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Domino Reaction of Pyrrolidinium Ylides: Michael Addition/[1,2]Stevens Rearrangement Anna Kowalkowska,*,† Andrzej Jończyk,† and Jan K. Maurin‡,§ †

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland National Medicines Institute, Chełmska St. 30/34, 00-725 Warsaw, Poland § National Centre for Nuclear Research, Andrzeja Sołtana 7 St., 05-400 Otwock, Poland ‡

S Supporting Information *

ABSTRACT: A novel domino reaction featuring a Michael addition/[1,2]-Stevens rearrangement reaction of pyrrolidinium ylides with electrophilic alkenes is described. Ylides generated under mild conditions from 2-aryl-N-cyanomethyl-N-methylpyrrolidinium salts entered the Michael addition, followed by a [1,3]-hydrogen shift and finally the [1,2]-Stevens rearrangement to give 3-aryl-2-cyano-2-(2-EWG-ethyl)-1-methylpiperidines.

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Scheme 1. Previously Described Reactions of Ammonium Ylides with Electrophilic Alkenes

omino reactions provide an opportunity to synthesize in one step relatively complicated products from simple precursors.1−3 Many well-known domino transformations are initiated by the Michael-type addition.1,3−10 Among anions undergoing a conjugate addition to electrophilic alkenes are sulfonium,8,10−13 sulfoxonium,8,10,12 arsonium,10−12,14,15 telluronium,8,10,11,16 phosphonium,10,12,13 pyridinium,8,17 and ammonium8,11,13,17,18 ylides, generated from respective salts upon treatment with a base. The anionic intermediates thus formed usually take part in Michael-initiated ring-closure (MIRC) reactions, affording cyclopropanes or undergoing other transformations,4,8,10−12,16 giving unexpected products, 19−35 mainly dihydrofuran and benzofuran derivatives.19,23,26,29,31−33 Ammonium ylides are generated by deprotonation of quaternary ammonium salts previously synthesized34−40 or formed in situ as quaternary derivatives of DABCO41−44 or cinchona alkaloids.43−46 They undergo inter-34−42,44,46 or intramolecular43,45 Michael additions. Among Michael acceptors, there are α,β-unsaturated aldehydes, 38,39,43,44 ketones, 35,38−40,43−46 esters, 35,37−39,43,44,46 α-nitroesters, 34 amides,37,44,45 sulfones,38,39,43,44 lactones and lactams,42 acrylonitrile,37−39,44 and para-quinone methides.36 Usually, as a result, racemic37−42,44 or optically active36,43−46 cyclopropanes are formed by MIRC13,17,18 (Scheme 1, path A). There are few examples of other transformations. An addition of the cinchona-derived ammonium ylide to 2-nitroacrylates leads to optically active isoxazoline N-oxides34 (Scheme 1, path B). Strained optically active N,N-dialkyl-2-cyanoazetidinium ylides undergo the Michael addition to α,β-unsaturated esters, which, followed by an intramolecular nucleophilic substitution, afford optically active 2-(2-(N,N-dialkylamino)ethyl)-2-cyanocyclopropanecarboxylates in good yields35 (Scheme 1, path C). Ylide generated from the five-membered homologue, N-benzylN-methyl-2-cyanopyrrolidinium trifluoromethanesulfonate, re© XXXX American Chemical Society

acts with diethyl fumarate, giving a propyl analogue in a low yield35 (Scheme 1, path D). Surprisingly, to the best of our knowledge, there are no reported examples of the Michael addition followed by an ylide sigmatropic rearrangement. In addition, there is only one report describing reactions of cyclic ammonium ylides with electrophilic alkenes.35 Cyanomethylide generated from azetidinium or pyrrolidinium salts undergo two-step transformation: addition to a Michael acceptor followed by a nucleophilic substitution, with betaine (not ylide) as the reactive intermediate35 (Scheme 2). In continuation of our work on the development of synthetic methods utilizing rearrangements of ammonium ylides,38,39 the reaction of N-cyanomethyl-N-methyl-2-phenylpyrrolidinium iodide (1a) with acrylonitrile (2a) was carried out in a 50% Received: December 28, 2017

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DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Mechanism of Reaction of αCyanocycloammonium Salts with Michael Acceptors35

Table 1. Optimization of Reaction of Salts 1a−c with Acrylonitrile (2a) entry

salt

2a/1 (mol/mol)

CH2Cl2 (mL)

1 2 3 4 5 6 7 8

1a 1a 1a 1a 1a 1a 1b 1c

2 5 10 22 10 10 10 10

5 5 5 5 2.5 10 5 5

aqueous NaOH/CH2Cl2 system. In addition to the [1,2]rearrangement product 3a,47 2-cyano-2-(2-cyanoethyl)-1-methyl-3-phenylpiperidine (4aa) was formed (Scheme 3). Scheme 3. Reaction of N-Cyanomethyl-N-methyl-2phenylpyrrolidinium Iodide (1a) and 2-Cyano-1-methyl-3phenylpiperidine (3a) with Acrylonitrile (2a)

a

content of 3 and 4 in the reaction mixture (%)b 4aa, 15 4aa, 62 4aa, 86 4aa, 40 4aa, 43 4aa, 61 4ab, 87 4ac, 89

3a, 64 3a, 22 3a, 7 3a, 2 3a, 2 3a, 5 3b, 6 3c, 5

a

Reaction conditions: a mixture of salt 1 (0.7 mmol), 2a (excess given in table), CH2Cl2 (volume given in table), and 50% aqueous NaOH (1.5 mL) was vigorously stirred at room temperature for 6 h. b Determined by GC.

