Iodine-Catalyzed Regioselective Synthesis of Multisubstiuted Pyrrole

Aug 24, 2017 - A highly regioselective iodine-mediated cascade reaction for the synthesis of multifunctional polyheterocyclic systems is developed by ...
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Iodine-Catalyzed Regioselective Synthesis of Multisubstiuted Pyrrole Polyheterocycles Free from Rotamers and Keto−Enol Tautomers Nitika Sharma and Rama Krishna Peddinti* Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667, India S Supporting Information *

ABSTRACT: A highly regioselective iodine-mediated cascade reaction for the synthesis of multifunctional polyheterocyclic systems is developed by employing 3-(2-oxo-2-arylethylidene)oxindoles and 1,4-benzoxazinone as starting materials. The polyheterocycles are skillfully embraced with oxindole, pyrrole, and coumarin scaffolds, which are well-known for their enriched biological activity. The current approach worked under mild reaction conditions. The reaction afforded a single product, and no rotameric and keto−enol isomeric products are formed. The method is environmentally benign and atomeconomical, and the only side product of this reaction is water. This protocol obviates the purification techniques such as column chromatography for the isolation of the products. The products were isolated by decantation of the solvent or by recrystallization. The reaction proceeds through inter- and intramolecular C−C and C−N bond formation.

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component coupling.13,14 Nonetheless, it is still a formidable challenge to design a ideal synthetic protocol that is environmentally friendly and step economic using less hazardous reagents under mild reaction conditions. The domino approach15 is one of the best choices for attaining atom and step economy and an efficient tool to construct complex systems enveloped with multiple heterocyclic units. Herein, we describe a molecular iodine-mediated, highly regioselective, environmentally benign, and competent domino reaction for the synthesis of novel multifunctional pyrrole polyheterocycles bearing oxindole and coumarin scaffolds as their structural motifs by employing 3(2-oxo-2-arylethylidene)oxindoles and 1,4-benzoheterocyles as starting materials. To the best of our knowledge, the combination of these three potent scaffolds in a single molecule is unique.

INTRODUCTION Nature is a hub of natural compounds providing potent scaffolds that can be combined, leading to polyheterocyclic/hybrid/ complex molecules that emerge as novel drugs in discovery approach.1 The design of molecules that connect potent scaffolds having manifold functionalities is a challenging theme in synthetic organic chemistry. Among the potent scaffolds, oxindole, coumarin, and pyrrole have a multitude of biological and pharmacological activities such as anti-inflammatory, antiviral, anxiolytic, antitumor, antileukemic, antitumoral, antiHIV, antibacterial, antifungal, antimalarial, antioxidant, and central nervous system stimulating activities.2−4 Moreover, pyrrole is the key structural fragment of porphyrins, corrins, and chlorins, which are found in heme, vitamin B12, and chlorophyll, respectively. In particular, the pyrrole scaffold is found in marine natural compounds lamellarins, ningalins, and lukianols, which possess significant biological properties, including cytotoxicity, antitumor activity, reversal of multidrug resistance (MDR) activity, cell division inhibition, immunomodulatory activity, etc.5,6 Apart from these properties, substituted pyrroles are also widely used in material science,7 bioorganic chemistry,8 and supramolecular chemistry.9 Because of the eloquent chemical and biological properties of these motifs, many efforts have been made to develop more efficient synthetic routes to obtain polyheterocycles based on pyrrole scaffolds. A variety of elegant methods for the synthesis of substituted pyrroles have been developed in the past decades.10,11 However, facile and efficient procedures for the synthesis of multisubstituted pyrroles remain highly desirable. The recent procedures for the synthesis of substituted pyrroles were mainly based on transition-metal-catalyzed cyclization12 and multi© 2017 American Chemical Society

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RESULTS AND DISCUSSION In a pilot experiment, oxindole 1a and 1,4-benzoxazinone 2a were taken as model substrates. The reaction of 1a and 2a in DCM in the presence of FeCl3 essentially led to the formation of regioselective polysubstituted pyrrole 3aa in 68% yield in 12 h (Table 1, entry 1). Fortified by the result obtained, we investigated the reaction with various catalysts. The replacement of FeCl3 with various Lewis acids and Brønsted acids such as ZnCl2, ZrCl4, p-TSA·H2O, and HCl demonstrated somewhat lower efficiency compared with FeCl3 (entries 2−5). However, no product formation was observed when the reaction was carried out with TFA (entry 6). Screening the reaction with BF3· OEt2 and I2 provided the product 3aa in acceptable yield (entries Received: June 21, 2017 Published: August 24, 2017 9360

DOI: 10.1021/acs.joc.7b01538 J. Org. Chem. 2017, 82, 9360−9366

Article

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

entry 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 a b

reagent

amt of reagent

T (°C)

time (h)

yieldb (%)

