Letter pubs.acs.org/OrgLett
Tunable and Diastereoselective Brønsted Acid Catalyzed Synthesis of β‑Enaminones Ye-Won Kang,† Yu Jin Cho,† Seung Jin Han,† and Hye-Young Jang*,†,‡ †
Department of Energy Systems Research, Ajou University, Suwon 443-749, Korea Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Korea
‡
S Supporting Information *
ABSTRACT: The Brønsted acid catalyzed Meyer−Schuster reaction of hemiaminals was studied for the stereoselective synthesis of β-enaminones. Hemiaminals were formed from propargyl aldehydes (or the oxidation of propargyl alcohols) and amines in the presence of Brønsted acids. A critical step to control the stereochemistry of the products is the protonation of the corresponding allenol intermediate, which is dictated by the Brønsted acid used, the steric effect of the amine, and the electronic effect of the propargyl aldehyde. alcohols, α-functionalized unsaturated carbonyl compounds have been obtained via Meyer−Schuster reaction followed by α-addition.5 β-Functionalized unsaturated carbonyl compounds are also synthesized by a tandem protocol involving nucleophilic addition to propargyl carbonyl compounds to form hemiaminal intermediates, which subsequently undergo Meyer−Schuster rearrangement. A gold-catalyzed reaction of propargyl aldehydes with primary amides and a metal-free reaction of propargyl aldehydes with amines were reported as recent examples of the synthesis of β-functionalized unsaturated carbonyl compounds.2l,6 Although classical Meyer−Schuster reactions are known to occur in the presence of Brønsted acids such as sulfuric acid, acetic acid, and formic acid, the effect of these acids on the stereochemistry of the product has not been extensively studied. In the case of the Meyer−Schuster reactions of hemiaminals, Z-alkenes have previously been observed as major products (Scheme 1).2l,6 In the gold-catalyzed rearrangement of hemiaminals, additional treatment of the reaction mixtures was required to alter the stereochemistry of the products.2l However, to the best of our knowledge, there is no catalytic reaction to direct the selective formation of E or Z isomers during the Meyer−Schuster rearrangement of hemiaminals. In this study, we present the stereocontrolled Brønsted acidcatalyzed rearrangement of hemiaminals to afford synthetically and biologically useful β-enaminones (Scheme 1).7−10 The reaction between phenylpropargyl aldehyde 1a and morpholine 1b was run in the presence of several Brønsted acid catalysts (0.25 equiv) at 80 °C in air (see Table 1). Optimization began with isopropyl alcohol (IPA) and hexafluoroisopropyl alcohol (HFIP) (entries 1 and 2, respectively). While sterically similar, the pKa values of these two alcohols are very different. Upon addition of HFIP, the
T
he classical Meyer−Schuster rearrangement has previously been employed to convert propargyl alcohols to α,βunsaturated carbonyl compounds under various metal-catalyzed and metal-free conditions.1−4 Extensive studies on the mechanism and investigation into efficient catalytic systems have been conducted. In addition to this simple rearrangement of propargyl alcohols to α,β-unsaturated carbonyl compounds, tandem approaches have been demonstrated (Scheme 1) involving the in situ formation of propargyl alcohols, which is followed by Meyer−Schuster rearrangement; this avoids the need for a separate synthesis of propargyl alcohols. By adding external electrophiles or organometallic species to propargyl Scheme 1. Meyer−Schuster Rearrangement
Received: December 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03445 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Synthesis of 1c
Scheme 2. Tandem Oxidation and Meyer−Schuster Rearrangement of 1a′
entry
acid catalysts
pKa*
yield (%)
ratio (E/Z)
1 2 3 4 5 6 7 8 9 10 11 12
IPA HFIP 4-OMePhOH PhOH 4-NO2PhOH phenylacetic acid PhCO2H 2-NO2PhCO2H TFA TsOH camphorsulfonic acid
16.5 9.3 10.2 9.95 7.1 4.76 4.2 2.2 −0.25 2.1 1.5
31 55 48 56 60 79 88 82 47 60 74 23
1:3.7 2.6:1 1:2.8 1:2.7 3.1:1 E only E only E only 1:3.2 1:12.5 1:6.3 1:2.7
benzoic acid was replaced with TsOH, Z-1c was exclusively obtained in 51% yield. Compared to the reaction using aldehydes, this tandem approach using both copper and Brønsted acid catalysts still suffers from copper-catalyzed oxidation-dealkynylation alongside the desired copper-catalyzed oxidation−Meyer−Schuster rearrangement, resulting in decreased yields. Nevertheless, the stereoselectivity was controlled by Brønsted acids in a similar manner to the analogous reaction of aldehydes. To probe the mechanism of the Brønsted acid catalyzed Meyer−Schuster reaction, an 18O-labeling experiment was conducted using aldehyde 1a (Scheme 3). The reaction of 1a
*
Evans’ pKa values in H2O.
