Synthesis of Piperidine Bound 3,4,5-Trisubstituted Isoxazolines Via  1,3- Dipolar Cycloaddition Reactions Catalyzed By N-Heterocyclic Carbene

 

Prasad Gundepaka^1,3, Shravankumar Kankala²*, Hanmanthu Guguloth², Shylaja Kotte², Vinutha Chakilam², Mukkanti Kagga¹, Ravinder Vadde²*, Chandra Sekhar Vasam³*

¹Centre for Pharmaceutical Science, Institute of Science and Technology, JNTU, Hyderabad, India.

²Department of Chemistry, Kakatiya University, Warangal, India -506 009,

³Department of Chemistry, Satavahana University, Karimnagar, India-505 001,

*Corresponding Author E-mail: shravankankala@yahoo.com, ravichemku@rediffmail.com, vasamcs@yahoo.co.in

A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with piperidine alkene alkaloids was developed for the regioselective synthesis of 3,4,5-trisubstituted isoxazolines. Triethylamine (Et₃N) was employed as an effective base to generate both nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety of substituents, including other biologically active fragments, onto the isoxazoline ring to selectively design multinucleus structures. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of isoxazolines was ascribed to a beneficial zwitterion intermediate developed by the interaction of the strongly nucleophilic organo-NHC catalyst with alkene followed by nitrile oxide.

 

 

INTRODUCTION:

Most of the nitrogen-containing heterocycles play an important role in pharmaceutical sciences and many other areas of organic chemistry. Among the most widely employed these five-membered rings are the isoxazoles and isoxazolines. Their preparation has been extensively discussed in the literature and typical access routes involve condensations with hydroxylamine, cyclizations of ketoxime dianions, and propargylic oximes, and in particular 1,3-dipolar cycloaddition reactions^1-10. Surprisingly, only few of the reported methods are general and versatile, as many suffer from low functional group tolerance, and modest regioselectivities and yields.

 

1,3-Dipolar cycloaddition of nitrile oxides with terminal alkynes catalyzed by Cu(I) (click chemistry) and Ru(II) catalysts is well established to obtain regioselectively the 3,5-di- and 3,4-disubstituted isoxazoles, respectively^7-10. The Ru(II) catalysts were also used in the cycloaddition of internal alkynes to obtain sterically crowded 3,4,5-trisubstituted isoxazoles⁷.

 

However, no investigations using organocatalysts to accelerate the 1,3-dipolar cycloaddition for alkenes have not been reported.

 

Considering the possible disproportionation by metal catalysts and the advantages found with organocatalysts in recent homogeneous catalysis^11-13, we intend to develop an effective organocatalyst for 1,3-dipolar cycloaddition.

 

Probably, a strong Lewis basic organocatalyst would be suitable to accelerate the reactivity of internal alkenes by forming an active zwitterion and thereby directing regioselective cycloaddition. The formation of zwitterions (alkenyl and alkyl ion) in the stoichiometric/catalytic reactions of Lewis basic nucleophiles, including NHCs, with alkynes in some organic syntheses has already been reported^14-16.

 

Within the context of Lewis base catalysis, N-heterocyclic carbenes (NHCs) are distinct Lewis base (nucleophilic) organocatalysts that have both σ basicity and π acidity characteristics^17-21. Further, the imidazolium salts, precursors to NHCs, are stable and easy to operate.

 

EXPERIMENTAL:

General:

All commercially available reagents were used without further purification.  Reaction solvents were dried by standard methods before use. Purity of the compounds was checked by TLC using Merck 60F254 silica gel plates. Elemental analyses were obtained with an Elemental Analyser Perkin-Elmer 240C apparatus. ¹H and ¹³C NMR spectra were recorded with a Mercuryplus 200 spectrometer (operating at 200 MHz for ¹H and 50 MHz for ¹³C); chemical shifts were referenced to TMS. EI (electron impact) mass spectra (at an ionising voltage of 70 eV) were obtained using a Shimadzu QP5050A quadrupole-based mass spectrometer. IR spectra were recorded with a Perkin-Elmer 881 spectrometer.

