Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

Article abstract of DOI:10.3762/bjoc.13.83

Intramolecular nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole esters is described. Efficient routes towards the synthesis of pyrrolopyrazinone, pyrrolotriazinone and pyrrolooxazinone have been developed. First, N-alkyne-substituted pyrrole ester derivatives were synthesized. Introduction of various substituents into the alkyne functionality was accomplished by a copper-catalyzed cross-coupling reaction. Nucleophilic cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with hydrazine afforded the 6-exo-dig/6-endo-dig cyclization products depending on the electronic nature of the substituents attached to the alkyne. On the other hand, cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with iodine only resulted in the formation of the 6-endo-dig cyclization product regardless of the substitution of the alkyne functionality.

Full text of DOI:10.3762/bjoc.13.83

Nucleophilic and electrophilic cyclization of N-alkyne-
substituted pyrrole derivatives: Synthesis of
pyrrolopyrazinone, pyrrolotriazinone, and
pyrrolooxazinone moieties
Işıl Yenice1, Sinan Basceken1,2 and Metin Balci*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 825–834.
1Department of Chemistry, Middle East Technical University, 06800
Ankara, Turkey and 2Department of Chemistry, Hitit University, 19030
Corum, Turkey
doi:10.3762/bjoc.13.83
Received: 23 January 2017
Accepted: 07 April 2017
Published: 04 May 2017
Email:
Metin Balci* - mbalci@metu.edu.tr
Associate Editor: T. J. J. Müller
* Corresponding author
© 2017 Yenice et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkyne cyclization; pyrrole; pyrrolooxazinone; pyrrolopyrazinone;
pyrrolotriazinone
Abstract
Intramolecular nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole esters is described. Efficient routes
towards the synthesis of pyrrolopyrazinone, pyrrolotriazinone and pyrrolooxazinone have been developed. First, N-alkyne-substi-
tuted pyrrole ester derivatives were synthesized. Introduction of various substituents into the alkyne functionality was accom-
plished by a copper-catalyzed cross-coupling reaction. Nucleophilic cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-
carboxylates with hydrazine afforded the 6-exo-dig/6-endo-dig cyclization products depending on the electronic nature of the sub-
stituents attached to the alkyne. On the other hand, cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with
iodine only resulted in the formation of the 6-endo-dig cyclization product regardless of the substitution of the alkyne functionality.
Introduction
Pyrrole has a great range of applications in organic synthesis phevalin (1) and tyrvalin (2), pyrazinone derivatives synthe-
because of its occurrence in many active natural products, syn- sized by a serious human pathogen, Staphylococcus aureus, act
thetic pharmaceuticals, and optoelectronic materials [1,2]. The as protein kinase inhibitors (Figure 1) [7,8].
pyrazinones derived from the pyrazine ring by single oxidation
of one carbon atom also show very important biological activi- Triazinone heterocycles are essential in organic synthesis
ties. Various microbes, reported in the literature, can accom- regarding their herbicide, anticancer, antimicrobial, and
plish the synthesis of pyrazinone derivatives [3-6]. For instance, antimetastatic activities. Metamitron (3) and metribuzin (4),
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Beilstein J. Org. Chem. 2017, 13, 825–834.
Figure 3: N-alkyne substituted pyrrole esters 7a–d.
Results and Discussion
The starting compound 8 was synthesized via a slightly modi-
fied route by acetylation of pyrrole with trichloroacetyl chlo-
ride in 89% yield [19,23]. The reaction of 8 with NaOMe in
Figure 1: Structures of some natural products containing pyrazinone
and aminotriazonone skeletons.
1,2,4-triazinone herbicides having an amino group, are absorbed methanol gave pyrrole ester 9 (Scheme 1) [19,24]. It is essen-
by the roots of plants and inhibit photosynthesis by inhibiting tial to use bromoalkynes for N-alkyne substitution of pyrrole
electron transport (Figure 1). They are used to control grasses ester 9. Substituted alkyne derivatives 10a and 10b were syn-
pre- and post-emergence [9,10].
thesized according to the literature. The Sonogashira coupling
reaction [25] of aryl iodides with terminal acetylene is an effec-
Pyrrole-fused pyrazinone heterocycles and their synthesis are of tive approach towards the synthesis of substituted arylalkynes.
great interest due to their natural presence and potent pharmaco- The reaction of 1-iodo-4-methoxybenzene and 1-iodo-4-
logical and biological activities. A natural product, nannozi- nitrobenzene with trimethylsilylacetylene under the Sono-
none B (5, Figure 2), containing a pyrrolopyrazinone moiety gashira coupling conditions followed by hydrolysis of the tri-
was isolated from a myxobacterium, Nannocystis pusilla [11]. methylsilyl groups with K2CO3 resulted in the formation of 10a
The alkaloid peramine (6, Figure 2), isolated from endophyte- and 10b [26-28]. Fortunately, terminal alkynes can be easily
infected perennial ryegrass, has feeding deterrent activity converted into bromoalkynes with N-bromosuccinimide in the
against insects [12,13].
presence of silver nitrate. The synthesized acetylenes 10a,b and
commercially available acetylenes 10c,d were converted into
bromoalkyne derivatives 11a–d according to the literature pro-
cedure (Scheme 1) [29,30].
