TMSOTf-catalyzed intramolecular seleno-arylation of tethered alkenes: A novel method for the solid-phase synthesis of dihydrocoumarins and coumarins

Article abstract of DOI:10.1016/j.cclet.2012.03.022

TMSOTf-catalyzed intramolecular seleno-arylation of tethered alkenes was performed using polystyrene-supported succinimidyl selenide as the selenium source. This catalytic process provides an efficient method for the regioselective synthesis of dihydrocoumarins possessing a seleno-functionality, followed by traceless cleavage of selenium linker to provide dihydrocoumarins and coumarins in good yields and purities.

Full text of DOI:10.1016/j.cclet.2012.03.022

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 631–634
www.elsevier.com/locate/cclet
Short communication
TMSOTf-catalyzed intramolecular seleno-arylation of
tethered alkenes: A novel method for the solid-phase
synthesis of dihydrocoumarins and coumarins
b
b
b
E Tang a,b, , Wen Li , Zhang Yong Gao , Xi Gu
*
a Key Laboratory of Medicinal Chemistry of Natural Resource (Yunnan University), Ministry of Education, China
b Department of Applied Chemistry, Yunnan University, Kunming 650091, China
Received 20 December 2011
Available online 14 May 2012
Abstract
TMSOTf-catalyzed intramolecular seleno-arylation of tethered alkenes was performed using polystyrene-supported succini-
midyl selenide as the selenium source. This catalytic process provides an efficient method for the regioselective synthesis of
dihydrocoumarins possessing a seleno-functionality, followed by traceless cleavage of selenium linker to provide dihydrocoumar-
ins and coumarins in good yields and purities.
# 2012 E Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Lewis acid; Seleno-arylation; Succinimidyl selenide; Solid-phase synthesis; Dihydrocoumarins; Coumarins
Solid-phase organic synthesis has emerged as a powerful tool for acceleration of drug discovery, allowing the
preparation of highly diversified compound libraries because of its simple workup and characteristic of parallel
synthesis [1]. As a ‘‘privileged’’ scaffold [2], benzopyran-2-ones such as dihydrocoumarins and coumarins are widely
distributed throughout the plant kingdom and exhibit interesting biological properties [3–8]. A growing number of
literatures have reported the preparation of the combinatorial library of dihydrocoumarins and coumarins [9].
However, dihydrocoumarins and coumarins have been prepared by modification of benzopyran-2-ones skeleton in
most of the reported solid-phase synthesis [10]. Watson and Christiansen [11] have reported a solid-phase synthesis of
dihydrocoumarins and coumarins from ethyl malonate bound to Wang resin by means of the Knoevenagel
condensation with 2-hydroxybenzaldehydes and cleavage with trifluoroacetic acid. But the yields of the products were
less than 40%. Since the first organoselenium resin [12] was reported in 1976, several groups have developed the
organoselenium resins as convenient linkers and reagents [13–15]. Recently, our research group has been interested in
the preparation of heterocyclic libraries from organoselenium resins [16]. We have developed polystyrene-supported
selenium-induced heteroatom-based cyclization reactions of tethered alkenes to prepare flavonoids and quinolones
[16a,16d]. Herein, we report an efficient approach for the solid-phase synthesis of dihydrocoumarins and coumarins by
polymer-supported selenium-induced carbon-based cyclization reactions and subsequent oxidative elimination and
* Corresponding author at: Key Laboratory of Medicinal Chemistry of Natural Resource (Yunnan University), Ministry of Education, China.
E-mail address: tange@ynu.edu.cn (E. Tang).
1001-8417/$ – see front matter # 2012 E Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.03.022

