Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(III

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Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(#) Nitrate as Nitration and Cyclization Reagent Zhenzhen Lai, Zhenxing Li, Yawei Liu, Pengkun Yang, Xiaomin Fang, Wenkai Zhang, Baoying Liu, Haibo Chang, Hao Xu, and Yuanqing Xu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02483 • Publication Date (Web): 09 Dec 2017 Downloaded from http://pubs.acs.org on December 9, 2017

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The Journal of Organic Chemistry

Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(Ⅲ) Nitrate as Nitration and Cyclization Reagent Zhenzhen Lai,a,‡ Zhenxing Li,b,‡ Yawei Liu,a,‡ Pengkun Yang,a Xiaomin Fang,a Wenkai Zhang,a Baoying Liu,a Haibo Chang,a Hao Xu*,a,b and Yuanqing Xu*,a a

College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, P. R. China.

b

State Key Laboratory of Heavy Oil Processing, China University of Petroleum-Beijing, Beijing

102249, P. R. China. E-mail : [email protected]; [email protected]

ABSTRACT: A simple and direct method for iron(Ⅲ) nitrate mediated synthesis of isoxazoles from alkynes has been developed; both self-coupling and cross-coupling products could be successfully prepared from alkynes. Meanwhile for cross-coupling and cyclizing of two different alkynes examined, the iron-mediated system shows good chemoselectivity for the synthesis of corresponding isoxazoles. In our method, cheap and ecofriendly iron(Ⅲ) nitrate is used as the nitration and cyclization reagent, KI is used as the additive; they both play a positive role in this transformation. Furthermore, a different mechanism for the formation of isoxazoles from alkynes has been proposed.

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INTRODUCTION Isoxazoles are core components of numerous pharmaceutically active molecules such as mofezolac, acivicin, zonisamide, broxaterol and leflunomide.1 Furthermore, they can serve as efficient building blocks in diverse functional materials.2 Therefore, various methods for the synthesis of isoxazoles have been developed.3 Normally, 1,3-dipolar cycloaddition of nitrile oxides with alkynes is the most direct route to access these heterocycles; and the nitrile oxides are always obtained in situ from precursors such as nitro compounds4 or substituted oximes.5 However, most of these methods suffer from the use of relatively unavailable starting materials, tedious workup, harsh conditions, or require employing the substrates as the solvent.3-5 Therefore, the development of a practical procedure to access isoxazoles from more readily available substrates is still highly desirable. Alkynes are a class of readily available substrates, and widely used in the preparation of various heterocycles.6 It will be a simple and direct approach to prepare isoxazoles from alkynes by employing suitable nitration and cyclization reagent. In 1993, gasparrini’s group developed a gold-catalyzed synthesis of 3,5-disubstituted isoxazoles via self-coupling and cyclizing of terminal alkynes, using excess nitric acid as nitration and dehydration reagent (Scheme 1A).7 Afterward the similar reaction was performed by combined treatment of terminal alkynes with SO3 and sodium nitrate in glacial acetic acid (Scheme 1B).8 In 2017, a simple method via self-coupling and cyclizing of aromatic terminal alkynes to prepare isoxazoles was developed, employing t-BuONO as nitration reagent and Sc(OTf)3 as cyclization reagent (Scheme 1C).9 Although the methods above are simple, few are selective and high yielding, and only a self-coupling product could be obtained from terminal alkynes. Recently, Xu’s group prepared isoxazoles via cross-coupling and cyclizing of aromatic terminal alkynes with electron-deficient alkynes or aliphatic terminal alkynes in benzonitrile under copper nitrate mediated conditions (Scheme 1D);10 however in order to avoid the self-coupling and cyclizing of aromatic terminal alkynes, excess amount 2


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of aromatic terminal alkynes should be added dropwise by using a syringe pump for 2.5-5h; so the chemoselectivity was relatively poor. Meanwhile in contrast to the reaction with electron-deficient olefins,11 the cross-coupling and cyclizing of terminal alkynes with electron-deficient alkynes is more difficult and poorly selective under copper nitrate mediated conditions. Given this, it is critical to develop alternate nitration and cyclization reagents for the chemoselective synthesis of isoxazoles from a variety of alkynes under mild conditions; a highly chemoselective mediated system for this transformation is certainly desirable. Previous work O

[t-Bu4N]AuCl4 (A) 2 R C CH + HNO3

(B) 2 R C CH + NaNO3

NaNO2, CH3NO2

2

O

AcOH as solvent

R

R N O 2 examples, 53-55% O

Sc(OTf)3 quinoline DCE, 80 oC

Ar

Ar N O 6 examples, 34-53%

Cu(NO3)2 3H2O

3

(D) Ar C CH + R

R N O 6 examples, 35-50%

SO3-dioxane

(C) 2 Ar C CH + t-BuONO

1

R

R

O

R2

1

Ar R3 PhCN as solvent N O R = H or EWG 60 oC, N2 R3 = EWG or Alkyl 38 examples, 29-97% 2

dropwise addition by using a syringe pump for 2.5-5h This work O

Fe(NO3)3 9H2O

(E) 2 Ar C CH

KI as additive THF, 60 oC, N2

Ar

Ar N O

R = Aryl or Alkyl

7 examples, 51-70%

1

2

(F) 2 Ar C CH + R

3

R

Fe(NO3)3 9H2O

O

R2

Ar1 R3 KI and t-BuCN N O R = H or EWG as additive R3 = EWG or Alkyl EtOAc/PhCN (1:1) 30 examples, 47-76% 70 oC, N2 2

Scheme 1. Direct synthesis of isoxazoles from alkynes

3



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Iron(Ⅲ) nitrate as nitration reagent has tremendous advantages owing to its inexpensive and environmentally friendly characteristics. And it could be used as a nitration reagent for electron-rich arene12 and liquid ketones13 (Scheme 2). However, the application of iron(Ⅲ) nitrate in the nitration of alkynes, was very rare due to relatively weak nitration-ability of iron(Ⅲ) nitrate and relatively strong boundelectron ability of alkynes. All of the above prompts us to explore the feasibility of synthesizing isoxazoles from alkynes under iron(Ⅲ) nitrate-mediated and mild conditions. In continuation of our endeavors to develop simple methods for the synthesis of N-heterocycles,14 we herein report a iron nitratemediated cascade synthesis of isoxazoles from alkynes (Scheme 1E-1F); both self-coupling and crosscoupling products could be successfully prepared from alkynes by this method.

