Rhodium(III)-catalyzed oxadiazole-directed alkenyl C-H activation for synthetic access to 2-acylamino and 2-amino pyridines

Article abstract of DOI:10.1021/acs.joc.7b01303

We report herein a Rh(III)-catalyzed alkenyl C-H activation protocol for the coupling of oxadiazoles with alkynes and synthesis of 2- acylamino and 2-amino pyridines, an important heterocyclic scaffold for various naturals products and synthetic pharmaceuticals bearing a readily reacting functional group. The selective protection/deprotection of amino groups through simple solvent switching, good functional group compatibility, superior product yield, and high regioselectivity are some of the notable synthetic features witnessed in this reaction protocol.

Full text of DOI:10.1021/acs.joc.7b01303

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Article
Rhodium(III)-Catalyzed Oxadiazole-Directed Alkenyl C-H Activation
for Synthetic Access to 2-Acylamino and 2-Amino Pyridines
Fan Yang, Jiaojiao Yu, Yun Liu, and Jin Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01303 • Publication Date (Web): 01 Sep 2017
Downloaded from http://pubs.acs.org on September 1, 2017
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Rhodium(III)-Catalyzed Oxadiazole-Directed Alkenyl C-H Activa-
tion for Synthetic Access to 2-Acylamino and 2-Amino Pyridines
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Fan Yang, Jiaojiao Yu, Yun Liu, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China.
Supporting Information Placeholder
ABSTRACT: We report herein a Rh(III)ꢀcatalyzed alkenyl CꢀH activation protocol for the coupling of oxadiazoles with alkynes
and synthesis of 2ꢀacylamino and 2ꢀamino pyridines, an important heterocyclic scaffold for various naturals products and synthetic
pharmaceuticals bearing a readily reacting functional group. The selective protection/deprotection of amino group through simple
solvent switching, good functional group compatibility, superior product yield, and high regioselectivity are some of the notable
synthetic features witnessed in this reaction protocol.
INTRODUCTION
2ꢀAcylamino and 2ꢀamino pyridines (2ꢀAcAPs and 2ꢀAPs) exist in various naturals products and synthetic pharmaceuticals (the
cores of 2ꢀAcAP and 2ꢀAP present in Savaysa, NꢀTocopherol, Xalkori and 6ꢀAminopyridinꢀ3ꢀols etc.) that possess diverse biologiꢀ
cal, physiological, and medicinal activities, and are used in treatment of lipid peroxidation, antiangiogenic activity, cancer, HIV,
asthma, inflammatory, and neurodegeneration diseases.1. Traditional synthetic approaches, including Chichibabin reaction,2 aminaꢀ
tion of pyridine Nꢀoxides,3 multicomponent condensations,4 BuchwaldꢀHartwig cross coupling reaction,5 etc (Scheme 1aꢀ1d), can
suffer from poor functional group tolerance (use of strong alkali metal base, drastic oxidation condition; Scheme 1a,b), severe enꢀ
vironmental consequences (employment of a potentially hazardous gaseous reagent, Scheme 1a), and requirement for specific arꢀ
rangement of a complex set of functionalities (preꢀsynthesis of oxide, restricted use of dual cyanoꢀbearing substrate, tedious preꢀ
assembly of a halide group, Scheme 1bꢀ1d), thus limiting their widespread applications. The search for more robust synthetic protoꢀ
cols for 2ꢀAcAPs and 2ꢀAPs have therefore become a pressing issue for the full realization of their therapeutic potentials.
Scheme 1. Synthetic Strategies for 2-AcAPs or 2-APs
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Recently, transition metalꢀcatalyzed directed CꢀH functionalization has emerged as a promising approach for expedient synthesis
of organic compounds.6 Many openꢀchain and heterocyclic moieties have been identified as effective directing groups (DGs) for
achieving the synthetic efficiency.7 In the context of heterocycle synthesis, typically an openꢀchain DG is used for both initial CꢀH
coupling and subsequent Cꢀheteroatom cyclization.8ꢀ10 Application of a heterocyclic DG in the construction of more useful target
heterocyclic products still constitutes a major challenge. In our previous work we have developed a NꢀO bond cleavꢀ
age/decarboxylative redoxꢀneutral sequence for the synthesis of 1ꢀaminoisoquinolines and 2ꢀamino pyridines by 1,2,4ꢀoxadiazolꢀ
5(4H)ꢀoneꢀdirected CꢀH coupling with alkynes (Scheme 1e).11a,b To expand synthetic applications of heterocyclic DGꢀbased strateꢀ
gy, we have also recently demonstrated 5ꢀmethylꢀ1,2,4ꢀoxadiazole (abbreviated herein as oxadiazole)ꢀdirected aromatic CꢀH couꢀ
pling with alkynes for the synthesis of 1ꢀaminoisoquinolines (Scheme 1e).11c Herein, we report the development of an oxadiazoleꢀ
directed alkenyl CꢀH functionalization protocol for efficient access to both 2ꢀAcAPs and 2ꢀAPs. Significantly, this protocol offers
the ability to synthesize both protected and deprotected 2ꢀAPs through a simple switch of the reaction solvent, thus potentially alꢀ
lowing further synthetic elaboration under different synthetic scenarios. Although no demonstrated synthesis of biologically active
compounds has been achieved at the current point, the chemistry community can benefit from the development of a new synthetic
methodology from various perspectives. For example, appendages other than those showcased in the exact currently proven biologꢀ
ically active target structures might be useful in other chemical, biological, and materials contexts.
RESULTS AND DISCUSSION
Rh(III)ꢀcatalyzed coupling between (E)ꢀ5ꢀmethylꢀ3ꢀstyrylꢀ1,2,4ꢀoxadiazole (1a) and 1,2ꢀdiphenylethyne (2a) was initially chosen
as the model reaction. The screening of reaction conditions (see supporting information, SI 1.1) identified a 32% yield production
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of 3a with [Cp*RhCl2]2/AgSbF6 as the catalyst precursor and KOAc as the additive, after reacting in AmylOH at 140 C for 18 h
(see SI, Table 1.1, entry 1). No product or very low yield was observed with the use of other solvents under otherwise identical
conditions. Switching of KOAc to Cu(OAc)2 proved to be essential for eliminating other side reactions and favor the exclusive
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formation of 3a (entries 1ꢀ3). Variation of the amount of additive and temperature shows that 20 mol % of Cu(OAc)2 and 110 C
can boost the yield to 80% (entries 5ꢀ9). Omitting AgSbF6 led to best 95% yield of 3a. Although the reaction can also proceed well
under [Cp*Rh(OAc)2]2/Cu(OAc)2 or [Cp*Rh(TFA)2]2/Cu(OAc)2 combination, the most convenient, commercially available
[Cp*RhCl2]2/Cu(OAc)2 combination is chosen to serve as the optimized catalyst precursor (entries 10ꢀ17). A series of Co(III) cataꢀ
lyst systems exhibit no catalytic activity (entries 18ꢀ20).
Scheme 2. Substrate Scope of Oxadiazole in tAmylOHa,b
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Scheme 3. Substrate Scope of Alkyne in tAmylOHa,b
Having the optimized reaction conditions established, we first examined the reaction scope of various substituted oxadiazole. A
wide range of oxadiazole derivatives are compatible with the protocol (Scheme 2), and both electronꢀ donating and electronꢀ
withdrawing groups at the para and meta positions (1a-1d, 1e, 1g, 1h-1j) are tolerated. Notably, the product yield is high for an
oxadiazole bearing a synthetically useful handle, including fluoro (1b), chloro (1c), and bromo (1d) group, thus potentially permitꢀ
ting further structural elaboration. The paraꢀmethylꢀ and orthoꢀfluoroꢀsubstituted oxadiazoles (1f, 1k) react in a sluggish manner
and provide the respective products in moderate yields. The naphthylꢀ, furanylꢀ, and thiophenylꢀcontaining oxadiazoles (1l-1n) are
also compatible. Next we examined the scope of alkynes (Scheme 3). Symmetrical diarylalkynes bearing electronꢀdonating or elecꢀ
tronꢀwithdrawing groups (2b-2h) as well as symmetrical dialklyalkynes (2i) can participate in the reactions in good yields. For unꢀ
symmetrical alkynes, the reactivity varies depending on the substituents (2jꢀ2n). The regioselectivity is apparently primarily dictatꢀ
ed by the steric factor. Thus, whereas 2k affords a mixture of regioisomers (isolable), 2j, 2l, and 2m furnish only one type of regioiꢀ
somers, and 2n provides regioisomers in 19:1 ratio. The demonstrated tolerance of halide groups in our rhodium catalytic chemistry
is mechanistically interesting compared with palladium catalytic chemistry, potentially permitting further structural elaboration
using halide groups as synthetic handles. The compatibility of functional structures such as carboxylate, carbonate, furanyl, and
thiophenyl demonstrates that oxygenꢀ and sulfurꢀcentered groups do not interfere in the docking of rhodium catalytic center and
that more synthetic manipulations are available.
