Cycloadditions and electrocyclizations of conjugated ketenes establish carbon-based or heteroaromatic rings from vinylketenes, allenylketenes, or alkynylketenes. Cycloadditions with ketenophiles in the [4 + 2] or [2 + 2] mode and electrocyclizations of dienylketenes are atom economical approaches to the construction of ring systems in organic compounds.
Because of the linear geometry of ketenes and their perpendicular C=C and C=O π systems, they are ideally suited for antarafacial [2 + 2] cycloaddtion reactions. A previous Organic Reactions chapter and summary describe catalytic asymmetric [2 + 2] and [4 + 2] cycloadditions of ketenes. In these reactions, the ketene serves primarily as the 2π component. Conjugated ketenes can react in a similar manner, but may also serve as the 4π component in [4 + 2] cycloaddition reactions or engage in 4π or 6π electrocyclization (Eq. 1). This summary focuses on the cycloaddition and electrocyclization reactions of conjugated ketenes, including vinylketenes, alkynylketenes, and allenylketenes.(1)
Vinylketenes were suggested as unobserved intermediates in several early annulation reactions and were observed directly in later studies. Both concerted and stepwise mechanisms are possible in cycloaddition reactions of these species. Allenyl- and alkynylketenes also engage in [2 + 2] and [4 + 2] cycloaddition reactions. Electrocyclizations of dienylketenes, which typically occur spontaneously upon generation of the ketene, afford phenols, hydroquinones, quinones, and other aromatic heterocycles. In the vast majority of cases the ketene is generated in the presence of other reagents such that it reacts immediately; however, silyl-substituted conjugated ketenes can be isolated in some instances.
Mechanism and Stereochemistry
Cycloadditions of ketenes and alkenes may involve either concerted or stepwise pathways, and it is often difficult to distinguish the two mechanistic possibilities. In pericyclic and concerted [2 + 2] cycloadditions, the ketene approaches the alkene such that the reaction occurs antarafacially at the ketene and suprafacially at the alkene. The larger ketene substituent points away from the alkene in transition state 1, leading to the more sterically hindered cyclobutanone product via kinetic control. In the stepwise [2 + 2] pathway, nucleophilic attack at the ketene carbonyl affords zwitterionic intermediate 2, which closes to form the cyclobutanone product (Eq. 2).(2)
Vinylketenes are often formed via thermal ring-opening of cyclobutenones; however, this process is typically thermoneutral with an activation barrier of approximately 20 kcal/mol (Eq. 3). Consumption of the vinylketene via cycloaddition or electrocyclization drives the ring-opening forward.(3)
Acyclic conjugated ketenes are unstable with respect to phenols and cyclohexadienones such that 6π electrocyclization is very favorable (Eq. 4). Although trans-dienylketene is slightly more stable than cis-dienylketene, a cis configuration of the central double bond is essential for electrocyclization.(4)
Thermally generated arylvinylketenes containing an enol undergo Friedel-Crafts-type electrocyclization to furnish naphthohydroquinones after tautomerization and naphthoquinones after oxidation in air (Eq. 5). More generally, benzo-fused dienylketenes are amenable to electrocyclization for the formation of naphthols and naphthoquinones.(5)
Electrocyclizations involving alkynes (e.g., alkynylenylketenes) are more complex than those of dienylketenes because a diradical intermediate is involved (Eq. 6). The diradical can undergo additional processes depending on the substitution pattern of the starting material, providing access to a variety of products.(6)
Periselectivity concerns the preference of a substrate to undergo a particular mode of cycloaddition. In cycloadditions of vinylketenes and related substrates, periselectivity is unclear in general, except in cases when steric or geometric factors favor either [4 + 2] or [2 + 2] cycloaddition. For example, vinylketenes that are restricted to an s-trans conformation engage solely in [2 + 2] cycloaddition with alkenes and alkynes.
