Acylation of pyrrolo[1,2-a]pyrazines

Article abstract of DOI:10.1007/s10593-008-0026-4

The acylation of pyrrolo[1,2-a]pyrazines with acetic anhydride and the acid chlorides of various carboxylic acids has been studied. It has been shown that pyrrole[1,2-a]pyrazines are selectively acylated at the α-position of the pyrrole ring when it is free. Products of the condensation of 1-methylsubstituted pyrrolo[1,2-a]pyrazines have been obtained for the first time in the process of acetylation.

Full text of DOI:10.1007/s10593-008-0026-4

Chemistry of Heterocyclic Compounds, Vol. 44, No. 2, 2008
ACYLATION OF PYRROLO[1,2-a]PYRAZINES
V. I. Terenin, M. A. Butkevich, A. S. Ivanov, and E. V. Kabanova
The acylation of pyrrolo[1,2-a]pyrazines with acetic anhydride and the acid chlorides of various
carboxylic acids has been studied. It has been shown that pyrrole[1,2-a]pyrazines are selectively
acylated at the α-position of the pyrrole ring when it is free. Products of the condensation of 1-methyl-
substituted pyrrolo[1,2-a]pyrazines have been obtained for the first time in the process of acetylation.
Keywords: pyrrolo[1,2-a]pyrazines, acylation, electrophilic substitution.
In a continuation of a study of the behavior of the pyrrolo[1,2-a]pyrazine system under electrophilic
substitution conditions, we have investigated the acylation of alkyl-, aryl-, and hetaryl-substituted pyrrolo-
[1,2-a]pyrazines. It was established previously that acetylation of 3,4-dihydropyrrolo[1,2-a]pyrazines with acetic
anhydride (in the presence of magnesium perchlorate as a Lewis acid) proceeded selectively at the pyrazine atom
N(2) and formed N-acyl-substituted derivatives in 25-87% yield [1].
In contrast to the hydrogenated system, acylation of aromatic pyrrolo[1,2-a]pyrazines occurs at the free
α-position of the pyrrole ring. For example boiling the pyrrolo[1,2-a]pyrazines 1a-c with acetic anhydride in the
presence of tin(IV) chloride or magnesium perchlorate proceeded selectively to give the monosubstituted
products 2-4, but the yields of the acyl derivatives did not exceed 14%.
Me
R
R
(MeCO)2O
N
N
O
N
SnCl4
or
N
Mg(ClO4)2
2–4
1a–c
1a, 2 R = Me; 1b, 3 R = Et; 1c, 4 R = Ph
Under analogous conditions 1-propylpyrrolo[1,2-a]pyrazine (1d) reacted with the formation of a mixture
of two products of acylation in low overall yield (10%) – 6-acetyl-1-propylpyrrolo[1,2-a]pyrazine (5) and
6,8-diacetyl-1-propylpyrrolo[1,2-a]pyrazine (6).
Me
O
Me
Me
Me
Me
Me
N
(MeCO)2O
SnCl4
N
N
O
O
+
N
N
N
5
6
1d
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, Moscow 119992; e-mail: vter@org.chem.msu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 263-272, February, 2008. Original article submitted April 16,
2007.
200
0009-3122/08/4402-0200©2008 Springer Science+Business Media, Inc.

Acetyl chloride in the presence of aluminum chloride was used as acylation reagent in an attempt to
increase the yields of products. The expected products of acetylation at the α-position of pyrrole ringwere
obtained in 33-74% yield on acetylation of 1-ethyl- (1b), 1-phenyl- (1c), 1-isopropyl- (1e), 1-benzyl- (1f), and
1-(2-thienyl)pyrrolo[1,2-a]pyrazines.
Me
R
R
MeCOCl
N
N
O
N
AlCl3
N
CH2Cl2
1b,c,e-g
3,4,7–9
1b, 3 R= Et; 1c, 4 R = Ph; 1e, 7 R = i-Pr; 1f, 8 R = CH2Ph; 1g, 9 R = 2-thienyl
As example the acylation of the most reactive 1-ethylpyrrolo[2,1-a]pyrazine (1b) with the chlorides of
benzoic, cinnamic, and 2-thiophenecarboxylic acids was investigated. The reaction proceeded selectively in all
cases with the formation exclusively of 6-acyl-1-ethylpyrrolo[1,2-a]pyrazines 10-12, but the yields of the
acylation products decreased to 8-29%.
