DOI: 10.1002/chem.201500326
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Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl-Substituted Diarylprolinol Silyl Ether Hiroaki Gotoh,[a] Tadafumi Uchimaru,[b] and Yujiro Hayashi*[c] Abstract: The reactions of a,b-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michaeltype reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethylsubstituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The
iminium ion from an a,b-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate-determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions.
Introduction The field of organocatalysis is still developing rapidly, and many kinds of organocatalysts with unique properties have been developed and applied to organic reactions.[1] There are two major reaction modes in secondary-amine-mediated reactions, namely, reactions involving enamine and iminium ion intermediates. In the reactions of iminium ion intermediates, MacMillan and co-workers proposed the LUMO activation mechanism and demonstrated an elegant Diels–Alder reaction in 2000.[2] After this proposal, a plethora of asymmetric reactions involving iminium-reactive intermediates have been developed.[3] In 2005, our group[4] and that of Jørgensen[5] independently developed diarylprolinol silyl ethers as effective organocatalysts[6] (Figure 1). This type of catalyst has been extensively employed in reactions involving both enamine and imi[a] Prof. Dr. H. Gotoh Department of Applied Chemistry, Yokohama National University 79-5 Tokiwadai, Hodogayaku, Yokohama 240-8501 (Japan) [b] Dr. T. Uchimaru Research Institute for Sustainable Chemistry National Institute of Advanced Industrial Science and Technology Tsukuba, Ibaraki 305-8565 (Japan) [c] Prof. Dr. Y. Hayashi Department of Chemistry, Graduate School of Science, Tohoku University 6–3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan) E-mail: [email protected] Homepage: http://www.ykbsc-chem.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500326. Chem. Eur. J. 2015, 21, 12337 – 12346
Figure 1. Organocatalysts examined in this study.
nium ion intermediates. Recently, we reported a systematic study of the silyl substituent of the diphenylprolinol silyl ether catalyst and proposed three reaction types (Figure 2).[7] The reactions involving iminium ions can be subdivided into two main types: One involving Michael-type reaction modes (type A) and the other involving cycloaddition reaction modes (type B). A third reaction (type C) involves enamines as intermediates. Notably, either a diphenylprolinol or trifluoromethylsubstituted diarylprolinol silyl ether is typically selected as a catalyst in these types of reactions, but their reactivities differ. Mayr and co-workers proposed the concept of electrophilicity (E) to explain the electrophilic reactivity of a,b-unsaturated iminium ions.[8] Because of the electron-withdrawing nature of the trifluoromethyl group, the trifluoromethyl-substituted diarylprolinol silyl ether is thought to be a more electron-deficient amine catalyst in comparison with diphenylprolinol silyl ether. This indicates that the iminium ion of the CF3-substituted catalyst should be more reactive than the one derived from the
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Full Paper catalytic reactions that generate formal Michael and Diels– Alder products.
Results and Discussion Diels–Alder product versus cyclopentadiene derivative
Figure 2. Three reaction types for diarylprolinol silyl ether mediated reactions.
The reaction of cinnamaldehyde and cyclopentadiene catalyzed by diarylprolinol silyl ethers was first investigated in detail; the effects of changing the catalyst, additive, and solvent are summarized in Table 1. The enantioselective Diels– Alder reaction proceeded smoothly when trifluoromethyl-substituted diarylprolinol silyl ethers 3 and 4 were employed in the presence of CF3CO2H to afford the Diels–Alder product with good exo selectivity and excellent enantioselectivity (Table 1, entries 8 and 9). Under the same reaction conditions, the cycloaddition reaction was very slow when diphenylprolinol silyl ether 2 was employed instead of 4 and a yield of only 10 % of the Diels–Alder product 6 was obtained (Table 1, entry 7). In contrast, the cyclopentadiene Michael adduct 5 was obtained when diphenylprolinol silyl ethers 1 and 2 were employed in methanol, and no Diels–Alder product 6 was generated at all (Table 1, entries 1–5). Although the reaction proceeds without additive (Table 1, entries 1 and 2), a weak acid and base, for example, p-nitrophenol and NaOAc, increased the yield to 84 and 81 %, respectively in the case of 2. To test the reactivity of catalysts 1 and 3 in the formation of cyclopentadiene derivative 5, their reactions were compared in situ. The reaction of cinnamaldehyde and cyclopentadiene was carried out in the presence of different ratios of trifluorometh-
unsubstituted diphenyl catalyst. Yet, in some reactions, excellent yields and enantioselectivities were obtained by using the former catalyst, whereas in other reactions the latter catalyst was found to be superior. To select the most appropriate catalyst to employ in a given synthesis, it is important to discern the different trends of these catalysts, including the origin of their reactivity. During our investigations of these catalysts in asymmetric synthesis, we encountered several interesting phenomena [see Eq. (1) in Table 1]. In the reaction of cinnamaldehyde and cyclopentadiene, the Diels–Alder adduct 6 and substituted cyclopentadiene (Michael-type) adduct 5 were obtained under slightly different conditions. When the reaction was performed in the presence of cataTable 1. Effect of catalyst and additive on the enantioselective reaction of cinnamaldehyde with cyclopentadielytic trifluoromethyl-substituted ne.[a] diarylprolinol silyl ether 4 and a strong acid like CF3CO2H in toluene, the Diels–Alder product 6 was obtained in good yield with excellent enantioselectivity.[9] In contrast, in the presence of catalytic diphenylprolinol silyl ether 2 with a weak acid like p-nitro5 6 Entry Catalyst Solvent Additive Yield a/b[c] ee Yield exo/endo[f] ee phenol in MeOH, the substituted [%][b] [%][d] [%][e] [%][g] cyclopentadiene derivative 5 1 1 MeOH – 83 56:44 83 0 – – was obtained in good yield with [10] 2 2 MeOH – 68 54:46 91 0 – – excellent enantioselectivity. In3 2 MeOH p-nitrophenol 84 70:30 92 0 – – itially, we suggested that the 4 2 MeOH NaHCO3 70 41:59 90 0 – – product 5 could be generated 5 2 MeOH NaOAc 81 64:36 92 0 – – 6 2 toluene – 0 – – 0 – – through an ene reaction. Howev7 2 toluene CF3CO2H 0 – – 10 79:21 79/88 er, in the course of this investi8 3 toluene CF3CO2H 0 – – 86 84:16 95/83 gation into the properties of 9 4 toluene CF3CO2H 0 – – 80 85:15 97/88 these two catalysts, we came to [a] Unless noted otherwise, the reaction was conducted by using cinnamaldehyde (0.7 mmol), catalyst the conclusion that adduct 5 is (0.07 mmol, 10 mol %), cyclopentadiene (2.1 mmol), and additive (0.14 mmol) in solvent (1.4 mL) at room temformed by a Michael addition reperature for 20 h. [b] Yield of an isolated mixture of 5 a and 5 b. [c] Determined by 1H NMR spectroscopy (400 MHz). [d] The ee was determined by chiral HPLC analysis after reduction and hydrogenation. [e] Yield of an action. Herein, we summarize isolated mixture of exo and endo isomers. [f] Determined by 1H NMR spectroscopy (400 MHz). [g] The ee was the trends and origin of the redetermined by chiral HPLC analysis. activity of the iminium-mediated Chem. Eur. J. 2015, 21, 12337 – 12346
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Full Paper Imimium ion formation
Table 2. Comparison of the reactivity of the catalysts 3 and ent-1.[a]
Entry
x [mol %][b]
y [mol %][c]
Yield [%][d]
ee [%][e]
1 2 3 4 5
0 10 12 14 16
10 10 8 6 4
83 93 78 70 33
83 79 79 75 79
[a] Unless noted otherwise, the reaction was conducted by using cinnamaldehyde (0.7 mmol), catalyst, and cyclopentadiene (2.1 mmol) in MeOH (1.4 mL) at room temperature for 20 h. [b] Amount of the catalyst 3. [c] Amount of the catalyst ent-1. [d] Yield of an isolated mixture of 5 a and 5 b. [e] The ee was determined by chiral HPLC analysis after reduction and hydrogenation. The S isomer is the major isomer.
