_________________________________Acta Chim. Slov. 2008, 55, 343-349_________________________________
Scientific paper
Carbonyl-Enamine a New Mode
for Azepine Ring Closure: Synthesis and Characterization
of Pyrazino[2,3-c]azepine, as a New Ring System
Mohamed Attia Waly*
Faculty of Science (Damiatta), Chemistry Department Mansoura University, Egypt.
* Corresponding author: E-mail: mohamedwaly7@yahoo.com
Received: 12-11-2007
Abstract
 Pyrazino [2,3-c] azepine and azepino[3,4-b]quinoxaline represent new ring systems and were prepared by fusing either of pyrazine ring onto azepine derivative or vice versa. Intramolecular 1,7-carbonyl-enamine cyclization was studied as a new mode for azepine ring closure. Various examples and reaction conditions were studied for this ring closure. Keywords: Synthesis, Condensation reaction, a-Bromoketone, Carbonyl-Enamine, Mode of ring closure, pyrazine,  quinoxaline, pyrazinoazepine, azepinoquinoxaline.
1. Introduction                                  2. Results and Discussion
Among a substantial number of bicyclic and tricyclic ring systems that incorporate the azepine ring, pyrazi-noazepine and azepino-quinoxaline ring systems are unknown with the exception of 1, which has a bridged nitrogen atom.1 As a part of our interest in the azepine chemistry,2 new ring systems pyrazino[2,3-c]azepine 2 and aze-pino[3,4-b]quinoxaline 3, have been synthesized as intermediates for the synthesis of new biologically potentially active compounds.
CCP   c"0
/    7                            I               x
1               \                                   2
3
Two obvious strategies for the synthesis of molecules of type 2 and 3 include construction of a pyrazine ring onto a pre-formed azepine derivative or elaboration of an azepine ring onto a suitably substituted pyrazine.
For the first strategy, the a-bromoazepandione 5 was prepared by bromination of 2,4-azepandione derivative 42 with bromine in glacial acetic acid. The product 5, however predominantly exists in its enol form 6. On the other hand, bromination with Br2/CHCl3 failed to give bromoa-zepandione 5, and the starting material was recovered. The 1H NMR spectra for compound 5 showed an exchangeable enolic hydroxyl proton at 8 12.3 ppm, while the solid IR spectrum reflects the ketone character for this compound and gave the carbonyl absorptions at 1732 cm–1 (CO, ketone) and 1680 cm–1 (CO, amide). Condensation of ethylene-diamine or o-phenylenediamine with the compound 5 gave the pyrazinoazepine 7 and azepinoquinoxaline 9 derivatives, respectively (Scheme 1). Both values of 1-NH and 4-NH in the 1H NMR spectra for compound 7 were upfield chemical shielded from the typical values of secondary aliphatic amines. Proton at 1-NH appears at 8 7.5 ppm, due to its enamine properties, and 4-NH appears at 8 8.2 ppm due to the effect of the neighboring group on the ß position (C-5 carbonyl group). Azepinoquinoxaline 9 did not show any exchangeable NH protons in its 1H NMR spectrum. This evidence supports air oxidation of the azepinoquinoxaline intermediate 8 to give compound 9.3
Waly:  Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...
344
Acta Chim. Slov. 2008, 55, 343–349
Shema 1
Ph
7, 56% 1,2-diaminoethane
d-
o
5, 75% o-phenylenediamine
Ph
6
o
9,   68%
Ph
For an example of the second strategy we report a new 1,7-carbonyl-enamine azepine ring closure, as a new mode for ring closure. The stereoselective azepine ring formation through the thermal 1,7-imino-ene and 1,7-car-bonyl-ene reactions has been reported.4 The present work describes a successful new extension of the azepine ring formation leading to functionalized heterocyclic fused azepine ring systems. The resonance forms 10 and 11 have structural features characteristic of tertiary enamines,5 and likewise could cyclize via favoured 7-exo-trig,6 forming the azepine ring derivative 12 in a new mode for ring closure (Scheme 3).
OEt
n^-:
R
Condensation of o-phenylenediamine with ethyl bromoacetoacetate (15)8 gives rise to a fully aromatized quinoxaline derivative 17, instead of 1,4-dihydroquinoxa-line derivative 16. This evidence supports air oxidation of the 1,4-dihydroquinoxaline derivative 16 to give compound 17 (Scheme 3).3 This reaction has to be initially carried out at low temperature, as elevated temperatures at the beginning of the reaction lead to black mass, which is insoluble in organic solvents.
