Solution-phase synthesis of a diverse library of benzisoxazoles utilizing the [3 + 2] cycloaddition of in situ-generated nitrile oxides and arynes

Article abstract of DOI:10.1021/co300159g

A library of benzisoxazoles has been synthesized by the [3 + 2] cycloaddition of nitrile oxides with arynes and further diversified by acylation/sulfonylation and palladium-catalyzed coupling processes. The eight key intermediate benzisoxazoles have been prepared by the reaction of o-(trimethylsilyl)aryl triflates and chlorooximes in the presence of CsF in good to excellent yields under mild reaction conditions. These building blocks have been used as the key components of a diverse set of 3,5,6-trisubstituted benzisoxazoles.

Full text of DOI:10.1021/co300159g

Research Article
pubs.acs.org/acscombsci
Solution-Phase Synthesis of a Diverse Library of Benzisoxazoles
Utilizing the [3 + 2] Cycloaddition of in Situ-Generated Nitrile
Oxides and Arynes
Anton V. Dubrovskiy,† Prashi Jain,§ Feng Shi,† Gerald H. Lushington,§ Conrad Santini,§
Patrick Porubsky,§ and Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
§The University of Kansas NIH Center of Excellence in Chemical Methodologies and Library Development, Lawrence, Kansas 66047,
United States
S
* Supporting Information
ABSTRACT: A library of benzisoxazoles has been synthe-
sized by the [3 + 2] cycloaddition of nitrile oxides with arynes
and further diversified by acylation/sulfonylation and palla-
dium-catalyzed coupling processes. The eight key intermediate
benzisoxazoles have been prepared by the reaction of o-
(trimethylsilyl)aryl triflates and chlorooximes in the presence
of CsF in good to excellent yields under mild reaction conditions.
These building blocks have been used as the key components of a
diverse set of 3,5,6-trisubstituted benzisoxazoles.
KEYWORDS: solution-phase synthesis, benzisoxazoles, [3 + 2] cycloaddition, palladium-catalyzed, library
Scheme 1. Aryne Methodology for the Synthesis of
Benzisoxazoles
INTRODUCTION
■
Low molecular weight heterocycles are among the most highly
recognized pharmacophores.1 Among them, the benzisoxazole
scaffold has evolved as a convenient cbioisosteric replacement for
the benzoyl functionality of some biologically active molecules.2
Benzisoxazoles, particularly their 3-alkyl and 3-aryl substituted
derivatives, have displayed a broad range of biological activities, such
as antipsychotic,2a,3 antitumor,4 anticonvulsant,5 antimicrobial,6
antibacterial,7 diuretic,8 antithrombotic,2c and acetylcholinesterase-
inhibition2b,9 (Alzheimer’s disease treatment) activities (Figure 1).
Various routes to 3-alkyl/aryl benzisoxazoles have been reported.
Most of the syntheses are 3 to 4 steps in length, usually involving
formation of the carbon−oxygen bond (through SNAr,8b,10 or
Pd-11 or CuI12-catalyzed reactions) or the oxygen−nitrogen bond
(through base-mediated cyclizations13 or intramolecular Mitsunobu14
reactions) via intermediate o-halo- or o-hydroxyaryl ketoximes
during the final steps. The syntheses of the corresponding
o-halo- or o-hydroxyaryl ketones often involve a strongly acidic
Friedel−Craft’s reaction and the use of one of the substrates as
a solvent, or in other cases require the use of strongly basic
organometallics.
to prepare and evaluate up to 36 members from a single
scaffold in a divergent manner.15
We have previously reported an efficient method leading to
3-alkyl- and 3-arylbenzisoxazoles by the [3 + 2] cycloaddition of
nitrile oxides and arynes.16 Both highly reactive components have
been generated in situ by fluoride anion from commercially available
aryne precursors and readily prepared chlorooximes (Scheme 1).
