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The synthesis of the central tricyclic core of the isatisine A: harmonious orchestration of [metal]-catalyzed reactions in a sequence
Tetrahedron 70 (2014) 510e516
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
The synthesis of the central tricyclic core of the isatisine A: harmonious orchestration of [metal]-catalyzed reactions in a sequence Pitambar Patel, B. Narendraprasad Reddy, C.V. Ramana * Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 July 2013 Received in revised form 28 October 2013 Accepted 10 November 2013 Available online 15 November 2013
Two sequential metal-catalyzed transformations, involving [In]-catalyzed FriedeleCrafts type addition of spiroaminol carbon to indole C3 followed by [Rh]-catalyzed dehydrogenative cyclization of the resulting g-amino alcohol culminated in the construction of the central tricyclic core isatisine A. The overall strategy employed three easily available starting compounds and delivered the complex tricyclic core in four stepsdwith all four steps being catalytic in nature. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Isatisine A Spiro-3-indolinone Indium chloride FriedeleCrafts reaction Dehydrogenative cyclization Rhodium
1. Introduction As an important indole derivative, pseudoindoxyl [2,2disubstituted indolin-3-one] represents a common structural feature of some of the indole alkaloids.1 The austamide, isatisine A, mersicarpine and notoamide O (Fig. 1) are some of the representative natural products.2 There have been several methods for the synthesis of pseudoindoxyl derivatives, amongst which the addition of C-centered nucleophiles to 2-arylindolone, or to spiro[furan/ pyran-2,20 -indolin]-30 -ones offer a great deal of flexibility in varying the C2-substituents.3,4 Isatisine A, a novel oxidized bis-indole alkaloid, was isolated by Chan and co-workers from the leaves of the Chinese plant Isatis indigotica Fort in 2007.5a The isatisine A acetonide, which was an artifact during the isolation, showed promising HIV-inhibitory activity. The central tricyclic core comprises a 2,2-disubstituted indolin-3-one (pseudoindoxyl) unit flanked with an indole ring at C2 and fused with a g-lactam ring through the N1 and C2. The promising biological activity of isatisine A, especially its unprecedented fused tetracyclic skeletondhas inspired several groups to work on its synthesis. All the reported total syntheses are characterized by methodology and/or strategy level innovations.6 We have recently reported the total synthesis of
* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail address: [email protected] (C.V. Ramana). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.11.026
Fig. 1. Natural products having pseudoindoxyl moiety.
isatisine A.6a In this synthesis, four metal-mediated transformations have been employed in sequence, especially at the final stage that addressed the synthesis of the central tricyclic core of isatisine A. The palladium-catalyzed nitroalkyne cycloisomerization for the synthesis of isatogens, [In]-mediated addition of indole to an isatogen and the palladium-catalyzed nitroalkynol cycloisomerization leading to spiroindolin-3-one derivatives are some of the methods
P. Patel et al. / Tetrahedron 70 (2014) 510e516
that have been developed in the context of this synthesis.7 The construction of the central lactam ring was the final event in our total synthesis. This reaction has been executed via a [Rh]-catalyzed dehydrogenative cyclization of a g-amino alcohol. Although the total synthesis has been reported, the detailed model studies conducted to arrive at the identification of this catalyst and the optimization the reaction conditions have not been disclosed in our previous report. In this manuscript, we describe the model studies that we conducted in dealing with the catalytic dehydrogenative cyclization of g-amino alcohols. As shown in Scheme 1, our model studies are focused on the utilization of a 4,5-dihydro-3H-spiro[furan-2,20 -indolin]-30 -one derivative 1a and a FriedeleCrafts type addition of spiral-aminol carbon to indole C3, followed by a [metal]-catalyzed dehydrogenative cyclization of the resulting g-amino alcohol, which constructs the key pyrrolidinone unit.8e12 Earlier, we have reported the synthesis of tetrahydrofuran/pyran-fused spiroindolin-3-one derivatives involving a novel [Pd]-catalyzed nitroalkynol cycloisomerization.7b Considering our experience with the InCl3catalyzed selective addition of indole C3 to isatogens,7c we reasoned that the same catalyst will serve the current purpose. While this work was in progress, You et al. reported a similar strategy for constructing the central tricyclic core of isatisine A by utilizing chiral phosphoric acid-catalyzed asymmetric FriedeleCrafts alkylation reaction of indoles with racemic spiroindolin-3-ones, followed by ruthenium-catalyzed oxidative cyclization by employing NMO as the oxidant in stoichiometric amounts.13
Scheme 1. Addition of indole to 4,5-dihydro-3H-spiro[furan-2,20 -indolin]-30 -one.
2. Results and discussion With this concept in mind, the known spiroindolin-3-one 1a was treated with indole for the alkylation reaction in the presence of catalytic amounts of InCl3 in different solvents under argon atmosphere. The alkylation of 1a was feasible in the solvents like CH2Cl2, 1,2-dichloroethane (DCE) and acetonitrile (Table 1). In acetone, toluene and THF solvents, there was no reaction. Out of all the solvents, the reaction in acetonitrile was clean and gave the best yields. Furthermore, the reaction was carried out in acetonitrile by varying the amount of InCl3 from catalytic to quantitative, and we observed that this only changed the reaction time. With 1 equiv of InCl3, the reaction was completed in 15 min and with 5 mol % of InCl3, the reaction took nearly 5 h for completion. The next objective was the metal-catalyzed lactamization of the g-amino alcohol 2a.11 Routinely, the formation of amide bond pursued the path of oxidation of alcohol to acid followed by Lewis Table 1 Optimization of the alkylation reaction Entry
InCl3 (mol %)
Solvent
Time
Yield (%)
1 2 3 4 5 6 7 8 9
10 10 10 10 10 5 10 50 100
CH2Cl2 DCE THF Acetone Toluene CH3CN CH3CN CH3CN CH3CN
3h 3h 24 h 24 h 24 h 5h 3h 45 min 15 min
45 37 No reaction No reaction No reaction 70 72 79 78
511
acid or base-mediated cyclization, leading to the lactams, which is also sometimes complicated when the intermediate is heavily functionalized. Therefore, in order to avoid such difficulties, we sketched our plan to install the crucial lactam through a metalcatalyzed dehydrogenative cyclization (Scheme 2).
Scheme 2. Catalyst screening for oxidative lactamization.
The catalytic dehydrogenative inter-/intramolecular condensation of amines and alcohols leading to amides/lactams is one of the contemporary areas that have been addressed mainly by ruthenium and rhodium complexes. For example, RuH2(PPh3)4 has been used for intramolecular lactamization using simple acyclic amino alcohols.14 On the other hand, [Ru(p-cymene)2Cl2]2 and HoveydaeGrubbs first generation catalysts are used for the intermolecular dehydrogenative coupling of primary (aliphatic and aromatic) amines and alcohols.15,16 The [Cp*RhCl2]2 and [Cp*IrCl2]2 have been employed for the cyclization of 2-amino phenethyl alcohols, leading to the benzo-fused lactams.17,18 Table 2 reveals our exploratory experiments related to the dehydrogenative cyclization of the g-amino alcohol 2a, employing the complexes mentioned above. For the initial screening, 5 mol % catalyst has been employed and also 5 mol % base was used wherever required. The solvent of the reaction has been chosen from the earlier reports. The reaction was sluggish with the ruthenium catalysts like RuH2(PPh3)4 (5 mol %) and [Ru(p-cymene)2Cl2]2 (5 mol %), using NaH as base and lactam 3a was obtained in poor yields (35%).14,15 The HoveydaeGrubbs first generation catalyst (5 mol %), and also the Ag-based heterogeneous catalyst (Ag/Al2O3), have been found to not be useful with the current substrate.16,19 The reaction was also facile with the [Cp*IrCl2]2 complex.18 However, product 2a was isolated in poor yields. The best result in terms of efficiency and reaction rate was obtained with [Cp*RhCl2]2 and product 2a was obtained in 55% yield (Table 2, entry 6).17 Increasing the amount of the complex was found to improve the product yield. The best results for the oxidative lactamization of 2a (69%) were obtained when 8 mol % of [Cp*RhCl2]2 was used. The employed conditions involve the heating of the reaction at 100 C in the presence of 8 mol % of the catalyst and 5 mol % of K2CO3 in acetone for 16 h in a screw-capped seal tube. It should be noted that the reaction could not be performed under simple thermal reaction conditions. The structure of the lactam 3a was confirmed by spectral and analytical data.13 Table 2 Optimization of the dehydrogenative cyclization Entry
Catalyst
Base
Solvent
Time (h)
Yield (%)
1 2 3 4 5 6 7
RuH2(PPh3)4 [Ru(p-cymene)2Cl2]2 [Cp*IrCl2]2 First Gen. HoveydaeGrubbs Ag/Al2O3 [Cp*RhCl2]2 [Cp*RhCl2]2 (8 mol %)
d d K2CO3 NaH Cs2CO3 K2CO3 K2CO3
DME CH3CN Toluene Toluene Xylene Acetone Acetone
6 24 25 24 24 12 12
32 36 25 d d 55 69
Table 3 provides the scope of the InCl3-mediated alkylation followed by the Rh(II)-catalyzed oxidative lactamization. With all the spiroindolinones employed, the indole-addition reactions are facile. The addition reactions with 2- and N-methyl indoles, 5-bromo-, 5-
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Table 3 Scope of substrates for alkylation and lactamization Entry Spiroindolin-3-one
Alkylation product
Table 3 (continued ) Entry Spiroindolin-3-one
Alkylation product
Cyclized product
2j (89%)*
3j (59%)
2j’ (76%)
3j’ (47%)
2j’’ (83 %)
3j’’ (56%)
Cyclized product
1
11
1b
2b (79%)
3b (63 %)
1j
2
1c
2c (86%)*
3c (67%)
12
1j 3
1a
2a’ (89%)
3a’ (65%) 13
1j 4 *The
1d
2d (88%)
instability of these compounds in CDCl3 solution has hampered their complete structural characterization.
