Direct C–H amination and C–H chloroamination of 7-deazapurines

Department of Organic Chemistry, Faculty Hlavova 8, CZ-12843 Prague 2, Czech Repu Institute of Organic Chemistry and Biochem Republic, Gilead & IOCB Research Center, Czech Republic. E-mail: hocek@uochb.cas.c † Electronic supplementary information part and characterization of all com structures, copies of NMR spectra. CC crystallographic data in CIF or o 10.1039/c4ra13143f Cite this: RSC Adv., 2014, 4, 62140

In order to have a choice of some more easily cleavable N-protecting groups, 15 we also tested 4-nitrophenylsulfonyl-(p-nosyl, pNs) and 2-nitrophenylsulfonyl (o-nosyl, oNs) chloroamides 3 and 4. The reaction of 1a with pNs reagent 3 (3 equiv.)gave the 8-p-nosylamino product 6a in acceptable 48% yield (entry 6).The reactions of 1a with oNs chloroamide 4 (2-3 equiv.)gave very low conversions (see Table S1 in ESI †), whereas the reaction with 5 equiv. of 4 gave a mixture of the desired product of 8-amination 7a (28%) accompanied by 7-chloro-8-amino-8a and 7-chloro-7-deazapurine 9a as side-products.Apparently, the chloroamide 4 in larger excess can act as an electrophilic chlorination reagent which halogenates the deazapurine at position 7 (similarly as it was shown in indoles 13 ).Therefore, we performed a detailed optimization of this reaction using different ratios of reagents, catalysts and additives and different conditions (see Table S1 in ESI †).The optimum protocol for aminations used 3 equiv.of 4 in presence of large excess of Na 2 CO 3 (7 equiv.) to give the desired product 7a in 60% yield (Table 1, entry 8).
The detailed optimization also revealed some ratios of reagents and conditions under which the chloroamination proceeds.Also inspired by the related work on indoles, 13 we employed CuCl as copper source, Ag 2 CO 3 as base and LiCl as additive (Table S1 in ESI †) to nd an optimum protocol leading exclusively to chloroamination, 13,16 employing 4 (3 equiv.) in presence of Pd(OAc) 2 , CuCl (10 mol%), LiCl (2 equiv.)and Ag 2 CO 3 (2 equiv.).
Then we tested the chloroamination protocol on the same series of deazapurines 1a-1e.The reactions with 4 (3 equiv.)were performed in presence of Pd(OAc) 2 , CuCl, LiCl and Ag 2 CO 3 .The reactions of 6-phenyl and 6-methoxy derivatives 1a,b proceeded well to get desired 7-chloro-8-(oNs)MeNH-7deazapurines 8a,b in acceptable yields of 51 and 42%, whereas the reaction of 6-methyl derivative 1c gave low conversion to inseparable mixture containing products of chlorination and chloroamination.Similarly, the reactions of 6chloro-and 6-aminodeazapurines 1d,e gave complex inseparable mixtures.Finally, 6-phenyl-7-chloro-7-deazapurine 9a was also converted to 7-chloro-8-aminated derivative 8a in 41% yield showing that the chlorine at position 7 is better tolerated (as it is less reactive toward nucleophiles) than the chlorine at position 6.
The last goal in this study was to test a deprotection of the sulfonamides and the stability of the corresponding 8-amino-7deazapurines (2-aminoindoles are prone to tautomerization 17 and oxidation 18 ).Any attempt to cleave the Ts-or pNs-groups in  compounds 5a or 6a according to literature 15 either did not work or led to decomposition of the heterocycles.Therefore, major part of this study was performed with oNs-group which is more easily cleavable. 15The deprotection of compound 7a was successfully performed using thiophenol and cesium carbonate 15d to afford 8methylamino-7-deazapurine 10a in 75% yield (Scheme 3).We performed also one-pot C-H amination deprotection sequence to furnish the desired compound 10a directly in 35% for two steps.The 8-(methylamino)-7-deazapurine 10a was reasonably stable under neutral conditions but quickly decomposed when exposed to even traces of acid (e.g. in chlorinated solvents).All new compounds were fully characterized by NMR spectroscopy including assignment of all signals.In addition, to conrm the regioselectivity of the reactions, single-crystal X-ray diffraction was performed with compounds 5a, 7a, 7b and 8a.Fig. 1 shows the crystal structures of compounds 7a and 8a (for structures of 5a and 7b, see ESI †).

Conclusions
In conclusion, we have developed selective protocols for palladium/copper-catalyzed direct C-H amination and C-H chloroamination of 7-deazapurines with N-chloro-N-alkylarylsulfoneamides.Reactions proceed under mild conditions regioselectively at position 8 of 7-deazapurines (in analogy to aminations at position 2 of indoles 13 ) and are applicable to 6aryl, -alkyl and -alkoxy 7-deazapurine derivatives.On the other hand, they are not compatible with 6-amino-and 6-chloro derivatives.Apart from the potential for the synthesis of series of 8-(arylsulfonyl)methylamino-7-deazapurines (and their 7chloro-derivatives), when using oNs sulfonamides, the deprotection is possible to 8-methylamino-7-deazapurines.These protocols nicely complement the current toolbox of reactions for modications of these privileged heterocycles and will be used for generation of libraries of compounds for biological activity screening.