In an extension of our previous studies, we hereby report the
synthesis of a solution-phase library using this methodology,
which includes preparation of benzisoxazole-containing blocks
4−6, followed by (a) their acylation/sulfonylation if the
building block possesses an amino functionality, such as the
piperidinyl-containing substrates 4 (their derivatives are
prevalent in the literature)17 or the L-proline-derived substrates
5, and (b) elaboration using Pd-catalyzed coupling processes if
Because of the extensive biological activity of benzisoxazoles,
it is likely that libraries of low molecular weight benzisoxazoles
will serve as valuable tools for drug discovery. However, the
limitations of present convergent literature syntheses of these
heterocycles have been an obstacle to expedient evaluation of
diverse benzisoxazoles for biological activity. It should be noted
that amino-containing benzisoxazoles have been produced and
simple alkylation/acylation derivatization steps have been used
Received: January 2, 2013
Revised: February 20, 2013
© XXXX American Chemical Society
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Scheme 2. Parent Benzisoxazole Scaffolds and Derivatization
Methodology
Scheme 3. Hartwig−Buchwald Amination of 13 and 14
Scheme 4. Sonogashira Coupling of 14
Scheme 5. Suzuki−Miyaura Coupling of 14
the building block possesses a Br/I handle, such as the 3-haloaryl-
substituted benzisoxazoles 6 (Scheme 2).
As such, we set out to construct a diverse 72-membered
library of benzisoxazoles to be screened for biological activity.
This is the first example of the use of aryne chemistry for
constructing a benzisoxazole library.
prediction of oral bioavailability.19 Lipinski calculations have
been performed based on the commercial availability of the
aryne precursors [the o-(trimethylsilyl)aryl triflates],20 acylat-
ing/sulfonylating agents, boronic acids (for Suzuki−Miyaura
coupling), amines and hydrazines (for Buchwald−Hartwig
amination), and terminal alkynes (for Sonogashira coupling).21
Four benzyne precursors, 52 acylating/sulfonylating agents, 21
boronic acids, 10 amines and hydrazines, and 10 terminal
alkynes have been used to generate a 2440-membered virtual
library. In silico analysis of this virtual set revealed 71 members
RESULTS AND DISCUSSION
■
To synthesize a library with greater chances for biological activity,
the substituted derivatives 4−6 have been evaluated computationally
for their drug-like properties using SYBYL,18 plus Lipinski’s
“rule of five” and Veber’s rule as additional guidelines for the
Figure 1. Examples of medicinally relevant benzisoxazoles.
B
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Figure 2. Desired benzisoxazole building blocks.
Figure 3. Distribution of the physicochemical and structural properties of our library entries.
with diversity scores22 <1.0 along with one having a slightly
higher score, allowing the synthesis of the target compounds
from only eight building blocks (Figure 2). The distributions of
the Lipinski and Veber parameters (molecular weight, cLogP,
number of rotatable bonds, H-bond donors and acceptors) are
shown in Figure 3. All compounds follow Lipinski’s and Veber’s
rules with no violations.
Synthesis of the Building Blocks. For practical purposes,
relatively stable benzisoxazole blocks were needed. Thus, we
chose to synthesize amine-containing starting benzisoxazoles as
their corresponding Boc-urethanes 7−12. The amounts of the
eight building blocks required were estimated assuming a 60%
yield in the final diversification step and our goal of preparing
35 mg of each compound for screening.
Despite the scalability issues inherent in the heterogeneous
CsF-promoted benzyne-mediated chemistry,23 running the
reactions in parallel at increased loadings (up to 4×) furnished
starting materials 9−14 in sufficient amounts for further
diversification (Table 1). Using our methodology, N-Boc-
piperidine-derived chlorooxime 15 afforded the desired
benzisoxazoles 7 and 8 in 88% and 59% yields, respectively,
with different aryne precursors when performed on a 0.25 mmol
scale (entries 1 and 3).
The coupling of the chiral proline-derived chlorooxime 16
with an array of symmetrical benzynes afforded the desired
chiral benzisoxazoles 9−12 in 33−88% yields (entries 5−10).
