Synthesis of 6,8-diarylimino-7H-pyrano[3,2-c:5,6-c'] dicoumarins; chemoselective hydrolysis of the ether-and imino-functions

Article abstract of DOI:10.3184/174751911X12964930076485

POCl₃-induced dehydration of 3,3′-methylenedi(2-arylamino- 4H-chromen-4-ones) gives 6,8-diarylimino-7H-pyrano[3,2-c:5,6-c']dicoumarins, which undergo chemoselective hydrolysis of the imino function to form 7H-pyrano[3,2-c:5,6-c']dicoumarins by heating with HCl in methanol However, cleavage of the ether function occurs upon heating in acetic acid to give 3,3′-methylenedi(2-arylamino-4H-chromen-4-ones).

Full text of DOI:10.3184/174751911X12964930076485

84 RESEARCH PAPER
FEBRUARY, 84–86
JOURNAL OF CHEMICAL RESEARCH 2011
Synthesis of 6,8-diarylimino-7H-pyrano[3,2-c:5,6-c’]dicoumarins;
chemoselective hydrolysis of the ether- and imino-functions
Sourav Maiti, Suman Kalyan Panja and Chandrakanta Bandyopadhyay*
Department of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata -700 118, West Bengal, India
POCl3-induced dehydration of 3,3′-methylenedi(2-arylamino-4H-chromen-4-ones) gives 6,8-diarylimino-7H-
pyrano[3,2-c:5,6-c’]dicoumarins, which undergo chemoselective hydrolysis of the imino function to form 7H-
pyrano[3,2-c:5,6-c’]dicoumarins by heating with HCl in methanol However, cleavage of the ether function occurs
upon heating in acetic acid to give 3,3′-methylenedi(2-arylamino-4H-chromen-4-ones).
Keywords: 2-aminochromone-3-carbaldehyde, coumarin, iminocoumarin, bischromone, 1-benzopyran, phosphorous
oxychloride
Iminocoumarins are an important class of compounds for a
variety of applications. Besides their antimicrobial activity,1
some iminocoumarin dyes act as photosensitisers for dye-
sensitised solar cells.2 Iminocoumarin-based zinc-sensors have
been developed, which are suitable for ratiometric fluores-
cence imaging of neuronal zinc.3 Recently, iminocoumarin-
based fluorescent probes have been developed for the selective
detection of dual specific protein-tyrosine phosphatases.4
Although derivatives of 3,3′-methylene-di(4-hydroxycou-
marin) (commonly known as dicoumarols) have been synthe-
sised readily from 4-hydroxycoumarin and an appropriate
aldehyde under various conditions,5 the corresponding di-
iminocoumarins are scarce in the literature. Iminocoumarins
are generally synthesised from salicylaldehyde by the action of
cyanoacetamide,1 malononitrile or ethyl cyanoacetate.6 They
have also been obtained by a Cu-catalysed multicomponent
reaction of o-hydroxyacetophenone, an appropriate alkyne and
an alkanesulfonyl azide.7
the synthesis of 3,3′-methylenedi(2-arylamino-4H-chromen-
4-ones) 2 by heating 2-arylaminochromone-3-carbaldehydes 1
with secondary amines such as sarcosine, piperidine or
diethylamine in the presence of formalin in DMF (Scheme 1).
We now report the synthesis of 6,8-diarylimino-7H-pyrano
[3,2-c:5,6-c′]dicoumarins 3 and their conversion into the
corresponding dicoumarins 4 which belong to the class of
nonpeptidic HIV protease inhibitors.10
On heating dichromones 2 in POCl3 at 60–80 °C for 5–6 h
subsequent work-up produced diiminocoumarins 3 in moder-
ate yields. The structure of the compounds was established on
1
the basis of IR, H and 13C NMR and mass spectral analyses.
Formation of 3 may be rationalised by considering the initial
attack of the vinylogous amide moiety in 2 on POCl3 to pro-
duce 5 which cyclises readily by the involvement of the second
vinylogus amide group (Scheme 1).
