Chemistry of Fluorinated Carbon Acids: Synthesis, Physicochemical

Vol. 63, No. 9 Chem. Pharm. Bull. 63, 649–662 (2015) 649 Review

Chemistry of Fluorinated Carbon Acids: Synthesis, Physicochemical Properties, and Catalysis Hikaru Yanai School of Pharmacy, Tokyo University of Pharmacy and Life Sciences; 1432–1 Horinouchi, Hachioji, Tokyo 192–0392, Japan. Received June 13, 2015

The bis[(triﬂuoromethyl)sulfonyl]methyl (Tf2CH; Tf SO2CF3) group is known to be one of the strongest carbon acid functionalities. The acidity of such carbon acids in the gas phase is stronger than that of sulfuric acid. Our recent investigations have demonstrated that this type of carbon acids work as novel acid catalysts. In this paper, recent achievements in carbon acid chemistry by our research group, including synthesis, physicochemical properties, and catalysis, are summarized.

Key words Brønsted acid; acidity; carbanion; catalyst; triﬂyl group

1. Introduction Tf2CH2 1 (Table 1). For example, the gas-phase acidity GA Brønsted acid is one of the most classical catalysts in or- (or ΔGacid) of sulfuric acid and Tf2CH2 1 was reported to be ganic synthesis. In this context, sulfuric acid has occupied a 302.2 kcal mol−1 and 300.6 kcal mol−1, respectively.9,10) These central position for a long time. On the other hand, organic values support the superacidity of 1 in the gas phase. In ad- chemists have dedicated substantial efforts to discovering dition, the pKa value of 1 in dimethyl sulfoxide (DMSO) (2.1) organic acids stronger than sulfuric acid. As a revolutionary suggested its markedly strong acidity in the solution phase; study, Haszeldine and Kidd reported trifluoromethanesulfonic the acidity of 1 was slightly weaker than that of sulfuric acid acid TfOH (Tf=CF3SO2) as a superacidic organic compound (pKa=1.4), although it worked as a stronger acid compared 1) 11,12) during the mid-1950s. The Hammett acidity function H0 of with CF3CO2H (pKa=3.45). TfOH was determined to be approximately −14.2) This value In terms of such aspects of carbon acid 1 in both the gas 3) means that it is more acidic than sulfuric acid (H0=−12). and solution phases, we were interested in catalysis of carbon Recent calculations have also proposed that the pKa value of acids bearing the Tf2CH group as an acidic functionality. In 4) TfOH in H2O is −14.2. In 1984, Foropoulos and DesMarteau the carbon acid structure, it is possible to incorporate a fourth reported research on bis(triflyl) imide Tf2NH, which was an- substituent R, which provides some additional functionalities other important example of a superacidic compound.5) to the acid, on the central carbon atom (Chart 1). In principle, Currently, these superacidic organic acids and their con- such a molecular design to develop highly effective acid cata- jugate bases are widely used in several fields of chemistry lysts would be difficult in the cases of the corresponding oxy- including catalysis, ionic liquids, and material sciences. Struc- gen and nitrogen acids. 6,7) 8) turally similar carbon acids such as Tf2CH2 1 and Tf3CH However, it is not easy to synthesize carbon acids with also have long histories. However, these carbon (C–H) acids structural diversity.13) For example, Koshar reported the 14) have not been thoroughly investigated. One of the major α-alkylation reaction of Tf2CH2 1 (Chart 2). Unfortunately, reasons for this is likely to be the lack of effective synthetic procedures. As an ongoing research program, we are studying Table 1. Acidities of Sulfuric Acid and Strong Organic Acids methods to synthesize carbon acid derivatives and their appli- Acid pK (DMSO) GA (kcal mol−1) cations as synthetically useful reagents and/or organocatalysts. a

The purpose of this review is to provide an outline of the car- H2SO4 1.4 302.2 bon acid chemistry studies undertaken by our research group. TfOH 0.3 299.5 Tf2NH — 286.5 2. Acidities and Synthetic Approaches to Carbon Acids Tf3CH — 289.0 Although active methylenes such as 1,3-dicarbonyl com- Tf2CH2 (1) 2.1 300.6 pounds react with organic/inorganic bases to give syntheti- CF3CO2H 3.45 — cally useful carbanion species, their acidities are not sufﬁcient (PhSO2)2CH2 12.25 — to catalyze typical acid-catalyzed reactions. However, some (EtO2C)2CH2 16.2 — acidity scales unexpectedly indicated considerable acidity of TfCH3 18.8 339.8

Chart 4. Synthesis of Tf2CHCH2CHTf2 3

Chart 1. Structures of Organic Acids Containing a Triﬂyl Group(s) acids served as Brønsted acid catalysts for several C–C bond- forming reactions. However, in this synthesis, strongly basic and ignitable t-BuLi was necessary for the α-triﬂylation step. This would narrow the functional group tolerance. Further- more, troublesome repeating reaction operations were required to obtain the desired carbon acids in pure form.

