Reactions of 5-Aminoisoxazoles with Î±-Diazocarbonyl Compounds

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Reactions of 5-Aminoisoxazoles with #-Diazocarbonyl Compounds: Wolff Rearrangement vs N-H Insertion Yun Ge, Wangbin Sun, Yang Chen, Yulin Huang, Zhuang Liu, Yaojia Jiang, and Teck-Peng Loh J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019

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The Journal of Organic Chemistry

Reactions of 5-Aminoisoxazoles with α-Diazocarbonyl Compounds: Wolff Rearrangement vs N–H Insertion Yun Ge,a# Wangbin Sun,a# Yang Chen,a Yulin Huang,a Zhuang Liu,a Yaojia Jianga* and Teck-Peng Loha, b*

a Institute

of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China E-mail: [email protected]

b

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore E-mail: [email protected]

Abstract: A highly chemoselective reaction between 5-aminoisoxazoles and -diazocarbonyl compounds has been described. Both Wolff rearrangement and N–H insertion products can be obtained selectively by the judicious choice of reaction conditions. In the case of the Wolff rearrangement reactions, the N-isoxazole amides are accessed as the sole products under thermal conditions. On the other hand, -amino acid derivatives of N-isoxazolescan be obtained through N–H insertion reactions in the presence of catalytic Rh2(Oct)4. Both reactions proceed under mild reaction conditions and feature a broad substrate scope.

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INTRODUCTION Isoxazole belongs to an important class of five-membered heterocycles found widely in a variety of biologically active compounds and therapeutic agents (Figure 1).1 Introducing of isoxazole rings to drug candidates contributes to decreased toxicity, increased efficacy and improved pharmacokinetic profiles.2 Thus, methods that allow the construction and modification of isoxazoles are highly desired.3 Although there are a plethora of efficient methods to prepare isoxazoles,4 modification of the isoxazole core itself has proven difficult. This would offer the possibility to access highly functionalized isoxazoles from simple starting materials.5 In our continuing interest in isoxazole chemistry,6 we explored the reactions of 5-aminoisoazoles with α-diazocarbonyl compounds to synthesize aminoisoxazoles bearing multiple functionalities.

N Me

O

Me

H N CN

Me O

Kinase inhibitors

N

O

Me Me CN

Me MeO H N S O O

N N

F F F

Cannabinoid receptor agonists

Ph

O

H N

O

O

O

Neuropeptide Y antagonists

Figure 1. Bioactive molecules carrying isoxazoles. α-Diazocarbonyl compounds are versatile building blocks that upon denitrogenation generate carbene species under thermal, photolytic or transition-metal catalyzed conditions.7 The reactivity of these diazos has been extensively studied and utilized in the development of new synthetic methods including cyclopropanations,8 cycloadditions,9 ylide formations,10 insertion reactions (C-H, N-H and NO insertions)11 and Wolff rearrangements.12 Due to the high reactivates of carbenes, the chemoselective reactions of α-diazocarbonyl compounds with aza-heterocycles represented a challenging task in organic synthesis.13 Davies group has elegantly demonstrated the N–O bond insertion reactions of isoxazoles


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with donor/acceptor type diazo compounds to give 4H-1,3-oxazines and pyridines (Scheme 1).14 Nevertheless, the chemistry of carbenes possessing acceptor/acceptor substituents has not been explored owing to their high thermal stability and low reactivity.15 Recently, we found that the aminoisoxazols could be efficiently transformed to 2H-azirine derivatives in the presence of ruthenium catalyst under visible light irradiation (Scheme 1).6 Herein, we describe the chemoselective reactions of

5-

aminoisoxazols with α-diazocarbonyl compounds. Both Wolff rearrangement and N-H insertion products could be obtained selectively by the judicious choice of the reaction conditions. Regarding the Wolff rearrangement reaction, the N-isoxazole amides are accessed as the sole products under thermal conditions. On the other hand, α-amino acid derivatives carrying N-isoxazoles could be obtained through N–H insertion reactions in the presence of catalytic Rh2(Oct)4. Davies' works: N

O

N2 +

R1

N

R

3

Ar

R2 O

[Rh]

R2

N2 +

Ar

Our previous work:

1.[Rh] / 2.DDQ

R2

EWG

R1

This work: catalyst-free

R

O NH2

R3

N

EWG

R1 R3 O Ar

R1

N

EWG O

Ar

[Ru]

N

visible light

O

NH2

O

EWG R1

H N

O

R2 O

R

N2

R1

N

N

O

Wolff rearrangement

R2 O

R N O R Rh2(Oct)4

NH R

1

R2

O O NH insertion

Scheme 1. Chemoselective reactions of isoxazoles.



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RESULTS AND DISCUSSION We began our study with 3-pheny-5-aminoisoxazol 1a and ethyl 2-diazo-3-oxobutanoate 2a as model substrates to explore the chemoselectivity of the competing Wolff rearrangement and N–H insertion reactions. Initially, the reaction was performed in the presence of Pd(OAc)2 catalyst in DCE at 60 。 C (Table 1, entry 1). The results showed that both Wolff rearrangement product 3aa and N–H insertion product 4aa could be obtained with low chemoselectivity (3aa/4aa = 9/30). Screening other metal catalysts, we found that while Cu(OAc)2 and Ag(OAc) could hardly promote the reaction (Table 1, entries 2–3), rhodium catalysts increased the yields and selectivity for the N–H insertion product 4aa significantly (Table 1, entries 4–5). Continuing screening the reaction conditions found that CH3CN was the optimal solvent compared to halogenic and aromatic solvents (Table 1, entries 6–8). The yield and selectivity of N–H insertion product 4aa could be dramatically increased to 88% (Table 1, entry 8). Interestingly, the Wolff rearrangement product 3aa could be obtained in 32% as sole product in the absence of any metal catalyst in CH3CN at 90

。 C.

Prolong the reaction time to 48 h, the product 3aa

could be obtained in up to 90% yield (Table 1, entry 10). Other solvents such as toluene and 1,4-dioxane failed to increase the reaction efficiency (Table 1, entries 11–12). Table 1. Optional reaction conditions[a] N

O

NH2

N2 + Me

OEt O

Ph 1a

metal solvent

O

N

O

OEt O

Ph

N O

Me

H N

Ph +

O

OEt

O 4aa

3aa

2a

NH Me

entry

catalyst

solvent

temp (oC)

yield (%)b 3aa 4aa

1

Pd(OAc)2

DCE

60

9

30

2

Cu(OAc)2

DCE

60

5c

0

3

AgOAc

DCE

60

0c

0

4

Rh2(OAc)4

DCE

60

10

41

5

Rh2(Oct)4

DCE

60

15

52

6

Rh2(Oct)4

DCM

60

20

49

7

Rh2(Oct)4

toluene

60

15

28

8

Rh2(Oct)4

CH3CN

60

0

88

CH3CN

90

32

0

9

-


O

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10

-

CH3CN

90

90d

0

11

-

toluene

90

28

0

-

1, 4-dioxane

90

0

0

12

[a] Conditions: A mixture of 1a (0.20 mmol, 1 equiv.), 2a (0.20 mmol, 1 equiv.), catalyst (1 mol %) and solvent (2 mL) were sealed in Schlenk tube under N2 atmosphere and the mixture was stirred for 24 h. [b] Yields were determined by 1H NMR, CH2Br2 was used an internal standard. [c] 10 mol % catalyst-loading. [d] The reaction time prolonged to 48 h, DCE = dichloroethane, DCM = dichloromethane.

With the optimal reaction conditions in hand, we explored the substrate scope of the Wolff rearrangement reaction of 5-aminoisoxazoles 1 and α-diazocarbonyl compounds 2 under metal-free conditions (Table 2). Generally, the reaction tolerated a broad range of substituted isoxazoles and diazo compounds with high chemoselectivity in good to excellent yields. Regarding the substituent effect on the 5-aminoisoxazole rings, various functional groups were examined in this transformation. Studying electronic effect, we found that the phenyl group with electron-withdrawing substituents (3da–3ea) gave lower yields compared to electron-donating groups (3ba–3ca). The halogen substituents (F, Cl, Br and I) on the para-site of phenyl ring reacted efficiently and afforded the desired products up to 95% yield (3fa–3ia). These aryl halides can be readily used in further coupling reactions,16 allowing access to functionalized isoxazole compounds. Naphthalenyl and heterocyclic (3ja–3la) substrates also provided the Wolff rearrangement products in good yields. Rather than aryl substituted isoxazoles, alkyl substrates also worked well and gave the corresponding products in moderate to good yields (3ma–3pa). Bulky groups such as tert-butyl (3oa) and adamantyl (3pa) did not hinder the reaction to give the desired products in 72% and 88% yields, respectively. Different α-diazocarbonyl compounds were also screened. Using ethyl 2-diazo-3-oxo-3-phenylpropanoate 2b instead of ethyl 2-diazo-3-oxobutanoate 2a, we found that the phenyl group had migrated during the Wolff rearranged process giving good to excellent yields



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of migrated products (3ab–3lb). The phenyl group bearing electron-withdrawing substituent (3ad) gave lower yield compared to electron-donating group (3ac). Diazodiketones were also investigated and found that alkyl groups tend to migrate compared to aryl groups (3ae–3ag). Unfortunately, donor/acceptor diazo compound 2h in the reaction failed to give the product. Table 2. Substrate scope for Wolff rearrangement reaction[a], [b] N

O

NH2

R +

R

N2

1

O

Me N

CO2Et O

Ph

O

Me O

4-CF3-C6H4

N

O

N

CO2Et

N

CO2Et

O

Me

H N

O

N

CO2Et

O

Me ( )6

N

O

N

CO2Et O

Ph

3ab, 88%

N

O

CO2Et O

Ph

O

H N

O

Ph O

N

O

N

H N

O

Ph

3af, 41%

O

O

CO2Et

Ph

O

Ph

H N

CO2Et O

3gb, 90%

N Ph

3ad, 52%

N

3ag, 95%

O

4-Cl-C6H4

4-NO2-C6H4 O

Ph

H N

N

CO2Et

3cb, 82%

4-MeO-C6H4 CO2Et

3pa, 88% Ph

O

4-MeO-C6H4

3ac, 92%

H N O

O

Ph

S 3lb, 82%

N

N

CO2Et O

H N

O

3bb, 90% Ph

H N

N

CO2Et

Me

H N

O

3oa, 72% Ph

O

4-Me-C6H4

N

CO2Et O

H N

O

3la, 75%

Me

H N

O

3na, 88%

Ph

CO2Et O

S

O

3ma, 67% H N

N

CO2Et

Me

H N

O

3ka, 87%

Me

H N

O

N

CO2Et

CO2Et O

3ha, 79%

O

N

Me

H N

O

3ja, 75%

3ia, 65%

O

4-Br-C6H4

Me

H N

O

O

O

N

3ga, 86% Me

H N

O

3da, 41%

CO2Et

4-Cl-C6H4

CO2Et O

4-NO2-C6H4

Me

H N

O

3fa, 95% Me

H N

4-I-C6H4

N

Me

H N

O

N

3ca, 91%

CO2Et

4-F-C6H4

3ea, 45% O

O

O

O 3

CO2Et

4-MeO-C6H4

Me

H N

O

N

CO2Et

R2

Me

H N

O

3ba, 95% H N

O

N

CO2Et

4-Me-C6H4

3aa, 90%

N

Me

H N

O

R1

H N

O

R

2

H N

O

N

O

1

N

CH3CN, 90 oC

R2

O

Me

H N

Ph O

O

3ae, 81%

Me

H N O

OMe

3ah, 0%c

[a] A mixture of 1 (0.20 mmol, 1.0 equiv.) and 2 (0.20 mmol, 1.0 equiv.) were stirred in 2 mL dry acetonitrile under N2 protection at 90 oC. [b] Isolated yield. [c] Both starting materials 1a and 2h unreacted.


