Ultrasonically Assisted N-Cyanoacylation and Synthesis of Alkyl(4-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)amino Acid Ester Derivatives.

This work represents the use of N-3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile as a cyanoacetylating agent for the synthesis of cyanoacetamide benzoic acid and benzophenone derivatives by two different methods, namely, conventional heating and ultrasonication. The cyanoacetamide derivatives were subjected to cyclization to produce N-substituted 2-pyridone derivatives under conventional heating and by an ultrasonic method as well. The ultrasonic method afforded the products in less reaction time with high yields and purities compared to the conventional method, as observed from their spectral data. N-(4-Carboxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone was coupled with different amino acid esters by the OxymaPure/DIC methodology under traditional and ultrasonic conditions. Again, ultrasonication assisted the coupling step and afforded the products with higher yields and purities compared to the traditional method. Fourier transform infrared spectroscopy, NMR (1H and 13C), elemental analysis, and LC-MS were used to determine the structures of all compounds. Finally, a feature of this protocol is exploring the utilization of ultrasonication as an eco-friendly alternative conventional heating method for N-cyanoacylation and synthesis of N-substituted pyridinone derivatives and as a coupling method for the formation of an amide bond, which might be of interest for many researchers.

Introduction

The conventional method used to carry out organic synthesis faces some disadvantages such as long reaction times, more solvent requirements, high temperatures, unsatisfactory yields, toxic reagent requirements, as well as the formation of inefficient products.[1] The essential challenge for today’s researchers is to make their methodology under environmentally conditions to avoid the use of severe reaction conditions and hazardous reagents.[2,3]

Ultrasonication is now considered an important tool to perform organic reactions; in addition, it is a cost-effective method to support numerous reactions that offer a facile, clean, green, and eco-friendly way for the synthesis of compounds with biological values.[4] Moreover, this process offers more advantages over the conventional heating method in terms of reaction rate and time.[5−11]

Ultrasound accelerates the reactions through the formation, growth, and implosive collapse of bubbles in liquids, which furnish hot spot regions.[12] Furthermore, these intense collapses of cavitation bubbles also increase the local temperature within the reaction mixture, which finally leads to cross the activation energy barrier.[13,14] Such valuable features as a whole have inspired organic researchers to explore the application of ultrasound for the synthesis of various organic scaffolds.

In the last few years, researchers have been involved in the exploration of the potential of activated nitriles in heterocyclic synthesis.[15−17] Especially, cyanoacetic hydrazide has been reported in many literature works as a good intermediate for the synthesis of numerous biologically active heterocyclic compounds and pharmaceutical agents.[18−26]

N-Cyanoacetylation of n class="Chemical">aromatic amines can be achieved by various reagents such as cyanoacetyl chloride, cyanoacetyl azide, cyanoacetic ester, N-(cyanoacetyl)imidazole, and 1-cyanoacetyl-3,5-dimethylpyrazole.[27] Among these reagents, 1-cyanoacetyl-3,5-dimethylpyrazole is commercially available, cheap, and nontoxic reagent that proved to be superior to other cyanoacetylating agents.[27] The advantages of using 1-cyanoacetyl-3,5-dimethylpyrazole are that it consumes less reaction time for the formation of N-cyanoacetylation products, the products can be collected in higher yields from the reaction medium, and the leaving group (3,5-dimethylpyrazole) is very soluble in most of the organic solvents and stay in the filtrate.[28−30]

On the other hand, 2-pyridones and their derivatives play an essential role in medicinal chemistry and are proven to possess several biological properties;[24,31−35] thus, despite the large number of methods known for their synthesis, new procedures are required to be developed. Many catalysts have been used in the synthesis of 2-pyridinone from 1,3-diketones, such methanesulfonic acid,[36] SiO2,[37] and triethylamine or piprazine.[38] Microwave irradiation in preparing N-substituted 2-pyridones has also been reported recently.[39] In addition, compounds containing a 4-aminobezoate moiety were reported to possess various biological and pharmacological activities.[40−42]

In this regard, we focus in this work on N-cyanoacylation of benzoate derivatives and N-substituted 2-pyridinone amino acid derivatives by taking the advantages of the ultrasonic method over the conventional method.

