A one-pot synthesis of 3,3′-methylenebis(2-arylamino-4H-chromen-4-one) from C-(4-oxo-4H-1-benzopyran-3-yl)-N-arylnitrone

Article abstract of DOI:10.1016/j.tetlet.2009.04.087

2-(Arylamino)-4-oxo-4H-chromene-3-carbaldehyde 3 (R² = aryl) produces 12H-chromeno[2,3-b]quinolin-12-one 4 when treated with sarcosine, piperidine or diethylamine, but produces 3,3′-methylenebis(2-arylamino-4H-chromen-4-one) 8 when treated with

Full text of DOI:10.1016/j.tetlet.2009.04.087

Tetrahedron Letters 50 (2009) 3966–3969
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Tetrahedron Letters
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A one-pot synthesis of 3,30-methylenebis(2-arylamino-4H-chromen-4-one)
from C-(4-oxo-4H-1-benzopyran-3-yl)-N-arylnitrone
*
Sourav Maiti, Suman Kalyan Panja, Chandrakanta Bandyopadhyay
Department of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata 700 118, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
2-(Arylamino)-4-oxo-4H-chromene-3-carbaldehyde 3 (R2 = aryl) produces 12H-chromeno[2,3-b]quino-
lin-12-one 4 when treated with sarcosine, piperidine or diethylamine, but produces 3,30-methylene-
bis(2-arylamino-4H-chromen-4-one) 8 when treated with the same amine in the presence of an excess
of formaldehyde. Compound 3 (R2 = alkyl) was found to be less reactive than the N-aryl analogues
towards the deformylative Mannich-type reaction.
Article history:
Received 17 February 2009
Revised 18 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitrones
Bischromones
Mannich reaction
Deformylation
3-Formylchromone
1-Benzopyran
(i) R2NHOH
O
(R2 = aryl)
(ii) R2NO2,
Pharmaceutical activities of bisbenzopyrans depend on the po-
sition of attachment of two benzopyran rings. Bisbenzopyrans cou-
pled through 3- and 30-positions have drawn much attention in
recent years because of their applications in different fields. 3,30-
Biscoumarinylketones are used as dyes and pigments, fluorescent
brighteners and photographic sensitizers.1 Some members of
3,30-bisbenzopyran family act as non-peptide HIV-1 protease
inhibitors,2 monoamine oxidase (MAO) inhibitors3 and anticoagu-
lant agents.4 Coupling between 3- and 30-positions of two benzo-
pyran rings by a methylene bridge has been achieved by the
reaction of formaldehyde on 4-hydroxycoumarin.5 Synthesis of
methylene-bridged bisnaphthopyrans has been reported by using
Mannich-type reaction on 3-N,N-dimethylamino-1H-naphtho[2,1-
b]pyran-1-one in acetic acid.6
In continuation with our earlier studies on nitrones 2 derived
from 4-oxo-4H-chromene-3-carbaldehyde (commonly known as
3-formylchromone) 17 and on the deformylative Mannich-type
reaction on 1,8 we were interested in studying the deformylative
Mannich-type reaction on 2-(alkyl/arylamino)-4-oxo-4H-chro-
mene-3-carbaldehyde 3, which can readily be obtained from nit-
rone 2 (Scheme 1).7c,9 Although some chemistry of 2-amino-4-
oxo-4H-chromene-3-carbaldehyde and 2-(N,N-dialkylamino)-4-
oxo-4H-chromene-3-carbaldehyde has been studied,10,11 chemis-
try of 2-(alkyl/arylamino)-4-oxo-4H-chromene-3-carbaldehyde 3
is little explored. Most of the work on 3 was carried out by convert-
O
(ref. 9)
or
O-
R1
+
R1
CHO
CH=N
Zn/AcOH/EtOH (R2 = alkyl)
(ref. 7b)
R2
1
O
O
2
EtOH/
(ref. 7c)
reflux
NHR2
O
N
O
NHR3R4
Z
R1
R1
CHO
O
O
3
4
a: R1 = Z = H
NHR3R4
H
b: R1 = Z = Me
N
O
R1
Z
+
NR3R4
O
5
H
N
+
H
N
O
O
R1
R1
Z
H
Z
NR3R4
NR3R4
O
O
6
7
* Corresponding author. Tel.: +91 3325925125.