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We then turned our attention to the substrate scope of the N–H insertion reaction of 5aminoisoxazoles 1 and α-diazocarbonyl compounds 2 (Table 3). For most substituents the trends observed for the Wolff rearrangement were replicated in the N–H insertion reactions as well. Electronic effects on the phenyl group of isoxazoles showed electron-donating groups (4ba and 4ca) performing well, giving the desired products in excellent yields, while electron-withdrawing groups decreased the yields (4da and 4ea). Notably, halogen substituents at the para-position of phenyl group worked well under standard conditions affording the desired products in good to excellent yields (4fa–4ia). Naphthalenyl (4ja) substrate could provide the product in 86% yield. Heterocycles, including furyl and thienyl groups, were also tolerated by the reaction, giving 81% and 76% yields, respectively (4ka and 4la). In addition to aryl substituted isoxazoles, alkyl substitutions proceeded smoothly and afforded the N-H insertion products in good yields (4ma–4pa). Also, like in the Wolff reaction, bulky groups such as tert-butyl (4oa) and adamantyl (4pa) gave the corresponding products in 72% and 70% yields, respectively. Fully substituted isoxazoles proceed well and double bonds remain intact under the reaction conditions to afford the amino acid derivatives in moderate yields (4qa–4ra). Ethyl 2-diazo-3-oxo-3phenylpropanoate 2b with different isoxazoles also gave the corresponding products in good to excellent yields (4ab–4lb). The phenyl group bearing MeO substituent of diazo (4ac) gave higher yield compared to NO2 group (4ad). As the same as the Wolff rearrangement reactions, donor/acceptor diazo compound 2h in the reaction failed to give the desired product 4ah.



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Table 3. Substrates scope for N–H insertion reactions a, b O

N

NH2 +

H N

O

Ph

O Me CO2Et

H N

O

4-CF3-C6H4

H N

O

4-I-C6H4

4ba, 92%

O Me CO2Et

H N

O

N 4-F-C6H4

O

O N

Me CO2Et

N

4-MeO-C6H4

Ph CO2Et

N

O

Ph

N

Me CO2Et

H N

O

4-NO2-C6H4 CO2Et

N Ph

O

H N O

N

Me CO2Et 4-NO2-C6H4

Me CO2Et

H N

O

N

N

H N

Me CO2Et

N Ph

O N

Me CO2Et

O N

Me CO2Et

N

S

O

H N

O Me CO2Et

O Me CO2Et

4la, 76%

H N

O

O Me CO2Et

4pa, 70%

O Ph CO2Et

H N

O

S

N

O

H N

4-Me-C6H4

4ab, 90%

O Ph CO2Et

H N

O

Me CO2Et

4ha, 81%

4oa, 72%

O

H N

O

4-Br-C6H4

4ka, 81%

O

O

4da, 53%

O

H N

H N

O

4ca, 94%

O

O

4gb, 85%

O

4ad, 53%

H N

4-Cl-C6H4

4cb, 94%

N

O

Me CO2Et

Ph

O

R1 CO2Et

4ga, 84%

4ra, 62%

H N

O

H N

R'

O

O

H N

4-Cl-C6H4

O

O

4qa, 58%

N

N

4na, 85%

Me CO2Et

Me

Ph

H N

H N

O

O

H N

Me CO2Et

4ja, 86%

4ma, 65%

O

R

O

4-MeO-C6H4

O

O

N

Me CO2Et

Me ( )6

N

Me CO2Et

N

4fa, 85%

H N

O

O

H N

4ia, 81%

N

H N

O

4

4-Me-C6H4

4ea, 42%

N

CH3CN, 60 oC

O

O

N

4aa, 88%

N

N

2

1

N

Rh2(Oct)4

OEt O

R'

R

N2

R1

O Ph CO2Et

4bb, 92%

O Ph CO2Et

N

O

Ph

4lb, 76%

H N

O 4-MeO-C6H4 CO2Et 4ac, 82%

4-MeO-C6H4 Me

4ah, 0%c

[a] Conditions: A mixture of 1 (0.20 mmol, 1.0 equiv.) and 2 (0.20 mmol, 1.0 equiv.), 1.0 mol % Rh2(Oct)4 were stirred in 2 mL dry acetonitrile under N2 protection at 60 oC. [b] Isolated yield. [c] 1a was decomposed to 2H-azirine as the major product. With these results in hand, we proposed a possible reaction pathway (Scheme 2-a). For the Wolff rearrangement reaction, a ketene intermediate B could be generated under thermal conditions from carbene A.

The ketene intermediate B could be attacked by 1a to afford the zwitterionic intermediate

C.Tautomerization of C results in the 3aa. On the other hand, 2a is known to give carbenoid intermediate


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D in the presence of Rh(II) catalyst upon denitrogenation. Intermediate D is then attacked by 5aminoisoxazole 1a to generate zwitterion E. The 4aa finally could be obtained via a proton transfer procedure.

O N N2 (a) Me

OEt O

Rh2(Oct)4

[Rh] Me

OEt O

O

O D

2a

N Thermal

Ph

Me

OEt O

O

O

O

H2 N

N

O

A

O

O

O

H N

Me

E

Ph

OEt 4aa

1a

OEt O

H

HN

NH2

Me

Wolff rearrangement

O

O

O N

Ph

[Rh] H2N Me OEt

Ph

Me OEt O

N

O Ph

OEt O

O 3aa

C

B

Me

Scheme 2. Proposed reaction mechanism.

Isoxazole derivatives are known synthons to prepare 2H-azirines through ring-contractions. To further demonstrate the synthetic utility of the developed protocol, we explored the synthesis of functionalized 2H-azirine in one-pot manner with our previous demonstrated method (Scheme 3).6 To our delight, the reaction proceeded smoothly in the presence of Rh(II) and Hoveyda–Grubbs II catalyst under visible light irradiation. The method provided the corresponding 2H-azirine product 5oa in 65% yield.

N2 Me N

O

NH2

CO2Et O 2a

Rh2(Oct)4 (1 mol %)

N

O

H N

O Me CO2Et

60 oC, CH3CN

1o

MesN NMes Cl Ru Cl i PrO

HG-II (1 mol %)

Green LED CH3CN, N2

4oa without isolation

Scheme 3. Transformation of isoxazole 1o to 2H-azirine 5oa.


N

H N O

O Me CO2Et

5oa, 65%


CONCLUSION In summary, a divergent method has been developed for the synthesis of amides and α-amino acids bearing N-isoxazole rings by orthogonal chemoselective reactions of 5-aminoisoxazoles and αdiazocarbonyl compounds. N-Isoxazole amides are accessed under thermal conditions via a Wolff rearrangement and α-amino acid derivatives carrying N-isoxazoles could be synthesized through an N– H insertion reaction in the presence of catalytic Rh2(Oct)4. Both reactions proceed under mild reaction conditions and feature a broad substrate scope.

EXPERIMENTAL SECTION General information. All reactions were carried out in flame or oven-dried glassware under nitrogen atmosphere with freshly distilled dry solvents under anhydrous conditions unless otherwise indicated. Flash column chromatography was performed with silica gel 60 (230 - 400 mesh). Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining with base solution of potassium permanganate and molybdate. NMR spectra were recorded at RT on 400 MHz Bruker spectrometers. The residual solvent signals were taken as the reference (7.26ppm for 1H NMR spectra and 77.0 ppm for 13C NMR spectra in CDCl3). Chemical shift (δ) is reported in ppm, coupling constants (J) are given in Hz. The following abbreviations classify the multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublet, q = quartet and br = broad signal. HRMS (ESI) spectra were recorded on a Waters Q-Tof premier TM mass spectrometer. General procedure for the synthesis of 3aa and 4aa Synthesis of 3aa: 1a (0.20 mmol, 32.0 mg) and 2a (0.20 mmol, 31.2 mg) were add to dry CH3CN (2 mL) in 10 ml Schlenk tube under N2 protection. The mixture was stirred at 90℃ oil bathuntil the total


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consumption of 1a by TLC (48h). The reaction mixture was evaporated in vacuum to remove the solvent. The crude reaction mixture was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate 1:10) to give the products 3aa (51.8 mg, 0.180 mmol, 90% yield). Synthesis of 4aa: 1a (0.20 mmol, 32.0 mg) and 2a (0.20 mmol, 31.2 mg) were add to dry CH3CN (2 mL) in 10 ml Schlenk tube under N2 protection. And then the Rh2(Oct)4 (1 mol %, 1.43 mg) was added to the mixture. The mixture was stirred at 60℃ oil bath until the total consumption of isoxazole by TLC (24h). The reaction mixture was filtered and then evaporated in vacuum to remove the solvent. The crude reaction mixture was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate 1:10) to give the products 4aa (50.7 mg, 0.176 mmol, 88% yield).

