COMMUNICATION DOI: 10.1002/ajoc.201402039
Phosphine-Initiated General-Base-Catalyzed Quinolone Synthesis San Khong and Ohyun Kwon*[a]
Abstract: Phosphinocatalysis provides a new approach toward 3-substituted-4-quinolones. A simple procedure, which uses Ph3P as an inexpensive catalyst and S-phenyl 2(N-tosylamido)benzothioates and activated alkynes as starting materials, provides direct access to several 3-aroyl-4quinolones and methyl 4-quinolone-3-carboxylate esters. The reaction presumably occurs through general base catalysis, with the initial addition of Ph3P to the activated alkyne generating the phosphonium enoate zwitterion, which acts as the strong base that initiates the reaction.
Introduction
Scheme 1. Examples of 3-substituted 4-quinolone therapeutic agents.
Since the discovery of the antibiotic nalidixic acid in 1962,[1] 3-substituted 4-quinolones have been the subject of extensive studies and modifications to deliver new generations of quinolone-based drugs with enhanced activity against microorganisms.[2] The therapeutic quinolones were not known or modeled based on any natural sources; they were entirely of synthetic origin.[3] At present, four generations of clinically approved 3-carboxy 4-quinolones have been developed and placed in highly profitable markets. Indeed, ciprofloxacin[4a] and levofloxacin[4b] are billion-dollar antimicrobial agents (Scheme 1). Among a number of conventional methods that can build the quinolone core structure, the Gould–Jacobs reaction[5] and Grohe–Heitzer reaction[6] remain the two most effective methods to approach 3-substituted 4-quinolones.[3] Despite the interesting medicinal activity of quinolones, especially of 3-carboxy-4-quinolones, relatively few methods have been developed for the synthesis of quinolone cores.[7] In light of our previous studies of phosphine catalysis quickly and efficiently providing access to 3-substituted and 3,4-disubstituted quinolines,[8] we envisioned that 3-substituted-4-quinolone structures could also be achieved through phosphine catalysis (Scheme 2).[9] In the case where R’ is
Scheme 2. Phosphine-catalyzed quinolone synthesis. EWG = electronwithdrawing group; Ts = p-toluenesulfonyl.
not a leaving group (i.e., R’ = H, alkyl, or aryl), the hemiaminal motif in the 4-hydroxy-1,4-dihydroquinoline 4 undergoes facile detosylation during acidic work-up to furnish the quinoline 5. In contrast, we suspected that the intermediate 4 could be converted immediately into the 3-substituted 4-quinolone 3 if R’ was ejected as a good leaving group. This method would provide rapid access to a new scaffold of N-tosylated 3-substituted 4-quinolones 3.
[a] S. Khong, Prof. Dr. O. Kwon Department of Chemistry and Biochemistry University of California, Los Angeles 607 Charles E. Young Dr. East Los Angeles, California 90095-1569 (USA) Fax: (+ 1) 310-206-3722 E-mail: [email protected]
Results and Discussion We began to test the viability of quinolone synthesis with the reaction between the phenyl thiobenzoate 1 a and the
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201402039.
Asian J. Org. Chem. 2014, 3, 453 – 457
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alkynone 2 a under the same reaction conditions that had been used previously for the quinoline synthesis.[8] Under such conditions, we mixed 1.5 equivalents of the alkynone 2 a with the thiobenzoate 1 a and 0.1 equivalents of Ph3P in a volume of MeCN that would make the concentration of 1 a 0.2 m at room temperature. Although the reaction did afford the desired quinolone adduct 3 aa, the yield was low. Notably, the supposedly excess coupling partner 2 a was completely consumed, whereas substrate 1 a remained present after the reaction. We suspect that the excess alkynone 2 a was consumed as a result of conjugate addition of benzenethiol, the reaction byproduct. Doubling the amount of the alkynone 2 a led to complete consumption of 1 a in the reaction mixture and conveniently doubled the yield of the quinolone product 3 aa (Scheme 3). Nevertheless, the reac-
Scheme 4. Reactions of the phenyl thiobenzoate 1 a with various alkynones 2. Isolated yields are shown. Bn = benzyl. Scheme 3. Preliminary results for the formation of a 3-substituted 4-quinolone.
