Letter pubs.acs.org/OrgLett
Tuning the Catalyst Reactivity of Imidazolylidene Catalysts through Substituent Effects on the N‑Aryl Groups Ryuji Kyan,† Kohei Sato,† Nobuyuki Mase,†,‡ Naoharu Watanabe,§ and Tetsuo Narumi*,†,‡ †
Department of Engineering, Graduate School of Integrated Science and Technology, ‡Research Institute of Green Science and Technology, and §Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, 432-8561 Shizuoka, Japan S Supporting Information *
ABSTRACT: A series of imidazolium salts with various N-aryl groups were synthesized, and their catalytic activities were evaluated to investigate the contribution of the N-aryl groups to the catalytic activity in the synthesis of γ-butyrolactone through an a3→d3-umpolung addition. Imidazolylidenes with 2,6-diethylphenyl groups were effective catalysts, and several mechanistic studies, including a deuterium kinetic isotope effect study, revealed that both steric and kinetic effects were responsible for the enhanced catalytic activity.
N
rational design of the NHC catalyst or by use of appropriate additives for cooperative catalysis. This is particularly true of imidazolylidene catalysts, of which only a few have been utilized effectively. One imidazolium salt frequently used for homoenolate-mediated reactions is the bismesityl imidazolium salt (IMesCl, 4). The bulky 2,4,6-trimethylphenyl (mesityl, Mes) groups of this salt control the reactivity of the distal position (d1 vs d3) on the conjugated Breslow intermediate. The imidazolium salt containing 2,6-bis(2-propyl)phenyl (Dipp) groups is also useful for homoenolate-mediated reactions because it provides a different diastereoselectivity from IMesCl (4).2 The 4,5-dialkylsubstituted imidazolium salts11 are also suitable precatalysts and show comparable or lower catalytic activity than IMesCl (4) in terms of chemical yields and diastereoselectivity. Although a study of modifications to the imidazolium backbone revealed the contributions of 4,5-dialkyl substitution to the electronic and steric properties of these NHCs and to their catalytic activity in the formation of γ-butyrolactone via a homoenolate intermediate, the N-aryl groups of imidazolium precatalysts stand essentially on Mes groups. The literature suggests that modification of the N-aryl group(s) of NHC catalysts has great potential for increasing their catalyst activity.12,13 We therefore believe that optimization of the N-aryl groups of imidazolylidene catalysts, which is expected to affect both their reactivity and
-Heterocyclic carbenes (NHCs) are powerful organocatalysts that can be used to generate various reactive species, such as acyl anions, homoenolates, enolates, and activated carboxylates, in reactions of aldehydes or α,βunsaturated aldehydes (α,β-enals).1 In particular, the homoenolate equivalents are synthetically valuable intermediates that offer both general and diastereoselective approaches to a wide range of heterocyclic and carbocyclic compounds. Imidazoliumderived NHCs (imidazolylidenes) were first employed as catalysts for the catalytic generation of homoenolate equivalents, which react with aldehydes and imines to afford disubstituted γbutyrolactones2 and γ-lactams,3 respectively. Furthermore, imidazolylidene catalysts promote various a3→d3-umpolung additions, including the efficient annulation of chalcones to form 1,3,4-trisubstituted cyclopentenes,4 [8 + 3] annulation of tropone to give bicyclic δ-lactones,5 formal [3 + 3] cycloaddition of 1,3-dipoles to provide pyridazinones,6 concise annulation of nitroso compounds to form isoxazolidin-5-ones,7 and others.8 In complementary efforts to develop asymmetric processes, chiral triazolium-derived NHCs have been used for homoenolatemediated asymmetric reactions.9 Cooperative catalysis by chiral triazolium salt-derived NHCs and Lewis or Brønsted acids is a particularly noteworthy strategy, and enables the stereoselective formation of trans-γ-lactams in high yields and high enantioselectivities.10 Despite these promising catalytic systems, there are few methods for tuning the catalyst reactivity of NHCs, either by © 2017 American Chemical Society
