Specific N-Alkylation of Hydroxypyridines Achieved by a Catalyst- and Base-Free Reaction with Organohalides

Article abstract of DOI:10.1021/acs.joc.8b00787

A specific N-alkylation of 2-hydroxypyridines is achieved by reacting with organohalides under catalyst- and base-free conditions. The observed HX-facilitated conversion of pyridyl ether intermediates to 2-pyridone products may account for the success and

Full text of DOI:10.1021/acs.joc.8b00787

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Note
Specific N-Alkylation of Hydroxypyridines Achieved by
a Catalyst- and Base-Free Reaction with Organohalides
Bin Feng, Yang Li, Huan Li, Xu Zhang, Huamei Xie, Hongen Cao, Lei Yu, and Qing Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00787 • Publication Date (Web): 16 May 2018
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Specific N-Alkylation of Hydroxypyridines Achieved by a Catalyst- and
Base-Free Reaction with Organohalides
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Bin Feng,† Yang Li,† Huan Li,† Xu Zhang,‡ Huamei Xie,† Hongen Cao,‡ Lei Yu,‡ and Qing
Xu†,‡,*
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†
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang
325035, P. R. China
‡
Institute of Pesticide of School of Chemistry and Chemical Engineering and School of
Horticulture and Plant Protection, Yangzhou University, Yangzhou, Jiangsu 225002, P. R. China
Abstract: A specific N-alkylation of 2-hydroxypyridines is achieved by reacting with
organohalides under catalyst- and base-free conditions. The observed HX-facilitated conversion
of pyridyl ether intermediates to 2-pyridone products may account for the success and specific
N-alkylation of the reaction under the unexpectedly simple conditions. This new reaction may
provide a useful alternative for the synthesis of 2-pyridones and analogous structures due to its
>99% N-selectivity, relatively broad scopes of both substrates, and no mandatory use of catalysts
and bases.
N-Substituted 2-pyridones and analogous pyridone structures not only present frequently in
biologically and pharmacologically active molecules1 as well as natural products having potent
antitumor and antivirus activities,2 they are also versatile reagents in synthesis3 such as in
Diels-Alder reactions4 and material sciences.5 Therefore, much attention has been focused on the
synthesis of N-substituted pyridones over the past decades. Conventionally, N-alkyl 2-pyridones
have been prepared by reacting 2-hydroxypyridines with alkyl halides under basic conditions
(Scheme 1A).6 The use of a base is required in these methods, but this can generate inorganic
salts as waste. Meanwhile, formation of the competing O-alkylated byproducts is also inevitable
due to the inherent ambident nature of the intermediate anions derived from the
2-hydroxypyridine and 2-pyridone tautomers (Scheme 1A).7 In some cases, O-alkylation can
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even become the dominant reaction.6e Therefore, N-selectivity is always an issue to be addressed.
Hence, various modified methods were developed to enhance the selectivity of the target
N-alkylation reaction. For example, CsF,8 LiBr,9 NaI,10 and TBAX (tetrabutylammonium
halides)11 were reported as effective additives. Alternative reaction conditions like ionic liquid12
and microwave irradiation,13 and the Mitsunobu method14 were also reported. Moreover,
mechanistic aspects of the reaction were also investigated to understand the nature of N- and
O-alkylation reactions.15 More recently, Ren and co-workers reported that Tween 20 (2% w/w)
could also be used as an effective additive to improve the N-selectivity of the conventional basic
reaction.16 Even though, generation of the O-alkylated byproducts could not be avoided
completely by these modifications.
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Scheme 1. Methods for N-Substituted 2-Pyridone Synthesis.
On the other hand, since 2-pyridyl ethers can be obtained by basic reaction of
2-halopyridines with alcohols,17,18 intramolecular O to N migratory rearrangement reactions of
2-pyridyl ethers have also been developed recently to achieve N-substituted 2-pyridones and
analogous pyridone structures (Scheme 1B).18-21 For example, the Anderson group developed a
transition-metal-free LiI-mediated method;18 Dong and co-workers disclosed the first efficient
catalytic migration reaction using Ru catalyst;19 Shibata and co-workers reported an Ir-catalyzed
rearrangement method for 2-pyridyl ethers bearing secondary O-alkyl groups.20 Other transition
metal catalysts such as Pt, Ag, Au, and Pd were also found to be active catalysts for similar
transformations.21 More recently, You and co-workers developed an elegant Ir-catalyzed
asymmetric allylic amination of 2-hydroxypyridines with allylic methyl carbonates for
enantioselective synthesis of N-substituted 2-pyridones.22 Although these methods generally
gave high selectivities of the N-substituted 2-pyridones, these reactions are in effect two-step
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procedures because the 2-pyridyl ether substrates have to be prepared first.17,18 Additionally,
these methods are limited by high loadings of the additives and the use of expensive noble metal
catalysts. Therefore, an efficient, practical, and highly N-selective one-step transition metal-free
method is still highly desirable in the field. Recently, a few transition-metal-catalyzed additions
of hydroxypyridines to unsaturated compounds have been developed to address some of the
above issues.23 Herein we report another advance in the research, that is, the anticipated specific
N-alkylation reaction of 2-hydroxypyridines can be achieved by reacting 2-hydroxypyridines
with organohalides under catalyst- and base-free conditions (Scheme 1C). In comparison with
the known methods, this new reaction may provide a useful alternative for the synthesis of
2-pyridones and analogous structures due to its >99% N-selectivity, the relatively broad scopes
of both the hydroxyheterocycle and organohalide substrates, and no mandatory use of bases.