Scope and Limitations
Historically, the scope of reactions that generate ketenes has placed limits on the the range of substrates amenable to ketene cycloadditions and electrocyclizations. The ketene is typically generated in the presence of the ketenophile such that it reacts immediately; thus, substrates that participate in cycloadditions must not react rapidly with the ketenophile or decompose under the conditions of ketene generation. Presently, conjugate ketenes can be prepared using many of the same methods available for simple ketenes. Other methods particular to conjugated ketenes, such as cyclobutenone ring-opening, are commonly used as well.
Dehydrochlorination is commonly used for the preparation of simple ketenes, and this method can be applied to allylic acid chlorides to prepare vinylketenes as well. For example, in the presence of proton sponge, a quinuclidine catalyst, and a Lewis acidic catalyst, 3-butenoylchloride undergoes dehydrochlorination and [2 + 2] cycloaddition with an imine to form a β-lactam (Eq. 7). This particular type of cycloaddition is a very important method for the preparation of β-lactams, and the vinyl group provides a handle for additional transformations.(7)
Electrocyclic ring-opening of cyclobutenones affords vinylketenes with ideal atom economy. The reversibility of ring-opening can prove advantageous when isolation of the cyclobutenone is important, as cyclobutenones can be synthesized from intermediate vinylketenes. In the example below, palladium-catalyzed carbonylation of an alkenyl triflate affords vinylketene 3, which closes spontaneously to yield the cyclobutenone 4. Subsequent heating in the presence of methanol as a trap for the vinylketene produces a 1:1 mixture of alkenic and allylic esters (Eq. 8).(8)
Vinylketenes can also engage in [4 + 2] cycloaddition with alkenes. The vinylketene below is generated via thermal activation of a cyclobutenone, and reacts with an α,β-unsaturated ketone to afford a phenol after metal-catalyzed dehydrogenation (Eq. 9).(9)
In concerted [2 + 2] cycloadditions of ketenes with alkenes, the rules of orbital symmetry suggest that the ketene reacts antarafacially and the alkene suprafacially. As a consequence, the lower-energy transition state in reactions of prochiral ketenes leads to the more sterically hindered diastereomer. As the size mismatch of substituents on the ketene increases, the effect becomes more pronounced (Eq. 10).(10)
Intramolecular cycloadditions of ketenes provide an efficient route to polyclic frameworks containing cyclobutanones, such as bicyclo[3.2.0]heptanone (Eq. 11). Subsequent ring-expansion of the cyclobutanone can yield cyclopentanones.(11)
Dienylketenes engage in 6π electrocyclization to afford hydroquinones, quinones, and phenols (the latter two after oxidation). Fusion of a benzene ring or heteroaromatic ring to the dienylketene moiety leads to polycyclic and/or heteroaromatic products. For example, a variety of heteroaromatic ring systems can be accessed via electrocyclic ring-closing of heteroaromatic vinylketenes. Hemiaminals derived from cyclobutenediones afford indolizine-5,8-diones after electrocyclization and oxidation (Eq. 12).(12)
Due to the pharmaceutical importance of β-lactams, there has been considerable interest in the [2 + 2] cycloaddition of ketenes with imines to form β-lactams. In many cases, vinylketenes react selectively with imines to form β-lactams rather than δ-lactams (which would form after [4 + 2] cycloaddition). In these reactions trans products are generally favored, although some cis product can be isolated at low temperatures (Eq. 13).(13)
Allenyl- and alkynylketenes can engage in cycloaddition and electrocyclization reactions as well. However, the practical scope of these reactions is more limited than reactions of vinylketenes because allenylketenes and alkynylketenes cannot be prepared via cyclobutenone ring-opening. Like other ketenes, allenylketenes are stabilized by silyl substituents. The isolable ketene below reacts with aldehydes in either the [2 + 2] or [4 + 2] mode in the presence of a Lewis acid catalyst, depending on the aldehyde substituent (Eq. 14).(14)
The ideal atom economy of cycloaddition and electrocyclization reactions makes them appealing candidates in the syntheses of natural products. [4 + 2] Cycloadditions of ketenes and alkenes in particular have been applied broadly for the synthesis of hydroxylated aromatic rings or quinones.