3. 1,1,3,3-Tetrakis(triﬂyl)propane: Synthesis, Acidity, and Catalysis Chart 2. α-Alkylation of Tf2CH2 1 On the basis of such pioneering works, we adopted

1,1,3,3-tetrakis(triﬂyl) propane (Tf2CHCH2CHTf2) 3 as the ﬁrst generation of our carbon acid catalysts (Chart 4). This compound was originally reported in 1976 by Koshar and Bar- 21) ber. Although Tf2CHCH2CHTf2 3 was easily synthesized in 22) multigram scale by the 2 : 1 reaction of Tf2CH2 1 with paraformaldehyde, followed by recrystallization from chloroben- zene, the applications and detailed physicochemical properties had not been described.23) According to Koshar’s procedure, we obtained

Tf2CHCH2CHTf2 3 as colorless crystals. Interestingly, this acid did not show deliquescent and fuming properties under an air atmosphere. The X-ray crystallographic structure of 3 is shown in Chart 5.24) The acidic C–H moieties are located in- side the molecular structure, while ﬂuorine and oxygen atoms occupy the outside. The gas-phase acidity of 3 was shown to be 290.2 kcal mol−1 using the Fourier transform-ion cyclotron resonance (FT-ICR) technique.25)

With Tf2CHCH2CHTf2 3 in our hands, its catalysis was evaluated in the vinylogous Mukaiyama–Michael (VMM) 26) Chart 3. Stepwise Construction of Tf2CH Functionality reaction of mesityl oxide 4a with 2-silyloxyfuran (Table 2). In the presence of a catalytic amount of TfOH and Tf2NH, the desired alkylation products were obtained in merely poor- the reaction gave the desired product 5a in only low yields. to-moderate yields since the carbanion derived from 1 was In contrast, when using 0.25 mol% of 3 instead of TfOH and significantly stabilized by two triflyl groups, and its nucleo- Tf2NH, 5a was obtained in 88% yield after acid treatment. philicity was not suitable for the subsequent substitution with The loading of 3 could be reduced to 0.05 mol% without sig- conventional alkyl halides. As an alternative approach to con- nificant loss of the product yield. This VMM reaction did not struct the carbon acid structure, Ishihara and Yamamoto de- occur in the absence of acid catalysts. Moreover, Lewis acids 15) veloped an α-triflylation reaction of monosulfones with Tf2O such as Me3Al required substoichiometric loading to achieve (Chart 3). This was fairly effective for the aryl-substituted car- acceptable consumption of the substrates. bon acids ArCHTf2 including pentafluorophenyl carbon acid Under the optimized conditions using Tf2CHCH2CHTf2 2a,16,17) fluorous-tagged carbon acids,18,19) and chiral derivative 3, several α,β-enones smoothly produced the desired VMM 2b.20) In addition, they also found that these types of carbon products in good-to-excellent yields (Chart 6). Upon treatment

Dr. Hikaru Yanai was born in 1980 in Tokyo, Japan. He received his B.S. degree in 2002 and a Ph.D. in 2008 from Tokyo University of Pharmacy and Life Sciences (TUPLS) under the supervision of Professor Takeo Taguchi. He was appointed as Research Assistant in Professor Taguchi’s group in 2005 and became Assistant Professor (2008) and Associate Professor (2014) at TUPLS. His current research subjects include the development of novel acid catalysts and unique synthetic methodologies for organoﬂuorine compounds.

Hikaru Yanai Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 651

(A) ORTEP drawing; (B) space-ﬁlling model, top view; (C) space-ﬁlling model, side view.

Chart 5. X-Ray Structure of Tf2CHCH2CHTf2 3

Table 2. Survey of Effective Acid Catalysts for the VMM Reaction

Entry Acid (mol%) Temp. (°C) Yielda) (%)

1 TfOH (0.25) −78 7

2 Tf2NH (0.25) −78 7

3 Tf2CHCH2CHTf2 3 (0.25) −78 88

4 Tf2CHCH2CHTf2 3 (0.05) −24 87 Chart 7. Zhai’s Synthesis of (±)-Merrilactone A 5 Tf2CH2 1 (1.0) −78 0

6 Tf2CHCH3 (1.0) −78 7

7 Tf2CHC6F5 2a (0.05) rt 36

8 Me3Al (40) −78 64 9 None rt NRb) a) Isolated yield. b) No reaction.

Chart 8. Tf2CHCH2CHTf2-Induced Mukaiyama Aldol Reactions

achieved C–C bond formation between sterically hindered substrates. As an elegant extension of our VMM chemistry, Zhai and colleagues used it as a key step for the synthesis of (±)-mer- 27) Chart 6. Tf2CHCH2CHTf2-Induced VMM Reaction rilactone A (Chart 7). In the presence of a catalytic amount of 3, the reaction of tricyclic silyloxyfuran 6 with methyl vinyl with 3-bromo-2-silyloxyfuran, β-alkylated enones 4 gave the ketone gave the VMM product 7 in 69% yield. They also corresponding VMM products 5 in a highly anti-selective found that the uses of typical Lewis acids instead of 3 were manner. Importantly, this carbon acid-induced reaction less effective for this transformation. 652 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

