Microwave assisted synthesis of novel 1,ω-bis(quinoxalin-2-yl)phenoxy)alkanes or arenes

Article abstract of DOI:10.24820/ark.5550190.p011.031

A synthesis of a novel series of bis(quinoxaline) derivatives by the reaction of o-phenylenediamine with the appropriate bis(α-bromoketones) was reported. The reactions were performed under thermal as well as under microwave irradiation conditions. The re

Full text of DOI:10.24820/ark.5550190.p011.031

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Arkivoc 2019, part vi, 0-0
Microwave assisted synthesis of novel 1,ω-bis(quinoxalin-2-yl)phenoxy)alkanes
or arenes
Nesma A. Abd El-Fatah, Ahmed F. Darweesh*, Mostafa E. Salem, Ismail A. Abdelhamid,* and Ahmed H. M.
Elwahy*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Email: darweesh10002000@yahoo.com, ismail_shafy@yahoo.com, aelwahy@hotmail.com
Received 07-25-2019
Accepted 09-12-2019
Published on line 12-15-2019
Abstract
A synthesis of a novel series of bis(quinoxaline) derivatives by the reaction of o-phenylenediamine with the
appropriate bis(α-bromoketones) was reported. The reactions were performed under thermal as well as under
microwave irradiation conditions. The reaction of bis(α-bromoketones) with 2,3-diaminopyridine proceeded
to give two regioisomers of the corresponding bis{(pyrido[2,3-b]pyrazinyl)phenoxy}methanes.
Keywords: Bis(quinoxalines), bis(α-bromoketones), bis{(pyrido[2,3-b]pyrazinyl)phenoxy}methanes, microwave
irradiation
DOI: https://doi.org/10.24820/ark.5550190.p011.031
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Introduction
Quinoxaline derivatives are an important class of heterocyclic compounds that are found in diverse library of
pharmacologically active molecules. Their potentially versatile biological activities, including antiviral,
anticancer, antibacterial and antiprotozoal properties are recently reported.1–11
The quinoxaline scaffold is present in several therapeutic and pharmacologically active compounds as well as
natural occurring compounds. The usefulness of some quinoxaline derivatives as medicines are well
established12–14 (Figure 1).
In addition, quinoxaline derivatives were used as building blocks for the synthesis of dyes,
electroluminescent material, anion receptors and organic semiconductors.15–18
A number of methods have been developed for the synthesis of quinoxaline derivatives. Among them,
condensation of 1,2-diamines with α-diketones19, 1,4-addition of 1,2-diamines to diazenylbutenes20,
cyclization–oxidation of phenacyl bromides21 and oxidative coupling of epoxides with ene-1,2-diamines22 are
still the most common methods. These reactions were also performed using green methodologies, including
recyclable catalysts, microwave-assisted synthesis and reactions in aqueous medium.1,23–29
Novel contributions to develop new, safe and effective methodology for novel quinoxaline scaffolds of
pharmacological importance for drug discovery programs are still in demand.
Motivated by these findings and in conjunction with our ongoing research work on bis(heterocycles)30–43
we report herein on the synthesis of novel bis(quinoxalines) which are linked via aliphatic or aromatic spacers
in a cost-effective manner. The synthesis of the target compounds were investigated under microwave
irradiation as well as by using traditional heating conditions.
Figure 1. Drugs containing the quinoxaline core.
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Results and Discussion
Two strategies were attempted for the synthesis of the novel bis(quinoxaline) 4. In the first strategy, we
studied the synthesis of 4-(quinoxalin-2-yl)phenol (3) which should then undergo reaction with 1,2-
dibromoethane under basic conditions to give 1,2-bis(4-(quinoxalin-2-yl)phenoxy)ethane (4) (Scheme 1).
Scheme 1. Attempts for the synthesis of the novel bis(quinoxalines) 4.
