Copper-Catalyzed Oxidative Coupling of β-Keto Esters with N-Methylamides for the Synthesis of Symmetrical 2,3,5,6-Tetrasubstituted Pyridines

Article abstract of DOI:10.1021/acs.joc.7b01516

A copper-catalyzed oxidative formal [2+2+1+1] cycloaddition for the synthesis of symmetrical tetrasubstituted pyridines was first demonstrated. The reaction is involved in a domino cross-dehydrogenative coupling (CDC) of β-keto esters and N-methylamides, the C-N bond cleavage, the Michael addition, and a condensation and oxidative aromatization process. Multiple C-C and C-N bonds were constructed in one pot via the C-H and C-N cleavage of N-methylamides, which were employed as the carbon source of pyridines. The preliminary mechanistic studies revealed that the C(sp³)-H bond cleavage of N-methylamides was the rate-determining step.

Full text of DOI:10.1021/acs.joc.7b01516

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Article
Copper-Catalyzed Oxidative Coupling of #-Keto Esters with N-Methylamides
for the Synthesis of Symmetrical 2,3,5,6-Tetrasubstituted Pyridines
Yizhe Yan, Hongyi Li, Zheng Li, Bin Niu, Miaomiao Shi, and Yanqi Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01516 • Publication Date (Web): 25 Jul 2017
Downloaded from http://pubs.acs.org on July 25, 2017
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CopperꢀCatalyzed Oxidative Coupling of βꢀKeto Esters with
NꢀMethylamides for the Synthesis of Symmetrical
2,3,5,6ꢀTetrasubstituted Pyridines
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Yizhe Yana,b*, Hongyi Lia, Zheng Lia, Bin Niub, Miaomiao Shia and Yanqi Liua,b*
a. School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou, 450000, P. R.
China.
b. Collaborative Innovation Centre for Food Production and Safety, Henan Province, Zhengzhou, 450000, P. R.
China
Eꢀmail: yanyizhe@mail.ustc.edu.cn, liuyanqi@zzuli.edu.cn
ABSTRACT： A copperꢀcatalyzed oxidative formal [2+2+1+1] cycloaddition for the synthesis of
symmetrical tetrasubstituted pyridines was first demonstrated. The reaction is involved in a
domino CDC of βꢀketo esters and Nꢀmethylamides, CꢀN cleavage, Michael addition,
condensation and oxidative aromatization process. Multiple CꢀC and CꢀN bonds were
constructed in one pot via CꢀH and CꢀN cleavage of Nꢀmethylamides, which was employed as
carbon source of pyridines. The preliminary mechanistic studies revealed that C(sp3)ꢀH bond
cleavage of Nꢀmethylamides was the rateꢀdetermining step.
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INTRODUCTION
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Pyridines represent an important and valuable class of nitrogenꢀcontaining heterocycles in
natural products, functional materials and medicinal chemistry.1 In particular, a variety of
symmetrical multisubstituted pyridines have been employed as fungicide and herbicide
because of good biological activity (Figure 1).2 Furthermore, it was also an useful ligand in
metalꢀcatalyzed organic reactions and its hydrogenated product could be used as reducing
reagents.3 Over the past decades, symmetrical tetrasubstituted pyridines were mainly
synthesized via condensation and aromatization of 1,3ꢀdicarbonyl compounds, formaldehyde
(such as formaldehyde, isobutyraldehyde 2ꢀphenylacetaldehyde and 2ꢀphenylacetaldehyde)
and ammonium salt in two steps or in one pot (Scheme 1a).4 However, substrate scope of
reaction were narrow with only akyl group as Cꢀ2 substitution group of pyridines. In 2014,
Guan’s group reported a novel and efficient rutheniumꢀcatalyzed cyclization of ketoxime
acetates with DMF for the synthesis of symmetrical 2,3,5,6ꢀtetrasubstituted pyridines (Scheme
1b).5 In this paper, Nꢀmethyl group of DMF was employed as Cꢀ4 source of pyridine ring.