3d (58 %)
5
1e
2e (89%)
3e (64%)
2f (87%)
3f (65%)
6
1f
nitro and 5-methoxyindoles are also facile. Coming to the [Rh]-catalyzed dehydrogenative cyclization, with both the 3-aminobutanol (entries 1e3) and 4-aminopentanol (entries 4e7) derivatives, the reactions proceeded smoothly and the corresponding g- and d-lactams, respectively, were obtained in very good yields. The bromo, nitro and methoxy substituents present on the indole were found to be intact under these conditions. However, with the 2-(2aminoethoxy)ethan-1-ol derivatives 1g and 1h (entries 8 and 9), the cyclization reaction was sluggish and the corresponding products were obtained in very poor yields along with the isolation of unreacted alcohols in substantial amounts. Increasing the reaction time to 40 h did not lead to improvement in the reaction. Increasing the reaction time or even increasing the catalyst amount to 1 equiv did not improve the yield of products substantially. 3. Conclusion
7
2e’ (86%)
3e’(59%)
2g (77%)
3g (5%) + 2g (52%)
8
1g
9
In summary, we have documented here the details of two metalcatalyzed reactions for the addition of indoles to spiroaminol derivatives, and the subsequent dehydrogenative cyclization of derived u-aminolalcohol derivatives. Taken together with the twostep synthesis of these starting spiroaminol derivatives (both being catalyzed by the [Pd]-complexes), the overall sequence comprises a four-step construction of the central tricyclic core of isatisine A from simple and readily available iodonitrobenzenes and alkynols. It is to be noted that all the four steps are catalytic in nature. Currently the work in the direction of developing a continuous flow version for this sequence is in progress. 4. Experimental section
1h
2h (79%)
3h (3%) + 2h (61%)
10
1i
2i (86%)*
3i (62%)
4.1. General Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in oven-dried glassware. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (100e200 mesh). 1H and 13C NMR spectroscopy measurements were carried out on Bruker AC 200 MHz or Bruker DRX
P. Patel et al. / Tetrahedron 70 (2014) 510e516
400 MHz spectrometers, and TMS was used as the internal standard. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) downfield from TMS and coupling constants (J) are reported in Hertz (Hz). The following abbreviations are used to designate signal multiplicity: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. The multiplicity of 13C NMR signals was assigned with the help of DEPT spectra and the abbreviations used were: s¼singlet, d¼doublet, t¼triplet, q¼quartet, represent C (quaternary), CH, CH2 and CH3, respectively. Mass spectroscopy was carried out on an API QStar Pulsar (Hybrid Quadrupole-TOF LC/MS/MS) spectrometer or UPLC coupled Mass Spectrometer (Waters) and HRMS on 4800 plus MALDI TOF/TOF Applied Biosystem spectrometer. 4.2. General procedure for indole addition To a solution of spiroindolin-3-one 1a (200 mg, 1.06 mmol), indole (185 mg, 1.59 mmol) in CH3CN (10 mL), anhydrous InCl3 (11.6 mg, 5 mol %) was added under argon atmosphere and stirred for 5 h at rt. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to afford 2a (227 mg, 70%). 4.3. Characterization data 4.3.1. 2-(3-Hydroxypropyl)-2-(1H-indol-3-yl)indolin-3-one (2a).13 Yellow solid, mp 130 C, 78% yield; IR (CHCl3): n 3325, 2927, 2220, 1690, 1608, 1526, 1345, 1250, 1120, 1056 cm1. 1H NMR (200 MHz, CD3OD): d 1.33e1.49 (m, 1H), 1.53e1.68 (m, 1H), 2.14e2.43 (m, 2H), 3.53 (t, J¼6.4 Hz, 2H), 6.74 (t, J¼7.3 Hz, 1H), 6.87e6.94 (m, 2H), 7.05 (t, J¼7.2 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J¼8.1 Hz, 1H), 7.42e7.55 (m, 3H) ppm. 13C NMR (50 MHz, CD3OD): d 27.2, 34.0, 62.6, 67.0, 112.1, 112.7, 114.2, 118.6, 119.6, 120.1, 120.6, 122.2, 123.5, 125.2, 125.6, 137.9, 138.6, 162.5, 206.0 ppm. ESI-MS: m/ z 329.3 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O2: 329.1266 ([MþNa]þ); found: 329.1258 ([MþNa]þ). 4.3.2. 2-(3-Hydroxypropyl)-2-(1H-indol-3-yl)-6-methylindolin-3one (2b).13 Yellow solid, mp 145 C, 79% yield; IR (CHCl3): n 3370, 3266, 2990, 2816, 1679, 1611, 1462, 1251, 1149, 933, 744 cm1. 1H NMR (400 MHz, CDCl3): d 1.42e1.49 (m, 1H), 1.60e1.69 (m, 1H), 2.21e2.28 (m, 1H), 2.33e2.40 (m, 1H), 2.93 (s, 3H), 3.56 (d, J¼5.4 Hz, 2H), 6.61 (d, J¼7.8 Hz, 1H), 6.80 (br s, 1H), 6.85 (s, 1H), 6.92 (t, J¼7.3 Hz, 1H), 7.07 (t, J¼7.5 Hz, 1H), 7.37 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼7.5 Hz, 1H), 7.65 (d, J¼8.1 Hz, 1H), 10.19 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 22.4, 28.1, 34.7, 62.7, 70.1, 112.3, 112.7, 115.9, 118.7, 119.6, 120.1, 121.6, 122.2, 123.6, 124.8, 126.4, 138.3, 149.1, 162.5, 202.4 ppm. ESI-MS: m/z 343.15 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O2: 343.1423 ([MþNa]þ), 359.1162 ([MþK]þ); found: 343.1389 ([MþNa]þ), 359.1359 ([MþK]þ). 4.3.3. Methyl 2-(3-hydroxypropyl)-2-(1H-indol-3-yl)-3-oxoindoline6-carboxylate (2c). Yellow liquid, 86% yield; IR (CHCl3): n 3361, 2425, 1683, 1462, 1365, 1215, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization, directly subjected for lactamization. ESI-MS: m/z 403.14 (100%, [MþK]þ). HRMS: calcd for C21H20N2O4: 387.1321 ([MþNa]þ); found: 387.1318 ([MþNa]þ). 4.3.4. 2-(3-Hydroxypropyl)-2-(1-methyl-1H-indol-3-yl)indolin-3one (2a0 ). Yellow liquid, 89% yield; IR (CHCl3): n 3392, 2933, 2879, 1681, 1620, 1478, 1468, 1326, 1100, 1055, 748 cm1. 1H NMR (200 MHz, CDCl3): d 1.42e2.01 (m, 2H), 2.20e2.44 (m, 2H), 3.59 (t, J¼5.9 Hz, 2H), 3.67 (s, 3H), 5.33 (br s, 1H), 6.79e6.9 (m, 2H), 6.97e7.09 (m, 2H), 7.14e7.26 (m, 2H), 7.44e7.51 (m, 2H), 7.63 (d,
513
J¼7.8 Hz, 1H) ppm. 13C NMR (50 MHz, CDCl3): d 26.6, 32.7, 33.6, 62.6, 68.9, 109.5, 112.4, 112.9, 118.9, 119.4, 119.9, 120.5, 121.7, 124.9, 125.3, 127.1, 137.4, 160.7, 203.2 ppm. ESI-MS: m/z 321.1 (100%, [MþH]þ). HRMS: calcd for C20H20N2O2: 321.1603 ([MþH]þ), 343.1422 ([MþNa]þ); found: 321.1595 ([MþH]þ), 343.1418 ([MþNa]þ). 4.3.5. 2-(4-Hydroxybutyl)-2-(1H-indol-3-yl)-6-methylindolin-3-one (2d). Yellow liquid, 88% yield; IR (CHCl3): n 3370, 3266, 3058, 2908, 2816, 1698, 1651, 1611, 1462, 1251, 1149, 857, 767 cm1. 1H NMR (500 MHz, CDCl3): d 2.01e2.06 (m, 1H), 2.17e2.23 (m, 1H), 2.25e2.33 (m, 2H), 2.38 (s, 3H), 3.40 (t, J¼6.4 Hz, 2H), 4.60 (br s, 2H), 6.59 (d, J¼8.1 Hz, 1H), 6.78 (s, 1H), 6.86 (t, J¼7.6 Hz, 1H), 7.03 (t, J¼7.4 Hz, 1H), 7.27 (s, 1H), 7.31 (d, J¼8.2 Hz, 1H), 7.39 (d, J¼7.9 Hz, 1H), 7.42 (br d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 22.6, 23.7, 33.9, 38.0, 62.8, 71.1, 112.4, 112.7, 114.7, 115.3, 118.3, 119.9, 120.6, 121.2, 122.5, 123.9, 125.2, 126.5, 138.7, 140.2, 151.2, 164.1, 206.2 ppm. ESI-MS: m/z 357.2 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O2: 357.1579 ([MþNa]þ); found: 357.1571 ([MþNa]þ). 4.3.6. Methyl 2-(4-hydroxybutyl)-2-(1H-indol-3-yl)-3-oxoindoline6-carboxylate (2e). Yellow solid, mp 167 C, 89% yield; IR (CHCl3): n 3358, 2925, 2854, 1916, 1710, 1622, 1458, 1282, 1089, 750 cm1. 1H NMR (200 MHz, CDCl3): d 1.47e1.60 (m, 2H), 2.23e2.44 (m, 2H), 3.50 (t, J¼6.0 Hz, 2H), 3.93 (s, 3H), 6.94 (ddd, J¼1.0, 7.1, 7.9 Hz, 1H), 7.04e7.12 (m, 1H), 7.21 (br s, 1H), 7.34e7.44 (m, 3H), 7.69 (d, J¼8.1 Hz, 1H), 7.65 (d, J¼7.1 Hz, 1H), 7.67 (s, 1H), 10.3 (br s, 1H) ppm. 13 C NMR (50 MHz, CDCl3): d 21.1, 33.9, 37.9, 52.7, 62.2, 71.0, 112.4, 113.8, 115.1, 118.7, 119.8, 121.4, 122.3, 123.6, 123.7, 125.1, 126.2, 138.3, 138.5, 161.5, 167.0, 206.4 ppm. ESI-MS: m/z 401.1 (100%, [MþNa]þ). HRMS: calcd for C22H22N2O4: 401.1478 ([MþNa]þ), 417.1217 ([MþK]þ); found: 401.1479 ([MþNa]þ), 417.1198 ([MþK]þ). 4.3.7. 2-(4-Hydroxybutyl)-2-(2-methyl-1H-indol-3-yl)indolin-3-one (2f). Yellow liquid, 87% yield; IR (CHCl3): n 3393, 3012, 2932, 1682, 1619, 1462, 1323, 1216, 1020, 755 cm1. 1H NMR (500 MHz, CDCl3): d 1.26e1.31 (m, 2H), 1.55e1.60 (m, 2H), 2.23e2.29 (m, 1H), 2.44e2.53 (m, 1H), 2.45 (s, 3H), 3.59 (t, J¼6.3 Hz, 2H), 5.12 (br s, 1H), 6.81e6.84 (m, 1H), 6.88 (d, J¼8.2 Hz, 1H), 7.0e7.03 (m, 1H), 7.06e7.09 (m, 1H), 7.22 (d, J¼7.9 Hz, 1H), 7.47 (ddd, J¼1.2, 7.2, 8.2 Hz, 1H), 7.63 (br d, J¼7.6 Hz, 1H), 7.67 (d, J¼8.0 Hz, 1H), 7.82 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.9, 20.1, 32.8, 37.4, 62.5, 70.7, 109.2, 110.5, 112.2, 118.9, 119.7, 119.9, 121.1, 121.3, 125.0, 127.4, 131.8, 134.9, 137.3, 160.2, 203.4 ppm. ESI-MS: m/z 357.11 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O2: 357.1579 ([MþNa]þ), found: 357.1570 ([MþNa]þ). 4.3.8. Methyl 2-(4-hydroxybutyl)-2-(2-methyl-1H-indol-3-yl)-3oxoindoline-6-carboxylate (2e0 ). Yellow liquid, 86% yield; IR (CHCl3): n 3368, 2929, 2857, 1707, 1682, 1622, 1458, 1322, 1290, 1090, 752 cm1. 1H NMR (500 MHz, CDCl3): d 1.35e1.40 (m, 2H), 1.53e1.58 (m, 2H), 2.56 (s, 3H), 3.50 (t, J¼6.3 Hz, 2H), 3.93 (s, 3H), 6.91 (ddd, J¼1.1, 7.1, 8.0 Hz, 1H), 6.99 (ddd, J¼1.1, 7.1, 8.0 Hz, 1H), 7.21 (s, 1H), 7.26 (d, J¼7.9 Hz, 1H), 7.34e7.36 (m, 1H), 7.57 (d, J¼8.2 Hz, 2H), 7.67 (s, 1H), 7.81 (d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.8, 21.4, 33.9, 38.4, 52.7, 62.3, 72.3, 108.8, 111.3, 113.5, 118.6, 119.6, 121.3, 121.5, 123.9, 125.2, 128.4, 133.4, 136.4, 138.6, 160.8, 167.1, 203.4 ppm. ESI-MS: m/z 415.06 (100%, [MþH]þ). HRMS: calcd for: C23H24N2O4: 415.1634 ([MþNa]þ), 431.1373 ([MþK]þ); found: 415.1603 ([MþNa]þ), 431.1536 ([MþK]þ). 4.3.9. 2-((2-Hydroxyethoxy)methyl)-2-(1H-indol-3-yl)indolin-3-one (2g). Yellow liquid, 77% yield; IR (CHCl3): n 3345, 2925, 2855, 1701, 1614, 1492, 1459, 1246, 1120, 1064, 748 cm1. 1H NMR (500 MHz, CDCl3): d 3.06e3.65 (m, 4H), 4.04 (d, J¼9.8 Hz, 1H), 4.21 (d, J¼9.8 Hz, 1H), 5.36 (br s, 1H), 6.88 (t, J¼7.3 Hz, 1H), 6.96 (d, J¼8.2 Hz, 1H), 7.06 (t, J¼7.6 Hz, 1H), 7.17 (t, J¼7.3 Hz, 1H), 7.29 (s, 1H), 7.35 (d, J¼8.2 Hz, 1H), 7.50 (t, J¼7.8 Hz, 1H), 7.58 (d, J¼8.2 Hz, 1H), 7.67
514
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(d, J¼7.8 Hz, 1H), 8.19 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 61.6, 69.9, 72.9, 74.6, 111.6, 111.9, 113.1, 113.9, 119.6, 119.8, 120.2, 121.0, 122.5, 122.9, 125.0, 125.3, 125.8, 128.7, 137.6, 146.4, 161.1, 204.8 ppm. ESI-MS: m/z 359.1 (100%, [MþK]þ). HRMS: calcd for C19H18N2O3: 345.1215 ([MþNa]þ), found: 345.1208 ([MþNa]þ).
(4.5 mg, 0.032 mmol) and acetone (8 mL) were placed and the cap was sealed. The mixture was stirred at 120 C (oil bath temp) for 12 h. After evaporation of the solvent, the products were isolated by column chromatography of the residue (using ethylacetate and petroleum ether as eluent) to afford 3a (138 mg, 69%).
