Solution-phase parallel synthesis of a multisubstituted cyclic imidate library

Article abstract of DOI:10.1021/co3001605

The solution-phase parallel synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I₂. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki-Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks.

Full text of DOI:10.1021/co3001605

Research Article
pubs.acs.org/acscombsci
Solution-Phase Parallel Synthesis of a Multisubstituted Cyclic Imidate
Library
Saurabh Mehta,†,‡ Jesse P. Waldo,† Benjamin Neuenswander,§ Gerald H. Lushington,§
and Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States.
‡Department of Applied Chemistry, Delhi Technological University, Delhi, 110042 India.
§The University of Kansas NIH Center of Excellence in Chemical Methodologies and Library Development, Lawrence, Kansas 66047,
United States
S
* Supporting Information
ABSTRACT: The solution-phase parallel synthesis of a diverse 71-member library
of multisubstituted cyclic imidates is described. The key intermediates,
3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent
yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides
and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic
imidates were further functionalized by palladium-catalyzed Suzuki−Miyaura,
Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of
commercially available building blocks.
KEYWORDS: solution-phase, parallel synthesis, iodocyclization, cyclic imidates, iminolactones, palladium coupling
Several research groups have reported various synthetic
routes for the synthesis of cyclic imidates.5 Although the
biological potential of this heterocyclic scaffold has not received
much attention, there have been a few reports in the literature
where interesting biological activities have been observed.
Representative biologically active examples are shown in Figure 1.6
INTRODUCTION
■
Heterocyclic compounds are of great importance in a variety of
areas, including medicinal chemistry, material science, etc.
There has been an increasing demand for new and efficient
strategies for the synthesis of important heterocyclic ring
systems for the purpose of exploring their potential applications
in the pharmaceutical industry and other relevant areas. We
have previously reported the generation of various important
heterocycles and carbocycles through very efficient electrophilic
cyclization chemistry using halogen, sulfur and selenium electro-
philes.1 In particular, we and others have recently found that the
iodocyclization of 2-(1-alkynyl)benzamides leads to the for-
mation of the corresponding cyclic imidates, also known in the
literature as iminolactones (Scheme 1), where electrophilic attack
occurs on oxygen, rather than nitrogen.2−4
Figure 1. Biologically active cyclic imidates.
Scheme 1. Synthesis of Cyclic Imidates by Electrophilic
Cyclization2
In our ongoing efforts to generate interesting libraries of
potentially biologically active heterocyles,7 we have used our
iodocylization strategy described above and further diversified
the resulting cyclic imidates to study the biological profile of
Received: January 3, 2013
Revised: March 17, 2013
© XXXX American Chemical Society
A
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Scheme 2. Library Design for Tetrasubstituted Cyclic Imidates
this interesting little-studied heterocyclic scaffold. Since there is
often a remarkable similarity in the reactivity pattern and
biological activities of certain nitrogen heterocycles and their
oxygen counterparts, these cyclic imidates might be expected to
have biological activities similar to those of their structurally
analogous isoindolin-1-one and isocoumarin counterparts.
Furthermore, to the best of our knowledge, a library of this
heterocyclic scaffold has not been reported previously in the
literature. Herein, we report our studies on the solution-phase
synthesis of a diverse 71-member library of cyclic imidates.
Table 1. Library Data for the 2-(1-Alkynyl)benzamides
3{1−6}
a
b
compd
R1
R2
Ph
R3
n-Pr
yield (%)
3{1}
3{2}
3{3}
3{4}
3{5}
3{6}
H
H
91
76
96
87
76
83
RESULTS AND DISCUSSION
■
Ph
TMS
TMS
Ph
Our strategy for library production is shown in Scheme 2. We
anticipated that our previously described iodocyclization
process should readily afford trisubstituted 3-iodomethylene-
containing cyclic imidates (4) as key intermediates. Further
functionalization can be achieved by taking advantage of the
iodine handle present on the exocyclic double bond at the
3-position, through various coupling reactions to generate a
library with four points of diversity.