General procedure for isoxazoles 1. NH2OH•HCl (3.0 mmol, 208.0 mg) and NaOAc (3.0 mmol, 246.0 mg) were stirred in CH3OH (3.0 mL) at room temperature for 1 hour and then β-ketonitrile (1.0 mmol) was added to the mixture. The reaction mixture was continued to react until the starting material was consumed completely by TLC detection. Then 10 mL water was added to quench the reaction and extracted with ethyl acetate, the organic layer was washed with brine and dried with anhydrous Na2SO4. The crude reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether = 1/5) to get product. 3-Phenylisoxazol-5-amine (1a): The title compound was prepared according to the general procedure. The product was obtained as white solid. Mp. 105 - 106 ºC. Yield 65% (104.0 mg). 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.71 (m, 2H), 7.43 - 7.40 (m, 3H), 5.43 (s, 1H), 4.37 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 163.9, 129.8, 129.7, 128.8, 126.6, 78.3; HRMS (ESI) m/z [M+H]+: Calcd for C9H9N2O: 161.0715. Found: 161.0711.



3-(p-Tolyl)isoxazol-5-amine (1b): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 149 - 150ºC. Yield 70% (121.9 mg); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 5.42 (s, 2H), 4.52 (s, 1H), 2.38 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 168.7, 139.8, 129.4, 126.8, 126.5, 78.2, 21.4; HRMS (ESI) m/z

[M+H]+: Calcd for C10H11N2O:175.0871. Found: 175.0873. 3-(4-Methoxyphenyl)isoxazol-5-amine (1c): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 136 - 137 ºC. Yield 70% (133.1 mg); 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.39 (s, 1H), 4.50 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.6, 163.5, 160.8, 128.0, 122.2, 114.1, 78.1, 55.3; HRMS (ESI) m/z [M+H]+: Calcd for C10H11N2O2:191.0821. Found: 191.0825. 3-(4-Nitrophenyl)isoxazol-5-amine (1d): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 187 - 188 ºC. Yield 60% (123.03 mg); 1H NMR (400 MHz, d6-DMSO) δ 8.30 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 6.99 (s, 2H), 5.56 (s, 1H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 172.1, 161.4, 148.4, 136.6, 127.9, 124.5, 75,9; HRMS (ESI) m/z [M+H]+: Calcd for C9H8N3O3: 206.0566. Found: 206.0566. 3-(4-(Trifluoromethyl)phenyl)isoxazol-5-amine (1e): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 144 - 145 ºC. Yield 65% (148.2 mg); 1H

NMR (400 MHz, d6-DMSO) δ 7.96 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 6.93 (s, 2H), 5.52

(s, 1H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 171.9, 161.8, 134.4, 130.1 (q, J = 31.8 Hz), 127.4, 126.1 (q, J = 3.9 Hz), 124.5 (d, J = 270.4 Hz), 75.7; 19F NMR (376 MHz, CDCl3) δ- 62.6;HRMS (ESI) m/z [M+H]+: Calcd for C10H8F3N2O: 229.0589. Found: 229.0584.


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3-(4-Fluorophenyl)isoxazol-5-amine (1f): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 104 - 105 ºC. Yield 65% (115.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 - 7.68 (m, 2H), 7.13 - 7.08 (m, 2H), 5.40 (s, 1H), 4.52 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 163.6(d, J = 248.4 Hz), 162.9, 128.5 (d, J = 8.2 Hz), 125.9 (d, J = 8.2 Hz), 115.9 (d, J = 21.8 Hz), 78.1; 19F NMR (376 MHz, CDCl3) δ- 110.9; HRMS (ESI) m/z [M+H]+: Calcd for C9H8FN2O: 179.0621. Found: 179.0621. 3-(4-Chlorophenyl)isoxazol-5-amine (1g): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 165 - 166 ºC. Yield 80% (155.2 mg); 1H NMR (400 MHz, d6-DMSO) δ 7.76 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.84 (s, 2H), 5.43 (s, 1H); 13C{1H}

NMR (100 MHz, d6-DMSO) δ 171.1, 161.5, 134.1, 128.8, 127.9, 126.2, 75.0; HRMS (ESI) m/z

[M+H]+: Calcd for C9H8ClN2O: 195.0325. Found: 195.0326. 3-(4-Bromophenyl)isoxazol-5-amine (1h): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 128 - 129 ºC. Yield 62% (147.2 mg); 1H NMR (400 MHz, d6-DMSO) δ 7.72 (q, J = 8.6 Hz, 4H), 6.91 (s, 2H), 5.48 (s, 1H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 171.6, 162.0, 132.2, 129.6, 128.7, 123.3, 75.5; HRMS (ESI) m/z [M+H]+: Calcd for C9H8BrN2O: 238.9820. Found: 238.9819. 3-(4-Iodophenyl)isoxazol-5-amine (1i): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 146 - 147 ºC. Yield 61% (174.4 mg); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.42 (s, 1H), 4.52 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 163.0, 137.9, 129.2, 128.2, 95.9, 78.0; HRMS (ESI) m/z [M+H]+: Calcd for C9H8IN2O: 286.9681. Found: 286.9682.



3-(Naphthalen-2-yl)isoxazol-5-amine (1j): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 132 - 134 ºC. Yield 82% (172.3 mg); 1H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 8.02 - 7.88 (m, 3H), 7.89 (dd, J1 = 8.5 Hz, J2 = 1.7 Hz, 1H), 7.56 (t, J = 3.2 Hz, 2H), 6.85 (s, 2H), 5,57 (s, 1H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 171.0, 162.5, 133.3, 132.8, 128.3, 128.3, 127.6, 127.4, 126.8, 126.6, 125.7, 123.6, 75.2; HRMS (ESI) m/z [M+H]+: Calcd for C13H11N2O: 211.0871. Found: 211.0873. 3-(Furan-2-yl)isoxazol-5-amine (1k): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 95 - 96 ºC. Yield 63% (94.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 1.2 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.48 (dd, J1 = 3.6 Hz, J2 = 2.0 Hz, 1H), 5.40 (s, 1H), 4.70 (s, 2H);

13C{1H}

NMR (100 MHz, CDCl3) δ 168.7, 156.2, 144.8, 143.5,

111.5, 109.7, 77.6; HRMS (ESI) m/z [M+H]+: Calcd for C7H7N2O2: 151.0508. Found: 151.0513. 3-(Thiophen-2-yl)isoxazol-5-amine (1l): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 85 - 87 ºC. Yield 65% (107.9 mg); 1H NMR (400 MHz, CDCl3) δ 7.37-7.36 (m, 2H), 7.08 (dd, J1= 4.8 Hz, J2= 4.0 Hz, 1H), 5.38 (s, 1H), 4.64 (s, 2H); 13C{1H}

NMR (100 MHz, CDCl3) δ 168.8, 159.0, 131.4, 127.5, 127.1, 127.1, 78.3; HRMS (ESI) m/z

[M+H]+: Calcd for C7H7N2OS: 167.0279. Found: 167.0276. 3-Heptylisoxazol-5-amine (1m): The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 70% (127.5 mg); 1H NMR (400 MHz, CDCl3) δ 4.98 (s, 1H), 4.37 (s, 2H), 2.51 (t, J = 7.7 Hz, 2H), 1.65 - 1.57 (m, 3H), 1.33 - 1.27 (m, 7H), 0.88 (t, J = 7.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 166.1, 79.8, 31.7, 29.2, 29.0, 28.2, 26.4, 22.6, 14.1; HRMS (ESI) m/z [M+H]+: Calcd for C10H19N2O: 183.1497. Found: 183.1496.


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3-Cyclohexylisoxazol-5-amine (1n): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 124 - 125 ºC. Yield 87% (144.5 mg); 1H NMR (400 MHz, CDCl3) δ 4.94 (s, 1H), 4.59 (s, 2H), 2.54 (s, 1H), 1.87 - 1.66 (m, 5H), 1.39 - 1.24 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 168.2, 78.3, 36.2, 32.0, 26.0, 25.9; HRMS (ESI) m/z [M+H]+: Calcd for C9H15N2O: 167.1184. Found: 167.1183. 3-(tert-butyl)isoxazol-5-amine (1o): The title compound was prepared according to the general procedure. The product was obtained as yellow solid, Mp. 56 - 57 ºC. Yield 75% (105.1 mg); 1H NMR (400 MHz, CDCl3) δ 4.94 (s, 1H), 4.81 (s, 2H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 168.6, 77.7, 32.1, 29.5; HRMS (ESI) m/z [M+H]+: Calcd for C7H13N2O: 141.1028. Found: 141.1028. 3-((3R,5R,7R)-Adamantan-1-yl)isoxazol-5-amine (1p): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 110 - 112 ºC.

Yield 68% (147.7

mg); 1H NMR (400 MHz, CDCl3) δ 5.01 (s, 1H), 4.45 (s, 2H), 2.04 (S, 3H), 1.90 (d, J = 2.4 Hz, 6H), 1.78 - 1.71 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 168.0, 77.4, 41.4, 36.7, 34.2, 28.3; HRMS (ESI) m/z [M+H]+: Calcd for C13H19N2O: 219.1417. Found: 219.1419. 4-Methyl-3-phenylisoxazol-5-amine (1q): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 89 - 90 ºC. Yield 65% (113.2 mg); 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.60 (m, 2H), 7.47 (m, 3H), 4.38 (s, 2H), 1.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 163.6, 130.3, 129.3, 128.7, 127.9, 87.2, 7.2; HRMS (ESI) m/z [M+H]+: Calcd for C10H11N2O: 175.0871. Found: 175.0875. 4-Allyl-3-phenylisoxazol-5-amine (1r): The title compound was prepared according to the general procedure. The product was obtained as white solid, Mp. 64 - 65 ºC. Yield 67% (134.1 mg); 1H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 4.0 Hz, 2H), 7.44 - 7.42 (m, 3H), 5.94 - 5.84 (m, 1H), 5.16 - 5.11(m,



2H), 4.40 (s, 2H), 3.11 (dt, J1 = 5.7, J2 = 1.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 163.9, 135.0, 129.9, 129.3, 128.6, 128.1, 116.1, 88.4, 26.2; HRMS (ESI) m/z [M+H]+: Calcd for C12H13N2O: 201.1028. Found: 201.1031.

