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Pyridin-2-one Synthesis Using Ester Enolates and Aryl Aminoaldehydes and Ketones Tushar Apsunde† and Ryan P. Wurz*,‡ †

Department of Chemistry, University of New Orleans, 2000 Lakeshore Drive, New Orleans, Louisiana 70148, United States Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States



S Supporting Information *

ABSTRACT: An aldol-like cyclocondensation has been used to prepare heterocyclic-fused pyridin-2-ones from aminoaldehydes and ketones upon treatment with a lithium enolate of ethyl acetate or α-substituted acetates. These motifs are present in a large number of biologically active natural products and synthetic compounds and can be accessed using mild reaction conditions using readily available starting materials. This methodology allows access to pyrimidinopyridin-2-ones, pyrazolopyridin-2-ones, and pyridopyridazine diones with varying substitution patterns. Scheme 1. Common Routes To Access Pyridin-2-onesa

T

he pyridin-2-one motif is present in a large number of naturally occurring and bioactive molecules.1 It can serve as a more polar replacement for a benzene ring and help modulate the properties of medicinally important molecules. As such, this motif has been incorporated into a large number of drug discovery programs targeting biochemical pathways associated with inflammatory disorders (p38, 1−2)2 and oncology (CDK4 33 and FGFR inhibitors 4,4 Figure 1) to highlight a few.

a

Conditions: (a) Ph3PCHCO2Et, THF, reflux; (b) DBU, i-Pr2NEt, 160 °C; (c) Ac2O, DMF, 140 °C; (d) ArBr(I), CuI, ligand, DMSO, 130 °C; (e) ArB(OH)2, CuI, ligand, dioxane, 110 °C.

with boronic acids (condition e).8 These methods are generally high yielding when R = alkyl, but far fewer examples exist for R = aryl and are much lower yielding.9 A number of recent reports have focused on the preparation of the pyridinone motif with more limited substitution patterns. These examples include the synthesis of naphthyridones,10 3,4-dihydroquinoline-2(1H)-ones,11 isoquinolin-1-(2H)-ones,12 benzofuro[3,2b]pyridines,13 substituted cyclopentyl-fused pyridinones,14 and pyrimidinopyridinones via ring expansions of isatins with diazo compounds.15 As part of one of our discovery programs, we sought a mild and scalable method to access compounds structurally related to compound 3. Our primary focus was on the ability to access compounds containing N-aryl substitution on the pyridinone ring. In addition, we were interested in developing a versatile method which would allow exploration of various substitution patterns in other positions of the pyridinone ring. Attempted application of known literature methods described above for the synthesis of 7 resulted in low yields of the desired product. Failure of these approaches was due, in part, to the thermal lability of the Boc-protected aniline present in 5a and the elevated reaction temperatures required for the incorporation of the pyridinone motif.

Figure 1. Pyridin-2-one containing compounds of medicinal interest.

Depending on the nature of the substitution on the pyridinone nitrogen, the synthesis of fused heterocyclic pyridin-2-ones such as 3 typically involves reaction sequences including (1) olefination of an aminoaldehyde followed by DBU-mediated cyclization (Scheme 1, conditions a,b),5 (2) treatment of an aminoaldehyde with Ac2O in DMF (condition c),6 (3) Cu-catalyzed arylation of pyridin-2-(1H)-ones with aryl halides (condition d),7 (4) metal-catalyzed coupling reactions © 2014 American Chemical Society

Received: February 5, 2014 Published: March 17, 2014 3260

dx.doi.org/10.1021/jo500284n | J. Org. Chem. 2014, 79, 3260−3266

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acidic N−H hydrogens present on the substrate. Other bases including NaHMDS, LDA, and LiOt-Bu were also briefly examined and produced the desired product 7a but with lower conversions after 2 h.18 Variation of the equivalents of enolate had little influence on the outcome of the reaction as 1.2 or 3.2 equiv of EtOAc gave essentially the same conversions as 2.2 equiv (entries 7 and 8 vs entry 1). This reaction was also conducted in three other polar aprotic solvents and found to give inferior conversions after 2 h reaction time presumably due to reduced solubility of the substrate in these solvents (entries 9−11). We then examined the scope of the reaction to determine the applicability of the present set of reaction conditions to the synthesis of structurally related N-arylpyrimidinoaldehyde and ketone substrates (5a−e). Replacement of R1 = NHBoc with R1 = NHMe gave modest yields of the desired product 7b (Table 2, entry 2). The cyclization also performed well with a ketone

We then turned to a milder approach using a lithium enolate of EtOAc15,16 as a method of introducing the requisite 2-carbon fragment to transform the aminoaldehyde 5a to the desired pyridin-2-one 7a. In this approach, addition of the enolate to the aldehyde would then be followed by cyclization and aromatization of intermediate 6 to provide 7a (Scheme 2). Scheme 2. Proposed Pyridin-2-one Synthesis