However, this method required preꢀsynthesized substrates and expensive transition metal with
only aryl group as Cꢀ2 substitution group of pyridine products. Recently, Wu’s group also
reported an efficient synthesis of symmetrical 2,3,5,6ꢀtetrasubstituted pyridines via C(sp3)–H
oxidation and C–S cleavage of DMSO (Scheme 1c).6a In this reaction, Sꢀmethyl group of
DMSO provided Cꢀ4 source of pyridine ring. Unfortunately, stoichiometric copper salts and
iodine were added to promote this process. In addition, Cꢀ2 substituted group on pyridine ring
remained limited to aryl group. At the same time, Yuan’s group aslo reported a similar
reaction with DMSO as Cꢀ4 source of pyridine ring promoted by NH4I.6b Therefore, the
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development of a simple and general protocol for symmetrical tetrasubstituted pyridines using
novel Cꢀ4 source remains highly desirable.
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Figure 1. Selected Examples of Symmetrical Multisubstituted Pyridines with Biological
Activity
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Scheme 1. Strategies for the Construction of Symmetrical 2,3,5,6ꢀTetrasubstituted
Pyridines
In recent years, transitionꢀmetalꢀcatalyzed or metalꢀfree cross dehydrogenative coupling
(CDC) has emerged as an important tool for direct construction of CꢀC bond.7 In particular,
intermolecular CDC reaction between αꢀC(sp3)ꢀH bond of 1,3ꢀdicarbonyl compounds and
activated C(sp3)ꢀH bond adjacent to heteroatom could give a αꢀfunctionalized product of
1,3ꢀdicarbonyl compounds.8 However, to the best of our knowledge, CDC reaction between
1,3ꢀdicarbonyl compounds and activated CꢀH bond for the synthesis of heterocycles has not
been reported to date.
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As our continuous efforts for heterocycles using novel carbon or nitrogen synthons,9 herein
we report a copperꢀcatalyzed oxidative formal [2+2+1+1] cycloaddition for the synthesis of
symmetrical tetrasubstituted pyridines (Scheme 1d). The reaction is involved in a domino
CDC of βꢀketo esters with Nꢀmethylamides, CꢀN cleavage, Michael addition, condensation
and oxidation process. Four chemical bonds are formed via CꢀH and CꢀN cleavage in one pot.
The extra nitrogen and carbon atom of pyridines originate from ammonium acetate and
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Nꢀmethyl group of Nꢀmethylamides, respectively.
A
series of symmetrical
2,3,5,6ꢀtetrasubstituted pyridines were obtained in moderate to excellent yields with good
functional group compatibility.
RESULTS AND DISCUSSION
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
N source
oxidant
solvent
yield(%)b
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Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(TFA)2
Cu(OTf)2
CuBr2
CuCl2
CuCl
CuI
CuBr
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
TBHP
DTBP
TBPB
DCP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMA
DEA
DMA
DMA
DMA
DMA
DMA
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13
trace
trace
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20
15
20
24
31
34
37
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
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n.d.
n.d.
11
NH4Cl
NH3(aq)
NH4I
trace
12
NH4OAc
56c, 25d
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Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
TBHP
TBHP
TBHP
TBHP
TBHP
DMA
DMA
DMA
DMA
DMA
45e, 40f
22
64g, 67h, 44i, 35j
23k
24l
25m
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82
68
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a
Reaction conditions: 1a (0.4 mmol), catalyst (10 mol%), oxidant (2 equiv.), N source (1
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c
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equiv.), solvent (1 mL), 120 °C, 24 h, in air. b Isolated yield; n.d.= not detected. 130 °C.
140 °C. 110 °C. f 100 °C. g DMA (0.5 mL). DMA (0.8 mL). i DMA (1.5 mL). DMA (2
e
h
j
mL). k TBHP (4 equiv.). NH4OAc (2 equiv.).m NH4OAc (1 equiv.) and HOAc (1 equiv.).
