N,N-Dimethylformamide Diethyl Acetal

(1; R1 = Et, R2 = Me)

[1188-33-6]  · C7H17NO2  · N,N-Dimethylformamide Diethyl Acetal  · (MW 147.25) (2; R1 = Me, R2 = Me)

[4637-24-5]  · C5H13NO2  · N,N-Dimethylformamide Dimethyl Acetal  · (MW 119.19) (3; R1 = PhCH2, R2 = Me)

[2016-04-8]  · C17H21NO2  · N,N-Dimethylformamide Dibenzyl Acetal  · (MW 271.39) (4; R1 = Et, R2 = Et)

[22630-13-3]  · C9H21NO2  · N,N-Diethylformamide Diethyl Acetal  · (MW 175.31)

(mild and selective reagents for alkylation, formylation, and aminomethylenation1)

Alternate Name: DMF diethyl acetal.

Physical Data: (1) bp 134-136 °C/760 mmHg; pKb 6.2.5 (2) bp 102-104 °C/720 mmHg; pKb 6.25.5 (3) bp 138-140 °C/0.5 mmHg; pKb 6.2.5 (4) bp 57-58 °C/20 mmHg; pKb 6.4.5

Solubility: sol a variety of inert solvents.

Form Supplied in: pure liquid.

Preparative Methods: (1) a solution of sodium alkoxide (1 mol) and the secondary amine (1.1 mol) in 200-300 mL of the respective alcohol is refluxed as chloroform (39.5 g, 0.33 mol) is added. The mixture is refluxed for 2 h and the filtrate obtained is distilled in vacuo. For example, N,N-diethylformamide diethyl acetal is obtained in 32% yield.7 (2) A solution of N,N-dialkyl(chloromethylene)ammonium chloride (Vilsmeier reagent, 1 mol) in 640-500 mL of chloroform is stirred while sodium alkoxide (2.1 mol) in 1 L of the respective alcohol is added. After 1 h at 20 °C the sodium chloride is separated and the mixture is distilled in vacuo. For example, the yield of DMF dimethyl acetal is 55%.2

Handling, Storage, and Precautions: most of the known orthoamide derivatives are colorless, distillable liquids with an amine-like smell. If moisture and presence of acids and high temperature are avoided, most of the reagents can be stored almost indefinitely. No significant toxicity has been reported.

Reactions and Synthetic Applications: General.

The formamide acetals enter into two main categories of reactions, namely alkylation and formylation, mostly via generation of aza-oxo-stabilized carbenium ions (eq 1).1-7 As alkylation reagents they have been used in the synthesis of esters from acids, in the synthesis of ethers and thioethers from phenols and aromatic and heterocyclic thiols, and in the alkylation of CH-active methines. As formylating agents, formamide acetals are useful in the synthesis of enamines from active methylene compounds and amidines from amines and amides, as well as in the formation and modification of many types of heterocyclic compounds. They can be used for the dehydrative decarboxylation of b-hydroxy carboxylic acids to alkenes, and for the cyclization of trans vicinal diols to epoxides.1 From the numerous literature reports on applications of these reagents,1-7 some representative reactions are discussed in the following sections.

Alkylation Reactions.

DMF dialkyl acetals undergo a variety of reactions with 1,2-diols.1 For example, the reaction of trans-cyclohexane-1,2-diol with DMF dimethyl acetal leads to the formation of cyclohexane epoxide (eq 2)8 with inversion of configuration. Similarly, meso-1,2-diphenyl-1,2-ethanediol gives trans-stilbene epoxide stereospecifically (eq 3).8,9a This method has also been applied in the synthesis of cholestane epoxide from vicinal diols.8 If the intermediate 2-dimethylamino-1,3-dioxolane is treated with Acetic Anhydride, reductive elimination to the alkene occurs with retention of stereochemistry (eq 4).9b