In the 1H NMR spectrum for compound 17 no exchangeable protons were observed, but C-3 methyl protons were characterized by a signal at d 1.75 ppm. Compound
Q    enamino-carbonyl R
cyclization
Shema 2
10
11
12
For the syntheses of pyrazine and quinoxaline derivatives having the enamino-ester structure 10, the bro-mopyrazine derivatives 137 and bromoquinoxaline 14 were selected. Compound 14 was synthesized via the synthetic procedure of compound 13.7
Ac
lV ^-C02Et
N i Ac
Br
17 was efficiently brominated with N-bromosuccinimide9 to give the bromomethylquinoxaline derivative 18 (Scheme 3). Methyl formate was used as a solvent for this bro-mination reaction since carbon tetrachloride did not dissolve compound 17.
The synthesis of an enamine-ester such as 20, by the reaction of the bromopiperazine derivative 13 with the preformed N-benzylvinylamine 19 in the presence of polar aprotic solvents (THF, acetonitrile or DMF) was unsuccessful. However, in absolute ethanol and with anhydrous sodium carbonate, the reaction affords a product consistent with the structure 22, rather than the enamine-
Waly:   Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...
Acta Chim. Slov. 2008, 55, 343–349
345
Br-.„, ,.C02Et     H2N
CH      2           *
&  "CH,         H,N
15
Shema 3
ISL   X02Et
X
N      CHj 18, 85%
Na2C03 CH3CN
NBS
H
N      C02Et
N      CH,
i                         ò
H
16
NL    X02Et
^^.l!^i^„,, „        methyl formate      ^ ^>k   <^k
^    N      CH2Br                                     ^^N^CHa
17,  72%
ester 20 (Scheme 4). TLC test during the reaction has shown instant appearance of an intermediate which disappeared by time.
The IR spectrum of 22 has shown three absorption bands due to three different carbonyl groups. Two of them are at 1660, 1665 cm–1 for two different acetyl groups in 4-NCOCH3 and 1-NCOCH3, respectively. The third peak is at 1689 cm–1, which can be attributed to an a,ß-unsatu-rated ketone at 9-C. The 1H NMR spectrum of compound 22 has shown two vinyl protons, for 8-CH and 7-CH at 8 5.20 and 5.90 ppm, respectively, characteristic for the ena-mine moiety. The 13C NMR spectrum of 22 showed an up-field chemical shift for 7-C at 8 171.3 ppm but downfield chemical shift for 8-C at 8 144.5 ppm. The proposed route for this new mode of ring closure may include the formation of an enamine-ester intermediate 20, which could form quaternary iminium ion 21. Based on the previous evidence, the reaction could proceed by 1,7-cyclization of 20 and formed the piperazinoazepine 22.
By the same mechanism, the bromo-quinoxaline derivative 18 reacted with N-benzyl enamine derivative 19 to
N
i Bn
give the azepino-quinoxaline derivative 25, via the intermediates 23 and 24 (Scheme 5). The IR spectrum of 25 indicated the presence of an a,ß-unsaturated ketone at 1682 cm–1 and its 1H NMR spectrum confirmed the appearance of two vinyl protons for 4-CH and 3-CH at 8 5.30 and 5.95 ppm, respectively. Also the 13C NMR data revealed an increase of the value of chemical shift of 3-C than 4-C atom. This new mode of ring closure in the synthesis of the non-fused azepine ring has been further explored by the fusion of N-benzylaminofumarate 2610 with ethyl 4-bro-mobutyrate, which afforded the azepine derivative 29. The proposed mechanism for this cyclization includes the ena-minoester 27 (Scheme 6), as was described above. The carbanion 28 (formed from tertiary enamine species),5 could add to the butyrate ester in a favoured 7-exo-trig6 mode, forming the azepine derivative 29. IR data for compound 29 reflect the presence of two different carbonyl absorptions for ester groups at 1721 and 1716 cm–1, in addition to the a,ß-unsaturated ketone at 1683 cm–1. 1H NMR spectrum for compound 29 showed the disappearance of ethyl ester protons but still contain the two
EtOH
Na2C03
19   75%
13
Ac   o
1,7-cyclization
Shema 4
Bn
22,   57%
21
Waly:  Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...
