Mechanistic Insights into the Reaction of N-Propargylated Pyrrole- and Indole-Carbaldehyde with Ammonia, Alkyl Amines, and Branched Amines: A Synthetic and Theoretical Investigation

Article abstract of DOI:10.1002/ejoc.201900084

The reaction of pyrrole- and indole-carbaldehydes having a propargyl group attached to the nitrogen atom with various amines was studied. The reaction with ammonia formed pyrrolo[1,2-a]pyrazine and pyrazino[1,2-a]indole while the reaction with alkylamines

Full text of DOI:10.1002/ejoc.201900084

A Journal of
Accepted Article
Title: Mechanistic Insights into the Reaction of N-Propargylated
Pyrrole- and Indole-carbaldehyde with Ammonia, Alkyl Amines
and Branched Amines: A Synthetic and Theoretical Investigation
Authors: Ozlem Sari, Ali Fatih Seybek, Serdal Kaya, Nurettin Menges,
Safiye Sag Erdem, and Metin Balci
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900084
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10.1002/ejoc.201900084
European Journal of Organic Chemistry
Mechanistic Insights into the Reaction of N-Propargylated
Pyrrole- and Indole-carbaldehyde with Ammonia, Alkyl
Amines and Branched Amines: A Synthetic and Theoretical
Investigation
Ozlem Sari,[a,b] Ali Fatih Seybek,[a] Serdal Kaya,[a,c] Nurettin Menges[a,d], Safiye Sag
Erdem,[f] and Metin Balci*[a]
Abstract: The reaction of pyrrole- and indole-carbaldehydes having a propargyl group
attached to the nitrogen atom with various amines was studied. The reaction with
ammonia formed pyrrolo[1,2-a]pyrazine and pyrazino[1,2-a]indole while the reaction
with alkyl amines such as methyl, ethyl, hexyl, and benzyl amines formed the
corresponding pyrazinone derivatives. Unexpectedly, the reaction with allylamine and
propargylamine formed pyrazine derivatives in which the allyl and propargyl groups
were removed from the molecule. On the other hand, the reaction of N-pyropargylated
pyrrole-carbaldehyde formed indolizine derivatives upon reaction with sterically bulky
adamantyl- and t-butyl amines. To understand the main factors causing these
differences in reactivity, the reaction mechanisms were studied by means of
computational methods. Our calculations showed that bulky amines tend to attack the
central carbon of allene formed by the isomerization of N-propargyl functionality, while
the attack on the carbonyl carbon by aliphatic amines is more profound.
[a] Dr. Ozlem Sari, Mr. Ali Fatih Seybek, Dr. Serdal Kaya, Dr. Nurettin Menges, Prof. Dr.
Metin Balci
Department of Chemistry, Middle East Technical University
06800 Ankara, Turkey
E-mail: mbalci@metu.edu.tr
http://users.metu.edu.tr/mbalci/
[b] Dr. Ozlem Sari
Department of Chemistry Kırşehir Ahi Evran University,
40100 Kırşehir, Turkey
[c] Dr. Serdal Kaya
Department of Chemistry, Giresun University,
28200 Giresun, Turkey
[d] Dr. Nurettin Menges
Faculty of Pharmacy, Van Yüzüncü Yil University,
65080, Van, Turkey
[e] Prof. Dr. Safiye Sag Erdem
Department of Chemistry, Marmara University
34722 Istanbul, Turkey
Supporting information (1H and 13C NMR spectra for the products (PDF) and Cartesian Coordinates
from the calculated structures) for this article is given via a link…………
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10.1002/ejoc.201900084
European Journal of Organic Chemistry
Graphical Abstract
TOC Text: Reactions of N-propargylated pyrrole and indole carbaldehydes with
different types of amines were investigated. The nature of products was determined by
the type of amine used. The reaction with alkyl amines formed corresponding
pyrazinone derivatives while branched amines led to the formation of indolizine
derivatives. The reaction mechanisms were studied by means of computational
methods.
Key Topic: Selective Cyclization
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Introduction
Heterocyclic molecules that include two nitrogen atoms in particular have emerged
recent decades as a source of biologically active and structurally diverse compounds,
including natural products.[1] Specifically, fused aromatic heterocycles exhibit various
biological activities. Among them, pyrrolo[1,2-a]pyrazine (1), a privileged heterocyclic
compound exhibits neuroleptic and cardiovascular activity.[2] The pyrrolo-pyrazinone 2
and its derivatives were found to have significant activity in the blockade of
apomorphine stereotype and apomorphine-induced climbing.[3] Bromopyrrole alkaloids
containing the pyrrolo[1,2-a]pyrazine structural fragment such as longamide B[4](3) and
peramine[5] (4) show immunosuppressive, antibacterial, and anti-insect defensive
activities (Figure 1).[6]
Figure 1. Important heterocycles bearing pyrrole, indole, and pyrazine skeletons.
Compounds derived from the pyrazino[1,2-a]indole 5 also exhibit wide-ranging
biological activity such as intra-arterial cardiovascular, antifungal, serotoninergic, anti-
inflammatory, and antiproliferative.[7] On the other hand, some pyrazino[1,2-
a]indolones 6 displayed the highest activity against cancer cell growth were the most
potent inhibitors of reactive oxygen species production, and showed notable
antioxidant activity.[8]
Pyrrolo[1,2-a]pyrazines were synthesized by the base-mediated N-alkylation of
pyrrole-2-carboxaldehyde with bromoacetophenones followed by dehydrative
cyclization with ammonium acetate.[9] A domino synthesis of pyrrolo[1,2-a]pyrazine
starting from 2-pyrrolecarbaldehyde was developed by the reaction with readily
synthesized vinyl azides.[10] An efficient synthesis of trisubstitued pyrrolo[1,2-
a]pyrazines through three-component cyclization and one-pot cascade reaction was
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presented by Ma et al. that produced moderate to good yields.[11] Intramolecular
cyclization of N-substituted pyrrole-2-carbonitrile derivatives gave pyrrolo[1,2-
a]pyrazin-1(2H)-one via Mumm-rearrangement.[12] Recently, Cetinkaya and Balci
developed a highly selective, convenient, and practical method to access N-substituted
pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives in high yields and in three steps starting
from N-propagylated pyrrole by alkyne cyclization in a simple reaction sequence.[13]
Trost et al. reported the synthesis of pyrrolo- and indolo-piperazinone derivatives by
asymmetric alkylation of pyrrole or indole with vinyl aziridine using a palladium
catalyst.[14] Verniest and Padwa reported the formation of 2H-pyrazino[1,2-a]indolone
in high yield upon treatment of N-propargylamidoindole with AuCl3.[15] Chauhan et al.
synthesized a library of biologically valuable indolo-pyrazinones derivatives using a
domino Ugi/post cyclization approach in an one-pot procedure.[16] In recent years, we
were interested in developing new synthetic strategies for the construction of novel
fused-heterocycles with unknown skeletons using gold-catalyzed and NaH-supported
alkyne cyclization reactions.[17] As a continuation of these works we describe the
reaction of N-propargylated pyrrole- and indole-2-carbaldehyde 9 and 11 with various
amines and the synthesis of pyrrole- and indole-fused pyrazine (1 and 5), pyrazinone
(2 and 6) and amino-indolizine (7) derivatives and their formation mechanism.
