One-step synthesis of furocoumarins via oxidative annulation of 4-hydroxycoumarins with DDQ

Accepted Manuscript One-step synthesis of furocoumarins via oxidative annulation of 4-hydroxycoumarins with DDQ Jiang-Sheng Li, Dong-Mei Fu, Yuan Xue, Zhi-Wei Li, Dao-Lin Li, Yu-Dong Da, Fan Yang, Ling Zhang, Cui-Hong Lu, Gang Li PII:

S0040-4020(15)00323-3

DOI:

10.1016/j.tet.2015.03.025

Reference:

TET 26507

To appear in:

Tetrahedron

Received Date: 22 December 2014 Revised Date:

4 February 2015

Accepted Date: 6 March 2015

Please cite this article as: Li J-S, Fu D-M, Xue Y, Li Z-W, Li D-L, Da Y-D, Yang F, Zhang L, Lu C-H, Li G, One-step synthesis of furocoumarins via oxidative annulation of 4-hydroxycoumarins with DDQ, Tetrahedron (2015), doi: 10.1016/j.tet.2015.03.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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Graphic abstract

Title

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One-step synthesis of furocoumarins via oxidative annulation of 4-hydroxycoumarins with DDQ

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Authors

Jiang-Sheng Li*, Dong-Mei Fu, Yuan Xue, Zhi-Wei Li, Dao-Lin Li, Yu-Dong Da, Fan Yang, Ling Zhang, Cui-Hong Lu, Gang Li Correspondance:

Jiang-Sheng Li, E-mail: [email protected]

Affiliations

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Fax: +86(731)85258733

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School of Chemistry and Biological Engineering, Changsha University of Science &

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Technology, Changsha, 410114 China

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ACCEPTED MANUSCRIPT Abstract A facile metal-free method for the synthesis of furo[3,2-c]coumarins has been developed in one step with high efficiency, treating accessible 4-hydroxycoumarins solely with DDQ. This transformation could proceed smoothly under very mild

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conditions, with good functional group tolerance, readily handling, and easy scale-up. Furthermore, such an oxidative annulation protocol can be extended to the efficient construction of furo[3,2-c]quinolinones.

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Keywords

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Furocoumarins, Furoquinolinones, 4-Hydroxycoumarins, DDQ, Oxidative annulation

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ACCEPTED MANUSCRIPT 1. Introduction The coumarin scaffold is a privileged structural unit occurring in numerous natural products, pharmaceuticals, and a large variety of biologically active substances.1 Coumarin derivatives have also been extensively used as functional materials such as

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fluorescent labeling probes2 and laser dyes3. Furo[3,2-c]coumarins, one of furocoumarins with a furan ring fused to the chromen-2-one unit, are of great interest owing to their potent biological and pharmacological activities, and thus represent a promising class of synthetic targets and lead structures for drug discovery.1d,4

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Naturally occurring neo-tanshinlactone and its analogues have been discovered to be a potent and selective anti-breast cancer agent.4b,4c In the past decade, great efforts have

the majority has

focused

on

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been devoted to construct furo[3,2-c]coumarin scaffolds (Scheme 1).4a,5 Among them, the intramolecular annulations/oxdiation

of

3-alkynyl-chromones,5a-c consecutive alkylation/annulation of 4-hydroxycoumarins with α-halo ketones,4a oxidative cycloaddition/oxidation of 4-hydroxycoumarins with alkenes,4a cascade cross-coupling/cyclization of (O-methylated) 3-prefunctionalized

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4-hydroxycoumarins with alkynes,4a,5d-f and the application of multicomponent reactions starting from 4-hydroxycoumarins, aldehydes and the others5g-m. However, most of these methods suffer from harsh conditions, low overall yields, relatively

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poorer substrate availability, or/and the requirement of transition metal catalyst. Therefore, the development of new methods for the rapid and efficient preparation of

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furo[3,2-c]coumarin derivatives under mild conditions are still highly desired.

Scheme 1 Synthetic methodologies available for the furo[3,2-c]coumarin scaffold

Recently, we and Deng’s group have individually succeeded on establishing an 3

ACCEPTED MANUSCRIPT efficient protocol to create furans from various ketones, particularly β-diketones, β-ketoacetates, β-ketonitriles, using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as maleonitrile building block.6 The fact that 4-hydroxycoumarins behave as 1,3-dicarbonyl systems in synthetic chemistry inspired us that a furo[3,2-c]coumarin

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scaffold might be achieved in one step by the treatment of 4-hydroxycoumarins with

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DDQ (Scheme 2). Herein, we report our endeavor on this oxidative annulation.