The substituted benzynes provided slightly lower yields than
the parent system, with the dimethoxybenzyne being the best of
C
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Table 1. Preparation of the Benzisoxazole Building Blocks 7−14
a
b
entry
chloro-oxime
R′
benzyne precursor
R
reaction scale (mmol)
product
yield (%)
1
15
15
15
15
16
16
16
16
16
16
17
17
18
18
4-(N-Boc-piperidinyl)
19
19
20
20
19
19
20
21
21
22
19
19
19
19
H
0.25
0.50
0.25
0.75
0.25
0.50
0.50
0.50
1.00
0.50
0.25
0.50
0.25
0.50
7
88
78
59
40
85
88
73
51
33
50
76
56
57
54
2
4-(N-Boc-piperidinyl)
H
7
3
4-(N-Boc-piperidinyl)
OMe
OMe
H
8
4
4-(N-Boc-piperidinyl)
8
5
(S)-2-(N-Boc-pyrrolidinyl)
(S)-2-(N-Boc-pyrrolidinyl)
(S)-2-(N-Boc-pyrrolidinyl)
(S)-2-(N-Boc-pyrrolidinyl)
(S)-2-(N-Boc-pyrrolidinyl)
(S)-2-(N-Boc-pyrrolidinyl)
3-iodo-4,5-dimethoxyphenyl
3-iodo-4,5-dimethoxyphenyl
5-bromo-2-fluorophenyl
9
6
H
9
7
OMe
Me
Me
C4H4
H
10
11
11
12
13
13
14
14
8
9
10
11
12
13
14
H
H
5-bromo-2-fluorophenyl
H
a
b
The amount of chlorooxime used. Isolated yields after normal phase column chromatography.
a
provided the desired benzisoxazoles 11 and 12 in 51% and 50%
yields, respectively, when allowed to react on a 0.50 mmol scale
(entries 8 and 10). The electron-rich dimethoxyiodo-
substituted chlorooxime 17 led to formation of the desired
benzisoxazole 13 in a 76% yield on a standard 0.25 mmol scale
(entry 11). The yield was significantly lower (56%) when the
reaction was run on a 0.50 mmol scale. The more electron-
deficient chlorooxime 18 afforded the benzisoxazole 14 in a
lower 57% yield, when run on a 0.25 mmol scale (compared to
54% on a 0.50 mmol scale, entry 14). With the benzisoxazole
building blocks 9−14 in hand, a 72-member library was designed.
The library was constructed by diversification of the 3-substituted
benzisoxazole core scaffold using acylation, sulfonylation and
metal-catalyzed cross-coupling reactions as outlined in Scheme 2.
This method permits the introduction of functional diversity to
generate benzisoxazoles with potential biological activity using
parallel synthesis.
Diversifications. Acylation/Sulfonylation. Our diversifica-
tion sequence involved TFA-mediated Boc-deprotection of the
cycloadducts 7−12 and subsequent N-acylation/sulfonylation
with various acyl/sulfonyl chlorides. This deprotection−
acylation procedure24 was best carried out in one pot: TFA
deprotection in DCM, addition of toluene, parallel concentration,
addition of fresh DCM followed by basification using triethylamine
(5.0 equiv), and finally the addition of an acyl/sulfonyl/sulfinyl
chloride (1.5 equiv). The reactions were carried out in 1-dram vials
using Mettler-Toledo Miniblocks in which the crude final reaction
mixtures were concentrated and purified via automated mass-
directed (MDF) LC/MS. Table 2 shows the chemset diversity
inputs for the substituted 3-(4-piperidinyl)benzisoxazoles. Amide/
sulfonamide products 23{1−17} (Figure 4) derived from the
starting blocks 7 and 8 were obtained in 3−95% yields and
excellent purities (88 to >99%) after MDF purification.
Table 2. Data for Library Compounds 23{1−17}
HRMS
(calcd)
HRMS
purity
c
yield
d
b
product
R
(found)
(%)
(%)
23{1}
23{2}
23{3}
23{4}
23{5}
23{6}
23{7}
23{8}
23{9}
23{10}
23{11}
23{12}
23{13}
23{14}
23{15}
23{16}
23{17}
H
298.0929
296.1161
272.1525
315.1583
313.1790
312.0932
306.1402
342.1038
348.0602
346.1100
347.0940
343.0991
497.9248
366.1579
358.1140
366.1613
346.1892
299.1051
297.1249
273.1619
316.1671
314.1880
313.1023
307.1512
343.1134
349.0710
347.1189
348.1025
344.1068
498.9355
367.1654
359.1227
367.1704
347.1986
99
>99
>99
>99
>99
88
24
35
52
31
36
(3)
21
32
26
52
48
29
H
H
H
H
H
H
95
H
>99
99
H
H
>99
97
H
H
95
e
H
96
62
e
H
99
95
OMe
OMe
OMe
88
(4)
33
>99
94
23
a
Reactions were performed on a 0.25 mmol scale. TFA deprotection:
0.5 mL of TFA and 1 mL of DCM were used. Acylation: Et3N (5 equiv),
b
acyl/sulfonyl chloride (1.5 equiv) and anhydrous CH2Cl2 were used. For
c
[M + H]+. UV purity determined at 214 nm after preparative HPLC.
d
Isolated yields after MDF column chromatography. Yields in parent-
heses are considered failed entries (<90% purity and/or <5 mg
quantity). Purified by normal phase column chromatography.
