Metal-Free Organocatalytic Oxidative Ugi Reaction Promoted by

Apr 24, 2017 - ... U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar, India 143005. § Department of Chemistry, India...
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Metal-Free Organocatalytic Oxidative Ugi Reaction Promoted by Hypervalent Iodine Karandeep Singh,†,‡ Amanpreet Kaur,§ Venus Singh Mithu,‡ and Siddharth Sharma*,† †

Department of Chemistry, Mohanlal Sukhadia University, Udaipur, India 313001 Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar, India 143005 § Department of Chemistry, Indian Institute of Technology Delhi, New Delhi, India 110016 ‡

S Supporting Information *

ABSTRACT: We report here a novel IBX-promoted oxidative coupling of primary amines and its utilization to Ugi reaction. Advantageously, the reaction could be carried out in choline chloride urea as a natural deep eutectic solvent. A range of imines and bisamides from pseudo-four-component oxidative Ugi reaction could be synthesized under mild and metal-free conditions. Advantageously, the oxidant (IBX) and solvent could be recycled up to five times with only a slight loss in activity.

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IBX,5 cyclization of N-aryl amides,6 oxidation of ketones and aldehydes to the corresponding α,β-unsaturated carbonyl compounds,7 and IBX-mediated methods for the generation of imines from secondary amines (Scheme 1).8 However, when primary amines were subjected to IBX or DMP, mixtures of corresponding nitriles and aldehydes or solely nitriles were afforded.9 We surmised that the oxidative process of amine could be exploited for the synthesis of imines by altering the reaction conditions and/or using additive. Imines are the most versatile synthetic intermediates in the variety of organic transformations from the synthesis of fine chemicals to pharmaceuticals. Therefore, the oxidation of primary amines to secondary imines has attracted much interest in recent years using different catalysts.10 The reported methods of this transformation have their own drawbacks, involving the metal-catalyzed oxidations involving dioxygen. However, metal is not the first choice in the pharmaceutical industry due to the possible contamination in the final drug molecule. In contrast to metal-mediated reactions for amine oxidation, recently, several metal-free and organocatalytic methods have been reported,11 but most of these metal-free catalysts are difficult to prepare, have complex structure, and are expensive. Evidently, there is a strong demand for a general and

INTRODUCTION Organocatalytic oxidations, the use of small organic molecules as catalysts for the oxidation reactions, are considered to be the major branch of organic synthesis along with transition metal catalysis. Despite their importance, oxidation reactions using organocatalysts have received limited synthetic attention with respect to their site-specific activity in asymmetric synthesis. Seminal works by Dess, Martin, Moriarty, Koser, and Varvoglis reignited the curiosity of organic chemists in the chemical reactivity of hypervalant iodine reagents under mild conditions.1 Furthermore, the reactivity of phenyliodonium diacetate (PIDA, I) and phenyliodine bis(trifluoroacetate) (PIFA, II) as λ3 iodanes and Dess−Martin periodinane (DMP, III) and o-iodoxybenzoic acid (IBX, IV) as λ5 iodanes have been extensively studied due to their low cost, mild reaction conditions, and excellent oxidizing abilities (Figure 1).2 Recenly, Zhdankin et al. utilized hypervalent iodine reagents for the oxidation of aldoximes to nitrile oxides, which on tandem reaction with alkenes and alkynes gave the corresponding isoxazolines and isoxazoles in moderate to good yields.3 More recently, Goti et al. has developed the IBX-promoted oxidation of N,N-disubstituted hydroxylamines to the corresponding nitrones.4 In particular, the Nicolaou group utilized intrinsic qualities of DMP and IBX for the number of widespread applications. Included in these methods are the selective oxidation of carbon adjacent to aromatic systems with © 2017 American Chemical Society

Received: March 13, 2017 Published: April 24, 2017 5285

DOI: 10.1021/acs.joc.7b00594 J. Org. Chem. 2017, 82, 5285−5293

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Figure 1. Hypervalent iodine reagents utilized in the reaction.

Scheme 1. Comparison of Hypervalent Iodine Mediated Oxidation of Amines with This Work

convenient approach to access the substituted imine derivatives that uses easily available catalysts and mild reaction conditions and gives high yield of products. As a part of our interest toward the development of isocyanide chemistry12 herein, we report a mild and selective oxidation of primary amines with IBX to access the corresponding imines in deep eutectic solvents, and the oxidation can be combined in one pot by the addition of isocyanides, affording oxidative Ugi reaction.

Table 1. Optimizations of Oxidants and Solvents for the Synthesis of 2a from Benzylamine 1aa

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RESULTS AND DISCUSSION Building upon the work of Nicolaou and co-workers, we started investigating the feasibility of the oxidation of benzylamine 1a with IBX. The results of control experiments for the oxidative coupling of benzylamine are illustrated in Table 1. Oxidation of 1 equiv of 1a with 1 equiv of IBX afforded mixtures of the corresponding aldehyde (18%) and nitrile (34%) in CH2Cl2 (Table 1, entry 1; yields are not shown in the table). Similarly, 2 equiv of 1a with 1 equiv of IBX afforded desired product 2a in 17% yield (Table 1, entry 2). Further experiments revealed that 2 equiv of 1a and addition of 0.1 equiv of benzoic acid to the reaction mixture gave 2a in 54% yield (Table 1, entry 3) in 12 h. The latter was assigned as imine structure 2a based on the standard spectroscopic analysis. Different hypervalent iodine reagents (Figure 1) were screened for the oxidation of benzylamine in order to compare the efficiency for the desired transformation (Table 1, entries 4−6). IBX and DMP were highly selective oxidants for the oxidative coupling reaction, which afforded the desired imine (2a) (Table 1, entries 3 and 6). Whereas the use of organic solvent afforded the desired product in moderate yield, we sought to further improve the yield of the reaction while avoiding the use of organic solvents. DESs (deep eutectic solvents) are gaining importance as green and biodegradable solvents for the synthesis of a wide

entry

oxidant

solvent

additive

yield (%)

