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Feb 16, 2018 - acetylenecarboxylate with 1H-indole-2-carboxaldehydes.3a,b,4. This reaction ... followed by an intramolecular Wittig reaction (Scheme 1...
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Phosphine-Promoted Synthesis of 9H‑Pyrrolo[1,2‑a]indole Derivatives via an γ‑Umpolung Addition/Intramolecular Wittig Reaction Charlotte Lorton and Arnaud Voituriez* Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 av. de la Terrasse, 91198 Gif-sur-Yvette, France S Supporting Information *

ABSTRACT: The synthesis of substituted 9H-pyrrolo[1,2-a]indole products from 1H-indole-2-carbaldehydes and allenoates is described, using a phosphine-promoted Michael addition/intramolecular Wittig reaction. This halide- and base-free methodology provides an efficient access to different tricyclic nitrogen-containing heterocycles (18 examples, 32−88% isolated yields).

T

Furthermore, in comparison with the classical Wittig reaction, which needs for the formation of the phosphorus ylide the use of stoichiometric amounts of a halide compound and a base, this synthetic approach can be viewed as a new and efficient halide- and base-free γ-umpolung addition,6 followed by an intramolecular Wittig reaction. At the outset of this study, we started the optimization of the phosphine-promoted reaction with the use of triphenylphosphine as a reagent. This phosphine is cheaper and more airstable than trialkylphosphines. The use of stoichiometric amounts of 1H-indole-2-carbaldehyde 1a, allenoate 2a, and PPh3 in toluene gave the desired cyclization product 3a in 53% isolated yield (Table 1, entry 1).

he pyrrolo[1,2-a]indole backbone is found in many natural products and bioactive molecules.1 Furthermore, this nitrogen-containing tricyclic structure proved to be a useful intermediate for the synthesis of more complex alkaloids. This explains the numerous methods developed recently for the synthesis of this tricyclic scaffold.2,3 Among them, we can mention the triphenylphosphine-promoted reaction of dialkyl acetylenecarboxylate with 1H-indole-2-carboxaldehydes.3a,b,4 This reaction proceeds via an umpolung addition of the conjugate base of the indole to the vinylphosphonium salt, followed by an intramolecular Wittig reaction (Scheme 1a). In the continuity of the work of many research groups in the field of phosphine-promoted reactions,5 it was questioned whether an allenoate substrate could be a good partner for the development of a new tandem Michael addition/Intramolecular Wittig reaction (Scheme 1b).

Table 1. Optimization of the Phosphine-Promoted Reaction of 1H-Indole-2-carbaldehyde 1a with 2,3-Butadienoate 2aa

Scheme 1. Strategies for the Synthesis of Pyrrolo[1,2a]indole Derivatives entry

2a (n equiv)

solvent

c (mol/L)

yield 3a (%)b

1 2 3 4 5 6 7 8

1.0 1.5 2.0 1.5 1.5 1.5 1.5 1.5

toluene toluene toluene THF CH2Cl2 toluene toluene toluene

0.1 0.1 0.1 0.1 0.1 0.05 0.15 0.1

53 80 73c 22 45 74 67 82d

a

Reaction conditions: 1a (1.0 equiv, 0.14 mmol), 2a (n equiv), PPh3 (1.0 equiv), and solvent at 60 °C for 3 h. bYield of isolated compound. c Presence of dimerization/oligomerization products of 2a. dReaction on a 1 mmol scale. Received: February 16, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.joc.8b00457 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

desired product 3m was obtained in an acceptable yield. In this transformation, the electronic nature and steric hindrance of substituents do not seem to have a significant impact on the reaction outcome. The reaction scope was then expanded to the use of αsubstituted allenoates, such as ethyl 2-benzylbuta-2,3-dienoate 4, ethyl 2-methylbuta-2,3-dienoate 5, and diethyl 2-vinylidenesuccinate 6 (Scheme 3).

Increasing the quantity of allenoate to 1.5 equiv gave a much better yield (entry 2). However, when 2 equiv of allenoate was used, the isolated yield was lower, due to the presence of a byproduct, which proved to be difficult to separate from 3a (entry 3). This nondesired product comes from the dimerization/oligomerization of allenoate 2a.7 Screening of other solvents (THF, dichloromethane) did not improve the reaction yield (entries 4 and 5). Finally, the use of a more diluted or more concentrated solution had no beneficial effects on the reaction yield (entries 6 and 7). The optimized protocol for this reaction was the use of 1.5 equiv of allenoate 2a with respect to the substrate 1a, in the presence of stoichiometric amounts of PPh3 at 60 °C in toluene (0.1 mol/L).8 The practicability of this new tandem reaction has been shown by a 1 mmol scale synthesis of the 9H-pyrrolo[1,2-a]indole derivative 3a (entry 8, 197 mg, 82% yield). With the optimized experimental conditions in hand, it was possible to realize a wide range of tandem Michael addition/intramolecular Wittig reactions, using diversely substituted indole derivatives and allenoates (Scheme 2).