tion yield remained only within the “fairly good” range because the steric bulk of the leaving group (thiophenolate) affected the acylation/cyclization; in our previous study we witnessed similar steric effects lowering the reaction yields when synthesizing 3,4-disubstituted quinolines.[8] By screening the reaction with other aryl acetylenyl ketones 2, we generated a number of quinolone structures (Scheme 4). In general, the reaction yields varied slightly when different substituents were positioned at various positions on the aromatic ring (3 aa vs. 3 ab–3 ai), but we could not discern any general trends. Electron-deficient aromatic rings tended to lower the reaction yields (3 aa vs. 3 ab–3 ag) whereas electron-rich aromatic rings led to slightly better yields (3 aa vs. 3 ah and 3 ai). Electron-withdrawing halide substituents, at the meta position in particular, revealed a contradictory trend. More electron-withdrawing halides increased the yields of quinolone formation (3 ae–3 ag). Various substituents at different positions on substrate 1 also affected the reaction yields (Scheme 5). A naphthalene ring, which has electronic properties similar to those of a benzene ring, led to a comparable yield of the corresponding quinolone product (3 aa vs. 3 ba). Having substituents at both the C4 and C5 positions of substrate 1, regardless of their electronic properties, led to lower yields (3 aa vs. 3 ca and 3 da). The presence of either an electron-donating or -withdrawing substituent at the C5 position of substrate 1 led to higher yields (3 aa vs. 3 ea–3 ha), whereas substitution at the C4 position lowered the reaction yield (3 ia). Because quinolone-based drugs contain 4-quinolone-3carboxylic acid as a structural unit,[10, 2j] we turned our atten-
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Scheme 5. Reactions of various substrates 1 with the alkynone 2 a. Isolated yields are shown.
tion toward the formation of methyl 4-quinolone-3-carboxylic ester 3 ak from the reaction between phenyl thiobenzoate 1 a and methyl propiolate (2 k). The current reaction conditions, however, provided an unsatisfactory yield of 3 ak (Table 1, entry 1).[11] With its potential for access to therapeutic quinolone reagents, we wished to optimize the synthesis of 3 ak. Again, we selected Ph3P and MeCN as the catalyst and solvent, respectively, for this transformation.[12]
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Table 1. Optimization of the reaction between 1 a and 2 k.
Entry
Conc. [m][a]
T [8C][b]
t [h]
PPh3 [mol %]
Yield [%][c]
1 2 3 4 5 6 7 8 9 10
0.2 neat 0.2 0.1 0.075 0.05 0.1 0.1 0.1 0.1
RT 72 72 72 72 72 82 82 82 82
12 2 2 2 2 2 2 4 2 2
10 10 10 10 10 10 10 10 20 5
30 0 44 55 46 42 61 61 54 59 Scheme 6. Variation of leaving groups in the reactions of 1 and 2 k. Isolated yields of the quinolone 3 ak are shown in parentheses. Bz = benzoyl.
[a] Concentration of substrate 1 a. [b] Temperature elevated using microwaves. [c] Isolated yield.