2. Results and discussion

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Scheme 2 Straightforward access to furo[3,2-c]coumarin scaffold via oxidative annulation

Before optimization of the reaction conditions, we have known from the literatures7 that the reactions between 4-hydroxycoumarins and DDQ might be solvent-dependent (Scheme 3). As is documented, 4-hydroxycoumarin was prone to the formation of a

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dimeric coumarin, [3,3'-bichroman]-2,2',4,4'-tetraone, in the presence of DDQ when MeOH was used as solvent,7a while the coumarin-DDQ adduct was obtained, with the DDQ as reactant precursor being incorporated into the final product structure, when

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reflux.7b

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the reaction was undertaken in EtOH combined with one drop of HOAc under

Scheme 3 Previously documented reactions of 4-Hydroxycoumarins with DDQ

With this idea in mind, we attempted to perform the reaction of 4-hydroxycoumarin 4

ACCEPTED MANUSCRIPT with DDQ under the reaction conditions previously employed in the DDQ-mediated synthesis of furan scaffolds6a,6c. Delightedly, when 4-hydroxycoumarin reacted with DDQ (3 equiv.) in acetonitrile (MeCN) at ambient temperature, the desired furo[3,2-c]coumarin 2a was obtained in a 89% yield. The product structure was

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confirmed by NMR, IR and MS analysis along with X-ray diffraction determination8 (Figure 1). Additionally, other aprotic solvents such as ethyl acetate (EtOAc), nitromethane (MeNO2), dichoromethane (DCM), and 1,2-dichloroethane (DCE) were tested in this transformation. It was found that all tested solvents were likewise

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suitable for this oxidative annulation, affording the desired product 2a in synthetically

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satisfactory yields (87%, 83%, 78% and 77%, respectively).

Figure 1 X-ray crystal structure of 2a

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Next, we applied the suitable reaction conditions to various 4-hydroxycoumarins

for exploring the substrate scope of such oxidative cyclization reactions (Table 1). In general, the 4-hydroxycoumarins tested could be smoothly converted, successfully furnishing the desired products in good yields. Varied alkyl groups such as methyl, iso-propyl and tert-butyl were well tolerated, although they, especially the iso-propyl, are susceptible to oxidation (Table 1, 2b-i). To be noted, the substrate 1j bearing methoxy group also reacted well to offer its corresponding product 2j in a 75% yield. In a similar manner, the chloro and bromo functional groups survived well in this oxidative cyclization (Table 1, 2l-o), providing good potential for further 5

ACCEPTED MANUSCRIPT functionalization of the products, for example, to create push-pull chromophores via amination catalyzed by transition metal catalysts.9 As shown in Table 1, the efficiency for the present transformation varied somewhat with the nature of substituents on the substrates. The electron-withdrawing groups (Cl and Br) are proved to be more

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favored than the electron-donating ones (OMe and alkyls) in yields. Different location of the groups have no significant impact on the reaction efficiency (Table 1, 2b-d, 2g-i, and 2l vs 2n).

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Table 1 Scope of 4-hydroxycoumarins for the synthesis of furo[3,2-c]coumarinsa

a

Reaction conditions: 1 (0.5 mmol) and DDQ (1.5 mmol) in MeCN (2 mL) stirred for overnight. The yield is for isolated cyclization product.

Furthermore, the present transformation was also investigated on a larger scale. At 6

ACCEPTED MANUSCRIPT ambient temperature, the reaction of 1a and DDQ was carried out on a gram scale (10 mmol, 1.62 g). The isolated yield of 85% for 2a was obtained after stirring overnight. After successfully establishing an efficient approach for the construction of furo[3,2-c]coumarin skeletons, we intended to extend the present oxidative

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cyclization strategy to the synthesis of furo[3,2-c]quinolinones (Scheme 4). Furoquinolinone alkaloids have been found to exhibit a range of biological activities, such as antimicrobial, antimalarial, insecticidal, antineoplastic, antidiuretic, antiarrhythmic and sedative.10 When 4-hydroxyquinolin-2(1H)-one 1p was used as

consumed,

but

no

evidence

for

the

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substrate, it was disappointed to find that the starting material 1p was completely formation

of

the

product

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4-oxo-4,5-dihydrofuro[3,2-c]quinoline-2,3-dicarbonitrile 2p was observed. Evidently, 4-hydroxyquinolin-2(1H)-one 1p, with no substituents attached to the N terminal, was found to be an unsuitable substrate for such oxidative cyclization. When a methyl group was introduced to the N atom of 1p, that is, 1q was used instead, the reaction smoothly proceeded and its corresponding product 2q was successfully achieved, with

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a furo[3,2-c]quinolinone skeleton. Based on these experimental results, it can be envisioned that such oxidative cyclization protocol is efficient for the construction of furo[3,2-c]quinolinone

derivatives

starting

from

N-substituted

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4-hydroxyquinolin-2(1H)-ones.

