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Pd-catalyzed dearomative arylborylation of indoles

Chong Shen a, Nicolas Zeidan b, Quan Wu a, Christian B. J. Breuers b, Ren-Rong Liu a, Yi-Xia Jia *ac and Mark Lautens *b
aCollege of Chemical Engineering, State Key Laboratory Breeding Base of Green-Chemical Synthesis Technology, Zhejiang University of Technology, Hangzhou 310014, China. E-mail: yxjia@zjut.edu.cn
bDepartment of Chemistry, University of Toronto, 80 St. George Street, Toronto, Canada. E-mail: mark.lautens@utoronto.ca
cShanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China

Received 22nd December 2018 , Accepted 23rd January 2019

First published on 25th January 2019


A palladium-catalyzed dearomative arylborylation of indoles is reported, which provides straightforward access to structurally diverse indolines bearing vicinal tetrasubstituted and borylated trisubstituted stereocenters in moderate to good yields with excellent diastereoselectivities. By using a BINOL-based chiral phosphoramidite ligand and an sp2–sp3 mixed-boron reagent, an enantioselective dearomative arylborylation was achieved and chiral boron-containing products were accessed in up to 94% ee. Synthetic tranformations of the resulting organoborons were conducted to afford a number of unique indoline derivatives.


Boron containing molecules serve as important building blocks due to their capability of participating in carbon–carbon and carbon–heteroatom bond forming reactions and thus are ubiquitous intermediates in the synthesis of various natural products and bioactive compounds.1 The palladium-catalyzed 1,2-difunctionalization of olefins involving Heck/anionic-capture sequences has been intensely studied and proceeds via a carbopalladation followed by the capture of the alkyl-Pd species with a variety of nucleophiles.2 Domino Heck-borylation reactions employing boron reagents as nucleophiles have enabled an efficient method to synthesize Csp3-based organoboron compounds (Scheme 1a).3,4 It is worthwhile to extend this methodology to the synthesis of structurally diverse, chiral organoboron heterocycles.
image file: c8sc05737k-s1.tif
Scheme 1 Palladium-catalyzed arylborylation of C[double bond, length as m-dash]C bonds.

The transition-metal-catalyzed dearomative functionalization of aromatics has recently emerged as a useful approach to the synthesis of unique aliphatic cyclic molecules.5 In this context, dearomative functionalization of indoles has rendered the synthesis of indolines, a frequently occurring key substructure of natural products and alkaloids, extremely straightforward and efficient.6 Documented reports include the intramolecular C3-arylation of an indolic enolate,7 the Heck arylation of N-tethered 2,3-disubstituted indoles,8 and the reductive-Heck reaction,9 which results in the dearomative mono-functionalization of indole derivatives. Furthermore, the dearomative difunctionalization of indoles was realized through the trapping of the benzyl-Pd intermediate of aryl-palladation using a series of trapping agents, such as cyanides,10 boroxines,11 terminal alkynes,12 propiolic acid,13 and heteroarenes,14 efficiently delivering 2,3-disubstituted indolines. While the formation of the C–H and C–C bonds is documented in the aforementioned reports, there are no examples reported for C–B bond formation to afford chiral organoboron compounds. We envisioned a dearomative Heck-borylation domino reaction of indole to provide benzylic-boron indolines; the protocol mainly relies on the capture of the in situ generated benzyl-Pd species with diboron compounds. Herein, we report this dearomative arylborylation reaction using bis(pinacolato)diboron (B2pin2), and its enantioselective variant with a pre-activated sp2–sp3 mixed-boron reagent and a new BINOL-based chiral phosphoramidite ligand, which leads to a series of structurally unique tetracyclic indolines in moderate to good yields, excellent diastereoselectivities, and good to excellent enantioselectivities (Scheme 1b).

The reaction of 1a with B2pin22 was chosen as the starting condition for optimization. An initial test using Pd(OAc)2 (5 mol%), PPh3 (10 mol%), and tBuOLi (2.0 equiv.) in CH2Cl2 (0.2 M) at 100 °C led to the desired arylborylation product 3a in 25% yield with >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr (Table 1, entry 1). To improve the yield, some bases were screened (entries 2–5). A poor yield was observed when using tBuOK (Table 1, entry 2), while K3PO4, K2CO3, and Na2CO3 significantly improve the yield with 3a isolated in 66% in the case of K2CO3 (Table 1, entries 3–5). Other commercially available ligands, such as P(p-tolyl)3, PtBu3, and PCy3, were then tested, none of which increased the yield (Table 1, entries 6–8). Moreover, poor yields were also observed for bidentate phosphine ligands, e.g. dppe and xantphos. A lower yield was observed when changing the catalyst from Pd(OAc)2 to Pd(dba)2 (Table 1, entry 9). Higher yields could be obtained by lowering the temperature and 3a was isolated in 83% yield when the reaction was run at 60 °C (Table 1, entries 10 and 11). Finally, the solvent effect was examined (Table 1, entries 12–15). Comparable yields were observed in toluene and CH3CN, while the best yield of 3a was achieved in DCE solvent (Table 1, entry 15).