l
Initially, we began our study with the reaction of one equivalent of methyl acetoacetate
(1a), one equivalent of NH4OAc, two equivalents of tertꢀbutyl hydroperoxide (TBHP, 70% in
aqueous) as the oxidant and 10 mol% of Cu(OAc)2 as the catalyst. When the reaction mixture
was heated in Nꢀmethyl pyrrolidone (NMP) at 120 °C for 24 h, dimethyl
2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2a) was obtained in 14% isolated yield (Table 1,
entry 1). Among the examination of various perꢀoxidants, such as diꢀtertꢀbutylperoxide
(DTBP), tertꢀbutyl peroxybenzoate (TBPB) and dicumyl peroxide (DCP), DTBP afforded 2a
in a similar yield to TBHP while TBPB and DCP gave trace amount of 2a (Table 1, entries
2ꢀ4). When various copper salts, such as Cu(TFA)2, Cu(OTf)2, CuBr2, CuCl2, CuCl, CuBr,
CuI and Cu2O, were used as the catalyst, Cu2O gave a highest yield of 34% (Table 1, entries
5–12). To examine the source of Cꢀ4 atom, various solvents were tested in the reaction. The
use of solvents N,Nꢀdimethylformamide (DMF) and N,Nꢀdimethylacetamide (DMA) gave the
desired product 2a, while DMA gave a highest 78% yield (Table 1, entries 13 and 14).
However, N,Nꢀdiethylacetamide (DEA) didn’t give the desired product (Table 1, entry 15).
These results implied that Cꢀ4 atom of 2a was presumedly originated from the N,Nꢀdimethyl
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moiety of solvents. In the absence of NH4OAc, no desired 2a was detected, which indicated
that NH4OAc provided the N source of pyridine ring (Table 1, entry 16). When various
nitrogen sources, such as NH4Cl, NH3 (aq) and NH4I, were examined, a negative influence on
reaction yields was obviouly observed (Table 1, entries 17ꢀ19). In addition, when the reaction
temperature was increased from 120 °C to 130 °C or 140 °C, the reaction yields obviously
decreased perhaps due to the generation of more byꢀproducts. (Table 1, entry 20). When the
reaction temperature was decreased from 120 °C to 110 °C or 100 °C, the reaction yields were
also decreased, which is because of low reactivity in lower temperature (Table 1, entry 21).
Moreover, the reaction concentration had a significant effect on reaction yields as well (Table
1, entry 22). High concentration might result in much byꢀproducts while low concentration
resulted in the reducing of reactivity. Increasing the amount of TBHP to four equivalents also
decreased the reaction yield because of further oxidation of the product 2a (Table 1, entry 23).
When two equivalents of NH4OAc was used, 2a was isolated in 82% yield (Table 1, entry 24).
Finally, when one equivalent of HOAc and one equivalent of NH4OAc were employed
together, the reaction yield decreased to 68% (Table 1, entry 25). Therefore, the optimal
conditions were established as described in entry 24.
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Table 2. The Substrate Scope of βꢀKeto Estersa
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a
Reaction conditions: 1 (0.4 mmol), Cu2O (10 mol%), TBHP (2 equiv.), NH4OAc (2 equiv.), DMA (1
mL), 120 °C, 24 h, in air; isolated yield. b 10 mmol scale.
Under the optimal reaction conditions, we explored the generality of these reaction
conditions for various βꢀketo esters (Table 2). First, various acetoacetate esters (1aꢀ1g) were
employed in this reaction, giving the desired products 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate
esters (2aꢀ2g) in moderate to good yields. For example, when R1 were primary, secondary and
tertiary alkyl groups, such as methyl, ethyl, isobutyl, tertꢀbutyl and isopropyl, the
corresponding pyridines 2aꢀ2e were obtained in good yields. Notably, the yields slightly
decreased with the increase of carbon chain length (Table 2, 2aꢀ2c). Moreover, tertiary
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alkylꢀsubstitued substrate gave a higher yield than primary or secondary alkylꢀ substitued
substrate. When R1 was a benzyl group, the product 2f was obtained in a moderate 55% yield.
Similarly, substrate 1g with an allyl group as R1 substituent also gave the desired product 2g
in 53% yield. Subsequently, various substrates bearing alkyl groups as R2 substituent were
also examined in this reaction. The reaction of substrates 1hꢀ1k afforded the desired products
2hꢀ2k in high yields. However, when R2 was a isobutyl group, the product 2k was obtained in
lower yield. Unfortunately, the reaction didn’t proceed smoothly with tertꢀbutyl as R2
substituent perhaps due to steric hindrance. It is noted that 2m having two CF3 groups at Cꢀ2
and Cꢀ6 position was isolated with a low 41% yield when ethyl 4,4,4ꢀtrifluoroꢀ3ꢀoxobutanoate
(1m) was employed as a substrate. In addition, ethyl benzoylacetates 1nꢀ1p also gave the
corresponding products 2nꢀ2p in 42%ꢀ45% yields. To investigate the practicability of this
method, a synthesis of 2a could be scalable from 0.4 mmol to 10 mmol with a 80% yield,
which indicated that this method could be widely applied during organic synthesis.
