Michael addition with an olefinic pyridine: organometallic nucleophiles and carbon electrophiles.

Abstract

The conjugate addition reactions of trans-1,2-di-(2-pyridyl)ethylene have been studied. This substrate reacts with organolithium nucleophiles and the resulting anionic intermediates may be trapped by proton or various carbonyl-based electrophiles. It is suggested that the dipyridyl structure stabilizes the intermediate carbanion, allowing the Michael adduct to be captured by an added electrophile.

Graphical Abstract

Michael or conjugate addition was first reported in the late 1800s.¹ These initial reports described the addition of nucleophiles to α,β-unsaturated carbonyl compounds. Subsequent developments extended this chemistry to a wide variety of nucleophiles and Michael acceptors.² In 1947, Doering and Weil reported the base-promoted conjugate addition of malonate esters with 2- and 4-vinylpyridine - demonstrating that olefinic N-heterocycles are effective Michael acceptors.³ Despite decades of work, the vast majority of conjugate addition reactions involve nucleophilic attack at the olefinic N-heterocycle followed a protonation to complete the addition.⁴ For example, Danishefsky and coworkers used 6-vinylpicoline in conjugate addition reactions to prepare steroid analogs. Generating a nucleophile from enone 1, the addition reaction was completed with a protonation (eq 1).⁵ Although more than 15

(1)

different types of N-heterocyclic systems have been shown to undergo conjugate additions at olefinic groups, there are very few examples of intermediate carbanionic species being captured in reactions with electrophiles other than proton.⁴ In contrast, it is common to use varied electrophiles in the conjugate addition reactions of α,β-unsaturated carbonyl compounds, as the enolate intermediates may be captured by electrophiles such as aldehydes, acid halides, and others.^2b Given the value of functionalized N-heterocycles in pharmaceutical and other applications, the development of this synthetic chemistry could be very useful. Nishiguchi and coworkers described an example of this chemistry by the zinc-promoted

(2)

coupling of vinylpyridines, alkyl iodides, and carbonyl electrophiles (eq 2).⁶ In these conversions, 2-vinylpyridine provides addition products such as the cyclohexanone adduct (3). A mechanism is proposed involving alkyl radical addition to the olefin (4), subsequent reduction to the anionic intermediate 5, and the reaction of 5 with the carbonyl electrophile. In the following Note, we describe conjugate addition reactions to an olefinic pyridine with organolithium nucleophiles and carbon-centered electrophiles. A key aspect of this chemistry involves the formation of a stabilized anionic intermediate following reaction with the organolithium reagent.

It has been previously reported that olefinic N-heterocycles react poorly with reagents such as organolithium and Grignard reagents.⁷ Our initial efforts to react olefinic N-heterocycles with organolithium olefinic N-heterocycles reagents were also unsuccessful. In an attempt to react 2-vinylpyridine with tBuLi and capture the anionic intermediate with a proton source, only a trace amount of the adduct 6 was obtained and the only major product isolated was the dimeric species 7 (eq 3). Clearly, product 7 is formed by nucleophilic attack by tBuLi at

(3)

2-vinylpyridine. However, the resulting anionic intermediate evidently reacts with a second equivalent of 2-vinylpyridine to eventually provide compound 7 from protonation. This suggested to us that the second carbanionic intermediate, species 8, must possess at least some kinetic stability – perhaps from internal stabilization of the carbon-lithium bond. With this consideration, we hypothesized that 1,2-di-(2-pyridyl)ethylene (9) could exhibit a similar kinetic stability and enable the resulting carbanionic intermediate (10) to be trapped efficiently with electrophiles (eq 4). To test this hypothesis, we reacted substrate 9 with a variety of

(4)

organolithium reagents and quenched the resulting solutions with aqueous acid (Table 1). The results indicate that 1,2-di-(2-pyridyl)ethylene (9) reacts efficiently with organometallic reagents – leading to addition products 11–15. This includes aliphatic and aromatic organolithium reagents. Product 15 is prepared from 2-picolyllithium and compound 9. The low yield of product 15 is due in part to difficulties in purifying 15 by silica gel chromatography. The generally good yields of the addition products suggest reasonably stable anionic intermediates and the potential for reactions with other electrophiles.

Table 1.

Products and yields from the reactions of 9with organolithium reagents.

When compound 9 is reacted with butyllithium followed by acid chlorides, the addition products (16–23 and 30) are formed in fair to good yields (Table 2). Thus, compound 9 reacts with BuLi and acetyl chloride to provide the addition product 16 in good yield. Optimization studies showed that it is necessary to add the solution of the butyllithium adduct to a solution of acetyl chloride. If acetyl chloride is added to a solution of the butyllithium adduct, product 16 is formed along with significant quantities of compound 12. Products 17–18, 21–23, and 30 are obtained as single diastereomers, but compounds 19 and 20 are obtained as the mixture of diastereomers. Each of these products are obtained from the respective acid chlorides.

Table 2.

Addition products and yields from compound 9and organolithium reagents and with carbon electrophiles.

^aIsolated as the single diastereomer (DL mixture).

^bIsolated as the diastereomeric mixture.

