University of Groningen
Copper-catalyzed enantioselective conjugate addition of Grignard reagent to non-activated acceptors
Yan, Xingchen
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Publication date: 2019
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Yan, X. (2019). Copper-catalyzed enantioselective conjugate addition of Grignard reagent to non-activated acceptors. University of Groningen.
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Chapter 5: Lewis acid enabled copper-catalyzed
enantioselective conjugate addition of Grignard reagent to
quinoline
This chapter introduces our strategy to activate quinoline based substrates to allow the first enantioselective 1,4-additions with Grignard reagent. Activated by Lewis acid and controlled by chiral copper catalyst, addition of EtMgBr to quinoline was successful, generating 1,4-addition product with a moderate regioselectivity and an excellent enantioselectivity. Low stability of the addition product was tackled by its in situ trapping with acyl chloride to form a stable chiral 1,4-dihydroqinoline derivatives.
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5.1 Introduction
Optically active hydroquinolines are important structural constructs found in a myriad of natural products and biologically active molecules1-18 and therefore their synthesis is of great interest for the pharmaceutical industry in the context of drug discovery. Some selected bioactive and natural hydroquinolines are shown in Figure 1.
Figure 1: selected examples of bioactive and natural products containing a chiral hydroquinoline core.
As a result, various procedures for the synthesis of chiral hydroquinolines have been described, such as aza-Diels–Alder,19 Michael-Aldol reactions,20,21 rearrangement of indolines,22 intramolecular ring opening of epoxides,23 radical addition,24 ring-closing metathesis,25 intramolecular cyclization,26-28 cycloaddition29-31 or asymmetric hydrogenation of substituted quinolones to name a few.32-36
Scheme 1: enantioselective 1,2-addition of organolithium reagents to quinoline with ligand L1-L5.
Among these methods, nucleophilic addition to quinolines is one of the most straightforward enantioselective approaches to synthesize chiral hydroquinolines. However, due to the low reactivity of quinolines, direct nucleophilic addition often poses problems. The first example of asymmetric direct addition to quinoline derivatives was reported by Alexakis et. al. using highly reactive organolithium reagents as the nucleophiles, obtaining 1,2-adducts 2 (Scheme 1).37,38 Because of the difficulty to control the enantioselectivity of the addition reaction 20−100 mol% of chiral catalyst L1-L5 was used with the highest ee achieved only 79%.
Activation of quinolines by N-acylation, followed by nucleophilic attack is the most common strategy to address its low reactivity in addition reactions. Shibasaki et. al.
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reported asymmetric 1,2-addition of TMSCN to a variety of acylated quinolinium salts utilizing the Lewis acid-Lewis base bifunctional catalyst L6-AlCl, and the Reissert products were obtained with yields of up to 99% and ees up to 96% (Scheme 2).39,40
Scheme 2: enantioselective Reissert reaction with Lewis acid-Lewis base bifunctional catalyst L6-AlCl.
Scheme 3: Cu-catalyzed asymmetric 1,2-addition of terminal alkynes to quinolinium salts with ligand L7.
Scheme 4: Cu-catalyzed asymmetric 1,2-addition of terminal alkynes to quinolinium salts with ligand L8.
Arndtsen et. al. reported Cu-catalyzed asymmetric 1,2-addition of terminal alkynes to quinolinium salts using chiral catalyst L7. A variety of enantioenriched 1,2-dihydroquinolines 6 were obtained with yields of up to 92% and ees up to 84% (Scheme 3).41 Later, a significant improvement was made for the same reaction by Aponick et. al. using a newly developed imidazole-based chiral biaryl P,N ligand L8 (Scheme 4). The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and achieves ees of over 90% .42
Scheme 5: rhodium-catalyzed asymmetric dearomative arylation or alkenylation of quinolinium salts with
ligand L9.
In 2016, Wang and Wei et. al. reported the rhodium-catalyzed asymmetric 1,2-addition of aryl or vinyl boronic acids to quinolinium salts with ligand L9 (Scheme 5).43 This reaction
152
provides an effective and practical approach to the synthesis of dihydroquinolines in up to 99% ee and for a wide range of substrates as well as boronic acids.
