Synthesis and anti-HIV activity of new homo acyclic nucleosides, 1-(pent-4-enyl)quinoxalin-2-ones and 2-(pent-4-enyloxy)quinoxalines

Article abstract of DOI:10.1007/s10593-007-0164-0

A series of acyclonucleosides 6,7-disubstituted 1-(pent-4-enyl)quinoxalin- 2-one derivatives and the O-analogs were synthesized by a one-step condensation of the corresponding quinoxaline bases with 5-bromo-1-pentene.The acyclonucleosides prepared were as

Full text of DOI:10.1007/s10593-007-0164-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 8, 2007
SYNTHESIS AND ANTI-HIV ACTIVITY
OF NEW HOMO ACYCLIC NUCLEOSIDES,
1-(PENT-4-ENYL)QUINOXALIN-2-ONES
AND 2-(PENT-4-ENYLOXY)QUINOXALINES
I. A. I. Ali1, I. A. Al-Masoudi2, H. Gh. Hassan3, N. A. Al-Masoudi4
A series of acyclonucleosides 6,7-disubstituted 1-(pent-4-enyl)quinoxalin-2-one derivatives and the
O-analogs were synthesized by a one-step condensation of the corresponding quinoxaline bases with
5-bromo-1-pentene.The acyclonucleosides prepared were assayed against HIV-1 and HIV-2 in MT-4
cells. 6,7-Dimethyl-2-(pent-4-enyloxy)quinoxaline showed inhibition of HIV-1 with EC50 value of
0.22 ± 0.08 µg/ml and a therapeutic index of 13. This means that it was cytotoxic to MT-4 cells at CC50
of 2.6 ± 0.1 µg/ml.
Keywords: acyclonucleosides, glycosides, quinoxalines, alkylation, antiviral activity.
The use of acyclonucleoside analogs as antiviral chemotherapeutic agents has stimulated extensive
research in the synthesis of this class of compounds [1-4]. The discovery of acyclovir (Zovirax®) [5, 6] as a
potent antiherpetic drug [7-9] was followed by a great number of chemical analogs of acyclovir such as (RS)-9-
[4-hydroxy-2-(hydroxymethyl)butyl]guanine (HBG) (1), 9-[(1,3-dihydroxy- 2-propoxy)methyl]guanine (DHPG) 2
[10, 11], 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and (S)-1-(3-hydroxy-2-phosphonylmethoxy-
propyl)adenine (HPMPA) [12] derivatives. Structure−activity relationship studies have shown that the side
chains of acyclonucleosides play a crucial role in the interaction of the acyclonucleosides with their antiviral
target enzymes [13] (phosphorylation). The orientation of the heterocyclic base about the glycosidic bond in
nucleosides is an important conformational parameter, and has been clearly delineated in a variety of enzymatic
reactions [14]. These studies prompted us to use the 1,2-dihydroquinoxalone as nucleobase carrying alkyl side
chains at N and O atoms, since some quinoxaline derivatives showed a remarkable biological activity [15, 16].
The pharmacological applications of quinoxalines include their use as angiotension II receptor antagonists [17],
N-methyl-D-aspartate (NMDA) antagonists [18], anti-inflammatory [19], antidepressant-tranquilizing [20, 21],
antitumor agents [22, 23], as well as the agents against hepatitis B virus (HBV) [24].
Recently, Ali and Fathalla [25] have reported the regioselective alkylation of quinoxalines with allyl
bromide in the presence of NaH to give a mixture of O- and N-allyl-substituted quinoxalines 3 (27-33%) and
__________________________________________________________________________________________
2
1Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt. College of
3
Veterinary Medicine, University of Basrah, Basrah, Iraq. College of Science, Department of Chemistry,
4
University of Sulaimania, Iraq. Fachbereich Chemie, Universität Konstanz, Postfach 5560, D-78457 Konstanz,
Germany, Formerly (Corresponding author); e-mail: Najim.Al-Masoudi@gmx.de. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 8, pp. 1243-1250, August, 2007. Original article submitted August 9, 2006.
In revised from January 4, 2007.
1052
0009-3122/07/4308-1052©2007 Springer Science+Business Media, Inc.

4 (56-72%), respectively, as promising antiviral acyclic N-nucleosides. As an on-going program for the synthesis
of acyclonucleosides [26-28] we report here the synthesis of new analogs of 1,2-dihydro-2-quinoxalinone
acyclonucleosides with evaluation of their anti-HIV activity.