Scheme 2. Employing iron(Ⅲ) nitrate as nitration reagent

RESULTS AND DISCUSSION As shown in Table 1, iron (Ⅲ) nitrate-mediated synthesis of isoxazole 3a via self-coupling and cyclizing of alkyne 1a was choose to optimize the conditions including solvents and additives. Firstly, different solvents were screened, and THF was the best choice (entries 1-6). The effect of additive was also investigated, and KI showed best activity (entries 4,7,8). Without addition of KI, the coupling efficiency decreased significantly (entry 9). Furthermore, only trace amount of product 3a was monitored by TLC in the absence of Fe(NO3)3·9H2O (entry 12). Moreover, when the reaction was performed in air, product 4


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3a was provided in moderate yield (59 %); the result suggested an inert atmosphere would benefit this transformation (compare entry 4 with entry 13), because the Glaser coupling of terminal alkynes was easy to occur in the presence of transition metal catalyst and molecular oxygen.15 In addition, the yield of 3a was also influenced by the loading of Fe(NO3)3·9H2O or KI. When the amount of Fe(NO3)3·9H2O or KI was decreased, the yield of 3a decreased obviously (entries 14,15,17). While the amount of Fe(NO3)3·9H2O was increased, the yield of 3a did not increase as expected (entry 16). Table 1. Optimization of conditions on Fe(NO3)3-mediated synthesis of 3-benzoyl-5-phenylisoxazole (3a) from phenylacetylene (1a)a

Entry

Solvent

Additive

Temp (oC)

Yield (%)

1

EtOAc

KI

70

55

2

Toluene

KI

100

50

3

EtOH

KI

70

39

4

THF

KI

60

70

5

DMF

KI

100

39

6

CH3CN

KI

60

51

7

THF

I2

60

63

8

THF

t-BuCN

60

60

9

THF

--

60

48

10

THF

KI

50

62

11

THF

KI

70

65

12b

THF

KI

60

trace

13c

THF

KI

60

59

14d

THF

KI

60

15 5



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15e

THF

KI

60

45

16f

THF

KI

60

70

17g

THF

KI

60

50

a

Reaction condition: 1a (0.3 mmol), Fe(NO3)3·9H2O (0.45 mmol), additive (0.15 mmol), solvent (1 mL), reaction time (16 h) under nitrogen atmosphere. b without addition of Fe(NO3)3·9H2O. c In air. d Fe(NO3)3·9H2O (0.075 mmol). e Fe(NO3)3·9H2O (0.30 mmol). f Fe(NO3)3·9H2O (0.60 mmol ). g KI (0.075 mmol).

The scope of iron(Ⅲ) nitrate-mediated synthesis of isoxazole 3 via self-coupling of alkyne 1 was investigated under the optimized conditions (KI as additive, THF as solvent, under nitrogen atmosphere). As shown in Table 2, the reaction worked well for the aromatic alkynes, and diverse electron-donating groups (Me, n-Bu; entries 2, 3) and electron-withdrawing groups (F, Cl; entries 4-6) on the phenyl group of aromatic alkynes was completely tolerated. Furthermore, the steric hindrance had an influence on the yield as well, and the ortho-substituted alkyne provide the relevant product (3d) in lower yield (compare entry 4 with entry 5). A heterocycle-containing alkyne (1g) could also be transformed to the corresponding isoxazole (entry 7). Table 2. Fe(NO3)3-mediated synthesis of isoxazole (3) from alkynes (1) via self-couplinga

Entry

1

3

Yield (%)

1

70

2

67

3

59

6


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4

51

5

65

6

63

7

51

a

Reaction condition: 1 (0.3 mmol), Fe(NO3)3·9H2O (0.45 mmol), KI (0.15 mmol), THF (1 mL), reaction time (16 h) at 60 oC under nitrogen atmosphere.

Subsequently, the cross-coupling of two different alkynes to afford the isoxazole 4 was also investigated under iron(Ⅲ) nitrate-mediated conditions. Phenylacetylene (1a) and methyl propiolate (2a) were chosen as the model substrates to optimize reaction conditions including catalysts, solvents, additives and atmospheres (Table S1 in Supporting Information); and Fe(NO3)3·9H2O showed higher activity than other metal nitrates (entries 1-7,29 in Table S1). The additive KI improved the efficiency of the catalyst system as well (entries 16-20,26,27 in Table S1). Furthermore, a moderate yield of cross-coupling product 4a could also be obtained under air (entry 28 in Table S1).15 With the optimized conditions in hand (KI/t-BuCN as additive, EtOAc/PhCN as solvent, under iron(Ⅲ) nitrate-mediated conditions), the substrate scope was studied (Scheme 3). All the reactions of aromatic terminal alkynes (1) with electrondeficient alkynes (2a-e) provided moderate to good yields (4a-4a’ in Scheme 3); even the heterocyclic terminal alkynes also worked well for this transformation (4i). Moreover, the position of the substituent (ortho vs meta vs para) on the aryl group of aromatic terminal alkynes did not affect the yield of corresponding product evidently (4e-4g). Substituted aliphatic alkynes (2f,2g) also worked well for the reaction with aromatic terminal alkynes (4b’-4d’). 7



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Scheme 3. Fe(NO3)3-mediated synthesis of isoxazoles (4) via cross-coupling of terminal alkynes (1) and electrondeficient alkynes (2).a

a

Reaction condition: 1 (0.3 mmol), 2 (0.6 mmol), Fe(NO3)3·9H2O (1.2 mmol), KI (0.3 mmol), t-BuCN (0.6 mmol), EtOAc/PhCN (0.5 mL/0.5 mL), reaction time (12 h) at 70 oC under nitrogen atmosphere.

