Abstract
A palladium-catalyzed synthesis of arylglyoxylic amides by the reaction of arylglyoxylates and N,N-dialkylamides in the presence of a 2,3-dihalopyridine has been realized for the first time. An anticipated 2,3-diaroylpyridine did not form in this reaction. The current study unveils an unprecedented role of 2,3-dihalopyridine toward this amidation. Our mechanistic study reveals that the arylglyoxylate could react with halopyridine to form a traceless activated pyridyl ester of arylglyoxylic acid, which upon subsequent reaction with amino surrogate, N,N-dialkylamides could form the arylglyoxylic amides.
Introduction
In the tabulated list of important functional groups available in any standard organic chemistry tutorial, the amide group would occupy a prominent position, not only as the backbone of proteins but also as an ubiquitous component of unnatural materials.1 Historically, amides have been prepared from carboxylic acids and amines, especially via activation of carboxylic acids in the presence of a coupling agent.2 An α-functionalized carboxylic acid may exert dissimilar reactivity toward amidation, which often could remain unnoticed (Scheme 1).3 Amide formation from arylglyoxylic acids containing an electron-withdrawing α-carbonyl functionality has been in line with the victory. The arylglyoxylic amides represent a key structural unit of many natural compounds and pharmaceuticals displaying a broad spectrum of biological activities.4 Among the various methods to prepare them,2 the most privileged method involves condensation of arylglyoxylic acids and amines using commonly used coupling agents.5 However, amide formation directly from arylglyoxylic acid and amines often causes impediment,6 as amines could undergo condensation with arylglyoxylic acids to form α-imino carboxylic acids. The synthesis of arylglyoxylic amides have also been reported using Cu(II)-catalyzed7,8 and tetrabutylammonium iodide-catalyzed reactions.9 Therefore, the advent of a new coupling agent that could facilitate arylglyoxylic amide preparation could be an incremental advance in amide chemistry.
Scheme 1. Arylglyoxylic Amides.
Previously, we demonstrated decarboxylative C- or N-acylation of arylglyoxylic acids under transition-metal-catalyzed or -free conditions.10 During on-going investigation, we recently found that arylglyoxylic amides could be prepared from arylglyoxylic acids and N,N-dialkylamides in the presence of 2,3-dihalopyridines under palladium-catalyzed conditions. The crucial role of 2,3-dihalopyridines is proposed to be associated with the formation of vulnerable activated pyridyl ester of arylglyoxylic acid. The use of weak nucleophilic N,N-dialkylamides as amine surrogates appears to be essential for the formation of activated ester under the palladium-catalyzed condition. A premature mechanistic study reveals that the activated ester upon reaction with N,N-dialkylamides could deliver arylglyoxylic amides.
Results and Discussion
Our initial investigation on palladium-catalyzed regioselective acylation of 2,3-dibromopyridine using arylglyoxylates in N,N-dimethylacetamide (DMA) via decarboxylation paved the way to the serendipitous synthesis of arylglyoxylic amides. Thus, heating the mixture of phenylglyoxylate 1a and 2,3-dibromopyridine A1 in the presence of Pd(OAc)2, P(o-tol)3, and CuI in DMA 2a, used as a solvent, gave arylglyoxylic amide 3a unexpectedly (Table 1, entry 1). Rather, the formation of 2,3-dibenzoylpyridine was the expected outcome. Exclusion of CuI gave a similar conversion to 3a (entry 2). The yield was improved in the presence of a more electrophilic palladium-catalyst, Pd(TFA)2 (entry 3). Reducing the amount of 2a in combination with the use of N-methyl-2-pyrrolidone (NMP) as solvent had an adverse effect (entry 4). A catalytic amount of 2,3-dibromopyridine had a detrimental effect (entries 5–6). Lowering the temperature was found to be ineffective (entries 7–8). The use of free acid in the presence of a base was not beneficial (entries 9–10). However, the use of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) as a radical quencher did not affect the yield of 3a suggesting a nonradical pathway (entry 11). The product arylglyoxylic amide was not formed in the absence of palladium (entry 12).
