Abstract
A facile, efficient, and practical method for nBu4NI-catalyzed direct C–H amination of benzoxazoles with tertiary amines has been developed. The system could be performed in the absence of metal catalyst and only requires tert-butyl hydroperoxide as oxidant under microwave irradiation. A variety of substituted benzoxazol-2-amines were synthesized with moderate to good yield.
1 Introduction
Oxazoles are extremely important structural motifs that are featured prominently in pharmaceuticals and organic materials [1, 2]. Among them, 2-aminobenzoxazoles display high activity, and some drug targets have been addressed by 2-aminated benzoxazoles (Scheme 1), such as small-molecule somatostatin receptor subtype 5 antagonists [3], and as partial antagonists for serotonin (5-hydroxytryptamine) receptors, which are promising targets for the treatment of Alzheimer disease and schizophrenia [4]. Therefore, the development of efficient methods for their preparation is highly important. Transition-metal-catalyzed C–H bond activation of heteroarenes are important in synthetic organic chemistry [5–7], which have been widely used in the synthesis of organic compounds and natural products. Generally, 2-aminobenzoxazole derivatives are synthesized by transition metal-catalyzed amination with N-chloroamines, amines, and amides or with O-acylated hydroxylamines and others [8–11]. As a complementary methodology of the above methods, transition metal-catalyzed (including Pd [12], Ni [13], Cu [14–20], Fe [21, 22], Ag [23], Co, Mn [24]) C–H direct amination has become the main strategy to construct 2-aminobenzoxazoles. Although significant advances have been achieved, some disadvantages remain, such as high temperature, long reaction time, poisonous ligands, strong acid or base, and non-economic effects. Additionally, heavy metal impurities in drug intermediates and harsh reaction conditions have limited the utility of such methods. Hence, the development of environmentally benign procedures based on transition metal-free catalysis to synthesize such compounds is highly desirable.
Recently, Studer et al. [25] have developed a metal-free protocol for the highly efficient direct amination of non-activated benzoxazoles and 1,3,4-oxadizaoles with secondary amines using catalytic amounts of triflic acid and 2,2,6,6-tetramethylpiperidine-N-oxoammonium tetrafluoroborate (TEMPO+BF4−) as an organic oxidant. Bhanage et al. [26] and Sun et al. [27] have synthesized substituted benzoxazol-2-amines using benzoxazoles with aliphatic secondary amines through the ring-opening step and further oxidative cyclization, and 2-iodoxybenzoic acid and N-bromosuccinimide were used as an oxidant, respectively. Lamani and Prabhu [28] and Nachtsheim et al. [29] have also reported a metal-free route of oxidative amination of benzoxazole with secondary or primary amines in the presence of catalytic iodine or tetrabutylammonium iodide (TBAI) using aqueous tert-butyl hydroperoxide (TBHP) as the oxidant. Subsequently, Wang et al. [30] have described an efficient TBAI/TBHP-mediated method for benzoxazoles amination under transition metal-free conditions using formamides as nitrogen sources [30]. Moreover, the direct amination of benzoxazoles with secondary amines using a catalytic amount of N-iodosuccinimide and aqueous H2O2 as an oxidant or using lithium tert-butoxide and iodine as the medium has also been reported [31, 32]. Despite the remarkable success achieved, a direct transition metal-free-catalyzed amination of benzoxazoles was rarely reported with tertiary amines as amino group sources. Given that tertiary amines are widely found in natural products and more easily available than primary or secondary amines in the laboratories, the synthesis of benzoxazol-2-amines from tertiary amines is more expected. Moreover, in view of the increasing attention to design environmentally benign and metal-free methods for the formation of C–N bonds and continuation of our research on green chemistry [33, 34], herein we report a facile, efficient, and practical method for nBu4NI-catalyzed direct amination of benzoxazoles with tertiary amines as nitrogen sources and a catalytic amount of TBAI/TBHP as the oxidant in acetic acid under microwave irradiation.
