Copper-Catalyzed Direct Oxidative C–H Amination of Benzoxazoles

NOTE pubs.acs.org/joc

Copper-Catalyzed Direct Oxidative C
H Amination of Benzoxazoles with Formamides or Secondary Amines under Mild Conditions Yaming Li,* Yusheng Xie, Rong Zhang, Kun Jin, Xiuna Wang, and Chunying Duan* State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, P. R. China

bS Supporting Information ABSTRACT: A facile, efficient, and practical method for copper-catalyzed direct C
H amination of benzoxazoles with formamides or secondary amines has been developed. The system can be performed in the absence of external base and only requires O2 or even air as oxidant. A variety of substituted benzoxazol-2-amines were synthesized with moderate to excellent yield.

T

he transition-metal-catalyzed selective C
N bond formation reaction of azoles is a highly important transformation in synthetic chemistry since five-membered heterocycles with amine group are widely employed in biological, pharmaceutical, and material sciences.1 Classically, methods to synthesize this skeleton include cyclocondensation reactions from two functionalized precursors (e.g., Hantszch aminothiazole synthesis),2 palladium-catalyzed Buchwald
Hartwig coupling,3 and coppercatalyzed Ullmann and Goldberg couplings.4 Although significant advances have been achieved, still there are some disadvantages, such as high temperature, long reaction time, poisonous ligands, and noneconomic effects. To find greener and more efficient methods, direct C
H amination of heteroarenes has been reported successively.5,6 For example, Mori7a and Schreiber7b independently provided a copper-catalyzed access to the heteroarylamines in the presence of ligand (Scheme 1A, a). Miura7c successfully developed a copper-catalyzed amination of azoles using chloroamines instead of the parent amines, albeit with the use of the strong base NaO-t-Bu (Scheme 1A, b). Recently, Chang8 reported a new and efficient access to C
H amination of azoles with stoichiometric amounts of a silver species and acid as additive (Scheme 1A, c). During the preparation of this manuscript, Chang9 reported the Co-catalyzed amination of azoles and the use of tert-butyl hydroperoxide as oxidant (Scheme 1A, d). On the basis of the above excellent works and our previous studies on the copper-catalyzed aminations,10 we describe herein our successful copper catalyst systems with O2 as oxidant, which can construct the C
N bond of azoles efficiently either by decarboxylative coupling with formamides or by a direct C
H amination protocol with secondary amines under mild reaction conditions (Scheme 1B). As it is known that Cu(II) can oxidate Pd(0) to Pd(II) and O2 can oxidate Cu(I) to Cu(II), we attempted to use Pd(II)/ Cu(II)/O2 as a catalytic system for direct C
H amination of azoles. When the C
H amination of benzoxazole with DMF as a nitrogen source was chosen as a model reaction, only 20% yield r 2011 American Chemical Society

Scheme 1. Transition-Metal-Mediated Amination

of the amination product of benzoxazole was obtained (Table 1, entry 1). On the other hand, when Cu(OAc)2 3 H2O was employed as catalyst, the yield was enhanced to 73% (Table 1, entry 2). Subsequent studies revealed that the amination proceeded smoothly with high yields even without Pd(OAc)2 (Table 1, entries 2 and 3), which indicated that Pd(OAc)2 has almost no effect on the reaction. Acid is essential since only 15% yield was obtained without addition of acid (Table 1, entry 12). Among different acids, (4-NO2)PhCO2H and PhCO2H were demonstrated to be better than other acids (Table 1, entries 6
11). The catalyst Cu(OAc)2 3 H2O and oxidant O2 are crucial for the amination reaction, which would not take place without Received: March 1, 2011 Published: May 27, 2011 5444

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The Journal of Organic Chemistry

NOTE

Table 1. Optimization of Reaction Conditions with Amide and Azolea

entry

cat. (equiv)

oxidant

yieldb (%)

1

Pd(OAc)2 (0.02), CuBr2 (0.4)