Table 2. Substrate Scope: N-Arylpyridin-2-one Analogues

Investigation of a number of reaction conditions focused initially on EtOAc as the source of the enolate. These reaction parameters included the identity and equivalents of base used along with a number of polar aprotic solvents. Formation of a lithium enolate by slow addition of EtOAc to a THF solution of LiHMDS at −78 °C followed by stirring for 20 min was found to be sufficient for enolate formation. The aminoaldehyde substrate 5a was then added to the enolate solution as a solid in one portion, and the reaction mixture was allowed to warm to ambient temperature and stirred 2 h. This protocol provided excellent yields of the desired pyrimidinopyridin-2-one 7a. It is noteworthy to mention that, in the presence of 3 equiv of LiHMDS, intermediate 6 slowly cyclizes and aromatizes during the duration of the reaction.17 Further investigation indicated that fewer equivalents of LiHMDS (Table 1, entries 2 and 3 vs entry 1) resulted in significant erosion in the LC conversion of the reaction presumably due to quenching of the enolate by the

variation from the “standard” conditions

% conversiona

1 2 3 4 5 6 7 8 9 10 11

none LiHMDS (2 equiv) LiHMDS (1 equiv) NaHMDS (3 equiv) LDA (3 equiv) LiOt-Bu (3 equiv) EtOAc (3.2 equiv) EtOAc (1.2 equiv) 2-MeTHF 1,4-dioxane Et2O

85 (84.5%)b 53 26 12 29 6 85 82 72 55 20

R

R1

product

yield (%)a

1 2 3 4 5

H H Me Me Me

NHBoc NHMe NHBoc OMe Br

7a 7b 7c 7d 7e

85 72 78 52b 35c,d

a Yield of purified product. b2.2 equiv of LiHMDS was used. c2.5 equiv of LiHMDS was used. dThe reaction time was extended to 4 h.

(5c, R = Me, entry 3).19 Reduced yields were observed when R1 = OMe or Br (entries 4 and 5). In an attempt to improve the yield of 7e, 5 equiv of LiHMDS and EtOAc was used, resulting in little deviation from the original result.20 Gratifyingly, good yields of 6-substituted pyridinones were possible with a variety of α-aryl-substituted esters (Table 3, entries 1−5).21,22 A significant decrease in yield was observed with the less acidic β-arylated substrate presumably due to slower rates of enolate formation under the standard reaction conditions (entry 6). To further demonstrate the utility of the pyridinone synthesis, substrates bearing N-methyl substitution (9a−e) were also submitted to the reaction conditions. Modest to excellent yields could be obtained using either an aldehyde (Table 4, entry 1) or a variety of ketones (entries 2−5). In these cases, 2 equiv of LiHMDS was sufficient to promote the cyclization. Finally, aminoaldehydes and ketones fused to other heterocycles were submitted to the standard reaction conditions and found to furnish the desired pyridinones. Accordingly, pyrazolopyridinones (Table 5, entry 1), pyridopyridazine diones (entry 2), and chloropyrimidinopyridinones (entry 3) could be prepared in modest yields. If desired, the 5,6-disubstitution pattern can also be accessed by use of the combination of aminoketones and α-substituted esters as reaction partners. In this particular case, the hydroxylated intermediate was found to be stable and could

Table 1. Optimization of Reaction Conditions

entry

entry

a

Percent conversion determined by LC-MS. bNumber in parentheses corresponds to an isolated yield. 3261

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Table 3. Substrate Scope: 6-Substituted N-Arylpyridinone Analogues

a

Table 5. Substrate Scope: Application to Other Fused Heterocyclic Pyridinone Analogues

Yield of purified product.

Table 4. Substrate Scope: N-Methylpyridinone Analogues

a c

a

entry

R

product

yield (%)a

1 2 3 4 5

H Me Ph Bn c-C5H9

10a 10b 10c l0d l0e

85 85 67 82 50b

Yield of purified product. bLiHMDS (3 equiv), 2 days reaction time. LiHMDS (2.5 equiv), 5 h reaction time.

In conclusion, we have described an alternative synthesis of pyridin-2-ones using an aldol-like cyclocondensation that proceeds under mild reaction conditions. The methodology uses readily available starting materials, furnishing modest to excellent yields for a range of 5-, 6-, and 5,6-disubstituted heterocyclic-fused pyridin-2-one products. It provides facile access to N-arylated pyridin-2-ones which are challenging to prepare using previously reported methodologies. Furthermore, this methodology does not require the use of heavy metals (e.g., Pd, Cu) nor does it produce byproducts such as triphenylphosphine oxide which may complicate purifications.

Yield of purified product. bThe reaction time was 4 h.

be dehydrated to product upon addition of Martin sulfurane (1 equiv) to the reaction mixture, thereby generating the 5,6disubstituted pyridin-2-one 13 in a one-pot reaction (eq 1).23



EXPERIMENTAL SECTION

General Procedures. All reactions were run under an atmosphere of nitrogen, with exclusion of moisture from reagents and glassware, using standard techniques for manipulating air-sensitive compounds, unless otherwise stated. Anhydrous tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane were purchased and used directly without further manipulation. Reagents were purchased and used without further purification. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by LC-MS analysis. Flash chromatography was performed using automated instrumentation using prepacked silica columns. NMR spectra were recorded at 400 MHz, calibrated using the resonance of residual protio solvents (e.g., CDCl3 at 7.27 ppm, DMSO-d6 at 2.50 ppm) and were reported in parts per million as follows: chemical shift (multiplicity, coupling constant (Hz), integration). The following abbreviations were used to explain