O
N
N
N
N
HN
H2N
HO
N
N
O
N
O
X
4
3
R
1, 2
1 R = H, X = CHCH2OH; 2 R = CH2OH, X = O
The reaction of the quinoxalines 5-10 with 5-bromo-1-pentene in the presence of NaH in DMF at 90°C
afforded a mixture of N- (11-16) and O-alkyl-substituted quinoxalines 17-22 (Scheme 1). The two alkylated
isomers were separated by silica gel column chromatography to give 11-16 in 54-62% yield and 17-22 in
22-32% yield.
The structures of the newly synthesized quinoxaline derivatives were confirmed by NOE experiments
and 13C NMR and mass spectra. The site of alkylation of 11-16 at N-1 was visible in the ROESY spectra, where
the 1'-CH2 protons at δH 4.16-4.25 showed cross signals to the aromatic H-8 at δH 7.98-7.46, but not to H-5 of the
quinoxaline ring. The proton spin system of compounds 11-16 was further identified from DFQ-COSY [29]
spectra, where the multiplets of the olefinic protons H-4' at the region δH 5.78-5.89 were found to correlate with
the singlets at δC 136.8-132.8 for C-4'. From the gradient selected HMBC [30] spectra of compounds 11-16, C-1'
at δC 41.0-41.9 showed heteronuclear long correlations to the H-4' at δH 5.78-5.89. Furthermore, 1'-CH2 proton at
3
2
δH 4.16-4.25 showed JC,H couplings with C=O at δC 158.2-154.1, and JC,H couplings with C-2' at δC 26.0. The
quinoxaline carbon atoms were fully analyzed and are in agreement with those of the known derivatives
prepared previously [25].
Scheme 1
R1
R
R
N
Br
+
N
H
O
5-10
NaH, DMF, 90°C, 6 h
4a
6
6
R1
3
R1
R
R
N
3
R
R
N
N
2'
8a
N
1
O
O
8
1
8
5'
4'
1'
17-22
11-16
5, 11, 17 R = R1 = H; 6, 12, 18 R = H, R1 = Me; 7, 13, 19 R = H, R1 = Ph;
8, 14, 20 R = Me, R1 = H; 9, 15, 21 R = R1 = Me; 10, 16, 22 R = Me, R1 = Ph
1053

The structures of the O-alkyl analogs 17-22 were confirmed from the NMR and mass spectra. In the 13C
NMR spectra, the C-2' resonated at relatively lower field (δC 65.9-65.1) in comparison to C-1' of the N-analogs
(δC 41.0-41.9 ppm) due to the difference in the deshielding nature between N and O atoms. Furthermore, the
multiplet of the 2'-CH2 protons at δH 4.48-4.38 showed 2JC,H couplings with C-2 at δC 157.2–155.2. The 3'-CH2 −
5'-CH2 were assigned by the HMBC correlation, whereas the protons and carbons of the quinoxaline ring were
analyzed from the NMR spectra as well as by comparison with the spectral date of compounds 11-16.
Alkylation of the base compound 8 with an excess of (E)-1,4-dichlorobut-2-ene (23) in the presence of
K2CO3 at 80°C led to the open-chain analog and gave compound 24 in 36% yield after chromatographic
purification (Scheme 2). The site of alkylation was confirmed by an NOE experiment as well as mass spectrum.
The ROESY spectrum of 24 revealed a cross signal between 1'-CH2 protons at δH 4.01 and the aromatic H-8 at
1
δH 7.45 ppm, but not to H-5, indicating the N- and not O-alkylation of the quinoxaline ring. In the H NMR
(HMQC) [31] spectrum of compound 24, two doublets of triplets appeared at δH 6.00 and 5.92 ppm (δC 128.1
and 130.4 ppm). They could be assigned to H-2' and H-3' (C-2' and C-3') by a spin decoupling experiment. These
NMR data are in agreement with those of 9-[(E)-4-chloro-2-butene-1-yl]adenine [32].
When the quinoxaline base 8 was treated with compound 23 in the presence of NaH, the N-butadienyl
derivative 25 (37%) was obtained as the result of dehydrochlorination of the intermediate 24. The structural
assignment follows from mass spectrum and a 2D NMR spectrum showing overlapping signals for the H-1' and
H-2' at δH 6.54 and δH 6.55 correlated with δC 128.1 and 109.2 ppm (C-1' and C-2'), respectively. Irradiation at δH
6.54 produced a 16% NOE effect on the signal at δH 7.44 ppm assigned to H-8, indicating that the conjugated
diene side-chain is attached to N-1. It proved to be difficult to assign the configuration of the N-vinyl group on the
basis of the NMR spectra (Scheme 2).