Scheme 4. Substrate Scope of Oxadiazole in TFEa,b
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Scheme 5. Competition Experiments
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With the replacement of AmylOH solvent to trifluoroethanol (TFE), The reaction between 1a-1n and 2i leads to the generation
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of a deacetylated 2ꢀAP derivative (Scheme 4). Similar to the reaction performed in AmylOH, both electronꢀdonating and electronꢀ
withdrawing groups at the para and meta positions (1aꢀ1j) are tolerated. In general, the reactivity in TFE is slightly inferior comꢀ
pared to that in AmylOH. The naphthylꢀ and thiophenylꢀcontaining oxadiazoles (5i, 5m) can also react effectively. The reaction
temperature involving 1c, 1e, 1h, 1i, and 1l needs to be elevated to 120 °C to ensure the complete conversion. Besides, many primaꢀ
ry and secondary alcohols have been tested in the optimization of reaction conditions (see SI 1.2). TFE is the best solvent in the
deacetylation reaction, whereas other primary and secondary alcohols yield minimal quantity of target product. A lower pKa value
for TFE compared to other nonꢀfluorinated alcohols suggests that the deacetylation most likely occurs through alcoholysis of amide
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To gain insight into the mechanistic pathways, several competition and H/D scrambling experiments were performed. An interꢀ
molecular competition experiment using oxadiazoles bearing electronꢀrich and electronꢀdeficient arenes witnesses no electronic
preference for reactivity, however, initial rate experiments indicate that the electroꢀrich arene reacts faster (Scheme 5a). The result
suggests that CꢀH activation occurs through electrophilic aromatic substitution, instead of concerted metalationꢀ
deprotonation.12a,b The electronic preference can also be observed on alkynes, where electronꢀrich alkyne reacts favorably (Scheme
5b). The result shows that more electronꢀrich alkynes are favored in the migratory insertion step.12c H/D scrambling experiments
starting from 1a and 1a-d6 witness no H/D scrambling under tAmylOH condition (Scheme 6a and 6b) but apparent H/D scrambling
under TFE condition (Scheme 6c and 6d), supporting CꢀH activation as a key catalytic step and dependence of the reversibility of
CꢀH activation step on the nature of the protic solvent. In addition, high intermolecular kinetic isotope effect (KIE) values of 2.4
(kH/kD for parallel experiments) and 1.8 (for competition experiment) provide evidence that the CꢀH bond cleavage step is rateꢀ
determining (Scheme 6e).
Scheme 6. H/D Scrambling and KIE Experiments
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Based on these observations and previous mechanistic proposals, a plausible reaction sequence can be proposed (Scheme 7):
generation of [RhCp*(OAc)]+ species (I) in situ from [RhCp*Cl2]2 and Cu(OAc)2,13 coordination of oxadiazole derivative (1a) to
give intermediate II, alkenyl CꢀH activation to get III, coordination of alkyne (2a) and migratory insertion to generate IV and V,
simultaneous CꢀN cyclization and ring opening of oxadiazole to afford acetylated product 3a (the labile NꢀO bond in oxadiazole
motif as an internal oxidant), deprotection of acetyl group under TFE to produce 5a (~100% conversion of 4i to 5a is observed unꢀ
der TFE).14 The amount of Cu(OAc)2 is only 40 mol%, arguing against the oxidant role of Cu2+. In addition, no reaction is observed
under air, excluding Cu2+ and oxygen as coꢀoxidants in the catalytic cycle. No reaction is identified for alkynes with either H2O or a
Schiff base under [Cp*RhCl2]2/Cu(OAc)2/tAmylOH condition, arguing against a [4+2] cycloaddition reaction mechanism. Howevꢀ
er, Cu2+ still likely plays a role of Lewis acid to activate alkyne coupling partner.15 Unlike oxadiazolone system, the product of
oxadiazole with Nꢀatom at the 4ꢀposition of the 1,2,4ꢀoxadiazole group coordinating to the Cp*Rh species is virtually nonꢀexistent,
therefore ensuring the operation of one cleavage mode for NꢀO bond.
Scheme 7. Proposed Reaction Mechanism
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CONCLUSION
In conclusion, we have developed a Rh(III)ꢀcatalyzed oxadiazoleꢀdirected alkenyl CꢀH activation strategy for the synthesis of
both 2ꢀAcAPs and 2ꢀAPs through solvent control of the reaction pathways. This reaction not only provides a novel method for the
construction of pyridine skeleton but also simultaneously supply a useful reaction handle for further synthetic manipulation. Good
functional group compatibility, superior product yield, and high regioselectivity are some of the notable synthetic features witꢀ
nessed in this reaction protocol. The rhodium catalytic chemistry described herein allows expedient access to structural diversity
not available based on traditional approaches, thus providing a more fertile testꢀbed for superior biological activity and materials
property.
EXPERIMENTAL SECTION
All reagents and solvents were purchased from commercial available sources and used without further purification unless otherꢀ
wise stated. 2ꢀMethylꢀ2ꢀbutanol (GC grade) and 2,2,2ꢀThifluoroethanol (GC grade) was used directly. AgSbF6 was purchased from
Acros and stored and manipulated in the glovebox. The other chemicals were obtained from local suppliers or synthesized accordꢀ
ing to the literature procedures. Abbreviations for the solvents and reagents: PE, petroleum ether; EA, ethyl acetate; DCE, 1,2ꢀ
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dichloroethane; THF, tetrahydrofuran; TFE, 2,2,2ꢀThifluoroethanol; AgOTFA, silver trifluoroacetate; AmylOH, 2ꢀMethylꢀ2ꢀ
butanol; TEA, Triethylamine. All Rh(III)ꢀcatalyzed reactions were carried out without any particular precautions to extrude moisꢀ
ture or oxygen. All reactions conducted above room temperature (r.t.) were run in oil baths with the temperatures calibrated with a
thermometer. Prior to an experiment, the oil bath was allowed to equilibrate to the desired temperature for 15 min. H, 13C NMR
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spectra were recorded in CDCl3 (with tetramethylsilane as internal standard), CD3CN solution on a Bruker AVANCE 400/500 MHz
spectrometer. The following notations were used: br ꢀ broad, s ꢀ singlet, d ꢀ doublet, t ꢀ triplet, q ꢀ quartet, m ꢀ multiplet, dd ꢀ doublet
of doublet, dt ꢀ doublet of triplet, td ꢀ triplet of doublet, dq ꢀ doublet of quartet, ddd ꢀ doublet of doublet of doublet. Highꢀresolution
mass spectra (HRMS) were obtained via ESI mode with a TOF mass analyzer. Melting points were obtained via Yu Hua X4 micro
melting point apparatus. Alkynes were purchased from commercial sources or synthesized according to the procedure reported by
Mikami and Lautens.16
Procedure for Competition Experiments of 1e and 1g Using Initial Rates. To a 13 × 150 mm test tube equipped with magnetic
stir bar were added 1e (25.4 mg, 0.1 mmol, 1 equiv), 1g (21.6 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5 equiv),
[Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol%) and Cu(OAc)2 (7.3 mg, 0.04 mmol, 40 mol%). The test tube was transferred to a
glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then a tAmylOH (0.5 mL) was
injected into the test tube via syringe. After stirred at 110 oC for 1 h, 2 h, 3h, 4 h, 5 h under an atmosphere of N2, respectively. The
mixture was concentrated the residue was purified by flash column chromatography on silica gel with PE/EA = 4/1 as the eluent to
give the 3e and 3g (see SI 1.3, Scheme 5a).
Procedure for Competition Experiments of 2b and 2e. To a 13 × 150 mm test tube equipped with magnetic stir bar were added
1a (32 mg, 0.2 mmol, 1 equiv), 2b (50 mg, 0.24 mmol, 1.2 equiv), 2e (52 mg, 0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025
mmol, 10 mol%) and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol%). The test tube was transferred to a glovebox under N2. The test tube
was sealed with a rubber septum and removed from the glovebox. Then a AmylOH (1 mL) was injected into the test tube via syꢀ
ringe. After stirred at 110 C for 9 h, the solvent was then removed under reduced pressure and the residue was purified by flash
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column chromatography on silica gel with PE/EA = 10/1 as the eluent to give the 4b (60% yield, 50.7 mg) and 4e (47% yield, 37.9
mg) (Scheme 5b).
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General Procedure for the Catalytic Deuterium Exchange Experiments for 1a (or 1a-d6) in AmylOH/CD3OD (or
tAmylOH/CH3OH) Condition. To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1a (16 mg, 0.1 mmol, 1
equiv) or 1a-d6 (19 mg, 0.1 mmol, 1 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol%) and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40
mol%). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the
glovebox. Then a tAmylOH/CD3OD = 0.45 mL/0.05 mL (or tAmylOH/CH3OH = 0.45 mL/0.05 mL) was injected into the test tube
via syringe. After stirred at 110 oC for 18 h. The solution was filtered through a celite pad and washed with 10~20 mL of dichloroꢀ
methane. The filtrate was concentrated and the residue was separated on a flash column with PE/EA = 20/1 as the eluent. The 1a
was determined by 1H NMR (400 MHz, CDCl3) (see SI 1.4.1 and 1.4.2, Scheme 6a and 6b).