This methodology has also been found to be useful in the preparation of pyridinones with radiolabels24 or deuterium. Use of EtOAc-d8 resulted in 74% isolated yield of the desired product 14 with 92% deuterium incorporation in the 6-position (eq 2). This observed slight erosion in deuterium content maybe related to quenching of the enolate by the acidic N−H protons and subsequent regeneration of the mixed D/H containing enolate with the remaining equivalent of LiHMDS.25 3262

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tert-Butyl (3-(5-Methyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (7c). The title compound was prepared according to the standard procedure affording the title compound as an off-white solid (4.29 g, 78%) after suspension of the crude material in Et2O followed by filtration of the resulting solid and washing with additional Et2O: mp 213−216 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (1 H, s), 8.98 (1 H, s), 7.42−7.48 (2 H, m), 7.35−7.42 (1 H, m), 6.88 (1 H, d, J = 7.6 Hz), 6.55−6.60 (1 H, m), 2.21 (3 H, s), 1.47 (9 H, s); note one Me signal under DMSO signal; 13 C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 161.6, 155.0, 154.7, 152.7, 146.4, 140.2, 136.0, 129.0, 122.5, 120.4, 118.2, 117.8, 109.9, 79.3, 28.1, 17.0, 13.4; HRMS (ESI) calcd for C20H22N4O3S [M + 1]+ m/z 399.1492, found 399.1493; IR (film, cm−1) 3290, 2977, 2928, 2361, 2361, 2338, 1667, 1570, 1523, 1523, 1159. 8-(3-Methoxyphenyl)-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (7d). The title compound was prepared according to the standard procedure, except only 2.0 equiv of LiHMDS was used, affording the title compound as a white crystalline solid (140 mg, 52%) following chromatography using a gradient of 0− 10% EtOAc in DCM: mp 177−179 °C; 1H NMR (400 MHz, DMSOd6) δ ppm 8.96 (1 H, s), 7.43 (1 H, t, J = 8.1 Hz), 7.04 (1 H, d, J = 8.4 Hz), 6.90 (1 H, br s), 6.85 (1 H, d, J = 7.4 Hz), 6.56 (1 H, s), 3.77 (3 H, s), 2.50 (3 H, s), 2.19 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.4, 161.6, 159.7, 154.9, 154.8, 146.3, 136.9, 129.5, 121.1, 120.5, 114.7, 114.0, 109.9, 55.4, 17.0, 13.4; HRMS (ESI) calcd for C16H15N3O2S [M + 1]+ m/z 314.0964, found 314.0957; IR (film, cm−1) 3290, 2977, 2925, 2835, 2361, 2338, 1668, 1568, 1522, 1431, 1352, 1260. 8-(3-Bromophenyl)-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (7e). The title compound was prepared according to the standard procedure, except that 2.5 equiv of LiHMDS was used and the reaction time was extended to 4 h, affording the title compound as an off-white solid (750 mg, 35%) following purification by chromatography (using a gradient of 0−20% EtOAc in dichloromethane): mp 206−214 °C; 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1 H, s), 7.57−7.64 (1 H, m), 7.42−7.46 (1 H, m), 7.37−7.42 (1 H, m), 7.17−7.23 (1 H, m), 6.56 (1 H, d, J = 1.2 Hz), 2.51 (3 H, d, J = 1.2 Hz), 2.19 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 161.5, 155.0, 154.7, 146.5, 137.2, 132.0, 131.2, 130.7, 128.4, 121.1, 120.4, 110.0, 17.0, 13.4; HRMS (ESI) calcd for C15H12BrN3OS [M + 1]+ m/z 361.9963, found 361.9962; IR (film, cm−1) 3056, 2925, 2361, 2337, 1665, 1567, 1437, 1363, 1175. tert-Butyl (3-(6-Methoxy-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8a). The title compound was prepared according to the standard procedure, affording the title compound as a white solid (1.70 g, 74%) following isolation by filtration of the quenched reaction mixture and washing the resulting solid with Et2O: mp 227−233 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (1 H, br s), 8.86 (1 H, br s), 7.28−7.58 (4 H, m), 6.92 (1 H, d, J = 6.7 Hz), 3.89 (3 H, br s), 2.20 (3 H, br s), 1.47 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 167.8, 157.9, 155.1, 152.7, 151.2, 148.3, 140.3, 136.0, 129.1, 122.4, 118.0, 109.7, 107.2, 79.3, 56.1, 28.1, 13.4; HRMS (ESI) calcd for C20H22N4O4S [M + 1]+ m/z 415.1441, found 415.1437; IR (film, cm−1) 3280, 3087, 2979, 2932, 2361, 2338, 1670, 1579, 1535, 1430,1165. tert-Butyl (3-(2-(Methylthio)-7-oxo-6-phenylpyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8b). The title compound was prepared according to the standard procedure, affording the title compound (255 mg, 81%) as a pale yellow solid after suspension of the crude product in Et2O and filtration: mp 244−246 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (1 H, br s), 8.96 (1 H, br s), 8.22 (1 H, br s), 7.62−7.79 (2 H, m), 7.54 (1 H, br s), 7.42 (5 H, br s), 6.96 (1 H, br s), 2.22 (3 H, br s), 1.45 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.2, 161.4, 157.2, 154.2, 152.7, 140.3, 136.4, 135.5, 134.3, 131.7, 129.0, 128.8, 128.4, 128.1, 122.5, 118.2, 118.0, 109.8, 79.3, 28.1, 13.5; HRMS (ESI) calcd for C25H24N4O3S [M + 1]+ m/z 461.1648, found 461.1653; IR (film, cm−1) 3286, 2979, 2926, 2362, 2337, 1609, 1572, 1531, 1433, 1160. tert-Butyl (3-(6-(4-Chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3d]pyrimidin-8(7H)-yl)phenyl)carbamate (8c). The title compound

