1 Introduction
N,
N-Dimethylformamide (DMF) is one of the most commonly used aprotic polar solvents in academic laboratories and the chemical industry due to its excellent thermal stability and superior solvating ability
[1]. In addition to serving as a highly efficient organic solvent, DMF also acts as a catalyst in organic synthesis
[2-4]. More importantly, DMF can also function as a versatile synthon participating in various transformations
[5-9]by providing CH
[10-11], O
[12], CONMe
2 [13], and NMe
2 [14-15]in reactions to synthesize various heterocyclic compounds with practical applications (
Figure 1). In these processes, different sites on DMF are activated, enabling the provision of one or more atoms during the construction of new target molecules.
In 2012, Jiao Ning’s research group
[16]published a comprehensive review that systematically summarized the types of reactions in which early DMF served as a synthon, such as an amine source or carbon source. In recent years, research on organic reactions involving DMF as a reaction precursor has made significant progress. For example, green synthesis strategies have been developed, including metal-free catalysis, electrochemistry, and visible-light-induced methods, which have reduced reaction costs and enhanced sustainability. Moreover, reactions using DMF as a dual synthon have been advanced, enabling the synergistic introduction of non-contiguous atoms and overcoming the limitations of earlier single-functional-group transfer approaches. The rapid development of this research area has made it one of the hotspots in organic chemistry. Based on this, the present review will systematically summarize the latest research advances over the past seven years (2017–2024) on the use of DMF as an amine source, carbon source, hydrogen source, oxygen source, and dual synthon. It is hoped that this review will provide a reference for chemists exploring new functions of DMF and expanding its synthetic applications.
2 Reactions of DMF as a Synthon
2.1 Reactions Using DMF as an Amine Source
As an amine source, DMF can undergo amination reactions with various substrates in organic synthesis, efficiently constructing organic compounds containing N, N-dimethyl groups. It can also react with 2H-azirines via cyclization to synthesize imidazole compounds.
2.1.1 Base-Mediated Amination Reactions
In 2019, Gong’s research group
[17]developed an alkali-mediated amination reaction of aromatic halides (
Scheme 1). In this reaction system, DMF serves as an efficient amino source and enables the functional-group transformation of various electron-deficient substituted aryl halides
1(X = F, Cl, Br, I) with excellent yields. Interestingly, in this reaction, the reactivity of the aromatic halides follows the order I > Br ≈ F > Cl, which differs significantly from the typical reactivity trend observed in conventional aromatic nucleophilic substitution (S
NAr) reactions. Through systematic mechanistic studies, the authors ruled out the possibility of a benzyne addition mechanism and a radical mechanism. Notably, this method also exhibits good regioselectivity in the amination of polyhalogenated aromatics. Furthermore, the reaction system offers advantages such as ease of operation, no need for transition-metal catalysts, and scalability, highlighting its potential for industrial applications.
2.1.2 Metal-Catalyzed Amination Reactions
In 2021, Dai’s research group
[18]reported a copper-catalyzed ortho C—H amination of aniline derivatives
2with DMF, affording the target product
3in moderate to good yields (
Scheme 2). Moreover, this catalytic system exhibits excellent functional-group compatibility, accommodating various heterocyclic scaffolds such as pyridine, benzothiazole, benzothiophene, quinoline, isoquinoline, and quinoxaline. However, when
N,
N-diethylformamide was used instead of DMF as the aminating reagent, the yield of the target product was only 25%; no desired product was formed when
N-methylformamide or
N-ethylformamide was employed. Notably, this method is not only suitable for gram-scale synthesis but can also be applied to late-stage structural modifications of drug molecules, fully demonstrating its potential application value in drug discovery and industrial production.
In 2023, Bao’s research group
[19]first achieved a palladium-catalyzed selective C—H amination of 1-chloromethylnaphthalene
4(
Scheme 3). In this reaction, DMF serves as the source of the dimethylamino group, and the amination occurs exclusively at the C—H bond at the 4-position of 1-chloromethylnaphthalene. The advantages of this method include mild reaction conditions, a green solvent system, a relatively short reaction time, and excellent yields. Notably, water molecules play a crucial role in the in situ generation of the dimethylamine species.
