Studies in large ring compounds: Synthesis of some new morphanthrindines and diazocines

Article abstract of DOI:10.1081/SCC-120004842

A novel method for the synthesis of 2 or 3-substituted 5,6-dihydro-6,11-dioxo-morphanthridines (2) involving the cyclisation of anilinic acid (1) with PPA/AcOH has been developed. A new heterocyclic system, 2 or 3-Substituted 5,6,11,12-tetrahydrodibenzo[b, f] [1,4]diazocine-6,11-diones(4) has been synthesized with excellent yields.

Full text of DOI:10.1081/SCC-120004842

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STUDIES IN LARGE RING COMPOUNDS: SYNTHESIS OF
SOME NEW MORPHANTHRINDINES AND DIAZOCINES
V. G. Pawar a , S. R. Bhusare a , R. P. Pawar a & B. M. Bhawal b
a Organic Synthesis Research Laboratory , Dnyanopasak College , Parbhani, 431 401, India
b Organic Chemistry Synthesis Division , National Chemical Laboratory , Pune, 411 008, India
Published online: 16 Aug 2006.
To cite this article: V. G. Pawar , S. R. Bhusare , R. P. Pawar & B. M. Bhawal (2002) STUDIES IN LARGE RING COMPOUNDS:
SYNTHESIS OF SOME NEW MORPHANTHRINDINES AND DIAZOCINES, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:13, 1929-1936, DOI: 10.1081/SCC-120004842
To link to this article: http://dx.doi.org/10.1081/SCC-120004842
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SYNTHETIC COMMUNICATIONS, 32(13), 1929–1936 (2002)
STUDIES IN LARGE RING COMPOUNDS:
SYNTHESIS OF SOME NEW
MORPHANTHRINDINES
AND DIAZOCINES
V. G. Pawar,1 S. R. Bhusare,1 R. P. Pawar,1
and B. M. Bhawal2,
*
1Organic Synthesis Research Laboratory, Dnyanopasak
College, Parbhani-431 401, India
2Organic Chemistry Synthesis Division, National
Chemical Laboratory, Pune-411 008, India
ABSTRACT
A novel methodfor the synthesis of 2 or 3-substituted
5,6-dihydro-6,11-dioxo-morphanthridines (2) involving the
cyclisation of anilinic acid( 1) with PPA/AcOH has been
developed. A new heterocyclic system, 2 or 3-Substituted
5,6,11,12-tetrahydrodibenzo[b, f] [1,4]diazocine-6,11-diones(4)
has been synthesizedwith excellent yields.
Key Words: Phthalic anhydride; Morphanthrindines; PPA;
Diazocine
Derivatives of 5,6-dihydro-6,11-dioxomorphanthridine-6-oxime (3) are
[1]
useful as a transquilizers andanticeteleptic agents.
In the preparation
of large number of pharmacodynamic compounds,[2,3] 5,6-dihydro-6,11-
dioxomorphanthridines (2) has been usedas a key intermediate. Earlier
*Corresponding author. E-mail: bhawal@dalton.ncl.res.in
1929
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1930
PAWAR ET AL.
workers have synthesized compound diazocinedione (4) by the Schmidt
reaction on anthraquinone[4,5] andBeckmann rearrangement on anthraqui-
none mono-oxime.[6,7] The derivatives of diazocine are used as a amoebici-
dal agents.[8] Several N-substitutedaryl acisd have been usedas non-
steriodal anti-inflammatory agents.[9–12] It was thus felt that the synthesis
of dimeric compounds of anthranilic acids i.e., 5,11-disubstituted dibenzo
[b, f] [1,4] diazocine 6,11-diones (4) wouldbe of considerable importance as
they couldposses pharmacological properties comparable to those of mono-
meric acids and could serve as prodrug capable of releasing anthranilic acid
as slow hydrolysis in vivo. These ‘slow release drugs’ would thus help to
obtain longer periods of action with smaller doses. We were interested to
synthesize some new derivatives of morphanthridines and diazocines.
Here we report the synthesis of some new morphanthridines (2) by
cyclisation of anilinic acids with PPA/AcOH and their conversion to diazo-
cines (4) via Beckmann rearrangement. Anilinic acid( 1) were obtainedin
almost quantitative yield by the condensation of cyclic anhydride with
aromatic amines.[13] The anilinic acidon condensation with PPA/AcOH
affords dioxomorphanthridines (2) in 65–81% yield.
Treatment with hydroxylamine hydrochloride yields the oxime deriva-
tive (3) in 65–85% yield. These oximes on Beckmann rearrangement under
condition afforded diazocines (4) in goodyield(Scheme 1).
EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncor-
rected. IR spectra were recorded in nujol on Perkin-Elmer 237
Spectrophotometer. 1H-NMR was recorded in CDCl3 on Perkin-Elmer-
R-32 Spectrophotometer using TMS as an internal standard. (Chemical
shift is given in d-ppm). Purity of all compounds was 80–95% recorded
on GC.
Synthesis of 3-Methyl-6,11-dioxo-5,6-dihydro-morphanthridine (2g)
A mixture 3-(N-3-methyl aryl carbomyl) benzoic acid(2.55 g,
0.01 mol) andPPA (preparedfrom 10 g P 2O5 and3 mL H PO4) was kept
3
at 95–100ꢀC for 2 h. The reaction mixture was cooledandpouredon
crushedice left for 2 h andfiltered. The solidwas washedwith water and
crystallizedfrom acetic acidto afford1.54 g (65%) of morphanthridine ( 2g),
m.p. 145ꢀC.