Unfortunately, repeated attempts to isolate pure sample of 3 were unsuccessful. Reaction of 2-bromo-1-
(4-hydroxyphenyl)ethanone (2) with one equivalent of o-phenylenediamine (1) in THF using DABCO as a
catalyst, according to the method described by Meshram et al.44 (Pathway A) did not lead to the formation of
3 and instead the quaternary salt 5 was obtained as a sole product. On the other hand, reaction of 1 with 2 in
acetonitrile at reflux in the presence of piperedine as a catalyst (Pathway B) led to the formation of 4-(1,4-
dihydroquinoxalin-2-yl)phenol (6) in good yield (Figure 2).
Figure 2. Structures of the quaternary salt 5 and 4-(1,4-dihydroquinoxalin-2-yl)phenol (6).
It is worth mentioning that compound 3 has been prepared recently using starting materials and/or
reagents that are not readily available in our laboratory.45–48 We then turned to the second strategy in which
1,1'-((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(2-bromoethanone) (8) was firstly prepared from the
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appropriate bis(acetophenone) precursor 7 by the reaction with N-Bromosuccinimide in the presence of p-
toluenesulfonic acid (p-TsOH) in acetonitrile.35 Compound 8 was allowed to react with o-phenylenediamine (1)
as a model reaction for the synthesis of 4 (Scheme 2). The reactions were performed under both conventional
heating (Method A) as well as MW irradiation (Method B).
Scheme 2. Reaction of 8 with 1 as a model reaction for the synthesis of bis(quinoxaline) 4.
To find the optimal reaction conditions, the reaction was performed in EtOH using a variety of bases
(DABCO, TEA, piperidine, pyridine and KOH) as outlined in Table 1. Compared with other bases, piperidine
was found to achieve the best yields and the cleanest products in short reaction time (2 hr.) (entry 3, table 1).
It is worthy to mention that prolonged reaction times (up to 7 hours) did not affect the yields of the target
products.
Table 1. Effect of base on the synthesis of bis-quinoxalline 4
Thermal
MW
Yieldbb 4
73
Run
Base
Yield%a 4
1
2
3
4
5
DABCO
TEA
Piperidine
Pyridine
KOH
64
71
76
61
67
79
87
67
78
aReaction conditions: 8 (1 mmole), 1 (2 mmole),
base (2 mmole), EtOH (25 mL), 2 hr. at reflux temp.
bReaction conditions: 8 (1 mmole), 1 (2 mmole),
base (2 mmole), EtOH (3 mL), microwave
irradiation (250 W) at 100 °C, 10 min.
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The reaction was also examined in different solvents (ethanol, dioxane, dichloromethane, acetonitrile,
water and DMF) as well as under solvent free conditions. The reaction was found to proceed in most solvents
but with different degrees of conversion and ethanol was proved to be the best solvent in terms of reaction
time and yield as outlined in Table 2. Under solvent free conditions, the reaction also proceeded to give the
target molecule 4 but in very low yield (entry 7, table 2). Moreover, attempts to synthesize 4 by direct reaction
of 8 with 1 in water without catalyst according to the method described by Kumar et al.49 were also
unsuccessful (entry 5, table 2).
Table 2. The Solvent effect for synthesis of bis-quinoxalline 4
Thermal
MW
Yieldbb 4
87
77
69
78
0
66
trace
Run
Solvent
Yield%a 4
1
2
3
4
5
6
7
Ethanol
Dioxane
Dichloromethane
Acetonitrile
Water
76
70
56
69
0
DMF
-
60
Trace
aReaction conditions: 8 (1 mmole), 1 (2 mmole),
piperidine (2 mmole), solvent (25 mL), 2 hr. at reflux
temp.
bReaction conditions: 8 (1 mmole), 1 (2 mmole),
piperidine (2 mmole), solvent (3 mL), microwave
irradiation (250 W) at 100 °C (EtOH and Acetonitrile),
120 °C (Dioxane and H2O), 50 °C (Dichloromethane), 160
°C (DMF) and 130 °C (solvent free), 10 min.
To explore the scope of this transformation, o-phenylenediamine (1) was allowed to react with various
bis(α-haloketones) under the optimized reaction conditions. Thus, bis(4,1-phenylene))bis(2-bromoethanones)
11 and 12 were prepared from the appropriate bis(acetophenones) 9 and 10 as previously reported by our
group.35 Reaction of compounds 11 and 12 with o-phenylenediamine (1) afforded bis(quinoxalines) 13 and 14,
respectively (Scheme 3).