The research group proposed a possible reaction mechanism (
Scheme 4b): First,
N-benzoyl cytosine
6 reacts with the Cu(II) catalyst to form a four-membered chelate complex
8. Simultaneously, a tert-butoxy radical abstracts a proton from DMF to generate an amidyl radical. This radical combines with the chelate complex
8 to form a Cu(III) intermediate
9. Next, the intermediate
9 undergoes reductive elimination to yield carbamate
10. Subsequently, under the action of TBHP, Cu(II) inserts into the C—O bond of carbamate
10, yielding intermediate
11. After intermediate
11 releases carbon dioxide, Cu(III) coordinates with the nitrogen atom in the diamine to form intermediate
12. Finally, intermediate
12 undergoes reductive elimination to afford the target product
7.
2.1.3 Iron-Catalyzed Amination/Cyclization Reactions
In 2024, Zhao’s research group
[21-22]reported a novel iron(II)-catalyzed method for the cyclization of 2,3-diaryl-2
H-azirine
13with DMF to synthesize 1-methyl-4,5-diaryl imidazole compound
14(
Scheme 5a). The reaction involves the cleavage of the C—N single bond in DMF and the C=N double bond in the 2
H-azirine, followed by the formation of new C—N single bonds and C=N double bonds. In mechanistic studies, the authors attempted to replace DMF with
N,
N-dimethylacetamide,
N,
N-dimethylaniline, and
N,
N-dibutylformamide as reaction substrates, but no reaction was observed. Notably, this reaction exhibits a degree of scalability: the 1-methyl-4,5-diaryl-1
H-imidazole can be further derivatized into 1-methyl-2,4,5-triaryl-1
H-imidazole.
The research group proposed a possible reaction mechanism (
Scheme 5b): Initially, in the presence of FeCl
2, 2
H-azirine
13 forms a cationic azirinium complex
15. Simultaneously, DMF decomposes at high temperature to form dimethylamine
16 and releases carbon monoxide. The complex
15 then undergoes nucleophilic attack by dimethylamine
16, forming intermediate
17. Under the action of di-tert-butyl peroxide (DTBP), intermediate
17 is oxidized to form imine intermediate
18. Subsequently, intermediate
18 undergoes intramolecular nucleophilic addition, accompanied by ring-opening, to yield the five-membered ring intermediate
19. Finally, intermediate
19 loses a molecule of hydrogen gas to afford the imidazole product
14, while releasing the catalyst FeCl
2 and completing the catalytic cycle.
2.2 Reactions using DMF as a carbon source
2.2.1 Construct CH, CH2, or CH3 sources
In 2017, Xie’s group
[23]first reported the cyclization reaction of 4-(anilino)-2
H-chromen-2-one
20with DMF under copper catalysis. In this reaction, the
N-methyl group of DMF serves as a C–H source, affording functionalized 6
H-chromeno[4,3-
b]quinolin-6-one
21in yields of 56%–81% (
Scheme 6). Moreover, this method offers advantages such as the use of an inexpensive and readily available metal catalyst, broad substrate scope, and good functional group compatibility.
In the same year, Fan’s group
[24]reported a highly efficient metal-free catalyzed, tert-butyl hydroperoxide-mediated [3+2+1] cycloaddition reaction of amidine
22, ketone
23, and DMF (
Scheme 7a). The reaction proceeds via C(sp
3)-H activation, promoted by Cs
2CO
3at 120 °C, to afford a series of pyrimidine compounds
24in moderate to good yields. This transformation involves the formation of novel C―C/C―N bonds and offers advantages such as the use of an environmentally friendly oxidant, inexpensive and readily available starting materials, and high atom economy.
