Trimethylsilyl Methanenitronate1

(R1 = R2 = H, R3Si = TMS)

[51146-35-1]  · C4H11NO2Si  · Trimethylsilyl Methanenitronate  · (MW 133.25) (R1 = C5H11, R2 = H, R3Si = TBDMS)

[75157-17-4]  · C12H27NO2Si  · t-Butyldimethylsilyl 1-Hexanenitronate  · (MW 245.49) (R1R2 = (CH2)5, R3Si = TBDMS)

[75157-19-6]  · C12H25NO2Si  · t-Butyldimethylsilyl Cyclohexanenitronate  · (MW 243.47)

(react with alkenes in a 1,3-dipolar cycloaddition reaction;1c,3-5 undergo Bu4NF-mediated diastereoselective carbonyl addition to aldehydes;6-12 react with alkyllithium reagents to give oximes;13 oxidative coupling leads to 1,2-dinitro alkanes;14,15 cross coupling with silyl enol ethers or enamines gives b-nitro carbonyl derivatives;15 conversion of thiocarbonyl to carbonyl groups;1c,16 can be converted into carbonyl compounds (cf. Nef reaction)17)

Alternate Name: [(trimethylsilyl)-aci-nitro]methane.

Physical Data: R1 = C5H11, R2 = H, R3Si = TBDMS: bp 80-90 °C/0.02 mmHg. R1R2 = (CH2)5, R3Si = TBDMS: bp 150 °C/0.01 mmHg. A more complete list of silyl nitronates is given by Torssell.1c

Solubility: sol pentane and in all nonprotic common organic solvents.

Preparative Methods: a large number of silylation conditions can be applied to primary or secondary nitroalkanes,1,2 including: R3SiCl/Et3N (or Ag+ or Li2S), R3SiOTf, LDA/R3SiCl, R3SiCl/DBU,17a silylated amides, etc. The first reports were published by Ioffe, Tartakovskii, and their colleagues in the early 1970s.1 The silyl nitronates are isolated by nonaqueous workup and purified by bulb-to-bulb distillation, with the TBDMS derivatives being much more thermally stable than the TMS derivatives.2 From crystal structure analyses and NMR studies it is concluded that the silyl group migrates rapidly from one nitronate oxygen to the other and that the more stable configuration of silyl nitronates derived from primary nitroalkanes is (E).2,8

Handling, Storage, and Precautions: although there are indications that some trimethylsilyl nitronates are thermally unstable,1c there have been no reports of violent decompositions. Silyl nitronates are, of course, extremely sensitive to moisture, and they are more resistant to base than to acid. All silyl nitronates should be kept under an inert atmosphere and stored in a freezer.

Reactions of Silyl Nitronates with C-C Bond Formation.

Silyl nitronates are synthetically equivalent to nitrile oxides in [3 + 2] cycloadditions. The [3 + 2] adducts shown in eq 1 lose trialkylsilanol very readily, with formation of D2-isoxazolines.1c,3-5 Silyl nitronates are somewhat less reactive than nitrile oxides, which is not a disadvantage in intramolecular cycloadditions.3 The reaction is also applicable to the CF3-substituted silyl nitronate (R1 = CF3, R2 = H).18 Depending upon the method of reduction, either the amino alcohol (1) or its epimer (2) can be obtained with a diastereoselectivity of ca. 4:1. When the silyl nitronate is derived from a secondary nitroalkane, no silanol elimination can occur; the corresponding isoxazolidines undergo a rearrangement to nitroso silyl ethers such as (3).1d,19 The isoxazolidines derived from primary nitroalkanes are not only precursors to amino alcohols but also to b-hydroxy ketones. Thus the nitrile oxide/silyl nitronate [3 + 2] cycloaddition route constitutes an alternative access to aldols.1c,20,21 This method becomes especially attractive when rendered enantioselective. Addition of a silyl nitronate from a primary nitroalkane to a chiral acrylamide (such as 10,2-Camphorsultam,4 trans-2,5-Dimethylpyrrolidine,22 or Kemp-Rebek acid derivatives5), silanol elimination, and reductive removal of the auxiliary gives 3-substituted D2-isoxazoline-5-methanols in either enantiomeric form (eq 2).

