DOI: 10.1002/adsc.200900310

N,N,N’,N’-Tetramethylchloroformamidinium Chloride-MediatedCyclizations of b-Oxo Amides: Facile and Divergent One-PotSynthesis of Substituted 2H-Pyrans, 4H-Pyrans and Pyridin-2(1H)-ones

Yan Wang,a,b Xin Xin,a,b Yongjiu Liang,a Yingjie Lin,b,* Haifeng Duan,b

and Dewen Donga,*a Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People�s Republic of China

Fax: (+86)-431-8569-3057; e-mail: dwdong@ciac.jl.cnb Department of Chemistry, Jilin University, 130012 Changchun, People�s Republic of China

Received: May 3, 2009; Published online: September 11, 2009

Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/adsc.200900310.

Abstract: An efficient and divergent one-pot synthe-sis of substituted 2H-pyrans, 4H-pyrans and pyridin-2(1H)-ones from b-oxo amides based on the selec-tion of the reaction conditions is reported. Mediatedby N,N,N’,N’-tetramethylchloroformamidinium chlo-ride, b-oxo amides underwent intermolecular cycliza-tions in the presence of triethylamine at room tem-perature to give substituted 2H-pyrans in high yields,

which could be converted into substituted 4H-pyransin the presence of sodium hydroxide in ethanol atroom temperature, or into substituted pyridin-2-ACHTUNGTRENNUNG(1 H)-ones under reflux.

Keywords: cyclization; iminium salts; b-oxo amides;2H-pyrans; 4H-pyrans; pyridin-2(1H)-ones

Introduction

The pyridin-2(1H)-one ring makes up the core struc-ture of numerous pharmaceutically active compounds,such as elfamycin and ilicolicin.[1,2] As an importantclass of heterocycles, functionalized pyridin-2(1H)-ones have been utilized as versatile intermediates inthe synthesis of a wide range of nitrogen-containingheterocycles, such as pyridine, piperidine, quinolizi-dine, and indolizidine alkaloids.[3,4] The developmentof efficient synthetic approaches for such nitrogen-containing heterocycles has been the focus of muchresearch for many decades and continues to be anactive area of research today. Recently, we reported afacile and efficient synthesis of substituted pyridin-2(1H)-ones via the Vilsmeier–Haack reactions of avariety of b-oxo amide derivatives, such as 1-acyl-1-carbamylcyclopropanes,[5] 5,6-dihydro-4H-pyrans,[6] a-mono- and a-unsubstituted b-oxo amides,[7] and a-(di-methylamino)methylene b-oxo amides.[8] Inspired bythese results and in continuation of our research inter-est in the synthesis of highly valuable heterocyclesfrom b-oxo amide derivatives, we examined the reac-tion behavior of the commercially available b-oxo

amides towards the iminium salt,[9] N,N,N’,N’-tetrame-thylchloroformamidinium chloride (TMC),[10] whichpossesses a similar structure to Vilsmeier reagentPOCl3-DMF (Figure 1).[11] In this research, we devel-oped efficient and divergent one-pot synthesis of sub-stituted 2H-pyrans, 4H-pyrans and pyridin-2(1H)-onesfrom b-oxo amides based on a selection of the reac-tion conditions. Herein, we wish to report our experi-mental results and present a proposed mechanism in-volved in the cyclizations.

Results and Discussion

The reaction of 3-oxo-N-phenylbutanamide 1a withTMC was initially attempted. Thus, 1a and TMC was

Figure 1.

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subjected to CH2Cl2 at room temperature, thentriethyl ACHTUNGTRENNUNGamine (Et3N) was loaded under stirring. Thereaction mixture quickly turned yellowish. However,as monitored by TLC, some of the substrate couldnot be consumed even after a prolonged reactiontime (48 h). Then the reaction was halted, a productwas obtained after work-up and subsequent purifica-tion by column chromatography of the resulting mix-ture. The product was characterized as the six-mem-bered oxaheterocyclic compound, 3-acetyl-6-methyl-4-(phenylamino)-2-(phenylimino)-2H-pyran 2a (37%),on the basis of its spectral and analytical data(Scheme 1).

To optimize the yield of 2a, the reaction of 1a wasthen carried out under various conditions. No reactionwas observed when 1a was treated with TMC inCH2Cl2 at room temperature without Et3N, as indicat-ed by TLC. The reaction of 1a could not proceed witha Lewis acid, such as TiCl4 and SnCl4, and Et3N. Toour delight, the reaction of 1a, TMC and Et3N wassignificantly speeded up when DMF was used as sol-vent instead of CH2Cl2. A series of experiments re-vealed that 1.0 equiv. of TMC/Et3N was effective forthe synthesis of 2a, and the optimal results were ob-tained when the reaction of 1a with 1.2 equiv. of TMCand 1.5 equiv. of Et3N was performed in DMF atroom temperature for 15 min, whereby the yield of 2areached 83% (Table 1, entry 1).