 

General procedure for the synthesis of isoxazolines substituted piperidines:

Alkenes 5a & 5b (1 mmol) and NHC Precursor (i) (5 mol %) in dry DCM (5 ml) under nitrogen atmosphere was added Et₃N (5 mol%). The mixture was stirred for 10 min.  The reaction mixture was cooled to 0-5 ºC and added dropwise to a solution of benzonitrile oxide 6a-c (1 mmol), generated in situ by the treatment of triethylamine (1.2 mmol) with the corresponding chloro oximes (1 mmol) in dry DCM (10 ml) over a period of 2 minutes while maintaining the temperature between 0-5 ºC. The reaction mass was allowed to attain room temperature and stirring was continued for 50 minutes. After conversion was complete, the mixture was quenched by addition of saturated solution of NH₄Cl (2 ml) and diluting with dichloromethane (40 ml). The organic layer was separated and the aqueous layer extracted with dichloromethane (2 x 20 ml). The combined organic layers were dried (anhydrous Na₂SO₄) and evaporated under reduced pressure to afford a crude product which was subjected to column chromatography (silica gel, 60-120 mesh, eluent; n-hexane/EtOAc gradient) to afford pure products (7a-f).

 

Compound (7a): ¹H NMR (200 MHz, CDCl₃): δ = 1.22-1.43 (m, 2H), 1.68-1.83 (m, 5H), 2.22-2.32 (m, 1H), 2.36 (s, 3H), 2.62 (m, 1H), 3.08 (br d, 1H), 3.26 (d, 1H), 5.45 (d, 1H), 6.82 (d, 2H, Ar-H), 7.15 (d, 2H, Ar-H), 7.56 (d, 2H, Ar-H), 8.10 (d, 2H, Ar-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 23.24, 24.80, 28.45, 35.41, 36.22, 52.35, 52.82, 67.60, 115.30, 123.52, 128.85, 129.20, 132.85, 136.32, 150.25, 153.10, 162.52 ppm. MS (EI, 70 eV): m/z (%) = 404 [M+Na]⁺. EA calcd (%) for C₂₁H₂₃N₃O₄: (381.17): C 66.13, H 6.08, N 11.02; found C 66.12, H 6.03, N 11.00.

 

Compound (7d): ¹H NMR (200 MHz, CDCl₃): δ = ¹H NMR (200 MHz, CDCl₃): δ = 0.98-1.20 (m, 2H), 1.12 (d, 3H), 1.28-1.40 (m, 2H), 1.35 (d, 3H), 1.54-1.59 (m, 2H), 2.04-2.07 (m, 1H), 3.24 (d, 1H), 4.36 (d, 1H), 7.56 (d, 2H, Ar-H), 8.10 (d, 2H, Ar-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 20.32, 21.22, 22.60, 30.91, 35.05, 39.44, 44.82, 47.45, 59.31, 123.64, 129.22, 136.56, 150.40, 164.20 ppm. MS (EI, 70 eV): m/z (%) = 326 [M+Na]⁺. EA calcd (%) for C₁₆H₂₁N₃O₃: (303.16): C 63.35, H 6.98, N 13.85; found C 63.33, H 6.96, N 13.82.

 

RESULTS AND DISCUSSION:

Herein we describe for the first time the usefulness of easily accessible nucleophilic organo-NHC catalysts in the click-type 1,3-dipolar cycloaddition of nitrile oxides with (+)-Caulophyllumine B (1a) and (+)-Pinidine (1b) contain an internal alkene linkage, we have employed them as dienophiles in 1,3-dipolar cycloadditions to produce regioselectively sterically crowded piperidine-bound 3,4,5-trisubstituted isoxazoline (Scheme 1). The reaction conditions optimized and the results obtained are depicted in Table 1. Nitrile oxides (2a-c) were prepared according to the literature methods and our report²².

 

 

Scheme 1 Synthesis of piperidine-bound 3,4,5-trisubstituted isxazolines

 

 

Two pilot reaction performed between (i) 2a with 1a and (ii) 2a with 1b in THF without a catalyst have produced the corresponding 3,4,5-trisubstituted isoxazolines up to a maximum yield of ~ 65% after ~ 12 h (Table 1, entries 1 and 2) as determined initially by TLC and then GC method. However, the regioselectivity was found to be a considerable problem specifically in the case of reaction of 2a with 1b i.e. with Pinidine (Table 4, entry 2). This could be due to the presence of sterically less crowded methyl group on 1b as compared to 1a.

