A base-promoted desalicyloylative dimerization of 3-(1-alkynyl)chromones: An unusual approach to 2-alkynyl xanthones

Article abstract of DOI:10.1039/b925234g

A novel base-promoted cascade desalicyloylative dimerization of 3-(1-alkynyl)chromones to produce 2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as Michael additions/ cyclizations/desalicyloylation without a transition metal catalyst and inert atmosphere.

Full text of DOI:10.1039/b925234g

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A base-promoted desalicyloylative dimerization of 3-(1-alkynyl)chromones:
An unusual approach to 2-alkynyl xanthones†
Fuchun Xie, Xuan Pan, Shijun Lin and Youhong Hu*
Received 13th October 2009, Accepted 3rd December 2009
First published as an Advance Article on the web 5th January 2010
DOI: 10.1039/b925234g
A novel base-promoted cascade desalicyloylative dimerization of 3-(1-alkynyl)chromones to produce
2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as
Michael additions/cyclizations/desalicyloylation without a transition metal catalyst and inert
atmosphere.
Table 1 Screening of the reaction conditionsa
Introduction
Entry Base (equiv.) Additive (equiv.) Solvent T/◦C T/h Yieldb (%)
Xanthone frameworks are a ubiquitous structure in a wide
variety of naturally occurring and synthetic compounds that
1c
2
DBU(1.0)
DBU(1.0)
DBU(1.0)
—
DBU(1.0)
DBU(1.0)
K2CO3(1.0) H2O(1.0)
KOH(1.0) H2O(1.0)
KOBut(1.0) H2O(1.0)
DBU(0.5) H2O(1.0)
H2O(1.0)
H2O(1.0)
H2O(1.0)
H2O(1.0)
H2O(1.0)
4A MS
DMF rt
DMF 50
DMF 90
DMF 90
20
3
1
20
5
5
5
5
5
5
41
50
50
0
89
<10
0
68
63
64
exhibit important biological activity.1 Consequently, there has
been continued interest in the development of efficient methods
for the synthesis of xanthones bearing multiple and diverse
substitution patterns.2 Our group has focused on functionalized
3-(1-alkynyl)chromones to generate natural product-like scaffolds
through cascade reactions.3 Recently, we have reported a novel
base-promoted tandem reaction to afford functionalized xan-
thones from 3-(1-alkynyl)chromones with 1,3-dicarbonyl com-
pounds under mild reaction conditions.4 We envisaged that an
arylamine as a nucleophile could attack at the 2-position of the
3-(1-alkynyl)chromone with the opening of the pyrone ring, and
then, substituted pyrrole may be formed by subsequent cyclization
of the amine with the triple bond. Contrary to our expectation,
the reaction (alkynyl compound 1a, aniline, and DBU in DMF
at 50% for 5 h, eqn (1)) failed to afford the desired pyrrole
product. Instead, an interesting and unexpected novel product
2a was obtained with 3a.
3
4c
5
THF
THF
THF
THF
THF
THF
50
50
50
50
50
50
6c
7
8
9
10c
a General conditions: 1a (0.6 mmol), H2O (1.0 equiv.) and base (1.0 equiv.)
in solvent (2 mL) at 50 ◦C. b Isolated yield. c With 1a recovered.
obtained in a 50% yield (Table 1, entries 2 and 3). On changing
the solvent to THF, the yield was significantly increased to 89%
(Table 1, entry 5). The reaction did not proceed well using K2CO3
as a base, or carrying out the reaction without a base and water
(Table 1, entries 4, 6 and 7), which indicated that water and base
may play a crucial role in the reaction. When using KOH and
KOBut as a base, the desired product 2a was obtained in 68% and
63% yields, respectively (Table 1, entries 8 and 9). On lowering the
amount of DBU (0.5 equiv.), the reaction did not go to completion
within a period of 5 h, and 2a was afforded in a 64% yield (Table 1,
entry 10). Among these reaction conditions, a trace amount of one
major by-product 3a was isolated and identified by using X-ray
crystal structure analysis (Fig. 1).