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To gain an insight into the mechanism, several control experiments were carried out
(Scheme 2). First, two possible intermediates dimethyl 2,4ꢀdiacetylpentanedioate (3) and
dimethyl 2,6ꢀdimethylꢀ1,4ꢀdihydropyridineꢀ3,5ꢀdicarboxylate (4) were preꢀsynthesized
according to known literatures.4d,10 Then the reaction of 3 or 4 under standard conditions gave
2a in 85% or 92% yield, respectively (Scheme 2a). This indicated that both 3 and 4 might be
the reaction intermediates. Subsequently, radical trapping experiments were also carried out
(Scheme 2b). It was observed that the reaction was obviously inhibited in the presence of one
equivalent of radical inhibitors, such as 2,2,6,6ꢀ tetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT). This implied that the reaction presumably underwent
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a radical pathway.
Scheme 2. Control Experiments for Mechanistic Studies
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Scheme 3. KIE and DꢀLabeling Experiment
On the other hand, a large intermolecular kinetics isotope effect (KIE, kH/kD = 3.3) was
observed from DMF and d7ꢀDMF (1:1) as coꢀsolvents, which indicated that the CꢀH cleavage
was a rateꢀdetermining step (Scheme 3a).11 Moreover, 32% yield of dꢀ2a was obtained in
Dꢀlabeling experiment under standard conditions, which unambiguously established that the
Cꢀ4 framework of pyridine was derived from Nꢀmethylamides (Scheme 3b). Notably, trace
amount of 2a remained obtained because hydrogen transfer probably occurs during the
reaction.
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Scheme 4. A Plausible Mechanism
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On the basis of the results above and previous reports,7,8,9a a plausible mechanism was
proposed (Scheme 4). Initially, the decomposition of tertꢀbutyl hydroperoxide generates a
tertꢀbutoxy radical and a hydroxyl anion in the presence of Cu(I), which is oxidized to Cu(II).
Then the tertꢀbutoxy radical abstracts a hydrogen atom of C(sp3)ꢀH bond adjacent to nitrogen
atom of Nꢀmethylamides to give a carbon radical A, which could generate an imine ion B via
a singleꢀelectronꢀtransfer (SET) process in the presence of Cu(II).9a,12 Subsequently, the
nucleophilic addition of 1a to B produces an amide intermediate C. A sequential CꢀN
cleavage of C can generate α,βꢀunsaturated ketone D (Scheme 4, path a). Then a Michael
addition of 1a to D provided an intermediate 3. However, 3 could also be formed directly via a
simple SN2 substitution of 1a to C (Scheme 4, path b). Finally, 3 could be converted to 2a
through tandem condensation and oxidative aromatization process.13 Overall, the Cu(I)ꢀCu(II)
redox process plays an important role in CꢀC bond construction of pyridine ring.
CONCLUSION
In summary, we have developed a copperꢀcatalyzed oxidative coupling of βꢀketo esters
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and Nꢀmethylamides, affording a variety of symmetrical tetrasubstituted pyridines in the
presence of ammonium acetate. Compared to previous reports, this novel protocol is
distinguished by 1) the use of inexpensive transition metal; 2) operational simplicity; 3) the
fact that an inert atmosphere or dry solvents are not required; 4) good functional groups
tolerance. Copperꢀcatalyzed oxidative coupling reactions for the synthesis of other
heterocycles using Nꢀmethylamides as carbon source are ongoing in our laboratory.
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EXPERIMENTAL SECTION
Unless otherwise indicated, all commercial reagents and solvents were used without additional
1
purification. HꢀNMR spectra were recorded with a Bruker AVIIIꢀ600 spectrometer. Chemical
shifts (in ppm) were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard.