Scheme 4 Attempt to the use of 1p, q for oxidative annulation

3. Conclusion In conclusion, we have demonstrated a novel and efficient strategy to readily access furocoumarin scaffold from available 4-hydroxycoumarins using DDQ under very mild conditions in one step. This methodology is also efficient for the oxidative 7

ACCEPTED MANUSCRIPT cyclization of N-substituted 4-hydroxyquinolin-2(1H)-ones. Further investigation into the application of such products and their phthalocyanine analogues in fluorescence probe and solar cell is ongoing in our laboratory.

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4. Experimental section 4.1. General

All solvents and reagents were purchased from the suppliers and used without further purification unless otherwise noted. All the 4-hydroxycoumarins and

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4-hydroxyquinolin-2(1H)-one were prepared according to the known procedures.11 4-Hydroxy-1-methylquinolin-2(1H)-one was commercially purchased. 1H NMR (400

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MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 or DMSO-d6 solvent at room temperature on Bruker Avance III 400 spectrometer using TMS as internal standard. IR spectra were recorded by Varian 3100 FT-IR. MS spectra were performed on a Agilent 6890/5973 GC-MS. Elemental analyses were measured on a Perkin

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Elmer 2400 series analyzer.

4.2. Typical procedure for the synthesis of furocoumarins. DDQ (341 mg, 1.5 mmol) was added to 4-hydroxycoumarin (0.5 mmol) in MeCN (2 mL). The resulting reaction mixture was stirred overnight during which time the

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precipitates were formed. Ethyl acetate (30 mL) was added and the resultant mixture was subsequently washed with saturated aqueous NaHCO3 (10 mL×3) and brine. The

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organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to recrystallization from CH2Cl2 to yield the corresponding product.

The reaction of 4-hydroxyquinolin-2(1H)-ones with DDQ was performed by a

similar method. 4.2.1. 4-Oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2a). Lightly yellow solid, mp 220-222 oC; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.61 – 7.46 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 160.3, 154.0, 153.6, 8

ACCEPTED MANUSCRIPT 134.7, 132.7, 125.9, 122.1, 118.1, 110.3, 109.2, 107.6, 107.3, 107.2; IR (KBr): ν 2254, 2238, 1758 cm-1; MS (EI): m/z 236 [M]+; Anal. Calcd for C13H4N2O3 C 66.11, H 1.71, N 11.86; Found: C 66.01, H 1.79, N 11.75%. 4.2.2. 8-Methyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2b). White solid,

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mp 252-254 oC; 1H NMR (400 MHz, DMSO-d6): δ 7.94 (d, J = 1.1 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 2.45 (s, 3H);

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C NMR (100 MHz,

DMSO-d6): δ 160.1 , 154.8 , 152.1 , 136.1 , 135.8 , 133.0 , 122.2 , 117.9 , 110.6 ,

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109.8 , 109.2 , 109.2 , 106.7 , 20.7; IR (KBr): ν 2251, 2245, 1757 cm-1; MS (EI): m/z 250 [M]+; Anal. Calcd for C14H6N2O3 C 67.20, H 2.42, N 11.20; Found: C 67.31, H

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2.48, N 11.12 %.

4.2.3. 7-Methyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2c). Yellow solid, mp 261-262 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 2.49 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 160.4, 154.8, 154.0, 146.4, 132.8, 127.4, 122.5, 118.0, 109.2, 109.1, 109.0, 108.4, 106.7,

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22.0; IR (KBr): ν 2248, 2238, 1753 cm-1；MS (EI): m/z 250 [M]+；Anal. Calcd for C14H6N2O3 C 67.20, H 2.42, N 11.20; Found: C 67.29, H 2.53, N 11.04 %. 4.2.4. 6-Methyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2d). White solid,

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mp 282-284 oC; 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J = 7.3 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, DMSO-d6):

