Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Dec 11.
Published in final edited form as: ACS Comb Sci. 2012 Jun 11;14(7):403–414. doi: 10.1021/co300040q

Solution-Phase Synthesis of a Highly Substituted Furan Library

Chul-Hee Cho †, Feng Shi †, Dai-Il Jung †,‡, Benjamin Neuenswander §, Gerald H Lushington §, Richard C Larock †,*
PMCID: PMC3437248  NIHMSID: NIHMS380579  PMID: 22612549

Abstract

graphic file with name nihms380579u1.jpg

A library of furans has been synthesized by iodocyclization and further diversified by palladium-catalyzed coupling processes. The key intermediate 3-iodofurans have been prepared by the electrophilic iodocyclization of 2-iodo-2-alken-1-ones in the presence of various nucleophiles in good to excellent yields under mild reaction conditions. These 3-iodofurans are the key components for library generation through subsequent elaboration by palladium-catalyzed processes, such as Suzuki–Miyaura, Sonagashira, Heck, aminocarbonylation and carboalkoxylation chemistry to afford a diverse set of 2,3,4,5-tetrasubstituted furans.

Keywords: solution-phase parallel synthesis, multisubstituted furans, 3-iodofurans, iodocyclization, electrophiles, nucleophiles

INTRODUCTION

Combinatorial chemistry and high-throughput screening (HTS) for drug discovery have made it possible to synthesize and/or screen large repositories of chemically diverse scaffolds in search of small molecules that disrupt or regulate macromolecular function.1, 2 Highly substituted furans are frequently found as subunits in many bioactive natural products and pharmaceutically important substances and they are also important building blocks in organic synthesis.3–11 Selected simple biologically active furan derivatives are shown in Figure 1. (+)-Furodysin (I) and (+)-furodysinin (II) are two sesquiterpenes isolated from pantropical marine sponges of the genus Dysidea.12 Their absolute configurations has been established by the synthesis of their (−)-isomers from (+)-9-bromocamphor.13 Interestingly, (−)-furodysinin was found in the Mediterranean D. tupha14 and both (−)-furodysin (III) and (−)-furodysinin (IV) have been shown to occur in D. herbacea.15 The pinguisane class have attracted interest because of their biological activity and rare carbon skeleton.16 Two examples of pinguisanes are pinguisone (V) and norpinguisone (VI), which exhibit antifeedant and antifungal activity respectively.17, 18 The hugely successful drug molecule Ranitidine (VII) (trade name Zantac),19 is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). Ranitidine is also known to give false positives for methamphetamine on drug tests.19–21

Figure 1.

Figure 1

Open in a new tab

Examples of Significant Furan-Containing Natural Products and Pharmaceuticals

For these reasons, the efficient synthesis of multiply substituted furans continues to attract the interest of synthetic chemists. Numerous heteroannulation protocols, including transition metal-catalyzed reactions, leading to multisubstituted furans have been reported.9, 22–35 Among the variety of oxygen-containing compounds that can be subjected to cyclization, unsaturated alcohols or ketones are substrates of major interest.25, 36–41 Previously, we found that analogous 2-(1-alkynyl)-2-alken-1-ones, which are easily prepared from simple, readily available starting materials, can be very efficiently coupled with a wide variety of nucleophiles using either catalytic amounts of AuCl338 or iodine40, 42, 43 as an electrophile to afford functionally-substituted furans (Scheme 1).

Scheme 1.

Scheme 1

Open in a new tab

Efficient Synthesis of Multisubstituted Furans by Electrophilic Cyclization of 2-(1-Alkynyl)-2-alken-1-ones in the Presence of Various Nucleophiles

Electrophilic iodocyclization is one of the most powerful methods for the efficient synthesis of a variety of functionalized carbocycles and heterocycles under mild conditions.4,39, 42, 44 Furthermore, we have demonstrated that the resulting iodine-containing products are very useful templates for further diversification by a variety of C–C, C–N, and C–O bond-forming processes and are thus valuable building blocks for combinatorial chemistry.45–51

Herein, in an extension of our previous studies,40 we wish to report the synthesis of a solution phase furan library using this methodology and subsequent elaboration of the resulting multisubstituted 3-iodofurans 2 by various palladium-catalyzed couplings to generate 2,3,4,5-tetrasubstituted furans 3. To synthesize a library with greater chances for biological activity, the multisubstituted furan template 3 has been evaluated computationally for its drug-like properties on the basis of Lipinski’s “rule of five”.52

RESULTS AND DISCUSSION

We hypothesized that our previously described iodocyclization process40 should readily afford 2,3,4,5-tetrasubstituted furans 3 as key intermediates to compounds of biological interest (Scheme 2). The alkynes 1{1–13} were prepared by the palladium/copper-catalyzed Sonogashira coupling of appropriate starting 2-iodo-2-alken-1-ones53 with various terminal alkynes. Heteroatoms were included in the acetylenes to impart drug-like, hydrogen bond donor or acceptor properties to the 2,3,4,5-tetrasubstituted furans 3. The results are summarized in Scheme 3.

Scheme 2.

Scheme 2

Open in a new tab

Library Design for the Tetrasubstituted Furans 3

Scheme 3.

Scheme 3

Open in a new tab

Preparation of 2-(1-Alkynyl)-2-alken-1-ones 1{1–13}

Accordingly, a set of tetrasubstituted 3-iodofurans 2{1–34} were efficiently prepared by electrophilic cyclization of the corresponding alkynes 1 in the presence of various nucleophiles including water, primary alcohols, acetic acid, and various diols using I2 for only 0.5 h under ambient conditions. The results of this iodocyclization process are summarized in Table 1 and Figure 2. All of the reactions were monitored by thin layer chromatography and the products purified by column chromatography. All compounds 2 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information for the experimental details).

Table 1.

Library Data for the 3-Iodofurans 2{1–34}a

graphic file with name nihms380579u2.jpg
entry alkyne 1 NuH iodofuran 2 yield (%)b entry alkyne 1 NuH iodofuran 2 yield (%)b
1 1{1} H2O 2{1} 42 18 1{3} n-C3H7OH 2{18} 49
2 1{2} H2O 2{2} 53c 19 1{8} CH3COOH 2{19} 85
3 1{3} H2O 2{3} 78 20 1{1} CH3COOH 2{20} 82
4 1{4} H2O 2{4} 89 21 1{5} CH3COOH 2{21} 77
5 1{5} H2O 2{5} 73 22 1{7} CH3COOH 2{22} 69
6 1{6} H2O 2{6} 47 23 1{1} HO(CH2)2OH 2{23} 86
7 1{7} H2O 2{7} 68 24 1{3} HO(CH2)2OH 2{24} 66
8 1{3} CH3OH 2{8} 53 25 1{4} HO(CH2)2OH 2{25} 83
9 1{8} CH3OH 2{9} 73 26 1{8} HO(CH2)2OH 2{26} 82
10 1{6} CH3OH 2{10} 59 27 1{7} HO(CH2)2OH 2{27} 82
11 1{7} CH3OH 2{11} 77c 28 1{9} HO(CH2)2OH 2{28} 87
12 1{9} CH3OH 2{12} 87 29 1{10} HO(CH2)2OH 2{29} 89
13 1{2} C2H5OH 2{13} 73 30 1{11} HO(CH2)2OH 2{30} 82
14 1{8} C2H5OH 2{14} 77 31 1{12} HO(CH2)2OH 2{31} 81
15 1{5} C2H5OH 2{15} 87 32 1{13} HO(CH2)2OH 2{32} 84
16 1{7} C2H5OH 2{16} 66 33 1{4} HO(CH2)4OH 2{33} 77
17 1{9} C2H5OH 2{17} 82 34 1{4} HO(CH2)5OH 2{34} 65
Open in a new tab
a

Unless otherwise noted, all of the reactions have been carried out using NaHCO3 (2.0 equiv), the nucleophile (4.0 equiv) and I2 (2.0 equiv) in MeCN (0.1 M conc.) at room temperature for 0.5 h.

b

Isolated yields after column chromatography.

c

An inseparable mixture was obtained. This material decomposes quickly in solution.

