Annulation of a Highly Functionalized Diazo Building Block with

Article Cite This: J. Org. Chem. 2018, 83, 12171−12183

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Annulation of a Highly Functionalized Diazo Building Block with Indoles under Sc(OTf)3/Rh2(OAc)4 Multicatalysis through Michael Addition/Cyclization Sequence Shanmugam Sakthivel and Rengarajan Balamurugan* School of Chemistry, University of Hyderabad, Gachibowli, Hyderabad 500046, India

J. Org. Chem. 2018.83:12171-12183. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/05/18. For personal use only.

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ABSTRACT: A highly functionalized and easily accessible six-carbon diazo building block has been developed and utilized as a 1,4-diacceptor for an efficient synthesis of functionalized tetrahydrocarbazoles, carbazoles, and tetrahydropyrido[1,2-a]indoles. The synthesis involves concurrent tandem catalysis by Sc(OTf)3 and Rh2(OAc)4. The role of Sc(OTf)3 is critical as it facilitates both the initial intermolecular Michael reaction of the indole and the subsequent Rh(II)-catalyzed intramolecular annulation. The products, tetrahydrocarbazoles and tetrahydropyridoindoles, are equipped with a β-ketoester and ester functionalities which can be utilized for further synthetic elaborations.

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INTRODUCTION α-Diazo carbonyl compounds are highly useful compounds having diverse reactivities and potential synthetic utilities.1 Diazo compounds find applications in chemical biology as well these days.2 Easy generation of reactive intermediates such as carbenes, carbenoids, and ylides are viable with diazo compounds. The advent of new methods for their generation, regiochemistry of their reactions, and new catalysts to tune their reactivities keep the field vibrant over the last 3 decades. Having attained such an advancement in the field of organic synthesis, development of functionalized diazo compounds is obviously a demanding aspect as quite complex structures could be accessed at ease using them. There are a few prominent diazo building blocks such as enoldiazoacetate, vinyldiazoacetate, diazoenal, and α,β-unsaturated diazocarbonyl compound which show potential applications.3 Despite their widespread applications, their usage in tandem one-pot reactions is limited.3,4 Mainly C−H functionalization/nucleophilic attack followed by Cope rearrangement has been used. Synthesis of some of the functionalized diazo carbonyl compounds involves multistep processes, and in some cases, it is difficult to make such as α,β-unsaturated diazoketones.3h Further, individual diazo precursors have to be made to make products with different substitutions. Herein, we report an easily accessible six-carbon diazo building block 1 which has a range of functionalities with different reactivities (Figure 1). To elaborate, it has two different ester functionalities, a β-keto ester moiety, a diazo moiety, Michael acceptor and trans-dienophile. Hence, this building block can be utilized in tandem reactions to form cyclic compounds by making use of the rich functionalities it has. After cyclization, once incorporated as rings, the product will still possess functional groups which could be used in subsequent synthetic elaborations. More importantly, this building block could be synthesized in multigram quantities starting from ethyl propiolate © 2018 American Chemical Society

Figure 1. Six-carbon diazo building block.

in 72% overall yield in three steps.5 Also, it is quite stable and can be stored for months.

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RESULTS AND DISCUSSION In this manuscript, we present one possibility of utilization of the six-carbon diazo building block 1 by making use of the Michael reaction on the double bond followed by annulation using the diazo carbon (Scheme 1). This way the building block can act either as a 1,4- or a 1,3-diacceptor unit. Indole, being a good substrate in Michael additions,6 was subjected to reaction with the building block 1 under Lewis acidic conditions followed by rhodium-catalyzed cyclization via annulation. Among the catalysts attempted for this two-step one-pot protocol 1 mol % Sc(OTf)3/2 mol % Rh2(OAc)4 resulted the tetrahydrocarbazole 3a in 80% yield along with less than 2% of the corresponding aromatized product (Table 1, entry 16). The product 3a existed in its enolic form exclusively. Catalyst Sc(OTf)3 was added to the reaction mixture first to effect the Michael reaction. After completion of the Michael addition, Rh2(OAc)4 was added to the reaction mixture to effect the cyclization. Although the substrate 1 has two sites for Michael Received: August 16, 2018 Published: September 4, 2018 12171

DOI: 10.1021/acs.joc.8b02127 J. Org. Chem. 2018, 83, 12171−12183

Article

The Journal of Organic Chemistry Scheme 1. One-Pot Annulation of Diazo Building Block with Indoles

Table 1. Optimization for Direct Annulation of Diazo Building Block 1 with Indolea

entry

catalyst (mol %)

solvent

time Michael addition/annulation

yield (%) (3a:4a)b

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

Rh2(OAc)4 (2) Cu(OTf)2 (5)/Rh2(OAc)4 (2) AgOTf (5)/Rh2(OAc)4 (2) Sc(OTf)3 (5)/Rh2(OAc)4 (2) In(OTf)3 (5)/Rh2(OAc)4 (2) Bi(OTf)3 (5)/Rh2(OAc)4 (2) Ln(OTf)3 (5)/Rh2(OAc)4 (2) Yb(OTf)3 (5)/Rh2(OAc)4 (2) binol phosphoric acid (5) CSA (5) Sc(OTf)3 (5) Sc(OTf)3 (2)/Rh2(OAc)4 (2) Sc(OTf)3 (2)/Rh2(OAc)4 (2) Sc(OTf)3 (2)/Rh2(OAc)4 (2) Sc(OTf)3 (2)/Rh2(OAc)4 (2) Sc(OTf)3 (1)/Rh2(OAc)4 (2) Sc(OTf)3 (1)/Rh2(Oct)4 (2) Sc(OTf)3 (1)/Rh2(TFA)4 (2) Sc(OTf)3 (1)/Rh2(esp)2 (2) Sc(OTf)3 (1)/Rh2(hfb)4 (2)

(CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 CH2Cl2 toluene CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

1h 23 h/1 h 23 h/1 h 30 min/2 h 30 min 6 h/18 h 24 h/2 h 24 h/2 h 24 h/2 h 33 h 20 h/4 h 30 min/4 h 30 min 45 min/6 h 15 min 45 min/7 h 15 min 24 h/2 h 1 h/23 h 1 h/16 h 1 h/9 h 1 h/18 h 1 h/4 h 1 h/21 h

c trace c 57 (98:2) 44 (95:5) c c c d c e 70 (98:2) 79 (97:3) 18 (96:4) 63 (97:3) 80 (98:2) 72 (97:3) 23(98:2) 66 (98:2) 41 (97:3)

a

Reaction condition: 1 (0.21 mmol), 2a (0.21 mmol), Lewis acid (1−5 mol %), Rh(II) salt (2 mol %), solvent (1.5 mL), room temperature. Calculated based on 1H NMR spectra of the product. cComplex reaction mixture. dIsolated 6% of Michael addition product. eIsolated 92% of Michael addition product. b

reaction, indole added exclusively at the carbon β to the keto group through its third position. While a complex product mixture was obtained when the reaction was attempted with Rh2(OAc)4 alone, Michael adduct 5 was the sole product even after 5 h when Sc(OTf)3 was used (Table 1, entries 1 and 11). In order to check whether Sc(OTf)3 has played any role in the Rh-catalyzed annulation step, the Michael adduct 5a was prepared separately and treated with different Rh catalysts. Surprisingly, except for Rh2(Oct)4 no other rhodium catalyst including Rh2(OAc)4 resulted in the expected carbazole product in an appreciable amount even at reflux (Table 2, entries 1−3). The worst thing is that the reaction resulted in a complex mixture of products. Whereas, interestingly, the substrate 5a in the presence of Sc(OTf)3 and Rh2(OAc)4 combination in DCE at room temperature resulted in smooth conversion into 3a indicating a certain role of Sc(OTf)3 in the formation of carbazole

product (Table 2, entries 5, 9, and 17). Recently, it has been reported that Lewis/Brønsted acids can be used to promote the reactions of Rh-azavinylcarbene intermediates.7 To the best of our knowledge, facilitation of reactivity of Rh-carbenoid generated from α-diazocarbonyl compounds in annulation reactions by Lewis acids has not been reported so far. Perhaps, the Lewis acid increases the reactivity of the rhodium carbenoid by complexing to the β-keto ester moiety. The above statement was evaluated with the annulation reaction already reported by Shanahan et al.9b It was reported that the reaction took 16 h at 40 °C by using Rh2(Oct)4 alone as the catalyst. When we carried out the same reaction using 1 mol % of Sc(OTf)3 and 2 mol % of Rh2(OAc)4 catalyst system it was completed in 11 h at room temperature itself resulting the product in 60% yield. It has to be noted that the reaction resulted in a trace amount of the product after 24 h of reflux in CH2Cl2 in the presence of 2 mol % of 12172


Article

The Journal of Organic Chemistry Table 2. Intramolecular Annulation of Indolyl α-Diazo Acetate 5aa

entry

catalyst (mol %)

solvent

temp (°C)

time (h)

yield (%) (3a:4a)b

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

Rh2(OAc)4 (2) Rh2(esp)4 (2) Rh2(Oct)4 (2) Sc(OTf)3 (5) Sc(OTf)3 (5)/Rh2(OAc)4 (2) Rh2(OAc)4 (2) SiO2 Cu(OTf)2 (10) Sc(OTf)3 (5)/Rh2(OAc)4 (2) Cu(OTf)2 (5)/Rh2(OAc)4 (2) Bi(OTf)3 (5)/Rh2(OAc)4 (2) Cu(OAc)2 (5)/Rh2(OAc)4 (2) In(OTf)3 (5)/Rh2(OAc)4 (2) Ln(OTf)3 (5)/Rh2(OAc)4 (2) AgOTf (5)/Rh2(OAc)4 (2) Yb(OTf)3 (5)/Rh2(OAc)4 (2) Sc(OTf)3 (1)/Rh2(OAc)4 (2)

(CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 CH2Cl2 CH2Cl2 CHCl3 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2 (CH2)2Cl2

reflux reflux reflux reflux reflux reflux reflux reflux rt rt rt rt rt rt rt rt rt

24 3 3 7 1 24 24 2 2 6 23 24 4 22 24 4 5

trace c 15 (98:2) NR 72 (98:2) c NR trace 78 (trace) 43 (37:63) 63 (95:5) NR 71 (96:4) 69 (92:8) NR 61 (95:5) 79 (99:1)

a

Reaction condition: 5a (0.14 mmol), Lewis acid (1−5 mol %), Rh(II) salt (2 mol %), solvent (1.5 mL). bCalculated based on 1H NMR signals. Complex mixture, NR no reaction.

c

products were also obtained which are inseparable from the actual tetrahydrocarbazole product. The extent of aromatization was noticed up to 10% for the substrates which required longer reaction time for annulation reactions (Figure 2, products 3d, 3f, and 3m). 5-Carbomethoxy indole took less time for both Michael and annulation reactions when the amount of Sc(OTf)3 was enhanced to 5 mol % (Figure 2, product 3e). N-Substituted indoles resulted in the expected products in moderate yields, and interestingly, the obtained products existed in their keto forms as a mixture of diastereomers mostly along with small amounts of the corresponding enol forms (Figure 2, products 3r−3t). It was observed that the tetrahydrocarbazole derivative 3a in the presence of 2 equiv of triethylamine in dichloromethane in open air at room temperature resulted in the formation of carbazole derivative 4a (Scheme 2). Since carbazoles are important class of biologically active heterocyclic compounds and their functionalized derivatives find applications as optical materials we pursued the aromatization of the tetrahydrocarbazoles.11 Selected tetrahydrocarbazole derivatives were subjected to treatment with trimethylamine under open atmosphere to get their corresponding carbazole derivatives (4a, 4c, 4h, 4j, 4l−4n, 4p, 4q) in good yields (Scheme 2). In fact the annulation and aromatization can be carried out in one pot by adding 2 equiv of trimethylamine to the reaction flask after the completion of the Michael and annulation reactions (Scheme 3). The aromatization strategy of tetrahydrocarbazoles can be extended to an interesting class of compounds containing indole fused anthrananilic acids. Anthranilic acid and their derivatives have been found to display a wide spectrum of biological activities.12 To mention few, mefenamic acid, tranilast, etofenamate, and furosemide are some of the commercially drugs available in the market having anthranilic acid in their structures. Treatment of compound 3a with a primary amine in the presence of Yb(OTf)3 catalyst resulted in the formation of corresponding derivatives of

Rh2(OAc)4 catalyst alone. Further, 30% of the starting material was recovered back. Hence, it is believed that there is a dual activation by Rh2(OAc)4 and Sc(OTf)3 catalysts during annulation step. It has to be mentioned that other Lewis acids such as Cu(OTf)2, In(OTf)3, and Ln(OTf)3 also assisted the Rh-catalyzed annulation, but slightly less effectively than Sc(OTf)3 (Table 2, entries 10, 11, 13, 14, and 16). Intermolecular carbenoid insertion on indole’s C-2/C-3 carbons are known for the preparation of substituted indoles.8 However, there are a very few reports on making carbazoles that utilize the annulation of rhodium carbenoid on indole. Both inter- and intramolcular annulations have been utilized.9 Our approach has its own advantage as the product is equipped with β-keto ester and ester moieties which can be utilized for later-stage functionalization using classical carbanion chemistry. A wide range of indoles having substituents with different electronic effects at different positions on the phenyl ring were subjected to direct one-pot annulation with functionalized diazo compound 1 using the condition mentioned in entry 16 of Table 1. These starting indoles are either commercially available or easily obtainable via trivial synthetic protocols.10 Indoles with substituents such as cyano, ester, fluoro, bromo, chloro, methyl, methoxy, and benzyloxy underwent one-pot sequential Sc(OTf)3/Rh2(OAc)4 catalyzed Michael addition/annulation to give corresponding tetrahydrocarbazole products (Figure 2). Protection of indole nitrogen is not required. In all the cases, except with the substrate having a CN group, the yields were moderate to good. Indoles with CN, CO2Me, and 4-Cl required more time for the initial Sc(OTf)3-catalyzed Michael reaction. Notably, 5-CN and 4-Cl substituted indoles required 5 mol % of Sc(OTf)3 in order to complete the Michael reaction in a reasonable time. However, the other substrates took less than 10 h for the Michael reactions with 1 mol % of Sc(OTf)3 (Figure 2). In most of the cases some amount of aromatized 12173


Article

The Journal of Organic Chemistry

Figure 2. Substrate scope. Figure annotations: a, ratio of tetrahydrocarbazole and carbazole from 1H NMR signals; b, reaction time for Michael reaction; c, reaction time for annulation; d, keto/enol ratio from 1H NMR spectra; e, diastereomeric ratio of the keto form.

compound 7a resulted in a diastereomeric mixture of fused tetracyclic compounds 9a and 9b (Scheme 6). The indolo[2,3b]carbazole derivatives are important class of compounds having applications in treating different type of cancers (SR13668) and viral infections (RSV and HCMV).16 They find applications in dye-sensitized solar cells (DSSC) as dyes as well.17 We then pursued the reactions of the building block 1 with 3-substituted indoles to make the second position of the indole to take part in the initial Michael reaction. Interestingly, this reaction underwent smooth Michael addition through the second position followed by insertion on the N−H bond of the indole to generate tetrahydropyridoindoles (Scheme 7). Indole alkaloids with a tetrahydropyrido[1,2-a]indole core such as goniomitine, vinpocetine, vincamine, etc. display interesting bioactivities.18

anthranilic acid fused indoles 6b and 6c (Scheme 4). On the other hand, reaction of 3a with ammonium acetate in acetic acid gave the aminocarbazole 6a along with 4a. It is believed that the synthesized indole anthranilic acid hybrid scaffold13 is expected to possess some interesting bioactivities. Moreover, these aminocarbazoles are fluorescent as well. It is known that aminocarbazoles find extensive application in material chemistry.14 The 1,3-dicarbonyl incorporated in the product provides an opportunity for the regioselective functionalization. To demonstrate this, alkylation was attempted on 3a. This compound underwent smooth C-alkylation at the active methylene carbon using K2CO3 base and alkylating agents (Scheme 5). Fischer indole synthesis was attempted on compounds 3a and 7a with phenylhydrazine in DMU/L-tartaric acid eutectic mixture.15 While 3a resulted in the corresponding indolo[2,3-b]carbazole 8a, 12174


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The Journal of Organic Chemistry Scheme 2. Aromatization of Tetrahydrocarbazoles

Scheme 3. One-Pot Direct Benzannulation of Indole to Carbazole

Scheme 4. Synthesis of Anthranilic Acid Fused Indoles

Scheme 5. Alkylation of Tetrahydrocarbazole 3a

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CONCLUSION In conclusion, we have developed a highly functionalized diazo building block and demonstrated its utility to make functionalized tetrahydrocarbazoles, carbazoles, and tetrahydropyrido[1,2-a]indole. The functionalities present in the cyclized

product could be advantageously used in further synthetic manipulations. Involvement of the catalyst Sc(OTf)3 in both the steps, i.e., Michael addition of indole on the building block and subsequent Rh-catalyzed annulation, favors a concurrent tandem catalysis mechanism. Exploration of synthetic possibilities such 12175


Article

The Journal of Organic Chemistry Scheme 6. Synthesis of Indolo, Pyrazolo[4,3-a]carbazoles

Scheme 7. Synthesis of Tetrahydropyrido[1,2-a]indoles

Sc(OTf)3 (2.0 mg, 0.004 mmol) was added at room temperature and maintained until the completion of starting material 1, and then Rh2(OAc)4 (3.7 mg, 0.008 mmol) was added. After completion of the reaction, solvent was removed under reduced pressure and the product was isolated by column chromatography using 12% ethyl acetate in hexanes. Yield (110 mg, 80%); yellow solid; mp = 86−87 °C; Rf = 0.56 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.03 (br s, 1H), 8.86 (br s, 1H), 7.59−7.57 (m, 1H), 7.34−7.32 (m, 1H), 7.16− 7.10 (m, 2H), 4.51−4.45 (m, 2H), 4.22−4.03 (m, 3H), 3.13 (dd, J = 17.5, 3.3 Hz, 1H), 3.06 (dd, J = 17.6, 8.4 Hz, 1H), 1.49 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.0, 172.9, 169.4, 135.7, 130.4, 126.3, 120.7, 120.1, 118.0, 110.8, 99.8, 94.4, 61.5, 61.0, 36.0, 32.4, 14.6, 14.2. IR (KBr, cm−1): υ 3468, 2982, 2899, 1722, 1645, 1593, 1448, 1221, 1076. HRMS (ESI-Q-TOF) m/z calcd for C18H20NO5 (M + H)+: 330.1336; found 330.1340. The above procedure was followed for the synthesis of other tetrahydrocarbazoles 3b−3t using 100 mg of 1 in each case. Diethyl 2-Hydroxy-6-methoxy-4,9-dihydro-3H-carbazole-1, 4-dicarboxylate (3b). Yield (96 mg, 65%); yellow solid; mp = 122− 123 °C; Rf = 0.48 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3): δ 13.00 (br s, 1H), 8.74 (br s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 4.48−4.40 (m, 2H), 4.18− 4.03 (m, 3H), 3.87 (s, 3H) 3.10 (dd, J = 17.5, 3.1 Hz, 1H), 3.04 (dd, J = 17.5, 8.4 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ 172.9, 169.5, 154.5, 131.1, 130.8, 126.8, 111.5, 110.6, 100.1, 99.6, 94.5, 61.6, 61.0, 55.8, 36.0, 32.3, 14.5, 14.2. IR (KBr, cm−1): υ 3401, 2972, 2931, 1717, 1640, 1211, 1149, 1082. HRMS (ESI-Q-TOF) m/z calcd for C19H22NO6 (M + H)+: 360.1442; found 360.1441. Diethyl 6-Bromo-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3c). Yield (122 mg, 72%); yellow solid; mp = 152−153 °C; Rf = 0.71 in 1:2 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.06 (br s, 1H), 8.84 (br s, 1H), 7.66 (s, 1H), 7.2−7.13 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.15−4.04 (m, 2H), 4.01 (dd, J = 8.5, 3.2 Hz, 3H) 3.11 (dd, J = 17.7, 3.2 Hz, 1H), 3.03 (dd, J = 17.7, 8.6 Hz, 1H), 1.50 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.7, 134.4, 131.8, 128.2, 123.4, 120.7, 113.5, 112.3, 99.4, 94.2, 61.8, 61.3, 35.9, 32.3, 14.6, 14.2. IR (KBr, cm−1): υ 3375, 2977, 1712, 1645, 1226, 1200, 1087. HRMS (ESI-Q-TOF) m/z calcd for C18H19BrNO5 (M + H)+: 408.0441; found 408.0439. Diethyl 6-Cyano-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3d). Yield (48 mg, 32%); yellow solid; mp = 188−189 °C; Rf = 0.23 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.08 (br s, 1H), 9.15 (br s, 1H), 7.87 (s, 1H), 7.36 (d, J = 8.4 Hz 1H), 7.30 (dd, J = 8.4, 1.4 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.18−4.03 (m, 3H), 3.16 (dd, J = 17.7, 3.1 Hz, 1H), 3.07 (dd, J = 17.8, 8.7 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.3, 137.5, 133.1, 126.3, 123.7, 123.4, 121.0, 111.7, 103.2, 100.2, 93.9, 61.9, 61.4, 35.8, 32.2, 14.6, 14.2. IR (KBr, cm−1): 3416,