4.3.10. 2-((2-Hydroxyethoxy)methyl)-2-(1H-indol-3-yl)-6methylindolin-3-one (2h). Yellow liquid, 79% yield; IR (CHCl3): n 3393, 3361, 2925, 1680, 1621, 1462, 1365, 1115, 745 cm1. 1H NMR (500 MHz, CDCl3): d NMR (500 MHz, CDCl3): d 2.37 (s, 3H), 3.58e3.63 (m, 4H), 4.00 (d, J¼9.8 Hz, 1H), 4.19 (d, J¼9.8 Hz, 1H), 5.30 (br s, 1H), 6.70 (d, J¼7.9 Hz, 1H), 6.73 (s, 1H), 7.04 (t, J¼7.6 Hz, 1H), 7.15 (t, J¼7.3 Hz, 1H), 7.22 (s, 1H), 7.32 (d, J¼7.9 Hz, 1H), 7.53 (t, J¼7.9 Hz, 1H), 7.55 (d, J¼7.9 Hz, 1H), 8.26 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 22.5, 61.5, 70.0, 72.9, 74.5, 111.7, 111.9, 113.1, 118.7, 119.7, 120.1, 121.4, 122.4, 123.1, 124.7, 136.6, 149.3, 161.6, 200.7 ppm. ESI-MS: m/z 359.3 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O3: 337.1552 ([MþH]þ) 359.1372 ([MþNa]þ), found: 337.1549 ([MþH]þ), 359.1253 ([MþNa]þ).
4.4.1. 9a-(1H-Indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a]indole3,9(2H)-dione (3a). Yellow liquid, 69% yield; IR (CHCl3): n 3342, 2926, 2854, 1727, 1675, 1608, 1458, 1378, 1291, 1086, 745 cm1. 1H NMR (500 MHz, CDCl3): d 2.49e2.63 (m, 2H), 2.86 (dd, J¼7.9, 11.9 Hz, 1H), 2.90e2.97 (m, 1H), 7.15e7.21 (m, 4H), 7.33 (d, J¼7.6 Hz, 1H), 7.66 (dt, J¼1.5, 8.2 Hz, 1H), 7.96 (d, J¼8.2 Hz, 1H), 8.00 (d, J¼7.6 Hz, 1H), 8.53 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.2, 34.6, 73.9, 111.7, 112.2, 116.4, 120.3, 120.6, 122.1, 122.7, 124.5, 124.9, 125.1, 125.4, 136.8, 137.3, 149.3, 173.8, 198.8 ppm. ESI-MS: m/z 325.4 (100%, [MþNa]þ). HRMS: calcd for C19H14N2O2: 303.1133 ([MþH]þ), 325.0953 ([MþNa]þ); found: 303.1149 ([MþH]þ), 325.0923 ([MþNa]þ).
4.3.11. 2 -(5-Bromo-1H-indol-3-yl)-2-(4-hydroxybutyl)-6methoxyindolin-3-one (2i). Yellow liquid, 86% yield; IR (CHCl3): n 3061, 2425, 1683, 1462, 1365, 1115, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization. ESI-MS: m/z 450.81 (100%, [MþNa]þ). HRMS: calcd for C21H22BrN2O3: 429.0808 ([MþH]þ), 451.0628 ([MþNa]þ); found: 429.0807 ([MþH]þ), 451.0623 ([MþNa]þ). 4.3.12. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-methoxy-2-methyl1H-indol-3-yl)indolin-3-one (2j). Yellow liquid, 89% yield; IR (CHCl3): n 3061, 2425, 1653, 1422, 1365, 1131, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization. ESI-MS: m/z 403.02 (100%, [MþNa]þ). HRMS: calcd for C22H24N2O4: 403.1628 ([MþNa]þ); found: 403.1625 ([MþNa]þ). 4.3.13. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-methoxy-1H-indol-3yl)indolin-3-one (2j0 ). Brown liquid, 76% yield; IR (CHCl3): n 3426, 2999, 2360, 1630, 1485, 1368, 1216, 1053, 1028, 748, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 2.08e2.22 (m, 3H), 2.23e2.44 (m, 1H), 3.42 (br s, 2H), 3.56 (s, 3H), 3.79 (s, 3H), 4.18 (s, 1H) 6.22 (dd, J¼8.6, 1.9 Hz, 1H), 6.33 (d, J¼1.9 Hz, 1H), 6.60 (dd, J¼8.7, 2.3 Hz, 1H), 6.85 (d, J¼2.3 Hz, 1H), 7.14 (d, J¼8.8 Hz, 1H), 7.18 (d, J¼2.1 Hz, 1H), 7.28 (s, 1H), 10.4 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSOd6): d 25.5, 31.7, 53.7, 54.3, 60.3, 67.9, 92.1, 100.9, 106.0, 109.7, 110.7, 111.7, 112.7, 122.2, 124.0, 124.1, 130.7, 151.6, 162.2, 166.2, 199.3 ppm. ESI-MS: m/z 388.98 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O4: 389.1472 ([MþNa]þ); found: 389.1468 ([MþNa]þ). 4.3.14. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-nitro-1H-indol-3-yl) indolin-3-one (2j00 ). Yellow gum, 83% yield; IR (CHCl3): n 3019, 2400, 2879,1612,1476,1325,1215, 758, 669 cm1. 1H NMR (200 MHz, CDCl3/ DMSO-d6): d 1.01e1.13 (m, 2H), 1.58e1.89 (m, 2H), 3.08 (br s, 2H), 3.41 (s, 3H), 3.79 (br s,1H), 5.86 (dd, J¼8.6, 2.0 Hz,1H), 5.97 (d, J¼1.9 Hz,1H), 6.93 (d, J¼2.9 Hz,1H), 6.96 (s,1H), 7.03 (d, J¼2.0 Hz,1H), 7.50 (dd, J¼9.1, 2.3 Hz,1H), 8.32 (d, J¼2.0 Hz,1H) 10.84 (s,1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 27.2, 34.4, 55.7, 61.8, 69.6, 94.0, 108.3, 111.9, 112.7, 116.9, 117.7, 118.5, 124.5, 126.1, 126.3, 140.5, 141.0, 163.7, 168.1, 200.4 ppm. ESI-MS: m/z 403.86 (100%, [MþNa]þ). HRMS: calcd for C20H20N3O5: 382.1397 ([MþH]þ), 404.1217 ([MþNa]þ); found: 382.1396 ([MþH]þ), 404.1212 ([MþNa]þ). 4.4. General procedure for dehydrogenative lactam synthesis Under an atmosphere of argon in a glass sealed tube, compound 2a (200 mg, 0.653 mmol), [Cp*RhCl2]2 (32 mg, 0.052 mmol), K2CO3
4.4.2. 9a-(1H-Indol-3-yl)-6-methyl-1,9a-dihydro-3H-pyrrolo[1,2-a] indole-3,9(2H)-dione (3b). Yellow liquid, 63% yield; IR (CHCl3): n 3368, 2955, 2856, 1707, 1682, 1608, 1471, 1361, 1254, 745 cm1. 1H NMR (500 MHz, (CD3)2CO): d 2.57 (dd, J¼7.6, 15.9 Hz, 1H), 2.52 (s, 3H), 2.63e2.69 (m, 1H), 2.83 (dd, J¼7.3, 11.6 Hz, 1H), 2.89e2.96 (m, 1H), 7.06 (ddd, J¼0.9, 7.0, 7.9 Hz, 1H), 7.06 (ddd, J¼0.9, 7.0, 7.9 Hz, 1H), 7.42e7.44 (m, 2H), 7.51 (d, J¼7.9 Hz, 1H), 7.76 (s, 1H), 7.87 (d, J¼7.9 Hz, 1H) ppm. 13C NMR (125 MHz, (CD3)2CO): d 22.4, 29.8, 35.1, 74.9, 112.7, 113.2, 120.2, 122.8, 123.6, 123.6, 125.4, 125.8, 126.8, 138.8, 149.2, 151.3, 174.2, 199.6 ppm. ESI-MS: m/z 339.05 (100%, [MþNa]þ). HRMS: calcd for C20H16N2O2: 317.1290 ([MþH]þ), 339.111 ([MþNa]þ); found: 317.1288 ([MþH]þ), 339.1113 ([MþNa]þ). 4.4.3. Methyl 9a-(1H-indol-3-yl)-3,9-dioxo-2,3,9,9a-tetrahydro-1Hpyrrolo[1,2-a]indole-6-carboxylate (3c). Yellow solid, mp 138 C, 67% yield; IR (CHCl3): n 3358, 2952, 1726, 1675, 1608, 1430, 1380, 1294, 1087, 746 cm1. 1H NMR (400 MHz, CDCl3): d 1.88e2.01 (m, 2H), 2.49e2.64 (m, 2H), 3.94 (s, 3H), 7.10e7.15 (m, 2H), 7.19 (dt, J¼1.1, 8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz, 1H), 7.7 (d, J¼8.0 Hz, 1H), 7.84e7.88 (m, 2H), 8.42 (br s, 1H), 9.15 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 28.3, 31.4, 52.7, 71.7, 111.7, 111.9, 119.1, 120.5, 122.9, 123.0, 124.0, 124.7, 125.2, 125.9, 137.2, 137.6, 150.9, 166.1, 169.8, 197.3 ppm. ESI-MS: m/z 383.05 (100%, [MþNa]þ). HRMS: calcd for C21H16N2O4: 383.1008 ([MþNa]þ); found: 383.1002 ([MþNa]þ). 4.4.4. 9a-(1-Methyl-1H-indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a] indole-3,9(2H)-dione (3a0 ). Yellow liquid, 65% yield; IR (CHCl3): n 3379, 3019, 2953, 1720, 1705, 1614, 1578, 1438, 1292, 1214, 754 cm1. 1 H NMR (200 MHz, CDCl3): d 2.50e2.63 (m, 2H), 2.83e2.87 (m, 1H), 2.93e3.0 (m, 1H), 3.70 (s, 3H), 7.18 (ddd, J¼1.2, 6.7, 7.9 Hz, 1H), 7.22 (dt, J¼0.8, 7.6 Hz, 1H), 7.26e7.30 (m, 1H), 7.63 (d, J¼7.6 Hz, 1H), 7.68 (ddd, J¼1.2, 7.5, 8.2 Hz, 1H), 7.97 (d, J¼8.2 Hz, 1H), 7.98 (d, J¼7.9 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.4, 32.9, 34.7, 74.0, 109.7, 110.6, 116.5, 120.0, 120.8, 122.4, 125.0, 125.1, 125.5, 126.6, 136.8, 138.0, 149.3, 173.8, 198.7 ppm. ESI-MS: m/z 339.3 (100%, [MþH]þ). HRMS: calcd for C20H16N2O2: 339.1109 ([MþNa]þ); found: 339.1103 ([MþNa]þ). 4.4.5. 9a-(1H-Indol-3-yl)-3-methyl-7,8,9,9a-tetrahydropyrido[1,2-a] indole-6,10-dione (3d). Off white solid, mp 112 C, 58% yield; IR (CHCl3): n 3422, 3276, 2927, 2834, 1909, 1648, 1603, 1457, 1424, 1377, 1024, 742 cm1. 1H NMR (400 MHz, (CD3)2CO): d 1.83e2.04 (m, 4H), 2.46e2.50 (m, 2H), 2.52 (s, 3H), 7.01 (d, J¼7.5 Hz, 1H), 7.10e7.14 (m, 2H), 7.34 (d, J¼2.3 Hz, 1H), 7.42 (d, J¼8.2 Hz, 1H), 7.55 (d, J¼7.8 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H), 8.43 (s, 1H), 10.47 (br s, 1H) ppm. 13C NMR (100 MHz, (CD3)2CO): d 18.0, 22.6, 28.8, 31.9,
P. Patel et al. / Tetrahedron 70 (2014) 510e516
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72.1, 112.8, 118.9, 120.3, 120.8, 121.1, 122.7, 124.5, 124.6, 124.9, 125.3, 126.5, 138.5, 149.4, 152.9, 169.9, 197.9 ppm. ESI-MS: m/z 353.04 (100%, [MþNa]þ). HRMS: calcd for C21H18N2O2: 353.1266 ([MþNa]þ); found: 353.1246 ([MþNa]þ).
(125 MHz, CDCl3): d 22.7, 66.8, 67.7, 69.9, 111.6, 111.7, 118.6, 120.3, 120.5, 120.6, 122.8, 123.2, 124.3, 124.7, 127.0, 137.0, 149.4, 151.3, 166.2, 194.7 ppm. ESI-MS: m/z 355.1 (100%, [MþNa]þ). HRMS: calcd for C20H16N2O3: 355.1059 ([MþNa]þ); found: 355.1041 ([MþNa]þ).
