Improvements in the hetero diels-alder reactions of 1-dimethylamino-1- azadienes in the presence of an electrophilic scavenger resin

Article abstract of DOI:10.1055/s-2000-6501

Reactions between 1-dimethylamino-1-azadienes and several quinones in the presence of a chloroformyl polystyrene resin proceeded with up to 2.5- fold increase in the isolated yields of the hetero Diels-Alder products, owing to efficient scavenging of dimethylamine liberated from the primary cycloadducts.

Full text of DOI:10.1055/s-2000-6501

LETTER
205
Improvements in the Hetero Diels-Alder Reactions of 1-Dimethylamino-1-
azadienes in the Presence of an Electrophilic Scavenger Resin
Eva Pascual-Alfonso, Carmen Avendaño, J. Carlos Menéndez
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34-91-394 18 22; E-mail: josecm@eucmax.sim.ucm.es
Received 1 December 1999
be replaced by an 1-acetylamino moiety, which does not
deliver nucleophilic species into the reaction medium, but
this modification results in a greatly diminished reactivity
Abstract: Reactions between 1-dimethylamino-1-azadienes and
several quinones in the presence of a chloroformyl polystyrene resin
proceeded with up to 2.5-fold increase in the isolated yields of the
hetero Diels-Alder products, owing to efficient scavenging of of the azadiene system.5b
dimethylamine liberated from the primary cycloadducts.
The current interest in the generation of libraries of com-
Key words: Diels-Alder reactions, quinolines, quinones, scavenger
resins
pounds for their use in the pharmaceutical and agrochem-
9
ical industries has prompted extensive studies on solid-
phase organic synthesis.10 Recently, an alternative ap-
proach based on the use of polymer-supported reagents11
1
The hetero Diels-Alder reaction is one of the most effi- has been employed in combinatorial chemistry, either in
1
2
cient methods for the construction of six-membered isolated steps of synthetic routes or in orchestrated
heterocyclic rings. In particular, 1-dimethylamino-1- multi-step syntheses.13 One of the recent applications of
2
azadienes have been extensively used in the synthesis of these polymer-supported reagents is their use as quench-
14
pyridines and fused pyridine systems through Diels-Alder ing and scavenging species. Within this context, we de-
3
reactions of normal electronic demand. Quinones are cided to attempt the use of a resin as a scavenger for
probably the main class of dienophiles employed in this dimethylamine in the hetero Diels-Alder reactions of sev-
4
type of reactions, but their use is hampered by the tenden- eral types of quinones.
cy of the primary Diels-Alder adduct to liberate dimethyl-
We were particularly interested in improving the hetero
5
amine, which then adds to the starting quinone or to the
Diels-Alder reactions using as dienophiles 2,5,8-quino-
6
reaction product, leading to diminished yields or prevent-
linetriones, because of the excellent antitumour properties
ing the isolation of the desired product (Scheme 1).
of the 1,8-diaza-2,5,8-quinolinetriones obtained in these
15
reactions. In an initial experiment, we performed the re-
action between crotonaldehyde dimethylhydrazone 1a
and 4-methyl-2,5,8(1H)-quinolinetrione 216 in the pres-
ence of Amberlyst 15, an acidic ion exchange resin, as a
potential dimethylamine trap. Unfortunately, this attempt
was unsuccessful and we decided to turn our attention to
the use of polystyrene resins. Although the use of modi-
fied Merrifield resins is gaining increasing importance,
few of them behave as electrophiles. Among them, poly-
O
O
O
O
R
R
+
N
N
NMe2
Me2N
O
O
R
Side products
Me2NH
17
mer-bound 4-benzyloxybenzaldehyde and polymer-
N
H
18
bound isocyanate may be mentioned, but they are not
well suited for trapping secondary amines. For this reason,
we decided to examine the less-known chloroformyl poly-
styrene, prepared by treatment of the corresponding car-
Scheme 1
1
9
20,21
boxylic acid with thionyl chloride.
The effects of this
Several experimental modifications have been proposed resin were initially studied on the hetero Diels-Alder reac-
to solve the problem of dimethylamine addition. The first tions of a series of 1-dimethylamino-1-azadienes 122 with
of them is based on its elimination from the reaction me- the model compound 2, and the results obtained with 4-
6
a
dium by means of a stream of an inert gas or by addition substituted 1-dimethylamino-1-azadienes (Scheme 2) are
6
b
7
of sodium bicarbonate or acetic anhydride, but these summarized in Table 1. The presence of the chloroformyl
methods lack general value. Good yields of the desired cy- resin leads to up to 2.5-fold increases in the isolated yields
cloadducts have been obtained in one case by carrying out of the desired 5,8-dihydro-1,8-diazaanthraquinone deriv-
the reaction in a silica gel support followed by immediate atives 3, and minimizes the formation of compound 4,
8
chromatography, but this method is restricted to cases arising from addition of dimethylamine to the starting
where the Diels-Alder reaction is very fast. In an alterna- quinone. The method, however, was not suitable for the
tive approach, the 1-dimethylamino activating group can less reactive 4-arylazadienes, for which reflux conditions
Synlett 2000, No. 2, 205–208 ISSN 0936-5214 © Thieme Stuttgart · New York

