 2 and 3
approximate to those observed in the crystals of comꢀ
pounds 3a and 4b, respectively; the difference in the bond
lengths does not exceed 0.01 Å.
Our calculations (Table 2) showed that the ratio of the
tricyclic and bicyclic forms can be entirely explained by
the energy differences between these products. Indeed, for
n = 2, tricyclic structures T1 are thermodynamically much
more favorable than the corresponding bicyclic structures
T2. Ring expansion by a unit (n = 3) reduces the energy
difference between structures T1 and T2, the difference
being smaller for compounds with R1 = H than for those
with R1 = Me. Finally, for n = 4, bicyclic form T2 is
substantially more favorable for R1 = H and has nearly the
same energy as tricyclic form T1 for R1 = Me. Thus, the
experimental and calculated data for structures T1 and T2
are in good agreement.
C (%)
7b
80
70
60
7a
50
40
30
20
10
5
10
15
20
25
30
35 τ/days
The next part of our study was devoted to some transꢀ
formations of heterocyclic compounds 3 and 4. We found
that catalytic hydrogenation of these compounds on 10%
Fig. 3. Plots of the percentages C of the tricyclic forms 7a and 7b
vs. the exposure time of solutions of a mixture of the correspondꢀ
ing tautomers 6 and 7.

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Mokrov et al.
Table 2. Correlation of the B3LYP/6ꢀ311++G(d,p)//
B3LYP/6ꢀ311++G(d,p)ꢀcalculated total energy differꢀ
ences for pairs of tautomers T1 and T2 with the observed
T1 : T2 ratio in their equilibrium solutions in CDCl3
imidazo[1,2ꢀa]pyrrolo[1,2ꢀd]pyrazines and 2,3,4,11ꢀtetꢀ
rahydroꢀ6Hꢀpyrrolo[1´,2´:4,5]pyrazino[1,2ꢀa]pyrimidines
(10), which were isolated as hydrooxalates. Earlier,5,6 such
ring closure transformations of amino lactams into amidꢀ
ines have been conducted in boiling aromatic solvents in
the presence of Lewis acids. Here we found that the forꢀ
mation of amidines 10 is a sufficiently rapid process reꢀ
quiring no catalysts and that the catalytic hydrogenation
of compound 4b is followed by in situ cyclization of the
corresponding amino lactam 9d (see Scheme 5).
R1
H
n
T1 : T2
Δ*/kcal mol–1
2
3
4
2
3
4
**
8 : 1
1 : 1.2
**
**
3.8:1
15.9
8.1
–1.8
16.9
9.1
Me
Apparently, the formation of amidine 10d is facilitated
by the presence of two methyl groups in the aminoalkyl
chain of compound 9d, which makes its molecular configꢀ
–0.4
* The energy difference is cited with allowance for the
energy of zeroꢀpoint vibrations.
** Only T1.
1
uration most favorable for this reaction. The H NMR
spectra of amidines 10 with R1 = H show a singlet at
δ 4.24—4.28 (CH2 group at the pyrrole C atom) and
a singlet at δ 4.50—4.77 (CH2 group at the pyrrole N atom).
Reduction of heterocyclic compounds 3 and 4 with
LiAlH4 gave cyclic aminals 11 (Scheme 6). When comꢀ
paring the 1H NMR spectra of compounds 11 with those
of structures 3 and 4, one should note that the signal for the
proton at the aminal C atom is shifted upfield (δ 3.8—4.7)
and that the methylene group resulting from the reduction
of the carbonyl function is manifested as a multiplet at
δ 2.5—3.2. In addition, the 1H NMR data for products 11
suggest that compound 11a is diastereomerically pure,
while compounds 11b and 11c are 3.3 : 1 and 2 : 1 mixꢀ
tures of diastereomers, respectively. Apparently, the parꢀ
tial racemization of the diastereomerically pure starting
compounds 4 results from ring—chain tautomerization,
either during their reduction or in final products 11.
Pd/C at an atmospheric pressure occurs only in the presꢀ
ence of equimolar amounts of acetic acid but fails under
neutral conditions. The reaction gave 2ꢀaminoalkylꢀ1,2ꢀ
dihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀones 9 (Scheme 5)
via hydrogenolysis of the aminal fragments in structures 3
and 4 (see Ref. 1). When refluxed in xylene, amino lacꢀ
tams 9 underwent cyclization into 2,10ꢀdihydroꢀ3H,5Hꢀ
Scheme 5
Scheme 6
11: R1 = Me, R2 = H (a, b); R1 = R2 = Me;
n = 0 (a), 1 (b, c)
Reagents and conditions: LiAlH4, anhydrous Et2O, 10 min.
To sum up, we obtained a number of heterocyclic strucꢀ
tures 3—7. Some of them show ring—chain tautomerism,
which has not been observed previously in such systems.
We demonstrated that the palladiumꢀcatalyzed hydrogeꢀ
nation of compounds 3 and 4 occurs in the presence of
acetic acid and, via hydrogenolysis of the aminal fragꢀ
ment, yields lactams 9. When heated, the latter undergo
cyclization into novel heterocyclic structures 10. Catalytic
hydrogenation of bicyclic compound 6a occurs under neuꢀ
tral conditions, giving macrocyclic amino lactam 8. The
9, 10: R1 = H, n = 2 (a); R1 = CH2Ph, n = 2 (b); R1 = H, n = 3 (c)
Reagents and conditions: i. H2, 10% Pd/C, EtOH, AcOH;
ii. oꢀxylene, reflux, 8 h.

