Access to Spiroindolines and Spirodihydrobenzofurans via Pd

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Access to Spiroindolines and Spirodihydrobenzofurans via PdCatalyzed Domino Heck Spiroyclization through C−H Activation and Carbene Insertion Jian-Guo Liu,†,‡ Wen-Wen Chen,*,‡ Chang-Xue Gu,†,‡ Bin Xu,*,† and Ming-Hua Xu*,‡ †

Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China

‡

S Supporting Information *

ABSTRACT: A new palladium-catalyzed domino approach for the synthesis of attractive spirocyclic indolines and dihydrobenzofurans was developed. The reaction proceeds through a sequential intramolecular Heck spirocyclization, remote C−H activation, and diazocarbonyl carbene insertion. Various spiroindolines and spirodihydrobenzofurans containing two quartenary carbon stereocenters were readily obtained in good to excellent yields. A preliminary study of asymmetric spirocyclization using chiral monophosphoramidite as a ligand was also conducted, enabling access to highly valuable chiral spiroindolines with up to 80% ee.

S

the cyclization can be further captured by other nucleophilic coupling partners or trapped through the insertion of unsaturated species (Scheme 1, routes a and b).4 Once the R

pirocycles are prominent structural motifs ubiquitously found in a number of natural products, pharmaceutically important compounds, and ligands in transition-metal catalyzed transformations.1 Among them, spiroindolines are one important type of privileged structure moiety that are present in various naturally occurring indole alkaloids and biologically active molecules, such as vindoline, strychnine, perophoramidine, and communesins (Figure 1).2 Therefore, considerable

Scheme 1. Domino Intramolecular Heck Reactions

substitution attached to the olefin is an aryl group, the adjacent sp2 C−H bond of this aromatic ring can be activated to further generate spirocyclic palladacycle B, which can generate cyclized product through reductive elimination5 or be trapped with appropriate nucleophiles such as diaziridinone,6 benzyne,7 alkyne,8 and CH2Br29 (Scheme 1, route c). As a consequence, the Pd-catalyzed domino Heck anion capture cascade has become a valuable strategy for the synthesis of useful heterocycles, especially spirocyclic compounds. Since our group has been involved in a drug discovery program with molecules having indole-based pharmacophores bearing a spirocyclic motif at the 3-position, we became interested in the development of a new and simple approach for the

Figure 1. Representative spiroindoline derivatives with biological activities.

efforts have been devoted to the synthesis of the spiroindoline scaffolds and some useful synthetic methods have been developed.3 However, there are increasing demands for facile and efficient protocols to construct this type of valuable spiroindoline molecules. Intramolecular Heck reaction of an aryl halide tethered with a terminal alkene group is a direct strategy to form a five- or sixmembered ring. The alkyl-palladium intermediate formed after © XXXX American Chemical Society

Received: March 22, 2018

A

DOI: 10.1021/acs.orglett.8b00935 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Conditions Optimizationa

synthesis of spiroindoline derivatives by Pd-catalyzed domino intramolecular Heck cyclization/C−H activation. α-Diazocarbonyl compounds, i.e. carbenoid precursors, have been successfully used in a variety of synthetic transformations since difunctionalization of the carbon center can be realized concomitantly, thus making it a versatile building block. Given our interest in C−H activation via palladium catalysis,10 we envisaged the possibility of employing α-diazocarbonyl compounds to trap the alkyl Pd(II) intermediate B to generate spiro[indoline-Indane] and spiro[dihydrobenzofuran-Indane] derivatives (Scheme 2a). During the process of our study, Scheme 2. Strategy to Spirocyclic Indolines and Dihydrobenzofurans and the Related Work

