Ion-Pair Extraction of Quaternary Ammoniums Using

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Ion-Pair Extraction of Quaternary Ammoniums Using Tetracyanocyclopentadienides and Synthetic Application for Complex Ammoniums

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Takeo Sakai,* Naotaka Noda, Chisato Fujimoto, Miho Ito, Harumi Takeuchi, Moeri Nishiwaki, and Yuji Mori Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan S Supporting Information *

ABSTRACT: A simple isolation method for quaternary ammonium cations via ion-pair extraction using tetracyanocyclopentadienide (TCCP) was established. Separation of tetraethylammonium and carbachol cations was achieved by the selective extraction of tetraethylammonium with ethoxycarbonyl TCCP, which was moderately lipophilic. The ion-pair extraction with TCCPs was applied to the synthesis of complex quaternary ammonium salts, including a spiro vinylammonium that is a precursor of the novel 3-aza-Cope−Mannich cascade.

Q

hydrophobic anions. While the ion-pair extraction of ammonium salts has mainly been investigated in the mechanistic studies of phase transfer catalysis and analytical purpose for ammonium compounds, applications in synthetic studies of quaternary ammonium species have been limited to date.6 As a lipophilic anion, we focused on tetracyanocyclopentadienide (C5R(CN)4−, TCCP), which is a superacid anion stabilized by the aromaticity of its Cp ring and the inductive and mesomeric effects of its cyano groups.7 From our previous studies on TCCPs, we have already established their high lipophilicity through their application in an anionic phasetransfer catalyst,8 and we also determined that sodium tetracyanocyclopentadienide (2a) is soluble in both EtOAc and H2O (Table 1). However, 2a proved to be completely insoluble in CH2Cl2 by a triphasic experiment using a U-shape apparatus.7a Tetraethylammonium chloride (1) and sodium

uaternary ammoniums play important roles in biological compounds and medicines for the enhancement of human health and well-being. As examples, betaine and choline are essential pharmacological compounds for maintaining the normal physiological state of a living system. Many cholinergic drugs and antibacterial materials that have been approved for use in clinical settings are composed of a quaternary ammonium structure.1,2 In synthetic organic chemistry, quaternary ammoniums are also key reaction intermediates in famous organic reactions such as Hofmann elimination and Stevens rearrangement.3 Furthermore, quaternary ammonium salts are used as sources of aryl and alkyl groups in cross-coupling reactions, 4 while asymmetric quaternary ammonium salts can be used as phase-transfer catalysts.5 Despite their significance, quaternary ammoniums are typically difficult to handle because they cannot be transformed into salt-free amines via alkalization like primary, secondary, and tertiary ammoniums (Figure 1). Thus, a new isolation method is required to facilitate further development of quaternary ammonium chemistry. One major problem in handling quaternary ammoniums is their high solubility in water and immiscibility in organic solvents. We are interested in ion-pair extraction using

Table 1. Solubility of Ionic Compounds 1−4 into CH2Cl2, EtOAc, and H2O

CH2Cl2 EtOAc H2O

1

2a

3a

4

insoluble insoluble soluble

insoluble soluble soluble

soluble soluble slightly soluble

insoluble insoluble soluble

Received: February 22, 2019

Figure 1. Ammonium salts. © XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b00686 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

