Part 6: Synthesis of spiro 1,5-benzodiazepine attached with different heterocyclic moeities

Article abstract of DOI:10.1080/00397910601055214

3-Oxime-4-phenyl-1(H)(l,5)benzodiazepin-2-one 2 was prepared and treated with malononitrile, arylidenenitriles, and bidentates to give the corresponding spiro-3,3′-isoxazolo-, thiadiazino-, and triazino-1,5-benzodiazepines 3-7. 3-Bromo-3-cyano-4-phenyl-l(H)(l,5)benzodiazepin-2-one 9a and 3-bromo-3-cyano-4-(4′-bromophenyl)-1(H)(l,5)benzodiazepin-2-one 9b were synthesized via the bromination of 3-cyano-4-phenyl-1(H)(l,5)benzodiazepin-2-one 8. Compounds 9a,b were reacted with bidentates or cyclopentanone to afford spiro piprazine, quinoxaline, thiazine, thiadiazine, imidazole, and cyclopentafuran derivatives 10-16. Treatment of compound 1 with p-tolyldiazonium chloride gave 3-(p-tolylazo)-4-phenyl-1(H)(1,5)-benzodiazepin-2-one 17, which in turn treated with nitriles, cyclopentanone, and S,S-acetal derivative to give the corresponding spiro pyrazole, cyclopentapyrazole, and thiadiazole derivatives 18-21. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601055214

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Part 6: Synthesis of Spiro 1,5‐Benzodiazepine
Attached with Different Heterocyclic Moeities
A. Khodairy a , A. M. El‐Sayed a , H. Salah a & H. Abdel‐Ghany a
a Department of Chemistry, Faculty of Science, Sohag, Egypt
Available online: 10 Sep 2007
To cite this article: A. Khodairy, A. M. El‐Sayed, H. Salah & H. Abdel‐Ghany (2007): Part 6: Synthesis of
Spiro 1,5‐Benzodiazepine Attached with Different Heterocyclic Moeities, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:18, 3245-3258
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Synthetic Communicationsw, 37: 3245–3258, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601055214
Part 6: Synthesis of Spiro
1,5-Benzodiazepine Attached with
Different Heterocyclic Moeities
A. Khodairy, A. M. El-Sayed, H. Salah, and H. Abdel-Ghany
Department of Chemistry, Faculty of Science, Sohag, Egypt
Abstract: 3-Oxime-4-phenyl-1(H)(l,5)benzodiazepin-2-one 2 was prepared and
treated with malononitrile, arylidenenitriles, and bidentates to give the corresponding
spiro-3,30-isoxazolo-, thiadiazino-, and triazino-1,5-benzodiazepines 3–7. 3-Bromo-
3-cyano-4-phenyl-l(H)(l,5)benzodiazepin-2-one 9a and 3-bromo-3-cyano-4-(40-
bromophenyl)-1(H)(l,5)benzodiazepin-2-one 9b were synthesized via the bromination
of 3-cyano-4-phenyl-1(H)(l,5)benzodiazepin-2-one 8. Compounds 9a,b were reacted
with bidentates or cyclopentanone to afford spiro piprazine, quinoxaline, thiazine, thia-
diazine, imidazole, and cyclopentafuran derivatives 10–16. Treatment of compound 1
with p-tolyldiazonium chloride gave 3-(p-tolylazo)-4-phenyl-1(H)(1,5)-benzodiaze-
pin-2-one 17, which in turn treated with nitriles, cyclopentanone, and S,S-acetal deriva-
tive to give the corresponding spiro pyrazole, cyclopentapyrazole, and thiadiazole
derivatives 18–21.
Keywords: 3-bromo-3-cyano-4-phenyl-l(H)(1,5)benzodiazepin-2-one, 3-oxime-4-
phenyl-1(H)(1,5)benzodiazepin-2-one, PTC, 3-(p-tolylazo)-4-phenyl-1(H)(1,5)benzo-
diazepin-2-one
1,5-Benzodiazepines are one of the most important classes of the therapeutic
agents.[1] It has anti-inflammatory,[2] analgesic,[2,3] antagonists,[4] and anti-
pyretic[5] properties. All these findings prompted us to continue our
previous work on the synthesis of fused and spiro-1,5 benzodiazepines.[6–10]
Received in the U.K. February 15, 2006
Address correspondence to H. Abdel-Ghany, Department of Chemistry, Faculty of
Science, Sohag 82524, Egypt. E-mail: khodairy@yahoo.com
3245