yield of 1c was increased compared to that upon addition of IPA. Furthermore, while the IPA-catalyzed reaction was found to favor the Z-isomer, the HFIP-catalyzed reaction predominately formed the E-isomer. Phenol (PhOH), which has similar acidity to HFIP, catalyzed the reaction to afford 1c in 56% yield, which is comparable to the HFIP-catalyzed reaction (55% yield); however, the Z-isomer was the major product (entries 2 and 4). Phenol derivatives possessing an electron-donating group (OMe) and an electron-withdrawing group (NO2) produced 1c in 48% (E/Z = 1:2.8) and 60% (E/Z = 3.1:1) yield, respectively (entries 3 and 5). Following the use of these alcohols as acid catalysts, several carboxylic acid derivatives were also tested; phenylacetic acid, benzoic acid, 2-nitrobenzoic acid, and trifluoroacetic acid (TFA) (entries 6−9). Except for TFA, these additives were found to improve the yield of 1c, favoring complete E-stereoselectivity. In the case of sulfonic acids, p-toluenesulfonic acid (TsOH), and camphorsulfonic acid, Z-1c was isolated as the major product (entries 10 and 11). In the absence of an acid catalyst, the reaction still proceeded to afford 1c in 23% yield with an E/Z ratio of 1:2.7 (entry 12). On the basis of the Brønsted acid screening, it is apparent that benzoic acid derivatives preferentially form E-1c, while sulfonic acids form Z-1c with synthetically useful selectivity. In our previous reports on oxidative coupling reactions using propargyl alcohols, we demonstrated that the combination of copper salts and TEMPO induces the oxidation of propargyl alcohols, which leads to good yield in the subsequent Cucatalyzed reaction.11 Among copper−TEMPO-catalyzed oxidative reactions, the dealkynylation of propargyl alcohols occurs via hemiacetal intermediates, which are the common intermediates of the Meyer−Schuster rearrangement.11b Various copper salts were tested in order to suppress undesired dealkynylation and promote the desired Meyer−Schuster rearrangement of hemiaminals. The best yield of the desired product was achieved in the presence of CuOTf·benzene (see the Supporting Information). Phenylpropargyl alcohol 1a′ was subjected to a tandem reaction involving CuOTf·benzenecatalyzed oxidation followed by Brønsted acid catalyzed Meyer−Schuster reaction (Scheme 2). The reaction of 1a′ and 1b in the presence of CuOTf·benzene and benzoic acid afforded exclusively E-1c in 41% yield. Conversely, when
Scheme 3. 18O-Labeling Experiment
and 1b in the presence of H218O provided 1c with the Z-isomer as the major product (E/Z = 1:3). In both Z and E isomers, more amounts of 16O-labeled 1c than 18O-labeled 1c were observed (see the Supporting Information). In light of these 18O-labeling experiments, the reaction mechanism is proposed in Scheme 4. Propargyl aldehyde 1a Scheme 4. Proposed Reaction Mechanism
undergoes an addition with an amine to afford hemiaminal I. This intermediate would be converted to allenol III, either through the complete dissociation of water or a 1,3-shift of the hydroxyl group across the triple bond. On the basis of 18Olabeling experiments, while both routes occur, the 1,3-shift is slightly more favored. To elucidate E/Z isomer formation, independently synthesized E and Z isomers were re-exposed to Brønsted acidic conditions, as shown in Scheme 5. The ability of TsOH to promote the formation of Z-isomers was applied to the reaction of E-1c, resulting in no isomerization. The reaction of benzoic acid with Z-1c also showed no isomerization. B
DOI: 10.1021/acs.orglett.5b03445 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 5. Reactions of E and Z Isomers with Brønsted Acids
mixture of E and Z isomers in the presence of benzoic acid (E:Z = 1.5:1). Applying bulky carboxylic acids, such as pivalic acid and adamantanecarboxylic acid (AdmCO2H) increased the proprtion of E-12c. Presumably, the reaction of diethylamine favors the reaction via intermediate V to afford Z-12c (Scheme 4). However, the coordination of a bulky counteranion to the protonated carbonyl group switches the preferred stereochemistry to the E-isomer. According to these results for different substrates, the E/Z stereoselectivity of this reaction is mainly controlled by the Brønsted acids used, but the size of the amine and the electronic properties of the propargyl aldehyde also have an impact on electrostatic interaction and intramolecular hydrogen bonding. In conclusion, we have presented the stereocontrolled Meyer−Schuster rearrangement of hemiaminals derived from propargyl aldehydes and amines, in which Brønsted acids increase the yield of the product and direct the stereochemistry of the resulting β-enaminones. A key factor controlling this stereochemistry is the intramolecular hydrogen bonding present in the protonated β-enaminone. Weak electrostatic interaction of the tosylate anion with the protonated βenaminone promotes intramolecular hydrogen bonding to afford Z-isomers, while strong electrostatic interactions favors formation of the E-isomer. In addition to the effect caused by various Brønsted acids, the steric effect of the amine and the electronic properties of the propargyl aldehyde affected the intramolecular hydrogen bonding of the intermediates to produce a different distribution of E/Z products.
