Formation of ylidenehydrazines enabled by manganese-catalyzed acceptorless dehydrogenative coupling

Abstract

Catalytic dehydrogenation, which exhibits highly atom-economical and chemo-selective properties, converts multiple green sustainable alcohols to critical molecules and is a highly desirable and elusive process; furthermore, the dehydrogenation of alcohols with hydrazines produces ylidenehydrazines, which are versatile building blocks in the formation of numerous pharmaceuticals. However, the syntheses of functionalized ylidenehydrazines involve multi-step reactions that require harsh conditions. Herein, we report a practical one-pot catalytic tandem dehydrogenative condensation coupling of hydrazines with alcohols and halides to form ylidenehydrazines via an acceptorless dehydrogenative coupling strategy, overcoming the challenge of selectivity in multicomponent reactions. The system is based on the Earth-abundant metal Mn, which is stabilized by a novel bench-stable PNN pincer ligand derived from aminoindazole. A large series of functionalized ylidenehydrazines is obtained in high yields with excellent selectivities, and gram-scale ylidenehydrazines are prepared using this protocol. Notably, using this protocol, several pharmaceuticals may be easily synthesized in a one-pot manner. This strategy significantly broadens the scope of Mn-catalyzed dehydrogenative condensation coupling for synthesizing unsaturated molecules.

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Introduction

Ylidenehydrazines, which exhibit remarkable biological activities, are frequently used in pharmaceuticals, agrochemicals, and functional materials (Fig. 1A).¹ They also serve as attractive precursors in a series of transformations that form various complex, functional compounds.² Owing to their scientific applications, considerable effort has been devoted to synthesizing these privileged scaffolds, particularly via metal-catalyzed dehydrogenative condensation and/or nucleophilic substitution strategies.³ However, most approaches require super stoichiometric amounts of external additives or harsh reaction conditions, particularly multi-step reactions, which undeniably result in decreased atom efficiency owing to complex operation processes and the formation of undesired waste byproducts (Fig. 1D).⁴ Therefore, a novel and direct method is required for one-pot synthesis of hydrazones using bulk raw materials.

Fig. 1 Current state of the field of hydrazones and the synthesis described herein. (A) Examples of hydrazones used in pharmaceuticals. (B) Types of dehydrogenation reactions. (C) This work. (D) Previous studies.

The efficient and highly selective conversion of alcohols to significant compounds is highly attractive because alcohols may be obtained from abundant lignocellulose biomass, which may reduce CO₂ emissions and conserve finite fossil carbon resources.⁵ An atom economical dehydrogenative reaction is a green method of transforming alcohols to produce H₂ or H₂O byproducts.⁶ Dehydrogenative transformations have been successfully developed over the past decades.⁷ Early catalytic dehydrogenation reactions were mostly based on the use of rare noble metals (Ir, Pt, Rh, and Ru) as catalysts (Fig. 1B).⁸ Recently, the use of abundant 3d metals (Fe, Co, and Ni) as efficient catalysts in these transformations has emerged.⁹ Mn metal catalytic systems have also been developed for use in catalytic dehydrogenative transformations, displaying novel patterns of selectivity compared to those of rare noble metals.¹⁰ Additionally, the sustainable generation of H₂via dehydrogenation is highly attractive because of its central role as an energy carrier and reducing agent. Therefore, novel reactions mediated by 3d metal catalysts that transform green or sustainable starting materials into significant classes of complex molecules via the dehydrogenation of alcohols and H₂ generation are highly desirable.

To the best of our knowledge, transition metal catalyzed dehydrogenative transformation of alcohols with hydrazines and halides remains unexplored. The evident challenge of this reaction is that the accelerator or catalyst is surrounded by a large excess of active substrates under the reaction conditions, and thus, undesired byproducts are easily generated. To overcome this challenge, improving the affinity between intermediate I (in situ-formed hydrazine with halides) and the aldehyde species (in situ dehydrogenation of the alcohol) is critical. Additionally, ensuring that (i) intermediate I is sufficiently stable in the reactive system and (ii) both dehydrogenation of the alcohol and condensation with I occur via similar rapid processes such that the formation of byproducts is largely suppressed is crucial. In this study, we report an efficient catalytic system that combines the Earth-abundant Mn metal with a readily available PN₃N pincer ligand. The catalytic system exhibits an unprecedented, practical catalytic condensation coupling of hydrazines with alcohols and halides to form ylidenehydrazines via an acceptorless dihydrogen coupling strategy; the challenge of selectivity in a one-pot multicomponent reaction is thus overcome (Fig. 1C).

