Diversified construction of chromeno[3,4-c]pyridin-5-one and benzo[c]chromen-6-one derivatives by domino reaction of 4-Alkynyl-2-oxo-2H- chromene-3-carbaldehydes

Article abstract of DOI:10.1002/adsc.201301171

Silver-catalyzed three-component, tandem reactions of 4-alkynyl-2-oxo-2H- chromene-3-carbaldehydes, amines and various nucleophiles result in the formation of highly functionalized chromeno[3,4-c]pyridin-5-ones in high yields. Gold-catalyzed [4+2] cycloadditions of 4-alkynyl-2-oxo-2H-chromene-3- carbaldehydes with alkynes or alkenes have also been achieved to afford benzo[c]chromen-6-ones efficiently.

Full text of DOI:10.1002/adsc.201301171

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DOI: 10.1002/adsc.201301171
Diversified Construction of Chromeno[3,4-c]pyridin-5-one and
G
Benzo[c]chromen-6-one Derivatives by Domino Reaction of
4-Alkynyl-2-oxo-2H-chromene-3-carbaldehydes
Jian Xiao,a,* Yuye Chen,a Shuai Zhu,a Liang Wang,a Lubin Xu,a and Hongtao Weia
a
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, Peopleꢀs Republic
of China
E-mail: chemjianxiao@gmail.com
Received: December 25, 2013; Revised: March 2, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301171.
Abstract: Silver-catalyzed three-component, tandem been achieved to afford benzo[c]chromen-6-ones ef-
reactions of 4-alkynyl-2-oxo-2H-chromene-3-carbal- ficiently.
dehydes, amines and various nucleophiles result in
the formation of highly functionalized chromeno
ACHTUNGTNER[NUNG 3,4-
c]pyridin-5-ones in high yields. Gold-catalyzed [4+2] Keywords: benzo[c]chromen-6-ones; chromenoACHTUNGTRENNUNG[3,4-
cycloadditions of 4-alkynyl-2-oxo-2H-chromene-3- c]pyridin-5-ones; coumarins; cycloaddition; Lewis
carbaldehydes with alkynes or alkenes have also acids
Introduction
macological properties such as antimicrobial and anti-
tumor activities,[12b] schumanniophytine C shows cen-
Propargylic compounds are important building blocks tral and autonomic nervous system depressant proper-
in synthetic chemistry due to their easy coordination ties and may have potential antiviral activity,[12g] alter-
with alkynophilic Lewis acids, leading to their sus- nariol D exhibits antifungal and phytotoxic activity,
ceptibility to nucleophilic addition and cycloaddition and is reported to inhibit cholinesterase enzymes,[13j]
etc.[1] A large number of alkynophilic Lewis acid-cata- gilvocarcin E is a kind of bactericidal and antitumor
lyzed reactions of propargylic compounds with di- natural product,[13k] and cannabinol F can be em-
verse nucleophiles have been developed in recent ployed clinically as an immunosuppressant. Due to
years for the construction of diverse heterocycles.[2] the great importance of the compounds of these fami-
Among these, ortho-alkynylaldehydes has been identi- lies, we wanted to develop new methodologies for the
fied by Wu and Larock as powerful building blocks to efficient construction of them.
