Design and synthesis of pyrrolotriazepine derivatives: An experimental and computational study

Article abstract of DOI:10.1021/jo4001228

The pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5] triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo[1,2- a]pyrazin-1(2H)-one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1- one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.

Full text of DOI:10.1021/jo4001228

Article
pubs.acs.org/joc
Design and Synthesis of Pyrrolotriazepine Derivatives:
An Experimental and Computational Study
Nurettin Menges,†,‡ Ozlem Sari,†,§ Yusif Abdullayev,†,∥ Safiye Sag Erdem,¶ and Metin Balci*,†
̆
†Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
‡Faculty of Pharmacy, Yuzuncuyıl University, 65080 Van, Turkey
̈
̈
̈
§Department of Chemistry, Ahi Evran University, 40100 Kırse
̧ hir, Turkey
∥Department of Chemical Engineering, Qafqaz University, 0101 Baku, Azerbaijan
¶Department of Chemistry, Marmara University, 34722 Istanbul, Turkey
S
* Supporting Information
ABSTRACT: The pyrrole derivatives having carbonyl groups
at the C-2 position were converted to N-propargyl pyrroles.
The reaction of those compounds with hydrazine mono-
hydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5]-
triazepine derivatives. The synthesis of these compounds was
accomplished in three steps starting from pyrrole. On the
other hand, attempted cyclization of a pyrrole ester substituted
with a propargyl group at the nitrogen atom gave,
unexpectedly, the six-membered cyclization product, 2-
amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one as the major
product. The expected cyclization product with a seven-
membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d]-
[1,2,5]triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation
mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.
Triazepine is a seven-membered heterocyclic compound with
three nitrogen atoms, where the position of nitrogen atoms can
vary. Various benzene-fused triazepine and triazepinone
derivatives were synthesized, and furthermore, it was shown
that a variety of biological activities and synthetic routes have
been established for the related benzotriazepines.3
INTRODUCTION
■
Nitrogen-containing heterocycles have attracted considerable
attention, particularly due to their wide range of pharmaco-
logical activities. Benzodiazepines are among the most widely
prescribed drugs for the treatment of anxiety and related
disorders.1 Further extensive investigation of seven-membered
ring N-heterocycles led to the development of a number of
pharmacologically active agents directed against the other
diseases, such as cancer, HIV, and cardiac arrhythmia.2
For example, 2-thioxobenzotriazepinone derivative 4 was
subjected to a ptosis test using clozapine (3) as a reference drug
to evaluate its antipsychotic activity. It was found that 4 has the
same antipsychotic activity as the reference drug clozapine, but
with lesser side effects.4 On the other hand, some 1,3,4-
benzotriazepine derivatives, such as 5, were found to be suitable
as a nonpeptide parathyroid hormone-1 receptor (PTH1R)
antagonist.5 Recent 3D QSAR studies of various 1,3,4-
Received: January 20, 2013
© XXXX American Chemical Society
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benzotriazepine derivatives showed their activity as a
cholecystokinin (CCK2) receptor antagonist.6
Because of the interest directed toward investigating the
synthesis and activity of benzene-fused triazepine derivatives,
we were interested in the synthesis of pyrrole-fused triazepine
and triazepinone derivatives.
data. Full assignment of 1H and 13C NMR spectra was done in
the case of 10a using 1D- and 2D-NMR spectra (DEPT,
COSY, HSQC, and HMBC). In particular, the HSQC and
HMBC spectra of 10a supported the proposed structure. The
proton signals of H-5 and H-5′ appearing at 5.70 and 4.34 ppm
correlate with the methylene carbon (C-5) at 53.8 ppm.
Furthermore, a correlation between the C-1 and H-9 proton
and the C-5 and H-7 proton in the HMBC spectrum supports
the proposed structure. The other correlations are also in
agreement with the structure 10a.
A tentative mechanism of the formation of 10a−10c is
outlined in Scheme 3. It is proposed that the first step is the
formation of hydrazones 11a−11c. We assume that the
terminal nitrogen atom of hydrazone cannot attack the triple
bond because of the increased electron density. However, the
terminal alkyne can undergo base-catalyzed isomerization15 to
give the terminal allenes 15a−15c, where the hydrazine/H2O
mixture acts as a base. Since the central carbon in the allene
moiety is electropositive, nucleophiles can easily attack this
carbon atom, as depicted in Scheme 3. To support this
proposal, the corresponding allene was synthesized independ-
ently and submitted to the cyclization reaction under the same
reaction conditions (Scheme 4).
Propargyl aldehyde 12a was reacted with NaH in DMF at 0
°C; the isomerized allene 18a was isolated as the main product
in 94% yield (Scheme 4). The structure was determined by
NMR spectral data. The allenic proton CH− resonated at
8.05 ppm as a triplet and the CCH2 protons at 5.44 as a
doublet. The measured coupling constant between the allenic
Pyrrolotriazepine derivatives are rarely found in the literature.
Benzopyrrolotriazepine derivatives 6 and 7 are reported to be
useful as neuroleptic agents in the treatment of psychotic
disturbances, such as schizophrenia.7,8 Unfortunately, in the
literature, only a single pyrrole condensed triazepine skeleton 8
is reported. Some substituted derivatives of 8 showed analgesic
activity in mice and anxiolytic and anticonvulsant activities.9 In
view of these important observations, we herein report a
synthetic methodology leading to the synthesis of derivatives of
a new class of compound, 5H-pyrrolo[2,1-d][1,2,5]triazepine 9.
4
protons of J = 6.6 Hz clearly indicated the formation of an
allene structure. Furthermore, the resonance frequencies
observed at 202.0, 98.6, and 87.4 ppm in the 13C NMR
spectrum fully supported the formation of an allene structure.
The isolated allene 18a was reacted with hydrazine
monohydrate under the same reaction conditions as reported
for the reaction with alkynes, and the same cyclization product
10a was formed in 65% yield. This finding supported the
formation of an allenic structure as an intermediate in the
formation of pyrrole-fused triazepine derivatives 10a−10c.
After successful completion of the synthesis of triazepine
derivatives 10a−10c, we turned our attention to the synthesis
of pyrrolotriazepinone scaffold 19. Thus, triazepine derivative
10a was submitted to SeO2 oxidation in dioxane (Scheme 5).
Unfortunately, only dicarbonyl compound 20 was formed as an
isolable product in 62% instead of the targeted oxidation
product 19. The structure of dicarbonyl compound 20 was
established beside the spectral data by independent synthesis of
20 by the reaction of pyrrole aldehyde 14a with chloroacetone
in the presence of K2CO3. Reaction of dicarbonyl compound
20 with hydrazine monohydrate provided the cyclization
product 10a in 51% yield.
RESULTS AND DISCUSSION
■
Our planned approach to 10 involved metal-free cyclization of
pyrrole hydrazone derivatives 11, synthesized by the reaction of
acylpyrroles 12 having an alkyne moiety attached to the
nitrogen atom of pyrrole with hydrazine. The retrosynthesis is
summarized in Scheme 1.