3246
A. Khodairy et al.
RESULTS AND DISCUSSION
Nitrosation of 1,3-dihydro-4-phenyl-1,5-benzodiazepin-2-one 1[11] with
sodium nitrite in acetic acid gave 3-oxime-4-phenyl-1(H)(1,5)-benzodiaze-
pin-2-one 2. 1H NMR spectrum (d, ppm) showed the following signals:
11.40 (s, 1H, NH); 10.3 (s, 1H, OH); 7.90–6.65 (m, 9H, arom.).
The action of active nitriles on compound 2 was studied. So, on treating
compound 2 with malononitrile in the presence of triethylamine, spiro[2-oxo-
4-phenyl-1(H)(1,5)benzodiazepine-3,30-(50-amino-cyano-20(H)isoxazole)]
3
was obtained. IR spectrum showed the following absorption bands at 3400–
3300 (br, 2NH), 3190, 3100 (NH2, 2215 (CN), and 1675 (CO). The
formation of compound 3 is believed to be via the addition of the active
CH2 group to the -C55Noxime bond followed by a nucleophilic attack of the
OHoxmine group to one of the cyano group. Similarly, compound 2 was
allowed to react with different arylidenenitriles, namely benzylidene(p-
chlorobenzylidene, p-nitrobenzylidene, p-methoxybenzylidene)malononitrile,
and benzyl-idenecyanothioacetamide in the presence of triethylamine to
afford spiro[2-oxo-4-phenyl-l(H)(1,5)benzodiazepine-3,30-(40-cyano-5-phenyl-
20(H)- isoxazole)] 4a, spiro[2-oxo-4-phenyl-1(H)(1,5)benzo-diazepine-3,30-(40-
cyano-50-(p-chlorophenyl)-20(H)-isoxazole)] 4b, spiro[2-oxo-4-phenyl-l(H)
(1,5)benzodiazepine-3,30-(40-cyano-50-(p-nitropheny1)-20(H)-isoxazole)] 4c,
spiro[2-oxo-4-phenyl-1(H)(1,5)-benzodiazepine-3,30-(40-cyano-50-(p-methox-
ypheny1)-20(H)-isoxazole)] 4d, and spiro[2-oxo-4-phenyl-1(H)(l,5) benzo-
diazepine-3,30-(50-phenyl-40-thiocarboxamide-20(H)isoxazole)] 5, respectively.
The reaction pathway was assumed to proceed via a nucleophilic attack of
the OHoxime group to the C55C bond of the arylidene derivative followed by
addition of the CH-Ar group to the C55Noxime with elimination of HCN
molecule (cf. Scheme 1, Table 1)
Compound 2 is a good starting material for the synthesis of spiro hetero-
cyclic systemes attached to the benzodiazepine moiety, where it was treated
with a variety of bidentates, namely o-aminothiophenol, o-phenylenediamine,
cystamine, and ethylenediamine, using triethylamine as a basic catalyst
to yield spiro[2-oxo-4-phenyl-1(H)(1,5)benzodiazepine-3,20-(30,40-dihydro
(10,30,40)benzothiadiazine)] 6a spiro[2-oxo-4-phenyl-1(H)(1,5)benzodiazepine-
3,30-(10,20,40-trihydro(10,20,40)-benzotriazine)] 6b, spiro[2-oxo-4-phenyl-1(H)
(1,5)benzodiazepine-3,20-(30,40,50,60-tetrahydro(10,30,40)-thiadiazine)] 7a, and
spiro [2-oxo-4-phenyl-1(H)(1,5)benzodiazepine-3,30-(10,20,40, 50,60-pentahy-
dro(10,20,40)triazine)] 7b, respectively (cf. Scheme 1, Table 1) Formation of
compounds 6a,b and 7a,b was attributed to the nucleophilic attack of the SH
group or NH2 group to the C55Noxime bond followed by elimination of a
water molecule.
Treatment of 3-bromo-4-phenyl-1(H)(1,5)benzodiazepin-2-one[8] with
potassium cyanide in dimethylsulfoxide as a solvent at 908C afforded
3-cyano-4-phenyl-l(H)(1,5)benzodiazepin-2-one 8. The IR spectrum showed
an absorption band corresponding to CN at 2210 cm21. Bromination of

