Atroposelective Organocatalytic Asymmetric Allylic Alkylation Reaction

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Atroposelective Organocatalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita–Baylis–Hillman Carbonates Shou-Lei Li, Chen Yang, Quan Wu, Hanliang Zheng, Xin Li, and Jin-Pei Cheng J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06014 • Publication Date (Web): 18 Sep 2018 Downloaded from http://pubs.acs.org on September 18, 2018

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Journal of the American Chemical Society

Atroposelective Catalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita–Baylis–Hillman Carbonates Shou‐Lei Li, Chen Yang, Quan Wu, Han‐Liang Zheng, Xin Li,* and Jin‐Pei Cheng State Key Laboratory of Elemento‐Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071(P. R. China).

ABSTRACT: A highly efficient method to access axially chiral anilides through asymmetric allylic alkylation reaction with achiral Morita–Baylis–Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl and benzyl, were generated with very good yields, moderate to excellent cis:trans ratios and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.

INTRODUCTION Axially chiral biaryl compounds, usually bearing C‐C chiral axes, are a kind of privileged scaffold widespread existing in natural products and biologically active molecules.1 Because of their extensive applications,1a,2 much attention has been focused on enantioselective synthesis of axially chiral biaryl backbones. As a result, numerous practical routes have been established, such as aryl–aryl coupling,3 chirality transfer,4 kinetic resolution,5 desymmetrization,5j,6 cycloaddition7 and so on.8 On the other hand, the non‐biaryl C‐N axially chiral compounds are promising organic molecules, which structures are frequently found in drugs, natural products and asymmetric synthesis (Figure 1a).9 Among them, axially chiral anilides have flourished gradually in recent years. However, in a sharp contrast with the well‐developed chiral biaryl skeletons, the enantioselective construction of axially chiral anilides is less explored (Figure 1b). Axially chiral anilides not only exist in bioactive compounds,9b,9c,9d,9e,10 but also can be applied to peptoid chemistry (Figure 1a).11 In addition, they can be used as chiral organocatalysts (Figure 1a).12 For example, catalyst A has been successfully applied in asymmetric fluorination.12a And catalyst B could efficiently promote asymmetric Friedel–Crafts amination and enantioselective Michael addition.12a,12b Furthermore, the synthetic utility of chiral anilides has been fully demonstrated and they can be employed as synthon for the reactions of chirality transfer (radical cyclization,13 Heck cyclization,14 photocyclization15), cycloaddition16 and radical coupling.17 Encouraged by the continually growing demand for axially chiral anilides, considerable efforts have been devoted to the development of effective methods for the synthesis of chiral anilide backbones. In 2002, Taguchi and Curran independently reported the first catalytic asymmetric methods for atropisomeric anilides by means of Pd‐catalyzed allylation strategy.18 Despite the excellent reactivities, the enantioselectivities were rather low. Nevertheless, the catalytic enantioselective methods for the synthesis of axially chiral anilides remain rare so far.12,18,19 And only very limited routes of effective formation of anilide atropisomers were accomplished.12b,19c,19d,19e However, the generality of the substrates in these reports is relatively narrow. More nucleophilic anilines, such as alkyl and styryl substituted substrates at acyl moiety, are frequently used. Especially, atropisomeric anilide product with the electron‐withdrawing

Figure 1. (a) The applications of chiral anilides and other kinds of C‐N axially chiral compounds; (b) Current status for the synthesis of chiral biaryls and chiral anilides; (c) Our strategy for chiral anilides.

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ester substituent (Figure 1c, R = COOMe) could not be accessed using previous methodology.19e Therefore, the exploration of more general strategies for axially chiral anilides, suitable for various types of substituents, is highly desirable.

results. 19c,19d However, the substituted benzamide type substrates’ outcomes were less satisfactory and only few examples were tested. When ortho‐methyl substituted benzoyl aniline substrate 1b was