 

There are some reports described the Lewis acid or base catalyzed 1,3-dipolar cycloaddition for the regioselective synthesis of isoxazolines. Recently, we have introduced the concept of organo-NHCs as Lewis basic nucleophilic catalysts in the 1,3-dipolar cycloaddition of both terminal and internal alkynes with nitrile oxides to synthesize 3,5-di and 3,4,5-trisubsituted isoxazoles regioselectively via forming an alkenyl zwitterion²². The nucleophilic interaction between an alkene and organo-NHC was also reported in some other organic transformations, but not in 1,3-dipolar cycloaddition. With this reference, we have introduced a NHC, N,N-ditertiarybutyl imidazol-2-ylidene, generated in situ by Et₃N base from the corresponding imidazolium salt (Figure 1, R = (i)), to the cycloaddition of 2a with 1b. In the presence of this organo-NHC catalyst, the reaction produced only a single regioisomer of isoxazoline product (3d) in 90% yield in a shorter reaction period of ~1 hr (Table 1, entry 6). Under the above optimized catalytic conditions, the cycloaddition of 2a with 1a also accomplished fast and gave 3a as a sole product (Table 1, entry 3). The cycloadditions of 1a and 1b conducted with other nitrile oxides also gave only a single regioisomer of corresponding trisubstituted isoxazoline products (3b-f) in moderate to good yields of 82-90% (Table 1, entry 4-8).

 

Table 1 Results of synthesis of piperidine substituted isoxazolines (3a-f) catalyzed by organo-NHC^a

Entry	Piperidine alkene	Nitrile oxide (Ar)	Product	Yield (%)b
1	1a	4-NO2C6H4 (2a)	3a	65 (9:1)c
2	1b	2a	3d	70 (7:3)c
3	1a	2a	3a	90
4	1a	C6H5 (2b)	3b	88
5	1a	4-OMeC6H4 (2c)	3c	82
6	1b	2a	3d	90
7	1b	2b	3e	89
8	1b	2c	3f	86

^aAll products were characterized by 1H/13C NMR and mass spectral analysis.

^bDetermined by G.C.

^cWith out NHC catalyst.

 

The new piperidine-linked isoxazolines were characterized by elemental analysis, ¹H & ¹³C NMR and Mass spectroscopic techniques. For example, the
molecular ions m/z values of 381 (3a of Caulophyllumine B) and 303 (3d of Pinidine) have the expected molecular formula. The ¹H & ¹³C NMR signals of internal olefin moiety of Caulophyllumine B and Pinidine were absent in their cycloaddition products. Instead, the two new signals observed at ~ d 3.2-5.4 in ¹H NMR and 60-125 in ¹³C-NMR spectra were assigned to 4,5-dihydro carbons of cycloadduct i.e. isoxazoline. Further, the C=N of isoxazolines was observed at ~ d 160-164.

 

Based on the above results and literature support, we have proposed a plausible mechanism (Scheme 2). Firstly the NHC generated in situ reacts with alkene and form an alkyl zwitterion. In the next step, the added nitrile oxide will facilitate the formation of another zwitterion via C-C bond formation, which then undergoes C-O heterocyclization to yield only a single regioisomer of isoxazoline. Importantly, the proposed mechanism has considered the stereo factors of the substituents on isoxazoline ring controlled by organo-NHC catalysts during the catalytic cycle.

 

 

Figure 1 NHC Precursors (imidazolium salts) and NHCs

 

Scheme 2 A plausible mechanism for the formation of piperidine substituted isoxazolines

 

CONCLUSION:

We have optimized the conditions for the convenient synthesis of alkene-alkaloids as dienophiles in 1,3-dipolar cycloaddition,  catalyzed by organo-NHC, to produce regioselectively the isoxazolines. This is the first effort introducing a nucleophilic organo catalysts in the 1,3-dipolar cycloaddition of alknenes in general.

 

ACKNOWLEDGEMENTS:

One of the authors S. Kankala thanks CSIR, New Delhi for the award of Research Associate.

 

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Accepted on 23.08.2013         © AJRC All right reserved