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1699
3J = 12.4 Hz); 4.95 (t, 1 H, CHCH2Ph, 3J = 5.0 Hz); 5.88
(m, 1 H, H(10)); 6.09 (m, 1 H, H(9)); 6.75 (m, 3 H, H(8),
HPh(2), HPh(6)); 7.09—7.25 (m, 3 H, HPh(3), HPh(4), HPh(5)).
IR, ν/cm–1: 3281 (NH); 3119, 3099, 3054 (pyrrole, Ph); 2947,
2920, 2887, 2842 (CH2, CH); 1657 (C=O).
carbonyl group in tricyclic compounds 3 and 4 was selecꢀ
tively reduced with LiAlH4, the aminal fragment remainꢀ
ing intact. The results obtained are promising for preparaꢀ
tive organic and medicinal chemistry.
1,3,4,11bꢀTetrahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]ꢀ
pyrimidinꢀ6(7H)ꢀone (4a) was obtained from ester 1a and 1,3ꢀ
diaminopropane. Yield 82%, white crystals, m.p. 165—167 °C.
Found (%): C, 62.66; H, 7.22; N, 21.91. C10H13N3O. Calculatꢀ
ed (%): C, 62.81; H, 6.85; N, 21.97. 1H NMR (DMSO), δ:
1.43—1.57 (m, 2 H, H2C(3)); 2.76—2.95 (m, 2 H, H2C(2)); 3.09
Experimental
1
H NMR spectra were recorded on a Bruker ACꢀ250 specꢀ
trometer in DMSOꢀd6 and CDCl3 with the signals for the residꢀ
ual protons of the solvents as the internal standards (δ 2.50 and
7.24, respectively). IR spectra were recorded on a Vertexꢀ70
spectrometer (Bruker) in KBr pellets. Melting points were deꢀ
termined on a Kofler hot stage and are given uncorrected. Mass
spectra were measured on a Kratos MSꢀ300 instrument (EI, 70 eV).
The course of the reactions was monitored and the purity of the
products was checked by TLC in toluene—acetone—heptane—triꢀ
ethylamine (14 : 9 : 3 : 1) on Kieselgel 60 F254 plates; spots were
visualized under UV light. Quantum chemical calculations were
performed with the Gaussian 03 program.7 The starting comꢀ
pounds methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)alkanoates (1) were
prepared as described earlier.1
2
(d, 1 H, HaC(4), J4a,4b = 13.0 Hz); 4.55 (d, 1 H, HbC(4),
2J4b,4a = 13.0 Hz); 4.61 (s, 2 H, H2C(7)); 5.29 (br.s, 1 H, H(11b));
6.02 (m, 1 H, H(11)); 6.10 (m, 1 H, H(10)); 6.65 (m, 1 H, H(9)).
IR, ν/cm–1: 3284 (NH); 3117, 3091 (pyrrole); 2947, 2933, 2865,
2828 (CH2, CH); 1643 (C=O).
3,4,5,6ꢀTetrahydropyrrolo[2,1ꢀc][1,4,7]triazecinꢀ7(8H)ꢀone
1
(5a), a bicyclic tautomer of compound 4a. H NMR (DMSO),
δ: 1.67 (m, 2 H, H2C(4)); 3.32 (m, 2 H, CH2NH); 3.48 (m, 2 H,
H2C(3)); 4.86 (s, 2 H, H2C(8)); 6.06 (m, 1 H, H(11)); 6.44 (m, 1 H,
3
H(12)); 6.89 (m, 1 H, H(10)); 7.67 (t, 1 H, NH, J = 6.1 Hz);
8.06 (s, 1 H, H(1)).
Reactions of methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)alkanoates
(1) with 1,2ꢀ and 1,3ꢀdiamines (general procedure). A solution of
methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)alkanoate (1) (20 mmol) and
1,2ꢀdiaminoethane or 1,3ꢀdiaminopropane (22 mmol) in ethaꢀ
nol (30 mL) was refluxed for 1 h. The reaction mixture was kept
at –4 °C for 48 h. The crystals that formed were filtered off,
washed with cold ethanol, and recrystallized (if needed).
1,2,3,10bꢀTetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]pyrazinꢀ
5(6H)ꢀone (3a) was obtained from ester 1a and 1,2ꢀdiaminoetꢀ
hane. Yield 83%, white crystals, m.p. 175—177 °C. Found (%):
C, 60.93; H, 6.52; N, 23.73. C9H11N3O. Calculated (%): C, 61.00;
H, 6.26; N, 23.71. 1H NMR (DMSO), δ: 2.91—3.23 (m, 2 H,
H2C(2)); 3.23—3.64 (m, 2 H, H2C(3)); 4.55, 4.64 (both d, 1 H each,
H2C(6), 2J = 16.0 Hz); 5.15 (d, 1 H, H(10b), 3J = 11.7 Hz); 6.04
(m, 1 H, H(10)); 6.12 (m, 1 H, H(9)); 6.79 (m, 1 H, H(8)). IR,
ν/cm–1: 3242 (NH); 3112, 3094 (pyrrole); 2976, 2959, 2882,
2857 (CH2, CH); 1643 (C=O).