Figure 2.

Figure 2

Open in a new tab

3-Iodofuran Library 2{1–34}

These iodocyclization products 2 are the key components for library generation through subsequent elaboration by palladium-catalyzed processes, such as Suzuki-Miyaura, Sonagashira, Heck, aminocarbonylation and carboalkoxylation reactions, affording a diverse set of 2,3,4,5-tetrasubstituted furans 3 (Scheme 4). Out of the numerous possible combinations, our efforts have been guided by using Lipinski’s rule of five and the commercial availability of boronic acids 4, terminal alkynes 5, styrenes 6, amines 7, and alcohols 8 (Figure 3). The purity of the reaction mixtures has been analyzed by thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LC-MS), and high performance liquid chromatography (HPLC). This data has been used to populate a virtual library of all theoretically possible products, giving roughly 8,000 unique potential compounds in a combinatorial fashion.

Scheme 4.

Scheme 4

Open in a new tab

Library Generation of Various Tetrasubstituted Furans 3 from the 3-Iodofurans 2a

a Method A (Suzuki–Miyaura coupling), 3{1–27,52–60,78–81,123–128}: 10 mol % Pd(PPh3)4, K2CO3 (2.5 equiv), boronic acid 4 (1.5 equiv), toluene/EtOH/H2O (20/5/1), 80 °C; Method B (Sonogashira coupling), 3{28–40,61–71,82–93,104–105,129–139}: 3 mol % PdCl2(PPh3)2, 6 mol % CuI, alkynes 5 (1.2 equiv), Et2NH, DMF, 100 °C, 20 min, using microwave irradiation; 3{106–110}: 5 mol % PdCl2(PPh3)2, 10 mol % CuI, (S)-prolinol (3.0 equiv), alkynes 5 (1.2 equiv), DMF/H2O (v/v, 5:1), 70 °C; Method C (Heck coupling), 3{41–43}: 5 mol % Pd(OAc)2, n-Bu4NI (1.0 equiv), Na2CO3 (2.5 equiv), styrenes 6 (1.2 equiv), DMF, 80 °C; Method D (aminocarbonylation), 3{72,94–96,140–141}: CO (1 atm), 10 mol % PdCl2(PPh3)2, PPh3 (0.2 equiv), amines 7 (1.5 equiv), DMF, Et3N (2.0 equiv), 80 °C; Method E (carboalkoxylation), 3{44–51,73–77,97–103,111–122,142–164}: CO (1 atm), 10 mol % Pd(OAc)2, 20 mol % PCy3, TEA (4.0 equiv), R3OH 13 (5–10 equiv), DMF, 110 °C.

Figure 3.

Figure 3

Open in a new tab

Sublibraries of Boronic Acids 4, Terminal Alkynes 5, Styrenes 6, Amines 7, and Alcohols 8

The results for the palladium-catalyzed coupling processes performed on the multisubstituted furans 3{1–158} are summarized in Tables 2–6. Various boronic acids 4 for the Suzuki-Miyaura coupling of the multisubstituted 3-iodofurans 2 were chosen on the basis of their commercial availability and their ability to give the desired products 3{1–27,52–60,78–81,123–128} (Method A, Scheme 4). Sonogashira coupling of the 3-iodofurans 2 with various terminal alkynes 5 provides the corresponding alkyne products 3{28–40,61–71,82–93,104–110,129–139} (Method B, Scheme 4). No reaction took place when the acetoxy-containing iodofurans 2{19–21} were subjected to these reaction conditions. The combination of DMF/water as the solvent and (S)-prolinol as the base was more effective than the use of Et2NH and organic solvents, such as DMF (Scheme 5).54 Olefin-containing furan products 3{41–43} also have been prepared by the Heck coupling of 3-iodofurans 2 with a small styrene sublibrary 6 (Method C, Scheme 4). Amide-containing products 3{72,94–96,140–141} have been prepared by the palladium-catalyzed aminocarbonylation of 3-iodofurans 2 using one atmosphere of carbon monoxide and the amines 7 (Method D, Scheme 4). In addition, carboalkoxylation of the 3-iodofurans 2 using one atmosphere of carbon monoxide and various alcohols 8 in the presence of a palladium catalyst afforded the ester-containing furan products 3{44–51,73–77,97–103,111–122,142–164} (Method E, Scheme 4). These processes have been performed in parallel on approximately a 35–45 mg scale, starting from the 3-iodofurans 2. All of the crude furan products 3 were isolated by either column chromatography or preparative HPLC.

Table 2.