In addition to acid chloride electrophiles, chloroformate electrophiles provide compounds 24–27 in fair yields. NMR analysis of crude products indicates that single diastereomers are formed in with 24–26 while a mixture of diastereomers are obtained with 27. A similar conversion utilizing diethylcarbamoyl chloride was not successful. A sulfonyl chloride has been shown to give the adduct 28 in fair yield as the mixture of diastereomers (3:2 ratio). The addition may also be accomplished with cyclohexanone, providing adduct 27 as a single diastereomer in 69% yield. In the synthesis of product 31, an ester was successfully used as the carbon electrophiles (ethyl picolinate).

The conversions above are consistent with the formation of a relatively stable anionic intermediate from nucleophilic attack by butyllithium and related organometallics. Although it has been previously reported that both organolithium and Grignard reagents fail to react with olefinic pyridines,⁷ substrate 9 evidently will react with organolithium reagents. Thus, butyllithium couples with 9 to provide the adduct, intermediate 32. Like the dimeric intermediate from 2-vinylpyridine (i.e., 8), it is plausible that species 32 is stabilized by favorable interactions between the pyridyl nitrogen and lithium cation. As such, intermediate 32 is sufficiently long-lived that it may be successfully captured by electrophiles. Regarding product stereochemistry, some addition products were isolated as racemic mixtures of a single compound while others were obtained as mixtures of diastereomers. It is suggested that these product distributions are the result of thermodynamic control for the carbonyl-substituted products. For example in the case of product 18, isomerization between epimers 18 (S,R) and 18 (S,S) is expected to occur readily, as the enol 33 benefits from a stabilizing hydrogen bond to the pyridyl group (eq 5). DFT calculations estimate the energy difference between the two

(5)

epimers to be 1.8 kcal/mol.⁸ While the enol tautomer (33) is just 13.4 kcal/mol above structure 18 (S,S). This should allow for rapid interconversion between 18 (S,R) and 18 (S,S) at ambient temperatures and the formation of thermodynamically controlled product mixtures.

Conclusions

We have found that 1,2-di-(2-pyridyl)ethylene (9) reacts effectively with organolithium reagents. It is suggested that the intermediate Michael adducts exhibit kinetic stability by stabilization of the carbanionic salts. With the long-lived intermediates, it becomes possible to complete the addition chemistry with electrophiles other than proton. Thus, we demonstrate that it is possible to expand the scope of Michael addition reactions with olefinic N-heterocycles, if the intermediate anionic species are stabilized by structural effects.

Experimental

Reagents and solvents were purchased from commercial suppliers and used as received. Synthetic reactions were done using oven dried glassware under an inert atmosphere. NMR spectra were obtained from Bruker Avance III NMR spectrometers (300 or 500 MHz). Low-resolution mass spectra were obtained from an Agilent 6890 gas chromatograph equipped with a 5973 mass-selective detector. High-resolution mass spectra were obtained from a Bruker Maxis Plus Quadrupole Time-of-Flight mass spectrometer.

2,2’-(5,5-Dimethylhexane-1,3-diyl)dipyridine (7).

A solution of tert-butyllithium 0.9 mL (1.5 M, 1.4 mmol) is cooled to 0 °C and to this solution is slowly added 2-vinylpyridine (0.075 mL, 0.696 mmol in 5 mL THF). After stirring for 1 hr, the mixture is quenched with deoxygenated water and diluted with dichloromethane. The organic phase is separated and washed twice with saturated brine, and then dried with Na₂SO₄. Silica gel chromatography (hexanes:ethyl acetate) yields compound 7 (0.032 g, 0.119 mmol, 17%) as an oil. ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.54 (d, J=3.99 Hz, 1H), 8.47 (d, J=4.34 Hz, 1H), 7.58–7.49 (m, 2H), 7.14 (d, J=7.85 Hz, 1H), 7.09–7.01 (m, 3H), 2.95–2.87 (m, 1H), 2.73–2.62 (m, 1H), 2.54–2.44 (m, 1H), 2.11–2.02 (m, 2H), 1.97 (t, J=4.94 Hz, 1H), 1.58 (dd, J=14.04 Hz, J=2.93 Hz, 1H), 0.74 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 166.2, 162.0, 149.2, 149.1, 136.2, 136.1, 123.1, 122.7, 121.0, 120.8, 49.3, 44.4, 38.5, 36.4, 31.2, 29.9. Low-Resolution MS (EI): 268 (M+), 253, 211, 197, 183, 176, 163, 154, 144. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₂₅N₂ 269.2018; Found, 269.2020.

General Procedure A.

A solution is prepared from anhydrous THF (3 mL) and 1,2-bis(2-pyridyl)ethylene (0.075 g, 0.41 mmol). The mixture is cooled to −78 °C and the organolithium reagent (0.5 mmol) is then slowly added. The solution is stirred for 1 hr, after which deoxygenated water is added, and the resulting mixture is allowed to warm to room temperature. To this solution is added 0.5 mL of saturated NH₄Cl and the product is partition between the aqueous phase and dichloromethane. The organic phase is separated and washed twice with saturated brine, and then dried with Na₂SO₄. Silica gel chromatography (hexanes:ethyl acetate) yields pure addition product.

2,2’-(3,3-Dimethylbutane-1,2-diyl)dipyridine (11).