3,3ꢀDimethylꢀ1,3,4,11bꢀtetrahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]ꢀ
pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (4b) was obtained from esꢀ
ter 1a and 1,3ꢀdiaminoꢀ2,2ꢀdimethylpropane. Yield 68%, white
crystals, m.p. > 250 °C. Found (%): C, 65.70; H, 7.90; N, 19.05.
C12H17N3O. Calculated (%): C, 65.73; H, 7.81; N, 19.16.
1H NMR (DMSO), δ: 0.84, 0.89 (both s, 3 H each, 2 Me);
2.55—2.86 (m, 3 H, H2C(2), HaC(4)); 4.24 (d, 1 H, HbC(4),
2J4b,4a = 12.7 Hz); 4.56, 4.63 (both d, 1 H each, H2C(7),
2J = 17.8 Hz); 5.22 (d, 1 H, H(11b), 3J = 11.0 Hz); 6.03 (m, 1 H,
H(11)); 6.13 (m, 1 H, H(10)); 6.67 (m, 1 H, H(9)). IR, ν/cm–1
:
3295 (NH); 3120, 3104 (pyrrole); 2972, 2952, 2932, 2870 (Me,
CH2, CH); 1637 (C=O).
4,4ꢀDimethylꢀ3,4,5,6ꢀtetrahydropyrrolo[2,1ꢀc][1,4,7]triꢀ
azecinꢀ7(8H)ꢀone (5b), a bicyclic tautomer of compound 4b.
1H NMR (DMSO), δ: 0.74 (s, 6 H, 2 Me); 3.03 (d, 2 H, CH2NH,
3J = 6.1 Hz); 3.11 (s, 2 H, H2C(3)); 4.97 (s, 2 H, H2C(8)); 6.10
(m, 1 H, H(11)); 6.48 (m, 1 H, H(12)); 6.95 (m, 1 H, H(10));
7.50 (t, 1 H, NH, 3J = 6.1 Hz); 8.03 (s, 1 H, H(1)).
6ꢀMethylꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]ꢀ
pyrazinꢀ5(6H)ꢀone (3b) was obtained from ester 1b and 1,2ꢀdiꢀ
aminoethane. Yield 70%, white crystals, m.p. 154—156 °C.
Found (%): C, 62.92; H, 6.94; N, 22.03. C10H13N3O. Calculatꢀ
ed (%): C, 62.81; H, 6.85; N, 21.97. 1H NMR (DMSO; the
signals for the pairs of diastereomers, which were detected upon
the addition of CF3COOD or AlCl3 to a solution of compound
3b in DMSO and used to determine the ratio of these diaꢀ
stereomers, are italicized), δ: 1.46 (1.53 and 1.67) (d, 3 H, Me,
3J = 7.1 Hz); 3.00, 3.13 (both m, 1 H each, H2C(2)); 3.20—3.34
7ꢀMethylꢀ1,3,4,11bꢀtetrahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]pyrꢀ
azino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (4c) was obtained from ester
1b and 1,3ꢀdiaminopropane. Yield 81%, white crystals, m.p.
92—95 °C. Found (%): C, 64.31; H, 7.38; N, 20.61. C11H15N3O.
Calculated (%): C, 64.37; H, 7.37; N, 20.47. 1H NMR (CDCl3;
the signals for the diastereomer detected in a solution of comꢀ
pound 4c after its keeping for two weeks are italicized), δ:
1.52—1.85 (m and d (1.64, 1.74), 5 H, H2C(3) and Me, 3J = 6.9
2
Hz); 2.89 (ddd, 1 H, HaC(4), J4a,4b
=
3J4a,3b = 12.9 Hz,
3
2
(m, 2 H, H2C(3)); 4.68 (q, 1 H, H(6), J = 7.1 Hz); 5.19 (5.86
3J4a,3a = 3.8 Hz); 3.01 (ddd, 1 H, HaC(2), J2a,2b = 11.9 Hz,
and 5.93) (d, 1 H, H(10b), 3J = 11.3 Hz); 6.02 (m, 1 H, H(10));
6.10 (m, 1 H, H(9)); 6.83 (7.00 and 7.05) (m, 1 H, H(8)). IR,
ν/cm–1: 3258 (NH); 3124, 3097 (pyrrole); 2990, 2978, 2949,
2886 (Me, CH2, CH); 1649 (C=O).
3J2a,3b = 11.7 Hz, J2a,3a = 3.5 Hz); 3.25 (dm, 1 H, HbC(2),
3
2J2b,2a = 11.9 Hz); 4.65, 4.69 (q, 1 H, CHMe, 3J = 6.9 Hz); 4.82
(dm, 1 H, HbC(4), J4b,4a = 12.9 Hz); 5.33, 5.35 (br.s, 1H,
2
H(11b)); 6.21 (m, 1 H, H(11)); 6.25 (m, 1 H, H(10)); 6.63 (m, 1 H,
H(9)). IR, ν/cm–1: 3302 (NH); 3122, 3101 (pyrrole); 2994, 2960,
2948, 2852 (Me, CH2, CH); 1640 (C=O).