FeCl3 ZnCl2 ZrCl4 p-TSA·H2O HCl TFA BF3·OEt2 I2 I2 or BF3·OEt2 I2 or BF3·OEt2 I2 or BF3·OEt2 I2 or BF3·OEt2 I2 or BF3·OEt2 I2 I2 I2 I2

1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv

rt rt rt rt rt rt rt rt rt rt rt 90 90 rt rt rt rt

12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12

68 47 45 56 56 nr 75 75 nd nd nd nd nd 57 63 55 57

I2 I2 I2 I2 I2 I2 I2 I2 I2 − −

1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 1.0 equiv 0.5 equiv 30 mol % 0.1 equiv − −

rt rt 90 rt 70 90 70 70 70 70 90

12 12 12 5 1 1 1 1 12 12 12

45 45 nr 85 93 93 93 93 25 nr nr

solvent DCM DCM DCM DCM DCM DCM DCM DCM methanol ethanol water ethanol water CHCl3 DCE toluene ethyl acetate THF hexane − ACN ACN ACN ACN ACN ACN ACN ACN

exponentially by raising the temperature of the reaction to 70 °C by enabling the formation of multisubstituted pyrrole 3aa in 93% yield in 1 h (entry 22). No increment in yield was noticed on increasing the temperature from 70 to 90 °C (entry 23). We further performed the experiments at 70 °C with varying amounts of molecular iodine (entries 24−26). Subsequently, with 30 mol % of iodine, the reaction of 3-phenacylideneoxindoles1a and 1,4-benzoxazinone 2a at 70 °C provided the polyheterocycle 3aa in optimum yield (entry 25). To test the role of catalyst in this protocol, the reaction was performed at different temperature conditions without catalyst. Even after 12 h, the reaction did not afford even traces of pyrrole embedded product 3aa, and the starting materials were found to be intact (entries 27 and 28). This justifies the significant role of the catalyst in the reaction. It should be highlighted that the isolation of the pyrrole polyheterocycle 3aa was achieved through simple decantation of acetonitrile or by recrystallization, and no column chromatography technique was used for purification. It is also worth mentioning that the polysubstituted pyrrrole 3aa was obtained with complete regioselectivity. Once the optimized reaction conditions were established, we investigated the substrate scope of the current protocol, and the results are summarized in Table 2. As shown, the reaction displayed a wide substrate scope. The reaction tolerated the employment of different substituents on different positions of the substrates. First, we focused our attention on 3-(2-oxo-2arylethylidene)oxindoles 1 so as to determine the electronic effects on the reaction. The role of the nature of the aryl substituents on substrate 1 was investigated, and we found that the reaction showed good acceptance for both electronwithdrawing and -releasing groups to furnish products 3 in highly regioselective manner in satisfactory yields (entries 1−4). The reaction also worked well with bromo and methoxy substituents on the oxindole moiety, and the reaction efficiency was similar to those examined for the unsubstituted system (entries 6, 7, and 16). With N-methyl-substituted oxindoles also, the reaction provided the polyhetrocyclic products (3ea, 3eb, and 3ec) in excellent yield (entries 5, 20, and 21). To further explore the versatility of this protocol, a feasibility investigation of substrate 1,4-benzoxazinone 2 by varying the substituents on the aromatic ring was also carried out (Table 2). By changing the substituents on the aromatic ring of substrate 2 at positions 4−and 6, the reactions were executed (entries 8− 22). Much to our satisfaction, the reaction demonstrated good compatibility for diverse substituents on benzoxazinones, and both electron-releasing and -withdrawing groups at different positions on the aryl ring worked well to furnish the products 3 in acceptable yields with complete regioselectivity (Table 2). The 5CN-substituted quinoxalinone 2e provided the product 3ae in comparatively low yields; the cyano group in 2e is probably para to −NH, and hence, the direct electron-withdrawing effect of the cyano group decreases the yield of reaction (entry 18). The nitro group substituted quinoxalinone 2d also afforded the product 3ad in lower yield with longer reaction time for completion, presumably due to the poor solubility of substrate (entry 17). To highlight the synthetic applicability of the current protocol, the reactions of 3-(2-oxo-2-arylethylidene)oxindoles 1a−c were performed with 1,4-benzoxazinone 2g (Table 3). Delightfully, the reaction worked well with 2g, and the lactams incorporated polyheterocyles 3ag−cg were obtained in high yields with complete regioselectivity. Structure Elucidation and Regioselectivity. The reaction of 3-(2-oxo-2-arylethylidene)oxindoles 1 with 1,4-benzoxazi-

Conditions: 1a (0.25 mmol), 2a (0.25 mmol), in 2.5 mL of solvent. Isolated yields.