32) The notable catalysis of Tf2CHCH2CHTf2 3 was observed tively gave the corresponding 1,2-adducts in good yields. not only in the VMM reaction but also in the Mukaiyama In contrast, the unexpected 1,4-adducts 12 were selectively 28) aldol reaction. Rhodes pointed out that the reaction of obtained by using Tf2CHCH2CHTf2 3 instead of BF3·OEt2 sterically bulky undecan-6-one 8a with a ketene silyl acetal (Chart 9). A high level of 1,4-selectivity was also observed in did not yield the corresponding aldol product under classical the reactions using 2-silyloxythiophene. 29) titanium tetrachloride (TiCl4)-mediated conditions (Chart As a plausible reaction pathway for the Tf2CHCH2CHTf2- 8). On the other hand, only 1.0 mol% of 3 was sufﬁcient to induced Mukaiyama aldol and related reactions, we proposed complete this reaction, giving rise to 9. Likewise, tetrasulfone the in-situ generation of silyl alkanide intermediate A as a cat- 3 was successfully applied to the diastereoselective vinylogous alytically active species (Chart 10). That is, initial protonation Mukaiyama aldol (VMA) reaction of α-alkylated cyclohexa- of ketene silyl acetals by carbon acid 3 and the subsequent nones such as 8b using 2-silyloxyfurans.30) silyl transfer reaction produced silyl alkanide A, which shows Surprisingly, a switching of the regioselectivity between a high level of silylating activity due to the intramolecular the carbon acid-catalyzed conditions and the typical Lewis strain (I-strain) between the trialkylsilyl group and sterically acid-mediated conditions was observed in the reaction of α,β- bulky gem-triﬂylated alkanide moiety.33,34) This species ac- unsaturated aldehydes with 2-silyloxyfurans.31) De Lera and tivates the carbonyl substrates via the O-silylation reaction, colleagues demonstrated that the reaction of aldehydes 11 with and then nucleophilic attack of unreacted ketene silyl acetals

3-bromo-2-silyloxyfuran in the presence of BF3·OEt2 selec- on the resulting silyl carboxonium B forms the C–C bond (formation of C). Furthermore, the silyl transfer reaction from intermediate C to unreacted carbonyl substrates regenerates intermediate B along with the formation of aldol (or Michael) product D.35) If highly Lewis acidic species A is inactivated by a trace amount of water existing in the reaction system, a self- repairing pathway through the protonation of ketene silyl ac-

etals by Tf2CHCH2CHTf2 3 will bring about the regeneration of catalytically active A.36) Although our efforts to observe intermediate A failed, some experimental results supported this plausible mechanism. First, in 1H- and 13C-NMR studies using a 1 : 1 mixture of mesityl oxide 4a and 3, considerable shifts of each NMR signal were not observed. Second, the VMM reaction was not impeded by the addition of 2,6-di- tert-butylpyridine as a speciﬁc proton scavenger. These data imply that electrophilic activation of the carbonyl substrates through protonation or hydrogen bonding by carbon acid 3 is not a major activation mode for the present C–C bond-forming reactions.

4. Carbon Acid Synthesis Based on in-Situ Generation of Tf2C=CH2 Compared with TfOH and Tf2NH, Tf2CHCH2CHTf2 3 could be used as more powerful acid catalyst for the Mukai- Chart 9. 1,4-Addition Reaction of α,β-Unsaturated Aldehydes yama aldol and related reactions. This ﬁnding encouraged us

Chart 10. Plausible Catalyst Cycles Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 653

Chart 11. Concept for Effective Introduction of Carbon Acid Functionality to develop practical synthetic strategies for novel carbon acid derivatives. To synthesize Tf2CH-based carbon acids with structural diversity, both synthetic reactions and purification methods should be considered. In most of the literature describing carbon acid synthesis, carbon acids were isolated by distillation, sublimation, or recrystallization. This indi- cates the difficulty in chromatographic purification of carbon acids.37) In other words, practical synthetic strategies for this type of carbon acids must meet specific requirements. First, essentially quantitative formation of carbon acids is required for the reaction itself. Second, side products formed by carbon acid synthesis must be easily removable using simple purification techniques. Third, carbon acid-incorporating reactions should be applicable to structurally complex substrates. To develop a satisfactory methodology, we were inter- 38) Squares, Tf2CHCH2CHTf2 3; diamonds, Tf2CH2 1; triangles, Tf2C=CH2 13. ested in 1,1-bis(triflyl) ethylene Tf2C=CH2 13, which was proposed as a reactive intermediate in Koshar’s synthesis of Chart 12. Reaction Profile in a 0.01 M Solution of Tf2CHCH2CHTf2 3 21) in CDCl3 at 40°C Tf2CHCH2CHTf2 3 (Chart 11). If Tf2C=CH2 13 generated in situ reacts with neutral nucleophiles, the corresponding carbon acids will be formed as adducts. After many attempts, we developed three different reactions for the generation of 13: 1) retro-Michael reaction of Tf2CHCH2CHTf2 3; 2) self-promoting condensation reaction of Tf2CH2 1 and formaldehyde; and 3) decomposition reaction of zwitterion 14a.

