Microwave-Enhanced On-Water Amination of 2

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Microwave-Enhanced On-Water Amination of 2Mercaptobenzoxazoles to Prepare 2-Aminobenzoxazoles Theeranon Tankam, Jakkrit Srisa, Mongkol Sukwattanasinitt, and Sumrit Wacharasindhu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01824 • Publication Date (Web): 07 Sep 2018 Downloaded from http://pubs.acs.org on September 7, 2018

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The Journal of Organic Chemistry

Microwave-Enhanced On-Water Amination of 2Mercaptobenzoxazoles to Prepare 2-Aminobenzoxazoles Theeranon Tankam, Jakkrit Srisa, Mongkol Sukwattanasinitt and Sumrit Wacharasindhu* Nanotec-CU Center of Excellence on Food and Agriculture, Department of Chemistry, Faculty of Science, Chulalongkorn University Bangkok 10330, Thailand [email protected]

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ToC Image:

Abstract In this work, we developed a catalyst free amination of 2-mercaptobenzoxazoles on water under microwave irradiation. The product, 2-aminobenzoxazoles, were successfully produced via direct amination with various amines in moderate to high yields. The formal synthesis of Suvorexant, a medication for the treatment of insomnia, was accomplished, using developed amination process. The reaction was completed in an hour at 100-150 ̊C in a microwave reactor without the use of external catalyst or additive. Key benefits of this process include an on-water reaction, short reaction time, scalable, catalyst free, and use of 2-mercaptobenzoxazoles as an inexpensive starting material having low environmental impact in its preparation.

KEYWORDS: Nucleophilic aromatic substitution; on water; catalyst-free; microwave; amination


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Introduction 2-aminobenzoxazoles are ubiquitous motifs in pharmaceutical compounds as they possess broad spectrum of biological activities. Some therapeutically important agents have been constructed from this scaffold such as KDR inhibitor 1 (tyrosine Kinase inhibitor with anticancer activity)1 and 5-HT3 receptor agonist 2 (treatment of Diarrhea)2 (Scheme 1). There are several approaches to convert 2-aminophenol (4) into 2-aminobenzoxazoles (7) however, each process has specific drawbacks. For example, 2aminobenzoxazole (7) can be synthesized from SNAr displacement of 2-substitiuted benzoxazoles3-6 (SO2Me, CCl3, Br and Cl). Although this is a very efficient route, the process requires multiple preparation steps and uses toxic halogenated reagents which often produces undesirable by-products during the reaction. Recently, direct C–H amination of benzoxazole (5) into target amino compound (7) was introduced, utilizing transition metal catalyst such as Cu, Ag, Mn and Co in just one step.7-11 Although this reaction has high atom economy, but toxic metals are used. Another important method is direct synthesis from 2-aminophenol (4) with either isocyanate or isocyanide as amine surrogates. Although the reaction is mild and can be operated in one step but the preparation of isocyanate reagent requires a strong oxidizing agent12-13 while starting from isocyanide needs Pd(0) as catalyst in the reaction.14 Moreover, direct synthesis of 2-aminobenzoxazoles (7) utilizing tertramethyl orthocabonate to generate reactive 2-metoxy benzoxazoles in situ from 2-aminophenol (4) has been reported. Although the reaction can be performed in one pot without the use of metal or any strong oxidizing agent but tertramethyl orthocabonate reagent is required in large amount as solvent in the reaction.15 From process chemistry perspective, the use of hazardous reagent, toxic metal and harmful organic solvent would increase operating cost in large scale production of pharmaceuticals as extra safety protocols and metal removal step are needed. Therefore, a mild, scalable and metal-free approach for 2-aminobenzoxazole synthesis would be highly desirable. Recently, our group become interested in the use of 2-mercaptobenzoxazole (6) as a starting material for the synthesis of 2-aminobenzoxazoles (7). Although an extra step is required for the preparation of starting material 6 from 2-aminophenol 4, but the process is relatively green and ACS Paragon Plus Environment

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economical involving the reaction between amino phenol and carbon disulfide in methanol/water reflux.16 Many reagents are commercially available at low cost. We successfully performed amination of 2-mercaptobenzoxazoles (6) with amine into 2-aminobenzoxazoles (7) using Rose Bengal as a photocatalyst under irradiation by visible light. Regardless of its many benefits, disadvantages of this reaction are use of acetonitrile as organic solvent, long reaction time and use of a strong organic base (DBU).17 Cl HN