1b 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17c 18d 19e

IBX IBX IBX PIDA PIFA DMP IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN toluene CH2Cl2/HFIP urea/ChCl DMU/ChCl imidazole/ChCl CA/ChCl urea/ChCl urea/ChCl urea/ChCl urea/ChCl urea/ChCl urea/ChCl

none none BA BA BA BA BA BA BA BA BA BA BA AcOH PTSA BF3·OEt2 BA BA BA

trace 17 54 33 26 52 39 44 57 84 58 37 NR 82f 77 38 84 82 84

a

Reaction conditions: a mixture of 1a (2.0 mmol), oxidant, additive (0.1 equiv), and solvent (5 mL) was stirred. b1 equiv of IBX and 1 mmol amine were used. ChCl, choline chloride; CA, citric acid; DMU, 1,3-dimethyl urea; HFIP, 1,1,1,3,3,3-hexafluoroisopropanol; BA, benzoic acid. c1 equiv of additive used. dReaction was done under N2. eReaction was done under O2. fProduct was 2-(N-benzylacetamido)-N-(tert-butyl)-2-phenylacetamide.

variety of useful and important compounds.13 Interestingly, IBX was soluble in DES (ChCl/urea), which is otherwise sparingly soluble in organic solvents. Poor solubility of IBX in organic 5286

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The Journal of Organic Chemistry Table 2. Oxidation of Primary Amines with IBXa

a

Reaction conditions: a mixture of 1a (2.0 mmol), IBX (1.0 mmol), additive (0.1 equiv), and solvent (5 mL) was stirred. b1 equiv of base (NEt3) was used.

dimers (Table 2). Electon-rich amines, such as p-methylbenzylamine (88%, entry 2) and o-methoxybenzylamine (94%, entry 4), and electron-deficient amines, such as m-fluorobenzylamine (81%, entry 3), were readily converted to the secondary imines in high yields. The heterocycle amines (1e) proceeded smoothly with good outcome of reaction yield (entry 5, 84%). The hydrochloride salt of benzylamine was unreactive toward oxidation, but good yield was obtained upon addition of 1 equiv of Brønsted base, such as Et3N (entry 6). No reaction was found with amine lacking α-H, such as aniline (entry 7). The successful synthesis of imine derivatives prompted us to apply this method to the more practical interest such as Ugi four-component reactions. Ugi reaction involves the condensation of a carbonyl and an amine to generate imine as an intermediate followed the reaction of an isocyanide and a carboxylic acid to form bis(amide)s. Upon subjecting benzylamine (1a, 2.0 equiv), benzoic acid (1.0 equiv), and tertbutylisonitrile (1.0 equiv) to the conditions of IBX-promoted oxidation reaction, the Ugi reaction product (4a) was obtained in 82% yield. Evidently, carboxylic acid in the reaction not only involves catalyzing the reaction but also acts as one of the components in the Ugi reaction.14 A range of diverse carboxylic acids and primary amines were suitable reaction partners. Electron-donating substituents, para-methoxy and para-methyl,

solvents and high solubility in a DES (ChCl/urea) inspired us to use DESs for the oxidation reaction under homogeneous conditions (Table 1, entries 7−13). A study on different types of DESs, for example, ChCl/CA (1:1), ChCl/imidazole (3:7), ChCl/urea (1:2), and ChCl/DMU (1:2) (Table 1, entries 10− 13) was demonstrated that the ChCl/urea (1:2) dramatically changes the results of this oxidation. Subsequently, various additives were evaluated such as benzoic acid, acetic acid, PTSA, and BF3·OEt2 (Table 1, entries 10, 14−16). Benzoic acid and acetic acid (Table 1, entries 10 and 14) caused rapid and complete conversion to afford a single, stable product. Increasing the amount of benzoic acid as additive did not alter the reaction yields (Table 1, entry 17). Reaction was equally effective under N2 and O2 atmosphere, indicating there is no involvement of O2 in the oxidation process (Table 1, entries 18 and 19). All of these systematic studies indicated that the combination of IBX in ChCl/urea (1:2) at room temperature for 12 h with a catalytic amount of carboxylic acid was the most effective system for the oxidative coupling of benzylamines to imines. The efficiency of the pilot reaction prompted us to explore the scope of the method and generality for the construction of the various imines. Under the optimized conditions, substituted benzylamines undergo oxidation to their secondary imine 5287

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Figure 2. Scope of the oxidative three-component Ugi reaction. Reaction conditions: a mixture of amines (2.0 mmol), IBX (1.0 mmol), acid (1.0 mmol), isocyanide (1.0 mmol), and solvent (5 mL) was stirred for 24 h.

pentylamine was used for the oxidation in place of substituted benzylamines. In view of green chemistry, a complete study was done to assess the reusability of DES (urea/ChCl). After completion of the reaction, water was added to the reaction mixture. The DES was soluble in water, and solid crude was precipitated. The obtained solid was separated by filtration. The DES was recovered from the filtrate by evaporating the water phase under vacuum. The recovered DES was then successfully used for the next five batches, and small losses in catalytic activity were observed for the desired compound 4a (Figure 3). Product and iodosylbenzoic acid (IBA, reduced form of IBX)

present on the benzylamines could be reacted under standard conditions to give the Ugi reaction products 4c and 4d in 80 and 85% yields, respectively (Figure 2). Electron-withdrawing substituents, meta- and para-trifluoromethyl, meta- and parafluoro, and para-chloro on the benzylamines (4e, 4i, 4g, 4b, and 4h), also smoothly coupled to yield the desired product in 78, 75, 76, 77, and 81% yields, respectively. The electronic properties of the carboxylic acid exerted some influence on this transformation; carboxylic acid bearing electron-withdrawing groups (4k, 4o) provided the corresponding bisamides in better yields of 81 and 87%, respectively, compared to those with electron-donating substituents (73% for 4l, 79% for 4p). More sterically hindered ortho-substituted benzylamine and benzoic acids were also amenable to this protocol, and the corresponding bisamides (4f, 4n, 4q, 4r) were obtained in good yields of 83, 82, 64, and 74%, respectively. This protocol was further extended to heteroaromatic methanamine (4j− 4m), and the desired products were obtained in moderate to good yields. Next, several isocyanide derivatives were evaluated for this transformation (4a, 4t, 4v, 4w, 4x). Isonitriles including tert-butylisonitrile (4a−4s), cyclohexyl isonitrile (4t, 4u), 1pentyl isocyanide (4v), 1,1,3,3-tetramethylbutyl isocyanide (4w), and ethyl isocyanoacetate (4x) were proven to be good substrates for the reaction, giving the products in good yields. Complex mixture was obtained when an aliphatic amine such as