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General Procedure for the Catalytic Deuterium Exchange Experiments for 1f (or 1a-d6) in TFE-d3 (or TFE) Condition. To a
13 × 150 mm test tube equipped with magnetic stir bar were added 1f (20 mg, 0.1 mmol, 1 equiv) or 1a-d6 (19 mg, 0.1 mmol, 1
equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol%) and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol%). The test tube was transferred
to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then a TFEꢀd3 = 0.5 mL
(or TFE) was injected into the test tube via syringe. After stirred at 110 oC for 18 h. The solution was filtered through a celite pad
and washed with 10~20 mL of dichloromethane. The filtrate was concentrated and the residue was separated on a flash column with
PE/EA = 20/1 as the eluent. The 1a was determined by 1H NMR (400 MHz, CDCl3) (see SI 1.4.3 and 1.4.4, Scheme 6c and 6d).
General Procedure for Kinetic Isotope Effect Experiments (competitive experiment). To a 13 × 150 mm test tube equipped
with magnetic stir bar were added 1a (19 mg, 0.1 mmol, 1 equiv), 1a-d6 (20 mg, 0.1 mmol, 1 equiv) and 2a (54 mg, 0.3 mmol, 1.5
equiv), [Cp*RhCl2]2 (3.1 mg, 0.0025 mmol, 2.5 mol%) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol%). The test tube was transferred
to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then a tAmylOH (0.5 mL)
was injected into the test tube via syringe. After stirred at 110 oC for 9 h. The solution was filtered through a celite pad and washed
with 10~20 mL of dichloromethane. The filtrate was concentrated and the residue was separated on a flash column with PE/EA =
20/1 as the eluent to give 51.3 mg of the mixture product 3a/3a-d5. The H/Dꢀincorporation in 3a/3a-d5 was determined by 1H NMR
(400 MHz, CDCl3). The kinetic isotopic effect of this reaction was determined to be kH/kD = 1.8 (see SI 1.5.1, Scheme 6e).
General Procedure for Kinetic Isotope Effect Experiments (parallel experiments). 1a under the standard conditions were perꢀ
formed: Suspensions of 1a (19 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5
mol%) and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol%). These test tubes were transferred to a glovebox and added under N2. Theses
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test tubes were sealed with a rubber septum and removed from the glovebox. Then AmylOH (0.5 mL) was injected into the test
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tube via syringe. After stirred at 110 C for 30 min, 90 min, 150 min, 210 min, 270 min under an atmosphere of N2, respectively.
The solution was filtered through a celite pad and washed with 10~20 mL of EA. The mixed filtrate was concentrated and the resiꢀ
due and (methylsulfonyl)methane (5.6 mg) was dissolved with CDCl3, was subjected to 1HNMR (400M) (see SI 1.5.2, Scheme 6e).
1a-d6 under the standard conditions were performed: Suspensions of 1a-d6 (19 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5
equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol%) and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol%). These test tubes were transꢀ
ferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the glovebox. Then
tAmylOH (0.5 mL) was injected into the test tube via syringe. After stirred at 110 oC for 180 min, 360 min, 540 min, 720 min, 900
min under an atmosphere of N2, respectively. The solution was filtered through a celite pad and washed with 10~20 mL of diꢀ
chloromethane. The mixed filtrate was concentrated and the residue and (methylsulfonyl)methane (5.6 mg) was dissolved with
CDCl3, was subjected to 1HNMR (400M) (see SI 1.5.2, Scheme 6e).
General Procedure for Effect of Cu(OAc)2 on alkyne. 2a under the standard conditions were performed: Suspensions of 2a (35.7
mg, 0.2 mmol, 1 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol%) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol%). These test
tubes were transferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the
glovebox. Then tAmylOH/H2O (0.9 mL/0.1 mL) was injected into the test tube via syringe. After stirred at 110 oC for 18 h under an
atmosphere of N2. No product was detected.
General Procedure for Effect of Cu(OAc)2 on nucleophile substrate (C=N type) with diphenyl acetylene. 2a under the standꢀ
ard conditions were performed: Suspensions of 6a (36.7 mg, 0.2 mmol, 1 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol%) and
Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol%). These test tubes were transferred to a glovebox and added under N2. Theses test tubes
were sealed with a rubber septum and removed from the glovebox. Then tAmylOH (1.0 mL) was injected into the test tube via syꢀ
ringe. After stirred at 110 oC for 18 h under an atmosphere of N2. No product was detected.
General Procedure for the Synthesis of Oxadiazole.17 To a suspension of NaH (60% in oil, 600 mg, 15 mmol, 1.5 equiv.) in THF
(5 mL), diethylꢀcyanomethylphosphonate (1.9 mL, 12 mmol, 1.2 equiv.) was added, and the mixture was stirred 0.5 h at 0 oC. benꢀ
o
zaldehyde (1.06 g, 10 mmol) was added at the same temperature, and the mixture was stirred for 2 h at 25 C. The reaction was
quenched with ice water (5 mL), and the slurry was stirred for 0.5 h. The twoꢀlayers mixture was extracted with DCM (3 × 20 mL).
The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and concentration, to give the
crude cinnamonitrile. To the solution of cinnamonitrile (10 mmol, 1.0 equiv.), in EtOH (0.1 M) was added 50% wt% aqueous hyꢀ
droxylamine solution (1.2 mL, 20 mmol, 2.0 equiv.). The mixture was stirred at reflux temperature for 3 h under nitrogen. After
completion of the reaction as monitored by TLC, the solution was cooled to room temperature, the reaction mixture was concentratꢀ
ed, the residue (without purification) reacted with AcCl (1.4 mL, 20 mmol, 2.0 equiv.) in pyridine (3 mL), The mixture was stirred
at reflux temperature for 24 h under nitrogen. The solid was dissolved in ethyl acetate (50 mL), then the organic layer was washed
with water (100 × 3 mL), brine (100 × 3 mL), dried (Na2SO4), and filtered. Removal of the solvent by evaporation under vacuum
and the residue was separated on a flash column with PE/EA (100/1) as the eluent to afford 1.
(E)-3-(4-fluorostyryl)-5-methyl-1,2,4-oxadiazole (1b). White solid, yield: 532 mg, 26%; (PE:EA 20:1, Rf 0.4); mp = 99 – 101oC;
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16.2 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.96 (d, J = 16.2 Hz, 1H),
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2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 167.8, 163.4 (d, J = 251.0 Hz), 137.6, 131.6 (d, J = 3.1 Hz), 129.2 (d, J = 8.3
Hz), 116.0 (d, J = 21.9 Hz), 112.6 (d, J = 1.5 Hz), 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C11H10FN2O 205.0772; Found 205.0772.
(E)-3-(4-bromostyryl)-5-methyl-1,2,4-oxadiazole (1d). White solid, yield: 661 mg, 25%; (PE:EA 20:1, Rf 0.5); mp = 130 –
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132oC; H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 16.2 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.43 – 7.39 (m, 2H), 7.02 (d, J = 16.2 Hz,
1H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 167.7, 137.6, 134.3, 132.1, 128.8, 123.5, 113.5, 12.3; HRMS (EI) m/z:
[M+H]+ Calcd for C11H10BrN2O 264.9971; Found 264.9971.
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(E)-5-methyl-3-(4-(trifluoromethyl)styryl)-1,2,4-oxadiazole (1e). White solid, yield: 507 mg, 20%; (PE:EA 20:1, Rf 0.4); mp =
131 – 133oC; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 16.3 Hz, 1H), 7.65 (s, 4H), 7.12 (d, J = 16.2 Hz, 1H), 2.63 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 176.2, 167.5, 138.7, 137.2, 131.0 (q, J =32.7 Hz), 127.6, 125.9 (d, J = 3.6 Hz), 123.9 (d, J = 273.0),
115.4, 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C12H10F3N2O 255.0740; Found 255.0739.
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(E)-5-methyl-3-(4-methylstyryl)-1,2,4-oxadiazole (1f). White solid, yield: 821 mg, 41%; (PE:EA 20:1, Rf 0.4); mp = 119 –
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121oC; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4
Hz, 1H), 7.03 (d, J = 16.2 Hz, 1H), 2.61 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 168.0, 139.7, 138.9, 132.6,
129.6, 127.4, 111.7, 21.4, 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C12H13N2O 201.1022; Found 201.1022.
(E)-3-(4-methoxystyryl)-5-methyl-1,2,4-oxadiazole (1g). White solid, yield: 756 mg, 36%; (PE:EA 20:1, Rf 0.5); mp = 97 – 99oC;
1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 16.2 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 3.0 Hz, 2H), 6.89 (d, J = 10.4 Hz,
1H), 3.84 (s, 3H), 2.61 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.7, 168.1, 160.7, 138.5, 128.9, 128.1, 114.3, 110.4, 55.4, 12.3;
HRMS (EI) m/z: [M+H]+ Calcd for C12H13N2O2 217.0972; Found 217.0971.
