Carbonylation of epoxides
Carbonylation of epoxides involves the ring-expanding formal insertion of carbon monoxide into one of the C–O bonds of an epoxide. In reactions catalyzed by Lewis acid cobaltate complexes, simple epoxides afford β-lactones while hydroxyl-substituted epoxides may afford larger lactones. γ-Lactones and δ-lactones may be the major products in reactions of alkenyl epoxides catalyzed by iron, palladium, or rhodium.
Although β-lactones are of great interest for their pharmaceutical properties, relatively few methods exist for the reliable synthesis of β-lactones. Ring-expanding carbonylation of epoxides is an atom economical and versatile method for construction of β-lactones, larger lactones, and other carbonyl-containing heterocycles (Eq. 1). Reactions catalyzed by Lewis acid cobaltate complexes exhibit stereospecifity and may be combined with stereocontrolled epoxidation to facilitate the rapid construction of lactones from simple starting materials.(1)
Carbonylation of epoxides requires a metal catalyst to facilitate insertion of CO into one of the C–O bonds of the epoxide. Well-defined complexes containing a Lewis acid and the tetracarbonylcobaltate anion have emerged as useful catalysts for site-selective and stereospecific carbonylation to form β-lactones. The Lewis acids in these catalysts are typically aluminum or chromium(III) cations coordinated by a salen or porphyrin ligand (Eq. 2).(2)
The number of catalysts available for epoxide carbonylation is very large, and the scope of the reaction is consequently expansive. This page focuses exclusively on reactions that afford β-, γ-, and δ-lactones. Reactions that afford succinic anhydrides, 1,3-oxazinane-2,4-diones, and 1,3-oxathiolan-2-ones are described in greater detail in the corresponding Organic Reactions chapter.
Mechanism and Stereochemistry
The generally accepted mechanism for reactions catalyzed by well defined Lewis acid cobaltate complexes begins with coordination of the epoxide to the Lewis acid followed by SN2-type opening of the epoxide at the less substituted carbon. Insertion of CO into the cobalt-carbon bond with coordination of a molecule of CO to cobalt affords a cobalt acyl complex, which is the resting state of the catalyst. Addition-elimination regenerates the catalyst and forms the β-lactone product (Eq. 3). Reactions of monosubstituted epoxides generally yield the β-substituted β-lactone, supporting the idea that opening of the epoxide occurs via an SN2 process.(3)
Although 1,2-disubstituted epoxides typically yield mixtures of constitutional isomers, these substrates can serve as useful stereochemical probes. trans-1,2-Disubstituted epoxides yield cis products exclusively (Eq. 4), suggesting that these reactions are stereospecific. Ring opening occurs with inversion of stereochemistry, again consistent with SN2-type attack by cobaltate.(4)
Iron, palladium, and rhodium complexes mediate or catalyze the ring-expanding carbonylation of epoxides with unsaturated substituents, including alkenyl and aryl epoxides. These reactions involve intermediate π-allyl complexes, which can be isolated from stoichiometric reactions with Fe2(CO)9. Oxidation of the diastereomeric complexes with ceric ammonium nitrate (CAN) affords a mixture of cis- and trans-β-lactones (Eq. 5). In these reactions, insertion of CO into a metal-oxygen bond occurs, followed by reductive elimination to establish the new carbon-carbon bond.(5)
Substrates containing hydroxyl groups proximal to the epoxide, such as glycidols and homoglycidols, may react to form γ- and δ-lactones respectively. The mechanisms of these reactions are analogous to the mechanism of β-lactone formation shown in Eq. 3, with a pendant hydroxyl group responsible for addition-elimination rather than the epoxide oxygen. The selectivity for larger lactone formation over β-lactone formation depends on the catalyst used. Rearrangement of initially formed β-lactones to form larger lactones under these conditions has been ruled out.
Reactions of alkenyl epoxides catalyzed by palladium and iron may afford δ-lactones if reductive elimination occurs at the far end of the allylic ligand.
