CHIRALITY 23:397–403 (2011)
Organocatalytic Aza-Michael/Retro-Aza-Michael Reaction: Pronounced Chirality Amplification in Aza-Michael Reaction and Racemization via Retro-Aza-Michael Reaction YONG-FENG CAI,1 LI LI,1,2 MENG-XIAN LUO,1 KE-FANG YANG,1 GUO-QIAO LAI,1 JIAN-XIONG JIANG,1 AND LI-WEN XU1* 1 Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, People’s Republic of China 2 College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, People’s Republic of China
ABSTRACT A detailed experimental investigation of an aza-Michael reaction of aniline and chalcone is presented. A series of Cinchona alkaloid-derived organocatalysts with different functional groups were prepared and used in the aza-Michael and retro-aza-Michael reaction. There was an interesting finding that a complete reversal of stereoselectivity when a benzoyl group was introduced to the cinchonine and cinchonidine. The chirality amplification vs. time proceeds in the quinine-derived organocatalyst containing silicon-based bulky group, QN-TBS, -catalyzed aza-Michael reaction under solvent-free conditions. In addition, we have demonstrated for the first time that racemization was occurred in suitable solvents under mild conditions due to retro-aza-Michael reaction of the Michael adduct of aniline with chalcone. These indicate the equilibrium of retro-aza-Michael reaction and aza-Michael reaction produce the happening of chirality amplification in aza-Michael reaction and racemization via retro-aza-Michael reaction under different conditions, which would be beneficial to the development of novel chiral cataC 2011 Wiley-Liss, Inc. lysts for the aza-Michael reactions. Chirality 23:397–403, 2011. V KEY WORDS: chirality amplification; racemization; aza-Michael reaction; retro-aza-Michael reaction; organocatalysis INTRODUCTION
Aza-Michael reaction is a convenient way to introduce an amine-based functionality to a b-carbon attached to an electro-withdrawing group and generate b-amino carbonyl compounds, such as b-amino acids.1,2 The first report on azaMichael reaction was published early in 1874,3,4 surprisingly, catalytic aza-Michael reaction was attracted much attention only in the past 20 years, and various nitrogen-centered sources, such as hydroxylamine derivatives,5–7 aliphatic and aromatic amines,8–11 azides,12–14 carbamates,15–19 aldoximes,20 N-heterocycles,21,22 has been used widely in aza-Michael reaction.23–26 However, while the catalytic asymmetric version of the classic Michael addition with carbon nucleophiles is well established, the highly enantioselective catalytic aza-Michael reaction is still presents a significant challenge in organic synthesis.27–29 Since the first example of asymmetric aza-Michael reaction of aromatic amines was published by Jørgensen in 2001,30 considerable effort has been directed towards the development of chiral catalyst systems especially with palladium complexes for the aza-Michael reaction of aromatic amines.31–38 It is worthy to note that Scettri et al. employed commercial available Cinchona alkaloids as the organocatalysts for the aza-Michael addition of aniline to chalcones under solvent-free conditions.39 The catalytic performance of six Cinchona alkaloids was tested under the same solventfree conditions, and the use of cinchonine was found to be gave the best results with moderate level of enantioselectivities (up to 58%ee). As a common theme, these Cinchona alkaloids with similar bifunctional chiral alcohol and tertiary amine, however, the enantioinduction is different dramatically from 0 to 58%ee. It is also interesting that the substituted MeO-group in 6-position and olefin group in Cinchona C 2011 Wiley-Liss, Inc. V
alkaloid gave strong impact on enantioselectivity. Despite some impressive demonstrations of the enantioselective aza-Michael reactions, this reaction still has a number of unaccountable features and unverified mechanistic details. In the present article, a series of protected Cinchona alkaloidderived organocatalysts were prepared and used in the aza-Michael and retro-aza-Michael reaction. Furthermore, we provided the direct findings and mechanistic discussion for the Cinchona alkaloids-derived organocatalysts-promoted aza-Michael reaction because there are no detailed mechanistic information on the organocatalytic aza-Michael reaction and factors responsible for chiral-control in the Cinchona alkaloid-catalyzed aza-Michael reaction. In addition, we first demonstrated that the chirality amplification happened in this aza-Micheal reaction and related racemization due to the retro-aza-Michael reaction. EXPERIMENTAL General Procedures All reagents and solvents were used directly without purification. Flash column chromatography was performed over silica (200–300
Contract grant sponsor: Natural Science Foundation of China; Contract grant number: 20973051 Contract grant sponsor: Zhejiang Provincial Natural Science Foundation of China; Contract grant number: Y409013 Contract grant sponsor: Hangzhou Science and Technology Program; Contract grant number: 20090231T03 *Correspondence to: Li-Wen Xu, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou. E-mail: [email protected]
, [email protected]
Received for publication 21 March 2010; Accepted 9 December 2010 DOI: 10.1002/chir.20940 Published online 4 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
CAI ET AL.
