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Cite this: Chem. Commun., 2014, 50, 12054 Received 19th March 2014, Accepted 19th May 2014
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Organocatalytic enantioselective and (Z)-selective allylation of 3-indolylmethanol via hydrogen-bond activation† Yan Liu,‡ab Hong-Hao Zhang,‡a Yu-Chen Zhang,‡a Yan Jiang,b Feng Shi*a and Shu-Jiang Tua
Published on 22 May 2014. Downloaded on 03/10/2014 12:11:55.
DOI: 10.1039/c4cc02056a www.rsc.org/chemcomm
An organocatalytic asymmetric allylation of 3-indolylmethanol has been established via hydrogen-bond activating mode, which directly assembles isatin-derived 3-indolylmethanols and o-hydroxystyrenes into chiral allyl-substituted oxindoles with one all-carbon quaternary stereogenic center and one newly formed CQC bond in excellent enantioselectivity and (Z)-selectivity (up to 97% ee, 420 : 1 Z/E ratio). This transformation provides an efficient strategy for asymmetric C3-functionalization of indoles and allylation of 3-indolylmethanols with precise control of the stereoselectivity in the formation of C–C and CQC bonds.
Indole skeleton represents one of the most fascinating heterocyclic frameworks, frequently found in numerous natural alkaloids, chiral pharmaceuticals and agrochemicals.1 As a result, a great deal of attention from chemists has been paid to the stereoselective functionalization of the indole core as well as the preparation of chiral indoles.2 In the last decade, 3-indolylmethanols have appeared to be active substrates capable of undergoing a variety of enantioselective transformations to access functionalized indoles by formation of either carbocation or vinyliminium intermediates in the presence of a Lewis acid (LA) or Brønsted acid (BH).3,4 However, previous studies on catalytic asymmetric substitutions of 3-indolylmethanols were mainly concentrated on their alkylation with carbonyl compounds (eqn (1)).4a–g In contrast, the catalytic asymmetric allylation of 3-indolylmethanol has met with little success (eqn (2)) despite that this transformation provides the simultaneous formation of C–C and CQC bonds with precise control of their stereochemistry. So far, only Chen and coworkers described a stereoselective substitution of 3-indolylmethanols with a
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, China b Jiangsu Provincial Key laboratory of Fine Petrochemical engineering, Changzhou University, Changzhou, 213164, China. E-mail: [email protected]; Fax: +86 516 83500065; Tel: +86 516 83500065 † Electronic supplementary information (ESI) available: Experimental details, characterization, original NMR and HPLC spectra of all products. CCDC 988256. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc02056a ‡ These authors contributed equally to the work.
12054 | Chem. Commun., 2014, 50, 12054--12057
a,b-unsaturated aldehydes using a,a-diphenylprolinol O-TMS ether as a catalyst, to generate enantioenriched allylation products via dienamine activation of enals (eqn (3)).5 In spite of this creative work, the catalytic asymmetric allylations of 3-indolylmethanols, especially those employing other strategies based on different activation modes, are still under-developed and thus in great demand due to the challenges in stereoselective C–C, CQC bond formation and C3-functionalization of indole motifs.
Chiral phosphoric acids6 (CPA) belong to a type of privileged organocatalysts based on H-bonding activation mode, and we have realized a series of CPA-catalyzed enantioselective multi-component or cascade transformations.7 Illuminated by this success, we envisaged that the vinyliminium intermediate and o-hydroxystyrene8 bearing allylic hydrogens could be simultaneously activated by CPA via hydrogen-bonding interactions to undergo asymmetric vinylogous Michael addition, generating a transient intermediate A, which would principally undergo an allylic hydrogen-elimination, again under the promotion of the same catalyst to achieve enantioselective and (Z/E)-selective allylation of 3-indolylmethanols (Scheme 1).
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Scheme 1 Design of CPA-catalyzed asymmetric allylation of 3-indolylmethanols.
