Nitroethane

EtNO2

[79-24-3]  · C2H5NO2  · Nitroethane  · (MW 75.08)

(building block in synthesis; polar solvent)

Physical Data: mp -90 °C; bp 115 °C; d 1.04 g cm-3; pKa 8.5.

Solubility: completely misc most organic solvents; slightly sol water; sol alkaline solution.

Form Supplied in: colorless liquid, widely available; contains 2-nitropropane as the chief contaminant.

Purification: by drying over MgSO4 and distillation at reduced pressure; a small acidic forerun is discarded.

Handling, Storage, and Precautions: stable compound. Flammable; toxic.

Introduction.

The reactions of nitroethane discussed here can, in principle, be applied to most primary nitroalkanes. Nitroethane reacts with metal alkoxides and hydroxides to form metal nitronates which are often applied as in situ generated reagents. They are unstable and it is advisable not to isolate them.

The Nitroaldol Reaction (Henry Reaction).1,2

Reactions with Aldehydes.

In the presence of base, nitroethane reacts with aliphatic aldehydes in an aldol-type reaction with formation of 2-nitro alcohols (nitroaldols). Due to its reversibility, the reaction is normally carried out in the presence of only catalytic quantities of base. The reaction of nitroethane with an aldehyde in the presence of one equivalent of base gives the salt of the aci-nitro tautomer of the product, which must be carefully acidified to avoid the Nef reaction. Alkali metal hydroxides, alkoxides, or carbonates and tertiary amines have been applied as catalysts.2a Elimination of water, the aldol reaction, and the Cannizzaro reaction are competing side reactions.2a,b 2-Nitro alcohols are unstable compounds and care has to be exercised during workup (decomposition during distillation). Higher yields are often obtained when the reaction is catalyzed in heterogeneous systems with catalysts such as powdered NaOH,3 Al2O3,4 and Al2O3-supported KF.5 The 2-nitro alcohols are readily converted into a variety of functionalities (eq 1).1b,4-10,13-17

Aromatic aldehydes react with nitroethane under the same conditions.11 Elimination of water to give b-nitrostyrenes takes place on acidification.2a Synthesis of b-nitrostyrenes can be accomplished in one step by heating aromatic aldehydes in acetic acid with NH4OAc as catalyst.12 In the presence of NaOAc in refluxing acetic acid, aldehydes are converted into nitriles (eq 2).12b

Dehydration of 2-nitro alcohols to nitroalkenes has been accomplished with Methanesulfonyl Chloride,13, phthalic anhydride,14 1,3-Dicyclohexylcarbodiimide,15 pivaloyl chloride,16 Trifluoroacetic Anhydride,17 and Acetic Anhydride.17 Heating 2-nitro alcohols in dichloromethane in the presence of basic aluminium oxide is another mild method for the synthesis of nitroalkenes.18 Nitroalkenes can be converted into a variety of functionalities (eq 3),2,19a,21-26 and have found utility as heterodienes in hetero Diels-Alder reactions and as reactants in Lewis acid promoted tandem [4 + 2]/[3 + 2] cycloadditions (eq 4).20

Nitroethane can be silylated to form stable trimethylsilyl or t-butyldimethylsilyl nitronates.27 In the presence of a catalytic amount of Tetra-n-butylammonium Fluoride at -78 °C in THF, the silyl nitronates react with aldehydes to give 2-nitro alcohol O-silyl ethers in high yields.6b,28 The TBDMS nitronate reacts in the presence of freshly dried Bu4NF to give the erythro-isomer of the product in >95% de (eq 5).