Scheme 1. Retrosynthesis of Pyrrolotriazepine Derivatives
For the synthesis of pyrrole-fused triazepine derivatives, the
starting materials were prepared according to the literature.
Pyrrole carbonyl compounds were prepared by application of
the Vilsmeier reaction.10 As depicted in Scheme 2, treatment of
the heterocyclic building blocks 14a−14c with propargyl
bromide afforded the alkyne derivatives 12a−12c.11,12
1-(2-Oxopropyl)-1H-pyrrole-2-carbaldehyde (20) looks to
be formed by hydrolysis of the starting material 10a. However,
it has been shown that triazepine 10a is stable under the
reaction conditions. We proposed the following mechanism for
the formation of 20 (Scheme 6).
It is proposed that SeO2 undergoes a [2 + 4] cycloaddition
reaction with the diazine unit in 10a to form a selenino lactone
21. This intermediate can easily undergo nitrogen extrusion,
which is observed during the reaction. At the final step,
oxidation of C−Se to a C−O bond takes place. This
mechanism is strongly supported by a recent observation that
1,3-diene systems form syn-1,2- and syn-1,4-diols upon reaction
To the best of our knowledge, the facile construction of this
new pyrrole-fused triazepine skeleton has not been previously
explored. Heating of synthesized propargyl derivatives 12a−12c
with hydrazine monohydrate in methanol at reflux temperature
produced the desired cyclization products 10a−10c, which
were isolated in good yields (63−69%) after chromatographic
purification. The structures were determined by NMR spectral
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Scheme 2. Synthesis of Pyrrole-Fused Triazepines
Scheme 3. Mechanism for the Formation of
Pyrrolotriazepine Derivatives 10a−10c
condensation products were formed in a ratio of 9:1. Careful
examination of the reaction mixture did not reveal the
formation of any trace of 26. Finally, to test the feasibility of
converting the allene 28 to 25, the propargyl ester 24 was
isomerized to the corresponding allene 28 in the presence of
NaH in DMF. The allene 28 was obtained in high yield and
submitted to cyclization reaction with hydrazine monohydrate.
Again, the six-membered cyclization product 25 was formed as
the sole product in 96% yield. It was interesting to observe that
the cyclization reaction took place with the less reactive
nitrogen atom, which is in conjugation with the carbonyl group.
Furthermore, we noted that the triazepinone derivative 26
was smoothly rearranged to the six-membered ring isomer 25
in quantitative yield upon standing at room temperature in
chloroform for 3 days. The calculations show that the isomer
25 is 4.28 kcal/mol more stable than the isomer 26 in
methanol. We assume that this rearrangement is catalyzed by
the trace amount of acid present in chloroform. A tentative
mechanism for the rearrangement is given in Scheme 8. The
more nucleophilic nitrogen atom in 29 may attack the carbonyl
group to form a diaziridine intermediate 30, which can easily
rearrange to the six-membered ring 25 during the regeneration
of the carbonyl group.19
Finally, we focused our attention on cyclization of ketoester
31, synthesized by reaction of 23 with chloroacetone in the
presence of K2CO3. The reaction of 31 with hydrazine
monohydrate at the reflux temperature of methanol resulted
in the formation of diazine derivative 32 (Scheme 9). The
desired product 26 was not formed. Because of the difference in
reactivity of the carbonyl groups in 31, intermolecular
condensation was preferred over the intramolecular cyclization
reaction.
Theoretical Calculations. Formation of pyrrolotriazepine
10, pyrrolopyrazine 25, and pyrrolotriazepinone 26 derivatives
was computationally investigated in an effort to clarify the
mechanism. Geometrical parameters of reactants, intermedi-
with SeO2, where the involvement of cyclic selenites is
proposed.16
After failure of the oxidation reaction of 10a with selenium
dioxide to give triazepinone derivatives, we turned our attention
to construction of the desired heterocyclic scaffold by
intramolecular ring cyclization reaction of a propargyl ester
2417 with hydrazine monohydrate. The key compound,
propargyl ester 24, was synthesized in high yield from the
reaction of methyl 1H-pyrrole-2-carboxylate 2318 with prop-
argyl bromide in the presence of NaH as a base (Scheme 7).
The next step was to investigate cyclization to the
corresponding triazepinone derivative 26. Indeed, this expected
product 26 was formed only in 16% yield. However, a
cyclization product 25 with a pyrrolopyrazinone structure was
formed as the major product in 62% yield. The structures were
proven by NMR spectral data. Further structural proof of the
presence of a −NH2 group was obtained when the product 25
was reacted with benzaldehyde in methanol. Two regioisomeric
Scheme 4. Isomerization of 12a to Allene 18a and Its Reaction with Hydrazine
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Scheme 5. Oxidation of Pyrrolotriazepine 10a with SeO2
Scheme 6. Tentative Mechanism for the Formation of 20
Scheme 7. Reaction of Pyrrolepropargyl Ester 24 with Hydrazine
Scheme 8. Tentative Mechanism for Rearrangement of 26 to 25
ates, transition states (TS), and products were fully optimized
in the gas phase (for isolated molecules) with the hybrid
density functional B3LYP20,21 (Becke-3-parameter−Lee−
Yang−Parr) method using the 6-31+G(d,p) basis set
implemented in Gaussian 09,22 for all structures, except
otherwise indicated. The solvent effect was considered
implicitly employing the polarizable continuum23 model
(PCM)23,24 with single-point energy calculations at the
optimized geometries of B3LYP/6-31+G(d,p), namely, PCM/
B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p). All possible cyc-
lization pathways have been considered in order to shed light
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Scheme 9. Reaction of Methyl N-Acetonylpyrrolecarboxylate 31 with Hydrazine
Scheme 10. Mechanism for the Propargyl−Allene Isomerization
Figure 1. Potential energy profile related to the propargyl−allene isomerization at the PCM/RHF/6-31+G(d))//RHF/6-31+G(d) level in
methanol. (Polarization effect of the solvent was considered implicitly.) Distances are given in angstroms; angles are in degrees.
on the mechanism. Computational details are given in the
Supporting Information.
propargyl systems, allene isomers can be more stable than the
propargyl isomer.26 The B3LYP/6-31+G(d,p) calculations
show that the allene isomer 15a is about 8.23 and 7.43 kcal/
mol (in the gas phase and methanol, respectively) more stable
than the propargyl isomer 11a. Vitkovskaya et al.25 proposed a
propargyl−allene isomerization mechanism that includes the
abstraction of a proton with a hydroxide ion from the sp3-
hybridized carbon atom. Similarly, we assume that propargyl−
allene isomerization starts with the abstraction of H-11 attached
to the sp3-hybridized carbon atom by a hydroxide ion (formed
from the proton abstraction of water by hydrazine) (Scheme
10). The resulting anion is stabilized by the electron-
Propargyl−Allene Isomerization. Prior to the cyclization
mechanism, we first modeled the propargyl−allene isomer-
ization from 11a to 15a proposed in Scheme 3. Prototropic
isomerization processes generally consist of two-stage trans-
formations including carbanions as intermediates.25 In un-
substituted MeCCH, although the most acidic proton is
known to be the proton attached to the sp-hybridized carbon
atom, the process also depends on the relative stability of the
anions formed, and proton abstraction from the sp3-hybridized
carbon atom is sometimes possible. In addition, in hetero-
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withdrawing effect of the adjacent pyrrole nitrogen as well as
the intermolecular hydrogen bonding with water. The potential
energy profile of this two-step process was obtained using
RHF/6-31+G(d) since the B3LYP/6-31+G(d,p) method could
not optimize the desired transition states (Figure 1).
respectively (for the potential energy profile, see the Supporting
Information).
