Base-promoted one-pot tandem reaction of 3-(1-alkynyl)chromones under microwave irradiation to functionalized amino-substituted xanthones

Article abstract of DOI:10.1021/jo1013614

Figure presented. A base-promoted one-pot tandem reaction has been developed from 3-(1-alkynyl)chromones with various acetonitriles to afford functionalized amino-substituted xanthones 3 under microwave irradiation. This tandem process involves multiple reactions, such as Michael addition/ cyclization/1,2-addition, without a transition metal catalyst. This method provides an efficient approach to build up natural product-like diversified amino-substituted xanthone scaffolds rapidly.

Full text of DOI:10.1021/jo1013614

pubs.acs.org/joc
highly substituted furans.3 Under basic conditions, the cas-
Base-Promoted One-Pot Tandem Reaction of
3-(1-Alkynyl)chromones under Microwave
Irradiation to Functionalized
cade reaction of these units with nucleophilic substrates
proceeded in different ways.4 Recently, we described a novel
base-promoted tandem reaction of 3-(1-alkynyl)chromones
with 1,3-dicarbonyl compounds to afford functionalized
xanthones.4d
Amino-Substituted Xanthones
Yang Liu, Liping Huang, Fuchun Xie, and Youhong Hu*
SCHEME 1. Proposed Mechanism
State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, 555 Zu Chong
Zhi Road, Shanghai, 201203, People’s Republic of China
yhhu@mail.shcnc.ac.cn
Received July 11, 2010
The xanthone framework is a ubiquitous structure that
occurs in a wide variety of naturally occurring and synthetic
compounds exhibiting important biological activity.5 Con-
sequently, there has been continued interest in the develop-
ment of efficient methods for the synthesis of xanthones
bearing multiple and diverse substitution patterns.6 Herein,
we report our recent achievement to build up diversified
amino-substituted xanthone scaffolds rapidly by a tandem
reaction of 3-(1-alkynyl)chromones with various acetoni-
triles under microwave irradiation through Michael addi-
tion/cyclization/1,2-addition reaction without a transition
metal catalyst (Scheme 1).
A base-promoted one-pot tandem reaction has been deve-
loped from 3-(1-alkynyl)chromones with various acetoni-
triles to afford functionalized amino-substituted xanthones
3 under microwave irradiation. This tandem process involves
multiple reactions, such as Michael addition/cyclization/1,2-
addition, without a transition metal catalyst. This method
provides an efficient approach to build up natural product-
like diversified amino-substituted xanthone scaffolds rapidly.
We investigated the reaction of 1a with 2-phenylacetoni-
trile 2a under different reaction conditions (Table 1). When
the reaction was carried out under the conditions used
Tandem reactions provide an efficient way to generate
molecular complexity from readily accessible intermediates.1
The combination of very efficient cascade or one-pot pro-
cesses with microwave-assisted organic synthesis should
provide a powerful tool for saving both energy and resources
and rapidly generating a diversified new target molecules
library to help speed up drug discovery projects in industry
and academia.2
(3) (a) Gao, H.; Zhao, X.; Yu, Y.; Zhang, J. Chem.;Eur. J. 2010, 16, 456.
(b) Liu, R.; Zhang, J. Chem.;Eur. J. 2009, 15, 9303. (c) Liu, F.; Yu, Y.;
Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 5505. (d) Xiao, Y.; Zhang, J.
Angew. Chem., Int. Ed. 2008, 47, 1903. (e) Cheng, G.; Hu, Y. J. Org. Chem.
2008, 73, 4732. (f) Cheng, G.; Hu, Y. Chem Commun. (Cambridge, U. K.).
2007, 3285. (g) Oh, C. H.; Reddy, V. R.; Kim, A.; Rhim, C. Y. Tetrahedron
Lett. 2006, 47, 5307. (h) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609. (i) Yao, T.;
Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679. (j) Patil, N. T.; Wu,
H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4531. (k) Yao, T.; Zhang, X.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164.
(4) (a) Li, W.; Xiao, Y.; Zhang, J. Adv. Synth. Catal. 2009, 351, 617. (b)
Xiao, Y.; Zhang, J. Chem. Commun. 2009, 3594. (c) Yu, X.; Ren, H.; Xiao,
Y.; Zhang, J. Chem.;Eur. J. 2008, 14, 8481. (d) Zhao, L.; Xie, F.; Cheng, G.;
Hu, Y. Angew. Chem., Int. Ed. 2009, 48, 6520. (e) Xie, F.; Pan, X.; Lin, S.; Hu,
Y. Org. Biomol. Chem. 2010, 8, 1378.
2-(1-Alkynyl)-2-alken-1-ones as special units were applied
in tandem reactions through a transition metal, an acid-
catalyzed or an electrophile-induced cascade process to form
(5) For recent studies, see: (a) Sousa, E.; Paiva, A.; Nazareth, N.; Gales,
L.; Damas, A. M.; Nascimento, M. S. J. Eur. J. Med. Chem. 2009, 44, 3830.
(b) Kondo, M.; Zhang, L.; Ji, H.; Kou, Y.; Ou, B. J. Agric. Food Chem. 2009,
57, 8788. (c) Zelefack, F.; Guilet, D.; Fabre, N. J. Nat. Prod. 2009, 72, 954. (d)
Ngoupayo, J.; Tabopda, T. K.; Ali, M. S. Bioorg. Med. Chem. 2009, 17, 5688.
(e) Ryu, Y. B.; Curtis-Long, M. J.; Lee, J. W. Bioorg. Med. Chem. 2009, 17,
2744. (f) Pouli, N.; Marakos, P. Anticancer Agents Med. Chem. 2009, 9, 77.
(6) For selected examples, see: (a) Masuo, R.; Ohmori, K.; Hintermann,
L.; Yoshida, S.; Suzuki, K. Angew. Chem., Int. Ed. 2009, 48, 3462. (b)
Okuma, K.; Nojima, A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009, 11, 169.
(c) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem.
2009, 16, 2642. (d) Barbero, N.; SanMartin, R.; Domınguez, E. Tetrahedron
2009, 65, 5729. (e) Mross, G.; Reinke, H.; Fischer, C.; Langer, P. Tetrahedron
2009, 65, 3910. (f) Xu, W. Z.; Huang, Z. T.; Zheng, Q. Y. J. Org. Chem. 2008,
73, 5606. (g) Dang, A. T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org.
Lett. 2008, 10, 233. (h) Swamy, N. K.; Tatini, L. K.; Babu, J. M.; Annamalai,
P.; Oal, M. Chem. Commun. 2007, 1035.
(1) For recent reviews, see: (a) Enders, D.; Grondal, C.; Huttl, M. R.
Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Wasilke, J.-C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (d) Nicolaou,
K. C.; Montagnon, T.; Snyder, S. A. Chem Commun. (Cambridge, U. K.)
2003, 551. (e) Eilbracht, P.; Barfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A.
Chem. Rev. 1999, 99, 3329. (f) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(g) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
(2) For recent review: (a) Kremsner, J. M.; Stadler, A.; Kappe, C. O. J.
Comb. Chem. 2007, 9, 285. (b) Mavandadi, F.; Pilotti, A. Drug Discovery
Today 2006, 11, 165. (c) Tierney, J. P. Lidstrom, P. Microwave Assisted
Organic Synthesis, Blackwell: Oxford, 2005. (d) Kappe, C. O. Angew. Chem.,
Int. Ed. 2004, 43, 6250. (e) NMchter, M.; Ondruschka, B.; Bonrath, W.;
Gum, A. Green Chem. 2004, 6, 128. (f) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron. 2001, 57, 9225.
6304 J. Org. Chem. 2010, 75, 6304–6307
Published on Web 08/26/2010
DOI: 10.1021/jo1013614
r
2010 American Chemical Society