yl-substituted diarylprolinol silyl ether 3 and one enantiomer of diphenylprolinol silyl ether ent-1 (Table 2). Similar enantiomeric excesses with opposite configurations were obtained, regardless of the ratio of catalysts 3 and ent-1. This result indicates that the reaction was catalyzed by diphenylprolinol silyl ether ent-1 alone and not by the trifluoromethyl-substituted diarylprolinol silyl ether 3. In this reaction, the formation of the iminium salt would be the rate-limiting step. Thus, diphenylprolinol silyl ether 1 is more reactive than the trifluoromethylsubstituted catalyst 3 because the former is more electron-rich and the formation of iminium ion is much faster. From the results and observations obtained thus far, the following two trends are apparent. 1) The Diels–Alder product 6 forms preferentially in the presence of the electron-deficient catalysts 3 and 4 and a relatively strong acid such as CF3CO2H, whereas the formal cyclopentadiene Michael adduct 5 forms preferentially in the presence of the relatively electron-rich catalysts 1 and 2 and a relatively weak acid or base. 2) There are no reaction conditions under which both the Diels–Alder product 6 and cyclopentadiene derivatives 5 form concurrently, which indicates that these two reactions proceed by different mechanisms. Furthermore, the substrates showed opposite trends in reactivity for these two reactions. As shown in Tables 3[9a] and 4,[10a,b] electron-deficient a,b-enals were more reactive in Diels– Alder reactions, whereas the reactions of electron-rich a,benals proceeded smoothly to generate cyclopentadiene adducts. These results also suggest two different reaction mechanisms for these two organocatalyzed addition reactions. To explain the different reactivities of the diphenylprolinol silyl ether 1 and the trifluoromethyl-substituted diarylprolinol silyl ether 3 in the Diels–Alder reaction, each reaction step was investigated in detail. Chem. Eur. J. 2015, 21, 12337 – 12346
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The formation of the iminium ion was examined by using diphenylprolinol silyl ether 1 and CF3CO2H as additive in several solvents, namely CDCl3, CD3OD, C6D5CD3, and CD3CN, and 1 H NMR spectra were recorded after certain times [Eq. (5), Figure 3]. The formation of iminium ions was fast in CD3OD, whereas they were formed only gradually in CDCl3. The reaction in toluene was very slow, affording the iminium ion in a maximum yield of 7 % without any further increase after 10 min. The effect of acid was examined by using the catalyst 1 in
Table 3. Reactivity of a,b-enals towards the Diels–Alder reaction.[a]
Entry
1 2 3
R
p-MeOC6H4 Ph p-NO2C6H4
Time [h]
Yield [%][b]
336 26 6
0 quant. 93
exo/endo[c] – 85/15 87/13
ee [%][d] – 97/88 94/73
[a] Data extracted from ref. [9a]. The reaction was conducted by using an a,b-unsaturated aldehyde (0.7 mmol), catalyst 4 (0.07 mmol, 10 mol %), cyclopentadiene (2.1 mmol), and CF3CO2H (0.14 mmol) in toluene (1.4 mL) at room temperature for the indicated time. [b] Yield of an isolated mixture of exo and endo isomers. [c] Determined by 1H NMR spectroscopy (400 MHz). [d] The ee was determined by HPLC analysis on chiral phase.
CDCl3 [Eq. (6), Figure 4]. Without acid, no iminium ion was formed. Among the acids examined, namely CH3CO2H, PhCO2H, CF3CO2H, CH3SO3H and HClO4, good results were obtained with strong acids such as HClO4, which afforded the iminium ion in a yield of 63 % in 30 min. Next, the effect of the catalyst 3 on iminium ion formation was investigated by using HClO4 as the acid in CDCl3 (Figure 4). The iminium ion was formed significantly faster with diphenylprolinol silyl ether 1 than with the trifluoromethyl-substituted diarylprolinol silyl ether 3. The faster generation of the iminium ion in the case of diphenylprolinol silyl ether 1 can likely be attributed to the higher nucleophilicity of the amine catalyst 1 in comparison with 3, which possesses electron-withdrawing CF3-substituted aryl groups.
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Full Paper Table 4. Reactivity of a,b-enals as Michael acceptors.[a]
Entry [c]
1 2[c] 3[d]
R
p-MeOC6H4 Ph p-NO2C6H4
Catalyst [mol %]
Time [h]
Yield [%][b]
ee [%]
10 10 20
8 20 3
82 84 60
99 95 90
[a] The reaction was conducted by using an a,b-unsaturated aldehyde (0.7 mmol), catalyst 2 (0.07 or 0.14 mmol, 10 or 20 mol %), cyclopentadiene (2.1 mmol), p-nitrophenol (0.14 mmol) in MeOH (1.4 mL) at room temperature for the indicated time. [b] Yield of an isolated mixture of diastereoisomers. [c] Data from ref. [10b]. [d] Data from ref. [10a].
Figure 4. Effect of acid and catalyst on the formation of the iminium ion in the reaction with diarylprolinol silyl ethers 1 and 3 in CDCl3. The yields were determined by 1H NMR spectroscopy (400 MHz).
Table 5. 13C NMR chemical shifts of the iminium ions 7 and 8 and cinnamaldehyde (9).[a]
Entry
1 2 3
Figure 3. Effect of solvent on the formation of the iminium ion in the reaction with diphenylprolinol silyl ether 1 with CF3CO2H. The yields were determined by 1H NMR spectroscopy (400 MHz).
Reactivity of the iminium ion with cyclopentadiene Next, the reactivities of the iminium ions were investigated. As the cinnamoylidene iminium ClO4¢ salts 7 can 8 can be isolated[11] as white powders by treatment of an ether solution of cinnamaldehyde and diphenylprolinol silyl ether 1 or the trifluoromethyl-substituted catalyst 3 with HClO4 at 0 8C, their reactivities towards cyclopentadiene were examined. The 13 C NMR chemical shifts of the iminium ions 7 and 8 and cinnamaldehyde are shown in Table 5. The chemical shifts of C1 and C3 of the iminium ion 8 generated with catalyst 3 appear at a lower field than those of iminium ion 7 derived from catalyst 1. These results indicate that the LUMO level of 8 is lower than that of 7, and that 8 is expected to be more reactive than 7 as a dienophile in the Diels–Alder reaction and as a Michael acceptor in the Michael reaction. Next, we investigated the LUMO levels of the iminium cations 7’ and 8’ of the iminium ClO4¢ salts 7 and 8. A conformaChem. Eur. J. 2015, 21, 12337 – 12346
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Substrate
7 8 9
C1
dC [ppm] C2
C3
168.3 170.3 193.5
117.1 116.3 128.5
161.4 164.4 152.6
[a] The 13C NMR data were measured in CDCl3.
tional analysis was performed on the isomers of 7’ and 8’ with E configurations of both the C=C and C=N double bonds[7] by using the CONFLEX program[12] together with the MMFF94s force field.[13] For the conformers with an energy within 3 kcal mol¢1 of the most stable conformer in the force field calculations, we carried out geometry optimizations at the B3LYP/631G(d) level of theory, and then single-point calculations were performed on the optimized structures at the HF/6-31G(d) level of theory.[14] Two and five conformers were obtained for the iminium cations 7’ and 8’, respectively. The energies of the LUMOs of these conformers are summarized in Table 6, and the structures of the lowest-energy conformers of 7’ and 8’ are shown in Figure 5. It was found that the LUMO of the iminium cation 8’, derived from the trifluoromethyl-substituted diarylprolinol silyl ether 3, is lower than that of the iminium cation 7’, derived from diphenylprolinol silyl ether 1, but there is little difference in the shapes of the orbitals of the LUMOs of the iminium cations 7’ and 8’ (see the Supporting Information).