Received: April 12, 2017 Published: May 9, 2017 2750
DOI: 10.1021/acs.orglett.7b01105 Org. Lett. 2017, 19, 2750−2753
Letter
Organic Letters
demanding imidazolylidene catalyst with 2,6-diphenylphenyl groups proved to be unreactive under the same conditions. This is probably due to the steric hindrance around the reaction site. Interestingly, 2-tert-butyl-substituted N-aryl catalyst 9 showed better diastereoselectivity, with an increased proportion of the cis isomer (87:13 dr), albeit in slightly lower chemical yield. Imidazolylidene catalysts bearing 2,3-dimethyl-, 2,4-dimethyl-, and 2,5-dimethyl-substituted; 4-substituted; and 3,5-dihalogensubstituted N-aryl groups showed poor or no reactivity with lower diastereoselectivity (0−70% yield, 66:34−79:21 dr; see the Supporting Information). These results suggest that (1) 2,6dialkyl substitution is important for efficient transformation and (2) the steric effects of o-alkyl group(s) on the N-aryl groups can change the stereochemical outcome of the transformation. A new finding is that the presence of an appropriately sized bulky substituent at the ortho-position of the N-aryl groups is also effective to promote this reaction. Because similar reaction efficiencies and diastereoselectivities were observed with 2,6-dialkyl-substituted N-aryl catalysts derived from IMesCl (4), IXyCl (5), and IEtCl (6), their catalytic activities and those of several derivatives were compared in a kinetic study (Figure 2).14 The reaction of cinnamaldehyde
diastereoselectivity, would be a valuable contribution to the rational design of novel imidazolylidene catalysts for homoenolate-mediated reactions. In this paper, we document the structural and kinetic investigation of a series of imidazolylidene catalysts with various N-aryl groups for homoenolate-mediated γ-butyrolactone formation. These studies reveal that the substituents on the Naryl groups of the imidazolylidene catalysts are largely responsible for the catalyst reactivity. In particular, the imidazolylidene catalysts bearing 2,6-diethylphenyl groups, such as IEt, show higher reactivity than the commonly used IMes. In addition, mechanistic experiments, including a study of the kinetic isotope effect (KIE), were conducted to investigate the effect of the 2,6-diethylphenyl groups on the homoenolate reactivity. These analyses suggest that (1) the enhanced catalytic activity of the 2,6-diethylphenyl-bearing imidazolylidene catalysts is not derived from electronic effects, but from steric and kinetic effects, (2) a different H/D KIE value was observed with IEt and IMes, and (3) the effect of the 2,6-diethylphenyl groups is likely to be involved in the hydrogen transfer step(s), which may accelerate the formation of the conjugated Breslow intermediate from the tetrahedral intermediate generated by nucleophilic attack of the NHC on the enal. To identify highly reactive imidazolylidene catalysts, we selected the formation of γ-butyrolactone2 from cinnamaldehyde (1) and p-bromobenzaldehyde (2a) as a standard reaction for evaluating the catalytic activity of a series of imidazolylidene catalysts with various substituents on their N-aryl groups (Figure 1). We slightly modified the reaction conditions from those
Figure 2. Kinetic profiles of γ-butyrolactone formation with precatalysts 4−6, 10, and 11.
