Modular synthesis of unsaturated aza-heterocycles via copper catalyzed multicomponent cascade reaction

Summary

The unsaturated aza-heterocycles such as tetrahydropyridines pose significant applications in both drug discovery and development. However, the methods to construct polyfunctionalized tetrahydropyridines are still limited. Herein, we report a modular synthesis of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. The reaction features mild conditions and broad substrate scope. In addition, the reaction could scale up to gram scale with similar yield. A variety of 1,2,5,6-tetrahydropyridines with C3 and C5 substituents could be assembled from simple starting materials. More importantly, the products could serve as versatile intermediate to access various functionalized aza-heterocycles which further demonstrates its utility.

Graphical abstract

Highlights

• •A copper catalyzed multi-component radical cascade reaction is realized to access 1,2,5,6-tetrahydropyridines
• •The reaction features with mild conditions and broad substrate scope
• •A various functionalized unsaturated piperidines could be assembled from readily available starting materials
• •Additionally, the products are versatile intermediates to access various functionalized aza-heterocycles which further demonstrates its utility

Chemical reaction; Catalysis; Chemical synthesis

Introduction

Non-aromatic aza-heterocycles are widely existent in a majority of bioactive natural products and pharmaceutical compounds.^1,2,3,4 These aza-heterocycles such as tetrahydropyridines and piperidines can be found in a number of FDA approved drugs such as Lisuride, Tadalafil, and Paroxetine (Figure 1A).^5,6,7 Moreover, tetrahydropyridines are versatile intermediates to provide a wide range of functionalized piperidines via well-established olefin functionalization,^8,9,10,11,12 which are the most prevalent nitrogen heterocycles found in pharmaceutical drugs.^{13,14,15,16,17} As a result, methods for the rapid assembly of diverse tetrahydropyridines from readily available starting materials are of high value to drug discovery and development.^18,19 Albeit considerable effort has been devoted to developing efficient methods of constructing azaheterocycles, the synthesis of 1,2,5,6-tetrahydropyridines with C3 or C5 substituents continues to be a significant challenge. Traditional methods mainly relied on the partial reduction of pre-functionalized pyridines and further reduction of N-alkyl-1,2-dihydropyridines via iminium intermediates.^{20,21,22,23,24,25,26,27,28,29,30} Recently, Ellman and Bergman developed an elegant cascade strategy which involving Rh-catalyzed C−H activation of α,β-unsaturated imines followed by addition across alkynes, in situ electrocyclization, and reduction or nucleophilic addition in the presence of acid to obtain highly substituted 1,2,5,6-tetrahydropyridines.^31,32,33,34 Alternatively, Donohoe et al. developed Iridium catalyzed reductive functionalization of pyridinium salts by harnessing the formation of a nucleophilic enamine intermediate to access C3 functionalized 1,2,5,6-tetrahydropyridines (Figure 1B)³⁵ Notwithstanding these elegant reports, a strategy for the quick assembly of 1,2,5,6-tetrahydropyridines with C3 and C5 substituents is still highly desirable.

Figure 1.

Background and methods to construct unsaturated Aza-heterocycles

(A) Representative drugs containing substituted 6-membered azaheterocycles.

(B) Or each panel or group of panels can be described separately The State-of-the-Art to construct unsaturated aza-heterocycles.

(C) Rational of copper catalyzed multicomponent radical cyclization (this work).

Multicomponent reactions represent one of the most efficient and practical synthetic methods in terms of atom- and step-economy for the expeditious construction of polyfunctionalized molecules with structural diversity from readily available starting materials.^{36,37,38,39,40,41} Thus, a multicomponent reaction approach would offer us an alternative solution to the modular synthesis of 1,2,5,6-tetrahydropyridines with various functionalities at C3, C4 and C5 positions. In the light of recent progress of copper catalyzed radical relay process which was initiated by generating N-centered radicals in C-H functionalization^{42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69} and difunctionalization of alkenes,^{70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87} we envisioned that a modular synthesis of valuable 1,2,5,6-tetrahydropyridines could be accomplished by a copper catalyzed radical cascade reaction involving three simple components (Figure 1C). Specifically, an F-masked 4-methyl-N-(2-phenylbuta-2,3-dien-1-yl)benzene-sulfonamide was designed to generate electrophilic N-centered radical via single electron transfer from copper catalyst. Followed by the N centered radical addition toward alkenes to trigger a radical 6-exo-dig cyclization. Finally, the formed allylic carbon radical reacted with a bulky Cu(II) complex to give the 1,2,5,6-tetrahydropyridines with various substituents at C3, C4, and C5 positions, which could provide a wealth of opportunities in both drug discovery and development (Figure 1C). Hence, we report a modular synthesis of functionalized tetrahydropyridines via copper catalyzed three components radical cascade reaction.

Results and discussion

Discovery

To test the feasibility of the proposed strategy, substrate 1a, 1b and TMSCN were as the model substrate. After a careful evaluation of various reaction parameters, the desired cyclization product 1c was isolated in 65% yield with Cu(CH₃CN)₄PF₆ as catalyst, L3 as the ligand, 1b (2 equiv) as coupling partner, TMSCN (2.5 equiv) as nucleophile and fluorobenzene as solvent (see equation in Table 1, entry 1). As expected, the ligand played a pivotal role in this reaction. While using ligands L1 and L2, no desired product was formed. The BOX ligand (L3) was proved to be optimal to give good yield and excellent regioselectivity while installing the cyanide group at less steric hindered primary carbon site. In addition, in line with the proposed mechanism, the use of a chiral ligand did not impart any enantioselectivity and the product was found to be racemic. Other solvents instead of fluorobenzene were less effective and gave diminished yield (entries 2–6). Lots of copper salts could be employed as catalyst to furnish the desired product albeit with decreased yield (entries 7–10). Elevating the reaction temperature to 50$°C$ made the reaction sluggish (entry 11). On the other hand, there was no reaction occurred at 0$°C$ (entry 12). In addition, no matter increasing or decreasing the loading of TMSCN would diminish the yield of the desired product (entries 13–14). Gratifyingly, while using the alkene as limiting reagent, the reaction proceeded smoothly to give the desired product with comparable yield (entries 15–17).

Table 1.

Optimization of copper catalyzed multicomponent cascade reaction^a

Entry	Variation from standard conditions	1c Yield [%]
1	None	69 (65)b
2	DME instead of PhF	33
3	DCM instead of PhF	46
4	CH3CN instead of PhF	46
5	benzene instead of PhF	62
6	PhCF3 instead of PhF	55
7	CuOAc instead of Cu(CH3CN)4PF6	44
8	CuI instead of Cu(CH3CN)4PF6	39
9	CuSCN instead of Cu(CH3CN)4PF6	20
10	Cu(OTf)2 instead of Cu(CH3CN)4PF6	22
11	50°C instead of 36°C	40
12	0°C instead of 36°C	ND
13	TMSCN 1.5 equiv	48
14	TMSCN 3.0 equiv	51
15	1a:1b = 1:1	56
16	1a:1b = 1.2:1	58
17	1a:1b = 1.5:1	61

ND stands for No desired product. Please define any abbreviations used.

^aGeneral conditions: 1a (0.1 mmol), 1b (0.2 mmol), TMSCN (0.25 mmol), solvent (1.0 mL), 36°C, 12 h.

^bIsolated yield.

Synthetic evaluation

After having established the optimal reaction conditions, we then investigated the generality of this copper catalyzed multicomponent radical cyclization reaction. To install different functional groups at C5 position of the 1,2,5,6-tetrahydropyridines, monosubstituted styrenes were first examined (Scheme 1), and the desired products (1c−8c) were obtained in moderate to good yields. Different substituents on the benzene ring, including the alkyl group (2c), halide (5c), alkyl halide group (6c), and alkoxyl group (3c, 7c, 8c) were all tolerated. The substrates bearing two or three substituents on the aromatic ring reacted smoothly with 1a to afford the desired products (9c-13c) in acceptable yields. An extended aromatic ring, such as 2- vinylnaphthalene, was a viable substrate and furnished the desired product 14c in a moderate yield. Alkenes bearing heterocyclic moieties worked nicely in this reaction, gave the corresponding products (15c−17c) in 49–75% yield. Notably, heterocycles commonly existing in therapeutics, such as benzofuran, benzothiophene and indole, were well tolerated under the current conditions, which once again showcased the robustness of our method. To our delight, the radical cyclization took place regio-selectively and obtained 18c in 61% yield when we commit our study with diene substrate. Furthermore, hetero atom substituents could be installed at the C5 position while using N-vinyl benzamide, N-vinly lactam and vinyl aryl ether as substrates, and the corresponding products 19c–21c could be obtained in medium yield.

Scheme 1.

Scope of alkenes and allenes^a,b

^aReaction conditions: 1a (0.2 mmol), 1b (0.4 mmol), TMSCN (0.5 mmol), solvent (2.0 mL), 36°C, 12 h. Isolated yield. ^bGram-scale reaction (5 mmol).

Next, a variety of F-masked sulfonamides were investigated to install different substituents on the C3 position of the 1,2,5,6-tetrahydropyridines (Scheme 1). A variety of functional groups including both electron donating groups and electron withdrawing groups on the para position of the aryl group were all compatible with the reaction conditions and furnished the corresponding products 22c–26c in moderate yields. While changing the substituent to meta and otho position, the reaction went smoothly to give the desired products 27c–28c in 77% and 63% yield respectively. The steric more hindered substituents such as naphthalene were tolerated as well 29c-30c. Unfortunately, there was no reaction occurred while changing the aryl group into an alkyl group 31c.

