In 2015, Feng’s group developed an asymmetric tandem [1,5]-hydride shift/cyclization reaction to produce chiral spirooxindole tetrahydroquinolines using chiral N, N′-dioxide/Sc(OTf)₃ as a catalytic system (Scheme 1) (Cao et al., 2015). As far as we know, this is the only report for the asymmetric version of tandem [1,5]-hydride shift/cyclization. The oxindole derivative 1 as a suitable hydride acceptor triggered the intramolecular tandem [1,5]-hydride shift/ring closure reaction. With the assistance of the chiral complex of N, N′-dioxide/Sc(OTf)₃, all reactions proceeded smoothly in dichloroethane (DCE) at 35°C, offering a wide range of optically active spirooxindole tetrahydroquinolines 2 with high yields of up to 97% and excellent stereoselectivies of up to 94% ee and >20:1 dr. Moreover, a gram-scale investigation of this strategy was smoothly operated with excellent reaction performance, which demonstrated the robustness of this tandem sequence toward spirocyclic tetrahydroquinolines. The author proposed a possible mechanism of chiral memory effect dominating a helical chirality in a cationic intermediate to explain the chiral information observed in optically active products.

In 2017, Tunge’s group revealed a Lewis acid-catalyzed synthesis of spiro tetrahydroquinoxalines from diamines 6 and isatins 7 (Scheme 2) (Ramakumar et al., 2017). The condensation of diamine 6 with the α-dicarbonyl substrate generated an imine intermediate 11 that is responsible for the [1,5]-hydride shift to nitrogen. Using FeCl₃ as a promoter, various substituents at different positions of both substrates were all tolerated, yielding corresponding spirocyclic compounds X with accepted to outstanding yields (55%–90%) and moderate to excellent diastereoselectivities (1.4:1 to 25:1). A hypothetical mechanism for the key step of cyclocondensation is depicted in Scheme 2.

One year later, Li’s group uncovered a fluorinated alcohol-mediated cascade [1,5]-hydride shift/cyclization reaction to prepare spiro-tetrahydroquinolines bearing oxindole moiety (Scheme 3) (Chen et al., 2018). Research indicated that hexafluoroisopropanol (HFIP) demonstrated a significant influence on the efficacy of the transformation. The Knoevenagel condensation of 2-(pyrrolidin-1-yl)benzaldehyde 13 and indolin-2-one 14 triggered a [1,5]-hydride shift/cyclization sequence to generate structurally diverse spirooxindole-fused tetrahydroquinolines. With the help of HFIP as a solvent, this strategy showed good tolerance of a variety of substrates, resulting in the corresponding products having moderate to good yields (32%–89% yield) with good to high diastereoselectivities (61:39 to >20:1 dr). A plausible mechanism displaying dual hydrogen bonds of HFIP with the enol moiety of intermediate TS1/2 was proposed in their study, which is depicted in Scheme 3.

Soon after, Xiao’s group uncovered the scandium-catalyzed redox-neutral cascade [1,5]-hydride shift/cyclization of C4-amine-substituted isatins 24 and 1,3-dicarbonyl compounds 25 (Scheme 4) (Zhu et al., 2019). In this process, the α,β-unsaturated 1,3-dicarbonyl intermediate 29 acted as a hydride acceptor. The optimized condition proved to be using dichloroethane (DCE) as solvent, 5-Å molecular sieves as additive, and Sc(OTf)₃ as catalyst, delivering diverse product 26 with acceptable to good yields (48%–99% yield) and acceptable to excellent diastereoselectivities (1:1 to >20:1 dr). Intriguingly, the substrates containing asymmetrical acyclic N-benzyl-N-methylamine were also tolerated in this reaction, which has never been achieved before in most hydride shift sequences. Besides, the chiral control of the reaction was also investigated using chiral phosphoric acid as catalyst; however, only poor enantioselectivity was observed in this process. The plausible reaction mechanism is described in Scheme 4.