Similarly, reaction of bis(2,1-phenylene))bis(2-bromoethanones) 18-20 (obtained from the appropriate bis
(acetophenones) 15-17 by bromination with NBS)35 with o-phenylenediamine (1) afforded the target products
21-23, respectively, in good yields, (Scheme 4).
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Scheme 3. Synthesis of bis(quinoxalines) 13 and 14.
Scheme 4. Synthesis of bis(quinoxalines) 21-23.
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Using a similar approach, reaction of bis(bromoacetyl) arenes 26 and 27 with o-phenylenediamine (1) in
the presence of piperidine in ethanol at reflux as well as under microwave reaction conditions afforded the
corresponding bis(quinoxalines) 28 and 29, respectively. Compounds 26 and 27 were obtained from the
corresponding bis(acetophenones) 24 and 25, respectively, upon treatment with N-bromosuccinimide (NBS) in
the presence of p-toluenesulfonic acid in acetonitrile50 (Scheme 5).
Scheme 5. Synthesis of bis(quinoxalines) 28 and 29.
The structure of the novel bis(quinoxalines) were confirmed by spectral tools as well as elemental
analyses. Thus, compound 4 as a representative example showed the correct molecular ion peak at m/z 470 in
its mass spectrum. The disappearance of peaks characteristic for CO and NH groups in the IR spectrum
confirms the cyclization as well as the aromatization reactions. Furthermore, the IR of compound 4 revealed a
1
peak at 1602 cm-1 characteristic for C=N stretching. Moreover, the H NMR of compound 4 featured the
methylene ether linkage OCH2 as a singlet signal at δ 4.50 ppm. The characteristic signal at δ 9.55 ppm is
referring to quinoxaline-H3. All other protons were seen at the expected chemical shifts and integral values
(See Experimental section and Supporting Information).
A plausible reaction mechanism for the formation of quinoxaline derivative 4 from o-phenylenediamine
(1) and bis(bromoacetyl) 8 is illustrated in Scheme 6. Initially a nucleophilic substitution occurs on the
phenacyl bromide to afford the intermediate I. Intermediate I was then cyclized to give 3-phenyl-1,2-
dihydroquinoxaline II. The latter compound underwent air oxidation to afford the aromatized bis(quinoxaline)
4 as the final product (Scheme 6).
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Scheme 6. A plausible mechanism for the formation of quinoxaline derivative 4.
It was noted that when symmetric diamine was used, the reaction proceeded smoothly in all the cases and
resulted in the formation of the corresponding bis(quinoxalines) as sole products in good yields. On the other
hand, when the reaction was further examined by employing the reaction of 2,3-diaminopyridine (30) as an
unsymmetrical diamine with bis(4,1-phenylene))bis(2-bromoethanones) 8, 11 and 12, an inseparable mixture
of two regioisomers were obtained with considerable difference in the isomer ratios (determined by 1H NMR)
depending on the structure of bis(2-bromoethanones). Thus, when 8 was used the two regioisomeric products
31 and 34 were obtained in a ratio of 4:1. On the other hand, the regioisomeric products 32 ∕ 35 and 33 ∕ 36
were obtained in ratios of 3:1 and 1:1, respectively, when 11 and 12 were used (Scheme 7).
The formation of the two regioisomers may be explained as a result of the difference in the reactivities of
the two amino groups of compound 30. The pyridine nitrogen may deactivate the amino group at position 2
and thus, the other amino group participates firstly in the reaction and leads to intermediate I which then
cyclized and oxidized affording the corresponding products 31-33. The reaction may also proceed through
intermediate II that affords the regioisomers 34-36 upon cyclization and oxidation (Scheme 7). Carrying out
these reactions under microwave irradiation did not provide a significant advantage in increasing the reaction
yield or in changing the regioselective ratio of the products. It is noteworthy to mention that we examined the
reaction by employing different substituted o-phenylene diamine but unfortunately, the reactions afforded in
all cases inseparable mixture of regioisomeric products.