E-mail address: kantachandra@rediffmail.com (C. Bandyopadhyay).
Scheme 1. Synthesis of 12H-chromeno[2,3-b]quinolin-12-one 4.7a,13
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.087

S. Maiti et al. / Tetrahedron Letters 50 (2009) 3966–3969
3967
Table 1
Results of the reactions of 3 with 2o-amines in the presence or absence of formaldehyde
Entry
R1
R2
2o-Amine (R3R4NH)
Additive
Solvent
Time (h)
Product (% yield)
Mps (oC)
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
H
H
Me
H
H
H
H
H
Me
H
H
H
Me
Me
H
H
H
H
Me
H
Ph
Ph
Ara
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ara
Ph
Ph
Ph
Ph
Ph
Ara
Ph
Ph
Et
Sarcosine
Sarcosine
Sarcosine
Piperidine
Piperidine
Et2NH
PhNHMe
Sarcosine
Sarcosine
Sarcosine
Sarcosine
Sarcosine
Sarcosine
Sarcosine
Sarcosine
—
—
—
—
—
—
—
—
EtOH
DMF
DMF
DMF
EtOH
EtOH
EtOH
MeOH
EtOH
AcOH
MeCN
DMF
DMF
DMF
Me2CO
DMF
DMF
EtOH
DMF
EtOH
EtOH
EtOH
DMF
EtOH
DMF
DMF
DMF
6
2
2
1
2
N.R.b
—
4a (70)
4b (72)
4a (90)
4a (92)
4a (89)
N.R.b
236–238
260–262
236–238
236–238
236–238
—
—
—
—
300–302
300–302
304–306
268–270
—
2
10
10
10
10
12
1
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
(CH2O)n
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
N.R.b
N.R.b
Not isolated
8a (10)
8a (65)
8b (79)
8c (70)
N.R.b
1
1
40
6
0.5
2.5
0.5
1
3.5
11
5
20
7
N.R.b
—
Piperidine
Piperidine
Et2NH
8a (90)
8a (58)
8b (92)
8a (60)
8a (30)
N.R.b
300–302
300–302
304–306
300–302
300–302
—
Et2NH
c
H
Piperidine
Sarcosine
Sarcosine
Piperidine
Piperidine
Piperidine
Piperidine
Me
Me
Me
Me
Me
H
Me
Et
Me
Et
N.R.b
—
—
N.R.b
8d (40)
8e (42)
8f (45)
>320
258–260
254–256
8
7
Et
a
Ar stands for 4-MeC6H4.
N.R. stands for no reaction.
Paraformaldehyde.
b
c
ing it into N,N-disubstituted analogue by alkylation.11a,c,d Forma-
tion of Schiff-bases from 3 involving primary diamines,11a and
reaction of 3 with ethyl (triphenylphosphoranylidene)acetate for
the synthesis of a chromenopyridine have been reported.11d The
reaction of N-methylglycine (sarcosine) with 1 has been studied
under different reaction conditions.12 We report herein the results
of the reaction of 3 with secondary amines in the presence or ab-
sence of formaldehyde.
change in 3 was observed (entries 8 and 9). No pure compound
could be isolated by making the medium acidic by using acetic acid
as solvent (entry 10). However, by heating in acetonitrile for 12 h,
small amount of a white solid 8 was isolated along with unreacted
3 (50%) (entry 11). Considering the necessity of a polar aprotic sol-
vent, the reaction was carried out in DMF and the reaction mixture
showed the absence of 3 (by TLC) only after heating for 1 h. After
usual work-up, compound 8 was obtained in 60–80% yield (entries
12–14). But in acetone, a relatively low boiling polar aprotic sol-
vent, no change in 3 was observed even after heating for 40 h (en-
try 15).
The structure of the compound 8 was determined on the basis
of IR, 1H NMR, 13C NMR and mass spectral analysis.14 The forma-
tion of 8 may be rationalized by either of the two pathways: (a)
hydroxymethylation of 3 (?9) followed by formyl transfer (?10)
and elimination of formic acid to generate Michael acceptor 11,
which is intercepted by the enamine moiety of 3 to produce 12.