Formation of 10a from 15a. After the formation of allene
structure 15a, the nucleophilic attack of N8 on the C2 atom via
TS3 takes place, and subsequent proton transfer, followed by a
1,3-H shift, leads to the desired product as described below.
During the formation of the C2−N8 bond, the bond distance
changed from 4.226 to 1.520 Å, where the elongation of the
C2−C3 bond from 1.314 to 1.394 Å and of the C1−C2 bond
from 1.308 to 1.368 Å in 15a and 16a, is observed (Figure 2).
This indicates the transfer of π-bond electrons to both C1 and
C3 carbon atoms. The Gibbs free activation energy barrier was
found to be 30.46 and 28.65 kcal/mol in the gas phase and
methanol, respectively.
The next step is the proton transfer from N8 to the C3. For
this process, the explicit consideration of solvent molecules
plays an important role because the solvent molecules may
function as a proton channel.26,27 Therefore, this step was
modeled with the assistance of methanol, which was used as a
solvent in our experimental study. The Gibbs free energy
barrier with respect to 15a was predicted to be 26.33 kcal/mol
in methanol. The last step (1,3-H shift from N8 to C1) was also
modeled with the assistance of methanol and exhibited a more
stable transition state. Collectively, the first step is the rate-
determining step, and the formation of triazepine 10a is
plausible as experimentally observed.
In the first step, one of the methylene protons is abstracted
by a hydroxide ion, forming a complex between 33a and H2O.
Product complex PC (33a + H2O) is less stable compared to
reactant complex RC (33a′ + H2O) due to the interactions of
H2O with different carbon atoms, namely, with C-3 in 33a and
with C-1 in 33a′. In the second step, the carbanion 33a′
abstracts a proton from H2O to generate the corresponding
allene 15a. The small activation energies in Figure 1 and
experimental evidence for the conversion of 18a to 10a
(Schemes 10 and 4) strongly support our proposal (Scheme 3)
that cyclization takes place through allene intermediate 15a.
Cyclization of 15a. According to the experimental proposal
in Scheme 3, the cyclization process occurs via the nucleophilic
attack of N8 on the most electrophilic carbon C-2 on the allene
moiety to give 10a. Mulliken charges calculated at the B3LYP/
6-31+G(d,p) level on atoms C-3, C-2, and C-1 are −0.160,
0.224, and −0.603, respectively. However, since the attack of
N8 on the less electropositive carbon C3 leads to the formation
of a stable six-membered ring 35, we also investigated this
reaction, and it is described below (Scheme 11). The Gibbs free
Scheme 11. Formation Mechanism of 35
Reaction of 24 with Hydrazine. We assume that the first
step is the formation of hydrazide 36, formed from the reaction
of 28 with hydrazine, followed by a cyclization reaction. For
those reactions, there are two possible nucleophilic centers in
36, namely, N7 and N8, and three possible electrophilic centers
of the allene moiety, namely, C1, C2, and C3. Mulliken charges
of C1, C2, and C3 in 36 (−0.693, 0.308, and −0.059) show
that C1 is much less electrophilic than C3 and C2. Therefore,
the C1 position of the allene is not susceptible to the
nucleophilic attack of N8, leading to the eight-membered
activation barrier associated with the cyclization step was found
to be 51.82 and 41.78 kcal/mol in the gas phase and methanol,
Figure 2. Potential energy profile related to formation of pyrrolotriazepine derivative 10a at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p)
level in methanol. The effect of methanol was considered both implicitly and explicitly. (Relative energies shown for 15a, TS3, and 16a include
Gibbs free energy of methanol.)
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heterocyclic product not being taken into account. Thus,
nucleophilic attacks of the more nucleophilic N8 on C2 and C3
centers were investigated. The nucleophilic attack of the less
nucleophilic atom N7 on the most electrophilic center of the
allene moiety, which results in the formation of a six-membered
product 25, is also considered.
However, the calculations show that 26 was about 10.59 kcal/
mol more stable than 40 in methanol.
The second step of the formation of triazepinone derivative
26 takes place via the six-membered transition state TS7 with
the assistance of methanol. The Gibbs free energy barrier with
respect to 36 was predicted to be 34.00 kcal/mol in methanol.
The third step was initially optimized without the assistance of
methanol, and the activation barrier was found to be quite high
(50.02 kcal/mol in the gas phase). Thus, it was also modeled
with the assistance of methanol via six-membered TS8. The
activation barrier decreased to 34.18 and 29.91 kcal/mol in the
gas phase and methanol, respectively. This step had a higher
activation barrier compared to the first and second steps;
however, when the overall reaction coordinate is considered,
the rate-determining step is considered to be the second step,
with an energy barrier of 34.0 kcal/mol relative to the reactants.
The overall process is quite exergonic, with an energy of 33.05
kcal/mol.
Formation of 25. The reaction starts with a nucleophilic
attack of the N7 on the C2 of the allene moiety. According to
the Mulliken charges, N7 (−0.244) is less nucleophilic than N8
(−0.670). However, we also modeled this path because it was
expected to produce a stable six-membered structure 25, which
was experimentally observed to be the main product.
The first step of the formation of pyrrolopyrazine has 32.89
kcal/mol activation barrier in methanol, whereas the transition
state TS10 involving the methanol-assisted proton transfer
from N7 to C1 is 33.70 kcal/mol higher than the initial
reactant. The overall process is quite exergonic with an energy
of 37.26 kcal/mol in methanol. Considering the comparable
relative energies in Figures 3 and 4, we presume that formation
of both 26 and 25 is plausible at the reflux conditions in
methanol. However, 25 is thermodynamically more stable than
26 by 4.28 kcal/mol. The fact that 26 smoothly rearranges to
25 in chloroform at room temperature supports this finding.