After the successful generation of alkynyl bromides 11a–d, the
next step was the synthesis of N-alkyne-substituted pyrrole de-
rivatives 7a–d. A practical method is the coupling reaction of
substituted pyrroles with alkynyl bromides using catalytic
CuSO4·5H2O and 1,10-phenanthroline [31]. When alkynylation
with 11a was carried out at 85 °C, the conversion was only
12%. We assume this is due to the presence of an electron-do-
nating group at the benzene ring. However, when the reaction
Figure 2: Structures of some natural products containing a pyrrolo-
pyrazinone moiety.
An efficient and straightforward synthetic method for the con- was carried out at the reflux temperature of toluene, the conver-
struction of the pyrrolopyrazinone core structure as well as for sion increased to 35%.
its derivatives is not described in the literature [14]. Recently,
we developed new synthetic methodologies for the synthesis of Next, we conducted cyclization reactions of N-alkyne substi-
various pyrrole-fused new heterocycles using alkyne cycliza- tuted carboxylate derivatives 7a–d via hydrazine monohydrate.
tion reactions [15-22]. In this article, we demonstrate for the Methyl 1-(phenylethynyl)-1H-pyrrole-2-carboxylate (7c) was
first time the concept of the cyclization of N-alkyne-substituted treated with hydrazine monohydrate in MeOH under N2 atmo-
pyrrole esters 7 (Figure 3) to provide a practical access to sphere at reflux temperature. Pyrrolopyrazinone 12c and
design pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazi- pyrrolotriazinone 13c skeletons were formed in 67% and 24%
none derivatives.
yields, respectively (Scheme 2).
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Beilstein J. Org. Chem. 2017, 13, 825–834.
Scheme 1: Synthesis of N-alkyne substituted methyl 1H-pyrrole-2-carboxylate derivatives 7a–d.
atoms resonating at 137.2 and 135.2 as well as with the aromat-
ic o-carbon atoms at 128.8 ppm indicating the structure 13c.
Figure 4: Correlations of olefinic proton in 12c and methylene protons
in 13c and 16 with the relevant carbon atoms (from the HMBC spec-
trum).
For further proof of the structure, 12c was submitted to an acet-
ylation reaction with acetic anhydride in pyridine to give the
acetylated compound 14 in 97% yield (Scheme 2). The NH-
proton resonance was now shifted to lower field (9.12 ppm) as
expected. Finally, the structure of 12c was further confirmed by
single-crystal X-ray analysis (Figure 5) [32].
Scheme 2: Nucleophilic cyclization reaction of compounds 7a–d and
acetylation of 12c.
The structures of cyclization products 12c and 13c were deter-
mined using NMR spectra. The exact locations of the olefinic
carbon (=CH) in 12c and methylene group in 13c were deter-
mined from 2D NMR (HSQC and HMBC) spectra. The
1H NMR spectrum of pyrrolopyrazinone derivative 12c shows
the presence of two NH2 protons resonating at 4.41 ppm as a
broad singlet. The double bond proton in 12c resonating at
6.94 ppm as a singlet shows strong correlation in the HMBC
spectrum with the quaternary carbon atoms resonating at 132.3,
130.8, and 123.1 as well as with the tertiary carbon atoms
(=CH) at 118.6 ppm (Figure 4). This information clearly shows
that the double bond (CH=C) is located between the pyrrole
nitrogen atom and the benzene ring (Figure 4). On the other
hand, the methylene protons in 13c resonating at 4.26 ppm as a
singlet shows strong correlation with the quaternary carbon
Figure 5: Single-crystal X-ray structure of 12c shown with 40% proba-
bility displacement ellipsoids.
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Beilstein J. Org. Chem. 2017, 13, 825–834.
The compound 13c could have the structure 16. However, in a We assume that an allenic intermediate 17 (Figure 6) formed
structure like 16 one would expect a correlation between the during the reaction is responsible for exclusive formation of
methylene protons and the pyrrole ring carbon atoms. As we 12d. Since the central carbon atom of an allene unit is more
were not able to observe such correlations in the HMBC spec- electropositive, the carbon atom can undergo an attack by the
trum we eliminated this structure. To assign the correct struc- amide nitrogen atom to form a six-membered ring. In the case
ture to the product 13c, we decided to synthesize 16 using a dif- of 7a–c, the formation of allenic intermediates is out of ques-
ferent approach and to compare the NMR spectra of 13c with tion [15].
those of 16. For this reason, 7c was first reacted with potassium
carbonate in MeOH/H2O solution to give the ketone 15. Treat- Based on our experimental results, we proposed the mechanism
ment of 15 with hydrazine monohydrate in methanol gave the outlined in Scheme 4 for the formation of compounds 12 and
expected product 16 in 57% yield (Scheme 3).
13. The first step is the formation of hydrazide 18. The elec-
tronic properties of the substituents designate the fate of the
The 1H NMR and 13C NMR spectra of these two compounds reaction at this step. The intermediate undergoes either 6-endo-
13c and 16 were completely different from each other. The dig or 6-exo-dig cyclizations to form the corresponding prod-
methylene protons in 16 resonating at 5.28 ppm showed strong ucts by attack of lone pair electrons of the internal nitrogen or
correlations with the imine carbon atom, the ipso-carbon atom terminal nitrogen atoms, respectively. The 6-endo-dig cycliza-
and two α-carbon atoms of the pyrrole ring, clearly indicating tion follows only a proton shift to yield pyrrolopyrazinone
that the methylene group is incorporated into the seven-mem- skeleton 12, while 6-exo-dig follows first a proton shift and then
bered ring. All this information shows that the methylene group an [1,3]-hydride shift to afford pyrrolotriazinone moiety 13.
is located between the pyrrole ring and the imine double bond.
