Direct synthesis of functional azaxanthones by using a domino three-component reaction

Article abstract of DOI:10.1021/ol3013099

NH aldimines, generated in situ from the corresponding aldehydes by reaction with ammonium acetate, serve as nitrogen nucleophiles in reactions with 3-(1-alkynyl)chromones and 3-cyanochromones that generate functionalized azaxanthones. These processes take place under mild conditions that do not require dry solvents. The products of the reactions described represent new chemical entities. We believe that the newly developed cascade process will serve as a potent method for the synthesis of N-heterocycles and in diversity-oriented synthesis.

Full text of DOI:10.1021/ol3013099

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3206–3209
Direct Synthesis of Functional
Azaxanthones by Using a Domino
Three-Component Reaction
Jianwei Yan, Ming Cheng, Feng Hu, and Youhong Hu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
yhhu@mail.shcnc.ac.cn
Received May 11, 2012
ABSTRACT
NH aldimines, generated in situ from the corresponding aldehydes by reaction with ammonium acetate, serve as nitrogen nucleophiles in
reactions with 3-(1-alkynyl)chromones and 3-cyanochromones that generate functionalized azaxanthones. These processes take place under mild
conditions that do not require dry solvents. The products of the reactions described represent new chemical entities. We believe that the newly
developed cascade process will serve as a potent method for the synthesis of N-heterocycles and in diversity-oriented synthesis.
One pot, multicomponent reactions (MCRs) are power-
ful tools for the preparation of biologically relevant,
natural product-like molecular frameworks.1 Based on
the properties of unique intermediates, these processes
can be rationally designed so that they serve as ideal
approaches for the efficient synthesis of structurally com-
plexand functionallydiversemoleculesthatplaythe roleof
lead compounds in drug discovery efforts.2 In this regard,
2-(1-alkynyl)-2-alken-1-ones are attractive starting materi-
als for multicomponent processes because they undergo
transition metal, Lewis acid,3 and electrophile-induced
cascade cyclization reactions4 promoted by nucleophiles
to form highly substituted furans. Also, cascade reactions
of these substances, initiated by additions of carbon and
oxygen nucleophiles under base conditions, are known to
proceed through domino-type Michael additionꢀcyclization
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Recent studies in our group have focused on the devel-
opment of cascade reactions of 3-(1-alkynyl) chromones
that have been utilized to generate diverse molecular
scaffolds. Due to their propensity to undergo ring-opening
and secondary cyclization reactions, chromones take part
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r
10.1021/ol3013099
Published on Web 06/05/2012
2012 American Chemical Society

