[57-14-7]  · C2H8N2  · N,N-Dimethylhydrazine  · (MW 60.1)

(useful reagent for the preparation of N,N-dimethylhydrazones;1-8 metalated derivatives are useful for stereoselective alkylations;9-11 useful nucleophile for electrophiles other than aldehydes and ketones;13-15 useful reagent for the formation of functionalized Wittig reagents16)

Physical Data: bp 63 °C; d 0.786 g cm-3.

Solubility: sol polar aprotic and nonpolar solvents.

Form Supplied in: colorless liquid, widely available.

Handling, Storage, and Precautions: highly toxic and is a cancer suspect agent. A well-ventilated fume hood should be used when handling this compound. Adequate skin and eye protection should also be worn.

Formation and Reactions of N,N-Dimethylhydrazones.

Hydrazones are easily prepared from carbonyl compounds and are susceptible to nucleophilic attack at the hydrazone carbon. Several recent examples are illustrative of this approach. For instance, treatment of hydrocinnamaldehyde with N,N-dimethylhydrazine afforded (E)-3-phenylpropanal N,N-dimethylhydrazone in 95% yield as a single isomer (eq 1).1 Subsequent addition of a variety of alkylcerium, alkyllithium, and Grignard reagents afforded the nucleophilic addition products. Treatment of (aR,2S,3S,5S)-1-(1-oxopropyl)-N-methoxy-N,3,5-trimethyl-a-ethyltetrahydro-2-furanacetamide with N,N-dimethylhydrazine afforded the hydrazone (aR,2S,3S,5S)-5-[1-(N,N-dimethylhydrazono)propyl]-N-methoxy-N,3,5-trimethyl-a-ethyltetrahydro-2-furanacetamide in 92% yield (eq 2), which was then used in the construction of the C(10)-C(23) synthon for the natural product ferensimycin B.2 Finally, reaction of Glyoxal with N,N-dimethylhydrazine afforded the monohydrazone, which was then treated with chiral 1,2-diamines to afford the chiral aminals (eq 3).3 Addition of organolithium reagents to these aminals afforded the nucleophilic addition products with high diastereomeric purity.

N,N-Dimethylhydrazones participate in a variety of cyclization reactions. For example, dimethylhydrazones derived from aldehydes and ketones undergo an efficient thermal [2 + 2] cyclization with phenoxyketene to afford b-lactams in good yields (eq 4).4 3,4-Dihydro-6-methoxy-2-(2-methyl-1-oxocyclopent-2-enyl)naphthalene-1-carbaldehyde N,N-dimethylhydrazone undergoes cycloaddition in refluxing bromobenzene to form 10,11-dihydro-2-methoxy-7-methyl-7H-benzo[h]cyclopent[c]isoquinolin-7-ol in 38% yield (eq 5).5 An efficient synthesis of piperidines was achieved through treatment of N,N-dimethylhydrazine with Glutaraldehyde and 2 equiv of benzotriazole (eq 6).6 The intermediate 2,6-bis(benzotriazolyl)piperidine was converted to dimethylaminopiperidine upon treatment with Sodium Borohydride in THF. Finally, the trifluoromethylated dimethylhydrazones derived from aryl aldehydes and N,N-dimethylhydrazine undergo cyclization to 4-trifluoroimidazoles upon refluxing in toluene (eq 7).7 Several other cyclization reactions involving N,N-dimethylhydrazones have been reported.8

Metaloenamines derived from dimethylhydrazones can be alkylated with alkyl halides. For example, treatment of acetone dimethylhydrazone with n-Butyllithium, followed by addition of 1,10-dibromodecane (0.5 equiv), afforded 2,15-hexadecanedione in 66% yield, after hydrolysis of the dihydrazone (eq 8).9 The dimethylhydrazone of 3-methylcyclohexanone was alkylated with 2-(2-bromoethyl)-1,3-dioxolane (BED) to afford two monoalkylated regioisomers (eq 9).10 Subsequent cyclization afforded two isomeric tetrahydroquinolines in an 8:92 ratio and 48% overall yield from 3-methylcyclohexanone. It is noteworthy that metalated Schiff base derivatives of conformationally locked cyclohexanones often display axial alkylation preferences exceeding 98%.11

Aldehydes can be converted to the corresponding nitriles by oxidation of the aldehyde dimethylhydrazones. For example, treatment of 2-naphthaldehyde N,N-dimethylhydrazone with aqueous Hydrogen Peroxide and a catalytic amount of Selenium(IV) Oxide afforded 2-cyanonaphthalene in 95% yield (eq 10).12 m-Chloroperbenzoic Acid could also be used to transform the dimethylhydrazone to the nitrile.