Figure 3. Reusability chart for the DES. 5288

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The Journal of Organic Chemistry were separated quantitatively by dissolving the Ugi reaction product in EtOAc followed by filtration. Solid IBA obtained from filtration was oxidized with aqueous oxone, precipitated by cooling, and isolated by filtration to obtained IBX. The recovered IBX was further reused five times for the oxidative Ugi reaction (Figure 4). To our delight, catalytic potential of

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CONCLUSION

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EXPERIMENTAL SECTION

In summary, we have developed a simple, efficient, and organocatalyzed protocol for the direct synthesis of useful imines using hypervalent iodine as an oxidant. The scope of the reaction was studied by performing an expedient one-pot protocol for oxidative three-component Ugi reaction. The clean and mild synthetic procedure described herein is expected to have broader implications for use in those syntheses where the metal has to be avoided, including isocyanide-based multicomponent reactions in drug discovery and heterocyle synthesis where imine is involved as an intermediate.

Materials and Methods. All reactions were carried out in oven- or flame-dried glassware in an open flask unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by analytical thin layer chromatography (TLC) using precoated silica gel glass plates (0.25 mm) with a F254 indicator. Visualization was accomplished by UV light (254 nm). Flash column chromatography was performed using silica gel (100−200 mesh). Yields refer to pure compounds, unless otherwise noted. Commercial grade reagents and solvents were used without further purification. 1H and 13C NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer using CDCl3/DMSO-d6 as a solvent for deuterium locking, with temperature at 298 K. Chemical shifts are given in parts per million with TMS as an internal reference. J values are given in hertz. 13C NMR spectra were recorded as solutions in CDCl3 with complete proton decoupling, 13C{1H NMR}. Mass spectra were recorded on a Bruker MicroTOF Q II mass spectrometer. The solutions were made/diluted in ACN/H2O (3:7) and directly injected to the ESI source through a pump. IBX was synthesized in the laboratory. PIDA, PIFA, and DMP were purchased and used directly. General Procedure for the Preparation of Urea/ChCl.15 A mixture of choline chloride (6.98 g, 50 mmol) and urea (6.00 g, 100 mmol) in a 1:2 molar ratio was placed in a round-bottom flask and heated to 80 °C for 30 min to give a colorless transparent liquid. The resulting eutectic solvent was then allowed to cool at room temperature and was used for the synthesis without further purification. General Procedure for the Imine Synthesis. Benzylamine 1a (214 mg, 2.0 mmol,), benzoic acid (12 mg, 0.1 mmol), and IBX (280 mg, 1.0 mmol) were placed in a 50 mL round-bottom flask containing 5 mL of DES. The reaction was stirred at room temperature for 12 h. The reaction was monitored by TLC. After completion of the reaction, water was added. The DES being soluble in water combines in the water layer. The solid was separated by filtration. The crude product was dissolved in ether and was filtered to remove IBA. Remaining filtrate was evaporated under reduced pressure, and the resulting crude was purified by column chromatography to obtain pure product 2a. Procedure for the Oxidatative Ugi Reaction. Benzylamine 1a (214 mg, 2.0 mmol), benzoic acid (122 mg, 1.0 mmol), tertbutylisonitrile (83 mg, 1.0 mmol), and IBX (280 mg, 1.0 mmol) were placed in a 50 mL round-bottom flask containing 5 mL of DES. The reaction was stirred at room temperature for 24 h. The reaction was

Figure 4. Reuse of regenerated IBX from IBA for oxidative Ugi reaction.

regenerated IBX was identical to freshly prepared IBX from oiodobenzoic acid for up to three cycles; however, yields were decreased for the fourth and fifth cycles. Thus, the insolubilities of IBX and IBA were exploited for the recycling of oxidant, and simultaneously, IBX was used under homogeneous conditions in DESs. The excellent selectivity for primary benzylic amines suggested that selective heterocoupling could be achieved through the IBX oxidation by combining two different benzylic amines. When the reaction of para-fluorobenzylamine (1h), benzylamine (1a, 1.5 equiv, slow addition), benzoic acid, and tert-butylisonitrile was performed in the presence of the IBX as the organocatalyst, the desired Ugi reaction product was obtained in 82% yield (Scheme 2) in 48 h. This result indicates that the proposed methodology here is applicable for the production of widely diverse Ugi reactions because heterocoupled imines are much less accessible by traditional transition metal catalysts with comparable chemoselectivity. A tentative mechanistic rationalization for the oxidative imine synthesis and Ugi reaction can be advanced as depicted in Scheme 3. The initial stage is similar to that proposed by Nicolaou and co-workers for the IBX oxidation.8 IBX (IV) undergoes a reaction with amine to afford intermediate 6. Further, 6 was hydrolyzed by the water, leading to the formation of corresponding aldehyde 7. Exposure to aromatic acid promotes dehydration reaction with amine in the acidic medium, forming Schiff base 2a. Eventually, imine reacts with acid and isocyanide to generate the desired Ugi reaction product.