as asymmetric Michael reaction using different nucleophiles followed by annulation sequence and other tandem processes like Diels−Alder/annulation using this six-carbon diazo building block are currently being pursued in our lab.

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EXPERIMENTAL SECTION

General Information. Chemicals and solvents were obtained from various commercial sources. Starting materials were prepared by following known literature procedures. THF and toluene were dried over sodium and freshly distilled before use. Dichloromethane and dichloroethane were dried over CaH2 and freshly distilled before use. 1 H and 13C spectra were recorded on 400 and 500 MHz spectrometers using solution in CDCl3 with tetramethylsilane (TMS) as an internal standard. IR spectra were recorded using an Fourier transform infrared (FT-IR) spectrometer. High-resolution mass spectra (HRMS) were recorded using the electrospray quadrupole time-of-flight (ESI-QTOF) technique. Melting points were determined by using a melting range apparatus and are uncorrected. For thin-layer chromatography (TLC), silica gel plates 60 F254 were used and compounds were visualized by UV light and/or by treatment with Seebach solution [phosphomolybdic acid (2.5 g), Ce(SO4)2 (1 g), concentrated H2SO4 (6 mL), and H2O (94 mL)] followed by heating. Column chromatography was performed on silica gel (100−200 mesh) using ethyl acetate and hexanes mixture as eluent. Procedure for the Synthesis of (E)-Diethyl 5-Diazo-4oxohex-2-enedioate 1. To the solution of (E)-diethyl 4-oxohex-2enedioate5b (1.6 g, 7.47 mmol) and p-toluene sulfonyl azide19 (1.36 g, 7.47 mmol) in dry CH2Cl2 (30 mL, 4 mL/mmol) at 0 °C, triethylamine (1.2 mL, 8.96 mmol) was added dropwise. The reaction temperature was brought to room temperature slowly and maintained at the same temperature for 5 h. After completion of the reaction as monitored by TLC, the reaction mass was evaporated under reduced pressure at room temperature. The obtained crude was purified by column chromatography using a mixture of 10% ethyl acetate in hexanes. Yield (1.53 g, 85%); light yellow liquid; Rf = 0.35 in 1:10 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 15.6 Hz, 1H), 6.85 (d, J = 15.6 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.3 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 180.8, 165.2, 160.7, 135.8, 131.1, 78.2, 62.0, 61.3, 14.3, 14.2. IR (neat, cm−1): υ 3370, 3266, 2975, 2142, 1715, 1643, 1298, 1163, 811. HRMS (ESI-Q-TOF) m/z calcd for C10H12N2NaO5+ (M + Na)+: 263.0638; found 263.0643. Indoles 2a−2i were purchased from a commercially available source and used as such. Indoles 2j−2l,10a,b 2m−2o,10c,d 2p, 2q,10e,f and 2r− 2t10g−i were prepared by following the literature procedure. General Procedure for the Synthesis of Diethyl 2-Hydroxy4,9-dihydro-3H-carbazole-1,4-dicarboxylate 3a. To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (100 mg, 0.42 mmol) and indole (2a) (48.8 mg, 0.42 mmol) in dry CH2Cl2 (3 mL, 7 mL/mmol), 12176


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32.3, 16.6, 14.5, 14.3. IR (KBr, cm−1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087. HRMS (ESI-Q-TOF) m/z calcd for C19H21BrNO5 (M + H)+: 422.0598; found 422.0595. Diethyl 5-Chloro-2-hydroxy-8-methyl-4,9-dihydro-3H-carbazole1,4-dicarboxylate (3k). Yield (80 mg, 51%); yellow solid; mp = 138− 139 °C; Rf = 0.66 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3): δ 12.93 (br s, 1H), 8.86 (br s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.56 (dd, J = 8.2, 2.5 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.17−4.11 (m, 1H), 4.06−4.0 (m, 1H), 3.13 (dd, J = 17.6, 8.3 Hz, 1H), 3.08 (dd, J = 17.5, 2.4 Hz, 1H), 2.41 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.0, 173.2, 136.1, 131.3, 123.3, 122.4, 122.0, 120.8, 118.5, 101.0, 94.6, 61.7, 61.1, 35.9, 33.2, 16.0, 14.4, 14.2. IR (KBr, cm−1): υ 3473, 2982, 2926, 1722, 1655, 1603, 1232, 1102, 860, 798. HRMS (ESI-Q-TOF) m/z calcd for C19H21ClNO5 (M + H)+: 378.1103; found 378.1106. Diethyl 9-Hydroxy-8,11-dihydro-7H-benzo[a]carbazole-7,10dicarboxylate (3l). Yield (112 mg, 71%); yellow solid; mp = 177− 178 °C; Rf = 0.64 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 12.88 (br s, 1H), 9.50 (br s, 1H), 7.90 (t, J = 7.8 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.53−7.49 (m, 2H), 7.40−7.36 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.18−4.02 (m, 3H), 3.16 (dd, J = 17.5, 3.5 Hz, 1H), 3.09 (dd, J = 17.5, 8.1 Hz, 1H), 1.58 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.2, 173.0, 169.6, 129.8, 129.1, 128.7, 125.6, 123.4, 122.4, 121.6, 121.0, 118.9, 118.7, 102.0, 94.7, 61.7, 61.2, 36.3, 32.4, 14.6, 14.2. IR(KBr, cm−1): υ 3473, 2981, 1729, 1652, 1609, 1382, 1226, 1073, 1027, 851, 805, 744. HRMS (ESI-QTOF) m/z calcd for C22H21NNaO5+ (M + Na)+: 402.1312; found 402.1318. Diethyl 2-Hydroxy-6-(4-methoxyphenyl)-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3m). Yield (111 mg, 61%); yellow gum; Rf = 0.46 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.06 (br s, 1H), 8.80 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.38− 7.30 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 4.17− 4.05 (m, 3H), 3.86 (s, 3H), 3.13 (dd, J = 17.6, 3.6 Hz, 1H), 3.17 (dd, J = 17.5, 8.1 Hz, 1H), 1.49 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3): δ 173.0, 169.6, 158.6, 135.4, 134.9, 133.4, 131.1, 128.5, 128.4, 126.9, 120.4, 116.1, 114.3, 114.2, 111.0, 100.1, 94.5, 61.7, 61.1, 55.5, 36.1, 32.5, 14.7, 14.3. IR (neat, cm−1): υ 3478, 3416, 2982, 2931, 1722, 1645, 1598, 1278, 1035, 803. HRMS (ESI-Q-TOF) m/z calcd for C25H25NNaO6 (M + Na)+: 458.1574; found 458.1579. Diethyl 2-Hydroxy-6-(p-tolyl)-4,9-dihydro-3H-carbazole-1,4dicarboxylate (3n). Yield (120 mg, 69%); yellow solid; mp = 97− 98 °C; Rf = 0.61 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3): δ 13.05 (br s, 1H), 8.81 (br s, 1H), 7.7 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.36−7.32 (m, 2H), 7.25 (m, 2H), 4.50−4.46 (m, 2H), 4.16−4.03 (m, 3H), 3.12 (dd, J = 17.4, 3.2 Hz, 1H), 3.06 (dd, J = 17.5, 8.4 Hz, 1H), 2.40 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.0, 139.9, 136.0, 135.2, 133.7, 131.1, 129.6, 129.5, 127.4, 127.2, 126.9, 120.6, 116.3, 111.0, 100.2, 94.5, 61.7, 61.2, 36.1, 32.5, 21.2, 14.7, 14.3. IR (KBr, cm−1): υ 3473, 3427, 2982, 1727, 1645, 1593, 1226, 798. HRMS (ESI-Q-TOF) m/z calcd for C25H26NO5 (M + H)+: 420.1805; found 420.1811. Diethyl 6-(4-Chlorophenyl)-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3o). Yield (140 mg, 76%); yellow solid; mp = 133−134 °C; Rf = 0.45 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.08 (br s, 1H), 8.91 (br s, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 4.21−4.05 (m, 3H), 3.15 (dd, J = 17.6, 3.1 Hz, 1H), 3.07 (dd, J = 17.5, 8.6 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.1, 172.8, 169.4, 141.1, 135.4, 132.3, 131.3, 128.8, 128.7, 128.6, 128.4, 126.9, 120.2, 116.3, 111.2, 100.0, 94.4, 61.6, 61.1, 36.0, 32.4, 14.5, 14.2. IR (KBr, cm−1): υ 3473, 2982, 1732, 1717, 1649, 1221, 1086, 519. HRMS (ESI-Q-TOF) m/z calcd for C24H23ClNO5 (M + H)+: 440.1259; found 440.1258. Diethyl 7-(Benzyloxy)-2-hydroxy-6-methoxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3p). Yield (150 mg, 77%); yellow gum; Rf = 0.41 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 12.90 (br s, 1H), 8.64 (br s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.35−7.24 (m, 3H),