TABLE 1. The enantioselectivities in Cinchona alkaloids derivatives (4-8) catalyzed aza-Michael reaction of chalcone and aniline Entrya
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
4a 4b 4c 4d 5a 5b 5b 5b 5b 6a 6b 7a 7b 7c 8
20 48 48 48 20 12 24 48 72 20 48 20 48 48 48
75 90 93 68 88 24 46 92 >99 >99 62 >99 98 94 99
49e 23 227 24 9e 35 41 44 55 3e 219 216e 19 18 13
– D 5 226 Inversion D 5 225 – D 5 126 D 5 132 D 5 135 D 5 146 – Inversion – Inversion Inversion D 5 110
Reaction conditions: chalcone (0.25 mmol), aniline (0.5 mmol), and catalysts (20 mol%)., solvent-free, at room temperature. b NMR yield. c Reported data in ref. 38. d Enantiomeric excess of the aza-Michael adduct determined by HPLC analysis using a chiral phase column.
mesh). 1H NMR and 13C NMR spectra were recorded at Bruker Avance 400 and 100 MHz, respectively, and were referenced to the internal solvent signals. IR spectra were recorded using a FTIR apparatus (Nicolot 5700). Thin layer chromatography was performed using silica gel; F254 TLC plates and visualized with ultraviolet light. HPLC was carried out with a Waters 2695 Millennium with photodiode array detector. All the Michael adducts and organocatalysts were known compounds and confirmed by GC-MS (Thermo Finnigan Trace DSQ) or ESI-MS, and usual spectral methods (NMR and IR).
Preparation of Cinchona Alkaloid-Derived Organocatalysts 4-8 The corresponding Cinchona alkaloid-derived compounds, catalysts 48 containing silicon-based bulky group (TBS, TMS),40,41 Bz,42 Ms,43 or primary amine,44 were synthesized from the corresponding Cinchona alkaloids via silylation, acylation or amination, respectively. All the organocatalysts 4-8 were known and confirmed by GC-MS, and usual spectral methods (NMR and IR).
General Method for Organocatalyzed Aza-Michael and Retro-Aza-Michael Reaction General procedure of Cinchona alkaloid-catalyzed aza-Michael reaction. A mixture of chalcone (0.25 mmol), aniline (0.5 mmol), and catalysts (20 mol%) was stirred for 12 to 72 hours (Table 1) under solvent-free conditions at room temperature. The resulting reaction mixture was monitored by TLC and HPLC. The ees of the aza-Michael products were determined by chiral-phase HPLC analysis [Chiralcel AD-H, hexane/2-propanol 5 95/5, 0.7 mL/min, k 5 254 nm, retention times: 28.2 min (major), 31.7 min (minor)]. The known compound was identified by comparison of spectral data with that of reported.45,46 General procedure of Cinchona alkaloid-catalyzed aza-Michael/retro-aza-Michael reaction of 3. A mixture of chalcone (0.25 mmol), aniline (0.5 mmol), and catalysts (20 mol%) was stirred for 24 to 96 hours (if appropriate) under solvent-free conditions at room temperature. Upon the completion, the different solvent was introduced Chirality DOI 10.1002/chir
in one portion to the residue. The ees of the aza-Michael products were determined by chiral-phase HPLC analysis every 12 or 24 hours after general work-up.
