Selective synthesis of N-substituted pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives via alkyne cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.10.044

A novel and efficient synthesis of N-substituted pyrrolo-pyrazinone derivatives has been developed. A trichloroacetyl group connected to the pyrrole ring was converted into the desired carboxamide derivatives. Promoted by NaH, the pyrrole carboxamide derivatives underwent a tandem reaction with propargyl bromide to afford pyrrolo-pyrazinones with high efficiency under very mild conditions. The mechanism for the formation of the products is discussed and supported by DFT calculations.

Full text of DOI:10.1016/j.tetlet.2014.10.044

Accepted Manuscript
Selective synthesis of N-substituted pyrrolo[1,2-a]pyrazin-1(2H)-one deriva-
tives via alkyne cyclization
Yasin Çetinkaya, Metin Balci
PII:
S0040-4039(14)01727-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.044
TETL 45273
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 July 2014
17 September 2014
8 October 2014
Please cite this article as: Çetinkaya, Y., Balci, M., Selective synthesis of N-substituted pyrrolo[1,2-
a]pyrazin-1(2H)-one derivatives via alkyne cyclization, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.10.044
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Selective synthesis of N-substituted pyrrolo[1,2-a]
pyrazin-1(2H)-one derivatives via alkyne cyclization
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Yasin Çetinkaya, Metin Balci

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Selective synthesis of N-substituted pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives via
alkyne cyclization
Yasin Çetinkayaa,b, Metin Balcia,*
aDepartment of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
bOltu Vocational School, Department of Food Technology, Atatürk University, 25240 Oltu-Erzurum, Turkey
ARTICLE INFO
ABSTRACT
A novel and efficient synthesis of N-substituted pyrrolo-pyrazinone derivatives has been
developed. A trichloroacetyl group connected to the pyrrole ring was converted into the desired
carboxamide derivatives. Promoted by NaH, the pyrrole carboxamide derivatives underwent a
tandem reaction with propargyl bromide to afford pyrrolo-pyrazinones with high efficiency
under very mild conditions. The mechanism for the formation of the products is discussed and
supported by DFT calculations.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Pyrrole
Pyrazine
2009 Elsevier Ltd. All rights reserved.
Pyrazinone
Pyrrolopyrazinone
Alkyne cyclization
Isoquinolines are found in several bioactive natural products
and they are an important family of alkaloids with key biological
activities in the central nervous system.1 The isoquinolinone
scaffold2 has been used as a basic building block for the synthesis
of various isoquinolinone ring systems.3 Some isoquinolinone
derivatives exhibit important biological effects such as antitumor,
antibiotic and cardiovascular activities.3 For example,
marinamide (1) is a novel isoquinolinone derivative that exhibits
significant antitumor activitiy.4 Ruprechstyril (2), having an
isoquinolinone structure, is a natural product isolated from
Ruprechtia tangarana; a bioassay showed that 2 had anticancer
activity.5 More recently, Threadgill et al. reported the synthesis
of a series of amino-isoquinolinone derivatives 3 substituted at
the amine group, which demonstrated selective inhibition of
PARP-2.6
Annulation of a pyrrole ring next to the carbonyl group of a
pyridin-2(1H)-one ring results in the formation of two
regioisomeric pyrrolo-pyridinones 4 and 5. The isomer 4 and
several derivatives are suitable as inhibitors of purine nucleoside
phosphorylase (PNP).7
The regioisomeric compound 5 has been used as the key
compound in the synthesis of pyrrolo[1,2-a]pyrazine systems,
which were found to have significant activity in the blockade of
apomorphine stereotype and apomorphine-induced climbing.8
Incorporation of the nitrogen atom of pyrrole into pyridin-
2(1H)-one gave compound 6. There is only one reference in the
literature9 for the synthesis of this compound starting from 1H-
pyrrole-2-carbonitrile. The procedure published by Romero et
al.10 was successfully applied to the synthesis of pyrrolo-pyrazine
derivative 7, which is a non-nucleoside inhibitor of HIV-1
reverse transcriptase.
More importantly, the range of the activity did not change
when the benzene ring in 1-3 was replaced by other heterocycles
such as furan, thiophene, and pyrrole rings.
_____________
Corresponding author. Tel.: +90 312 2105140; fax: +90 312 2103200
E-mail address: mbalci@metu.edu.tr