PhCO2H (5)

air

20

2

Pd(OAc)2 (0.02), Cu(OAc)2 3 H2O (0.4)

PhCO2H (5)

air

73

3

Cu(OAc)2 3 H2O (0.4)

PhCO2H (5)

air

73

4

Cu(OAc)2 3 H2O (0.4)

PhCO2H (5)

O2

79

5

Cu(OAc)2 3 H2O (0.2)

PhCO2H (5)

O2

76

6 7

Cu(OAc)2 3 H2O (0.2) Cu(OAc)2 3 H2O (0.2)

PhCO2H (2) (4-OH)PhCO2H (2)

O2 O2

70 15

8

Cu(OAc)2 3 H2O (0.2)

(4-CH3O)PhCO2H (2)

O2

60

9

Cu(OAc)2 3 H2O (0.2)

(4-NO2)PhCO2H (2)

O2

70

10

Cu(OAc)2 3 H2O (0.2)

2-PyCO2H (2)

O2

nd

11

Cu(OAc)2 3 H2O (0.2)

L-proline

O2

nd

12

Cu(OAc)2 3 H2O (0.2)

13 14 a

acid (equiv)

Cu(OAc)2 3 H2O (0.2)

(2)

O2

15

PhCO2H (2)

O2

nd

PhCO2H (2)

N2

trace

Reaction conditions: With 1 (0.5 mmol) and 2 (2 mL), O2 balloon, 130 °C, 12 h. b Isolated yield.

Cu(OAc)2 3 H2O or oxidant O2 (Table 1, entries 13 and 14). Through the optimization of the reaction conditions, the best condition is PhCO2H (5 equiv)/Cu(OAc)2 3 H2O (40 mol %)/ O2 (Table 1, entry 4). While from the viewpoint of economy and practicality of the catalyst and oxidant in laboratory synthesis and industrial applications, we chose Cu(OAc)2 3 H2O (20 mol %) and PhCO2H (2 equiv) and O2 as optimized conditions. Under the optimized reaction conditions, we investigated the substrate scope of benzoxazoles in the decarbonylative amination with amides (Scheme 2). A range of azole derivatives were obtained with moderate yields. First, DMF reacted with benzoxazole slightly easier than the N,N-diethylformamide. Second, it was obvious that benzoxazoles bearing electron-donating groups, such as methyl and tert-butyl could react much easier than those bearing electron-withdrawing groups, such as 5-chloro (Scheme 2, 4b
d,g
i). Oxazolo[4,5-b]pyridine even failed to react with formamide or acetamide (Scheme 2, 4e or 4j), which indicated that there may be a balance between the acidity at position 2 of azoles and the ability to coordinate with copper. Lastly, when N,N-dimethylacetamide instead of DMF was subjected to reaction with benzoxazole under the reaction conditions, the N,N-dimethyl-2-aminobenzoxazole product was obtained in 30% yield, indicating that deacetylation is feasible under the reaction conditions. On the basis of the results of reactions of benzoxazoles with amides, we believed that amines may directly react with azoles under low temperature, since decarbonylation releases amine from amide at high temperature.8 After benzoxazole reacted with di-n-butylamine at 70 °C for 12 h, the desired product was obtained in a high GC yield of 89% (Table 2, entry 1) under conditions of Cu(OAc)2 3 H2O (20 mol %), PhCO2H (2equiv), and O2 as oxidant. Other copper salts, CuBr2 and CuCl2 3 H2O, were less effective than Cu(OAc)2 3 H2O (Table 2, entries 1
3), which agreed with the basicity of the anion of the copper salt. Addition of CH3CO2H instead of PhCO2H enhanced the GC yields from 89% to 96% (Table 2, entries 1 and 4), while under

Scheme 2. Copper-Catalyzed Direct C
H Amination of Azoles with Amides*

* Reaction conditions: azoles (0.5 mmol), amides (2 mL), Cu(OAc)2 3 H2O (20 mol %), PhCO2H (2 equiv), O2 balloon, 130 °C, 12 h. a Isolated yield in parentheses. b N,N-Dimethylacetamide as nitrogen source and solvent.

