Preparation of a Spiroisoxazolinopiperidinylbenzamide-Based Scaffold

Abstract

A route to spiroisoxazolinopiperidinylbenzamides has been developed. N-Boc-4-piperidone underwent a Wittig olefination and Boc-deprotection followed by a nucleophilic substitution reaction with 4-fluoro-3-nitrobenzoic acid to yield the starting scaffold 3 in excellent yields. Diversification of the acid with primary amines, followed nitrile oxide formation in situ (aryl oximes treated with bleach) and subsequent 1,3-dipolar cycloaddition to the exo­methylene moiety delivered the spiroisoxazolinopiperdines. Reduction of the arylnitro group followed by acylation with acid chlorides or reductive amination with aldehydes yielded the spiroisoxazolinopiperidinylbenzamide library.

Key words

nitrile oxide - isoxazolines - nucleophilic substitution - cycloaddition - piperidines

References and Notes

• 1a Hwang IT. Hong KS. Choi JS. Kim HR. Jeon DJ. Cho KY. Pestic. Biochem. Physiol.  2004,  80:  123 
• 1b Hwang IT. Kim HR. Jeon DJ. Hong KS. Song JH. Cho KY. J. Agric. Food. Chem.  2005,  53:  8639 
• 2a Dabideen DR. Cheng KF. Aljabari B. Miller EJ. Pavlov VA. Al-Abed Y. J. Med. Chem.  2007,  50:  1993 
• 2b Shin HI, Choi HW, Heo TH, Lee KW, Lee JH, and Park KS. inventors; Isoxazoline derivative and novel process for its preparation. PCT Int. Appl. WO 2006/090997  A1. 
• 2c Habeeb AG. Rao PNP. Knaus EE. J. Med. Chem.  2001,  44:  2921 
• 3 Tangallapally RP. Sun D. Rakesh Budha N. Lee REB. Lenaerts AJM. Meibohm B. Lee RE. Bioorg. Med. Chem. Lett.  2007,  17:  6683 
• 4a Mishra RC. Tewari N. Verma SS. Tripathi RP. Kumar M. Shukla PK. J. Carbohydr. Chem.  2004,  23:  353 
• 4b Zadrożna I. Kurkowska J. Kruszewska H. Makuch I. Farmaco  2000,  55:  499 
• 4c Gaonkar SL. Rai KML. Prabhuswamy B. Med. Chem. Res.  2007,  15:  407 
• 4d Basappa Sadashiva MP. Mantelingu K. Swamy SN. Rangappa KS. Bioorg. Med. Chem.  2003,  11:  4539 
• 5 Kai H. Matsumoto H. Hattori N. Takase A. Fujiwara T. Sugimoto H. Bioorg. Med. Chem. Lett.  2001,  11:  1997 
• 6a

  Structures for these compounds are depicted in Figure
  SI-1 in the Supporting Information file

• 6b Xu J. Wang J. Ellis ED. Hamme AT. Synthesis  2006,  3815 
• 7a

  Structures for these compounds are depicted in Figure
  SI-2 in the Supporting Information file