Liu et al.
JOCNote
TABLE 1. Optimization of the Tandem Reaction to Form Amino-
Substituted Xanthone 3aa
TABLE 2. Tandem Reaction of 1a with Various Acetonitriles 2 to Form
Amino-Substituted Xanthones 3a
entry
solvent
base
temp/timea
yield (%)c
1b
2b
3
4
5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
1 equiv DBU
1 equiv DBU
1 equiv DBU
3 equiv DBU
1 equiv t-BuOK
3 equiv t-BuOK
3 equiv t-BuOK
1 equiv MeONa
3 equiv MeONa
1 equiv K2CO3
3 equiv K2CO3
3 equiv DBU
3 equiv DBU
3 equiv DBU
45 °C, 18 h
42
50
60
90
51
82
69
46
68
20
35
73
76
69
100 °C, 2 h
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 8 h
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
90 °C, 10 min
6
7b
8
9
10
11
12
13
14
toluene
MeCN
aUnless otherwise noted, the reactions were carried out under micro-
b
c
wave irradiation. Reactions were carried out in an oil bath. Yield of
isolated product based on 1a.
previously,4d in which 1 equiv of DBU was used as the base in
DMF at 45 °C, the desired product 3aa was observed in 42%
yield with slow transformation. When the reaction tempera-
ture was increased to 100 °C, the reaction was completed in 2
h and 3aa was obtained in 50% yield with a dimeric
byproduct.4e Since 2-phenylacetonitrile is less nucleophlic
than a 1,3-dicarbonyl compound, and 1,2-addition to a
cyano group is harder than to a carbonyl group in the last
step, the cascade process should need more energy. Under
microwave irradiation at 90 °C, the reaction was rapidly
completed in 10 min and gave 3aa in 60% yield. By increasing
the amount of DBU from 1 equiv to 3 equiv, the yield was
improved significantly, to 90%. The reaction heating at
90 °C under an oil bath and using 3 equiv of t-BuOK gave
the desired product 3aa in 69% yield. Among the different
bases such as DBU, t-BuOK, NaOMe, and K2CO3, DBU
generally performed the best (Table 1, entries 3-11). The
optimized conditions to amino-substituted xanthones 3 were
defined as carrying out the reaction in DMF at 90 °C for
10 min with 3 equiv of DBU under microwave irradiation.
Using the optimized reaction conditions, various substi-
tuted acetonitriles 2 were treated with 1a to extend the scope
of this tandem reaction (Table 2). Good to excellent yields
were obtained when R1 was an aromatic group (Table 2,
entries 1-4). Obviously, substrate 2d, with an electron-
donating group at the para position of the aryl ring, de-
creased the nucleophilicity to give a lower yield than the
others. Especially when R1 was an amide or cyano group,
functional xanthones 3ae and 3af were obtained in 86% and
88% yield, respectively (Table 2, entries 5, 6). Compound 3ae
was further condensed with various aldehydes to form the
linear heterocyclic xanthones 4 in good yields (Scheme 2),
which can rapidly generate a structurally diverse and medici-
nally interesting new small-molecule library.
aUnless otherwise noted, the reactions were carried out under stan-
dard conditions. bYield of isolated product based on 1a.
SCHEME 2. Synthetic Application for 3ae
were obtained in 65-96% yields (Table 3). It was noted that
the electron effect of the R2 group did not influence the
reaction efficacy under microwave irradiation. When R2 was
a sterically hindering tert-butyl group, the uncyclized inter-
mediate D was obtained at 90 °C under microwave irradia-
tion. By increasing the reaction temperature to 130 °C and
prolonging the irradiation time to 15 min, the desired
product 3bf was obtained in 65% yield (Table 3, entry 5).
In addition, reactions with various substituents on the aryl
Furhermore, we applied 2b with various 3-(1-alkynyl)chro-
mones to extend the tandem reaction for generating func-
tionalized amino-substituted xanthones. Products 3bb-3bj
J. Org. Chem. Vol. 75, No. 18, 2010 6305