Spiro 1,5-Benzodiazepine
3247
Scheme 1.
compound 8 with an equimolar amount of bromine, gave a mixture of
3-bromo-3-cyano-4-phenyl-1(H)(l,5)benzo-diazepin-2-one 9a and 3-bromo-
3-cyano-4-(40-bromophenyl)-1(H)(1,5)benzodiazepin-2-one 9b, respectively.
Compounds 9a,b were tested as starting material for the synthesis of spiro
heterocyclic systems attached to benzodiazepine moeity. So, compounds
9a,b were treated with ethylenediamine, o-phenylenediamine, o-aminothio-
phenol, cystamine, thiosemicarbazide, guanidine, or cyclopentanone to give
spiro[2-oxo-4-phenyl- 1(H)(1,5)-benzodiazepine-3,20-(30-amino-10,50,60-trihy-
dro(l0,40)piprazine)] 10, spiro[2-oxo-4-(p-bromopheny1)-1(H)(1,5)benzo-
diazepine-3,20-(30-amino-10(H)quinoxaline)] 11, spiro[2-oxo-4-phenyl-1(H)

Table 1. Analytical and spectral data of the new compounds
Analytical datab cal./found
Product
no.
Yield Mole. form.
(Mol.wt.)
M. P. (8C)a (%)
C
H
N
S
IR (cm21 c
)
1H-NMR @ (ppm)d
2
3
244 acetic
acid
90
C
15 H11N3O2
(265.27)
67.92
67.66
4.18
4.22
15.84
15.99
3485 (OH); 3192 (NH);
1673 (CO)
11.40 (s, 1H, NH); 10.35 (s, 1H,
OH); 7.90–6.65 (m, 9H,
arom.)
251
70 C18H13N5O2
(331.33)
65.25
65.5
3.95
3.82
21.14
21.36
3400–3300 (br, 2NH);
3190, 3100 (NH2); 2215
(CN); 1675 (CO)
10.00 (s, 1H, NH); 8.15 (s, 1H,
NH); 7.90–6.40 (m, 9H,
arom.); 4.35–3.75 (br, 2H,
NH2)
dioxane
4a
4b
4c
4d
5
148 ethanol 30 C24H16N4O2
(392.41)
73.46
73.49
4.11
4.35
14.28
14.08
3320, 3192 (2NH); 2206
(CN); 1678 (CO)
12.60 (s, 1H, NH); 11.70 (s, 1H,
NH); 8.00–6.80 (m, 14H,
arom.)
262 ethanol 86 C24H15N4O2Cl 67.53
(426.86)
3.54
3.32
13.12
13.25
3340, 3183 (2NH); 2220
(CN); 1674 (CO)
12.85 (s, 1H, NH); 11.60 (s, 1H,
NH); 8.40–7.20 (m, 13H,
arom.)
67.80
125
methanol
55 C24H15N5O4
(437.41)
65.9
65.98
3.45
3.64
16.01
16.30
3328, 3198 (2NH); 2202
(CN); 1688(CO)
8.60 (s, 1H, NH); 8.50 –7.25
(m, 13H, arom.); 6.70 (s, 1H,
NH)
212 ethanol 63 C25H18N4O3
(422.43)
71.10
71.31
4.29
4.50
13.26
13.04
3305, 3174 (2NH); 2920
(CHaliph.); 2207 (CN);
1697 (CO)
12.30 (s, 1H, NH); 11.00 (s, 1H,
NH); 8.20–7.00 (m, 13H,
arom.); 3.45 (s, 3H, CH3)
12.85 (s, 1H, NH); 11.70 (s, 1H,
NH); 8.90–6.60 (m, 14H,
arom.); 4.45–4.15 (br, 2H,
NH2)
230 ethanol 82 C24H18N4O2S
(426.49)
67.59
67.40
4.25
4.00
13.14
13.35
7.52 3430, 3340, 3210, 3176
7.70 (2NH, NH2); 1671 (CO)