• 7b Longeon A. Guyot M. Vacelet J. Experientia  1990,  46:  548 
• 7c Kobayashi J. Tsuda M. Agemi K. Shigemori H. Ishibashi M. Sasaki T. Mikami Y. Tetrahedron  1991,  47:  6617 
• 8 Viegas C. Silva DHS. Pivatto M. de Rezende A. Castro-Gambôa I. Bolzani VS. Nair MG. J. Nat. Prod.  2007,  70:  2026 
• 9 Mochizuki A. Nakamoto Y. Naito H. Uoto K. Ohta T. Bioorg. Med. Chem. Lett.  2008,  18:  782 
• 10 Kazmierski W. Bifulco N. Yang H. Boon L. DeAnda F. Watson Ch. Kenakin T. Bioorg. Med. Chem.  2003,  11:  2663 
• 11a Krafft EA. Kurt A. Maier A. Thomas AW. Zimmerli D. Synthesis  2005,  3245 
• 11b DeSimone RW. Currie KS. Mitchell SA. Darrow JW. Pippin DA. Comb. Chem. High Throughput Screening  2004,  7:  473 
• 12a Bruncko M. Oost TK. Belli BA. Ding H. Joseph MK. Kunzer a. Martineau D. McClellan WJ. Mitten M. Ng S.-C. Nimmer PM. Oltersdorf T. Park C.-M. Petros AM. Shoemaker AR. Song X. Wang X. Wendt MD. Zhang H. Feski SW. Rosenberg SH. Elmore SW. J. Med. Chem.  2007,  50:  651 
• 12b De Amici M. Conti P. Vistoli G. Carrea G. Ottolina G. De Micheli C. Med. Chem. Res.  2001,  10:  615 
• 12c De Amici M. Frølund B. Hjeds H. Krogsgaard-Larsen P. Eur. J. Med. Chem.  1991,  26:  625 
• 12d Fišera L. Sauter F. Fröhlich J. Feng Y. Ertl P. Mereiter K. Monatsh. Chem.  1994,  125:  553 
• 12e Robins LI. Kurth MJ. Org. Lett.  2007,  9:  171 
• 12f Hwang SH. Lehman A. Cong X. Olmstead MM. Lam KS. Lebrilla CB. Kurth MJ. Org. Lett.  2004,  6:  3829 
• 12g Tsukamoto S.-I. Nagoka H. Igarashi S. Wanibuchi F. Hidaka K. Tamura T. Chem. Pharm. Bull.  1995,  43:  1523 
• 13a Lessel U. Wellenzohn B. Lilienthal M. Claussen H. J. Chem. Inf. Model.  2009,  49:  270 
• 13b Boehm M. Wu T.-Y. Claussen H. Lemmen C. J. Med. Chem.  2008,  51:  2468 
• 13c Spandl RJ. Bender A. Spring DR. Org. Biomol. Chem.  2008,  6:  1149 
• 13d Yoo CL. Yu GJ. Yang B. Robins LI. Verkman AS. Kurth MJ. Bioorg. Med. Chem. Lett.  2008,  18:  2610 
• 14a Mineno T. Miller MJ. J. Org Chem.  2003,  68:  6591 
• 14b Quan C. Kurth MJ. J. Org. Chem.  2004,  69:  1470 
• 14c Sammelson RE. Miller RB. Kurth MJ. J. Org. Chem.  2000,  65:  2225 
• 14d Cheng J.-F. Mjalli AMM. Tetrahedron Lett.  1998,  39:  939 
• 15 Dixon SM. Milinkevich KA. Fujii J. Liu R. Yao N. Lam KS. Kurth MJ. J. Comb. Chem.  2007,  9:  143 
• 16 Beccalli EM. Broggini G. Martinelli M. Masciocchi N. Sottocornola S. Org. Lett.  2006,  8:  4521 
• 17a Alberola A. Gonzalez AM. Laguna MA. Pulido FJ. Synthesis  1983,  413 
• 17b Antonevich IP. Chem. Heterocyl. Compd.  2003,  39:  1355 
• 17c Churykau DH. Zinovich VG. Kulinkovich OG. Synlett  2004,  1949 
• 18a Wu X.-H. Liu G. Zhang J. Wang Z.-G. Xu S. Zhang S.-D. Zhang L. Wang L. Mol. Diversity  2004,  8:  165 
• 18b Bellamy FD. Ou K. Tetrahedron Lett.  1984,  25:  839 

19

Procedure for Olefin Synthesis: tert -Butyl 4-Methylenepiperidine-1-carboxylate (2). Methyltriphenylphosphonium bromide (35.86 g, 110.4 mmol) was dissolved in anhydrous THF (100 mL) and cooled in an ice bath. Potassium tert-butoxide (1.0 M in THF, 105.4 mL, 105.4 mmol) was added and the reaction mixture was stirred at 0 ˚C for 30 min, then warmed to room temperature for 30 min, and warmed to reflux for 1 h.
The reaction mixture was cooled in an ice bath and a solution of N-Boc-4-piperidone (10.00 g, 50.19 mmol) in anhydrous THF (50 mL) was added. The mixture was removed from the ice bath and warmed to reflux until TLC showed the reaction was complete (˜4 h). The reaction mixture was diluted with water, concentrated by rotary evaporation, and extracted with EtOAc (3×). The combined organic layers were dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (EtOAc-hexane, 1:9) gave 2 as a colorless oil (8.76 g, 88% yield). IR (neat): 2977, 2940, 2907, 2865, 1692, 1652, 1416, 1365, 1235, 1165, 1114 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 4.74 (s, 2 H), 3.42 (t, J = 5.7 Hz, 4 H), 2.18 (t, J = 5.7 Hz, 4 H), 1.47 (s, 9 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 154.9, 145.5, 109.2, 79.6, 45.5, 34.7, 28.6; MS (ESI): m/z = 198 [C₁₁H₂₀NO₂ ⁺]. Purity was determined to be 89% by HPLC analysis.
Procedure for Scaffold Synthesis: 4-(4-Methylene-piperidin-1-yl)-3-nitrobenzoic Acid (3). tert-Butyl 4-methylenepiperidine-1-carboxylate (2; 4.71 g, 23.9 mmol) was dissolved in CH₂Cl₂ (50 mL) and trifluoroacetic acid (50 mL) was added. The reaction mixture was stirred at room temperature for 2 h after which it was concentrated by rotary evaporation. The residue was dissolved in CH₂Cl₂ (20 mL) and triethylamine was added until the solution reached pH 8. 4-Fluoro-3-nitrobenzoic acid (2.21 g, 12.0 mmol) was dissolved in a separate flask in CH₂Cl₂ (20 mL) and DIPEA (8.33 mL, 47.8 mmol) was added at 0 ˚C. The mixture was stirred for 30 min at which time the pH 8 solution of deprotected amine was added dropwise and stirred overnight while warming to room temperature. The reaction mixture was concentrated by rotary evaporation, the crude oil was dissolved in ethyl acetate and water, and the pH was adjusted to pH ˜3 with 1 M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (MeOH-CHCl₃, 1:9) gave 3 as a bright orange solid (2.95 g, 94% yield). A small portion of the product was further purified for analytical purposes; mp 137-138 ˚C; IR (neat): 2949, 2905, 2854, 2168, 1676, 1600, 1526, 1491, 1428, 1388, 1348, 1293, 1264, 1231, 1206, 1160, 1127, 1065 cm^-¹; ^¹H NMR (600 MHz, DMSO-d ₆): δ = 13.08 (s, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 8.00 (dd, J = 9.0, 1.8 Hz, 1 H), 7.34 (d, J = 9.0 Hz, 1 H), 4.81 (s, 2 H), 3.18 (t, J = 5.4 Hz, 4 H), 2.32 (t, J = 5.4 Hz, 4 H); ^¹³C NMR (150 MHz, DMSO-d ₆): δ = 165.7, 148.1, 144.1, 139.0, 134.2, 127.8, 121.1, 120.5, 109.6, 51.7, 33.6; MS (ESI): m/z = 263 [C₁₃H₁₅N₂O₄ ⁺]. Purity was determined to be ˜100% by HPLC analysis.