The dilithium salt of nitroethane is formed by treatment of nitroethane with 2 mol equiv of n-Butyllithium in THF/HMPA at -90 °C.28,29 It reacts with aldehydes at -70 to -60 °C to form the doubly deprotonated nitro alcohols which must be carefully acidified at -90 °C with acetic acid. The dilithium salt is a much harder carbon nucleophile than the sodium nitronate and the reaction with carbonyl compounds is irreversible; this often leads to higher yields of 2-nitro alcohols than the conventional Henry reaction. The reaction proceeds diastereoselectively to give the threo and erythro isomers in a ratio of characteristically 3-5:1 (eq 6).28

Diastereomeric mixtures of nitro alcohols derived from nitroethane can be transformed to the threo-isomer, predominantly, by double deprotonation and protonation or to the erythro-isomer by double deprotonation, silylation with t-Butyldimethylchlorosilane, protonation, and desilylation (eq 7).28

Nitroethane can react with two mol equiv of formaldehyde.2a With acetaldehyde and higher analogs, the reaction with a second molecule is difficult.2b,d

Dialdehydes derived from periodate cleavage of a sugar react with nitroethane in an one-pot cyclization reaction to give predominantly one stereoisomer (eq 8).30

meso-1,5-Dialdehydes react with nitroethane in methanol in the presence of a catalytic amount of NaOH to give a crude mixture of 2,6-dihydroxynitrocyclohexanes from which the major trans,trans-isomer precipitates (eq 9).31 The diacetate of 2,6-dihydroxy-1-methyl-1-nitrocyclohexane formed by this reaction can be saponified enantioselectively with pig liver esterase (PLE) to give the monoacetate of >95% ee (eq 9).31

In the presence of primary or secondary amines, aldehydes react with nitroethane in a Mannich-type reaction.2d

Reactions with Ketones.

The reaction is complex and depends on the ratio of reactants, base, temperature, and time (eq 10).2a

With alkali metal hydroxides or alkoxides, quaternary ammonium hydroxides, or primary or tertiary amines, low yields (10-30%) of nitro alcohols are normally obtained.2a,b Nitroethane reacts with methylcyclohexanones under pressure with TBAF as catalyst to give nitro alcohols in 41-87% yields.32 With N,N-dimethylethylenediamine as base, it is possible to selectively synthesize allylic nitro compounds in moderate to high yields from both acyclic and alicyclic ketones (eq 11).33 The doubly deprotonated forms of primary nitroalkanes give (with nitromethane as an exception) higher yields of 2-nitro alcohols in the reaction with ketones.34

Michael Reactions.

Conjugate addition of nitroethane to activated double bonds is an important C-C bond forming reaction (eq 12).

Michael additions with nitroethane are catalyzed in homogeneous solution with catalysts such as alkali metal hydroxides in alcohol,35 organic nitrogen bases,36 fluoride ion,37 and sodium hydride.8 The reaction is also catalyzed in heterogeneous systems with alumina38 and Al2O3-supported KF or CsF.39 When combined with the Nef reaction,1a,9 synthetically useful 1,4-dicarbonyl compounds can be synthesized. Nitroethane reacts with 2 mol equiv of Michael acceptors to give a variety of coupling products (eq 13).37

Acylation of Nitroethane.

With few exceptions, acylation of sodium ethanenitronate with acyl halides or anhydrides occurs on oxygen. The unstable products rearrange into hydroxamic acid derivatives.40 C-Acylation can be accomplished with acylimidazoles41 and acyl cyanide (eq 14).42 Carboxylation can be accomplished by reaction with methoxymagnesium methyl carbonate (Stiles reagent).43

The dilithium salts of nitroethane and higher primary nitroalkanes react with carboxylic esters, anhydrides, and dialkyl carbonates to form b-oxo nitronates or b-carboxy nitronates, which must be carefully acidified at -90 °C to avoid Nef reaction with acetic acid.34

Alkylation of Nitroethane.