Asymmetric allylic alkylation (AAA) reaction with Morita– Baylis–Hillman (MBH) carbonates or acetates, usually catalyzed by Lewis base, has been developed as an effective way to stereoselective synthesis.20 However, all the reported examples are restricted to the formation of centrally chiral compounds. The reason for this situation is that racemic MBH adducts were the most frequently used allylation reagent. In sharp contrast, the use of achiral MBH adducts was less developed.20d It should be noted that if we use AAA reaction to construct a chiral axis, MBH products don’t need to have a stereogenic center, which will increase the scope of MBH products that can be used. We speculated that the privileged axially chiral anilide skeletons could be generated via AAA reaction between ortho‐substituted anilide and achiral MBH carbonates (Figure 1c). The main challenge of this atroposelective catalysis strategy is that the rotation barriers of C‐N axis of the aniline is usually very small, thus the selection of the positions and steric hindrance of substituted groups on aniline aromatic rings is particularly important for the stereoselective induction and the preservation of enantiopurity. Herein, we report a highly efficient and general method for the atroposelective synthesis of axially chiral anilides by a biscinchona alkaloid21 type Lewis base catalyzed AAA reaction.

Scheme 1. The initial research with 1a and 2a

Table 1. Condition optimizationa

entry

cat.

solvent

time

yield (%)b

cis/ transc

ee(%)d

1

3a

CH3CN

18 h

92

10:1

87 (87)

2

3b

CH3CN

20 h

94

10:1

-86 (-86)

3

3c

CH3CN

10 h

92

9:1

72 (72)

4

3d

CH3CN

10 h

94

10:1

-68 (-68)

5

3e

CH3CN

5h

96

10:1

70 (71)

6

3f

CH3CN

3h

95

9:1

-60 (-60)

7

3a

toluene

3d

trace

-

-

8

3a

DCM

2d

90

10:1

60 (60)

9

3a

THF

3d

NRg

-

-

10

3a

DMSO

4h

82

9:1

87 (87)

11e

3a

CH3CN

7d

93

10:1

95 (95)

12e

3a

CH3CN/DMSO = 9/1

4d

92

10:1

94 (94)

13e,f

3a

CH3CN/DMSO = 9/1

4d

92

10:1

94 (95)

RESULTS AND DISCUSSION Optimization of the Reaction Conditions. We initiated our research by conducting the reaction of 2‐tert‐butylanilide 1a with MBH carbonate 2a in CH3CN at 25 oC in the presence of 10 mol% of (DHQ)2PYR (3a). To our delight, the desired allylation product 4a was obtained with 92% yield and 87% ee (Scheme 1). It should be noted that the amide cis‐trans isomerism was observed by 1H NMR with a cis:trans ratio of 10:1.22 However, despite our best efforts, the amide isomers could not be separated on either column chromatography or HPLC. To verify the reliability of the enantioselectivity, an experiment of derivatization was carried out. As a result, 4a can easily react with CH2N2, generating the cycloaddition product within 5 min, in which the amide isomers of 5 can be isolated by column chromatography.23 Then the enantioselectivity of cis‐isomer 5a was measured as 87%, demonstrating that the enantioselectivity of the allylation product 4a was believable.24 Then five other biscinchona alkaloid catalysts 3b‐f were assessed (Table 1, entries 2‐6), showing that the initial used catalyst 3a was the optimal one. After that, we moved on to investigate the effect of solvents (Table 1, entries 1 and 7‐10) and found that the solvent had a great influence on the reactivity and enantioselectivity, in which CH3CN gave the best yield and ee value (Table 1, entry 1). When the temperature was decreased to ‐ 10 oC, a higher enantioselectivity of 95% was obtained albeit with a longer reaction time (Table 1, entry 11). In order to improve the efficiency of the reaction, the mixture solvent of CH3CN and DMSO was applied. As expected, the reaction time was shortened to 96 hours with the retaining yield and stereoselectivity (Table 1, entry 12). Moreover, reducing catalyst loading to 5 mol% had no negative effect on the reaction outcome (Table 1, entry 13). Reaction Scope. With the optimal conditions in hand, a variety of substituted anilides and MBH carbonates were examined (Table 2).25 We first investigated the substitutents at acyl moiety. In previous works, more nucleophilic anilines such as alkyl and styryl substituted acyl substrates usually gave the good

a

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), 3 (10 mol%), in 1 mL solvent at 25 oC. All reactions were conducted for one time. b Isolated yields. c Determined by 1H NMR analysis. d Determined by HPLC analysis. The number in parenthesis was the ee value of 5a. e The reaction was conducted at ‐10 oC. f The reaction was conducted with 5 mol% of catalyst. g NR = no reaction.