under the basic reaction conditions.[13] Surprisingly, substrates 1 o and 1 p, containing excellent leaving groups and highly reactive carbonyl groups, did not undergo the reaction. Although the yield from the reaction of substrate 1 m in the quinolone synthesis was slightly better than that from substrate 1 a, we opted to use derivatives of the thiobenzoate 1 a for our generation of 4-quinolone-3-carboxylates, because of easy access to thiophenol. Again, we used the available substrates 1 from Scheme 5 in reactions with methyl propiolate (2 k) to access various methyl 4-quinolone-3-carboxylic esters (Scheme 7). In general, there was a similar trend to that in Scheme 5 in terms of the reactivity of the substrates toward the formation of
Table 1 lists the other reaction parameters that we screened to improve the yield of 3 ak. We found that the reaction yields were influenced by the concentration of substrate 1 a (entries 2–6). The reaction provided no quinolone product under neat conditions (entry 2). By diluting the reaction mixture, the yield of the quinolone product 3 ak improved accordingly until the concentration reached 0.1 m (entries 3 and 4), decreasing thereafter (entries 5 and 6). The reaction yield improved slightly at elevated temperature under microwave-assisted conditions (entry 1 vs. entry 3). A longer reaction time had no effect on the reaction yield (entry 7 vs. entry 8), which confirmed that the quinolone product did not decompose under the reaction conditions. Loading more Ph3P catalyst did not benefit the reaction yield, whereas a lower catalyst loading decreased slightly the amount of product formed (entry 7 vs. entries 9 and 10). It is known, when making 3,4-disubstituted quinolines, that the steric bulk of the R’ group (Scheme 2) lowers the efficiency of the cyclization to form the quinoline ring. Therefore, only a reasonable range of reaction yields can be obtained with the relative bulky benzenethiolate group in 1 a.[8] Quinolone formation is influenced not only by the steric effect of the R’ group but also by its leaving-group ability. Consequentially, we prepared a set of substrates 1 j– p and screened them to study the effect of the leaving group R on quinolone formation (Scheme 6). As expected, the reaction of substrate 1 j, with its poor leaving group (methoxide), provided the quinolone product in only a trace amount, whereas those of substrates 1 k and 1 l, which have slightly better leaving groups (electron-deficient phenoxide and ethanethiolate, respectively), provided slightly better yields (15 and 20 %, respectively). Accordingly, we prepared the substrates 1 m and 1 n containing electron-deficient benzenethiolates. Whereas the reaction of substrate 1 m provided a slight improvement in the reaction yield (61 % vs. 65 %), that of substrate 1 n, with its even better leaving group, provided only a low product yield (22 %), presumably because of dimerization of 1 n
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Scheme 7. Variation of the substituents on substrate 1 in its reactions with 2 k. Isolated yields are shown. Reaction time was 4 h for 3 ck and 3 ik.
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the new set of quinolones. The similar electronic properties of naphthalene and benzene rings led to comparable yields of their quinolone products (Scheme 7, 3 ak vs. 3 bk). The presence of substituents at both the C4 and C5 positions of substrate 1, regardless of their electronic properties, lowered the reactions yields (3 ak vs. 3 ck and 3 dk). Again, the general trend was that we obtained better yields when a substituent was present at the C5 position of substrate 1 (3 ek, 3 gk, and 3 hk), although an electron-donating methoxy group at this position provided the opposite trend, giving a slightly lower yield (3 fk). Similar to the trend in Scheme 5, substitution at the C4 position led to a lower reaction yield (3 ik). Notably, electron-deficient substrates 1 were less reactive and required longer reaction times (3 ck and 3 ik). Similar to the quinoline syntheses in our previous study, we believe that quinolone formation occurs through a general-base catalysis (Scheme 8). Nucleophilic addition of Ph3P
San Khong and Ohyun Kwon
Alternatively, the leaving group X might, by itself, function as a base to activate another molecule of the pronucleophile 1. In such a case, the generation of the proton donor HX would possibly facilitate proton transfer, which leads to more of the byproduct 6. The ion pair D may also undergo addition/elimination to generate the byproduct 7 and regenerate the Ph3P initiator.
Conclusions We have generated an array of S-phenyl 2-(N-tosylamido)benzothioates 1 that provide direct access to the structures of 3-aroyl-4-quinolones and 4-quinolone-3-carboxylates 3. We believe that the formation of quinolones in the presence of a substoichiometric amount of Ph3P occurs through general-base catalysis, initiated upon nucleophilic addition of Ph3P to the activated acetylene.
