Solution-phase synthesis of a highly substituted furan library

Article abstract of DOI:10.1021/co300040q

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 presen

Full text of DOI:10.1021/co300040q

Research Article
pubs.acs.org/acscombsci
Solution-Phase Synthesis of a Highly Substituted Furan Library
Chul-Hee Cho,† Feng Shi,† Dai-Il Jung,†,‡ Benjamin Neuenswander,§ Gerald H. Lushington,§
and Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
‡Department of Chemistry, Dong-A University, Saha-Gu, Busan 604-714, Korea
§NIH Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, Lawrence, Kansas 66047,
United States
S
* Supporting Information
ABSTRACT: 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 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 pharmaceuti-
cally important substances, and they are also important building
blocks in organic synthesis.3−11 Selected simple biologically
Figure 1. Examples of significant furan-containing natural products and
pharmaceuticals.
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 gastresophageal reflux disease (GERD). Ranitidine is
also known to give false positives for methamphetamine on drug
tests.19−21
Scheme 1. Efficient Synthesis of Multisubstituted Furans by
Electrophilic Cyclization of 2-(1-Alkynyl)-2-alken-1-ones in
the Presence of Various Nucleophiles
For these reasons, the efficient synthesis of multiply
substituted furans continues to attract the interest of synthetic
Received: April 9, 2012
Revised: May 17, 2012
Published: May 21, 2012
© 2012 American Chemical Society
403
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ACS Combinatorial Science
Research Article
Scheme 2. Library Design for the Tetrasubstituted Furans 3
a
Table 1. Library Data for the 3-Iodofurans 2{1−34}
b
b
entry
alkyne 1
NuH
H2O
iodofuran 2
yield (%)
42
entry
alkyne 1
NuH
iodofuran 2
yield (%)
1
1{1}
1{2}
1{3}
1{4}
1{5}
1{6}
1{7}
1{3}
1{8}
1{6}
1{7}
1{9}
1{2}
1{8}
1{5}
1{7}
1{9}
2{1}
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
1{3}
1{8}
1{1}
1{5}
1{7}
1{1}
1{3}
1{4}
1{8}
1{7}
1{9}
1{10}
1{11}
1{12}
1{13}
1{4}
1{4}
n-C3H7OH
2{18}
2{19}
2{20}
2{21}
2{22}
2{23}
2{24}
2{25}
2{26}
2{27}
2{28}
2{29}
2{30}
2{31}
2{32}
2{33}
2{34}
49
85
82
77
69
86
66
83
82
82
87
89
82
81
84
77
65
c
2
H2O
2{2}
53
CH3COOH
3
H2O
2{3}
78
89
73
47
68
53
73
59
CH3COOH
4
H2O
2{4}
CH3COOH
5
H2O
2{5}
CH3COOH
6
H2O
2{6}
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)4OH
HO(CH2)5OH
7
H2O
2{7}
8
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
2{8}
9
2{9}
10
11
12
13
14
15
16
17
2{10}
2{11}
2{12}
2{13}
2{14}
2{15}
2{16}
2{17}
c
77
87
73
77
87
66
82
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
b
c
MeCN (0.1 M conc.) at room temperature for 0.5 h. Isolated yields after column chromatography. An inseparable mixture was obtained. This
material decomposes quickly in solution.
chemists. Numerous heteroannulation protocols, including
transition metal-catalyzed reactions, leading to multisubsti-
tuted furans have been reported.9,22−35 Among the variety of
oxygen-containing compounds that can be subjected to cycliza-
tion, 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
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
Scheme 3. Preparation of 2-(1-Alkynyl)-2-alken-1-ones
1{1−13}
38
of AuCl3 or iodine40,42,43 as an electrophile to afford func-
tionally substituted furans (Scheme 1).
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
404
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ACS Combinatorial Science
Research Article
Figure 2. 3-Iodofuran Library 2{1−34}.
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.
Accordingly, a set of tetrasubstituted 3-iodofurans 2{1−34}
were efficiently prepared by electrophilic cyclization of the corre-
sponding 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 iodocycliza-
tion 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).
(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 chromato-
graphy (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 8000 unique
potential compounds in a combinatorial fashion.