́ Garcia-Ló pez’s group reported a Pd-catalyzed cascade reaction of N-arylamides with α-diazocarbonyl compounds, which allows the synthesis of spiro[oxoindole-Indane] derivatives in 45−95% yield (Scheme 2b).11 However, this method is not applicable to the synthesis of spiroindolines.12 With the use of substrate 1a lacking a carbonyl functionality between nitrogen and the alkene, the reaction simply afforded complex mixtures, including the decomposed product N-(2-bromophenyl)-4methylbenzenesulfonamide C under the reported standard conditions (Scheme 2c). Herein, we describe our success in accessing the spiro[indoline-Indane] and spiro[dihydrobenzofuran-Indane] skeletons from alkene tethered N-arylsulfamides and arylethers via a Pd-catalyzed domino Heck spirocyclization. Moreover, a promising asymmetric process using a chiral spiro monophosphoramidate as ligand was developed, providing access to highly valuable chiral spiroindolines with up to 80% ee. Initially, our investigation was carried out by examining the reaction of alkene-tethered aryl bromide 1a with methyl αdiazophenylacetate 2a in the presence of 10 mol % of Pd(OAc)2, 15 mol % of DPPF, and 1.5 equiv of Cs2CO3 in toluene. To our delight, the reaction occurred at 80 °C and gave the desired spirocyclized product 3a, albeit in only 21% yield with a 58:42 diastereoisomeric ratio (dr) (Table 1, entry 1). This result suggests that the reaction could indeed undergo the desired spirocyclization through a domino Heck coupling/ C−H activation/insertion pathway. Changing the ligand to PPh3 led to a slight improvement of the yield to 34% (entry 2). With the use of MeCN as solvent, however, only a trace amount of product was formed (entry 3).11 After careful examination, we recognized that the low yield was attributed to the considerable decomposition of the starting substrate 1a to N-(2-bromophenyl)-4-methylbenzenesulfonamide. Unlike the case of N-arylamides,11 it seems that the undesired oxidative addition of palladium(0) to allyl amine takes place predominantly, thus leading to the formation of a large majority of

entry

ligand

base

solvent

yieldb(%)

drc

1d 2d 3d,e 4 5 6 7 8 9 10 11 12 13f 14f,g 15f,h 16f 17f 18f

DPPFi PPh3 PPh3 PPh3 DPPFi BINAPi L1 PCy3 P(o-tol)3 P(p-tol)3 PPh3 PPh3 PPh3 PPh3 PPh3 L2 L2 L2

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Na2CO3 CsF CsF CsF CsF CsF CsF

toluene toluene MeCN toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene MeCN THF

21 34 trace 69 18 trace trace trace trace 67 27 trace 82 41 33 94 72 69

58:42 57:43 − 57:43 58:42 − − − − 52:48 57:43 − 57:43 54:46 52:48 61:39 38:62 52:48

a

The reaction was performed with 1b (0.1 mmol, 1 equiv), 2a (0.2 mmol, 2 equiv), Pd(OAc)2 (10 mol %), ligand (30 mol %), and base (1.5 equiv) in toluene (1 mL) at 80 °C for 3 h. bIsolated yield. c Determined by LC-MS or HPLC analysis. d1a was employed as the substrate. ePd(OAc)2 (5 mol %), PPh3 (10 mol %), base (1.0 equiv) at 100 °C. f3 equiv of base. gPd(dba)2 (10 mol %). hPd(TFA)2 (10 mol %). i15 mol %.

decomposed product. To facilitate the desired oxidative addition to form the corresponding aryl-palladium intermediate, we considered switching the substrate from aryl bromide to iodide. Accordingly, alkene-tethered aryl iodide 1b was prepared and employed. To our delight, a dramatic improvement of the reaction yield was observed and the desired product 3a was isolated in 69% yield under similar conditions (entry 4). It is worth mentioning that the ligand was found to have a strong impact on the reaction. When bidentate phosphorus ligands were employed, the yield decreased dramatically (entries 5−7). An electron-rich or a sterically hindered monophosphine ligand was not effective for the reaction (entries 8, 9), while P(p-tol)3 gave a comparable yield with PPh3 (entry 10). Examination of base additives revealed that CsF was the best choice, which can remarkably improve the yield to 82% (entries 11−13). To achieve a better yield, further screening with respect to the palladium source and ligands was carried out. A preliminary investigation reveals that Pd(OAc)2 exhibited the best catalytic activity (entries 13−15). Very gratifyingly, we discovered that monophosphoramidite ligand L2 could display unique catalytic activity and furnish the spiroindoline product 3a in excellent yield (94%) with 61:39 dr (entry 16). Employing other solvent such as MeCN and THF resulted in diminished yields (entries 17, 18). With the optimal conditions in hand, we then investigated the reaction generality (Scheme 3). First, we examined the B


Letter

Organic Letters Scheme 3. Pd-Catalyzed Spirocyclization for Synthesis of Spiroindolinesa,b,c

Figure 2. X-ray structures of the two diastereomers 3aa and 3ab.

