Lorena
Alonso-Marañón
,
Luis A.
Sarandeses
,
M. Montserrat
Martínez
* and
José
Pérez Sestelo
*
Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química Fundamental, Universidade da Coruña, E-15071 A Coruña, Spain. E-mail: mmartinezc@udc.es; sestelo@udc.es
First published on 26th December 2016
A sequential one-pot indium-catalyzed intramolecular hydroarylation (IMHA) of bromopropargyl aryl ethers and amines, and palladium-catalyzed cross-coupling reaction using triorganoindium reagents (R3In) has been developed. In this transformation, the IMHA of 3-bromo-2-propynyl aryl ethers under indium(III) catalysis, proceeds regioselectively through a 6-endo dig pathway to afford 4-bromo-2H-chromenes. Subsequent palladium-catalyzed cross-coupling with R3In gives 4-substituted-2H-chromenes in one-pot. This sequential transformation was extended to 3-bromo-2-propynyl-N-tosylanilines to afford 4-substituted-1,2-dihydroquinolines. The dual-catalyzed procedure takes place efficiently with a variety of propargyl aryl ethers and amines and R3In (R = aryl, heteroaryl, alkyl or alkynyl), showing the efficiency of these organometallics and proving the compatibility of indium and palladium in catalysis.
Recently, we reported the indium-catalyzed intramolecular hydroarylation (IMHA) of propargyl aryl ethers for the synthesis of 2H-chromenes.4 The reaction is highly versatile and takes place regioselectively with terminal and internal alkynes bearing electron-rich and electron-deficient substituents in the arene and alkyne affording the 6-endo dig cyclization product. Recent computational studies support a mechanism based on indium(III) activation of the alkyne.5 In addition, indium catalysis offers significant advantages in terms of cost and low toxicity.6 Interestingly, the reaction of halopropargyl aryl ethers gives 4-halo-2H-chromenes in high yields without 1,2-halogen migration, a side reaction usually observed under gold catalysis.7 Taking advantage of the halo-substituents, and in combination with our research on metal-catalyzed cross-coupling reactions with triorganoindium reagents (R3In),8 we envisioned a sequential one-pot indium-catalyzed IMHA of 3-halopropynyl aryl ethers with a palladium-catalyzed cross-coupling reaction using R3In (Scheme 1). Additionally, we also propose the extension of this procedure to halopropargyl anilines. The IMHA of N-propargyl-N-tosylanilines has been reported using precious metals (Au, Pt, Rh) with variable yields based on the alkyne and arene substitution and catalyst loading.9 The gold-catalyzed IMHA of N-(3-iodoprop-2-ynyl)-N-tosylanilines takes place with iodide migration affording 3-iodo-1,2-dihydroquinolines.9g This methodology should offer a straightforward route to 4-functionalized 2H-chromenes and 1,2-dihydroquinolines – structural motifs present in a large number of naturally occurring and biologically active compounds.10
During the last few years, the palladium-catalyzed cross-coupling reaction of triorganoindium reagents (R3In), discovered by this research group,8a has gained increasing utility in organic synthesis.11 R3In can be easily prepared from the corresponding organolithium using InCl3, or organic halides and the indium metal. Particular features of R3In are the high efficiency, versatility and selectivity in transferring the three organic groups attached to indium. In comparison with other organometallics, aryl–aryl and aryl–alkenyl couplings using R3In have become an efficient alternative.12
Entry | R–M | (Equiv.) | [Pd] cat. | Product | Yielda (%) |
---|---|---|---|---|---|
a Isolated yields. b Toluene at 100 °C. c Toluene/THF 2:1. d Na2CO3 (6.0 equiv.) in toluene/EtOH 2:1. | |||||
1 | Ph3In | 0.5 | Pd(PPh3)2Cl2 | 3a | 88 |
2 | Ph3In | 0.5 | Pd(PPh3)4 | 3a | 87 |
3 | (2-Thienyl)3In | 0.5 | Pd(PPh3)2Cl2 | 3b | 89 |
4 | (PhCC)3In | 0.5 | Pd(dppf)Cl2 | 3c | 67 |
5 | Bu3In | 0.5 | Pd(PPh3)2Cl2 | 3d | 60 |
6 | PhSnBu3b | 4.0 | Pd(PPh3)4 | 3a | 30 |
7 | PhZnClc | 4.0 | Pd(PPh3)4 | 3a | 40 |
8 | PhB(OH)2d | 2.2 | Pd(PPh3)4 | 3a | 87 |
Once the reaction conditions for the Pd-catalyzed coupling of R3In with the 4-bromo-2H-chromene 2a had been established, the sequential one-pot In-catalyzed IMHA and Pd-catalyzed cross-coupling was explored (Table 2). In this scenario, we found that hydroarylation of the 3-bromo-2-propynyl aryl ether 1a using InCl3 (5 mol%) in toluene at 60 °C for 2 hours, followed by the addition of Ph3In (THF solution, 0.5 equiv.) and Pd(PPh3)2Cl2 (5 mol%) gave the 4-phenyl-2H-chromene 3a in 95% overall yield after 18 h at 80 °C (entry 1). Using InBr3 or InI3 as catalysts the sequential transformation also afforded the desired product 3a but in lower yields (57% and 60% respectively, entries 2 and 3). These results can be explained by the higher reactivity of these indium(III) halides, which led to the formation of by-products. Overall, these results demonstrate the compatibility of palladium cross-coupling with the indium IHMA reaction conditions.