4.1. Retro-Michael Reaction of Tf2CHCH2CHTf2 (3) Although our first-generation catalyst Tf2CHCH2CHTf2 3 was a bench-stable chemical as crystals, it provided an equilibrium mixture of Tf2CH2 1/Tf2C=CH2 13 and Tf2CHCH2CHTf2 3 in diluted solutions in several organic solvents at higher tem- 1 perature. As shown in Chart 12, H-NMR analysis of a 0.01 M Chart 13. 2,2-Bis(triflyl)ethylation Reaction of 2,6-Disubstituted Phe- solution of Tf2CHCH2CHTf2 3 in CDCl3 at 40°C revealed this nols −3 equilibrium profile (Keq=3.21×10 ). A similar NMR study of a 0.01 M solution in CD3CN revealed rapid, complete dissocia- carbon acid 15a as well as inseparable diarylmethane as a tion of 3, giving rise to Tf2CH2 1 and Tf2C=CH2 13. side product. In the latter case, relatively slow formation of In actuality, Tf2CHCH2CHTf2 3 worked as an effective Tf2C=CH2 13 would result in competitive formation of the reagent to incorporate the 2,2-bis(triflyl) ethyl group(s) into side product. Some carbon acids with high boiling points were electronically rich arene frameworks.39) When 2,6-xylenol was also synthesized and isolated on the basis of this reaction. For treated with 3 in acetonitrile at room temperature, the desired example, acceptably pure 2,6-diphenyl derivative 15b was carbon acid 15a was obtained in 94% yield after bulb-to-bulb obtained in 97% yield by the reaction of 2,6-diphenylphenol distillation using a Kugelrohr oven (Chart 13). Meanwhile, with 3, followed by the removal of Tf2CH2 1 using a Kugel- Tf2CH2 1 was recovered in 90% yield. The three-component rohr oven. reaction of 2,6-xylenol, 1, and paraformaldehyde yielded Selected results of the 2,2-bis(triflyl) ethylating reaction of 654 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

Chart 14. Synthesis of Arene-Based Carbon Acids

Chart 15. 2,2-Bis(triﬂyl)ethylation Reaction of Active Methylenes and Succinic Imide electronically rich arenes such as phenols and aryl ethers with monium moieties in the molecular structure were isolated41)

Tf2CHCH2CHTf2 3 are summarized in Chart 14. Interestingly, (Chart 16). Their zwitterionic structures were fully conﬁrmed the reaction of 4-substituted phenol with 1 equiv. of 3 gave the by X-ray crystallography and/or NMR analysis. When N,N- monosubstituted product 15c in 99% yield. Under similar con- dimethylaniline was treated with an equimolar amount of 3 in ditions, the 1 : 2 reaction of 4-tert-butylphenol with 3 predomi- acetonitrile for 3 h at 80°C, the para-substituted product 21a nantly gave disubstituted product 16. Triple-carbon acid 17 was quantitatively formed as white precipitates after evapora- was also obtained by the reaction of benzene-1,3,5-triol with tion to remove the solvent and Tf2CH2 1. The zwitterion 21a 3 equiv. of 3. The present methodology was markedly effec- was isolated in 95% yield by washing the precipitates with tive for the carbon acid introduction of structurally complex chloroform. As shown in Chart 17, X-ray crystallographic aromatics; e.g., estrone-based carbon acid 15g and bis-carbon analysis of 21a fully supported the sp2-hybridizing nature acid 18 were synthesized in good yields, respectively. of anionic C1 because the bond angles around the C1 were We found that 1,3-dicarbonyl compounds and succinic 120.5° (C2–C1–S1), 120.3° (S1–C1–S2), and 119.2° (S2–C1– imide served as acceptable reaction partners.40) As shown C2), respectively. At the same time, the bond angles around in Chart 15, highly functionalized carbon acids bearing the the cationic N1 (114.3° for C6–N1–C9, 110.3° for C9–N1–C10,

Tf2CH group were easily obtained using our method. and 110.4° for C10–N1–C6) suggested its tetrahedral struc- By treating aniline derivatives with Tf2CHCH2CHTf2 3, ture. Furthermore, the hydrogen on the N1 atom was found unusual zwitterions bearing both stabilized carbanion and am- from the crystallographic data. Likewise, several N-substi- Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 655

Chart 16. Synthesis of Anilinium-Type Zwitterions

decreased due to the competitive polymerization of isoprene. It should be noted that only the para-adduct was obtained in a regiospecific manner. Several 1,3-dienes were also subjected to this three-component synthesis. In particular, the reaction using less reactive ethyl sorbate as the diene component gave the desired cyclohexene 22d in excellent yield. Under similar conditions, not only paraformaldehyde but also some aromatic and aliphatic aldehydes could be used as effective reaction substrates. The gem-bis(trifly) cyclohexenes thus obtained were easily converted into the corresponding triflylarenes (Chart 19). For example, 2,4-dialkylated triflylbenzenes 24e–h were obtained in good overall yields from the cyclohexenes through the thermal elimination of trifluoromethanesulfinic acid and subsequent aromatization using Corey’s procedure.43,44) Recently, triflylated aromatics including navitoclax Chart 17. ORTEP Drawing of 21a (ABT-263) and ponazuril have attracted a great deal of atten- tion in medicinal chemistry (Chart 20). Such highly substitut- tuted anilines were smoothly converted to the corresponding ed triflylarenes were traditionally synthesized through a com- zwitterions 21b–i in good-to-excellent yields. bination of aromatic electrophilic substitution reactions. In our