2 Results and discussion
We began our investigation with the reaction of benzoxazole (1a) with trimethylamine (2a) as a model reaction. As seen in Table 1, a variety of reaction conditions were employed to achieve the optimal conditions. Initial screening of the solvents revealed that the solvents such as THF, PhCl, and 1,2-dichloroethane (DCE) are not suitable for this reaction (Table 1, entries 1–3). Further investigation has shown that the reaction proceeds well in acetonitrile in the presence of AcOH (2.0 equiv) using catalytic amounts of TBAI (5 mol%) and TBHP (2.0 equiv) as the oxidant (Table 1, entries 4–6). Unfortunately, replacement of TBHP with H2O2, di-tert-butylperoxide (DTBP), AIBN, K2S2O8, or (NH4)2S2O8 proved to be ineffective, which led to a dramatically decreased yield or no product at all (Table 1, entries 7–11). When potassium iodide or iodine was employed instead of TBAI, the corresponding reaction also proceeded smoothly, presumably due to their similar capability to promote the reaction with TBAI (Table 1, entries 12 and 13). Gratifyingly, increasing the amount of TBAI (10 mol%) resulted in high yields, indicating the significance of a catalyst in the reaction (Table 1, entries 14 and 15). The screening of the amount of TBHP showed that a good yield (65 %) of the product 3a was obtained when 2.0 equiv of TBHP was employed, and excessive or less amounts of the oxidant caused decreased conversion (Table 1, entries 14 and 16). Furthermore, various additives were investigated, which, compared to AcOH, PhCO2H, and hydrochloric acid, were less effective, whereas a strong acid, such as trifluoroacetic acid (TFA), was a completely ineffective additive (Table 1, entries 17–19). The reaction of benzoxazole 1a and trimethylamine 2a in the absence of AcOH resulted in a trace amount of 3a, indicating the significance of the acid additive in the reaction (Table 1, entry 20). Notably, excessive or less amounts of additive would lead to a slight decreased yield, and 2.0 equiv of additive AcOH was the optimized choice (Table 1, entries 14 and 21). In addition, increasing the temperature from 20 to 120 °C could enhance the reaction efficacy, and a good yield of 65 % could be obtained at 100 °C (Table 1, entries 14 and 22–25). Amination of benzoxazole 1a was not observed in the absence of either TBHP or TBAI, indicating that the TBAI/TBHP combination is crucial for the reaction (Table 1, entries 26 and 27). When the microwave irradiation was not used, only a 50 % yield was obtained after 12 h (Table 1, entry 28). Microwave-assisted direct amination of benzoxazoles was an effective technique, which led to shorter reaction time and increased yield, matched with green chemistry protocols.
Entry | Catalyst (mol%) | [O] (equiv) | Additive (equiv) | Solvent | Temperature (°C) | Yielda (%) |
---|---|---|---|---|---|---|
1 | TBAI (5) | TBHPb (2) | AcOH (2) | THF | 100 | Trace |
2 | TBAI (5) | TBHP (2) | AcOH (2) | PhCl | 100 | Trace |
3 | TBAI (5) | TBHP (2) | AcOH (2) | DCE | 100 | Trace |
4 | TBAI (5) | TBHP (2) | AcOH (2) | Dioxane | 100 | 30 |
5 | TBAI (5) | TBHP (2) | AcOH (2) | DMSO | 100 | 28 |
6 | TBAI (5) | TBHP (2) | AcOH (2) | CH3CN | 100 | 57 |
7 | TBAI (5) | H2O2 (2) | AcOH (2) | CH3CN | 100 | <10 |
8 | TBAI (5) | DTBP (2) | AcOH (2) | CH3CN | 100 | Trace |
9 | TBAI (5) | AIBN (2) | AcOH (2) | CH3CN | 100 | <5 |
10 | TBAI (5) | K2S2O8 (2) | AcOH (2) | CH3CN | 100 | Trace |
11 | TBAI (5) | (NH4)2S2O8 (2) | AcOH (2) | CH3CN | 100 | <5 |
12 | KI (5) | TBHP (2) | AcOH (2) | CH3CN | 100 | 54 |
13 | I2 (5) | TBHP (2) | AcOH (2) | CH3CN | 100 | 53 |
14 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 100 | 65 |
15 | TBAI (15) | TBHP (2) | AcOH (2) | CH3CN | 100 | 50 |
16 | TBAI (10) | TBHP (1:1.5:2.5:3) | AcOH (2) | CH3CN | 100 | 43:53:52:51c |
17 | TBAI (10) | TBHP (2) | TFA (2) | CH3CN | 100 | Trace |
18 | TBAI (10) | TBHP (2) | PhCO2H (2) | CH3CN | 100 | 56 |
19 | TBAI (10) | TBHP (2) | HCl (2) | CH3CN | 100 | <10 |
20 | TBAI (10) | TBHP (2) | None | CH3CN | 100 | Trace |
21 | TBAI (10) | TBHP (2) | AcOH (1:1.5:2.5:3) | CH3CN | 100 | 46:52:56:53d |
22 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 20 | <5 |
23 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 60 | 22 |
24 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 80 | 53 |
25 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 120 | 45 |
26 | TBAI (10) | None | AcOH (2) | CH3CN | 100 | nre |
27 | None | TBHP (2) | AcOH (2) | CH3CN | 100 | nre |
28 | TBAI (10) | TBHP (2) | AcOH (2) | CH3CN | 100 | 50f |
Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), catalyst, oxidant, and acid additive was stirred in solvent (1.5 mL) for 20 min under microwave irradiation. The given equivalents (equiv) and mol% are related to 1a.
