A Divergent Duo: Palladium Catalyzed Carboamination in Enantioselective Desymmetrization and Regiodivergent Catalysis

We describe a regiodivergent synthesis of pseudo‐C2‐symmetrical and pseudo‐meso bis‐indoline scaffolds from norbornadiene and substituted o‐iodo‐anilines. The Pd(0)/Josiphos system enables the highly regioselective catalyst controlled carboaminations required for the two step synthesis of the scaffolds.

The design of catalytic sequences that enable access to small molecules with high chemo-and stereoselectivity is a central topic in chemistry. This is especially so if specific classes of compounds can be obtained and branching points for diversityoriented synthesis (DOS) are provided. [1] To this end, regiodivergent catalysis is an excellent tool. [2] The basic idea of this approach is the highly selective synthesis of regioisomeric products from one enantiomer of a substrate by the action of the enantiomers of a catalyst. This allows not only a highly selective preparation of particular synthetic targets but also the generation of structural diversity from a single compound by changing the absolute configuration of a catalyst.
In this publication, we highlight these points by adding catalyst controlled Pd-catalyzed regioselective carboamination reactions to the repertoire of enantioselective catalysis in a synthesis of bis-indoline scaffolds [3] (Scheme 1). Syntheses of indolines are of particular interest, because of the heterocycle's presence in about 4 % of all commercial drugs. [4] Norbornadiene with its two double bonds that can be functionalized in subsequent steps is an ideal starting material for regiodivergent catalysis if two critical conditions can be met.
The first condition is that the initial desymmetrizing carboamination proceeds with high enantioselectivity. To the best of our knowledge such a method has not yet been described. Catellani and others have described the achiral version of this reaction. [5] The desired selectivity can be realized if the carboamination proceeds with high regioselectivity (CÀ Cbond formation at one of the homotopic C 1 positions and CÀ Nbond formation at the corresponding homotopic C 2 position as shown for the example in Scheme 1) in the presence of a Pd catalyst and an enantiomerically pure ligand L. In this manner, indoline scaffolds 1 that constitute the pivotal branching points for bis-indoline synthesis are obtained.
The second critical aspect for efficient regiodivergent catalysis is that the carboamination of 1, a substituted norbornene, also has to proceed with catalyst-controlled selectivity. Using ligand L should lead to CÀ C bond formation at C 1 ' and CÀ N bond formation at C 2 ' to provide the pseudo-C 2 symmetrical product 2. Employing the enantiomer of the ligand ent-L will result in the synthesis of the pseudo-meso product 3. Since norbornenes are less strained and less reactive than norbornadienes, it may be necessary to employ a different catalyst system for the second carboamination.
From the analysis of Scheme 1, it is clear that in order to generate molecular diversity in a general way, the synthesis of the bis-indolines needs to be carried out stepwise. In one-pot reactions, only products with C 2 -symmetry and, hence, identical substitution patterns of the arenes can be obtained.
We started our investigations with a screening of Pdprecatalysts, ligands and reaction conditions for the monocarboamination to yield 1 a from norbornadiene (Table 1, see Supporting Information for details of the optimization).
The Josiphos ligands [6] L1-L3 showed a strong influence of the substitution pattern on the enantioselectivity. While L1 gave only moderate selectivity, the sterically demanding tBu groups in L2 prevented a reaction. Gratifyingly, the Josiphos ligand L3 gave 1 a in high enantioselectivity (95 : 5) as a single diastereoisomer (see Supporting Information for structural assignments) despite the harsh reaction conditions (100°C). However, we note that the enantioselectivity of the carboamination is sensitive to the purity of L3 that should be stored under Ar. With samples of L3 containing phosphine oxides, lower e.r. values in the range of 91 : 9 were obtained. We recommend that L3 is occasionally checked for the presence of phosphine oxides by 31 P-NMR spectroscopy. These impurities should be removed by crystallization. (R)-BINAP [7] L4 and (R)-Segphos [7b,8] L5 gave only very low enantioselectivity.
The carboamination of norbornadiene is broad in scope and tolerates a number of substituents on the aniline and works well with N-alkylated substrates as summarized in Table 2. The enantioselectivity of the reaction (e.r. = 93 : 7-96 : 4) is largely independent of the substrates' substitution. Methyl and fluorine substituents in S1 are tolerated (entries 1-5). An o-Methyl substituent does not affect the outcome of the reaction (entry 5). Moreover, S1 may be N-alkylated (entry 6). All products were obtained as the single diastereoisomer shown (see Supporting Information for details).
As pointed out above, the second critical condition for the regiodivergent synthesis of the bis-indolines is that the norbornene derivatives 1 also undergo highly selective carboamination reactions.
We did not want to optimize the reaction conditions with the valuable indolines 1 and chose to investigate reactions with norbornene as a simple model substrate for 1 in the carboamination reaction because it should display a similar reactivity. As summarized in Table 3, norbornene is indeed a suitable substrate for the carboamination. The catalytic system is identical to the norbornadiene reactions with the sole difference that the use of H 2 O as an additive becomes redundant. Importantly, the enantioselectivities of the carboamination are in the range of 93 : 7-96 : 4 and do not differ significantly from those observed in the reaction with norbornadiene. Products 4 are obtained as single diastereoisomers (see Supporting Information for details of compound characterization). The reaction tolerates a number of substituents on the arene (À Me, entry 3; À F, entry 2; À Cl, entry 5) and the aniline (S1) may be Nalkylated (entry 4).
