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Catalytic Direct α‑Amination of Arylacetic Acid Synthons with Anilines Jogendra Kumar, Eringathodi Suresh, and Sukalyan Bhadra* Cite This: https://dx.doi.org/10.1021/acs.joc.0c02122

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ABSTRACT: A unique α-amination approach using various anilines has been developed for arylacetic acids via adaptation as benzazoles. The reaction proceeds through a single electron transfer mechanism utilizing an iron-based catalyst system to access α-(N-arylamino)acetic acid equivalents. Modification of approved drugs, facile cleavage of the benzazole auxiliary, and tolerance of amide linkage forming conditions constitute the potential applicability of this strategy.

M

trapping of a stabilized C-centered radical by anilines, providing an expedient access to α-(N-arylamino)acetic acids that serve as structural motifs in bioactive compounds and pharmaceutical agents (Scheme 1).9 We commenced our study with an iron-based catalyst system given the high abundance, low cost, and documented abilities of those systems in promoting amination reactions as

odern discoveries on the comparatively passive C−H bond functionalization of common aliphatic substrates, e.g. carboxylic acids, ketones, amines, etc. have significantly simplified the retrosynthesis of tailored molecular targets.1 The general approach to trigger a specific alkyl C−H bond primarily relies on the design of a tethered directing group, which assists a transition metal catalyst to selectively cleave the C−H bond situated typically at the β- or γ-position via the thermodynamically preferred five- or six-membered metallacycle intermediates.2 Unfortunately, an analogous directed approach cannot be foretold for the α-C−H functionalization of alkyl substrates due to the prerequisite of a stressed fourmembered metallacycle intermediate.3 In addition, for aliphatic substrates, holding an aryl substituent close to the directing group as in arylacetic acids, the activation of more acidic orthoprotons of the aromatic ring is facilitated via classical sixmembered metallacycle intermediates.4 Thus, the regiospecific α-C−H functionalization of arylacetic acids possesses substantial challenges. The site-selective amination by functionalizing a specific C− H bond of an aliphatic carboxylic acid synthon arguably represents an applauded transformation, given the importance of the aminated product as a building block in constructing uncountable natural and synthetic systems, pertinent drug molecules, and functional materials.5 An impressive list of developments on transition metal catalyzed directed C−H amination of carboxylate equivalents has led to several β- and/ or γ-lactams (intramolecular C−H amination) and a few βaminated acids (intermolecular C−H amination).6,7 In contrast to the directed approach, the metal catalyzed αamination of carboxylate synthons is primarily based on enolate chemistry and often lacks generality.8 However, numerous classes of weakly basic amines, namely anilines, remain that cannot be introduced directly by using any of these amination techniques. Herein, we describe a novel α-C−H amination approach of phenylacetic acid equivalents via © XXXX American Chemical Society

Scheme 1. Catalytic C−H Functionalization Strategies of Carboxylate Equivalents with an Emphasis on Amination

Received: September 3, 2020

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https://dx.doi.org/10.1021/acs.joc.0c02122 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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electron mediators.10 To identify the appropriate α-carboradical source, we studied the iron catalyzed amination of various phenylacetic acid derivatives with aniline (Scheme 2).

delight, the amination was equally effective when the oxidant was used in marginally excess of the substrate (entry 8). Notably, in every case, monoamination took place regiospecifically at the C(sp3)−H bond next to the azole ring with no concurrent aromatic ring amination. With an effective reaction condition in hand, we investigated the scope of the amination with regard to both aniline as well as benzazole substrates (Scheme 3). An array of diversely decorated anilines with numerous functional groups including fluoro, chloro, bromo, iodo, methyl, ester, pyridyl, etc. were swiftly installed at the desired position. It is noteworthy to mention that both sterically hindered anilines (8bo, 8bp, 8ao− 8jo, 8ko, 8qo−8to) and acids (8md, 8nj, 8od, 8ph, 8vc) were equally reactive under the optimized conditions. Importantly, the cross-coupling sensitive C−X bonds (X = Cl, Br, I) in the aromatic rings of both arylacetic acids and anilines remained unaffected under the amination conditions. By applying the new technique, a few nonsteroidal anti-inflammatory drug derivatives, e.g. ibuprofen and naproxen, were structurally modified with different anilines (8od, 8ph). However, aliphatic carboxylic acid-derived benzazoles, primary aliphatic amines, and secondary anilines remained unreactive in the title transformation. To comprehend the mechanism, we conducted a series of experiments (see Supporting Information). The addition of radical scavengers, e.g. 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) (2.0 equiv each), totally inhibited the arylamination process, indicating the participation of radical intermediates. HRMS (ESI) analysis indicated the formation of TEMPO-6b adduct, while GC-MS analysis showed the formation of both BHT(aniline) and BHT-6b adducts in the amination of 6b with aniline in the presence of TEMPO and BHT, respectively (see Supporting Information). Furthermore, benzylic substrates, e.g. diphenylmethane and 2-benzylpyridine, in addition to substrates 1−5 in Scheme 2, could not be aminated under the optimized conditions (see Supporting Information, Scheme S1). These experimental evidence further support that the carbo-radicals formed in the case of 2-benzylazoles are relatively stabilized by the azole ring.11b Moreover, a stabilized amine radical species, such as aniline radical cation, might be involved, because the attempted amination with primary and/ or secondary aliphatic amines failed to deliver the desired aminated products. The kinetic isotope effect (KIE) derived from the amination of 2-benzylbenzoxazole (6b) and 2-benzylbenzoxazole-d2 (6bd2) with aniline was determined to be 1.6 (see Supporting Information, Schemes S2 and S3).12 The absence of H/D scrambling in the starting material (6b) during the amination with aniline in the presence of D2O corroborates that the C−H abstraction is an irreversible event (see Supporting Information, Scheme S4). Based on these mechanistic studies and literature precedence, we propose a catalytic cycle illustrated in Scheme 4.10a A carbo-radical (Ia) is formed from 6 by the action of tBuO radical, initially generated upon the cleavage of DTBP by Fe2+ species, in a fashion similar to that of diarylmethanes as described by Bolm et al.10b Subsequently, a single electron transfer is believed to proceed from Ia to Fe3+, leading to a benzylic cation II, which is trapped with aniline to furnish 8 (path A). Alternatively, Ia may react with the in situ formed aniline radical cation to give the aminated product 8 (path B).10c−e

Scheme 2. Identification of the Appropriate Acid Equivalenta

a Reaction conditions: acid derivative (0.5 mmol), PhNH2 (1.0 mmol), FeCl3 (10 mol %), DTBP (1.0 mmol), DCE (2.5 mL), N2 atm., 100 °C, 3 h. DTBP = Di-tert-butyl peroxide, DCE = 1,2dichloroethane, NHQ = 8-aminoquinolinyl.

However, the free acid, simple ester, and amides were not effective (1−5). Gratifyingly, 2-benzylbenzoxazole gave the desired aminated product 8aa in satisfactory yield. This is apparently attributed to the formation of a carbo-radical that is rather stabilized by the azole ring and is in agreement with our recent findings on related methoxylation and chalcogenation reactions.11 After recognizing the active carboxylate equivalent, we studied the reaction between a reasonably hindered benzoxazole 6b having two nonequivalent benzylic groups and aniline 7a (Table 1 and Table TS1, Supporting Information). Table 1. Optimization of the Reaction Conditionsa

entry

deviation from the conditions given in the table scheme above

8ba (%)

1 2 3 4 5 6 7 8

none DCE instead of toluene FeCl2 instead of FeCl3 K2S2O8 instead of DTBP reaction under air no FeCl3 no DTBP 1.2 equiv of DTBP

90 55 85 25 68 0 10 91

Note

a Reaction conditions: 6b (0.5 mmol), 7a (0.75 mmol), FeCl3 (10 mol %), DTBP (1.0 mmol), toluene (2.5 mL), N2 atm., 100 °C, 3 h. BO = benzoxazole. TBHP = tert-butylhydroperoxide.

Pleasingly, replacing DCE with a nonpolar solvent, e.g. toluene, gave rise to noticeably enhanced yield of 8ba (entries 1 and 2). However, alteration of the iron salt or the oxidant was not found beneficial (entries 3 and 4). The presence of air in the reaction medium results in diminished yield (entry 5). Without iron, the amination does not proceed, while the absence of DTBP produced 8ba in only 10% yield, indicating that the true catalytic constituent is formed upon the addition of both FeCl3 and DTBP (entries 6 and 7). Variation of other reaction parameters such as temperature, use of other metal salts, catalyst loading, etc. exhibited a deleterious effect in the product formation (see Supporting Information). To our B



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Scheme 3. Iron Catalyzed α-Amination of Phenylacetic Acids via Benzazole Derivatives with Anilinesa

Reaction conditions: 6 (0.5 mmol), 7 (0.75 mmol), FeCl3 (10 mol %), DTBP (0.6 mmol), toluene (2.5 mL), N2 atm., 100 °C, 3 h. bTwelve hours. cFour hours. dFive mol % FeCl3, 1 h. eTen hours. fSupported by an X-ray crystallographic structure (see Supporting Information). BT = benzothiazole a

Scheme 4. Plausible Mechanism

Scheme 5. Transformations of α-(N-Arylamino)acetic Acids

Finally, the potential applicability of the new strategy has been exemplified via the gram-level preparation of 8ba, from which the benzazole auxiliary was effectively removed to furnish the corresponding α-amino acid 9. Further, compound 9 was found tolerant of the amide bond condensation conditions and thus serves as a remarkable precursor for α(N-arylamino)acetic acid amides that are prevalent in bioactive scaffolds (Scheme 5).13,14 In another approach, 8ua was prepared in gram-scale and was subsequently functionalized with common protecting groups. In conclusion, we unveiled a regiospecific α-amination approach for phenylacetic acids via transforming them as benzazoles. The key role of the iron-based catalyst system is to facilitate the formation of the α-carbo-radical from 2benzylbenzazoles, leading to the α-amination with various anilines. To our knowledge, this strategy constitutes the first

and a rare example of an α-amination of carboxylic acid equivalents with various anilines. The synthetic utility has been validated via (1) modification of drug candidates, (2) scaled-up synthesis and successive cleavage of the azole group to α-(Narylamino)acetic acids, and (3) synthesis of α-(N-arylamino)acetic acid amides and a few active intermediates. We envision that the new method would be particularly intriguing in α-(Narylamino)acetic acid-based drug discovery in the future. C