Organocatalysts are also reported to be efficient in enantioselective 1,2-additions to quinolinium salts. Takemoto et. al. reported a similar reaction using vinyl boronic acids as the nucleophiles with a newly designed thiourea catalyst L10 (Scheme 6).44 This catalyst can facilitate stereocontrol in the Petasis transformation of quinolines as a result of the catalytic generation of a chiral complex as well as the dual activation of the electrophile quinolinium salts and the nucleophile boronic acids.
Scheme 6: enantioselective 1,2-addition of vinyl boronic acids to quinolinium salts with thiourea catalyst L10.
Scheme 7: enantioselective 1,2-addition of TBS enolates to quinolinium salts with anion-binding catalyst L11.
Scheme 8: asymmetric 1,2-addition of phosphorus nucleophiles to quinolinium salts with anion-binding
catalyst L11.
Mancheño et. al. designed a structurally unique chiral oligotriazole as C−H bond-based anion-binding catalyst L11 (Scheme 7). This rotationally flexible catalyst adopts a reinforced chiral helical conformation upon binding to a chloride anion, allowing high levels of chirality transfer via a close chiral anion-pair complex with a preformed ionic substrate. This catalyst was successfully applied in 1,2-addition of TBS enolates to a variety
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of quinolinium salts, providing the desired products with excellent yields and ees.45 Later, this catalyst was also applied to 1,2-addition of phosphorus nucleophiles to a variety of quinolinium salts (Scheme 8).46 The corresponding products were obtained in complete or high regioselectivities and with up to 94% ee, allowing for rapid access to substituted chiral cyclic α-amino phosphonates.
Although there are several reports on catalytic asymmetric 1,2-addition to quinolines or quinolinium salts, examples of enantioselective 1,4-addition are still missing. This is attributed to not only the difficulty to control the regioselectivity but also the difficulty to control the enantioselectivity. In the case of organometallic reagents such as organolithiums and Grignard reagents, these additions are known to occur predominantly at the 2-position to form 2-substituted 1,2-dihydroquinolines. In 1999, Mani et. al. reported that the reaction between some bulky silyl Lewis acids and quinolines can generate quinolinium salts that can shield the 2-position. Therefore, the attack of Grignard reagents can be forced to occur preferentially at the 4-position.47 The same authors also found that when TMSOTf was used, the ratio of 1,2-adducts:1,4-adducts was 2.6:1. In contrast, when TMSOTf was replaced by the very bulky Ph3SiOTf, the 1,4-adducts were predominant with a ratio of 1,2-adducts:1,4-adducts of 1:1.7. Another problem found in this reaction was the instability of the 1,4- and 1,2-addition products 16 and 17 respectively (Scheme 9). Products 16 and 17 undergo an intermolecular redox reaction to give 18 and 19 as the two main products. To solve this problem, methylchloroformate was used to stabilize the intermediate by protecting the nitrogen atom after addition.37,38
Scheme 9: nucleophilic addition of EtMgBr to quinolines activated by silyl Lewis acids.
Following the recent developments in our group in the field of Lewis acid enabled nucleophilic additions to various electrophiles we decided to tackle the issue of controling the 1,4-regioselectivity in the addition reactions to quinolines, if possible preferentially in an enantioselective fashion.
5.2 Results and discussions
Aiming at the development of catalytic enantioselective 1,4-addition to quinolines we first explored the reactivity of quinoline 1 towards addition of EtMgBr in DCM at −78 °C, followed by addition of acetyl chloride to trap the intermediates 16a and 17a and to obtain stable products 20 and 21. We found that in absence of the chiral catalyst and Lewis acid, the ratio of 1:20:21 was 37:53:10 (Table 1, entry 1). Although there is some reactivity towards 1,4-addition, the main product of the reaction was the 1,2-addition product 20. When TMSOTf was used, the ratio of 1:20:21 became 1:93:6. The conversion is higher, but 1,2-addition is still the main product (Table 1, entry 2).
