Highly Diastereoselective Synthesis of Tetrahydroquinoline Derivatives via [4 + 2] Annulation of Ortho-Tosylaminophenyl-Substituted Para-Quinone Methides and Cyanoalkenes

As a privileged structural motif, tetrahydroquinoline skeletons widely exist in biologically active natural products and pharmaceuticals. In this protocol, a highly diastereoselective [4 + 2] annulation of ortho-tosylaminophenyl-substituted p-QMs and cyanoalkenes to construct tetrahydroquinoline derivatives has been successfully achieved. This strategy proceeds efficiently under mild condition, offering straightforward route to a variety of 4-aryl-substituted tetrahydroquinolines with high yields, excellent diastereoselectivities, broad functional group tolerance as well as gram-scale capacity. Moreover, a one-pot reaction sequence utilizing in situ generated p-QMs under the similar condition to build tetrahydroquinoline framework is smoothly conducted with good reaction performance as well as step and atom economy.


INTRODUCTION
As privileged structural motifs, nitrogen-containing heterocycles widely exist in biologically active natural products and pharmaceuticals (Noolvi et al., 2011;Solomon and Lee, 2011;Afzal et al., 2015;Murlykina et al., 2018;Harikandei et al., 2019;Staskiewicz et al., 2021). Among them, 4phenyl-substituted tetrahydroquinolines are of great importance owing to their wide range of applications in medicinal chemistry, exhibiting antitumor and antibacterial properties (Figure 1). For example, 4-phenylquinolin-2 (1H)-one I shows potential as a specific allosteric inhibitor of Akt (Huang et al., 2017). Compound II has been designed as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase (Chen et al., 2013). As a rationally developed antitumoral agent, compound III displays excellent bioactivity to kill parasite 14DM (Kraus et al., 2009). Known as a novel synthetic molecule, compound IV exhibits antitumoral and antiplasmodial activities (Vladimir et al., 2010). The well-designed compound V owns good antibacterial activity against microorganisms of Escherichia coli (Ramesh et al., 2009). Peniprequinolone VI, isolated from Penicillium sp. FKI-2140, demonstrates impressive insecticidal activity (Uchida et al., 2006). Thus, considering the significant research value of tetrahydroquinolines derivatives in medicinal chemistry, the development of efficient and facile methods to build these valuable skeletons is highly demanded.