Table 1. Optimization Studya.
| entry | catalyst | ligand | temp/time (°C/h) | yieldb (%) |
|---|---|---|---|---|
| 1c | Pd(OAc)2 | P(o-Tol)3 | 150/24 | 55 |
| 2 | Pd(OAc)2 | P(o-Tol)3 | 150/24 | 56 |
| 3 | Pd(TFA)2 | P(o-Tol)3 | 150/24 | 71 |
| 4d | Pd(TFA)2 | P(o-Tol)3 | 150/24 | 25 |
| 5e | Pd(OAc)2 | P(o-Tol)3 | 150/24 | 42 |
| 6f | Pd(OAc)2 | P(o-Tol)3 | 150/24 | 29 |
| 7 | Pd(TFA)2 | P(o-Tol)3 | 130/24 | 32 |
| 8 | Pd(TFA)2 | P(o-Tol)3 | 100/24 | 00 |
| 9g | Pd(TFA)2 | P(o-Tol)3 | 150/24 | 00 |
| 10h | Pd(TFA)2 | P(o-Tol)3 | 150/24 | 32 |
| 11i | Pd(TFA)2 | P(o-Tol)3 | 150/24 | 69 |
| 12 | 150/24 | 00 |
Reaction conditions: 1a (0.25 mmol), 2a (1 mL), Pd-catalyst (5 mol %), ligand (10 mol %), 2,3-dibromopyridine A1 (1 equiv), 24 h.
Isolated yield.
CuI (15 mol %) used.
2a (2 equiv), NMP (1 mL) used.
A1 (0.5 equiv) used.
A1 (0.25 equiv) used.
Instead of 1a, phenylglyoxylic acid (0.25 mmol) and K2CO3 (1 equiv) used.
Instead of 1a, phenylglyoxylic acid (0.25 mmol) and KOt-Bu (1 equiv) used.
TEMPO (10 equiv) used.
We further explored the scope of other pyridine substrates that could help promote the formation of arylglyoxylic amides (Scheme 2). Similar to 2,3-dibromopyridine, 2,3-dichloropyridine A2 also produced 3a in 64% yield under the reaction condition. While a mono-bromopyridine (2- or 3-bromopyridine) A3–A4 and its derivative A5 gave 3a in varying yields along with the formation of their corresponding benzoylpyridines, mono-chloropyridine A6 failed to give 3a. Likewise, pyridine itself or its derivative lacking any bromo-substituent A7–A13 failed to give 3a. These substrates collectively unravel the requirement of mono-bromopyridines or 2,3-dihalopyridines as coupling additives for effective formation of 3a. Interestingly, 1,2-dibromobenzene A14 did not give 3a under the optimized condition.
Scheme 2. Additive Screening.
Next, we explored the substrate scope of arylglyoxylates that could participate in the reaction (Scheme 3). The arylglyoxylates containing both electron-rich and electron-poor substituents reacted with 2a yielding arylglyoxylic amides 3b–3n in good-to-excellent yields. The arylglyoxylates containing substituents at the 2-position afforded 3b–3c in 79–84% yield. An arylglyoxylate containing an OMe group at the 3-position delivered 3d in 78% yield. Furthermore, the arylglyoxylates bearing electron-donating groups at the 4-position afforded 3e–3h in 62–81% yield. However, acids having electron-withdrawing groups at the 4-position yielded 3i–3j in moderate yields. Interestingly, halogen groups that are otherwise often incompatible in metal-catalyzed reactions were tolerated to give 3k–3l in 45–54% yield. Moreover, when 2-(naphthalen-2-yl)-2-oxoacetic acid was exposed to 2a, the product 3m was isolated in excellent (88%) yield. Heteroarylglyoxylic acids, 2-oxo-2-(thiophen-2-yl)acetic acid and 2-(furan-2-yl)-2-oxoacetic acid were also viable substrates giving 3n and 3o, respectively, in 61–66% yields.