2
Tetrahedron
NH2R1, Et3N
60 oC, 16 h
ClCOCCl3
O
O
O
Et2O, 20 h
rt, 95%
O
N
H
N
H
N
H
R1
HN
CCl3
HN
NH
NH2
N
N
13
15a-e
14
N
N
NH2R2
Br
NH
NH
CH3CN/H2O
24 h, rt
NaH, DMF
rt, 24 h
HN
peramine 8
phakellin 9
O
R2
The alkaloid peramine (8)11 containing a pyrrolo-pyrazinone
Br
O
O
N
N
H
N
NaH, DMF
rt, 20 h
N
skeleton with a guanidino group was isolated from perennial rye
grass and is an insect feeding deterrent.12 On the other hand, the
R2
HN
R1
HN
H
17a,b
18a,b
16a-e
imidazole-condensed
dihydropyrrolo-pyrazine
derivative
R2= a CH3
b C2H5
phakellin (9) belongs to the family of marine sponge derived
alkaloids13 and it has attracted significant interest from both
synthetic and biological perspectives because of its intriguing
structural and potent biological activities.14
O
O
N
R1
R2
N
Because of the structural diversity of compound 6, we herein
describe a methodology for the synthesis of pyrrolo-pyrazinone
derivatives substituted at the N-atom via alkyne cyclization.
In our previous studies, we synthesized triazepinone
derivative 12 by an intramolecular ring cyclization reaction of a
propargyl ester 10 with hydrazine monohydrate.15 The expected
product 12 was formed in 16% yield. Furthermore, triazepinone
derivative 12 was smoothly rearranged into the six-membered
ring isomer 11 in quantitative yield. Calculations showed that the
isomer 11 was 4.28 kcal/mol more stable than the isomer 12
(Scheme 1).
N
N
19a-e
R1= a propargyl
20a,b
R2= a CH3
b C2H5
b allyl
c benzyl
d cyclohexyl
e isopropyl
Scheme 2. Synthesis of pyrrolopyrazinone derivatives 19a-e and
20a,b.
Treatment of 22 with NaH in DMF under the same reaction
conditions resulted in the formation of the ring-closed product
19a. Unfortunately, an allene having the structure 25 (see
Scheme 4 and Table 1) was not found among the products. We
assume that the allene formed as an intermediate is highly
reactive such that it immediately undergoes a cyclization
reaction. The formation of 22 (17% yield) is attributed to the
consumption of NaH in the reaction mixture. Furthermore, the
isolation of this product shows that 22 cannot undergo a
spontaneous cyclization reaction. For cyclization, either the NH
proton must be abstracted or the alkyne must undergo
isomerization into the allene. Furthermore, the reaction of the
amide 23,23 synthesized by the reaction of 14 with NH3, with
propargyl bromide and NaH also gave the cyclization products
19a (52%) and 21 (32%).24
Scheme 1. Reaction of 10 with hydrazine
On the basis of this experience, we decided to investigate the
reaction of 14 possessing a better leaving group, i.e., -CCl3, with
substituted amines and to develop a general methodology for the
synthesis of pyrrolo[1,2-a]pyrazin-1(2H)-ones substituted at the
N-atom. The synthesis of the key compound 14 was
accomplished via a slightly modified route, as previously
reported, in high yield starting from pyrrole.16 The acetylation of
pyrrole (13) with trichloroacetyl chloride gave 2-
(trichloroacetyl)pyrrole (14) in 95% yield.
Next, the reaction of 14 with various primary amines in the
presence of triethylamine gave the corresponding amides 15a-e17-
21
in 76-88% yields (Scheme 2). However, the reaction with
methylamine and ethylamine did not proceed as well as in the
case of the other amines. The reactions with methylamine and
ethylamine were instead carried out in acetonitrile to give the
amides 17a22 and 17b21 in yields of 76% and 91%, respectively.
Treatment of the synthesized pyrrole-2-carboxamides 15 and
17 with NaH in DMF followed by addition of propargyl bromide
did not lead to the expected propargyl substituted
pyrrolecarboxamides 16 and 18. But fortunately, the desired
cyclization products, pyrrolo-pyrazinone derivatives 19 and 20,
were formed by a domino reaction.
We also examined the reaction of 15a with excess propargyl
bromide in the presence of NaH. The reaction was carried out
under the same conditions in DMF at room temperature. Besides
the expected ring-closure product 19a, we isolated two additional
products, 21 and 22; the yields were 43%, 32% and 17%,
respectively (Scheme 3 and Table 1).
Scheme 3. Reaction of 15a with excess propargyl bromide.
A tentative mechanism for the formation of compounds 19
and 20 is outlined in Schemes 4 and 5. It is proposed that the first
step is the formation of allene 25. We assume that the nitrogen
atom of the carboxyamide or an anion cannot attack the triple
bond because of the increased electron density. However, the
terminal alkyne 18a can undergo a base-induced isomerization to
give the terminal allene 25.