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120.0, 110.7, 35.1 ppm. HRMS (ESI): m/z calcd for C20H16NO3S [M + H]+, 350.0840; found, 350.0846. (4-(Benzo[d]oxazol-2-ylmethyl)phenyl)(phenyl)methanone (6i). Compound 6i was prepared by Goossen’s method.18 A 25 mL round-bottom flask was charged with 6g (576 mg, 2.0 mmol, 1.0 equiv), potassium 2-oxo-2-phenylacetate (565 mg, 3.0 mmol, 1.5 equiv), CuBr (43.0 mg, 0.3 mmol, 0.15 equiv), 1, 10-phenanthroline (54 mg, 0.3 mmol, 0.15 equiv), Pd(acac)2 (6 mg, 1 mol %), P(o-Tol)3 (18 mg, 3 mol %) and the vessel was evacuated and backfilled with nitrogen (3×), then a mixture of NMP (3.6 mL) and quinoline (0.84 mL) was added to it and the reaction mixture was heated overnight at 170 °C (checked by TLC). After completion of the reaction, it was cooled and filtered through Celite, and the filter cake was rinsed with diethyl ether. The filtrate was washed with 1 M hydrochloric acid (3 × 20 mL), and the aqueous phases were extracted with diethyl ether (3 × 20 mL). The combined organic phases were washed with 100 mL saturated sodium chloride solution, dried over Na2CO3 and filtered. The crude reaction mixture was purified by column chromatography to give 6i as a brown thick liquid: 6i (407 mg, 1.3 mmol, 65%). Rf = 0.4 (Hexane:Et2O = 8:2). IR (neat): ν = 2929, 2339, 1657, 1454, 1281 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.77−7.80 (m, 4H), 7.69−7.71 (m, 1H), 7.54−7.58 (m, 1H), 7.43−7.52 (m, 5H), 7.29− 7.32 (m, 2H), 4.35 (s, 2H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 196.2, 164.4, 151.1, 141.3, 139.5, 137.5, 136.7, 132.5, 130.7 (2C), 130.0 (2C), 129.1 (2C), 128.3 (2C), 125.0, 124.4, 119.9, 110.6, 35.2 ppm. HRMS (ESI): m/z calcd for C21H16NO2 [M + H]+, 314.1176; found, 314.1181. 2-Benzhydrylbenzo[d]oxazole (6n). To a solution of 2,2-diphenylacetic acid (4.24 g, 20 mmol, 1 equiv) in dry CH2Cl2 (77 mL) at 0 °C under N2 was added dropwise oxalyl chloride (3.8 g, 3.75 mmol, 1.5 equiv) followed by a catalytic amount of dry DMF (5 drops). The reaction mixture was stirred at room temperature until the reaction was complete (typically 4 h). The volatiles were evaporated under reduced pressure and the resulting crude acid chloride was used directly for the next step without further purification. To the resulting residue, anhydrous dioxane (40 mL), 2aminophenol (2.2 g, 20 mmol, 1 equiv) and CH3SO3H (4 mL) were added successively. The resultant mixture was stirred at 100 °C for 3 h (TLC). After completion of the reaction, dioxane was removed and the residue was diluted with EtOAc (10 mL), followed by saturated aq. NaHCO3 until neutralization. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were washed with H2O (3 × 5 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to furnish the compound 6n (4.28 g, 15.0 mmol, 74%) as a colorless liquid. Rf = 0.6 (Hexane:Et2O = 9:1). IR (neat): ν = 3030, 1567, 1455, 753, 692 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.72− 7.74 (m, 1H), 7.46−7.48 (m, 1H), 7.23−7.34 (m, 12H), 5.77 (s, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.8, 151.1, 141.4, 139.3 (2C), 128.9 (4C), 128.9 (4C), 127.6 (2C), 125.0, 124.4, 120.3, 110.8, 51.7 ppm. HRMS (ESI): m/z calcd for C20H15NONa [M + Na]+, 308.1046; found, 308.1073. 2-(1-(4-Isobutylphenyl)ethyl)benzo[d]oxazole (6o). To a solution of 2-(4-isobutylcyclohexa-1,5-dien-1-yl)propanoic acid (4.27 g, 20 mmol, 1 equiv) in dry CH2Cl2 (77 mL) at 0 °C under N2 was added dropwise oxalyl chloride (3.8 g, 3.75 mmol, 1.5 equiv) followed by a catalytic amount of dry DMF (5 drops). The reaction mixture was stirred at room temperature until the reaction was complete (typically 4 h). The volatiles were evaporated under reduced pressure and the resulting crude acid chloride was used directly for the next step without further purification. To the resulting residue, anhydrous dioxane (40 mL), 2aminophenol (2.2 g, 20 mmol, 1 equiv) and CH3SO3H (4 mL) were added successively. The resultant mixture was stirred at 100 °C for 3 h (TLC). After completion of the reaction, dioxane was removed and the residue was diluted with EtOAc (10 mL), followed by saturated aq. NaHCO3 until neutralization. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were washed with H2O (3 × 5

EXPERIMENTAL SECTION

General Methods. IR spectra were recorded on a PerkinElmer Spectrum GX FT-IR spectrophotometer. NMR spectra were recorded on Jeol Resonance ECZ 600R spectrometer (600 MHz for 1H NMR, 151 MHz for 13C NMR, 565 MHz for 19F) and Bruker AvanceII 500 spectrometer (500 MHz for 1H NMR, 121 MHz for 13C NMR). Chemical shifts were reported in ppm on the δ scale relative to Me4Si (δ = 0.00 for 1H NMR), CDCl3 (δ = 77.160 for 13C NMR), and DMSO-d6 (δ = 39.52 for 13C NMR). Additional peaks at δ = 1.56− 1.61 ppm in 1H NMR spectra of compounds recorded in CDCl3 and δ = 3.39 ppm in 1H NMR spectra of compounds recorded in DMSOd6 correspond to water present, if any. Multiplicities are indicated as br (broad), s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). Coupling constants (J) are reported in Hertz (Hz). HRMS (ESI) spectra were recorded on a Micromass Q-Tof microTM instrument. GCMS spectral data were acquired on a Shimadzu GC2010 Plus coupled with GCMS-TQ8040 instrument. Elemental analyses were done using a Vario MICRO cube CHNS analyzer. Single crystal structures were determined using a Bruker D8 QUEST (CCD) diffractometer. All reactions that required heating were conducted in an oil bath under continuous stirring by a magnetic stirrer equipped with a hot plate and temperature controller. All low temperature reactions were performed in a Siskin Profichill RFC-90 immersion cooler instrument. For thin-layer chromatography (TLC) analysis throughout this work, Macherey-Nagel precoated TLC plates (silica gel 60 F254 0.25 mm) were used. Solvents, e.g. DMF, DMSO, toluene, THF, Dioxan, and DCM, were dried by standard drying techniques.15 All other solvents and commercially available compounds were used without further purification. The recrystallization of compounds 8md and 8ua were performed by dissolving the compound in DCM and layered with hexane at +4 °C. Preparation of Substrates. Substrates 6a−6g, 6j−6m, and 6q−6v were prepared by reported methods and were characterized by matching their 1H and 13C NMR spectral data with that of the reported compounds.16,17 Substrates 6h, 6i, 6n, 6o, and 6p were prepared as follows: 2-(4-(Phenylsulfonyl)benzyl)benzo[d]oxazole (6h) [via the Synthesis of 2-(4-(Phenylthio)benzyl)benzo[d]oxazole (6g′)]. A 25 mL round-bottom flask was charged with 6g (1.15 g, 4.0 mmol, 1.0 equiv), Cu(OAc)2 (291 mg, 0.8 mmol, 0.2 equiv), K2CO3 (1.11 g, 8.0 mmol, 2 equiv) and the vessel was evacuated and backfilled with nitrogen (3×). To it, anhydrous DMF (10 mL) and thiophenol (661 mg, 6 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 120 °C for 16 h (monitored by TLC). Subsequently, water was added to it and extracted with EtOAc (3 × 50 mL), organic layers were combined, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to furnish the compound 2-(4(phenylthio)benzyl)benzo[d]oxazole (6g′) (698 mg, 2.2 mmol, 55%) as a thick liquid. Rf = 0.5 (Hexane:Et2O = 9:1). IR (neat): ν = 2980, 1750, 1362, 1240, 1047, 803 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.68−7.69 (m, 1H), 7.45−7.48 (m, 1H), 7.33−7.35 (m, 2H), 7.27− 7.31 (m, 8H), 7.23−7.25 (m, 1H), 4.2 (s, 2H).ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 164.9, 151.2, 141.4, 135.5, 135.2, 133.7, 131.4 (2C), 131.4 (2C), 130.0 (2C), 129.4 (2C), 127.3, 124.9, 124.4, 120.0, 110.6, 34.9.ppm. HRMS (ESI): m/z calcd for C20H16NOS [M + H]+, 318.0947; found, 318.0941. Compound 6h was prepared via the oxidation of 6g′.11b To the resulting compound 6g′ (600 mg, 1.9 mmol) in dichloromethane, mCPBA (984 mg, 5.7 mmol, 3 equiv) was added at 0 °C. The resultant mixture was stirred at room temperature for 3 h (checked by TLC). The solvent was evaporated by rotary-evaporator and the residue was purified by column chromatography over silica gel. Colorless solid 6h (421 mg, 1.2 mmol, 63%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 126 °C. IR (KBr): ν = 3417, 2927, 1563, 1447, 1302, 1149, 581 cm−1. 1H NMR (600 MHz, CDCl3) δ 7.92−7.94 (m, 4H), 7.67−7.68 (m, 1H), 7.45−7.50 (m, 6H), 7.30−7.31 (m, 2H), 4.32 (s, 2H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 163.9, 151.1, 141.6, 141.1, 140.8, 140.5, 133.4, 130.1 (2C), 129.4 (2C), 128.4 (2C), 127.8 (2C), 125.2, 124.6, D



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mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to furnish the compound 6o (3.97 g, 14.2 mmol, 71%) as a thick liquid. Rf = 0.6 (Hexane:Et2O = 9:1). IR (neat): ν = 2954, 2908, 1566, 1455, 1241, 741 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70− 7.72 (m, 1H), 7.42−7.44 (m, 1H), 7.24−7.30 (m, 4H), 7.09−7.11 (m, 2H), 4.37−4.41 (m, 1H), 2.43 (d, J = 7.0 Hz, 2H), 1.81−1.87 (m, 4H), 0.88 (d, J = 6.5 Hz, 6H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 169.1, 151.0, 141.3, 140.8, 138.5, 129.6 (2C), 127.2 (2C), 124.7, 124.2, 119.9, 110.6, 45.1, 39.8, 30.3, 22.5 (2C), 19.9 ppm. HRMS (ESI): m/z calcd for C19H21KNO [M + K]+, 318.1255; found, 318.1260. 2-(1-(6-Methoxynaphthalen-2-yl)ethyl)benzo[d]oxazole (6p). To a solution of 2-(6-methoxynaphthalen-2-yl) propanoic acid (4.61 g, 20 mmol, 1 equiv) in dry CH2Cl2 (77 mL) at 0 °C under N2 was added dropwise oxalyl chloride (3.8 g, 3.75 mmol, 1.5 equiv) followed by a catalytic amount of dry DMF (5 drops). The reaction mixture was stirred at room temperature until the reaction was complete (typically 4 h). The volatiles were evaporated under reduced pressure and the resulting crude acid chloride was used directly for the next stepwithout further purification. To the resulting residue, anhydrous dioxane (40 mL), 2aminophenol (2.2 g, 20 mmol, 1 equiv) and CH3SO3H (4 mL) were added successively. The resultant mixture was stirred at 100 °C for 3 h (TLC). After completion of the reaction, dioxane was removed and the residue was diluted with EtOAc (10 mL), followed by saturated aq. NaHCO3 until neutralization. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were washed with H2O (3 × 5 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to furnish the compound 6p (3.64 g, 12.0 mmol, 60%). Rf = 0.3 (Hexane:Et2O = 9:1). MP = 131 °C. IR (KBr): ν = 2978, 2930, 1606, 1455, 754 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.69−7.74 (m, 4H), 7.42−7.46 (m, 2H), 7.26−7.30 (m, 2H), 7.10−7.15 (m, 2H), 4.53− 4.57 (m, 1H), 3.90 (s, 3H), 1.90 (d, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 169.1, 157.9, 151.1, 141.4, 136.5, 133.9, 129.5, 129.1, 127.6, 126.2, 126.1, 124.8, 124.3, 120.0, 119.2, 110.7, 105.8, 55.5, 40.2, 19.9 ppm. HRMS (ESI): m/z calcd for C20H17KNO2 [M + K]+, 342.0891; found, 342.0892. Amination of 2-Benzylbenzoxazoles and 2-Benzylbenzothiazole Derivatives with Various Anilines. General Procedure A. A 15 mL reaction tube was charged with 2-benzylbenzoxazole or 2abenzylbenzothiazole derivative (0.5 mmol, 1.0 equiv), FeCl3 (8 mg, 0.05 mmol, 0.1 equiv) and the vessel was evacuated and backfilled with nitrogen (3×), then add anhydrous toluene (2.5 mL) to it, subsequently, DTBP (88 mg, 1.2 mmol, 0.6 equiv) and aniline derivative (0.75 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 100 °C until completion (monitored by TLC). After cooling the reaction mixture solvent was removed by rota evaporator and residue was purified by flash column chromatography on silica gel to provide the corresponding aminated product. Characterization of Amine-Functionalized Benzoxazoles/Benzothiazoles. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)aniline (8ba). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with aniline 7a for 3 h. Colorless solid (143 mg, 0.45 mmol, 91%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 99 °C. IR (KBr): ν = 3404, 3336, 1598, 1507, 1240, 753 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.46−7.48 (m, 1H), 7.41−7.43 (m, 1H), 7.30−7.32 (m, 2H), 7.20−7.25 (m, 2H), 7.13−7.18 (m, 3H), 6.73 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 6.04 (s, 1H), 4.87 (s, 1H), 2.59 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.1, 151.1, 146.4, 140.9, 136.5 (2C), 131.2, 129.5 (2C), 128.6, 127.0, 126.9, 125.2, 124.6, 120.3, 118.7, 113.5 (2C), 111.0, 54.0, 19.6 ppm. HRMS (ESI): m/z calcd for C21H19N2O [M + H]+, 315.1492, found, 315.1522 N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-4-chloroaniline (8bc). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as