Experimental Section General Procedure for the Synthesis of 3-Aroyl-4-quinolones (Scheme 4 and 5) An S-phenyl thiobenzoate (1, 0.3 mmol), PPh3 (7.9 mg, 10 mol %), MeCN (3 mL), and an aryl acetylenyl ketone 2 a–i (0.9 mmol) were added sequentially to an oven-dried round-bottomed flask. The solution was stirred at room temperature for 6 h before it was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexanes, gradient from 20–30 %) to afford the quinolone 3. General Procedure for the Synthesis of Methyl 4-quinolone-3-carboxylic Esters (Scheme 7) An S-phenyl thiobenzoate (1, 0.3 mmol), PPh3 (7.9 mg, 10 mol %), MeCN (3 mL), and methyl propiolate 2 k (81 mL, 0.9 mmol) were added sequentially to an oven-dried microwave vessel; unless otherwise noted, the solution was subjected to microwave irradiation at 82 8C for 2 h before it was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexanes, gradient from 30–50 %) to afford the quinolone 3.
Scheme 8. Proposed mechanistic pathway for the reaction of 1 and 2.
Acknowledgements We thank the NIH (GM071779) for financial support.
onto the activated alkyne 2 generates the phosphonium zwitterion A, which then acts as a strong base to deprotonate and activate the pronucleophile 1. The resulting nucleophile in the ion pair B then adds to the activated alkyne 2 to generate the ion pair C. Whereas subsequent cyclization outcompetes protonation in the case of dihydroquinoline formation (X = H, alkyl, aryl),[8] the cyclization/acyl substitution sequence (X = SPh) to form the corresponding quinolone 3 is accompanied by protonation, which leads to the Michael adduct 6 as a byproduct. Upon formation of the quinolone 3, the leaving group X is released into the reaction mixture in the form of the ion pair D, which then adds to the free activated acetylene 2 to regenerate the base (in the form of the ion pair E) to continue the catalytic cycle.
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Keywords: 4-quinolone · acyl substitution addition · phosphine catalysis · quinoline
·
michael
[1] G. Y. Lesher, E. J. Froelich, M. D. Gruett, J. H. Bailey, R. P. Brundage, J. Med. Chem. 1962, 5, 1063 – 1065. [2] a) T. A. Vincent, Clin. Infect. Dis. 2005, 41, S113; b) C. M. Oliphant, C. M. Green, Am. Fam. Physician 2002, 65, 455 – 465; c) P. C. Appelbaum, P. A. Hunter, Int. J. Antimicrob. Agents 2000, 16, 5 – 15; d) P. Ball, J. Antimicrob. Chemother. 2000, 46, S17 – 24; e) K. Bush, R. Goldschmidt, Curr. Opin. Invest. Drugs 2000, 1, 22 – 30; f) D. C. Hooper, Clin. Infect. Dis. 2000, 31, S24 – S28; g) K. E. Pickerill, J. A. Paladino, J. J. Schentag, Pharmacotherapy 2000, 20, 417 – 428; h) E. Varon, L. Gutmann, Res. Microbiol. 2000, 151, 471 – 473;
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Swamy, N. N. Bhuvan Kumar, E. Balaraman, K. V. P. Pavan Kumar, Chem. Rev. 2009, 109, 2551 – 2651; j) B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102 – 3116; k) A. Marinetti, A. Voituriez, Synlett 2010, 174 – 194; l) B. Kolesinska, Cent. Eur. J. Chem. 2010, 8, 1147 – 1171; m) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005 – 1018; n) T. M. V. D. Pinho e Melo, Monatsh. Chem. 2011, 142, 681 – 697; o) C. Lalli, J. Brioche, G. Bernadat, G. Masson, Curr. Org. Chem. 2011, 15, 4108 – 4127; p) S.-X. Wang, X. Han, F. Zhong, Y. Wang, Y. Lu, Synlett 2011, 2766 – 2778; q) F. Lpez, J. L. MascareÇas, Chem. Eur. J. 2011, 17, 418 – 428; r) Z. Chai, G. Zhao, Catal. Sci. Technol. 2012, 2, 29 – 41; s) Phosphine Catalysis. Y. C. Fan, O. Kwon in Science of Synthesis (Ed.: B. List), Thieme, Stuttgart, 2012, Asymmetric Organocatalysis, Vol 1, Lewis Base and Acid Catalysts, pp. 723 – 782; t) S. Xu, Z. He, Chin. J. Org. Chem. 2012, 32, 1159 – 1168; u) Q.