RESULTS AND DISCUSSION
In a first set of experiments, we prepared several Cinchona alkaloids derived organocatalysts according to reported methods40–44 and examined the aza-Michael reaction of Scheme 1 using aniline and chalcone as model reaction. As shown in Scheme 1, Cinchona alkaloid-derived catalysts 4-8, containing silicon-based bulky group (TBS, TMS),40,41 Bz,42 Ms,43 or primary amine,44 gave different enantioselectivities in the aza-Michael reaction of aniline to chalcone. In comparison to corresponding parent Cinchona alkaloids, the introduction of TMS, Ms, Bz (catalysts 4b-d) resulted in lower enantioselectivities (Table 1, entries 1-4), which showed the alcohol group in cinchonine (4a) with hydrogen bonding play crucial to the obtaining promising enantioselectivity. However, catalysts 5b and 6b, that derived from the protection of alcohol of quinine (5a) and quinidine (5b) with bulkyl TBS group, the enantioselectivity was increased dramatically (Table 1, entries 5 and 6, 44%ee versus 9%ee, and entries 10 and 11, 219%ee versus 3%ee) in comparison to that of corresponding parent quinine or quinidine, in which the difference including the inversion of the enantioselectivity could be obviously due to the contribution of silicon-based bulky group. It should be noted that a complete reversal of stereoselectivity was observed in the presence of catalytic 4c, 6b, 7b, and 7c (Table 1, entries 3, 11, 13, 14). For example, benzoyl-substituted cinchonine derivative 4c and benzoyl-substituted cinchonidine 7c derivative gave 27%ee and 18% ee along with a changeover of enantioselectivity. This remarkable result obtained with benzoyl-modified organocatalysts maybe due to weak interaction, such as p-p stacking, between phenyl ring of catalyst 4c or 7c and chalcone. Similarly, the TMS-protected cinchonidine derivative 7b gave 18%ee of aza-Michael adduct in (R)-form with a complete reversal of stereoselectivity in comparison to that of parent cinchonidine (216% ee). These results showed the reasonable utilization of steric function is very important in the design of chiral catalyst, which could fine-tune the catalytic efficiency and enantioselectivity of functional molecules dramatically.47 During the screening studies of Cinchona alkaloid-derived catalysts and inspired by the iminium catalysis with primary amine organocatalysts,48 we prepared the privileged primary amine catalyst 8 for the aza-Michael reaction, however, the enantio-induction of 8 is not good, although the enhancement in enantioselectivity was obviously in comparison to that of 5a or 6a. In an earlier study, we found that the catalyst 5b or 6b was not perfect in terms of efficiency after 48 h and therefore we performed the aza-Michael reaction by increasing the time to 72 hours (Table 1, entry 9). As expected, the yield is excellent (>99% yield). Interestingly, the enantioselectivity was increased from 44 to 55%ee. It is an exciting finding that the amplification of enantioselectivity is observed clearly in this QN-TBS (5b) catalyzed aza-Michael reaction aniline to chalcone under solvent-free conditions. As shown in Table 1 (Entries 6-9), when the resulting reaction mixture was monitored for certain time, the enantioselectivity is found to be increased corresponding to time, as it were, chirality amplification is occurred in this case. This showed that the competi-
ORGANOCATALYTIC AZA-MICHAEL/RETRO-AZA-MICHAEL REACTION
Scheme 1. Cinchona alkaloid derivatives catalyzed aza-Michael reaction of aniline to chalcone.