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Figure 5. Structures of the lowest-energy conformers of a) the iminium cation 7’ and b) the iminium cation 8’ (entry 1 in Table 6). The structures of the other major conformers of the iminium cations 7’ and 8’ given in Table 6, including the X-ray crystal structures, are very similar to one another (see the Supporting Information).[15]
Table 6. Calculated relative energies and the LUMO energies of conformers of the iminium cations 7’ and 8’. Entry
1 2 3 4 5
Iminium cation 7’ Erel [kcal mol¢1][a] ELUMO [eV][b] 0.00 ¢2.3013 (0.02) – 0.17 ¢2.2447 (0.00) – – – – – – – – – – – – –
Figure 6. Diels–Alder reaction of iminium ions 7 and 8 with cyclopentadiene. The yields were determined by 1H NMR spectroscopy (400 MHz).
Iminium cation 8’ Erel [kcal mol¢1][a] ELUMO [eV][b] 0.00 ¢2.6515 (0.00) – 0.08 ¢2.6501 (0.03) – 0.37 ¢2.6058 (0.34) – 0.41 ¢2.6044 (0.37) – 2.53 ¢2.6474 (1.58) –
tion of iminium ions in the case of trifluoromethyl-substituted diarylprolinol silyl ether 3 is slower than with the diphenylprolinol silyl ether 1. 2) The Diels–Alder reaction of the isolated iminium ion of the trifluoromethyl-substituted diarylprolinol silyl ether 3 is faster than with the diphenylprolinol silyl ether 1. 3) By using catalytic amounts of diarylprolinol silyl ethers, the reactivity of the trifluoromethyl-substituted diarylprolinol silyl ether 3 is significantly higher than with the diphenylprolinol silyl ether 1.
[a] Relative energies calculated at the HF/6-31G(d) and (in parentheses) B3LYP/6-31G(d) levels of theory. [b] LUMO energies calculated at the HF/ 6-31G(d) level of theory.
Next, the reactivities of these iminium ions towards cyclopentadiene were investigated. The iminium ions 7 and 8 were treated with cyclopentadiene in CDCl3 and the progress of the reactions was monitored by 1H NMR spectroscopy (Figure 6). Starting from 7 and 8 only the Diels–Alder reaction proceeded, without the formation of the cyclopentadiene Michael adduct 5. The iminium ion 8, generated from trifluoromethyl-substituted diarylprolinol silyl ether 3, was found to be more reactive than the iminium ion 7, derived from diphenylprolinol silyl ether 1; the Diels–Alder adduct was obtained in a yield of 82 % after 11 h in the case of 8 with a 95 % ee of the major exo isomer, whereas the product was obtained in a yield of only 15 % in the case of 7 with an 86 % ee of the exo isomer. The diastereoselectivities and enantioselectivities of these two reactions starting from the isolated iminium ion salts 7 and 8 and cyclopentadiene closely match those observed for the reactions carried out in the presence of catalytic amounts of 1 and 3. The amine catalyst and a,b-enal first react to generate the iminium ion, which then reacts with cyclopentadiene to afford the Diels–Alder adduct after hydrolysis of the newly formed iminium ion (Scheme 1). In this reaction, the following observations were made from the above experiments: 1) The generaChem. Eur. J. 2015, 21, 12337 – 12346
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Reaction mechanism for the generation of cyclopentadiene derivative 5 Next, we investigated the mechanism for the generation of the cyclopentadiene derivative 5 [see Eq. (1) in Table 1]. One possible reaction mechanism is an organocatalyzed Michael reaction between the cyclopentadienyl anion and the a,b-enal [Eq. (8)], that is, the organocatalytic amine acts as a base to deprotonate the cyclopentadiene and the cyclopentadienyl anion thus generated reacts with cinnamaldehyde in a conjugate 1,4-addition to provide the substituted cyclopentadiene derivative 5. If this is the mechanism, the reaction should proceed faster when the LUMO level of the a,b-unsaturated aldehyde is lower. However, the reaction proceeds faster with an acrolein with an electron-rich aryl group at the b position than with an electron-deficient group (Table 4). Thus, this mechanism can be ruled out. The other possible paths are an ene reaction, a Friedel– Crafts type reaction, a Diels–Alder reaction followed by rearrangement, and a Michael reaction, all of which involve a common iminium ion intermediate. We discuss each of these reaction mechanisms below. 1) Ene reaction: As a result of our study of the generation of cyclopentadiene derivative 5 by using catalyst 2,[10a] we
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Full Paper LUMO of the iminium ion is lower. However, electron-rich a,b-enals were found to be more reactive (Table 4), which indicates that the reaction does not proceed by a Friedel–Crafts-type reaction. 3) Diels–Alder reaction, followed by rearrangement: The Diels–Alder product 6 might undergo a rearrangement to afford the cyclopentadiene derivative 5 (Scheme 3). When the Diels–Alder product 6 was treated with diphenylprolinol silyl ether 1 under the conditions used for the formation of 5, no reaction occurred. Moreover, when the cyclopentadiene derivative 5 was treated with the trifluoromethyl-substituted diarylprolinol silyl ether 3 under the Diels–Alder reaction conditions, no reaction proceeded and the starting material was recovered. Thus, the generation of 5 by a rearrangement of the Diels–Alder product 6 could be ruled out. 4) Michael reaction via iminium ion intermediate (Scheme 4): The first step of iminium ion formation from catalyst 2 and cinnamaldehyde has already been demonstrated to be a relatively slow reaction (see above, Figure 4). The cyclopentadienyl anion would be formed from cyclopentadiene and catalyst 2, which would attack the iminium ion in a 1,4-addition manner to provide an enamine. The enamine would then be hydrolyzed by water to afford the Michael product and regenerate the catalyst 2.
Scheme 1. Mechanism of the iminium-mediated Diels–Alder reaction.
proposed that an ene reaction[16] would occur. We then found that the Diels–Alder reaction occurs in the presence of the diarylprolinol silyl ether catalyst 4. The ene and Diels–Alder reactions are mechanistically related as both reactions are concerted, proceeding through cyclic transition states involving six electrons (Figure 7),[16c] which would indicate the same reactivity profiles for a,b-enals. The activation energy of the ene reaction is higher than that of the Diels–Alder reaction. Therefore, typically, higher reaction temperatures are required. As the reactivity profiles of our reactions were found to differ significantly, and the cyclopentadiene derivative 5 is generated under mild reaction conditions in comparison with the Diels–Alder reaction, the present reaction is unlikely to proceed by the ene reaction. 2) Friedel–Crafts-type reaction: If a Friedel–Crafts-type reaction[17] Figure 7. Transition state proceeds (Scheme 2), the reacformed during the ene reaction. tion should be faster when the Chem. Eur. J. 2015, 21, 12337 – 12346
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As the pKa values of cyclopentadiene, p-nitrophenol, and pyrrolidinium ion in DMSO are 18,[18] 10.8,[19] and 11.1,[20] respectively, the generation of cyclopentadienyl anions in the presence of p-nitrophenol would be expected to be unfavorable, although still possible. The generation of the cyclopentadienyl anion was investigated by the deuteration of cyclopentadiene in CD3OD in the absence of catalyst and additive, with catalyst 2 alone, with catalyst 2 and p-nitrophenol together, and with catalyst 2 and TsOH together, respectively (Equation (9), Figure 8). Diphenylprolinol silyl ether 2 deprotonates cyclopentadiene to afford deuterated [D6]cyclopentadiene in a yield of 80 % after 500 min. The deprotonation proceeds efficiently even in the presence of p-nitrophenol, providing the deuterated [D6]cyclopentadiene at the same rate, whereas the deprotonation is relatively slow in the presence of the strong
Scheme 2. Mechanism of the Friedel–Crafts-type reaction.