Results and Discussion
The starting materials, N-propargylated pyrrole- and indole-2-carbaldehyde 9[17a,18] and
11,[17e,19] were formed by substitution reactions of corresponding aldehydes 8 and 10
with propargyl bromide in the presence of NaH (Scheme 1).
Scheme 1. Propargylation of pyrrole and indole aldehyde 8 and 10.
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We first examined the reaction of N-propargyl carbaldehydes 9 and 11 with
ammonia. The treatment of 9 with ammonia led to the formation of 3-methylpyrrolo[1,2-
a]pyrazine[9,20] (12) in 81% yield (Scheme 2). The reaction of 11 with ammonia in the
presence of Cs2CO3 in ethanol resulted in the formation of 3-methylpyrazino[1,2-
a]indole (13) in 76% yield. Abbiati et al.[21] synthesized 13 by the reaction of 11 with
dry ammonia in methanol in a sealed tube at 100 C in 80% yield. However, microwave
heating in a sealed tube at 150 C decreased the reaction time and increased the yield
to 100%.
Scheme 2. Cyclization of N-propargylated pyrrole- and indole-2-carbaldehyde with ammonia
After determining the optimal conditions for cyclization with ammonia, we turned
our attention to the scope and limitation of this transformation. Then we investigated
the cyclization reaction of a range of substituted amines. Amines bearing alkyl chains
such as methyl, ethyl, hexyl, and benzylamines, showed different behavior. Upon
treatment of 9 and 11 with those alkyl amines, surprisingly pyrrolo- and indolo-
pyrazinones 14[13] and 15 were formed in very low yields as shown in Scheme 3.
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Scheme 3. Formation of pyrrolo- and indolo-pyrazinones 14 and 15.
We propose the following cascade mechanism. The mechanism is initiated with
base-catalyzed propargyl-allene isomerization to form N-allene carbaldehyde 16. Then
the nitrogen atom of the amine attacks the carbonyl carbon of 16 to generate a
hemiaminal 17. The order of these two reactions may be changed. Since the
nucleophilicity of the nitrogen atom is increased due to the presence of an alkyl group,
the nitrogen atom attacks the central carbon atom of the allene unit, forming the
cyclization product 19 via 18. The final step includes autoxidation of 19 to form the
product 14 (Scheme 4).
Scheme 4. Proposed mechanism for the formation of 14 (and 15)
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As a consequence of the formation of pyrrolo- and indolo-pyrazinones 14 and 15
instead of substituted pyrazine derivatives (Scheme 2), our attention was next directed
toward another class of amines bearing allyl and alkyne groups. With this in mind,
allylamine and propargylamine were reacted with 9 and 11 in methanol.[24]
Interestingly, the same cyclization products, 12 and 13, obtained from the reaction of
9 and 11 with ammonia, were formed in yields of 72% and 65% with allylamine and
81% and 51% with propargylamine, respectively (Scheme 5). The exciting feature of
these reactions was that the allyl and propargyl units were removed from the nitrogen
atom during the reaction.[25]
Scheme 5. Cyclization reactions of 9 and 11 with allylamine and propargylamine.
In order to determine the fate of allyl or propargyl groups and understand the
reaction mechanism, the side products were examined. For this purpose, a sample
from the reaction medium, from the reaction of 9 with allylamine, was analyzed by GC-
Mass spectroscopy. The results showed that diallyl amine (21) was formed as the side
product. On the basis of this finding, we proposed the reaction mechanism shown in
Scheme 6. At the beginning, the initially formed imine nitrogen atom attacks the central
carbon atom of the allene unit to form the ammonium salt 20. The active methylene
group in 20 easily undergoes a substitution reaction by the attack of allylamine to form
the neutral compounds 12 and 21.[26]
Scheme 6. Mechanism for the formation of 21
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To further test the scope of this alkyne cyclization process via imine intermediates,
compound 9 was treated with sterically bulky t-butylamine and adamantylamine under
the same reaction conditions. Unexpectedly, N-(t-butyl)indolizin-6-amine (22a) and N-
(adamantan-1-yl)indolizin-6-amine (22b) were formed in 63% and 67% yields,
respectively (Scheme 7). The structure of 22a was determined by 1D and 2D (DEPT,
HSQC, and HMBC) NMR spectral data.
Scheme 7. Reaction of 9 with t-butylamine and adamantylamine.
Based on these structures, we propose the following cyclization mechanism (Scheme
8). The reaction starts with the isomerization of the alkyne unit into the corresponding
allene 16. Since the central carbon atom in the allene moiety is the most electropositive
carbon, a logical mechanism for this process would involve a nucleophilic attack of
sterically bulky t-butylamine and adamantylamine on the central carbon atom of the
allene unit instead of the aldehyde carbon atom to initially form a carbanion. The
formed carbanion then attacks the carbonyl group to complete the cyclization process.
Scheme 8. Mechanism for the formation of 22a (and 22b).
After obtaining a variety of different products upon cyclization of 9 and 11 with
different amines such as primary amines, sterically bulky amines, allylamine, and
propargylamine, we decided to introduce a benzene ring into the alkyne moiety to see
the effect of the substituent on the mode of the reaction. The 3-(phenylpropyn1yl)-1H-
pyrrole-2-carbaldehyde (23) and the 1-(3-phenylpropynlyl)-1H-indole-2-carbaldehyde
(25) were synthesized by a palladium-catalyzed Sonogashira coupling[27] reaction
(Scheme 9). After successful synthesis of coupling products 23[28,17e] and 25[21,17e] they
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were reacted with propargylamine at the reflux temperature of methanol. The
cyclization products 24[29] and 26[21] were obtained in 65% and 38% yields, respectively
(Scheme 9).
Scheme 9. Synthesis of 23 and 25 and their reaction with propargylamine to give 24 and 26.
Amine-selective cyclization of N-propargyl-pyrrole- and indole-2-carbaldehyde 9
and 11 underwent three different pathways, resulting in the formation of three different
types of cyclic products namely pyrrolo- and indolopyrazine, pyrrolo- and
indolopyrazinones, and amino indolizines. These outcomes inspired us to carry out
quantum chemical calculations in an effort to uncover the reaction pathways and to
understand the factors controlling the cyclization reactions.
