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Mediated Domino Reaction of Benzoxazinones ... - ACS Publications

Department of Chemistry, Indian Institute of Technology, Roorkee Roorkee, 247667 Uttarakhand, India. J. Org. Chem. , 2017, 82 (24), pp 13617–13625. ...
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FeCl3‑Mediated Domino Reaction of Benzoxazinones with Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines Shweta Bisht and Rama Krishna Peddinti* Department of Chemistry, Indian Institute of Technology, Roorkee Roorkee, 247667 Uttarakhand, India S Supporting Information *

ABSTRACT: An efficient domino approach for the synthesis of pyrrolobenzoxazine derivatives is described. The FeCl3promoted domino reaction between aroylmethylidene malonates and benzoxazinones has been successfully established to afford the title compounds in good to excellent yield under mild reaction conditions. The domino protocol provides a concise and straightforward access to highly substituted pyrrolobenzoxazines with high efficiency and excellent functional group tolerance.

T

various reacting partners.10 In view of their high reactivity and efficiency, the development of new reacting partners would be highly anticipated. Iron(III) chloride is the simplest iron compound, which is an effective, low-cost, and ecologically benign Lewis acid and has high functional group tolerance ability for a variety of domino reactions.11 Inspired by the advantages of domino protocol12 and in continuation to our own efforts on the domino reaction of benzoxazinones,13 herein we report FeCl3-promoted domino reaction of benzoxazinones with aroylmethylidene malonates to furnish benzoxazine fused pyrroles. To establish the optimum reaction conditions, we commenced our research by investigating the reaction using benzoylmethylidene malonate 1a and benzoxazinone 2 as model substrates. When the reaction was performed in TFA in DCE for 12 h at 80 °C, pyrrolobenzoxazine 9a was obtained in 50% yield (Table 1, entry 1). The heterocycle 9a was obtained via Michael addition of benzoxazinone 2 to benzoylmethylidene malonate 1a followed by intramolecular cyclization. Encouraged by this initial finding, several acids including MeSO3H, ptoluenesulfonic acid monohydrate (PTSA.H2O), FeCl3, SnCl4, ZrCl4, and ZnCl2 were examined to evaluate their effect in the reaction (entries 2−9). In case of ZrCl4 and ZnCl2, reaction was very slow and the polyheterocycle 9a was obtained in 30 and 25% yield, respectively (entries 6 and 7). After screening of the acids,

he compounds containing nitrogen heterocycles play preponderant role in drug discovery and this heterocycle edifies the main structure in various natural products.1 Among them, pyrroles are a class of compounds endowed with broad and decisive biological and pharmacological activities, such as antimicrobial, analgesic, antibacterial, antitubercular, anticancer, antidiabetic, fungicidal, anti-inflammatory, antiviral, antibiotic, cholesterol reduction, and antioxidant and antihypoxic activity.2,3 Moreover pyrroles can serve as intermediates in natural product synthesis and are building blocks for the synthesis of porphyrins.4 Owing to their wide spectrum of biological activity, the synthesis of pyrrole derivatives attracted tremendous attention in the field of organic synthesis. Consequently, myriad methods have been developed for the synthesis of diversely structured pyrroles.5 Among the pyrrolefused derivatives, pyrrole-fused benzoxazinones, benzothiazine, and benzoxazepines attracted considerable attention because they exhibit a wide range of pharmacological activities.6−8 The incorporation of two or more different heterocyclic moieties in a single molecule may amplify the biological activity appreciably.9 The development of more convenient and efficient protocols for these useful polyheterocyclic compounds from simple substrates is a great challenge and is still an active research area in current synthetic and medicinal chemistry. All these engrossing eccentricity of this moiety embolden us to develop routes to these polyheterocycles. Aroylmethylidene malonates have been amply deployed for the synthesis of furans, quinoxalines, imidazoles, benzo[1,4]thiazines, and 2,4,5-trisubstituted oxazole derivatives with © 2017 American Chemical Society

Received: September 1, 2017 Published: November 21, 2017 13617

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

Note

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

entry

reagent (equiv)

solvent

time (h)

yieldb (%)

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

TFA (1.0) MeSO3H (1.0) PTSA·H2O (1.0) BF3·OEt2 (1.0) BF3·OEt2 (2.0) ZrCl4 (1.0) ZnCl2 (1.0) FeCl3 (1.0) SnCl4 (1.0) Iodine (1.0) FeCl3 (1.0) FeCl3 (1.0) FeCl3 (1.0) FeCl3 (1.0) FeCl3 (1.0) FeCl3 (1.0) FeCl3 (0.5) FeCl3 (1.5) FeCl3 (1.0) FeCl3 (1.0)

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE CH3CN THF Toluene EtOH MeOH DMF DCE DCE DCE DCE

12 8 12 4 4 24 24 3 3 24 3 4 4 12 12 6 8 3 3 7

50 55 45 60 55 30 25 85 53 Nr 70 57 40 Nr Nr Nr 50 79 77 80

FeCl3 was found to be superior in furnishing the cyclized product 9a in 85% yield (entry 8). The use of iodine did not drive the reaction (entry 10). Subsequently, to evaluate the solvent effect, the reaction was studied by performing the reaction in different solvents, (entries 11−16). DCE was identified as the optimal solvent, producing the heterocycle 9a in highest yield after 3 h (entry 8). In case of polar solvents such as MeOH, EtOH, and DMF, the reaction failed to proceed (entries 14−16). Encouraged by the promising results, we further varied the amount of FeCl3 and found that no appreciable variation in the yield of the product ensued by increasing or decreasing the amount of reagent in the reaction. When 0.5 equiv of FeCl3 was used, the pyrrolobenzoxazine 9a was obtained in a diminished yield of 50% (entry17), and further increase in the reagent loading to 1.5 equiv resulted in the formation of 9a in 79% yield (entry 18). Thus, 1 equiv of FeCl3 found to be optimal loading to provide the desired product in very high yield. Further, screening of the reaction at higher or lower temperature led to no improvement (entries 19 and 20). The structure of 9a was further confirmed by NMR and single crystal analysis.14 With the optimal conditions established for this domino reaction, the substrate scope was explored by using various aroylmethylidene malonates with benzoxazinone 2. As shown in Scheme 1, a variety of aroylmethylidene malonates bearing electron-rich groups, such as methyl, methoxy, hydroxy (1b− d), and electron-deficient group (1e) at the para position of benzene ring, were amenable to the reaction and produced 10b−13e with yields in the range of 75−92% in 30 min to 2 h. Notably, the acceptors 1f with 2-chloro substituent and 1g with 2,4-dichloro substituents in aromatic ring could also be well tolerated, and the corresponding products 14f and 15g were obtained in 2 h in 68 and 66% yield, respectively.