Library Data for Compounds 3{1–51}

graphic file with name nihms380579u3.jpg
product 3 n R3 building blocks method ion HRMS calcd for HRMS found HRMS purity (%)a yield (%)b
3{1} 1 4-MeOC6H4 4{2} A [M+H]+ 350.1518 351.1530 97 74f
3{2} 1 4-MeOC6H4 4{5} A [M+H]+ 396.1373 397.1388 99 66f
3{3} 1 4-MeOC6H4 4{17} A [M+H]+ 338.1267 339.1351 >99 62
3{4} 1 3-thiophenyl 4{9} A [M+H]+ 372.1031 373.1043 99 58f
3{5} 1 3-thiophenyl 4{10} A [M+H]+ 372.0832 373.0903 97 19
3{6} 1 3-thiophenyl 4{16} A [M+H]+ 326.1089 327.1175 82 41
3{7} 1 4-Me2NC6H4 4{4} A [M+H]+ 367.1584 368.1592 99 52
3{8} 2 C6H5 4{1} A - 348.1362 - - 67f
3{9} 2 C6H5 4{9} A [2M+H]+ 380.1623 761.3345 >99 72
3{10} 2 C6H5 4{11} A [M]+ 348.1362 348.1372 - 81f
3{11} 2 C6H5 4{18} A [M+Na]+ 308.1049 331.0943 98 61
3{12} 2 3-MeOC6H4 4{4} A [M+H]+[-H2O]c 368.1424 385.1464 99 77
3{13} 2 3-MeOC6H4 4{6} A [M+H]+[-H2O] 378.1467 361.1430 >99 39
3{14} 2 3-MeOC6H4 4{7} A [M+H]+[-H2O] 378.1467 361.1431 84 26
3{15} 2 3-MeOC6H4 4{11} A [M+H]+ 362.1519 363.1598 98 75f
3{16} 2 3-MeOC6H4 4{13} A [M+H]+ 378.1467 379.1553 99 61
3{17} 2 3-MeOC6H4 4{14} A [M+H]+ 399.0470 400.0532 >99 13
3{18} 2 3-MeOC6H4 4{15} A [M+H]+ 351.1471 352.1545 >99 88f
3{19} 2 3-MeOC6H4 4{17} A [M+H]+ 352.1423 353.1506 78 41
3{20} 2 3-MeOC6H4 4{18} A [M+H]+ 338.1143 339.1222 62 24
3{21} 2 3,5-(MeO)2C6H3 4{8} A [M+H]+ 386.1330 387.1343 97 56
3{22} 2 3-thiophenyl 4{3} A [M+H]+ 354.0926 355.0939 98 61
3{23} 2 3-thiophenyl 4{4} A [M+H]+ 344.0882 345.0891 97 53
3{24} 2 3-thiophenyl 4{6} A [M+H]+[-H2O] 354.0926 337.0890 >99 26
3{25} 2 3-thiophenyl 4{14} A [M+H]+d 374.9929 377.9978 88 23
3{26} 2 3-thiophenyl 4{15} A [M+H]+ 327.0929 328.0996 92 36
3{27} 2 3-thiophenyl 4{18} A [M+Na]+ 314.0613 337.0500 83 12
3{28} 1 4-MeOC6H4 5{2} B [M+H]+ 298.1205 299.1275 >99 26
3{29} 1 3-thiophenyl 5{2} B [M+H]+ 274.0664 275.0742 27 3
3{30} 1 3-thiophenyl 5{9} B [M]+ 321.0823 321.0831 91 67f
3{31} 2 3-MeOC6H4 5{1} B [M+H]+ 298.1205 299.1340 >99 78f
3{32} 2 3-MeOC6H4 5{2} B [M+H]+ 312.1362 313.1434 97 17
3{33} 2 3-MeOC6H4 5{5} B [M+H]+ 326.1518 327.1650 >99 81f
3{34} 2 3-MeOC6H4 5{6} B [M+H]+[-H2O] 366.1831 349.1793 >99 62
3{35} 2 3-MeOC6H4 5{7} B [M+H]+ 365.1991 366.2099 >99 23
3{36} 2 3-MeOC6H4 5{8} B [M+H]+ 359.1521 360.1620 79 38
3{37} 2 3-MeOC6H4 5{10} B [M+H]+ 387.1834 388.1902 84 14
3{38} 2 3-MeOC6H4 5{11} B [M+H]+ 345.1365 346.1444 94 12
3{39} 2 3,5-(MeO)2C6H4 5{6} B [M+H]+[-H2O] 396.1937 379.1900 86 51
3{40} 2 3-thiophenyl 5{5} B [M+H]+[-H2O] 302.0977 285.0938 >99 3
3{41} 1 4-MeOC6H4 6{3} C [M+H]+ 390.1467 391.1480 72 43f
3{42} 2 3-MeOC6H4 6{1} C [M+H]+ 406.1780 407.1876 >99 56
3{43} 2 3-thiophenyl 6{1} C [M+H]+ 323.0980 324.0988 78 28
3{44} 1 3-thiophenyl 8{3} E [M+NH4]+ 320.1082 338.1432 >99 15
3{45} 1 3-thiophenyl 8{5} E [M+H]+[-H2O] 320.1092 303.1043 >99 29f
3{46} 1 4-Me2NC6H4 8{4} E [M+H]+ 358.1893 359.2002 98 47
3{47} 2 C6H5 8{11} E [M]+ 302.1154 302.1160 99 73f
3{48} 2 3-MeOC6H4 8{2} E [M+H]+[-CH4O]e 316.1311 285.1115 >99 48f
3{49} 2 3-MeOC6H4 8{4} E [M+H]+ 359.1733 360.1814 >99 53f
3{50} 2 3-MeOC6H4 8{6} E [M+H]+ 399.2046 400.2121 99 71
3{51} 2 3-MeOC6H4 8{10} E [M+H]+ 368.1260 369.1418 >99 55f
Open in a new tab
a

UV purity determined at 214 nm after preparative HPLC.

b

Isolated yield after preparative HPLC.

c

Isotope: [A+(−17)]

d

Isotope: [A+2]

e

Isotope: [A+(−31)]

f

Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information).

Table 6.

Library Data for Compounds 3{123–164}

graphic file with name nihms380579u7.jpg
product 3 n m R3 building blocks method ion HRMS calcd for HRMS found HRMS purity (%)a yield (%)b
3{123} 1 2 4-MeOC6H4 4{6} A [M+H]+ 408.1573 409.1588 98 23
3{124} 1 2 4-MeOC6H4 4{17} A [M+H]+ 382.1529 383.1538 92 41
3{125} 2 5 C6H5 4{11} A [M]+ 418.2144 418.2156 99 46c
3{126} 2 4 C6H5 4{18} A [M+Na]+ 380.1624 403.1515 99 29
3{127} 2 2 4-Me2NC6H4 4{12} A [M+H]+ 420.2049 421.2125 95 53
3{128} 2 2 4-Me2NC6H4 4{17} A [M+H]+ 409.2001 410.2076 65 47
3{129} 1 2 4-MeOC6H4 5{4} B [M+H]+ 370.1780 371.1851 97 46
3{130} 1 2 4-MeOC6H4 5{5} B [M+H]+ 356.1634 357.1693 99 41
3{131} 1 2 4-MeOC6H4 5{6} B [M+H]+ 396.1937 397.1997 98 7
3{132} 1 2 4-Me2NC6H4 5{2} B [M+H]+ 355.1784 356.1801 >99 23
3{133} 2 2 C6H5 5{2} B [M+H]+ 326.1518 327.1530 99 76c
3{134} 2 2 C6H5 5{6} B [M+NH4]+ 380.1988 398.2320 >99 58
3{135} 2 2 4-MeOC6H4 5{2} B [M+H]+ 356.1624 357.1683 >99 8
3{136} 2 2 4-MeOC6H4 5{5} B [M+H]+ 370.1780 371.1842 91 31
3{137} 2 2 4-Me2NC6H4 5{5} B [M+H]+ 383.2097 384.2105 98 46
3{138} 2 2 4-Me2NC6H4 5{12} B [M+H]+ 405.2052 406.2061 65 12
3{139} 2 2 4-Me2NC6H4 5{7} B [M+H]+ 422.2569 423.2581 96 23
3{140} 2 5 C6H5 7{3} D [M]+ 415.2359 415.2370 99 47c
3{141} 2 5 C6H5 7{4} D [M]+ 470.2781 470.2793 >99 53c
3{142} 1 2 4-MeOC6H4 8{11} E [M]+ 362.1366 362.1354 99 67c
3{143} 1 2 4-Me2NC6H4 8{1} E [M]+ 345.1576 345.1583 99 73c
3{144} 1 2 4-Me2NC6H4 8{6} E [M]+ 442.2468 442.2470 97 35
3{145} 1 2 4-Me2NC6H4 8{11} E [M]+ 375.1682 375.1691 >99 85c
3{146} 2 2 4-Me2NC6H4 8{1} E [M]+ 359.1733 359.1737 >99 76c
3{147} 2 2 4-Me2NC6H4 8{11} E [M]+ 389.1838 389.1841 >99 81c
3{148} 2 2 4-Me2NC6H4 8{12} E [M]+ 403.1995 403.2002 97 77c
3{149} 2 2 3-MeOC6H4 8{1} E [M]+ 346.1416 346.1423 >99 72c
3{150} 2 2 4-MeOC6H4 8{1} E [M]+ 346.1416 346.1423 99 81c
3{151} 2 2 4-MeOC6H4 8{11} E [M]+ 376.1522 376.1534 >99 76c
3{152} 2 2 4-MeOC6H4 8{12} E [M]+ 390.1679 390.1688 >99 74c
3{153} 2 2 4-MeOC6H4 8{13} E [M]+ 404.1835 404.1838 >99 68c
3{154} 2 2 4-MeOC6H4 8{14} E [M]+ 418.1992 418.2005 99 72c
3{155} 2 2 3-thiophenyl 8{1} E [M]+ 308.0718 308.0725 99 71c
3{156} 2 2 3-thiophenyl 8{1} E [M]+ 322.0875 322.0880 99 68c
3{157} 2 2 3-thiophenyl 8{11} E [M]+ 352.0981 352.0985 >99 78
3{158} 2 2 4-NCC6H4 8{12} E [M]+ 385.1525 385.1534 98 66c
3{159} 2 2 1-cyclohexenyl 8{1} E [M]+ 320.1624 320.1632 - 71c
3{160} 2 2 1-cyclohexenyl 8{11} E [M]+ 350.1729 350.1737 - 82c
3{161} - 2 C6H5 8{11} E [M]+ 348.1573 348.1580 - 37c
3{162} - 2 4-MeOC6H4 8{1} E [M]+ 348.1573 348.1580 99 82c
3{163} - 2 4-MeOC6H4 8{11} E [M]+ 378.1679 378.1686 99 82c
3{164} - 2 4-MeOC6H4 8{14} E [M]+ 420.2148 420.2158 >99 82c
Open in a new tab
a

UV purity determined at 214 nm after preparative HPLC.

b

Isolated yield after preparative HPLC.

c

Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information).