4.2. Self-promoting Condensation Reaction of Tf2CH2 present synthesis, the relative configuration of each substituent and Aldehydes Tf2CHCH2CHTf2 3 itself could be prepared including the triflyl group on the benzene ring was perfectly by the 2 : 1 reaction of Tf2CH2 1 and paraformaldehyde in mul- controlled in the Diels–Alder reaction step. The reaction pro- tigram scale. This suggested the possibility of the self-promot- vided a new entryway to synthesize highly substituted triflyl- ing condensation reaction of Tf2CH2 1 and paraformaldehyde arenes without the formation of undesired regioisomers. as another choice for the generation of Tf2C=CH2 13. How- That success inspired us to explore stable, isolable ever, compared with our methodology using Tf2CHCH2CHTf2 1,1-bis(triflyl) alkenes bearing substituents on the sulfone 3, the reaction rate of this condensation was significantly β-carbon. In fact, Koshar pointed out the difficulties in isolat- 37) slow, and a 1 : 1 reaction of 1 with paraformaldehyde gave ing Tf2C=CH2 13 and its handling. Zhu also reported that only an equilibrium mixture of Tf2CH2 1, Tf2C=CH2 13, and β-phenylated 1,1-bis(triflyl) alkene was easily hydrolyzed by Tf2CHCH2CHTf2 3. Well-considered choices of nucleophiles moisture under an air atmosphere to give Tf2CH2 1 and benz- were obviously required in this case. aldehyde.45) If stable, isolable 1,1-bis(triflyl) alkenes are found,

First, we found the Diels–Alder reaction of Tf2C=CH2 13 systematic investigations of their reactions with a wide range with 1,3-dienes42) (Chart 18). By mixing 1, paraformaldehyde, of nucleophiles including strongly basic and/or anionic nucleo- and isoprene, the desired three-component reaction including philes will be possible. the in-situ generation of 13 followed by cycloaddition pro- To improve the stability of the 1,1-bis(triflyl) alkenes, we ceeded to give gem-bis(triflyl)cyclohexene 22a in 76% yield. focused on 1,1-bis(triflyl) alkadienes derived from Tf2CH2 1 A similar transformation occurred from Tf2CHCH2CHTf2 3 and α,β-unsaturated aldehydes. Here the alkadienes would with isoprene, although the yield of 22a (61%) was slightly show higher stability to water because their thermodynamic 656 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

Chart 18. Three-Component Synthesis of gem-Bis(triﬂyl)cyclohexenes

Chart 21. Kinetic and Thermodynamic Stabilization of 1,1-Bis(triﬂyl)- alkadienes

Chart 19. Synthesis of Polysubstituted Triﬂylarenes

Chart 22. Self-promoting Condensation of Tf2CH2 1 with Aldehydes

As a result, we successfully isolated the 1,1-bis(triﬂyl)- alkadienes by reaction with cinnamaldehyde derivatives.46,47)

The reaction of cinnamaldehyde with Tf2CH2 1 in 1,2-dichlo- roethane (DCE) gave the desired alkadiene 25a in 95% yield. This product was obtained as yellow crystals, and we did not observe their decomposition under an air atmosphere during a period of at least several months. In contrast, a similar reaction of benzaldehyde gave the alkene product in only 7% yield. This sharp contrast in the reaction outcomes indicated the significantly improved stability of 25a (Chart 22). Moreover, substituted cinnamaldehydes smoothly gave 1,1-bis(triflyl) alkadienes 25 in good-to-excellent yields (Chart Chart 20. Biologically Active Triflylarenes 23). This condensation reaction proceeded without touching acid-sensitive functionalities such as the tert-butyl ester, un- stability possibly improved with a sterically less hindered saturated ester, and furan moieties. π-conjugation system. At the same time, an improvement in The obtained alkadienes 25 could be used as effective their kinetic stability could also be considerable (Chart 21). building blocks for carbon acids through reactions with sev- Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 657

Chart 25. Synthesis of Koshar’s Zwitterion 14b

Chart 23. Synthesis of 1,1-Bis(triﬂyl)alkadienes

Chart 26. Three-Component Synthesis of Pyridinium-Type Zwitterions

the reaction of neutral nucleophiles such as electron-rich

aromatics and active methylenes with Tf2CHCH2CHTf2 3 resulted in the clean formation of carbon acids, Tf2CH2 1 was also recovered as a side product. In order to reuse this Tf2CH2 1 for the same purpose, this compound should be converted into the tetrasulfone 3 since the self-promoting condensation reaction of 1 and paraformaldehyde was relatively slow and Chart 24. Carbon Acid Synthesis through Regioselective Reduction and Alkylation acceptable nucleophiles in this case were signiﬁcantly limited. Such problems to be resolved led us to make further efforts for developing a more effective reagent. We took note of eral anionic nucleophiles (Chart 24). To give examples, the pyridinium type zwitterions as the third entry of Tf2C=CH2 selective 1,4-reduction of 25a was achieved by treatment with precursors. In 1976, Koshar and co-workers reported that the

