nBu4NI-catalyzed direct amination of benzoxazoles with tertiary amines using TBHP as oxidant under microwave irradiation

DOI: 10.1515/znb-2015-0212

Source and publish data:

Zeitschrift fur Naturforschung, B: Chemical Sciences p. 317 - 325 (2016)

Update date:2022-08-03

Topics:

Authors:

Yuan, Jin-Wei

Jin, Ming

Yin, Qiu-Yue

Mao, Pu Mao, Pu

Qu, Ling-Bo

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Article abstract of DOI:10.1515/znb-2015-0212

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

Full text of DOI:10.1515/znb-2015-0212

Z. Naturforsch. 2016; 71(4)b: 317–325

Jin-Wei Yuan*, Ming Jin, Qiu-Yue Yin, Pu Mao and Ling-Bo Qu*

ⁿBu₄NI-catalyzed direct amination of benzoxazoles

with tertiary amines using TBHP as oxidant under

microwave irradiation

DOI 10.1515/znb-2015-0212

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,

Received December 16, 2015; accepted January 22, 2016

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 micro-

wave irradiation. A variety of substituted benzoxazol-

2-amines were synthesized with moderate to good yield.

Keywords: benzoxazole; microwave irradiation; Bu₄NI the development of environmentally benign procedures

catalysis; tertiary amine.

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

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-mol-

ecule 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 prepara-

tion 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. Gen-

erally, 2-aminobenzoxazole derivatives are synthesized by

transition metal-catalyzed amination with N-chloroamines,

amines, and amides or with O-acylated hydroxylamines

−

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 oxida-

tive amination of benzoxazole with secondary or primary

amines in the presence of catalytic iodine or tetrabu-

tylammonium 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 tran-

sition metal-free conditions using formamides as nitrogen

sources [30]. Moreover, the direct amination of benzoxa-

zoles with secondary amines using a catalytic amount of

N-iodosuccinimide and aqueous H₂O₂as 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 ter-

tiary amines as amino group sources. Given that tertiary

amines are widely found in natural products and more

*Corresponding authors: Jin-Wei Yuan and Ling-Bo Qu, School

of Chemistry and Chemical Engineering, Henan University of

Technology, Zhengzhou 450001, P. R. China, Fax: +86 371 67756718,

E-mail: yuanjinweigs@126.com (J.-W. Yuan),

qulingbo@haut.edu.cn (L.-B. Qu)

Ming Jin, Qiu-Yue Yin and Pu Mao: School of Chemistry and

Chemical Engineering, Henan University of Technology, Zhengzhou

450001, P. R. China

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ꢀJ.-W. Yuan et al.: Direct amination of benzoxazoles with tertiary amines

R⁴

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 benzoxa-

zoles with tertiary amines as nitrogen sources and a cata-

lytic amount of TBAI/TBHP as the oxidant in acetic acid

under microwave irradiation.

R³

R²

R¹

Somatostatin receptor subtype 5 antagonists

Serotonin receptors

Scheme 1:ꢀTwo bioactive 2-aminobenzoxazole derivatives.

2 Results and discussion

easily available than primary or secondary amines in the

laboratories, the synthesis of benzoxazol-2-amines from We began our investigation with the reaction of benzo-

tertiary amines is more expected. Moreover, in view of the xazole (1a) with trimethylamine (2a) as a model reac-

increasing attention to design environmentally benign tion. As seen in Table 1, a variety of reaction conditions

and metal-free methods for the formation of C–N bonds were employed to achieve the optimal conditions. Initial

Table 1:ꢀOptimization of reaction conditions.