A series of 3-(pyrrolidin-2-yl)-benzisoxazoles (Table 3) was
prepared using the same procedure utilized for the synthesis of
the 3-(4-piperidinyl)benzisoxazoles. The yields of N-acylated
and N-sulfonylated benzisoxazoles 24{1−41} (Figure 5) ranged
from 1 to 57% with 60 to >99% purities obtained after MDF
e
the three (73% yield of the corresponding benzisoxazole 10,
entry 7). The dimethylbenzyne and the symmetrical naphthalyne
D
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Figure 4. Derivatized 3-(4-piperidinyl)benzisoxazoles.
Table 3. Data for Library Compounds 24{1−41}
a
HRMS
(calcd)
purity
c
yield
d
b
product
R
HRMS (found)
293.1335
not found
(%)
(%)
f
24{19.2}
24{20}
24{21}
24{22}
24{23}
24{24}
24{25}
24{26}
24{27.1}
24{27.2}
24{28}
24{29}
24{30}
24{31}
24{32}
24{33}
24{34}
24{35.1}
24{35.2}
24{36}
24{37}
24{38}
24{39}
24{40.1}
24{40.2}
24{41}
H
H
292.1245
94
37
(nd)
28
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
430.0528
332.1736
344.0984
388.1093
432.0991
406.0999
352.1457
352.1457
312.1085
300.1837
327.1946
300.1837
328.1535
329.1739
362.0758
320.1558
320.1558
365.1375
361.1096
387.1219
334.0929
342.1402
342.1402
350.1379
431.0629
333.1831
345.1090
389.1180
433.1060
407.1081
353.1548
353.1553
313.1180
301.1925
328.2033
301.1941
329.1629
330.1854
363.0855
321.1657
321.1650
366.1476
362.1197
388.1332
335.1029
343.1505
343.1513
351.1490
99
>99
>99
>99
99
30
34
(5)
(3)
34
HRMS
(calcd)
purity
yield
d
b
c
product
R
HRMS (found)
(%)
(%)
e
24{1}
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
337.1063
284.0773
282.1004
317.1164
338.1152
285.0860
283.1085
318.1272
96
>99
>99
>99
27
41
26
51
(nd)
38
52
41
56
28
33
43
44
24
45
43
38
57
37
>99
>99
>99
>99
>99
>99
92
f
24{2}
28
f
24{3}
28
24{4}
(3)
40
24{5}
not found
Me
24{6}
299.1634
258.1368
324.1274
360.1086
306.1368
360.1086
301.1426
300.1222
298.0776
332.0943
334.0446
328.0882
346.0787
292.1245
300.1737
259.1455
325.1378
361.1174
307.1478
361.1164
302.1525
301.1306
299.0862
333.1033
335.0540
329.0983
347.0879
293.1357
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
Me
43
24{7}
Me
(7)
(1)
32
24{8}
Me
60
24{9}
Me
>99
94
24{10}
24{11}
24{12}
24{13}
24{14}
24{15}
24{16}
24{17}
24{18}
24{19.1}
Me
27
f
Me
>99
95
46
f
Me
46
Me
92
39
36
29
36
Me
96
C4H4
C4H4
C4H4
C4H4
C4H4
>99
>99
>99
92
f
>99
>99
96
37
f
(37)
f
>99
10
a
Reactions were performed on a 0.25 mmol scale. TFA deprotection: 0.5 mL of TFA and 1 mL of DCM were used. Acylation: Et3N
b
c
(5 equiv), acyl/sulfonyl chloride (1.5 equiv) and anhydrous CH2Cl2 were used. For [M + H]+. UV purity determined at 214 nm after preparative
d
HPLC. Isolated yields after MDF column chromatography. Yields in parentheses are considered failed entries (<90% purity and <5 mg quantity).
e
f
Purified by normal phase column chromatography. Combined yield for the two diastereomers formed.
purification. In the case of sulfinylamides 24{19, 27, 35, and 40},
mixtures of diastereomers were obtained, which were separable by
MDF separation. The relative stereochemical assignments of the
diastereomers were not determined.