ammonium ylides corresponding to the quaternary ammonium cations. NaTCCPs with negative LogD values (2a and 2b) could form an extractable ion pair only with low-polarity ammoniums whose CLogP values are more than 1.24 (1, 5, and 6). When CLogP values are around 0.3, NaTCCPs with positive LogD values (2c and 2d) are necessary for the extraction. N,N,N-Trimethylglycinium 9 having the smallest CLogP value (0.24) was extracted only with the most lipophilic 2d. To compare with another lipophilic acid anion, sodium tetrakis(bis-3,5-(trifluoromethyl)phenyl)borate (NaBArF)10 was also examined instead of TCCPs. However, the extraction of 1 with 2 equiv of NaBArF afforded a mixture of sodium and tetraethylammonium salts of BArF because NaBArF is soluble in most organic solvents, including CH2Cl2. Sodium picrate is a traditional reagent for the ionpair extraction.6 Actually, the extraction of 1 with sodium picrate afforded tetraethylammonium picrate in good yield (92%). However, picrate has an explosive nature and could not extract choline 7. Sodium lauryl sulfate formed an emulsion during the extraction because it is a surfactant. No extract was obtained in the extraction of 1 using sodium tetrafluoroborate or sodium p-toluenesulfonate instead of TCCPs. Based on the results presented in Table 3, we demonstrated the separation of quaternary ammonium species via extraction using a separatory funnel (Scheme 1). Upon treating an aqueous solution of 1 and 8 with a slight excess of 2a, 3a was selectively extracted. A second extraction from the aqueous layer was performed after the addition of 2d. The carbachol salt 13d was in turn efficiently extracted with CH2Cl2 in good yield. Thus, these results demonstrate that the separation of quaternary ammoniums 1 and 8 was achieved using only a separatory funnel without chromatography. Our next challenge was the synthesis of complex quaternary vinyl ammonium salts as substrates for the 3-aza-Cope− Mannich cascade.11 At present, the 3-aza-Cope−Mannich cascade is rarely utilized because of the difficult preparation required for the starting vinylammonium.12 We assumed that our TCCP ion-pair extraction would be a powerful tool for the preparation of such complex quaternary ammoniums. We first synthesized (chloroethyl)ammonium 19 from a pipecolic acid derivative 15 (Scheme 2). Tebbe’s methylenation of 15 followed by deprotection of the Boc group afforded piperidine derivative 16. N-Chloroethylation was furnished by reductive amination with chloroacetaldehyde. The obtained compound 17 was treated with methyl triflate for the formation of quaternary ammonium salt 18. An antiselective alkylation product was obtained predominantly according to the early transition state model, wherein the methyl triflate approaches from the axial side of the nitrogen. The excess toxic methyl triflate was quenched with saturated aqueous bicarbonate, and the TCCP ion-pair extraction with 2b13 afforded 19 in good yield. Methylation with methyl iodide instead of methyl triflate progressed very slowly and resulted in lower diastereoselectivity. The elimination reaction14 of 19 was performed with sodium methoxide at −40 °C. After an aqueous workup and extraction with CH2Cl2, we obtained the unstable vinylammonium salt 20, which underwent a gradual change into ammonium 24 through a cascade reaction involving (1) 3-aza-Cope rearrangement to macrocyclic iminium 21, (2) Mannich reaction to vinyl ether 23, and (3) elimination to ammonium 24.15 The intermediate oxonium 22 and the corresponding ketone could not be detected by 1H

chloride (4) obviously have a high solubility in water but not in organic solvents. Based on these known solubilities, we anticipated that lipophilic tetraethylammonium TCCP (3a) would be selectively extracted from the aqueous mixture of ion pairs 1, 2a, 3a, and 4 using CH2Cl2. We herein report a new isolation method for quaternary ammonium cations by solvent extraction9 using TCCP salts. We also demonstrate synthetic application examples of complex quaternary ammonium salts. The study began with the investigation of an extraction solvent system for the selective transfer of ion pair 3a to the organic phase (Table 2). We used a double equivalent of 1 in Table 2. Screening of Extraction Solvents

entry

1 (equiv)

2a (equiv)

1 2

2.0 2.0

1.0 1.0

3 4 5 6 7

2.0 2.0 2.0 2.0 1.0

1.0 1.0 1.0 1.0 2.0

solvent EtOAc/H2O EtOAc-n-hex (1:1) /H2O 4-MeTHP/H2O CPME/H2O Et2O/H2O CH2Cl2/H2O CH2Cl2/H2O

extract to organic solvent 3a (34), 2a (66)a 3a (26), 2a (74)a 3a (26), 2a (74)a precipitate precipitate 3a (93) 3a (87)

a

Ratio of 3a and 2a determined by 1H NMR of extract.