tion of retro-aza-Michael and aza-Michael addition might lead to higher level of enantioselectivity (55%ee). Encouraged by these results, we then conducted experiments to access the influence of additives with different structure in the aza-Michael reaction or the retro-aza-Michael reaction. Lewis base (DBU, Et3N) and Brønsted acids with hydrogen bonding (Boc- phenylalanine, S- or R-BINOL) was added to the mixture of aniline, chalcone, and catalytic QN-TBS (2) under solvent-free conditions, however, there are no any enantioselectivity after 24 hours despite the conversion is excellent to >99%. These results further confirm that Cinchona alkaoids-catalyzed aza-Michael reaction is not through iminium catalysis or hydrogen bonding activation of chalcone but with tertiary amine of Lewis base activation of aniline. To search the direct evidence for the equilibrium in azaMichael reaction and retro-aza-Michael reaction, we added the benzaldehyde 9 in the aza-Michael adduct obtained from the product of chalcone/aniline (1:1) under solvent-free conditions, as expected, the aldimine 10 was obtained in high yield after 2 days (Scheme 2). The control experiment showed the aza-Michael reaction is reversible and retro-azaMichael released chalcone and aniline slowly. Therefore in asymmetric aza-Micahel reaction, the major problem is the possible reversibility for the chiral aza-Michael adducts, which usually resulted in the loss or enhancement of enantioselectivity. The example of chirality amplification in QN-TBS (5b)-catalyzed aza-Michael reaction aniline to chalcone under solvent-free conditions is a good case in this context. Our results support the supposition that the stereochemical outcome of the aza-Michael addition of aniline and chalcone
depends on the equilibrium in aza-Michael reaction and retro-aza-Michael reaction. Based on our experimental results, a suggested mechanism of organocatalyst catalyzed aza-Michael reaction is proposed in Scheme 3. As illustrated in Scheme 3, the catalytic cycle consists of an important initiation phase that generation of the active complex i-1 through hydrogen bonding between catalyst 5 and aniline. And then it interacts with chalcone via p-p stacking of aromatic rings and hydrogen bonding to finish the Michael addition. To gain support for the hypothesis of the interaction of catalyst and aniline, we made use of 29Si-NMR analysis. In the NMR investigation, we simply compared the 29Si NMR of the pure TMS-substituted catalyst 4b and the mixture of 4b and aniline (1:2). As shown in Figure 1, the pure catalyst 4b showed two signals at 19.651 and 19.407 ppm due to the possible weak Si-N coordination at silicon atom.49 By comparison with the starting catalyst 4b, there is slightly difference after the addition of excess aniline. This assignment is
Scheme 2. Catalytic retro-aza-Michael reaction in the presence of benzaldehyde. Chirality DOI 10.1002/chir
Scheme 3. Proposed Mechanism of Catalytic aza-Michael and retro-aza-Michael reaction.
Si-NMR spectrum for CN-TMS (4b) and the mixture of 4b and aniline (1:2).
ORGANOCATALYTIC AZA-MICHAEL/RETRO-AZA-MICHAEL REACTION
supported by the fact that the hydrogen bonding interaction of catalyst 4b and aniline. The complex i-1 gives rise to the signals at around 19.767 and 19.528 ppm, respectively. To obtained more information in support of the proposed tentative mechanism of Scheme 3, the retro-aza-Michael reaction was carried out. Foremost among the factors that can produce the possible chirality amplification and racemization in organocatalytic retro-aza-Michael reaction are the solvents and catalysts, therefore we decide to carry out the reaction in the presence of different solvent. In general, different enantioselectivities were obtained due to the low enantioselectivity of the catalysts. Initially, we have found catalytic amount of Cinchona alkaloids and its derivatives (4-8) showed poor catalytic activity in organic media, which maybe due to the fast retro-aza-Michael reaction. For example, the aza-Michael reaction was not complete (70–80% yields) in MeOH or toluene even with 100 mol% of base catalyst for 24h, and unfortunately, the enantioselectivity obtained was low (22%ee in MeOH, 31%ee in toluene). As described above, the equilibrium in aza-Michael reaction and retro-aza-Michael reaction is unavoidable, and the role of catalyst is important in this equilibrium, which would be resulted in the chirality racemization and amplification. Therefore, the retro-aza-Michael raection of 3 is designed to study the equilibrium of aza-Michael reaction and retro-azaMichael reaction: the aza-Michael reaction was carried out firstly at room temperature for 72 or 24 hours under solvent-