4.4.6. Methyl 9a-(1H-indol-3-yl)-6,10-dioxo-6,7,8,9,9a,10hexahydropyrido[1,2-a]indole-3-carboxylate (3e). Yellow solid, mp 87 C, 64% yield; IR (CHCl3): n 3379, 3019, 2953, 1720, 1705, 1614, 1578, 1438, 1292, 1214, 754 cm1. 1H NMR (200 MHz, CDCl3): d 2.53e2.71 (m, 4H), 2.86e2.99 (m, 2H), 3.98 (s, 3H), 7.26e7.20 (m, 3H), 7.41e7.36 (m, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.9 (dd, J¼8.0 Hz, 1H), 7.99e8.03 (m, 1H), 8.38 (br s, 1H), 8.59 (s, 1H) ppm. 13C NMR (50 MHz, (CD3)2CO): d 21.1, 39.0, 38.0, 52.8, 71.1, 112.5, 113.8, 115.2, 118.8, 119.8, 121.4, 122.4, 123.6, 123.8, 125.2, 126.3, 138.4, 138.6, 161.6, 167.1, 203.2 ppm. ESI-MS: m/z 397.1 (100%, [MþNa]þ). HRMS: calcd for C22H18N2O4: 397.1164 ([MþNa]þ); found: 397.1127 ([MþNa]þ).
4.4.11. 9a-(5-Bromo-1H-indol-3-yl)-3-methoxy-7,8,9,9a-tetrahydropyrido[1,2-a]indole-6,10-dione (3i). Yellow solid, mp 123 C, 62% yield; IR (CHCl3): n 3392, 2998, 2400, 1681, 1619, 1496, 1216, 1059, 1010, 758, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.82e1.97 (m, 3H), 2.38 (t, J¼7.4 Hz, 2H), 2.75e2.84 (m, 1H), 3.86 (s, 3H), 6.74 (dd, J¼8.6, 2.3 Hz, 1H), 7.10 (dd, J¼8.67, 1.9 Hz, 1H), 7.24e7.29 (m, 2H), 7.47 (d, J¼8.6 Hz, 1H), 7.78 (d, J¼1.6 Hz, 1H), 8.00 (d, J¼2.3 Hz, 1H), 11.10 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/ DMSO-d6): d 17.0, 27.9, 31.0, 55.7, 71.3, 101.9, 111.8, 112.2, 113.9, 115.0, 122.6, 124.3, 125.3, 125.8, 125.9, 136.3, 153.7, 167.2, 169.3, 195.5 ppm. ESI-MS: m/z 446.93 (100%, [MþNa]þ). HRMS: calcd for C21H18BrN2O3: 425.0495 ([MþH]þ), 447.0315 ([MþNa]þ); found: 425.0495 ([MþH]þ), 447.0313 ([MþNa]þ).
4.4.7. 9a-(2-Methyl-1H-indol-3-yl)-7,8,9,9a-tetrahydropyrido[1,2-a] indole-6,10-dione (3f). Yellow liquid, 65% yield; IR (CHCl3): n 3334, 2956, 2927, 1726, 1682, 1619, 1462, 1378, 1293, 1123, 743 cm1. 1H NMR (500 MHz, CDCl3): d 1.77e1.88 (m, 2H), 1.90e1.96 (m, 1H), 2.38 (s, 3H), 2.53 (t, J¼6.9 Hz, 2H), 3.17e3.21 (m, 1H), 7.04e7.1 (m, 2H), 7.19e7.23 (m, 2H), 7.68e7.72 (m, 2H), 7.84 (d, J¼6.2 Hz, 1H), 8.14 (s, 1H), 8.60 (d, J¼8.4 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 13.9, 17.2, 28.7, 31.5, 71.7, 105.6, 110.5, 118.3, 120.1, 120.2, 121.6, 123.2, 124.7, 124.8, 126.3, 132.7, 135.1, 137.0, 151.0, 170.1, 197.8 ppm. ESIMS: m/z 353.02 (100%, [MþNa]þ). HRMS: calcd for C21H18N2O2: 331.1446 ([MþH]þ), 353.0693 ([MþNa]þ); found: 331.1458 ([MþH]þ), 353.1085 ([MþNa]þ). 4.4.8. Methyl 9a-(2-methyl-1H-indol-3-yl)-6,10-dioxo-6,7,8,9,9a,10hexahydropyrido [1,2-a]indole-3-carboxylate (3e0 ). Yellow liquid, 59% yield; IR (CHCl3): n 3325, 2927, 2220, 1754, 1608, 1526, 1345, 1250, 1120, 1056 cm1. 1H NMR (500 MHz, CDCl3): d 1.79e1.86 (m, 2H), 1.88e1.97 (m, 2H), 2.39 (s, 3H), 2.55e2.58 (m, 2H), 3.97 (s, 3H), 7.07e7.03 (m, 2H), 7.22e7.24 (m, 1H), 7.74 (d, J¼7.9 Hz, 1H), 7.83 (br s, 1H), 7.89 (dd, J¼1.2, 7.9 Hz, 1H), 7.79 (s, 1H), 9.20 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.1, 17.2, 28.7, 31.6, 52.7, 72.3, 105.2, 110.6, 119.3, 120.1, 120.5, 121.8, 124.7, 125.9, 126.2, 126.4, 132.8, 135.1, 137.6, 150.8, 166.1, 169.9, 197.1 ppm. ESI-MS: m/z 411.07 (100%, [MþNa]þ). HRMS: calcd for C23H20N2O4: 388.1423 ([M]þ), 411.1321 ([MþNa]þ); found: 388.1424 ([M]þ), 411.1308 ([MþNa]þ). 4.4.9. 10a-(1H-Indol-3-yl)-1,10a-dihydro-10H-[1,4]oxazino[4,3-a]indole-4,10(3H)-dione (3g). Yellow liquid, 5% yield; IR (CHCl3): n 3452, 2924, 1716, 1657, 1599, 1458, 1378, 1124, 856 cm1. 1H NMR (500 MHz, CDCl3): d 3.95 (d, J¼11.3 Hz, 1H), 4.30 (d, J¼17.4 Hz, 1H), 4.43 (d, J¼17.4 Hz, 1H), 4.92 (d, J¼11.3 Hz, 1H), 7.14 (dt, J¼0.9, 7.0 Hz, 1H), 7.19 (dt, J¼1.2, 8.2 Hz, 1H), 7.23 (d, J¼2.7 Hz, 1H), 7.28 (dt, J¼0.7, 7.2 Hz, 1H), 7.34 (d, J¼8.2 Hz, 1H), 7.69e7.75 (m, 2H), 7.85 (d, J¼8.0 Hz, 1H), 8.26 (br s, 1H), 8.47 (d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 66.9, 67.6, 69.7, 111.3, 111.8, 118.4, 120.3, 120.7, 122.7, 122.9, 123.3, 124.2, 125.0, 125.7, 137.0, 137.3, 150.9, 166.1, 195.2 ppm. ESI-MS: m/z 319.1 (100%, [MþH]þ). HRMS: calcd for C19H14N2O3: 319.1082 ([MþH]þ), 341.0902 ([MþNa]þ); found: 319.3093 ([MþH]þ), 341.0873 ([MþNa]þ). 4.4.10. 10a-(1H-Indol-3-yl)-7-methyl-1,10a-dihydro-10H-[1,4]oxazino[4,3-a]indole-4,10(3H)-dione (3h). Yellow liquid, 3% yield; IR (CHCl3): n 3378, 2972, 2928, 2858, 1719, 1699, 1619, 1458, 1425, 1113, 823, 744 cm1. 1H NMR (500 MHz, CDCl3): d 2.51 (s, 3H), 3.93 (d, J¼11.6 Hz, 1H), 4.28 (d, J¼17.4 Hz, 1H), 4.41 (d, J¼17.4 Hz, 1H), 4.89 (d, J¼11.6 Hz, 1H), 7.10 (d, J¼7.9 Hz, 1H), 7.11e7.14 (m, 1H), 7.18 (dt, J¼0.9, 7.9 Hz, 1H), 7.23 (d, J¼2.7 Hz, 1H), 7.33 (d, J¼7.9 Hz, 1H), 7.59 (d, J¼7.6 Hz, 1H), 7.82 (d, J¼8.2 Hz, 1H), 8.29 (br s, 2H) ppm. 13C NMR
4.4.12. 3-Methoxy-9a-(5-methoxy-2-methyl-1H-indol-3-yl)7,8,9,9a-tetrahydropyrido [1,2-a]indole-6,10-dione (3j). Off white solid, mp 197 C, 59% yield; IR (CHCl3): n 3424, 2998, 2360, 1630, 1478, 1368, 1216, 1053, 1028, 758, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.47 (s, 3H), 1.59e1.64 (m, 2H), 1.84e1.89 (m, 2H), 2.86 (s, 3H), 3.03 (s, 3H), 5.73 (d, J¼8.2 Hz, 1H), 5.89 (d, J¼6.4 Hz, 1H), 6.22 (d, J¼7.8 Hz, 1H), 6.49 (s, 1H), 6.61 (d, J¼8.2 Hz, 1H), 9.92 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 11.5, 27.6, 32.7, 53.4, 54.2, 72.9, 98.0, 100.2, 102.9, 108.2, 109.5, 110.5, 116.7, 124.7, 128.4, 131.9, 149.0, 151.3, 164.7, 170.8, 194.5 ppm. ESIMS: m/z 398.9 (100%, [MþNa]þ). HRMS: calcd for C22H21N2O4: 377.1496 ([MþH]þ), 399.1315 ([MþNa]þ); found: 377.1492 ([MþH]þ), 399.1311 ([MþNa]þ). 4.4.13. 3-Methoxy-9a-(5-methoxy-1H-indol-3-yl)-7,8,9,9a-tetrahydropyrido[1,2-a]indole-6,10-dione (3j0 ). Brown-red liquid, 47% yield; IR (CHCl3): n 3466, 3019, 2400, 1704, 1603, 1486, 1363, 1215, 757, 627 cm1. 1H NMR (200 MHz, CDCl3): d 2.48e2.68 (m, 2H), 2.78e2.94 (m, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 6.73 (dd, J¼8.6, 2.3 Hz, 1H), 6.85 (dd, J¼8.7, 2.4 Hz, 1H), 7.20 (d, J¼2.5 Hz, 1H), 7.44 (d, J¼2.0, 1H), 7.53 (d, J¼8.6 Hz, 1H), 8.20 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.3, 34.8, 55.8, 56.1, 74.5, 100.1, 102.2, 112.3, 112.7, 113.3, 113.5, 117.7, 122.3, 125.1, 126.8, 132.3, 151.9, 154.4, 167.2, 174.0, 197.2 ppm. ESI-MS: m/z 384.96 (100%, [MþNa]þ); HRMS: calcd for C21H19N2O4: 363.1339 ([MþH]þ), 385.1159 ([MþNa]þ); found: 363.1336 ([MþH]þ), 385.1155 ([MþNa]þ). 4.4.14. 6-Methoxy-9a-(5-nitro-1H-indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a]indole-3,9(2H)-dione (3j00 ). Yellow liquid, 56% yield; IR (CHCl3): n 3020, 2400, 1603, 1523, 1423, 1215, 928, 762, 669 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.84e1.93 (m, 3H), 2.02e2.10 (m, 1H), 3.22 (s, 3H), 6.03 (dd, J¼8.6, 2.1 Hz, 1H), 6.68e6.70 (m, 2H), 6.74 (d, J¼7.4 Hz, 1H), 6.80 (d, J¼1.8 Hz, 1H), 7.29 (d, J¼9.1, 2.1 Hz, 1H), 8.17 (d, J¼2.0 Hz, 1H), 10.65 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 28.8, 33.6, 55.2, 73.1, 99.5, 111.3, 112.4, 113.8, 116.2, 116.4, 117.0, 122.9, 124.9, 125.7, 139.9, 140.4, 151.2, 166.4, 172.7, 195.8 ppm. ESI-MS: m/z 399.96 (100%, [MþNa]þ). HRMS: calcd for C20H16N3O5: 378.1084 ([MþH]þ), 400.0904 ([MþNa]þ); found: 378.1078 ([MþH]þ), 400.0897 ([MþNa]þ). Acknowledgements The authors would like to acknowledge the CSIR (India) for providing the financial support for this project under ORIGIN program of 12FYP (CSC0108). P.P. thanks UGC (New Delhi) and B.N.R. thanks CSIR (New Delhi) for the financial assistance in the form of Research Fellowships.
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Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.026.
