Michael addition with an olefinic pyridine: Organometallic nucleophiles and carbon electrophiles

Article abstract of DOI:10.1021/acs.joc.0c00823

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

Full text of DOI:10.1021/acs.joc.0c00823

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Note
Michael addition with an olefinic pyridine:
organometallic nucleophiles and carbon electrophiles
Michael R. Stentzel, and Douglas A. Klumpp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00823 • Publication Date (Web): 03 Sep 2020
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Michael addition with an olefinic pyridine: organometallic nucleophiles and
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carbon electrophiles.
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Michael R. Stentzel and Douglas A. Klumpp*
Department of Chemistry and Biochemistry
Northern Illinois University
DeKalb, Illinois 60115
Email: dklumpp@niu.edu ORCHID ID: https://orcid.org/0000-0001-5271-699X
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.
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Michael or conjugate addition was first reported in the late 1800s.1 These initial reports
described the addition of nucleophiles to -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
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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 -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
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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
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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
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
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Table 1. Products and yields from the reactions of 9 with organolithium reagents.
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and the potential for reactions with other electrophiles.
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.
In addition to acid chloride electrophiles, chloroformate electrophiles provide
compounds 24-27 in fair yields. NMR analysis of crude products indicates that single
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Table 2. Addition products and yields from compound 9 and organolithium reagents and with
carbon electrophiles.
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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
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diastereomer in 69% yield. In the synthesis of product 31, an ester was successfully used as the
carbon electrophiles (ethyl picolinate).
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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
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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
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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.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at:
•1H and 13C NMR spectra for new compounds.
•Computational methods and results.
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Experimental
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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.
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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, 25oC): 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 oC): 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.
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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.
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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,
25oC): 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 oC): 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, 25oC): δ 8.49
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(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,
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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,
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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, 25oC): 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
oC): 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, 25oC): 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,
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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 oC): 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.
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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 oC 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 oC) 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, 25oC): 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
oC): 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.
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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).
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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, 25oC): 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 oC): 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.
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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, 25oC): 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 oC): 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.
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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, 25oC): 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 oC): 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.
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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, 25oC): 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 oC): 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.
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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, 25oC): 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 oC): 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,
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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.
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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, 25oC): 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 oC): 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,
25oC): 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 oC): δ 197.1, 163.5, 162.0, 157.9,
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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.
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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, 25oC): 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 oC): 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, 25oC): 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),
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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 oC): 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.
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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, 25oC): 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 oC):
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
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an orange oil after silica gel chromatography (hexanes:ethyl acetate). 1H NMR (300 MHz, CDCl3,
25oC): 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 oC): 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.
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(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
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chromatography (hexanes:ethyl acetate). H NMR (300 MHz, CDCl3 with 1% TMS, 25oC): 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 oC): 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.
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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, 25oC): 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 oC): 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.
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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, 25oC): 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,
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CDCl3, 25 oC): 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.
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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, 25oC): 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 oC): 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
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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, 25oC):
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 oC): 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.
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Acknowledgements. The support of the NIGMS-NIH(1R15GM126498-01) is gratefully
acknowledged. We also acknowledge the generous support from the NSF MRI program (award
no. CHE:1726931) for the purchase of the high-resolution mass spectrometer and Northern
Illinois University for the support of the Molecular Analysis Core Facility.
References
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For details regarding the calculations, see Supporting Information.
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Graphical Abstract
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1. nBuLi
N
N
N
O
2.
N
N
-
N
+
O
Cl
Li
9
stable anionic
intermediate
62%
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