Substituent-Directed Regioselective Azidation - ACS Publications

Dec 5, 2017 - Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India. •S Supporting Information. ABSTRACT...
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Article Cite This: J. Org. Chem. 2018, 83, 228−235

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Substituent-Directed Regioselective Azidation: Copper-Catalyzed C−H Azidation and Iodine-Catalyzed Dearomatizative Azidation of Indole Jayaraman Dhineshkumar, Karthik Gadde, and Kandikere Ramaiah Prabhu* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India S Supporting Information *

ABSTRACT: Azidation of indoles using iodine and copper bromide as catalysts under ambient reaction conditions is presented. The regioselectivity is directed by the substituent at the C3-position of indole. A radical stabilizing group such as an ester or ketone moiety at the C3-position of indole leads to azidation at the C2-position, whereas a less radical stabilizing group such as an alkyl or amide group at the C3-position of indole furnishes the 3-azidooxindole product. This protocol is mild and efficient to obtain several 2-azidoindole derivatives and 3-azidooxindole derivatives in moderate to good yields. The reaction conditions hold well for gram-scale synthesis.

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Since the discovery of the “click” reaction of azides and its applications in peptide chemistry, polymer chemistry, and drug discovery, the introduction of the azide group into organic molecules has received considerable attention.14 In this regard, azidation of indole has been reported using an excess amount of heavy metal reagents such as ceric ammonium nitrate (CAN) for synthesizing 2-azidoindoline derivatives.15 Recently, Sudalai et al.16 reported a regioselective azidation of indoles at the C3position using a stoichiometric amount of iodine. In continuation of our work,17 we envisioned a reaction of 3substituted indole derivatives with (TMS)N3, and the results are described in the following section (Scheme 1).

INTRODUCTION The carbon−nitrogen bond is ubiquitous, and the aryl amine moiety is widespread in synthetic as well as naturally occurring bioactive molecules.1 Other than Ullman and Goldberg,2 the pioneering work on sp2 C−N bond formation was accomplished by Buchwald and Hartwig in 1994 using Pd catalyst.3 Since then, a plethora of C−N bond-forming reactions have been reported in the literature. 4,5 Direct C−H bond functionalization has become one of the important areas of research and has played a pivotal role in direct C−H amination reactions.6 Owing to the presence of indole moieties in a variety of biologically and medicinally active compounds, synthesis and functionalization have received great attention.7,8 Selective functionalization of indole is a challenging task due to its inherent electronic nature.9a To address this issue, directing group strategies have been employed efficiently, which have led to the selective functionalization of indole derivatives at the C2-, C4-, and C7-positions.9 Direct conversion of sp2 C−H bonds to C−N bonds in indole moieties is an important approach, as several 2-aminoindole-derived compounds are found in biologically active natural products such as gliocladins B, mollenine A, and NITD609 (Figure 1).10 Amination of prefunctionalized precursors such as 2-haloindole derivatives has been well explored using harsh or modified Buchwald− Hartwig reaction conditions.11 Among the direct C−H aminations,12,13 the iodine-mediated amination reaction has been reported by Liang et al.12a and others12 for synthesizing aminated indole derivatives. Liang et al. developed a Pd-catalyzed reaction by employing N-chloroN-methyltosyl derivatives as amine sources at room temperature.13 © 2017 American Chemical Society

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RESULTS AND DISCUSSION In continuation of our work,17 screening studies were started by employing methyl 1-methyl-1H-indole-3-carboxylate (1a), (TMS)N3 as an azide source, CuBr (5 mol %) as a catalyst, and aq TBHP (1 equiv) as an oxidant in CH3CN solvent. However, instead of the expected dearomatizative azidated product, a C−H functionalization of indoles occurred, furnishing the corresponding 2-azido derivative, methyl 2azido-1-methyl-1H-indole-3-carboxylate (2a), in 68% yield (entry 1, Table 1). Increasing the amount of CuBr to 10 mol % furnished the expected azidated indole 2a in 95% NMR yield (entry 2). Solvents such as 1,4-dioxane and DCE furnished the expected product 2a in poor yields (entries 3 and 4), whereas other solvents such as H2O, DMF, and MeOH failed to furnish the expected product (entries 5−7). Cu(I) salts such as CuCl Received: October 11, 2017 Published: December 5, 2017 228

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry

Figure 1. Biologically important compounds.