the CH3CO2Na conditions the desired product was only obtained in 54% GC yield (Table 2, entry 5). For the reaction of benzoxazole with formamide, without addition of acid, the amination yield decreased from 70% to 15%, while for the reaction of benzoxazole with di-n-butylamine, without addition of acid, the yield decreased from 96% to 83% (Table 2, entries 4 and 7). This implied that the reaction process may be a coppercatalyzed C
H activation pathway other than the process of nucleophilic attack of amine to the intermediate of the protonated azole (Scheme 5). Either copper source or oxidant O2 plays a crucial role in the reaction process since without copper source 5445

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The Journal of Organic Chemistry

NOTE

Table 2. Optimization of Reaction Conditions of Dibutylamine and Azolea

entry

additive (equiv)

oxidant

yieldb (%)

1

PhCO2H (2)

Cu(OAc)2 3 H2O (0.2)

O2

89

2

PhCO2H (2)

CuBr2 (0.2)

O2

80

3 4

PhCO2H (2) CH3CO2H (2)

CuCl2 3 H2O (0.2) Cu(OAc)2 3 H2O (0.2)

O2 O2

84 96

5

CH3CO2Na (2)

Cu(OAc)2 3 H2O (0.2)

O2

54

6

CH3CO2H (2)

Cu(OAc)2 (0.2)

O2

95

Cu(OAc)2 3 H2O (0.2)

O2

83

7

a

cat. (equiv)

8

CH3CO2H (2)

9

CH3CO2H (2)

Cu(OAc)2 3 H2O (0.2)

O2

8

N2

23

Scheme 3. Substrate Scope of Amines*

Reaction conditions: With 1 (0.5 mmol), 3 (0.6 mmol), CH3CN (2 mL), 70 °C, 12 h. b GC yield.

or O2 the desired product yields decreased from 96% to 8% or from 96% to 23%, respectively (Table 2, entries 8 and 9). Under the optimized reaction conditions, a variety of amines were tested for the direct amination of benzoxazole (Scheme 3, 4f, 5a
k). The reactions of morpholine, piperidine, di-n-butylamine, 4-methylpiperdine, and diethylamine with benzoxazole proceeded smoothly to yield the desired products 5a
d and 4f in good yields (55
85%). Pyrrolidine gave the corresponding functionalized amine product 5e in a yield of 45% because ofthe steric hindrance of five-membered ring. Regretfully, diallylamine afforded the product 5h only in 20% GC yield, which may be caused by the lower nucleophilicity of diallylamine. Notably, unsymmetrical amines such as N-methylbenzylamine and N-methyl-2-chlorobenzylamine gave the products 5f and 5g in yields of 65% and 57%, respectively. In sharp contrast to the above results of secondary aliphatic amines, no desired products were obtained when either primary amines (e.g., 5i, 5j) or aromatic amine (e.g., 5k) were employed under the reaction conditions, which may be caused by decrease of nucleophilicity of amine, and related works are still underway in our group. Next, the scope of this reaction was investigated with respect to azole under the same conditions as those shown in Scheme 4 (5c, 6a
h). Benzoxazoles bearing the substituents at position 5 were aminated effectively in excellent yield (5c, 6a
c, e
f, 75
94% yield). It is also observed that electron-withdrawing groups attached to the position-5 of benzoxazole resulted in lower conversion, 5-chlorobenzoxazole yielded the desired products 6c and 6f in 76% and 75% yields, respectively. Oxazolo[4,5b]pyridine even gave the product 6d only in 48% yield. In contrast to benzoxazoles, benzothiazole or N-ethylbenzimidazole afforded the desired products 6g and 6h in 15% and 0% GC yield, respectively. The lower reactivity of those substrates observed here is may caused by their weaker acidity. The interesting experiment results obtained above could help us elucidate the mechanistic details of the present reaction. First, the role of acid in the reaction of benzoxazoles with amines is less important than that with amides, indicating that acid plays an important role in the release of amine from amides by decarbonylation other than C
H activation. Second, whether azoles reacted with amines or with amides, both Cu(OAc)2 3 H2O