Liu et al.
JOCNote
TABLE 3. Tandem Reaction of 2b with Various 3-(1-Alkynyl) chromones.a
SCHEME 3. Tandem Reaction of 2b with 2-Methyl-3-(1-alkynyl)-
chromones
When the base was changed to t-BuOK (1 equiv), the reaction
at 150 °C under microwave irradiation proceeded smoothly to
give the desired product 3bk only in 74% yield. Also, the
substrate 1l, with an aliphatic chain, gave the product 3bl in
60% yield. These conditions could extend the tandem reaction
to the sterically hindering 2-methyl-3-(1-alkynyl)chromones
to afford polysubstituted amino-xanthones (Scheme 3).
In conclusion, we have developed a novel base-promoted
tandem reaction from 3-(1-alkynyl)chromones with various
acetonitriles under microwave irradiation to afford functiona-
lized amino-substituted xanthones. Notably, this tandem pro-
cess involves multiple reactions, such as a Michael addition/
cyclization/1,2-addition without a transition metal catalyst.
This method provides an efficient approach to build up natural
product-like diversified polysubstituted amino-xanthone scaf-
folds rapidly. The functionalized amino-substituted xanthone
3ae can be easily condensed with various aldehydes to generate
the linear heterocyclic xanthones. Further library generation
and biological evaluation of the diversified xanthones are under
investigation.
Experimental Section
General Procedure of the Tandem Reaction of 3-(1-Alkynyl)
Chromones with Various Acetonitriles to Amino-Substituted
Xanthones. Typical procedure for the preparation of 3aa: To a
solutionof2-phenylacetonitrile2a(24mg, 0.2mmol) indry DMF
(1 mL) was added DBU (0.1 mL, 0.6 mmol) at room temperature
under nitrogen atmosphere. After stirring for 5 min, compound
1a (50 mg, 0.2 mmol) was added, and the resulting dark red
solution was irradiated for 10 min at 90 °C (monitored by TLC).
The mixture was extracted with ethyl acetate (3 ꢀ 10 mL). 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 chroma-
tography(petroleum ether/ethyl acetate, 8:1) toafford compound
1
3aa as a white solid (66 mg, 90%): mp 157-158 °C; H NMR
(300 MHz, CDCl3) δ 8.31 (dd, J = 1.7, 8.0 Hz, 1H), 8.15 (s, 1H),
7.4-7.6 (m, 11H), 7.31 (t, J = 7.0 Hz, 1H), 7.18 (d, J = 8.3 Hz,
1H), 4.40 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 176.3, 156.0,
154.2, 148.0, 137.9, 133.6, 133.1, 130.7, 129.3, 129.2, 129.1, 128.1,
127.9, 127.6, 126.4, 125.1, 123.5, 121.8, 117.7, 113.3, 112.9;
HRMS [M]þ calcd for C25H17NO2 363.1259, found 363.1264.
General Procedure of the Tandem Reaction of 2-Methyl-3-(1-
Alkynyl) Chromones with 2b to Amino-Substituted Xanthones.
Typical procedure for the preparation of 3bk: To a solution of
2-(3-bromophenyl)acetonitrile (2b) (40 mg, 0.2 mmol) in dry
DMF (1 mL) was added t-BuOK (23 mg, 0.2 mmol) at room
temperature under nitrogen atmosphere. After stirring for 5 min,
compound 1k (52 mg, 0.2 mmol) was added, and the resulting
dark red solution was irradiated for 15 min at 150 °C (monitored
by TLC). The mixture was extracted with ethyl acetate (3 ꢀ
10 mL). The combined organic layers were washed with brine
(10mL), dried over anhydrous Na2SO4, filtered, and concentrated
to give the crude product, which was further purified by column
aUnless otherwise noted, the reactions were carried out under stan-
dard conditions. bYield of isolated productbased on 1. cThe reaction was
irradiated for 15 min at 130 °C.
ring of the 3-(1-alkynyl)chromones also proceeded smoothly
in good to excellent yields (Table 3, entries 6-9). When the
reaction was applied to 2-methyl-3-(2-phenylethynyl)-4H-
chromen-4-one (1k), the intermediate D was formed along
with the dimeric product.7 By increasing the reaction tem-
perature to 130 °C, no desired product 3bk was afforded.
(7) Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010, 12, 3086.
6306 J. Org. Chem. Vol. 75, No. 18, 2010