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The synthesis of the central tricyclic core of the isatisine A: harmonious orchestration of [metal]-catalyzed reactions in a sequence Pitambar Patel, B. Narendraprasad Reddy, C.V. Ramana * Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 July 2013 Received in revised form 28 October 2013 Accepted 10 November 2013 Available online 15 November 2013
Two sequential metal-catalyzed transformations, involving [In]-catalyzed FriedeleCrafts type addition of spiroaminol carbon to indole C3 followed by [Rh]-catalyzed dehydrogenative cyclization of the resulting g-amino alcohol culminated in the construction of the central tricyclic core isatisine A. The overall strategy employed three easily available starting compounds and delivered the complex tricyclic core in four stepsdwith all four steps being catalytic in nature. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Isatisine A Spiro-3-indolinone Indium chloride FriedeleCrafts reaction Dehydrogenative cyclization Rhodium
1. Introduction As an important indole derivative, pseudoindoxyl [2,2disubstituted indolin-3-one] represents a common structural feature of some of the indole alkaloids.1 The austamide, isatisine A, mersicarpine and notoamide O (Fig. 1) are some of the representative natural products.2 There have been several methods for the synthesis of pseudoindoxyl derivatives, amongst which the addition of C-centered nucleophiles to 2-arylindolone, or to spiro[furan/ pyran-2,20 -indolin]-30 -ones offer a great deal of flexibility in varying the C2-substituents.3,4 Isatisine A, a novel oxidized bis-indole alkaloid, was isolated by Chan and co-workers from the leaves of the Chinese plant Isatis indigotica Fort in 2007.5a The isatisine A acetonide, which was an artifact during the isolation, showed promising HIV-inhibitory activity. The central tricyclic core comprises a 2,2-disubstituted indolin-3-one (pseudoindoxyl) unit flanked with an indole ring at C2 and fused with a g-lactam ring through the N1 and C2. The promising biological activity of isatisine A, especially its unprecedented fused tetracyclic skeletondhas inspired several groups to work on its synthesis. All the reported total syntheses are characterized by methodology and/or strategy level innovations.6 We have recently reported the total synthesis of
* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail address: [email protected] (C.V. Ramana). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.11.026
Fig. 1. Natural products having pseudoindoxyl moiety.
isatisine A.6a In this synthesis, four metal-mediated transformations have been employed in sequence, especially at the final stage that addressed the synthesis of the central tricyclic core of isatisine A. The palladium-catalyzed nitroalkyne cycloisomerization for the synthesis of isatogens, [In]-mediated addition of indole to an isatogen and the palladium-catalyzed nitroalkynol cycloisomerization leading to spiroindolin-3-one derivatives are some of the methods
P. Patel et al. / Tetrahedron 70 (2014) 510e516
that have been developed in the context of this synthesis.7 The construction of the central lactam ring was the final event in our total synthesis. This reaction has been executed via a [Rh]-catalyzed dehydrogenative cyclization of a g-amino alcohol. Although the total synthesis has been reported, the detailed model studies conducted to arrive at the identification of this catalyst and the optimization the reaction conditions have not been disclosed in our previous report. In this manuscript, we describe the model studies that we conducted in dealing with the catalytic dehydrogenative cyclization of g-amino alcohols. As shown in Scheme 1, our model studies are focused on the utilization of a 4,5-dihydro-3H-spiro[furan-2,20 -indolin]-30 -one derivative 1a and a FriedeleCrafts type addition of spiral-aminol carbon to indole C3, followed by a [metal]-catalyzed dehydrogenative cyclization of the resulting g-amino alcohol, which constructs the key pyrrolidinone unit.8e12 Earlier, we have reported the synthesis of tetrahydrofuran/pyran-fused spiroindolin-3-one derivatives involving a novel [Pd]-catalyzed nitroalkynol cycloisomerization.7b Considering our experience with the InCl3catalyzed selective addition of indole C3 to isatogens,7c we reasoned that the same catalyst will serve the current purpose. While this work was in progress, You et al. reported a similar strategy for constructing the central tricyclic core of isatisine A by utilizing chiral phosphoric acid-catalyzed asymmetric FriedeleCrafts alkylation reaction of indoles with racemic spiroindolin-3-ones, followed by ruthenium-catalyzed oxidative cyclization by employing NMO as the oxidant in stoichiometric amounts.13
Scheme 1. Addition of indole to 4,5-dihydro-3H-spiro[furan-2,20 -indolin]-30 -one.
2. Results and discussion With this concept in mind, the known spiroindolin-3-one 1a was treated with indole for the alkylation reaction in the presence of catalytic amounts of InCl3 in different solvents under argon atmosphere. The alkylation of 1a was feasible in the solvents like CH2Cl2, 1,2-dichloroethane (DCE) and acetonitrile (Table 1). In acetone, toluene and THF solvents, there was no reaction. Out of all the solvents, the reaction in acetonitrile was clean and gave the best yields. Furthermore, the reaction was carried out in acetonitrile by varying the amount of InCl3 from catalytic to quantitative, and we observed that this only changed the reaction time. With 1 equiv of InCl3, the reaction was completed in 15 min and with 5 mol % of InCl3, the reaction took nearly 5 h for completion. The next objective was the metal-catalyzed lactamization of the g-amino alcohol 2a.11 Routinely, the formation of amide bond pursued the path of oxidation of alcohol to acid followed by Lewis Table 1 Optimization of the alkylation reaction Entry
InCl3 (mol %)
Solvent
Time
Yield (%)
1 2 3 4 5 6 7 8 9
10 10 10 10 10 5 10 50 100
CH2Cl2 DCE THF Acetone Toluene CH3CN CH3CN CH3CN CH3CN
3h 3h 24 h 24 h 24 h 5h 3h 45 min 15 min
45 37 No reaction No reaction No reaction 70 72 79 78
511
acid or base-mediated cyclization, leading to the lactams, which is also sometimes complicated when the intermediate is heavily functionalized. Therefore, in order to avoid such difficulties, we sketched our plan to install the crucial lactam through a metalcatalyzed dehydrogenative cyclization (Scheme 2).
Scheme 2. Catalyst screening for oxidative lactamization.
The catalytic dehydrogenative inter-/intramolecular condensation of amines and alcohols leading to amides/lactams is one of the contemporary areas that have been addressed mainly by ruthenium and rhodium complexes. For example, RuH2(PPh3)4 has been used for intramolecular lactamization using simple acyclic amino alcohols.14 On the other hand, [Ru(p-cymene)2Cl2]2 and HoveydaeGrubbs first generation catalysts are used for the intermolecular dehydrogenative coupling of primary (aliphatic and aromatic) amines and alcohols.15,16 The [Cp*RhCl2]2 and [Cp*IrCl2]2 have been employed for the cyclization of 2-amino phenethyl alcohols, leading to the benzo-fused lactams.17,18 Table 2 reveals our exploratory experiments related to the dehydrogenative cyclization of the g-amino alcohol 2a, employing the complexes mentioned above. For the initial screening, 5 mol % catalyst has been employed and also 5 mol % base was used wherever required. The solvent of the reaction has been chosen from the earlier reports. The reaction was sluggish with the ruthenium catalysts like RuH2(PPh3)4 (5 mol %) and [Ru(p-cymene)2Cl2]2 (5 mol %), using NaH as base and lactam 3a was obtained in poor yields (35%).14,15 The HoveydaeGrubbs first generation catalyst (5 mol %), and also the Ag-based heterogeneous catalyst (Ag/Al2O3), have been found to not be useful with the current substrate.16,19 The reaction was also facile with the [Cp*IrCl2]2 complex.18 However, product 2a was isolated in poor yields. The best result in terms of efficiency and reaction rate was obtained with [Cp*RhCl2]2 and product 2a was obtained in 55% yield (Table 2, entry 6).17 Increasing the amount of the complex was found to improve the product yield. The best results for the oxidative lactamization of 2a (69%) were obtained when 8 mol % of [Cp*RhCl2]2 was used. The employed conditions involve the heating of the reaction at 100 C in the presence of 8 mol % of the catalyst and 5 mol % of K2CO3 in acetone for 16 h in a screw-capped seal tube. It should be noted that the reaction could not be performed under simple thermal reaction conditions. The structure of the lactam 3a was confirmed by spectral and analytical data.13 Table 2 Optimization of the dehydrogenative cyclization Entry
Catalyst
Base
Solvent
Time (h)
Yield (%)
1 2 3 4 5 6 7
RuH2(PPh3)4 [Ru(p-cymene)2Cl2]2 [Cp*IrCl2]2 First Gen. HoveydaeGrubbs Ag/Al2O3 [Cp*RhCl2]2 [Cp*RhCl2]2 (8 mol %)
d d K2CO3 NaH Cs2CO3 K2CO3 K2CO3
DME CH3CN Toluene Toluene Xylene Acetone Acetone
6 24 25 24 24 12 12
32 36 25 d d 55 69
Table 3 provides the scope of the InCl3-mediated alkylation followed by the Rh(II)-catalyzed oxidative lactamization. With all the spiroindolinones employed, the indole-addition reactions are facile. The addition reactions with 2- and N-methyl indoles, 5-bromo-, 5-
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Table 3 Scope of substrates for alkylation and lactamization Entry Spiroindolin-3-one
Alkylation product
Table 3 (continued ) Entry Spiroindolin-3-one
Alkylation product
Cyclized product
2j (89%)*
3j (59%)
2j’ (76%)
3j’ (47%)
2j’’ (83 %)
3j’’ (56%)
Cyclized product
1
11
1b
2b (79%)
3b (63 %)
1j
2
1c
2c (86%)*
3c (67%)
12
1j 3
1a
2a’ (89%)
3a’ (65%) 13
1j 4 *The
1d
2d (88%)
instability of these compounds in CDCl3 solution has hampered their complete structural characterization.