a

Reaction condition: Unless otherwise specified, all reactions were carried out using 1a (0.25 mmol), 2 (0.3 mmol), and reagent in 2 mL solvent. bIsolated yield. Nr: No reaction was observed. cTemp: 100 °C. dTemp: 60 °C.

Scheme 1. Scope of Aroylmethylidene Malonates with Benzoxazinones 2aa,b

a

Reaction was carried out using 1 (0.25 mmol), 2a (0.3 mmol), and FeCl3 (0.25 mmol) in 2 mL DCE at 80 °C. bIsolated yield. 13618

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

Note

The Journal of Organic Chemistry Scheme 2. Scope of Various Benzoxazinoes with Benzoylmethylidene Malonate 1aa,b

a

Reaction was carried out using 1 (0.25 mmol), 2a (0.3 mmol, 1.2 equiv), and FeCl3 (0.25 mmol) in 2 mL DCE at 80 °C. bIsolated yields.

Table 2. Synthesis of Pyrrolobenzoxazine Derivativesa

a

entry

R1

R3

R4

time

yieldb %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Me Me Me Me Me OMe OMe OMe OMe OMe OH OH OH Cl Cl Cl Cl Cl

Me H Cl CO2Me NO2 Me H Cl CO2Me NO2 Me H CO2Me Me H Cl CO2Me NO2

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

1.5 h 1.5 h 40 min 1.5 h 3h 30 min 30 min 30 min 30 min 30 min 30 min 30 min 30 min 40 min 40 min 30 min 40 min 2h

22b, 80 23b, 82 24b, 85 25b, 90 26b, 77 27c, 94 28c, 92 29c, 88 30c, 90 31c, 80 32d, 77 33d, 73 34d, 72 35e, 79 36e, 80 37e, 75 38e, 73 39e, 65

Reaction was carried out using 1 (0.25 mmol), 2a (0.3 mmol), and FeCl3 (0.25 mmol) in 2 mL DCE at 80 °C. bIsolated yields.

Then we explored the scope of benzoxazinone derivatives 3− 8 with benzoylmethylidene malonate 1a (Scheme 2). As expected, the reaction proceeds smoothly under the optimized reaction conditions to provide the corresponding products in good to excellent yields. We examined the reactivity of

benzoxazinone derivatives, 3 and 4 with methyl substitution where slight differences were observed in the yield of the corresponding products, 16a and 17a. These results encouraged us to continue to study the electronic environment of benzoxazinone substituent. The reaction of benzoxazinone 5 13619

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

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The Journal of Organic Chemistry Scheme 3. Scope of Various Benzoxazinoes with Thenoylmethylidene Malonate 40a,b

a

Reaction was carried out using 40 (0.25 mmol), 2/4/6 (0.3 mmol), and FeCl3 (0.25 mmol) in 2 mL of DCE at 80 °C. bIsolated yield.

Scheme 4. Gram-Scale Synthesis of 22b

Scheme 5. Proposed Reaction Mechanism

and 6 bearing Cl and CO2Me substituents with 1a worked well and afforded the products 18a and 19a, in 82 and 89% yield, respectively. However, when nitro substituted benzoxazinone 7 was employed as a substrate; the reaction, under similar reaction conditions, furnished pyrrolobenzoxazine 20a in 3 h in 75% yield. The marginal reduction in the chemical yield may be ascribed to the less solubility of nitro derivative 7. The benzoxazinone 8 bearing 7-cyano group gave the tricycle 21a in 2 h in 78% yield. The reaction has a broad substrate scope and worked well with various aroylmethylidene malonates 1a−g possessing electron-donating as well as electron-withdrawing groups, and benzoxazinones 3−7 (Table 2). Methyl substituted benzoylmethylidene malonate 1b, reacted with various benzoxazinones and produced 22b−26b in good yield in 1.5−3 h. The reaction was very efficient in case of 4-methoxy substituted benzoylmethylidene malonate 1c, and afforded products 27c−31c in excellent yield in 30 min. In case of hydroxyl substituted

benzoylmethylidene malonate 1d, reaction was completed within 30 min and produced the desired products 32d−34d in good yield. Similarly the reaction with chloro-substituted benzoylmethylidene malonate 1e worked well and produced the products 35e−39e in moderate yield. Further, we extended the scope of this domino protocol with heteroaromatic thenoylmethylidene malonate 40 to react with benzoxazinones 2, 4, and 6. To our delight, the reaction showed excellent compatibility and produced pyrrolobenzoxazines 41−43 in good yield (Scheme 3). For more insight into the utility of this reaction, we carried out the gram-scale reaction of 1b and 3 under the same reaction conditions and the reaction proceeded smoothly to furnish 22b in 78% yield (Scheme 4). A plausible mechanism for this transformation is illustrated in Scheme 5. Initially the FeCl3 coordinates with ester moiety of benzoylmethylidene malonate 1a, and enhances the electrophilicity at α-carbon of benzoylmethylidene malonate and 13620

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

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The Journal of Organic Chemistry

