Preparation of thieno[2,3-b]pyrazines as bioisosteres for quinoxaline derivatives with reverse transcriptase inhibition

Article abstract of DOI:10.3987/COM-01-9371

Replacement of the fused aromatic moiety in GW-420867X, a HIV-1 specific nonnucleoside reverse transcriptase inhibitor, with thiophene provided 2-oxo-1,2,3,4-tetrahydrothieno[2,3-b]pyrazine derivatives. The synthesis starts with the reaction of 5-acyl-2-chloro-3-nitrothiophene and different amino acid derivatives. The resulting substitution products are reduced, cyclized and N-acylated to give the desired compounds (27-33).

Full text of DOI:10.3987/COM-01-9371

HETEROCYCLES, Vol. 57, No. 1, 2002, pp. 97 - 110, Received, 25th October, 2001
PREPARATION OF THIENO[2,3-b]PYRAZINES AS
BIOISOSTERES FOR QUINOXALINE DERIVATIVES WITH
REVERSE TRANSCRIPTASE INHIBITION1
Thomas Erker* and Karin Trinkl
Institute of Pharmaceutical Chemistry, University of Vienna
Althanstraße 14, A-1090 Wien, Austria
thomas.erker@univie.ac.at
Abstract – Replacement of the fused aromatic moiety in GW-420867X, a HIV-1
specific nonnucleoside reverse transcriptase inhibitor, with thiophene provided 2-
oxo-1,2,3,4-tetrahydrothieno[2,3-b]pyrazine derivatives. The synthesis starts with the
reaction of 5-acyl-2-chloro-3-nitrothiophene and different amino acid derivatives.
The resulting substitution products are reduced, cyclized and N-acylated to give the
desired compounds (27 – 33).
Remarkable effort has been focused over the past fifteen years on the development of the HIV-1 specific
nonnucleoside reverse transcriptase inhibitors due to their desirable safety, selectivity, and antiviral
profiles, for the treatment of humanimmunodeficiency viruses infection. A number of different structural
classes of nonnucleoside analogues i.e. quinoxaline derivatives, have been identified as potent and highly
specific inhibitors of HIV-1 replication. Moreover, long-term treatment with all of these agents has led to
drug-resistent HIV strains, and primary infections can occur with AZT-resistant HIV strains. The need for
new candidates with improved selectivity and activity for anti-HIV therapy is therefore evident. GW-
420867X,2 a follow-up to the known compound HBY-097,3 is a new member of the quinoxaline class
H
N
H
N
H
N
S
O
O
R1
CH3
S
CH3
R2
H
O
N
CH3
F
N
S
N
O
O
O
O
O
R3
CH3
HBY-097
CH3
CH3
CH3
GW-420867X

of nonnucleoside reverse transcriptase inhibitors with potent antiviral activity (IC50 = 33.5 nM) in vitro in
the presence of human serum.4
A replacement of the benzene nucleus by a thiophene ring might result in a different biochemical profile
and/ or a further elimination of side effects. This research was to prepare the shown thienoanalogous
derivatives.
To realize this project, nucleophilic subtituion reactions with thiophene derivatives had to be studied in
order to select the best reaction conditions.
5-Acetyl-2-chloro-3-nitrothiophene5 (1) was chosen for an initial trial since the acetyl group (another
electron withdrawing substituent) was supposed to support the nucleophilic attack at the aromatic ring.
Furthermore alkyl groups at the 6-position of the bicycle, as observed in various cases,6 should intensify
any biological activity.
1 were stirred with L-alanine methyl ester hydrochloride or L-phenylalanine methyl ester hydrochloride at
room temperature using N,N-dimethylformamide (dried over molecular sieves) as a solvent, until TLC
analysis indicated that all of the starting material was consumed. Beside the desired substitution products
(2 and 3; 15 % and 41% yield) two compounds (4 and 5) in small amounts could also be isolated.
NO2
NO2
H
NO2
Cl
CH3
R
R
O
+
O
CH3
H
N
CH3
CH3
S
O
O
N
H
S
S
O2N
CH3
O
O
O
O
S
1
2: R = methyl
3: R = benzyl
CH3
4: R = methyl
5: R = benzyl
In order to increase the yields of 2 and 3 and to avoid the formation of by-products (4 and 5) other
solvents and reaction temperatures were tried out. The best results (71% and 75%) were achieved by
means of potassium carbonate in dry acetonitrile at 400C. Under these reaction conditiones no traces of
compound (4) or (5) could be dedected.

The surprisingly good results that were reached by a nucleophilic substitution of the chloro atom on the π-
excessive heterocycle were also observed by using other amino acid derivatives. Thus reaction of the
thiophene derivatives (1 and 67) with L-phenylalanine ethyl ester hydrochloride, L-phenylalanine, L-
methionine methyl ester hydrochloride, S-methyl-L-cysteine or glycine ethyl ester hydrochloride gave
compounds (7 – 14).
NO2
H
NO2
Cl
R2
O
R1
N
H
R1
S
S
R3
O
1: R1 = acetyl
6: R1 = benzoyl
7 (93 %): R1 = acetyl
8 (81 %): R1 = acetyl
9 (96 %): R1 = acetyl
10 (86 %): R1 = acetyl
11 (71 %): R1 = acetyl
12 (59 %): R1 = benzoyl R2 = H
13 (29 %): R1 = benzoyl
14 (57 %): R1 = benzoyl
R2 = benzyl
R2 = benzyl
R2 = -CH2-CH2-SCH3 R3 = methyl
R2 = -CH2-SCH3
R2 = H
R3 = ethyl
R3 = H
R3 = H
R3 = ethyl
R3 = ethyl
R3 = methyl
R3 = methyl
R2 = methyl
R2 = benzyl
5- Acetyl-2-chloro-3-nitrothiophene (1) reacted with L-proline in a similar way to give the substitution
product (15) too. Treatment of 1 with L-cystine dimethyl ester dihydrochloride gave not the expected
condensation product but the symmetrical compound (16).
NO2
NO2
O2N
S
CH3
N
H
S
S
S
O
O
CH3
CH3
O
HO
15
O
16
To accomplish the necessary lactam linkage the nitro group of substances (2, 3 and 9 – 15) were reduced
by treatment with iron powder in glacial acetic acid/ water at 70°C. After working up the bicycles (17 -
24) could be isolated. This approach provides a possibility to synthesize till now unknown thieno[2,3-
b]pyrazine-2(1H)-ones.

