Regioselective Halogenation of 1,4-Benzodiazepinones via CH Activation

This article reports an efficient CH activation process for regioselective halogenation of 1,4-benzodiazepinones. Direct halogenation with NXS (X = Br, I) affords halogenated benzodiazepinones on the central aromatic ring whereas catalyst (Pd(OAc)2) controlled CH activation furnishes regioselectively ortho halogenated benzodiazepinones on the phenyl side chain.


Results and discussion
The palladium-catalyzed directed CH activation/halogenation reactions on model compounds usually proceed in good yield and with complete control of regioselectivity 9 . We therefore started with unsubstituted benzodiazepinone 1 to find the best experimental conditions to get halogenation of the C phenyl ring with minimum amount of side reaction on the A phenyl ring. Microwave heating was preferred to conventional heating to lower the reaction time and the amount of degradation compounds.
Few palladium catalysts were initially tested with NIS as halogenating agent but only palladium acetate afforded the halogenated compound albeit with low yield. Reaction performed in acetonitrile with 1.5 equivalents of NIS at 80 °C for 15 minutes afforded solely the monohalogenated compound 1-I (Table 1, entry 1). Raising the reaction temperature to 100 °C fully converted the starting material but 15% of the 2′ ,6′ -dihalogenated compound 1-II was also observed (Table 1, entry 2). Upon warming to 120 °C dimerization of the starting material was observed along with degradation (Table 1, entry 3). Finally reaction at 100 °C without palladium catalyst never yielded iodination even with two equivalents of NIS and prolonged reaction time (Table 1, entries 4 and 5).
The ortho position of the iodine was assigned by NMR analysis and unambiguously confirmed from X-Ray crystallography (see Fig. 2). Surprisingly, a drop of reactivity was observed when NBS and NCS were used as halogenating agents. Using the previously optimized conditions in the presence of NBS gave less conversion to 1-Br (50% of starting material left) along with some brominated compound on the central phenyl ring 2 (Table 1, entry  6). Increasing the amount of NBS to 5 equivalents, prolonged heating (1 hour) and replacing CH 3 CN by DMF resulted in more compound 2 (Table 1, entry 7). Interestingly, reaction performed without palladium acetate only resulted in compound 2 (Table 1, entry 8). To the best of our knowledge, no direct halogenation of 1,4-benzodiazepinone on the 7-position was reported (compound 2). The 7-bromo position was unequivocally identified by comparison with NMR spectra of 7-bromo-1,3-dihydro-5-phenyl-2 H-1,4-benzodiazepin-2-one obtained from 2-amino-4-bromobenzophenone. This regioselective control affords a straightforward access to 7-brominated benzodiazepinones. Replacing NBS by another brominating agent, CuBr 2 , gave the starting material unchanged (Table 1, entry 9). Reaction with NCS at 100 °C in CH 3 CN only afforded the mono-chlorinated compound 1-Cl as traces whereas the same reaction without palladium acetate in DMF only yielded untractable mixture of monochlorinated compounds.
Having the best experimental conditions (NIS, palladium acetate, MW heating at 100 °C for 15 minutes) in hand, we decided to check the scope and limitation of this iodination process on differently substituted benzodiazepinones (Table 2). Each starting material was synthetized from the corresponding aminobenzophenones [20][21] .
It is worth noting that radioiodinated ( 123 I, 125 I or 131 I) benzodiazepinones have been widely used in binding assays 13 . The strategies used in the synthesis of these radioiodinated benzodiazepinones always involve an isotopic exchange with Na 125 I, the parent iodinated compound being synthesized from simple iodinated precursors such as iodobenzoic acid [22][23][24] .
Our previously optimized iodinating conditions ( Table 2, entry 1) allowed a clean conversion of the 7-bromo compound 2 into the monoiodinated compound 2-I with 61% yield along with 3% of the diiodinated compound 2-II (Table 2, entry 2). Notably, when one ortho position of the ring was   already substituted slightly lower yield was experienced ( Table 2, entry 3). Introduction of a methyl group on the 4′ position does not alter the course of the reaction giving also fair yield and had no impact of the ratio of mono and diiodinated compounds 4-I and 4-II (Table 2, entry 4). Interestingly, the iodination also proceeds satisfactorily in the presence of a secondary amide (no methyl group on nitrogen 1) ( Table 2, entry 5) even if the use of a benzyl protecting group allows the formation of the desired iodinated compound 7-I with a better yield (   drug was also envisioned. Therefore diazepam was submitted to NIS/Pd(OAc) 2 and clean conversion to the mono-iodinated analog 6-I ( Table 2, entry 6) was also successfully observed. It is worth precising here that this iodinated derivative showed higher receptor affinity than diazepam (IC 50 0.74 nM versus 6.70 nM) 22 . Finally, the 4′ -methylated analog afforded comparable yield and ratio of 8-I and 8-II compounds compared to unsubstituted benzodiazepinones ( Table 2, entry 8). A copy of 1 H and 13 C NMR spectra of all new compounds are available in the supplementary material from page S2 to S17. The putative mechanism involves a CH activation assisted by the chelation of the nitrogen atom of the imino moiety of the benzodiazepinone. The insertion of a molecule of N-iodosuccinimide 25 allows the formation of complex B on which the Pd(II) was oxidized to Pd(IV). Then, ligand exchange provides dimeric intermediate C whose formation was confirmed by LC-MS. Finally, a reductive elimination occurs to afford mono-iodinated compound that can enter a new catalytic cycle to afford the diiodinated product (Fig. 3).
In this mechanism, we suggest that the oxidation of Pd(II) to Pd(IV) is prior to the ligand exchange step because the dimer formation, via a homoleptic complex, was not detected when benzodiazepine 1 was treated with Pd(OAc) 2 in the absence of NIS. Once we suggested the formation of complex C we investigated whether the dimer would be formed from a reductive elimination or a simple homocoupling from the iodinated compound. For this purpose the same reaction was performed starting from compound 1-I and only non-iodinated dimer was formed strongly supporting the homocoupling process [26][27][28] .