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δ 160.5, 154.6, 152.2, 135.9, 133.2, 127.2, 125.9, 120.4, 110.7, 109.7, 109.2, 109.2, 106.7, 16.0; IR (KBr): ν 2253, 2242, 1759 cm-1; MS (EI): m/z 250 [M]+; Anal. Calcd for C14H6N2O3 C 67.20, H 2.42, N 11.20; Found: C 67.31, H 2.54, N 11.04 %. 4.2.5. 8-(Tert-butyl)-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2e). Colorless crystal, mp 221-222 oC; 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.7, 153.9, 152.2, 149.6, 132.6, 132.5, 118.2, 117.7, 109.8, 108.9, 107.7, 107.4, 107.3, 35.0, 31.2 (3 C); IR (KBr): ν2249 (strong peak, overlapped), 1760 cm-1; MS (EI): m/z 9

ACCEPTED MANUSCRIPT 292 [M]+; Anal. Calcd for C17H12N2O3 C 69.86, H 4.14, N 9.58; Found: C 69.73, H 4.27, N 9.43 %. 4.2.6. 6-Isopropyl-9-methyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2f). Off-white solid, mp 220-221 oC; 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, J = 7.9

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Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 3.47 (hept, J = 6.9 Hz, 1H), 2.71 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): δ 161.5, 154.5, 151.7, 134.5, 133.3, 132.8, 131.2, 127.8, 110.4, 109.7, 109.3, 109.2, 106.3, 27.1, 22.7 (2 C), 20.7; IR

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(KBr): ν 2251, 2239, 1743 cm-1; MS (EI): m/z 292 [M]+; Anal. Calcd for C17H12N2O3 C 69.86, H 4.14, N 9.58; Found: C 70.02, H 4.31%, N 9.43%.

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4.2.7. 6,9-Dimethyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2g). Lightly yellow solid, mp 223-225 oC; 1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 2.69 (s, 3H), 2.39 (s, 3H);

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C NMR (100 MHz,

DMSO-d6): δ 161.3, 154.5, 152.7, 135.2, 133.3, 132.8, 127.5, 124.4, 110.3, 109.7, 109.3, 109.2, 106.3, 20.7, 15.9; IR (KBr): ν 2254, 2233, 1745 cm-1; MS (EI): m/z 264

N 10.45%.

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[M]+; Anal. Calcd for C15H8N2O3 C 68.18, H 3.05, N 10.6; Found: C 68.29, H 3.17 %,

4.2.8. 7,8-Dimethyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2h). White

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solid, mp 243-245 oC; 1H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.49 (s, 1H), 2.39 (s, 3H), 2.35 (s, 3H);

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C NMR (100 MHz, DMSO-d6): δ 161.3, 154.5, 152.7,

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135.2, 133.3, 132.8, 127.5, 124.4, 110.3, 109.7, 109.3, 109.2, 106.3, 20.7, 15.9; IR (KBr): ν 2250, 2237, 1740 cm-1; MS (EI): m/z 264 [M]+; Anal. Calcd for C15H8N2O3 C 68.18, H 3.05, N 10.6; Found: C 68.30, H 3.18, N 10.50%. 4.2.9. 6,8-Dimethyl-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2i). Off-white solid, mp 226-228 oC; 1H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 7.41 (s, 1H), 2.49 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 153.9, 150.8, 137.3, 135.6, 132.5, 127.7, 119.2, 109.8, 108.8, 107.8, 107.5, 107.2, 20.9, 16.0; IR (KBr): ν 2249, 2241, 1759 cm-1; MS (EI): m/z 264 [M]+; Anal. Calcd for C15H8N2O3 C 68.18, H 3.05, 10

ACCEPTED MANUSCRIPT N 10.6; Found: C 68.27, H 3.19, N 10.52%. 4.2.10. 7-Methoxy-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2j). Yellow solid, mp 254-255 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H); 13C NMR (100 MHz, DMSO-d6):

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δ 164.8, 160.7, 156.1, 154.9, 132.3, 124.1, 114.5, 109.3, 109.2, 107.1, 106.7, 104.0, 102.4, 56.9; IR (KBr): ν 2250, 2235, 1753 cm-1; MS (EI): m/z 266 [M]+; Anal. Calcd for C14H6N2O4 C 63.16, H 2.27, N 10.52; Found: C 63.31, H 2.38, N 10.40%.

