Synthesis of N-Arylisatins Using Nay Heterogeneous Catalyst Under Microwave Irradiations

Introduction

Isatin have both biological and medical properties including antifungal, antiviral, anti-HIV, anti-, AIDS, antiprotozoal, anticancer and antileukema.^1-7

In recent years, Isatin have been synthesized by different methods but they require tedious work up and long reaction time.^8-17 Microwave assisted organic synthesis is currently gaining ground in synthetic organic chemistry largely due to the dramatic reduction in time (from days or hours to minutes or seconds).^18-19

As a part of our ongoing research “roll of microwave technique in synthesis of organic compounds in presence of zeolites”, we report a microwave assisted synthesis of N-Arylisatin by reaction of Arynes with Methyl-2-oxo-2-(arylamino)acetate. Excellent yield of N-Arylisatins were achieved in shorter time.

Scheme 1 Click here to View scheme

 

Table 1: Reaction of various Methyl 2-oxo-2(aryl amino)acetates with 2-(Trimethylallyl)phenyl Trifluoromethanesulfonate

S.No.	Substrate(R2)		Time (Minutes)	Yield (%)	M.pt. (OC)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17		H 4-Me 4-Oph 4-F 4-Cl 4-Br 4-I 2-1 4-CN 4-CO2Et 4-CF3 3-CF3 2-t-Bu 2-Ph 2,5-(Ome)2 2,4,6-Me3 2,3-(CH)4	7 6 5 6 7 7 7 7 4 10 8 9 8 8 5 5 5	91 95 95 97 81 83 87 94 86 88 71 75 94 89 91 82 98	136-139 137-139 145-148 235-237 194-197 178-180 198-201 173-176 282-284 127-129 177-181 124-127 109-113 157-162 114-117 164-168 130-133

 

Result and discussion

we started our work by reacting methyl-2-oxo(phenyl amino)acetate with 2-(trimethylallyl)phenyltrifluoromethanesulphonat in presence of NaY zeolite under microwave irradiation selected power(400W) for 7 minutes. We obtained N-phenylisatin in high yield(91) in lower reaction time (7min). The probable reaction mechanism is:

Scheme 2  Click here to View scheme

 

Take another compound and observed percentage yield and other properties. No side product is obtained by controlling temperature in the temperature monitoring microwave oven. Acetonitrile was the best solvent used for this reaction. Here electron-rich substituent seems to promote this reaction to a small extent, whereas electron deficient group lower the yield of the reaction in same way as in ordinary conditions.

It is believed that two mechanisms are possible for this process, routes A and B in Scheme 3. Both suggested rouetes share a common first step, nucleophilic attack by nitrogen on the benzyne, resulting in an Aryl carbanion. From there, at least two posibilities exist with regard to how the desired isatin is formed. Route Asuggests that the Aryl carbanion attacks the distant ester carbony and displaces a methoxy group. This type of mechanism has also been suggested in our earlier work. On the other hand, Greany’s work(eq. 1) suggests another possibility, route B. This route involves attack of the aryl carbanion onto thenearest caronyl group, the amide carbonyl, forming a strained four-membered ring intermediate, which then fragments into a structure where the nitrogen can now attack the ester carbonyl. Both routes eventually lead to the desired isatin. However, the carbonyl groups end up in different places depending on the route. Further efforts are underway in order to shed light on this process.

Experimental section:

General. The ¹H and ¹³C NMR spectra were recorded at 300 and 75.5MHz or 400 and 100MHz, respectively. Thin layer chromatography was performed using commercially prepared 60-mesh silica gel plates, and visualization was effected with short wavelength UV light(254nm). All melting points uncorrected. All reagents are used directly as obtained commercially.

Typical procedure for synthesis of the Isatin derivatives 1-17. To a dry s dram vial containing a solution of the amide (0.5mmol) and the aryn precursor (1.0mmol) in MeCN (5.0ml, anhydrous) was added NaHCO₃ (1.0mmol) and CsF (3.0mmol). The vial was sealed and allowed to stir for 24H at rt. The reaction mixture was then filtered through a lug of silica gel using ethyl acetate, concentrated in vacuo, and purified by flash chromatography using gradient solvent combinations of ethyl acetate/Hexanes or dichloromethane/Hexanes.