Herein, we report the first catalytic asymmetric allylation of 3-indolylmethanols via hydrogen-bond activating mode, which directly assembles isatin-derived 3-indolylmethanols and o-hydroxystyrenes into chiral allyl-substituted oxindoles with concomitant formation of an all-carbon quaternary stereogenic center and a newly formed CQC bond in excellent enantioselectivities and (Z)-selectivities (up to 97% ee, 420 : 1 Z/E ratio). The initial experiment to testify our hypothesis commenced with a reaction of N-benzyl isatin-derived 3-indolylmethanol 1a Table 1
Screening of catalysts and optimization of conditionsa
and o-hydroxystyrene derivative 2a in 1,2-dichloroethane (DCE) catalyzed by CPA 4a. Although the reaction occurred, the desired allylation product 3aa was isolated in a low yield and moderate enantioselectivity (Table 1, entry 1). The subsequent screening of different BINOL-derived CPAs 4 (entries 1–7) found that catalyst 4e with 1-naphthyl groups at 3,30 -positions of the BINOL backbone was much superior to the others in terms of enantioselectivity (entry 5). In particular, the variation of o-hydroxystyrene derivative 2a to 2b not only led to a much enhanced yield and enantioselectivity, but also incurred a good Z/E selectivity of the newly formed carbon–carbon double bond (entry 8). The evaluation of reaction media (entries 8–11) revealed that the use of ethyl acetate as a solvent could further ameliorate the yield and enantioselectivity (entry 11). The examination of other parameters including temperature and the mole ratio of the reactants (entries 12–14) found that 35 1C and a 1.5 : 1 mole ratio of 1a to 2b were the best conditions for the reaction (entry 14). Finally, changing the BINOL backbone of the catalyst to structurally more rigid H8-BINOL and SPINOL9 backbones resulted in a remarkably increased enantioselectivity and (Z)-selectivity (entries 15 and 16). In particular, H8-BINOL-derived CPA 5a exhibited the highest level of catalytic activity, giving rise to the product 3ab in a high yield of 71%, excellent stereoselectivity of 97% ee and a 420 : 1 Z/E ratio (entry 15). With the optimal reaction conditions in hand, the substrate scope with respect to isatin-derived 3-indolylmethanols 1 was investigated (Table 2). Firstly, N-benzyl, alkyl and aryl isatinderived 3-indolylmethanols were examined. As exemplified by 1a–1c, the reaction proceeded smoothly to deliver chiral products
Table 2
Entry 1 2 3 4 5 6 7 8 9 10 11 12 f 13g 14h 15h 16h
Cat. 4a 4b 4c 4d 4e 4f 4g 4e 4e 4e 4e 4e 4e 4e 5a 6a
3 (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (R)-3ab
Solvent DCE DCE DCE DCE DCE DCE DCE DCE Toluene CH3CN AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt
Yieldb (%) 25 44 9 10 33 31 37 64 57 40 69 67 53 67 71 62
a
Z/Ec e
— —e —e —e —e —e —e 6:1 6:1 7:1 6:1 6:1 7:1 8:1 420 : 1 10 : 1
eed (%) 47 58 44 50 76 70 71 83 81 45 84 84 80 87 97 93
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 4–6 in solvent (1 mL) at 35 1C for 12 h, and the mole ratio of 1a : 2 was 1 : 3. b Isolated yield. c The Z/E ratio was determined by HPLC. d The ee value was determined by HPLC. e No Z/E isomers could be formed for product 3aa. f Performed at 50 1C. g Performed at 15 1C. h The mole ratio of 1a : 2b was 1.5 : 1.
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Substrate scope of isatin-derived 3-indolylmethanols 1a
Entry 3
R/R1/R2 (1)
Yieldb (%) Z/Ec
1 2 3 4e 5e 6e 7e 8 9 10 11 12 13 14 15 16 17 18 19
Bn/H/H (1a) Me/H/H (1b) Ph/H/H (1c) p-BrC6H4CH2/H/H (1d) p-ClC6H4CH2/H/H (1e) m-ClC6H4CH2/H/H (1f) m,p-Cl2C6H3CH2/H/H (1g) Bn/5-F/H (1h) Bn/5-Me/H (1i) Bn/6-Br/H (1j) Bn/7-F/H (1k) Bn/7-Me/H (1l) Bn/H/5 0 -Me (1m) Bn/H/5 0 -Cl (1n) Bn/H/6 0 -Me (1o) Bn/H/6 0 -F (1p) Bn/H/6 0 -Br (1q) Bn/H/7 0 -Me (1r) Bn/H/7 0 -Br (1s)
71 76 62 82 70 64 68 84 59 45 58 71 71 54 60 87 64 53 44
(S)-3ab (S)-3bb (S)-3cb (R)-3db (R)-3eb (R)-3fb (R)-3gb (S)-3hb (S)-3ib (S)-3jb (S)-3kb (S)-3lb (S)-3mb (S)-3nb (S)-3ob (S)-3pb (S)-3qb (S)-3rb (S)-3sb
420 : 1 420 : 1 5:1 8:1 7:1 9:1 8:1 10 : 1 15 : 1 10 : 1 420 : 1 420 : 1 420 : 1 5:1 420 : 1 420 : 1 420 : 1 420 : 1 420 : 1
eed (%) 97 94 94 95 91 92 95 93 94 91 95 93 95 96 93 92 91 86 93
a
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 5a in AcOEt (1 mL) at 35 1C for 12 h, and the mole ratio of 1 : 2b was 1.5 : 1. b Isolated yield. c The Z/E ratio was determined by 1H NMR. d The ee value was determined by HPLC. e Catalyzed by 10 mol% 6a.