°C; 1H NMR (CDCl3, 400 MHz): δ 7.38−7.31 (m, 3H), 7.20 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.87 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.57 (s, 1H), 3.93 (s, 6H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 163.9 (CO), 161.0 (C), 151.7 (C), 143.1 (C), 134.4 (C), 132.0 (CH), 126.7 (CH), 124.1 (CH), 122.6 (C), 122.5 (C), 121.0 (C), 120.1 (CH), 118.1 (CH), 116.9 (C), 114.9 (CH), 55.3 (OCH3), 52.8 (2*OCH3), 52.2 (OCH3), 48.4 (CH) ppm; HRMS (ESI+): m/z calcd for C25H21NO9Na [M +Na]+: 502.1108, found: 502.1106. Dimethyl 2-(1-(4-Hydroxyphenyl)-3-(methoxycarbonyl)-4-oxo4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (12d). Reaction time: 30 min; Yield: 0.087 g (75%) as light yellow solid; mp: 207−209 °C; 1H NMR (CDCl3, 400 MHz): δ 9.20 (s, 1H), 7.28−7.25 (m, 1H), 7.20−7.12 (m, 2H), 7.00 (d, J = 7.6 Hz, 2H), 6.84−6.76 (m, 2H), 4.53 (s, 1H), 3.87 (s, 3H), 3.66 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.8 (2*CO), 164.0 (CO), 159.5 (C), 152.0 (C), 143.2 (C), 135.3 (C), 131.9 (CH), 126.8 (CH), 124.3 (CH), 122.7 (C), 122.5 (C), 120.1 (C), 119.4 (C), 118.1 (CH), 117.2 (CH), 116.8 (CH), 115.9 (C), 52.8 (2*OCH3), 52.3 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C24H19NO9Na [M+Na]+: 488.0952, found: 488.0940. Dimethyl 2-(1-(4-Chlorophenyl)-3-(methoxycarbonyl)-4-oxo-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (13e). Reaction time: 1 h; Yield: 0.094 g (78%) as light yellow solid; mp: 125−127 °C;. 1H NMR (CDCl3, 400 MHz): δ 7.55 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.25−7.19 (m, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.51 (s, 1H), 3.92 (s, 3H), 3.68 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.8 (CO), 151.6 (C), 143.3 (C), 137.0 (C), 132.9 (C), 132.2 (CH), 129.9 (CH), 127.9 (C), 127.0 (CH), 124.3 (CH), 122.8 (C), 122.5 (C), 120.3 (C), 118.5 (CH), 116.8 (CH), 116.6 (C), 52.9 (2*OCH3), 52.5 (OCH3), 48.4 (CH) ppm; HRMS (ESI+): m/z calcd for C24H18O8NClNa [M+Na]+: 506.0613, found: 506.0619. Dimethyl 2-(1-(2-Chlorophenyl)-3-(methoxycarbonyl)-4-oxo-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (14f). Reaction time: 2 h; Yield: 0.082 g (68%) as light yellow solid; mp: 148−150 °C; 1H NMR (CDCl3, 400 MHz): δ 7.61−7.49 (m, 3H), 7.35 (d, J = 8.8 Hz, 1H), 7.26−7.20 (m, 2H), 6.88 (t, J = 8.4 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 4.43 (s, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 3.66 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.5 (CO), 167.3 (CO), 163.9 (CO), 151.7 (C), 143.1 (C), 136.1 (C), 132.9 (CH), 132.3 (CH), 131.1 (C), 130.4 (CH), 128.9 (C), 127.9 (CH), 127.0 (CH), 124.6 (CH), 122.7 (C), 122.7 (C), 120.6 (C), 118.5 (CH), 116.9 (C), 115.6 (CH), 52.9 (2*OCH3), 52.4 (OCH3), 48.5 (CH); HRMS (ESI+): m/z calcd for C24H18ClNO8Na [M+Na]+: 506.0613, found: 506.0607. Dimethyl 2-(1-(2,4-Dichlorophenyl)-3-(methoxycarbonyl)-4-oxo4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (15g). Reaction time: 2 h; Yield: 0.085 g (66%) as light yellow solid; mp: 125− 126 °C; 1H NMR (CDCl3, 400 MHz): δ 7.63 (s, 1H), 7.54−7.48 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.27−7.23 (m, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.42 (s, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.66 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.4 (CO), 167.3 (CO), 163.8 (CO), 151.6 (C), 143.1 (C), 138.0 (C), 137.0 (C), 133.8 (CH), 130.5 (CH), 129.7 (C), 128.5 (CH), 127.4 (CH), 124.7 (CH), 122.8 (C), 122.6 (C), 120.8 (C), 118.7 (CH), 117.1 (C), 115.4 (CH), 52.9 (2*OCH3), 52.5 (OCH3), 48.5 (CH); HRMS (ESI+): m/z calcd for C24H17Cl2NO8Na [M+Na]+: 540.0223, found: 540.0236. Dimethyl 2-(3-(Methoxycarbonyl)-8-methyl-4-oxo-1-phenyl-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (16a). Reaction time: 2 h; Yield: 0.096 g (83%) as light yellow solid; mp: 186−188 °C; 1H NMR (CDCl3, 400 MHz): δ 7.65−7.56 (m, 3H), 7.44 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.35 (s, 1H), 4.56 (s, 1H), 3.92 (s, 3H), 3.69 (s, 6H), 1.97 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 164.0 (CO), 151.9 (C), 141.1 (C), 134.2 (C), 133.9 (C), 130.8 (CH), 130.4 (CH), 129.5 (CH), 129.4 (C), 127.4 (CH), 122.5 (C), 122.0 (C), 119.6 (C), 117.7 (CH), 117.4 (CH), 116.3 (C), 52.8 (2*OCH3), 52.3 (OCH3), 48.5 (CH), 20.9 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H21NO8Na [M+Na]+: 486.1159, found: 486.1136.

facilitates benzoxazinone 2 to attack at this position to generate the intermediate A. Proton shift occurs in this species to generate adduct B whose formation was confirmed by HRMS as well as 1H NMR. This species B undergoes tautomerization to form intermediate C. The subsequent intramolecular cyclization of C generates aminol intermediate D, which upon dehydration liberates the product 9a. In conclusion we have developed domino reaction of aroylmethylidene malonates and benzoxazinones affording the pyrrolobenzoxazine derivatives in good to excellent yields. In this domino reaction, water is the only byproduct. This reaction proceeds under mild conditions and it has wide substrate scope. The present methodology has the prospective to pave the way for the endowment of biologically important scaffolds.

