Alcohols are among the most important feedstocks in organic synthesis because they are abundant, inexpensive, and readily accessible from both petrochemical and renewable resources, and they can be converted into a wide range of functional groups.^[1] Consequently, the direct transformation of alcohols has long been a central topic in modern organic chemistry. Although numerous methods have been developed for the nucleophilic substitution of activated alcohols, such as allylic and benzylic alcohols,^[2] the direct substitution of unactivated aliphatic alcohols, especially primary alcohols remains challenging due to their intrinsic thermodynamic and kinetic barriers.^[3] The deoxyamination of alcohols has emerged as a reliable and straightforward strategy for constructing sp³-C—N bonds. This transformation is highly significant, as nitrogen-con- taining moieties are widely found in natural products, pharmaceuticals, and functional materials. Conventional approaches to sp³-C—N bond formation typically rely on classical methods, including nucleophilic substitution reactions between nitrogen nucleophiles and alkyl halides,^[4] Mitsunobu alkylations of alcohols,^[5] as well as reductive amination of carbonyl compounds or olefin hydroamination.^[6] Recently, new developments in sp³-C—N bond formation have emerged,^[7] such as metal-catalyzed allylic C—H amination and 1,1'-spirobiindane-7,7'-diol (SPINOL)-derived chiral phosphoric acid-catalyzed asymmetric N—H hydroxyalkylation methodologies. While these methods are powerful and widely applied, the development of new strategies that enable efficient sp³-C—N bond formation directly from inexpensive and readily available alcohols remains a significant and ongoing challenge.

Benzotriazoles constitute an important class of nitrogen- containing heterocycles that have found broad applications in synthetic organic chemistry, materials science, and pharmaceutical research. Owing to their unique structural features, high reactivity, and notable biological activities, including anticancer properties, N-substituted benzotriazoles have attracted sustained interest.^[8] Pioneering studies by Katritzky^[9] established benzotriazoles as versatile synthetic auxiliaries in organic synthesis, thereby laying the foundation for their extensive subsequent development. A particularly distinctive feature of benzotriazoles is their ability to undergo N—N single-bond cleavage (ring opening) through a Dimroth-type equilibrium, generating highly reactive diazonium or diazo intermediates.^[10] Over the past two decades, this unique reactivity has been extensively exploited, leading to the development of numerous denitrogenative functionalization strategies based on benzotriazole scaffolds (Figure 1).^[11]

Recently, we developed the metal-free cascade reactions between N1-Tf-substituted benzotriazoles (Tf=triflyl) and alkyl bromides, enabling the divergent synthesis of 3-sub- stituted 1,2,4-benzotriazines and N1-alkylated benzotria-zoles under different basic conditions.^[12] Specifically, LiOH-mediated cascade processes involving sequential N—N bond cleavage, substitution, and elimination smoo- thly afforded 1,2,4-benzotriazine derivatives. In contrast, Cs₂CO₃ promoted a desulfonylative substitution via N—S bond cleavage, efficiently delivering N1-alkyl benzotriazoles. Building on these findings, we hypothesized that N1-Tf-substituted benzotriazoles could undergo direct deoxyamination with alcohols under basic conditions, thereby enabling the construction of sp³-C—N bonds from readily available alcohol feedstocks.

To probe the feasibility of the proposed deoxyamination strategy, N1-Tf-substituted benzotriazole 1a and benzyl alcohol 2a were chosen as model substrates. Initial experiments employing Cs₂CO₃ (1.0 equiv.) in 1,2-dichloro- ethane (DCE) at room temperature afforded the desired product 3a in 68% yield (Table 1, Entry 1). Subsequent solvent screening revealed 1,4-dioxane to be optimal, providing 3a in 77% yield (Table 1, Entry 6). Examination of various bases demonstrated a pronounced dependence on base identity: NaOMe was ineffective, whereas K₂CO₃, NaOH, t-BuOK, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Table 1, Entries 7~11) furnished 3a in lower yields compared to Cs₂CO₃. Further optimization of the reaction stoichiometry proved crucial, and adjusting the ratio of 1a, 2a, and Cs₂CO₃ to 2∶1∶2 resulted in a dramatic increase in efficiency, delivering 3a in 99% yield (Table 1, Entry 14).

