A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Protocol for Weakly Nucleophilic Amines that is Amenable to the Parallel Synthesis of Di(hetero)arylamides

Abstract

The reaction of a 2-pyridinone-based acid fluoride with the N–TMS derivatives of different weakly nucleophilic heteroaryl/arylamines in acetonitrile containing catalytic fluoride ion provides a clean, efficient and simple means to access a diverse range of polar di(hetero)arylamide structures. This amide bond forming protocol is readily amenable to the parallel synthesis of compound libraries.

Key words

amide coupling - di(hetero)arylamide - acid fluoride - heteroarylamine - N-TMS activation - parallel synthesis

The screening of compound libraries has repeatedly demonstrated its effectiveness as a research tool in drug discovery. In particular, when mechanistic and/or structural details for the therapeutic target are lacking, compound library screening is one of very few options possible to identify new and/or groundbreaking avenues for drug development. In our laboratory, parallel synthesis is used to connect and functionalize novel scaffolds into libraries of bioactive molecules containing different architectures. In particular, amide bond formation was used to generate molecules that possess a di(hetero)arylamide (DHA) substructure. The screening of a 256-membered library containing 119 DHA compounds identified four novel and related molecules 1–4 (Figure [1]) that block HIV-1 replication by a mechanism involving perturbation of the alternative splicing events leading to production of key HIV regulatory proteins.[1a] [b]

Figure 1 IDC16 (indole compound 16) mimics: di(hetero)arylamide-type anti-HIV compounds 1–4

For the construction of the amide bond, a wide range of peptide (amide) bond forming reagents and conditions are available.[2] However, in our library project, where electron-deficient (weakly nucleophilic) heterocyclic amines were engaged,[3] the yield of the DHA product in reactions using the acid chloride method and different peptide coupling reagents rarely exceeded 10–30%. In fact, the formation of complex mixtures of polar compounds was generally observed, complicating workup and isolation/purification of the desired product. To advance the anti-HIV project, and other applications for the DHA library, it became important to develop a new amide synthesis protocol.

In this report, we describe the development of such a protocol for amide bond construction that is efficient and amenable to the parallel synthesis of novel di(hetero)arylamides. The procedure is based on the reaction of readily available N-trimethylsilylamines with acid fluorides in the presence of catalytic fluoride ion. Formally, the fluoride ion reacts with the silylated amine to form a ‘hypervalent’ silicon species,[4] which readily decomposes to produce volatile TMSF and an amine anion intermediate, which is higher in energy and more nucleophilic/reactive than the corresponding free amine. Although often stable to water, and less reactive than acid chlorides toward alcohols, acid fluorides react efficiently with amines to give the expected amide products.[5] [6] An additional attractive feature of the use of acid fluorides and silylated amines as the coupling partners is that these heterocyclic components are nonpolar relative to their amine/acid precursors and to the amide products that are generated. Consequently, by choosing a reaction solvent in which the polar di(hetero)arylamide product selectively precipitates, its isolation is reduced to a simple filtration. For development of the protocol, the acid fluoride derivative of 2-pyridinone-5-carboxylic acid (6) was used as the acid component, as beyond the discovery of compound 4 [1] (Figure [1]) relatively little development of this scaffold in amide synthesis has been described.[7]

Carboxylic acid 6 was prepared (Scheme [1]) by O4-alkylation of 2-pyridinone ester 5 [1] [7] with 1-bromo-2-meth­oxyethane (DMF, Cs₂CO₃) and subsequent hydrolysis of the ester group using LiOH in THF–H₂O (2:1). Conversion of 6 to acid fluoride 7 was best achieved through reaction with fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TFFH)[8] and cesium fluoride (CsF) in anhydrous MeCN at room temperature for 5 hours. The presence of added fluoride ion was mandatory in order to avoid competing formation of the symmetrical anhydride 8.[9] Compound 7 was isolated pure as a colorless solid (90%) by washing the crude product mixture with hexane to remove the tetramethylurea formed, and then taking the solid material up in dichloromethane, filtering to remove the excess CsF, and concentrating to dryness. The structure of 7 was confirmed by the presence of a peak at 25.43 ppm in the ¹⁹F NMR spectrum, and by the up-field shift (Δδ 0.14 ppm) from δ = 8.34 for the peak for H-6 in the ¹H NMR spectrum. As expected, acid fluoride 7 was much more stable than the corresponding (and corrosive) acid chloride derivative, and could be conveniently stored for periods exceeding one month in an airtight container at 4 °C. In fact, when dissolved in dichloromethane and washed with ice water, it was recovered in greater than 90% yield (purity check by ¹H NMR spectroscopy).