346
Acta Chim. Slov. 2008, 55, ???–???
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
N^/C02Et
CH2Br
N'
i Bn
19
s=        EtOH
Na2C03

1,7-cyclization
Bn
Shema 5
25   76%
methyl ester protons at 8 3.72 and 3.85 ppm for 3-C and 2-C ester groups.
Azepine derivative 32 has been formed by a further refluxing of ethyl acetoacetate with ethyl N-phenyl-4-aminobutyrate 302b in toluene and in the presence of p-to-luenesulfonic acid, by the same mechanism of formation as for compound 29. The enaminoester 31 was detected by TLC test during the reaction and could cyclize to the azepine derivative 32 (Scheme 7). The IR spectrum for compound 32 showed the carbonyl absorption for ester at 1712 cm–1 and for a,ß-unsaturated ketone at 1679 cm–1. 1H NMR spectrum for compound 32 showed the presence for one set of ethyl ester protons in addition to the upfield chemical shielding of the allylic methyl group protons to 8 2.34 ppm.
3. Conclusion
It can be concluded that tertiary enamines could exist in the quaternary resonating structure with a negative
Me02C
C02Me
+   Br{CH2)3C02Et
fusion
NH
i Bn
26
Me02C
7-exo-trig
Shema 6
Me02C      N' Bn
29   46%
24
charge on their ß carbon.5 This will lead to a great efficiency of an intramolecular attack on the esters carbonyl group, forming azepine ring. The yields in the case of the fused azepines are somewhat higher than for the non-fused azepines obtained by the described method. This new cyclization can be referred to as a carbonyl-enamine ring closure and will be further utilized in the syntheses of various ring sizes in future work.
4. Experimental
Silica gel plates (Merck F 254) and silica gel 60 (Merck, 70–230 mesh) were used for TLC and column chromatography, respectively. All melting points were determined on a Gallenkamp melting point apparatus. Microanalyses were performed with a Perkin-Elmer 260 elemental analyzer for C, H, and N, and the results were within ±0.4% of the theoretical values. The IR spectra were recorded with a Perkin-Elmer 1420 spectrometer in Nujol
C02Me
120°C
Me02C      N
Bn 27
Me02C
"COpEt
Me02C      N     ^     C02Et Bn
28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Waly:   Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...
Acta Chim. Slov. 2008, 55, ???–???
347
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
me
C02Et
+ o
PhNH(CH2)3C02Et
30
TsOH
Toluene
C02Et
Shema 6
mulls for the solids and on KBr discs in the case of liquids, peaks are expressed in cm–1. The 1H NMR spectra were recorded with Varian EM 390 instrument at 200 MHz using CDCl3 as a solvent. 13C NMR spectra were recorded at 50 MHz. The chemical shifts are reported in 8 (ppm). All the exchangeable protons were confirmed by addition of D2O.
3-Bromo-1-phenylazepane-2,4-dione (5)
To a solution of 2,4-azepanedione (4, 4.06 g, 0.02 mol) in glacial acetic acid (15 mL) a solution of bromine (3.2 g, 0.02 mol) in glacial acetic acid (15 mL) was added with stirring during 15 min at room temperature. The reaction mixture was stirred for further 3 h and poured into water-ice mixture (100 mL). The crude product 5 was collected by filtration and recrystallized from ethyl acetate to give pure product 5 (4.2 g, 75%), mp 50-53 °C. IR (Nujol) v 1732 (CO, ketone), 1680 (CO, amide) cm–1. 1H NMR (200 MHz, CDCl3) S 1.91 (t, 2H, J = 10.1 Hz, 5-CH2), 2.21 (m, 2H, 6-CH2), 2.52 (t, 2H, J = 10.1 Hz, 7-CH2), 7.32 (m, 5H, Ph), 12.36 (br, 1H, exch. OH). Anal. Calcd for C12H12BrNO2 (281.133): C, 51.09; H, 4.29; Br, 28.32; N, 4.96. Found: C, 51.32; H, 4.30; Br, 28.53; N, 4.61.