We serendipitously encountered this new reaction during our ongoing studies on N-, C-, O-,
and S-alkylation reactions24 and the need to obtain pyridyl ethers.17d As shown in Table 1,
initially, 2-hydroxypyridine 1a and PhCH2Br (2a-Br) were directly heated under the air
atmosphere without solvent and base (entry 1). Under these conditions we originally reasoned
that no reaction would occur. To our surprise, the reaction afforded a considerable yield of a new
product, which was later determined to be N-benzyl 2-pyridone 3a. Realizing that a selective
N-alkylation reaction might have occurred with possible formation of the O-alkylated ether
4a,6,8-16 we repeated the reaction to determine the N/O selectivity. To our surprise again, 4a could
not be observed at all by TLC and GC-MS analysis (entry 1, 3a/4a >99/1, 3a and 4a17 can be
easily distinguished25). This result suggested that this is a specific N-alkylation reaction of
2-hydroxypyridine realized by only one step under the catalyst- and base-free conditions!
Realizing that this new finding may serve as a good alternative for synthesis of the N-substituted
2-pyridones and analogous pyridone structures,6,8-16,18-21 we further optimized the reaction
conditions.
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Table 1. Conditions Screening and Optimization.a
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entry PhCH2X (equiv.)
T
3a/4a b
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
3a%c
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1
PhCH2Br (1.2)
PhCH2Br (1.2)
PhCH2Br (1.2)
PhCH2Br (1.2)
PhCH2Br (1.0)
PhCH2Br (1.5)
PhCH2Br (2.0)
PhCH2Cl (2.0)
PhCH2Br (1.5)
PhCH2Br (1.5)
PhCH2Br (1.5)
60 oC
80 oC
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120 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
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Unless otherwise noted, the neat mixture of 2-hydroxypyridine 1a (2 mmol) and benzyl halide
2a sealed under air in a 10 mL Schlenk tube was directly heated for 24 h. b Ratios determined by
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GC-MS analysis. Yields based on 1a. 12 h. Normal solvents like toluene, EtOH, DMF,
1,4-dioxane, THF, MeOH, DCE, DCM, CH3CN (1 mL) were investigated. f Under N2.
o
As shown in Table 1, temperature screening showed that 100 C is optimal (entries 1-4).
Screening of PhCH2Br loading (entries 3, 5-7) showed that 1.5 equiv. is the best (entry 6). No
improvement of the product yield was observed even with more PhCH2Br (entry 7). Using
PhCH2Cl instead of PhCH2Br gave a decreased yield of 3a (entry 8), showing that the bromide is
more reactive than the chloride. Screening of reaction time showed that 24 h is necessary (entry
9). The effect of solvent was also investigated but only lower yields were obtained with the
normal solvents tested (entry 10). When the reaction was performed under nitrogen, a slightly
higher yield of 3a was obtained (entry 11), which suggests that this reaction is insensitive to air.
Therefore, entry 6 was chosen as the optimal conditions as the operation of the reaction can be
greatly simplified by performing the reaction under air. It should also be pointed out that no 4a
was observed in all these reactions.
The optimized conditions (Table 1, entry 6) were then extended to various organohalides to
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test the scope of this new method. As shown in Table 2, similar to PhCH2Br (entry 1), most
electron-rich and –deficient benzylic bromides including the sterically-hindered ones (entries 2
and 8) and the one with a very reactive nitro group (entry 11) could also afford the target
N-substituted 2-pyridones in good to high yields (entries 2-4, 7-11). In the reaction of
p-MeOC6H4CH2Br, the yield of the product 3e was very low, which may be attributed to the
observed instability of the bromide in the reaction (entry 5). Alternatively, when the more stable
chloride p-MeOC6H4CH2Cl was used instead, the reaction gave a much higher yield of 3e (50%)
under N2, which could be enhanced further to 70% by performing the reaction at a higher
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temperature of 120 C (entry 6). Using allyl bromide as the alkylating reagent also afforded the
N-allyl 2-pyridone 3k in an acceptable yield (entry 12). Possibly due to the more unstable and
reactive nature of the allyl bromide, the reaction was performed better at a lower temperature,
giving a higher yield of 3k (entry 12, the result in parenthesis). This is especially the case with
the reaction of cinnamyl bromide, which was even less effective under the standard conditions
(entry 13). Thus, an acceptable yield of the product was obtained at an even lower temperature of
60 oC (entry 13, the result in parenthesis).
This method could also be extended to less reactive alkyl bromides, but the yields were
generally lower (entry 14-17). Nevertheless, we found that the yields of the products could be
improved by running the reactions at a higher temperature (entry 14), using the corresponding
more reactive alkyl iodide (entry 16), or by adding TBAI (tetrabutylammonium iodide) as the
additive (entries 15-17). Similarly, the reactions of the sterically more bulky secondary alkyl
bromides were also ineffective under the standard conditions, thus requiring a higher reaction
temperature or additive TBAI to obtain moderate to high yields of the products (entries 18-20).
Due to the higher melting points of the substrates and high viscosity of the reaction mixture, the
reaction of 9-bromofluorene was better carried out by using DMF as the solvent (entry 20).
Moreover, functionalized bromides could also be used as the alkylating reagents in this specific
N-alkylation reaction. Thus, the reaction of bromoacetophenone afforded a moderate 64% yield
of the target 3s (entry 21), while the more bulky phenyl-substituted bromoacetophenone and
2-bromopentan-3-one only afforded lower yields of 3t and 3u (entries 22-23). Surprisingly, the
similarly bulky secondary bromide, ethyl 2-bromopropanoate, showed very high reactivity in the
reaction, giving a much higher yield of the product (entry 24) than the preceding secondary
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bromides (entries 22-23).