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
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
405
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ACS Combinatorial Science
Research Article
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.
Scheme 4. Library Generation of Various Tetrasubstituted
Furans 3 from the 3-Iodofurans 2
a
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.
CONCLUSIONS
■
a
Method A (Suzuki−Miyaura coupling): 3{1−27,52−60,78−81,123−
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 carboal-
koxylation 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.
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 %
Scheme 5. Sonogashira Coupling Using the Acetoxy-
Containing 3-Iodofurans 2{19−21} to Form Alkyne-
Containing Furans 3{106−110}
EXPERIMENTAL PROCEDURES
■
General Procedure for Sonogashira Coupling to Form
the 2-(1-Alkynyl)-2-alken-1-ones 1{1−13}. The desired pro-
ducts 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 EtOAc/
hexanes as the eluent to afford the corresponding 2-(1-alkynyl)-2-
alken-1-ones 1.
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
Alkyne [1{1}]. The product was obtained as a pale red solid
1
(92% yield): mp =99−100 °C (uncorrected); H NMR (400
MHz, CDCl3) δ 2.41−2.47 (m, 2H), 2.66−2.73 (m, 2H), 3.77
406
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Research Article
Table 2. Library Data for Compounds 3{1−51}
a
b
product 3
n
R3
building blocks method
ion HRMS
[M + H]+
calcd for HRMS found HRMS purity (%)
yield (%)
f
3{1}
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
2
2
2
2
2
2
2
2
2
2
1
2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-Me2NC6H4
C6H5
4{2}
4{5}
4{17}
4{9}
4{10}
4{16}
4{4}
4{1}
4{9}
4{11}
4{18}
4{4}
4{6}
4{7}
4{11}
4{13}
4{14}
4{15}
4{17}
4{18}
4{8}
4{3}
4{4}
4{6}
4{14}
4{15}
4{18}
5{2}
5{2}
5{9}
5{1}
5{2}
5{5}
5{6}
5{7}
5{8}
5{10}
5{11}
5{6}
5{5}
6{3}
6{1}
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
C
C
350.1518
396.1373
338.1267
372.1031
372.0832
326.1089
367.1584
348.1362
380.1623
348.1362
308.1049
368.1424
378.1467
378.1467
362.1519
378.1467
399.0470
351.1471
352.1423
338.1143
386.1330
354.0926
344.0882
354.0926
374.9929
327.0929
314.0613
298.1205
274.0664
321.0823
298.1205
312.1362
326.1518
366.1831
365.1991
359.1521
387.1834
345.1365
396.1937
302.0977
390.1467
406.1780
351.1530
397.1388
339.1351
373.1043
373.0903
327.1175
368.1592
97
99
74
f
3{2}
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
66
3{3}
>99
99
62
f
3{4}
58
3{5}
97
19
41
52
3{6}
82
3{7}
99
f
3{8}
67
3{9}
C6H5
[2M + H]+
[M]+
[M + Na]+
[M + H]+[−H2O]
[M + H]+[−H2O]
[M + H]+[−H2O]
[M + H]+
761.3345
348.1372
331.0943
385.1464
361.1430
361.1431
363.1598
379.1553
400.0532
352.1545
353.1506
339.1222
387.1343
355.0939
345.0891
337.0890
377.9978
328.0996
337.0500
299.1275
275.0742
321.0831
299.1340
313.1434
327.1650
349.1793
366.2099
360.1620
388.1902
346.1444
379.1900
285.0938
391.1480
407.1876
>99
72
f
3{10}
3{11}
3{12}
3{13}
3{14}
3{15}
3{16}
3{17}
3{18}
3{19}
3{20}
3{21}
3{22}
3{23}
3{24}
3{25}
3{26}
3{27}
3{28}
3{29}
3{30}
3{31}
3{32}
3{33}
3{34}
3{35}
3{36}
3{37}
3{38}
3{39}
3{40}
3{41}
3{42}
C6H5
81
C6H5
98
99
61
77
39
26
c
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3,5-(MeO)2C6H3
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-MeOC6H4
3-thiophenyl
3-thiophenyl