Encouraged by the above results that copper catalyst could trap the allylic carbon radical efficiently and regioselectively, we turned our attention to testing the coupling of allylic carbon radical with other nucleophiles (Scheme 2). TMSN₃ and TMSSCN were used as nucleophiles in this reaction, affording the desired product 32c-33c in medium yield. Considering the attractive properties of SCF₃ group, AgSCF₃ was then examined which could install SCF₃ group 34c under slightly modified conditions with acceptable yield as well. At last, a wide array of alkynylating reagents (alkynyltrimethoxysilane) with different substituents on the C−C triple bond, such as tBu, nBu, phenyl, TMS, and cyclopropyl groups, were applied to this multicomponent radical cyclization reaction. As shown in Scheme 2, the reactions proceeded smoothly and yielded the corresponding alkynylation products (35c-39c) in moderate to good yields (43−76%).

Scheme 2.

Scope of nucleophiles^a

^aDetailed reaction conditions see supplemental information.

Synthetic utility

To demonstrate the potential synthetic utility of our present method, further transformations of the tetrahydropyridines products were conducted (Figure 2). For example, the reaction of 3c and H₂O₂ could produce the corresponding amide 40 compound in 72% yield. The Ts group on the nitrogen atom could be removed by Mg/MeOH to give 41 in 83% yield. The Compound 3c could also undergo a dehydrogenation process by DDQ to form 42 in 70% yield. Finally, the 3c treated with oxone and HBr led to an unexpected dihydropyridine 43 in 56% yield. The structure and configuration of 43 were determined by single-crystal X-ray diffraction analysis (see supplemental information).

Figure 2.

Transformations of the 1,2,5,6-tetrahydropyridines

(A) 30% H2O2, NaOH (aq.), MeOH; (B) mg, MeOH; (C) DDQ, PhMe; (D) oxone, HBr, DCM.

Conclusions

In summary, we have developed a copper catalyzed multicomponent radical cascade reaction. Various alkenes, F-masked allenes sufonylamides, and nucleophiles could be assembled to give important unsaturated nitrogen-containing heterocycles under mild conditions. The reaction involved an N-centered radical addition toward alkenes, 6-exo-dig cyclization, and regioselective cross coupling of the formed allylic radical. The transformations of the products and gram scale set up were further showcased the utility of this reaction.

Limitations of the study

This work reports a highly efficient and regioselective method for the preparation of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. Although a good substrate scope of alkenes and nucleophiles has been demonstrated, this method shows limitations on substrates of F-masked sulfonamides. Further optimization of catalysts and reaction conditions is needed to expand the scope of F-masked sulfonamides and improve the applicability of the method.

STAR★Methods

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Chemical reagents and characterization instruments
Cu(CH3CN)4PF6	Energy Chemical	CAS: 64443-05-6
CuOAc	Energy Chemical	CAS: 598-54-9
CuI	Energy Chemical	CAS: 7681-65-4
CuSCN	Energy Chemical	CAS: 1111-67-7
Cu(OTf)2	Energy Chemical	CAS: 34946-82-2
TMSCN	bidepharm	CAS: 7677-24-9
TMSN3	Energy Chemical	CAS: 4648-54-8
AgSCF3	Energy Chemical	CAS: 811-68-7
Styrene	Energy Chemical	CAS: 100-42-5
4-Acetoxystyrene	Energy Chemical	CAS: 2628-16-2
4-Chlorostyrene	Energy Chemical	CAS: 1073-67-2
4-tert-Butylstyrene	Energy Chemical	CAS: 1746-23-2
4-Methylstyrene	Energy Chemical	CAS: 622-97-9
4-Methoxystyrene	Energy Chemical	CAS: 637-69-4
2-Vinylnaphthalene	Energy Chemical	CAS: 827-54-3
4-Vinylbenzyl chloride	Energy Chemical	CAS: 1592-20-7
DME	Energy Chemical	CAS: 110-71-4
DCM	Energy Chemical	CAS: 75-09-2
CH3CN	Energy Chemical	CAS: 75-05-8
Benzene	Energy Chemical	CAS: 71-43-2
PhCF3	Energy Chemical	CAS: 98-08-8
PhF	Energy Chemical	CAS: 462-06-6
2,2′-Bipyridine	Energy Chemical	CAS: 366-18-7
o-Phenanthroline	bidepharm	CAS: 66-71-7
Deposited data
CIF of 3a	CCDC 2192306	https://www.ccdc.cam.ac.uk/structures/
CIF of 43	CCDC 2192304	https://www.ccdc.cam.ac.uk/structures/
Other
Silica gel (200-300 mesh)	Shanxi Nuotai
thin layer chromatography using TLC silica gel plates	Shanxi Nuotai
AVIII 400 MHz	Bruker	https://bruker.com
AVIII 600 MHz	Bruker	https://bruker.com
X-ray diffraction	Bruker	https://bruker.com
HRMS	Agilent	https://www.agilent.com.cn/

Resource availability

Lead contact

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Zuxiao Zhang (zhangzx@zjnu.edu.cn).

Materials availability

All other datasupporting the findings of this study are available within the article and the supplemental information or from the lead contact upon reasonable request.

Method details

Preparation of substrates

General procedure for the synthesis of N-F.

These substrates can be synthesized from Mitsunobu Reaction with 2-Aryl-2,3-butadien-1-ol and TsNHBoc, then the Boc protecting group can be removed by TFA.1.

2-Phenyl-2, 3-butadien-1-ol (1.46g, 10 mmol), TsNHBoc (3.53g, 13 mmol) and PPh3 (3.41g 13 mmol) were suspended in THF (15 ml). The mixture was cooled to 0°C and diethyl azodicarboxylate (DEAD 2.61g, 15 mmol) was added dropwisely. Then the reaction mixture was allowed to warm to room temperature. Water was added when the starting material was disappeared and the mixture was extracted with Et₂O. The combined organic extracts were dried overMgSO₄. After solvent evaporated, the residue was purified through silica gel to give the allenyl imide product. The allenyl imide was treated with TFA following the process described as above to give the product (1.94g, 65% for two steps).

In an oven dried round bottom flask with stir bar, sodium hydride (10 mmol, 2 equiv.) was taken. The sodium hydride was washed with pentane (2 times) and dried under vacuum and filled with nitrogen. Then dry DCM (40 mL) was added to it. A solution of sulfonamide (1 equiv.) in dry DCM (0.5 M) was added dropwise to the NaH suspension in DCM. The total reaction was stirred at room temperature for 30 mins. Then, a solution of NFSI (3 eq.) in dry DCM (0.5 M) was added to dropwise to the reaction mixture at room temperature. The total reaction mixture was stirred for overnight at room temperature. The reaction was quenched with ice with constant stirring. Then 50 mL of water was added to the reaction mixture. The organic part was washed with 30 mL NaHCO₃, and 30 mL brine solution respectively. The organic part was concentrated in rotary evaporator and performed silica gel flash column chromatography to isolate the desired N-F (fluorosulfonamide, 25%-50% yield) using hexanes/ethyl acetate mixture as eluent.

Preparation of products

General procedure for the synthesis of products. Related to Scheme 1, 2.

Procedure A

In a dried sealed 10 mL Schlenk tube, Cu(CH₃CN)₄PF₆ (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), styrene (1b, 42.0mg, 0.4 mmol, 2.0 eq.) and TMSCN (67 μl, 0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36°C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc = 10:1) to give the desired product 1c in 65% yield (55.8 mg).

Procedure A-1

In a dried sealed 10 mL Schlenk tube, Cu(CH3CN)4PF6 (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), styrene (1b 42.0mg, 0.4 mmol, 2.0 eq.) and TMSN3 (0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36°C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc = 10:1) to give the desired product 32c in 66% yield (58.9mg).

Procedure A-2

In a dried sealed 10 mL Schlenk tube, Cu(CH₃CN)₄PF₆ (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N₂ atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.) and TMSSCN (0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36°C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc =5:1) to give the desired product 33c in 60% yield (59.0 mg).

Procedure B

In a dried sealed 10 mL Schlenk tube, Cu(OTf)₂ (10 mol %), bpy (15 mol %) were dissolved in a mixed solvent of DCE (2.0 mL) under a N₂ atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), AgSCF₃ (83 mg, 0.4 mmol, 2.0 eq.) and CsBr (127 mg, 0.6 mmol, 3.0 eq.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 60°C for another 18 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and diethyl ether (Petroleum ether: diethyl ether = 15:1) to give the desired product 34c in 40% yield (42.7 mg).

Procedure C

In a dried sealed 10 mL Schlenk tube, Cu(CH₃CN)₄PF₆ (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of DCM and DMA (9:1, 2.0 mL, v/v = 9:1) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and alkynyltrimethoxysilane (0.4 mmol, 2.0 eq.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate to give the desired product 35c-39c.

Transformations of products

General procedure for the transformations of 3c and 20c. Related to Figure 2.

3c (45.8 mg, 0.1 mmol) was dissolved in 1 mL methanol followed by the addition of 0.15 mL 30% H₂O₂, and the pH of the solution is adjusted to 8 by 1 drop of 2 M NaOH solution. The mixture was stirred for 12hat room temperature. Then, the solvent was removed under vacuum and the residue was subject to a short plug of silica gel, eluted with EtOAc in petroleum ether to give the product 40 in 72% yield as a white solid (34.3 mg). Rf = 0.15 (Petroleum ether: EtOAc = 1:1)

To a solution of 20c (87.0 mg, 0.2 mmol) in anhydride methanol (2 mL) was added Mg turnings (6.0 eq.) and the reaction mixture was stirred under sonication for 5h at room temperature. After the completion of the reaction, the mixture was quenched with brine, and extracted with DCM. The combined organic layers were dried overNa₂SO₄ and concentrated in vacuum. The residue was purified by column chromatography to provide the desired product 41 as a yellow solid (46.6 mg, 83% yield). Rf = 0.1 (MeOH: DCM =1:9)

To a solution of 3c (45.8 mg, 0.1 mmol) in 2 mL of PhMe was added DDQ (45.4mg, 0.20 mmol), and the reaction was stirred at 100°C for 12 hourstill 3c was completely consumed (monitored by TLC). The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude residue was purified via column chromatography on silica gel (8:1 hexanes/EtOAc) to afford the desired product 42 with 70% (32.0 mg) yield.