4,5-(OMe)2
4,5-(OMe)2
4,5-(OMe)2
4,5-(OMe)2
PMB
Me
Me
Me
2-py
3-thienyl
a
All reactions were carried out on a 5.0 mmol scale using 1.2 equiv of
the alkyne, 2 mol % PdCl2(PPh3)2, 1 mol % CuI, and DIPA (4 equiv)
in DMF (25 mL) at 65 °C (see the Experimental section and
b
Supporting Information for the detailed procedures). Isolated yields
The starting o-iodobenzamides (1) were conveniently
prepared from the corresponding commercially available
carboxylic acids by first refluxing the acid with thionyl chloride,
followed in the same pot by reaction with the corresponding
amine.2,8 The alkynes 3 required for cyclization are readily
prepared by the palladium/copper-catalyzed Sonogashira cross-
coupling9 of the o-iodobenzamides 1 with terminal alkynes 2
and the results are summarized in Table 1. As shown in the
Table, the requisite alkynes 3{1−6} are readily obtained in
good to excellent yields by this straightforward approach.
As the key step in our library synthesis, variously substituted
iodo cyclic imidates 4 have been efficiently prepared within 1−2 h
by electrophilic cyclization of the corresponding o-(1-alkynyl)-
benzamides 3{1−6} using I2/NaHCO3 in MeCN at ambient
temperature (Table 2). All of the cyclized products 4 have been
purified by column chromatography. The reaction works well for
all substrates containing alkyl, aryl, TMS or heteroaryl groups at
the distal end of the carbon−carbon triple bond. It is noteworthy
that in the presence of electron-donating methoxy groups on the
amide phenyl ring 3{3−6}, only 5-membered cyclic imidates
were isolated exclusively. In fact, the electron-donating effect of the
para-methoxy group (with respect to the alkyne) should increase
the electron density on C-2 of the arylethynyl group, thus favoring
intramolecular nucleophilic attack of the amide oxygen on C-1.
The structure of the cyclized iodo imidates 4{2} and 4{4} has
been confirmed by single crystal X-ray crystallography.2
after column chromatography.
Table 2. Library Data for Compounds 4{1−6}
a
b
compd
R1
R2
Ph
R3
n-Pr
yield (%) 4 + 5
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
H
H
92 + 6
77 + 7
80 + 0
79 + 0
91 + 0
93 + 0
Ph
TMS
TMS
Ph
5,6-(OMe)2
5,6-(OMe)2
5,6-(OMe)2
5,6-(OMe)2
PMB
Me
Me
Me
2-py
3-thienyl
a
All reactions were carried out on a 4.0 mmol scale using I2 (3 equiv)
and NaHCO3 (3 equiv) in MeCN (20 mL) at 25 °C for 1−2 h.
b
Isolated yields after column chromatography.
Furthermore, the trimethylsilyl-containing cyclic imidates 4{2}
and 4{3} were treated with fluoride to afford the corresponding
deprotected cyclic imidates 4{7} and 4{8}, respectively, in good
yields (eq 1). The sublibrary of 3-iodomethylene-containing cyclic
Imidates 4{1−8} is shown in Figure 2.
B
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products 9 were analyzed by LC/MS, followed by purification by
either column chromatography or preparative HPLC. The results of
this parallel library synthesis are summarized in Table 3, which
indicates that the products 9 can be obtained in modest to good
yields with high purities.
Sonogashira coupling of the 3-iodomethylene-containing cyclic
imidates 4 with various terminal acetylenes 2 affords the
corresponding alkynyl products 9{1−17} (method A). Suzuki−
Miyaura coupling of the 3-iodomethylene-containing cyclic
imidates 4 with various arylboronic acids 6 proceeded smoothly
to give the desired products 9{18−62} in modest yields. Most
reactions were complete within 2 h at 80 °C in DMF (method B).
The reaction was also examined using a boronate ester 6{21}.
However, the yield of the isolated compound 9{62} was very low
in this case. The structure of one of the products from the
Suzuki−Miyaura coupling 9{24} was confirmed using single
crystal X-ray crystallography (see the Supporting Information for
details). The stereochemistry around the C−C and C−N double
bonds was found to be preserved during the Suzuki−Miyaura
cross-coupling. Next, in an effort to synthesize amide-containing
The 3-iodomethylene-containing cyclic imidates 4 can be further
elaborated by using a variety of palladium-catalyzed processes, such
as Sonogashira coupling,9 Suzuki−Miyaura coupling,10 carbonylative
amidation,11 Heck coupling,12 and amination13 (Scheme 3). The
reagents used (e.g., terminal alkynes 2, boronic acids 6, styrenes 7,
and amines 8) for substitution of the iodine-containing products 4
were chosen on the basis of their commercial availability, functional
group diversity and potential drug-like properties (Figure 3). This
could result in a library of ∼1300 theoretically possible products.