(determined by GC) was lower. Selected optimum conditions were applied for reactions of 1b,c with 2a, affording equally satisfactory results (Table 1, entries 7 and 8). The 50% aqueous NaOH/CH2Cl2 system was found to be unsuitable for the reaction of 1a with methyl acrylate (2d). Therefore, further experiments were carried out in a K2CO3/ DMSO system. Gradual decrease of the molar ratio of methyl acrylate (2d) to salt 1a and simultaneous reduction of the volume of DMSO gave a good content of expected product 4da in the reaction mixture. Using the K2CO3/DMSO system, a molar ratio of 2d/1a = 2, and with 0.5 mL of DMSO per 0.25 mmol of 1a, 77% content of 4ad in the reaction mixture was obtained. The selected conditions were also suitable for a reaction of 1b and 1c with methyl acrylate (2d).48 Similarly, a 50% aqueous NaOH/CH2Cl2 system gave disappointing results for the reaction of 1a with t-butyl acrylate (2c). On the other hand, using the K2CO3/DMSO system for reactions of salts 1a−c, the content of corresponding products 4ca, 4cb, and 4cc was from 74 to 79%.48 Finally, we checked the reactions of salt 1a with various vinyl ketones. Reactions of salt 1a with methyl vinyl ketone (2f) in the K2CO3/DMSO system, under conditions described above for acrylates 2c,d, gave mixtures containing 50−61% of 4fa. Moreover, reactions of salts 1 with phenyl vinyl ketone and its derivatives (4-methylphenyl and 4-chlorophenyl) were also investigated. In all cases, regardless of the reaction conditions according to TLC analysis, complicated mixtures of products were formed. Additionally, GC analysis suggested that the desired products were not formed. Having established the optimized reaction conditions, the scope of the reaction between 2-arylpyrrolidinium salts 1 and electrophilic alkenes 2 in systems A or B was investigated. The results are summarized in Table 2. Reactions of salts 1a−d with 10 equiv of acrylonitrile (2a) in a 50% aqueous NaOH/CH2Cl2 system (A) proceeded smoothly, affording crude mixtures containing 85−91% of 2(2-cyanoethyl) derivatives 4aa−4ad and less than 5% of Stevens products 3a−d. Crude products were passed through a short pad of silica gel and then crystallized. Tetrasubstituted piperidines 4aa−4ad were obtained in 64−71% yields. Carrying out reactions of salts 1a−c with acrylonitrile (2a) in a K2CO3/ DMSO system (B) resulted in lower yields of the desired products 4aa−4ac (58−64%). Reactions with phenyl vinyl sulfone (2b) were carried out also in a 50% aqueous NaOH/ CH2Cl2 system with equimolar amounts of substrates 1 and 2b.

In the initial research, it was shown that compound 4aa is not formed by the Michael addition of an anion generated from aminonitrile 3a to acrylonitrile (2a). 2-Cyano-1-methyl-3phenylpiperidine (3a) formed via a [1,2]-sigmatropic rearrangement of cyanomethylide, generated from N-cyanomethylN-methyl-2-phenylpyrrolidinum iodide (1a), underwent the reaction with acrylonitrile (2a) in a 50% aqueous NaOH/ CH2Cl2 system.47 Regardless of the reaction conditions, such as excess acrylonitrile, temperature, and time, product 4aa was not formed. With this result taken into account, the aim of our studies was an examination of reactions of pyrrolidinium ylides with electrophilic alkenes in order to synthesize 3-aryl-2-cyano-2-(2EWG-ethyl)-1-methylpiperidines 4. Knowing that rearrangements of salts 1 proceed smoothly in 50% aqueous NaOH/ CH2Cl2 and K2CO3/DMSO systems, the same conditions were chosen for reactions of 2-aryl-N-cyanomethyl-N-methylpyrrolidinium salts 1 with electrophilic alkenes 2 (Scheme 4). Scheme 4. Reactions of Salts 1a−e with Electrophilic Alkenes 2a−g

The studies began with a screening of optimum reaction conditions using salt 1a (Ar = Ph) and acrylonitrile (2a, electron-withdrawing group (EWG) = CN). The impact of excess electrophilic alkene and volume of solvent was investigated in a 50% aqueous NaOH/CH2Cl2 system at room temperature. It appeared that the highest content of 4aa in the reaction mixture (86%) was achieved for a 10/1 ratio of 2a to 1 and using 0.7 mmol of 1a in 5 mL of the solvent (Table 1, entry 3). Under other conditions (summarized in Table 1, entries 1, 2, 4−6), the amount of 4aa in the reaction mixtures B

DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 2. Reactions of Salts 1a−e with Electrophilic Alkenes 2a−g entry

1, Ar

2, EWG

system

ratio of 2/1 (mol/mol)

time (h)

product

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

a, Ph a, Ph a, Ph a, Ph a, Ph b, 4-MeOC6H4 b, 4-MeOC6H4 b, 4-MeOC6H4 c, 4-ClC6H4 c, 4-ClC6H4 d, 4-MeC6H4 d, 4-MeC6H4 d, 4-MeC6H4 e, 2-C4H3S

a, CN b, SO2Ph c, CO2t-Bu d, CO2Me f, COMe a, CN b, SO2Ph e, CO2Et a, CN c, CO2t-Bu a, CN b, SO2Ph g, COEt f, COMe

Aa A Bb B B A A B A B A A B B

10 1 2 2 2 10 1 2 10 2 10 1 2 2

6 7 17 17 17 6 7 17 6 17 6 7 17 17

4aa 4ba 4ca 4da 4fa 4ab 4bb 4eb 4ac 4cc 4ad 4bd 4gd 4fe

71 48 65 45 38 69 55 36 66 69 64 46 34 31

a Reaction conditions: a mixture of salt 1 (1 mmol), 2 (1 or 10 equiv), CH2Cl2 (7 mL), and 50% aqueous NaOH (2 mL) was vigorously stirred at room temperature for 6 or 7 h. bReaction conditions: a mixture of salt 1 (1 mmol), 2 (2 equiv), DMSO (2 mL), and K2CO3 (10 equiv) was stirred at room temperature for 17 h.