Nucleophilic Attack by N,N-Dimethylhydrazine.

N,N-Dimethylhydrazine is a useful nucleophile for electrophiles other than aldehydes and ketones. 1,4,2-Dithiazolium salts react with N,N-dimethylhydrazine to form two products (eq 11).13 The major 5-imino-1,4,2-dithiazole is formed by nucleophilic displacement of the dimethylamino group by the N,N-dimethylhydrazine. The minor thiourea derivative is formed by spontaneous fragmentation of the dithiazole ring; benzonitrile and sulfur are also produced. Treatment of 2-chloro-9-(4-hydroxy-3-hydroxymethylbutyl)hypoxanthine with N,N-dimethylhydrazine affords a mixture of 2-N-amino-9-(4-hydroxy-3-hydroxymethylbutyl)-2-N-methylguanine (12%) and 9-(4-hydroxy-3-hydroxymethylbutyl)-2-N-dimethylguanine (11% yield; eq 12.14 Treatment of 4,4-disubstituted thiazolidine-2,5-dithiones with N,N-dimethylhydrazine in ethanol affords the 5,5-disubstituted 3-dialkylaminoimidazolidine-2,4-dithiones in 67-98% yields (eq 13).15 Finally, N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine undergoes a nucleophilic aromatic N-N exchange reaction with N,N-dimethylhydrazine to afford N,N-dimethyl-N-[2,4-bis(trifluoroacetyl)-1-naphthyl]hydrazine in quantitative yield (eq 14).16 This product underwent an acid-promoted cyclization to afford the 2H-benz[g]indazole derivative upon refluxing in xylenes.

Formation of Functionalized Wittig Reagents.

Treatment of 1,2-vinylenebis(triphenylphosphonium) bromide with N,N-dimethylhydrazine afforded the functionalized phosphonium salt, along with triphenylphosphine (eq 15).17 The Wittig derivative was obtained by treatment with Potassium t-Butoxide, and addition of a variety of aldehydes and ketones afforded the a,b-unsaturated hydrazones in 8-82% yields.

1. Denmark, S. E.; Edwards, J. P.; Nicaise, O. JOC 1993, 58, 569.
2. Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.; Mathre, D. J. JACS 1991, 113, 7613.
3. Alexakis, A.; Lensen, N.; Mangeney, P. TL 1991, 32, 1171.
4. Sharma, S. D.; Pandhi, S. B. JOC 1990, 55, 2196.
5. Gilchrist, T. L.; Healy, M. A. M. JCS(P1) 1992, 749.
6. Katrizky, A. R.; Fan, W.-Q. JOC 1990, 55, 3205.
7. Kamitori, Y.; Hojo, M.; Masuda, R.; Kawamure, Y.; Fang, X. H 1990, 31, 2103.
8. (a) Nagarajan, K.; Shah, R. K. JIC 1989, 66, 681. (b) Krapcho, A. P.; Avery, K. L., Jr.; Shaw, K. J.; Andrews, J. D. JOC 1990, 55, 4960.
9. Yamashita, M.; Matsumiya, K.; Morimoto, H.; Suemitsu, R. BCJ 1989, 62, 1668.
10. Chelucci, G.; Cossu, S.; Scano, G.; Soccolini, F. H 1990, 31, 1397.
11. (a) Whitesell, J. K.; Whitesell, M. A. S 1983, 517. (b) Wanat, R. A.; Collum, D. B. JACS 1985, 107, 2078.
12. Said, S. B.; Skarzewski, J.; Mlochowski, J. S 1989, 223.
13. Tonemoto, K.; Shibuya, I. BCJ 1988, 61, 4043.
14. Harnden, M. R.; Jarvest, R. L. JCS(P1) 1989, 2207.
15. Yamamoto, T.; Imagawa, M. T.; Yabe, Y. T.; Suwabe, E. M.; Muraoka, M. JCS(P1) 1990, 3003.
16. Hojo, M.; Masuda, R.; Okada, E. S 1990, 481.
17. Cristau, H.-J.; Gasc, M.-B. TL 1990, 31, 341.

Charles H. Winter

Wayne State University, Detroit, MI, USA

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