Electrocyclization of a benzo analogue of a dienylketene is used as a key step in the synthesis of (–)-nanaomycin D. The natural product is formed after deprotection, oxidation, and demethylation of the hydroquinone intermediate (Eq. 15).(15)
The ability of cycloaddition to afford complex cyclic structures with potential for future reactivity is nicely illustrated in a synthesis of (+)-retigeranic acid. After [2 + 2] cycloaddition to form the cyclobutenone, expansion of the four-membered ring and contraction of the six-membered ring afford the natural product (Eq. 16).(16)
Comparison to Other Methods
Vinylketene cycloaddititions and electrocyclizations provide a useful alternative to nucleophilic aromatic substitution and Friedel-Crafts reactions for the synthesis of substituted phenols. For products with certain substitution patterns, [2 + 2] cycloaddition to form β-lactams or -lactones can be used instead of nucleophilic addition methods.
Metal-coordinated vinylketenes can be generated from Fischer carbenes and can close to form phenols or quinones (Eq. 17). Reaction yields in general are slightly higher for reactions starting from Fischer carbenes, but the substrate scope of these reactions is lower in general than reactions involving free vinylketenes. In addition, the use of free ketenes obviates the need for a metal catalyst or promoter.(17)
Diels-Alder cycloadditions of slightly different precursors can sometimes replace vinylketene cycloadditions for the synthesis of phenols. For example, the natural product furaquinocin C can be synthesized via a vinylketene cycloaddition or a Diels-Alder reaction followed by elimination (Eq. 18).(18)
Although the reaction of ketenes with imines is one of the most common methods for the synthesis of β-lactams, examples involving alternative modes of cycloaddition are known. For example, copper(I)-mediated Kinegusa cycloaddition of a nitrone with an alkyne affords β-lactams (Eq. 19).(19)
Experimental Conditions and Procedure
The most popular methods for generation of vinylketenes involve cyclobutenone ring opening, dehydrochlorination of acid chlorides, or Wolff rearrangement. In all cases, anhydrous solvents and inert atmosphere are essential. Vinylketenes may be generated either thermally or photochemically, and in some cases both are used to ensure that reactions that give light-absorbing products proceed to completion. A variety of solvents may be used, including aromatic and aliphatic hydrocarbons, chlorocarbons, acetonitrile, and ethers. In general, high-boiling aromatic hydrocarbons are used for cyclobutenone ring opening, while lower-boiling chlorocarbons are best for acid chloride dehydrochlorinations.
A solution of 2-bromo-2-butenoyl chloride (1.83 g, 10.0 mmol) in CH2Cl2 (10 mL) was added over 1 h to a solution of 1-(2-methyl-1-propenyl)pyrrolidine (1.25 g, 10.0 mmol) and triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (20 mL) at rt. The mixture was allowed to stand for 6 h at rt, after which time it was washed with H2O (20 mL) and saturated, aqueous NaHCO3. The amine was extracted from the organic phase with 5% aqueous HCl (2 × 20 mL) and the combined extracts were washed with Et2O (2 × 10 mL), basified by addition of excess solid K2CO3, and extracted with CH2Cl2. Drying and evaporation of the organic layer afforded crude product (2.50 g, 92%) as a dark-colored oil: UV (EtOH) λmax (log ε) 247 nm (4200); IR (film) 1680 (s) cm–1; 1H NMR (CDCl3) δ 7.28 (t, J = 4.5 Hz, 1H), 3.15 (t, J = 5 Hz, 1H), 2.7–1.4 (m, 10H), 1.23 (s, 3H), 1.17 (s, 3H); LRMS-EI (m/z): M+ 271. Hydrochloride: mp 186–188 ºC. Anal. Calcd for C12H19BrClNO: C, 46.70; H, 6.21; N, 4.54. Found: C, 47.28; H, 5.89; N, 4.56.