After completion of the nucleophilic cyclization reactions, we
With these encouraging results in hand, we embarked on the desired to activate the triple bond with iodine to synthesize
evaluation of the substrate scope for this useful transformation. pyrrolooxazinone derivatives via an electrophilic intramolecu-
The compounds 7a, 7b, and 7d were submitted to a cyclization lar cyclization reaction. For this purpose, N-alkyne-substituted
reaction under the same reaction conditions applied to com- methyl 1H-pyrrole-2-carboxylate derivatives 7b–d were treated
pound 7c. As shown in Scheme 2, compounds 7a and 7d with iodine in dichloromethane to yield the corresponding
formed 2-aminopyrrolopyrazinone derivatives 12a and 12d, pyrrolooxazinone derivatives 19b–d in yields of 76–79%
whereas 7b furnished pyrrolotriazinone derivative 13b. The (Scheme 5).
electronic nature of the substituents attached to the alkyne de-
termines the mode of the cyclization reaction. Since the elec-
tron-donating methoxy group increases the electron density at
the alkyne unit, cyclization takes place with the less nucleo-
philic nitrogen atom of the hydrazide group. On the other hand,
the nitro group decreases the electron density, making the
alkyne carbon atom next to the pyrrole nitrogen atom elec-
tropositive, and cyclization takes place with the terminal
nitrogen atom forming a six-membered ring. Moreover, the
Figure 6: The structure of allene 17 formed during the reaction of 7d
with a base.
n-butyl-substituted alkyne carbon atom undergoes a reaction to
form 6-endo-dig cyclization product 12d.
Scheme 3: Synthesis of 16.
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Beilstein J. Org. Chem. 2017, 13, 825–834.
Scheme 4: Proposed reaction mechanism of nucleophilic cyclization reaction of 7.
All cyclization reactions of 7b–d with iodine underwent a
6-endo-dig cyclization. No 5-exo-dig cyclization was observed.
To address this issue we performed some DFT calculations.
Geometrical parameters of reactants, transition states (TS), and
products were fully optimized in dichloromethane with the M06
method using the GEN basis set combination 6-31+G(d) and
LANL2DZ in the Gaussian 09 software package [33]. Compu-
tational details are given in Supporting Information File 1.
Scheme 5: Electrophilic cyclization reactions of 19a–c with iodine.
According to the suggested mechanism in Scheme 6, the cycli-
zation process occurs via the electrophilic attack of iodine to
Spectral data of 19b–d were in complete agreement with the alkyne to form the complex 20. Mulliken charges calculated at
proposed structures. The structure of 19c was further confirmed the M06/6-31+G(d)/LANL2DZ (I) level on alkyne carbon
by single-crystal X-ray analysis (Figure 7) [32].
atoms C-2 and C-1 are 0.943 and −1.714, respectively. The dis-
tance between the alkyne carbon atom C-2 and the iodine atom
in 20 is longer (2.80 Å) than that between the alkyne carbon
atom C-1 and the iodine atom, indicating that the positive
charge is more localized on the carbon atom C-2 (Figure 8). In
the next step, the cyclization process occurs via the nucleo-
philic attack of the ester oxygen atom on the most electrophilic
C-2 carbon atom to yield a 6-endo-dig cyclization product while
iodine remains on the structure 21. During the formation of the
C2–O bond, the bond distance was shortened from 2.284 to
1.444 Å. On the other hand, the lengthening of the C2−I interac-
tion from 2.801 to 3.001 Å and of the C1−C2 bond from 1.304
to 1.339 Å in 20 and 21 was observed (Figure 8). The activa-
tion barrier for the formation of 21 is 1.61 kcal/mol in dichloro-
methane and the transition state TS2 is 10.51 kcal/mol lower
Figure 7: Single-crystal X-ray structure of 19c shown with 40% proba-
bility displacement ellipsoids.
The following reaction mechanism was proposed for the forma- than the initial reactant. In the second step, the iodide anion,
tion of 19c (Scheme 6). The reaction starts with the π-activa- which already exists in the reaction media attacks the proto-
tion of the triple bond by iodine to form the intermediate 20, nated methoxy group and removes the methyl group from the
which undergoes an intramolecular addition of the ester oxygen structure to yield the corresponding pyrrolooxazinone skeleton
atom to the alkyne functionality to form the intermediate 21. In 19c. The formation of 19c is quite exergonic with a Gibbs free
the next step, a nucleophilic attack on the methyl group by energy of 52.52 kcal/mol in dichloromethane. Comparison of
iodide forms the product 19c.
the relative energies given in Figure 8, shows that the forma-
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Beilstein J. Org. Chem. 2017, 13, 825–834.
Scheme 6: Proposed reaction mechanism of electrophilic cyclization reaction of 7c.
Figure 8: Potential energy profile related to the formation of pyrrolooxazinone 19c in the polarizable continuum model (PCM) [34,35] with the hybrid
functional M06 [36] using 6-31+G(d)/LANL2DZ level in dichloromethane. Distances are given in angstroms. (Relative energies shown for 20, TS1, and
21).
tion of 19c is plausible under the given reaction conditions in Experimental
dichloromethane.