Results and Discussion

N-Cyanoacylation

N-Cyanoacetylation of n class="Chemical">4-aminobenzoic acid and its ester derivative or 4-aminoacetophenone with 1-cyanoacetyl-3,5-dimethylpyrazole 1 is a useful preparative method for the synthesis of difficultly available N-substituted cyanoacetamides. This method appeared to be more convenient and economical and occurs at a much faster rate to afford a good yield of the product when compared with other cyanoacetylating agents.[27]

In the present study, cyanoacetylating agent 1 was prepared as described in Method S1 (Supporting information) following the reported procedure in literature works,[43,44] where cyanoacetyl hydrazide was prepared from the ethylacetoacetate first and then reacted with acetylacetone via condensation–cyclization in water containing a catalytic amount of HCl. The spectral data agreed with the reported data (Figure S1, Supporting information). Cyanoacetylating agent 1 was reacted ethyl-4-aminobenzoate 2, 4-aminoacetophenone 5, or 4-aminobenzoic acid 8 in dry toluene employing conventional heating and ultrasonication to give cyanoacylating products 3, 6, and 9, respectively (Scheme ). The ultrasonic method afforded the products in less reaction time with high yields and purities, as shown in Table . The spectral data of the products (Figures S2–S4, Supporting information) agreed with the reported data [ref (26) for compound 6: mp 225 °C, yield 91%; ref (45) for compound 9: 267–269 °C, yield 90%].

Scheme 1

Synthetic Pathways for Pyridinone Derivatives

Table 1

Yield (%) and Reaction Time during Conventional Heating and the Ultrasonic Method for N-Cyanoacylation and Formation of N-Substituted 2-Pyridone Derivatives

compd	conventional heating (time, h)	yield (%)	ultrasonic method (time, min)	yield (%)
3	4	82	20	91
6	4	88	20	96
9	6	86	30	93
4	10	84	1.5	93
7	10	82	1.5	94
10	12	85	2	91

Figure indicates that the ultrasonic method affords compound 3 in higher purity, as shown in Figure B, compared to that obtained by conventional heating (Figure A).

Figure 1

1H NMR spectrum of compound 3. (A) Product obtained from conventional heating (S = starting material) and (B) product obtained from the ultrasonic method.

1H n class="Chemical">NMR spectrum of compound 3. (A) Product obtained from conventional heating (S = starting material) and (B) product obtained from the ultrasonic method.

The 1H NMR spectrum of compound 3 (Figures and S2, Supporting information) showed a triplet at δ 1.29 and a quartet at δ 4.25 for the ethyl ester residue (CH2CH3). The singlet peak at δ 3.92 represented the protons of the methylene group, the two doublets at δ 7.65 and δ 7.93 were related to the four aromatic protons (H, and H, respectively), and the singlet at δ 10.62 represented NHCO. The 13C NMR spectrum (Figure S2, Supporting information) showed peaks at δ 14.1 (methyl of the ethyl ester residue), 26.8 (CH2), 60.7 (methylene group of the ethyl ester residue), 103.9 (related to the carbon of the active methylene group; −CO–CH2–CN), 114.4 (representing the carbon of the cyano group; N), 118.9 (Ca), 125.9 (C–COOC2H5), 130.8 (C), 141.8 (C–NH), 160.2 (representing the carbonyl ester residue), and 165.9 ppm (representing the carbonyl; CO).

Figure 2

Structure of compound 3.

Synthesis of N-Substituted 2-Pyridone Derivatives

The synthesis of 2-pyridone derivatives (4, 7, and 10) was accomplished by the reaction of acetylacetone with N-cyanoacetamide derivatives 3, 6, or 9 in ethanol as a solvent and in the presence of the catalytic amount of triethylamine (0.7 equiv.) using conventional heating as well as the ultrasonic method (Scheme ). Again, the ultrasonic method afforded 4, 7, and 10 in less reaction time with high yield and purity compared with the conventional method, as shown in Table .