TABLE 2. Chirality amplification and racemization in organocatalytic aza-Michael/retro-aza-Michael adduct of aniline to chalconea Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 a
Mcat. (1022 mol/L)
4a 5b 8 4d 4c 7c 4b 7b 6b 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b 4a
MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH Toluene i-PrOH MeOH MeOH MeOH MeOH THF Toluene i-PrOH EA MeOH
1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 3.4 3.4 3.4 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0
24 24 24 24 24 24 24 24 24 24 24 24 17 39 62 39 39 39 39 24
19 76 5 4 28 6 7 2 25 7 29 36 39 43 44 44 42 43 42 44
–d – – – – – – – – – 14 31 47 32 – 33 34 35 42 86
Reaction conditions44,45: The mixture of 0.25 mmol of chalcone, 0.5 mmol of aniline, and catalysts (20 mol%) was stirred for 72 h (entries 1–9) or 24 h (entries 10–20) under solvent-free conditions, and then the different solvents was added to the reaction mixture, the reaction was stirred at room temperature. b The enantiomeric excess was determined by HPLC using chiral AD-H column. c NMR yields. d The yield is not determined because the enantioselectivity of aza-Michael adduct 3 was determined directly with solution by HPLC without purification or separation by flash column chromatography.
TABLE 3. The pronounced solvent effects in catalyst 4a-catalyzed retro-aza-Michael reaction of 3 Solvent-free
1 2 3 4 5 6
4a 4a 4a 4a 4a 4a
0 12 24 48 72 96
>99 >99 >99 >99 >99 >99
49 49 47 50 48 43
90 77 86 90 91 89
49 46 44 40 39 36
The reaction condition as Table 1 described. The reaction was carried out in MeOH (0.25 M) and under solvent-free conditions, respectively. b NMR yields. c The enantiomeric excess was determined by HPLC using chiral AD-H column.
free conditions, and then different solvents was added to the reaction mixtures of 3 with catalyst, the enantiomer excesses of resulting solution was monitored directly by HPLC after suitable time. As shown in Table 2, the resulted enantioselectivities of various Cinchona alkaloid-derived organocatalysts are different according to solvent effect50 and the concentration of the chiral organocatalysts. The loss in enantiomeric excess for the aza-Michael reaction shown in Table 2 occurred under very specific conditions that the concentration of organocatalyst was low (Entries 3-9). Under the same conditions (Entries 10-12), toluene and i-propanol resulted in the obvious loss in enantiomeric excess. Unfortunately, no clear trend emerges from these data, as the relative racemization or amplification does not correlate with the concentration of the catalyst. When the concentration of catalyst or aza-Michael adduct is enough high, there are no racemization but with maintenance of enantioselectivity even with longer time (Entries 13-19). Similarly, the loss of enantioselectivity of 3 was slightly in the presence of catalyst 4a. As shown in Table 3, the solvent effect in cinchonine (4a)-catalyzed retro-aza-Michael reaction is pronounced that the enantioselectivity is decreasing in MeOH when the reaction time is longer. CONCLUSIONS
In summary, we prepared a series of Cinchona alkaloidderived organocatalysts with different functional groups for the aza-Michael of aniline and chalcone and demonstrated the mechanism of this reaction based on a detailed experimental investigation and 29Si NMR analysis. In addition, there was an interesting finding that a complete reversal of stereoselectivity when a benzoyl group was introduced to the cinchonine and cinchonidine. It was found that the chirality amplification vs. time proceeds in the quinine-derived organocatalyst containing silicon-based bulky group, QN-TBS, -catalyzed aza-Michael reaction under solvent-free conditions. All these results suggested that the enantioselectivity could be fine-tuned by the introduction of different group due to the changing of different populations of transition states. To this end, we have demonstrated for the first time that racemization was occurred in suitable solvents under mild conditions due to retro-aza-Michael reaction of the Michael adduct of aniline with chalcone. These indicate the equilibrium of retroaza-Michael reaction and aza-Michael reaction produce the Chirality DOI 10.1002/chir
CAI ET AL.
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Chirality DOI 10.1002/chir