synthesize a wide variety of heterocyclic and carbocy-
With great interest in manipulation of coumarin
clic compounds through rationally designed domino blocks, recently we have successfully achieved a facile
3
reactions or cycloadditions.[3]
catalyst-free sp C H activation of 2-alkylazaarenes
À
Coumarin (2H-chromen-2-one) is a core moiety of with (thio)coumarin-3-carboxylic acids for the effi-
many biologically important compounds and members cient construction of azaarenes-substituted 3,4-
of coumarin families are widely utilized as antican- dihydro
cer,[6] antimicrobial,[7] antioxidation,[8] anti-HIV[9] work and our efforts for developing new methodolo-
agents, fluorescent probes,[10] and triplet sensitizers,[11] gies to construct biologically important heterocyclic
etc. Among these derivatives, chromeno
[3,4-c]pyridin- compounds,[14] we planned to design a new type of b-
5-one[12] and benzo[c]-chromen-6-ones[13] are two alkynyl aldehyde compounds as the key intermediate
classes of special families which are present in a varie- to synthesize various chromeno[3,4-c]pyridin-5-one
ty of natural products and bioactive molecules with and benzo[c]chromen-6-one derivatives, thus 4-alkyn-
important applications in medicinal chemistry yl-2-oxo-2H-chromene-3-carbaldehyde came to
(Figure 1). For example, chromeno[3,4-c]pyridin-5- mind and eventually was identified as the key inter-
(thio)coumarins.[14a] As a continuation of this
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1
AHCTUNGTRENNUNG
one A can act not only as a selective human dopa- mediate for diversified electrophilic cyclization and
mine D4 receptor antagonist, but also as a potential cycloaddition reactions, with which a series of domino
antipsychotic agent,[12a] B shows a wide range of phar- reactions and cycloaddition reactions were developed
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to construct various chromenoACTHUNTGRNEUNG[3,4-c]pyridin-5-one
and benzo[c]chromen-6-one derivatives efficiently
(Figure 2).
Results and Discussion
4-Alkynyl-2-oxo-2H-chromene-3-carbaldehyde could
be prepared from 4-hydroxycoumarin in two steps in-
Figure 1. Natural products and bioactive molecules possess-
ing chromenone core structures.
Scheme 1. Preparation of 1a.
Figure 2. Diversified synthesis of chromenoACTHNUTRGNEUNG
[3,4-c]pyridin-5-one[15] and benzo[c]chromen-6-one derivatives.
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Diversified Construction of ChromenoACTHNUGRTENUNG[3,4-c]pyridin-5-one and Benzo[c]chromen-6-one
volving formylation, chlorination and Sonogashira at 608C using 10 mol% AgOTf and 10 mol% l-pro-
coupling (Scheme 1).[15] Treatment of 4-hydroxycou- line as catalysts with the hope of achieving enantiose-
marin with POCl3 in DMF to furnish 4-chloro-2-oxo- lectivity (Table 1, entry 1). To our delight, the desired
2H-chromene-3-carbaldehyde in 73% isolated yield[16] product was obtained in 86% yield, although as a race-
was followed by a Sonogashira coupling with phenyl- mic compound. The employment of other solvents did
ACHTUNGTRENNUNGacetylene catalyzed by PdACHUTGNTREN(NUGN PPh3)2Cl2 and CuI not lead to any improvement in yield (Table 1, en-
(7 mol%) which afforded the desired 4-alkynyl-2-oxo- tries 2–9). When AgNO3 was exploited as a catalyst at
2H-chromene-3-carbaldehyde 1a as a yellow solid 608C, the yield rose to 93% (Table 1, entry 10). Both
which can be stored at 48C for several months with- increasing the temperature and lowering the tempera-
out notice
G
ture only led to lower isolated yields due to side reac-
With this key intermediate in hand, the reaction of tions (Table 1, entries 11 and 12). When primary
1a, amine 2a and ketone 3a was conducted in ethanol amines a–d were used as organocatalysts, only a trace
Table 1. Screening of the reaction conditions.[a]
Entry
Catalyst
Organocatalyst
Solvent
Temperature [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AuCl3
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
primary amine a
primary amine b
primary amine c
primary amine d
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
–
l-proline
EtOH
MeOH
MeCN
toluene
THF
60
60
60
60
60
60
60
60
60
60
80
30
60
60
60
60
60
60
60
60
60
60
60
60
86
77
78
61
54
73
52
66
81
93
82
8
trace
trace
trace
trace
10
16
23
12
18
7
12
NR
DCM
DMF
1,4-dioxane
acetone
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
9
10
11
12
13
14
15
16
17[c]
18
19
20
21
22[d]
23
24
PdCl2
Pd
A
Cu
A
InBr3
TfOH
AgNO3
–
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3a (1.8 mmol), Lewis acid (10 mol%), organocatalyst (10 mol%), 2 mL
solvent, 30–608C, 8 h.