*

Reaction conditions: benzoxazoles (0.5 mmol), amines (0.6 mmol), Cu(OAc)2 3 H2O (20 mol %), CH2CO2H (2 equiv), O2 balloon, solvent (2 mL), 70 °C, 12 h. a Isolated yield in parentheses. b GC yield.

Scheme 4. Substrate Scope of Azoles*

* Reaction conditions: azoles (0.5 mmol), amines (0.6 mmol), Cu(OAc)2 3 H2O (20 mol %), CH3CO2H (2 equiv), O2 balloon, CH2CN (2 mL), 70 °C, 12 h. a Isolated yield in parentheses. b GC yield.

catalyst and O2 oxidant were crucial, which was observed from the great diminishment of the desired product yield in the absence of copper source or O2. Third, it was also observed that electron-donating groups attached to azoles resulted in higher 5446

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The Journal of Organic Chemistry Scheme 5. Possible Mechanism for Copper-Catalyzed Direct C
H Amination of Azoles

conversion in the C
H amination reactions of azoles with amines or amides, which implied that there is a balance between the acidity at position 2 of azoles and the ability to coordinate with copper. Therefore, a plausible pathway similar to the reaction of tertiary amine reported by Huang11 can be proposed (Scheme 5). At the beginning of the reaction, the copper catalyst is oxidized by oxygen to form [LnCunþ1] composed of the copper salt and molecular oxygen.11,12 Then the copper species coordinates with the secondary amine and give the intermediate A by elimination of water assisted by CH3CO2H. Second, intermediate A coordinates to azole to give B, and its subsequent deprotonation/ rearrangement yields C and regenerates CH3CO2H. Lastly, C affords product by reductive elimination and regenerate the copper catalyst to complete the catalytic cycle.7b,c In conclusion, an efficient and copper-catalyzed direct C
H amination of azoles with amides or secondary amines as nitrogen group sources has been developed in good to excellent yields. The use of inexpensive copper catalyst and O2 even air as the oxidant is a green and significant practical advantage. This reaction can be performed in the absence of an external base at 70 °C. The present reaction provides a powerful tool for the synthesis of 2-aminoazole derivatives.

’ EXPERIMENTAL SECTION General Procedure for Copper-Catalyzed Amination of Benzoxazoles with Formamides. A dried Schlenk test tube containing a magnetic stirring bar was charged under air with benzoxazole (0.5 mmol), formamide (2 mL), Cu(OAc)2 3 H2O (20 mol %), and acid additive (2 equiv). Then O2 was introduced to the tube to form an O2 balloon, the tube was sealed, and the mixture was treated at 130 °C for 12 h. The resulting mixture was allowed to cool to room temperature, washed with a saturated solution of NaHCO3, and extracted with ethyl acetate three times. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with EtOAc/ petroleum (1/2
1/30) to provide the desired product.