7 and 8). We further checked the performance of the reaction with a series of solvents. In polar protic solvents like methanol, ethanol, and water, the reaction was found to be unfavorable for the formation of pyrrole heterocycle 3aa at room temperature as well as at higher temperature; and starting materials were recovered (entries 9−13). Returning to the use of halogenated solvents like chloroform and DCE, the reaction afforded the multisubstituted pyrrole 3aa in moderate yields (entries 14 and 15). Successive screening of the reaction in solvents like toluene, ethyl acetate, THF, and hexane with I2 as catalyst furnished the polyheterocycle 3aa in 55%, 57%, 45%, and 45% yield in 12 h, respectively (entries 16−19). The reaction, when performed under solvent-free conditions, did not provide the product, and the starting materials were recovered (entry 20). Surprisingly, ACN facilitated the reaction, and polysubstituted pyrrole 3aa was obtained in satisfactory yield in only 5 h simply by decantation of the solvent (entry 21). Satisfied with the results obtained from the reaction in ACN, we further optimized the reaction at elevated temperature; notably, the reaction rate was increased 9361

DOI: 10.1021/acs.joc.7b01538 J. Org. Chem. 2017, 82, 9360−9366

Article

The Journal of Organic Chemistry Table 2. . Substrate Scopea

3-phenacylideneoxindoles 1 entry

R

R2

R3

R4 in 2

product 3

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17c 18d 19d 20 21 22d

H H H H Me H H H H H H H H H H H H H H Me Me H

H H H H H 5-OMe 5-Br H H H H H H H H 5-OMe H H H H H H

H 4-Me 4-Cl 4-F H H H H 4-Me 4-Cl 4-F H 4-Me 4-Cl 4-F 4-Me H H H H H Me

H H H H H H H 4-Me 4-Me 4-Me 4-Me 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 5-NO2 5-CN 4-CN,6-OMe 4-Me 4-Cl 4-CN,6-OMe

3aa 3ba 3ca 3da 3ea 3fa 3ga 3ab 3bb 3cb 3db 3ac 3bc 3cc 3dc 3 fc 3ad 3ae 3af 3eb 3ec 3bf

93 88 89 88 87 90 87 92 96 92 90 82 84 81 83 79 60 69 75 83 77 76

1

a Reactions were performed with 1 (0.25 mmol) and 2 (0.25 mmol) in the presence of 30 mol % iodine in 2.5 mL acetonitrile for 1 h, unless otherwise mentioned. bIsolated yield. cReaction time: 7 h. dReaction time: 3 h.

mixture of these. Notably, the current protocol is completely regioselective and furnished product 3aa exclusively in excellent yield. The structure of product 3aa was assigned by 1H and 13 C{1H} NMR spectral analysis. The singlet at δ 4.53 ppm in 1H NMR (100 MHz) of product 3aa accounts for the proton situated at the third position of the oxindole moiety. The peak at δ 43.3 ppm in the 13C NMR (100 MHz) spectrum of the polyheterocycle 3aa corresponds to the carbon located at the third position of the oxindole moiety. Finally, the structure of 3aa was unambiguously confirmed by single-crystal X-ray analysis16 (see the Supporting Information). The structures of products 3ba−cg were determined by analogy (see Supporting Information). Another worth mentioning structural feature of polyheterocycle pyrroles 3 was their tendency to exist as conformer mixtures owing to restricted rotation around the pyrrole-oxindole bond i.e., rotamers14b and also keto−enol tautomeric17 products could be expected which may be attributed to the equilibrium of the keto−enol tautomers existing in the oxindole moiety. To our delight, only single product was observed in each case without any rotameric and tautomeric isomers. Careful examination of the 1H NMR of all the products revealed that only single set of peaks characterizing the product 3 was observed and no extra peaks corresponding to rotamers and

Table 3. Reaction of 3-(2-Oxo-2-arylethylidene)oxindoles 1a−c with 1,4-Benzoxazinone 2g

none 2 may undergo multiple pathways on the basis of compatible reactive sites available on 1 and 2 (Figure 1). The reaction, in principle, may generate products A, B, or 3aa or 9362

DOI: 10.1021/acs.joc.7b01538 J. Org. Chem. 2017, 82, 9360−9366

Article

The Journal of Organic Chemistry

Figure 1. Reactivity of 3-phenacylideneoxindoles 1 with 1,4-benzoxazinone 2.