Scheme 5.

Scheme 5

Open in a new tab

Sonogashira Coupling Using the Acetoxy-Containing 3-Iodofurans 2{19–21} to Form Alkyne-Containing Furans 3{106–110}

We have used Lipinski’s rule of five as a general guide for bioavailability, because compounds with poor bioavailability face more of a challenge in becoming successful clinical candidates. The distributions of molecular weight, clogP, hydrogen donors, hydrogen acceptors, and rotatable bonds for the synthesis library derived from 3{1–164} are shown in Figure 4. The molecular weight (less than 500), clogP (less than 5), number of hydrogen bond donors (less than 5 H) and acceptors (less than 10 H), and the number of rotatable bonds (less than 10) have been calculated for each of the library members using the SYBYL program.20 As can be seen by viewing the data, most of the key parameters for members of the library within the range of those predicted for biologically active furan candidates.

Figure 4.

Figure 4

Open in a new tab

Distribution of physicochemical and structural properties across the library entries

CONCLUSIONS

In summary, we have designed a novel multisubstituted furan library, which has been rapidly constructed by solution-phase synthesis utilizing iodocyclization and palladium-catalyzed couplings. Various substituent 3-iodofurans 2 have been easily prepared through the iodocyclization of 2-(1-alkynyl)-2-alken-1-ones using I2 as the electrophile in the presence of various nucleophiles. The multisubstituted furans 3 have been synthesized by palladium-catalyzed couplings, such as Suzuki-Miyaura, Sonogashira, Heck, aminocarbonylation and carboalkoxylation chemistry, on a diverse set of 3-iodofuran 2 building blocks, which has provided about 20+ mg pure samples of each library compound. The elaborated multisubstituted furan 3 library members have been added to the collection of the Kansas University NIH Center for Chemical Methodologies and Library Development (KU CMLD) and will be submitted to the National Institutes of Health Molecular Library Screening Center Network (MLSCN) for evaluation by a broad range of assays. We expect this basic methodology to find extensive application in the fields of combinatorial chemistry, diversity-oriented synthesis and drug discovery.

EXPERIMENTAL PROCEDURES

General Procedure for Sonogashira Coupling to Form the 2-(1-Alkynyl)-2-alken-1-ones 1{1–13}

The desired products 1 were prepared by a literature procedure.42 The appropriate 2-iodo-2-alken-1-one53 (10.0 mmol), 2 mol % PdCl2(PPh3)2, 2 mol % CuI and the terminal alkyne (15.0 mmol) were added to THF (50 mL) at 0 °C and then diisopropylamine (3.0 equiv) was added. The reaction mixture was stirred for 1 h at 0 °C and allowed to warm to room temperature to complete the reaction, which was monitored by TLC analysis. After the reaction was over, the resulting mixture was diluted with EtOAc (2 × 200 mL). The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding 2-(1-alkynyl)-2-alken-1-ones 1.

Alkyne [1{1}]

The product was obtained as a pale red solid (92% yield): mp = 99–100 °C (uncorrected); 1H NMR (400 MHz, CDCl3) δ 2.41–2.47 (m, 2H), 2.66–2.73 (m, 2H), 3.77 (s, 3H), 6.84 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.77 (t, J = 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 27.3, 34.0, 55.2, 78.8, 95.6, 113.9 (×2), 114.4, 129.9, 133.2 (×2), 159.9, 164.6, 205.6.

General Procedure for I2-Induced Cyclization to the 3-Iodofurans 2{1–34}

The iodofurans 2 were prepared by a modified literature procedure.40, 42 To a mixture of the 2-(1-alkynyl)-2-alken-1-one 1 (2.0 mmol), I2 (4.0 mmol), and NaHCO3 (4.0 mmol) was added a solution of the appropriate diol (8.0 mmol) in MeCN (20 mL). The resulting mixture was stirred at room temperature for 0.5 h, unless otherwise specified. The reaction was monitored by TLC to establish completion. The mixture was diluted with EtOAc (250 mL). The excess I2 was removed by washing with satd aq Na2S2O3. The combined organic layers were dried over anhydrous MgSO4 and concentrated under a vacuum to yield the crude product, which was purified by flash chromatography on silica gel using EtOAc/hexanes as the eluent to afford the 3-iodofurans 2

3-Iodofuran [2{1}]

The product was obtained as a pale yellow oil (42% yield): 1H NMR (400 MHz, CDCl3) δ 1.87 (d, J = 5.5 Hz, 1 H), 2.28–2.35 (m, 1 H), 2.66–2.73 (m, 1 H), 2.85–2.94 (m, 1 H), 2.98–3.05 (m, 1 H), 3.84 (s, 3 H), 5.08 (br s, 1 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.83 (d, J = 8.9 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 24.0, 38.7, 55.5, 57.1, 69.8, 114.0 (×2), 123.8, 127.8 (×2), 134.1, 156.0, 159.6, 160.5; HRMS calcd for C14H13IO3 [M]+, 355.9909, found 355.9919.

General procedure for Suzuki-Miyaura coupling to prepare furans 3{1–27, 52–60, 78–81, 123–128}

To a 4 dram vial was added the 3-iodofuran 2 (0.2 mmol), boronic acid (0.3 mmol), K2CO3 (0.5 mmol) and 10 mol % Pd(PPh3)4 in 20:5:1 toluene/ethanol/H2O (20 mL). The solution was vigorously stirred for 5 min at room temperature, flushed with argon, and then heated to 80 °C for 12 h. Upon cooling to room temperature, the resulting reaction mixture was extracted with EtOAc. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the heteroatom ring-containing furans 3.

Heteroatom ring-containing furan [3{1}]

The product was obtained as slightly yellow solid (74% yield): 1H NMR (400 MHz, CDCl3) δ 2.33–2.38 (m, 1 H), 2.65–2.71 (m, 1 H), 2.86–3.04 (m, 2 H), 3.43 (s, 3 H), 3.80 (s, 3 H), 4.44 (s, 2 H), 5.17 (d, J = 6.6 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 23.6, 39.6, 55.4, 58.6, 69.6, 74.8, 114.1 (×2), 118.7, 124.7, 128.2 (×2), 128.3 (×2), 128.9 (×2), 130.6, 133.1, 136.9, 153.4, 159.2, 160.3; HRMS calcd for C22H22O4 [M+H]+, 350.1518, found 351.1530.