This number was arrived at by determining all possible
combinations of the R group and available starting materials.
However, only a small subset of 71 compounds out of these 1300
virtual structures was actually prepared in the laboratory. The crude
Figure 2. Sublibrary of 3-iodomethylene-containing cyclic imidates 4{1−8}.
a
Scheme 3. Synthesis of Cyclic Imidates 9 Using Various Palladium-Catalyzed Reactions
a
Method A (Sonogashira coupling): 3 mol % PdCl2(PPh3)2, 2 mol % CuI, DIPA (4 equiv), R4CCH (2, 1.2 equiv), DMF, 70 °C, 2 h. Method B
(Suzuki−Miyaura coupling): 5 mol % PdCl2, KHCO3 (1.4 equiv), R4B(OH)2 (6, 1.2 equiv), 4:1 DMF/H2O, 80 °C, 2 h. Method C (carbonylative
amidation): CO (1 atm), 5 mol % PdCl2(PPh3)2, R4NH2 (7, 0.25 mL), DMF, 65 °C, 3−6 h. Method D (Heck coupling): 5 mol % Pd(OAc)2,
n-Bu4NCl (1.0 equiv), Na2CO3 (2.5 equiv), R4CHCH2 (8, 4 equiv), DMF, 85 °C, 5−24 h. Method E (amination): 5 mol % Pd2(dba)3·CHCl3,
5 mol % BINAP, t-BuONa (1.4 equiv), R4NH2 (7, 1.2 equiv), DMF, 80 °C, 2.5 h.
C
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cyclic imidates, carbonylative amidation of the 3-iodomethylene-
containing cyclic imidates 4 using one atmosphere of carbon
monoxide and various amines 7 in the presence of catalytic
amounts of PdCl2(PPh3)2 was investigated (method C). However,
the reaction product was isolated in only one case 9{64} and only
in a low yield. By allowing the compounds 4 to react under Heck
reaction conditions in the presence of the styrenes 8, we obtained
the substituted olefin-containing cyclic imidate products 9{66−73}
(method D). Palladium-catalyzed amination reactions have also
been attempted to introduce amino substituents into the library
(method E). However, the reaction did not proceed well and the
process resulted in complex reaction mixtures.
Because of our interest in the synthesis of potentially
biologically active heterocycles for their use in high-throughput
Figure 3. continued
D
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Figure 3. Diverse terminal alkynes 2{1−12}, boronic acids 6{1−2}, boronate ester 6{21}, amines 7{1−4}, and styrenes 8{1−6} used for library
synthesis.
screening, an in silico evaluation of the library members was
carried out to check their conformity with Lipinski’s “rule of
five” and Veber’s rules.14,15 The molecular weight, clogP,
number of hydrogen bond donors and acceptors, and the
number of rotatable bonds were calculated for each of the
library members using the SYBYL program.16 Most of the 71
cyclic imidate library members were found to have either zero
or one Lipinski violation. In addition, the cell monolayer
absorption model Caco-2, a parameter indicating the ability of a
compound to passively permeate epithelial cells, that is, skin
and muscle sheaths, was also calculated.17 The mean values, as
well as the range of these parameters for this cyclic imidate
library, is provided in Table 4.
In conclusion, a highly substituted 71-member library of cyclic
imidates 9 with four points of diversity has been synthesized.
3-Iodomethylene-containing cyclic imidates 4 are readily prepared
by iodocyclization chemistry. We have demonstrated the
diversification of these 3-iodomethylene-containing cyclic imidates
4 with various building blocks, for example, terminal alkynes 2,
boronic acids 6, carbon monoxide plus amines 7, and styrenes 8,
to construct a diverse library through a variety of C−C bond
forming reactions. The cyclic imidate library members 9 will be
evaluated against various biological screens by the National
Institutes of Health Molecular Library Screening Center Network.
under vacuum to give the crude product, which was purified by
column chromatography on silica gel using hexane−EtOAc as the
eluent.