The ambident ethanenitronate ion reacts with alkyl iodides to give a mixture of C-alkylated and, primarily, O-alkylated compounds. The alkyl nitronates of nitroethane are unstable and decompose to carbonyl compounds and acetaldoxime.44 The reaction has found some utility in the oxidation of primary alkyl iodides to aldehydes.45 The methyl and ethyl nitronate of nitroethane are stable below -78 °C and can be synthesized from the sodium nitronate and Trimethyloxonium Tetrafluoroborate and Triethyloxonium Tetrafluoroborate, respectively, at -60 °C in excellent yields.44 The sodium salt of nitroethane can selectively be C-benzylated with 1-benzyl-2,4,6-triphenylpyridinium tetrafluoroborate in moderate yields.46 The pyridinium cations are readily available from 2,4,6-Triphenylpyrylium Tetrafluoroborate and the corresponding benzylamines. The dilithium salts of primary nitroalkanes are C-alkylated with primary iodo- and bromoalkanes.47 A homoallylic nitro compound is formed when nitroethane, after treatment with lithium methoxide in methanol, reacts with cinnamyl acetate in the presence of 10 mol % Tetrakis(triphenylphosphine)palladium(0) as catalyst (eq 15).48

1,3-Dipolar Cycloadditions of Nitroethane.49

The in situ generated trimethylsilyl ethanenitronate reacts with activated terminal alkenes in a 1,3-dipolar cycloaddition to form 5-substituted 3-methyl-N-trimethylsilyloxyisoxazolidines which, upon acid treatment or heating, give isoxazolines.27a,50 Asymmetric isoxazolines have been synthesized in this manner. The cycloaddition of N-acryloyl-(2R)-bornane-10,2-sultam (acrylate of 10,2-Camphorsultam) with the silyl nitronate, followed by acid-catalyzed elimination of trimethylsilyl alcohol, gives the corresponding isoxazoline in high yields and 78% ee of the C-5 (R)-isomer (eq 16).51

Acetonitrile N-Oxide is formed when nitroethane is treated with Phenyl Isocyanate in the presence of Triethylamine in the Mukayiama reaction.52 The nitrile oxide is a potent dipole and reacts with alkenes and alkynes to give isoxazolines and isoxazoles, respectively. With terminal alkenes or alkynes, the reaction is regioselective, giving 5-substituted 3-methylisoxazolines or -isoxazoles. 1,2-Disubstituted cis- and trans-alkenes react in a stereospecific manner giving cis- and trans-4,5-substituted isoxazolines, respectively.49 Acetonitrile oxide reacts stereoselectively with optically active acrylic esters and amides to give the isoxazolines illustrated in eq 17.53-56 With Curran's bis-lactam chiral auxiliaries, products with about 98% ee are obtained (eq 17).53

3-Methylisoxazolines can easily be reduced to b-hydroxy ketones (an alternative route to the products from aldol reactions with acetone)57 and 3-amino alcohols (eq 18).58

Related Reagents.

t-Butyldimethylsilyl Ethylnitronate; Lithium a-Lithiomethanenitronate; O,O-Dilithio-1-nitropropene; Nitromethane; 1-Nitropropane; 1-Nitro-1-propene.