Scheme 3. Substrate Scope of Arylglyoxylic Acids.
To demonstrate further the greater synthetic potential of the protocol, different acyclic or cyclic acetamides were screened (Scheme 4). It was found that when 1a reacted with lower amount of 2a (4 equiv) in the presence of mesitylene as solvent also gave 3a in comparable (65%) yield. Other N,N-dialkylacetamide such as N,N-diethylacetamide 2b, N,N-diisopropylacetamide 2c, and N,N-dibenzylacetamide 2d worked well affording 3p–3r in 59–69% yields. Interestingly, cyclic acetamides were also found to be workable substrates. N-Acylpiperidines 2e–2f reacted smoothly with 1a to give the desired arylglyoxylic amide 3s in excellent yields. Likewise, N-acetyl pyrrolidine 2g, morpholine 2h, and N-methyl piperazine 2i were also viable substrates yielding 3t–3v in 71–79% yields. Notably, N,N-dimethyl-2-phenylacetamide 2j also worked under the reaction condition to give product 3a in 78% yield. Similarly, N,N-dimethyl-2-(pyridin-2-yl)acetamide 2k underwent reaction furnishing the product 3a in moderate yield. However, N,N-dimethylbenzamide 2l did not undergo the reaction under the optimized condition. Central to this investigation was the ability of various weak N,N-dialkylamides to serve as amino surrogates to form arylglyoxylic amides.
Scheme 4. Substrate Scope of Tertiary Alkylamides.
To understand the possible pathway to the formation of 3a, the identification of any putative intermediate that could form in this reaction and undergo subsequent reaction to form 3a was sought (Scheme 5). As benzoylpyridines were isolated as minor sideproducts when monobromopyrdines were used as additives (path A), we envisaged that benzoylpyridines could be the possible intermediates to the formation of 3a (Scheme 5). However, a control experiment involving the reaction of analytically pure 2-benzoylpyridine 3aa under optimized condition did not afford 3a (eq 1). Furthermore, N,N-dimethyl-2-(pyridin-2-yl)acetamide 3ab could be a possible intermediate11 in this reaction, which could be generated in the reaction of N,N-dialkylacetamide and 2-bromopyridine (path B). However, the attempted reaction of 3ab and 1a under the optimized condition did not give 3a (eq 1). These two experiments precluded the formation arylglyoxylic amides from any putative intermediate proposed herein. Moreover, control experiments excluding either 2a or 1a performed under the optimized condition did not yield any isolable intermediate (eqs 2 and 3).
Scheme 5. Control Experiments.
On the basis of the mechanistic information available with the cross-decarboxylative acylation of aryl halides using arylglyoxylic acids12 and our own observations, we propose herein the following plausible reaction mechanism (Scheme 6). Initially, an oxidative addition of palladium(0) could occur at the 2-position of 2,3-dibromopyridine yielding I. However, palladium insertion at the 3-position of 2,3-dibromopyridine is not ruled out. Evidence for the formation of intermediate I warranted trapping the proposed intermediate. Thus, reaction of 1a and 2a under the standard condition in the presence of an additional amine, morpholine 2j gave two aminated products of 2,3-dibromopyridine 3ac and 3ad as opposed to 3a (Scheme 7). The regiochemistry of morpholine substitution in compound 3ac is not known. It is important to note that only a limited data were obtained for compounds 3ac and 3ad. However, 3ac and 3ad were not formed in the absence of palladium and ligand. This rules out the possibility of SNAr reactions in this case.
Scheme 6. Plausible Reaction Mechanism.
Scheme 7. Evidence for the Formation of Intermediate I.