H
N
NO2
H
O
R2
R1
R2
S
N
H
H
O
R1
N
H
S
R3
O
17 (64 %): R1 = acetyl
18 (81 %): R1 = acetyl
19 (56 %): R1 = acetyl
20 (39 %): R1 = acetyl
21 (50 %): R1 = acetyl
R2 = methyl
R2 = benzyl
R2 = -CH2-CH2-SCH3
R2 = -CH2-SCH3
R2 = H
7 - 14
22 (65 %): R1 = benzoyl R2 = H
R2 = methyl
R2 = benzyl
23 (51 %): R1 = benzoyl
24 (65 %): R1 = benzoyl
Compound (15) had to be esterified to substance (25). After this reduction and cyclisation led to 26.
NO2
H
N
O
CH3
CH3
N
S
H
S
O
N
O
H
CH3
O
O
25
26
The N-acylation of the bicycles (17 – 21 and 23, 24) was initially carried out with acyl chlorides in THF in
the presence of triethylamine. However, higher yields were obtained when the reactions were conducted
without any bases in dry dioxane at 400C.
H
H
N
O
N
O
R1
R1
R2
H
R2
H
S
S
N
N
H
O
R3
17 - 20 and 22 - 24
R2 = methyl
R2 = benzyl
R2 = -CH2-CH2-SCH3 R3 = -OCH=CH2
R2 = -CH2-SCH3
R2 = H
R2 = methyl
R3 = -OCH=CH2
R3 = -OCH=CH2
27 (46 %): R1 = acetyl
28 (61 %): R1 = acetyl
29 (38 %): R1 = acetyl
30 (13 %): R1 = acetyl
31 (38 %): R1 = acetyl
32 (72 %): R1 = benzoyl
33 (58 %): R1 = benzoyl
R3 = -O-isopropyl
R3 = -cyclopropyl
R3 = -OCH=CH2
R3 = -OCH=CH2
R = benzyl
2

EXPERIMENTAL
Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. 1H-NMR and 13C-
NMR spectra were recorded on a Varian UnityPlus 300 spectrometer (using TMS as internal reference, δ
values in ppm). MS spectra were obtained by a Shimadzu QP 5000 or a Hewlett Packard 5970
spectrometer. Analytical TLC was performed on silica gel F254 plates, psc on silica gel F254s plates.
Column chromatography was done on Merck silica gel 60, 0.063- 0.200 mm. Evaporation refers to
evaporation under reduced pressure, and drying of solutions refers to the use of anhydrous sodium sulfate.
Optical rotations were measured on Perkin-Elmer 241 polarimeter at 200C.
General procedure for the synthesis of compounds (2 - 5 and 7 - 15)
To a suspension of the amino acid derivative (8 mmol) and potassium carbonate (2.208 g, 16 mmol) in
absolute acetonitrile (15 mL) 5- acetyl-2-chloro-3-nitrothiophene (0.512 g, 2.5 mmol) was added and the
mixture was stirred under argon atmosphere at rt. After the reaction was completed (TLC analysis) the
organic solvent was removed under reduced pressure. Then the residue was diluted with water and
extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 the solvent was
evaporated.
(2S)-Methyl 2-[(5-acetyl-3-nitro-2-thienyl)amino]propionate (2)
The mixture of 1 (0.512 g, 2.5 mmol) and L-alanine methyl ester hydrochloride (1.117 g, 8 mmol) was
stirred at 400C for 16 h. After crystallization from methanol 2 (483 mg, 71 %) was obtained; mp 79-800C;
[α]D +2.5 0 ( c 1.0, toluene); MS: m/z (rel. int.) 272 (M+, 42), 213 (100), 169 (53), 153 (30); 1H-NMR
(CDCl3, 300 MHz): δ 8.87 (br d, 1H, J = 7.2 Hz, NH), 7.94 (s, 1H, thiophene-H), 4.19 (quint, 1H, J = 7.2
Hz, CH), 3.84 (s, 3H, CH3), 2.48 (s, 3H, CH3), 1.67 (d, 3H, J = 7.2 Hz, CH3); 13C-NMR (CDCl3): δ 210.3,
189.6, 170.6, 162.0, 128.4, 125.6, 55.7, 53.2, 24.9, 17.7; Anal. Calcd for C10H12N2O5S: C, 44.11; H, 4.44;
N, 10.29. Found: C, 44.37; H, 4.26; N, 10.21.
(2S)-Methyl 2-[(5-acetyl-3-nitro-2-thienyl)amino]-3-phenylpropionate (3)
The mixture of 1 (0.512 g, 2.5 mmol) and L-phenylalanine methyl ester hydrochloride (1.725 g, 8 mmol)
was stirred at 400C for 45 h. After crystallization from methanol 3 (653 mg, 75 %) was obtained; mp
1300C; [α]D –28.8 0 ( c 1.0, toluene); MS: m/z (rel. int.) 348 (M+, 51), 289 (23), 257 (46), 91 (100); 1H-
NMR (CDCl3, 300 MHz): δ 8.86–8.77 (m, 1H, NH), 7.89 (s, 1H, thiophene-H), 7.37–7.24 (m, 3H,
phenyl-H), 7.21–7.12 (m, phenyl-H, 2H), 4.40-4.30 (m, 1H, CH), 3.79 (s, 3H, CH3), 3.30 (AB-system,