In conclusion, a practical three-step synthesis for 5H-
pyrrolo[2,1-d][1,2,5]triazepine derivatives has been developed
Formation of 38. The first step is the formation of the
unstable zwitterionic intermediate 37 and exhibits a high Gibbs
free energy barrier (49.49 kcal/mol) in methanol (for the
potential energy profile, see the Supporting Information). Thus,
the path from 36 to 38 is not plausible since transition states of
both steps are quite unstable, leading to high barriers.
Formation of 26. This path is proposed based on the
intramolecular attack of N8 to C2 of 36. The first step includes
cyclization of 36, giving rise to a seven-membered heterocyclic
intermediate with activation energies of 34.03 and 31.63 kcal/
mol in the gas phase and methanol, respectively (Figure 3). As
N8 attacks with its lone pair of electrons on the electron-
deficient C2 of the allene moiety, the C5−N4−C3−C2
dihedral angle alters from 11.2° in 36 to −164.3° in 39. The
C1−C2−C3 angle decreased from 178.2° to 143.2° and 136.7°
in 36, TS6, and 39, respectively, which demonstrated the
change in the hybridization of C2. From the attack of N8 on C2
in 36, the isomeric triazepinone derivative 40 might also form.
Figure 3. Potential energy profile related to formation of pyrrolotriazepinone derivative at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p)
level in methanol. The effect of methanol was considered both implicitly and explicitly. (Relative energies shown for 36, TS6, and 39 include Gibbs
free energy of methanol.)
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Figure 4. Potential energy profile related to formation of pyrrolopyrazine derivative at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level
in methanol. The effect of methanol was considered both implicitly and explicitly. (Relative energies shown for 36, TS9, and 42 include Gibbs free
energy of methanol.)
washed with brine (6 × 15 mL), dried over MgSO4, and evaporated.
The crude product was chromatographed on silica gel eluting with
hexane/EtOAc (5/1) to give 12a as a yellow liquid (11.01 g; isolated
yield: 75%; crude yield: 89%).11 1H NMR (400 MHz, CDCl3) δ 9.49
starting from pyrrole. The pyrrole derivatives having carbonyl
groups at the C-2 position were converted to N-propargyl
pyrroles. The reaction of those compounds with hydrazine
monohydrate resulted in the formation of 5H-pyrrolo[2,1-
d][1,2,5]triazepine derivatives. Mechanistic studies indicated
that the propargyl group first undergoes isomerization to give
the corresponding allene, which can be trapped by nucleophilic
attack of the nitrogen atom of the initially formed hydrazones.
On the other hand, the reaction of ester 24 with hydrazine
monohydrate gave, unexpectedly, the six-membered cyclization
product 25 as the major product. However, the desired
cyclization product 26 was formed in 16% yield, which
rearranged to the thermodynamically more stable compound
25. The formation mechanism of the products was investigated,
and the results obtained were also supported by theoretical
calculations.
(bd, J = 1.2 Hz, 1H, CHO), 7.20−7.19 (m, 1H, H-5), 6.90 (dd, J5,4
=
4.0, J3,4 = 1.6 Hz, 1H, H-3), 6.22 (dd, J4,3 = 4.0, J4,5 = 2.4 Hz, 1H, H-4),
5.14 (d, J = 2.6 Hz, 2H, CH2), 2.39 (t, J = 2.6 Hz, 1H, CCH); 13
C
NMR (100 MHz, CDCl3) δ 179.5, 131.1, 130.4, 124.9, 110.1, 77.8,
74.4, 38.1.
1-(1-(Prop-2-yn-1-yl)-1H-pyrrol-2-yl)ethanone (12b). To a
stirred solution of POCl3 (16.2 g, 0.1 mol) and dimethyl acetamide
(DMA) (10.44 g, 0.12 mol) in dry ether (100 mL) was added pyrrole
(10.0 g, 0.15 mol) dropwise at 0 °C. The mixture was stirred at room
temperature for 16 h. The reaction mixture was worked up as
described above to give the acetyl compound 14b (6.98 g, 63%), which
was used without further purification for the next step. To a solution of
14b in DMF (75 mL) was added NaH (60%, 2.53 g, 0.11 mol) at 0 °C
portionwise over 1 h. The resulting mixture was stirred at 0 °C for 0.5
h, and to the reaction flask was added a solution of propargyl bromide
(80% in xylene, 10.21 g, 0.086 mol) in DMF (30 mL) dropwise over
0.5 h. The reaction mixture was stirred at room temperature for 16 h,
and after adding water (50 mL), the mixture was extracted with EtOAc
(4 × 25 mL). The extracts were washed with brine (4 × 15 mL), dried
over MgSO4, and evaporated. The crude product was chromato-
graphed on silica gel eluting with hexane/EtOAc (5/1) to give 12b as
an orange-yellow liquid (6.45 g; isolated yield: 69%; crude yield:
EXPERIMENTAL SECTION
■
1-(Prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde (12a). To a
stirred solution of POCl3 (23.1 g, 0.15 mol) and DMF (12.0 g, 0.16
mol) in dry ether (100 mL) was added pyrrole (13) (10.0 g, 0.15 mol)
dropwise at 0 °C. The mixture was stirred at room temperature for 16
h. After completion of the reaction, the saturated solution of NaHCO3
was added until a basic medium was obtained. The reaction mixture
was extracted with EtOAc (4 × 25 mL). The extracts were washed
with brine (3 × 15 mL) and dried over MgSO4, and the solvent was
evaporated to give 1H-pyrrole 2-carbaldehyde (10.35 g, 73%) (14a),
which was used without further purification for the next step. To a
solution of pyrrole-2-carbaldehyde (10.35 g, 0.11 mol) (14a) in DMF
(85 mL) was added NaH (60%, 4.32 g, 0.18 mol) at 0 °C portionwise
over 1 h. The resulting mixture was stirred at 0 °C for 0.5 h, and to the
reaction flask was added a solution of propargyl bromide (17.02 g, 0.14
mol) in DMF (30 mL) dropwise over 0.5 h. The reaction mixture was
stirred at room temperature for 16 h, and after adding water (50 mL),
the mixture was extracted with EtOAc (4 × 25 mL). The extracts were
80%).12 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J5,4 = 2.4 Hz, J5,3
=
2.0 Hz, 1H, H-5), 6.92 (dd, J3,4 = 4.0 and J3,5 = 2.0 Hz, 1H, H-3), 6.12
(dd, J4,3 = 4.0 and J4,5 = 2.4 Hz, 1H, H-4), 5.15 (d, J6,8 = 2.6 Hz, 2H,
CH2), 2.37 (s, 3H, CH3), 2.36 (t, J8,6 = 2.6 Hz, 1H, H-8); 13C NMR
(100 MHz, CDCl3) δ 187.6, 129.0, 128.2, 119.5, 107.6, 77.2, 72.9,
37.8, 26.1.