Scheme 3. Extension of the Reaction Scope to Different αSubstituted Allenoatesb

Scheme 2. Scope of the Cyclization Reaction for the Formation of Various 9H-Pyrrolo[1,2-a]indole Derivativesa

Classical heating at 120 °C for 48 h. Yield of isolated compound. Reaction conditions: 1 (1 equiv, 0.14 mmol), 4−6 (1.5 equiv), and PPh3 (1.0 equiv) in toluene, microwave heating (150 °C, 1 h). a b

In reaction with substrates 1a−b, allenoate 4, in the presence of a stoichiometric amount of PPh3, gave the cyclization products 3n and 3o in 65% and 43% yields, respectively. It is notable that α-substituted allenoate proved to be less reactive than the substrates 2a−c. To obtain a decent yield, microwave heating (150 °C, 1 h) was used. Using the classical heating, if no conversion was observed at 60 °C, increasing the reaction temperature to 120 °C also afforded the desired product 3n (58% yield), but with a reaction time lengthened to 48 h. A lower reactivity was observed with the α-methyl-allenoate 5 (product 3p, 32% yield). PnBu3 instead of PPh3 was tested in this reaction, without remarkable effects on the reaction yield. On the other hand, with the use of diethyl 2-vinylidenesuccinate 6, the products 3q and 3r were isolated in 82% and 53% yields. With the aim at developing a greener approach of our newly developed reaction, we wondered if the use of a supported phosphine9 was compatible with the reaction conditions developed in this study (Scheme 4a). In the presence of 1.5 equiv of the commercially available polymer-supported triphenylphosphine (100−200 mesh; ∼3.2 mmol/g loading), the desired product 3a was obtained in 56% yield. This method simplifies the purification step, and the crude product can be isolated after filtration, without any trace of triphenylphosphine oxide byproduct. For a more sustainable chemistry, we also envisioned the development of the same reaction with the use of substoichiometric amounts of phosphine (Scheme 4b). Since the ground-breaking work of O’Brien in 2009, who developed the first catalytic Wittig reaction,10a many different phosphinepromoted reactions were rendered catalytic by the in situ reduction of the phosphine oxide generated during the reaction

a

Reaction conditions: 1a (1 equiv, 0.14 mmol), 2a (1.5 equiv), and PPh3 (1.0 equiv) in toluene at 60 °C for 3 h. Yield of isolated compound.

As shown in Scheme 2, 1H-indole-2-carbaldehydes 1a−i reacted smoothly with buta-2,3-dienoates 2a−c, affording the corresponding pyrrolo[1,2-a]indole derivatives 3a−m in good to excellent isolated yields. Three differently substituted allenoates 2a−c (R4 = ethyl, benzyl, and cyclohexyl) reacted with 1H-indole-2-carbaldehyde and its 5-methoxy analogue to furnish the corresponding products 3a−f in 53−88% yields. Indoles substituted with electron-withdrawing groups such as halogens (Br, Cl, F) were also tolerated and gave the corresponding products 3g−i in 61−78% yields. In the reaction with ethyl allenoate 2a, 5-methyl-, 5-benzyloxy-, and 6methoxy-indole derivatives gave the cyclization products 3j−l in 75−77% yields. To our delight, the 3-methyl-1H-indole-2carbaldehyde substrate was subjected to this reaction and the B

DOI: 10.1021/acs.joc.8b00457 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Scheme 4. Toward the Development of a More Sustainable Synthesis of 3a