Scope and Limitations
Epoxide carbonylation is catalyzed by many different types of metal complexes, and the structure of the catalyst and substitution pattern of the epoxide both affect the structure of the major product. This section focuses on reactions that afford four-, five-, and six-membered lactones and emphasizes the role of substrate structure in determining the product distribution of carbonylation reactions. More subtle details of catalyst structure are addressed in the corresponding Organic Reactions chapter.
Carbonylation reactions employing Lewis acid cobaltate catalysts and monosubstituted epoxides generally give the β-substituted lactone rather than the α-substituted lactone. SN2-type substitution at the less substituted carbon of the epoxide leads ultimately to the β-substituted lactone. Epoxides that can form stabilized carbocations upon ring opening may form the α-substituted isomer upon carbonylation. For example, aryl epoxides react via an SN1-type pathway to afford α-aryl-β-lactones (Eq. 6).(6)
Well defined Lewis acid cobaltate catalysts are more active than catalysts generated in situ and exhibit good functional group tolerance. Esters, amides, nitriles, halogens, acetals, and distant hydroxyl groups are well tolerated. Strongly Lewis basic functional groups such as amines interfere with carbonylations.
1,1-Disubstituted epoxides often form mixtures of isomeric β-lactone products in the presence of Lewis acid cobaltate catalysts (Eq. 7). SN1-type reactivity via a carbocation intermediate competes with the SN2-type reactivity characteristic of monosubstituted alkyl epoxides.(7)
1,2-Disubstituted alkyl epoxides do not generally react with site selectivity. However, one recent report has identified catalysts that exhibit site selectivity in reactions of epoxides with substituents of different sizes.
Cyclic epoxides sometimes represent an exception to the rule of stereochemical inversion in carbonylations with Lewis acid cobaltate catalysts, if the resulting β-lactone would possess considerable ring strain. For example, cis-cyclopentene oxide gives the cis-β-lactone product via a carbocation intermediate after very long reaction time. cis-Cyclohexene oxide is completely unreactive and cis-cyclooctene oxide forms the corresponding trans-β-lactone relatively rapidly (Eq. 8).(8)
The palladium complex Pd2(C4H7)2Cl2 catalyzes carbonylation of alkenyl epoxides; however this reaction is not always the major process that occurs (Eq. 9). Reaction with the alcoholic solvent can lead to ring opening or β,γ-unsaturated ester formation.(9)
Glycidols contain a hydroxyl group in the appropriate position to form γ-lactones. Because glycidols can also form β-lactones, a judicious choice of catalyst is critical to favor the γ-lactone. Substrates with substitution in the hydroxymethyl substituent tend to exhibit lower yields than glycidol itself. Co4(CO)12 has been identified as a catalyst for the selective formation of γ-lactones from glycidols (Eq. 10). Dehydration of the resulting 3-hydroxy-δ-lactones affords butenolides, an important class of γ-lactones.(10)
Ynolates generated in situ via treatment of diazo compounds with butyllithium and carbon monoxide react with epoxides to form γ-lactones (Eq. 11). This reaction occurs with inversion at the carbon attacked by ynolate, but unselective protonation gives a mixture of diastereomeric α-silyl esters.(11)
Homoglycidols can react analogously to glycidols to afford δ-lactones. Reactions employing Lewis acid cobaltate complexes give mixtures of β- and δ-lactones when homoglycidols are used as substrates, but the acidic cobalt tetracarbonyl hydride has been shown to selectively catalyze δ-lactone formation (Eq. 12).(12)
The iron carbonyl complexes Fe(CO)5 and Fe2(CO)9 promote the carbonylation of alkenyl epoxides to β- or δ-lactones. Substitution is well tolerated throughout the alkenyl epoxide, and selectivity for the δ-lactone can be achieved through careful choice of the catalyst (Eq. 13).(13)
β-Lactones are synthetically valuable both as lipase inhibitors and as monomers for biodegradable polyesters. However, the β-lactone moiety presents a synthetic challenge because of its considerable ring strain and propensity to open under acidic or basic conditions. To survive a synthesis, β-lactones generally must be installed at a late stage. Epoxide carbonylation is an attractive method for the synthesis of β-lactones owing to the atom economy, functional group tolerance, and accessible starting materials of the transformation.