Furthermore, dehydrogenative condensation cross-coupling reactions may add to the existing synthesis concepts used in generating H₂ in chemical reactions, such as alcohol dehydrogenation,¹¹ dehydrogenative condensation,¹² rearrangement,¹³ and coupling reactions (Fig. 1B).¹⁴

Results and discussion

Based on our experience with Mn-promoted dehydrogenative coupling reactions,¹⁵ phenyl methanol (A1), phenylhydrazine (B1), and (bromomethyl)benzene (C1) were used as model substrates, and dehydrogenative condensation was performed in the presence of Mn(CO)₅Br with bi- or tridentate ligands (Table 1). The desired product was obtained in a trace amount using a P–N-based accessory ligand (L1), and the reaction efficiency was improved when using L2 as a ligand (entries 1 and 2). The use of other tridentate ligands (L3–L5) functionalized on the pyridyl moiety did not improve the reactivity under similar reaction conditions (entries 3–5). Similar results were obtained using other P–N–N (L6–L9)-based ligands with different indazole phenyl groups, indicating that the conversion is insensitive to the electrical properties of the indazole backbone (entries 6–9). Evaluation of the P–N–N ligands with different phosphine groups on the amine of the indazole revealed that the conversion is sensitive to the electrostatic and steric hindrance of the ligand, with L10–L11 providing optimal regioselectivity toward the condensation product. L11 is the most effective, affording the desired D1 in 91% yield and with excellent selectivity (E1, 1,2-dibenzyl-1-phenylhydrazine). D1 is obtained in 96% yield after a prolonged reaction time, and only a trace amount of the desired product is obtained in the absence of the Mn catalyst or ligand. Furthermore, the desired product D1 is not obtained when MnBr₂ is stabilized using L11 (entry 14). The optimal results in terms of the hydrazone adducts are obtained after the final optimization of the reaction parameters, with L11 being the most active ligand (ESI†).¹⁶

Table 1 Optimization of reaction conditions

Entry	Pre-catalyst	Ligand	D1 (%)	D1 : E1^a
a Conditions: A1 (0.8 mmol), B1 (0.5 mmol), C1 (0.7 mmol), Mn(CO)5Br (1.0 mol%), L1–L11 (1.2 mol%), ^tBuOK (1.0 mmol), THF (3.0 mL), 100 °C, 6 h. The yields of D1 were determined via GC using n-cetane as the internal standard. b 12 h.
1	Mn(CO)5Br	L1	<5	8 : 1
2	Mn(CO)5Br	L2	62 (66)^b	>20 : 1
3	Mn(CO)5Br	L3	41	>20 : 1
4	Mn(CO)5Br	L4	54	18 : 1
5	Mn(CO)5Br	L5	22	19 : 1
6	Mn(CO)5Br	L6	60	18 : 1
7	Mn(CO)5Br	L7	63	18 : 1
8	Mn(CO)5Br	L8	51	17 : 1
9	Mn(CO)5Br	L9	47	18 : 1
10	Mn(CO)5Br	L10	82 (85)^b	19 : 1
11	Mn(CO)5Br	L11	91 (96)^b	>20 : 1
12	Mn(CO)5Br	—	0	—
13	—	L11	0	—
14	MnB2	L11	0	—

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The generality and limitations of the dehydrogenative condensation were investigated. Initially, C1 and B1 were used as model reagents with various primary alcohols (Scheme 1). Fortunately, benzyl alcohols bearing electron-donating and -withdrawing groups are tolerated well under the reaction conditions, affording the desired corresponding products in high to excellent yields (D1–D16). The electronic properties of the phenyl rings in the benzyl alcohols do not affect the reaction. Critically, benzyl alcohols with various substituents at their ortho-positions are transformed smoothly under the standard conditions, but hindrance at the phenyl ring affects the transformation efficiencies (D20–D24). The dehydrogenative transformations with halo-substituted alcohols proceed smoothly to generate the corresponding desired hydrazones in 74–94% yields (D6–D9, D22–D24), thus enabling further possible complex transformations, such as metal catalyzed carbonylation or cross-coupling reactions. Notably, the use of an alcohol with a free amino or hydroxyl moiety on the phenyl group, respectively, produces D10 or D15 in a high yield. Amino, trifluoromethoxy, trifluoromethyl, and cyano groups tolerate this conversion, and their corresponding products are obtained in high yields. Meanwhile, heterocyclic moieties, including pyridine, furan, and thiofuran, may be smoothly incorporated into the hydrazone molecules using the corresponding alcohols (D27–D31). Naphthyl, anthryl, and carbazolyl groups are tolerated under the standard catalytic conditions, yielding the desired products D32–D35 in high to excellent yields. To further explore the synthetic potential of this transformation, more challenging aliphatic alcohol substrates were used under the standard reaction conditions. Alkyl alcohols are good dehydrogenation partners, providing D36–D38 in good yields. Alkyl alcohols bearing various types of C=C bonds are also good coupling partners, providing D39–D42 in good to high yields, while the internal double bonds remain intact. The structures of D4 and D26 were confirmed using single-crystal X-ray diffraction.¹⁷ Gram-scale reactions using this Mn catalytic system are successful, producing D2 and D12 in high yields.¹⁶ Disappointingly, secondary alcohols did not work under the standard reaction conditions.