NaBH4 in EtOAc at −78°C, and cinnamyl carbon acids 26a reaction of Tf2CH2 1 and paraformaldehyde gave a mixture 44) were isolated in 80% yield after bulb-to-bulb distillation. of 13 and Tf2CHCH3 in a ratio of 42 : 58, and the subsequent Likewise, the reaction of 25a with organocerium reagents pre- treatment of this mixture with a large excess of pyridine gave 38) pared from Grignard reagents and anhydrous CeCl3 produced 14b in 41% yield (Chart 25). In that report, they proposed the β-branched carbon acids 26b and c.47) In this nucleophilic its zwitterionic structure bearing an unusual carbanion moi- alkylation chemistry, we had to employ column chromatog- ety on the basis of elemental analysis alone. We reexamined raphy on neutral silica gel to separate the desired β-alkylated this reaction. After several attempts, we found that by mixing carbon acids and a small amount of impurity mainly contain- Tf2CH2 1, paraformaldehyde, and pyridine for 4 h at 60°C, 14b ing γ-alkylation products. After defined experiments, it was was formed in quantitative yield. The molecular structure of found that carbon acids were eluted as the corresponding Ca2+ 14b was fully confirmed in X-ray crystallographic analysis. salts during usual column chromatography. The free carbon Our three-component reaction could be applied to several acids were obtained by reacidification of the Ca2+ salts with nitrogen-containing heterocycles (Chart 26). For example, the 10% hydrochloric acid. reactions of 2-substituted pyridines gave the corresponding 4.3. 2-Fluoropyridinium: An Effective Reagent for zwitterions 14a–g. Under similar conditions, quinolinium 14h, in-Situ Generation of Tf2C=CH2 The in-situ generation oxazolium 14i, and imidazolium 14j were isolated in essen- of Tf2C=CH2 13 using Tf2CHCH2CHTf2 3 or Tf2CH2 1/ tially quantitative yields, respectively. paraformaldehyde became the carbon acid synthesis. Although Among these, 2-fluoropyridinum 14a could be used as 658 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

Chart 27. Availability of 2-Fluoropyridinium 14a for 2,2-Bis(triﬂyl)ethylation

rather than the phenolic hydroxyl group. On the other hand,

the pKa value of acidic zwitterion 21a was determined to be 2.4. This zwitterion was a slightly weaker acid than carbon

acids. Interestingly, by increasing in the number of the Tf2CH groups on the benzene ring, the acidity was slightly enhanced. A key structural unit to intensify the acidity was also found in comparisons of the GA. Experimentally determined GA values of 15d and 16 were 294.8 kcal mol−1 and 291.5 kcal mol−1, respectively.25) Unfortunately, the GA value of triple-carbon acid 17 was not determined in this experimental manner, but it was predicted to be 278.9 kcal mol−1 by a high-level density functional theory (DFT) calculation.53) In this computation, it was revealed that the conjugate base of 17 was highly stabilized by two hydrogen bonds between phenolic hydroxyl groups and sulfonic oxygens. The proximate hydroxyl groups on the

Chart 28. Cycloaddition Chemistry of Tf2C=CH2 13 Generated from benzene ring played an important role in achieving notable 2-Fluoropyridinium 14a enhancement of the acidity. Such phenol-derived carbon acids and acidic zwitterions a markedly effective reagent for the in-situ generation of could be used as real Brønsted acid catalysts. For example,

Tf2C=CH2 13. The reaction of 14a with p-cresol rapidly gave both triple-carbon acid 17 and N,N-dipropylated zwitterion the desired carbon acid 15c in 92% yield, whereas nonfluori- 21c nicely catalyzed the acetal-forming reaction of 3-phen- nated pyridinium 14b did not give 15c under the same condi- ylpropanal, which was a typical example of Brønsted acid- tions (Chart 27). This reagent has the following advantages: catalyzed reactions39) (Chart 30). Moreover, triple-carbon acid 1) a stable crystalline compound without deliquescent proper- 17 served as an effective catalyst for the esterification reaction ties; 2) significantly fast rate for the formation of Tf2C=CH2 of menthol. It is known that this reaction is not catalyzed by 13 in several organic solvents; and 3) low boiling point of the strongly acidic polymer Nafion SAC-13.17) 2-fluoropyridine, which was formed as a side product during 5.2. Carbon Acid- and Zwitterion-Catalyzed Mukai- the 2,2-bis(triflyl) ethylation reaction, and its remarkably weak yama Aldol-Type Reactions Next, we examined the utility 48) basicity (pKaH in H2O=−0.44). of the carbon acid derivatives in the Mukaiyama aldol-type Recently, Alcaide and Almendros have reported interest- reactions. As mentioned above, our carbon acids could be ing cycloaddition chemistry using our 2-fluoropyridinium used as real Brønsted acid catalysts. However, the activation

