Isoindolinones via Copper-Catalyzed Intramolecular Benzylic C-H Sulfamidation.

2-Benzyl-N-tosylbenzamides and related substrates undergo copper-catalyzed intramolecular sulfamidation at the benzylic methylene to give N-arylsuflonyl-1-arylisoindolinones, which can be N-deprotected using samarium iodide to generate the free 1-arylisoindolinones. Preliminary mechanistic studies indicate that the rate-determining step is not C-H bond cleavage but are instead consistent with slow oxidation of a copper π-arene intermediate.


Introduction
The isoindolinone core is a privileged structure with examples showing a range of biological functions and medicinal applications. 1 For instance pazinaclone (Figure 1) has demonstrated anxiolytic properties, 2 1 is a dopamine receptor antagonist, 3 2 shows antiretroviral activity, 4 lenalidomide is used in the treatment of multiple myeloma, 5 whilst pestalachloride A, isolated from the fungus Pestalotiopsis adusta, is reported to have significant anti-microbial activity. 6 Catalytic intramolecular sp 3 -C-H amidation represent an excellent approach to the synthesis of N-heterocycles, 7 and inspired by recent reports of catalytic benzylic C-H amination, 8,9 we wondered whether such an approach could be applied to the synthesis of N-sufonyl isoindolinones via C-H sulfamidation. Such sulfamidation routes would be preferable to recently reported catalyzed or catalyst-free amidation reactions with N-aryl substrates, 10,11 as the products should undergo comparatively facile N-deprotection to yield the free isoindolinones.

Results and Discussion
In the first instance, we undertook an optimisation study, examining the copper-catalysed 12 cyclisation of substrate 3a, which could be easily prepared in one step from benzylbenzoic acid and p-toluenesulfonyl isocyanate, to the isoindolinone 4a, and the results from this study are summarised in Table 1.
DCE 120 0 In the absence of catalyst, no conversion to the desired product was observed under air, using four equivalents of phenylidonium diacetate as the oxidant and 1,2-dichloroethane (DCE) as the solvent (entry 1). Adding a high loading of copper (II) triflate (50 mol%, entry 2) led to a reasonable amount of the desired product, however the reaction was clearly not catalytic. Repeating the reaction under inert conditions or under O2 proved deleterious (entries 3 and 4). Replacing PhI(OAc)2 with either hydroxy(tosyloxy)iodobenzene (HTIB) or PhI(O2CCF3)2 (PIFA) shut down the reaction (entries 5 and 6). While the use of neat acetic acid as solvent was deleterious (entry 7), the use of acetic acid in chlorinated solvents proved beneficial (entries 8 -10), with the best activity obtained using chlorobenzene. With this solvent system, both the amount of oxidant (2 equiv.) and the catalyst loading (20 mol%) could be reduced, to give the optimum conditions indicated in entry 12. Reducing the catalyst loading further proved to be detrimental, as did either replacing acetic acid with trifluoroacetic acid (entry 14) or changing the temperature (entries 15 and 16).
With optimised conditions in hand, we next briefly explored the range of substrates that undergo the intramolecular sulfamidation reaction. The successful results are summarised in Table 2, whilst the substrates that failed to cyclise are shown in Figure 2.
Diarylmethane-based substrates with electronwithdrawing and -donating groups on either of the aryl rings underwent the desired reaction to generate the isoindolinones 4a -4i. Interestingly, C-H functionalization at a tertiary carbon center was also achieved, yielding the product 4j in moderate yield. In contrast with Kondo's related amidation reactions with N-aryl precursors, 10 the sulfamidation reaction fails for the substrate 3m. While it is tempting to conclude from this that two aryl groups are required at the benzylic center for electronic reasons, this is clearly not the case in the formation of the 4k. Instead it appears that a 'pro-exocyclic' arene substituent is required for activity. In addition to the requirement for a pro-exocyclic arene, it appears that the benzylic site of C-H functionalization must be incorporated into a structurally rigid framework. Thus while 4k is formed, no cyclisation is observed with the conformationally flexible substrate 4n, suggesting that the transition state for C-H activation requires a sulfonamide-coordinated copper complex to be held in close proximity to the reactive center.  The formation of 4l demonstrates that the reaction can be extended to sulfamidation with the p-nosyl function. Importantly, both 4l and the related tosyl-containing 4b undergo 'instantaneous' samarium-mediated deprotection 13 to yield the free NH-isoindolinone, 5 (Scheme 1).