O
Cl
S
S
N
Me
N
Me
N
AlCl3
CH2Cl2
O
N
1b
12 (8%)
PhCH=CHCOCl
PhCOCl
AlCl3
AlCl3
CH2Cl2
CH2Cl2
N
Me
N
Me
O
O
N
N
11 (29%)
10 (8%)
On acylation of 1-methylpyrrolo[1,2-a]pyrazine (1a) with acetyl chloride, apart from the products of
substitution of the pyrrole ring at position α and β' 2 and 13, the unexpected heterocycle 14, the product of
condensation of two molecules, was obtained in 8% yield.
O
O
Me
7'
Me
Me
8'
8
Me
Me
Me
6
1'
Me
Me
MeCOCl
N
N
N
N
1
N
O
O
+
+
N
N
4
AlCl3
CH2Cl2
N
N
4'
N
3
3'
1a
2
(49%)
O
Me
14 (8%)
13 (7%)
201

1
The H NMR spectrum of compound 14 contained double sets of signals of the pyrrole and pyrazine
rings, four singlets of the methyl group protons, and two doublets at 3.60 and 4.32 ppm with J = 13.20 Hz,
corresponding to the two protons of the bridging carbon atom. The peak at m/z 390 in the mass spectrum
corresponds to the molecular mass of compound 14. The 13C NMR spectrum showed the presence of a signal for
the carbon atom in position 1' at 152.77 ppm (J = 4.13, J =10.98 Hz), appearing as a doublet of triplets, on the
basis of which it was concluded that the molecules are bonded through the methyl substituent in position 1 of the
heterocycle molecule. The structure of the compound obtained was confirmed by X-ray crystallography.
Fig. 1. Structural model of the molecule of compound 14 with numbering of the atoms.
Table 1. Crystallographic Characteristics of Compound 14
Characteristic
Molecular formula
Molecular mass
Crystal color
C22H22N4O3
390.44
Colorless
Size, mm
0.26×0.16×0.14
Monoclinic
Crystal system
Unit cell parameters
a, Å
9.744(2)
b, Å
21.301(4)
c, Å
9.601(2)
β, deg
95.86(3)
Volume of unit cell, V, Å3
Space group
1982.3(7)
P2(1)/c
Molecules per unit cell, Z
Density, d, g/cm3
Absorption coefficient, µ, mm-1
Final R factors [I>2σ(I)]
R factors (all data)
4
1.308
0.089
R1 = 0.0297, wR2 = 0.0703
R1 = 0.1270, wR2 = 0.0800
202

Table 2 Bond Lengths (l) in the Structure of Compound 14
Bond
l, Å
Bond
l, Å
O(1)–C(9)
O(2)–C(8)
1.205(2)
1.228(2)
1.228(2)
1.387(2)
1.400(2)
1.5033(19)
1.358(2)
1.3785(18)
1.395(2)
1.380(2)
1.386(2)
1.386(2)
1.317(2)
1.369(2)
1.507(2)
1.526(2)
C(1)–C(11)
C(2)–C(3)
(4)–C(5)
1.563(2)
1.316(2)
1.373(2)
1.420(2)
1.449(2)
1.354(2)
1.489(3)
1.502(3)
1.499(2)
1.408(2)
1.391(2)
1.375(2)
1.397(2)
1.435(2)
1.338(2)
1.495(3)
O(2)–C(8)
C
N(1)–C(9)
N(1)–C(2)
C(5)–C(6)
C(5)–C(8)
N(1)–C(1)
C(6)–C(7)
N(2)–C(4)
N(2)–C(7)
C(8)–C(20)
C(9)–C(21)
N(2)–C(3)
C(11)–C(12)
N(3)–C(17)
N(3)–C(16)
C(12)–C(13)
C(13)–C(14)
N(3)–C(16)
C(14)–C(15)
N(4)–C(12)
N(4)–C(18)
C(15)–C(16)
C(16)–C(19)
C
(1)–C(7)
C
(17)–C(18)
C(1)–C(10)
C(19)–C(22)
Table 3. Bond Valence (ω) in the Structure of Compound 14
Angle
ω, deg.
Angle
ω,deg.