14a (Chart 28). For example, Tf2C=CH2 13 generated in situ of carbonyl substrates through protonation or hydrogen bond- from 14a smoothly reacted with the internal alkyne to give ing by carbon acids would not stand out compared with other gem-bis(triflyl)cyclobutene 27.49) Likewise, the reaction with common acids (Chart 31). On the other hand, as shown in benzyl azide gave triflyl-1,2,3-triazole 28 through (3+2) cyclo- the Tf2CHCH2CHTf2-induced reactions, silicon Lewis acids addition, followed by desulfinylation under mild conditions.50) derived from carbon acids would become a rational approach These results clearly demonstrated an advantage of our zwit- for notably strong activation of the carbonyl substrates. Such terion in the synthesis of not only carbon acids but also tri- reaction systems were the formal Brønsted acid catalysis by flylated chemicals. carbon acids. In particular, the relationship between the molecular structures of a series of carbon acid derivatives and 5. Catalysis of Carbon Acid Derivatives their catalytic performances was an interesting aspect. 5.1. Acidities of Carbon Acid Derivatives and Their To provide insight into the structure–catalyst activity rela- Brønsted Acid Catalysis We also evaluated the acidity tionship, we evaluated the catalyst performance of the phenol- of several carbon acid derivatives in both gas and solution derived carbon acids in the VMA reaction of cyclohexanone phases. Selected data are summarized in Chart 29. In a series 8c with 2-silyloxyfuran39) (Table 3). In this reaction, our of phenol-derived carbon acids 15d, 16, and 17, the pKa values first-generation catalyst Tf2CHCH2CHTf2 3 had shown higher in DMSO solution were determined to be 2.3, 2.1, and 2.0, efficiency than TfOH and Tf2NH (entry 1 vs. entries 2, 3). The respectively,39) using an electrochemical method.51,52) Com- use of monocarbon acid 15a with a carbon acid moiety at the pared with the pKa values of Tf2CH2 1 (2.1) and phenol (18) in para position to the hydroxyl group instead of tetrasulfone 3 DMSO solutions,11) the values measured in our acids suggest- did not show good consumption of 8c and acceptable isolated ed that the major acidic functionality was the Tf2CH group yield of 29, whereas carbon acid 15c gave a better yield of 29 Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 659

Chart 29. pKa (DMSO) and GA Values of Phenol-Based Carbon Acids 15d, 16, 17, and Anilinium-Type Zwitterion 21a Calculated GA values (B3LYP/6-311++G** level) are shown in parentheses.

Chart 31. Real and Formal Brønsted Acid Catalysis by Carbon Acid Derivatives

Chart 30. Brønsted Acid Catalysis of Carbon Acids and Anilinium- Type Zwitterion under similar conditions (entries 4, 5). Notably, double-carbon acid 16 and triple-carbon acid 17 were highly effective for this transformation (entries 6, 7). Under optimized conditions, only Chart 32. Reaction of Esters with Ketene Silyl Acetals 0.05 mol% loading of 17 was sufficient to complete the VMA reaction (entry 8). analysis (Table 4, entry 1). Interestingly, silyl acetal 31a was These results confirmed that triple-carbon acid 17 showed rapidly converted to vinyl ether 32a by additional stirring at a high level of performance as both real and formal Brønsted room temperature. In this case, vinyl ether 32a was isolated acid catalysts. In addition, the higher thermal stability of 17 in 51% yield along with the recovery of 31a. The uses of other over Tf2CHCH2CHTf2 3 in several solvents was an important acids such as TfOH, Tf2NH, and Tf2CHC6F5 2a instead of 17 point in its catalyst usage. As an example to illustrate the resulted in poor conversion of 31a (entries 2–4). Furthermore, distinguishing features of 17, we found the unusual olefination in the case of Tf2CHCH2CHTf2 3, higher loading was required reaction of lactones using ketene silyl acetals.54) In general, to obtain essentially the same result (entry 5). After optimiza- the reactions of carboxylic acid derivatives with silicon eno- tion of the reaction conditions with triple-carbon acid 17, we lates give the corresponding Claisen condensation product finally obtained (Z)-vinyl ether 32a in 85% yield (entry 7). E55,56) (Chart 32). In similar reactions, silyl acetal D, which is As shown in Chart 33, the present olefination reaction of a simple adduct of the silicon enolate to the starting ester, was lactone carbonyls could be applied to several arene-fused often isolated.57,58) Furthermore, a few examples demonstrated lactones 30. Importantly, the decomposition of the resulting the olefination reaction giving rise to vinyl ether F.59) vinyl ether moiety in products 32 was not observed during the When isochroman-1-one 30a was treated with a ketene reaction. silyl acetal in the presence of 1 mol% of triple-carbon acid Isocoumarins 30g and h, which had vinyl ester function- 17 at 0°C, formation of the adduct 31a was observed in TLC alities, were also converted to the corresponding olefination 660 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

Table 3. Catalyst Efﬁciency of Triﬂylated Organic Acids in the VMA Reaction

Entry Organic acid (mol%) Temp. (°C) Time (h) Yield of 29a) (%)

1 Tf2CHCH2CHTf2 3 (0.5) −24 2.5 82 2 TfOH (0.5) −24 2.5 25

3 Tf2NH (0.5) −24 2.5 63 4 15a (1.0) rt 2 30 5 15c (1.0) rt 2 51 6 16 (1.0) rt 2 82 7 17 (1.0) rt 2 83 8 17 (0.05) rt 2 83 a) Combined yield of 29-H (R=H) and 29-Si (R=TBS).