■

EXPERIMENTAL SECTION

General Information. Unless otherwise noted, chemicals were purchased from the highest purity grade available and were used without further purification. Thin layer chromatography was performed on Merck precoated 0.25 mm silica gel plates (60F-254) using UV light as visualizing agent. Silica gel (100−200 mesh) was used for column chromatography. NMR spectra were recorded in CDCl3 using TMS as an internal standard on JEOL (400 MHz) instrument. Chemical shifts (δ) were reported as parts per million (ppm) in δ scale downfield from TMS. 1H NMR spectra were referenced to CDCl3 (7.26 ppm) and 13C NMR spectra were referenced to CDCl3 (77.0 ppm, the middle peak). Coupling constants were expressed in Hz. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, m = multiplet. High-resolution mass spectra (HRMS) were obtained on a Brüker micrOTOF-Q II mass spectrometer (ESI-MS). General Experimental Procedure for the Synthesis of Pyrrolobenzoxazine Derivatives 9−43. To a mixture of benzoylmethylidene malonate 1 (0.25 mmol) and benzoxazinone 2 (0.3 mmol) in 2 mL of DCE, was added FeCl3 (0.25 mmol) and the contents were stirred at 80 °C for appropriate time. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure, the crude product was purified by column chromatography on silica gel using 10−40% ethyl acetate in hexanes to afford pyrrolobenzoxazine 9−39 and 41−43 as a solid. Dimethyl 2-(3-(Methoxycarbonyl)-4-oxo-1-phenyl-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (9a). Reaction time: 3 h; Yield: 0.095 g (85%) as light yellow solid; mp: 197−199 °C; 1H NMR (CDCl3, 400 MHz): δ 7.64−7.56 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.54 (s, 1H), 3.93 (s, 3H), 3.69 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 163.9 (CO), 151.7 (C), 143.2 (C), 134.4 (C), 130.7 (CH), 130.5 (CH), 129.6 (CH), 129.4 (C), 126.8 (CH), 124.1 (CH), 122.7 (C), 122.5 (C), 120.0 (C), 118.2 (CH), 116.9 (CH), 116.3 (C), 52.8 (2*OCH3), 52.3 (OCH 3 ), 48.4 (CH) ppm; HRMS (ESI+): m/z calcd for C24H19NO8Na [M+Na]+: 472.1003, found: 472.0980. Dimethyl 2-(3-(Methoxycarbonyl)-4-oxo-1-(p-tolyl)-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (10b). Reaction time: 2 h; Yield: 0.099 g (86%) as light yellow solid; mp: 180−182 °C; 1H NMR (CDCl3, 400 MHz): δ 7.38−7.30 (m, 5H), 7.19 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.53 (s, 1H), 3.92 (s, 3H), 3.69 (s, 6H), 2.50 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.7 (2*CO), 164.0 (CO), 151.8 (C), 143.3 (C), 140.8 (C), 134.7 (C), 130.5 (CH), 130.3 (CH), 126.7 (C), 126.4 (CH), 124.0 (CH), 122.7 (C), 122.7 (C), 120.0 (C), 118.2 (CH), 117.0 (C), 116.2 (CH), 52.8 (2*OCH3), 52.3 (OCH3), 48.5 (CH), 21.5 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H21NO8Na [M+Na]+: 486.1159, found: 486.1135. Dimethyl 2-(3-(Methoxycarbonyl)-1-(4-methoxyphenyl)-4-oxo4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (11c). Reaction time: 30 min; Yield: 0.110 g (92%) as light yellow solid; mp: 153−155 13621