Phenyl(1H-pyrrol-2-yl)methanone (14c). Pyrrole (4.7 g, 70
mmol), phosphorylchloride (10.7 g, 70 mmol), and N,N-dimethyl-
benzamide (10.44 g, 70 mmol) were dissolved in ethylene chloride (25
mL) in a 100 mL round-bottom flask. The resulting mixture was
stirred at 60 °C for 18 h. After cooling to room temperature, water and
H
dx.doi.org/10.1021/jo4001228 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
a solution of K2CO3 were added slowly to the reaction mixture until
the pH of the solution reached a value of pH = 7. The mixture was
extracted with ethyl acetate (3 × 30 mL). After evaporation of the
solvent, the residue was purified by silica gel column chromatography
eluting with hexane/ethyl acetate (2:1) to give dark green crystals of
14c,13 (mp 74−75 °C; Lit. 78−79 °C14) (7.2 g, 40%), which were
used for the next reaction.
CH3); 13C NMR (100 MHz, CDCl3) δ 168.6, 159.4, 130.4, 128.5,
115.7, 108.5, 53.4, 20.0, 13.9; IR (ATR, cm−1) 2918, 1619, 1566, 1460,
1420, 1398, 1359, 1331, 1247, 1089, 1037, 982, 907; HRMS Calcd for
(C9H12N3) [M + H]+: 162.1025; Found: 162.1016.
4-Methyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine (10c).
To a solution of 12c (1.02 g, 5.84 mmol) in n-propanol (20 mL)
was added hydrazine monohydrate (2.75 g, 70%, 55 mmol). The
reaction mixture was heated at reflux temperature for 48 h. After
completion of the reaction, the solvent was evaporated and the residue
was chromatographed on a silica gel column eluting with EtOAc/n-
hexane (1:1) to give the triazepine derivative 10c (0.71 g, 63%)
Phenyl(1-(prop-2-yn-1-yl)-1H-pyrrol-2-yl)methanone (12c).
Pyrrole derivative 14c (1.0 g, 5.86 mmol) was dissolved in
dimethylformamide (DMF) (30 mL). NaH (0.14 g, 5.86 mmol) was
added to the solution, and the mixture was stirred in a ice bath for 30
min. Gas evolution was observed. After completion of the reaction,
propargyl bromide (0.87 g, 6.2 mmol) in DMF (5 mL) was added
dropwise at room temperature, and the solution was stirred for 24 h.
Water was (50 mL) added, and the solution was extracted with ethyl
acetate (3 × 25 mL). The combined organic extracts were washed with
brine and dried over MgSO4. The solvent was evaporated to give a
crude product (1.12 g), which was purified by column chromatography
eluting with EtOAc/hexane (4:1). As the first fraction, the pyrrole
1
(orange solid, mp 132−134 °C) from chloroform/hexane (5/1). H
NMR (400 MHz, CDCl3) δ 7.79−7.77 (m, 2H, aromatic), 7.40−7.31
(m, 3H, aromatic), 6.72 (dd, J7,8 = 2.6 and J7,9 = 1.4 Hz, 1H, H-7), 6.33
(dd, J9,8 = 3.9 and J9,7 = 1.4 Hz, 1H, H-9), 6.26 (dd, J8,9 = 3.9 and J8,7
=
2.6 Hz, 1H, H-8), 4.40 (s, 2H, CH2), 2.13 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 153.7, 151.2, 137.6, 130.4. 129.6, 128.2, 126.3,
121.2, 113.7, 110.0, 49.1, 23.3; IR (ATR, cm−1) 3125, 3000, 2924,
1611, 1539, 1403, 1328, 1270, 1074; HRMS Calcd for C14H13N3 [M +
H]+: 224.1182; Found: 224.1172.
1
derivative 12c was isolated as a dark brown liquid (0.65 g, 53%). H
NMR (400 MHz, CDCl3) δ 7.74−7.71 (m, 2H, aromatic), 7.45 (tt, J =
7.4 and 1.3 Hz, 1H, aromatic), 7.39−7.34 (m, 2H, aromatic), 7.22 (dd,
J = 2.6 and 1.7 Hz, H-5), δ 6.70 (dd, J = 4.0 and 1.7 Hz, 1H, H-3), 6.14
(dd, J = 4.0 and 2.6 Hz, 1H, H-4), 5.22 (d, J = 2.5 Hz, 2H, CH2), 2.38
(t, J = 2.5 Hz, 1H, CCH); 13C NMR (100 MHz, CDCl3) δ 183.4,
137.4, 129.2, 127.4, 126.8, 125.7, 121.2, 106.4, 75.9, 71.7, 36.3; IR
(ATR, cm−1) 1622, 1574, 1524, 1407, 1343, 1237, 1139, 1081, 1024;
HRMS Calcd for C14H11NO [M + H]+: 210.0913; Found: 210.0904.
Phenyl(1-(propa-1,2-dien-1-yl)-1H-pyrrol-2-yl)methanone
(18c). The second fraction gave the allene derivative (0.27 g, 22%) as a
1-(Propa-1,2-dien-1-yl)-1H-pyrrole-2-carbaldehyde (18a). To
a solution of propargyl carbaldehyde (12a) (0.133 g, 1 mmol) in DMF
(3 mL) was added NaH (0.038 g, 1.6 mmol) at 0 °C portionwise. The
resulting mixture was stirred at room temperature for 3 h. Water (10
mL) was then added, and the mixture was extracted with EtOAc (2 ×
10 mL). The combined extracts were washed with brine (4 × 10 mL),
dried over MgSO4, and evaporated. The crude product was
chromatographed on silica gel eluting with hexane/EtOAc (4/1) to
give a yellow viscous liquid (0.111 g, 83%; crude yield 94%). 1H NMR
(400 MHz, CDCl3) δ 9.49 (d, J = 1.0 Hz, 1H, CHO), 8.06 (t, J6,8 = J6,8′
= 6.6 Hz, 1H, CH), 7.14 (m, 1H, H-5), 6.90 (dd, J3,4 = 4.0 and ve
J3,5 = 1.4 Hz, 1H, H-3), 6.23 (dd, J4,3 = 4.0 and J4,5 = 2.6 Hz, 1H, H-4),
5.44 (d, J86 = 6.6 Hz, 2H, =CH2); 13C NMR (100 MHz, CDCl3) δ
202.8 (C), 179.8 (CHO), 130.8, 128.0, 125.4, 111.2, 98.6, 87.4;
IR (ATR, cm−1) 2925, 1650, 1528, 1476, 1402, 1368, 1336, 1313,
1218, 1074; HRMS Calcd for (C16H14N2O2Na) [2M + Na]+:
289.0948; Found: 289.0977.
Reaction of 1-(Propa-1,2-dien-1-yl)-1H-pyrrole-2-carbalde-
hyde (18a) with Water. To a solution of allene 18a (0.1 g, 0.75
mmol) in methanol (7 mL) was added water (0.135 g, 7.5 mmol). The
resulting mixture was heated at reflux temperature for 8 h. After
removal of the solvent, the residue was analyzed by NMR
spectroscopy. The starting material was recovered unchanged.
