Letter pubs.acs.org/OrgLett
Catalytic Aerobic Chemoselective α‑Oxidation of Acylpyrazoles en Route to α‑Hydroxy Acid Derivatives Seiya Taninokuchi, Ryo Yazaki,* and Takashi Ohshima* Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan S Supporting Information *
ABSTRACT: Catalytic aerobic chemoselective α-oxidation of acylpyrazoles is described. Acylpyrazoles, carboxylic acid oxidation state substrates, were efficiently oxidized under aerobic conditions using TEMPO as an oxygenating agent. The mild catalytic conditions of the present catalysis were amenable to late-stage αoxidation of various pharmaceutical agents and natural products, leading to previously unreported α-hydroxy acid derivatives in short steps. Preliminary mechanistic studies revealed that in situ generated copper(II) peroxo species served as a Lewis acid/ Brønsted base cooperative catalyst. α-Hydroxy acid is frequently found in bioactive natural and non-natural compounds and utilized in a diverse set of synthetic intermediates.1 Various approaches toward this important class of α-hydroxy acids have been developed, such as (1) substitution reaction of prefunctionalized carboxylic acid derivatives with hydroxide, (2) nucleophilic addition/reduction of α-ketoacid derivatives, and (3) alkylation of glycolic acid derivatives.2 A more advantageous straightforward method is αoxidation of carboxylic acid derivatives, such as the Rubottom oxidation3 and Davis oxidation (Scheme 1a).4 Although these
As an oxygenating agent, a commercially available TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) free radical has received much attention for the synthesis of α-secondary-α-hydroxy carbonyls.6 TEMPO was initially used for α-oxidation of strong base-mediated preactivated esters with stoichiometric amounts of metal oxidants to capture the single electrons (Scheme 1c).7 Recently, a soft enolization methodology was applied to TEMPO oxidation using a titanium reagent (Scheme 1c).8 Subsequently, a chiral amine-catalyzed enantioselective αoxidation of aldehydes was reported under aerobic conditions without the need for stoichiometric amounts of metal oxidants.9,10 Although these reaction conditions were very mild and only a catalytic amount of transition metals was required, the scope of the carbonyls was limited to aldehydes.11 Thus, the direct use of α-monosubstituted carboxylic acid derivatives in catalytic α-oxidation has remained a formidable challenge. Herein, we report the development of a highly chemoselective and late-stage catalytic aerobic α-oxidation of acylpyrazoles (Scheme 1d).12 We first evaluated various copper salts under aerobic conditions using acylpyrazole 1a and TEMPO (2) (Table 1). Cationic copper(II) triflate afforded the product 3a in only low yield (entry 1). Copper(II) acetate, which would potentially serve as a Lewis acid/Brønsted base cooperative catalyst, turned out to be a better catalyst, affording 3a in 63% yield (entry 3).13,14 These different propensities for our α-amination reaction15 led us to hypothesize that the Brønsted basicity rather than Lewis acidity of the catalyst was important for efficient promotion of the reaction. Thus, to generate active Lewis acid/Brønsted base copper species under aerobic conditions, we investigated copper(I) salts (entries 4−8).16 Although cationic copper(I) triflate afforded the product 3a in low yield (entry 4), other copper(I) catalysts produced 3a in better yield (entries 5−8). Among them, copper(I) chloride
Scheme 1. α-Oxidation of Carboxylic Acid Oxidation State Substrates to Access α-Hydroxy Acid Derivatives
α-oxidation methods are reliable and have widespread applications, the necessary preactivation by stoichiometric amounts of a strong base limits their functional group compatibility. Catalytic aerobic α-oxidation reactions were recently reported (Scheme 1b).5 These reactions are highly atom-economical because they use O2 as an oxygenating agent, allowing for the direct introduction of a protecting group free hydroxy group. The substrate scope of these reactions is limited to readily enolizable ketones and α-aryl substituted esters for the efficient nucleophilic activation of carbonyls. In addition, these methods are applicable only to α,α-disubstituted carbonyls, affording α-tertiary-α-hydroxy carbonyls. © 2017 American Chemical Society
Received: May 2, 2017 Published: May 30, 2017 3187
DOI: 10.1021/acs.orglett.7b01293 Org. Lett. 2017, 19, 3187−3190
Letter
Organic Letters Table 1. Conditions Optimizationa
Scheme 2. Substrate Scopea
entry
catalyst
yield (%)
entry
catalyst
yield (%)
1 2 3 4 5
Cu(OTf)2 Cu(OCOCF3)2 Cu(OAc)2 CuOTf CuOOAc
18 22 63 35 55
6 7 8 9 10b
CuI CuBr CuCl CuCl2 CuCl
50 55 73 33 80c
a
Conditions: 1a (0.4 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h. Yields were determined by 1H NMR analysis using 2-methoxynaphthalene as an internal standard. b0.3 mmol of 1a and molecular sieves 4 Å were used. Reaction was performed under oxygen atmosphere. c Isolated yield. TMP = 1-oxy-2,2,6,6-tetramethylpiperidine.