3d (58 %)
5
1e
2e (89%)
3e (64%)
2f (87%)
3f (65%)
6
1f
nitro and 5-methoxyindoles are also facile. Coming to the [Rh]-catalyzed dehydrogenative cyclization, with both the 3-aminobutanol (entries 1e3) and 4-aminopentanol (entries 4e7) derivatives, the reactions proceeded smoothly and the corresponding g- and d-lactams, respectively, were obtained in very good yields. The bromo, nitro and methoxy substituents present on the indole were found to be intact under these conditions. However, with the 2-(2aminoethoxy)ethan-1-ol derivatives 1g and 1h (entries 8 and 9), the cyclization reaction was sluggish and the corresponding products were obtained in very poor yields along with the isolation of unreacted alcohols in substantial amounts. Increasing the reaction time to 40 h did not lead to improvement in the reaction. Increasing the reaction time or even increasing the catalyst amount to 1 equiv did not improve the yield of products substantially. 3. Conclusion
7
2e’ (86%)
3e’(59%)
2g (77%)
3g (5%) + 2g (52%)
8
1g
9
In summary, we have documented here the details of two metalcatalyzed reactions for the addition of indoles to spiroaminol derivatives, and the subsequent dehydrogenative cyclization of derived u-aminolalcohol derivatives. Taken together with the twostep synthesis of these starting spiroaminol derivatives (both being catalyzed by the [Pd]-complexes), the overall sequence comprises a four-step construction of the central tricyclic core of isatisine A from simple and readily available iodonitrobenzenes and alkynols. It is to be noted that all the four steps are catalytic in nature. Currently the work in the direction of developing a continuous flow version for this sequence is in progress. 4. Experimental section
1h
2h (79%)
3h (3%) + 2h (61%)
10
1i
2i (86%)*
3i (62%)
4.1. General Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in oven-dried glassware. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (100e200 mesh). 1H and 13C NMR spectroscopy measurements were carried out on Bruker AC 200 MHz or Bruker DRX
P. Patel et al. / Tetrahedron 70 (2014) 510e516
400 MHz spectrometers, and TMS was used as the internal standard. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) downfield from TMS and coupling constants (J) are reported in Hertz (Hz). The following abbreviations are used to designate signal multiplicity: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. The multiplicity of 13C NMR signals was assigned with the help of DEPT spectra and the abbreviations used were: s¼singlet, d¼doublet, t¼triplet, q¼quartet, represent C (quaternary), CH, CH2 and CH3, respectively. Mass spectroscopy was carried out on an API QStar Pulsar (Hybrid Quadrupole-TOF LC/MS/MS) spectrometer or UPLC coupled Mass Spectrometer (Waters) and HRMS on 4800 plus MALDI TOF/TOF Applied Biosystem spectrometer. 4.2. General procedure for indole addition To a solution of spiroindolin-3-one 1a (200 mg, 1.06 mmol), indole (185 mg, 1.59 mmol) in CH3CN (10 mL), anhydrous InCl3 (11.6 mg, 5 mol %) was added under argon atmosphere and stirred for 5 h at rt. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to afford 2a (227 mg, 70%). 4.3. Characterization data 4.3.1. 2-(3-Hydroxypropyl)-2-(1H-indol-3-yl)indolin-3-one (2a).13 Yellow solid, mp 130 C, 78% yield; IR (CHCl3): n 3325, 2927, 2220, 1690, 1608, 1526, 1345, 1250, 1120, 1056 cm1. 1H NMR (200 MHz, CD3OD): d 1.33e1.49 (m, 1H), 1.53e1.68 (m, 1H), 2.14e2.43 (m, 2H), 3.53 (t, J¼6.4 Hz, 2H), 6.74 (t, J¼7.3 Hz, 1H), 6.87e6.94 (m, 2H), 7.05 (t, J¼7.2 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J¼8.1 Hz, 1H), 7.42e7.55 (m, 3H) ppm. 13C NMR (50 MHz, CD3OD): d 27.2, 34.0, 62.6, 67.0, 112.1, 112.7, 114.2, 118.6, 119.6, 120.1, 120.6, 122.2, 123.5, 125.2, 125.6, 137.9, 138.6, 162.5, 206.0 ppm. ESI-MS: m/ z 329.3 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O2: 329.1266 ([MþNa]þ); found: 329.1258 ([MþNa]þ). 4.3.2. 2-(3-Hydroxypropyl)-2-(1H-indol-3-yl)-6-methylindolin-3one (2b).13 Yellow solid, mp 145 C, 79% yield; IR (CHCl3): n 3370, 3266, 2990, 2816, 1679, 1611, 1462, 1251, 1149, 933, 744 cm1. 1H NMR (400 MHz, CDCl3): d 1.42e1.49 (m, 1H), 1.60e1.69 (m, 1H), 2.21e2.28 (m, 1H), 2.33e2.40 (m, 1H), 2.93 (s, 3H), 3.56 (d, J¼5.4 Hz, 2H), 6.61 (d, J¼7.8 Hz, 1H), 6.80 (br s, 1H), 6.85 (s, 1H), 6.92 (t, J¼7.3 Hz, 1H), 7.07 (t, J¼7.5 Hz, 1H), 7.37 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼7.5 Hz, 1H), 7.65 (d, J¼8.1 Hz, 1H), 10.19 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 22.4, 28.1, 34.7, 62.7, 70.1, 112.3, 112.7, 115.9, 118.7, 119.6, 120.1, 121.6, 122.2, 123.6, 124.8, 126.4, 138.3, 149.1, 162.5, 202.4 ppm. ESI-MS: m/z 343.15 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O2: 343.1423 ([MþNa]þ), 359.1162 ([MþK]þ); found: 343.1389 ([MþNa]þ), 359.1359 ([MþK]þ). 4.3.3. Methyl 2-(3-hydroxypropyl)-2-(1H-indol-3-yl)-3-oxoindoline6-carboxylate (2c). Yellow liquid, 86% yield; IR (CHCl3): n 3361, 2425, 1683, 1462, 1365, 1215, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization, directly subjected for lactamization. ESI-MS: m/z 403.14 (100%, [MþK]þ). HRMS: calcd for C21H20N2O4: 387.1321 ([MþNa]þ); found: 387.1318 ([MþNa]þ). 4.3.4. 2-(3-Hydroxypropyl)-2-(1-methyl-1H-indol-3-yl)indolin-3one (2a0 ). Yellow liquid, 89% yield; IR (CHCl3): n 3392, 2933, 2879, 1681, 1620, 1478, 1468, 1326, 1100, 1055, 748 cm1. 1H NMR (200 MHz, CDCl3): d 1.42e2.01 (m, 2H), 2.20e2.44 (m, 2H), 3.59 (t, J¼5.9 Hz, 2H), 3.67 (s, 3H), 5.33 (br s, 1H), 6.79e6.9 (m, 2H), 6.97e7.09 (m, 2H), 7.14e7.26 (m, 2H), 7.44e7.51 (m, 2H), 7.63 (d,
513
J¼7.8 Hz, 1H) ppm. 13C NMR (50 MHz, CDCl3): d 26.6, 32.7, 33.6, 62.6, 68.9, 109.5, 112.4, 112.9, 118.9, 119.4, 119.9, 120.5, 121.7, 124.9, 125.3, 127.1, 137.4, 160.7, 203.2 ppm. ESI-MS: m/z 321.1 (100%, [MþH]þ). HRMS: calcd for C20H20N2O2: 321.1603 ([MþH]þ), 343.1422 ([MþNa]þ); found: 321.1595 ([MþH]þ), 343.1418 ([MþNa]þ). 4.3.5. 2-(4-Hydroxybutyl)-2-(1H-indol-3-yl)-6-methylindolin-3-one (2d). Yellow liquid, 88% yield; IR (CHCl3): n 3370, 3266, 3058, 2908, 2816, 1698, 1651, 1611, 1462, 1251, 1149, 857, 767 cm1. 1H NMR (500 MHz, CDCl3): d 2.01e2.06 (m, 1H), 2.17e2.23 (m, 1H), 2.25e2.33 (m, 2H), 2.38 (s, 3H), 3.40 (t, J¼6.4 Hz, 2H), 4.60 (br s, 2H), 6.59 (d, J¼8.1 Hz, 1H), 6.78 (s, 1H), 6.86 (t, J¼7.6 Hz, 1H), 7.03 (t, J¼7.4 Hz, 1H), 7.27 (s, 1H), 7.31 (d, J¼8.2 Hz, 1H), 7.39 (d, J¼7.9 Hz, 1H), 7.42 (br d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 22.6, 23.7, 33.9, 38.0, 62.8, 71.1, 112.4, 112.7, 114.7, 115.3, 118.3, 119.9, 120.6, 121.2, 122.5, 123.9, 125.2, 126.5, 138.7, 140.2, 151.2, 164.1, 206.2 ppm. ESI-MS: m/z 357.2 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O2: 357.1579 ([MþNa]þ); found: 357.1571 ([MþNa]þ). 4.3.6. Methyl 2-(4-hydroxybutyl)-2-(1H-indol-3-yl)-3-oxoindoline6-carboxylate (2e). Yellow solid, mp 167 C, 89% yield; IR (CHCl3): n 3358, 2925, 2854, 1916, 1710, 1622, 1458, 1282, 1089, 750 cm1. 1H NMR (200 MHz, CDCl3): d 1.47e1.60 (m, 2H), 2.23e2.44 (m, 2H), 3.50 (t, J¼6.0 Hz, 2H), 3.93 (s, 3H), 6.94 (ddd, J¼1.0, 7.1, 7.9 Hz, 1H), 7.04e7.12 (m, 1H), 7.21 (br s, 1H), 7.34e7.44 (m, 3H), 7.69 (d, J¼8.1 Hz, 1H), 7.65 (d, J¼7.1 Hz, 1H), 7.67 (s, 1H), 10.3 (br s, 1H) ppm. 13 C NMR (50 MHz, CDCl3): d 21.1, 33.9, 37.9, 52.7, 62.2, 71.0, 112.4, 113.8, 115.1, 118.7, 119.8, 121.4, 122.3, 123.6, 123.7, 125.1, 126.2, 138.3, 138.5, 161.5, 167.0, 206.4 ppm. ESI-MS: m/z 401.1 (100%, [MþNa]þ). HRMS: calcd for C22H22N2O4: 401.1478 ([MþNa]þ), 417.1217 ([MþK]þ); found: 401.1479 ([MþNa]þ), 417.1198 ([MþK]þ). 4.3.7. 2-(4-Hydroxybutyl)-2-(2-methyl-1H-indol-3-yl)indolin-3-one (2f). Yellow liquid, 87% yield; IR (CHCl3): n 3393, 3012, 2932, 1682, 1619, 1462, 1323, 1216, 1020, 755 cm1. 1H NMR (500 MHz, CDCl3): d 1.26e1.31 (m, 2H), 1.55e1.60 (m, 2H), 2.23e2.29 (m, 1H), 2.44e2.53 (m, 1H), 2.45 (s, 3H), 3.59 (t, J¼6.3 Hz, 2H), 5.12 (br s, 1H), 6.81e6.84 (m, 1H), 6.88 (d, J¼8.2 Hz, 1H), 7.0e7.03 (m, 1H), 7.06e7.09 (m, 1H), 7.22 (d, J¼7.9 Hz, 1H), 7.47 (ddd, J¼1.2, 7.2, 8.2 Hz, 1H), 7.63 (br d, J¼7.6 Hz, 1H), 7.67 (d, J¼8.0 Hz, 1H), 7.82 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.9, 20.1, 32.8, 37.4, 62.5, 70.7, 109.2, 110.5, 112.2, 118.9, 119.7, 119.9, 121.1, 121.3, 125.0, 127.4, 131.8, 134.9, 137.3, 160.2, 203.4 ppm. ESI-MS: m/z 357.11 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O2: 357.1579 ([MþNa]þ), found: 357.1570 ([MþNa]þ). 4.3.8. Methyl 2-(4-hydroxybutyl)-2-(2-methyl-1H-indol-3-yl)-3oxoindoline-6-carboxylate (2e0 ). Yellow liquid, 86% yield; IR (CHCl3): n 3368, 2929, 2857, 1707, 1682, 1622, 1458, 1322, 1290, 1090, 752 cm1. 1H NMR (500 MHz, CDCl3): d 1.35e1.40 (m, 2H), 1.53e1.58 (m, 2H), 2.56 (s, 3H), 3.50 (t, J¼6.3 Hz, 2H), 3.93 (s, 3H), 6.91 (ddd, J¼1.1, 7.1, 8.0 Hz, 1H), 6.99 (ddd, J¼1.1, 7.1, 8.0 Hz, 1H), 7.21 (s, 1H), 7.26 (d, J¼7.9 Hz, 1H), 7.34e7.36 (m, 1H), 7.57 (d, J¼8.2 Hz, 2H), 7.67 (s, 1H), 7.81 (d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.8, 21.4, 33.9, 38.4, 52.7, 62.3, 72.3, 108.8, 111.3, 113.5, 118.6, 119.6, 121.3, 121.5, 123.9, 125.2, 128.4, 133.4, 136.4, 138.6, 160.8, 167.1, 203.4 ppm. ESI-MS: m/z 415.06 (100%, [MþH]þ). HRMS: calcd for: C23H24N2O4: 415.1634 ([MþNa]þ), 431.1373 ([MþK]þ); found: 415.1603 ([MþNa]þ), 431.1536 ([MþK]þ). 4.3.9. 2-((2-Hydroxyethoxy)methyl)-2-(1H-indol-3-yl)indolin-3-one (2g). Yellow liquid, 77% yield; IR (CHCl3): n 3345, 2925, 2855, 1701, 1614, 1492, 1459, 1246, 1120, 1064, 748 cm1. 1H NMR (500 MHz, CDCl3): d 3.06e3.65 (m, 4H), 4.04 (d, J¼9.8 Hz, 1H), 4.21 (d, J¼9.8 Hz, 1H), 5.36 (br s, 1H), 6.88 (t, J¼7.3 Hz, 1H), 6.96 (d, J¼8.2 Hz, 1H), 7.06 (t, J¼7.6 Hz, 1H), 7.17 (t, J¼7.3 Hz, 1H), 7.29 (s, 1H), 7.35 (d, J¼8.2 Hz, 1H), 7.50 (t, J¼7.8 Hz, 1H), 7.58 (d, J¼8.2 Hz, 1H), 7.67
514
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(d, J¼7.8 Hz, 1H), 8.19 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 61.6, 69.9, 72.9, 74.6, 111.6, 111.9, 113.1, 113.9, 119.6, 119.8, 120.2, 121.0, 122.5, 122.9, 125.0, 125.3, 125.8, 128.7, 137.6, 146.4, 161.1, 204.8 ppm. ESI-MS: m/z 359.1 (100%, [MþK]þ). HRMS: calcd for C19H18N2O3: 345.1215 ([MþNa]þ), found: 345.1208 ([MþNa]þ).
(4.5 mg, 0.032 mmol) and acetone (8 mL) were placed and the cap was sealed. The mixture was stirred at 120 C (oil bath temp) for 12 h. After evaporation of the solvent, the products were isolated by column chromatography of the residue (using ethylacetate and petroleum ether as eluent) to afford 3a (138 mg, 69%).