The second most important synthetic application of silyl nitronates in C-C bond-forming reactions is their fluoride-mediated addition to aldehydes.6-12 Silyl nitronates from secondary nitroalkanes lead to free nitro aldols such as (4),8 while those from primary nitro alkanes give silylated products. In contrast to the classical Henry reaction, the silyl variant is highly diastereoselective with aldehydes, furnishing erythro-O-silylated nitro aldols (e.g. 5).9 It is important that the reaction temperature does not rise above 0 °C, otherwise threo/erythro equilibration takes place. The same erythro-nitro aldol derivatives are available by diastereoselective protonation of silyloxy nitronates (eq 3) (usually the dr is >20:1), while the nonsilylated threo-epimers (R3 = H, dr = 7:3-20:1) are formed by kinetic protonation of lithioxy lithio nitronates in THF/DMPU (eq 4).9 Other recent modifications of the nitroaldol addition using titanium nitronates23 or ClSiR3 in situ24 are less selective. It should also be mentioned that there are recent reports25 about the enantioselective addition of nitromethane to aldehydes in the presence of rare earth binaphthol complexes.

Reactions of Silyl Nitronates with Strong Base.13

With 2 equiv of an alkyllithium, the nitronates from primary nitroalkanes give oximes with the newly introduced alkyl group attached to the oxime carbon (eq 5). The analogous reaction of silyl nitronates from secondary nitroalkanes produces oximes in which chain extension has occurred in the a-position (eq 6). These reactions take place when alkyllithium is added to 0.1 molar silyl nitronate in THF at dry-ice temperature, with subsequent warming to room temperature before aqueous workup. Probably a nitrile oxide is the intermediate in the first case and a nitroso alkene in the second case. Finally, oxidative cross couplings of silyl nitronates with silyl enol ethers, ketene acetals, or enamines produce b-nitro carbonyl compounds (eq 7) or, by HNO2 elimination, a,b-unsaturated ketones and esters.15

Functionalization Reactions of Silyl Nitronates.

Silyl nitronates can be used for a number of transformations in which the carbon skeleton is not changed. Thus they are intermediates en route from nitroalkanes to ketones (the transform26 of the Nef reaction). Peroxy acid treatment converts silyl nitronates, which would not survive the classical conditions of the Nef reaction, to ketones17a (eq 8). Aldehydes can be obtained analogously, using stannyl nitronates.17b

Silyl nitronates can also be further silylated to the interesting N,N-bis(silyloxy)enamines (eq 9).27 In contrast to the N,N-bis(lithioxy)enamines, the double bond in the bis(silyloxy)enamines appears to have electrophilic rather than nucleophilic reactivity. With primary and secondary amines, a-amino oximes are produced (eq 9)27 in a kind of SN substitution, followed by hydrolytic desilylation. In this manner, the bis(silyloxy)enamine is reacting as a nitroso alkene.

Conversion of Thioketones to Ketones.16

Thioketones generated by a Norrish-type photofragmentation of a sulfenyl acetophenone are trapped in situ by [3 + 2] dipolar cycloaddition with a silyl nitronate (eq 10). Fluoride treatment of the resulting heterocycle produces the ketone.16b This transformation is compatible with a variety of functional groups and has been used as part of a synthetic manipulation in which an a-acyl cyclic thioether is converted stereoselectively, with ring enlargement, to a ketolactone (methynolide synthesis).16a

Silyl Nitronate Reactivity Pattern.

As illustrated by the examples described above, silyl nitronates provide a1 and d1 acyl and aminoalkyl synthons (6 and 7), as well as a2 a-carbonyl and aminoalkyl synthetic building blocks (8 and 9).1e,28

Related Reagents.

