Chloroacetaldehyde

ClCH2CHO

[107-20-0]  · C2H3ClO  · Chloroacetaldehyde  · (MW 78.50)

(bifunctional electrophile; heterocycle building block;4-10 a-chloro nitrone precursor15)

Alternate Name: 2-chloroethanal.

Physical Data: bp 85-86 °C.

Solubility: sol water and most organic solvents.

Form Supplied in: aqueous solution (45-55%).

Analysis of Reagent Purity: oxime titration.

Preparative Methods: Water-free chloroacetaldehyde can be prepared by periodate oxidation of a-chlorhydrin1 or through pyrolysis (200 °C) of 4-chloro-1,3-dioxolan-2-one.2 Extraction of aqueous solutions of chloroacetaldehyde with organic solvents provides the hemiacetal.3

Handling, Storage, and Precautions: intensely irritating. Highly prone to polymerization, should be used immediately after preparation. This reagent should be used in a fume hood.

Heterocycles.

Chloroacetaldehyde is a building block for many types of heterocycles such as pyrroles,4 furans,5 thiophenes,6 imidazoles,7 thiazolines,8 thiazoles,9 or indoles.10

Wittig Reaction.

Alkoxycarbonylalkylidenephosphoranes react with chloroacetaldehyde in high yield to give g-chlorotiglates. The trans/cis ratio is greater than 0.94 (eq 1).11

a-Cyanoenamines.

a-Cyanoenamines,12 easily prepared from a-chloroacetaldehyde (eq 2), can be used for the synthesis of higher ketones,13 1,2-diketones,13 1,4-diketones,14 and 1,5-diketones.12

a-Chloro Nitrones.

a-Chloroaldehydes are easily converted into the corresponding a-chloro nitrones with various hydroxylamines. (eq 3).15 The lower representatives (R = H, Me) are unstable and should be stored at -20 °C.

The Ag+ mediated reaction of a-chloro nitrones with unactivated alkenes results either in a [4 + 2] cycloaddition (eq 4)15 -19 or, especially in solvents like SO2 or MeNO2, in a substitution (eq 5).16,17 Mono-, 1,2-di-, or tetrasubstituted alkenes predominantly react via cycloaddition, whereas with 1,1-di- or trisubstituted alkenes, substitution becomes the main reaction, thereby giving access to b,g-unsaturated aldehydes. The configuration of the alkene is retained in both cases.

With strong bases, the cycloadducts are converted with potassium t-butoxide into iminolactones which upon hydrolysis furnish g-lactones (eq 6).16,17,19

Treatment of the cyano 1,2-oxazine cycloadducts with Ag+ followed by sodium tetraphenylborate results in the formation of easily crystallizable iminium salts.15 Deprotonation of these salts with weak bases furnish tetrahydro-1,2-oxazines which undergo cycloreversion at slightly elevated temperature to give mono-a,b-unsaturated dialdehydes after hydrolysis (eq 7).20

The cycloaddition-cycloreversion sequence has been used to synthesize indoles from 1,4-dihydro-5-nitronaphthalene.21

Slightly activated benzene derivatives furnish b-arylaldehydes upon treatment with a-chloro nitrones and AgBF4 (eq 8).18 Following the same procedure, p-cresol furnishes benzofurans (eq 9).18 Electrophilic aromatic substitution reactions of chloro nitrones have also been described for furans22 and indoles.23

The Ag+-induced cycloaddition of a-chloro nitrones to alkynes followed by chromatography through deactivated alumina furnishes a,b-unsaturated ketones (eq 10).24

a-Chloro nitrones are alkylated by anions of dialkyl malonates, providing easy access to a-alkoxycarbonyl-b-formyl-carboxylic acid esters (eq 11).25

Related Reagents.

2,3-Dichloropropionaldehyde.


1. Hatch, L. F.; Alexander, H. E. JACS, 1945, 67, 688.
2. Weygand, C.; Hilgetag, G.; Preparative Organic Chemistry, 4th ed.; Martini, A.; Ed.; Wiley: New York, 1973; p 185.
3. Natterer, E. M 1882, 3, 447.
4. Quijano, M. L.; Nogueras, M.; Sanchez, A.; Alvarez de Cienfuegos, G.; Melgarejo, M. JHC 1990, 27, 1079.
5. (a) Bisagni E.; Rivalle, C. BSF 1974, 519. (b) Padwa, A.; Gasdaska, J. R. T 1988, 44, 4147. (c) Matsumoto, M.; Wanatabe, N. H 1984, 22, 2313.
6. (a) Hirota, K.; Shirahashi, M.; Senda, S.; Yogo, M. JHC 1990, 27, 717. (b) Waldvogel, E. HCA 1992, 75, 907.
7 (a) Kluge, A. F. JHC 1978, 15, 119. (b) Senga, K.; Robins, R. K.; O'Brien, D. E. JHC 1975, 12, 1043.
8. (a) Martens, J.; Offermanns, H.; Scherberich, P.; AG 1981, 93, 680. (b) Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 6, p 314.
9. (a) Begtrup, M.; Hansen, L. B. L. ACS 1992, 46, 372. (b) Brandsma, L.; De Jong, R. L. P.; VerKruijsse, H. D. S 1985, 948.
10. Wender, P. A.; White, A. W. T 1983, 39, 3767.
11. Stotter, P. L.; Hill, K. A.; TL 1975, 1679.
12. Ahlbrecht, H.; Dietz, M.; Weber, L. S 1987, 251.
13. (a) Ahlbrecht, H.; Pfaff, K. S 1978, 897. (b) Ghosez, L., Toyé, J. JACS 1975, 97, 2276.
14. Ahlbrecht, H.; Pfaff, K. S 1980, 413.
15. Kempe, U. M.; Das Gupta, T. K.; Blatt, K.; Gygax, P.; Felix, D.; Eschenmoser, A. HCA 1972, 55, 2187.
16. Das Gupta, T. K.; Felix, D.; Kempe, U. M.; Eschenmoser, A. HCA 1972, 55, 2198.
17. Petrzilka, M.; Felix, D.; Eschenmoser, A. HCA 1973, 56, 2950.
18. Shatzmiller, S.; Gygax, P.; Hall, D.; Eschenmoser, A. HCA 1973, 56, 2961.
19. Rüttimann, A.; Ginsburg, D. HCA 1975, 58, 2237.
20. Gygax, P.; Das Gupta, T. K.; Eschenmoser, A. HCA 1972, 55, 2205.
21. Hattingh, W. C.; Holzapfel, C. W.; van Dyk, M. S. SC 1987, 17, 1491.
22. Gerlach, H.; Wetter, H. HCA 1974, 57, 2306.
23. Holzapfel, C. W.; van Dyk, M. S. SC 1987, 17, 1349.
24. Shatzmiller, S.; Eschenmoser, A. HCA 1973, 56, 2975.
25. Lidor, R.; Shatzmiller, S. LA 1982, 226.

Peter Gygax

Givandan-Roure Research, Dübendorf, Switzerland



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