4.3.10. 2-((2-Hydroxyethoxy)methyl)-2-(1H-indol-3-yl)-6methylindolin-3-one (2h). Yellow liquid, 79% yield; IR (CHCl3): n 3393, 3361, 2925, 1680, 1621, 1462, 1365, 1115, 745 cm1. 1H NMR (500 MHz, CDCl3): d NMR (500 MHz, CDCl3): d 2.37 (s, 3H), 3.58e3.63 (m, 4H), 4.00 (d, J¼9.8 Hz, 1H), 4.19 (d, J¼9.8 Hz, 1H), 5.30 (br s, 1H), 6.70 (d, J¼7.9 Hz, 1H), 6.73 (s, 1H), 7.04 (t, J¼7.6 Hz, 1H), 7.15 (t, J¼7.3 Hz, 1H), 7.22 (s, 1H), 7.32 (d, J¼7.9 Hz, 1H), 7.53 (t, J¼7.9 Hz, 1H), 7.55 (d, J¼7.9 Hz, 1H), 8.26 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 22.5, 61.5, 70.0, 72.9, 74.5, 111.7, 111.9, 113.1, 118.7, 119.7, 120.1, 121.4, 122.4, 123.1, 124.7, 136.6, 149.3, 161.6, 200.7 ppm. ESI-MS: m/z 359.3 (100%, [MþNa]þ). HRMS: calcd for C20H20N2O3: 337.1552 ([MþH]þ) 359.1372 ([MþNa]þ), found: 337.1549 ([MþH]þ), 359.1253 ([MþNa]þ).
4.4.1. 9a-(1H-Indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a]indole3,9(2H)-dione (3a). Yellow liquid, 69% yield; IR (CHCl3): n 3342, 2926, 2854, 1727, 1675, 1608, 1458, 1378, 1291, 1086, 745 cm1. 1H NMR (500 MHz, CDCl3): d 2.49e2.63 (m, 2H), 2.86 (dd, J¼7.9, 11.9 Hz, 1H), 2.90e2.97 (m, 1H), 7.15e7.21 (m, 4H), 7.33 (d, J¼7.6 Hz, 1H), 7.66 (dt, J¼1.5, 8.2 Hz, 1H), 7.96 (d, J¼8.2 Hz, 1H), 8.00 (d, J¼7.6 Hz, 1H), 8.53 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.2, 34.6, 73.9, 111.7, 112.2, 116.4, 120.3, 120.6, 122.1, 122.7, 124.5, 124.9, 125.1, 125.4, 136.8, 137.3, 149.3, 173.8, 198.8 ppm. ESI-MS: m/z 325.4 (100%, [MþNa]þ). HRMS: calcd for C19H14N2O2: 303.1133 ([MþH]þ), 325.0953 ([MþNa]þ); found: 303.1149 ([MþH]þ), 325.0923 ([MþNa]þ).
4.3.11. 2 -(5-Bromo-1H-indol-3-yl)-2-(4-hydroxybutyl)-6methoxyindolin-3-one (2i). Yellow liquid, 86% yield; IR (CHCl3): n 3061, 2425, 1683, 1462, 1365, 1115, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization. ESI-MS: m/z 450.81 (100%, [MþNa]þ). HRMS: calcd for C21H22BrN2O3: 429.0808 ([MþH]þ), 451.0628 ([MþNa]þ); found: 429.0807 ([MþH]þ), 451.0623 ([MþNa]þ). 4.3.12. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-methoxy-2-methyl1H-indol-3-yl)indolin-3-one (2j). Yellow liquid, 89% yield; IR (CHCl3): n 3061, 2425, 1653, 1422, 1365, 1131, 745 cm1. The instability of this compound in CDCl3 solution has hampered its completed structural characterization. ESI-MS: m/z 403.02 (100%, [MþNa]þ). HRMS: calcd for C22H24N2O4: 403.1628 ([MþNa]þ); found: 403.1625 ([MþNa]þ). 4.3.13. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-methoxy-1H-indol-3yl)indolin-3-one (2j0 ). Brown liquid, 76% yield; IR (CHCl3): n 3426, 2999, 2360, 1630, 1485, 1368, 1216, 1053, 1028, 748, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 2.08e2.22 (m, 3H), 2.23e2.44 (m, 1H), 3.42 (br s, 2H), 3.56 (s, 3H), 3.79 (s, 3H), 4.18 (s, 1H) 6.22 (dd, J¼8.6, 1.9 Hz, 1H), 6.33 (d, J¼1.9 Hz, 1H), 6.60 (dd, J¼8.7, 2.3 Hz, 1H), 6.85 (d, J¼2.3 Hz, 1H), 7.14 (d, J¼8.8 Hz, 1H), 7.18 (d, J¼2.1 Hz, 1H), 7.28 (s, 1H), 10.4 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSOd6): d 25.5, 31.7, 53.7, 54.3, 60.3, 67.9, 92.1, 100.9, 106.0, 109.7, 110.7, 111.7, 112.7, 122.2, 124.0, 124.1, 130.7, 151.6, 162.2, 166.2, 199.3 ppm. ESI-MS: m/z 388.98 (100%, [MþNa]þ). HRMS: calcd for C21H22N2O4: 389.1472 ([MþNa]þ); found: 389.1468 ([MþNa]þ). 4.3.14. 2-(3-Hydroxypropyl)-6-methoxy-2-(5-nitro-1H-indol-3-yl) indolin-3-one (2j00 ). Yellow gum, 83% yield; IR (CHCl3): n 3019, 2400, 2879,1612,1476,1325,1215, 758, 669 cm1. 1H NMR (200 MHz, CDCl3/ DMSO-d6): d 1.01e1.13 (m, 2H), 1.58e1.89 (m, 2H), 3.08 (br s, 2H), 3.41 (s, 3H), 3.79 (br s,1H), 5.86 (dd, J¼8.6, 2.0 Hz,1H), 5.97 (d, J¼1.9 Hz,1H), 6.93 (d, J¼2.9 Hz,1H), 6.96 (s,1H), 7.03 (d, J¼2.0 Hz,1H), 7.50 (dd, J¼9.1, 2.3 Hz,1H), 8.32 (d, J¼2.0 Hz,1H) 10.84 (s,1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 27.2, 34.4, 55.7, 61.8, 69.6, 94.0, 108.3, 111.9, 112.7, 116.9, 117.7, 118.5, 124.5, 126.1, 126.3, 140.5, 141.0, 163.7, 168.1, 200.4 ppm. ESI-MS: m/z 403.86 (100%, [MþNa]þ). HRMS: calcd for C20H20N3O5: 382.1397 ([MþH]þ), 404.1217 ([MþNa]þ); found: 382.1396 ([MþH]þ), 404.1212 ([MþNa]þ). 4.4. General procedure for dehydrogenative lactam synthesis Under an atmosphere of argon in a glass sealed tube, compound 2a (200 mg, 0.653 mmol), [Cp*RhCl2]2 (32 mg, 0.052 mmol), K2CO3
4.4.2. 9a-(1H-Indol-3-yl)-6-methyl-1,9a-dihydro-3H-pyrrolo[1,2-a] indole-3,9(2H)-dione (3b). Yellow liquid, 63% yield; IR (CHCl3): n 3368, 2955, 2856, 1707, 1682, 1608, 1471, 1361, 1254, 745 cm1. 1H NMR (500 MHz, (CD3)2CO): d 2.57 (dd, J¼7.6, 15.9 Hz, 1H), 2.52 (s, 3H), 2.63e2.69 (m, 1H), 2.83 (dd, J¼7.3, 11.6 Hz, 1H), 2.89e2.96 (m, 1H), 7.06 (ddd, J¼0.9, 7.0, 7.9 Hz, 1H), 7.06 (ddd, J¼0.9, 7.0, 7.9 Hz, 1H), 7.42e7.44 (m, 2H), 7.51 (d, J¼7.9 Hz, 1H), 7.76 (s, 1H), 7.87 (d, J¼7.9 Hz, 1H) ppm. 13C NMR (125 MHz, (CD3)2CO): d 22.4, 29.8, 35.1, 74.9, 112.7, 113.2, 120.2, 122.8, 123.6, 123.6, 125.4, 125.8, 126.8, 138.8, 149.2, 151.3, 174.2, 199.6 ppm. ESI-MS: m/z 339.05 (100%, [MþNa]þ). HRMS: calcd for C20H16N2O2: 317.1290 ([MþH]þ), 339.111 ([MþNa]þ); found: 317.1288 ([MþH]þ), 339.1113 ([MþNa]þ). 4.4.3. Methyl 9a-(1H-indol-3-yl)-3,9-dioxo-2,3,9,9a-tetrahydro-1Hpyrrolo[1,2-a]indole-6-carboxylate (3c). Yellow solid, mp 138 C, 67% yield; IR (CHCl3): n 3358, 2952, 1726, 1675, 1608, 1430, 1380, 1294, 1087, 746 cm1. 1H NMR (400 MHz, CDCl3): d 1.88e2.01 (m, 2H), 2.49e2.64 (m, 2H), 3.94 (s, 3H), 7.10e7.15 (m, 2H), 7.19 (dt, J¼1.1, 8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz, 1H), 7.7 (d, J¼8.0 Hz, 1H), 7.84e7.88 (m, 2H), 8.42 (br s, 1H), 9.15 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 28.3, 31.4, 52.7, 71.7, 111.7, 111.9, 119.1, 120.5, 122.9, 123.0, 124.0, 124.7, 125.2, 125.9, 137.2, 137.6, 150.9, 166.1, 169.8, 197.3 ppm. ESI-MS: m/z 383.05 (100%, [MþNa]þ). HRMS: calcd for C21H16N2O4: 383.1008 ([MþNa]þ); found: 383.1002 ([MþNa]þ). 4.4.4. 9a-(1-Methyl-1H-indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a] indole-3,9(2H)-dione (3a0 ). Yellow liquid, 65% yield; IR (CHCl3): n 3379, 3019, 2953, 1720, 1705, 1614, 1578, 1438, 1292, 1214, 754 cm1. 1 H NMR (200 MHz, CDCl3): d 2.50e2.63 (m, 2H), 2.83e2.87 (m, 1H), 2.93e3.0 (m, 1H), 3.70 (s, 3H), 7.18 (ddd, J¼1.2, 6.7, 7.9 Hz, 1H), 7.22 (dt, J¼0.8, 7.6 Hz, 1H), 7.26e7.30 (m, 1H), 7.63 (d, J¼7.6 Hz, 1H), 7.68 (ddd, J¼1.2, 7.5, 8.2 Hz, 1H), 7.97 (d, J¼8.2 Hz, 1H), 7.98 (d, J¼7.9 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.4, 32.9, 34.7, 74.0, 109.7, 110.6, 116.5, 120.0, 120.8, 122.4, 125.0, 125.1, 125.5, 126.6, 136.8, 138.0, 149.3, 173.8, 198.7 ppm. ESI-MS: m/z 339.3 (100%, [MþH]þ). HRMS: calcd for C20H16N2O2: 339.1109 ([MþNa]þ); found: 339.1103 ([MþNa]þ). 4.4.5. 9a-(1H-Indol-3-yl)-3-methyl-7,8,9,9a-tetrahydropyrido[1,2-a] indole-6,10-dione (3d). Off white solid, mp 112 C, 58% yield; IR (CHCl3): n 3422, 3276, 2927, 2834, 1909, 1648, 1603, 1457, 1424, 1377, 1024, 742 cm1. 1H NMR (400 MHz, (CD3)2CO): d 1.83e2.04 (m, 4H), 2.46e2.50 (m, 2H), 2.52 (s, 3H), 7.01 (d, J¼7.5 Hz, 1H), 7.10e7.14 (m, 2H), 7.34 (d, J¼2.3 Hz, 1H), 7.42 (d, J¼8.2 Hz, 1H), 7.55 (d, J¼7.8 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H), 8.43 (s, 1H), 10.47 (br s, 1H) ppm. 13C NMR (100 MHz, (CD3)2CO): d 18.0, 22.6, 28.8, 31.9,
P. Patel et al. / Tetrahedron 70 (2014) 510e516
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72.1, 112.8, 118.9, 120.3, 120.8, 121.1, 122.7, 124.5, 124.6, 124.9, 125.3, 126.5, 138.5, 149.4, 152.9, 169.9, 197.9 ppm. ESI-MS: m/z 353.04 (100%, [MþNa]þ). HRMS: calcd for C21H18N2O2: 353.1266 ([MþNa]þ); found: 353.1246 ([MþNa]þ).
(125 MHz, CDCl3): d 22.7, 66.8, 67.7, 69.9, 111.6, 111.7, 118.6, 120.3, 120.5, 120.6, 122.8, 123.2, 124.3, 124.7, 127.0, 137.0, 149.4, 151.3, 166.2, 194.7 ppm. ESI-MS: m/z 355.1 (100%, [MþNa]þ). HRMS: calcd for C20H16N2O3: 355.1059 ([MþNa]þ); found: 355.1041 ([MþNa]þ).