Scheme 2
N
N
N
4a
6
N
23, ii
23, i
3
O
N
H
O
N1
O
8
1'
1'
Cl
8
3'
Cl
3'
Cl
24
25
23
i K2CO3, DMF, 80°C; ii NaH, DMF
Compounds 11-22 were evaluated for their in vitro anti-HIV activity using the MT-4/MTT assay [33].
The results are summarized Table 1, in which the data for efavirenz [34] and capravirine [35] were included for
comparison. All the tested compounds are inactive, except 20, which was found to be the only compound from
the series inhibiting HIV-1 replication in cell culture. Compound 20 showed an EC50 of 0.22 ± 0.08 µg/ml and a
CC50 of 2.6 ± 0.1 µg/ml, resulting in a selectivity index of 13.
Based on the chemical structure and the fact that compound 20 inhibits HIV-1, but not HIV-2, replication,
this molecule can be proposed to act as a non-nucleoside reverse transcriptase inhibitor (NNRTI). This
hypothesis was further confirmed by assaying the compound against a typical NNRTI-resistant HIV-1 strain
(double mutation in RT: K103N and Y181C). Compound 20 completely lost its inhibitory activity against this
resistant strain.
1054

TABLE 1. In vitro anti-HIV-1 and HIV-2 of Some New Alkylated
Quinoxalines*
Compound
Virus strain
EC50, µg/ml
CC50, µg/ml
SI
11
IIIB
>2.5
2.5 ± 0.1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
13
<1
<1
<1
<1
<1
ROD
IIIB
>2.5
2.5 ± 0.1
12
13
14
15
16
17
18
19
20
21
22
>97.7
>97.7
>48.0
>48.0
>102.0
>102.0
>117.0
>117.0
>16.9
>16.9
>96.2
>96.2
>121.0
>121.0
>101.0
>101.0
0.22 ± 0.08
>2.6
97.7 ± 12.9
97.7 ± 12.9
48.0 ± 6.1
48.0 ± 6.1
102.0 ± 12.5
102.0 ± 12.5
117.0 ± 4.2
117.0 ± 4.2
16.9 ± 3.2
16.9 ± 3.2
96.2 ± 9.7
96.2 ± 9.7
121.0 ± 0.7
121.0 ± 0.7
101.0 ± 19.6
101.0 ± 19.6
2.6 ± 0.1
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
2.6 ± 0.1
>2.2
2.2 ± 0.1
ROD
IIIB
>2.2
2.2 ± 0.1
>2.0
2.0 ± 0.3
ROD
IIIB
IIIB
>2.0
2.0 ± 0.3
Efavirenz [32]
Capravirine [33]
0.003
0.0014
40
11
13 333
7 857
_______
* Anti-HIV-1 activity measured with strain IIIB; anti-HIV-2 activity
measured with strain ROD. EC50 − compound concentration required to
achieve 50% protection of MT-4 cells from the HIV-1- and 2-induced
cytopathogenic effect. CC50 − compound concentration that reduces the
viability of mock-infected MT-4 cells by 50%. SI − selectivity index
(CC50/EC50).
EXPERIMENTAL
Melting points were determined on a Büchi 510 melting point apparatus and the values are uncorrected.
NMR spectra were measured with Bruker AC 250 (250 MHz) in CDCl3 (Compounds 11-22) and DMSO-d6
(Compounds 24, 25) using TMS as an internal standard. Mass spectra were determined with FAB-MS modified
Finningan MAT 312/ AMD 5000 spectrometer at 790 eV and T = 70 MALDI-MS using Na+ as dropping ion.
Alkylation Reaction (General Method). A mixture of compounds 5-11 (10.0 mmol) and NaH
(10.0 mmol) in dry DMF (15 ml) was stirred at 90°C for 1 h. After cooling, 5-bromo-2-pentene (1.79 g,
12.0 mmol) was added and the mixture was stirred at 90°C for 5 h. After cooling the solution was evaporated to
dryness and the residue was partitioned between CHCl3 (3×30 ml) and water (30 ml). The combined organic
extract was dried, filtered and evaporated to dryness and the residue was poured on silica gel column (20 g).