Scheme 1 Preparation of acyl fluoride 7 and its reaction with TMS-9a–r

The diversity set of 18 trimethylsilylated heteroaryl/arylamines 9a–r (Table [1]) used in this study was prepared by reacting 0.5 mmol of the requisite amine in neat trimethylsilyl cyanide (TMSCN) (0.5 mL) at 70 °C (30 to 180 min) (Table [1]).[10] The advancement of each reaction was monitored by ¹H NMR spectroscopy (CDCl₃). Interestingly, the time required to observe complete dissolution of the amine, that is, an indicator of complete N-silylation, appeared to be a function of both the reactivity of the amine and its solubility. Indeed, the duration of reaction required did not follow a clear linear relationship to the electron density on the exocyclic amine nitrogen (as calculated using Spartan software[11]) (see calculated e^–-density values in Table [1]). With the exception of TMS-amines 9m and 9p, the polar amine substrates dissolved in TMSCN as the reaction progressed. As the only by-product of the reaction was volatile HCN, it and the residual TMSCN were removed under vacuum.

Table 1 Synthesis of Di(hetero)arylamides 4 and 10 from TMS-Amines 9a–r

	TMS-amine 9 a	Electron density	N-Silylation time	Amidea,b (yield, %)
TMS-9a		140.1	7 (91%)c	10a (78)
TMS-9b [12]		132.2	30	10b (7)
TMS-9c		120	30	10c (27)
TMS-9d		119.5	15	10d (34)
TMS-9e		115	30	10e (53)
TMS-9f [13a] [b] [c] [d]		112.8	30	10f (55)
TMS-9g [14]		105.9	180	10g (89)
TMS-9h [13a]		100.5	90	10h (42)
TMS-9i		98	120	10i (62)
TMS-9j		97.8	30	10j (71)
TMS-9k		96	180 (96%)c	10k (85)
TMS-9l [15]		92.9	30	10l (87)
TMS-9m [1b]		88.8	30	4 (60)[1a] [b]
TMS-9n		88.7	30	10n (92)
TMS-9o [13a]		80.4	180	10o (81)
TMS-9p		77.3	60	10p (63)
TMS-9q		74.7	30	10q (44)
TMS-9r		58.4	360 (85%)c	10r (67)

^a All known compounds are cited by literature references.

^b Amide formation: TMS-amine (0.5 mmol) + acid fluoride (0.89 mmol) in MeCN (5 mL), 50 °C, overnight, (isolated yield).

^c Percent conversion to TMS-amine.

As alluded to already, reactions where the acid chloride derivative of carboxylic acid 6 (and the related compound containing a 4-OMe substituent[1]) was coupled to amines 9 using different solvents (DMF, CH₂Cl₂, THF) and bases (Et₃N, pyridine, K₂CO₃) at room temperature, or with heating, resulted in incomplete conversion to the desired amide products. Under these conditions, the product mixture contained unreacted amine/acid, as well as copious amounts of unidentified polar material. This, plus the fact that the product mixtures were poorly soluble, complicated purification and limited applicability to synthesis or parallel synthesis. In contrast, the reaction of the four (nonsilylated) amines 9c, 9g, 9l, and 9n with excess of acid fluoride 7 in acetonitrile at 50 °C was remarkably efficient. Under these conditions the product precipitated from the medium as the reaction progressed, and was contaminated with much smaller quantities (up to 15%) of residual amine. Encouraged by this result, the reaction of TMS-9n with an excess (1.8 equiv) of acid fluoride 7 was evaluated. It was observed that any residual amine that may not have reacted remained in solution, as amide 10n was isolated pure after filtration and drying in 47% yield. Further, a significant improvement in product yield (47% to 92%) was achieved by addition of a catalytic amount of TBAF (2 mol%) at the outset, to initiate reaction of fluoride ion with silicon and formation of the putative amine anion. The protocol that was subsequently employed for the synthesis of the new DHA molecules involved adding acid fluoride 7 (0.89 mmol) in acetonitrile (5 mL) to the requisite TMS-amine TMS-9a–r (0.5 mmol) (prepared immediately before the reaction). TBAF was then added, and the resulting mixture was heated at 50 °C overnight. After cooling, the precipitated material was collected by suction filtration and dried. As product purity, and not quantity, was the principle criterion for these reactions, efforts were generally not made to improve the amide product yields beyond those indicated in Table [1]. In this context, it was interesting to observe that the yield for the preparation of amide 10a from the electron-rich amine TMS-9a was comparable to that for the preparation of 10r from the electron-deficient amine TMS-9r. In fact, the initial yield for 10a was 38%, but could be brought up to 78% by washing with a mixture of MeCN/Et₂O. This reflected the fact that amide 10a is more soluble in MeCN than amide 10r. The relatively lower yields for the isolation of amides 10b–d also reflects their significant solubility in MeCN. For our purposes, ¹H NMR spectroscopy was used to determine product purity. In the large majority of cases, no impurities were detected, and in the few cases where the presence of the amine component persisted, only trace amounts were detectable (purity >95%) (see Supporting Information for copies of the ¹H NMR spectra for amides 10a–l, 4, and 10n–r, isolated by filtration).