General procedure for Sonogashira coupling to prepare furans 3

Method A (using Et2NH and DMF): the 3-iodofurans 2 (0.2 mmol), the alkynes 5 (0.24 mmol), 3 mol % PdCl2(PPh3)2, 6 mol % CuI, DMF (1.5 mL) and Et2NH (1.5 mL) were mixed in a 0.5–2.0 mL Biotage microwave vial equipped with a magnetic stirrer. The vessel was placed in the microwave reactor and irradiated to ramp the temperature from room temperature to 100 °C and then held at that temperature for 20 min. The mixture was then cooled down and diluted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by either column chromatography or preparative HPLC to afford the corresponding furans 3{28–40, 61–71, 82–93, 104–105, 129–139}.

Method B (using (S)-prolinol and DMF/H2O): to a 4 dram vial was added the 3-iodofurans 2{19–21} (0.2 mmol), alkynes 5 (0.24 mmol), 5 mol % PdCl2(PPh3)2, 10 mol % CuI, (S)-prolinol (0.6 mmol), and DMF-H2O (v/v, 5:1, 1.2 mL). The solution was stirred at room temperature, flushed with argon, and then heated to 70 °C for 3 h. Upon cooling to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by preparative HPLC to afford the corresponding furans 3{106–110}.

Alkyne-containing furan [3{105}]

The product was obtained as a pale yellow oil that solidified upon standing to an ivory solid (63% yield): 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz, 3H), 1.57–1.66 (m, 2H), 2.35–2.46 (m, 1H), 2.59–2.69 (m, 1H), 2.75–2.98 (m, 3H), 3.00 (s, 6H), 3.46–3.57 (m, 1H), 3.71 (s, 3H), 4.86 (d, J = 6.9 Hz, 1H), 6.72 (d, J = 8.9 Hz, 2H), 7.41–7.56 (m, 2H), 7.90 (d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 11.0, 23.5, 23.8, 32.4, 36.2, 40.5 (×2), 70.9, 76.1, 90.8, 97.4, 112.1 (×2), 119.6, 126.2 (×2), 128.6, 128.7, 129.6, 132.3, 132.4, 150.3, 159.7, 161.0; HRMS calcd for C24H27N3O2 [M+H]+, 389.2103, found 390.2172.

General procedure for Heck coupling to prepare the furans 3{41–43}

To a 4 dram vial was added the appropriate 3-iodofuran 2 (1.0 mmol), the styrene 6 (1.2 mmol), 5 mol % Pd(OAc)2, n-Bu4NI (1.0 mmol), Na2CO3 (2.5 mmol) and DMF (1.5 mL). The solution was stirred at room temperature and flushed with argon, and then heated to 80 °C until TLC revealed complete conversion of the starting material. The solution was allowed to cool and diluted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by either column chromatography or preparative HPLC to afford the olefin-containing furans 3.

Olefin-containing furan [3{41}]

The product was obtained as a pale yellow oil that solidified upon standing to an ivory solid (43% yield): 1H NMR (400 MHz, CDCl3) δ 1.78 (d, J = 5.5 Hz, 1 H), 2.30 (s, 3 H), 2.34–2.45 (m, 1 H), 2.62–2.74 (m, 1 H), 2.91–3.05 (m, 2 H), 3.86 (s, 3 H), 5.32 (br s, 1 H), 6.99 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H), 7.07–7.18 (m, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H); HRMS calcd for C24H22O5 [M+H]+, 390.1467, found 391.1480.

General procedure for aminocarbonylation to prepare furans 3{72, 94–96, 140–141}

A mixture of the appropriate 3-iodofurans 2 (0.8–1.2 mmol), 10 mol % Pd(OAc)2, 20 mol % PPh3, TEA (2.0 equiv), and the amine (1.5 equiv) in DMF (1.0 mL) was flushed with an atmosphere of carbon monoxide for 2 min. The solution was stirred at room temperature and then heated to 80 °C until TLC revealed complete conversion of the starting material. Then, the solution was allowed to cool and diluted with EtOAc. The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by either column chromatography or preparative HPLC to afford the corresponding amide-containing furans 3.

General procedure for carboalkoxylation to prepare furans 3{44–51, 73–77, 97–103, 111–122, 142–164}

A stirred mixture of the appropriate 3-iodofuran 2 (0.10 mmol), 10 mol % Pd(OAc)2, 20 mol % PCy3, TEA (0.40 mmol), and excess R4OH (0.50–1.0 mmol) in DMF (2.0 mL) was charged in a 50 mL long flask at room temperature. The mixture was flushed with CO gas for 2 min, and the flask was fitted with a balloon of CO gas. The reaction mixture was heated at 110 °C with vigorous stirring. Upon cooling to room temperature, the resulting reaction mixture was extracted with EtOAc (2 × 20 mL). The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the ester-containing furans 3.

Ester-containing furan [3{111}]

The product was obtained as a pale yellow oil that solidified upon standing to an ivory solid (53% yield): 1H NMR (400 MHz, CDCl3) δ 1.77–2.02 (m, 3H), 2.03–2.11 (m, 1H), 2.04 (s, 3H), 2.54–2.63 (m, 1H), 2.73–2.81 (m, 1H), 3.75 (s, 3H), 3.85 (s, 3H), 6.17 (br s, 1H), 6.94 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 18.3, 21.5, 23.1, 29.3, 51.6, 55.5, 65.5, 111.3, 113.7 (×2), 117.2, 122.7, 130.2 (×2), 154.0, 157.7, 160.6, 164.3, 170.5; HRMS calcd for C19H20O6 [M+H]+[–C2H4O2], 344.1260, found 285.1116.

Supplementary Material

1_si_001
2_si_002

Table 3.

Library Data for Compounds 3{52–77}

graphic file with name nihms380579u4.jpg
product 3 n R3 building blocks method ion HRMS calcd for HRMS found HRMS purity (%)a yield (%)b
3{52} 2 4-MeOC6H4 4{2} A [M+H]+[-CH4O] 378.1831 347.1636 95 66c
3{53} 2 4-MeOC6H4 4{3} A [M+H]+ 392.1624 393.1683 >99 58
3{54} 2 4-MeOC6H4 4{4} A [M+H]+ 382.1580 383.1592 99 52
3{55} 2 4-MeOC6H4 4{6} A [M+H]+ 392.1624 393.1695 84 20
3{56} 2 4-MeOC6H4 4{8} A [M+H]+ 370.1380 371.1390 99 61
3{57} 2 4-MeOC6H4 4{13} A [M+H]+ 392.1624 393.1713 95 17
3{58} 2 3,5-(MeO)2C6H4 4{15} A [M+H]+ 395.1733 396.1745 96 38
3{59} 2 4-Me2NC6H4 4{2} A [M+H]+[-CH4O] 391.2147 360.1955 69 52
3{60} 2 4-Me2NC6H4 4{18} A [M+Na]+ 365.1627 388.1609 92 12
3{61} 1 4-Me2NC6H4 5{2} B [M+H]+ 325.1678 376.1744 66 28
3{62} 1 4-Me2NC6H4 5{4} B [M+H]+ 353.1991 354.2057 81 55c
3{63} 1 4-Me2NC6H4 5{5} B [M+H]+ 339.1834 340.1904 76 61
3{64} 2 4-MeOC6H4 5{1} B [M+H]+ 312.1362 313.1434 >99 12
3{65} 2 4-MeOC6H4 5{4} B [M+H]+ 354.1831 355.1899 >99 16
3{66} 2 4-MeOC6H4 5{5} B [M+H]+ 340.1675 341.1763 99 27
3{67} 2 4-MeOC6H4 5{6} B [M+H]+ 380.1988 381.2058 99 22
3{68} 2 3,5-(MeO)2C6H4 5{2} B [M+H]+ 392.1736 393.1749 99 58
3{69} 2 3-thiophenyl 5{1} B [M+H]+ 288.0820 289.0907 99 77c
3{70} 2 4-Me2NC6H4 5{2} B [M+H]+ 339.1834 340.1902 97 51
3{71} 2 4-Me2NC6H4 5{4} B [M+H]+[-CH4O] 367.2147 336.1952 67 43
3{72} 2 4-MeOC6H4 7{2} D [M+H]+ 399.2158 400.2166 93 36
3{73} 1 4-Me2NC6H4 8{1} E [M+H]+ 315.1471 316.1541 34 11
3{74} 1 4-Me2NC6H4 8{2} E [M+H]+ 329.1627 330.1693 >99 61c
3{75} 2 4-MeOC6H4 8{2} E [M+H]+ 330.1467 331.1529 99 20
3{76} 2 4-Me2NC6H4 8{1} E [M+H]+ 329.1627 330.1694 89 25
3{77} 2 4-Me2NC6H4 8{2} E [M+H]+[-CH4O] 343.1784 312.1588 69 14
Open in a new tab
a

UV purity determined at 214 nm after preparative HPLC.

b

Isolated yield after preparative HPLC

c

Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information).