exhibited the highest catalytic performance, and the desired product 3a was obtained in 73% yield (entry 8), while the corresponding copper(II) chloride exhibited poor catalytic performance (entry 9). During the course of catalyst evaluation, we found that partial hydrolysis of the acylpyrazoles 1a and 3a proceeded, leading to the formation of the corresponding carboxylic acids. Thus, we performed the reaction under dried oxygen with molecular sieves as a desiccant, and product 3a was isolated in 80% yield with a reduced amount of 1a (1.5 equiv, entry 10).17 With the optimal conditions in hand, we next examined the scope of acylpyrazoles (Scheme 2). The present catalysis proceeded on gram scale without any detrimental effects, and product 3a was isolated in 87% yield. Lactic acid derivative 3b was obtained in high yield. An alkyl bromide functional group survived during the course of the reaction (3c). The reactions of sterically congested substrates afforded products 3d and 3e in synthetically useful yields by increasing the catalyst loading to 10 mol %. Oxygen functionalities, such as ethyl ether and TBS ether, were compatible (3f and 3g). An α-hydroxy acid derivative with primary amino group 3h was isolated in high yield. Indole and boronate ester functionalities were incorporated (3i and 3j). It is noteworthy that reactive aldehyde, which potentially serves as an aldol acceptor under basic conditions, survived (3k), although the chemical yield was moderate. Chemoselective α-oxidation was investigated next using substrates bearing an acidic α-proton (3l−r). Highly reactive nitroalkyl functionalities that could be deprotonated by catalytic amounts of a mild base such as triethylamine15,18 did not react under the optimized conditions, and the desired α-oxyacylpyrazole 3l was isolated in high yield.19 Substrates with aliphatic or aromatic ketones afforded a high yield (3m−o). Other electron-withdrawing groups, such as ester, nitrile, and sulfone, were also compatible, affording the corresponding αhydroxy acid derivatives chemoselectively (3p−r) and demonstrating the highly chemoselective nature of our α-oxidation method. We then investigated late-stage α-oxidation of a variety of pharmaceutical agents and natural products (Scheme 3). The present catalysis could be efficiently applied to an α-aryl substrate at room temperature.20 A felbinac derivative and isoxepac derivative afforded the products 3s and 3t in high yield. Catalytic α-oxidation of felbinac derivative under air atmosphere was also achieved, although the yield was decreased. The rather acidic diaryl NH proton in a diclofenac derivative was tolerated (3u). α-Heteroaryl substrates (in-
a Conditions: 1a (0.3 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h. Isolated yields are shown. bReaction time was 48 h. cGram scale (5.0 mmol) synthesis. 48 h. d10 mol % of CuCl was used. TMP = 1-oxy2,2,6,6-tetramethylpiperidine. X = 3,5-dimethylpyrazolyl group.
domethacin and zomepirac derivatives) were efficiently oxidized under mild conditions (3v and 3w). An α-lipoic acid derivative, which serves as an antioxidant, was chemoselectively oxidized at the α-position over oxidation-labile cyclic disulfide functionality (3x). Other α-aliphatic pharmaceutical agents and natural product derivatives were efficiently converted to the corresponding α-hydroxy acid derivatives (3y−β). Further transformation of the products was performed (Scheme 4). Conversion of an acylpyrazole functionality to the corresponding methyl ester was catalyzed by Sm(OTf)3 under mild conditions.21 Both α-alkyl- (3a and 3β) and α-arylsubstituted (3s) α-oxy acylpyrazoles were efficiently transformed into methyl esters 4, followed by treatment with zinc dust in AcOH to give α-hydroxy esters 5 in high yield.7c To gain insight into in situ-generated copper species, various control experiments were investigated (Scheme 5). First, the reaction was performed under N2 using 5 mol % of CuCl, but the product 3a was not detected. Even when a substoichiometric amount of CuCl (50 mol %) was used, 3a was obtained in only 3% yield. These results were different from the previously reported chiral amine-catalyzed reaction,9a,c suggesting that an oxygen was critical to promote the present Cu catalysis. On the other hand, 50 mol % of CuCl2, which provided inferior results under standard reaction conditions (Table 1, entry 9), afforded 3a in moderate yield. These results 3188
DOI: 10.1021/acs.orglett.7b01293 Org. Lett. 2017, 19, 3187−3190
Letter
Organic Letters Scheme 3. Late-Stage α-Oxidation of Acylpyrazolesa
resulting copper species were subjected to the standard reaction conditions under N2 atmosphere (Scheme 6). Preparation of a Scheme 6. Actual Catalyst Generation under Oxygen