NOTE

General Procedure for Copper-Catalyzed Direct Amination of Benzoxazoles with Secondary Amines. A dried Schlenk test tube containing a magnetic stirring bar was charged under air with benzoxazole (0.5 mmol), amine (0.6 mmol), Cu(OAc)2 3 H2O (20 mol %), CH3CO2H (2 equiv), and CH3CN (2 mL). Then the O2 was introduced to the tube to form an O2 balloon, the tube was sealed, and the mixture was treated at 70 °C for 12 h. The resulting mixture was allowed to cool to room temperature and washed with a saturated solution of NaHCO3, extracted with ethyl acetate for three times. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with EtOAc/petroleum (1/1
1/30) to provide the desired product. N,N-Dimethylbenzoxazol-2-amine8 (4a). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow solid: 70% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.18 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.0, 149.0, 143.3, 123.9, 120.3, 116.0, 108.7, 37.8; HRMS (ESI) calcd for C9H10N2O [M þ H]þ 163.0871, found 163.0867. N,N,5-Trimethylbenzoxazol-2-amine8 (4b). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a light yellow solid: 53% isolated yield; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.16 (s, 6H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.3, 147.3, 143.8, 133.5, 120.9, 116.5, 108.0, 37.7, 21.6; GC
MS (EI) m/z = 176 [M]þ. 5-tert-butyl-N,N-dimethylbenzoxazol-2-amine (4c). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow solid: 64% isolated yield; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.16 (s, 6H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.3, 147.3, 147.0, 143.3, 117.4, 113.2, 107.7, 37.7, 34.8, 31.8; HRMS (ESI) calcd for C13H18N2O [M þ H]þ 219.1497, found 219.1493; mp 70
72 °C. 5-Chloro-N,N-dimethylbenzoxazol-2-amine8 (4d). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow solid: 42% isolated yield; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.18 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.8, 147.7, 145.1, 129.2, 120.0, 116.1, 109.1, 37.7; GC
MS (EI) m/z = 196 [M]þ. N,N-Diethylbenzoxazol-2-amine11 (4f). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides and amines to give a yellow liquid in 52% and 84% isolated yield, respectively: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 3.55
3.60 (q, 4H), 1.27 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.0, 148.7, 143.5, 123.6, 119.8, 115.6, 108.4, 42.8, 13.4; GC
MS (EI) m/z = 190 [M]þ. 5-tert-Butyl-N,N-diethylbenzoxazol-2-amine (4g). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow liquid: 54% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.53
3.58 (q, 4H), 1.33 (s, 9H), 1.26 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.5, 147.2, 146.8, 143.4, 117.1, 113.0, 107.6, 43.0, 34.8, 31.9, 13.8; HRMS (ESI) calcd for C15H22N2O [M þ H]þ 247.1810, found 247.1805. N,N-Diethyl-5-methylbenzoxazol-2-amine (4h). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow liquid: 49% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.14 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.53
3.58 (q, 4H), 2.37 (s, 3H), 5447