General procedure for N-alkyne-substituted methyl
1H-pyrrole-2-carboxylate derivatives 7a–d. To a solution of
bromoalkyne derivatives 11 (1.1 equiv) in freshly distilled an-
Conclusion
The synthetic strategy described in this paper shows the impor- hydrous toluene (20 mL), methyl 1H-pyrrole-2-carboxylate (9,
tance of intramolecular alkyne cyclization for the formation of 1.0 equiv), K3PO4 (2 equiv), CuSO4·5H2O (0.1 equiv) and
interesting heterocyclic systems. We have developed an effi- 1,10-phenanthroline monohydrate (0.2 equiv) were added under
cient method for the construction of pyrrolopyrazinone, pyrrolo- N2 atmosphere. The reaction mixture was heated to 85 °C and
triazinone, and pyrrolooxazinone moieties starting from stirred for 48 h. Then, the reaction mixture was cooled to room
N-alkyne substituted pyrrole esters. A mechanism was pro- temperature and diluted with DCM (30 mL). The resulting mix-
posed for the formation of the title compounds. Furthermore, ture was filtered through celite and the filtrate was concentrated
the methods reported here can be used for the introduction in vacuum. Then, the crude product was purified via column
of further substituents at various positions of the target struc- chromatography (SiO2, hexane) to give N-alkyne-substituted
tures.
methyl 1H-pyrrole-2-carboxylate derivatives 7.
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Methyl 1-[(4-methoxyphenyl)ethynyl]-1H-pyrrole-2-carbox- δ 7.61–7.47 (m, 2H, arom.), 7.39–7.29 (m, 3H, arom.),
ylate (7a). To a solution of 1-(bromoethynyl)-4-methoxyben- 7.18–7.10 (m, 1H, arom.), 7.00 (dd, J = 3.9, 1.6 Hz, 1H, H-3),
zene (11a, 0.272 g, 1.290 mmol) in freshly distilled anhydrous 6.28–6.22 (m, 1H, arom.), 3.88 (s, 3H, OCH3); 13C NMR
toluene (20 mL), methyl 1H-pyrrole-2-carboxylate (9, 0.147 g, (100 MHz, CDCl3) δ 160.1, 131.6, 131.4, 128.5, 128.4, 125.8,
1.170 mmol), K3PO4 (0.497 g, 2.340 mmol), CuSO4·5H2O 122.3, 118.6, 110.8, 81.4, 69.7, 51.6; IR (ATR): 2259, 1719,
(0.030 g, 0.120 mmol) and 1,10-phenantroline monohydrate 1458, 1438, 1360, 1264, 1168, 1100, 1069, 751, 733, 689.
(0.045 g, 0.230 mmol) were added and the mixture was reacted HRMS: [M + H]+ calcd for C14H11NO2, 226.08626; found,
as described above. Then, the crude product was purified via 226.08840.
column chromatography (SiO2, hexane/EtOAc, 20:1) to obtain
7a (0.104 g, 35% (99% based on 35% conversion)) as a Methyl 1-(hex-1-yn-1-yl)-1H-pyrrole-2-carboxylate (7d). To
yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 7.52–7.43 (m, a solution of 1-bromohex-1-yne (11d, 1.23 g, 7.65 mmol) in
2H, arom.), 7.12 (dd, J = 2.8, 1.7 Hz, 1H, H-5), 6.98 (dd, J = freshly distilled anhydrous toluene (30 mL), methyl 1H-pyrrole-
3.9, 1.7 Hz, 1H, H-3), 6.90–6.83 (m, 2H, arom.), 6.24 (dd, J = 2-carboxylate (9, 0.87 g, 6.95 mmol), K3PO4 (2.95 g,
3.9, 2.8 Hz, 1H, H-4), 3.86 (s, 3H, OCH3), 3.81 (s, 3H, OCH3); 13.9 mmol), CuSO4·5H2O (0.17 g, 0.69 mmol) and 1,10-
13C NMR (100 MHz, CDCl3) δ 160.2, 159.8, 133.3, 131.4, phenantroline monohydrate (0.27 g, 1.39 mmol) were added
125.7, 118.5, 114.3, 114.1, 110.6, 80.2, 69.5, 55.4, 51.6; and the resulting mixture was reacted as described above to
IR (ATR): 2951, 2257, 1719, 1605, 1543, 1515, 1458, 1438, obtain 7d (0.83 g, 58% (92% isolated yield based on 63%
1416, 1361, 1334, 1265, 1246, 1179, 1168, 1100, 1069, 1027, conversion)) as a colorless liquid. 1H NMR (400 MHz, CDCl3)
948, 830, 735, 598, 583; HRMS: [M + H]+ calcd for δ 7.02 (dd, J = 2.8, 1.7 Hz, 1H, H-5), 6.90 (dd, J = 3.9, 1.7 Hz,
C14H11NO2, 256.09682; found, 256.09730.