Condensation of 1,2-diamine with OC-bromoketone
To a solution of the diamine (0.01 mol) in acetoni-trile (20 mL) and sodium carbonate (3 gm) in dry ice bath (-78 °C) a solution of the corresponding a-bromoketone (0.01 mol) in acetonitrile (10 mL) was added dropwise during 10 min. After the addition was completed, the reaction mixture was left to reach room temperature and the room temperature was maintained for 8 h with continuous stirring. The solid material was removed by filtration and the solvent was removed in vacuo. The crude material was purified by the column chromatography and recrystallized from proper solvent to give the desired pure product.
CO? Et
32,   49%
l,2,3,4,6,7,8,9-Octahydro-6-phenyl-5H-pyrazino[2,3-c]azepin-5-one (7)
Compound 7 was prepared from the reaction of compound 5 with 1,2-diaminoethane following the procedure described above. The product was recrystallized from ethyl acetate to give yellow powder (1.36 g, 56%), mp 130-133 °C (ethyl acetate). IR (Nujol) v 1660 (CO, amide) cm–1. 1H NMR (200 MHz, CDCl3) 8 2.04 (m, 2H, 8-CH2), 2.43 (t, 2H, J= 10.1 Hz, 9-CH2), 3.05-3.34 (2m, 4H, 2-CH2, 3-CH2), 3.62 (t, 2H, J= 10.1 Hz, 7-CH2), 7.51 (br, 1H, exch. 1-NH), 8.26 (br, 1H, exch. 4-NH), 7.73 (m, 5H, Ph). 13C NMR (50 MHz, CDCl3) 8 171.8, 142.5, 140.2, 133.2, 128.4, 125.3, 121.5, 55.2, 54.5, 48.2, 36.2, 31.4. Anal. Calcd for C14H17N3O (243.304): C, 69.11; H, 7.04; N, 17.27. Found: C, 69.32; H, 7.22; N, 17.04.
2,3,4,5-Tetrahydro-2-phenyl-lH-azepino[3,4-b]quino-xalin-1-one (9)
Compound 9 was prepared from the reaction of compound 5 with o-phenylenediamine following the procedure described above. The product was recystallized from ethyl acetate to give brownish powder (1.95 g, 68%), mp 195-197 °C (ethyl acetate-methanol). IR (Nujol) v 1680 (CO, amide) cm–1. 1H NMR (200 MHz, CDC-l3) 8 1.94 (m, 2H, 4-CH2), 2.46 (t, 2H, J = 10.1 Hz, 5-CH2), 3.52 (t, 2H, J = 10.1 Hz, 3-CH2), 6.84-7.06 (m, 4H, Ar), 7.21 (m, 5H, Ph). 13C NMR (50 MHz, CDCl3) 8
175.4,  155.8, 148.3, 146.1, 142.5, 140.1, 138.2, 136.6,
133.5,  131.2, 128.4, 125.5, 125.5, 48.2, 44.4, 30.2. MS (m/z) 290 (100%, M+). Anal. Calcd for C18H15N3O (289.33): C, 74.72; H, 5.23; N, 14.52. Found: C, 74.80; H, 5.42; N, 14.35.
Ethyl 3-methylquinoxaline-2-carboxylate (17)
Compound 17 was prepared from the reaction of ethyl bromoacetoacetate (15)6 with o-phenylenediamine following the procedure described above. The product was recrystallized from ethanol (95%) to give brownish
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Waly:  Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...
348 __________________________________Acta Chim. Slov.
powder (1.55 g, 72%), mp 220-222 °C. IR (Nujol) v 1694 (CO, aromatic ester) cm–1. 1H NMR (200 MHz, CDCl3) 8 1.13 (t, 3H, J= 7.1 Hz, OCH2CH3), 1.75 (s, 3H, 3-CH3), 4.23 (m, 2H, OCH2CH3), 6.72-6.91 (m, 4H, Ar). 13C NMR (50 MHz, CDCl3) 8 173.3, 160.3, 152.3, 150.2, 144.3, 135.2, 133.4, 131.1, 130.1, 64.2, 22.4, 18.2. Anal. Calcd for C12H12N2O2 (216.236): C, 66.65; H, 5.59; N, 12.96. Found: C, 66.43; H, 5.76; N, 12.88.