aIsolated yields. b70 % TBHP aqueous solution. cWhen 1.0, 1.5, 2.5, and 3.0 equiv TBHP were added, the yields of product were 43, 53, 52, and 51 %, respectively. dWhen 1.0, 1.5, 2.5, and 3.0 equiv AcOH were added, the yields of product were 46, 52, 56, and 53 %, respectively. enr = no reaction. fNo microwave irradiation; reaction time is 12 h.
Under the optimized conditions, the scope of this oxidative C–H amination reaction was investigated with respect to azole under the same conditions (Table 1, entry 14). Regarding the benzoxazole moiety, several functional groups including electron-donating (methyl, tert-butyl) and electron-withdrawing (chloro, nitro) substituents were tolerated well (Table 2). Notably, the electronic nature of the substituents on the phenyl ring of benzoxazoles affected the reaction yield, such as 5-methylbenzoxazole and 5-tert-butylbenzoxazole, containing the electron-donating substituents, increased the yields of products (Table 2, 3b and 3c); the effect is the reverse with electron-withdrawing substituents (Table 2, 3d and 3e). A reaction with 5-nitrobenzoxazole afforded the corresponding product with a sharply lower yield (45 %). It is noteworthy that a chloro substituent was compatible under standard conditions to give the corresponding functionalized amine products such as 3d in good yield. Unfortunately, benzothiazole did not afford the desired products 3f. The lower reactivity of the substrate observed here is probably due to their weaker acidity.
Reaction conditions: 1 (0.25 mmol), trimethylamine 2a (0.75 mmol), TBAI (10 mol%), TBHP (2.0 equiv), and AcOH (2.0 equiv) in 1.5 mL CH3CN solvent at 100 °C under microwave irradiation for 20 min.
aIsolated yields.
Next, the scope of this reaction with a variety of tertiary amines was investigated. As shown in Table 3, almost all linear alkyl tertiary amines with linear alkyl substituents, bearing α-H adjacent to the nitrogen atom, provided the desired products 4a–4d, 4f–4h, 4j, 4l, and 4m in 48–63 % yield. Furthermore, with the carbon chain of acyclic tertiary amines increasing, the yield of products decreased from 65 to 48 % (Table 2, 3a, and Table 3, 4a–4c). This might be attributed to the steric hindrance of tertiary amines. In addition to acyclic tertiary amines, cyclic amines could be used in this transformation. It was gratifying to find that N-methyl morpholine reacted exclusively at the exocyclic C–N bond to give cyclic amines 4e, 4i, and 4k in 61–65 % yield. Unfortunately, no product 4n formation was observed with triphenylamine as an amino group source, in which no C–H bond in the α-position of the nitrogen atom is contained, thus suggesting that α-H is essential for the C–H amination under these conditions. However, when N,N-dimethylaniline as an amino source was employed, no product 4o was obtained. Moreover, 2-(dimethylamino)ethanol with an unprotected hydroxyl group was not tolerated under the standard oxidizing reaction condition, no product 4p was produced.