Scheme 2. Organocatalytic Cross-Coupling of Amines for Ugi Reaction

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The Journal of Organic Chemistry Scheme 3. Mechanism for the Oxidative Ugi Reaction

7.03−7.09 (m, 3H), 7.24 (q, J1 = 6 Hz, J2 = 11.2 Hz, 1H), 7.31 (q, J1 = 6.4 Hz, J2 = 11.2 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 64.1, 113.8 (d, 2 JC‑F = 80 HZ), 114.2 (d, 2JC‑F = 90 HZ), 114.7 (d, 2JC‑F = 85 HZ), 117.7 (d, 2JC‑F = 85 HZ), 123.4 (d, 4JC‑F = 10 HZ), 124.4 (d, 4JC‑F = 10 HZ), 129.9 (d, 3JC‑F = 35 HZ), 130.1 (d, 3JC‑F = 35 HZ) 138.4 (d, 3JC‑F = 30 HZ), 141.7 (d, 3JC‑F = 30 HZ), 160.9 (d, 4JC‑F = 10 HZ), 162.0 (d, 1JC‑F = 98 HZ), 162.1 (d, 1JC‑F = 98 HZ) ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H11F2N 232.0932; found 232.0946. (E)-N-(2-Methoxybenzyl)-1-(2-methoxyphenyl)methanimine (2d).16a Yield: 240 mg, 94%; yellow liquid; Rf = 0.58 (hexanes/EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 6H), 4.94 (s, 2H), 6.92 (t, J = 6 Hz, 2H), 7.01−7.07 (m, 2H), 7.29 (d, J = 6 Hz, 2H), 7.41− 7.44 (m, 2H), 8.14 (d, J = 6 Hz, 1H), 8.95 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 55.3, 55.5, 59.7, 110.3, 111.1, 120.6, 120.8, 125.0, 127.5, 128.0, 128.2, 129.2, 131.8,157.1, 158.3, 158.8 ppm. (Z)-1-(Furan-3-yl)-N-(furan-3-ylmethyl)methanimine (2e).16a Yield: 147 mg, 84%; oil; Rf = 0.54 (hexanes/EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) δ 4.74 (s, 2H), 6.26 (d, J = 2.4 Hz, 1H), 6.32 (s, 1H), 6.45 (s, 1H), 6.77 (d, J = 2.8 Hz, 1H), 7.36 (s, 1H), 7.49 (s, 1H), 8.10 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 56.8, 107.8, 110.3, 111.6, 114.3, 142.2, 144.8, 151.2, 151.5, 151.8 ppm. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide (4a).17 Yield: 328 mg, 82%; white solid; mp 112−114 °C; Rf = 0.6 (hexanes/EtOAc, 3:2); 1H NMR (500 MHz, CDCl3) δ 1.28 (s, 9H), 4.47 (s, 1H), 4.73 (d, J = 15 Hz, 1H), 5.52 (s, 1H), 5.81 (s, 1H), 6.99 (s, 2H), 7.08−7.14 (m, 4H), 7.25−7.32 (m, 8H), 7.44 (d, J = 6.5 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ 28.5, 51.5, 126.6, 126.8, 127.0, 128.2, 128.4, 128.7, 129.6, 129.7, 135.2, 136.4, 137.5, 168.4, 173.2 ppm. N-(2-(tert-Butylamino)-1-(4-fluorophenyl)-2-oxoethyl)-N-(4fluorobenzyl)benzamide (4b).18 Yield: 336 mg, 77%; white solid; mp 112−114 °C; Rf = 0.54 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.32 (s, 9H), 4.39 (d, J = 16.5 Hz, 1H), 4.74 (d, J = 10 Hz, 1H), 5.49 (s, 2H), 6.80 (td, J1 = 2 Hz, J2 = 7.5 Hz, 2H), 6.94−6.97 (m, 4H), 7.26−7.43 (m, 7H); 13C NMR (500 MHz, CDCl3) δ 28.6, 51.9, 115.1 (d, 2JC‑F = 85 HZ), 115.7 (d, 2JC‑F = 85 HZ), 126.6, 128.7, 130.0, 131.1, 131.5 (d, 3JC‑F = 30 HZ), 136.2, 160.9 (d, 1JC‑F = 97 HZ), 161.8 (d, 1JC‑F = 99 HZ), 168.3, 173.2 ppm; 19F NMR (500 MHz, CDCl3) δ −112.6, −115.4. N-(2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-(4methoxybenzyl)benzamide (4c).18 Yield: 368 mg, 80%; white solid; mp 130−132 °C; Rf = 0.54 (hexanes/EtOAc, 13:7); 1H NMR (500 MHz, CDCl3) δ 1.30 (s, 9H), 3.75 (s, 3H), 3.79 (s, 3H), 4.37 (s, 1H), 4.61 (d, J = 16 Hz, 1H), 5.37 (s, 1H), 5.62 (s, 1H), 6.70 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.94 (s, 2H), 7.35−7.46 (m, 7H); 13C NMR (500 MHz, CDCl3) δ 28.7, 51.6, 55.3, 55.4, 113.8, 114.2, 114.4, 126.7, 127.5, 128.5, 129.7, 131.0, 136.7, 158.7, 159.7, 168.8, 173.2 ppm.