1H, H-3), 6.16 (dd, J = 3.9, 2.8 Hz, 1H, H-4), 3.84 (s, 3H,
OCH3), 2.41 (t, J = 7.2 Hz, 2H, CH2), 1.60 (q, J = 7.2 Hz, 2H,
Methyl 1-[(4-nitrophenyl)ethynyl]-1H-pyrrole-2-carboxyl- CH2), 1.48 (h, J = 7.2 Hz, 2H, CH2), 0.94 (t, J = 7.3 Hz, 3H,
ate (7b). To a solution of 1-(bromoethynyl)-4-nitrobenzene CH3); 13C NMR (100 MHz, CDCl3) δ 160.3, 131.8, 125.5,
(11b, 0.658 g, 2.910 mmol) in freshly distilled anhydrous tolu- 118.0, 110.0, 72.6, 69.7, 51.5, 30.9, 22.1, 18.2, 13.7; IR (ATR):
ene (40 mL), methyl 1H-pyrrole-2-carboxylate (9, 0.330 g, 2955, 2872, 2273, 1720, 1542, 1464, 1438, 1416, 1197, 1105,
2.640 mmol), K3PO4 (1.121 g, 5.280 mmol), CuSO4·5H2O 926, 732, 601; HRMS: [M + H]+ calcd for C12H15NO2,
(0.065 g, 0.260 mmol) and 1,10-phenantroline monohydrate 206.11756; found, 206.11960.
(0.105 g, 0.530 mmol) were added and reacted as described
above. Then, the crude product was purified via column chro- Methyl 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carboxylate
matography (SiO2, hexane/EtOAc, 20:1) to give 7b (0.394 g, (15). To a solution of K2CO3 (0.246 g, 1.780 mmol) in water
55% (92% isolated yield based on 59% conversion)) and recrys- (15 mL) was added a solution of methyl 1-(phenylethynyl)-1H-
tallized as yellowish needles from chloroform, mp: 103–104 °C; pyrrole-2-carboxylate (7c, 0.250 g, 1.110 mmol) in MeOH
1H NMR (400 MHz, CDCl3) δ 8.21 (quasi d, J = 8.9 Hz, 2H, (15 mL) and the reaction mixture was stirred at room tempera-
arom.), 7.67 (quasi d, J = 8.9 Hz, 2H, arom.), 7.16 (dd, J = 2.9, ture overnight. Then HCl (25 mL, 3 N) was added to the reac-
1.6 Hz, 1H, H-5), 7.02 (dd, J = 3.8, 1.6 Hz, 1H, H-3), 6.31 (dd, tion mixture and extracted with EtOAc (3 × 25 mL) and the
J = 3.8, 2.9 Hz, 1H, H-4), 3.89 (s, 3H, OCH3); 13C NMR combined organic phase was washed with brine. The resulting
(100 MHz, CDCl3) δ 160.0, 147.0, 131.9, 131.2, 129.6, 126.1, mixture was dried over Na2SO4 and concentrated in vacuum.
123.8, 119.3, 111.6, 86.4, 68.9, 51.8; IR (ATR): 3135, 3107, Then, the product was eluted over SiO2 (hexane) and concen-
2259, 1717, 1594, 1512, 1456, 1440, 1420, 1338, 1265, 1188, trated in vacuum to give 7c (0.182 g, 0.748 mmol, 96%). White
1170, 1100, 1071, 943, 852, 754, 743, 686, 593, 517; HRMS: needles from chloroform, mp: 109–110 °C (Lit. [15]
[M + H]+ calcd for C14H10N2O4, 271.07133; found, 271.07200. 105–106 °C); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.5
Hz, 2H, arom.), 7.62 (t, J = 7.5 Hz, 1H, arom.), 7.51 (t, J = 7.5
Methyl 1-(phenylethynyl)-1H-pyrrole-2-carboxylate (7c). To Hz, 2H, arom.), 7.05 (dd, J = 3.5, 1.1 Hz, 1H, H-5), 6.85 (bs,
a solution of (bromoethynyl)benzene (11c, 0.91 g, 5.02 mmol) 1H, H-3), 6.26 (dd, J = 3.5, 2.5 Hz, 1H, H-4), 5.76 (s, 2H,
in freshly distilled anhydrous toluene (20 mL), methyl CH2), 3.72 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 193.5,
1H-pyrrole-2-carboxylate (9, 0.57 g, 4.56 mmol), K3PO4 161.9, 135.0, 133.7, 129.9, 129.0, 128.1, 122.3, 118.4, 108.9,
(1.94 g, 9.12 mmol), CuSO4·5H2O (0.11 g, 0.46 mmol) and 55.2, 51.2.
1,10-phenanthroline monohydrate (0.18 g, 0.91 mmol) were
added and the resulting mixture was reacted as described above General procedure for nucleophilic cyclization reactions of
to obtain 7c (0.61 g, 59% (80% isolated yield based on 74% 7a–d with hydrazine. To a solution of N-alkyne-substituted
conversion)) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) methyl 1H-pyrrole-2-carboxylate derivatives 7a–d (1.0 equiv)
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Beilstein J. Org. Chem. 2017, 13, 825–834.