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Table 2. Substrate scopea

a

Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), 3a (5 mol%), in 1 mL mixture solvent at ‐10 oC. All reactions were conducted for one time. Isolated yields. The cis:trans ratio was determined by 1H NMR. The ee value was determined by HPLC analysis. The number in parenthesis was the ee value of the cis‐amide 5.



used in this reaction, good yield and enantioselectivity was obtained for corresponding product 4b companied with low cis:trans ratio of 1.2:1. When meta‐ and para‐substituted benzoyl anilides were employed, regardless of the electronic properties of substituents on the aromatic ring, the corresponding products 4c‐ 4n were obtained in good yields (58‐95%) with excellent stereoselectivities (up to 18:1 cis:trans ratio and 92‐98% ee). Furthermore, the naphthyl substituted anilide 1o, which has not been used as substrate in the strategies for the construction of axially chiral aniline before, was also carried out with good result (4o, 82% yield, cis:trans = 10:1, 90% ee). Next, other acyl anilines with different types of substituents at the acyl moiety were examined. To our delight, the substrate containing alkenyl group (1p) was well tolerated in this AAA strategy. More importantly, the ester group substituted anilide with a weaker nucleophilicity also worked in this AAA strategy, delivering the product 4q in high yield with very good stereoselectivity. Then, our attention was focused on the substrates bearing different substituents on the aromatic ring of anilides. From the results of 4r‐4w, we found that the steric hindrance of ortho‐ groups had an obvious effect on enantioselectivity. The substrates with bulky groups, such as tBu and I, usually afforded higher enantioselectivities (4r‐4t). When the smaller Br atom was used, the relatively low ee values were obtained (4u‐4w). Further comparison of the results of 4a, 4r and 4s, 4t, revealed that the steric hindrance of para‐groups also had a slight influence on the outcomes, in which the attachment of large group to para‐ position of aromatic ring was detrimental to stereoselectivity. Finally, the achiral MBH carbonates were evaluated. As a result, all the examined MBH carbonates can deliver the products 4x‐4aa with very good yields and stereoselectivities. The absolute configuration was determined by X‐ray diffraction analysis of 4n and 5d, and those of the other products were assigned by analogy.26 On the other hand, there were also some cases, in which only a single cis‐isomer was obtained (Table 3). The corresponding Table 3. Additional substratesa

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products 4ab‐4aj were generated with excellent cis:trans ratio (>99:1) and good enantioselectivities (81‐91% ee). The thienyl substituted anilide was first examined in our reaction, delivering the desired product with very good result (4ab). It should be noted that the ethyl substituted product was gained with only 40% yield in spite of the good enantioselectivity (4ad). The reason for the bad yield was maybe due to the fact that the acidity of N‐H bond of ethyl substituted substrate was lower than the others, which leaded to a weak reactivity. As for styryl and benzyl substituted acyl anilides, substrates with the electron‐donating groups on aromatic ring seemed to be more favorable, which gave better ee values (4ae‐4aj). Racemization Experiment. In order to investigate the stereochemical stability of these axially chiral aniline compounds, we carried out the racemization experiment in isopropanol at 80 o C. From the result in Scheme 2, we found that not only the steric hindrance, but also the electronic property and the position of substituent had an effect on stereochemical stability. Comparison of the rotation barriers of 4a (27.3 kcal/mol), 4g (27.0 kcal/mol) and 4i (27.5 kcal/mol), indicated that the product with electron‐ withdrawing group on aromatic ring of benzoyl was stable than the product with electron‐donating group. The 1.3 kcal/mol energy gap between 4e and 4i showed that the 3‐position substituted chiral anilide had a better stability than 4‐position substituted chiral anilide. The reason for this phenomenon is maybe due to the fact that the 3‐position substituted phenyl possessed a bigger steric hindrance, leading to a stronger interaction with tert‐butyl group. The importance of steric hindrance on stereochemical stability was also demonstrated by the examples of 4s and 4v, in which the racemization of the iodide substituted product 4s was acquired with higher energy and longer half‐life than the bromine substituted product 4v. Although the stability of this kind of chiral backbone seemed to be weak in isopropanol at 80 oC, they were stable at 25 oC in a solid form. For example, only three percent of ee value of 4e was decreased after three months.

a

Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), 3a (5 mol%), in 1 mL mixture solvent at ‐10 oC. All reactions were conducted for one time. Isolated yields. The cis:trans ratio was determined by 1H NMR. The ee value was determined by HPLC analysis. b The reaction was conducted at 5 oC.


