Organobase-catalyzed three-component reactions for the synthesis of 4H-2-aminopyrans, condensed pyrans and polysubstituted benzenes

Article abstract of DOI:10.3762/bjoc.10.11

Novel routes for the preparation of 2-amino-4H-pyran-3-carbonitrile 9, amino-arylbenzoic acid ester derivatives 13a,b, 2-aminotetrahydro-4H-chromene-3- carbonitrile 18, 3-amino-4-cyanotetrahydronaphthalene-2-carboxylic acid ester 26 and 4-amino-3,5-dicyan

Full text of DOI:10.3762/bjoc.10.11

Organobase-catalyzed three-component reactions for
the synthesis of 4H-2-aminopyrans, condensed
pyrans and polysubstituted benzenes
Moustafa Sherief Moustafa1, Saleh Mohammed Al-Mousawi*1,
Maghraby Ali Selim2, Ahmed Mohamed Mosallam2
and Mohamed Hilmy Elnagdi*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 141–149.
1Department of Chemistry, Faculty of Science; University of Kuwait,
Safat, 13060, P.O. Box 5969, Kuwait and 2Department of Chemistry,
Faculty of Science at Qena, South Valley University, P.O. Box 83523,
Qena, Egypt
doi:10.3762/bjoc.10.11
Received: 28 July 2013
Accepted: 26 November 2013
Published: 14 January 2014
Email:
Saleh Mohammed Al-Mousawi* - salehalmousawi@hotmail.com;
Mohamed Hilmy Elnagdi* - shelmi1941@yahoo.com
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
* Corresponding author
© 2014 Moustafa et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aminopyranes; arylbenzoic acid; DABCO; L-proline; multicomponent;
tetrahydronaphthalene; three-component reaction
Abstract
Novel routes for the preparation of 2-amino-4H-pyran-3-carbonitrile 9, amino-arylbenzoic acid ester derivatives 13a,b, 2-aminote-
trahydro-4H-chromene-3-carbonitrile 18, 3-amino-4-cyanotetrahydronaphthalene-2-carboxylic acid ester 26 and 4-amino-3,5-
dicyanophthalic acid ester derivatives 37a–c were developed. The synthetic methods utilize one-pot reactions of acetylene
carboxylic acid esters, α,β-unsaturated nitriles and/or active methylenenitriles in the presence of L-proline or DABCO. Plausible
mechanisms are suggested for the formation of the products. Finally, these compounds were used for the efficient synthesis of
6-amino-5-cyanonicotinic acid ester derivatives 31a,b, ethyl 4-amino-5H-pyrano[2,3-d]pyrimidine-6-carboxylates 33a,b, 4-amino-
6H-pyrrolo[3,4-g]quinazoline-9-carbonitrile 39, and 1,7-diamino-6-(N'-hydroxycarbamimidoyl)-3-oxo-5-phenyl-3H-isoindole-4-
carboxylate (40).
Introduction
The reaction of arylidenemalononitriles with active methyl and been surveyed. Since the first report describing the preparation
methylene compounds was extensively utilized for the of 2-amino-4H-pyrans by the addition of active methylene-
syntheses of otherwise non-readily obtainable pyrans [1-3], nitriles to α,β-unsaturated ketones [8], 2-amino-4H-pyrans 1
pyridines [3-5] and polysubstituted aromatics [6,7]. The syn- (Scheme 1) have become the central focus of a number of
thesis of 2-amino-4H-pyrans by these reactions has recently chemical and biological investigations [9,10].
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Beilstein J. Org. Chem. 2014, 10, 141–149.
2-amino-4H-pyran 9 can be generated using a one-pot reaction
involving condensation of ethyl propiolate (4a) with benzyl-
idenemalononitrile (7a) in the presence of L-proline (5)
(Scheme 4) [4].
It is believed that the pathway followed in this process involves
conjugate addition of proline to the propiolate to yield adduct 6
which then reacts with 7a to form the enamino ester 8a. Hydrol-
ysis of 8a followed by cyclization affords 9 in 85% yield. The
structure of 9 was unambiguously assigned by X-ray crystallo-
Scheme 1: Reaction of active methylenenitriles with α,β-unsaturated
ketones 1.
Perez et al. recently reported an interesting method for the syn- graphic methods (Figure 1).
thesis of condensed pyridines 2 through a three-component
reaction of malononitrile with benzaldehyde and cyclic ketones
[11] (Scheme 2).