E
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Figure 5. Derivatized 3-(2-pyrrolidinyl)benzisoxazoles.
Pd/Cu-Catalyzed Cross-Couplings. To prepare libraries
derived from 3-(3-iodo-4,5-dimethoxyphenyl)benzisoxazole
(13) and 3-(2-fluoro-5-iodophenyl)benzisoxazole (14), we
utilized various Pd/Cu-catalyzed cross-coupling reaction sequen-
ces, such as Suzuki−Miyaura coupling with aryl boronic acids,
Hartwig−Buchwald coupling with alkyl hydrazines, and Sonogashira
coupling with terminal alkynes. The data for the compounds
(Figure 6) obtained through these diversification procedures are
combined in Table 4.
Hartwig−Buchwald coupling25 of 3-(3-iodo-4,5-dimeth-
oxyphenyl)benzisoxazole (13) with morpholin-4-amine afforded
the desired product 25{1} in a 41% yield (Scheme 3). With
optimized conditions in hand, we employed this method for
coupling of 3-(2-fluoro-5-iodophenyl)benzisoxazole (14) with
appropriate alkyl hydrazines. While we were unable to isolate any
F
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Figure 6. Benzisoxazoles derivatized through Pd/Cu-catalyzed coupling.
a
Table 4. Data for Library Compounds 25{1−9}
b
c
c
product
reaction
HRMS (calcd)
HRMS (found)
purity (%)
yield (%)
d
25{1}
25{2}
25{3}
25{4}
25{5}
25{6}
25{7}
25{8}
25{9}
amination
355.1532
313.1226
335.1322
334.1481
356.1635
314.1322
336.1407
335.1555
>99
97
41
d
e
amination
14
f
f
f
f
Sonogashira
Sonogashira
Sonogashira
Sonogashira
98
39
30
90
not found
(nd)
16
281.0852
290.0855
291.0808
282.0927
291.0941
292.0885
280.0992
>99
>99
>99
>99
g
g
g
Suzuki−Miyaura
Suzuki−Miyaura
Suzuki−Miyaura
32
25
279.0696
7
a
b
c
Reactions were performed on a 0.25 mmol scale. For [M+H]+. Yield/purities as in Table 1. Yields in parentheses are considered failed entries
d
(<90% purity or <5 mg quantity). For Hartwig−Buchwald coupling: alkyl hydrazine (2.0 equiv), LiCl (4.0 equiv), Pd2(dba)3 (2.5 mol %), xantphos
e
f
(5 mol %), NaOtBu (2.0 equiv), dioxane, 85 °C, 33 h. Purified by normal phase column chromatography. For Sonogashira coupling: CuI (3 mol %),
g
PdCl2(PPh3)2 (2 mol %), terminal alkyne (1.5 equiv), Et3N (1 mL), DMF, 80 °C. For Suzuki−Miyaura coupling: aryl boronic acid (1.5 equiv),
Pd(PPh3)4 (5 mol %), K2CO3 (2.5 equiv), Tol/EtOH/H2O (20:5:1), 80 °C, 18 h.
of the desired compounds after MDF purification, we were able to
obtain 25{2} in a 14% yield after purification using normal phase
chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization of a representative 20
library members, including full H and 13C NMR spectra and
1
Scheme 4 describes the synthesis of 4 analogues of 3-(2-
fluoro-5-iodophenyl)benzisoxazole (14) using a Sonogashira
coupling26 with 16−39% yields for successful entries in 90 to
>99% purities after MDF chromatography. The generation of 3
analogues based on Sonogashira couplings of 3-(3-iodo-4,5-
dimethoxyphenyl)benzisoxazole (13) with terminal alkynes provided
unfavorable results, and we were not able to isolate the desired
products.
conditions for their high throughput liquid chromatography
purification. 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.
Author Contributions
■
The Suzuki−Miyaura coupling27 of 3-(2-fluoro-5-iodophenyl)-
benzisoxazole (14) with aryl boronic acids afforded the desired
products 25{7−9} in 7−32% yields in excellent purities via
preparative MDF purification (Scheme 5).
A.V.D. and P.J. should be considered to be equal contributors
to this work.
Funding
We are grateful to the National Institute of General Medical
Sciences for their generous financial support through grants
GM079593 and GM070620 to R.C.L. and to the NIH
Chemical Methodologies and Library Development Center at
the University of Kansas (P50 GM069663).