To a solution of 3c (45.8 mg, 0.1 mmol) in 2 mL of DCM was added oxone (1.6 eq.), was added 2N HBr (2 eq.) in one portion result in dark colored solution. The reaction was stirred at room temperature for 18 hourstill 3c was completely consumed (monitored by TLC). Then, the reaction was quenched with 5 mL sodium thiosulfate saturated solution, and extracted with DCM. The combined organic layers were dried overNa₂SO₄ and concentrated in vacuum. The residue was purified via column chromatography on silica gel (10:1 hexanes/EtOAc) to afford the desired product 43 with 56% (30 mg) yield.

Characterization of substrates 2a-10a

N-fluoro-4-methyl-N-(2-(p-tolyl)buta-2,3-dien-1-yl)benzenesulfonamide (2a)

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.7 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.16 (d, J = 7.4 Hz, 2H), 5.16 (s, 2H), 4.26 (d, J = 39.8 Hz, 2H), 2.49 (s, 3H), 2.34 (s, 3H).

¹³C NMR (151 MHz, CDCl₃) δ 210.62, 146.45, 137.15, 130.21, 130.07, 130.00, 129.34, 128.91, 126.06, 98.13, 79.24, 54.74 (d, J = 13.1 Hz), 21.85, 21.14.

¹⁹F NMR (377 MHz, Chloroform-d) δ -46.98 (t, J = 39.8 Hz).

HRMS (ESI) for C₁₈H₁₉FNO₂S[M+H]⁺m/z: calcd 332.1115, found 332.1100.

N-fluoro-N-(2-(4-methoxyphenyl)buta-2,3-dien-1-yl)-4-methylbenzenesulfonamide (3a)

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.24 (d, J = 39.9 Hz, 2H), 3.81 (s, 3H), 2.49 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 210.46, 158.95, 146.48, 130.10, 130.01, 128.88, 127.40, 125.39, 114.11, 97.82, 79.26, 55.35, 54.94 (d, J = 13.3 Hz), 21.86.

¹⁹F NMR (377 MHz, CDCl₃) δ -47.01 (t, J = 39.9 Hz).

N-fluoro-N-(2-(4-fluorophenyl)buta-2,3-dien-1-yl)-4-methylbenzenesulfonamide (4a)

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.3 Hz, 2H), 7.46 – 7.39 (m, 4H), 7.04 (t, J = 8.7 Hz, 2H), 5.18 (s, 2H), 4.25 (d, J = 39.6 Hz, 2H), 2.49 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 210.71, 162.12 (d, J = 247.2 Hz), 146.57, 130.12, 130.00, 129.21 (d, J = 3.2 Hz), 128.85, 127.87 (d, J = 8.1 Hz), 115.57 (d, J = 21.7 Hz), 97.53, 79.48, 54.82 (d, J = 13.2 Hz), 21.84.

¹⁹F NMR (377 MHz, Chloroform-d) δ -46.99 (t, J = 39.6 Hz),-114.91 – -115.03 (m).

HRMS (ESI) for C₁₇H₁₆F₂NO₂S[M+H]⁺m/z: calcd 336.0864, found 336.0869.

N-fluoro-N-(2-(4-chlorophenyl)buta-2,3-dien-1-yl)- 4-methylbenzenesulfonamide (5a)

¹H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 5.19 (s, 2H), 4.25 (d, J = 39.6 Hz, 2H), 2.49 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 210.84, 146.63, 133.15, 131.78, 130.15, 130.00, 128.77, 127.49, 97.56, 79.73, 54.58 (d, J = 13.3 Hz), 21.87.

¹⁹F NMR (377 MHz, Chloroform-d) δ -47.09 (t, J = 39.6 Hz).

HRMS (ESI) for C₁₇H₁₆ClFNO₂S[M+H]⁺m/z: calcd 352.0569, found 352.0561.

ethyl 4-(1-((N-fluoro-4-methylphenyl)sulfonamido)buta-2,3-dien-2-yl)benzoate (6a)

¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 5.25 (s, 2H), 4.46 – 4.31 (m, 2H), 4.26 (s, 2H), 2.49 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 211.59, 166.35, 146.61, 138.03, 130.13, 130.00, 129.83, 129.19, 128.90, 126.02, 98.04, 79.84, 60.98, 54.32 (d, J = 12.7 Hz), 21.86, 14.35.

¹⁹F NMR (377 MHz, CDCl₃) δ -46.95 (t, J = 39.5 Hz).

HRMS (ESI) for C₂₀H₂₁FNO₄S[M+H]⁺m/z: calcd 390.1170, found 390.1145.

N-fluoro-4-methyl-N-(2-(m-tolyl)buta-2,3-dien-1-yl)benzenesulfonamide (7a)

¹H NMR (600 MHz, CDCl₃) δ 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.28 – 7.24 (m, 3H), 7.07 (s, 1H), 5.17 (s, 2H), 4.27 (d, J = 39.8 Hz, 2H), 2.49 (s, 3H), 2.36 (s, 3H).

¹³C NMR (151 MHz, CDCl₃) δ 210.81, 146.47, 138.20, 133.14, 130.09, 130.00, 128.91, 128.52, 128.17, 126.97, 123.17, 98.28, 79.25, 54.73 (d, J = 12.9 Hz), 21.85, 21.54.

¹⁹F NMR (377 MHz, Chloroform-d) δ -46.99.

HRMS (ESI) for C₁₈H₁₉FNO₂S[M+H]⁺m/z: calcd 332.1115, found 332.1100.

N-fluoro-4-methyl-N-(2-(o-tolyl)buta-2,3-dien-1-yl)benzenesulfonamide (8a)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.26 – 7.16 (m, 4H), 4.94 (s, 2H), 4.13 (d, J = 40.1 Hz, 2H), 2.48 (s, 3H), 2.33 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 209.20, 146.43, 136.66, 133.71, 130.67, 130.07, 129.99, 128.93, 128.30, 127.77, 126.05, 97.20, 77.01, 57.23 (d, J = 12.3 Hz), 21.83, 20.26.

¹⁹F NMR (377 MHz, CDCl₃) δ -46.78 (t, J = 40.1 Hz).

HRMS (ESI) for C₁₈H₁₉FNO₂S[M+H]⁺m/z: calcd 332.1115, found 332.1101.

N-fluoro-4-methyl-N-(2-(naphthalen-1-yl)buta-2,3-dien-1-yl)benzenesulfonamide (9a)

¹H NMR (400 MHz, Chloroform-d) δ 8.08 – 8.03 (m, 1H), 7.88 – 7.84 (m, 1H), 7.81 (d, J = 8.2 Hz, 3H), 7.51 – 7.46 (m, 4H), 7.38 (d, J = 7.8 Hz, 2H), 5.03 (t, J = 2.4 Hz, 2H), 4.25 (d, J = 39.9 Hz, 2H), 2.47 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 209.70, 146.40, 133.96, 132.21, 131.34, 130.04, 129.99, 128.97, 128.54, 128.37, 126.35, 126.29, 125.91, 125.42, 125.00, 96.29, 77.17, 57.49 (d, J = 12.5 Hz), 21.81.

¹⁹F NMR (377 MHz, Chloroform-d) δ -46.28 (t, J = 39.9 Hz).

HRMS (ESI) for C₂₁H₁₉FNO₂S[M+H]⁺m/z: calcd 368.1115, found 368.1092.

N-fluoro-4-methyl-N-(2-(naphthalen-2-yl)buta-2,3-dien-1-yl)benzenesulfonamide (10a)

¹H NMR (400 MHz, Chloroform-d) δ 8.00 – 7.83 (m, 4H), 7.79 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 5.27 (s, 2H), 4.41 (d, J = 39.7 Hz, 2H), 2.49 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 211.42, 146.51, 133.48, 132.57, 130.58, 130.11, 130.03, 129.03, 128.29, 128.15, 127.56, 126.31, 126.09, 124.80, 124.44, 98.58, 79.69, 54.67 (d, J = 13.1 Hz), 21.84.

¹⁹F NMR (377 MHz, Chloroform-d) δ -46.48 (t, J = 39.8 Hz).

HRMS (ESI) for C₂₁H₁₉FNO2S[M+H]⁺m/z: calcd 368.1115, found 368.1095.

Characterization of products 1c-39c

2-(3,5-diphenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (1c)

Prepared following general procedure A.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.3 Hz, 2H), 7.45 – 7.27 (m, 10H), 7.25 – 7.21 (m, 2H), 4.07 (d, J = 16.7 Hz, 1H), 3.80 (s, 1H), 3.66 (d, J = 16.7 Hz, 1H), 3.48 (dd, J = 11.8, 4.5 Hz, 1H), 3.35 (dd, J = 11.8, 4.9 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.99, 139.30, 137.22, 136.81, 132.74, 129.84, 129.13, 129.07, 128.68, 128.55, 128.37, 127.93, 127.74, 124.33, 117.29, 49.91, 49.66, 44.09, 21.58, 20.42.

HRMS (ESI) for C₂₆H₂₅N₂O₂S[M+H]⁺m/z: calcd 429.1631, found 429.1638.

2-(5-phenyl-3-(p-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (2c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 2b (48 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 2c (61.0 mg, 69% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =10:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.2 Hz, 2H), 7.46 – 7.35 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.24 – 7.14 (m, 6H), 4.04 (d, J = 16.6 Hz, 1H), 3.77 (s, 1H), 3.67 (d, J = 16.6 Hz, 1H), 3.42 (dd, J = 11.8, 4.7 Hz, 1H), 3.36 (dd, J = 11.8, 5.0 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.95, 137.60, 137.30, 136.60, 136.22, 132.81, 129.82, 129.74, 129.11, 128.64, 128.41, 128.38, 127.73, 124.55, 117.33, 50.04, 49.68, 43.74, 21.57, 21.15, 20.36.

