Catalyst- and Additive-Free Reduction of Carboxylic Acids and Amides Using Ammonia Borane as Hydrogen Source

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Data may be preliminary. 4 February 2026 V1 Latest version Share on Catalyst- and Additive-Free Reduction of Carboxylic Acids and Amides Using Ammonia Borane as Hydrogen Source Authors : Wanzhen Guo , Xing Lu , Hui Zhou , Nana Wei , Xin Liu , Zhiqiang Ren , and Bo Han 0000-0003-1247-7095 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177018493.39645406/v1 Published Organic & Biomolecular Chemistry Version of record Peer review timeline 196 views 73 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The study reports an economical synthetic protocol an economical synthetic protocol employing air-stable NH 3 ·BH 3 as an H 2 equivalent for the catalyst- and additive-free reduction of both aliphatic and aromatic carboxylic acids, offering a series of structurally diverse corresponding primary alcohols. The designed system has been reported to selectively reduce secondary and tertiary amides into amines, providing moderate to high production yield. The reaction is readily scalable, highly selective, and tolerant of sensitive functional groups, such as bromine, chlorine, fluorine, iodine, nitro, and cyano groups. Mechanistic investigations demonstrated a stepwise hydride-transfer pathway proceeding through a 6-membered cyclic transition state, with aldehyde and imine species as key intermediates, respectively. The proposed operationally simple, metal-free strategy offers a practical and economical route for the production of valuable alcohol and amine building blocks. Cite this paper: Chin. J. Chem. 2024 , 41 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Catalyst- and Additive-Free Reduction of Carboxylic Acids and Amides Using Ammonia Borane as Hydrogen Source Wanzhen Guo, Xing Lu, Hui Zhou, Nana Wei, Xin Liu, Zhiqiang Ren and Bo Han* Laboratory of New Energy & New Function Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan’an University, Yan’an, Shaanxi,716000, P. R. China Keywords Catalyst-free | Additive-free | Carboxylic acids | Amides | Reduction | Ammonia borane Comprehensive Summary The study reports an economical synthetic protocol an economical synthetic protocol employing air-stable NH 3 ·BH 3 as an H 2 equivalent for the catalyst- and additive-free reduction of both aliphatic and aromatic carboxylic acids, offering a series of structurally diverse corresponding primary alcohols. The designed system has been reported to selectively reduce secondary and tertiary amides into amines, providing moderate to high production yield. The reaction is readily scalable, highly selective, and tolerant of sensitive functional groups, such as bromine, chlorine, fluorine, iodine, nitro, and cyano groups. Mechanistic investigations demonstrated a stepwise hydride-transfer pathway proceeding through a 6-membered cyclic transition state, with aldehyde and imine species as key intermediates, respectively. The proposed operationally simple, metal-free strategy offers a practical and economical route for the production of valuable alcohol and amine building blocks. Background and Originality Content Various biologically active natural products, pharmaceuticals, and agrochemicals are extensively comprised of alcohol and amine skeletons. [1] These groups are considered versatile structural units in organic synthesis, providing the formation of various sophisticated and complex molecules with diverse significance. [2] Therefore, cost-effective and high-performance strategies for constructing alcohol and amine frameworks have attracted sustained attention in modern synthetic chemistry. [3] Among all the proposed approaches, the transformation of carboxylic acid derivatives, including carboxylic acids and amides, into their corresponding alcohols and amines represents the most fundamental approach in organic synthesis. [4] The reduction of amides and carboxylic acids into amines and alcohols remains a major challenge in synthetic