Instead of the oxindole unit, indole substrates could also participate in the [1,5]-hydride shift/cyclization sequence. In 2015, Sun and Xu’s group revealed a concise approach to construct a spiro-tetrahydroquinolines incorporated indolenine moiety 34 via the [1,5]-hydride shift/cyclization sequence (Scheme 5) (Wang P.-F. et al., 2015). The hydride acceptor iminium 38, formed through dehydration of substrates, induced the hydride shift/cyclization process under acidic conditions. Employing 2-substituted indoles 32 and 2-(pyrrolidin-1-yl)benzaldehydes 33 as substrates, p-TsOH·H₂O as catalyst, and DCE as solvent, a wide range of desired target products 34 were successfully obtained with good to excellent yields and moderate diastereoselectivities. Interestingly, when the inseparable mixture of diastereoisomers was washed with isopropyl ether after rapid chromatography, the isolated products 35 could be obtained in up to >20:1 dr. An asymmetric version utilizing chiral BINOL-derived phosphoric acid was also conducted under the same condition, but only delivering the corresponding compound with low enantioselectivity. A plausible mechanism of this methodology is proposed in Scheme 5.

Recently, Xiao’s group reported the first regioselective dearomatization between 4-hydroxindoles 43 or 4-hydroxycarbazole 45 and 2-aminobenzaldehydes 42 to construct spiro-tetrahydroquinolines via an aromatization-driven hydride shift strategy (Scheme 6) (Duan et al., 2020b). Under the catalysis of scandium complex and HFIP, a variety of spirocyclic molecules incorporating indoles and carbazole moieties were provided with moderate to high yields, respectively. Meanwhile, the author found that the protection of the OH group of 4-hydroxyindole with formic ester was preferred to the generation of the spiroindolenine in HFIP. To further explore the switchable dearomatization of indoles in the carbocyclic ring and pyrrole ring, a variety of 2-aminobenzaldehydes 42 reacting with ethyl (1H-indol-4-yl) carbonate 47 were examined, giving the corresponding spiroindolenines 48 a 62%–81% yield with up to >20:1 dr. A plausible mechanism indicated that the protection of the hydroxyl group of 47 shifted the direction to another reaction site and guaranteed the conduction of this reaction at the electron-rich C-3 position of indole. Undoubtedly, this strategy provided an answer to the limitation of switchable dearomatization of fused bicyclic aromatic compounds.

The divergent synthesis of tetrahydroquinoline-fused spiroindolenines through cascade dearomatization of indoles with ortho-aminobenzaldehydes driven by the dearomatization force was also achieved by the same group (Scheme 7) (Shen et al., 2019). The type of substrate and catalyst was a critical factor in the regulation of divergent synthesis of the final spirocyclic products. Under the catalysis of HFIP acting as both solvent and reaction promoter, an array of tetrahydroquinoline-fused spiroindolenines 57 that contain diverse electron properties on the aromatical ring of both substrates 55 and 56 were efficiently synthesized at a 47%–97% yield with up to >20:1 dr. Moreover, the addition of TsOH·H₂O could further enable the transformation of THQ-fused spiroindolenine to ring-expanded derivatives 58 via the 1,2-migration process. When adding Sc(OTf)₃ as catalyst into the reaction instead of HFIP in DCE at room temperature, the three-component reactions for the assembly of tetrahydroquinoline-fused indolenines 59 were successfully achieved, giving the corresponding product a 54%–66% yield with 2:1 to 3:1 dr. The plausible mechanisms were described as shown in Scheme 7 to explain this divergent synthesis. The process of synthesizing products 57 mainly contained a Friedel-Crafts alkylation/hydrolyzation/[1,5]-hydride shift/spirocyclization sequence, which was similar to a previous work by Xiao’s group with the assistance of HFIP. As for product 69, due to its strong Lewis acidity, Sc(OTf)₃ was beneficial for generating the α,β-unsaturated indolenine intermediate 67 and then initiated [1,5]-hydride transfer/cyclization processes to provide the target products 69.

