Chemoselective transfer hydrogenation and transfer deuteration of substituted quinolines using Hantzsch ester and D₂O

Abstract

A novel strategy for the chemoselective transfer hydrogenation of complex quinolines using Hantzsch ester as a H-donor under ambient conditions is introduced. This approach provides a wide range of commercially important 1,2,3,4-tetrahydroquinolines in high yields up to 96%. Additionally, the deuteration of the quinoline ring positioned in densely functionalized multi-ring systems is also reported.

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Chemoselective transformation is a highly desirable strategy to generate diversified complex molecules without the use of elaborate protecting groups.¹ Among various N-heteroarenes, functionalized quinolines are most prevalent in pharmaceuticals as well as in natural products that can be further reduced to their corresponding 1,2,3,4-tetrahydroquinolines. In this way, another type of N-heterocycles can be accessed in a wide variety of biologically relevant compounds.^2,3 Despite significant progress in the chemoselective saturation of quinolines, many challenges still persist. For instance, the selective reduction of quinolines in the presence of reactive functional groups is less documented.^4,5 Also, late-stage reduction of quinoline rings in drug-like molecules is rare and even more challenging.⁴

Traditionally, molecular hydrogen is used as a reducing agent in the presence of both noble and earth-abundant first-row transition metals to reduce quinolines at elevated temperatures (Fig. 1a).^4,6–9 However, these reactions often suffer from issues related to chemoselectivity. On the other hand, hydrogen donors such as hydrosilanes,¹⁰ hydroboranes,¹¹ formates/formic acid,¹² ethanol,¹³ ammonia- borane derivatives^14–16 and Hantzsch ester^17–19 have been exploited as competent alternatives to gaseous hydrogen in quinoline reduction chemistry (Fig. 1a). Furthermore, some of these methods encounter scalability issues and involve the use of costly metals, toxic reagents, lengthy reaction times, rigorously dried solvents, and high temperatures.

Fig. 1 An overview of the reduction of quinolines ((a) previous reports vs. (b) this work).

Hantzsch ester (Et-HE) (1,4-dihydropyridines) as a hydride donor reagent has been explored for a variety of reduction transformations in organic synthesis.²⁰ In the context of the non-asymmetric reduction of quinolines, the presence of a transition metal, organocatalyst, and/or boric acid enables the reduction of basic substituted quinolines between 40 and 60 °C.^17–19 However, the chemoselectivity aspects have still remained underexplored up to now. Therefore, there is a great need to explore new possible ways or search for new protocols to enhance chemoselectivity under mild reaction conditions with a high level of functional group tolerance. Accomplishing this objective would be highly beneficial for the chemical and pharmaceutical industry.

In recent years, the concept of “Escape from Flatland” has gained more power, emphasizing the importance of increasing the saturation and tridimensionality (3D) space in complex substrates.²¹ This approach aims to enhance the clinical success of drug candidates by creating more carbon bond saturation (Fsp³). Therefore, ring saturation is a promising strategy for increasing the Fsp³ proportion in complex quinolines. Moreover, ever since the discovery of FDA approval of deuterated drugs (deutetrabenazine in 2017; deucravacitinib in 2022), the replacement of C–H bonds with C–D bonds in simple and late-stage molecules has become the subject matter of intense research.²² Combining both reduction and deuteration in complex quinolines in one step presents a valuable opportunity in drug discovery (Fig. 1b). This approach provides a straightforward method to access deuterium-labelled saturated heterocycles.⁵ By introducing deuterium during the reduction step, the method not only simplifies the synthesis pathway but also improves drug-like properties such as metabolic stability and pharmacokinetic factors that are remarkable in the development of modern therapeutics.²⁹ By considering this, we aimed to incorporate deuterium into complex molecules alongside the reduction of nitrogen rings in quinolines. To our knowledge, there are seldom reports on the high-level chemoselective reduction (e.g., tolerance of aldehyde, nitrile, azo, nitro, and halo groups) and deuteration of quinolines and their applications in late-stage saturation for the synthesis of bioactive molecules at room temperature and under metal-free conditions. Inspired by the above-mentioned excellent reports and concepts, as well as our long-term interest in the reduction of heteroarenes,^15,23,24 herein, we report for the first time a new and scalable platform for the unprecedented chemoselective nitrogen ring saturation of complex quinolines using the combination of HOTf and Et-HE. The aim of this study is to explore a new strategy for the reduction of quinolines with a special emphasis devoted to enhance the chemoselectivity via a hydrogen transfer mechanism using Et-HE as a H-donor.