General procedure for α-diazo compounds 2 Method A: β-ketoester or ketone (1.0 mmol) and 4-methylbenzenesulfonyl azide (1.2 mmol, 236.4 mg) were stirred in CH3CN at 0℃ and DBU (1.2 equiv.) was added dropwise under nitrogen. The resulting solution was stirred at 0℃ for 3 h and slowly brought to RT. Upon completion as indicated by thin layer chromatography (TLC), the reaction was quenched with water, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by column chromatography (hexane/ethyl acetate = 9:1). Method B: β-ketoester or ketone (1.0 mmol) and 4-methylbenzenesulfonyl azide (1.2 mmol, 236.4 mg) were stirred in ethanol at 0℃ and triethylamine (1.2 equiv.) was added dropwise under nitrogen. The resulting solution was stirred at 0℃ for 3 h and slowly brought to RT. Upon completion as indicated by thin layer chromatography (TLC), the reaction was quenched with water, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by column chromatography (hexane/ethyl acetate = 9:1). Ethyl 2-diazo-3-oxobutanoate (2a): The title compound was prepared according to Method A. The product was obtained as yellow oil, 132.6 mg, Yield 85%; 1H NMR (400 MHz, CDCl3) δ 4.26 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 161.4, 76.3, 61.4, 28.2, 14.3; HRMS (ESI) m/z [M+H]+: Calcd for C6H9N2O3: 157.0613. Found: 157.0613.


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Ethyl 2-diazo-3-oxo-3-phenylpropanoate (2b): The title compound was prepared according to Method A. The product was obtained as yellow oil, 178.8 mg, Yield 82%; 1H NMR (400 MHz, CDCl3) δ 7.63 7.61 (m, 2H), 7.54 - 7.44 (m, 1H), 7.43 - 7.40 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 187.0, 161.0, 137.1, 132.3, 128.4, 127.9, 76.2, 61.7, 14.2; HRMS

(ESI) m/z [M+H]+: Calcd for C11H11N2O3: 219.0770. Found: 219.0771. Ethyl 2-diazo-3-(4-methoxyphenyl)-3-oxopropanoate (2c): The title compound was prepared according to Method A. The product was obtained as yellow oil, 198.4 mg, Yield 80%; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 163.1, 161.3, 131.0, 129.4, 113.1, 75.6, 61.5, 55.4, 14.3; HRMS (ESI) m/z [M+H]+: Calcd for C9H15N2O: 167.1184. Found: 167.1185. Ethyl 2-diazo-3-(4-nitrophenyl)-3-oxopropanoate (2d): The title compound was prepared according to Method A. The product was obtained as yellow oil, 186.7 mg, Yield 71%; 1H NMR (400 MHz, CDCl3) δ 8.26 - 8.23 (m, 2H), 7.74 - 7.72 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.6, 160.3, 149.5, 142.6, 129.8, 123.1, 62.0, 14.2; HRMS (ESI) m/z [M+H]+: Calcd for C11H10N3O5: 264.0620. Found: 264.0621. 2-Diazo-1-phenylbutane-1,3-dione (2e): The title compound was prepared according to Method A. The product was obtained as yellow solid, Mp. 124 - 125 ºC, 169.2 mg, Yield 90%; 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.44 (m, 5H), 2.54 (d, J = 4.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.8, 185.1, 137.3, 132.7, 128.9, 127.4, 83.7, 29.2; HRMS (ESI) m/z [M+H]+: Calcd for C10H9N2O2: 189.0664. Found: 189.0665. 1-Cyclohexyl-2-diazo-3-phenylpropane-1,3-dione (2f): The title compound was prepared according to Method A. The product was obtained as yellow oil, 184.3 mg, Yield 72% (144.5 mg); 1H NMR (400



MHz, CDCl3) δ 7.62 - 7.44 (m, 5H), 3.40 - 3.32 (m, 1H), 1.88 - 1.66 (m, 5H), 1.48 - 1.26 (m, 5H); 13C{1H}

NMR (100 MHz, CDCl3) δ 196.5, 185.0, 137.7, 132.6, 128.9, 127.3, 82.5, 47.7, 28.9, 25.9, 25.8;

HRMS (ESI) m/z [M+H]+: Calcd for C15H17N2O2: 257.1290. Found: 257.1291 2-diazocyclohexane-1,3-dione (2g): The title compound was prepared according to Method B. The product was obtained as yellow solid, Mp. 124 - 125 ºC, 103.5 mg, Yield 75%; 1H NMR (400 MHz, CDCl3) δ 2.52 - 2.49 (m, 4H), 2.03 - 1.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 85.0, 36.8, 18.6; HRMS (ESI) m/z [M+H]+: Calcd for C6H7N2O2: 139.0508. Found: 139.0509.

General procedure for the Wolff rearrangement products 3. Isoxazole 1 (0.20 mmol) and diazo compound 2 (0.20 mmol) were add to dry CH3CN (2 mL) in 10 ml Schlenk tube under N2 protection. The mixture was stirred at 90℃ oil bath until the total consumption of isoxazole by TLC (48h). The reaction mixture was evaporated in vacuum to remove the solvent. The crude reaction mixture was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate 1:10) to give the products. Ethyl 2-methyl-3-oxo-3-((3-phenylisoxazol-5-yl)amino)propanoate (3aa): The title compound was prepared according to the general procedure for reaction in 48 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 90% (51.8 mg); 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.99 – 7.66 (m, 2H), 7.50 – 7.42 (m, 3H), 6.73 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.54 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.3, 163.7, 160.2, 130.2, 129.0, 128.9, 126.2, 62.5, 87.4, 46.5, 15.3, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H17N2O4: 289.1188. Found: 289.1189. Ethyl 2-methyl-3-oxo-3-((3-(p-tolyl)isoxazol-5-yl)amino)propanoate (3ba): The title compound was


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prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 95% (57.6 mg); 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.42 – 7.16 (m, 2H), 6.70 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.53 (q, J = 7.4 Hz, 1H), 2.40 (s, 3H), 1.59 (d, J = 7.3 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.3, 163.7, 159.8, 130.2, 129.5, 126.7, 126.2, 87.4, 62.4, 46.5, 21.5, 15.3, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H19N2O4: 303.1345. Found: 303.1346. Ethyl

3-((3-(4-methoxyphenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate

(3ca):

The

title

compound was prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.5). The product was obtained as yellow oil. Yield 91% (58.1 mg); 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.54 (q, J = 7.3 Hz, 1H), 1.57 (d, J = 7.3 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 165.5, 163.3, 161.1, 160.0, 128.2, 121.5, 114.3, 87.3, 62.4, 55.4, 46.6, 15.1, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H19N2O5: 319.1294. Found: 319.1295. Ethyl 2-methyl-3-((3-(4-nitrophenyl)isoxazol-5-yl)amino)-3-oxopropanoate (3da): The title compound was prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 41% (27.3 mg); 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.56 (q, J = 7.1 Hz, 1H), 1.60 (d, J = 7.4 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 165.5, 163.3, 161.1, 160.0, 128.2, 121.5, 114.3, 87.3, 62.4, 55.4, 46.6, 15.1, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16N3O6: 334.1039. Found: 334.1040. Ethyl 2-methyl-3-oxo-3-((3-(4-(trifluoromethyl)phenyl)isoxazol-5-yl)amino)propanoate (3ea): The title compound was prepared according to the general procedure for reaction in 44 h (EA/PE = 20%, Rf =



0.6). The product was obtained as yellow solid, Mp. 82 - 83 ºC. Yield 45% (32.0 mg); 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 6.77 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.54 (q, J = 7.4 Hz, 1H), 1.60 (d, J = 7.4 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.4, 162.5, 160.7, 132.5, 132.0 (d, J = 32.7 Hz), 127.1, 125.9 (q, J = 3.9 Hz), 123.8 (q, J = 270.4 Hz), 87.4, 62.5, 46.5, 15.4, 14.0; 19F NMR (376 MHz, CDCl3) δ- 62.7; HRMS (ESI) m/z [M+H]+: Calcd for C16H16F3N2O4: 357.1062. Found: 357.1063. Ethyl 3-((3-(4-fluorophenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3fa): The title compound was prepared according to the general procedure for reaction in 44 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 95% (58.2 mg). The reaction was also performed in large scale (6 mmol) in 48h and gave the 3fa 82% yield (1.51 g). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.99 – 7.65 (m, 2H), 7.14 (t, J = 8.7 Hz, 2H), 6.69 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.54 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.4, 163.9 (d, J = 248.6 Hz), 161.5(d, J = 248.3 Hz), 128.7 (d, J = 8.6 Hz), 125.2 (d, J = 3.3 Hz), 116.0 (d, J = 21.9 Hz), 87.3, 62.5, 46.5, 15.3, 14.0; 19F NMR (376 MHz, CDCl3) δ - 109.2; HRMS (ESI) m/z [M+H]+: Calcd for C15H16FN2O4: 307.1094. Found: 307.1095. Ethyl 3-((3-(4-chlorophenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ga): The title compound was prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 86% (57.1 mg); 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 6.70 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.53 (q, J = 7.4 Hz, 1H), 1.59 (d, J = 7.4 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).; 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.4, 162.7, 160.4, 136.2, 129.2, 128.0, 127.5, 87.3, 62.5, 46.5, 15.3, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16ClN2O4: 323.0799. Found: 323.0800.


Page 20 of 47

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Ethyl 3-((3-(4-bromophenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ha): The title compound was prepared according to the general procedure for reaction in 48 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 79% (58.0 mg); 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 6.70 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.55 (q, J = 7.3 Hz, 1H), 1.57 (d, J = 7.4 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 165.5, 162.8, 160.5, 132.1, 128.3, 127.9, 124.5, 87.3, 62.4, 46.5, 15.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16BrN2O4: 367.0293. Found: 367.0294. Ethyl 3-((3-(4-iodophenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ia): The title compound was prepared according to the general procedure for reaction in 44 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 65% (53.8 mg); 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.52 (q, J = 7.4 Hz, 1H), 1.59 (d, J = 7.6 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.3, 162.9, 160.4, 138.1, 128.5, 128.3, 96.4, 87.2, 62.5, 46.5, 15.4, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16IN2O4: 415.0155. Found: 415.0156. Ethyl 3-((3-(4-iodophenyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ja): The title compound was prepared according to the general procedure for reaction in 48 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil. Yield 75% (50.7 mg); 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.27 (s, 1H), 8.07 – 7.76 (m, 4H), 7.61 – 7.49 (m, 2H), 6.87 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.55 (q, J = 7.4 Hz, 1H), 1.61 (d, J = 7.4 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 165.3, 163.7, 160.2, 134.1, 133.2, 128.7, 128.6, 127.8, 127.1, 126.8, 126.7, 126.4, 123.7, 87.5, 62.5, 46.5, 15.4, 14.1; HRMS (ESI) m/z [M+H]+: Calcd for C19H19N2O4: 339.1345. Found: 339.1346. Ethyl 3-((3-(furan-2-yl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ka): The title compound was