(E)-3-(3-fluorostyryl)-5-methyl-1,2,4-oxadiazole (1h). White solid, yield: 490 mg, 24%; (PE:EA 20:1, Rf 0.4); mp = 48 – 50oC;
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16.2 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.24 (dd, J = 9.8, 2.0 Hz, 1H), 7.10 – 7.00 (m, 2H),
2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 167.6, 164.3, 161.9, 137.6, 130.4 (d, J = 8.3 Hz), 123.4 (d, J = 2.3 Hz), 116.3 (d,
J = 21.4 Hz), 114.2, 113.8 (d, J = 22.0 Hz), 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C11H10FN2O 205.0772; Found 205.0771.
(E)-5-methyl-3-(3-methylstyryl)-1,2,4-oxadiazole (1i). White solid, yield: 722 mg, 36%; (PE:EA 20:1, Rf 0.5); mp = 60 – 62oC;
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz,
1H), 7.03 (d, J = 16.2 Hz, 1H), 2.61 (d, J = 0.4 Hz, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 167.9, 139.1, 138.5,
135.3, 130.3, 128.8, 128.0, 124.7, 112.6, 21.4, 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C12H13N2O: [M+H]+, 201.1022; Found:
m/z 201.1022.
(E)-3-(3-methoxystyryl)-5-methyl-1,2,4-oxadiazole (1j). White solid, yield: 733 mg, 34%; (PE:EA 20:1, Rf 0.4); mp = 63 – 65oC;
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.08 (t, J = 1.7 Hz, 2H),
6.91 (dd, J = 8.1, 2.3 Hz, 1H), 3.84 (s, 3H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 167.8, 159.9, 138.9, 136.7, 129.9,
120.1, 115.3, 113.1, 112.5, 55.3, 12.3. HRMS (EI) m/z: [M+H]+ Calcd for C12H13N2O2 217.0972; Found 217.0971.
(E)-3-(2-fluorostyryl)-5-methyl-1,2,4-oxadiazole (1k). White solid, yield: 450 mg, 22%; (PE:EA 20:1, Rf 0.4); mp = 90 – 92oC;
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 16.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.32 (m, 1H), 7.17 (m, 2H), 7.10 (m, 1H), 2.62 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 167.9, 161.1 (d, J = 253.8 Hz), 131.7, 130.8 (d, J = 8.6 Hz), 128.5 (d, J = 2.6 Hz),
124.4(d, J = 13.2 Hz), 123.3 (d, J = 11.8 Hz), 116.1(d, J = 22.0 Hz), 115.5 (d, J = 7.0 Hz), 12.3; HRMS (EI) m/z: [M+H]+ Calcd for
C11H10FN2O 205.0772; Found 205.0771.
(E)-3-(2-(6-methoxynaphthalen-2-yl)vinyl)-5-methyl-1,2,4-oxadiazole (1l). White solid, yield: 479 mg, 18%; (PE:EA 20:1, Rf
0.4); mp = 153 – 155oC; 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.78 (d, J = 16.2 Hz, 1H), 7.74 (dd, J = 8.8, 4.1 Hz, 2H), 7.69
(dd, J = 8.6, 1.6 Hz, 1H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 7.11 (dd, J = 11.6, 9.3 Hz, 2H), 3.93 (s, 3H), 2.62 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 175.8, 168.1, 158.5, 139.1, 135.2, 130.7, 130.0, 128.8, 128.5, 127.5, 124.0, 119.4, 111.9, 106.0, 55.4, 12.4; HRMS
(EI) m/z: [M+H]+ Calcd for C16H15N2O2 267.1128; Found 267.1128.
(E)-5-methyl-3-(2-(thiophen-2-yl)vinyl)-1,2,4-oxadiazole (1m). Brown solid, yield: 482 mg, 25%; (PE:EA 20:1, Rf 0.4); mp = 38
– 40oC; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 15.9 Hz, 1H), 7.33 (d, J = 5.1 Hz, 1H), 7.22 – 7.20 (m, 1H), 7.04 (dd, J = 5.1, 3.6
Hz, 1H), 6.83 (d, J = 15.9 Hz, 1H), 2.59 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 167.6, 140.6, 131.6, 129.2, 127.9, 127.1,
111.9, 12.3; HRMS (EI) m/z: [M+H]+ Calcd for C9H9N2OS 193.0430; Found m/z 193.0430.
(E)-3-(2-(furan-2-yl) vinyl)-5-methyl-1,2,4-oxadiazole (1n). Yellow solid, yield: 263 mg, 15%; (PE:EA 20:1, Rf 0.4); mp = 67 –
69oC; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 15.9 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 6.53 (d, J = 3.4
Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 2.60 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.7, 167.8, 151.5, 143.9, 125.9, 112.6,
112.0, 110.8, 12.3. HRMS (EI) m/z: [M+H]+ Calcd for C9H9N2O2 177.0659; Found 177.0659.
General Procedure for the Synthesis of 1a-d6.18
To tolueneꢀd8 (5 g, 50 mmol, 1 equiv.) in 3.5 M HNO3 (50 mL) was added Ce(NH4)2(NO3)2 (110 g, 200 mmol, 4.0 equiv.) in 3.5
M HNO3 (500 mL). After stirring for 5 h at 80 °C, the solution was cooled to room temperature, extracted with chloroform (3 × 100
mL), and the combined organic layers were washed with water until pH≈7. The orange extract was dried over Na2SO4 and the solꢀ
vent was removed under vacuum. The resulting red residue was distilled to give benzaldehydeꢀd6, which was used without purificaꢀ
tion. NaH (1.5 equiv.) was placed in an overꢀdried 250 mL twoꢀneck round bottom flask. THF (50 mL) was added under nitrogen.
The reaction mixture was cooled and diethyl cyanomethylphosphonate (1.2 equiv.) was added dropwise while stirring at 0 °C. The
solution was stirred at room temperature for 1 h until gas evolution had ceased. And then, the corresponding aldehyde (1.0 equiv.)
was added to the solution dropwise, and maintained below 25 °C. The solution was stirred at room temperature until no starting
material was detected by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined orꢀ
ganic layers were washed with brine, dried over Na2SO4, and concentrated. This residue was pure enough for the further reaction.
The cinnamonitrileꢀd6 (without purification) reacted with 50 wt% aqueous hydroxylamine solution (6.2 mL, 100 mmol, 2.0 equiv)
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The Journal of Organic Chemistry
in EtOH (0.1 M). The mixture was stirred at reflux temperature for 3 h under nitrogen. After cooling to room temperature, the reacꢀ
tion mixture was concentrated, the residue (without purification) reacted with acetyl chloride (7 mL, 100 mmol, 2.0 equiv.) in pyriꢀ
dine (15 mL), The mixture was stirred at reflux temperature for 24 h under nitrogen. The solid was dissolved in ethyl acetate (200
mL), then the organic layer was washed with water (3 × 50 mL), brine (3 × 50 mL), dried (Na2SO4), and filtered. Removal of the
solvent by evaporation under vacuum and the residue was separated on a flash column with PE/EA (100/1) as the eluent to give 1a-
d6.
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(E)-5-methyl-3-(2-(phenyl-d5) vinyl-2-d)-1,2,4-oxadiazole (1a-d6). White solid, yield: 517 mg, 27%; (PE:EA 20:1, Rf 0.4); mp =
68 – 70oC; 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 2.2 Hz, 1H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 167.9, 138.6
(t, J = 23.9 Hz), 135.1, 128.9 (t, J = 19.2 Hz), 128.4 (t, J = 24.8 Hz), 126.7 (t, J = 24.0 Hz), 112.7, 12.3; HRMS (EI) m/z: [M+H]+
Calcd for C11H5D6N2O 193.1242; Found 193.1242.
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General Procedure for the Synthesis of 3aꢀ3n, 4aꢀ4n. To a 13 × 150 mm test tube equipped with magnetic stir bar was added
the oxadiazole substrate if the substrate is a solid (for solid such as 1a, 37 mg, 0.2 mmol, 1 equiv) and alkyne (for example, 2a, 54
mg, 0.3 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). The test
tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then
tAmylOH (1.0 mL) was injected into the test tube via syringe. The reaction mixture was allowed to stir at 110 oC, stirred for 24 h,
during which time a constant checking by TLC was performed. Once the reaction proceeded to a desired degree, the reaction mixꢀ
ture was filtered over celite. The solvent was then removed under reduce pressure and the residue was purified by flash column
chromatography on silica gel with PE: EA = 2: 1 as the eluent to give the product 3 or 4.
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N-(4,5,6-triphenylpyridin-2-yl)acetamide (3a): White solid, yield: 69 mg, 95%; (PE:EA 2:1, Rf 0.4); mp = 84 – 86oC; H NMR
(400 MHz, CDCl3) δ 8.91 (s, 1H), 8.27 (s, 1H), 7.24 – 7.14 (m, 8H), 7.11ꢀ7.09 (m, 2H), 7.07 – 7.00 (m, 3H), 6.86 (dd, J = 7.8, 1.6
Hz, 2H), 1.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.4, 152.7, 150.1, 140.0, 139.4, 137.4, 131.6 129.8, 129.4, 127.8,
127.7, 127.4, 126.6, 114.0, 24.4; HRMS (EI) m/z: [M+H]+ Calcd for C25H21N2O 365.1648; Found 365.1647.