1. (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, H. C 1979, 33, 1. (b) Rosini, G.; Ballini, R. S 1988, 833.
2. (a) v. Schickh, O.; Apel, G.; Padeken, H. G.; Schwarz H. H.; Segnitz, A. MOC 1971, 10/1. (b) Rosini, G. COS 1991, 2, 321. (c) Jones, G. OR 1967, 15, 204. (d) Baer, H. H.; Urbas, L. In The Chemistry of the Nitro and Nitroso Groups; Feuer, H., Ed.; Wiley: New York, 1970; Part 2, p 75. (e) Hass, H. B.; Riley, E. F. CR 1943, 32, 373.
3. Bachman, G. B.; Maleski, R. J. JOC 1972, 37, 2810.
4. (a) Rosini, G.; Ballini, R.; Petrini, M.; Sorrenti, P. S 1985, 515. (b) Rosini, G.; Ballini, R.; Sorrenti, P. S 1983, 1014.
5. Melot, J.-M.; Texier-Boullet, F.; Foucaud, A. TL 1986, 27, 493.
6. (a) Dauben, H. J.; Ringold, H. J.; Wade, R. H.; Pearson, D. L.; Anderson, A. G. JACS 1951, 73, 2359. (b) Colvin, E. W.; Seebach, D. CC 1978, 689. (c) Colvin, E. W.; Beck, A. K.; Seebach, D. HCA 1981, 64, 2264.
7. (a) Noland, W. E. CR 1955, 55, 137. (b) Ballini, R.; Petrini, M TL 1989, 30, 5329. (c) Clark, J. H.; Cork, D. G. JCS(P1) 1983, 2253.
8. Petrini, M.; Ballini, R.; Rosini, G. S 1987, 713.
9. Rosini, G.; Ballini, R.; Sorrenti, P.; Petrini, M. S 1984, 607.
10. Ono, N.; Kaji, A. S 1986, 693.
11. Schales, O.; Graefe. H. A. JACS 1952, 74, 4486.
12. (a) Raiford, L. C.; Fox, D. E. JOC 1944, 9, 170. (b) Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S. S 1985, 510.
13. Melton, J.; McMurry, J. E. JOC 1975, 40, 2138.
14. Buckley, G. D.; Scaife, C. W. JCS 1947, 1471.
15. Knochel, P.; Seebach, D. S 1982, 1017.
16. Knochel, P.; Seebach, D. TL 1982, 23, 3897.
17. Denmark, S. E.; Moon, Y.-C.; Cramer, C. J.; Dappen, M. S.; Senanayake, C. B. W. T 1990, 46, 7373.
18. Ballini, R.; Castagnani, R.; Petrini, M. JOC 1992, 57, 2160.
19. (a) Barrett, A. G.; Graboski, G. G. M. CR 1986, 86, 751. (b) Posner, G. H.; Crouch, R. D. T 1990, 46, 7509.
20. (a) Denmark, S. E.; Senanayake, C. B. W.; Ho, G.-D. T 1990, 46, 4857. (b) Denmark, S. E.; Senanayake, C. B. W. JOC 1993, 58, 1853.
21. (a) Kabalka, G. W.; Guindi, L. H. M. Varma, R. S. T 1990, 46, 7443. (b) Rylander, P. Catalytic Hydrogenation in Organic Synthesis; Academic: New York, 1979. (c) Erne, M.; Ramirez, F. HCA 1950, 33, 912.
22. Aizpurua, J. M.; Oiarbide, M.; Palomo, C. TL 1987, 28, 5365.
23. Torii, S.; Tanaka, H.; Katoh, T. CL 1983, 607.
24. Varma, R. S.; Varma, M.; Kabalka, G. W. TL 1985, 26, 3777.
25. Ono, N.; Kamimura, A.; Kaji, A. TL 1984, 25, 5319.
26. Ono, N.; Miyake, H.; Kaji, A. CC 1982, 33.
27. (a) Torssell, K. B. G.; Zeuthen, O. ACS 1978, B32, 118. (b) Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz; J. D. HCA 1980, 63, 697.
28. Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HCA 1982, 65, 1101.
29. Seebach, D.; Lehr, F. AG 1976, 88, 540.
30. (a) Lichtenthaler, F. W.; Zinke, H. AG(E) 1966, 5, 737. (b) Baer, H. H.; Rao, G. V. LA 1965, 686, 210.