1H, JAB = 6.0 Hz, benzyl-CH2), 3.24 (AB-system, 1H, JAB = 6.0 Hz, benzyl-CH2), 2.46 (s, 3H, CH3); 13C-
NMR (CDCl3): δ 189.6, 169.3, 162.4, 134.2, 129.1, 129.0, 128.3, 127.8, 124.7, 61.5, 53.0, 37.8, 24.9;
Anal. Calcd for C16H16N2O5S: C, 55.16; H, 4.63; N, 8.04. Found: C, 55.01; H, 4.52; N, 7.91.
Methyl 2-(5-acetyl-3-nitro-2-thienyl)-2-[(5-acetyl-3-nitro-2-thienyl)amino]propionate (4)
The mixture of 1 (0.512 g, 2.5 mmol) and L-alanine methyl ester hydrochloride (1.117 g, 8 mmol) was
stirred in dry DMF (5 mL) at rt for 16 h. After purification on a silica gel column eluting with toluene/
ethyl acetate ( 8 + 2) 4 (66 mg, 6 %) was obtained; mp 230-2320C (ethanol); MS: m/z (rel. int.) 441 (M+,
31), 382 (100); 1H-NMR (CDCl3, 300 MHz): δ 10.28 (s, 1H, NH), 8.12 (s, 1H, thiophene-H), 7.88 (s, 1H,
thiophene-H), 3.88 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.26 (s, 3H, CH3); 13C-NMR
(CDCl3): δ 189.6, 189.1, 169.3, 157.2, 148.0, 144.1, 142.3, 128.4, 128.3, 128.0, 125.2, 62.2, 54.7, 26.2,
25.1, 23.4; Anal. Calcd for C16H15N3O8S2: C, 43.53; H, 3.43; N, 9.52. Found: C, 43.59; H, 3.41; N, 9.30.
Methyl 2-(5-acetyl-3-nitro-2-thienyl)-2-[(5-acetyl-3-nitro-2-thienyl)amino]-2-phenylpropionate (5)
The mixture of 1 (0.512 g, 2.5 mmol) and L-phenylalanine methyl ester hydrochloride (1.726 g, 8 mmol)
was stirred in dry DMF (5 mL) at rt for 24 h. After purification on a silica gel column eluting with
toluene/ ethyl acetate ( 8 + 2) 5 (78 mg, 6 %) was obtained; mp 2290C (ethanol); MS: m/z (rel. int.) 518
(M+, 4), 427 (98), 198 (100), 91 (68); 1H-NMR (CDCl3, 300 MHz): δ 9.97 (br s, 1H, NH), 8.12 (s, 1H,
thiophene-H), 7.96 (s, 1H, thiophene-H), 7.34-7.23 (m, 3H, phenyl-H), 6.95-6.87 (m, 2H, phenyl-H), 4.21
(AB-system, 1H, JAB = 13.1 Hz, benzyl-CH2), 3.72 (AB-system, 1H, JAB = 13.1 Hz, benzyl-CH2), 3.78 (s,
3H, CH3), 2.66 (s, 3H, CH3), 2.46 (s, 3H, CH3); 13C-NMR (CDCl3): δ 189.6, 189.1, 166.9, 157.1, 147.0,
144.7, 142.7, 131.8, 129.6, 128.9, 128.7, 128.3, 128.2, 128.1, 125.6, 66.8, 54.2, 40.8, 26.3, 25.2; Anal.
Calcd for C22H19N3O8S2: C, 51.06; H, 3.70; N, 8.12. Found: C, 50.86; H, 3.74; N, 7.91.
(2S)-Ethyl 2-[(5-acetyl-3-nitro-2-thienyl)amino]-3-phenylpropionate (7)
The mixture of 1 (0.512 g, 2.5 mmol) and L-phenylalanine ethyl ester hydrochloride (1.837 g, 8 mmol)
was stirred at 400C for 48 h. After crystallization from ethanol 6 (842 mg, 93 %) was obtained; mp 930C;
[α]D –46.0 0 ( c 1.0, toluene); MS: m/z (rel. int.) 362 (M+, 45), 289 (31), 271 (42), 91 (100); 1H-NMR
(CDCl3, 300 MHz): δ 8.85 (d, 1H, J = 7.9 Hz, NH), 7.89 (s, 1H, thiophene-H), 7.38–7.11 (m, 5H, phenyl-
H), 4.38-4.29 (m, 1H, CH), 4.24 (q, 2H, J = 6.2 Hz, CH3), 3.35 (AB-system, 1H, JAB = 6.2 Hz, benzyl-
CH2), 3.24 (AB-system, 1H, JAB = 6.2 Hz, benzyl-CH2), 2.45 (s, 3H, CH3), 1.26 (t, 3H, J = 7.1 Hz, CH3);
13C-NMR (CDCl3): δ 189.5, 168.8, 162.3, 134.2, 129.1, 128.9, 127.7, 126.8, 124.5, 62.4, 61.5, 37.8, 24.9,
13.9; Anal. Calcd for C17H18N2O5S: C, 56.34; H, 5.01; N, 7.73. Found: C, 56.21; H, 5.00; N, 7.65.