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. Melting points are given as ranges, are uncorrected, and are reported in °C. High-resolution mass spectral analysis was acquired using a QTOF operated in positive ion mode. IR data (υmax) are reported in cm−1 and were collected on a FTIR spectrophotometer. Thin films were prepared by evaporation of solutions of the compound in dichloromethane. tert-Butyl (3-((5-Formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (5a). This compound was prepared according to a previously reported literature method, affording the title compound as an off-white crystalline solid:26 mp 140−148 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (1 H, s), 9.85 (1 H, s), 9.45 (1 H, s), 8.72 (1 H, s), 7.94 (1 H, s), 7.36 (1 H, dd, J = 8.1, 1.1 Hz), 7.26 (1 H, t, J = 8.1 Hz), 7.10−7.19 (1 H, m), 2.53 (3 H, s), 1.48 (9 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 192.7, 176.7, 163.9, 156.4, 152.7, 140.1, 137.4, 129.0, 115.6, 114.6, 111.4, 109.3, 79.2, 28.1, 13.9; HRMS (ESI) calcd for C17H20N4O3S [M + 1]+ m/z 361.1335, found 361.1335; IR (film, cm−1) 3287, 2978, 2929, 2361, 2338, 1724, 1653, 1589, 1566, 1369, 1234, 1158, 1125. 4-((3-(Methylamino)phenyl)amino)-2-(methylthio)pyrimidine-5carbaldehyde (5b). This compound was prepared according to a similar procedure used for 5a, except the LiAlH4 reduction was allowed to stir and warm to room temperature overnight, affording the title compound as a yellow-orange solid (304 mg, 28%): mp 129−147 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.46 (1 H, s), 9.78−9.88 (1 H, m), 8.64−8.74 (1 H, m), 7.09 (1 H, t, J = 8.0 Hz), 6.94 (1 H, s), 6.86 (1 H, d, J = 7.8 Hz), 6.37 (1 H, d, J = 7.8 Hz), 5.78 (1 H, d, J = 4.1 Hz), 2.64−2.75 (3 H, s), 2.53−2.60 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 192.7, 176.6, 164.0, 156.3, 150.5, 137.9, 129.2, 109.3, 108.9, 108.7, 104.3, 29.7, 28.1, 14.0; HRMS (ESI) calcd for C13H14N4OS [M + 1]+ m/z 275.0966, found 275.0967; IR (film, cm−1) 3395, 2361, 2338, 1653, 1590, 1566, 1372, 1125. General Procedure for the Aldol-like Condensation and Cyclization Reaction. LiHMDS (1.0 M in THF, 0.83 mL, 0.83 mmol) was added to THF (2.7 mL), cooled to −78 °C, and treated with ethyl acetate (0.06 mL, 0.61 mmol) slowly dropwise. The solution was stirred at −78 °C for 25 min, then solid tert-butyl (3-((5formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (5a, 100 mg, 0.277 mmol) was added in one portion, and the solution was removed from the cooling bath and allowed to warm to room temperature. After 2 h, the reaction was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2 × 15 mL), dried over MgSO4, filtered, and concentrated. The reaction was purified on silica gel (25 g column, using a gradient of 0−80% EtOAc in hexanes) affording tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin8(7H)-yl)phenyl)carbamate (7a, 91 mg, 0.24 mmol, 85% yield) as a pale yellow crystalline solid. tert-Butyl (3-(2-(Methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)yl)phenyl)carbamate (7a). The title compound was prepared according to the standard procedure affording the title compound as an off-white solid (91 mg, 85%): mp 225−229 °C; 1H NMR (400 MHz, chloroform-d) δ ppm 8.66 (1 H, s), 7.70 (1 H, d, J = 9.4 Hz), 7.52 (1 H, br s), 7.43 (1 H, t, J = 8.0 Hz), 7.27−7.32 (1 H, m), 6.93 (1 H, dt, J = 7.8, 0.9 Hz), 6.74 (1 H, d, J = 9.6 Hz), 6.66 (1 H, s), 2.19 (3 H, s), 1.50 (9 H, s); 13C NMR (101 MHz, chloroform-d) δ ppm 173.5, 162.8, 156.0, 155.3, 152.5, 139.6, 136.1, 136.0, 129.6, 123.0, 122.4, 118.5, 109.2, 81.0, 77.4, 77.3, 77.0, 76.7, 28.3, 14.1; HRMS (ESI) calcd for C19H20N4O3S [M + 1]+ m/z 385.1335, found 385.1335; IR (film, cm−1) 3292, 2978, 2928, 2361, 2337, 1668, 1571, 1522, 1154. 8-(3-(Methylamino)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (7b). The title compound was prepared according to the standard procedure affording the title compound as a yellow solid (161 mg, 72%): mp 134−164 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (1 H, s), 8.01 (1 H, d, J = 9.2 Hz), 7.22 (1 H, t, J = 7.6 Hz), 6.68 (1 H, d, J = 9.4 Hz), 6.63 (1 H, d, J = 7.8 Hz), 6.33− 6.50 (2 H, m), 5.68−5.88 (1 H, m), 2.68 (3 H, br s), 2.24 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 162.0, 156.9, 154.9, 150.7, 136.8, 136.5, 129.2, 121.9, 115.5, 111.6, 109.4, 29.8, 13.5; HRMS (ESI) calcd for C15H14N4OS [M + 1]+ m/z 299.0967, found 299.0967. 3263