Scheme 1. Reaction Development: Azidation of Indoles via C−H Functionalization

and CuI did not afford the expected azidated product (entries 8 and 9), whereas the reaction of 1a with CuBr2 (10 mol %) proceeded smoothly, furnishing 2a in 88% NMR yield (entry 10). The reaction of 1a with other copper salts such as Cu(OAc)2 or Cu(OTf)2 did not furnish the expected product (entries 11 and 12). Thus, the screening study clearly indicated that both copper(I) and copper(II) bromide salts are suitable for this oxidative functionalization and the bromide counteranion plays a crucial role. The azidation reaction using molecular iodine as a catalyst was not fruitful (entry 13). Furthermore, it was found that NaN3 is not a useful azide source for this reaction (entry 14). Using molecular oxygen instead of aq TBHP failed to furnish the azidated product (entry 15). The reaction in the absence of CuBr or aq TBHP failed to furnish the product 2a, indicating that both the catalyst and the oxidant are indispensable for the reaction (entries 16 and 17). Therefore, the optimal reaction conditions were found to be 2 equiv of (TMS)N3, CuBr (10 mol %), and aq TBHP (1 equiv), using CH3CN as the solvent at room temperature. Having found the optimal reaction conditions, the scope and limitations of the reaction were explored using a variety of indole derivatives. Thereby, methyl 1-methyl-1H-indole-3carboxylate (1a) under the optimal reaction conditions afforded the expected 2-azidated product 2a in 95% yield (Scheme 2). 5Bromo and 6-bromo derivatives of methyl 1-methyl-1H-indole3-carboxylate (1b and 1c, respectively) underwent a smooth reaction, furnishing the expected azidated products 2b and 2c in excellent yields (99% and 92% yields, respectively). 3Substituted carboxylic esters such as ethyl, allyl, propargyl, and benzyl ester derivatives of indole furnished the azidated products in excellent yields, (2g, 2h, 2i, and 2j in 95%, 96%, 90%, and 88% yields, respectively). After a successful azidation of indole-3-carboxylate esters, similar azidation reactions were attempted using C3-acylated indole derivatives. Thus, under the same reaction conditions, several 1-(1-alkyl-1H-indol-3-yl)ethan-1-ones furnished the azidated products 2k, 2l, 2m, 2n,

and 2o, respectively, in moderate yields (68%, 63%, 64%, 46%, and 38% yields, respectively, Scheme 2). Enthused by the reaction of azidation of indole-3-carboxylate esters and C3-acylated indole derivatives, a 3-alkylindole derivative such as 1,3-dimethyl-1H-indole was subjected to the optimal reaction conditions, which failed to furnish the expected product (Scheme 3). Nevertheless, the reaction furnished the dearomatized 3-azido-1,3-dimethylindolin-2-one (4a) in 32% yield. Most of the other derivatives of 3-methyl-Nalkylindoles furnished the dearomatized products 4b, 4c, and 4d in poor yields (29%, 23%, and 18% yields, respectively, Scheme 4). Attempts to improve the yields by employing different copper salts were futile. However, when molecular iodine was employed as a catalyst in place of CuBr, the 3-azidooxindole products, via dearomatization, were obtained in good yields. Thereby, several N-alkyl-3-methylindole derivatives furnished their corresponding 3-azidooxindole derivatives (4a, 4b, 4c, 4d, 4e, and 4f) in good yields (76%, 62%, 91%, 48%, 83%, and 79% yields, respectively). 3-Cyclohexyl-1-methyl-1H-indole furnished the expected product 4g in 32% yield (using CuBr as a catalyst) and 74% yield (using I2 as a catalyst). The reaction of N,1-dimethyl-1H-indole-3-carboxamide using CuBr as a catalyst furnished the expected product 4h in 39% yield, and a similar reaction using I2 furnished the product 4h in 42% yield. The reactions of N-methylindole and 3-methylindole under the standard reaction conditions (either CuBr or I2 catalysis conditions) failed to furnish the expected products 4i and 4j. A gram-scale experiment has been performed for showcasing the utility of the reaction (Scheme 5). Hence, the reaction of methyl 1-methyl-1H-indole-3-carboxylate (1a) and 1,3-dimethyl-1H-indole (3a) under the optimal reaction conditions (Cu conditions and I2 conditions) furnished the expected product 2a and 4a in 88% and 75% yields, respectively. To understand the reaction pathway, radical inhibition studies were carried out using BHT and TEMPO under the optimal reaction conditions (Scheme 6). In these reactions, the 229