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The Journal of Organic Chemistry 1.26 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.4, 147.0, 143.8, 133.4, 120.6, 116.3, 107.9, 43.0, 21.6, 13.8; HRMS (ESI) calcd for C12H16N2O [M þ H]þ 205.1341, found 205.1338. 5-Chloro-N,N-diethylbenzoxazol-2-amine (4i). The title compound was prepared according to the general procedure for amination of benzoxazoles with formamides to give a yellow liquid: 29% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.29 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.54
3.59 (q, 4H), 1.28 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.0, 147.5, 145.1, 129.1, 119.8, 115.9, 109.0, 43.0, 13.5; HRMS (ESI) calcd for C11H13ClN2O [M þ H]þ 225.0795, found 225.0788. 2-Morpholinobenzoxazole7c (5a). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 55% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.38 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 3.81 (t, J = 4.4 Hz, 4H), 3.68 (t, J = 4.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.1, 148.8, 142.9, 124.2, 121.0, 116.6, 108.9, 66.3, 45.8; HRMS (ESI) calcd for C11H12N2O2 [M þ H]þ 205.0977, found 205.0977. 2-(Piperidin-1-yl)benzoxazole7c (5b). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 84% isolated yield; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.34 (d, j = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 3.61
3.62 (m, 4H), 1.63 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.3, 148.6, 143.3, 123.7, 120.2, 115.9, 108.5, 46.5, 25.1, 24.0; GC
MS (EI) m/z = 202 [M]þ. N,N-Dibutylbenzoxazol-2-amine7c (5c). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow liquid: 85% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 3.46
3.50 (t, 4H), 1.60
1.68 (m, 4H), 1.32
1.41 (m, 4H), 0.95 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.6, 148.7, 143.7, 123.7, 119.8, 115.7, 108.4, 48.3, 30.1, 20.0, 13.8; GC
MS (EI) m/z = 246 [M]þ. 2-(4-Methylpiperdin-1-yl)benzoxazole (5d). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a white solid: 83% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.34 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 4.25 (d, J = 13.2 Hz, 2H), 3.02 (t, J = 12 Hz, 2H), 1.71 (d, J = 12.8 Hz, 2H), 1.57
1.60 (m, 1H), 1.19
1.30 (m, 2H), 0.96 (d, j = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.4, 148.7, 143.4, 123.8, 120.2, 116.0, 108.5, 46.0, 33.6, 21.8; HRMS (ESI) calcd for C13H16N2O [M þ H]þ 217.1341, found 217.1340; mp 65
67 °C. 2-(Pyrrolidin-1-yl)benzoxazole13 (5e). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a white solid: 45% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 3.64 (t, J = 6.4 Hz, 4H), 2.02 (t, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 161.1, 149.1, 143.7, 123.9, 120.1, 116.0, 108.6, 47.5, 25.7; GC
MS (EI) m/z = 188 [M]þ. N-Benzyl-N-methylbenzoxazol-2-amine13 (5f). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 65% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.39 (d, J = 7.6 Hz, 1H), 7.23
7.34 (m, 6H), 7.17 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 4.74 (s, 2H), 3.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.0, 149.0, 143.6, 136.5, 128.8, 127.8, 127.7, 124.0, 120.5, 116.2, 108.8, 53.9, 35.2; GC
MS (EI) m/z = 238 [M]þ. N-(2-Chorobenzyl)-N-methylbenzoxazol-2-amine (5g). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 57%

NOTE

isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37
7.39 (m, 2H), 7.14
7.26 (m, 5H), 7.01 (t, J = 8.0 Hz, 1H), 4.87 (s, 2H), 3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.9, 149.1, 143.5, 134.0, 133.5, 129.8, 128.9, 128.4, 127.2, 124.1, 120.6, 116.3, 108.9, 51.4, 35.8; HRMS (ESI) calcd for C15H13ClN2O [M þ H]þ 273.0795, found 273.0798; mp 82
84 °C. N,N-Dibutyl-5-methylbenzoxazol-2-amine (6a). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a white solid: 94% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.15 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 2.37 (s, 3H), 1.60
1.67 (m, 4H), 1.32
1.41 (m, 4H), 0.95 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.8, 146.9, 143.9, 133.2, 120.4, 116.2, 107.8, 48.3, 30.1, 21.5, 20.0, 13.9; HRMS (ESI) calcd for C16H24N2O [M þ H]þ 261.1967, found 261.1969; mp 73
75 °C. 5-tert-Butyl-N,N-dibutylbenzoxazol-2-amine (6b). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow liquid: 84% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.49 (t, J = 7.2 Hz, 4H), 1.61
1.68 (m, 4H), 1.33
1.40 (m, 13H), 0.95 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.9, 147.1, 146.7, 143.5, 116.9, 113.0, 107.5, 48.3, 34.8, 31.9, 30.2, 20.0, 13.9; HRMS (ESI) calcd for C19H30N2O [M þ H]þ 303.2436, found 303.2444. N,N-Dibutyl-5-chlorobenzoxazol-2-amine (6c). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 76% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), 1.60
1.68 (m, 4H), 1.32
1.41 (m, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.4, 147.4, 145.2, 129.0, 119.6, 115.8, 108.9, 48.4, 30.1, 20.0, 13.9; HRMS (ESI) calcd for C15H21ClN2O [M þ H]þ 281.1421, found 281.1425; mp 63
65 °C. N,N-Dibutyloxazolo[4,5-b]pyridin-2-amine (6d). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow liquid: 48% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.19 (S, 1H), 7.39 (d, J = 7.6 Hz, 1H), 6.84
6.87 (m, 1H), 3.54 (t, J = 7.2 Hz, 4H), 1.64
1.71 (m, 4H), 1.33
1.43 (m, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 164.1, 158.8, 144.4, 141.4, 115.0, 114.4, 48.5, 30.1, 20.0, 13.9; HRMS (ESI) calcd for C14H21N3O [M þ H]þ 248.1763, found 248.1764. N-Benzyl-N,5-dimethylbenzoxazol-2-amine (6e). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 78% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.25
7.32 (m, 5H), 7.18 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 3.08 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.1, 147.2, 143.7, 136.5, 133.6, 128.7, 127.7, 127.6, 121.0, 116.6, 108.1, 53.8, 35.1, 21.6; HRMS (ESI) calcd for C16H16N2O [M þ 1] 253.1341, found 253.1342; mp 55
57 °C. N-Benzyl-5-chloro-N-methylbenzoxazol-2-amine14 (6f). The title compound was prepared according to the general procedure for direct amination of benzoxazoles with amines to give a yellow solid: 75% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.26
7.32 (m, 6H), 7.12 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.70 (s, 2H), 3.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.7, 147.6, 145.0, 136.1, 129.2, 128.8, 127.9, 127.7, 120.1, 116.2, 109.2, 53.8, 35.1; HRMS (ESI) calcd for C15H13ClN2O [M þ H]þ 273.0795, found 273.0793. 5-Methylbenzoxazole: light yellow solid; 62% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (s, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 152.5, 148.0, 140.1, 134.1, 126.5, 120.2, 110.0, 21.2; GC
MS (EI) m/z = 133 [M]þ. 5448