-Y. Zhao, Z. Lian, Y. Wei, M. Shi, Chem. Commun. 2012, 48, 1724 – 1732; v) S. Xu, Z. He, RSC Adv. 2013, 3, 16885 – 16904; w) Y. Wang, J. Pan, Z. Chen, X. Sun, Z. Wang, MiniRev. Med. Chem. 2013, 13, 836 – 844; x) Phosphine Organocatalysis as a Platform for Diversity-Oriented Synthesis. Z. Wang, O. Kwon in Diversity-Oriented Synthesis: Basics and Applications in Organic Synthesis Drug Discovery, and Chemical Biology (Ed.: A. Trabocchi), Wiley, Hoboken, NJ, 2013, pp. 97 – 133; y) Y. C. Fan, O. Kwon, Chem. Commun. 2013, 49, 11588 – 11619; z) Z. Wang, X. Xu, O. Kwon, Chem. Soc. Rev. 2014, DOI: 10.1039/c4s00054d. a) C. Mugnaini, S. Pasquini, F. Corelli, Curr. Med. Chem. 2009, 16, 1746 – 1767; b) S. Emami, A. Shafiee, A. Foroumadi, Iran. J. Pharm. Res. 2005, 3, 123 – 136. The reactivity of methyl propiolate was lower than that alkynones, which is consistent with our results in the quinoline synthesis; see ref. [8]. We also screened THF, toluene, 1,2-dichloroethane (DCE), EtOAc, chlorobenzene, and N,N-dimethylformamide (DMF) as potential solvents. In addition, we tested PBn3, Ph2PEt, PACHTUNGRE(4-FC6H4)3, and P(4-MeOC6H4)3 as potential catalytic phosphines for this reaction. Significant dimerization of substrate 1 n occurred during its preparation under basic conditions. Careful control and decreased basicity enabled the formation of 1 n. Received: March 12, 2014
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Phosphine-Initiated General-Base-Catalyzed Quinolone Synthesis San Khong and Ohyun Kwon*[a]
Abstract: Phosphinocatalysis provides a new approach toward 3-substituted-4-quinolones. A simple procedure, which uses Ph3P as an inexpensive catalyst and S-phenyl 2(N-tosylamido)benzothioates and activated alkynes as starting materials, provides direct access to several 3-aroyl-4quinolones and methyl 4-quinolone-3-carboxylate esters. The reaction presumably occurs through general base catalysis, with the initial addition of Ph3P to the activated alkyne generating the phosphonium enoate zwitterion, which acts as the strong base that initiates the reaction.
Introduction
Scheme 1. Examples of 3-substituted 4-quinolone therapeutic agents.
Since the discovery of the antibiotic nalidixic acid in 1962,[1] 3-substituted 4-quinolones have been the subject of extensive studies and modifications to deliver new generations of quinolone-based drugs with enhanced activity against microorganisms.[2] The therapeutic quinolones were not known or modeled based on any natural sources; they were entirely of synthetic origin.[3] At present, four generations of clinically approved 3-carboxy 4-quinolones have been developed and placed in highly profitable markets. Indeed, ciprofloxacin[4a] and levofloxacin[4b] are billion-dollar antimicrobial agents (Scheme 1). Among a number of conventional methods that can build the quinolone core structure, the Gould–Jacobs reaction[5] and Grohe–Heitzer reaction[6] remain the two most effective methods to approach 3-substituted 4-quinolones.[3] Despite the interesting medicinal activity of quinolones, especially of 3-carboxy-4-quinolones, relatively few methods have been developed for the synthesis of quinolone cores.[7] In light of our previous studies of phosphine catalysis quickly and efficiently providing access to 3-substituted and 3,4-disubstituted quinolines,[8] we envisioned that 3-substituted-4-quinolone structures could also be achieved through phosphine catalysis (Scheme 2).[9] In the case where R’ is
Scheme 2. Phosphine-catalyzed quinolone synthesis. EWG = electronwithdrawing group; Ts = p-toluenesulfonyl.