N-(4-(4-fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3b). Pale yellow sticky oil, yield: 73 mg, 95%; (PE:EA 2:1, Rf 0.6);
1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.25 (s, 1H), 7.18 (dq, J = 9.2, 5.9 Hz, 5H), 7.11 – 7.03 (m, 5H), 6.87 (dd, J = 9.7, 7.6
Hz, 4H), 1.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 163.4, 161.0, 156.6, 151.6, 150.3, 139.9, 137.3, 135.4 (d, J = 2.9 Hz),
131.5, 131.2 (d, J = 8.1 Hz), 130.8, 129.8, 127.8 (d, J = 14.2 Hz), 126.7, 115.1, 114.9 (d, J = 21.5 Hz), 113.9, 24.3; HRMS (EI) m/z:
[M+H]+ Calcd for C25H20FN2O 383.1554; Found 383.1553.
N-(4-(4-chlorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3c). White solid, yield: 75 mg, 94%; (PE:EA 2:1, Rf 0.5); mp = 126 –
128oC; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.23 (s, 1H), 7.23 – 7.13 (m, 7H), 7.10 – 7.00 (m, 5H), 6.85 (dd, J = 7.8, 1.5 Hz,
2H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.6, 151.3, 150.2, 139.8, 137.9, 137.2, 133.7, 131.5, 130.7, 129.7, 128.1,
127.9, 127.8, 126.8, 113.7, 24.4; HRMS (EI) m/z: [M+H]+ Calcd for C25H20ClN2O 399.1259; Found 399.1259.
N-(4-(4-bromophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3d). White solid, yield: 81 mg, 91%; (PE: EA 2:1, Rf 0.5); mp = 142
– 144oC; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (s, 1H), 7.36 – 7.28 (m, 2H), 7.22 – 7.14 (m, 5H), 7.10 – 7.03 (m, 3H),
7.00 – 6.95 (m, 2H), 6.87 – 6.82 (m, 2H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.7, 151.3, 150.00, 139.8, 138.4,
137.1, 131.4, 131.1, 131.0, 130.6, 129.6, 127.9, 127.8, 126.8, 122.0, 113.4, 24.6. HRMS (EI) m/z: [M+H]+ Calcd for C25H20BrN2O
443.0754; Found 443.0753.
N-(5,6-diphenyl-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl) acetamide (3e). Colorless oil, yield: 73 mg, 84%; (PE:EA 2:1, Rf 0.5);
1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.26 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.25 – 7.15 (m, 7H), 7.12 – 7.01 (m, 3H), 6.87ꢀ
6.82 (m, 2H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.8, 151.1, 150.3, 143.2, 139.7, 136.9, 131.5, 130.7, 129.7,
129.4, 128.0, 127.9, 126.9, 125.4, 124.8 (d, J = 3.4 Hz), 122.7, 113.7, 24.4; HRMS (EI) m/z: [M+H]+ Calcd for C26H20F3N2O
433.1522; Found 433.1521.
N-(5,6-diphenyl-4-(p-tolyl)pyridin-2-yl)acetamide (3f). White solid, yield: 41 mg, 54%; (PE:EA 2:1, Rf 0.4); mp = 185 – 187oC;
1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.25 (s, 1H), 7.24 – 7.13 (m, 5H), 7.09 – 7.02 (m, 3H), 6.99 (s, 4H), 6.87 (dt, J = 3.8,
2.2 Hz, 2H), 2.28 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.5, 152.6, 150.1, 140.2, 137.7, 137.3, 136.5,
131.6, 130.8, 129.7, 129.4, 128.6, 127.7, 127.6, 126.5, 113.9, 24.4, 21.2; HRMS (EI) m/z: [M+H]+ Calcd for C26H23N2O 379.1805;
Found 379.1803.
N-(4-(4-methoxyphenyl)-5,6-diphenylpyridin-2-yl)acetamide (3g). White solid, yield: 64 mg, 81%; (PE:EA 2:1, Rf 0.5); mp = 201
– 203oC; 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.25 (s, 1H), 7.24 – 7.13 (m, 5H), 7.09 – 7.00 (m, 5H), 6.87 (dd, J = 7.5, 1.9
Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 159.1, 156.3, 152.4, 150.0,
139.9, 137.6, 131.6, 130.8, 129.7, 127.8, 127.7, 127.6, 126.6, 113.9, 113.3, 55.2, 24.4; HRMS (EI) m/z: [M+H]+ Calcd for
C26H23N2O2 395.1754; Found 395.1753.
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N-(4-(3-fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3h). Colorless oil, yield: 70 mg, 92%; (PE:EA 2:1, Rf 0.5); H NMR
(400 MHz, CDCl3) δ 8.83 (s, 1H), 8.25 (s, 1H), 7.24 – 7.11 (m, 6H), 7.09 – 7.02 (m, 3H), 6.94 – 6.77 (m, 5H), 2.02 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 169.1, 162.2 (d, J = 246.9 Hz), 156.6, 151.3, 150.2, 141.6 (d, J = 7.8 Hz), 139.8, 137.1, 131.4, 130.7,
129.8, 129.4 (d, J = 8.2 Hz), 127.9, 127.8, 126.8, 125.2 (d, J = 2.2 Hz), 116.4 (d, J = 22.5 Hz), 114.4 (d, J = 22.1 Hz), 113.7, 24.4;
HRMS (EI) m/z: [M+H]+ Calcd for C25H20FN2O 383.1554; Found 383.1553.
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N-(5,6-diphenyl-4-(m-tolyl)pyridin-2-yl)acetamide (3i). Colorless oil, yield: 73 mg, 97%; (PE:EA 2:1, Rf 0.5); H NMR (400
MHz, CDCl3) δ 9.05 (s, 1H), 8.26 (s, 1H), 7.20 (ddt, J = 13.4, 12.4, 4.5 Hz, 5H), 7.03 (ddd, J = 15.5, 10.1, 6.3 Hz, 6H), 6.89 – 6.81
(m, 3H), 2.22 (s, 3H), 1.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.4, 152.8, 150.2, 140.1, 139.3, 137.6, 137.5, 131.6,
130.8, 130.2, 129.8, 128.2, 127.7, 127.6, 126.6, 126.5, 114.0, 24.3, 21.3. HRMS (EI) m/z: [M+H]+ Calcd for C26H23N2O 379.1805;
Found 379.1805.
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N-(4-(3-methoxyphenyl)-5,6-diphenylpyridin-2-yl)acetamide (3j). White solid, yield: 77 mg, 98%; (PE:EA 2:1, Rf 0.5); mp = 187
– 189oC; 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.28 (s, 1H), 7.24 – 7.14 (m, 5H), 7.13 – 7.01 (m, 4H), 6.92 – 6.85 (m, 2H),
6.79 – 6.72 (m, 2H), 6.61 – 6.54 (m, 1H), 3.55 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 158.9, 156.5, 152.4,
150.2, 140.7, 140.0, 137.6, 131.5, 130.7, 129.8, 129.0, 129.0, 127.8, 127.7, 126.6, 122.0, 114.5, 114.0, 113.9, 55.1, 24.3; HRMS
(EI) m/z: [M+H]+ Calcd for C26H23N2O2 395.1754; Found 395.1752.
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N-(4-(2-fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3k). Colorless oil, yield: 28 mg, 36%; (PE:EA 2:1, Rf 0.5); H NMR
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(400 MHz, CDCl3) δ 8.55 (s, 1H), 8.25 (s, 1H), 7.25 – 7.15 (m, 6H), 7.09 (td, J = 7.5, 1.7 Hz, 1H), 7.06 – 6.98 (m, 4H), 6.89 (dd, J
= 9.8, 8.5 Hz, 3H), 2.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 160.2, 157.7, 156.2, 149.8, 147.4, 139.8, 137.2, 132.0, 131.2
(d, J = 2.6 Hz), 130.9, 129.7, 127.8, 127.5, 127.3, 126.7, 123.7 (d, J = 3.2 Hz), 115.5, 115.3, 114.1, 24.5; HRMS (EI) m/z: [M+H]+
Calcd for C25H20FN2O 383.1554; Found 383.1551.
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N-(4-(6-methoxynaphthalen-2-yl)-5,6-diphenylpyridin-2-yl)acetamide (3l). White solid, yield: 81 mg, 91%; (PE:EA 2:1, Rf 0.3);
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mp = 167 – 169oC; H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J = 66.8, 8.8 Hz, 2H), 7.27 –
7.17 (m, 5H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 7.06 – 6.97 (m, 5H), 6.89 (dd, J = 7.9, 1.5 Hz, 2H), 3.88 (s, 3H), 2.03 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 169.1, 158.1, 156.5, 152.6, 150.1, 140.1, 137.5, 134.7, 133.7, 131.6, 130.9, 129.8, 128.7, 128.5, 127.8,
127.7, 127.6, 126.6, 126.0, 119.0, 114.1, 105.5, 55.3, 24.5; HRMS (EI) m/z: [M+H]+ Calcd for C30H25N2O2 445.1911; Found
445.1909.