In addition to Xiao’s elegant work above, a controllable synthesis of spiroindolenines and benzazepinoindoles via HFIP-mediated cascade [1,5]-hydride shift/cyclization was successfully developed by the team of Li and Wang (Scheme 8) (Bai et al., 2019). As shown in Scheme 8 (top line), the controllable process of the two privileged skeletons 72/73 features high efficiency, mild reaction conditions, and good substrate tolerance, giving these two individual products a moderate to high yield (with moderate to excellent diastereoselectivities for product 73). The proposed mechanism of rationalizing the formation of two products 72/73 was illustrated, and the addition of TsOH·H₂O played an important role in this controllable process (Scheme 8, bottom line). As for the mechanism of spiroindolenines (Scheme 8, right column), the reactive intermediate 80 was formed by the promotion of HFIP-mediated H-bonding interaction between compounds 78 and 79, followed by the result of vinylogous imine 81, which was generated through dual hydrogen bond-promoted dehydration and served as a hydride acceptor. Under the activation of HFIP, the electrophilic iminium intermediate 82 was obtained via a [1,5]-hydride shift process, and then the dearomatization product 83 was furnished after the nucleophilic attack at the C3 of the indole moiety and cyclization sequence. As for the mechanism of benzazepinoindoles, the protonation of spiroindolenine 73 gave the intermediate 74, which generated an iminium intermediate 75 after the bond cleavage of C3–C8 promoted by rearomatization. Then, the final thermodynamic benzazepinoindole 72 was offered after an attack of iminium moiety on the C2 position of the indole ring (path A). The author also proposed two alternative competitive migration processes based on the observed phenomenon (pathways B and C), which might furnish two possible products 72 and 76 via the “three-center-two-electron” transition state. However, in fact, there was no possible product 76 observed in this reaction. Notably, the N−H bond in intermediate 77 could chelate the OH group of HFIP with the addition of TsOH·H₂O in the reaction medium, which served as a significant steric hindrance to block the nucleophilic attack of C2 of indole to the iminium moiety, and only delivered spiroindolenines 73 rather than benzazepinoindoles 72 (pathway D).

In 2020, Deb’s group reported a diastereoselective olefination/[1,5]-hydride shift/cyclization sequence to synthesize spiroheterocycles from reaction of ortho amino benzaldehydes 84 or olefins 85/87 with active methylene compounds 86/88 (Scheme 9) (Bhowmik et al., 2021). The α,β-unsaturated electron-deficient alkene used as a hydride acceptor enabled the synthesis of novel spiro tetrahydroquinolines bearing 2- or 3-coumaranone moieties with good to excellent yields (up to 99% yield). Moreover, the employment of 4-hydroxycoumarin or 3-isochromanone substituted olefins as substrates in the presence of Yb(OTf)₃ successfully provided access to a wide range of spiro-tetrahydroquinolines 90/92 containing chromanone or 3-isochromanone moieties with excellent to good yields and diastereoselectivities.

Soon after, an efficient access to tetrahydroquinoline spiro-heterocycles via the hydride shift cyclizations of aurones 94 was developed by Xiao’s group (Scheme 10) (Duan et al., 2020a). With low loading of Sc(OTf)₃ in 2 mol%, a series of biologically important spiro-heterocycles were achieved with good yield (up to 95%) and good diastereoselectivities (up to >20:1 dr) under mild conditions. The researchers proposed a plausible mechanism for this reaction, as described in Scheme 10. Again, this work shows great potential of the driving force of aromatization in hydride shift cyclization strategy.

The structure of pyrazolone derivatives is widely seen in pharmaceuticals and drugs; hence, merging this valuable unit into a spiro-tetrahydroquinoline skeleton by a [1,5]-hydride shift/cyclization strategy could be a promising direction for the discovery of new drugs. In 2015, a zinc chloride-catalyzed protocol to synthesize a range of pyrazolone-fused spiro-terahydroquinolines via a tandem [1,5]-hydride shift/cyclization process was documented by Wang’s group (Scheme 11A) (Zhao et al., 2015). The α,β-unsaturated pyrazolone intermediate 101 served as a hydride acceptor and engaged in the 1,5-hydride shift/cyclization sequence. This methodology features broad substrate scope, high yields (up to 95% yield), good to excellent diastereoselectivities (up to >95:5 dr), as well as gram-scale capacity. Also, the reduction of one of the spirocyclic compounds 101 using LiAlH₄ in refluxing THF condition was successfully realized, resulting in the corresponding novel spiro-terahydroquinoline 102 having a good reaction performance. However, efforts to explore an enantioselective version of this reaction are still being developed. The proposed mechanism for the construction of spiro-tetrahydroquinoline is shown in Scheme 11A.

Very recently, Smirnov’s group reported an intramolecular tandem [1,5]-hydride shift and cyclization to form spirocyclic tetrahydroquinoline derivatives 107 under the promotion of TiCl₄ (Scheme 11B) (Zaitseva et al., 2021). The hydride shift process was triggered by reactive α,β-unsaturated imidazole fragments 105. This reaction demonstrated impressive substrate tolerance, giving the desirable spirocyclic compounds a 25%–95% yield under mild conditions. Moreover, a gram-scale reaction was successfully conducted with up to 93% yield, paving the way to potential research of antibacterial activity of those bioactive molecules.