Under the optimal conditions, we carried out aseries of reactions of 1 to determine its scope with re-spect to the amide moiety. As shown in Table 1, thecyclization reaction proved to be suitable for b-oxoamides 1b–g bearing varied arylamide groups, afford-ing the corresponding substituted 2H-pyrans 2b–g ingood to high yields (Table 1, entries 2–7). However,no reaction was observed when N-alkyl b-oxo amidewas subjected to the above conditions. It is worthmentioning that the structure of 2c was elucidated bymeans of an X-ray single crystal analysis (Figure 2),and further confirmed by its NMR spectra.

Therefore, we have provided a simple and efficientone-pot synthesis of substituted 2H-pyrans under verymild conditions. Actually, 2H-pyran derivatives repre-sent an important class of six-membered oxaheterocy-cles possessing useful biological activities.[12,13] Itshould be noted that the richness of the functionality,for example, acetyl, amino, and arylimino groups, onthe 2H-pyrans of type 2 may render them extremelyversatile as synthons in further synthetic transforma-tions.

Encouraged by this, we selected 2e as a model com-pound to examine its behavior under basic conditions.Thus, 2e was treated with NaOH (3.0 equiv.) in etha-nol at room temperature for 5.0 h. The reaction fur-nished a white solid, which was characterized as N-(2-methoxyphenyl)-4-(2-methoxyphenylimino)-2,6-di-methyl-4H-pyran-3-carboxamide 3e (94% yield), an-other type of six-membered oxaheterocyclic com-pound (Scheme 2). The structure of 3e was estab-lished by means of an X-ray single crystal analysis(Figure 3), and further confirmed by its NMR spectra.

Scheme 1. Reaction of 1a with TMC and triethylamine.

Table 1. Synthesis of substituted 2H-pyrans 2.[a]

Entry 1 Ar Time [min] 2 Yield[b] [%]

1 1a Ph 15 2a 832 1b 4-MeC6H4 15 2b 863 1c 4-MeOC6H4 20 2c 814 1d 2-MeC6H4 15 2d 825 1e 2-MeOC6H4 20 2e 806 1f 2,4-Me2C6H3 15 2f 927 1g 5-Cl-2-MeOC6H3 30 2g 75

[a] Reagents and conditions: 1a (5.0 mmol), TMC(6.0 mmol), DMF (10.0 mL), Et3N (7.5 mmol), room tem-perature.

[b] Isolated yields.

Figure 2. ORTEP drawing of 2c.

Scheme 2. Reaction of 2e with NaOH/EtOH.

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Under the identical conditions, a series of thenewly synthesized 2H-pyrans 2 were converted intothe corresponding substituted 4H-pyrans 3 in highyields (Table 2). The 4H-pyran derivatives are impor-tant six-membered oxaheterocycles due to their pres-ence in numerous natural products and synthetic or-ganic compounds along with diverse bio- and pharma-cological activities.[12,14] We have provided a novelentry to the synthesis of 4H-pyrans.

It was interesting to note that when the reaction of2e and NaOH (3.0 equiv.) was conducted in ethanolunder reflux, we obtained a single product instead of3e. The product was characterized as 3-acetyl-1-(4-methoxyphenyl)-4-(4-methoxyphenylamino)-6-meth-ylpyridin-2(1H)-one 4e (88% yield). Under the identi-cal conditions, a series of the newly synthesized 2H-pyrans 2 were converted into the corresponding sub-stituted pyridin-2(1H)-ones 4 in high yields (Table 3).It should be mentioned that treatment of 3e withNaOH (1.5 equiv.) in ethanol under reflux for 4.0 hcould also afford 4e in 90% yield.

Moreover, we attempted one-pot synthesis of sub-stituted 4H-pyrans 3 and pyridin-2(1H)-ones 4 direct-ly from b-oxo amides 1. In a representative experi-ment, 1a was treated with TMC (1.2 equiv.) and Et3N(1.5 equiv.) in DMF at room temperature for 15 min,then NaOH (4.5 equiv.) in ethanol were loaded. Thereaction mixture was stirred at room temperature forfurther 5.0 h to afford 3a, whereas stirring at 75 8C for4.0 h gave 4a (Scheme 3).