prepared according to the general procedure for reaction in 4 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil. Yield 87% (48.5 mg); 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.54 (d, J = 1.5 Hz, 1H), 6.88 (d, J = 3.4 Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.55 (q, J = 7.3 Hz, 1H), 1.57 (d, J = 7.4 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 165.5, 160.0, 155.9, 144.1, 144.1, 111.7, 110.9, 86.9, 62.4, 46.5, 15.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H15N2O5: 279.0981. Found: 279.0982. Ethyl 2-methyl-3-oxo-3-((3-(thiophen-2-yl)isoxazol-5-yl)amino)propanoate (3la): The title compound was prepared according to the general procedure for reaction in 42 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil. Yield 75% (44.3 mg); 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.47 (dd, J1 = 3.7 Hz, J2 = 1.2 Hz, 1H), 7.41 (dd, J1 = 5.1 Hz, J2 = 1.1 Hz, 1H), 7.11 (dd, J1 = 5.1 Hz, J2 = 3.6 Hz, 1H), 6.67 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.54 (q, J = 7.3 Hz, 1H), 1.58 (d, J = 7.4 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.1, 165.4, 160.1, 158.9, 130.7, 127.8, 127.7, 127.7, 87.5, 62.5, 46.5, 15.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H15N2O4S: 295.0753. Found: 295.0754. Ethyl 3-((3-heptylisoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3ma): The title compound was prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.8). The product was obtained as yellow oil. Yield 67% (40.3 mg); 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 6.23 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.50 (q, J = 7.3 Hz, 1H), 2.67 – 2.55 (m, 2H), 1.68– 1.59 (m, 2H), 1.55 (d, J = 7.4 Hz, 3H), 1.38 – 1.21 (m, 11H), 0.86 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 165.9, 165.2, 159.4, 88.9, 62.3, 46.5, 31.7, 29.1, 28.9, 28.1, 26.4, 22.6, 15.2, 14.1, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H27N2O4: 311.1971. Found: 311.1972. Ethyl 3-((3-heptylisoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3na): The title compound was


Page 22 of 47

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prepared according to the general procedure for reaction in 32 h (EA/PE = 20%, Rf = 0.8). The product was obtained as yellow oil. Yield 88% (51.8 mg); 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 6.24 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.49 (q, J = 7.4 Hz, 1H), 2.75 – 2.63 (m, 1H), 2.00 – 1.90 (m, 2H), 1.87 – 1.75 (m, 2H), 1.75 – 1.66 (m, 1H), 1.54 (d, J = 7.3 Hz, 3H), 1.50 – 1.33 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H), 1.27 – 1.20 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 170.1, 165.3, 159.3, 87.7, 62.3, 46.6, 36.3, 31.8, 31.8, 25.9, 25.8, 15.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H23N2O4: 295.1658. Found: 295.1659. Ethyl 3-((3-(tert-butyl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3oa): The title compound was prepared according to the general procedure for reaction in 38 h (EA/PE = 20%, Rf = 0.8). The product was obtained as yellow oil. Yield 72% (38.8 mg); 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 6.30 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.51 (q, J = 7.3 Hz, 1H), 1.54 (d, J = 7.3 Hz, 3H), 1.30 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 171.9, 165.4, 159.3, 87.4, 62.3, 46.6, 32.4, 29.3, 15.1, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H21N2O4: 269.1501. Found: 269.1502. Ethyl 3-((3-((3R,5R,7R)-adamantan-1-yl)isoxazol-5-yl)amino)-2-methyl-3-oxopropanoate (3pa): The title compound was prepared according to the general procedure for reaction in 38 h (EA/PE = 20%, Rf = 0.8). The product was obtained as yellow oil. Yield 88% (60.9 mg); 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 6.27 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.52 (q, J = 7.3 Hz, 1H), 2.08 – 1.99 (m, 3H), 1.92 (d, J = 2.9 Hz, 6H), 1.80 – 1.66 (m, 6H), 1.51 (d, J = 7.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.5, 171.77, 165.5, 159.3, 86.8, 62.2, 46.6, 41.2, 36.5, 34.4, 28.2, 15.0, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C19H27N2O4: 347.1971. Found: 347.1972. Ethyl 3-oxo-2-phenyl-3-((3-phenylisoxazol-5-yl)amino)propanoate (3ab): The title compound was prepared according to the general procedure for reaction in 48 h (EA/PE = 20%, Rf = 0.6). The product



Page 24 of 47

was obtained as yellow oil. Yield 88% (61.6 mg); 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.80 7.78 (m, 2H), 7.45 - 7.39 (m, 8H), 6.72 (s, 1H), 4.71 (s, 1H), 4.32 - 4.26 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 163.7, 163.5, 160.0, 132.9, 130.2, 129.5, 129.0, 128.9, 128.9, 128.0, 126.8, 87.7, 62.8, 57.9, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C20H19N2O4: 351.1345. Found: 351.1346. Ethyl 3-oxo-2-phenyl-3-((3-(p-tolyl)isoxazol-5-yl)amino)propanoate (3bb): The title compound was prepared according to the general procedure for reaction in 48 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 88% (65.5 mg); 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.45 - 7.37 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 4.70 (s, 1H), 4.36 - 4.21 (m, 2H), 2.39 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 163.7, 163.5, 159.8, 140.3, 132.9, 129.6, 129.5, 128.9, 128.0, 126.7, 126.1, 87.6, 62.7, 57.9, 21.5, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O4: 365.1501. Found: 365.1502. Ethyl

3-((3-(4-methoxyphenyl)isoxazol-5-yl)amino)-3-oxo-2-phenylpropanoate

(3cb):

The

title

compound was prepared according to the general procedure for reaction in 36 h (EA/PE = 20%, Rf = 0.5). The product was obtained as yellow oil. Yield 82% (62.3 mg); 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.54 – 7.32 (m, 5H), 6.95 (d, J = 8.9 Hz, 2H), 6.67 (s, 1H), 4.71 (s, 1H), 4.49 – 4.14 (m, 2H), 3.83 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 163.7, 163.3, 161.2, 159.8, 132.9, 129.4, 128.9, 128.2, 128.1, 121.4, 114.3, 87.5, 62.7, 57.9, 55.4, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O5: 381.1450. Found: 381.1451. Ethyl 3-((3-(4-chlorophenyl)isoxazol-5-yl)amino)-3-oxo-2-phenylpropanoate (3gb): The title compound was prepared according to the general procedure for reaction in 32 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 90% (69.1 mg); 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H),


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7.72 (d, J = 8.6 Hz, 2H), 7.57 – 7.34 (m, 7H), 6.69 (s, 1H), 4.70 (s, 1H), 4.48 – 4.02 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 170.8, 163.6, 162.7, 160.2, 136.2, 132.9, 129.5,

129.2, 128.9, 128.0, 127.9, 127.5, 87.5, 62.8, 57.8, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C20H18ClN2O4: 385.0955. Found: 385.0956. Ethyl 3-oxo-2-phenyl-3-((3-(thiophen-2-yl)isoxazol-5-yl)amino)propanoate (3lb): The title compound was prepared according to the general procedure for reaction in 30 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 82% (58.4 mg); 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.55 – 7.30 (m, 7H), 7.10 (t, J = 4.4 Hz, 1H), 6.65 (s, 1H), 4.70 (s, 1H), 4.44 – 3.92 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 163.5, 159.9, 158.9, 132.8, 130.7, 129.5, 128.9, 128.0, 128.0, 127.8, 127.7, 127.6, 87.7, 62.8, 57.8, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C18H17N2O4S: 357.0909. Found: 357.0910. Ethyl

2-(4-methoxyphenyl)-3-oxo-3-((3-phenylisoxazol-5-yl)amino)propanoate

(3ac):

The

title

compound was prepared according to the general procedure for reaction in 44 h (EA/PE = 20%, Rf = 0.5). The product was obtained as yellow oil. Yield 92% (70.0 mg); 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.87 – 7.70 (m, 2H), 7.51 – 7.41 (m, 3H), 7.36 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 4.64 (s, 1H), 4.41 – 4.17 (m, 2H), 3.81 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.5, 171.77, 165.5, 159.3, 86.8, 62.2, 46.6, 41.2, 36.5, 34.4, 28.2, 15.0, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O5: 381.1450. Found: 381.1451. Ethyl 2-(4-nitrophenyl)-3-oxo-3-((3-phenylisoxazol-5-yl)amino)propanoate (3ad): The title compound was prepared according to the general procedure for reaction in 45 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 52% (41.1 mg); 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.52 – 8.0 (m, 2H), 7.80 –7.74 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.52 – 7.35 (m, 3H), 6.71 (s, 1H), 4.84



(s, 1H), 4.41 – 4.17 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.5, 171.77, 165.5, 159.3, 86.8, 62.2, 46.6, 41.2, 36.5, 34.4, 28.2, 15.0, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C20H18N3O6: 396.1196. Found: 396.1197. 2-Methyl-3-oxo-3-phenyl-N-(3-phenylisoxazol-5-yl)propanamide (3ae): The title compound was prepared according to the general procedure for reaction in 46 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil. Yield 82% (51.9 mg); 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.82 – 7.77 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.47 – 7.42 (m, 3H), 6.73 (s, 1H), 4.62 (q, J = 7.4 Hz, 1H), 1.68 (d, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.6, 166.7, 163.7, 160.3, 135.0, 134.6, 130.2, 129.1, 129.1, 128.9, 128.8, 126.8, 87.5, 48.5, 18.0; HRMS (ESI) m/z [M+H]+: Calcd for C19H17N2O3: 321.1239. Found: 321.1240. 2-Cyclohexyl-3-oxo-3-phenyl-N-(3-phenylisoxazol-5-yl)propanamide (3af): The title compound was prepared according to the general procedure for reaction in 38 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil. Yield 41% (31.8 mg); 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.07 – 8.02 (m, 2H), 7.84 – 7.77 (m, 2H), 7.69 – 7.63 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.47 – 7.42 (m, 3H), 6.71 (s, 1H), 4.44 (d, J = 9.3 Hz, 1H), 2.26 – 2.13 (m, 1H), 1.87 – 1.73 (m, 2H), 1.72 – 1.61 (m, 3H), 1.37 – 0.99 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.4, 164.5, 163.7, 160.3, 136.8, 134.7, 130.1, 129.1, 128.9, 128.8, 126.8, 87.2, 61.1, 43.3, 31.9, 30.7, 26.0, 25.9, 25.8; HRMS (ESI) m/z [M+H]+: Calcd for C24H25N2O3: 389.1865. Found: 389.1866. 2-Oxo-N-(3-phenylisoxazol-5-yl)cyclopentane-1-carboxamide (3ag): The title compound was prepared according to the general procedure for reaction in 41 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil. Yield 95% (51.3 mg); 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.80 - 7.78(m, 2H), 7.44 - 7.42(m, 3H), 6.67(s, 1H), 3.26 - 3.22 (m, 1H), 2.47 - 2.30 (m, 2H), 2.13 - 2.09 (m, 2H), 1.92


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- 1.87 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 215.5, 163.6, 163.2, 160.2, 130.1, 129.1, 128.9, 126.8, 87.3, 55.4, 54.4, 38.8, 38.8, 25.5, 25.4, 25.3, 20.2, 20.1; HRMS (ESI) m/z [M+H]+: Calcd for C15H15N2O3: 271.1083. Found: 271.1084.