in base promoted cascade reactions that afford a diverse
array of xanthones,7 a structural unit found in a large
numberofnaturallyoccurringandsyntheticbioactivecom-
pounds.8 Introduction of a nitrogen atom in the xanthone
framework with a pyridine or pyrimidine core would
lead to a more drug-like skeleton with the hope that it
can be employed in the discovery of lead compounds.
Below, we describe the results of a recent study that has
led to the development of a direct method for the synthesis
of diverse functionalized azaxanthones that employs a
domino, three-component reaction.
Prior to the current investigation, a few examples involv-
ing reactions initiated by Michael addition of nitrogen
to 2-(1-alkynyl)-2-alken-1-ones9 had been described. We
envisaged that in situ generated N-unsubstituted aryl
aldimines10 would act as nucleophiles11 in Michael addi-
tion reactions with 3-(1-alkynyl)chromones that would
initiate a novel cascade sequence to produce azaxanthones.
In order to test this proposal, a mixture of 3-(1-alkynyl)-
chromone (1a), benzaldehyde (2a) (1.5 equiv), and
H2NCO2NH4 (2 equiv) in DMF was stirred at 100 °C
for 15 h (eq 1). The process occurring under these condi-
tions did indeed generate the azaxanthone 3aa in 44%
yield. The structure of 3aa was assigned by using X-ray
crystallographic analysis.12
The proposed mechanism for this process, depicted in
Scheme 1, begins with the addition of the NH aldimine A,
formed in situ by condensation of the aldehyde with
ammonia, to 3-(1-alkynyl)chromone serving as a Michael
acceptor. Thisstepisfollowed bythe opening of the pyrone
ring in B to afford intermediate C, which then undergoes
regioselective intramolecular cyclization to produce 2-aza-
triene intermediate D. Finally, 6π-electrocyclization of D
followed by dehydrogenation13 of the dihydropyridine
ring in E affords 2-azaxanthone 3. To the best of our
knowledge, this is the first example of a process that forms
an azaxanthone through a domino sequence initiated by
reaction of a 3-(1-alkynyl)chromone with an NH aldimine.
Moreover, this new cascade reaction represents a concise
method for the construction of the natural product-like,
functionallized 2-azaxanthone framework.14
Studies were carried out to determine the optimal con-
ditionsfor the2-azaxanthone forming reaction. The results
obtained from screening several ammonia sources showed
that NH2CO2NH4, AcONH4, HCO2NH4, and NH4HCO3
all promote the tandem process with 3 equiv of AcONH4
giving optimal results (Table 1, entries 1ꢀ6, 9ꢀ10). A poor
efficiency was observed for the reaction in which NH4Cl
or (NH4)2SO4 was employed (Table 1, entries 7ꢀ8).
DMF was found to be a superior solvent for the reac-
tion in contrast to ethanol, DMSO, toluene, and dioxane
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Scheme 1. A Proposed Reaction Mechanism
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Org. Lett., Vol. 14, No. 12, 2012
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(Table 1, entries 5, 11ꢀ14). In addition, the yield of the
processisnot sensitivetothe presence ofmoisture(Table 1,
entry 15). The findings arising in this exploratory study
indicate that optimized conditions for the 2-azaxanthone
forming reaction starting with 1a (1 equiv) and the alde-
hyde (1.5 equiv) involve the use of 3 equiv of AcONH4 in
DMF at 100 °C for 15 h.
Finally, when paraformaldehyde is employed as the alde-
hyde starting material, reaction of 1a produces the corre-
sponding 2-azaxanthone 3ap in 56% yield (Scheme 2).
The enolizable aldehydes, such as phenylacetaldehyde
and valeraldehyde, and R,β-unsaturated aldehydes, such
as crotonaldehyde, all give complicated results due to the
instability of their NH aldimines.10
Scheme 2. Synthesis of Substituted 2-Azaxanthonesa
Table 1. Optimization of the 2-Azaxanthone Forming,
Three-Component Reactiona
entry
solvent
[NH4þ] (equiv)
temp/time
yield (%)b
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
DMSO
PhMe
dioxane
DMF
NH2CO2NH4(2)
NH2CO2NH4(5)
NH2CO2NH4 (10)
AcONH4 (2)
AcONH4 (3)
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
100 °C/15 h
80 °C/24 h
44
2
49
3
44
4
43
5
80
6
AcONH4 (5)
78
7
NH4Cl (3)
NRc
NR
67
8
(NH4)2SO4 (2)
NH4HCO3 (3)
HCO2NH4 (3)
AcONH4 (3)
9
10
11
12
13
14
15d
64
76
AcONH4 (3)
100 °C/24 h
100 °C/24 h
100 °C/24 h
100 °C/15 h
57
AcONH4 (3)
AcONH4 (3)
NR
NR
75
a Reaction conditions: a mixture of 1 (0.5 mmol), aldehyde (0.75 mmol),
and ammonium acetate (1.5 mmol) in DMF (10 mL) was stirred at 100 °C
for 15 h. bParaformaldehyde (75 mg) was used. c1.05 equiv of 4-methoxy-
benzaldehyde was used.
AcONH4 (3)
a Reaction conditions: a mixture of 1a (0.5 mmol), 2a (0.75 mmol),
and ammonia source was stirred at the indicated temperature and time.
b Isolated yields. c No reaction. d 4 A molecular sieves were present.
ꢀ
Reactions utilizing various 3-(1-alkynyl)chromones
were studied to explore the scope of the new domino
reaction. Good yields of products were observed for reac-
tions of 3-(1-alkynyl)chromone 1a containing aromatic
substituents (R2) on the acetylene moiety (Scheme 2, 3aa,
3bdꢀ3cd). However, when R2 is a linear or sterically
hindered (tert-butyl) alkyl group, reactions take place to
form 2-azaxanthones (3ddꢀ3ed) in lower yields with com-
plicated byproducts (Scheme 2). The R2 = trimethylsilyl
substituted chromone (1f) undergoes reaction to generate
the corresponding desilylated product 3fd in 47% yield
(Scheme 2). Finally, the process also tolerates various
substituents (R3) on the arene ring of the 3-(1-alkynyl)-
chromone (Scheme 2, 3gdꢀ3id).
Reactions of 3-(1-alkynyl)chromone 1a with various
substituted aromatic aldehydes 2 were investigated using
the optimized conditions (Scheme 2). The results show that
although the efficiency of the reaction is not influenced
by the steric bulkiness of the benzaldehyde derivatives, it
is significantly sensitive to electronic properties of the
aldehydes. Specifically, benzaldehydes containing strongly
electron-donating groups, regardless of their position on
the arene ring, react to give products (3abꢀ3ag) in high
yields (Scheme 2). In contrast, electron-withdrawing group
substituted benzaldehydes afford 2-azaxanthone products
(3akꢀ3am) in only moderate yields (Scheme 2) with the
dimeric byproduct of 1a.7b The latter effect may be a
consequence of the weak nucleophilicity of electron-poor
NH aldimines. The results of this exploratory investigation
demonstrate that the new cascade reaction is compatible
with hydroxy, chlorine, bromine, amino, and ester sub-
stituted benzaldehydes that react to form products
(3aeꢀ3ak and 3anꢀ3ao) in acceptable yields (Scheme 2).
During the exploratory study, we observed that treat-
ment of chromone 1f with an excess (2.5 equiv) of 4-meth-
oxybenzaldehyde (2d) and AcONH4 (3 equiv) in DMF at
100 °C leads to formation of the corresponding 2-azax-
anthone 3fd, along with the byproduct 4 in 29% yield
(Scheme 3). It is likely that 4 is generated by a sequence in
which the dihydropyridine intermediate F undergoes con-
densation with 4-methoxybenzaldehyde to generate G,
which then aromatizes (Scheme 3).
´
(14) Payne, D. J.; Hueso-Rodrıguez, J. A.; Boyd, H.; Concha, N. O.;
Janson, C. A.; Gilpin, M.; Bateson, J. H.; Cheever, C.; Niconovich,
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The success of the new cascade reaction encouraged us
to carry out the studies aimed at extending the scope of the
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Org. Lett., Vol. 14, No. 12, 2012