On the basis of all the results obtained, a plausiblemechanism for the cyclization of b-oxo amides to 2H-pyrans, 4H-pyrans and pyridin-2(1H)-ones is present-ed in Scheme 4. In the presence of Et3N, the attack ofoxygen of the carbamoyl group of 1 on the electron-deficient carbon of TMC generates iminium saltA,[9a–d] which undegoes intermolecular addition-elimi-nation reaction to give iminium salt B. The intramo-lecular cyclization of B leads the formation of 2H-pyran 2 via the intermediate C. In the presence ofNaOH/EtOH, a ring-opening reaction of 2H-pyran 2occurs to give intermediates D and D’, as a pair of

Figure 3. ORTEP drawing of 3e.

Table 2. Synthesis of 4H-pyrans 3 from 2H-pyrans 2.[a]

Entry 2 Ar Time [h] 3 Yield[b] [%]

1 2a Ph 4.5 3a 932 2b 4-MeC6H4 4.5 3b 923 2c 4-MeOC6H4 5.0 3c 904 2d 2-MeC6H4 4.5 3d 915 2e 2-MeOC6H4 5.0 3e 946 2f 2,4-Me2C6H3 4.5 3f 957 2g 5-Cl-2-MeOC6H3 5.5 3g 92

[a] Reagents and conditions: 2 (2.0 mmol), NaOH(6.0 mmol), EtOH (5.0 mL), room temperature.

[b] Isolated yields.

Table 3. Synthesis of pyridin-2(1H)-ones 4 from 2.[a]

Entry 2 Ar Time [h] 4 Yield[b] [%]

1 2a Ph 3.0 4a 912 2b 4-MeC6H4 3.5 4b 943 2c 4-MeOC6H4 3.0 4c 894 2d 2-MeC6H4 3.5 4d 915 2e 2-MeOC6H4 3.0 4e 886 2f 2,4-MeC6H3 2.5 4f 967 2g 2-MeO-5-ClC6H3 4.0 4g 87

[a] Reagents and conditions: 2 (2.0 mmol), NaOH(6.0 mmol), EtOH (5.0 mL), reflux.

[b] Isolated yields.

Scheme 3. One-pot synthesis of 4H-pyran 3a and pyridin-2-ACHTUNGTRENNUNG(1 H)-ones 4a from b-oxo amide 1a.

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Z/E isomers, at different temperatures, which thenundergo intramolecular cyclizations to afford 4H-pyrans 3 and pyridin-2(1H)-ones 4, respectively.[15]

Conclusions

In summary, the intermolecular cyclization of b-oxoamides 1 mediated by TMC/Et3N in DMF is disclosedfor the first time, and thus a novel and divergent one-pot synthesis of substituted 2H-pyrans 2, 4H-pyrans 3and pyridin-2(1H)-ones 4 from b-oxo amides 1 hasbeen developed based on a selection of the reactionconditions. The one-pot protocol features commercial-ly available starting materials, mild conditions, highyields and rich functionality of the products. Furtherwork on the potential utilization of the products 2–4as synthetic scaffolds and the evaluation of their bio-logical activity is currently underway in our laborato-ry.

Experimental Section

General

All reagents were purchased from commercial sources andused without treatment, unless otherwise indicated.1H NMR and 13C NMR spectra were recorded at 25 8C at300 MHz and 75 MHz, respectively, using TMS as internalstandard. IR spectra (KBr) were recorded on an FT-IRspectrophotometer in the range of 400–4000 cm�1. Massspectra were recorded on an LCMsD mass spectrometer.

Typical Procedure for the Preparation of 2H-Pyrans 2(2a as an Example)

To a solution of 1a (0.89 g, 5.0 mmol) and N, N, N’, N’-tetra-methylchloroformamidinium chloride (1.03 g, 6.0 mmol) indry DMF (10 mL) at room temperature was added Et3N(1.04 mL, 7.5 mmol) in one portion. The mixture was stirredat room temperature for 15 min and then poured into satu-rated aqueous NaCl (20 mL), which was extracted with di-chloromethane (3 � 20 mL). The combined organic phasewas washed with water (3 � 20 mL), dried over MgSO4, fil-tered and concentrated under vacuum. The crude productwas purified by flash chromatography (silica gel, petroleumether:diethyl ether= 10:1) to give 2a ; yield: 0.66 g (83%).

Scheme 4. Proposed mechanism for the reaction of 1 with TMC and triethylamine.