Elution with petroleum ether−ethyl acetate (50:1) afforded first the 2-(pent-4-enyloxy)quinoxaline derivatives
(17-22) followed by the N-analogs, 1-(pent-4-enyl)quinoxalin-2-one derivatives (11-16).
1055

1-(Pent-4-enyl)quinoxalin-2-one (11) and 2-(Pent-4-enyloxy)quinoxaline (17). From 5 (1.47 g).
Compound 11. Yield 1.2 g (56%); yellow oil. 1H NMR, δ, ppm (J, Hz): 8.20 (1H, s, H-3); 7.80 (1H, dd,
J = 1.5, J = 8.5, H-8); 7.51 (1H, m, H-6); 7.29-7.47 (2H, m, H-5,7); 5.78 (1H, m, H-4'); 5.06 (1H, dd, J4',5' = 1.6,
J5',5'' = 14.5, H-5'); 4.99 (1H, dd, J4',5" = 10.5, H-5"); 4.16 (2H, dd, J = 1.9, J = 9.7, 1'-CH2); 2.57 (3H, s, CH3);
13
2.18 (2H, dd, J = 7.0, J = 14.0, 3'-CH2); 1.84 (2H, m, 2'-CH2). C NMR, δ, ppm: 154.5 (C=O); 149.9 (C-3);
136.7 (C-4a); 133.4 (C-4'); 132.1 (C-8a); 130.8 (C-7); 130.4 (C-6); 123.3 (C-8); 115.6 (C-5); 113.5 (C-5'); 41.2
(C-1'); 30.7 (C-3'); 26.0 (C-2'). Mass spectrum, m/z (Irel, %): 237 [M+Na]+ (85). Found, %: C 72.59; H 6.44;
N 12.76. C13H14N2O. Calculated, %: C 72.87; H 6.59; N 13.07.
Compound 17. Yield 0.49 g (23%); colorless oil. 1H NMR, δ, ppm (J, Hz): 8.42 (1H, s, H-3); 7.98 (1H,
dd, J = 1.3, J = 8.0, H-8); 7.79 (1H, dd, J = 1.4, J = 8.0, H-6); 7.76-7.44 (2H, m, H-6,7); 5.93-5.76 (1H, m, H-5');
5.10 (1H, dd, J5',6' = 1.6, J6',6" = 14.3, H-6'); 5.02 (1H, dd, J5',6" = 9.0, H-6"); 4.44 (2H, m, 2'-CH2); 2.23 (2H, m,
13
4'-CH2); 1.94 (2H, m, 3'-CH2). C NMR, δ, ppm: 157.2 (C-2); 140.2 (C-8a); 139.7 (C-4a); 138.7 (C-3); 137.4
(C-4a); 129.7 (C-7); 128.8 (C-5); 127.0 (C-8); 126.1 (C-6); 115.1 (C-5'); 65.6 (C-2'); 30.0 (C-4'); 27.8 (C-3').
Mass spectrum, m/z (Irel, %): 237 [M+Na]+ (90). Found, %: C 72.55; H 6.49; N 12.83. C13H14N2O. Calculated, %:
C 72.87; H 6.59; N 13.07.
3-Methyl-1-(pent-4-enyl)quinoxalin-2-one (12) and 3-Methyl-3-(pent-4-enyloxy)quinoxaline (18).
From 6 (1.61 g).
1
Compound 12. Yield 1.41 g (62%); brown oil. H NMR, δ, ppm (J, Hz): 7.79 (1H, dd, J = 1.0, J = 8.5,
H-8); 7.48 (1H, m, H-6); 7.31-7.24 (2H, m, H-5,7); 5.85 (1H, m, H-4'); 5.06 (1H, dd, J4',5' = 1.5, J5',5" = 15.0, H-5');
5.03 (1H, dd, J4',5" = 9.0, H-5"); 4.20 (2H, d, J = 1.5, J = 10.0, 1'-CH2); 2.15 (2H, dd, J = 7.0, J = 14.4, 3'-CH2); 1.77
13
(2H, m, 2'-CH2). C NMR, δ, ppm: 158.2 (C=O); 154.8 (C-3); 136.7 (C-4a); 132.8 (C-4'); 132.2 (C-8a); 129.6
(C-7); 129.4 (C-6); 123.3 (C-8); 115.6 (C-5); 113.5 (C-5'); 41.7 (C-1'); 30.9 (C-3'); 26.0 (C-2'), 21.3 (CH3). Mass
spectrum, m/z (Irel, %): 251 [M+Na]+ (87). Found, %: C 73.41; H 6.94; N 11.97. C14H16N2O. Calculated, %:
C 73.66; H 7.06; N 12.27.