6a
6b
288
benzene
74 C21H16N4OS
(372.44)
67.72
67.99
4.33
4.10
15.04
15.12
8.61 3373, 3289, 3180 (3NH); 12.75 (s, 1H, NH); 11.60 (s, 1H,
8.40
1672 (CO)
NH); 8.60 (s, 1H, NH); 8.25–
6.40 (m, 13H, arom.)
290
benzene
79 C21H17N5O
(355.39)
70.97
70.77
4.82
4.60
19.71
19.51
3430, 3390, 3280, 3200
(4NH); 1670 (CO)
12.40 (s, 1H, NH); 11.15 (s, 1H,
NH); 8.10–6.90 (m, 13H,
arom.); 6.70 (s, 1H, NH); 6.50
(s, 1H, NH)
7a
7b
8
278 ethanol 63 C17H16N4OS
(324.40)
62.94
62.99
4.97
4.88
17.27
17.35
9.88 3420, 3360, 3191 (3NH); 12.55 (s, 1H, NH); 11.60 (s, 1H,
9.96
2906 (CHaliph.); 1672
(CO)
NH); 8.90 (s, 1H, NH); 8.55 –
7.30 (m, 9H, arom.); 2.60–
1.80 (br, 4H, 2CH2)
258
dioxane
68 C17H17N5O
(307.35)
66.43
66.55
5.57
5.62
22.79
22.91
3440, 3380, 3188, 3150
(4NH); 2906 (CHaliph.);
1672 (CO)
8.90 (s, 1H, NH); 8.25 –6.90
(m,10H, arom.þ NH); 6.20 –
5.55 (br, 2H, 2NH); 3.70–3.15
(m, 4H, 2CH2)
150 ethanol 96 C16H11N3O
(261.28)
73.55
73.35
4.24
4.52
16.08
16.18
3206 (NH); 2214 (CN);
1715 (CO)
10.60 (s, 1H, NH); 8.00–6.40
(m, 9H, arom.); 6.10 (s, 1H,
CH)
9a
9b
10
84 CHCl3
53 C16H10N3OBr
(340.18)
56.49
56.52
45.86
45.9
2.96
2.84
2.16
2.31
5.37
5.12
12.35
12.55
10.03
10.22
21.93
21.80
3196 (NH); 2208 (CN);
1697 (CO); 697 (C–Br)
3198 (NH); 2217 (CN);
1689 (CO); 692 (C–Br)
3421, 3360, 3165, 3065
(2NH, NH2); 2980
10.40 (s, 1H, NH); 8.30–6.85
(m, 9H, arom.)
132 CHCl3
40 C16H9N3OBr2
(419.07)
11.00 (s, 1H, NH); 8.60–6.70
(m, 8H, arom.)
158 ethanol 71 C18H17N5O
(319.36)
67.7
67.82
11.35 (s, 1H, NH); 8.30–7.30
(m, 9H, arom.); 7.20 (s, 2H,
NH2); 7.00 (s, 1H, NH); 2.60–
2.20 (m, 4H, 2CH2)
(CHaliph.); 1695 (CO)
(continued)