Catalyst, Additive

[O], MW

Entryꢁ

Catalyst (mol%)ꢁ

[O] (equiv)

ꢁ

Additive (equiv)

ꢁ

Solvent ꢁ

Temperature (°C)ꢁ

Yield^a(%)

ꢂ

TBAI (5)

KI (5)

ꢂ

TBHP^b(2)

TBHP (2)

H₂O₂(2)

DTBP (2)

AIBN (2)

K₂S₂O₈(2)

ꢂ

AcOH (2)

TFA (2)

ꢂ

THF

PhCl

DCE

ꢂ

100ꢂ

20ꢂ

Trace

Dioxaneꢂ

DMSO

CH₃CN

ꢂ

ꢂ<ꢂ10

Trace

ꢂ<ꢂ5

Trace

(NH₄)₂S₂O₈(2)

TBHP (2)

ꢂ<ꢂ5

I₂(5)

TBHP (2)

TBAI (10)

TBAI (15)

TBAI (10)

None

TBHP (2)

TBHP (1:1.5:2.5:3)ꢂ

43:53:52:51^c

TBHP (2)

None

ꢂ

Trace

PhCO₂H (2)

HCl (2)

None

ꢂ<ꢂ10

Trace

AcOH (1:1.5:2.5:3)ꢂ

46:52:56:53^d

AcOH (2)

ꢂ

ꢂ<ꢂ5

nr^e

50^f

60ꢂ

80ꢂ

120ꢂ

100ꢂ

TBHP (2)

TBAI (10)

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 ꢂ=ꢂ no reaction. ^fNo microwave irradiation; reaction time is 12 h.

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screening of the solvents revealed that the solvents such nature of the substituents on the phenyl ring of benzo-

as THF, PhCl, and 1,2-dichloroethane (DCE) are not suit- xazoles affected the reaction yield, such as 5-methylb-

able for this reaction (Table 1, entries 1–3). Further inves- enzoxazole and 5-tert-butylbenzoxazole, containing the

tigation has shown that the reaction proceeds well in electron-donating substituents, increased the yields of

acetonitrile in the presence of AcOH (2.0 equiv) using cat- products (Table 2, 3b and 3c); the effect is the reverse

alytic amounts of TBAI (5 mol%) and TBHP (2.0 equiv) as with electron-withdrawing substituents (Table 2, 3d and

the oxidant (Table 1, entries 4–6). Unfortunately, replace- 3e). A reaction with 5-nitrobenzoxazole afforded the cor-

ment of TBHP with H₂O₂, di-tert-butylperoxide (DTBP), responding product with a sharply lower yield (45 %).

AIBN, K₂S₂O₈, or (NH₄)₂S₂O₈proved to be ineffective, which It is noteworthy that a chloro substituent was compat-

led to a dramatically decreased yield or no product at all ible under standard conditions to give the corresponding

(Table 1, entries 7–11). When potassium iodide or iodine functionalized amine products such as 3d in good yield.

was employed instead of TBAI, the corresponding reac- Unfortunately, benzothiazole did not afford the desired

tion also proceeded smoothly, presumably due to their products 3f. The lower reactivity of the substrate observed

similar capability to promote the reaction with TBAI (Table here is probably due to their weaker acidity.

1, entries 12 and 13). Gratifyingly, increasing the amount

Next, the scope of this reaction with a variety of

of TBAI (10 mol%) resulted in high yields, indicating the tertiary amines was investigated. As shown in Table 3,

significance of a catalyst in the reaction (Table 1, entries almost all linear alkyl tertiary amines with linear alkyl

14 and 15). The screening of the amount of TBHP showed substituents, bearing α-H adjacent to the nitrogen atom,

that a good yield (65 %) of the product 3a was obtained provided the desired products 4a–4d, 4f–4h, 4j, 4l, and

when 2.0 equiv of TBHP was employed, and excessive or 4m in 48–63 % yield. Furthermore, with the carbon chain

less amounts of the oxidant caused decreased conversion of acyclic tertiary amines increasing, the yield of prod-