General procedure for N-H insertion products Isoxazole (0.20 mmol), diazo compounds (0.20 mmol) were add to dry CH3CN (2 mL) in 10ml Schlenk tube under N2 protection. And then the catalyst (1 mol %) was added to the mixture. The mixture was stirred at 60 ℃ oil bath until the total consumption of isoxazole by TLC (24h). The reaction mixture was filtered and then evaporated in vacuum to remove the solvent. The crude reaction mixture was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate 1:10) to give the products. Ethyl 3-oxo-2-((3-phenylisoxazol-5-yl)amino)butanoate (4aa): The title compound was prepared according to the general procedure for reaction in 24 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone:enol ratio of 58 : 42. Yield 88% (50.7 mg); 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 0.42H), 7.77 – 7.68 (m, 2H), 7.46– 7.38 (m, 3H), 5.92 (d, J = 6.8 Hz, 0.58H), 5.53 (s, 0.42H), 5.37 & 5.25 (s, 1H), 4.95 (d, J = 6.8 Hz, 0.58H), 4.36 – 4.19 (m, 2H), 2.41 & 2.13 (s, 3H), 1.31 & 1.25 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 176.2, 170.7, 170.1, 167.5, 166.2, 163.8, 163.7, 129.9, 129.8, 129.6, 129.4, 128.7, 128.7, 126.6, 126.6, 102.9, 76.7, 66.9, 63.1, 61.4, 27.1, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16N2O4: 288.1110. Found: 288.1110. & 4.95 (d, J = 6.8 Hz & 6.8 Hz, 1H) Ethyl 3-oxo-2-((3-phenylisoxazol-5-yl)amino)butanoate (4ba): The title compound was prepared according to the general procedure for reaction in 14 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone:enol ratio of 69 : 31. Yield 92% (55.6 mg); 1H NMR (400 MHz, CDCl3)



δ 12.39 (s, 0.31H), 7.61 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 5.90 (d, J = 6.9 Hz, 0.69H), 5.53 (s, 0.31H), 5.34 & 5.22 (s, 1H), 4.94 (d, J = 6.9 Hz, 0.69H), 4.36 – 4.18 (m, 2H), 2.40 & 2.13 (s, 3H), 2.38 (s, 3H), 1.31 & 1.24 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 176.1, 170.8, 170.0, 167.4, 166.3, 163.7, 163.6, 140.0, 139.9, 126.6, 126.5, 103.0, 76.6, 66.9, 63.1, 61.4, 27.1, 21.4, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H19N2O4: 303.1345. Found: 303.1346. Ethyl 2-((3-(4-methoxyphenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4ca): The title compound was prepared according to the general procedure for reaction in 16 h (EA/PE = 20%, Rf = 0.5). The product was obtained as yellow oil in a ketone:enol ratio of 41 : 59. Yield 92% (58.7 mg); 1H NMR (400 MHz, CDCl3) δ 12.39 (s, 0.59H), 7.70 –7.62 (m, 2H), 6.99 – 6.88 (m, 2H), 5.88 (d, J = 6.9 Hz, 0.41H), 5.49 (s, 0.59H), 5.31 & 5.19 (s, 1H), 4.93 (d, J = 6.8 Hz, 0.41H), 4.36 – 4.18 (m, 2H), 3.84 (s, 3H), 2.40 & 2.13 (s, 3H), 1.31 & 1.24 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 176.1, 170.8, 169.9, 167.3, 166.3, 163.4, 163.3, 160.9, 160.8, 128.0, 128.0, 122.2, 121.9, 114.1, 114.1, 103.0, 76.5, 66.9, 63.1, 61.4, 55.3, 27.1, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H19N2O5: 319.1294. Found: 319.1295. Ethyl 2-((3-(4-nitrophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4da): The title compound was prepared according to the general procedure for reaction in 26 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone:enol ratio of 73 : 27. Yield 53% (35.4 mg); 1H NMR (400 MHz, CDCl3) δ 12.4 (s, 0.27H), 8.35 – 8.22 (m, 2H), 7.94 – 7.84 (m, 2H), 6.05 (d, J = 6.9 Hz, 0.73H), 5.67 (s, 0.27H),

5.43 & 5.32 (s, 1H), 4.98 (d, J = 6.9 Hz, 0.73H), 4.39 – 4.19 (m, 2H), 2.43 & 2.13 (s, 3H), 1.32

& 1.24 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 176.4, 170.8, 170.6, 168.2, 166.0, 161.8, 161.8, 148.6, 135.8, 135.6, 131.2, 127.5, 127.4, 124.0, 123.6, 76.7, 66.7, 63.2, 61.5, 27.2, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16N3O6: 334.1039. Found: 334.1040.


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Ethyl 2-((3-(4-nitrophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4ea): The title compound was prepared according to the general procedure for reaction in 28 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow solid in a ketone : enol ratio of 37 : 63, Mp. 76 - 77 ºC. Yield 42% (30.0 mg); 1H NMR (400 MHz, CDCl3) δ 12.41 (s, 0.63H), 7.84 (t, J = 8.3 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 5.99 (d, J = 6.9 Hz, 0.37H), 5.60 (s, 0.63H), 5.40 & 5.29 (s, 1H),

4.97 (d, J = 6.8 Hz, 0.37H), 4.37 – 4.19 (m,

2H), 2.42 & 2.14 (s, 3H), 1.32 & 1.25 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 176.3, 170.6, 170.5, 167.9, 166.1, 162.5, 162.5, 133.1, 132.9, 131.8, 131.7, 131.5, 131.4, 126.9, 126.9, 125.7 (p, J = 3.6 Hz), 123.9 (d, J = 272.2 Hz), 123.9 (d, J = 272.2 Hz), 102.7, 66.8, 63.2, 61.4, 27.2, 17.8, 14.2, 14.0; 19F NMR (376 MHz, CDCl3) δ - 62.6, 62.7; HRMS (ESI) m/z [M+H]+: Calcd for C16H16F3N2O4: 357.1062. Found: 357.1063. Ethyl 2-((3-(4-fluorophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4fa): The title compound was prepared according to the general procedure for reaction in 14 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow solid in a ketone:enol ratio of 73 : 27, Mp. 56 - 58 ºC. Yield 85% (52.2 mg). The reaction was also performed in large scale (6 mmol) in 20h and gave the 4fa 80% yield (1.47 g). 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 0.27H), 7.76 – 7.65 (m, 2H), 7.10 (t, J = 8.7 Hz, 2H), 5.94 (d, J = 6.9 Hz, 0.73H), 5.56 (s, 0.27H), 5.33 & 5.21 (s, 1H), 4.95 (d, J = 6.8 Hz, 0.73H), 4.39 – 4.18 (m, 2H), 2.41 & 2.13 (s, 3H), 1.31 & 1.24 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 176.2, 170.7, 170.2, 166.9 (d, J = 144.3 Hz), 164.9(d, J = 4.2 Hz), 162.8(d, J = 7.1 Hz), 128.5(q, J = 4.4 Hz), 125.6(d, J = 19.9 Hz), 115.9(q, J = 3.6 Hz), 102.8, 76.6, 66.8, 63.1, 61.4, 27.1, 17.8, 14.2, 14.0; 19F NMR (376 MHz, CDCl3) δ - 108.4, 112.4; HRMS (ESI) m/z [M+H]+: Calcd for C15H16FN2O4: 307.1094. Found: 307.1095. Ethyl 2-((3-(4-chlorophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4ga): The title compound was



prepared according to the general procedure for reaction in 17 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone:enol ratio of 54 : 46. Yield 84% (54.3 mg); 1H NMR (400 MHz, CDCl3) δ 12.39 (s, 0.46H), 7.68 – 7.61 (m, 2H), 7.40 – 7.35 (m, 2H), 5.97 (d, J = 6.9 Hz, 0.54H), 5.61 (s, 0.46H), 5.33 & 5.22 (s, 1H), 4.94 (d, J = 6.9 Hz, 0.54H), 4.38 – 4.18 (m, 2H), 2.41& 2.12 (s, 3H), 1.31 & 1.23 (t, J = 7.2 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 176.2, 170.7, 170.3, 167.7, 162.7, 162.7, 135.8, 135.7, 129.0, 129.0, 128.1, 127.9, 127.9, 127.9, 102.8, 76.7, 76.5, 66.8, 63.1, 61.4, 27.2, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16ClN2O4: 323.0799. Found: 323.0800. Ethyl 2-((3-(4-bromophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4ha): The title compound was prepared according to the general procedure for reaction in 24 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 39 : 61. Yield 70% (51.4 mg); 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 0.61H), 7.68 – 7.50 (m, 4H), 5.94 (d, J = 6.9 Hz, 0.39H), 5.55 (s, 0.61H), 5.34 & 5.22 (s, 1H), 4.94 (d, J = 6.8 Hz, 0.39H), 4.37 – 4.18 (m, 2H), 2.41 & 2.13 (s, 3H), 1.31 & 1.24 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.8, 176.2, 170.7, 170.3, 167.7, 166.1, 162.8, 162.7, 132.0, 131.9, 128.6, 128.4, 128.2, 128.1, 124.1, 124.0, 102.8, 76.5, 66.8, 63.1, 61.4, 27.2, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16BrN2O4: 367.0293. Found: 367.0294. Ethyl 2-((3-(4-iodophenyl)isoxazol-5-yl)amino)-3-oxobutanoate (4ia): The title compound was prepared according to the general procedure for reaction in 24 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 62 : 38. Yield 68% (56.4 mg); 1H NMR (400 MHz, CDCl3) δ 12.39 (s, 0.38H), 7.76 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.9 Hz, 2H), 5.92 (d, J = 6.9 Hz, 0.62H), 5.50 (s, 0.38H), 5.34 & 5.22 (s, 1H), 4.94 (d, J = 6.8 Hz, 0.62H), 4.40 – 4.18 (m, 2H), 2.41 & 2.13 (s, 3H), 1.31 & 1.25 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.8, 176.2, 170.7,