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry Table 1. Optimization Studiesa

a

Reaction conditions: 1a (0.25 mmol), (TMS)N3 (0.5 mmol), aq TBHP (70% in water, 1 equiv), CuBr (10 mol %), CH3CN (1 mL), at rt, 12 h. NMR yields, calculated using terephthalaldehyde as an internal standard. Nd = not detected. cA 5 mol % concentration of CuBr was employed. d NaN3 was used instead of (TMS)N3. b

Similarly, a tentative mechanism has been proposed on the basis of the literature prcedence16 and the control experiments. In this reaction, I2 and trimethylsilyl azide react to generate IN3 species. The IN3 species reacts with the substrate I to form the intermediates A and A′, which are in equilibrium. Nucleophilic azide displaces the iodonium ion to form the intermediates B and B′, which are in equilibrium. Furthermore, the intermediate B′ reacts with aq TBHP and undergoes rapid oxidation to furnish the 3-azidooxindole product D (Scheme 8). Similarly, a tentative mechanism has been proposed for the copper-catalyzed C3-azidation of indole derivatives. We believe that, through the single electron transfer (SET) mechanism, the reaction leads to the intermediate A, which further transforms to iminium ion intermediate B. The intermediate B reacts with aq TBHP and undergoes rapid oxidation to furnish the 3azidooxindole product D (Scheme 9). In summary, a direct C−H functionalization and dearomatization of indole derivatives have been achieved using CuBr and I2 as catalysts and aq TBHP as an oxidant. When the substitution on the third position of indole is a radicalstabilizing group such as an ester or ketone moiety, the reaction

azidated products were obtained in only 15% and 10% yields, respectively (NMR yields), for copper-catalyzed C−H azidation reactions, and no radical intercepted products were obtained. This suggests that the reaction may go through a radical pathway. The radical inhibition studies for an I2-catalyzed reaction furnished 12% 3-azido oxindole derivative using BHT (1 equiv) and 68% 3-azidooxindole derivative using TEMPO (1 equiv). These experiments suggest an ionic pathway for the iodine-catalyzed reaction. On the basis of literature precedence18 and the control experiments, a tentative mechanism has been proposed wherein CuBr and trimethylsilyl azide react to generate CuN3 species. The CuN3 species generates an azide radical, which adds onto the substrate I to form the intermediate II, which is stabilized by an ester or ketone moiety. This may be the reason for the formation of different products in the reactions of C3-alkylated or C3-amidated indole derivatives (3-azidooxindole-derived) as the radical intermediate generated in these cases would be less stable. Furthermore, the intermediate II undergoes a radical hydrogen cleavage to form the stable 2-azido product III (Scheme 7). 230

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry Scheme 2. Substrate Scope: Regioselective Azidation of Indoles Using CuBr as a Catalysta

a

Reaction conditions: 1 (0.25 mmol), (TMS)N3 (0.5 mmol, 2 equiv), CuBr (10 mol %), aq TBHP (70% in water, 1 equiv), and CH3CN (1 mL).

Scheme 3. Reaction Development: Azidation of Indoles via Dearomatization

crude product was purified on a silica gel flash column chromatograph using hexane/EtOAc to obtain the pure product. Typical Experimental Procedure for the Synthesis of 3Azidooxindole Derivatives (Procedure b). (TMS)N3 (2 equiv, 0.50 mmol) was added to a well-stirred solution of indole derivative (0.25 mmol) and I2 (0.1 equiv, 0.025 mmol) in CH3CN (1 mL). Then aq TBHP (70% in water, 2 equiv, 0.5 mmol) was added dropwise into the reaction mixture, and the resulting mixture was stirred at room temperature for 48 h (monitored by TLC). After completion of the reaction (monitored by TLC), the reaction mixture was quenched using aqueous Na2S2O3 and washed with EtOAc (3 × 20 mL). The combined organic layer was dried over anhyd Na 2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel flash column chromatograph using hexane/EtOAc to obtain the pure product. Characterization Data for C2-Azidation of Indole Derivatives. Methyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2a). Brown solid. Yield: 95% (52 mg). Mp: 69−71 °C. Rf (10% EtOAc/ hexane): 0.5. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2130, 1694, 1454. 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 3 H), 3.97 (s, 3 H), 7.24−7.26 (m, 3 H), 8.05−8.07 (m, 1 H). 13 C NMR (100 MHz, CDCl3): δ 29, 51, 96.4, 109.2, 121, 122.3, 122.7, 125.5, 133.7, 140.6, 165. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C11H10N4O2Na 253.0701, found 253.0701. Methyl 2-Azido-5-bromo-1-methyl-1H-indole-3-carboxylate (2b). Brown solid. Yield: 99% (76 mg). Mp: 148−150 °C. Rf (10% EtOAc/