chemistry owing to the resonance-stabilized carbonyl system, decreasing their electrophilic character. [5] The conversion of carboxylic acids and amides into the alcohols and amines is carried out through the utilization of strong reducing agents, including LiAlH 4 , [6,5a] NaBH 4 , [7] or boranes (Scheme 1a). [8] These reducing agents are not ideal for reducing carboxylic acid derivatives, and their further application is limited due to their large stoichiometry and poor selectivity. [9] Currently, the amides and carboxylic acids have been reported to be reduced through the reactions catalyzed by transition metals, [10] rare-earth metals, [11] and main-group metals, [12] using hydrogen as a reducing agent (Scheme 1a). However, hydrogen-based reduction reactions require specialized equipment, high temperatures, and high pressures, [13] which further restrict their practical applicability, necessitating a potential alternative to H 2 to avoid the use of high pressure and temperature. Over the past two decades, various hydrogen equivalents, including silanes, [14,15] HCOOH/Et 3 N, [16] and pinacolborane (HBpin), [17,18] have been reported to reduce carboxylic acids or amides. Scheme 1 An overview of synthetic strategies employed for the reduction of carboxylic acids and amides. Ammonia borane (H 3 N·BH 3 ), a readily accessible solid with outstanding stability in air and moisture, has attracted significant interest as an ideal hydrogen surrogate in synthetic chemistry due to its high hydrogen storage potential (19.6 wt%) and low molecular weight. [19] Furthermore, ammonia borane has also been reported as a promising mild reductant for hydrogenation of various substrates including nitroarenes, [20] nitriles, [21] imines, [22] aldehydes, [23] ketones, [24] alkenes, [25] alkynes, [26] pyridines, [27] indoles, [28] quinolines, [29] and azoarenes. [30] To our knowledge, despite the significant advancement of ammonia borane-based reduction of amides and carboxylic acids, these transformations still rely on the usage of transition-metal catalysis. A recent study by Ramachandran et al. demonstrated that titanium catalysts can achieve highly efficient and chemoselective reduction of carboxylic acids, employing ammonia borane as the hydrogen source (Scheme 1b). [31] Our research group reported the formation of primary alcohols through the hydrogenation of carboxylic acids and esters catalyzed by a copper N -heterocyclic carbene complex, using ammonia borane as a hydrogen source. [32] The reduction of amide required the NH 3 ·BH 3 as the hydrogen source in the presence of various catalysts using B(C 6 F 5 ) 3 /BF 3 ·OEt 2 , I 2 , and TiCl 4 (Scheme 1b). [33-36] However, the research reporting the reduction of carboxylic acid derivatives with ammonia borane in the absence of catalysts remains scarce. The Natte group reported a user-friendly, catalyst- and base-free protocol for the reduction of esters to primary alcohols, employing bench-stable NH 3 ·BH 3 . [37] Mukherjee’s research group established a protocol of amide reduction using Me 2 NH·BH 3 as a hydrogen source, with applicability for primary, secondary, and tertiary amides. [38] Therefore, the development of efficient reduction methods for carboxylic acids and amides with the sole usage of hydride transfer, without relying on catalysts or additives, represents an economically viable approach. This study reports a reduction strategy of carboxylic acid employing ammonia borane as a H 2 equivalent, while also demonstrating its selectivity for reducing secondary and tertiary amides(Scheme 1c). Results and Discussion This study selected the reduction of 3‑phenylpropanoic acid ( 1a ) into 3‑phenylpropan‑1‑ol ( 2a ) as a model transformation for optimizing catalyst‑free protocol (Table 1). The reaction was initiated using 3.0 equivalents of the reductant in diethyl ether (Et₂O) and heated at 70 °C for 24 h, resulting in the formation of 2a with 88% yield (entry 1). Reducing the content to 2.0 equivalents significantly decreased the yield to 