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Table 2. Scope of the Organohalides.a
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a
Unless otherwise noted, the corresponding RBr was used. See entry 6 of Table 1 for detailed
conditions. Yields based on 1a. The corresponding RCl was used instead under N2. c 120 oC. d
b
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N2, 80 C. N2, 60 C. N2, 130 C. N2, 1.0 equiv. TBAI added. The corresponding RI was
used instead under N2. i 0.5 equiv. TBAI added. j DMF (0.5 mL) added.
The scope of the hydroxyheterocycles (5) was our next concern. Substituted
2-hydroxypyridines were firstly investigated. As shown in Table 3, 2-hydroxypyridines with
electron-donating or -withdrawing groups at the 3-, 4-, 5-, 6-positions all afforded the target
products 6a-g in moderate to high yields under the standard or modified conditions (entries 1-7).
The yields of the products of 3- and 6-methyl 2-hydroxypyridines were relatively lower under
the standard conditions most possibly due to the steric hindrance derived from the adjacent
methyl groups (entries 1 and 4). Similar to the case of 9-bromofluorene (Table 2, entry 20), the
reaction of 5-nitro-2-hydroxypyridine also required the addition of DMF as the solvent, and a
high yield of the product 6g was obtained (Table 3, entry 7).
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Table 3. Scope of the Hydroxyheterocycles.a
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a Unless otherwise noted, see entry 6 of Table 1 for detailed conditions. Yields based on 5. b 48 h.
c DMF (1 mL) added. d N2, 1.0 equiv. TBAI. e 130 oC.
We then investigated 3- and 4-hydroxypyridines. In the case of 3-hydroxypyridine, no product
was observed at all; whereas, 4-hydroxypyridine could afford a high yield of the target N-benzyl
4-pyridone 6i in DMF (Table 3, entry 8). This is clearly due to the mismatched positions of the N
and OH moieties in 3-hydroxypyridine that can not fulfill the dearomatization of the
hydroxypyridine structure to the pyridone structure. In addition, other hydroxyheterocycles such
as 2-hydroxyquinoline, 3-hydroxypyridazine, and 2-hydroxy pyrimidine could also react with
benzyl bromide to give moderate to high yields of the products in the presence of TBAI (entries
9-11).
Preliminary mechanistic studies revealed that the O-alkylated pyridyl ether 4 was most likely
generated as the initial product, being the key intermediate of this specific N-alkylation reaction
(Scheme 2, step i), because 4a was observed as the major product in the reaction of 1a and 2a at
o
a lower temperature of 30 C (eq. 1). 4a could then be effectively converted into 3a in >99%
selectivity upon heating in the presence of another byproduct HX (Scheme 2, step ii), as this was
also confirmed by the reaction of 4a with the in situ generated HBr from NaBr and H3PO4 (eq. 2,
entry 1).26 In contrast, no reaction occurred at all in the absence of HBr with recovery of 87% 4a
(eq. 2, entry 2),27 revealing the key role of HBr in the conversion of pyridyl ether intermediate 4
to product 3. These interesting results (eq. 2) and complete production of 3a at higher
temperatures (Table 1) can account for why the present reaction can undergo a specific
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N-alkylation reaction to effectively afford 2-pyridone products under the unexpectedly simple
catalyst- and base-free conditions.
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Scheme 2. Possible Reaction Paths.
In conclusion, we serendipitously discovered and then developed a specific N-alkylation
method for one-step and efficient synthesis of the useful N-substituted 2-pyridones and
analogous pyridone structures, which can be easily achieved by reacting hydroxyheterocycles
with organohalides under catalyst- and base-free conditions. In comparison with known
methods, this new reaction may be a good advance in the field and a useful alternative for
the synthesis of 2-pyridones and analogous structures due to its >99% N-selectivity, the
relatively broad scopes of both the hydroxyheterocycle and organohalide substrates, and no
mandatory use of bases. Preliminary mechanistic studies revealed that byproduct HX may
work to facilitate the complete conversion of the pyridyl ether intermediates to the pyridone
products, which can well explain why no base is needed in this new method. Deeper mechanistic
studies of this interesting reaction is our next concern as it may help to further enhance the
reaction efficiency of some less reactive and bulky substrates and broaden the scope of the
substrates.
Experimental Section
General. Unless otherwise noted, the chemicals were purchased from Energy Chemical,
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Alfa Aesar, TCI, and other chemical companies and used without further purification.
2-Bromo-1,2-diphenylethan-1-one and 2-bromopentan-3-one (used in entries 22-23 in Table 2)
were prepared by the literature method.28 Unless otherwise specified, all reactions were carried
out in sealed Schlenk tubes (10 mL) under the air atmosphere and monitored by TLC and/or
GC-MS. Products were purified by column chromatography on silica gel using petroleum ether
and ethyl acetate as the eluent. 1H and 13C NMR spectra were measured on a Bruker Avance-III
500 instrument (500 MHz for 1H and 125.4 MHz for 13C NMR spectroscopy) using CDCl3 as the
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solvent. Chemical shifts for H and 13C NMR were referred to internal Me4Si (0 ppm) as the
standard. Mass spectra were measured on a Shimadzu GC-MS-QP2010 Plus spectrometer (EI).
HRMS (ESI) analysis was measured on a Bruker micrOTOF-Q II instrument. Melting points
were measured on microcomputer melting point apparatuses WRS-1C (Shanghai Shenguang)
and X-4 (Beijing Taike).
Typical Procedure for N-Alkylation of 2-Hydroxypyridines with Organohalides. To a 10
mL Schlenk tube was add 2-hydroxypyridine 1a (190 mg, 2.0 mmol) and benzyl bromide 2a-Br
(356 μL, 3.0 mmol, 1.5 equiv.) under air. The mixture was then sealed and directly heated for 24
h. The reaction was monitored by TLC and GC-MS. The reaction mixture was purified by flash
column chromatography using hexane/EtOAc (2/1) as eluent to give 1-benzylpyridin-2(1H)-one
3a (313 mg, 84%) as a white solid.