the formation of 3a to ensure that an excess amount of 1 did not influence the purity of the extract. When EtOAc was used to extract an aqueous solution of 1 and 2a, a 34:66 mixture of 3a and 2a was transferred to the organic layer (entry 1). The mixture of 3a and 2a in the extract was attributed to the high solubility of both 3a and 2a in EtOAc. An EtOAc−n-hexane (1:1) cosolvent system and 4-methyltetrahydropyran (4MeTHP) also afforded a mixture of 3a and 2a (entries 2 and 3). Salt 3a did not dissolve in the low-polarity ethers, Et2O and CPME (entries 4 and 5, respectively). As we had initially expected, 3a was selectively extracted using CH2Cl2 as an extraction solvent (entry 6). The 3a salt was also extracted with good purity using an excess amount of 2a over 1 (entry 7). We next examined the extraction range for various quaternary ammonium salts using several TCCPs (Table 3). Four different NaTCCPs 2a−2d with different lipophilic substitutions at R were examined. Compound 1, acetyl choline (5), and trimethyl(vinyl)ammonium (6), wherein no hydrophilic functional groups existed, were extracted efficiently with all the NaTCCPs 2a−2d (entries 1, 3, and 4). Tetraethylammonium salts 3a−3d were also obtained in good purity with excess amounts of TCCPs 2a−2d (Scheme 2). Choline (7) and carbachol (8) were not extracted efficiently with 2a or pentacyanocyclopentadienide (2b). The hydrophilic ammoniums 7 and 8 were extracted using the lipophilic TCCPs 2c− d (entries 5 and 6, respectively). Extraction of the N,N,Ntrimethylglycinium cation was achieved with highly lipophilic salts such as a menthoxycarbonyl TCCP 2d (entry 7). Thus, the range of extractable ammoniums was estimated using the distribution coefficients (LogD) of NaTCCPs and CLogP of B

DOI: 10.1021/acs.orglett.9b00686 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 3. Scope of the Extraction of Quaternary Ammonium Salts Using TCCPs

a CLogP of ammonium ylides corresponding to the quaternary ammonium cations 1 and 5−9 calculated using ChemBioDraw 17. The structures of ammonium ylides are shown in the Supporting Information. bLogD of NaTCCPs 2a−2d between 1-octanol and water determined by employing the shake-flask method. cAn excess amount of sodium salts 2a−2d (2.0 equiv) was used based on quaternary ammonium salt 1 (1.0 equiv) in entry 2.

Scheme 2. Synthesis of Quaternary N(Chloroethyl)ammonium Species 19 and Cascade Reaction to Ammonium 24

Scheme 1. Separation of Quaternary Ammonium Cations 1 and 8 by the Ion-Pair Extraction with TCCPs

NMR monitoring of a CD3CN solution of 20. An attempted in situ reduction or alkylation of 22 was unsuccessful. We next synthesized the more complex quaternary spiro ammonium species 28 (Scheme 3). Piperidine 16 and tribromide 25 were heated in the presence of i-Pr2NEt to afford spiro ammonium 26. The unreacted tribromide 25 was removed by back-extraction of 26 into an aqueous layer from CH2Cl2 solution. The TCCP ion-pair extraction of 26 using 2c from the aqueous layer followed by an elimination reaction

with sodium methoxide provided 28 in good isolated yield as a 66:34 mixture of syn- and anti-isomers. Finally, 28 was heated C

DOI: 10.1021/acs.orglett.9b00686 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Scheme 3. Synthesis of Spiro Vinylammonium 28 and 3-azaCope−Mannich Cascade to Tricyclic Amino Ketone 30

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takeo Sakai: 0000-0002-9006-8249 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was partially supported by Grant-in-Aids for Scientific Research (C) (16K08182 and 16K08183) from the Japan Society for the Promotion of Science (JSPS) and the Research Foundation for Pharmaceutical Sciences. We thank Ms. Tatsuko Sakai (Meijo University) for performing the elemental analysis of ammonium salts.

