N,N-Dimethylformamide1

[68-12-2]  · C3H7NO  · N,N-Dimethylformamide  · (MW 73.11)

(formylating agent for certain organometallics2-5; used in combination with POCl3 or acid halides to form the reactive Vilsmeier reagent8,9)

Alternate Name: DMF.

Physical Data: mp -61 °C; bp 153 °C; d 0.944 g cm-3; fp 57 °C.

Solubility: miscible with water and most organic solvents.

Form Supplied in: clear liquid; both d7 and 13C forms are available commercially; widely available.

Purification: decomposes slightly at its normal boiling point to give small quantities of of dimethylamine and carbon monoxide. The decomposition is catalyzed by acidic or basic materials so that even at rt DMF is appreciably decomposed if allowed to stand for several hours with solid KOH, NaOH, or CaH2. Drying agents suitable for DMF are CaSO4, MgSO4, silica gel, and 4Å molecular sieves. After drying, distillation under reduced pressure will give reasonably dry DMF adequate for most laboratory purposes. Anhydrous DMF can be prepared by using certain desiccants.1b

Handling, Storage, and Precautions: anhydrous DMF should be stored under a nitrogen atmosphere in sure seal bottles or metallic cylinders; vapors are harmful, irritating to skin, eyes, and mucous membranes; it is suspected to be a carcinogen; use in a fume hood.

Reaction with Organometallics.

DMF is a good formylating agent for certain organometallic compounds. Even though formylation of some alkyllithium or Grignard reagents with DMF does not always give good yields of products due to side reactions,1 sonication of a mixture of alkyl or aryl halide, lithium, and DMF substantially increases the rate of organometallic formation and yield of the formylated product.2 Allenyl and vinyl organolithiums undergo formylation with DMF to produce good yields of unsaturated aldehydes.3 DMF can be added to the dianion of cyclohexanone oxime to give an isoxazole in good yield (eq 1).4 Many organometallic compounds have been formylated on reaction with DMF.5

Alkali metal reduction of arylalkenes in the presence of DMF results in a-hydroxy amides in high yield (eq 2).6 Through a novel three-component alkene formation involving DMF, an organolithium reagent, and a Wittig reagent, alkenes can be synthesized in high yield (eq 3).7

Vilsmeier Reaction.

A Vilsmeier reagent is generated when DMF is treated with Phosphorus Oxychloride or other acid chlorides; this reagent has found extensive use as a formylating, halogenating, and dehydroxylating agent (see also Dimethylchloromethyleneammonium Chloride).8

Formylation.

Formylation can be achieved using the Vilsmeier reagent generated by treating DMF with an acid chloride. Indoles substituted at C-3 react with DMF-POCl3 at 100 °C to give 2-formylindoles (eq 4).9a Similarly, 1,2-dihydropyridines9b-d and 1,4-dihydropyridines9d have been regioselectively formylated using DMF-POCl3.

Alcohols undergo O-formylation when treated with DMF and benzoyl chloride, providing good yields of formates (eq 5).10

A similar transformation can be achieved by treating an amine with Chlorotrimethylsilane and Imidazole in DMF.11 In contrast, primary amines form the formamidine on treatment with DMF-POCl3 (eq 6).12 Phthalimides undergo a one-pot deprotection and N-formylation on reaction with DMF and hydrazine.13

Reaction with Alcohols.

Alkyl halides can be easily synthesized on reaction of an alcohol with DMF and Phosgene.14 In an analogous manner, 1-triptycyl carbinols undergo a deoxygenative rearrangement and halogenation on treatment with Thionyl Chloride-DMF.15

Reaction with Enolizable Ketones.

