Morpholine Amides: Classical but Underexplored Acylating Intermediates in Organic Synthesis

Abstract

Morpholine amides are classical yet underexplored acylating agents in organic synthesis. Compared to other amides, such as Weinreb amides, morpholine amides offer distinct advantages such as high water solubility, economic accessibility, and operational stability. This review highlights recent advancements in the use of morpholine amides for the synthesis of ketones, aldehydes, and acylsilanes via selective mono-addition of organometallic or hydride reagents. Their applications in key steps of complex molecule synthesis, including natural product synthesis, Vilsmeier–Haack reactions, and polymer recycling processes, are also discussed. Particular attention is paid to the unique reactivity and chemoselectivity of morpholine amides that distinguish them from other amide derivatives, offering practical and scalable strategies in modern synthetic chemistry.

 

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Keywords

Morpholine amide - Acylating agent - Mono-addition - Ketone synthesis - Weinreb alternative - Divergent building block - Hydride reduction

1

Introduction

The reaction of carboxylic acid derivatives with organometallic reagents represents one of the most fundamental and widely employed methods for the synthesis of carbonyl compounds, including ketones and aldehydes. Both ketones and aldehydes are pivotal intermediates in organic synthesis, serving as strategic building blocks in the preparation of pharmaceuticals, natural products, and functional materials.[1] Despite their value, the direct synthesis of ketones via nucleophilic acyl substitution with organometallic reagents often suffers from a fundamental challenge: over-addition ([Scheme 1A]). This over-addition typically occurs because the initially formed ketone (or aldehyde) is more electrophilic than the starting carboxylic acid derivative and remains reactive under the reaction conditions, leading to uncontrolled double addition. Attempts to mitigate this issue by controlling stoichiometry or reaction temperature are often unreliable, especially on larger or more complex substrates.

Scheme 1 Strategies to prevent over-addition in ketone synthesis. (A) Classical issues, and chelation-controlled approaches using (B) Weinreb and (C) morpholine amides, and (D) their typical preparation methods and the precursors.

The selective mono-addition of organometallic reagents to carboxylic acid derivatives represents a cornerstone transformation in synthetic organic chemistry. To address this limitation, various strategies have been devised, among which chelation-controlled acylation has proven especially effective. Among the most influential examples are the Weinreb amides, N-methoxy-N-methylamides, first reported by Weinreb in 1981 ([Scheme 1B]).[2] [3] Upon treatment with organometallic reagents, Weinreb amides form a stable tetrahedral intermediate chelated by the O-atoms. This chelation prevents collapse to the carbonyl intermediates and effectively blocks further nucleophilic attack, thereby enabling highly selective mono-addition to form ketones or aldehydes in excellent yield. In addition to Weinreb amides, several other chelation strategies have been developed, such as 2-thiopyridyl esters,[4] 2-pyridylamides,[5] and N-acylbenzotriazoles,[6] etc.[1c]

Morpholine amides, N-acyl morpholines, have also been utilized as alternative acylating agents, and several reports have demonstrated the utility of morpholine amides in the synthesis of carbonyl compounds via the Weinreb-type mono-addition strategy with organometallic reagents, such as Grignard and organolithium reagents ([Scheme 1C]). Also, due to the high hydrophilicity of the morpholine ring, morpholine amides often exhibit water solubility, which is in contrast to the lower aqueous solubility of the more hydrophobic Weinreb amides.

While numerous examples have been reported and several review articles are available on Weinreb amides, studies on morpholine amides remain relatively few, with no specialized review currently available. Furthermore, the significance of their unique properties has remained relatively underexplored.

