p-Nitrobenzyl 2-Diazo-3-trimethylsilyloxy-3-butenoate

[93788-47-7]  · C14H17N3O5Si  · p-Nitrobenzyl 2-Diazo-3-trimethylsilyloxy-3-butenoate  · (MW 335.43)

(annulation of b-lactams1 and aromatic aldehydes and ketones13)

Physical Data: mp 75 °C (dec).4 The corresponding TBDMS ether has mp 133 °C (dec).

Solubility: sol acetonitrile, ethyl acetate, ether, methylene chloride, toluene; poorly sol hexane.4 The reagent hydrolyzes in water and protic solvents, whereas the TBDMS enol ether is stable to neutral aqueous workup.2

Form Supplied in: stored and used in methylene chloride or toluene solution. p-Nitrobenzyl 2-diazoacetoacetate, the hydrolysis product, is the expected impurity.

Analysis of Reagent Purity: 1H NMR.1,2

Preparative Methods: by silylation of the corresponding diazoacetoacetate2 with a silyl triflate (Trimethylsilyl Trifluoromethanesulfonate or t-Butyldimethylsilyl Trifluoromethanesulfonate) and Triethylamine in CH2Cl2.2 For large scale preparations the use of Chlorotrimethylsilane, Potassium Iodide (one equivalent), and Et3N in acetonitrile is more advantageous.6

Handling, Storage, and Precautions: should be stored in solution in a dry, dark, cold place. The solid form is stable for several months in the refrigerator. The solid reagent is not shock sensitive but exothermic decomposition takes place on melting, generating 200 cal g-1 (138 cal g-1 for the TBDMS ether).5 Decomposition can also be initiated by metallic impurities (Cu, Rh, etc.).

Annulation of b-Lactams.

This bifunctional reagent was developed for the stereospecific construction of the carbapenem skeleton in the conversion of penicillin to thienamycin.1a The annulation scheme is based on condensation of the enol silane with the iminium ion intermediate followed by ring closure via rhodium-catalyzed carbenoid insertion into the NH bond (eq 1).

Subsequently, it was shown that the condensation is more facile when the nitrogen is not silylated1b,7 and that acetoxy1b or benzoyloxy8 groups may serve as the leaving group for generation of the iminium ion. Lewis acids such as ZnCl2, ZnBr2, ZnI2, and TMSOTf in CH2Cl2 initiate the reaction (eq 2). This mode of annulation has formed the basis of the syntheses of thienamycin [R = MeCH(OH)-],1,2,7-9 asparenomycin [R = HOCH2C(Me)=],10 PS-5 (R = Et),3,11,12 and PS-6 (R = i-Pr).3 The [3R(1R),4R]-4-acetoxy-3-(1-hydroxyethyl)-2-azetidinone is commercially available. The patent literature contains numerous examples of this type of annulation. Variations of this annulation scheme, such as condensation of the b-lactam with bis-silylated acetoacetate (unstable reagent), followed by diazo transfer1a and nucleophilic displacement with the lithium enolate of diazoacetoacetate (3.2-14.1% yield),12 are clearly inferior alternatives.

Annulation of Aldehydes and Ketones.13

Titanium(IV) Chloride-catalyzed condensation of the reagent and aldehydes or ketones followed by rhodium-catalyzed carbene insertion into the OH bond affords furanone derivatives (eq 3).

Analogous condensation with benzophenone using 2 equiv of TiCl4 yields the unsaturated diazo ketone in 80% yield. Boron Trifluoride-initiated ring closure produces the b-naphthol analog, while rhodium-promoted reaction generates the isomeric a-naphthol via Wolff rearrangement, followed by ketene cyclization, in quantitative yield (eq 4).

It is expected that this versatile bifunctional reagent will find application in other areas of synthetic chemistry. The t-butyldimethylsilyl ether analog is frequently used. The benzyl,1 p-methoxybenzyl,2 diphenylmethyl,3 allyl,2 and trimethylsilyl esters2 have also been used.


1. (a) Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M. JACS 1981, 103, 6765. (b) Reider, P. J.; Grabowski, E. J. J. TL 1982, 23, 2293.
2. Ueda, Y.; Roberge, R.; Vinet, V. CJC 1984, 62, 2936.
3. Andreoli, P.; Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. JOC 1991, 56, 5984.
4. Hughes, D. L.; Lynch, J. E., Merck Research Laboratories, personal communication.
5. Tuma, L. D., Merck Research Laboratories, personal communication.
6. Hughes, D. L., Eur. Patent Appl. 0 409 331 A2, 1991.
7. Endo, M. CJC 1987, 65, 2140.
8. Tschaen, D. M.; Fuentes, L. M.; Lynch, J. E.; Laswell, W. L.; Volante, R. P.; Shinkai, I. TL 1988, 29, 2779.
9. (a) Chiba, T.; Nagatsuma, M.; Nakai, T. CL 1985, 1343. (b) Hart, D. J.; Deok-Chan, H. TL 1985, 26, 5493.
10. Buynak, J. D.; Rao, M.; Pajouhesh, H.; Chandrasekara, R. Y.; Finn, K. JOC 1985, 50, 4245.
11. (a) Georg, G.; Kant, J. JOC 1988, 53, 692. (b) Chiba, T.; Nakai, T. CL 1987, 2187. (c) Cainelli, F.; Panunzio, M. JACS 1988, 110, 6879.
12. Kametani, T.; Honda, T.; Nakayama, A.; Sasakai, Y.; Mochizuki, T.; Fukumoto, K. JCS(P1) 1981, 2228.
13. Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M. Abstracts of Papers, ACS National Meeting, Dallas, TX; 1989 Abstract 234.

Sandor Karady & Joseph S. Amato

Merck Research Laboratories, Rahway, NJ, USA



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