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Scheme 3. Rearrangement of the Diels–Alder product in the presence of catalyst 1.
Scheme 4. Mechanism of the Michael reaction.
acid TsOH. These results strongly support the involvement of the cyclopentadienyl anion in the reaction. Thus, the Michael reaction is considered the most probable route, with the generation of the iminium ion the likely rate-determining step. This is in good agreement with the fact that the diphenylprolinol silyl ether is a more effective catalyst than the trifluoromethyl-substituted diarylprolinol and that a,b-unsaturated aldehydes with electron-rich substituents are more reactive.
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Comparison of the two reaction mechanisms In the organocatalyst-mediated reactions involving the iminium ion intermediate, there are two different reaction mechanisms that operate. One is a Diels–Alder reaction, in which strong acidic conditions can be employed (type B reaction, Figure 2), and the other is a formal Michael addition of an anionic nucleophile (type A reaction). In the Diels–Alder reaction, the reactivity increases with the use of the trifluoromethyl-substituted catalyst 4, owing to the electron-withdrawing nature of the trifluoromethyl substituents lowering the LUMO level of the iminium ion.[21] As the
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Figure 8. Effect of amine catalyst and acid additive on the generation of deuterated [D6]cyclopentadiene.
LUMO level of the iminium ion is key to determining the relative reactivity, the reaction is slow in the case of electron-rich a,b-unsaturated aldehydes. Thus, the trifluoromethyl-substituted diarylprolinol silyl ether is a better catalyst than the diphenylprolinol silyl ether in iminium/neutral nucleophilic reactions such as the Diels–Alder reaction. The 1,3-dipolar cycloaddition of nitrones to a,b-unsaturated aldehydes also belongs to this class of reactions. Nevalainen and co-workers reported that the reaction of N-benzylidenebenzylamine N-oxide and crotonaldehyde was catalyzed by a diphenylprolinol silyl ether in combination with HOTf in 1 day, affording the product with 95 % ee.[22] This reaction would be classified as a type B reaction. If this was so, a trifluoromethyl-substituted diarylprolinol silyl ether would be a superior catalyst. When we performed this reaction, we found that diarylprolinol silyl ether 4 is indeed a more reactive catalyst than diphenylprolinol silyl ether 1, promoting the reaction in only 20 min [Eq. (10)].
In most of the iminium ion/anionic nucleophilic reactions (type A), an acid additive accelerates the reaction because acid accelerates the formation of the iminium ion, which is faster in Chem. Eur. J. 2015, 21, 12337 – 12346
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the case of electron-rich a,b-unsaturated aldehydes. Diphenylprolinol silyl ether 1 is a better catalyst than the trifluoromethyl-substituted 4 because the former is more electron-rich and the formation of the iminium ion is significantly faster. Although acid accelerates the generation of iminium ions, it reduces the generation of anionic nucleophiles by protonation. Thus, the best acid depends on the reaction substrates and optimization of the acid additive is therefore highly recommended. In this class of organocatalyzed reactions (type A), we have developed asymmetric Michael reactions with several pro-nucleophiles. For example, nitromethane,[23] ene-carbamate,[24] dimethyl 3-oxopentanedioate,[25] and the 2-oxazoline-5-one derivative[26] are all suitable Michael donors for reactions with a,b-unsaturated aldehydes. In all of these reactions, the diphenylprolinol silyl ether was found to be a superior catalyst than the diarylprolinol silyl ether, and the optimal acid additive needed to be determined according to the pro-nucleophile and aldehyde substrate. For reactions involving enamines as intermediates (type C), the nucleophilicity of the enamine is a key factor in the reaction.[27] As the diphenylprolinol silyl ether is more electron-rich than the trifluoromethyl-substituted diarylprolinol silyl ether, the HOMO of the enamine derived from a diphenylprolinol silyl ether is higher and the enamine thus more reactive. If the addition of the enamine to the electrophile is the rate-determining step in a type C reaction, a diphenylprolinol silyl ether would be the preferred catalyst. However, enamine addition is not always the rate-determining step: In the reaction of aldehydes and nitroalkenes, the rate-determining step is not the addition of the enamine to the nitroalkene, but the ring-opening of the first formed [2+ +2] cycloadditive cyclobutane intermediate.[28] Thus, in general, the preferred catalyst in type C reactions is a diphenylprolinol silyl ether,[4b] but a trifluoromethyl-substituted diarylprolinol silyl ether should also be considered if the diphenylprolinol silyl ether does not work efficiently.
Conclusion In the reactions of a,b-unsaturated aldehydes with cyclopentadiene in the presence of diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers as amine organocatalysts, we found that the reactions involving iminium ions as intermediates can be divided into two types; one involving cycloaddition modes (type B) and one involving Michael-type reaction modes (type A). The LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower than that derived from diphenylprolinol silyl ether owing to the electron-withdrawing nature of the trifluoromethyl groups. This was confirmed by ab initio calculations. Thus, the iminium ion of the former catalyst is more reactive, and the catalyst with trifluoromethyl groups is better selected for Diels–Alder type B reactions. The generation of iminium ions from a,b-unsaturated aldehydes is faster with the more electron-rich diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. In the Michael re-
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Full Paper action, the diphenylprolinol silyl ether catalyst is preferred. Because the generation of iminium ions is promoted by acid, acid accelerates the reaction. However, in the Michael-type reaction (type A), acid also reduces the concentration of anionic nucleophiles by protonation. Thus, the appropriate selection of acid is advisable. In general, a diphenylprolinol silyl ether is the superior catalyst in type A reactions, whereas a trifluoromethylsubstituted diarylprolinol silyl ether is preferred in type B reactions.[29]
Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts by The Ministry of Education, Culture, Sports, Science and Technology, Japan (23105010). We thank Prof. Dieter Seebach at ETH-Zurich for significant discussions and the Tsukuba Advanced Computing Center (TACC) for providing computational facilities. Keywords: asymmetric synthesis · iminium organocatalysis · reaction mechanisms · silyl ethers
ions
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Full Paper Beilstein J. Org. Chem. 2012, 8, 1458; c) H. Carneros, D. Sanchez, J. Vilarrasa, Org. Lett. 2014, 16, 2900. [28] a) K. Patora-Komisarska, M. Benohoud, H. Ishikawa, D. Seebach, Y. Hayashi, Helv. Chim. Acta 2011, 94, 719; b) D. Seebach, X. Sun, M.-O. Ebert, W. B. Schweizer, N. Purkayastha, A. K. Beck, J. Duschmale, H. Wennemers, T. Mukaiyama, M. Benohoud, Y. Hayashi, M. Reiher, Helv. Chim. Acta 2013, 96, 799; c) J. Bur¦s, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2011, 133, 8822; d) J. Bur¦s, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2012, 134, 6741.
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[29] Note added in proof (Apr 3, 2015): Since this manuscript was accepted for publication, Erden and co-workers have reported the 1,2- and 1,4addition reactions of cyclopentadiene and a,b-unsaturated carbonyl compounds catalyzed by pyrrolidine: N. Coskun, M. C¸etin, S. Gronert, J. Ma, I. Erden, Tetrahedron 2015, 71, 2636.