Both acyclic and cyclic enolizable ketones react with DMF-POCl3 to form the b-chloro-a,b-unsaturated aldehydes. The regioselectivity of this reaction in substituted cyclohexanones is dependent on steric effects (eq 7).16

Several unsaturated alkenones have been converted to chlorobenzene mono-, di-, and tricarbaldehydes.8 An illustrative example is the conversion of 2-hexen-4-one to 5-methyl-4-chloro-1,3-benzenedicarbaldehyde using DMF-POCl3 (eq 8).17

Benzofurans result on reaction of a-phenoxyacetophenones with DMF-POCl3 (eq 9).18

Tetrahydro-4H-thiopyran-1-one and tetrahydro-4H-pyran-4-one are converted to the respective chlorovinyl aldehydes on treatment with DMF-POCl3 at ambient temperature.19 Thiachroman-4-one affords the b-chlorovinyl aldehyde on treatment with DMF-POCl3 below 50 °C, but at 100 °C 3-formylthiachromone is formed in modest yield (eq 10).19

Certain ketones can be converted to chloroalkenes on reaction with the Vilsmeier reagent. 3-Halo-2-cyclopenten-1-one has been prepared in excellent yield by reaction of cyclopentene-1,3-dione with DMF and Oxalyl Chloride or Oxalyl Bromide.20 In contrast, cyclohexane-1,3-diones afford cross-conjugated dialdehydes on treatment with DMF-POCl3 (eq 11).21

In a similar manner, 2,3-dihydro-4-pyridones have been converted to 4-chloro-1,2-dihydropyridines on treatment with DMF-POCl3 (eq 12).22

Reaction with Amides.

Quinoline-3-carbaldehydes can be prepared by reaction of acylanilides with DMF-POCl3 (eq 13).23

In an analogous manner, dihydroisoquinolin-3-ones can be treated with DMF-POCl3 followed by oxidation to give 3-chloro-4-formylisoquinolines.24 Pyridines and related systems can be prepared using the reaction of the DMF-acid chloride adduct with carboxamides.8

Reaction with Acids.

The adduct generated from DMF and oxalyl chloride easily converts a carboxylic acid to its acid chloride.25 The same adduct in combination with a hydride reagent can be used to reduce acids to aldehydes.26 DMF and SOCl2 convert a carboxylic acid to an acyl azide in the presence of Sodium Azide, pyridine, and tetrabutylammonium chloride as a catalyst.27 Using the dehydrating ability of the DMF-SOCl2 adduct, b-lactams can be synthesized from an imine and a carboxylic acid in the presence of Triethylamine (eq 14).27 Generally a mixture of cis- and trans-azetidinones is formed.

1,4-Dihydrobenzoic acids react with DMF-POCl3 to give benzene mono-, di-, and tricarbaldehydes. This procedure also affords naphthalenedicarbaldehyde (eq 15).28

Reaction with Esters and Lactonic Carbonyl Groups.

Esters are normally inert to DMF-POCl3 in the presence of other reactive groups.29 The reaction of coumarone and DMF-POCl3 gives a mixture of products.30 1,3-Oxazin-6-ones can be obtained by reaction of isoxazolin-5-ones with DMF-POCl3 (eq 16).31

In contrast, 3-phenyl-5-isoxazolinone reacts with DMF-POCl3 to give different products depending on conditions (eq 17).32

Miscellaneous Reactions.

DMF reacts with a-bromopropionamides in presence of Sodium Hydride or Silver(I) Oxide to form oxazolidinones, where the carbonyl group of DMF becomes incorporated (eq 18).33

Formylation of secondary amines can be achieved on reaction with DMF and 2,3-dihydro-1,4-phthalazinedione.34 The combination of DMF and SOCl2 can dehydrate oximes to nitriles.27 Trifluoromethylsulfonylalkynes react with DMF to form enamides.35 N,N-Bis(trimethylsilyl)enamines give azabutadienes on reaction with Sodium Methoxide in DMF.36 a,a-Dichlorination of ketones can be achieved with Chlorine using DMF as solvent or as catalyst at 80-100 °C.37 Reaction of an a-bromo ketone with Lithium Bromide and Lithium Carbonate in DMF at 140 °C results in a cyclic ether (eq 19).38

Related Reagents.

Acetic Formic Anhydride; Dimethylbromomethyleneammonium Bromide; Dimethylchloromethyleneammonium Chloride; Formyl Chloride; N-Formylpiperidine; N-Methylformanilide; Methyl Formate; N-Methyl-N-phenyl(chloromethylene)ammonium Phosphorochloridate; N-Methyl-N-(2-pyridyl)formamide.


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Daniel L. Comins & Sajan P. Joseph

North Carolina State University, Raleigh, NC, USA



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