8


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A series of control experiments were performed to understand the mechanism. Firstly, the reaction of 1a with 2a was chose to conduct the scale-up experiment under Fe(NO3)3-mediated conditions (Scheme 4A); and the cross-coupling product 4a was isolated in 50% yield, the iodide M-1 and αnitroacetophenone M-2 was also obtained in 22% and 7% yields respectively (reaction time 30 min). The species 4a, M-1 and M-2 were also identified by corresponding peaks in the ESI-HRMS chromatograms (See Figure S1,S2 in Supporting Information). Meanwhile when the reaction time was prolonged to 12 h, the yield of 4a was increased to 70% under condition A. So the M-1 and M-2 might be the intermediates for the formation of target product 4a. Furthermore, 1a could be transformed to M-1 in the presence of KI and NaNO3;16 and then M-1 could be transformed into product 4a successfully without addition of KI under Fe(NO3)3-mediated conditions (Scheme 4B); the result also implied the M-1 should be the intermediate, and the KI was not necessary in the subsequent formation of isoxazole 4a after the intermediate M-1 was generated. Moreover, several reactions for the preparation of 4a from M2 was also performed (Scheme 4C); the results proved the positive role played by Fe(NO3)3·9H2O and KI for this transformation, and isoxazole 4a could also be generated without addition of KI after the intermediate M-2 was formed. The cross-coupling reaction of 1a with 2a was carried out again (Scheme 4D), the product 4a could be prepared smoothly and the only 8% yield of self-coupling byproduct 3a was isolated; therefore, our method showed good chemoselectivity for the cross-coupling of two different alkynes examined (compared with entry 28 in Table S1). Based on the control experiments above and contrast experiments (entries 4,9 in Table 1, entry 16,20,24,26 in Table S1 of Supporting Information), the addition of KI would make easier the formation of intermediate M-2, which could be transformed into the relevant product 3 smoothly under iron-catalyzed conditions. At last, addition of 1 equiv of TEMPO (radical scavenger) had no obvious effect for the formation of product 4a from substrates 1a and 2a (Scheme 4E). Several control experiments about self-coupling and cyclizing of aromatic terminal 9



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alkynes was also performed, and the intermediate M-1 and M-2 could successfully react with aromatic alkyne 1 as well (please see Scheme S1 in Supporting Information).

Scheme 4. Control experiments for mechanism study. [Condition A: Fe(NO3)3·9H2O (6 mmol), KI (1.5 mmol), tBuCN (3 mmol), EA/PhCN (2.5 mL/2.5 mL), reaction temperature (70 oC) under nitrogen atmosphere; Condition B: NaNO3 (3 equiv), KI (1.5 equiv), acetic acid as solvent, reaction time (3h) at 85 oC in air; Condition C: Fe(NO3)3·9H2O (1.2 mmol), KI (0.3 mmol), t-BuCN (0.6 mmol), EA/PhCN (0.5 mL/0.5 mL), reaction time (12 h) at 70 oC under nitrogen atmosphere.]

A plausible reaction mechanism is proposed on the basis of the above control experiments and previous reports (Scheme 5).10,11,16 Initially, aromatic terminal alkynes 1 is transformed into adduct M-1 in the presence of Fe(NO3)3 and KI. Then M-1 reacts with H2O under iron-mediated conditions, and the intermediate M-2 was formed. Subsequently, a dehydration process is proceeded under Fe(NO3)3 me-

10


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diated conditions, to afford nitrile oxides M-5. Finally, the product 3 is generated via 1,3-dipolar cycloaddition of M-5 with alkynes 1 or another alkynes 2 under iron-catalyzed conditions. I

Fe(NO3)3/KI

Ar1

ref. 16

1

Ar

H 1

Fe(NO3)3/H2O HO 1

NO2

Ar

H

O NO2

1

Ar

NO2

M-2

M-1 (O3N)2Fe O

Fe(NO3)3

O N

Ar1

2

Fe(NO3)3 as catalyst

H2O

Ar1

Fe(NO3)2

M-4

O

R3

Fe(NO3)3/KI

NO3 N O

OH

M-3

NO3

1 or R2

O

O

Ar1

Ar1

C

N O nitrile oxides M-5

R2

1 Ar or Ar

N O 3a-3g

O

R3 N O 4a-4d'

Scheme 5. Possible mechanism for the synthesis of products 3 or 4

CONCLUSION In conclusion, we have developed a simple and direct method for Iron(Ⅲ) nitrate mediated synthesis of isoxazoles from alkynes; both self-coupling and cross-coupling products could be successfully prepared from alkynes. Meanwhile for cross-coupling and cyclizing of aromatic terminal alkynes with electron-deficient alkynes or aliphatic terminal alkynes, the iron-mediated system shows good chemoselectivity for the synthesis of corresponding isoxazoles 4; and the selective synthesis of isoxazoles from two different alkynes were hard to be performed in the previous methods. Furthermore for the self-coupling and cyclizing of aromatic terminal alkynes, which is more difficult than the cross-coupling and cyclizing of aromatic terminal alkynes with electron-deficient alkynes, the iron-mediated system shows good activity as well (Scheme 1E). In our method, cheap and eco-friendly iron(Ⅲ) nitrate is used as the nitration and cyclization reagent, and the nitration of alkynes by iron(Ⅲ) nitrate has not been reported before due to relatively weak nitration-ability of iron(Ⅲ) nitrate and relatively strong bound-electron ability of alkynes. Moreover for getting satisfied yields, KI is employed as the additive; and a different mechan11



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ism for the formation of isoxazoles has been proposed. In addition, the homo-coupling and crosscoupling products could be afforded in moderate yields as well. In general, the Glaser coupling of terminal alkynes is easy to occur in the presence of transition metal catalyst and molecular oxygen. Finally, this method can tolerate diverse functional groups, and presents a simple protocol for the direct synthesis of isoxazole derivatives from the same or different alkynes. EXPERIMENTAL SECTION General experimental procedures: All reactions were carried out under N2 atmosphere. Proton and carbon magnetic resonance spectra (1H NMR and

13

C NMR) were recorded using tetramethylsilane

(TMS) in the solvent of CDCl3 as the internal standard (1H NMR: TMS at 0.00 ppm,CHCl3 at 7.26 ppm; 13

C NMR: CDCl3 at 77.16 ppm) or were recorded using tetramethylsilane (TMS) in the solvent of d6-

DMSO as the internal standard (1H NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; 13C NMR: DMSO at 39.51 ppm). HRMS were recorded on Thermo QExactive Orbitrap mass spectrometer (for 4i, 4o, 4p, 4x, 4y, 4z, 4d') or Waters Xevo G2 QTOF mass spectrometer (for others). Melting points were recorded on a Beijing Tech X-5 melting point apparatus. General procedure for synthesis of compounds 3a-g: 1 (0.3 mmol), Fe(NO3)3·9H2O (0.45 mmol, 182 mg), KI (0.15 mmol, 25 mg) and THF (1 mL) were added to a sealed Schlenk tube and stirred at 60℃ for 16 hours under N2 atmosphere, and the reaction was monitored by TLC. The resulting solution was quenched with saturated aqueous solution of Na2S2O3. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel employing petroleum ether/ethyl acetate as eluent to afford target product 3a-g.