C(9)–N(1)–C(2)
C(9)–N(1)–C(1)
(2)–N(1)–C(1)
119.37(14)
119.44(13)
118.64(13)
109.51(12)
129.19(13)
120.97(13)
131.25(14)
119.60(14)
109.15(13)
116.81(15)
108.80(12)
112.50(13)
106.35(13)
109.09(12)
110.61(13)
109.46(12)
124.24(15)
119.14(14)
108.47(13)
106.14(14)
127.59(15)
126.26(15)
108.66(13)
107.21(13)
131.22(13)
N(2)–C(7)–C(1)
O(2)–C(8)–C(5)
O(2)–C(8)–C(20)
21.30(13)
120.84(15)
120.76(16)
118.40(16)
121.62(17)
120.58(17)
117.79(17)
114.48(12)
122.65(15)
116.84(15)
120.47(14)
107.37(14)
134.76(15)
117.86(14)
107.69(14)
109.60(15)
106.19(14)
122.96(15)
130.82(16)
117.84(15)
125.23(15)
122.99(17)
119.42(17)
117.58(16)
C
C(4)–N(2)–C(7)
C(4)–N(2)–C(3)
C(5)–C(8)–C(20)
O(1)–C(9)–N(1)
C
(7)–N(2)–C(3)
O(1)–C(9)–C(21)
C(17)–N(3)–C(16)
C(17)–N(3)–C(13)
N(1)–C(9)–C(21)
C(12)–C(11)–C(1)
C
(16)–N(3)–C(13)
N(4)–C(12)–C(13)
C(12)–N(4)–C(18)
N(4)–C(12)–C(11)
N
(1)–C(1)–C(7)
(1)–C(1)–C(10)
C
C
(13)–C(12)–C(11)
(14)–C(13)–N(3)
N
C(7)–C(1)–C(10)
N(1)–C(1)–C(11)
C(14)–C(13)–C(12)
N(3)–C(13)–C(12)
C
(7)–C(1)–C(11)
C(15)–C(14)–C(13)
C(10)–C(1)–C(11)
C(3)–C(2)–N(1)
C(14)–C(15)–C(16)
N(3)–C(16)–C(15)
C
(2)–C(3)–N(2)
N(3)–C(16)–C(19)
N(2)–C(4)–C(5)
C(4)–C(5)–C(6)
C(15)–C(16)–C(19)
C(18)–C(17)–N(3)
C
(4)–C(5)–C(8)
C(17)–C(18)–N(4)
C(6)–C(5)–C(8)
C(7)–C(6)–C(5)
O(3)–C(19)–C(16)
O(3)–C(19)–C(22)
C
(6)–C(7)–N(2)
C(16)–C(19)–C(22)
C(6)–C(7)–C(1)
A similar picture was observed on acetylation of 1,6-dimethylpyrrolo[1,2-a]pyrazine (1h) with acetyl
chloride: a mixture of two compounds was formed – 8-acetyl-1,6-dimethylpyrrolo[1,2-a]pyrazine (15) (yield
26%) and the pyrrolopyrazine 16 (yield 6%). The low overall yield of the reaction may be explained by the
lower reactivity of the β'-position in the acylation reaction, while the α-position is occupied by the methyl
substituent.
203

O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
N
N
MeCOCl
N
N
+
N
N
N
N
AlCl3
CH2Cl2
15 (26%)
O
Me
16 (6%)
1h
Formation of condensed compounds was observed only when a methyl group is found in position 1 of
pyrrolo[1,2-a]pyrazine and acetyl chloride is used as the acylation reagent. When compound 1a was acylated
with propionyl chloride under analogous conditions compound 17 (43% yield), product of the substitution in the
α-position of the pyrrole ring was the only product.
Et
Me
Me
EtCOCl
N
N
O
N
AlCl3
N
CH2Cl2
17 (43%)
1a
Acetylation of 1-ethyl-6-methylpyrrolo[1,2-a]pyrazine (1i) with acetyl chloride, in contrast to
1,6-dimethylpyrrolo[1,2-a]pyrazine (1h), gave only the 8-acetyl derivative 18.
O
Me
Me
Me
MeCOCl
N
Me
N
Me
AlCl3
CH2Cl2
N
N
1h
18 (47%)
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker Avance-400 machine (400 and 100 MHz
respectively) in CDCl3 (compounds 2-13, 17, and 18), acetone-d6, DMSO-d6, and CD3OD with TMS as internal
standard. Mass spectra were recorded on a Kratos MS-30 with an ionization energy of 70 eV (T = 210°C).
Reactions were monitored by TLC on Silufol UV-254 plates in 1:1 benzene–ethyl acetate.
Acetylation with Acetic Anhydride. A. To a stirred solution of pyrrolo[1,2-a]pyrazine (2 mmol) in
acetic anhydride (20 ml), magnesium perchlorate (2 mmol) was added at 20°C or tin(IV) chloride (2 mmol) at
0°C. The reaction mixture was boiled for 12 h, cooled to room temperature, and poured into cold water. The
aqueous solution was neutralized with sodium carbonate, extracted with benzene, dried over 3Å molecular
sieves, and the solvent was evaporated. The residue was chromatographed on a Silpearl silica gel column with
3:1 benzene-ethyl acetate.