4.4.6. Methyl 9a-(1H-indol-3-yl)-6,10-dioxo-6,7,8,9,9a,10hexahydropyrido[1,2-a]indole-3-carboxylate (3e). Yellow solid, mp 87 C, 64% yield; IR (CHCl3): n 3379, 3019, 2953, 1720, 1705, 1614, 1578, 1438, 1292, 1214, 754 cm1. 1H NMR (200 MHz, CDCl3): d 2.53e2.71 (m, 4H), 2.86e2.99 (m, 2H), 3.98 (s, 3H), 7.26e7.20 (m, 3H), 7.41e7.36 (m, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.9 (dd, J¼8.0 Hz, 1H), 7.99e8.03 (m, 1H), 8.38 (br s, 1H), 8.59 (s, 1H) ppm. 13C NMR (50 MHz, (CD3)2CO): d 21.1, 39.0, 38.0, 52.8, 71.1, 112.5, 113.8, 115.2, 118.8, 119.8, 121.4, 122.4, 123.6, 123.8, 125.2, 126.3, 138.4, 138.6, 161.6, 167.1, 203.2 ppm. ESI-MS: m/z 397.1 (100%, [MþNa]þ). HRMS: calcd for C22H18N2O4: 397.1164 ([MþNa]þ); found: 397.1127 ([MþNa]þ).
4.4.11. 9a-(5-Bromo-1H-indol-3-yl)-3-methoxy-7,8,9,9a-tetrahydropyrido[1,2-a]indole-6,10-dione (3i). Yellow solid, mp 123 C, 62% yield; IR (CHCl3): n 3392, 2998, 2400, 1681, 1619, 1496, 1216, 1059, 1010, 758, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.82e1.97 (m, 3H), 2.38 (t, J¼7.4 Hz, 2H), 2.75e2.84 (m, 1H), 3.86 (s, 3H), 6.74 (dd, J¼8.6, 2.3 Hz, 1H), 7.10 (dd, J¼8.67, 1.9 Hz, 1H), 7.24e7.29 (m, 2H), 7.47 (d, J¼8.6 Hz, 1H), 7.78 (d, J¼1.6 Hz, 1H), 8.00 (d, J¼2.3 Hz, 1H), 11.10 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/ DMSO-d6): d 17.0, 27.9, 31.0, 55.7, 71.3, 101.9, 111.8, 112.2, 113.9, 115.0, 122.6, 124.3, 125.3, 125.8, 125.9, 136.3, 153.7, 167.2, 169.3, 195.5 ppm. ESI-MS: m/z 446.93 (100%, [MþNa]þ). HRMS: calcd for C21H18BrN2O3: 425.0495 ([MþH]þ), 447.0315 ([MþNa]þ); found: 425.0495 ([MþH]þ), 447.0313 ([MþNa]þ).
4.4.7. 9a-(2-Methyl-1H-indol-3-yl)-7,8,9,9a-tetrahydropyrido[1,2-a] indole-6,10-dione (3f). Yellow liquid, 65% yield; IR (CHCl3): n 3334, 2956, 2927, 1726, 1682, 1619, 1462, 1378, 1293, 1123, 743 cm1. 1H NMR (500 MHz, CDCl3): d 1.77e1.88 (m, 2H), 1.90e1.96 (m, 1H), 2.38 (s, 3H), 2.53 (t, J¼6.9 Hz, 2H), 3.17e3.21 (m, 1H), 7.04e7.1 (m, 2H), 7.19e7.23 (m, 2H), 7.68e7.72 (m, 2H), 7.84 (d, J¼6.2 Hz, 1H), 8.14 (s, 1H), 8.60 (d, J¼8.4 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 13.9, 17.2, 28.7, 31.5, 71.7, 105.6, 110.5, 118.3, 120.1, 120.2, 121.6, 123.2, 124.7, 124.8, 126.3, 132.7, 135.1, 137.0, 151.0, 170.1, 197.8 ppm. ESIMS: m/z 353.02 (100%, [MþNa]þ). HRMS: calcd for C21H18N2O2: 331.1446 ([MþH]þ), 353.0693 ([MþNa]þ); found: 331.1458 ([MþH]þ), 353.1085 ([MþNa]þ). 4.4.8. Methyl 9a-(2-methyl-1H-indol-3-yl)-6,10-dioxo-6,7,8,9,9a,10hexahydropyrido [1,2-a]indole-3-carboxylate (3e0 ). Yellow liquid, 59% yield; IR (CHCl3): n 3325, 2927, 2220, 1754, 1608, 1526, 1345, 1250, 1120, 1056 cm1. 1H NMR (500 MHz, CDCl3): d 1.79e1.86 (m, 2H), 1.88e1.97 (m, 2H), 2.39 (s, 3H), 2.55e2.58 (m, 2H), 3.97 (s, 3H), 7.07e7.03 (m, 2H), 7.22e7.24 (m, 1H), 7.74 (d, J¼7.9 Hz, 1H), 7.83 (br s, 1H), 7.89 (dd, J¼1.2, 7.9 Hz, 1H), 7.79 (s, 1H), 9.20 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 14.1, 17.2, 28.7, 31.6, 52.7, 72.3, 105.2, 110.6, 119.3, 120.1, 120.5, 121.8, 124.7, 125.9, 126.2, 126.4, 132.8, 135.1, 137.6, 150.8, 166.1, 169.9, 197.1 ppm. ESI-MS: m/z 411.07 (100%, [MþNa]þ). HRMS: calcd for C23H20N2O4: 388.1423 ([M]þ), 411.1321 ([MþNa]þ); found: 388.1424 ([M]þ), 411.1308 ([MþNa]þ). 4.4.9. 10a-(1H-Indol-3-yl)-1,10a-dihydro-10H-[1,4]oxazino[4,3-a]indole-4,10(3H)-dione (3g). Yellow liquid, 5% yield; IR (CHCl3): n 3452, 2924, 1716, 1657, 1599, 1458, 1378, 1124, 856 cm1. 1H NMR (500 MHz, CDCl3): d 3.95 (d, J¼11.3 Hz, 1H), 4.30 (d, J¼17.4 Hz, 1H), 4.43 (d, J¼17.4 Hz, 1H), 4.92 (d, J¼11.3 Hz, 1H), 7.14 (dt, J¼0.9, 7.0 Hz, 1H), 7.19 (dt, J¼1.2, 8.2 Hz, 1H), 7.23 (d, J¼2.7 Hz, 1H), 7.28 (dt, J¼0.7, 7.2 Hz, 1H), 7.34 (d, J¼8.2 Hz, 1H), 7.69e7.75 (m, 2H), 7.85 (d, J¼8.0 Hz, 1H), 8.26 (br s, 1H), 8.47 (d, J¼8.2 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 66.9, 67.6, 69.7, 111.3, 111.8, 118.4, 120.3, 120.7, 122.7, 122.9, 123.3, 124.2, 125.0, 125.7, 137.0, 137.3, 150.9, 166.1, 195.2 ppm. ESI-MS: m/z 319.1 (100%, [MþH]þ). HRMS: calcd for C19H14N2O3: 319.1082 ([MþH]þ), 341.0902 ([MþNa]þ); found: 319.3093 ([MþH]þ), 341.0873 ([MþNa]þ). 4.4.10. 10a-(1H-Indol-3-yl)-7-methyl-1,10a-dihydro-10H-[1,4]oxazino[4,3-a]indole-4,10(3H)-dione (3h). Yellow liquid, 3% yield; IR (CHCl3): n 3378, 2972, 2928, 2858, 1719, 1699, 1619, 1458, 1425, 1113, 823, 744 cm1. 1H NMR (500 MHz, CDCl3): d 2.51 (s, 3H), 3.93 (d, J¼11.6 Hz, 1H), 4.28 (d, J¼17.4 Hz, 1H), 4.41 (d, J¼17.4 Hz, 1H), 4.89 (d, J¼11.6 Hz, 1H), 7.10 (d, J¼7.9 Hz, 1H), 7.11e7.14 (m, 1H), 7.18 (dt, J¼0.9, 7.9 Hz, 1H), 7.23 (d, J¼2.7 Hz, 1H), 7.33 (d, J¼7.9 Hz, 1H), 7.59 (d, J¼7.6 Hz, 1H), 7.82 (d, J¼8.2 Hz, 1H), 8.29 (br s, 2H) ppm. 13C NMR
4.4.12. 3-Methoxy-9a-(5-methoxy-2-methyl-1H-indol-3-yl)7,8,9,9a-tetrahydropyrido [1,2-a]indole-6,10-dione (3j). Off white solid, mp 197 C, 59% yield; IR (CHCl3): n 3424, 2998, 2360, 1630, 1478, 1368, 1216, 1053, 1028, 758, 667 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.47 (s, 3H), 1.59e1.64 (m, 2H), 1.84e1.89 (m, 2H), 2.86 (s, 3H), 3.03 (s, 3H), 5.73 (d, J¼8.2 Hz, 1H), 5.89 (d, J¼6.4 Hz, 1H), 6.22 (d, J¼7.8 Hz, 1H), 6.49 (s, 1H), 6.61 (d, J¼8.2 Hz, 1H), 9.92 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 11.5, 27.6, 32.7, 53.4, 54.2, 72.9, 98.0, 100.2, 102.9, 108.2, 109.5, 110.5, 116.7, 124.7, 128.4, 131.9, 149.0, 151.3, 164.7, 170.8, 194.5 ppm. ESIMS: m/z 398.9 (100%, [MþNa]þ). HRMS: calcd for C22H21N2O4: 377.1496 ([MþH]þ), 399.1315 ([MþNa]þ); found: 377.1492 ([MþH]þ), 399.1311 ([MþNa]þ). 4.4.13. 3-Methoxy-9a-(5-methoxy-1H-indol-3-yl)-7,8,9,9a-tetrahydropyrido[1,2-a]indole-6,10-dione (3j0 ). Brown-red liquid, 47% yield; IR (CHCl3): n 3466, 3019, 2400, 1704, 1603, 1486, 1363, 1215, 757, 627 cm1. 1H NMR (200 MHz, CDCl3): d 2.48e2.68 (m, 2H), 2.78e2.94 (m, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 6.73 (dd, J¼8.6, 2.3 Hz, 1H), 6.85 (dd, J¼8.7, 2.4 Hz, 1H), 7.20 (d, J¼2.5 Hz, 1H), 7.44 (d, J¼2.0, 1H), 7.53 (d, J¼8.6 Hz, 1H), 8.20 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 29.3, 34.8, 55.8, 56.1, 74.5, 100.1, 102.2, 112.3, 112.7, 113.3, 113.5, 117.7, 122.3, 125.1, 126.8, 132.3, 151.9, 154.4, 167.2, 174.0, 197.2 ppm. ESI-MS: m/z 384.96 (100%, [MþNa]þ); HRMS: calcd for C21H19N2O4: 363.1339 ([MþH]þ), 385.1159 ([MþNa]þ); found: 363.1336 ([MþH]þ), 385.1155 ([MþNa]þ). 4.4.14. 6-Methoxy-9a-(5-nitro-1H-indol-3-yl)-1,9a-dihydro-3H-pyrrolo[1,2-a]indole-3,9(2H)-dione (3j00 ). Yellow liquid, 56% yield; IR (CHCl3): n 3020, 2400, 1603, 1523, 1423, 1215, 928, 762, 669 cm1. 1H NMR (200 MHz, CDCl3/DMSO-d6): d 1.84e1.93 (m, 3H), 2.02e2.10 (m, 1H), 3.22 (s, 3H), 6.03 (dd, J¼8.6, 2.1 Hz, 1H), 6.68e6.70 (m, 2H), 6.74 (d, J¼7.4 Hz, 1H), 6.80 (d, J¼1.8 Hz, 1H), 7.29 (d, J¼9.1, 2.1 Hz, 1H), 8.17 (d, J¼2.0 Hz, 1H), 10.65 (br s, 1H) ppm. 13C NMR (50 MHz, CDCl3/DMSO-d6): d 28.8, 33.6, 55.2, 73.1, 99.5, 111.3, 112.4, 113.8, 116.2, 116.4, 117.0, 122.9, 124.9, 125.7, 139.9, 140.4, 151.2, 166.4, 172.7, 195.8 ppm. ESI-MS: m/z 399.96 (100%, [MþNa]þ). HRMS: calcd for C20H16N3O5: 378.1084 ([MþH]þ), 400.0904 ([MþNa]þ); found: 378.1078 ([MþH]þ), 400.0897 ([MþNa]þ). Acknowledgements The authors would like to acknowledge the CSIR (India) for providing the financial support for this project under ORIGIN program of 12FYP (CSC0108). P.P. thanks UGC (New Delhi) and B.N.R. thanks CSIR (New Delhi) for the financial assistance in the form of Research Fellowships.
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Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.026.
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