Studies with polyfunctionally substituted heteroaromatics: Synthesis of new heterocyclic aromatic amines as potential intermediates for preparation of dyes for thermal diffusion printing

Article abstract of DOI:10.1139/v98-095

Several new dibenzopyrans as well as novel thiadiazaacenaphthenes are obtained via 4 + 2 addition of the thienocoumarins (1) and thienopyridazines (2) to electron-poor olefins.

Full text of DOI:10.1139/v98-095

1038
Studies with polyfunctionally substituted
heteroaromatics: synthesis of new heterocyclic
aromatic amines as potential intermediates for
preparation of dyes for thermal diffusion
printing
Ayman Wahba Erian, Ebtisam Abdul Aziz Hafez, Elham Sayed Darwish, and
Mohamed Hilmy Elnagdi
Abstract: Several new dibenzopyrans as well as novel thiadiazaacenaphthenes are obtained via 4 + 2 addition of the
thienocoumarins (1) and thienopyridazines (2) to electron-poor olefins.
Key words : pyridazines, thienopyridazines, phthalazines, coumarines, thiadiazaacenaphthenes.
Résumé : L’addition 4 + 2 de thiénocoumarines (1) et de thiénopyridazines (2) sur des oléfines pauvres en électron
permet d’obtenir plusieurs dibenzopyranes et thiadiazaacénaphtènes nouveaux.
Mots clés : pyridazines, thiénopyridazines, phtalazines, coumarines, thiadiazaacénaphtènes.
[Traduit par la Rédaction] Erian et al. 1041
3 h) (1 bar = 100 kPa) (12). However, it should be noted that
at atmospheric pressure diene reactivity towards compounds
Heterocyclic aromatic amines are interesting compounds
because of considerable utility as intermediates in both the
pharmaceutical and dye industries (1–6). In the last years we
were involved in a program to develop new polyfunctional
substituted heterocyclic amines for use as agrochemicals and
as intermediates in the dye industry (7–9). During this phase
of our research we have developed a synthesis of benzo-
fused azines via addition of electron-poor olefins and acet-
ylenes to aminothienoazines. It is well documented that
thiophene and its derivatives are reluctant partners in [4+2]
cycloadditions with dienophiles containing a double bond in
general and with dimethyl fumarate in particular. For in-
stance, Gaertner and Tonkyn (10) failed to add maleic anhy-
dride to tetramethylthiophene even when the reaction was
carried out in boiling nitrobenzene (bp 211°C). A similar
failure was also reported by Clapp (11), who attempted to
induce tetraphenylthiophene to react with maleic anhydride.
Similarly, thiophene fails to undergo [4+2] cycloaddition
with dienophiles (12) such as dimethyl maleate, dimethyl
fumarate, methyl acrylate, acrylonitrile, or acrylaldehyde,
even under high pressure. A Diels–Alder adduct was ob-
tained, however, with maleic anhydride (100°C, 15 kbar,
containing a double bond has been observed with 2,5-
dimethoxythiophene (13), 2,4-bis-(N-isopropyl-N-phenyl-
amino)thiophene (14), and 2,3,4,5-di(naphthalene-1,8-
diyl)thiophene (15). However, aminothienopyridazines, be-
ing both electron-rich and strained molecules, add readily to
electron-poor olefins to yield aminophthalazines via [4+2]
cycloaddition reaction followed by ring opening and
aromatization through loss of hydrogen sulfide or elimina-
tion of hydrogen depending on the nature of the reagent and
applied reaction condition (15, 16). To our knowledge this
was the first reported addition of an electron-rich strained
thiophene to an electron-poor olefin. Recently Dopp and co-
workers (17) have reported the addition of dimethyl
fumarate and dimethyl acetylenedicarboxylate to 3-amino-4-
imino-4H-thieno[3,4-c]-benzopyran. Although the reaction
of dimethyl fumarate afforded dibenzopyran via a reaction
sequence similar to that observed earlier by us (15), the
cycloadduct from reaction with dimethyl acetylene dicarbo-
xylate underwent a novel type of rearrangement that af-
forded benzopyrano-thiepine (17). In conjunction of this
work we reported here synthesis of 3-aminothieno[3,4-
c]coumarin (1) and thieno[3,4-d]pyridazin-1-carboxylates
(2) and their reactivity toward electron-poor olefins.