MORPHANTHRINDINES AND DIAZOCINES
1931
Scheme 1.
IR (neat): 3200, 1700, 1685, 1650 cmꢁ1. 1H NMR (CDCl3) d: 1.7 (s, 1H,
CONH), 7.27–8.0 (m, 7H, Ar–H), 2.3 (s, 3H, Ar-CH3). Anal. Calcdfor
C15H11NO2 (237.26): C, 75.94; H, 4.67; N, 5.90. Found: C, 75.91; H, 4.64;
N, 5.85.
2a. 73%, m.p. 203ꢀC; IR (neat): 3200, 1705, 1680, 1655 cmꢁ1
NMR (CDCl3) d: 1.8 (s, 1H, CONH), 7.0–8.0 (m, 8H, Ar–H).
Anal. Calcdfor C 14H9NO2 (223.23): C, 75.33; H, 4.06; N, 6.27.
.
1H
Found: C, 75.31; H, 4.10; N, 6.25.
2b. 79%, m.p. 262ꢀC; IR (neat): 3210, 1705, 1680, 1645 cmꢁ1. 1H NMR
(CDCl3) d: 1.7 (s, 1H, CONH), 7.2–8.0 (m, 7H, Ar–H).
Anal. Calcdfor C 15H9NO4 (267.24): C, 67.42; H, 3.39; N, 5.24.
Found: C, 67.41; H, 3.40; N, 5.25.
2c. 80%, m.p. 215ꢀC; IR (neat): 3205, 1710, 1685, 1650 cmꢁ1. 1H NMR
(CDCl3) d: 1.8 (s, 1H, CONH), 7.3–8.0 (m, 7H, Ar–H).