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Physical Data of Compounds Isolated

2a: Yellowish oil; 1H NMR (300 MHz, CDCl3): d=1.94 (s,3 H), 2.76 (s, 3 H), 5.70 (s, 1 H), 7.04 (t, J= 7.2 Hz, 3 H), 7.17(d, J=7.2 Hz, 2 H), 7.30 (t, J=7.5 Hz, 3 H), 7.42 (t, J=7.2 Hz, 2 H); 13C NMR (75 MHz, CDCl3): d=19.7, 32.8,94.8, 96.6, 122.3, 122.4, 125.8, 126.8, 128.5, 129.4, 137.1,147.0, 149.7, 157.0, 162.5, 200.2; anal. calcd. for C20H18N2O2:C 75.45, H 5.70, N 8.80; found: C 75.68, H 5.72, N, 8.62.

2b: Yellowish solid; mp 170–172 8C; 1H NMR (300 MHz,CDCl3): d=1.93 (s, 3 H), 2.32 (s, 3 H), 2.37 (s, 3 H), 2.74 (s,3 H), 5.66 (s, 1 H), 6.96 (d, J= 8.1 Hz, 2 H), 7.03–7.11 (q, J=8.1 Hz, 4 H), 7.20 (d, J= 7.8 Hz, 2 H), 13.02 (s, 1 H);13C NMR (75 MHz, CDCl3) d =19.7, 20.8, 21.0, 32.7, 94.8,96.5, 122.3, 125.8, 129.1, 130.0, 131.6, 134.5, 136.7, 144.3,157.1, 162.4, 200.1; IR (KBr): n=826, 966, 1018, 1269, 1548,1637, 1676 cm�1; anal. calcd. for C22H22N2O2: C 76.28, H6.40, N 8.09; found: C 76.43, H 6.50, N, 8.11.

2c: Yellow solid; mp 128–130 8C; 1H NMR (300 MHz,CDCl3): d=1.95 (s, 3 H), 2.74 (s, 3 H), 3.80 (s, 3 H), 3.83 (s,3 H), 5.59 (s, 1 H), 6.84 (d, J=9.0 Hz, 2 H), 6.92 (d, J=7.8 Hz, 2 H), 7.06 (t, J=9.6 Hz, 4 H), 12.92 (s, 1 H);13C NMR (75 MHz, CDCl3): d= 19.7, 32.6, 55.3, 55.4, 94.8,96.4, 113.8, 114.5, 123.5, 127.3, 129.8, 140.0, 149.3, 155.1,157.4, 158.3, 162.2, 199.8; anal. calcd. for C22H22N2O4: C69.83, H 5.86, N 7.40; found: C 70.02, H 5.78, N 7.27. Crystaldata for 2c : C22H22N2O4, yellow crystal, M=346.42, mono-clinic, P21/c, a= 10.9714(13) �, b=20.036(2) �, c=9.5699(12) �, b=112.140(2)8. CCDC 719422 contains thesupplementary crystallographic data for this compound.These data can be obtained free of charge from The Cam-bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

2d: Yellow solid; mp 133–134 8C; 1H NMR (300 MHz,CDCl3): d=1.85 (s, 3 H), 2.23 (s, 3 H), 2.28 (s, 3 H), 2.79 (s,3 H), 5.45 (s, 1 H), 6.92 (q, J=4.2 Hz, 2 H), 7.11 (t, J=4.5 Hz, 2 H), 7.17 (d, J=7.2 Hz, 1 H), 7.23 (t, J= 5.1 Hz,2 H), 7.28 (d, J=4.5 Hz, 1 H), 13.07 ACHTUNGTRENNUNG(s, 1 H); 13C NMR(75 MHz, CDCl3): d=17.7, 18.4, 19.5, 32.9, 94.4, 95.7, 121.0,121.9, 125.7, 126.5, 126.6, 127.1, 129.2, 129.7, 130.9, 134.2,135.6, 146.1, 149.0, 157.3, 162.4, 199.8; IR (KBr): n= 727,759, 964, 1010, 1268, 1349, 1534, 1667 cm�1; anal. calcd. forC22H22N2O2: C 76.28, H 6.40, N 8.09; found: C 76.63, H 6.47,N, 8.21.