Received July 2, 1997.
A.W. Erian,1 E.A.A. Hafez, and E.S. Darwish. Department
of Chemistry, Faculty of Science, Cairo University, Giza,
Egypt.
M.H. Elnagdi. Department of Chemistry, Faculty of Science,
University of Kuwait, P.O. Box 5965, Safat 13060, Kuwait.
Thus, we have found that 4-methylcoumarin-3-carbo-
nitrile (3) reacts readily with sulfur in refluxing dimethyl-
formamide in the presence of ethanolic piperidine to yield
the thienobenzopyran derivative 1 via the intermediate 4.
This compound readily added N-phenylmaleimide and
1Author to whom correspondence may be addressed.
Telephone: 5932216. Fax: 3601614.
Can. J. Chem. 76: 1038–1041 (1998)
© 1998 NRC Canada

Erian et al.
1039
maleic anhydride to yield the condensed dibenzopyran 6a,b.
Formation of 6 is assumed to proceed via initial [4+2]
cycloaddition of the olefinic double bond to diene system of
1, yielding intermediate cycloadducts 5a and 5b that then
loses hydrogen sulfide to yield the final isolable product.
This is similar to the recently reported (17) behaviour of 3-
amino-4-imino-4H-thieno[3,4-c][1]benzopyran toward di-
methyl fumarate. Similar to this, it has also found that 1 re-
acts with dimethyl fumarate to yield the dibenzopyrane
derivative 8, most likely via the intermediate of the cyclo-
adduct 7.
believed that the methanol eliminated during formation of
12 effects ring opening of the anhydride ring.
Compound 2 reacted with benzoyl isothiocyanate to yield
1
a 1:1 adduct. The H NMR of this adduct revealed the pres-
ence of two lower field D2O exchangeable hydrogen atoms
at δ 12.10 and 15.20 ppm. The absence of any amino hydro-
gens excludes the possibility that the cycloadduct 14 was
formed. It is most likely that this product is the benzoyl
thiourea derivative 13. This assumption is further supported
by 13C NMR data, which did not show any signals for sp3
hybridized besides carbons those of the methyl and methoxy
group (further detail cf. experimentat section).
Compound 2 reacted with methyl acrylate when refluxed
in dioxane containing few drops of acetic acid to yield prod-
ucts of addition and methanol elimination. These are as-
signed structure 11 and are assumed to be formed via
rearrangement of the initially formed cycloadduct 9 to 10 in
presence of acid medium. The latter cyclized via loss of
methanol to give 11. If 10 would lose hydrogen sulphide to
yield a phthalazine, the methyl and ester function in this
product would experience large steric interactions. The
structure proposed for compound 11 was established with
All melting points are uncorrected, IR spectra were ob-
tained on a Pye Unicam SP 1000 spectrophotometer using
KBr discs. The 1H NMR were recorded on a varian EM 390-
90 MHz, and Bruker WM 300 MHz using TMS as internal
reference. The chemical shifts were expressed as a δ ppm
GCMS-QP 1000-EX Shimadzu, Japan. Analytical data were
obtained from the microanalytical data unit at Cairo Univer-
sity.
1
13C NMR. Furthermore H NMR showed an AB multiplet
near δ 3.00 ppm for CH2 protons at position C-8. Similarly,
the reaction of maleic anhydride with 2 afforded 12. It is
© 1998 NRC Canada

1040
Can. J. Chem. Vol. 76, 1998
3-Aminothieno[3,4-c]coumarin (1)
9-(N-Phenyl)-8,10-dioxoisoindolo[5,6-c]coumarin-7-
amine (6a)
To a solution of 3 (1.8 g, 0.01 mol) in DMF (15 mL) con-
taining few drops of piperidine was added elemental sulfur
(0.32 g, 0.01 mol). The reaction mixture was heated under
reflux for 5 h, then left to cool. The resulting solution was
poured on ice water and acidified with few drops of hydro-
chloric acid. The resulting precipitate was collected by filtra-
tion and crystallized from ethanol to give yellow plates
(1.9 g, 87%), mp 195°C. IR, ν (KBr): 3400–3300 (NH2) and
1680 cm–1 (CϭO). 1H NMR (DMSO), δ: 3.45 (br, 2H, NH2),
6.9–8.15 ppm (M, 5H, Ar-H, and thiophene H). Anal. calcd.