Theoretical Calculations
All of the calculations were carried out with the software package Gaussian 09[30]
Geometry optimizations of reactants, intermediates, transition states (TS), and
products were performed using the B3LYP[31] (Becke-3-parameter-Lee-Yang-Parr)
hybrid functional in conjunction with the 6-31+G(d,p) basis set in gas phase. In order
to classify the nature of every stationary point, harmonic vibrational frequencies were
calculated using analytical second derivatives at 25 °C and 1 atm. Intrinsic reaction
coordinates[32] (IRC) were traced in order to confirm that each transition state connects
the corresponding reactant and the product. The effect of solvation was taken into
account both implicitly and explicitly, employing the conductor-like polarizable
continuum model[33] (CPCM) with single-point energy calculations at the optimized
geometries of CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level with methanol
solvent since it was used in the experimental study. Gibbs free energy corrections
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calculated for the gas phase stationary points were added to single point CPCM
energies in order to compute Gibbs free energy values in the solution phase. The
optimized geometry structures are illustrated by Chemcraft.[34]
Formation of 3-methyl-pyrrolo[1,2-a]pyrazine (12) by the reaction of 9 with allylamine
and indolizine derivative 22b was investigated by means of theoretical calculations in
order to provide insight into the reaction mechanism.
Formation of 12. We suggest two different reaction paths for the formation of pyrrolo-
pyrazine derivative 12 (Scheme 10). The first three steps for the formation of 29 are
common to all pathways proposed.
Scheme 10. Possible pathways for the formation of 12. Path 2 is the preferred path as revealed
by DFT calculations.
Initial Common Steps. Our previous computational work demonstrated that
propargyl-allene isomerization is feasible in the presence of a base.[17a] Therefore, this
step was not modeled in the present study. The geometries of the structures for the
remaining steps from 16 to 12 were optimized and the overall reaction energy profile
is given in Figure 2.
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Figure 2. Potential energy profile and relative Gibbs free energies (kcal/mol) in methanol
related to the formation of pyrrolo-pyrazine derivative 12 at CPCM/B3LYP/6-
31+G(d,p)//B3LYP/6-31+G(d,p) level. Black, common steps; red, path 1; green, path 2.
Imine Formation: Cyclization occurs via the imine intermediate based on NMR
analysis of the crude product. Cyclization product 12 could not be observed in dry THF,
DMF or acetonitrile.[24] For this purpose, imine formation from N-propargyl pyrrole and
allyl amine was modeled with and without the explicit solvent molecule. The imine
formation mechanism includes two steps. The first step is the nucleophilic attack of
allylamine nitrogen on the carbonyl carbon atom of 16, resulting in the formation of
hemiaminal 27. The second step is the elimination of water to give imine 28 (Scheme
10). According to our calculations, the first step proceeded with a 26.4 kcal/mol Gibbs
free activation energy barrier with respect to RC (16+Allylamine+MeOH) with the
assistance of methanol. Without explicit methanol, the barrier was calculated to be 38.8
kcal/mol. The lowering of the barrier by methanol can be attributed to two factors: (1)
formation of the more stable six-membered ring transition state instead of the less
stable four-membered ring transition state, (2) activation of the carbonyl group by
hydrogen bonding with methanol. The optimized geometries are shown in Figure 3.[35]
R
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RC (16+Allylamine+MeOH)
TS1
PC (27+MeOH)
Figure 3. Optimized geometries for the stationary points for the formation of hemiaminal 27 at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms.
The second step gave rise to imine (or aldimine) formation through a 28.1
kcal/mol free energy barrier with respect to the RC (16+Allylamine+MeOH). However,
the intrinsic free energy barrier for the formation of imine from heminal complex was
low (17.4 kcal/mol with respect to the RC (27+MeOH)) with the explicit effect of
methanol. The non-catalyzed barrier (with respect to the initial complex RC
(16+Allylamine+MeOH)) was calculated to be 31.6 kcal/mol, indicating that methanol
has a stabilizing effect on the transition state. Therefore, the dehydration reaction also
takes place through the assistance of the methanol molecule via the hydrogen-bond
network. The optimized geometries are shown in Figure 4. The activation barrier for
the alcohol-assisted dehydration step is approximately 15 kcal/mol less than that for
the direct dehydration step.
RC (27+MeOH)
TS2
PC (28+MeOH+H2O)
Figure 4. Optimized geometries for the stationary points for the formation of imine 28 at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms.
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Intramolecular Cyclization. The cyclization reaction occurs via the nucleophilic attack
of the imine nitrogen atom on the central carbon atom of the allene moiety, since it is
more electropositive as shown in our previous study.[17a] The calculated energy barrier
for this step in methanol via transition state TS3 is 14.9 kcal/mol (Figure 2). The
optimized geometries are shown in Figure 5.
28
TS3
29
Figure 5. Optimized geometries of the stationary points for the formation of 29 at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms; angles are in degrees.
The remaining steps of the mechanism (path 1 and path 2) were modeled via allyl
amine since diallylamine was observed as a side product in GC. Path 1 proceeds via
transition state, TS4 which involves a concerted SN2' type allylic substitution reaction.
Nucleophilic attack by allyl amine on olefinic carbon C7 and proton abstraction of
carbanion C3 from allylamine occur at the same time. The concerted reaction pathway
exhibits an activation barrier of 36.2 kcal/mol relative to the initial reactant complex.
The optimized geometries for path 1 are shown in Figure 6.
RC (29+Allylamine)
TS4
PC (12+21)
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Figure 6. Optimized geometries of the stationary points of the Path 2 at CPCM/B3LYP/6-
31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in angstroms.
On the other hand, path 2 follows two steps. The first step is proton transfer from
C5 to the C3-carbon atom of 29, since C5 protons are acidic due to the electron-
withdrawing effect of the iminium group as well as the mesomeric stabilization of the
initially formed allylic anion. The proposed transition state for the formation of 30 is
shown in Scheme 10. The optimized geometries are shown in Figure 7.
RC (29+Allylamine)
TS5
PC (30+Allylamine)
Figure 7. Optimized geometries of the stationary points of the formation of 30 at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms.
In the final step, proton abstraction from allylamine to C5 and the SN2 reaction of
allylamine with 30 occurs in a concerted way as shown in Scheme 10. The optimized
geometries are shown in Figure 8. It is likely that methanol can also catalyze this step,
giving rise to allyl methyl ether; however, no trace of allyl methyl ether could be
detected by GC-analysis.
RC (30+Allylamine)
TS6
PC (12+21)
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Figure 8. Optimized geometries of the stationary points of the formation of 3-methyl-
pyrrolo[1,2-a]pyrazine (11a) at CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in
methanol. Distances are given in angstroms.
According to our results, path 1, which involves a relatively high-energy transition
state TS4, is less plausible when compared to path 2. Therefore, we suggest that the
final product is formed by an SN2 type reaction between 30 and allylamine.
Formation of 22b. Formation of 22b reveals that a different cyclization mechanism
occurs with bulky amines. In order to clarify the mechanism, two competing pathways
were modeled: nucleophilic attack at the central carbon atom of allene moiety (TS7)
and at the aldehyde carbon atom (TS8 or TS8-MeOH) (Scheme 11).
Scheme 11. Possible transition states for the reaction of 16 with 31.