As important heterocyclic structures, isoxazol-5-one and tetrahydroquinoline scaffolds are found in a wide range of medicines and bioactive natural products (Sridharan et al., 2011). Hence, merging these two structures to synthesize novel spirocyclic molecules could be attractive for the discovery of lead compounds. In 2013, an intramolecular tandem 1,5-hydride transfer/cyclization process catalyzed by Lewis acid Sc(OTf)₃ to construct isoxazolone-tetrahydroquinolines and 3-amino-3-carboxytetrahydroquinoline derivatives has been established by the group of Yuan (Scheme 12) (Han et al., 2013). In this method, the (Z)-alkylidene azlactone 111 served as both a hydride donor and an acceptor, offering an array of tetracyclic and pentacyclic heterocycles containing two stereogenic centers and spirocyclic skeletons with up to 99% yield with diastereoselectivities ranging from 57:43 to 73:27. To demonstrate the synthetic utility of this method, transformation of several spirocyclic products to 3-amino-3-carboxytetrahydroquinoline derivatives 113 was also demonstrated through an efficient ring opening process using MeONa as base in MeOH with up to 97% yield, and 70:30 to 75:25 dr.

Three years later, Wang’s group designed a ZnCl₂-tatalyzed Knoevenagel condensation/[1,5]-hydride shift/cyclization sequence to synthesize a series of novel spiroisoxazol-5-one tetrahydroquinolines (Scheme 13) (Zhao et al., 2016). In their strategy, the condensation of 2-(pyrrolidin-1-yl)benzaldehyde 118 and 3-methylisoxazol-5(4H)-one 119 changed the reactive intermediate 120 into a hydride donor and acceptor, which underwent a subsequent [1,5]-hydride shift/cyclization process to furnish the final product 122. As a result, this reaction featured a broad substrate scope and a simple reaction operation, providing the target spirocyclic products 117 with up to 97% yield and up to >95:5 dr, which demonstrated the high efficiency of this methodology.

In 2017, Xiao’s group developed an innovative and operationally practical on-water catalysis to efficiently construct important spiro-tetrahydroquinoline compounds through a novel cascade S_NAr/Knoevenagel condensation/[1,5]-hydride shift/cyclization sequence (Scheme 14) (Zhu et al., 2017). Compared with previous work, this reaction offered an example of cascade C(sp³)–H functionalization sequence operated on water under mild conditions instead of complex and harsh reaction conditions. The Knoevenagel condensation of 2-aminobenzaldehydes 123 and 1,3-dicarbonyl 124/126 compounds generated the reactive electron-deficient alkenes, which further initialized the subsequent [1,5]-hydride shift/cyclization route. Most of the substrates could be well-tolerated and produce the required spirocyclic compounds 128/129 with good yield and acceptable dr values as well as good atom and step economy in one operation. Moreover, the construction of the anti-bacterial agent (−)-PNU-286607 was also smoothly conducted with an excellent yield of 93%, which further demonstrated the power of this strategy.

To further expand the potential of that practical strategy, in 2021, the same group developed a similar work that used environmental-friendly EtOH as solvent for the efficient construction of the pharmaceutically significant spirocyclic tetrahydroquinolines 147 (Scheme 15) (Yu et al., 2022). This strategy featured high efficiency, mild reaction conditions, high step and atom economy, and good substrate tolerance as well, producing the target spirocyclic tetrahydroquinolines containing different pharmaceutically interesting moieties with impressive results. Moreover, this strategy has been smoothly applied for the preparation of PUN-286607, affording the target molecule 151 with up to 92% yield, which demonstrated the powerful applicability of this method.

In 2020, Wang’s group developed a catalyst-free tandem 1,5-hydride shift/cyclization process to form polycyclic spiro skeletons (Scheme 16) (Liu et al., 2020). The generated α,β-unsaturated chroman intermediate 157 acted as a hydride acceptor in the reaction process. This reaction features high atom and step economy, and mild conditions, providing access to a series of new spiro benzoquinolizidine-chromanones 154 with satisfactory yields (up to 91% yield) and excellent diastereoselectivities (up to >20:1 dr). Notably, both the gram-scale reaction and derivatization of the spirocyclic products were smoothly conducted with satisfactory reaction performance, which demonstrated the robustness of this methodology. A plausible mechanistic pathway was proposed by Wang and co-workers in Scheme 16.