Received: January 15, 2015 Published online on June 19, 2015
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& Reaction Mechanisms | Hot Paper |
Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl-Substituted Diarylprolinol Silyl Ether Hiroaki Gotoh,[a] Tadafumi Uchimaru,[b] and Yujiro Hayashi*[c] Abstract: The reactions of a,b-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michaeltype reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethylsubstituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The
iminium ion from an a,b-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate-determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions.
Introduction The field of organocatalysis is still developing rapidly, and many kinds of organocatalysts with unique properties have been developed and applied to organic reactions.[1] There are two major reaction modes in secondary-amine-mediated reactions, namely, reactions involving enamine and iminium ion intermediates. In the reactions of iminium ion intermediates, MacMillan and co-workers proposed the LUMO activation mechanism and demonstrated an elegant Diels–Alder reaction in 2000.[2] After this proposal, a plethora of asymmetric reactions involving iminium-reactive intermediates have been developed.[3] In 2005, our group[4] and that of Jørgensen[5] independently developed diarylprolinol silyl ethers as effective organocatalysts[6] (Figure 1). This type of catalyst has been extensively employed in reactions involving both enamine and imi[a] Prof. Dr. H. Gotoh Department of Applied Chemistry, Yokohama National University 79-5 Tokiwadai, Hodogayaku, Yokohama 240-8501 (Japan) [b] Dr. T. Uchimaru Research Institute for Sustainable Chemistry National Institute of Advanced Industrial Science and Technology Tsukuba, Ibaraki 305-8565 (Japan) [c] Prof. Dr. Y. Hayashi Department of Chemistry, Graduate School of Science, Tohoku University 6–3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan) E-mail: [email protected] Homepage: http://www.ykbsc-chem.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500326. Chem. Eur. J. 2015, 21, 12337 – 12346
Figure 1. Organocatalysts examined in this study.
nium ion intermediates. Recently, we reported a systematic study of the silyl substituent of the diphenylprolinol silyl ether catalyst and proposed three reaction types (Figure 2).[7] The reactions involving iminium ions can be subdivided into two main types: One involving Michael-type reaction modes (type A) and the other involving cycloaddition reaction modes (type B). A third reaction (type C) involves enamines as intermediates. Notably, either a diphenylprolinol or trifluoromethylsubstituted diarylprolinol silyl ether is typically selected as a catalyst in these types of reactions, but their reactivities differ. Mayr and co-workers proposed the concept of electrophilicity (E) to explain the electrophilic reactivity of a,b-unsaturated iminium ions.[8] Because of the electron-withdrawing nature of the trifluoromethyl group, the trifluoromethyl-substituted diarylprolinol silyl ether is thought to be a more electron-deficient amine catalyst in comparison with diphenylprolinol silyl ether. This indicates that the iminium ion of the CF3-substituted catalyst should be more reactive than the one derived from the
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Full Paper catalytic reactions that generate formal Michael and Diels– Alder products.
Results and Discussion Diels–Alder product versus cyclopentadiene derivative
Figure 2. Three reaction types for diarylprolinol silyl ether mediated reactions.
The reaction of cinnamaldehyde and cyclopentadiene catalyzed by diarylprolinol silyl ethers was first investigated in detail; the effects of changing the catalyst, additive, and solvent are summarized in Table 1. The enantioselective Diels– Alder reaction proceeded smoothly when trifluoromethyl-substituted diarylprolinol silyl ethers 3 and 4 were employed in the presence of CF3CO2H to afford the Diels–Alder product with good exo selectivity and excellent enantioselectivity (Table 1, entries 8 and 9). Under the same reaction conditions, the cycloaddition reaction was very slow when diphenylprolinol silyl ether 2 was employed instead of 4 and a yield of only 10 % of the Diels–Alder product 6 was obtained (Table 1, entry 7). In contrast, the cyclopentadiene Michael adduct 5 was obtained when diphenylprolinol silyl ethers 1 and 2 were employed in methanol, and no Diels–Alder product 6 was generated at all (Table 1, entries 1–5). Although the reaction proceeds without additive (Table 1, entries 1 and 2), a weak acid and base, for example, p-nitrophenol and NaOAc, increased the yield to 84 and 81 %, respectively in the case of 2. To test the reactivity of catalysts 1 and 3 in the formation of cyclopentadiene derivative 5, their reactions were compared in situ. The reaction of cinnamaldehyde and cyclopentadiene was carried out in the presence of different ratios of trifluorometh-
unsubstituted diphenyl catalyst. Yet, in some reactions, excellent yields and enantioselectivities were obtained by using the former catalyst, whereas in other reactions the latter catalyst was found to be superior. To select the most appropriate catalyst to employ in a given synthesis, it is important to discern the different trends of these catalysts, including the origin of their reactivity. During our investigations of these catalysts in asymmetric synthesis, we encountered several interesting phenomena [see Eq. (1) in Table 1]. In the reaction of cinnamaldehyde and cyclopentadiene, the Diels–Alder adduct 6 and substituted cyclopentadiene (Michael-type) adduct 5 were obtained under slightly different conditions. When the reaction was performed in the presence of cataTable 1. Effect of catalyst and additive on the enantioselective reaction of cinnamaldehyde with cyclopentadielytic trifluoromethyl-substituted ne.[a] diarylprolinol silyl ether 4 and a strong acid like CF3CO2H in toluene, the Diels–Alder product 6 was obtained in good yield with excellent enantioselectivity.[9] In contrast, in the presence of catalytic diphenylprolinol silyl ether 2 with a weak acid like p-nitro5 6 Entry Catalyst Solvent Additive Yield a/b[c] ee Yield exo/endo[f] ee phenol in MeOH, the substituted [%][b] [%][d] [%][e] [%][g] cyclopentadiene derivative 5 1 1 MeOH – 83 56:44 83 0 – – was obtained in good yield with [10] 2 2 MeOH – 68 54:46 91 0 – – excellent enantioselectivity. In3 2 MeOH p-nitrophenol 84 70:30 92 0 – – itially, we suggested that the 4 2 MeOH NaHCO3 70 41:59 90 0 – – product 5 could be generated 5 2 MeOH NaOAc 81 64:36 92 0 – – 6 2 toluene – 0 – – 0 – – through an ene reaction. Howev7 2 toluene CF3CO2H 0 – – 10 79:21 79/88 er, in the course of this investi8 3 toluene CF3CO2H 0 – – 86 84:16 95/83 gation into the properties of 9 4 toluene CF3CO2H 0 – – 80 85:15 97/88 these two catalysts, we came to [a] Unless noted otherwise, the reaction was conducted by using cinnamaldehyde (0.7 mmol), catalyst the conclusion that adduct 5 is (0.07 mmol, 10 mol %), cyclopentadiene (2.1 mmol), and additive (0.14 mmol) in solvent (1.4 mL) at room temformed by a Michael addition reperature for 20 h. [b] Yield of an isolated mixture of 5 a and 5 b. [c] Determined by 1H NMR spectroscopy (400 MHz). [d] The ee was determined by chiral HPLC analysis after reduction and hydrogenation. [e] Yield of an action. Herein, we summarize isolated mixture of exo and endo isomers. [f] Determined by 1H NMR spectroscopy (400 MHz). [g] The ee was the trends and origin of the redetermined by chiral HPLC analysis. activity of the iminium-mediated Chem. Eur. J. 2015, 21, 12337 – 12346
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Table 2. Comparison of the reactivity of the catalysts 3 and ent-1.[a]
Entry
x [mol %][b]
y [mol %][c]
Yield [%][d]
ee [%][e]
1 2 3 4 5
0 10 12 14 16
10 10 8 6 4
83 93 78 70 33
83 79 79 75 79
[a] Unless noted otherwise, the reaction was conducted by using cinnamaldehyde (0.7 mmol), catalyst, and cyclopentadiene (2.1 mmol) in MeOH (1.4 mL) at room temperature for 20 h. [b] Amount of the catalyst 3. [c] Amount of the catalyst ent-1. [d] Yield of an isolated mixture of 5 a and 5 b. [e] The ee was determined by chiral HPLC analysis after reduction and hydrogenation. The S isomer is the major isomer.