1-Benzylpyridin-2(1H)-one (3a).19 White solid (313 mg, 84%). Mp 72.3-72.8 °C. 1H NMR
(500 MHz, CDCl3): δ 7.35-7.28 (m, 7H), 6.63 (d, J = 9.5 Hz, 1H), 6.15 (t, J = 6.5 Hz, 1H), 5.14
(s, 1H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.7, 139.5, 137.3, 136.4, 128.9, 128.1, 128.0,
121.1, 106.3, 51.9. MS (EI): m/z (%) 186 (7), 185 (52), 184 (33), 92 (9), 91 (100), 89 (7), 80 (7),
79 (25), 51 (7).
1-(2-Methylbenzyl)pyridin-2(1H)-one (3b).18a White solid (290.6 mg, 73%). Mp 85.2-85.3
°C. 1H NMR (500 MHz, CDCl3): δ 7.34-7.30 (m, 1H), 7.23-7.16 (m, 3H), 7.07 (m, 1H), 7.02 (m,
13
1H), 6.62 (m, 1H), 6.14-6.11 (m, 1H), 5.12 (s, 2H), 2.26 (s, 3H). C{1H}NMR (125.4 MHz,
CDCl3): δ 162.8, 139.4, 136.8, 136.7, 133.8, 130.8, 128.8, 128.3, 126.5, 120.8, 106.3, 49.6, 19.1.
MS (EI): m/z (%) 199 (16), 198 (13), 197 (45), 196 (14), 182 (10), 181 (18), 105 (64), 104 (100),
103 (24), 79 (10).
1-(3-Methylbenzyl)pyridin-2(1H)-one (3c).18a Colorless oil (346.2 mg, 87%). 1H NMR (500
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MHz, CDCl3): δ 7.21-7.19 (m, 2H), 7.15-7.11 (m, 1H), 7.02-7.0 (m, 3H), 6.54-6.50 (m, 1H),
6.07-6.04 (m, 1H), 5.03-5.00 (m, 2H), 2.25-2.22 (m, 3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ
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162.6, 139.4, 138.5, 137. 5, 136.4, 128.8, 128.7, 125.1, 120.9, 106.1, 51.7, 21.3. MS (EI): m/z (%)
199 (26), 198 (31), 197 (90), 196 (57), 106 (10), 105 (100), 103 (13), 98 (10), 79 (20, 77 (10).
1-(4-Methylbenzyl)pyridin-2(1H)-one (3d).18a White solid (350.2 mg, 88%). Mp 73.1-73.2
°C. 1H NMR (500 MHz, CDCl3): δ 7.37 (ddd, J = 9.0 Hz, J = 6.5 Hz, J = 2.0 Hz, 1H), 7.30
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(dd, J 1 = 7.0 Hz, J 2 = 2.0 Hz ,1H), 7.20 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 6.78 (d, J =
13
9.5 Hz, 1H), 6.22 (t, J = 6.5 Hz, 1H), 5.13 (s, 2H), 2.33 (s, 3H). C{1H}NMR (125.4 MHz,
CDCl3): δ 162.6, 139.9, 138.1, 137.2, 132.9, 129.6, 128.3, 120.8, 107.2, 52.1, 21.1. MS (EI): m/z
(%) 199 (18), 198 (20), 197 (61), 196 (26), 106 (9), 105 (100), 104 (14), 103 (10), 79 (11), 77
(7).
1-(4-Methoxybenzyl)pyridin-2(1H)-one (3e).18a White solid (301 mg, 70%). Mp 75.3-75.8
°C. 1H NMR (500 MHz, CDCl3): δ 7.31 (ddd, J 1 = 15.5 Hz, J 2 = 6.5 Hz, J 3 = 2.0 Hz, 1H), 7.26
(dd, J 1 = 7.0 Hz, J 2 = 2.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H ), 6.63 (d, J
= 9.0 Hz, 1H), 6.14 (t, J = 6.5 Hz, 1H), 5.10 (s, 2H), 2.33 (s, 3H). 13C{1H}NMR (125.4 MHz,
CDCl3): δ 162.7, 139.4, 137.8, 137.1, 133.3, 129.6, 128.2, 121.1, 106.3, 51.7, 21.1. MS (EI): m/z
(%) 215 (6), 214 (6), 213 (24), 212 (5), 122 (12), 121 (100), 120 (18), 91 (5), 78(3), 77 (4), 51
(1).
1-(4-Fluorobenzyl)pyridin-2(1H)-one (3f).19 White solid (328.6 mg, 81%). Mp 84.5-85.2 °C.
1H NMR (500 MHz, CDCl3): δ 7.35-7.27 (m, 4H), 7.01 (t, J = 8.5 Hz, 2H), 6.65 (d, J = 9.0 Hz,
13
1H), 6.18 (t, J = 6.5 Hz, 1H), 5.10 (s, 2H). C{1H}NMR (125.4 MHz, CDCl3): δ 163.5, 162.6,
161.6, 139.8, 137.1, 132.0 (J = 3.8 Hz), 130.0 (J = 8.8 Hz), 121.1, 115.8 (J = 21.3Hz),106.9 ,51.6.
MS (EI): m/z (%) 203 (13), 202 (16), 201 (54), 200 (21), 110 (9), 109 (100), 108 (13), 107 (6),
83 (9), 79 (10).
1-(2-Chlorobenzyl)pyridin-2(1H)-one (3g).18a White solid (346 mg, 79%). Mp 71.8-72.3 °C.