1-Phenylindoline-2,3-dione(1): The product was isolated as an orange solid.¹H NMR (300MHz,CDCl₃)δ 7.70 (ddd,j=0.6, 1.3, 7.5Hz,1H), 7.60-7.41(m, 6H), 7.18(td,j= 0.8,7.6Hz, 1H), 6.91(d,j= 8.1Hz, 1H), ¹³C NMR (75MHz,CDCl₃)  δ 183.1, 157.5, 151.9, 138.5, 133.4, 130.2, 129.0, 126.2, 125.8, 124.5, 117.5; HRMS(EI) calcd for [M+H]⁺ (M=C₁₄H₉NO₂) 224.0706, found 224.0707

1-p-Tolylindoline-2,3-dione(2): The product was isolated as a red-orange solid.¹H NMR (400MHz,CDCl₃)δ 7.80 (d,j=7.5Hz,1H), 7.66(t,j=7.3Hz,1H), 7.49(d,j= 8.2Hz,2H), 7.42(d,j= 8.3Hz, 2H), 7.30(d,j=7.5Hz,1H) 7.00(d,j=8.1Hz,1H) 2.56(s,3H), ¹³C NMR (100MHz,CDCl₃)  δ 183.2, 157.6, 152.0, 139.1, 138.5, 130.7, 130.3, 126.0, 125.6, 124.3, 117.6, 111.4, 21.4; HRMS(EI) calcd for C₁₈H₁₁NO₂ 237.0790, found 237.0791

1-(4-phenoxyphenyl)indoline-2,3-dione(3): The product was isolated as a yellow-orange solid.¹H NMR (400MHz,CDCl₃)δ 7.66 (d,j=7.4Hz,1H), 7.54(t,j=7.8Hz,1H), 7.40-7.34(m,4H), 7.18-7.11(m,4H), 7.07(d,j= 8.2Hz,2H), 6.88(d,j= 7.97Hz, 1H), ¹³C NMR (100MHz,CDCl₃)  δ 183.0, 157.9, 157.6, 156.2, 151.8, 138.5, 130.1, 127.7, 127.4, 125.6, 124.4, 124.3, 119.8, 119.5, 117.5, 111.3, HRMS(EI) calcd for C₂₀H₁₃NO3 315.0895, found 315.0899

1-(4-Fluorophenyl)indoline-2,3-dione(4): The product was isolated as a bright orange solid.¹H NMR (400MHz,CDCl₃)δ 7.72(d,j=7.5Hz,1H), 7.57(t,j=7.8Hz,1H), 7.44-7.40(m,2H), 7.29-7.24(m,2H), 7.20(t,j= 7.6Hz,1H), 6.86(d,j= 8.0Hz, 1H), ¹³C NMR (100MHz,CDCl₃ extra peaks due to C-F coupling) δ 182.8, 163.7, 161.2, 157.6, 151.7, 138.6, 129.0, 128.9, 128.3, 128.2, 125.9, 124.7, 117.7, 117.4, 117.2, 111.3, HRMS(EI) calcd for C₁₄H₈FNO₂ 241.0539, found 241.0539

1-(4-Chlorophenyl)indoline-2,3-dione(5): The product was isolated as an orange solid.¹H NMR (400MHz,CDCl₃)δ 7.71(d,j=7.5Hz,1H), 7.59-7.53(m, 3H), 7.39(d,j=8.6Hz, 2H), 7.20(t,j=7.6Hz,1H), 6.90(d,j=6.9Hz, 1H); ¹³C NMR (100MHz,CDCl₃) δ 128.6, 157.4, 151.3, 138.6, 134.7, 131.5, 134.4, 137.5, 126.0, 124.7, 117.7, 111.3 HRMS(EI) calcd for C₁₄H₈ClNO₂ 257.0244, found 257.0248

1-(4-Bromophenyl)indoline-2,3-dione(6): The product was isolated as a light orange solid.¹H NMR (400MHz,CDCl₃)δ 7.69-7.66(m,3H) 7.56(t,j=7.8Hz, 1H), 7.32(d,j=8.5Hz,2H), 7.20(t,j=7.5Hz, 1H), 6.90(d,j=8.0Hz, 1H); ¹³C NMR (100MHz,CDCl₃) δ 182.5, 157.2,. 151.1, 138.6, 133.3, 132.0, 127.7, 125.9, 124.7, 122.6, 117.6, 111.3, HRMS(EI) calcd for C₁₄H₈BrNO₂ 300.9738, found 300.9742

