Synthesis of unsymmetrical methylene derivatives of benzopyran-4-ones from mannich bases

Article abstract of DOI:10.1002/jhet.5570380232

The formation of methylene-bis derivatives of benzopyran-4-ones from their Mannich bases was studied. On these grounds, unsymmetrical methylene derivatives have been synthesized by reacting Mannich bases of benzopyran-4-ones with structurally related comp

Full text of DOI:10.1002/jhet.5570380232

Mar-Apr 2001
Synthesis of Unsymmetrical Methylene
Derivatives of Benzopyran-4-ones from Mannich Bases
Mauro Mazzei*, Ramona Dondero and Alessandro Balbi
499
Department of Pharmaceutical Sciences, Viale Benedetto XV, 3 - 16132 Genova (Italy)
Gian Maria Bonora
Department of Chemical Sciences, Via Giorgieri, 1- 34127 Trieste (Italy)
Received August 10, 1999
The formation of methylene-bis derivatives of benzopyran-4-ones from their Mannich bases was studied.
On these grounds, unsymmetrical methylene derivatives have been synthesized by reacting Mannich bases
of benzopyran-4-ones with structurally related compounds lacking the dialkylaminomethyl group.
J. Heterocyclic Chem., 38, 499 (2001).
Introduction.
been reported that a methylene-bis derivative was formed as
a by-product along with the acetoxy derivatives [6]. When
Mannich bases of 2-(dialkylamino)chromones were treated
with acetic anhydride under similar conditions, the opposite
result was observed. In these cases, the methylene-bis
derivatives were obtained as the main products and the
acetoxy derivative was isolated only in one case [7-9]. In this
study, we focused our attention on the formation of unsym-
metrical methylene derivatives through the treatment of
certain Mannich bases with acetic anhydride.
One of the simplest ways to obtain methylene-bis
derivatives is through the reaction of compounds bearing an
acidic hydrogen with formaldehyde. For instance, some
benzopyrans may easily react with formaldehyde to yield the
corresponding methylene-bis derivatives [1]. In particular,
N'-(chromon-2-yl)-1-piperidine-1-carboxamide gave the
methylene-bis derivative in good yield [2], whereas
2
-(dialkylamino)chromones do not react efficiently with
formaldehyde [3]. Mannich bases, which are well known as
reactive substances for many interesting reactions [4],
generate methylene-bis derivatives as by-products in their
preparation. By treating Mannich bases with acetic
anhydride it is possible to obtain their acetoxy derivatives as
the main product [5]. However, by treating some Mannich
bases of 3-hydroxycoumarin with acetic anhydride, it has
Results and Discussion.
All formulas presented in this work are depicted in
Scheme 1. To explain the formation of the methylene-
bis derivatives, we propose the mechanism shown in
Scheme 2, where the carbocation derived through

5
00
M. Mazzei, R. Dondero, A. Balbi and G. M. Bonora
Vol. 38
deamination of the Mannich base reacts with the amino-
chromone derived through deaminomethylation of the
Mannich base.
The mechanism shown in Scheme 2 indicates that the
yield of the methylene-bis derivatives might be increased
by addition of the chromone (formed by deamino-
methylation) to the Mannich base in acetic anhydride, as
shown in Scheme 3 (X = Y).
hplc produced a chromatogram showing four peaks. The
main product (71%), isolated by crystallization, showed
signals for the methoxy at 3.88 ppm and H-10 at
1
10.25 ppm in the H nmr. The structure was determined to
be the unsymmetrical di-substituted methylene derivative
5. By comparing the retention times of authentic samples,
the other three minor products were assigned to the
symmetrical methylene-bis derivative 4 (17%), the
symmetrical methylene-bis derivative 6 (10%) and the
naphtho[2,1-b]pyran-1-one 3 (2%), respectively.
In fact, the addition of 3-(diethylamino)-2-morpholi-
nomethyl-1H-naphtho[2,1-b]pyran-1-one 1 to a solution of
3
-(diethylamino)-1H-naphtho[2,1-b]pyran-1-one 3 in
It is interesting to note that the Mannich base 1 is not
present at the end of the reaction. The formation of the
symmetrical derivative 6 might indicate that a retro
reaction takes place, where the unsymmetrical product 5
decomposes to give the chromone 3 and the carbocation
corresponding to 2. The presence of a residual amount of
chromone 3 in the final mixture supports this hypothesis.
Use of another Mannich base 7, having the
piperidinomethyl group, instead of Mannich base 1,
showed a similar pattern for the reaction. Moreover, the
reaction of the chromone, 2-(dimethylamino)- or 2-(1-
piperidinyl)-7-methoxychromone (8a or 8b), with
Mannich base 1 similarly gave the corresponding
unsymmetrical derivative 9a and 9b in good yields.
acetic anhydride gave the corresponding methylene-bis
derivative 4 in almost doubled yield (data not shown). This
observation supports our proposed mechanism. If
deaminomethylation of the Mannich base to form the
corresponding chromone is the rate-determining step in this
reaction, then the addition of a different chromone may
allow one to produce an unsymmetrically di-substituted
methylene derivative (Scheme 3, X different from Y).
To verify our results, the reaction of the bicyclic
Mannich base 10 with the tricyclic chromone,
naphtho[2,1-b]pyran-1-one 3 in acetic anhydride was
similarly studied. Analysis of the crude products by hplc
produced a chromatogram with three peaks, identical with
the unsymmetrical methylene-bis derivative 5 (52%), the
symmetrical derivative 4 (32%) and 6 (16%), respectively.
The low yield of 5 may be due to low stability of the
corresponding carbocation intermediate.
Conclusion.
To test this hypothesis, the Mannich base 1 was added to
a solution of 2-(diethylamino)-7-methoxychromone 2 in
acetic anhydride. Analysis of the crude products by
Some Mannich bases, derived from various chromones,
were reacted with other chromones in the presence of
acetic anhydride to give the corresponding unsymmetrical