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E. Tang et al. / Chinese Chemical Letters 23 (2012) 631–634
Scheme 1. Conditions and regents: (a) (i) NaBH4, THF, DMF, 40 8C; (ii) allyl bromide, THF, r.t.; (b) (i) NCS, CH2Cl2, 0 8C–r.t.; (ii) filtrating and
washing in nitrogen atmosphere; (c) 10 mol% TMSOTf, CH2Cl2, ꢀ78 8C to ꢀ20 8C; (d) 30% H2O2, 0 8C–r.t.; (e) n-Bu3SnH, AIBN, toluene, 90 8C.
free radical hydrogenation reaction. And to the best of our knowledge, the same method of synthesis of
dihydrocoumarins and coumarins in solution has not been reported.
Firstly, substituted phenyl acrylates 1 were synthesized by the reaction of acryloyl chlorides with substituted
phenols in the presence of sodium hydroxide at 40 8C [17]. Pale-yellow polystyrene-supported allyl selenide 2 (FTIR:
3019 cmꢀ1) was prepared almost quantitatively by the allylation of polystyrene-supported selenenyl bromide [13] (Br:
0.99 mmol/g) with NaBH4 and allyl bromide [16c]. And then, resin 2 reacted smoothly with N-chlorosuccinimide
(NCS) to give polystyrene-supported succinimidyl selenide (PSSS) 3 (FTIR: 1707 cmꢀ1 with the disappearance of
3019 cmꢀ1). In this process, we found that 3-chloroprop-1-ene was the only by-product and resin 3 (PSSS) was
sensitive to moisture while resin 2 was very stable. A one-pot synthesis of polymer-supported cyclized product 4 was
employed. As shown in Scheme 1, after completion of the reaction of resin 2 with NCS, resin 3 was obtained and
subjected to the cyclization reaction only after being washed with dry CH2Cl2 for several times in a nitrogen
atmosphere without removal from the reaction flask. In the presence of 10 mol% TMSOTf, 1 was treated with PSSS in
dry CH2Cl2 at ꢀ78 8C for 2 h and then at ꢀ20 8C for 8 h to afford the resin 4. The cyclization reaction was monitored
by FT-IR, which showed a strong band of the carbonyl absorption at 1740 cmꢀ1. After being washed with various
solvents, 4 was then treated with 30% H2O2 at 0 8C to room temperature in dry THF to afford coumarins 5 in good
yield and high purity. In addition, in the presence of 2,20-azodiisobutyronitrile (AIBN), the intermediate 4 was also
treated with tri-n-butylstannane in toluene at 90 8C to afford dihydrocoumarins 6 in good yields and purities.
The results were summarized in Table 1. It was obvious when R1 was H and donating-electron substituents such as
alkoxyl and alkyl substituents, the carbon-based ring-closure reactionproceeded smoothly (Table 1, entries 1–6 and 8–13).
Table 1
Solid-phase synthesis of coumarins [18] and dihydrocoumarins [19].
Entry
R1
R2
Product
Yield (%)a
Purity (%)b
1
2
H
Ph
5a
5b
5c
5d
5e
5f
75
59
52
78
80
77
–
>95
>90
>90
>95
>95
>95
–
6-Me
6-Me
6-Me
6-MeO
H
Me
3
H
4
Ph
5
Ph
6
p-MeOC6H4
7
8-CHO
H
Ph
5g
6a
6b
6c
6d
6e
6f
8
Ph
76
55
50
78
81
75
–
>90
>85
>80
>90
>90
>90
–
9
H
Me
10
11
12
13
14
H
H
6-Me
6-MeO
H
Ph
Ph
p-MeOC6H4
8-CHO
Ph
6g
a
Total yields of the crude products based on the loading of polystyrene-supported selenenyl bromide (Br, 0.99 mmol/g).
Purity determined by HPLC analysis of crude products.
b