1H NMR (500 MHz, CDCl3): δ 7.37-7.28 (m, 6H), 6.61 (t, J = 8.5 Hz, 1H), 6.7-6.13 (m, 1H),
5.23 (d, J = 5.5 Hz, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.7 139.7, 137.6, 133.7, 133.4,
130.0, 129.6, 129.3, 127.3, 121.1, 106.3, 49.6. MS (EI): m/z (%) 184 (46), 183 (100), 182 (24),
155 (6), 127 (11), 89 (8).
1-(3-Chlorobenzyl)pyridin-2(1H)-one (3h).19 White solid (337.2 mg, 77%). Mp 73.0-73.2
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°C. 1H NMR (500 MHz, CDCl3): δ 7.35 (ddd, J = 9.0 Hz, J = 6.5 Hz , J = 2.0 Hz, 1H),
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1H), 5.11(s, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.5, 139.7, 138.3137.2, 134.8, 130.2,
128.2, 128.1, 126.2, 121.3, 106.7, 51.6. MS (EI): m/z (%) 219 (45), 218 (48), 217 (92), 216 (65),
126 (17), 125 (100), 124 (19), 89 (20), 79 (29).
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1-(4-Chlorobenzyl)pyridin-2(1H)-one (3i).19 White solid (332.8 mg, 76%). Mp 83.4-84.2 °C.
1H NMR (500 MHz, CDCl3): δ 7.38-7.24 (m, 6H), 6.70 (d, J = 9.0 Hz, 1H), 6.21 (t, J = 6.5 Hz,
1H), 5.12 (s, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.6, 139.8, 137.2, 134.9, 133.9, 129.5,
129.0, 121.2, 106.7, 51.5. MS (EI): m/z (%) 219 (27), 218 (22), 217 (55), 216 (25), 127 (36), 126
(16), 125 (100), 124 (16), 89 (14), 79 (16).
1-(4-Nitrobenzyl)pyridin-2(1H)-one (3j). White solid (405.4 mg, 89%). Mp 141.5-141.6 °C.
1H NMR (500 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.38-7.35 (m,
1H), 7.31 (d, J = 6.5 Hz, 1H), 6.62 (d, J = 9.5 Hz, 1H), 6.22 (t, J = 8.0 Hz, 1H), 5.21 (s, 2H).
13C{1H}NMR (125.4 MHz, CDCl3): δ 162.4, 147.7, 143.6, 140.1, 137.3, 128.6, 124.0, 121.5,
107.0, 51.9. MS (EI): m/z (%) 230 (18), 229 (31), 228 (72), 227 (100), 226 (47), 182 (25), 106
(26), 89 (34), 79 (28), 78 (20). HRMS Calcd for C12H11N2O3 (M+H): 231.0764; found:
231.0829.
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1-Allylpyridin-2(1H)-one (3k).10 Colorless oil (186.4 mg, 69%). H NMR (500 MHz,
CDCl3): δ 7.37-7.32 (m, 1H), 7.28-7.26 (m, 1H), 6.60 (m, 1H), 6.22-6.18 (m, 1H), 6.00-5.91 (m,
1H), 5.28-5.25 (m, 1H), 5.21-5.16 (m, 1H), 4.59-5.57 (m, 2H). 13C{1H}NMR (125.4 MHz,
CDCl3): δ 162.4, 139.5, 137.1, 132.5, 121.0, 118.4, 106.2, 51.0. MS (EI): m/z (%) 211 (22), 210
(42), 209 (9), 120 (36), 118 (10), 117 (100), 116 (66), 115 (99), 96 (46), 91 (21).
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1-Cinnamylpyridin-2(1H)-one (3l).21f Colorless oil (249 mg, 59%). H NMR (500 MHz,
CDCl3 : δ 7.36-7.21 (m, 7H), 6.60-6.54 (m, 2H), 6.32-6.27 (m, 1H), 6.17-6.15 (m, 1H), 4.70 (d, J
13
= 6.5 Hz, 2H). C{1H}NMR (125.4 MHz, CDCl3): δ 162.5, 139.6, 137.2, 136.0, 134.0, 128.6,
128.1, 126.6, 123.6, 120.9, 106.3, 50.7. MS (EI): m/z (%) 211 (12), 210 (30), 118 (10), 117 (100),
116 (64), 115 (96), 114 (8), 96 (45), 78 (6), 51 (5).
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1-Phenethylpyridin-2(1H)-one (3m).19 White solid (179.2 mg, 45%). Mp 86.7-87.1 °C. H
NMR (500 MHz, CDCl3): δ 7.33-7.26 (m, 3H), 7.24-7.21 (m, 1H ), 7.14 (d, J = 7.5 Hz, 2H), 6.90
(dd, J 1 = 7.0 Hz, J 2= 1.5 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H), 6.02 (t, J = 6.5 Hz, 1H ), 4.15 (t, J =
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7.0 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.5, 139.6, 137.9,
128.7, 126.7, 120.8, 105.7, 52.0, 35.0. MS (EI): m/z (%) 199 (11), 105 (11), 104 (100), 103 (7),
80 (13), 79 (4), 78 (15), 77 (7), 53 (9), 51 (5).
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1-Pentylpyridin-2(1H)-one (3n).13 Colorless oil (165 mg, 50%). H NMR (500 MHz,
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CDCl3): δ 7.35-7.31 (ddd, J 1 = 9.0 Hz, J 2 = 7.0 Hz, J 3 = 2.0 Hz, 1H), 7.28 (d, J = 6.0 Hz, 1H),
6.62 (d, J = 9.0 Hz, 1H), 6.18 (t, J = 6.5 Hz, 1H), 3.93 (t, J = 7.5 Hz, 2H), 1.78-1.72 (m, 2H),
1.38-1.32 (m, 4H), 0.90 (m, 3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.6, 139.4, 137.5,
121.0, 106.1, 50.0, 29.0, 28.8, 22.3, 13.9. MS (EI): m/z (%) 164 (36), 147 (35), 147 (35), 135
(22), 122 (20), 96 (50), 78 (30), 67 (33), 55 (8), 53 (14).