Table 4.

Library Data for Compounds 3{78–105}

graphic file with name nihms380579u5.jpg
product 3 n R3 building blocks method ion HRMS calcd for HRMS found HRMS purity (%)a yield (%)b
3{78} 1 3-thiophenyl 4{2} A [M+H]+ 354.1290 355.1298 95 63d
3{79} 1 3-thiophenyl 4{6} A [M+H]+ 368.1082 369.1141 86 21d
3{80} 1 3-thiophenyl 4{18} A [M+H]+ 328.0769 329.0850 97 6
3{81} 2 3-thiophenyl 4{17} A [M+H]+ 356.1195 357.1254 99 68d
3{82} 1 3-thiophenyl 5{1} B [M+H]+ 288.0820 289.0828 96 48
3{83} 1 3-thiophenyl 5{4} B [M+H]+[-C2H6O]c 330.1290 285.0941 >99 67
3{84} 1 3-thiophenyl 5{5} B [M+H]+ 316.1133 317.1202 99 55
3{85} 2 4-MeOC6H4 5{2} B [M+H]+ 340.1675 341.1734 >99 53d
3{86} 2 4-MeOC6H4 5{5} B [M+H]+ 354.1831 355.1901 >99 39
3{87} 2 4-MeOC6H4 5{11} B [M+Na]+ 373.1678 396.1560 97 26
3{88} 2 4-Me2NC6H4 5{4} B [M+H]+ 381.2304 382.2365 72 30
3{89} 2 4-Me2NC6H4 5{7} B [M+H]+ 406.2620 407.2629 83 22
3{90} 2 3-MeOC6H4 5{1} B [M+H]+ 326.1518 327.1603 68 14
3{91} 2 3-MeOC6H4 5{4} B [M+H]+ 368.1988 369.2079 97 17
3{92} 2 3-MeOC6H4 5{7} B [M+H]+ 393.2304 394.2380 96 28
3{93} 2 3-thiophenyl 5{5} B [M+H]+ 330.1290 331.1366 86 25
3{94} 2 4-MeOC6H4 7{1} D [M+H]+ 400.1998 401.2061 85 6
3{95} 2 4-MeOC6H4 7{2} D [M+H]+ 413.2315 414.2388 >99 56
3{96} 2 4-MeOC6H4 7{3} D [M+H]+ 387.2046 388.2115 96 31
3{97} 1 3-thiophenyl 8{1} E [M+H]+[-C2H6O] 292.0769 247.0418 >99 62
3{98} 1 3-thiophenyl 8{8} E [M+H]+ 428.1294 429.1366 98 12
3{99} 1 3-thiophenyl 8{9} E [M+H]+[-C2H6O] 412.1344 367.0993 92 8
3{100} 2 4-MeOC6H4 8{1} E [M+H]+[-C2H6O] 330.1467 285.1119 >99 78
3{101} 2 4-MeOC6H4 8{2} E [M+Na]+ 344.1624 367.1498 97 62d
3{102} 2 4-Me2NC6H4 8{1} E [M+H]+[-CH4O] 343.1784 312.1580 92 39
3{103} 2 4-Me2NC6H4 8{2} E [M+H]+ 357.1940 358.1995 87 66
3{104} 1 4-Me2NC6H4 5{4} B [M+H]+ 381.2303 382.2389 74 8
3{105} 1 4-Me2NC6H4 5{12} B [M+H]+ 389.2103 390.2172 76 63d
Open in a new tab
a

UV purity determined at 214 nm after preparative HPLC.

b

Isolated yield after preparative HPLC.

c

Isotope: [A+(−45)]

d

Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information).

Table 5.

Library Data for Compounds 3{106–122}

graphic file with name nihms380579u6.jpg
product 3 n R3 building blocks method ion HRMS calcd for HRMS found HRMS purity (%)a yield (%)b
3{106} 1 4-MeOC6H4 5{2} B [M+H]+ 340.1311 341.1320 >99 23
3{107} 1 4-MeOC6H4 5{6} B [M+H]+[-C2H4O2] 394.1780 335.1642 99 34
3{108} 1 4-MeOC6H4 5{7} B [2M+H]+ 393.1940 787.3894 98 16
3{109} 2 4-MeOC6H4 5{6} B [M+H]+[-C2H4O2] 408.1937 349.1797 98 43
3{110} 2 3-MeOC6H4 5{9} B [2M+H]+ 401.1627 803.3313 >99 31
3{111} 2 4-MeOC6H4 8{1} E [M+H]+[-C2H4O2] 344.1260 285.1116 98 53c
3{112} 2 4-MeOC6H4 8{2} E [M+Na]+ 358.1416 381.1305 98 38
3{113} 2 4-MeOC6H4 8{5} E [M+Na]+ 400.1886 423.1766 >99 46c
3{114} 2 4-MeOC6H4 8{9} E [M+NH4]+ 464.1835 482.2159 95 11
3{115} 2 4-MeOC6H4 8{7} E [M+Na]+ 443.1944 466.1744 96 44
3{116} 2 3-MeOC6H4 8{1} E [M+H]+[-C2H4O2] 344.1260 285.1116 98 26
3{117} 2 3-MeOC6H4 8{2} E [M+Na]+ 358.1416 381.1312 69 47
3{118} 2 3-thiophenyl 8{1} E [M+H]+[-C2H4O2] 320.0718 261.0576 98 41
3{119} 2 3-thiophenyl 8{2} E [M+H]+[-C2H4O2] 334.0875 275.0731 >99 34
3{120} 2 3-thiophenyl 8{3} E [M+Na]+ 376.1344 399.1223 >99 28
3{121} 2 3-thiophenyl 8{7} E [M+Na]+ 419.1403 442.1203 97 33
3{122} 2 3-thiophenyl 8{9} E [M+NH4]+ 440.1294 458.1622 98 28c
Open in a new tab
a

UV purity determined at 214 nm after preparative HPLC.

b

Isolated yield after preparative HPLC

c

Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the Supporting Information).

Acknowledgments

Funding Sources

Financial support of this work was provided by the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Center of Excellence for Chemical Methodologies and Library Development (GM069663).

We thank Johnson Matthey, Inc. and Kawaken Fine Chemicals Co. Ltd. for donations of palladium catalysts; and Frontier Scientific and Synthonix for donations of boronic acids.

Footnotes

Supporting Information. Synthetic methods, spectral assignments, and copies of 1H and 13C NMR spectra for all previously unreported starting materials and products. This material is available free of charge via the Internet at http://pubs.acs.org.