Figure 1. Crystal structure of piperidines 4aa, 4bb, and 4ca.

reactions of salt 1a (trans/cis 3.3:1 or 4.6:1) with Michael acceptors 2b−d,f. GC analysis indicated the presence of one diastereoisomer of 4 in the crude reaction mixtures. The intensity of the other peaks on the GC chromatograms with retention times similar to those of isolated products 4 was typically below 1%. The structures of compounds 4 were confirmed by 1H NMR, 13 C NMR, and IR spectra and by elemental analysis. The analysis of plausible structures of single diastereoisomers 4 was made based on the conformational energies of the substituents and our previous results.47 It indicated cis configuration of two bulky substituents, 2-(EWG-ethyl) and aryl groups. It was unequivocally confirmed by X-ray crystallography (Figure 1).48 A plausible mechanism shown in Scheme 5 in the first step involves the deprotonation of pyrrolidinium salt 1 with generation of ylide 1+−, which subsequently undergoes the Michael addition to the electrophilic alkene 2 with a formation of betaine 5+−. The next step consists of a [1,3]-H transfer providing a better stabilized carbanion, ylide 6+−. The [1,2]Stevens rearrangement of pyrrolidinium ylide 6+− affords the final product 4.47 The mechanism of [1,2]-Stevens rearrangement has not been sufficiently explained. Most of the experimental data indicate the radical mechanism, but concerted and ion-pair mechanisms have not been fully excluded.49−51 Recently, West suggested that the [1,2]-Stevens rearrangement proceeds by heterolytic bond cleavage.52 Thus, it is difficult to solve a mechanistic

The reactions were monitored by TLC. The full conversion of sulfone 2b was achieved after approximately 7 h, whereas only traces of products 3a−d were observed. The products 4ba− 4bd, purified like previously described, were obtained in 46− 55% yields. Reactions of salts 1a−e with Michael acceptors 2c−g were accomplished in the presence of K2CO3 in DMSO (system B). In reactions of t-butyl acrylate (2c) with salts 1a,c, mixtures containing 77−78% of desired products 4ca and 4cc were obtained, whereas in the case of methyl or ethyl acrylates (2d, 2e), many more byproducts were formed. The content of desired products 4da and 4eb did not exceed 73%. The content of Stevens products 3a−c in reactions with all acrylates 2c−e was similar, typically ca. 5−8%. Further, reactions of pyrrolidinium salts 1 with α,β-unsaturated ketones were examined. Reactions of salts 1a,d,e with alkyl vinyl ketones 2f,g afforded mixtures containing no more than 60% of the expected products 4fa, 4fe, and 4gd and ca. 5−7% of piperidines 3a, 3d, and 3e. The above-mentioned products 4ac−4gd were purified by column chromatography followed by crystallization and were finally obtained in 31−69% yields. The regiochemical outcome was found to be independent of the trans/cis ratio of salt 1. It was checked carefully in the case of salts 1a−c with at least three different trans/cis ratios (trans/ cis from 7.3 to 1.5). In reactions with acrylonitrile (2a) carried out in both systems (A and B) one diastereoisomer 4 was observed using GC analysis. The same was observed in C

DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

experiments. After diffraction data were collected, the intensities were corrected for Lorentz polarization effects and were consecutively used for solving and refining crystal and molecular structures. Structures were solved using direct methods from the SHELXS-97 program.58 All heavy atoms were localized and located from the initial E-maps. Further isotropic and anisotropic refinements of the respective models by application of the SHELXL-97 program58 enabled localization of hydrogen atoms. In final refinement cycles, the non-hydrogen atom positions were refined together with their anisotropic displacement parameters, whereas the hydrogen was localized using standard geometrical criteria and isotropic displacement parameters tied to the respective carbon atoms to which they are bonded. The conformations of the molecules of the respective compounds are shown in Figure 1. The molecule of 4ca is partially disordered in its tbutyl fragment. For clarity of the drawing, only the geometry of the more populated orientation is shown. Experimental data are collected in Table S3.48 The detailed crystallographic data for the aforementioned structures were deposited with the Cambridge Crystallographic Data Centre under the numbers CCDC 1822278, CCDC 1822279, and CCDC 1822280. Reactions in System A (50% NaOH/CH2Cl2). To a vigorously stirred mixture of salt 1 (1 mmol), acrylonitrile (2a) (10 mmol, 0.53 g, 0.66 mL), or phenyl vinyl sulfone (2b) (1 mmol, 0.168 g) in CH2Cl2 (7 mL) was added 50% aqueous NaOH (2 mL) dropwise for ca. 5 min at room temperature (18−22 °C). The stirring was continued for 6 h (acrylonitrile) or 7 h (phenyl vinyl sulfone). Water (15 mL) was added; phases were separated; the water phase was extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases were washed with water (3 × 10 mL), dried with MgSO4, filtered, and evaporated. The residue was passed through a short pad of silica gel (with hexane/ EtOAc 100/0 to 70/30 as eluent), followed by crystallization from hexane/ethyl acetate (15/1) or MeOH. Reactions in System B (K2CO3/DMSO). To a magnetically stirred solution of salt 1 (1 mmol) and electrophilic alkenes 2c−g (2 mmol) in DMSO (2 mL) was added powdered K2CO3 (10 mmol, 1.38 g) at room temperature (18−22 °C). The stirring was continued for 17 h. Water (25 mL) was added; the water−DMSO phase was extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases were washed with water (4 × 10 mL), dried with MgSO4, filtered, and evaporated. The crude products were purified by column chromatography on silica gel (hexane/EtOAc gradient, 100/0 to 85/15) and crystallized from hexane. 2-Cyano-2-(2-cyanoethyl)-1-methyl-3-phenylpiperidine (4aa): Yield 71% (180 mg), colorless crystals, mp 122−123 °C (MeOH); 1 H NMR (500 MHz, CDCl3) δH = 1.69 (qt, J = 12.7, J = 4.2, 1H), 1.76−1.91 (m, 3H), 2.02 (qd, J = 13.0, J = 3.9, 1H), 2.13 (ddd, J = 14.9, J = 10.8, J = 4.9, 1H), 2.34 (s, 3H), 2.48 (ddd, J = 17.1, J = 10.8, J = 6.1, 1H), 2.58 (ddd, J = 17.4, J = 10.8, J = 4.9, 1H), 2.62 (td, J = 12.5, J = 3.2, 1H), 2.70 (dd, J = 12.7, J = 3.4, 1H), 2.88 (dm, J = ca. 12.2, 1H), 7.32−7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) δ = 10.0, 25.0, 29.1, 29.2, 40.0, 47.4, 53.0, 66.1, 116.5, 118.7, 128.2, 128.2, 129.1, 139.1; IR (nujol, cm−1) 2247. Anal. Calcd for C16H19N3: C, 75.85; H, 7.56; N, 16.59. Found: C, 75.78, H, 7.61; N, 16.60. 2-Cyano-2-(2-cyanoethyl)-3-(4-methoxyphenyl)-1-methylpiperidine (4ab): Yield 196 mg (69%), colorless crystals, mp 120−121 °C (MeOH); 1H NMR (500 MHz, CDCl3) δ = 1.68 (qt, J = 12.7, J = 4.2, 1H), 1.74−1.85 (m, 2H), 1.90 (ddd, J = 14.9, J = 10.5, J = 6.1, 1H), 1.97 (ddd, J = 12.9, J = 3.9, 1H), 2.11 (ddd, J = 14.9, J = 10.5, J = 4.9, 1H), 2.32 (s, 3H), 2.47 (ddd, J = 17.1, J = 10.5, J = 6.1, 1H), 2.56 (ddd, J = 17.1, J = 10.5, J = 4.9, 1H), 2.59 (td, J = 12.5, J = 3.2, 1H), 2.65 (dd, J = 12.7, J = 3.4, 1H), 2.86 (dm, J = ca. 12.3, 1H), 3.82 (s, 3H), 6.90−6.92 (m, 2H), 7.30−7.33 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 9.9, 25.0, 29.0, 29.3, 40.0, 46.4, 52.9, 55.2, 66.4, 114.3, 116.5, 118.8, 129.3, 131.0, 159.3; IR (nujol, cm−1) 2252, 2215. Anal. Calcd for C17H21N3O: C, 72.06; H, 7.47; N, 14.83. Found: C, 71.98; H, 7.45; N, 14.75. 3-(4-Chlorophenyl)-2-cyano-2-(2-cyanoethyl)-1-methylpiperidine (4ac): Yield 190 mg (66%), colorless crystals, mp 123−124 °C (hexane/ethyl acetate 15/1); 1H NMR (400 MHz, CDCl3) δ = 1.67 (qt, J = 12.8, J = 4.0, 1H), 1.74−1.88 (m, 3H), 1.95 (qd, J = 13.2, J =

Scheme 5

model rationalizing the production of only one diastereoisomer 4. The formation of two geometrically different transition states, followed by the rearrangement proceeding through the one with the lower energy, can be suggested. Stereoselectivity of the previously described [1,2]-Stevens rearrangements of ammonium ylides has been explained based on steric hindrance of two possible transition states or differences in rates of radical recombination and their diffusion out of the solvent cage.53−57 In conclusion, we have developed a novel domino reaction: the Michael addition/[1,2]-Stevens rearrangement of pyrrolidinium ylide. The cyanomethylide generated by the action of a base from 2-aryl-N-cyanomethyl-N-methylpyrrolidinium salt undergoes conjugate addition to an electrophilic alkene, followed by the proton transfer within the betaine intermediate and completed by the [1,2]-Stevens rearrangement. This methodology provides an easy access to 3-aryl-2-cyano-2-(2EWG-ethyl)-1-methylpiperidines in 31−71% yields. All starting materials are easily available. The reactions were carried out under mild conditions, with 50% aqueous NaOH/CH2Cl2 or K2CO3/DMSO systems at room temperature for 6−17 h.