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Table 1: effect of the different ligands on the Cu-catalyzed 1,4-addition of EtMgBr to 1a
Entry L/Cu(I) LA 1:20:21b ee (20) [%]c ee (21) [%]c
1 − − 37:53:10 − −
2 − TMSOTf 1:93:6 − −
3 L12/Cu(I) − 97:2:1 − − 4 L12/Cu(I) TMSOTf 49:27:24 7 77 5 L13/Cu(I) TMSOTf 0:87:13 Rac Rac 6 L14/Cu(I) TMSOTf 0:81:19 Rac Rac 7 L15/Cu(I) TMSOTf 0:88:12 7 45
aReaction conditions: 0.1 M of 1 in DCM, CuBr·SMe2 (5 mol%), L (6 mol%), LA (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess was determined by HPLC on a chiral stationary phase. Absolute
configuration was not determined.
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Figure 3: 1H-13C-HMBC spectrum of product 20. Correlations of Hb with Ca, Cc and Cd are highlighted.
156
Figure 5: 1H-13C-HMBC spectrum of product 21. Correlations of Hb with Ca, Cc, Cd and Ce are highlighted.
The structure of the two products was verified by NMR, using the 1H-13C-HSQC and 1H-13 C-HMBC methods. As shown in Figures 2 and 3, the proton at the b position (Hb) in product
20 only correlates with the carbon atoms at the a, c and d positions (Ca, Cc and Cd); no
correlation of Hb with any aromatic carbon was observed, proving that product 20 is the 1,2-addition product. In contrast, Hb correlates not only with Ca, Cc and Cd in case of product 21, but also with the aromatic Ce, proving that product 21 is the 1,4-addition product (Figures 4 and 5).
Having established the structure of the two products we proceeded to study the effect of a chiral copper catalyst on the reaction outcome. We first tested the chiral catalyst L12/Cu(I) and performed the reaction in the same conditions as the blank reaction above. Surprisingly, almost no conversion to either product 20 or 21 was observed (Table 1, entry 3). At this point we introduced LA to explore the activation of quinoline towards additions. When TMSOTf was used in combination with the chiral copper catalyst, an immense acceleration of the addition reaction was observed, providing products 20 and 21 in a ratio of almost 1:1 (Table 1, entry 4). Importantly, apart from giving a higher fraction of the 1,4-addition product, the catalytic pathway also resulted in the asymmetric 1,4-1,4-addition product 21 to be obtained with 77% enantioselectivity. In contrast, the 1,2-addition product 20 was obtained with only 7% ee, indicating that 1,4-addition is mainly due to the catalytic reaction, while 1,2-addition is mainly produced by the non-catalyzed blank reaction. This result suggested that by optimizing the catalyst and/or reaction conditions to accelerate the catalytic 1,4-addition pathway, both the enantioselectivity and the regioselectivity could be improved.
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Bearing this in mind, we started to optimize the reaction, first exloring the reactivity of various chiral ligands, L13−L15, in the presence of TMSOTf (Table 1, entries 5−7). The reactions with ligands L13 and L14 both afforded mainly 1,2-addition product 20 and both products 20 and 21 were racemic. The reaction with ligand L15 also mainly provided the 1,2-addition product 20, but the 1,4-addition 21 still had a moderate enantioselectivity of 45%. These results clearly indicated ligand L12 to be an outstanding choice for achieving increased 1,4-selectivity and higher enantioselectivity.
Table 2: effect of the different solvents on the Cu-catalyzed asymmetric 1,4-addition of EtMgBr to 1a
Entry Solvent 1:20:21b ee (20) [%]c ee (21) [%]c 1 DCM 49:27:24 7 77 2 THF 0:78:22 Rac Rac 3 2-Me-THF 0:66:34 Rac 34 4 Toluene 17:57:26 Rac 76 5 Et2O 9:60:31 Rac 76 6 MTBE 19:42:39 3 87 7 O(i-Pr)2 89:6:5 − − 8 MTBE:DCM = 3:1 2:76:22 10 90
aReaction conditions: 0.1 M of 1, CuBr·SMe2 (5 mol%), L12 (6 mol%), TMSOTf (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess were determined by HPLC on a chiral stationary phase.
