Letter Cite This: Org. Lett. 2018, 20, 6502−6505
pubs.acs.org/OrgLett
Directing Effects on the Copper-Catalyzed Site-Selective Arylation of Indoles Ting Wang,† Liyan Zhou,† Youqing Yang,‡ Xinhao Zhang,*,† Zhuangzhi Shi,*,‡ and Yun-Dong Wu*,†,§
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†
Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China ‡ State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China § College of Chemistry, Peking University, Beijing 100871, China S Supporting Information *
ABSTRACT: Different site selectivities have been reported for indoles with different directing groups in copper-catalyzed siteselective C−H arylations. Computational and mass spectrometric studies have been conducted in an effort to understand the origin of site selectivity and the effects of the directing groups. A Heck-like mechanism involving a four-membered ring is found in all three of the cases studied. For N-acetyl indole with a weak directing group, a neutral Heck-like mechanism is controlled by an electronic effect resulting in C2 site selectivity. In contrast, indole with a N-P(O)tBu2 group and N-benzyl-3pivaloyl indole prefer a cationic Heck-like reaction in which a favorable six-membered chelation between the directing group and the CuIII center determines the C6 and C5 site selectivities.
D
Scheme 1. Site-Selective C−H Arylation of Indoles with Different Directing Groups
ue to its common appearance in natural products and a wide range of biochemical, biological, and medicinal structures for pharmaceuticals, pesticides, and functionalized materials, indole is one of the most widely studied nitrogencontaining heterocycles.1,2 There are two main strategies for the synthesis of a functionalized indole scaffold: (a) construction of the indole framework from benzenoid precursors or other substrates3 and (b) direct functionalization of an existing indole framework.4 In particular, transitionmetal-catalyzed direct site-selective C−H functionalization of the indole nucleus, including the C2 to C3 (pyrrole ring) and C4 to C7 (benzene ring) positions, can be of great synthetic value.4e−i Site selectivity can be achieved by using different catalysts4e,5 or ligands6 or by introducing directing groups (DGs).4g,7 In this study, we focus on the site selectivity of the copper-catalyzed C−H arylation that is controlled by the introduction of a directing group on the indole scaffold. In 2008, Gaunt and co-workers reported a CuII-catalyzed C2-selective arylation of N-acetyl indole with diaryliodonium salts (Scheme 1).8 The C2:C3 selectivity ratio in this case is about 9 to 1. In 2016, Shi reported the first efficient C6selective C−H arylation of indoles by employing a sterically hindered, removable N-P(O)tBu2 directing group (TBPO) under similar reaction conditions.9 More recently, we have also reported the specific C5 arylation of indole with an N-benzyltype protecting group and a sterically hindered pivaloyl directing group at C3 (N-Bn-3-Piv indole).10 However, the exact mechanism and the effects of the directing groups for © 2018 American Chemical Society
different site-selective C−H activations remain unclear. To explore the possible mechanisms for the Cu-catalyzed C−H arylation and the role of directing groups for site selectivity, a combined density functional theory (DFT)11 and mass spectrometric (MS)12 study was conducted. A CuI/CuIII cycle is proposed for the C−H arylation with diaryliodonium salts (Scheme 2).8,13 The active CuI catalyst can be initially generated from the disproportionation of CuII Received: September 5, 2018 Published: October 10, 2018 6502
DOI: 10.1021/acs.orglett.8b02825 Org. Lett. 2018, 20, 6502−6505
Letter
Organic Letters Scheme 2. Proposed CuI/CuIII Catalytic Cycle
Figure 2. Neutral Heck-like transition states of C−H activation/ arylation of N-Ac indole and N-TBPO indole. Relative free energies and electronic energies (in parentheses) are in kcal/mol.