HRMS (ESI) for C₂₇H₂₇N₂O₂S[M+H]+ m/z: calcd 443.1788, found 443.1176.

2-(3-(4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (3c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 3b (54 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 3c (70.7 mg, 77% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.2 Hz, 2H), 7.46 – 7.35 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 8.3 Hz, 4H), 6.89 (d, J = 8.6 Hz, 2H), 4.05 (d, J = 16.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 1H), 3.65 (d, J = 16.7 Hz, 1H), 3.43 (dd, J = 11.8, 4.5 Hz, 1H), 3.33 (dd, J = 11.7, 4.9 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.24, 143.98, 137.29, 136.47, 132.77, 131.27, 129.84, 129.58, 129.12, 128.65, 128.38, 127.73, 124.69, 117.35, 114.43, 55.31, 50.09, 49.67, 43.32, 21.57, 20.36.

HRMS (ESI) for C₂₇H₂₇N₂O₃S[M+H]⁺m/z: calcd 459.1737, found 459.1724.

2-(3-(4-(tert-butyl)phenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (4c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 4b (64 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 4c (55.2 mg, 57% yield) as a white solid. Rf = 0.3 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.3 Hz, 2H), 7.45 – 7.34 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 – 7.20 (m, 4H), 4.04 (d, J = 16.6 Hz, 1H), 3.78 (s, 1H), 3.67 (d, J = 16.6 Hz, 1H), 3.45 (dd, J = 11.7, 4.7 Hz, 1H), 3.37 (dd, J = 11.8, 5.0 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H), 1.32 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 150.72, 143.97, 137.34, 136.40, 136.21, 132.71, 129.83, 129.09, 128.62, 128.39, 128.20, 127.79, 125.95, 124.67, 117.38, 49.90, 49.66, 43.56, 34.55, 31.37, 21.58, 20.38.

2-(3-(4-chlorophenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile(5c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 5b (56 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the title compound 5c (52.8 mg, 57% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc =10:1).

¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 8.3 Hz, 2H), 7.46 – 7.36 (m, 3H), 7.36 – 7.26 (m, 6H), 7.25 – 7.20 (m, 2H), 4.15 (d, J = 16.7 Hz, 1H), 3.77 (s, 1H), 3.61 – 3.50 (m, 2H), 3.24 (dd, J = 11.8, 4.7 Hz, 1H), 2.99 (d, J = 17.3 Hz, 1H), 2.56 (d, J = 17.4 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 144.12, 137.91, 137.20, 136.95, 133.84, 132.66, 129.87, 129.82, 129.23, 129.19, 128.81, 128.31, 127.70, 123.79, 117.17, 49.69, 49.59, 43.42, 21.58, 20.48.

HRMS (ESI) for C₂₆H₂₄ClN₂O₂S[M+H]+ m/z: calcd 463.1242, found 463.1227.

2-(3-(4-(chloromethyl)phenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (6c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 6b (61 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 6c (68.4 mg, 72% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =10:1).

¹H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.46 – 7.37 (m, 5H), 7.35 – 7.29 (m, 4H), 7.24 – 7.21 (m, 2H), 4.59 (s, 2H), 4.11 (d, J = 16.6 Hz, 1H), 3.81 (s, 1H), 3.61 (d, J = 16.7 Hz, 1H), 3.51 (dd, J = 11.8, 4.0 Hz, 1H), 3.29 (dd, J = 11.8, 4.8 Hz, 1H), 2.98 (d, J = 17.3 Hz, 1H), 2.57 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 144.07, 139.68, 137.16, 137.07, 137.01, 132.65, 129.87, 129.29, 129.16, 128.92, 128.75, 128.33, 127.73, 124.02, 117.22, 49.76, 49.62, 45.84, 43.74, 21.57, 20.47.

4-(4-(cyanomethyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-yl)phenyl acetate (7c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 7b (65 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 7c (63.3 mg, 65% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.46 – 7.33 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 – 7.19 (m, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.08 (d, J = 16.7 Hz, 1H), 3.81 (s, 1H), 3.62 (d, J = 16.7 Hz, 1H), 3.48 (dd, J = 11.8, 4.2 Hz, 1H), 3.31 (dd, J = 11.8, 4.8 Hz, 1H), 2.98 (d, J = 17.3 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.42, 150.30, 144.10, 137.08, 136.91, 136.86, 132.56, 129.89, 129.55, 129.16, 128.74, 128.33, 127.75, 124.17, 122.16, 117.24, 49.82, 49.64, 43.43, 21.57, 21.21, 20.44.

HRMS (ESI) for C₂₈H₂₇N₂O₄S[M+H]+ m/z: calcd 487.1686, found 487.1668.

2-(3-(3-((3-fluorobenzyl)oxy)phenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (8c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 8b (92 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 8c (67.2 mg, 61% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.3 Hz, 2H), 7.46 – 7.33 (m, 4H), 7.32 – 7.26 (m, 3H), 7.26 – 7.15 (m, 5H), 7.02 (td, J = 8.3, 2.0 Hz, 1H), 6.98 – 6.93 (m, 2H), 5.06 (s, 2H), 4.07 (d, J = 16.6 Hz, 1H), 3.76 (s, 1H), 3.63 (d, J = 16.6 Hz, 1H), 3.46 (dd, J = 11.7, 4.4 Hz, 1H), 3.31 (dd, J = 11.7, 4.8 Hz, 1H), 2.96 (d, J = 17.2 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 164.24, 161.80, 158.21, 144.01, 139.56 (d, J = 7.2 Hz), 137.24, 136.52, 132.70, 131.87, 130.21 (d, J = 8.3 Hz), 129.85, 129.68, 129.12, 128.67, 128.38, 127.74, 124.59, 122.80 (d, J = 2.9 Hz), 117.36, 115.30, 114.90 (d, J = 21.0 Hz), 114.28 (d, J = 21.9 Hz), 69.27, 50.03, 49.67, 43.31, 21.58, 20.40.

¹⁹F NMR (377 MHz, CDCl3) δ -112.71 (td, J = 9.2, 6.0 Hz).

HRMS (ESI) for C₃₃H₃₀FN₂O₃S[M+H]+ m/z: calcd 553.1956, found 553.1937.

2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (9c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 9b (65 mg, 0.4 mmol). After 16 hours, the reaction mixture was purified by column chromatography to provide the compound 9c (69.0 mg, 71% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =6:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.2 Hz, 2H), 7.45 – 7.34 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.24 – 7.19 (m, 2H), 6.87 – 6.75 (m, 3H), 4.31 – 4.20 (m, 4H), 4.02 (d, J = 16.6 Hz, 1H), 3.69 (s, 1H), 3.63 (d, J = 16.7 Hz, 1H), 3.41 (dd, J = 11.7, 4.6 Hz, 1H), 3.32 (dd, J = 11.7, 4.9 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.97, 143.75, 143.26, 137.25, 136.62, 132.70, 132.44, 129.83, 129.09, 128.64, 128.39, 127.77, 124.49, 121.60, 117.76, 117.35, 117.11, 64.37, 64.32, 50.01, 49.65, 43.39, 21.58, 20.34.

HRMS (ESI) for C₂₈H₂₇N₂O₄S[M+H]+ m/z: calcd 487.1686, found 487.1680.

2-(3-(2-fluoro-4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (10c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 10b (61 mg, 0.4 mmol). After 16 hours, the reaction mixture was purified by column chromatography to provide the compound 10c (59.0 mg, 62% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =8:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.46 – 7.35 (m, 3H), 7.30 (d, J = 8.2 Hz, 2H), 7.26 – 7.17 (m, 3H), 6.70 (dd, J = 8.5, 2.5 Hz, 1H), 6.65 (dd, J = 12.0, 2.5 Hz, 1H), 4.10 (d, J = 14.9 Hz, 2H), 3.80 (s, 3H), 3.60 (d, J = 16.4 Hz, 1H), 3.53 (dd, J = 11.8, 4.2 Hz, 1H), 3.25 (dd, J = 11.7, 4.5 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.63 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 162.66, 160.55 (d, J = 11.1 Hz), 160.22, 144.01, 137.22 (d, J = 17.4 Hz), 132.82, 130.39 (d, J = 5.7 Hz), 129.85, 129.14, 128.72, 128.34, 127.68, 123.56, 117.57 (d, J = 14.5 Hz), 117.15, 110.34 (d, J = 2.9 Hz), 102.02 (d, J = 25.8 Hz), 55.61, 49.58, 48.79, 36.65, 21.57, 20.48.

¹⁹F NMR (565 MHz, Chloroform-d) δ -116.30 (t, J = 10.3 Hz).

HRMS (ESI) for C₂₇H₂₆FN2O₃S[M+H]+ m/z: calcd 477.1643, found 477.1635.

2-(3-(2,3-dihydrobenzofuran-6-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (11c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 11b (59 mg, 0.4 mmol). After 18 hours, the reaction mixture was purified by column chromatography to provide the title compound 11c (49.0 mg, 52% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.45 – 7.35 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.25 – 7.20 (m, 2H), 7.16 (s, 1H), 7.01 (dd, J = 8.2, 1.6 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 4.58 (t, J = 8.8 Hz, 2H), 4.03 (d, J = 16.6 Hz, 1H), 3.73 (s, 1H), 3.65 (d, J = 16.6 Hz, 1H), 3.41 (dd, J = 11.7, 4.6 Hz, 1H), 3.33 (dd, J = 11.7, 4.9 Hz, 1H), 3.27 – 3.16 (m, 2H), 2.95 (d, J = 17.2 Hz, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 159.86, 143.98, 137.32, 136.37, 132.73, 131.19, 129.82, 129.10, 128.63, 128.39, 128.20, 127.87, 127.76, 125.10, 124.84, 117.41, 109.57, 71.43, 50.24, 49.68, 43.58, 29.77, 21.58, 20.36.