3,3,7ꢀTrimethylꢀ1,3,4,11bꢀtetrahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]ꢀ
pyrazino[1,2ꢀa]pyrimidinꢀ6(7H)ꢀone (4d) was obtained from ester
1b and 1,3ꢀdiaminoꢀ2,2ꢀdimethylpropane. Yield 74%, white
crystals, m.p. 66—69 °C. Found (%): C, 66.79; H, 8.27; N, 17.88.
C13H19N3O. Calculated (%): C, 66.92; H, 8.21; N, 18.01. MS,
6ꢀBenzylꢀ1,2,3,10bꢀtetrahydroimidazo[1,2ꢀa]pyrrolo[2,1ꢀc]ꢀ
pyrazinꢀ5(6H)ꢀone (3c) was obtained from ester 1c and 1,2ꢀdiꢀ
aminoethane. Yield 63%, white crystals, m.p. 82—84 °C. Found (%):
C, 72.21; H, 6.30; N, 15.73. C16H17N3O. Calculated (%): C, 71.89;
H, 6.41; N, 15.72. MS, m/z: 267 [M]+, 176 [M – CH2Ph]+.
1H NMR (DMSO), δ: 2.69, 2.97 (both m, 1 H each, H2C(2));
3.06—3.29 (m, 4 H, H2C(3), CH2Ph); 3.83 (d, 1 H, H(10b),

1700
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
Mokrov et al.
m/z: 233 [M]+, 218 [M – Me]+, 203 [M – 2 Me]+, 189 [M – 3 Me]+.
1H NMR (DMSO; the signals for the pairs of diastereomers,
which were detected upon the addition of CF3COOD or AlCl3
to a solution of compound 4d in DMSO and used to determine
the ratio of these diastereomers, are italicized), δ: 0.84, 0.87
(1.04 and 1.15, 1.19) (both s, 3 H each, Me2C(3)); 1.53 (1.75 and
1.92) (d, 3 H, MeCH, 3J = 7.0 Hz); 2.53—2.75 (m and d (2.61),
9ꢀMethylꢀ4,5,6,7ꢀtetrahydroꢀ3Hꢀpyrrolo[2,1ꢀc][1,4,7]triꢀ
azacycloundecinꢀ8(9H)ꢀone (6b). 1H NMR (CDCl3), δ: 1.42—1.85
(m and d (1.62), 7 H, H2C(4), H2C(5), Me, 3J = 7.0 Hz);
2.90—3.60 (m, 4 H, H2C(3), H2C(6)); 5.80 (q, 1 H, CHMe,
3J = 7.0 Hz); 6.19 (m, 1 H, H(12)); 6.44 (m, 1 H, H(13)); 7.06
3
(m, 1 H, H(11)); 7.97 (t, 1 H, NH, JNH,6 = 6.0 Hz); 8.08
(s, 1 H, H(1)).
2
3 H, H2C(2) and HaC(4), J4a,4b = 12.7 Hz); 4.20 (d, 1 H,
8ꢀMethylꢀ1,2,3,4,5,12bꢀhexahydropyrrolo[2´,1´:3,4]pyrꢀ
azino[1,2ꢀa][1,3]diazepinꢀ7(8H)ꢀone (7b). 1H NMR (CDCl3;
the signals for the minor diastereomer are italicized), δ: 1.37—1.88
(m and d (1.58, 1.74), 7 H, H2C(3), H2C(4), Me, 3J = 7.1 Hz);
2.61—3.19 (m, 3 H, H2C(2), HaC(5)); 4.32 (m, 1 H, HbC(5));
4.59, 4.67 (q, 1 H, CHMe, 3J = 7.1 Hz); 5.32, 5.39 (s, 1 H,
H(12b)); 6.10, 6.13 (m, 1 H, H(12)); 6.19 (m, 1 H, H(11)); 6.62
(m, 1 H, H(10)).
HbC(4), 2J4b,4a = 12.7 Hz); 4.70 (4.74 and 5.16) (q, 1 H, HC(7),
3J = 7.0 Hz); 5.22 (d, 1 H, H(11b), 3J = 9.8 Hz); 6.05 (m, 1 H,
H(11)); 6.14 (m, 1 H, H(10)); 6.80 (m, 1 H, H(9)). IR, ν/cm–1
:
3260 (NH); 3119, 3107 (pyrrole); 2976, 2953, 2927, 2872 (Me,
CH2, CH); 1627 (C=O).
4,4,8ꢀTrimethylꢀ3,4,5,6ꢀtetrahydropyrrolo[2,1ꢀc][1,4,7]ꢀ
triazecinꢀ7(8H)ꢀone (5d), a bicyclic tautomer of compound 4d.