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Scheme 7. Regioorientation in the addition reaction of 2,3-diaminopyridine to bis(α-bromoketones).
Conclusions
In conclusion, we synthesized a new series of bis(quinoxaline) derivatives by the reaction of o-
phenylenediamine or 2,3-diaminopyridine with the appropriate bis(α-bromoketones) under thermal heating
as well as under microwave irradiation conditions. The reaction proceeded via initially substitution reaction
followed by cyclization and subsequent aromatization in a one-pot process under basic conditions.
Experimental Section
General. Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The infrared
spectra were recorded in potassium bromide disks on a Pye Unicam SP 3-300 and Shimaduz FTIR 8101 PC
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infrared spectrophotometer. NMR spectra were recorded using a Varian Mercury VXR-300 NMR spectrometer
or Bruker Ultrashield 400 MHz or Ascend 400 MHz (1H: 300 or 400 MHz, 13C: 75 or 100.6 MHz) instruments
using DMSO-d6 as solvent. Capillary GC analyses were performed with a Shimadzu GC-14A or GC-14B, a
Shimadzu C-R6A Integrator, and a HP 5 column (25 m length, 0.25 mm i.d., 0.25 μm film) or recorded with an
Agilent GC 6890N. Mass spectra (EI) were obtained at 70 eV using a type Shimadzu GCMQP 1000 EX
Spectrometer. Microwave experiments were carried out using a CEM Discover LabmateTM microwave
apparatus (300 W with ChemDriverTM Software). Elemental analyses were performed on a Perkin-Elmer 240
micoanalyser at the Micro analytical Center of Cairo University. Compounds 8, 11, 12 and 18-20 were prepared
according to literature.35 Compounds 26 and 27 were prepared according to literature.50
Attempts for synthesis of 4-(quinoxalin-2-yl)phenol (3)
Pathway A. A mixture of o-phenylenediamine (1) (1 mmol), 2-bromo-1-(4-hydroxyphenyl)ethanone (2) (1
mmol) and DABCO (20% mol) in THF (20 ml) was stirred at room temperature for 1 hr.44 The solid residue was
collected and proved to be the quaternary salt 5.
l4 l4
2-(4-Bromo-1 ,4 -diazabicyclo[2.2.2]octan-1-yl)-1-(4-hydroxyphenyl)ethan-1-one quaternary salt (5)
Colorless powder (83%); mp > 300 ºC; IR (KBr) u 3417, 2987, 1681, 1597, 1458 cm-1; 1H NMR (300 MHz, DMSO-
d6) δ 3.12 (t, 6H, CH2N, J = 6.9 Hz), 3.60 (t, 6H, CH2N, J = 7.2 Hz), 5.14 (s, 2H, COCH2N), 7.12 (d, 2H, ArH, J = 8.7
Hz), 7.87 (d, 2H, ArH, J = 6.6 Hz), 10.81 (s, 1H, OH); MS m/z (%) 326 (M+). Anal. Calcd for C14H19BrN2O2: C,
51.39; H, 5.85; Br, 24.42; N, 8.56. Found: C, 51.48; H, 5.71; Br, 24.35; N, 8.44%
Pathway B. A mixture of o-phenylenediamine (1) (1 mmol) and 2-bromo-1-(4-hydroxyphenyl)ethanone (2) (1
mmol) in acetonitrile (25 mL) in the presence of piperidine (0.1 ml, 1 mmol) was heated at reflux for 5 hr. The
solvent was then evaporated in vacuo and the solid residue was collected and recrystallized from acetonitrile
to give 4-(1,4-dihydroquinoxalin-2-yl)phenol (6) in good yield.
4-(1,4-Dihydroquinoxalin-2-yl)phenol (6) Creamy powder (71%); mp 262 ºC; IR (KBr) u 3425, 3218, 3024,
1597, 1404 cm-1; 1H NMR (300 MHz, DMSOd6) δ 6.46 (s, 2H, NH), 7.19-9.01 (m, 9H, ArH & dihydro quinoxaline-
3-H), 11.58 (s, 1H, OH); MS m/z (%) 224 (M+). Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C,
74.85; H, 5.26; N, 12.57%
Synthesis of bis(2 and 4-(quinoxalin-2-yl)phenoxy)alkane 4, 13, 14 and 21-23.