O O

N

Cl

N N

N

N

N O

O

NH

O H

CH3 5-HT3 Receptor Agonist 2

KDR Inhibitor 1 Previous works

X 3

O N H O

5 N SH 6

O

R 1 R2 NCS

R 1 R2 NH

N

R N C N Microwave irradiation

X = SO2 Me, CCl3, Cl Chloroform or acetonitrile R 1R2NH

N

metal or strong oxidant acetonitrile

O 7

R1 N

R 1R 2NH

R2

R 1R2NH water Microwave irradiation

10% RB, DBU white LED acetonitrile

NH2

R 2 N+C 5% Pd(PPh 3) 4 Dioxane

OH 4

R 1 R2 NH C(OCH 3) 4 HOAc

N SH 6

O

This work

Scheme 1. 2-Aminobenzoxazole derivatives with biological activities and synthetic approaches

Water is the solvent of choice for green synthesis as its low cost, non-toxic and nonflammable.18-19 An on-water reaction whereby water is used as the sole solvent without any additive, has recently received numerous attention as it is convenient to perform and interesting reactivity has been observed in several cases.20-42 In view of this new development, herein we report an efficient on-water route for the preparation of 2-aminobenzoxazole (7) using 2-mercaptobenzoxazoles (6) and corresponding amines as starting materials. The reaction was accelerated with microwave and performed without any catalyst, oxidizing agent or extra additive. Our method, when combined with typical synthesis of starting material 2-mercaptobenzoxazoles (6), which required only CS2 and 2-aminophenol (4) in EtOH/H2O, offers a convenient and economical route for the preparation of 2-aminobenzoxazole (7). ACS Paragon Plus Environment

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Result and discussion We selected the reaction between 2-mercaptobenzoxazole (6) and n-butylamine as a representative catalyst-free amination on-water reaction for the optimization study (Table 1). When the reaction was performed at 100 ̊C for 24 hours in conventional heat (oil bath), all starting materials were consumed to produce 7a in 85% yield (Table 1, entry 1). Reducing reaction time to 1 hour under conventional heat resulted in almost no reaction (Table 1, entry 2). Switching to microwave reactor, the reaction was completed within 1 hour providing the desired amination product in 91 % yield (Table 1, entry 3). This observation clearly demonstrated the acceleration of amination by microwave irradiation. The increase in reaction rate and yield observed under microwave treatment is probably caused by an increase in efficiency of energy transfer and more even distribution of heat by microwave irradiation. This also leads to higher pressure and temperature generated rapidly during the reaction, thereby decreasing the hydrophobic effects. A notable decrease in hydrophobic effects enable the reaction to proceed “in water” without requiring organic solvents.24-25 The reduction of the reaction temperature and time resulted in incomplete conversion of thiol 6 and lower yield of 7a (Table 1, Entry 4 and 5). The amount of butyl amine nucleophile could be reduced from 3.0 to 1.5 equivalent without significant drop of the yield (Table 1 Entry 6), and this amount was used for further study. We would like to emphasize here that this on-water reaction significantly simplified the product isolation. After the reaction, the crude products were separated as a top layer on the water surface (Figure S1) using only small amount of ethyl acetate and pasture pipette to transfer to silica gel column for further chromatography. This reduces the use of organic solvent for extraction. The reaction at 1 gram scale required higher reaction temperatures of 150 ̊C and prolonged reaction time of 2 hour to ensure the completion of the reaction the gave 7a in 81% isolated yield (Table 1, Entry 7). This result suggested that the process may be upscaled with a proper microwave reactor (Table 1, Entry 7).


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Table 1. Optimization of the reaction conditiona Water

N SH H2N O 6

N NH

Temp, Time Microwave irradiation

O 7a

Entry

Temp (̊C)

Time (h.)

Yieldb

1c

100

24

85

2c

100

1

0

3

100

1

91

4d

80

1

69

5d

100

0.5

37

6e

100

1

90

7f

150

2

81

a

Reaction conditions: 2-mercaptobenzoxazole (1.0 equiv. 50 mg) and n-buthylamine (3.0 equiv.) in water (0.55 M) under microwave irradiation. bIsolated yield after silica gel c chromatography. Conventional heat. d e Incomplete reaction. n-buthylamine (1.5 equiv.) in water (1.1 M). f 1 gram of 6 With the optimized reaction conditions in hand, we next studied the scope of this amination by subjecting a panel of amines to 2-aminobenzoxazoles derivatives (7a-l, 8a, ,9a, 10a). As shown in Scheme 2, primary and secondary amines such as benzylamine, N-benzylmethylamine, piperidine and morpholine reacted smoothly with 6 under the optimized conditions, giving the desired products (7b-e) in good to excellent yields (80-89%). For ethanolamine, which contains both N and O nucleophilic atoms, only C-N bond formation occurred selectively, affording 7f in 85% yield. Unfortunately, a less reactive nucleophile such as aniline failed to react. However, aromatic amines containing electron donating group such as 4-aminophenol, p-toluidine and 1,4-phenylenediamine reacted with 6 at 150 ̊C to provide the corresponding products (7h-j) in moderate yields (48-66%). Stearic hindrance on ortho position of 1,2-phenylenediamine had little effect on the reaction yield as 7k was obtained in satisfactory yield (58%). Interestingly, the reaction between 6 and piperazine exclusively gave the double amination ACS Paragon Plus Environment

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product 7l in good yield. The reactions of substituted 2-mercaptobenzoxazoles such as 8 (methoxy), 9 (fluoro) and 10 (chloro) with n-butylamines also proceeded smoothly to afford the desired products 8a, 9a and 10a in moderate to good yields (56-79%).