HRMS (ESI) for C₂₈H₂₇N₂O₃S[M+H]⁺m/z: calcd 471.1737, found 471.1726.

2-(5-phenyl-1-tosyl-3-(3,4,5-trimethoxyphenyl)-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (12c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 12b (78 mg, 0.4 mmol). After 8 hours, the reaction mixture was purified by column chromatography to provide the compound 12c (68.5 mg, 66% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =2:1).

¹H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.46 – 7.35 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 – 7.17 (m, 2H), 6.60 (s, 2H), 4.12 (d, J = 16.6 Hz, 1H), 3.88 (s, 6H), 3.85 (s, 3H), 3.69 (s, 1H), 3.63 – 3.55 (m, 2H), 3.28 (dd, J = 11.8, 4.8 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.65 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 153.52, 144.06, 137.59, 137.17, 136.48, 135.19, 132.82, 129.88, 129.17, 128.74, 128.30, 127.66, 124.59, 117.53, 105.52, 60.89, 56.27, 49.57, 49.54, 44.16, 21.57, 20.43.

HRMS (ESI) for C₂₉H₃₁N₂O₅S[M+H]⁺m/z: calcd 519.1948, found 519.1927.

2-(3-(2-bromo-3,4-dimethoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (13c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 13b (98 mg, 0.4 mmol). After 5 hours, the reaction mixture was purified by column chromatography to provide the compound 13c (72.4 mg, 64% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =4:1).

¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 8.2 Hz, 2H), 7.48 – 7.36 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.25 – 7.21 (m, 2H), 7.06 (s, 1H), 6.93 (s, 1H), 4.24 (s, 2H), 3.88 (s, 6H), 3.71 (d, J = 11.2 Hz, 1H), 3.52 (d, J = 17.0 Hz, 1H), 3.18 (s, 1H), 2.93 (d, J = 17.1 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 149.21, 148.65, 144.03, 137.37, 137.00, 133.06, 130.10, 129.87, 129.24, 128.82, 128.21, 127.53, 124.42, 117.36, 115.68, 114.77, 112.39, 56.20, 53.50, 49.49, 48.41, 42.56, 21.58, 20.51.

HRMS (ESI) for C₂₈H₂₈BrN₂O₄S[M+H]⁺m/z: calcd 567.0948, found 567.0933.

2-(3-(naphthalen-2-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitril-e (14c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 14b (62 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 14c (53.0 mg, 56% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 10:1).

¹H NMR (400 MHz, Chloroform-d) δ 7.88 – 7.78 (m, 3H), 7.74 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.54 – 7.37 (m, 6H), 7.28 (d, J = 6.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.14 (d, J = 16.8 Hz, 1H), 3.99 (s, 1H), 3.74 (d, J = 16.7 Hz, 1H), 3.56 (dd, J = 11.9, 4.5 Hz, 1H), 3.45 (dd, J = 11.9, 5.0 Hz, 1H), 3.02 (d, J = 17.2 Hz, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.39 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 143.99, 137.22, 137.13, 136.74, 133.46, 132.99, 132.78, 129.79, 129.17, 129.03, 128.74, 128.39, 127.90, 127.78, 127.74, 127.71, 126.45, 126.21, 125.94, 124.22, 117.31, 49.88, 49.67, 44.21, 21.56, 20.49.

HRMS (ESI) for C₃₀H₂₇N₂O₂S[M+H]⁺m/z: calcd 479.1788, found 478.1812.

2-(3-(benzo[b]thiophen-2-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (15c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 15b (64 mg, 0.4 mmol). After 16 hours, the reaction mixture was purified by column chromatography to provide the compound 15c (47.3 mg, 49% yield) as a yellow solid. Rf = 0.25 (Petroleum ether: EtOAc =10:1).

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 7.6 Hz, 1H), 7.74 (dd, J = 7.0, 1.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.46 – 7.29 (m, 5H), 7.29-7.25 (m, 3H), 7.24 – 7.20 (m, 2H), 4.26 – 4.14 (m, 2H), 3.86 (dd, J = 11.7, 3.2 Hz, 1H), 3.55 (d, J = 16.7 Hz, 1H), 3.26 (dd, J = 11.8, 4.2 Hz, 1H), 3.05 (d, J = 17.4 Hz, 1H), 2.80 (d, J = 17.4 Hz, 1H), 2.40 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 144.14, 143.26, 140.16, 139.17, 136.87, 136.80, 132.63, 129.85, 129.17, 128.83, 128.24, 127.77, 124.46, 124.41, 124.06, 123.47, 123.35, 122.45, 117.28, 49.52, 49.26, 40.17, 21.58, 20.39.

HRMS (ESI) for C₂₈H₂₅N₂O₂S₂[M+H]⁺m/z: calcd 485.1352, found 485.1337.

2-(3-(benzofuran-2-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitril-e (16c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 16b (58 mg, 0.4 mmol). After 10 hours, the reaction mixture was purified by column chromatography to provide the compound 16c (70.3 mg, 75% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =10:1).

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 7.3 Hz, 1H), 7.48 – 7.36 (m, 4H), 7.31 – 7.20 (m, 6H), 6.75 (s, 1H), 4.04 (d, J = 17.9 Hz, 2H), 3.81 (dd, J = 11.9, 4.8 Hz, 1H), 3.71 (d, J = 16.6 Hz, 1H), 3.40 (dd, J = 12.0, 4.5 Hz, 1H), 3.10 (d, J = 17.3 Hz, 1H), 2.92 (d, J = 17.3 Hz, 1H), 2.40 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 155.04, 154.87, 144.13, 137.73, 136.86, 132.79, 129.87, 129.18, 128.83, 128.23, 128.21, 127.68, 124.30, 123.01, 121.98, 121.12, 117.16, 111.16, 105.49, 49.40, 46.82, 38.23, 21.59, 20.78.

HRMS (ESI) for C₂₈H₂₅N₂O₃S[M+H]⁺m/z: calcd 469.1580, found 469.1537.

2-(5-phenyl-1-tosyl-3-(1-tosyl-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (17c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 17b (120 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 17c (70.8 mg, 57% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.64 – 7.51 (m, 4H), 7.49 – 7.38 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 5H), 7.25 (s, 2H), 4.25 (d, J = 16.7 Hz, 1H), 4.06 (s, 1H), 3.68 – 3.52 (m, 2H), 3.19 (dd, J = 11.7, 4.1 Hz, 1H), 3.03 (d, J = 17.3 Hz, 1H), 2.66 (d, J = 17.3 Hz, 1H), 2.41 (s, 3H), 2.32 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 145.07, 144.11, 136.84, 136.73, 135.22, 134.79, 132.85, 130.12, 129.89, 129.57, 129.20, 128.87, 128.39, 127.61, 127.04, 125.53, 125.15, 123.78, 123.57, 120.33, 118.82, 117.45, 114.03, 49.51, 48.16, 34.94, 21.63, 21.59, 20.64.

HRMS (ESI) for C₃₅H₃₂N₃O₄S₂[M+H]⁺m/z: calcd 622.1829, found 622.1769.

(E)-2-(3-(4-methoxystyryl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (18c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 18b (64 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 18c (59.3 mg, 61% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 8.2 Hz, 2H), 7.44 – 7.30 (m, 7H), 7.20 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 15.8 Hz, 1H), 6.08 (dd, J =15.8, 9.3 Hz, 1H), 4.03 (d, J = 16.6 Hz, 1H), 3.82 (s, 3H), 3.58 – 3.48 (m, 2H), 3.33 – 3.24 (m, 1H), 3.14 (dd, J = 11.6, 4.2 Hz, 1H), 2.96 (s, 2H), 2.43 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.51, 144.03, 137.28, 135.94, 133.16, 132.67, 129.89, 129.12, 129.08, 128.62, 128.35, 127.83, 127.76, 124.94, 124.23, 117.77, 114.06, 55.37, 49.64, 48.13, 42.42, 21.59, 20.20.

HRMS (ESI) for C₂₉H₂₉N₂O₃S[M+H]⁺m/z: calcd 485.1893, found 485.1853.

N-(4-(cyanomethyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-yl)-N-methylbenzamide (19c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 19b (65 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 19c (65.0 mg, 67% yield) as a yellow solid. Rf = 0.25 (Petroleum ether: EtOAc =1:1).

¹H NMR (600 MHz, CDCl₃) δ 7.66 (d, J = 8.1 Hz, 2H), 7.53 (dd, J = 6.4, 2.8 Hz, 2H), 7.47 – 7.38 (m, 6H), 7.35 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 6.9 Hz, 2H), 5.47 (s, 1H), 4.21 (d, J = 16.7 Hz, 1H), 3.99 (d, J = 12.4 Hz, 1H), 3.36 (d, J = 16.6 Hz, 1H), 3.15 (s, 3H), 3.08 – 2.96 (m, 3H), 2.44 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.92, 144.43, 141.27, 136.57, 135.72, 131.88, 130.06, 130.03, 129.29, 129.03, 128.56, 127.82 (d, J = 9.9 Hz), 127.09, 120.76, 117.12, 50.72, 49.54, 48.14, 35.15, 21.62, 19.88.

HRMS (ESI) for C₂₈H₂₈N₃O₃S[M+H]⁺m/z: calcd 486.1846, found 486.1833.

2-(3-(2-oxopyrrolidin-1-yl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (20c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 20b (45 mg, 0.4 mmol). After 18 hours, the reaction mixture was purified by column chromatography to provide the compound 20c (60.0 mg, 69% yield) as a yellow solid. Rf = 0.15 (Petroleum ether: EtOAc =1:1).