13CꢀNMR spectra were obtained by the same NMR spectrometer and were calibrated with CDCl3
(δ = 77.00 ppm). HRMS (ESI) were recorded on a WaterTM QꢀTOF Premier Mass Spectrometer.
Melting point was recorded on a Hanon MP430 Auto Melting Point System.
General Procedure for the Synthesis of Symmetrical 2,3,5,6ꢀTetrasubstituted Pyridines
βꢀketo esters 1 (0.4 mmol), Cu2O (10 mol%, 0.04 mmol), NH4OAc (2 equiv., 0.8 mmol) and
TBHP (2 equiv., 0.8 mmol) were added to a 10 mL Schlenk tube, followed by addition of DMA
(1.0 mL). The mixture was stirred was stirred at 120 °C for 24 h. The solution was then cooled to
r.t., quenched by a Na2SO3 aqueous solution and extracted with EtOAc (3×10 mL). The combined
organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was
purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 6:1) to afford
the desired products 2.
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Characterization Data for Products
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dimethyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2a)4d: Yield (82%, 36.5mg); White solid;
mp:100ꢀ101°C; 1H NMR (600 MHz, CDCl3): δ 8.71 (s, 1H), 3.93 (s, 6H), 2.86 (s, 6H); 13C NMR
(150 MHz, CDCl3): δ 166.2, 162.6, 141.0, 122.6, 52.3, 24.9; GCꢀMS (EI): m/z 223.1, 208.1, 195.1,
178.1, 151.1, 106.1, 77.0, 63.0; IR (film, cmꢀ1): ν 1725, 1548, 1286, 1105; UV (nm): λmax 209.
diethyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2b)4d: Yield (79%, 39.6mg); Yellowish solid;
mp: 67ꢀ68 °C; 1H NMR (600 MHz, CDCl3): δ 8.68 (s, 1H), 4.40 (q, J = 7.2 Hz, 4H), 2.85 (s, 6H),
1.42 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 165.9, 162.2, 140.9, 123.0, 61.4, 24.9,
14.2; GCꢀMS (EI): m/z 251.1, 236.1, 223.1, 206.1, 195.1, 178.1, 151.1, 106.1, 77.0, 63.0; IR (film,
cmꢀ1): ν 2978, 2928, 1719, 1591, 1223, 773; UV (nm): λmax 205, 207, 360.
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diisobutyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2c): Yield (72%, 44.2mg); Yellow oil; H
NMR (600 MHz, CDCl3): δ 8.74 (s, 1H), 4.12 (d, J = 6.0 Hz, 4H), 2.87 (s, 6H), 2.10 (m, J = 6.6
Hz, 2H), 1.04 (d, J = 7.2 Hz, 12H); 13C NMR (150 MHz, CDCl3): δ 165.8, 162.3, 141.0, 122.9,
71.4, 27.7, 25.0, 19.2; HRMS (ESI): calcd for C17H26NO4 [M+H]+ 308.1856, found 308.1861; IR
(film, cmꢀ1): ν 2978, 2934, 1718, 1594, 1224, 774; UV (nm): λmax 208.
diisopropyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2d)4d: Yield (70%, 39.1mg); Yellowish
solid; mp: 64ꢀ65 °C; 1H NMR (600 MHz, CDCl3): δ 8.62 (s, 1H), 5.27 (hept, J = 6.3 Hz, 2H), 2.84
(s, 6H), 1.39 (d, J = 6.3 Hz, 12H); 13C NMR (150 MHz, CDCl3): δ 165.6, 161.7, 140.8, 123.5,
69.1, 24.9, 21.9; GCꢀMS (EI): m/z 279.1, 237.1, 220.1, 195.1, 178.1, 151.1, 133.0, 105.0, 77.0,
63.0, 43.1; IR (film, cmꢀ1): ν 2987, 2938 1715, 1224, 1107, 777; UV (nm): λmax 360,
366.diꢀtertꢀbutyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2e)4d: Yield (86%, 52.8mg); Yellow
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solid; mp: 107ꢀ108 °C; H NMR (600 MHz, CDCl3): δ 8.53 (s, 1H), 2.81 (s, 6H), 1.61 (s, 18H);
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13C NMR (150 MHz, CDCl3): δ 165.4, 161.1, 140.7, 124.6, 82.0, 28.1, 25.0; LCꢀMS (ESI):
[M+H]+ 308.2; IR (film, cmꢀ1): ν 2978 2934 1710, 1596, 1266, 1158, 847, 777; UV (nm): λmax 201,
360.