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frequently found in natural products and bioactive molecules,28 by chirality transfer under reductive Heck condition. As a result, 7 was obtained with 70% yield and 91% ee. The chiral transfer rate is 97%. Furthermore, we also tested the applications of 5s. Firstly, 5s can be converted into α‐amino acid derivative 8. Secondly, it can be used as chiral hypervalent iodine catalyst in asymmetric reaction.22

In addition, we also tested the effects of solvents on stereochemical stability. When 4a and 4e were treated in toluene and dioxane at 80 oC, lower rotation barriers and shorter half‐ times were given (Scheme 2, footnotes b and c). At last, we also calculated the rotation barrier of 4a, which was consistent with the experimental value.27 Scheme 2. The rotation barriers and half‐times of chiral anilidesa

The linear free energy relationship (LFER) analysis. During the discussion of the substrate scope, we found that the steric hindrance of 2‐substituted groups on aromatic ring of anilides had an impact on the enantioselectivity. To investigate the effect of steric factor on the stereoselectivity, we synthesized anilides with different 2‐substituents on aromatic rings and conducted the free energy relationship analysis29 (Table 4). We first try to relate the enantioselectivities with the extensively used Charton values.30 Unfortunately, there was no correlation when all the ten compounds are taken into account (Figure 2a).31 Further examination of the data, we found that the enantioselectivities and Charton values of four halogen substituted substrates have a good correlation (R2 = 0.99). On the other hand, except for the isobutyl substituted substrate, the enantioselectivities and Charton values of the other five alkyl substituted substrates can also be correlated (R2 = 0.98). It seems that: i) the effect of steric hindrance of substituent group on stereoselectivity may exist in current studied system, but Charton values are unsuitable for the steric analysis; ii) the single steric effect does not accurately describe the influence of substrate properties on stereocontrol, there may exist some other factors, such as electronic effect.

a Measured at 80 oC in isopropanol. b Toluene (80 oC): ΔG≠ =

26.3 kcal/mol, t1/2 = 0.23 h; dioxane (80 oC): ΔG = 26.4 kcal/mol, t1/2 = 0.32 h. c All measurements of ≠ 4e were conducted for two times. Toluene (80 oC): ΔG = 27.3 kcal/mol, t1/2 = 0.98 h; dioxane (80 oC): ΔG≠ = 27.6 kcal/mol, t1/2 = 1.57 h. Averaged over two runs. ≠

Scheme 3. The gram‐scale reactions and transformations

Table 4. Examination of steric effect on enantioselectivitya

entry 1g 2

3

4 5 6 7

Large‐scale Reaction and Transformation. To evaluate the practicality of the developed strategy, a range of gram‐scale experiments and transformations were conducted. Firstly, the gram‐scale reaction of 1a with 2b was operated (Scheme 3a), delivering 4x with maintained stereoselectivity (94% yield, cis:trans=10:1 and 91% ee). When 4x was treated with CH2N2, a large scale cis‐product 5x was produced, which could be easily reducted to alcohol 6 with excellent enantioselectivity (94% ee). Then, another gram‐scale reaction of 1s with 2a was carried out (Scheme 3b). As expected, the axially chiral anilide 4s was acquired successfully. In addition, the studied axially chiral anilide could be converted into chiral indoline building block with a quaternary stereogenic center, which structure had been

8

R 1s: R1 = I, R2 = CH3 1u: R1 = Br, R2 = H 1ag: R1 = Cl, R2 = H 1ah: R1 = F, R2 = H 1ai: R1= tBu, R2 = H 1aj: R1 = iPr, R2 = H 1ak: R1 = nPr, R2 = H 1al: R1 = Et, R2 = H 1am: R1 = Bu,

yield

cis:

(%)b

transc

4s: 79

ΔΔG≠(er)

erd

Charton valuee

(kcal/mol)f

10:1

90.3:9.7

0.73

1.32

4u: 83

12:1

87.8:12.2

0.65

1.17

4ak: 87

13:1

79.1:20.9

0.55

0.79

4al: 86

33:1

50.7:49.3

0.27

0.02

4am: 34

10:1

88.2:11.8

1.24

1.19

4an: 67

13:1

65.3:34.7

0.76

0.37

4ao: 68

20:1

55.9:44.1

0.68

0.14

4ap: 75

21:1

54.1:45.9

0.56

0.10

4aq: 64

13:1

61.1:38.9

0.98

0.27

4ar: 79

20:1

73.3:26.7

0.87

0.60

i

9

R2 = H 1an: R1 = C6H11, c

10

R2 = H

Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), 3a (5 mol%), in 1 mL solvent at 25 C. All reactions were conducted for two times. b Isolated yields, averaged over two runs. Determined by 1H NMR analysis, averaged over two runs. d Determined by HPLC analysis, averaged over two runs. e Reference 29. fΔΔG≠ = RTln(er), R = 0.001986 kcal K1 mol-1, T = 298.15 K. g We have tried the substrate with R1 = I, R2 = H. But the enantiomer cannot be separated by HPLC. According to the results of 4u-4w in Table 2, the introduction of 4-position methyl had almost no effect on enantioselectivity. Therefore, the result of product 4s was selected for the examination. a o c



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the positions of substituents for the preservation of enantiopurity. The practicality and synthetic application of the process were demonstrated by the large‐scale experiments and transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.

ASSOCIATED CONTENT Supporting Information. Experimental procedures and characterization data for all reactions and products, including 1H, 13C and 19F NMR spectra, IR spectra, HPLC spectra and X-ray crystallographic data for 4n and 5d, Cartesian coordinates of all the optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author E‐mail: [email protected].

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT

Figure 2. Correlation of normalized substrate parameters to enantioselectivity. Pioneered by Sigman, LFER analysis introducing IR vibrations, NBO charges and other structural properties, which can unite steric and electronic effects, has been considered as an efficient physical organic experimental tool that allowed accurate quantitative understanding of how structural changes affect reaction outcomes.32 We then tried to develop a new model to elucidate stereoselectivity trends by introducing other molecule’s structural features. The regression analysis was made with nine data ((Table 4, entries 1‐9, 1s‐1am). After a stepwise regression analysis, Eq. (1) was obtained, in which Sterimol parameter B1 and chemical shift value δNH were included.33 The good correlation between the predicted and experimental stereoselectivities indicates that this model is predictive and satisfactory (Figure 2b, slope = 0.96, intercept = 0.02, R2 = 0.96), which was corroborated by the analysis of additional data (Table 4, entry 10).34 As illustrated by the coefficient in the regression model, increasing the Sterimol B1 of the R1 group of anilides results in higher enantioselectivity. Furthermore, the combination of steric and electronic effects is described by the δNH value. A possible transition state was proposed in which the bulky group on the ortho‐position of aniline aromatic ring is crucial to induce enantioselectivity.35 ΔΔG≠ = 0.49*B1 + 0.42*δNH + 0.59 Eq. (1) CONCLUSION In summary, we have developed a general and highly efficient reaction for atroposelective construction of axially chiral anilides via AAA strategy of achiral MBH carbonates. The substrate scope was substantial, and the corresponding chiral anilide products containing various substituents were afforded with very good yields (up to 98%) and stereoselectivities (up to >99:1 cis:trans ratio and up to 98% ee). The experiments of racemization exhibited the importance of steric hindrance, electronic effect and

This work is dedicated to Professor K. N. Houk. We are grateful to the NNSFC (Grant No. 21390400) for financial support. We also thank Mrs Zhi‐Yan Li in ICCAS for HRMS analysis.

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(32) For pioneered work, see: (a) Milo, A.; Bess, E. N.; Sigman, M. S. Nature. 2014, 507, 210. For selected examples, see: (b) Crawford, J. M.; Stone, E. A.; Metrano, A.; Miller, S. J.; Sigman, M. S. J. Am. Chem. Soc. 2018, 140, 868. (c) Orlandi, M.; Hilton, M. J.; Yamamoto, E.; Toste, F. D.; Sigman, M. S. J. Am. Chem. Soc. 2017, 139, 12688. (d) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 7290. (33) Sterimol parameters were calculated data. Chemical shifts of NH of substrates were experimental data. For details, see Supporting Information. (34) The tenth data (1an) was used to validate the obtained equation. The predicted enantioselectivity (0.52 kcal/mol) with the equation is close to the experimental enantioselectivity (0.60 kcal/mol), indicating the obtained equation is reliable. (35) DFT calculations were conducted to support the proposed transition state. For details, please see the Supporting Information.


Atroposelective Organocatalytic Asymmetric Allylic Alkylation Reaction

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