system, C2-TSNAc is computed to be the most stable C−H activation/arylation transition state in this neutral Heck-like model. The free energy barrier for C3-TSNAc is 1.1 kcal/mol higher than that of C2-TSNAc, which is consistent with the experimentally observed preference (C2:C3 > 9:1). However, for the N-TBPO indole, the calculated free energies of the Heck-like four-membered-ring transition states, C6-TSNTBPO and C2-TSNTBPO, are very close to each other (Figure 2). Thus, the neutral Heck-like model does not reproduce the experimental result that the C6-arylated isomer is the main product. We investigated an alternative pathway in which OTf− acts as a good leaving group in the presence of a strong electron-donating directing group, and a cationic Heck-like mechanism operates. Mass spectrometric (MS) investigations were carried out to obtain insight into the dissociation of OTf−. Several 1:2 mixtures in methanol of Cu(OTf)2 with indole substrates involving different directing groups were subjected to ESI-MS analysis. Representative spectra of Cu(OTf)2 with N-TBPO indole, N-Bn-3-Piv indole, and N-Ac indole are shown in Figure 3. Complexes combining the copper salt and indole substrate with dissociation of one OTf− anion were both detected in the mass spectra of N-TBPO indole and N-Bn-3Piv indole (Figure 3a, [CuIIOTf, N-TBPO indole]+, m/z = 489.1 and Figure 3b, [CuIIOTf, N-Bn-3-Piv indole]+, m/z = 503.1). No species corresponding to [CuIIOTf, N-Ac indole]+
or the reduction of CuII by the nucleophile.8,14 Then this CuI species undergoes oxidative addition to the highly electrophilic diaryl-iodine reagent, which gives a CuIII-aryl intermediate.14c,d,15 Due to different directing effects, the CuIII center preferentially binds to different carbons in indole and then transfers the aryl group to the indole, regenerating the CuI catalyst. There are two possible pathways, namely, a Heck-like, four-membered-ring mechanism16 and a concerted metalation−deprotonation (CMD) mechanism17 for the C−H arylation. Our earlier studies on the related Cu-catalyzed meta-arylation of anilides suggested that a Heck-like process is preferred over the CMD pathway.13d,16b In this study, we also compared the pathway of C−H bond activation on the indole ring through the Heck-like model and the CMD model. The relative free energies of the transition states for C−H activation at different positions of the indole are shown in Figure 1, in which the solid lines represent the Heck-like
Figure 1. Comparison of the Heck-like model and the CMD model for C−H activation. Relative free energies in solution are given in kcal/mol.
model, while the dashed lines represent the CMD model. The blue lines and the red lines refer to the N-TBPO indole system and the N-Ac indole system, respectively. Similar to the previously studied anilide case,13d the calculations show that the free energies of the Heck-like mechanism for C−H activation are much lower than those of the CMD mechanism in both N-TBPO indole and the N-Ac indole system. Consequently, our studies are based on the Heck-like mechanism. Next, we investigated the site selectivity of C−H arylation of indoles involving different directing groups. Figure 2 shows the transition states of C−H arylation for four relevant positions, C7, C6, C3, and C2. Among the different possible transition structures, the directing group (DG) is coordinated with the Cu center in C6-TSN and C3-TSN. For the N-Ac indole
Figure 3. Mass spectra of 1:2 mixtures of Cu(OTf)2 with (a) NTBPO indole, (b) N-Bn-3-Piv indole, and (c) N-Ac indole in methanol. Numbers in parentheses are theoretical m/z values for related ions. 6503
DOI: 10.1021/acs.orglett.8b02825 Org. Lett. 2018, 20, 6502−6505
Letter
Organic Letters (m/z = 371.0) was found in the case of the N-Ac indole (Figure 3c). DFT calculated binding energies also indicated that the binding of the copper center to N-TBPO indole and N-Bn-3-Piv indole is stronger than that of the N-Ac indole (see Figure S1). Thus, N-TBPO indole and N-Bn-3-Piv indole are the most likely to release an OTf− anion, while the dissociation of OTf− from N-Ac indole requires high energy. A change of catalytically active species in the presence of a coordination partner has been demonstrated by Schoenebeck and others.18 On the basis of the experimental and computational studies, we hypothesize that the N-Ac indole proceeds along a neutral Heck-like pathway without dissociation of an OTf− anion, while N-TBPO indole and N-Bn-3-Piv indole with a strong directing group favor a cationic Heck-like pathway. Thus, we examined the cationic Heck-like model to evaluate the regioselectivity of Cu-catalyzed arylation of N-TBPO indole and N-Bn-3-Piv indole. As shown in Figures 4 and S2,
Figure 5. Optimized cationic Heck-like transition states of C−H activation/arylation of N-P(O)tBu2 indole. Some H atoms are hidden for clarity. Relative free energy and electronic energy (in parentheses) are in kcal/mol. Distances and angles are in Å and °, respectively.