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3,5-(MeO)2C6H4
3-thiophenyl
4-MeOC6H4
3-MeOC6H4
>99
84
f
98
75
[M + H]+
[M + H]+
99
61
13
>99
>99
78
f
[M + H]+
88
[M + H]+
41
24
56
61
53
26
23
36
12
26
3
[M + H]+
62
[M + H]+
97
[M + H]+
[M + H]+
98
97
[M + H]+[−H2O]
>99
88
[M + H]+
d
[M + H]+
92
[M + Na]+
[M + H]+
83
>99
27
[M + H]+
f
[M]+
91
67
f
[M + H]+
>99
97
78
[M + H]+
17
f
[M + H]+
>99
>99
>99
79
81
[M + H]+[−H2O]
62
23
38
14
12
51
3
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+[−H2O]
[M + H]+[−H2O]
[M + H]+
[M + H]+
[M + H]+
84
94
86
>99
72
f
43
>99
56
28
15
3{43}
3{44}
3{45}
3{46}
3{47}
3{48}
3{49}
3{50}
3{51}
2
1
1
1
2
2
2
2
2
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-Me2NC6H4
C6H5
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
6{1}
8{3}
8{5}
8{4}
8{11}
8{2}
8{4}
8{6}
8{10}
C
E
E
E
E
E
E
E
323.0980
320.1082
320.1092
358.1893
302.1154
316.1311
359.1733
399.2046
324.0988
338.1432
303.1043
359.2002
302.1160
285.1115
360.1814
400.2121
369.1418
78
>99
>99
98
[M + NH4]+
[M + H]+[−H2O]
[M + H]+
f
29
47
f
[M]+
99
73
48
e
f
[M + H]+[−CH4O]
>99
>99
99
f
[M + H]+
53
[M + H]+
71
55
f
E
[M + H]+
368.1260
>99
a
b
c
d
e
UV purity determined at 214 nm after preparative HPLC. Isolated yield after preparative HPLC. Isotope: [A+(−17)]. Isotope: [A+2]. Isotope:
f
[A+(−31)] Isolated yield after column chromatography. Isolated desired products 3 were characterized by 1H and 13C NMR spectroscopy (see the
Supporting Information).
407
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Table 3. Library Data for Compounds 3{52−77}
a
b
product 3
n
R3
building blocks method
ion HRMS
calcd for HRMS found HRMS purity (%)
yield (%)
c
3{52}
3{53}
3{54}
3{55}
3{56}
3{57}
3{58}
3{59}
3{60}
3{61}
3{62}
3{63}
3{64}
3{65}
3{66}
3{67}
3{68}
3{69}
3{70}
3{71}
3{72}
3{73}
3{74}
3{75}
3{76}
3{77}
2
2
2
2
2
2
2
2
2
1
1
1
2
2
2
2
2
2
2
2
2
1
1
2
2
2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3,5-(MeO)2C6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3,5-(MeO)2C6H4
3-thiophenyl
4-Me2NC6H4
4-Me2NC6H4
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4{2}
4{3}
4{4}
4{6}
4{8}
4{13}
4{15}
4{2}
4{18}
5{2}
5{4}
5{5}
5{1}
5{4}
5{5}
5{6}
5{2}
5{1}
5{2}
5{4}
7{2}
8{1}
8{2}
8{2}
8{1}
8{2}
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
D
E
E
E
E
E
[M + H]+[−CH4O]
378.1831
392.1624
382.1580
392.1624
370.1380
392.1624
395.1733
391.2147
365.1627
325.1678
353.1991
339.1834
312.1362
354.1831
340.1675
380.1988
392.1736
288.0820
339.1834
367.2147
399.2158
315.1471
329.1627
330.1467
329.1627
343.1784
347.1636
393.1683
383.1592
393.1695
371.1390
393.1713
396.1745
360.1955
388.1609
376.1744
354.2057
340.1904
313.1434
355.1899
341.1763
381.2058
393.1749
289.0907
340.1902
336.1952
400.2166
316.1541
330.1693
331.1529
330.1694
312.1588
95
>99
99
66
[M + H]+
58
52
20
61
17
38
52
12
28
[M + H]+
[M + H]+
84
[M + H]+
99
[M + H]+
95
[M + H]+
96
[M + H]+[−CH4O]
[M + Na]+
[M + H]+
69
92
66
81
c
[M + H]+
55
[M + H]+
76
61
12
16
27
22
58
[M + H]+
>99
>99
99
[M + H]+
[M + H]+
[M + H]+
99
[M + H]+
99
c
[M + H]+
99
77
[M + H]+
97
51
43
36
11
[M + H]+[−CH4O]
67
[M + H]+
93
[M + H]+
34
c
[M + H]+
>99
99
89
61
[M + H]+
20
25
14
[M + H]+
[M + H]+[−CH4O]
69
a
b
c
UV purity determined at 214 nm after preparative HPLC. Isolated yield after preparative HPLC. Isolated yield after column chromatography.