Both Weinreb amides and morpholine amides are typically synthesized via acylation of the corresponding amine with an activated carboxylic acid derivative, or palladium-catalyzed carbonylative coupling with organic halides ([Scheme 1D]).[7] Therefore, the starting amine component is a critical determinant of the practical feasibility of amide synthesis. N,O-Dimethylhydroxylamine, used in the preparation of Weinreb amides, is a synthetically specialized compound. It is relatively expensive and less stable, being both a hygroscopic and hydrochloride salt. Although commercially available, its purification and storage present operational challenges, especially in large-scale settings. In contrast, morpholine is an industrial commodity, manufactured on a large scale through a straightforward reaction between diethylene glycol and ammonia. It is inexpensive, chemically stable, and readily available from multiple suppliers worldwide.[8] Considering the low cost, wide availability, and operational robustness of morpholine, its incorporation into ketone synthesis protocols offers a compelling alternative to the Weinreb approach, particularly in industrial or cost-sensitive environments.[9] Although Weinreb amides remain indispensable for certain highly sensitive transformations, morpholine amides provide a practical and scalable substitute in many routine applications.

In this review, I summarize the reactivity and utility of morpholine amides as acylating agents, and sometimes compare their performance to Weinreb amides and other related systems, highlight recent developments in their synthetic application, and assess their potential as practical alternatives in modern organic synthesis.

 

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2

Ketone Formation from Morpholine Amides and Organometallic Reagents

Reactions involving morpholine amides and organometallic reagents have been known for a long time. To the best of this author’s knowledge, Brown first reported the synthesis of ketones using morpholine amides in 1992. This group demonstrated that the reaction of morpholine amides, derived from lactic acid, with aryl lithium, which was prepared from the corresponding aryl bromide and ⁿ BuLi, could efficiently produce unsymmetrical ketones in high yields while suppressing over-addition ([Scheme 2]).[10]

Scheme 2 Ketone synthesis from morpholine amides and an aryllithium (Brown, 1992).

An example of a Grignard reaction using morpholine amides was reported in 1993 by Tasaka and coworkers at Takeda, a Japanese pharmaceutical company. They successfully synthesized the corresponding ketones from a morpholine amide derivative of a THP-protected lactone with several aryl magnesium bromides ([Scheme 3]).[11]

Scheme 3 Ketone synthesis from morpholine amides and Grignard reagents (Tasaka, 1993).

A key study by Romea and Urpí in 1997 clearly highlighted the synthetic utility of morpholine amides as efficient acylating agents for ketone synthesis from organometallic reagents.[12] They described the use of morpholine amide derived from benzoic acid and the corresponding pyrrolidine derivatives in reactions with methyl Grignard reagents to demonstrate the superiority of morpholine amides in selective ketone synthesis ([Scheme 4]).

Scheme 4 Comparison of a morpholine amide and pyrrolidine amide in the Grignard reaction (Romea and Urpí, 1997).

They also showed that various organometallic reagents, including allyl-, aryl-, and vinylmagnesium bromide, as well as vinyl- and alkenyl lithium reagents, can react with aliphatic carboxylic acid–derived morpholine amides to afford ketones ([Scheme 5]).

Scheme 5 Scope of the organometallic reagents for ketone synthesis using morpholine amides.

Later in 2000, Gomtsyan reported the formation of a β-aminoketone from a morpholine amide with vinylmagnesium bromide. The author proposed that the reaction proceeded through the formation of an α,β-unsaturated ketone via morpholine amide ketone synthesis, followed by a subsequent 1,4-addition of the resulting magnesium amide ([Scheme 6]).[13] This indicates that this type of addition reaction should also be considered when employing vinyl organometallic reagents.

Scheme 6 Formation of β-aminoketone from a morpholine amide and vinylmagnesium bromide via conjugate addition (Gomtsyan, 2000).

Amino acid derivatives could also be applicable to the morpholine-based organometallic reaction. Sengupta and coworkers demonstrated that morpholine amides from a wide range of protected α-amino acids successfully reacted with organolithium to produce the corresponding α-amino ketones ([Scheme 7]).[14]

Scheme 7 Synthesis of α-amino ketones from protected amino acid–derived morpholine amides (Sengupta, 1999).