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3ab–3cb in excellent enantioselectivities and high (Z)-selectivities (entries 1–3). Among them, N-benzyl isatin-derived 3-indolylmethanol 1a gave the highest stereoselectivity (entry 1), whereas N-phenyl isatin-derived substrate 1c showed a decreased (Z)-selectivity (entry 3). Besides, different N-benzyl isatin-derived 3-indolylmethanols 1d–1g could undergo the reaction (entries 4–7) to furnish the desired products in high yields (64–82%) and excellent stereoselectivities (91–95% ee, 7 : 1 to 9 : 1 Z/E ratio). Then, a series of N-benzyl isatin-derived 3-indolylmethanols 1h–1s with various substituents at different positions of both isatin and indole moieties were utilized in the reaction. The position and the electronic nature of the substituents on the oxindole moiety seemingly had little effect on the stereoselectivity since C5-, C6- or C7-substituted 3-indolylmethanols 1h–1l delivered the target products in uniformly excellent stereoselectivities of 91–95% ee and a 10 : 1 to 420 : 1 Z/E ratio (entries 8–12). Nevertheless, the position of the substituents linked to the indole core exerted some influence on the enantioselectivity. Basically, C50 -substituted 3-indolylmethanols were superior to C60 - and C70 -substituted analogues in terms of enantioselectivity (entries 13 and 14 vs. 15 and 19), while the latter also showed perfect (Z)-selectivities of a 420 : 1 Z/E ratio. As to C70 -substituted 3-indolylmethanols, the electronic nature of the substituents considerably affected the enantioselectivity, because 70 -bromo-substituted 3-indolylmethanol exhibited higher enantioselectivity than 70 -methyl-substituted one (entry 19 vs. 18). Next, the generality of the reaction for o-hydroxystyrene derivatives 2 bearing allylic hydrogens was examined (Table 3). Several o-hydroxystyrenes with different alkyl groups at the allylic position (entries 1–4) or bearing different substituents on their benzene rings (entries 5 and 6) were accommodated in the reaction, leading to the generation of the desired products in high enantioselectivities and good (Z)-selectivities (89–97% ee, 6 : 1 to 420 : 1 Z/E ratio). In general, o-hydroxystyrenes 2b–2c with small alkyl groups at the allylic position delivered higher enantioselectivity than those without substituents (entries 2 and 3 vs. 1, 5 and 6). Besides, o-hydroxystyrene 2d with a bulky benzyl group could also Table 3
Substrate scope of o-hydroxystyrene derivatives 2a
Entry
3
R/R1 (2)
Yieldb (%)
Z/Ec
eed (%)
1 2f 3 4 5g 6h
(R)-3aa (S)-3ab (R)-3ac (R)-3ad (R)-3ed (R)-3de
H/H (2a) Me/H (2b) Et/H (2c) Bn/H (2d) H/Me (2d) H/OMe (2e)
77 71 62 75 47 47
—e 420 : 1 6:1 6:1 —e —e
90 97 97 90 89 89
a
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 6a in AcOEt (1 mL) at 35 1C for 12 h, and the mole ratio of 1 : 2 was 1.5 : 1. b Isolated yield. c The Z/E ratio was determined by 1H NMR. d The ee value was determined by HPLC. e No Z/E isomers could be formed. f Catalyzed by 10 mol% 5a. g 3-Indolylmethanol 1e was used as a reactant. h 3-Indolylmethanol 1d was used as a reactant.
12056 | Chem. Commun., 2014, 50, 12054--12057
Scheme 2
Proposed transition state.
participate in the desired reaction albeit with a slightly decreased enantioselectivity of 90% ee (entry 4). More significantly, such alkyl groups at the allylic position provided a good challenge and opportunity for precisely controlling both the enantioselectivity and the Z/E selectivity, which is crucial and fundamental in C–C bond formation as well as allylation. o-Hydroxystyrenes 2e–2f with substituents on their benzene rings were also tolerated with high enantioselectivities, but the yields were lower than their unsubstituted counterpart 2a (entries 5 and 6 vs. 1). The absolute configuration and olefin geometry of product 3qb (499% ee after recrystallization) were unambiguously determined to be (S) and (Z) by single crystal X-ray diffraction analysis.10 The absolute configuration and olefin geometry of other products 3 were assigned by analogy. Based on the experimental results, we proposed a possible transition state to account for the stereochemistry of this catalytic asymmetric reaction. As exemplified by the formation of product 3qb (Scheme 2), CPA 5a served as a Brønsted acid/Lewis base bifunctional catalyst to simultaneously activate both the vinyliminium intermediate and o-hydroxystyrene 2b by hydrogen-bonding interactions. Because of the chiral environment created by the (R)-H8-BINOL backbone and the 3,3 0 -(1-napthyl)-substituents of CPA 5a, an enantioselective and (Z/E)-selective tandem vinylogous Michael addition/hydrogen-elimination occurred thereby delivering the experimentally observed (S,Z)-configured product 3qb. In order to demonstrate the roles of the O–H group in o-hydroxystyrenes 2 and the N–H group in the indole moiety of 3-indolylmethanols 1 as well as to verify the suggested activating mode, two control experiments were carried out under the optimal reaction conditions (Scheme 3). Firstly, o-methoxystyrene 2f instead of o-hydroxystyrene 2a was employed in the reaction with 3-indolylmethanols 1a, which still afforded the desired product 3af, but in a low yield and with extremely low enantioselectivity (eqn (4)). This result indicated that the O–H group in o-hydroxystyrenes 2 was very important to the reactivity and enantioselectivity of the reaction via forming a hydrogen-bond with CPA 5a, but the presence of the O–H group was not a decisive factor to the reaction since the desired product 3af could be generated in the absence of an O–H group. Then, N-benzyl-protected 3-indolylmethanol 1t in the place of
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enantioselectivities and (Z)-selectivities (up to 97% ee, 420 : 1 Z/E ratio). This transformation involves a tandem vinylogous Michael addition/hydrogen-elimination sequence based on hydrogen-bond activation, thus providing an efficient, atomeconomic and stereoselective method for asymmetric allylation of 3-indolylmethanols and C3-functionalization of indoles. Besides, this approach is applicable to a wide range of substrates to offer enantioenriched indole derivatives with structural diversity. The excellent enantio- and (Z/E)-selectivity of the reaction will provide a powerful tool for precise control of the stereoselectivity in the formation of C–C and CQC bonds. We are grateful for financial support from NSFC (21372002 and 21232007), PAPD of Jiangsu Province, Open Foundation of Jiangsu Key Laboratory (K201314).
