Sodium Methyl Carbonate as an Effective C1 Synthon. Synthesis of

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Sodium Methyl Carbonate as an Effective C1 Synthon. Synthesis of Carboxylic Acids, Benzophenones, and Unsymmetrical Ketones Timothy E. Hurst, Julie A. Deichert, Lucas Kapeniak, Roland Lee,† Jesse Harris, Philip G. Jessop,* and Victor Snieckus* Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, ON, Canada K7L 3N6 S Supporting Information *

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ABSTRACT: Reported is the synthesis of carboxylic acids, symmetrical ketones, and unsymmetrical ketones with selectivity achieved by exploiting the differential reactivity of sodium methyl carbonate with Grignard and organolithium reagents.

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he use of carbon dioxide as a C1 synthon in organic synthesis has a rich history stemming from its low cost, high abundance, and low toxicity.1 The Kolbe−Schmitt synthesis of salicylic acid derivatives from phenols and the Bosch−Mesier process for the production of urea from ammonia and carbon dioxide constitute key examples of industrial processes using CO2 as a reagent.2,3 The importance of CO2 as a building block is also evident in the traditional synthesis of carboxylic acids from CO2 and nucleophilic organometallic reagents, in particular highly reactive organolithium and Grignard reagents.4,5 In recent years, the directed ortho metalation (DoM) reaction, a powerful strategy for the construction of highly substituted aromatic and heteroaromatic compounds, has been used to apply carboxylation with CO2 as a wide-ranging method for the regioselective synthesis of 2substituted benzoic acids.6 Likewise, synthetic equivalents of the carbonyl dication CO+ + C1 synthon [e.g., (tri)phosgene, CDI, and dialkyl formamides] have proven to be invaluable in the synthesis of symmetrical ketones from organometallic species. Conversely, a general one-pot synthesis of unsymmetrical ketones under this reaction manifold has proven to be challenging. This problem has been addressed by Sarpong, whose carbonyl linchpin N,Odimethylhydroxylamine pyrrole (CLAmP) reagent allows the one-pot synthesis of unsymmetrical ketones from organolithium and Grignard reagents with a broad substrate scope.7 However, the synthesis of CLAmP involves a two-step procedure from costly reagents and requires purification via silica-gel chromatography. We considered metal alkyl carbonates 1 (Figure 1), which are stable solids at room temperature, to represent an attractive and inexpensive source of the C1 synthon. They are easily prepared by exposure of an alcoholic solution of the corresponding metal © XXXX American Chemical Society

Figure 1. Synthesis and reactivity of alkyl metal carbonates.

alkoxide to CO2 (pellets or gas) and simple filtration of the resulting solid product.8 In this manner, control over the desired electronic and steric properties of the alkyl metal carbonate is Received: March 1, 2019

A

DOI: 10.1021/acs.orglett.9b00773 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Synthesis of Carboxylic Acids from Sodium Methyl Carbonate (SMC) and Grignard Reagents

a

Commercially available Grignard reagent. bGrignard reagent prepared from the corresponding aryl bromide via magnesium−halogen exchange. Grignard reagent prepared from the corresponding alkyne via direct magnesiation.