(Table 1, entries 14 and 16). Furthermore, various additives ucts decreased from 65 to 48 % (Table 2, 3a, and Table 3,

were investigated, which, compared to AcOH, PhCO₂H, 4a–4c). This might be attributed to the steric hindrance

and hydrochloric acid, were less effective, whereas a of tertiary amines. In addition to acyclic tertiary amines,

strong acid, such as trifluoroacetic acid (TFA), was a com- cyclic amines could be used in this transformation. It was

pletely ineffective additive (Table 1, entries 17–19). The gratifying to find that N-methyl morpholine reacted exclu-

reaction of benzoxazole 1a and trimethylamine 2a in the sively at the exocyclic C–N bond to give cyclic amines 4e,

absence of AcOH resulted in a trace amount of 3a, indi- 4i, and 4k in 61–65 % yield. Unfortunately, no product 4n

cating the significance of the acid additive in the reaction formation was observed with triphenylamine as an amino

(Table 1, entry 20). Notably, excessive or less amounts of group source, in which no C–H bond in the α-position of

additive would lead to a slight decreased yield, and 2.0 the nitrogen atom is contained, thus suggesting that α-H

equiv of additive AcOH was the optimized choice (Table 1,

entries 14 and 21). In addition, increasing the temperature

Table 2:ꢀSynthesis of N,N-dimethyl azole-2-amines from substi-

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, indi-

cating 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.

tuted benzoxazoles and trimethylamine.

TBAI (10 mol %)

TBHP (2.0 equiv)

AcOH (2.0 equiv)

CH₃CN, 100 ^o

MW, 20 min

3a (65 %^a)

3b (67 %)

3c (69 %)

O₂

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

3d (62 %)

3e (45 %)

3f (0 %)

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.

were tolerated well (Table 2). Notably, the electronic ^aIsolated yields.

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320ꢀ ꢀJ.-W. Yuan et al.: Direct amination of benzoxazoles with tertiary amines

Table 3:ꢀSynthesis of benzoxazol-2-amine derivatives from benzo-

xazoles and tertiary amines.

to the fact that a sterically less hindered methyl group is

much more facile for cleavage.

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 condi-

tions, and N,N-dimethyl-benzoxazol-2-amine 3a was pro-

duced successfully, which indicated that dimethylamine

was an important intermediate for the reaction of benzo-

xazole with trimethylamine. Meanwhile, when the radical

scavenger TEMPO (2,2,6,6-tetramethylpiperidin-N-oxyl)

was added to the reaction system, the reaction was inhib-

ited (Scheme 2, Eq. b), which implies that the reaction pre-

sumably proceeds via a radical intermediate.

TBAI (10 mol %)

TBHP (2.0 equiv)

AcOH (2.0 equiv)

R²

R³

R⁴

²N

R¹

R³

CH₃CN, 100 °C

MW, 20 min

4a (62 %^a)

4b (55 %)

4c (48 %)

On the basis of the above results and previous reports

[35–37], a plausible mechanism for this reaction is illus-

trated 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, ben-

zoxazole 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.

4d (53 %)

4e (65 %)

4f (63 %)

4g (57 %)

4h (53 %)

4i (63 %)

4j (54 %)

4k (61 %)

4l (58 %)

4m (50 %)

4n (0 %)

4o (0 %)

3 Conclusion

We have developed a mild, efficient, and green ⁿBu₄NI-cat-

alyzed direct oxidative amination of benzoxazole with ter-

tiary amines to form a 2-aminobenzoxazole derivative under

microwave radiation. A wide range of benzoxazole deriva-

tives containing electron-donating and electron-withdraw-

ing 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.

4p (0 %)

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.

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.

4 Experimental section

The bulky N,N-dimethyl-1-phenylmethanamine con-

taining two kinds of α-H afforded two types of products 4.1 General

(Table 4), 5 and 3, with an almost 4:3 ratio, which indi-

cated that the C–N bond of II position is broken more Anhydrous solvents were obtained by standard pro-

easily than that of I position. This might be attributed cedure. All substrates were purchased from J & K

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Table 4:ꢀDirect amination of benzoxazole with N,N-dimethyl-1-phenylmethanamine.