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EXPERIMENTAL SECTION

General Remarks. Commercially available reagents (Aldrich, Fluka, and POCH) were used without further purification. Melting points were obtained with a capillary apparatus and were not corrected. The chromatographic analyses (GLC) were performed with an HP series II 5890 instrument equipped with a flame ionization detector and fitted with a HP-50+ (30 m) semipolar column. Helium (2 L/min) was used as the carrier gas. Column chromatography was performed using 40−63 μm silica gel 60 (Merck). A mixture of hexane/ethyl acetate was used as eluent (100/0 to 40/60, v/v). Thin-layer chromatography was carried on TLC aluminum plates with silica gel Kieselgel 60 F254 (Merck) (0.2 mm thick film). 1 H and 13C NMR spectra were measured with a Varian Mercury 400BB or Varian 500 MHz spectrometer operating at 400 or 500 MHz for 1H and 100 or 125 MHz for 13C nuclei. Chemical shifts (δ) are given in parts per million (ppm) related to tetramethylsilane (TMS) as internal standard; signal multiplicity assignments: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and related permutations; coupling constants (J) are given in hertz (Hz). Elemental analyses were performed with a PerkinElmer 2004 series II CHNS/O microanalyzer. Infrared (IR) spectra were taken on a Carl Zeiss Specord M80 instrument. 2-Aryl-N-cyanomethyl-N-methylpyrrolidinum salts (1a−e) and 2-cyano-1-methyl-3-phenylpiperidine (3a) were synthesized according to the literature method.47 For preparative reactions, salts 1 were used as trans/cis mixtures: 1a (3.3/1 or 4.6/1), 1b (2.3/1), 1c (3.0/1), 1d (4.8/1), 1e (3.5/1). Crystallographic Studies. Carefully selected crystals of compounds 4aa, 4bb, and 4ca were submitted to X-ray diffraction studies. Crystals were mounted on the goniometer of an Xcalibur Ruby κ-axis single-crystal diffractometer from Oxford Diffraction. The monochromatic Cu Kα radiation was used at room temperature in all D

DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

1H), 2.83 (dm, J = ca. 12.2, 1H), 7.30−7.35 (m, 4H); 13C NMR (125 MHz, CDCl3) δ = 25.1, 27.9, 28.0, 28.8, 29.4, 39.8, 46.9, 53.0, 66.6, 80.8, 117.3, 128.9, 129.7, 133.6, 138.4, 171.6; IR (nujol, cm−1) 2215, 1728. Anal. Calcd for C20H27ClN2O2; C, 66.19; H, 7.50; N, 7.72. Found: C, 66.20, H, 7.55; N, 7.75. 2-Cyano-2-(2-methoxycarbonylethyl)-1-methyl-3-phenylpiperidine (4da): Yield 129 mg (45%), colorless crystals, mp 75−77 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.58−1.86 (m, 4H), 2.01 (qd, J = 12.8, J = 4.0, 1H), 2.17 (ddd, J = 14.8, J = 12.0, J = 4.0, 1H), 2.32 (s, 3H), 2.40−2.48 (m, 1H), 2.54−2.66 (m, 2H), 2.72 (dd, J = 12.8, J = 3.2, 1H), 2.84 (dm, J = ca. 12.0, 1H), 3.64 (s, 3H), 7.25−7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) δ = 25.1, 26.3, 28.5, 29.4, 39.8, 47.6, 51.8, 53.0, 66.5, 117.4, 127.8, 128.3, 128.8, 139.8, 172.9; IR (nujol, cm−1) 2215, 1736. Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.25; H, 7.70; N, 9.76. 2-Cyano-2-(2-ethoxycarbonylethyl)-3-(4-methoxyphenyl)-1methylpiperidine (4eb): Yield 119 mg (36%), colorless crystals, mp 104−106 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.23 (t, J = 7.2, 3H), 1.60−1.83 (m, 4H), 1.97 (qd, J = 12.8, J = 4.0, 1H), 2.15 (ddd, J = 15.6, J = 12.0, J = 4.4, 1H), 2.32 (s, 3H), 2.41 (ddd, J = 16.4, J = 11.6, J = 5.6, 1H), 2.52−2.63 (m, 2H), 2.68 (dd, J = 12.8, J = 3.2, 1H), 2.82 (dm, J = ca. 12.0, 1H), 3.80 (s, 3H), 4.10 (q, J = 7.2, 2H), 6.84−6.89 (m, 2H), 7.29−7.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 14.2, 25.2, 26.6, 28.5, 29.5, 39.9, 46.6, 53.0, 55.2, 60.7, 66.9, 114.0, 117.5, 129.3, 131.9, 159.0, 172.5; IR (nujol, cm−1) 2212, 1728. Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N, 8.48. Found: C, 69.13; H, 7.89; N, 8.43. 2-Cyano-1-methyl-2-(3-oxobutyl)-3-phenylpiperidine (4fa): Yield 103 mg (38%), colorless crystals, mp 83.5−85 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.60 (ddd, J = 15.2, J = 10.4, J = 6.4, 1H), 1.65−1.85 (m, 3H), 1.95−2.06 (m, 1H), 2.13 (s, 3H), 2.15 (ddd, J = 15.2, J = 10.8, J = 4.4, 1H), 2.27 (s, 3H), 2.55−2.66 (m, 3H), 2.72 (dd, J = 12.8, J = 3.6, 1H), 2.84 (dm, J = ca. 12.0, 1H), 7.27−7.40 (m, 5H); 13 C NMR (100 MHz, CDCl3) δ = 25.1, 27.0, 29.4, 30.1, 35.5, 39.9, 48.0, 53.0, 66.6, 117.5, 127.8, 128.2, 128.8, 139.9, 206.6; IR (film, cm−1) 2241, 1704. Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N, 10.36. Found: C, 75.45; H, 8.16: N, 10.40. 2-Cyano-1-methyl-2-(3-oxobutyl)-3-(thiophen-2-yl)piperidine (4fe): Yield 86 mg (31%), colorless crystals, mp 80.5−81.5 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.60−1.82 (m, 3H), 1.92−2.01 (m, 2H), 2.14−2.30 (m, 1H) 2.16 (s, 3H), 2.27 (s, 3H), 2.55−2.66 (m, 3H), 2.81 (dm, J = ca. 12.0, 1H), 2.97−3.04 (m, 1H), 6.98 (dd, J = 5.2, J = 4.8, 1H), 7.07 (dm, J = ca. 3.6, 1H), 7.18 (dm, J = ca. 5.2, 1H); 13C NMR (100 MHz, CDCl3) δ = 25.0, 27.1, 30.2, 30.9, 35.3, 40.1, 42.8, 52.8, 67.4, 117.1, 123.9, 125.4, 127.2, 141.9, 206.6; IR (nujol, cm−1) 2215, 1708. Anal. Calcd for C15H20N2OS: C, 65.18; H, 7.29; N, 10.14. Found: C, 64.98; H, 7.12; N, 10.09. 2-Cyano-1-methyl-3-(4-methylphenyl)-2-(3-oxopentyl)piperidine (4gd): Yield 102 mg (34%), colorless crystals, mp 118−120 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.03 (t, J = 7.2, 3H), 1.57−1.82 (m, 4H), 1.99 (qd, J = 12.8, J = 4.4, 1H), 2.15 (ddd, J = 14.8, J = 10.4, J = 4.8, 1H), 2.26 (s, 3H), 2.32 (s, 3H), 2.38−2.45 (m, 2H), 2.52−2.64 (m, 3H), 2.69 (dd, J = 12.8, J = 3.2, 1H), 2.83 (dm, J = ca. 12.0, 1H), 7.10−7.15 (m, 2H), 7.22−7.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 7.8, 21.0, 25.2, 27.2, 29.5, 34.1, 36.1, 39.9, 47.5, 53.0, 66.7, 117.6, 128.1, 129.4, 136.9, 137.4, 200.5; IR (film, cm−1) 2218, 1712. Anal. Calcd for C19H26N2O: C, 76.47; H, 8.78; N, 9.39. Found: C, 76.42; H, 8.73; N, 9.40.