This on subsequent deformylation gives 8 (Scheme 2, path (a)
or (b) initially formed iminium ion 13 is involved in Mannich-
type reaction to form 14, which can also produce the Michael-
type acceptor 11 via 15 and finally produces 8 (path b). To check
the necessity of amine, compound 3 was heated with excess
formaldehyde in DMF for 6 h, but compound 3 remained un-
changed (entry 16), which rules out path a. In support of path
b, compound 3 was heated in DMF with piperidine (instead of
with sarcosine) in the presence of excess aqueous formaldehyde
solution. The reaction completed within 30 min with an excellent
yield of 8 (entry 17). Interestingly on performing this reaction in
ethanol instead of in DMF, the reaction was complete in 2.5 h
with a moderate yield, (entry 18), but use of sarcosine instead
of piperidine in alcohol failed to show any change (entries 8
and 9). Use of diethylamine instead of piperidine also produced
similar results (entries 19 and 20), but use of paraformaldehyde
instead of aqueous formaldehyde required more time and gave
poor yield of 8 (entry 21).
Although no change was observed when compound 3 was
heated under reflux with equimolar amounts of sarcosine in etha-
nol for 6 h (Table 1, entry 1), the same reaction mixture led to the
formation of chromenoquinolone 4 on heating in DMF instead of in
ethanol at 80–100 °C for 2 h (entries 2 and 3). Transformation of 3
to 4 has earlier been achieved by treating 3 with AlCl3 followed by
9
H2SO4 or only with H2SO4.7a,13 Assuming the secondary amine
function in sarcosine to be responsible for this cyclization reaction
(Scheme 1), compound 3 was heated with piperidine in DMF and
surprisingly, the conversion was accomplished within 1 h (entry
4). The same conversion could also be achieved in excellent yield
by heating 3 with piperidine or diethylamine in ethanol for 2 h (en-
tries 5 and 6). The yellow solid 4 can be isolated simply by filtra-
tion from the reaction mixture after cooling. The formation of 4
from 3 may be rationalized as follows. Aldehyde function of 3 re-
acts with secondary amine to produce the iminium ion 5, which
then induces cyclization to 4 via 6 and 7 (Scheme 1). It has to be
mentioned here that the weaker nucleophile N-methylaniline fails
to carry out this transformation even after heating for 10 h in eth-
anol (entry 7). This process for the formation of 4 from 3 compares
well with the earlier reports.7a,9,11a,13
As an extension of our recent report on the deformylative Man-
nich-type reaction,8 the above results gave us an impetus to study
how this aldehyde 3 would behave with secondary amines in the
presence of formaldehyde. So, an equimolar mixture of 3 and sar-
cosine was heated in methanol or ethanol in the presence of excess
amount of 37% aqueous formaldehyde solution for 10 h, but no

3968
S. Maiti et al. / Tetrahedron Letters 50 (2009) 3966–3969
path a
+
NHR2
O
NHR2
OCHO
NHR2
CH2O
O
O
R1
R1
OH
R1
CHO
H
O
O
O
O
9
10
3
NHR2
NHR2
O
O
+
O
NHR2
O
R1
R1
R1
CH2
O
8
O
d: R1 = R2 = Me
11
a: R1 = H; R2 = Ph
e: R1 = Me; R2 = Et
f: R1 = H; R2 = Et
b: R1 = Me; R2 =4-MeC6H4
c: R1 = Me; R2 = Ph
deformylation
NHR2
NHR2
O
+
NHR2
CH2
O
O
+
O
3
R1
R1
R1
O
OHC
12
O
11a
path b
NHR2
N+HR2
NR3R
O
O
3
CH2O + R3R4NH
CH2=N+R3R4
N+R3R4
CHO
13
4 R1
R1
CHO
O
15
O
14
deformylation
3
11
12
8
Scheme 2. Synthesis of 3,30-methylenebis(2-N-alkyl-/arylamino-4H-chromen-4-one) 8.