TBAI (10 mol %)

TBHP (2.0 equiv)

AcOH (2.0 equiv)

R¹

CH₃CN, 100 °C

MW, 20 min

5a (35 %^a)

5b (37 %)

5c (38 %)

O₂

5d (33 %)

5e (30 %)

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.

(HRMS) were obtained on a Q-TOF instrument using the

ESI technique. IR spectra were recorded on a Shima-

dazu IR-408 Fourier transform infrared spectrophotom-

eter using a thin film supported on KBr pellets. Melting

points were measured on an XT4A microscopic appara-

tus and are uncorrected.

Standard conditions

Yield: 95 %

TEMPO (2.0 equiv)

Standard conditions

Yield: trace

Scheme 2:ꢀInvestigation of the reaction mechanism.

4.2 General procedure for the synthesis

of benzoxazol-2-amine derivatives

Scientific Ltd. and were used without further purifica-

tion. Column chromatography was performed using Benzoxazole 1 (0.25 mmol), tertiary amines 2 (0.75 mmol),

200–300 mesh silica with the indicated solvent system TBAI (0.025 mmol, 10 mg), TBHP (70 % aqueous solu-

according to standard techniques. Analytical thin-layer tion, 0.5 mmol), and AcOH (0.5 mmol, 30 mg) in CH₃CN

chromatography was performed on precoated, glass- (1.5 mL) were added to a 5-mL microwave reaction tube.

backed silica gel plates. Visualization of the developed The reaction mixture was put into a microwave reactor at

chromatogram was performed by UV absorbance (254 100 °C for 20 min. After completion of the reaction, the

or 365 nm). Nuclear magnetic resonance (NMR) spectra mixture was quenched by addition of a saturated solu-

were recorded on Bruker Avance 400-MHz spectrometer. tion of sodium disulfite (1.0 mL) and a saturated solution

Chemical shifts for ¹H NMR spectra are recorded in parts of sodium hydrogen carbonate (2.0 mL). Then the mixture

per million from tetramethylsilane. Data were reported was extracted with ethyl acetate (3 ꢀ×ꢀ 5 mL), combined

as follows: chemical shift, multiplicity (s ꢀ=ꢀ singlet, d ꢀ=ꢀ organic phases were dried over anhydrous Na₂SO₄, and

doublet, t ꢀ=ꢀ triplet, m ꢀ=ꢀ multiplet, and br ꢀ=ꢀ broad), cou- the organic solvent was removed under vacuum. The

pling constants in hertz and integration. Chemical shifts crude residue was purified by chromatography on a silica

for ¹³C NMR spectra were recorded in parts per million gel column using ethyl acetate-petroleum ether (1:5 to 2:1)

from tetramethylsilane. High-resolution mass spectra as eluant to obtain the desired product.

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^tBuOOH

^tBuO

I⁻

1/2

₂O

^tBuOO

^tBuO

^tBuOOH

SET

R¹

CHR³

R¹

CHR³

R¹

R³

CH₂

R²

^tBuOH

(I)

(II)

₂O

H⁺

R¹

CHR³

R²

R³

CHO

(IV)

(III)

R¹

^tBuOO

^tBuO

R¹

R²

R¹

R²

AcOH

R²

^tBuOH

^tBuOOH

AcOH

OAc

(V)

(VI)

Scheme 3:ꢀProposed mechanism for the amination reaction of benzoxazole.

4.2.1 N,N-dimethylbenzo[d]oxazol-2-amine (3a)

(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

Orange solid; m.p. 83–84 °C (from chloroform; lit. [23]: (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 163.3, 147.3, 147.0, 143.3, 117.3

80–82 °C). – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.35 (dd, J ꢀ=ꢀ (CH), 113.2 (CH), 107.6 (CH), 37.6 (CH₃), 34.7, 31.8 (CH₃).