Acylation with Acid Chlorides. B. The corresponding acid chloride (20 mmol) was added dropwise
with stirring at 20°C to a solution of pyrrolo[1,2-a]pyrazine (2 mmol) in methylene chloride (20 ml) , and then
204

aluminum chloride (20 mmol) was added over 30 min. The reaction mixture was stirred for 24 h at 20°C and
then poured onto crushed ice. The aqueous solution was neutralized with sodium carbonate, the precipitate was
filtered off and washed with methylene chloride. The mother liquor was extracted with methylene chloride, dried
over 3Å molecular sieves, the solvent was evaporated, and the residue recrystallized from hexane.
In the case of 1-methylpyrrolo[1,2-a]pyrazine (1a) the oil remaining after evaporation of the solvent was
recrystallized from hexane to give 6-acetyl-1-methylpyrrolo[1,2-a]pyrazine (2) and 8-acetyl-1-methyl-
pyrrolo[1,2-a]pyrazine (13). On addition of acetone to the residue after recrystallization precipitation of 14
occurred.
In the case of 1,6-dimethylpyrrolo[1,2-a]pyrazine (1h) the residue after evaporation of the solvent was
chromatographed on a column of Silpearl silica gel with 1:1 benzene–ethyl acetate.
6-Acetyl-1-methylpyrrolo[1,2-a]pyrazine (2). Yield by method A 7%, by method B 49%; mp 96-97 °C
(dec.). H NMR spectrum, δ, ppm (J, Hz): 2.61 (3H, s, COCH3); 2.76 (3H, s, 1-CH3); 6.79 (1H, d, J8,7 = 4.51,
1
H-8); 7.50 (1H, d, J7,8 = 4.51, H-7); 7.80 (1H, d, J3,4 = 4.79, H-3); 9.43 (1H, d, J4,3 = 4.79, H-4). Mass spectrum,
m/z (Irel, %): 174 [M+] (85.09), 159 (100), 131 (37.44), 117 (2.30), 104 (28.93), 90 (10.01), 77 (64.06). Found,
%: C 68.82; H 5.75; N 15.88. C10H10N2O. Calculated, %: C 68.97; H 5.75; N 16.09.
6-Acetyl-1-ethylpyrrolo[2,1-a]pyrazine (3). Yield by method A 14%, by method B 74 %; mp 92-95°C.
1H NMR spectrum, δ, ppm, (J, Hz): 1.43 (3H, t, J =7.58, CH2CH3); 2.61 (3H, s, COCH3); 3.08 (2H, q, J = 7.58,
CH2CH3); 6.82 (1H, d, J8,7 = 4.60, H-8); 7.50 (1H, d, J7,8 = 4.60, H-7); 7.84 (1H, d, J3,4 = 4.89, H-3); 9.44 (1H, d,
J4,3 = 4.89, H-4). 13C NMR spectrum, δ, ppm: 12.02 (CH2CH3); 26.38 (CH2CH3); 28.93 (COCH3); 103.39,
118.42, 122.16, 124.22, 130.37, 157.65, 188.45 (COCH3). Mass spectrum, m/z,(Irel, %): [188 M+] (100), 173
(34.78), 145 (17.32), 131 (3.00), 118 (14.50), 104 (6.89), 90 (9.57), 69 (5.41). Found, %: C 70.63; H 5.90;
N 14.31. C11H12N2O. Calculated, %: C 70.21; H 5.38; N 14.89.
6-Acetyl-1-phenylpyrrolo[2,1-a]-pyrazine (4). Yield by method A 5%, by method B 45%; mp 81-82°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.62 (3H, s, COCH3); 6.97 (1H, dd, J8,7 = 4.79, J8,4 = 0.74, H-8); 7.52-7.54
(4H, m, H-3, m-, p-C6H5); 7.90-7.93 (1H, m, H-o-C6H5); 8.01 (1H, d, J7,8 = 4.79, H-7); 9.57 (1H, dd, J4,3 = 4.91,
J
4,8 =0.74, H-4). Mass spectrum, m/z (Irel, %): 236 [M+] (100), 221 (75.26), 193 (30.90), 168 (34.27), 152 (3.65),
140 (15.99), 115 (8.93), 103 (7.61), 89 (4.53), 76 (7.26). Found, %: C 76.35; H 4.91; N 12.03. C15H12N2O.
Calculated, %: C 76.27; H 5.08; N 11.86.