References

  • 1.Steven AS. High-throughput and ultra-high-throughput screening: solution- and cell-based approaches. Curr Opin Biotechnol. 2000;11:47–53. doi: 10.1016/s0958-1669(99)00051-8. [DOI] [PubMed] [Google Scholar]
  • 2.Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci USA. 2006;103:11473–11478. doi: 10.1073/pnas.0604348103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Donnelly DMX, Meegan MJ. In: Comprehensive Heterocyclic Chemistry. Katritzky AR, Rees CW, editors. Vol. 4. Pergamon; Oxford: 1984. pp. 657–712. [Google Scholar]
  • 4.Lipshutz BH. Five-membered heteroaromatic rings as intermediates in organic synthesis. Chem Rev. 1986;86:795–819. [Google Scholar]
  • 5.Bird CW. Five-Membered Ring Systems: Furans and Benzo Derivatives. Prog Heterocyclic Chem. 1990;2:87–101. [Google Scholar]
  • 6.Brown TH, Armitage MA, Blakemore RC, Blurton P, Durant GJ, Ganellin CR, Ife RJ, Parsons ME, Rawlings DA, Slingsby BP. Isocytosine H2-receptor histamine antagonists. III. The synthesis and biological activity of lupitidine (SK&F 93479) and related compounds. Eur J Med Chem. 1990;25:217–226. [Google Scholar]
  • 7.Friedrichsen W, Pagel K. Five-Membered Ring Systems: Furans and Benzo Derivatives. Prog Heterocyclic Chem. 1995;7:130–147. [Google Scholar]
  • 8.Keay BA, Dibble PW. In: Comprehensive Heterocyclic Chemistry II. Katritzky AR, Rees CW, Scriven EFV, editors. Vol. 2. Elsevier; Oxford: 1997. pp. 395–436. [Google Scholar]
  • 9.Hou XL, Cheung HY, Hon TY, Kwan PL, Lo TH, Tong SY, Wong HNC. Regioselective syntheses of substituted furans. Tetrahedron. 1998;54:1955–2020. [Google Scholar]
  • 10.Greve SRS, Friedrichsen W. Five-Membered Ring Systems: Furans Benzofurans. Prog Heterocyclic Chem. 1998;10:129–152. [Google Scholar]
  • 11.Hou XL, Yang Z, Wong HNC. In: Progress in Heterocyclic Chemistry. Gribble GW, Gilchrist TL, editors. Vol. 15. Pergamon; Oxford: 2003. pp. 167–205. [Google Scholar]
  • 12.Kazlauskas R, Murphy PT, Wells RJ, Daly JJ, Schönholzer P. Two sesquiterpene furans with new carbocyclic ring systems and related thiol acetates from a species of the sponge genus dysidea. Tetrahedron Lett. 1978;19:4951–4954. [Google Scholar]
  • 13.Vaillancourt V, Agharahimi MR, Sundram UN, Richou O, Faulkner DJ, Albizati KF. Synthesis and absolute configuration of the antiparasitic furanosesquiterpenes (−)-furodysin and (−)-furodysinin. Camphor as a six-membered ring chiral pool template. J Org Chem. 1991;56:378–387. [Google Scholar]
  • 14.Guella G, Mancini I, Guerriero A, Pietra F. New furano-sesquiterpenoids from Mediterranean sponges. Helv Chim Acta. 1985;68:1276–1282. [Google Scholar]
  • 15.Horton P, Inman WD, Crews P. Enantiomeric relationships and anthelmintic activity of dysinin derivatives from Dysidea marine sponges. J Nat Prod. 1990;53:143–151. [Google Scholar]
  • 16.Asakawa Y. “Chemical Constituents of Hepaticae”, Progress in the Chemistry of Organic Natural Products. Springer-Verlag Wien; New York: 1982. p. 42. [Google Scholar]
  • 77.Wada K, Munakata K. Insect feeding inhibitors in plants. III. Feeding inhibitory activity of terpenoids in plants. Agric Biol Chem. 1971;35:115–118. [Google Scholar]
  • 18.Asakawa Y, Aratani T. Sesquiterpenes of Porella vernicosa (Hepaticae) Bull Soc Chim Fr. 1976:1469–1470. [Google Scholar]
  • 19.Poklis A, Hall KV, Still J, Binder SR. Ranitidine Interference with the Monoclonal EMIT d.a.u. Amphetamine/Methamphetamine Immunoassay. J Anal Toxicol. 1991;15:101–103. doi: 10.1093/jat/15.2.101. [DOI] [PubMed] [Google Scholar]
  • 20.Jakob SM, Parviainen I, Ruokonen E, Uusaro A, Takala J. Lack of effect of ranitidine on gastric luminal pH and mucosal PCO2 during the first day in the ICU. Acta Anaesth Scand. 2005;49:390–396. doi: 10.1111/j.1399-6576.2005.00651.x. [DOI] [PubMed] [Google Scholar]
  • 21.Mitchell SL, Rockwood K. The association between antiulcer medication and initiation of cobalamin replacement in older persons. J Clin Epidemiol. 2001;54:531–534. doi: 10.1016/s0895-4356(00)00340-1. [DOI] [PubMed] [Google Scholar]
  • 22.Keay BA. Synthesis of multi-substituted furan rings: the role of silicon. Chem Soc Rev. 1999;28:209–215. [Google Scholar]
  • 23.Marshall JA, Robinson ED. A mild method for the synthesis of furans. Application to 2,5-bridged furano macrocyclic compounds. J Org Chem. 1990;55:3450–3451. [Google Scholar]
  • 24.Ma S, Li L. Palladium-Catalyzed Cyclization Reaction of Allylic Bromides with 1,2-Dienyl Ketones. An Efficient Synthesis of 3-Allylic Polysubstituted Furans. Org Lett. 2000;2:941–944. doi: 10.1021/ol0055871. [DOI] [PubMed] [Google Scholar]
  • 25.Kel’i AV, Gevorgyan V. Efficient Synthesis of 2-Mono- and 2,5-Disubstituted Furans via the CuI-Catalyzed Cycloisomerization of Alkynyl Ketones. J Org Chem. 2002;67:95–98. doi: 10.1021/jo010832v. [DOI] [PubMed] [Google Scholar]
  • 26.Sromek AW, Rubina M, Gevorgyan V. 1,2-Halogen Migration in Haloallenyl Ketones: Regiodivergent Synthesis of Halofurans. J Am Chem Soc. 2005;127:10500–10501. doi: 10.1021/ja053290y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Schwier T, Sromek AW, Yap DML, Chernyak D, Gevorgyan V. Mechanistically Diverse Copper-, Silver-, and Gold-Catalyzed Acyloxy and Phosphatyloxy Migrations: Efficient Synthesis of Heterocycles via Cascade Migration/Cycloisomerization Approach. J Am Chem Soc. 2007;129:9868–9878. doi: 10.1021/ja072446m. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Dudnik AS, Sromek AW, Rubina M, Kim JT, Kel’i AV, Gevorgyan V. Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in Allenyl Systems as a New Paradigm toward Densely Functionalized Heterocycles. J Am Chem Soc. 2008;130:1440–1452. doi: 10.1021/ja0773507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Lee CF, Yang LM, Hwu TY, Feng AS, Tseng JC, Luh TY. One-Pot Synthesis of Substituted Furans and Pyrroles from Propargylic Dithioacetals. New Annulation Route to Highly Photoluminescent Oligoaryls. J Am Chem Soc. 2000;122:4992–4993. [Google Scholar]
  • 30.Luh TY. Annulation of propargylic dithioacetals leading to furan-containing oligoaryls. Pure Appl Chem. 2005;77:1213–1219. [Google Scholar]