dx.doi.org/10.1021/jo200447x |J. Org. Chem. 2011, 76, 5444–5449

The Journal of Organic Chemistry 5-tert-Butylbenzoxazole: yellow liquid; 94% isolated yield; 1H NMR (400 MHz, CDCl3) yellow liquid δ (ppm) 8.06 (s, 1H), 7.81 (s, 1H), 7.43
7.50 (m, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 152.7, 148.2, 148.1, 140.0, 123.5, 117.1, 110.1, 35.0, 31.9; GC
MS (EI) m/z = 175 [M]þ. 5-Chlorobenzoxazole: light yellow solid; 53% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.12 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 153.8, 148.6, 141.2, 130.2, 126.1, 120.7, 111.8; GC
MS (EI) m/z = 153 [M]þ. Oxazolo[4,5-b]pyridine. light yellow solid; 90% isolated yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.64 (s, 1H), 8.39 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.37
7.40 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 155.4, 154.5, 147.0, 142.1, 120.8, 119.1; GC-MS (EI) m/z = 120 [M]þ.

’ ASSOCIATED CONTENT

bS

Supporting Information. Experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for the aminated products. This material is available free of charge via the Internet at http://pubs.acs.org.

NOTE

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’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; [email protected].

’ ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Project Nos. 20876021, 20923006) and the Education Department of Liaoning Province (2009S021). ’ REFERENCES (1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Amino Group Chemistry, From Synthesis to the Life Sciences; Ricci, A., Eds.; WileyVCH: Weinheim, 2007. (c) Seregin, I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36, 1173 and references therein. (2) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282. (3) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (4) Selected examples: (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (d) Ma, D. W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (e) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8472. (f) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (g) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 1114. (h) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (5) Selected examples: (a) Ayker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692. (c) Ritleng, V.; Sirlin, C.; Pfeffer, G. Chem. Rev. 2002, 102, 1731. (d) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (e) Thansandote, P.; Lautens, M. Chem.—Eur. J. 2009, 15, 5874. (f) Bouffard, J.; Itami, K. Top. Curr. Chem. 2010, 292, 231. (g) Beck, E. M.; Gaunt, M. J. Top. Curr. Chem. 2010, 292, 85. (6) For reviews on direct C
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