Base-Promoted Tandem Reaction Involving Insertion into Carbon–Carbon σ-Bonds: Synthesis of Xanthone and Chromone Derivatives

Article abstract of DOI:10.1002/chem.201602064

Tandem reactions using base-promoted processes have been developed for the synthesis of xanthone and chromone derivatives. The first examples of base-promoted insertion reactions of isolated carbon–carbon triple bonds into carbon–carbon σ-bonds have been reported. Using these approaches, polycyclic structures can be prepared. This reaction has the potential to become a general synthetic protocol for the preparation of multi-substituted xanthones and chromones due to the abundance of easily accessible starting materials possessing diverse substituent groups.

Full text of DOI:10.1002/chem.201602064

DOI: 10.1002/chem.201602064
Communication
&
Heterocycles
Base-Promoted Tandem Reaction Involving Insertion into Carbon–
Carbon s-Bonds: Synthesis of Xanthone and Chromone
Derivatives
Xingcan Cheng, Yuanyuan Zhou, Fangfang Zhang, Kai Zhu, Yuanyuan Liu, and
Yanzhong Li*[a]
Abstract: Tandem reactions using base-promoted process-
es have been developed for the synthesis of xanthone
and chromone derivatives. The first examples of base-pro-
moted insertion reactions of isolated carbon–carbon triple
bonds into carbon–carbon s-bonds have been reported.
Using these approaches, polycyclic structures can be pre-
pared. This reaction has the potential to become a general
synthetic protocol for the preparation of multi-substituted
xanthones and chromones due to the abundance of easily
accessible starting materials possessing diverse substitu-
ent groups.
Scheme 1. Insertion reactions into a carbon–carbon s-bond.
Chemical transformations starting from selective carbon–
carbon bond cleavage and subsequent functionalization are
important and highly efficient methods in organic chemistry
because CÀC bonds constitute the fundamental skeletons of
organic compounds. However, these chemical transformations
are challenging because of the inert and stable properties of
CÀC bonds (both kinetically and thermodynamically). Over the
past few decades, significant progress has been made in this
area, particularly for transition-metal-catalyzed reactions of
strained systems.[1] With regards to unstrained systems, inser-
tion reactions involving acetylenes are limited to rhenium or
nickel catalysis.[2] The Takai and Kuninobu groups[2b–e] have de-
veloped excellent rhenium-catalyzed insertion reactions using
unstrained cyclic compounds; terminal acetylenes[2e] and inter-
nal alkynes[2d] insert into a carbon–carbon single bond posi-
tioned next to a carbonyl group (Scheme 1a). However, transi-
tion-metal-free carbon–carbon s-bond-insertion reactions with
internal alkynes are rare, with the exception of highly reactive
arynes.[3] Utilizing the properties of dicarbonyl compounds, we
developed a base-promoted and transition-metal-free insertion
reaction of internal alkynes with b-diketone compounds to
give xanthone derivatives 4 (Scheme 1b). When b-keto esters
were employed in place of b-diketones, chromone derivatives
5 were obtained. The addition of Fe(ClO4)3·xH2O was able to
significantly improve the yields of chromone 5 (Scheme 1c).
Xanthone (9H-xanthen-9-one) and chromone derivatives are
prevalent in natural products and are widely recognized as
candidates for drug development due to their excellent biolog-
ical and pharmacological activities. For example, siamchro-
mones[4] with anti-tobacco mosaic virus (anti-TMV) and anti-
HIV-1 activities, and a-mangiferin,[5] which has potent anti-bac-
terial, anti-tumor and anti-allergy properties (Figure 1). Thus,
the synthesis of such xanthone and chromone substructures
are synthetically attractive.[6,7]
Figure 1. Chemical structures of natural products containing core xanthone
and chromone skeletons.