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EXPERIMENTAL SECTION

General Information. All nonaqueous reactions were run under a positive pressure of argon, using standard techniques for manipulating air-sensitive compounds. Toluene was distilled over sodium under an argon atmosphere. All other reagents and solvents were of commercial quality and used without further purification. Analytical thin-layer chromatography (TLC) was performed on plates precoated with silica gel layers. The developed chromatogram was visualized by UV absorbance and/or vanillin stain. Purification of compounds was performed with an automated chromatography system using prepacked silica columns. Nuclear magnetic resonance spectra (1H and 13C) were recorded with a 500 or 300 MHz spectrometer. Chemical shifts are reported in parts per million relative to an internal standard of residual chloroform (δ = 7.26 ppm for 1H NMR and 77.16 ppm for 13C NMR) and acetone (δ = 2.05 ppm for 1H NMR; 206.26 and 29.84 ppm for 13C NMR). IR spectra were recorded using an IR spectrometer (diamond plate) and are reported in reciprocal centimeters (cm−1). High-resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) and a time-of-flight (TOF) analyzer, in positive-ion or negative-ion detection mode. Microwave-assisted reactions were performed in a Monowave 300 microwave reactor, using borosilicate glass standard vials G10. Sealed reaction vessels were used. The reaction temperature (150 °C for the synthesis of compounds 3n−p) was monitored with an external surface sensor and was maintained in each experiment. Indole carbaldehydes 1a−i [1a (R1 = R2 = R3 = H),12a 1b (R1 = H, R2 = OMe, R3 = H),12b 1c (R1 = H, R2 = Br, R3 = H),12a 1d (R1 = H, R2 = Cl, R3 = H),12a 1e (R1 = H, R2 = F, R3 = H),12c 1f (R1 = H, R2 = Me, R3 = H),12d 1g (R1 = H, R2 = OBn, R3 = H),12e 1h (R1 = H, R2 = H, R3 = OMe),12f and 1i (R1 = Me, R2 = H, R3 = H)12g and allenoates 413a and 513b were prepared according to literature procedures. Representative Procedure for the Reaction of Indole Carbaldehyde Derivatives 1 with Buta-2,3-dienoate 2 To Form Products 3. In a Schlenk tube, indole carbaldehyde (0.14 mmol, 1 equiv), triphenylphosphine (0.14 mmol, 1 equiv), and freshly distilled degassed toluene (0.1 M) were added. Then, the buta-2,3dienoate (0.21 mmol, 1.5 equiv) was added using a microsyringe. The reaction mixture was then heated for 3 h at 60 °C, and the crude reaction mixture was concentrated and purified by flash chromatography using a silica gel prepacked column and EtOAc/heptanes as an eluent (0−20% of EtOAc over 25 min, 14 mL/min). Ethyl 2-(9H-Pyrrolo[1,2-a]indol-2-yl)acetate (3a): 27 mg, 80% yield on a 0.14 mmol scale; 197 mg, 82% yield on a 1 mmol scale, yellow oil; Rf 0.44 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.43 (1H, d, J = 7.3 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.31 (1H, t, J = 7.9 Hz), 7.19−7.17 (1H, m), 7.08 (1H, td, J = 7.3, 1.1 Hz), 6.04−6.01 (1H, m), 4.11 (2H, q, J = 7.1 Hz), 3.81 (2H, bs), 3.51 (2H, s), 1.23 (3H, t, J = 7.1 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (CO), 142.0 (C), 136.1 (C), 135.4 (C), 128.3 (CH), 126.7 (CH), 123.8 (CH), 122.1 (C), 110.4 (CH), 109.6 (CH), 103.9 (CH), 60.8 (CH2), 34.2 (CH2), 29.5 (CH2), 14.6 (CH3); IR νmax 2983, 2920, 1731, 1618, 1508, 1468, 1176, 1032, 751 cm−1; HRMS (ESI) calcd for C15H16NO2 [M + H]+ 242.1181, found 242.1175. Benzyl 2-(9H-Pyrrolo[1,2-a]indol-2-yl)acetate (3b): 23 mg, 53% yield, colorless oil; Rf 0.37 (20% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ 7.31−7.16 (7H, m), 7.10 (1H, d, J = 7.5 Hz), 6.99 (1H, dd, J = 7.3, 1.1 Hz), 6.97−6.94 (1H, m), 6.00−5.97 (1H, m), 5.08 (2H, s), 3.72 (2H, bs), 3.55 (2H, s); 13C NMR (75 MHz, CDCl3) δ 172.3 (CO), 141.2 (C), 136.2 (C), 135.8 (C), 134.6 (C), 128.7 (CH), 128.4 (CH), 128.3 (CH), 127.5 (CH), 125.9 (CH), 123.1 (CH), 120.6 (C), 109.7 (CH), 108.9 (CH), 103.1 (CH), 66.7 (CH2), 33.9 (CH2), 29.4 (CH2); IR νmax 2925, 1733, 1618, 1508, 1468, 1313, 1256, 1221, 1167, 1135, 986, 749, 697 cm−1; HRMS (ESI) calcd for C20H18NO2 [M + H]+ 304.1338, found 304.1332. Cyclohexyl 2-(9H-Pyrrolo[1,2-a]indol-2-yl)acetate (3c): 25 mg, 60% yield, yellow oil; Rf 0.50 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.43 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 7.5 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.21−7.16 (1H, m), 7.08 (1H, td, J = 7.5, 1.1 Hz), 6.05−6.02 (1H, m), 4.76−4.68 (1H, m), 3.81 (2H, bs), 3.49 (2H, s), 1.91−1.80 (2H, m), 1.75−1.60 (2H, m), 1.59−1.22 (6H, m); 13C

