The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles

There is a continuous need for designing new and improved synthetic methods aiming at minimizing reaction steps while increasing molecular complexity. In this respect, catalytic, one-pot cascade methodologies constitute an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. Herein, we describe two general and efficient cascade procedures for the synthesis of spiro-fused heterocylces. This transformation combines selective nucleophilic substitution (SN2′), palladium-catalyzed Heck and C–H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts are key to the success of the transformations. The synthetic utility of these methodologies is showcased by the preparation of 48 spiro-fused dihydrobenzofuranes and indolines including a variety of fluorinated derivatives.

T he development of novel chemical transformations increasing molecular complexity enables significant innovation potential in life and material sciences. In this respect, catalytic cascade or domino processes offer strong impetus for new methodology developments [1][2][3] . Compared to traditional consecutive procedures, they permit several practical advantages: In addition to improved step-economy, waste generation from multiple iterations of reaction, workup, and purification procedures are minimized. Consequently, diverse and complex organic molecules can be assembled not only in a faster, but also more sustainable way.
Herein, we describe our recent efforts to establish a palladiumcatalyzed allylic substitution/Heck/C-H activation(/alkyne) cascade processes for the synthesis of spiro-fused heterocycles. Key challenges of such processes are obviously the compatibility of the well-matched reactant partners 39 , the required conditions of the individual reactions, the development of a general catalyst system able to promote all three (or four) transformations efficiently, and to achieve the needed high chemo-selectivity, regio-selectivity, and stereoselectivity throughout all elementary steps.

Results
Reaction development. Recently, Lautens, Schoenebeck and coworkers reported the synthesis of spiro-fused heterocycles through an intramolecular Heck/C-H activation sequence using specific alkene-tethered aryl iodides (Fig. 1a) [40][41][42] . Regarding the starting materials, those substrates might be preferably prepared through an initial palladium-catalyzed Tsuji-Trost allylation of 2halophenols, which would provide a more efficient and stepeconomic way [43][44][45] . Following this initial idea, we investigated the coupling of 2-iodophenol (1a) with 2-phenylallyl acetate (2a) in the presence of PdBr 2 /L1 (Fig. 2a)  fused product 4a was observed and no conversion took place. Similar results were obtained when the tert-butyl (2-phenylallyl) carbonate (2b) was used instead of 2a. When more reactive 2phenylallyl bromide 2c was introduced, only the alkene-tethered aryl iodide 3a was isolated in 73% yield instead of product 4a. To improve the reactivity of the starting material further on, other allylic leaving groups were considered. In this respect, allylic ammonium salts, which have been largely neglected in intermolecular palladium-catalyzed allylic substitutions, attracted our attention 39,46,47 . This class of compounds are in general highly stable and can be conveniently prepared from a variety of amines. Surprisingly, testing 2d in the presence of the PdBr 2 /L1 catalyst, the desired cascade process took place and product 4b was obtained in 87% isolated yield! This means that each individual step proceeds with an efficiency of at least 95%. At this point, it should be mentioned that allylic ammonium salts are also known to undergo direct S N 2-substitution or S N 2'-substitution reactions under basic conditions [48][49][50] . To understand whether the first reaction step is really palladium-catalyzed, 2d was treated with 1a in the presence of 1 equiv. of base. Interestingly, the allyl aryl ether 3b was obtained in high yield (95%). Subsequent reaction in the presence of our regular palladium catalyst led to full consumption of 3b, providing the desired spiro-benzocyclobutane 4b in 87% yield (Fig. 2b). Obviously, applying substrate 2d does not allow to distinguish between S N 2-mechanism and S N 2'-mechanism in the first reaction step due to its symmetry. Based on the The reaction was performed at 90 °C. actual interest in fluorinated building blocks [51][52][53] , the gemdifluorinated allylic ammonium salt 2e 39 was reacted with 2iodophenol, which gave product 3c in 99% yield and excellent regioselectivity. Again, the following palladium-catalyzed steps took place smoothly and provided 4c in high yield (80%). Similarly, the direct conversion of 2e proceeded efficiently to give 4c in 83% isolated yield (Fig. 2a, entry 5). It should be noted that related fluorinated heterocycles in general cannot be easily prepared 54 and that to the best of our knowledge no example of such spiro compounds has been reported yet. Apart from 2e, other related ammonium salts 2f-2i underwent similar coupling processes to provide the desired product 4c in slight lower yield (62-75%) (for details see Supplementary Information, Supplementary Table 2). To obtain optimal results, an extensive evaluation of the reaction conditions of the model systems was performed (for details see Supplementary Information, Supplementary Tables 1-9) and revealed three significant points: (1) The catalyst system is crucial in this cascade process and only in the presence of sterically hindered and electron-rich diadamantyl phosphines such as L1, the desired product was obtained in high yield. (2) Cs 2 CO 3 and toluene were independently identified as the most effective base and solvent, which nearly doubled the product yield compared to other common bases and solvents. (3) In addition, the concentrations of substrates are decisive. Using an equimolar amount of both substrates led to the best result while an excess of either ammonium salt or aryl halide considerably decreased the yield of 4. Based on all these observations, a plausible mechanism for the formation of benzocyclobutane derivative 4 is proposed in Fig. 2c: Initially, 2-iodophenol 1 and ammonium salt 2 underwent a base mediated S N 2' allylic substitution in a highly regioselective manner. To further confirm the S N 2' route, deuterium substituted ammonium salt was tested, details see Supplementary Information, Supplementary Fig. 1. Next, intramolecular palladiumcatalyzed Heck reaction of the in situ generated compound 3 followed by site-selective C-H activation forms the spiropalladacycle III. Final reductive elimination regenerates the palladium species and produces the desired product 40 . Noteworthily, this novel cascade reaction is a rare example of a domino process involving S N 2´substitution with subsequent metal-catalyzed transformations 55,56 .