The results obtained with the test set of 18 different N-trimethylsilylated heteroaryl/arylamines in acetonitrile demonstrate the simplicity of the protocol and suggests its general applicability to a wide range of amines expressing weak nucleophilic character. Further, as extractive workup can be avoided and minimum waste is produced. This ‘green’ chemistry method[16] can be readily adapted to rapid parallel synthesis of libraries of di(hetero)arylamide-based compounds.

All chemicals were purchased from Sigma Aldrich or Oakwood Chemicals and were used without purification, unless otherwise mentioned. All solvents were dried and kept under N₂. ¹H and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker AC 400 Ultrashield 10 spectrometer. Chemical shifts are expressed in ppm (δ scale). Standard abbreviations are used to report peak multiplicities. Coupling constants are reported in hertz (Hz). High-resolution mass spectra was recorded on a Thermo Scientific Q Exactive Orbitrap­ High Resolution Mass Spectrometer. IR spectra (cm^–1) were recorded on a Agilent Technologies (Cary 600 series) FT-IR spectrometer, using a PIKE MIRacle ATR accessory for sampling. Melting points were obtained using a Mel-Temp II apparatus.

4-(2-Methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl Fluoride (7)

A mixture of 6 [1a] [b] (1.0 g, 4.40 mmol), TFFH (1.18 g, 4.40 mmol), and CsF (1.57 g, 10.3 mmol) in MeCN (22 mL) was stirred for 12 h at r.t. The mixture was then concentrated under reduced pressure and washed with hexanes to remove the tetramethylurea formed. The product mixture was then dissolved in CH₂Cl₂ and filtered to remove the excess CsF. The filtrate was concentrated and dried under high vacuum for 2 days to afford 7 as a beige solid (0.91 g, 90%).

IR (ATR): 1814, 1778, 1678, 1617, 1530 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.20 (s, 1 H), 5.91 (s, 1 H), 4.13 (t, J = 4.3 Hz, 2 H), 3.81 (t, J = 4.3 Hz, 2 H), 3.57 (s, 3 H), 3.46 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 163.5, 154.1, 150.8, 148.1, 97.3, 70.1, 69.0, 59.6, 37.8.

¹⁹F NMR (400 MHz, CDCl₃): δ = 25.43.

N-Trimethylsilylated Heteroaryl/arylamines TMS-9a–r; General Procedure

The starting amines were dried under high vacuum for 12 h. Then, a solution/mixture of the requisite amine (0.5 mmol) in Me₃SiCN (0.5 mL) was heated at 70 °C for the required time (Table [1]). Without removing the hot oil bath, the resulting solution was flushed with N₂ for 15 min and then concentrated under high vacuum The percent conversion of each amine to its N-silylated derivative was determined by ¹H NMR analysis in CDCl₃ (passed through a basic alumina column prior to use).

N-[(6-Chloropyridin-3-yl)methyl]-1,1,1-trimethylsilanamine (TMS-9a)

Heated for 7 min; yellow oil; 91% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 8.22 (s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 3.85 (d, J = 8.2 Hz, 2 H), 0.00 (s, 9 H).