Benzamide 3{1}. 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J =
7.6 Hz, 3H), 1.53−1.59 (m, 2H), 2.40 (t, J = 7.2 Hz, 2H), 7.09
(t, J = 7.6 Hz, 1H), 7.27−7.33 (m, 4H), 7.41−7.43 (m, 1H),
7.67 (d, J = 8.0 Hz, 2H), 7.95−7.97 (m, 1H), 9.43 (br s, 1H);
13C NMR (100 MHz, CDCl3) δ 13.5, 21.5, 21.9, 79.2, 97.9,
119.8, 120.2, 124.1, 128.0, 128.8, 129.7, 130.5, 133.5, 135.5,
138.0, 164.4. HRMS Calcd for C18H17NO: 263.13101. Found:
263.13162.
General Iodocyclization Procedure Used for Prepara-
tion of the Cyclic Imidates 4{1−6}. To a solution of the
starting alkyne 3 (4.0 mmol) in MeCN (20 mL) were added I2
(3.0 equiv) and NaHCO3 (3.0 equiv). The reaction mixture
was allowed to stir at 25 °C and the reaction was monitored by
TLC for completion. The excess I2 was removed by washing
with satd aq Na2S2O3. The mixture was then extracted by
EtOAc, and the combined organic layers were dried over
anhydrous MgSO4 and concentrated under vacuum to yield the
crude product, which was purified by flash chromatography on
silica gel using hexane−EtOAc as the eluent.
1
Cyclic Imidate 4{1}. H NMR (400 MHz, CDCl3) δ 0.91
(t, J = 7.6 Hz, 3H), 1.56−1.62 (m, 2H), 2.81 (t, J = 7.6 Hz, 2H),
7.13 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.42−7.51 (m,
4H), 7.94 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.2, 22.5, 41.6, 82.2, 123.7, 123.9,
124.2, 124.8, 128.7, 129.9, 131.6, 132.2, 135.3, 145.5, 147.3,
152.1. HRMS Calcd for C18H16INO: 389.02766. Found:
389.02853.
General Sonogashira Coupling Procedure Used for the
Preparation of Alkynes 9{1−17}. To a solution of the appropr-
iate 3-iodomethylene-containing cyclic imidate 4 (0.25 mmol)
in DMF (4 mL) were added PdCl2(PPh3)2 (3 mol %) and CuI
(2 mol %). The reaction vial was flushed with Ar and the
reaction mixture was stirred for 5 min at room temperature.
DIPA (4.0 equiv) was added by syringe. The reaction mixture
was heated to 70 °C. A solution of alkyne 2 (1.2 equiv) in DMF
EXPERIMENTAL PROCEDURES
■
General Sonogashira Coupling Procedure Used for
Preparation of the 2-(1-Alkynyl)benzamides 3{1−6}. To a
solution of the appropriate o-iodobenzamide 1 (5.0 mmol) in
DMF (20 mL) were added PdCl2(PPh3)2 (2 mol %) and CuI
(1 mol %). The reaction vial was flushed with Ar and the reaction
mixture was stirred for 5 min at room temperature. DIPA
(4.0 equiv) was added by syringe. The reaction mixture was then
heated to 65 °C. A solution of alkyne 2 (1.2 equiv) in DMF
(5 mL) was added dropwise over 10 min, and the mixture was
allowed to stir at 65 °C for 2 h. After cooling, the reaction mixture
was diluted with EtOAc, and washed with satd aq NH4Cl and
water. The organic layer was dried over MgSO4 and concentrated
E
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Table 3. Library Data for Compounds 9{1−75}
a
b
c
a
b
c
compd
4
building block method
yield (%) purity (%)
compd
4
building block method
yield (%) purity (%)
9{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{6}
4{6}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{4}
4{4}
4{4}
4{5}
2{1}
2{5}
2{7}
2{8}
2{9}
2{10}
2{11}
2{12}
2{4}
2{6}
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
6{1}
6{2}
6{3}
6{4}
6{5}
6{6}
6{7}
6{9}
6{10}
6{11}
6{12}
