Methyl 3-Nitropropanoate1

(1; X = OMe)

[20497-95-4]  · C4H7NO4  · Methyl 3-Nitropropanoate  · (MW 133.12) (2; X = OH)

[504-88-1]  · C3H5NO4  · 3-Nitropropanoic Acid  · (MW 119.09) (3; X = OEt)

[3590-37-2]  · C5H9NO4  · Ethyl 3-Nitropropanoate  · (MW 147.15) (4; X = Cl)

[51834-15-2]  · C3H4ClNO3  · 3-Nitropropanoyl Chloride  · (MW 137.53)

(nitroaldol additions,2,3 condensation4 reactions, and Michael additions5 involving the NO2-substituted carbon; the a-carbonyl carbon in dilithionitronate enolates of the esters undergoes alkylations,6-9 double alkylations,6,8 and aldol6,8 and Michael additions;6,8 elimination of HNO2 from the products gives a,b-unsaturated esters with substituents in either the b-2,3a,5b or the a-position,8,9 thus making the reagent a synthetic equivalent of acrylate anions with d3 or d2 reactivity;8,10 precursor to nitrile oxide for [3 + 2] cycloadditions;11 3-nitropropanoyl chloride can be used for enolate acylation12-15 and five-membered ring annulation14)

Physical Data: (1) bp 63 °C/0.5 mmHg. (2) mp 65-68 °C. (3) bp 146 °C/760 mmHg. (4) bp 123 °C/10 mmHg.

Solubility: sol most organic solvents.

Preparative Methods: the acid (2) and its esters (1) and (3) are prepared from the corresponding 3-halopropanoic acid derivatives with nitrite. (2) is a commercial product and can be esterified8 and converted to the acid chloride (4)15,18 and anhydride15 by conventional methods.

Handling, Storage, and Precautions: the acid (2) is a natural, toxic metabolite of aspartic acid in plants16 and in fungi.17 The nitropropanoic acid derivatives should be handled with caution, as should all nitro compounds of low molecular weight. They are stable when stored in dark bottles in a refrigerator. Acid chloride (4) should be stored with exclusion of air and moisture.

Reactions of the Esters (1) and (3) at C-3.

Although the 3-nitropropanoate esters readily undergo HNO2 elimination to acrylates, it is possible to carry out typical nitronate transformations such as the Henry reaction and the Michael addition to enones. The resulting chain-elongated b-nitro esters (5) can then be subjected to b-elimination, so that the carbon skeleton of the compound introduced as an electrophile has been elongated by a b-acrylate unit (eq 1).

Alternatively, the original adducts can be converted without loss of the nitrogen functionality; for example, reduction of NO2 to NH2 leads to b-amino acid derivatives. Thus, nitropropanoate esters (1) and (3) have been used for the synthesis of amino sugars, e.g. (6),3b,3c of macrolides such as brefeldin,2b of macrodiolides such as pyrenophorin via the intermediate (7),2a and of bicyclo[3.3.0]octane-2,8-dione (9) (by Michael addition of (3) with cyclopentenone, HNO2 elimination to (8), hydrogenation, and Dieckmann condensation) (eq 2).5b

Reactions of the Esters (1) and (3) at C-2.

Double deprotonation of 3-nitropropanoate esters to nitronate enolates (10) enables alkylation (by alkyl halides and enones) and hydroxyalkylation (by aldehydes and ketones) at the 2-position, to give a-substituted acrylates (11) (eq 3).8,9

The reaction with alkyl iodides and bromides to give monoalkylated products (12) is so efficient that an in situ double alkylation is possible; for instance, a 71% yield of (13) (R1 = Me, R2 = Bn) is obtained.8 Addition to aldehydes to give (14) (R2 = H) gives better yields (50-85%) than addition to ketones (<30%). The products (15) and (16) of HNO2 elimination are formed in high yields when Eiter bases19 are employed. The overall yield for the preparation of (15) (R = CH2CH=CH2) from methyl 3-nitropropanoate (1) and allyl bromide is 64%, and that for the preparation of the hydroxy methylene ester (16) (R = C5H11) from (1) and hexanal is 71%.

Lithium Enolate Acylation and Five-Membered Ring Annulation.