Aiming to develop a selective reduction of complex quinolines, 4-(4-(quinolin-2-yl)phenyl)morpholine (1a) was chosen as the model substrate to optimize the reaction conditions. To our delight, the corresponding desired product 4-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)morpholine (1b) was obtained in 95% isolated yield by reacting 1a with HOTf (0.5 equiv.) and Hantzsch ester (2.5 equiv.) in a DCM/H₂O (1 : 1) mixture at room temperature within a short duration of 2 h (Table 1, entry 1). Reducing the concentration of HOTf resulted in a low to moderate yield of 1b (entries 2 and 3). By replacing HOTf with organic acids, relatively low yields (19–44%) of 1b were obtained (entries 4 and 5). However, inorganic acids were found to be completely unsuitable; only a trace of 1b was detected (entries 6 and 7). Upon lowering the equivalents of Hantzsch ester (from 0.5 to 2), the yield of 1b was also significantly decreased (entries 8–10). The selection of solvents has also shown a notable effect on the yield of 1b, as exemplified by acetonitrile (MeCN), toluene, hexafluoroisopropanol (HFIP), tetrahydrofuran (THF), trifluoroethanol (TFE), dichloromethane (DCM), and water (H₂O) (entries 11–17). It should be noted that the presence of water along with DCM in the reaction mixture increases the activity by establishing strong hydrogen bonding interactions. We assume that water molecules might assist in stabilizing the protonated ion-pair intermediate and enable interaction with the Et-HE.

Table 1 Optimization of the reaction conditions for the reduction of a complex quinoline^a

Entry	Deviation from the standard conditions	Yield 1b (%)
a Reaction conditions: 0.5 mmol 1a, 0.5 equiv. HOTf, 2.5 equiv. Et-HE, 1.5 mL DCM, 1.5 mL H2O, RT, 2 h, and isolated yields.
1	None	95
2	HOTf (0.1 equiv.)	29
3	HOTf (0.3 equiv.)	63
4	CF3COOH instead of HOTf	44
5	CH3COOH instead of HOTf	19
6	HCl instead of HOTf	trace
7	HNO3 instead of HOTf	trace
8	Et-HE (0.5 equiv.)	18
9	Et-HE (1 equiv.)	32
10	Et-HE (2 equiv.)	71
11	MeCN instead of DCM/H2O	17
12	Toluene instead of DCM/H2O	26
13	HFIP instead of DCM/H2O	12
14	THF instead of DCM/H2O	31
15	TFE instead of DCM/H2O	16
16	DCM instead of DCM/H2O	24
17	H2O instead of DCM/H2O	36

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After optimizing the reaction conditions, we explored the scope of functionalized quinolines (Scheme 1). Simple 2-methylquinoline and 2-phenylquinoline were reduced smoothly, affording the corresponding 1,2,3,4-tetrahydroquinolines with excellent reactivity and chemoselectivity (2 and 3). Remarkably, aldehyde was well tolerated, resulting in the formation of 1,2,3,4-tetrahydroquinoline-6-carbaldehyde with 89% isolated yield (4). On the 5 g scale, a 73% isolated yield was obtained. To the best of our knowledge, this level of chemoselectivity is unparalleled and is scarcely reported. Undoubtedly, this is the first scalable approach to product 4 so far.

Scheme 1 Reaction scope for the synthesis of functionalized 1,2,3,4-tetrahydroquinolines.^{a,b a} Reaction conditions: 0.5 mmol substrate, 0.5 equiv. HOTf, 2.5 equiv. Et-HE, 1 mL DCM, 1 mL H₂O, RT, 2 h, and isolated yields. ^b Reaction conditions: 0.5 mmol 1a, 0.5 equiv. HOTf, 2.5 equiv. Et-HE, 1 mL DCM, 1 mL H₂O, RT, 6 h, and isolated yields.

Moreover, the quinoline reduction was remarkably chemoselective, even in the presence of reactive functional groups such as ketone, acid, amide, nitrile, ester, and nitro groups, which are typically more reactive towards reduction (entries 5–10). No reduction of other functional groups was observed in any of these reactions. On the 5 g scale, the reduction of 6-quinoline carboxylic acid gave a 75% isolated yield of 6, displaying the ease of the method. Next, 6-halo-substituted quinolines gave the corresponding 1,2,3,4-tetrahydroquinolines in excellent yields (entries 11–15). It is noteworthy that halogens (–I, –Br, –Cl, –F) were preserved, and not even a trace of reductive dehalogenation was observed. Furthermore, the chloro and bromo moieties located at the 3rd position of the reducible quinoline ring also exhibited exceptional chemoselectivity. This allowed for the exclusive reduction of the quinoline ring without any occurrence of hydrodehalogenation (entries 16 and 17). Furthermore, the reactions with 3-methoxyquinoline, 6-fluoro-2-methylquinoline, 6-bromo-2-methylquinoline, and 7-chloro-2-methylquinoline proceeded smoothly to provide the corresponding reduced products 18–21 in excellent yields. Interestingly, complex quinolines comprising azo and SO₂ with NO₂ functional groups together were tolerated well, yielding the desired products in 80% and 85% isolated yields (22 and 23), respectively. Interestingly, these two products were formed without significant side reactions in such densely functionalized aromatic compounds, which is usually not possible with the conventional metal-based catalysts. This novel transformation expands to the range of tetrahydroquinolines and offers an attractive strategy for the increase of Fsp³ character in N-heteroarenes, which is a desired option in drug design. Other related N-heterocycles could be successfully converted to the targeted N-saturated compounds under the optimized conditions (entries 24 and 25). Surprisingly, when 2-bromo and 2-chloroquinolines were subjected to the reduction, an unexpected product, 3,4-dihydroquinolin-2(1H)-one, was formed in high yields (26–27).