Note

the starting material with 4-chloroaniline 7c for 3 h. Colorless solid (148 mg, 0.42 mmol, 85%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 130 °C. IR (KBr): ν = 3295, 1597, 1506, 1312, 1241, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.72 (m, 1H), 7.46−7.48 (m, 1H), 7.36− 7.39 (m, 1H), 7.30−7.33 (m, 2H), 7.21−7.25 (m, 2H), 7.15−7.18 (m, 1H), 7.07−7.09 (m, 2H), 6.56−6.58 (m, 2H), 5.98 (d, J = 6.0 Hz, 1H), 4.92 (d, J = 6.0 Hz, 1H), 2.58 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.7, 151.1, 144.9, 140.8, 136.5, 136.1, 131.3, 129.3 (2C), 128.7, 127.0 (2C), 125.3, 124.7, 123.3, 120.3, 114.6 (2C), 111.0, 54.0, 19.5 ppm. HRMS (ESI): m/z calcd for C21H17ClNaN2O [M + Na]+, 371.0922, found, 371.0942. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-4-bromoaniline (8bd). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 4-bromoaniline 7d for 3 h. Brown solid (173 mg, 0.44 mmol, 88%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 122 °C. IR (KBr): ν = 3416, 1606, 1496, 1243, 803, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.46−7.48 (m, 1H), 7.36−7.38 (m, 1H), 7.31−7.33 (m, 2H), 7.20−7.25 (m, 4H), 7.15−7.18 (m, 1H) 6.51−6.53 (m, 2H), 5.98 (d, J = 6.0 Hz, 1H), 4.93 (d, J = 6.0 Hz, 1H), 2.58 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.7, 151.0, 145.4, 140.8, 136.5, 136.1, 132.2 (2C), 131.3, 128.7, 127.0, 126.9, 125.3, 124.7, 120.3, 115.1 (2C), 111.0, 110.4, 53.9, 19.5 ppm. HRMS (ESI): m/z calcd for C21H17BrNaN2O [M + Na]+, 415.0416, found, 415.0417. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-4-iodoaniline (8be). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 4-Iodoaniline 7e for 3 h. Colorless solid (152 mg, 0.35 mmol, 69%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 139 °C. IR (KBr): ν = 3407, 1586, 1485, 1240, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.46−7.48 (m, 1H), 7.31−7.41 (m, 5H), 7.21−7.26 (m, 2H), 7.15−7.18 (m, 1H), 6.42−6.45 (m, 2H), 5.98 (d, J = 5.5 Hz, 1H), 4.95 (d, J = 6.0 Hz, 1H), 2.58 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.6, 151.1, 146.0, 140.8, 138.1 (2C), 136.5, 136.0, 131.3, 128.8, 127.0, 126.9, 125.4, 124.7, 120.3, 115.7 (2C), 111.0, 79.7, 53.7, 19.5 ppm. HRMS (ESI): m/z calcd for C21H17INaN2O [M + Na]+, 463.0278, found, 463.0266. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-3-chloroaniline (8bf). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 3-chloroaniline 7f for 3 h. Brown solid (131 mg, 0.38 mmol, 75%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 128 °C. IR (KBr): ν = 3284, 1596, 1444, 1241, 833, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.46−7.48 (m, 1H), 7.29−7.37 (m, 3H), 7.15−7.26 (m, 3H), 7.03 (t, J = 8.0 Hz, 1H), 6.64−6.70 (m, 2H), 6.49−6.52 (m, 1H), 6.00 (d, J = 6.0 Hz, 1H), 4.99 (d, J = 6.5 Hz, 1H), 2.59 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.6, 151.1, 147.5, 140.8, 136.5, 136.1, 135.2, 131.3, 130.5, 128.8, 127.0 (2C), 125.3, 124.7, 120.3, 118.6, 113.4, 111.5, 111.0, 53.8, 19.5 ppm. HRMS (ESI): m/z calcd for C21H18ClN2O [M + H]+, 349.1102, found, 349.1120. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-2-fluoroaniline (8bg). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 2-fluoroaniline 7g for 3 h. Brown solid (130 mg, 0.39 mmol, 78%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 116 °C. IR (KBr): ν = 3416, 1617, 1515, 1241, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.72−7.74 (m, 1H), 7.43−7.48 (m, 2H), 7.29−7.33 (m, 2H), 7.17−7.25 (m, 3H), 6.98−7.02 (m, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.58−6.67 (m, 2H), 6.05−6.06 (m, 1H), 5.10−5.12 (m, 1H), 2.59 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.6, 151.8 (d, JC−F = 240.5 Hz), 151.1, 140.9, 136.5, 136.1, 134.9 (d, JC−F = 12.1 Hz), 131.3, 128.7, 127.0 (2C), 125.3, 124.8, 124.7, 120.4, 118.2 (d, JC−F = 7.3 Hz), 114.9 (d, JC−F = 18.7 Hz), 112.8, 111.0, 53.8, 19.5 ppm. 19F NMR (565 MHz, CDCl3) δ −136.92 ppm. HRMS (ESI): m/z calcd for C21H17NaFN2O [M + Na]+, 355.1217, found, 355.1245. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-3-chloro-4-fluoroaniline (8bh). The compound was prepared according to the general E



pubs.acs.org/joc

Note

(ESI): m/z calcd for C23H22KN2O[M + K]+, 381.1364, found, 381.1413. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-3-isopropylaniline (8bm). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 3-isopropylaniline 7m for 3 h. Brown solid (118 mg, 0.33 mmol, 66%). Rf = 0.5 (Hexane:Et2O = 9:1). = 118 °C. IR (KBr): ν = 3406, 2959, 1606, 1455, 1231, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.28−7.32 (m, 2H), 7.15−7.24 (m, 3H), 7.06 (t, J = 8.0 Hz, 1H), 6.56−6.62 (m, 2H), 6.46 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 4.86 (d, J = 5.5 Hz, 1H), 2.76−2.80 (m, 1H), 2.60 (s, 3H), 1.16 (m, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.3, 151.6, 150.2, 146.5, 140.9, 136.8, 136.5, 131.1, 129.4, 128.5, 127.1, 126.9, 125.2, 124.6, 120.3, 117.0, 112.2, 110.9, 110.5, 54.6, 34.2, 24.0 (2C), 19.6 ppm. HRMS (ESI): m/z calcd for C24H24KN2O [M + K]+, 395.1520, found, 395.1542. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-4-(tert-butyl)aniline (8bn). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 4-tert-butylaniline 7n for 3 h. Brown solid (113 mg, 0.30 mmol, 61%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 140 °C. IR (KBr): ν = 3386, 2959, 1515, 1230, 824, 734 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.44−7.48 (m, 2H), 7.28−7.32 (m, 2H), 7.15−7.24 (m, 5H), 6.60−6.62 (m, 2H), 6.02 (d, J = 5.5 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H), 2.59 (s, 3H), 1.24 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.3, 151.1, 144.1, 141.3, 141.0, 136.8, 136.5, 131.2, 128.5, 127.1, 126.9, 126.3 (2C), 125.1, 124.6, 120.3, 113.2 (2C), 111.0, 54.2, 34.0, 31.6 (3C), 19.6 ppm. HRMS (ESI): m/z calcd for C25H27N2O [M + H]+, 371.2118, found, 371.2152. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-2,4,6-trimethylaniline (8bo). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with aniline 7o for 4 h. thick liquid (102 mg, 0.29 mmol, 57%). Rf = 0.5 (Hexane:Et2O = 19:1). IR (neat): ν = 3386, 2908, 1485, 1241, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.72 (m, 1H), 7.62−7.64 (m, 1H), 7.44−7.46 (m, 1H), 7.28−7.32 (m, 2H), 7.19−7.25 (m, 2H), 7.14−7.15 (m, 1H), 6.76 (s, 2H), 5.73 (s, 1H), 4.12 (s, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 2.11 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.9, 150.8, 142.8 (2C), 141.1, 141.0, 137.9, 135.9, 130.9, 128.2, 127.0, 126.9, 125.6, 124.5 (2C), 123.8 (2C), 120.3, 110.8, 60.1, 27.9, 24.3, 24.2, 19.5 ppm. HRMS (ESI): m/z calcd for C24H24KN2O [M + K]+, 395.1520; found, 395.1559. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-2,6-diisopropylaniline (8bp). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 2,6-diisopropylaniline 7p for 3 h. Yellow solid (122 mg, 0.31 mmol, 61%). Rf = 0.5 (Hexane:Et2O = 19:1). MP = 109 °C. IR (KBr): ν = 3345, 2959, 1455, 1241, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.65−7.67 (m, 1H), 7.43−7.44 (m, 1H), 7.26−7.32 (m, 3H), 7.19−7.23 (m, 1H), 7.12−7.13 (m, 1H), 7.04−7.05 (m, 3H), 5.57 (d, J = 6.5 Hz, 1H), 4.20 (d, J = 6.5 Hz, 1H), 3.01−3.07 (m, 2H), 2.15 (s, 3H), 1.04−1.06 (m, 12H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.9, 150.8, 142.8 (2C), 141.1, 141.0, 137.9, 135.9, 130.9, 128.2, 127.0, 126.9, 125.1, 124.5 (2C), 123.8 (2C), 120.3, 110.8, 60.1, 27.9 (2C), 24.3 (2C), 24.2 (2C), 19.5 ppm. HRMS (ESI): m/z calcd for C27H30NaN2O [M + Na]+, 421.2250; found, 421.2257. N-(Benzo[d]oxazol-2-yl(phenyl)methyl)-2,4,6-trimethylaniline (8ao). The compound was prepared according to the general procedure A using 2-benzylbenzo[d]oxazole 6a (105 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Brown solid (140 mg,, 0.41 mmol, 82%). Rf = 0.4 (Hexane:Et2O = 9:1). MP = 76 °C. IR (KBr): ν = 3388, 2920, 1430, 1271, 765 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.74 (m, 1H), 7.44−7.47 (m, 3H), 7.24− 7.35 (m, 5H), 6.75−6.76 (m, 2H), 5.58 (s, 1H), 4.22 (s, 1H) 2.18 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.9, 150.9, 141.2, 141.1, 139.5, 131.9, 129.9 (2C), 129.7 (2C), 128.9 (2C), 128.3, 127.2

procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 3-chloro 4-fluoroaniline 7h for 3 h. Brown solid (147 mg, 0.40 mmol, 80%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 126 °C. IR (KBr): ν = 3404, 2919, 1504, 1220, 742 cm−1. 1 H NMR (500 MHz, CDCl3) δ 7.71−7.74 (m, 1H) 7.47−7.49 (m, 1H), 7.32−7.36 (m, 3H), 7.16−7.26 (m, 3H), 6.91 (t, J = 8.5 Hz, 1H), 6.65−6.67 (m, 1H), 6.45−6.48 (m, 1H), 5.94 (d, J = 6.5 Hz, 1H), 4.87 (d, J = 6.0 Hz, 1H), 2.59 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.5, 151.7 (d, JC−F = 239.3 Hz), 151.1, 143.3, 140.8, 136.5, 135.9, 131.4, 128.9, 127.0 (d, JC−F = 11.2 Hz, 2C), 125.4, 124.8, 121.4 (d, JC−F = 18.9 Hz), 120.3, 117.1 (d, JC−F = 22.3 Hz), 114.9, 112.6 (d, JC−F = 6.3 Hz), 111.0, 54.3, 19.5 ppm. 19F NMR (565 MHz, CDCl3) δ −131.44 ppm. Anal. Calcd for C21H16ClFN2O, C, 68.76; H, 4.40; N, 7.64; found, C, 68.46; H, 4.28; N, 7.57. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)pyridin-3-amine (8bi). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 3-aminopyridine 7i for 12 h. Brown solid (98 mg, 0.31 mmol, 62%). Rf = 0.4 (Hexane:Et2O = 9:1). MP = 128 °C. IR (KBr): ν = 3305, 1617, 1444, 1119, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.46−7.47 (m, 1H), 7.38−7.40 (m, 1H), 7.30−7.32 (m, 2H), 7.15−7.26 (m, 4H), 6.95 (d, J = 7.5 Hz, 1H), 6.88−6.89 (m, 1H), 6.74−6.76 (m, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.19 (d, J = 6.0 Hz, 1H), 2.60 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.5, 151.1, 146.5, 140.7, 136.5, 135.9, 131.3, 130.0, 128.8, 127.0, 127.0, 125.4, 124.7, 120.3, 116.0, 115.0, 111.0, 110.2, 53.8, 19.5 ppm. Anal. Calcd for C20H17N3O, C, 76.17; H, 5.43; N, 13.32; found, C, 76.05; H, 5.37; N, 13.28. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-4-methylaniline (8bj). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 4-methylaniline 7j for 3 h. Yellow solid (128 mg, 0.39 mmol, 78%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 121 °C. IR (KBr): ν = 3407, 2919, 1517, 1454, 1231, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.47−7.48 (m, 1H), 7.39− 7.41 (m, 1H), 7.29−7.33 (m, 2H), 7.15−7.25 (m, 3H), 6.94−6.96 (m, 2H), 6.57−6.60 (m, 2H), 6.02 (s, 1H), 2.59 (s, 3H), 2.20 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.3, 151.1, 144.2, 141.0, 136.7, 136.6, 131.2, 130.0 (2C), 128.5, 127.9, 127.0, 126.9, 125.2, 124.6, 120.3, 113.6 (2C), 111.0, 54.2, 20.5, 19.6 ppm. Anal. Calcd for C22H20N2O, C, 80.46; H, 6.14; N, 8.53; found, C, 80.37; H, 6.10; N, 8.48. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-2-methylaniline (8bk). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 2-methylaniline 7k for 3 h. Yellow solid (135 mg, 0.41 mmol, 82%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 126 °C. IR (KBr): ν = 3407, 1506, 1455, 1242, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.72−7.73 (m, 1H), 7.44−7.48 (m, 2H), 7.28−7.33 (m, 2H), 7.16−7.25 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.68 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.07 (d, J = 5.5 Hz, 1H), 4.79 (d, J = 5.5 Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.2, 151.1, 144.5, 141.0, 136.7, 136.5, 131.2, 130.4, 128.5, 127.3, 126.9 (2C), 125.2, 124.6, 122.8, 120.3, 118.2, 111.0, 110.6, 54.0, 19.5, 17.8 ppm. HRMS (ESI): m/z calcd for C22H20NaN2O [M + Na]+, 351.1468, found, 351.1459. N-(Benzo[d]oxazol-2-yl(o-tolyl)methyl)-3-ethylaniline (8bl). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6b (112 mg, 0.5 mmol) as the starting material with 3-ethylaniline 7l for 3 h. Brown solid (106 mg, 0.31 mmol, 62%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 88 °C. IR (KBr): ν = 3406, 2959, 1606, 1455, 1242, 732 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.72 (m, 1H), 7.41−7.47 (m, 2H), 7.27−7.32 (m, 2H), 7.16−7.24 (m, 3H), 7.05 (t, J = 8.0 Hz, 1H), 6.53−6.59 (m, 2H), 6.45−6.47 (m, 1H), 6.05 (d, J = 6.0 Hz, 1H), 4.83 (d, J = 6.0 Hz, 1H), 2.59 (s, 3H), 2.50−2.55 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.2, 151.0, 146.5, 145.6, 140.9, 136.7, 136.5, 131.1, 129.4, 128.5, 127.0, 126.9, 125.1, 124.6, 120.3, 118.4, 113.4, 110.9, 110.5, 54.0, 29.0, 19.5, 15.4 ppm. HRMS F



pubs.acs.org/joc

(2C), 125.2, 124.5, 120.4, 110.8, 60.4, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C23H22NaN2O [M + Na]+, 365.1624, found, 365.1620. N-(Benzo[d]oxazol-2-yl(m-tolyl)methyl)-2,4,6-trimethylaniline (8co). The compound was prepared according to the general procedure A using 2-(3-methylbenzyl)benzo[d]oxazole 6c (112 mg, 0.5 mmol) as the starting material with aniline 7o for 3 h. Thick liquid (130 mg, 0.36 mmol, 73%). Rf = 0.6 (Hexane:Et2O = 9:1). IR (KBr): ν = 3376, 2919, 2328, 1647, 731 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.72 (m, 1H), 7.45−7.47 (m, 1H), 7.22−7.31 (m, 5H), 7.09− 7.11 (m, 1H), 6.75 (s, 2H), 5.54 (s, 1H), 4.21 (s, 1H), 2.32 (s, 3H), 2.18 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 167.1, 150.9, 141.3, 141.1, 139.4, 138.6, 131.9, 129.8 (2C), 129.7 (2C), 129.0, 128.8, 127.7, 125.1, 124.5, 124.2, 120.3, 110.8, 60.4, 21.6, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C24H24NaN2O [M + Na]+, 379.1781; found, 379.1780. N-(Benzo[d]oxazol-2-yl(4-methoxyphenyl)methyl)-2,4,6-trimethylaniline (8do). The compound was prepared according to the general procedure A using 2-(4-methoxybenzyl)benzo[d]oxazole 6d (120 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Yellow solid (143 mg, 0.38 mmol, 77%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 148 °C. IR (KBr): ν = 3427, 2919, 1627, 1250, 743 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.73 (m, 1H), 7.45−7.47 (m, 1H), 7.28−7.36 (m, 4H), 6.84−6.86 (m, 2H), 6.75 (s, 2H), 5.53 (s, 1H), 4.17 (s, 1H), 3.77 (s, 3H), 2.17−2.18 (m, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 167.1, 159.5, 150.9, 141.2, 141.1, 131.9, 131.7, 129.9 (2C), 129.7 (2C), 128.4 (2C), 125.1, 124.5, 120.3, 114.2 (2C), 110.8, 59.8, 55.4, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C24H24NaN2O2 [M + Na]+, 395.1730, found, 395.1724. N-(Benzo[d]oxazol-2-yl(4-fluorophenyl)methyl)-2,4,6-trimethylaniline (8eo). The compound was prepared according to the general procedure A using 2-(4-fluorobenzyl)benzo[d]oxazole 6e (112 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Yellow solid (135 mg, 0.37 mmol, 75%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 79 °C. IR (KBr): ν = 3406, 2921, 1596, 1220, 752 cm−1. 1 H NMR (500 MHz, CDCl3) δ 7.70−7.74 (m, 1H), 7.40−7.47 (m, 3H), 7.28−7.33 (m, 2H), 6.98−7.03 (m, 2H), 6.75 (s, 2H), 5.55 (s, 1H), 4.20 (s, 1H), 2.16−2.18 (m, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.7, 162.6 (d, JC−F = 247.5 Hz), 150.9, 141.0, 140.9, 135.3, 132.1, 129.9 (2C), 129.8 (2C), 128.9 (d, JC−F = 8.1 Hz, 2C), 125.3, 124.6, 120.4, 115.8 (d, JC−F = 21.5 Hz, 2C), 110.8, 59.7, 20.7, 18.6 (2C) ppm. 19F NMR (565 MHz, CDCl3) δ −118.40 to − 118.44 ppm. HRMS (ESI): m/z calcd for C23H21FNaN2O [M + Na]+, 383.1530, found, 383.1523. N-(Benzo[d]oxazol-2-yl(4-chlorophenyl)methyl)-2,4,6-trimethylaniline (8fo). The compound was prepared according to the general procedure A using 2-(4-chlorobenzyl)benzo[d]oxazole 6f (122 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Colorless solid (143 mg, 0.38 mmol, 76%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 86 °C. IR (KBr): ν = 3426, 2919, 1485, 1221, 865, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.73 (m, 1H), 7.44−7.48 (m, 1H), 7.38−7.41 (m, 2H), 7.28−7.33 (m, 4H), 6.75 (s, 2H), 5.54 (s, 1H), 4.21 (s, 1H), 2.15−2.18 (m, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.4, 150.9, 140.9, 140.9, 137.9, 134.1, 132.2, 129.9 (2C), 129.8 (2C), 129.0 (2C), 128.6 (2C), 125.3, 124.6, 120.4, 110.8, 59.7, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C23H21ClNaN2O [M + Na]+, 399.1235, found, 399.1225. N-(Benzo[d]oxazol-2-yl(4-bromophenyl)methyl)-2,4,6-trimethylaniline (8go). The compound was prepared according to the general procedure A using 2-(4-bromobenzyl)benzo[d]oxazole 6g (112 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Colorless solid (129 mg, 0.31 mmol, 61%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 100 °C. IR (KBr): ν = 3355, 2919, 1485, 1233, 864, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.73 (m, 1H), 7.44−7.48 (m, 3H), 7.29−7.35 (m, 4H), 6.75 (s, 2H), 5.52 (s, 1H), 4.21 (s, 1H), 2.18 (s, 3H), 2.15 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.4, 150.9, 140.9, 140.9, 138.4, 132.2, 132.0 (2C), 130.0 (2C), 129.8 (2C), 128.9 (2C), 125.3, 124.7, 122.3, 120.4, 110.9, 59.8, 20.7,