7.8 Hz, J ꢀ=ꢀ 0.7 Hz, 1H), 7.23 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 7.14 (td, J ꢀ=ꢀ – MS ((+)-ESI): m/z ꢀ=ꢀ 219.3 (calcd. 219.1 for C₁₃H₁₉N₂O,

7.8 Hz, J ꢀ=ꢀ 1.2 Hz, 1H), 6.98 (td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 1.2 Hz, 1H), [M+H] ).

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, 4.2.4 5-Chloro-N,N-dimethylbenzo[d]oxazol-2-amine (3d)

[M+H] ).

White solid; m.p. 84–85 °C (from chloroform; lit. [23]:

83–85 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.29 (d, J ꢀ=ꢀ

4.2.2 N,N,5-trimethylbenzo[d]oxazol-2-amine (3b)

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). – C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ

Light orange solid; m.p. 70–71 °C (from chloroform; lit. 163.7, 147.7, 145.0, 129.1, 119.9 (CH), 116.0 (CH), 109.0 (CH),

[23]: 68–70 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.15 37.6 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 197.2 (calcd. 197.0 for

(s, 1H), 7.10 (d, J ꢀ=ꢀ 8.1 Hz, 1H), 6.78 (dd, J ꢀ=ꢀ 8.1 Hz, J ꢀ=ꢀ 0.8 C₉H₁₀ClN₂O, [M+H] ).

Hz, 1H), 3.16 (s, 6H), 2.37 (s, 3H). – C 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 4.2.5 N,N-dimethyl-5-nitrobenzo[d]oxazol-2-amine (3e)

(calcd. 177.1 for C₁₀H₁₃N₂O, [M+H] ).

Yellow solid; m.p. 168–170 °C (from chloroform; lit. [23]:

166–168 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 8.12 (d,

4.2.3 5-(tert-Butyl)-N,N-dimethylbenzo[d]oxazol-

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

2-amine (3c)

Colorless solid; m.p. 68–69 °C (from chloroform; lit. (CH), 37.6 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 208.2 (calcd. 208.1

[20]: 70–72 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.42 for C₉H₁₀N₃O₃, [M+H] ).

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4.2.6 N,N-diethylbenzo[d]oxazol-2-amine (4a) [13]

4.2.10 2-Morpholinobenzo[d]oxazole (4e)

Colorless liquid. – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.35 Pale yellow solid; m.p. 91–92 °C (from chloroform; lit. [28]:

(dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 0.6 Hz, 1H), 7.24 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 7.14 90–94 °C). – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.37 (dd, J ꢀ=ꢀ

(td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 1.2 Hz, 1H), 6.98 (td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 1.2 Hz, 7.8 Hz, J ꢀ=ꢀ 0.6 Hz, 1H), 7.27 (d, J ꢀ=ꢀ 6.4 Hz, 1H), 7.18 (td, J ꢀ=ꢀ

1H), 3.58 (q, J ꢀ=ꢀ 7.1 Hz, 4H), 1.28 (t, J ꢀ=ꢀ 7.1 Hz, 6H). – C 7.8 Hz, J ꢀ=ꢀ 1.0 Hz, 1H), 7.04 (td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 1.0 Hz, 1H),

NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.2, 148.8, 143.6, 123.8 3.83–3.81 (m, 4H), 3.70–3.68 (m, 4H). – ¹³C NMR (100.61

(CH), 119.9 (CH), 115.8 (CH), 108.5 (CH), 42.9 (CH₂), 13.5 MHz, CDCl₃): δ ꢀ=ꢀ 162.1, 148.7, 142.8, 124.0 (CH), 120.9 (CH),

(CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 191.3 (calcd. 191.1 for C₁₁H₁₅N₂O, 116.5 (CH), 108.8 (CH), 66.2 (CH₂), 45.7 (CH₂). – MS ((+)-

[M+H] ).