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.2 Hz, 2H), 7.45 – 7.37 (m, 3H), 7.33 (d, J = 8.1 Hz, 2H), 7.20 – 7.15 (m, 2H), 4.91 (s, 1H), 4.20 (d, J = 16.7 Hz, 1H), 3.94 – 3.81 (m, 2H), 3.48 (ddd, J = 9.8, 7.8, 5.3 Hz, 1H), 3.24 (d, J = 16.6 Hz, 1H), 2.95 (d, J = 17.0 Hz, 1H), 2.85 – 2.75 (m, 2H), 2.47 (t, J = 8.1 Hz, 2H), 2.42 (s, 3H), 2.14 – 2.04 (m, 2H).

¹³C NMR (101 MHz, CDCl₃) δ 176.07, 144.44, 140.77, 136.46, 131.75, 130.05, 129.26, 129.01, 127.82, 127.73, 120.58, 117.00, 49.49, 48.24, 48.05, 45.08, 30.94, 21.59, 19.71, 18.24.

HRMS (ESI) for C₂₄H₂₆N₃O₃S[M+H]⁺m/z: calcd 436.1689, found 436.1674.

2-(3-(benzyloxy)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (21c)

Prepared following general Procedure A using 1a (63.4 mg, 0.2 mmol), 21b (54 mg, 0.4 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 21c (58.4 mg, 64% yield) as a yellow solid. Rf = 0.25 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 6.0 Hz, 2H), 7.47 – 7.28 (m, 10H), 7.15 (d, J = 6.7 Hz, 2H), 4.79 (dd, J = 11.1, 2.1 Hz, 1H), 4.65 (dd, J =11.1, 2.2 Hz, 1H), 4.29 (s, 1H), 3.86 (d, J = 16.7 Hz, 1H), 3.66 (d, J =17.0 Hz, 1H), 3.56 – 3.45 (m, 1H), 3.37 (d, J = 12.0 Hz, 1H), 3.14 (d, J = 17.1 Hz, 1H), 2.93 (dd, J = 17.1, 1.9 Hz, 1H), 2.43 (s, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 144.14, 138.54, 137.25, 136.44, 132.96, 129.93, 129.10, 128.86, 128.70, 128.43, 128.27, 128.10, 127.72, 123.52, 117.56, 72.25, 71.54, 49.46, 46.09, 21.60, 18.76.

HRMS (ESI) for C₂₇H₂₇N₂O₃S[M+H]⁺m/z: calcd 459.1737, found 459.1671.

2-(3-(4-methoxyphenyl)-5-(p-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (22c)

Prepared following general Procedure A using N-F (66.2 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 22c (64.3 mg, 68% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.28 – 7.22 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 4.06 (d, J = 16.6 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 1H), 3.64 (d, J = 16.6 Hz, 1H), 3.45 (dd, J = 11.7, 4.5 Hz, 1H), 3.33 (dd, J = 11.7, 4.9 Hz, 1H), 3.00 (d, J = 17.2 Hz, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 159.22, 143.193, 138.60, 136.40, 134.27, 132.77, 131.35, 129.80, 129.74, 129.58, 128.27, 127.73, 124.41, 117.45, 114.193, 55.30, 50.08, 49.71, 43.34, 21.56, 21.23, 20.193.

HRMS (ESI) for C₂₈H₂₉N₂O₃S[M+H]⁺m/z: calcd 473.1893, found 473.1864.

2-(3,5-bis(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (23c)

Prepared following general Procedure A using N-F (69.4 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 23c (62.5 mg, 64% yield) as a yellow solid. Rf = 0.2 (Petroleum ether: EtOAc =5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.03 (d, J = 16.6 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.73 (s, 1H), 3.60 (d, J = 16.7 Hz, 1H), 3.42 (dd, J = 11.7, 4.4 Hz, 1H), 3.29 (dd, J = 11.7, 4.8 Hz, 1H), 2.98 (d, J = 17.2 Hz, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.73, 159.20, 143.94, 136.04, 132.69, 131.37, 129.82, 129.67, 129.58, 129.29, 127.74, 124.45, 117.54, 114.44, 114.38, 55.40, 55.31, 50.07, 49.75, 43.39, 21.58, 20.40.

HRMS (ESI) for C₂₈H₂₉N₂O₄S[M+H]⁺m/z: calcd 489.1843, found 489.1848.

2-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (24c)

Prepared following general Procedure A using substrate (67.0 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 24c (43.0 mg, 45% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 8:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 – 7.17 (m, 4H), 7.11 (t, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 4.02 (d, J = 16.7 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 1H), 3.61 (d, J = 16.6 Hz, 1H), 3.43 (dd, J = 11.8, 4.4 Hz, 1H), 3.31 (dd, J = 11.7, 4.8 Hz, 1H), 2.91 (d, J = 17.2 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 162.69 (d, J = 248.7 Hz), 159.29, 144.02, 135.51, 133.14 (d, J = 3.5 Hz), 132.72, 131.08, 130.24 (d, J =8.3 Hz), 129.85, 129.54, 127.72, 125.38, 117.19, 116.22 (d, J = 21.7 Hz), 114.46, 55.30, 50.01, 49.69, 43.40, 21.57, 20.34.

19F NMR (377 MHz, CDCl₃) δ -112.22 – -112.37 (m).

HRMS (ESI) for C₂₇H₂₆FN₂O₃S[M+H]⁺m/z: calcd 477.1643, found 477.1607.

2-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (25c)

Prepared following general Procedure A using N-F (70.4 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 25c (56.1 mg, 57% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.00 (d, J = 16.6 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 1H), 3.61 (d, J = 16.6 Hz, 1H), 3.41 (dd, J = 11.8, 4.5 Hz, 1H), 3.32 (dd, J = 11.8, 4.9 Hz, 1H), 2.90 (d, J = 17.2 Hz, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.29, 144.08, 135.61, 135.38, 134.76, 132.64, 131.00, 129.88, 129.81, 129.56, 129.40, 127.72, 125.52, 117.12, 114.47, 55.31, 50.01, 49.54, 43.40, 21.59, 20.35.

HRMS (ESI) for C₂₇H₂₆ClN₂O₃S[M+H]⁺m/z: calcd 493.1347, found 493.1323.

ethyl-4-(4-(cyanomethyl)-5-(4-methoxyphenyl)-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl)benzoate (26c)

Prepared following general Procedure A using N-F (77.8 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 26c (54.1 mg, 51% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 8:1).

¹H NMR (600 MHz, CDCl₃) δ 8.09 (d, J = 8.2 Hz, 2H), 7.59 (t, J = 9.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 4H), 7.23 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 16.7 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 1H), 3.64 (d, J = 16.7 Hz, 1H), 3.43 (dd, J = 11.8, 4.5 Hz, 1H), 3.34 (dd, J = 11.8, 4.9 Hz, 1H), 2.88 (d, J = 17.3 Hz, 1H), 2.61 (d, J = 17.4 Hz, 1H), 2.42 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

¹³C NMR (151 MHz, CDCl₃) δ 165.85, 159.30, 144.07, 141.74, 135.70, 132.68, 130.93, 130.80, 130.31, 129.86, 129.54, 128.46, 127.70, 125.63, 116.96, 114.48, 61.30, 55.30, 50.00, 49.35, 43.36, 21.56, 20.34, 14.33.

HRMS (ESI) for C₃₀H₃₁N₂O₅S[M+H]⁺m/z: calcd 531.1948, found 531.1917.

2-(3-(4-methoxyphenyl)-5-(m-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (27c)

Prepared following general Procedure A using N-F (66.2 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 27c (72.8 mg, 77% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.32 – 7.27 (m, 3H), 7.24 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 4.04 (d, J = 16.6 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 1H), 3.62 (d, J = 16.6 Hz, 1H), 3.43 (dd, J = 11.7, 4.5 Hz, 1H), 3.31 (dd, J = 11.7, 4.9 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.22, 143.93, 138.95, 137.24, 136.58, 132.77, 131.33, 129.81, 129.57, 129.35, 128.96, 128.94, 127.74, 125.42, 124.40, 117.42, 114.41, 55.30, 50.09, 49.70, 43.28, 21.56, 21.39, 20.37.

HRMS (ESI) for C₂₈H₂₉N₂O₃S[M+H]⁺m/z: calcd 473.1893, found 473.1862.

2-(3-(4-methoxyphenyl)-5-(o-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (28c)

Prepared following general Procedure A using N-F (66.2 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 28c (59.6 mg, 63% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, Chloroform-d) major: δ 7.66 – 7.59 (t, 2H), 7.36 – 7.21 (m, 7H), 7.10 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 3.6 Hz, 2H), 3.98 (d, J = 16.5 Hz, 1H), 3.89 – 3.80 (m, 4H), 3.75 (s, 1H), 3.58 – 3.53 (m, 1H), 3.34 (d, J = 5.2 Hz, 1H), 2.73 (d, J = 17.1 Hz, 1H), 2.57 (s, 1H), 2.45 (s, 3H), 2.27 (s, 3H). minor: 1H NMR (400 MHz, Chloroform-d) δ 7.65 – 7.53 (t, 2H), 7.34 – 7.16 (m, 7H), 7.02 (d, J = 7.4 Hz, 1H), 6.89 (d, J = 3.6 Hz, 2H), 3.88 – 3.77 (m, 5H), 3.66 (d, J = 16.8 Hz, 1H), 3.49 – 3.44 (m, 1H), 3.29 (d, J = 5.1 Hz, 1H), 2.77 (d, J = 17.3 Hz, 1H), 2.50 (s, 1H), 2.42 (s, 3H), 2.26 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 159.25, 159.23, 143.96, 143.88, 136.51, 136.45, 136.23, 135.93, 135.76, 135.43, 132.92, 132.86, 131.62, 131.06, 130.87, 130.72, 129.82, 129.79, 129.56, 129.53, 128.76, 128.72, 128.64, 127.72, 126.70, 126.46, 125.09, 125.03, 116.97, 116.78, 114.47, 55.30, 50.28, 50.09, 49.17, 43.24, 43.16, 21.57, 19.94, 19.89, 19.36, 19.20.