Selective insertion of deuterium into organic molecules is indeed a valuable approach to improve drug properties, including reduced toxicity and enhanced stability, which is essential in medicinal chemistry and drug discovery.^5,22 In this context, we applied our reduction method with a slight modification (DCM/D₂O in a 1 : 1 ratio) to expand the spectrum of valuable deuterated three-dimensional molecules (3D) derived from flat aromatic compounds (2D). As depicted in Scheme 2, a variety of functional groups, –CF₃, –F, –CH₃, –OMe, –SiMe₃, –OH, –SMe, –OCF₃, –Ph-Cy, diphenyl ether, –SO₂Me, and triphenylphosphine oxide that are present on the reducible quinoline ring were well tolerated. The corresponding quinoline ring saturated products 28–40 (compound 40 confirmed by ScXRD, CCDC 2428955†) were achieved in good to excellent yields (82–96%) with a 99% D ratio at the 3rd position of the reduced quinoline ring. Deuterium incorporation at the N–H position was also observed in the range of 2–30%, which can be attributed to the lability and exchangeability of the N–H/N–D bond under the reaction and work-up conditions. Additionally, for certain products (31–38), deuterium incorporation was detected on the phenyl ring, which is likely the result of hydrogen isotope exchange (HIE) processes facilitated by the DOTf present in the reaction mixture.³¹ Furthermore, we also synthesized the deuterated analogue of the drug intermediate 2-methyl-1,2,3,4-tetrahydroquinoline 41, achieving excellent deuterium incorporation at the 3rd position, along with full deuteration of the methyl group. The deuteration of the methyl group proceeds via a tautomeric process or reversible proton–deuteron exchange, potentially involving an enamine–imine like intermediate. This deuterated analogue can be readily transformed into a known antitrypanosomal agent,²⁵ highlighting the practical utility of our method for generating deuterium-labeled drug molecules. Overall, such a simple and straightforward conversion to produce Fsp³-enriched deuterated tetrahydroquinolines is seldom reported in the literature.

Scheme 2 Reduction and deuteration of complex quinolines. Reaction conditions: 0.5 mmol substrate, 0.5 equiv. HOTf, 2.5 equiv. Et-HE, 1 mL DCM, 1 mL D₂O (110 equiv.), RT, 6 h, and isolated yields.

To understand the reaction mechanism, we conducted a series of deuterium labeling experiments under optimized conditions (see Scheme S1, ESI†). These experiments aimed to examine the role of proton exchange and its influence on the reaction pathway. Based on the literature survey,^26–30 a plausible mechanistic pathway is proposed now in Fig. 2. The reaction begins with a strong acid–proton interaction between triflic acid and the nitrogen atom of the 4-(4-(quinolin-2-yl)phenyl)morpholine substrate (A) (Fig. 2), leading to the formation of an ion-pair intermediate (B). The ion-pair intermediate interacts with the Hantzsch ester, facilitating the formation of a transition state (C). In this transition state, the triflic acid molecule transfers its strongly bonded proton to the nitrogen atom of 4-(4-(quinolin-2-yl)phenyl)morpholine, while simultaneously interacting with the proton attached to the nitrogen atom of the Hantzsch ester. This two-sided interaction promotes the hydride transfer from the 4th position of the Hantzsch ester to the 4th position of 4-(4-(quinolin-2-yl)phenyl)morpholine, resulting in the formation of 4-(4-(1,4-dihydroquinolin-2-yl)phenyl)morpholine (D) and the elimination of diethyl 2,6-dimethylpyridine-3,5-dicarboxylate. The 4-(4-(1,4-dihydroquinolin-2-yl)phenyl)morpholine intermediate then undergoes a 1,3-proton shift, leading to the formation of 4-(4-(3,4-dihydroquinolin-2-yl)phenyl)morpholine (E). This molecule subsequently enters the next catalytic cycle, reacting with HOTf and another molecule of Hantzsch ester to produce the final desired product, 4-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)morpholine (1b) (confirmed by ScXRD, CCDC 2428954)†. In addition, we also conducted experiments to measure the kinetic isotope effects (KIE) (see Fig. S5, ESI†) using the initial rate of formation of product 1b to confirm the significance of proton interactions. Based on these results, a reasonable KIE was observed, with k_HOTf/k_DOTf = 2.65, with DOTf being used as the deuterated counterpart.