E. Tang et al. / Chinese Chemical Letters 23 (2012) 631–634
633
No cyclized products were obtained when R1 was the electron-withdrawing substituents such as formacyl (Table 1, entries
7 and 14). The yield of product 5 and 6 apparently decreased when R2 was H and alkyl (Table 1, entries 2, 3, 9, and 10).
In summary, we have developed a highly regioselective selenium-induced intramolecular Friedel–Crafts alkylation
of substituted phenyl acrylates using a polymer-supported organoselenium reagent as a selenium source.
Dihydrocoumarins and coumarins were obtained in good yields and purities by the cleavage of the selenium linker.
Furthermore, the easy workup procedure and easily prepared substrates provide an approach that is well-suited for
building the parallel libraries upon the basis of further transformation of polymer-supported 3,4-dihydrocoumarins 4.
The further modifications of resin 4 are still underway.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Nos. 20802063, 21162032) and the
Foundation of the Key Laboratory of Medicinal Chemistry of Natural Resource (Yunnan University), Ministry of
Education, China.
References
¨
[1] (a) F.Z. Dorwald, Organic Synthesis on Solid-Phase, Wiley-VCH, Weinheim, 2000;
(b) K.C. Nicolaou, R. Hanko, W. Hartwig, Handbook of Combinatorial Chemistry, Wiley-VCH, Weinheim, 2002;
(c) J.J.V. Eynde, D. Rutot, Tetrahedron 55 (1999) 2687.
[2] L. Zhang, T.H. Meng, R.H. Fan, J. Org. Chem. 72 (2007) 7279.
[3] M.M. Garazd, Y.L. Garazd, V.P. Khilya, Khim. Prir. Soedin. 39 (2003) 47.
[4] A.D. Patil, A.J. Freyer, D.S. Eggleston, J. Med. Chem. 36 (1993) 4131.
[5] J. Wu, Z. Yang, R. Fathi, Q. Zhu, US Pat. Appl. (2004) 2538.
´ ´
[6] D. Guilet, J.J. Helesbeux, D. Seraphin, J. Nat. Prod. 64 (2001) 563.
¨
[7] (a) I. Kohler, K. Jenett-Siems, F.P. Mockenhaupt, Planta Med. 67 (2001) 89;
´
´ ´
(b) R. Argotte-Ramos, G. Ramırez-Avila, M.D.C. Rodrıguez-Gutierrez, J. Nat. Prod. 69 (2006) 1442.
[8] L. Verotta, E. Lovaglio, G. Vidari, Phytochemistry 65 (2004) 2867.
[9] (a) J. Wu, Y. Liao, Z. Yang, J. Org. Chem. 66 (2001) 3642;
(b) J.C. Bussolari, D.C. Rehborn, D.W. Combs, Tetrahedron Lett. 40 (1999) 1241.
[10] (a) A. Song, J.H. Zhang, K.S. Lam, J. Comb. Chem. 6 (2004) 112;
(b) A. Song, J.H. Zhang, C.B. Lebrilla, J. Comb. Chem. 6 (2004) 604.
[11] B.T. Watson, G.E. Christiansen, Tetrahedron Lett. 39 (1998) 6087.
[12] R. Michels, M. Kato, W. Heitz, Makromol. Chem. 177 (1976) 2311.
[13] K.C. Nicolaou, J. Pastor, S. Barluenga, Chem. Commun. (1998) 1947.
[14] T. Ruhland, K. Andersen, H. Pedersen, J. Org. Chem. 63 (1998) 9204.
[15] (a) R.J. Cohen, D.L. Fox, R.N. Salvatore, J. Org. Chem. 69 (2004) 4265;
(b) K.C. Nicolaou, J.A. Pfefferkorn, H.J. Mitchell, J. Am. Chem. Soc. 122 (2000) 9954;
(c) X. Huang, Y.G. Wang, J. Comb. Chem. 9 (2007) 121;
(d) J. Cao, X. Huang, J. Comb. Chem. 10 (2008) 526;
(e) X. Huang, J.F. Xu, J. Comb. Chem. 11 (2009) 350;
(f) X. Huang, J. Cao, J.Q. Huang, J. Comb. Chem. 11 (2009) 515;
(h) J. Cao, X. Huang, J. Comb. Chem. 12 (2010) 1.
[16] (a) X. Huang, E. Tang, W.M. Xu, J. Comb. Chem. 7 (2005) 802;
(b) E. Tang, X. Huang, W.M. Xu, Tetrahedron 60 (2004) 9963;
(c) W.M. Xu, X. Huang, E. Tang, J. Comb. Chem. 7 (2005) 726;
(d) E. Tang, B.Z. Chen, L.P. Zhang, Synlett 5 (2011) 707;
(e) W.M. Xu, E. Tang, X. Huang, Tetrahedron 61 (2005) 501;
(f) J. Cao, E. Tang, X. Huang, et al. Chin. Chem. Lett. 17 (2006) 857.
[17] P.L. Majumder, S. Chatterjee, N. Mukhoti, J. Indian Chem. Soc. 78 (2001) 743.
[18] General procedure for the preparation of coumarins 5: to a suspension of the swollen polystyrene-supported selenenyl bromide (Br: 0.99 mmol/
g, 2.5 g) in dry THF/DMF (v/v = 5:1, 30 mL) was added NaBH4 (5 mmol) in a nitrogen atmosphere at 40 8C. After stirring for 8 h at 40 8C,
allyl bormide (5.5 mmol) was added dropwise and stirred for another 12 h. The resin 2 was collected by filtration, washed with THF
(20 mL ꢁ 2), MeOH (20 mL ꢁ 2) and CH2Cl2 (20 mL ꢁ 2) and dried in vacuum. To a suspension of the swollen resin 2 (1.0 g) in dry CH2Cl2
(15 mL) was added NCS (0.668 g, 5.0 mmol) at 0 8C. The mixture was stirred for 0.5 h at 0 8C and 2 h at room temperature. After filtrating and
washing with dry CH2Cl2 (15 mL ꢁ 3), resin 3 was suspended with dry CH2Cl2 (15 mL) and cool at ꢀ78 8C. TMSOTf (0.022 g, 0.10 mmol)
was added. After stirring for 0.5 h at ꢀ78 8C, substituted phenyl acrylate 1 (5.0 mmol) was added in a nitrogen atmosphere. The suspension was
stirred for another 2 h at ꢀ78 8C and then stored in a freezer at ꢀ20 8C for 8 h. Saturated aqueous NaHCO3 (5 mL) was poured into the flask to
quench reaction mixture. 3-Polystyrene-supported seleno-3,4-dihydrocoumarin 4 was collected by filtration, washed with THF (20 mL ꢁ 2),