(1)
Various 3-(1-alkynyl)chromones 1 were used to extend the scope
of this reaction under the optimized conditions. Moderate to
excellent yields were obtained when R1 was an aromatic group
on the acetylene moiety (Table 2, entries 1–3). The structure of 2b
was further confirmed by X-ray crystal structure analysis (Fig. 1).
When R1 was an aliphatic chain, the reaction could also give good
yields (Table 2, entries 4 and 5). Substitution with a sterically
hindering group, (tert-butyl), afforded the desired product 2f in
a 38% yield, along with 3f in a 27% yield (Table 2, entry 6).
When R1 was a trimethylsilyl group, the desilylated product 2g
was obtained in a 48% yield with two desilylated by-products 3g1
Results and discussion
We examined the reaction under different conditions using 3-
(1-alkynyl)chromone 1a as a substrate (Table 1). The reaction
proceeded slowly at room temperature (Table 1, entry 1). On
increasing the reaction temperature, the desired product was
Shanghai Institute of Materia Medica, Chinese Academy of Science,
555 Zu Chong Zhi Road, Shanghai, 201203, China. E-mail: yhhu@
mail.shcnc.ac.cn; Fax: +86-21-5080-5896; Tel: +86-21-5080-5896
† Electronic supplementary information (ESI) available: Synthesis and
1H and 13C NMR spectra of compounds 2 and 3. CCDC reference
numbers 747501–747503. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b925234g
6
and 3g2 in 16% and 26% yields, respectively. The structure of 3g1
was determined using X-ray crystal structure analysis (Fig. 1). In
addition, reactions with various substituents on the aryl ring of
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Table 2 Scope of the reactiona
Entry
1
Product, yieldb (%)
Entry
7c
Product, yieldb (%)
Fig. 1 X-Ray crystal structures of 3a, 2b, 3g1. Ellipsoid probability: 50%.
the 3-(1-alkynyl)chromones proceeded smoothly in good yields
(Table 2, entries 8–12).
We envisioned that this dimerization reaction involves a domino
process of Michael additions, cyclizations and desalicyloylation
as shown in Scheme 1. First, the 3-(1-alkynyl)chromone 1 as a
Michael acceptor could be attacked directly by a base to generate
the corresponding carbanion, which subsequently attacks a second
molecule at the 2-position through 1,4-addition and followed
by the pyrone ring opening to afford 4. Next, the phenol ion
of 4 processes the cascade cyclizations with the alkynyl bond
and intramolecular SN2 by leaving the base to generate 5. In
the presence of a base and water, intermediate 5 undergoes
desalicyloylation affording the product 2 and 2-hydroxybenzoic
acid (Path a, Scheme 1).5 In addition, the alkynyl bond of 5 can be
added by water and then isomerized into 6, which can be promoted
by a base through deacylative pyrone ring opening to generate 3
(Path b, Scheme 1). Through Path b, 3f and 3g2 that were obviously
found in the reaction may be due to steric effects. In addition, the
phenol ion 4g (R = H) could also process double cyclization with
alkynyl bonds, along with the hydrolysis opening of the pyrone ring
to generate 7, which undergoes deformylation in the presence of a
base and water, forming 3g1. The deuterium labeling experiment of
1g with D2O also verified our proposed mechanism, as the methyl
group of 3g1 was deuterized (see ESI for 1H NMR spectra of the
deuterated 2g and 3g1†).
2
8
3
4
9
10
5
6
11
12
a Reaction conditions: 1, H2O (1.0 equiv.), DBU (1.0 equiv.), THF (2 mL),
50 ◦C, 5 h. b Isolated yields. c The reaction was carried out on the 1.0 mmol
scale at rt.