(1) (1.0 equiv) with p-bromobenzaldehyde (2a) (2.0 equiv) was carried out in the presence of 10 mol % of the imidazolium salt and 25 mol % of DBU in THF-d8 (0.5 M) at 25 °C. 4-tertButylanisole was used as an internal standard, and the conversion was monitored by 1H NMR spectroscopy. The reaction was repeated at least three times for each precatalyst, and the average rate constant was obtained. Kinetic analysis revealed that the reaction promoted by the tested catalysts had a first-order dependence on the conversion of cinnamaldehyde (1) to γbutyrolactones 3a versus time over half-lives. The observed rate constant of the reaction with IMesCl (4) was 3.57 × 10−2 min−1. The catalytic activity of IXyCl 5 was lower than that of IMesCl (4) (kIXy = 1.93 × 10−2 min−1; kIXy/kIMes = 0.54), presumably because of the lower solubility of IXyCl 5 in THF. In contrast, the activity of IEtCl 6 was higher than that of IMesCl (4) (kIEt = 7.45 × 10−2 min−1; kIEt/kIMes = 2.09). This result clearly indicates that introduction of 2,6-diethylphenyl groups as N-aryl substituents increases the catalytic activity of imidazolylidene catalysts in homoenolate-mediated γ-butyrolactone formation. Furthermore, 2,6-diethylphenyl- and Mes-bearing heteroaryl precatalyst
Figure 1. Catalyst reactivity of imidazolium salts. Reactions were performed on a 0.3 mmol scale at 25 °C for 3 h. The conversions and yields were determined by 1H NMR analysis of the crude reaction mixture with 4-tert-butylanisole as an internal standard.
described in the literature by increasing the amount of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) used to deprotonate the precatalyst (25 mol %). This gave results comparable to those of prior reports with IMesCl (4), in which the desired γbutyrolactone 3a was obtained in 92% yield with an 80:20 diastereomeric ratio (dr) that favored the cis isomer. As expected, 2,6-dialkyl-substituted N-aryl catalysts derived from IXyCl (5) and IEtCl (6) exhibited high catalytic activity and furnished 3a with a similar diastereoselectivity. Although 2,6-Dipp-substituted N-aryl catalysts based on IPrCl (7) provide 3a in excellent yields with the trans isomer being favored, the more sterically 2751
DOI: 10.1021/acs.orglett.7b01105 Org. Lett. 2017, 19, 2750−2753
Letter
Organic Letters 10 was prepared by Fürstner’s protocol,15 and its catalytic activity was examined. The activity of precatalyst 10 was lower than those of IEtCl (6) and IMesCl (4) (k10 = 2.60 × 10−2 min−1; k10/kIEt = 0.35, k10/kMes = 0.73). We also examined the activity of precatalyst 11, which has a symmetric structure and contains 2ethyl-6-methylphenyl groups. The precatalyst 11 had a lower activity than IEtCl (6) (k11 = 3.21 × 10−2 min−1; k11/kIEt = 0.43), but this value is higher than that of precatalyst 10 and comparable to that of IMesCl (4) (k10/k11 = 1.23, k11/kIMes = 0.90). These results suggest that a symmetric structure is necessary to enhance the homoenolate reactivity of imidazolylidene catalysts by substitution with 2,6-diethylphenyl groups. Although we did not fully examine the effect of para substitution of the N-aryl moieties on the catalytic activity, we were pleased to find that the electron-withdrawing bromo group was a suitable para substituent for the 2,6-diethylphenyl groups and the bromo-substituted precatalyst showed higher activity than IEtCl (6) (Figure 3). The catalytic activity of precatalyst 12
Scheme 1. Kinetic Competition Studies with Regioisomeric Chlorobenzaldehydes16
IMesCl (4) (krel = 2.22, kIEt/kIMes). A similar trend was observed with more sterically demanding o-chlorobenzaldehyde (2d) (krel = 1.45, kIEt/kIMes). The experiments shown in Scheme 1 suggest that the reaction rate is strongly influenced by not only the steric effects of the 2,6substituents of the N-aryl groups but also by the substituent position on the aryl aldehyde. One possible explanation for the superior reactivity of IEtCl (6) compared with that of IMesCl (4) in the reaction with m-chlorobenzaldehyde (2c) is that nucleophilic attack of the NHC catalyst on the aryl aldehyde, which would generate the undesired Breslow intermediate, can be suppressed by steric repulsion between the 2,6-diethylphenyl groups of the catalyst and the meta substituent of the aryl aldehyde. This would allow the chemoselective formation of the conjugated Breslow intermediate. To gain further information about the role of the 2,6diethylphenyl groups, the H/D KIE studies were conducted under standard conditions using 1-deuterated cinnamaldehyde 1-D (>95%-d) (Scheme 2). Mechanistically, hydrogen transfer from tetrahedral intermediate 14, which is generated by nucleophilic addition of the NHC to the α,β-enal, is believed to be the first irreversible step,9h,17 and results in the formation of the conjugated Breslow intermediate. The value of kH/kD for IMesCl (4) was 1.65, which indicates that hydrogen transfer
Figure 3. Kinetic profiles of γ-butyrolactone formation with precatalysts 4, 6, 12, and 13 under conditions identical to those in Figure 2.