Table 1 Optimization of the reaction conditionsa

image file: c8sc05737k-u1.tif

Entry Base L T (°C) Solvent Yield (%)
a Reaction conditions: 1a (0.2 mmol), 2 (2 eq.), 5 mol% Pd(OAc)2, 10 mol% ligand, and 2 eq. base in solvent (2 mL) at 100 °C; isolated yield, dr > 20[thin space (1/6-em)]:[thin space (1/6-em)]1; DCE = 1,2-dichloroethane. b 5 mol% Pd(dba)2 was used.
1 t BuOLi PPh3 100 CH2Cl2 25
2 t BuOK PPh3 100 CH2Cl2 27
3 K3PO4 PPh3 100 CH2Cl2 57
4 K2CO3 PPh3 100 CH2Cl2 66
5 Na2CO3 PPh3 100 CH2Cl2 43
6 K2CO3 P(p-tolyl)3 100 CH2Cl2 53
7 K2CO3 PtBu3·HBF4 100 CH2Cl2 24
8 K2CO3 PCy3·HBF4 100 CH2Cl2 17
9b K2CO3 PPh3 100 CH2Cl2 38
10 K2CO3 PPh3 80 CH2Cl2 74
11 K2CO3 PPh3 60 CH2Cl2 83
12 K2CO3 PPh3 60 THF 68
13 K2CO3 PPh3 60 toluene 84
14 K2CO3 PPh3 60 MeCN 83
15 K2CO3 PPh3 60 DCE 87


With the optimal conditions in hand, we then examined the scope of the reaction by varying the substituents on the halobenzene and indole rings. As shown in Scheme 2, substituent effect on the benzene ring of the 2-bromobenzoyl moiety was first investigated. Moderate to excellent yields of products 3a–3h were achieved for indoles bearing substituents (methyl, methoxyl, and chloride) at the C3–C5 position of the benzene ring. Higher yields were generally obtained for substrates having an electron-donating group than for those bearing an electron-withdrawing substituent (3e and 3gvs.3b–3d and 3f). Product 3h having two methoxyl groups was isolated in 92% yield. Of note, 3b, having a sterically congested methyl group at the C3 position of the bromobenzoyl moiety, was obtained in 78% yield. Next, the substituent effect on the indole ring was examined. A range of C2-alkylated and C2-arylated indoles were subjected to the reaction at 70 °C, which led to the arylborylated products 3i–3n in moderate yields. In contrast, the yields of these borylated indolines were lower than those achieved for 2-methyl products 3a–3h. It is noteworthy that the reaction of a 2-furyl indole substrate successfully delivered 3n in 53% yield. Moreover, the substituent at the C5-position of 2-substituted indoles was examined and the reactions of substrates having MeO, iPr, and Me groups afforded 3o–3q in moderate yields.


image file: c8sc05737k-s2.tif
Scheme 2 Scope of the indole substituent. aReaction conditions: 1 (0.2 mmol), 2 (2.0 equiv.), 5 mol% Pd(OAc)2, 10 mol% PPh3, and 2 eq. K2CO3 in DCE (2.0 mL) at 60 °C for 12–72 h. bIsolated yield, dr > 20[thin space (1/6-em)]:[thin space (1/6-em)]1. cIn DCE (2 mL) at 70 °C for 18–96 h.

To demonstrate the synthetic utility of this reaction, a gram-scale reaction (4.0 mmol) was carried out under the optimal conditions and afforded 3a in 77% yield (Scheme 3). Synthetic transformations of 3a were then conducted. Oxidation of 3a using NaBO3·4H2O in THF/H2O led to alcohol 4 as a single isomer in almost quantitative yield.15 Compound 4 was further oxidized to ketone 5 in 85% yield with PCC as an oxidant at room temperature. Subjecting 3a to KHF2 in THF/H2O led to the corresponding potassium trifluoroborate 6 in 91% yield. Compound 6 was further converted to amide 7 in MeCN with 64% yield, as a single isomer through a Cu(OAc)2-promoted oxidative nucleophilic substitution.16 The relative configurations of alcohol 4 and amide 7 were determined from their 2D-NOESY spectra.


image file: c8sc05737k-s3.tif
Scheme 3 Gram-scale synthesis of 3a and transformations of 3a. PCC: pyridinium chlorochromate.

An enantioselective Heck/borylation reaction of 1a was then investigated using phosphoramidite L1 as the chiral ligand12b (Table 2, for more details see the ESI). Early on, we observed that the benzylic boron was susceptible to inorganic-base promoted proto-deborylation at the high temperatures necessary for this metal–ligand system (vide infra). In order to avoid the use of the inorganic base necessary to activate B2Pin2, we utilized an sp2–sp3 mixed boron reagent first reported by Santos for copper-catalyzed hydroboration reactions.17 To the best of our knowledge, this reagent has not been used in palladium-catalyzed borylations. It was necessary to change the solvent from DCE to MTBE since the former was not efficient in the enantioselective variant (Table 2, entry 1 and 2). Although the bromo- and iodo- substrates 1a and 1a′′ delivered product in higher yields than the aryl-chloride, it was evident that the smaller halide improved the enantioselectivities (Table 2, entries 2–4). The absolute stereochemistry of 3a was assigned by single-crystal X-ray analysis.18