Lithium a-Lithiomethanenitronate; Nitroethane; Nitromethane; 1-Nitropropane; Phenylsulfonylnitromethane.

1. (a) Colvin, E. W. Silicon in Organic Synthesis; Butterworths: London, 1981. (b) Colvin, E. W. In The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Ed.; Wiley: Chichester, 1987; Vol. 4, Chapter 6, p 539. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH: Weinheim, 1988. (d) Döpp, D.; Döpp, H. MOC 1990, E14b, 780. (e) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. C 1979, 33, 1.
2. Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz, J. D. HCA 1980, 63, 697.
3. Dehaen, W.; Hassner, A. TL 1990, 31, 743.
4. Kim, B. H.; Lee, J. Y. TA 1991, 2, 1359.
5. Stack, J. A.; Heffner, T. A.; Geib, S. J.; Curran, D. P. T 1993, 49, 995.
6. Colvin, E. W.; Seebach, D. CC 1978, 689.
7. Seebach, D.; Beck, A. K.; Lehr, F.; Weller, T.; Colvin, E. W. AG(E) 1981, 20, 397.
8. Colvin, E. W.; Beck, A. K.; Seebach, D. HCA 1981, 64, 2264.
9. Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HCA 1982, 65, 1101.
10. &OOuml;hrlein, R.; Jäger, V. TL 1988, 29, 6083.
11. Martin, O. R.; Khamis, F. E.; El-Shenawy, H. A.; Rao, S. P. TL 1989, 30, 6139.
12. Martin, O. R.; Khamis, F. E.; Rao, S. P. TL 1989, 30, 6143.
13. Colvin, E. W.; Robertson, A. D.; Seebach, D.; Beck, A. K. CC 1981, 952.
14. Kai, Y.; Knochel, P.; Kwiatkowski, S.; Dunitz, J. D.; Oth, J. F. M.; Seebach, D.; Kalinowski, H.-O. HCA 1982, 65, 137. In this paper a procedure for the coupling of lithio nitronates with Pb(OAc)4 is given; silyl nitronates can be coupled in the same way.
15. Narasaka, K.; Iwakura, K.; Okauchi, T. CL 1991, 423.
16. (a) Vedejs, E.; Buchanan, R. A.; Watanabe, Y. JACS 1989, 111, 8430. (b) Vedejs, E.; Perry, D. A. JOC 1984, 49, 573.
17. (a) Aizpurua, J. M.; Oiarbide, M.; Palomo, C. TL 1987, 28, 5361. (b) Aizpurua, J. M.; Oiarbide, M.; Palomo, C. TL 1987, 28, 5365.
18. Originally, we had problems reproducing the preparation of F3CCH=N(O)OTBDMS (Beck, A. K.; Seebach, D. CB 1991, 124, 2897; CA 1992, 116, 40 553c); using Torsell's procedure we are able to prepare this silyl nitronate: Marti, R. E.; Heiner, J.; Seebach, D. LA 1995, in press.
19. Mukerji, S. K.; Torssell, K. B. G. ACS 1981, B35, 643.
20. Curran, D. P. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1988; Vol. 1, p 129.
21. Jäger, V.; Müller, I.; Schohe, R.; Frey, M.; Ehrler, R.; Häfele, B.; Schröter, D. Lect. Heterocycl. Chem. 1985, 8, 79.
22. Whitesell, J. K. CRV 1989, 89, 1581.
23. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. JOC 1989, 54, 1233.
24. Fernández, R.; Gasch, C.; Gómez-Sánchez, A.; Vílchez, J. E. TL 1991, 32, 3225.
25. (a) Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. TL 1993, 34, 2657. (b) Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. TL 1993, 34, 855. (c) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. TL 1993, 34, 851. (d) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. JACS 1992, 114, 4418. (e) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. JACS 1993, 115, 10 372.
26. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New York, 1989.
27. Feger, H.; Simchen, G. LA 1986, 1456 (CA 1987, 106, 33 161p).
28. Seebach, D. AG(E) 1979, 18, 239.

Albert K. Beck & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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