With our best ligand L12, we continued to optimize the system by screening various solvents (Table 2). Changing the solvent from DCM to THF led to very high reactivity, giving 100% conversion and a higher fraction of addition product. However, both the 1,addition product 20 and the 1,4-1,addition product 21 were racemic. The reaction in 2-methyl-tetrahydrofuran also afforded 100% conversion, but the enantioselectivity of 1,4-addition was 34%. The reactions in toluene and Et2O provided higher conversion but a lower fraction of 1,4-addition, and the enantioselectivity of the 1,4-addition was not improved. Finally, we were pleased to find that using MTBE as the solvent resulted in a significant improvement for both the conversion and the ee of the 1,4-addition product 21. We also performed the reaction in the more bulky solvent di-i-propyl ether, but very low conversion was observed. Thus, MTBE was established as the optimal solvent. However, the chiral catalyst L12/Cu(I) has a very low solubility in MTBE, which is a problem for the reaction. In order to increase the solubility of the catalyst, a small amount of DCM was added to the reaction mixture. We found that with a mixture of solvents, namely MTBE:DCM = 3:1, the catalyst is completely solubilised, total conversion of 20 and 21 increases to 98% and the ee of 21 improves to 90%. Unfortunately, the regioselectivity
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towards 1,4-addition decreases dramatically, thus disqualifying the mixed solvent as a better choice.
Table 3: effect of the different Lewis acids on the Cu-catalyzed asymmetric 1,4-addition of EtMgBr to 1a Entry LA T [°C] 1:20:21b ee (21) [%]c 1 TMSOTf −78 19:42:39 87 2 TMSBr −78 97:1:2 − 3 TMSNTf2 −78 100:0:0 − 4 TESOTf −78 32:30:37 33 5 TBSOTf −78 89:0:11 74 6 TBSOTf 0d 70:10:20 53 7 TIPSOTf −78 100:0:0 − 8 TBDPSOTf −78 95:3:2 −
9 BF3·Et2O −78 Complex mixture −
10 SiCl4 −78 100:0:0 − 11 Sc(OTf)3 −78 88:10:2 − 12 TMSOTf −50 23:40:37 79 13 TMSOTfe −78 22:46:32 67 14f TMSOTf −78 33:16:51 90 15g TMSOTf −78 26:38:36 78 16h TMSOTf −78 36:19:45 93 17i TMSOTf −78 94:2:4 −
aReaction conditions: 0.1 M of 1 in MTBE, CuBr·SMe2 (5 mol%), L12 (6 mol%), LA (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess were determined by HPLC on a chiral stationary phase. dIn this case the
reaction was performed at 0 °C for 2 h. eIn this case 3.0 euqiv. of TMSOTf and 3.0 euqiv. of EtMgBr was used. fIn this case EtMgBr was diluted with MTBE to 1.0 mL and added with syringe pump in 1 h. gIn this case the
mixture of substrate and TMSOTf was added to the mixture of catalyst and Grignard. hIn this case EtMgBr was
added first, followed by addition of TMSOTf. iIn this case EtMgBr was added first, then TMSOTf was diluted
with MTBE to 1.0 mL and added with syringe pump in 1 h.
Then we moved on to optimizing the Lewis acid by performing the reaction in MTBE (Table 3). When similar Lewis acids TMSBr and TMSNTf2 were used, almost no conversion towards products 20 and 21 was observed. We also tested several silyl based Lewis acids with OTf− as the counter ion but different steric hindrance. The reaction with TESOTf has similar conversion, but the ee of product 21 is only 33%. Using the more bulky Lewis acid TBSOTf led to the formation of only 1,4-addition product 21, with only 11% conversion and a a slightly decreased ee. Since 1,4-selectivity was the best in TBSOTf, we tried to improve the conversion of this reaction by increasing the temperature to 0 °C. Unfortunately, both the regioselectivity as well as enantioselectivity of the reaction decreased at this high temperature. Further investigations into how the nature of the lewis
159
acids affects the reaction outcome confirmed TMSOTf as the best LA for this catalytic system.