process.4,10 As a preliminary result, with the use of 10 mol % Pphenylphospholene, phenylsilane as a reducing agent, and 10 mol % bis(4-nitrophenyl)phosphate (to facilitate the reduction of the PO bond) in toluene at 60 °C, a low yield of 18% was obtained. We did not efficiently manage to develop a catalytic version of this new reaction, probably because of incompatibilities between the silane and the reaction intermediates. On the other hand, the development of a new phosphine catalyst and optimization of the reaction conditions should render this catalytic process possible. With this purpose, Kwon developed in 2018 a new bicyclic phosphine and used it successfully in a catalytic γ-umpolung addition/Wittig reaction, for the synthesis of 1,2-dihydroquinolines.11 Finally, we proposed a mechanism for this tandem reaction, which is shown in Scheme 5. The triphenylphosphine was Scheme 5. Mechanistic Proposal

added to the electron-deficient allene 2 to form the zwitterionic species (I). The deprotonation of the indolic proton of the substrate 1 by I generated the nucleophile (II) and the phosphonium (III). Consequently, the addition of II to III formed the ylide intermediate (IV), which reacts intermolecularly via a Wittig reaction to form V, and the phosphine oxide was released concomitantly. After isomerization, the final product 3 was isolated. In conclusion, we have demonstrated that a wide range of 9H-pyrrolo[1,2-a]indole derivatives could be easily synthesized via a new PPh3-promoted tandem Michael addition/intramolecular Wittig reaction. The reaction tolerates different substituents both on the indole and the allenoate partner, with good yields. This synthetic method complements well the few methods already described for the synthesis of these heterocycles of interest. C