According to the gas phase optimizations, TS8 (Scheme 11) was found 12.6
kcal/mol higher in energy than TS7. In TS7, the bulky adamantyl group approaches 16
from the sterically less crowded side (Scheme 12); thus, there is no steric repulsion
between 16 and the adamantyl group.
The other reason for this preference is that TS8 forms a four-membered ring.
Moreover, methanol-assisted transition state TS8-MeOH, which also forms a relatively
more stable six-membered ring, was also modeled. TS8-MeOH was 10 kcal/mol more
stable than TS8 but still less stable (1.6 kcal/mol) than TS7. TS8 and TS8-MeOH suffer
from steric repulsions between the adamantyl group and the pyrrole ring. Combining
the computational results with the experimental observations, we propose that
adamantylamine preferentially attacks the sterically less hindered central carbon atom
in the allene moiety, which affords indolizine derivative 22b. After the formation of 34,
two alternative paths were proposed for the formation of 22b as shown in Scheme 12.
The first and final steps are common to both pathways.
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Scheme 12. Proposed mechanisms for the formation of 22b.
In the first step of the reaction, nucleophilic attack by amine nitrogen at the central
carbon atom C2 of the allene unit in 16 takes place. The C2-N bond distance (1.81 Å)
in TS7 is only slightly longer than the C2-N bond distance (1.52 Å) in the product,
indicating a product-like transition state. The C1-C2-C3 angle changes from 177.9° in
RC (16+31) to 139.0° and 132.5° in TS7 and 32, respectively. The optimized structures
are depicted in Figure 9. The potential energy profile (Figure 10) shows that the
activation barrier is 32.5 kcal/mol and the reaction is considerably endergonic by 27.8
kcal/mol in methanol.
RC(16+31)
TS7
32
Figure 9. Optimized geometries of the stationary points of the first step for the formation of 32
at CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms, angles are given in degrees.
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Figure 10. Potential energy profile and relative Gibbs free energies (kcal/mol) in methanol
related to formation of indolizine derivative 22b at CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-
31+G(d,p) level. Black, common steps; red, path 1; green, path 2.
Path 1 involves a concerted reaction to form six-membered heterocyclic
intermediate 33 through transition state TS9 with an activation energy of 15.4 kcal/mol
with respect to 32. Nucleophilic attack by carbanion C3 on the carbonyl carbon and
proton transfer from nitrogen to the carbonyl oxygen atom occurs at the same time.
The optimized geometries are shown in Figure 11.
32
TS9
33
Figure 11. Optimized geometries of the stationary points of the second step for the formation
of 34 at CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are
given in angstroms, angles are given in degrees
Path 2: In this stepwise path (Scheme 12), the intermediate 33 is formed after
passing through two barriers, namely proton transfer and intramolecular cyclization.
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Proton transfer from the nitrogen atom to the carbonyl oxygen occurs with the
assistance of methanol which gives rise to 34a. As shown in Figure 9, the calculated
activation barrier is 8.7 kcal/mol with respect to 32. The optimized structures are
depicted in Figure 12.
RC (32+MeOH)
TS11
PC (34a+MeOH)
Figure 12. Optimized geometries of the stationary points for the formation of 34a at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms.
Then, 34a undergoes a C-C bond rotation, changing the orientation of O4 and H8
(to form 34b. This step was not modeled because we assume that the conformational
change from 34a to 34b is not restricted and occurs spontaneously. Therefore, we
directly modeled the nucleophilic attack by C3 on activated carbonyl carbon atom
through TS12. This process requires a small intrinsic activation barrier of only 2.3
kcal/mol. The optimized geometries for the formation of 33 are illustrated in Figure 13.
34b
TS12
33
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Figure 13. Optimized geometries of the stationary points for the formation of 33 at
CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol. Distances are given in
angstroms.
Elimination of Water. The third step which is common to path 1 and path 2,
involves the elimination of water from RC (33+MeOH). This step proceeds through
transition state TS10 and has a free energy of activation of 31.6 kcal/mol with respect
to RC(33+MeOH). It is also more feasible with the assistance of methanol and is
strongly exergonic with an energy of 27.0 kcal/mol. The optimized geometries are
shown in Figure 14.
RC(33+MeOH)
TS10
PC(22b+MeOH+H2O)
Figure 14. Optimized geometries of the stationary points for the formation of indolizine
derivative 22b at CPCM/B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level in methanol.
Distances are given in angstroms.
It can be seen from Figure 9 that path 2 exhibits much smaller activation energies
than path 1 does. Therefore, we propose that the formation of indolizine derivative 22b
proceeds in stepwise manner.
Conclusions
Reactions of N-propargyl carbaldehydes 9 and 11 with different types of amines were
investigated. It is noteworthy that the nature of products is determined by the type of
amine used. The reaction with alkyl amines such as methyl, ethyl, hexyl, and benzyl
amines formed corresponding pyrazinone derivatives in low yields. On the other hand,
the reaction of 9 and 11 with allylamine and propargylamine gave pyrazine derivatives
in which the allyl and propargyl groups were removed from the molecule. The reaction
of 9 with adamantyl or tert-butyl amine led to the formation of indolizine derivatives in
good yields. To elucidate the main factors contributing to this difference in reactivity,
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10.1002/ejoc.201900084
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the reaction mechanisms were studied by means of computational methods. The
results reveal that bulky amines tend to attack the central carbon of allene formed by
the isomerization of N-propargyl functionality, while the attack on carbonyl carbon by
aliphatic amines is more profound.
Experimental Section
General consideration. All reagents were used as purchased from commercial
suppliers without further purification. Proton nuclear magnetic resonance spectra (1H-
NMR) were recorded on an instrument 400 MHz and chemical shifts are reported in
parts per million (ppm) downfield from TMS, using CDCl3 as internal standard. Proton-
decoupled carbon nuclear magnetic resonance spectra (13C-NMR) spectra were
recorded on an instrument 100 MHz. Column chromatography was performed on silica
gel (60-mesh). TLC was carried out on 0.2 mm silica gel 60 F254 analytical aluminum
plates. High resolution mass spectra were recorded by LC-MS TOF electrospray
ionization technique. Infrared (IR) spectra were recorded in the range of 4000-600 cm-
1
via ATR diamond. Melting points (uncorrected) were measured using melting point
apparatus.