1H NMR (DMSO; the signals that are not masked by those of
major tautomer 4d are cited only), δ: 1.60 (d, 3 H, MeCH,
2,3,4,5,6,7ꢀHexahydroꢀ1Hꢀpyrrolo[2,1ꢀc][1,4,7]triazacycloꢀ
undecinꢀ8(9H)ꢀone (8). A catalyst (10% Pd/C, 0.2 g) was added
to a solution of compound 6a (0.51 g, 2.5 mmol) in DMF
(30 mL). Hydrogen was bubbled through the reaction mixture
until its theoretical amount was consumed. The catalyst was
filtered off and the solution was evaporated to dryness. The resiꢀ
due was chromatographed on alumina with chloroform (150 mL)
as an eluent. The eluate was evaporated to dryness and the resiꢀ
due was recrystallized from ethanol (7 mL). Yield 80%, white
crystals, m.p. 147—151 °C. Found (%): C, 61.22; H, 8.66;
N, 19.60. C11H17N3O•1/2H2O. Calculated (%): C, 61.09; H,
8.39; N, 19.43. 1H NMR (CDCl3), δ: 1.45 (m, 5 H, H2C(4),
H2C(5), NH); 2.65 (t, 2 H, H2C(3), 3J = 6.1 Hz); 3.16 (m, 2 H,
H2C(6)); 3.67 (s, 2 H, H2C(1)); 4.50 (s, 2 H, H2C(9)); 6.04 (dd,
3
3J = 7.0 Hz); 5.73 (q, 1 H, HC(8), J = 7.0 Hz); 6.20 (m, 1 H,
H(11)); 6.57 (m, 1 H, H(12)); 7.20 (m, 1 H, H(10)); 7.71 (t, 1 H,
NH, 3J = 6.1 Hz); 8.19 (s, 1 H, H(1)).
Reaction of methyl 2ꢀ(2ꢀformylpyrrolꢀ1ꢀyl)acetate (1a) with
1,4ꢀdiaminobutane. A solution of methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrꢀ
rolꢀ1ꢀyl)acetate 1a (1.67 g, 10 mmol) and 1,4ꢀdiaminobutane
(0.97 g, 11 mmol) in ethanol (15 mL) was refluxed for 4 h. The
reaction mixture was diluted with water (10 mL) and kept at
–5 °C for two weeks. The precipitate that formed was filtered off
and washed with ethanol. The yield of 4,5,6,7ꢀtetrahydroꢀ3Hꢀ
pyrrolo[2,1ꢀc][1,4,7]triazacycloundecinꢀ8(9H)ꢀone (6a) was 1.25 g
(61%), light yellow powder, m.p. 128—132 °C. Found (%):
C, 64.16; H, 7.22; N, 20.18. C11H15N3O. Calculated (%): C, 64.37;
H, 7.37; N, 20.47. MS, m/z: 205 [M]+. 1H NMR (CDCl3), δ:
1.35—1.80 (m, 4 H, H2C(4), H2C(5)); 3.19 (dt, 2 H, H2C(6),
3
4
1 H, H(13), J13,12 = 3.4 Hz, J13,11 = 1.7 Hz); 6.10 (dd, 1 H,
H(12), 3J12,13 = 3.4 Hz, 3J12,11 = 2.8 Hz); 6.70 (dd, 1 H, H(11),
3J11,12 = 2.8 Hz, 4J11,13 = 1.7 Hz); 7.91 (t, 1 H, CONH, 3J = 5.3 Hz).
IR, ν/cm–1: 3270 (NH); 3088 (pyrrole); 2921, 2858 (CH2); 1656
(C=O); 719 ((CH2)4).
3
3
3J6,NH = 6.0 Hz, J6,5 = 7.1 Hz); 3.47 (t, 2 H, H2C(3), J3,4
=
=
= 6.4 Hz); 4.88 (s, 2 H, H2C(9)); 6.20 (dd, 1 H, H(12), 3J12,13
= 3.8 Hz, 3J12,11 = 2.7 Hz); 6.49 (dd, 1 H, H(13), 3J13,12 = 3.8 Hz,
Catalytic hydrogenation of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloꢀ
alkano[1,2ꢀa]pyrazinones (3 and 4) (general procedure). Acetic
acid (7.2 mL, 120 mmol) and 10% Pd/C (0.5 g) were added to
a solution of compound 3 or 4 (20 mmol) in ethanol (90 mL).
Hydrogen was bubbled through the reaction mixture until its
theoretical amount was consumed. The catalyst was filtered off
and the solution was evaporated to dryness. A 40% aqueous soluꢀ
tion of NaOH (10 mL) was added to the residue and the product
was extracted with chloroform (2×20 mL). The combined orꢀ
ganic extracts were washed with water (8 mL), filtered through
a folded filter, and evaporated to dryness.
3J13,11 = 1.7 Hz); 6.88 (dd, 1 H, H(11), J11,12 = 2.7 Hz,
3
3J11,13 = 1.7 Hz); 7.61 (t, 1 H, NH, JNH,6 = 6.0 Hz); 8.10
3
(s, 1 H, H(1)). IR, ν/cm–1: 3294 (NH); 3098 (pyrrole); 2927,
2856 (CH2); 1657 (C=O); 1640 (C=N); 733 ((CH2)4).