Notes and references
Scheme 3
Control experiments.
N-unprotected 3-indolylmethanol 1a was used as a substrate to react with o-hydroxystyrene 2b, but no desired product was observed (eqn (5)). Besides, using t-butoxy carbonyl (Boc) as an electron-withdrawing group instead of benzyl as a N-protective group also led to the failure of the reaction (eqn (5)). In both cases, no reaction (N. R.) occurred. This outcome implied that the N–H group in the indole moiety of 3-indolylmethanols 1 played a crucial role in the reaction, which was essentially important for generating a hydrogen-bond with CPA 5a as shown in the transition state (Scheme 2). Finally, to investigate the influence of the isatin moiety of 3-indolylmethanol on the reaction, a benzaldehyde-derived 3-indolylmethanol 1v was employed as a substrate instead of its isatin-derived counterpart in the reaction under the optimal reaction conditions. However, the 1v-involed tandem reaction was unsuccessful and the desired reaction did not occur (eqn (6)), which indicated that the isatin moiety of 3-indolylmethanol imposed a decisive effect on the reactivity of the allylation reaction. This result may largely be ascribed to the fact that the amide group in the isatin moiety would increase the positive charge density on the C3-position, which rendered the isatin-derived intermediate more electrophilic than benzaldehyde-derived one (in Scheme 3),4f thus facilitating the nucleophilic addition of o-hydroxystyrene. In summary, we have established the first chiral Brønsted acid-catalyzed asymmetric allylation of 3-indolylmethanols with o-hydroxystyrenes, leading to the production of chiral allyl-substituted oxindoles with concomitant generation of one all-carbon quaternary stereogenic center and one newly formed CQC bond in excellent
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1 For reviews, see: (a) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (b) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608; (c) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489. 2 For reviews, see: (a) M. Zeng and S.-L. You, Synlett, 2010, 1289; (b) M. Amat, M. Perez and J. Bosch, Synlett, 2011, 143; (c) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003; C. J. C. Loh and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 46. 3 For a review, see: (a) A. Palmieri, M. Petrini and R. R. Shaikh, Org. Biomol. Chem., 2010, 8, 1259. For some examples, see: (b) X. Han, H. Li, R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51, 10390; (c) B. Xu, Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng and Q.-X. Guo, Angew. Chem., Int. Ed., 2012, 51, 1059. 4 For catalytic asymmetric alkylations: (a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng and L.-Z. Gong, Org. Lett., 2009, 11, 4620; (b) P. G. Cozzi, F. Benfatti and L. Zoli, Angew. Chem., Int. Ed., 2009, 48, 1313; (c) D.-S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan and G.-F. Jiang, Chem. Sci., 2011, 2, 803; (d) J. Xiao, K. Zhao and T.-P. Loh, Chem. – Asian J., 2011, 6, 2890; (e) J. Xiao, Org. Lett., 2012, 14, 1716; ( f ) L. Song, Q.-X. Guo, X.-C. Li, J. Tian and Y.-G. Peng, Angew. Chem., Int. Ed., 2012, 51, 1899; ( g) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.-W. Luo and L.-Z. Gong, Angew. Chem., Int. Ed., 2012, 51, 1046. For other catalytic asymmetric transformations: (h) J. Huang, S. Luo and L. Gong, Acta Chim. Sin., 2013, 71, 879; (i) F. Shi, R.-Y. Zhu, W. Dai, C.-S. Wang and S.-J. Tu, Chem. – Eur. J., 2014, 20, 2597. 5 B. Han, Y.-C. Xiao, Y. Yao and Y.-C. Chen, Angew. Chem., Int. Ed., 2010, 49, 10189. 6 For early examples, see: (a) T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566; (b) D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126, 5356. For reviews, see: (c) T. Akiyama, Chem. Rev., 2007, 107, 5744; (d) M. Terada, Chem. Commun., 2008, 4097; (e) M. Terada, Synthesis, 2010, 1929; ( f ) J. Yu, F. Shi and L.-Z. Gong, Acc. Chem. Res., 2011, 44, 1156. 7 (a) F. Shi, S.-W. Luo, Z.-L. Tao, L. He, J. Yu, S.-J. Tu and L.-Z. Gong, Org. Lett., 2011, 13, 4680; (b) F. Shi, Z.-L. Tao, S.-W. Luo, S.-J. Tu and L.