Scheme 2. Substrate scope of aminationa

a

Reaction conditions :2-mercaptobenzoxazole (1.0 equiv. 100 mg) and n-buthylamine (1.5

equiv.) in water (1.1 M) under microwave irradiation. b150 ̊C

With these promising results in hand, we demonstrated the formal synthesis of Suvorexant, Merck’s drug for the treatment of insomnia, using our microwave-enhanced on-water amination process. In Merck’s process, the key intermediate 10f were prepared via three-step synthesis starting from condensation of aminophenol 4f with trimethyl orthoformate followed by bromination. Then SNAr displacement of 2-bromo-benzoxazole with ethanolamine provided the alcohol 10f in 80% yields (Scheme 3).43 Using our developed method, we were able to intercept the synthesis of a key intermediate 10f. We successfully performed amination using our method to convert commercially available 6chloro-2-mercaptobenzoxazole (10) into 10f in moderate yields. As mentioned above, commercially available chloro 10 can also be prepared from corresponding aminophenol 4f via simple condensation with carbon disulfide in water/EtOH.16 Therefore, combining above process with our method, the ACS Paragon Plus Environment

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preparation of 10f from 4f could be carried out with rather mild reagents and in a safe solvent (water/EtOH)

without the need of metal or additive, thereby offering a more sustainable and more

economical method for industrial large-scale production. Scheme3. Formal Synthesis of Suvorexant

Merk process Cl

CS2, EtOH:water 80 oC ref.16

NH2 OH

4f

1.p-TsOH, HC(OMe)3 2.LiHMDS, THF. hexane then NBS, THF 3. OH H2 N 80% overall yield ref.43

Our process Cl

OH

N SH O 10 commercially avialable

H2N

OH

Cl

N NH

water, microwave 100 oC 30 min, 57%

O 10f

4 steps ref.43

Cl

N N O Suvorexant

N

O

N N N

To shed light on the mechanism, several mechanistic experiments were conducted (Scheme 4). We performed our reaction using 2-(methylthio)benzo[d]oxazole (11) as a starting material under the optimized condition. No product 7a was observed and only starting material 11 was recovered. This result suggusted that simple SNAr is precluded, as SMe group in 11 is considered as better leaving group than SH moetiey in 6. Moreover, when bidentate amine such as N,N’-diethylethylenediamineas were used as a nucleophile, aminophenol 4 was isolated as the sole product in 69% yield (Scheme 4, eq. 2). It indicated that the reaction perhaps proceeded through the ring-opening mechanism.44 In addition, when o-phenolicthiourea 13b was subjected to the reaction condition without external amine, the cyclized product 7b were obtained in good yield indicating that the 13b could serve as the intermediate ACS Paragon Plus Environment

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in the reaction (Scheme 4, eq. 3). Finally, the addition of Pb(NO3)2 into the reaction resulted in the formation of PbS as confirm by EDX-XRD (Figure S2). With unpleasent smell after the reaction and the isolation of PbS, hydrogensulfide was likely liberated in the reaction. Scheme 4. Control Experiments water 1.1 M

CH3

N S

N

100 oC, 1h H2N

O 11 N O

NH2

S

N

water 1.1 M 100 oC, 1h

H NH

N

Microwave irradiation OH

(2)

OH 4, 69 %

Microwave irradiation

6

(1)

O 7a, 0%

water 1.1 M 100 oC, 1h

NH HN

SH

NH

Microwave irradiation

O

13b

(3) N H

7b, 64 %

With the above experiments, we then proposed the mechanism of this amination as seen in scheme 5. Initially, the addition of amine into 2-mercaptobenzoxazole (6) generates adduct 12 as an intermediate. The ring opening of oxazole motif provides the o-phenolicthiourea intermidate 13 which in turn cyclize and lose hydrogensulfide as a by-product during ring-closing process to provide the product 7. The proposed mechanism is also supported by experiment motioned above as shown in scheme 4 (eq. 2). When N,N’ diethylethylenediamine were used as nucleophile, the cyclization of intermediate 13 into 7 was prevented. It appears that nucleophilic attack from N atom occurred instead, resulting in the synthesis of product 4, that was separated in good yield. Scheme 5. Plausible mechanism