prefers to form 2-azido products. However, when the substitution on the C3-position of indole is less radical stabilizing, such as an alkyl or amide group, then the reaction prefers to furnish the 3-azidooxindole product. In conclusion, we discovered that substitution on the C3-position of indole causes the difference in reactivity under the same reaction conditions to afford two completely different products. By employing this protocol, several 2-azidoindole derivatives and 3-azidooxindole derivatives are obtained in good to moderate yields. The developed protocol was also efficient in a gram-scale experiment. Further studies to improve the substrate scope and generality are currently under way in our laboratory.

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EXPERIMENTAL SECTION

Typical Experimental Procedure for the Synthesis of 2Azidoindole Derivatives (Procedure a). (TMS)N3 (2 equiv, 0.50 mmol) was added to a well-stirred solution of indole derivative (0.25 mmol) and CuBr (0.1 equiv, 0.025 mmol) in CH3CN (1 mL). Then aq TBHP (70% in water, 1 equiv, 0.25 mmol) was added dropwise into the reaction mixture, and the resulting mixture was stirred at room temperature for 12 h (monitored by TLC). After completion of the reaction (monitored by TLC), the reaction mixture was passed through a short pad of Celite and extracted with 50% EtOAc and petroleum ether (3 × 20 mL). The combined organic layer was dried over anhyd Na2SO4 and concentrated under reduced pressure. The 231

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry Scheme 4. Substrate Scope: Regioselective Azidation of Indoles Using Iodine as a Catalysta

a

Reaction conditions: 3 (0.25 mmol), (TMS)N3 (0.5 mmol, 2 equiv), I2 (10 mol %) or CuBr (10 mol %), aq TBHP (70% in water, 2 equiv), and CH3CN (1 mL), at rt for 48 h.

Scheme 5. Gram-Scale Experiments

Scheme 6. Radical Inhibition Studies

IR (KBr, cm−1): 2139, 1695, 1458. 1H NMR (400 MHz, CDCl3): δ 3.56 (s, 3 H), 3.95 (s, 3 H), 7.30−7.34 (m, 2 H), 7.87−7.89 (m, 1 H). 13 C NMR (100 MHz, CDCl3): δ 29.1, 51, 96.5, 112.2, 115.9, 122.3, 124.3, 125.4, 134.4, 140.9, 164.5. HRMS (ESI-TOF) ( m/z): [M]+ calcd for C11H9BrN4O2 307.9909, found 307.9909. Methyl 2-Azido-1-ethyl-1H-indole-3-carboxylate (2d). Brown oil. Yield: 80% (49 mg). Rf (10% EtOAc/hexane): 0.6. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2948, 2138, 1693. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J = 7.33 Hz, 3 H), 3.96 (s, 3 H), 4.11−4.17 (m, 2 H), 7.22−7.24 (m, 3 H), 8.06−8.08 (m, 1

hexane): 0.4. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2922, 2140, 1689, 1454. 1H NMR (400 MHz, CDCl3): δ 3.59 (s, 3 H), 3.96 (s, 3 H), 7.06 (d, J = 8.85 Hz, 1 H), 7.31 (dd, J = 8.54, 1.83 Hz, 1 H), 8.16 (s, J = 1.83 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 29.1, 51.1, 96, 110.6, 115.8, 123.5, 125.5, 127, 132.4, 141.3, 164.5. HRMS (ESI-TOF) ( m/z): [M]+ calcd for C11H9BrN4O2 307.9909, found 307.9909. Methyl 2-Azido-6-bromo-1-methyl-1H-indole-3-carboxylate (2c). Brown solid. Yield: 92% (71 mg). Mp: 119−121 °C. Rf (10% EtOAc/ hexane): 0.4. Prepared as shown in general experimental procedure a. 232