For ynone synthesis by morpholine amides with the alkynyllithium reagent, in 2002, Roberts found an equilibrium between the starting morpholine amides and alkynyllithiums with the adducts: the tetrahedral intermediates, unlike the reaction of Weinreb amides.[15] In reactions with 1.1 equiv of alkynyllithium reagents, Weinreb amides undergo complete conversion to the corresponding ynones within 1 h at 0 °C ([Scheme 8A]). In contrast, morpholine amides under the same conditions show incomplete conversion, with 6–25% of the starting amide remaining ([Scheme 8B]). Increasing the equivalents of alkynyllithium gradually improved the conversions to the ynones ([Scheme 8C]).

Scheme 8 Reactions of alkynyllithium with (A) Weinreb amide and (B) morpholine amide, and (C) the effect of the equivalents of alkynyllithium (Roberts, 2002).

When a morpholine amide derived from benzoic acid is reacted with an alkynyllithium reagent, the corresponding ynone is formed in 95% yield, with 5% of the starting amide remaining ([Scheme 9A]). However, if a Weinreb amide derived from the different carboxylic acid is added to the reaction mixture before quenching and the mixture is then warmed to 0 °C, only the ynone from the Weinreb amide is observed, and the morpholine amide is fully regenerated ([Scheme 9B]). This behavior clearly indicates that the reaction involving morpholine amides takes place in equilibrium ([Scheme 9C]).

Scheme 9 Reaction of alkynyllithium with (A) morpholine amide and (B) the cross-over reaction with additional Weinreb amide, and (C) the equilibrium between morpholine amides and alkynyllithium with the tetrahedral intermediates.

Concellón and coworkers described the use of morpholine-derived cyclopropanecarboxamides enabled efficient synthesis of cyclopropyl ketones through reactions with organolithium reagents ([Scheme 10]).[16]

Scheme 10 Formation of ketones from morpholine amide bearing cyclopropane-substituents (Concellón, 2007).

For the addition of perfluoroalkyl lithium reagent, Weinreb and morpholine amides stood out for the synthesis of polyfluorinated ketones. In 2008, Kokotos and coworkers investigated the reaction of carboxylic acids with perfluoroalkyl lithium, which is prepared from the corresponding iodide with MeLi · LiBr. Among the various acyl derivatives, such as carboxylic acid, esters, acyl fluoride, anhydride, and several amides, they found both Weinreb and morpholine amides consistently afforded the desired perfluoro ketones rather than the over-addition ([Scheme 11]).[17]

Scheme 11 Synthesis of perfluorinated ketones using morpholine or Weinreb amides (Kokotos, 2008).

 

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3

Ketone Formation in Complex Molecular Synthesis

The use of morpholine amides for ketone synthesis has proven valuable as a key step in the multistep synthesis of complex molecules. For example, in 1998, Kishi and coworkers employed this strategy in the total synthesis of batrachotoxin A, where treatment of the morpholine amide with an excess of MeLi in the presence of CeCl₃,[18] which provided “MeCeCl₂” in situ, afforded the desired methyl ketone in the final stages of the synthesis ([Scheme 12A]).[19] In contrast, attempts using the corresponding Weinreb amide under the similar conditions were unsuccessful ([Scheme 12B]).

Scheme 12 Total synthesis of batrachotoxin A via methyl ketone formation of (A) the morpholine amide with MeLi/CeCl₃, and (B) the initial attempt by using the Weinreb amide (Kishi, 1998).

The Kishi’s method, utilizing morpholine amide and “MeCeCl₂” from MeLi with CeCl₃, could be applied by Marcantoni in 2002. The research group has successfully applied the reaction to morpholine amides containing long-chain hydrocarbons and n-propylmagnesium chloride with CeCl₃, to synthesize long-chain saturated and polyunsaturated pheromones ([Scheme 13]).[20]

Scheme 13 Morpholine-based synthesis of pheromones via Grignard/CeCl₃ (Marcantoni, 2002).