R N SH

N H

O 6

R

S

R R H N N SH O

R

N

OH 13

12

R

HS N

N O

N

R

N

7

R

NH

R

-H2 S

R

OH 14


9


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To extend the scope this on-water amination, we switched the starting matrial into 4mercaptoquinazoline (16) to prepare 4-aminoquinazolines (17) which is also an important scaffold composing in many therapeutic agents.45 The classical methods to prepare 4-aminoquinazolines (17) rely on the displacement of amine via SNAr with either corresponding halogenated46 or phosponium quinazolines which are derived from 4-hydroxyquinazoline starting material (15).47 However, toxic and expensive reagent are required in those methods. Herein, 4-mercaptoquinazoline (16) was prepared from 4-hydroxyquinazoline (15) using Lawesson’s reagent (scheme 6).48 The microwave-enhanced “on water” amination of 16 proceeded smoothly with various amines including n-butylamine, piperidine and morpholine giving the 4-aminoquinazolines 17a-c in excellent yields (78-87%). Scheme 6. Amination of 4-mercaptoquinazoline 16a

N N 15

R2 N H Water 1.1 M R1

SH

OH

N

Lawesson's reagent Pyridine, 150 oC, 0.5 h. Microwave irradiation 85%

R1

N

R2 N

100 oC, 1 h. Microwave irradiation

16

N

N 17a-c O

NH N N 17a, 87%

a

N

N N

N 17b, 84%

N N 17c, 78%

Reaction conditions: 4-mercaptoquinazoline (1.0 equiv. 100 mg) and n-buthylamine (1.5 equiv.) in water

(1.1 M) under microwave irradiation.

Conclusions

In summary, we developed a novel microwave-enhanced on-water amination reaction and applied it to the synthesis of 2-aminobenzoxazoles. We employed 2-mercaptobenzoxazole derivatives as starting materials due to its low cost, wide availability and low environmental impact in its preparation. The amination reaction of 2-mercaptobenzoxazole was conducted on water under microwave irradiation ACS Paragon Plus Environment

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without any additive or catalyst to yield various 2-aminobenzoxazoles in moderate to good yields. We also successfully extended this method to 4-mercaptoquinazoline, allowing us to access 4aminoquinazolines. In addition, a formal synthesis of Suvorexant, a major pharmaceutical ingredient in sleeping pills, was accomplished using this newly developed reaction. Our preliminary result also indicated that the reaction can be successfully scale up to one gram providing an alternative highly atom economical process for chemical industries. Further studies on microwave-enhanced on water amination reaction to more challenging and important amino heterocycles are currently on-going and will be reported in due course.

Experimental Section Materials and methods All chemicals were obtained from commercial suppliers (Sigma Aldrich, Fluka, or Merck) and were used without further purify cation. All solvents were used directly without drying .Analytical thinlayer chromatography (TLC) was performed on Kieselgel F254 pre-coated plastic TLC plates from EM Science . Visualization was performed with a 254 nm ultraviolet lamp. Column chromatography was carried out with silica gel (60, 230–400 mesh) from ICN Silitech. The 1H and

13

C NMR spectra were

recorded on a Varian Mercury 400 or Bruker Avance 400 for 1H (400 MHz) and Bruker Avance 400 for 13

C (100 MHz) in CDCl3, CD3CO2, CD3OD or CD3SO2 solution. Mass spectrometry was performed

with a MicroTOF Bruker mass spectrometer and triple quadrupole GC/MS from Agilent technologies. Microwave reactions were performed with CEM Discover. All microwave reactions were performed in a sealed tube reaction condition, and the reaction temperatures were monitored by an internal probe and the temperature was maintained in each experiment. General procedure for synthesis of 2-aminobenzoxazoles (General Procedure A) In 10 mL microwave vessel, a mixture of 2-mercaptobenzoxazole (1.0 equiv., 0.661 mmol) and amine (1.5 equiv., 0.992 mmol) was suspended in 0.6 mL of water followed by sealing of the vessel and heating to to 100 ̊C for 1 hour in a microwave reactor. The reaction temperature increased from 25 to ACS Paragon Plus Environment

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100 ̊C in 120 s and was maintained at 100 ̊C for 1 hour. The reaction was cooled to room temperature and then added 1 mL of ethyl acetate. The organic layer was transferred using posture pipet and evaporated under reduced pressure to give the crude product, which was further purified by column chromatography (eluted with ethyl acetate/hexane1:4) to afford the desired compound. General procedure for synthesis of 4-aminoquinazolines (General Procedure B) In 10 mL microwave vessel, a mixture of 4-mercapquinazoline (1.0 equiv., 0.617 mmol) and amine (1.5 equiv., 0.926 mmol) was suspended in 0.6 mL of water followed by sealing of the vessel and heating to to 100 ̊C for 1 hour in a microwave reactor. The reaction temperature increased from 25 to 100 ̊C in 120 s and was maintained at 100 ̊C for 1 hour. The reaction was cooled to room temperature and then added 1 mL of ethyl acetate. The organic layer was transferred using posture pipet and evaporated under reduced pressure to give the crude product, which was further purified by column chromatography (eluted with ethyl acetate/hexane 1:2) to afford the desired compound.