Mar-Apr 2001
Unsymmetrical Methylene Derivatives of Benzopyran-4-ones from Mannich Bases
501
di-substituted methylene derivatives. In these reactions, it
appears convenient to use the Mannich base that upon
deamination will derive the more stable carbocation.
2-[2'-(Dimethylamino)-7'-methoxychromon-3'-yl]methyl-3-
(diethylamino)-1H-naphtho[2,1-b]pyran-1-one (9a).
Compound 9a was prepared by mixing the following starting
materials according to the general proceedure A: 0.18 g of
2-(dimethylamino)-7-methoxychromone 8a [3]; B: 0.30 g of
EXPERIMENTAL
3
1
-(diethylamino)-2-morpholinomethyl-1H-naphtho[2,1-b]pyran-
-one 1 [11]; 68% yield (hplc); 9a: mp 181-182 °C; ir (potassium
Melting points were determined using an Electrothermal
apparatus and are uncorrected. Microanalyses were carried out on
a Carlo Erba 1106 elemental analyzer. H nmr spectra were
performed on a Hitachi Perkin-Elmer R 600 (60 MHz)
spectrometer using tetramethylsilane as the internal standard
-1 1
bromide): ν 1630, 1610 cm ; H nmr (deuteriochloroform): δ
1
CH -CH ), 3.87 (s, 3H, OCH ), 4.21 (s, 2H, CH ), 6.68-8.23
.00 (t, 6H, CH -CH ), 2.85 (s, 6H, NCH ), 3.25 (q, 4H,
1
2
3
3
2
3
3
2
(m, 8H, aromatic), 10.26 (d, 1H, H-10).
Anal. Calcd. for C H N O : C, 72.27; H, 6.06; N, 5.62.
3
0 30 2 5
(δ = 0). Infrared spectra were recorded on a Perkin-Elmer 398
Found: C, 72.07; H, 6.01; N, 5.61.
spectrophotometer. The hplc analyses were carried out at room
temperature on a Perkin-Elmer Series 4 equipped with a
Rheodine 7125 injector valve with a 20-µl loop. The uv detector
is a Perkin-Elmer LC-85B set at 254 nm. The eluent consisted of
acetonitrile/water (85:15). The flow-rate was 1.0 ml/minute.
Retention times and peak areas were recorded on Perkin-Elmer
LCI-100 integrator.
2-[2'-(1-Piperidinyl)-7'-methoxychromon-3'-yl]methyl-3-
(diethylamino)-1H-naphtho[2,1-b]pyran-1-one (9b).
Compound 9b was prepared by mixing the following starting
materials according to the general proceedure A: 0.18 g of 2-(1-
piperidinyl)-7-methoxychromone 8b [3]; B: 0.30 g of 3-(diethyl-
amino)-2-morpholinomethyl-1H-naphtho[2,1-b]pyran-1-one 1
[11]; 65% yield (hplc); 9b: mp 189-190 °C; ir (potassium bromide):
General Procedure.
-1 1
ν 1630, 1610 cm ; H nmr (deuteriochloroform): δ 0.95 (t, 6H,
To a solution of 0.82 mmoles of chromone (A) in 5 ml of freshly
distilled acetic anhydride, 0.82 mmoles of Mannich base (B) were
added and the mixture was stirred at 90 °C for 1.5 hours [10]. The
resulting brown solution was poured onto crushed ice and stirred.
The solids were collected by filtration and washed well with water.
For each crude product, approximately 5 mg of precipitate was
dissolved in 20 ml of acetonitrile and an aliquot was subjected to