(IBEtCl) was about 1.6-fold greater than that of IEtCl (6) (kIBEt = 12.24 × 10−2 min−1, kIBEt/kIEt = 1.64), which suggests that finetuning of the para substituents of the N-aryl moieties could accelerate the formation of γ-butyrolactones. The effect of the p-bromo substituents was further investigated by preparation of the corresponding IXy-derived catalyst (IBXCl, 13). However, enhanced catalytic activity was not obtained with IBXCl (13), which indicates the importance of the 2,6diethylphenyl groups. Further investigations that aim to delineate the para substituent effects on the catalytic activity are currently underway. It was unclear which effects were the source of the enhanced activity of IEt. First, to investigate the electronic effect of the 2,6diethylphenyl groups, we prepared the Ir(CO)2(IEt) complex and examined its electron-donating ability by comparing the Tolman electronic parameter (TEP) of the IEt complex with that of the IMes complex.1d The TEP value for Ir(CO)2(IEt) was 2051.1, which is comparable to that of the IMes complex (2050.7), and indicates that electronic effects are not the main cause of the enhanced activity of IEt. To explore the steric effect of the 2,6-diethylphenyl groups, we conducted a kinetic study using IMesCl (4) and IEtCl (6) and a series of substituted aryl aldehydes (Scheme 1). With pchlorobenzaldehyde (2b), there were no major differences in the reactivity or diastereoselectivity, and the reaction rates were almost the same (krel = 1.15, kIEt/kIMes). In contrast, with mchlorobenzaldehyde (2c), IEtCl (6) provided the desired product in higher yield than did IMesCl (4), and the rate constant of IEtCl (6) was considerably higher than that of
Scheme 2. Deuterium Isotope Effect Competition Studies16
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Acc. Chem. Res. 2014, 47, 696. (g) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (h) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (i) Menon, R. S.; Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444. (j) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (2) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370. (3) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. (4) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736. (5) Nair, V.; Poonoth, M.; Vellalath, S.; Suresh, E.; Thirumalai, R. J. Org. Chem. 2006, 71, 8964. (6) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334. (7) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 953. (8) (a) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507. (b) Nair, V.; Babu, B. P.; Vellalath, S.; Suresh, E. Chem. Commun. 2008, 747. (c) Yang, L.; Tan, B.; Wang, F.; Zhong, G. J. Org. Chem. 2009, 74, 1744. (d) Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.; Waseem, M. A.; Singh, R. K. P. Synlett 2013, 24, 2586. (e) Ikota, H.; Ishida, T.; Tsukano, C.; Takemoto, Y. Chem. Commun. 2014, 50, 8871. (9) For triazolylidene-catalyzed asymmetric homoenolate addition, see: (a) Lv, H.; Jia, W.-Q.; Sun, L.-H.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 8607. (b) Goodman, C. G.; Walker, M. M.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 122. (c) Guo, C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, F. Nat. Chem. 2015, 7, 842. (d) Xu, J.; Yuan, S.; Miao, M.; Chen, Z. J. Org. Chem. 2016, 81, 11454. (e) Wang, C.; Zhu, S.; Wang, G.; Li, Z.; Hui, X.-P. Eur. J. Org. Chem. 2016, 34, 5653. (f) Wang, L.; Li, S.; Blümel, M.; Philipps, A. R.; Wang, A.; Puttreddy, R.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 11110. (g) Guo, C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, G. J. Am. Chem. Soc. 2016, 138, 7840. (h) Guo, C.; Janssen-Müller, D.; Fleige, M.; Lerchen, A.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 4443. (10) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat. Chem. 2010, 2, 766. (11) Urban, S.; Tursky, M.; Fröhlich, R.; Glorius, F. Dalton Trans. 