67% (entry 5), while only traces of product were obtained with 1.0 equivalent content (entry 6). Further increasing the content to 4.0 equivalents demonstrated no significant enhancement in the product yield (entry 3), identifying 3.0 equivalents as the optimal stoichiometry ratio. However, the selection of solvent demonstrated a pronounced influence on the production yield, with toluene revealing a comparable yield of 86% (entry 7), while THF or CHCl₃ resulted in significantly lower yield of 24 and 60%, respectively (entries 8–9). Furthermore, polar protic solvents, including EtOH, significantly suppressed the product yield (entry 10). Similarly, strongly coordinating aprotic solvents, such as CH₃CN, were found to be ineffective in promoting hydrogenation, yielding 36% of synthesized alcohols (entry 11). The activation barrier can be overcome by increasing the reaction temperature, demonstrating only traces of product at 45 °C (entry 14). Similarly, increasing the temperature to 80 °C demonstrated no significant enhancement in the product yield compared with 70 °C (entry 12). A 10 h time duration for the reaction resulted in incomplete conversion, demonstrating decreased yield of 53% (entry 15), while a 24 h reaction time provided complete conversion of carboxylic acid, yielding 88% of alcohol yield (entry 16). Similarly, the optimized condition for amide reduction was identified as the 4.0 equivalents of NH₃·BH₃ in Et₂O at 70 °C for 12 h, resulting in the formation secondary amine with 74% yield (entry 1, last column). Table 1 a Optimization table for hydrogenation of 3-phenylpropanoic acid ( 1a ) and N -phenylbenzamide ( 3a ) a Entry Deviation from standard conditions Yield of 2a Yield of 4a 1 none 88 74 2 5.0 equiv. NH 3 ·BH 3 - 65 3 4.0 equiv. NH 3 ·BH 3 85 74 4 3.0 equiv. NH 3 ·BH 3 88 55 5 2.0 equiv. NH 3 ·BH 3 67 47 6 1.0 equiv. NH 3 ·BH 3 trace 32 7 Toluene 86 28 8 THF 24 trace 9 CHCl 3 60 26 10 EtOH nd b nd b 11 CH 3 CN 36 nd b 12 80 o C reaction temperature 88 72 13 60 o C reaction temperature 52 56 14 45 o C reaction temperature trace trace 15 Reaction time: 10 h 53 58 16 Reaction time: 24 h 88 74 a Reaction conditions: 1a or 3a (0.2 mmol), NH 3 ·BH 3 (3.0 equiv. or 4.0 equiv.), solvent (2.5 mL), isolated yields were calculated based on 1a or 3a . b Not detected. The applicability of the proposed method was investigated after the successful optimization of the catalyst-free reduction of carboxylic acids (Table 2). Initially, the influence of various substituents on the aromatic ring of the carboxylic acid was investigated, with diverse electron-donating methyl, ethyl, and methoxy groups demonstrating the production of their corresponding alcohols in moderate to good yields ( 2b – 2e , 57–78%), confirming the compatibility of these substituents with the reaction conditions. The presence of substituents, such as methyl, ethyl, and phenyl at the α -position of carboxylic acids, exerted no steric hindrance, yielding alcohols 2f – 2j with 64–90% yield. Substrate 2-(p-tolyl)propan-1-ol ( 1g ) was reacted with 20 mmol scale at 90 o C for the duration of 48 h, yielding the desired compound ( 2g ) in 94% yield, confirming its significant potential for industrial application. The carboxylic acid substrate ( 1k - 1l ) with para substitution of -NO 2 and -CN groups demonstrated 73% and 45% yields for their corresponding alcohols, respectively ( 2k and 2l ). The structures of byproducts could not be determined under standard conditions when using 1l as the substrate. The optimal conditions remained unaffected by the presence of halogen substituents (F, Cl, Br, and I) on aromatic carboxylic acid substrates, retaining efficiency of the reaction and providing corresponding primary alcohol derivatives 2m - 2p in moderate to good yields (64%–98%). The reduction of 2-(naphthalen-1-yl)acetic acid ( 1q ) with NH 3 ·BH₃ yielded 60% of 2q , while benzyl alcohol was obtained in significant yield using benzoic acid as a substrate ( 2s , 97%). The extended-conjugation homologue 2-naphthoic acid ( 1t ) was converted to the corresponding alcohols in 62% yield. Furthermore, methyl, methoxy, n-propyl, and tert-butyl (electron-donating) substituted benzoic acid resulted in the formation of their corresponding alcohols 2u , 2v , 2w , and 2x in 65%, 86%, 75% and 68% yields, respectively. However, 4-Nitrobenzoic acid (electron-withdrawing group) yielded 53% primary alcohol, avoiding the reduction of the nitro group. Indane-2-carboxylic acid ( 1z ), alicyclic carboxylic acid, yielded the corresponding primary alcohol in 60% yield ( 2z ). Formation of various drug molecules was carried out through this approach, including 2aa and 2ab , with respective yields of 51 and 42%. Table 2 Substrate scope for hydrogenation of carboxylic acids a a Each reaction was conducted using carboxylic acids 1 (0.2 mmol), ammonia borane (3.0 equiv.), Et 2 O (2.5 mL), 70 o C, 24 h. Isolated yields were calculated based on 1 . Variations in substituent patterns around the amide carbonyl were examined to evaluate their influence on reactivity, and the obtained results were compared with the standard yield (74%) obtained through the reduction of standard substrate 3a into 4a . The reaction of 20 mmol N -phenylbenzamide ( 3a ) at 85 o C for 48 h demonstrated a slight decrease in the product yield (65%). Halogens were found to be compatible and yielded significant amines, while avoiding potential dehalogenation ( 4b – 4e , 64%–70%). The secondary amides ( 3f – 3g ) with electron-donating (Me) and electron-withdrawing (NO 2 ) groups at the para position were evaluated and produced corresponding amines with 67 and 74% yield, respectively ( 4f – 4g ). The reaction of compound 3h was carried out at 85 o C for 12 h, resulting in the formation of secondary amine 4h with 67% yield. Furthermore, the influence of substituents on the aniline skeleton of the secondary amides substrate on the reaction was evaluated, and found that secondary amides containing electron-withdrawing 4- and 2-fluorine ( 3i and 3j ), 4-chloro, 4-bromine, and 4-nitro ( 3k – 3m ) groups resulted in the formation of their corresponding amines in moderate yields (71%–86%). Amide substrates with electron-donating substitutions at various positions demonstrated significant yields of hydrogenated products ( 4n – 4r , 60%–84%). The presence of either electron-donating or electron-withdrawing substituents on the carbonyl-linked aryl ring or the aryl amine moiety demonstrated no adverse effect on the reduction, providing the corresponding reduced products in moderate to good yields ( 4t – 4z , 60–82%). The secondary amides, derived from phenylacetyl chloride, phenylpropionyl chloride, and other aliphatic acyl chlorides, were investigated to examine the effects of substituents on the amide carbonyl carbon. The findings demonstrated a smooth reaction progress, affording the corresponding amines ( 4aa – 4af , 69%–84%). The aliphatic secondary amides demonstrated the production yield of 70% to 84% ( 4ag – 4ai ). The scope extended to heteroaromatic systems, with 2-furamide ( 3aj ) providing 68% yield of the corresponding heterocyclic amines ( 4aj ). Furthermore, the reduction was extended to lactams for the synthesis of cyclic amines, which are critical precursors employed in the synthetic chemical industry, achieving a good yields for products 4ak – 4am derived from dihydroquinolin-2( 1H )-one ( 3ak , 3al ) and 2H-benzo[ b ][1,4]oxazin- 3(4H)-one ( 3am ) (60%–81%). The applicability of the reaction was further extended for the deoxyreduction of various tertiary amides, which were carried out at 85 o C for 12 h, producing a series of tertiary amines in moderate yields ( 4an – 4aq , 61–73%). Table 3 Substrate scope of hydrogenation of amide a a Each reaction was conducted using amide 3 (0.2 mmol), ammonia borane (4.0 equiv.), Et 2 O (2.5 mL), 70 o C, 12 h. Isolated yields were calculated based on 3 . b Reactions performed at 70 o C for 24 h. c 85 o C for 12 h. d 85 o C for 48 h. For better comprehension regarding the underlying reaction mechanism, the N -phenylbenzamide ( 3a ) was reduced under standard conditions in the presence of 2.0 equivalents of (2,6-di-tert-butyl-4-methylphenol) BHT or (2,2,6,6-tetramethyl -piperidin-1-oxyl) TEMPO, yielding the target products in 73% and 65% yields, respectively (Schemes 2a and 2b). The findings highlight that the reaction does not involve a free radical mechanism. Furthermore, the deoxygenative reduction of N -phenylbenzamide ( 3a ) with NH 3 ·BD 3 yielded a product 4a (60%) with 81% deuterium incorporation at the α -CH 2 position (Scheme 2c), under the standard reaction conditions. Deuterated D 3 N·BH 3 provided 61% yield of the product 4a with 47% deuterium incorporation (Scheme 2d), consistent with the results derived from the utilization of NMe 3 BH 3 as the hydrogen source (Scheme 2e). The observed finding indicated the imine as the key intermediate in the reaction, which was supported by the conversion of 5 (or 6 ) into 4a (or 4l ) under the same reaction conditions (Schemes 2f and 2g). Another possible mechanism includes the reduction of amide into an amine and an alcohol through a hemiacetal intermediate, followed by the reductive amination through a hydrogen-borrowing process. Using benzyl alcohol and aniline under the standard reaction conditions failed to produce the target compound, confirming that this pathway does not contribute to the observed transformation (Scheme 2h). Scheme 2 Control experiments for amide reduction. ¹H NMR confirmed the formation of primary alcohols by the reaction of 3‑phenylpropanoic acid 1a with HN₃·BD₃ under standard conditions, showing 84% deuterium incorporation in the CH₂ group (Scheme 3a). Using deuterated D₃N·BH₃ instead of ammonia borane, incorporation of deuterium was observed at the newly formed group with 30% incorporation (Scheme 3b). Therefore, the use of these deuterium‑labeling suggested that acetals and aldehydes are possible intermediates in the reduction pathway of carboxylic acids, further verified by the conversion of compound 9 into 2a under identical reaction conditions (Scheme 3d). The possible reduction mechanism of amides and carboxylic acids in the presence of ammonia borane is depicted in Scheme 4, in accordance with experimental data and previous reports. [16,31,37,38] The amide or carboxylic acid initially reacted with ammonia borane, resulting in the formation of 6-membered cyclic transition state TS-1 or TS-2 , forming intermediate α -hydroxylamine ( 10 ) or acetal ( 11 ) by leaving NH 2 BH 2 . The transformation was further confirmed by 11 B NMR, with the corresponding signal detected at a chemical shift of -11.40 [37] . Furthermore, the elimination of the H 2 O molecule resulted in the formation of key intermediate imine ( 5 ) or aldehyde ( 9 ). The last step of the reaction is proposed to proceed via a concerted double hydrogen transfer from NH 3 ·BH 3 to the imine ( 5 ) or aldehyde (9 ) intermediate via another 6-membered cyclic transition state, TS-3 or TS-4 , yielding a secondary amine ( 4a ) or primary alcohol ( 2a ) as the main products, along with an NH 2 BH 2 or its polymer as byproducts. The observed findings are consistent with the results derived from the deuteration experiments and 11 B NMR spectroscopy. Scheme 3 . Control experiments for carboxylic acid reduction. Scheme 4 Proposed reaction mechanism for the reduction of amide and carboxylic acid. Time-dependent and kinetic studies were performed to further verify the possible reduction mechanisms of amide and carboxylic acid. Compounds 3a and 1a were used as model substrates to examine the reaction profiles under different time conditions (Figure 1), providing only the trace of N -benzylaniline ( 4a ) within the initial hour, while achieving 58% yield over the next 8 hours (Figure 1a). Reduction of 1a provided a 32% yield of 2a after one hour, followed by a subsequent increase to 82% within the next 8 h (Figure 1b). Initially, the carboxylic acid demonstrated better reactivity than the amide, consistent with the results derived from the competitive experiments (Scheme 3e). The initial rate against the initial concentration of NH 3 BH 3 , ranging from 0.16 to 0.4 M, showed a clear first-order dependence on the concentration of NH 3 ·BH 3 , indicating its involvement in the rate-determining step of the reaction, or it may play a key role in the early stage of amide hydrogenation (Figure 1c). Similarly, the reaction rate of the carboxylic acid hydrogenation demonstrated a first-order dependence on the NH 3 ·BH 3 concentration (Figure 1d). Figure 1 (a) Reaction profiles of reduction of N -phenylbenzamide ( 3a ); (b) Reaction profiles of reduction of 3‑phenylpropanoic acid ( 1a ); (c) The initial reduction rate of 3a vs concentration of NH 3 ·BH 3 ; (d) The initial reduction rate of 1a vs concentration of NH 3 ·BH 3 . Conclusions In summary, this study established a practical, catalyst- and additive-free protocol for the reduction of carboxylic acids and amides using ammonia borane. The developed method demonstrated broad functional group tolerance, including halogens, nitro, and cyano groups, yielding the transformation of diverse substrates into their respective alcohols and amines. Mechanistic analysis clarified a stepwise hydride-transfer pathway involving aldehyde or imine intermediates in the reduction processes of carboxylic acids and amides, respectively. The developed metal- and ligand-free approach, which requires no specialized equipment, represents an economical and green alternative to traditional reduction methods, highlighting the synthetic potential of ammonia borane in sustainable organic synthesis. Experimental General procedure for hydrogenation of carboxylic acids and amides. A mixture of carboxylic acid derivatives (0.2 mmol) or amide derivatives (0.2 mmol) and NH 3 ·BH 3 (0.0185 g, 3.0 equiv.) or NH 3 ·BH 3 (0.0246 g, 4.0 equiv.) were added to an oven dried schlenk tube under atmosphere of nitrogen. Et 2 O (2.5 mL) were added by syringe. The reaction mixture was stirred at 70 o C for 24 h or 12 h. After quenching with saturated NH 4 Cl/H 2 O (10 mL), the crude product was extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under vacuum, the crude product was purified by column chromatography to afford the desired hydrogenation compound. 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Unlocking an additive-free and catalyst-free dual approach for reduction of amides to amines. Chem. Commun . 2025 , 61 , 1605−1608. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Accepted manuscript online: XXXX, 2024 Version of record online: XXXX, 2024 Entry for the Table of Contents Catalyst- and Additive-Free Reduction of Carboxylic Acids and Amides Using Ammonia Borane as Hydrogen Source Wanzhen Guo, Xing Lu, Hui Zhou, Nana Wei, Xin Liu, Zhiqiang Ren and Bo Han* Chin. J. Chem. 2026 , 44 , XXX—XXX. DOI: 10.1002/cjoc.202300XXX We report a cost-effective, safe, sustainable, and environmentally friendly strategy for the efficient and selective reduction of carboxylic acids and amides using ammonia borane as hydrogen source without the use of catalyst and additives. Information & Authors Information Version history V1 Version 1 04 February 2026 Peer review timeline Published Organic & Biomolecular Chemistry Version of Record 1 Jan 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords additive-free amides ammonia boran carboxylic acids catalyst-free reduction Authors Affiliations Wanzhen Guo Yan'an University View all articles by this author Xing Lu Yan'an University View all articles by this author Hui Zhou Yan'an University View all articles by this author Nana Wei Yan'an University View all articles by this author Xin Liu Yan'an University View all articles by this author Zhiqiang Ren Yan'an University View all articles by this author Bo Han 0000-0003-1247-7095 [email protected] Yan'an University View all articles by this author Metrics & Citations Metrics Article Usage 196 views 73 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wanzhen Guo, Xing Lu, Hui Zhou, et al. 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