6-Acetyl-1-propylpyrrolo[1,2-a]pyrazine (5). Yield by method A 7% (accordind to 1H NMR spectrum
data). H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, t, J = 7.43, CH2CH2CH3)); 1.88 (2H, sext. J = 7.43,
1
CH2CH2CH3); 2.59 (3H, s, COCH3); 3.01 (2H, t, J = 7.43, CH2CH2CH3); 6.80 (1H, d, J8,7 = 4.66, H-8); 7.48
(1H, d, J7,8 = 4.88, H-7); 7.82 (1H, d, J3,4 = 4.88, H-3); 9.41 (1H, d, J4,3 = 4.46, H-4).
1
6,8-Diacetyl-1-pyrrolo[1,2-a]pyrazine (6). Yield by method A 3% (accordind to H NMR spectrum
1
data). H NMR spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.50, CH2CH2CH3); 1.73 (2H, sext, J = 7.50,
CH2CH2CH3); 2.65 (3H, s, 6-COCH3); 2.69 (3H, s, 8-COCH3) , 3.39 (2H, t, J = 7.50, CH2CH2CH3); 7.90 (1H, s,
H-7); 8.06 (1H, d, J3,4 = 4.46, H-3); 9.62 (1H, d, J4,3 = 4.46, H-4).
1
6-Acetyl-1-isopropylpyrrolo[1,2-a]pyrazine (7). Yield by method B 51%; mp 61-62°C. H NMR
spectrum, δ, ppm (J, Hz): 1.40 (6H, d, J = 6.87, CH(CH3)2); 2.59 (3H, s COCH3); 3.94 (1H, sept, J = 6.87,
CH(CH3)2); 6.82 (1H, d, J8,7 = 4.37, H-8); 7.48 (1H, d, J7,8 = 4.37, H-7); 7.86 (1H, d, J3,4 = 4.75, H-3); 9.42 (1H,
d, J4,3 = 4.75, H-4). Mass spectrum, m/z (Irel, %): 202 [M+] (100), 187 (61.05), 174 (86.62), 159 (21.08), 144
(45.93), 131 (17.70), 117 (29.54), 104 (14.97), 89 (21.58), 77 (16.47), 64 (26.97). Found, %: C 71.22; H 7.31;
N 13.98. C12H14N2O. Calculated, %: C 71.29; H 6.93; N 13.86.
1
6-Acetyl-1-benzylpyrrolo[1,2-a]pyrazine (8). Yield by method B 33%; mp 98-99°C. H NMR
spectrum, ppm (J, Hz): 2.59 (3H, s, COCH3); 4.40 (2H, s, CH2Ph); 6.77 (1H, d, J8,7 = 4.80, H-8); 7.21-7.39 (5H,
m, H-C6H5); 7.46 (1H, d, J7,8 = 4.80, H-7); 7.87 (1H, d, J3,4 = 4.50, H-3); 9.47 (1H, d, J4,3 = 4.50, H-4). Mass
spectrum, m/z (Irel, %): 250 [M+] (53.75), 249 (100), 235 (4.00), 219 (2.50), 206 (88.39), 178 (13.11), 151
(13.01), 133 (3.20), 118 (3.30), 104 (6.81), 99 (11.81), 78 (15.32). Found, %: C 77.22; H 5.69; N 10.98.
C16H14N2O. Calculated, %: C 76.80, 5.60; N 11.20.
205

1
6-Acetyl-1-(2-thienyl)pyrrolo[1,2-a]pyrazine (9). Yield by method B 51%; mp 112-114°C. H NMR
spectrum, δ, ppm (J, Hz): 2.63 (3H, s, COCH3); 7.19 (1H, dd, J8,7 = 4.72, J8,4 = 0.72, H-8); 7,23 (1H, dd,
Jβ'α' = 5.05, Jβ'β = 3.76, H-β'-Th); 7.56 (1H, dd, Jα'β' = 5.05, Jα'β = 1.05, H-α'-Th); 7.57 (1H, d, J7,8 = 4.72, H-7);
7.88 (1H, dd, Jββ' = 3.76, Jβα' = 1.05, H-β-Th); 7.93 (1H, d, J3,4 = 4.77, H-3); 9.54 (1H, dd, J4,3 = 4.77, J4,8 = 0.72,
H-4). Mass spectrum, m/z (Irel, %): 242 [M+] (91.66), 227 (100), 199 (68.75), 172 (24.31), 155 (31.94), 145
(18.06), 128 (21.53), 101 (14.58), 77 (11.81). Found, %: C 64.86; H 4.29; N 11.12. C13H10N2OS. Calculated, %:
C 64.46; H 4.13; N 11.34.