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

Note

The Journal of Organic Chemistry

+): m/z calcd for C26H23NO8Na [M+Na]+: 500.1315, found: 500.1327. Dimethyl 2-(3-(Methoxycarbonyl)-7-methyl-4-oxo-1-(p-tolyl)-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (23b). Reaction time: 1.5 h; Yield: 0.098 g (82%) as light yellow solid; mp: 176− 177 °C; 1H NMR (CDCl3, 400 MHz): δ 7.35 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.12 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 4.53 (s, 1H), 3.92 (s, 3H), 3.68 (s, 6H), 2.49 (s, 3H), 2.29 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.7 (2*CO), 164.0 (CO), 152.0 (C), 143.2 (C), 140.6 (C), 137.2 (C), 134.4 (C), 130.5 (CH), 130.2 (CH), 126.4 (C), 124.9 (CH), 122.4 (C), 120.3 (C), 119.7 (C), 118.3 (CH), 116.7 (CH), 116.0 (C), 52.7 (2*OCH3), 52.2 (OCH3) 48.5 (CH), 21.5 (CH3), 20.7 (CH3) ppm; HRMS (ESI +): m/z calcd for C26H23NO8Na [M+Na]+: 500.1315, found: 500.1323. Dimethyl 2-(8-Chloro-3-(methoxycarbonyl)-4-oxo-1-(p-tolyl)-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (24b). Reaction time: 40 min; Yield: 0.105 g (85%) as light yellow solid; mp: 186− 187 °C; 1H NMR (CDCl3, 400 MHz): δ 7.39 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.62 (s, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.68 (s, 6H), 2.50 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.8 (CO), 151.2 (C), 141.8 (C), 141.2 (C), 134.9 (C), 130.4 (CH), 130.4 (CH), 129.2 (C), 126.7 (CH), 125.6 (C), 123.2 (C), 123.2 (C), 120.3 (C), 119.2 (CH), 117.3 (CH), 116.0 (C), 52.8 (2*OCH3), 52.4 (OCH3), 48.5 (CH), 21.5 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H20NO8ClNa [M+Na]+: 520.0769, found: 520.0777. Dimethyl 2-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-4-oxo-1-(ptolyl)-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (25b). Reaction time: 1.5 h; Yield: 0.117 g (90%) as light yellow solid; mp: 176−177 °C; 1H NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 8.4 Hz, 1H), 7.45−7.43 (m, 3H), 7.38−7.27 (m, 3H), 4.60 (s, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 3.71 (s, 6H), 2.55 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 164.8 (CO), 163.7 (CO), 150.9 (C), 146.3 (C), 140.9 (C), 135.2 (C), 130.4 (CH), 130.4 (CH), 127.8 (CH), 126.0 (C), 125.8 (C), 123.2 (C), 122.3 (C), 120.2 (C), 118.8 (CH), 118.2 (CH), 115.7 (C), 52.8 (2*OCH3), 52.3 (OCH3), 52.0 (OCH3), 48.4 (CH), 21.4 (CH3) ppm; HRMS (ESI+): m/z calcd for C27H23NO10Na [M+Na]+: 544.1214, found: 544.1215. Dimethyl 2-(3-(Methoxycarbonyl)-8-nitro-4-oxo-1-(p-tolyl)-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (26b). Reaction time: 3 h; Yield: 0.097 g (76%) as light yellow solid; mp: 193−195 °C; 1H NMR (CDCl3, 400 MHz): δ 8.19 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 2.0, 9.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 9.2 Hz, 1H), 4.53 (s, 1H), 3.94 (s, 3H), 3.70 (s, 6H), 2.52 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.6 (CO), 150.6 (C), 145.0 (C), 143.4 (C), 141.7 (C), 135.8 (C), 130.8 (CH), 130.6 (CH), 127.5 (C), 125.6 (C), 124.5 (C), 121.5 (C), 119.4 (CH), 117.6 (CH), 116.0 (C), 114.2 (CH), 53.1 (2*OCH3), 52.7 (OCH3), 48.5 (CH), 21.7 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H20N2O10Na [M+Na]+: 531.1010, found: 531.0982. Dimethyl 2-(3-(Methoxycarbonyl)-1-(4-methoxyphenyl)-8-methyl-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (27c). Reaction time: 30 min; Yield: 0.116 g (94%) as light yellow solid; mp: 147−148 °C; 1H NMR (CDCl3, 400 MHz): δ 7.34 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H), 4.57 (s, 1H), 3.92 (s, 6H), 3.69 (s, 6H), 2.02 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.7 (2*CO), 164.0 (CO), 161.1 (C), 151.9 (C), 141.1 (C), 134.3 (C), 133.8 (C), 132.1 (CH), 127.3 (CH), 122.4 (C), 122.1 (C), 121.2 (C), 119.9 (C), 117.7 (CH), 117.4 (CH), 116.1 (C), 114.8 (CH), 55.4 (2*OCH3), 53.0 (OCH3), 52.2 (OCH3), 48.5 (CH), 21.1 (CH3), ppm; HRMS (ESI+): m/z calcd for C26H23NO9Na [M+Na]+: 516.1265, found: 516.1262. Dimethyl 2-(3-(Methoxycarbonyl)-1-(4-methoxyphenyl)-7-methyl-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (28c). Reaction time: 30 min; Yield: 0.113 (92%) as light yellow solid; mp: 173−175 °C; 1H NMR (CDCl3, 400 MHz): δ 7.33 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.56 (s, 1H), 3.92 (s, 6H), 3.69 (s, 6H), 2.30 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.8 (2*CO), 164.1