monitored by TLC. After completion of the reaction, water was added. The DES being soluble in water combines in the water layer. The solid was separated by filtration. The crude product was dissolved in ethyl acetate, and the residue was filtered to remove IBA. Remaining filtrate was evaporated under reduced pressure, and the resulting crude was washed with cold ether to obtain pure product 4a. Recycling Studies of Deep Eutectic Solvent Urea/ChCl. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL). The DES being soluble in water combines in the water layer. Product was obtained by filtration. The DES was recovered easily from filtrate by evaporating the water at 80 °C under vacuum. The recovered DES was then successfully used for the next batch and showed no significant loss of yield. Recycling Studies of IBX. In a representative case, the IBX and IBX byproducts were recovered essentially quantitatively by filtration from the oxidation of benzylamine with 1.0 equiv of IBX in EtOAc. 1H NMR analysis of the crude mixture indicates the primary component to be IBA. The recovered solids were oxidized with aqueous oxone, precipitated by cooling, isolated by filtration, and reused without further purification. Procedure for the Heterocoupled Oxidatative Ugi Reaction. para-Fluorobenzylamine 1h (125 mg, 1.0 mmol), benzoic acid (122 mg, 1.0 mmol), and IBX (280 mg, 1.0 mmol) were placed in a 50 mL round-bottom flask containing 3 mL of DES. The reaction was stirred at room temperature for 5 min. Afterward, benzylamine (1a, 161 mg, 1.5 equiv) dissolved in 2 mL of DES was slowly added (15 min/ mmol) to the reaction mixture, followed by isocyanide (83 mg, 1.0 mmol). The reaction was further stirred for 48 h. After completion of the reaction, water was added. The DES being soluble in water combines in the water layer. The solid was separated by filtration. The crude product was dissolved in ethyl acetate, and the residue was filtered to remove IBA. Remaining filtrate was evaporated under reduced pressure, and the resulting crude was washed with cold ether to obtain pure product 4z. Product Characterization Data. (E)-N-Benzyl-1-phenylmethanimine (2a).16a Yield: 164 mg, 84%; yellow liquid; Rf = 0.56 (hexanes/ EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) δ 4.82 (s, 2H), 7.24−7.27 (m, 1H), 7.37 (d, J = 3.2 Hz, 4H), 7.40−7.41 (m, 3H), 7.77−7.79 (m, 2H), 8.39 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 65.1, 127.1, 128.1, 128.4, 128.6, 128.7, 130.8, 136.3, 139.4, 162.1 ppm. (E)-N-(4-Methylbenzyl)-1-(p-tolyl)methanimine (2b).16a Yield: 196 mg, 88%; white solid; Rf = 0.50 (hexanes/EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.37 (s, 3H), 4.76 (s, 2H), 7.13 (d, J = 6 Hz, 2H), 7.19−7.22 (m, 4H), 7.65 (d, J = 6 Hz, 2H), 8.33 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 21.1, 21.5, 64.8, 127.9, 128.2, 129.1, 129.3, 133.7, 136.4, 136.5, 141.0 161.6 ppm. (E)-N-(3-Fluorobenzyl)-1-(3-fluorophenyl)methanimine (2c).16b Yield: 187 mg, 81%; yellow liquid; Rf = 0.50 (hexanes/EtOAc, 9:1); 1 H NMR (400 MHz, CDCl3) δ 4.75 (s, 2H), 6.91 (t, J = 6.8 Hz, 1H), 5290

DOI: 10.1021/acs.joc.7b00594 J. Org. Chem. 2017, 82, 5285−5293

Article

The Journal of Organic Chemistry

HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H24N2O4 381.1809; found 381.1814. N-(2-(tert-Butylamino)-1-(furan-2-yl)-2-oxoethyl)-4-fluoro-N(furan-2-ylmethyl)benzamide (4k). Yield: 322 mg, 81%; white solid; mp 142−144 °C; Rf = 0.63 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 4.45 (d, J = 16.5 Hz, 1H), 4.56 (d, J = 16.5 Hz, 1H), 5.80 (s, 1H), 5.91−5.97 (m, 2H), 6.20 (s, 1H), 6.33− 6.34 (m, 1H), 6.52 (s, 1H), 7.05 (t, J = 8.5 Hz, 1H), 7.24 (d, J = 1 Hz, 1H), 7.34 (d, J = 1 Hz, 1H), 7.54−7.57 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 28.7, 51.8, 108.2, 110.6, 110.8, 