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4.2.11. 4-Oxo-4H-benzo[f]furo[3,2-c]chromene-2,3-dicarbonitrile (2k). White solid, mp >280 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J = 8.5 Hz, 1H), 8.40 (d, J =

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9.1 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.78-7.32 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.0, 154.8, 154.7, 136.2, 132.9, 130.7, 130.5, 129.9, 127.7, 126.3, 124.8, 117.6, 109.9, 109.3, 109.2, 106.5, 105.6; IR (KBr): ν 2249, 2238, 1760 cm-1; MS (EI): m/z 286 [M]+; Anal. Calcd for C17H6N2O3 C 71.33, H 2.11, N

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9.79; Found: C 71.47, H 2.24, N 9.70 %.

4.2.12. 8-Chloro-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2l). Colorless crystal, mp >280 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 2.5 Hz, 1H), 7.88

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(dd, J = 9.0, 2.5 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 158.9, 154.4, 152.5, 134.5, 133.5, 130.4, 122.2, 120.2, 112.3, 110.8, 109.1, 109.0, 106.7; IR (KBr): ν 2252, 2238, 1761 cm-1; MS (EI): m/z 270 [M]+; Anal. Calcd for

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C13H3ClN2O3 C 57.70, H 1.12, N 10.35; Found: C 57.62, H 1.23, N 10.29%. 4.2.13.

8-Bromo-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2m).

Yellow

crystal, mp >280 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.9, 2.4 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 158.8, 154.3, 152.9, 137.3, 133.5, 125.1, 120.3, 118.1, 112.7, 110.7, 109.1, 109.0, 106.7; IR (KBr): ν 2251, 2236, 1769 cm-1; MS (EI): m/z 314 [M]+; Anal. Calcd for C13H3BrN2O3 C 49.56, H 0.96, N 8.89; Found: C 49.40, H 1.07, N 8.81%.

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ACCEPTED MANUSCRIPT 4.2.14. 7-Chloro-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile (2n). White solid, mp 207-208 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.16 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.64 (dd, J = 8.5, 1.9 Hz, 1H);

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C NMR (100 MHz, DMSO-d6): δ

159.5, 154.3, 154.2, 139.1, 133.3, 126.6, 124.3, 118.4, 110.1, 110.0, 109.1, 109.0,

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106.6; IR (KBr): ν 2248, 2239, 1754 cm-1; MS (EI): m/z 270 [M]+; Anal. Calcd for C13H3ClN2O3 C 57.70, H 1.12, N 10.35; Found: C 57.82, H 1.19, N 10.23%. 4.2.15.

6,9-Dichloro-4-oxo-4H-furo[3,2-c]chromene-2,3-dicarbonitrile

(2o).

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Colorless crystal, mp >280 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.6, 153.2, 150.2, 134.4, 133.7, 128.1, 127.5, 120.9, 112.23, 112.16, 109.0, 108.8, 106.2; IR (KBr): ν

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2254, 2238, 1768 cm-1; MS (EI): m/z 304 [M]+; Anal. Calcd for C13H2Cl2N2O3 C 51.18, H 0.66, N 9.18; Found: C 51.30, H 0.75, N 9.12 %. 4.2.15.

5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]quinoline-2,3-dicarbonitrile

Yellow solid, mp

(2q).

266-267 oC; 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 7.9, 1.4

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Hz, 1H), 7.80 (ddd, J = 8.7, 7.3, 1.5 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 3.83 (s, 3H);

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C NMR (100 MHz, CDCl3) δ 157.6, 155.9, 140.1, 133.3,

132.0, 123.6, 122.4, 115.8, 113.2, 110.7, 108.24, 108.17, 107.2, 29.8; IR (KBr): ν

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2246, 2229, 1661 cm-1; MS (EI): m/z 249 [M]+; Anal. Calcd for C14H7N3O2 C 67.47,

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H 2.83, N 16.86; Found: C 67.59, H 3.01, N 16.58 %. Acknowledgements

Financial support from National Natural Science Foundation of China (21202010)

and Hunan Provincial Natural Science Foundation of China

(12JJ4021 &

2015JJ3012) is gratefully acknowledged. References and notes 1. (a) Curini, M.; Cravotto, G.; Epifano, F.; Giannone, G. Curr. Med. Chem. 2006, 13, 199-222; (b) Borges, F.; Roleira, F.; Milhazes, N.; Uriarte, E.; Santana, L. Front. Med. Chem. 2009, 4, 23-85; (c) Riveiro, M. E.; De Kimpe, N.; Moglioni, A.; Vazquez, R.; Monczor, F.; Shayo, C.; Davio, C. Curr. Med. Chem. 2010, 17, 1325-38; (d) Conforti, F.; Marrelli, M.; Menichini, F.; Bonesi, M.; Statti, G.; 12