Reaction conditions: 1 (0.25 mmol), tertiary amine 2 (0.75 mmol), TBAI (10 mol%), TBHP (2.0 equiv), and AcOH (2.0 equiv) in 1.5 mL of CH3CN at 100 °C under microwave irradiation for 20 min.
aIsolated yields.
The bulky N,N-dimethyl-1-phenylmethanamine containing two kinds of α-H afforded two types of products (Table 4), 5 and 3, with an almost 4:3 ratio, which indicated that the C–N bond of II position is broken more easily than that of I position. This might be attributed to the fact that a sterically less hindered methyl group is much more facile for cleavage.
Reaction conditions: 1 (0.25 mmol), N,N-dimethyl-1-phenylmethanamine 2i (0.75 mmol), TBAI (10 mol%), TBHP (2.0 equiv), and AcOH (2.0 equiv) in 1.5 mL of CH3CN solvent at 100 °C under microwave irradiation for 20 min.
aIsolated yields.
To gain an insight into the reaction mechanism, the following control experiments were performed under the standard reaction conditions. First, benzoxazole reacted with dimethylamine under the standard reaction conditions, and N,N-dimethyl-benzoxazol-2-amine 3a was produced successfully, which indicated that dimethylamine was an important intermediate for the reaction of benzoxazole with trimethylamine. Meanwhile, when the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-N-oxyl) was added to the reaction system, the reaction was inhibited (Scheme 2, Eq. b), which implies that the reaction presumably proceeds via a radical intermediate.
On the basis of the above results and previous reports [35–37], a plausible mechanism for this reaction is illustrated in Scheme 3. Initially, the tert-butoxyl and tert-butylperoxyl radicals were formed by the promotion of TBAI through I2-I− redox process. The generated tert-butoxy radical abstracts an α-H adjacent to the nitrogen atom of trimethylamine to afford radical I, followed by a single electron transfer oxidation to give an iminium intermediate II. Subsequently, the secondary amine IV is generated by hydrolysis of II through III. In the presence of AcOH, benzoxazole is protonated to form the reactive intermediate V. Then, the secondary amine IV immediately combines with the reactive intermediate V, leading to the intermediate VI. Finally, the desired amide product is produced through an oxidation process of the intermediate VI.
3 Conclusion
We have developed a mild, efficient, and green nBu4NI-catalyzed direct oxidative amination of benzoxazole with tertiary amines to form a 2-aminobenzoxazole derivative under microwave radiation. A wide range of benzoxazole derivatives containing electron-donating and electron-withdrawing groups were coupled with various tertiary amines, which included linear and cyclic amines. The present method constitutes a user-friendly and environmentally benign reaction for C–N bond formation of benzoxazoles.
4 Experimental section
4.1 General
Anhydrous solvents were obtained by standard procedure. All substrates were purchased from J & K Scientific Ltd. and were used without further purification. Column chromatography was performed using 200–300 mesh silica with the indicated solvent system according to standard techniques. Analytical thin-layer chromatography was performed on precoated, glass-backed silica gel plates. Visualization of the developed chromatogram was performed by UV absorbance (254 or 365 nm). Nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance 400-MHz spectrometer. Chemical shifts for 1H NMR spectra are recorded in parts per million from tetramethylsilane. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, and br = broad), coupling constants in hertz and integration. Chemical shifts for 13C NMR spectra were recorded in parts per million from tetramethylsilane. High-resolution mass spectra (HRMS) were obtained on a Q-TOF instrument using the ESI technique. IR spectra were recorded on a Shimadazu IR-408 Fourier transform infrared spectrophotometer using a thin film supported on KBr pellets. Melting points were measured on an XT4A microscopic apparatus and are uncorrected.