Using General Procedure A, 1,2-bis(2-pyridyl)ethylene (0.08 g, 0.44 mmol) provides compound 11(95.2 mg, 0.396 mmol, 90%) as a yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.49 (dd, J= 4.91 Hz, J=0.96 Hz, 1H), 8.39 (d, J=3.95 Hz, 1H), 7.34 (td, J=8.39 Hz, J=1.82 Hz, 1H), 6.97–6.92 (m, 1H), 6.90–6.84 (m, 2H), 6.76 (d, J=7.92 Hz, 1H), 3.47–3.39 (m, 1H), 3.25–3.11 (m, 2H), 0.99 (s, 9H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 162.2, 161.6, 148.9, 148.4, 135.6, 135.0, 125.4, 123.6, 120.9, 120.5, 57.8, 38.0, 34.2, 28.3. Low-Resolution MS (EI): 240 (M+), 225, 218, 209, 195, 184, 169, 156, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₆H₂₁N₂ 241.1705; Found, 241.1701.

2,2’-(Hexane-1,2-diyl)dipyridine (12).

Using General Procedure A, 1,2-bis(2-pyridyl)ethylene (73.2 mg, 0.402 mmol) provides compound 12 (87.6 mg, 0.366 mmol, 91%) as a light-yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.49 (d, J=4.59 Hz, 1H), 8.46 (d, J=4.33 Hz, 1H), 7.34–7.45 (m, 2H), 7.02–6.90 (m, 3H), 6.82 (d, J=7.85 Hz, 1H), 3.31–3.20 (m, 1H), 3.18–3.06 (m, 2H), 1.88–1.75 (m, 1H), 1.71–1.59 (m, 1H), 1.28–0.99 (m, 4H), 0.75 (t, J=7.35 Hz, 3H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 164.1, 160.6, 149.3, 149.1, 135.8, 123.6, 123.5, 121.1, 120.8, 48.1, 44.3, 34.8, 29.7, 22.6, 13.9. Low-Resolution MS (EI): 240 (M+), 225, 211, 197, 183, 169, 154, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₆H₂₁N₂ 241.1705; Found, 241.1703.

2,2’-(1-Phenylethane-1,2-diyl)dipyridine (13).

Using General Procedure A, 1,2-bis(2-pyridyl)ethylene (79.2 mg, 0.435 mmol) provides compound 13 (101.83 mg, 0.391 mmol, 90%) as a light yellow solid after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.56 (d, J= 4.21 Hz, 1H), 8.49, (d, J= 4.32 Hz, 1H), 7.45 (td, J=8.39 Hz, J= 1.72, 1H), 7.36–7.34 (m, 3H), 7.25–7.19 (m, 2H), 7.16–7.11 (m, 2H), 7.04–6.91 (m, 3H), 4.77 (t, J=7.80 Hz, 1H), 3.82 (q, J=7.05 Hz, 1H), 3.53 (q, J=6.83 Hz, 1H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 162.8, 160.1, 149.1, 143.3, 136.2, 135.9, 128.7, 128.4, 128.1, 127.1, 126.4, 123.5, 121.3, 121.0, 53.2, 43.5. Low-Resolution MS (EI): 260 (M+), 245, 230, 217, 204, 193, 182, 167, 152. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₁₇N₂ 261.1392; Found, 261.1385.

2,2’-(1-(Thiophen-2-yl)ethane-1,2-diyl)dipyridine (14).

Using General Procedure A with modification (2-thienyllithium is reacted with substrate 9 at 25 °C for 12 hrs), 1,2-bis(2-pyridyl)ethylene (74.8 mg, 0.411 mmol) provides compound 14 (89.76 mg, 0.337 mmol, 82%) as a light tan solid after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.60 (d, J=3.89 Hz, 1H), 8.52 (d, J=4.20 Hz, 1H), 7.53 (td, J=8.59 Hz, J=1.76 Hz, 1H), 7.42 (td, J=8.32 Hz, J=1.66 Hz, 1H), 7.18–7.02 (m, 4H), 6.94 (d, J=7.72 Hz, 1H), 6.86 (d, J=3.41 Hz, 2H), 5.03 (t, J=7.76 Hz, 1H), 3.66 (ddd, J=31.98 Hz, J=8.05 Hz, J=5.50 Hz, 2H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 162.1, 159.4, 149.3, 149.2, 146.6, 136.5, 136.0, 126.4, 124.6, 124.2, 123.9, 123.0, 121.7, 121.2, 48.8, 45.1. Low-Resolution MS (EI): 266 (M+), 251, 233, 219, 207, 188, 174, 154. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₆H₁₅N₂S 267.0956; Found, 267.0947.

2,2’,2”-(Propane-1,2,3-triyl)tripyridine (15).