5-Methyl-N-(trimethylsilyl)isoxazol-3-amine (TMS-9b)[12]

Heated for 30 min; yellow solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 5.46 (s, 1 H), 3.75 (s, 1 H), 2.24 (s, 3 H), 0.23 (s, 9 H).

N-(Trimethylsilyl)isoquinolin-4-amine (TMS-9c)

Heated for 30 min; yellow solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (s, 1 H), 8.03 (s, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.46 (d, J = 7.7 Hz, 1 H), 3.88 (s, 1 H), 0.30 (s, 9 H).

4-Methyl-N-(trimethylsilyl)thiazol-2-amine (TMS-9d)

Heated for 15 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 5.95 (s, 1 H), 4.84 (s, 1 H), 2.14 (s, 3 H), 0.23 (s, 9 H).

3-Methyl-N-(trimethylsilyl)isoxazol-5-amine (TMS-9e)

Heated for 30 min; orange solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 4.78 (s, 1 H), 4.30 (s, 1 H), 2.08 (s, 3 H), 0.21 (s, 9 H).

N-(Trimethylsilyl)thiazol-2-amine (TMS-9f)[13a] [b] [c] [d]

Heated for 30 min; orange oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.02 (s, 1 H), 6.40 (s, 1 H), 5.20 (s, 1 H), 0.25 (s, 9 H).

Methyl 4-[(Trimethylsilyl)amino]benzoate (TMS-9g)[14]

Heated for 180 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 7.8 Hz, 2 H), 6.48 (d, J = 7.9 Hz, 2 H), 3.69 (s, 4 H), 0.14 (s, 9 H).

N-(Trimethylsilyl)pyrazin-2-amine (TMS-9h)[13a]

Heated for 90 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.83 (t, J = 1.2 Hz, 3 H), 4.23 (s, 1 H), 0.24 (s, 9 H).

6-Chloro-N-(trimethylsilyl)pyridin-3-amine (TMS-9i)

Heated for 120 min; purple solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (s, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 3.44 (s, 1 H), 0.20 (s, 9 H).

N-(Trimethylsilyl)benzo[d]thiazol-2-amine (TMS-9j)

Heated for 30 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.41 (s, 2 H), 7.13 (s, 1 H), 6.93 (s, 1 H), 4.91 (s, 1 H), 0.21 (s, 9 H).

3-[(Trimethylsilyl)amino]benzonitrile (TMS-9k)

Heated for 180 min; yellow oil; 96% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.03 (t, J = 7.8 Hz, 1 H), 6.81 (d, J = 7.5 Hz, 1 H), 6.69 (m, 2 H), 3.51 (s, 1 H), 0.13 (s, 9 H).

N-(Trimethylsilyl)-1,3,4-thiadiazol-2-amine (TMS-9l)[15]

Heated for 30 min; yellow solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 8.35 (s, 1 H), 6.01 (s, 1 H), 0.32 (s, 9 H).

5-Nitro-N-(trimethylsilyl)benzo[d]isothiazol-3-amine (TMS-9m)[1b]

Heated for 30 min; red/orange solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (s, 1 H), 7.99 (s, 1 H), 7.40 (s, 1 H), 5.96 (s, 1 H), 0.43 (s, 9 H).

4-Chloro-N-(trimethylsilyl)benzo[d]thiazol-2-amine (TMS-9n)

Heated for 30 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 7.7 Hz, 1 H), 7.23 (d, J =7.8 Hz, 1 H), 6.92 (t, J = 7.7 Hz, 1 H), 5.22 (s, 1 H), 0.30 (s, 9 H).

4-[(Trimethylsilyl)amino]benzonitrile (TMS-9o)[13a]

Heated for 180 min; yellow oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 8.0 Hz, 2 H), 6.49 (d, J = 8.0 Hz, 2 H), 3.79 (s, 1 H), 0.14 (s, 9 H).

5-(2-Chlorophenyl)-N-(trimethylsilyl)-1,3,4-oxadiazol-2-amine (TMS-9p)

Heated for 60 min; white solid; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 7.3 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.30 (m, 2 H), 5.45 (s, 1 H), 0.32 (s, 9 H).