2009, 6934. (12) For a discussion regarding N-aryl effects on triazolylidene catalyst for α,β-unsaturated aldehydes, see: Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192. (13) For a discussion of the role of the N-aryl substituent in triazolylidene catalysis, see: (a) Rovis, T. Chem. Lett. 2008, 37, 2. (b) Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.; O’Donoghue, A-M. C.; Smith, A. D. Chem. Sci. 2013, 4, 1514. (c) Collett, C. J.; Massey, R. S.; Taylor, J. E.; Maguire, O. R.; O’Donoghue, A-M. C.; Smith, A. D. Angew. Chem., Int. Ed. 2015, 54, 6887. (14) See the Supporting Information for the details including the comparison experiments with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5ene (MTBD) instead of DBU. Similar selectivity and slightly higher catalyst reactivity were observed with MTBD. (15) Fürstner, A.; Alcarazo, M.; César, V.; Lehmann, C. W. Chem. Commun. 2006, 20, 2176. (16) See the Supporting Information for complete experimental details. (17) For a discussion on the first irreversible step with triazolylidene catalyst, see: Moore, J. L.; Silvestri, A. P.; de Alaniz, J. R.; DiRocco, D. A.; Rovis, T. Org. Lett. 2011, 13, 1742. (18) For a discussion on the magnitude of kinetic isotope effects, see: Westheimer, F. H. Chem. Rev. 1961, 61, 265. (19) Collins, C. J.; Bowman, N. S. Isotope Effects in Chemical Reactions; Van Nostrand Reinhold Co.: New York, 1970.
from tetrahedral intermediate 14 is at least partially turnoverlimiting in this reaction. Interestingly, IEtCl (6) showed an increased KIE, with a kH/kD value of 2.41, which suggests that the transition state for the reaction with IEtCl (6) is later than that for the reaction with IMesCl (4.) Furthermore, the change in the value of the KIE for IEtCl (6) implies that the effect of the ethyl groups is likely to affect the hydrogen transfer step. In addition, the higher value suggests that only the hydrogen-transfer step is rate limiting, because the high KIE value does not take into account other rate-influencing steps.18,19 Thus, the introduction of 2,6-diethylphenyl groups kinetically enhances the formation of the conjugated Breslow intermediate. In summary, we have prepared a series of imidazolium salts with various N-aryl groups and identified a novel class of effective imidazolylidene catalysts with 2,6-diethylphenyl groups that are suitable for the direct annulation of enals and arylaldehydes in an a3→d3-umpolung addition. The utility of 2,6-diethylphenyl groups in homoenolate reactivity is likely to arise from both steric factors, which increase the chemoselectivity of the first nucleophilic attack of the carbenes on the enals, and kinetic effects, which accelerate the formation of the conjugated Breslow intermediate. Modification of the catalyst itself is quite simple and has the potential for fine-tuning the catalyst activity. These findings will thus have an impact on the development of novel NHC catalysts for other a3→d3-umpolung additions. Investigations involving the development of novel catalysts based on the presented kinetic analysis and their application to asymmetric catalysis are currently underway.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01105. Experimental details, synthetic procedures, and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Tetsuo Narumi: 0000-0003-2412-4035 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from The Ministry of Education, Culture, Sports, Science and Technology, Japan. R.K. is grateful for the Amano Institute of Technology scholarship. We are grateful to Prof. Hirokazu Tamamura and Dr. Takuya Kobayakawa (Tokyo Medical and Dental University) for their assistance in accurate mass measurement.
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REFERENCES
(1) For selected recent reviews on NHC catalysis, see: (a) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (b) Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (c) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (d) Dröge, T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940. (e) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53. (f) Mahatthananchai, J.; Bode, J. W. 2753
DOI: 10.1021/acs.orglett.7b01105 Org. Lett. 2017, 19, 2750−2753