This experiment reveals that a strong nucleophile like morpholine 2j could react with I to form 3ac and 3ad. However, in the absence of any other nucleophile, 1a could react with the intermediate I to generate the intermediate II, which upon decarboxylation following a conventional pathway could form 2-benzoylpyridine. If decarboxylation is not facilitated under the condition, inadvertent reductive elimination of palladium(0) could occur with concomitant formation of the key pyridyl ester III. Amine nucleophile, which could be generated in situ from DMA in the presence of phenoxide IV, could react with the activated pyridyl ester III to deliver 3a. While the proposed activated pyridyl ester of arylglyoxylic acid is unprecedented, the preparation of aryl carboxamides from pyridyl ester via activation to pyridinium salts13 could be a reasonable evidence of the proof-of-concept. However, further study is required to confirm the hypothesis.
In conclusion, a palladium-catalyzed amidation of arylglyoxylic acids with N,N-dialkylamides in the presence of halopyridines has been developed. The salient features of this work may include (a) clear distinction from the previous reports of arylglyoxylic amide preparation, (b) use of weak nucleophilic N,N-dialkylamides as amino surrogates, and (c) novel activation of arylglyoxylic acids in the presence of halopyridines. Various other α-functionalized amides via activated pyridyl ester, their applications to the synthesis of pharmaceuticals, and detailed understanding of the mechanism could be a subject of intensive future research.
Experimental Section
General
Unless stated otherwise, all reagents and solvents were obtained from commercial sources and used as it is. All reactions were carried out in a screw capped tube. The 1H and 13C NMR spectra were obtained in CDCl3 as a solvent using a 400 MHz spectrometer with tetramethylsilane as an internal standard. Coupling constants (J values) are described in Hz. Silica gel (60–120#, 100–200#, and 230–400#) was used to perform column chromatography. High-resolution mass spectra (HRMS) were obtained by the use of electron spray ionization and time-of-flight mass analyzer. IR spectra are stated in cm–1 units.
Preparation of Substituted α-Oxocarboxylic Acids (1b–1n)
All substituted α-oxocarboxylic acids were prepared using the literature protocol.14
General Procedure for the Synthesis of Potassium Salts of the α-Oxocarboxylic Acids (1a–1n)
Following a literature procedure,15 a solution of potassium tert-butoxide (1 mmol) in ethanol (1 mL) was added drop-by-drop to a solution of α-oxocarboxylic acids (1 mmol) in ethanol (1 mL) over 30 min. After complete addition, the reaction mixture was stirred for another 2 h at room temperature. A gradual formation of a precipitate was observed. The resulting solid was collected by filtration, washed with ethanol (2 × 10.0 mL) and diethyl ether (10.0 mL), transferred to a round-bottom flask, and dried under vacuum to give corresponding potassium salts of α-oxocarboxylic acids.2
General Procedure for the Synthesis of α-Ketoamides (3a–3o)
A reaction tube was charged with α-oxocarboxylic acid (0.25 mmol), 2,3-dibromo pyridine (1 equiv), Pd(TFA)2 (5 mol %), and P(o-Tol)3 (10 mol %). The tube was evacuated and backfilled with nitrogen. DMA (1 mL) was added by syringe under flow of nitrogen. The tube was sealed and the mixture was heated at 150 °C for 24 h. The reaction mixture was cooled down to room temperature, and the residue was diluted with ethyl acetate (10 mL), washed with saturated sodium carbonate solution (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified through column chromatography [100–200# silica, ethyl acetate/hexane = 3:7/4:6] to afford the desired α-ketoamides product.
General Procedure for the Synthesis of α-Ketoamides Using N,N-Dialkyacetamides (Scheme 5: 3a, 3p–3v)
A reaction tube was charged with α-oxocarboxylic acid (0.25 mmol), N,N-dialkylacetamide (4 equiv), 2,3-dibromo pyridine (1 equiv), Pd(TFA)2 (5 mol %), and P(o-Tol)3 (10 mol %). The tube was evacuated and backfilled with nitrogen. Mesitylene (1 mL) was added by syringe under flow of nitrogen. The tube was sealed and the mixture was heated at 150 °C for 24 h. The reaction mixture was cooled down to room temperature, and the residue was diluted with ethyl acetate (10 mL), washed with saturated sodium carbonate solution (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified through column chromatography [100–200# silica, ethyl acetate/hexane = 3:7/4:6] to afford the desired α-ketoamides product.