Accordingly, the stereochemistry of the β-enaminone products may be determined during the protonation of allenol III. The intramolecular hydrogen bonding of intermediate V results in Z-stereoselectivity, while E-isomers are formed via intermediate IV. The cationic intermediates IV and V are presumed to exist alongside a counteranion. Depending on the electrostatic interaction of the counter-anions with the corresponding cationic intermediates, the ratio between IV and V can be varied, resulting in a different ratio of E/Z products. Benzoates may bind tightly to the cation, which builds up the steric hindrance on the protonated carbonyl group to prevent intramolecular hydrogen bonding. Sulfonates may act as weakly bound anions to promote the intramolecular hydrogen bonding required for the formation of Z-products.12 Because this reaction is conducted in a nonpolar solvent, toluene, electrostatic interactions play an important role in controlling the stereochemistry of the product. Next, the scope of the reaction was examined (Figure 1). Substituted aromatic propargyl aldehydes were subjected to the
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03445. Experimental procedures and spectra of 1c−12c, copper salts screening results for Scheme 2, and the mass spectra of 18O-/16O-labeled 1c (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This study was supported by the Korea CCS R&D Center (KCRC) grant by the Korea government Ministry of Education, Science and Technology (No. 2015M1A8A1048886), C1 gas refinery program by the Korea government Ministry of Science, ICT & Future Planning (No. 2015M3D3A1A01065436), and the Human Resources Development of the Korea Institute of Energy Technology Evaluation and Planning (KETEP) grant by the Korea government Ministry of Trade, Industry & Energy (No.20154010200820).
Figure 1. Substrate scope.
established Brønsted acid catalyzed Meyer−Schuster rearrangement conditions to afford β-enaminones 1c−6c in good yields with high stereoselectivities. The benzoic acid catalyzed reaction favored the formation of E isomers in good yields, while the TsOH-catalyzed reaction provided the desired products in slightly lower yields with good Z-selectivity. In contrast, aliphatic propargyl aldehydes afforded 7c and 8c with E-selectivity, regardless of the Brønsted acid catalyst used. Following this, different amines were screened; piperidine, pyrrolidine, and N-benzylmethylamines showed a similar product distribution upon the addition of benzoic acid and TsOH (9c−11c). The reactions of diethylamine with propargyl aldehyde afforded Z-12c in the presence of TsOH and a
■
REFERENCES
(1) For selected review articles on the Meyer−Schuster rearrangement, see: (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429−438. (b) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149−4158. (c) Cadierno, V.; Crochet, P.; García-Garrido, S. E.; C
DOI: 10.1021/acs.orglett.5b03445 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Gimeno, J. Dalton Trans. 2010, 39, 4015−4031. (d) Zhu, Y.; Sun, L.; Lu, P.; Wang, Y. ACS Catal. 2014, 4, 1911−1925. (2) For selected articles on the Au-catalyzed Meyer−Schuster rearrangement, see: (a) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027−4029. (b) Lee, S. I.; Baek, J. Y.; Sim, S. H.; Chung, Y. K. Synthesis 2007, 2007, 2107−2114. (c) Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949−953. (d) Marion, N.; Carlqvist, P.; Gealageas, R.; de Frémont, P.; Maseras, F.; Nolan, S. P. Chem. - Eur. J. 2007, 13, 6437−6451. (e) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10, 1867−1870. (f) Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew. Chem., Int. Ed. 2009, 48, 3112−3115. (g) Ramón, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767−1773. (h) Ramón, R. S.; Gaillard, S.; Slawin, A. M. Z.; Porta, A.; D’Alfonso, A.; Zanoni, G.; Nolan, S. P. Organometallics 2010, 29, 3665−3668. (i) Pennell, M. N.; Unthank, M. G.; Turner, P.; Sheppard, T. D. J. Org. Chem. 2011, 76, 1479−1482. (j) Gómez-Suárez, A.; Oonishi, Y.; Meiries, S.; Nolan, S. P. Organometallics 2013, 32, 1106−1111. (k) Hansmann, M. M.; Hashmi, A. S. K.; Lautens, M. Org. Lett. 2013, 15, 3226−3229. (l) Kim, S. M.; Lee, D.; Hong, S. H. Org. Lett. 2014, 16, 6168−6171. (m) An, J.