In an attempt to convert the central pyran ring in 3 into a
pyridine ring, compound 3a was heated with urea in AcOH for
1 h. But surprisingly, compound 3a only gave 2a. The same
reaction took place when 3 was heated with ammonium acetate
In continuation of our studies on the deformylative Mannich
reaction on chromone-3-carbaldehyde,8 we have reported9
Scheme 1
* Correspondent. E-mail: kantachandra@rediffmail.com

JOURNAL OF CHEMICAL RESEARCH 2011 85
Table 1 Chemoselective hydrolysis of 3 under different con-
266–268 °C; IR: νmax 3029, 1676, 1643, 1584 cm−1; 1H NMR:
δ (CDCl3) 2.39 (6 H, s, 2 × CH3), 3.42 (2 H, s, CH2), 6.91 (2 H, br. d,
J = 7.2 Hz, ArH), 7.10–7.16 (2 H, m, ArH), 7.21–7.24 (4 H, m, ArH),
7.28–7.39 (6 H, m, ArH), 7.50 (2 H, br. s, 1-H + 13-H); 13C NMR:
δ 20.4, 21.0, 105.0, 114.5, 115.6, 121.3, 123.3, 123.6, 128.3, 128.5,
133.2, 146.5, 147.9, 148.6, 150.6; MS (Positive ion electrospray): m/z
497 [M+H]+, 519 [M+Na]+. Anal. Calcd for C33H24N2O3: C, 79.82;
H, 4.87; N, 5.64. Found: C, 79.53; H, 4.79; N, 5.56%.
6,8-Di(N-phenylimino)-7H-pyrano[3,2-c:5,6-c′]dicoumarin (3b):
Pale yellow crystalline solid (295 mg, 63%); m.p. > 320 °C; IR: νmax
3010, 1680, 1650, 1560 cm−1; 1H NMR: δ (CDCl3) 3.62 (2 H, s, CH2),
7.10–7.15 (4 H, m, ArH), 7.19–7.29 (6 H, m, ArH), 7.31–7.47 (6 H, m,
ArH), 7.87 (2 H, br. d, J = 7.8 Hz, 1-H + 13-H); MS (Positive ion
electrospray): m/z 469 [M+H]+, 491 [M+Na]+. Anal. Calcd for
C31H20N2O3: C, 79.47; H, 4.30; N, 5.98. Found: C, 79.33; H, 4.22; N,
5.90%.
ditions
Entry R1
R2 Method Product
Yield / % M.p./ °C
(lit. M.p./ °C)
1
2
H
H
Ph
Ph
A
B
2b
4b
80
70
300–302
(300–302) 9
322–324
(321–323)11
314–316
322–324
268–270
(268–270) 9
>325
3
4
5
H
H
Ara
Ar
A
B
A
2c
4b
2a
78
72
77
Me Ph
6
7
Me Ph
Me Ar
B
A
4a
2d
66
77
304–306
(304–306) 9
>325
8
Me Ar
B
4a
70
6,8-Di[N-(4-methylphenyl)imino]-7H-pyrano[3,2-c:5,6-c′]dicou-
marin (3c): Pale yellow fine crystalline solid (225 mg, 45%);
aAr = 4-MeC6H4.
Method A: AcOH, reflux, 30 min.
1
m.p. 252–254 °C; IR: νmax 3014, 1672, 1640, 1570 cm−1; H NMR:
Method B: HCl/MeOH, reflux, 30 min.