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dibenzyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2f)4d: Yield (55%, 41.2mg); White solid; mp:
83ꢀ84 °C; 1H NMR (600 MHz, CDCl3): δ 8.75 (s, 1H), 7.44ꢀ7.41 (m, 4H), 7.40ꢀ7.35 (m, 6H), 5.35
(s, 4H), 2.85 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 165.6, 162.6, 141.2, 135.5, 128.7, 128.4,
128.3, 122.7, 67.1, 25.0; LCꢀMS (ESI): [M+H]+ 376.1; IR (film, cmꢀ1): ν 2966, 2946, 1726, 1594,
1297, 1218, 733; UV (nm): λmax 209.
diallyl 2,6ꢀdimethylpyridineꢀ3,5ꢀdicarboxylate (2g)4d: Yield (53%, 29.2mg); Yellow solid; mp:
60ꢀ61 °C; 1H NMR (600 MHz, CDCl3): δ 8.75 (s, 1H), 6.09ꢀ6.01 (m, 2H), 5.42 (dq, J1 = 17.2 Hz,
J2 = 1.4 Hz, 2H), 5.32 (dq, J1 = 10.4 Hz, J2 = 1.3 Hz, 2H), 4.84 (dt, J1 = 5.7 Hz, J2 = 1.3 Hz, 4H),
2.86 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 165.4, 162.6, 141.1, 131.8, 122.7, 118.9, 66.0, 25.0;
GCꢀMS (EI): m/z 275.1, 260.1, 234.1, 191.1, 178.1, 133.1, 105.1, 63.0, 41.1; IR (film, cmꢀ1): ν
2961, 2926, 1720, 1594, 1222, 771; UV (nm): λmax 204, 360, 365.
diethyl 2,6ꢀdiethylpyridineꢀ3,5ꢀdicarboxylate (2h)4d: Yield (88%, 49.2mg); Light yellow oil; 1H
NMR (600 MHz, CDCl3): δ 8.61 (s, 1H), 4.40 (q, J = 7.1 Hz, 4H), 3.20 (q, J = 7.5 Hz, 4H), 1.41 (t,
J = 7.1 Hz, 6H), 1.31 (t, J = 7.5 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 166.8, 166.0, 141.1,
122.6, 61.4, 30.4, 14.2, 13.8; GCꢀMS (EI): m/z 279.1, 264.1, 250.1, 223.1, 179.1, 134.1, 77.0,
63.0; IR (film, cmꢀ1): ν 2978, 2926, 1725, 1593, 1236, 810; UV (nm): λmax 202.
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diethyl 2,6ꢀdipropylpyridineꢀ3,5ꢀdicarboxylate (2i): Yield (84%, 51.6mg); Light yellow oil; H
NMR (600 MHz, CDCl3): δ 8.61 (s, 1H), 4.40 (q, J = 7.2 Hz, 4H), 3.15 (t, J = 7.8 Hz, 4H),
1.78ꢀ1.70 (m, 4H), 1.41 (t, J = 7.2 Hz, 6H), 1.00 (t, J = 7.4 Hz, 6H); 13C NMR (150 MHz, CDCl3):
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δ 166.2, 165.5, 141.1, 122.8, 61.3, 38.9, 23.2, 14.2, 14.1; HRMS (ESI): calcd for C17H26NO4
[M+H]+ 308.1856, found 308.1857; IR (film, cmꢀ1): ν 2964, 2929, 1724, 1594, 1288, 1232, 1108;
UV (nm): λmax 360.