Method A. To a solution of o-phenylenediamine (1) (2 mmol) and bis(2-bromoethanone) derivatives 8, 11, 12
or 18-20 (1 mmol) in ethanol (25 mL), piperidine (0.19 mL, 2 mmol) was added. The reaction mixture was
heated at reflux for 2 hr. The solvent was evaporated in vacuo, and the solid residue was collected by filtration
and recrystallized from ethanol/DMF to give the corresponding products 4, 13, 14 and 21-23.
Method B. A mixture of o-phenylenediamine (1) (2 mmol), bis(2-bromoethanone) derivatives 8, 11, 12 or 18-
20 (1 mmol) and piperidine (0.19 mL, 2 mmol) in ethanol (3 mL) was placed in a closed vessel and irradiated in
o
a focused microwave reactor for 10 min. at 100 C (250 W). The crude solid was isolated and recrystallized
from EtOH/DMF to give corresponding products 4, 13, 14 and 21-23.
1,2-Bis(4-(quinoxalin-2-yl)phenoxy)ethane (4). Colorless powder (A, 76%; B, 87%); mp 247-250 ºC; IR (KBr) u
1
3053, 1602, 1542, 1431, 1236 cm-1; H NMR (400 MHz, DMSO-d6) δ 4.50 (s, 4H, O-CH2), 7.10-8.35 (m, 16H,
ArH), 9.55 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 67.0, 114.8, 115.6, 129.3, 129.4, 129.5,
130.6, 131.0, 141.2, 141.9, 143.9, 151.1, 160.7; MS m/z (%) 470 (M+). Anal. Calcd for C30H22N4O2: C, 76.58; H,
4.71; N, 11.91. Found: C, 76.46; H, 4.55; N, 11.71%.
1,3-Bis(4-(quinoxalin-2-yl)phenoxy)propane (13). Colorless powder (A, 78%; B, 89%); mp 196-200 ºC; IR (KBr)
u 3052, 1604, 1538, 1428, 1244 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 2.26-2.30 (m, 2H, CH2), 4.29 (t, 4H, OCH2,
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J = 5.7 Hz), 7.17-8.33 (m, 16H, ArH), 9.53 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 64.9, 115.6,
128.9, 129.3, 129.4, 129.5, 129.8, 130.9, 141.1, 141.9, 143.9, 151.1, 160.9; MS m/z (%) 484 (M+). Anal. Calcd
for C31H24N4O2: C, 76.84; H, 4.99; N, 11.56. Found: C, 76.75; H, 4.89; N, 11.41%.
1,4-Bis(4-(quinoxalin-2-yl)phenoxy)butane (14). Pale yellow powder (A, 80%; B, 91%); mp 188-192 ºC; IR (KBr)
1
u 3052, 1602, 1509, 1393, 1245 cm-1; H NMR (400 MHz, DMSO-d6) δ 1.96 (br. s, 4H, CH2), 4.18 (br. s, 4H,
OCH2), 7.14-8.32 (m, 16H, ArH), 9.53 (s, 2H, quinoxaline-3-H); MS m/z (%) 498 (M+). Anal. Calcd for C32H26N4O2:
C, 77.09; H, 5.26; N, 11.24. Found: C, 76.98; H, 5.08; N, 11.05%.
1,2-Bis(2-(quinoxalin-2-yl)phenoxy)ethane (21). Pale yellow crystals (A, 71%; B, 83%); mp 178-180 ºC; IR (KBr)
1
u 3047, 1595, 1547, 1498, 1234 cm-1; H NMR (400 MHz, DMSO-d6) δ 4.54 (s, 4H, O-CH2), 7.14-8.05 (m, 16H,
ArH), 9.25 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 67.4, 114.9, 117.7, 129.0, 129.5, 130.0,
130.4, 131.9, 132.1, 135.4, 140.8, 142.3, 147.0, 151.7, 156.6; MS m/z (%) 470 (M+). Anal. Calcd for C30H22N4O2:
C, 76.58; H, 4.71; N, 11.91. Found: C, 76.40; H, 4.59; N, 11.77%.