20
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1-(Prop-2-ynyl)-1H-pyrrole-2-carbaldehyde (9).[17a,18] To a stirred mixture of 1H-
pyrrole-2-carbaldehyde (8) (9.3 g, 0.098 mol) in DMF (50 mL) was added NaH (3.95 g,
0.165 mol) at 0 °C portionwise. The reaction mixture was stirred at 0 °C for 20 minutes
and propargyl bromide (15 g, 0.126 mol) in DMF (20 mL) was added to the reaction
flask dropwise over a period of 30 min. After stirring for 16 h at room temperature,
solvent was removed. The resulting mixture was diluted with water (100 mL) and
extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with
brine (4 × 50 mL) and dried over MgSO4 and filtered. The solvent was evaporated and
the crude product was purified over silica gel eluting with hexane/EtOAc (5/1) to give
1
9 as a light yellow liquid. (9.13 g, isolated yield 70%). H NMR (400 MHz, CDCl3) δ
9.55 (bd, J = 0.8 Hz, 1H, CHO), 7.26 (bs, 1H, H-5), 6.96 (dd, J3,4 = 4.0 Hz, J3,5 =1.7
Hz, 1H, H-3), 6.28 (dd, J4,3 = 4.0 Hz, J4,5 = 2.7 Hz, 1H, H-4), 5.21 (d, J = 2.6 Hz, 2H,
CH2), 2.47 (t, J= 2.6 Hz, 1H, C≡CH); 13C NMR (100 MHz, CDCl3) δ 179.6, 131.1, 130.4,
125.0, 110.1, 77.5, 74.4, 38.1.
1-(Prop-2-yn-1-yl)-1H-indole-2-carbaldehyde (11). To a stirred solution of 1H-
indole-2-carbaldehyde (10) (2.64 g, 18.2 mmol) in dry DMF (20 mL), solid NaH was
added (0.48 g, 20 mmol) piecewise. After a while, at the end of releasing of H2 gas,
propargyl bromide (80 wt. % in toluene) (2.4 mL, 21.8 mmol) was diluted with 1:3 ratio
of dry DMF and added to the stirring solution over 30 min. After the completion of the
reaction (6 h), water (100 mL) was added and the mixture was extracted with EtOAc
(3 × 30 mL). The collected organic phases were washed with brine, water, and dried
over MgSO4. Removal of the solvent gave 1-prop-2-ynyl-1H-indole-2-carbaldehyde
(11) (2.56 g, 97%) as a pale yellow solid from EtOAc, mp = 101-103 °C; 1H NMR (400
MHz, CDCl3) δ 9.81 (s, 1H, CHO), 7.68 (dt, J4,5 = 8.0, and J4,6 = J4,3 = 0.9 Hz, 1H, H-
4), 7.47 (dd, J7,6 = 8.4 and J7,5 = 1.0 Hz, 1H, H-7), 7.40 (ddd, J6,7 = 8.4, J6,5 = 7.0 and
J6,4 = 0.9 Hz, 1H, H-6), 7.22 (d, J3,4 = 0.9 Hz, 1H, H-3), 7.15 (ddd, J5,4 = 8.0, J5,6 = 7.0
4
4
and J5,7 = 1.0 Hz, 1H, H-5), 5.39 (d, J9,11 = 2.5 Hz, 2H, H-9), 2.20 (t, J11,9 = 2.5 Hz,
1H, H-11); 13C NMR (100 MHz, CDCl3) δ 182.6, 140.1, 134.5, 127.4, 126.6, 123.5,
121.5, 118.7, 110.8, 78.2, 72.5, 33.9; IR (ATR, cmˉ1) 3238, 2923, 2851, 2120, 1661,
1478, 1461, 1162, 1123, 1110, 757, 728; HRMS calcd for C12H9NO [M+H]+: 184,0777.
Found: 184,07569.
Reaction of 1-(Prop-2-ynyl)-1H-pyrrole-2-carbaldehyde (9) with Ammonia.
Synthesis of 3-methylpyrrolo[1,2-a]pyrazine (12). To a solution of 1-(prop-2-ynyl)-1H-
pyrrole-2-carbaldehyde (9) (0.133 g, 1.0 mmol) in ethanol (10 mL) was added ammonia
21
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10.1002/ejoc.201900084
European Journal of Organic Chemistry
solution (32%) (0.255 g, 15.0 mmol) and Cs2CO3 (0.326 g, 1.0 mmol). The mixture was
stirred at reflux temperature of ethanol for 24 h. After completion of the reaction, solvent
was removed. The mixture was diluted with water (15 mL) and extracted with EtOAc
(3 × 15 mL). The collected organic layers were combined and washed with brine (15
mL), dried over MgSO4. The solvent was removed by vacuum to give the product 12[22]
as a brown solid (0.107 g, crude yield: 81%), mp = 79-81 C, Lit mp = 76-81 C[36] and
82.3-82.6 C. [9]
Reaction of 1-(prop-2-yn-1-yl)-1H-indole-2-carbaldehyde (11) with Ammonia:
Synthesis of 3-methylpyrazino[1,2-a]indole (13). To a solution of of 1-(prop-2-yn-1-yl)-
1H-indole-2-carbaldehyde (11) (520 mg, 2.84 mmol) in MeOH (30 mL), K2CO3 (430
mg, 3.12 mmol) was added. After addition of 5 mL of NH3 (24%), the mixture was
heated at reflux temperature for 12 h. After completion of the reaction monitoring by
TLC, the solvent was removed under reduced pressure. The residue was extracted
with EtOAc (3 × 30 mL). After combination of the organic phases, the solution was
dried over MgSO4, and the solvent was removed under the reduced pressure. The
crude product was then purified by column chromatography on silica gel eluting with
hexane:EtOAc (3:1) to give 3-methylpyrazino[1,2-a]indole (13). Pale yellow solid, 395
mg, 76% from ethyl acetate/n-hexane, mp = 163-165 °C (Lit mp = 173 °C).[21] 1H NMR
(400 MHz, CDCl3) δ 8.99 (d, J1,10 = 1.2 Hz, 1H, H-1), 7.98 (bs, 1H, H-4), 7.94 – 7.85
(m, 2H), 7.46 – 7.34 (m, 2H), 6.96 (bs, 1H, H-10), 2.51 (d, J1a,4 = 1.0 Hz 3H, CH3); 13C
NMR (100 MHz, CDCl3) δ 146.4, 132.3, 129.3, 129.0, 128.4, 123.5, 122.3, 122.1,
113.4, 110.8, 94.8, 20.7.
Synthesis of 2,3-Dimethylpyrrolo[1,2-a]pyrazin-1(2H)-one (14a). To a solution of
1-(prop-2-ynyl)-1H-pyrrole-2-carbaldehyde (9) (0.133 g, 1.0 mmol) in methanol (10 mL)
was added excess methylamine (0.9 mL, 40%) and Cs2CO3 (0.326 g, 1.0 mmol). The
mixture was stirred at reflux temperature of methanol for 24 h, and then solvent was
removed. The mixture was diluted with water (15 mL) and extracted with EtOAc (3 ×
15 mL). The collected organic layers were washed with brine (15 mL). Solvent was
dried over MgSO4 and removed by vacuum. The resulting mixture was purified over
silica gel eluting with hexane/EtOAc (3/1) to give 14a as a light brown solid (0.017 g;
isolated yield: 10%), mp = 172-175 °C, (Lit. mp =169-171 °C[13] and 181-183 °C[5b]).