(2S)-2-[(5-Acetyl-3-nitro-2-thienyl)amino]-3-phenylpropionic acid (8)
The mixture of 1 (0.512 g, 2.5 mmol) and L-phenylalanine (1.322 g, 8 mmol) was stirred at rt for 5 d.
After crystallization from ethanol 8 (676 mg, 81 %) was obtained; mp 2330C; [α]D –48.6 0 ( c 1.0,
methanol); MS: m/z (rel. int.) 334 (M+, 31), 289 (18), 288 (49), 241 (100); 1H-NMR (CDCl3, 300 MHz):
δ 8.85 (d, 1H, J = 7.9 Hz, NH), 8.75 (s, 1H, OH), 7.89 (s, 1H, thiophene-H), 7.42–7.07 (m, 5H, phenyl-H),
4.45-4.31 (m, 1H, CH), 3.49-3.34 (m, 1H, benzyl-CH2), 3.32-3.20 (m, 1H, benzyl-CH2), 2.44 (s, 3H,
CH3); 13C-NMR (CDCl3): δ 190.5, 172.6, 162.7, 134.1, 129.2, 129.0, 128.8, 127.8, 127.0, 124.3, 61.3,
37.5, 24.9; Anal. Calcd for C15H14N2O5S: C, 53.89; H, 4.22; N, 8.38. Found: C, 53.73; H, 4.11; N, 8.15.
(2S)-Methyl (5-acetyl-3-nitro-2-thienyl)aminomethylsulfanylethylacetate (9)
The mixture of 1 (0. 512g, 2.5 mmol) and L-methionine methyl ester hydrochloride (1.598 g, 8 mmol)
was stirred at rt for 4 d. After purification on a silica gel column eluting with toluene/ ethyl acetate ( 8 +
2) 9 (797 mg, 96 %) was obtained as an oil; [α]D –41.7 0 ( c 0.8, acetone); MS: m/z (rel. int.) 332 (M+, 16),
273 (33), 170 (59), 62 (100); 1H-NMR (CDCl3, 300 MHz): δ 8.90 (d, 1H, J = 8.3 Hz, NH), 7.94 (s, 1H,
thiophene-H), 4.44-4.34 (m, 1H, CH), 3.84 (s, 3H, CH3), 2.72-2.53 (m, 2H, CH2), 2.49 (s, 3H, CH3), 2.44-
2.17 (m, 2H, CH2), 2.12 (s, 3H, CH3); 13C-NMR (CDCl3): δ 189.6, 169.9, 162.6, 128.3, 127.0, 124.8,
59.1, 53.2, 30.8, 29.7, 24.9, 15.4; Anal. Calcd for C12H16N2O5S: C, 43.36; H, 4.85; N, 8.43. Found: C,
43.58; H, 4.70; N, 8.28.
(2S)-2-[(5-Acetyl-3-nitro-2-thienyl)amino]-3-(methylsulfanyl)propionic acid (10)
The mixture of 1 (0.512 g, 2.5 mmol) and S-methyl-L-cysteine (1.082 g, 8 mmol) was stirred at 400C for
4 d. After purification on a silica gel column eluting with methanol/ ethyl acetate ( 3 + 7) 10 (654 mg,
86 %) was obtained; mp 1500C (diluted ethanol); [α]D –13.3 0 ( c 0.8, methanol); MS: m/z (rel. int.) 304
(M+, 100), 181 (100); 1H-NMR (DMSO-d6/ CDCl3, 300 MHz): δ 9.51 (d, 1H, J = 6.9 Hz, NH), 7.97 (s,
1H, thiophene-H), 4.11-4.07 (m, 1H, CH), 3.89 (br s, 1H, OH), 3.18 (m, 2H, CH2), 2.45 (s, 3H, CH3),
2.02 (s, 3H, CH3); 13C-NMR (CDCl3): δ 188.1, 170.4, 161.2, 127.5, 124.8, 121.8, 61.1, 34.6, 23.6, 15.0;
Anal. Calcd for C10H12N2O5S2: C, 39.47; H, 3.97; N, 9.20. Found: C, 39.15; H, 3.93; N, 8.88.
Ethyl (5-acetyl-3-nitro-2-thienyl)aminoacetate (11)
The mixture of 1 (0.512 g, 2.5 mmol) and glycine ethyl ester hydrochloride (1.117 g, 8 mmol) was stirred
at 400C for 18 h. After crystallization from ethanol 11 (483 mg, 71 %) was obtained; mp 1650C; MS: m/z
(rel. int.) 272 (M+, 1), 227 (11), 44 (100); 1H-NMR (CDCl3, 300 MHz): δ 8.86 (br s, 1H, NH), 7.95 (s,
1H, thiophene-H), 4.33 (q, 2H, J = 7.1 Hz, CH2), 4.14 (d, 2H, J = 5.3 Hz, CH2), 2.49 (s, 3H, CH3), 1.35 (t,

3H, J = 7.1 Hz, CH3); 13C-NMR (CDCl3): δ 189.7, 166.9, 162.8, 128.4, 126.7, 124.7, 62.5, 48.1, 24.9,
14.0; Anal. Calcd for C10H12N2O5S: C, 44.11; H, 4.44; N, 10.29. Found: C, 44.35; H, 4.20; N, 10.22.
Ethyl (5-benzoyl-3-nitro-2-thienyl)aminoacetate (12)
The mixture of 1 (0.512 g, 2.5 mmol) and glycine ethyl ester hydrochloride (1.117 g, 8 mmol) was stirred
at 400C for 4 h. After crystallization from ethanol 12 (493 mg, 59 %) was obtained; mp 1270C; MS: m/z
(rel. int.) 334 (M+, 20), 261 (15), 105 (49), 69 (100); 1H-NMR (CDCl3, 300 MHz): δ 8.92 (br s, 1H, NH),
7.89 (s, 1H, thiophene-H), 7.83-7.75 (m, 2H, phenyl-H), 7.66-7.47 (m, 3H, phenyl-H), 4.34 (q, 2H, J = 7.1
Hz, CH2), 4.19 (d, 2H, J = 5.3 Hz, CH2), 1.35 (t, 3H, J = 7.1 Hz, CH3); 13C-NMR (CDCl3): δ 186.9,
166.9, 162.9, 136.4, 132.5, 130.7, 128.7, 127.1, 124.3, 62.6, 48.2, 14.1; Anal. Calcd for C15H14N2O5S: C,
53.89; H, 4.22; N, 8.38. Found: C, 53.73; H, 4.20; N, 8.38.
(2S)-Methyl 2-[(5-benzoyl-3-nitro-2-thienyl)amino]propionate (13)
The mixture of 1 (0.512 g, 2.5 mmol) and L-alanine methyl ester hydrochloride (1.117 g, 8 mmol) was
stirred at 400C for 6 h. After purification on a silica gel column eluting with toluene/ ethyl acetate ( 8 + 2)
13 (242 mg, 29 %) as an oil was obtained; [α]D –8.0 0 ( c 0.6, methanol); MS: m/z (rel. int.) 334 (M+,
100), 275 (65), 105 (3); 1H-NMR (CDCl3, 300 MHz): δ 8.94 (d, 1H, J = 7.7 Hz, NH), 7.88 (s, 1H,
thiophene-H), 7.83-7.76 (m, 2H, phenyl-H), 7.66-7.46 (m, 3H, phenyl-H), 4.27 (quint, 1H, J = 7.1 Hz,
CH), 3.86 (s, 3H, CH3), 1.70 (d, 3H, J = 7.1 Hz, CH3); 13C-NMR (CDCl3): δ 186.8, 170.6, 163.1, 136.5,
132.5, 130.7, 128.7, 128.6, 127.2, 124.1, 55.8, 53.2, 17.8; Anal. Calcd for C15H14N2O5S: C, 53.89; H,
4.22; N, 8.38. Found: C, 53.70; H, 4.12; N, 8.32.
(2S)-Methyl 2-[(5-benzoyl-3-nitro-2-thienyl)amino]-3-phenylpropionate (14)
The mixture of 1 (0.512 g, 2.5 mmol) and L-phenylalanine methyl ester hydrochloride (1.726 g, 8 mmol)
was stirred at 400C for 46 h. After crystallization from methanol 14 (584 mg, 57 %) was obtained; mp
116-1170C; [α]D –35.0 0 ( c 0.55, toluene); MS: m/z (rel. int.) 410 (M+, 3), 231 (8), 105 (81), 77 (100); 1H-
NMR (CDCl3, 300 MHz): δ 8.96-8.81 (m, 1H, NH), 7.83 (s, 1H, thiophene-H), 7.80-7.73 (m, 2H, phenyl-
H), 7.64-7.44 (m, 3H, phenyl-H), 7.39-7.25 (m, 3H, phenyl-H), 7.23-7.19 (m, 2H, phenyl-H), 4.49-4.36
(m, 1H, CH), 3.80 (s, 3H, CH3), 3.39 (AB-system, 1H, JAB = 14 Hz, benzyl-CH2), 3.28 (AB-system, 1H,
JAB = 14 Hz, benzyl-CH2); 13C-NMR (CDCl3): δ 186.8, 169.3, 162.4, 136.4, 134.2, 132.5, 130.6, 129.1,
129.0, 128.7, 128.6, 127.8, 127.3, 124.1, 61.6, 53.0, 37.8; Anal. Calcd for C21H18N2O5S: C, 61.45; H,
4.42; N, 6.83. Found: C, 61.34; H, 4.32; N, 6.92.