Typical Procedure for the Competitive Experiment
A reaction tube was charged with α-oxocarboxylic acid (0.25 mmol), DMA (4 equiv), morpholine (4 equiv), 2,3-dibromo pyridine (1 equiv), Pd(TFA)2 (5 mol %), and P(o-Tol)3 (10 mol %). The tube was evacuated and backfilled with nitrogen. Mesitylene (1 mL) was added by syringe under flow of nitrogen. The tube was sealed and the mixture was heated at 150 °C for 24 h. The reaction mixture was cooled down to room temperature, and the residue was diluted with ethyl acetate (10 mL), washed with saturated sodium carbonate solution (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified through column chromatography [100–200# silica, ethyl acetate/hexane = 1:9] to give the C–H aminated products.
Characterization of Synthesized Compounds
N,N-Dimethyl-2-oxo-2-phenylacetamide (3a)7
Yellow oil; yield 71% (30 mg); 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.9 Hz, 2H), 7.65 (tt, J = 7.4, 1.1 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 191.8, 167.0, 134.7, 133.0, 129.6, 129.0, 37.0, 34.0.
N,N-Dimethyl-2-oxo-2-(o-tolyl)acetamide (3b)7
Yellow oil; yield 84% (40 mg); 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.34–7.31 (m, 2H), 3.12 (s, 3H), 2.99 (s, 3H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 193.7, 167.8, 141.4, 133.6, 132.5, 131.6, 126.1, 37.0, 34.0, 21.6.
2-(2-Ethoxyphenyl)-N,N-dimethyl-2-oxoacetamide (3c)
Yellow oil; yield 79% (43 mg); 1H NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.55 (td, J = 7.3, 1.8 Hz, 1H), 7.07 (td, J = 7.9, 0.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.06 (s, 3H), 2.99 (s, 3H), 1.41 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 190.9, 168.8, 159.6, 135.9, 131.0, 123.4, 121.0, 112.5, 64.2, 36.8, 33.8; HRMS: calcd for C12H16NO3 [M + H]+, 222.1130; found, 222.1138; IR (KBr): 1675, 1648, 1436, 1210, 1144 cm–1.
2-(3-Methoxyphenyl)-N,N-dimethyl-2-oxoacetamide (3d)8
Yellow oil; yield 78% (40 mg); 1H NMR (400 MHz, CDCl3): δ 7.51–7.44 (m, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.22–7.19 (m, 1H), 3.88 (s, 3H), 3.13 (s, 3H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.6, 167.0, 160.1, 134.4, 130.0, 122.8, 121.6, 112.7, 55.5, 37.0, 34.0.
N,N-Dimethyl-2-oxo-2-(p-tolyl)acetamide (3e)9
Yellow oil; yield 64% (30 mg); 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 3.12 (s, 3H), 2.96 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.5, 167.2, 145.9, 130.6, 129.7, 129.7, 37.0, 33.9, 21.8.
2-(4-Methoxyphenyl)-N,N-dimethyl-2-oxoacetamide (3f)9
Yellow oil; yield 62% (32 mg); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.12 (s, 3H), 2.97 (s, 3H).
2-(4-Ethoxyphenyl)-N,N-dimethyl-2-oxoacetamide (3g)
Yellow oil; yield 67% (37 mg); 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.0 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.11 (s, 3H), 2.97 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 190.5, 167.4, 164.3, 132.1, 125.9, 114.7, 64.00, 37.1, 33.9, 14.6; HRMS: calcd for C12H16NO3 [M + H]+, 222.1130; found, 222.1135; IR (KBr): 1679, 1650, 1444, 1132 cm–1.
N,N-Dimethyl-2-oxo-2-(4-(trifluoromethoxy)phenyl)acetamide (3h)
Yellow oil; yield 81% (53 mg); 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.14 (s, 3H), 3.00 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.9, 166.4, 153.7, 131.8, 131.2, 130.0, 128.5, 121.5, 120.6, 118.9; HRMS: calcd for C11H11F3NO3 [M + H]+, 262.0691; found, 262.0699; IR (KBr): 1680, 1647, 1432, 1140 cm–1.