A solution containing 2-picoline (37.4 mg, 0.411 mmol) and 3 mL THF is cooled to −78 °C and n-BuLi solution (0.493 mmol) is added dropwise. The resulting mixture is stirred 1 hr and then transferred slowly to a cold (−78 °C) solution of 1,2-bis(2-pyridyl)ethylene (74.9 mg, 0.411 mmol) in 3 mL THF. The solution is stirred for 1 hr, after which deoxygenated water is added, and the resulting mixture is allowed to warm to room temperature. To this solution is added 0.5 mL of saturated NH₄Cl and the product is partition between the aqueous phase and dichloromethane. The organic phase is separated and washed twice with saturated brine, and then dried with Na₂SO₄. Following column chromatography (hexanes:ethyl acetate), compound 15 (44.14 mg, 0.16 mmol, 39%) is isolated as a yellow oil. ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.55 (d, J=4.83 Hz, 1H), 8.46 (d, J= 4.81 Hz, 1H), 7.43–7.31 (m, 3H), 7.01–6.97 (m, 3H), 6.92 (d, J=7.78 Hz, 2H), 6.81 (d, J=7.88 Hz, 1H), 3.96–3.86 (m, 1H), 3.26 (ddd, J=17.69 Hz, J=7.31 Hz, J=5.77 Hz, 3H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 162.9, 160.2, 149.3, 149.2, 135.9, 135.8, 123.7, 123.7, 121.3, 120.9, 48.0, 43.5. Low-Resolution MS (EI): 275 (M+), 219, 207, 195, 183, 169, 154. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₁₈N₃ 276.1501; Found, 276.1509.

General Procedure B.

A solution of 1,2-bis(2-pyridyl)ethylene (75 mg, 0.41 mmol) on 7 mL THF is cooled to −78 °C and n-BuLi solution (0.49 mmol) is slowly added. After stirring for 1 hr, the mixture is slowly transferred to a cold solution (−78 °C) of the electrophilic reagent (1 mmol) in THF (3 mL). The solution is stirred for 1 hr, after which deoxygenated water is added, and the resulting mixture is allowed to warm to room temperature. The product mixture is then partitioned between dilute sodium bicarbonate and dichloromethane. The aqueous phase is extracted three times with portions of dichloromethane, the organic extracts are combined, and washed with brine, dried over anhydrous sodium sulfate. After filtration and removal of solvent, the crude product is isolated by column chromatography (hexanes:ethyl acetate).

3,4-Di(pyridin-2-yl)octan-2-one (16).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (75 mg, 0.41 mmol) provides compound 16 (92.6mg, 0.328 mmol, 80%) as an orange oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.42 (d, J=4.79 Hz, 1H), 8.38 (d, J=4.67 Hz, 1H), 7.36–7.25 (m, 2H), 6.98 (d, J=7.82 Hz, 1H), 6.93–6.86 (m, 2H), 6.83 (d, J=7.71 Hz, 1H), 4.46 (d, J=11.04 Hz, 1H), 3.75 (td, J=11.07 Hz, J=3.29 Hz, 1H), 2.19 (s, 3H), 1.89–1.80 (m, 1H), 1.78–1.68 (m, 1H), 1.34–1.06 (m, 4H), 1.01–0.84 (m, 2H), 0.77 (t, J=7.81 Hz, 2H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 206.8, 161.8, 157.1, 149.3, 149.1, 136.1, 135.5, 124.6, 124.2, 121.6, 120.9, 66.7, 48.9, 33.4, 30.3, 29.6, 22.5, 13.9. Low-Resolution MS (EI): 282 (M+), 267, 239, 225, 210, 195, 183, 169, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₂₃N₂O 283.1810; Found, 283.1809.

7,8-Di(pyridin-2-yl)dodecan-6-one (17).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (98.3 mg, 0.54 mmol) provides compound 17 (116.9 mg, 0.346 mmol, 64%) as the mixture diastereomers and yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8..43–8.41 (m, 1H), 8.34–8.32 (m, 1H), 7.37–7.26 (m, 2H), 7.07 (d, J=7.84 Hz, 1H), 6.92–6.85 (m, 3H), 4.51 (d, J=11.08 Hz, 1H), 3.75 (td, J=10.95 Hz, J=3.38 Hz, 1H), 2.48–2.42 (m, 2H), 2.34 (t, J=7.57 Hz, 2H), 1.86–1.71 (m, 1H), 1.69–1.62 (m, 2H), 1.56–1.44 (m, 2H), 1.65–1.29 (m, 4H), 1.24–1.08 (m, 7H), 0.89–0.84 (m, 4H), 0.79–0.71 (m, 6H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 208.8, 161.5, 156.8, 148.9, 148.5, 136.5, 136.1, 124.6, 124.2, 121.7, 121.2, 65.4, 48.9, 43.4, 34.4, 33.4, 31.4, 31.1, 29.6, 24.7, 22.3, 13.8, 13.8. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₂H₃₁N₂O 339.2436; Found 339.2427.

2,2-Dimethyl-4,5-di(pyridin-2-yl)nonan-3-one (18).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (76.3 mg, 0.419 mmol) to provide compound 18 (95.07 mg, 0.233 mmol, 56%) as a yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.47 (d, J=3.97 Hz, 1H), 8.28 (d, J=3.97 Hz, 1H), 7.34–7.22 (m, 2H), 7.05 (d, J=7.91 Hz, 1H), 6.92–6.83 (m, 2H), 6.69 (d, J=7.75 Hz, 1H), 4.83 (d, J=11.05 Hz, 1H), 3.66 (td, J=12.08 Hz, J=2.94 Hz, 1H), 1.97–1.84 (m, 1H), 1.62–1.52 (m, 1H), 1.29–1.12 (m, 3H), 1.08 (s, 9H), 0.93–0.84 (m, 1H), 0.77 (t, J=7.28 Hz, 3H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 213.5, 161.7, 157.9, 148.9, 135.9, 135.6, 124.6, 123.7, 121.2, 121.0, 60.9, 51.4, 45.6, 33.4, 29.8, 26.5, 22.5, 13.9. Low-Resolution MS (EI): 324 (M+), 309, 267, 239, 224, 210, 195, 183, 169, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₁H₂₉N₂O 325.2280; Found, 325.2279.