N-butylbenzo[d]oxazole-2-amine (7a)17 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and n-butylamine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 7a (113 mg, 0.595 mmol, 90%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.28 (m, 1H), 7.18 (m, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 3.43 (t, J = 7.2 Hz, 2H), 1.61 (m, 2H), 1.36 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 161.6, 147.9, 140.5, 124.4, 121.3, 115.6, 109.0, 43.0, 31.7, 19.9, 13.7. IR (ATR, cm-1): 3158, 3064, 2947, 2925, 2864, 1693, 1583, 1461, 1353, 1328, 1243, 944, 725, 693.GC-MS: m/z: 189.9 [M]+ (calcd for [C11H14N2O]+ 190.11).

N-benzylbenzo[d]oxazol-2-amine (7b)49 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and benzylamine (108 µL, 0.992 mmol) in water (0.6 mL) to afford 7b (118 mg, 0.529 mmol, 80%) as a white solid;1H NMR (400 MHz, CD3OD): δ ppm 7.27-6.92 (m, 9H), 4.47 (s, 2H).

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C NMR (100 MHz, CD3OD): δ ppm 164.3, 149.7, 143.6, 139.7, ACS Paragon Plus Environment

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128.5, 128.4, 125.1, 122.1, 116.5, 109.7, 47.4. IR (ATR, cm-1): 3279, 3057, 2918, 2867, 1663, 1544, 1454, 1335, 1248, 949, 736.ESI-MS: m/z: 225.14 [M+H]+ (calcd for [C11H13N2O2]+ 225.10).

N-benzyl-N-methylbenzo[d]oxazol-2-amine (7c)49 Synthesized according to General Procedure A using 2-mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and N-benzylmethylamine (128 µL, 0.992 mmol) in water (0.6 mL) to afford 2e (127 mg, 0.535 mmol, 81%)as a white solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.42-7.05 (m, 9H), 4.79 (s, 2H)3.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 162.8, 148.9, 143.2, 136.1, 128.8, 127.5, 124.0, 120.4, 116.2, 108.8, 53.9, 35.1. IR (ATR, cm-1): 3110, 2918, 1640, 1578, 1232, 1128, 931, 736. ESI-MS: m/z: 239.12 [M+H]+ (calcd for [C11H13N2O2]+ 239.12).

2-(piperidin-1-yl)benzo[d]oxazole (7d)17 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and piperidine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 7d (117 mg, 0.582 mmol, 88%)as a white solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.26 (d,J = 8.0 Hz, 1H), 7.15 (d,J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 3.59 (m, 4H), 1.61 (m, 6H).

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C NMR (100 MHz, CDCl3): δ ppm 162.5, 148.7, 143.4, 123.8, 120.3, 116.0, 108.5,

46.2, 25.2. IR (ATR, cm-1):2926, 2855, 1636, 1576, 1459, 1243, 737.ESI-MS: m/z: 203.12 [M+H]+ (calcd for [C13H11N2O2]+ 203.12).

2-morpholinobenzo[d]oxazole (7e)17 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and morpholine (86 µL, 0.992 mmol) in water (0.6 mL) to afford 7e (120 mg, 0.588 mmol, 89%)as a colorless solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.40 (m, 1H), 7.28 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 3.84 (m, 4H), 3.73 (m, 4H). 13C NMR (100 MHz, CDCl3): δ ppm 161.8, 148.6, 142.1, 124.2, 121.2, 116.4, 108.9, 66.2, 45.8. IR (ATR, cm-1): 2960, 2914, 2873, 1636, 1574, 1454, 1286, 1105, 797, 739.ESI-MS: m/z: 205.11 [M+H]+ (calcd for [C11H13N2O2]+ 205.10).


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2-(benzo[d]oxazol-2-ylamino)ethanol (7f)17 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and ethanolamine (113 µL, 0.992 mmol) in water (0.6 mL) to afford 7f (100 mg, 0.561 mmol, 85%)as a white solid; 1H NMR (400 MHz, CD3OD): δ ppm 7.26 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H),7.04 (t, J = 8.0 Hz, 1H), 3.77 (t, J = 4.0 Hz, 2H),3.52 (t, J = 4.0 Hz, 2H).

