[138723-90-7]  · C6H12N2O3  · (MW 160.17)

(carbonyl 1,1-dipole equivalent: synthesis of heterocycles, e.g. hydroindolones, hydantoin, ring expansion, alkylate enols, formation of orthoformates, and cyclopropanation)

Alternate Name: 2,2-dimethoxy-5,5-dimethyl-2,5-dihydro-[1,3,4]oxadiazole.

Physical Data: bp 51-52 °C/7 mmHg.

Solubility: benzene, toluene, xylene, chlorobenzene, hexafluorobenzene, cyclohexane, and mesitylene.

Form Supplied in: clear oil.

Analysis of Reagent Purity: 1H and 13C NMR, IR, UV, elemental analysis.

Preparative Methods: the title reagent can be prepared by oxidation of acetone(methoxycarbonyl)hydrazone with lead tetraacetate or phenyl iododiacetate. The hydrazone in methanol was added to a solution of lead tetraacetate in methanol at 0 °C and stirred at rt for 2 h. Then KOH was added and the reaction was stirred for an additional 2 h. Methanol was evaporated and the resulting solid was dissolved in CH2Cl2 and filtered through celite, washed with H2O, dried, and concentrated.1-3 Alternative preparation: the hydrazone and iodobenzene diacetate in methanol was stirred at 0 °C for 20 min, then the solvent was evaporated. The resulting crude product was dissolved in CH2Cl2 and the solution was washed with sodium hydrogen carbonate and then concentrated (1).4,5

Purification: distillation under vacuum3 or column chromatography with neutral alumina or silica neutralized with a small amount of triethyl amine.4

Handling, Storage, and Precautions: shelf-stable,2 used in a fume hood. Evolves N2 gas upon fragmentation to the dimethoxy carbene.


The title reagent 1 is used either thermally2 or photolytically6,7 to generate dimethoxycarbene (DMC) (4), which is a singlet state nucleophilic carbene (2). During the thermal (and/or photolytic) fragmentation of the oxadiazoline (1), the oxadiazoline will first lose N2 to afford a carbonyl ylide intermediate 3, which fragments to give the dimethoxy carbene (4) as the reactive reagent and acetone as a by-product.2

DMC (4) undergoes a [4 + 1] cycloaddition with vinyl isocyanates to afford hydroindolones. DMC is also used in the synthesis of hydantoins and orthoformates. Furthermore, DMC (4) can be employed for ring expansion, alkylation of enols, and some cyclopropanations. The carbonyl ylide (3) that is formed first in the fragmentation of the oxadiazoline can be used to synthesize orthoesters.

Synthesis of Hydroindolones

Thermolysis of excess of 1 in the presence of 1-cyclohexene-1-isocyanate (5) generates 4, which undergoes nucleophilic addition to the carbonyl group of the isocyanate followed by a cyclization. Subsequent N-H insertion of a second equivalent of the carbene afforded hydroindolone (6a) as a 2:1 carbene/isocyanate adduct in 80% yield.8 When 1 was used stoichiometrically, only a small amount of the 1:1 adduct 6b was isolated (3).8 This [4 + 1] cycloaddition reaction of the dimethoxy carbene was utilized in the preparation of the azepinoindole core of the Stemona alkaloids.9

This reaction can also be carried out with substituted cyclohexene-isocyanates. The dimethoxy carbene is presumed to undergo a nucleophilic addition to the carbonyl carbon of the isocyanate to give a zwitterionic intermediate that cyclizes to afford the substituted hydroindolone. In this case, a second equivalent of the carbene also does a rapid N-H insertion to give the expected 2:1 adduct of carbene/cyclohexene-isocyanate in 81% yield.8

It is noteworthy that the Curtius rearrangement used to form the vinyl isocyanate from the vinyl acyl azide intermediate and the cycloaddition can be carried out in one operation. This reaction was performed by refluxing the vinyl acyl azide intermediate (7) with an excess of 1 in xylene, resulting in a 63% yield of the [4 + 1] cycloadduct 8. In addition, this reaction has been successful in generating a quaternary carbon in the resulting hydroindolone (8) 4.8