On the basis of above results and previous literature,15,18 the mechanistic proposal for the current cascade protocol is outlined (Figure 2). Initially, molecular iodine activates both ylidene oxindole and 1,4-benzoxazinone. After activation, the process involves the Michael attack of substrate 2 on the α-position of oxindole 1 to generate intermediate C. Consequently, C undergoes cyclization through intramolecular attack of benzoxazinone nitrogen on carbonyl moiety to generate intermediate D. The aromatization of pyrroline moiety to the pyrrole ring by the elimination of water molecule results in the formation of novel polyheterocycle 3.

tautomers were noticed, thus confirming the regioselectivity of the current protocol (see Supporting Information). To test the practical utility of the reaction, a gram-scale reaction was carried out using 3-phenacylideneoxindoles 1a (4.2 mmol) with quinoxalinone 2a (4.2 mmol) under optimum conditions (Scheme 1). Delightfully, polyheterocycle pyrrole 3aa was obtained in 1 h and isolated in 92% yield by decantation of solvent. Scheme 1. Gram-Scale Synthesis of 3aa

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CONCLUSIONS

An iodine-mediated efficient, regioselective approach for the synthesis of polyheterocyles embraced with biologically potent scaffolds, viz. oxindole, coumarin, and pyrrole, was accomplished under mild conditions. The protocol provided products free from rotamers and keto−enol tautomers. The methodology follows an eco-friendly approach and avoids the use of column chromatography techniques for the isolation of products. The

Figure 2. Plausible mechanism for the formation of polyheterocycle 3. 9363

DOI: 10.1021/acs.joc.7b01538 J. Org. Chem. 2017, 82, 9360−9366

Article

The Journal of Organic Chemistry

7.24−7.17 (m, 2H), 7.07 (s, 1H), 6.99 (t, J = 7.2 Hz, 2H), 6.83−6.74 (m, 3H), 4.52 (s, 1H), 3.37 (s, 3H), 3.17 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 175.3, 163.7, 151.9, 143.3, 130.8, 130.1, 129.6, 128.9, 128.3, 126.7, 124.1, 124.0, 122.7, 122.5, 118.3, 117.0, 107.7, 52.2, 43.2, 26.2 ppm. HRMS (ESI+): m/z calcd for C28H20N2O5Na+ [M + Na]+ 487.126, found 487.126. 3fa. Yield: 108 mg (90%) as white solid. Mp: 303−305 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 9.64 (s, 1H), 7.78 (s, 1H), 7.43−7.33 (m, 4H), 7.19 (d, J = 8.0 Hz, 1H), 7.09−7.05 (m, 1H), 6.72−6.41 (m, 5H), 4.24 (s, 1H), 3.54 (s, 3H), 3.22 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3+DMSO-d6): 176.1, 163.1, 154.7, 151.6, 143.0, 136.1, 130.8, 130.3, 129.6, 129.4, 126.8, 124.2, 122.5, 122.2, 118.2, 116.5, 115.3, 113.0, 111.0, 109.5, 55.5, 51.5, 43.8 ppm. HRMS (ESI+): m/z calcd for C28H20N2O6K+ [M + K]+ 519.095, found 519.095. 3ga. Yield: 115 mg (87%) as white solid. Mp: 235−238 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 9.97 (s, 1H), 7.09−7.03 (m, 4H), 6.92−6.76 (m, 4H), 6.57 (s, 1H), 6.39−6.24 (m, 3H), 3.91 (s, 1H), 2.94 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3+DMSO-d6): δ 175.5, 162.3, 150.6, 142.0, 141.0, 129.9, 129.7, 129.4, 129.3, 128.3, 128.2, 125.8, 123.2, 121.4, 117.0, 115.9, 114.5, 112.6, 110.0, 50.7, 42.6 ppm. HRMS (ESI+): m/z calcd for C27H17 BrN2O5Na [M + Na]+ 551.021, found 551.020. 