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry Scheme 7. Proposed Tentative Reaction Mechanism for CuBr-Catalyzed C−H Azidation

Scheme 8. Proposed Tentative Reaction Mechanism for I2Catalyzed Dearomatizative Azidation

Scheme 9. Proposed Tentative Reaction Mechanism for CuCatalyzed Dearomatizative Azidation

H). 13C NMR (100 MHz, CDCl3): δ 14.6, 37.7, 50.9, 96.4, 109.2, 121.1, 122.1, 122.6, 125.7, 132.6, 139.9, 165. HRMS (ESI-TOF) ( m/ z): [M + Na]+ calcd for C12H12N4O2Na 267.0858, found 267.0854. Methyl 1-Allyl-2-azido-1H-indole-3-carboxylate (2e). Brown oil. Yield: 74% (47 mg). Rf (10% EtOAc/hexane): 0.4. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2137, 1694, 1453. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3 H), 4.70 (dt, J = 4.96, 1.79 Hz, 2 H), 4.95−5.00 (m, 1 H), 5.16−5.19 (m, 1H), 5.79−5.98 (m, 1 H), 7.11−7.30 (m, 3 H) 7.99−8.13 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 44.9, 51, 96.6, 109.6, 117.3, 121.1, 122.3, 122.8, 125.6, 131.7, 133.1, 140.1, 164.9. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C13H12N4O2Na 279.0858, found 279.0858. Methyl 2-Azido-1-benzyl-1H-indole-3-carboxylate (2f). Oily liquid. Yield: 93% (71 mg). Rf (10% EtOAc/hexane): 0.6. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2140, 1682, 1431. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3 H), 5.30 (s, 2 H) 7.11 (d, J = 6.71 Hz, 2 H), 7.18−7.21 (m, 2 H), 7.21−7.36 (m, 4

H), 8.09 (d, J = 7.93 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 46.2, 51, 96.8, 109.8, 121.1, 122.4, 122.9, 125.7, 126.5, 127.8, 128.9, 133.3, 136, 140.3, 164.9. HRMS (ESI-TOF) (m/z): [M + K]+ calcd for C17H14N4O2K 345.0754, found 345.0752. Ethyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2g). Brown solid. Yield: 95% (58 mg). Mp: 65−67 °C. Rf (10% EtOAc/hexane): 0.5. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2137, 1686, 1450. 1H NMR (400 MHz, CDCl3): δ 1.46 (t, J = 7.02 Hz, 3 H), 3.59 (s, 3 H), 4.44 (q, J = 7.2, 2 H), 7.15−7.30 (m, 3 H), 8.02−8.12 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 14.6, 28.9, 59.8, 96.6, 109.1, 121, 122.2, 122.6, 125.5, 133.7, 140.4, 164.5. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C12H13N4O2 245.1039, found 245.1038. Allyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2h). Brown solid. Yield: 96% (62 mg). Mp: 121−123 °C. Rf (10% EtOAc/ hexane): 0.6. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2129, 1680, 1519. 1H NMR (400 MHz, CDCl3): δ 3.63 (s, 3 H), 4.90 (d, J = 5.49 Hz, 2 H), 5.29 (d, J = 10.38 Hz, 1 H), 5.44 (d, J = 17.40 Hz, 1 H), 6.07−6.16 (m, 1 H), 7.23−7.26 (m, 3 H), 8.07−8.09 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 29, 64.6, 96.3, 109.2, 118.1, 121.1, 122.3, 122.7, 125.5, 132.8, 133.7, 140.8, 164.2. 233