This reaction was utilized in the total synthesis of (±)-tazettine.10 The construction of the [2]benzopyrano[3,4-c]hydroindolone ring system was carried out by heating excess oxadiazoline in the presence of the corresponding vinyl acyl azide in mesitylene to afford the substituted hydroindolone as a 2:1 carbene/isocyanate adduct.8,10

Synthesis of Pyrrolinones

Dimethoxy carbene-based [4 + 1] cyclizations have been used to rapidly synthesize highly functionalized pyrrolinonederivatives.8 The oxadiazoline was fragmented in the presence of an acyclic vinyl isocyanate (9). The carbene underwent an [4 + 1] addition to the isocyanate followed by a rapid N-H insertion to provide the pyrrolinone (10) as a 2:1 carbene/isocyanate adduct in 80% yield (5).8

Also, the Curtius rearrangement of the acyclic vinyl acyl azide intermediate to form the vinyl isocyanate and the cyclization to the pyrrolinone can be carried out in one operation. Heating excess of 1 in the presence of an acyclic vinyl acyl azide (11) afforded the highly substituted pyrrolinone (12) as 2:1 carbene/isocyanate adduct in good yield (6).8

Synthesis of Hydantoins

Dimethoxy carbene does not undergo a [4 + 1] cycloaddition when reacted with phenyl isocyanate as it does with other vinyl isocyanates. When 1 was fragmented in the presence of phenyl isocyanate (13) in a sealed tube, it underwent a nucleophilic addition to the carbon of the isocyanate group and then second molecule of phenyl isocyanate was added via a postulated zwitterionic intermediate to afford the hydantoin (14) in 65% yield (7).2,4,11

Hydantoins are occasionally observed in trace amount in other reactions between dimethoxy carbene and vinyl isocyanates.8

Reactions with Ketones

When 1 was reacted with strained ketones it resulted in a carbon-carbon bond insertion of the dimethoxy carbene. This reaction was carried out by thermally fragmenting 1 in the presence of cyclobutanone (15). The dimethoxy carbene (4) formed undergoes a nucleophilic attack at the carbonyl carbon giving rise to a zwitterionic intermediate that undergoes a bond-migration to give rise to the ring-expanded product 16 in 75% yield (8).6,12 This ring expansion reaction also works with cyclopropanone, cyclopropenone, and cyclobutane-1,3-dione.12

Furthermore, 1 was heated in a sealed tube at 110 °C in the presence of the bicyclic compound 17 to afford the ring-expanded product 18 in quantitative yield.13 It is believed that the mechanism of the reaction is a nucleophilic attack of the carbene at the carbonyl carbon of 17 to give a zwitterionic intermediate, which then rearranges via a 1,2-carbon migration with retention of stereochemistry to give 18. This is an example of an overall carbon-carbon bond insertion of dimethoxy carbene (9).13

However, when 1 is thermally fragmented in the presence of tropone the dimethoxy carbene undergoes a [4 + 1] cycloaddition with tropone (19) to afford the bicyclic compound (20) (10).13,14

Thermolysis of 1 in the presence of 9-fluorenone (21) affords 4, which adds to the carbonyl group of the 9-fluorenone to give the epoxide 22 as an intermediate that subsequently rearranges to the oxirane (23) (11).15 The net result of this reaction is an [2 + 1] addition to a carbonyl group giving rise to the oxirane in 24% yield as determined by NMR spectroscopy.15

Reactions with Anhydrides4

Heating of 1 with a stoichiometric amount of cyclic anhydride (24) in a sealed tube resulted in a carbene insertion to the carbonyl carbon anhydride oxygen bond to provide a ring-expanded product 25 in moderate to good yield (12). The ring-expansion works well with both substituted and unsubstituted cyclic anhydrides. However, the yields of these reactions are higher when the reactions are carried out with substituted anhydrides. For example, when R1 = R2 = H the ring-expanded product was obtained in 40% yield, but when R1 = R2 = Cl or CH3 the reaction gave 60% and 75% yield of the ring-expanded product, respectively (1). Furthermore, this reaction was carried out with tetrahydrophthalic anhydride, which afforded the ring-expanded product in 40% yield. Also, the yields for these reactions are higher when the reaction is carried out using substituted phthalic anhydrides.4