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C NMR (100 MHz, CD3OD): δ ppm 164.4, 149.7, 143.6, 125.0, 122.0, 116.4, 109.7, 61.5,

46.2. IR (ATR, cm-1): 3369, 3301, 2915, 2844, 2568, 1750, 1460, 1267, 1026.ESI-MS: m/z: 179.09 [M+H]+ (calcd for [C11H13N2O2]+ 179.08).

4-(benzo[d]oxazol-2-ylamino)phenol (7h)50 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 4-aminophenol (108 mg, 0.992 mmol) in water (0.6 mL) to afford 7h (108 mg, 0.476 mmol, 48%)as a brown solid; 1H NMR (400 MHz, (CD3)3SO): δ ppm 10.25 (s, 1H), 9.18 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.19 (m, 1H), 7.08 (m, 1H), 6.77 (d, J = 7.8 Hz, 2H).

13

C NMR (100 MHz, (CD3)3SO): δ ppm 158.7,

152.9, 147.2, 142.8, 130.0, 123.5, 121.1, 119.7, 116.3, 115.4, 108.5. IR (ATR, cm-1):3375, 3298, 3279, 3047, 2922, 1763, 1634, 1573, 1505, 1460, 1216, 891, 733. ESI-MS: m/z: 221.17 [M+H]+ (calcd for [C13H11N2O2]+ 227.08).

N-(p-tolyl)benzo[d]oxazol-2-amine (7i)50 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and p-toluidine (106 mg, 0.992 mmol) in water (0.6 mL) to afford 7i (75.5 mg, 0.337 mmol, 51%) as a yellow solid;1H NMR (400 MHz, (CD3)3SO): δ ppm7.64 (d, J = 7.8 Hz, 2H), 7.46 (m, 2H), 7.19-7.12 (m, 4H), 2.28 (s, 3H). 13C NMR (100 MHz, (CD3)3SO): δ ppm 158.1, 147.0, 142.5, 136.2, 131.0, 129.3, 123.9, 121.4, 117.6, 116.4, 108.8, 20.3. IR (ATR, cm-1): ESI-MS: m/z: 225.10 [M+H]+ (calcd for [C13H11N2O2]+ 225.10).

N1-(benzo[d]oxazol-2-yl)benzene-1,2-diamine (7j)50 Synthesized according to General Procedure A using 2-mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 1,2-phenylenediamine (107 mg, 0.992 ACS Paragon Plus Environment

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mmol) in water (0.6 mL) to afford 7j (86.2 mg, 0.383 mmol, 58%) as a yellow solid;1H NMR (400 MHz, (CD3)3SO): δ ppm12.53 (s, 1H), 8,98 (s, 1H), 7.13 (m, 4H), 6.63 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.40 (m, 1H).13C NMR (100 MHz, (CD3)3SO): δ ppm 168.1, 144.0, 136.4, 132.2, 122.3, 119.5, 116.5, 114.5, 114.4, 109.5. IR (ATR, cm-1): ESI-MS: m/z: 226.10 [M+H]+ (calcd for [C13H11N2O2]+ 226.10).

N1-(benzo[d]oxazol-2-yl)benzene-1,4-diamine (7k)50 Synthesized according to General Procedure A using 2-mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 1,4-phenylenediamine (107 mg, 0.992 mmol) in water (0.6 mL) to afford 7k (98.1 mg, 0.436 mmol, 66%) as a brown solid;1H NMR (400 MHz, (CD3)3SO): δ ppm10.05 (s, 1H), 7.36 (m, 4H), 7.17 (m, 1H), 7.05 (m, 1H), 6.61 (d, J = 8.0 Hz, 1H).

13

C NMR (100 MHz, (CD3)3SO): δ ppm158.8, 147.1, 144.2, 142.9, 127.9, 123.7, 120.8, 119.7,

115.9, 114.2, 108.5. IR (ATR, cm-1): ESI-MS: m/z: 226.10 [M+H]+ (calcd for [C13H11N2O2]+ 226.10).

1,4-bis(benzo[d]oxazol-2-yl)piperazine (7l)50 Synthesized according to General Procedure A using 2mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and piperazine (85 mg, 0.992 mmol) in water (0.6 mL) to afford 7l (75 mg, 0.234 mmol, 71%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.44 (d, J = 8.0 Hz, 2H), 7.32 (d,J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H), 3.93 (m, 8H). 13

C NMR (100 MHz, CDCl3): δ ppm 167.8, 161.3, 148.6, 124.4, 121.5, 116.5, 109.1, 45.2. IR (ATR,

cm-1): ESI-MS: m/z: 321.16 [M+H]+ (calcd for [C13H11N2O2]+ 321.14).