2972, 2931, 2208, 1717, 1650, 1206, 1082. HRMS (ESI-Q-TOF) m/z calcd for C19H19N2O5 (M + H)+: 355.1288; found 355.1285. 1,4-Diethyl 6-Methyl-2-hydroxy-4,9-dihydro-3H-carbazole-1,4, 6-tricarboxylate (3e). Yield (104 mg, 65%); yellow solid; mp = 129−130 °C; Rf = 0.29 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3): δ 12.99 (br s, 1H), 9.05 (br s, 1H), 8.30 (s, 1H), 7.78 (d, J = 8.5 Hz 1H), 7.28 (dd, J = 8.4, 0.8 Hz, 1H), 4.47−4.42 (m, 2H), 4.15− 4.06 (m, 3H), 3.92 (s, 3H), 3.14 (dd, J = 17.6, 3.2 Hz, 1H), 3.04 (dd, J = 17.7, 8.9 Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ 172.2, 172.7, 169.2, 168.3, 138.4, 132.0, 126.0, 122.2, 122.1, 121.0, 110.5, 100.8, 94.2, 66.7, 61.3, 51.8, 36.0, 32.3, 14.6, 14.1. IR (KBr, cm−1): υ 3416, 2982, 2946, 1722, 1696, 1655, 1206, 1097. HRMS (ESI-Q-TOF) m/z calcd for C20H22NO7 (M + H)+: 388.1381; found 388.1394. Diethyl 6-Fluoro-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3f). Yield (77 mg, 54%); yellow solid; mp = 137−138 °C; Rf = 0.33 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.04 (br s, 1H), 8.81 (br s, 1H), 7.22−7.17 (m, 2H), 6.81 (td, J = 9.1, 2.5 Hz 1H), 4.50−4.44 (m, 2H), 4.18−4.00 (m, 3H), 3.11 (dd, J = 17.6, 3.3 Hz, 1H), 3.04 (dd, J = 17.6, J2 = 8.4 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 158.3 (d, J = 232 Hz), 132.3, 132.2, 126.9 (d, J = 11 Hz), 112.0, 111.3 (d, J = 9.9 Hz), 108.8 (d, J = 26 Hz), 103.1 (d, J = 24.1 Hz), 100.0 (d, J = 4.7 Hz), 94.3, 61.7, 61.2, 36.0, 32.3, 14.6, 14.2. IR (KBr, cm−1): υ 3452, 3390, 2977, 2905, 1717, 1645, 1216, 1149, 1082. HRMS (ESI-Q-TOF) m/z calcd for C18H19FNO5 (M + H)+: 348.1242; found 348.1239. Diethyl 6-Chloro-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3g). Yield (100 mg, 66%); yellow solid; mp = 142−143 °C; Rf = 0.33 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 13.04 (br s, 1H), 8.87 (br s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 1.7 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.18−3.99 (m, 3H), 3.06 (dd, J = 17.6, 3.1 Hz, 1H), 3.02 (dd, J = 17.7, 8.6 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.3, 172.7, 169.2, 134.1, 131.9, 127.4, 125.8, 120.8, 117.5, 111.8, 99.4, 94.2, 61.7, 61.2, 35.9, 32.2, 14.5, 14.2. IR (KBr, cm−1): υ 3375, 2982, 1722, 1645, 1237, 1206, 1082, 1030. HRMS (ESI-Q-TOF) m/z calcd for C18H18ClNNaO5 (M + Na)+: 386.0766; found 386.0765. Diethyl 8-Methyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3h). Yield (108 mg, 76%); yellow solid; mp = 125−126 °C; Rf = 0.58 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 12.93 (br s, 1H), 8.78 (br s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.2, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.16− 4.00 (m, 3H), 3.12 (dd, J = 17.5, 3.6 Hz, 1H), 3.05 (dd, J = 17.5, 8.2 Hz, 1H), 2.48 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3): δ 173.0, 169.6, 135.2, 130.1, 125.9, 121.5, 120.4, 119.8, 116.0, 100.4, 94.5, 61.5, 61.1, 36.3, 32.5, 16.4, 14.4, 14.3. IR (KBr, cm−1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087. HRMS (ESI-Q-TOF) m/z calcd for C19H22NO5 (M + H)+: 344.1492; found 344.1497. Diethyl 8-Bromo-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3i). Yield (113 mg, 68%); yellow solid; mp = 154−155 °C; Rf = 0.61 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 12.96 (br s, 1H), 9.01 (br s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.8, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.16−4.0 (m, 3H), 3.12 (dd, J = 17.6, 3.4 Hz, 1H), 3.04 (dd, J = 17.6, 8.4 Hz, 1H), 1.52 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.3, 172.6, 169.4, 134.4, 131.2, 127.6, 122.9, 121.3, 117.3, 104.4, 100.8, 94.2, 61.8, 61.2, 36.2, 32.3, 14.4, 14.2. IR (KBr, cm−1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087. HRMS (ESIQ-TOF) m/z calcd for C18H18BrNO5Na (M + Na)+: 430.0261; found 430.0268. Diethyl 7-Bromo-2-hydroxy-8-methyl-4,9-dihydro-3H-carbazole1,4-dicarboxylate (3j). Yield (115 mg, 66%); yellow solid; mp = 150− 151 °C; Rf = 0.62 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3): δ 12.94 (br s, 1H), 8.78 (br s, 1H), 7.25−7.23 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.15−4.0 (m, 3H), 3.11 (dd, J = 17.6, 3.2 Hz, 1H), 3.04 (dd, J = 17.6, 8.6 Hz, 1H), 2.45 (s, 3H), 1.5 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 135.7, 130.8, 125.2, 124.5, 119.6, 117.0, 116.5, 100.5, 94.3, 61.7, 61.2, 36.1, 12177