1-(4-Iodophenyl)indoline-2,3-dione(7): The product was isolated as an orange solid.¹H NMR (400MHz,CDCl₃)δ 7.88(d,j=8.5Hz, 2H), 7.69(d,j=7.51Hz, 1H), 7.56(t,j=7.8Hz,1H), 7.21-7.17(m, 3H), 6.90(d,j=8.0Hz, 1H); ¹³C NMR (100MHz,CDCl₃) δ 182.5, 157.2, 151.1, 139.3, 138.6, 132.7, 127.8, 126.0, 124.8, 117.6, 11.3, 94.1; HRMS(EI) calcd for C₁₄H₈INO₂ 348.9600, found 348.9601

1-(2-Iodophenyl)indoline-2,3-dione(8). The product was isolated as a ruby red solid.¹H NMR(400MHz,CDCl₃) δ 8.01(d,j=7.9Hz,1H), 7.70(d,j=7.4Hz, 1H), 7.53-7.51(m, 2H), 7.36(d,j=7.6Hz, iH), 7.26-7.15(m, 2H), 6.49(d,j=8.0Hz, 1H); ¹³C NMR(100MHz,CDCl_3­)δ 182.6, 157.0, 151.3, 140.8, 138.7, 136.2, 131.5, 130.2, 129.7, 125.8, 124.5, 117.2, 111.8, 98.1; HRMS(EI) calcd for [M+Na]⁺ (M=C₁₄H₈INO₂) 371.9492,found 371.9497

4-(2,3-dioxoindolin-1-yl)benzonitrile(9): The product was isolated as a light orange solid.¹H NMR (400MHz,CDCl₃)δ 8.08(d,j=8.3Hz, 2H), 7.714-7.705(m, 3H), 7.64(t,j=7.8Hz, 1H), 7.23(t,j=7.51Hz,1H), 6.99(d,j=7.9Hz, 1H); ¹³C NMR (100MHz,CDCl₃) δ 181.9, 157.2, 150.0, 137.9, 137.6, 133.8, 127.0, 124.9, 124.1, 118.4, 117.9, 110.9, 110.5,; HRMS(EI) calcd for [M+H]⁺(M=C₁₅H₈N₂O₂) 249.0659, found 249.0656

Ethyl-4-(2,3-dioxoindolin-1-yl)benzoate(10): The product was isolated as a light orange solid.¹H NMR (400MHz,CDCl₃)δ 8.21(d,j=8.6Hz, 2H), 7.70(d,j=7.5Hz, 1H), 7.59-7.52(m, 3H), 7.20(t,j=7.51Hz,1H), 6.97(d,j=8.1Hz, 1H), 4.40(d,j=7.1Hz, 2H), 1.41(t,j=7.1Hz, 3H) ¹³C NMR (100MHz,CDCl₃) δ 182.3, 165.6, 157.1, 150.9, 138.6, 136.9, 131.3, 130.6, 126.0, 125.5, 124.8, 117.7, 111.4, 61.5, 14.5; HRMS(EI) calcd for C₁₇H₁₃NO₄ 295.0839, found 295.0845

1-[4-(Trifluoromethyl)phenyl]indolin-2,3-dione(11): The product was isolated as a bright orange solid.¹H NMR (400MHz,CDCl₃)δ 7.84(d,j=8.4Hz, 2H), 7.73(d,j=6.9Hz, 1H), 7.62-7.59(m, 3H), 7.23(t,j=7.5Hz,1H), 6.98(d,j=8.1Hz, 1H); ¹³C NMR (100MHz,CDCl_3, extra peaks due to C-F coupling) δ 182.2, 157.2, 150.8, 138.7, 136.2, 131.0, 130.6, 128.9, 127.33, 127.29, 127.26, 127.22, 126.3, 126.1, 125.1, 125.0, 122.4, 117.7, 111.3, HRMS(EI) calcd for C₁₅H₈F₃NO₂ 291.0507, found 291.0509

1-[3-(Trifluoromethyl)phenyl]indolin-2,3-dione(12): The product was isolated as a yellow orange solid.¹H NMR (400MHz,CDCl₃)δ 7.74-7.65(m, 5H), 7.60(td,j=1.2,8.0Hz, 1H), 7.23(t,j=7.6Hz, 1H), 6.92(d,j=8.1Hz, 1H); ¹³C NMR (100MHz,CDCl_3, extra peaks due to C-F coupling) δ 182.3, 157.3, 150.9, 138.7, 133.7, 130.9, 129.6, 126.1, 125.74, 125.70, 125.0, 123.04, 123.00, 117.7, 111.2;  HRMS(EI) calcd for C₁₅H₈F₃NO₂ 291.0507, found 291.0507

