Abstract
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.
Introduction
Low molecular weight heterocycles are among the most highly recognized pharmacophores.1 Among them, the benzisoxazole scaffold has evolved as a convenient bioisosteric 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).
Figure 1.
Examples of medicinally relevant benzisoxazoles.
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.
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 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).
Scheme 1.
Aryne Methodology for the Synthesis of Benzisoxazoles.
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; b) elaboration using Pd-catalyzed coupling processes if the building block possesses a Br/I handle, such as the 3-haloaryl-substituted benzisoxazoles 6 (Scheme 2).
Scheme 2.
Parent Benzisoxazole Scaffolds and Derivatization Methodology.
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.
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 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 acylating/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 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.
Figure 2.
Desired Benzisoxazole Building Blocks.
Figure 3.
Distribution of the Physicochemical and Structural Properties of our Library Entries.
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 4x) 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).
Table 1.
Preparation of the Benzisoxazole Building Blocks 7-14.
| Entry | Chloro- oxime |
R’ | Benzyne Precursor |
R | Reaction Scale (mmol)a |
Product | Yield (%)b |
|---|---|---|---|---|---|---|---|
| 1 | 15 | 4-(N-Boc-piperidinyl) | 19 | H | 0.25 | 7 | 88 |
| 2 | 15 | ” | 19 | H | 0.50 | 7 | 78 |
| 3 | 15 | ” | 20 | OMe | 0.25 | 8 | 59 |
| 4 | 15 | ” | 20 | OMe | 0.75 | 8 | 40 |
| 5 | 16 | (S)-2-(N-Boc-pyrrolidmyl) | 19 | H | 0.25 | 9 | 85 |
| 6 | 16 | ” | 19 | H | 0.50 | 9 | 88 |
| 7 | 16 | ” | 20 | OMe | 0.50 | 10 | 73 |
| 8 | 16 | ” | 21 | Me | 0.50 | 11 | 51 |
| 9 | 16 | ” | 21 | Me | 1.00 | 11 | 33 |
| 10 | 16 | ” | 22 | C4H4 | 0.50 | 12 | 50 |
| 11 | 17 | 3-iodo-4,5-dimethoxyphenyl | 19 | H | 0.25 | 13 | 76 |
| 12 | 17 | ” | 19 | H | 0.50 | 13 | 56 |
| 13 | 18 | 5-bromo-2-fluorophenyl | 19 | H | 0.25 | 14 | 57 |
| 14 | 18 | ” | 19 | H | 0.50 | 14 | 54 |
The amount of chlorooxime used.
Isolated yields after normal phase column chromatography.
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 the three (73% yield of the corresponding benzisoxazole 10, entry 7). The dimethylbenzyne and the symmetrical naphthalyne 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 diversification 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, parallel concentration, addition of fresh DCM followed by basification using triethylamine (5.0 equiv), and finally the addition of an acyl/sulfonyl 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 3495% yields and excellent purities (88 to >99%) after MDF purification.
Table 2.
Data for library compounds 21 {1-17}.
| Product | R | HRMS (calcd) |
HRMS (found)a |
Purity (%)b |
Yield (%)c |
|---|---|---|---|---|---|
| 23{1} | H | 298.0929 | 299.1051 | 99 | 24 |
| 23{2} | H | 296.1161 | 297.1249 | >99 | 35 |
| 23{3} | H | 272.1525 | 273.1619 | >99 | 52 |
| 23{4} | H | 315.1583 | 316.1671 | >99 | 31 |
| 23{5} | H | 313.1790 | 314.1880 | >99 | 36 |
| 23{6} | H | 312.0932 | 313.1023 | 88 | (3) |
| 23{7} | H | 306.1402 | 307.1512 | 95 | 21 |
| 23{8} | H | 342.1038 | 343.1134 | >99 | 32 |
| 23{9} | H | 348.0602 | 349.0710 | 99 | 26 |
| 23{10} | H | 346.1100 | 347.1189 | >99 | 52 |
| 23{11} | H | 347.0940 | 348.1025 | 97 | 48 |
| 23{12} | H | 343.0991 | 344.1068 | 95 | 29 |
| 23{13} | H | 497.9248 | 498.9355 | 96 | 62d |
| 23{14} | H | 366.1579 | 367.1654 | 99 | 95d |
| 23{15} | OMe | 358.1140 | 359.1227 | 88 | (4) |
| 23{16} | OMe | 366.1613 | 367.1704 | >99 | 33 |
| 23{17} | OMe | 346.1892 | 347.1986 | 94 | 23 |
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), acyl/sulfonyl chloride (1.5 equiv) and anhydrous CH2Cl2 were used.
