Methyl 4-Nitrobutanoate1

(1; X = OMe)

[13013-02-0]  · C5H9NO4  · Methyl 4-Nitrobutanoate  · (MW 147.15) (2; X = OH)

[16488-43-0]  · C4H7NO4  · 4-Nitrobutanoic Acid  · (MW 133.12) (3; X = OEt)

[2832-16-8]  · C6H11NO4  · Ethyl 4-Nitrobutanoate  · (MW 161.18) (4; X = Cl)

[75938-95-3]  · C4H6ClNO3  · 4-Nitrobutanoyl Chloride  · (MW 151.56)

(bifunctional C4 synthetic building blocks with d4 reactivity; preparation of functionalized carbo-2,3 and heterocyclic4 compounds; undergoes nitroaldol,5 Michael addition, and ketone acylation reactions6; the a-NO2 position has also been acylated;7 the mononitrile oxide can be trapped by alkene and alkyne groups to give isoxazoline and isoxazole derivatives8,9)

Physical Data: (1) bp 106-110 °C/9 mmHg. (2) bp 120 °C/0.04 mmHg. (3) bp 97-98 °C/1 mmHg. (4) bp 70 °C/0.03 mmHg.

Solubility: sol most common organic solvents.

Form Supplied in: the methyl ester (1) is commercially available.

Preparative Methods: the esters (1) and (3) are prepared by Michael addition of Nitromethane to the corresponding acrylates10 (higher primary and secondary nitroalkanes can be added likewise); (2) is obtained by acid-catalyzed hydrolysis of the ester; the acid chloride (4) is prepared from the acid (2) and Thionyl Chloride.6

Handling, Storage, and Precautions: as for the 3-nitropropanoic acid derivatives (see Methyl 3-Nitropropanoate).

Ring Forming Reactions of 4-Nitrobutanoic Acid Derivatives.

The nucleophilic reactivity of the a-NO2 position in the esters (1) and (3) or the electrophilicity of the acid chloride carbonyl group in (4) may be used to form the first bond of a new ring. In the second step, an intramolecular acylation or Henry reaction leads to ring formation.

Thus a Mannich-type variation of the nitroaldol addition of (3) to aromatic aldehydes produces a trans-substituted aryl-nitro-valerolactam, the nitro group of which can be reduced to give the lactam (5), a 4,5-diamino acid derivative (eq 1).4

Michael addition of the ethyl ester (3) to enones to afford (6) and Dieckmann condensation produces nitro diketones (7) with a bicyclo[4.3.0]nonane, -[4.4.0]decane, or -[5.4.0]undecane skeleton in ca. 20% overall yield (eq 2).3

Ketone lithium enolate acylation with the acid chloride (4) under conditions as specified in the article Methyl 3-Nitropropanoate furnishes 6-nitro 1,3-diketones (8), as demonstrated with numerous examples (yields 40-85%).6,11 Those products of type (8) containing no ring or a six- or a twelve-membered ring, but not the cyclopentanone, -heptanone, and -octanone derivatives, undergo cyclization (NaHCO3)/THF/H2O) to give hydroxy-nitro ketones such as (9) and (10).2 The 8-methyl-substituted decalin (9), isolated as a single diastereoisomer in 50% yield, reacts with Methyltitanium Triisopropoxide to give the nitrodiol (11) containing five stereogenic centers also as a single diastereoisomer.12,13 Acetalization and Raney Nickel catalyzed hydrogenation of the nitro group of (9) (R = H) lead to the amino alcohol (12) (77% overall), the oxalate salt of which undergoes Tieffeneau-Demjanov rearrangement upon treatment with NaNO2/H2O; after acetal cleavage, the trans-fused bicyclic diketone (13) is isolated in 80% yield.

The 1,2-, 1,4-, and 1,6-distances between functional groups in the products (5)-(13) show that 4-nitrobutanoic acid is a reagent with reactivity umpolung (d1),14 which is itself prepared by a reaction involving reactivity umpolung (d1 reactivity when nitromethane is added to acrylate).

1. Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. C 1979, 33, 1.
2. Weller, T.; Seebach, D; Davis, R. E.; Laird, B. B. HCA 1981, 64, 736 (CA 1981, 95, 219 793f).
3. Schank, K.; Lorig, W. LA 1983, 112 (CA 1983, 98, 106 853u).
4. Mühlstädt, M.; Schulze, B. JPR 1975, 317, 919 (CA 1976, 84, 89 768m). Bhagwatheeswaran, H.; Gaur, S. P.; Jain, P. C. S 1976, 615.
5. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. JOC 1989, 54, 1233. Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama, K. T 1990, 46, 7483.
6. Seebach, D.; Weller, T.; Protschuk, G.; Beck, A. K.; Hoekstra, M. S. HCA 1981, 64, 716 (CA 1981, 95, 186 681n).
7. Ono, N.; Fujii, M.; Kaji, A. S 1987, 532.
8. Kawakami, H.; Hirokawa, S.; Asaoka, M.; Takei, H. CL 1987, 85. Padwa, A.; Dean, D. C. JOC 1990, 55, 405. Madsen, U.; Wong, E. H. F. JMC 1992, 35, 107.
9. Reactions not involving C-C bond formation such as (a) CH2NO2 -> CHO, (b) CH2NO2 -> CH=NOH, (c) CH2NO2 -> CN, and (d) CH2NO2 -> CSNHOH can only be alluded to here: (a) Simoneau, B.; Brassard, P. T 1988, 44, 1015. (b) Kende, A. S.; Mendoza, J. S. TL 1991, 32, 1699. (c) Wehrli, P. A.; Schaer, P. JOC 1977, 42, 3956. (d) Hwu, J. R.; Tsay, S.-C. T 1990, 46, 7413.
10. Colonge, J.; Pouchol, J. M. BSF 1962, 596 (CA 1962, 57, 4534a). Chasar, D. W. S 1982, 841. Bergbreiter, D. E.; Lalonde, J. J. JOC 1987, 52, 1601. Padeken, H. G.; Schickh, O. von; Segnitz, A. In MOC 1971, 10/1, 182.
11. The same nitro diketones (8) can also be prepared by Michael addition of doubly deprotonated 1,3-diketones to nitroethylene: Ehrig, V.; Seebach, D. CB 1975, 108, 1961 (CA 1975, 83, 96 645b).
12. Weidmann, B.; Maycock, C. D.; Seebach, D. HCA 1981, 64, 1552 (CA 1982, 96, 5735k). Seebach, D.; Weidmann, B.; Widler, D. In Modern Synthetic Methods 1983, Scheffold, R., Ed.; Wiley: New York, 1983; Vol. 3, pp 217.
13. Since the enantiomeric Li enolates of 4-methylcyclohexanone can now be generated selectively (review: Koga, K. In Organic Synthesis in Japan: Past, Present, and Future, Noyori, R., Ed.; Tokyo Kagaku Dozin: Tokyo, 1992; p 195), the corresponding products (9) and (11) become available in enantiomerically pure form.
14. Seebach, D. AG(E) 1979, 18, 239.

Albert K. Beck, Robert Dahinden & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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