The IR spectra of compound 10 (Figure S7, Supporting information) showed an absorption band in the region 3067 cm–1 related to OH carboxylic; 2222 cm–1 related to CN; and broad 1728, 1643, and 1608 cm–1 for the two carbonyls and a phenyl residue[39] The 1H NMR spectrum of compound 10 (Figures and S8, Supporting information) showed two singlet peaks at δ 1.96 and 2.38 for the two methyl groups (a′ and b′, Figure ), a singlet peak at δ 6.46 related to (CH), two doublet peaks at δ 7.45 and 8.08 for the four aromatic protons (H and H, respectively), and a broad singlet peak at δ 13.21 for the carboxylic group (COOH). The 13C NMR spectrum of 10 (Figure S8, Supporting information) showed peaks at δ 20.6 and 21.4 for the two carbons (a′ and b′), 100.0 (C5), 109.1 (C–CN), 115.8 (CN), 128.5 (Ca), (–COOH), 130.7 (C), 131.5, 141.2 (C6), 151.8 (C(phenyl)–N), 160.0 (C4), 160.4 (CO), and 166.6 (CO, carboxylic).

Figure 3

Structure of 10.

Synthesis of Alkyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl) Amino Acid Ester Derivatives

To explore the utility of employing ultrasonication in organic synthesis, especially for amide bond formation, compound 10 was coupled with an equimolecular amount of a different amino acid ester hydrochloride by OxymaPure/DIC as a coupling reagent, N,N-dimethylformamide (DMF) as a solvent, and diisopropylethylamine (DIEA) as a base at room temperature[46] and the ultrasonic method at 30 °C as well to afford the target products 11a–h (Scheme ). The ultrasonic method was very efficient and afforded the target products in less reaction time with high yields and purities compared to the traditional method (Table ).

Scheme 2

Coupling of 10 with Amino Acid Ester Derivatives

Table 2

Yield (%) and Reaction Time during Conventional Heating and the Ultrasonic Method for Coupling N-Substituted 2-Pyridone Derivatives with Amino Acid Esters

compd	conventional overnight at RT, yield (%)	ultrasonic method (1–2 h) at 30 °C, yield (%)
11a	83	93
11b	81	95
11c	80	94
11d	80	92
11e	80	94
11f	82	95
11g	80	93
11h	78	92

The IR spectra of compound 11a (Figure S9, Supporting information) showed an absorption band in the region 3367 cm–1 related to NH, 2218 cm–1 related to the CN, 1751 cm–1 related to the ester group, and 1650 and 1608 cm–1 for the carbonyl and phenyl residues. The 1H NMR spectrum of compound 11a (Figure , Figure S10, Supporting information) as a prototype showed two singlet peaks at δ 1.97 and 2.39 for the two methyl group (pyridone residue), a singlet at δ 3.66 representing the three protons of methyl ester (OCH3), a peak at δ 4.04 related to the methylene group (glycine residue), a singlet peak at δ 6.47 representing H, two doublet peaks at δ 7.45 and 7.99 related to the four aromatic protons (H and H), and a triplet at δ 9.11 representing NH. The 13C NMR spectrum of 11a (Figure S10, Supporting information) showed peaks at δ 20.7 and 21.3 for the two methyl groups, 41.5 for the methylene group of the glycine residue, 51.8 for the methyl ester, 99.9 for the carbon (C5, pyridone residue), 109.0 for C–CN (C3), 115.7 for the cyano group (CN), 128.2 and 128.6 for the two carbons (C3 and C5), 134.2 (C4), 140.0 (C6), 151.8 (C4), 159.9 (Co, pyridine residue), 165.7 (CO, amide), and 170.3 (CO, ester).

Figure 4

Structure of compound 11a.

Conclusions

This work described the synthesis of cyanocetamide benzoic acid derivatives and the synthesis of the cyanoacetamide benzophenone and their corresponding 2-pyridone derivatives by employing two different methods, namely, conventional heating and ultrasonication. The ultrasonic method afforded the product in less reaction time with high yield and purity compared to the conventional method. In addition, it gave a better yield compared to the previously reported method using microwave irradiation.[39] The ultrasonic method also assisted the coupling of the weak carboxylic group of compound 10 with different amino acid esters using the OxymaPure/DIC methodology and afforded the reaction product in less reaction time with higher yield and purity compared to the traditional method.

Finally, the feature of this protocol is exploring the utilization of ultrasonication as an eco-friendly alternative method for the conventional heating or traditional technique to assist N-cyanoacylation and synthesis of N-substituted 2-pyridone derivatives and as a coupling method for the formation of an amide bond.