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The Journal of Organic Chemistry 7.03 (s, 1H), 6.84 (s, 1H), 5.11 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 4.16− 3.99 (m, 3H), 3.93 (s, 3H), 3.31 (dd, J = 17.5, 3.2 Hz, 1H), 2.99 (dd, J = 17.6, 8.4 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ 175.7, 172.9, 169.4, 146.1, 145.0, 137.7, 129.9, 129.2, 128.6, 128.5, 127.7, 127.3, 127.2, 120.1, 100.9, 99.7, 98.1, 94.7, 71.9, 61.5, 61.0, 56.6, 36.2, 32.3, 14.6, 14.3. IR (neat, cm−1): υ 3395, 2982, 2931, 1722, 1645, 1242, 1211, 1020. HRMS (ESI-QTOF) m/z calcd for C26H27NNaO7 (M + Na)+: 488.1680; found 488.1685. Diethyl 7-Hydroxy-8,9-dihydro-5H-[1,3]dioxolo[4,5-b]carbazole6,9-dicarboxylate (3q). Yield (107 mg, 67%); yellow solid; mp = 153− 154 °C; Rf = 0.48 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 12.86 (br s, 1H), 8.66 (br s, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 5.91 (s, 2H), 4.47−4.42 (m, 2H), 4.18−4.02 (m, 2H), 3.96 (dd, J = 8.1, 3.7 Hz, 1H), 3.08 (dd, J = 17.5, 3.6 Hz, 1H), 3.01 (dd, J = 17.6, 8.1 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.6, 172.9, 169.5, 143.8, 143.1, 130.4, 129.0, 120.6, 100.6, 100.2, 97.1, 94.7, 92.2, 61.5, 61.1, 36.2, 32.3, 14.6, 14.3. IR (KBr, cm−1): υ 3468, 3430, 2981, 2879, 1726, 1648, 1597, 1460, 1327, 1258, 1036. HRMS (ESI-Q-TOF) m/z calcd for C 19 H 20 NO 7 (M + H)+: 374.1234; found 374.1234. Diethyl 9-Methyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4dicarboxylate (3r). Yield (77 mg, 54%); dr = 1:0.8; keto/enol forms = 94:6; yellow solid; mp = 109−110 °C; Rf = 0.39 in 1:3 EtOAc/ hexanes. 1H NMR (500 MHz, CDCl3) major isomer: δ 7.68 (d, J = 3.7 Hz, 1H), 7.33−7.25 (m, 2H), 7.19−7.15 (m, 1H), 4.66 (s, 1H), 4.42 (dd, J = 6.8, 2.2 Hz, 1H), 4.29−4.17 (m, 2H), 4.14−4.01 (m, 2H), 3.63 (s, 3H), 3.15 (dd, J = 14.3, 6.7 Hz, 1H), 2.95 (dd, J = 14.3, 1.8 Hz, 1H), 1.30−1.26 (m, 3H), 1.22−1.17 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 199.7, 173.1, 166.9, 138.1, 131.0, 125.3, 122.6, 120.1, 119.3, 109.4, 107.8, 62.6, 61.5, 54.8, 40.1, 39.0, 29.9, 14.1. 1 H NMR (500 MHz, CDCl3) minor isomer: δ 7.70 (d, J = 3.7 Hz, 1H), 7.33−7.25 (m, 2H), 7.19−7.15 (m, 1H), 4.65 (s, 1H), 4.31 (dd, J = 6.7, 3.5 Hz, 1H), 4.29−4.17 (m, 2H), 4.14−4.01 (m, 2H), 3.64 (s, 3H), 3.24 (dd, J = 15.0, 3.6 Hz, 1H), 2.79 (dd, J = 15.0, 6.8 Hz, 1H), 1.30− 1.26 (m, 3H), 1.22−1.17 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 200.2, 172.3, 167.0, 138.0, 131.0, 125.4, 122.6, 120.1, 119.3, 109.5, 107.9, 62.4, 61.4, 54.5, 40.8, 38.4, 29.8, 14.1. IR (KBr, cm−1): υ 3050, 2972, 2931, 1727, 1588, 1469, 1175, 1030. HRMS (ESIQ-TOF) m/z calcd for C19H21NNaO5 (M + Na)+: 366.1312; found 366.1312. Diethyl 9-Benzyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4dicarboxylate (3s). Yield (87 mg, 50%); dr = 1:0.68; keto/enol forms = 94:6; yellow solid; mp = 111−112 °C; Rf = 0.45 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3) major isomer: δ 7.76−7.73 (m, 1H), 7.24−7.16 (m, 6H), 6.90−6.88 (m, 2H), 5.37−5.14 (m, 2H), 4.57 (s, 1H), 4.47 (dd, J = 6.7, 2.0 Hz, 1H), 4.15−3.88 (m, 2H), 3.80− 3.73 (m, 2H), 3.27−3.20 (m, 1H), 2.93 (dd, J = 14.3, 1.9 HZ, 1H), 1.22−1.03 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 199.6, 172.9, 166.6, 137.9, 136.7, 131.1, 128.7, 127.5, 125.6, 125.4, 122.9, 120.3, 119.4, 110.2, 108.6, 62.5, 61.4, 54.8, 46.8, 39.9, 39.0, 14.0, 13.7. 1H NMR (400 MHz, CDCl3) minor isomer: δ 7.76−7.73 (m, 1H), 7.24−7.16 (m, 6H), 6.96−6.94 (m, 2H), 5.37−5.14 (m, 2H), 4.51 (s, 1H), 4.33 (dd, J = 6.7, 3.5 Hz, 1H), 4.15−3.88 (m, 2H), 3.80− 3.73 (m, 2H), 3.27−3.20 (m, 1H), 2.73 (dd, J = 15.2, 6.8 HZ, 1H), 1.22−1.03 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 200.1, 172.1, 166.7, 137.9, 136.8, 130.9, 128.8, 127.6, 126.1, 125.6, 122.8, 120.3, 119.4, 110.0, 108.7, 62.1, 61.3, 54.4, 46.8, 40.5, 38.3, 14.1, 13.8. IR (KBr, cm−1): υ 3050, 2972, 1738, 1717, 1562, 1469, 1185, 1154, 1036. HRMS (ESI-Q-TOF) m/z calcd for C25H25NNaO5 (M + Na)+: 442.1625; found 442.1624. Diethyl 9-Allyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3t). Yield (46 mg, 60%); dr = 1:0.67; keto/enol forms = 97:3; yellow gum; Rf = 0.64 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3) major isomer: δ 7.73 (d, J = 7.7 Hz, 1H), 7.34−7.25 (m, 2H), 7.22−7.19 (m, 1H), 5.93−5.84 (m, 1H), 5.17−5.14 (m, 1H), 4.87− 4.83 (m, 1H), 4.75−4.72 (m, 1H), 4.67−4.60 (m, 2H), 4.47 (dd, J = 6.7, 2.0 Hz, 1H), 4.29−4.13 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.24 (dd, J = 14.3, 6.8 Hz, 1H), 2.96 (dd, J = 14.3, 2.1 Hz, 1H), 1.30−1.18 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 199.8,

172.0, 166.9, 137.6, 132.6, 130.8, 125.5, 122.8, 120.2, 119.4, 116.8, 110.1, 108.3, 62.7, 61.5, 54.9, 45.9, 40.0, 39.1, 14.1; 1H NMR (500 MHz, CDCl3) minor isomer: δ 7.75 (d, J = 7.2 Hz, 1H), 7.34− 7.25 (m, 2H), 7.22−7.19 (m, 1H), 5.93−5.84 (m, 1H), 5.17−5.14 (m, 1H), 4.95−4.91 (m, 1H), 4.78−4.75 (m, 1H), 4.67−4.60 (m, 2H), 4.35 (dd, J = 6.8, 3.4 Hz, 1H), 4.29−4.13 (m, 2H), 3.29 (dd, J = 15.2, 3.5 Hz, 1H), 2.80 (dd, J = 15.2, 6.8 Hz, 1H), 1.30−1.18 (m, 6H). 13 C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 200.3, 172.2, 166.9, 137.5, 132.8, 130.6, 125.7, 122.7, 120.3, 119.4, 117.0, 110.0, 108.4, 62.4, 61.5, 54.5, 45.8, 40.7, 38.3, 14.2. HRMS (ESI-Q-TOF) m/z calcd for C21H23NNaO5 (M + Na)+: 392.1468; found 392.1465. General Procedure for the Synthesis of Carabzoles (4a, 4c, 4h, 4j, 4l−4n, 4p, 4q). To a solution of tetrahydrocarbazole (3a) (50 mg, 0.15 mmol) in dry CH2Cl2 (1 mL, 7 mL/mmol) triethylamine (43 μL, 0.30 mmol) was added at room temperature and stirred for 2 h. After completion of the reaction, as monitored by the 1H NMR signal of the reaction mixture, solvent was evaporated and the obtained crude was purified using a mixture of ethyl acetate/hexanes by silica gel column chromatography. Diethyl 2-Hydroxy-9H-carbazole-1,4-dicarboxylate (4a). Yield (39 mg, 76%); yellow solid; mp = 124−125 °C; Rf = 0.56 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 10.86 (br s, 1H), 9.33 (br s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 7.39−7.36 (m, 2H), 7.23−7.20 (m, 2H), 4.57−4.48 (m, 4H), 1.54 (t, J = 7.1 Hz, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.3, 140.2, 139.4, 131.9, 125.7, 124.2, 121.6, 120.5, 114.9, 111.5, 110.5, 98.8, 62.5, 61.7, 14.6, 14.4. IR (KBr, cm−1): υ 3478, 2982, 1717, 1665, 1459, 1371, 1025. HRMS (ESI-Q-TOF) m/z calcd for C18H18NO5+ (M + H)+: 328.1179; found 328.1189. Diethyl 6-Bromo-2-hydroxy-9H-carbazole-1,4-dicarboxylate (4c). The reaction was carried out using 28 mg of 3c. Yield (21 mg, 72%); yellow solid; mp = 178−179 °C; Rf = 0.46 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 10.89 (br s, 1H), 9.38 (br s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.52 (q, J = 7.1 Hz, 2H), 1.58 (t, J = 7.1 Hz, 3H), 1.50 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 166.5, 160.8, 140.4, 137.9, 131.9, 128.3, 127.0, 123.3, 113.9, 113.4, 112.4, 111.8, 99.0, 62.7, 61.9, 14.6, 14.4. IR (KBr, cm−1): υ 3469, 2987, 1721, 1671, 1589, 1450, 1291, 1206, 1156, 1084, 1028. HRMS (ESI-Q-TOF) m/z calcd for C18H17BrNO5+ (M + H)+: 406.0285; found 406.0289. Diethyl 2-Hydroxy-8-methyl-9H-carbazole-1,4-dicarboxylate (4h). The reaction was carried out using 27 mg of 3h. Yield (24 mg, 71%); yellow solid; mp = 135−136 °C; Rf = 0.64 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 10.82 (br s, 1H), 9.34 (br s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.20−7.13 (m, 2H), 4.58 (q, J = 7.1 Hz, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.59 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.2, 140.1, 138.7, 132.1, 126.3, 121.8, 121.1, 120.6, 119.2, 115.4, 111.5, 98.8, 61.4, 61.7, 16.5, 14.4, 14.3. IR (KBr, cm−1): υ 3480, 2974, 1719, 1663, 1579, 1424, 1372, 1282, 1220, 1166, 1103, 1046, 863, 776, 747. HRMS (ESI-Q-TOF) m/z calcd for C19H20NO5+ (M + H)+: 342.1336; found 342.1334. Diethyl 7-Bromo-2-hydroxy-8-methyl-9H-carbazole-1,4-dicarboxylate (4j). The reaction was carried out using 31 mg of 3j. Yield (28 mg, 89%); yellow solid; mp = 209−210 °C; Rf = 0.67 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3): δ 10.78 (br s, 1H), 9.22 (br s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.35−7.26 (m, 1H), 4.57 (q, J = 7.1 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.59 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 166.5, 160.2, 140.1, 139.1, 131.7, 124.5, 123.1, 121.6, 120.3, 119.0, 115.1, 112.3, 98.9, 62.6, 61.8, 16.6, 14.4. IR (KBr, cm−1): υ 3474, 1727, 1669, 1583, 1425, 1376, 1226, 1167, 1097, 1040, 1015. HRMS (ESI-Q-TOF) m/z calcd for C19H19BrNO5+ (M + H)+: 420.0441; found 420.0442. Diethyl 9-Hydroxy-11H-benzo[a]carbazole-7,10-dicarboxylate (4l). The reaction was carried out using 24 mg of 3l. Yield (21 mg, 90%); yellow solid; mp = 215−216 °C; Rf = 0.59 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 10.75 (br s, 1H), 9.86 (br s, 1H), 8.56 (d, J = 8.9 Hz, 1H) 7.96−7.93 (m, 1H), 7.8−7.92 (m, 1H), 7.58 12178