2-(4-Cyanophenyl)-N,N-dimethyl-2-oxoacetamide (3i)
Yellow oil; yield 47% (24 mg); 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 3.13 (s, 3H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.5, 140.6, 132.3, 127.7, 118.1, 113.3, 39.3, 35.3; HRMS: calcd for C11H11N2O2 [M + H]+, 203.0821; found, 203.0831; IR (KBr): 2237, 1683, 1645, 1442, 1218, 1136 cm–1.
N,N-Dimethyl-2-(4-nitrophenyl)-2-oxoacetamide (3j)9
Yellow solid; yield 57% (31 mg); 1H NMR (400 MHz, CDCl3): δ 8.27 (dd, J = 6.8, 1.8 Hz, 2H), 7.58 (dd, J = 6.8, 1.9 Hz, 2H), 3.14 (s, 3H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.2, 148.3, 142.4, 128.0, 123.8, 39.3, 35.3.
2-(4-Chlorophenyl)-N,N-dimethyl-2-oxoacetamide (3k)9
Yellow oil; yield 54% (28 mg); 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 3.08 (s, 3H), 2.93 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.3, 166.4, 141.3, 131.4, 131.0, 129.3, 37.0, 34.0.
2-(4-Fluorophenyl)-N,N-dimethyl-2-oxoacetamide (3l)9
White solid; yield 45% (22 mg); 1H NMR (400 MHz, CDCl3): δ 8.03–7.99 (m, 2H), 7.22–7.18 (m, 2H), 3.14 (s, 3H), 2.99 (s, 3H).
N,N-Dimethyl-2-(naphthalen-2-yl)-2-oxoacetamide (3m)7
Yellow solid; yield 88% (50 mg); 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.05 (dd, J = 8.6, 1.7 Hz, 1H), 8.01–7.95 (m, 2H), 7.92 (d, J = 7.1 Hz, 1H), 7.67 (td, J = 7.0, 1.2 Hz, 1H), 7.59 (td, J = 8.1, 1.1 Hz), 3.20 (s, 3H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.8, 167.1, 136.3, 133.0, 132.4, 130.4, 129.9, 129.3, 129.0, 127.9, 127.1, 123.6, 37.1, 34.1.
N,N-Dimethyl-2-oxo-2-(thiophen-2-yl)acetamide (3n)7
Yellow oil; yield 61% (29 mg); 1H NMR (400 MHz, CDCl3): δ 7.79–7.74 (m, 1H), 7.72–7.71 (m, 1H), 7.12–7.10 (m, 1H), 3.03 (s, 3H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 183.4, 165.8, 140.3, 136.3, 136.1, 128.6, 37.3, 34.5.
2-(Furan-2-yl)-N,N-dimethyl-2-oxoacetamide (3o)7
Yellow oil; yield 66% (28 mg); 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 1.0 Hz, 1H), 7.37 (d, J = 3.7 Hz, 1H), 6.62–6.60 (m, 1H), 3.08 (s, 3H), 3.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 178.5, 165.4, 150.1, 148.7, 37.2, 34.5.
N,N-Diethyl-2-oxo-2-phenylacetamide (3p)9
Yellow oil; yield 62% (31 mg); 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 2H), 7.65–7.61 (m, 1H), 7.51 (t, J = 7.7 Hz, 1H), 3.56 (q, J = 7.2 Hz, 2H), 3.24 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 191.6, 166.7, 134.5, 133.2, 129.6, 128.9, 42.1, 38.8, 14.1, 12.8.
N,N-Diisopropyl-2-oxo-2-phenylacetamide (3q)16
Colorless solid; yield 69% (40 mg); 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.3 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 3.70 (q, J = 6.8 Hz, 1H), 3.60 (q, J = 6.8 Hz, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 191.0, 166.9, 134.4, 133.3, 129.5, 128.9, 50.2, 46.0, 20.5, 20.3.