111.7, 115.6 (d, 2JC‑F = 85 HZ), 129.5 (d, 3JC‑F = 35 HZ), 131.7 (d, 4JC‑F = 15 HZ), 141.9, 143.1, 148.5, 150.4, 162.7 (d, 1JC‑F = 99 HZ), 166.3, 172.0 ppm; 19F NMR (500 MHz, CDCl3) δ −109.88; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H23FN2O4 399.1715; found 399.1719. N-(2-(tert-Butylamino)-1-(furan-2-yl)-2-oxoethyl)-4-ethoxy-N(furan-2-lmethyl)benzamide (4l). Yield: 309 mg, 73%; white solid; mp 133−135 °C; Rf = 0.51 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.33 (s, 9H), 1.39 (t, J = 7 Hz, 3H), 4.02 (q, J1 = 7 Hz, J2 = 14 Hz, 2H), 4.42 (d, J = 16.5 Hz, 1H), 4.60 (d, J = 16.5 Hz, 1H), 5.78 (s, 1H), 5.99 (s, 1H), 6.14 (s, 1H), 6.21 (t, J = 2 Hz, 1H), 6.32 (q, J1 = 1.5 Hz, J2 = 3 Hz, 1H), 6.52 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 1 Hz, 1H), 7.34 (d, J = 1 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ 14.8, 28.7, 51.7, 63.7, 108.3, 110.6, 110.7, 111.5, 114.4, 127.5, 129.2, 141.8, 142.9, 148.7, 150.8, 160.6, 166.5, 172.9 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H28N2O5 425.2071; found 425.2072. N-(2-(tert-Butylamino)-2-oxo-1-(thiophen-2-yl)ethyl)-N-(thiophen-2-ylmethyl)benzamide (4m). Yield: 309 mg, 75%; white solid; mp 123−125 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.30 (s, 9H), 4.75−4.78 (m, 2H), 5.71 (s, 1H), 6.00 (s, 1H), 6.74 (d, J = 3 Hz, 1H), 6.81−6.83 (m, 1H), 6.97−6.99 (m, 1H), 7.10 (s, 1H), 7.13 (d, J = 5 Hz, 1H), 7.33 (d, J = 5 Hz, 1H), 7.38−7.41 (m, 3H), 7.48−7.50 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 28.6, 51.7, 125.5, 126.6, 126.8, 126.9, 127.7, 128.7, 129.4, 130.2, 135.7, 137.3, 140.3, 167.4, 172.6 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H24N2O2S2 413.1352; found 413.1358. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-nitrobenzamide (4n).18 Yield: 365 mg, 82%; white solid; mp 156−158 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 4.45 (d, J = 15 Hz, 1H), 4.65 (d, J = 15 Hz, 1H), 5.47 (s, 1H), 5.71 (s, 1H), 6.86 (s, 2H), 7.10 (s, 3H), 7.33−7.47 (m, 6H), 7.74 (s, 1H), 8.19 (s, 2H); 13C NMR (500 MHz, CDCl3) δ 28.7, 29.8, 52.0, 122.1, 124.4, 126.9, 127.3, 128.5, 129.1, 129.2, 129.6, 129.9, 132.5, 134.9, 138.2, 148.0, 168.1, 170.8 ppm. N-Benzyl-4-bromo-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide (4o). Yield: 415 mg, 87%; white solid; mp 144−146 °C; Rf = 0.61 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 9H), 4.43 (d, J = 16 Hz, 1H), 4.69 (d, J = 16 Hz, 1H), 5.50 (s, 2H), 6.97 (s, 2H), 7.12−7.16 (m, 3H), 7.28−7.45 (m, 9H); 13C NMR (500 MHz, CDCl3) δ 28.7, 51.8, 124.2, 127.0, 128.4, 128.5, 128.8, 129.0, 129.8, 131.7, 135.1, 135.3, 168.3, 172.3 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H27BrN2O2 479.1329; found 479.1336. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-methoxybenzamide (4p). Yield: 339 mg, 79%; white solid; mp 135−137 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.30 (s, 9H), 3.64 (s, 3H), 4.45 (s, 1H), 4.71 (d, J = 16.5 Hz, 1H), 5.46 (s, 1H), 5.62 (s, 1H), 6.90 (d, J = 21 Hz, 2H), 7.04−7.08 (m, 3H), 7.12− 7.18 (m, 3H), 7.26−7.39 (m, 6H); 13C NMR (500 MHz, CDCl3) δ 28.7, 51.7, 55.3, 111.8, 116.3, 119.0, 127.0, 128.4, 128.6, 128.9, 129.7, 135.4, 137.6, 159.6, 168.4, 173.1 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H30N2O3 431.2329; found 431.2330. N-Benzyl-2-(tert-butyl)-N-(2-(tert-butylamino)-2-oxo-1phenylethyl)benzamide (4q). Yield: 292 mg, 64%; white solid; mp 136−138 °C; Rf = 0.65 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.29 (s, 18H), 4.46 (s, 1H), 4.76 (s, 1H), 5.45 (s, 1H), 5.71 (s, 1H), 7.06 (s, 2H), 7.13−7.18 (m, 3H), 7.25−7.44 (m, 9H); 13C NMR (500 MHz, CDCl3) δ 28.6, 31.3, 34.9, 51.6, 125.5, 126.7, 127.0, 128.4, 128.5, 128.8, 129.6, 133.3, 135.4, 153.3, 168.6, 173.5 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H36N2O2 457.2850; found 457.2863.