Note

18.7 (2C) ppm. Anal. Calcd for C23H21BrN2O, C, 65.57; H, 5.02; N, 6.65; found, C, 65.23; H, 4.97; N, 6.59. N-(Benzo[d]oxazol-2-yl(4-(phenylsulfonyl)phenyl)methyl)-2,4,6trimethylaniline (8ho). The compound was prepared according to the general procedure A using 2-(4-(phenylsulfonyl)benzyl)benzo[d]oxazole 6h (175 mg, 0.5 mmol) as the starting material with 2,4,6trimethylaniline 7o for 12 h. brown thick liquid (176 mg, 0.37 mmol, 73%). Rf = 0.6 (Hexane:EtOAc = 8:2). IR (KBr): ν = 2989, 1750, 1373, 1242, 1048 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.91−7.94 (m, 4H), 7.69−7.71 (m, 1H), 7.63−7.65 (m, 2H), 7.54−7.57 (m, 1H), 7.45−7.51 (m, 3H) 7.32−7.34 (m, 2H), 6.75 (s, 2H), 5.58 (s, 1H), 4.22 (s, 1H) 2.18 (s, 3H), 2.11 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.8, 150.8, 144.9, 141.5, 141.4, 140.8, 140.7, 133.4, 132.5, 129.9 (4C), 129.4 (2C), 128.2 (2C), 128.1 (2C), 127.9 (2C), 125.6, 124.8, 120.5, 110.9, 59.9, 20.7, 18.6 (2C) ppm. HRMS (ESI): m/z calcd for C29H27N2O3S [M + H]+, 483.1737; found, 483.1743. (4-(Benzo[d]oxazol-2-yl(mesitylamino)methyl)phenyl)(phenyl)methanone (8io). The compound was prepared according to the general procedure A using (4-(benzo[d]oxazol-2-ylmethyl)phenyl)(phenyl)methanone 6i (157 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 12 h. yellow solid (156 mg, 0.35 mmol, 70%). Rf = 0.4 (Hexane:Et2O = 8:2). MP = 152 °C, IR (KBr): ν = 2918, 2308, 1738, 1566, 1454, 1242 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.76−7.80 (m, 4H), 7.73−7.75 (m, 1H),7.56−7.61 (m, 3H), 7.45−7.51 (m, 3H), 7.33−7.35 (m, 2H), 6.77 (s, 2H), 5.64 (s, 1H), 4.30 (s, 1H) 2.18−2.19 (m, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 196.3, 166.3, 150.9, 143.8, 141.0, 140.9, 137.6, 137.4, 132.7, 132.3, 130.7 (2C), 130.2 (2C), 129.9 (2C), 129.9 (2C), 128.4 (2C), 127.2 (2C), 125.4, 124.7, 120.5, 110.9, 60.2, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C30H27N2O2 [M + H]+, 447.2067; found, 447.2063. N-(Benzo[d]oxazol-2-yl(thiophen-3-yl)methyl)-2,4,6-trimethylaniline (8jo). The compound was prepared according to the general procedure A using 2-(thiophen-3-ylmethyl)benzo[d]oxazole 6j (130 mg, 0.5 mmol) as the starting material with aniline 7o for 4 h. Thick liquid (96 mg, 0.28 mmol, 55%). Rf = 0.5 (Hexane:Et2O = 9:1). IR (KBr): ν = 3377, 2918, 1444, 1230, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.70−7.71 (m, 1H), 7.46−7.48 (m, 1H), 7.25−7.31 (m, 4H), 7.09−7.10 (m, 1H), 6.75 (s, 2H), 5.65 (s, 1H), 4.13 (s, 1H), 2.17−2.19 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.5, 150.7, 141.0, 140.8, 140.0, 132.1, 130.0 (2C), 129.7 (2C), 126.6, 126.5, 125.2, 124.5, 122.8, 120.3, 110.8, 56.3, 20.6, 18.4 (2C) ppm. HRMS (ESI): m/z calcd for C21H20KN2OS [M + K]+, 387.0928; found, 387.0923 N-(Benzo[d]oxazol-2-yl(phenyl)methyl)aniline (8aa). The compound was prepared according to the general procedure A using 2benzylbenzo[d]oxazole 6a (105 mg, 0.5 mmol) as the starting material with aniline 7a by using 5 mol % FeCl3 for 3 h. Colorless solid (96 mg, 0.32 mmol, 64%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 176 °C. IR (KBr): ν = 3409, 3325, 2919, 1600, 1501, 1456, 1240, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.71−7.73 (m, 1H), 7.57−7.59 (m, 2H), 7.47−7.49 (m, 1H), 7.36−7.39 (m, 2H), 7.30−7.34 (m, 3H), 7.14−7.17 (m, 2H), 6.69−6.76 (m, 3H), 5.85 (d, J = 5.0 Hz, 1H), 5.07 (d, J = 5.5 Hz, 1H), ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 165.9, 151.1, 146.2, 140.9, 138.4, 129.4 (2C), 129.2 (2C), 128.7, 127.4(2C), 125.3, 124.7, 120.3, 118.7, 113.8 (2C), 111.0, 57.2 ppm. HRMS (ESI): m/z calcd for C20H17N2O [M + H]+, 301.1335, found, 301.1346. Methyl 4-((Benzo[d]oxazolyl(phenyl)methyl)amino)benzoate (8aq). The compound was prepared according to the general procedure A using 2-benzylbenzo[d]oxazole 6a (105 mg, 0.5 mmol) as the starting material with methyl 4-aminobenzoate 7q for 12 h. Colorless solid (82 mg, 0.23 mmol, 46%). Rf = 0.5 (Hexane:Et2O = 7:3). MP = 176 °C. IR (KBr): ν = 3421, 1708, 1617, 1281, 1099, 753 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.83−7.85 (m, 2H), 7.71−7.72 (m, 1H), 7.55−7.57 (m, 2H), 7.47−7.48 (m, 1H), 7.31−7.40 (m, 5H), 6.65−6.68 (m, 2H), 5.89 (d, J = 6.0 Hz, 1H), 5.61−5.63 (m, 1H), 3.82 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 167.2, 165.1, 151.1, 149.9, 140.7, 137.6, 131.6 (2C), 129.4 (2C), 128.9, G



pubs.acs.org/joc

Note

(2C), 125.3, 124.6, 120.3, 117.5 (2C), 111.0, 110.3, 59.9, 45.1, 30.2, 25.9, 22.5 (2C) ppm. Anal. Calcd for C25H25BrN2O, C, 66.82; H, 5.61; N, 6.23; found, C, 66.75; H, 5.58; N, 6.21; found, C, 65.23; H, 4.97; N, 6.59. N-(1-(Benzo[d]oxazol-2-yl)-1-(6-methoxynaphthalen-2-yl)ethyl)3-chloro-4-fluoroaniline (8ph). The compound was prepared according to the general procedure A using 2-(1-(6-methoxynaphthalen-2-yl)ethyl)benzo[d]oxazole 6p (140 mg, 0.5 mmol) as the starting material with 3-chloro 4-fluoroaniline 7h for10 h. gummy liquid (116 mg, 0.26 mmol, 52%). Rf = 0.3 (Hexane:Et2O = 9:1). IR (KBr): ν = 3355, 2922, 2319, 1738, 1648, 1037, 803 cm−1. 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.66−7.76 (m, 4H), 7.41−7.45 (m, 1H), 7.27−7.34 (m, 2H), 7.11−7.18 (m, 2H), 6.76 (t, J = 9.0 Hz, 1H), 6.65−6.66 (m, 1H), 6.35−6.37 (m, 1H), 5.37 (s, 1H), 3.91 (s, 3H), 2.26 (s, 3H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 168.9, 158.3, 151.8 (d, JC−F = 239.9 Hz), 151.2, 141.7, 140.6, 136.8, 134.2, 130.0, 128.9, 127.8, 125.6, 125.4, 125.2, 124.7, 120.9 (d, JC−F = 18.6 Hz), 120.3, 119.4, 117.9, 116.6 (d, JC−F = 21.7 Hz), 115.4 (d, JC−F = 6.3 Hz), 111.0, 105.7, 60.3, 55.5, 25.7 ppm. 19F NMR (565 MHz, CDCl3) δ −129.366129.35. HRMS (ESI): m/z calcd for C26H20NaClFN2O2 [M + Na]+, 469.1090; found, 469.1087. N-(Benzo[d]thiazol-2-yl(o-tolyl)methyl)-2,4,6-trimethylaniline (8qo). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6q (120 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Colorless solid (130 mg, 0.35 mmol, 70%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 104 °C. IR (KBr): ν = 3408, 2925, 1482, 1223, 753 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.96−7.98 (m, 1H), 7.88−7.90 (m, 1H), 7.43−7.46 (m, 1H), 7.35−7.38 (m, 1H), 7.27−7.29 (m, 1H), 7.17−7.19 (m, 2H), 7.11−7.13 (m, 1H), 6.77 (s, 2H), 5.72− 5.73 (m, 1H), 3.97−3.99 (m, 1H), 2.21 (s, 3H), 2.07 (s, 3H), 2.01 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 176.7, 154.2, 141.9, 141.3, 135.9, 135.4, 132.1, 130.9, 130.0 (2C), 129.7 (2C), 128.0, 127.5, 126.9, 126.0, 124.9, 123.3, 121.8, 62.1, 20.7, 19.6, 18.5 (2C) ppm. HRMS (ESI): m/z calcd for C24H25N2S [M + H]+, 373.1733; found, 373.1722. N-(Benzo[d]thiazol-2-yl(phenyl)methyl)-2,4,6-trimethylaniline (8ro). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6r (113 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Brown solid (111 mg, 0.31 mmol, 62%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 155 °C. IR (KBr): ν = 3376, 2928, 1485, 1221, 763 cm−1. 1 H NMR (500 MHz, CDCl3) δ 7.99−8.01 (m, 1H), 7.88−7.90 (m, 1H), 7.44−7.47 (m, 1H), 7.35−7.38 (m, 1H), 7.23−7.31 (m, 5H), 6.77 (s, 2H), 5.48−5.49 (m, 1H), 4.06−4.08 (m, 1H), 2.21 (s, 3H), 2.03 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 175.8, 154.0, 142.2, 141.6, 135.4, 132.0, 130.0 (2C), 129.7 (2C), 129.0 (2C), 128.1, 127.5 (2C), 126.1, 125.0, 123.3, 121.8, 65.5, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C23H22NaN2S [M + Na]+, 381.1396; found, 381.1400. N-(Benzo[d]thiazol-2-yl(thiophen-3-yl)methyl)-2,4,6-trimethylaniline (8so). The compound was prepared according to the general procedure A using 2-(thiophen-3-ylmethyl)benzo[d]thiazole 6s (116 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Brown solid (100 mg, 0.27 mmol, 55%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 127 °C. IR (KBr): ν = 3416, 2908, 1484, 1098, 763 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.00−8.02 (m, 1H), 7.88−7.90 (m, 1H), 7.45−7.48 (m, 1H), 7.36−7.39 (m, 1H), 7.23−7.28 (m, 1H), 7.14−7.15 (m, 1H), 6.97−6.98 (m, 1H), 6.78 (s, 2H), 5.60−5.61 (m, 1H), 3.99−4.01 (m, 1H), 2.21 (s, 3H), 2.07 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 175.0, 153.9, 142.2, 141.3, 135.3, 132.2, 130.1 (2C), 129.8 (2C), 126.7, 126.6, 126.1, 125.1, 123.3, 122.9, 121.8, 60.7, 20.7, 18.5 (2C) ppm. HRMS (ESI): m/z calcd for C21H20NaN2S2 [M + Na]+, 387.0960; found, 387.0982. N-((5-Chlorobenzo[d]thiazol-2-yl)(phenyl)methyl)-2,4,6-trimethylaniline (8to). The compound was prepared according to the general procedure A using 2-benzyl-5-chlorobenzo[d]thiazole 6t (130 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7o for 4 h. Colorless solid (102 mg, 0.26 mmol, 52%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 136 °C. IR (KBr): ν = 3427, 2919, 1434,