[a] X. Cheng, Y. Zhou, F. Zhang, K. Zhu, Dr. Y. Liu, Prof. Dr. Y. Li
Shanghai Key Laboratory of Green Chemistry and Chemical Processes
School of Chemistry and Molecular Engineering
East China Normal University, 500 Dongchuan Road
Shanghai, 200241(China)
Initially, the reaction conditions were investigated using 1-(2-
bromophenyl)-3-phenylprop-2-yn-1-one (1a) and pentane-2,4-
dione (2a) as the model substrates. The ratio of 1a :2a was
screened from 1.0:0.6 to 1.0:2.0 and the amount of base varied
(see the Supporting Information, Table S1, entries 1–10). When
the reaction was performed with a ratio of 1a :2a=1.0:1.0 in
E-mail: yzli@chem.ecnu.edu.cn
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201602064.
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DMF using Cs2CO3 (2.0 equiv) as the base in air at 1008C, xan-
thone 4a was obtained in 73% isolated yield within 3 h. In ad-
dition, decreasing the reaction temperature to 508C resulted in
a longer reaction time (30 h) with the desired product being
obtained in moderate yield. However, reaction activity did not
increase with an increased reaction temperature (see the Sup-
porting Information, Table S1, entries 11 and 12). The effect of
different bases and solvents was studied at 1008C in air
(Table 1).
Table 2. Synthesis of xanthone derivatives 4.[a]
Entry
4
Time Yield of 4
[h]
[%][b]
Yield of 6
[%][b]
1
2
4a R1 =Ph
4b R1 =pMe-
C6H4
3
2
73
59
10
11
3
4
4c R1 =oMe-
C6H4
3
2
63
61
16
11
Table 1. Screening of bases and solvents.[a]
4d R1 =pMeO-
C6H4
5
6
4e R1 =pCl-C6H4
4 f R1 =1-naph-
thyl
4g R1 =nBu
4h R1 =tBu
4i R1 =Ph,
R2 =7-F
4j R1 =Ph,
R2 =6,7-diMeO
4k R2 =6,7-
diMeO
3
3
54
47
15
33
[c]
7
8
27
8
20
63
–
–
Yield [%][b]
73
[c]
Entry
Base
Cs2CO3
K2CO3
K3PO4
NaOH
tBuOK
NaH
DABCO
DMAP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Solvent
DMF
Time [h]
9
4
4
55
57
20
4
1
2
3
4
5
6
7
8
3
6
3
3
3
1
8
8
3
3
8
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
49
56
50
13
10
11
5
74
4
6
R1 =3,4,5-
triMeO-C6H2
4l X=CH
complex mixture
complex mixture
[c]
12
13
3
2
52
49
–
9
56
65
41
R3 =Me, R4 =Et
4m X=N
10
11
12
DMSO
toluene
1,4-dioxane
[c]
–
R3 =H, R4 =Me
trace
[a] Reactions were conducted on a 0.6 mmol scale with the ratio of 1:2=
1:1 in 5.0 mL of DMF at 1008C in air. [b] Isolated yield. [c] Not detected.
[a] Reactions were conducted on a 0.6 mmol scale with the ratio of
1a :2a=1:1 in 5.0 mL of solvent at 1008C in air. [b] Isolated yield.
The reaction was determined by the alkalinity of the base.
Full conversion of 1a was observed within 1 h using sodium
hydride as a base, but unfortunately the yield of xanthone 4a
decreased to 6% (Table 1, entry 6). When K2CO3 was employed
in the reaction, a longer reaction time (6 h) was required and
the desired product was obtained in moderate yield (49%)
(Table 1, entry 2). The results were slightly better when K3PO4
(3 h, 56%) or NaOH (3 h, 50%) were used (Table 1, entries 3,4).
Conversely, organic bases such as DABCO (1,4-diazabicy-
clo[2.2.2]octane) and DMAP (4-dimethylaminopyridine) were in-
effective, requiring long reactions times and giving complex re-
action mixtures (Table 1, entries 7 and 8). Next, solvents were
screened using Cs2CO3 (2.0 equiv) as a base. From those
tested, DMF proved to be the most effective (Table 1, en-
tries 1,9–12). Xanthone 4a was obtained in moderate to good
yields if the reaction was performed in DMA (dimethylacet-
amide), DMSO or toluene, although a longer reaction time was
required with toluene solvent (8 h, 41%). Only a trace amount
of product was obtained when the reaction was performed in
1,4-dioxane.