The authors propose a possible reaction mechanism (
Scheme 7b): Initially, DMF is oxidized by TBHP to yield an imine-type intermediate
25. Subsequently, intermediate
25 undergoes a nucleophilic addition reaction with amidine compound
22, forming intermediate
26. N-protonation of intermediate
26 facilitates cleavage of the C―N bond, and the elimination of one molecule of
N-methylformamide generates iminium cation
27. Next, iminium cation
27 reacts with ketone compound
23, and through addition and dehydration steps, intermediate
28 is formed. Finally, intermediate
28 undergoes oxidation to yield the desired product, pyrimidine compound
24.
In 2018, Li’s research group
[25]reported a highly efficient metal-free catalyzed three-component coupling cyclization reaction involving the reactive methylene compound
29, DMF, and 1,1-dichloro-2-nitroethylene
30, successfully constructing a series of phenolic derivatives
31(
Scheme 8). The reaction proceeds under mild conditions, with yields ranging from 35% to 75%. Notably, in this transformation, DMF not only serves as the reaction solvent but also acts as a key carbon synthon for the benzene ring scaffold, demonstrating its unique dual role.
In 2019, Jiang’s research group26developed an efficient copper-catalyzed cyclization reaction of hydrazine compounds 32with DMF, successfully constructing a series of 1,3,4-oxadiazole compounds 33that have significant application value (Scheme 9a).The reaction conditions are mild, the reaction time is short, and DMF serves as the key carbon-hydrogen (CH) source. However, when the authors attempted to replace DMF with N,N-dimethylacetamide or N,N-dimethylaniline as the carbon source, the yield of the target product was lower. In addition, this catalytic system can be further extended to the synthesis of 1,3,4-oxadiazole-2(3H)‑one compounds, demonstrating good substrate generality and reaction versatility.
The possible mechanism of this reaction is as follows (
Scheme 9b): First, DMF undergoes a single-electron transfer with Cu(II) to generate intermediate
34and Cu(I). Then, under oxidation by persulfate, imine
35is formed. Subsequently, benzoylhydrazine
32undergoes nucleophilic addition to imine
35to yield intermediate
36; intermediate
36is further oxidized to form imine intermediate
37. Intermediate
37undergoes cyclization to afford intermediate
38. Finally, under the action of a proton, intermediate
38eliminates one molecule of CH
3NHCHO to give the desired product, the 1,3,4-oxadiazole compound
33.
In 2019, Wang’s group
[27]reported a method in which DMF/Me
2NH-BH
3 39, serving as a cooperative methylene source, enabled the direct C(sp
3)-H methylenation of 2-arylacetamides
40, yielding 2-arylacrylamides
41 in 30%–89% yield (
Scheme 10a). In this transformation, the formyl group of DMF contributes one carbon atom and one hydrogen atom, while Me
2NH-BH
3provides another crucial hydrogen atom; together, they cooperatively accomplish the introduction of the methylene group.
The research group proposed a possible reaction mechanism (
Scheme 10b): Initially, N,2-diphenylacetamide
40 is deprotonated by
t-BuOK to generate the carbanion
42. Subsequently, a nucleophilic attack occurs at the formyl group of DMF, yielding the intermediate
43. Next, a hydroxyl group is eliminated to form the imine intermediate
44, which is then reduced by Me
2NH-BH
3 40 to afford the
α-dimethylaminomethyl-substituted arylacetamide
45. Finally, an E1cB elimination reaction yields the target product, 2-arylacrylamide
41.
In 2019, Wang’s group
[28]reported a novel rhodium-catalyzed [3+2+1] cycloaddition reaction (
Scheme 11a). This reaction uses 3-methyl-1-phenyl-1
H-pyrazole-5-amine
46, a cyclic 1,3-diketone-2-diazo compound
47, and DMF as the three-component substrates, with the methyl carbon of DMF serving as the CH source for constructing the pyridine ring. Notably, the reaction employs environmentally friendly air as the oxidant and efficiently synthesizes a series of structurally diverse pyrazolo[3,4-
b]pyridine derivatives
48under mild conditions.