Scheme 1 Substrate scope of hydrazones derived from various alcohols. ^a Conditions: A (0.8 mmol), B1 (0.5 mmol), C1 (0.7 mmol), Mn(CO)₅Br (1.0 mol%), L11 (1.2 mol%), ^tBuOK (1.0 mmol), THF (3.0 mL), 100 °C, 12 h. Isolated yields. ^b 10 mmol scale, 24 h. ^c tBuOK (1.8 mmol).

The scope of tandem dehydrogenation condensation with respect to alkyl halide substrates is shown in Scheme 2. A1 and B1 were employed with a series of alkyl halide derivatives, leading to the efficient production of various hydrazones and demonstrating the excellent tolerance of different functional groups. Generally, the yields obtained using benzyl bromides containing electron-withdrawing groups (D43, D44, and D49) are higher than those obtained using benzyl bromides containing electron-donating groups (D46–D48). Additionally, compared to the results obtained using para- and meta-substituted substrates, steric hindrance is observed when the ortho-position of the benzyl bromide is substituted (D54 andD56). The halide groups, in particular, survive well under the standard reaction conditions, leading to the formation of the corresponding desired products in good to excellent yields, which may be used in further transformations to synthesize complicated molecules. The substitution of F₃C⁻ and F₃CO⁻ has no significant influence on the transformation (D48 andD49), and the naphthyl group is smoothly incorporated into D57, resulting in high yields. Substrates containing two bromide groups are successfully transformed into the corresponding bis-hydrazones D64 andD65 in isolated yields of 74% and 76%, respectively. The allyl and cinnamyl groups also survive the standard procedure, leading to the formation of D60–D63 in high yields, while the internal double bonds remain intact. Additionally, the desired hydrazones D44–D63 are obtained in good to high yields when using more challenging benzyl chloride substrates as reaction partners. Scaled-up reactions (10 mmol scale) proceed easily, furnishing 84% and 83% yields of the hydrazones D43 and D46, respectively.

Scheme 2 Substrate scope of hydrazones with respect to halides. ^a Conditions: A1 (0.8 mmol), B1 (0.5 mmol), C (0.7 mmol), Mn(CO)₅Br (1.0 mol%), L11 (1.2 mol%), ^tBuOK (1.0 mmol), THF (3.0 mL), 100 °C, 12 h. Isolated yields. ^b 10 mmol scale, 24 h. ^c A1 (1.6 mmol), B1 (1.0 mmol), ^tBuOK (2.0 mmol), 36 h. ^d C (0.7 mmol), ^tBuOK (1.5 mmol), 130 °C, 24 h.