ACCEPTED MANUSCRIPT Provenzano, E.; Menichini, F. Curr. Drug Ther. 2009, 4, 38-58; (e) Joao Matos, M.; Vazquez-Rodriguez, S.; Santana, L.; Uriarte, E.; Fuentes-Edfuf, C.; Santos, Y.; Munoz-Crego, A. Med. Chem. 2012, 8, 1140-1145. 2. (a) Chen, Y.; Clouthier, C. M.; Tsao, K.; Strmiskova, M.; Lachance, H.; Keillor, J. W. Angew. Chem. Int. Ed. 2014; (b) Li, J.; Zhang, C.-F.; Yang, S.-H.; Yang, W.-C.; Yang, G.-F. Anal. Chem. 2014, 86, 3037-3042. 3. (a) Liu, X.; Cole, J. M.; Waddell, P. G.; Lin, T.-C.; Radia, J.; Zeidler, A. J. Phys. Chem. A 2011, 116,

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727-737; (b) Anufrik, S.; Tarkovsky, V.; Sazonko, G.; Asimov, M. J. Appl. Spectrosc. 2012, 79, 46-52.

4. (a) Santana, L.; Uriarte, E.; Roleira, F.; Milhazes, N.; Borges, F. Curr. Med. Chem. 2004, 11, 3239-3261; (b) Wang, X.; Bastow, K. F.; Sun, C.-M.; Lin, Y.-L.; Yu, H.-J.; Don, M.-J.; Wu, T.-S.; Nakamura, S.; Lee, K.-H. J. Med. Chem. 2004, 47, 5816-5819; (c) Wang, X.; Nakagawa-Goto, K.;

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Bastow, K. F.; Don, M.-J.; Lin, Y.-L.; Wu, T.-S.; Lee, K.-H. J. Med. Chem. 2006, 49, 5631-5634; (d) Wang, X.; Morris-Natschke, S. L.; Lee, K.-H. Med. Res. Rev. 2007, 27, 133-148; (e) Gambari, R.; Lampronti, I.; Bianchi, N.; Zuccato, C.; Viola, G.; Vedaldi, D.; Dall'Acqua, F. In Bioactive Heterocycles III; Khan, M. Ed.; Springer: Berlin Heidelberg, 2007; pp. 265-276; (f) Dong, Y.; Shi,

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Q.; Pai, H.-C.; Peng, C.-Y.; Pan, S.-L.; Teng, C.-M.; Nakagawa-Goto, K.; Yu, D.; Liu, Y.-N.; Wu, P.-C.; Bastow, K. F.; Morris-Natschke, S. L.; Brossi, A.; Lang, J.-Y.; Hsu, J. L.; Hung, M.-C.; Lee, E. Y. H. P.; Lee, K.-H. J. Med. Chem. 2010, 53, 2299-2308.

5. (a) Raffa, G.; Rusch, M.; Balme, G.; Monteiro, N. Org. Lett. 2009, 11, 5254-5257; (b) Cheng, G.; Hu, Y. J Org Chem 2008, 73, 4732-5; (c) Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285-7; (d) Peng, S.; Gao, T.; Sun, S.; Peng, Y.; Wu, M.; Guo, H.; Wang, J. Adv. Synth. Catal. 2014, 356, 319-324; (e) Conreaux, D.; Belot, S.; Desbordes, P.; Monteiro, N.; Balme, G. J. Org. Chem. 2008, 73, 8619-22;

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(f) Chen, L.; Li, Y.; Xu, M. H. Org. Biomol. Chem. 2010, 8, 3073-7; (g) Zhou, Z.; Liu, H.; Li, Y.; Liu, J.; Li, Y.; Liu, J.; Yao, J.; Wang, C. ACS Comb. Sci. 2013, 15, 363-369; (h) Zareai, Z.; Khoobi, M.; Ramazani, A.; Foroumadi, A.; Souldozi, A.; Ślepokura, K.; Lis, T.; Shafiee, A. Tetrahedron 2012, 68, 6721-6726; (i) Rajesh, S. M.; Perumal, S.; Menéndez, J. C.; Pandian, S.; Murugesan, R. Tetrahedron 2012, 68, 5631-5636; (j) Lee, C.-J.; Jang, Y.-J.; Wu, Z.-Z.; Lin, W. Org. Lett. 2012, 14,