Isolated desired products 3 were characterized by H and 13C NMR spectroscopy (see the Supporting Information).
Table 4. Library Data for Compounds 3{78−105}
1
a
b
product 3
n
R3
building blocks method
ion HRMS
[M + H]+
calcd for HRMS found HRMS purity (%)
yield (%)
d
3{78}
3{79}
3{80}
3{81}
3{82}
3{83}
3{84}
3{85}
3{86}
3{87}
3{88}
3{89}
3{90}
3{91}
3{92}
3{93}
3{94}
3{95}
3{96}
1
1
1
2
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-thiophenyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4{2}
4{6}
4{18}
4{17}
5{1}
5{4}
5{5}
5{2}
5{5}
5{11}
5{4}
5{7}
5{1}
5{4}
5{7}
5{5}
7{1}
7{2}
7{3}
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
D
D
D
354.1290
368.1082
328.0769
356.1195
288.0820
330.1290
316.1133
340.1675
354.1831
373.1678
381.2304
406.2620
326.1518
368.1988
393.2304
330.1290
400.1998
413.2315
387.2046
355.1298
369.1141
329.0850
357.1254
289.0828
285.0941
317.1202
341.1734
355.1901
396.1560
382.2365
407.2629
327.1603
369.2079
394.2380
331.1366
401.2061
414.2388
388.2115
95
86
63
d
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+[−C2H6O]
[M + H]+
[M + H]+
[M + H]+
[M + Na]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
21
97
6
d
99
96
68
48
67
55
c
>99
99
d
>99
>99
97
53
39
26
30
22
14
17
28
25
6
72
83
68
97
96
86
85
>99
96
56
31
408
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ACS Combinatorial Science
Research Article
Table 4. continued
a
b
product 3
n
R3
building blocks method
ion HRMS
calcd for HRMS found HRMS purity (%)
yield (%)
3{97}
1
1
1
2
2
2
2
1
1
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-MeOC6H4
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
8{1}
8{8}
8{9}
8{1}
8{2}
8{1}
8{2}
5{4}
5{12}
E
E
E
E
E
E
E
B
B
[M + H]+[−C2H6O]
292.0769
428.1294
412.1344
330.1467
344.1624
343.1784
357.1940
381.2303
389.2103
247.0418
429.1366
367.0993
285.1119
367.1498
312.1580
358.1995
382.2389
390.2172
>99
98
62
12
8
3{98}
[M + H]+
3{99}
[M + H]+[−C2H6O]
[M + H]+[−C2H6O]
[M + Na]+
92
3{100}
3{101}
3{102}
3{103}
3{104}
3{105}
>99
97
78
d
62
[M + H]+[−CH4O]
92
39
66
8
[M + H]+
87
[M + H]+
74
d
[M + H]+
76
63
a
b
c
d
UV purity determined at 214 nm after preparative HPLC. Isolated yield after preparative HPLC. Isotope: [A+(−45)] Isolated yield after column
chromatography. Isolated desired products 3 were characterized by H and 13C NMR spectroscopy (see the Supporting Information).