N-butyl-5-methoxybenzo[d]oxazol-2-amine (8a)17 Synthesized according to General Procedure A using 5-methoxybenzoxazole-2-thiol 8 (100 mg, 0.552 mmol) and n-butylamine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 8a (68 mg, 0.309 mmol, 56%) as a brown solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d,J = 4.0 Hz, 1H), 6.53 (dd, J = 8.0, 4.0 Hz, 1H), 3.73 (s, 1H), 3.40 (t, J = 8.0 Hz, 2H), 1.59 (m, 2H)1.35 (m, 2H), 0.89(t, J = 8.0 Hz, 3H).

13

C NMR (100 MHz,

CDCl3): δ 162.8, 157.1, 143.4, 142.9, 108.6, 107.3, 101.4, 55.9, 42.1, 31.8, 19.9, 13.7.IR (ATR, cm-1): ACS Paragon Plus Environment

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3044, 2925, 2867, 1699, 1596, 1435, 1155, 949, 785.ESI-MS: m/z: 221.13 [M+H]+(calcd for [C13H11N2O2]+ 221.13).

N-butyl-5-fluorobenzo[d]oxazol-2-amine (9a)17 Synthesized according to General Procedure A using 5-fluorobenzoxazole-2-thiol (100 mg, 0.591 mmol) 9 and n-butylamine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 9a (92 mg, 0.443 mmol, 75%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.04 (dd,J = 8.0, 4.0 Hz, 1H), 6.95 (dd, J = 8.0, 4.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 5.72 (brs, 1H)3.40 (t, J = 8.0 Hz, 2H), 1.59 (m, 2H)1.37 (m, 2H), 0.88(t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 167.8, 161.3, 148.6, 124.4, 121.5, 116.5, 109.1, 45.2. IR (ATR, cm-1): 2951, 2925, 2867, 1692, 1583, 1454, 1245, 1145, 1129, 968, 839, 736.ESI-MS: m/z: 209.11 [M+H]+ (calcd for [C13H11N2O2]+ 209.11).

N-butyl-5-chlorobenzo[d]oxazol-2-amine (10a)17 Synthesized according to General Procedure A using 5-chlorobenzoxazole-2-thiol 10 (100 mg, 0.591 mmol) and n-butylamine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 10a (105 mg, 0.467 mmol, 79%) as a white solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.30 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.62 (brs, 1H) 3.47 (t, J = 8.0 Hz, 2H), 1.66 (m, 2H), 1.43 (m, 2H) 0.96 (t, J = 8.0 Hz, 3H).

13

C NMR (100 MHz, CDCl3): δ ppm 163.0, 147.0, 144.0,

129.3, 120.6, 116.2, 109.2, 42.9, 31.7, 19.9, 13.7. IR (ATR, cm-1): 3158, 3064, 2947, 2925, 2864, 1693, 1583, 1461, 1353, 1328, 1243, 944, 725. ESI-MS: m/z: 225.08 [M+H]+ (calcd for [C13H11N2O2]+ 225.08).

2-(5-chlorobenzo[d]oxazol-2-ylamino)ethanol (10f)17 Synthesized according to General Procedure A using 5-fluorobenzoxazole-2-thiol 9 (100 mg, 0.591 mmol) and n-butylamine (98 µL, 0.992 mmol) in water (0.6 mL) to afford 10f (71 mg, 0.337 mmol, 57%) as a white solid; 1H NMR (400 MHz, CD3OD): δ ppm 7.21 (d,J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.75 (t, J = 4.0 Hz, 2H), 3.50 (t, J


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= 4.0 Hz, 2H).

The Journal of Organic Chemistry 13

C NMR (100 MHz, CDCl3): δ ppm 165.4, 148.4, 145.3, 130.4, 121.6, 116.3, 110.5,

61,4, 46.2. IR (ATR, cm-1): ESI-MS: m/z: 213.04 [M+H]+ (calcd for [C13H11N2O2]+ 213.04).

2-(methylthio)benzo[d]oxazole (11)49 2-mercaptobenzoxazole 6 (200 mg, 1.32 mmol) and iodomethane (187 mg, 1.32 mmol) were stirred in ethyl acetate (10 mL) at room temperature for 1 hour. The reaction mixture was then quenched with water (10 mL) and extracted with EtOAc. The residues were dried with Na2SO4 and evaporated under reduced pressure to give the crude product, which was further purified by column chromatography (eluted with ethyl acetate/hexane) to afford 3 (194 mg, 1.17 mmol, 89%) as a yellow liquid: 1H NMR (400 MHz, CDCl3): δ ppm 7.60 (d,J = 8.0 Hz, 1H), 7.42 (d,J = 8.0 Hz, 1H), 7.26 (m, 2H), 2.76 (s, 3H).