Encouraged by the success in assembling the spiro[indolineIndane] framework, we next turned our attention to construct the spiro[dihydrobenzofuran-Indane] skeleton. Accordingly, several alkene tethered oxygen-linked aryl iodides were prepared and examined as representative substrates. To our disappointment, the reaction is sensitive to the linker, and no product was formed when employing 4a and α-diazoester 2a under the above-mentioned optimized conditions. After careful investigation, we were pleased to find that the reaction could proceed smoothly in the presence of PPh3 ligand with Cs2CO3 as the base and THF as the solvent, enabling access to the expected spirocyclic dihydrobenzofurans in good yields (Scheme 4). For example, spirocyclic dihydrobenzofuran-

a

The reaction was performed with 1 (0.1 mmol, 1 equiv), 2 (0.2 mmol, 2 equiv), Pd(OAc)2 (10 mol %), L2 (30 mol %), and CsF (3 equiv) in toluene (1 mL) at 80 °C for 3 h. bIsolated yield. c Determined by LC-MS or HPLC analysis.

substrates bearing different substituents on the iodobenzene ring (Ar1). Both electron-donating and -withdrawing groups at the meta- or para-position were compatible, affording the corresponding spiro[indoline-Indane] products (3b−3h) in good to excellent yields (63−91%) with a moderate diastereoisomeric ratio. It is fascinating to note that even the bromo group survived in this domino Heck spirocyclization and furnished the desired product (3g) in high yield (86%). Next, substrates possessing various substituents on the aryl ring attached to the alkene (Ar2) were also examined. Notably, the reaction can tolerate a series of substrates that contain either an electron-donating or -withdrawing group at the para-position, providing the corresponding spiroindoline products (3i−3l) in good to high yields (69−85%). Lastly, the compatibility of αdiazoesters 2 was tested. The yield decreased along with the increase of steric hindrance of the ester group (3a: 94%; 3m: 80%; 3n: 56%) albeit with little influence on the diastereoisomeric ratio. A variety of α-diazoesters 2 bearing substituents with diverse electronic and steric properties all perform well to furnish the spiroindolines in good to excellent yields (3o−3s: 65−92%). It is worth noting that almost all of the two diastereomers (except 3n) generated from each reaction are separable by silica gel column chromatography (see Supporting Information (SI) for characterization). Very interestingly, when Ar2 is 1-naphthyl, a completely different spirocyclic product (3t) was isolated in 84% yield. In this case, the α-diazoester (2a) insertion did not take place. This result indicates that the C−H bond at the C-8 position of the naphthyl group rather than the C−H at C-2 is preferentially activated. The structures of both two diastereomers of spiroindoline product 3a (3aa (CCDC 1831089) and 3ab (CCDC 1831090)) were confirmed by single crystal X-ray diffraction, and their relative configurations were unambiguously determined (Figure 2). In the major diastereomer (3aa), the methyl ester group attached to the indene nucleus is placed in the anti position relative to the p-tosylamide moiety, while in the minor diastereomer (3ab) these two are in the syn position.

Scheme 4. Pd-Catalyzed Spirocyclization for Synthesis of Spirodihydrobenzofuransa,b,c

a

The reaction was performed with 4 (0.1 mmol, 1 equiv), 2 (0.2 mmol, 2 equiv), Pd(OAc)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (1.5 equiv) in THF (1 mL) at 70 °C for 3 h. bIsolated yield. c Determined by HPLC analysis.

Indane 5a was obtained in 87% yield with 57:43 dr. In accordance with the findings on the spiroindolines, αdiazoesters with diverse electronic properties are all well tolerated in this process (5d−f, 62−78%). Finally, an attempt for asymmetric spirocyclization with a chiral monophosphoramidite ligand was conducted. It should be noted that it is often difficult to achieve this type of domino process involving intramolecular carbopalladation in a highly enantioselective manner; successful examples remain very C


Letter

Organic Letters few.13 Preliminary study disclosed that moderate enantiocontrol could be achieved when enantiopure (R)-L2 was applied (94% yield for 3a, 60:40 dr, 3aa: 55% ee, 3ab: 35% ee). With the use of chiral spiro monophosphoramidite ligand (R,R,R)L3, higher levels of enantioselectivity can be obtained (Scheme 5). In the case of 3a, chiral spiroindolines containing two all-

charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

Scheme 5. Asymmetric Spirocyclization for Synthesis of Chiral Spiroindolinesa,b,c

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Bin Xu: 0000-0002-9251-6930 Ming-Hua Xu: 0000-0002-1692-2718 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21472205, 81521005, 21325209) and SA-SIBS Scholarship Program (for W.-W.C.) is greatly acknowledged.