Cl) on substrate 1 (X=CH, R1 =Ph, R2 =H) were investigated
for reaction with pentane-2,4-dione (2a) under the optimized
reaction conditions. Xanthones 4a (LG=F, 53%; Cl, 55%) were
obtained in moderate yields. An insignificant quantity of p-
acetyl arylol 6a was detected when fluoride was the leaving
group, p-acetyl arylol 6a was obtained with isolated yields of
10% (LG=Br, entry 1) and 15% (LG=Cl), respectively. Overall,
1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) with a bro-
mide leaving group gave the desired product 4a in higher
yield and greater chemoselectivity. Thus, the following investi-
gations concerning substituents effects were carried out using
substrate 1 bearing the bromide leaving group.
Various multisubstituted xanthone derivatives 4 were ob-
tained in moderate to good yields. Firstly, the effect of the sub-
stituent R1 of the alkynyl functional group was explored
(Table 2, entries 1–8). Both electron-donating and -withdrawing
groups on the aryl substituent R1 were tolerated under the
tested conditions with yields ranging between 63 and 54%.
Additionally, ortho- and para-substituents made little difference
to the selectivity and reactivity (Table 2, entries 2–5) in the re-
action. Ring-fused substituents such as 1-naphthyl could also
be successfully employed, although the ratio of the desired
xanthone derivative 4 f to p-acetyl arylol 6 f was 4:3 (Table 2,
entry 6). Notably, substrates 1g and 1h bearing an alkyl R1
substituent selectively gave xanthones 4g and 4h, with no p-
With the optimized reaction conditions in hand (Table 1,
entry 1), we next looked to expand the substrate scope to syn-
thesize substituted xanthone derivatives 4 (Table 2). In some
cases, the desired xanthones 4 were obtained with the accom-
panying p-acetyl arylols 6. Different leaving groups (LG=Br, F,
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acetyl arylol being detected even with prolonged re-
action times (Table 2, entries 7 and 8). Subsequently,
the R2 substituent on the aryl ring was explored
(Table 2, entries 9–11). The introduction of an elec-
tron-withdrawing substituent (R2 =7-F) in substrate
4i led to an increase of the yield of the p-acetyl
arylol product 6i (4i: 55%, 6i: 20%). Conversely, the
substrates 4j and 4k possessing electron-donating
substituents (R2 =6,7-OMe) limited the yield of p-
acetyl arylols to 4%. In addition, 6k was obtained as
a yellow solid and characterized by X-ray crystallogra-
phy[8] (see the Supporting Information, including CIF
files). In the case of heptane-3,5-dione (2b), the reac-
tion proceeded smoothly to give a moderate yield of
the desired xanthone 4l (Table 2, entries 12). Reaction
of 1-(2-bromopyridin-3-yl)-3-phenylprop-2-yn-1-one
(1m) also proceeded, affording the desired product
4m in 49% yield within 2 h (Table 2, entry 13).
Scheme 3. Plausible reaction mechanism.
enolization, intramolecular nucleophilic addition occurs, fol-
lowed by dehydration to give intermediate E, bearing a multi-
substituted aryl ring with a hydroxyl group. Nucleophilic aro-
matic substitution (SNAr)[10] leads to the desired product xan-
thone 4a. An alternative pathway involving the nucleophilic
addition of 1a gives the p-acetyl arylol 6a by cyclization.
We next expanded the reaction scope to oxobutanoate
compounds. The first attempt utilized ethyl 3-oxobutanoate
(2c) as the model substrate using the aforementioned opti-
mized reaction conditions, from which chromone 5a was ob-
tained with an isolated yield of 43% within 3 h (Table 3,
Table 3. Screening of reaction conditions.[a]
Scheme 2. Mechanistic investigation.