ESI): m/z ꢀ=ꢀ 205.2 (calcd. 205.0 for C₁₁H₁₃N₂O₂, [M+H] ).

4.2.7 N,N-dipropylbenzo[d]oxazol-2-amine (4b) [13]

4.2.11 N,N-diethyl-5-methylbenzo[d]oxazol-2-amine

(4f) [20]

Light yellow liquid. – H 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 ꢀ=ꢀ Yellow viscous liquid. – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ

7.8 Hz, J ꢀ=ꢀ 1.0 Hz, 1H), 6.97 (td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 1.0 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J ꢀ=ꢀ 8.0 Hz, 1H), 6.78 (dd, J ꢀ=ꢀ 8.0 Hz, J ꢀ=ꢀ

3.48 (t, J ꢀ=ꢀ 7.6 Hz, 4H), 1.71 (m, 4H), 0.96 (t, J ꢀ=ꢀ 7.6 Hz, 6H). 0.9 Hz, 1H), 3.57 (q, J ꢀ=ꢀ 7.1 Hz, 4H), 2.38 (s, 3H), 1.27 (t, J ꢀ=ꢀ

– ¹³C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.7, 148.7, 143.7, 123.7 7.1 Hz, 4H). – ¹³C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.4, 146.9,

(CH), 119.9 (CH), 115.8 (CH), 108.5 (CH), 50.3 (CH₂), 21.2 143.7, 133.4, 120.5 (CH), 116.2 (CH), 107.8 (CH), 42.9 (CH₂),

(CH₂), 11.2 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 219.3 (calcd. 219.1 21.5 (CH₃), 13.5 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 205.2 (calcd.

for C₁₃H₁₉N₂O, [M+H] ).

205.1 for C₁₂H₁₇N₂O, [M+H] ).

4.2.12 5-Methyl-N,N-dipropylbenzo[d]oxazol-2-

4.2.8 N,N-dibutylbenzo[d]oxazol-2-amine (4c) [13]

amine (4g)

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):

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). – C 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

m/z ꢀ=ꢀ 247.1 (calcd. 247.2 for C₁₅H₂₃N₂O, [M+H] ).

(calcd. 233.1 for C₁₄H₂₁N₂O, [M+H] ).

4.2.9 N-cyclohexyl-N-methylbenzo[d]oxazol-2-

4.2.13 N,N-dibutyl-5-methylbenzo[d]oxazol-2-

amine (4d) [38]

amine (4h)

Yellow viscous liquid. – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ Colorless solid; m.p. 60–61 °C (from chloroform; lit. [13]:

7.34 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 7.23 (d, J ꢀ=ꢀ 7.8 Hz, 1H), 7.13 (td, J ꢀ=ꢀ 58–60 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.14 (s,

7.8 Hz, J ꢀ=ꢀ 0.9 Hz, 1H), 6.97 (td, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 0.9 Hz, 1H), 1H), 7.09 (d, J ꢀ=ꢀ 8.0 Hz, 1H), 6.76 (d, J ꢀ=ꢀ 8.0 Hz, 1H), 3.48

4.17–4.09 (m, 1H), 3.06 (s, 3H), 1.87–1.82 (m, 4H), 1.70 (d, (t, J ꢀ=ꢀ 7.6 Hz, 4H), 2.37 (s, 3H), 1.68–1.60 (m, 4H), 1.42–1.32

J ꢀ=ꢀ 13.0 Hz, 1H), 1.68–1.42 (m, 4H), 1.18–1.13 (m, 1H). – C (m, 4H), 0.95 (t, J ꢀ=ꢀ 7.6 Hz, 6H). – C NMR (100.61 MHz,

NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.7, 148.7, 143.6, 123.8 (CH), CDCl₃): δ ꢀ=ꢀ 162.8, 146.9, 143.8, 133.3, 120.4 (CH), 116.2 (CH),

119.9 (CH), 115.8 (CH), 108.5 (CH), 56.7 (CH), 29.9 (CH₂), 29.5 107.8 (CH), 48.3 (CH₂), 30.2 (CH₂), 21.5 (CH₃), 20.0 (CH₂),

(CH), 25.6 (CH₂), 25.5 (CH₂). – MS ((+)-ESI): m/z ꢀ=ꢀ 231.2 13.9 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 261.3 (calcd. 261.1 for

(calcd. 231.1 for C₁₄H₁₉N₂O, [M+H] ).