6{13}
6{14}
6{15}
6{17}
6{18}
6{20}
6{1}
6{10}
6{16}
6{6}
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
B
B
B
B
B
B
B
B
34
26
30
34
27
21
14
8
89
98
9{39}
9{40}
9{41}
9{42}
9{43}
9{44}
9{45}
9{46}
9{47}
9{48}
9{49}
9{50}
9{51}
9{52}
9{53}
9{54}
9{55}
9{56}
9{57}
9{58}
9{59}
9{60}
9{61}
9{62}
9{63}
9{64}
9{65}
9{66}
9{67}
9{68}
9{69}
9{70}
9{71}
9{72}
9{73}
9{74}
9{75}
4{5}
4{5}
4{5}
4{6}
4{6}
4{6}
4{6}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{7}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{7}
4{7}
4{7}
4{7}
4{7}
6{10}
6{14}
6{16}
6{1}
6{6}
6{10}
6{19}
6{1}
6{2}
6{3}
6{4}
6 {5}
6{6}
6{7}
6{8}
6{9}
6{10}
6{11}
6{12}
6{13}
6{14}
6{15}
6{20}
6{21}
7{2}
7{3}
7{4}
8{1}
8{2}
8{3}
8{4}
8{5}
8{2}
8{5}
8{6}
7{1}
7{2}
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
C
C
C
D
D
D
D
D
D
D
D
E
32
26
36
22
30
39
32
27
33
57
18
43
29
14
25
52
32
48
38
7
64
54
60
94
84
93
81
100
96
88
95
98
93
71
98
98
87
100
82
75
85
91
99
81
9{2}
9{3}
98
9{4}
100
97
9{5}
9{6}
99
9{7}
100
91
9{8}
9{9}
51
19
55
59
38
63
16
69
8
87
9{10}
9{11}
9{12}
9{13}
9{14}
9{15}
9{16}
9{17}
9{18}
9{19}
9{20}
9{21}
9{22}
9{23}
9{24}
9{25}
9{26}
9{27}
9{28}
9{29}
9{30}
9{31}
9{32}
9{33}
9{34}
9{35}
9{36}
9{37}
9{38}
89
97
100
91
80
97
100
98
43
28
62
7
100
100
99
94
34
43
36
4
52
73
67
25
59
62
78
16
64
13
52
7
100
100
100
98
0
99
14
0
90
100
100
100
61
41
50
46
20
10
50
14
31
0
85
95
86
98
92
95
96
100
99
80
49
30
28
92
15
100
78
100
97
58
E
0
84
a
b
Method A, Sonogashira coupling; B, Suzuki−Miyaura coupling; C, carbonylative amidation; D, Heck coupling; E, amination. Isolated yield after
c
preparative HPLC. UV purity determined at 214 nm after preparative HPLC.
(1 mL) was added dropwise over 10 min, and the mixture was
allowed to stir at 70 °C for 2 h. After cooling, the reaction mixture
was diluted with EtOAc, and washed with satd aq NH4Cl and
water. The organic layer was dried over MgSO4 and concentrated
under vacuum to give the crude product, which was either purified
by column chromatography on silica gel using hexane-EtOAc as
the eluent, or was flushed through a short silica gel plug and
purified by preparative HPLC.
General Suzuki−Miyaura Coupling Procedure Used
for the Preparation of Imidates 9{18−62}. To a 4-dram vial
were added the appropriate 3-iodomethylene-containing cyclic
imidate 4 (0.25 mmol), the boronic acid 6 (0.30 mmol),
KHCO3 (0.35 mmol), and PdCl2 (0.0125 mmol) in 4:1 DMF/
H2O (2.5 mL). The reaction mixture was stirred for 5 min at
room temperature and flushed with Ar and then heated to 80 °C
for 2 h. After it was cooled, the reaction mixture was diluted with
EtOAc and washed with satd aq NH4Cl and water. The organic
layer was dried over MgSO4 and concentrated under vacuum to
give the crude product, which was either purified by column
Table 4. In Silico Data for Lipinski and Cell Permeability
Parameters
parameter
mean
range
optimum value
mol. weight
H-bond acceptors
H-bond donors
ClogP
391.3
3.9
315.3−510.6
2−7
1−3
2.9−9.2
2−7
≤500
≤10
≤5
≤5.0
≤10
≥0.4
1.5
5.7
rotatable bonds
Caco-2
4.8
1.2
0.2−2.1
chromatography on silica gel using hexane−EtOAc as the eluent or
was flushed through a short silica gel plug and purified by
preparative HPLC.