Entry | InX3 | R–M (0.5 equiv.) | [Pd] cat. | Product | Yielda (%) |
---|---|---|---|---|---|
a Isolated yield. b 4.0 equiv. of PhZnCl. c 4.0 equiv. of PhSnBu3 at 100 °C. d 2.2 equiv. of PhB(OH)2, Na2CO3 (6 equiv.) in toluene:EtOH (2:1). | |||||
1 | InCl3 | Ph3In | Pd(PPh3)2Cl2 | 3a | 95 |
2 | InBr3 | Ph3In | Pd(PPh3)2Cl2 | 3a | 57 |
3 | InI3 | Ph3In | Pd(PPh3)2Cl2 | 3a | 60 |
4 | InCl3 | (2-Thienyl)3In | Pd(PPh3)2Cl2 | 3b | 85 |
5 | InCl3 | (PhCC)3In | Pd(dppf)Cl2 | 3c | 72 |
6 | InCl3 | Bu3In | Pd(PPh3)2Cl2 | 3d | 70 |
7 | InCl3 | Me3In | Pd(PPh3)2Cl2 | 3e | 89 |
8 | InCl3 | PhZnClb | Pd(PPh3)4 | 3a | 40 |
9 | InCl3 | PhSnBu3c | Pd(PPh3)4 | 3a | 40 |
10 | InCl3 | PhB(OH)2d | Pd(PPh3)4 | 3a | 87 |
Under the previously developed reaction conditions, the one-pot sequence was assessed with a variety of R3In reagents (Table 2). The procedure using tri(2-thienyl)indium (0.5 equiv.) gave the corresponding 2H-chromene 3b in 85% overall yield (entry 4). The reaction with tri(phenylethynyl)indium also gave the 4-phenylethynyl-2H-chromene 3c on using Pd(dppf)Cl2 as the catalyst (72%, entry 5). The reaction with trialkylindium reagents such as tributylindium and trimethylindium afforded the 4-substituted-2H-chromenes 3d and 3e in 70% and 89% yields, respectively (entries 6 and 7). In all of these examples the yields for the two-step one-pot sequence compare favourably with procedures where each step was performed separately and required isolation of the intermediate. The reactivity and compatibility of other organometallic reagents in this sequential process was also evaluated. The use of phenylzinc chloride (4 equiv.) and Pd(PPh3)4 (5 mol%) provided the coupling product 3a in a modest 40% isolated yield (entry 8). Analogously, the reaction with tributylphenyltin (4.0 equiv.) at 100 °C gave only 40% yield (entry 9). The use of phenylboronic acid (2.2 equiv.), Na2CO3 (6.0 equiv.) and Pd(PPh3)4 (5 mol%) in a mixture of toluene and ethanol gave the 4-phenyl-2H-chromene 3a in 87% yield (entry 10). These results demonstrate the compatibility of palladium-catalyzed coupling reactions with the indium-catalyzed IMHA in a one-pot protocol and triorganoindium compounds are shown as the reagents of choice.
In an effort to increase the chemical diversity of this sequential dual-catalyzed In/Pd protocol, the methodology was then studied with 3-bromopropargyl anilines. This sequential transformation should allow the synthesis of 4-substituted-1,2-dihydroquinolines, a structural unit present in naturally occurring products, pharmaceuticals and also used as building blocks in organic synthesis.10 In our initial experiments we found that the IMHA of N-(3-bromoprop-2-ynyl)-N-tosylaniline 4 using InCl3 (5 mol%) takes place at 100 °C to give the 4-bromo-1,2-dihydroquinoline 7 in 95% yield (Table 3, entry 1). In comparison with the IMHA of propargyl aryl ethers, the amines are less reactive, probably due to electronic effects. The use of InBr3 or InI3 (5 mol%) as catalysts at 100 °C also gave 7 in shorter reaction times and high yields (92% and 80% respectively, entries 2 and 3). With these results in mind, the sequential IMHA-coupling using the different indium(III) halides in toluene at 100 °C and reaction with Ph3In (THF solution, 0.5 equiv.) and Pd(PPh3)4 (5 mol%) at 80 °C was tested. Under these conditions, the cross-coupling step was not complete after 18 h and the desired 4-phenyl-1,2-dihydroquinoline 10a was obtained in moderate yield. Optimal results were obtained using 0.7 equiv. of Ph3In and InBr3 as the catalyst (92%), although the use of InCl3 or InI3 also gave satisfactory yields (Table 3, entries 4–6).