δ (CDCl3) 2.37 (6 H, s, 2 × CH3), 3.57 (2 H, s, CH2), 7.12 (2 H, br. d,
J = 8.1 Hz, 4-H + 10-H), 7.13–7.19 (6 H, m, ArH), 7.23–7.28 (4 H, m,
ArH), 7.39–7.44 (2 H, m, 3-H + 11-H), 7.82 (2 H, br. d, J = 7.5 Hz,
1-H + 13-H); 13C NMR: 20.4, 21.0, 105.1, 114.8, 115.9, 121.4, 123.2,
123.5, 129.2, 130.9, 133.2, 143.5, 147.7, 148.2, 152.4. Anal. Calcd
for C33H24N2O3: C, 79.82; H, 4.87; N, 5.64. Found: C, 79.69; H, 4.80;
N, 5.50%.
in acetic acid or with thiourea in acetic acid. It appeared to be
a case of acid-catalysed hydrolysis of the central pyran ring
and AcOH was supposed to be responsible for this reversion.
Indeed, compound 3 gave 2 in good yields when heated in
glacial AcOH for only 0.5 h (Scheme 1, Method A) (Table 1,
entries 1, 3, 5 and 7).
2,12-Dimethyl-6,8-di[N-(4-methylphenyl)imino]-7H-pyrano[3,2-
c:5,6-c′]dicoumarin (3d): Yellow fine crystalline solid (245 mg,
1
47%); m.p. 280–282 °C; IR: νmax 3000, 1680, 1640, 1590 cm−1; H
Regarding the synthesis of 7H-pyrano[3,2-c:5,6-c′]
dicoumarins 4, an earlier report revealed that dicoumarol
cyclises to 4 on treatment with (PhO)2POCl/pyridine or KHSO4
or P/I2.11 Dicoumarols derived from 4-hydroxycoumarin and
an aldehyde other than formaldehyde can be cyclised to 4
(having a substituent at its 7-position) by pyridine-acetic
anhydride.12 Diglucosides of dicoumarol also produce 4 and
glucose when treated with Ba(OCH3)2 in methanol.13 All these
methods have shortcomings due to harsh reaction conditions,
tedious work-up or poor yields. The synthesis of 3 gave us
an impetus to check whether 4 can be obtained from 3 by
chemoselective hydrolysis. In compound 3, the arylimino
functions and the ether linkage are susceptible towards hydro-
lysis. The ether function was found to hydrolyse selectively by
heating in acetic acid (Table 1, entries 1, 3, 5 and 7). To hydro-
lyse the arylimino function, mineral acid was considered.
Indeed, compound 4 was obtained in good yield by heating 3
in methanol in the presence of HCl (Scheme 1, Method B)
(Table 1, entries 2, 4, 6 and 8).
NMR: δ (CDCl3) 2.36 (6 H, s, 2 × CH3), 2.46 (6 H, s, 2 × CH3), 3.55
(2 H, s, CH2), 7.01 (2 H, d, J = 8.4 Hz, 4-H + 10-H), 7.16–7.19 (8 H,
m, ArH), 7.21 (2 H, br. d, J = 8.4 Hz, 3-H + 11-H), 7.59 (2 H, br. s,
1-H + 13-H). Anal. Calcd for C35H28N2O3: C, 80.13; H, 5.38; N, 5.34.
Found: C, 79.95; H, 5.28; N, 5.26%.
Synthesis of 7H-pyrano[3,2-c:5,6-c′]dicoumarins 4 by hydrolysis of
3
Four drops of conc. HCl were added to a methanolic suspension
(25 mL) of 3 (1 mmol), at room temperature whereupon an orange-
yellow coloured, clear solution was formed. The resultant solution
was heated under reflux for 0.5 h; a white solid separated. The product
was filtered whilst hot, washed with methanol and crystallised from
benzene-light petroleum (2:1) to afford 4 in good yield. Compounds
3a and 3d produced the same compound, 4a in 66 and 70% yields,
respectively; similarly compounds 3b and 3c produced 4b in 70 and
72% yields, respectively.