3ab. Yield: 106 mg (92%) as white solid. Mp: 301−304 °C. 1H NMR (500 MHz, CDCl3): δ 8.00 (s, 1H), 7.80 (s, 1H), 7.56−7.46 (m, 4H), 7.23−7.17 (m, 2H), 7.01−6.94 (m, 3H), 6.82 (s, 1H), 6.51 (s, 1H), 4.55 (s, 1H), 3.43 (s, 3H), 2.00 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6): δ 176.4, 163.2, 151.7, 142.8, 140.9, 133.3, 130.9, 130.8, 130.3, 129.6, 129.3, 128.1, 127.3, 124.0, 122.2, 122.0, 121.2, 117.8, 116.9, 115.2, 115.1, 109.2, 51.6, 43.3, 20.7 ppm. HRMS (ESI+): m/z calcd for C28H20N2O5Na [M + Na]+ 487.126, found 487.127. 3bb. Yield: 115 mg (96%) as white solid. Mp: 313−315 °C. 1H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H), 7.73 (s, 1H), 7.33 (s, 3H), 7.22− 7.17 (m, 2H), 6.97 (dd, J = 8.0, 21.0 Hz, 3H), 6.83 (s, 1H), 6.60 (s, 1H), 4.53 (s, 1H), 3.42 (s, 3H), 2.46 (s, 3H), 2.02 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3+DMSO-d6): δ 176.8, 162.7, 151.3, 141.9, 140.3, 139.6, 133.2, 130.3, 129.6, 129.3, 129.0, 127.8, 127.3, 126.6, 125.9, 123.1, 122.0, 121.4, 121.1, 120.9, 116.9, 116.8, 114.8, 108.8, 51.0, 43.0, 20.7, 20.3 ppm. HRMS (ESI+): m/z calcd for C29H22N2O5Na [M + Na]+ 501.142, found 501.140. 3cb. Yield: 114 mg (92%) as white solid. Mp: 308−310 °C. 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.83 (s, 1H), 7.50−7.41 (m, 3H), 7.19 (s, 2H), 7.02−7.00 (m, 3H), 6.83 (s, 1H), 6.58 (s, 1H), 4.47 (s, 1H), 3.39 (s, 3H), 2.06 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3+DMSO-d6): δ 175.5, 161.8, 150.3, 141.5, 139.5, 134.7, 132.5, 131.3, 130.8, 127.8, 126.8, 126.7, 126.1, 122.6, 121.4, 120.5, 120.1, 116.3, 115.7, 114.2, 108.1, 50.2, 42.2, 19.6 ppm. HRMS (ESI+): m/z calcd for C28H19ClN2O5Na [M + Na]+ 521.087, found 521.086. 3db. Yield: 108 mg (90%) as white solid. Mp: 312−315 °C. 1H NMR (500 MHz, CDCl3): δ 7.99 (s, 1H), 7.45 (s, 1H), 7.24−7.17 (m, 4H), 7.03−6.97 (m, 4H), 6.81 (s, 1H), 6.53 (s, 1H), 4.45 (s, 1H), 3.40 (s, 3H), 2.05 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3 + DMSOd6): δ 175.5, 162.0 (d, 1JC−F = 250.0 Hz), 161.8, 150.3, 141.4, 139.5, 132.5, 132.0, 131.5, 126.7, 126.0, 124.3, 122.5, 120.6, 120.0, 116.3, 115.7, 114.9 (d, 2JC−F = 23.0 Hz), 114.0, 108.0, 50.2, 42.2, 19.6 ppm. HRMS (ESI+): m/z calcd for C28H19FN2O5Na+ [M + Na]+ 505.117, found 505.115. 3ac. Yield: 99 mg (82%) as white solid. Mp: 323−325 °C. 1H NMR (400 MHz, CDCl3+DMSO−d6): δ 9.69 (s, 1H), 7.77 (s, 1H), 7.48−7.45 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.07−7.02 (m, 2H), 6.85−6.77 (m, 2H), 6.71 (s, 1H), 6.59 (s, 1H), 4.36 (s, 1H), 3.30 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6): δ 175.0, 161.5, 149.5, 141.3, 140.2, 129.4, 128.9, 127.8, 127.4, 126.9, 126.5, 124.9, 122.3, 121.6, 121.4, 119.8, 117.8, 115.3, 113.6, 107.8, 50.1, 41.9 ppm. HRMS (ESI+): m/z calcd for C27H17 ClN2O5K [M + K]+ 523.045, found 523.047. 3bc. Yield: 104 mg (84%) as white solid. Mp: 266−268 °C. 1H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H), 7.71 (s, 1H), 7.31 (s, 3H), 7.24 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.94 (dd, J = 6.5, 14.0 Hz, 2H), 6.79 (s, 2H), 4.53 (s, 1H), 3.43 (s, 3H), 2.45 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 177.7, 163.6, 151.4, 141.9, 141.5, 141.0, 131.1, 130.2,