N-(5,6-diphenyl-4-(thiophen-2-yl)pyridin-2-yl)acetamide (3m). Pale yellow solid, yield: 62 mg, 83%; (PE:EA 2:1, Rf 0.7); mp =
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176 – 178oC; H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.46 (s, 1H), 7.27 – 7.13 (m, 10H), 7.03 (dd, J = 7.9, 1.5 Hz, 2H), 6.86
(dd, J = 5.2, 2.7 Hz, 2H), 1.95 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.3, 156.9, 150.4, 145.0, 140.7, 139.8, 137.4, 131.5, 130.0,
129.7, 128.8, 128.2, 127.9, 127.7, 127.6, 127.4, 126.9, 113.0, 24.3. HRMS (EI) m/z: [M+H]+ Calcd for C23H19N2OS 371.1213;
Found 371.1211.
N-(4-(furan-2-yl)-5,6-diphenylpyridin-2-yl)acetamide (3n). Yellow solid, yield: 70 mg, 98%; (PE:EA 2:1, Rf 0.6); mp = 140 –
142oC; 1H NMR (400 MHz, CD3CN) δ 8.81 (s, 1H), 8.61 (s, 1H), 7.54 (dd, J = 1.8, 0.6 Hz, 1H), 7.32 – 7.28 (m, 3H), 7.23 –
7.11 (m, 7H), 6.26 (dd, J = 3.5, 1.8 Hz, 1H), 5.23 (dd, J = 3.5, 0.5 Hz, 1H), 2.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.5,
158.1, 152.0, 151.5, 144.4, 141.6, 140.3, 139.4, 131.7, 130.5, 129.4, 128.6, 128.5, 128.3, 118.3, 113.4, 112.8, 108.7, 24.6;
HRMS (EI) m/z: [M+H]+ Calcd for C23H19N2O2 355.1441; Found 355.1440.
N-(4-phenyl-5,6-di-p-tolylpyridin-2-yl)acetamide (4a). White solid, yield: 46 mg, 58%; (PE:EA 2:1, Rf 0.5); mp = 168 – 170oC;
1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.22 (s, 1H), 7.21 – 7.15 (m, 3H), 7.13 – 7.07 (m, 4H), 6.99 (d, J = 8.0 Hz, 2H), 6.84 (d,
J = 7.9 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.1,
153.0, 149.6, 139.6, 137.5, 136.9, 136.1, 134.3, 131.3, 130.8, 129.6, 129.4, 128.5, 127.8, 127.4, 113.6, 24.6, 21.2, 21.1. HRMS (EI)
m/z: [M+H]+ Calcd for C27H25N2O 393.1961; Found 393.1959.
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N-(5,6-bis(4-methoxyphenyl)-4-phenylpyridin-2-yl)acetamide (4b). Pale yellow oil, yield: 62 mg, 73%; (PE:EA 2:1, Rf 0.4); H
NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.21 (s, 1H), 7.18 (ddd, J = 12.2, 6.3, 2.3 Hz, 5H), 7.10 (dd, J = 6.6, 3.0 Hz, 2H), 6.78 –
6.70 (m, 4H), 6.63 – 6.58 (m, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 159.1, 158.1,
156.1, 152.7, 149.8, 139.8, 132.6, 131.1, 130.2, 129.9, 129.4, 127.8, 127.3, 113.5, 113.3, 113.2, 55.2, 55.1, 24.5. HRMS (EI) m/z:
[M+H]+ Calcd for C27H25N2O3 425.1860; Found 425.1856.
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N-(5,6-bis(3-methoxyphenyl)-4-phenylpyridin-2-yl) acetamide (4c). Pale yellow oil, yield: 72 mg, 85%; (PE:EA 2:1, Rf 0.4); H
NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (s, 1H), 7.23 – 7.17 (m, 3H), 7.15 – 7.09 (m, 3H), 6.96 (t, J = 7.9 Hz, 1H), 6.87 (d, J =
7.7 Hz, 1H), 6.79 – 6.73 (m, 2H), 6.62 (dd, J = 8.1, 2.2 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.42 – 6.39 (m, 1H), 3.57 (s, 3H), 3.48 (s,
3H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.0, 159.0, 158.9, 156.0, 152.7, 149.9, 141.2, 139.4, 138.7, 130.6, 129.3, 128.8,
128.7, 127.9, 127.5, 124.2, 122.1, 116.8, 114.6, 114.3, 113.9, 113.0, 55.1, 55.0, 24.5. HRMS (EI) m/z: [M+H]+ Calcd for
C27H25N2O3 425.1860; Found 425.1857.
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N-(5,6-bis(2-methoxyphenyl)-4-phenylpyridin-2-yl)acetamide (4d). Pale yellow oil, yield: 76 mg, 89%; (PE:EA 2:1, Rf 0.5); H
NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.25 (s, 1H), 7.24 – 7.13 (m, 7H), 7.04 – 6.98 (m, 1H), 6.87 – 6.75 (m, 2H), 6.60 (ddd, J =
9.6, 8.3, 4.6 Hz, 2H), 6.50 (d, J = 8.2 Hz, 1H), 3.41 (s, 3H), 3.28 (s, 3H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.7,
156.3, 155.3, 152.5, 150.0, 139.9, 132.0, 130.7, 129.3, 128.8, 128.5, 127.5, 127.4, 126.7 120.0, 119.5, 113.6, 110.3, 110.0, 54.8,
24.4. HRMS (EI) m/z: [M+H]+ Calcd for C27H25N2O3 425.1860; Found 425.1857.
N-(5,6-bis(4-fluorophenyl)-4-phenylpyridin-2-yl)acetamide (4e). Colorless oil, yield: 61 mg, 76%; (PE:EA 2:1, Rf 0.6); 1H NMR
(400 MHz, CDCl3) δ 8.43 (s, 1H), 8.27 (s, 1H), 7.23 – 7.17 (m, 5H), 7.09 – 7.05 (m, 2H), 6.93 – 6.86 (m, 2H), 6.83 – 6.73 (m,
4H), 2.15 (s, 3H).;
13C NMR (101 MHz, CDCl3) δ 168.8, 163.2 (d, J = 71.8 Hz), 160.7 (d, J = 70.8 Hz), 155.4, 153.0, 150.0,
139.1, 135.8 (d, J = 2.7 Hz), 133.0 (d, J = 8.0 Hz), 133.5 (d, J = 8.1 Hz), 129.7, 129.3, 128.0, 127.7, 115.0 (q, J = 21.5, 12.1
Hz), 113.9, 24.65. HRMS (EI) m/z: [M+H]+ Calcd for C25H19F2N2O 401.1460; Found 401.1454.
N-(5,6-bis(4-chlorophenyl)-4-phenylpyridin-2-yl)acetamide (4f). White solid, yield: 79 mg, 91%; (PE:EA 2:1, Rf 0.4); mp = 182
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– 184oC; H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.28 (s, 1H), 7.25 – 7.12 (m, 7H), 7.09 – 7.01 (m, 4H), 6.77 (d, J = 8.4 Hz,
2H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.7, 155.2, 152.8, 150.2, 139.0, 138.3, 135.8, 134.0, 132.9, 132.8, 131.0, 129.5,
129.3, 128.2, 128.1, 128.0, 127.7, 114.0, 24.7. HRMS (EI) m/z: [M+H]+ Calcd for C25H19Cl2N2O 433.0869; Found 433.0869.
N-(5,6-bis(4-bromophenyl)-4-phenylpyridin-2-yl)acetamide (4g). White solid, yield: 65 mg, 62%; (PE:EA 2:1, Rf 0.4); mp = 218
– 220oC; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.28 (s, 1H), 7.38 – 7.31 (m, 2H), 7.25 – 7.18 (m, 5H), 7.10 – 7.04 (m, 4H),
6.74 – 6.69 (m, 2H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 154.9, 153.0, 150.2, 138.8, 138.5, 136.1, 133.1, 131.3,
131.2, 131.1, 129.5, 129.3, 128.1, 127.8, 122.4, 121.2, 114.1, 24.7; HRMS (EI) m/z: [M+H]+ Calcd for C25H19Br2N2O 520.9859;
Found 520.9859.
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N-(4-phenyl-5,6-di(thiophen-2-yl)pyridin-2-yl)acetamide (4h). Pale yellow oil, yield: 31 mg, 40%; (PE:EA 2:1, Rf 0.6); 1H NMR
(400 MHz, CDCl3) δ 8.42 (s, 1H), 8.16 (s, 1H), 7.36 – 7.27 (m, 2H), 7.25 – 7.16 (m, 5H), 6.93 (dd, J = 5.1, 3.5 Hz, 1H), 6.86 (dd, J
= 5.0, 3.9 Hz, 1H), 6.79 (dd, J = 3.4, 1.0 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.0,
155.2, 150.0, 139.0, 138.0, 129.7, 128.8, 128.5, 128.3, 128.1, 127.8, 127.6, 127.3, 127.1, 121.7, 112.8, 24.8; HRMS (EI) m/z:
[M+H]+ Calcd for C21H17N2OS2 377.0777; Found 377.0775.