127.3 (2C), 125.5, 124.8, 120.3, 119.9, 112.7 (2C), 111.0, 56.6, 51.7 ppm. HRMS (ESI): m/z calcd for C22H18NaN2O3 [M + Na]+, 381.1210, found, 381.1216. N-(Benzo[d]oxazol-2-yldiphenylmethyl)-4-methylaniline (8ko). The compound was prepared according to the general procedure A using 2-benzhydrylbenzo[d]oxazole 6k (143 mg, 0.5 mmol) as the starting material with 4-methylaniline 7o for 4 h. Thick liquid (93 mg, 0.26 mmol, 52%). Rf = 0.5 (Hexane:Et2O = 19:1). IR (KBr): ν = 3390, 2890, 1435, 1277, 738 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H), 7.43−7.45 (m, 2H), 7.27−7.34 (m, 4H), 7.10−7.12 (m, 1H), 6.75 (s, 2H), 5.55 (s, 1H), 4.19 (s, 1H), 2.45 (s, 3H), 2.16−2.18 (m, 9H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 167.0, 149.1, 141.3, 141.2, 139.5, 134.4, 131.9, 129.9 (2C), 129.7 (2C), 128.9 (2C), 128.2, 127.2 (2C), 126.2, 120.3, 110.2, 60.4, 21.6, 20.7, 18.7 (2C) ppm. HRMS (ESI): m/z calcd for C24H25N2O [M + H]+, 357.1961; found, 357.1932. N-(Benzo[d]oxazol-2-yl(naphthalen-1-yl)methyl)aniline (8la). The compound was prepared according to the general procedure A using 2-(naphthalen-1-ylmethyl)benzo[d]oxazole 6l (130 mg, 0.5 mmol) as the starting material with aniline 3a for 3 h. Colorless solid (128 mg, 0.37 mmol, 73%). Rf = 0.5 (Hexane:Et2O = 9:1).MP = 152 °C. IR (KBr): ν = 3396, 3274, 1596, 1242, 742 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.32−8.34 (m, 1H), 7.87−7.89 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.72−7.73 (m, 1H), 7.50−7.59 (m, 3H), 7.34−7.44 (m, 2H), 7.26−7.31 (m, 2H), 7.11−7.15 (m, 2H), 6.68−6.75 (m, 3H), 6.61 (s, 1H), 5.03 (br, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 166.1, 151.0, 146.4, 140.9, 134.2, 133.8, 131.2, 129.5 (3C), 129.2, 127.1, 126.2, 125.7, 125.5, 125.3, 124.6, 123.2, 120.3, 118.7, 113.5 (2C), 111.0, 54.0 ppm. HRMS (ESI): m/z calcd for C24H19N2O [M + H]+, 351.1492; found, 351.1490. N-(1-(Benzo[d]oxazol-2-yl)-1-phenylethyl)-4-bromoaniline (8md). The compound was prepared according to the general procedure A using 2-(1-phenylethyl)benzo[d]oxazole 6m (112 mg, 0.5 mmol) as the starting material with 4-bromoaniline 7d for 10 h. Yellow solid (144 mg, 0.37 mmol, 73%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 151 °C. IR (KBr): ν = 3399, 1488, 1234, 1082, 745 cm−1. 1 H NMR (500 MHz, CDCl3) δ 7.72−7.74 (m, 1H), 7.61−7.63 (m, 2H), 7.41−7.43 (m, 1H), 7.35−7.38 (m, 2H), 7.28−7.31 (m, 3H), 7.10−7.12 (m, 2H), 6.40−6.42 (m, 2H), 5.34 (s, 1H), 2.19 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 168.8, 151.1, 143.8, 141.6, 140.6, 131.7 (2C), 129.0 (2C), 128.1, 126.7 (2C), 125.3, 124.6, 120.3, 117.5 (2C), 111.0, 110.4, 60.1, 26.2 ppm. HRMS (ESI): m/z calcd for C21H17NaBrN2O [M + Na]+, 415.0416; found, 415.0424. The identity of the compound 8md was further supported by X-ray crystallographic determination (CCDC 1990591). N-(Benzo[d]oxazol-2-yldiphenylmethyl)-4-methylaniline (8nj). The compound was prepared according to the general procedure A using 2-benzhydrylbenzo[d]oxazole 6n (143 mg, 0.5 mmol) as the starting material with 4-methylaniline 7j for 10 h. Colorless solid (129 mg, 0.33 mmol, 66%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 162 °C. IR (KBr): ν = 3380, 2922, 1513, 1444, 698 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.76−7.78 (m, 1H), 7.57−7.60 (m, 4H), 7.39−7.41 (m, 1H), 7.24−7.34 (m, 8H), 6.75 (d, J = 8.5 Hz, 2H), 6.45−6.47 (m, 2H), 5.39 (s, 1H), 2.10 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 167.9, 151.0, 142.8, 142.0 (2C), 140.6, 129.3 (2C), 128.5 (4C), 128.2 (4C), 127.8 (2C), 127.7, 125.3, 124.5, 120.6, 116.1 (2C), 111.1, 68.2, 20.5 ppm. HRMS (ESI): m/z calcd for C27H22KN2O [M + K]+, 429.1369; found, 429.1364. N-(1-(Benzo[d]oxazol-2-yl)-1-(4-isobutylphenyl)ethyl)-4-bromoaniline (8od). The compound was prepared according to the general procedure A using 2-(1-(4-isobutylphenyl)ethyl)benzo[d]oxazole 6o (140 mg, 0.5 mmol) as the starting material with 4bromoaniline 7d for 10 h. Colorless solid (135 mg, 0.30 mmol, 60%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 128 °C. IR (KBr): ν = 3395, 1490, 1237, 1084, 740 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.73− 7.75 (m, 1H), 7.49−7.52 (m, 2H), 7.43−7.45 (m, 1H), 7.25−7.34 (m, 2H), 7.10−7.15 (m, 4H), 6.40−6.42 (m, 2H), 5.29−5.30 (m, 1H), 2.45−2.47 (m, 2H), 2.18−2.19 (m, 3H), 1.81−1.89 (m, 1H), 0.88−0.90 (m, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 169.0, 151.2, 144.0, 141.7, 140.7, 139.0, 131.7 (2C), 129.7 (2C), 126.4 H



pubs.acs.org/joc

1068, 855, 690 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.29−7.35 (m, 4H), 7.22−7.24 (m, 2H), 6.77 (s, 2H), 5.45 (s, 1H), 4.04−4.05 (m, 1H), 2.21 (s, 3H), 2.02 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 178.1, 154.9, 141.9, 141.4, 133.7, 132.2, 132.1, 130.1 (2C), 129.8 (2C), 129.1 (2C), 128.2, 127.4 (2C), 125.5, 123.2, 122.5, 65.5, 20.7, 18.6 (2C) ppm. HRMS (ESI): m/z calcd for C23H21ClNaN2S [M + Na]+, 415.1006; found, 415.1004 N-(Benzo[d]thiazol-2-yl(naphthalen-1-yl)methyl)aniline (8ua). The compound was prepared according to the general procedure A using 2-(naphthalen-1-ylmethyl)benzo[d]thiazole 6u (138 mg, 0.5 mmol) as the starting material with aniline 7a for 3 h. Colorless solid (137 mg, 0.37 mmol, 75%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 156 °C. IR (KBr): ν = 3295, 1596, 1495, 1325, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.16−8.18 (m, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.82− 7.92 (m, 3H), 7.37−7.55 (m, 6H), 7.16−7.19 (m, 2H), 6.65−6.81 (m, 4H), 4.88−4.89 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 176.0, 153.8, 146.8, 136.2, 135.5, 134.3, 131.1, 129.5 (2C), 129.4, 129.2, 127.2, 126.2 (2C), 125.8, 125.7, 125.2, 123.3, 123.3, 122.0, 119.1, 113.8 (2C), 58.5 ppm. HRMS (ESI): m/z calcd for C24H18NaN2S [M + Na]+, 389.1083; found, 389.1080. The identity of the compound 8ua was further supported by X-ray crystallographic determination (CCDC 1990638). N-(Benzo[d]thiazol-2-yl(naphthalen-1-yl)methyl)-3-chloro-4-fluoroaniline (8uh). The compound was prepared according to the general procedure A using 2-(naphthalen-1-ylmethyl)benzo[d]thiazole 6u (138 mg, 0.5 mmol) as the starting material with 3chloro 4-fluoroaniline 7h for 3 h. Yellow solid (186 mg, 0.44 mmol, 89%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 174 °C. IR (KBr): ν = 3409, 2919, 1504, 1225, 744 cm−1. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99−8.00 (m, 1H), 7.93−7.95 (m, 2H), 7.40−7.61 (m, 5H), 7.25 (d, J = 7.0 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 6.99−7.00 (m, 1H), 6.87 (d, J = 7.0 Hz, 1H), 6.78−6.81 (m, 1H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 175.3, 153.1, 149.9 (d, JC−F = 236.0 Hz), 144.8, 135.9, 134.8, 133.6, 130.9, 128.7 (2C), 126.8, 126.2, 126.1, 125.5 (2C), 125.2, 123.5, 122.7, 122.4, 119.5 (d, JC−F = 18.3 Hz), 117.0 (d, JC−F = 21.5 Hz), 113.8 (d, JC−F = 11.0 Hz), 112.8, 56.5 ppm. 19F NMR (565 MHz, DMSO-d6) δ −127.06 to −127.03 ppm. HRMS (ESI): m/z calcd for C24H16ClFKN2S [M + K]+, 457.0338; found, 457.0328. N-(1-(Benzo[d]thiazol-2-yl)-1-phenylethyl)-4-chloroaniline (8vc). The compound was prepared according to the general procedure A using 2-(2-methylbenzyl)benzo[d]oxazole 6v (120 mg, 0.5 mmol) as the starting material with 2,4,6-trimethylaniline 7c for 10 h. Yellow solid (111 mg, 0.30 mmol, 61%). Rf = 0.5 (Hexane:Et2O = 9:1). MP = 169 °C. IR (KBr): ν = 3385, 1596, 1496, 813, 763 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.03−8.05 (m, 1H), 7.75−7.77 (m, 1H), 7.65− 7.68 (m, 2H), 7.31−7.48 (m, 5H), 6.98−7.00 (m, 2H), 6.43−6.44 (m, 2H), 5.53 (s, 1H), 2.20 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 172.0, 145.7, 137.1, 136.6, 129.1, 122.1 (2C), 121.8 (2C), 121.2, 119.8 (2C), 119.2, 118.3, 116.3, 116.1, 114.8, 110.2 (2C), 56.1, 20.0 ppm. HRMS (ESI): m/z calcd for C21H17KClN2S [M + K]+, 403.0433; found 403.0421. Representative Procedure for the Gram-Scale Synthesis of 8ba. A 100 mL round-bottom flask was charged with 2-(2methylbenzyl)benzo[d]oxazole (1.34 g, 6.0 mmol, 1.0 equiv) and FeCl3 (97 mg, 0.6 mmol, 0.1 equiv). The vessel was evacuated and backfilled with nitrogen (3×). Then, to it, anhydrous toluene (30 mL), DTBP (1.1 g, 7.2 mmol, 1.2 equiv), and aniline (838 mg, 9 mmol, 1.5 equiv) were added successively, and the reaction mixture was stirred at 100 °C until completion (monitored by TLC). After cooling, the solvent was removed using a rotary evaporator, and the residue was purified by flash column chromatography on silica gel to provide 8ba as a colorless solid (1.64 g, 5.2 mmol, 87%). Representative Procedure for the Removal of Benzoxazole Auxiliary from 8ba. A 25 mL R.B. flask was charged with N(benzo[d]oxazol-2-yl(o-tolyl)methyl)aniline (8ba) (314 mg, 1.0 mmol, 1.0 equiv), ZnCl2 (273 mg, 2.0 mmol, 2.0 equiv), 14% HCl (8.5 mL), and EtOH (8.5 mL). The reaction mixture was stirred at 100 °C using a coil-condenser for 16 h. After completion, the