12


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Phenyl(5-phenylisoxazol-3-yl)methanone (3a).9 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 26 mg (70%) Yellow solid, mp 80.5-82.0 oC (lit.9 m.p. 78.4-82.9 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.38-8.32 (m, 2H), 7.88-7.83 (m, 2H), 7.68-7.64 (m, 1H), 7.57-7.49 (m, 5H), 7.05 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.7, 169.7, 161.4, 134.7, 133.0, 129.7, 128.1, 127.5, 125.7, 125.0, 99.2. APCI-MS [M+H]+ m/z 250.07. p-Tolyl[5-(p-tolyl)isoxazol-3-yl]methanone (3b).17 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.40. Yield 28 mg (67%) White solid, mp 110.9-112.4 oC (lit.17 m.p.110.3-111.8 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.32-8.19 (m, 2H), 7.77-7.70 (m, 2H), 7.36-7.28 (m, 4H), 6.97 (s, 1H), 2.44 (d, J = 12.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 185.5, 170.8, 162.5, 145.1, 141.1, 133.3, 130.8, 129.8, 129.3, 125.9, 124.1, 99.7, 21.8, 21.5. APCI-MS [M+H]+ m/z 278.13. (4-Butylphenyl)[5-(4-butylphenyl)isoxazol-3-yl]methanone (3c). Eluent: petroleum ether/ethyl acetate (30:1), Rf = 0.40. Yield 32 mg (59%) White solid, mp 53.7-54.8 oC. 1H NMR (400 MHz, CDCl3, 25 o

C) δ 8.22-8.16 (m, 2H), 7.71-7.65 (m, 2H), 7.29-7.20 (m, 4H), 6.90 (s, 1H), 2.67-2.55 (m, 4H), 1.60-

1.52 (m, 4H) (m, 4H), 1.34-1.25 (m, 4H), 0.89-0.84 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 185.5, 170.9, 162.6, 150.0, 146.0, 133.5, 130.9, 129.2, 128.7, 126.0, 124.3, 99.7, 35.8, 35.6, 33.3, 33.2, 22.3, 13.9. ESI-HRMS [M+H]+ m/z calcd for C24H28NO2 362.2115, found 362.2129. (2-Fluorophenyl)[5-(2-fluorophenyl)isoxazol-3-yl]methanone (3d). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 22 mg (51%) White solid, mp 88.8-89.6 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.11-8.05 (m, 1H), 8.00-7.93 (m, 1H), 7.70-7.64 (m, 1H), 7.59-7.52 (m, 1H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.6, 165.3, 162.8, 162.5, 160.5, 159.9, 158.0, 134.7 (d, J = 8.9 Hz), 132.3 (d, J = 8.7 Hz), 131.5 (d, J = 1.8 Hz), 127.6 (d, J = 1.9 Hz), 125.6 (d, J = 11.8 Hz), 124.8 (d, J = 3.7 Hz), 124.2 (d, J = 3.8 Hz), 116.8, 116.6 (d, J = 4.3 Hz), 116.4, 115.2 (d, J 13



Page 14 of 26

= 12.1 Hz), 103.2 (d, J = 4.3 Hz). ESI-HRMS [M+H]+ m/z calcd for C16H10F2NO2 286.0674, found 286.0686. (4-Fluorophenyl)[5-(4-fluorophenyl)isoxazol-3-yl]methanone (3e).9 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.50. Yield 28 mg (65%) White solid, mp 175.8-176.7 oC. (lit.9 White oil). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.47-8.39 (m, 2H), 7.88-7.81 (m, 2H), 7.24-7.17 (m, 4H), 7.00 (s, 1H). 13

C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.9, 169.9, 167.8, 165.4, 165.2, 162.9, 162.4, 133.6, 133.5,

132.0, 128.2, 128.1, 123.1, 123.0, 116.6, 116.4, 116.0, 115.7, 100.1. APCI-MS [M+H]+ m/z 286.13. (4-Chlorophenyl)[5-(4-chlorophenyl)isoxazol-3-yl]methanone (3f). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.50. Yield 30 mg (63%) White solid, mp 196.4-197.7 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.40-8.25 (m, 2H), 7.84-7.73 (m, 2H), 7.51 (t, J = 8.9 Hz, 4H), 7.04 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.2, 168.8, 161.3, 139.8, 136.0, 132.8, 131.1, 128.5, 128.0, 126.2, 124.0, 99.5. ESI-HRMS [M+H]+ m/z calcd for C16H10Cl2NO2 318.0083, found 318.0066. Thiophen-2-yl[5-(thiophen-2-yl)isoxazol-3-yl]methanone (3g). Eluent: petroleum ether/ethyl acetate (8:1), Rf = 0.30. Yield 20 mg (51%) Yellow solid, mp 110.5-112.2 oC. 1H NMR (400 MHz, d6DMSO, 25 oC) δ 8.40-8.36 (m, 1H), 8.28-8.23 (m, 1H), 7.94-7.86 (m, 2H), 7.41-7.36 (m, 2H), 7.32-7.29 (m, 1H). 13C{1H} NMR (100 MHz, d6-DMSO, 25 oC) δ176.9, 166.3, 162.3, 141.3, 138.4, 137.5, 130.9, 129.7, 129.6, 129.2, 127.7, 100.1. ESI-HRMS [M+H]+ m/z calcd for C12H8NO2S2 261.9991, found 262.0000. General procedure for synthesis of compounds 4a-d'. 1 (0.3 mmol), 2 (0.6 mmol), Fe(NO3)3·9H2O (1.2 mmol, 485 mg), t-BuCN (0.6 mmol, 50 mg), KI (0.3 mmol, 50 mg), PhCN (0.5 mL) and EA (0.5 mL) were added to a sealed Schlenk tube and stirred at 70 ℃ for 12 hours under N2 atmosphere, and the reaction was monitored by TLC. The resulting solution was quenched with saturated aqueous solution 14


Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of Na2S2O3. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel employing petroleum ether/ethyl acetate as eluent to afford target product 4a-d'. Methyl 3-benzoylisoxazole-5-carboxylate (4a).10 Eluent: petroleum ether/ethyl acetate (30:1), Rf = 0.2. Yield 53 mg (76%) White solid, mp 95.8-97.2 oC (lit.10 m.p. 96-97 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.34-8.28 (m, 2H), 7.74-7.64 (m, 1H), 7.55 (m, J = 8.5, 7.2 Hz, 2H), 7.45 (s, 1H), 4.03 (s, 3H). 13


53.2. APCI-MS [M+H]+ m/z 231.97. Methyl 3-(4-methylbenzoyl)isoxazoe-5-carboxylate (4b). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 55 mg (75%) White solid, mp 94.5-95.5 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.34-8.13 (m, 2H), 7.42 (s, 1H), 7.38-7.30 (m, 2H), 4.02 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.0, 162.3, 160.6, 156.7, 145.7, 132.7, 130.9, 129.5, 110.3, 53.2, 21.9. ESIHRMS [M+H]+ m/z calcd for C13H12NO4 246.0761, found 246.0765. Methyl 3-(4-butylbenzoyl)isoxazole-5-carboxylate (4c). Eluent: petroleum ether/ethyl acetate (40:1), Rf = 0.20. Yield 51 mg (59%) White liquid. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.28-8.16 (m, 2H), 7.42 (s, 1H), 7.37-7.30 (m, 2H), 4.01 (s, 3H), 2.73-2.66 (m, 2H), 1.67-1.61 (m, 2H), 1.41-1.31 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.0, 162.3, 160.6, 156.7, 150.6, 132.8, 130.9, 128.9, 110.3, 53.2, 35.9, 33.1, 22.3, 13.9. ESI-HRMS [M+H]+ m/z calcd for C16H18NO4 288.1230, found 288.1236. Methyl 3-(4-methoxybenzoyl)isoxazole-5-carboxylate (4d). Eluent: petroleum ether/ethyl acetate (15:1), Rf = 0.20. Yield 57 mg (73%) White solid, mp 104.1-105.5 oC. 1H NMR (400 MHz, CDCl3, 25 15



o

Page 16 of 26

C) δ 8.37-8.29 (m, 2H), 7.40 (s, 1H), 7.02-6.98 (m, 2H), 4.01 (s, 3H), 3.90 (s, 3H). 13C{1H} NMR (100

MHz, CDCl3, 25 oC) δ 182.6, 164.8, 162.5, 160.5, 156.8, 133.3, 128.1, 114.1, 110.4, 55.6, 53.1. ESIHRMS [M+H]+ m/z calcd for C13H12NO5 262.0710, found 262.0720. Methyl 3-(2-fluorobenzoyl)isoxazole-5-carboxylate (4e). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 55 mg (74%) White liquid.1H NMR (400 MHz, CDCl3, 25 oC) δ 7.90-7.83 (m, 1H), 7.65-7.57 (m, 1H), 7.40 (s, 1H), 7.32-7.27 (m, 1H), 7.22-7.17 (m, 1H), 4.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.4, 162.6, 162.3, 161.2, 160.0, 156.6, 135.3, 135.2, 131.5, 125.0, 124.9, 124.4, 124.3, 116.9, 116.7, 109.1, 53.2. ESI-HRMS [M+H]+ m/z calcd for C12H9FNO4 250.0510, found 250.0515. Methyl 3-(3-fluorobenzoyl)isoxazole-5-carboxylate (4f). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 52 mg (70%) White solid, mp 73.3-74.5 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.19-8.12 (m, 1H), 8.06-7.98 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (s, 1H), 7.42-7.35 (m, 1H), 4.02 (s, 3H). 13


130.4, 126.7, 121.7, 121.5, 117.4, 117.2, 110.2, 53.3. ESI-HRMS [M+H]+ m/z calcd for C12H9FNO4 250.0510, found 250.0519. Methyl 3-(4-fluorobenzoyl)isoxazole-5-carboxylate (4g). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 50 mg (67%) White solid, mp 97.1-98.5 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.44-8.33 (m, 2H), 7.43 (s, 1H), 7.24-7.18 (m, 2H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 o

C) δ 182.7, 167.9, 165.4, 162.1, 160.8, 156.6, 133.7, 133.6, 131.5, 116.2, 115.9, 110.3, 53.2. ESI-

HRMS [M+H]+ m/z calcd for C12H9FNO4 250.0510, found 250.0515. Methyl 3-(4-chlorobenzoyl)isoxazole-5-carboxylate (4h). Eluent: petroleum ether/ethyl acetate (40:1), Rf = 0.20. Yield 49 mg (61%) White solid, mp 93.8-95.1 oC.1H NMR (400 MHz, CDCl3, 25 oC) 16


Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


δ 8.30-8.26 (m, 2H), 7.53-7.48 (m, 2H), 7.43 (s, 1H), 4.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 o

C) δ 182.0, 161.0, 159.8, 155.6, 140.2, 132.3, 131.1, 128.1, 109.2, 52.2. ESI-HRMS [M-Cl]+ m/z calcd

for C12H8NO4 230.0448, found 230.0467. Methyl 3-(thiophene-2-carbonyl)isoxazole-5-carboxylate (4i). Eluent: petroleum ether/ethyl acetate (40:1), Rf = 0.20.Yield 42 mg (59%) Yellow solid, mp 102.1-103.5 oC. 1H NMR (400 MHz, CDCl3, 25 o

C) δ 8.50-8.43 (m, 1H), 7.87-7.80 (m, 1H), 7.42 (s, 1H), 7.25-7.21 (m, 1H), 4.01 (s, 3H). 13C{1H}