dx.doi.org/10.1021/jo500284n | J. Org. Chem. 2014, 79, 3260−3266

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procedure. The crude material was suspended in Et2O and filtered using a medium porosity sintered glass frit and washed with Et2O, affording the title compound (1.45 g, 85%) as a tan solid: mp 181−195 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1 H, s), 6.46−6.53 (1 H, s), 3.56 (3 H, s), 2.61 (3 H, s), 2.40−2.47 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.8, 161.9, 154.8, 154.0, 145.4, 119.9, 110.0, 27.2, 16.8, 13.8; HRMS (ESI) calcd for C10H11N3OS [M + 1]+ m/z 222.0702, found 222.0701; IR (film, cm−1) 3041, 2927, 2361, 2337, 1657, 1572, 1451, 1372, 1194. 8-Methyl-2-(methylthio)-5-phenylpyrido[2,3-d]pyrimidin-7(8H)one (10c). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (184 mg, 67%) as a light yellow solid: mp 119−135 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (1 H, s), 7.49−7.61 (6 H, m), 6.55 (1 H, s), 2.61 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 172.0, 161.6, 155.5, 154.4, 147.9, 134.1, 129.5, 129.0, 128.8, 119.9, 108.9, 27.5, 13.9; HRMS (ESI) calcd for C15H13N3OS [M + 1]+ m/z 284.0858, found 284.0862; IR (film, cm−1) 3057, 2927, 2361, 2337, 1665, 1597, 1565, 1520, 1352, 1203. 5-Benzyl-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (10d). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (223 mg, 82%) as a pale yellow solid: mp 178−180 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1 H, s), 7.28−7.36 (4 H, m), 7.19−7.28 (1 H, m), 6.41 (1 H, s), 4.23 (2 H, s), 3.56 (3 H, s), 2.58 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.7, 161.9, 154.8, 154.3, 147.8, 137.7, 128.9, 128.7, 126.7, 120.3, 109.1, 35.7, 27.3, 13.8; HRMS (ESI) calcd for C16H15N3OS [M + 1]+ m/z 298.1015, found 298.1011; IR (film, cm−1) 3028, 2926, 2362, 2337, 1664, 1567, 1525, 1454, 1360, 1183. 5-Cyclopentyl-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin7(8H)-one (10e). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (136 mg, 50%) as an off-white solid: mp 141−145 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (1 H, s), 6.45 (1 H, s), 3.56 (3 H, s), 3.44−3.54 (1 H, m), 2.60 (3 H, s), 1.99−2.15 (2 H, m), 1.72 (4 H, d, J = 6.8 Hz), 1.51−1.65 (2 H, m); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 162.1, 154.6, 154.2, 152.5, 115.7, 109.5, 31.9, 27.3, 24.9, 13.8; HRMS (ESI) calcd for C14H17N3OS [M + 1]+ m/z 276.1171, found 276.1170; IR (film, cm−1) 3459, 2946, 2920, 2866, 2361, 2336, 1653, 1566, 1522, 1448, 1363, 1188. 1-(2,4-Difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (12a). The title compound was prepared according to the standard procedure, except 3 equiv of LiHMDS was used and the reaction was allowed to run for 2 days. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (160 mg, 58%) as a yellow solid: mp 203−214 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (1 H, br s), 8.19 (1 H, br s), 8.10 (1 H, d, J = 7.6 Hz), 7.66−7.84 (1 H, m), 7.57 (1 H, br s), 7.31 (1 H, br s), 6.57 (1 H, d, J = 7.6 Hz); 13C NMR (101 MHz, DMSO-d6) δ ppm 164.1, 161.9 (dd, J = 0.001, 0.02, Hz), 156.9 (dd, J = 0.001, 0.02, Hz), 149.5, 134.5 (d, J = 0.019, Hz), 130.5 (d, J = 0.001, Hz), 112.1 (dd, J = 0.0004, 0.002, Hz), 108.5 (d, J = 0.015, Hz), 105.2 (dd, J = 0.002, 0.003, Hz); HRMS (ESI) calcd for C12H7F2N3O [M + 1]+ m/z 248.0636, found 248.0635; IR (film, cm−1) 3063, 2786, 2361, 2338, 1653, 1528, 1264, 1193, 1107. 1-Cyclopropyl-7-(4-methoxybenzyl)pyrido[2,3-d]pyridazine-2,8(1H,7H)-dione (12b). The title compound was prepared according to the standard procedure, except 2.5 equiv of LiHMDS was used and the reaction was allowed to run for 5 h. The crude material was chromatographed (using a gradient of 0−30% EtOAc in hexanes), affording the title compound (127 mg, 52%) as a light yellow crystalline solid: mp 140−158 °C; 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (1 H, s), 7.42 (3 H, d, J = 5.3 Hz), 6.85 (2 H, d, J = 7.0 Hz), 6.80 (1 H, d, J = 9.4 Hz), 5.24−5.34 (2 H, m), 3.78 (3 H, s), 3.50−3.61 (1 H, m), 1.19−1.36 (2 H, m), 0.62 (2 H, br s); 13C NMR (101 MHz, chloroform-d) δ ppm 163.5, 159.4, 153.7, 137.6, 135.2,