Using TMSOTf, we also varied the reaction conditions or the methods of reagent addition. Increasing the reaction temperature to −50 °C or using 3.0 equiv. of TMSOTf failed to improve the conversion and also the enantioselectivity of the 1,4-addition decreased dramatically, probably due to the faster non-catalyzed reaction. Subsequently, we tried to dilute EtMgBr with MTBE to 1.0 mL and added it by syringe pump in 1 h. Interestingly, a decrease of the conversion was observed, but the regioselectivity towards 1,4-addition was improved dramatically and the enantioselectivity increased to 90%. When performing the reaction by adding the mixture of substrate and TMSOTf to the mixture of catalyst and Grignard, no improvement was obtained. However, when we performed the reaction by first adding EtMgBr followed by TMSOTf, results similar to that obtained with slow addition of EtMgBr were obtained. In order to further improve the reaction outcome, we first added EtMgBr, then diluted TMSOTf with MTBE to 1.0 mL and added it with syringe pump in 1 h. To our surprise, very low conversion was obtained in this case.
Figure 6: ligands used for further screening.
Table 4: further screening of the ligands for Cu-catalyzed asymmetric 1,4-addition of EtMgBr to 1a
Entry L/Cu(I) 1:20:21b ee (21) [%]c
1 L12/Cu(I) 19:42:39 87 2 L13/Cu(I) 5:78:17 46 3 L14/Cu(I) 6:75:19 5
160 4 L15/Cu(I) 9:71:20 Rac 5 L16/Cu(I) 8:79:13 Rac 6 L17/Cu(I) 20:46:34 65 7 L18/Cu(I) 8:81:11 Rac 8 L19/Cu(I) 9:68:13 6 9 L20/Cu(I) 5:71:14 Rac 10 L21/Cu(I) 8:74:18 Rac 11 L22/Cu(I) 11:68:21 Rac 12 L23/Cu(I) 4:85:11 32 13 L24/Cu(I) 6:79:15 Rac 14 L25/Cu(I) 34:46:20 Rac 15 L26/Cu(I) 5:76:19 Rac 16 L27/Cu(I) 8:75:17 21
aReaction conditions: 0.1 M of 1 in MTBE, CuBr·SMe2 (5 mol%), L (6 mol%), TMSOTf (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess was determined by HPLC on a chiral stationary phase.
With the optimised conditions and procedure we continued to screen the chiral ligands shown in Figure 6. To compare with the previous results, we still first added TMSOTf followed by Grignard (Table 4). The reactions with L13, L17, L23 and L27 as chiral ligands afforded the 1,4-addition product 21 with some ee, but lower than that using ligand L12. The 1,4 addition products obtained from the reactions with other ligands were nearly racemic.
Table 5: effect of the different copper salts on the Cu-catalyzed asymmetric 1,4-addition of EtMgBr to 1a Entry [Cu] 1:20:21b ee (21) [%]c 1 CuBr·SMe2 19:42:39 87 2 Cu(CH3CN)4BF4 7:60:23 48 3 (CuOTf)2·Toluene 20:34:46 80 4 CuI 0:84:16 88 5 Cu(OTf)2 5:80:15 33 6 Cu(OAc)2 4:81:15 74 7 Copper(I) thiophenolate 21:76:24 79 8 CuTc 8:51:41 92 9d CuTc 9:46:45 96
aReaction conditions: 0.1 M of 1 in MTBE, [Cu] (5 mol%), L12 (6 mol%), TMSOTf (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess was determined by HPLC on a chiral stationary phase. dIn this case
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Since screening of the ligands failed to improve the results, we looked into the role of the copper source, a factor that was neglected until now (Table 5). The reactions with Cu(CH3CN)4BF4, (CuOTf)2·Toluene, CuI, Cu(OTf)2, Cu(OAc)2 or copper(I) thiophenolate gave either lower regioselectivity towards 1,4-addition or lower enantioselectivity. Surprisingly, using CuTc led to a 8:51:41 ratio of 1:20:21, as well as an excellent enantioselectivity of 92% for the 1,4-addition product. Since catalyst L12/CuTc is also soluble in MTBE, the better performance of the reaction should be attributed to the improved solubility in CuTc. After switching the sequence by adding EtMgBr first, followed by the addition of TMSOTf, the enantioselectivity of th 1,4-addition pathway was further improved to 96%.