As early as 2009, the Kamilar research group developed a practical two-step route for the asymmetric synthesis of the (-)-PNU-286607 166, a promising spirocyclic tetrahydroquinoline compound bearing barbituric acid moiety (Scheme 17A) (Ruble et al., 2009). This is a limited case that applied the cascade [1,5]-hydride shift/cyclization sequence to prepare the chiral barbituric acid-fused spiro tetrahydroquinoline. The whole reaction route started with chiral trans-dimethylmorpholine 161 in MeCN as a reaction mediated at a temperature of 65°C, and resulted in desirable chiral molecule 163 with excellent stereochemical control after a comprehensive study on the stereochemical process. Notably, the isomerization of 166 using n-BuOH as solvent delivered the diastereoisomer 165 with excellent reaction performance and excellent ee value. The condensation of aldehyde 160 and barbituric acid 164 led to the production of unsaturated barbituric acid intermediate 162 as a hydride acceptor. This exploration demonstrated the potential of [1,5]-hydride shift/cyclization-involved C(sp³)–H activation to construct valuable spiro-tetrahydroquinoline molecules.

Inspired by Kamilar’s unprecedented work, a sequential Knoevenagel condensation/[1,5]-prototropic shift of tetramates 167 with aminobenzaldehydes 168 to furnish the functionalized spirocyclic tetramates 170 was reported by Moloney’s group in 2019 (Scheme 17B) (Josa-Cullere et al., 2019). The α,β-unsaturated 1,3-dicarbonyl intermediate 169 served as a hydride acceptor and started the sequential reaction under optimized conditions. Interestingly, the stability of isolated major products was dependent on the solvent and on the nature of the azacycle, and the final products were obtained with low to good yields and up to 98:2 dr.

One year later, Xiao’s group developed a rapid buildup of polycyclic skeleton directly from phenols 171 and ortho-aminobenzaldehydes 172 via cascade [1,5]-hydride shift/dearomative cyclizations (Scheme 18) (Li et al., 2018a). HFIP was used as both reaction promoter and solvent, enabling one-step construction of structurally diverse spiro-tetrahydroquinolines with a good yield (up to 98%) and with high diastereoselectivities (up to >20:1), good functional group compatibilities, as well as gram-scale capacity. Importantly, this is an unprecedented strategy that employed in situ generated o-QMs 173 as novel hydride acceptors and aromatization as the driving force to initiate the hydride shift/cyclization sequence. Undoubtedly, this novel method opens a new avenue for the assembly of complex molecules via a cascade hydride shift/cyclization strategy. The researchers proposed a possible mechanism to point out the significance of HFIP (Scheme 18).

In 2019, based on previous works, the same group continued to use HFIP as the solvent to develop p-QMs-triggered cascade [1,5]-hydride shift/spirocyclization and hydrolysis reaction. This strategy enabled the synthesis of spirocyclic products 181 with good to high yields (52%–99%) under mild conditions, featuring room temperature, additive-free, and good functional group tolerance (Scheme 19) (Lv et al., 2019). Interestingly, an array of ortho-benzylated anilines 183 were obtained with high yields when using acyclic amines incorporating N,N′-dibenzyl, N-methyl-N′-benzyl, and N,N′-diethyl groups. The plausible reaction mechanism indicated that the rearomatic complex 185 with iminium ion generated by the intramolecular [1,5]-hydride transfer underwent two reaction process to produce the dearomatic product 187 (path A) and the hydrolysis process product 188 (path B, R ² = Me or Ph) based on the properties of R ² groups. Undoubtedly, Xiao’s work demonstrated that aromatization serving as a powerful driving force could trigger hydride shift-involved cascade reactions for the buildup of architecturally complex molecules.

In addition to the above works, the [1,5]-hydride shift strategy can also be used for the construction of spirocyclic tetrahydroquinolines containing cycloalkane units. In 2006, Tverdokhlebov and co-authors disclosed an interaction of ortho-aminobenzaldehydes 189 with substituted acetonitriles 190 promoted by Et₃N in EtOH to yield tetrahydroquinoline-2-spirocycloalkanes 192 with high yields (Scheme 20) (Tverdokhlebov et al., 2006). According to the tert-amino effect mechanism, the reaction was assumed to move forward via sequential Knoevenagel condensation/[1,5]-hydrogen shift/ring closure of the formed adduct.