Rh(III)-Catalyzed Coupling of N-Chloroimines with α-Diazo-α-Phosphonoacetates for Skeleton-Oriented Synthesis of 2H-Isoindoles

: A major hurdle for realizing the full potential of transition metal-catalyzed, directed C-H functionalization synthesis of heterocycles is the blocking of ability for designated structural elaboration by the reactivity-assisting group-derived, unintended appendages. We communicate herein Rh(III)-catalyzed coupling of N-chloroimines with α-diazo-α-phosphonoacetates for skeleton-oriented synthesis (SOS) of 2H-isoindoles. Comprehensive mechanistic studies with rhodacycle intermediates support an associative covalent relay mechanism for this first reported N-chloroimine-directed C-H functionalization reaction. The initial dechlorination/dephosphonation under Rh(III) catalysis and subsequent deesterification under Ni(II) catalysis allow the complete elimination of unintended appendages and full exposure of reactivity for C3 and N2 ring atoms. The proof-of-concept utility has been demonstrated with electrophilic substitution at the C3 site (formylation, azo derivatization) and nucleophilic reaction (methylation) at the N2 site, showcasing the enormous synthetic potential of SOS for attaching structurally unrelated appendages and enabling entry to distinct chemical space.

For reaction development, the creation of polarity and reactivity for a coupling site typically needs assistance from the neighboring groups. However, these groups, when installed in the product as unintended appendages, can be a major hurdle for further planning of structural functionalization and diversification, thus impeding the achievement of both TOS and DOS.
Transition metal-catalyzed directed C-H functionalization has recently emerged as a promising step-economic strategy for the synthesis of diverse range of structures. [3][4][5][6][7][8][9][10][11][12] Heterocycles have been the center of focus in this nascent field for their role as privileged pharmaceutical scaffolds. Forward reactivity analysis, a process of streamlining multi-step reaction steps/pathways in silico based on projected matching of reactivity between directing groups and coupling partners, can instill an element of rationality into reaction design. 13 However, this level of reasoning has not been routinely practiced in the context of appendage planning.
Appendage planning should be an important guiding principle for reaction development as without this, the synthetic utility of painstakingly established protocols can be seriously compromised. Indeed, unintended appendages from the directing groups and/or coupling partners have been frequently stuck in the heterocyclic skeletons: they not only are relatively inert to designated transformations but also can completely block the inherent high reactivity of ring atoms. [3][4][5][6][7][8][9][10][11][12] Considering the thoroughly demonstrated enormous synthetic power from the heterocyclic ring atoms, a synthetically useful approach to reaction 4 development is skeleton-oriented synthesis (SOS): SOS refers to a traceless appendage planning synthetic strategy for fabricating molecular skeletons without unintended appendages from the reactivity-assisting groups and using, subsequently, the reactivity of exposed ring atoms for attaching intended appendages.
We envisioned that Rh(III)-catalyzed coupling of N-chloroimines (Nchloroimine group is used herein for the first time for directed C-H activation) with α-diazo-α-phosphonoacetates would allow the achievement of SOS ( Fig. 1 1m, 1p, 1q, 1r) whereas regioisomers are identified for sterically less bulky ones (1n, 1o). Ortho substitution is also 7 synthetically compatible (F, 1s), albeit with a slightly lower yield compared to the para and meta counterparts. Di-substitution (1t) further hinders the reactivity. The alteration of imino C-Me group to either C-Et (1u), C-n Pr (1v), or C-Ph (1w) group results in a diminished yield, suggestive of a steric effect. The steric effect is more pronounced for a fused ring system (1x  Structural elaboration of 2H-isoindole skeleton. The goal of SOS is to construct molecular skeletons without undesired appendages from the reactivity-assisting groups and exploit the reactivity of ring atoms for further structural elaboration ( Fig. 6). To this end, the ester groups on the C3 site of 2H-isoindoles should therefore be eliminated first. For proof-of-concept demonstration, 3wd was selected and subjected to deesterification reaction. The ester group can be removed to afford SOS target product 4 under Ni(OAc) 2 /dcype/Ph 3 SiH catalysis. 37 Unlike 3wd, 4 exhibits high reactivity at the C3 site, which also renders itself an unstable molecule against chromatography. 38 However, electrophilic substitution can proceed on 4 without purification. For example, reaction between the crude product of 4 and Vilsmeier reagent affords a C3-dimethylaminomethylidene derivative 5. 39 Hydrolysis of 5 in NaOH generates C3-formyl derivative 6. 39 6 can be deprotonated at the N2 site with NaH and undergo further nucleophilic methylation with CH 3 I to produce 7. Collectively, these transformations have allowed the complete erasure of any trace of original reactivity-assisting groups and installation of structually completely unrelated appendages, thus offering an enabling tool for accessing distinct chemical space. As a second illustrative 13 example, 4 can also undergo initial azo derivatization at the C3 site 40 and subsequent methylation at the N2 site, affording 8 and 9, respectively.

Discussion
In summary, we have developed herein a SOS strategy for 2H-isoindoles based on Rh(III)-catalyzed coupling of N-chloroimines with α-diazo-αphosphonoacetates. The initial dechlorination/dephosphonation from the directing group/installed group and subsequent deesterification allow the full removal of unwanted appendages from the 2H-isoindole skeleton. The tremendous synthetic potential of SOS is exemplified by the ability to achieve electrophilic substitution and nucleophilic reaction at the C3 and N2 ring atoms for the installation of structurally distinct appendages. Given the generally high reactivity of ring atoms for heterocycles, SOS is expected to become an important guiding concept in future development of synthetically useful reactions for TOS and DOS applications.