Ethyl 3-(bromomethyl)quinoxaline-2-carboxylate (18) A mixture of compound 17 (2.16 g, 0.01 mol), N-bromosuccinimide (2.1 g, 0.012 mol) and bibenzoyl peroxide as catalyst (0.01 g) in methyl formate (20 mL) was irradiated with lamp (60 W) for 2 h. Cold water (50 mL) and chloroform (50 mL) were added and the organic layer was separated, washed with cold water (20 × 3 mL), dried over anhydrous Na2SO4 and evaporated in vacuo. The pure product 18 was obtained by recrystallization from ethyl acetate (2.5 g, 85%), mp 102-105 °C. IR (Nujol) v 1700 (CO, ester) cm–1. 1H NMR (200 MHz, CDCl3) 8 1.24 (t, 3H, J = 7.1 Hz, OCH2CH3), 4.21 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.43 (s, 2H, CH2Br), 6.72-6.91 (m, 4H, Ar). Anal. Calcd for C12H11BrN2O2 (295.132): C, 48.84; H, 3.76; Br, 27.07; N, 9.49. Found: C, 49.11; H, 3.60; Br, 27.23; N, 9.40.
N-Benzylethenamine (19)
Benzylamine (10 g, 0.1 mol), vinyl acetate (8.6 g, 0.1 mol) and sodium carbonate (15 g) in absolute ethanol (30 mL) were refluxed for 1 h and stirred for further 8 h at room temperature. The reaction mixture was poured into water (100 mL), extracted with chloroform, dried over anhydrous Na2SO4 and evaporated in vacuo to give pure yellow oil (Rf035, dichloromethane : ethanol : ammonia = 300 : 8 : 1) (10 g, 75%). IR (neat) v 3321 (br, NH), 1610 (C=C) cm–1. 1H NMR (200 MHz, CDCl3) 8 4.02 (s, 2H, CH2Ph), 5.21-5.48 (dd, 2H, J1 = 6.4 Hz, J2 = 9.7 Hz, N-CH=CH2), 5.76 (br, 1H, exch. NH), 6.39 (d, 1H, J = 6.4 Hz, N-CH=CH2), 7.29 (m, 5H, Ph). Anal. Calcd for C9H11N (133.19): C, 81.16; H, 8.32; N, 10.52. Found: C, 81.32; H, 8.43; N, 10.45.
l,4-Diacetyl-6-benzyl-l,2,3,4,5,6-hexahydro-9H-pyra-zino[2,3-c]azepin-9-one (22)
A solution of the bromopiperazine derivative 13 (3.47 g, 0.01 mol), N-benzyl enamine 19 (1.33 g, 0.01 mol) in absolute ethanol (50 mL) and sodium carbonate (3 g) was refluxed for 6 h. After cooling, the reaction mixture was poured into cold water (100 mL) and the precipitate was filtered off. The pure product 22 was obtained by crystallization from ethanol (95%) (2 g, 57%), mp 240-242 °C. IR (Nujol) v 1660 (CO, 4-NCOCH3), 1665 (CO, 1-NCOCH3), 1689 (CO, 9-C) cm–1. 1H NMR (200 MHz, CDCl3) 8 2.25-2.27 (2s, 6H, 4-NCOCH3, 1-NCOCH3), 3.03-3.32 (m, 4H, 2-CH2, 3-CH2), 3.69 (s, 2H, 5-CH2), 4.22 (s, 2H, CH2Ph), 5.20 (d, 1H, J = 8.6 Hz, 8-
Waly:   Carbonyl-Enamine a New Mode for Azepine
2008, 55, 343-349
CH), 5.90 (d, 1H, J = 8.6 Hz, 7-CH), 7.55 (m, 5H, Ar). 13C NMR (50 MHz, CDCl3) 8   180.2, 177.4, 172.4, 171.3,
144.5,  140.6, 138.1, 136.2, 133.4, 130.8, 120.9, 118.7, 50.2, 48.8, 47.3, 28.4, 23.3. Anal. Calcd for C19H21N3O3 (339.388): C, 67.24; H, 6.24; N, 12.38. Found: C, 67.30; H, 6.11; N, 12.42.