for C11H7NO2S (217): C 60.8, H 3.2, N 6.4, S 14.7; found:
C 60.7, H 3.1, N 6.2, S 14.5.
A solution of 1 (2.17 g, 0.01 mol) in a mixture of acetic
acid (10 mL) and dioxane (10 mL) was treated with N-
phenylmaleimide (1.7 g, 0.01 mol) and refluxed for 8 h. Af-
ter evaporation of the solvents the solid product was col-
lected by filtration and crystallized from dioxane to give
yellow needles (3.3 g, 94%), mp > 300°C. IR, ν (KBr):
3440–3322 (NH2), 3043 (CH aromatic), 1760–1709 (3
1
CϭO), and 1630 cm–1 (CϭC). H NMR (DMSO), δ: 7.74–
7.39 (m, 9H, Ar-H), 8.06 (s, 1H, H-11), and 8.60 ppm (br,
2H, NH2). Anal. calcd. for C21H12N2O4 (356): C 70.7, H 3.3,
N 7.8; found: C 70.7, H 3.2, N 7.5. Mass, m/z: 356 (M+).
4-Methylcoumarin-3-carbonitrile (3)
8,10-Dioxoisobenzofuro[5,6-c]coumarin-7-amine (6b)
A solution of 1 (2.17 g, 0.01 mol) in a mixture of acetic
acid (10 mL) was treated with maleic anhydride (0.98 g,
0.01 mol) and refluxed for 3 h. The solvents were evapo-
rated, and the solid product was washed with ethanol, col-
lected by filtration, and crystallized from ethanol to give
yellow needles (2.2 g, 78%), mp 194°C. IR, ν (KBr): 3433–
3340 (NH2), 3084 (CH aromatic), 1835–1763(3 CϭO), and
In a flask fitted with a Dean–Stark trap, a solution of o-
hydroxy-acetophenone (1.36 g, 0.01 mol) in a mixture of
acetic acid (10 mL) and toluene (10 mL), ammonium acetate
(2 g), and malononitrile (0.66 g, 0.01 mol) was refluxed for
6 h. The solvents were evaporated in vacuo, and the remain-
ing solid was collected and crystallized from acetic acid to
give yellow needles, mp 184°C.
© 1998 NRC Canada

Erian et al.
1041
1
1630 cm–1 (CϭC). H NMR (DMSO), δ: 7.20–7.82 (m, 4H,
Ar-H), 8.00 (s, 1H, H-11), and 8.50 ppm (br, 2H, NH2).
Anal. calcd. for C15H7NO5 (281): C 64.0, H 2.4, N 4.9;
found: C 63.9, H 2.3, N 4.7. Mass, m/z: 281 (M+).
moiety). Anal. calcd. for C20H17N3O6S (427): C 56.2, H 3.9,
N 9.8, S 7.4; found: C 56.0, H 3.6, N 9.5, S 7.1. Mass, m/z:
427 (M+).