N-(2-(tert-Butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(4methylbenzyl)benzamide (4d). Yield: 364 mg, 85%; white solid; mp 114−116 °C; Rf = 0.54 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.28 (s, 9H), 2.26 (s, 3H), 2.32 (s, 3H), 4.38 (s, 1H), 4.62 (s, 1H), 5.36 (s, 1H), 5.68 (s, 1H), 6.95−6.99 (m, 4H), 7.09 (d, J = 8 Hz, 3H), 7.25−7.37 (m, 4H), 7.45 (d, J = 9 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ 21.1, 21.2, 28.6, 51.6, 126.8, 127.1, 128.5, 129.1, 129.5, 129.6, 129.7, 132.4, 136.6, 136.7, 138.4, 168.6, 173.2 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H32N2O2 429.2537; found 429.2542. N-(2-(tert-Butylamino)-2-oxo-1-(3-(trifluoromethyl)phenyl)ethyl)N-(3-(trifluoromethyl)benzyl)benzamide (4e). Yield: 418 mg, 78%; white solid; mp 112−114 °C; Rf = 0.64 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 4.54 (s, 1H), 4.89 (s, 1H), 5.75 (s, 1H), 5.95 (s, 1H), 6.95 (s, 1H), 7.09−7.10 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.29−7.44 (m, 9H), 7.54−7.56 (m, 1H); 13C NMR (500 MHz, CDCl3) δ 28.6, 52.2, 122.8, 123.7, 124.7, 125.0, 125.6, 126.5, 126.7, 128.7, 128.8, 129.4, 130.1, 130.4, 130.6, 131.1, 131.4, 133.0, 135.9, 168.0, 173.4 ppm; 19F NMR (500 MHz, CDCl3) δ −62.89, −62.96; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H26F6N2O2 537.1971; found 537.1975. N-(2-(tert-Butylamino)-1-(2-methoxyphenyl)-2-oxoethyl)-N-(2methoxybenzyl)benzamide (4f). Yield: 382 mg, 83%; white solid; mp 112−114 °C; Rf = 0.50 (hexanes/EtOAc, 13:7); 1H NMR (500 MHz, CDCl3) δ 1.26 (s, 9H), 3.60−3.73 (m, 6H), 4.59−4.74 (m, 2H), 5.37−6.00 (m, 2H), 6.56 (d, J = 8 Hz, 2H), 6.80 (s, 2H),7.06−7.53 (m, 9H); 13C NMR (500 MHz, CDCl3) δ 28.5, 51.2, 54.9, 109.6, 109.8, 120.0, 120.3, 126.9, 128.2, 129.5, 130.3, 156.5, 156.6, 157.6, 169.1, 173.4 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H32N2O4 461.2435; found 461.2428. N-(2-(tert-Butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-N-(3fluorobenzyl)benzamide (4g). Yield: 331 mg, 76%; white solid; mp 112−114 °C; Rf = 0.58 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.33 (s, 9H), 4.45 (d, J = 16.5 Hz, 1H), 4.78 (d, J = 16 Hz, 1H), 5.60−5.79 (m, 2H), 6.66 (s, 1H), 6.78 (td, J1 = 8.5 Hz, J2 = 1 Hz, 2H), 6.95 (t, J = 7 Hz, 1H), 7.07−7.14 (m, 2H), 7.24−7.25 (m, 2H), 7.36−7.43 (m, 5H); 13C NMR (500 MHz, CDCl3) δ 28.6, 51.9, 113.8 (d, 2JC‑F = 85 HZ), 115.6 (d, 2JC‑F = 80 HZ), 116.6 (d, 2JC‑F = 90 HZ), 122.7, 125.3, 126.7, 128.7, 129.8 (d, 3JC‑F = 30 HZ), 130.1, 130.4 (d, 3 JC‑F = 30 HZ), 136.0, 137.6, 140.4, 161.8 (d, 1JC‑F = 98 HZ), 161.9 (d, 1 JC‑F = 98 HZ), 167.9, 172.3 ppm; 19F NMR (500 MHz, CDCl3) δ −111.7, −113.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H26F2N2O2 437.2035; found 437.2037. N-(2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(4chlorobenzyl)benzamide (4h).18 Yield: 379 mg, 81%; white solid; mp 164−166 °C; Rf = 0.59 (hexanes/EtOAc, 13:7); 1H NMR (500 MHz, CDCl3) δ 1.32 (s, 9H), 4.37 (d, J = 16.5 Hz, 1H), 4.74 (d, J = 10.5 Hz, 1H), 5.46 (s, 1H), 5.69 (s, 1H), 6.92 (s, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.26−7.43 (m, 9H); 13C NMR (500 MHz, CDCl3) δ 28.7, 51.9, 126.7, 128.5, 128.7, 129.1, 130.1, 131.0, 132.9, 133.7, 134.8, 136.1, 168.1, 173.2 ppm. N-(2-(tert-Butylamino)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)N-(4-(trifluoromethyl)benzyl)benzamide (4i). Yield: 402 mg, 75%; white solid; mp 122−124 °C; Rf = 0.58 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 4.49 (d, J = 16 Hz, 1H), 4.91 (s, 1H), 5.72 (s, 2H), 7.05 (d, J = 6.5 Hz, 2H), 7.34−7.46 (m, 11H); 13 C NMR (500 MHz, CDCl3) δ 28.7, 52.1, 122.7, 123.0, 124.8, 125.2, 125.7, 125.8, 126.7, 127.4, 128.8, 130.0, 130.3, 130.9, 131.2, 135.8, 139.0, 167.8, 173.3 ppm; 19F NMR (500 MHz, CDCl3) δ −62.70, −62.98; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H26F6N2O2 537.1971; found 537.1968. N-(2-(tert-Butylamino)-1-(furan-2-yl)-2-oxoethyl)-N-(furan-2ylmethyl)benzamide (4j). Yield: 288 mg, 76%; white solid; mp 130− 131 °C; Rf = 0.58 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.33 (s, 9H), 4.44 (d, J = 16 Hz, 1H), 4.58 (d, J = 16.5 Hz, 1H), 5.91−6.03 (m, 3H), 6.19 (s, 1H), 6.32 (dd, 1H), 6.54 (s, 1H), 7.24 (s, 1H), 7.34−7.41 (m, 4H), 7.51−7.53 (d, J = 7.5 HZ, 2H); 13C NMR (500 MHz, CDCl3) δ 28.6, 51.7, 108.2, 110.5, 110.8, 111.7, 127.1, 130.1, 135.7, 141.8, 143.0, 148.5, 150.5, 166.3, 172.9 ppm; 5291