1
Compound 18. Yield 0.71 g (32%); yellow oil. H NMR, δ, ppm (J, Hz): 7.92 (1H, dd, J = 1.0, J = 7.9,
H-7); 7.88 (1H, dd, J = 1.0, J = 7.9, H-6); 7.78-7.46 (2H, m, H-5,8); 5.95 (1H, m, H-5'); 5.11 (1H, dd, J5',6' = 1.3,
J6',6" = 17.3, H-6'); 5.04 (1H, dd, J5’,6’’ = 10.3, H-6"); 4.46 (2H, t, J = 6.5, 2'-CH2); 2.61 (3H, s, CH3); 2.25 (m,
13
4'-CH2); 1.94 (2H, m, 3'-CH2). C NMR, δ, ppm: 156.0 (C-2); 147.8 (C-3); 139.7 (C-8a); 138.2 (C-4a); 137.4
(C-5'); 128.4 (C-7); 127.8 (C-5); 126.5 (C-8); 125.9 (C-6); 115.0 (C-6'); 65.5 (C-2'); 30.1 (C-4'); 27.8 (C-3'),
20.1 (CH3). Mass spectrum, m/z (Irel, %): 251 [M+Na]+ (80). Found, %: C 73.37; H 6.91; N 11.89. C14H16N2O.
Calculated, %: C 73.66; H 7.06; N 12.27.
1-(Pent-4-enyl)-3-phenylquinoxalin-2-one (13) and 2-(Pent-4-enyloxy)-3-phenylquinoxaline (19).
From 7 (2.22 g).
Compound 13. Yield 1.60 g (55%); mp 40-43°C. 1H NMR), δ, ppm (J, Hz): 8.35–8.30 (2H, m, Ph-H);
7.92 (1H, dd, J = 1.4, J = 7.7, H-8); 7.57-7.24 (6H, m, H-5,6,7, Ph-H); 5.89 (1H, m, H-4'); 5.13 (1H, dd,
J
4',5' = 1.5, J5',5" = 14.5, H-5'); 5.02 (1H, dd, J4',5" = 10.2, H-5"); 4.25 (2H, m, 1'-CH2); 2.20 (2H, dd, J = 8.0,
J = 14.0, 3'-CH2); 1.84 (2H, m, 2'-CH2). 13C NMR, δ, ppm: 154.2 (C-2); 153.7 (C-3); 136.9 (C-4a); 135.9 (C-4');
133.2 (Ar-C); 132.3 (C-8a); 130.5, 130.1, 129.4 (Ar-C); 127.9 (C-7); 123.3 (C-6); 115.7 (C-5); 113.5 (C-5');
41.9 (C-1'); 30.9 (C-3'); 26.0 (C-2'). Mass spectrum, m/z (Irel, %): 291 [M+H]+ (92). Found, %: C 78.37; H 6.15;
N 9.40. C19H18N2O. Calculated, %: C 78.59; H 6.25; N 9.65.
Compound 19. 0.81 g (28%); colorless oil. 1H NMR, δ, ppm (J, Hz): 8.02-7.93 (2H, m, Ph-H); 7.89 (1H,
dd, J = 1.4, J = 8.0, H-8); 7.65 (1H, dd, J = 1.4, J = 8.0, H-5); 7.45-7.26 (5H, m, H-6,7, Ph-H); 5.70 (1H, m, H-5');
4.93 (1H, dd, J5',6' = 1.6, J6',6" = 15.7, H-6'); 4.88 (1H, dd, J5',6" = 15.2, H-6"); 4.38 (2H, t, J = 6.5, 2'-CH2); 2.08
(2H, m, 4'-CH2); 1.80 (2H, m, 3'-CH2). 13C NMR, δ, ppm: 155.3 (C-2); 146.2 (C-3); 139.8 (C-8a); 138.7 (C-4a);
137.5 (C-5'); 136.0 (Ar-C); 129.6 (C-7); 129.4, 129.3, 129.0, 126.5, 126.4 (C-5,6,8, Ar-C); 115.1 (C-6'); 65.9
(C-2'); 30.2 (C-4'); 27.8 (C-3'). Mass spectrum, m/z (Irel, %): 313 [M+Na]+ (80). Found, %: C 78.30; H 6.12;
N 9.37. C19H18N2O. Calculated, %: C 78.59; H 6.25; N 9.65.