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The Journal of Organic Chemistry (d, J = 8.9 Hz, 1H), 7.54−7.49 (m, 2H), 7.31 (s, 1H), 4.58−4.49 (m, 4H), 1.61 (t, J = 7.2 Hz, 3H), 1.50 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.4, 166.9, 159.8, 138.7, 134.7, 132.0, 131.4, 128.8, 125.6, 125.5, 122.8, 120.6, 120.4, 120.0, 117.1, 115.8, 112.6, 99.2, 62.5, 61.7, 14.5, 14.4. IR (KBr, cm−1): υ 3471, 1721, 1666, 1585, 1511, 1423, 1371, 1283, 1219, 1169, 1115, 1081. HRMS (ESI-QTOF) m/z calcd for C22H20NO5+ (M + H)+: 378.1336; found 378.1334. Diethyl 2-Hydroxy-6-(4-methoxyphenyl)-9H-carbazole-1,4-dicarboxylate (4m). The reaction was carried out using 60 mg of 3m. Yield (46 mg, 76%); yellow solid; mp = 146−147 °C; Rf = 0.41 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3): δ 10.91 (br s, 1H), 9.55 (br s, 1H), 8.79 (s, 1H), 7.64−7.61 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 4.68 (q, J = 7.0 Hz, 2H), 4.54 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.62 (t, J = 7.0 Hz, 3H), 1.48 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.4, 158.7, 140.7, 138.5, 135.0, 133.6, 132.1, 128.4, 125.0, 122.3, 122.1, 115.0, 114.3, 111.6, 110.7, 98.9, 62.6, 61.8, 55.5, 14.6, 14.4. IR (KBr, cm−1): υ 3462, 2971, 1716, 1670, 1582, 1468, 1293, 1236, 1200. HRMS (ESI-QTOF) m/z calcd for C25H23NNaO6+ (M + Na)+: 456.1418; found 456.1418. Diethyl 2-Hydroxy-6-(p-tolyl)-9H-carbazole-1,4-dicarboxylate (4n). The reaction was carried out using 40 mg of 3n. Yield (30 mg, 79%); yellow solid; mp = 120−121 °C; Rf = 0.51 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 10.91 (br s, 1H), 9.50 (br s, 1H), 8.80 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J = 7.9 Hz, 2H), 4.64 (q, J = 7.2 Hz, 2H), 4.53 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.59 (t, J = 7.2 Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.5, 140.8, 139.5, 138.7, 136.3, 134.0, 132.3, 129.6, 127.4, 125.2, 122.6, 122.2, 115.1, 111.7, 110.7, 99.0, 62.6, 61.8, 21.2, 14.7, 14.5. IR (KBr, cm−1): υ 3471, 3421, 2981, 2925, 1723, 1670, 1587, 1470, 1415, 1374, 1293, 1203, 1153, 801. HRMS (ESI-Q-TOF) m/z calcd for C25H24NO5+ (M + H)+: 418.1649; found 418.1648. Diethyl 7-(Benzyloxy)-2-hydroxy-6-methoxy-9H-carbazole-1,4dicarboxylate (4p). The reaction was carried out using 23 mg of 3p. Yield (16 mg, 69%); yellow solid; mp = 163−164 °C; Rf = 0.41 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 10.76 (br s, 1H), 9.33 (br s, 1H), 8.29 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.39−7.35 (m, 3H), 7.32−7.30 (m, 1H), 6.93 (s, 1H), 5.24 (s, 2H), 4.62 (q, J = 7.1 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.56 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 167.0, 159.2, 148.4, 145.2, 140.2, 137.2, 134.4, 130.7, 128.7, 128.0, 127.3, 115.8, 114.6, 111.4, 107.7, 99.1, 96.4, 71.3, 62.5, 61.7, 56.8, 14.7, 14.5. IR (KBr, cm−1): υ 3472, 3404, 2985, 2941, 2900, 1721, 1668, 1590, 1480, 1423, 1374, 1345, 1204, 1146, 1014. HRMS (ESI-Q-TOF) m/z calcd for C26H26NO7+ (M + H)+: 464.1704; found 464.1707. Diethyl 7-Hydroxy-5H-[1,3]dioxolo[4,5-b]carbazole-6,9-dicarboxylate (4q). The reaction was carried out using 40 mg of 3q. Yield (24 mg, 60%); yellow solid; mp = 208−209 °C; Rf = 0.41 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3): δ 10.74 (br s, 1H), 9.33 (br s, 1H), 8.04 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 6.01 (s, 2H), 4.63 (q, J = 7.1 Hz, 2H), 4.50 (q, J = 7.2 Hz, 2H), 1.58 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.1, 159.1, 147.1, 143.1, 140.0, 135.1, 130.7, 115.6, 115.0, 111.4, 103.6, 101.3, 99.0, 91.6, 62.5, 61.7, 14.7, 14.4. IR (KBr, cm−1): υ 3473, 1714, 1671, 1583, 1494, 1283, 1188, 1148. HRMS (ESI-Q-TOF) m/z calcd for C19H18NO7+ (M + H)+: 372.1078; found 372.1074. Synthesis of Diethyl 2-Diazo-5-(1H-indol-3-yl)-3-oxohexanedioate (5a). To a solution of (E)-diethyl 5-diazo-4-oxohex-2enedioate (1) (500 mg, 2.10 mmol) and indole (2a) (245.0 mg, 2.10 mmol) in dry CH2Cl2 (12.6 mL, 6 mL/mmol), Sc(OTf)3 (20.0 mg, 0.042 mmol) was added at room temperature, and the mixture was stirred for 1 h. Then, solvent was evaporated under reduced pressure and the obtained crude was purified by silica gel column chromatography using 1:3 mixture of ethyl acetate/hexanes. Yield (744 mg, 96%); brown solid; mp = 86−87 °C; Rf = 0.56 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 8.41 (br s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.21−7.12 (m, 2H), 7.07 (s, 1H), 4.49 (dd, J = 10.8, 3.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.22−4.04 (m, 2H),

3.96 (dd, J = 18.5, 10.8 Hz, 1H), 3.27 (dd, J = 18.4, 4.0 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 191.1, 174.0, 161.4, 136.3, 126.3, 122.4, 122.2, 119.7, 119.3, 112.6, 111.4, 76.3, 61.6, 61.1, 43.2, 37.9, 14.4, 14.1. IR (KBr, cm−1): υ 3377, 2982, 2936, 2134, 1171, 1650, 1300, 1172, 1094. HRMS (ESI-QTOF) m/z calcd for C18H19N3NaO5 (M + Na)+: 380.1217; found 380.1218. Synthesis of Diethyl 2-Amino-9H-carbazole-1,4-dicarboxylate (6a). Tetrahydrocarbazole (3a) (50 mg, 0.15 mmol), NH4OAc (234 mg, 3.0 mmol), and acetic acid (3.5 μL, 0.15 mmol) were taken in ethanol (2 mL, 14 mL/mmol) and refluxed for 20 h. The reaction mass was cooled, and 10 mL of water was added. Then, the reaction mass was extracted using ethyl acetate (6 mL). The combined organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure. The obtained crude product was purified by silica gel chromatography using a mixture of ethyl acetate/hexanes. Yield (15 mg, 30%); yellow solid; mp = 125−126 °C; Rf = 0.46 in 1:3 EtOAc/hexanes. 1 H NMR (500 MHz, CDCl3): δ 10.03 (br s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.35 (td, J = 7.1, 1.0 Hz 1H), 7.22−7.19 (m, 1H), 7.05 (s, 1H), 5.88 (br s, 2H), 4.58−4.51 (m, 4H), 1.54 (t, J = 7.1 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.0, 167.5, 149.1, 142.4, 139.0, 131.2, 124.8, 123.4, 122.0, 120.2, 112.5, 111.6, 110.5, 97.0, 61.6, 61.4, 14.8, 14.5. IR (KBr, cm−1): υ 3365, 2977, 2910, 1738, 1459, 1231, 1030, 751. HRMS (ESI-Q-TOF) m/z calcd for C18H19N2O4+ (M + H)+: 327.1339; found 327.1341. Synthesis of Diethyl 2-(Phenylamino)-9H-carbazole-1,4dicarboxylate (6b). Tetrahydrocarbazole (3a) (40 mg, 0.12 mmol), benzylamine (16 μL, 0.26 mmol), and Yb(OTf)3 (3.7 mg, 0.006 mmol) were taken in benzene (1.0 mL, 8 mL/mmol) in a round-bottom flask fitted with a DS apparatus. The reaction mass was heated to reflux temperature for 13 h. The reaction mass was cooled, and the solvent was evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using a mixture of ethyl acetate/hexanes. Yield (39 mg, 80%); yellow solid; mp = 172−173 °C; Rf = 0.56 in 1:3 EtOAc/hexanes. 1 H NMR (400 MHz, CDCl3): δ 9.90 (br s, 1H), 9.59 (br s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.44−7.31 (m, 5H), 7.25−7.20 (m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 167.7, 146.8, 142.3, 140.8, 139.2, 131.1, 129.6, 125.1, 124.1, 123.4, 122.6, 121.9, 120.3, 113.3, 110.4, 109.0, 97.9, 61.7, 61.6, 14.7, 14.4. IR (KBr, cm−1): υ 3466, 3450, 1722, 1679, 1593, 1497, 1322, 1257, 1147. HRMS (ESI-Q-TOF) m/z calcd for C24H23N2O4+ (M + H)+: 403.1652; found 403.1647. Diethyl 2-(Benzylamino)-9H-carbazole-1,4-dicarboxylate (6c). The above procedure was followed using 40 mg of 3a. It took 16 h for the completion of the reaction. Yield (36 mg, 74%); yellow gum; Rf = 0.50 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 9.94 (br s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.22 (br s, 1H), 7.43−7.28 (m, 7H), 7.20 (t, J = 8.0 Hz, 1H), 7.10 (s, 1H), 4.55 (s, 2H), 4.53−4.47 (m, 4H), 1.48 (t, J = 7.1 Hz, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 167.9, 149.9, 142.8, 139.0, 138.6, 131.5, 128.9, 127.6, 124.8, 123.2, 122.0, 120.1, 111.9, 110.3, 106.6, 96.0, 61.6, 61.3, 48.0, 14.7, 14.4. IR (KBr, cm−1): υ 3470, 3427, 2978, 1722, 1677, 1603, 1462, 1256, 1172. HRMS (ESI-Q-TOF) m/z calcd for C25H25N2O4+ (M + H)+: 417.1809; found 417.1808. Synthesis of Diethyl 1-Methyl-2-oxo-2,3,4,9-tetrahydro-1Hcarbazole-1,4-dicarboxylate (7a). Tetrahydrocarbazole (3a) (50 mg, 0.15 mmol) and K2CO3 (48 mg, 0.34 mmol) were taken in dry CH3CN (1 mL, 7 mL/mmol) and stirred at room temperature. After stirring the reaction mixture for 30 min, methyl iodide (lot-1) (40 μL, 0.30 mmol) was added, and the stirring was continued for 1 h. Again, methyl iodide (lot-2) (40 μL, 0.30 mmol) was added, and the mixture was stirred for 1.5 h. Then, the reaction mass was filtered. The obtained filtrate was evaporated, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate/ hexanes. Yield (44.0 mg, 85%); dr = 1:0.88; yellow gum; Rf = 0.45 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3) major isomer: δ 8.65 (br s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.40−7.37 (m, 1H), 7.28−7.16 (m, 2H), 4.31 (t, J = 6.0 Hz, 1H), 4.32−4.08 (m, 4H), 3.32 (dd, J = 14.6, 12179