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170.3, 167.7, 166.1, 162.9, 162.8, 137.9, 137.9, 129.2, 128.9, 128.2, 128.2, 102.8, 96.0, 95.9, 76.7, 76.5, 66.8, 63.1, 61.4, 27.2, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H16IN2O4: 415.0155. Found: 415.0156. Ethyl 2-((3-(naphthalen-2-yl)isoxazol-5-yl)amino)-3-oxobutanoate (4ja): The title compound was prepared according to the general procedure for reaction in 20 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 46 : 54. Yield 51% (34.6 mg); 1H NMR (400 MHz, CDCl3) δ 12.43 (s, 0.54H), 8.17& 8.15 (s, 1H), 8.00 – 7.81 (m, 4H), 7.56 – 7.45 (m, 2H), 5.97 (d, J = 6.9 Hz, 0.46H), 5.58 (s, 0.54H), 5.50 & 5.39 (s, 1H), 4.98 (d, J = 6.8 Hz, 0.46H), 4.41 – 4.19 (m, 2H), 2.42 & 2.16 (s, 3H), 1.32 & 1.25 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 176.2, 170.8, 170.2, 167.6, 166.3, 163.8, 134.0, 134.0, 133.2, 133.1, 128.5, 128.5, 128.5, 128.4, 127.8, 127.0, 126.9, 126.8, 126.7, 126.5, 126.4, 126.3, 123.8, 103.0, 76.8, 76.7, 66.9, 63.1, 61.4, 27.1, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C19H19N2O4: 339.1345. Found: 339.1346. Ethyl 3-oxo-2-((3-(thiophen-2-yl)isoxazol-5-yl)amino)butanoate (4la): The title compound was prepared according to the general procedure for reaction in 26 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 67 : 33. Yield 72% (42.5 mg); 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 0.33H), 7.40 – 7.36 (m, 2H), 7.08 (dd, J1 = 4.9 Hz, J2= 3.8 Hz, 1H), 5.91 (d, J = 6.9 Hz, 0.67H), 5.52 (s, 0.33H), 5.31 & 5.19 (s, 1H), 4.93 (d, J = 6.8 Hz, 0.67H),

4.36 – 4.18 (m, 2H), 2.41

& 2.13 (s, 3H), 1.31 & 1.25 (t, J = 7.2 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 176.2, 170.7, 170.0, 167.4, 166.1, 158.9, 158.9, 131.4, 131.2, 127.5, 127.4, 127.3, 127.2, 127.1, 127.1, 102.8, 76.8, 76.7, 66.8, 63.1, 61.4, 27.1, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H15N2O4S: 295.0573. Found: 295.0574. Ethyl 2-((3-heptylisoxazol-5-yl)amino)-3-oxobutanoate (4ma): The title compound was prepared



according to the general procedure for reaction in 16 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil in a ketone:enol ratio of 44 : 56. Yield 65% (40.3 mg); 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 0.56H), 5.76 (d, J = 6.9 Hz, 0.44H), 5.41 (s, 0.56H), 4.85 (d, J = 6.9 Hz, 0.44H), 4.89 & 4.76 (s, 1H), 4.35 – 4.16 (m, 2H), 2.48 (t, J = 7.7 Hz, 2H), 2.36 & 2.08 (s, 3H), 1.64 – 1.52 (m, 2H), 1.37 – 1.21 (m, 11H), 0.86 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 175.9, 170.8, 169.4, 166.9, 166.3, 166.0, 103.1, 78.6, 78.1, 76.7, 66.9, 62.9, 61.2, 31.7, 29.2, 29.2, 29.0, 28.2, 27.1, 26.4, 26.4, 22.6, 17.7, 14.2, 14.1, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C16H27N2O4: 311.1971. Found: 311.1972. Ethyl 2-((3-cyclohexylisoxazol-5-yl)amino)-3-oxobutanoate (4na): The title compound was prepared according to the general procedure for reaction in 17 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil in a ketone : enol ratio of 67 : 33. Yield 85% (50.0 mg); 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 0.33H), 5.75 (d, J = 6.8 Hz, 0.67H), 5.39 (s, 0.33H), 4.84 (d, J = 6.8 Hz, 0.67H), 4.89 & 4.76 (s, 1H), 4.36 – 4.16 (m, 2H), 2.67 – 2.48 (m, 1H), 2.36 & 2.08 (s, 3H), 1.98 – 1.63 (m, 6H), 1.47 – 1.14 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3, 175.8, 170.8, 170.2, 169.2, 166.7, 166.4, 103.1, 76.8, 76.7, 66.9, 62.9, 61.2, 36.3, 36.2, 32.0, 27.1, 26.0, 26.0, 25.9, 25.9, 17.8, 14.2, 14.0, 1.0; HRMS (ESI) m/z [M+H]+: Calcd for C15H23N2O4: 295.1658. Found: 295.1659. Ethyl 2-((3-(tert-butyl)isoxazol-5-yl)amino)-3-oxobutanoate (4oa): The title compound was prepared according to the general procedure for reaction in 23 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil in a ketone : enol ratio of 50 : 50. Yield 68% (36.5 mg); 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 0.50H), 5.74 (d, J = 6.8 Hz, 0.50H), 5.38 (s, 0.50H), 4.84 (d, J = 6.8 Hz, 0.50H), 4.93 & 4.79 (s, 1H), 4.37 – 4.14 (m, 2H), 2.37 & 2.09 (s, 3H), 1.37 – 1.17 (m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 175.8, 173.8, 170.8, 169.2, 166.6, 166.4, 103.2, 76.2, 75.8, 66.9, 62.9, 62.9, 61.2,


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41.4, 41.4, 36.7, 36.6, 34.3, 28.3, 28.2, 27.1, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H21N2O4: 269.1501. Found: 269.1502. Ethyl 2-((3-(tert-butyl)isoxazol-5-yl)amino)-3-oxobutanoate (4pa): The title compound was prepared according to the general procedure for reaction in 26 h (EA/PE = 20%, Rf = 0.7). The product was obtained as yellow oil in a ketone : enol ratio of 47 : 53. Yield 70% (48.5 mg); 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 0.53H), 5.73 (d, J = 6.8 Hz, 0.47H), 5.36 (s, 0.53H), 4.83 (d, J = 6.8 Hz, 0.47H), 4.92 & 4.78 (s, 1H), 4.36 – 4.14 (m, 2H), 2.36 & 2.08 (s, 3H), 2.06 – 1.99 (m, 3H), 1.97 – 1.81 (m, 6H), 1.80 – 1.67 (m, 6H), 1.29 & 1.23 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 175.8, 173.8, 170.8, 169.3, 166.8, 166.4, 103.2, 76.7, 76.4, 66.9, 62.9, 61.2, 32.2, 29.4, 29.3, 27.1, 17.8, 14.2, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C19H27N2O4: 347.1971. Found: 347.1972. Eethyl 2-((4-methyl-3-phenylisoxazol-5-yl)amino)-3-oxobutanoate (4qa): The title compound was prepared according to the general procedure for reaction in 18 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 78 : 22. Yield 58% (32.0 mg); 1H NMR (400 MHz, CDCl3) δ 12.31 (s, 0.22H), 7.65 – 7.55 (m, 2H), 7.50 – 7.37 (m, 3H), 5.44 (d, J = 7.8 Hz, 0.78H), 5.43 (s, 0.22H), 5.20 (d, J = 7.7 Hz, 0.78H),

4.40 – 4.15 (m, 2H), 2.45 & 2.17 (s, 3H), 1.98 & 1.92 (s, 3H),

1.32 & 1.23 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.8, 176.0, 170.8, 166.6, 165.6, 164.2, 163.9, 163.8, 130.0, 129.3, 129.2, 128.6, 128.6, 128.1, 102.6, 86.9, 86.8, 65.9, 62.9, 61.2; HRMS (ESI) m/z [M+H]+: Calcd for C16H19N2O4: 303.1345. Found: 303.1346. Ethyl 2-((4-allyl-3-phenylisoxazol-5-yl)amino)-3-oxobutanoate (4ra): The title compound was prepared according to the general procedure for reaction in 15 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 66 : 34. Yield 62% (40.8 mg); 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 0.34H), 7.60 – 7.51 (m, 2H), 7.48 – 7.39 (m, 3H), 6.01 – 5.84 (m, 1H), 5.61 (d, J =



Page 34 of 47

7.7 Hz, 0.66H), 5.60 (s, 0.34H), 5.21 (d, J = 7.7 Hz, 0.66H), 5.28 – 5.10 (m, 2H), 4.38 – 4.14 (m, 2H), 3.16 & 3.12 (dt, J1= 5.7 Hz & 5.4 Hz , J2= 1.8 Hz & 1.8 Hz, 2H), 2.45 & 2.16 (s, 3H), 1.32 & 1.25 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.5, 166.4, 166.3, 164.9, 164.1, 135.5, 134.8, 129.7, 129.4, 128.7, 128.2, 128.1, 116.5, 116.1, 88.1, 87.8, 65.9, 62.9, 61.2, 27.8, 26.1, 26.0, 18.2, 14.2, 14.0 ; HRMS (ESI) m/z [M+H]+: Calcd for C18H21N2O4: 329.1501. Found: 329.1502. Ethyl 3-oxo-3-phenyl-2-((3-phenylisoxazol-5-yl)amino)propanoate (4ab): The title compound was prepared according to the general procedure for reaction in 16 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow. Yield 90% (63.0 mg); 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.07 (m, 2H), 7.77 – 7.70 (m, 2H), 7.69 – 7.63 (m, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.46 – 7.36 (m, 3H), 6.20 (d, J = 7.9 Hz, 1H), 5.80 (d, J = 7.9 Hz, 1H), 5.49 (s, 1H), 4.18 (qd, J1 = 7.1 Hz, J2 = 1.5 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 167.8, 166.7, 163.8, 134.8, 133.6,

