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Synthesis of fused tetracyclic spiroindoles via palladium-catalysed cascade cyclisation† Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii* and Hiroaki Ohno*

Received 26th August 2013, Accepted 27th October 2013 DOI: 10.1039/c3cc46511j www.rsc.org/chemcomm

Efficient palladium-catalysed cascade cyclisation to form spiroindoles is developed. Treatment of indoles bearing a propargyl chloride side chain at the 3-position with various external nucleophiles in the presence of a catalytic amount of Pd2(dba)3CHCl3/dppb and Cs2CO3 in THF gives fused tetracyclic spiroindoles in moderate to good yields.

Spiroheterocyclic compounds have been reported to exhibit broad biological activity.1 Among them, fused spiroindoles are important structures that are present in various alkaloids such as perophoramidine and communesins,2 as well as other biologically active compounds.2 Many synthetic chemists have therefore devoted considerable efforts to developing syntheses of fused spiroindoles. Recent advances in transition-metal chemistry have revealed that indoles are suitable nucleophiles for transition-metal-catalysed allylic substitution reactions.3–7 In 2005, Tamaru and co-workers reported a C-3 selective palladium-catalysed allylation of indoles promoted by triethylborane using allyl alcohols.4a Soon after, Trost and Quancard described an asymmetric version of this reaction.4b In 2006, Bandini and co-workers reported a palladium-catalysed intramolecular asymmetric allylation of 2-substituted indoles to form tetrahydro-b-carbolines.5a Rawal and co-workers reported the intermolecular reaction of 2,3-disubstituted indoles with allylic carbonates to give the C-3 allylation products.5b You et al.6 showed that indoles bearing a reactive side chain at the 3-position can form spiroindoles by iridium-catalysed intramolecular allylation (eqn (1), Scheme 1). In contrast, the reaction of propargylic compounds with indoles was unprecedented until quite recently: in 2013, Hamada and co-workers reported a palladium-catalysed intramolecular reaction of phenols and indoles to produce spiroindoles bearing a 1,3-butadiene moiety (eqn (2)).7,8 However, palladium-catalysed cascade cyclisation of propargylic compounds accompanying the construction of spiroindoles has not been reported.9

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: [email protected], [email protected]; Fax: +81 75 753 4570; Tel: +81 75 753 4571 † Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all new compounds. See DOI: 10.1039/c3cc46511j

298 | Chem. Commun., 2014, 50, 298--300

Scheme 1 Spiroindole formation by transition-metal-catalysed intramolecular allylic substitution.

In 2003, the author’s group reported that bromoallenes, synthetic equivalents of propargylic compounds, are extremely useful for the synthesis of medium-sized rings.10 We have also shown that the propargylic–allenic compounds bearing two nucleophilic functionalities undergo cascade cyclisation to produce bicyclic compounds.11 Based on these findings, we designed a palladium-catalysed spirocyclisation– nucleophilic cyclisation cascade of indole-substituted propargyl compounds. Herein, we report the synthesis of fused tetracyclic spiroindoles via the palladium-catalysed cascade reaction of propargyl chloride using a sulfonamide as an external nucleophile (eqn (3)). We initially investigated the reaction of propargyl chloride 1a as a model substrate using 10 mol% of phosphorus ligand with 5 mol% of Pd(dba)2, 2 equiv. of base and 1 equiv. of TsNH2 in THF (Table 1). When the bidentate ligand 1,10 -bis(diphenylphosphino)ferrocene (dppf) was used, the spirocyclisation–nucleophilic cyclisation reaction proceeded to produce the desired product 2a in moderate yield (47%, entry 2). Screening of inorganic bases (entries 3–5) revealed that Cs2CO3 was optimal for the cascade cyclisation. Next, we examined

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Table 1

ChemComm

Optimisation of reaction conditions using 1

Yielda (%) Entry

Subst.

Ligand

Base

T (1C)

Time (h)

2a

3a

1b 2 3 4 5 6 7 8 9 10 11c 12c 13c

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c

(PPh3) dppf dppf dppf dppf dppm dppe dppp dppb dpppe dppb dppb dppb

Cs2CO3 Cs2CO3 K2CO3 CaCO3 NaHCO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

50 50 50 60 60 60 60 50 rt 50 rt 60 60

24 0.5 3 24 24 24 7 1 2.5 5 3 15 3

0 47 15 0 0 0 22 29 ca. 72 37 72 14 8

0 5 6 0 0 17 62 6 3 2 5 6 0

a

Isolated yields. b Reaction was performed using Pd(PPh3)4. c Reactions were carried out using 2.5 mol% Pd2(dba)3CHCl3 and 1.5 equiv. of TsNH2 at 0.067 M.