Table 6: further screening of other type of Lewis acids for Cu-catalyzed asymmetric 1,4-addition of EtMgBr to 1a
Entry LA [Equiv.] Equiv. of EtMgBr Solvent T [°C] 1:20:21b ee (21) [%]c
1 TMSOTf (2.0) 2.0 MTBE −78 8:51:41 92
2 SnCl4 (2.0) 2.0 MTBE −78 100:0:0 −
3 TiCl4 (2.0) 2.0 MTBE −78 100:0:0 −
4 CeCl3 (2.0) 2.0 MTBE −78 Complex mixture −
5 MgCl2 (2.0) 2.0 MTBE −78 100:0:0 − 6 ZnCl2 (2.0) 2.0 MTBE −78 90:8:2 − 7 Zn(OTf)2 2.0 MTBE −78 100:0:0 − 8 TMSOTf (1.2) 2.0 MTBE −78 13:36:51 96 9 TMSOTf (1.2) 1.2 MTBE −78 27:23:50 94 10 TMSOTf (1.2)d 2.0 MTBE −78 36:18:46 92 11 TMSOTf (1.2)d 1.2 MTBE −78 22:35:43 95 12 TMSOTf (1.2) 2.0e MTBE −78 30:14:56 94 13 AlCl3 (2.0) 2.0 MTBE −78 79:0:21 96 14 AlCl3 (1.0) 2.0 MTBE −78 79:0:21 98 15 AlCl3 (2.0) 2.0e MTBE −78 88:0:12 92 16 AlCl3 (2.0) 2.0 MTBE −50 91:0:9 99 17 AlCl3 (2.0) 2.0 DCM −78 89:0:11 97 18 AlCl3 (2.0) 2.0 Et2O −78 90:0:10 96 19 AlCl3 (2.0) 2.0 Toluene −78 87:0:13 95 20 EtAlCl2 (2.0) 2.0 MTBE −78 88:0:12 95
21 Me2AlCl (2.0) 2.0 MTBE −78 26:62:12 Rac
22 AlMe3 (2.0) 2.0 MTBE −78 25:61:14 Rac
23 AlBr3 2.0 MTBE −78 100:0:0 −
24 TMSOTf (1.0)/AlCl3 (1.0) 2.0 MTBE −78 27:7:66 98
25 TMSOTf (1.0)/AlCl3 (0.5) 2.0 MTBE −78 20:18:62 98
26 TMSOTf (1.5)/AlCl3 (0.5) 2.0 MTBE −78 6:25:69 97
27 TMSOTf (1.5)/AlCl3 (0.5) 2.0e MTBE −78 48:4:48 98
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29 TMSOTf (1.5)/AlCl3 (0.5) 2.0e DCM −78 22:23:55 94
30 TMSOTf (1.5)/AlCl3 (0.5) 2.0e MTBE −50 43:7:50 96 aReaction conditions: 0.1 M of 1 in MTBE, [Cu] (5 mol%), L12 (6 mol%), TMSOTf (2.0 equiv.), EtMgBr (2.0
equiv.) at −78 °C for 16 h, then ClCOMe (5.0 equiv.) at RT for 2 h. bThe ratio was determined by 1H NMR of
reaction crude. cEnantiomeric excess were determined by HPLC on a chiral stationary phase. dIn this case
EtMgBr was added first, followed by addition of TMSOTf. eIn this case EtMgBr was diluted with MTBE to 1.0
mL and added with syringe pump in 1 h.