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N-(4-phenyl-5,6-dipropylpyridin-2-yl)acetamide (4i). White solid, yield: 47 mg, 80%; (PE:EA 2:1, Rf 0.5); mp = 154 – 156oC; 1H
NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.85 (s, 1H), 7.45 – 7.32 (m, 3H), 7.29 – 7.24 (m, 2H), 2.72 (dd, J = 8.9, 6.8 Hz, 2H), 2.52
– 2.45 (m, 2H), 2.16 (s, 3H), 1.81 – 1.69 (m, 2H), 1.41 – 1.30 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 168.4, 158.8, 152.9, 147.9, 140.4, 129.6, 128.5, 128.1, 127.5, 112.5, 36.8, 30.5, 24.7, 24.3, 23.1, 14.3, 14.2;
HRMS (EI) m/z: [M+H]+ Calcd for C19H25N2O 297.1961; Found 297.1961.
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ethyl 6-acetamido-2,4-diphenylnicotinate (4j). White solid, yield: 27 mg, 38%; (PE:EA 2:1, Rf 0.3); mp = 144 – 146oC; 1H NMR
(400 MHz, CDCl3) δ 9.00 (s, 1H), 8.25 (s, 1H), 7.65 – 7.51 (m, 2H), 7.48 – 7.35 (m, 8H), 3.94 (q, J = 7.1 Hz, 2H), 1.91 (s, 3H),
0.85 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 168.3, 155.6, 151.9, 151.4, 139.0, 138.4, 129.1, 128.7, 128.5, 128.4,
128.1, 124.7, 112.9, 61.5, 24.3, 13.4; HRMS (EI) m/z: [M+H]+ Calcd for C22H21N2O3 361.1547. Found 361.1545.
N-(6-ethyl-5-methyl-4-phenylpyridin-2-yl)acetamide (4ka). White solid, yield: 25 mg, 98%; (PE:EA 2:1, Rf 0.5); mp = 126 –
128oC; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.94 (s, 1H), 7.45 – 7.35 (m, 3H), 7.33 – 7.28 (m, 2H), 2.80 (q, J = 7.5 Hz, 2H),
2.19 (s, 3H), 2.16 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 159.7, 153.0, 147.9, 140.0, 128.8, 128.3,
127.8, 124.2, 112.3, 28.6, 24.7, 15.2, 12.9; HRMS (EI) m/z: [M+H]+ Calcd for C16H19N2O 255.1492; Found 255.1492.
N-(5-ethyl-6-methyl-4-phenylpyridin-2-yl)acetamide (4kb). White solid, yield: 25 mg, 98%; (PE:EA 2:1, Rf 0.4); mp = 175 –
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177oC; H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.89 (s, 1H), 7.48 – 7.34 (m, 3H), 7.29 – 7.26 (m, 2H), 2.57 – 2.51 (m, 5H),
2.18 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 154.6, 153.0, 147.6, 140.0, 131.4, 128.4, 128.1, 127.7,
112.7, 24.7, 22.0, 21.9, 14.4; HRMS (EI) m/z: [M+H]+ Calcd for C16H19N2O 255.1492; Found 255.1492.
N-(5-methyl-4,6-diphenylpyridin-2-yl)acetamide (4l). White solid, yield: 45 mg, 74%; (PE:EA 2:1, Rf 0.5); mp = 157 – 159oC; 1H
NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.10 (s, 1H), 7.52 (dd, J = 8.0, 1.4 Hz, 2H), 7.47 – 7.35 (m, 8H), 2.17 (s, 3H), 1.87 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 169.1, 157.4, 153.7, 148.9, 140.3, 140.0, 129.2, 128.8, 128.4, 128.3, 113.8, 24.2, 17.7; HRMS (EI)
m/z: [M+H]+ Calcd for C20H19N2O 303.1492; Found 303.1492.
N-(5-(tert-butyl)-6-methyl-4-phenylpyridin-2-yl)acetamide (4m). Colorless oil, yield: 26 mg, 46%; (PE:EA 2:1, Rf 0.4); 1H NMR
(400 MHz, CDCl3) δ 7.87 (s, 2H), 7.44 – 7.32 (m, 3H), 7.28 – 7.24 (m, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.44 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 168.4, 164.3, 154.3, 146.5, 141.0, 128.7, 128.2, 127.5, 124.6, 112.0, 38.9, 30.1, 24.7, 18.2; HRMS (EI) m/z:
[M+H]+ Calcd for C18H23N2O 283.1805; Found 283.1805.
(6-acetamido-2,4-diphenylpyridin-3-yl)methyl tert-butyl carbonate (4n). Pale yellow oil, yield: 50 mg, 60%; (PE:EA 2:1, Rf 0.5);
1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.19 (s, 1H), 7.57 (dd, J = 6.5, 3.0 Hz, 2H), 7.48 – 7.41 (m, 8H), 4.80 (s, 2H), 2.01 (s,
3H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.0, 160.0, 156.0, 152.6, 150.6, 139.0, 138.6, 129.0, 128.8, 128.5, 128.4, 122.2,
113.7, 82.2, 63.7, 27.8, 24.5; HRMS (EI) m/z: [M+H]+ Calcd for C25H27N2O4 419.1965; Found 419.1965.
General Procedure for the Synthesis of 5aꢀ5c, 5eꢀ5m. To a 13 × 150 mm test tube equipped with magnetic stir bar was added
the oxadiazole substrate if the substrate is a solid (for solid such as 1a, 37 mg, 0.2 mmol, 1 equiv) and alkyne (for example, 2a, 54
mg, 0.3 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). The test
tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then
TFE (1.0 mL) was injected into the test tube via syringe. The reaction mixture was allowed to stir at 110 oC, stirred for 24 h, during
which time a constant checking by TLC was performed. Once the reaction proceeded to a desired degree, the reaction mixture was
filtered over celite. The solvent was then removed under reduce pressure and the residue was purified by flash column chromatogꢀ
raphy on silica gel with DCM: MeOH = 100: 1 as the eluent to give the product 5.
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4-phenyl-5,6-dipropylpyridin-2-amine (5a). Colorless oil, yield: 45 mg, 88%; (DCM:MeOH 20:1, Rf 0.5); H NMR (400 MHz,
CDCl3) δ 7.39 (tt, J = 7.5, 3.7 Hz, 3H), 7.25 – 7.21 (m, 2H), 6.25 (s, 1H), 4.79 (s, 2H), 2.70 – 2.64 (m, 2H), 2.42 – 2.34 (m, 2H),
1.80 – 1.71 (m, 2H), 1.33 – 1.25 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 157.3,
154.8, 153.6, 140.5, 128.2, 128.1, 127.5, 123.6, 108.1, 36.5, 30.1, 24.5, 23.5, 14.4, 14.2; HRMS (EI) m/z: [M+H]+ Calcd for
C17H23N2 255.1856; Found 255.1856.
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4-(4-fluorophenyl)-5,6-dipropylpyridin-2-amine (5b). Pale yellow oil, yield: 42 mg, 76%; (DCM:MeOH 50:1, Rf 0.3); H NMR
(400 MHz, CDCl3) δ 7.23 – 7.17 (m, 2H), 7.08 (t, J = 8.7 Hz, 2H), 6.18 (s, 1H), 4.43 (s, 2H), 2.69 – 2.62 (m, 2H), 2.41 – 2.33 (m,
2H), 1.79 – 1.69 (m, 2H), 1.33 – 1.25 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
163.4, 159.8 (d, J = 222.2 Hz), 155.2, 151.7, 136.8 (d, J = 3.1 Hz), 130.0 (d, J = 8.0 Hz), 115.0 (d, J = 21.4 Hz), 107.6, 37.0, 30.2,
24.5, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M+H]+ Calcd for C17H22FN2 273.1762; Found 273.1762.
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4-(4-chlorophenyl)-5,6-dipropylpyridin-2-amine (5c). Colorless oil, yield: 34 mg, 59%; (DCM:MeOH 20:1, Rf 0.5); H NMR
(400 MHz, CDCl3) δ 7.43 – 7.33 (m, 2H), 7.22 – 7.14 (m, 2H), 6.18 (s, 1H), 4.50 (s, 2H), 2.69 – 2.61 (m, 2H), 2.40 – 2.34 (m, 2H),
1.79 – 1.68 (m, 2H), 1.33 – 1.27 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.6,
155.1, 151.7, 139.2, 133.5, 129.7, 128.3, 123.4, 107.5, 36.9, 30.1, 24.6, 23.4, 14.4, 14.3; HRMS (EI) m/z: [M+H]+ Calcd for
C17H22ClN2 289.1466; Found 289.1466.