NMR (100 MHz, CDCl3, 25 oC) δ175.8, 162.0, 160.9, 156.6, 141.2, 137.1, 136.8, 128.9, 109.7, 53.2. ESI-HRMS [M+H]+ m/z calcd for C10H8NO4S 238.0169, found 238.0170. Ethyl 3-benzoylisoxazole-5-carboxylate (4j).10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 51 mg (70%) White solid, mp 69.1-70.5 oC (lit.10 m.p.68-69 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.34-8.28 (m, 2H), 7.71-7.63 (m, 1H), 7.58-7.50 (m, 2H), 7.43 (s, 1H), 4.55-4.42 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.5, 162.2, 161.1, 156.3, 135.2, 134.4, 130.7, 128.7, 110.1, 62.7, 14.1.ESI-MS [M+H]+ m/z 246.12. Ethyl 3-(4-butylbenzoyl)isoxazole-5-carboxylate (4k). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 52 mg (58%) Yellow liquid. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.26-8.19 (m, 2H), 7.41 (s, 1H), 7.35-7.31 (m, 2H), 4.50-4.44 (m, 2H), 2.72-2.67 (m, 2H), 1.67-1.60 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.40-1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

13

C{1H} NMR (100 MHz, CDCl3, 25 oC) δ

184.0, 162.3, 161.0, 156.3, 150.6, 132.8, 130.9, 128.9, 110.2, 62.6, 35.9, 33.1, 22.3, 14.1, 13.9. ESIHRMS [M+H]+ m/z calcd for C17H20NO4 302.1387, found 302.1389. Ethyl 3-(4-methoxybenzoyl)isoxazole-5-carboxylate (4l).10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 50 mg (60%) Yellow solid, mp 91.7-92.6 oC (lit.10 m.p.92-94 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.51-8.16 (m, 2H), 7.40 (s, 1H), 7.06-6.93 (m, 2H), 4.50-4.44 (m, 2H), 3.90 (s, 17



3H), 1.43 (t, J = 7.1 Hz, 3H).

13

Page 18 of 26

C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 182.6, 164.7, 162.4, 160.8,

156.3, 133.3, 128.1, 114.1, 110.2, 62.6, 55.6, 14.1. ESI-MS [M+H]+ m/z 276.18. Ethyl 3-(4-fluorobenzoyl)isoxazole-5-carboxylate (4m).10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 58 mg (74%) White solid, mp 59.5-60.1 oC (lit.10 m.p.61-62 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.40-8.26 (m, 2H), 7.36 (s, 1H), 7.18-7.11 (m, 2H), 4.46-4.36 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 182.7, 167.9, 165.3, 162.1, 161.2, 156.2, 133.7, 133.6, 131.5, 116.1, 115.9, 110.1, 62.7, 14.1.ESI-MS [M+H]+ m/z 264.14. Ethyl 3-(4-chlorobenzoyl)isoxazole-5-carboxylate (4n).10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 50 mg (60%) White solid, mp 65.5-66.8 oC (lit.10 m.p.64-66 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.34-8.24 (m, 2H), 7.55-7.48 (m, 2H), 7.42 (s, 1H), 4.51-4.44 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.1, 162.0, 161.2, 156.2, 141.2, 133.4, 132.1, 129.1, 110.1, 62.7, 14.1. APCI-MS [M+H]+ m/z 280.11. Benzyl 3-benzoylisoxazole-5-carboxylate (4o). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 53 mg (58%) White solid, mp 79.3-80.4 oC.1H NMR (400 MHz, CDCl3, 25 oC) δ 8.35-8.24 (m, 2H), 7.70-7.64 (m, 1H), 7.56-7.51 (m, 2H), 7.51-7.35 (m, 6H), 5.44 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.4, 162.2, 160.8, 156.1, 135.1, 134.5, 134.4, 130.7, 128.9, 128.8, 128.7, 128.7, 110.4, 68.1. ESI-HRMS [M+H]+ m/z calcd for C18H14NO4 308.0917, found 308.0917. Benzyl 3-(4-butylbenzoyl)isoxazole-5-carboxylate (4p). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.40. Yield 82 mg (75%) Yellow solid, mp 53.7-54.2oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.268.18 (m, 2H), 7.50-7.37 (m, 6H), 7.36-7.31 (m, 2H), 5.43 (s, 2H), 2.80-2.60 (m, 2H), 1.76-1.53 (m, 2H), 1.40-1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 184.0, 162.3,

18


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160.7, 156.2, 150.6, 134.4, 132.8, 130.9, 128.9, 128.8, 128.7, 110.5, 68.1, 35.9, 33.2, 22.4, 14.0. ESIHRMS [M+H]+ m/z calcd for C22H22NO4 364.1543, found 364.1542. Benzyl 3-(4-methoxybenzoyl)isoxazole-5-carboxylate (4q). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 60 mg (59%) White solid, mp 106.4-107.1 oC. 1H NMR (400 MHz, CDCl3, 25 o

C) δ 8.39-8.28 (m, 2H), 7.49-7.37 (m, 6H), 7.03-6.97 (m, 2H), 5.43 (s, 2H), 3.90 (s, 3H). 13C{1H}

NMR (100 MHz, CDCl3, 25 oC) δ 182.6, 164.8, 162.5, 160.6, 156.2, 134.4, 133.3, 128.9, 128.8, 128.6, 128.1, 114.1, 110.6, 68.1, 55.6. ESI-HRMS [M+H]+ m/z calcd for C19H16NO5 338.1023, found 338.1030. Benzyl 3-(3-fluorobenzoyl)isoxazole-5-carboxylate (4r). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 56 mg (57%) White liquid.1H NMR (400 MHz, CDCl3, 25 oC) δ 8.18-8.12 (m, 1H), 8.03-7.98 (m, 1H), 7.55-7.35 (m, 8H), 5.44 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.1, 163.9, 161.9, 161.4, 161.0, 156.0, 136.9, 136.8, 134.3, 130.5, 130.4, 129.0, 128.8, 128.7, 126.7, 121.7, 121.5, 117.4, 117.2, 110.4, 68.2. ESI-HRMS [M+H]+ m/z calcd for C18H13FNO4 326.0823, found 326.0845. Benzyl 3-(4-fluorobenzoyl)isoxazole-5-carboxylate (4s). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 65 mg (67%) Yellow liquid.1H NMR (400 MHz, CDCl3, 25 oC) δ 8.45-8.33 (m, 2H), 7.51-7.34 (m, 6H), 7.23-7.17 (m, 2H), 5.43 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 182.7, 167.9, 165.4, 162.1, 160.9, 156.0, 134.3, 133.7, 133.6, 131.5, 131.4, 129.0, 128.8, 128.7, 116.2, 115.9, 110.5, 68.2. ESI-HRMS [M+H]+ m/z calcd for C18H13FNO4 326.0823, found 326.0845. Benzyl 3-(4-chlorobenzoyl)isoxazole-5-carboxylate (4t). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 72 mg (70%) White solid, mp 82.4-83.0 oC. 1H NMR (400 MHz, CDCl3, 25 o