Table 1. Continued
Analytical datab cal./found
Product
no.
Yield Mole. form.
(Mol.wt.)
M. P. (8C)a (%)
C
H
N
S
IR (cm21 c
)
1H-NMR @ (ppm)d
11
149
methanol
73 C22H16N5OBr
(446.31)
59.21
59.15
3.61
3.82
15.69
15.87
3422, 3260, 3179, 3100
(2NH, NH2); 1710 (CO)
11.90 (s, 1H, NH); 8.50–6.20
(m, 13H, arom.þ NH); 3.80–
3.20 (br, 2H, NH2)
12
13
Sub. at 320 81 C22H16N4OS
CHCl3
68.73
68.60
4.19
4.22
14.57
14.32
8.34 3260, 3165, 3100 (NH,
8.45 NH2); 1694 (CO)
11.15 (s, 1H, NH); 8.30–6.35
(m, 13H, arom.); 4.15–3.35
(br, 2H, NH2)
(384.45)
140
dioxane
62 C18H16N4OS
(336.41)
64.27
64.30
4.79
4.83
16.65
16.34
9.53 3400, 3350, 3166 (NH,
NH2); 2926, 2861
9.56 (CHaliph.); 1699 (CO)
11.60 (s, 1H, NH); 8.40–6.70
(m, 9H, arom.); 6.45–6.00 (br,
2H, NH2); 3.65–2.35 (m, 4H,
2CH2)
14
15
170
benzene
50 C17H13N6
OSBr
(429.31)
47.56
47.69
3.05
3.18
19.58
19.37
7.47 3350, 3300, 3290, 3240,
7.66
11.00 (s, 1H, NH); 8.25–6.75
(m, 8H, arom.); 3.80–3.20
(m, 4H, 2NH2)
3200 (NH, 2NH2); 1715
(CO)
170
benzene
60 C17H13N6OBr
(397.24)
51.40
51.46
3.30
3.50
21.16
21.39
3300, 3250, 3220, 3180,
3100 (3NH, NH2); 1720
(CO)
11.25 (s, 1H, NH); 10.00 (s, 1H,
NH); 8.15–7.30 (m, 8H,
arom.); 7.20 (s, 1H, NH);
4.50–4.25 (br, 2H, NH2)
16
193 ethanol 66 C21H17N3O2
(343.38)
73.45
73.25
4.99
4.86
12.24
12.31
3290, 3180 (2NH); 2973, 10.15 (s, 1H, NH); 7.90–6.75
2920 (CHaliph.); 1685
(CO)
(m, 9H, arom.); 6.00 (s, 1H,
NH); 2.70–2.10 (m, 4H,
2CH2); 1.30–0.85 (m, 2H,
CH2)

17
18
170 Acetic
acid
87 C22H18N4O
(354.41)
74.56
74.26
5.12
5.23
15.81
16.01
3220, 3183(2NH); 2865
(CHaliph.); 1682 (CO)
11.30 (s, 1H, NH); 10.80 (s, 1H,
NH); 8.60–7.15 (m, 13H,
arom.); 2.55 (s, 3H, CH3)
10.80 (s, 1H, NH); 7.65–7.10
(m, 13H, arom.); 6.90 (s, 1H,
NH); 4.00 (s, 2H, NH2); 2.50
(s, 3H, CH3)
218 ethanol 70 C25H20N6O
(420.47)
71.41
71.6
4.79
4.99
19.99
19.7
3441, 3320, 3203, 3110
(2NH, NH2); 2919
(CHaliph.); 2201 (CN); 1672
(CO)
19
20
21
205
benzene
66 C25H21N7O
(435.49)
68.95
68.85
4.86
4.59
22.51
22.72
3447, 3300, 3190 (3NH); 11.00 (s, 1H, NH); 8.50–7.10
2914 (CHaliph.); 1662
(CO)
(m, 14H, arom. þNH); 3.65
(s, 2H, CH2); 3.40 (s, 1H, NH);
2.60 (s, 3H, CH3)
222
benzene
53 C27H24N4O
(420.51)
77.12
77.33
5.75
5.83
13.32
13.50
3300, 3198 (2NH); 2910
(CHaliph.); 1660 (CO)
10.50 (s, 1H, NH); 7.70–7.05
(m, 13H, arom.); 6.85 (s, 1H,
NH); 2.60 (s, 3H, CH3); 2.0–
0.90 (m, 6H, CH2cyclic
)
200
dioxane
79 C26H18N6OS
(462.53)
67.52
67.77
3.92
3.7
18.17
18.33
6.93 3300, 3198 (2NH); 2210
6.98
10.1 (s, 1H, NH); 7.70–7.05
(m, 13H, arom.); 6.2 (s, 1H,
NH); 2.60 (s, 3H, CH3)
(CN); 1670 (CO)
aUncorrected.
bSatisfactory microanalysis obtained C; + 0.35, H; + 0.4, N; + 0.2, S; + 0. 2.
cMeasured by Nicolet FT-IR 710 Spectrophotometer.
dMeasured by a Varian EM 360 L spectrometer at 60 MHZ using TMS as internal standard and DMSO as a solvent.