was prepared according to the standard procedure, affording the title compound (316 mg, 92%) as a pale yellow solid after suspension of the crude product in Et2O and filtration: mp 225−231 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (1 H, s), 8.98 (1 H, s), 8.28 (1 H, s), 7.76 (2 H, d, J = 8.4 Hz), 7.49−7.60 (3 H, m), 7.35−7.48 (2 H, m), 7.05 (1 H, br s), 6.96 (1 H, d, J = 6.5 Hz), 2.23 (3 H, s), 1.46 (9 H, s); 13 C NMR (101 MHz, DMSO-d6) δ ppm 171.4, 161.3, 157.3, 154.2, 152.7, 140.3, 136.3, 134.6, 134.3, 133.1, 130.5, 130.3, 129.0, 128.1, 122.5, 118.1, 109.7, 79.3, 67.0, 28.1, 25.1, 13.5; HRMS (ESI) calcd for C25H23ClN4O3S [M + 1]+ m/z 495.1258, found 495.1255; IR (film, cm−1) 3284, 3064, 2981, 2926, 2361, 2337, 1708, 1650, 1574, 1244, 1160. tert-Butyl (3-(6-(4-Methoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8d). The title compound was prepared according to the standard procedure, affording the title compound (275 mg, 81%) as a pale yellow solid after suspension of the crude product in Et2O and filtration: mp 214−218 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (1 H, br s), 8.95 (1 H, br s), 8.17 (1 H, br s), 7.62−7.79 (2 H, m), 7.55 (1 H, br s), 7.45 (2 H, br s), 6.83−7.09 (3 H, m), 3.81 (3 H, br s), 2.23 (3 H, br s), 1.47 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 170.7, 161.5, 159.4, 156.9, 153.9, 152.7, 140.3, 136.5, 132.9, 131.2, 130.0, 129.0, 127.7, 122.5, 118.2, 117.9, 113.5, 109.9, 79.3, 55.2, 38.9, 28.1, 13.5; HRMS (ESI) calcd for C26H26N4O4S [M + 1]+ m/z 491.1754, found 491.1755; IR (film, cm−1) 3277, 3077, 2977, 2930, 2361, 2337, 1705, 1652, 1571, 1243, 1158. tert-Butyl (3-(2-(Methylthio)-7-oxo-6-(thiophen-3-yl)pyrido[2,3d]pyrimidin-8(7H)-yl)phenyl)carbamate (8e). The title compound was prepared according to the standard procedure, affording the title compound (240 mg, 76%) as a pale yellow solid after suspension of the crude product in Et2O and filtration: mp 236−243 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (1 H, br s), 8.97 (1 H, br s), 8.51 (1 H, br s), 8.31 (1 H, br s), 7.72 (1 H, br s), 7.67 (1 H, br s), 7.55 (1 H, br s), 7.38−7.51 (2 H, m), 6.89−7.08 (1 H, m), 2.24 (3 H, br s), 1.48 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 170.9, 161.1, 156.9, 153.6, 152.7, 140.3, 136.4, 135.3, 132.2, 129.0, 127.0, 126.0, 125.9, 125.6, 122.5, 118.2, 118.0, 109.7, 79.3, 67.0, 28.1, 25.1, 13.5; HRMS (ESI) calcd for C23H22N4O3S2 [M + 1]+ m/z 467.1212, found 467.1207; IR (film, cm−1) 3273, 2978, 2928, 2362, 2337, 1695, 1653, 1576, 1537, 1438, 1290, 1243, 1158. tert-Butyl (3-(6-Benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8f). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 0−10% EtOAc in DCM). This material was contaminated with unreacted starting material. The solid was suspended in Et2O with sonication, filtered using a medium porosity sintered glass frit, and washed with Et2O, affording the title compound (825 mg, 31%) as a fine white solid: mp 244−251 °C; 1H NMR (400 MHz, MeOH/CDCl3 mixture) δ ppm 8.52 (1 H, s), 7.48 (1 H, br s), 7.30−7.42 (6 H, m), 7.22−7.30 (3 H, m), 6.82−6.90 (1 H, m), 3.91 (2 H, s), 2.14 (3 H, s), 1.41−1.54 (9 H, s); 13C NMR (101 MHz, MeOH/CDCl3 mixture) δ ppm 172.2, 163.3, 155.6, 154.2, 153.3, 140.2, 137.8, 136.1, 134.8, 132.8, 129.4, 129.3, 128.7, 126.7, 122.4, 118.5, 109.3, 36.5, 28.1, 13.7; HRMS (ESI) calcd for C26H26N4O3S [M + 1]+ m/z 475.1805, found 475.1801; IR (film, cm−1) 3292, 2980, 2922, 2361, 2338, 1704, 1652, 1575, 1549, 1531, 1436, 1368, 1287, 1244, 1167, 1154. 8-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10a). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 20−100% EtOAc in hexanes), affording the title compound (950 mg, 85%) as a yellow crystalline solid: mp 177−192 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (1 H, s), 7.94 (1 H, d, J = 9.6 Hz), 6.64 (1 H, d, J = 9.6 Hz), 3.60 (3 H, s), 2.61 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.8, 162.2, 157.0, 154.2, 136.1, 121.1, 109.5, 27.4, 13.9; HRMS (ESI) calcd for C9H9N3OS [M + 1]+ m/z 208.0545, found 208.0548; IR (film, cm−1) 2930, 2362, 2337, 1672, 1611, 1571, 1530, 1368, 1283, 1170, 1131. 5,8-Dimethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10b). The title compound was prepared according to the standard 3264