- ↑ Fu, N.; Tidwell, T. T. Org. React. 2015, 87, 2. (link)
- ↑ Nelson, S. G.; Dura, R. D.; Peelen, T. J. Org. React. 2013, 82, 1. (link)
- ↑ Jenny, E. F.; Roberts, J. D. J. Am. Chem. Soc. 1956, 78, 2005.
- ↑ Chapman, O. L.; Lassila, J. D. J. Am. Chem. Soc. 1968, 90, 2449.
- ↑ Tidwell, T. T. Ketenes, 2nd ed.; Wiley: Hoboken, NJ, 2006.
- ↑ Nguyen, M. T.; Ha, T. K.; More O'Ferrall, R. A. J. Org. Chem. 1990, 55, 3251.
- ↑ Parker, J. K.; Davis, S. R. J. Am. Chem. Soc. 1999, 121, 4271.
- ↑ Mohamed, M.; Gonsalves, T. P.; Whitby, R. J.; Sneddon, H. F. Harrowven, H. C. Chem.—Eur. J. 2011, 17, 13698.
- ↑ Karlsson, J. O.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. J. Am. Chem. Soc. 1985, 107, 3392.
- ↑ Wuest, J. D. Tetrahedron 1980, 36, 2291.
- ↑ France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206.
- ↑ Quinkert, G.; Scherer, S.; Reichert, D.; Nestler, H.-P.; Wennemers, H.; Ebel, A.; Urbahns, K.; Wagner, K.; Michaelis, K.-P.; Wiech, G.; Prescher, G.; Bronstert, B.; Freitag, B.-J.; Wicke, I.; Lisch, D.; Belik, P.; Crecelius, T.; Hörstermann, D.; Zimmermann, G.; Bats, J. W.; Dürner, G.; Rehm, D. Helv. Chim. Acta 1997, 80, 1683.
- ↑ Marsden, S. P.; Pang, W.-K. Chem. Commun. (Cambridge) 1999, 1199.
- ↑ Toivola, R. J.; Savilampi, S. K.; Koskinen, A. M. P. Tetrahedron Lett. 2000, 41, 6207.
- ↑ Kondo, T.; Niimi, M.; Nomura, M.; Wada, K.; Mitsudo, T.-A. Tetrahedron Lett. 2007, 48, 2837.
- ↑ Danheiser, R. L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37, 3943.
- ↑ Huston, R.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1982, 65, 451.
- ↑ Lee, S. Y.; Kulkarni, Y. S.; Burbaum, B. W.; Johnston, M. I.; Snider, B. B. J. Org. Chem. 1988, 53, 1848.
- ↑ Yerxa, B. R.; Moore, H. W. Tetrahedron Lett. 1992, 33, 7811.
- ↑ Zamboni, R.; Just, G. Can. J. Chem. 1979, 57, 1945.
- ↑ Huang, W.; Tidwell, T. T. Synthesis 2000, 457.
- ↑ Winters, M. P.; Stranberg, M.; Moore, H. W. J. Org. Chem. 1994, 59, 7572.
- ↑ Corey, E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339.
- ↑ King, J.; Quayle, P.; Malone, J. F. Tetrahedron Lett. 1990, 31, 5221.
- ↑ Smith, A. B., III; Sestelo, J. P.; Dormer, P. G. J. Am. Chem. Soc. 1995, 117, 10755.
- ↑ Michalak, M.; Stodulski, M.; Stecko, S.; Mames, A.; Panfil, I.; Mikozajczyk, P.; Soluch, M.; Furman, B.; Chmielewski, M. J. Org. Chem. 2011, 76, 6931.
- ↑ Berge, J. M.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1982, 65, 2230.