A prototypical example of the use of epoxide carbonylation for organic synthesis is found in a synthesis of (–)-valilactone. Ring-expanding carbonylation using stoichiometric Fe2(CO)9 was followed by peptide coupling, deprotection of the amino group, and formylation. Although the yield of the carbonylation step was only 26%, this step was critical in establishing the β-lactone core of the target.(14)
Comparison to Other Methods
Carbonylative ring expansion of epoxides is generally an efficient method for the synthesis of lactones. Nonetheless, a huge variety of methods exist for the synthesis of lactones, each with its own advantages and disadvantages. This section focuses on a limited number of popular alternatives for the synthesis of β-, γ-, and δ-lactones.
β-Lactones may be formed via ring closure of β-hydroxy carboxylic acids or β-haloacids. The latter methods have been superseded by the former, which are generally based on a Mitsunobu approach that inverts the configuration of the carbon bearing the hydroxyl group. Mitsunobu conditions can be problematic, however, as activation of the carboxylic acid group can compete with activation of the hydroxyl group. Arenesulfonyl chlorides selectively activate the carboxylic acid.
β-Lactones are the products of \[2+2\] cycloaddition of ketenes with aldehydes. Highly enantioselective variants of this reaction have been developed, and cycloaddition is arguably the most efficient way to establish the β-lactone skeleton. Enantioselective reactions generally rely on chiral quinine or quinidine catalysts (Eq. 16) and exhibit remarkably high enantioselectivity. However, generation of complex substituted ketenes is typically accomplished through dehydrohalogenation of acid chlorides, which may require harsh reaction conditions.(16)
Because γ-lactones lack ring strain, a large number of methods exist for the synthesis of these five-membered heterocycles. Some useful methods include Mitsunobu reactions, halolactonization, acid-activating agents such as dicyclohexylcarbodiimide, Baeyer-Villiger oxidations of cyclobutanones, and desymmetrizing reductions of succinic anhydrides.
One approach that is conceptually similar to glycidol carbonylation involves the enantioselective dihydroxylation of a β,γ-unsaturated ester followed by lactonization. 3-Hydroxy-γ-lactones are formed with high enantioselectivity and in excellent yield.(17)
δ-Lactones may be synthesized via ring opening of an epoxide by a homoenolate equivalent followed by lactonization (Eq. 18). In the example below, after deprotonation of the acidic α-carbon of the sulfonate and opening of the epoxide, the orthoester is unmasked to an ester and lactonization is facilitated by tosic acid. Subsequent elimination of sulfonate affords an unsaturated δ-lactone.(18)
Experimental Conditions and Procedure
Carbonylations of epoxides are universally performed in environments free of water and oxygen to avoid catalyst decomposition and side reactions. Reactions may be prepared either in a drybox or using standard Schlenk techniques. Carbon monoxide is a highly toxic, odorless, and invisible gas, so these reactions should be conducted in a well-ventilated fume hood or box equipped with a CO detector. High pressures of CO (10-60 atm) are generally required to achieve selective carbonylation; at low pressures, isomerization of epoxides to ketones or other side reactions may occur. A variety of different solvents have been used, as solvent can affect the relative rates of carbonylation and competing processes.