(2S)-1-(5-Acetyl-3-nitro-2-thienyl)-2-pyrrolidinecarboxylic acid (15)
The mixture of 1 (0.512 g, 2.5 mmol) and L-proline (920 mg, 8 mmol) was stirred at rt for 20 h. After
crystallization from diluted ethanol 15 (554 mg, 78 %) was obtained; mp 1000C; [α]D –427.5 0 ( c 1.0,
methanol); MS: m/z (rel. int.) 284 (M+, 31), 239 (100); 1H-NMR (DMSO-d6, 300 MHz): δ 13.17 (br s,
1H, OH), 8.26 (s, 1H, thiophene-H), 4.89-4.80 (m, 1H, proline-CH), 3.79-3.66 (m, 1H, proline-CH2),
3.64-3.53 (m, 1H, proline-CH2), 2.52 (s, 3H, CH3), 2.19-2.02 (m, 4H, proline-CH2); 13C-NMR (CDCl3): δ
189.3, 171.8, 160.3, 130.9, 128.0, 123.9, 65.4, 55.9, 31.3, 24.6, 23.8; Anal. Calcd for C12H16N2O5S x 1
H2O: C, 43.70; H, 4.67; N, 9.27. Found: C, 43.73; H, 4.43; N, 9.12.
’
1,1 -[Thiobis(3-nitro-2,5-thiophendiyl)]bis-(1-ethanone) (16)
To a suspension of L-cystine dimethyl ester dihydrochloride (2.730 g, 8 mmol) and potassium carbonate
(2.208 g, 16 mmol) in absolute acetonitrile (15 mL) 5- acetyl-2-chloro-3-nitrothiophene (0.512 g, 2.5
mmol) was added and the mixtuture was stirred under argon atmosphere. After the reaction was
completed (TLC analysis) the organic solvent was removed under reduced pressure. Then the residue was
diluted with water and extracted with ethyl acetate. The combined organic layers were dried and the
solvent was evaporated. After crystallization from methanol 16 (177 mg, 38 %) was obtained; mp 1900C;
MS: m/z (rel. int.) 372 (M+, 74), 186 (100); 1H-NMR (CDCl3, 300 MHz): δ 8.18 (s, 1H, thiophene-H),
2.61 (s, 3H, CH3); Anal. Calcd for C12H8N2O6S3: C, 38.71; H, 2.17; N, 7.52. Found: C, 38.61; H, 2.04; N,
7.22.
General procedure for the synthesis of compounds (17 – 24 and 26)
Iron powder (1.562 g) was added in small portions to a suspension of the amino acid derivative (4 mmol)
in glacial acetic acid (14 mL) and water (1.5 mL). Then the reaction mixture was heated at 700C for 1.5 h,
filtered in hot, washed with water and allowed to cool. The resulting precipitate was filtered off and
recrystallized.
(3S)-6-Acetyl-3-methyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (17)
After crystallization from methanol 17 (537 mg, 64 %) was obtained; mp 2400C (decomp); [α]D –56.9 0 (c
0.5, DMSO); MS: m/z (rel. int.) 210 (M+, 15), 195 (99), 167 (100); 1H-NMR (DMSO-d6, 300 MHz): δ
10.37 (br s, 1H, NH), 7.64 (br s, 1H, NH), 7.19 (s, 1H, thiophene-H), 4.08 (dq, 1H, J = 1.5 Hz, J = 6.6 Hz,
CH), 2.37 (s, 3H, CH3), 1.36 (d, 3H, J = 6.6 Hz, CH3); 13C-NMR (CDCl3/ DMSO-d6): δ 185.9, 164.6,
142.3, 122.6, 121.2, 119.1, 51.2, 23.6, 16.8; Anal. Calcd for C9H10N2O2S: C, 51.41; H, 4.79; N, 13.32.
Found: C, 51.55; H, 4.68; N, 13.19.