Dimethyl 2-(3-(Methoxycarbonyl)-7-methyl-4-oxo-1-phenyl-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (17a). Reaction time: 2 h; Yield: 0.099 g (86%) as light yellow solid; mp: 179−181 °C; 1H NMR (CDCl3, 400 MHz): δ 7.63−7.54 (m, 3H), 7.43 (d, J = 7.2 Hz, 2H), 7.12 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.54 (s, 1H), 3.92 (s, 3H), 3.68 (s, 6H), 2.29 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 164.0 (CO), 151.9 (C), 143.1 (C), 137.3 (C), 134.1 (C), 130.8 (CH), 130.4 (CH), 129.4 (CH), 124.9 (CH), 122.4 (C), 120.2 (C), 119.7 (C), 118.3 (CH), 116.6 (CH), 116.1 (C), 52.8 (2*OCH3), 52.3 (OCH3), 48.5 (CH), 20.64 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H21NO8Na [M +Na]+: 486.1159, found: 486.1151. Dimethyl 2-(8-Chloro-3-(methoxycarbonyl)-4-oxo-1-phenyl-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (18a). Reaction time: 2 h; Yield: 0.099 g (82%) as light yellow solid; mp: 179−180 °C; 1H NMR (CDCl3, 400 MHz): δ 7.69−7.60 (m, 3H), 7.45 (d, J = 7.2 Hz, 2H), 7.28−7.26 (m, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H), 4.57 (s, 1H), 3.94 (s, 3H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.7 (CO), 151.2 (C), 141.9 (C), 134.7 (C), 130.9 (CH), 130.7 (CH), 129.8 (CH), 129.3 (C), 128.8 (C), 126.8 (CH), 123.3 (C), 123.1 (C), 120.3 (C), 119.3 (CH), 117.3 (CH), 116.1 (C), 52.9 (2*OCH3), 52.5 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C24H18NO8ClNa [M+Na]+: 506.0613, found: 506.0611. Dimethyl 2-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-4-oxo-1-phenyl-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (19a). Reaction time: 2 h; Yield: 0.112 g (89%) as light yellow solid; mp: 175−176 °C; 1H NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.4 Hz, 1H), 7.72−7.61 (m, 3H), 7.46 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 9.2 Hz, 2H), 4.59 (s, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 164.8 (CO), 163.7 (CO), 150.9 (C), 146.3 (C), 134.9 (C), 130.6 (CH), 129.8 (CH), 128.9 (C), 127.9 (CH), 126.0 (C), 123.2 (C), 122.3 (C), 120.3 (C), 118.9 (CH), 118.2 (CH), 115.9 (C), 52.9 (2*OCH3), 52.4 (OCH3), 52.1 (OCH3), 48.4 (CH) ppm; HRMS (ESI+): m/z calcd for C26H21NO10Na [M +Na]+: 530.1057, found: 530.1055. Dimethyl 2-(3-(Methoxycarbonyl)-8-nitro-4-oxo-1-phenyl-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (20a). Reaction time: 3 h; Yield: 0.092 g (75%) as light yellow solid; mp: 161−163; 1 H NMR (CDCl3, 400 MHz): δ 8.20 (s, 1H), 7.75−7.60 (m, 4H), 7.45 (d, J = 7.2 Hz, 2H), 6.80 (d, J = 9.2 Hz, 1H), 4.54 (s, 1H), 3.95 (s, 3H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.3 (2*CO), 163.4 (CO), 150.4 (C), 144.8 (C), 143.2 (C), 135.4 (C), 131.2 (CH), 130.6 (CH), 130.0 (CH), 128.5 (C), 127.2 (C), 124.4 (C), 121.4 (C), 119.3 (CH), 117.4 (CH), 116.0 (C), 114.1 (CH), 53.0 (2*OCH3), 52.6 (OCH3), 48.3 (CH) ppm; HRMS (ESI+): m/z calcd for C24H18N2O10Na [M+Na]+: 517.0853, found: 517.0835. Dimethyl 2-(7-Cyano-3-(methoxycarbonyl)-4-oxo-1-phenyl-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (21a). Reaction time: 3 h; Yield: 0.092 g (78%) as light yellow solid; mp: 201−203; 1 H NMR (CDCl3, 400 MHz): δ 7.67−7.60 (m, 3H), 7.44 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.02−6.97 (m, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.53 (s, 1H), 3.94 (s, 3H), 3.70 (s, 6H) ppm;13C NMR (CDCl3, 100 MHz): 167.4 (2*CO), 163.5 (CO), 150.4 (C), 143.3 (C), 135.2 (C), 131.1 (CH), 130.6 (CH), 129.9 (CH), 128.7 (C), 128.0 (C), 127.8 (CH), 126.1 (C), 124.2 (C), 122.1 (CH), 117.8 (CH), 116.8 (C), 116.1 (C), 110.2 (C), 53.0 (2*OCH3), 52.9 (OCH3), 52.6 (OCH3), 48.4(CH); HRMS (ESI+): m/z calcd for C25H18N2O8Na [M+Na]+: 497.0955, found: 497.0977. Dimethyl 2-(3-(Methoxycarbonyl)-8-methyl-4-oxo-1-(p-tolyl)-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (22b). Reaction time: 1.5 h; Yield: 0.095 g (80%) as light yellow solid; mp: 202− 204 °C; 1H NMR (CDCl3, 400 MHz): δ 7.37 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 4.55 (s, 1H), 3.91 (s, 3H), 3.69 (s, 6H), 2.50 (s, 3H), 1.99 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 164.0 (CO), 151.9 (C), 141.1 (C), 140.7 (C), 134.5 (C), 133.8 (C), 130.6 (CH), 130.0 (CH), 127.3 (CH), 126.4 (C), 122.4 (C), 122.1 (C), 119.7 (C), 117.6 (CH), 117.4 (CH), 116.2 (C), 52.7 (2*OCH3), 52.2 (OCH3), 48.5 (CH), 21.4 (CH3), 20.9 (CH3) ppm; HRMS (ESI 13622

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

Note

The Journal of Organic Chemistry

7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 4.52 (s, 1H), 3.83 (s, 3H), 3.64 (s, 3H), 3.59 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 164.7 (CO), 163.5 (CO), 159.6 (C), 151.0 (C), 146.1 (C), 135.6 (C), 131.6 (CH), 127.6 (CH), 125.9 (C), 122.8 (C), 122.2 (C), 120.0 (C), 118.9 (CH), 118.6 (C), 117.9 (CH), 116.7 (CH), 115.3 (C), 52.6 (2*OCH3), 52.1 (OCH3), 51.9 (OCH 3 ), 48.2 (CH) ppm; HRMS (ESI+): m/z calcd for C26H21NO11Na [M+Na]+: 546.1001, found: 546.0974. Dimethyl 2-(1-(4-Chlorophenyl)-3-(methoxycarbonyl)-8-methyl4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (35e). Reaction time: 40 min; Yield: 0.098 g (79%) as light yellow solid; mp: 183−185 °C; 1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.60−7.53 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 4.88 (s, 1H), 4.27 (s, 3H), 4.03 (s, 6H), 2.38 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.8 (CO), 151.7 (C), 141.0 (C), 136.8 (C), 134.1 (C), 132.7 (C), 132.2 (CH), 129.7 (CH), 127.9 (C), 127.6 (CH), 122.5 (C), 121.8 (C), 119.9 (C), 117.9 (CH), 117.1 (CH), 116.6 (C), 52.8 (2*OCH3), 52.3 (OCH3), 48.4 (CH), 21.0 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H20NO8ClNa [M+Na]+: 520.0769, found: 520.0778. Dimethyl 2-(1-(4-Chlorophenyl)-3-(methoxycarbonyl)-7-methyl4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (36e). Reaction time: 40 min; Yield: 0.099 g (80%) as light yellow solid; mp: 147−149 °C; 1H NMR (CDCl3, 400 MHz): δ 7.55 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.13 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.54 (s, J = 8.4 Hz, 1H),4.51 (s, 1H), 3.92 (s, 3H), 3.68 (s, 6H), 2.30 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.9 (CO), 151.9 (C), 143.2 (C), 137.6 (C), 136.9 (C), 132.7 (C), 132.3 (CH), 129.9 (CH), 128.0 (C), 125.1 (CH), 122.6 (C), 120.1 (C), 120.0 (C), 118.6 (CH), 116.5 (CH), 52.9 (2*OCH3), 52.4 (OCH3), 48.5 (CH), 20.7 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H20NO8ClNa [M+Na]+: 520.0769, found: 520.0772. Dimethyl 2-(8-Chloro-1-(4-chlorophenyl)-3-(methoxycarbonyl)4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (37e). Reaction time: 30 min; Yield: 0.096 g (74%) as light yellow solid; mp:166−168 °C; 1H NMR (CDCl3, 400 MHz): δ 7.56 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 4.8 Hz, 1H), 7.15 (d, J = 10.0 Hz, 1H), 6.60 (s, 1H), 4.49 (s, 1H), 3.90 (s, 3H), 3.66 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.3 (2*CO), 163.6 (CO), 151.1 (C), 141.8 (C), 137.4 (C), 133.2 (C), 132.1 (CH), 130.1 (CH), 129.4 (C), 127.2 (CH), 127.2 (C), 123.3 (C), 122.9 (C), 120.6 (C), 119.5 (CH), 117.0 (CH), 116.4 (C), 53.0 (2*OCH3), 52.5 (OCH3), 48.4 (CH) ppm; HRMS (ESI+): m/z calcd for C24H17NO8Cl2Na [M +Na]+: 540.0223, found: 540.0228. Dimethyl 1-(4-Chlorophenyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (38e). Reaction time: 40 min; Yield: 0.098 g (73%) as light yellow solid; mp: 185−187 °C; 1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 4.60 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.4 (2*CO), 164.8 (CO), 163.6 (CO), 150.9 (C), 146.4 (C), 137.2 (C), 133.5 (C), 132.3 (CH), 130.1 (CH), 128.2 (CH), 127.5 (C), 126.2 (C), 123.4 (C), 122.2 (C), 120.5 (C), 118.6 (CH), 118.5 (CH), 116.2 (C), 52.9 (2*OCH3), 52.6 (OCH3), 52.4 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C26H20NO10ClNa [M+Na]+: 564.0667, found: 564.0687. Dimethyl 2-(1-(4-Chlorophenyl)-3-(methoxycarbonyl)-8-nitro-4oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (39e). Reaction time: 2 h; Yield: 0.085 g (64%) as light yellow solid; mp: 198− 200 °C; 1H NMR (CDCl3, 400 MHz): δ 8.21 (s, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 9.2 Hz, 1H), 4.53 (s, 1H), 3.95 (s, 3H), 3.70 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 167.3 (2*CO), 163.4 (CO), 150.3 (C), 145.2 (C), 143.5 (C), 137.8 (C), 134.1 (C), 132.2 (CH), 130.5 (CH), 127.3 (C), 127.2 (C), 124.6 (C), 121.8 (C), 119.5 (CH), 117.4 (CH), 116.4 (C), 114.4 (CH), 53.2 (2*OCH3), 52.8 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C24H17ClN2O10Na [M+Na]+: 551.0463, found: 551.0479.