Conclusions
In conclusion, we have described herein an efficient protocol for regioselective halogenation of benzodiazepinones. This protocol takes advantage of CH activation with palladium acetate. Since radio-iodinated NIS is easily prepared, the CH activation described here offers a straightforward route to radioiodinated benzodiazepinones. Halogenated benzodiazepinones also represent ideal starting materials for more functionalized analogs via metal catalyzed cross-coupling reactions and this CH activation based approach opens new possibilities in this area. In this case, sequential halogenation/coupling procedures at the 7 then at the 2′ position or vice versa could gain libraries of benzodiazepinones.

Methods
General remarks. The products were isolated by flash silica gel column chromatography (0.040-0.063 mm). Reactions were run without exclusion of air/moisture in a microwave tube. Reactions were monitored by NMR. 1 H and 13 C NMR spectra were recorded using a Bruker Avance 400 MHz Ultrashield spectrometer in CD 3 CN for all compounds except for compound 5-I whose NMR analysis were conducted in (CD 3 ) 2 SO for solubility reasons. The following abbreviations are used in reporting NMR data: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d appt, doublet of apparent triplet; m, multiplet. Infrared spectra were recorded on an FT-IR spectrophotometer. HPLC-MS analysis and purification were performed using a Waters system (2525 binary gradient module, in-line degasser, 2767 sample manager, 2996 Photodiode Array Detector) with a binary gradient solvent delivery system. This system was coupled with a Waters Micromass ZQ system with a ZQ2000 quadrupole analyzer. The ionization was performed by electrospray and the other parameters were as follows: source temperature 120 °C, cone voltage 20 V, and continuous sample injection at 0.3 mL∕ min flow rate. Mass spectra were recorded in both positive and negative ion mode in the m/z 100-2,000 range and treated with the Mass Lynx 4.1 software. High-resolution mass spectrometry (HRMS) was performed using the Imagif platform (CNRS, Gif-sur-Yvette, France), and recorded on ESI/TOF LCP premier XE mass spectrometer (Waters) using flow injection analysis mode.

7-bromo
Crystal data for compound 1-I. C  Note † Electronic supplementary information (ESI) available: Experimental procedures and characterisation data for all products, including copies of 1 H and 13 C NMR spectra and X-ray structural information of 1-I (CIF). CCDC 1014605.