(3S)-6-Acetyl-3-benzyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (18)
After crystallization from methanol 18 (927 mg, 81 %) was obtained; mp 2100C; [α]D +199.4 0 ( c 1.0,
DMSO); MS: m/z (rel. int.) 286 (M+, 15), 195 (100), 91 (18); 1H-NMR (DMSO-d6, 300 MHz): δ 10.42
(br s, 1H, NH), 7.62 (br s, 1H, NH), 7.41-7.19 (m, 5H, phenyl-H), 7.17 (s, 1H, thiophene-H), 4.36 (br s,
1H, CH), 3.04 (s, 2H, CH2), 2.33 (s, 3H, CH3); 13C-NMR (DMSO-d6): δ 186.9, 164.3, 143.0, 136.6,
129.6, 128.1, 126.4, 123.5, 122.3, 119.6, 57.7, 38.0, 24.9; Anal. Calcd for C15H14N2O2S x 0.25 methanol:
C, 62.23; H, 5.14; N, 9.52. Found: C, 62.06; H, 4.85; N, 9.61.
(3S)-6-Acetyl-3-[(2-methylsulfanyl)ethyl]-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (19)
After crystallization from methanol 19 (605 mg, 56 %) was obtained; mp 150-1520C; [α]D +98.6 0 ( c 0.5,
DMSO); MS: m/z (rel. int.) 270 (M+, 100), 222 (63), 195 (97); 1H-NMR (DMSO-d6, 300 MHz): δ 10.44
(br s, 1H, NH), 7.70 (br s, 1H, NH), 7.17 (s, 1H, thiophene-H), 4.17-4.07 (m, 1H, CH), 2.69-2.54 (m, 2H,
CH2), 2.35 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.02-1.89 (m, 2H, CH2); 13C-NMR (DMSO-d6): δ 187.2,
164.6. 142.7, 123.7, 122.5, 119.8, 55.3, 31.3, 28.7, 25.0, 14.4; Anal. Calcd for C11H14N2O2S2: C, 48.87;
H, 5.22; N, 10.36. Found: C, 48.66; H, 5.06; N, 10.09.
(3S)-6-Acetyl-3-[(methylsulfanyl)methyl]-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (20)
After crystallization from methanol 20 (399 mg, 39 %) was obtained; mp 1830C; [α]D +83.2 0 ( c 0.5,
DMSO); MS: m/z (rel. int.) 256 (M+, 28), 195 (100); 1H-NMR (DMSO-d6, 300 MHz): δ 10.53 (br s, 1H,
NH), 7.83 (br s, 1H, NH), 7.16 (s, 1H, thiophene-H), 4.40-4.29 (m, 1H, CH), 3.01-2.82 (m, 2H, CH2),
2.36 (s, 3H, CH3), 2.17 (s, 3H, CH3); 13C-NMR (DMSO-d6): δ 187.0, 163.8, 142.9, 123.4, 122.5, 119.5,
56.4, 37.0, 25.0, 15.9; Anal. Calcd for C10H12N2O2S2: C, 46.86; H, 4.72; N, 10.93. Found: C, 46.93; H,
4.57 N, 10.66.
6-Acetyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (21)
After crystallization from methanol 21 (392 mg, 50 %) was obtained; mp 240 0C (decomp); MS: m/z (rel.
int.) 196 (M+, 11), 179 (6), 69 (10), 44 (100); 1H-NMR (DMSO-d6, 300 MHz): δ 10.37 (br s, 1H, NH),
7.53 (br s, 1H, NH), 7.15 (s, 1H, thiophene-H), 3.97 (m, 2H, CH2), 2.33 (s, 3H, CH3); 13C-NMR (DMSO-
d6): δ 186.9, 163.1, 143.9, 123.2, 122.6, 120.1, 46.6, 25.9; Anal. Calcd for C8H8N2O2S: C, 48.97; H, 4.11;
N, 14.28. Found: C, 46.14; H, 3.99; N, 14.21.
6-Benzoyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (22)
After crystallization from ethanol 22 (671 mg, 65 %) was obtained; mp 215 0C; MS: m/z (rel. int.) 258

(M+, 57), 256 (44), 105 (100), 77 (99); 1H-NMR (DMSO-d6, 300 MHz): δ 10.31 (br s, 1H, NH), 7.90 (br
s, 1H, NH), 7.80-7.45 (m, 5H, phenyl-H ), 7.00 (s, 1H, thiophene-H), 4.07 (s, 2H, CH2); 13C-NMR
(DMSO-d6): δ 184.1, 162.7, 145.6, 138.8, 130.9, 128.4, 127.9, 124.5, 121.8, 120.7, 46.5; Anal. Calcd for
C13H10N2O2S: C, 60.45; H, 3.90; N, 10.85. Found: C, 60.19; H, 3.95; N, 10.56.
(3S)-6-Benzoyl-3-methyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (23)
After crystallization from ethanol 23 (555 mg, 51 %) was obtained; mp 240 0C (decomp); [α]D -60.0 0 ( c
0.5, DMSO); MS: m/z (rel. int.) 272 (M+, 10), 229 (21), 105 (58), 77 (100); 1H-NMR (DMSO-d6, 300
MHz): δ 10.29 (br s, 1H, NH), 7.98 (br s, 1H, NH), 7.83-7.50 (m, 5H, phenyl-H ), 7.02 (s, 1H, thiophene-
H), 4.17 (d, 1H, J = 6.4 Hz, CH), 1.40 (d, 2H, J = 6.4 Hz, CH3); 13C-NMR (DMSO-d6): δ 184.3, 165.3,
144.9, 138.7, 130.9, 128.4, 127.9, 124.5, 122.4, 120.9, 52.1, 18.2; Anal. Calcd for C14H12N2O2S: C,
61.75; H, 4.44; N, 10.29. Found: C, 61.53; H, 4.57; N, 10.14.
(3S)-6-Benzoyl-3-benzyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (24)
After crystallization from diluted ethanol 24 (905 mg, 65 %) was obtained; mp 190 0C; [α]D -46.0 0 ( c
0.5, DMSO); MS: m/z (rel. int.) 348 (M+, 8), 257 (100), 105 (65), 91 (29); 1H-NMR (DMSO-d6, 300
MHz): δ 10.31 (br s, 1H, NH), 7.95 (br s, 1H, NH), 7.77-7.50 (m, 5H, phenyl-H ), 7.46-7.19 (m, 5H,
phenyl-H ), 6.89 (s, 1H, thiophene-H), 4.46 (s, 1H, CH), 3.07 (s, 2H, CH2); 13C-NMR (DMSO-d6): δ
184.1, 164.0, 144.9, 138.8, 136.4, 130.9, 129.7, 128.3, 128.1, 127.9, 126.5, 124.2, 122.1, 120.3, 57.7,
38.3; Anal. Calcd for C20H16N2O2S: C, 68.95; H, 4.63; N, 8.04. Found: C, 68.69; H, 4.66; N, 8.07.
(2S)-Methyl 1-(5-acetyl-3-nitro-2-thienyl)-2-pyrrolidinecarboxylate (25)
A solution of compound (15) (1.136 g, 4 mmol) in methanol (10 mL) and 2 drops of concentrated sulfuric
acid was refluxed for 20 h. After the reaction was completed (TLC analysis) the organic solvent was
removed under reduced pressure. Then the residue was diluted with water and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. After
crystallization from methanol 25 (858 mg, 72 %) was obtained; mp 97-980C; [α]D –420.1 0 ( c 1.0,
acetone); MS: m/z (rel. int.) 298 (M+, 20), 239 (100); 1H-NMR (CDCl3, 300 MHz): δ 7.97 (s, 1H,
thiophene-H), 4.99-4.92 (m, 1H, proline-CH), 3.73 (s, 3H, CH3), 3.82-3.71 (m, 1H, proline-H), 3.61-3.51
(m, 1H, proline-H), 2.52 (s, 3H, CH3), 2.56-2.41 (m, 1H, proline-H); 2.28-2.06 (m, 3H, proline-H); 13C-
NMR (CDCl3): δ 189.5, 170.9, 160.4, 131.0, 128.3, 124.7, 65.4, 56.0, 52.7, 31.5, 24.9, 23.9; Anal. Calcd
for C121H14N2O5S: C, 48.32; H, 4.73; N, 9.39. Found: C, 48.17; H, 4.58; N, 9.24.