2-Chloro-N-(trimethylsilyl)pyridin-4-amine (TMS-9q)

Heated for 30 min; orange oil; 100% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 5.7 Hz, 1 H), 6.47 (s, 1 H), 6.38 (d, J = 5.6 Hz, 1 H), 4.09 (s, 1 H), 0.24 (s, 9 H).

5-[(Trimethylsilyl)amino]picolinonitrile (TMS-9r)

Heated for 6 h; orange solid; 85% conversion.

¹H NMR (400 MHz, CDCl₃): δ = 8.01 (s, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 3.99 (s, 1 H), 0.26 (s, 9 H).

Di(hetero)arylamides 10a–r; General Procedure

Acid fluoride 7 (200 mg, 0.89 mmol) in MeCN (5 mL) was added in one portion to the silylated amine 9a–r (0.50 mmol) at r.t. This was quickly followed by addition of 1 M TBAF in THF (10 μL, 0.01 mmol). The reaction mixture/solution was stirred at 50 °C for 12 h. The precipitated product was collected with suction filtration and washed with MeCN or the specified solvent (Table [1]).

N-[(6-Chloropyridin-3-yl)methyl]-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10a)

From TMS-amine 9a. The precipitated product was washed with MeCN/Et₂O (1:1) to afford 10a as a white solid; yield: 274 mg (78%); mp 187–188 °C.

IR (ATR): 3393, 1675, 1632, 1528 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.37 (d, J = 2.4 Hz, 1 H), 8.28 (m, 2 H), 7.78 (dd, J = 2.5, 8.2 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 5.92 (s, 1 H), 4.49 (d, J = 5.9 Hz, 2 H), 4.19 (m, 2 H), 3.67 (m, 2 H), 3.42 (s, 3 H), 3.19 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.7, 162.7, 162.5, 148.9, 148.8, 144.5, 138.9, 134.5, 124.0, 105.7, 96.3, 69.3, 68.0, 58.1, 36.3.

HRMS (HESI): m/z [M – H]^– calcd for C₁₆H₁₇ClN₃O₄: 350.0913; found: 350.0916.

4-(2-Methoxyethoxy)-1-methyl-N-(5-methylisoxazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (10b)

From TMS-amine 9b. The precipitated product was washed with MeCN to afford 10b as a pale yellow solid; yield: 21 mg (7%); mp 179–181 °C.

IR (ATR): 3337, 1685, 1660, 1612, 1548 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.98 (s, 1 H), 8.36 (s, 1 H), 6.71 (s, 1 H), 5.94 (s, 1 H), 4.24 (t, J = 3.8 Hz, 2 H), 3.85 (t, J = 3.7 Hz, 2 H), 3.58 (s, 3 H), 3.54 (s, 3 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.8, 163.9, 163.8, 160.8, 158.2, 145.9, 105.6, 97.3, 97.1, 69.6, 68.7, 59.6, 37.7, 12.8.

HRMS (HESI): m/z [M – H]⁺ calcd for C₁₄H₁₆N₃O₅: 306.1095; found: 306.1102.

N-(Isoquinolin-4-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10c)

From TMS-amine 9c. The precipitated product was washed with Et₂O to afford 10c as a white solid; yield: 95 mg (27%); mp 213–214 °C.

IR (ATR): 3286, 1664, 1627, 1543 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.88 (s, 1 H), 9.20 (s, 1 H), 8.85 (s, 1 H), 8.48 (s, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.87 (d, J = 15.2 Hz, 1 H), 7.75 (d, J = 15.2 Hz, 1 H), 6.07 (s, 1 H), 4.36 (m, 2 H), 3.80 (m, 2 H), 3.50 (s, 3 H), 3.19 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.6, 162.8, 161.8, 149.5, 145.3, 138.4, 130.7, 130.0, 128.4, 128.3, 127.9, 127.7, 121.3, 105.8, 96.5, 69.4, 68.5, 58.2, 36.4.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₉H₂₀N₃O₄: 354.1448; found: 354.1449.

4-(2-Methoxyethoxy)-1-methyl-N-(4-methylthiazol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (10d)

From TMS-amine 9d. The precipitated product was washed with Et₂O to afford 10d as a yellow solid; yield: 110 mg (34%); mp 189–190 °C.

