Download PDF
Synlett 2010(7): 1071-1074  
DOI: 10.1055/s-0029-1219778
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Copper(I)-Catalyzed Synthesis of Polysubstituted Furans from Alkynoates and 1,3-Dicarbonyl Compounds in the Presence of Oxygen

Rulong Yan, Jing Huang, Jia Luo, Ping Wen, Guosheng Huang*, Yongmin Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(931)8912582; e-Mail: hgs@lzu.edu.cn; e-Mail: liangym@lzu.edu.cn;

Further Information

Publication History

Received 15 January 2010
Publication Date:
17 March 2010 (online)

 PDF Download Permissions and Reprints All articles of this category

Abstract

A novel and straightforward synthesis of polysubstituted furans was achieved easily from the oxidative cyclization of 1,3-dicarbonyl compound and alkynoate catalyzed by CuI in the presence of O2.

Key words

polysubstituted furans - oxidant - copper catalysis - oxygen.

Polysubstituted furans are one of the important structural units as well as broadly found in many natural products and pharmaceutical substances. [¹] Furthermore many of polysubstituted furans as important reaction intermediates have been widely used in the total synthesis and synthetic industry. [²] Due to the importance in organic chemistry, it has drawn considerable interest for synthetic chemists. Classical methods for the synthesis of polysubstituted furans included the cyclocondensation of dicarbonyl compounds [³] and coupling to the exiting furan ring. [4] In the past several years, many efforts for the synthesis of polysubstituted furans have been made to explore the cycloisomerization of alkyne- and allene-containing catalyzed by transition metals [5] such as palladium, copper, gold, silver, and ruthenium.

Table 1 Optimization of Reaction Conditionsa

Entry Catalyst Oxidant Solvent Temp (˚C) Yield (%)b
 1c CuI Air DMF  80 72
 2 CuI O2 DMF  80 85
 3 CuI O2 DMF 110 89
 4 CuI Air DMF r.t. 12
 5 CuBr O2 DMF 110 76
 6 CuCl O2 DMF 110 61
 7 CuOTf O2 DMF 110 63
 8 Cu(OTf)2 O2 DMF 110 47
 9 Cu(OAc)2 O2 DMF 110 45
10d CuI H2O2 DMF 110 74
11d CuI PhI(OAc)2 DMF 110 n.r.e
12 CuI O2 THF 110 7
13 CuI O2 toluene 110 trace
14 CuI O2 CHCl3 110 16
15 CuI O2 MeCN 110 13
16 FeCl2 O2 DMF 110 n.r.e
17 Pd(OAc)2 O2 DMF 110 n.r.e
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalysts (10 mol%) in 2 mL of solvent for 4 h.
b Isolated yields.
c Reaction time: 2 h.
d Under N2.
e n.r.: no reaction.

Recently the C-H activation and cross dehydrogenative coupling reaction [6] for the construction of heterocycles with simple and readily accessible substrates have received great attention and would have a brilliant prospect for its economic, sustainable, and environmentally friendly features. Oxygen is a very ideal oxidant and offers attractive interest to chemists in term of its tremendous importance in industry. [7] However, using O2 as the oxidant still remains a challenging research area, and there are very rare reports about the construction of the polysubstituted furans via oxidation with O2. So, it will have great significance to explore the new and efficient strategies for the synthesis of the furans oxidized by O2. In our ongoing efforts to explore mild and efficient methodologies for the synthesis of furans, [8] we wish to report a novel and straightforward method under the mild conditions to synthesize polysubstituted furans in the presence of O2 with the commercial starting materials.

Our preliminary studies focused on the reaction of 1,3-diphenyl-1,3-propanedione (1a) and dimethyl but-2-­yndioate (2a) using air as the oxidant in DMF at 80 ˚C (Table  [¹] , entry 1). Fortunately, the expected substituted furan 3aa was obtained in 72% yield in the presence of CuI. When O2 was employed as the oxidant, to our delight, 85% of 3aa was isolated after 4 hours (entry 2). Other organic and inorganic oxidants such as PhI(OAc)2, Cu(OTf)2, Cu(OAc)2, and H2O2 were also evaluated (entries 8-11).