-H.; Yun, H.; Shin, S.; Shin, S. Adv. Synth. Catal. 2014, 356, 3749−3754. (n) Yu, Y.; Yang, W.; Pflästerer, D.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2014, 53, 1144−1147. (3) For selected articles on Sc- and Bi-catalyzed Meyer_Schuster rearrangements, see: (a) Engel, D. A.; Lopez, S. S.; Dudley, G. B. Tetrahedron 2008, 64, 6988−6996. (b) Okamoto, N.; Sueda, T.; Yanada, R. J. Org. Chem. 2014, 79, 9854−9859. (4) For the metal-free Meyer_Schuster rearrangement, see: Huang, X.; Jiao, N. Org. Biomol. Chem. 2014, 12, 4324−4328. (5) (a) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J. Angew. Chem., Int. Ed. 2013, 52, 5799−5802. (b) Xiong, Y.-P.; Wu, M.-Y.; Zhang, X.-Y.; Ma, C.-L.; Huang, L.; Zhao, L.-J.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16, 1000−1003. (c) Chen, M.; Peng, J.; Mao, T.; Huang, J. Org. Lett. 2014, 16, 6286−6289. (6) Shi, W.; Sun, S.; Wu, M.; Catano, B.; Li, W.; Wang, J.; Guo, H.; Xing, Y. Tetrahedron Lett. 2015, 56, 468−471. (7) For review articles on enaminone synthesis, see: (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277−294. (b) Elassar, A. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463−8480. (8) For selected recent articles on enaminone synthesis, see: (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629−2632. (b) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512−15513. (c) Koduri, N. D.; Scott, H.; Hileman, B.; Cox, J. D.; Coffin, M.; Glicksberg, L.; Hussaini, S. R. Org. Lett. 2012, 14, 440−443. (d) Xu, X.; Du, P.; Cheng, D.; Wang, H.; Li, X. Chem. Commun. 2012, 48, 1811−1813. (e) Yu, D.; Sum, Y. N.; Ean, A. C. C.; Chin, M. P.; Zhang, Y. Angew. Chem., Int. Ed. 2013, 52, 5125−5128. (9) For selected recent articles on heterocyclic compound synthesis using enaminones, see: (a) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6793−6805. (b) Lu, J.; Cai, X.; Hecht, S. M. Org. Lett. 2010, 12, 5189−5191. (c) Pettersson, B.; Hasimbegovic, V.; Bergman, J. J. Org. Chem. 2011, 76, 1554−1561. (d) Gayon, E.; Szymczyk, M.; Gérard, H.; Vrancken, E.; Campagne, J.-M. J. Org. Chem. 2012, 77, 9205−9220. (e) Xiang, D.; Xin, X.; Liu, X.; Zhang, R.; Yang, J.; Dong, D. Org. Lett. 2012, 14, 644−647. (f) Bezenšek, J.; Stare, K.; Svete, J.; Stanovnik, B. Tetrahedron 2012, 68, 516−522. (10) For selected articles on the synthesis of natural products using enaminones, see: (a) Caplan, J. F.; Zheng, R.; Blanchard, J. S.; Vederas, J. C. Org. Lett. 2000, 2, 3857−3860. (b) Li, G.; Hsung, R. P.; Slafer, B. W.; Sagamanova, I. K. Org. Lett. 2008, 10, 4991. (c) Moreau, J.; Hubert, C.; Batany, J.; Toupet, L.; Roisnel, T.; Hurvois, J.-P.; Renaud, J.-L. J. Org. Chem. 2009, 74, 8963−8973. (d) Tsukanov, S. V.; Comins, D. L. Angew. Chem., Int. Ed. 2011, 50, 8626−8628. (e) Edwankar, R. V.; Edwankar, C. R.; Namjoshi, O. A.; Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2012, 75, 181−188. (11) (a) Kang, Y.-W.; Choi, Y.-J.; Jang, H.-Y. Org. Lett. 2014, 16, 4842−4845. (b) Kang, Y.-W.; Cho, Y. J.; Ko, K.-Y.; Jang, H.-Y. Catal. Sci. Technol. 2015, 5, 3931−3934.
(12) (a) Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072− 7080. (b) Kathmann, E. E.; White, L. A.; McCormick, C. L. Macromolecules 1996, 29, 5273−5278.
D
DOI: 10.1021/acs.orglett.5b03445 Org. Lett. XXXX, XXX, XXX−XXX