DOI: 10.1021/acs.joc.8b00457 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry NMR (75 MHz, (CD3)2CO) δ 171.6 (CO), 150.2 (C), 142.0 (C), 136.0 (C), 128.3 (CH), 126.7 (CH), 123.7 (CH), 122.3 (C), 110.3 (CH), 109.6 (CH), 103.8 (CH), 72.9 (CH), 34.6 (CH2), 32.3 (CH2), 29.4 (CH2), 26.1 (CH2), 24.3 (CH2); IR νmax 2936, 2858, 1726, 1617, 1507, 1453, 1257, 1175, 1122, 1038, 1017, 750 cm−1; HRMS (ESI) calcd for C19H22NO2 [M + H]+ 296.1651, found 296.1642. Ethyl 2-(7-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3d): 33 mg, 88% yield, yellow oil; Rf 0.30 (20% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ 7.10 (1H, d, J = 8.5 Hz), 7.00−6.93 (2H, m), 6.80 (1H, dd, J = 8.5, 2.4 Hz), 6.06−6.04 (1H, m), 4.18 (2H, q, J = 7.2 Hz), 3.81 (3H, s), 3.79 (2H, bs), 3.56 (2H, s), 1.29 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl3) δ 172.6 (CO), 156.3 (C), 136.1 (C), 135.43 (C), 135.36 (C), 120.2 (C), 112.8 (CH), 112.1 (CH), 109.7 (CH), 108.6 (CH), 102.9 (CH), 60.8 (CH2), 55.9 (CH3), 33.9 (CH2), 29.6 (CH2), 14.4 (CH3); IR νmax 2924, 1731, 1509, 1491, 1462, 1425, 1281, 1243, 1172, 1136, 1033, 804, 706 cm−1; HRMS (ESI) calcd for C16H18NO3 [M + H]+ 272.1287, found 272.1276. Benzyl 2-(7-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3e): 26 mg, 55% yield, yellow oil; Rf 0.24 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.41−7.31 (5H, m), 7.28 (1H, d, J = 8.5 Hz), 7.13−7.10 (1H, m), 7.08−7.04 (1H, m), 6.86 (1H, dd, J = 8.5, 2.4 Hz), 6.02−5.97 (1H, m), 5.14 (2H, s), 5.81−3.78 (5H, m), 3.57 (2H, s); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (CO), 157.4 (C), 137.7 (C), 136.9 (C), 135.95 (C), 135.85 (C), 129.3 (CH), 128.8 (CH), 128.7 (CH), 121.2 (C), 113.5 (CH), 112.9 (CH), 110.5 (CH), 109.6 (CH), 103.7 (CH), 66.6 (CH2), 56.0 (CH3), 34.2 (CH2), 29.8 (CH2); IR νmax 2924, 2854, 1730, 1491, 1456, 1376, 1359, 1243, 1217, 1168, 1138, 1034, 806, 739, 699 cm−1; HRMS (ESI) calcd for C21H20NO3 [M + H]+ 334.1443, found 334.1427. Cyclohexyl 2-(7-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3f): 30 mg, 65% yield, yellow oil; Rf 0.38 (20% EtOAc/heptanes); 1 H NMR (300 MHz, (CD3)2CO) δ 7.28 (1H, d, J = 8.5 Hz), 7.12− 7.08 (1H, m), 7.07−7.03 (1H, m), 6.86 (1H, dd, J = 8.5, 2.4 Hz), 6.01−5.98 (1H, m), 4.77−4.64 (1H, m), 3.81−3.77 (5H, m), 3.47 (2H, bs), 1.88−1.78 (2H, m), 1.77−1.65 (2H, m), 1.57−1.22 (6H, m); 13C NMR (75 MHz, (CD3)2CO) δ 171.7 (CO), 157.3 (C), 136.9 (C), 135.9 (C), 135.7 (C), 121.5 (C), 113.5 (CH), 112.9 (CH), 110.5 (CH), 109.3 (CH), 103.6 (CH), 72.9 (CH), 56.0 (CH3), 34.6 (CH2), 32.2 (CH2), 29.8 (CH2), 26.1 (CH2), 24.3 (CH2); IR νmax 2924, 2853, 1728, 1510, 1492, 1465, 1271, 1139, 1038, 808 cm−1; HRMS (ESI) calcd for C20H24NO3 [M + H]+ 326.1756, found 326.1752. Ethyl 2-(7-Bromo-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3g): 27 mg, 61% yield, yellow oil; Rf 0.38 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.61−7.55 (1H, m), 7.46 (1H, dm, J = 8.3 Hz), 7.33 (1H, d, J = 8.3 Hz), 7.19−7.16 (1H, m), 6.05−6.02 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 3.83 (2H, bs), 3.50 (2H, s), 1.23 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.1 (CO), 141.2 (C), 138.0 (C), 136.0 (C), 131.1 (CH), 129.8 (CH), 122.7 (C), 115.8 (C), 111.9 (CH), 110.0 (CH), 104.2 (CH), 60.9 (CH2), 34.2 (CH2), 29.4 (CH2), 14.6 (CH3); IR νmax 2925, 1728, 1508, 1447, 1368, 1205, 1177, 1030, 808 cm−1; HRMS (ESI) calcd for C15H15BrNO2 [M + H]+ 320.0286, found 320.0274. Ethyl 2-(7-Chloro-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3h): 30 mg, 78% yield, colorless oil; Rf 0.44 (30% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.47−7.43 (1H, m), 7.37 (1H, d, J = 8.3 Hz), 7.31 (1H, dd, J = 8.3, 2.5 Hz), 7.19−7.16 (1H, m), 6.05−6.02 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 3.82 (2H, bs), 3.50 (2H, s), 1.23 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.1 (CO), 104.8 (C), 137.6 (C), 136.1 (C), 128.4 (C), 128.2 (CH), 126.9 (CH), 122.6 (C), 111.4 (CH), 110.0 (CH), 104.2 (CH), 60.8 (CH2), 34.1 (CH2), 29.5 (CH2), 14.6 (CH3); IR νmax 2982, 2919, 1726, 1507, 1491, 1478, 1369, 1252, 1168, 1030, 866, 811, 696 cm−1; HRMS (ESI) calcd for C15H15ClNO2 [M + H]+ 276.0791, found 276.0798. Ethyl 2-(7-Fluoro-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3i): 27 mg, 74% yield, yellow oil; Rf 0.42 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.37 (1H, dd, J = 8.7, 4.5 Hz), 7.25 (1H, dm, JH−F = 8.7 Hz), 7.19−7.14 (1H, m), 7.04 (1H, ddd, JH−H = 8.7, 2.6 Hz, JH−F = 8.7 Hz), 6.04−6.01 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 3.83 (2H, bs), 3.50 (2H, s), 1.30 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (CO), 160.0 (C, d, JC−F = 238 Hz), 138.5 (C),