in dry MeOH (15 mL), hydrazine monohydrate (10 equiv) was snowflakes from chloroform, mp: 169.7–170.5 °C; 1H NMR
added under N2 atmosphere. The reaction mixture was stirred at (400 MHz, CDCl3) δ 9.12 (bs, 1H, NH), 7.51–7.35 (m, 5H,
reflux temperature for 24 h. After completion of the reaction, arom.), 7.18 (bd, J = 3.8 Hz, 1H, H-8), 7.13 (dd, J = 2.4, 1.5 Hz,
water (20 mL) was added. Then, MeOH was removed from the 1H, H-6), 6.94 (s, 1H, H-4), 6.59 (dd, J = 3.8, 2.4 Hz, 1H, H-7),
resulting mixture in vacuum. The residue was extracted with 1.89 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 170.1, 155.9,
ethyl acetate (3 × 25 mL) and the organic phase was concen- 131.5, 131.4, 129.5, 129.3, 128.4, 123.0, 119.9, 113.4, 112.5,
trated in vacuum. The resulting crude mixture was separated 108.0, 20.6; IR (ATR): 3367, 2971, 1473, 1373, 1341, 1315,
gradiently via column chromatography (SiO2, ethyl acetate/ 1281, 1081, 1040, 774, 722, 710, 632, 546; HRMS: [M + H]+
hexane, 1:4 to 1:1) and concentrated in vacuum to give the cor- calcd for C15H13N3O2, 268.10805; found, 268.11080.
responding pyrrolopyrazinone and/or pyrrolotriazinone deriva-
tives.
4-Phenyl-2,5-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1-
one (16). To a solution of methyl 1-(2-oxo-2-phenylethyl)-1H-
2-Amino-3-phenylpyrrolo[1,2-a]pyrazin-1-(2H)-one (12c) pyrrole-2-carboxylate (15, 0.127 g, 0.522 mmol) in dry MeOH
and 4-benzylpyrrolo-[1,2-d][1,2,4]triazin-1(2H)-one (13c). (10 mL), hydrazine monohydrate (0.261 g, 5.220 mmol) was
Methyl 1-(phenylethynyl)-1H-pyrrole-2-carboxylate (7c, 0.32 g, added under N2 atmosphere. The reaction mixture was stirred at
1.42 mmol) in dry MeOH (15 mL) reacted with hydrazine reflux temperature for 24 h, then water (20 mL) was added. The
monohydrate (0.71 g, 14.2 mmol) as described above to give solvent was removed in vacuum. The residue was extracted
12c (0.21g, 67%) as colorless cubes from ethyl acetate, mp: with ethyl acetate (3 × 20 mL) and the organic phase was
167–168 °C; 1H NMR (400 MHz, CDCl3) δ 7.51–7.47 (m, 2H, concentrated in vacuum. The resulting crude mixture was sepa-
arom.), 7.47–7.42 (m, 3H, arom.), 7.14 (bd, J = 4.0 Hz, 1H, rated gradiently via column chromatography (SiO2, ethyl
H-8), 7.12 (dd, J = 2.5, 1.5 Hz, 1H, H-6), 6.94 (s, 1H, H-4), acetate/hexane, 1:4 to 1:1) and concentrated in vacuum to give
6.61 (dd, J = 4.0, 2.5 Hz, 1H, H-7), 4.41 (bs, 2H, NH2); 16 (0.032 g, 0.142 mmol, 57%) as a white solid from chloro-
13C NMR (100 MHz, CDCl3) δ 156.3, 132.3, 130.8, 129.8, form, mp: 224–225 °C; 1H NMR (400 MHz, DMSO-d6) δ
129.0, 128.3, 123.1, 118.6, 113.2, 110.4, 107.4; IR (ATR) 3297, 10.89 (s, 1H, NH), 7.95–7.87 (m, 2H, arom.), 7.51–7.43 (m,
3097, 1664, 1630, 1430, 1376, 1347, 1294, 1184, 1009, 753, 3H, arom.), 7.34–7.27 (m, 1H), 6.82 (dd, J = 3.8, 1.7 Hz, 1H,
732, 697, 627; HRMS: [M + H]+ calcd for C13H11N3O, H-9), 6.22 (dd, J = 3.8, 2.5 Hz, 1H, H-8), 5.28 (s, 2H, CH2);
226.09749; found, 226.09990.
13C NMR (100 MHz, DMSO-d6) δ 159.7, 155.1, 134.7, 130.5,
129.0, 126.7, 126.4, 125.0, 115.7, 109.7, 44.9; IR (ATR):
4-Benzylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (13c). 3206, 3069, 2929, 1634, 1604, 1537, 1409, 1372, 1347, 1307,
(0.077 g, 24%), white needles from chloroform, mp: 1179, 1074, 1023, 875, 831, 816, 749, 735, 687, 626, 577;
199–200 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H, HRMS: [M + H]+ calcd for C13H11N3O, 226.09749; found,
N-H), 7.72–7.46 (m, 1H, H-8), 7.36 (bd, J = 7.3, 2H, arom.), 226.09850.