hplc analysis. For the preparation of unsymmetrical derivative 5 by
the route I (see below), the following retention times in minutes
were found: 5.70 (6), 7.80 (3), 9.00 (5), 15.95 (4). Regardless of
minor components, the other unsymmetrical derivatives 9a and 9b
had retention times 6.55 and 10.10, respectively. After hplc
analysis, the crude precipitates were crystallized from ethyl acetate
to yield colorless crystals.
CH -CH ), 1.20-1.55 (m, 6H, β- and γ-piperidine), 2.85-3.43
2
3
(
m, 8H, α-piperidine, CH -CH ), 3.86 (s, 3H, OCH ), 4.17 (s, 2H,
2 3 3
CH ), 6.57-8.21 (m, 8H, aromatic), 10.23 (d, 1H, H-10).
2
Anal. Calcd. for C33H34N O : C, 73.59, H, 6.36, N, 5.20.
2
5
Found: C, 73.68; H, 6.28; N, 5.25.
Acknowledgements.
This work was supported by grants from Italian M.U.R.S.T.
REFERENCES AND NOTES
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70 (1941).
[
2
-[2'-(Diethylamino)-7'-methoxychromon-3'-yl]methyl-3-
(diethylamino)-1H-naphtho[2,1-b]pyran-1-one (5).
[
Compound 5 was obtained by three routes (I-III) using different
starting materials: (I) A: 0.20 g of 2-(diethylamino)-7-methoxy-
chromone 2 [3]; B: 0.30 g of 3-(diethylamino)-2-morpholinomethyl-
[
2
[6] G. M. Cingolani, F. Gualtieri and M. Pigini, J. Med. Chem.,
1H-naphtho[2,1-b]pyran-1-one 1 [11]; 71% yield (hplc). (II) A:
0.20 g of 2-(diethylamino)-7-methoxychromone 2 [3]; B: 0.30 g of
3-(diethylamino)-2-piperidinomethyl-1H-naphtho[2,1-b]pyran-1-
1
2, 531 (1969).
[
7] A. Ermili, G. Roma and A. Balbi, Il Farmaco Ed. Sc., 29, 247
1974).
[8] M. Mazzei, E. Sottofattori, M. Di Braccio, A. Balbi, G.
Leoncini, E. Buzzi and M. Maresca, Eur. J. Med. Chem., 25, 617 (1990).
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Passerini, Il Farmaco Ed. Sc., 30, 1001 (1975).
10] To minimize the formation of symmetrical methylene-bis
(
one 7 [11]; 64% yield (hplc). and (III) A: 0.22 g of 3-(diethylamino)-
H-naphtho[2,1-b]pyran-1-one 3 [12]; B: 0.28 g of 2-(diethyl-
1
[
amino)-3-morpholinomethyl-7-methoxychromone 10 [3]; 52%
yield (hplc); 5: mp 182-183 °C; ir (potassium bromide): ν 1630,
[
-
1 1
1
610 cm ; H nmr (deuteriochloroform): δ 0.75-1.18 (m, 12H,
derivatives, it is better to dissolve in acetic anhydride firstly the reagent
without the dialkylaminomethyl substituent.
[11] A. Ermili, G. Roma, M. Mazzei, A. Ambrosini and N.
Passerini, Il Farmaco, Ed. Sc., 29, 237 (1974).
CH -CH ), 2.95-3.53 (m, 8H, CH -CH ), 3.88 (s, 3H, OCH ), 4.18
2
3
2
3
3
(
s, 2H, CH ), 6.67-8.20 (m, 8H, aromatic), 10.25 (d, 1H, H-10).
2
Anal. Calcd. for C H N O : C, 72.98; H, 6.51; N, 5.32;
3
2 34 2 5
Found: C, 73.12; H, 6.55; N, 5.26.
[12] A. Ermili and G. Roma, Gazz. Chim. Ital., 101 269 (1971).