1,1,1-Trichloro-3,4-di(pyridin-2-yl)octan-2-one (19).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (75.5 mg, 0.415 mmol) provides compound 19 (75.09 mg, 0.195 mmol, 47%) as the mixture of diastereomers and yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.46 (dd, J=4.78 Hz, J=0.90 Hz, 1H), 8.42 (dd, J=4.63 Hz, J=0.75 Hz, 1H), 7.43–7.30 (m, 2H), 7.04 (d, J=7.81 Hz, 1H), 7.00–6.96 (m, 1H), 6.94–6.89 (m, 1H), 6.87 (d, J=7.81 Hz, 1H), 5.30 (d, J=9.64 Hz, 1H), 3.63 (td, J=10.08 Hz, J=3.29 Hz, 1H), 2.32–2.21 (m, 1H), 2.05–1.92 (m, 1H), 1.36–1.19 (m, 2H), 1.17–0.95 (m, 2H), 0.79 (t, J=7.32 Hz, 3H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 161.1, 160.8, 149.9, 149.5, 149.3, 149.2, 136.8, 136.2, 135.9, 135.7, 125.2, 124.6, 123.1, 123.1, 122.7, 122.5, 121.8, 121.4, 67.2, 66.4, 53.7, 32.3, 31.7, 29.4, 29.2, 22.5, 22.3, 13.9, 13.7 Low-Resolution MS (EI): 239, 233, 209, 195, 183, 169, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₂₀Cl₃N₂O 385.0641; Found 385.0678.

1-Cyclopropyl-2,3-di(pyridin-2-yl)heptan-1-one (20).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (98.6 mg, 0.542 mmol) provide compound 20 (103.6 mg, 0.336 mmol, 62%) as a mixture of diastereomers and pale-yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.38–8.36 (m, 1H), 8.33–8.30 (m, 1H), 7.32–7.19 (m, 2H), 6.98 (d, J=8.08 Hz, 1H), 6.87–6.84 (m, 1H), 6.83–6.79 (m, 2H), 4.53 (d, J=11.05 Hz, 1H), 3.74 (td, J=10.88 Hz, J=3.33 Hz, 1H), 3.13–3.08 (m, 1H), 2.14–2.05 (m, 1H), 1.89–1.58 (m, 3H), 1.23–1.13 (m, 3H), 1.02–0.92 (m, 3H), 0.72 (t, J=7.25 Hz, 3H). ¹³C NMR{¹H} (75 MHz, CDCl₃, 25 °C): δ 208.8, 164.0, 161.9, 160.6, 149.3, 149.2, 149.0, 136.0, 135.8, 135.4, 124.6, 124.1, 123.6, 123.4, 121.4, 121.1, 120.8, 66.7, 48.8, 48.1, 44.2, 34.7, 33.5, 29.6, 29.6, 22.6, 22.5, 21.1, 13.9, 11.2, 11.0. Low-Resolution MS (EI): 240, 225, 211, 197, 183, 169, 154, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₀H₂₅N₂O 309.1967; Found 309.1963.

1-Phenyl-2,3-di(pyridin-2-yl)heptan-1-one (21).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (76.1 mg, 0.418 mmol) provides compound 21 (90.71 mg, 0.263 mmol, 63%) as light-yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.48 (d, J=4.78 Hz, 1H), 8.29 (d, J=4.95 Hz, 1H), 8.13 (d, J=7.26 Hz, 2H), 7.47 (t, d=8.17 Hz, 1H), 7.38 (t, J=8.15 Hz, 2H), 7.33–7.26 (m, 2H), 7.15 (d, J=7.85 Hz, 1H), 6.92–6.79 (m, 3H), 5.39 (d, J=10.93 Hz, 1H), 3.92 (td, J=11.74 Hz, J=3.16Hz, 1H), 1.99–1.86 (m, 1H), 1.81–1.72 (m, 1H), 1.29–1.09 (m, 3H), 1.01–0.88 (m, 1H), 0.74 (t, J=7.19 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 198.5, 161.9, 157.6, 149.2, 149.2, 137.4, 136.1, 135.5, 133.0, 128.9, 128.5, 124.7, 123.7, 121.3, 121.0, 61.1, 50.3, 33.7, 29.8, 22.5, 13.9. Low-Resolution MS (EI): 344 (M+), 287, 259, 239, 224, 209, 196, 183, 169. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₃H₂₅N₂O 345.1967; Found, 345.1964.