4.2 General procedure for the synthesis of benzoxazol-2-amine derivatives
Benzoxazole 1 (0.25 mmol), tertiary amines 2 (0.75 mmol), TBAI (0.025 mmol, 10 mg), TBHP (70 % aqueous solution, 0.5 mmol), and AcOH (0.5 mmol, 30 mg) in CH3CN (1.5 mL) were added to a 5-mL microwave reaction tube. The reaction mixture was put into a microwave reactor at 100 °C for 20 min. After completion of the reaction, the mixture was quenched by addition of a saturated solution of sodium disulfite (1.0 mL) and a saturated solution of sodium hydrogen carbonate (2.0 mL). Then the mixture was extracted with ethyl acetate (3 × 5 mL), combined organic phases were dried over anhydrous Na2SO4, and the organic solvent was removed under vacuum. The crude residue was purified by chromatography on a silica gel column using ethyl acetate-petroleum ether (1:5 to 2:1) as eluant to obtain the desired product.
4.2.1 N,N-dimethylbenzo[d]oxazol-2-amine (3a)
Orange solid; m.p. 83–84 °C (from chloroform; lit. [23]: 80–82 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.35 (dd, J = 7.8 Hz, J = 0.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 6.98 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 3.17 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.1, 149.1, 143.6, 123.8 (CH), 120.2 (CH), 115.9 (CH), 108.6 (CH), 37.7 (CH3). – MS ((+)-ESI): m/z = 163.3 (calcd. 163.1 for C9H11N2O, [M+H]+).
4.2.2 N,N,5-trimethylbenzo[d]oxazol-2-amine (3b)
Light orange solid; m.p. 70–71 °C (from chloroform; lit. [23]: 68–70 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.15 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 8.1 Hz, J = 0.8 Hz, 1H), 3.16 (s, 6H), 2.37 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.2, 147.2, 143.7, 133.5, 120.8 (CH), 116.4 (CH), 107.9 (CH), 37.6 (CH3), 21.5 (CH3). – MS ((+)-ESI): m/z = 177.2 (calcd. 177.1 for C10H13N2O, [M+H]+).
4.2.3 5-(tert-Butyl)-N,N-dimethylbenzo[d]oxazol- 2-amine (3c)
Colorless solid; m.p. 68–69 °C (from chloroform; lit. [20]: 70–72 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.42 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 3.16 (s, 6H), 1.33 (s, 9H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.3, 147.3, 147.0, 143.3, 117.3 (CH), 113.2 (CH), 107.6 (CH), 37.6 (CH3), 34.7, 31.8 (CH3). – MS ((+)-ESI): m/z = 219.3 (calcd. 219.1 for C13H19N2O, [M+H]+).
4.2.4 5-Chloro-N,N-dimethylbenzo[d]oxazol-2-amine (3d)
White solid; m.p. 84–85 °C (from chloroform; lit. [23]: 83–85 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.29 (d, J = 2.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4, J = 2.1 Hz, 1H), 3.18 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.7, 147.7, 145.0, 129.1, 119.9 (CH), 116.0 (CH), 109.0 (CH), 37.6 (CH3). – MS ((+)-ESI): m/z = 197.2 (calcd. 197.0 for C9H10ClN2O, [M+H]+).
4.2.5 N,N-dimethyl-5-nitrobenzo[d]oxazol-2-amine (3e)
Yellow solid; m.p. 168–170 °C (from chloroform; lit. [23]: 166–168 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 8.12 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.4 Hz, J = 2.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.23 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 164.4, 153.0, 145.0, 144.5, 116.7 (CH), 111.3 (CH), 109.0 (CH), 37.6 (CH3). – MS ((+)-ESI): m/z = 208.2 (calcd. 208.1 for C9H10N3O3, [M+H]+).
4.2.6 N,N-diethylbenzo[d]oxazol-2-amine (4a) [13]
Colorless liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.35 (dd, J = 7.8 Hz, J = 0.6 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 6.98 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 3.58 (q, J = 7.1 Hz, 4H), 1.28 (t, J = 7.1 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.2, 148.8, 143.6, 123.8 (CH), 119.9 (CH), 115.8 (CH), 108.5 (CH), 42.9 (CH2), 13.5 (CH3). – MS ((+)-ESI): m/z = 191.3 (calcd. 191.1 for C11H15N2O, [M+H]+).