1,2,3,4,5,12bꢀHexahydropyrrolo[2´,1´:3,4]pyrazino[1,2ꢀa]ꢀ
1
[1,3]diazepinꢀ7(8H)ꢀone (7a). H NMR (CDCl3; the spectrum
was obtained by subtracting the spectrum of compound 6a
from the spectrum of 6a+7a recorded after a solution of comꢀ
pound 6a in CDCl3 had been kept for a month), δ: 1.47—1.90
(m, 4 H, H2C(3), H2C(4)); 2.76—3.04 (m, 2 H, H2C(2));
3.06—3.15 (m, 1 H, HaC(5)); 4.40 (m, 1 H, HbC(5)); 4.57,
4.67 (both d, 1 H each, H2C(8), 2J = 17.2 Hz); 5.40 (s, 1 H,
H(12b)); 6.14 (m, 1 H, H(12)); 6.21 (m, 1 H, H(11)); 6.60
(m, 1 H, H(10)).
2ꢀ(2ꢀAminoethyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀ
one (9a) was obtained in 76% yield by catalytic hydrogenation of
compound 3a. The physical constants and 1H NMR spectrum of
compound 9a agree with the literature data.1
Reaction of methyl 2ꢀ(2ꢀformylꢀ1Hꢀpyrrolꢀ1ꢀyl)propionate
(1b) with 1,4ꢀdiaminobutane. A solution of compound 1b
(10 mmol) and 1,4ꢀdiaminobutane (11 mmol) in ethanol (15 mL)
was refluxed for 6 h. The reaction mixture was diluted with water
(15 mL). The oil that formed on the bottom of the reaction
vessel was separated by decanting the supernatant. The oil with
the residual amounts of the supernatant was evaporated to dryꢀ
ness to give a light orange viscous oil containing a 2 : 1 mixture
of bicyclic form 6b and tricyclic form 7b (a pair of diastereꢀ
omers) (1H NMR, CDCl3). The yield was 90%. Found (%):
C, 65.60; H, 7.92; N, 19.32. C12H17N3O. Calculated (%):
C, 65.73; H, 7.81; N, 19.16.
2ꢀ(2ꢀAminoethyl)ꢀ4ꢀbenzylꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrꢀ
azinꢀ3(4H)ꢀone (9b) was obtained by catalytic hydrogenation of
compound 3c. Yield 73%, light yellow powder, m.p. 98—100 °C.
Found (%): C, 71.47; H, 7.02; N, 15.59. C16H19N3O. Calculatꢀ
ed (%): C, 71.35; H, 7.11; N, 15.60. 1H NMR (CDCl3), δ: 1.93
(br.s, 2 H, NH2); 2.86 (m, 2 H, CH2NH2); 3.13—3.42 (m, 3 H,
CH2Ph, HaC(1)); 3.54 (m, 2 H, CH2CH2NH2); 4.05 (d, 1 H,
HbC(1), J = 15.4 Hz); 4.96 (t, 1 H, HC(4), J = 4.2 Hz); 5.78
(m, 1 H, H(8)); 6.24 (m, 1 H, H(7)); 6.62 (m, 1 H, H(6)), 6.65—7.22
(m, 5 H, Ph).
2
3
2ꢀ(3ꢀAminopropyl)ꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ3(4H)ꢀ
one (9c) was obtained in 80% yield by catalytic hydrogenation of

Pyrrolo[2,1ꢀc]azacycloalkano[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
1701
compound 4a. The physical constants and 1H NMR spectrum of
compound 9c agree with the literature data.1
4.50 (s, 2 H, H2C(11)); 5.92 (m, 1 H, H(7)); 6.13 (m, 1 H, H(8));
6.59 (m, 1 H, H(9)).
Cyclization of 2ꢀaminoalkylꢀ1,2ꢀdihydropyrrolo[1,2ꢀa]pyrꢀ
azinꢀ3(4H)ꢀones (9) (general procedure). A solution of compound 9
(20 mmol) in oꢀxylene (30 mL) was refluxed for 8 h and evapoꢀ
rated to dryness. The residue was distilled when needed.
2,10ꢀDihydroꢀ3H,5Hꢀimidazo[1,2ꢀa]pyrrolo[1,2ꢀd]pyrazine
(10a) was obtained by cyclization of compound 9a. Yield 62%,
colorless viscous oil, b.p. 136—137 °C (1.5 Torr). 1H NMR
(CDCl3), δ: 3.41 (t, 2 H, H2C(3), 3J = 9.4 Hz); 3.84 (t, 2 H,
H2C(2), 3J = 9.4 Hz); 4.26 (s, 2 H, H2C(5)); 4.77 (s, 2 H,
H2C(10)); 5.96 (m, 1 H, H(6)); 6.20 (m, 1 H, H(7)); 6.61 (m, 1 H,
H(8)).
Hydrooxalate: m.p. 187—189 °C. Found (%): C, 54.45;
H, 5.63; N, 15.77. C10H13N3•C2H2O4. Calculated (%): C, 54.33;
H, 5.70; N, 15.84.