HRMS (ESI) for C₂₈H₂₉N₂O₃S[M+H]⁺m/z: calcd 473.1893, found 473.1862.

2-(3-(4-methoxyphenyl)-5-(naphthalen-1-yl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (29c)

Prepared following general Procedure A using N-F (73.4 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 29c (60 mg, 59% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 5:1).

¹H NMR (600 MHz, Chloroform-d) major: δ 7.94 – 7.84 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.62 – 7.41 (m, 6H), 7.36 – 7.27 (m, 4H), 6.97 (d, J = 8.6 Hz, 2H), 4.19 (d, J = 16.7 Hz, 1H), 3.94 (d, J = 17.0 Hz, 1H), 3.84 (s, 3H), 3.69 – 3.61 (m, 1H), 3.59 (d, J = 16.7 Hz, 1H), 3.39 – 3.33 (m, 1H), 2.69 (d, J = 3.6 Hz, 1H), 2.51 (d, J = 17.3 Hz, 1H), 2.43 (s, 3H). minor: δ 7.94 – 7.84 (m, 2H), 7.78 (d, J = 9.5 Hz, 1H), 7.62 – 7.41 (m, 6H), 7.36 – 7.27 (m, 4H), 6.92 (d, J = 8.6 Hz, 2H), 4.00 (s, 1H), 3.87 (s, 1H), 3.82 (s, 4H), 3.69 – 3.61 (m, 1H), 3.39 – 3.33 (m, 1H), 2.72 (d, J = 3.6 Hz, 1H), 2.56 (d, J =17.3 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (151 MHz, Chloroform-d) major: δ 159.29, 143.99, 134.70, 134.40, 133.85, 131.72, 130.65, 129.85, 129.59, 129.08, 129.00, 128.61, 127.75, 127.38, 126.70, 126.65, 125.69, 125.40, 123.87, 117.15, 114.58, 55.34, 50.21, 49.81, 43.29, 21.57, 20.29. minor: 159.29, 143.90, 134.98, 134.59, 133.81, 130.95, 130.58, 129.85, 129.67, 129.05, 128.76, 128.03, 127.72, 127.50, 126.77, 126.50, 125.71, 125.40, 124.33, 116.78, 114.51, 55.32, 50.44, 49.85, 43.52, 21.57, 20.40.

HRMS (ESI) for C₃₁H₂₉N₂O₃S[M+H]⁺m/z: calcd 509.1893, found 509.1858.

2-(3-(4-methoxyphenyl)-5-(naphthalen-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (30c)

Prepared following general Procedure A using N-F (73.4 mg, 0.2 mmol). After 12 hours, the reaction mixture was purified by column chromatography to provide the compound 30c (64.0 mg, 63% yield) as a white solid. Rf = 0.2 (Petroleum ether: EtOAc = 5:1).

¹H NMR (400 MHz, CDCl₃) δ 7.95 – 7.82 (m, 3H), 7.71 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58 – 7.51 (m, 2H), 7.35 – 7.27 (m, 5H), 6.92 (d, J =8.4 Hz, 2H), 4.16 (d, J =16.6 Hz, 1H), 3.82 (s, 4H), 3.73 (d, J = 16.7 Hz, 1H), 3.48 (dd, J = 11.7, 4.4 Hz, 1H), 3.37 (dd, J =11.7, 4.9 Hz, 1H), 3.01 (d, J = 17.2 Hz, 1H), 2.64 (d, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.27, 144.01, 136.45, 134.58, 133.19, 132.97, 132.69, 131.28, 129.86, 129.63, 129.03, 128.01, 127.83, 127.76, 127.70, 126.94, 126.90, 125.87, 125.12, 117.37, 114.46, 55.33, 50.15, 49.76, 43.41, 21.58, 20.48.

HRMS (ESI) for C₃₁H₂₉N₂O₃S[M+H]⁺m/z: calcd 509.1893, found 509.1856.

4-(azidomethyl)-3,5-diphenyl-1-tosyl-1,2,3,6-tetrahydropyridine (32c)

¹H NMR (400 MHz, CDCl3) δ 7.60 (d, J =8.2 Hz, 2H), 7.44 – 7.27 (m, 10H), 7.21 (d, J =6.6 Hz, 2H), 4.04 (d, J =16.7 Hz, 1H), 3.85 – 3.75 (m, 2H), 3.70 (d, J = 16.7 Hz, 1H), 3.44 (dd, J =11.7, 4.6 Hz, 1H), 3.33 (dd, J = 11.7, 4.8 Hz, 1H), 3.22 (d, J = 13.1 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl3) δ 143.85, 140.16, 137.50, 136.74, 132.74, 129.80, 129.46, 128.75 (t, J = 12.1 Hz), 128.31, 127.77, 127.52, 50.57, 49.94, 49.62, 42.82, 21.60.

HRMS (ESI) for C₂₅H₂₅N₄O₂S[M+H]⁺m/z: calcd 445.1693, found 445.1671.

3-(4-methoxyphenyl)-5-phenyl-4-(thiocyanatomethyl)-1-tosyl-1,2,3,6-tetrahydropyridine (33c)

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J =8.1 Hz, 2H), 7.45 – 7.34 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 4H), 6.89 (d, J =8.5 Hz, 2H), 4.01 (d, J = 16.9 Hz, 1H), 3.91 (s, 1H), 3.81 (s, 3H), 3.76 – 3.68 (m, 2H), 3.42 (dd, J =11.7, 4.7 Hz, 1H), 3.35 (dd, J = 11.7, 4.8 Hz, 1H), 2.92 (d, J = 12.7 Hz, 1H), 2.43 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.17, 143.99, 138.78, 137.03, 132.67, 131.47, 129.89, 129.62, 129.01, 128.78, 128.54, 128.17, 127.73, 114.44, 111.72, 55.33, 50.08, 41.57, 34.74, 21.61.

HRMS (ESI) for C₂₇H₂₇N₂O₃S₂[M+H]⁺m/z: calcd 491.1458, found 491.1413.

3-(4-methoxyphenyl)-5-phenyl-1-tosyl-4-(((trifluoromethyl)thio)methyl)-1,2,3,6-tetrahydropyridine (34c)

¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 8.2 Hz, 2H), 7.43 – 7.32 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.21 – 7.16 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.98 (d, J = 16.7 Hz, 1H), 3.89 (s, 1H), 3.81 (s, 3H), 3.67 (d, J = 16.7 Hz, 1H), 3.57 (d, J = 12.8 Hz, 1H), 3.34 (ddd, J = 28.9, 11.7, 4.9 Hz, 2H), 2.91 (d, J = 12.9 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.03, 143.81, 137.62, 136.39, 132.93, 131.89, 129.77, 129.62, 128.79, 128.63, 128.42, 128.32, 127.74, 114.27, 55.27, 50.17, 49.90, 41.78, 30.84, 21.55.

19F NMR (377 MHz, CDCl3) δ -41.21 (s).

HRMS (ESI) for C₂₇H₂₇F₃NO₃S₂[M+H]⁺m/z: calcd 534.1379, found 534.1383.

4-(4,4-dimethylpent-2-yn-1-yl)-3-(4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (35c)

Prepared following general Procedure C using 1a (63.4 mg, 0.2 mmol), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and (3,3-dimethylbut-1-yn-1-yl)trimethoxysilane (81 mg, 0.4 mmol, 2.0 eq.). After 12 hours, the reaction mixture was purified by column chromatography to provide the title compound 35c (44.5 mg, 43% yield) as a white solid. Rf = 0.3 (Petroleum ether: EtOAc =5:1)

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.39 – 7.27 (m, 5H), 7.26 – 7.22 (m, 4H), 6.86 (d, J = 8.7 Hz, 2H), 3.99 (d, J = 15.9 Hz, 1H), 3.90 (s, 1H), 3.81 (s, 3H), 3.59 (d, J = 15.9 Hz, 1H), 3.38 (dd, J = 11.4, 4.5 Hz, 1H), 3.26 (dd, J =11.4, 4.8 Hz, 1H), 2.80 (d, J = 17.1 Hz, 1H), 2.42 – 2.38 (m, 4H), 1.16 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 158.69, 143.58, 138.72, 133.04, 132.83, 131.20, 131.04, 129.71, 129.67, 128.80, 128.52, 127.85, 127.71, 113.89, 89.85, 75.55, 55.25, 50.43, 49.49, 42.74, 31.25, 27.37, 21.58, 21.55.

HRMS (ESI) for C₃₂H₃₆NO₃S[M+H]⁺m/z: calcd 514.2410, found 514.2342.

4-(hept-2-yn-1-yl)-3-(4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (36c)

Prepared following general Procedure C using 1a (63.4 mg, 0.2 mmol), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and hex-1-yn-1-yltrimethoxysilane (81 mg, 0.4 mmol, 2.0 eq.). After 12 hours, the reaction mixture was purified by column chromatography to provide the title compound 36c (63.7 mg, 62% yield) as a white solid. Rf = 0.3 (Petroleum ether: EtOAc =5:1)

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J =8.1 Hz, 2H), 7.42 – 7.32 (m, 3H), 7.31 – 7.26 (m, 6H), 6.89 (d, J =8.5 Hz, 2H), 4.08 (d, J =16.0 Hz, 1H), 3.93 (s, 1H), 3.83 (s, 3H), 3.56 (d, J =16.0 Hz, 1H), 3.48 (dd, J =11.4, 3.9 Hz, 1H), 3.23 (dd, J = 11.4, 4.7 Hz, 1H), 2.83 (d, J = 17.0 Hz, 1H), 2.43 – 2.39 (m, 4H), 2.13 (t, J =6.7 Hz, 2H), 1.52 – 1.35 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 158.68, 143.58, 138.66, 133.09, 132.78, 131.21, 130.96, 129.65, 128.78, 128.54, 127.84, 127.75, 113.90, 81.27, 77.21, 55.25, 50.29, 49.41, 42.57, 31.09, 21.99, 21.60, 21.55, 18.48, 13.67.