Scheme 3. In Situ Trapping of Dihydropyridine Intermediate F
Scheme 4. Synthesis of Substituted 2,4-Diazaxanthonesa
process to other Michael acceptors. The results of this
effort showed that 3-cyanochromone 5 (R4 = H) reacts
with benzaldehyde derivative 2 (R1 = 4-MeOC6H4) to
form 2,4-diazaxanthones 6ad (Table S1 in the Supporting
Information). A brief optimization effort demonstrated
that the yield of the 2,4-diazaxanthone forming reaction
could be increased to 85% when 1.2 equiv of CuCl2 was
present as an oxidant in the reaction mixture.15 Reactions
of cyanochromone 5a (R4 = H) with a wide range of
electron-rich, -neutral, and -deficient benzaldehydes 2,
under the optimized conditions, were found to generate
the corresponding products 6aaꢀ6am in good to excellent
yields (Scheme 4). When paraformaldehyde is employed as
the aldehyde, the unsubstituted 2,4-diazaxanthone 6ap is
producedin74%yield(Scheme 4). Thisprocesstakesplace
efficiently when 3-cyanochromones containing a variety
of arene ring substituents serve as starting materials
(Scheme 4, 6bdꢀ6fd). The structure of 6ad was unambigu-
ously elucidated by using X-ray crystal structure analysis.16
In conclusion, the observations made in this investigation
show that NH aldimines, generated in situ by condensations
of the corresponding aldehydes with ammonium acetate,
serve as nitrogen nucleophiles in efficient cascade reactions
a Reaction conditions: 5 (0.5 mmol), aldehyde (0.75 mmol), ammo-
nium acetate (1.5 mmol), CuCl2 (0.6 mmol), DMF (10 mL), 100 °C, 15 h.
bParaformaldehyde (75 mg) was used.
with 3-(1-alkynyl)chromones and 3-cyanochromones.
Importantly, these processes, which generate diverse func-
tionalized azaxanthones, take place under mild conditions
and without the need for dry solvents. Moreover, the
results open the door for the use of unsubstituted aldimines
in other types of tandem processes. Further investigations
probing the scope and synthetic applications of the reac-
tion and the biological properties of new substances pro-
duced are underway and will be described in due course.
Acknowledgment. This work was supported by a grant
from National Natural Science Foundation of China
(21172232).
Supporting Information Available. Experimental pro-
cedures and characterization data of compounds 3aaꢀ3id,
4, and 6aaꢀ6fd; X-ray structure and crystallographic
data in CIF format of compounds 3aa and 6ad. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
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5942–5947. (b) Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285–3287.
(c) Cheng, G.; Hu, Y. J. Org. Chem. 2008, 73, 4732–4735.
(16) CCDC 883773 (6ad) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/services/structure_deposit/.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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