domino reaction involves the formation C−N bond and C−C bond with concomitant removal of one water molecule.

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, chemicals were purchased from commercial suppliers at the highest purity grade available and were used without further purification. 3-(2-Oxo-2arylethylidene) oxindoles 1 and 1,4-benzoxazinones 2 were synthesized by a literature method (see the Supporting Information). Thin-layer chromatography was performed on precoated 0.25 mm silica gel plates (60F-254) using UV light as visualizing agent and/or iodine as developing agent. Silica gel (100−200 mesh) was used for column chromatography. Melting points were uncorrected. 1H and 13C NMR spectra were recorded on 400 or 500 MHz NMR spectrometers. Spectra were referenced internally to the residual proton resonance in CDCl3 (δ 7.26 ppm), DMSO-d6 (δ 2.50 ppm), or with tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard. Chemical shifts (δ) were reported as part per million (ppm) on the δ scale downfield from TMS. 13C NMR spectra were referenced to CDCl3 (δ 77.0 ppm, the middle peak) and DMSO-d6 (δ 39.5 ppm, the middle peak). Coupling constants are expressed in Hz. The following abbreviations are used to explain the multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublet. High-resolution mass spectra (HRMS) were obtained on a Brüker micrOTOF-Q II. General Procedure. To a mixture of 1,4-benzoxazinone (0.25 mmol) and 3-(2-oxo-2-arylethylidene)oxindole derivative (0.25 mmol) in 2.5 mL of acetonitrile was added iodine (19 mg, 0.075 mmol), and the reaction mixture was stirred at 70 °C for the appropriate time (Table S1). After completion of the reaction, as indicated by the TLC, the crude product was filtered. The solid was recrystallized in ethyl acetate/ methanol to afford pure product. In the case of 1,4-benzoxazinones 2d and 2e (Table 2, entries 17, 19, and 22), where the reactions were incomplete, the pure product was obtained by double recrystallization or subjecting the crude reaction mixture to column chromatography on silica gel (100−200 mesh) using ethyl acetate/hexanes (40:60) as the eluting system. 3aa. Yield: 104 mg (93%) as white solid. Mp: 328−330 °C. 1 H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.49 (dd, J = 6.0, 25.0 Hz, 4H), 7.35 (d, J = 8.0 Hz, 1H), 7.22−7.15 (m, 3H), 7.00−6.94 (m, 2H), 6.85−6.80 (m, 3H), 4.53 (s, 1H), 3.47 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.4, 163.2, 151.6, 143.0, 142.8, 130.8, 130.7, 130.4, 129.5, 129.4, 128.4, 128.1, 126.8, 124.1, 124.0, 122.5, 122.4, 121.2, 118.2, 116.4, 115.2, 109.2, 51.6, 43.3 ppm. 3ba. Yield: 102 mg (88%) as white solid. Mp: 227−229 °C. 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 2H), 7.33 (s, 4H), 7.23−7.16 (m, 2H), 6.97−6.81 (m, 4H), 4.54 (s, 1H), 3.44 (s, 3H), 2.46 (s, 3H) ppm. 13 C{1H} NMR (100 MHz, CDCl3 + DMSO-d6): δ 177.1, 162.8, 151.4, 142.5, 142.0, 139.8, 130.4, 129.6, 129.4, 127.9, 127.5, 126.1, 125.9, 123.6, 123.2, 122.3, 122.0, 121.1, 117.5, 116.5, 115.0, 109.0, 51.2, 43.2, 20.9 ppm. HRMS (ESI+): m/z calcd for C28H20N2O5Na+ [M + Na]+ 487.126, found 487.127. 3ca. Yield: 108 mg (89%) as white solid. Mp: 257−260 °C. 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.50 (s, 2H), 7.42−7.36 (m, 3H), 7.24−7.19 (m, 2H), 6.98−6.92 (m, 4H), 6.84 (s, 1H), 4.47 (s, 1H), 3.42 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6): δ 176.5, 162.5, 151.0, 142.3, 142.0, 135.6, 131.9, 131.2, 128.7, 127.4, 127.3, 126.2, 123.6, 123.2, 121.7, 120.9, 117.5, 116.1, 108.9, 51.0, 42.9 ppm. HRMS (ESI+): m/z calcd for C27H17ClN2O5K+ [M + K]+ 523.045, found 523.046. 3da. Yield: 103 mg (88%) as white solid. Mp: 291−293 °C. 1H NMR (500 MHz, CDCl3): δ 8.02 (s, 2H), 7.46 (s, 1H), 7.36 (s, 1H), 7.23− 7.19 (m, 3H), 7.00−6.80 (m, 6H), 4.46 (s, 1H), 3.38 (s, 3H) ppm. 13 C{1H} NMR (100 MHz, CDCl3 + DMSO-d6): δ 177.1, 163.7(d, 1JC−F = 252.0 Hz), 163.2, 151.6,142.9, 142.2, 133.2, 132.3, 128.0, 126.6, 125.4, 124.0, 123.7, 122.3, 121.6, 118.1, 116.5, 116.3, 116.1, 115.5 (d, 3JC−F = 4.7 Hz), 109.4, 51.7, 43.5 ppm. HRMS (ESI+): m/z calcd for C27H17FN2O5K+ [M + K]+ 507.075, found 507.075. 3ea. Yield: 101 mg (87%) as white solid. Mp: 263−265 °C. 1H NMR (400 MHz, CDCl3): δ 7.51−7.44 (m, 4H), 7.34 (d, J = 8.4 Hz, 1H), 9364