Scheme 1 Plausible reaction mechanism
An experiment with a mixture of 1i and 1d was carried out under
the standard reaction conditions (eqn (2)). Three products, 2i, 2id
and 2d, were obtained in 40%, 15% and 52% yields, respectively.
The formation of 2id was a heterodimerization of 1i with 1d.
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7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 199.37, 176.62,
163.19, 155.77, 154.90, 136.61, 135.82, 135.265, 135.20, 133.21,
133.16, 132.36, 129.57, 128.55, 128.43, 127.82, 126.68, 124.69,
121.51, 121.38, 119.04, 118.87, 118.53, 118.23; HRMS calcd for
C26H16O4:392.1049, found: 392.1045.
Synthesis of deuterated [D]2g, [D]3g1 and [D]3g2: 3-(1-
Alkynyl)chromone 1g (242 mg, 1 mmol), dry THF (4 mL),
D2O (92 mL, 5 mmol) and DBU (300 mL, 2 mmol) were added
sequentially to a 10 mL microwave vial containing a magnetic stir
bar. The vial was sealed and then the resulting mixture was stirred
at room temperature for 5 h. When the reaction was complete
(as monitored by TLC), it was quenched by water (20 mL). The
resulting mixture was extracted with dichloromethane (25 mL¥3)
and the combined organic layers were washed with brine (20 mL),
dried over anhydrous Na2SO4, filtered and concentrated to give
the crude product, which was further purified by column chro-
matography (petroleum ether/ethyl acetate 20 : 1 to petroleum
ether/ethyl acetate 10 : 1) to afford 53 mg (48%) of compound
(2)
In conclusion, we have discovered a novel base-promoted cas-
cade desalicyloylative dimerization of 3-(1-alkynyl)chromones to
produce 2-alkynyl xanthones. The products were unambiguously
established using X-ray crystal structure analysis. This unusual
tandem process involves multiple reactions without the necessity
for a transition metal and inert atmosphere. Further application
of 1 to generate novel natural product-like compounds by tandem
reaction is ongoing in our laboratory.
Experimental
◦
1
[D]2g as a white solid; m.p. 155–157 C; H NMR (300 MHz,
CDCl3): d = 8.45 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H),
7.77 (s, 1H), 7.72 (td, J = 7.8, 0.8 Hz, 1H), 7.47 (d, J = 8.6 Hz,
1H), 7.38 (t, J = 7.3 Hz, 1H), 3.13 (s, 0.2 H); 13C NMR (100 MHz,
CDCl3): d = 176.02, 155.79, 155.63, 137.60, 134.91, 130.60, 126.60,
General information
All reactions were performed under nitrogen atmosphere. Dry
solvents were distilled prior to use: DMF was dried over
microwave-dried molecular sieve; THF was distilled from sodium-
benzophenone; Petroleum ether refers to the fraction with boiling
point in the range 60–90 ◦C. All 1H NMR and 13C NMR spectra
were measured in CDCl3 with TMS as the internal standard.
Chemical shifts are expressed in ppm and J values are given in
Hz. High resolution mass spectra were recorded on a Finnigan
MAT 95 mass spectrometer (EI). Column chromatography was
performed with 200–300 mesh silica gel using flash column
techniques. Melting points are uncorrected.