Cyclization of Allene 18a with Hydrazine. A solution of allene
18a (0.2 g, 1.51 mmol) and hydrazine monohydrate (0.31 g, 7.52
mmol) in methanol (7 mL) was heated at reflux temperature for 36 h.
After completion of the reaction (controlled by TLC), the solvent was
evaporated and water (10 mL) was added. The mixture was extracted
with EtOAc (3 × 10 mL), and organic extracts were washed with brine
(2 × 10 mL) and dried over MgSO4 and evaporated. The residue was
purified by column chromatography using hexane/ethylacetate (1/1).
The cyclization product, 4-methyl-5H-pyrrolo[2,1-d][1,2,5]triazepine
(10a) (143 mg, 65%), was isolated. The spectral data of this
compound matched exactly with data of those compounds obtained by
the reaction of 12a with hydrazine.
Reaction of Pyrrolotriazepine 10a with SeO2. To a solution of
pyrrolotriazepine 10a (0.2 g, 1.36 mmol) in 1,4-dioxane (5 mL) was
added SeO2 (0.45 g, 4.08 mmol) portionwise over 10 min at rt. The
reaction mixture was stirred for 3 h at rt. During this period, the color
of the reaction mixture was changed from yellow to purple and gas
evolution was observed. The purple-colored precipitate formed during
the reaction was filtered off, and the solvent was evaporated. Crude
product was purified by silica gel column chromatography eluting with
hexane/EtOAc (4/1) to give 1-(2-oxopropyl)-1H-pyrrole-2-carbalde-
hyde 20 as colorless needle-like crystals (127 mg, 62%) (mp 60−61
°C). 1H NMR (400 MHz, CDCl3) δ 9.43 (d, J9,5 = 1.2 Hz, 1H, CHO),
6.93 (dd, J3,4 = 4.0 and J3,5 1.6 = Hz, 1H, H-3), 6.78 (ddd, J5,6 = 2.5, J5,7
=1.6 and J5,9 = 1.2 Hz, 1H, H-5), 6.25 (dd, J 4,3 = 4.0 and J4,5 = 2.5 Hz,
1H, H-4), 5.02 (s, 2H, CH2), 2.16 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 201.6, 179.8, 132.1, 131.4, 124.6, 110.3, 57.9, 26.9; IR (ATR,
1
yellow liquid. H NMR (400 MHz, CDCl3) δ 8.12 (t, J = 6.5 Hz,1H,
HCCC), 7.71−7.69 (m, 2H, aromatic), 7.44 (tt, J = 7.3 and 1.3
Hz, 1H, aromatic), 7.37−7.33 (m, 2 H, aromatic), 7.17 (dd, J = 2.8
and 1.6 Hz, H-5), 6.68 (dd, J = 3.9 and 1.6 Hz, 1H, H-3), 6.15 (dd, J =
3.9 and 2.8 Hz, 1H, H-4), 5.42 (d, J = 6.5 Hz, 2H, CCCH2); 13
C
NMR (100 MHz, CDCl3) δ 203.1, 186.4, 139. 7, 131.7, 129.7, 129.2,
128.1, 127.7, 124.2, 110.1, 99.4, 87.0; IR (ATR, cm−1) 1623, 1573,
1446, 1407, 1340, 1239, 1023; HRMS Calcd for C28H22N2NaO2 [2M
+ Na]+: 441.1580; Found: 441.1599.
4-Methyl-5H-pyrrolo[2,1-d][1,2,5]triazepine (10a). To a sol-
ution of carbaldehyde 12a (0.5 g, 3.7 mmol) in methanol (7 mL) was
added hydrazine monohydrate (0.92 g, 18.5 mmol). The reaction
mixture was heated at reflux temperature for 48 h. After completion of
the reaction, water (20 mL) was added and the mixture was extracted
with EtOAc (3 × 15 mL), and then the extracts were dried over
MgSO4. Evaporation of the solvent and purification of the yellow
residue by silica gel chromatography with hexane/EtOAc (1/1) as
eluent afforded a yellow powder 10a (0.38 g 69%) (mp 219−221 °C)
1
from chloroform/hexane (5/1). H NMR (400 MHz, CDCl3) δ 7.91
(s, 1H, H-1), 6.68 (dd, J7,8 = 2.4 and J7,9 = 2.0 Hz, 1H, H-7), 6.21 (dd,
J9,8 = 4.0 and J9,7 = 2.0 Hz, 1H, H-9), 6.05 (dd, J8,9 = 4.0, J8,7 = 2.4 Hz,
1H, H-8), 5.70 (bd, A-part of AB-system, J = 18.0 Hz, 1H, H-5), 4.34
(bd, B-part of AB-system, J = 18.0 Hz, 1H, H-5′), 1.62 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 169.3 (C-4), 151.3 (C-1), 129.8 (C-
7), 127.1 (C-10), 120.4 (C-9), 109.4 (C-8), 53.8 (C-5), 19.3 (CH3);
IR (ATR, cm−1) 2914, 1623, 1590, 1525, 1463, 1421, 1361, 1257,
1243, 1213, 1078, 1025, 966, 905; HRMS Calcd for C8H10N3 [M +
H]+:148.0869; Found: 148.0873.
1,4-Dimethyl-5H-pyrrolo[2,1-d][1,2,5]triazepine (10b).
Acetylpyrrole (0.8 g, 5.44 mmol) and hydrazine monohydrate (1.36
g, 27.2 mmol) in methanol (10 mL) were reacted as described above
(see the synthesis of 10a). Chromatography of the residue and
purification of the yellow residue by silica gel chromatography eluting
with hexane/EtOAc (1/1) as eluent afforded yellow cubic crystals
(0.36 g, 41% isolated yield; 0.59 g, 67% crude yield) (mp 239−240
1
°C) from chloroform/hexane (5/1). H NMR (400 MHz, CDCl3) δ
6.60 (dd, J7,8= 2.4 and J7,9 = 1.7 Hz, 1H, H-7), 6.48 (dd, J9,8 = 3.9 and
J9,7 = 1.7 Hz, 1H, H-9), 6.10 (dd, J8,9 = 3.9 and J8,7 = 2.4 Hz 1H, H-8),
5.28 (d, A-part of AB-system, J = 19.0 Hz, 1H, H-5), 4.57 (d, B-part of
AB-system, J = 19.0 Hz, 1H, H-5′), 1.81 (s, 3H, CH3), 1.71 (s, 3H,
I
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cm−1) 2938, 2797, 1718, 1645, 1526, 1479, 1397, 1362, 1320, 1222,
1172, 1077; HRMS Calcd for (C8H10NO2) [M + H]+: 152.0706;
Found: 152.0712.