CONCLUSIONS
■
The aryne-mediated preparation and subsequent acylation/
sulfonylation and palladium-catalyzed reactions of benzisox-
azoles with various cross-coupling partners has enabled the
construction of a 72-member library of diverse 3-substituted
benzisoxazoles with potential biological activity. We anticipate
that this methodology will be applicable in future diversity-
oriented parallel synthesis for discovery purposes. The overall
success rate for the library was 83% and the average purity after
preparative MDF-HPLC was 99%.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The
combinatorial synthesis of bicyclic privileged structures or privileged
G
dx.doi.org/10.1021/co300159g | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
substructures. Chem. Rev. 2003, 103, 893−930. (b) Dolle, R. E.
Comprehensive survey of combinatorial library synthesis: 2002. J.
dioxolo[4,5-f ]-1,2-benzisoxazole-6-carboxylic acids and 1,3-dioxolo-
[4,5-g]-1,2-benzisoxazole-7-carboxylic acids. Chem. Pharm. Bull. 1992,
40, 109−116.
(9) Rangappa, K. S.; Basappa.. New cholinesterase inhibitors:
Synthesis and structure−activity relationship studies of 1,2-benzisox-
azole series and novel imidazolyl-d2-isoxazolines. J. Phys. Chem. 2005,
18, 773−778.
(10) Bunnet, J. F.; Yih, S. Y. Kinetics of cyclization of o-
halobenzophenone oximes to 3-phenyl-1,2-benzisoxazole. J. Am.
Chem. Soc. 1961, 83, 3805−3807.
(11) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.;
Sakamoto, T. Synthesis of 3-substituted indazoles and benzisoxazoles
via Pd-catalyzed cyclization reactions: application to the synthesis of
nigellicine. Tetrahedron 2007, 63, 2695−2711.
Comb. Chem. 2003, 5, 693−753. (c) D’Souza, D. M.; Muller, T. J.
̈
Multi-component syntheses of heterocycles by transition-metal
catalysis. J. Chem. Soc. Rev. 2007, 36, 1095−1108.
(2) (a) Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B.
L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F.
P.; Dunn, R. W. Synthesis and neuroleptic activity of 3-(1-substituted-
4-piperidinyl)-1,2-benzisoxazoles. J. Med. Chem. 1985, 28, 761−769.
(b) Villalobos, A.; Blake, J. F.; Biggers, C. K.; Butler, T. W.; Chapin, D.
S.; Chen, Y. L.; Ives, J. L.; Jones, S. B.; Liston, D. R.; Nagel, A. A.;
Nason, D. M.; Nielsen, J. A.; Shalaby, I. A.; White, W. F. Novel
benzisoxazole derivatives as potent and selective inhibitors of
acetylcholinesterase. J. Med. Chem. 1994, 37, 2721−2734. (c) Nuhrich,
A.; Varache-Lembege, M.; Renard, P.; Devaux, G. Synthesis and
inhibitory effects on platelet aggregation of 3-(2-thienyl)- and 3-(1-
imidazolyl)-1,2-benzisoxazole derivatives. Eur. J. Med. Chem. 1994, 29,
75−83.
(12) De, P.; Nonappa; Pandurangan, K.; Maitra, U.; Wailes, S. CuI-
Mediated cross-coupling of aryl halides with oximes: a direct access to
o-aryloximes. Org. Lett. 2007, 9, 2767−2770.
(13) (a) Roman, G.; Comanita, E.; Comanita, B. Synthesis and
reactivity of Mannich bases. Part 15: synthesis of 3-(2-(1-pyrazolyl)-
ethyl)-1,2-benzisoxazoles. Tetrahedron 2002, 58, 1617−1622.
(b) Shelke, K. F.; Sapkal, S. B.; Shitole, N .V.; Shingate, B. B.;
Shingare, M. S. Microwave-assisted synthesis of 1,2-benzisoxazole
derivatives in ionic liquid. Org. Commun. 2009, 2, 72−78. (c) Dale, T.
J.; Sather, A. C.; Rebek, J. Synthesis of novel aryl-1,2-oxazoles from
ortho-hydroxyaryloximes. Tetrahedron Lett. 2009, 50, 6173−6175.
(14) Poissonnet, G. A simple and convenient synthesis of 1,2-
benzisoxazoles via intramolecular Mitsunobu reaction from salicylal-
doximes and ortho-hydroxyarylketoximes. Synth. Commun. 1997, 27,
3839−3846.