4.2.7 N,N-dipropylbenzo[d]oxazol-2-amine (4b) [13]
Light yellow liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.34 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.13 (td, J = 7.8 Hz, J = 1.0 Hz, 1H), 6.97 (td, J = 7.8 Hz, J = 1.0 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 1.71 (m, 4H), 0.96 (t, J = 7.6 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.7, 148.7, 143.7, 123.7 (CH), 119.9 (CH), 115.8 (CH), 108.5 (CH), 50.3 (CH2), 21.2 (CH2), 11.2 (CH3). – MS ((+)-ESI): m/z = 219.3 (calcd. 219.1 for C13H19N2O, [M+H]+).
4.2.8 N,N-dibutylbenzo[d]oxazol-2-amine (4c) [13]
Light yellow liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.34 (dd, J = 7.8 Hz, J = 0.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.13 (td, J = 7.8 Hz, J = 1.1 Hz, 1H), 6.97 (td, J = 7.8 Hz, J = 1.1 Hz, 1H), 3.50 (t, J = 7.5 Hz, 4H), 1.66 (m, 4H), 1.37 (m, 4H), 0.96 (t, J = 7.5 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.7, 148.7, 143.7, 123.7 (CH), 119.8 (CH), 115.8 (CH), 108.5 (CH), 48.3 (CH2), 30.1 (CH2), 20.0 (CH2), 13.9 (CH3). – MS ((+)-ESI): m/z = 247.1 (calcd. 247.2 for C15H23N2O, [M+H]+).
4.2.9 N-cyclohexyl-N-methylbenzo[d]oxazol-2- amine (4d) [38]
Yellow viscous liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.34 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.13 (td, J = 7.8 Hz, J = 0.9 Hz, 1H), 6.97 (td, J = 7.8 Hz, J = 0.9 Hz, 1H), 4.17–4.09 (m, 1H), 3.06 (s, 3H), 1.87–1.82 (m, 4H), 1.70 (d, J = 13.0 Hz, 1H), 1.68–1.42 (m, 4H), 1.18–1.13 (m, 1H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.7, 148.7, 143.6, 123.8 (CH), 119.9 (CH), 115.8 (CH), 108.5 (CH), 56.7 (CH), 29.9 (CH2), 29.5 (CH), 25.6 (CH2), 25.5 (CH2). – MS ((+)-ESI): m/z = 231.2 (calcd. 231.1 for C14H19N2O, [M+H]+).
4.2.10 2-Morpholinobenzo[d]oxazole (4e)
Pale yellow solid; m.p. 91–92 °C (from chloroform; lit. [28]: 90–94 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.37 (dd, J = 7.8 Hz, J = 0.6 Hz, 1H), 7.27 (d, J = 6.4 Hz, 1H), 7.18 (td, J = 7.8 Hz, J = 1.0 Hz, 1H), 7.04 (td, J = 7.8 Hz, J = 1.0 Hz, 1H), 3.83–3.81 (m, 4H), 3.70–3.68 (m, 4H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.1, 148.7, 142.8, 124.0 (CH), 120.9 (CH), 116.5 (CH), 108.8 (CH), 66.2 (CH2), 45.7 (CH2). – MS ((+)-ESI): m/z = 205.2 (calcd. 205.0 for C11H13N2O2, [M+H]+).
4.2.11 N,N-diethyl-5-methylbenzo[d]oxazol-2-amine (4f) [20]
Yellow viscous liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 8.0 Hz, J = 0.9 Hz, 1H), 3.57 (q, J = 7.1 Hz, 4H), 2.38 (s, 3H), 1.27 (t, J = 7.1 Hz, 4H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.4, 146.9, 143.7, 133.4, 120.5 (CH), 116.2 (CH), 107.8 (CH), 42.9 (CH2), 21.5 (CH3), 13.5 (CH3). – MS ((+)-ESI): m/z = 205.2 (calcd. 205.1 for C12H17N2O, [M+H]+).
4.2.12 5-Methyl-N,N-dipropylbenzo[d]oxazol-2- amine (4g)
Colorless solid; m.p. 39–40 °C (from chloroform; lit. [13]: 38–40 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 3.46 (t, J = 7.4 Hz, 4H), 2.38 (s, 6H), 1.75–1.65 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.9, 146.9, 143.9, 133.4, 120.5 (CH), 116.2 (CH), 107.8 (CH), 50.3 (CH2), 21.5 (CH3), 21.2 (CH2), 11.2 (CH3). – MS ((+)-ESI): m/z = 233.3 (calcd. 233.1 for C14H21N2O, [M+H]+).