Isolated yield after column chromatography.
5 mmol% catalyst.
[b]
[c]
[d]
20 mmol% catalyst.
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Table 2. Reactions of 1, amines 2 and acetone 3.[a]
[a]
Reaction conditions: 4-alkynyl-2-oxo-2H-chromene-3-carbaldehyde 1 (0.3 mmol), aniline 2 (0.3 mmol), acetone 3
(1.8 mmol), AgNO3 (10 mol%), l-proline (10 mol%), ethanol 2 mL, 608C, 8 h.
Isolated yield after column chromatography.
[b]
of the desired product 5a could be achieved (Table 1, well tolerated (Table 2, entries 2 and 3); both elec-
entries 13–16). The employment of other Lewis acids tron-poor and electron-rich anilines were good sub-
such as AuCl3, ScACHTNURTGENUNG(OTf)3 and InBr3 as well as the strates and gave similar yields; para-toluidine and
Brønsted acid catalyst TfOH only resulted in inferior para-anisidine gave the desired products 5d and 5e in
results (Table 1, entries 17–22). Remarkably, 5a was 92% and 85% yields (Table 2, entries 4 and 5). Simi-
obtained merely in 12% yield only with AgNO3, and larly, 1a reacted with 4-chloroaniline, 4-bromoaniline
no reaction occurred at all only with l-proline, indi- and 4-iodoaniline smoothly, giving rise to the desired
cating the importance of cooperative dual catalysis by products in 95%, 97% and 76% yields (Table 2, en-
À
AgNO3 and l-proline in this reaction.
tries 6–8). This would be more desirable as the C X
With the optimized conditions in hand, the general- (X=Br or I) bonds are versatile synthetic handles for
ity of this reaction was investigated (Table 2). Elec- further elaborations. Furthermore, 4-nitroaniline was
tron-donating groups on the arylalkyne moiety were
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Diversified Construction of ChromenoACTHNUGRTENUNG[3,4-c]pyridin-5-one and Benzo[c]chromen-6-one
Table 3. Optimization of the reaction conditions.[a]
Entry
Catalyst (10 mol%)
Yield [%][b]of 6a
Yield [%][b]of 11a
1
2
3
AgNO3
AgOTf
PdCl2
82
96
15
21
14
19
0
0
0
0
39
24
4
Pd
N
5[c]
6[c]
AuCl3
AuBr3
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), 4a (1.8 mmol), catalysts (10 mol%), acetonitrile 2 mL, 608C, 8 h.
Isolated yield after column chromatography.
5 mmol% catalyst.
[b]
[c]
also tolerated under the standard reaction condition, fords the intermediate A. Because of high alkynophi-
albeit with somewhat lower yield (Table 2, entry 9). licity of Ag(I), the p-complex B undergoes a 6-endo-
We reasoned that terminal alkynes and acetone dig cyclization to furnish intermediate C. Ultimately,
would be of comparable reactivity as pronucleophiles the nucleophile attacks the electrophilic moiety of in-
in the present protocol. Indeed, a clean reaction be- termediate C, furnishing the final products D with si-
tween 1-phenylethyne 4a, 4-alkynyl-2-oxo-2H-chro- multaneous regeneration of the catalyst.