Entry | Substrate | InX3 | R1 | R2 | R3 | R4–M (0.7 equiv.) | Product | Yielda (%) |
---|---|---|---|---|---|---|---|---|
a Isolated yields. b Pd(dppf)Cl2 (5 mol%) as the catalyst. c 2.2 equiv. of PhB(OH)2, Na2CO3 (6.0 equiv.) in toluene/EtOH 2:1 at 80 °C. d 4.0 equiv. of PhSnBu3 at 100 °C for 24 h. | ||||||||
1 | 4 | InCl3 | H | OMe | H | — | 7 | 95 |
2 | 4 | InBr3 | H | OMe | H | — | 7 | 92 |
3 | 4 | InI3 | H | OMe | H | — | 7 | 80 |
4 | 4 | InBr3 | H | OMe | H | Ph3In | 10a | 92 |
5 | 4 | InI3 | H | OMe | H | Ph3In | 10a | 80 |
6 | 4 | InCl3 | H | OMe | H | Ph3In | 10a | 70 |
7 | 4 | InBr3 | H | OMe | H | (2-Thienyl)3In | 10b | 86 |
8 | 4 | InBr3 | H | OMe | H | (PhCC)3In | 10c | 65b |
9 | 4 | InBr3 | H | OMe | H | Bu3In | 10d | 60 |
10 | 4 | InBr3 | H | OMe | H | Me3In | 10e | 72 |
11 | 4 | InBr3 | H | OMe | H | PhSnBu3 | 10a | 38d |
12 | 4 | InBr3 | H | OMe | H | PhB(OH)2 | 10a | 80c |
13 | 5 | InBr3 | H | H | H | Ph3In | 11a | 92 |
14 | 5 | InBr3 | H | H | H | (2-Thienyl)3In | 11b | 98 |
15 | 5 | InBr3 | H | H | H | (PhCC)3In | 11c | 78 |
16 | 5 | InBr3 | H | H | H | Bu3In | 11d | 74 |
17 | 5 | InBr3 | H | H | H | Me3In | 11e | 85 |
18 | 6 | InI3 | OMe | H | OMe | Ph3In | 12a | 75 |
19 | 6 | InI3 | OMe | H | OMe | (2-Thienyl)3In | 12b | 55 |
20 | 6 | InI3 | OMe | H | OMe | Me3In | 12e | 67 |
Under the previously developed conditions, the sequential procedure was tested using different triorganoindium reagents. The reaction using heteroarylindium reagents such as tri(2-thienyl)indium (0.7 equiv.) gave the 4-thienyldihydroquinoline 10b in 86% yield (entry 7). The use of trialkynylindium reagents such as tri(phenylethynyl)indium also afforded the dihydroquinoline 10c in 65% yield with Pd(dppf)2Cl2 as the catalyst (entry 8). The reaction with tributylindium and trimethylindium also gave the corresponding 4-substituted dihydroquinolines 10d and 10e in 60% and 72% yields respectively (entries 9 and 10), thus showing the utility of indium organometallics in the cross-coupling with alkyl nucleophiles. This sequential transformation was also assessed employing other organometallic reagents. Interestingly, the reaction using tributylphenyltin gave a low isolated yield (38%) (entry 11), and only the reaction of phenylboronic acid worked efficiently using Na2CO3 as the base (80%, entry 12).
With the purpose to expand the synthetic utility of the methodology, we tested the procedure with other bromopropargyl anilines. The indium-catalyzed IMHA of N-(3-bromoprop-2-ynyl)-N-tosylaniline 5 using InBr3 (5 mol%) in toluene at 100 °C for 2 h, followed by the addition of triphenylindium (THF solution, 0.7 equiv.) and Pd(PPh3)4 (5 mol%) overnight at 80 °C, afforded N-tosyl-4-phenyl-1,2-dihydroquinoline (11a) in an excellent 92% yield (entry 13).13 Analogously, the use of tri(2-thienyl)indium gave the corresponding dihydroquinoline 11b in 98% yield (entry 14). The dual-catalyzed process with the tri(phenylethynyl)indium reagent also gave 4-phenylethynyldihydroquinoline 11c in 78% yield (entry 15). Furthermore, butyl- and methyldihydroquinolines 11d and 11e were successfully prepared by using tributylindium and trimethylindium reagents in 74% and 85% yields (entries 16 and 17), respectively.
Additionally, the one-pot sequence with N-(3-bromo-2-propynyl)-3,5-dimethoxy-N-tosylaniline 6 also proceeded efficiently to give the desired dihydroquinolines. In this case, the best yields were obtained using InI3 as the catalyst and the 4-phenyl-1,2-dihydroquinoline 12a was obtained in 75% overall yield (entry 18).13 Under the established conditions, the reaction with tri(2-thienyl)indium and trimethylindium provided 12b and 12e in 55% and 67% overall yields (entries 19 and 20), respectively. These results show the versatility of this novel sequential one-pot In/Pd catalyzed IMHA-cross-coupling reaction using indium organometallics and demonstrate its application to the synthesis of 4-substituted-1,2-dihydroquinolines.
Footnote |
† Electronic supplementary information (ESI) available: General methods, characterization data and copies of the 1H, 13C NMR and DEPT-135 spectra for all compounds prepared. See DOI: 10.1039/c6qo00721j |
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