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

Article

The Journal of Organic Chemistry HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C13H12N2O2Na 251.0796, found 251.0796. Prop-2-yn-1-yl 2-Azido-1-methyl-1H-indole-3-carboxylate (2i). Brown solid. Yield: 90% (57 mg). Mp: 60−63 °C. Rf (10% EtOAc/ hexane): 0.5. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2123, 1680, 1091. 1H NMR (400 MHz, CDCl3): δ 2.52 (t, J = 2.44 Hz, 1 H), 3.64 (s, 3 H), 4.99 (d, J = 2.44 Hz, 2 H), 7.22−7.30 (m, 3 H), 8.10 (dd, J = 6.56, 2.59 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 29.1, 51.3, 74.7, 78.2, 95.70, 109.2, 121.2, 122.5, 122.9, 125.4, 133.8, 141.3, 163.5. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C13H10N4O2Na 277.0701, found 277.0703. Benzyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2j). Brown solid. Yield: 88% (67 mg). Mp: 114−116 °C. Rf (10% EtOAc/ hexane): 0.6. Prepared as shown in general experimental procedure a. IR (KBr, cm−1): 2124, 1674, 1452. 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 3 H), 5.44 (s, 2 H), 7.20−7.24 (m, 3 H), 7.30−7.40 (m, 3 H), 7.49 (d, J = 7.02 Hz, 2 H), 8.03−8.05 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 29, 65.6, 96.3, 109.2, 121.1, 122.4, 122.7, 125.5, 128.0, 128.2, 128.5, 133.7, 136.6, 141, 164.3. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C17H14N4O2Na 329.1014, found 329.1018. 1-(2-Azido-1-methyl-1H-indol-3-yl)ethan-1-one (2k). Brown oil. Yield: 68% (36 mg). Rf (30% EtOAc/hexane): 0.8. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2133, 1754, 1464. 1H NMR (400 MHz, CDCl3):δ 2.70 (s, 3 H), 3.64 (s, 3 H), 7.25−7.30 (m, 3 H), 7.82−7.84 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 28.8, 31.1, 106.4, 109.7, 119.9, 122.4, 122.5, 125, 133.9, 141.2, 192.9. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C11H10N4ONa 237.0752, found 237.0754. 1-(2-Azido-1-ethyl-1H-indol-3-yl)ethan-1-one (2l). Brown oil. Yield: 63% (36 mg). Rf (30% EtOAc/hexane): 0.7. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2145, 1734, 1642, 1485, 1429. 1H NMR (400 MHz, CDCl3): δ 1.36 (t, J = 7.2 Hz, 3 H), 2.71 (s, 3 H), 4.17 (q, J = 7.2 Hz, 2 H), 7.25−7.32 (m, 3 H), 7.84−7.86 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 14.5, 31.2, 37.5, 106.5, 109.7, 120.1, 122.3, 122.5, 125.2, 132.8, 140.6, 193.1. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C12H12N4ONa 251.0909, found 521.0912. 1-(2-Azido-1-benzyl-1H-indol-3-yl)ethan-1-one (2m). Brown oil. Yield: 64% (46 mg). Rf (30% EtOAc/hexane): 0.7. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2145, 1642, 1489, 1456. 1H NMR (400 MHz, CDCl3): δ 2.74 (s, 3 H), 5.32 (s, 2 H), 7.14 (d, J = 7.2 Hz, 3 H), 7.22−7.33 (m, 7 H), 7.87 (d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 31.2, 46.0, 106.6, 110.4, 120., 122.5, 122.7, 125.1, 126.6, 127.8, 128.9, 133.4, 135.7, 140.9, 193.2. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C17H14N4ONa 313.1065, found 313.1062. 1-(2-Azido-1-pentyl-1H-indol-3-yl)ethan-1-one (2n). Brown oil. Yield: 46% (31 mg). Rf (10% EtOAc/hexane): 0.5. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2140, 1731, 1642, 1426. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 6.8 Hz, 3 H), 1.21−1.42 (m, 4 H), 1.72−1.77 (m, 2 H), 2.71 (s, 3 H), 4.09 (t, J = 7.2 Hz, 2 H), 7.25−7.30 (m, 3 H), 7.82−7.85 (m, 1 H) . 13C NMR (100 MHz, CDCl3): δ 13.9, 22.3, 28.9, 28.9, 31.1, 42.7, 106.3, 109.9, 120, 122.3, 122.4, 125.1, 133.2, 140.9, 193. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C15H18N4ONa 293.1378, found 293.1380. 1-(2-Azido-6-bromo-1-methyl-1H-indol-3-yl)ethan-1-one (2o). Brown oil. Yield: 38% (28 mg). Rf (20% EtOAc/hexane): 0.7. Prepared as shown in general experimental procedure a. IR (neat, cm−1): 2148, 1763, 1450. 1H NMR (400 MHz, CDCl3) δ 2.65 (s, 3 H), 3.60 (s, 3 H), 7.27−7.45 (m, 2 H), 7.65 (dd, J = 8.39, 2.90 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 29, 31, 106.4, 112.7, 115.8, 121.1, 123.8, 125.5, 134.7, 141.6, 192.6. HRMS (ESI-TOF) ( m/z): [M + H]+ calcd for C11H10BrN2O 264.9976, found 264.9974. 3-Azido-1,3-dimethylindolin-2-one (4a). Brown oil. Yield: 76% (38 mg). Rf (30% EtOAc/hexane): 0.3. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2102, 1726, 1614, 1244. 1 H NMR (400 MHz, CDCl3): δ 1.56 (s, 3 H), 3.22 (s, 3 H), 6.76 (d,J = 7.6 Hz,1 H), 6.98 (t, J = 8.4, Hz, 1 H), 7.30−7.33 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 24.4, 27.0, 65.9, 107.5, 121.2, 123.2,