-Z. Gong, Chem. – Eur. J., 2012, 18, 6885; (c) F. Shi, W. Tan, R.-Y. Zhu, G.-J. Xing and S.-J. Tu, Adv. Synth. Catal., 2013, 355, 1605. 8 (a) F. Shi, G.-J. Xing, Z.-L. Tao, S.-W. Luo, S.-J. Tu and L.-Z. Gong, J. Org. Chem., 2012, 77, 6970; (b) F. Shi, G.-J. Xing, R.-Y. Zhu, W. Tan and S.-J. Tu, Org. Lett., 2013, 15, 128; (c) S.-Y. Yu, H. Zhang, Y. Gao, L. Mo, S. Wang and Z.-J. Yao, J. Am. Chem. Soc., 2013, 135, 11402. ˇ oric ´, S. Mu ¨ller and B. List, J. Am. Chem. Soc., 2010, 132, 17370; 9 (a) I. C (b) C. Xing, Y. Liao, J. Ng and Q. Hu, J. Org. Chem., 2011, 76, 4125; (c) B. Xu, S. Zhu, X. Xie, J. Shen and Q.-L. Zhou, Angew. Chem., Int. Ed., 2011, 50, 11483; (d) F. Xu, D. Huang, C. Han, W. Shen, X. F. Lin and Y. Wang, J. Org. Chem., 2010, 75, 8677. 10 CCDC 988256, see ESI† for details.
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Cite this: Chem. Commun., 2014, 50, 12054 Received 19th March 2014, Accepted 19th May 2014
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Organocatalytic enantioselective and (Z)-selective allylation of 3-indolylmethanol via hydrogen-bond activation† Yan Liu,‡ab Hong-Hao Zhang,‡a Yu-Chen Zhang,‡a Yan Jiang,b Feng Shi*a and Shu-Jiang Tua
Published on 22 May 2014. Downloaded on 03/10/2014 12:11:55.
DOI: 10.1039/c4cc02056a www.rsc.org/chemcomm
An organocatalytic asymmetric allylation of 3-indolylmethanol has been established via hydrogen-bond activating mode, which directly assembles isatin-derived 3-indolylmethanols and o-hydroxystyrenes into chiral allyl-substituted oxindoles with one all-carbon quaternary stereogenic center and one newly formed CQC bond in excellent enantioselectivity and (Z)-selectivity (up to 97% ee, 420 : 1 Z/E ratio). This transformation provides an efficient strategy for asymmetric C3-functionalization of indoles and allylation of 3-indolylmethanols with precise control of the stereoselectivity in the formation of C–C and CQC bonds.
Indole skeleton represents one of the most fascinating heterocyclic frameworks, frequently found in numerous natural alkaloids, chiral pharmaceuticals and agrochemicals.1 As a result, a great deal of attention from chemists has been paid to the stereoselective functionalization of the indole core as well as the preparation of chiral indoles.2 In the last decade, 3-indolylmethanols have appeared to be active substrates capable of undergoing a variety of enantioselective transformations to access functionalized indoles by formation of either carbocation or vinyliminium intermediates in the presence of a Lewis acid (LA) or Brønsted acid (BH).3,4 However, previous studies on catalytic asymmetric substitutions of 3-indolylmethanols were mainly concentrated on their alkylation with carbonyl compounds (eqn (1)).4a–g In contrast, the catalytic asymmetric allylation of 3-indolylmethanol has met with little success (eqn (2)) despite that this transformation provides the simultaneous formation of C–C and CQC bonds with precise control of their stereochemistry. So far, only Chen and coworkers described a stereoselective substitution of 3-indolylmethanols with a
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, China b Jiangsu Provincial Key laboratory of Fine Petrochemical engineering, Changzhou University, Changzhou, 213164, China. E-mail: [email protected]; Fax: +86 516 83500065; Tel: +86 516 83500065 † Electronic supplementary information (ESI) available: Experimental details, characterization, original NMR and HPLC spectra of all products. CCDC 988256. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc02056a ‡ These authors contributed equally to the work.
12054 | Chem. Commun., 2014, 50, 12054--12057
a,b-unsaturated aldehydes using a,a-diphenylprolinol O-TMS ether as a catalyst, to generate enantioenriched allylation products via dienamine activation of enals (eqn (3)).5 In spite of this creative work, the catalytic asymmetric allylations of 3-indolylmethanols, especially those employing other strategies based on different activation modes, are still under-developed and thus in great demand due to the challenges in stereoselective C–C, CQC bond formation and C3-functionalization of indole motifs.