Having an insight on the transformation of 3 to 8, attempts
Acknowledgments
were made to synthesize 8 directly from nitrone 2 in a one-pot
reaction. Nitrone 2 (R2 = aryl) was heated in ethanol for 2 h, then
piperidine (1 equiv) and 37% aqueous formaldehyde solution (ex-
cess) were added and heating was continued for another 3 h. In-
deed, the reaction mixture produced 8 in good to excellent
yield.15 This sequential one-pot reaction involves rearrangement
of nitrone 2 to aminoaldehyde 3,7c,9 and a tandem Mannich-type
reaction, Michael reaction and deformylation reaction. It is worth
mentioning that when nitrone 2, piperidine and formalin were
all taken together and heated either in ethanol or in DMF, the yield
of 8 was quite low (20–25%).
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 authorities for providing
research facilities.
References and notes
1. Chandrasekhar, A.; Padmanavan, S.; Seshadri, S. Dyes Pigments 1986, 7, 13–21.
2. (a) Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.; Nicklaus, M. C.; Graham, L.;
Rice, W. G. J. Med. Chem. 1996, 39, 2047–2054; (b) Klopman, G.; Tu, M. J. Med.
Chem. 1999, 42, 992–998.
The deformylative Mannich-type reaction was then applied to 3
(R2 = alkyl). Surprisingly, the reactions with N-alkyl derivatives are
very slow. Compound 3 (R1 = Me; R2 = Et, Me) failed to react with
sarcosine in ethanol or DMF (entries 22 and 23). It failed to react
even with piperidine in ethanol (entry 24), but it reacted with
piperidine in DMF to produce 8 (entries 25–27). The lesser reactiv-
ity of 3 (R2 = alkyl) in comparison to that of 3 (R2 = aryl) towards
the formation of 8 may be due to a competitive formation of imin-
ium ion involving the alkylamino group of 3 (R2 = alkyl) and form-
aldehyde, but it could not be ascertained.
In conclusion, we have developed a new convenient method for
the cyclization of 3 (R2 = aryl) to 4 and also synthesized bischro-
mone 8 from nitrone 2 by a sequential one-pot reaction involving
a deformylative Mannich-type reaction. Extension of this synthetic
strategy towards new biologically active heterocycles is in
progress.
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459–460. J. Chem. Res.(M), 2003, 0847–0856; (b) Ghosh, T.; Patra, R.;
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S. Maiti et al. / Tetrahedron Letters 50 (2009) 3966–3969
3969
11. (a) Singh, G.; Singh, L.; Ishar, M. P. S. Tetrahedron 2002, 58, 7883–7890; (b)
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1558 cmꢀ1 1H NMR (CDCl3) d 4.03 (2H, s, CH2), 7.13–7.23 (2H, m, ArH), 7.30–
;
7.49 (8H, m, ArH), 7.53–7.70 (6H, m, ArH), 8.30 (2H, br d, J = 7.8 Hz, 2ꢁ5-H),
12.02 (2H, s, exchangeable, 2 ꢁ N–H); 13C NMR (CDCl3) d 18.3, 100.3, 116.5,
121.3, 122.4, 124.1, 124.9, 125.5, 129.1, 132.1, 138.2, 152.7, 160.6, 176.7; mass
m/z: 487 (M++H), 509 (M++Na).
15. General procedure for the synthesis of
8 in a one-pot reaction: Nitrone 2
(R2 = aryl) (1 mmol) was heated under reflux in ethanol (25 mL) for 2 h and
complete conversion of 2 to 3 was observed by TLC. Under this condition,
piperidine (85 mg, 1 mmol) and 37% aqueous formaldehyde solution
(1.5 mL) were added to the reaction mixture and heated under reflux for
another 3 h, when a white solid separated out. The solid was filtered and
13. Singh, G.; Singh, R.; Girdhar, N. K.; Ishar, M. P. S. Tetrahedron 2002, 58, 2471–
2480.
14. 3,30-Methylenebis(2-N-phenylamino-4H-chromen-4-one)
8a:
crystalline solid, Anal. Calcd for C31H22N2O4: C, 76.53; H, 4.56; N, 5.76.
Found: C, 76.33; H, 4.40; N, 5.61. IR (KBr) max: 3438, 3048, 2758, 1654, 1605,
White
fine
crystallized from benzene–petroleum ether (10:1) to afford
yields.
8 in 80–90%
m