This reaction can also be performed on nonsymmetrical cyclic anhydrides (26) to give a mixture of the two regioisomers 27 and 28. When R=CH3 the reaction gave a ratio of 3:1 of regioisomers 27 and 28, respectively, in 81% overall yield. When R=Br, a 4.5:1 ratio of the regioisomers 27 and 28, respectively, was obtained in 43% overall yield (2). The results of these nonsymmetrical anhydride reactions showed that the dimethoxy carbene adds preferentially to the most electron-deficient carbonyl carbon of the anhydride. Since there is a preference for dimethoxy carbene to attack adjacent to a substituent it indicates that the electronic factors are strong enough to overcome steric factors associated with attack at the carbonyl group (13).4

Reaction with Perchlorinated Olefines and Ketones

Thermolysis of 1 in the presence of 2 equiv of hexachlorocyclopentadiene (29) afforded a mixture of compounds 30, 31, and 32 as determined by GS-MS. The products 30, 31, and 32 were isolated by radial chromatography in 24%, 29%, and 34% yields, respectively. However, when the reaction was carried out with a 10-fold excess of the oxadiazoline the product distribution changes to 12% isolated yield of 31 and 76% yield of 32. Compound 30 was only detected in trace amount by GS-MS (14).6,13

Heating of 1 with an excess of octachloroheptatriene (33) in a sealed tube for 24 h afforded compounds 34 and 35 in 12% and 56% yields, respectively (15).13

When 1 was heated in the presence of hexachlorotropone (36), carbene 4 was presumably added to the carbonyl carbon of 36. This was followed by rearrangement to the ring-contracted ester (37) in 44% isolated yield (16).13,16

Tetrachloro-1,4-benzoquinone (38) was aromatized when heated in a sealed tube with 1 for 24 h to give a mixture of products 39, 40, and 41 in 82%, 5%, and 1% isolated yields, respectively. This aromatization of 38 presumably occurs by an initial attack of DMC at a carbonyl carbon to give a dipolar intermediate that rearranges to the observed products (17).13

Alkylation of Enols

Dimethoxy carbene has been used to alkylate enols.6,17 When 1 is heated in the presence of enol 42, carbene 4 is presumably protonated and the subsequent ion-pair collapses on the carbon of the enol to provide the alkylated product 43. These reactions work well when R1=Me or Ph, R2=H or Me, and R3=Me, Ph or OH and afford the alkylated product in 24-56% yields as determined by NMR spectroscopy (18).6,17

Synthesis of Orthoformates

Orthoformates are synthesized by heating 1 in the presence of alcohols or phenols. The dimethoxy carbene (4) generated under these thermal conditions will undergo an O-H bond insertion to afford the orthoformates (45) in good to excellent yields. This reaction works with most alcohols and phenols (19).2,6

Reaction with Tetrazine

When 1 is refluxed in the presence of tetrazine (46) in chlorobenzene the dimethoxy carbene (4) formed underwent a [4 + 1] addition to 46. When R = Ph, the isolated product is 47; however, when R=SMe, the [4 + 1] adduct expelled nitrogen which resulted in the formation of pyrazole (48) in good yield (20).4,18,19

Reaction with Olefins

Dimethoxy carbene undergoes addition with tetrasubstituted alkenes. When the 1 and 1.5-2 equiv of an alkene were heated in benzene for 24 h, cyclopropane adducts were observed.1 Oxadiazoline (1) also reacted with an a,b-unsaturated ester (49) to give orthoester (50) as the major product and cyclobutane (51) as the minor product. It is believed that the carbonyl ylide (3) first formed when fragmenting 1 does a Michael addition to the double bond of the a,b-unsaturated ester, which competes with further fragmentation to the dimethoxy carbene (4) and acetone (21).1