Chiral phosphoric acids6 (CPA) belong to a type of privileged organocatalysts based on H-bonding activation mode, and we have realized a series of CPA-catalyzed enantioselective multi-component or cascade transformations.7 Illuminated by this success, we envisaged that the vinyliminium intermediate and o-hydroxystyrene8 bearing allylic hydrogens could be simultaneously activated by CPA via hydrogen-bonding interactions to undergo asymmetric vinylogous Michael addition, generating a transient intermediate A, which would principally undergo an allylic hydrogen-elimination, again under the promotion of the same catalyst to achieve enantioselective and (Z/E)-selective allylation of 3-indolylmethanols (Scheme 1).
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Scheme 1 Design of CPA-catalyzed asymmetric allylation of 3-indolylmethanols.
Herein, we report the first catalytic asymmetric allylation of 3-indolylmethanols via hydrogen-bond activating mode, which directly assembles isatin-derived 3-indolylmethanols and o-hydroxystyrenes into chiral allyl-substituted oxindoles with concomitant formation of an all-carbon quaternary stereogenic center and a newly formed CQC bond in excellent enantioselectivities and (Z)-selectivities (up to 97% ee, 420 : 1 Z/E ratio). The initial experiment to testify our hypothesis commenced with a reaction of N-benzyl isatin-derived 3-indolylmethanol 1a Table 1
Screening of catalysts and optimization of conditionsa
and o-hydroxystyrene derivative 2a in 1,2-dichloroethane (DCE) catalyzed by CPA 4a. Although the reaction occurred, the desired allylation product 3aa was isolated in a low yield and moderate enantioselectivity (Table 1, entry 1). The subsequent screening of different BINOL-derived CPAs 4 (entries 1–7) found that catalyst 4e with 1-naphthyl groups at 3,30 -positions of the BINOL backbone was much superior to the others in terms of enantioselectivity (entry 5). In particular, the variation of o-hydroxystyrene derivative 2a to 2b not only led to a much enhanced yield and enantioselectivity, but also incurred a good Z/E selectivity of the newly formed carbon–carbon double bond (entry 8). The evaluation of reaction media (entries 8–11) revealed that the use of ethyl acetate as a solvent could further ameliorate the yield and enantioselectivity (entry 11). The examination of other parameters including temperature and the mole ratio of the reactants (entries 12–14) found that 35 1C and a 1.5 : 1 mole ratio of 1a to 2b were the best conditions for the reaction (entry 14). Finally, changing the BINOL backbone of the catalyst to structurally more rigid H8-BINOL and SPINOL9 backbones resulted in a remarkably increased enantioselectivity and (Z)-selectivity (entries 15 and 16). In particular, H8-BINOL-derived CPA 5a exhibited the highest level of catalytic activity, giving rise to the product 3ab in a high yield of 71%, excellent stereoselectivity of 97% ee and a 420 : 1 Z/E ratio (entry 15). With the optimal reaction conditions in hand, the substrate scope with respect to isatin-derived 3-indolylmethanols 1 was investigated (Table 2). Firstly, N-benzyl, alkyl and aryl isatinderived 3-indolylmethanols were examined. As exemplified by 1a–1c, the reaction proceeded smoothly to deliver chiral products
Table 2
Entry 1 2 3 4 5 6 7 8 9 10 11 12 f 13g 14h 15h 16h
Cat. 4a 4b 4c 4d 4e 4f 4g 4e 4e 4e 4e 4e 4e 4e 5a 6a
3 (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3aa (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (S)-3ab (R)-3ab
Solvent DCE DCE DCE DCE DCE DCE DCE DCE Toluene CH3CN AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt
Yieldb (%) 25 44 9 10 33 31 37 64 57 40 69 67 53 67 71 62
a
Z/Ec e
— —e —e —e —e —e —e 6:1 6:1 7:1 6:1 6:1 7:1 8:1 420 : 1 10 : 1
eed (%) 47 58 44 50 76 70 71 83 81 45 84 84 80 87 97 93
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 4–6 in solvent (1 mL) at 35 1C for 12 h, and the mole ratio of 1a : 2 was 1 : 3. b Isolated yield. c The Z/E ratio was determined by HPLC. d The ee value was determined by HPLC. e No Z/E isomers could be formed for product 3aa. f Performed at 50 1C. g Performed at 15 1C. h The mole ratio of 1a : 2b was 1.5 : 1.