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The Journal of Organic Chemistry 5.8 Hz, 1H), 2.96 (dd, J = 14.7, 6.5 Hz, 1H), 1.79 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) major isomer: δ 204.2, 172.3, 170.7, 137.0, 134.0, 125.7, 123.0, 120.5, 120.4, 119.4, 119.0, 111.5, 107.7, 62.5, 61.4, 55.7, 38.8, 38.6, 22.0, 14.2, 13.9. 1H NMR (500 MHz, CDCl3) minor isomer: δ 8.66 (br s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.40−7.37 (m, 1H), 7.28−7.16 (m, 2H), 4.38 (dd, J = 6.4, 1.8 Hz, 1H), 4.26−4.08 (m, 4H), 3.17 (dd, J = 14.7, 6.6 Hz, 1H), 3.04 (dd, J = 14.6, 1.6 Hz, 1H), 1.79 (s, 3H), 1.22−1.19 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3) minor isomer: δ 203.8, 173.0, 170.9, 136.7, 134.8, 125.7, 123.0, 120.4, 119.0, 111.4, 107.8, 62.6, 61.5, 55.0, 41.2, 40.0, 22.0, 14.1, 14.0. IR (KBr, cm−1): υ 3377, 2983, 1736, 1458, 1242, 1180, 1099, 1029. HRMS (ESI-Q-TOF) m/z calcd for C19H21NNaO5+ (M + Na)+: 366.1312; found 366.1316. Synthesis of C-Alkylated Carbazoles (7b−7d). The reactions were carried out using 50 mg of 3a in each experiment and 1.1 equiv of corresponding alkyl bromide using in single lot. It took, respectively, 5, 5, and 6 h for the synthesis of 7b, 7c, and 7d. Diethyl 1-Allyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7b). Yield (49 mg, 88%); dr = 1:0.61; colorless gum; Rf = 0.64 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3) major isomer: δ 8.56 (br s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.37−7.35 (m, 1H), 7.25− 7.21 (m, 1H), 7.18−7.14 (m, 1H), 5.46−5.38 (m, 1H), 5.07−4.96 (m, 2H), 4.25 (t, J = 6.2 Hz, 1H), 4.22−4.04 (m, 4H), 3.26−3.20 (m, 1H), 3.11−2.98 (m, 2H), 2.77 (dd, J = 15.0, 6.3 Hz, 1H), 1.26− 1.15 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3) major isomer: δ 203.5, 172.3, 169.9, 137.1, 132.5, 132.0, 125.8, 123.0, 120.4, 119.4, 119.2, 111.5, 109.5, 62.5, 61.4, 59.9, 41.9, 40.1, 38.4, 14.3, 13.9. 1 H NMR (500 MHz, CDCl3) minor isomer: δ 8.51 (br s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.37−7.35 (m, 1H), 7.25−7.21 (m, 1H), 7.18−7.14 (m, 1H), 5.61−5.52 (m, 1H), 5.03−4.96 (m, 2H), 4.89−4.86 (m, 1H), 4.34 (dd, J = 6.1, 2.8 Hz, 1H), 4.22−4.04 (m, 4H), 3.24−3.20 (m, 1H), 3.11−2.98 (m, 2H), 1.26−1.15 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3) minor isomer: δ 202.3, 172.6, 169.9, 136.9, 132.5, 132.0, 125.9, 123.0, 120.1, 119.4, 119.2, 111.4, 109.4, 62.7, 61.4, 59.4, 41.1, 39.3, 38.5, 14.2, 14.0. IR (KBr, cm−1): υ 3370, 3091, 2987, 1727, 1459, 1024, 850. HRMS (ESI-Q-TOF) m/z calcd for C21H24NO5 (M + H)+: 370.1649; found 370.1644. Diethyl 1-(3-Methylbut-2-en-1-yl)-2-oxo-2,3,4,9-tetrahydro-1Hcarbazole-1,4-dicarboxylate (7c). Yield (54 mg, 90%); dr = 1:0.46; colorless gum; Rf = 0.56 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3) major isomer: δ 8.21 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24−7.22 (m, 1H), 7.12−7.14 (m, 1H), 4.76−4.72 (m, 1H), 4.24−4.03 (m, 5H), 3.19 (dd, J = 15.0, 5.4 Hz, 1H), 3.15− 3.08 (m, 1H), 2.86 (dd, J = 14.5, 5.3 Hz, 1H), 2.72 (dd, J = 15.0, 6.4 Hz, 1H), 1.52 (s, 6H), 1.26−1.16 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 204.1, 172.4, 170.3, 137.0, 136.8, 132.6, 125.9, 122.8, 120.2, 117.4, 111.4, 109.2, 62.4, 61.4, 59.7, 41.8, 38.3, 34.8, 25.9, 18.0, 14.2, 13.9. 1H NMR (400 MHz, CDCl3) minor isomer: δ 8.29 (br s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26−7.21 (m, 1H), 7.12−7.14 (m, 1H), 4.88−4.84 (m, 1H), 4.32 (dd, J = 5.9, 3.0 Hz, 1H), 4.24−4.03 (m, 5H), 3.15−3.08 (m, 1H), 3.05−3.00 (m, 2H), 2.93 (dd, J = 14.6, 6.6 Hz, 1H), 1.56 (s, 6H), 1.26−1.16 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 202.8, 172.5, 170.3, 136.9, 135.8, 133.0, 126.0, 122.9, 119.4, 118.0, 111.4, 109.1, 62.5, 61.3, 59.4, 41.1, 38.3, 33.9, 25.9, 17.9, 14.2, 14.0. IR (KBr, cm−1): υ 3370, 2982, 2915, 1732, 1459, 1226, 1025, 741. HRMS (ESI-Q-TOF) m/z calcd for C23H28NO5 (M + H)+: 398.1962; found 398.1961. Diethyl 2-Oxo-1-(prop-2-yn-1-yl)-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7d). Yield (46 mg, 83%); dr = 1:0.59; colorless gum; Rf = 0.61 in 1:3 EtOAc/hexanes. 1H NMR (500 MHz, CDCl3) major isomer: δ 8.65 (br s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.30−7.25 (m, 1H), 7.23−7.17 (m, 1H), 4.36 (t, J = 6.0 Hz, 1H), 4.31−4.07 (m, 4H), 3.35−3.28 (m, 2H), 3.14−2.90 (m, 2H), 2.01 (t, J = 2.6 Hz, 1H), 1.30−1.18 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3) major isomer: δ 202.4, 172.2, 168.7, 137.0, 131.5, 125.6, 123.2, 120.4, 119.5, 111.6, 109.8, 79.3, 72.5, 62.9, 61.5, 59.0, 41.2, 38.5, 25.6, 14.3, 13.9. 1H NMR (500 MHz, CDCl3) minor isomer: δ 8.80 (br s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.30−7.25 (m, 1H), 7.23−7.17 (m, 1H), 4.40 (dd, J = 6.2, 2.4 Hz, 1H),