4.2.13 N,N-dibutyl-5-methylbenzo[d]oxazol-2- amine (4h)
Colorless solid; m.p. 60–61 °C (from chloroform; lit. [13]: 58–60 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.14 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 2.37 (s, 3H), 1.68–1.60 (m, 4H), 1.42–1.32 (m, 4H), 0.95 (t, J = 7.6 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.8, 146.9, 143.8, 133.3, 120.4 (CH), 116.2 (CH), 107.8 (CH), 48.3 (CH2), 30.2 (CH2), 21.5 (CH3), 20.0 (CH2), 13.9 (CH3). – MS ((+)-ESI): m/z = 261.3 (calcd. 261.1 for C16H25N2O, [M+H]+).
4.2.14 5-Methyl-2-morpholinobenzo[d]oxazole (4i)
White solid; m.p. 120–121 °C (from chloroform; lit. [24]: 119–122 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.16 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.82–3.80 (m, 4H), 3.68–3.66 (m, 4H), 2.39 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.2, 146.9, 142.9, 133.7, 121.6 (CH), 116.8 (CH), 108.1 (CH), 66.2 (CH2), 45.7 (CH2), 21.5 (CH3). – MS ((+)-ESI): m/z = 219.3 (calcd. 219.1 for C12H15N2O2, [M+H]+).
4.2.15 5-(tert-Butyl)-N,N-dibutylbenzo[d]oxazol-2- amine (4j) [13]
Colorless viscous liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.42 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 3.49 (t, J = 7.5 Hz, 4H), 1.68–1.61 (m, 4H), 1.41–1.36 (m, 4H), 1.33 (s, 9H), 0.95 (t, J = 7.5 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.9, 147.1, 146.7, 143.5, 116.9 (CH), 112.9 (CH), 107.5 (CH), 48.3 (CH2), 34.7, 31.8 (CH3), 30.1 (CH2), 20.0 (CH2), 13.9 (CH3). – MS ((+)-ESI): m/z = 303.3 (calcd. 303.2 for C19H31N2O, [M+H]+).
4.2.16 5-(tert-Butyl)-2-morpholinobenzo[d]oxazole (4k) [39]
Colorless solid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.43 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.81 (t, J = 4.6 Hz, 4H), 3.67 (t, J = 4.6 Hz, 4H), 1.34 (s, 9H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.3, 147.5, 146.7, 142.6, 118.1 (CH), 113.6 (CH), 107.9 (CH), 66.2 (CH2), 45.8 (CH2), 34.8, 31.7 (CH3). – MS ((+)-ESI): m/z = 261.3 (calcd. 261.2 for C15H21N2O2, [M+H]+).
4.2.17 5-Chloro-N,N-diethylbenzo[d]oxazol-2-amine (4l) [24]
Yellow liquid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.29 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 3.57 (q, J = 7.1 Hz, 4H), 1.28 (t, J = 7.1 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 162.9, 147.5, 145.0, 129.1, 119.7 (CH), 115.9 (CH), 108.9 (CH), 43.0 (CH2), 13.4 (CH3). – MS ((+)-ESI): m/z = 225.2 (calcd. 225.1 for C11H14ClN2O, [M+H]+).
4.2.18 N,N-dibutyl-5-chlorobenzo[d]oxazol-2-amine (4m)
White solid; m.p. 63–65 °C (from chloroform; lit. [13]: 60–61 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.29 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 3.49 (t, J = 7.5 Hz, 4H), 1.69–1.61 (m, 4H), 1.42–1.33 (m, 4H), 0.96 (t, J = 7.5 Hz, 6H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.3, 147.4, 129.0, 119.6 (CH), 115.8 (CH), 108.9 (CH), 48.4 (CH2), 30.0 (CH2), 19.9 (CH2), 13.9 (CH3). – MS ((+)-ESI): m/z = 281.2 (calcd. for C15H22N2O, [M+H]+).
