Synthesis of pyrrolo-pyrrolo-pyrazines via the Pd/C-catalyzed cyclization of N-propargyl pyrrolinyl-pyrrole derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.01.004

A novel and efficient synthesis of N-substituted dipyrrolo[1,2-a:2′,1′-c]pyrazine derivatives has been developed. The synthetic strategy relies on the synthesis of 4′,5′-dihydro-1H,3′H-2,2′-bipyrrole, followed by the reaction with propargyl bromide. Various substituents were introduced to the alkyne functionality using the Sonogashira coupling reaction. Aromatization of the dihydropyrrole ring followed by an intramolecular cyclization reaction between the alkyne functionality and the pyrrole nitrogen atom was catalyzed by Pd/C at high temperature to furnish the desired dipyrrolo-pyrazine skeleton.

Full text of DOI:10.1016/j.tetlet.2019.01.004

Tetrahedron Letters 60 (2019) 449–451
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of pyrrolo-pyrrolo-pyrazines via the Pd/C-catalyzed
cyclization of N-propargyl pyrrolinyl-pyrrole derivatives
Furgan Aslanoglu a,b, Sinan Basceken a,c, Metin Balci a,
⇑
a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
b Department of Chemistry, Mus Alparslan University, 49250 Mus, Turkey
c Department of Chemistry, Hitit University, 19030 Corum, Turkey
a r t i c l e i n f o
a b s t r a c t
A novel and efficient synthesis of N-substituted dipyrrolo[1,2-a:20,10-c]pyrazine derivatives has been
developed. The synthetic strategy relies on the synthesis of 40,50-dihydro-1H,30H-2,20-bipyrrole, followed
by the reaction with propargyl bromide. Various substituents were introduced to the alkyne functionality
using the Sonogashira coupling reaction. Aromatization of the dihydropyrrole ring followed by an
intramolecular cyclization reaction between the alkyne functionality and the pyrrole nitrogen atom
was catalyzed by Pd/C at high temperature to furnish the desired dipyrrolo-pyrazine skeleton.
Ó 2019 Elsevier Ltd. All rights reserved.
Article history:
Received 27 November 2018
Revised 21 December 2018
Accepted 3 January 2019
Available online 4 January 2019
Keywords:
Pyrrole
Bipyrrole
Pyrazine
Dipyrrolopyrazine
Alkyne cyclization
Nitrogen containing heterocycles have received considerable
attention because of their important biological and pharmacologi-
cal properties. Pyrrole and its derivatives are an active area of
research in heteroaromatic chemistry, and this fundamental con-
struction unit appears in a large number of pharmaceutical agents
and natural products [1]. Compounds containing a pyrrole ring [2]
display interesting biological and pharmacological properties such
as antitumor [3], antibacterial [4], antioxidative [5], anti-inflam-
matory [6], and antifungal activities [7]. Nitrogen-containing pol-
yaromatic compounds also are of particular interest since the
introduction of heteroatoms into aromatic frameworks drastically
affects their electronic nature without modifying the structure of
the parent hydrocarbons.
For example, the pyrrole-fused heterocyclic compounds, dipyr-
rolo- and diindolo-quinoxalines (2 and 4) exhibit fluorescence with
good quantum yields [8–10]. Furthermore, hexapyrrolohexaaza-
coronene 5 is of potential interest as an electrochromic molecule
and a charge-carrier material in organic electronics [11]. Recently,
we succeeded in synthesizing 3 by a gold-catalyzed and a NaH-
promoted intramolecular cyclization of N-propargyl indole deriva-
tives with a pyrrole unit attached to indole [12]. As a part of our
continued focus on novel pyrrole-fused heterocycles we were
interested in the synthesis of derivatives of dipyrrolo[1,2-a:20,10-
c]pyrazine (1) which is a substructure of several heterocycles such
as 2–5 (Fig. 1).
A number of methods have been developed to synthesize this
structural motif. An early route to skeleton 1 was accomplished
from 2,3-dimethylpyrazine (6); the two pyrrole rings were formed
in two subsequent reactions by condensation of the methyl group
with the carbonyl groups of ethyl pyruvate (Scheme 1) [13]. Com-
pound 10 was synthesized by employing a Cu-assisted double
cycloisomerization from 2,3-dichloroprazine (8) [14]. Alvarez-
Builla and co-workers [15] synthesized the core structure 1 by
the cycloaddition of 11 with methyl propiolate. Moreover, pyr-
rolo[1,2-a]pyrazinium quaternary salt 11 proved to be a suitable
starting compound for the production of dipyrrolo-pyrazine (12)
(Scheme 2) [16,17].
However, a simple and effective approach for the synthesis of
compound 1 remains relatively challenging, and the development
of a general and divergent method is desirable. Herein, we describe
a simple and short synthesis for producing dipyrrolo-pyrazine
skeleton 1.
Our initial intention was the synthesis of 2,2-bipyrrole (16) via
the coupling of two pyrrole moieties and subsequent incorporation
of a single propargyl group, which is the key functional group for
cyclization [18–26]. However, it was difficult to control the reac-
tion at the stage of the monopropargylation reaction. Therefore,
we turned our attention to the precursor 2,20-(10-pyrrolinyl)pyrrole
(15) synthesized via the reaction of pyrrole with 2-pyrrolidine (14)
according to a literature procedure (Scheme 3) [27,28].
⇑
Corresponding author.
E-mail address: mbalci@metu.edu.tr (M. Balci).
https://doi.org/10.1016/j.tetlet.2019.01.004
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