1056

6,7-Dimethyl-1-(pent-4-enyl)quinoxalin-2-one (14) and 6,7-Dimethyl-2-(pent-4-enyloxy)quino-
xaline (20). From 8 (1.75 g).
1
Compound 14. Yield 1.31 g (54%); mp 71-73°C. H NMR, δ, ppm (J, Hz): 8.15 (1H, s, H-3); 7.56 (1H,
bs, H-8); 7.06 (1H, bs, H-5); 5.86 (1H, m, H-4'); 5.14 (1H, dd, J4',5' = 1.4, J5',5" = 12.7, H-5'); 5.07 (1H, dd,
J
4',5" = 10.7, H-5"); 4.16 (2H, m, 1'-CH2); 2.41, 2.32 (6H, 2 s, 2 CH3); 2.21 (2H, dd, J = 7.1, J = 14.6, 3'-CH2);
13
1.80 (2H, m, 2'-CH2). C NMR, δ, ppm: 154.6 (C=O); 148.7 (C-3); 140.6 (C-4a); 136.8 (C-7,4'); 132.2 (C-6);
130.4 (C-8a); 130.1 (C-5); 115.5 (C-8); 113.5 (C-5'); 41.0 (C-1'); 30.7 (C-3'); 26.0 (C-2'), 20.4, 18.8 (2CH3).
Mass spectrum, m/z (Irel, %): 243 [M+H]+ (82). Found, %: C 74.12; H 7.35; N 11.32. C15H18N2O. Calculated, %:
C 74.35; H 7.49; N 11.56.
Compound 20. Yield 0.70 g (29%); mp 56-58°C. 1H NMR, δ, ppm (J, Hz): 8.35 (1H, s, H-3); 7.73 (1H,
bs, H-8); 7.58 (1H, bs, H-6); 5.85 (1H, m, H-5'); 5.11 (1H, dd, J5',6' = 1.5, J6',6" = 13.3, H-6'); 5.03 (1H, dd,
J
5',6" = 13.1, H-6"); 4.45 (2H, t, J5',6' = 6.6, 2'-CH2); 2.42 (6H, s, 2 CH3); 2.25 (2H, m, H2-4'); 1.94 (2H, m,
13
J5',6' = 1.5, 3'-CH2). C NMR, δ, ppm: 156.2 (C-2); 148.2 (C-7); 143.6 (C-6); 139.1 (C-4a); 138.9 (C-3); 135.7
(C-4a); 134.3 (C-5'); 128.0 (C-5); 127.2 (C-8); 115.1 (C-6'); 65.1 (C-2'); 30.3 (C-3'); 26.2 (C-2'), 20.2, 18.9
(2CH3). Mass spectrum, m/z (Irel, %): 243 [M+H]+ (80). Found, %: C 74.06; H 7.40; N 11.33. C15H18N2O.
Calculated, %: C 74.35; H 7.49; N 11.56.
3,6,7-Trimethyl-1-(pent-4-enyl)quinoxalin-2-one (15) and 3,6,7-Trimethyl-3-(pent-4-enyloxy)-
quinoxaline (21). From 9 (1.89 g).
1
Compound 15. Yield 1.48 g (58%); mp 43-46°C. H NMR, δ, ppm (J, Hz): 7.53 (1H, s, H-8); 7.02 (1H, s,
H-5); 5.87 (1H, m, H-4'); 5.16 (1H, dd, J4',5' = 1.6, J5',5" = 13.2, H-5'); 5.08 (1H, dd, J4',5" = 10.1, H-5"); 4.20 (2H,
m, 1'-CH2); 2.56, 2.40, 2.18 (9H, 3 s, 2CH3); 2.20 (2H, dd, J = 6.8, J = 14.0, 3'-CH2); 1.85 (2H, m, 2'-CH2). 13C
NMR, δ, ppm: 156.5 (C=O); 154.5 (C-3); 138.7 (C-4a); 136.9 (C-7, C-4'); 131.8 (C-6); 131.0 (C-8a); 129.9 (C-5);
115.4 (C-8); 113.7 (C-5'); 41.2 (C-1'); 30.7 (C-3'); 25.9 (C-2'), 20.1, 20.2, 18.8 (3 CH3). Mass spectrum, m/z (Irel,
%): 257 [M+H]+ (72). Found, %: C 74.75; H 7.77; N 10.73. C16H20N2O. Calculated, %: C 74.97; H 7.86;
N 10.93.