Miscellaneous Reactions

Oxadiazoline (1) has been used to form methane fullerene ketals.20,21 The oxadiazoline and C60 were refluxed in chlorobenzene for 24 h, which resulted in dimethoxymethanofullerene in 69% yield.20

In addition, it has been shown that the dimethoxy carbene (4) reacts with bis-ketenes. The oxadiazoline (1) was heated in benzene in the presence of bis-ketene (52). The dimethoxy carbene (4) undergoes a nucleophilic addition to the carbonyl carbon of 52 affording a zwitterionic intermediate that cyclized to give the observed product 53 (22).22

Dimethoxy carbene (4) can undergo nucleophilic aromatic substitution by displacing fluoride from an aromatic ring. For this reaction to occur the aromatic ring must be activated by an electron-withdrawing group. This reaction was carried out by heating 1 and excess Sangers reagent (54) in benzene at 100 °C for 24 h using a sealed tube and the reaction afforded acetal (55) in 10% yield, determined by NMR spectroscopy (23).

1. (a) de Meijere, A.; Kozhushkov, S. I.; Yufit, D. S.; Boese, R.; Haumann, T.; Pole, D. L.; Sharma, P. K.; Warkentin, J., Liebigs Ann. 1996, 601. (b) Warkentin, J., In Advances in Carbene Chemistry; Brinker, U. H., Ed.; JAI Press, Inc: Connecticut, 1998; p 245-295.
2. El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J., J. Am. Chem. Soc. 1992, 114, 8751.
3. Chiba, T.; Okimoto, M., J. Org. Chem. 1992, 57, 1375.
4. Pole, D. L.; Warkentin, J., Liebigs Ann. 1995, 1907.
5. Yang, R. Y.; Dai, L. X., J.Org. Chem. 1993, 58, 3381.
6. Warkentin, J., J. Chem. Soc., Perkin Tran. 1 2000, 2161.
7. Hoffmann, R. W.; Luthardt, H. J., Chem. Ber. 1968, 101, 3861.
8. Rigby, J. H.; Cavezza, A.; Ahmed, G., J. Am. Chem. Soc. 1996, 110, 12848.
9. Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J., J. Org. Chem. 1998, 63, 5587.
10. Rigby, J. H.; Cavezza, A.; Heeg, M. J., J. Am. Chem. Soc. 1998, 110, 3664.
11. Er, H. T.; Pole, D. L.; Warkentin, J., Can. J. Chem. 1996, 74, 1480.
12. Venneri, P. C.; Warkentin, J., Can. J. Chem. 2000, 78, 1194.
13. Dunn, J. A.; Pezacki, J. P.; McGlinchey, M. J.; Warkentin, J., J. Org. Chem. 1999, 64, 4344.
14. Lilienblum, W.; Hoffmann, R. W., Chem. Ber. 1977, 110, 3405.
15. Pole, D. L.; Warkentin, J., J. Org. Chem. 1997, 62, 4065.
16. Ross, J. P.; Couture, P.; Warkentin, J., Can. J. Chem. 1997, 75, 1331.
17. Couture, P.; Pole, D. L.; Warkentin, J., J. Chem. Soc., Perkin Trans. 2 1997, 1565.
18. Kümmell, A.; Meyer-Dulheuer, C.; Seitz, G., Arch. Pharm. 1994, 327, 597.
19. Frenzen, G.; Gerninghaus, C.; Meyer-Dulheuer, C.; Paulus, E. F.; Seitz, G., Liebigs Ann. 1995, 1313.
20. Win, W. W.; Kao, M.; Eiermann, M.; McNamara, J. J.; Wudl, F.; Pole, D. L.; Kassam, K.; Warkentin, J., J. Org. Chem. 1994, 59, 5871.
21. Isaacs, L.; Diedrich, F., Helv. Chim. Acta 1993, 76, 2454.
22. Colomcakos, J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J., J. Org. Chem. 1996, 61, 9522.

Mona Aasmul

Wayne State University, Detroit, MI, USA

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