IR (ATR): 3308, 1680, 1635, 1530 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.07 (s, 1 H), 8.48 (s, 1 H), 6.81 (s, 1 H), 6.00 (s, 1 H), 4.27 (m, 2 H), 3.75 (m, 2 H), 3.47 (s, 3 H), 3.40 (s, 3 H), 2.27 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 160.3, 156.5, 147.0, 145.8, 108.4, 104.0, 96.4, 69.4, 68.5, 58.5, 36.5, 16.9.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₄H₁₈N₃O₄S: 324.1013; found: 324.1015.

4-(2-Methoxyethoxy)-1-methyl-N-(3-methylisoxazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (10e)

From TMS-amine 9e. The precipitated product was washed with Et₂O to afford 10e as a white solid; yield: 163 mg (53%); mp 211–213 °C.

IR (ATR): 3306, 1694, 1656, 1610, 1528 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.72 (s, 1 H), 8.42 (s, 1 H), 6.24 (s, 1 H), 5.99 (s, 1 H), 4.25 (m, 2 H), 3.74 (m, 2 H), 3.46 (s, 3 H), 3.36 (s, 3 H), 2.21 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.7, 160.8, 160.4, 159.1, 145.7, 104.6, 96.4, 89.3, 69.4, 68.3, 58.3, 36.5, 11.4.

HRMS (HESI): m/z [M – H]^– calcd for C₁₄H₁₆N₃O₅: 306.1095; found: 306.1102.

4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(thiazol-2-yl)-1,6-dihydropyridine-3-carboxamide (10f)

From TMS-amine 9f. The precipitated product was washed with Et₂O to afford 10f as a pale yellow solid; yield: 170 mg (55%); mp 185–186 °C.

IR (ATR): 3311, 1678, 1632, 1612, 1530 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.14 (s, 1 H), 8.50 (s, 1 H), 7.50 (d, J = 3.5 Hz, 1 H), 7.27 (d, J = 3.5 Hz, 1 H), 6.01 (s, 1 H), 4.28 (m, 2 H), 3.76 (m, 2 H), 3.47 (s, 3 H), 3.38 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 160.4, 157.3, 145.8, 138.0, 114.2, 104.0, 96.4, 69.4, 68.5, 58.5, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₃H₁₄N₃O₄S: 308.0711; found: 308.0696.

Methyl 4-[4-(2-Methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamido]benzoate (10g)

From TMS-amine 9g. The precipitated product was washed with MeCN to afford 10g as a white solid; yield: 321 mg (89%); mp 213–215 °C.

IR (ATR): 3348, 1688, 1656, 1592, 1527 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.76 (s, 1 H), 8.41 (s, 1 H), 8.03 (d, J = 8.6 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 2 H), 6.04 (s, 1 H), 4.28 (t, J = 3.9 Hz, 2 H), 3.90 (m, 5 H), 3.61 (s, 3 H), 3.53 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 163.9, 163.7, 161.1, 145.7, 142.7, 130.9, 125.6, 119.5, 106.3, 97.3, 69.8, 68.0, 59.1, 52.2, 37.7.

HRMS (HESI): m/z [M – H]^– calcd for C₁₈H₁₉N₂O₆: 359.1249; found: 359.1251.

4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxamide (10h)

From TMS-amine 9h. The precipitated product was washed with Et₂O to afford 10h as a white solid; yield: 128 mg (42%); mp 191–193 °C.

IR (ATR): 3331, 1693, 1645, 1528 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.20 (s, 1 H), 9.44 (d, J = 1.5 Hz, 1 H), 8.53 (s, 1 H), 8.43 (m, 2 H), 6.01 (s, 1 H), 4.29 (m, 2 H), 3.76 (m, 2 H), 3.49 (s, 3 H), 3.36 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 161.1, 148.3, 146.2, 142.9, 140.2, 136.3, 104.5, 96.4, 69.5, 68.8, 58.4, 36.6.

HRMS (HESI): m/z [M + Na]⁺ calcd for C₁₄H₁₆N₄O₄Na: 327.1064; found: 327.1062.

N-(6-Chloropyridin-3-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10i)

From TMS-amine 9i. The precipitated product was washed with MeCN to afford 10i as a white solid; yield: 209 mg (62%); mp 195–196 °C.