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Substrate scope of isatin-derived 3-indolylmethanols 1a
Entry 3
R/R1/R2 (1)
Yieldb (%) Z/Ec
1 2 3 4e 5e 6e 7e 8 9 10 11 12 13 14 15 16 17 18 19
Bn/H/H (1a) Me/H/H (1b) Ph/H/H (1c) p-BrC6H4CH2/H/H (1d) p-ClC6H4CH2/H/H (1e) m-ClC6H4CH2/H/H (1f) m,p-Cl2C6H3CH2/H/H (1g) Bn/5-F/H (1h) Bn/5-Me/H (1i) Bn/6-Br/H (1j) Bn/7-F/H (1k) Bn/7-Me/H (1l) Bn/H/5 0 -Me (1m) Bn/H/5 0 -Cl (1n) Bn/H/6 0 -Me (1o) Bn/H/6 0 -F (1p) Bn/H/6 0 -Br (1q) Bn/H/7 0 -Me (1r) Bn/H/7 0 -Br (1s)
71 76 62 82 70 64 68 84 59 45 58 71 71 54 60 87 64 53 44
(S)-3ab (S)-3bb (S)-3cb (R)-3db (R)-3eb (R)-3fb (R)-3gb (S)-3hb (S)-3ib (S)-3jb (S)-3kb (S)-3lb (S)-3mb (S)-3nb (S)-3ob (S)-3pb (S)-3qb (S)-3rb (S)-3sb
420 : 1 420 : 1 5:1 8:1 7:1 9:1 8:1 10 : 1 15 : 1 10 : 1 420 : 1 420 : 1 420 : 1 5:1 420 : 1 420 : 1 420 : 1 420 : 1 420 : 1
eed (%) 97 94 94 95 91 92 95 93 94 91 95 93 95 96 93 92 91 86 93
a
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 5a in AcOEt (1 mL) at 35 1C for 12 h, and the mole ratio of 1 : 2b was 1.5 : 1. b Isolated yield. c The Z/E ratio was determined by 1H NMR. d The ee value was determined by HPLC. e Catalyzed by 10 mol% 6a.
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3ab–3cb in excellent enantioselectivities and high (Z)-selectivities (entries 1–3). Among them, N-benzyl isatin-derived 3-indolylmethanol 1a gave the highest stereoselectivity (entry 1), whereas N-phenyl isatin-derived substrate 1c showed a decreased (Z)-selectivity (entry 3). Besides, different N-benzyl isatin-derived 3-indolylmethanols 1d–1g could undergo the reaction (entries 4–7) to furnish the desired products in high yields (64–82%) and excellent stereoselectivities (91–95% ee, 7 : 1 to 9 : 1 Z/E ratio). Then, a series of N-benzyl isatin-derived 3-indolylmethanols 1h–1s with various substituents at different positions of both isatin and indole moieties were utilized in the reaction. The position and the electronic nature of the substituents on the oxindole moiety seemingly had little effect on the stereoselectivity since C5-, C6- or C7-substituted 3-indolylmethanols 1h–1l delivered the target products in uniformly excellent stereoselectivities of 91–95% ee and a 10 : 1 to 420 : 1 Z/E ratio (entries 8–12). Nevertheless, the position of the substituents linked to the indole core exerted some influence on the enantioselectivity. Basically, C50 -substituted 3-indolylmethanols were superior to C60 - and C70 -substituted analogues in terms of enantioselectivity (entries 13 and 14 vs. 15 and 19), while the latter also showed perfect (Z)-selectivities of a 420 : 1 Z/E ratio. As to C70 -substituted 3-indolylmethanols, the electronic nature of the substituents considerably affected the enantioselectivity, because 70 -bromo-substituted 3-indolylmethanol exhibited higher enantioselectivity than 70 -methyl-substituted one (entry 19 vs. 18). Next, the generality of the reaction for o-hydroxystyrene derivatives 2 bearing allylic hydrogens was examined (Table 3). Several o-hydroxystyrenes with different alkyl groups at the allylic position (entries 1–4) or bearing different substituents on their benzene rings (entries 5 and 6) were accommodated in the reaction, leading to the generation of the desired products in high enantioselectivities and good (Z)-selectivities (89–97% ee, 6 : 1 to 420 : 1 Z/E ratio). In general, o-hydroxystyrenes 2b–2c with small alkyl groups at the allylic position delivered higher enantioselectivity than those without substituents (entries 2 and 3 vs. 1, 5 and 6). Besides, o-hydroxystyrene 2d with a bulky benzyl group could also Table 3
Substrate scope of o-hydroxystyrene derivatives 2a
Entry
3
R/R1 (2)
Yieldb (%)
Z/Ec
eed (%)
1 2f 3 4 5g 6h
(R)-3aa (S)-3ab (R)-3ac (R)-3ad (R)-3ed (R)-3de
H/H (2a) Me/H (2b) Et/H (2c) Bn/H (2d) H/Me (2d) H/OMe (2e)
77 71 62 75 47 47
—e 420 : 1 6:1 6:1 —e —e
90 97 97 90 89 89
a
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale catalyzed by 10 mol% 6a in AcOEt (1 mL) at 35 1C for 12 h, and the mole ratio of 1 : 2 was 1.5 : 1. b Isolated yield. c The Z/E ratio was determined by 1H NMR. d The ee value was determined by HPLC. e No Z/E isomers could be formed. f Catalyzed by 10 mol% 5a. g 3-Indolylmethanol 1e was used as a reactant. h 3-Indolylmethanol 1d was used as a reactant.