Table 5. Library Data for Compounds 3{106−122}
1
a
b
product 3
n
R3
building blocks
method
ion HRMS
[M + H]+
calcd for HRMS
found HRMS
purity (%)
yield (%)
3{106}
3{107}
3{108}
3{109}
3{110}
3{111}
3{112}
3{113}
3{114}
3{115}
3{116}
3{117}
3{118}
3{119}
3{120}
3{121}
3{122}
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
3-thiophenyl
5{2}
5{6}
5{7}
5{6}
5{9}
8{1}
8{2}
8{5}
8{9}
8{7}
8{1}
8{2}
8{1}
8{2}
8{3}
8{7}
8{9}
B
B
B
B
B
E
E
E
E
E
E
E
E
E
E
E
E
340.1311
394.1780
393.1940
408.1937
401.1627
344.1260
358.1416
400.1886
464.1835
443.1944
344.1260
358.1416
320.0718
334.0875
376.1344
419.1403
341.1320
335.1642
787.3894
349.1797
803.3313
285.1116
381.1305
423.1766
482.2159
466.1744
285.1116
381.1312
261.0576
275.0731
399.1223
442.1203
458.1622
>99
99
23
34
16
43
31
[M + H]+[−C2H4O2]
[2M + H]+
98
[M + H]+[−C2H4O2]
[2M + H]+
98
>99
98
c
[M + H]+[−C2H4O2]
53
[M + Na]+
98
38
c
[M + Na]+
>99
95
46
[M + NH4]+
11
44
26
47
41
34
28
33
[M + Na]+
96
[M + H]+[−C2H4O2]
98
[M + Na]+
69
[M + H]+[−C2H4O2]
[M + H]+[−C2H4O2]
[M + Na]+
98
>99
>99
97
[M + Na]+
[M + NH4]+
c
440.1294
98
28
a
b
c
UV purity determined at 214 nm after preparative HPLC. Isolated yield after preparative HPLC. Isolated yield after column chromatography.
Isolated desired products 3 were characterized by H and 13C NMR spectroscopy (see the Supporting Information).
1
(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.
Hz, 1H), 2.28−2.35 (m, 1H), 2.66−2.73 (m, 1H), 2.85−2.94 (m,
1H), 2.98−3.05 (m, 1H), 3.84 (s, 3H), 5.08 (br s, 1H), 6.95 (d,
J = 8.9 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H); 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 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 saturated 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.
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 chromatog-
raphy on silica gel using EtOAc/hexanes as the eluent to afford
the heteroatom ring-containing furans 3.
Heteroatom Ring-Containing Furan [3{1}]. The product was
1
3-Iodofuran [2{1}]. The product was obtained as a pale yellow
obtained as slightly yellow solid (74% yield): H NMR (400
oil (42% yield): 1H NMR (400 MHz, CDCl3) δ 1.87 (d, J = 5.5
MHz, CDCl3) δ 2.33−2.38 (m, 1H), 2.65−2.71 (m, 1H), 2.86−3.04
409
dx.doi.org/10.1021/co300040q | ACS Comb. Sci. 2012, 14, 403−414

ACS Combinatorial Science
Research Article
Table 6. Library Data for Compounds 3{123−164}
a
b
product 3
n
m
R3
building blocks
method
ion HRMS
calcd for HRMS
found HRMS
purity (%)
yield (%)
3{123}
3{124}
3{125}
3{126}
3{127}
3{128}
3{129}
3{130}
3{131}
3{132}
3{133}
3{134}
3{135}
3{136}
3{137}
3{138}
3{139}
3{140}
3{141}
3{142}
3{143}
3{144}
3{145}
3{146}
3{147}
3{148}
3{149}
3{150}
3{151}
3{152}
3{153}
3{154}
3{155}
3{156}
3{157}
3{158}
3{159}
3{160}
3{161}
3{162}
3{163}
3{164}
1
1
2
2
2
2
1
1
1
1
2
2
2
2
2
2
2
2
2
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
4
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4-MeOC6H4
4-MeOC6H4
C6H5
4{6}
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
D
D
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
[M + H]+
[M + H]+
[M]+
408.1573
382.1529
418.2144
380.1624
420.2049
409.2001
370.1780
356.1634
396.1937
355.1784
326.1518
380.1988
356.1624
370.1780
383.2097
405.2052
422.2569
415.2359
470.2781
362.1366
345.1576
442.2468
375.1682
359.1733
389.1838
403.1995
346.1416
346.1416
376.1522
390.1679
404.1835
418.1992
308.0718
322.0875
352.0981
385.1525
320.1624
350.1729
348.1573
348.1573
378.1679
409.1588
383.1538
418.2156
403.1515
421.2125
410.2076
371.1851
357.1693
397.1997
356.1801
327.1530
398.2320
357.1683
371.1842
384.2105
406.2061
423.2581
415.2370
470.2793
362.1354
345.1583
442.2470
375.1691
359.1737
389.1841