Scheme 2: Synthesis of 2-amino-4-phenyl-3-cyanopyridines 2.
In contrast, MW-irradiation-promoted reactions of ketones,
aldehydes and malononitrile are known to afford polysubsti-
tuted benzenes 3 (Scheme 3) [12].
Figure 1: X-ray crystal structure of 9.
Scheme 3: Synthesis of polysubstituted benzenes 3.
In contrast, we found that the p-nitrophenyl-substituted
Elnagdi et al. reported [13] that reaction of alkyl azenyl analogue 7b reacts with ethyl propiolate (4a) in the presence of
carbonitrile with arylidene malononitrile afforded benzo-fused L-proline to produce the penta-substituted benzene derivative
azenes. Based on these studies several surveys were published 13b in 60% yield (Scheme 4). In order to explain this unusual
during the last decade [10,14-19].
finding, we proposed that malononitrile, perhaps formed under
the reaction conditions by C–C bond cleavage promoted frag-
mentation of 8, adds to 9 to generate 10 that cyclizes to form
Results and Discussion
Very recently we reported that the reaction of dimethylacety- 12. Subsequent aromatization of 12 produces the benzoate
lene dicarboxylate (DMADC) with benzylidenemalononitrile derivative 13b. Alternatively, 8 could react with malononitrile
afforded 2-amino-4H-pyran 9 and that the yield of the process to yield 11 that then serve as a precursor to 13 (Scheme 4). In
can be improved if equimolar amounts of DMADC, benzyl- support of the former mechanistic proposal, it was observed that
idenemalononitrile and malononitrile are used [20]. Similar 2-amino-4H-pyran 9 reacts with malononitrile to yield 13a
observations have been made in previous studies of these reac- (Scheme 4), whose structure was unambiguously assigned by
tions using 1-methylimidazole [21]. Recently we observed that X-ray crystallographic analysis (Figure 2).
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Beilstein J. Org. Chem. 2014, 10, 141–149.
Scheme 4: Syntheses of compound 9 and compounds 13a,b.
This finding led to the development of a procedure for the high
yielding preparation of 13b that involves the addition of one
equivalent of malononitrile to the reaction mixture containing
ethyl propiolate (4a) and 7b.
The observations described above prompted us to extend the
synthetic potential of these types of condensation reactions. In
the following studies, we found that 5,5-dimethylcyclohexane-
1,3-dione (14) reacts with enaminonitrile 15 and malononitrile
in the presence of L-proline or DABCO to yield the 2-amino-
4H-pyran 18 whose structure was assigned by X-ray crystallo-
graphic methods (Figure 3).
We assumed that in this process 14 and 15 undergo an initial
condensation to yield dione 16 that reacts with malononitrile to
afford adduct 17, which subsequently cyclizes to produce 18. It
is of value to note that, when the reaction of 14 and 15 is
Figure 2: X-ray crystal structure of 13a.
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Beilstein J. Org. Chem. 2014, 10, 141–149.
Figure 3: X-ray crystal structure of 18.
conducted in the absence of malononitrile, dihydroquinolinone
21 is generated through a pathway involving the intermediate
imines 19 and 20 (Scheme 5). The structure of 21 was deter-
mined by X-ray crystallographic methods (Figure 4).
Figure 4: X-ray crystal structure of 21.
An attempt to prepare the bicyclic 2-amino-4H-pyran 24 by the
reaction of dione 14 with ethyl propiolate (4a) in the presence
of malononitrile and L-proline or DABCO was not successful.
Instead, these substances reacted to the fused benzoic acid ester
26, which was characterized by X-ray crystallography
(Figure 5).
Figure 5: X-ray crystal structure of 26.
It appears that in this process, ethyl propiolate (4a) reacts with
dione 14 initially to form adduct 22 which then adds to
malononitrile to produce 25. The latter undergoes cyclization to
afford 26 (Scheme 6).
Scheme 5: Syntheses of compounds 18 and 21.
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Figure 6: X-ray crystal structure of 27a.
Scheme 6: Syntheses of compound 26.
It is interesting that the 2-amino-4H-pyrans, generated in the
reactions described above, serve as excellent precursors to
uniquely substituted nicotinate derivatives. For example, both
pyrans 9a and 9b [22] react with hydroxylamine hydrochloride
in ethanolic solutions containing sodium acetate to yield the
respective amidoximes 27a and 27b. The structures of these
compounds were assigned by X-ray crystallographic methods
(Figure 6). In addition, these substances can be transformed to
the corresponding ethyl 6-amino-5-carbamoyl-4-phenylnicoti-
nate derivatives 28a and 28b by stirring in refluxing DMF
(Scheme 7, Figure 7).