4.2.19 N-benzyl-N-methylbenzo[d]oxazol-2-amine (5a)
White solid; m.p. 52–53 °C (from chloroform; lit. [28]: 50–54 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.45 (d, J = 7.8 Hz, 1H), 7.39–7.29 (m, 6H), 7.21 (td, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.05 (td, J = 7.8 Hz, J = 1.1 Hz, 1H), 4.77 (s, 2H), 3.15 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.0, 149.0, 143.5, 136.5, 128.8 (CH), 127.8 (CH), 127.7 (CH), 124.0 (CH), 120.4 (CH), 116.2 (CH), 108.8 (CH), 53.9 (CH2), 35.2 (CH3). – MS ((+)-ESI): m/z = 239.3 (calcd. 239.1 for C15H15N2O, [M+H]+).
4.2.20 N-benzyl-N,5-dimethylbenzo[d]oxazol-2- amine (5b)
White solid; m.p. 51–52 °C (from chloroform; lit. [13]: 50–51 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.39–7.31 (m, 5H), 7.21 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.77 (s, 2H), 3.15 (s, 3H), 2.43 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.2, 147.2, 143.6, 136.5, 133.6, 128.7 (CH), 127.7 (CH), 127.6 (CH), 121.0 (CH), 116.5 (CH), 108.1 (CH), 53.8 (CH2), 35.2 (CH3), 21.6 (CH3). – MS ((+)-ESI): m/z = 253.3 (calcd. 253.1 for C16H17N2O, [M+H]+).
4.2.21 N-benzyl-5-(tert-butyl)-N-methylbenzo[d]oxazol-2-amine (5c)
Colorless solid. – 1H NMR (400.13 MHz, CDCl3): δ = 7.55 (s, 1H), 7.38–7.31 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.4 Hz, J = 2.3 Hz, 1H), 4.77 (s, 2H), 3.14 (s, 3H), 1.41 (s, 9H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.2, 147.4, 147.0, 143.4, 136.5, 128.7 (CH), 127.7 (CH), 127.6 (CH), 117.6 (CH), 113.3 (CH), 107.8 (CH), 53.8 (CH2), 35.1 (CH3), 34.8, 31.9 (CH3). – HRMS ((+)-ESI): m/z = 295.1807 (calcd. 295.1805 for C19H23N2O, [M+H]+).
4.2.22 N-benzyl-5-chloro-N-methylbenzo[d]oxazol-2-amine (5d)
Pale brown solid, mp 71–72 °C (from chloroform; lit. [40]: 69–70 °C). – 1H NMR (400.13 MHz, CDCl3): δ = 7.35–7.25 (m, 6H), 7.15 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.4 Hz, J = 2.5 Hz, 1H), 4.74 (s, 2H), 3.12 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 163.7, 147.6, 144.9, 136.1, 129.3, 128.8 (CH), 127.8 (CH), 127.6 (CH), 120.1 (CH), 116.2 (CH), 109.1 (CH), 53.8 (CH2), 35.2 (CH3). – MS ((+)-ESI): m/z = 273.3 (calcd. 273.1 for C15H14ClN2O, [M+H]+).
4.2.23 N-benzyl-N-methyl-5-nitrobenzo[d]oxazol- 2-amine (5e)
Colorless solid. – 1H NMR (400.13 MHz, CDCl3): δ = 8.19 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 7.39–7.26 (m, 6H), 4.78 (s, 2H), 3.17 (s, 3H). – 13C NMR (100.61 MHz, CDCl3): δ = 164.5, 152.9, 145.2, 144.5, 135.6, 128.9 (CH), 128.1 (CH), 127.7 (CH), 116.9 (CH), 111.6 (CH), 108.3 (CH), 54.0 (CH2), 35.2 (CH3). – HRMS ((+)-ESI): m/z = 284.1032 (calcd. 284.1030 for C15H14N3O3, [M+H]+).
5 Supporting information
1H NMR and 13C NMR spectra of 3a–3e, 4a–4m, and 5a–5e are given as supporting information available online (DOI: 10.1515/znb-2015-0212).
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 21172055 and 21302042), Natural Science foundation of Henan Scientific Committee (No. 142102210410), Natural Science Foundation of Henan Educational Committee (No. 14B150053), the Program for Innovative Research Team from Zhengzhou (No. 131PCXTD605), and Scientific Fund Project of Zhengzhou Science and Technology Bureau (No. 20130883).
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