HRMS (ESI) for C₃₂H₃₆NO₃S[M+H]⁺m/z: calcd 514.2410, found 514.2338.

3-(4-methoxyphenyl)-5-phenyl-4-(3-phenylprop-2-yn-1-yl)-1-tosyl-1,2,3,6-tetrahydropyridine (37c)

Prepared following general Procedure C using 1a (63.4 mg, 0.2 mmol), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and trimethoxy(phenylethynyl)silane (90 mg, 0.4 mmol, 2.0 eq.). After 12 hours, the reaction mixture was purified by column chromatography using 7% EtOAc in PE to provide the title compound 37c (81.2 mg, 76% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc =6:1)

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.2 Hz, 2H), 7.43 – 7.26 (m, 14H), 6.89 (d, J =8.6 Hz, 2H), 4.07 (d, J = 16.1 Hz, 1H), 3.98 (s, 1H), 3.81 (s, 3H), 3.62 (d, J = 16.1 Hz, 1H), 3.46 (dd, J = 11.5, 4.3 Hz, 1H), 3.29 (dd, J =11.5, 4.8 Hz, 1H), 3.07 (d, J = 17.3 Hz, 1H), 2.68 (d, J = 17.4 Hz, 1H), 2.40 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 158.80, 143.66, 138.54, 132.86, 132.79, 132.13, 131.58, 130.22, 129.71 (d, J = 1.8 Hz), 128.80, 128.67, 128.24, 127.92, 127.83, 127.80, 123.67, 114.02, 87.35, 81.42, 55.28, 50.37, 49.55, 42.90, 22.33, 21.55.

HRMS (ESI) for C₃₄H₃₂NO₃S[M+H]⁺m/z: calcd 534.2097, found 534.2024.

3-(4-methoxyphenyl)-5-phenyl-1-tosyl-4-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2,3,6-tetrahydropyridine (38c)

Prepared following general Procedure C using 1a (63.4 mg, 0.2 mmol), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and trimethoxy((trimethylsilyl)ethynyl)silane (88 mg, 0.4 mmol, 2.0 eq.). After 12 hours, the reaction mixture was purified by column chromatography using 6% EtOAc in PE to provide the title compound 38c (60.4 mg, 57% yield) as a white solid. Rf = 0.25 (Petroleum ether: EtOAc =5:1)

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.1 Hz, 2H), 7.40 – 7.31 (m, 3H), 7.30 – 7.22 (m, 6H), 6.87 (d, J = 8.5 Hz, 2H), 4.01 (d, J =16.1 Hz, 1H), 3.91 (s, 1H), 3.81 (s, 3H), 3.59 (d, J =16.0 Hz, 1H), 3.40 (dd, J = 11.4, 4.3 Hz, 1H), 3.27 (dd, J = 11.4, 4.8 Hz, 1H), 2.88 (d, J =17.5 Hz, 1H), 2.48 (d, J = 17.6 Hz, 1H), 2.41 (s, 3H), 0.14 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 158.75, 143.67, 138.47, 132.78, 132.67, 132.00, 129.92, 129.74, 129.71, 128.77, 128.61, 127.85, 113.94, 104.06, 85.64, 55.26, 50.36, 49.54, 42.76, 22.82, 21.57, 0.12.

HRMS (ESI) for C₃₁H₃₆NO₃SSi[M+H]⁺m/z: calcd 530.2180, found 530.2105.

4-(3-cyclopropylprop-2-yn-1-yl)-3-(4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (39c)

Prepared following general Procedure C using sing 1a (63.4 mg, 0.2 mmol), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and (cyclopropylethynyl)trimethoxysilane (76 mg, 0.4 mmol, 2.0 eq.). After 12 hours, the reaction mixture was purified by column chromatography using 6% EtOAc in PE to provide the title compound 39c (49.8 mg, 50% yield) as a white solid. Rf = 0.3 (Petroleum ether: EtOAc =5:1)

¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J =8.1 Hz, 2H), 7.39 – 7.30 (m, 3H), 7.29 – 7.21 (m, 6H), 6.86 (d, J =8.5 Hz, 2H), 4.03 (d, J = 16.0 Hz, 1H), 3.88 (s, 1H), 3.80 (s, 3H), 3.55 (d, J = 16.0 Hz, 1H), 3.42 (dd, J =11.4, 4.1 Hz, 1H), 3.23 (dd, J = 11.4, 4.7 Hz, 1H), 2.78 (d, J = 17.1 Hz, 1H), 2.41 – 2.34 (m, 4H), 1.19 – 1.09 (m, 1H), 0.74 – 0.65 (m, 2H), 0.61 – 0.52 (m, 2H).

¹³C NMR (101 MHz, CDCl₃) δ 158.69, 143.61, 138.62, 133.03, 132.75, 131.32, 130.78, 129.67, 129.65, 128.76, 128.56, 127.84, 127.76, 113.91, 84.24, 72.59, 55.26, 50.33, 49.45, 42.59, 21.60, 21.56, 8.05, 7.98.

HRMS (ESI) for C₃₁H₃₂NO₃S[M+H]⁺m/z: calcd 498.2097, found 498.2026.

Characterization of products 40-43

2-(3-(4-methoxyphenyl)-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)acetamide (40)

¹H NMR (600 MHz, Chloroform-d) δ 7.58 (d, J = 6.4 Hz, 2H), 7.38 – 7.34 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.28 – 7.24 (m, 4H), 7.22 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.53 (s, 1H), 5.25 (s, 1H), 4.07 (d, J = 16.3 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 1H), 3.56 (d, J = 16.4 Hz, 1H), 3.44 (dd, J = 11.5, 4.2 Hz, 1H), 3.24 (dd, J = 11.6, 4.7 Hz, 1H), 2.88 (d, J = 15.8 Hz, 1H), 2.46 (d, J = 16.2 Hz, 1H), 2.41 (s, 3H).

¹³C NMR (151 MHz, Chloroform-d) δ 172.85, 158.84, 143.75, 138.54, 134.67, 132.83, 132.74, 129.70, 129.67, 129.00, 128.74, 128.69, 127.98, 127.79, 114.12, 55.26, 50.15, 49.65, 43.70, 37.90, 21.53.

HRMS (ESI) for C₂₇H₂₉FN₂O₄S[M+H]⁺m/z: calcd 477.1843, found 477.1833.

2-(3-(2-oxopyrrolidin-1-yl)-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)acetonitrile (41)

¹H NMR (400 MHz, CDCl₃) δ 7.40 -7 .36 (m, 2H), 7.35 – 7.29 (m, 1H), 7.21 – 7.16 (m, 2H), 4.68 (s, 1H), 3.73 – 3.63 (m, 1H), 3.59 – 3.48 (m, 3H), 3.22 – 3.09 (m, 2H), 2.97 (d, J = 16.9 Hz, 1H), 2.81 (d, J = 16.9 Hz, 1H), 2.55 – 2.36 (m, 2H), 2.19-2.02 (3H).

¹³C NMR (101 MHz, CDCl₃) δ 176.08, 144.99, 138.21, 128.95, 128.25, 127.65, 120.40, 117.94, 50.64, 48.57, 47.79, 45.57, 31.11, 19.89, 18.06.

HRMS (ESI) for C₁₇H₂₀N₃O [M+H]⁺m/z: calcd 282.1601, found 282.1584.

2-(3-(4-methoxyphenyl)-5-phenyl-1-tosyl-2,3-dihydropyridin-4(1H)-ylidene)acetonitrile (42)

¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.3 Hz, 1H), 7.43 – 7.33 (m, 2H), 7.23 (dd, J = 7.8, 1.6 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 5.09 (s, 1H), 4.31 (d, J = 1.6 Hz, 1H), 4.13 (d, J = 12.7 Hz, 1H), 3.78 (s, 3H), 3.56 (dd, J = 12.6, 4.0 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 158.92, 153.76, 144.61, 136.04, 134.46, 130.74, 130.40, 129.97, 129.53, 128.91, 128.25, 128.01, 126.97, 119.52, 117.48, 114.17, 93.11, 55.19, 48.72, 41.27, 21.57.

HRMS (ESI) for C₂₇H₂₅N₂O₃S [M+H]⁺m/z: calcd 457.1580, found 457.1617.

2-bromo-2-(5-(4-methoxyphenyl)-3-phenyl-1-tosyl-1,2-dihydropyridin-4-yl)acetonitrile (43)

¹H NMR (600 MHz, Chloroform-d) δ 7.54 (d, J =8.1 Hz, 2H), 7.43 – 7.37 (m, 3H), 7.26 – 7.19 (m, 4H), 7.12 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 4.36 (s, 1H), 4.22 (d, J = 14.5 Hz, 1H), 3.80 (s, 3H), 3.48 (dd, J = 13.0, 4.1 Hz, 1H), 2.44 (s, 3H).

¹³C NMR (151 MHz, Chloroform-d) δ 159.07, 149.85, 144.88, 136.45, 134.10, 131.59, 130.11, 129.84, 128.76, 128.71, 128.29, 128.00, 126.99, 117.55, 114.67, 114.33, 86.48, 55.22, 47.75, 42.01, 21.61.

HRMS (ESI) for C₂₇H₂₄BrN₂O₃S [M+H]⁺m/z: calcd 535.0686, found 535.0621.

Published: February 9, 2023

Data and code availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under accession numbers CCDC 2192306 (3a), 2192304 (43). Copies of the data can be obtained free of charge from https://www.ccdc.cam.ac.uk/structures/. All other data are available from the lead contact upon reasonable request.