1-(2-tert-Butylphenyl)indolin-2,3-dione(13): The product was isolated as a light orange solid.¹H NMR (400MHz,CDCl₃)δ 7.66(t,j=7.9Hz, 2H), 7.51(td,j=1.1, 7.8Hz, 1H), 7.44(t,j=7.7Hz, 1H), 7.34(td,j=1.3,7.5Hz, 1H), 7.14(t,j=7.5Hz, 1H), 7.05(dd,j=1.4,7.8Hz, 1H), 6.42(d,j=8.0Hz, 1H), 1.32(s, 9H); ¹³C NMR (100MHz,CDCl_3, δ 183.4, 159.2, 154.1, 149.6, 138.7, 131.7, 130.5, 130.2, 129.4, 128.4, 125.4, 124.2, 11.8, 112.7, 35.8, 31.9;  HRMS(EI) calcd for C₁₈H₁₇NO₂ 279.1259, found 279.1259

1-((1,1^/-Biphenyl)-2-Yl]indoline-2,3-dione(14). The product was isolated as a red solid.¹H NMR(400MHz,CDCl₃) δ 7.56-7.53(m,4H), 7.40-7.36(m,2H), 7.26-7.23(m,5H), 7.03(t,j=7.3Hz,1H), 6.48(d,j=7.5Hz,1H), ¹³C NMR(100MHz,CDCl_3­)δ 182.8, 158.0, 152.2, 141.1, 138.3, 138.2, 131.7, 130.6, 130.1, 129.3, 128.74, 128.69, 128.2, 128.1, 125.4, 124.1, 117.2, 111.6, HRMS(EI) calcd for C₃₀H₁₁NO₂ 299.0946, found 299.0946

1-(2,4-Dimethoxyphenyl)indoline-2,3-dione(15). The product was isolated as a orange solid.¹H NMR(400MHz,CDCl₃) δ 7.64(dd,j=7,7.5Hz,1H), 7.49(t,j=1.4,7.9Hz,1H), 7.11(td,j=0.73,7.5Hz, iH), 7.02-6.96(m,2H), 6.86(d,j=2.6Hz,1H), 6.59(d,j=8.0Hz,1H), 3.77(s, 3H), 3.73(s, 3H);  ¹³C NMR(100MHz,CDCl_3­)δ 183.1, 157.7, 154.0, 152.2, 149.3, 138.4, 125.3, 124.0, 121.6, 117.6, 116.0, 114.7, 113.7, 111.8, 56.4, 56.0; HRMS(EI) calcd for C₁₆H₁₃NO₄ 283.0845 found 283.0839

1-Mesitylindoline-2,3-dione(16). The product was isolated as a yellow orange solid.¹H NMR(400MHz,CDCl₃) δ 7.70(d,j=7.2Hz,1H), 7.51(t,j=7.7Hz, 1H), 7.16(t,j=7.5Hz, iH), 7.03(s,2H), 6.4(d,j=7.8Hz,1H), 2.35(s, 3H), 2.14(s, 6H);  ¹³C NMR(100MHz,CDCl_3­)δ 13.2, 157.5, 151.7, 139.8, 138.8, 136.3, 129.9, 128.0, 125.8, 124.3, 117.7, 111.2, 21.3, 18.1; HRMS(EI) calcd for C₁₇H₁₅NO₂ 265.1100 found 265.1103

1-(Naphthalen-1-yl)indoline-2,3-dione(17). The product was isolated as an orange solid.¹H NMR(400MHz,CDCl₃) δ 8.02(d,j=8.2Hz,1H), 7.98(d,j=8.2Hz, 1H), 7.75(d,j=7.3Hz, iH), 7.70(t,j=8.4Hz, 1H), 7.64-7.49(3,4H), 7.45(td,j=1.1,7.9Hz,1H), 7.17(t,j=7.5Hz, 1H), 6.44(d,j=8.0Hz, 1H), 6H);  ¹³C NMR(100MHz,CDCl_3­)δ 183.1, 158.2, 152.8, 138.8, 135.0, 130.4, 129.5, 129.0, 127.6, 127.1, 126.0,. 125.7, 124.4, 122.6, 117.6, 112.0; HRMS(EI) calcd for C₁₈H₁₁NO₂ 273.0790 found 273.0786

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