The authors propose a possible reaction mechanism (
Scheme 11b): Initially, the diazonium compound
47 coordinates with the Rh(II) center to form the rhodium carbene intermediate
48. Intermediate
49 inserts into the methyl C–H bond of DMF to generate intermediate
50. Subsequently, an
β-N elimination reaction yields intermediate
51. This intermediate then undergoes a Friedel–Crafts–type nucleophilic addition with 3-methyl-1-phenyl-1
H-pyrazol-5-amine
46, forming intermediate
52, which then undergoes intramolecular condensation to yield intermediate
53. Finally, an aromatization-driven oxidation reaction affords the desired product, the pyrazolo[3,4-
b]pyridine derivative
48.
In 2020, Qiao’s research group
[29]developed a highly efficient [4+1] cycloaddition reaction between the 2-hydrazinopyridine compound
54and DMF, successfully constructing the 1,2,4-triazolo[3,4-
a]pyridine derivative
55(Figure S12). This reaction features the following characteristics: (1) DMF serves both as a solvent and as a carbon source; (2) a mild imidazole hydrochloride salt is used as the catalyst; (3) it exhibits excellent substrate generality.
In 2020, Ackermann’s research group
[30]developed an environmentally friendly electrochemical synthesis strategy (
Scheme 13a). Under conditions devoid of oxidants and transition-metal catalysts, DMF serves as a methyl source, undergoing an electrocyclic reaction with 4-(anilino)-2
H-chromen-2-one
56, thereby enabling the efficient synthesis of 6
H-chromeno[4,3-
b]quinolin-6-one derivatives
57. The reaction exhibits excellent yields (up to 92%) and outstanding functional-group compatibility.
The authors propose a possible reaction mechanism (
Scheme 13b): First, the iodine radical generated at the anode attacks substrate
56, forming intermediate
58. After intermediate
58 releases an iodide anion, it is converted into intermediate
59. Meanwhile, the iminium intermediate
60, generated from DMF via anodic oxidation, undergoes electrophilic addition to form intermediate
61. Subsequently, the release of a MeNHCHO molecule yields intermediate
62, which then reacts with NaHSO
3 to afford intermediate
63. Next, intramolecular cyclization occurs to generate the dihydroquinoline intermediate
64. Finally, anodic oxidation and aromatization yield the desired product
57. Simultaneously, protons are reduced at the cathode, releasing hydrogen gas.
In 2020, Wang’s research group
[31]further developed the Me
3N-BH
3/
65/DMF system as a synergistic methyl source, successfully achieving the selective
N-methylation of arylamines
66(
Scheme 14a). By precisely tuning the reaction system (Me
3N-BH
3/d
7-DMF, Me
3N-BD
3/DMF, and Me
3N-BD
3/d
7-DMF), N-CH
2D, N-CHD
2, and N-CD
3groups can be introduced selectively, demonstrating excellent deuterium-labeling efficiency and regioselectivity.
The possible reaction mechanism for this reaction is as follows (
Scheme 14b): Initially, the arylamine
66is deprotonated by NaH to form the nitrogen anion
68, which attacks the formyl group of DMF to generate the intermediate
69. An equilibrium is established between the intermediates
69and
70via intramolecular hydrogen migration. One hydroxyl group in
70is eliminated, yielding the imine
71. Subsequently, reduction of
65by Me
3N-BH
3affords the amine
72. Base-promoted elimination of the dimethylamino anion from
72generates the imine
73. Finally, a second hydride reduction of the intermediate
73affords the desired
N-methylphenylamine
67.
In 2023, Jiang’s research group
[32]reported a palladium-catalyzed acetylation of 2-(
N-aryl)aminopyridine
74(
Scheme 15a). In this reaction, DMF serves as both the carbon source and the solvent, while carbon monoxide acts as the carbonyl source. Mechanistic studies indicate that DMF is superior to DMSO as the methyl source in the reaction. The reaction not only exhibits good functional group tolerance but also maintains high yields even in gram-scale experiments.