1-(4-Methoxyphenyl)-2,3-di(pyridin-2-yl)heptan-1-one (22).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (94.2 mg, 0.518 mmol) provides compound 22 (110.47 mg, 0.295 mmol, 57%) as an oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.47–8.45 (m, 1H), 8.27–8.25 (m, 1H), 8.13 (d, J=8.93 Hz, 2H), 7.33–7.25 (m, 2H), 7.17 (d, J=7.97 Hz, 1H), 6.91–6.78 (m, 5H), 5.35 (d, J=10.87 Hz, 1H), 3.89 (td, J=10.87 Hz, J=3.38 Hz, 1H), 3.78 (s, 3H), 1.98 (s, 1H), 1.93–1.82 (m, 1H), 1.78–1.68 (m, 1H), 1.23.1.13 (m, 2H), 0.99–0.84 (m, 1H), 0.73 (t, J=7.49 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 197.1, 163.5, 162.0, 157.9, 149.1, 149.1, 136.1, 135.5, 131.3, 130.3, 124.7, 123.5, 121.3, 121.0, 113.7, 60.6, 55.4, 50.3, 33.7, 29.8, 22.5, 13.9. Low-Resolution MS (EI): 240, 225, 211, 197, 183, 169, 154, 148. HRMS (ESI) m/z: [M +H]+ Calcd for C₂₄H₂₇N₂O₂ 375.2073; Found 375.2066.

1-([1,1’-Biphenyl]-4-yl)-2,3-di(pyridin-2-yl)heptan-1-one (23).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (98.3 mg, 0.54 mmol) provides compound 23 (102.2 mg, 0.243 mmol, 45%) as a yellow oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.52 (dd, J=5.00 Hz, J=0.96 Hz, 1H), 8.33 (dd, J=5.00 Hz, J=0.77 Hz, 1H), 8.25 (d, J=8.46 Hz, 2H), 7.64 (d, J=8.46 Hz, 2H), 7.59–7.57 (m, 2H), 7.46–7.30 (m, 5H), 7.22 (d, J=7.69 Hz, 1H), 6.96–6.84 (m, 3H), 5.47 (d, J=10.95 Hz, 1H), 3.97 (td, J=10.76 Hz, J=3.27 Hz, 1H), 1.99–1.91 (m, 1H), 1.86–1.76 (m, 1H), 1.31–1.14 (m, 3H), 1.02–0.94 (m, 1H), 0.78 (t, J=7.25 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 198.1, 161.9, 157.6, 149.3, 149.2, 145.7, 139.8, 136.2, 136.0, 135.6, 129.6, 128.9, 128.2, 127.2, 127.2, 124.7, 123.7, 121.4, 121.1, 61.1, 50.4, 33.8, 29.8, 22.5, 13.9. Low-Resolution MS (EI): 240, 197, 183, 154, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₉H₂₉N₂O 421.2280; Found 421.2272.

Benzyl 2,3-di(pyridin-2-yl)heptanoate (24).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (78.4 mg, 0.431 mmol) provides compound 24 (88.75 mg, 0.237 mmol, 55%) as a mixture of diastereomers and bronze oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.64–863 (m, 1H), 8.52–8.51 (m, 1H), 8.43–8.39 (m, 2H), 7.65 (td, J=7.66 Hz, J=1.78 Hz, 1H), 7.52 (td, J=7.76 Hz, J=1.78 Hz, 1H), 7.43 (d, J=7.79 Hz, 1H), 7.36–7.33 (m, 1H), 7.27 (s, 6H), 7.19–7.16 (m, 4H), 7.08–7.02 (m, 3H), 6.95–6.86 (m, 6H), 5.18 (d, J=10.12 Hz, 2H), 4.86 (d, J=7.66 Hz, 2H), 4.52 (d, J=11.35 Hz, 1H), 4.39 (11.21 Hz, 1H), 3.76 (td, J=10.94 Hz, J=3.14 Hz, 2H), 1.99–1.87 (m, 1H), 1.82–1.73 (m, 1H), 1.64–1.52 (m, 1H), 1.26–1.14 (m, 4H), 1.15–1.05 (m, 3H), 0.98–0.88 (m, 4H), 0.76 (t, J=7.11 Hz, 3H), 0.65 (t, J=7.25 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 172.0, 171.6, 162.5, 161.4, 157.4, 157.1, 149.8, 149.1, 136.6, 136.0, 136.0, 135.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 126.9, 124.9, 124.7, 124.5, 124.1, 122.3, 121.7, 121.4, 121.1, 66.5, 66.0, 59.0, 58.5, 49.6, 48.6, 33.4, 32.2, 29.5, 29.9, 22.5, 22.4, 13.9, 13.8. HRMS (ESI) m/z: [M + H]+ calcd for C₂₄H₂₇N₂O₂, 375.2073, found, 375.2067.

Ethyl 2,3-di(pyridin-2-yl)heptanoate (25).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (76.0 mg, 0.417 mmol) to provide compound 25 (67.79 mg, 0.217 mmol, 52%) as an orange oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.41 (d, J=3.98 Hz, 1H), 8.38 (d, J=3.90 Hz, 1H), 7.35–7.26 (m, 2H), 7.03 (d, J=7.98 Hz, 1H), 6.93–6.84 (m, 3H), 4.28 (d, J=11.29 Hz, 1H), 4.22–4.09 (m, 2H), 3.72 (td, J=11.10 Hz, J=3.31 Hz, 1H), 1.99–1.87 (m, 1H), 1.85–1.74 (m, 1H), 1.34–1.25 (m, 2H, 1.19 (t, J=6.79 Hz, 3H), 1.17–1.05 (m, 1H), 1.01–0.92 (m, 1H), 0.77 (t, J=7.28 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 172.2, 161.4, 157.3, 149.1, 149.0, 135.9, 135.5, 124.7, 123.9, 121.6, 121.0, 60.8, 59.1, 49.6, 33.3, 29.5, 22.5, 14.1, 13.9. Low-Resolution MS (EI): 312 (M+), 283, 267, 256, 239, 223, 210, 195, 183, 165, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₉H₂₅N₂O₂ 313.1916; Found, 313.1911.