General Procedure for Amine Coupling to 5{1-2}. Compound 3 (1 equiv), HOBt (1.4 equiv), and EDC (1.4 equiv) were dissolved in a mixture of CH₂Cl₂-DMF (4:1, 50 mL) at 0 ˚C and stirred for 30 min. The requisite amine (1.8 equiv) was added dropwise and the solution was stirred overnight while warming to room temperature. The resulting solution was concentrated by rotary evaporation and taken up in EtOAc (50 mL). The solution was then extracted with saturated aq. NaHCO₃ (50 mL), 1 M HCl (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (EtOAc-hexane) gave 5{1-2} in 78-98% yield.
General Procedure for Isoxazoline Synthesis to give 7{1-2,1-2}. Compound 5{1-2} (1 equiv) was dissolved in CH₂Cl₂ (5 mL) and bleach (laboratory grade, 5.65%, 4 equiv) was added at 0 ˚C. A solution of the requisite oxime 6{1-2} (2 equiv) in CH₂Cl₂ (5 mL) was added via addition funnel to the reaction mixture. The resulting solution was stirred overnight. Water (20 mL) and CH₂Cl₂ (20 mL) were added and the layers were separated. The organic layer was extracted with water (2×) and the combined organic layers were dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (EtOAc-hexane) gave 7{1-2,1-2} in 50-89% yield.
General Procedure for Aryl Nitro Reduction to give 8{1-2,1-2}. Compound 7{1-2,1-2} (1 equiv) and tin(II) chloride dihydrate (3 equiv) were dissolved in MeOH (10 mL) and stirred for 10 min. Concentrated HCl (6 equiv) was added dropwise and the mixture was warmed to reflux until TLC showed the reaction was complete. The solution was cooled to room temperature and concentrated by rotary evaporation. The resulting oil was dissolved in CH₂Cl₂ (10 mL) and water (10 mL) and the mixture was adjusted to pH ˜7 with 1 M NaOH. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2×). The combined organic layers were dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (EtOAc-hexane) gave 8{1-2,1-2} in 74-93% yield.
General Procedure for Acid Chloride Coupling to give 10{1-2,1-2,1-9}. Compound 8{1-2,1-2} (1 equiv) was dissolved in anhydrous THF (5 mL) and pyridine (1.5 equiv) was added. The solution was cooled to 0 ˚C and the requisite acid chloride (1.2 equiv) was added dropwise. The mixture was stirred overnight, after which time TLC showed the reaction was complete. Water (5 mL) and diethyl ether (5 mL) were added and the solution was adjusted to pH ˜7 with 1 M NaOH. The layers were separated and the aqueous layer was extracted with diethyl ether (2×). The combined organic layers were dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by flash chromatography (EtOAc-hexane) gave 10{1-2,1-2,1-9} in 47-94% yield.
General Procedure for Reductive Amination to give 12{2,1-2,1-4}. Compound 8{2,1-2} (1 equiv) was dissolved in CH₂Cl₂ (5 mL) and the requisite aldehyde (1.5 equiv) and acetic acid (4 equiv) were added. The solution was stirred for 6 h after which time sodium cyanoborohydride (5 equiv) was added. The mixture was stirred overnight, concentrated by rotary evaporation, and taken up in ethyl acetate (10 mL). The organic layer was washed with saturated aq. NaHCO₃, 1M HCl, and brine. The organic layer was dried over MgSO₄, filtered, and concentrated by rotary evaporation. Purification by MPLC gave 12{2,1-2,1-4} in 48-62% yield.