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1906-1909; (k) Adib, M.; Mahdavi, M.; Bagherzadeh, S.; Bijanzadeh, H. R. Synlett 2009, 2009, 2542-2544; (l) Wu, J. Chem. Lett. 2006, 35, 118-119; (m) Nair, V.; Menon, R. S.; Vinod, A. U.; Viji, S. Tetrahedron Lett. 2002, 43, 2293-2295. (a) Wang, Z.-L.; Li, H.-L.; Ge, L.-S.; An, X.-L.; Zhang, Z.-G.; Luo, X.; Fossey, J. S.; Deng, W.-P. J.

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6.

Org. Chem. 2014, 79, 1156-1165; (b) Li, J.-S.; Cai, F.-F.; Li, Z.-W.; Liu, W.-D.; Simpson, J.; Xue,

Y.; Pang, H.-L.; Huang, P.-M.; Cao, Z.; Li, D.-L. RSC Adv. 2014, 4, 474-478; (c) Li, J.-S.; Xue, Y.;

Li, Z.-W.; Liu, W.-D.; Lu, C.-H.; Zhao, P.-X. Synlett 2013, 24, 2003-2005.

7.

(a) Zanten, B.; Nauta, W. T. Arzneimittel-Forsch 1964, 14, 29-31; (b) Zhang, S.-L.; An, L.-K.;

Huang, Z.-S.; Ma, L.; Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Tetrahedron 2005, 61, 3087-3090.

8. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1023302. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union

Road,

Cambridge

CB2

1EZ,

UK,

(fax:

+44-(0)1223-336033

or

e-mail:

[email protected]). 9. (a) Diederich, F.; Stang, P. Metal-catalyzed cross-coupling reactions; Wiley-VCH: Weinheim, 2008; (b) Beller, M.; Bolm, C. Transition metals for organic synthesis; Wiley-VCH: Weinheim, 2004. 13

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(a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605-618; (b) Butenschön, I.; Möller, K.; Hänsel, W. J.Med. Chem. 2001, 44, 1249-1256.

11. (a) Gao, W. T; Hou, W. D.; Zheng, M. R.. Chin. J. Org. Chem. 2008, 28, 2011-2015; (b) Gong, D.

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H.; Zhang, L.; Li, J. F.; Yuan, J. Y.; Yuan, C. Y. Chin. J. Chem. 2004, 22, 925-931.

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Supporting Information One-step synthesis of furocoumarins via oxidative annulation of 4-hydroxycoumarins with DDQ

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Jiang-Sheng Li*, Dong-Mei Fu, Yuan Xue, Zhi-Wei Li, Dao-Lin Li, Yu-Dong Da, Fan Yang, Ling Zhang, Cui-Hong Lu, Gang Li

Contents

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Correspondance: [email protected] (Dr J.S. Li)

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1) General information…………………………………………………………………………………………..2 2) Experimental details of the intermediates ……………………………………………………..2–3 3) Proposed mechanism for this oxidative annulation……………………………………………4 4) Copies of NMR spectra of the fused furans……………………………………………….5–20

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5) A checkCIF report regarding compound 2a…………………………………………………21–22

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All solvents and reagents were purchased from the suppliers and used without further purification unless otherwise noted. All the 4-hydroxycoumarins and 4-hydroxyquinolin-2-one were prepared according to the known procedures. 4-Hydroxy-1-methylquinolin-2(1H)-one was commercially purchased. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 or DMSO-d6 solvent at room temperature on Bruker Avance III 400 spectrometer using TMS as internal standard. IR spectra were recorded by Varian 3100 FT-IR. MS spectra were performed on a Agilent 6890/5973 GC-MS. Elemental analyses were measured on a Perkin Elmer 2400 series analyzer.

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2. Experimental details of the intermediates

1) General procedure for synthesis of 4-hydroxycoumarins 1b, d-i, k (Method 1) O

O

O R

R O 3

O

OH O

O

4

1b: R = 4-Me 1d: R = 2-Me 1e: R = 4-tert-Bu 1f: R = 2-iso-Pr-5-Me

Eaton's

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OH

OH

R O

O

1

1g: R = 2,5-Me2 1h: R = 3,4-Me2 1i: R = 2,4-Me 2 1k: naphthalen-2-ol

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Scheme 1 A route to the synthesis of 4-hydroxycoumarins bearing electron-donating groups on the benzene ring

A mixture of phenol 3 (10 mmol) and Meldrum’s acid (10 mmol) was stirred at 90 o

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C (monitored by TLC) until the reaction completion. Then it was allowed to cool and

poured into cool water. The precipitate 4 was collected, washed several times with

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water, and dried under vacuum for next step. Acid 4 (4 mmol) was stirred in Eaton’s reagent (8 mL) at 70 oC for 5h. Then it was

allowed to cool, and poured into an ice-water mixture. The solid formed was collected, washed several times with water, dissolved in 1 N NaOH, and the insoluble suspension was removed by fitration. The filtrate was acidified with concentrated HCl, and precipitate collected.