128.3, 130.2, 145.0, 170.5. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C10H10N4ONa 225.0752, found 225.0748. 3-Azido-1-ethyl-3-methylindolin-2-one (4b). Yellow oil. Yield: 62% (34 mg). Rf (20% EtOAc/hexane): 0.2. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2098, 1719, 1656, 1606. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3 H) 1.56 (s, 3 H) 3.74−3.85 (m, 2 H) 6.9 (d, J = 8 Hz, 1 H) 6.99 (t, J = 7.2 Hz, 1 H) 7.30−7.33 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 11.8, 24.4, 35.4, 66.0, 107.6, 121.1, 123.4, 128.6, 130.2, 144.1, 169.6. HRMS (ESITOF) ( m/z): [M]+ calcd for C11H12N4O 216.1011, found 216.1012. 1-Allyl-3-azido-3-methylindolin-2-one (4c). Brown oil. Yield: 91% (52 mg). Rf (30% EtOAc/hexane): 0.3. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2096, 1658, 1606, 1483. 1 H NMR (400 MHz, CDCl3): δ 1.59 (s, 3 H), 4.32−4.42 (m, 2 H), 5.15−5.22 (m, 2 H), 5.81−5.90 (m, 1 H), 6.75 (d, J = 7.6 Hz, 1 H), 7.02 (t, J = 7.2 Hz, 1 H), 7.27−7.31 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 24.6, 42.9, 66.1, 108.3, 116.9, 121.4, 123.3, 128.3, 130.2, 130.8, 144.3, 169.8. HRMS (ESI-TOF) ( m/z): [M]+ calcd for C12H12N4O 228.1011, found 228.1010. 3-Azido-1-benzyl-3-methylindolin-2-one (4d). Brown oil. Yield: 48% (33 mg). Rf (30% EtOAc/hexane): 0.6. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2095, 1657, 1606, 1490. 1H NMR (400 MHz, CDCl3): δ 1.63 (s, 3 H), 4.93−5.02 (m, 2 H), 6.68 (d, J = 7.6 Hz, 1 H), 7.01 (t, J = 7.2 Hz, 1 H), 7.27−7.35 (m, 7 H). 13C NMR (100 MHz, CDCl3): δ 24.7, 44.3, 66.2, 108.4, 121.5, 123.4, 126.8, 127.4, 128.3, 128.7, 130.3, 135.9, 144.3, 170.3. HRMS (ESI-TOF) (m/z): [M]+ calcd for C16H14N4O 278.1168, found 278.1169. 3-Azido-3-methyl-1-pentylindolin-2-one (4e). Brown oil. Yield: 83% (54 mg). Rf (10% EtOAc/hexane): 0.2. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2097, 1723, 1655, 1607, 1467. 1H NMR (400 MHz, CDCl3): δ 0.87−0.91 (m, 3 H), 1.26−1.40 (m, 4 H), 1.56 (s, 3 H), 1.66−1.71 (m, 2 H), 3.65−3.78 (m, 2 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.97 (t, J = 6.8 Hz, 1 H), 7.27− 7.32 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 13.9, 22.4, 24.4, 26.4, 29.1, 40.7, 66.0, 107.7, 121.0, 123.3, 128.5, 130.1, 144.5, 169.9. HRMS (ESI-TOF) (m/z): [M]+ calcd for C14H18N4O 258.1481, found 258.1485. 3-Azido-1-(4-(benzyloxy)butyl)-3-methylindolin-2-one (4f). Brown oil. Yield: 79% (69 mg). Rf (30% EtOAc/hexane): 0.3. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2098, 1653, 1608, 1466. 