C)δ 8.31-8.26 (m, 2H), 7.53-7.49 (m, 2H), 7.48-7.36 (m, 6H), 5.44 (s, 2H). 13C{1H} NMR (100 MHz,

19



Page 20 of 26

CDCl3, 25 oC) δ 183.1, 162.0, 161.0, 156.0, 141.2, 134.3, 133.4, 132.1, 129.1, 129.0, 128.9, 128.7, 110.4, 68.2. ESI-HRMS [M+H]+ m/z calcd for C18H13ClNO4 342.0528, found 342.0519. Dimethyl 3-benzoylisoxazole-4,5-dicarboxylate (4u).10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 52 mg (60%) White solid, mp 94.6-95.4 oC (lit.10 m.p.92-93 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.22-8.12 (m, 2H), 7.71-7.64 (m, 1H), 7.54 (t, J = 7.8 Hz, 2H), 4.04 (s, 3H), 3.91 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.8, 160.2, 159.9, 159.0, 155.9, 134.9, 134.8, 130.5, 128.9, 117.7, 53.7, 53.3. APCI-MS [M+H]+ m/z 290.15. Dimethyl 3-(4-methylbenzoyl)isoxazole-4,5-dicarboxylate (4v). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 52 mg (57%) White solid, mp 109.4-110.6 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.10-8.04 (m, 2H), 7.36-7.31 (m, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 183.3, 160.3, 160.0, 158.9, 155.9, 146.2, 132.4, 130.7, 129.6, 117.6, 53.7, 53.3, 21.9. ESI-HRMS [M+H]+ m/z calcd for C15H14NO6 304.0816, found 304.0823. Dimethyl 3-(4-methoxybenzoyl)isoxazole-4,5-dicarboxylate (4w). Eluent: petroleum ether/ethyl acetate (8:1), Rf = 0.25. Yield 66 mg (69%) White solid, mp 104.8-105.6 oC. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.23-8.14 (m, 2H), 7.03-6.98 (m, 2H), 4.04 (s, 3H), 3.91 (d, J = 1.7 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 181.9, 165.1, 160.4, 160.2, 158.8, 156.0, 133.1, 127.9, 117.7, 114.2, 55.7, 53.6, 53.3. ESI-HRMS [M+H]+ m/z calcd for C15H14NO7 320.0765, found 320.0770. Dimethyl 3-(3-fluorobenzoyl)isoxazole-4,5-dicarboxylate (4x). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 50 mg (54%) Yellow liquid. 1H NMR (400 MHz, CDCl3, 25 oC) δ 8.02-7.97 (m, 1H), 7.92-7.85 (m, 1H), 7.56-7.50 (m, 1H), 7.42-7.36 (m, 1H), 4.04 (s, 3H), 3.93 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 182.5, 182.5, 163.9, 161.5, 160.1, 159.5, 159.1, 155.8, 136.6, 136.6,

20


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130.6, 130.6, 126.6, 126.5, 122.1, 121.8, 117.7, 117.1, 116.9, 53.7, 53.4. ESI-HRMS [M+H]+ m/z calcd for C14H11FNO6 308.0565, found 308.0566. Dimethyl 3-(4-fluorobenzoyl)isoxazole-4,5-dicarboxylate (4y). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.25. Yield 46 mg (50%) White solid, mp 78.6-79.5 oC. 1H NMR (400 MHz, CDCl3, 25 o

C) δ 8.29-8.22 (m, 2H), 7.26-7.18 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,

25 oC) δ 182.0, 168.1, 165.6, 160.2, 159.7, 159.0, 155.8, 133.5, 133.4, 131.2, 117.8, 116.3, 116.1, 53.7, 53.4. ESI-HRMS [M+H]+ m/z calcd for C14H11FNO6 308.0565, found 308.0566. 3-Benzoylisoxazole-5-carboxamide (4z). Eluent: petroleum ether/ethyl acetate (8:1), Rf = 0.20. Yield 30 mg (47%) White solid, mp 168.9-170.1 oC. 1H NMR (400 MHz, DMSO-d6, 25 oC) δ 8.49 (s, 1H), 8.18-8.14 (m, 2H), 8.12 (s, 1H), 7.81-7.74 (m, 1H), 7.63 (t, J = 7.7 Hz, 2H), 7.52 (s, 1H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 185.5, 164.9, 162.3, 157.0, 135.6, 135.0, 130.7, 129.3, 107.1. ESI-HRMS [M+H]+ m/z calcd for C11H9N2O3 217.0608, found 217.0610. 3-(4-Fluorobenzoyl)isoxazole-5-carboxamide (4a'). Eluent: petroleum ether/ethyl acetate (8:1), Rf = 0.20. Yield 37 mg (52%) White solid, mp 234.2-235.5 oC. 1H NMR (400 MHz, DMSO-d6, 25 oC) δ 8.51 (s, 1H), 8.34-8.22 (m, 2H), 8.14 (s, 1H), 7.53 (s, 1H), 7.47 (t, J = 8.8 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 183.8, 167.5, 165.0, 164.9, 162.3, 156.9, 133.9, 133.8, 132.3, 132.2, 116.6, 116.4, 107.1. ESI-HRMS [M+H]+ m/z calcd for C11H8FN2O3 235.0513, found 235.0515. [5-(Chloromethyl)isoxazol-3-yl](phenyl)methanone (4b').10 Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.30. Yield 41 mg (62%) White solid, mp 45.5-47.2 oC (lit.10 m.p.46-47 oC). 1H NMR (400 MHz, DMSO-d6, 25 oC) δ 8.20-8.11 (m, 2H), 7.80-7.74 (m, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.09 (s, 1H), 5.09 (s, 2H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 185.7, 169.5, 162.1, 135.6, 134.9, 130.6, 129.3, 105.3, 34.5. APCI-MS [M+H]+ m/z 221.98. 21