7.32 (bt, J = 7.5 Hz, 2H, arom.), 7.24 (bt, J = 7.5 Hz, 1H,
arom.), 7.03 (bd, J = 3.7 Hz, 1H, H-6), 6.82–6.53 (m, 1H, H-7), 2-Amino-3-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazin-1(2H)-
4.26 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 154.3, one (12a). Methyl 1-[(4-methoxyphenyl)ethynyl]-1H-pyrrole-2-
137.2, 135.2, 128.8, 128.6, 126.9, 123.5, 118.1, 114.1, 110.5, carboxylate (7a, 0.080 g, 0.313 mmol) was reacted with
35.9; IR (ATR); 3668, 3170, 3120, 2987, 2902, 1644, 1554, hydrazine monohydrate (0,157 g, 3.130 mmol) as described
1455, 1415, 1380, 1072, 846, 803, 695, 642, 598; HRMS: above and the resulting crude mixture was separated gradiently
[M + H]+ calcd for C13H11N3O, 226.09749; found, 226.09760. via column chromatography (SiO2, ethyl acetate/hexane, 1:10 to
1:2) and concentrated in vacuum to give 12a (0.072 g,
N-(1-Oxo-3-phenylpyrrolo[1,2-a]pyrazin-2(1H)-yl)acet- 0.282 mmol, 90%) as brownish needles from chloroform,
amide (14). 2-Amino-3-phenylpyrrolo[1,2-a]pyrazin-1-(2H)- mp: 168–169 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (quasi d,
one (12c, 0.200 g, 0.888 mmol) was dissolved in pyridine J = 8.7 Hz, 2H, arom.), 7.13 (bd, J = 4.0 Hz, 1H, H-8), 7.11 (dd,
(5 mL) and then acetic anhydride (0.136 g, 1.332 mmol) was J = 2.5, 1.4 Hz, 1H, H-6), 6.96 (quasi d, J = 8.7 Hz, 2H, arom.),
added at room temperature. The reaction mixture was stirred 6.91 (s, 1H, H-4), 6.60 (dd, J = 4.0, 2.5 Hz, 1H, H-7), 4.56 (bs,
over 2 days, and then HCl (10 mL, 3 N) was added to the reac- 2H, NH2), 3.84 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
tion mixture and the resulting solution was extracted with δ 160.2, 156.2, 131.2, 130.4, 124.4, 123.0, 118.4, 113.7, 113.1,
EtOAc (3 × 20 mL) and washed with brine. The organic phase 110.2, 107.2, 55.4; IR (ATR): 3314, 3107, 2920, 1670, 1605,
was dried over Na2SO4 and concentrated in vacuum. Then, the 1510, 1473, 1373, 1341, 1242, 1176, 1021, 965, 830, 800, 736,
product was eluted over SiO2 (ethyl acetate/hexane, 1:3) and 634, 595; HRMS: [M + H]+ calcd for C13H8INO2, 256.10805;
concentrated in vacuum to give 14 (0.229 g, 0.856 mmol, 97%), found, 256.10860.
832

Beilstein J. Org. Chem. 2017, 13, 825–834.
4-(4-Nitrobenzyl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one 13C NMR (100 MHz, CDCl3) δ 153.3, 142.6, 131.8, 129.1,
(13b). Methyl 1-[(4-nitrophenyl)ethynyl]-1H-pyrrole-2-carbox- 129.0, 127.2, 125.8, 116.8, 116.4, 111.7, 68.3; IR (ATR) 3664,
ylate (7b, 0.30 g, 1.46 mmol) in dry MeOH (15 mL) was 2969, 2918, 1708, 1450, 1371, 1332, 1089, 1055, 766, 729, 696,
reacted with hydrazine monohydrate (0.205 g, 0.758 mmol) as 685; HRMS: [M + H]+ calcd for C13H8INO2, 337.96791;
described above to give 13b (0.190 g, 0.703 mmol, 97%), found, 337.97070.
yellowish pellets from chloroform, mp: 237–238 °C; 1H NMR
(400 MHz, DMSO-d6) δ 10.92 (s, 1H, NH), 7.42–7.25 (m, 2H, 4-Iodo-3-(4-nitrophenyl)-1H-pyrrolo[2,1-c][1,4]oxazin-1-one
arom.), 6.86–6.71 (m, 3H, arom. and H-6), 6.19 (dd, J = 3.7, 1.2 (19b). To a solution of methyl 1-[(4-nitrophenyl)ethynyl]-1H-
Hz, 1H, H-8), 5.88 (dd, J = 3.7, 3.1 Hz, 1H, H-7), 3.59 (s, 2H, pyrrole-2-carboxylate (7b, 0.108 g, 0.400 mmol) in DCM
CH2); 13C NMR (100 MHz, DMSO-d6) δ 154.4, 146.7, 143.2, (20 mL), I2 (0.101 g, 0.400 mmol) was added and the reaction
136.6, 130.6, 123.6, 123.6, 118.1, 114.4, 110.8, 35.5; IR (ATR): mixture was stirred for 5 h. The crude product was purified as
3144, 3110, 2259, 1717, 1594, 1512, 1457, 1440, 1420, 1339, described above to give 19b (0.116 g, 76%) as yellowish needle
1265, 1220, 1170, 1100, 1071, 943, 852, 754, 743, 686, 593; from chloroform, mp: 171–172 °C; 1H NMR (400 MHz,
HRMS: [M + H]+ calcd for C13H10N4O3, 271.08257; found, CDCl3) δ 8.32 (quasi d, J = 8.9 Hz, 2H, arom.), 7.90 (quasi d,
271.08380.