1
6-Benzoyl-1-ethylpyrrolo[1,2-a]pyrazine (10). Yield by method B 8%; mp 137-140°C. H NMR
spectrum, δ, ppm (J, Hz): 1.45 (3H, t, J = 7.55, CH2CH3); 3.13 (2H, q, J = 7.55, CH2CH3); 6.84 (1H, d,
J8,7 = 4.60, H-8); 7.37 (1H, d, J7,8 = 4.60, H-7); 7.52 (2H, m, H-m-C6H5); 7.59 (2H, m, H-p-C6H5); 7.84 (1H, dd,
Jo,m = 8.41, Jo,p = 1.36, J-o-C6H5); 7.92 (1H, d, J3,4 = 4.69, H-3); 9.51 (1H, d, J4,3 = 4.69, H-4). Mass spectrum,
m/z (Irel, %): 250 [M+] (84.58), 249 (100), 222 (8.51), 173 (19.42), 145 (21.02), 117 (26.13), 105 (29.13), 85
(9.81), 77 (38.94). Found, %: C 77.02; H 5.55; N 11.34. C16H14N2O. Calculated, %: C 76.80; H 5.55; N 11.34.
(2E)-1-(1-Ethylpyrrolo[1,2-a]pyrazin-6-yl)-3-phenyl-2-propen-1-one (11). Yield by method B 29%;
1
mp 131-133°C. H NMR spectrum, δ, ppm (J, Hz): 1.43 (3H, t, J = 7.55, CH2CH3); 3.10 (2H, q, J = 7.55,
CH2CH3); 6.87 (1H, d, J8,7 = 4.70, H-8); 7.41-7.43 (3H, m, H-m,p-C6H5); 7.50 (1H, d, J = 15.46, CH=CHC6H5);
7.65-7.67 (3H, m, H-o-C6H5 and H-7); 7.86 (1H, d, J =15.46, CH=CHC6H5); 7.89 (1H, d, J3,4 = 4.70, H-3); 9.61
(1H, d, J4,3 = 4.70, H-4). Mass spectrum, m/z (Irel, %): 276 [M+] (100), 248 (24.52), 173 (4.80), 146 (27.33), 131
(16.72), 117 (11.91), 102 (21.62), 77 (24.62). Found, %: C 78.09; H 5.69; N 10.27. C18H16N2O. Calculated, %:
C 78.26; H 5.80; N 10.14.
1-Ethylpyrrolo[1,2-a]pyrazin-6-yl 2-Thienyl Ketone (12). Yield by method B 8%; mp 230-232°C
(dec.). 1H NMR spectrum, δ, ppm (J, Hz): 1.66 (3H, t, J = 7.67, CH2CH3); 3.56 (2H, q, J = 7.67, CH2CH3); 7.30
(1H, m, H-β'-Th); 7.51 (1H, d, J8,7 = 4.21, H-8); 7.81 (1H, d, J3,4 = 4.38, H-3); 7.86 (1H, d, J7,8 = 4.21, H-7); 7.92
(1H, d, Jβ,β' =3.13, 1-H-β-Th); 7.94 (1H, d, Jα',β' = 4.69, 1-H-α'-Th); 9.57 (1H, d, J4,3 = 4.38, H-4). Mass spectrum,
m/z, (Irel, %): 256 [M+] (100), 228 (19.52), 199 (5.71), 173 (17.92), 145 (54.55), 128 (11.31), 118 (13.11), 111
(72.17), 90 (10.71), 77 (8.51), 65 (12.02). Found, %: C 65.10; H 4.82; N 10.77. C14H12N2OS. Calculated, %:
C 65.63; H 4.69; N 10.94.
1
8-Acetyl-1-methylpyrrolo[1,2-a]pyrazine (13). Yield by method B 7% (according to H NMR
1
spectrum data). H NMR spectrum, δ, ppm (J, Hz): 2.63 (3H, s, COCH3); 3.04 (3H, s, 1-CH3); 7.25 (1H, d,
J6,7 = 2.83, H-6); 7.36 (1H, d, J7,6 = 2.83, H-7); 7.69 (1H, d, J3,4 = 4.52, H-3); 7.77 (1H, d, J4,3 = 4.52, H-4).