Materials and Methods

All reagents, chemicals, and solvents were purchased from commercial suppliers. Reactions were monitored using TLC (silica gel 60-F254-protected aluminum sheets). All melting points were determined in open capillary tubes using a Gallenkamp melting point apparatus (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) and were uncorrected. Fourier transform infrared (FTIR) spectra were recorded on a Nicolet 6700 spectrometer using KBr disks. 1H and 13C NMR spectra were recorded on a Jeol instrument. Elemental analyses were recorded on a PerkinElmer 2400 elemental analyzer (PerkinElmer Inc., Waltham, MA). An ultrasonic bath was purchased from Selecta (Barcelona, Spain).

Synthesis of 3-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile (1)

First, cyanoacetic hydrazide was prepared following the reported method[43] as follows.

Hydrazine hydrate (0.1 mol) in n class="Chemical">ethanol–ether (1:2, 300 mL) was added dropwise to ethyl cyanoacetate (0.1 mol) in ethanol (50 mL) at 5–10 °C under vigorous stirring. The resulting reaction mixture was stirred at 5–10 °C for 30 min and then at rt for 2h. Filtered and washed ether to obtain the product as a white solid in yield 73%.

Then, an equimolar amount of 2-cyanoacetohydrazide was mixed with n class="Chemical">acetylacetone in water (15 mL) and in the presence of a catalytic amount of HCl at 0 °C.[44] The mixture was stirred at room temperature for 2 h. The white precipitate was filtered, washed with ice-cold water, and then dried under vacuum.

White solid in yield 91%, mp 113–114 °C; 1H n class="Chemical">NMR (400 MHz, CDCl3) ppm: δ 2.20 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.26 (s, 2H, CH2–CN), 6.03 (s, 1H, pyrazole-H).13C NMR (100 MHz, CDCl3) (ppm): δ13.7 (CH3), 14.0 (CH3), 26.8 (CH2), 112.4 (C=C), 113.4 (CN), 144.7 (CH3–C=C–N), 153.8 (C=C–N–N), 162.4 (C=O).

General Method N-Cyanoacetylation

Conventional Method

A solution of p-aminobezoic acid derivatives (10 mmol) or n class="Chemical">p-aminoacetophenone (10 mmol) in dry toluene (30 mL) was added to a solution of 1-cyanoacetyl-3,5-dimethylpyrazole 2 (1.63 g, 10 mmol) in the same solvent (30 mL), and the mixture was heated under reflux for 6 h. After cooling, the solid product was isolated and washed with ethanol and then dried.

Ultrasonic Method

A solution of p-aminobezoic acid derivatives (10 mmol) or p-aminoacetophenone (10 mmol) in dry toluene (20 mL) was added to a solution of 1-cyano-acetyl-3,5-dimethylpyrazole 2 (10 mmol) in the same solvent (20 mL) at rt, and then, the reaction mixture was subjected to ultrasound irradiation (20–30 min) at 60 °C. TLC was used to monitor the completion of reaction followed by a workup similar to the conventional methodology to obtain products with high yields (90–95%) and purities.

Ethyl 4-(2-Cyanoacetamido)benzoate (3)

White solid in yields 82% (conventional heating, 6 h) and 91% (US 30 min at 60 °C), mp 163–164 °C [ref[42]: mp. 162 °C, yield 92%]. 1H n class="Chemical">NMR (400 MHz, CDCl3) δ: 1.29 (t, 3H, J = 7.2 Hz, CH3), 3.54 (s, 2H, CH2), 4.26 (q, 2H, CH2), 7.55 (d, 2H, J = 8.8 Hz, Ar), 7.42–7.89 (d, 2H, J = 8.8 Hz, Ar), 10.09 (s, 1H, NH) ppm; 13C NMR (100 MHz, CDCl3) δ: 14.1, 26.8, 60.7, 103.9, 114.4, 118.9, 125.9, 130.4, 141.8, 144.2, 160.2, 165.9 ppm.

N-(4-Acetylphenyl)-2-cyanoacetamide (6)

White solid in yields 88% (conventional heating, 4 h) and 95% (US, 20 min), mp 226–227 °C [ref (26): 225 °C, yield 91%]. 1H n class="Chemical">NMR (400 MHz, DMSO-d6) δ: 2.49 (s, 3H, CH3), 3.92 (s, 2H, CH2), 7.64 (d, 2H, J = 8.8 Hz, Ar), 7.42–7.91 (d, 2H, J = 8.8 Hz, Ar), 10.59 (s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6) δ: 26.5, 27.0, 115.6, 118.5, 129.7, 132.3, 142.6, 161.7, 197.6 ppm.