not a leaving group (i.e., R’ = H, alkyl, or aryl), the hemiaminal motif in the 4-hydroxy-1,4-dihydroquinoline 4 undergoes facile detosylation during acidic work-up to furnish the quinoline 5. In contrast, we suspected that the intermediate 4 could be converted immediately into the 3-substituted 4-quinolone 3 if R’ was ejected as a good leaving group. This method would provide rapid access to a new scaffold of N-tosylated 3-substituted 4-quinolones 3.
[a] S. Khong, Prof. Dr. O. Kwon Department of Chemistry and Biochemistry University of California, Los Angeles 607 Charles E. Young Dr. East Los Angeles, California 90095-1569 (USA) Fax: (+ 1) 310-206-3722 E-mail: [email protected]
Results and Discussion We began to test the viability of quinolone synthesis with the reaction between the phenyl thiobenzoate 1 a and the
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201402039.
Asian J. Org. Chem. 2014, 3, 453 – 457
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alkynone 2 a under the same reaction conditions that had been used previously for the quinoline synthesis.[8] Under such conditions, we mixed 1.5 equivalents of the alkynone 2 a with the thiobenzoate 1 a and 0.1 equivalents of Ph3P in a volume of MeCN that would make the concentration of 1 a 0.2 m at room temperature. Although the reaction did afford the desired quinolone adduct 3 aa, the yield was low. Notably, the supposedly excess coupling partner 2 a was completely consumed, whereas substrate 1 a remained present after the reaction. We suspect that the excess alkynone 2 a was consumed as a result of conjugate addition of benzenethiol, the reaction byproduct. Doubling the amount of the alkynone 2 a led to complete consumption of 1 a in the reaction mixture and conveniently doubled the yield of the quinolone product 3 aa (Scheme 3). Nevertheless, the reac-
Scheme 4. Reactions of the phenyl thiobenzoate 1 a with various alkynones 2. Isolated yields are shown. Bn = benzyl. Scheme 3. Preliminary results for the formation of a 3-substituted 4-quinolone.
tion yield remained only within the “fairly good” range because the steric bulk of the leaving group (thiophenolate) affected the acylation/cyclization; in our previous study we witnessed similar steric effects lowering the reaction yields when synthesizing 3,4-disubstituted quinolines.[8] By screening the reaction with other aryl acetylenyl ketones 2, we generated a number of quinolone structures (Scheme 4). In general, the reaction yields varied slightly when different substituents were positioned at various positions on the aromatic ring (3 aa vs. 3 ab–3 ai), but we could not discern any general trends. Electron-deficient aromatic rings tended to lower the reaction yields (3 aa vs. 3 ab–3 ag) whereas electron-rich aromatic rings led to slightly better yields (3 aa vs. 3 ah and 3 ai). Electron-withdrawing halide substituents, at the meta position in particular, revealed a contradictory trend. More electron-withdrawing halides increased the yields of quinolone formation (3 ae–3 ag). Various substituents at different positions on substrate 1 also affected the reaction yields (Scheme 5). A naphthalene ring, which has electronic properties similar to those of a benzene ring, led to a comparable yield of the corresponding quinolone product (3 aa vs. 3 ba). Having substituents at both the C4 and C5 positions of substrate 1, regardless of their electronic properties, led to lower yields (3 aa vs. 3 ca and 3 da). The presence of either an electron-donating or -withdrawing substituent at the C5 position of substrate 1 led to higher yields (3 aa vs. 3 ea–3 ha), whereas substitution at the C4 position lowered the reaction yield (3 ia). Because quinolone-based drugs contain 4-quinolone-3carboxylic acid as a structural unit,[10, 2j] we turned our atten-
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Scheme 5. Reactions of various substrates 1 with the alkynone 2 a. Isolated yields are shown.