yl-substituted diarylprolinol silyl ether 3 and one enantiomer of diphenylprolinol silyl ether ent-1 (Table 2). Similar enantiomeric excesses with opposite configurations were obtained, regardless of the ratio of catalysts 3 and ent-1. This result indicates that the reaction was catalyzed by diphenylprolinol silyl ether ent-1 alone and not by the trifluoromethyl-substituted diarylprolinol silyl ether 3. In this reaction, the formation of the iminium salt would be the rate-limiting step. Thus, diphenylprolinol silyl ether 1 is more reactive than the trifluoromethylsubstituted catalyst 3 because the former is more electron-rich and the formation of iminium ion is much faster. From the results and observations obtained thus far, the following two trends are apparent. 1) The Diels–Alder product 6 forms preferentially in the presence of the electron-deficient catalysts 3 and 4 and a relatively strong acid such as CF3CO2H, whereas the formal cyclopentadiene Michael adduct 5 forms preferentially in the presence of the relatively electron-rich catalysts 1 and 2 and a relatively weak acid or base. 2) There are no reaction conditions under which both the Diels–Alder product 6 and cyclopentadiene derivatives 5 form concurrently, which indicates that these two reactions proceed by different mechanisms. Furthermore, the substrates showed opposite trends in reactivity for these two reactions. As shown in Tables 3[9a] and 4,[10a,b] electron-deficient a,b-enals were more reactive in Diels– Alder reactions, whereas the reactions of electron-rich a,benals proceeded smoothly to generate cyclopentadiene adducts. These results also suggest two different reaction mechanisms for these two organocatalyzed addition reactions. To explain the different reactivities of the diphenylprolinol silyl ether 1 and the trifluoromethyl-substituted diarylprolinol silyl ether 3 in the Diels–Alder reaction, each reaction step was investigated in detail. Chem. Eur. J. 2015, 21, 12337 – 12346
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The formation of the iminium ion was examined by using diphenylprolinol silyl ether 1 and CF3CO2H as additive in several solvents, namely CDCl3, CD3OD, C6D5CD3, and CD3CN, and 1 H NMR spectra were recorded after certain times [Eq. (5), Figure 3]. The formation of iminium ions was fast in CD3OD, whereas they were formed only gradually in CDCl3. The reaction in toluene was very slow, affording the iminium ion in a maximum yield of 7 % without any further increase after 10 min. The effect of acid was examined by using the catalyst 1 in
Table 3. Reactivity of a,b-enals towards the Diels–Alder reaction.[a]
Entry
1 2 3
R
p-MeOC6H4 Ph p-NO2C6H4
Time [h]
Yield [%][b]
336 26 6
0 quant. 93
exo/endo[c] – 85/15 87/13
ee [%][d] – 97/88 94/73
[a] Data extracted from ref. [9a]. The reaction was conducted by using an a,b-unsaturated aldehyde (0.7 mmol), catalyst 4 (0.07 mmol, 10 mol %), cyclopentadiene (2.1 mmol), and CF3CO2H (0.14 mmol) in toluene (1.4 mL) at room temperature for the indicated time. [b] Yield of an isolated mixture of exo and endo isomers. [c] Determined by 1H NMR spectroscopy (400 MHz). [d] The ee was determined by HPLC analysis on chiral phase.
CDCl3 [Eq. (6), Figure 4]. Without acid, no iminium ion was formed. Among the acids examined, namely CH3CO2H, PhCO2H, CF3CO2H, CH3SO3H and HClO4, good results were obtained with strong acids such as HClO4, which afforded the iminium ion in a yield of 63 % in 30 min. Next, the effect of the catalyst 3 on iminium ion formation was investigated by using HClO4 as the acid in CDCl3 (Figure 4). The iminium ion was formed significantly faster with diphenylprolinol silyl ether 1 than with the trifluoromethyl-substituted diarylprolinol silyl ether 3. The faster generation of the iminium ion in the case of diphenylprolinol silyl ether 1 can likely be attributed to the higher nucleophilicity of the amine catalyst 1 in comparison with 3, which possesses electron-withdrawing CF3-substituted aryl groups.
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Full Paper Table 4. Reactivity of a,b-enals as Michael acceptors.[a]
Entry [c]
1 2[c] 3[d]
R
p-MeOC6H4 Ph p-NO2C6H4
Catalyst [mol %]
Time [h]
Yield [%][b]
ee [%]
10 10 20
8 20 3
82 84 60
99 95 90
[a] The reaction was conducted by using an a,b-unsaturated aldehyde (0.7 mmol), catalyst 2 (0.07 or 0.14 mmol, 10 or 20 mol %), cyclopentadiene (2.1 mmol), p-nitrophenol (0.14 mmol) in MeOH (1.4 mL) at room temperature for the indicated time. [b] Yield of an isolated mixture of diastereoisomers. [c] Data from ref. [10b]. [d] Data from ref. [10a].
Figure 4. Effect of acid and catalyst on the formation of the iminium ion in the reaction with diarylprolinol silyl ethers 1 and 3 in CDCl3. The yields were determined by 1H NMR spectroscopy (400 MHz).
Table 5. 13C NMR chemical shifts of the iminium ions 7 and 8 and cinnamaldehyde (9).[a]
Entry
1 2 3
Figure 3. Effect of solvent on the formation of the iminium ion in the reaction with diphenylprolinol silyl ether 1 with CF3CO2H. The yields were determined by 1H NMR spectroscopy (400 MHz).
Reactivity of the iminium ion with cyclopentadiene Next, the reactivities of the iminium ions were investigated. As the cinnamoylidene iminium ClO4¢ salts 7 can 8 can be isolated[11] as white powders by treatment of an ether solution of cinnamaldehyde and diphenylprolinol silyl ether 1 or the trifluoromethyl-substituted catalyst 3 with HClO4 at 0 8C, their reactivities towards cyclopentadiene were examined. The 13 C NMR chemical shifts of the iminium ions 7 and 8 and cinnamaldehyde are shown in Table 5. The chemical shifts of C1 and C3 of the iminium ion 8 generated with catalyst 3 appear at a lower field than those of iminium ion 7 derived from catalyst 1. These results indicate that the LUMO level of 8 is lower than that of 7, and that 8 is expected to be more reactive than 7 as a dienophile in the Diels–Alder reaction and as a Michael acceptor in the Michael reaction. Next, we investigated the LUMO levels of the iminium cations 7’ and 8’ of the iminium ClO4¢ salts 7 and 8. A conformaChem. Eur. J. 2015, 21, 12337 – 12346
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Substrate
7 8 9
C1
dC [ppm] C2
C3
168.3 170.3 193.5
117.1 116.3 128.5
161.4 164.4 152.6
[a] The 13C NMR data were measured in CDCl3.
tional analysis was performed on the isomers of 7’ and 8’ with E configurations of both the C=C and C=N double bonds[7] by using the CONFLEX program[12] together with the MMFF94s force field.[13] For the conformers with an energy within 3 kcal mol¢1 of the most stable conformer in the force field calculations, we carried out geometry optimizations at the B3LYP/631G(d) level of theory, and then single-point calculations were performed on the optimized structures at the HF/6-31G(d) level of theory.[14] Two and five conformers were obtained for the iminium cations 7’ and 8’, respectively. The energies of the LUMOs of these conformers are summarized in Table 6, and the structures of the lowest-energy conformers of 7’ and 8’ are shown in Figure 5. It was found that the LUMO of the iminium cation 8’, derived from the trifluoromethyl-substituted diarylprolinol silyl ether 3, is lower than that of the iminium cation 7’, derived from diphenylprolinol silyl ether 1, but there is little difference in the shapes of the orbitals of the LUMOs of the iminium cations 7’ and 8’ (see the Supporting Information).