Scheme 1. Deprotection of N-sulfonyl isoindolinones.
In order to gain further mechanistic insight, we followed the formation of the products 4a -f against time from their precursors 3a -f, and the results of this study are summarized in Figure 3. It is immediately apparent that the reaction is favored by electron-donating groups on the pro-exocyclic arene, with the p-anisyl-based substrate 3c giving by far the highest rate, with maximum conversion obtained prior to the first sampling point. Furthermore, the reactions with all the other substrates examined show pronounced induction periods of around 5 -10 minutes before onset of catalytic activity. Whatever the catalyst activation process is, it is clear that it is substrate-dependent. The role of the electronics of the pro-exocyclic ring on the rate-determining step of the reaction was probed by a Hammett analysis of the reactions (Figure 4), based on the observed maximum rates. The plot against  gave a poor correlation whilst that against  + gave a moderate R 2 of 0.79, and  ≈ -1.4. 14 This suggests that rate-determining step involves loss of electron density. 15 In order to determine whether or not C-H bondcleavage features in the rate-limiting step in the catalytic cycle, we undertook a variety of kinetic isotope effect studies. Subjecting 3a and its di-deuterated analog 3a-D2 to cyclisation under identical conditions gave the same rate of formation of the products 3a and 3a-D (kH = 0.062 mM/min; kD = 0.063 mM/min). 16 Similarly, a competition reaction, containing equal amounts of 3a and 3a-D2, quenched at approximately 30% conversion, gave a product mixture containing equal amounts of 4a and 4a-D. The lack of a kinetic isotope effect in both cases indicates that C-H bond-cleavage is not involved in the rate-determining step. 17 By contrast, subjecting the 2:1 mixture of the deuterium-enriched substrate 3a-HD and 3a to the standard reaction gave a 3:2 ratio of 4a and 4a-D, which corresponds to a KIE of 1.5. These KIE data are consistent with the ratedetermining step involving substrate interaction with the copper and occurring prior to the C-H functionalization step. 17 Consistent with this suggestion is the observation that the relative rate data above shows a strong influence of the electronics of the exocyclic arene on the rate of catalysis.
Cl H Any mechanistic proposal must address the following observations: A pro-exocyclic aryl group is essential for activity; (ii) The sulfonamide and benzyl functions must be held proximate within a stereochemically rigid framework; (iii) The rate-determining step is accelerated by increasing electron-density on the pro-exocyclic aryl ring, but does not involve C-H cleavage and likely occurs before C-H activation; (iv) The high sensitivity of the reaction to the precise nature of the oxidant.
One possible explanation that can satisfy all of these criteria is the involvement of an  n -arene-coordinated copper intermediate of the type I ( Figure 5), which undergoes slow oxidation, facilitated by increasing electron-density on the aryl ring. It has been suggested that a copper (I)/(III) manifold is active in many C-H functionalization processes, 18 in which case I would contain Cu(I). While we do not have direct evidence for such a species at present, stable Cu(I) arene -complexes with  1 -,  2 -and even  6 -arene interactions are known. 19 Meanwhile a DFT examination of a model of I, I* (L = H2O; phenylene backbone) 16 returned a plausible ground-state structure with an  2 -arene interaction ( Figure 5).
The calculated Cu-C distances of 2.15 and 2.25 Å are comparable with the bond metrics associated with previously reported, structurally characterized Cu(I) arene complexes, 6. 19e The DFT analysis suggests that the bonding interaction between the  2 -arene function and the copper center has both  and -symmetry components. Interestingly, Fukuzumi and Itoh showed that both the redox potential and the rate of oxidation of the complexes 6 is strongly dependent on the electronic properties of the substituted arene, with more facile oxidation occurring with inductive substituents. 19e In the reaction of 6 with oxygen, the oxidation rate increases with decreasing Cu-arene stability, which is in turn associated with a less electron-rich arene, suggesting that formation of the bridging peroxo LCu-O2-CuL occurs after arene dissociation. 19e In contrast, our data indicate an increased rate of reaction with more electron-rich arenes suggesting that the oxidation of the copper occurs prior to arene decoordination, consistent with Fukuzumi and Itoh's electrochemical oxidations. 19e With regards to the subsequent C-H activation step, this may well occur by a radical pathway as evidenced by the suppression of cyclization of 3a in the presence of two equivalents of TEMPO and the recovery of >95% of the starting material.

Conclusion
In summary we have developed the copper-catalyzed synthesis of isoindolinones via a tolylsulfonamide-or nosylsulfonamide-directed C-H functionalization, a process in which the sulfonamide acts as both the directing group and the functionalizing reagent. Subsequent samarium-mediated removal of the sulfonyl function leads to the free isoindolinone. The substrate scope of the reaction and the results from preliminary mechanistic and computational studies point to the possible involvement of arene -coordination in the rate-determining step of the reaction, which may well be oxidation of the copper center. We are currently probing this putative mechanism more deeply with a view to exploiting it in novel catalytic processes, and the results of these studies will be presented in due course.

Experimental Section
General Experimental Information. Reagents were used as supplied from commercial sources. Anhydrous THF was obtained from a purification column composed of activated alumina and subsequently stored under nitrogen. All other anhydrous solvents were prepared by drying the corresponding reagent grade solvent over molecular sieves.
Mass Spectrometry was carried out with a MicrOTOF II spectrometer (Electrospray (ESI), with a time-of-flight (TOF) analyzer type.