4-(2-Cyanoacetamido)benzoic Acid (9)

Off-white powder in yield 86% (conventional heating, 6 h) and 93% (US, 30 min), mp 261–263 [ref (45): mp 267–269 °C, yield 90%]. IR (KBr, cm–1): 3322 (NH), 3100 (OH), 2260 (CN), broad 1695, 1650 (2CO); 1H NMR (400 MHz, DMSO-d6) δ 3.92 (s, 2H, CH2), 7.64 (d, 2H, J = 8.8 Hz, Ar-H), 7.95 (d, 2H, J = 8.8 Ar-H), 10.59 (s, 1H, NHCO), 12.77 (brs, 1H, COOH) ppm. 13C NMR (100 MHz, DMSO-d6) δ 27.0, 115.8, 118.5, 125.8, 130.6, 142.4, 161.7, 166.8 (CO) ppm. Anal. Calcd. for C10H8N2O3 (204.19). Found C, 58.97; H, 4.06; N, 13.93.

General Method for the Synthesis of 2-Pyridone Derivatives (4, 7, and 10)

Conventional Heating

To a mixture of compounds 3, 6, or 9 (5 mmol) and acetylacetone (0.51 mL, 5.5 mmol) in absolute ethanol (30 mL) was added triethylamine (0.5 mL, 1.5 equiv. in case of an acid 2 equiv of DIEA was used). The reaction mixture was refluxed for 10–12 h, then cooled down to room temperature, and poured onto (100 mL) ice/water, and the medium was neutralized by dilute HCl. The obtained solid was filtered off, washed with water, and recrystallized from ethanol to afford the target compound.

Ultrasonic Method

Compound 3, 6, or 9 (5 mmol) was mixed with acetylacetone (5.5 mmol) in ethanol (20 mL), and then, triethylamine was added (1.5 equiv.) at rt with stirring. The reaction mixture was subjected to ultrasonic irradiation (1–2 h) at 60 °C. TLC was used to monitor the completion of reaction followed by workup similar to conventional methodology to obtain products with high yields (90–95%) and purities.

Ethyl 4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoate (4)

Off-white solid in yields 84% (conventional heating, 10 h), 93% (US, 1.5 h at 60 °C), mp 223–224 °C. 1H NMR (100 MHz, DMSO-d6): δ 1.33 (t, 3H, J = 7.2 Hz, CH3) 1.93 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.34 (q, 2H, J = 6.4, 7.7 Hz, CH2), 6.47 (s, 1H, CH), 7.48 (d, 2H, J = 8.4 Hz, Ar), 8.10 (d, 2H, J = 8.4 Hz, Ar) ppm; 13C NMR (100 MHz, DMSO-d6): δ 14.1, 20.7, 21.4, 61.1, 100.0, 109.1, 115.7, 128.7, 130.6, 141.4, 151.7, 160.0, 160.3, 165.0 ppm. Anal. Calcd for C17H16N2O3 (296.33) C, 68.91; H, 5.44; N, 9.45. Found C, 68.74; H, 5.51; N, 9.67.

1-(4-Acetylphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (7)

White solid in yields 82% (conventional heating, 10 h) and 94% (US, 1.5 h at 60 °C), mp 262 °C [ref:[39] mp 259–261, yields 80% (conventional heating) and 91% (MW). 1H NMR (400 MHz, DMSO-d6): δ 1.96 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.48 (s, 1H, CH), 7.49 (d, 2H, J = 8.0 Hz, Ar), 8.11 (d, 2H, J = 8.4 Hz, Ar) ppm; 13C NMR (100 MHz, DMSO-d6): δ 20.7, 21.4, 26.5, 100.0, 115.8, 128.4, 137.2, 141.3, 151.7, 159.9, 160.3, 197.4 ppm. Anal. Calcd for C16H14N2O2 (266.11) C, 72.17; H, 5.30; N, 10.52. Found C, 72.32; H, 5.41; N, 10.77.