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2) General procedure for synthesis of 4-hydroxycoumarins 1c, j, l-o (Method 2)

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Scheme 2 An alternative route to the synthesis of 4-hydroxycoumarins, especially bearing electron-withdrawing groups on the benzene ring

A solution of phenol 3 (20 mmol), acetic anhydride (25 mmol) and concentrated

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H2SO4 (one drop) was heated at 120 oC for 5-10 minutes (monitored by TLC). Usual work-up led to acetate 5, without purification for next step.

Dried acetate 5 (12 mmol) was stirred with anhydrous AlCl3 (20 mmol) at 130~160 o

C for 3 h. Work-up by quenching with 5% HCl (aq.) followed by flash column

chromatography or recystallization gave 2-hydroxyketone 6.

To a mixture of 2-hydroxyketone 6 (5 mmol, 1 equiv.) and pulverized sodium (50

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mmol, 10 equiv.) was added dropwise diethyl carbonate (20 mL) at 0~5 oC whilst stirring. Then the resultant system was heated to 90 oC for several hours (monitored by TLC). After completion, it was allowed to cool to room temperature, followed by

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careful addition of ethanol. When the residual metallic sodium was disappeared, the reaction solution was poured into an ice-water mixture. Neutralization with dilute

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HCl resulted in solid precipitation, and filtration combined with recrystallization from methanol provided corresponding 4-hydroxycoumarin, suitable to be used in next step.

3) 4-hydroxyquinolin-2-one 1p was prepared similarly using Method 1.

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3. Proposed mechanism for this oxidative annulation

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Figure 1

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References: See reference 6 in the text.

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4. Copies of NMR spectra of the furocoumarins

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Structure factors have been supplied for datablock(s) shelxl

Cell:

C-C = 0.0020 A

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Bond precision:

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No syntax errors found. CIF dictionary Please wait while processing .... Interpreting this report Structure factor report Datablock: shelxl

Wavelength=0.71075

a=6.3900(7)

b=9.8310(11)

c=32.790(3)

alpha=90

beta=90

gamma=90

Temperature: 113 K

Reported

Volume

2059.9(4)

Space group

Cmca

Hall group

-C 2bc 2

-C 2bc 2

Moiety formula

C13 H4 N2 O3

C13 H4 N2 O3

Sum formula

C13 H4 N2 O3

C13 H4 N2 O3

Mr

236.18

236.18

Dx,g cm-3

1.523

1.523

8

8

0.112

0.112

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Calculated

960.0

Mu (mm-1)

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Cmca

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Z

2059.9(4)

F000

960.0

F000'

960.51

h,k,lmax

8,13,45

8,13,44

Nref

1511

1491

Tmin,Tmax

0.963,0.980

0.814,0.980

Tmin'

0.963

Correction method= MULTI-SCAN Data completeness= 0.987 R(reflections)= 0.0411( 1358) S = 1.105

Theta(max)= 29.206 wR2(reflections)= 0.1268( 1491)

Npar= 109

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Alert level C PLAT906_ALERT_3_C Large K value in the Analysis of Variance ...... 2.227 Check PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L= 0.600 2 Report PLAT913_ALERT_3_C Missing # of Very Strong Reflections in FCF .... 1 Note PLAT918_ALERT_3_C Reflection(s) with I(obs) much smaller I(calc) . 1 Check PLAT934_ALERT_3_C Number of (Iobs-Icalc)/SigmaW > 10 Outliers .... 1 Check

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The following ALERTS were generated. Each ALERT has the format test-name_ALERT_alert-type_alert-level. Click on the hyperlinks for more details of the test.

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Alert level G PLAT180_ALERT_4_G Check Cell Rounding: # of Values Ending with 0 = 3 PLAT912_ALERT_4_G Missing # of FCF Reflections Above STh/L= 0.600 18 Note

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