137.6 (C, d, JC−F = 9.1 Hz), 136.1 (C), 122.1 (C), 114.6 (CH, d, JC−F = 6.6 Hz), 114.2 (CH, d, JC−F = 7.1 Hz), 110.9 (CH, d, JC−F = 8.2 Hz), 109.8 (CH), 104.2 (CH), 60.8 (CH2), 34.2 (CH2), 29.8 (CH2), 14.6 (CH3); IR νmax 2923, 1714, 1508, 1486, 1474, 1446, 1223, 1169, 1125, 1027, 856, 808, 734, 706 cm−1; HRMS (ESI) calcd for C15H15FNO2 [M + H]+ 260.1087, found 260.1092. Ethyl 2-(7-Methyl-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3j): 25 mg, 75% yield, yellow oil; Rf 0.40 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.28−7.22 (2H, m), 7.15−7.08 (2H, m), 6.03− 5.98 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 3.76 (2H, bs), 3.49 (2H, s), 2.33 (3H, s), 1.23 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.3 (CO), 139.9 (C), 136.0 (C), 135.5 (C), 133.2 (C), 128.6 (CH), 127.4 (CH), 121.7 (C), 110.0 (CH), 109.5 (CH), 103.7 (CH), 60.8 (CH2), 34.2 (CH2), 29.3 (CH2), 21.1 (CH3), 14.6 (CH3); IR νmax 2980, 2917, 1732, 1508, 1407, 1253, 1172, 1123, 1033, 807, 704 cm−1; HRMS (ESI) calcd for C16H18NO2 [M + H]+ 256.1338, found 256.1365. Ethyl 2-(7-(Benzyloxy)-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3k): 38 mg, 77% yield, yellow oil; Rf 0.31 (20% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ 7.47−7.30 (5H, m), 7.10 (1H, d, J = 8.5 Hz), 7.06−7.04 (1H, m), 6.99 (1H, bs), 6.88 (1H, dd, J = 8.5, 2.4 Hz), 6.07−6.04 (1H, m), 5.06 (2H, s), 4.19 (2H, q, J = 7.2 Hz), 3.79 (2H, bs), 3.57 (2H, s), 1.29 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 172.6 (CO), 155.5 (C), 137.2 (C), 136.1 (C), 135.6 (C), 135.5 (C), 128.7 (CH), 128.1 (CH), 127.6 (CH), 120.3 (C), 113.9 (CH), 113.4 (CH), 109.8 (CH), 108.7 (CH), 103.0 (CH), 71.0 (CH2), 60.8 (CH2), 34.0 (CH2), 29.6 (CH2), 14.4 (CH3); IR νmax 2981, 2903, 1729, 1509, 1491, 1279, 1239, 1173, 1137, 1026, 935, 802, 735, 697 cm−1; HRMS (ESI) calcd for C22H22NO3 [M + H]+ 348.1600, found 348.1613. Ethyl 2-(6-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3l): 29 mg, 77% yield, yellow oil; Rf 0.35 (20% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ 7.23 (1H, d, J = 8.3 Hz), 7.01 (1H, bs), 6.78 (1H, d, J = 2.3 Hz), 6.59 (1H, dd, J = 8.3, 2.3 Hz), 6.07−6.03 (1H, m), 4.18 (2H, q, J = 7.0 Hz), 3.84 (3H, s), 3.73 (2H, bs), 3.57 (2H, s), 1.29 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 172.5 (CO), 159.9 (C), 142.3 (C), 136.9 (C), 126.4 (C), 126.0 (CH), 120.9 (C), 108.7 (CH), 107.9 (CH), 103.1 (CH), 97.0 (CH), 60.8 (CH2), 55.8 (CH3), 34.0 (CH2), 28.6 (CH2), 14.4 (CH3); IR νmax 2930, 1732, 1629, 1596, 1508, 1391, 1367, 1277, 1211, 1179, 1156, 1031, 825, 791 cm−1; HRMS (ESI) calcd for C16H18NO3 [M + H]+ 272.1287, found 272.1277. Ethyl 2-(9-Methyl-9H-pyrrolo[1,2-a]indol-2-yl)acetate (3m): 18 mg, 51% yield, colorless oil; Rf 0.36 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.43 (1H, d, J = 7.5 Hz), 7.37 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.5 Hz), 7.17−7.10 (1H, m), 7.08 (1H, dd, J = 7.5, 1.3 Hz), 6.07−6.02 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 3.99 (1H, q, J = 7.2 Hz), 3.50 (2H, s), 1.23 (3H, d, J = 7.2 Hz), 1.23 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (CO), 142.3 (C), 141.2 (C), 141.1 (C), 128.4 (CH), 125.6 (CH), 123.9 (CH), 122.1 (C), 110.3 (CH), 109.5 (CH), 103.1 (CH), 60.8 (CH2), 36.3 (CH), 34.2 (CH2), 19.4 (CH3), 14.6 (CH3); IR νmax 2972, 2928, 1732, 1617, 1596, 1507, 1489, 1467, 1252, 1172, 1132, 1100, 1031, 749, 702 cm−1; HRMS (ESI) calcd for C16H18NO2 [M + H]+ 256.1338, found 256.1340. Ethyl 3-Phenyl-2-(9H-pyrrolo[1,2-a]indol-2-yl)propanoate (3n): 30 mg, 65% yield, yellow oil; Rf 0.49 (20% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.48−7.39 (2H, m), 7.31 (1H, t, J = 7.5 Hz), 7.29−7.13 (6H, m), 7.09 (1H, td, J = 7.5, 0.9 Hz), 6.14−6.09 (1H, m), 4.08−3.97 (2H, m), 3.88 (1H, dd, J = 10.1, 6.2 Hz), 3.82 (2H, bs), 3.31 (1H, dd, J = 13.6, 10.1 Hz), 3.07 (1H, dd, J = 13.6, 6.2 Hz), 1.11 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 174.1 (CO), 141.9 (C), 140.7 (C), 136.1 (C), 135.4 (C), 129.8 (CH), 129.0 (CH), 128.3 (CH), 127.7 (C), 127.0 (CH), 126.7 (CH), 123.9 (CH), 110.5 (CH), 108.9 (CH), 102.4 (CH), 60.8 (CH2), 47.9 (CH), 40.7 (CH2), 29.5 (CH2), 14.4 (CH3); IR νmax 2924, 2853, 1730, 1618, 1506, 1468, 1149, 1020, 748, 699 cm−1; HRMS (ESI) calcd for C22H22NO2 [M + H]+ 332.1651, found 332.1662. Ethyl 2-(7-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)-3-phenylpropanoate (3o): 22 mg, 43% yield, yellow oil; Rf 0.43 (20% EtOAc/ D