3252
A. Khodairy et al.
(1,5)benzodiazepine-3,20-(30-amino(l0,40)benzothiazine)] 12, spiro[2-oxo-4-phe-
nyl-1(H)(1,5)-benzodiazepine-3,20-(30-amino-50,60-dihydro(10,40) thiazine)] 13,
spiro[2-oxo-4-(p-bromopheny1)-1 (H)(1,5)benzo diazepine-3,60-(20,50-diamino-
(10,30,40)thiadiazine)] 14, spiro [2-oxo-4-(p-bromopheny1)-1 (H)(1,5)-benzo-
diazepine-3,50-(40-amino-20-imino-10(H)imidazole)] 15, and spiro[2-oxo-4-phe-
ny1-1(H)(1,5)-benzodiazepine-3,30-(20-imino-40,50,60-trihydrocyclopentafuran)]
16, respectively (cf. Scheme 2, Table 1). The reaction pathway of the
formation of compounds 10–15 was assumed to proceed via a nucleophilic
attack of the NH2 or the SH groups at the C-Br bond with elimination of the
HBr molecule, followed by intramolecular cyclization through the nucleophilic
addition of the NH2 group at the CN group.
Compound 1 was reacted with p-tolyldiazonium chloride to give
3-(p-tolylazo)-4-phenyl-1(H)(1,5)benzodiazepin-2-one 17. The reaction of
compound 17 with active nitriles, namely malononitrile, cyanoacetamide, or
cyanothioacetamide, gave the same product: spiro [2-oxo-4-phenyl-
1(H)(1,5)benzodiazepine-3,30-(50aino-40-cyano-10-(p-tolyl)-20(H)-pyrazole)] 18.
Treatment of compound 17 with cyanoacetohydrazide afforded spiro[2-oxo-
4-phenyl-1(H)(1,5)benzodiazepine-3,30-(20,60-dihydro-50-imino-40-(p-tolyl)
pyrazole][40,30-b]pyrazole)] 19. Moreover, the reaction of compound 17 with
cyclopentanone and TEA in dioxane yielded spiro[2-oxo-4-phenyl-
1(H)(1,5)benzodiazepine-3,30-(10-(p-tolyl)-20,40,50,60-tetrahydrocyclopentap-
yrazole)] 20 (cf. Scheme 3, Table 1). The reaction pathway of compound 18
was assumed to follow a preliminary formation of carbanion of the active
methylene group, which was added at the -C55N-bondbenzodiazepine followed
by a nucleophilic attack of the NH group at the CN, CO, and CS groups
with the elimination of the water molecule in the case of cyanoacetamide or
the H2S molecule in the case of cyanothioacetamide.
The reaction of compound 17 with CS2 and malononitrile in 1:1:1 molar
ratio under phas-transfer-catalysis (PTC) conditions [dioxane/potassium
carbonate/tetrabutylammonium bromide (TBAB)] gave spiro[2-oxo-4-
phenyl-1(H)(1,5)benzodiazepine-3,20-(40-(p-tolyl)-30 (H)(10,30,40)-thiadiazol-
50-ylidenemalononitrile)] 21 (cf. Scheme 3, Table 1). The reaction pathway
was assumed to proceed via the addition of the SH group to the -C55N-NH-
Ar bond followed by a nucleophilic attack of the NH group to the ethylenic
bond of the dithioacetal with elimination of the H2S molecule.
EXPERIMENTAL
Synthesis of Compound 2
To a stirred cold solution of compound 1 (0.01 mol, 2.36 g) in glacial acetic
acid (20 mL), sodium nitrite (0.012 mol, 0.83 g) was added over 10 min.
The stirring was continued for 30 min in an ice bath and for 2 h at room