IR (ATR): 3329, 1694, 1649, 1596, 1529 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.96 (s, 1 H), 8.63 (d, J = 2.5 Hz, 1 H), 8.41 (s, 1 H), 8.16 (dd, J = 2.8, 8.7 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 6.00 (s, 1 H), 4.27 (m, 2 H), 3.79 (m, 2 H), 3.47 (s, 3 H), 3.33 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 161.4, 145.2, 143.9, 140.8, 134.9, 130.2, 124.3, 105.6, 96.3, 69.4, 67.9, 58.1, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₅H₁₅ClN₃O₄: 336.0757; found: 336.0765.

N-(Benzo[d]thiazol-2-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10j)

From TMS-amine 9j. The precipitated product was washed with MeCN to afford 10j as a white solid; yield: 255 mg (71%); mp 209–211 °C.

IR (ATR): 3302, 1684, 1640, 1600, 1530 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 11.01 (s, 1 H), 8.45 (s, 1 H), 7.81 (dd, J = 7.9, 19.0 Hz, 2 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 5.99 (s, 1 H), 4.34 (s, 2 H), 3.94 (s, 2 H), 3.64 (s, 3 H), 3.60 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.7, 161.1, 157.8, 148.4, 146.3, 132.4, 126.3, 124.1, 121.5, 121.1, 104.4, 97.5, 69.8, 68.9, 59.7, 37.8.

HRMS (HESI): m/z [M – H]^– calcd for C₁₇H₁₆N₃O₄S: 358.0867; found: 358.0849.

N-(3-Cyanophenyl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10k)

From TMS-amine 9k. The precipitated product was washed with MeCN and MeOH to afford 10k as a white solid; yield: 278 mg (85%); mp 236–238 °C.

IR (ATR): 3356, 2227, 1690, 1649, 1591, 1555 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.98 (s, 1 H), 8.40 (s, 1 H), 8.09 (s, 1 H), 7.90 (td, J = 1.9, 7.6 Hz, 1 H), 7.58 (m, 2 H), 5.99 (s, 1 H), 4.27 (m, 2 H), 3.80 (m, 2 H), 3.47 (s, 3 H), 3.35 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 161.3, 145.2, 139.4, 130.4, 127.2, 124.1, 122.3, 118.6, 111.7, 105.7, 96.3, 69.4, 68.0, 58.0, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₇H₁₆N₃O₄: 326.1146; found: 326.1152.

4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(1,3,4-thiadiazol-2-yl)-1,6-dihydropyridine-3-carboxamide (10l)

From TMS-amine 9l. The precipitated product was washed with MeCN to afford 10l as a white solid; yield: 270 mg (87%); mp 234–236 °C.

IR (ATR): 3308, 1686, 1636, 1611, 1528 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.51 (s, 1 H), 9.20 (s, 1 H), 8.51 (s, 1 H), 6.01 (s, 1 H), 4.28 (m, 2 H), 3.76 (m, 2 H), 3.47 (s, 3 H), 3.39 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.4, 162.7, 160.9, 158.2, 149.2, 146.0, 103.8, 96.4, 69.4, 68.5, 58.5, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₂H₁₃N₄O₄S: 309.0663; found: 309.0647.

4-(2-Methoxyethoxy)-1-methyl-N-(5-nitrobenzo[d]isothiazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (4)[1a] [b]

From TMS-amine 9m. The precipitated product was washed with MeCN and acetone to afford 4 as a yellow solid; yield: 242 mg (60%); mp 296–298 °C.

IR (ATR): 3297, 1692, 1638, 1610, 1511 cm^–1.

¹H/¹³C NMR: See references 1a,b.

HRMS (HESI): m/z [M – H]^– calcd for C₁₇H₁₅N₄O₆S: 403.0718; found: 403.0695.

N-(4-Chlorobenzo[d]thiazol-2-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10n)

From TMS-amine 9n. The precipitated product was washed with MeCN to afford 10n as a white solid; yield: 362 mg (92%); mp 266–267 °C.

IR (ATR): 3288, 1684, 1638, 1589, 1527 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.61 (s, 1 H), 8.55 (s, 1 H), 7.99 (dd, J = 1.0, 7.9 Hz, 1 H), 7.54 (dd, J = 1.0, 7.8 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 1 H), 6.02 (s, 1 H), 4.29 (m, 2 H), 3.79 (m, 2 H), 3.48 (s, 6 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.4, 162.7, 161.7, 158.4, 146.2, 145.4, 133.4, 126.3, 124.6, 124.5, 120.9, 103.8, 96.4, 69.5, 68.6, 58.8, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₇H₁₅ClN₃O₄S: 392.0477; found: 392.0461.