C₁₆H₂₅N₂O, [M+H] ).

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324ꢀ ꢀJ.-W. Yuan et al.: Direct amination of benzoxazoles with tertiary amines

4.2.14 5-Methyl-2-morpholinobenzo[d]oxazole (4i)

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),

White solid; m.p. 120–121 °C (from chloroform; lit. [24]: 1.42–1.33 (m, 4H), 0.96 (t, J ꢀ=ꢀ 7.5 Hz, 6H). – ¹³C NMR (100.61

119–122 °C). – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.16 (s, 1H), MHz, CDCl₃): δ ꢀ=ꢀ 163.3, 147.4, 129.0, 119.6 (CH), 115.8 (CH),

7.12 (d, J ꢀ=ꢀ 8.1 Hz, 1H), 6.84 (d, J ꢀ=ꢀ 8.0 Hz, 1H), 3.82–3.80 108.9 (CH), 48.4 (CH₂), 30.0 (CH₂), 19.9 (CH₂), 13.9 (CH₃).

(m, 4H), 3.68–3.66 (m, 4H), 2.39 (s, 3H). – ¹³C NMR (100.61 – MS ((+)-ESI): m/z ꢀ=ꢀ 281.2 (calcd. for C₁₅H₂₂N₂O, [M+H] ).

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] ).

4.2.19 N-benzyl-N-methylbenzo[d]oxazol-2-amine (5a)

White solid; m.p. 52–53 °C (from chloroform; lit. [28]:

4.2.15 5-(tert-Butyl)-N,N-dibutylbenzo[d]oxazol-2-

50–54 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.45 (d, J ꢀ=ꢀ

amine (4j) [13]

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,

Colorless viscous liquid. – H NMR (400.13 MHz, CDCl₃): 3H). – ¹³C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 163.0, 149.0, 143.5,

δ ꢀ=ꢀ 7.42 (d, J ꢀ=ꢀ 1.2 Hz, 1H), 7.14 (d, J ꢀ=ꢀ 8.4 Hz, 1H), 7.01 (dd, 136.5, 128.8 (CH), 127.8 (CH), 127.7 (CH), 124.0 (CH), 120.4

J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 1.2 Hz, 1H), 3.49 (t, J ꢀ=ꢀ 7.5 Hz, 4H), 1.68–1.61 (CH), 116.2 (CH), 108.8 (CH), 53.9 (CH₂), 35.2 (CH₃). – MS

(m, 4H), 1.41–1.36 (m, 4H), 1.33 (s, 9H), 0.95 (t, J ꢀ=ꢀ 7.5 Hz, ((+)-ESI): m/z ꢀ=ꢀ 239.3 (calcd. 239.1 for C₁₅H₁₅N₂O, [M+H] ).

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): 4.2.20 N-benzyl-N,5-dimethylbenzo[d]oxazol-2-

m/z ꢀ=ꢀ 303.3 (calcd. 303.2 for C₁₉H₃₁N₂O, [M+H] ).