2-Benzyl-1,2-dihydro-5H-azepino [3,4-b ]quinoxalin-5-
one (25)
A solution of the bromoquinoxaline derivative 18 (2.95 g, 0.01 mol), N-benzyl enamine 19 (1.33 g, 0.01 mol) and sodium carbonate (3 g) in absolute ethanol (50 mL) was refluxed for 9 h. After cooling, the reaction mixture was poured into cold water (100 mL) and the precipitate was filtered off. The pure product 25 was obtained by crystallization from absolute ethanol (2.3 g, 76%), mp 193-200 °C. IR (Nujol) v 1682 (CO, 6-C) cm–1. 1H NMR (200 MHz, CDCl3) 8 3.03 (s, 2H, 1-CH2), 4.22 (s, 2H, CH2Ph), 5.30 (d, 1H, J = 8.6 Hz, 4-CH), 5.95 (d, 1H, J = 8.6 Hz, 3-CH), 6.72-7.76 (m, 9H, Ar). 13C NMR (50 MHz, CDCl3) 8 193.2, 172.2, 160.6, 158.2, 144.1, 141.3, 136.4, 134.8, 133.7, 132.8, 132.6, 130.1, 129.5, 129.3, 129.1, 110.6, 50.3. Anal. Calcd for C19H15N3O (301.342): C, 75.73; H, 5.02; N, 13.94. Found: C, 75.54; H, 5.20; N, 14.10.
Dimethyl 1-benzyl-4,5,6,7-tetrahydro-4-oxo-1H-azepi-ne-2,3-dicarboxylate (29)
A mixture of compound 26 (2.49 g, 0.01 mol) and ethyl 4-bromobutyrate (1.95 g, 0.01 mol) was heated at 120 °C for 6 h. After cooling, the reaction mixture was purified by column chromatography using mixture of dichloromethane, ethanol and ammonia (300 : 8 : 1) to give pure yellow oil (Rf= 0.2) (1.45 g, 46%). IR (neat) v 1721 (CO, 2-C-ester), 1716 (CO, 3-C-ester), 1683 (CO, 4-C-ketone) cm–1. 1H NMR (200 MHz, CDCl3) 8 1.92 (m, 2H, 6-CH2), 2.63 (t, 2H, J = 9.6 Hz, 5-CH2), 3.11 (t, 2H, J = 9.6 Hz, 7-CH2), 3.72 (s, 3H, 3-CO2CH3), 3.85 (s, 3H, 2-CO2CH3), 4.23 (s, 2H, N-CH2Ph), 7.33-7.53 (m, 5H, Ar). 13C NMR (50 MHz, CDCl3) 8 211.3, 178.2, 173.3, 170.3,
140.6,  133.2, 130.5, 125.2, 110.1, 58.9, 55.3, 54.2, 53.3, 45.4, 28.3. Anal. Calcd for C17H19NO5 (317.34): C, 64.34; H, 6.03; N, 4.41. Found: C, 64.25; H, 6.42; N, 4.65.
Ethyl 4,5,6,7-tetrahydro-2-methyl-4-oxo-1-phenyl-1H-azepine-3-carboxylate (32)
A solution of ethyl acetoacetate (1.13 g, 0.01 mol) and ethyl 4-(N-phenylamino)butyrate (2.07 g, 0.01 mol) in dry toluene (20 mL) in the presence of p-toluenesul-fonylchloride (0.05 g, catalyst) was refluxed for 12 h. After cooling, the reaction mixture was washed with water (3 × 10 mL), dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography using mixture of dichloromethane, ethanol and ammonia (300 : 8 : 1) to produced pure product 32 (Rf= 0.3) (1.33 g, 49%). IR (neat) v 1712 (CO, ester), 1679
Ring Closure: Synthesis and Characterization ...
Acta Chim. Slov. 2008, 55, 343–349
349
(CO, ketone) cm–1. 1H NMR (200 MHz, CDCl3) d 1.33 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.76 (m, 2H, 6-CH2), 2.34 (s, 3H, 2-CH3), 2.78 (t, 2H, J = 9.6 Hz, 5-CH2), 3.37 (t, 2H, J = 9.6 Hz, 7-CH2), 4.21 (q, 2H, J = 7.1 Hz, OCH2CH3), 7.67–7.83 (m, 5H, Ar). 13C NMR (50 MHz, CDCl3) d 210.3, 175.5, 168.3, 150.4, 133.6, 120.5, 120.2, 108.8, 63.2, 50.6, 44.3, 28.3, 27.4, 17.2. Anal. Calcd. for C16H19NO3 (273.33) C, 70.31; H, 7.01; N, 5.12. Found: C, 70.43; H, 7.26; N, 5.37.