1H NMR (400 MHz, CDCl3) δ 7.04 (bd, J8,7 = 3.9 Hz, 1H, H-8), 6.99 (dd, J6,7 = 2.4 Hz,
J6,8 = 1.5 Hz, 1H, H-6), 6.82 (bs, 1H, H-4), 6.50 (dd, J7,8 = 3.9 Hz, J7,6 = 2.4 Hz, 1H, H-
22
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7), 3.45 (s, 3H, CH3), 2.22 (bd, J1b,4 = 1.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
157.1, 124.7, 123.1, 117.2, 112.1, 109.7, 105.9, 29.2, 17.4.
Synthesis of 2-Ethyl-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (14b). To a solution of 1-
(prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde (9) (0.133 g, 1.0 mmol) in methanol (10
mL) was added excess aqueous ethylamine (1 mL, 70%) and Cs2CO3 (0.326 g, 1.0
mmol). The mixture was stirred at reflux temperature of methanol for 24 h, solvent was
removed. The mixture was diluted with water (15 mL) and extracted with EtOAc (3 ×
15 mL). The collected organic layers were washed with brine (15 mL). Solvent was
dried over MgSO4 and removed by vacuum. The resulting mixture was purified over
silica gel eluting with hexane/EtOAc (3/1) to give 14b as a brown solid. (0.014 g;
isolated yield: 8%), mp = 83-85 °C, (Lit. mp = 86-88 °C[13]. 1H NMR (400 MHz, CDCl3)
δ 7.04 (bd, J8,7 = 4.0, 1H, H-8), 6.99 (dd, J6,7 = 2.5 and J6,8 = 1.5 Hz, 1H, H-6), 6.80
(bs, 1H, H-4, -CH), 6.51 (dd, J7,8 = 4.0, J7,6 = 2.5 Hz, 1H, H-7), 4.02 (q, J = 7.1 Hz, 2H,
CH2), 2.25 (bd, J1b,4 = 1.1 Hz, H-1b, CH3), 1.28 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 156.6, 124.2, 123.4, 117.1, 112.0, 109.5, 106.1, 37.5, 16.9, 14.5.
Synthesis of 2-benzyl-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (14c).
Same
procedure of 14b was followed. The resulting mixture was purified over silica gel eluting
with hexane/EtOAc (5/1) to give 14c as a yellow viscous liquid. (0.054 g; isolated yield:
23%). 1H-NMR (400 MHz, CDCl3) δ 7.31-7.21 (m, 3H, Ph), 7.20-7.18 (m, 2H, Ph), 7.13-
7.11 (m, 1H, pyrrole), 7.28 (dd, J = 1.5 and 2.5 Hz, 1H, pyrrole), 6.81 (bs, 1H, C=CH),
5.25 (s, 2H, CH2), 2.11 (d, J = 1.1 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3) δ 157.1,
137.6, 128.7, 127.2, 126.5, 124.8, 123.1, 117.6, 112.2, 110.4, 106.3, 45.4, 17.1; FT-
IR (ATR) 3092, 2980, 2895, 1651, 1610, 1595, 1433
Synthesis of 2-methyl-3-methylpyrazino[1,2-a]indol-1(2H)-one (15a). To a stirred
solution of 1-prop-2-ynyl-1H-indole-2-carbaldehyde (11) (0.360 g, 1.97 mmol) in EtOH
(20 mL), solid Cs2CO3 was added (0.64 g, 1.97 mmol) piecewise. Methylamine (40%
in H2O, 0.85 mL, 9.85 mmol) was diluted with EtOH and added to the stirring solution
dropwise. The reaction mixture was stirred overnight. After completion of the reaction
monitoring by TLC, solvent was removed and water (50 mL) was added. The resulting
mixture was extracted with ethyl acetate (3 × 30 mL). The organic extracts were
combined and dried over MgSO4, then filtered. After evaporation of the solvent, the
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product was chromatographed on a silica gel column eluting with hexane/EtOAc (4:1)
to give 2,3-dimethylpyrazino[1,2-a]indol-1(2H)-one (15a) (42 mg, 10%) as a dark
yellow solid, mp = 198-201 C (Lit. mp = 206-207.5 C[22]). 1H NMR (400 MHz, CDCl3)
δ 7.80 (dt, J9,8 = 8.0, J9,7 = J9,10 = 1.0 Hz, 1H, H-9), 7.59 (dd, J6,7 = 8.4, J6,8 = 1.0 Hz, 1H,
H-6), 7.36 (ddd, J7,6 = 8.4, J7,8 = 7.0, J7,9 = 1.0 Hz, 1H, H-7), 7.34 (bs, 1H, H-10), 7.28
(ddd, J8,9 = 8.0, J8,7 = 7.0, J8,6 = 1.0 Hz, 1H, H-8), 7.09 (bs, 1H, H-4), 3.47 (s, 3H, NCH3),
2.27 (d, J1a,4 = 0.8, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 158.0, 131.5, 127.5, 126.9,
123.5, 122.6, 122.4, 122.1, 110.4, 103.6, 101.8, 29.5, 17.6.
Synthesis of 2-benzyl-3-methylpyrazino[1,2-a]indol-1(2H)-one (15b). To a stirred
solution of 1-prop-2-ynyl-1H-indole-2-carbaldehyde (11) (0.360 g, 1.97 mmol) in EtOH
(20 mL), solid Cs2CO3 was added (0.64 g, 1.97 mmol) piecewise. Benzylamine (1.08
mL, 9.85 mmol) was diluted with EtOH and added to the stirring solution dropwise. The
reaction mixture was stirred overnight. After completion of the reaction monitoring by
TLC, the solvent was removed and water (50 mL) was added. The resulting mixture
was extracted with ethyl acetate (3 × 30 mL). The organic extracts were combined and
dried over MgSO4, then filtered. After evaporation of the solvent, the product was
chromatographed on a silica gel column eluting with hexane/EtOAc (6:1) to give 15b
1
as a yellow solid (0.142 g, 25%) from ethyl acetate/n-hexane, mp = 182-184 C. H
NMR (400 MHz, CDCl3) δ 7.76 (dt, J9,8 = 8.1, J9,7 = J9,10 = 1.0 Hz, 1H, H-9), 7.57 (dd,
J6,7 = 8.4, J6,8 = 1.0 Hz, 1H, H-6), 7.35 (bs, 1H, H-10), 7.32 (ddd, J7,6 = 8.4, J7,8 = 7.0,
J7,9 = 1.0 Hz, 1H, H-7), 7.27 – 7.12 (m, 6H), 7.08 (bs, 1H, H-4), 5.26 (s, 2H, CH2), 2.14
(d, J1a,4 = 0.8, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 158.2, 137.3, 131.7, 128.8,
127.6, 127.3, 126.8, 126.4, 123.8, 122.7, 122.4, 122.3, 110.4, 104.1, 102.7, 45.7, 17.3.