Entry Lewis Acid
Base
Solvent Time [h] Yield [%][b]
1[c]
2[c]
3
4
5
–
–
–
Cs2CO3
DMF
3
2
2
2
2
2
2
2
2
2
43
48
53
35
66
46
76
81
The mechanism of this process was investigated and is
shown in Scheme 2. To identify intermediates in this reaction,
the experiment was carried out using the optimized reaction
conditions at room temperature. Full conversion of 1a oc-
curred within 15 min as monitored by TLC. Intermediates 3a
and 7a, the structures of which were characterized by X-ray
crystallography[9] (see the Supporting Information, including
CIF files), were isolated in 58 and 30% yield, respectively.
These intermediates were used separately as starting materials
and subjected to the general reaction conditions of our
system. Products, 4a and 6a were thus obtained in 84 and
72% yield, respectively. This indicates that once the intermedi-
ate 7a is formed, the formation of p-acetyl arylol 6a cannot be
avoided.
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
CuI (10mol%)
FeCl3·6H2O (10mol%)
Fe(acac)3 (10mol%)
Fe(ClO4)3·xH2O (10mol%) Cs2CO3 DMA
Fe(ClO4)3·xH2O (20mol%) Cs2CO3 DMA
Fe(ClO4)3·xH2O (5mol%) Cs2CO3 DMA
6
7[d]
8[d]
9[d]
10[d]
70
NR[e]
Fe(ClO4)3·xH2O (20mol%)
–
DMA
[a] Reactions were conducted on a 0.3 mmol scale with the ratio of
1a :2c=1.0:1.0 in 3.0 mL of DMA at 1008C under N2. [b] Isolated yield of
mixture of E/Z-isomers. [c] In air. [d] The amount of Lewis acid was calcu-
lated as Fe(ClO4)3·9H2O. [e] No reaction.
On the basis of the reported work[3] and our experimental
results, a plausible mechanism for this reaction has been pro-
posed (Scheme 3). The substrate 1a is first attacked by the nu-
cleophilic diketone 2a to give intermediate A, which presum-
ably undergoes an intramolecular nucleophilic addition/frag-
mentation cascade resulting in an alkyne insertion into the a,b
carbon–carbon s-bond of the diketone to give 3a.[3c] After
entry 1). To improve the yield of chromone 5a, different sol-
vents were screened (see the Supporting Information, Table S2,
entries 8–14). When DMA was used, the desired product 5a
was obtained in 48% yield in air and 53% yield under N2
(Table 3, entries 2 and 3). The addition of the Lewis acid, Fe-
(ClO4)3·xH2O (20% mol), resulted in a dramatic increase in the
yield to 81% (Table 3, entries 4–9). Additionally, the alkalinity
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and the amount of base greatly influenced reactivity;
2.0 equivalents of Cs2CO3 was essential for this process (see
the Supporting Information, Table S2, entries 15–21). No reac-
tion occurred in the absence of a base (Table 3, entry 10).
With the optimized reaction conditions in hand (Table 3,
entry 8), we next engaged in the synthesis of a series of chro-
mone derivatives 5 bearing different substituents (Table 4).
obtained in good to moderate yields using easily prepared
starting materials. A plausible mechanism for this process has
been proposed for the formation of xanthones and p-acetyl ar-
ylols when pentane-2,4-diones are used as substrates. This re-
action provides a new strategy for the preparation of xanthone
and chromone core structures and has the potential to be
used widely in organic synthesis.
Table 4. Synthesis of chromone derivatives 5.[a]
Experimental Section
Preparation of xanthone derivatives 4
In a Schlenk tube 1-aryl-3-phenylprop-2-yn-1-one 1 (0.6 mmol),
pentane-2,4-dione 2 (0.6 mmol), and Cs2CO3 (391.0 mg, 1.2 mmol)
in DMF (5.0 mL) was stirred at 1008C in air. After the reaction was
complete as monitored by thin-layer chromatography, the reaction
mixture was then cooled to room temperature, water was added
and the crude product was extracted with ethyl acetate (3ꢁ
10 mL). The combined organic layers were washed with brine and
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (appro-
priate mixture of petroleum ether/ethyl acetate/dichloromethane)
to afford the corresponding xanthone derivative 4.