mene-3-carbaldehydes 1a and aniline 2a was achieved
Inspired by the recent development of the dioxy-
at 608C in the presence of 10 mol% AgOTf, and the gen/copper system[17a,b] and the Ag/Cu co-catalyzed
adduct 6a could be isolated in 96% yield (Table 3). reaction reported by Wu,[17c] we found that reaction of
When other Lewis acid catalysts such as AgNO3, 1a with TsNHNH2 could proceed in the presence of
AuCl3 and AuBr3 were used in this reaction, 5 mol% AgOTf and 5 mol% CuCl2 in DCE to furnish
a [4+2]cycloaddition also occurred, giving rise to 10- 9 in 58% yield at 608C with a 16% yield of 10
benzoyl-8-phenyl-6H-benzo[c]chromen-6-one 11a in (Scheme 4). In addition, when ammonia reacted with
39% and 24% yields. The scope of the conversion of 1a, a clean reaction was achieved to afford product 10
1 to 6 is reported in Table 4. Various alkynes and ani- in 91% yield.[18] Following the identification of ben-
lines afforded the target products in high yield zo[c]chromen-6-one 11a as by-product (Table 3, en-
(Table 4). Notably, benzylamine also worked very tries 5 and 6), as this structure is the core moiety of
well and the desired product 6j was isolated in 88% many natural products,[19] we decided to seek the opti-
yield (Table 4, entry 10). Different aryl-substituted mal reaction conditions for its synthesis. Ultimately
terminal alkynes also reacted with 1a and 2a with we found that in the presence of 10 mol% of AuCl3 at
comparable efficiency (6k–6m), affording the desired 608C the target product 11a was formed in 87% yield
products in good yields (Table 4, entries 11–13).
(Scheme 5). Other alkynes were also tolerated and
Moreover, other nucleophiles, for example, nitro- the corresponding benzannulation products 11b–11d
methane and silyl enol ether, could also be employed could be produced in good yields. Besides gold cataly-
in this reaction and the corresponding products 7 and sis, iodonium activation could also be utilized to con-
8 were obtained in 83% and 95% yields (Scheme 2). struct the identical compound skeletons.[20] These
A plausible reaction mechanistic pathway was pro- alkyne-based halocyclization reactions are versatile
posed according to the experimental results and can be viewed as metal-free alternatives of gold
(Scheme 3). Firstly, condensation of 1 with amine af- catalyzed alkyne cyclizations. Unfortunately, when the
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Table 4. Reactions of 1, amines 2 and alkynes 4.[a]
[a]
Reaction conditions: 4-alkynyl-2-oxo-2H-chromene-3-carbaldehyde 1 (0.3 mmol), aniline 2 (0.3 mmol), terminal alkyne 4
(0.6 mmol), AgOTf (10 mol%), acetonitrile 2 mL, 608C, 8 h.
Isolated yield after column chromatography.
[b]
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Diversified Construction of ChromenoACTHNUGRTENUNG[3,4-c]pyridin-5-one and Benzo[c]chromen-6-one
Scheme 2. Reactions of 1a, 2a and other nucleophiles.
reaction was carried out using 2 equiv. of I2 instead of
AuCl3 catalyst, the desired product 11a was not ob-
tained, whereas another clean reaction was observed
and the unexpected adduct 12a was isolated in 88%
Scheme 3. Proposed mechanistic pathway.
Scheme 5. Synthesis of products 11.
Scheme 4. Synthesis of products 9 and 10.
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and it was found that 12b and 12c could also be ob-
tained in moderate to good yields (Scheme 6).
Moreover, when styrene was exploited instead of
phenylacetylene, the reaction with 4-alkynyl-2-oxo-
2H-chromene-3-carbaldehydes 1a afforded the same
product 11a in 91% yield.[22] Intriguingly, when
2 equiv. of I2 were employed instead of AuCl3, the
identical product 11a was isolated in 86% yield
(Scheme 7).
According to these experimental results, a plausible
mechanism was proposed: Firstly, the activation of
alkyne 1a by Lewis acid, followed by 6-endo-dig cycli-
Scheme 6. Synthesis of products 12.
yield (Scheme 6).[21] Notably, unlike other iodide-cata- zation can give rise to zwitterionic intermediate B
lyzed cycloaddition reactions, no iodine atom was in- which works as the precursor of a Diels–Alder reac-
corporated into the final product, which might be as- tion to trap dienophilic phenylacetylene or styrene,
cribed to the high reaction temperature and long re- producing the cycloaddition intermediate E or F. A
action time. To further investigate the substrate scope subsequent elimination of metal or iodine results in
of this reaction, some other alkynes were examined
Scheme 7. Synthesis of products 11 and a plausible mechanistic pathway.