However, O2 was proved to be the most efficient oxidant in this reaction. Furthermore, different copper salts such as CuI, CuBr, and CuOTf were examined (entries 5-7) and other transition metals were also investigated (entries 16 and 17). No better results were obtained. Changing the solvent to THF, toluene, MeCN, and CHCl3 failed to improve the yields (entries 12-15). The results indicated that the reaction was sensitive to the solvent medium, and the use of DMF as a solvent led to high yield. When the reaction was run at room temperature, the product 3aa was obtained in 12% yield even though the reaction was prolonged to 15 hours (entry 4). Increasing the temperature to 110 ˚C, the reaction also proceeded smoothly and gave the desired furan in 89% yield quickly. The studies revealed that the preferred temperature for the reaction was 110 ˚C, and lower temperature led to long reaction time and lower yield. Hence, we selected the following conditions for further experiments: using O2 (1 atm), 1a (0.5 mmol) and 2a (0.5 mmol) catalyzed by CuI (10 mol%) in DMF (2 mL) at 110 ˚C.

Table 2 Synthesis of Polysubstituted Furans from Alkynoates and 1,3-Dicarbonyl Compoundsa

Entry 1 2 3 Yield (%)b
 1 1a 2a 3aa 89
 2 1b 2a 3ba 62
 3 1c 2a 3ca 64
 4 1d 2a 3da 45
 5 1e 2a 3ea 43
 6 1f 2a 3fa 47
 7 1g 2a 3ga 53
 8 1h 2a 3ha n.r.c
 9 1a 2b 3ab 86
10 1b 2b 3bb 58
11 1a 2c 3ac trace
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol).
b Isolated yield.
c n.r.: no reaction.

Under the optimized reaction conditions in hand, we turned our attention to investigate the scope of the oxidations reactions, and the results are shown in Table  [²] . 1,3-Dicarbonyl compounds bearing either phenyl, alkyl, or heteroatom groups also reacted smoothly and completely to give polysubstituted furans in fair to good yields. It seems that the electron density on the 1,3-dicarbonyl compounds drastically affects the reaction and electron-rich groups play a positive role in the reaction. As an extreme comparison, the 1,3-diphenyl-1,3-propanedione (1a) afforded 89% of the desired product 3aa, [¹¹] whereas the di­methyl but-2-yndioate (2a) was converted to 3da only in 45% yield (Table  [²] , entries 1 and 4). In addition, the ­di­fferent alkynoates were also surveyed in the reaction. The results showed that the reaction of 1,3-dicarbonyl compound and dimethyl but-2-yndioate (2a) gave higher yield than the diethyl but-2-yndioate (2b) and diphenyl­acetylene (2c). In comparison, the acetylene bearing two more electron-withdrawing groups will transfer more easily and lead to higher yield.

A plausible mechanism of this reaction is illustrated in Scheme  [¹] . The reaction may undergo the following steps. i) the 1,3-dicarbonyl compound is activated with Cu(I) to give complex 4; [9] ii) complex 4 then couples with alkynoate 3 to produce 5 via Michael addition, and the Cu catalyst is regenerated, which enters to the next cycle; iii) a keto-enol equilibrium exists between 5 and 6; iv) compound 6 undergoes a hydride abstraction to form the intermediates 7 and 9 under the oxidation conditions; [¹0] v) compound 8 is formed from 7 through radical addition; vi) finally, the furan 3 is generated from the dehydrogenation process.

Scheme 1 Plausible reaction mechanism

In conclusion, we have developed a facile and direct method for the construction of polysubstituted furans. Oxygen is firstly used as the oxidant in the synthesis of polysubstituted furans. The procedure is simple, sustainable, and environmentally benign. In addition, the starting materials are readily available. This reaction proceeds smoothly in moderate to good yields. Further applications for the methodology to synthesize natural pharmaceutical compounds are ongoing in our laboratory, and the results will be reported in due course.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

We thank the State Key Laboratory of Applied Organic Chemistry for financial support. We also thank our reviewers’ suggestions.