After establishing the optimal reaction conditions, the substrate scope with respect to the alcohol component was first investigated. In general, a wide range of primary, secondary, and tertiary alcohols participated smoothly in this transformation to afford the corresponding deoxyamination products. As shown in Table 2, diverse primary alcohols proved to be efficient substrates, delivering N-alkyl heteroaryl derivatives 3a~3ab in moderate to excellent yields with complete regioselectivity in all cases. Particular, various saturated primary alcohols readily reacted with 1a to afford the desired products in excellent yields (3a~3e). Notably, this protocol exhibited broad functional group compatibility, tolerating terminal alkenes (3f, 3g), internal alkenes (3h~3j), terminal alkynes (3k, 3l), internal alkynes (3m), an allene (3n), phenolic hydroxyl groups (3o, 3p), esters (3s, 3t), protected amines (3q), and various heterocycles (3r, 3u~3w). Furthermore, the synthetic utility of the method was highlighted by its successful application to structurally complex, natural product derived alcohols bearing ketone and internal alkene functionalities, which underwent efficient deoxyamination to afford products 3x~3ab in 35%~71% yields. Subsequently, the scope of secondary alcohols as alkylating agents was examined. Both benzylic and aliphatic secondary alcohols were well tolerated, furnishing mixtures of N1- and N2- alkylated products 3ac~3ah in 58%~90% yields. In addition, secondary alcohols derived from complex molecular scaffolds also underwent efficient deoxyamination, affording products 3ai~3am in 58%~93% yields. A range of cyclic secondary alcohols, including five- and six-mem- bered rings, were likewise compatible, providing the corresponding N-cycloalkylated products 3an~3ao in 51%~71% yields. The reaction of oxetan-3-ol proceeded smoo- thly to give a mixture of 3ap/3ap' in 53% combined yield. Interestingly, treatment of cyclobutanol with 1a afforded two distinct products: one arising from direct C—N bond formation (3aq) and the other resulting from rearrangement of the four-membered ring (3aq'). A cyclobutyl cation is generated within the reaction manifold and can undergo rearrangement to a cyclopropylcarbinyl cation, ultimately leading to the formation of the corresponding 3aq' product.^[13] Similarly, cyclopropanol delivered both the direct C—N coupling product (3ar) and the corresponding ring-opened three-membered analogue (3ar'). The cyclopropyl cation underwent a concerted rearrangement into the more thermodynamically stable allyl cation.^[14] Sterically congested tertiary alcohols were also competent substrates for C—N bond formation, albeit affording the desired product (3as) in relatively low yield; notably, a cyclopentene derivative (3as') arising from the tertiary carbocation’s elimination was isolated in these cases. Collectively, these observations suggest that some of the desired products formed in the reactions of secondary and tertiary alcohols with 1a are generated via a carbocation-mediated pathway.

The scope of benzotriazole substrates was evaluated. Benzotriazoles bearing two substituents (Me, F, Cl) at the para positions relative to N1 and N3 reacted smoothly with 2a, furnishing the corresponding products 5a~5c in good yields (Table 3). To further demonstrate the generality of this transformation, other nitrogen nucleophiles were examined as coupling partners. Gratifyingly, a range of N- heterocycles, including pyrazoles and indazoles (Table 3), were competent substrates, undergoing efficient C—N coupling with alcohols to afford the corresponding N-alk- ylated heteroarenes (5d~5j) in 50%~72% yields. These results underscore the generality of this strategy as a versatile alkylation platform for diverse nitrogen nucleophiles.

Now, we sought to gain deeper insight into the reaction mechanism. When 4k was used in place of 1a under the standard conditions, products 5k/5k' were detected, which is consistent with the resonance structures of the benzotriazolate anion (Scheme 1A). In addition, compound 10 was synthesized and reacted with benzotriazole (1f), delivering the desired product 3e in 68% yield under the standard condition, the reaction outcome strongly implies the in-situ formation of a ROTf intermediate during the reaction process (Scheme 1B). Then optically pure 2ac was subjected to the reaction with 1a, affording the target product 3ac in 60% yield with 68% ee (Scheme 1C). This result suggests that the reaction between the secondary alcohol 2ac and 1a does not proceed through a purely S_N2 pathway; rather, partial formation of a carbocation intermediate is involved. Based on the above experiments, for the reaction of primary alcohols, a plausible reaction mechanism is proposed in Scheme 1D. Initially, 2a reacts with the base to generate alkoxide I, which attacks the N—S bond of 1a to produce benzotriazolate anion (II) and benzyl trifluoromethanesulfonate (III). Subsequently, II undergoes an intermolecular S_N2 nucleophilic substitution with III to furnish the product 3a.

Based on the proposed reaction mechanism, primary alcohols are expected to generate ROTf intermediates during the transformation. It was therefore hypothesized that intramolecular interception of the OTf functionality could be achieved, enabling the construction of heterocyclic frame- works through a cyclization pathway.^[15] Under basic conditions, vicinal diols undergo efficient cyclization in the presence of N1-Tf-substituted benzotriazole (1a) to afford epoxide derivatives 7a~7c (Scheme 2), whereas direct treatment of vicinal diols with trifluoromethanesulfonic anhydride fails to produce the corresponding epoxides. Similarly, 1,4-diols can be smoothly transformed into tetrahydrofuran derivative 7d under comparable conditions. Beyond diols, 2-aminophenethanol undergoes intramolecular cyclization in the presence of 1a and base to furnish indoline derivatives 9a~9b, and [2-(amino-methyl)phen- yl]methanol serves as a suitable precursor for the synthesis of isoindoline derivative 9c. Notably, this methodology is also applicable to the construction of other nitrogen-con- taining heterocycles, including tetrahydroquinolines 9d~9e and tetrahydroisoquinoline scaffold 9f.

In conclusion, a practical and efficient strategy for constructing sp³-C—N bonds through the coupling of N1-tri- flylbenzotriazoles with readily accessible alcohols has been developed. This transformation proceeds under mild conditions and accommodates a broad range of substrates. Moreover, indazole and pyrazole were also demonstrated to be competent nucleophiles for sp³-C—N bond formation with alcohols. Additionally, N1-Tf-substituted benzotriazole could be used for the synthesis of diverse heterocycles.