Scheme 7: Syntheses of compound 28a,b.
Furthermore, 9a and 9b rearrange to the corresponding nico-
tinic acid derivatives 31a and 31b when they are stirred in
refluxing acetic acid containing ammonium acetate. The struc-
tures of both of the products were assigned by employing X-ray
crystallographic methods (Figure 8 and Figure 9).
We believe that the nicotinic acid esters are generated in these
reactions by ring opening of 9a and 9b to yield the respective
amidines 29a and 29b, which then cyclize to produce 30a and
Figure 7: X-ray crystal structure of 28b.
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Beilstein J. Org. Chem. 2014, 10, 141–149.
Scheme 8: Syntheses of compound 31a,b.
Figure 8: X-ray crystal structure of 31a.
Scheme 9: Syntheses of compound 33a,b.
Figure 9: X-ray crystal structure of 31b.
30b. The latter compounds readily undergo autooxidation to
form 31a and 31b (Scheme 8).
Finally, the pyranopyrimidines 33a and 33b were efficiently
produced by a sequence including an initial condensation reac-
tion of the 2-amino-4H-pyrans 9a and 9b with dimethylform-
amide dimethylacetal (DMFDMA) to yield the amidine-substi-
tuted derivatives 32a and 32b. Stirring solutions of these
substances in refluxing AcOH/NH4OAc gave the respective
pyranopyrimidines 33a and 33b (Scheme 9, Figure 10).
In an exploratory study aimed at expanding the chemistry
shown in Scheme 4, we observed that diethyl acetylenedicar-
Figure 10: X-ray crystal structure of 33a.
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Beilstein J. Org. Chem. 2014, 10, 141–149.
boxylate (DEAD, 4b) does not react with benzylidenemalono-
nitrile (7a) in the presence of L-proline. However, when
DABCO was employed as the amine nucleophile, reaction of
DEAD with 7a readily took place and the substituted phthalate
diester 37a was obtained in 80% yield. The structure of 37a was
determined by X-ray crystallographic analysis (Scheme 10 and
Figure 11).
Figure 11: X-ray crystal structure of 37a.
Scheme 10: Syntheses of compound 37a–c.
In a similar fashion, DEAD was observed to react with the
p-nitro- and p-chloro-benzylidenemalononitriles 7b and 7c in
the presence of DABCO to yield the corresponding phthalate
diesters 37b and 37c (Figure 12).
Figure 12: X-ray crystal structure of 37b.
A plausible mechanistic route for the formation of 37a involves
an initial addition of DABCO to DEAD to yield the intermedi-
ate zwitterionic enammonium diester 34, which then adds to 7a DMFDMA to form amidine 38, which undergoes cyclization in
to produce zwitterion 35a. Reaction of 35a or its protonated refluxing AcOH/NH4OAc to form the 1-amino-pyrrolo[3,4-
form with malononitrile, which is likely generated by hydrol- f]quinazoline 39. We also found that 37a reacts with hydroxyl-
ysis of 7a, then forms 36a that cyclizes and aromatizes by loss amine hydrochloride in ethanolic sodium acetate solution to
of HCN to yield 37a. This sequence is closely related to the one form isoindolone derivative 40 (Scheme 11 and Figure 13).
described above for the formation of benzoic acid derivatives
13a and 13b (Scheme 6). Although they have potential utility in Conclusion
the field of polymer chemistry, to the best of our knowledge the In the current investigation, we have developed new and effi-
preparation and chemical reactivity of only a few tetrasubsti- cient methods for the synthesis of polyfunctionalized 2-amino-
tuted phthalic acid diesters have been described previously. In 4H-pyrans and aminobenzoic acids. In addition, we have
this effort, we observed that phthalate 37a reacts with explored the preparative potential of these substances as inter-
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Beilstein J. Org. Chem. 2014, 10, 141–149.
Supporting Information
Supporting Information File 1
Experimental.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-11-S1.pdf]
Acknowledgements
The authors are grateful to Kuwait University Research Admin-
istration for financial support of project SC01/10. Analytical
facilities provided by GFS projects No. GS 03/08, GS 01/01,
GS 01/03 & GS 01/05 are greatly appreciated. The authors are
grateful to the Chemistry Department, Faculty of Science at
Qena, South Valley University for supporting them.
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