129.9, 129.5, 128.9,

128.7, 126.7, 76.7, 62.9, 62.6, 13.8; HRMS (ESI) m/z [M+H]+: Calcd for C20H19N2O4: 351.1345. Found: 351.1346. Ethyl 3-oxo-3-phenyl-2-((3-(p-tolyl)isoxazol-5-yl)amino)propanoate (4bb): The title compound was prepared according to the general procedure for reaction in 24 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow. Yield 92% (67.0 mg); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz, 2H), 7.71 – 7.58 (m, 3H), 7.54 (t, J = 7.6 Hz, 2H), 7.28 – 7.19 (m, 2H), 6.15 (d, J = 7.9 Hz, 1H), 5.78 (d, J = 7.9 Hz, 1H), 5.46 (s, 1H), 4.23 – 4.13 (m, 2H), 2.38 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 167.6, 166.7, 163.7, 139.9, 134.8, 133.6, 129.5, 129.4, 128.9, 126.7, 126.5, 76.7, 62.9, 62.6, 21.4, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O4: 365.1501. Found: 365.1502. Ethyl

2-((3-(4-methoxyphenyl)isoxazol-5-yl)amino)-3-oxo-3-phenylpropanoate

(4cb):

The

title

compound was prepared according to the general procedure for reaction in 22 h (EA/PE = 20%, Rf =


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0.5). The product was obtained as yellow. Yield 94% (72.8 mg); 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.12 (m, 2H), 7.73 – 7.63 (m, 3H), 7.59 – 7.51 (m, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.19 (d, J = 7.7 Hz, 1H), 5.80 (d, J = 7.9 Hz, 1H), 5.45 (s, 1H), 4.20 (qd, J1 = 7.1 Hz, J2 = 1.4 Hz, 2H), 3.85 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 167.6, 166.8, 163.4, 160.9, 134.8, 133.6, 129.5, 129.4, 128.9, 126.7, 126.5, 76.7, 62.9, 62.6, 21.4, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O5: 381.1450. Found: 381.1451. Ethyl 2-((3-(4-chlorophenyl)isoxazol-5-yl)amino)-3-oxo-3-phenylpropanoate (4gb): The title compound was prepared according to the general procedure for reaction in 20 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow. Yield 85% (65.3 mg); 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.10 (m, 2H), 7.71 – 7.61 (m, 3H), 7.54 (t, J = 7.8 Hz, 2H), 7.44 – 7.34 (m, 2H), 6.20 (d, J = 7.8 Hz, 1H), 5.78 (d, J = 7.8 Hz, 1H), 5.45 (s, 1H), 4.18 (qd, J1 = 7.1 Hz, J2 = 1.1Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 167.9, 166.6, 162.8, 135.8, 134.8, 133.5, 129.5, 129.0, 129.0, 128.0, 127.9, 62.9, 62.5, 13.8; HRMS (ESI) m/z [M+H]+: Calcd for C20H18ClN2O4: 385.0955. Found: 385.0956. Ethyl 3-oxo-3-phenyl-2-((3-(thiophen-2-yl)isoxazol-5-yl)amino)propanoate (4lb): The title compound was prepared according to the general procedure for reaction in 16 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow. Yield 70% (53.8 mg); 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.09 (m, 2H), 7.71 – 7.63 (m, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.42 – 7.34 (m, 2H), 7.11 – 7.05 (m, 1H), 6.19 (d, J = 7.8 Hz, 1H), 5.77 (d, J = 7.9 Hz, 1H), 5.43 (s, 1H), 4.24 – 4.12 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 167.6, 158.9, 134.8, 133.5, 131.2, 129.5, 129.0, 127.5, 127.2, 127.2, 76.7, 62.9, 62.5, 13.8; HRMS (ESI) m/z [M+H]+: Calcd for C18H17N2O4S: 357.0909. Found: 357.0907 Ethyl

3-(4-methoxyphenyl)-3-oxo-2-((3-phenylisoxazol-5-yl)amino)propanoate

(4ac):

The

title

compound was prepared according to the general procedure for reaction in 20 h (EA/PE = 20%, Rf =



0.5). The product was obtained as yellow. Yield 82% (62.3 mg); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.0 Hz, 2H), 7.77 – 7.69 (m, 2H), 7.45 – 7.38 (m, 3H), 7.00 (d, J = 8.9 Hz, 2H), 6.19 (d, J = 7.9 Hz, 1H), 5.74 (d, J = 7.9 Hz, 1H), 5.47 (s, 1H), 4.18 (qd, J1= 7.1 Hz, J2 = 1.8 Hz, 2H), 3.91 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.2, 167.9, 167.0, 164.9, 163.8, 132.0, 129.8, 129.6, 128.7, 126.7, 126.4, 114.2, 62.8, 62.2, 55.7, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C21H21N2O5: 381.1450. Found: 381.1451. Ethyl 3-(4-nitrophenyl)-3-oxo-2-((3-phenylisoxazol-5-yl)amino)propanoate (4ad): The title compound was prepared according to the general procedure for reaction in 18 h (EA/PE = 20%, Rf = 0.6). The product was obtained as yellow oil in a ketone : enol ratio of 67 : 33. Yield 52% (41.1 mg); 1H NMR (400 MHz, CDCl3) δ 12.92 (s, 0.33H), 8.38 & 8.23 (d, J = 8.9 Hz & 8.9 Hz, 2H), 8.31 & 7.99 (d, J = 8.9 Hz & 8.9 Hz, 2H), 7.76 – 7.66 (m, 2H), 7.48 – 7.38 (m, 3H), 6.08 (d, J = 7.8 Hz, 0.67H), 5.83 (d, J = 7.8 Hz, 0.67H), 5.65 (s, 0.33H), 5.51 & 5.33 (s, 1H), 4.34 & 4.22 (q, J = 7.1 Hz & 7.1 Hz, 2H), 1.29 & 1.17 (t, J = 7.1 Hz & 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.8, 171.4, 169.4, 168.5, 167.3, 165.9, 163.9, 163.7, 151.1, 138.5, 138.1, 130.5, 130.0, 129.5, 129.3, 128.8, 126.6, 124.1, 123.5, 104.3,77.0, 76.7, 63.4, 62.9, 62.4, 14.2, 13.9; HRMS (ESI) m/z [M+H]+: Calcd for C20H18N3O6: 396.1196. Found: 396.1197. General procedure for 2H-azirines A mixture of isoxazole (0.20 mmol), diazo compound (0.2 mmol) and catalyst (1 mol %) in dry CH3CN (2 mL) was added to a 10 ml schlenk tube and stirred for 24 h. The mixture was added Hoveyda–Grubbs catalystII (1 mol %) and stirred under 36 W Green LEDs for 48h. Then the solvent was removed in vacuum, the residue was purified by column chromatography using dichloromehane/ethyl acetate eluent to afford the pure product 5oa. Ethyl 3-(3-(tert-butyl)-2H-azirine-2-carboxamido)-2-methyl-4-oxopentanoateethyl (5oa): The title


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compound was prepared according to the general procedure for reaction in 40 h (EA/PE = 60%, Rf = 0.2). The product was obtained as yellow oil. Yield 65% (38.5 mg); 1H NMR (400 MHz, CDCl3) δ 6.59 (d, J = 6.5 Hz, 1H), 5.24 (t, J = 6.7 Hz, 1H), 4.36 – 4.09 (m, 2H), 2.49 (d, J = 2.3 Hz, 1H), 2.36 (s, 3H), 1.31 (s, 9H), 1.35 – 1.23 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 198.1, 170.9, 170.2, 170.1, 165.8, 165.8, 63.0, 62.8, 62.7, 33.3, 31.3, 28.2, 27.9, 25.8, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C13H21N2O4: 269.1501. Found: 269.1500.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxx. 1H

and 13C NMR spectra of all the products (PDF)

AUTHOR INFORMATION Corresponding Authors *[email protected]; *[email protected] #Those

authors are contributed equally to this work.

ORCID Teck-Peng Loh: 0000-0002-2936-337X Yaojia Jiang: 0000-0003-0695-0069 Notes The authors declare no competing financial interest.



ACKNOWLEDGMENTS The authors gratefully acknowledge funding from the National Natural Science Foundation of China (21502089), Jiangsu Province Funds Surface Project (BK 20161541) and the Starting Funding of Research (39837107) from Nanjing Tech University. Dr. Juha (Rice University, US) is thanked for proofreading. References and notes (1) (a) Agrawal, N.; Mishra, P. The synthetic and therapeutic expedition of isoxazole and its analogs. Med. Chem. Res. 2018, 27, 1309. (b) Hamama, W. S.; Ibrahim, M. E.; Zoorob, H. H. Advances in the chemistry of aminoisoxazole. Synth. Commun. 2013, 43, 2393. (c) Frolund, B.; Jorgensen, A. T.; Tagmose, L. T. B.; Stensbol, H.; Vestergaad, T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; KrogsgaardLarsen, P.; Liljefors, T. Novel class of potent 4-Arylalkyl substituted 3-isoxazolol GABAA antagonists: synthesis, pharmacology, and molecular modelling. J. Med. Chem. 2002, 45, 2454. (d) Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V. M. C.; Mangano, N. G.; Caruso, A. Synthesis and pharmacological activities of novel 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives. Arch. Pharm. 1999, 332, 50. (e) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.; Marwood, R.; Patel. S.; Ragan. C. 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl) isoxazole: A potent, selective antagonist at human cloned dopamine D4 receptors. J. Med. Chem. 1996, 39, 1943. (f) Carlsen, L.; Dopp, D.; Dopp, H.; Duus, F.; Hartmann, H.; Lang-Fugmann, S.; Schulze, B.; Smalley, R. K.; Wakefield, B. J. In houben-weyl methods in organic chemistry; E. Schaumann (Ed.); Georg Thieme Verlag: Stuttgart, Germany, 1992; vol. E8a, pp. 45. (g) Jacobsen, N.; Pedersen, L. E. K.; Wengel, A. Insecticidal activity of 3-isoxazolyl methanesulfonates and related compounds. Pesticide Sci. 1990, 29, 95.


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catalyst-free CH3CN, 90 oC R N R

O

NH2

R O

O

R2 O

O

R

N2

1

N

R1

H N

O

2

Wolff rearrangement 26 examples, up to 95% yield Broad substrate scope

R = aryl, alkyl and heterocyclic R1 = aryl, alkyl, R2 = OEt, alkyl

No/Low catalyst-loading Highly chemoselectivity

N O R 1.0 mol % Rh2(Oct)4 o

CH3CN, 60 C

NH R1

OEt O

O


N-H insertion 25 examples, up to 94% yield

Reactions of 5-Aminoisoxazoles with Î±-Diazocarbonyl Compounds

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