(5aS)-2-Acetyl-5a, 6, 7, 8-tetrahydropyrrolo[1,2-a]thieno[3,2-e]pyrazin-5(4H)-one (26)
After crystallization from diluted ethanol 26 (642 mg, 68 %) was obtained; mp 205-210 0C (decomp);
[α]D -486.6 0 ( c 0.5, DMSO); MS: m/z (rel. int.) 236 (M+, 100), 193 (12), 165 (66); 1H-NMR (DMSO-d6,
300 MHz): δ 10.34 (br s, 1H, NH), 7.14 (s, 1H, thiophene-H), 4.10-4.01 (m, 1H, CH), 3.53-3.38 (m, 2H,
CH2), 2.39-2.29 (m, 1H, CH), 2.35 (s, 3H, CH3), 2.17-1.99 (m, 3H, CH/ CH2); 13C-NMR (DMSO-d6): δ
186.1, 162.3, 143.0, 123.7, 121.2, 119.6, 60.0, 49.2, 27.3, 23.9, 22.1; Anal. Calcd for C11H12N2O2S: C,
55.92; H, 5.12; N, 11.86. Found: C, 55.55; H, 5.00; N, 11.65.
General procedure for the synthesis of compounds (27 – 33)
To a solution of the corresponding lactam (17 – 21 and 23, 24) (4 mmol) in dry 1,4-dioxane (15 mL) the
acyl chloride derivative (8 mmol) was added. Then the reaction mixture was heated at 400C for 24 h.
After the reaction was completed (TLC analysis) the organic solvent was removed under reduced
pressure. Then the residue was diluted with water and extracted with ethyl acetate. The combined organic
layers were dried over Na2SO4 and the solvent was evaporated.
(3S)-Vinyl 6-acetyl-3-methyl-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-b]pyrazine-4-carboxylate (27)
After crystallization from methanol 27 (515 mg, 46 %) was obtained; mp 1620C; [α]D +184.1 0 ( c 1.0,
acetone); MS: m/z (rel. int.) 280 (M+, 100), 209 (36), 71 (33); 1H-NMR (CDCl3, 300 MHz): δ 10.34-10.12
(m, 1H, NH), 7.36-7.15 (m, 2H, thiophene-H/ vinyl-H), 5.21-4.95 (m, 2H, vinyl-CH2), 4.73 (dd, 1H, J =
12.2 Hz, J = 6.2 Hz, CH), 2.51 (s, 3H, CH3), 1.59-1.38 (m, 3H, CH3); 13C-NMR (CDCl3): δ 190.3, 167.6,
149.5, 141.3, 135.1, 127.8, 123.9, 120.0, 98.8, 54.9, 26.1, 17.6; Anal. Calcd for C12H12N2O4S: C, 51.42;
H, 4.32; N, 9.99. Found: C, 51.45; H, 4.35; N, 9.93.
(3S)-Vinyl 6-acetyl-3-benzyl-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-b]pyrazine-4-carboxylate (28)
After crystallization from acetone / water 28 (870 mg, 61 %) was obtained; mp 800C; [α]D +125.9 0 ( c
1.0, toluene); MS: m/z (rel. int.) 356 (M+, 34), 265 (34), 195 (100); 1H-NMR (CDCl3, 300 MHz): δ 9.86-
9.68 (m, 1H, NH), 7.31-7.05 (m, 6H, thiophene-H/ phenyl-H), 6.74 (dd, 1H, J = 6.2 Hz, J = 13.7 Hz, CH),
5.24-5.17 (m, 1H, CH), 4.66 (dd, 1H, J = 2.3 Hz, J = 13.7 Hz, CH), 4.46 (dd, 1H, J = 2.3 Hz, J = 6.2 Hz,
CH), 3.20-3.12 (m, 1H, benzyl-CH2), 3.00-2.91 (m, 1H, benzyl-CH2), 2.52 (s, 3H, CH3); 13C-NMR
(CDCl3): δ 190.2, 166.6, 149.8, 140.8, 135.6, 134.2, 129.3, 128.6, 127.5, 124.4, 119.9, 98.2, 60.2, 37.4,
26.2; Anal. Calcd for C18H16N2O4S: C, 60.66; H, 4.53; N, 7.86. Found: C, 60.58; H, 4.43; N, 7.60.
(3S)-Vinyl 6-acetyl-3-[2-methylsulfanyl)ethyl]-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-b]pyrazine-4-
carboxylate (29)