In 2007, Tius and colleagues reported the reaction of morpholine amides with propargyl lithium. The products, propargyl vinyl ketones, serve as precursors for the Nazarov-type cyclization after isomerization to allenyl vinyl ketones ([Scheme 14]).[21]

Scheme 14 Preparation of propargyl ketones from morpholine amide for Nazarov-type cyclization (Tius, 2007).

The total synthesis of aculeatins A and B by Yadav and coworkers in 2010 highlights the utility of morpholine amides as acylating agents in complex molecule construction. The key step involves the coupling of a morpholine amide with an alkynyllithium, prepared from the alkyne with ⁿ BuLi and BF₃·OEt₂ ([Scheme 15]).[22]

Scheme 15 Synthesis of aculeatins via alkynyl ketone formation from morpholine amide (Yadav, 2010).

Barker’s research group has focused on morpholine amides as key intermediates for the synthesis of highly substituted heterocycles such as tetrahydrofuran and pyrrole derivatives from γ,δ-unsaturated morpholine amides. For example, they demonstrated the synthesis of (+)-galbelin through a reaction of a chiral 2,3-dimethylpentenamide with lithiated 4-bromoveratrole to give the corresponding ketone ([Scheme 16]).[23]

Scheme 16 Synthesis of (+)-galbelin via ketone formation using γ,δ-unsaturated morpholine amide (Barker, 2011).

The same strategy could not be applied to the 2,3-diphenyl-substituted γ,δ-unsaturated morpholine amide, as no substitution of the morpholine group was observed upon treatment with phenyllithium ([Scheme 17A]). This was attributed to steric hindrance from the 2-phenyl group. To overcome this limitation, they converted the alkene moiety into the corresponding aldehyde, followed by the addition of phenyllithium. The resulting in situ lithium alkoxide then reacted intramolecularly with the morpholine amide, affording the lactone in 69% yield. Subsequent reactions produced tetraphenyl tetrahydrofuran. This highlights an additional utility of morpholine amides, not only in ketone synthesis but also in ester formation via oxygen nucleophiles ([Scheme 17B]).[24]

Scheme 17 Reactions of (A) 2,3-diphenyl-substituted γ,δ-unsaturated morpholine amide, and (B) lactone formation via internal nucleophilic attack after aldehyde generation.

They have also reported the synthesis of substituted pyrroles via ketone formation from the reaction of morpholine amides with aryllithium reagents, followed by several transformations including the Paal–Knorr reaction ([Scheme 18]).[25]

Scheme 18 Pyrrole synthesis via Paal–Knorr reaction from morpholine-derived ketones.

 

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Ketone Formation from Morpholine Amides via Vilsmeier–Haack Reaction

Morpholine amides can also be used in Vilsmeier–Haack acylation. In 1993, Smith and coworkers demonstrated that the Vilsmeier reagent, prepared from morpholine amides derived from benzoic acids and phosphoryl chloride, reacts with pyrrole to afford 2-acylpyrroles. Using this reaction as a key step, they synthesized tetraarylporphyrins ([Scheme 19]).[26] Similarly, Bröring carried out comparable syntheses in 2000.[27]

Scheme 19 Vilsmeier–Haack reaction using morpholine amides for synthesis of tetraarylporphyrins (Smith, 1993).

 

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5

Aldehyde Formation from Morpholine Amides and Hydride Reducing Agents

Aldehydes can also be synthesized from morpholine amides by employing hydride reducing agents, such as LiAlH₄ and DIBAL-H, in place of carbon organometallic reagents such as Grignard or organolithium reagents.