Compound 21. Yield 0.56 g (22%); mp 35–38°C. 1H NMR, δ, ppm (J, Hz): 7.61 (1H, s, H-8); 7.46 (1H, s,
H-5); 5.85 (1H, m, H-5'); 5.07 (1H, dd, J5',6' = 1.7, J6',6" = 17.1, H-6'); 4.99 (1H, dd, J5',6" = 11.1, H-5"); 4.42 (2H, t,
J = 6.5, CH2-2'); 2.56, 2.34 (9H, 2 s, 3 CH3); 2.23 (2H, m, 4'-CH2); 1.91 (2H, m, 3'-CH2). 13C NMR, δ, ppm: 156.1
(C-2); 146.8 (C-3); 138.6 (C-7); 138.4 (C-6); 137.8 (C-8a); 137.2 (C-4a); 135.8 (C-5'); 127.5, (C-5); 126.3
(C-8); 115.1 (C-6'); 65.6 (C-2'); 30.3 (C-4'); 28.1 (C-3'), 20.2, 20.1, 19.9 (3 CH3). Mass spectrum, m/z (Irel, %):
257 [M+H]+ (79). Found, %: C 74.78; H 7.76; N 10.72. C16H20N2O. Calculated, %: C 74.97; H 7.86; N 10.93.
6,7-Dimethyl-1-(pent-4-enyl)-3-phenylquinoxalin-2-one (16) and 6,7-Dimethyl-2-(pent-4-enyloxy)-
3-phenylquinoxaline (22). From 10 (2.52 g).
1
Compound 16. Yield 1.94 g (61%); mp 98-100°C. H NMR, δ, ppm (J, Hz): 8.32 (2H, m, Ph-H); 7.60
(1H, s, H-8); 7.47-7.41 (3H, m, Ph-H); 6.96 (1H, s, H-5); 5.85 (1H, m, H-4'); 5.06 (1H, dd, J4',5' = 1.2,
J
5',5" = 13.5, H-5'); 5.01 (1H, dd, J4',5" = 10.5, H-5"); 4.18 (2H, m, 1'-CH2); 2.32, 2.26 (6H, 2 s, 2 CH3); 2.20 (2H,
13
dd, J = 6.9, J = 14.2, 3'-CH2); 1.84 (2H, m, 2'-CH2). C NMR, δ, ppm: 154.1 (C=O); 152.2 (C-3); 139.9 (C-4a);
137.0 (C-7); 136.1 (C-4'); 132.2 (C-6); 131.6 (C-6); 130.4 (C-8a); 129.6, 129.3 (Ar-C); 127.7 (C-5); 115.5 (C-8);
113.7 (C-5'); 41.6 (C-1'); 30.8 (C-3'); 26.0 (C-2'), 20.4, 18.9 (2CH3). Mass spectrum, m/z (Irel, %): 319 [M+H]+
(69). Found, %: C 78.93; H 6.78; N 8.61. C21H22N2O. Calculated, %: C 79.21; H 6.96; N 8.80.
Compound 22. Yield 0.73 g (23%); mp 45-47°C. 1H NMR, δ, ppm (J, Hz): 8.11 (2H, m, Ph-H); 7.64 (1H,
s, H-8); 7.53 (1H, s, H-5); 7.49-7.38 (3H, m, Ph-H); 5.82 (1H, m, H-5'); 5.02 (1H, dd, J5',6' = 1.2, J6',6" = 18.2,
H-6'); 4.96 (1H, dd, J5',6" = 10.2, H-6"); 4.48 (2H, t, J = 6.5, 2'-CH2); 2.36 (6H, s, 2CH3); 2.21 (2H, m, 4'-CH2);
1.94 (2H, m, 3'-CH2). 13C NMR, δ, ppm: 155.2 (C-2); 145.1 (C-3); 139.6 (C-7); 138.5 (C-6); 137.7 (C-8a); 137.6
(C-4a); 136.4 (C-5'); 129.6, 129.2, 128.8, 128.3 (Ar-C); 127.9 (C-5); 126.0 (C-8); 115.1 (C-6'); 65.8 (C-2'); 30.3
(C-4'); 28.0 (C-3'), 20.1, 19.8 (2CH3). Mass spectrum, m/z (Irel, %): 319 [M+H]+ (81). Found, %: C 78.96;
H 6.89; N 8.65. C21H22N2O. Calculated, %: C 79.21; H 6.96; N 8.80.