2,7-Diacetyl-1-[(6-acetylpyrrolo[1,2-a]pyrazin-1-yl)methyl]-1-methyl-1,2-dihydropyrrolo[1,2-a]-
1
pyrazine (14). Yield by method B 8%; mp 215-216°C (dec., ethanol). H NMR spectrum (acetone-d6)), δ, ppm
(J, Hz): 2.29 (3H, s, 1-CH3); 2.36 (3H, s; NCOCH3); 2.63 (3H, s, 6′-COCH3); 2.93 (3H, s, 7-COCH3); 3.60 (1H,
d, J9,10 = 13.20, H-9(10)); 4.32 (1H, d, J9,10 =13.20, H9(10)); 6.13 (1H, dd, J4,3 = 6.58, J4,8 = 0.82, H-4); 6.33 (1H,
d, J3,4 = 6.58, H-3); 6.64 (1H, dd, J8,7' = 4.69, J8',4' =0.78, H-8′); 6.70 (1H, dd, J8,6 = 1.76, J8,4 = 0.82, H-8); 7.26
(1H, d, J6,8 =1.76, H-6); 7.68 (1H, d, J7′,8′ = 4.69, H-7'); 7.83 (1H, d, J3′,4′ = 4.89, H-3'); 9.47 (1H, dd, J4',3' = 4.89,
J4′,8′ = 0.78, H-4′). 13C NMR spectrum (DMSO-d6); δ, ppm (J, Hz): 25.12 (CH3); 27.29 (CH3); 27.54 (CH3);
27.88 (CH3); 44.22 (CH2); 60.99 (C(1)); 104.05, 105.71, 106.80, 116.96, 118.09, 122.16, 123.39, 123.74, 125.95,
130.74, 132.06, 132,11, 153.77 (1C, dt, JCH =4.13, JCH =10.98, C(1′)); 170.73 (NCOCH3); 188.83 (COCH3-7);
192.29 (COCH3-6'). Mass spectrum, m/z (Irel, %): 390 [M+] (32.61), 375 (4.35), 347 (10.87), 333 (8.69), 305
(4.31), 289 (8.72), 263 (2.71), 175 (100), 146 (4.29), 132 (11.00), 104 (6.52). Found, %: C 67.77; H 5.75;
N 14.48. C22H22N4O3. Calculated, %: C 67.69; H 5.64; N 14.36.
1
8-Acetyl-1,6-dimethylpyrrolo[1,2-a]pyrazine (15). Yield by method B 47%; mp 104-105°C. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.49 (3H, s, 6-CH3); 2.61 (3H, s, COCH3); 2.98 (3H, s, 1-CH3); 7.04 (1H, s,
1
H-7); 7.56 (1H, d, J3,4 = 4.60, H-3); 7.75 (1H, d, J4,3 = 4.60, H-4). H NMR spectrum (acetone-d6), δ, ppm
(J (Hz): 2.53 (3H, s, 6-CH3); 2.56 (3H, s, COCH3); 2.86 (3H, s, 1-CH3); 7.22 (1H, s, H-7); 7.71 (1H, d,
J
3,4 = 4.70, H-3); 7.90 (1H, d, J4,3 = 4.70, H-4). Mass spectrum, m/z (Irel, %): 188 [M+] (75.87), 173 (100), 143
206

(5.91), 117 (4.50), 104 (17.12), 91 (6.11), 77 (15.92). Found, %: C 70.06; H 6.26; N 14.84. C11H12N2O.
Calculated, %: C 70.21; H 6.38; N 14.89.
2-Acetyl-1-[(8-acetyl-6-methylpyrrolo[1,2-a]pyrazin-1-yl)methyl]-1,6-dimethyl-1,2-dihydropyrrolo-
1
[1,2-a]pyrazine (16). Yield by method B 6%. H NMR spectrum (CDCl3), δ ppm (J, Hz): 2.11 (3H, s, 1-CH3);
2.29 (3H, s; NCOCH3); 2.35 (3H, s, 6′-CH3); 2.36 (3H, s, 6-CH3); 2.41 (3H, s, 8′-COCH3); 3.25 (1H, d,
J9,10 = 12.91, H-9(10)); 3.90 (1H, d, J10,9 = 12.91, H-10(9)); 5.76 (1H, d, J4,3 = 5.76, H-4); 5.80 (1H, d,
J3,4 = 5.76, H-3); 6.35 (1H, s, H-7′); 6.40 (1H, d, J8,7 = 3.91, H-8); 6.50 (1H, d, J7,8 = 3.91, H-7); 7.30 (1H, d,
J
3',4' = 4.89, H-3′); 7.43 (1H, d, J4′,3′ = 4.89, H-4′). 13C NMR spectrum (CD3OD); δ, ppm (J, Hz): 9.04 (CH3); 9.65
(CH3); 23.44 (CH3); 25.68 (CH3); 27.17 (CH3); 44.65 (CH2); 61.34 (C(1)); 102.96, 103.07, 108.35, 113.95,
114.02, 115.98, 120.91, 123.55, 124.89, 128.24, 129.17, 131.06, 151.57 (1C, dt, JCH = 5.86, JCH = 9.51, C-1′);
171.57 (NCOCH3); 196.12 (COCH3-8′). Mass spectrum, m/z (Irel,%): 376 [M+] (3.20), 245 (1.70), 231 (47.05),
189 (100), 173 (18.32), 159 (3.10), 145 (53.45), 131 (2.50), 104 (5.91), 91 (11.11). Found, %: C 71.69; H 6.43;
N 15.03. C22H24N4O2. Calculated, %: C 71.21; H 6.38; N 14.89.