Synthesis of 2-hexyl-3-methylpyrazino[1,2-a]indol-1(2H)-one (15c). To a stirred
solution of 1-prop-2-ynyl-1H-indole-2-carbaldehyde (11) (0.360 g, 1.97 mmol) in EtOH
(20 mL), solid Cs2CO3 was added (0.64 g, 1.97 mmol) piecewise. Hexylamine (1.3 mL,
9.85 mmol) was diluted with EtOH and added to the stirring solution dropwise. The
reaction mixture was stirred overnight. After completion of the reaction monitoring by
TLC, solvent was removed and water (50 mL) was added. The resulting mixture was
extracted with ethyl acetate (3 × 30 mL). The organic extracts were combined and dried
over MgSO4, then filtered. After evaporation of the solvent, the crude product was
chromatographed on a silica gel column, eluting with hexane/EtOAc (4:1) to give 15c
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(0.117 g, 21%) as a dark green viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (dt, J9,8
= 8.0, J9,7 = J9,10 = 1.0 Hz, 1H, H-9), 7.55 (dd, J6,7 = 8.4, J6,8 = 1.0 Hz, 1H, H-6), 7.29
(ddd, J7,6 = 8.4, J7,8 = 7.0, J7,9 = 1.0 Hz, 1H, H-7), 7.21 (ddd, J8,9 = 8.0, J8,7 = 7.0, J8,6
=
1.0 Hz, 1H, H-8), 7.19 (bs, 1H, H-10), 7.05 (bs, 1H, H-9), 3.94 – 3.88 (quasi t, 2H, CH2),
2.27 (d, J = 0.9 Hz, 3H, CH3), 1.63 (quin, J = 7.6 Hz, CH2), 1.38 – 1.17 (m, 3 CH2),
0.82 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 156.7, 130.5, 126.6, 126.2,
122.4, 121.6, 121.1, 121.0, 109.3, 102.9, 100.8, 42.0, 30.5, 28.3, 25.6, 21.5, 16.2, 13.0;
IR (ATR) 2916, 2850, 1707, 1637, 1457, 1391, 1195, 1179, 802, 740; HRMS calcd for
C18H22N2O [M+H]+: 283.18049. Found: 283.18575.
General procedure for the reaction of 9 and 11 with allylamine and propargylamine. To
a solution of 9 or 11 (1.0 mmol) in methanol (10 mL) was added allylamine (0.058 g,
1.0 mmol) and Cs2CO3 (0.326 g, 1.0 mmol). The mixture was stirred at reflux
temperature of methanol. After stirring for 24 h, the solvent was removed. The mixture
was diluted with water (15 mL) and extracted with EtOAc (3 × 15 mL). The collected
organic layers were washed with brine (15 mL) and dried over MgSO4. Removal of the
solvent by vacuum gave the product. Reaction of 1-(Prop-2-ynyl)-1H-pyrrole-2-
carbaldehyde (9) with Allyl amine. Formation of 3-Methyl-pyrrolo[1,2-a]pyrazine (12).
A solution of 9 (0.133 g, 1.0 mmol), allylamine (0.058 g, 1.0 mmol) and Cs2CO3 (0.326
g, 1.0 mmol) in methanol (15 mL) was reacted as described above. The product 12
was isolated as a brown solid (0.095 g, crude yield: 72%).
Reaction of 1-(Prop-2-ynyl)-1H-pyrrole-2-carbaldehyde (9) with Propargylamine.
Formation of 3-Methyl-pyrrolo[1,2-a]pyrazine (12). A solution of 9 (0.666 g, 5.0 mmol),
propargylamine (0.32 mL, 5.0 mmol) and Cs2CO3 (1.63 g, 5.0 mmol) in methanol (75
mL) was reacted as described above. The product 12 was isolated as a brown solid
(0.095 g, (0.535 g, crude yield: 81%).
Reaction of 1-(Prop-2-yn-1-yl)-1H-indole-2-carbaldehyde (11) with Allylamine.
Formation of of 3-Methylpyrazino[1,2-a]indole (13). A solution of 11 (0.360 g, 1.97
mmol), Cs2CO3 (0.64 g, 1.97 mmol) and allylamine (0.30 mL, 3.94 mmol) in EtOH (20
mL), was reacted as described above. Silica gel column chromatography eluting with
hexane/EtOAc (4:1) gave 13 as yellow solid (0.233 g, 65%).
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Reaction
of
1-(Prop-2-yn-1-yl)-1H-indole-2-carbaldehyde
(11)
with
Propargylamine. Formation of of 3-Methylpyrazino[1,2-a]indole (13). A solution of 11
(0.360 g, 1.97 mmol) Cs2CO3 (0.64 g, 1.97 mmol), and propargyl amine (0.25 mL,
3.94 mmol) in EtOH (20 mL), was reacted as described above. Silica gel column
chromatography eluting with hexane/EtOAc (4:1) gave 13 as yellow solid (0.183 g,
51%).
N-(t-Butyl)indolizine-6-amine (22a). To a solution of 1-(prop-2-yn-1-yl)-1H-pyrrole-
2-carbaldehyde (9) (0.5 g, 3.76 mmol) in 5 mL methanol was added tert-butylamine
(0.275 g, 3.76 mmol) and Cs2CO3 (1.22 g, 3.76 mmol). The reaction mixture was
heated at reflux temperature of methanol for 16 h. After completion of the reaction
water (10 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The
collected organic layers were washed with brine (15 mL) and dried over MgSO4.
Removal of the solvent by vacuum gave the product which was purified column
chromatography eluting with hexan/EtOAc (7:1) to give black viscous liquid (0.45 g ,
63%). 1H-NMR (400 MHz, CDCl3) δ 7.49 (quasi t, J5,5 = J5,3 = 1.4 Hz, 1H, H-5), 7.15-
7.13 (m, 2H, H-3 and H-8), 6.62 (dd, J2,1 = 3.9 Hz and J2,3 = 2.6 Hz, 1H, H-2), 6.32 (dd,
J7,8 = 9.6 Hz ve J7,5 = 1.6 Hz, 1H, H-7), 6.28 (dd, J1,2 = 3.9 Hz and J1,3 = 1.7 Hz, 1H, H-
13
7), 3.95 (bs, 1H, NH), 1.17 (s, 9H, t-Bu); C NMR (100 MHz, CDCl3) 130.6, 130.4,
118.7, 116.6, 116.5, 112.9, 112.4, 98.4, 52.9, 29.8. IR (ATR, cm-1) 3015, 2959, 2926,
2854, 1729, 1659, 1554, 1462, 1366, 1246, 1214, 1032; HRMS m/z (M+H)+: (C12H17N2)
calculated: 189.1386; found: 189.1386.
N-(Adamantan-1-yl)indolizin-6-amine (22b). Same procedure of 22a was followed.