N,N-Dibenzyl-2-oxo-2-phenylacetamide (3r)17
Yellow oil; yield 57% (47 mg); 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.8 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.44–7.42 (m, 2H), 7.41–7.32 (m, 6H), 7.28–7.26 (m, 2H), 4.65 (s, 2H), 4.30 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 191.3, 167.4, 135.9, 134.8, 134.7, 134.5, 133.2, 131.2, 129.7, 129.0, 128.9, 128.8, 128.7, 128.5, 128.2, 128.1, 127.9, 127.8, 50.0, 46.0.
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3s)9
Yellow oil; yield 83% (45 mg); 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (d, J = 7.8 Hz, 2H), 3.72 (br s, 2H), 3.31 (t, J = 5.5 Hz, 2H), 1.72–1.67 (m, 4H), 1.58–1.51 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 191.9, 165.4, 134.6, 133.2, 129.5, 129.0, 128.4, 47.0, 42.1, 26.2, 25.4, 24.3.
1-Phenyl-2-(pyrrolidin-1-yl)ethane-1,2-dione (3t)18
Yellow oil; yield 71% (36 mg); 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.5 Hz, 2H), 7.65 (tt, J = 7.4, 1.2 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 3.68 (t, J = 6.9 Hz, 2H), 3.45 (t, J = 6.2 Hz, 2H), 2.00–1.94 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 191.5, 164.9, 134.6, 132.9, 129.9, 128.9, 46.6, 45.2, 25.9, 24.0.
1-Morpholino-2-phenylethane-1,2-dione (3u)9
Yellow oil; yield 74% (40 mg); 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.5 Hz, 2H), 7.66 (tt, J = 7.4 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 3.80 (s, 4H), 3.66 (t, J = 4.7 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 191.1, 165.4, 134.9, 133.0, 129.6, 129.1, 66.7, 66.6, 46.2, 41.6.
1-(4-Methylpiperazin-1-yl)-2-phenylethane-1,2-dione (3v)18
Yield 79% (46 mg); 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.4 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (d, J = 7.8 Hz, 2H), 3.82 (t, J = 4.8 Hz, 2H), 3.40 (t, J = 4.8 Hz, 2H), 2.55 (t, J = 5.1 Hz, 2H), 2.41 (t, J = 5.0 Hz, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.4, 165.3, 134.8, 133.0, 129.6, 129.0, 54.8, 54.4, 45.9, 45.7, 41.0.
Phenyl(pyridin-2-yl)methanone (3aa)19
Yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 4.7 Hz, 1H), 8.07–8.03 (m, 3H), 7.90 (td, J = 7.7, 1.6 Hz, 1H), 7.61–7.57 (m, 1H), 7.50–7.47 (m, 3H).
4-(2- or 3-Bromopyridin-2-yl)morpholine (3ac)
Yellow oil; yield 35% (21 mg); 1H NMR (400 MHz, CDCl3): δ 8.25 (dd, J = 4.7, 1.4 Hz, 1H), 7.80 (dd, J = 7.7, 1.5 Hz, 1H), 6.82–6.79 (m, 1H), 3.88 (t, J = 4.6 Hz, 4H), 3.35 (t, J = 4.6 Hz, 4H). (Note only a limited data obtained for the mixture).
4-(Pyridin-2-yl)morpholine (3ad)
Yellow oil; yield 35% (14 mg); 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 3.7 Hz, 1H), 7.52 (dt, J = 8.7, 1.9 Hz, 1H), 6.70–6.65 (m, 2H), 3.85 (t, J = 4.7 Hz, 4H), 3.51 (t, J = 4.7 Hz, 4H). (Note only a limited data obtained for the compound).
Acknowledgments
The financial support from the SERB, New Delhi, is greatly appreciated.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00894.
Experimental procedures, characterization data of new compounds, and copies of 1H and 13C NMR spectra (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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