N-(4-Carboxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone (10)

Off-white solid in yield 85% (conventional heating, 12 h reflux) and 91% (US, 2 h), mp 321 °C (dec) [ref:[39] mp 325 °C, yields 78% (MW) and 13% (conventional heating, in the presence of piepridine as a base]. 1H NMR (400 MHz, DMSO-d6): δ 1.96 (s, 3H, CH3), 2.38 (s, 3H, CH3), 6.46 (s, 1H, CH), 7.45 (d, 2H, J = 8.8 Hz, Ar), 8.08 (d, 2H, J = 8.8 Hz, Ar), 13.21 (br.s. 1H, COOH) ppm; 13C NMR (DMSO-d6): δ 20.6, 21.4, 100.0, 109.1, 115.8, 128.5, 130.7, 131.5, 141.2, 151.8, 160.0, 160.4, 166.6 ppm. Anal. Calcd for C15H12N2O3 (268.27) C, 67.16; H, 4.51; N, 10.44. Found C, 67.30; H, 4.62; N, 10.64

General Method for the Reaction of 10 with Amino Acid Esters Using OxymaPure/DIC

Traditional Method (TM)

A mixture of an acid 10 (1 mmol) and OxymaPure (1 mmol) was dissolved in 5 mL of DMF at 0 °C, followed by the dropwise addition of DIC (1.1 mmol) at 0 °C. The reaction mixture was preactivated for 5 min, and then, a mixture of 1 mmol amine acid ester hydrochloride and 1 mmol DIEA in DMF (3 mL) was added dropwise at the same temperature. After that, the mixture was stirred at 0 °C for 1 h and then left overnight under stirring at rt. The progress of the reaction was followed by TLC (ethylacetate–n-hexane, 4:6; or MeOH–CHCl3, 1:9). Excess water was added, and the solid product was filtered or extracted with ethylacetate, washed with water, and then dried and recrystallized from ethylacetate.

Ultrasonic Method (US)

A mixture of an acid 10 (1 mmol) and OxymaPure (1 mmol) was dissolved in 5 mL of DMF at 0 °C, followed by the dropwise addition of DIC (1.1 mmol) at 0 °C. The reaction mixture was preactivated for 5 min, and then, a mixture of 1 mmol amine acid ester hydrochloride and 1 mmol DIEA in DMF (3 mL) was added dropwise at the same temperature. After that, the mixture was stirred at 0 °C for 1 h and then the reaction mixture was subjected to ultrasound irradiation (1–2 h) at 30 °C. TLC was used to monitor the completion of reaction followed by a workup similar to the traditional methodology to obtain products with higher yields (92–95%) and purities.

Methyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)glycinate (11a)

Off-white solid in yields 83% (TM) and 93% (US), mp 256–258 °C; FTIR (KBr): 3258 (NH), 2260 (Cn class="Chemical">N, cyano), 1730 (CO, ester), 1620 (C–N, amide), 1650 (CO, pyridine), 1371 (O–CH3) cm–1; 1H NMR (400 MHz, DMSO-d6): δ 1.97(s, 3H, CH3), 2.39 (s, 3H, CH3), 3.66 (s, 3H,OCH3), 4.04 (d, 2H, J = 6.0 Hz, CH2), 6.47 (s, 1H, CH), 7.45 (d, 2H, J = 8.0 Hz, Ar), 8.0 (d, 2H, J = 8.0 Hz, Ar), 9.11 (t, 1H, J = 5.6 Hz, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 20.7, 21.5, 41.2, 51.8, 99.9, 109.0, 115.8, 128.3, 128.7, 134.3, 140.0, 151.9, 159.9, 160.4, 165.9, 170.3 ppm. LC/MS (ESI): 340.25 [M + H]+. Anal. Calcd for C18H17N3O4 (339.35) C, 63.71; H, 5.05; N, 12.38. Found C, 63.71; H, 5.05; N, 12.38.

Methyl 3-(4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzamido)propanoate (11b)