2,12-Dimethyl-7H-pyrano[3,2-c:5,6-c′]dicoumarin (4a): White
crystalline solid (250 mg, 72%); m.p. > 325 °C; νmax 2987, 2910, 1725,
1
1630, 1590 cm−1; H NMR: δ (CDCl3) 2.55 (6 H, s, 2 × CH3), 3.57
(2 H, s, CH2), 7.31 (2 H, d, J = 7.8 Hz, 4-H + 10-H), 7.44 (2 H, br. d,
J = 7.8 Hz, 3-H + 11-H), 7.73 (2 H, br. s, 1-H + 13-H); MS (Positive
ion electrospray): m/z 347 [M+H]+, 369 [M+Na]+. Anal. Calcd for
C21H14O5: C, 72.83; H, 4.07. Found: C, 72.66; H, 3.98%.
In conclusion, we have achieved an easy route for the syn-
thesis of 6,8-diarylimino-7H-pyrano[3,2-c:5,6-c′]dicoumarins
3 and their chemoselective hydrolysis to 3,3′-methylenedi
7H-Pyrano[3,2-c:5,6-c′]dicoumarin (4b): White crystalline solid
(250 mg, 78%); m.p 322–324 °C (lit11 m.p. 321–323 °C); νmax 3060,
2924, 1724, 1619, 1586 cm−1; 1H NMR: δ (CDCl3) 3.61 (2 H, s, CH2),
7.38–7.48 (4 H, m, ArH), 7.61–7.69 (2 H, m, 3-H + 11-H), 7.99 (2 H,
dd, J = 7.8, 1.5 Hz, 1-H + 13-H); 13C NMR: 18.5, 102.1, 113.3, 117.2,
122.1, 124.6, 132.7, 152.5, 154.2, 179.6. Anal. Calcd for C19H10O5:
C, 71.70; H, 3.17. Found: C, 71.58; H, 3.25%.
(2-arylamino-4H-chromen-4-ones)
c:5,6-c′]dicoumarins 4.
2 and 7H-pyrano[3,2-
Experimental
The recorded melting points are uncorrected. IR spectra were recorded
in KBr on a Beckman IR 20A spectrophotometer. H and 13C NMR
1
spectra were obtained on a Bruker spectrometer at 300 MHz and
75 MHz respectively. Mass spectra were recorded on a Qtof Micro
YA 263 instrument and elemental analysis on a Perkin Elmer 240c
elemental analyser. Light petroleum refers to the fraction with b.p.
60–80 °C. All chemicals used were of commercial grade and were
used as such.
Hydrolysis of 3 to produce 2
Compound 3 (1 mmol) was heated in glacial acetic acid (15 mL) for
0.5 h under reflux. On cooling, the reaction mixture afforded a white
solid. The precipitated solid was filtered off, washed with methanol,
dried in air and crystallised from benzene-petroleum ether (10:1) to
afford 2a–d, which were found to be identical in all respects with the
corresponding compounds 2 from which compound 3 was obtained by
treatment with POCl3.
Reaction of dichromone 2 with POCl3; general procedure
Dichromone 2 (1 mmol) was heated with POCl3 (10 mL) in an oil bath
at 60–80 °C for 5–6 h. The reaction mixture was cooled to room tem-
perature and poured into crushed ice (100 g). The separated solid
was filtered, washed with water, dried in air and crystallised from
benzene-light petroleum (6:1) to afford 3.
2,12-Dimethyl-6,8-di(N-phenylimino)-7H-pyrano[3,2-c:5,6-c′]
dicoumarin (3a): Pale yellow crystalline solid (285 mg, 57%); m.p.
We gratefully acknowledge CSIR, New Delhi [project no.
01(2206)/07/EMR-II] for financial assistance; IICB, Jadavpur
for spectral analysis and finally the college authority for
providing research facilities.

86 JOURNAL OF CHEMICAL RESEARCH 2011
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J. Volmajer, R. Toplak, S. Bittner, I. Leban and A.M. Le Marechal,
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Received 21 September 2010; accepted 2 December 2010
Paper 1000367 doi: 10.3184/174751911X12964930076485
Published online: 10 February 2011
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