1,3-Bis(2-(quinoxalin-2-yl)phenoxy)propane (22). Colorless powder (A, 73%; B, 87%); mp 128-132 ºC; IR (KBr)
u 3045, 1596, 1546, 1450, 1258 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 2.19-2.21 (m, 2H, CH2), 4.23 (t, 4H, OCH2,
J = 6.3 Hz), 7.13-8.09 (m, 16H, ArH), 9.29 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 28.8, 65.6,
113.3, 121.7, 126.4, 129.2, 129.5, 130.2, 130.6, 131.7, 132.0, 140.8, 142.3, 147.3, 152.2, 156.7; MS m/z (%)
484 (M+). Anal. Calcd for C31H24N4O2: C, 76.84; H, 4.99; N, 11.56. Found: C, 76.69; H, 4.88; N, 11.43%.
1,4-Bis(2-(quinoxalin-2-yl)phenoxy)butane (23). Yellow powder (A, 79%; B, 90%); mp 97-100 ºC; IR (KBr) u
3048, 1597, 1548, 1452, 1240 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 1.87 (br. s, 4H, CH2), 4.13 (br. s, 4H, OCH2),
7.10-8.08 (m, 16H, ArH), 9.31 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 25.9, 68.3, 113.2, 121.5,
126.1, 129.2, 129.5, 130.2, 130.6, 131.7, 132.0, 142.4, 147.3, 152.2, 156.8; MS m/z (%) 498 (M+). Anal. Calcd
for C32H26N4O2: C, 77.09; H, 5.26; N, 11.24. Found: C, 77.22; H, 5.35; N, 11.08%.
Synthesis of 1,3 and 1,4-bis((4-(quinoxalin-2-yl)phenoxy)methyl)benzene 28, 29
Method A. To a solution of o-phenylenediamine (1) (2 mmol) and bis(bromoacetyl) arenes derivatives 26 or 27
(1 mmol) in ethanol (25 mL), piperidine (0.19 mL, 2 mmol) was added. The reaction mixture was heated at
reflux for 3 hr. The solvent was evaporated in vacuo, and the solid residue was collected by filtration and
recrystallized from EtOH/DMF to give compounds 28 and 29.
Method B. A mixture of o-phenylenediamine (1) (2 mmol), bis(bromoacetyl) arenes derivatives 26 or 27 (1
mmol) and piperidine (0.19 mL, 2 mmol) in ethanol (3 mL) was placed in a closed vessel and irradiated in a
focused microwave reactor for 20 min. at 100 oC (250 W). The crude solid was isolated and recrystallized from
ethanol/DMF to give corresponding products 28 and 29.
1,4-Bis((4-(quinoxalin-2-yl)phenoxy)methyl)benzene (28). Brown powder (A, 71%; B, 85%); mp 208-210 ºC; IR
1
(KBr) u 3039, 1597, 1504, 1427, 1242 cm-1; H NMR (400 MHz, DMSO-d6) δ 5.26 (s, 4H, OCH2), 7.22-8.34 (m,
20H, ArH), 9.56 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 69.5, 115.6, 115.9, 128.4, 129.1,
129.2, 129.4, 129.5, 131.0, 131.1, 141.1, 141.9, 143.9, 151.1, 161.1; MS m/z (%) 546 (M+). Anal. Calcd for
C36H26N4O2: C, 79.10; H, 4.79; N, 10.25. Found: C, 78.98; H, 4.67; N, 10.08%.
1,3-Bis((4-(quinoxalin-2-yl)phenoxy)methyl)benzene (29). Brown powder (A, 69%; B, 81%); mp 170-174 ºC; IR
1
(KBr) u 3055, 1604, 1543, 1465, 1242 cm-1; H NMR (400 MHz, DMSO-d6) δ 5.28 (s, 4H, OCH2), 7.23-8.33 (m,
20H, ArH), 9.54 (s, 2H, quinoxaline-3-H); 13C NMR (100 MHz, DMSO-d6) δ 69.7, 115.9, 127.4, 127.8, 129.1,
129.2, 129.3, 129.4, 129.8, 130.9, 137.5, 141.1, 141.8, 143.9, 151.0, 160.7; MS m/z (%) 546 (M+). Anal. Calcd
for C36H26N4O2: C, 79.10; H, 4.79; N, 10.25. Found: C, 78.85; H, 4.57; N, 10.07%.