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1-Heptylpyridin-2(1H)-one (3o).13 Colorless oil (347.2 mg, 63%). H NMR (500 MHz,
CDCl3): δ 7.34-7.30 (m, 1H), 7.28-7.27 (m, 1H), 6.58 (d, J = 9.5 Hz, 1H), 6.17 (t, J = 7.0 Hz,
1H), 3.92 (t, J = 7.5 Hz,2H), 1.77-1.71 (m, 2H), 1.33-1.27 (m, 8H), 0.87 ( t, J = 7.0 Hz, 3H).
13C{1H}NMR (125.4 MHz, CDCl3): δ 162.6, 139.2, 137.5, 121.0, 105.8, 49.9, 31.6, 29.3, 28.9,
26.6, 22.5, 14.0. MS (EI): m/z (%) 193 (27), 192 (69), 191 (41), 176 (46), 175 (69), 136 (39), 122
(35), 109 (100), 96 (51), 95 (56), 78 (12), 53 (3).
1-(1-Phenylethyl)pyridin-2(1H)-one (3p).18a White solid (207 mg, 52%). Mp 79.4-80.3 °C.
1H NMR (500 MHz, CDCl3): δ 7.38-7.31 (m, 6H), 7.14 (d, J = 6.0 Hz, 1H), 6.76 (d, J = 9.0 Hz,
13
1H), 6.46 (q, J = 7.0 Hz, 1H), 6.19 (t, J = 6.5 Hz, 1H), 1.73 (d, J = 7.0 Hz, 3H). C{1H}NMR
(125.4 MHz, CDCl3): δ 162.4, 139.8, 139.3, 134.4, 128.9, 128.1, 127.5, 120.4, 107.3, 53.1, 19.0.
MS (EI): m/z (%) 199 (19), 198 (19), 197 (12), 105 (100), 95 (19), 79 (13), 78 (11), 77 (15), 51
(2).
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1-Benzhydrylpyridin-2(1H)-one (3q).15a White solid (438.4 mg, 84%). Mp 240.1 °C. H
NMR (500 MHz, CDCl3): δ 7.51 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38-7.32 (m, 6H), 7.21 (d, J =
7.0 Hz, 1H), 7.13 (d, J = 7.0 Hz, 4H), 6.87 (d, J = 9.0 Hz , 1H), 6.25 (t, J = 7.0 Hz , 1H).
13C{1H}NMR (125.4 MHz, CDCl3): δ 162.5, 139.9, 138.2, 136.1, 128.9, 128.8, 128.2, 120.3,
107.2, 62.7. MS (EI): m/z (%) 261 (7), 260 (9), 259 (31), 258 (12), 167 (45), 166 (100), 165 (57),
164 (50), 163 (25), 152 (18), 151 (11), 115 (2), 77 (0.5), 51 (0.2).
1-(9H-fluoren-9-yl)pyridin-2(1H)-one (3r). White solid (424.7 mg, 82%). Mp 221.7-222.5
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°C. H NMR (500 MHz, CDCl3): δ 7.76 (d, J = 7.5 Hz, 2H), 7.46-7.42 (m, 4H), 7.33-7.29 (m,
4H), 6.77 (d, J = 9.0 Hz, 1H), 6.48 (dd, J = 7.0 Hz, J = 2.0 Hz, 1H), 5.97-5.94 (m, 1H).
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13C{1H}NMR (125.4 MHz, CDCl3): δ 163.5, 143.2, 141.2, 139.5, 134.6, 129.2, 128.1, 125.3,
120.8, 120.3, 106.5, 59.3. MS (EI): m/z (%) 259 (8), 258 (10), 257 (37), 256 (15), 167 (6), 166
(53), 165 (100), 164 (79), 163 (20), 115 (3). HRMS Calcd for C18H14NO (M+H): 260.1070;
found: 260.1083.
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1-(2-Oxo-2-phenylethyl)pyridin-2(1H)-one (3s).29 White solid (272.6 mg, 64%). Mp
150.4-151.3 °C. 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.0 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H),
7.49 (t, J = 7.5 Hz, 2H), 7.40 (ddd, J 1 = 9.5 Hz , J 2 = 6.5 Hz, J 3 = 1.5 Hz ,1H), 7.23 (dd, J 1 =
6.5 Hz, J = 2.0 Hz ,1H), 6.63 (d, J = 9.5 Hz, 1H), 6.24 (t, J = 6.5 Hz, 1H), 5.38 (s, 2H).
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13C{1H}NMR (125.4 MHz, CDCl3): δ 192.3, 162.4, 140.2, 138.4, 134.8, 134.0, 128.9, 128.2,
120.7, 106.3, 54.4. MS (EI): m/z (%) 212 (7), 211 (13), 184 (14), 118 (11), 106 (8), 105 (100),
104 (9), 80 (8), 77 (28),53 (6).
1-(3-Oxobutan-2-yl)pyridin-2(1H)-one (3t). White solid (110.1 mg, 19%). Mp 170.9-171.6
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°C. H NMR (500 MHz, CDCl3): δ 8.0 (d, J = 7.5 Hz, 2H), 7.75 (s, 1H), 7.55-7.52 (m, 1H),
7.43-7.34 (m, 8H), 7.07 (d, J = 7.0 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 6.15 (t, J = 7.0 Hz, , 1H).