Preparation of chromone derivatives 5
In a Schlenk tube 1-aryl-3-phenylprop-2-yn-1-one 1 (0.3 mmol), 3-
oxobutanoate 2 (0.3 mmol), and Cs2CO3 (195.5 mg, 0.6 mmol) in
DMF (3.0 mL) was stirred at 1008C under N2. After the reaction was
complete as monitored by thin-layer chromatography, the reaction
mixture was then cooled to room temperature, water was added
and the crude product was extracted with ethyl acetate (3ꢁ
10 mL). The combined organic layers were washed with brine and
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (appro-
priate mixture of petroleum ether/ethyl acetate/dichloromethane)
to afford the corresponding chromone derivative 5.
[a] Reactions were conducted on a 0.3 mmol scale with the ratio of 1:2=
1.0:1.0 in 3.0 mL of DMA at 1008C under N2. [b] The amount of Lewis
acid was calculated as Fe(ClO4)3·9H2O. [c] Isolated yield of mixture of E/Z-
isomers.
Acknowledgements
Good to moderate yields and selectivities (Z/E=10:1) of chro-
mone 5 were obtained irrespective of the presence of elec-
tron-donating or -withdrawing groups on the aryl ring of the
chromone skeleton, or on the R1 substituent. In addition, the
desired products could be obtained as single Z-isomers in the
cases of substrates 5d (71% yield), 5e (60% yield), 5h (61%
yield), and 5k (62% yield). Structural identification of Z-5 f was
carried out by X-ray crystallography[11] (see Supporting Informa-
tion, including CIF files). When methyl 3-oxobutanoate (2d)
was employed, a slight decrease in the yield of the corre-
sponding products was observed (5i: 76 vs. 5a: 81%). The re-
action also proceeded smoothly with methyl 3-oxo-3-phenyl-
propanoate (2e), giving only the corresponding product Z-5k
in 62% isolated yield within 3 h.
We thank the National Natural Science Foundation of China
(grant no. 21272074) and the university Program for Chang-
jiang Scholars and Innovative Research Team (PCSIRT) for finan-
cial support.
Keywords: base-promoted reaction
insertion · tandem reactions · xanthone
·
CÀC activation
·
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C. F. Marcos, J. Org. Chem. 2015, 80, 6165; b) C. A. Menꢆndez, F. Nador,
G. Radivoy, D. C. Gerbino, Org. Lett. 2014, 16, 2846; c) H. Rao, X. Ma, Q.
Liu, Z. Li, S. Cao, C.-J. Li, Adv. Synth. Catal. 2013, 355, 2191; d) H. Zhang,
R. Shi, P. Gan, C. Liu, A. Ding, Q. Wang, A. Lei, Angew. Chem. Int. Ed.
2012, 51, 5204; Angew. Chem. 2012, 124, 5294; e) J. Hu, E. A. Adogla, Y.
Ju, D. Fan, Q. Wang, Chem. Commun. 2012, 48, 11256; f) C. M. G. Azeve-
do, C. M. M. Afonso, M. M. M. Pinto, Curr. Org. Chem. 2012, 16, 2818 and
references therein; g) P. Wang, H. Rao, R. Hua, C.-J. Li, Org. Lett. 2012,
14, 902; h) J. Yang, C. Dong, H. Li, H. Li, Y. Li, Chin. Sci. Bull. 2012, 57,
[10] a) F. Li, Q. Wang, Z. Ding, F. Tao, Org. Lett. 2003, 5, 2169; b) P. Wipf, S. M.
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Org. Chem. 2015, 80, 4213.
[11] CCDC 1450970 contains the supplementary crystallographic data for 5 f.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre.
Received: May 3, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Heterocycles
X. Cheng, Y. Zhou, F. Zhang, K. Zhu, Y. Liu,
Y. Li*
&& – &&
Base-Promoted Tandem Reaction
Involving Insertion into Carbon–
Carbon s-Bonds: Synthesis of
Tandem partners: Tandem reactions
using a base-promoted process have
been developed for the synthesis of
xanthone and chromone derivatives
(see scheme). These reactions represent
the first examples of base-promoted in-
sertion reactions of isolated internal al-
kynes into carbon–carbon s-bonds.
Polycyclic structures can be prepared
using this process.
Xanthone and Chromone Derivatives
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&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!