1932
PAWAR ET AL.
Anal. Calcdfor C 15H9NO4 (267.24): C, 67.42; H, 3.39; N, 5.24.
Found: C, 67.45; H, 3.42; N, 5.30.
2d. 75%, m.p. 220ꢀC; IR (neat): 3215, 1710, 1680, 1650 cmꢁ1. 1H NMR
(CDCl3) d: 1.9 (s, 1H, CONH), 6.8–7.8 (m, 7H, Ar–H), 9.4 (s, 1H,
OH).
Anal. Calcdfor C 14H9NO3 (239.23): C, 70.29; H, 3.79; N, 5.85.
Found: C, 70.31; H, 3.81; N, 5.87.
2e. 70%, m.p. 186ꢀC; IR (neat): 3200, 1707, 1690, 1660 cmꢁ1. 1H NMR
(CDCl3) d: 2.1 (s, 1H, CONH), 7.2–7.8 (m, 7H, Ar–H).
Anal. Calcdfor C 14H8N2O4 (268.23): C, 62.69; H, 3.01; N, 10.44.
Found: C, 62.65; H, 3.05; N, 10.45.
2f. 81%, m.p. 181ꢀC; IR (neat): 3210, 1695, 1685, 1650 cmꢁ1. 1H NMR
(CDCl3) d: 1.9 (s, 1H, CONH), 7.2–8.2 (m, 7H, Ar–H).
Anal. Calcdfor C 15H11NO2 (237.26): C, 75.94; H, 4.67; N, 5.90
Found: C, 75.91; H, 4.71; N, 5.95.
2h. 77%, m.p. 168ꢀC; IR (neat): 3220, 1702, 1680, 1660 cmꢁ1. 1H NMR
(CDCl3) d: 2.2 (s, 1H, CONH), 7.0–8.0 (m, 7H, Ar–H), 3.9 (s, 3H, OCH3).
Anal. Calcdfor C 15H11NO3 (253.26): C, 71.14; H, 4.38; N, 5.53.
Found: C, 71.11; H, 4.35; N, 5.55.
2i. 68%, m.p. 172ꢀC; IR (neat): 3200, 1702, 1685, 1653 cmꢁ1. 1H NMR
(CDCl3) d: 1.8 (s, 1H, CONH), 7.0–7.8 (m, 7H, Ar–H).
Anal. Calcdfor C 14H8NO2Br (302.13): C, 55.66; H, 2.67; N, 4.64;
Br, 26.45. Found: C, 55.61; H, 2.63; N, 4.60; Br, 26.42.
2j. 70%, m.p. 132ꢀC; IR (neat): 3200, 1710, 1680, 1647 cmꢁ1. 1H NMR
(CDCl3) d: 1.9 (s, 1H, CONH), 7.0–8.0 (m, 7H, Ar–H).
Anal. Calcdfor C 14H8NO2Cl (257.68): C, 65.26; H, 3.13; N, 5.44;
Cl, 13.76. Found: C, 65.31; H, 3.10; N, 5.45; Cl, 13.78.
Synthesis of Oxime of Dioxomorphanthridines (3g)
A mixture of dioxomorphanthridines 2g (2.37 g, 0.01 mol), hydroxyl
amine hydrochloride (0.7 g, 0.01 mol), ethanol (20 mL) and 0.5 mL of pyri-
dine was refluxed on water bath for 20 min ethanol was removed by distilla-
tion on water bath. Residue was treated with water (5 mL) and stirred in an
ice bath until the crystals appear. The solidwas filtered, washedwith water
andrecrystallisedfrom alcohol to give 1.76 g (70%) of monoxime ( 3g), m.p.
254ꢀC. IR (neat): 3585, 3225, 3010, 1680, 1662 cmꢁ1. 1H NMR (CDCl3) d: 2.2
(s, 3H, CH3), 2.7 (s, 2H, CONH), 7.5–8.5 (m, 7H, Ar–H), 9.2 (s, 1H, ¼N–OH).