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Diversified Construction of ChromenoACTHNUGRTENUNG[3,4-c]pyridin-5-one and Benzo[c]chromen-6-one
(3.0 mmol) in DCE (1.0 mL) were added. The mixture was
then stirred at 858C for 12 h. Subsequently the mixture was
diluted with CH2Cl2 (10 mL) and filtered through celite. All
the volatiles were removed under vacuum. Purification was
performed by flash column chromatography on silica gel
using EtOAc and petroleum ether.
rearomatization and formation of the desired product
11a.
Conclusions
In conclusion, we have identified 4-alkynyl-2-oxo-2H-
chromene-3-carbaldehydes as the key intermediates
to participate in a series of domino reactions and cy-
cloadditions for efficient syntheses of biologically im-
Procedure for the Synthesis of Compound 10
To a 25-mL pressure tube equipped with a magnetic stirrer
bar were added 1a (0.3 mmol), AgNO3 (0.03 mmol), acetoni-
trile (2 mL) and NH3 (6 mmol, 28% NH3 in H2O). The mix-
ture was then stirred at 608C in air for 8 h. Subsequently the
mixture was diluted with CH2Cl2 (10 mL) and filtered
through celite, followed by removal of all volatiles under re-
duced pressure. Purification was performed by flash column
chromatography on silica gel using EtOAc and petroleum
ether.
portant chromenoACTHNUTRGNEUNG[3,4-c]pyridin-5-one and benzo[c]-
chromen-6-one derivatives. Silver-catalyzed three-
component, tandem reactions of 4-alkynyl-2-oxo-2H-
chromene-3-carbaldehydes with amines and various
nucleophiles provided a facile synthesis of highly
functionalized chromenoACTHNURGTNE[NUG 3,4-c]pyridin-5-ones in good
yields. Gold-catalyzed [4+2]cycloadditions of 4-alkyn-
yl-2-oxo-2H-chromene-3-carbaldehydes with alkynes
or alkenes have also been achieved to afford ben-
zo[c]chromen-6-ones efficiently. These methods
should find applications in the synthesis of biological-
ly important structures and future work will be fo-
cused on the enantioselective synthesis of these prod-
ucts using chiral catalysts.
Procedure for the Synthesis of Compound 11a
To a 25-mL flask equipped with a magnetic bar were added
1a (0.3 mmol), AuCl3 (0.03 mmol), dichloromethane (2 mL)
and phenylethyne (0.6 mmol), respectively. The mixture was
then stirred at 608C in air for 6 h. Subsequently the mixture
was diluted with CH2Cl2 (10 mL) and filtered through celite,
afterwards solvent was removed under vacuum. Purification
was performed by flash column chromatography on silica
gel using EtOAc and petroleum ether.
Experimental Section
Procedure for the Synthesis of Compound 12a
Procedure for the Synthesis of Compound 5a
To a 25-mL flask equipped with a magnetic bar were added
1a (0.3 mmol), iodine (0.6 mmol), dichloromethane (2 mL)
and phenylethyne (0.6 mmol), respectively. The mixture was
then stirred at 608C in air for 6 h. Subsequently the mixture
was diluted with CH2Cl2 (10 mL) and filtered through celite
and all the volatiles was evaporated under vacuum. Purifica-
tion was performed by flash column chromatography on
silica gel using EtOAc and petroleum ether.