31. Eberle, M.; Egli, M.; Seebach, D. HCA 1988, 71, 1.
32. Matsumoto, K. AG 1984, 96, 599.
33. Tamura, R.; Sato, M.; Oda, D. JOC 1986, 51, 4368.
34. Lehr. F.; Gonnermann, J.; Seebach, D. HCA 1979, 62, 2258.
35. Asaoka, M.; Mukuta, T.; Takei, H. TL 1981, 22, 735.
36. (a) Bäckvall, J.-E.; Ericsson, A. M.; Plobeck, N. A.; Juntunen, S. K. TL 1992, 33, 131. (b) Ono, N.; Kamimura, A.; Miyake, H.; Hamamoto, I.; Kaji, A. JOC 1985, 50, 3692. (c) Ono, N.; Kamimura, A.; Kaji, A. S 1984, 226.
37. (a) Anderson, D. A.; Hwu, J. R. JOC 1990, 55, 511. (b) Anderson, D. A.; Hwu, J. R. JCS(P1) 1989, 1694. (c) Clark, J. H.; Miller, J. M.; So, K. H. JCS(P1) 1978, 941. (d) Colonna, S.; Hiemstra, H.; Wynberg, H. CC 1978, 238. (e) Belsky, I. CC 1977, 237.
38. Rosini, G.; Ballini, R.; Petrini, M.; Marotta. E. AG 1986, 98, 935.
39. (a) Bergbreiter, D. E.; Lalonde, J. J. JOC 1987, 52, 1601. (b) Clark, J. H.; Cork, D. G.; Robertson, M. S. CL 1983, 1145.
40. McKillop, A.; Kobylecki, R. J. T 1974, 30, 1365.
41. Baker, D. C.; Putt, S. R. S 1978, 478; Crumbie, R. L.; Nimitz, J. S.;, Mosher, H. S. JOC 1982, 47, 4040.
42. Backman, G. B.; Hokama, T. JACS 1959, 81, 4882.
43. Stiles, M.; Finkbeiner, H. L. JACS 1959, 81, 505.
44. (a) Kerber, R. C.; Urry, G. W.; Kornblum, N. JACS 1965, 87, 4520. (b) Kornblum, N.; Brown, R. A. JACS 1964, 86, 2681. (c) Kornblum, N.; Brown, R. A. JACS 1963, 85, 1359.
45. Liebermann, S. V. JACS 1955, 77, 1114.
46. Katritzky, A. R.; De Ville, G.; Patel, R. C. CC 1979, 602.
47. Seebach, D.; Henning, R.; Lehr, F.; Gonnermann, J. TL 1977, 1161.
48. Wade, P. A.; Morrow, S. D.; Hardinger, S. A. JOC 1982, 47, 365.
49. (a) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH: New York, 1988. (b) Caramella, P.; Grünhanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984.
50. Andersen, S. H.; Das, N. B.; Jørgensen, R. D.; Kjeldsen, G.; Knudsen, J. S.; Sharma, S. C.; Torssell, K. B. G. ACS 1982, B36, 1.
51. (a) Kim, B. H.; Lee, J. Y.; Kim, K.; Whang, D. TA 1991, 2, 27. (b) Kim, B. H.; Lee, J. Y. TA 1991, 2, 1359.
52. Mukaiyama, T.; Hoshino, T JACS 1960, 82, 5339.
53. (a) Stack, J. A.; Heffner, T. A.; Geib, S. J.; Curran, D. P. T 1993, 49, 995. (b) Curran, D. P.; Jeong, K.-S.; Heffner, T. A.; Rebek, J., Jr. JACS 1989, 111, 9238.
54. Olsson, T.; Stern, K. JOC 1988, 53, 2468.
55. Akiyama, T.; Okada, K.; Ozaki, S. TL 1992, 33, 5763.
56. (a) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. TL 1991, 32, 4893. (b) Kim, K. S.; Kim, B. H.; Park, W. M.; Cho, S. J.; Mhin, B. J. JACS 1993, 115, 7472.
57. Curran, D. P.; Zhang, J. JCS(P1) 1991, 2613.
58. Jäger, V.; Buss, V.; Schwab, W. LA 1980, 122.

Kurt B. G. Torssell & Kurt V. Gothelf

Aarhus University, Denmark



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.