2
06
E. Pascual-Alfonso et al.
LETTER
must be employed. For instance, the reaction between
compounds 1f and 2 led to consumption of the starting
quinone after 2 days at 60 °C, but the expected reaction
product 3f could not be isolated. This can be attributed to
covalent bonding of the N-8 atom of the reaction product
to the electrophilic resin, which acquired the deep green
colour characteristic of compounds 3 and showed a new
IR band at 1643 cm , assignable to an amide carbonyl.
Unfortunately, all attempts at liberating 3f from the resin
by hydrolysis were unsuccessful.
O
O
CH3
Cmpd. R3
R3
1
1
1i
g
h
H
Me
Et
+
N
N
H
O
1j
n-Bu
NMe2
2
i (CHCl3, r.t., 5 min), or
ii (
COCl,CHCl3, r.t., 5 min)
-
1
O
CH3
O
CH3
Cmpd. R3
R3
2
Me N
5a
H
+
5b
Me
5
5
c
d
Et
n-Bu
N
N
H
O
N
H
O
O
O
R4
4
O
CH3
Cmpd. R3 R4
R3
Scheme 3
1
1
1
1
1
a
b
c
d
e
H
H
H
H
Me
Et
+
n-Pr
n-Bu
N
N
H
O
Me Et
Ph
O
NMe2
1
f
H
2
In order to extend the scope of the method, we decided to
examine briefly other hetero Diels-Alder reactions where
interference from dimethylamine has been described. This
is the case, for instance, of the reactions of bromoqui-
nones, which often give poor yields that have sometimes
been ascribed to the formation of dimethylamine ad-
i (CHCl3, r.t., 5 min), or
ii (
COCl,CHCl3, r.t., 5 min)
R4
O
CH3
Cmpd. R3 R4
O
CH3
R3
2
Me N
+
3a
3b
3c
3d
3e
H
H
H
H
Me
Et
n-Pr
n-Bu
N
H
N
H
O
N
H
O
Me Et
6b
O
O
ducts. We have studied some reactions of 2-bromonaph-
thoquinone,23 with the results summarized in Scheme 4.
Comparison of our results with the literature data for the
synthesis of the natural product cleistopholin 9a2
shows that the yield of 9a was actually lower in the pres-
ence of the resin, owing to the formation of the dimeric
product 10 (14%). This can be ascribed to the higher acid-
ity of the reaction medium due to trapping of dimethyl-
amine by the resin; protonation of the nitrogen atom in 9a
would increase the electrophilicity of its C-2 position, al-
lowing nucleophilic attack from the enamine portion of
the 1,4-dihydro derivative of 9a, which are known to form
as intermediates in this type of Diels-Alder reactions;6b
4
Scheme 2
4,25
Table 1 Reactions of 4-substituted 1-dimethylamino-1-azadienes
with 4-methyl-2,5,8(1H)-quinolinetrione
a
b
See reference 5b. Use of unmodified Merrifield resin led to 38 % of the dimeric species thus originated would finally evolve to
3
e and 37 % of 4.
10 by dismutation. Our results show that these side reac-
4
tions are limited to the synthesis of 9a, and R substituents
larger than a methyl group prevent them. For instance, the
preparation of the homo analogue of cleistopholine 9b24
shows a more than two-fold increase in the isolated yield
in the presence of the resin. Similarly, the C-3 substituted
derivative 9e is not suited for the side reaction, and hence
the increase in yield in the presence of the resin (42% vs.
The related reaction between the 3-substituted derivatives
5
b
1
g-j led, as expected, to the aromatic derivatives 5. The
yields obtained were excellent (Scheme 3 and Table 2)
and, as above, the workup was very simple (filtration,
evaporation and chromatography to eliminate the excess
azadiene).
2
8%) observed for the reaction between 2-methyl-2-pen-
tenal dimethyl-hydrazone 1e and quinone 8, leading to
compound 9e. In this case, both methods gave equal
yields (33%) of compound 11, whose formation can be
explained by acid-induced isomerization of 1e to 2-prop-
ylacrolein dimethylhydrazone.26
Table 2 Reactions of 4-unsubstituted 1-dimethylamino-1-azadienes
with 4-methyl-2,5,8(1H)-quinolinetrione
Finally, we decided to study the Diels-Alder reactions of
benzoquinone derivatives as a route to quinolinequinone
derivatives. These quinones are very important com-
pounds because of their wide spectrum of biological activ-
ities and also because a quinolinequinone unit plays an
essential role in the antitumour activity of several natural
products, such as streptonigrin and lavendamycin. Re-
a
b
c
See reference 7a. See reference 15a. See reference 5b.
Synlett 2000, No. 2, 205–208 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Improvements in the Hetero Diels-Alder Reactions of 1-Dimethylamino-1-azadienes
207
R4
Representative procedures:
6-Ethyl-4-methyl-1,8-diazaanthracene-2,9,10-trione
5c). To a stirred suspension of 4-methyl-2,5,8(1H)-quin-
olinetrione (2, 50 mg, 0.26 mmol) and the chloroformyl
polystyrene resin (1.25 g, 5 eq) in chloroform (30 mL)
was added 2-ethylacrolein dimethylhydrazone (1i, 80 mg,