As tandem dehydrogenative condensation is compatible with a wide range of alkyl halides and alcohols, the scope with respect to the hydrazine was investigated (Scheme 3). With most aromatic hydrazines, the condensation proceeds smoothly to furnish the corresponding desired hydrazones in good to excellent yields. Although numerous hydrazines are in the form of hydrochlorides, hydrazones may be obtained in good to high yields in the presence of 1.5 equivalents of the base. The electronic properties of the phenyl rings of the hydrazines exhibit negligible effects on the reaction. The positions of the substituted functional groups on the phenyl ring clearly influence the efficacy of the transformation, and the corresponding hydrazones (D74–D77) are generated in moderate to good yields. Gram-scale reactions are successful, yielding D67 and D81 in high amounts.¹⁶ The transformations with halo-substituted hydrazines proceed smoothly to produce the corresponding desired products in 67–92% yields, thus enabling further complex reactions. Additionally, the F₃C⁻ group survives well the standard procedure, with the desired adducts D73 and D79 formed in good yields, and the naphthyl moieties may be smoothly incorporated into hydrazones. Meanwhile, several heterocyclic moieties, including pyridine and benzothiazole, are smoothly incorporated into the hydrazone molecules (D80–D81) using the corresponding hydrazines. Benzo hydrazide is less reactive with D82 isolated in a moderate yield. In addition, the desired hydrazone adducts, D84–D89, are obtained in moderate to good yields when using more challenging aliphatic hydrazine substrates. These results confirm the viability of the transformation for use in preparing highly functionalized hydrazone derivatives. Furthermore, various allyl halides are compatible with this catalytic dehydrogenation system with various hydrazines, and the desired adducts are isolated in moderate to high yields with excellent regioselectivities (D90–D92). Using this tandem dehydrogenation–condensation procedure, gram-scale reactions were successful, yielding D67 and D81 in high amounts.¹⁶

Scheme 3 Substrate scope of hydrazones derived from hydrazines. ^a Conditions: A1 (0.8 mmol), B (0.5 mmol), C (0.7 mmol), Mn(CO)₅Br (1.0 mol%), L11 (1.2 mol%), ^tBuOK (1.0 mmol), THF (3.0 mL), 100 °C, 12 h. Isolated yields. ^b B·HCl (0.5 mmol), ^tBuOK (1.5 mmol). ^c 10 mmol scale, 24 h. ^d B·HCl (0.5 mmol), ^tBuOK (2.0 mmol), 130 °C, 24 h.

Several mechanistic investigations were performed under the optimal reaction conditions to yield additional data regarding this dehydrogenative condensation, and the results are shown in Fig. 2. Initially, H₂ was analyzed using gas chromatography under the standard conditions, and D1 could be obtained in an excellent yield, with H₂ detected in 81% yield [eqn (1)], and thus, dehydrogenation may be involved in the catalytic cycle. Additionally, the transformation of A1 under similar conditions produces D93 in a moderate yield, and H₂ is detected in 42% yield, with similar results obtained in the presence of a catalytic amount of base [eqn (2)]. These results suggest that (i) dehydrogenation is not only promoted by the Mn catalyst and ligand but also by the catalytic amount of base and (ii) the base may accelerate the condensation process. As 1-benzyl-1-phenylhydrazine (D94) is detected when the reaction parameters are optimized, D94 is employed in combination with A1. A high yield of the desired product D1 is obtained under the standard conditions, but the reaction shuts down in the absence of the Mn catalyst or ligand, and D94 may be recovered in significant quantity. Similar results can be observed in the presence of a catalytic amount of base, and hydrogen is detected in 78% yield [eqn (3)].

Fig. 2 Mechanistic investigations.

Additionally, D93 may be employed as a partner for smooth condensation with D94 in the presence or absence of a catalyst, ligand, or base [eqn (4)]. However, only trace amounts of D1 are detected with a benzyl bromide partner, and D98 is obtained in a high yield [eqn (5)]. Hence, (i) D94 (in situ-generated) may be the intermediate because its transformation to D1 is distinctly observed in the time conversion plot (Fig. 3b); (ii) additives are unnecessary for the condensation process; and (iii) benzyl bromide does not condense under the standard conditions but undergoes nucleophilic substitution in the presence of a base. Furthermore, only trace amounts of D1 are detected with 1-benzylidene-2-phenylhydrazine (D95) as the coupling partner, and H₂ is detected in a moderate yield. This is attributed to the lower nucleophilic attack activity of the NH condensation site of D95 towards an aldehyde group, and dehydrogenation is unaffected [eqn (6)]. Notably, benzyl bromide as a substrate reacts with D95, generating 87% yield of D1. D1 is obtained in a high yield in the absence of a Mn catalyst or a ligand, but the reaction stops in the absence of a base [eqn (7)]. Thus, (i) D95 could be the intermediate, as its transformation to D1 is undetected in the time conversion plot (Fig. 3b); (ii) a base is necessary for nucleophilic substitution; and (iii) A1 is involved in the hydrazone backbone that should undergo dehydrogenation.