The possible reaction mechanism for this reaction is as follows (
Scheme 15b): First, under palladium catalysis, the substrate
74 undergoes N—H bond activation to generate intermediate
76. Subsequently, with the cooperative action of the pyridine group, CO undergoes a coordination-insertion process to form intermediate
77. DMF is oxidized to intermediate
78, which then interacts with intermediate
77 to yield intermediate
79. Intermediate
79 undergoes reductive elimination to produce carbonylated intermediate
80. Intermediate
80 is then oxidized via a single-electron transfer process to form intermediate
81, which ultimately undergoes further transformation to yield the target product
75.
In 2024, Yuan’s research group
[33]reported a highly efficient iron-catalyzed [3+2+1] cycloaddition reaction involving 2-amino benzimidazole
82, acetophenone
83, and DMF (
Scheme 16a). This one-pot cascade reaction was used to synthesize a series of benz[4,5]imidazo[1,2-
a]pyrimidine derivatives
84with distinctive spectral properties.
The research group proposed a possible reaction mechanism (
Scheme 16b): First, DMF is oxidized by (NH
4)
2S
2O
8 to yield imine intermediate
85. Meanwhile, acetophenone tautomerizes to enol
86. Next, intermediate
85 undergoes a nucleophilic addition reaction with enol
86, forming intermediate
87. Subsequently, intermediate
87 eliminates one molecule of
N-methylformamide to generate intermediate
88. Then, intermediate
88 reacts with 2-aminobenzimidazole
82 via addition and dehydration to form intermediate
89. Following this, intermediate
89 undergoes an intramolecular Michael addition to yield intermediate
90. Finally, intermediate
90 undergoes an aromatization reaction to afford the target product
84.
In the same year, Chen’s research group
[34]developed an iron-catalyzed three-component oxidative cascade reaction involving NH
-1,2,3-triazole
91, arylmethyl ketone
92, and DMF, which efficiently constructs
β-(1,2,3-triazolyl) ketone compounds (
Scheme 17a). In this reaction, DMF serves as a key carbon synthon. The study found that by modulating the substituents on the triazole ring, the chemoselectivity of the reaction can be effectively controlled, providing an effective strategy for the diverse synthesis of products.
The authors speculate that the reaction proceeds via two parallel pathways (
Scheme 17b): First, DMF is converted to intermediate
93 under the action of the Fe(III)/K
2S
2O
8 oxidation system. In Path A, intermediate
93 undergoes nucleophilic attack by NH-1,2,3-triazole
91, yielding intermediate
94; intermediate
94 then undergoes a Mannich-like reaction with acetophenone
92, ultimately forming the N2-substituted product. In Path B, intermediate
93 first undergoes nucleophilic addition with acetophenone
92, followed by elimination of one molecule of
N-methylformamide to generate intermediate
95, which can further undergo a Michael addition reaction with NH-1,2,3-triazole
91, ultimately yielding the N2- and N1-disubstituted product.
2.2.2 Construct CN source
In 2019, Cheng’s research group
[35]developed a copper-catalyzed cyanation of
96 C—H bonds in heteroarenes (
Scheme 18a). The reaction employs ammonium iodide/DMF as a safe and efficient composite cyanide source, with ammonium iodide providing the nitrogen atom and DMF supplying the carbon atom. This catalytic system exhibits broad substrate scope and is compatible with various functional groups. Moreover, this method enables the efficient synthesis of a series of cyanated heterocyclic compounds, including 2-cyanoindoles, 2-cyanopyrroles, 1-cyanocarbazoles, and 2-cyano-1-pyridinylbenzene derivatives, among others.