1
124.12, 121.51, 121.48, 117.96, 117.95 (t, JCD = 25.1 Hz, 1C)
117.87, 82.04, 81.60, 77.895; HRMS calcd for C15H8O2:220.0524,
found: 220.0526, calcd for C15H7DO2:221.0587, found: 221.0589,
calcd for C15H6D2O2: 222.0650, found: 222.0649. 28 mg (17%) of
◦
1
compound [D]3g1 as a white solid; m.p. 175–176 C; H NMR
(300 MHz, CDCl3): d = 12.12 (s, 1H), 8.33 (dd, J = 8.1, 1.8 Hz,
1H), 8.28 (s, 1H), 7.76 (td, J = 7.8, 1.6 Hz, 1H), 7.57–7.49 (m,
2H), 7.41 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 8.0, 1.5 Hz, 1H), 7.08
(d, J = 8.3 Hz, 1H), 6.83 (t, J = 7.6 Hz), 2.50–2.45 (m, 0.1 H); 13
C
NMR (100 MHz, CDCl3): d = 202.10, 176.34, 163.45, 156.63,
General procedure for the desalicyloylative dimerization reaction
155.99, 144.13, 137.12, 135.06, 133.83, 133.45, 126.76, 126.68,
1
Synthesis of 2a and 3a: 3-(1-alkynyl)chromone 1a (148 mg,
0.6 mmol), dry THF (3 mL), water (11 mL, 0.6 mmol) and
DBU (90 mL, 0.6 mmol) were added sequentially to a 10 mL
microwave vial containing a magnetic stir bar. The vial was sealed
and then the resulting mixture was stirred at 50 ◦C for 5 h.
When the reaction was complete (as monitored by TLC), it was
quenched by water (20 mL). The resulting mixture was extracted
with dichloromethane (15 mL¥3) and the combined organic
layers were washed with brine (10 mL), dried over anhydrous
Na2SO4, filtered and concentrated to give the crude product,
which was further purified by column chromatography (petroleum
ether/ethyl acetate 20 : 1 to petroleum ether/ethyl acetate 8 : 1)
to afford◦99 mg (89%) of compound 2a as a white solid; m.p.
124.31, 121.79, 119.73 (t, JCD = 25.9 Hz, 1C), 119.67, 119.08,
119.00, 118.44, 118.01, 19.50 (h, J = 19.6 Hz, 1C); HRMS calcd
for C21H12D2O4: 332.1018, found: 332.1010, calcd for C21H11D3O4:
333.1080, found: 333.1072, calcd for C21H10D4O4: 334.1143, found:
334.1136. 41 mg (26%) of compound [D] 3g2 as a white solid; m.p.
183–184 ◦C; 1H NMR (300 MHz, CDCl3): d = 11.87 (s, 1H), 8.67
(d, J = 1.7 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.13–8.08 (m, 1H),
7.79 (t, J = 7.9 Hz, 1H), 7.66–7.50 (m, 3H), 7.44 (t, J = 7.6 Hz,
1H), 7.10 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 199.32, 176.44, 163.15, 157.99, 155.93,
136.59, 135.35, 135.13, 135.03, 133.30, 133.17, 128.82, 126.76,
124.61, 121.71, 120.975, 119.00, 118.83, 118.79, 118.52, 118.09;
HRMS calcd for C20H12O4:316.0736, found: 316.0734, calcd for
C20H11DO4: 317.0798, found: 317.0802.
1
196–198 C; H NMR (300 MHz, CDCl3): d = 8.52 (d, J =
2.1 Hz, 1H), 8.36 (dd, J = 8.1, 1.8 Hz, 1H), 7.9 (d, J = 2.2 Hz,
1H), 7.74–7.64 (m, 3H), 7.60–7.44 (m, 5H), 7.43–7.34 (m, 5H);
13C NMR (100 MHz, CDCl3): d = 176.44, 155.70, 152.375,
138.215, 135.44, 134.83, 131.76, 131.575, 129.53, 129.03, 128.44,
128.39, 128.32, 128.12, 126.58, 124.18, 122.75, 122.13, 121.26,
119.13, 118.08, 90.12, 87.87; HRMS calcd for C27H16O2:372.1150,
foun◦d: 372.1142; and trace 3a as a light yellow solid; m.p. 185–
Acknowledgements
We are grateful for financial supports from Major Projects in
National Science and Technology, “Creation of major new drugs”
(No.2009ZX09501-010).
1
186 C; H NMR (300 MHz, CDCl3): d = 11.90 (s, 1H), 8.68
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