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134.3, 130.2, 128.5, 127.6, 117.3, 114.0, 55.3, 31.4, 10.9; HRMS (ESI) calcd for C18H17N3O3 [M + 1]+ m/z 324.1349, found 324.1344; IR (film, cm−1) 2955, 2836, 2362, 2338, 1673, 1652, 1610, 1512, 1247. 2-Chloro-8-ethyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (12c). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 20−80% EtOAc in hexanes), affording the title compound (444 mg, 58%) as a white crystalline solid: mp 180−181 °C; 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (1 H, s), 6.58 (1 H, s), 4.44 (2 H, q, J = 7.0 Hz), 2.47 (3 H, s), 1.54 (2 H, s), 1.32 (3 H, t, J = 6.9 Hz); 13C NMR (101 MHz, DMSO-d6) δ ppm 161.1, 159.2, 157.4, 155.2, 145.1, 122.1, 113.0, 35.7, 16.9, 12.8; HRMS (ESI) calcd for C10H10ClN3O [M + 1]+ m/z 224.0591, found 224.0588; IR (film, cm−1) 3338, 2980, 2935, 2361, 2338, 1665, 1580, 1460, 1378, 1330, 1265, 1198. 2-Chloro-8-isopropyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (12d). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 20−80% EtOAc in hexanes), affording the title compound (265 mg, 71%) as a light yellow solid: mp 142−144 °C; 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1 H, s), 6.53 (1 H, d, J = 1.2 Hz), 5.74 (1 H, dt, J = 13.8, 6.9 Hz), 2.44 (3 H, d, J = 1.4 Hz), 1.61 (6 H, d, J = 6.8 Hz); 13C NMR (101 MHz, DMSO-d6) δ ppm 161.8, 158.4, 157.4, 155.6, 144.7, 122.9, 113.3, 45.5, 19.1, 16.7; HRMS (ESI) calcd for C11H12ClN3O [M + 1]+ m/z 238.0748, found 238.0749; IR (film, cm−1) 3429, 3332, 3214, 3068, 2985, 2940, 2362, 2338, 1667, 1594, 1568, 1524, 1509, 1434, 1302. 2-Chloro-8-(2,4-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (12e). The title compound was prepared according to the standard procedure. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (148 mg, 62%) as a pale yellow crystalline solid: mp 164−187 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (1 H, s), 6.71 (1 H, s), 6.60 (1 H, s), 6.50 (1 H, d, J = 8.2 Hz), 6.34 (1 H, d, J = 8.2 Hz), 5.30 (2 H, s), 3.85 (3 H, s), 3.72 (3 H, s), 2.52 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 161.3, 159.6, 159.1, 157.5, 155.7, 145.6, 126.4, 122.1, 115.9, 113.0, 104.5, 98.4, 55.6, 55.2, 17.0; HRMS (ESI) calcd for C17H16ClN3O3 [M + 1]+ m/z 346.0959, found 346.0959; IR (film, cm−1) 2957, 2837, 2361, 2336, 1671, 1616, 1568, 1534, 1508, 1460, 1358. tert-Butyl (3-(6-Methoxy-5-methyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (13). The title compound was prepared according to the standard procedure, except at 2 h reaction time, Martin sulfurane (1.0 equiv) was added to the reaction mixture and it was allowed to stir at room temperature for 3 h. The crude material was chromatographed (using a gradient of 0−60% EtOAc in hexanes), affording the title compound (142 mg, 50%) as an off-white crystalline solid: mp 188−194 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (1 H, br s), 8.98 (1 H, s), 7.34−7.53 (3 H, m), 6.91 (1 H, d, J = 7.4 Hz), 3.83 (3 H, s), 2.43 (3 H, s), 2.20 (3 H, s), 1.47 (9 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 169.6, 158.7, 154.7, 152.7, 152.2, 144.9, 140.2, 136.0, 131.3, 129.0, 122.5, 118.2, 118.0, 110.0, 79.3, 59.6, 28.1, 13.4, 10.2; HRMS (ESI) calcd for C21H24N4O4S [M + 1]+ m/z 429.1597, found 429.1591; IR (film, cm−1) 3304, 2977, 2929, 1724, 1662, 1607, 1571, 1527, 1429, 1161. tert-Butyl (3-(6-Deuterio-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (14). The title compound was prepared according to the standard procedure using deuterio EtOAc in place of EtOAc. The crude material was chromatographed (using a gradient of 0−80% EtOAc in hexanes), affording the title compound (198 mg, 74%) as a pale yellow crystalline solid: mp 217− 226 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (1 H, br s), 8.94 (1 H, s), 8.04 (1 H, s), 7.33−7.57 (3 H, m), 6.85−6.97 (1 H, m), 2.21 (3 H, s), 1.47 (9 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 162.0, 157.0, 154.9, 152.7, 140.3, 136.9, 135.9, 129.0, 122.4, 118.1, 117.9, 109.5, 79.3, 40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9, 28.1, 13.5; HRMS (ESI) calcd for C19H19DN4O3S [M + 1]+ m/z 386.1398, found 386.1395; IR (film, cm−1) 3291, 2977, 2928, 2362, 2338, 1721, 1662, 1605, 1571, 1430, 1362, 1161.