The research group proposed a possible reaction mechanism (
Scheme 18b): First, after Cu(OAc)
2 coordinates with the N atom, the C―H bond at the 2-position of arene
96 cleaves to form intermediate
98. Simultaneously, DMF is oxidized by Cu(OAc)
2 to yield imine intermediate
99. Under the action of O
2, intermediate
99 reacts with NH
3 to form intermediate
100, which releases CN
- via C―N bond cleavage. Subsequently, AcO
- in
98 is replaced by CN
-, generating intermediate
101. Next, intermediate
101 is oxidized by O
2 to yield Cu(III) intermediate
102. Finally, Cu(III) intermediate
102 undergoes reductive elimination to release
97, while Cu(I) is produced, which is then oxidized by O
2 to Cu(II), completing the catalytic cycle.
In 2020, Jiang’s group
[36]achieved the selective functionalization of imidazo[1,2-
a]pyridine
103in a copper-mediated oxidation system (
Scheme 19). The reaction established two transformation pathways: (1) C—H cyanation using ammonium iodide/DMF as a composite cyano source; and (2) C—H formylation using DMF as a formylating agent. Mechanistic studies indicate that the cyanation reaction proceeds via a sequential iodination-cyanation two-step process and exhibits excellent functional group compatibility. Notably, the formylation reaction employs DMF as the formyl source and environmentally friendly O
2 as the oxidant. This strategy also provides an efficient and straightforward synthetic route for the clinical drug saliphen.
In 2021, Bora’s research group
[37]reported a novel Cu(II) salt–catalyzed cyanation of aryl iodides/bromides
104(
Scheme 20a). The reaction employs ammonium cerium(IV) nitrate (CAN) and DMF as a composite cyanide source, with CAN serving both as an oxidant and a nitrogen source, while DMF acts as a carbon source. This strategy enables the synthesis of a series of aryl nitrile derivatives
105in moderate to good yields. This catalytic system represents the first instance of synergistic action between CAN and DMF, offering a new approach to the cyanation of aryl halides.
The possible reaction mechanism for this process is as follows (
Scheme 20b): First, ceric ammonium nitrate reacts with potassium carbonate to form ammonium carbonate, which then thermally decomposes to release NH
3. Under Cu(II) catalysis, ammonia combines with DMF to generate CN
-, while Cu(II) is reduced to Cu(I). Subsequently, aryl iodide
104 undergoes oxidative addition with the Cu(I) catalyst to form intermediate
106. Finally, intermediate
106 yields aryl nitrile
105 via ligand exchange and reductive elimination. The reduced Cu(I) is then reoxidized by Ce(IV) back to Cu(II), completing the catalytic cycle.
2.3 Reactions using DMF as a hydrogen source
In 2018, Bakavoli’s research group
[38]developed a metal-free catalyzed debromination reaction of 5-bromo-2,4-diamino-6-methyl-substituted pyrimidine
107,successfully synthesizing 2,4-diamino-6-methyl-substituted pyrimidine derivative
108(
Scheme 21). The reaction employs triethylamine (Et
3N) as the base and DMF as the solvent, proceeding efficiently under mild conditions. Moreover, this study revealed that the DMF/Et
3N combination can serve as an efficient metal-free reduction system, offering a new perspective for green chemical synthesis.
In 2022, Wang’s group
[39]reported a highly efficient method for the radical hydrotetrafluoromethylation of enamine
109to synthesize
β-CF
3enamine compound
110(
Scheme 22a). In this reaction, PhICF
3Cl is used as the trifluoromethylating reagent and DMF as the hydrogen source; under the action of NaH, the enamine undergoes reductive trifluoromethylation to afford
β-CF
3enamine
110. Subsequently, mediated by trifluoroacetic acid (TFA), further reduction with triethylsilane (Et
3SiH) yields
β-CF
3amine
111. This method not only features mild reaction conditions but also exhibits excellent functional-group compatibility, providing a new route for the synthesis of fluorinated amine compounds.