Direct 1:1 acylation of amine-free solutions of ketone lithium enolates by addition to a 3-nitropropanoyl chloride (4) solution in THF (both cooled to temperatures between -78 and -100 °C) gives 5-nitro 1,3-diketones (17) in yields of 40-80% (eq 4). The enolates may be derived from open-chain ketones such as diethyl ketone, or from cyclic ketones with, for instance, six-, seven-, eight-, and twelve-membered rings.12-15

Meerwein acylation of ketones with the anhydride of 3-nitropropanoic acid/BF3 is also feasible.15,20 The products of type (17) undergo nitroaldol cyclization with formation of a hydroxynitrocyclopentanone ring which, depending upon the particular structure and upon the conditions used, may lose HNO2 to give a hydroxycyclopentenone derivative. Examples are the annulation products (18) (mp 155-156 °C) and (19) (mp 68-70 °C) of cyclododecanone and cycloheptanone. The hydroxy enone with a tertiary hydroxy group may rearrange to the isomer with a secondary hydroxy group, e.g. (20) obtained from cyclohexanone. Pure products (as single diastereoisomers, where applicable) can be isolated in yields of 15-90%.14

Related Reagents.

Lithium a-Lithiomethanenitronate; O,O-Dilithio-1-nitropropene; Methyl 4-Nitrobutanoate; Nitroethane; Nitromethane.

1. Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. C 1979, 33, 1.
2. Nitroaldol addition of (2) to aldehydes for generation of allylic alcohol units: (a) Bakuzis, P.; Bakuzis, M. L. F.; Weingartner, T. F. TL 1978, 2371. (b) Kitahara, T.; Mori, K. T 1984, 40, 2935.
3. In carbohydrate synthesis: (a) Just, G.; Potvin, P. CJC 1980, 58, 2173. (b) Brandänge, S.; Lindqvist, B. ACS 1985, B39, 589. (c) Hanessian, S.; Kloss, J. TL 1985, 26, 1261.
4. Mühlstädt, M.; Schulze, B. JPR 1975, 317, 919 (CA 1976, 84, 89 768m); Kienzle, F. HCA 1980, 63, 2364 (CA 1981, 95, 6881w).
5. (a) Sakai, K.; Oida, S.; Ohki, E. CPB 1968, 16, 1048. (b) Duthaler, R. O.; Maienfisch, P. HCA 1984, 67, 856.
6. Seebach, D.; Henning, R.; Lehr, F.; Gonnermann, J. TL 1977, 1161.
7. Mukhopadhyay, T.; Seebach, D. HCA 1982, 65, 385.
8. Seebach, D.; Henning, R.; Mukhopadhyay, T. CB 1982, 115, 1705.
9. Campbell, M. M.; Rabiasz, H. S.; Sainsbury, M.; Searle, P. A. T 1992, 48, 9363.
10. Seebach, D. AG(E) 1979, 18, 239.
11. Madsen, U.; Wong, E. H. F. JMC 1992, 35, 107.
12. Seebach, D.; Hidber, A. C 1983, 37, 449 (CA 1984, 100, 155 854p).
13. Beck, A. K.; Hoekstra, M. S.; Seebach, D. TL 1977, 1187.
14. Seebach, D.; Hoekstra, M. S.; Protschuk, G. AG(E) 1977, 16, 321.
15. Seebach, D.; Weller, T.; Protschuk, G.; Beck, A. K.; Hoekstra, M. S. HCA 1981, 64, 716 (CA 1981, 95, 186 681n).
16. Carter, C. L.; McChesney, W. J. Nature 1949, 164, 575.
17. Turner, W. B. Fungal Metabolites; Academic: New York, 1971; Turner, W. B.; Aldridge, D. C. Fungal Metabolites II; Academic: New York, 1983.
18. Barger, G.; Tutin, F. BJ 1918, 12, 402.
19. Review: Oediger, H.; Möller, F.; Eiter, K. S 1972, 591.
20. At least 2 equiv of the anhydride, i.e. four 3-nitropropanoyl units, are necessary with this method of ketone alkylation: Meerwein, H.; Vossen, D. JPR 1934, 141, 149 (CA 1935, 29, 10616); Hauser, C. R.; Swamer, F. W.; Adams J. T. OR 1954, 8, 59.

Albert K. Beck, Roger E. Marti & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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