Isobutyl 2,3-di(pyridin-2-yl)heptanoate (26).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (75.9 mg, 0.419 mmol) provides compound 26 (78.31 mg, 0.23 mmol, 55%) as an orange oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.42 (d, J=4.21 Hz, 1H), 8.37 (d, J=4.00 Hz, 1H), 7.36–7.26 (m, 2H), 7.04 (d, J=7.81 Hz, 1H), 6.92–6.85 (m, 3H), 4.31 (d, J=11.05 Hz, 1H), 3.88 (sept, J= 6.27 Hz, 2H), 3.73 (td, J=10.99 Hz, J=3.37 Hz, 1H), 1.96–1.78 (m, 3H), 1.29–1.12 (m, 3H), 1.01–0.91 (m, 1H), 0.81 (d, J=6.81 Hz, 6H), 0.77 (t, J=7.26 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 172.3, 161.5, 157.4, 149.1, 135.9, 135.5, 124.7, 123.9, 121.6, 121.0, 70.8, 59.1, 49.5, 33.4, 29.5, 27.7, 22.5, 18.9, 18.9, 13.9. Low-Resolution MS (EI): 340 (M+), 297, 283, 267, 239, 220, 210, 195, 183, 169, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₁H₂₉N₂O₂ 341.2229; Found 341.2226.

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4,4-dimethyl-2,3-di(pyridin-2-yl)pentanoate (27).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (225 mg, 1.23 mmol) provides compound 29 (159 mg, 0.377 mmol, 31%) as a mixture of diastereomers and oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃ with 1% TMS, 25°C): 8.58–8.60 (m, 1H), 8.47–8.49 (m, 1H), 7.48–7.63 (m, 3H), 0.04 (s, 2H), 7.26–7.30 (m, 1H), 7.11–7.16 (m, 1H), 7.02–7.07 (m, 1H), 4.71–4.80 (m, 1H), 4.16–4.28 (m, 1H), 3.77–3.83 (m, 1H), 1.35–1.55 (m, 2H), 1.0–1.35 (m, 3H), 0.52–0.90 (m, 17H), 0.50 (d, J= 6.9 Hz, 1H), 0.26 (d, J= 6.9 Hz, 1H), 0.20 (d, J= 6.9 Hz, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃ with 1% TMS, 25 °C): 171.8, 171.5, 163.0, 162.9, 159.1, 158.9, 149.3, 149.2, 148.2, 148.0, 136.4, 136.3, 126.1, 135.0, 135.0, 125.9, 124.5, 124.2, 122.1, 122.1, 121.0, 120.9, 73.9, 73.9, 73.7, 57.1, 57.0, 56.9, 56.7, 46.8, 46.5, 40.2, 39.6, 34.4, 34.1, 34.1, 31.1, 31.0, 29.2, 29.2, 25.3, 25.2, 23.0, 22.2, 21.8, 20.8, 20.5, 15.6, 15.5, 0.97. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₇H₃₉N₂O₂ 423.3012; Found, 423.3019.

2,2’-(1-(Naphthalen-1-ylsulfonyl)hexane-1,2-diyl)dipyridine (28).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (90.8 mg, 0.499 mmol) provides compound 28 (120.13 mg, 0.279 mmol, 56%) as a mixture of diastereomers and a bronze oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.67 (dq, J= 4.85 Hz, J= 0.85 Hz, 1H), 8.62 (dq, J= 4.87 Hz, J= 0.92 Hz, 1H), 8.46 (dq, J= 4.84 Hz, J= 0.90 Hz, 1H), 8.43 (dq, J= 4.86 Hz, J= 0.90 Hz, 1H), 7.71–7.59 (m, 2H), 7.44–7.31 (m, 4H), 7.27–7.21 (m, 2H), 7.19–7.14 (m, 1H), 7.06 (d, J= 7.76 Hz, 1H), 7.02–6.97 (m, 1H), 6.95–6.91 (m, 1H), 6.88 (d, J= 7.82 Hz, 1H), 5.33 (d, J= 10.19 Hz, 1H), 5.31 (d, J= 9.72 Hz, 1H), 3.64 (td, J= 11.31 Hz, J= 3.35 Hz, 2H), 2.32–2.21 (m, 1H), 2.06–1.93 (m, 1H), 1.76–1.63 (m, 1H), 1.38–1.16 (m, 5H), 1.15–0.93 (m, 6H), 0.80 (t, J= 7.38 Hz, 5H), 0.66 (t, J= 7.38 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 161.1, 160.8, 159.0, 149.9, 149.5, 149.3, 149.2, 136.8, 136.2, 135.9, 135.7, 125.2, 124.6, 123.2, 123.1, 122.8, 122.5, 121.8, 121.4, 67.2, 66.4, 53.8, 32.3, 31.7, 29.4, 29.2, 22.5, 22.3, 13.9, 13.7. Low-Resolution MS (EI): 430 (M+), 239, 225, 210, 197, 183, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₆H₂₇N₂O₂S 431.1793; Found, 3431.1787.