The research group proposed a possible reaction mechanism (
Scheme 22b): Initially, PhICF
3Cl is reduced by NaH, releasing a trifluoromethyl radical that induces the enamine
109, generating an alkenyl radical
112. At the same time, iodobenzene and hydrogen gas are produced, indicating that NaH acts as a reductant for PhICF
3Cl via an electron-transfer pathway. Subsequently, the intermediate
112 combines with a hydrogen atom from the solvent DMF to yield the hydrotrifluoromethylated enamine product
110. The carbon radical released by DMF will further undergo dimerization, oxidation, hydrolysis, or other processes, thereby forming a mixture of products.
2.4 Reactions using DMF as an oxygen source
In 2022, Tang’s research group
[40]reported a four-component cascade reaction under visible-light irradiation involving vinyl cyclopropane
113,
N-(acyloxy)phthalimide ester
114, DMF, and water (
Scheme 23). Through the processes of radical ring-opening of the vinyl cyclopropane, decarboxylative alkylation, and esterification, this reaction efficiently constructs ester compound
115. In this reaction, DMF serves both as the reaction solvent and as a source of oxygen atoms and CH groups, while the carbonyl oxygen in the product ester originates from water molecules. Moreover, the reaction exhibits good functional-group compatibility under ambient conditions.
2.5 The reaction of DMF as a bis-synthon
As a versatile dual synthon, DMF can collaboratively construct complex structures. The formyl and dimethylamino groups in its molecule can serve as distinct synthetic building blocks participating in reactions. Through a “one-pot, multi-step” cooperative transformation process, this approach not only simplifies operational steps but also enhances the atom economy of the reaction.
2.5.1 Metal-Free Cascade/Cyclization Reactions
In 2018, Chandrasekhar’s group
[41]reported a cesium fluoride–promoted sequential [2+2]/[4+1] cycloaddition reaction involving arylyne
116,thiirane ylide
117, and DMF, thereby establishing a highly efficient new synthetic strategy for benzofuran
118 (
Scheme 24a). This transformation exhibits good functional-group compatibility and broad substrate scope. Notably, the reaction can be successfully applied to the selective functionalization of the natural product estrone and to the synthesis of CYP19 aromatase inhibitors, highlighting the significant value of this reaction system in the construction of drug molecules.
The research group proposed a possible reaction mechanism (
Scheme 24b): Initially, the in situ-generated benzyne
119 from
116 undergoes a [2+2] cycloaddition with DMF to form a four-membered ring intermediate
119. Subsequently, the intermediate
120 undergoes ring-opening to yield compound
121, which then undergoes a [4+1] cycloaddition with the thia ylide
117 to afford the 2,3-dihydrobenzofuran
122. Finally, aromatization yields the benzofuran
118.
In 2022, Huang’s group
[42]reported a three-component cascade reaction involving arylyne
123, the
β-ketosulfonyl fluoride compound
124, and DMF (
Scheme 25). Under potassium fluoride catalysis at 40 ℃ for 6 hours, this reaction successfully constructed a series of structurally diverse sulfonyl coumarin derivatives
125.
In 2019, the Gogoi group
[43]developed a transition-metal-free catalyzed three-component cascade reaction involving arylyne
126, activated olefin
127, and DMF, which efficiently constructs ortho-formyl-substituted allylic aryl ether compounds
128(
Scheme 26). This reaction involves the cleavage of C—O and C—C bonds, as well as the formation of new C—C bonds and double C—O bonds. Moreover, this strategy can be further extended for the one-pot synthesis of 2
H-chromen-2-ol derivatives.
The research group proposed a possible reaction mechanism (
Scheme 27b): First, styrene
129 is oxidized to intermediate
131. In the presence of K
2S
2O
8, intermediate
131 reacts with DMF to form intermediate
132. Simultaneously, DMF decomposes at high temperature into dimethylamine
133 and methylamine
134. Next, intermediate
132 and methylamine
134 undergo condensation to yield the imine intermediate
135. Subsequently, styrene
129 undergoes a [
4 +
2] cycloaddition reaction with intermediate
135, thereby forming intermediate
136. Then, in the presence of KI, intermediate
136 undergoes demethylation to yield intermediate
137. Finally, intermediate
137 undergoes aromatization to afford the product, the 3,5-diphenylpyridine compound
130.