N-(4-Cyanophenyl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10o)

From TMS-amine 9o. The precipitated product was washed with MeOH to afford 10o as a white solid; yield: 265 mg (81%); mp 249–251 °C.

IR (ATR): 3364, 2219, 1687, 1645, 1589, 1527 cm^-1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.06 (s, 1 H), 8.40 (s, 1 H), 7.83 (s, 4 H), 5.99 (s, 1 H), 4.27 (m, 2 H), 3.78 (m, 2 H), 3.47 (s, 3 H), 3.33 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 161.4, 145.2, 142.8, 133.4, 119.6, 119.0, 105.9, 105.4, 96.3, 69.4, 68.0, 58.1, 36.4.

HRMS (HESI): m/z [M – H]^– calcd for C₁₇H₁₆N₃O₄: 326.1146; found: 326.1153.

N-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-(2-methoxy­ethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10p)

From TMS-amine 9p. The precipitated product was washed with MeCN to afford 10p as a pale yellow solid; yield: 255 mg (63%); mp 190–192 °C.

IR (ATR): 3289, 1698, 1667, 1594, 1528 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.09 (s, 1 H), 8.41 (s, 1 H), 7.93 (dd, J = 1.7, 7.7 Hz, 1 H), 7.64 (dddd, J = 1.2, 7.8, 15.0, 27 Hz, 3 H), 5.98 (s, 1 H), 4.22 (m, 2 H), 3.71 (m, 2 H), 3.46 (s, 3 H), 3.31 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 162.7, 160.4, 158.9, 157.6, 145.6, 133.1, 131.6, 131.1, 131.0, 127.9, 122.5, 105.1, 96.3, 69.4, 68.4, 58.3, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₈H₁₆ClN₄O₅: 403.0815; found: 403.0823.

N-(2-Chloropyridin-4-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10q)

From TMS-amine 9q. The precipitated product was washed with MeCN to afford 10q as a white solid; yield: 148 mg (44%); mp 228–229 °C.

IR (ATR): 3332, 1700, 1655, 1580, 1509 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.16 (s, 1 H), 8.41 (s, 1 H), 8.32 (d, J = 5.6 Hz, 1 H), 7.75 (d, J = 1.5 Hz, 1 H), 7.58 (dd, J = 1.7, 5.6 Hz, 1 H), 6.00 (s, 1 H), 4.26 (m, 2 H), 3.78 (m, 2 H), 3.47 (s, 3 H), 3.34 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.7, 163.1, 162.5, 151.5, 151.0, 148.2, 146.0, 113.5, 113.3, 106.0, 96.7, 69.9, 68.5, 58.5, 37.0.

HRMS (HESI): m/z [M – H]^– calcd for C₁₅H₁₅ClN₃O₄: 336.0757; found: 336.0764.

N-(6-Cyanopyridin-3-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10r)

From TMS-amine 9r. The precipitated product was washed with MeCN/Et₂O (1:1) to afford 10r as a pale yellow solid; yield: 220 mg (67%); mp 255–256 °C.

IR (ATR): 3312, 2225, 1684, 1648, 1580, 1540 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.22 (s, 1 H), 8.87 (d, J = 2.1 Hz, 1 H), 8.43 (s, 1 H), 8.36 (dd, J = 2.3, 8.6 Hz, 1 H), 8.05 (d, J = 8.7 Hz, 1 H), 6.01 (s, 1 H), 4.27 (m, 2 H), 3.79 (m, 2 H), 3.47 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.2, 162.7, 161.9, 145.4, 142.3, 138.5, 129.8, 126.3, 126.2, 117.7, 105.5, 96.3, 69.4, 68.0, 58.0, 36.5.

HRMS (HESI): m/z [M – H]^– calcd for C₁₆H₁₅N₄O₄: 327.1099; found: 327.1106.

Acknowledgment

This work was generously supported by grants from the Canadian Institutes of Health Research (CIHR) (and HOP90183 and HOP120238).

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