4.0, 1H), 2.13 (ddd, J = 15.2, J = 10.0, J = 4.8, 1H), 2.32 (s, 3H), 2.45 (ddd, J = 17.6, J = 10.0, J = 6.0, 1H), 2.53−2.61 (m, 1H), 2.59 (dd, J = 12.4, J = 3.2, 1H), 2.70 (dd, J = 12.4, J = 3.2, 1H), 2.87 (dm, J = ca. 12.4, 1H), 7.35 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ = 9.9, 24.8, 29.0, 29.2, 40.0, 46.6, 52.8, 65.9, 116.3, 118.6, 129.2, 129.6, 134.1, 137.5; IR (nujol, cm−1) 2248. Anal. Calcd for C16H18ClN3: C, 66.78; H, 6.30; N, 14.60. Found: C, 66.49; H, 6.27; N, 14.45. 2-Cyano-2-(2-cyanoethyl)-1-methyl-3-(4-methylphenyl)piperidine (4ad): Yield 172 mg (64%), colorless crystals, mp 117−118 °C (hexane/ethyl acetate 15/1); 1H NMR (500 MHz, CDCl3) δ = 1.67 (qt, J = 13.2, J = 4.4, 1H), 1.74−1.91 (m, 3H), 1.99 (qd, J = 13.2, J = 3.2, 1H), 2.10 (ddd, J = 14.7, J = 10.8, J = 4.9, 1H), 2.32 (s, 3H), 2.35 (s, 3H), 2.43−2.50 (m, 1H), 2.53−2.58 (m, 1H), 2.60 (td, J = 12.2, J = 2.9, 1H), 2.65 (dd, J = 12.7, J = 3.4, 1H), 2.86 (dm, J = ca. 12.2, 1H), 7.16−7.20 (m, 2H), 7.26−7.29 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 9.9, 21.0, 25.0, 29.1, 29.2, 40.0, 46.9, 52.9, 66.2, 116.5, 118.8, 128.1, 129.7, 136.0, 137.9; IR (nujol, cm−1) 2247, 2215. Anal. Calcd for C17H21N3: C, 76.37; H, 7.92; N, 15.72. Found: C, 76.22; H, 7.83; N, 15.82. 2-Cyano-1-methyl-3-phenyl-2-(2-phenylsulfonylethyl)piperidine (4ba): Yield 177 mg (48%), colorless crystals, mp 147−148 °C (MeOH) (decomp.); 1H NMR (400 MHz, CDCl3) δ = 1.58−1.82 (m, 4H), 1.90−2.01 (m, 1H), 2.10−2.19 (m, 1H), 2.20 (s, 3H), 2.53−2.60 (m, 2H), 2.81 (dm, J = ca. 12.0, 1H), 3.23 (ddd, J = 14.0, J = 12.4, J = 5.6, 1H), 3.30−3.39 (m, 1H), 7.21 (br s, 5H), 7.50−7.56 (m, 2H), 7.62−7.67 (m, 1H), 7.80−7.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 24.9, 27.1, 29.1, 39.6, 47.8, 49.3, 53.0, 66.0, 116.6, 127.9, 128.0, 128.8, 129.4, 133.9, 138.2, 138.8; IR (nujol, cm−1) 2218, 1304, 1148. Anal. Calcd for C21H24N2O2S: C, 68.45; H, 6.56; N, 7.60. Found: C, 68.38; H, 6.47; N, 7.65. 2-Cyano-3-(4-methoxyphenyl)-1-methyl-2-(2phenylsulfonylethyl)piperidine (4bb): Yield 220 mg (55%), colorless crystals, mp 138−139 °C (MeOH) (decomp.); 1H NMR (500 MHz, CDCl3) δ = 1.56−1.80 (m, 4H), 1.88−1.96 (m, 1H), 2.10−2.16 (1H, m), 2.19 (3H, s), 2.51−2.57 (m, 2H), 2.80 (dm, J = ca. 12.2, 1H), 3.22 (ddd, J = 14.4, J = 12.7, J = 5.4, 1H), 3.30−3.36 (m, 1H), 3.78 (s, 3H), 6.73−6.75 (m, 2H), 7.11−7.15 (m, 2H), 7.54−7.57 (m, 2H), 7.65− 7.68 (m, 1H), 7.83−7.