DMF dimethyl acetal is an effective methylating reagent. For example, heterocyclic thiols are transformed to S-methyl heterocycles in high yields (76-86%).10 DMF dibenzyl acetal is an interesting reagent for selective protection of nucleosides. For example, uridine and guanosine are selectively blocked at the -CONH function (eq 5).11

In a very simple procedure, carboxylic acids can be esterified under mild conditions with DMF dialkyl acetals. Some interesting uses are the conversion of carboxylic acids to ethyl and benzyl esters with DMF diethyl and dibenzyl acetals (yield 64-75%).12 The dibenzyl acetal has been widely used as protecting group reagent for the carboxyl end group in peptides.13 In several cases, DMF bis(4-dodecylbenzyl) acetal has also been used.13,14 Some examples are given in Table 1.

DMF dineopentyl acetal has been used as a reagent for dehydrative decarboxylation in order to avoid the possibility of competing O-alkylation of the carboxyl group.15 This conversion of b-hydroxy carboxylic acids to alkenes by reaction with a DMF acetal involves an anti elimination, and it is thus complementary to the syn elimination of these hydroxy acids via the b-lactone. These reactions have been used to obtain both (E)- and (Z)-1-alkoxy-1,3-butadienes (eq 6).15 For additional examples of alkenes obtained from b-hydroxy acids with DMF acetals, see Scheeren et al.7

Formylation Reactions.

DMF dialkyl acetals exhibit reactivity as a formyl cation synthon by introducing a C1 unit at many nucleophilic centers (e.g. at N, S, O, or CH). For example, DMF dimethyl acetal can be used instead of formic acid for conversion of o-disubstituted aromatic systems into annulated heterocycles (eq 7).16

A nonacidic and regioselective route to Mannich bases from ketones and esters involves reaction with DMF acetals at a high temperature to form enamino ketones which are readily reduced by Lithium Aluminum Hydride to the Mannich bases (eq 8).17

CH-acidic groups (including methyl) react with DMF acetals via carbon-carbon bond formation and subsequent elimination of the respective alkanols to form enamines (aminomethylenation). Thus 2,4,7-trimethyl-1,3-dithia-5,6-diazepine reacts with DMF dialkyl acetals to give mono- or bis-aminomethylenated products depending on the amount of reagent and the reaction conditions (eq 9).18a The same reagents convert the more nucleophilic 2,5-dimethyl-1,3,4-thiadiazolium salts to the monoenamines (eq 10).18a Similarly, 1,2-dimethyl-3-cyano-5-nitroindole condenses with DMF diethyl acetal to give the (E)-indol-2-yl enamine (eq 11).18b

A general indole synthesis involves reaction of an o-nitrotoluene derivative with DMF dimethyl acetal in refluxing DMF (eq 12).19,20 The initially formed o-nitroaryl-substituted (E)-N,N-dimethylenamine is submitted to catalytic hydrogenation to give the indole by spontaneous cyclization. According to a variation of this methodology,20 2-arylindoles are readily available by reaction of o-nitrotoluene with DMF diethyl acetal and o-halobenzoyl chloride. This reaction proceeds via benzoylation of the respective enamine.

4-Dimethylamino-2-azabutadienes are readily accessible by the reaction of azomethines (imines) with DMF diethyl acetal (eq 13).21 1-Dimethylamino-1,3-butadienes can be synthesized in the same manner.21 Reactions of 2-azavinamidinium salts with DMF diethyl acetal give rise to 2-aza- and 2,4-diazapentamethinium salts (eq 14).22

Miscellaneous Reactions.

DMF acetals catalyze rearrangement reactions of allylic alcohols to b,g-unsaturated amides.23 This reaction, which involves a [2,3]-sigmatropic rearrangement, occurs with complete transfer of chirality. Thus the reaction of the (R,Z)-allylic alcohol (eq 15) with DMF dimethyl acetal gives the enantiomerically pure (R,E)-b,g-unsaturated amide as the only product. The (S,E)-isomer also rearranges mainly to the (R,E)-amide, with only a trace of the (S,Z)-isomer. It has been suggested that both rearrangements proceed via a five-membered cyclic transition state with a carbene-like function.23

Enol acetates of oxo nucleosides are readily accessible by reaction of the nucleoside with DMF acetal and then with acetic anhydride (eq 16).24 However, this method is limited to compounds with an oxo group in the 4-position and with a free CO-NH group in the pyrimidine ring. This reaction is the first synthesis of oxo nucleoside enol acetates by direct enolization. Previous methods of enol formation fail with oxo nucleosides because of their instability in alkaline media.