13C{1H}NMR (125.4 MHz, CDCl3): δ 194.7, 162.5, 139.8, 136.4, 135.2, 133.7, 133.5, 130.2,
129.8, 129.5, 129.0, 128.8, 119.9, 105.8, 63.5. MS (EI): m/z (%) 289 (33), 287 (21), 286 (74),
285 (38), 278 (11), 269 (13), 205 (17), 184 (49), 183 (86), 166 (27), 165 (34), 164 (19), 105
(100), 78 (20), 77 (17). HRMS Calcd for C19H16NO2 (M+H): 290.1181; found: 290.1204.
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1-(3-Oxopentan-2-yl)pyridin-2(1H)-one (3u). Colorless oil (82.4 mg, 23%). H NMR (500
MHz, CDCl3): δ 7.35 (ddd, J 1= 14.0 Hz, J2 = 6.5 Hz, J3= 2.0 Hz, 1H), 7.22 (dd, J 1 = 7.0 Hz, J 2
= 1.5 Hz, 1H), 6.59 (d, J = 9.0 Hz, 1H), 6.24 (td, J 1 = 7.0 Hz, J 2 = 1.5 Hz , 1H), 5.56 (q, J = 7.5
Hz, 1H), 2.53 (qd, J = 7.5 Hz, J2 = 1.5 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.0 Hz,
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3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 207.1, 162.2, 139.6, 134.5, 120.6, 106.5, 58.6, 33.0,
15.5, 7.5. MS (EI): m/z (%) 179 (14), 178 (18), 150 (41), 149 (23), 123 (59), 122 (100), 121 (45),
104 (14), 95 (31), 78 (29). HRMS Calcd for C10H14NO2 (M+H): 180.1019; found: 180.1043.
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Ethyl-2-(2-oxopyridin-1(2H)-yl)propanoate (3v)..14c,15b Colorless oil (253.6 mg, 65%). H
NMR (500 MHz, CDCl3): δ 7.35-7.30 (m, 2H), 6.58 (d, J = 9.0 Hz, 1H), 6.23 (t, J = 6.5 Hz, 1H),
5.54 (q, J = 7.5 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 1.62 (d, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz,
3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 170.6, 162.2, 139.6, 134.9, 120.6, 106.4, 61.8, 53.7,
16.7, 14.1. MS (EI): m/z (%) 195 (16), 194 (48), 149 (68), 148 (50), 123 (20), 122 (100), 121
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1-Benzyl-3-methylpyridin-2(1H)-one (6a).19 White solid (199 mg, 50%). Mp 65.7-66.4 °C.
1H NMR (500 MHz, CDCl3): δ 7.31-7.24 (m, 4H), 7.15 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 9.5 Hz,
1H), 6.04 (d, J = 6.5 Hz, 1H), 5.35 (s, 2H), 2.26 (s, 3H ). 13C{1H}NMR (125.4 MHz, CDCl3): δ
164.0, 146.7, 139.2, 136.4, 128.8, 127.3, 126.5, 117.8, 107.0, 47.2, 20.6. MS (EI): m/z (%) 200
(8), 199 (53), 198 (26), 182 (3), 122 (5), 93 (20), 91 (100, 65 (16), 53 (3).
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1-Benzyl-4-methylpyridin-2(1H)-one (6b).19 White solid (306.4 mg, 77%). Mp 64.5-64.8 °C.
1H NMR (500 MHz, CDCl3): δ 7.34-7.26 (m, 5H), 7.15 (d, J = 7.0 Hz, 1H), 6.47 (s, 1H),
6.02-6.0 (m, 1H), 5.1 (s, 2H), 2.17 (s, 3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 162.6, 151.3,
136.5, 136.2, 128.9, 128.1, 127.9, 119.4, 109.1, 51.5, 21.2. MS (EI): m/z (%) 200 (9), 199 (28),
198 (37), 197 (100), 196 (79), 122 (11), 93 (36), 91 (88), 65 (10).
1-Benzyl-5-methylpyridin-2(1H)-one (6c).19 White solid (374.2 mg, 94%). Mp 67.6-67.9 °C.
1H NMR (500 MHz, CDCl3): δ 7.20-7.17 (m, 5H), 7.05-7.03 (m, 1H), 6.97 (s, 1H), 6.44 (d, J =
9.5 Hz, 1H), 4.99 (s, 2H), 1.89 (s, 3H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 161.8, 142.2,
136.7, 134.9, 128.7, 127.9, 127.7, 120.4, 51.6, 16.9. MS (EI): m/z (%) 199 (24), 198 (31), 197
(86), 196 (60), 195 (9), 122 (13), 93 (26), 92 (10), 91 (100), 65 (10).
1-Benzyl-6-methylpyridin-2(1H)-one (6d).18a White solid (238.8 mg, 60%). Mp
103.1-103.9 °C. 1H NMR (500 MHz, CDCl3): δ 731-7.24 (m, 4H), 7.15 (d, J = 7.5 Hz , 2H), 6.56
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(d, J = 9.0 Hz, 1H), 6.04 (d, J = 6.5 Hz , 1H), 5.35 (s, 2H), 2.26 (s, 3H). C{1H}NMR (125.4
MHz, CDCl3): δ 163.0, 136.71, 136.67, 134.7, 130.1, 128.8, 128.1, 127.9, 105.9, 52.2, 17.4. MS
(EI): m/z (%) 199 (14), 198 (31), 197 (100), 196 (52), 184 (8), 183 (18), 122 (16), 93 (20), 92 (9),
91 (91), 65 (8), 51 (0.5).