In 2000, Martinez and coworkers reported a new method for synthesizing N-protected α-amino aldehydes by the reaction of morpholine amides with LiAlH₄. This approach is compatible with common protecting groups such as Boc, Z, and Fmoc. In particular, they emphasized the cost-effectiveness of this method compared to the Weinreb amide approach, owing to the easy and inexpensive preparation of morpholine amides ([Scheme 20]).[28]

Scheme 20 Formation of N-protected α-amino aldehydes from morpholine amides with LiAlH₄ (Martinez, 2000).

An and coworkers developed a facile partial reduction method of carboxylic acid derivatives, such as acid chlorides, esters, and amides, to aldehydes using a combination of DIBAL-H ( ⁱ Bu₂AlH) and morpholine system. Upon mixing at ambient temperature, morpholine was considered to react with DIBAL-H to generate diisobutyl(morpholino)aluminum species. This morpholino-aluminum complex and carboxylic acids were believed to provide morpholine amide in situ, and the following reduction gave the corresponding aldehydes ([Scheme 21]).[29] [30]

Scheme 21 Synthesis of aldehydes from carboxylic acid derivatives with DIBAL-H via morpholino-aluminum species and morpholine amide (An, 2022).

 

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6

Acylsilane Formation from Morpholine Amides and a Silyllithium Reagent

The addition of anionic silyl nucleophiles to amides has also been explored, though examples remain limited. In 2004, Scheidt reported a direct and efficient synthesis of acylsilanes from morpholine amides and PhMe₂SiLi. Morpholine amides were uniquely effective in this transformation and other common amides, including Weinreb amides, failed to give the desired products ([Scheme 22A]). The method provided acylsilanes in good yields from a range of alkyl morpholine amides. In contrast, aromatic amides exhibited low reactivity, likely due to a nonproductive Brook rearrangement ([Scheme 22B]).[31]

Scheme 22 Reactions of silyllithium with (A) Weinreb amide and (B) morpholine amides for synthesis of acylsilane (Scheidt, 2004).

 

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7

Selective and Divergent Transformations of Morpholine Amides

As shown in the above chapters, morpholine amides are versatile intermediates that undergo various transformations, including acyl substitutions and hydride reductions. Divergent transformations of morpholine amides, enabled by their unique reactivity and versatility, have also been demonstrated. In 2022, Morken and coworkers reported the use of β-tert-boryl morpholine amides as substrates, which were synthesized via their original palladium-catalyzed reaction between α-substituted alkenyl boron “ate” complexes and carbamoyl chlorides. They performed Kishi’s Grignard reaction (MeLi/CeCl₃) on the morpholine amides to afford the corresponding methyl ketones ([Scheme 23A]), and demonstrated reductive conversions to either the corresponding aldehyde using DIBAL-H ([Scheme 23B]) or the tertiary amine using BH₃·SMe₂ ([Scheme 23C]), respectively.[32] [33]

Scheme 23 Divergent conversions of β-boryl morpholine amide: (A) ketone formation with MeLi/CeCl₃, (B) aldehyde formation with DIBAL-H, and (C) amine formation with BH₃·SMe₂ (Morken, 2022).

In 2023, this author reported morpholine amides as key synthetic intermediates in recycling/upcycling chemistry of polyesters. We focused on the morpholine amides, which were prepared from polyesters, such as polyethylene terephthalate (PET), through catalytic depolymerization, and demonstrated practical and selective transformations of PET into various chemicals via the morpholine amide as a divergent intermediate ([Scheme 24]).[34] The morpholine amide from PET was a very air- and moisture-stable crystal (CCDC: 2201082) and was completely soluble in water at 100 °C. Upon addition of hydrochloric acid and continued heating for 24 h, highly pure terephthalic acid (TPA) precipitated directly from the reaction mixture and was isolated by simple filtration in 98% yield ([Scheme 24A]). This approach overcomes a major challenge in TPA purification, as standard isolation techniques such as recrystallization, extraction, or chromatography are ineffective due to the poor solubility of TPA toward most solvents. Here, the water solubility of morpholine amide enables an efficient and scalable method for chemical recycling of PET. A key feature of this methodology lies in the unique aqueous solubility of the morpholine amide, which distinguishes it from conventional amide derivatives such as Weinreb amides that are typically water insoluble. Selective reductions of the morpholine amide were also demonstrated. When treated with 4 equiv of DIBAL-H at −78 °C, the morpholine amide underwent hydride substitution at both morpholine positions to afford terephthalaldehyde ([Scheme 24B]). In contrast, performing the reaction at 0 °C with 5 equiv of DIBAL-H led to a complete deoxygenative reduction, furnishing the corresponding benzylic amine in high yield and selectivity ([Scheme 24C]). These outcomes highlight the temperature-dependent chemoselectivity of DIBAL-H reduction on morpholine amides. In a further transformation, the morpholine amide reacted cleanly with phenylmagnesium bromide (PhMgBr) to afford 1,4-dibenzoylbenzene in 65% isolated yield without over-addition to the corresponding alcohol ([Scheme 24D]).