other bidentate phosphorus ligands. Among the ligands examined, dppb proved to be the most suitable for this reaction. The desired product 2a was obtained in ca. 72% yield (entry 9), although the reproducibility of the reaction was poor. Assuming that this was related to the purity of Pd(dba)2,12 we examined the reaction using Pd2(dba)3 CHCl3 and obtained the desired product 2a in 72% yield reproducibly (entry 11; for more detailed results of screening of the reaction conditions, see ESI†). Propargyl carbonate 1b and bromoallene 1c were less effective substrates for this reaction (entries 12 and 13) than 1a. As shown in Table 2 and Scheme 2, we next investigated various nucleophiles under the optimised reaction conditions. Sulfonamides were generally good nucleophiles, producing fused tetracyclic spiroindoles 2 in moderate yield (entries 1–4), although a higher reaction temperature (60 1C) was required in some cases (entries 3 and 4). However, benzylamine was unsuitable for the cascade cyclisation

Scheme 2

reaction, affording only the b-elimination product 3a (54%, entry 5). It should be noted that the palladium-catalysed cascade cyclisation using dimethyl malonate gave, contrary to our expectation, the other regioisomer 4a (17%) along with b-elimination product 3a (15%) and some unidentified products without producing the usual spirocyclic product 2g (Scheme 2). Furthermore, the use of acetylacetone, a more acidic carbon nucleophile than dimethyl malonate, provided 4b as the sole isomer in 50% yield along with 3a (20%). Having established the reaction conditions and suitable nucleophiles for the cyclisation, we next examined the scope and limitations of the indole substrates (Table 3). The N-substituted indoles 1d and 1e were not applicable (entries 1 and 2). Conversely, reactions of substrates substituted with an electron withdrawing fluorine group (1f) or electron donating methoxy group (1h) proceeded well under the same conditions, affording the corresponding spirocyclic products in good yields (entries 3 and 5). However, compound 1g bearing a bromine group gave a slightly lower yield of the desired product 2l (43%, entry 4). This is attributed to side reactions initiated by the oxidative addition of the aryl bromide moiety in the substrate or the product. These results led us to propose a plausible mechanism for this reaction (Fig. 1). First, oxidative addition of 1a to palladium(0) gives the Z3-propargylpalladium complex A.8 Deprotonation at the indole nitrogen promotes the first intramolecular nucleophilic

Table 3 Table 2

Reaction with carbon nucleophiles.

Reaction of various indolesa

Reaction of various nitrogen nucleophiles

Yieldb (%) Yielda (%) Entry

RNH2 (1.5 equiv.)

T (1C)

Time (h)

2

3a

1 2 3 4 5

PhSO2NH2 MtsNH2b NsNH2 MsNH2 BnNH2

rt rt 60 60 60

5 3.5 2 24 7

2b (64) 2c (55) 2d (43) 2e (68) 2f (0)

6 9 15 10 54

a

Isolated yields.

b

Mts = 2,4,6-trimethylbenzenesulfonyl.

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Entry

Substrate

R1

R2

T (1C)

Time (h)

2

3

1 2 3 4 5

1d 1e 1f 1g 1h

Boc Me H H H

H H F Br OMe

60 60 rt 60 rt

24 24 3 3 2.5

2i (0) 2j (0) 2k (71) 2l (43) 2m (71)

3a (0) 3a (0) 3b (5) 3c (6) 3d (20)

a Reactions were carried out using propargyl chloride 1d–h with Pd2(dba)3CHCl3 (2.5 mol%), dppb (10 mol%), Cs2CO3 (2 equiv.) and TsNH2 (1.5 equiv.) in THF (0.067 M). b Isolated yields.

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Notes and references

Fig. 1

Proposed mechanism for palladium-catalysed domino cyclisation.

addition of the indole to the central carbon atom of the propargylic moiety of the complex A to produce Z3-allyl palladium complex B. This is followed by intermolecular nucleophilic attack affording intermediate C (path a) or D (path b), while b-hydride elimination from B produces 3a (path c). Intermediates C and D would be the precursors of tetracyclic spiroindoles 2 and 4. When sulfonamide was used as an external nucleophile, tetracyclic spiroindole 2 was obtained without producing the isomeric tetracyclic product 4. This regioselectivity can be partly explained by unfavourable steric interaction between the indole proton at the 4-position (HA) and the flagpole hydrogen (HB) of the cyclohexene moiety, which would destabilise isomer 4 (as well as the transition state to 4). In contrast, the opposite regioselectivity of the reaction when using carbon nucleophiles to afford isomer 4 can be understood by considering the steric bulk of the carbon nucleophiles, because the neighbouring quaternary carbon centre prohibits nucleophilic attack at the sterically hindered imine carbon (path a). The soft character of the carbon nucleophiles favouring the reaction with the Z3-allylpalladium complex (path b) might be another important factor for the opposite selectivity obtained using carbon nucleophiles rather than nitrogen ones.13 In conclusion, we have developed a novel palladium-catalysed cascade reaction to construct fused tetracyclic spiroindoles. Nucleophilic attack proceeds sequentially with initial reaction of the internal indole and the second reaction with the external sulfonamide. The regioselectivity of the second cyclisation was changed when a carbon nucleophile was used instead of a nitrogen one. This cascade reaction is now being applied to synthesis of biologically active compounds. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas ‘‘Integrated Organic Synthesis based on Reaction Integration’’ (No. 2105) (H.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. A.I. and S.I. are grateful to Research Fellowships of the Japan Society for the Promotion of Science (JSPS) for Young Scientists.

300 | Chem. Commun., 2014, 50, 298--300

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