Carbonylative Amidation Procedure Used for the
Preparation of Amide 9{64}. To a 4-dram vial were added
the appropriate 3-iodomethylene-containing cyclic imidate 4
(0.25 mmol), PdCl2(PPh3)2 (5 mol %), DMF (1 mL), and the
amine 7 (0.25 mL). The reaction mixture was stirred for 2 min at
F
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of Isobenzofuran-1(3H)-imines and 1H-Isochromen-1-imines Instead of
Lactams. J. Org. Chem. 2012, 77, 10118−10124.
room temperature and flushed with carbon monoxide. A balloon
of carbon monoxide was placed on the vial, which was heated to
65 °C for 3 h. After it was cooled, the reaction mixture was diluted
with EtOAc and washed with satd aq NH4Cl and water. The
organic layer was dried over MgSO4 and concentrated under
vacuum to give the crude product, which was flushed through a
short silica gel plug and purified by preparative HPLC.
General Heck Coupling Procedure Used for the
Preparation of Alkenes 9{66−73}. To a 4-dram vial were
added the appropriate 3-iodomethylene-containing cyclic imidate 4
(0.25 mmol), the styrene 8 (1.0 mmol), Pd(OAc)2 (5 mol %),
n-Bu4NCl (0.25 mmol), Na2CO3 (0.625 mmol), and DMF (2 mL).
The reaction mixture was then heated to 85 °C for 5−24 h. After it
was cooled, the reaction mixture was diluted with EtOAc (20 mL)
and washed with satd aq NH4Cl and water. The organic layer was
dried over MgSO4 and concentrated under vacuum to give the crude
product, which was flushed through a short silica gel plug and purified
by preparative HPLC.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, conditions for the high throughput liquid
chromatography purification, X-ray crystallographic data for
compound 9{24}, and the characterization data for all
previously unreported starting materials, intermediate com-
pounds, and a representative 20 library members. This material
is available free of charge via the Internet at http://pubs.acs.org.
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A.; Jagt, D. L. V. Comparison of the Antiviral Activities of 3′-Azido-3′-
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W. B. Cyclic Imidate Derivatives of 5-Amino-2,6-bis(polyfluoroalkyl)-
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60−69.
(7) (a) Cho, C.-H.; Shi, F.; Jung, D.-I.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. Solution-Phase Synthesis of a Highly
Substituted Furan Library. ACS Comb. Sci. 2012, 14, 403−414.
(b) Cho, C.-H.; Jung, D.-I.; Neuenswander, B.; Larock, R. C. Parallel
Synthesis of a Desketoraloxifene Analogue Library via Iodocyclization/
Palladium-Catalyzed Coupling. ACS Comb. Sci. 2011, 13, 501−510.
(c) Markina, N. A.; Mancuso, R.; Neuenswander, B.; Lushington, G.
H.; Larock, R. C. Solution-Phase Parallel Synthesis of a Diverse Library
of 1,2-Dihydroisoquinolines. ACS Comb. Sci. 2011, 13, 265−271.
(d) Cho, C.-H.; Neuenswander, B.; Lushington, G. H.; Larock, R. C.
Solution-Phase Parallel Synthesis of a Multi-substituted Benzo[b]-
thiophene Library. J. Comb. Chem. 2009, 11, 900−906. (e) Waldo, J.
P.; Mehta, S.; Neuenswander, B.; Lushington, G. H.; Larock, R. C.
Solution Phase Synthesis of a Diverse Library of Highly Substituted
Isoxazoles. J. Comb. Chem. 2008, 10, 658−663. (f) Yao, T.; Yue, D.;
Larock, R. C. Solid-Phase Synthesis of 1,2,3-Trisubstituted Indoles and
2,3-Disubstituted Benzofurans via Iodocyclization. J. Comb. Chem.
2005, 7, 809−812.
AUTHOR INFORMATION
Corresponding Author
*Phone: (515) 294-4660. E-mail: larock@iastate.edu.
Funding
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the University of Kansas
National Institutes of Health Center of Excellence in Chemical
Methodologies and Library Development (GM069663) for support
of this research.
■
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. We also
thank Dr. Frank Schoenen (University of Kansas) for helpful
discussions and Dr. Arkady Ellern and the Molecular Structure
Laboratory of Iowa State University for providing X-ray
crystallographic data for product 9{24}.
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