Off-white solid in yields 81% (TM) and 95% (US), mp 176–167 °C; FTIR (KBr): 3265 (NH), 2264 (Cn class="Chemical">N, cyano), 1735 (CO, ester), 1620 (C–N, amide), 1654 (CO, pyridine), 1371 (O–CH3) cm–1; 1H NMR (400 MHz, CDCl3): δ 1.97(s, 3H, CH3), 2.42 (s, 3H, CH3), 2.64 (t, 2H, J = 6.0 Hz, CH2), 3.66 (m, 5H, CH2, OCH3), 6.14 (s, 1H, CH), 7.11 (t, 1H, J = 5.6 Hz, NH), 7.17 (d, 2H, J = 8.8 Hz, Ar), 7.86 (d, 2H, J = 8.8 Hz, Ar) ppm; 13C NMR (100 MHz, CDCl3): δ 21.2, 21.9, 335, 35.5, 51.8, 101.0, 109.2, 114.9, 127.8, 128.9, 135.7, 139.7, 150.5, 159.7, 160.9, 166.3, 173.1 ppm. LC/MS (ESI): 354.46 [M + H]+. Anal. Calcd for C19H19N3O4 (353.38) C, 64.58; H, 5.42; N, 11.89. Found C, 64.69; H, 5.49; N, 11.74.

Methyl 4-(4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzamido)butanoate (11c)

Off-white solid in yields 80% (TM) and 94% (US), mp 201–202 °C; FTIR (KBr): 3262 (NH), 2263(Cn class="Chemical">N, cyano), 1736 (CO, ester), 1620 (C–N, amide), 1645 (CO, pyridine), 1375 (O–CH3) cm–1; 1H NMR (400 MHz, DMSO-d6): δ 1.78–1.80 (m, 2H, CH2), 1.96(s, 3H, CH3), 2.36–2.39 (m, 2H, CH2, CH3), 3.27–3.30 (m, 2H, CH2), 3.57 (s, 3H, OCH3), 6.46 (s, 1H, CH), 7.41 (d, 2H, J = 8.8 Hz, Ar), 7.96 (d, 2H, J = 8.8 Hz, Ar), 8.63 (t, 1H, J = 5.6 Hz, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 20.7, 21.4, 24.4, 30.8, 38.6, 51.3, 99.9, 109.0, 115.8, 128.0, 128.5, 1352, 139.6, 151.9, 159.7, 160.4, 165.4, 173.2 ppm. LC/MS (ESI): 368.46 [M + H]+. Anal. Calcd for C20H21N3O4 (367.41) C, 65.38; H, 5.76; N, 11.44. Found C, 65.55; H, 5.89; N, 11.23.

Methyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)alaninate (11d)

Off-white solid in yields 80% (TM) and 92% (US), mp 206–208 °C; FTIR (KBr): 3258 (NH), 2260 (Cn class="Chemical">N, cyano), 1730 (CO, ester), 1620 (C–N, amide), 1650 (CO, pyridine), 1371 (O–CH3) cm–1; 1H NMR (400 MHz, CDCl3): δ 1.51 (d, 3H, 2H, J = 6.8 Hz, CH3), 1.98 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.71–4.75 (m, H, CH), 6.16 (s, 1H, NH), 7.17 (m, 2H, Ar), 7.24 (m, 1H, J = 5.6 Hz, NH), 7.90–7.92 (m, 2H, Ar) ppm; 13C NMR (100 MHz, CDCl3): δ 18.2, 21.2, 23.3, 42.2, 52.5, 102.3, 109.5, 114.9, 127.9, 129.2, 135.2, 139.8, 150.6, 159.7, 160.9, 165.9, 173.4 ppm. LC/MS (ESI): 354.48 [M + H]+. Anal. Calcd for C19H19N3O4 (353.38) C, 64.58; H, 5.42; N, 11.89. Found C, 64.32; H, 5.51; N, 11.99.

Methyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)valinate (11e)

Off-white solid in yields 80% (TM) and 94% (US), mp 242–243 °C; FTIR (KBr): 3258 (NH), 2260 (Cn class="Chemical">N, cyano), 1730 (CO, ester), 1620 (C–N, amide), 1650 (CO, pyridine), 1371 (O–CH3) cm–1; 1H NMR (400 MHz, CDCl3): δ 0.97–0.99 (m, 6H, 2CH3), 1.96 (s, 3H, CH3), 2.22–2.25 (m, 1H, CH), 2.44 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.65–4.68 (m, H, CH), 6.14 (s, 1H, CH), 6.96 (m, 1H, NH), 7.17–7.27 (m, 2H, Ar), 7.89–7.92 (m, 2H, Ar) ppm; 13C NMR (100 MHz, CDCl3): δ 17.7, 21.1, 23.3, 31.1, 42.2, 58.2, 102.2, 109.7, 114.9, 127.9, 128.8, 135.3, 139.8, 150.5, 157.0, 159.6, 160.9, 166.2, 172.5 ppm. LC/MS (ESI): 382.36 [M + H]+. Anal. Calcd for C21H23N3O4 (381.43) C, 66.13; H, 6.08; N, 11.02. Found C, 66.30; H, 6.19; N, 11.33.

Methyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)phenylalaninate (11f)

Off-white solid in yields 82% (TM) and 95% (US), mp 115–116 °C; FTIR (KBr): 3264 (NH), 2265 (Cn class="Chemical">N, cyano), 1735 (CO, ester), 1620 (C–N, amide), 1645 (CO, pyridine), 1375 (O–CH3) cm–1; 1H NMR (400 MHz, DMSO-d6): δ 1.95 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.06–3.3.21 (m, 2H, CH2), 3.63 (s, 3H, OCH3), 4.68–4.70 (m, 1H, CH), 6.46 (s, 1H, CH), 7.19 (m, 1H, Ar), 7.28–7.43 (m, 4H, Ar), 7.42 (d, 2H, J = 8.8 Hz, Ar), 7.89–7.94 (m, 2H, Ar), 9.00 (d, 1H, J = 8.0 Hz, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 21.4, 23.3, 38.6, 40.2, 52.0, 99.9, 109.0, 115.8, 126.5, 128.1, 128.2, 128.7, 129.0, 134.3, 137.6, 139.9, 151.8, 159.8, 160.4, 165.7, 172.0 ppm. LC/MS (ESI): 430.52 [M + H]+. Anal. Calcd for C25H23N3O4 (429.48): C, 69.92; H, 5.40; N, 9.78. Found C, 69.82; H, 5.33; N, 9.92.

tert-Butyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)phenylalaninate (11g)

Off-white solid in yields 80% (TM) and 93% (US), mp 165–167 °C; FTIR (KBr): 3264 (NH), 2265 (Cn class="Chemical">N, cyano), 1736 (CO, ester), 1620 (C–N, amide), 1645 (CO, pyridine), 1370 (O–CH3) cm–1; 1H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H, t-Bu), 1.96 (s, 3H, CH3), 2.43 (s, 3H, CH3), 4.34–4.38 (m, H, CH), 6.16 (s, 1H, CH), 6.79 (d, 1H, J = 7.6 Hz, NH), 7.19–7.26 (m, 7H, Ar), 7.81–7.87 (m, 2H, Ar) ppm; 13C NMR (100 MHz, CDCl3): δ 21.5, 24.5, 27.9, 37.8, 102.3, 109.3, 114.9, 128.4, 128.8, 129.2, 135.3, 135.9, 139.9, 151.0, 157.3, 159.6, 160.9, 165.6, 170.7 ppm. LC/MS (ESI): 472.43 [M + H]+. Anal. Calcd for C28H29N3O4 (471.56): C, 71.32; H, 6.20; N, 8.91. Found C, 71.50; H, 6.31; N, 8.75.

Dimethyl (4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzoyl)aspartate (11h)

Off-white solid in yields 78% (TM) and 92% (US), mp 167–168 °C; FTIR (KBr): 3264 (NH), 2255 (Cn class="Chemical">N, cyano), 1743, 1738 (CO, ester), 1625 (C–N, amide), 1650 (CO, pyridine), 1371 (O–CH3) cm–1; 1H NMR (400 MHz, CDCl3): δ 1.99 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.97 (dd, H, J = 4.4, 4.2 Hz, CH), 3.11 (dd, H, J = 4.4, 4.2 Hz, CH), 3.70 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 5.03–5.05 (m, 1H, CH), 6.15 (s, 1H, CH), 7.29–7.26 (m, 2H, Ar), 7.36 (d, 1H, J = 8.0 Hz, NH), 7.93–7.97 (m, 2H, Ar) ppm; 13C NMR (100 MHz, CDCl3): δ 22.0, 23.5, 41.9, 51.3, 52.2, 102.3, 109.0, 114.9, 128.1, 129.2, 134.9, 140.1, 150.3, 156.9, 159.6, 160.8, 165.8, 171.0, 171.6 ppm. LC/MS (ESI): 413.50 [M + 2H]+. Anal. Calcd for C21H21N3O6 (411.41): C, 61.31; H, 5.15; N, 10.21. Found C, 61.53; H, 5.24; N, 10.43.