1-Benzyl-5-fluoropyridin-2(1H)-one (6e). White solid (349.2 mg, 86%). Mp 121.4 -122.0
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°C. H NMR (500 MHz, CDCl3): δ 7.37-7.24 (m, 6H), 7.17 (m, 1H), 6.63-6.60 (dd, J = 10.0
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Hz , J = 5.5 Hz, 1H), 5.10 (s, 2H). C{1H}NMR (125.4 MHz, CDCl3): δ 160.8, 148.4 (J =
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231.3 Hz), 135.6, 131.39 (J = 23.8 Hz), 129.1, 128.38, 128.36, 122.4 (J = 36.4 Hz), 121.7 (J =
6.3 Hz), 52.2. MS (EI): m/z 203 (10), 202 (19), 201 (66), 200 (31), 91 (100), 65 (8), 51 (1).
HRMS Calcd for C12H11FNO (M+H): 204.0819; found: 204.0835.
1-Benzyl-5-chloropyridin-2(1H)-one (6f).19 White solid (346 mg, 79%). Mp 89.2-89.7 °C.
1H NMR (500 MHz, CDCl3): δ 7.38-7.25 (m, 7H), 6.61 (d, J = 9.5 Hz, 1H), 5.10 (s, 2H).
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13C{1H}NMR (125.4 MHz, CDCl3): δ 161.1, 140.5, 135.6, 134.7, 129.1, 128.4, 128.3, 121.9,
112.7, 52.2. MS (EI): m/z (%) 221 (9), 220 (8), 219 (27), 218 (12), 184 (1), 92 (8), 91 (100), 89
(4), 65 (13), 51 (3).
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1-Benzyl-5-nitropyridin-2(1H)-one (6g).30 White solid (427.5 mg, 93%). Mp 99.8-101.4 °C.
1H NMR (500 MHz, CDCl3): δ 8.58 (d, J = 3.0 Hz, 1H), 8.07 (dd, J = 10.0 Hz, J = 3.0 Hz,
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1H), 7.42-7.34 (m, 5H), 6.60 (d, J = 10.0 Hz, 1H), 5.19 (s, 2H). 13C{1H}NMR (125.4 MHz,
CDCl3): δ 161.5, 138.9, 134.3, 133.1, 130.9, 129.4, 129.0, 128.6, 119.8, 53.2. MS (EI): m/z (%)
230 (7), 229 (8), 228 (34), 227 (9), 182 (5), 153 (2), 124 (4), 91 (100), 65 (7), 51 (1).
1
1-Benzylpyridin-4(1H)-one (6h).31 White solid (336.8 mg, 91%). Mp 108.7-109.5 °C. H
NMR (500 MHz, CDCl3): δ 7.48 (d, J = 7.5 Hz, 2H), 7.35-7.31 (m, 3H), 7.18 (d, J = 6.5 Hz, 2H),
6.43 (d, J = 7.5 Hz, 2H), 5.02 (s, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 178.4, 140.6, 134.7,
129.3, 129.0, 127.6, 118.5, 60.3. MS (EI): m/z (%) 185 (5), 184 (22), 92 (8), 91 (100), 90 (8), 89
(2), 77 (2), 65 (14), 51 (2).
1
1-Benzylquinolin-2(1H)-one (6i).32 Colorless oil (380.8 mg, 81%). H NMR (500 MHz,
CDCl3): δ 7.73 (d, J = 9.5Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.30-7.16
13
(m, 7H), 6.80 (d, J = 9.5 Hz, 1H), 5.55 (s, 2H). C{1H}NMR (125.4 MHz, CDCl3): δ 162.5,
139.5, 136.4, 130.6, 128.82, 128.78, 127.3, 126.6, 122.2, 121.7, 121.0, 115.0, 45.9. MS (EI): m/z
(%) 235 (18), 234 (29), 233 (100), 232 (67), 214 (8), 158 (20), 157 (10), 130 (23), 129 (96), 128
(42), 91 (79).
1
2-Benzylpyridazin-3(2H)-one (6j).33 White solid (197.1 mg, 53%). Mp 35-36 °C. H NMR
(500 MHz, CDCl3): δ 7.77-7.76 (m, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.34-7.28 (m, 3H), 7.16 (dd, J
1 = 9.5 Hz, J 2 = 4.0 Hz, 1H), 6.94 (d, J = 9.5Hz, 1H), 5.33 (s, 2H). 13C{1H}NMR (125.4 MHz,
CDCl3): δ 160.4, 136.23, 136.19, 131.1, 130.2, 128.7, 128.6, 127.9, 55.2. MS (EI): m/z (%) 186
(45), 185 (100), 184 (22), 157 (16), 130 (14), 106 (21), 104 (13), 92 (13), 91 (53), 82 (45), 77
(6).
1
1-Benzylpyrimidin-2(1H)-one (6k).18a White solid (327.3 mg, 88%). Mp 128.1-128.5 °C. H
NMR (500 MHz, CDCl3): δ 8.58-8.56 (m, 1H), 7.62-7.59 (d, J = 4.5 Hz, 1H), 7.39-7.32 (m, 5H),
6.28-6.26 (m, 1H), 5.10 (s, 2H). 13C{1H}NMR (125.4 MHz, CDCl3): δ 165.8, 156.3, 147.3,
134.7, 129.2, 128.74, 104.2, 54.0. MS (EI): m/z (%) 186 (49), 185 (13), 157 (4), 92 (10), 91
(100), 89 (6), 81 (15), 80 (9), 65 (22), 77 (2).
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AUTHOR INFORMATION
Corresponding Author
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* Email: qing-xu@wzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank NNSFC (21672163, 21502143) and Natural Science Foundation of Zhejiang Province
for Distinguished Young Scholars (LR14B020002) for financial support.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/xxxxxxxxx.
Comparison data of product 3a and byproduct 4a, preliminary mechanistic studies, and copies of
1H NMR and 13C{1H}NMR spectra of the products.
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