2e: Yellow solid; mp 166–168 8C; 1H NMR (300 MHz,CDCl3): d=1.87 (s, 3 H), 2.80 (s, 3 H), 3.81 (s, 3 H), 3.85 (s,3 H), 5.65 (s, 1 H), 6.89–6.99 (m, 6 H), 7.15 (d, J= 7.2 Hz,1 H), 7.23 (m, 1 H), 12.88 (s, 1 H); 13C NMR (75 MHz,CDCl3): d =19.7, 32.6, 55.7, 55.8, 94.9, 96.8, 111.5, 111.7,120.4, 120.6, 122.6, 122.8, 126.1, 126.6, 127.7, 137.1, 151.1,153.7, 157.0, 162.1, 200.1; IR (KBr): n=756, 1020, 1248,1492, 1547, 1584, 1675 cm�1; anal. calcd. for C22H22N2O4: C69.83, H 5.86, N 7.40; found: C 69.99, H 5.79, N 7.52.

2f: Yellow solid; mp 150–152 8C; 1H NMR (300 MHz,CDCl3): d=1.87 (s, 3 H), 2.20 (s, 3 H), 2.23 (s, 3 H), 2.29 (s,3 H), 2.35 (s, 3 H), 2.78 (s, 3 H), 5.43 (s, 1 H), 6.83 (d, J=8.1 Hz, 1 H), 6.93 (d, J=7.8 Hz, 1 H), 7.00 (m, 3 H), 7.10 (s,1 H), 12.96 (s, 1 H); 13C NMR (75 MHz, CDCl3): d= 17.9,18.6, 19.8, 20.8, 21.0, 33.1, 94.7, 96.0, 121.1, 126.4, 126.8,127.3, 129.5, 130.8, 131.3, 131.7, 133.3, 134.2, 137.2, 143.6,149.1, 157.8, 162.5, 200.1; IR (KBr): n= 789, 963, 1018, 1269,1318, 1540, 1588, 1674 cm�1; anal. calcd. for C24H26N2O2: C

76.98, H 7.00, N 7.48; found: C 76.83, H 7.05, N 7.39: MS:m/z= 375.2, calcd. for [M+ +1]: 374.2.

2g: Yellow solid; mp 192–193 8C; 1H NMR (300 MHz,CDCl3): d=1.94 (s, 3 H), 2.76 (s, 3 H), 3.79 (s, 3 H), 3.84 (s,3 H), 5.68 (s, 1 H), 6.80 (d, J=6.3 Hz, 1 H), 6.92 (t, J=7.2 Hz, 3 H), 7.16–7.23 (m, 2 H), 12.90 (s, 1 H); 13C NMR(75 MHz, CDCl3): d=19.8, 32.8, 56.0, 94.9, 97.1, 112.2,112.6, 122.3, 122.6, 125.2, 125.3, 126.2, 127.3, 138.2, 150.0,152.4, 156.8, 162.6, 200.5; anal. calcd. for C22H20Cl2N2O4: C59.07, H 4.51, N 6.26; found: C 58.89, H 4.57, N 6.36.

Typical Procedure for the Preparation of 4H-Pyrans 3(3a as an Example)

To a solution of 2a (0.64 g, 2.0 mmol) in EtOH (5.0 mL) atroom temperature was added NaOH (0.24 g, 6.0 mmol) inone portion. The mixture was stirred at room temperaturefor 4.5 h and then poured into saturated aqueous NaCl(20 mL), which was extracted with dichloromethane (3 �20 mL). The combined organic phase was washed withwater (3 � 20 mL), dried over MgSO4, filtered and concen-trated under vacuum. The crude product was purified byflash chromatography (silica gel, petroleum ether:diethylether= 10: 3) to give 3a ; yield: 0.59 g (93%).

Physical Data of Compounds Isolated

3a: White solid; mp 165–166 8C; 1H NMR (300 MHz,CDCl3): d=2.08 (s, 3 H), 2.77 (s, 3 H), 6.04 (s, 1 H), 6.87 (d,J=8.1 Hz, 2 H), 7.05 (t, J=7.2 Hz, 1 H), 7.12 (t, J= 8.1 Hz,1 H), 7.30 (d, J= 8.1 Hz, 2 H), 7.37 (t, J=8.1 Hz, 2 H), 7.62(d, J=8.1 Hz, 2 H), 13.29 (s, 1 H); 13C NMR (75 MHz,CDCl3): d = 19.3, 21.7, 103.8, 122.7, 120.6, 121.4, 123.5,123.7, 128.8, 129.4, 138.9, 148.9, 154.2, 159.4, 163.2, 169.2; IR(KBr): n=695, 702, 761, 1169, 1388, 1486, 1555, 1572,1689 cm�1; anal. calcd. for C20H18N2O2: C 75.45, H 5.70, N8.80; found: C 75.28, H 5.65, N 8.99.