4.29−4.07 (m, 4H), 3.54 (dd, J = 17, 2.7 Hz, 1H), 3.14−2.90 (m, 2H), 2.13 (t, J = 2.6 Hz, 1H), 1.30−1.18 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3) minor isomer: δ 200.7, 172.7, 168.1, 136.7, 132.6, 125.4, 123.2, 120.4, 119.3, 111.6, 109.3, 79.3, 72.5, 63.0, 61.6, 58.9, 40.6, 38.7, 25.0, 14.2, 14.0. IR (neat, cm−1): υ 3375, 3282, 2981, 2937, 2906, 1723, 1456, 1231, 1184, 1030. HRMS (ESI-Q-TOF) m/z calcd for C21H21NNaO5+ (M + Na)+: 390.1312; found 390.1312. Synthesis of Diethyl 5,7-Dihydroindolo[2,3-b]carbazole6,12-dicarboxylate (8a). A 70:30 mixture of dimethylurea and L-tartaric acid (1.5 g) was taken in a round-bottom flask and heated to 85 °C until the solids melt to liquid. Then, phenylhydrazine hydrochloride (47.5 mg, 0.33 mmol) and compound 3a (100 mg, 0.30 mmol) were added in sequence at 85 °C and maintained at the same temperature for 2 h. After completion of the reaction as monitored by TLC, H2O (5 mL) was added to the reaction mass at 85 °C, and the mixture was stirred for another 10 min and brought to room temperature. Then, the product from the reaction mass was extracted using ethyl acetate (10 mL). The organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using a mixture of ethyl acetate/hexanes. Yield (42 mg, 35%); fluorescent yellow solid; mp = 232−233 °C; Rf = 0.51 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 9.94 (br s, 2H), 8.01−7.99 (m, 2H), 7.53−7.51 (m, 2H), 7.46−7.42 (m, 2H), 7.29− 7.25 (m, 2H), 4.82 (q, J = 7.2 Hz, 2H), 4.68 (q, J = 7.2 Hz, 2H), 1.64 (t, J = 7.2 Hz, 3H), 1.57 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.0, 167.4, 140.3, 140.0, 125.9, 125.6, 121.7, 121.1, 120.4, 114.8, 111.0, 94.3, 62.4, 61.7, 15.0, 14.4. IR (KBr, cm−1): υ 3465, 3424, 2981, 1725, 1686, 1605, 1461, 1322, 1244, 1179, 1025. HRMS (ESI-QTOF) m/z calcd for C24H20N2NaO4+ (M + Na)+: 423.1315; found 423.1316. Synthesis of Pyrazolo[4,3-a] Carbazole (9a and 9b). A 70:30 mixture of dimethylurea and L-tartaric acid (1.5 g) was taken in a roundbottom flask and heated to 85 °C until the solids melt to liquid. Then, phenylhydrazine hydrochloride (35.2 mg, 0.24 mmol) and compound 7a (76 mg, 0.22 mmol) were added in sequence at 85 °C and reacted at the same temperature for 2 h. After completion of the reaction as monitored by TLC, H2O (5 mL) was added to the reaction mass at 85 °C, and the mixture was stirred for another 10 min and brought to room temperature. Then, the product from the reaction mass was extracted using (2 × 5 mL) of ethyl acetate. The combined organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using a mixture of ethyl acetate/hexanes to separate 9a and 9b in 40 mg (48%) and 36 mg (42%), respectively. 9a: Colorless solid; mp = 199−200 °C; Rf = 0.67 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3): δ 9.03 (br s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.43−7.39 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.23−7.18 (m, 2H), 7.13−7.10 (m, 1H), 4.36−4.24 (m, 3H), 3.39−3.28 (m, 2H), 1.87 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3): δ 173.9, 173.3, 164.4, 137.9, 137.0, 131.5, 129.1, 125.7, 125.6, 123.0, 120.4, 119.4, 119.1, 111.8, 107.6, 61.8, 50.7, 41.8, 26.8, 23.6, 13.4. IR (KBr, cm−1): υ 3355, 2978, 1697, 1596, 1496, 1456, 1179, 1032. HRMS (ESI-Q-TOF) m/z calcd for C23H22N3O3+ (M + H)+: 388.1656; found 388.1655. 9b: Colorless solid; mp = 185−186 °C; Rf = 0.54 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3): δ 8.74 (br s, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.43−7.37 (m, 3H), 7.24−7.18 (m, 2H), 7.15−7.11 (m, 1H), 4.39−4.37 (m, 1H), 4.12−4.04 (m, 2H), 3.35−3.31 (m, 1H), 3.12−3.07 (m, 1H), 1.76 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 172.3, 163.9, 138.1, 137.2, 131.8, 129.0, 126.0, 125.5, 123.0, 120.3, 119.6, 119.3, 111.8, 107.3, 61.4, 50.8, 40.4, 26.7, 24.4, 14.2. IR (KBr, cm−1): υ 3340, 2980, 2269, 1695, 1497, 1367, 1319, 1284, 1779. HRMS (ESI-Q-TOF) m/z calcd for C23H22N3O3+ (M + H)+: 388.1656; found 388.1653. Synthesis of Diethyl 10-Methyl-7-oxo-6,7,8, 9-tetrahydropyrido[1,2-a]indole-6,9-dicarboxylate (11a). To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (50 mg, 0.21 mmol) and 3-methylindole (10a) (32.8 mg, 0.25 mmol) in dry 12180


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CH2Cl2 (1.5 mL, 7 mL/mmol), Sc(OTf)3 (2.0 mg, 0.004 mmol) was added at room temperature and heated to reflux. The reaction mass was maintained at reflux for 3 h. The reaction mass was cooled to room temperature. Rh2(Oct)4 (3.3 mg, 0.004 mmol) was added to the reaction mass at room temperature and maintained at the same temperature for 1 h. Then, the solvent was removed under reduced pressure and the product was isolated by column chromatography using a mixture of ethyl acetate and hexanes. Yield (48 mg, 67%); brown solid; mp = 127− 128 °C; Rf = 0.57 in 1:3 EtOAc/hexanes. 1H NMR (400 MHz, CDCl3) major isomer: δ 7.60−7.56 (m, 1H), 7.23−7.15 (m, 2H), 7.08 (d, J = 7.9, 1H), 5.53 (s, 1H), 4.40 (dd, J = 5.8, 1.9 Hz, 1H), 4.30−4.17 (m, 2H), 4.15−4.05 (m, 2H), 3.20 (dd, J = 16.6, 1.7 Hz, 1H), 2.73 (dd, J = 16.5, 5.7 Hz, 1H), 2.41 (s, 3H), 1.28−1.19 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 196.9, 170.9, 165.1, 135.8, 129.3, 126.9, 122.5, 120.5, 119.4, 109.7, 109.1, 108.4, 65.0, 62.8, 62.1, 39.4, 37.4, 14.0, 8.7. 1H NMR (400 MHz, CDCl3) minor isomer: δ 7.60−7.56 (m, 1H), 7.23−7.15 (m, 2H), 7.08 (d, J = 7.9, 1H), 5.50 (s, 1H), 4.50 (dd, J = 5.5, 2.9 Hz, 1H), 4.30−4.17 (m, 2H), 4.15−4.05 (m, 2H), 3.10 (dd, J = 15.0, 5.6 Hz, 1H), 3.01 (dd, J = 15.0, 2.9 Hz, 1H), 2.36 (s, 3H), 1.28−1.19 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 197.0, 171.2, 165.9, 135.6, 129.4, 126.8, 125.9, 122.7, 120.5, 119.4, 109.6, 109.1, 66.9, 63.1, 62.1, 39.1, 38.7, 14.2, 8.6. IR(KBr, cm−1): υ 2982, 2931, 1738, 1459, 1367, 1335, 1299, 1190, 1020, 746. HRMS (ESI-Q-TOF) m/z calcd for C19H22NO5 (M + H)+: 344.1492; found 344.1492. Diethyl 2-Methoxy-10-methyl-7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6,9-dicarboxylate (11b). To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (60 mg, 0.25 mmol) and 5-methoxy-3methyl-1H-indole (10b) (48 mg, 0.30 mmol) in dry CH2Cl2 (1.8 mL, 7 mL/mmol), Sc(OTf)3 (2.5 mg, 0.005 mmol) was added at room temperature and heated to reflux. The reaction mass was maintained at reflux for 6 h. The reaction mass was cooled to room temperature. Rh2(Oct)4 (3.9 mg, 0.005 mmol) was added to the reaction mass at room temperature and maintained at the same temperature for 2 h. Then, the solvent was removed under reduced pressure and the product was isolated by column chromatography using a mixture of ethyl acetate and hexanes. Yield (60 mg, 65%); brown gum; Rf = 0.42 in 1:3 EtOAc/ hexanes. 1H NMR (400 MHz, CDCl3) major isomer: δ 7.03−6.97 (m, 3H), 5.48 (s, 1H), 4.39 (dd, J = 5.7, 2.0 Hz, 1H), 4.31−4.16 (m, 2H), 4.14−4.03 (m, 2H), 3.87 (s, 3H), 3.18 (dd, J = 16.5, 2.0 Hz, 1H), 2.73 (dd, J = 16.5, 5.7 Hz, 1H), 2.37 (s, 3H), 1.27−1.19 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) major isomer: δ 197.0, 171.2, 165.1, 154.9, 131.0, 129.8, 127.6, 112.5, 109.9, 109.2, 101.6, 65.0, 62.7, 62.1, 56.1, 39.3, 37.5, 14.1, 8.8. 1H NMR (400 MHz, CDCl3) minor isomer: δ 6.87−6.83 (m, 3H), 5.44 (s, 1H), 4.47 (dd, J = 5.8, 2.9 Hz, 1H), 4.31− 4.16 (m, 2H), 4.14−4.03 (m, 2H), 3.86 (s, 3H), 3.09 (dd, J = 15.1, 5.7 Hz, 1H), 2.98 (dd, J = 15.0, 3.0 Hz, 1H), 2.32 (s, 3H), 1.27−1.19 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) minor isomer: δ 197.1, 171.2, 166.0, 154.9, 130.8, 129.9, 126.6, 112.5, 109.9, 109.4, 101.5, 66.9, 63.0, 62.1, 56.0, 39.2, 38.6, 14.2, 8.7. IR(neat, cm−1): υ 3360, 2978, 2931, 1737, 1680, 1620, 1482, 1370, 1236, 1190, 1030, 859, 806. HRMS (ESI-Q-TOF) m/z calcd for C20H24NO6 (M + H)+: 374.1598; found 374.1592.

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Rengarajan Balamurugan: 0000-0002-8373-5736 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank UPE II-UGC, PURSE-DST and SERB (EMR/2017/003142/OC) for financial support. S.S. thanks the Council of Scientific and Industrial Research (CSIR), India for a fellowship.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02127. NMR data of all the prepared compounds with spectra (PDF) X-ray crystallographic data of 3l (CIF) X-ray crystallographic data of 8a (CIF) X-ray crystallographic data of 9a (CIF)

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Annulation of a Highly Functionalized Diazo Building Block with

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