After purification on a silica gel column eluting with toluene/ ethyl acetate ( 2 + 8) 29 (517 mg, 38 %)
was obtained as an oil; [α]D +220.2 0 ( c 1.0, toluene); MS: m/z (rel. int.) 340 (M+, 75), 266 (61), 221
(100); 1H-NMR (CDCl3, 300 MHz): δ 10.20-9.97 (m, 1H, NH), 7.33-7.16 (m, 2H, thiophene-H/ vinyl-H),
5.25-4.99 (m, 2H, CH2), 4.76-4.71 (m, 1H, CH), 2.62-2.47 (m, 5H, CH3/ CH2), 2.09 (s, 5H, CH3/ CH2);
13C-NMR (CDCl3): δ 190.2, 166.4, 149.7, 141.2, 135.6, 128.0, 124.4, 119.9, 98.7, 57.8, 31.2, 29.5, 26.1,
15.4; Anal. Calcd for C14H16N2O4S2: C, 49.40; H, 4.74; N, 8.23. Found: C, 49.29; H, 4.66; N, 8.02.
(3S)-Isopropyl 6-acetyl-3-[2-methylsulfanyl)methyl]-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-
b]pyrazine-4-carboxylate (30)
After purification on a silica gel column eluting with toluene/ ethyl acetate ( 2 + 8) 30 (172 mg, 13 %)
was obtained as an oil; MS: m/z (rel. int.) 342 (M+, 32), 195 (100), 61 (64); 1H-NMR (CDCl3, 300 MHz):
δ 10.18-9.99 (m, 1H, NH), 7.34-7.19 (m, 2H, thiophene-H), 5.28-5.00 (m, 2H, 2 CH), 2.89-2.68 (m, 2H,
CH2), 2.50 (s, 3H, CH3), 2.12 (m, 3H, CH3), 1.52-1.23 (m, 6H, 2 CH3); 13C-NMR (CDCl3): δ 190.2,
166.7, 152.1, 134.5, 129.4, 123.4, 119.8, 72.3, 57.4, 36.1, 26.1, 21.8, 16.6; Anal. Calcd for C14H18N2O4S2:
C, 49.11; H, 5.30; N, 8.18. Found: C, 49.21; H, 5.17; N, 8.07.
6-Acetyl-4-cyclopropylcarbonyl-3, 4-dihydrothieno[2,3-b]pyrazin-2(1H)-one (31)
After crystallization from diluted ethanol 31 (402 mg, 38 %) was obtained; mp 2600C (decomp); MS: m/z
(rel. int.) 264 (M+, 5), 196 (23), 69 (100); 1H-NMR (DMSO-d6, 300 MHz): δ 10.91 (m, 1H, NH), 7.32 (s,
1H, thiophene-H), 4.91 (s, 2H, CH2), 2.49 (s, 3H, CH3), 2.29-2.17 (m, 1H, CH), 1.08-0.97 (m, 4H, 2
CH2); 13C-NMR (DMSO-d6): δ 190.3, 171.4, 162.9, 132.2, 127.3, 124.1, 120.3, 48.5, 26.0, 11.4, 8.9;
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found: C, 54.53; H, 4.55; N, 10.34.
(3S)-Vinyl 6-benzoyl-3-methyl-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-b]pyrazine-4-carboxylate (32)
After purification on a silica gel column eluting with toluene/ ethyl acetate (6 + 4) 30 (986 mg, 72 %) was
obtained as an oil; [α]D +233.7 0 ( c 0.4, toluene); MS: m/z (rel. int.) 342 (M+, 9), 271 (12), 105 (100); 1H-
NMR (CDCl3, 300 MHz): δ 9.91 (s, 1H, NH), 7.81 (s, 1H, thiophene-H), 7.90-7.71 (m, 1H, vinyl-CH),
7.64-7.41 (m, 3H, phenyl-H), 7.33-7.11 (m, 2H, phenyl-H), 5.19-4.94 (m, 2H, vinyl-CH2), 4.73-4.67 (m,
1H, CH), 1.59 (m, 3H, CH3); 13C-NMR (CDCl3): δ 187.7, 167.4, 149.6, 141.4, 137.7, 134.3, 132.2, 128.8,
128.5, 123.9, 122.3, 98.7, 55.1, 17.8; Anal. Calcd for C17H14N2O4S: C, 59.64; H, 4.12; N, 8.18. Found: C,
59.45; H, 4.35; N, 8.03.
(3S)-Vinyl 6-benzoyl-3-benzyl-2-oxo-1, 2, 3, 4-tetrahydrothieno[2,3-b]pyrazine-4-carboxylate (33)
After purification on a silica gel column eluting with toluene/ ethyl acetate (6 + 4) 30 (971 mg, 58 %) was

obtained as an oil; [α]D +105.2 0 ( c 1.0, toluene); MS: m/z (rel. int.) 418 (M+, 6), 179 (1), 105 (100); 1H-
NMR (CDCl3, 300 MHz): δ 10.08-9.92 (m, 1H, NH), 7.80 (s, 1H, thiophene-H), 7.90-7.68 (m, 1H, vinyl-
H), 7.63-7.42 (m, 4H, phenyl-H), 7.29-7.04 (m, 6H, phenyl-H), 5.32-5.03 (m, 1H, CH), 4.72-4.40 (m, 2H,
CH2), 3.20-2.90 (m, 2H, CH2); 13C-NMR (CDCl3): δ 187.7, 166.4, 149.8, 140.8, 137.7, 134.7, 134.3,
132.1, 129.3, 128.9, 128.8, 128.6, 128.5, 127.4, 124.5, 98.3, 60.2, 37.6; Anal. Calcd for C23H18N2O4S: C,
66.02; H, 4.34; N, 6.69. Found: C, 66.29; H, 4.47; N, 6.55.
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C. D. Hurd and K. L. Kreuz, J. Am. Chem. Soc, 1952, 74, 2965.
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