RESULTS AND DISCUSSION
To verify the feasibility of our protocol, a serial of reaction parameters was investigated to explore the best condition for the [4 + 2] annulation. Initially, we established the model reaction using ortho-tosylaminophenyl-p-QMs 1a and α,α-dicyanoalkenes 2a as substrates (Table 1). To our delight, with the help of Cs 2 CO 3 as base, the desired product 3a was successfully obtained in DCM at room temperature in 80% yield with excellent diastereoselectivity of >20:1 ( Table 1, entry 1). Encouraged by this promising result, different bases were systematically evaluated, and we found that Na 2 CO 3 , pyrolidine, and triethylamine (TEA) were inefficient for this reaction compared to Cs 2 CO 3 (entries 2-4). Delightfully, the organic base 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) was beneficial to this transformation, generating product 3a in 89% yield (entry 5). Then, we switched attention to solvents screening to further improve reaction efficiency (entries 6-10), and the toluene serving as reaction mediate performed best with up to 96% yield (entry 8). After the confirmation of the optimized base and solvent, the factors of temperature and substrate ratio in this base-mediated catalyst-free protocol was subsequently investigated, and it was found that none of improvement of reaction efficiency was observed when applying other temperature or substrate ratio (entries 11-14). Furthermore, we found that reducing the DBU loading to 0.01 mmol and raising the reaction temperature led to slight decrease in yield with prolonged reaction time (entries 15-16).
With the optimal reaction conditions in hand ( Table 1, entry 8), we started to explore the substrate scope of this [4 + 2] annulation reaction (Scheme 2). Firstly, the scope of the α, a-dicyanoalkenes part was examined, and we were pleased to find that this protocol tolerated a wide range of α, a-dicyanoalkenes 2, which could readily react with 1a to afford 3a-3u in 55-96% yields. In detail, the α, a-dicyanoalkenes 2 bearing electron-withdrawing (F, Cl, Br, I, ethynyl) and electrondonating (Me, MeO) groups at the phenyl ring could be efficiently converted into the desired products 3a-3n in 62-96% yields (Scheme 2, line 1). The relative configuration of 3a (CCDC 2100705) was determined by X-ray crystallographic analysis, and the relative configurations of other products three were tentatively assigned by analogy. Besides, the α, a-dicyanoalkenes 2 containing challenging disubstituted groups.
Were also available, giving the corresponding products 3o-3r in consistent high yields (Scheme 2, line 1). Moreover, aromatic series (naphthyl, furyl, and thienyl) could also participate in this [4 + 2] annulation sequence to provide expected products 3s, 3t and 3u in 79, 55 and 65% yields, respectively (Scheme 2, line 2). Subsequently, several ortho-tosylaminophenyl-p-QMs 1 were investigated to further verify the generality of this method. The results indicated that electronic-withdrawing substituents on the phenyl ring of substrate 1 showed rare affection on efficiency, delivering target products 3v and 3w in high yields (Scheme 2, line 2). Changing the type of protecting group still resulted in desire compound 3x with excellent reaction performance (Scheme 2, line 2). However, the unavailability of dimethyl substituted substrate failed to provide the expected product 3y. To evaluate the general utility and robustness of this protocol, we also conducted the gram-scale reaction under the standard condition, and the target product 3a could be smoothly isolated in 93% yield.
To enrich the diversification of this protocol towards functionalized tetrahydroquinoline derivatives, we established the verification with represented substrates 2 (Scheme 3). Fixed different electronic properties groups (such as nitro, benzoxyl and COOEt groups) on the position of R 2 and/or R 3 , all reaction could move forward the production of compounds 3z-3bb under optimal condition in 42, 90 and 92% yields, respectively (Scheme 3A). However, substrate containing two ester groups could not offer the target product 3cc under this condition. The relative configuration of 3aa (CCDC 2100706) was determined by X-ray crystallographic analysis, and the relative configurations of 3z-3bb were tentatively assigned by analogy. Moreover, we attempted to construct valuable spirocyclic frameworks employing tetra-substituted substrates four and six within the established condition, and successfully obtained desirable products five and seven in 90 and 62% yields, respectively (Scheme 3B). Regretfully, we failed to accurately assign the relative configuration of compound 5 and 7 with limited information (for details please see ESI). In order to further explore the robustness of this methodology, a preliminary attempt of one-pot synthesis of functionalized tetrahydroquinoline compound starting from precursor 1a was successfully conducted, producing target molecule 3a in 63% yield (Scheme 3C, Wang et al., 2018).
Meanwhile, the successful transformation of reducing cyan group into primary amine delivered the valuable product 8 with good reaction performance and undefined-relative configur-ation (for details please see ESI), which may show the potential application in medicinal chemistry (Scheme 4, right column). However, the removal of para-toluene sulfonamide and di-tertiary butyl groups failed to provide the expected products 9 and 10 (Scheme 4, left column).
Scheme 3 | Diversification of multifunctional (A) and spirocyclic (B) tetrahydroquinoline derivatives, and one-pot synthesis of compound 3a (C). All the reactions were conducted under the standard condition, dr > 20:1.
Frontiers in Chemistry | www.frontiersin.org November 2021 | Volume 9 | Article 764866 5 CONCLUSION In conclusion, we have developed a DBU-mediated catalyst-free [4 + 2] annulation between ortho-tosylaminophenyl-substituted p-QMs and cyanoalkenes for synthesis of valuable tetrahydroquinoline derivatives through an aza-Michael/1,6conjugate addition sequence. This protocol features broad of tolerance and diversification on substrates, offering straightforward route to various of 4-aryl-substituted tetrahydroquinolines with high yields, excellent diastereoselectivities as well as gram-scale capacity. Moreover, a one-pot reaction sequence utilizing in situ generated p-QMs under the similar condition to build tetrahydroquinoline framework is smoothly conducted with good reaction performance as well as step and atom economy. Further studies on the bioactivity of those promising tetrahydroquinolines will be reported in due course.

General Information
NMR data were obtained for 1 H at 400 MHz and for 13 C at 100 MHz, or for 1 H at 600 MHz and for 13 C at 150 MHz. Chemical shifts were reported in parts per million (ppm) using tetramethyl silane as internal standard with solvent resonance in CDCl 3 . UV detection was performed at 254 nm. ESI-HRMS spectra were measured with a Q-TOF instrument. Column chromatography was performed on a silica gel (200-300 mesh) using an eluent of ethyl acetate and petroleum ether. TLC was performed on glass-backed silica plates; products were visualized using UV light. Melting points were determined on a Mel-Temp apparatus. All reagents and solvents were obtained from commercial sources and used without further purification. Substrates 1 and precursor 1a were prepared according to the literature procedures (Wang et al., 2018;Wang J.-Y. et al., 2020).