tion toward the formation of methyl 4-quinolone-3-carboxylic ester 3 ak from the reaction between phenyl thiobenzoate 1 a and methyl propiolate (2 k). The current reaction conditions, however, provided an unsatisfactory yield of 3 ak (Table 1, entry 1).[11] With its potential for access to therapeutic quinolone reagents, we wished to optimize the synthesis of 3 ak. Again, we selected Ph3P and MeCN as the catalyst and solvent, respectively, for this transformation.[12]
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Table 1. Optimization of the reaction between 1 a and 2 k.
Entry
Conc. [m][a]
T [8C][b]
t [h]
PPh3 [mol %]
Yield [%][c]
1 2 3 4 5 6 7 8 9 10
0.2 neat 0.2 0.1 0.075 0.05 0.1 0.1 0.1 0.1
RT 72 72 72 72 72 82 82 82 82
12 2 2 2 2 2 2 4 2 2
10 10 10 10 10 10 10 10 20 5
30 0 44 55 46 42 61 61 54 59 Scheme 6. Variation of leaving groups in the reactions of 1 and 2 k. Isolated yields of the quinolone 3 ak are shown in parentheses. Bz = benzoyl.
[a] Concentration of substrate 1 a. [b] Temperature elevated using microwaves. [c] Isolated yield.
under the basic reaction conditions.[13] Surprisingly, substrates 1 o and 1 p, containing excellent leaving groups and highly reactive carbonyl groups, did not undergo the reaction. Although the yield from the reaction of substrate 1 m in the quinolone synthesis was slightly better than that from substrate 1 a, we opted to use derivatives of the thiobenzoate 1 a for our generation of 4-quinolone-3-carboxylates, because of easy access to thiophenol. Again, we used the available substrates 1 from Scheme 5 in reactions with methyl propiolate (2 k) to access various methyl 4-quinolone-3-carboxylic esters (Scheme 7). In general, there was a similar trend to that in Scheme 5 in terms of the reactivity of the substrates toward the formation of
Table 1 lists the other reaction parameters that we screened to improve the yield of 3 ak. We found that the reaction yields were influenced by the concentration of substrate 1 a (entries 2–6). The reaction provided no quinolone product under neat conditions (entry 2). By diluting the reaction mixture, the yield of the quinolone product 3 ak improved accordingly until the concentration reached 0.1 m (entries 3 and 4), decreasing thereafter (entries 5 and 6). The reaction yield improved slightly at elevated temperature under microwave-assisted conditions (entry 1 vs. entry 3). A longer reaction time had no effect on the reaction yield (entry 7 vs. entry 8), which confirmed that the quinolone product did not decompose under the reaction conditions. Loading more Ph3P catalyst did not benefit the reaction yield, whereas a lower catalyst loading decreased slightly the amount of product formed (entry 7 vs. entries 9 and 10). It is known, when making 3,4-disubstituted quinolines, that the steric bulk of the R’ group (Scheme 2) lowers the efficiency of the cyclization to form the quinoline ring. Therefore, only a reasonable range of reaction yields can be obtained with the relative bulky benzenethiolate group in 1 a.[8] Quinolone formation is influenced not only by the steric effect of the R’ group but also by its leaving-group ability. Consequentially, we prepared a set of substrates 1 j– p and screened them to study the effect of the leaving group R on quinolone formation (Scheme 6). As expected, the reaction of substrate 1 j, with its poor leaving group (methoxide), provided the quinolone product in only a trace amount, whereas those of substrates 1 k and 1 l, which have slightly better leaving groups (electron-deficient phenoxide and ethanethiolate, respectively), provided slightly better yields (15 and 20 %, respectively). Accordingly, we prepared the substrates 1 m and 1 n containing electron-deficient benzenethiolates. Whereas the reaction of substrate 1 m provided a slight improvement in the reaction yield (61 % vs. 65 %), that of substrate 1 n, with its even better leaving group, provided only a low product yield (22 %), presumably because of dimerization of 1 n
Asian J. Org. Chem. 2014, 3, 453 – 457
Scheme 7. Variation of the substituents on substrate 1 in its reactions with 2 k. Isolated yields are shown. Reaction time was 4 h for 3 ck and 3 ik.