MORPHANTHRINDINES AND DIAZOCINES
1933
Anal. Calcdfor C 15H12N2O2 (252.28): C, 71,42; H, 4.79; N, 11.10.
Found: C, 71.51; H, 4.60; N, 11.12.
3a. 85%, m.p. 136ꢀC; IR (neat): 3575, 3230, 3005, 1675, 1640 cmꢁ1
.
1H NMR (CDCl3) d: 2.8 (s, 2H, CONH), 7.5–8.2 (m, 8H, Ar–H), 9.1 (s, 1H,
¼N–OH).
Anal. Calcdfor C 14H10N2O2 (238.25): C, 70.58; H, 4.23; N, 11.76.
Found: C, 70.52; H, 4.35; N, 11.73.
3b. 70%, m.p. 155ꢀC; IR (neat): 3580, 3220, 3010, 2675, 1685,
1
1645 cmꢁ1. H NMR (CDCl3) d: 2.75 (s, 2H, CONH), 7.1–8.2 (m, 7H,
Ar–H), 8.8 (s, 1H, ¼N–OH), 12.5 (s, 1H, OH).
Anal. Calcdfor C 15H10N2O4 (282.26): C, 63.83; H, 3.57; N, 9.92.
Found: C, 63.82; H, 3.60; N, 9.85.
3c. 80%, m.p. 95ꢀC; IR (neat): 3590, 3220, 2690, 1685, 1648 cmꢁ1
.
1H NMR (CDCl3) d: 2.6 (s, 2H, CONH), 7.0–8.5 (m, 7H, Ar–H), 9.5
(s, 1H, ¼N–OH), 12.2 (s, 1H, COOH).
Anal. Calcdfor C 15H10N2O4 (282.26): C, 63.83; H, 3.57; N, 9.92.
Found: C, 63.80; H, 3.65; N, 9.83.
3d. 78%, m.p. 72ꢀC; IR (neat): 3582, 3230, 3015, 1680, 1649 cmꢁ1
.
1H NMR (CDCl3) d: 2.8 (s, 2H, CONH), 7.2–8.5 (m, 7H, Ar–H), 9.3
(s, 1H, ¼N–OH), 8.3 (s, 1H, Ar-OH).
Anal. Calcdfor C 14H10N2O3 (254.25): C, 66.14; H, 3.0; N, 11.02.
Found: C, 66.11; H, 3.06; N, 11.10.
3e. 75%, m.p. 168ꢀC; IR (neat): 3584, 3235, 3010, 1680, 1653 cmꢁ1
.
1H NMR (CDCl3) d: 2.75 (s, 2H, CONH), 7.1–8.6 (m, 7H, Ar–H), 9.4 (s, 1H,
¼N–OH).
Anal. Calcdfor C 14H9N3O4 (283.25): C, 59.37; H, 3.20; N, 14.84.
Found: C, 59.32; H, 3.16; N, 14.82.
3f. 60%, m.p. 198ꢀC; IR (neat): 3585, 3225, 3010, 1685, 1650 cmꢁ1
.
1H NMR (CDCl3) d: 2.2 (s, 3H, CH3), 2.8 (s, 2H, CONH), 7.2–8.7 (m, 7H,
Ar–H), 9.1 (s, 1H, ¼N–OH).
Anal. Calcdfor C 15H12N2O2 (252.28): C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.52; H, 4.69; N, 11.06.
3h. 70%, m.p. 158ꢀC; IR (neat): 3590, 3250, 3020, 1690, 1660 cmꢁ1
.
1H NMR (CDCl3) d: 4.2 (s, 3H, OCH3), 2.73 (s, 2H, CONH), 7.0–7.9
(m, 7H, Ar–H), 9.0 (s, 1H, ¼N–OH).
Anal. Calcdfor C 15H12N2O3 (268.27): C, 67.16; H, 4.51; N, 10.44.
Found: C, 67.11; H, 4.62; N, 10.42.
3i. 65%, m.p. 192ꢀC; IR (neat): 3575, 3230, 3000, 1680,
1655 cmꢁ1 1H NMR (CDCl3) d: 2.65 (s, 2H, CONH), 7.2–8.2 (m, 7H,
.
Ar–H), 9.6 (s, 1H, ¼N–OH).
Anal. Calcdfor C 14H9N2O2Br (317.14): C, 53.02; H, 2.86; N, 8.83.
Found: C, 53.08; H, 2.76; N, 8.92.