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 24.9, 27.0, 29.1, 39.6, 46.8, 49.3, 52.9, 55.2, 66.3, 114.1, 116.6, 128.0, 129.0, 129.4, 130.8, 133.9, 138.2, 159.0; IR (nujol, cm−1) 2218, 1312, 1148. Anal. Calcd for C22H26N2O3S: C, 66.30; H, 6.58; N, 7.03. Found: C, 66.38; H, 6.47; N, 6.86. 2-Cyano-1-methyl-3-(4-methylphenyl)-2-(2-phenylsulfonylethyl)piperidine (4bd): Yield 176 mg (46%), colorless crystals, mp 137−139 °C (MeOH) (decomp.); 1H NMR (500 MHz, CDCl3) δ = 1.56−1.80 (m, 4H), 1.93 (qd, J = 13.2, J = 3.4, 1H), 2.10−2.16 (m, 1H), 2.18 (s, 3H), 2.29 (s, 3H), 2.51−2.57 (m, 2H), 2.80 (dm, J = ca. 12.2, 1H), 3.18−3.25 (m, 1H), 3.29−3.35 (m, 1H), 7.00−7.10 (m, 4H), 7.52− 7.55 (m, 2H), 7.64−7.67 (m, 1H), 7.80−7.82 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.0, 25.0, 27.1, 29.1, 39.6, 47.5, 49.4, 52.9, 66.2, 116.6, 127.8, 128.0, 129.4, 129.5, 133.8, 135.8, 137.6, 138.4; IR (nujol, cm−1) 2215, 1312, 1152. Anal. Calcd for C22H26N2O2S: C, 69.08; H, 6.85; N, 7.32. Found: C, 68.94; H, 6.77; N, 7.43. 2-(2-tert-Butoxycarbonylethyl)-2-cyano-1-methyl-3-phenylpiperidine (4ca): Yield 214 mg (65%), colorless crystals, mp 90−92 °C (hexane); 1H NMR (400 MHz, CDCl3) δ = 1.40 (s, 9H), 1.60−1.84 (m, 4H), 1.94−2.06 (m, 1H), 2.11 (ddd, J = 14.8, J = 11.6, J = 4.4, 1H), 2.32 (s, 3H), 2.30−2.38 (m, 1H), 2.47 (ddd, J = 15.6, J = 11.6, J = 4.0, 1H), 2.60 (td, J = 12.4, J = 3.6, 1H), 2.73 (dd, J = 12.8, J = 3.2, 1H), 2.83 (dm, J = ca. 12, 1H), 7.27−7.44 (m, 5H); 13C NMR (100 MHz, CDCl3) δ = 25.1, 27.8, 28.0, 28.7, 29.3, 39.8, 47.4, 53.0, 66.7, 80.7, 117.5, 127.7, 128.4, 128.7, 139.9, 171.7; IR (nujol, cm−1) 2218, 1716. Anal. Calcd for C20H28N2O2: C, 73.14; H, 8.59; N, 8.53. Found: C, 72.99; H, 8.51; N, 8.50. 2-(2-tert-Butoxycarbonylethyl)-3-(4-chlorophenyl)-2-cyano-1methylpiperidine (4cc): Yield 251 mg (69%), colorless crystals, mp 85−86 °C (hexane); 1H NMR (500 MHz, CDCl3) δ = 1.41 (s, 9H), 1.59−1.82 (m, 4H), 1.95 (dd, J = 13.2, J = 3.9, 1H), 2.09−2.15 (m, 1H), 2.26−2.34 (m, 1H), 2.32 (s, 3H), 2.46 (ddd, J = 16.1, J = 11.3, J = 3.9, 1H), 2.60 (td, J = 12.7, J = 2.9, 1H), 2.72 (dd, J = 12.7, J = 2.9,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03278. Tables with results of optimization reactions, copies of 1 H NMR and 13C NMR spectra for compounds 4, and Xray crystallography information (PDF) X-ray data for 4aa (CIF) X-ray data for 4ca (CIF) E

DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX

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(29) Zhang, J.; Yang, S.; Zhang, K.; Chen, J.; Deng, H.; Shao, M.; Zhang, H.; Cao, W. Tetrahedron 2012, 68, 2121−2127. (30) Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron 2000, 56, 9669−9674. (31) Vinosha, B. M.; Perumal, S.; Renuga, S.; Almansour, A. I. Tetrahedron Lett. 2013, 54, 2837−2840. (32) Wang, Q.-F.; Hou, H.; Hui, L.; Yan, C.-G. J. Org. Chem. 2009, 74, 7403−7406. (33) Zhu, J.-B.; Wang, P.; Liao, S.; Tang, Y. Org. Lett. 2013, 15, 3054−3057. (34) Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y. Chem. Commun. 2008, 738−740. (35) Couty, F.; David, O.; Larmanjat, B.; Marrot, J. J. Org. Chem. 2007, 72, 1058−1061. (36) Roiser, L.; Waser, M. Org. Lett. 2017, 19, 2338−2341. (37) Ferrary, T.; David, E.; Milanole, G.; Besset, T.; Jubault, P.; Pannecoucke, X. Org. Lett. 2013, 15, 5598−5601. (38) Kowalkowska, A.; Suchołbiak, D.; Jończyk, A. Eur. J. Org. Chem. 2005, 2005, 925−933. (39) Jończyk, A.; Konarska, A. Synlett 1999, 1999, 1085−1087. (40) Bhattacharjee, S. S.; Ila, H.; Junjappa, H. Synthesis 1982, 1982, 301−303. (41) Kim, S.; Ikuhisa, N.; Chiba, K. Chem. Lett. 2011, 40, 1077− 1078. (42) Suarez del Villar, I.; Gradillas, A.; Domínguez, G.; PérezCastells, J. Tetrahedron Lett. 2010, 51, 3095−3098. (43) Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 2681−2684. (44) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828−831. (45) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024−6028. (46) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 4641−4644. (47) Kowalkowska, A.; Jończyk, A. Tetrahedron 2015, 71, 9630− 9637. (48) See the Supporting Information for details. (49) Biswas, B.; Collins, S. C.; Singleton, D. A. J. Am. Chem. Soc. 2014, 136, 3740−3743. (50) Ghigo, G.; Cagnina, S.; Maranzana, A.; Tonachini, G. J. Org. Chem. 2010, 75, 3608−3617. (51) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62, 1043−1062. (52) Hosseini, S. N.; Johnston, J. R.; West, F. G. Chem. Commun. 2017, 53, 12654−12656. (53) Bott, T. M.; Vanecko, J. A.; West, F. G. J. Org. Chem. 2009, 74, 2832−2836. (54) Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4, 2813−2816. (55) Chelucci, G.; Saba, A.; Valenti, R.; Bacchi, A. Tetrahedron: Asymmetry 2000, 11, 3449−3453. (56) Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31−33. (57) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116, 8420− 8421. (58) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122.

X-ray data for 4bb (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +48 22 234 7677. ORCID

Anna Kowalkowska: 0000-0002-8835-6495 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by Warsaw University of Technology. REFERENCES

(1) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134−7186. (2) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (3) Bunce, R. A. Tetrahedron 1995, 51, 13103−13159. (4) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390−2431. (5) Pellissier, H. Tetrahedron 2013, 69, 7171−7210. (6) Zeng, X. Chem. Rev. 2013, 113, 6864−6900. (7) Bhanja, C.; Jena, S.; Nayak, S.; Mohapatra, S. Beilstein J. Org. Chem. 2012, 8, 1668−1694. (8) Pellissier, H. Tetrahedron 2008, 64, 7041−7095. (9) Pellissier, H. Tetrahedron 2007, 63, 9267−9331. (10) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977−1050. (11) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937−948. (12) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341−2372. (13) Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 7626−7630. (14) He, H. S.; Chung, C. W. Y.; But, T. Y. S.; Toy, P. H. Tetrahedron 2005, 61, 1385−1405. (15) Huang, Y. Z.; Shen, Y. C. Adv. Organomet. Chem. 1982, 20, 115−157. (16) Tang, Y.; Ye, S.; Huang, Z.-Z.; Huang, Y.-Z. Heteroat. Chem. 2002, 13, 463−466. (17) Jiang, K.; Chen, Y.-C. Tetrahedron Lett. 2014, 55, 2049−2055. (18) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596− 5605. (19) Zheng, J.-C.; Zhu, C.-Y.; Sun, X.-L.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2008, 73, 6909−6912. (20) Wang, Q.-G.; Deng, X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Zhu, C.-Y.; Shen, Q.; Tang, Y. J. Am. Chem. Soc. 2008, 130, 5408−5409. (21) Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Tang, Y. J. Org. Chem. 2007, 72, 1335−1340. (22) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006, 8, 3853−3856. (23) Chagarovsky, A. O.; Budynina, E. M.; Ivanova, O. A.; Villemson, E. V.; Rybakov, V. B.; Trushkov, I. V.; Melnikov, M. Y. Org. Lett. 2014, 16, 2830−2833. (24) Yamashita, M.; Okuyama, K.; Kawajiri, T.; Takada, A.; Inagaki, Y.; Nakano, H.; Tomiyama, M.; Ohnaka, A.; Terayama, I.; Kawasaki, I.; Ohta, S. Tetrahedron 2002, 58, 1497−1505. (25) Zhu, B.-H.; Zhou, R.; Zheng, J.-C.; Deng, X.-M.; Sun, X.-L.; Shen, Q.; Tang, Y. J. Org. Chem. 2010, 75, 3454−3457. (26) Redon, S.; Leleu, S.; Pannecoucke, X.; Franck, X.; Outurquin, F. Tetrahedron 2008, 64, 9293−9304. (27) Nagao, T.; Suenaga, T.; Ichihashi, T.; Fujimoto, T.; Yamamoto, I.; Kakehi, A.; Iriye, R. J. Org. Chem. 2001, 66, 890−893. (28) Fujimoto, T.; Kodama, Y.-i.; Yamamoto, I.; Kakehi, A. J. Org. Chem. 1997, 62, 6627−6630. F

DOI: 10.1021/acs.joc.7b03278 J. Org. Chem. XXXX, XXX, XXX−XXX