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Synthesis of bis(4-(pyrido[2,3-b]pyrazinyl)phenoxy)alkane 31-36. To a solution of 2,3-diaminopyridine (30) (2
mmol) and bis(2-bromoethanone) derivatives 8, 11 or 12 (1 mmol) in ethanol (25 mL), piperidine (0.19 mL, 2
mmol) was added. The reaction mixture was heated at reflux for 2 hr. The solvent was evaporated in vacuo,
and the solid residue was collected by filtration and recrystallized from EtOH/DMF to give compounds 31-36.
1,2-Bis(4-(pyrido[2,3-b]pyrazin-3-yl)phenoxy)ethane
(31)
and
1,2-bis(4-(pyrido[2,3-b]pyrazin-2-
yl)phenoxy)ethane (34). Colorless powder (63%); mp 266-270 ºC; IR (KBr) u 3055, 1604, 1566, 1404, 1242 cm-
1
1; H NMR (300 MHz, DMSO-d6) δ 4.52 (s, 4H, OCH2), 7.10-9.15 (m, 14H, ArH & pyridine-H), 9.68, 9.74 (two s,
2H, pyrazine-2-H, pyrazine-3-H isomeric ratio 4:1); MS m/z (%) 472 (M+). Anal. Calcd for C28H20N6O2: C, 71.17;
H, 4.27; N, 17.79. Found: C, 71.43; H, 4.59; N, 17.99%.
1,3-Bis(4-(pyrido[2,3-b]pyrazin-3-yl)phenoxy)propane
(32)
and
1,3-bis(4-(pyrido[2,3-b]pyrazin-2-
yl)phenoxy)propane (35). Brown powder (69%); mp 216-221 ºC; IR (KBr) u 3055, 1604, 1465, 1404, 1242 cm-1;
1H NMR (300 MHz, DMSO-d6) δ 2.28-2.29 (m, 2H, CH2), 4.31 (t, 4H, OCH2, J = 6.0 Hz), 7.18-9.13 (m, 14H, ArH &
pyridine-H), 9.66, 9.71 (two s, 2H, pyrazine-2-H, pyrazine-3-H isomeric ratio 3:1); MS m/z (%) 486 (M+). Anal.
Calcd for C29H22N6O2: C, 71.59; H, 4.56; N, 17.27. Found: C, 71.77; H, 4.68; N, 17.50%.
1,4-Bis(4-(pyrido[2,3-b]pyrazin-3-yl)phenoxy)butane
(33)
and
1,4-bis(4-(pyrido[2,3-b]pyrazin-2-
yl)phenoxy)butane (36). Brown powder (72%); mp 210-214 ºC; IR (KBr) u 3032, 1604, 1566, 1473, 1249 cm-1;
1H NMR (300 MHz, DMSO-d6) δ 1.97 (br. s, 4H, CH2), 4.20 (br. s, 4H, OCH2), 7.16-8.53 (m, 14H, ArH & pyridine-
H), 9.66, 9.72 (two s, 2H, pyrazine-2-H, pyrazine-3-H isomeric ratio 1:1); 13C NMR (DMSO-d6) δ 25.8, 67.9,
115.6, 115.7, 125.3, 126.5, 128.1, 128.3, 129.7, 130.0, 136.3, 137.2, 138.3, 138.5, 145.0, 146.7, 150.1, 152.0,
153.8, 161.4, 161.6; MS m/z (%) 500 (M+). Anal. Calcd for C30H24N6O2: C, 71.98; H, 4.83; N, 16.79. Found: C,
72.16; H, 5.03; N, 16.91%.
Supplementary Material
Supplementary material related to this article, including Nuclear Magnetic Resonance (1H and 13C NMR) figures
for compounds 4; 6; 13; 14; 21; 22; 23; 28; 29; 31 and 33 are available in the online version of the text.
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