1-(1,2-Di(pyridin-2-yl)hexyl)cyclohexanol (29).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (75.2 mg, 0.413 mmol) provides compound 27 (96.47 mg, 0.285 mmol, 69%) as a pale yellow solid after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.19 (d, J= 3.93 Hz, 1H), 8.12 (d, J=3.70 Hz, 1H), 7.35–7.26 (m, 2H), 6.89–6.81 (m, 4H), 5.72 (s, 1H), 3.70 (hept, J=4.60 Hz, 1H), 3.08 (d, J=3.73 Hz, 1H), 2.15–2.08 (m, 1H), 2.05–1.93 (m, 1H), 1.90–1.82 (m, 1H), 1.81–1.70 (m, 1H), 1.66–1.59 (m, 2H), 1.56–1.46 (m, 2H), 1.32–1.17 (m, 6H), 1.10–1.06 (m, 2H), 1.03–0.95 (m, 2H), 0.79 (t, J=7.28 Hz, 3H).; ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 163.4, 161.8, 147.9, 147.4, 135.3, 135.0, 125.9, 125.4, 120.7, 120.3, 74.0, 59.3, 46.7, 38.2, 36.9, 35.3, 30.2, 25.9, 22.7, 22.3, 22.2, 14.0. Low-Resolution MS (EI): 338 (M+), 295, 281, 239, 225, 210, 197, 183, 162, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₂H₃₁N₂O 339.2436; Found, 339.2433.

1,3-Diphenyl-2,3-di(pyridin-2-yl)propan-1-one (30).

Using General Procedure B, 1,2-bis(2-pyridyl)ethylene (225 mg, 1.23 mmol) provides compound 29 (159 mg, 0. mmol, 67%) as a mixture of diastereomers and bronze oil after silica gel chromatography (hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃, 25°C): δ 8.47 (d, J= 3.97 Hz, 1H), 8.41 (d, J= 4.63 Hz, 1H), 8.18 (td, J= 9.29 Hz, J= 1.43 Hz, 1H), 8.07 (d, J= 7.25 Hz, 2H), 7.84 (d, J= 7.05 Hz, 1H), 7.61 (d, J= 7.26 Hz, 2H), 7.51–7.48 (m, 2H), 7.45–7.40 (m, 5H), 7.34 (t, J= 7.94 Hz, 3H), 7.19 (t, J= 7.60 Hz, 3H), 7.07 (t, J= 7.43 Hz, 1H), 6.95–6.91 (m, 2H), 6.35 (d, J= 11.66 Hz, 1H), 5.38 (d, J= 11.76 Hz, 1h). ¹³C{¹H} NMR (75 MHz, CDCl₃, 25 °C): δ 197.5, 169.8, 160.9, 157.0, 149.2, 148.6, 141.4, 137.0, 136.6, 133.0, 132.0, 130.0, 128.9, 128.6, 128.5, 128.4, 128.4, 127.41, 126.7, 124.2, 121.8, 121.4, 59.5, 55.4. Low-Resolution MS (EI): 364 (M+), 239, 225, 210, 197, 183, 148. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₅H₂₁N₂O 365.1654; Found, 365.1648.

3-Phenyl-1,2,3-tri(pyridin-2-yl)propan-1-one (31).

A solution of 1,2-bis(2-pyridyl)ethylene (1.0 g, 5.49 mmol) on 20 mL THF is cooled to −78 °C and PhLi solution (5.5 mmol) is slowly added. After stirring for 2 hr, ethyl picolinate (6 mmol) is added. The solution is stirred for 3 hr and allowed to warm to room temperature. The mixture is the quenched with 20 mL of deoxygenated water and further diluted with 20 mL of ethyl ether. Following extracting of the organic products, the aqueous phase is extracted a second time with ethyl ether. The organic extracts are washed twice with brine solution, dried over anhydrous sodium sulfate, and filtered. All but ca. 15 mL of solvent is removed using a rotary evaporator and the resulting reddish solution is place in a sealed flask and cooled to −20°C. After one week, a crop of red crystals are filtered off and compound 31 is isolated (0.79 g, 2.16 mmol, 39%) as the mixture of diastereomers in a 1.4:1.0 ratio. MP 148–151 °C (THF : ether). ¹H NMR (500 MHz, CDCl₃, 25°C): δ 8.69–8.71 (m), 8.44–8.50 (m), 8.33–8.34 (m), 7.95 (d, J = 7.8 Hz), 7.87 (d, J = 7.9 Hz), 7.64–7.73 (m), 7.49–7.52 (m), 7.27–7.39 (m), 7.15–7.24 (m), 6.98–7.10 (m), 6.88–6.93 (m), 6.70 (d, J = 10 Hz), 5.39–5.43 (m).). ¹³C{¹H} NMR (125 MHz, CDCl₃ with 1% TMS, 25 °C): major isomer, δ 198.4, 162.3, 157.5, 153.3, 149.2, 149.1, 148.8, 141.9, 136.6, 136.2, 135.9, 128.9, 128.0, 126.5, 126.4, 126.3, 124.3, 122.5, 121.3, 121.1, 58.0, 55.1. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₇H₃₉N₂O₂ 366.1601; Found 366.1610.