c

readily achieved through simple selection of the appropriate metal counterion (Li, Na, K, or Mg) and alcohol solvent (primary, secondary, or tertiary). Furthermore, the ambiphilic nature of alkyl metal carbonates allows their use as a C1 synthon under a variety of different reaction manifolds (Figure 1). For example, lithium ethyl carbonate acts as a nucleophile upon treatment with alkyl halides, giving rise to an efficient synthesis of unsymmetrical carbonates (1 → 2).9 The electrophilic nature of sodium ethyl carbonate has been demonstrated in the synthesis of salicylic acid derivatives (1 → 3),10 which may be considered as analogous to the Kolbe−Schmitt process. Similarly, magnesium methyl carbonate (commercially available as a solution in DMF) has frequently been used in the carboxylation of activated methylene compounds, e.g., nitroalkanes, ketones, and enol ethers (1 → 4).11 More recently, potassium methyl carbonate has found application in the copper-catalyzed carboxylation of aryl boronates (1 → 5),12 and sodium tert-butyl carbonate was shown to be a unique base in the first catalytic Wittig reaction.13 Nevertheless, alkyl metal carbonates remain an underexplored class of reagents whose utility is ripe for further exploitation. Herein, we report the ability of sodium methyl carbonate (SMC) to act selectively as either a HCO2+ or a CO++ synthon in reactions with Grignard and organolithium species. Thus, we show that the reaction of SMC with Grignard reagents gives rise to the formation of carboxylic acids (including a 13C-labeled benzoic acid), while reaction with aryllithium reagents affords symmetrical ketones. Furthermore, we demonstrate the orthogonal reactivity of SMC with different organometallic nucleophiles and exploit it in a one-pot synthesis of unsymmetrical ketones. In view of the ready availability of reactants and procedural ease and convenience, the protocol is anticipated to be of considerable utility and application. In the initial experiment, addition of commercially available phenylmagnesium bromide to a suspension of sodium methyl carbonate (2 equiv) in THF (0.5 M) at room temperature afforded benzoic acid 6a in 88% yield. Decreasing the amount of

SMC to 1.2 equiv proved to be detrimental to the reaction, giving benzoic acid in a reduced yield of 63%. In pursuit of generalization of the reaction, the addition of variously substituted aryl Grignard reagents to SMC was undertaken (Scheme 1). The sterically encumbered mesityl Grignard (6c) was well tolerated, as were aromatics bearing electron-donating (6e−g) and electron-withdrawing substituents (6h−k). Addition of commercially available [3-bis(trimethylsilyl)amino]phenylmagnesium chloride to the SMC electrophile afforded 3-aminobenzoic acid (6e) due to cleavage of the TMS groups upon acidic workup. Furthermore, the alkenyl Grignard reagent 1-methyl-1-propenylmagnesium bromide proved to be an equally viable substrate, producing an inseparable 2:1 mixture of tiglic (6m) and angelic (6m′) acids in a combined 82% yield. To further explore the scope of SMC as a CO2 surrogate electrophile, both primary and secondary aliphatic Grignard reagents were exposed to our standard conditions to furnish the corresponding carboxylic acids (6n−p) in excellent yields. Finally, alkynyl Grignards were also reactive substrates, delivering propiolic acids bearing at the terminus aromatic (6q), vinylic (6r), or aliphatic (6s and 6t) groups. Efforts to expand the scope of this method to a number of heterocyclic substrates, prepared by either direct magnesiation or magnesium−halogen exchange, proved to be unsuccessful. From a comparative practical point of view, these reactions (a) proceed at room temperature with only 2 equiv of SMC whereas, in stark contrast, carboxylations with CO2 often require low-temperature conditions (−78 or −45 °C), (b) require minimal organic solvent, being routinely run at a concentration of 0.5 M, and (c) afford pure carboxylic acids that require no purification by column chromatography. Taken in sum, these results demonstrate SMC as an effective CO2 surrogate electrophile. The use of SMC to facilitate the synthesis of a 13C-labeled carboxylic acid was also achieved (Scheme 2). [13C]SMC was prepared by exposing a methanolic solution of NaOMe to 13CO2 B

DOI: 10.1021/acs.orglett.9b00773 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Synthesis of 13C-Labeled Mesitoic Acid (13C-6c) from [13C]Sodium Methyl Carbonate (13C-SMC)