With the best copper source established for this reaction in terms of both the 1,4-regioselectivity as well as the enantioselectivity of the 1,4-addition product, we decided to revisit the Lewis acid optimisation studies and to carry out further experiments with other types of Lewis acids (Table 6). First we tested the Lewis acids SnCl4, TiCl4, CeCl3, MgCl2, ZnCl2 and Zn(OTf)2, only to find that all reactions gave either a complex mixture or very low conversion. Since this indicates that these Lewis acids are not compatible with Grignard reagents, we switched to TMSOTf again and optimized the equivalents of TMSOTf and EtMgBr. Upon using 1.2 euqivalent of TMSOTf, an improvement of the regioselectivity to 43%−51% and enantioselectivity to 92%−96% for the 1,4-addition product 21 was observed, regardless of whether 1.2 or 2.0 equivalents of EtMgBr was used and the sequence of adding TMSOTf and EtMgBr was switched. Interestingly, when we tried the reaction with AlCl3, only 1,4-addition product 21 was obtained with an excellent ee of 96%. However, the conversion was only 21%. Reducing the amount of AlCl3 to 1.0 equivalent gave exactly the same conversion and 98% ee. Slow addition or increasing the reaction temperature to −50 °C also does not increase the conversion. The reaction was also performed in different solvents such as DCM, Et2O and toluene, but again the conversion was not increased. Other aluminum based Lewis acids like EtAlCl2, Me2AlCl, Me3Al and AlBr3 either gave low conversion or racemic product for the 1,4-addition. When we tried the reaction with the Lewis acid mixture of TMSOTf (1.0 equiv.)/AlCl3 (1.0 equiv.), an improvement of 1,4-addition was obtained, giving 66% regioselectivity and 98% enantioselectivity. Changing the ratio of TMSOTf:EtMgBr to 1.0:0.5 or 1.5:0.5 afforded slightly better results with 69% conversion and 97% ee towards 1,4-addition. Further optimization by slow addition of EtMgBr in 1 h with different ratios of TMSOTf:EtMgBr or different solvents or higher temperature all gave similar results.
5.3 Conclusions
We have presented the first enantioselective 1,4-addition of Grignard to quinolines by combining Lewis acids and copper catalysis. Activated by Lewis acid and controlled by a chiral copper catalyst, addition of EtMgBr to quinoline, followed by trapping with acetyl chloride was successful, generating the stable 1,4-addition product with excellent enantioselectivity. Following thorough optimisation studies of various reaction parameters, we established that a combination of chiral Cu catalyst with a mixture of Lewis acids such as TMSOTf (1.5 equiv.)/AlCl3 (0.5 equiv.) provides only moderate regioselectivity of 31:69 for the 1,2/1,4 addition products, indicating the need for further studies of this reaction.
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5.4 Experimental section
5.4.1 General experimental information
All reactions using oxygen- and/or moisture-sensitive materials were carried out with anhydrous solvents (vide infra) under a nitrogen atmosphere using oven-dried glassware and standard Schlenk techniques. Flash column chromatography was performed using Merck 60 Å 230−400 mesh silica gel. Thin layer chromatography was performed using 0.25 mm E. Merck silica plates (60F-254). The products were visualized by UV and KMnO4 staining. NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 100.58 MHz) equipped with a 5 mm z-gradient broadband probe. Chemical shifts are reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm). Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, d: doublet, t: triplet, m: multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI ionization. Enantiomeric excess were determined by chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.
5.4.2 Chemicals
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried P2O5 nitrogen gas. Grignard reagent was purchased from Sigma-Aldrich: EtMgBr (3.0 M in Et2O). The Grignard reagent was titrated by 1H NMR before use. Chiral ligands (L12−L27) were purchased from Sigma Aldrich and Solvias. All compounds were fully characterized by 1H and 13C NMR and HRMS techniques.