450
F. Aslanoglu et al. / Tetrahedron Letters 60 (2019) 449–451
For the synthesis of the target molecules 18a,b, first the dihy-
dropyrrole units in 17a,b should be aromatized followed by
cyclization. For this reason, propargylated compounds 17a,b were
reacted with Pd/C at 150 °C. Interestingly, the cyclization products
18a,b were formed in 79–70% yield instead of the expected dehy-
drogenation products 19a,b. This result was important because the
two-step reaction was completed in one step (Scheme 3). The NMR
spectra of 18a and 18b showed that the resonances of the acetyle-
nic carbons had disappeared and olefinic proton resonances
appeared. Furthermore, the methylene protons of the pyrrolinyl
group also disappeared and pyrrole protons were observed instead.
Encouraged by these results we decided to extend the scope of
this dehydrogenation and cyclization reaction. To evaluate the
effect of substituents conjugated with the alkyne we introduced
substituted aromatic groups into the terminal carbon of the acety-
lene unit. The most suitable methodology for the derivatization of
compound 17a was the Sonogashira coupling reaction [29]. A cop-
per-co-catalyzed coupling reaction was utilised with Pd as catalyst
and CuI as co-catalyst in THF in the presence of a base. Substituted
iodobenzene derivatives were used as the coupling components.
The starting materials 20a–d were successfully synthesized in
good yields (Scheme 4).
Fig. 1. Selected compounds containing the dipyrrolo-pyrazine unit 1–5.
Comparison of the 1H NMR spectrum of 17a with that of com-
pound 20a clearly showed that the acetylenic proton resonance
[30] at 2.37 ppm disappeared and benzene protons were present
instead. The proton resonances of the pyrrole ring and dihydropy-
rrole ring did not change significantly.
Compounds 20a–d underwent facile cyclization upon treatment
with Pd/C in diglyme at reflux to give the corresponding 6-exo-dig
cyclization products 21a–d in good yields (Scheme 4). Careful
inspection of the crude reaction mixture did not reveal the forma-
tion of the product formed by 7-endo-cyclization. The 1H- and 13C
NMR spectra of compounds 21a were in agreement with the pro-
posed structures.
Scheme 1. Synthesis of 1 and 10 from pyrazine derivatives 6 and 8.
For the formation of cyclization products 18a,b and 21a-d we
propose the following reaction mechanism. These reactions are
generally thought to proceed via a stepwise mechanism involving
electrophilic activation of the alkyne carbon–carbon triple bond
followed by intramolecular nucleophilic attack to form new CAN
and CAPd bonds. Protonolysis of the carbonApalladium bond gives
the desired product and regenerates the catalyst.
The Pd/C catalyst first dehydrogenates the methylene protons of
Scheme 2. Synthesis of 12 from 11.
the pyrrolinyl unit to afford compound 19. Subsequent
p
coordina-
tion of the alkynyl group with Pd produces the alkyne
p-complex
22. Next, the nitrogen atom of the pyrrole attacks the activated
alkyne -complex to produce 6-exo-dig cyclization product 23, fol-
p
lowed by isomerization to form compound 18 (Scheme 5).
To understand this regioselectivity, i.e. the 6-exo-dig cycliza-
tion, geometry optimization, frequency and Mulliken charge calcu-
lations of complexes 22 were performed using the m062x hybrid
levels with the 6–31 + G(d,p) and LANL2DZ (Pd) basis set. All calcu-
lations were performed using the Gaussian 09 program [31]. In the
case of the 22a + Pd complex the distances between the palladium
atom and the terminal carbon (2.13 Å) as well as the internal
alkyne carbon (2.14 Å) atoms are approximately the same
(Fig. 2). However, the internal carbon atom is positively charged,
Scheme 3. Synthesis of dipyrrolo[1,2-a:20,10-c]pyrazine derivatives 17.
After the synthesis of 15 the next step was the incorporation of
propargyl groups. According to the literature procedure [18], 15
was first reacted with NaH in DMF followed by addition of 3-bro-
moprop-1-yne or 1-bromobut-2-yne to give 17a and 17b in 77%
and 63% yield, respectively (Scheme 3).
Scheme 4. Synthesis of dipyrrolo[1,2-a:20,10-c]pyrazine derivatives 21a–d.

F. Aslanoglu et al. / Tetrahedron Letters 60 (2019) 449–451
451
alkyne carbon atoms are positively charged. On the basis of this
charge separation one can understand the exclusive formation of
the 6-exo-dig cyclization product.
In conclusion, we have developed a concise synthetic methodol-
ogy towards the pyrrolo-pyrrolo-pyrazine skeleton via intramolec-
ular cyclization of N-propargyl 2,20-(10-pyrrolinyl) pyrroles in the
presence of Pd/C.
Acknowledgments
Financial support from the Scientific and Technological
Research Council of Turkey (TUBITAK, Grant No. TBAG-112T360),
the Turkish Academy of Sciences (TUBA), and Middle East Techni-
cal University (METU) is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.01.004.
Scheme 5. Proposed reaction mechanism for the Pd/C-catalyzed cyclization.
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Fig. 2. Geometry optimized structures of 22a–c + Pd complexes and Mulliken
charges.
whereas the terminal carbon atom has a negative charge. There-
fore, the pyrrole nitrogen atom attacks exclusively the internal car-
bon atom, forming the 6-exo-dig cyclization product. Substitution
of the alkyne proton with a methyl group (22b) or phenyl group
(22c) does not alter the charge polarization. Again, the internal