  • 31.Qing FL, Gao WZ, Ying J. Synthesis of 3-Trifluoroethylfurans by Palladium-Catalyzed Cyclization-Isomerization of (Z)-2-Alkynyl-3-trifluoromethyl Allylic Alcohols. J Org Chem. 2000;65:2003–2006. doi: 10.1021/jo991463u. [DOI] [PubMed] [Google Scholar]
  • 32.Arimitsu S, Jacobsen JM, Hammond GB. Synthesis of 2,4,5-Trisubstituted 3-Fluorofurans via Sequential Iodocyclization and Cross-Coupling of gem-Difluorohomopropargyl Alcohols. J Org Chem. 2008;73:2886–2889. doi: 10.1021/jo800088y. [DOI] [PubMed] [Google Scholar]
  • 33.Xia Y, Dudnik AS, Gevorgyan V, Li Y. Mechanistic Insights into the Gold-Catalyzed Cycloisomerization of Bromoallenyl Ketones: Ligand-Controlled Regioselectivity. J Am Chem Soc. 2008;130:6940–6941. doi: 10.1021/ja802144t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Zhang X, Lu Z, Fu C, Ma S. Synthesis of Polysubstituted Furans Based on a Stepwise Sonogashira Coupling of (Z)-3-Iodoalk-2-en-1-ols with Terminal Propargylic Alcohols and Subsequent Au(I)- or Pd(II)-Catalyzed Cyclization-Aromatization via Elimination of H2O. J Org Chem. 2010;75:2589–2598. doi: 10.1021/jo100146p. [DOI] [PubMed] [Google Scholar]
  • 35.Godoi B, Schumacher RF, Zeni G. Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes Containing Heteroatom. Chem Rev. 2011;111:2937–2980. doi: 10.1021/cr100214d. [DOI] [PubMed] [Google Scholar]
  • 36.Fukuda Y, Shiragami H, Utimoto K, Nozaki H. Synthesis of substituted furans by palladium-catalyzed cyclization of acetylenic ketones. J Org Chem. 1991;56:5816–5819. [Google Scholar]
  • 37.Bossharth E, Desbordes P, Monteiro N, Balme G. Palladium-Mediated Three-Component Synthesis of Furo[2,3-b]pyridones by One-Pot Coupling of 3-Iodopyridones, Alkynes, and Organic Halides. Org Lett. 2003;5:2441–2444. doi: 10.1021/ol034644y. [DOI] [PubMed] [Google Scholar]
  • 38.Yao T, Zhang X, Larock RC. AuCl3-Catalyzed Synthesis of Highly Substituted Furans from 2-(1-Alkynyl)-2-alken-1-ones. J Am Chem Soc. 2004;126:11164–11165. doi: 10.1021/ja0466964. [DOI] [PubMed] [Google Scholar]
  • 39.Zeni G, Larock RC. Synthesis of Heterocycles via Palladium π-Olefin and π-Alkyne Chemistry. Chem Rev. 2004;104:2285–2310. doi: 10.1021/cr020085h. [DOI] [PubMed] [Google Scholar]
  • 40.Yao T, Zhang X, Larock RC. Synthesis of Highly Substituted Furans by the Electrophile-Induced Coupling of 2-(1-Alkynyl)-2-alken-1-ones and Nucleophiles. J Org Chem. 2005;70:7679–7685. doi: 10.1021/jo0510585. [DOI] [PubMed] [Google Scholar]
  • 41.Sniady A, Wheeler KA, Dembinski R. 5-Endo-Dig Electrophilic Cyclization of 1,4-Disubstituted But-3-yn-1-ones: Regiocontrolled Synthesis of 2,5-Disubstituted 3-Bromo- and 3-Iodofurans. Org Lett. 2005;7:1769–1772. doi: 10.1021/ol050372i. [DOI] [PubMed] [Google Scholar]
  • 42.Cho CH, Larock RC. Highly Substituted Lactone/Ester-Containing Furan Library by the Palladium-Catalyzed Carbonylation of Hydroxyl-Substituted 3-Iodofurans. ACS Comb Sci. 2011;13:272–279. doi: 10.1021/co100088q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Cho CH, Larock RC. A convenient synthetic route to furan esters and lactones by palladium-catalyzed carboalkoxylation or cyclocarbonylation of hydroxyl-substituted 3-iodofurans. Tetrahedron Lett. 2010;51:3417–3421. doi: 10.1016/j.tetlet.2010.04.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Cho CH, Jung DI, Neuenswander B, Larock RC. Parallel Synthesis of a Desketoraloxifene Analogue Library via Iodocyclization/Palladium-Catalyzed Coupling. ACS Comb Sci. 2011;13:501–510. doi: 10.1021/co200090p. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Waldo JP, Mehta S, Neuenswander B, Lushington GH, Larock RC. Solution Phase Synthesis of a Diverse Library of Highly Substituted Isoxazoles. J Comb Chem. 2008;10:658–663. doi: 10.1021/cc800055x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Cho CH, Neuenswander B, Lushington GH, Larock RC. Parallel Synthesis of a Multi-Substituted Benzo[b]furan Library. J Comb Chem. 2008;10:941–947. doi: 10.1021/cc800120y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Cho CH, Neuenswander B, Lushington GH, Larock RC. Solution-Phase Parallel Synthesis of a Multi-substituted Benzo[b]thiophene Library. J Comb Chem. 2009;11:900–906. doi: 10.1021/cc9000604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Roy S, Roy S, Neuenswander B, Hill D, Larock RC. Solution-Phase Synthesis of a Diverse Isocoumarin Library. J Comb Chem. 2009;11:1128–1135. doi: 10.1021/cc9001197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Cho CH, Neuenswander B, Larock RC. Diverse Methyl Sulfone-Containing Benzo[b]thiophene Library via Iodocyclization and Palladium-Catalyzed Coupling. J Comb Chem. 2010;12:278–285. doi: 10.1021/cc900172u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Markina NA, Mancuso R, Neuenswander B, Lushington GH, Larock RC. Solution-Phase Parallel Synthesis of a Diverse Library of 1,2-Dihydroisoquinolines. ACS Comb Sci. 2011;13:265–271. doi: 10.1021/co1000794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Worlikar SA, Neuenswander B, Lushington GH, Larock RC. Highly Substituted Indole Library Synthesis by Palladium-Catalyzed Coupling Reactions in Solution and on a Solid Support. J Comb Chem. 2009;11:875–879. doi: 10.1021/cc900057n. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Lipinski CA, Lombardo F, Dominay BW, Feeney PJ. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv Drug Delivery Rev. 1997;23:3–25. doi: 10.1016/s0169-409x(00)00129-0. [DOI] [PubMed] [Google Scholar]
  • 53.Krafft ME, Cran JW. A Convenient Protocol for the α-Iodination of α,β-Unsaturated Carbonyl Compounds with I2 in an Aqueous Medium. Synlett. 2005:1263–1266. [Google Scholar]
  • 54.Batchu VR, Subramanian V, Parasuraman K, Swamy NK, Kumar S, Pal M. Pd/C-mediated coupling of aryl halides with terminal alkynes in water. Tetrahedron. 2005;61:9869–9877. [Google Scholar]
  • 55.SYBYL, version 8.0. The Tripos Associate; St. Louis, MO: 2007. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1_si_001
NIHMS380579-supplement-1_si_001.msw (8.6MB, msw)
2_si_002
NIHMS380579-supplement-2_si_002.pdf (4.4MB, pdf)

RESOURCES