DOI: 10.1021/acs.joc.7b01538 J. Org. Chem. 2017, 82, 9360−9366

Article

The Journal of Organic Chemistry

Hz, 1H), 7.02 (s, 1H), 6.95−6.91 (m, 3H), 6.84 (s, 1H), 6.74 (s, 1H), 4.49 (s, 1H), 3.96 (s, 3H), 3.38 (s, 3H), 2.46 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 177.7, 163.2, 150.1, 149.0, 141.6, 141.4, 136.7, 131.0, 130.3, 130.0, 128.4, 125.6, 124.0, 123.9, 122.4, 117.5, 115.3, 113.5, 112.0, 109.7, 107.3, 56.7, 52.3, 43.8, 21.5 ppm. HRMS (ESI+): m/ z calcd for C30H21N3O6Na [M + Na]+ 542.132, found 542.130. 3ag. Yield: 95 mg (85%) as white solid. Mp: 360−362 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 10.83 (s, 1H), 9.82 (s, 1H), 7.52 (s, 2H), 7.20−7.12 (m, 3H), 6.98 (t, J = 8.0 Hz, 1H), 6.81−6.78 (m, 2H), 6.61−6.38 (m, 5H), 4.03 (s, 1H), 2.96 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.6, 164.2, 153.6, 142.8, 130.9, 130.8, 129.9, 129.4, 128.5, 128.0, 126.0, 124.2, 122.6, 121.8, 121.2, 117.0, 116.5, 109.1, 51.3, 43.4 ppm. HRMS (ESI+): m/z calcd for C27H19N3O4Na [M + Na]+ 472.126, found 472.127. 3bg. Yield: 101 mg (87%) as white solid. Mp: 374−377 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 10.82 (s, 1H), 9.83 (s, 1H), 7.34 (s, 1H), 6.95 (d, J = 8.8 Hz, 3H), 6.76 (t, J = 7.6 Hz, 2H), 6.57−6.36 (m, 6H), 4.00 (s, 1H), 2.90 (s, 3H), 2.10 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.6, 164.2, 153.6, 142.8. 139.4, 133.3, 130.9, 130.7, 129.9, 129.3, 128.6, 127.9, 127.8, 126.0, 124.1,122.7, 121.8, 121.2, 116.9, 116.5, 109.0, 51.2, 43.4, 21.1 ppm. HRMS (ESI+): m/z calcd for C28H21N3O4K+ [M + K]+ 502.116, found 502.116. 3cg. Yield: 95 mg (79%) as white solid. Mp: 380−383 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 10.89 (s,1H), 9.88 (s, 1H), 7.54 (s, 1H), 7.15−7.06 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.2 Hz, 2H), 6.60−6.44 (m, 6H), 3.96 (s, 1H), 2.90 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3+DMSO-d6): δ 176.6, 164.0, 153.6, 142.9, 134.8, 132.8, 129.6, 129.4, 128.0, 126.1, 124.2, 122.5, 122.0, 121.4, 121.2, 117.0, 116.5, 109.1, 51.2, 43.3; HRMS (ESI+): m/z calcd for C27H18 ClN3O4Na+ [M + Na]+ 506.087, found 506.088.