1-Benzyl-5-[7-methyl-3,4-dihydro-7-methyl-3-(p-tolyl)-4-
oxo-thieno[3,4-d]pyridazin-1-carboxylate]-3-ylthiourea
(13)
Dimethyl 4-aminobenzo[c]coumarin-2,3-dicarboxylate (8)
A mixture of 1 (2.17 g, 0.01 mol) and dimethyl fumarate
(1.44 g, 0.01 mol) was heated in an oil bath at 170°C for
4 h. The reaction mixture was cooled, then triturated with
ethanol. The solid product, so formed, was collected by fil-
tration and crystallized from dioxane as brown needles,
(2.5 g, 76%), mp > 300°C. IR, ν (KBr): 3464–3351 (NH2),
3095 (CH aromatic), and 1721–1608 cm–1 (3 CϭO). 1H
NMR (300 MHz, CDCl3), δ: 3.68 (3 H, s, CO2Me), 3.74
(3H, s, CO2Me), 6.69–7.06 (1H, dd, J = 8.19 and 1.15, 7-H),
7.02 (1H, s, 1-H), 7.05–7.15 (1H, ddd, J = 7.91, 7.69, and
1.18, 9-H), 7.27–7.36 (1H, ddd, J = 8.16, 7.75, and 1.47, 8-
H), 7.74–7.78 (1H, dd, J = 8.11 and 1.41, 10-H), 9.05 (2H,
br s, NH2). Anal. calcd. for C17H13NO6 (327): C 62.3, H 3.9,
N 4.2; found: C 62.2, H 3.8, N 4.1. Mass, m/z: 327 (M+).
To a suspension of ammonium thiocyanate (0.76 g, 0.01
mol) in dry acetone (20 mL), benzoyl chloride (1.4 g, 0.01
mol) was added. The reaction mixture was refluxed for
5 min then treated with 2 (3.2 g, 0.01 mol). The reaction
mixture was refluxed for 3 h, then left to cool. The resulting
solution was poured onto ice water. The solid product, so
formed, was collected by filtration and crystallized from
dioxane as yellow needles (4.8 g, 97%), mp 270°C. IR, ν
(KBr): 3350–3220 (2 NH), 2948 (CH3), 1732 (ester CO),
1
1675 (2 CϭO), and 1641 cm–1 (CϭC). H NMR (DMSO),
δ: 2.40 (s, 3H, CH3), 3.30 (s, 3H, CH3), 3.98 (s, 3H, OCH3),
7.3–7.7 (m, 9H, Ar-H), 12.10 (br, 1H, NH), and 15.20 ppm
(br, 1H, NH). 13C NMR, δ: 177.08 (CϭO), 174.32 (CϭO),
169.26 (CϭS), 165.71 (ring CϭO), 159.12 (C-1), 147.95
(C-5), 139.31–125.65 (phenyl ring), 121.96 (C-7), 117.38
(C-7a), 106.42 (C-4a), 54.65 (CH3), 22.26 (CH3), 14.92
(CH3). Anal. calcd. for C24H20N4S2O4(492): C 58.5, H 4.0,
N 11.3, S 13.0; found: C 58.2, H 3.9, N 11.1, S 12.6. Mass,
m/z: 492(M+).
Methyl 6-amino-8,8a-dihydro-2,5-dioxo-8a-methyl-4-(p-
tolyl)-1,3,4-thiadiazaacenaphthene-7-carboxylate (11)
A solution of 2 (3.2 g, 0.01 mol) in dioxane (20 mL) and
few drops of acetic acid was treated with methyl acrylate
(0.86 g, 0.01 mol). The reaction mixture was refluxed for
10 h, then evaporated in vacuo. The remaining product was
triturated with water, and the resulting solid product was
collected by filtration and crystallized from dioxane as red
needles (3 g, 79%), mp 201°C. IR, ν (KBr): 3402–3292
(NH2), 2987 (CH3), 1711 (CϭO), 1676 (ring CO), 1675
1. A.G. Gilman and L.S. Goodman. The pharmaceutical basis of
therapeutics. Macmillan, New York. 1985. p. 1109.
2. J.M. Domagala and P. Peterson. J. Heterocycl. Chem. 26, 1147
(1989), and refs. cited therein.
3 W.F. von Oettingen. The therapeutic agents of the quinoline
group. Chemical Catalog Co., New York. 1933.
4. R.B. Woodward and W.E. Doering. J. Am. Chem. Soc. 67, 860
(1945).
5. E. Hahn. In Lectures in heterocyclic chemistry IX. Edited by
R.N. Castle. 1990. p. 13.