Fig. 3 Proposed mechanism and possible transformations. (a) Standard conditions. (b) N-Methyl-N-((phenylsulfonyl)oxy) sulfonamide, Na₂HPO₄, fac-Ir(ppy)₃, DCE, 5 W blue light irradiation, 25 °C, 90 h. (c) Cu(OTf)₂, toluene, 110 °C, 5 h. (d) Pd/C, H₂, MeOH, 60 °C, 4 h. (e) RVC anode, Pt cathode, TMSN₃, LiClO₄, MeCN, MeOH, I (10 mA), 2 h. (f) NaNO₂, CH₃COOH, H₂O, 25 °C, 24 h.

Additionally, a Hg drop experiment was performed, resulting in acceptable yields of the desired product D1 without causing a significant decrease in yields. These results demonstrate the significant role of the Mn catalyst in promoting the dehydrogenative reaction. Thereafter, TEMPO was added as the radical scavenger under the standard conditions, and D1 was obtained in good yield, suggesting that this dehydrogenation could not be a free radical process [eqn (8)]. The time conversion plot reveals that the concentration of the intermediate D94 initially increases and then decreases with increasing reaction time. The concentration of D93 is maintained at trace levels, indicating that the condensation of the aldehyde with D94 is relatively rapid. These results further confirm that the formation of the intermediate D94 and the dehydrogenation are the rate-determining steps in the transformation reaction. Furthermore, only a trace amount of the product D98 was obtained when using D1 as the partner in the presence of H₂ or ⁱPrOH as the solvent under the standard conditions [eqn (9)]. These results show that the catalytic system is not sufficiently active for the catalytic reductive hydrogenation of ylidenehydrazines.

Although the precise mechanism remains unclear, a possible mechanism of the tandem dehydrogenation condensation is shown in Fig. 3a. Initially, the Mn species I is produced from Mn(CO)₅Br and L11 in the presence of a base under catalytic reaction conditions. The oxidative addition of the alcohol to I generates the key alkoxy-Mn species II. The putative Mn species III may be generated via β-hydrogen elimination and release the aldehyde. Subsequent reductive elimination releases I and H₂. Thereafter, I is re-oxidized to regenerate the active Mn catalyst for use in the next catalytic cycle. Aldehyde condensation with in situ-generated D94 from hydrazine and benzyl bromide produces the desired product. Another pathway involves the direct condensation of the aldehyde with hydrazine to produce D95, which yields the product via nucleophilic substitution with benzyl bromide in the presence of a base.

To further demonstrate the robustness of the tandem dehydrogenation condensation reaction, we conducted a reaction on a gram scale to produce D1 in a high yield (11.88 g) (Fig. 3).¹⁶ Ylidenehydrazines are attractive reactive building blocks that may be readily utilized in synthesizing functionalized complex products (Fig. 3c). D1 may be easily converted to functional nitrogenous heterocyclic compounds, such as benzimidazole (D97) and tetrazole (D99), via cyclization reactions. D98 is obtained in an excellent yield via reductive conversion; furthermore, a high yield of D96 is obtained via sulfonamidation. The CVB-5 pharmaceutical (D100) could be synthesis from D97.¹⁸ Furthermore, D98 could be produced into the desired inhibitory activity adrenoceptor pharmaceutical (D101).¹⁹ Additionally, with the newly developed catalytic system, the desired product (D102) was isolated in 86% yield, which could be transformed into the KDM4C inhibitor pharmaceutical toxoflavin (D103) in an acceptable isolated yield (Fig. 3d).²⁰

Conclusions

In summary, we have initiated the unprecedented transition metal Mn-catalyzed tandem dehydrogenative condensation coupling of hydrazines with alcohols and halides to generate trisubstituted hydrazones, overcoming the challenge of selectivity in multicomponent reactions. Based on the complexation of the Earth-abundant Mn with a readily available PNN pincer ligand, this catalytic system not only provides an efficient method for preparing gram-scale (11.88 g) hydrazones but also facilitates the preparation of various novel hydrazone derivatives. Using this protocol, several pharmaceuticals may be easily synthesized. These are the first direct one-pot syntheses of hydrazones via dehydrogenation, liberating H₂. This strategy significantly broadens the scope of Mn-catalyzed dehydrogenative condensation coupling for synthesizing unsaturated molecules. Studies aimed at obtaining a detailed mechanistic understanding of these tandem dehydrogenative condensation coupling reactions and the application of this strategy in other transformations are currently ongoing.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22002067 and 22202228), the Hundred-Talent Program of the Chinese Academy of Sciences, the Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province (20220052), the Science and Technology Project of Shanxi Province (202103021223457), and the State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences (2021BWZ011).

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2288831 and 2288839. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01890c

‡ These authors contributed equally to this work.

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