1057

1-(E)-4-Chlorobut-2-enyl)-6,7-dimethylquinoxalin-2-one (24). A mixture of 8 (0.50 g, 2.86 mmol),
K2CO3 (1.0 g, 7.23 mmol), and 1,4-dichlorobut-2-ene (23) (1.77 g, 14.3 mmol) in abs. DMF (5 ml) was stirred
under N2 at 80°C for 10 h. After cooling, the mixture was acidified with 1 M HCl to pH 1, then diluted with water
(50 ml) and extracted with ethyl acetate (4×20 ml). The combined organic extract was dried (Na2SO4), filtered off,
and evaporated to dryness. The residue was purified by column chromatography on silica gel column (50 g)
using, in gradient, MeOH (0-10%) in CHCl3 as an eluent to give compound 24 (0.27 g, 36%); mp 65-68°C.
1H NMR, δ, ppm (J, Hz): 8.10 (1H, s, H-3); 7.45 (1H, bs, H-8); 7.02 (1H, bs, H-5); 6.00 (dt, J2',3' = 15.2, H-2');
5.92 (1H, dt, J3',4' = 7.2, H-3'); 4.10 (2H, d, J4',3' = 7.2, 4'-CH2); 4.01 (2H, d, J1',2' = 5.5, 1'-CH2); 2.38, 2.30 (6H,
13
2s, 2CH3). C NMR, δ, ppm: 158.2 (C=O); 148.9 (C-3); 140.8 (C-4a); 136.5 (C-7); 132.8 (C-6); 130.4 (C-3');
130.2 (C-8a); 130.0 (C-5); 128.1 (C-2'); 115.2 (C-8); 54.2 (C-4'); 44.2 (C-1'); 20.1, 18.5 (2CH3). Mass spectrum,
m/z (Irel, %): 262/264 [M+H]+ (62). Found, %: C 63.80; H 5.66; N 10.42. C14H15ClN2O. Calculated, %: C 64.00;
H 5.75; N 10.66.
1-Butadienyl-6,7-dimethylquinoxalin-2-one (25). To a stirred solution of compound 8 (0.60 g, 3.44
mmol), in abs. DMF (15 ml) was added dry NaH (0.18 g, 7.50 mmol). When the evolution of H2 has ceased, the
mixture was stirred at 23°C for 1 h. After addition of compound 23 (1.71 g, 13.68 mmol), the mixture was stirred
under N2 at 60°C for 2 h. Work up in the manner described for 24 furnished compound 25 (0.28 g, 37%); mp 85-
1
88°C (dec.). H NMR, δ, ppm (J, Hz): 8.13 (1H, s, H-3); 7.44 (1H, bs, H-8); 7.10 (1H, bs, H-5); 6.54 (2H, m, H-
1',2'); 6.20 (1H, dt, J3',4' = 1.1, H-3'); 5.63 (1H, dt, J4',4" = 14.1, H-4'); 5.45 (1H, dd, J3',4" = 5.2, H-4"); 2.37, 2.32
(6H, 2s, 2CH3). 13C NMR, δ, ppm: 158.7 (C=O); 149.1 (C-3); 140.3 (C-4a); 136.7 (C-7); 132.8 (C-6); 132.3 (C-3');
130.2 (C-8a); 130.0 (C-5); 128.1 (C-1'); 125.6 (C-4'); 115.2 (C-8); 109.2 (C-2'); 20.4, 18.8 (2CH3). Mass
spectrum, m/z (Irel, %): 227 [M+H]+ (89). Found, %: C 73.89; H 6.19; N 12.11. C14H14N2O. Calculated %:
C 74.31; H 6.24; N 12.38.
We thank Professor E. De Clercq and Professor C. Pannecouque of Rega Institute of Medical Research,
Katholieke Universiteit, Leuven, Belgium, for the anti-HIV screening. Miss Firemel of Konstanz University
(Germany) is gratefully acknowledged for the 2D NMR experiments.
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