5. References
1. (a) J. Pawlowska, Z. Czarnocki, K. Wojtasiewicz, J. K. Maurin, Tetrahedron Asymmetry 2003, 14, 3335–3342. (b) J. Y. Lee, S. H. Bang, S. J. Lee, Y. S. Song, C. Jin, H. Park, Y. S. Lee, Bull. Korean Chem. Soc. 2002, 23, 1623–1628.
2. (a) M. A. Waly, M. N. Khodier, M. S. el-Hossini, Chinese Pharm. J. 1994. 96, 135–144. (b) M. A. Waly, J. Prakt. Chem. 1994, 336, 86–88. (b) M. A. Waly, S. B. Said, S. N. Ayyad, Polish J. Chem. 1996, 70, 296–301. (c) M. A. Waly, M. A. Mashaly, M. N. Khodier, A. Omar, Bull. Chim. Farm. 1994, 133, 698–703.
3. The Chemistry of Heterocyclic Compounds, Volume 61, Quinoxalines: Supplement II D. J. Brown, E. C. Taylor, P. Wipf, John Wiley & Sons, Inc.: Hoboken 2004.
4. (a) T. Inazumi, K. Yamada, Y. Kuroki, A. Kakchi, M. Noguc-hi, J. Chem. Soc. Perkin Trans. 1, 1994, 557–564. (b) T. Ina-zumi, E. Harada, T. Mizukoshi, A. Kakchi, M. Noguchi, J. Chem. Soc., Perkin Trans. 1 1994, 565–570. (c) M. Noguchi, T. Mizukoshi, A. Kakchi, Tetrahedron 1996, 52, 13081– 13096. (d) Y. Kuroki, R. Akao, T. Inazumi, M. Noguchi, Te -trahedron 1994, 50, 1063–1072. (e) M. Noguchi, T. Mizu-koshi, T. Uchida, Y. Kuroki, Tetrahedron 1996, 52, 13097– 13110. (f) M. Noguchi, T. Mizukoshi, S. Nakagawa, A. Kakchi, Tetrahedron 1996, 52, 13111–13120. (g) M. Noguc-hi, H. Yamada, S. Takamura, T. Uchida, M. Hironaka, A. Kakchi, H. Yamada, H. Yamamoto, Eur. J. Org. Chem. 2000, 1489–1496. (h) M. Noguchi, S. Takamura, K. Okada, A. Kakchi, H. Yamamoto, Tetrahedron 2000, 56, 1299–1307.
5. Enamines: Synthesis, Structure and Reactions, A. G. I. Cook, published by Marcel Dekker, New York, 1969.
6. J. E. Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734.
7. M. A. Waly, Acta Chim. Slov. 2007, 54, 811–817.
8. (a) B. Das, K. Venkateswarlu, G. Mahender, I. Mahender, Te -trahedron Lett. 2005, 46, 3041–3044. (b) S. S. Arbuj, S. B. Waghmode, A. V. Ramaswamy, Tetrahedron Lett. 2007, 48, 1411–1415.
9. M. Lorige, S. Piras, G. Paglietti, M. P. Costi, A. Venturelli, Il Farmaco 2003, 58, 51–61.
10. Y. Iwanami, Nippon Kagaku Zasshi 1961, 82, 632–634 (Chem. Abstr. 1962, 56, 53075).
Povzetek
Pirazino[2,3-c]azepin in azepino[3,4-b]kinoksalin predstavljata nova obro~na sistema, ki sta bila pripravljena s pomo~jo spajanja pirazinskega obro~a z azepinskim derivatom ali pa obratno. Kot nov na~in za pripravo azepinskih ciklov je bila prou~evana intramolekularna 1,7-karbonil-enaminska ciklizacija. Raziskani so bili razli~ni primeri in razli~ni reakcijski pogoji za to ciklizacijo.
Waly:  Carbonyl-Enamine a New Mode for Azepine Ring Closure: Synthesis and Characterization ...