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the new set of quinolones. The similar electronic properties of naphthalene and benzene rings led to comparable yields of their quinolone products (Scheme 7, 3 ak vs. 3 bk). The presence of substituents at both the C4 and C5 positions of substrate 1, regardless of their electronic properties, lowered the reactions yields (3 ak vs. 3 ck and 3 dk). Again, the general trend was that we obtained better yields when a substituent was present at the C5 position of substrate 1 (3 ek, 3 gk, and 3 hk), although an electron-donating methoxy group at this position provided the opposite trend, giving a slightly lower yield (3 fk). Similar to the trend in Scheme 5, substitution at the C4 position led to a lower reaction yield (3 ik). Notably, electron-deficient substrates 1 were less reactive and required longer reaction times (3 ck and 3 ik). Similar to the quinoline syntheses in our previous study, we believe that quinolone formation occurs through a general-base catalysis (Scheme 8). Nucleophilic addition of Ph3P
San Khong and Ohyun Kwon
Alternatively, the leaving group X might, by itself, function as a base to activate another molecule of the pronucleophile 1. In such a case, the generation of the proton donor HX would possibly facilitate proton transfer, which leads to more of the byproduct 6. The ion pair D may also undergo addition/elimination to generate the byproduct 7 and regenerate the Ph3P initiator.
Conclusions We have generated an array of S-phenyl 2-(N-tosylamido)benzothioates 1 that provide direct access to the structures of 3-aroyl-4-quinolones and 4-quinolone-3-carboxylates 3. We believe that the formation of quinolones in the presence of a substoichiometric amount of Ph3P occurs through general-base catalysis, initiated upon nucleophilic addition of Ph3P to the activated acetylene.
Experimental Section General Procedure for the Synthesis of 3-Aroyl-4-quinolones (Scheme 4 and 5) An S-phenyl thiobenzoate (1, 0.3 mmol), PPh3 (7.9 mg, 10 mol %), MeCN (3 mL), and an aryl acetylenyl ketone 2 a–i (0.9 mmol) were added sequentially to an oven-dried round-bottomed flask. The solution was stirred at room temperature for 6 h before it was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexanes, gradient from 20–30 %) to afford the quinolone 3. General Procedure for the Synthesis of Methyl 4-quinolone-3-carboxylic Esters (Scheme 7) An S-phenyl thiobenzoate (1, 0.3 mmol), PPh3 (7.9 mg, 10 mol %), MeCN (3 mL), and methyl propiolate 2 k (81 mL, 0.9 mmol) were added sequentially to an oven-dried microwave vessel; unless otherwise noted, the solution was subjected to microwave irradiation at 82 8C for 2 h before it was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexanes, gradient from 30–50 %) to afford the quinolone 3.
Scheme 8. Proposed mechanistic pathway for the reaction of 1 and 2.
Acknowledgements We thank the NIH (GM071779) for financial support.
onto the activated alkyne 2 generates the phosphonium zwitterion A, which then acts as a strong base to deprotonate and activate the pronucleophile 1. The resulting nucleophile in the ion pair B then adds to the activated alkyne 2 to generate the ion pair C. Whereas subsequent cyclization outcompetes protonation in the case of dihydroquinoline formation (X = H, alkyl, aryl),[8] the cyclization/acyl substitution sequence (X = SPh) to form the corresponding quinolone 3 is accompanied by protonation, which leads to the Michael adduct 6 as a byproduct. Upon formation of the quinolone 3, the leaving group X is released into the reaction mixture in the form of the ion pair D, which then adds to the free activated acetylene 2 to regenerate the base (in the form of the ion pair E) to continue the catalytic cycle.
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Keywords: 4-quinolone · acyl substitution addition · phosphine catalysis · quinoline
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michael
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