1H NMR (400 MHz, CDCl3): δ 1.57 (s, 3 H), 1.59−1.74 (m, 2 H), 1.78−1.84 (m, 2 H), 3.52 (t, J = 6.4 Hz, 2 H), 3.76−3.80 (m, 2 H), 4.50 (s, 2 H) 6.79 (d, J = 8.2 Hz, 1 H), 7.03 (t, J = 6.8 Hz, 1 H), 7.28−7.37 (m, 7 H). 13C NMR (100 MHz, CDCl3): δ 23.8, 24.4, 26.9, 40.8, 66.2, 69.9, 72.9, 108.1, 121.5, 123.3, 127.5, 127.6, 128.3, 128.5, 130.3, 138.3, 144.2, 170.0. HRMS (ESITOF) ( m/z): [M]+ calcd for C20H22N4O2 350.1743, found 350.1741. 3-Azido-3-cyclohexyl-1-methylindolin-2-one (4g). Yellow oil. Yield: 74% (50 mg). Rf (50% EtOAc/hexane): 0.4. Prepared as shown in general experimental procedure b. IR (neat, cm−1): 2101, 1656, 1605. 1H NMR (400 MHz, CDCl3): δ 0.63 (qd, J = 3.2 Hz, 1 H), 1.15−1.27 (m, 4 H), 1.53−1.91 (m, 6 H), 3.23 (s, 3 H), 6.76 (d, J = 7.6 Hz, 1 H), 6.98 (t, J = 7.2 Hz, 1 H), 7.27−7.34 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 25.9, 26.0, 26.1, 26.4, 26.5, 27.00, 47.0, 73.5, 107.3, 120.8, 124.6, 125.6, 130.1, 146.1, 170.2. HRMS (ESITOF) (m/z): [M]+ calcd for C15H18N4O 270.1481, found 270.1482. 3-Azido-N,1-dimethyl-2-oxoindoline-3-carboxamide (4h). Brown solid. Yield: 42% (26 mg). Mp: 125−127 °C. Rf (50% EtOAc/hexane): 0.3. Prepared as shown in general experimental procedure b. IR (KBr, cm−1): 2102, 1711, 1699, 1465, 1249. 1H NMR (400 MHz, CDCl3): δ 2.87 (d, J = 4.8 Hz, 3 H), 3.25 (s, 3 H), 6.91 (d, J = 8.0 Hz, 2 H), 7.16 (t, J = 8.1 Hz,1 H), 7.42 (t, J = 8.02, 1 H), 7.49 (d, J = 7.2 Hz, 1 H). 13 C NMR (100 MHz, CDCl3): δ 26.7, 26.7, 68.7, 109.2, 123.8, 124.4, 125.3, 131.0, 144.0, 164.9, 171.1. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C11H11N5O2Na 268.0810, found 268.0812. 234

DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235

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The Journal of Organic Chemistry

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02591. General experimental information and 1H and 13C spectra and spectral data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +91-8022932887. Fax: +91-80-23600529. ORCID

Karthik Gadde: 0000-0001-6624-4129 Kandikere Ramaiah Prabhu: 0000-0002-8342-1534 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by SERB (Grant No. SB/S1/OC-56/ 2013), New Delhi, CSIR (Grant No. 02(0226)15/EMR-II), New Delhi, the Indian Institute of Science, RL Fine Chem, Bangalore, Synovation Chemicals, and Sourcing Pvt Ltd., Bangalore. We thank Dr. A. R. Ramesha (RL Fine Chem) for useful discussions. We thank Mr. N. Muniraj for performing a few experiments at the revision stage of the manuscript. J.D. thanks CSIR, New Delhi, for his senior research fellowship.

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DOI: 10.1021/acs.joc.7b02591 J. Org. Chem. 2018, 83, 228−235