DOI: 10.1021/acs.joc.8b00457 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.31 (1H, d, J = 8.5 Hz), 7.27−7.21 (4H, m), 7.20−7.12 (2H, m), 7.09−7.04 (1H, m), 6.87 (1H, dd, J = 8.5, 2.6 Hz), 6.08−6.06 (1H, m), 4.09−3.93 (2H, m), 3.85 (1H, dd, J = 9.6, 6.0 Hz), 3.81−3.77 (5H, bs), 3.29 (1H, dd, J = 14.5, 9.6 Hz), 3.04 (1H, dd, J = 14.5, 6.0 Hz), 1.10 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 174.2 (CO), 157.4 (C), 140.8 (C), 136.9 (C), 135.8 (C), 129.8 (CH), 129.0 (CH), 127.7 (C), 127.0 (C), 127.0 (CH), 113.5 (CH), 113.0 (CH), 110.6 (CH), 108.6 (CH), 102.3 (CH), 60.7 (CH2), 56.0 (CH3), 47.9 (CH), 40.8 (CH2), 29.3 (CH2), 14.4 (CH3); IR νmax 2924, 1728, 1508, 1438, 1184, 1250, 1185, 1150, 1036, 722, 700 cm−1; HRMS (ESI) calcd for C23H24NO3 [M + H]+ 362.1756, found 362.1769. Ethyl 2-(9H-Pyrrolo[1,2-a]indol-2-yl)propanoate (3p): 11 mg, 32% yield, yellow oil; Rf 0.74 (20% EtOAc/heptanes); 1H NMR (600 MHz, (CD3)2CO) δ 7.44 (1H, d, J = 7.5 Hz), 7.42 (1H, d, J = 7.5 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.18 (1H, bs), 7.09 (1H, t, J = 7.5 Hz), 6.06−6.03 (1H, m), 4.12−4.06 (2H, m), 3.81 (2H, bs), 3.68 (1H, q, J = 7.0 Hz), 1.42 (3H, d, J = 7.0 Hz), 1.21 (3H, t, J = 7.2 Hz); 13C NMR (150 MHz, (CD3)2CO) δ 175.1 (CO), 142.0 (C), 136.0 (C), 135.3 (C), 129.5 (C), 128.3 (CH), 126.7 (CH), 123.8 (CH), 110.4 (CH), 108.2 (CH), 102.2 (CH), 60.7 (CH2), 39.5 (CH), 30.3 (CH2), 18.9 (CH3), 14.5 (CH3); IR νmax 2978, 2927, 1732, 1619, 1506, 1468, 1180, 1153, 1027, 750 cm−1; HRMS (ESI) calcd for C16H18NO2 [M + H]+ 256.1338, found 256.1330. Diethyl 2-(9H-Pyrrolo[1,2-a]indol-2-yl)succinate (3q): 38 mg, 82% yield, yellow oil; Rf 0.24 (30% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.47−7.40 (2H, m), 7.32 (1H, t, J = 7.5 Hz), 7.24−7.20 (1H, m), 7.10 (1H, td, J = 7.5, 0.9 Hz), 6.07−6.04 (1H, m), 4.10 (4H, q, J = 7.5 Hz), 4.00 (1H, dd, J = 10.4, 5.1 Hz), 3.82 (2H, bs), 3.07 (1H, dd, J = 16.8, 10.4 Hz), 2.70 (1H, dd, J = 16.8, 5.1 Hz), 1.21 (3H, t, J = 7.5 Hz), 1.20 (3H, t, J = 7.5 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 173.8 (CO), 172.0 (CO), 128.4 (CH), 126.8 (CH), 126.5 (C), 124.0 (CH), 110.5 (CH), 108.8 (CH), 102.2 (CH), 61.1 (CH2), 60.8 (CH2), 41.5 (CH), 38.4 (CH2), 29.3 (CH2), 14.50 (CH3), 14.47 (CH3); IR νmax 2925, 1731, 1507, 1467, 1370, 1257, 1190, 1157, 1030, 751 cm−1; HRMS (ESI) calcd for C19H22NO4 [M + H]+ 328.1549, found 328.1552. Diethyl 2-(7-Methoxy-9H-pyrrolo[1,2-a]indol-2-yl)succinate (3r): 27 mg, 53% yield, yellow oil; Rf 0.45 (30% EtOAc/heptanes); 1H NMR (300 MHz, (CD3)2CO) δ 7.32 (1H, d, J = 8.5 Hz), 7.16−7.12 (1H, m), 7.10−7.05 (1H, m), 6.88 (1H, dd, J = 8.5, 