In a drybox, salphCr (182 mg, 0.200 mmol) was weighed into a 500-mL, oven-dried, three-neck round-bottomed flask with a magnetic stir bar. A dry, 50-mL addition funnel was attached, along with a stopper and a rubber septum. DME (9.0 mL) was drawn into a Gastight syringe while phenyl glycidyl ether (1.50 g, 10.0 mmol) was drawn into a separate syringe with 1.0 mL DME. The flask was removed to a fume hood where the flask was sparged with CO for 10 min before a double balloon of CO was attached to the flask using a needle to puncture the septum. The flask was then placed into an ice bath, the DME was added to the catalyst, and the mixture was stirred for 10 min. The epoxide solution was added dropwise at 0 °C via the addition funnel over the course of 30 min while stirring. After epoxide addition was complete, the ice bath was removed and the flask was allowed to warm to rt and was stirred for 24 h. The flask was vented in a fume hood and the reaction mixture was concentrated under vacuum to an oil. The crude oil was purified by chromatography through silica gel with CH2Cl2, and then was recrystallized from CH2Cl2/hexanes to afford 4-phenoxymethyl-2-propiolactone (1.5 g, 84%): mp 75–77 °C; IR (neat, NaCl) 1818 (C=O) cm–1; 1H NMR (CDCl3, 300 MHz) δ 7.31 (t, 3J = 7.9 Hz, 2H), 7.00 (t, 3J = 7.3 Hz, 1H), 6.92 (d, 3J = 8.2 Hz, 2H), 4.83 (dddd, 3J = 3.0, 4.4, 5.1, 9.5 Hz, 1H), 4.32 (dd, 2J = 11.1 Hz, 3J = 3.0 Hz, 1H), 4.19 (dd, 2J = 11.1 Hz, 3J = 4.2 Hz, 1H), 3.55 (d, 3J = 5.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 167.5, 158.1, 129.8, 121.8, 114.8, 68.5, 67.3, 40.0; HRMS (EI) m/z: calcd for C10H10O3, 178.0630; found, 178.0630.
- ↑ Kramer, J. W.; Rowley, J. M.; Coates, G. W. Org. React. 2015, 86, 1. (link)
- ↑ Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174. (link)
- ↑ a b Rowley, J. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129, 4948.
- ↑ a b Kramer, J. W.; Treitler, D. S.; Coates, G. W. Org. Synth. 2009, 86, 287.
- ↑ Kramer, J. W.; Lobkovsky, E. B.; Coates, G. W. Org. Lett. 2006, 8, 3709.
- ↑ a b Shimizu, I.; Maruyama, T.; Makuta, T.; Yamamoto, A. Tetrahedron Lett. 1993, 34, 2135.
- ↑ a b Bates, R. W.; Fernandez-Moro, R.; Ley, S. V. Tetrahedron 1991, 47, 9929.
- ↑ a b Brima, T. S. U.S. Patent 4968817 (1990).
- ↑ Annis, G. D.; Ley, S. V.; Self, C. R.; Sivaramakrishnan, R. J. Chem. Soc., Perkin Trans. 1 1981, 270.
- ↑ Mulzer, M.; Coates, G. W. J. Org. Chem. 2014, ASAP. (link)
- ↑ Schmidt, J. A. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2005, 127, 11426.
- ↑ Kai, H.; Iwamoto, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 1996, 118, 7634.
- ↑ Kramer, J. W.; Joh, D. Y.; Coates, G. W. Org. Lett. 2007, 9, 5581.
- ↑ Aumann, R.; Ring, H.; Kruger, C.; Goddard, R. Chem. Ber. 1979, 112, 3644.
- ↑ Wu, Y.; Sun, Y.-P. J. Org. Chem. 2006, 71, 5748.
- ↑ Muller, H.-M.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1993, 32, 477.
- ↑ Mulzer, J.; Bruentrup, G.; Chucholowski, A. Angew. Chem. 1979, 91, 654.
- ↑ Black, T. H.; Hall, J. A.; Sheu, R. G. J. Org. Chem. 1988, 53, 2371.
- ↑ Nelson, S. G.; Dura, R. D.; Peelen, T. J. Org. React. 2013, 82, 1. (link)
- ↑ Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352.
- ↑ Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603.
- ↑ Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C. J. Am. Chem. Soc. 1983, 105, 5819.
- ↑ Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem. Soc. 1999, 121, 4724.
- ↑ Belluš, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797.
- ↑ Bailey, D. M.; Johnson, R. E. J. Org. Chem. 1970, 35, 3574.
- ↑ Carretero, J. C.; Ghosez, L. Tetrahedron Lett. 1988, 29, 2059.
- ↑ Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129, 8156.