Heck reaction & C-H activation & Reductive elimination
Scope for the formation of spiro-fused benzocyclobutene derivatives. With the optimized reaction conditions in hand, the general feasibility of this approach was examined. As shown in Fig. 3, allylic ammonium salts with different substituents in 3position including H, F, CF 3 , directly afforded 4b-4e in all cases in good to high isolated yields. For disubstituted substrate 2j with -F and -CF 3 substituents in 3-position, high diastereoselectivity for two adjacent quaternary carbon centers was obtained (4e, 71%). Next, the reaction of gem-difluorinated allylic ammonium salts 2k-2u with aryl halides 1a-1o (for details see Supplementary Information, Supplementary Fig. 2) was investigated. Most of the ammonium salts were conveniently obtained from commercially available phenylboronic acid and vinyl bromides via Suzuki reaction, base-mediated amination, and final N-methylation 39 . With regard to the cascade reaction, both electron-donating groups including alkyl, aryl, alkoxy and aryloxy and electronwithdrawing groups including fluoro and chloro were perfectly compatible with the conditions, and the corresponding products 4f-4l were obtained in 53 − 86% yield. The molecular structure of these highly strained 5,4-spirocycles was unambiguously confirmed by X-ray crystal structure analysis of 4f. Both diphenylamino-substituted and trimethylsilyl-substituted spiro compounds 4m and 4n were successfully formed in high yield. Furthermore, dibenzofuran-derived ammonium salt underwent the cascade process, leading to the construction of the heterocycle-embedded tetracyclic framework 4o in 60% yield. Gratifyingly, the more complex derivative 4p containing two spiro-fused benzocyclobutanes was smoothly generated in 51% yield via a consecutive two-fold cascade process using the corresponding bis-ammonium salt as the reagent.
Next, we explored the scope of our methodology with respect to the aryl halide coupling partner. In addition to 2-iodophenols 1a-1l, 2-bromophenol 1m, 2-chlorophenol 1n, and 2-iodoaniline 1o were also investigated. The latter case highlights the possibility to construct 3-spiro-indolines, specifically 2-fluorinated indolines (4ad and 4ae), which are of interest as natural products and pharmaceutical molecules 57,58 . As depicted in Fig. 3, several different aryl halides gave the expected tetracyclic products under the standard conditions. Interestingly, considering the three-step cascade, these transformations proceeded in good to excellent yields with either electron-rich or electron-deficient substituents. Notably, substrates containing heteroarenes, such as the quinoline derivative 1k, provided the N,O-fused heterocycle 4ab in 60% yield. Moreover, the L-tyrosine derived product 4ac was obtained by a concise cascade transformation (dr = 1:1).