2.8 Hz), 6.03− 6.00 (1H, m), 4.10 (2H, q, J = 7.0 Hz), 4.09 (2H, q, J = 7.0 Hz), 3.99 (1H, dd, J = 10.5, 5.1 Hz), 3.81−3.78 (5H, m), 3.06 (1H, dd, J = 16.8, 10.5 Hz), 2.68 (1H, dd, J = 16.8, 5.1 Hz), 1.21 (3H, t, J = 7.0 Hz), 1.20 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, (CD3)2CO) δ 173.9 (CO), 172.0 (CO), 157.4 (C), 136.9 (C), 136.0 (C), 135.8 (C), 125.8 (C), 113.5 (CH), 113.0 (CH), 110.7 (CH), 108.5 (CH), 102.0 (CH), 61.0 (CH2), 60.8 (CH2), 56.0 (CH3), 41.5 (CH), 38.5 (CH2), 29.8 (CH2), 14.51 (CH3), 14.47 (CH3); IR νmax 2981, 2931, 1728, 1509, 1300, 1283, 1251, 1183, 1156, 1033, 805 cm−1; HRMS (ESI) calcd for C20H24NO5 [M + H]+ 358.1654, found 358.1681. Procedure for the Use of Supported Phosphine (Scheme 4a). In a Schlenk tube, indole carbaldehyde 1a (0.14 mmol, 1 equiv), polymer-supported triphenylphosphine (100−200 mesh; ∼3.2 mmol/ g loading) (1.5 equiv), and freshly distilled degassed toluene (0.1 M) were added. Then, allenoate 2a (0.21 mmol, 1.5 equiv) was added using a microsyringe. The reaction mixture was then heated for 3 h at 60 °C, and the crude reaction mixture was filtered and concentrated. The product was then purified by flash chromatography. Procedure for the Phosphine-Catalyzed Reaction (Scheme 4b). In a Schlenk tube, 1a (0.14 mmol, 1 equiv), 4-methyl-1-phenyl2,3-dihydrophosphole 1-oxide (10 mol %), bis(4-nitrophenyl)phosphate (10 mol %), and freshly distilled degassed toluene (0.15 M) were added. Then, allenoate 2a (1.5 equiv) and phenylsilane (1.5 equiv) were added using a microsyringe. The reaction mixture was then heated at 60 °C for 72 h, and the crude reaction mixture was concentrated and purified by flash chromatography using a silica gel prepacked column and EtOAc/heptanes as an eluent (0−20% of EtOAc over 25 min, 14 mL/min).

Note

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00457. Copies of 1H NMR and 13C NMR spectra of the products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Arnaud Voituriez: 0000-0002-7330-0819 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the support of the French “Agence Nationale de la Recherche” (ANR) for funding (HUISPHOS project no. ANR-13-JS07-0008, program nos. ANR-11-IDEX0003-02 and CHARMMMAT ANR-11-LABX-0039) and the Centre National de la Recherche Scientifique (CNRS). C.L. thanks CHARMMMAT Labex for a Master fellowship. Nidal Saleh is thanked for preliminary experiments.

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REFERENCES

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Note

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DOI: 10.1021/acs.joc.8b00457 J. Org. Chem. XXXX, XXX, XXX−XXX