5.4.3 Procedure for Cu-catalyzed asymmetric addition of EtMgBr to quinoline
In a flame-dried Schlenk tube equipped with septum and magnetic stirring bar, copper salt (5 mol%, 0.01 mmol) and the chiral ligand (6 mol%, 0.012 mmol) were dissolved in the solvent (2 mL, final concentration of quinoline is 0.1 M) and stirred under nitrogen atmosphere for 20 min. The substrate was added at once. After stirring for 5 min. at RT the reaction mixture was cooled down, followed by addition of LA (2.0 equiv., 0.4 mmol). After 20 min., EtMgBr (2.0 equiv., 0.4 mmol) was added by hand in about 1 min. After stirring for 16 h, acetyl chloride (5.0 equiv., 1.0 mmol) was added and the reaction mixture was warmed up to RT. After stirring for 2 h, the resulting reaction mixture was quenched with saturated NaHCO3 aqueous solution (2.0 mL) and stirred at RT for 1 h to remove the LA bound to quinoline. The mixture was extracted with DCM (10.0 mL × 3). The combined organic phase was dried over MgSO4, filtered and evaporated on rotary evaporator. Products 20 and 21 were obtained as a colorless oil after column chromatography (SiO2, pentane:Et2O = 10:1).
164 1-(2-ethylquinolin-1(2H)-yl)ethan-1-one (20) 1H NMR (CDCl3, 400 MHz): δ 7.21-6.98 (m, 4H, CHAr), 6.43 (d, J = 9.5 Hz, 1H, CHCH=CH), 6.11 (dd, J = 9.6, 5.8 Hz, 1H, CHCH=), 5.38-5.17 (m, 1H, CH=CHCH), 2.18 (s, 3H, COCH3), 1.51-1.37 (m, 1H, CH3CHH), 1.37-1.21 (m, 1H, CH3CHH), 0.83 (t, J = 7.4 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz): δ 170.2, 135.3, 132.4, 128.6, 127.0, 126.3, 125.4, 124.8, 124.3, 51.7, 25.3, 22.8, 9.9. HRMS (ESI, m/Z): calcd. for C13H16NO [M+H]+: 202.1226, found: 202.1225. HPLC: Chiracel-ASH, n-heptane/i-PrOH 95:5, 0.5 mL/min., 40 °C, detection at 235 nm. Retention time (min): 13.5 (major) and 14.7 (minor).
1-(4-ethylquinolin-1(4H)-yl)ethan-1-one (21)
1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 9.3 Hz, 1H, CHAr), 7.27-7.19 (m, 2H, CHAr), 7.19-7.08 (m, 2H, CHAr), 6.89 (d, J = 7.5 Hz, 1H, NCH=), 5.52 (dd, J = 7.5, 5.9 Hz, 1H, NCH=CH), 3.30-3.23 (m, 1H, CH=CHCH), 2.36 (s, 3H, COCH3), 1.69-1.51 (m, 2H, CH3CH2), 0.88 (t, J = 7.4 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz): δ 168.4, 136.8, 133.1, 128.3, 127.0, 126.0, 125.4, 122.9, 116.6, 39.9, 30.3, 24.2, 10.8. HRMS (ESI, m/Z): calcd. for C13H16NO [M+H]+: 202.1226, found: 202.1224. HPLC: Chiracel-ASH, n-heptane/i-PrOH 95:5, 0.5 mL/min., 40 °C, detection at 251 nm. Retention time (min): 11.1 (major) and 12.5 (minor).
5.4.4 Procedure for the synthesis of racemic products
In a flame-dried Schlenk tube equipped with septum and magnetic stirring bar, the substrate was dissolved in the solvent (2 mL, final concentration of quinoline is 0.1 M). The temperature was cooled down to −50 °C and TMSOTf (2.0 equiv., 0.4 mmol) was added. After 20 min., EtMgBr (2.0 equiv., 0.4 mmol) was added by hand in about 1 min. After stirring for 16 h, acetyl chloride (5.0 equiv., 1.0 mmol) was added and the reaction mixture was warmed up to RT. After stirring for 2 h, the resulting reaction mixture was quenched with saturated NaHCO3 aqueous solution (2.0 mL) and stirred at RT for 1 h to remove the TMS bound to quinoline. The mixture was extracted with DCM (10.0 mL × 3). The combined organic phase was dried over MgSO4, filtered and evaporated on rotary evaporator. Products 20 and 21 were obtained as a colorless oil after column chromatography (SiO2, pentane:Et2O = 10:1) [20:21 = 83:17 in the crude product].
165
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