2.5.2 Acid-Catalyzed Reductive Amination Reactions
In 2020, Nguyen’s research group
[45]reported a trifluoromethanesulfonic acid–catalyzed reductive amination reaction between carbonyl compound
138and formamide
139,which successfully synthesized a series of tertiary amine derivatives
140(Figure S28). In this reaction, formamide
139serves both as an amine source and as a reducing agent. Notably, this catalytic system exhibits excellent substrate compatibility: regardless of whether the substituents on carbonyl compound
138are electron-withdrawing or electron-donating groups, they can be efficiently converted into tertiary amine products, with yields unaffected by electronic effects.
2.5.3 Copper-Catalyzed Cyclization Reactions
In 2020, Lin’s research group
[46]developed a copper(I)-catalyzed regioselective cyclization reaction of
β-(2-aminophenyl)-
α,
β-ynones
141with DMF, which efficiently constructs 3-acyl-4-aminoquinolines
142(
Scheme 29a). The reaction is carried out in DMSO solvent under oxidative conditions with oxygen, where DMF serves as a dual synthon, providing both the CH unit and the
N,
N-dimethyl functional group.
The research group proposed a possible reaction mechanism (
Scheme 29b): Initially, in the presence of DMSO and O
2, Cu(I) is oxidized to Cu(II), which then reacts with DMF to form iminium ion
143. Subsequently,
β-(2-aminophenyl)-
α,
β-ynone
141 undergoes nucleophilic addition to iminium ion
143, yielding intermediate
144. Next, intermediate
144 eliminates dimethylamine to form intermediate
145. Following this, intermediate
145 undergoes an aza-Michael addition with dimethylamine, and under the assistance of Cu(I), a 6-endo-dig cyclization occurs, affording intermediate
146. Finally, in the presence of Cu/DMSO/O
2, intermediate
146 is oxidized to yield the desired product, 3-acyl-4-aminoquinoline
142.
3 Conclusion and Outlook
This article provides a systematic review of research progress over the past seven years on DMF as a versatile synthetic building block in organic synthesis, with a focus on its diverse applications as an amine source, carbon source, hydrogen source, oxygen source, and dual synthetic building block. A comprehensive analysis reveals that DMF, as a synthetic building block, offers advantages in flexibility and efficiency, primarily manifested in the following aspects: (1) DMF’s core advantage lies in its molecular structure, which simultaneously contains both a formyl group and a dimethylamino functional group, enabling it to participate in various types of chemical reactions; (2) In reactions, DMF often serves a dual role as both a solvent and a reaction substrate, effectively simplifying the reaction system and enhancing the atom economy of the reaction.
Although DMF has already yielded a series of research achievements as a synthon, we believe there is still room for further exploration and development in this field: (1) There are relatively few reports on the use of DMF as an amine source in cyclization reactions to construct nitrogen-containing heterocycles. In the future, in light of drug synthesis needs, “one-pot” reactions using DMF as the amine source could be designed to directly construct bioactive nitrogen-containing heterocycles from simple starting materials; (2) Few reaction types involve DMF as an oxygen or hydrogen source. In the future, acid-mediated or photo-induced hydrogen transfer mechanisms could be designed to achieve selective hydrogenation of compounds; (3) Research on reaction mechanisms still needs to be deepened. It is recommended to combine density functional theory (DFT) calculations to elucidate the activation pathways of functional groups in DMF, thereby providing theoretical guidance for designing highly selective reactions. With the advancement of science and technology, catalytic systems that utilize DMF as a synthon will have even broader application prospects in important fields such as organic synthesis, drug synthesis, and materials science.
National Natural Science Foundation of China(22201012)
Innovation Capability Support Program of Shaanxi-Young Science and Technology Star Project(2024ZC-KJXX-039)
Support Program for Outstanding Young Talents in Shaanxi Universities (2025QJ-02(inside))
High-level Talents Program of Xi’an International University(XAIU202419)
PDF