Chart 33. Carbon Acid-Induced Olefination Reaction of Lactones products 32g and h, respectively, without any problems (Chart were easily synthesized. Our studies provided systematic syn- 34). In contrast, less acidic zwitterion 21d achieved selec- thesis of a series of carbon acids. The relationship between the tive formation of silyl acetals 31g and h.60) The later addition molecular structures and their catalyst performances was also chemistry provided a useful synthetic strategy for polysubsti- defined. In addition, we found that some zwitterions bearing a tuted naphthalenes. For example, by treating the adduct 31g gem-bis(triflyl) ated carbanion moiety were stable and isolable with tetrabutylammonium fluoride (TBAF), 1,2,3-trisubstitued chemical species. naphthalene 33 was obtained in 91% yield. As another dem- In several fields of chemistry, strong but easily handled onstration, we successfully carried out the zwitterion-induced acids have great potential demand. We are continuing system- addition reaction, followed by treatment with fluoride to syn- atic research on carbon acid derivatives aimed at the develop- thesize tricyclic compound 34 (Chart 35). ment of highly effective organic acid catalysts.

Conclusion Acknowledgments The author expresses sincere apprecia- Chemistry of the strongly acidic carbon acids including tion to Professor Emeritus Takeo Taguchi (Tokyo University

Tf2CH-substituted compounds has been extremely limited for of Pharmacy and Life Sciences, TUPLS) and Professor Ta- many years, even though such acids were discovered much kashi Matsumoto (TUPLS) for their continued support and earlier (the mid-1950s). In order to study carbon acids, we ﬁrst useful discussions. The author is also grateful to Professor developed an effective synthetic methodology via the in-situ Emeritus Fumiyo Kusu (TUPLS), Dr. Akira Kotani (TUPLS), generation of highly electrophilic Tf2C=CH2 13, followed by Professor Emeritus Masaaki Mishima (Kyushu University), addition reactions with neutral nucleophiles. On the basis of and Professor Emeritus Takaaki Sonoda (Kyushu University) this, carbon acids with a wide range of structural diversity for acidity measurements. The research reported here was Vol. 63, No. 9 (2015) Chem. Pharm. Bull. 661

Chart 34. Reaction of Isocoumarins

Table 4. Catalyst Efﬁciency of Triﬂylated Organic Acids in the VMA Reaction

Chart 35. Synthesis of Tricyclic Lactone 34 Entry Organic acid (mol%) Yielda) (%) 1 Carbon acid 17 (1.0) 51 for Innovative Area “Advanced Molecular Transformation by 2 TfOH (4.0) 3b) Organocatalysis” from the Japan Society for the Promotion 3 Tf2NH (4.0) 25 of Science, as well as Grants from Mitsubishi Gas Chemical b) 4 Tf2CHC6F5 2a (4.0) 30 Co., Ltd., Asahi Glass Foundation, Kurata Memorial Hitachi 5 Tf2CHCH2CHTf2 3 (4.0) 53 Science and Technology Foundation, and Hoansha Foundation. 6 Carbon acid 17 (2.0) 72 c) 7 Carbon acid 17 (2.0) 85 Conflict of Interest The author declares no conflict of a) Isolated yield. b) Based 1H-NMR analysis of crude mixture. c) 2.0 eq of ketene interest. silyl acetal. References and Notes 1) Haszeldine R. N., Kidd J. M., J. Chem. Soc., 1954, 4228–4232 (1954). 2) Engelbrecht V. A., Tschager E. Z., Zeitschrift für Anorganische und Allgemeine Chemie, 433, 19–25 (1977). 3) Olah G. A., Prakash G. K. S., Sommer J., Molnar A., “Superacid Chemistry,” 2nd ed., Wiley-VCH, Hoboken, NJ, 2009. made possible by the contributions of several collaborators, 4) Gutowski K. E., Dixon D. A., J. Phys. Chem. A, 110, 12044–12054 including students whose names are acknowledged in the (2006). publications cited. Central Glass Co., Ltd. kindly provided 5) Foropoulos J. Jr., DesMarteau D. D., Inorg. Chem., 23, 3720–3723 us Tf2CH2 1 as the gift. The present work was supported (1984). in part by a Grant-in-Aid for Young Scientists (B) from the 6) Brice T. J., Trott P. W., U.S. Patent 2 732 398 (1956). Ministry of Education, Culture, Sports, Science and Technol- 7) Gramstad T., Haszeldine R. M., J. Chem. Soc., 1957, 4069 (1957). ogy of Japan, a Grant-in-Aid for Scientific Research (C) and 8) Turowsky L., Seppelt K., Inorg. Chem., 27, 2135–2137 (1988). 662 Chem. Pharm. Bull. Vol. 63, No. 9 (2015)

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