(CO), 161.0 (C), 152.1 (C), 143.2 (C), 137.3 (C), 134.2 (C), 132.0 (CH), 125.0 (CH), 122.3 (C), 121.2 (C), 120.4 (C), 119.9 (C), 118.4 (CH), 116.6 (CH), 116.0 (C), 114.9 (CH), 55.4 (2*OCH3), 52.9 (OCH3), 52.4 (OCH3), 48.5 (CH), 20.8 (CH3) ppm; HRMS (ESI+): m/z calcd for C26H23NO9Na [M+Na]+: 516.1265, found: 516.1262. Dimethyl 2-(8-Chloro-3-(methoxycarbonyl)-1-(4-methoxyphenyl)-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (29c). Reaction time: 30 min; Yield: 0.112 (88%) as light yellow solid; mp: 133−135 °C; 1H NMR (CDCl3, 400 MHz): δ 7.34 (d, J = 8.8 Hz, 2H), 7.27−7.26 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.68(d, J = 2.0 Hz, 1H), 4.58 (s, 1H), 3.93 (s, 6H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6 (2*CO), 163.8 (CO), 161.4 (C), 151.3 (C), 141.9 (C), 134.8 (C), 132.1 (CH), 129.3 (C), 126.7 (CH), 123.3 (C), 123.2 (C), 120.6 (C), 120.4 (C), 119.3 (CH), 117.3 (CH), 115.9 (C), 115.2 (CH), 55.5 (2*OCH3), 53.0 (OCH3), 52.5 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C25H20NO9ClNa [M+Na]+: 536.0718, found: 536.0703. Dimethyl 2-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-1-(4-methoxyphenyl)-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (30c). Reaction time: 30 min; Yield: 0.120 g (90%) as light yellow solid; mp: 152−154 °C; 1H NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.37−7.35 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 4.62 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 3.70 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.7 (2*CO), 164.9 (CO), 163.8 (CO), 161.5 (C), 151.1 (C), 146.4 (C), 135.1 (C), 132.1 (CH), 128.0 (CH), 126.1 (C), 123.2 (C), 122.4 (C), 120.6 (C), 120.5 (C), 118.9 (CH), 118.2 (CH), 115.7 (C), 115.2 (CH), 55.5 (2*OCH3), 52.9 (OCH3), 52.5 (OCH3), 52.1 (OCH3), 48.5 (CH) ppm; HRMS (ESI+): m/z calcd for C27H23NO11Na [M+Na]+: 560.1163, found: 560.1160. Dimethyl 2-(3-(Methoxycarbonyl)-1-(4-methoxyphenyl)-8-nitro4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (31c). Reaction time: 2 h; Yield: 0.104 g (80%) as light yellow solid; mp: 151−153; 1H NMR (CDCl3, 400 MHz): δ 8.03 (s, 1H), 7.63 (d, J = 9.2 Hz, 1H); 7.21 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 9.6 Hz, 1H), 4.40 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.55 (s, 6H); 13C NMR (CDCl3, 100 MHz): 167.5 (2*CO), 163.6 (CO), 161.6 (C), 150.5 (C), 144.9 (C), 143.4 (C), 135.6 (C), 132.1 (CH), 127.5 (C), 124.4 (C), 121.6 (C), 120.2(C), 119.4 (CH), 117.5 (CH), 115.9 (CH), 115.5 (C), 114.1 (CH), 55.5 (2*OCH3), 53.0 (OCH3), 52.7 (OCH 3 ), 48.5(CH); HRMS (ESI+): m/z calcd for C25H20N2O11Na [M+Na]+: 547.0959, found: 547.0988. Dimethyl 2-(1-(4-Hydroxyphenyl)-3-(methoxycarbonyl)-8-methyl-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (32d). Reaction time: 30 min; Yield: 0.092 g (77%) as light yellow solid; mp: 204−206 °C; 1H NMR (CDCl3, 400 MHz): δ 9.24 (s, 1H), 7.20−7.13 (m, 2H), 7.01−6.93 (m, 3H), 6.54 (s, 1H), 4.55 (s, 1H), 3.87 (s, 3H), 3.66 (s, 6H), 2.00 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.3 (2*CO), 163.6 (CO), 159.0 (C), 151.6 (C), 140.5 (C), 134.7 (C), 133.5 (C), 131.5 (CH), 126.9 (CH), 121.8 (C), 121.7 (C), 119.3 (C), 118.9 (C), 117.1 (CH), 116.1 (CH), 115.4 (C), 52.3 (2*OCH3), 51.7 (OCH3), 48.0 (CH), 20.6 (CH3) ppm; HRMS (ESI +): m/z calcd for C25H21NO9Na [M+Na]+: 502.1108, found: 502.1107. Dimethyl 2-(1-(4-Hydroxyphenyl)-3-(methoxycarbonyl)-7-methyl-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (33d). Reaction time: 30 min; Yield: 0.087 g (73%) as light yellow solid; mp: 193−195 °C; 1H NMR (CDCl3, 400 MHz): δ 8.86 (s, 1H), 6.74 (d, J = 7.2 Hz, 2H), 6.64 (s, 1H), 6.57−6.55 (m, 2H), 6.24−6.20 (m, 2H), 4.10 (s, 1H), 3.43 (s, 3H), 3.22 (s, 6H), 1.83 (s, 3H) ppm; 13 C NMR (CDCl3, 100 MHz): δ 167.8 (2*CO), 164.1 (CO), 159.4 (C), 152.1 (C), 143.1 (C), 137.2 (C), 135.0 (C), 132.0 (CH), 125.1 (CH), 122.2 (C), 120.4 (C), 119.8 (C), 119.4 (C), 118.2 (CH), 116.9 (CH), 116.7 (CH), 115.7 (C), 52.8 (2*OCH3), 52.2 (OCH3), 48.5 (CH), 20.8 (CH3) ppm; HRMS (ESI+): m/z calcd for C25H21NO9Na [M+Na]+: 502.1108, found: 502.1080. Dimethyl 2-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-1-(4-hydroxyphenyl)-4-oxo-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (34d). Reaction time: 30 min; Yield: 0.086 g (72%) as light yellow solid; mp: 214−216 °C; 1H NMR (CDCl3+DMSO-d6, 400 MHz): δ 9.44 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.26− 13623