Three-component spirocyclization reaction.
Considering the versatility of the in-situ-generated palladacycles III 16,26,27 , subsequent functionalization including carbene and alkyne insertion should allow for the efficient construction of other classes of novel spiro compounds 29,30,41,42 . To demonstrate this synthetic potential, we performed the reaction of 1a and 2e with two equiv. of an additional unsymmetrical alkyne 5a (ethyl 3-phenyl-propynoate). Indeed, the envisioned cascade process combining S N 2' substitution, palladium-catalyzed Heck/C-H activation and final alkyne insertion provided in a straightforward manner only one regioisomer of the respective 6,5-spirocycles 6 (regioselectivity: >20:1). Under standard conditions, the desired product 6a was obtained in 73% yield; however, in this case the highly reactive palladacycle III also underwent minor reductive elimination and the 5,4-spirocycle 4c was detected in 14% yield. Pleasantly, increasing substrate concentration in the presence of the extended ligand L3 provided exclusively 6a in high yield (85% isolated yield; for a brief evaluation of reaction conditions see Supplementary Information, Supplementary Table 10).
The generality of this second three-component cascade procedure is shown by variation of five aryl iodides, nine ammonium salts and six alkynes (Fig. 4). In all cases, the domino reaction proceeded smoothly with valuable substituents and functional groups, including alkoxy, aryloxy, halide, silyl, and amino, giving the corresponding products 6a-6h in good to high yields with excellent regioselectivities. The molecular structure of 6a was confirmed by X-ray crystallography. Substituents on the phenyl ring of aryl iodide displayed only a minor influence on the reactivity and provided 6i-6k in high yields. Notably, various unsymmetrical alkynes with different substituents on the triple bond afforded 6l-6q with excellent degrees of both chemoselectivities and regioselectivities. For example, internal alkynes bearing −COPh, −COCH 3 , and −CO 2 Me substituents gave the corresponding products 6l-6n in 79%, 45 and 79% isolated yield, respectively. It is worthy to note that 3-phenyl-2-propynenitrile and 1,3-diynes were compatible in this transformation, affording 6o-6q in 40-94% isolated yield. Finally, the construction of 3spiro-indoline 6r was also achieved in 54% yield.

Methods
General procedure for the preparation of spiro-fused benzocyclobutanes 4. To a 25 ml oven-dried pressure tube equipped with a magnetic stir bar were added 2-halophenol or aniline 1 (0.2 mmol), ammonium salt 2 (0.2 mmol), Cs 2 CO 3 (130 mg, 0.4 mmol), PdBr 2 (2.7 mg, 0.01 mmol), L1 (7.2 mg, 0.02 mmol), and then degassed toluene (2.5 mL) was introduced under argon atmosphere. The sealed pressure tube was heated and stirred at 110°C for 22 h. The reaction mixture was allowed cooling to room temperature, diluted with ethyl acetate (10 ml), and filtered through a short pad of celite eluting with ethyl acetate (3 × 10 ml). After evaporation, the residue was purified by chromatography on basic aluminum oxide (It is worthy to note that the 2-fluorinated product can only be separated without decomposition using basic aluminum oxide) to afford the desired product 4.

Data availability
The authors declare that all the data supporting this study, including the experimental details, data analysis, and spectra for all unknow compounds, see Supplementary Files. All data underlying the findings of this work are available from the corresponding author upon reasonable request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2006609 (4f) and 2006610 (6a). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/ structures.