5,6-dipropyl-4-(4-(trifluoromethyl)phenyl)pyridin-2-amine (5e). White solid, yield: 48 mg, 75%; (DCM:MeOH 20:1, Rf 0.6); mp
= 94 – 96oC; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.17 (s, 1H), 4.47 (s, 2H), 2.71 – 2.63
(m, 2H), 2.39 – 2.31 (m, 2H), 1.82 – 1.72 (m, 2H), 1.33 – 1.26 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR
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(101 MHz, CDCl3) δ 159.1, 151.2, 144.6, 129.6 (q, J = 18.9 Hz), 128.8, 125.1, 125.0, 123.1, 107.1, 37.0, 30.1, 24.6, 23.4, 14.4,
14.2; HRMS (EI) m/z: [M+H]+ Calcd for C18H22F3N2 323.1730; Found 323.1729.
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5,6-dipropyl-4-(p-tolyl)pyridin-2-amine (5f). White solid, yield: 43 mg, 80%; (DCM:MeOH 20:1, Rf 0.5); mp = 61 – 63oC; H
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NMR (400 MHz, CDCl3) δ 7.19 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.20 (s, 1H), 4.45 (s, 2H), 2.69 – 2.63 (m, 2H), 2.38
(d, J = 8.2 Hz, 5H), 1.81 – 1.68 (m, 2H), 1.34 – 1.27 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 158.3, 155.1, 152.9, 137.9, 137.0, 128.7, 128.2, 123.7, 107.8, 37.0, 30.2, 24.6, 23.5, 21.2, 14.4, 14.3; HRMS (EI) m/z:
[M+H]+ Calcd for C18H25N2 269.2012; Found 269.2012.
4-(4-methoxyphenyl)-5,6-dipropylpyridin-2-amine (5g). White solid, yield: 39 mg, 68%; (DCM:MeOH 20:1, Rf 0.5); mp = 121 –
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123oC; H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.21 (s, 1H), 4.48 (s, 2H), 3.85 (s, 3H),
2.69 – 2.63 (m, 2H), 2.43 – 2.37 (m, 2H), 1.74 (dd, J = 15.6, 7.6 Hz, 2H), 1.31 (dd, J = 15.8, 7.6 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H),
0.76 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.9, 158.3, 155.1, 152.6, 133.2, 129.5, 123.9, 113.5, 107.9, 55.3, 37.0,
30.2, 24.5, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M+H]+ Calcd for C18H25N2O 285.1961; Found 285.1961.
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4-(3-fluorophenyl)-5,6-dipropylpyridin-2-amine (5h). Pale yellow oil, yield: 41 mg, 75%; (DCM:MeOH 50:1, Rf 0.4); H NMR
(400 MHz, CDCl3) δ 7.35 (td, J = 7.9, 6.0 Hz, 1H), 7.11 – 6.87 (m, 3H), 6.19 (s, 1H), 4.53 (s, 2H), 2.69 – 2.63 (m, 2H), 2.41 – 2.35
(m, 2H), 1.79 – 1.68 (m, 2H), 1.31 (ddd, J = 10.9, 7.6, 5.5 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 163.6, 155.9 (d, J = 251.6 Hz), 155.2, 151.5, 142.9 (d, J = 7.5 Hz), 129.6 (d, J = 8.3 Hz), 124.2 (d, J = 2.4 Hz),
123.3, 115.5 (d, J = 21.9 Hz), 114.3 (d, J = 21.3 Hz), 107.4, 36.9, 30.1, 24.6, 23.4, 14.4, 14.3 ; HRMS (EI) m/z: [M+H]+ Calcd for
C17H22FN2 273.1762; Found 273.1762.
5,6-dipropyl-4-(m-tolyl)pyridin-2-amine (5i). Colorless oil, yield: 39 mg, 72%; (DCM:MeOH 20:1, Rf 0.5); 1H NMR (400 MHz,
CDCl3) δ 7.27 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.21 (s, 1H), 4.50 (s, 2H), 2.69 – 2.63 (m, 2H),
2.41 – 2.36 (m, 5H), 1.80 – 1.69 (m, 2H), 1.37 – 1.27 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 158.2, 155.1, 153.1, 140.7, 137.7, 129.0, 128.0, 127.9, 125.4, 123.6, 107.7, 36.9, 30.2, 24.6, 23.5, 21.5, 14.4, 14.3;
HRMS (EI) m/z: [M+H]+ Calcd for C18H25N2 269.2012; Found 269.2012.
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4-(3-methoxyphenyl)-5,6-dipropylpyridin-2-amine (5j). Colorless oil, yield: 49 mg, 86%; (DCM:MeOH 20:1, Rf 0.4); H NMR
(400 MHz, CDCl3) δ 7.32 – 7.27 (m, 1H), 6.90 (ddd, J = 8.3, 2.6, 0.8 Hz, 1H), 6.83 – 6.76 (m, 2H), 6.21 (s, 1H), 4.49 (s, 2H), 3.82
(s, 3H), 2.69 – 2.63 (m, 2H), 2.42 – 2.37 (m, 2H), 1.78 – 1.70 (m, 2H), 1.33 (ddd, J = 11.0, 7.6, 5.4 Hz, 2H), 1.02 (t, J = 7.4 Hz,
3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.2, 158.5, 155.1, 152.7, 142.2, 129.1, 123.5, 120.8, 114.0, 112.9,
107.5, 55.3, 36.9, 30.2, 24.7, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M+H]+ Calcd for C18H25N2O 285.1961; Found 285.1961.
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4-(2-fluorophenyl)-5,6-dipropylpyridin-2-amine (5k). Colorless oil, yield: 29 mg, 53%; (DCM:MeOH 50:1, Rf 0.3); H NMR
(400 MHz, CDCl3) δ 7.39 – 7.31 (m, 1H), 7.20 – 7.09 (m, 3H), 6.23 (s, 1H), 4.57 (s, 2H), 2.67 (dd, J = 9.1, 6.8 Hz, 2H), 2.33 (s,
2H), 1.75 (dd, J = 15.8, 7.5 Hz, 2H), 1.26 (s, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
160.2, 158.2, 156.5 (d, J = 261.7 Hz), 155.2, 146.8, 130.8 (d, J = 3.4 Hz), 129.6 (d, J = 7.9 Hz), 128.0 (d, J = 16.8 Hz), 124.3, 123.9
(d, J = 3.6 Hz), 115.6 (d, J = 22.1 Hz), 108.1, 36.8, 30.6, 24.1, 23.4, 14.4, 14.2; HRMS (EI) m/z: [M+H]+ Calcd for C17H22FN2
273.1762; Found 273.1762.
4-(6-methoxynaphthalen-2-yl)-5,6-dipropylpyridin-2-amine (5l). White solid, yield: 47 mg, 70%; (DCM:MeOH 20:1, Rf 0.5);
mp = 102 – 102oC; 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 8.7, 6.4 Hz, 2H), 7.62 (d, J = 1.2 Hz, 1H), 7.33 (dd, J = 8.4, 1.7 Hz,
1H), 7.21 – 7.15 (m, 2H), 6.28 (s, 1H), 4.52 (s, 2H), 3.93 (s, 3H), 2.72 – 2.65 (m, 2H), 2.48 – 2.41 (m, 2H), 1.77 (dp, J = 10.3, 7.4
Hz, 2H), 1.38 – 1.29 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.4, 157.9, 155.2,
152.9, 136.1, 133.7, 129.5, 128.5, 127.2, 127.0, 126.4, 123.8, 119.2, 108.0, 105.6, 55.4, 36.9, 30.3, 24.8, 23.5, 14.4, 14.3; HRMS
(EI) m/z: [M+H]+ Calcd for C22H27N2O 335.2118; Found 335.2117.
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5,6-dipropyl-4-(thiophen-2-yl)pyridin-2-amine (5m). Pale yellow oil, yield: 18 mg, 35%; (DCM:MeOH 20:1, Rf 0.6); H NMR
(400 MHz, CDCl3) δ 7.38 (dd, J = 5.0, 1.2 Hz, 1H), 7.07 (ddd, J = 4.8, 4.3, 2.4 Hz, 2H), 6.41 (s, 1H), 4.72 (s, 2H), 2.70 – 2.66 (m,
2H), 2.58 – 2.53 (m, 2H), 1.78 – 1.71 (m, 2H), 1.48 – 1.41 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 157.9, 154.9, 145.5, 140.9, 127.1, 127.0, 126.1, 124.0, 108.7, 36.6, 30.4, 24.7, 23.4, 14.3, 14.2; HRMS (EI) m/z:
[M+H]+ Calcd for C15H21N2S 261.1420; Found 261.1420.
Mechanistic Experiments. The raw data and spectra of mechanistic experiments including competition experiment, kinetic isoꢀ
topic effect (KIE) experiments, H/D scrambling are described in the Supporting Information.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1H and 13C NMR spectra for substrates and products (PDF)
AUTHOR INFORMATION
Corresponding Author
Email: jinz@nju.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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The Journal of Organic Chemistry
J.Z. gratefully acknowledge support from the National Natural Science Foundation of China (21425415, 21274058) and the National Basic
Research Program of China (2015CB856303)
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