DOI: 10.1021/acs.joc.7b02207 J. Org. Chem. 2017, 82, 13617−13625

Note

The Journal of Organic Chemistry Dimethyl 2-(3-(Methoxycarbonyl)-4-oxo-1-(thiophen-2-yl)-4Hbenzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (41). Reaction time: 1 h; Yield: 0.085 g (75%) as light white solid; mp: 166−168 °C; 1H NMR (CDCl3, 400 MHz): δ 7.70 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28−7.27 (m, 2H), 7.23−7.21 (m, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.72 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.7 (CO), 151.6 (C), 143.3 (C), 132.4 (CH), 130.8 (CH), 128.8 (C), 128.3 (CH), 127.1 (CH), 126.6 (C), 124.4 (CH), 122.6 (C), 122.5 (C), 122.4 (C), 118.3 (CH), 117.3 (C), 116.7 (C), 53.0 (2*OCH3), 52.5 (OCH 3 ), 48.6 (CH) ppm; HRMS (ESI+): m/z calcd for C22H17NO8SNa [M+Na]+: 478.0567, found: 478.0572. Dimethyl 2-(3-(Methoxycarbonyl)-7-methyl-4-oxo-1-(thiophen2-yl)-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-2-yl)malonate (42). Reaction time: 1 h; Yield: 0.091 g (78%) as light white solid; mp: 160− 162 °C; 1H NMR (CDCl3, 400 MHz): δ 7.68 (dd, J = 1.6, 4.8 Hz, 1H), 7.27−7.25 (m, 2H), 7.14 (s, 1H), 6.74 (dd, J = 2.0, 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.65 (s, 1H), 3.92 (s, 3H), 3.72 (s, 6H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.5 (2*CO), 163.8 (CO), 151.8 (C), 143.2 (C), 137.6 (C), 132.3 (CH), 130.8 (C), 128.9 (C), 128.2 (CH), 126.2 (C), 125.2 (CH), 122.3 (C), 120.1 (C), 118.4 (CH), 117.2 (C), 116.4 (CH), 52.9 (2*OCH3), 52.4 (OCH3), 48.6 (CH) 20.8 (CH3) ppm; HRMS (ESI+): m/z calcd for C23H19NO8SNa [M+Na]+: 492.0723, found: 492.0728. Dimethyl 2-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-4-oxo-1-(thiophen-2-yl)-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-3,8-dicarboxylate (43). Reaction time: 1 h; Yield: 0.097 g (76%) as light white solid; mp: 170−172 °C; 1H NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 12.4 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.35−7.32 (m, 2H), 4.69 (s, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.73 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 167.3 (2*CO), 165.1 (CO), 163.5 (CO), 150.8 (C), 146.4 (C), 132.5 (CH), 131.0 (CH), 128.4 (CH), 128.3 (CH), 128.2 (C), 127.2 (C), 126.4 (C), 123.1 (C), 123.0 (C), 122.2 (C), 118.9 (CH), 118.3 (CH), 116.9 (C), 53.0 (2*OCH3), 52.5 (OCH3), 52.3 (OCH3), 48.6 (CH) ppm; HRMS (ESI+): m/z calcd for C24H19NO10SNa [M+Na]+: 536.0621, found: 536.0629.

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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.7b02207. The ORTEP plot of the crystal structure of 9a, 1H and 13 C NMR spectra for all products, and 1H and HRMS spectra for intermediate B (PDF) X-ray crystallographic data for pyrrolobenzoxazine derivative 9a (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 We sincerely thank CSIR, New Delhi, for financial support and DST-FIST program for HRMS facility. S.B. thanks CSIR for research fellowship.

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REFERENCES

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