Spiro 1,5-Benzodiazepine
3253
Scheme 2.

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A. Khodairy et al.
Scheme 3.
temperature. The solid precipitate was filtered off, washed with water, dried,
and crystallized (cf. Scheme 1, Table 1).
Synthesis of Compounds 3–5
Compound 2 (0.002 mol, 0.7 g) was added to a solution of the active nitrile
(0.002 mol), namely malononitrile (0.13 g), benzylidenemalononitrile
(0.3 g), p-chlorobenzylidenemalononitrile (0.37 g), p-nitro-benzylidenemalo-
nonitrile (0.39 g), p-methoxybenzyl-idenemalononitrile (0.36 g), or benzy-
lidenecyanothioacetamide (0.37 g), along with a catalytic amount of
triethylamine in dioxane (20 mL). The reaction mixture was refluxed for
4 h, and the solvent was evaporated in vacuo. The formed solid was filtered
off and crystallized from the proper solvent (cf. Scheme 1, Table 1).

Spiro 1,5-Benzodiazepine
3255
Synthesis of Compounds 6a,b and 7a,b
To a stirred solution of compound 2 (0.02 mol, 0.53 g) in dioxane (20 mL), the
appropriate bidentate reagent (0.02 mol) [namely o-aminothiophenol (0.22 mL),
o-phenelenediamine (0.21 g), cystamine hydrochloride (0.22 g), or ethylenedia-
mine (0.13 g)] and a catalytic amount of triethylamine were added. The reaction
mixture was refluxed for 4 h and evaporated in vacuo, and the solid product was
crystallized from the suitable solvent (cf. Scheme 2, Table 1). Note: In case of
cystamine hydrochloride, triethylamine (3 mL, 0.022 mol) was added.
Synthesis of Compound 8
To a stirred suspension of potassium cyanide (0.002 mol, 0.156 g) in
dimethylsulfoxide
(10 mL),
3-bromo-1,3-dihydro-4-phenyl-1,5-benzo-
diazepin-2-one (0.002 mol, 0.63 g) was added dropwise at 908C. The
reaction mixture was further stirred for 30 min and poured into a mixture of
ice-cold water (100 mL). The separated solid was collected by filtration and
crystallized (cf. Scheme 2, Table 1).
Synthesis of Compounds 9a,b
To a stirred solution of compound 8 (0.02 mol, 5.22 g) in chloroform (50 mL),
a solution of bromine (0.02 mol, 1.03 mL) in chloroform (15 mL) was added
dropwise. The stirring was continued until the evolution of HBr gas ceased.
The precipitated solid was filtered off, washed with dilute sodium bicarbonate
solution (20 mL), and crystallized to give compound 9a. The filtrate was eva-
porated in vacuo, and the residual solid was washed with water and crystal-
lized to give compound 9b (cf. Scheme 2, Table 1).
Synthesis of Compound 10
To a solution of compound 9a (0.01 mol, 3.4 g) in dioxane (20 mL), ethylene-
diamine (0.01 mol, 0.67 mL) was added at room temperature. The reaction
mixture was stirred for 4 h, the solvent was evaporated in vacuo, and the
residual mass was treated with water. The separated solid was filtered off
and crystallized (cf. Scheme 2, Table 1).
Synthesis of Compound 11
To a suspension of compound 9b (0.01 mol, 4.19 g) in sodium ethoxide
solution (0.30 g of Na in 30 mL of absolute ethanol), o-phenylenediamine