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dimethyl 2,6ꢀdipropylpyridineꢀ3,5ꢀdicarboxylate (2j): Yield (99%, 55.3mg); Light yellow oil;
1H NMR (600 MHz, CDCl3): δ 8.64 (s, 1H), 3.92 (s, 6H), 3.16 (t, J = 7.8 Hz, 4H), 1.78ꢀ1.70 (m,
4H), 1.00 (t, J = 7.4 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 166.3, 166.0, 141.2, 122.3, 52.2,
38.8, 23.1, 14.1; HRMS (ESI): calcd for C15H22NO4 [M+H]+ 280.1543, found 280.1545; IR (film,
cmꢀ1): ν 2959, 2923, 2853, 1727, 1240, 1114, 740; UV (nm): λmax 213, 360.
diethyl 2,6ꢀdiisopropylpyridineꢀ3,5ꢀdicarboxylate (2k): Yield (58%, 35.6mg); Light yellow oil;
1H NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 4.38 (q, J = 7.2 Hz, 4H), 3.87 (t, J = 6.6 Hz, 2H),
1.40 (t, J = 7.2 Hz, 6H), 1.29 (d, J = 6.6 Hz, 12H); 13C NMR (150 MHz, CDCl3): δ 166.3, 166.6,
140.1, 121.9, 61.3, 32.8, 22.1, 14.2; HRMS (ESI): calcd for C17H26NO4 [M+H]+ 308.1856, found
308.1860. IR (film, cmꢀ1): ν 2965, 2925, 2853, 1722, 1594, 1242, 1094, 802, 741; UV (nm): λmax
202, 360.
diethyl 2,6ꢀbis(trifluoromethyl)pyridineꢀ3,5ꢀdicarboxylate (2m): Yield (41%, 29.4mg); Light
yellow oil; 1H NMR (600 MHz, CDCl3): δ 8.51 (s, 1H), 4.48 (q, J = 7.2 Hz, 4H), 1.42 (t, J = 7.2
Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 163.5, 146.1 (q, J = 37.1 Hz), 141.2, 122.9 (q, J = 7.2
Hz), 120.0 (q, J = 274.4 Hz), 63.4, 13.8; HRMS (ESI): calcd for C13H12F6NO4 [M+H]+ 360.0665,
found 360.0669. IR (film, cmꢀ1): ν 2990, 1743, 1269, 1154, 1096, 861, 809; UV (nm): λmax 209,
358.
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diethyl 2,6ꢀdiphenylpyridineꢀ3,5ꢀdicarboxylate (2n)6: Yield (45%, 33.7mg); Colorless oil; H
NMR (600 MHz, CDCl3): δ 8.54 (s, 1H), 7.65ꢀ7.61 (m, 4H), 7.46ꢀ7.42 (m, 6H), 4.21 (q, J = 7.2
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Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 167.4, 159.8, 140.3, 139.4,
129.2, 128.9, 128.1, 124.8, 61.7, 13.7; LCꢀMS (ESI): [M+H]+ 376.1; IR (film, cmꢀ1): ν 2923, 1724,
1591, 1247, 699; UV (nm): λmax 209, 360.
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diethyl 2,6ꢀbis(3,4ꢀdimethoxyphenyl)pyridineꢀ3,5ꢀdicarboxylate (2o): Yield (42%, 41.6mg);
Colorless oil; 1H NMR (600 MHz, CDCl3): δ 8.45 (s, 1H), 7.30 (d, J = 1.8 Hz, 2H), 7.20 (dd, J1 =
8.3 Hz, J2 = 2.0 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 4.24 (d, J = 7.2 Hz, 4H), 3.94 (s, 6H), 3.92 (s,
6H), 1.17 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 167.9, 158.7, 150.2, 148.7, 140.2,
131.9, 123.9, 122.1, 112.1, 110.5, 61.6, 55.9, 13.9; HRMS (ESI): calcd for C27H30NO8 [M+H]+
496.1966, found 496.1974. IR (film, cmꢀ1): ν 2921, 2850, 1721, 1541, 1247, 1025, 736; UV (nm):
λmax 209.
diethyl 2,6ꢀbis(3ꢀfluorophenyl)pyridineꢀ3,5ꢀdicarboxylate (2p): Yield (44%, 36.2mg);
Colorless oil; 1H NMR (600 MHz, CDCl3): δ 8.57 (s, 1H), 7.43ꢀ7.35 (m, 6H), 7.18ꢀ7.14 (m, 2H),
4.21 (q, J = 7.2 Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 166.8, 162.5 (d,
J = 244.9 Hz), 158.4 (d, J = 2.0 Hz), 141.2 (d, J = 7.9 Hz), 140.6, 129.6 (d, J = 8.3 Hz), 125.4,
124.7 (d, J = 2.7 Hz), 116.2 (d, J = 20.9 Hz), 116.0 (d, J = 22.9 Hz), 61.9, 13.7; HRMS (ESI):
calcd for C23H20F2NO4 [M+H]+ 412.1355, found 412.1358. IR (film, cmꢀ1): ν 2923, 2853, 1726,
1584, 1251, 1106, 739; UV (nm): λmax 203, 209, 360.