3b: White solid; mp 165–167 8C; 1H NMR (300 MHz,CDCl3): d=2.07 (s, 3 H), 2.30 (s, 3 H), 2.36 (s, 3 H), 2.76 (s,3 H), 6.07 (s, 1 H), 6.77 (d, J=7.2 Hz, 2 H), 7.08 (d, J=7.8 Hz, 2 H), 7.18 (d, J=7.8 Hz, 2 H), 7.51 (d, J= 7.5 Hz,2 H), 13.31 (s, 1 H); 13C NMR (75 MHz, CDCl3): d= 19.2,20.8, 21.6, 103.7, 112.7, 120.5, 121.2, 129.2, 129.9, 132.9,133.1, 136.4, 146.2, 154.2, 159.1, 163.1, 168.9; IR (KBr): n=827, 1166, 1318, 1381, 1507, 1561, 1602, 1653, 1685 cm�1;anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N 8.09; found:C 76.59, H 6.28, N 8.23.

3c: White solid; mp 144–146 8C; 1H NMR (300 MHz,CDCl3): d=2.04 (s, 3 H), 2.75 (s, 3 H), 3.75 (s, 3 H), 3.80 (s,3 H), 6.08 (s, 1 H), 6.79–6.84 (m, 4 H), 6.91 (d, J= 8.4 Hz,2 H), 7.54 (d, J= 8.4 Hz, 2 H), 13.35 (s, 1 H); 13C NMR(75 MHz, CDCl3): d= 19.1, 21.5, 55.26, 55.3, 103.5, 113.8,113.9, 114.5, 121.9, 122.1, 132.2, 141.9, 156.4, 155.7, 155.9,159.0, 162.8, 168.6; anal. calcd. for C22H22N2O4: C 69.83, H5.86, N 7.40; found: C 69.64, H 5.90, N 7.47.

3d: White solid; mp 157–159 8C; 1H NMR (300 MHz,CDCl3): d=2.01 (s, 3 H), 2.09 (s, 3 H), 2.20 (s, 3 H), 2.78 (s,3 H), 5.77 (s, 1 H), 6.71 (d, J=7.5 Hz, 1 H), 7.00 (q, J=7.5 Hz, 2 H), 7.11 (d, J=6.9 Hz, 1 H), 7.15–7.22 (m, 3 H),8.19 (d, J=8.1 Hz, 1 H), 13.12 (s, 1 H); 13C NMR (75 MHz,CDCl3): d= 17.9, 18.9, 19.2, 21.7, 104.0, 112.9, 120.7, 122.4,123.5, 124.0, 126.3, 126.8, 128.9, 129.0, 130.2, 130.7, 137.5,147.8, 154.0, 159.2, 163.4, 169.2; IR (KBr): n=758, 1029,

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1114, 1169, 1246, 1388, 1484, 1590, 1691 cm�1; anal. calcd.for C22H22N2O2: C 76.28, H 6.40, N 8.09; found: C 76.44, H6.43, N 8.00.

3e: White solid; mp 154–156 8C; 1H NMR (300 MHz,CDCl3): d=2.07 (s, 3 H), 2.76 (s, 3 H), 3.65 (s, 3 H), 3.77 (s,3 H), 5.83 (s, 1 H), 6.82 (d, J=8.1 Hz, 1 H), 6.89 (d, J=7.5 Hz, 1 H), 6.94–6.97 (m, 4 H), 7.07(d, J=7.2 Hz, 1 H), 8.50(d, J=8.1 Hz, 1 H), 13.46 (s, 1 H); 13C NMR (75 MHz,CDCl3): d= 19.1, 21.4, 55.67, 55.7, 104.6, 110.3, 112.0, 113.4,120.7, 121.1, 122.5, 123.1, 123.9, 129.2, 138.2, 149.4, 150.3,154.3, 158.3, 163.2, 168.3; anal. calcd. for C22H22N2O4: C69.83, H 5.86, N 7.40; found: C 70.13, H 5.90, N 7.31. Crystaldata for 3e : C22H22N2O2, white crystal, M=346.42, mono-clinic, P-1, a=10.334(3) �, b=10.420(3) �, c=11.131(3) �,a= 64.783(4)8, b=71.969(4)8, g= 65.832(4)8. CCDC 719427contains the supplementary crystallographic data for thiscompound. These data can be obtained free of charge fromThe Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.