(3) (a) Davis, L.; Effland, R. C.; Klein, J. T.; Dunn, R. W.; Geyer, H.
M., III; Petko, W. M. 3-Substituted-1,2-benzisoxazoles: Novel
antipsychotic agents. Drug Des. Discovery 1992, 8, 225−239.
(b) Janssen, P. A. J.; Niemegeers, C. J. E.; Awouters, F.; Schellekens,
K. H. L.; Megens, A. A. H. P.; Meert, T. F. Biochemical profile of
Risperidone, a new antipsychotic. J. Pharmacol. Exp. Ther. 1988, 244,
661−670. (c) Strupczewski, J. T.; Bordeau, K. J.; Chiang, Y.;
Glamkowski, E. J.; Conway, P. G.; Corbett, R.; Hartman, H. B.;
Szewczak, M. R.; Wilmot, C. A.; Helsley, G. C. 3-[[(Aryloxy)alkyl]-
piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with poten-
tial atypical antipsychotic activity: antipsychotic profile of Iloperidone
(HP 873). J. Med. Chem. 1995, 38, 1119−1131.
(4) (a) Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.;
Johnson, M.; Lee, F.; Nilakantan, R.; Petersen, R.; Svenson, K.;
Chopra, R.; Tam, M. S.; Wen, Y.; Ellingboe, J.; Arndt, K.; Boschelli, F.
Discovery of benzisoxazoles as potent inhibitors of Chaperone heat
shock protein 90. J. Med. Chem. 2008, 51, 373−375. (b) Jain, M.;
Kwon, C.-H. 1,2-Benzisoxazole phosphorodiamidates as novel
anticancer prodrugs requiring bioreductive activation. J. Med. Chem.
2003, 46, 5428−5436. (c) Benaka Prasad, S. B.; Vinaya, K.; Ananda
Kumar, C. S.; Swarup, S.; Rangappa, K. S. Synthesis of novel 6-fluoro-
3-(4-piperidinyl)-1,2-benzisoxazole derivatives as antiproliferative
agents: A structure−activity relationship study. Invest. New Drugs
2009, 27, 534−542.
(5) (a) Stiff, D. D.; Zemaitis, M. A. Metabolism of the anticonvulsant
agent zonisamide in the rat. Drug Metab. Dispos. 1990, 18, 888−894.
(b) Masuda, Y.; Nishimura, H. Studies on 3-substituted 1,2-
benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-
benzisoxazole derivatives and their anticonvulsant activities. J. Med.
Chem. 1979, 22, 180−183.
(6) (a) Priya, B. S.; Basappa; Swamy, S. N.; Rangappa, K. S. Synthesis
and characterization of novel 6-fluoro-4-piperidinyl-1,2-benzisoxazole
amides and 6-fluoro-chroman-2-carboxamides: antimicrobial studies.
Bioorg. Med. Chem. 2005, 13, 2623−2628. (b) Suhas, R.;
Chandrashekar, S.; Gowda, D. C. Synthesis of elastin based peptides
conjugated to benzisoxazole as a new class of potent antimicrobials
A novel approach to enhance biocompatibility. Eur. J. Med. Chem.
2011, 46, 704−711.
(15) See refs 2a, 3c, 4c, 6a, and 9.
(16) Dubrovskiy, A. V.; Larock, R. C. Synthesis of benzisoxazoles by
the [3 + 2] cycloaddition of in situ generated nitrile oxides and arynes.
Org. Lett. 2010, 12, 1180−1183.
(17) See refs 2a, 2b, 3c, 4c, 6, and 9.
(18) SYBYL, version 8.0; Tripos International: St. Louis, MO, U.S.A.
(19) (a) Lipinski, C. A.; Lombardo, F.; Dominay, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv. Drug
Delivery Rev. 1997, 23, 3−25. (b) Veber, D. F.; Johnson, S. R.; Cheng,
H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties
that influence the oral bioavailability of drug candidates. J. Med. Chem.
2002, 45, 2615−2623.
(20) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced 1,2-
elimination of o-trimethylsilylphenyl triflate to benzyne under mild
conditions. Chem. Lett. 1983, 1211−1214.
(21) See examples of the use of these procedures for the synthesis of
combinatorial libraries in: Dubrovskiy, A. V.; Markina, N. A.; Larock,
R. C. Iodocyclization, followed by palladium-catalyzed coupling: a
versatile strategy for heterocyclic library construction. Comb. Chem.