Kinetics Isotope Effect (KIE)
methyl acetoacetate 1a (0.4 mmol), Cu2O (10 mol%, 0.04 mmol), NH4OAc (2 equiv., 0.8 mmol)
and TBHP (2 equiv., 0.8 mmol) were added to a 10 mL Schlenk tube, followed by addition of
DMF (0.5 mL) and d7ꢀDMF (0.5 mL). The mixture was stirred was stirred at 120 °C for 12 h. The
solution was then cooled to r.t., quenched by a Na2SO3 aqueous solution and extracted with EtOAc
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(3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under
vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl
acetate = 6:1) to afford the mixture of 2a and dꢀ2a. The 1H NMR analysis showed that the ratio of
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2a to dꢀ2a was 3.3:1 when compared with the standard H NMR spectrum of 2a, in which the
integration of the peak at 9.39 ppm was 0.77 instead of 1.00.
DꢀLabeled Experiment
methyl acetoacetate 1a (0.4 mmol), Cu2O (10 mol%, 0.04 mmol), NH4OAc (2 equiv., 0.8 mmol)
and TBHP (2 equiv., 0.8 mmol) were added to a 10 mL Schlenk tube, followed by addition of
d7ꢀDMF (0.5 mL). The mixture was stirred was stirred at 120 C for 24 h. The solution was then
°
cooled to r.t., quenched by a Na2SO3 aqueous solution and extracted with EtOAc (3×10 mL). The
combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The
residue was purified by column chromatography on silica gel (petroleum ether : ethyl acetate = 6:1)
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to afford dꢀ2a. dꢀ2a (92% deuterated): Yield (32%, 14.3mg); White solid; mp:100ꢀ101°C; H
NMR (600 MHz, CDCl3): δ 8.73 (s, 0.08H), 3.94 (s, 6H), 2.87 (s, 6H); 13C NMR (150 MHz,
CDCl3): δ 171.1, 166.1, 162.6, 122.6, 52.3, 24.8.
ASSOCIATED CONTENT
Supporting Information Available. H and 13C NMR spectra. This material is available free of
1
charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (21502177), the Science
and Technology Research Key Project of the Department of Education of Henan Province
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(15A150005), the Doctoral Research Foundation of Zhengzhou University of Light Industry
(2014BSJJ032) and Grants Program of Youth Backbone Teachers Training Object of
Zhengzhou University of Light Industry.
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Rev. 2011, 111, 1780. (d) Girard, S. A.; Knauber, T.; Li, C.ꢀJ. Angew. Chem., Int. Ed. 2014, 53,
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G.; Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 10429. (e) Li, Z.; Li, H.; Guo, X.;
Cao, L.; Yu, R.; Li, H.; Pan, S. Org. Lett. 2008, 10, 803. (f) Richter, H.; Rohlmann, R.;
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Yan, Y.; Xu, Y.; Niu, B.; Xie, H.; Liu, Y. J. Org. Chem.; 2015, 80, 5581. (c) Yan, Y.; Niu, B.;
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11 A similar kinetics isotope effect of DMF and d7ꢀDMF was also reported in our previous report
(see reference 9a for details).
12 (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272. (b) Kim, J.; Choi, J.; Shin, K.;
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133, 12374.
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S.ꢀB.; Wang, J.; Chen, Y.; Li, J.ꢀH. J. Chem. Res. 2013, 37, 409. (b) Miyamura, H.; Maehata,
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K.; Kobayashi, S. Chem. Commun. 2010, 46, 8052. (c) Bai, C.ꢀB.; Wang, N.ꢀX.; Wang, Y.ꢀJ.;
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