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Figure 5. Structures of the lowest-energy conformers of a) the iminium cation 7’ and b) the iminium cation 8’ (entry 1 in Table 6). The structures of the other major conformers of the iminium cations 7’ and 8’ given in Table 6, including the X-ray crystal structures, are very similar to one another (see the Supporting Information).[15]
Table 6. Calculated relative energies and the LUMO energies of conformers of the iminium cations 7’ and 8’. Entry
1 2 3 4 5
Iminium cation 7’ Erel [kcal mol¢1][a] ELUMO [eV][b] 0.00 ¢2.3013 (0.02) – 0.17 ¢2.2447 (0.00) – – – – – – – – – – – – –
Figure 6. Diels–Alder reaction of iminium ions 7 and 8 with cyclopentadiene. The yields were determined by 1H NMR spectroscopy (400 MHz).
Iminium cation 8’ Erel [kcal mol¢1][a] ELUMO [eV][b] 0.00 ¢2.6515 (0.00) – 0.08 ¢2.6501 (0.03) – 0.37 ¢2.6058 (0.34) – 0.41 ¢2.6044 (0.37) – 2.53 ¢2.6474 (1.58) –
tion of iminium ions in the case of trifluoromethyl-substituted diarylprolinol silyl ether 3 is slower than with the diphenylprolinol silyl ether 1. 2) The Diels–Alder reaction of the isolated iminium ion of the trifluoromethyl-substituted diarylprolinol silyl ether 3 is faster than with the diphenylprolinol silyl ether 1. 3) By using catalytic amounts of diarylprolinol silyl ethers, the reactivity of the trifluoromethyl-substituted diarylprolinol silyl ether 3 is significantly higher than with the diphenylprolinol silyl ether 1.
[a] Relative energies calculated at the HF/6-31G(d) and (in parentheses) B3LYP/6-31G(d) levels of theory. [b] LUMO energies calculated at the HF/ 6-31G(d) level of theory.
Next, the reactivities of these iminium ions towards cyclopentadiene were investigated. The iminium ions 7 and 8 were treated with cyclopentadiene in CDCl3 and the progress of the reactions was monitored by 1H NMR spectroscopy (Figure 6). Starting from 7 and 8 only the Diels–Alder reaction proceeded, without the formation of the cyclopentadiene Michael adduct 5. The iminium ion 8, generated from trifluoromethyl-substituted diarylprolinol silyl ether 3, was found to be more reactive than the iminium ion 7, derived from diphenylprolinol silyl ether 1; the Diels–Alder adduct was obtained in a yield of 82 % after 11 h in the case of 8 with a 95 % ee of the major exo isomer, whereas the product was obtained in a yield of only 15 % in the case of 7 with an 86 % ee of the exo isomer. The diastereoselectivities and enantioselectivities of these two reactions starting from the isolated iminium ion salts 7 and 8 and cyclopentadiene closely match those observed for the reactions carried out in the presence of catalytic amounts of 1 and 3. The amine catalyst and a,b-enal first react to generate the iminium ion, which then reacts with cyclopentadiene to afford the Diels–Alder adduct after hydrolysis of the newly formed iminium ion (Scheme 1). In this reaction, the following observations were made from the above experiments: 1) The generaChem. Eur. J. 2015, 21, 12337 – 12346
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Reaction mechanism for the generation of cyclopentadiene derivative 5 Next, we investigated the mechanism for the generation of the cyclopentadiene derivative 5 [see Eq. (1) in Table 1]. One possible reaction mechanism is an organocatalyzed Michael reaction between the cyclopentadienyl anion and the a,b-enal [Eq. (8)], that is, the organocatalytic amine acts as a base to deprotonate the cyclopentadiene and the cyclopentadienyl anion thus generated reacts with cinnamaldehyde in a conjugate 1,4-addition to provide the substituted cyclopentadiene derivative 5. If this is the mechanism, the reaction should proceed faster when the LUMO level of the a,b-unsaturated aldehyde is lower. However, the reaction proceeds faster with an acrolein with an electron-rich aryl group at the b position than with an electron-deficient group (Table 4). Thus, this mechanism can be ruled out. The other possible paths are an ene reaction, a Friedel– Crafts type reaction, a Diels–Alder reaction followed by rearrangement, and a Michael reaction, all of which involve a common iminium ion intermediate. We discuss each of these reaction mechanisms below. 1) Ene reaction: As a result of our study of the generation of cyclopentadiene derivative 5 by using catalyst 2,[10a] we
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Full Paper LUMO of the iminium ion is lower. However, electron-rich a,b-enals were found to be more reactive (Table 4), which indicates that the reaction does not proceed by a Friedel–Crafts-type reaction. 3) Diels–Alder reaction, followed by rearrangement: The Diels–Alder product 6 might undergo a rearrangement to afford the cyclopentadiene derivative 5 (Scheme 3). When the Diels–Alder product 6 was treated with diphenylprolinol silyl ether 1 under the conditions used for the formation of 5, no reaction occurred. Moreover, when the cyclopentadiene derivative 5 was treated with the trifluoromethyl-substituted diarylprolinol silyl ether 3 under the Diels–Alder reaction conditions, no reaction proceeded and the starting material was recovered. Thus, the generation of 5 by a rearrangement of the Diels–Alder product 6 could be ruled out. 4) Michael reaction via iminium ion intermediate (Scheme 4): The first step of iminium ion formation from catalyst 2 and cinnamaldehyde has already been demonstrated to be a relatively slow reaction (see above, Figure 4). The cyclopentadienyl anion would be formed from cyclopentadiene and catalyst 2, which would attack the iminium ion in a 1,4-addition manner to provide an enamine. The enamine would then be hydrolyzed by water to afford the Michael product and regenerate the catalyst 2.
Scheme 1. Mechanism of the iminium-mediated Diels–Alder reaction.
proposed that an ene reaction[16] would occur. We then found that the Diels–Alder reaction occurs in the presence of the diarylprolinol silyl ether catalyst 4. The ene and Diels–Alder reactions are mechanistically related as both reactions are concerted, proceeding through cyclic transition states involving six electrons (Figure 7),[16c] which would indicate the same reactivity profiles for a,b-enals. The activation energy of the ene reaction is higher than that of the Diels–Alder reaction. Therefore, typically, higher reaction temperatures are required. As the reactivity profiles of our reactions were found to differ significantly, and the cyclopentadiene derivative 5 is generated under mild reaction conditions in comparison with the Diels–Alder reaction, the present reaction is unlikely to proceed by the ene reaction. 2) Friedel–Crafts-type reaction: If a Friedel–Crafts-type reaction[17] Figure 7. Transition state proceeds (Scheme 2), the reacformed during the ene reaction. tion should be faster when the Chem. Eur. J. 2015, 21, 12337 – 12346
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As the pKa values of cyclopentadiene, p-nitrophenol, and pyrrolidinium ion in DMSO are 18,[18] 10.8,[19] and 11.1,[20] respectively, the generation of cyclopentadienyl anions in the presence of p-nitrophenol would be expected to be unfavorable, although still possible. The generation of the cyclopentadienyl anion was investigated by the deuteration of cyclopentadiene in CD3OD in the absence of catalyst and additive, with catalyst 2 alone, with catalyst 2 and p-nitrophenol together, and with catalyst 2 and TsOH together, respectively (Equation (9), Figure 8). Diphenylprolinol silyl ether 2 deprotonates cyclopentadiene to afford deuterated [D6]cyclopentadiene in a yield of 80 % after 500 min. The deprotonation proceeds efficiently even in the presence of p-nitrophenol, providing the deuterated [D6]cyclopentadiene at the same rate, whereas the deprotonation is relatively slow in the presence of the strong
Scheme 2. Mechanism of the Friedel–Crafts-type reaction.