Note

resulting mixture was diluted with DCM (25 mL) and extracted with saturated aqueous NaHCO3 solution (3 × 40 mL). The combined aqueous layer was acidified with concentrated HCl and then extracted with DCM (3 × 40 mL). The combined organic layers (1st DCM extract and last 3 DCM extracts) were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude amide, which was further purified by column chromatography over silica gel to obtain the amide. Colorless solid (283 mg, 0.85 mmol, 85%). MP = 202 °C. Rf = 0.5 (Hexane:EtOAc = 4:1). IR (KBr): ν = 3356, 1658, 1536, 1455, 752 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.29 (s, 1H), 9.06 (s, 1H), 7.35−7.37 (m, 1H), 7.23−7.30 (m, 5H), 7.12−7.15 (m, 1H), 7.02−7.04 (m, 1H), 6.91−6.94 (m, 2H), 6.82−6.85 (m, 1H), 6.74− 6.76 (m, 2H), 5.11 (s, 1H), 4.18 (s, 1H), 2.39 (s, 3H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 172.5, 149.3, 146.5, 137.2, 136.5, 131.5, 129.9 (2C), 129.2, 127.7, 127.2, 126.5, 125.1, 122.5, 120.7, 120.5, 120.2, 114.1 (2C), 61.9, 19.8 ppm. HRMS (ESI): m/z calcd for C21H20NaN2O2 [M + Na]+, 355.1417; found, 355.1421. In a 15 mL reaction tube, the resulting compound N-(2hydroxyphenyl)-2-(phenylamino)-2-(o-tolyl)acetamide (283 mg, 0.85 mmol, 1.0 equiv) and crushed NaOH (170 mg, 4.25 mmol, 5.0 equiv) were heated in ethanol (9.4 mL) for 16 h at 100 °C. After completion, water was added to the reaction mixture followed by extraction with diethyl ether (3 × 25 mL). These ether extracts were discarded. Aqueous layer was acidified with 1 (N) NaHSO4 until pH ∼2 followed by extraction with diethyl ether (3 × 25 mL). These ether extracts from the acidified aqueous layer were combined and dried over Na2SO4. The solvents were concentrated in vacuum to give the crude acid, which was further purified by column chromatography over silica gel. Brown solid 9 (169 mg, 0.70 mmol, 82%; Overall yield starting from 8ba = 70%). Rf = 0.5 (Hexane:EtOAc = 3:2). MP = 190 °C. IR (KBr): ν = 3355, 1647, 1535, 1443, 752 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 1H), 7.13−7.25 (m, 5H), 6.69− 6.75 (m, 1H), 6.54 (d, J = 7.5 Hz, 2H), 2.58 (s, 1H), 2.52 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 176.5, 146.1, 136.9, 135.5, 131.2, 129.5 (2C), 128.7, 126.9, 126.5, 118.8, 113.5 (2C), 57.7, 19.7 ppm. HRMS (ESI): m/z calcd for C15H15NaNO2 [M + Na]+, 264.1000; found, 264.1001. Synthesis of Amide 10. To a stirred solution of 9 (100 mg, 0.41 mmol) in dry CH2Cl2 (1.8 mL) at 0 °C were added consecutively 1hydroxybenzotriazole (HOBt) (55 mg, 0.41 mmol), (S)-methyl phenylalaninate (79 mg, 0.41 mmol), Et3N (42 mg, 0.41 mmol), and dicyclohexylcarbodiimide (DCC) (86 mg, 0.41 mmol). The reaction mixture was left stirring at 0 °C for 1 h and then warmed to room temperature and left stirring for another 18 h. The solvents were evaporated under reduced pressure, and the crude product was dissolved in EtOAc (30 mL). After filtration, the organic layer was washed with aq H2SO4 (5%, 5 mL), H2O (5 mL), aq NaHCO3 (5%, 5 mL), and brine (5 mL). After evaporation of the solvent, the crude ester was purified using column chromatography.19 White solid 10 (106 mg, 0.26 mmol, 64%). Rf = 0.4 (Hexane:EtOAc = 8:2). MP = 118 °C. IR (KBr): ν = 3376, 3265, 1739, 1637, 1495, 742 cm−1. 1H NMR (600 MHz, CDCl3) δ 7.28−7.31 (m, 2H), 7.16−7.23 (m, 5H), 7.12−7.13 (m, 2H), 7.02−7.06 (m, 1H), 6.81−6.86 (m, 1H), 6.73− 6.75 (m, 1H), 6.64 (d, J = 7.8 Hz, 2H), 4.95−4.98 (m, 1H), 4.90 (s, 1H), 3.66 (s, 3H), 3.29−3.32 (m, 1H), 3.97−3.00 (m, 1H), 2.31 (s, 3H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 171.6, 147.1, 137.0, 136.9, 136.2, 131.2, 129.4 (2C), 129.3 (2C), 128.9 (2C), 128.5, 127.3, 126.9, 126.6, 119.6, 114.1 (2C), 61.4, 53.2, 52.5, 37.8, 19.7 ppm. HRMS (ESI): m/z calcd for C25H27N2O3 [M + H]+, 403.2016; found, 403.2017. Representative Procedure for the Gram-Scale Synthesis of 8ua. A 100 mL round-bottom flask, equipped with a magnetic stirring bar and a rubber septum, was charged with 6s (2-(naphthalen-1ylmethyl)benzo[d]thiazole, 2.2 g, 8.0 mmol, 1 equiv) and FeCl3 (130 mg, 0.8 mmol, 0.1 equiv). The flask was evacuated and backfilled with nitrogen (3×). To it, anhydrous toluene (40 mL), DTBP (1.4 g, 9.6 mmol, 1.2 equiv), and aniline (1.12 g, 12 mmol, 1.5 equiv) were added, and the reaction mixture was stirred at 100 °C until completion (monitored by TLC). After cooling, the solvent was removed using a rotary evaporator, and residue was purified by flash I



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column chromatography on silica gel to provide 8ua as a colorless solid (1.76 g, 4.8 mmol, 60%). Benzyl Protection of 8ua. A 10 mL reaction tube was charged with a magnetic bar, 8ua (175 mg, 0.5 mmol), catalytic n-Bu4NI (0.05 mmol, 10 mol %), BnBr (171 mg, 1.0 mmol, 2 equiv), and K2CO3 (138 mg, 1 mmol, 2 equiv). The reaction tube was equipped with a reflux condenser and was subsequently evacuated and backfilled with nitrogen (3×). To it, anhydrous THF (3 mL) was added, and the resulting mixture was refluxed for 12 h. After completion of the reaction, THF was evaporated and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by column chromatography.20 Colorless solid 11 (139 mg, 0.30 mmol, 61%). Rf = 0.6 (Hexane:Et2O = 9:1). MP = 218 °C. IR (KBr): ν = 3366, 1606, 1495, 752 702 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 9.0 Hz, 1H), 8.17−8.19 (m, 1H), 7.86−7.93 (m, 2H), 7.75−7.77 (m, 1H), 7.62−7.65 (m, 2H), 7.38−7.41 (m, 1H), 7.26−7.29 (m, 2H), 7.10−7.15 (m, 2H), 6.94−6.99 (m, 4H), 6.48−6.57 (m, 5H), 6.08 (s, 1H), 4.51 (d, J = 12.5 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H) ppm. 13 C{1H} NMR (126 MHz, CDCl3) δ 176.6, 151.4, 145.5, 139.5, 135.9, 135.5, 134.8, 132.1, 130.8 (2C), 130.6, 129.1 (2C), 128.9, 127.6 (2C), 126.9, 126.3, 126.0 (2C), 125.9, 125.2, 125.1, 124.9, 123.3, 121.8, 117.3, 114.8 (2C), 65.8, 44.7 ppm. HRMS (ESI): m/z calcd for C31H24NaN2S [M + Na]+, 479.1552, found, 479.1558. Benzoyl Protection of 8ua. To a stirred solution of 8ua (175 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (2.5 mL) was added diisopropylethylamine (65 mg, 0.5 mmol, 1.0 equiv) at room temperature. The solution was stirred at this temperature for 10 min, and subsequently, benzoyl chloride (105 mg, 0.75 mmol, 1.5 equiv) was added, and the resulting solution was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with diethyl ether (5 mL) and washed with brine (2 × 2.0 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in a rotary evaporator. Purification of the residue by column chromatography provided 12 (138 mg, 0.29 mmol, 59%) as a colorless solid.21 Rf = 0.5 (Hexane:Et2O = 8:2). MP = 212 °C. IR (KBr): ν = 3346, 1647, 1496, 1322, 763 cm−1. 1H NMR (600 MHz, CDCl3) δ 8.55 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.11−8.14 (m, 3H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.61−7.71 (m, 3H), 7.47−7.56 (m, 4H), 7.42−7.44 (m, 2H), 7.13−7.21 (m, 4H), 6.79−6.86 (m, 2H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 171.4, 171.2, 153.4, 140.0, 136.2, 135.8, 133.6, 132.5, 132.1, 130.5 (2C), 130.1, 129.7, 129.5, 129.1, 128.8 (2C), 127.9 (2C), 127.8 (2C), 127.4, 127.2, 126.2, 126.1, 125.4, 124.8, 123.6, 123.2, 121.7, 59.2 ppm. HRMS (ESI): m/z calcd for C31H23N2OS [M + H]+, 471.1526; found, 471.1533.

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AUTHOR INFORMATION

Corresponding Author

Sukalyan Bhadra − Inorganic Materials and Catalysis Division, CSIR-Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar, Gujarat 364002, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; orcid.org/0000-0003-1266-0930; Email: [email protected] Authors

Jogendra Kumar − Inorganic Materials and Catalysis Division, CSIR-Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar, Gujarat 364002, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India Eringathodi Suresh − Analytical and Environmental Science Division and Centralized Instrument Facility, CSIR-Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar, Gujarat 364002, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; orcid.org/0000-0002-1934-6832 Complete contact information is available at: https://pubs.acs.org/10.1021/acs.joc.0c02122 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We sincerely thank DST (Grant DST/INSPIRE/04/2015/ 002248), CSIR (CSMCRI project no. MLP 0028), UGC (for a fellowship to J.K.), and “Analytical and Environmental Science Division and Centralized Instrument Facility” of CSIRCSMCRI for providing instrument facilities. CSIR-CSMCRI communication no. 57/2020.

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REFERENCES

(1) For an overview, see: (a) Kapdi, A.; Maiti, D., Eds. Strategies for Palladium-Catalyzed Non-directed and Directed C−H Bond Functionalization; Elsevier: Amsterdam, 2017. (b) Yu, J. Q., Shi, Z., Eds. C−H Activation; Springer: Berlin, Germany, 2010. (2) For selected reviews, see: (a) Kumar, J.; Rahaman, A.; Singh, A. K.; Bhadra, S. Catalytic Approaches for the Direct Heterofunctionalization of Aliphatic Carboxylic Acids and Their Equivalents with Group 16 Elements. Chem. - Asian J. 2020, 15, 673−689. (b) Uttry, A.; van Gemmeren, M. Direct C (sp3)−H Activation of Carboxylic Acids. Synthesis 2020, 30, 479−488. (c) Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp3)-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62−101. (d) Xu, Y.; Dong, G. sp3 C−H Activation via ExoType Directing Groups. Chem. Sci. 2018, 9, 1424−1432. (e) Bhadra, S.; Yamamoto, S. Substrate Directed Asymmetric Reactions. Chem. Rev. 2018, 118, 3391−3446. (f) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C− H Bonds. Chem. Rev. 2017, 117, 8754−8786. (3) (a) Song, G.; Zheng, Z.; Wang, Y.; Yu, X. Pd-Catalyzed SiteSelective p-Hydroxyphenyloxylation of Benzylic α-C(sp3)−H Bonds with 1,4-Benzoquinone. Org. Lett. 2016, 18, 6002−6005. (b) Smalley, A. P.; Gaunt, M. J. Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C−H Activation. J. Am. Chem. Soc. 2015, 137, 10632−10641. (c) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Palladium-Catalysed C−H Activation of Aliphatic Amines to Give Strained Nitrogen Heterocycles. Nature 2014, 510, 129−133.

ASSOCIATED CONTENT

* Supporting Information sı

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.0c02122. Optimization table, mechanistic investigation, and 1H and 13C{1H} spectral data for all new compounds (PDF) Crystallographic information file for 8md (CIF) Crystallographic information file for 8ua (CIF) FAIR data, including the primary NMR FID files, for compounds 6g′, 6h, 6i, 6n, 6o, 8aa, 8ba−8bp, 8ao, 8co−8ko, 8ua, 8uh, 8vc, 8la, 8md, 8aq, 8nj, 8od, 8ph, 8qo−8to, and 9−12 (ZIP) Accession Codes

CCDC 1990591 and 1990638 contain the supplementary crystallographic data for this paper. J