2-(Benzylideneamino)-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-
one (27). To a solution of pyrrolopyrazine derivative 25 (80 mg, 0.49
mmol) in ethanol (5 mL) was added benzaldehyde (53 mg, 0.5
mmol). The mixture was heated at 50 °C for 8 h. After completion of
the reaction, the solvent was evaporated and yellowish powder was
purified by column chromatography on silica gel eluting with hexane/
EtOAc (7/1) to give the condensation product 27 as bright yellow
1-(2-Oxopropyl)-1H-pyrrole-2-carbaldehyde (20). To a sol-
ution of 1H-pyrrole-2-carbaldehyde 14a (0.95 g, 10 mmol) in acetone
(20 mL) was added chloroacetone (1.02 g, 11 mmol) and K2CO3 (1.4
g, 10 mmol). The reaction mixture was heated at reflux temperature
for 24 h. After cooling to room temperature, the solid was filtered off
and the solvent was evaporated. The residue was extracted with EtOAc
(3 × 10 mL), and extracts were dried over MgSO4 and evaporated.
The crude product was chromatographed on a silica gel column
eluting with hexane/EtOAc (4/1) to give dicarbonyl compound 20 as
white needles (1.16 g, 77%) (mp 61−62 °C) from chloroform/hexane
(5:1).
Reaction of 1-(2-Oxopropyl)-1H-pyrrole-2-carbaldehyde
with Hydrazine: Synthesis of 4-Methyl-5H-pyrrolo[2,1-d]-
[1,2,5]triazepine (10a). To a solution of 1-(2-oxopropyl)-1H-
pyrrole-2-carbaldehyde (20) (0.3 g, 2 mmol) in methanol (7 mL)
was added hydrazine monohydrate (0.3 g, 6 mmol). The reaction flask
was heated at reflux temperature for 36 h. After completion of the
reaction, water (10 mL) was added. The mixture was extracted with
EtOAc (3 × 10 mL), and organic extracts were washed with brine (3 ×
10 mL). After evaporating the organic solvent, the residue was purified
by silica gel column chromatography eluting with hexane/EtOAc(1/1)
to give the cyclization product 10a (149 mg, 51%). The spectral data
of this compound were identical with those of the product obtained by
reaction of 12a with hydrazine.
1
crystals (0.117 g, 95%) (mp 123.5−125 °C). (E/Z mixture, 9/1). H
NMR (400 MHz, CDCl3) δ 9.30 (s, 1H, NCH), 7.75 (bdd, J = 7.3
and 1.7 Hz, 2H, aromatic), 7.41−7.37 (m, 3H, aromatic), 7.06 (ddd,
J8,7 = 4.0, J8,6 = 1.5 and J8,4 = 1.1 Hz, 1H, H-8), 6.98 (dd, J6,7 = 2.5 and
J6,8 = 1.5 Hz, 1H, H-6), 6.78 (qui, J4,CH3 = 1.1 = J4,8 Hz, 1H, H-4), 6.46
(dd, J7,7 = 4.0 Hz, J7,6 = 2.5 Hz, 1H, H-7), 2.24 (d, JCH3,4 = 1.1 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) 161.6, 154.3, 134.2, 131.3, 128.7,
128.2, 127.0, 123.6, 117.9, 112.4, 111.6, 105.3, 17.0; IR (ATR, cm−1)
3104, 2924, 1684, 1622, 1525, 1480, 1407, 1358; HRMS [M + H]
Calcd for C15H14N3O: 252.1131; Found: 252.1135
Methyl 1-(Propa-1,2-dien-1-yl)-1H-pyrrole-2-carboxylate
(28). Propargyl-pyrrole-2-carboxylate 25 (0.163 g, 1 mmol) was
reacted with NaH (0.038 g, 1.6 mmol) as described above. The
rearranged product allene 28 was isolated as a colorless viscous liquid
1
(0.138 g, 93%). H NMR (400 MHz, CDCl3) δ 8.06 (t, J = 6.6 Hz,
1H, CCCH), 7.05 (dd, J = 2.7 and 1.9 Hz, 1H, H-5), 6.93 (dd, J
= 3.9 and 1.9 Hz, 1H, H-3), 6.14 (dd, J = 3.9 and 2.7 Hz, 1H, H-4),
5.43 (d, J = 6.6 Hz, 2H, =CH2), 3.7 (s, 3H, OMe); 13C NMR (100
MHz, CDCl3) δ 202.9, 161.5, 125.8, 121.6, 119.0, 109.8, 98.8, 86.8,
51.2; IR (ATR, cm−1) 3010, 2985, 1715, 1601, 1595, 1510, 1490,
1440, 1396, 1331, 1295, 1230, 1187, 1070, 985, 910; HRMS Calcd for
C18H18N2NaO4 [2M + Na]: 349.1159; Found: 349.1194.
Cyclization of Allene 28 with Hydrazine. A solution of allene
28 (0.2 g, 1.23 mmol) and hydrazine monohydrate (0.31 g, 6.14
mmol) in methanol (7 mL) was heated at reflux temperature for 36 h.
After completion of the reaction, the solvent was evaporated and water
(10 mL) was added. The mixture was extracted with EtOAc (3 × 10
mL), and organic extracts were washed with brine (2 × 10 mL).
Organic extracts were dried with MgSO4 and evaporated. The residue
was purified with column chromatography using hexane/ethylacetate
(1/1) to give 2-amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (25)
(193 mg, 96%) as the sole product. The spectral data of these
compound matched with those obtained by the reaction of hydrazine
with propargyl derivative 24.
Methyl 1-(Prop-2-yn-1-yl)-1H-pyrrole-2-carboxylate (24). To
a solution of methyl 1H-pyrrole-2-carboxylate (23)16 (16.19 g, 0.13
mol) in DMF (50 mL) was added NaH (4.99 g, 0.21 mol) portionwise
at 0 °C over 0.5 h. The reaction mixture was stirred at room
temperature for 1 h. To this solution was then added a solution of
propargyl bromide (20.11 g, 0.17 mol) in DMF (15 mL) dropwise,
and the resulting mixture was stirred at room temperature for 18 h.
Water (50 mL) was added, and the mixture was extracted with EtOAc
(6 × 25 mL). Organic extracts were washed with brine (4 × 15 mL)
and dried over MgSO4. Evaporation of solvent gave propargyl-pyrrole-
2-carboxylate (24)17 as an orange-colored liquid (16.89 g, 80%). H
1
NMR (400 MHz, CDCl3) δ 7.05 (dd, J = 2.8 and 1.8 Hz, 1H, H-5),
6.90 (dd, J = 4.0 and 1.8 Hz, 1H, H-3), 6.11 (dd, J = 4.0 and 2.8 Hz,
1H, H-4), 5.10 (d, J = 2.5 Hz, 2H, CH2), 3.75 (s, 3H, OCH3), 2.36 (t,
J = 2.5 Hz, 1H, CCH); 13C NMR (100 MHz, CDCl3) 161.5, 127.9,
121.6, 118.5, 108.6, 78.2, 73.7, 51.1, 38.1.