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Scheme 3. Rearrangement of the Diels–Alder product in the presence of catalyst 1.
Scheme 4. Mechanism of the Michael reaction.
acid TsOH. These results strongly support the involvement of the cyclopentadienyl anion in the reaction. Thus, the Michael reaction is considered the most probable route, with the generation of the iminium ion the likely rate-determining step. This is in good agreement with the fact that the diphenylprolinol silyl ether is a more effective catalyst than the trifluoromethyl-substituted diarylprolinol and that a,b-unsaturated aldehydes with electron-rich substituents are more reactive.
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Comparison of the two reaction mechanisms In the organocatalyst-mediated reactions involving the iminium ion intermediate, there are two different reaction mechanisms that operate. One is a Diels–Alder reaction, in which strong acidic conditions can be employed (type B reaction, Figure 2), and the other is a formal Michael addition of an anionic nucleophile (type A reaction). In the Diels–Alder reaction, the reactivity increases with the use of the trifluoromethyl-substituted catalyst 4, owing to the electron-withdrawing nature of the trifluoromethyl substituents lowering the LUMO level of the iminium ion.[21] As the
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Figure 8. Effect of amine catalyst and acid additive on the generation of deuterated [D6]cyclopentadiene.
LUMO level of the iminium ion is key to determining the relative reactivity, the reaction is slow in the case of electron-rich a,b-unsaturated aldehydes. Thus, the trifluoromethyl-substituted diarylprolinol silyl ether is a better catalyst than the diphenylprolinol silyl ether in iminium/neutral nucleophilic reactions such as the Diels–Alder reaction. The 1,3-dipolar cycloaddition of nitrones to a,b-unsaturated aldehydes also belongs to this class of reactions. Nevalainen and co-workers reported that the reaction of N-benzylidenebenzylamine N-oxide and crotonaldehyde was catalyzed by a diphenylprolinol silyl ether in combination with HOTf in 1 day, affording the product with 95 % ee.[22] This reaction would be classified as a type B reaction. If this was so, a trifluoromethyl-substituted diarylprolinol silyl ether would be a superior catalyst. When we performed this reaction, we found that diarylprolinol silyl ether 4 is indeed a more reactive catalyst than diphenylprolinol silyl ether 1, promoting the reaction in only 20 min [Eq. (10)].
In most of the iminium ion/anionic nucleophilic reactions (type A), an acid additive accelerates the reaction because acid accelerates the formation of the iminium ion, which is faster in Chem. Eur. J. 2015, 21, 12337 – 12346
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the case of electron-rich a,b-unsaturated aldehydes. Diphenylprolinol silyl ether 1 is a better catalyst than the trifluoromethyl-substituted 4 because the former is more electron-rich and the formation of the iminium ion is significantly faster. Although acid accelerates the generation of iminium ions, it reduces the generation of anionic nucleophiles by protonation. Thus, the best acid depends on the reaction substrates and optimization of the acid additive is therefore highly recommended. In this class of organocatalyzed reactions (type A), we have developed asymmetric Michael reactions with several pro-nucleophiles. For example, nitromethane,[23] ene-carbamate,[24] dimethyl 3-oxopentanedioate,[25] and the 2-oxazoline-5-one derivative[26] are all suitable Michael donors for reactions with a,b-unsaturated aldehydes. In all of these reactions, the diphenylprolinol silyl ether was found to be a superior catalyst than the diarylprolinol silyl ether, and the optimal acid additive needed to be determined according to the pro-nucleophile and aldehyde substrate. For reactions involving enamines as intermediates (type C), the nucleophilicity of the enamine is a key factor in the reaction.[27] As the diphenylprolinol silyl ether is more electron-rich than the trifluoromethyl-substituted diarylprolinol silyl ether, the HOMO of the enamine derived from a diphenylprolinol silyl ether is higher and the enamine thus more reactive. If the addition of the enamine to the electrophile is the rate-determining step in a type C reaction, a diphenylprolinol silyl ether would be the preferred catalyst. However, enamine addition is not always the rate-determining step: In the reaction of aldehydes and nitroalkenes, the rate-determining step is not the addition of the enamine to the nitroalkene, but the ring-opening of the first formed [2+ +2] cycloadditive cyclobutane intermediate.[28] Thus, in general, the preferred catalyst in type C reactions is a diphenylprolinol silyl ether,[4b] but a trifluoromethyl-substituted diarylprolinol silyl ether should also be considered if the diphenylprolinol silyl ether does not work efficiently.
Conclusion In the reactions of a,b-unsaturated aldehydes with cyclopentadiene in the presence of diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers as amine organocatalysts, we found that the reactions involving iminium ions as intermediates can be divided into two types; one involving cycloaddition modes (type B) and one involving Michael-type reaction modes (type A). The LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower than that derived from diphenylprolinol silyl ether owing to the electron-withdrawing nature of the trifluoromethyl groups. This was confirmed by ab initio calculations. Thus, the iminium ion of the former catalyst is more reactive, and the catalyst with trifluoromethyl groups is better selected for Diels–Alder type B reactions. The generation of iminium ions from a,b-unsaturated aldehydes is faster with the more electron-rich diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. In the Michael re-
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Full Paper action, the diphenylprolinol silyl ether catalyst is preferred. Because the generation of iminium ions is promoted by acid, acid accelerates the reaction. However, in the Michael-type reaction (type A), acid also reduces the concentration of anionic nucleophiles by protonation. Thus, the appropriate selection of acid is advisable. In general, a diphenylprolinol silyl ether is the superior catalyst in type A reactions, whereas a trifluoromethylsubstituted diarylprolinol silyl ether is preferred in type B reactions.[29]
Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts by The Ministry of Education, Culture, Sports, Science and Technology, Japan (23105010). We thank Prof. Dieter Seebach at ETH-Zurich for significant discussions and the Tsukuba Advanced Computing Center (TACC) for providing computational facilities. Keywords: asymmetric synthesis · iminium organocatalysis · reaction mechanisms · silyl ethers
ions
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Full Paper Beilstein J. Org. Chem. 2012, 8, 1458; c) H. Carneros, D. Sanchez, J. Vilarrasa, Org. Lett. 2014, 16, 2900. [28] a) K. Patora-Komisarska, M. Benohoud, H. Ishikawa, D. Seebach, Y. Hayashi, Helv. Chim. Acta 2011, 94, 719; b) D. Seebach, X. Sun, M.-O. Ebert, W. B. Schweizer, N. Purkayastha, A. K. Beck, J. Duschmale, H. Wennemers, T. Mukaiyama, M. Benohoud, Y. Hayashi, M. Reiher, Helv. Chim. Acta 2013, 96, 799; c) J. Bur¦s, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2011, 133, 8822; d) J. Bur¦s, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2012, 134, 6741.
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[29] Note added in proof (Apr 3, 2015): Since this manuscript was accepted for publication, Erden and co-workers have reported the 1,2- and 1,4addition reactions of cyclopentadiene and a,b-unsaturated carbonyl compounds catalyzed by pyrrolidine: N. Coskun, M. C¸etin, S. Gronert, J. Ma, I. Erden, Tetrahedron 2015, 71, 2636.
Received: January 15, 2015 Published online on June 19, 2015
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