3f: White solid; mp 157–159 8C; 1H NMR (300 MHz,CDCl3): d=2.04 (s, 6 H), 2.17 (s, 3 H), 2.27 (s, 3 H), 2.32 (s,3 H), 2.77 (s, 3 H), 5.80 (s, 1 H), 6.60 (q, J= 7.5 Hz, 1 H),6.95–7.04 (m, 4 H), 8.02 (d, J=8.1 Hz, 1 H), 13.09 (s, 1 H);13C NMR (75 MHz, CDCl3): d= 17.8, 18.8, 19.1, 20.8, 21.6,103.9, 112.8, 120.4, 122.3, 126.7, 127.3, 128.6, 128.9, 130.9,131.3, 132.7, 133.3, 134.8, 145.1, 154.0, 158.9, 163.4, 168.8;anal. calcd. for C24H26N2O2: C 76.98, H 7.00, N 7.48; found:C 77.05, H 7.03, N 7.39; MS: m/z =375.2, calcd. for [M+ +1]:374.2.

3g: White solid; mp 247–249 8C; 1H NMR (300 MHz,CDCl3): d=2.11 (s, 3 H), 2.77 (s, 3 H), 3.66 (s, 3 H), 3.75 (s,3 H), 5.80 (s, 1 H), 6.72 (d, J=8.7 Hz, 1 H), 6.88 (q, J=8.7 Hz, 2 H), 6.94 (t, J=5.7 Hz, 1 H), 7.03 (m, 1 H), 8.60 (d,J=2.4 Hz, 1 H), 13.40 (s, 1 H); 13C NMR (75 MHz, CDCl3):d= 19.3, 21.6, 55.97, 56.0, 92.7, 95.1, 104.7, 110.8, 112.9,120.4, 122.6, 123.5, 125.7, 130.0, 139.1, 147.1, 149.1, 154.9,159.0, 163.2, 169.2; anal. calcd. for C22H20Cl2N2O4: C 59.07,H 4.51, N 6.26; found: C 58.93, H 4.41, N 6.11.

Typical Procedure for the Pyridin-2(1H)-ones 4 (4a asan Example)

To a flask equipped with a condenser were added 2a (0.64 g,6.0 mmol), NaOH (0.24 g, 6.0 mmol) and EtOH (10 mL).The mixture was heated to reflux and stirred for about 3.0 hand then poured into saturated aqueous NaCl (20 mL),which was extracted with dichloromethane (3 �20 mL). Thecombined organic phase was washed with water (3 �20 mL), dried over MgSO4, filtered and concentrated undervacuum. The crude product was purified by flash chroma-tography (silica gel, petroleum ether: diethyl ether= 10: 3)to give 4a ; yield: 0.62 g (91%).

Physical Data of Compounds Isolated

4a: White solid; mp 198–200 8C; 1H NMR (300 MHz,CDCl3): d=1.83 (s, 3 H), 2.70 (s, 3 H), 5.90 (s, 1 H), 7.18–7.31(m, 5 H), 7.41–7.51 (m, 5 H), 12.65 (s, 1 H); 13C NMR(75 MHz, CDCl3): d= 22.3, 33.4, 95.5, 102.4, 125.9, 126.5,128.4, 128.6, 129.5, 129.7, 137.9, 138.7, 150.3, 158.3, 164.5,202.5; anal. calcd. for C20H18N2O2: C 75.45, H 5.70, N 8.80;found: C 75.77, H 5.65, N 8.39.

4b: White solid; mp 204–205 8C; 1H NMR (300 MHz,CDCl3): d=1.83 (s, 3 H), 2.39 (s, 6 H), 2.69 (s, 3 H), 5.84 (s,1 H), 7.06 (d, J=7.5 Hz, 2 H), 7.13 (d, J= 8.1 Hz, 2 H), 7.21–7.30 (m, 4 H), 12.54 (s, 1 H); 13C NMR (75 MHz, CDCl3):d= 21.0, 21.2, 22.3, 33.4, 95.5, 102.2, 125.9, 128.1, 130.1,130.3, 135.2, 136.1, 136.4, 138.5, 150.4, 158.4, 164.6, 202.4; IR(KBr): n=800, 952, 1021, 1257, 1408, 1510, 1553, 1623,1655 cm�1; anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N8.09; found: C 76.55, H 6.26, N 8.15.

4c: White solid; mp 200–202 8C; 1H NMR (300 MHz,CDCl3): d =1.84 (s, 3 H), 2.69 (s, 3 H), 3.84 (s, 6 H), 5.76 (s,1 H), 6.94 (d, J=8.7 Hz, 2 H), 7.00 (d, J= 8.7 Hz, 2 H), 7.10(d, J= 8.7 Hz, 2 H), 7.16 (d, J= 9.0 Hz, 2 H), 12.45 (s, 1 H);13C NMR (75 MHz, CDCl3): d =22.3, 33.5, 55.4, 95.4, 102.0,114.6, 114.8, 127.5, 129.3, 130.4, 131.2, 150.6, 158.1, 158.8,159.3, 164.7, 202.4; IR (KBr): n=802, 832, 1023, 1250, 1402,1511, 1544, 1622, 1654 cm�1; anal. calcd for C22H22N2O4: C69.83, H 5.86, N 7.40; found: C 69.69, H 5.91, N, 7.34.