11

General Procedure for the Preparation of Dimethyl But-2-yndioate and 1,3-Diphenyl-1,3-propanedione (3aa)
An oven-dried Schlenk tube was charged with CuI (9.5 mg, 0.05 mmol), 1a (0.50 mmol), and 2a (0.50 mmol). The Schlenk tube was sealed and then evacuated and backfilled with oxygen (3 cycles). Then DMF (2 mL) was added to the reaction system. The reaction was stirred at 110 ˚C under O2 (1 atm) for 4 h. After cooling to r.t., the solvent diluted with Et2O (10 mL) and washed with brine (5 mL) and dried over anhyd Na2SO4. After the solvent was evaporated in vacuo, the residues were purified by column chromatography, eluting with PE-EtOAc (10:1) to afford pure 3aa.
Dimethyl 4-Benzoyl-5-phenylfuran-2, 3-dicarboxylate (3aa) Yellow viscous oil. ¹H NMR (400 MHz CDCl3): δ = 3.61 (s, 3 H), 3.96 (s, 3 H), 7.29-7.39 (m, 5 H), 7.50-7.54 (m, 1 H), 7.61-7.63 (m, 2 H), 7.79-7.81 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 52.4, 52.5, 121.5, 126.2, 127.4, 127.6, 128.5, 128.6, 129.3, 130.2, 133.6, 136.7, 141.1, 155.3, 157.7, 161.9, 190.0. IR (neat): 694, 772, 899, 1080, 1167, 1235, 1443, 1666, 1730, 2953, 3004, 3062 cm-¹. HRMS (EI): m/z calcd for C21H16O6 [M + H]+: 365.1020; found: 365.1029.
The ¹H NMR, ¹³C NMR, IR, and HRMS data of 3aa-bb can be found in the Supporting Information.

11

General Procedure for the Preparation of Dimethyl But-2-yndioate and 1,3-Diphenyl-1,3-propanedione (3aa)
An oven-dried Schlenk tube was charged with CuI (9.5 mg, 0.05 mmol), 1a (0.50 mmol), and 2a (0.50 mmol). The Schlenk tube was sealed and then evacuated and backfilled with oxygen (3 cycles). Then DMF (2 mL) was added to the reaction system. The reaction was stirred at 110 ˚C under O2 (1 atm) for 4 h. After cooling to r.t., the solvent diluted with Et2O (10 mL) and washed with brine (5 mL) and dried over anhyd Na2SO4. After the solvent was evaporated in vacuo, the residues were purified by column chromatography, eluting with PE-EtOAc (10:1) to afford pure 3aa.
Dimethyl 4-Benzoyl-5-phenylfuran-2, 3-dicarboxylate (3aa) Yellow viscous oil. ¹H NMR (400 MHz CDCl3): δ = 3.61 (s, 3 H), 3.96 (s, 3 H), 7.29-7.39 (m, 5 H), 7.50-7.54 (m, 1 H), 7.61-7.63 (m, 2 H), 7.79-7.81 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 52.4, 52.5, 121.5, 126.2, 127.4, 127.6, 128.5, 128.6, 129.3, 130.2, 133.6, 136.7, 141.1, 155.3, 157.7, 161.9, 190.0. IR (neat): 694, 772, 899, 1080, 1167, 1235, 1443, 1666, 1730, 2953, 3004, 3062 cm-¹. HRMS (EI): m/z calcd for C21H16O6 [M + H]+: 365.1020; found: 365.1029.
The ¹H NMR, ¹³C NMR, IR, and HRMS data of 3aa-bb can be found in the Supporting Information.

   Permissions and Reprints All articles of this category

Scheme 1 Plausible reaction mechanism