Crude product was purified by column chromatography (hexane:EtOAc (10:1 then
5:1)). Dark brown viscous liquid, yield: (0.210 g, 67%). 1H-NMR (400 MHz, CDCl3) δ
7.50 (bs, 1H, H-5), 7.18-7.16 (m, 2H, H-3, and H-8), 6.65 J2,1 = 3.8 Hz and J2,3 = 2.7
Hz, 1H, H-2), 6.37 (dd, J7,8 = 9.4 Hz ve J7,5 = 1.5 Hz, 1H, H-7), 6.32-6.31 (m, 1H, H-7),
2.05 (bs, 3H, CH), 1.70-1.54 (m, 13H, NH and CH2); 13C-NMR (CDCl3-100 MHz) δ
130.8, 129.4, 119.8, 118.1, 117.8, 112.9, 112.2, 98.4, 52.9, 43.6, 36.4, 29.7; FT-IR
(ATR, cm-1) 3019, 2922, 2910, 2841, 1711, 1666, 1520, 1451, 1360, 1239, 1025;
HRMS (ESI) (M+H): C18H23N2, calculated: 267.1861, found: 267.1840.
Synthesis of 1-(3-Phenylprop-2-ynyl)-1H-pyrrole-2-carbaldehyde (23).[28,17e]
Cuprous iodide (3.8 mg, 0.02 mmol) of palladium acetate (4.5 mg, 0.02 mmol), and
triphenylphosphine (13.1 mg, 0.05 mmol) were placed in a two necked round bottom
flask under nitrogen atmosphere. In another flask, 1-(prop-2-ynyl)-1H-pyrrole-2-
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10.1002/ejoc.201900084
European Journal of Organic Chemistry
carbaldehyde (9) (0.266 g, 2.0 mmol) and iodobenzene (0.24 mL, 2.18 mmol) and
diisopropylamine (1 mL, 7.0 mmol) were dissolved in dry THF (20 mL), and then added
to the mixture prepared above. The mixture was heated and stirred at the reflux
temperature of THF and then filtered through celite. The crude product was purified by
column chromatography eluting with hexane/EtOAc (5/1) to give 14a as a yellowish
liquid (0.246 g, isolated yield: 59%). 1H NMR (400 MHz, CDCl3) δ 9.58 (bs, 1H, CHO),
7.47-7.42 (m, 2H, Ar-H), 7.36 (bs, 1H, Ar-H), 7.34-7.28 (m, 2H, Ar-H), 6.98 (dd, J3,4
=
4.0 Hz, J3,5 = 1.7 Hz, 1H, H-3, -CH), 6.29 (dd, J4,3 = 4.0 Hz, J4,5 = 2.6 Hz, 1H, H-4),
5.43 (bs, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ 179.6, 131.8, 131.2, 130.4, 128.8,
128.4, 125.0, 122.2, 110.1, 86.1, 82.7, 39.0.
Synthesis of 1-(3-phenylprop-2-ynyl)-1H-indole-2-carbaldehyde (25).[21,17e] 1-Prop-
2-ynyl-1H-indole-2-carbaldehyde (11) (0.360 g, 1.97 mmol) was reacted under the
same reaction conditions as described above at the reflux temperature and of THF for
3 h. The product 1-(3-phenylprop-2-ynyl)-1H-indole-2-carbaldehyde (25) was isolated
1
as a yellow solid (0,357 g, 70%) from ethyl acetate/n-hexane, mp = 101-103 C. H
NMR (400 MHz, CDCl3) δ 9.89 (s, 1H, CHO), 7.75 (dt, J4,5 = 8.0, J4,6 = J4,3= 0.9 Hz, 1H,
H-4), 7.62 (dd, J7,6 = 8.4, J7,5 = 0.9 Hz, 1H, H-7), 7.46 (ddd, J6,7 = 8.4, J6,5 = 7.0, J6,4
=
0.9 Hz, 1H, H-6), 7.34 (m, 2H), 7.28 (d, J3,4 = 0.9 Hz, 1H, H-3), 7.26 – 7.19 (m, 4H),
13
5.66 (s, 2H, CH2); C NMR (100 MHz, CDCl3) δ 182.7, 140.3, 134.6, 131.8, 128.4,
128.2, 127.3, 126.7, 123.5, 122.5, 121.5, 118.6, 111.1, 84.2, 83.7, 34.8.
Synthesis of 3-Benzylpyrrolo[1,2-a]pyrazine (24).[29] To a solution of 1-(3-
phenylprop-2-ynyl)-1H-pyrrole-2-carbaldehyde (23) (0.163 g, 0.78 mmol) in methanol
(10 mL) was added propargylamine (0.08 mL, 1.2 mmol) and Cs2CO3 (0.254 g, 0.78
mmol). The reaction mixture was heated at the reflux temperature of methanol for 24
h while stirring. After completion of the reaction, solvent was removed. The resulting
mixture was purified over silica gel eluting with hexane/EtOAc (3/1) to give 24 as a
1
brown solid (crude yield: 0.105 g 65%; isolated yield: 0.052 g, 32%). H NMR (400
MHz, CDCl3) δ 8.68 (s, 1H, H-1), 7.43 (s, 1H, H-4), 7.27 – 7.20 (m, 5H, Ar-H), 7.19 –
7.13 (m, 1H, H-6), 6.74, (dd, J7,8 = 3.8 Hz, J7,6 = 2.5 Hz, 1H, H-7), 6.68 (d, J8,7 = 3.8
13
Hz, 1H, H-8), 3.96 (s, 2H, CH2); C NMR (100 MHz, CDCl3) δ 144.3, 138.8, 138.4,
129.2, 128.7, 126.6, 115.9, 115.1, 103.8, 40.8.
27
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900084
European Journal of Organic Chemistry
Synthesis of 3-benzylpyrazino[1,2-a]indole (26).[21] To a stirred solution of 1-(3-
phenylprop-2-ynyl)-1H-indole-2-carbaldehyde (25) (0.260 g, 1 mmol) in EtOH (20 mL),
propargylamine (110 mg, 2 mmol) Cs2CO3 was added (0.33 g, 1 mmol). The reaction
mixture was heated at the reflux temperature of ethanol for 24 h while stirring. After
completion of the reaction monitoring by TLC, solvent was removed and water (50 mL)
was added. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The
organic extracts were combined and dried over MgSO4, then filtered. After evaporation
of the solvent, the product was chromatographed on silica gel column eluting with
hexane/EtOAc (6:1) to give 26. Orange solid (0.098 g, 38%) from ethyl acetate/hexane,
mp = 86-87 C (Lit. mp = 89 C[21]). 1H NMR (400 MHz, CDCl3) δ 8.93 (bs, 1H, H-1),
7.84 – 7.79 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.35 – 7.27 (m, 5H), 7.22 – 7.15 (m, 2H),
6.90 (s, 1H, H-10), 4.05 (s, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ 146.7, 139.0,
135.6, 129.3, 129.3, 129.1, 128.7, 128.6, 126.6, 123.6, 122.3, 122.3, 114.4, 110.8,
95.3, 40.9.
Acknowledgments
Financial support from the Scientific and Technological Research Council of Turkey
(TUBITAK, grant no. TBAG-112 T360), the Turkish Academy of Sciences (TUBA), and
the Middle East Technical University (METU) is gratefully acknowledged.
Keywords: Pyrrolo[1,2-a]pyrazine • Allenes • Imine • Density functional calculations •
Reaction mechanisms
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