R4
O
O
O
R3
R3
i or ii
(
+
N
Br
N
NMe2
O
8
Yield, %
Cmpd. R3 R4
Cmpd. R3 R4
i
ii
43
0
.64 mmol). The suspension was stirred at room tempera-
1
1
1
a
b
e
H
H
Me
Et
24
25
9
a
H
Me 52
ture for 5 min and filtered. The filtrate was evaporated and
chromatographed on silica gel, eluting with a gradient
from 1:1 ethyl acetate-petroleum ether to neat ethyl ace-
tate, yielding 70 mg (100%) of compound 5c, as yellow
crystals.
6
0
Me Et
24
9
9
b
e
H
Et 17
38
Me Et
28 42
CH3
O
O
O
Pr
O
CH3
N
3
-Methyl-5,8-quinolinequinone (13a). To a stirred sus-
N
H
N
pension of benzoquinone (50 mg, 0.46 mmol) and the
chloroformyl polystyrene resin (0.92 g, 5 eq) in ethanol
O
1
1 (33 %, i or ii)
(
1
25 mL) was added methacrolein dimethylhydrazone (1h,
03 mg, 0.92 mmol). The suspension was stirred at room
O
10 (14 %)
i. Xylene, reflux, 6 h for (a)24,25 and (b) ; CHCl , reflux, 1 day for
24
3
temperature for 30 min and then refluxed for 30 min,
cooled and filtered. The filtrate was evaporated and the
residue of crude 12a was dissolved in acetonitrile (2.5
mL). This solution was cooled to 0 °C and a solution of
cerium ammonium nitrate (0.5 g, 0.9 mmol) in water (2
mL) was added. The orange solution was stirred at 0 °C
for 15 min, diluted with water (2 mL) and basified with
30% aqueous ammonium hydroxide. Extraction with
chloroform (4 × 5 mL) followed by drying over sodium
sulfate and evaporation afforded 60 mg (75%) of quinone
13a, as orange crystals.
(
e). ii. Resin, CHCl , reflux, 3 days.
3
Scheme 4
search into the synthesis of quinolinequinone derivatives
has normally been restricted to 6- and 7-substituted sys-
tems, and the current methods for the preparation of the
,7-unsubstituted derivatives are not efficient. The reac-
tion between azadiene 1h and benzoquinone is known in
the literature, but it gives 6-dimethylamino-3-methyl-
quinolinequinone because of the addition of dimethyl-
amine to the expected reaction product. However, starting
from either 1h or 1j and trapping dimethylamine by addi-
tion of the electrophilic resin resulted in an efficient syn-
thesis of hydroquinones 12a,b, which were oxidized
without purification to the corresponding quinones 13a,b.
2
7
2
8
6
6
a
Acknowledgement
This work was supported by CICYT (grant PTR-95-0230). We
thank Dr. Esteban Domínguez (Lilly, Spain) for helpful suggestions
and Dr. M. M. Blanco for an early experiment in this area.
Not unexpectedly, an attempt to use C -substituted aza-
4
References and Notes
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(
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2
9
by chloro substituents.
O
OH
O
R3
R3
R3
i
ii
+
N
N
N
NMe2
O
OH
O
Cmpd. R3
Cmpd. R3
12a Me
12b Et
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Me
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13a Me
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75
73
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Scheme 5
(
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scavenger resin provides a convenient and efficient meth-
od for minimizing or completely suppressing dimethyl-
amine-derived side products in the reactions between 1-
dimethylamino-1-azadienes and quinones.
(
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Synlett 2000, No. 2, 205–208 ISSN 0936-5214 © Thieme Stuttgart · New York

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08
E. Pascual-Alfonso et al.
LETTER
(
(
(
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(
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1
9
(20) A suspension of carboxy polystyrene resin (5.0 g) in dry
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argon atmosphere for 30 min. Thionyl chloride (22 mL) was
added, and the suspension was refluxed for 24 h with vigorous
stirring, then cooled and filtered. The resin was washed with
toluene (2 × 25 mL) and ethyl ether (2 × 25 mL). If stored at
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significant loss of activity.
(
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(
1
b) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
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(
1
(
(
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1
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(
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(
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Article Identifier:
1
437-2096,E;2000,0,02,0205,0208,ftx,en;L22999ST.pdf
Synlett 2000, No. 2, 205–208 ISSN 0936-5214 © Thieme Stuttgart · New York