1-benzyl-3-(2-hydroxyphenyl)thiourea (13b)50 Benzylisothiocyanate (200 mg, 1.342 mmol) and 2aminophenol (220 mg, 2.02 mmol) were stirred in ethyl acetate (10 mL) at room temperature for 30 minutes. The solvent was evaporated and crude solid was then washed with hexane several times to afford 5 (215 mg, 0.833mmol, 62%) as a white solid;1H NMR (400 MHz, (CD3)3CO): δ ppm7.53 (m, 1H), 7.24-7.38 (m, 5H), 7.07 (m, 1H), 6.95 (m, 1H), 6.84 (m, 1H), 4.87 (s, 2H).

quinazoline-4-thiol (16)48 4- hydroxyquinazoline (15) (500 mg, 3.42 mmol) and Lawesson’s reagent (2,075 mg, 5.13 mmol) in pyridine (5 mL) was heated under microwave irradiation 150 °C for 30 minutes. After cooling, water (100 mL) was added to the reaction mixture, and the precipitated yellow solid was filtered. The solid was redissolved in 3 M NaOH solution (10 mL × 3). The aqueous solution was neutralized with 1 M HCl solution (15 mL × 3) until complete precipitation occurred. After filtration, yellow solid was then rinsed with MeOH and dried to afford 16 (493 mg, 3.04 mmol, 85%) as a yellow solid: 1 H NMR (CDCl3, 400 MHz) δ 13.8 (brs, 1H,), 8.52 (d, J = 8.0 Hz, 1H,), 8.11 (s, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H).


17


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4-(n-butylamino)quinazoline (17a)17 Synthesized according to General Procedure B using 4mercaptoquinazoline 16 (100 mg, 0.617 mmol) and n-butylamine (91 µL, 0.926 mmol) in water (0.6 mL) to afford 17a (108 mg, 0.595 mmol, 87%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 8.59 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (m, 2H), 7.37 (m, 1H), 5.92 (s, 1H), 3.59 (m, 2H), 1.64 (m, 2H), 1.41 (m, 2H), 0.91 (d, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 159.5, 155.2, 149.1, 132.5, 128.3, 125.9, 120.8, 115.0, 41.0, 31.4, 20.3, 13.8. ESI-MS: m/z: 202.14 [M+H]+ (calcd for [C12H16N3]+ 202.13).

4-(piperidin-1-yl)quinazoline (17b)17 Synthesized according to General Procedure B using 4mercaptoquinazoline 16 (100 mg, 0.617 mmol) and piperidine (91 µL, 0.926 mmol) in water (0.6 mL) to afford 17b (110 mg, 0.518 mmol, 84%) as a yellow liquid; 1H NMR (400 MHz, CDCl3): δ ppm 8.72 (s, 1H), 7.90 (m, 2H), 7.74 (m, 1H), 7.46 (m, 1H), 3.76 (m, 4H), 1.81 (m, 4H).

13

C NMR (100 MHz,

CDCl3): δ ppm 164.9, 153.8, 151.2, 132.2, 127.9, 125.4, 125.1, 116.7, 51.0, 26.0, 24.3. ESI-MS: m/z: 214.14 [M+H]+ (calcd for [C13H14N3]+ 214.13).

4-(quinazolin-4-yl)morpholine (17c)17 Synthesized according to General Procedure B using 4mercaptoquinazoline 16 (100 mg, 0.617 mmol) and morpholine (91 µL, 0.926 mmol) in water (0.6 mL) to afford 17c (103 mg, 0.481 mmol, 78%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 8.75 (s, 1H), 7.94(m, 1H) 7.88 (m, 1H), 7.75 (m, 1H), 7.47 (m, 1H), 3.90 (m, 4H), 3.80 (m, 4H). 13C NMR (100 MHz, CDCl3): δ ppm 164.6, 153.8, 151.4, 132.7, 128.6, 125.7, 127.4, 116.4, 66.8, 50.3. ESI-MS: m/z: 216.12 [M+H]+ (calcd for [C13H14N3]+ 216.11).

ASSOCIATED CONTENT


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The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Copies of 1H, 13C NMR spectra of compounds 7a-l, 8-10a, 10f, 11, 13b, 16, 17a-c, picture of reaction mixture, and spectrum of EDX-SEM from PbS.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

Acknowledgements This study was financially supported by Thailand Research Fund (RSA6080018 and RTA6180007) and National Nanotechnology Centre (NANOTEC), NSTDA, Ministry of Science and Technology, Thailand, through its program of the Centre of Excellence Network. This work was also partially supported by a Grant for International Research Integration: Chula Research Scholar and Theeranon Tankam was supported by from Science Achievement Scholarship of Thailand.

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Microwave-Enhanced On-Water Amination of 2

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