five-membered chelate will result in greater distortion of the TBPO group, reflected by the restricted bond angles of ∠C1− N−P and ∠N−P−O in C3-TSTBPO. (2) The steric repulsion between the tert-butyl group on the TBPO directing group and the indole ring is smaller in C6-TSTBPO (C6-TSTBPO, H−H: 2.14 Å; C3-TSTBPO, H−H: 2.04 Å). Similarly, the C5-selective arylation of N-Bn-3-Piv indole takes place because the pivaloyl substituent blocks the reactive C3 position on the indole scaffold (Figure S3). In addition, it directs the CuIII center at the C4 position to form a favorable six-membered chelation (highlighted in yellow), which then leads to the C5-arylation product through the Heck-like four-membered-ring transition state. The N-Ac indole with a weak directing group undergoes a neutral Heck-like four-membered ring mechanism for C−H activation/arylation. When the directing effect is weak, the electronic effects dictate selectivity. The electrophilic CuIII center tends to coordinate with the most electron-rich C3 carbon (Hirshfeld charge:19 −0.072, in Figure S4), which then leads to the C2-delivery of the phenyl group to the indole ring in a Heck-like process. In summary, the mechanisms and directing effects of the Cucatalyzed site-selective arylation of indoles with a directing group either at the C3 or the N position have been investigated through theoretical calculations and mass spectrometric experiments. Our studies suggest that N-Ac indole with a weak directing group tends to undergo a neutral Heck-like four-membered ring mechanism. The electronic effects dictate the C2 selectivity. In contrast, the C−H activation/arylation of the N-TBPO indole and N-Bn-3-Piv indole proceeds through a cationic Heck-like pathway in which the directing group leads the CuIII center to the favorable position.
Figure 4. Cationic Heck-like transition states of C−H activation/ arylation of N-TBPO indole and N-Bn-3-Piv indole. Activation free energy and electronic energy (in parentheses) are given in kcal/mol.
the computed activation energies for the C−H activation/ arylation of N-TBPO indole at the C7 and C2 sites via C7TSTBPO and C2-TSTBPO (21.5 and 18.7 kcal/mol) are both higher than those of C6-TSTBPO or C3-TSTBPO. The C6selective arylation pathway via C6-TSTBPO has a free energy of activation of 13.5 kcal/mol, which is 2.4 kcal/mol lower in free energy than the pathway leading to C3-arylated product via C3-TSTBPO. The calculated preference agrees with the observed reaction outcome that the C6-arylated product is the major one (C6:C3 > 85:3). For N-Bn-3-Piv indole, C5TSPiv was found to be lower in free energy than other transition states by at least 1.9 kcal/mol, which is consistent with the experimental observations. The cationic Heck-like model successfully reproduced the highly selective C6-arylation of N-TBPO indole and C5arylation of N-Bn-3-Piv indole. To gain detailed insight into the origins of the site selectivity of N-TBPO indole and N-Bn3-Piv indole, analysis of the cationic Heck-like transition states was carried out, and this indicated that the electron-rich oxygen atom on the TBPO directing group coordinates with the electron-deficient CuIII center forming a chelated metal ring (Figure 5, highlighted in yellow), stabilizing the cationic Heck-like transition states C6-TSTBPO and C3-TSTBPO more than C7-TSTBPO and C2-TSTBPO. The phenyl delivery with the five-membered chelate C3-TSTBPO is disfavored by 2.4 kcal/ mol compared to the corresponding six-membered chelate C6TSTBPO. This can be attributed mainly to two factors: (1) The sixmembered chelation is more favorable, and the formation of a
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02825. Computational and experimental details and data are included (PDF) 6504
DOI: 10.1021/acs.orglett.8b02825 Org. Lett. 2018, 20, 6502−6505
Letter
Organic Letters
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xinhao Zhang: 0000-0002-8210-2531 Zhuangzhi Shi: 0000-0003-4571-4413 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Prof. O. Wiest of University of Notre Dame and Prof. Yong Liang of Nanjing University for helpful comments and discussions. The research was supported by the Shenzhen STIC (JCYJ20170412150507046, JCYJ20170412150343516) and the NSF of China (Grant 2167020084).
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DOI: 10.1021/acs.orglett.8b02825 Org. Lett. 2018, 20, 6502−6505