Reaction of Methyl 1-(Prop-2-yn-1-yl)-1H-pyrrole-2-carbox-
ylate (24) with Hydrazine. Progargyl-pyrrole-2-carboxylate (24)
(0.7 g, 4.3 mmol) in methanol (15 mL) was reacted with hydrazine
monohydrate (1.51 g, 30.1 mmol). The reaction mixture was heated at
reflux temperature for 36 h. After cooling to room temperature, the
solvent was removed and the residue was chromatographed on a silica
gel column eluting with hexane/EtOAc (2/1) to give 25 (437 mg,
62%, isolated yield) as the first fraction.
Methyl 1-(2-Oxopropyl)-1H-pyrrole-2-carboxylate (31). To a
solution of methyl 1H-pyrrole-2-carboxylate (23) (1.25 g, 10 mmol) in
acetone (20 mL) was added chloroacetone (1.02 g, 11 mmol) and
K2CO3 (1.4 g, 10 mmol). The reaction mixture was heated at reflux
temperature for 24 h. After cooling to room temperature, the solid was
filtered off, and solvent was evaporated. The residue was extracted with
EtOAc (3 × 10 mL), and extracts were dried with MgSO4 and
evaporated. The crude product was chromatographed on a silica gel
column eluting with hexane/EtOAc (4/1) to give ketoester 31 as a
1
colored viscous liquid (1.34 g, 74%). H NMR (400 MHz, CDCl3) δ
6.90 (dd, J3,4 = 4.0 and J3,5 = 1.8 Hz, 1H, H-3), 6.70 (dd, J5,4 = 2.8 and
J5,3 = 1.8 Hz, 1H, H-5), 6.11 (dd, J4,3 = 4.0 and J4,5 = 2.8 Hz, 1H, H-4),
4.9 (s, 2H, CH2), 3.7 (s, 3H, OCH3), 2.1 (s, 3H, CH3);13C NMR (100
MHz, CDCl3) δ 202.4, 161.7, 129.5, 121.9, 118.2, 108.7, 60.3, 51.1,
26.7; IR (ATR, cm−1) 3011, 2925, 1775, 1680, 1595, 1510, 1488,
1410, 1395, 1310, 1288, 1066, 1010, 990; HRMS Calcd for
(C9H12NO3) [M + H]+: 182.0811; Found: 182.0834.
Reaction of Methyl 1-(2-Oxopropyl)-1H-pyrrole-2-carboxy-
late (31) with Hydrazine. To a solution of methyl 1-(2-oxopropyl)-
1H-pyrrole-2-carboxylate (31) (0.4 g, 2.21 mmol) in methanol (7 mL)
was added hydrazine monohydrate (0.33 g, 6.63 mmol). The reaction
mixture was heated at reflux temperature for 24 h. After completion of
the reaction, water (20 mL) was added and the mixture was extracted
with EtOAc (3 × 10 mL). The extracts were washed with brine (3 ×
10 mL), dried over MgSO4, and evaporated to give the diazine
derivative 31 as a yellow viscous liquid (0.35 g, 88%).
2-Amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (25). Col-
1
orless needles, mp 190−192 °C. H NMR (400 MHz, CDCl3) δ 6.99
(ddd, J8,7 = 3.9, J8,6 = 1.5, and J8,4 = 1.1 Hz, 1H, H-8), 6.98 (dd, J6,7
=
2.5 and J6,8 = 1.5 Hz, 1H, H-6), 6.73 (qui, J4,CH3 = J4,8 = 1.1 Hz, 1H, H-
4), 6.46 (dd, J7,8 = 3.9 and J7,6 = 2.5 Hz, 1H, H-7), 4.44 (bs, 2H, NH2),
2.21 (d, J11,4 = 1.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
154.5, 124.7, 120.9, 115.6, 110.2, 107.7, 102.8, 14.2; IR (ATR, cm−1)
3302, 3193, 3094, 2924, 1674, 1607, 1475, 1380, 1329, 1245, 1033;
HRMS Calcd for (C8H9N3NaO) [M + Na]+: 186.0638; Found:
186.0636.
4-Methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1-
one (26). 26 was isolated as the second fraction (0.112 g, 16% isolated
yield) as colorless needles, which rearranged quantitatively to 25 upon
standing in chloroform at room temperature for 3 days. 1H NMR (400
MHz, CDCl3) δ 8.01 (bs, 1H, NH), 7.08 (dd, J = 4.0 and 1.8 Hz, 1H),
6.76 (dd, J = 2.3 and 1.8 Hz, 1H), 6.28 (dd, J = 4.0 and 2.3 Hz, 1H),
4.62 (s, 2H, CH2), 2.15 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
160.6, 156.7, 126.1, 124.3, 117.5, 110.2, 49.1, 23.2.
Dimethyl 1,1′-((2E,2′E)-Hydrazine-1,2-diylidenebis(propan-
1-yl-2-ylidene))bis-(1H-pyrrole-2-carboxylate) (32). 1H NMR
(400 MHz, CDCl3) δ 6.90 (dd, J3,4 = 3.9 and J3,5 = 1.9 Hz, 2H, H-
J
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3), 6.80 (dd, J5,4 = 2.6 and J5,3 = 1.8 Hz, 2H, H-5), 6.11 (dd, J4,3 = 3.9
and J4,5 = 2.6 Hz, 2H, H-4), 5.01 (s, 4H, CH2), 3.74 (s, 6H, CH3), 1.61
(s, 6H, CH3); 13C NMR (100 MHz, CDCl3) δ 161.7, 147.1, 128.9,
122.3, 118.2, 108.7, 53.9, 51.1, 11.5; IR (ATR, cm−1) 2949, 1699,
1534, 1471, 1438, 1409, 1365, 1331, 1259, 1217, 1196, 1178, 1110,
1082; HRMS Calcd for (C18H22N4NaO4) [M + Na]+: 381.1533;
Found: 381.1529.
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) for all new compounds and tables
of atom coordinates and absolute energies of the calculated
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(c) Loaiza, P. R.; Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med.
̈
̈
Chem. 2007, 15, 7248−7257.
(12) (a) Alfonsi, M.; Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati,
G.; Rossi, E. Eur. J. Org. Chem. 2009, 2852−2862. (b) Abbiati, G.;
Casoni, A.; Canevari, V.; Nava, D.; Rossi, E. Org. Lett. 2006, 8, 4839−
4842.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mbalci@metu.edu.tr.
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Lett. 1989, 30, 2411−2412. (b) Shi, X. J.; Su, W. K.; Shan, W. G. J.
Indian Chem. Soc. 2005, 82, 77−78.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are indebted to the Scientific and Technological Research
Council of Turkey (TUBITAK, Grant No. TBAG-112 T36),
the Middle East Technical University, and the Turkish
Academy of Sciences (TUBA) for financial support of this
work. Furthermore, N.M. and Y.A. are grateful for a scholarship
provided by BIDEB-TUBITAK.
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