Table 2 Optimization of the enantioselecitive arylborylationa

image file: c8sc05737k-u2.tif

Entry X Additive Changes to condition Yield (%) ee (%)
a Standard conditions: 1 (0.2 mmol), mixed-boron reagent (2 eq.), 5 mol% Pd(dba)2, 6 mol% L1, and additive in MTBE (2 mL) at 100 °C for 18 h; isolated yield; ee was determined by chiral HPLC; TMG = tetramethyl guanidine; n.r. = no reaction.
1 Br None None 73 64
2 Br None DCE as solvent 34 20
3 I None None 40 50
4 Cl None None 15 88
5 Cl K2CO3 (2 eq.) B2Pin2·(2 eq.) n.r.
6 Cl NEt3 (3 eq.) None 50 88
7 Cl NEt3 (3 eq.) using L2 65 88
[thin space (1/6-em)]
Entries 8–11 using L2
8 Cl i Pr2NEt (3 eq.) None 27
9 Cl NEt3 (3 eq.) 80 °C n.r.
10 Cl NEt3 (3 eq.) 10 mol% L2 68 91
11 Cl NEt3 (5 eq.) 3 eq. mixed-boron reagent 74 94
[thin space (1/6-em)]
Entries 12–15 using conditions in entry 11
12 Cl NEt3 (5 eq.) L3 17 78
13 Cl NEt3 (5 eq.) L4 70 91
14 Cl NEt3 (5 eq.) L5 Trace
15 Cl NEt3 (5 eq.) L6 Trace


In the case of aryl-chloride, there was no reaction using B2Pin2 (Table 2, entry 5). We employed an organic base to neutralize the by-product of the boron-reagent and the conversion was improved to 50% while maintaining the ee (Table 2, entry 6). Further increasing the steric bulk of the ligand improved the yield of the reaction (Table 2, entry 7). Other amines (Table 2, entry 8) or lowering the temperature (Table 2, entry 9) were not effective. By increasing ligand and reagent loading the product was delivered in 74% yield and 94% ee (Table 2, entry 10 and 11). With respect to the ligand, the nitro variant L3 was not an effective ligand for the transformation (Table 2, entry 12). The 3,3′-orthoanisole ligand L4 also did not improve the yield (Table 2, entry 13). The importance of the 3,3′ rings was evident as the simple BINOL-derived phosphoramidite L5 did not produce the product (Table 2, entry 14). Contrary to the dearomative reductive-Heck,9a BINAP was not effective in catalyzing the reaction (Table 2, entry 15).

We then examined the scope of the Heck/borylation on various aryl-chloride substrates (Scheme 4). The steric influence at the halide (3r), as well as functionalities para to the amide tether (3d and 3s) provided products in diminished enantioselectivities. In contrast, the substitution para to chloride (3t) or on the indole moiety yielded 3t–3v in moderate yields and excellent enantioselectivities. The aryl functionality at R2 resulted in 3j and 3w in moderate and good yields with excellent enantioselectivities. Finally, heterocycle containing scaffold 3x was accessed in good yield albeit in a diminished enantioselectivity. Oxidation of compound 3a provided the chiral alcohol (+)-4 and ketone (+)-5 with no loss in enantiomeric excess.


image file: c8sc05737k-s4.tif
Scheme 4 Scope of Heck/borylation of indoles. Reaction conditions: 1a′ (0.2 mmol), (mixed-boron reagent) (0.6 mmol), Pd(dba)2 (5 mol%), L2 (10 mol%), NEt3 (5 eq.), 100 °C, 18 h. [a] Reaction of 4a (0.5 mmol) with NaBO3 (5 eq.), THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (1[thin space (1/6-em)]:[thin space (1/6-em)]1), rt. [b] Reaction of 5 (0.2 mmol) with PCC (3 eq.), CHCl3, 35 °C.

Conclusions

In conclusion, we have developed a dearomative difunctionalization of indoles through a palladium-catalyzed intramolecular arylborylation reaction. Indolines possessing vicinal borylated trisubstituted and tetrasubstituted stereocenters were accessed in good yields and excellent diastereoselectivities. The asymmetric variant of this reaction was explored with a new BINOL-based chiral phosphoramidite ligand and moderate to excellent enantioselectivities were obtained (up to 94% ee). Transformations of the benzylic boron to alcohol and amide were presented to show the synthetic utilities of this reaction.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for generous support from the National Natural Science Foundation of China (nos. 21522207, 21702184, and 21772175). We thank the Natural Science and Engineering Research Council (NSERC), the University of Toronto, and Alphora Inc. for financial support. N. Z acknowledges the province of Ontario for a Graduate Scholarship (OGS). N. Z. thanks Dr Darcy Burns and the NMR staff at the University of Toronto, as well as Dr Alan Lough for the X-ray results.

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Footnotes

Electronic supplementary information (ESI) available. CCDC 1855293. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8sc05737k
Contributed equally to this work.

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