1934
PAWAR ET AL.
3j. 67%, m.p. 145ꢀC; IR (neat): 3585, 3225, 3010, 1675, 1652 cmꢁ1
.
1H NMR (CDCl3) d: 2.82 (s, 2H, CONH), 7.3–8.2 (m, 7H, Ar–H), 9.2 (s,
1H, ¼N–OH).
Anal. Calcdfor C 14H9N2O2Cl (272.69): C, 61.66; H, 3.33; N, 10.27.
Found: C, 61.41; H, 3.30; N, 10.19.
Synthesis of 2-Methyl 5,6,11,12 Tetrahydrodibenzo (b–f ) [1,4]
Diazocine-6,11-dione (4g)
Oxime 3g (2.52 g 0.01 mol) was dissolved in anhydrous ether (20 mL)
in a small conical flask and pure thionyl chloride (3 mL) was added to it and
stirred for half-hours. Solvent and other volatile products were distilled off
on water bath. The reaction mixture was treatedwith (25 mL) of water and
boiled for few minutes. Then precipitated product was filtered, washed and
recrystallisedfrom acetic acidto give 1.71 g (68%) of idazocine (
m.p. 124ꢀC.
4g),
IR (neat): 3230, 1680, 1647 cmꢁ1 1H NMR (CDCl3) d: 6.5–7.5
.
(m, 8H, Ar–H), 2.5 (3H, s, Ar–CH3).
Anal. Calcdfor C 15H12N2O2 (252.28): C, 71.42; H, 4.79; N, 11.10;
Found: C, 71.41; H, 4.75; N, 11.14.
4a. 76%, m.p. 115ꢀC; IR (neat): 3200, 1685, 1642 cmꢁ1
(CDCl3) d: 2.75 (s, 2H, CONH), 6.5–7.5 (m, 7H, Ar–H).
Anal. Calcdfor C 14H10N2O2 (238.25): C, 70.58; H, 4.23; N, 11.76.
.
1H NMR
Found: C, 70.51; H, 4.20; N, 11.72.
4b. 75%, m.p. 230ꢀC; IR (neat): 3220, 1680, 1648 cmꢁ1
(CDCl3) d: 2.7 (s, 2H, CONH), 6.5–7.5 (m, 7H, Ar–H).
Anal. Calcdfor C 15H10N2O4 (228.26): C, 63.83; H, 3.57; N, 9.92.
.
1H NMR
Found: C, 63.81; H, 3.50; N, 9.85.
4c. 70%, m.p. 158ꢀC; IR (neat): 3210, 1675, 1650 cmꢁ1
(CDCl3) d: 2.8 (s, 2H, CONH), 6.5–7.7 (m, 7H, Ar–H).
Anal. Calcdfor C 15H10N2O4 (228.26): C, 63.83; H, 3.57; N, 9.92.
.
1H NMR
Found: C, 63.89; H, 3.60; N, 9.96.
4d. 69%, m.p. 172ꢀC; IR (neat): 3200, 1680, 1645 cmꢁ1 1H NMR
.
(CDCl3) d: 2.75 (s, 2H, CONH), 6.7–7.5 (m, 7H, Ar–H), 9.6 (s, 1H, OH).
Anal. Calcdfor C 14H10N2O3 (254.25): C, 66.14; H, 3.96; N, 11.02.
Found: C, 66.18; H, 3.92; N, 11.05.
4e. 74%, m.p. 150ꢀC; IR (neat): 3225, 1685, 1635 cmꢁ1
(CDCl3) d: 2.75 (s, 2H, CONH), 6.6–7.5 (m, 7H, Ar–H).
Anal. Calcdfor C 14H9N3O4 (283.25): C, 59.37; H, 3.20; N, 14.84.
.
1H NMR
Found: C, 59.31; H, 3.22; N, 14.82.

MORPHANTHRINDINES AND DIAZOCINES
1935
4f. 80%, m.p. 152ꢀC; IR (neat): 3210, 1690, 1660 cmꢁ1
.
1H NMR
(CDCl3) d: 2.65 (s, 2H, CONH), 6.5–7.5 (m, 7H, Ar–H), 2.4 (s, 3H, CH3).
Anal. Calcdfor C 15H12N2O2 (252.28): C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.41; H, 4.75; N, 11.12.
4h. 78%, m.p. 173ꢀC; IR (neat): 3200, 1685, 1652 cmꢁ1 1H NMR
.
(CDCl3) d: 2.75 (s, 2H, CONH), 6.5–7.5 (m, 7H, Ar–H), 4.1 (s, 3H, OCH3).
Anal. Calcdfor C 15H12N2O3 (268.27): C, 67.16; H, 4.51; N, 10.44.
Found: C, 67.12; H, 4.52; N, 10.43.
4i. 72%, m.p. 135ꢀC; IR (neat): 3225, 1675, 1645 cmꢁ1
(CDCl3) d: 2.8 (s, 2H, CONH), 6.7–7.7 (m, 7H, Ar–H).
Anal. Calcdfor C 14H9N2O2Br (317.14): C, 53.02; H, 2.86; N, 8.83;
.
1H NMR
Br, 25.19. Found: C, 53.10; H, 2.80; N, 8.85; Br, 25.15.
4j. 75%, m.p. 119ꢀC; IR (neat): 3200, 1685, 1651 cmꢁ1
(CDCl3) d: 2.9 (s, 2H, CONH), 6.6–7.8 (m, 7H, Ar–H).
Anal. Calcdfor C 14H9N2O2Cl (272.69): C, 61.66; H, 3.33; N, 10.27;
.
1H NMR
Cl, 13.00. Found: C, 61.63; H, 3.30; N, 10.25; Cl, 13.04.
ACKNOWLEDGMENT
Wethank Dr. Y. B. Vibhute, Yeshwant Mahavidhylaya Nanded, Dr. W.
N. Jadhav, DnyanopasakCollege, ParbhaniandDr. P. P. Wadgaonkar, NCL,
Pune for their valuable suggestions.
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Receivedin the USA June 23, 2001