To a 25-mL flask equipped with a magnetic bar were added
1a (0.3 mmol), AgNO3 (0.03 mmol), l-proline (0.03 mmol),
ethanol (2 mL), aniline 2a (0.3 mmol) and acetone
(1.8 mmol). The mixture was then stirred at 608C in air for
8 h. Subsequently the mixture was diluted with CH2Cl2
(10 mL) and filtered through celite. Afterwards the solvent
was removed under vacuum. Purification was performed
with flash column chromatography on silica gel using
EtOAc and petroleum ether as eluent.
Procedure for the Synthesis of Compound 11a under
Conditions A
Procedure for the Synthesis of Compound 6a
To a 25-mL flask equipped with a magnetic stirrer bar were
added 1a (0.3 mmol), AuCl3 (0.03 mmol), dichloromethane
(2 mL) and styrene (0.6 mmol), respectively. The mixture
was then stirred at 608C in air for 6 h. Subsequently the
mixture was diluted with CH2Cl2 (10 mL) and filtered
through celite, followed by removal of all volatiles under
vacuum. Purification was performed by flash column chro-
matography on silica gel using EtOAc and petroleum ether.
To a 25-mL flask equipped with a magnetic bar were added
1a (0.3 mmol), AgOTf (0.03 mmol), acetonitrile (2 mL), ani-
line 2a (0.3 mmol) and phenylethyne (0.6 mmol). The mix-
ture was then stirred at 608C in air for 8 h. Subsequently the
mixture was diluted with CH2Cl2 (10 mL) and filtered
through celite. All the volatiles were evaporated under
vacuum. Purification was performed by flash column chro-
matography on silica gel using EtOAc and petroleum ether
as eluent.
Procedure for the Synthesis of Compound 11a under
Conditions B
Procedure for the Synthesis of Compounds 9 and 10
1a (0.30 mmol) was added to a solution of 4-methylbenzene-
sulfonohydrazide (0.30 mmol) in DCE (1.0 mL). The mix-
ture was stirred at room temperature in air for 10 min. Then
AgOTf (5 mol%) was added and the solution was stirred at
608C in air for 30 min. After the reaction mixture had been
cooled to 308C, CuCl2 (10 mol%), and tertiary amine
To a 25-mL flask equipped with a magnetic bar were added
1a (0.3 mmol), iodine (0.6 mmol), dichloromethane (2 mL)
and styrene (0.6 mmol), respectively. The mixture was then
stirred at 608C in air for 6 h. Subsequently the mixture was
diluted with CH2Cl2 (10 mL) and filtered through celite, fol-
lowed by removal of all volatiles under vacuum. Purification
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was performed by flash column chromatography on silica
gel using EtOAc and petroleum ether.
2008, 73, 2947; m) S. Roy, S. Roy, B. Neuenswander, D.
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Acknowledgements
We are grateful to the National Natural Science Foundation
of China (No. 21102142) and the Outstanding Young Scien-
tist Award Foundation of Shandong Province (No.
BS2013YY002). Financial support from Talents of High
Level Scientific Research Foundation of Qingdao Agricultur-
al University (No. 631223) is also gratefully acknowledged.
[4] Q. Ding, J. Wu, Org. Lett. 2007, 9, 4959.
[5] A. K. Verma, S. K. R. Kotla, D. Choudhary, M. Patel,
R. K. Tiwari, J. Org. Chem. 2013, 78, 4386.
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These are not the final page numbers!

FULL PAPERS
Diversified Construction of ChromenoACTHNUGRTENUNG[3,4-c]pyridin-5-one and Benzo[c]chromen-6-one
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asc.wiley-vch.de
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ÞÞ
These are not the final page numbers!

FULL PAPERS
12 Diversified Construction of ChromenoACTHNUTRGNEUNG[3,4-c]pyridin-5-one
and Benzo[c]chromen-6-one Derivatives by Domino
Reaction of 4-Alkynyl-2-oxo-2H-chromene-3-carbaldehydes
Adv. Synth. Catal. 2014, 356, 1 – 12
Jian Xiao,* Yuye Chen, Shuai Zhu, Liang Wang, Lubin Xu,
Hongtao Wei
12
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!