for [M+H]+
UV purity determined at 214 nm after preparative HPLC.
Isolated yields after MDF column chromatography. Yields in parentheses are considered failed entries (<90% purity and/or <5 mg quantity).
Purified by normal phase column chromatography.
Figure 4.
Derivatized 3-(4-Piperidinyl)benzisoxazoles.
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 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.
Table 3.
Data for library compounds 24{1-41}.
| Product | R | HRMS (calcd) |
HRMS (found)a |
Purity (%)b |
Yield (%)c |
|---|---|---|---|---|---|
| 24{1} | H | 337.1063 | 338.1152 | 96 | 27d |
| 24{2} | H | 284.0773 | 285.0860 | >99 | 41 |
| 24{3} | H | 282.1004 | 283.1085 | >99 | 26 |
| 24{4} | H | 317.1164 | 318.1272 | >99 | 51 |
| 24{5} | H | Not found | - | (nd) | |
| 24{6} | H | 299.1634 | 300.1737 | >99 | 38 |
| 24{7} | H | 258.1368 | 259.1455 | >99 | 52 |
| 24{8} | H | 324.1274 | 325.1378 | >99 | 41 |
| 24{9} | H | 360.1086 | 361.1174 | >99 | 56 |
| 24{10} | H | 306.1368 | 307.1478 | >99 | 28 |
| 24{11} | H | 360.1086 | 361.1164 | >99 | 33 |
| 24{12} | H | 301.1426 | 302.1525 | >99 | 43 |
| 24{13} | H | 300.1222 | 301.1306 | >99 | 44 |
| 24{14} | H | 298.0776 | 299.0862 | >99 | 24 |
| 24{15} | H | 332.0943 | 333.1033 | >99 | 45 |
| 24{16} | H | 334.0446 | 335.0540 | 98 | 43 |
| 24{17} | H | 328.0882 | 329.0983 | >99 | 38 |
| 24{18} | H | 346.0787 | 347.0879 | >99 | 57 |
| 24{19.1} | H | 292.1245 | 293.1357 | 96 | 37e |
| 24{19.2} | H | 292.1245 | 293.1335 | 94 | 37e |
| 24{20} | H | Not found | - | (nd) | |
| 24{21} | OMe | 430.0528 | 431.0629 | 99 | 28 |
| 24{22} | OMe | 332.1736 | 333.1831 | >99 | 30 |
| 24{23} | OMe | 344.0984 | 345.1090 | >99 | 34 |
| 24{24} | OMe | 388.1093 | 389.1180 | >99 | (5) |
| 24{25} | OMe | 432.0991 | 433.1060 | 99 | (3) |
| 24{26} | OMe | 406.0999 | 407.1081 | >99 | 34 |
| 24{27.1} | OMe | 352.1457 | 353.1548 | >99 | 28e |
| 24{27.2} | OMe | 352.1457 | 353.1553 | >99 | 28e |
| 24{28} | Me | 312.1085 | 313.1180 | >99 | (3) |
| 24{29} | Me | 300.1837 | 301.1925 | >99 | 40 |
| 24{30} | Me | 327.1946 | 328.2033 | >99 | 43 |
| 24{31} | Me | 300.1837 | 301.1941 | 92 | (7) |
| 24{32} | Me | 328.1535 | 329.1629 | 60 | (1) |
| 24{33} | Me | 329.1739 | 330.1854 | >99 | 32 |
| 24{34} | Me | 362.0758 | 363.0855 | 94 | 27 |
| 24{35.1} | Me | 320.1558 | 321.1657 | >99 | 46e |
| 24{35.2} | Me | 320.1558 | 321.1650 | 95 | 46e |
| 24{36} | Me | 365.1375 | 366.1476 | 92 | 39 |
| 24{37} | Me | 361.1096 | 362.1197 | 96 | 36 |
| 24{38} | C4H4 | 387.1219 | 388.1332 | >99 | 29 |
| 24{39} | C4H4 | 334.0929 | 335.1029 | >99 | 36 |
| 24{40.1} | C4H4 | 342.1402 | 343.1505 | >99 | 37e |
| 24{40.2} | C4H4 | 342.1402 | 343.1513 | 92 | (37)e |
| 24{41} | C4H4 | 350.1319 | 351.1490 | >99 | 10 |
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), acyl/sulfonyl chloride (1.5 equiv) and anhydrous CH2Cl2 were used.