403.2002
346.1423
346.1423
376.1534
390.1688
404.1838
418.2005
308.0725
322.0880
352.0985
385.1534
320.1632
350.1737
348.1580
348.1580
378.1686
420.2158
98
92
23
41
4{17}
4{11}
4{18}
4{12}
4{17}
5{4}
c
99
46
C6H5
[M + Na]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + NH4]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M + H]+
[M]+
99
29
53
47
46
41
7
4-Me2NC6H4
4-Me2NC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-Me2NC6H4
C6H5
95
65
97
5{5}
99
5{6}
98
5{2}
>99
99
23
c
5{2}
76
C6H5
5{6}
>99
>99
91
58
8
4-MeOC6H4
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
C6H5
5{2}
5{5}
31
46
12
23
5{5}
98
5{12}
5{7}
65
96
c
7{3}
99
47
c
C6H5
7{4}
[M]+
>99
99
53
c
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
3-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-thiophenyl
3-thiophenyl
3-thiophenyl
4-NCC6H4
1-cyclohexenyl
1-cyclohexenyl
C6H5
8{11}
8{1}
[M]+
67
c
[M]+
99
73
8{6}
[M]+
97
35
c
8{11}
8{1}
[M]+
>99
>99
>99
97
85
c
[M]+
76
c
8{11}
8{12}
8{1}
[M]+
81
c
[M]+
77
c
[M]+
>99
99
72
c
8{1}
[M]+
81
c
8{11}
8{12}
8{13}
8{14}
8{1}
[M]+
>99
>99
>99
99
76
c
[M]+
74
c
[M]+
68
c
[M]+
72
c
[M]+
99
71
c
8{1}
[M]+
99
68
8{11}
8{12}
8{1}
[M]+
>99
98
78
c
[M]+
66
c
[M]+
71
c
8{11}
8{11}
8{1}
[M]+
82
c
[M]+
37
c
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
[M]+
99
99
82
c
8{11}
8{14}
[M]+
82
c
[M]+
420.2148
>99
82
a
b
c
UV purity determined at 214 nm after preparative HPLC. Isolated yield after preparative HPLC. Isolated yield after column chromatography.
Isolated desired products 3 were characterized by H and 13C NMR spectroscopy (see the Supporting Information).
1
(m, 2H), 3.43 (s, 3H), 3.80 (s, 3H), 4.44 (s, 2H), 5.17 (d, J = 6.6 Hz,
1H), 6.82 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8
Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H); 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
410
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ACS Combinatorial Science
Research Article
Figure 3. Sublibraries of boronic acids 4, terminal alkynes 5, styrenes 6, amines 7, and alcohols 8.
1
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}.
ivory solid (63% yield): H 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.
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}.
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,
Alkyne-Containing Furan [3{105}]. The product was
obtained as a pale yellow oil that solidified upon standing to an
411
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ACS Combinatorial Science
Research Article
Figure 4. Distribution of physicochemical and structural properties across the library entries.
1H), 2.30 (s, 3H), 2.34−2.45 (m, 1H), 2.62−2.74 (m, 1H),
2.91−3.05 (m, 2H), 3.86 (s, 3H), 5.32 (br s, 1H), 6.99 (d, J =
8.8 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.07−7.18 (m, 2H), 7.46
(d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H); HRMS calcd for
C24H22O5 [M + H]+, 390.1467, found 391.1480.
HRMS calcd for C19H20O6 [M + H]+[−C2H4O2], 344.1260,
found 285.1116.
ASSOCIATED CONTENT
■
S
* Supporting Information
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 correspond-
ing 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 chromatog-
raphy on silica gel using ethyl acetate/hexanes as the eluent to
afford the ester-containing furans 3.
1
Synthetic methods, spectral assignments, and copies of H 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: larock@iastate.edu. Phone: (515) 294-4660. Fax: (515)
294-0105.
Funding
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).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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.
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