6. F. Fanger, S. Nicklen, and A.R. Coulson. Proc. Natl. Acad.
Sci. U.S.A. 74, 5463 (1977).
1
(CO), and 1620 cm–1 (CϭC). H NMR (300 MHz, DMSO),
δ: 1.82 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.95 and 3.16 (AB
system, 2H, CH2, JAB = 15.7 Hz), 3.70 (s, 3H, OCH3),
7.31–7.68 (m, 4H, aromatic protons), and 8.10 ppm (br, 2H,
NH2); 13C NMR, δ: 194.20 (C-2), 171.35 (CϭO ester),
163.29 (C-5), 153.07 (C-2a), 146.01 (C-6), 144.22, 133.11,
131.20, 129.42 (aromatic ring), 124.35 (C-5a), 104.0 (C-7),
80.56 (C-8a), 50.91 (C-8), 54.82 (CH3), 15.48 (CH3). Anal.
calcd. for C19H17N3O4S (383): C 59.5, H 4.4, N 10.9, S 8.3;
found: C 59.3, H 4.2, N 10.8, S 8.2. Mass, m/z: 383 (M+).
7. M.H. Elnagdi, M.R.H. Elmoghayar, and G.E.H. Elgemeie.
Chemistry of pyrazolopyrimidines. In Advances in
heterocyclic chemistry. Vol. 41. Edited by A.R. Katritzky. Aca-
demic Press, New York. 1987. p. 319.
8. M.H. Elnagdi, N.S. Ibrahim, F.M. Abdelrazek, and A.W.
Erian. Liebigs Ann. Chem. 909 (1988).
9. M.H. Elnagdi and K.U. Sadek. Synthesis, 483 (1988).
10. R. Gaertner and R.G. Tonkyn. J. Am. Chem. Soc. 73, 5872
(1951).
11. D.B. Clapp. J. Am. Chem. Soc. 61, 2733 (1939).
12. H. Kotsuki, S. Kitagawa, H. Nishizawa, and T. Tokoroyama. J.
Org. Chem. 43, 1471 (1978).
13. J.M. Barker, P.R. Huddleston, and S.W. Shutler. J. Chem. Soc.
Perkin Trans. 1, 2483 (1975).
Methyl 6-amino-8,8a-dihydro-2,5-dioxo-8a-methyl-4-(p-
tolyl)-1,3,4-thiadiazaacenaphthene-7-carboxy-8-
carboxylate (12)
A solution of 2 (3.2 g, 0.01 mol) in a mixture of acetic
acid (10 mL) and dioxane (10 mL) was treated with maleic
anhydride (0.98 g, 0.01 mol). The reaction mixture was
refluxed for 10 h. The reaction mixture was evaporated, then
washed with ethanol. The solid product, so formed, was col-
lected by filtration and crystallized from ethanol–dioxane as
orange needles (3 g, 71%), mp 280°C. IR, ν (KBr): 3446–
3251 (NH2), 3035 (CH aromatic), 2953 (CH3), 1830–1731–
14. J.P. Chupp. J. Heterocycl. Chem. 7, 285 (1970).
15. M.H. Elnagdi, A.M. Negm, and K.U. Sadek. Synlett, 27
(1994).
1
1673 (4 CϭO), and 1637 cm–1 (CϭC). H NMR (DMSO),
16. M.H. Elnagdi, R.M. Mohareb, F.A. Abdel Aal, and H.A.
Mohamed. Phosphorus and sulfur. 82, 195 (1993).
17. E. Nyiondi-Bonguen, F.E. Sopbue, F.Z. Tanee, and D. Dopp. J.
Chem. Soc. Perkin Trans. 1, 2191 (1994).
δ: 2.40 (s, 3H, CH3), 2.79 (s, 3H, CH3), 3.40 (s, 3H, OCH3),
3.98 (s, 1H, C-8), 7.3–7.7 (m, 4H, Ar-H), 8.88 (br, protons
of NH2), and 11.70 ppm (s, 1H, COOH) (the downfield shift
of the amino group due to the effect of the amino acid
© 1998 NRC Canada