DOI: 10.1021/acs.joc.7b00594 J. Org. Chem. 2017, 82, 5285−5293

Article

The Journal of Organic Chemistry

14.1, 41.7, 61.7, 115.1 (d, 2JC‑F = 85 HZ), 115.8 (d, 2JC‑F = 85 HZ), 126.8, 128.7 (d, 3JC‑F = 30 HZ), 130.1, 130.3 (d, 4JC‑F = 15 HZ), 131.6 (d, 3JC‑F = 30 HZ), 135.8, 160.9 (d, 1JC‑F = 97 HZ), 161.8 (d, 1JC‑F = 99 HZ), 169.2, 169.5, 173.1 ppm; 19F NMR (500 MHz, CDCl3) δ −112.32, −115.15; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H24F2N2O4 467.1777; found 467.1786.

N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-2-fluorobenzamide (4r). Yield: 309 mg, 74%; white solid; mp 125−127 °C; Rf = 0.60 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 4.38 (d, J = 16.5 Hz, 1H), 4.61 (d, J = 16 Hz, 1H), 5.69 (s, 1H), 5.86 (s, 1H), 6.84 (s, 1H), 7.04−7.08 (m, 4H), 7.18−7.29 (m, 7H), 7.42 (d, J = 6 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ 28.6, 44.2, 51.6, 64.3, 115.7 (d, 2JC‑F = 85 HZ), 124.4 (d, 4JC‑F = 10 HZ), 124.6 (d, 2 JC‑F = 70 HZ), 127.0, 127.4, 127.7, 128.2, 128.4 (d, 3JC‑F = 40 HZ), 128.5, 128.7, 129.5, 131.1 (d, 3JC‑F = 35 HZ), 135.0, 136.8, 157.2 (d, 1 JC‑F = 97 HZ), 157.4, 168.1 (d, 3JC‑F = 16 HZ) ppm; 19F NMR (500 MHz, CDCl3) δ −115.18; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H27FN2O2 419.2129; found 419.2143. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-methylbenzamide (4s). Yield: 364 mg, 88%; white solid; mp 134−136 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.29 (s, 9H), 2.30 (s, 3H), 4.45 (s, 1H), 4.69 (d, J = 15 Hz, 1H), 5.47 (s, 1H), 5.67 (s, 1H), 7.00−7.04 (m, 2H), 7.11−7.21 (m, 5H), 7.22−7.34 (m, 7H); 13C NMR (500 MHz, CDCl3) δ 21.4, 28.6, 51.7, 123.6, 126.9, 127.3, 127.8, 128.3, 128.5, 128.8, 129.7, 130.5, 135.4, 136.4, 138.4, 168.5, 173.5 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H30N2O2 415.2380; found 415.2385. N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)benzamide (4t).18 Yield: 362 mg, 85%; white solid; mp 128−130 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); 1H NMR (400 MHz, CDCl3) δ 1.03−1.13 (m, 3H), 1.25−1.37 (m, 2H), 1.55−1.65 (m, 3H), 1.80− 1.90 (m, 2H), 3.78−3.84 (m, 1H), 4.47 (s, 1H), 4.70 (s, 1H), 5.50 (s, 1H), 5.72 (s, 1H), 7.07 (d, J = 4.8 Hz, 2H), 7.12−7.19 (m, 4H), 7.29 (m, 4H), 7.33−7.39 (m, 3H), 7.46 (d, J = 5.2 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 24.7, 24.8, 25.5, 32.7, 48.6, 126.7, 126.9, 127.1, 128.3, 128.4, 128.5, 128.8, 129.5, 129.7, 135.1, 136.3, 168.2, 173.2 ppm. N-(2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-(4methoxybenzyl)benzamide (4u). Yield: 427 mg, 88%; white solid; mp 156−158 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); 1H NMR (500 MHz, CDCl3) δ 1.02−1.09 (m, 3H), 1.25−1.35 (m, 2H), 1.54−1.63 (m, 3H), 1.80−1.89 (m, 2H), 2.27 (s, 3H), 3.77 (s, 4H), 4.36 (s, 1H), 4.63 (s, 1H), 5.38 (s, 1H), 5.75 (s, 1H), 6.81 (d, J = 8.5 Hz, 2H), 7.00 (s, 4H), 7.26−7.33 (m, 5H), 7.45 (d, J = 7 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ 21.0, 24.7, 24.8, 25.5, 32.7, 48.5, 55.3, 114.2, 126.7, 127.2, 128.4, 129.0, 129.7, 131.0, 136.4, 136.6, 159.7, 168.5, 173.1 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H34N2O4 487.2591; found 487.2597. N-Benzyl-N-(2-oxo-2-(pentylamino)-1-phenylethyl)benzamide (4v). Yield: 269 mg, 65%; white solid; mp 138−140 °C; Rf = 0.50 (hexanes/EtOAc, 7:3); 1H NMR (400 MHz, CDCl3) δ 0.85 (d, J = 6 HZ, 3H), 1.22 (d, J = 18 Hz, 4H), 1.43 (s, 2H), 3.20 (s, 2H), 4.45 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 13.6 Hz, 1H), 5.62 (s, 1H), 6.40 (s, 1H), 6.98 (s, 2H), 7.11 (s, 3H), 7.26−7.44 (m, 10H); 13C NMR (400 MHz, CDCl3) δ 14.0, 22.2, 28.9, 29.0, 39.6, 126.6, 127.0, 128.1, 128.5, 128.6, 128.7, 129.6, 129.7, 135.2, 136.4, 169.3, 173.1 ppm; HRMS (ESITOF) m/z [M + H]+ calcd for C27H30N2O2 415.2380; found 415.2383. N-Benzyl-4-bromo-N-(2-oxo-1-phenyl-2-((2,4,4-trimethylpentan2-yl)amino)ethyl)benzamide (4w). Yield: 416 mg, 78%; white solid; mp 153−155 °C; Rf = 0.60 (hexanes/EtOAc, 4:1); 1H NMR (500 MHz, CDCl3) δ 0.86 (s, 9H), 1.38 (s, 3H), 1.43 (s, 3H), 1.48 (d, J = 15 Hz, 1H), 1.67 (d, J = 15 Hz, 1H), 4.41 (d, J = 17 Hz, 1H), 4.71 (s, 1H), 5.36 (s, 1H), 5.56 (s, 1H), 3.75−3.85 (m, 4H), 4.38 (s, 1H), 4.63 (s, 1H), 5.38 (s, 1H), 5.75 (s, 1H), 7.01 (d, J = 6.5 Hz, 2H), 7.12−7.17 (m, 3H), 7.28−7.42 (m, 9H); 13C NMR (500 MHz, CDCl3) δ 28.3, 28.6, 31.4, 31.7, 53.0, 55.8, 65.0, 124.0, 127.0, 128.2, 128.3, 128.4, 128.5, 128.5, 128.7, 128.9, 129.8, 130.7, 131.6, 135.2, 162.0, 167.7, 172.1 ppm; HRMS (ESI-TOF) m/z [M + H] + calcd for C30H35BrN2O2 535.1955; found 535.1954. Ethyl(2-(N-(4-fluorobenzyl)benzamido)-2-(4-fluorophenyl)acetyl)glycinate (4x). Yield: 386 mg, 83%; white solid; mp 127−129 °C; Rf = 0.50 (hexanes/EtOAc, 7:13); 1H NMR (500 MHz, CDCl3) δ 1.26 (t, J = 7 Hz, 3H), 4.01−4.03 (m, 2H), 4.17 (q, J1 = 7 Hz, J2 = 14 Hz, 2H), 4.40 (d, J = 16 Hz, 1H), 4.73 (d, J = 15 HZ, 1H), 5.58 (s, 1H), 6.37 (s, 1H), 6.83 (t, J = 8.5 HZ, 2H), 6.97−7.00 (m, 4H), 7.35− 7.39 (m, 5H), 7.45 (d, J = 7 Hz, 2H); 13C NMR (500 MHz, CDCl3) δ

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00594. Copies of 1H NMR and 13C NMR of all the synthesized compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Siddharth Sharma: 0000-0003-2759-4155 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a grant from the DST-India in the form of INSPIRE Faculty (IFA-13, CH-116) to S.S. Authors acknowledge MLSU-Udaipur, Rajasthan, for giving infrastructure support. Authors also acknowledge Prof. S.S. Chimni and Prof. Palwinder Singh from GNDU-Amritsar for scientific guidance. K.S. is a registered Ph.D. scholar in GNDU, Amritsar.

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REFERENCES

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