130.1, 129.3, 128.4, 126.7, 125.9, 124.1, 123.3, 122.5, 119.3, 117.4, 115.6, 109.6, 52.2, 43.8, 21.5 ppm. HRMS (ESI+): m/z calcd for C28H19 ClN2O5Na [M + Na]+ 521.087, found 521.085. 3cc. Yield: 105 mg (81%) as white solid. Mp: 302−305 °C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 9.84 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.10−7.03 (m, 2H), 6.81−6.68 (m, 4H), 4.27 (s, 1H), 3.23 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.2, 163.0, 151.2, 142.8, 142.1, 135.5, 132.8, 132.7, 129.5, 128.2, 127.9, 127.6, 126.4, 124.1, 123.4, 122.8, 121.3, 119.8, 116.3, 115.4, 109.2, 51.7, 43.2.ppm. HRMS (ESI+): m/z calcd for C27H16Cl2N2O5Na [M + Na]+ 541.032, found 541.031. 3dc. Yield: 104 mg (83%) as white solid. Mp: 297−300 °C. 1H NMR (400 MHz, CDCl3 + DMSO-d6): δ 9.91 (s, 1H), 7.76 (s, 2H), 7.30 (s, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.04−6.96 (m, 2H), 6.77−6.56 (s, 1H), 4.23 (s, 1H), 3.21 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.2, 163.3 (d, 1JC−F = 248.0 Hz), 163.1, 151.2, 142.8,142.0, 133.5, 133.4, 133.3, 128.4, 128.2, 127.6, 126.4, 125.4, 124.1, 123.4, 122.9, 121.3, 119.7, 116.7, 116.5, 116.3, 115.2, 109.2, 51.7, 43.2 ppm. HRMS (ESI+): m/z calcd for C27H16FClN2O5Na+ [M + Na]+ 525.062, found 525.061. 3fc. Yield: 102 mg (79%) as white solid. Mp: 354−356 °C. 1H NMR (400 MHz, CDCl3 + DMSO-d6): δ 9.69 (s, 1H), 7.74 (s, 1H), 7.45−7.40 (m, 3H), 7.31 (d, J = 6.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 9.4 Hz, 1H), 6.59−6.40 (m, 4H), 4.22 (s, 1H), 3.52 (s, 3H), 3.20 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 176.0, 163.0, 154.7, 151.3, 142.0, 136.2, 131.0, 130.7, 130.6, 129.6, 129.4, 129.1, 127.6, 126.3, 123.4, 122.4, 119.7, 116.4, 115.2, 113.0, 111.0, 109.5, 55.5, 51.6, 43.7 ppm. HRMS (ESI+): m/z calcd for C28H19 ClN2O6Na [M + Na]+ 537.082, found 537.082. 3ad. Yield: 74 mg (60%) as white solid. Mp: 223−225 °C. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62−7.55 (m, 4H), 7.45 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.00−6.82 (m, 4H), 4.55 (s, 1H), 3.45 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 177.3, 163.2, 150.6, 144.9, 143.3, 141.5, 131.3, 131.0, 130.3, 129.6, 128.8, 128.6, 127.4, 124.2, 122.6, 122.4, 119.4, 117.5, 115.6, 114.2, 109.7, 52.4, 43.7 ppm. HRMS (ESI+): m/z calcd for C27H17N3O7Na [M + Na]+ 518.095, found 518.095. 3ae. Yield: 82 mg (69%) as white solid. Mp: 332−335 °C. 1H NMR (400 MHz, CDCl3): δ 7.62−7.54 (m, 4H), 7.43 (d, J = 7.2 Hz, 3H), 7.22−7.13 (m, 2H), 7.04−6.78 (m, 3H), 4.52 (s, 1H), 3.48 (s, 3H) ppm. 13 C{1H} NMR (100 MHz, CDCl3+DMSO-d6): δ 176.0,162.6, 150.4, 142.9,142.6, 130.6, 130.3, 130.1, 129.1, 128.6, 127.8, 127.7, 126.0, 123.6, 123.2, 121.7, 121.0, 119.6, 117.3, 116.8, 116.6, 115.1, 109.0, 51.4, 43.1 ppm. HRMS (ESI+): m/z calcd for C28H17N3O5Na [M + Na]+ 498.106, found 498.105. 3af. Yield: 94 mg (75%) as white solid. Mp: 237−240 °C. 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.64−7.55 (m, 3H), 7.43 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.01−6.93 (m, 3H), 6.82 (s, 1H), 6.62 (s, 1H), 4.52 (s, 1H), 3.97 (s, 3H), 3.42 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 177.4, 163.2, 150.1, 149.1, 141.5, 136.7, 131.0, 130.2, 129.6, 128.7, 128.5, 124.2, 123.8, 123.5, 122.5, 117.4, 115.5, 113.4, 112.0, 109.7, 107.4, 56.8, 52.3, 43.7 ppm. HRMS (ESI+): m/z calcd for C29H19N3O6Na [M + Na]+ 528.116 found 528.116. 3eb. Yield: 99 mg (83%) as white solid. Mp: 280−282 °C. 1H NMR (400 MHz, CDCl3): δ 7.51−7.45 (m, 4H), 7.24−7.20 (m, 2H), 7.09− 6.97 (m, 4H), 6.74 (s, 1H), 6.48 (s, 1H), 4.59 (s, 1H), 3.39 (s, 3H), 3.15 (s, 3H), 1.98 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 175.4, 164.0, 152.1, 144.2, 141.2, 133.9, 130.8, 130.0, 129.8, 128.8, 128.3, 127.3,124.0, 122.5, 122.2, 117.9, 117.4, 107.7, 52.2, 43.2, 26.2, 21.0 ppm. HRMS (ESI+): m/z calcd for C29H22N2O5Na [M + Na]+ 501.142, found 501.139. 3ec. Yield: 96 mg (77%) as white solid. Mp: 280−283 °C. 1H NMR (400 MHz, CDCl3): δ 7.54 (s, 3H), 7.44 (d, J = 5.2 Hz, 2H), 7.28−7.27 (m, 1H), 7.25−7.23 (m, 1H), 7.16 (dd, J = 2.0, 8.8 Hz, 1H), 7.07 (s, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.66 (s, 2H), 4.58 (s 1H), 3.45(s, 3H), 3.12 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 175.2, 163.6, 151.4, 144.2, 141.9, 131.3, 130.5, 129.3, 129.1, 129.0, 128.4, 126.7, 124.1, 123.3, 122.5, 119.3, 117.3, 107.8, 52.3, 43.2, 26.3 ppm. HRMS (ESI+): m/z calcd for C28H19ClN2O5K [M + K]+ 537.061, found 537.058. 3bf: Yield: 99 mg (76%) as white solid. Mp: 200−202 °C. 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 7.34−7.29 (m, 3H), 7.16 (t, J = 8.0

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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.7b01538. 1 H and 13C{1H} NMR spectra for all new products, ORTEP diagram, and X-ray data for polyheterocycle 3aa (PDF) X-ray data for polyheterocycle 3aa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Rama Krishna Peddinti: 0000-0001-7340-1516 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors sincerely thank SERB, New Delhi, for financial support and DST for providing the HRMS facility in the FIST program. N.S. thanks UGC for a research fellowship.

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REFERENCES

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