Scheme 4. Synthesis of Symmetrical Ketones from Sodium Methyl Carbonate (SMC) and Aryllithium Reagents

gas and subsequent filtration of the product. During the process, treatment of mesitylmagnesium bromide with [13C]SMC delivered carboxylic acid [13C]6c in 52% yield, thus demonstrating the ability of SMC to act as an effective carrier for isotopic labeling. The carboxylation reaction of Grignard reagents was then compared to the corresponding reaction of organolithiums, commencing with commercially available phenyllithium (9; Ar = Ph) as the standard substrate. In stark contrast to the reaction of Grignard reagents, the addition of PhLi to SMC provided the corresponding symmetrical ketone 7a in 76% yield (Scheme 3). Scheme 3. Reaction of Sodium Methyl Carbonate (SMC) with Phenyllithium (PhLi) a

Commercially available aryllithium reagent. bAryllithium reagent prepared from the corresponding aryl bromide via lithium−halogen exchange.

corresponding reaction of 1-lithionaphthalene gave 1-butylnaphthalene (55% yield) as the major product, along with 1naphthoic acid (24%). The formation of the alkylated product was rationalized by preferential reaction of the aryllithium with bromobutane formed as a byproduct during the lithium− halogen exchange. However, preparation of 2,2′-disubstituted benzophenones was not precluded entirely, with the addition of 2-lithioanisole to SMC giving 2,2′-dimethoxybenzophenone 7e in 46% yield. The lower yield of isolated 7f, derived from a more highly electron-rich aryllithium, is due to impedance of the second addition to the carboxylate intermediate, as evidenced by isolation of the corresponding carboxylic acid as the major product. Interestingly, the reaction of 2,2′-dilithiobiphenyl with SMC affords fluorenone 7g in modest yield through an intramolecular cyclization reaction.15 Having established the utility of SMC as both a HCO2+ and a CO++ synthon owing to its differential reactivity with Grignard reagents and alkyllithiums, we found the possibility of making unsymmetrical ketones in a one-pot procedure to be an attractive prospect. During the process, addition of an initial Grignard reagent (8) to SMC delivered the expected intermediate carboxylate salt (10), which remains stable under the reaction conditions. Subsequent addition of the organolithium to the reaction medium initiates nucleophilic attack on the carboxylate salt and generated an unsymmetrical ketone (11) in a single pot (Scheme 5). To generalize, the addition of variously substituted aromatic Grignard reagents to SMC followed by addition of PhLi delivered the unsymmetrical benzophenone derivatives 11a−c in synthetically useful yields (Scheme 5). Incorporation of a

This result was unexpected, because the classical reaction of PhLi with CO2 delivers benzoic acid as the sole product. The exclusive ketone formation may be rationalized by reference to the textbook reaction of lithio carboxylates with RLi reagents. In our case, presumably due to the attenuated electrophilicity of SMC compared to CO2, reaction of the intermediate lithio carboxylates with the organolithium reagent is fast compared to that with SMC itself. This is in contrast to the reaction of the less nucleophilic Grignard reagents. Attempts to retard the second addition of PhLi to the carboxylate intermediate by varying the stoichiometry, temperature, and solvent were explored and proved to be unsuccessful.14 When the reaction was performed in less polar solvents such as hexane or diethyl ether, benzophenone formation once again prevailed. With this result in hand, we established the generality of the reaction of aryllithiums with SMC to give symmetrical benzophenones (Scheme 4). The reaction was found to be applicable also to organolithium reagents prepared from the corresponding bromides via lithium−halogen exchange, giving symmetrical ketones 7b−d in moderate yield. In contrast to the formation of carboxylic acids, the synthesis of ketones proved to be more sensitive to steric effects. For example, while 2lithionaphthalene delivered ketone 7d in 43% yield, the C

DOI: 10.1021/acs.orglett.9b00773 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 5. One-Pot Synthesis of Unsymmetrical Ketones by Sequential Addition of Grignard and Aryllithium Reagents to Sodium Methyl Carbonate (SMC)

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Experimental procedures (PDF) Copies of 1H and 13C NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Philip G. Jessop: 0000-0002-5323-5095 Victor Snieckus: 0000-0002-6448-9832 Present Address †

