[[[(Dimethylamino)methylene]amino]methylene]dimethylammonium Chloride1

[20353-93-9]  · C6H14ClN3  · [[[(Dimethylamino)methylene]amino]methylene]dimethylammonium Chloride  · (MW 163.65)

(b-dimethylaminomethylenating agent for ketones and amines;2 yields enamino derivatives of esters and lactones;3 converts Grignard reagents to aldehydes4)

Alternate Name: Gold's reagent.

Physical Data: mp 100-102 °C.

Solubility: sol water, chloroform; insol nonpolar organic solvents.

Form Supplied in: tan to dark brown solid; commercially available.

Preparative Methods: 5 a 1 L, one-necked, round-bottomed flask is equipped with a Claisen adapter, mechanical stirrer, reflux condenser, and mineral oil bubbler. The flask is charged with cyanuric chloride (73.8 g, 0.4 mol) (Caution: cyanuric chloride is a lachrymator and causes burns on contact with the skin), N,N-Dimethylformamide (175.4 g, 2.4 mol) and 1,4-dioxane (100 mL). The resulting solution is stirred and heated at 85 °C for 2-3 h while a considerable amount of carbon dioxide is evolved. When gas evolution is minimal, the reaction mixture is allowed to cool to room temperature; the product rapidly solidifies (eq 1). The flask which contains the solid product is connected to an isopropyl alcohol/dry ice trap and the solvent is removed by evacuating the system to approximately 0.05 mmHg. The crude product weighs 186-187 g (95% yield). Another method of isolating the product is by rapid filtration and washing with acetone.

Analysis of Reagent Purity: 1H NMR (CDCl3) d 3.27 (s, 6H, two CH3), 3.43 (s, 6H, two CH3), 9.57 (s, 2H, -CH=N).

Handling, Storage, and Precautions: Gold's reagent is very hygroscopic and should be handled under a moisture-free environment. If kept dry, it has a substantial shelf-life. Store in desiccator over anhydrous calcium sulfate.

Reaction with Mononucleophiles.

Gold's reagent (GR) is a general b-dimethylaminomethylenating agent which reacts successfully with anions derived from ketones (eq 2)2 to produce enaminones, and with amides (eq 3)2 to produce acylamidines. The stoichiometry of the reactions involves using 1 equiv of Gold's reagent and 1 equiv of base which was prepared by a reaction of the appropriate alcohol with sodium metal.

Gold's reagent also reacts with amines (eq 4)2 to produce amidines. This reaction has been utilized in the preparation of a chiral formamidine from L-valinol t-butyl ether. Reports of the use of this chiral auxiliary in the asymmetric syntheses of indole,6,7 isoquinoline,8-10 and pyrrolidine11 alkaloids have appeared.

The reaction with anions derived from unsymmetrical ketones (eq 5)12 proceeds with complete regioselectivity to produce the least substituted enaminone. Use of other similar reagents result in mixtures.13

The reaction with anions derived from esters (eq 6) and lactones (eq 7)3 also result in b-dimethylaminomethylenation. These reactions are interesting in that enamino lactones can be converted to a-methylene lactones.14,15

Reaction of Gold's reagent with the anion of o,p-nitrotoluenes (eq 8)3 results in the formation of phenyl enamines. It has been shown that o-nitrophenyl enamines can be converted to indoles.16

Other effective b-dimethylaminomethylenating agents include the formamide acetals,17 some of which are also commercially available. They are, however, expensive, moisture and heat sensitive, and require potent, mutagenic alkylating agents for their preparation. Under some circumstances they also necessitate high reaction temperatures and long reaction times. Alternatively, Gold's reagent is prepared in a single step, and in nearly quantitative yield, without purification, from inexpensive raw materials. The reaction of Gold's reagent with an amine or other substrate can be carried out at relatively low temperatures (65-90 °C) and moderate reaction times (12-24 h).

Reaction with Grignard Reagents.

The reaction of Gold's reagent with Grignard reagents (eq 9)4 produced one-carbon homologated aldehydes upon acid hydrolysis of the intermediates. This is general for aromatic, benzylic, and aliphatic Grignard reagents. This is an advantage over a method using 2-oxazolines,18 which only works for aromatic and benzylic Grignard reagents. Another reagent used in formylating Grignard reagents is N-Methyl-N-(2-pyridyl)formamide,19 which was developed by Meyers. This reagent, however, is somewhat expensive and is prepared in two steps in 80% overall yield and usually involves recovery of a byproduct.

Reaction with Dinucleophiles.

The reaction of Gold's reagent with 1,2- and 1,3-dinucleophiles incorporates a CH=N-CH unit into a ring. Upon reaction with Phenylhydrazine (eq 10) and Guanidine (eq 11),20 the corresponding triazole and triazine are produced. The mechanism can be viewed as the two nucleophilic sites displacing the two dimethylamino groups. In the reaction with 2-(cyanomethyl)pyrrole (eq 12),21 a 6-azaindolizine is formed. An alternative mechanism for cyclization was postulated involving a [1,5]-sigmatropic hydrogen shift followed by a 6p-electrocyclic ring closure.

Gold's reagent also reacts with 1,4- and 1,5-dinucleophiles. In the reaction with o-aminophenols (eq 13) and o-hydroxyacetophenones (eq 14),22 it serves as a one-atom linchpin to form the corresponding oxazoles and pyranones. Gold's reagent reacts initially to form a b-dimethylaminomethylene derivative, which undergoes intramolecular cyclization to form the fused ring. In the case of anthranilic acid (eq 15),23 Gold's reagent serves as a two-atom linchpin. The resulting azalactone reacts with N,N-dimethylformamidine, which is produced in the initial reaction with Gold's reagent. The final product is a quinazolinone.

There are other reagents such as DMF acetals24 and Dimethylchloromethyleneammonium Chloride25 which (in some cases) accomplish similar functions. Gold's reagent has some distinct advantages over these compounds. It is a well defined, stable, and preformed salt which reacts cleanly with a variety of nucleophiles under basic conditions with significant regioselective control. It is also an efficient, economical and clean alternative to analogous reagents.

Related Reagents.

t-Butoxybis(dimethylamino)methane; N,N-Dimethylformamide Diethyl Acetal; N-Formylpiperidine; N-Methylformanilide.


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24. Jutz, C. In Advances in Organic Chemistry: Methods and Results; Böhme, H.; Viehe, H. G., Eds.; Wiley: New York, 1976; Vol. 9, Part 1, pp 225-342.
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John T. Gupton & Scott A. Petrich

University of Central Florida, Orlando, FL, USA



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