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a

The reaction was performed with 1 (0.1 mmol, 1 equiv), 2 (0.2 mmol, 2 equiv), Pd(OAc)2 (10 mol %), L3 (30 mol %), and CsF (3 equiv) in toluene (1 mL) at 80 °C for 3 h. bIsolated yield. c Determined by chiral HPLC analysis. dAfter one recrystallization. e After recrystallization twice.

carbon quaternary stereocenters were attained with much improved enantiopurity (3aa: 74% ee, 3ab: 42% ee). Remarkably, optically pure spirocyclic products 3aa and 3ab (99.9% ee) can be obtained simply after recrystallization from petroleum ether/EtOAc. In summary, we have developed an unprecedented Pdcatalyzed domino Heck spirocyclization approach for the synthesis of attractive spirocyclic indolines and dihydrobenzofurans. The reaction proceeds through a sequential carbopalladation, remote C−H activation, and carbene insertion. This methodology enables efficient access to a broad range of spiroindolines and spirodihydrobenzofurans containing two quartenary stereogenic centers in good to excellent yields. Our preliminary results of asymmetric enantioselective spirocyclization reveal that the use of a chiral spiro phosphoramidite ligand can furnish optically active spiroindolines with up to 80% ee. Efforts to further extend the reaction scope and improve enantioselectivity are currently ongoing.

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REFERENCES

(1) (a) Smith, L. K.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 9907. (b) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. (c) Ding, K.; Han, Z.; Wang, Z. Chem. - Asian J. 2009, 4, 32. (2) (a) Saxton, J. E. In The Alkaloids, Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol. 51, pp 1−197. (b) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. (c) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67, 78. (d) Powell, N. A.; Kohrt, J. T.; Filipski, K. J.; Kaufman, M.; Sheehan, D.; Edmunds, J. E.; Delaney, A.; Wang, Y.; Bourbonais, F.; Lee, D.-Y.; Schwende, D.; Sun, F.; McConnell, P.; Catana, C.; Chen, H.; Ohren, J.; Perrin, L. A. Bioorg. Med. Chem. Lett. 2012, 22, 190. (e) Cassayre, J.; Molleyres, L.-P.; Maienfisch, P.; Cederbaum, F. WO Patent 2005061512, 2005. (3) Trost, B. M.; Brennan, M. K. Synthesis 2009, 2009, 3003. (4) For selected examples, see: (a) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.; Neuville, L.; Zhu, J. Chem. - Eur. J. 2010, 16, 5863. (b) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778. (c) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Org. Lett. 2013, 15, 4814. (d) Grigg, R.; Köppen, I.; Rasparini, M.; Sridharan, V. Chem. Commun. 2001, 964. (e) Seashore-Ludlow, B.; Danielsson, J.; Somfai, P. Adv. Synth. Catal. 2012, 354, 205. (f) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714. (5) For selected examples, see: (a) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Nat. Chem. 2017, 9, 361. (b) Piou, T.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 3760. (c) Bunescu, A.; Piou, T.; Wang, Q.; Zhu, J. Org. Lett. 2015, 17, 334. (6) Zheng, H.; Zhu, Y.; Shi, Y. Angew. Chem., Int. Ed. 2014, 53, 11280. (7) (a) Pérez-Gómez, M.; García-López, J.-A. Angew. Chem., Int. Ed. 2016, 55, 14389. (b) Yoon, H.; Lossouarn, A.; Landau, F.; Lautens, M. Org. Lett. 2016, 18, 6324. For related mechanistic studies, see: (c) Franzoni, I.; Yoon, H.; García-López, J.-A.; Poblador-Bahamonde, A. I.; Lautens, M. Chem. Sci. 2018, 9, 1496. (d) Pérez-Gómez, M.; Navarro, L.; Saura-Llamas, I.; Bautista, D.; Lautens, M.; García-López, J.-A. Organometallics 2017, 36, 4465. (8) Yoon, H.; Rölz, M.; Landau, F.; Lautens, M. Angew. Chem., Int. Ed. 2017, 56, 10920. (9) Shao, C.; Wu, Z.; Ji, X.; Zhou, B.; Zhang, Y. Chem. Commun. 2017, 53, 10429.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00935. Experimental procedures and spectroscopic data of all new compounds (PDF) Accession Codes

CCDC 1831089−1831090 contain the supplementary crystallographic data for this paper. These data can be obtained free of D


Letter

Organic Letters (10) (a) Cheng, C.; Chen, W.-W.; Xu, B.; Xu, M.-H. Org. Chem. Front. 2016, 3, 1111. (b) Cheng, C.; Chen, W.-W.; Xu, B.; Xu, M.-H. J. Org. Chem. 2016, 81, 11501. (11) Pérez-Gómez, M.; Hernandez-Ponte, S.; Bautista, D.; GarcíaLópez, J.-A. Chem. Commun. 2017, 53, 2842. (12) The authors stated in their paper that expanding the scope of the reaction to other substrates, such as alkenes tethered to arylethers or N-arylsulfamides instead of N-arylamides, was not successful, as the reactions afforded more complex mixtures. (13) For leading examples, see: (a) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 16028. (b) Tong, S.; Limouni, A.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 14192.

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Access to Spiroindolines and Spirodihydrobenzofurans via Pd

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