for [M+H]+
UV purity determined at 214 nm after preparative HPLC.
Isolated yields after MDF column chromatography. Yields in parentheses are considered failed entries (<90% purity and/or <5 mg quantity).
Purified by normal phase column chromatography.
Combined yield for the two diastereomers formed.
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 sequences, 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.
Figure 6.
Benzisoxazoles Derivatized through Pd/Cu-Catalyzed Coupling.
Table 4.
Data for library compounds 25{1-9}.
| Product | Reaction | HRMS (calcd) |
HRMS (found)a |
Purity (%)b |
Yield (%)c |
|---|---|---|---|---|---|
| 25{1} | Aminationd | 355.1532 | 356.1635 | >99 | 41 |
| 25{2} | ” | 313.1226 | 314.1322 | 97 | 14e |
| 25{3} | Sonogashiraf | 335.1322 | 336.1407 | 98 | 39 |
| 25{4} | ” | 334.1481 | 335.1555 | 90 | 30 |
| 25{5} | ” | Not found | - | (nd) | |
| 25{6} | ” | 281.0852 | 282.0927 | >99 | 16 |
| 25{7} | Suzuki-Miyaurag | 290.0855 | 291.0941 | >99 | 32 |
| 25{8} | ” | 291.0808 | 292.0885 | >99 | 25 |
| 25{9} | ” | 279.0696 | 280.0992 | >99 | 7 |
Reactions were performed on a 0.25 mmol scale.
for [M+H]+.
Yield/Purities as in a. Yields in parentheses are considered failed entries (<90% purity and/or <5 mg quantity).
Yield/Purities as in a. Yields in parentheses are considered failed entries (<90% purity and/or <5 mg quantity).
For Hartwig-Buchwald coupling: alkyl hydrazine (2.0 equiv), LiCl (4.0 equiv), Pd2(dba)3 (2.5 mol%), Xantphos (5 mol%), NaOtBu (2.0 equiv), dioxane, 85 °C, 33 h.
Purified by normal phase column chromatography.
For Sonogashira coupling: CuI (3 mol%), 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.
Hartwig-Buchwald coupling 25 of 3-(3-iodo-4,5-dimethoxyphenyl)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 of the desired compounds after MDF purification, we were able to obtain 25{2} in a 14% yield after purification using normal phase chromatography.
Scheme 3.
Hartwig-Buchwald Amination of 13 and 14.
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.
Scheme 4.
Sonogashira coupling of 14.
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).
Scheme 5.
Suzuki-Miyaura coupling of 14.
Conclusions
The aryne-mediated preparation and subsequent acylation/sulfonylation and palladium-catalyzed reactions of benzisoxazoles 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%.
Supplementary Material
Acknowledgments
Funding Sources
We are grateful to the National Institute of General Medical Sciences for their generous financial support through grants GM079593 and GM070620 to RCL and to the NIH Chemical Methodologies and Library Development Center at the University of Kansas (P50 GM069663).
Footnotes
Supporting Information. Experimental details and characterization of a representative 20 library members, including full 1H and 13C NMR spectra and conditions for their high throughput liquid chromatography purification. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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