4d: White solid; mp 164–166 8C; 1H NMR (300 MHz,CDCl3): d=1.75 (s, 3 H), 2.14 (s, 3 H), 2.32 (s, 3 H), 2.72 (s,3 H), 5.68 (s, 1 H), 7.11 (t, J= 4.5 Hz, 1 H), 7.25–7.34 (m,7 H), 12.52 (s, 1 H); 13C NMR (75 MHz, CDCl3): d= 17.5,18.1, 21.8, 33.4, 95.5, 102.1, 126.8, 126.9, 127.1, 127.3, 128.3,128.9, 131.2, 134.6, 135.7, 136.5, 137.9, 150.3, 158.7, 163.8,202.4; IR (KBr): n=752, 1258, 1328, 1402, 1544, 1617,1651 cm�1; anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N8.09; found: C 76.33, H 6.32, N 8.15; MS: m/z =347.2, calcd.for [M+ + 1]: 346.2.

4e: White solid; mp 149–152 8C; 1H NMR (300 MHz,CDCl3): d=1.81 (s, 3 H), 2.71 (s, 3 H), 3.82 (s, 3 H), 3.88 (s,3 H), 5.94 (s, 1 H), 6.96–7.08 (m, 4 H), 7.15 (d, J= 7.2 Hz,1 H), 7.22 (d, J=8.1 Hz, 1 H), 7.32 (d, J= 8.1 Hz, 1 H), 7.32(d, J=8.1 Hz, 1 H), 12.48 (s, 1 H); 13C NMR (75 MHz,CDCl3): d= 21.5, 33.4, 55.7, 95.4, 102.8, 111.8, 112.1, 120.5,121.2, 126.2, 126.9, 127.1, 129.9, 130.1, 150.9, 153.7, 154.9,158.1, 164.1, 202.3; anal. calcd. for C22H22N2O4: C 69.83, H5.86, N 7.40; found: C 69.71, H 5.83, N 7.49.

4f: White solid; mp 128–130 8C; 1H NMR (300 MHz,CDCl3): d=1.74 (s, 3 H), 2.08 (s, 3 H), 2.25 (s, 3 H), 2.35 (s,6 H), 2.70 (s, 3 H), 5.63 (s, 1 H), 6.96 (d, J= 8.1 Hz, 1 H),7.03–7.12 (m, 5 H), 12.38 (s, 1 H); 13C NMR (75 MHz,CDCl3): d= 17.3, 17.8, 20.9, 21.0, 21.6, 33.3, 95.2, 101.9,126.8, 127.3, 127.8, 127.9, 131.7, 131.8, 133.8, 134.3, 135.0,135.1, 136.8, 138.6, 150.3, 158.8, 163.9, 202.4: IR (KBr): n=803, 825, 1226, 1404, 1539, 1621, 1651 cm�1; anal. calcd. forC24H26N2O2: C 76.98, H 7.00, N 7.48; found: C 76.27, H 6.93,N 7.54.

4g: White solid; mp 228–230 8C; 1H NMR (300 MHz,CDCl3): d=1.86 (s, 3 H), 2.69 (s, 3 H), 3.82 (s, 3 H), 3.88 (s,3 H), 5.94 (s, 1 H), 6.93 (q, J=9.0 Hz, 2 H), 7.18 (d, J=9.0 Hz, 2 H), 7.31 (s, 1 H), 7.37 (d, J= 8.7 Hz, 1 H), 12.53 (s,1 H); 13C NMR (75 MHz, CDCl3): d= 21.5, 33.4, 56.0, 95.4,102.8, 112.5, 113.0, 125.0, 125.6, 125.7, 126.6, 127.9, 129.8,130.1, 150.8, 152.2, 153.7, 157.7, 163.7, 202.3; anal. calcd. forC22H20Cl2N2O4: C 59.07, H 4.51, N 6.26; found: C 59.15, H4.47, N 6.40.

2222 asc.wiley-vch.de � 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2009, 351, 2217 – 2223

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Acknowledgements

Financial support of this research by the National NaturalScience Foundation of China (20572013 and 20872136) isgreatly acknowledged.

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