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

4.2.16 5-(tert-Butyl)-2-morpholinobenzo[d]oxazole

(4k) [39]

Colorless solid. – ¹H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.43 (s, MHz, CDCl₃): δ ꢀ=ꢀ 163.2, 147.2, 143.6, 136.5, 133.6, 128.7 (CH),

1H), 7.17 (d, J ꢀ=ꢀ 8.4 Hz, 1H), 7.08 (d, J ꢀ=ꢀ 8.4 Hz, 1H), 3.81 127.7 (CH), 127.6 (CH), 121.0 (CH), 116.5 (CH), 108.1 (CH), 53.8

(t, J ꢀ=ꢀ 4.6 Hz, 4H), 3.67 (t, J ꢀ=ꢀ 4.6 Hz, 4H), 1.34 (s, 9H). (CH₂), 35.2 (CH₃), 21.6 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 253.3

– ¹³C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.3, 147.5, 146.7, 142.6, (calcd. 253.1 for C₁₆H₁₇N₂O, [M+H] ).

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

4.2.21 N-benzyl-5-(tert-butyl)-N-methylbenzo[d]oxazol-

for C₁₅H₂₁N₂O₂, [M+H] ).

2-amine (5c)

4.2.17 5-Chloro-N,N-diethylbenzo[d]oxazol-2-amine

Colorless solid. – H 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,

(4l) [24]

J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 2.3 Hz, 1H), 4.77 (s, 2H), 3.14 (s, 3H), 1.41

Yellow liquid. – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.29 (d, (s, 9H). – C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 163.2, 147.4,

J ꢀ=ꢀ 2.0 Hz, 1H), 7.12 (d, J ꢀ=ꢀ 8.4 Hz, 1H), 6.93 (dd, J ꢀ=ꢀ 8.4 147.0, 143.4, 136.5, 128.7 (CH), 127.7 (CH), 127.6 (CH), 117.6

Hz, J ꢀ=ꢀ 2.0 Hz, 1H), 3.57 (q, J ꢀ=ꢀ 7.1 Hz, 4H), 1.28 (t, J ꢀ=ꢀ 7.1 (CH), 113.3 (CH), 107.8 (CH), 53.8 (CH₂), 35.1 (CH₃), 34.8, 31.9

Hz, 6H). – C NMR (100.61 MHz, CDCl₃): δ ꢀ=ꢀ 162.9, 147.5, (CH₃). – HRMS ((+)-ESI): m/z ꢀ=ꢀ 295.1807 (calcd. 295.1805

145.0, 129.1, 119.7 (CH), 115.9 (CH), 108.9 (CH), 43.0 (CH₂), for C₁₉H₂₃N₂O, [M+H] ).

13.4 (CH₃). – MS ((+)-ESI): m/z ꢀ=ꢀ 225.2 (calcd. 225.1 for

C₁₁H₁₄ClN₂O, [M+H] ).

4.2.22 N-benzyl-5-chloro-N-methylbenzo[d]oxazol-2-

amine (5d)

4.2.18 N,N-dibutyl-5-chlorobenzo[d]oxazol-2-amine (4m)

Pale brown solid, mp 71–72 °C (from chloroform; lit. [40]:

White solid; m.p. 63–65 °C (from chloroform; lit. [13]: 69–70 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.35–7.25

60–61 °C). – H NMR (400.13 MHz, CDCl₃): δ ꢀ=ꢀ 7.29 (d, J ꢀ=ꢀ (m, 6H), 7.15 (d, J ꢀ=ꢀ 8.4 Hz, 1H), 6.95 (dd, J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 2.5

Unauthenticated

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J.-W. Yuan et al.: Direct amination of benzoxazoles with tertiary aminesꢃ

ꢃ325

[9] D. Monguchi, T. Fujiwara, H. Furukawa, A. Mori, Org. Lett. 2009,

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Hz, 1H), 4.74 (s, 2H), 3.12 (s, 3H). – C 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

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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). – C 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

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5 Supporting information

¹H NMR and ¹³C NMR spectra of 3a–3e, 4a–4m, and 5a–5e

are given as supporting information available online

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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 Scien-

tific Fund Project of Zhengzhou Science and Technology

Bureau (No. 20130883).

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