12056 | Chem. Commun., 2014, 50, 12054--12057
Scheme 2
Proposed transition state.
participate in the desired reaction albeit with a slightly decreased enantioselectivity of 90% ee (entry 4). More significantly, such alkyl groups at the allylic position provided a good challenge and opportunity for precisely controlling both the enantioselectivity and the Z/E selectivity, which is crucial and fundamental in C–C bond formation as well as allylation. o-Hydroxystyrenes 2e–2f with substituents on their benzene rings were also tolerated with high enantioselectivities, but the yields were lower than their unsubstituted counterpart 2a (entries 5 and 6 vs. 1). The absolute configuration and olefin geometry of product 3qb (499% ee after recrystallization) were unambiguously determined to be (S) and (Z) by single crystal X-ray diffraction analysis.10 The absolute configuration and olefin geometry of other products 3 were assigned by analogy. Based on the experimental results, we proposed a possible transition state to account for the stereochemistry of this catalytic asymmetric reaction. As exemplified by the formation of product 3qb (Scheme 2), CPA 5a served as a Brønsted acid/Lewis base bifunctional catalyst to simultaneously activate both the vinyliminium intermediate and o-hydroxystyrene 2b by hydrogen-bonding interactions. Because of the chiral environment created by the (R)-H8-BINOL backbone and the 3,3 0 -(1-napthyl)-substituents of CPA 5a, an enantioselective and (Z/E)-selective tandem vinylogous Michael addition/hydrogen-elimination occurred thereby delivering the experimentally observed (S,Z)-configured product 3qb. In order to demonstrate the roles of the O–H group in o-hydroxystyrenes 2 and the N–H group in the indole moiety of 3-indolylmethanols 1 as well as to verify the suggested activating mode, two control experiments were carried out under the optimal reaction conditions (Scheme 3). Firstly, o-methoxystyrene 2f instead of o-hydroxystyrene 2a was employed in the reaction with 3-indolylmethanols 1a, which still afforded the desired product 3af, but in a low yield and with extremely low enantioselectivity (eqn (4)). This result indicated that the O–H group in o-hydroxystyrenes 2 was very important to the reactivity and enantioselectivity of the reaction via forming a hydrogen-bond with CPA 5a, but the presence of the O–H group was not a decisive factor to the reaction since the desired product 3af could be generated in the absence of an O–H group. Then, N-benzyl-protected 3-indolylmethanol 1t in the place of
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enantioselectivities and (Z)-selectivities (up to 97% ee, 420 : 1 Z/E ratio). This transformation involves a tandem vinylogous Michael addition/hydrogen-elimination sequence based on hydrogen-bond activation, thus providing an efficient, atomeconomic and stereoselective method for asymmetric allylation of 3-indolylmethanols and C3-functionalization of indoles. Besides, this approach is applicable to a wide range of substrates to offer enantioenriched indole derivatives with structural diversity. The excellent enantio- and (Z/E)-selectivity of the reaction will provide a powerful tool for precise control of the stereoselectivity in the formation of C–C and CQC bonds. We are grateful for financial support from NSFC (21372002 and 21232007), PAPD of Jiangsu Province, Open Foundation of Jiangsu Key Laboratory (K201314).
Notes and references
Scheme 3
Control experiments.
N-unprotected 3-indolylmethanol 1a was used as a substrate to react with o-hydroxystyrene 2b, but no desired product was observed (eqn (5)). Besides, using t-butoxy carbonyl (Boc) as an electron-withdrawing group instead of benzyl as a N-protective group also led to the failure of the reaction (eqn (5)). In both cases, no reaction (N. R.) occurred. This outcome implied that the N–H group in the indole moiety of 3-indolylmethanols 1 played a crucial role in the reaction, which was essentially important for generating a hydrogen-bond with CPA 5a as shown in the transition state (Scheme 2). Finally, to investigate the influence of the isatin moiety of 3-indolylmethanol on the reaction, a benzaldehyde-derived 3-indolylmethanol 1v was employed as a substrate instead of its isatin-derived counterpart in the reaction under the optimal reaction conditions. However, the 1v-involed tandem reaction was unsuccessful and the desired reaction did not occur (eqn (6)), which indicated that the isatin moiety of 3-indolylmethanol imposed a decisive effect on the reactivity of the allylation reaction. This result may largely be ascribed to the fact that the amide group in the isatin moiety would increase the positive charge density on the C3-position, which rendered the isatin-derived intermediate more electrophilic than benzaldehyde-derived one (in Scheme 3),4f thus facilitating the nucleophilic addition of o-hydroxystyrene. In summary, we have established the first chiral Brønsted acid-catalyzed asymmetric allylation of 3-indolylmethanols with o-hydroxystyrenes, leading to the production of chiral allyl-substituted oxindoles with concomitant generation of one all-carbon quaternary stereogenic center and one newly formed CQC bond in excellent
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