R.L.: Department of Physical Sciences, MacEwan University, 5138S, City Centre Campus, 10700-104 Avenue, Edmonton, AB, Canada T5J 4S2. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS V.S. thanks NSERC DG for continuing support of synthetic programs. P.G.J. thanks the Canada Research Chairs Program. (1) (a) Niemi, T.; Repo, T. Eur. J. Org. Chem. 2019, 2019, 1180. (b) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat. Commun. 2015, 6, 5933. (c) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (2) Lindsey, A. S.; Jeskey, H. Chem. Rev. 1957, 57, 583. (3) Clark, K. G.; Hetherington, H. C. J. Am. Chem. Soc. 1927, 49, 1909. (4) Correa, A.; Martín, R. Angew. Chem., Int. Ed. 2009, 48, 6201. (5) Grignard, V. Ann. Chim. 1901, 24, 433. (6) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: New York, 2002; p 330. (7) Heller, S. T.; Newton, J. N.; Fu, T.; Sarpong, R. Angew. Chem., Int. Ed. 2015, 54, 9839. (8) (a) Ziebart, C.; Federsel, C.; Anbarasan, P.; Jackstell, R.; Baumann, W.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2012, 134, 20701. (b) Brillon, D.; Sauvé, G. J. Org. Chem. 1990, 55, 2246. (9) Yildirimyan, H.; Gattow, G. Z. Z. Anorg. Allg. Chem. 1985, 521, 135. (10) Suerbaev, K. A.; Aldabergenov, M. K.; Kudaibergenov, N. Zh. Green Process. Synth. 2015, 4, 91. (11) (a) Isaacs, R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938. (b) Stiles, M.; Finkbeiner, H. L. J. Am. Chem. Soc. 1959, 81, 505. (12) Duong, H. A.; Nguyen, T. M.; Rosman, N. Z. B.; Tan, L. J. L. Synthesis 2014, 46, 1881. (13) Coyle, E. E.; Doonan, B. J.; Holohan, A. J.; Walsh, K. A.; Lavigne, F.; Krenske, E. H.; O’Brien, C. J. Angew. Chem., Int. Ed. 2014, 53, 12907. (14) See the Supporting Information for details. (15) The attempted synthesis of symmetrical aliphatic ketones (e.g., by reaction of s-BuLi or n-HexLi with SMC) failed, with only decomposition products being observed.

heterocycle was also accomplished through the use of 2thienyllithium to give 11d in 40% yield. As a further extension of this methodology, the synthesis of acetophenone derivatives was examined. Crucially, the aliphatic group could be introduced either as the organolithium or Grignard reagent. Thus, treatment of SMC first with phenylmagnesium bromide and then with hexyl- or s-butyllithium delivered 11e and 11f in good yields. In a similar manner, addition first of cyclohexylmagnesium chloride and then PhLi gave unsymmetrical ketone 11g in 48% yield. Finally, unsymmetrical aliphatic ketone 11h was also prepared in 37% yield via treatment of SMC with phenethylmagnesium chloride followed by n-hexyllithium. In summary, we have demonstrated the utility of SMC as a simple and effective C1 synthon in the synthesis of carboxylic acids and symmetrical ketones. The attenuated electrophilicity of SMC compared to that of CO2 allows its selective application as either a HCO2+ or a CO++ synthon simply by choice of the appropriate organometallic coupling partner. In addition, we established this differential reactivity in a one-pot synthesis of unsymmetrical benzophenone and acetophenone derivatives. SMC is easy to prepare, using inexpensive reagents and isolation by simple filtration, in contrast to alternative reagents that require multistep syntheses from toxic and expensive precursors (phosgene and CDI) and chromatography. We anticipate that this method will complement or surpass traditional methods (e.g., Friedel−Crafts), enjoy broad application, and stimulate further studies on the use of alkyl metal carbonates in organic synthesis.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00773. D

DOI: 10.1021/acs.orglett.9b00773 Org. Lett. XXXX, XXX, XXX−XXX