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A. Khodairy et al.
(0.01 mol, 1.08 g) was added. The reaction mixture was refluxed for 2 h; the
solid that formed after cooling was collected by filtration, washed with water,
and crystallized (cf. Scheme 2, Table 1).
Synthesis of Compound 12
To a suspension of compound 9a (0.01 mol, 3.4 g) in sodium ethoxide solution
(0.3 g of Na in 30 mL of absolute ethanol), o-aminothiophenol (0.01 mol,
1.07 mL) was added. The reaction mixture was refluxed for 4 h wand
worked up as before (cf. Scheme 2, Table 1).
Synthesis of Compound 13
A mixture of a compound 9a (0.01 mol, 3.4 g), cystamine hydrochloride
(0.01 mol, 1.13 g), anhydrous potassium carbonate (3 g), a catalytic amount
of tetrabutyl ammounium bromide (TBAB), and dioxane (20 mL) was
stirred for 40 min at rt. The reaction mixture was further stirred for 4 h at
608C and filtered off, and the organic layer was evaporated in vacuo. The
residual solid was washed with water, collected by filtration, and crystallized
(Scheme 2, Table 1).
Synthesis of Compounds 14 and 15
To a stirred solution of compound 9b (0.01 mol, 4.19 g) in dioxane (20 mL),
thiosemicarbazide (0.01 mol, 0.91 g) or guanidine hydrochloride (0.01 mol,
0.95 g) along with a catalytic amount of triethylamine were added. The
reaction mixture was refluxed for 4 h and evaporated in vacuo, and the
residual solid was collected by filtration and crystallized from the proper
solvent (cf. Scheme 2, Table 1). Note: In case of guanidine hydrochloride,
triethylamine (1.5 mL, 0.011 mol) was added.
Synthesis of Compound 16
To a stirred solution of compound 9a (0.01 mol, 3.4 g) in dioxane (15 mL),
cyclopentanone (0.01 mol, 0.86 mL) and a catalytic amount of triethylamine
were added. The reaction mixture was refluxed for 4 h and worked up as
before (cf. Scheme 2, Table 1).
Synthesis of Compound 17
To a cold mixture of compound 1 (0.01 mol, 2.36 g) and HC1 (4N, 40 mL), a
solution of p-tolyldiazonium chloride (a mixture of 0.01 mol, 1.07 g of

Spiro 1,5-Benzodiazepine
3257
p-toluidine in 10 mL HCl and 0.7 g of NaNO2 in 5 mL of H2O) was added
dropwise with stirring over 15 min. The stirring continued for 30 min, and
the reaction mixture was allowed to stand for 2 h at room temperature. The
precipitated solid was collected by filtration, washed with water, and crystal-
lized (cf. Scheme 3, Table 1).
Synthesis of Compounds 18–20
To a solution of compound 17 (0.002 mol, 0.71 g) in dioxane (20 mL), the
appropriate active methylene (0.002 mol) [namely malononitrile (0.13 g),
cyanoacetamide (0.17 g), cyanothioacetamide (0.2 g), cyanoacetohydrazide
(0.19 g), or cycloheptanone (0.17 mL)] and two drops of triethylamine were
added. The reaction mixture was refluxed for 3 h and cooled to room tempera-
ture. The precipitated solid was collected by filtration and crystallized from
the proper solvent (cf. Scheme 3, Table 1).
Synthesis of Compound 21
A mixture of malononitrile (0.04 mol, 2.64 g), CS2 (0.045 mol, 2.7 mL),
anhydrous potassium carbonate (3 g), a catalytic amount of TBAB, and
dioxane (20 mL) was stirred for 40 min at 608C. Compound 17 (0.02 mol,
0.71 g) was added to the dianionic ambident. The reaction mixture was
stirred for 6 h at 408C and filtered. The solvent was evaporated in vacuo.
The residual solid was washed with water, collected by filtration, and crystal-
lized (cf. Scheme 3, Table 1).
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