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E. Tang et al. / Chinese Chemical Letters 23 (2012) 631–634
ether (20 mL ꢁ 2), THF/H2O (3:1) (20 mL ꢁ 2), H2O (20 mL ꢁ 2), THF (20 mL ꢁ 2), benzene (20 mL ꢁ 2), MeOH (20 mL ꢁ 2), and
CH2Cl2 (20 mL ꢁ 2), and dried in vacuum. The washed resin 4 was suspended in THF (15 mL). To the mixture was added 30% aqueous H2O2
(1.2 mL) and stirred for 1 h at 0 8C, and then stirred for another 20 min at room temperature. The mixture was filtered and the resin was washed
with CH2Cl2 (15 mL ꢁ 2). The filtrate was washed with H2O (30 mL ꢁ 2), dried over MgSO4, and evaporated to dryness in vacuum to afford
coumarins 5.
[19] General procedure for the preparation of dihydrocoumarins 6: an oven-dried schlenk tube was charged with a suspension of the swollen resin 4
(0.5 g) in dry toluene (10 mL) under nitrogen atmosphere, and tri-n-butylstannane (0.291 g, 1.0 mmol) and 2,20-azodiisobutyronitrile (AIBN)
(0.082 g, 0.5 mmol) were added after which the reaction mixture was heated to 90 8C for 2 h. After cooling, the suspension was poured into a
fritted funnel and the resin was washed with CH2Cl2 (10 mL ꢁ 2). The filtrate was then concentrated and 10% HCl (5 mL) was added and the
resulting solution was washed with hexanes (10 mL ꢁ 3). The aqueous phase was then neutralized with 10% NaOH and extracted with ethyl
ether (10 mL ꢁ 2). The combined organic layers were washed with brine (10 mL), dry over MgSO4, and concentrated to afford the product 6.