1-Methyl-6-propionylpyrrolo[1,2-a]pyrazine (17). Yield by method B 43%; mp 119-120°C (dec.).
1H NMR spectrum, δ ppm, (J, Hz): 1.29 (3H, t, J = 7.43, COCH2CH3); 2.77 (3H, s, CH3-1); 2.99 (2H, q,
J = 7.43, COCH2CH3); 6.80 (1H, dd, J8,7 = 4.63, J8,4 = 0.69, H-8); 7.52 (1H, d, J7,8 = 4.63, H-7); 7.80 (1H, d,
J
3,4 = 4.89, H-3); 9.46 (1H, d, J4,3 = 4.89, H-4). 13C NMR spectrum, δ, ppm (J, Hz): 8.88 (COCH2CH3); 21.78
(1-CH3); 32.87 (COCH2CH3); 103.78, 118.56, 121.38, 123.97, 130.16, 131.45, 153.14, 192.15 (COCH2CH3).
Mass spectrum, m/z (Irel,%): 188 [M+] (58.56), 173 (25.73), 159 (100), 145 (14.01), 131 (35.04), 117 (9.2), 104
(36.24), 91 (10.51), 77 (36.54), 63 (20.22). Found, %: C 69.94; H 6.47; N 14.76. C11H12N2O. Calculated, %:
C 70.21; H 6.38; N 14.89.
1
8-Acetyl-1-ethyl-6-methyl-pyrrolo[1,2-a]pyrazine (18). Yield by method B 47%; mp 104-105°C. H
NMR spectrum, δ, ppm (J, Hz): 1.31 (3H, t, J = 7.43, CH2CH3); 2.48 (3H, s, 6-CH3); 2.62 (3H, s, COCH3); 3.44
13
(2H, q, J = 7.43, CH2CH3); 7.06 (1H, s, H-7); 7.56 (1H, d, J3,4 = 4.70, H-3); 7.81 (1H, d, J4,3 = 4.70, H-4). C
NMR spectrum, δ, ppm (J, Hz): 11.28 (CH2CH3); 13.26 (6-CH3); 29.81 (CH2CH3); 30.93 (COCH3); 113.22,
117.53, 117.94, 122.36, 129.24, 160.06, 193.84 (COCH3). Mass spectrum, m/z (Irel, %): 202 [M+] (100), 186
(14.41), 174 (24.43), 160 (28.53), 145 (8.71), 132 (6.41), 116 (3.80), 102 (5.1), 86 (4.80). Found, %: C 71.11;
H 7.27; N 14.05. C12H14N2O. Calculated, %: 71.29; H 6.93; N 13.86.
X-ray Structural Investigation. Monocrystal of compound 14 was grown from CH2Cl2. The diffraction
pattern was obtained at 293 K using an Engraft Nonius CAD4 diffractometer (MoKα radiation, θ interval for all
data from 1.91 to 25.47°). The structure was solved by direct method with full matrix least squares in the
anisotropic approximation. Calculations were carried out with the SHELX97 suite of programs [2]. Complete
crystallographic information has been deposited in the Cambridge Structural Database (No. CCDC 644154).
Interatomic distances and valence angles are given in Tables 2 and 3.
REFERENCES
1.
2.
V. I. Terenin, E. V. Kabanova, N. A. Tselishcheva, M. A. Kovalkina, and A. P. Pleshkova. Khim.
Geterotsikl. Soed., 431 (20040. [Chem. Heterocycl. Comp., 40, 351 (2004)].
G. M. Sheldrick, SHELX97. PC Version. A System of Computer Programs for the Crystal Structure
Solution and Refinement. Rev. 2 (1998).
207