3,3ꢀDimethylꢀ2,3,4,11ꢀtetrahydroꢀ6Hꢀpyrrolo[1´,2´:4,5]ꢀ
pyrazino[1,2ꢀa]pyrimidine (10d) was obtained by catalytic hydroꢀ
genation of compound 4b as described above. The reaction prodꢀ
uct was distilled. Yield 55%, colorless oil, b.p. 152—154 °C
(1.5 Torr). 1H NMR (CDCl3), δ: 0.95 (s, 6 H, 2 Me); 2.94, 3.04
(both s, 2 H each, H2C(2), H2C(4)); 4.28 (s, 2 H, H2C(6)); 4.62
(s, 2 H, H2C(11)); 5.93 (m, 1 H, H(7)); 6.14 (m, 1 H, H(8)); 6.60
(m, 1 H, H(9)).
Hydrooxalate: m.p. 209—212 °C. Found (%): C, 52.38;
H, 5.30; N, 16.53. C9H11N3•C2H2O4. Calculated (%): C, 52.59;
H, 5.22; N, 16.73.
Hydrooxalate: m.p. 193—195 °C. Found (%): C, 57.18;
H, 6.69; N, 14.59. C12H17N3•C2H2O4. Calculated (%): C, 57.33;
H, 6.53; N, 14.33.
10ꢀBenzylꢀ2,10ꢀdihydroꢀ3H,5Hꢀimidazo[1,2ꢀa]pyrrolo[1,2ꢀd]ꢀ
pyrazine (10b) was obtained by cyclization of compound 9b. Yield
49%, light yellow oil. 1H NMR (CDCl3), δ: 2.67 (d, 1 H, HaC(5),
2J = 13.4 Hz); 2.90 (m, 1 H, HaC(3)); 3.18—3.40 (m, 3 H,
HbC(3), CH2Ph); 3.67—4.02 (m and d (3.85), 3 H, H2C(2),
HbC(5), J = 13.4 Hz); 5.23 (t, 1 H, H(10), J = 4.0 Hz); 5.76
(m, 1 H, H(6)); 6.21 (m, 1 H, H(7)); 6.61—7.22 (m, 6 H, H(8), Ph).
Hydrooxalate: m.p. 192—194 °C. Found (%): C, 63.09;
H, 5.79; N, 12.56. C16H17N3•C2H2O4. Calculated (%): C, 63.33;
H, 5.61; N, 12.31.
2,3,4,11ꢀTetrahydroꢀ6Hꢀpyrrolo[1´,2´:4,5]pyrazino[1,2ꢀa]ꢀ
pyrimidine (10c) was obtained by cyclization of compound 9c.
Yield 54%, light yellow oil, b.p. 150—153 °C (1.5 Torr). 1H NMR
(CDCl3), δ: 1.87 (m, 2 H, H2C(3)); 3.29, 3.36 (both t, 2 H each,
H2C(2), H2C(4), 3J = 6.1 Hz, 3J = 5.5 Hz); 4.24 (s, 2 H, H2C(6));
Reduction of pyrrolo[2,1ꢀc]ꢀ1,3ꢀdiazacycloalkano[1,2ꢀa]ꢀ
pyrazinones (3 and 4) with LiAlH4 (general procedure). Lithium
aluminum hydride (0.15 g, 4 mmol) was added to a solution of
compound 3 or 4 (1 mmol) in toluene (6 mL) and anhydrous
ether (6 mL). The reaction mixture was stirred at room temperaꢀ
ture for 10 min, whereupon 20% aqueous NaOH (0.3 mL) and
water (2 mL) were added. The precipitate that formed was sepaꢀ
rated by decanting the supernatant. Ether (5 mL) was added to
the precipitate and the mixture was stirred for 5 min. Then the
ether was decanted from the precipitate. The combined soluꢀ
tions were evaporated to dryness.
2
3
6ꢀMethylꢀ1,2,3,5,6,10bꢀhexahydroimidazo[1,2ꢀa]pyrroloꢀ
[2,1ꢀc]pyrazine (11a) was obtained by reduction of compound 3b.
Yield 90%, yellow oil. Found (%): C, 67.84; H, 8.71; N, 23.51.
C10H15N3. Calculated (%): C, 67.76; H, 8.53; N, 23.71. 1H NMR
Table 3. Crystallographic parameters and the data collection statistics for compounds 3a and 4b
Parameter
3a
4b
Molecular formula
Molecular weight
T/K
C9H11N3O
177.21
293
C12H17N3O
219.29
100
Crystal system
Space group
Monoclinic
P21/c
Monoclinic
P21/c
Z
4
4
a/Å
b/Å
c/Å
β/deg
9.6221(19)
7.1615(14)
14.445(5)
120.05(2)
861.6(4)
1.366
18.478(5)
5.7428(14)
11.247(3)
107.043(5)
1141.1(5)
1.276
3
V/Å
dcalc/g cm–3
μ/cm–1
0.94
0.84
F(000)
376
472
2θmax/deg
60
60
Number of measured reflections
2655
7077
Number of independent reflections
2522
3316
Number of reflections with I > 2σ(I)
1631
2426
Rint
0.0192
118
0.0339
151
Number of parameters refined
R1
wR2
GOOF
0.0378
0.0992
1.001
0.0515
0.1173
1.003
Residual electron density, e Å–3(dmax/dmin
)
0.146/–0.156
0.415/–0.260

1702
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 8, August, 2011
Mokrov et al.