3
Formation of pyrrolo-pyrazinone derivative 20a25 was
investigated computationally in an effort to clarify the
mechanism. First we calculated the heat of formation energies of
the alkyne 18a and the corresponding allene 25, and found that
the allene was about 2.8 kcal/mol (in DMF) more stable than the
propargyl isomer 18a. The geometrical parameters of the
reactants, intermediates, transition states (TS) and products were
fully optimized with the hybrid density functional B3LYP26,27
method using the 6-31+G(d,p) basis set implemented in Gaussian
09,28 for all structures.
Figure 2. Potential energy profile for the cyclization of 25 into 20a.
In conclusion we have established a highly selective,
convenient and practical method to access N-substituted pyrrolo-
pyrazinone derivatives in high yields and in three steps starting
from pyrrole by alkyne cyclization in a simple reaction sequence.
We assume that the methods developed herein will find frequent
applications in heterocyclic chemistry and related areas.
Scheme 4. Mechanism for the isomerization of 18a into 25.
Table 1. Reactions of pyrrole-carboxamides with propargyl bromide
Entry
1
Pyrrolo-pyrazinone Yield (%)
Pyrrole-2-
carboxamide
77
O
N
Figure 1. Potential energy profile related to propargyl-allene
isomerization
2
3
84
70
H
NH
15b
We first modeled propargyl-allene isomerization from 18a
into 25 as shown in Scheme 4. We propose a mechanism that
includes the abstraction of a proton with a hydride ion from an
sp3-hybridized carbon atom to form a complex between 24 and
H2O present in DMF. In the second step, the carbanion 24b
abstracts a proton from H2O to generate the corresponding allene
25. The small activation energies in Figure 1 (TS1) strongly
support that cyclization takes place through allene intermediate
25. After the formation of allene 25, the reaction proceeds with
nucleophilic attack of the nitrogen atom in 26 on the central
carbon atom of the allene moiety (Scheme 5). The central carbon
atom of an allene unit resonates at about 195-215 ppm, whereas
terminal sp2-carbon atoms appear at about 90 ppm. This large
chemical shift difference shows the electropositive character of
the central carbon atom in allenes. Therefore, the nucleophilic
nitrogen atom can attack this central carbon atom and form the
products. The activation barrier for this cyclization process was
found to be 6.3 kcal/mol (TS3) (Figure 2). The next step is the
proton transfer to give 27. This step was modeled with the
assistance of H2O, which is present in the reaction medium.
4
5
88
76
6
7
76
82
Acknowledgements
This work was supported by TUBITAK (Scientific and
Technological Research Council of Turkey Grant Nr. TBAG 112
T 360 and TUBA (Turkish Academy of Sciences). We thank
Research Assistant Ozlem Sari for her help with the calculations.
Scheme 5. Mechanism for the cyclization of 25 into 20a.
Supplementary data

4
Tetrahedron
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Supplementary data [experimental conditions, spectroscopic
data (1H and 13C NMR spectra), and tables of atom coordinates
and absolute energies of the calculated compounds associated
with this article can be found, in the online version, at …..
20.
21.
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