Related Reagents.

t-Butoxybis(dimethylamino)methane; N,N-Dimethylacetamide Dimethyl Acetal; Dimethylchloromethyleneammonium Chloride; N,N-Dimethylpropionamide Dimethyl Acetal; Triethyl Orthoformate; Tris(dimethylamino)methane; Tris(formylamino)methane.

1. Abdulla, R. F.; Brinkmeyer, R. S. T 1979, 35, 1675.
2. Eilingsfeld, H.; Seefelder, M.; Weidinger, H. CB 1963, 96, 2671.
3. DeWolfe, R. H. Carboxylic Ortho Acid Derivatives, Academic: New York 1970.
4. Kantlehner, W. In The Chemistry of Acid Derivatives, Patai, S., Ed.; Wiley: Chichester 1979, Part 1, Suppl. B, p 533.
5. Simchen, G. In Iminium Salts in Organic Chemistry; Böhme, H.; Viehe, H. G., Eds.; Wiley: New York, 1979; p 393.
6. Pindur, U. In The Chemistry of Acid Derivatives, Patai, S. Ed.; Wiley: Chichester, 1992; Vol. 2, Suppl. B, p 1005.
7. Scheeren, J. W.; Nivard, R. J. F. RTC 1969, 88, 289.
8. Neumann, H. C 1969, 23, 267.
9. (a) Harvey, R. G.; Goh, S. H.; Cortez, C. JACS 1975, 97, 3468. (b) Eastwood, W.; Harrington, K. I.; Josan, J. S.; Pura, I. L. TL 1970, 5223.
10. Holý, A. TL 1972, 585.
11. Philips, K. D.; Horwitz, J. P. JOC 1975, 40, 1856.
12. (a) Vorbrüggen, H. AG(E) 1963, 2, 211. (b) Vorbrüggen, H. LA 1974, 821.
13. (a) Brechbühler, H.; Büchi, H.; Hatz, E.; Schreiber, J.; Eschenmoser, A. AG(E) 1963, 2, 212; (b) Büchi, H.; Steen, K.; Eschenmoser, A. AG(E) 1964, 3, 62.
14. Brechbühler, H.; Büchi, H.; Hatz, E.; Schreiber, J., Eschenmoser, A. HCA 1965, 48, 1746.
15. (a) Luengo, J. L.; Koreeda, M. TL 1984, 25, 4881. (b) Koreeda, M.; Luengo, J. L. JOC 1984, 49, 2079.
16. Stanovnik, B.; Tisler, M. S 1974, 120.
17. Schuda, P. F.; Ebner, C. B.; Morgan, T. M. TL 1986, 27, 2567.
18. (a) Kantlehner, W.; Haug, E.; Hagen, H. LA 1982, 298. (b) Krichevski, E. S.; Granik, V. G. KGS 1992, 502.
19. Batcho, A. D.; Leimgruber, W. U.S. Patent 3 976 639, 1973; 3 732 245, 1973.
20. Garcia, E. E.; Fryer, R. I. JHC 1974, 11, 219.
21. Gompper, R.; Heinemann, U. AG(E) 1981, 20, 296.
22. Gompper, R.; Heinemann, U. AG(E) 1981, 20, 297.
23. Yamamoto, H.; Kitatani, K.; Hiyama, T.; Nozaki, H. JACS 1977, 99, 5816.
24. Bessodes, M.; Ollapally, A.; Antonakis, K. CC 1979, 835.

Ulf Pindur

University of Mainz, Germany

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