Note

ASSOCIATED CONTENT

S Supporting Information *

1

H and 13C NMR spectra of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS T.A. is grateful to Philip Tagari for supporting the summer internship program at Amgen. The authors would also like to thank Dr. Liping Pettus and Dr. Andrew Tasker for helpful discussions.



REFERENCES

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The Journal of Organic Chemistry

Note

Org. Lett. 2013, 15, 3710−3713. (c) Liu, L.; Lu, H.; Wang, H.; Yang, C.; Zhang, X.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2013, 15, 2906−2909. (d) Acker, T. M.; Khatri, A.; Vance, K. M.; Slabber, C.; Bacsa, J.; Snyder, J. P.; Traynelis, S. F.; Liotta, D. C. J. Med. Chem. 2013, 56, 6434−6456. (11) Park, J. O.; Youn, S. W. Org. Lett. 2010, 12, 2258−2261. (12) Li, D. Y.; Shang, X. S.; Chen, G. R.; Liu, P. N. Org. Lett. 2013, 15, 3848−3851. (13) Mederski, W. W. K. R.; Osswald, M.; Dorsch, D.; Christadler, M.; Schmitges, C.-J.; Wilm, C. Bioorg. Med. Chem. Lett. 1999, 9, 619− 622. (14) Alvarez, S.; Medina, S.; Domínguez, G.; Pérez-Castells, J. J. Org. Chem. 2013, 78, 9995−10001. (15) A single literature report exists involving reaction of the lithium enolate of ethyl methoxyacetate with pyridine/benzene-derived aminoaldehydes and ketones. See: Duplantier, A. J.; Becker, S. L.; Bohanon, M. J.; Borzilleri, K. A.; Chrunyk, B. A.; Downs, J. T.; Hu, L.Y.; El-Kattan, A.; James, L. C.; Liu, S.; Lu, J.; Maklad, N.; Mansour, M. N.; Mente, S.; Piotrowski, M. A.; Sakya, S. M.; Sheehan, S.; Steyn, S. J.; Strick, C. A.; Williams, V. A.; Zhang, L. J. Med. Chem. 2009, 52, 3576− 3585. This report does not contain any examples involving substitution on N-1 of the pyridinone. (16) For a discussion on the preparation of a lithium enolate of ethyl acetate using LiHMDS, see: Rathke, M. W. J. Am. Chem. Soc. 1970, 92, 3222−3223. (17) LC-MS analysis of the reaction mixtures at earlier time points (e.g., 30 min) shows a mass consistent with protonated form of intermediate 6. This intermediate gradually disappears as the reaction progress, and the intensity of the desired product 7a increases. (18) Generation of an enolate from catalytic amounts of TBAF and trimethylsilyl ethylacetate in situ also gave the desired product 7a but with lower yields (ca. 50%). For leading references using this approach, see: (a) Nakamura, E.; Shimizu, M.; Kuwajima, I. Tetrahedron Lett. 1976, 17, 1699−1702. (b) Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009, 74, 4368−4371. (19) This reaction was successfully run on an 80 g scale to furnish 7c in comparable yields following extraction of the reaction mixture with EtOAc, suspension of the product in Et2O, and filtration. (20) The mass balance was unreacted starting material from this reaction. (21) The conditions outlined in ref 4 (K2CO3, DMF, 110 °C, 3 h) did not furnish product due to the decreased reactivities of Nbis(arylated) aminoaldehydes. (22) Use of ethyl 4-nitrophenylacetate was also attempted at a reviewer’s request and found not to be a competent substrate for the cyclization (unreacted starting material was recovered). (23) Other dehydrating agents also are effective as well as including commercially available Burgess reagent (1 equiv, 40% yield after 8 h). (24) This methodology has been used successfully to install a 13C radiolabel into compound 7a (data not shown). (25) When the reaction was run on a 0.5 g scale using 3 equiv of EtOAc-d8 and otherwise identical conditions, a 93:7 ratio of deuterio/ nondeuterio 14 was observed (isolated yield = 72%). (26) Chang, S.; Zhang, L.; Xu, S.; Luo, J.; Lu, X.; Zhang, Z.; Xu, T.; Liu, Y.; Tu, Z.; Xu, Y.; Ren, X.; Geng, M.; Ding, J.; Pei, D.; Ding, K. J. Med. Chem. 2012, 55, 2711−2723.

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dx.doi.org/10.1021/jo500284n | J. Org. Chem. 2014, 79, 3260−3266

Pyridin-2-one synthesis using ester enolates and aryl aminoaldehydes and ketones.

An aldol-like cyclocondensation has been used to prepare heterocyclic-fused pyridin-2-ones from aminoaldehydes and ketones upon treatment with a lithi...
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