Scheme 24 Divergent transformations of PET-derived morpholine amide: (A) hydrolysis by H₃O⁺ for terephthalic acid, selective reduction by DIBAL-H into (B) aldehyde and (C) tert-amine, and (D) Grignard reaction for diketone (Ogiwara, 2023).

Recently, in 2025, Teichert and coworkers developed a catalytic and selective hydrogenation of morpholine amides. For example, a terephthalic acid derivative bearing both a morpholine amide and a piperidine amide was treated under 100 bar of H₂ with a copper(I)/NHC catalyst bearing a guanidine moiety. The reduction proceeded site-selectively at the morpholine amide rather than the piperidine amide ([Scheme 25A] and B). This selectivity was proposed to result from hydrogen bonding between the morpholine amide and the guanidine unit of the catalyst ([Scheme 25C]). In contrast, stoichiometric reduction using DIBAL-H did not show such high selectivity ([Scheme 25D]).[35]

Scheme 25 Reductive transformations of morpholine amides: (A) chemoselective hydrogenation, (B) copper(I)/NHC catalyst bearing a guanidine moiety, (C) recognition of the morpholine amide through hydrogen bonding, and (D) control experiment with DIBAL-H (Teichert, 2025).

 

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8

Conclusion and Outlook

In this review, I have highlighted the diverse reactivity of morpholine amides across a range of transformations. In several cases, these transformations are inaccessible using Weinreb amides, demonstrating the complementary nature of the two classes of acylating agents. Beyond their reactivity, morpholine amides also offer clear advantages in terms of cost, stability, and scalability. Nonetheless, it is my personal impression that the unique features and potential of morpholine amides remain significantly underappreciated compared to Weinreb amides. In particular, since most reported studies have focused on reactions with organometallic reagents under strictly anhydrous conditions, very few examples have explored the use of morpholine amides in transformations that take advantage of their water solubility. I believe that significant opportunities remain for the development of new methodologies that leverage this unique property – especially in the context of catalytic reactions conducted in the presence of water.

I hope that this review will stimulate further exploration and the broader recognition of morpholine amides in synthetic organic chemistry.

 

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Yohei Ogiwara

Yohei Ogiwara received his PhD in 2014 from Keio University under the supervision of Prof. Fumitoshi Kakiuchi. He subsequently served as an Assistant Professor at Tokyo University of Science with Prof. Norio Sakai from 2014 to 2023. In 2023, he joined Tokyo Metropolitan University as a Project Associate Professor with Prof. Kotohiro Nomura. Since 2024, he has been appointed as an Associate Professor and Principal Investigator at Gifu University. He is one of the Thieme Chemistry Journals Awardees 2025. His research interests include the development of novel transition metal–catalyzed molecular transformations.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publikationsverlauf

Eingereicht: 24. Juni 2025

Angenommen nach Revision: 28. Juli 2025

Accepted Manuscript online:
03. August 2025

Artikel online veröffentlicht:
28. August 2025