J = 8.9 Hz, 2H, arom.), 7.58–7.48 (m, 2H, H-6 and H-8), 6.67
(dd, J = 3.9, 2.9 Hz, 1H, H-7); 13C NMR (100 MHz, CDCl3) δ
2-Amino-3-butylpyrrolo[1,2-a]pyrazin-1(2H)-one (12d). 153.5, 148.4, 141.4, 138.9, 131.2, 127.2, 123.5, 118.6, 117.3,
Methyl 1-(hex-1-yn-1-yl)-1H-pyrrole-2-carboxylate (7d, 0.30 g, 113.3, 70.8; IR (ATR): 3144, 1731, 1594, 1447, 1406, 1332,
1.46 mmol) in dry MeOH (15 mL) was reacted with hydrazine 1249, 1182, 1107, 1074, 1033, 1011, 939, 855, 738, 707, 694,
monohydrate (0.73 g, 14.6 mmol) as described above to obtain 676, 598; HRMS: [M + H]+ calcd for C13H7IN2O4, 382.95233;
2-amino-3-butylpyrrolo[1,2-a]pyrazin-1(2H)-one (12d, 0.26 g, found, 382.95660.
87%), colorless needles from chloroform, mp: 119–120 °C;
1H NMR (400 MHz, CDCl3) δ 7.09–6.93 (m, 2H, arom.), 6.71 4-Iodo-3-butyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (19d). To
(s, 1H, H-4), 6.52–6.46 (m, 1H, arom.), 4.54 (s, 2H, NH2), 2.59 a solution of methyl 1-(hex-1-yn-1-yl)-1H-pyrrole-2-carboxyl-
(t, J = 7.4 Hz, 2H, CH2), 1.58 (qui, J = 7.4 Hz, 2H, CH2), 1.40 ate (7d, 0.120 g, 0.585 mmol) in CHCl3 (15 mL), I2 (0.15 g,
(h, J = 7.4 Hz, 2H, CH2), 0.93 (t, J = 7.4 Hz, 3H, CH3); 0.59 mmol) was added and the reaction mixture was stirred for
13C NMR (100 MHz, CDCl3) δ 156.8, 130.7, 122.9, 117.7, 5 h. The crude product was purified as described above to give
112.3, 109.5, 104.8, 30.7, 29.5, 22.3, 13.9; IR (ATR): 3287, 19d (58.9 mg, 79%) as colorless cubes from chloroform, mp:
3204, 3111, 2950, 2934, 2867, 1670, 1618, 1596, 1414, 1371, 176–178 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 4.1,
1346, 1232, 1071, 971, 878, 742, 690, 639; HRMS: [M + H]+ 1.6 Hz, 1H, H-8), 7.33 (dd, J = 2.7, 1.6 Hz, 1H, H-6), 6.52 (dd,
calcd for C11H15N3O, 206.12879; found, 206.13010.
J = 4.1, 2.7 Hz, 1H, H-7), 2.70 (t, J = 7.5 Hz, 2H, CH2), 1.66
(qui, J = 7.5 Hz, 2H, CH2), 1.39 (h, J = 7.5 Hz, 2H, CH2), 0.93
General procedure for electrophilic cyclization reactions of (t, J = 7.5 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 154.7,
7 with iodine. To a solution of N-alkyne-substituted methyl 145.7, 125.9, 117.6, 117.4, 112.3, 68.6, 34.0, 29.3, 22.1, 13.9;
1H-pyrrole-2-carboxylate derivatives 7 in dichloromethane IR (ATR) 2956, 2928, 2869, 1635, 1534, 1455, 1402, 1339,
(10 mL), I2 (1.0 equiv) was added. The reaction mixture was 1229, 1023, 1084, 1027, 997, 896, 620, 596; HRMS: [M + H]+
stirred at room temperature for 2 h. After completion of the calcd for C11H12INO2, 317.99855; found, 317.99880.
reaction, the mixture was concentrated in vacuum. Then, the
crude product was purified via column chromatography (SiO2,
Supporting Information
ethyl acetate/hexane, 1:5) and concentrated in vacuum to obtain
the corresponding iodine-substituted pyrrolo-oxazinone deriva-
Supporting Information File 1
tives 19.
NMR spectra, X-ray crystallographic data, and Cartesian
Coordinates for the optimized structures.
4-Iodo-3-phenyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (19c).
To a solution of methyl 1-(phenylethynyl)-1H-pyrrole-2-
carboxylate (7c, 50.0 mg, 0.22 mmol) in dichloromethane
(10 mL), I2 (56.3 mg, 0.22 mmol) was added and treated as de-
scribed above to give 19c (58.9 mg, 79%) as colorless cubes
from chloroform, mp: 176–178 °C; 1H NMR (400 MHz,
CDCl3) δ 7.69–7.59 (m, 2H, arom.), 7.52–7.47 (m, 2H, arom.),
7.47–7.42 (m, 3H, arom.), 6.61 (dd, J = 4.0, 2.8 Hz, 1H, H-7);
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-83-S1.pdf]
Acknowledgments
Financial support from the Scientific and Technological
Research Council of Turkey (TUBITAK, grant no. TBAG112
T360), the Turkish Academy of Sciences (TUBA), and
833

Beilstein J. Org. Chem. 2017, 13, 825–834.
22.Ozer, M. S.; Menges, N.; Keskin, S.; Sahin, E.; Balci, M. Org. Lett.
2016, 18, 408. doi:10.1021/acs.orglett.5b03434
23.Hewlett, N. M.; Tepe, J. J. Org. Lett. 2011, 13, 4550.
doi:10.1021/ol201741r
Middle East Technical University (METU) is gratefully ac-
knowledged.
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