Letter pubs.acs.org/OrgLett
Difluoromethylation of Carboxylic Acids via the Addition of Difluorinated Phosphorus Ylide to Acyl Chlorides Alexey L. Trifonov,†,‡ Vitalij V. Levin,† Marina I. Struchkova,† and Alexander D. Dilman*,† †
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation D. Mendeleev University of Chemical Technology of Russia, Higher Chemical College, Miusskaya sq. 9, 125047 Moscow, Russian Federation
‡
S Supporting Information *
ABSTRACT: A one-step protocol for the difluoromethylation of carboxylic acids is described. The reaction involves the interaction of intermediate acyl chlorides with in situ generated difluorinated phosphorus ylide Ph3PCF2. Aromatic acids can be selectively transformed within one step either to bis-difluoromethylated alcohols or to difluorinated ketones depending on the particular reaction conditions. For bulky α-branched carboxylic acids, only ketones are produced. ucleophilic fluoroalkylation reactions have emerged as a powerful tool for the direct introduction of fluorinated fragments by their addition to common functional groups.1 In response to the needs of medicinal chemistry over the past 20 years,2 major effort was devoted to the synthesis of CF3substituted compounds.3,4 In recent times, the difluoromethyl group has attracted significant attention, primarily, because of its unique stereoelectronic properties and ability to serve as a lipophilic hydrogen bond donor.5 Concerning synthetic aspects, despite the seemingly little difference between CF3 and CF2H groups, methods for their introduction frequently require completely different conditions.6,7 Recently, we described a general approach for the introduction of the CF2H-group based on the application of difluorinated phosphorus ylide 18 (Scheme 1). This unstable
N
on reaction conditions. Given the increasing number of biologically active substances bearing the difluoromethyl11 and a polyfluorinated isopropyl group,12 compounds 3 and 4 would likely be interesting for medicinal chemistry and related fields.13 It should also be pointed out that known methods toward alcohols 3 are rare.14 Ylide 1 can be generated by different protocols,8−10 among which a combination of (bromodifluoromethyl)trimethylsilane (Me 3SiCF 2 Br),15 triphenylphosphine, and DMPU (1,3dimethylpropyleneurea) constitutes the mildest conditions8b (Scheme 2). When 4-methoxybenzoyl chloride was treated with 1 equiv of in situ generated ylide in acetonitrile at room temperature, a mixture of mono- and diphosphonium salts 5 and 6 was obtained according to 19F NMR spectroscopy. The predominant formation of double-addition salt 6 suggests the higher reactivity of primary product 5 compared to starting acyl
Scheme 1. Difluoromethylation Using Phosphorus Ylide 1
Scheme 2. Reaction of 4-Methoxybenzoyl Chloride
species9 can be trapped with various electrophiles,8,10 whereas the CF2H-group is formed upon facile hydrolysis of the C−P bond. Aldehydes and ketones proved to be good electrophiles for the coupling with ylide 1 furnishing CF2H-substituted alcohols.8 Herein we report the application of this concept to nucleophilic difluoromethylation of acyl chlorides 2 affording either mono- or double-addition products 3 and 4 depending © 2017 American Chemical Society
Received: August 22, 2017 Published: September 15, 2017 5304
DOI: 10.1021/acs.orglett.7b02601 Org. Lett. 2017, 19, 5304−5307
Letter
Organic Letters Table 1. Synthesis of Alcohols 3
a
Isolated yield.
chloride. Use of 2.5 equiv of the silane/phosphine system, which is equal to 1.25 equiv of the ylide required for the double addition, led to the formation of salt 6 as a single product. Though acyl chlorides can be used as isolated reagents, we decided to generate them from carboxylic acids by treatment with oxalyl chloride in the presence of catalytic amounts of DMF. The obtained acyl chlorides were subjected to difluoromethylation in the same flask without purification (Table 1). The intermediate diphosphonium salts 6 were dephosphorylated and desilylated by the addition of pyridine and water followed by brief heating at 80 °C. The dephosphorylation likely proceeds through the hydroxide attack at the positively charged phosphorus followed by protonation of the polarized C−P bond. Using this protocol, aromatic and heteroaromatic substrates provided alcohols 3 in high yields based on carboxylic acids. Cyano and nitro groups, as well as methyl ester, remained unaffected (entries 3−5). Aliphatic and α,β-unsaturated substrates gave reduced yields of products (entries 13 and 14). When the typical procedure was applied to bulky acyl chlorides (for example, from 1-adamantanecarboxylic acid), the corresponding monoaddition salt 5 did not undergo further reaction of the ylide even under forcing conditions (Scheme 3). It was also found that diphosphonium salts 6 derived from aromatic acyl chlorides can be converted back to monophosphonium salts 5 when heated at 100 °C. Another specific example was noted for phenyl acetic acid chloride. Thus, under typical conditions, phosphonium salt 7 was formed, likely
Scheme 3. Generation of Monophoshopnium Salts
resulting from the addition to intermediate ketene. Protodephosphorilation of salts 5 and 7 with pyridine/water afforded corresponding difluoroketones. Using these procedures (method A, conventional conditions; method B, heating of the double addition intermediate), a series of carboxylic acids were converted to α,α-difluorinated ketones 4 in good yields within one experimental step (Table 2). The standard conditions were applied to phthalic anhydride (Scheme 4). In this case, the reaction required a longer time than in the case with acyl chlorides and, after hydrolysis, furnished lactone 9, presumably, through the intermediacy of ring-opened diphosphonium salt 8. In summary, a method for the one-step conversion of carboxylic acids to valuable compounds based on difluorinated phosphorus ylide is described. Aromatic acids can be converted 5305
DOI: 10.1021/acs.orglett.7b02601 Org. Lett. 2017, 19, 5304−5307
Organic Letters Table 2. Synthesis of Difluorinated Ketones 4
Letter
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ACKNOWLEDGMENTS
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REFERENCES
This work was supported by the Russian Science Foundation (Project 17-13-01041). We are grateful to Mr. Artem Zemtsov (N. D. Zelinsky Institute of organic chemistry) for experimental assistance.
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a Conditions for the difluoromethylation step: (Method A) MeCN, rt, 5 h; (Method B) MeCN, rt, 5 h, then DMF, 100 °C, 1.5 h. bIsolated yield.
Scheme 4. Difluoromethylation of Phthalic Anhydride
either to bis(difluoromethyl)-substituted alcohols or to difluorinated ketones depending on reaction conditions. At the same time, the reaction of bulky acids stops at the monoaddition step leading to ketones as single products.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02601. Experimental procedures, compound characterization data, copies of NMR spectra for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Alexander D. Dilman: 0000-0001-8048-7223 Notes
The authors declare no competing financial interest. 5306
DOI: 10.1021/acs.orglett.7b02601 Org. Lett. 2017, 19, 5304−5307
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