High Throughput Screening 2012, 15, 451−472.
(22) (a) Pearlman, R. S.; Smith, K. M. Novel software tools for
chemical diversity. Perspect. Drug Discovery Des. 1998, 339−353.
(b) Pearlman, R. S.; Smith, K. M. Metric validation and the receptor-
relevant subspace concept. J. Chem. Inf. Comput. Sci. 1999, 39, 28−35.
(c) Schnur, D. Design and diversity analysis of large combinatorial
libraries using cell-based methods. J. Chem. Inf. Comp. Sci. 1999, 39,
36−45. (d) Menard, P. R.; Mason, J. S.; Morize, I.; Bauerschmidt, S.
Chemistry space metrics in diversity analysis, library design, and
compound selection. J. Chem. Inf. Comp. Sci. 1998, 38, 1204−1213.
(23) See, for example: Shi, F.; Larock, R. C. Synthesis of substituted
indazoles via [3 + 2] cycloaddition of benzyne and diazo compounds.
[1H-Indazole-3-carboxylic acid, ethyl ester]. Org. Synth. 2010, 87, 95.
(24) Adapted from Carpenter, R. D.; DeBerdt, P. B.; Holden, J. B.;
Milinkevich, K. A.; Min, T.; Willenbring, D.; Fettinger, J. C.; Tantillo,
D. J.; Kurth, M. J. Design and synthesis of propeller-shaped
dispiroisoxazolinopiperidinochromanones. J. Comb. Chem. 2008, 10,
225−229.
(7) Vaidya, S. D.; Kumar, B. V. S.; Kumar, R. V.; Bhise, U. N.;
Mashelkar, U. C. Synthesis, anti-bacterial, anti-asthmatic, and anti-
diabetic activities of novel N-substituted-2-(benzo[d]isoxazol-3-
ylmethyl)-1H-benzimidazoles. J. Heterocycl. Chem. 2007, 44, 685−691.
(8) (a) Shutske, G. M.; Setescak, L. L.; Allen, R. C.; Davis, L.;
Effland, R. C.; Ranbom, K.; Kitzen, J. M.; Wilker, J. C.; Novick, W. J.
[(3-Aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids. A new diuretic series. J.
Med. Chem. 1982, 25, 36−44. (b) Plattner, J. J.; Fung, A. K. L.; Parks,
J. A.; Pariza, R. J.; Crowley, S. R.; Pernet, A. G.; Bunnell, P. R.; Dodge,
P. W. Substituted 5,6-dihydrofuro[3,2-f ]-1,2-benzisoxazole-6-carbox-
ylic acids: high-ceiling diuretics with uricosuric activity. J. Med. Chem.
1984, 27, 1016−1026. (c) Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.;
Aoki, B.; Koga, H. Studies on uricosuric diuretics. III. Substituted 1,3-
(25) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Licandro, E.; Maiorana,
S.; Perdicchia, D. Synthesis of N,N-dialkyl-N′-arylhydrazines via
H
dx.doi.org/10.1021/co300159g | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
palladium-catalyzed N-arylation by using N,N-dialkylhydrazines/2LiCl
adducts. Org. Lett. 2005, 7, 1497−1500.
(26) (a) 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. (b) Tretyakov, E. V.; Tkachev, A. V.; Rybalova, T. V.;
Gatilov, Y. V.; Knight, D. W.; Vasilevsky, S. F. Reaction of
arylpropargyl aldehydes with 2,3-bis-hydroxylamino-2,3-dimethylbu-
tane: synthesis of 2-(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2-
ylidene)-1-arylethanones. Tetrahedron 2000, 56, 10075−10080.
(c) Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.;
Gram, H.; Hiestand, P.; Manning, U.; Neumann, U.; Rucklin, G.
Pyrazoloheteroaryls: Novel p38α MAP kinase inhibiting scaffolds with
oral activity. Bioorg. Med. Chem. Lett. 2006, 16, 262−266.
(27) Marchais-Oberwinkler, S.; Wetzel, M.; Ziegler, E.; Kruchten, P.;
Werth, R.; Henn, C.; Hartmann, R. W.; Frotscher, M. New drug-like
hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-
hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of
estrogen-dependent diseases. J. Med. Chem. 2011, 54, 534−547.
I
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