Liu et al.
JOCNote
chromatography (petroleum ether/ethyl acetate, 6:1) to afford
compound 3bk as a yellow solid (67 mg, 74%): mp 165-166 °C;
1H NMR (300 MHz, CDCl3) δ 8.25 (dd, J = 1.4, 8.0 Hz, 1H),
7.4-7.6 (m, 9H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.8 Hz,
1H), 7.09 (d, J = 7.8 Hz, 1H), 3.97 (s, 2H), 2.64 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 178.0, 155.5, 154.9, 147.4, 140.3, 139.6,
133.4, 133.3, 131.1, 130.8, 130.4, 129.5, 129.2, 129.1, 128.0, 127.9,
126.5, 123.8, 123.5, 123.4, 122.9, 117.1, 20.4; HRMS [M]þ calcd
for C26H18BrNO2 455.0521, found 455.0511.
General Procedure of the Synthetic Application of 3ae. Typical
procedure for the preparation of 4a: 3ae (66 mg, 0.2 mmol) and
benzaldehyde (22 mg, 0.2 mmol) were suspended in methanol
(10 mL) and refluxed in the presence of catalytic amounts of
p-toluenesulfonic acid (4 mg, 10%) overnight. After the reaction
mixture was filtered and washed with cold methanol, 4a was
obtained as a light brown solid (72 mg, 85%): mp 257-258 °C;
1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 8.29 (d, J = 8.0 Hz,
1H), 7.3-7.7 (m, 12H), 7.15 (d, J = 8.3 Hz, 1H), 6.24 (s, 1H),
5.93 (s, 1H) 4.89 (s, 1H); 13C NMR (100 MHz, d6-DMSO) δ
174.7, 161.7, 155.9, 155.3, 149.0, 142.7, 134.8, 131.1, 130.9,
130.2, 129.2, 128.5, 128.3, 128.1, 126.7, 125.8, 125.7, 124.3,
120.9, 117.7, 112.9, 112.6, 112.4, 65.2; HRMS [M]þ calcd for
C27H18N2O3 418.1317, found 418.1324.
Acknowledgment. Financial support of this research pro-
vided by the NST Major Project “Key New Drug Creation
and Manufacturing Program” (2009ZX09301-001) and Na-
tional Natural Science Foundation of China (30873142) is
gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 18, 2010 6307