copper catalyst by premixing CuCl under O2 atmosphere resulted in poor catalytic performance. Premixed CuCl catalyst with acylpyrazole 1a under O2 atmosphere afforded product 3a in only 3% yield. Finally, premixing CuCl with TEMPO under O2 atmosphere delivered product 3a in 31% yield. On the other hand, premixing them under N2 atmosphere did not promote the reaction. These results suggested that TEMPO is essential to generate an actual copper(II) species with the assistance of O2.23,24 The ESI-mass spectrum of a mixed solution of [Cu(CH3CN)4]PF6 with TEMPO under O2 atmosphere showed the peak at 252 m/z ([Cu(TEMPO) (OOH)]+), verifying the generation of copper(II) peroxo species.25 Although the exact structure of the active copper(II) species22 remains unclear, we propose that the copper(II) peroxo complex serves as a Lewis acid/Brønsted base cooperative catalyst, allowing for chemoselective and facilitated nucleophilic activation of acylpyrazole.26,27 In conclusion, we developed a highly chemoselective αoxidation of acylpyrazoles under aerobic conditions using an in situ generated copper(II) species serving as a Lewis acid/ Brønsted base cooperative catalyst. Further applications of in situ generated copper(II) peroxo species to the deprotonative activation reactions and development of enantioselective variants are underway in our laboratory.28
a Conditions: 1a (0.3 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h. Isolated yields are shown. bReaction was performed at room temperature. cReaction was performed under air atmosphere instead of oxygen atmosphere. dReaction time was 48 h. e10 mol % of CuCl was used. TMP = 1-oxy-2,2,6,6-tetramethylpiperidine. X = for 3,5dimethylpyrazolyl group.
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Scheme 4. Transformation of the Products
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01293. Experimental details, characterizations, and NMR spectra of all products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected].
Scheme 5. Copper-Mediated Reaction under Nitrogen
ORCID
Ryo Yazaki: 0000-0001-9405-1383 Takashi Ohshima: 0000-0001-9817-6984 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant No. JP15H05846 in Middle Molecular Strategy, JP16H01032 in Precisely Designed Catalysts with Customized Scaffolding, Grant-in-Aid for Scientific Research (C) (No. 16K08166) and
indicated that copper(I) salts are oxidized in situ by molecular oxygen, and the resulting copper(II) salts are the actual catalytic species.22 We also prepared several copper(II) catalysts by premixing CuCl under distinct conditions (O2 atmosphere), and the 3189
DOI: 10.1021/acs.orglett.7b01293 Org. Lett. 2017, 19, 3187−3190
Letter
Organic Letters
(15) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016, 138, 2664. (16) For detailed optimization studies, see the Supporting Information. (17) For a review on aerobic copper-catalyzed reactions, see: Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234. (18) (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006. (b) Do, H.-Q.; Tran-vu, H.; Daugulis, O. Organometallics 2012, 31, 7816. (19) TA trace amount of α-oxidation product of nitroalkane was detected. (20) When the reaction was performed at 40 °C using α-aryl substrate, various side products such as keto acid derivative were detected. (21) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Côté, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671. (22) For reviews on copper dioxygen complexes, see: (a) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013. (b) Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004, 104, 1047. (c) Hatcher, L. Q.; Karlin, K. D. Adv. Inorg. Chem. 2006, 58, 131. (23) TEMPO is proposed to remain coordinated to copper complex throughout the catalytic cycles in copper/TEMPO-catalyzed oxidation of alcohols; see: Iron, M.; Szpilman, A. M. Chem. - Eur. J. 2017, 23, 1368. (24) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Org. Biomol. Chem. 2003, 1, 3232. (25) See the Supporting Information for details. (26) Copper(II) peroxo complexes as Brønsted bases, see: Comba, P.; Haaf, C.; Helmle, S.; Karlin, K. D.; Pandian, S.; Waleska, A. Inorg. Chem. 2012, 51, 2841. (b) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357. (27) Cu(OH)2, Cu2O, and CuO did not afford the product, suggesting that copper hydroxide and μ-hydroxo complex were not actual catalytic species. Also see: (a) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. ACS Catal. 2013, 3, 2599. (b) Xu, B.; Hartigan, E. M.; Feula, G.; Huang, Z.; Lumb, J.-P.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2016, 55, 15802. (28) After submission of this manuscript, Maulide et al. reported the Tf2O-mediated chemoselective oxidation of amide. For details, see: de la Torre, A.; Kaiser, D.; Maulide, N. J. Am. Chem. Soc. 2017, 139, 6578.
Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT. R.Y. thanks Ube Industries, Ltd. Award in Synthetic Organic Chemistry, Japan.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01293 Org. Lett. 2017, 19, 3187−3190