Fig. 2 Plausible mechanistic pathway.

In conclusion, a general and mild protocol for the chemoselective transfer hydrogenation of quinolines has been developed using HOTf and Et-HE. This novel metal-free approach exhibits broad functional group tolerance, including aldehyde, nitrile, iodo, and many other functional groups. Its versatility facilitates late-stage reduction and deuteration of complex quinolines. Control experiments and mechanistic studies indicate that the strong proton interactions of triflic acid are crucial in stabilizing the transition state, enhancing substrate reactivity, improving chemoselectivity, and accelerating the reaction under ambient conditions. So far, this is the most chemoselective and scalable approach toward functionalized 1,2,3,4-tetrahydroquinolines under metal-free conditions.

K. N. acknowledges CRG/2023/005734 from the Anusandhan National Research Foundation (ANRF) for financial support. T. B. is thankful to PMRF. We acknowledge P. S. Ramana Babu for helping with the crystal structure analysis. We acknowledge Md. Samiuddin, Ashok Yeligeti, and Dr. B. Surender for measuring NMR.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the ESI.†

References

1. J. Mahatthananchai, et al. , Angew. Chem., Int. Ed., 2012, 51, 10954–10990.
2. P. Yadav and K. Shah, Bioorg. Chem., 2021, 109, 104639.
3. I. Muthukrishnan, et al. , Chem. Rev., 2019, 119, 5057–5191.
4. M. El-Shahat, J. Heterocycl. Chem., 2022, 59, 399–421.
5. F. Bu, et al. , Nature, 2024, 634, 592–599.
6. Z. Wei, et al. , Chin. J. Catal., 2019, 40, 980–1002.
7. R. Adam, et al. , Angew. Chem., Int. Ed., 2017, 56, 3216–3220.
8. D. Ren, et al. , J. Am. Chem. Soc., 2012, 134, 17592–17598.
9. A. Karakulina, et al. , Angew. Chem., Int. Ed., 2016, 55, 292–296.
10. Y. Wang, et al. , Org. Lett., 2019, 21, 3631–3634.
11. C.-H. Yang, et al. , Chem. Commun., 2018, 54, 8622–8625.
12. R. Luo, et al. , Organometallics, 2024, 43, 2097–2103.
13. S. Yadav, et al. , Chem. Commun., 2022, 58, 4255–4258.
14. V. Vermaak, et al. , Adv. Synth. Catal., 2020, 362, 5788–5793.
15. T. Bhatt, et al. , J. Catal., 2025, 443, 115937.
16. X. Cui, et al. , Org. Chem. Front., 2021, 8, 5002–5007.
17. D. Bhattacharyya, et al. , Org. Biomol. Chem., 2020, 18, 1214–1220.
18. B. Patel, et al. , Chem. Sci., 2023, 14, 540–549.
19. R. He, et al. , Tetrahedron Lett., 2017, 58, 3571–3573.
20. C. Zheng and S.-L. You, Chem. Soc. Rev., 2012, 41, 2498–2518.
21. F. Lovering, et al. , J. Med. Chem., 2009, 52, 6752–6756.
22. S. Kopf, et al. , Chem. Rev., 2022, 122, 6634–6718.
23. T. Bhatt and K. Natte, Org. Lett., 2024, 26, 866–871.
24. B. Singh, et al. , ACS Catal., 2023, 13, 9724–9744.
25. S. Chen, et al. , ChemSusChem, 2022, 15, e202201522.
26. C. T. Ser, et al. , J. Org. Chem., 2019, 84, 10338–10348.
27. M. Franta, et al. , J. Am. Chem. Soc., 2025, 147, 2549–2558.
28. N. Sorgenfrei, et al. , J. Am. Chem. Soc., 2016, 138, 16345–16354.
29. M. Rueping, et al. , Angew. Chem., Int. Ed., 2006, 45, 3683–3686.
30. D. Jansen, et al. , Chem. Sci., 2020, 11, 4381–4390.
31. E. Appert, et al. , Chem. – Eur. J., 2022, 28, e202201583.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2428954 and 2428955. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5cc03315b

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