The suggested mechanism (Figure 1) rationalizes the results. The intermolecular carbopalladation of norbornadiene or norbornene leading to A is the enantioselective CÀ C bondforming event of the reaction. [9] The generation of the palladaheterocycle B by deprotonation of the pending NÀ H is essential for CÀ N bond formation through reductive elimination.
lectivities have been obtained in intramolecular carboaminations where the attack of an N-atom on a pending Pdcomplexed olefin is the selectivity determining step. [11] The enantioselective carboaminations of norbornadiene and norbornene set the scene for the regiodivergent bis-indoline synthesis. As shown in Scheme 1, the (pseudo)-C 2 -symmetrical products or the (pseudo)-meso products can be obtained by choice of L with the appropriate absolute configuration.
Accordingly, the (pseudo)-C 2 -symmetrical bis-indolines can be obtained from 1 in the presence of L3 (Table 4). They were obtained with excellent (> 99.5: < 0.5 except for entry 4) enantiomeric ratios and as single diastereoisomers (see Sup-porting Information for details of characterization). The pseudomeso-side products are significantly more polar and can be easily removed by chromatography.
A highly beneficial side effect of these reactions is the improvement of the enantiomeric ratio from substrate to product. Thus, they can be used to remove the minor, unwanted enantiomer by converting it to an easy to separate regioisomer. The selectivity is caused by the formation of the major enantiomer of 2 through by the favored pathway of the major enantiomer of 1 and the disfavored pathway of the minor enantiomer of 1. This implies that the ratio of 2 : 3 is lower than the e.r. of 1 as was indeed verified for the cases when 2 could be isolated in pure form (2 b: 2 : 3 = 89 : 11 (68 : 8) vs. e.r. (1 a) = 9 : 91, entry 2) and 2 e: (2 : 3 = 83 : 17 (60 : 12) vs. e.r. (1 a) = 6 : 94, entry 5). This increase in e.r. is practically especially valuable when the enantiomeric purity of the substrate is relatively low. Therefore, we employed 1 a with an e.r. of only 9 : 91 that had been prepared with L3 of lower quality.
A synthetically important aspect of the products 2 is their potential for further functionalization. When derivatives of 2 are obtained with two NÀ H groups, it is difficult to regioselectively functionalize one NÀ H bond. Therefore, it is important to note that with our method, N-methylated bis-indolines can be readily prepared in excellent enantioselectivities (R 1 = Me, entries 2, 3, 5-8). These compounds can be readily functionalized further by reactions with the remaining NÀ H bond.
To fully explore and exploit the scope of the regiodivergent carboamination, we used ent-L3 in synthesis of the pseudomeso compounds 3. If the second carboamination proceeds under catalyst control, these compounds will be obtained with high selectivities similar to those observed for 2.
As envisioned the pseudo-meso indolines 3 (see Supporting Information for details of structural characterization) were obtained almost as single enantiomers (e.r. = 99.5:0.5 or higher in all cases) and as single diastereoisomers (Table 5). The reactions leading to 3 in the presence of ent-L3 closely parallel those of the syntheses of the (pseudo)-C 2 -symmetrical bisindolines 2 in the presence of L3. Thus, essentially the same degree of catalyst control is exerted in both sets of reactions. Hence, the influence of the substrate on the regioselectivity of the carboamination of 1 can be overruled by the enantiomerically pure catalyst.
In order to provide bis-indoline 3 buildings blocks that are amenable to straightforward functionalization, we mainly prepared products with one of the N-atoms methylated (R 1 = Me). However, products with two NÀ H bonds (R 1 = H) can also be accessed (entries 3 and 4). Substituents on the arene are readily tolerated.
Recently, it has been shown that ligands based on selectively functionalized meso-compounds can be used with excellent success as substitutes for C 2 -symmetrical salen ligands in organocatalysis and metal catalyzed epoxidations. [12] This exciting finding suggests that such pseudo-meso compounds in enantiomerically pure form have been neglected in applications in stereoselective synthesis.
Our sequence of reactions provides a synthetic entry to such compounds in very high enantioselectivity and complete  diastereoselectivity. Moreover, because of its modular nature, our method allows a simple way to modify the electronic properties of both N-atoms through variation of the arenes' substituents and the synthesis of selectively alkylated bisindoline scaffolds by employing N-alkylated anilines as substrates. In summary, highly enantioselective carboaminations of norbornadiene and norbornene as well as highly selective regiodivergent carboaminations of substituted norbornenes can be accomplished with the catalytic system Pd(OAc) 2 /L3 or ent-L3. The selectivity determining step of the cycle is a carbopalladation. Its regioselectivity is controlled by the absolute configuration of the ligand. This key-feature not only allows the synthesis of the bis-indolines in almost enantiomerically pure form but also provides the pivotal branching point for diversity-oriented synthesis (DOS).