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(1) (a) Pappano, A. J. Cholinoceptor-Activating & CholinesteraseInhibiting Drugs. In Basic & Chlinical Pharmacology; Katzung, B. G., Trevor, A. J., Eds.; McGram-Hill Education: New York, 2015; Chapter 7, pp 105−120. (b) Pappano, A. J. Cholinoceptor-Blocking Drugs. In Basic & Chlinical Pharmacology; Katzung, B. G., Trevor, A. J., Eds.; McGram-Hill Education: New York, 2015; Chapter 8, pp 121−132. (2) (a) Jennings, M. C.; Minbiole, K. P.; Wuest, W. M. Quaternary Ammonium Compounds: An Antimicrobial Mainstay and Platform for Innovation to Address Bacterial Resistance. ACS Infect. Dis. 2015, 1, 288−303. (b) Jiao, Y.; Niu, L.; Ma, S.; Li, J.; Tay, F. R.; Chen, J.-H. Quaternary Ammonium-Based Biomedical Materials: State-of-the-Art, Toxicological Aspects and Antimicrobial Resistance. Prog. Polym. Sci. 2017, 71, 53−90. (3) Li, J. J. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications, 5th ed.; Springer: Switzerland, 2014. (4) Ouyang, K.; Hao, W.; Zhang, W.-X.; Xi, Z. Transition-MetalCatalyzed Cleavage of C−N Single Bonds. Chem. Rev. 2015, 115, 12045−12090. (5) (a) Asymmetric Phase Transfer Catalyst; Maruoka, K., Ed.; WileyVCH: Weinheim, 2008. (b) Zong, L.; Tan, C.-H. Phase-Transfer and Ion-Pairing Catalysis of Pentanidiums and Bisguanidiniums. Acc. Chem. Res. 2017, 50, 842−856. (6) Representative papers of ion-pair extraction: (a) Ballard, C. W.; Isaacs, B. J.; Scott, P. G. W. The Photomeric Determination of Quaternary Ammonium Salts and of Certain Amines by Compound Formation with Indicators. Part 1. Quaternary Ammonium Salts. J. Pharm. Pharmacol. 1954, 6, 971−985. (b) Higuchi, T.; Michaelis, A.; Tan, T.; Hurwitz, A. Ion Pair Extraction of Pharmaceutical Amines. Role of Dipolar Solvating Agents in Extraction of Dextromethorphan. Anal. Chem. 1967, 39, 974−979. (c) Gustavii, K.; Brändström, A.; Allansson, S. Ion Pair Extraction in Preparative Organic Chemistry Part VII. Separation and Purification of Amines from Reaction Mixtures. Acta Chem. Scand. 1971, 25, 77−84. (d) Brändström, A. Prinsiples of Phase-Transfer Catalysis by Quaternary Ammonium Salts. Adv. Phys. Org. Chem. 1977, 15, 267−330. (e) Brandström, A.; Strandlund, G. Ion Pair Extraction in Preparative Organic Chemistry. XI. Extraction of Sulfonic Acids as Ion Pairs with Amines. Acta Chem. Scand. 1978, 32B, 489−498. (f) Mohammad, H. Y.; Cantwell, F. F. Photometric Ion-Pair Titrations in the Presence of an Immiscible Solvent and Their Application to Drug Analysis. Anal. Chem. 1979, 51, 1006−1012. (g) Brändström, A. Ion-Pair Extraction as a Tool for the study of Mechanisms of Reactions Related to Phase Transfer Catalysis. Pure Appl. Chem. 1982, 54, 1769−1782. (h) Sakai, T. Spectrophotometric Determination of Trace Amounts of Quaternary Ammonium Salts in Drugs by Ion-Pair Extraction with Bromophenol Blue and Quinine. Analyst 1983, 108, 608−614.

at 100 °C in a toluene/acetonitrile cosolvent system in the presence of i-Pr2NEt and water to afford the desired tricyclic amino ketone 30 through the 3-aza-Cope-Mannich cascade. The 63:37 enantiomeric ratio16 of 30 was almost identical to the syn/anti ratio of 28. In conclusion, we established the ion-pair extraction of quaternary ammonium using TCCPs. The range of extractable ammoniums was strongly correlated to the lipophilicity of NaTCCPs. Separation of a mixture of tetraethylammonium and carbachol cations was achieved by selective extraction of a higher lipophilic tetraethylammonium cation with ethoxycarbonyl TCCP 2a. The TCCP ion-pair extraction was applied in the synthesis of complex quaternary spiro ammonium salt 28, which was the substrate of the novel 3-aza-Cope−Mannich cascade to afford tricyclic amino ketone 30. Using our method, the produced ion pairs of quaternary ammoniums and TCCPs could be subjected to reactions that require an aqueous workup and chromatographic purifications. In other words, a great amount of previous knowledge and techniques used for synthesis and characterization in organic reactions of neutral compounds are made applicable to the synthesis of quaternary ammoniums by this method. This is a large step toward the precise synthesis of complex quaternary ammonium compounds that were not easily accessible up to now. There is still much room for development in the chemistry of quaternary ammonium salts. The TCCP ion-pair extraction presented in this paper could become a key technique for future studies on the syntheses and reactions of complex quaternary ammonium salts. Further studies related to TCCPs and quaternary ammoniums are ongoing in our laboratory.

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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.9b00686. Experimental procedures, spectral data, determination of LogD values for 2a−2d, and details regarding chromatography of ammonium salts (PDF) D

DOI: 10.1021/acs.orglett.9b00686 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b00686 Org. Lett. XXXX, XXX, XXX−XXX