(CDCl3), δ: 1.48 (d, 3 H, Me, 3J = 6.5 Hz); 2.25 (br.s, 1 H, NH);
References
2
2.65 (dd, 1 H, HaC(5), J = 11.5 Hz, 3J = 8.0 Hz); 2.88—3.18
(m, 5 H, H2C(2), H2C(3), HbC(5)); 4.17 (m, 1 H, H(6)); 4.70
(s, 1 H, H(10b)); 6.16 (m, 2 H, H(9), H(10)); 6.68 (m, 1 H, H(8)).
7ꢀMethylꢀ1,3,4,6,7,11bꢀhexahydroꢀ2Hꢀpyrrolo[2´,1´:3,4]ꢀ
pyrazino[1,2ꢀa]pyrimidine (a mixture of diastereomers in a ratio
of 3.3 : 1) (11b) was obtained by reduction of compound 4c.
Yield 98%, white powder, m.p. 63—65 °C. Found (%): C, 68.83;
H, 9.14; N, 21.83. C11H17N3. Calculated (%): C, 69.07; H, 8.96;
1. G. V. Mokrov, A. M. Likhosherstov, V. P. Lezina, T. A. Gudaꢀ
sheva, I. S. Bushmarinov, M. Yu. Antipin, Izv. Akad. Nauk,
Ser. Khim., 2010, 1228 [Russ. Chem. Bull., Int. Ed., 2010,
59, 1254].
2. P. Aeberly, W. J. Houlihan, J. Org. Chem., 1969, 34, 165.
3. L. F. Tietze, C. Bärtels, J. Fennen, Liebigs Ann. Chem.,
1989, 1241.
4. A. J. Kirby, The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen, Springer Berlin, 1983.
5. F. Z. Basha, J. F. DeBernardis, J. Heterocycl. Chem., 1987,
24, 789.
1
N, 21.97. H NMR (CDCl3; the signals for the minor diastereꢀ
omer are italicized), δ: 1.42, 1.47 (d, 3 H, Me, 3J = 6.5 Hz);
1.53—1.87 (m, 3 H, NH, H2C(3)); 2.27—3.23 (m, 6 H, H2C(2),
H2C(4), H2C(6)); 3.96 (s, 1 H, H(11b)); 4.19 (m, 1 H, H(7));
6.04, 6.08 (m, 1 H, H(11)); 6.14 (m, 1 H, H(10)); 6.55, 6.67
(m, 1 H, H(9)).
6. Y. Nishikawa, M. Kitajima, N. Kogure, H. Takayama, Tetraꢀ
hedron, 2009, 65, 1608.
3,3,7ꢀTrimethylꢀ1,3,4,6,7,11bꢀhexahydroꢀ2Hꢀpyrroloꢀ
[2´,1´:3,4]pyrazino[1,2ꢀa]pyrimidine (a mixture of diastereomers
in a ratio of 2 : 1) (11c) was obtained by reduction of compound
4d. Yield 97%, colorless oil. Found (%): C, 71.27; H, 9.45;
N, 19.01. C13H21N3. Calculated (%): C, 71.19; H, 9.65; N, 19.16.
1H NMR (CDCl3; the signals for the minor diastereomer are
italicized), δ: 0.84 and 1.08 (1.11) (both s, 3 H each, Me2C(3));
7. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. Montgomery, T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramilꢀ
lo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Moroꢀ
kuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G.
Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskoꢀ
rz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Alꢀ
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M.
W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez,
J. A. Pople, Gaussian 03, Revision E.01, Gaussian, Inc., Wallꢀ
ingford, CT, 2004.
3
1.41, 1.51 (d, 3 H, MeC(7), J = 6.4 Hz); 2.04—2.81 (m, 6 H,
H2C(2), H2C(4), H2C(6)); 3.81 (s, 1 H, H(11b)); 4.18 (m, 1 H,
H(7)); 6.08, 6.13 (m, 1 H, H(11)); 6.17 (m, 1 H, H(10)); 6.56,
6.69 (m, 1 H, H(9)).
Xꢀray diffraction studies. Single crystals of compounds 3a
and 4b suitable for crystallographic experiments were obtained
by recrystallization from ethanol. Lowꢀtemperature Xꢀray difꢀ
fraction from compound 3a was measured on a Syntex P21 difꢀ
fractometer (MoKα radiation, graphite monochromator, θ/2θ
scan mode). Analogous studies for compound 4b were carried
out on a SMART APEX II CCD diffractometer (MoKα radiaꢀ
tion, graphite monochromator, ω scan mode). The structures
were solved by the direct methods and refined by the leastꢀsquares
method in the anisotropic fullꢀmatrix approximation on F 2
.
hkl
8. G. Sheldrick, Acta Cryst. Sect. A, 64, 2008, 112.
The hydrogen atoms were located from difference electronꢀdenꢀ
sity maps and refined using a riding model. Selected crystalloꢀ
graphic parameters and the data collection statistics for strucꢀ
tures 3a and 4b are given in Table 3. All calculations were perꢀ
formed with the SHELXTL PLUS program package.8
Received March 1, 2011;
in revised form June 7, 2011