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[5-(Chloromethyl)isoxazol-3-yl](4-fluorophenyl)methanone (4c'). Eluent: petroleum ether/ethyl acetate (20:1), Rf = 0.20. Yield 43 mg (60%) White liquid. 1H NMR (400 MHz, DMSO-d6, 25 oC) δ 8.30-8.21 (m, 2H), 7.50-7.38 (m, 2H), 7.08 (s, 1H), 5.08 (d, J = 1.7 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 184.0, 169.5, 167.5, 164.9, 162.1, 133.8, 133.7, 132.3, 116.6, 116.4, 105.3, 34.4. ESIHRMS [M+H]+ m/z calcd for C11H8ClFNO2 240.0222, found 240.0239. 2-(3-Benzoylisoxazol-5-yl)ethyl 4-methylbenzenesulfonate (4d'). Eluent: petroleum ether/ethyl acetate (8:1), Rf = 0.20. Yield 75 mg (67%) Yellow liquid. 1H NMR (400 MHz, DMSO-d6, 25 oC) δ 8.18-8.13 (m, 2H), 7.80-7.73 (m, 3H), 7.62 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.70 (s, 1H), 4.42 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 5.9 Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 185.9, 170.9, 161.9, 145.6, 135.8, 134.8, 132.5, 130.6, 129.3, 128.1, 103.5, 68.1, 26.6, 21.5. ESIHRMS [M+H]+ m/z calcd for C19H18NO5S 372.0900, found 372.0899. Procedures for scale-up experiment of 3a. 1a (1.5 mmol, 165 μl), Fe(NO3)3·9H2O (2.25 mmol, 909 mg), KI (0.75 mmol, 125mg), THF (5 mL) were added to a sealed Schlenk tube and stirred at 60 ℃ under N2 atmosphere, and the reaction was monitored by TLC. The resulting solution was quenched with saturated aqueous solution of Na2S2O3. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel employing petroleum ether/ethyl acetate (30:1) as eluent. When reaction time was 30 min, the cross-coupling product 3a was isolated (88 mg, 47%), and the iodide M-1 and α-nitroacetophenone M-2 was also obtained (37 mg, 18% for M-1; 11 mg, 9% for M-2). When the reaction time was prolonged to 16 h, the yield of 3a was isolated in 68% yield (127 mg).

22


Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Procedures for scale-up experiment of 4a. 1a (1.5 mmol, 165 μl), 2a (3 mmol, 268 μl), Fe(NO3)3·9H2O (6 mmol, 2424 mg), t-BuCN (3 mmol, 249 mg), KI (1.5 mmol, 250 mg), PhCN (2.5 mL) and EA (2.5 mL) were added to a sealed Schlenk tube and stirred at 70 ℃ under N2 atmosphere, and the reaction was monitored by TLC. The resulting solution was quenched with saturated aqueous solution of Na2S2O3. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel employing petroleum ether/ethyl acetate (30:1) as eluent. When reaction time was 30 min, the cross-coupling product 4a was isolated (173 mg, 50%), and the iodide M-1 and α-nitroacetophenone M-2 was also obtained (91 mg, 22% for M-1; 17 mg, 7% for M-2). When the reaction time was prolonged to 12 h, the yield of 4a was isolated in 70% yield (243 mg). M-1, Yellow solid, mp 48.5-50.0 oC (lit.1 m.p.49-50 oC). 1H NMR (400 MHz, CDCl3, 25 oC) δ 7.71 (s, 1H), 7.38-7.33 (m, 3H), 7.32-7.28 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ 143.0, 138.5, 130.3, 128.6, 127.3, 113.8. ESI-HRMS [M-I]+ m/z calcd for C8H6NO2 148.0393, found 148.0395. Anal. Calcd for C8H6INO2: C, 34.94; H, 2.20; N, 5.09. Found: C, 35.22; H, 1.96. N, 5.09. M-2, Yellow solid, m.p. 106.2-107.5 oC (lit.2 m.p. 105-107 oC). 1H NMR (400 MHz, DMSO, 25 oC) δ 8.01-7.89 (m, 2H), 7.827.70 (m, 1H), 7.61 (t, J = 7.8 Hz, 2H), 6.55 (s, 2H). 13C{1H} NMR (100 MHz, DMSO, 25 oC) δ 188.9, 135.3, 133.9, 129.5, 128.9, 83.3. ESI-MS [M-H]- m/z 164.22. AUTHOR INFORMATION Corresponding Author * E-mail : [email protected]; [email protected]. ORCID Hao Xu: 0000-0002-6069-3246 23



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Author Contributions ‡

Zhenzhen Lai, Zhenxing Li and Yawei Liu contributed equally to this work.

Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS This work was supported by National Natural Science Foundation of China (Grant No. 21502042, 51403051, 21204018), Scientific Research Key Project Fund of Henan Provincial Education Department (Grant No. 15A150041, 16A150003), Scientific Research Fund of Henan University (No. 2013YBZR008). ASSOCIATED CONTENT Supporting Information. Optimization table of reaction conditions for the product 4, the 1H and 13C NMR spectra of these synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES (1) (a) Cingolani, C.; Panella, A.; Perrone, M. G.; Vitale, P.; Mauro G. D.; Fortuna, C. G.; Armen, R. S.; Ferorelli, S.; Smith, W. L.; Scilimati, A. Eur. J. Med. Chem. 2017, 138, 661. (b) Kreuzer, J.; Bach, N. C.; Forler, D.; Sieber, S. A. Chem. Sci. 2015, 6, 237. (c) Sani, R. N.; Keramati, K.; Saberi, N.; Moezifar, M.; Mahdavi, A. Neurosci. Lett. 2018, 664, 91. (d) De Amici, M.; Conti, P.; Dallanoce, C.; Kassi, L.; Castellano, S.; Stefancich, G.; De Micheli, C. Med. Chem. Res. 2000, 10, 69. (e) Jiang, L. -Y.; Zhang, W. -L.; Li, W.; Ling, C. -H.; Jiang, M. Toxicol. Lett. 2018, 282, 154. (f) Brito, A. M. S.; Godin, A. M.; Augusto, P. S. A.; Menezes, R. R.; Melo, I. S. F.; Dutra, M. G. M. B.; Costa, S. O. A. M.; Goulart, F. A.; Rodrigues, F. F.; Morais, M. Í.; Machado, R. R.; Coelho, M. M. Eur. J. Pharmacol. 2018, 818, 17. 24


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Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(III

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