pubs.acs.org/joc

Note

Lett. 2014, 16, 2000−2002. (c) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Synthesis of Oxindoles by Iron-Catalyzed Oxidative 1,2-Alkylarylation of Activated Alkenes with an Aryl C(sp2)−H Bond and a C(sp3))H Bond Adjacent to a Heteroatom. Angew. Chem., Int. Ed. 2013, 52, 3638−3641. (d) Xia, Q.; Chen, W.; Qiu, H. Direct C−N Coupling of Imidazoles and Benzylic Compounds via Iron-Catalyzed Oxidative Activation of C−H Bonds. J. Org. Chem. 2011, 76, 7577−7582. (e) Pan, S.; Liu, J.; Li, H.; Wang, Z.; Guo, X.; Li, Z. Iron-Catalyzed N-Alkylation of Azoles via Oxidation of C-H Bond Adjacent to an Oxygen Atom. Org. Lett. 2010, 12, 1932−1935. (11) (a) Kumar, J.; Gupta, A.; Bhadra, S. PdII-Catalyzed Methoxylation of C(sp3)−H Bonds Adjacent to Benzoxazoles and Benzothiazoles. Org. Biomol. Chem. 2019, 17, 3314−3318. (b) Gupta, A.; Rahaman, A.; Bhadra, S. Direct α-Chalcogenation of Aliphatic Carboxylic Acid Equivalents. Org. Lett. 2019, 21, 6164−6168. (12) While the intermolecular KIE (see Supporting Information, Scheme S2) was found as 1.58, the independent parallel experiment gave the observed KIE = 1.63 (see Supporting Information, Scheme S3 and Figure S1). (13) (a) Yamamoto, E.; Wakafuji, K.; Furutachi, Y.; Kobayashi, K.; Kamachi, T.; Tokunaga, M. Dynamic Kinetic Resolution of NProtected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis. ACS Catal. 2018, 8, 5708−5713. (b) Mandai, H.; Hongo, K.; Fujiwara, T.; Fujii, K.; Mitsudo, K.; Suga, S. Dynamic Kinetic Resolution of Azlactones by a Chiral N, N-Dimethyl-4-aminopyridine Derivative Containing a 1,1′-Binaphthyl Unit: Importance of Amide Groups. Org. Lett. 2018, 20, 4811−4814 and refs cited therein.. (14) For a review, see: Al Toma, R. S.; Brieke, C.; Cryle, M. J.; Sü ssmuth, R. D. Structural Aspects of Phenylglycines, Their Biosynthesis and Occurrence in Peptide Natural Products. Nat. Prod. Rep. 2015, 32, 1207−123. (15) Armarego, L. F.; Perrin, D. D. In Purification of Laboratory Chemicals; Butterworth-Heinemann, Oxford: United States, 2000. (16) (a) Øpstad, C. L.; Melø, T.-B.; Sliwka, H.-R.; Partali, V. Formation of DMSO and DMF Radicals with Minute Amounts of Base. Tetrahedron 2009, 65, 7616−7619. (b) Reshma, R. S.; Jeankumar, V. U.; Kapoor, N.; Saxena, S.; Bobesh, K. A.; Vachaspathy, A. R.; Kolattukudy, P. E.; Sriram, D. Mycobacterium tuberculosis Lysine-ε-aminotransferase a Potential Target in Dormancy: Benzothiazole Based Inhibitors. Bioorg. Med. Chem. 2017, 25, 2761−2771. (c) Kumar, D.; Rudrawar, S.; Chakraborti, A. K. One-Pot Synthesis of 2-Substituted Benzoxazoles Directly from Carboxylic Acids. Aust. J. Chem. 2008, 61, 881−887. (17) (a) Nguyen, T. B.; Retailleau, P. Elemental Sulfur-Promoted Oxidative Rearranging Coupling between o-Aminophenols and Ketones: A Synthesis of 2-Alkyl Benzoxazoles under Mild Conditions. Org. Lett. 2017, 19, 3887−3890. (b) Babu, K. R.; Zhu, N.; Bao, H. Iron-Catalyzed C−H Alkylation of Heterocyclic C−H Bonds. Org. Lett. 2017, 19, 46−49. (c) Vijaykumar, G.; Jose, A.; Vardhanapu, P. K.; Sreejyothi, P.; Mandal, S. K. Abnormal-NHC-Supported Nickel Catalysts for Hydroheteroarylation of Vinylarenes. Organometallics 2017, 36, 4753−4758. (d) Mayo, M. S.X.; Yu Zhou, X.; Feng, X.; Yamamoto, Y.; Bao, M. Convenient Synthesis of Benzothiazoles and Benzimidazoles through Brønsted Acid Catalyzed Cyclization of 2Amino Thiophenols/Anilines with β-Diketones. Org. Lett. 2014, 16, 764−767. (e) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. CopperCatalyzed Direct Benzylation or Allylation of 1,3-Azoles with NTosylhydrazones. J. Am. Chem. Soc. 2011, 133, 3296−3299. (f) Evindar, G.; Batey, R. A. Parallel Synthesis of a Library of Benzoxazoles and Benzothiazoles Using Ligand-Accelerated CopperCatalyzed Cyclizations of ortho-Halobenzanilides. J. Org. Chem. 2006, 71, 1802−1808. (g) Saha, P.; Ramana, T.; Purkait, N.; Ali, Md A.; Paul, R.; Punniyamurthy, T. Ligand-Free Copper-Catalyzed Synthesis of Substituted Benzimidazoles, 2-Aminobenzimidazoles, 2-Aminobenzothiazoles, and Benzoxazoles. J. Org. Chem. 2009, 74, 8719− 8725. (h) Obora, Y.; Ogawa, S.; Yamamoto, N. Iridium-Catalyzed Alkylation of Methylquinolines with Alcohols. J. Org. Chem. 2012, 77, 9429−9433. (i) Aksenov, N. A.; Aksenov, A. V.; Nadein, O. N.;

(4) (a) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. PalladiumCatalyzed Aryl C−H Olefination with Unactivated, Aliphatic Alkenes. J. Am. Chem. Soc. 2014, 136, 13602−13605. (b) Wang, X.; Mei, T.-S.; Yu, J.-Q. Versatile Pd(OTf)2·2H2O-Catalyzed ortho-Fluorination Using NMP as a Promoter. J. Am. Chem. Soc. 2009, 131, 7520− 7521. (c) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. LigandEnabled Reactivity and Selectivity in a Synthetically Versatile Aryl C− H Olefination. Science 2010, 327, 315−319. (5) For a review, see: (a) de la Torre, A.; Tona, V.; Maulide, N. Reversing Polarity: Carbonyl α-Aminations with Nitrogen Nucleophiles. Angew. Chem., Int. Ed. 2017, 56, 12416−12423. (b) Janey, J. M. Advances in Catalytic, Enantioselective α Aminations and α Oxygenations of Carbonyl Compounds. Angew. Chem., Int. Ed. 2005, 44, 4292−4300. (6) (a) Ling, P.-X.; Fang, S.-L.; Yin, X.-S.; Zhang, Q.; Chen, K.; Shi, B.-F. Palladium-Catalyzed Sequential Monoarylation/Amidation of C(sp3)−H Bonds: Stereoselective Synthesis of α-Amino-β-Lactams and anti-α-β-Diamino Acid. Chem. Commun. 2017, 53, 6351−6354. (b) Zhang, S.-J.; Sun, W.-W.; Cao, P.; Dong, X.-P.; Liu, J.-K.; Wu, B. Stereoselective Synthesis of Diazabicyclic β-Lactams through Intramolecular Amination of Unactivated C(sp3)−H Bonds of Carboxamides by Palladium Catalysis. J. Org. Chem. 2016, 81, 956−968. (c) Wang, C.; Yang, Y.; Qin, D.; He, Z.; You, J. Copper-Catalyzed Intramolecular Dehydrogenative Amidation of Unactivated C(sp3)− H Bonds Using O2 as the Sole Oxidant. J. Org. Chem. 2015, 80, 8424−8429. (d) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. CopperCatalyzed Intramolecular C(sp3)−H and C(sp2)−H Amidation by Oxidative Cyclization. Angew. Chem., Int. Ed. 2014, 53, 3496−3499. (e) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Use of a Readily Removable Auxiliary Group for the Synthesis of Pyrrolidones by the Palladium-Catalyzed Intramolecular Amination of Unactivated γ C(sp3)−H Bonds. Angew. Chem., Int. Ed. 2013, 52, 11124−11128. (7) (a) Bai, H.-Y.; Ma, Z.-G.; Yi, M.; Lin, J.-B.; Zhang, S.-Y. Palladium-Catalyzed Direct Intermolecular Amination of Unactivated Methylene C(sp3)−H Bonds with Azodiformates via BidentateChelation Assistance. ACS Catal. 2017, 7, 2042−2046. (b) Gou, Q.; Liu, G.; Liu, Z.-N.; Qin, J. PdII-Catalyzed Intermolecular Amination of Unactivated C(sp3)−H Bonds. Chem. - Eur. J. 2015, 21, 15491− 15495. (c) He, J.; Shigenari, T.; Yu, J.-Q. Palladium(0)/PAr3Catalyzed Intermolecular Amination of C(sp3)−H Bonds: Synthesis of β-Amino Acids. Angew. Chem., Int. Ed. 2015, 54, 6545−6549. (8) (a) Ford, R. L.; Alt, I.; Jana, N.; Driver, T. G. Intramolecular PdCatalyzed Reductive Amination of Enolizable sp3-C−H Bonds. Org. Lett. 2019, 21, 8827−8831. (b) Tokumasu, K.; Yazaki, R.; Ohshima, T. Direct Catalytic Chemoselective α-Amination of Acylpyrazoles: A Concise Route to Unnatural α-Amino Acid Derivatives. J. Am. Chem. Soc. 2016, 138, 2664−2669. (c) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W. C. Simple Catalytic Mechanism for the Direct Coupling of α-Carbonyls with Functionalized Amines: A One-Step Synthesis of Plavix. J. Am. Chem. Soc. 2013, 135, 16074−16077. (d) Ton, T. M. U.; Tejo, C.; Tiong, D. L. Y.; Chan, P. W. H. Copper(II) Triflate Catalyzed Amination and Aziridination of 2-Alkyl Substituted 1,3-Dicarbonyl Compounds. J. Am. Chem. Soc. 2012, 134, 7244−7350. (9) (a) Glunz, P. W.; Cheng, X.; Cheney, D. L.; Weigelt, C. A.; Wei, A.; Luettgen, J. M.; Wong, P. C.; Wexler, R. R.; Priestley, E. S. Design and Synthesis of Potent, Selective Phenylimidazole-Based FVIIa Inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 2169−2173. (b) Dhanoa, D. S.; Bagley, S. W.; Chang, R. S. L.; Lotti, V. J.; Chen, T. B.; Kivlighn, S. D.; Zingaro, G. J.; Siegl, P. K. S.; Patchett, A. A.; Greenlee, W. J. Non-Peptide Angiotensin II Receptor Antagonists. 2. Design, Synthesis, and Biological Activity of N-Substituted (Phenylamino)Phenylacetic Acids and Acyl Sulfonamides. J. Med. Chem. 1993, 36, 4239−4249. (10) (a) Shang, R.; Ilies, L.; Nakamura, E. Iron-Catalyzed C−H Bond Activation. Chem. Rev. 2017, 117, 9086−9139. (b) Cheng, Y.; Dong, W.; Wang, L.; Parthasarathy, K.; Bolm, C. Iron-Catalyzed Hetero-Cross-Dehydrogenative Coupling Reactions of Sulfoximines with Diarylmethanes: A New Route to N-Alkylated Sulfoximines. Org. K



pubs.acs.org/joc

Note

Aksenov, D. A.; Smirnov, A. N.; Rubin, M. One-Pot Synthesis of Benzoxazoles via the Metal-Free ortho-C−H Functionalization of Phenols with Nitroalkanes. RSC Adv. 2015, 5, 71620−71626. (18) Gooßen, L. J.; Rudolphi, F.; Oppel, C.; Rodriguez, N. Synthesis of Ketones from α-Oxocarboxylates and Aryl Bromides by Cu/PdCatalyzed Decarboxylative Cross-Coupling. Angew. Chem., Int. Ed. 2008, 47, 3043−3045. (19) Revelou, P.; Kokotos, C. G.; Moutevelis-Minakakis, P. Novel Prolinamide−Ureas as Organocatalysts for the Asymmetric Aldol Reaction. Tetrahedron 2012, 68, 8732−8738. (20) Wang, H.; Zhang, J.; Shi, J.; Li, F.; Zhang, S.; Xu, K. Organic Photoredox-Catalyzed Synthesis of δ-Fluoromethylated Alcohols and Amines via 1,5-Hydrogen-Transfer Radical Relay. Org. Lett. 2019, 21, 5116−5120. (21) Rivas, F. R.; Riaz, U.; Giessert, A.; Smulik, J.; Diver, S. T. A Versatile Synthesis of Substituted Benzimidazolium Salts by an Amination/Ring Closure Sequence. Org. Lett. 2001, 3, 2673−2676.

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Incorrect table title.

Title X: a critical difference.

CT scanners vie for title.

What makes a good title?

What's in a title--Mr or Dr?

Writing style: what's in a title?

[Funktionsoberarzt. Pseudo-title or meaningful position?].

Futurist Art: Motion and Aesthetics As a Function of Title.

The anatomy of an article: title, abstract, and introduction.

"The chronic patient": in search of a title.

Citations-be sure to have a good title.

World title boxing: from early beginnings to the first bell.

Peer bids for protection of title 'veterinary nurse'.

Barriers to effective outreach in Title VII nutrition programs.

Article title misstates the role of pavement sealers.

Title and Abstract Screening and Evaluation in Systematic Reviews (TASER): a pilot randomised controlled trial of title and abstract screening by medical students.

No title

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