DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

An intriguing DABCO-catalyzed and DBU-promoted one-pot synthesis of an important class of (2-hydroxyaryl)pyridine derivatives bearing a carboxylate or a nitrile group suitably placed at C3 position of the aza-ring has been achieved in acceptable chemical yields with a broad functional group tolerance. This sequential C–C/C–N bond making process proceeds through a regioselective allylic alkylation/aza-Michael reaction between MBH carbonates derived from an acrylate/acrylonitrile and N-sulfonyl ketimines as C,N-binucleophiles catalyzed by DABCO, followed by elimination of SO2 under the influence of base and subsequent aromatization in an open atmosphere.


Scheme 2:
A possible mechanism for this sequential reaction.
Gratifyingly, high yields (88%) of cyclized product 4a and a trace amount of desired nicotinate 5aa (2% yield) were obtained when the reaction was conducted at 60 °C (entry 2, Table 1). By increasing the temperature as well as the loading of DABCO (1.0 equiv, entry 3, Table 1), a similar result was observed. At this situation, we surmised that step II may require a stronger base like DBU which will facilitate the aromatization process. For this purpose, DBU (1.2 equiv, entry 4, Table 1) was added to the reaction mixture at 60 °C after completion of step I. Pleasantly, 76% yield of wanted 5aa was isolated after 5 h. Attempts to optimize the reaction conditions using several solvents (THF, MeCN, DMF and DMSO) all led to lower yields (19-68%, entries 5-8, Table 1) as compared to the toluene-mediated reaction (76%, entry 4, Table 1). Next, several N/P-containing Lewis bases such as Et 3 N, DMAP, DBU and PPh 3 were tested for this reaction in toluene and resulted in very poor yields (5-21%, entries 9-12).
Based on the above experimental results as well as our previous report on DABCO-catalyzed reactions of cyclic sulfamidate imines with MBH carbonates of isatins [75], a plausible mechanism is presented and depicted in Scheme 2. For the first step, the nucleophilic Lewis base DABCO reacts with 2a in an S N 2' fashion to make a very reactive allyl ammonium intermediate 6. With the optimization reaction conditions in hand, we decided to explore the generality and scope of the reaction by reacting several aryl/heteroaryl-substituted MBH carbonates derived from acrylates 2a-j and 4-methyl-N-sulfonyl ketimines 1a-e under present sequential reaction conditions. The results are incorporated in Scheme 3. The regioselective allylic alkylation/ aromatization reaction between 4-methyl-N-sulfonyl ketimine 1a and several aryl-substituted MBH carbonates having electron donating (Me, MeO and BnO) and withdrawing substituents (F, Br, CN and NO 2 ) on the benzene rings proceeded smoothly under the present conditions. The results showed that electron donating substituents of MBH carbonates produced 65-73% yields of the corresponding (2-hydroxyphenyl)nicotinates 5ab-5ad which are slightly lower yields as compared to electron withdrawing ones (74-79% yields, 5ae-5ah) under identical conditions. Furthermore, heteroaryl-substituted MBH carbonates 2i and 2j also afforded 68% and 70% yields of 5ai and 5aj, respectively.
Interestingly, the coupling reaction proceeded nicely not only with N-sulfonyl ketamine 1d bearing an electron poor Br atom but also substrates 1b and 1c having electron donating substituents (Me, MeO) on the aryl rings, although the latter produced better yields than the former one. By this C-C/C-N bonds forming procedure, N-sulfonyl ketimine derived from a bulky
α-naphthol moiety was found to be a suitable coupling reagent, leading to the corresponding α-naphthol-substituted nicotinate derivatives 5ea and 5ee in 71% and 74% yields, respectively.

Conclusion
In the current manuscript, a unique one-pot two-step sequential reaction of 4-methyl N-sulfonyl ketimines with MBH carbonates of acrylate/acrylonitrile catalyzed by DABCO, followed by aromatization using DBU as a base in an open-flask has been developed. This smart oxidant metal-free C-C/C-N bond forming process leads to an array of functionalized nicotinates/ nicotinonitriles possessing an interesting phenolic moiety at C6 position in good to high yields. Moreover, the current process is mild enough to be applied on a broad range of functional groups. Further studies on the application of this reaction with broader substrate scope as well as the biological evaluation of the synthesized pyridines are in progress which will be documented in due course of time.

Supporting Information
Supporting Information File 1 Synthetic protocols, characterization data and copies of 1 H and 13 C NMR spectra.