CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence

Article abstract of DOI:10.1021/jacs.8b11838

Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a significant challenge, since there is an intrinsic preference for alkylation at C3, the most nucleophilic position. Furthermore, selective and predictable access to either N- or C3-alkylated chiral indoles using catalyst control has been a long-standing goal in indole functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to conventional alkylation reactions in which indoles are employed as nucleophiles, this transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling partners. N- or C3-alkylated indoles are prepared with high levels of regio- and enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled regiodivergence.

Full text of DOI:10.1021/jacs.8b11838

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Article
CuH-Catalyzed Enantioselective Alkylation of Indole
Derivatives with Ligand-Controlled Regiodivergence
Yuxuan Ye, Seoung-Tae Kim, Jinhoon Jeong, Mu-Hyun Baik, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2019
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CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives
with Ligand-Controlled Regiodivergence
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Yuxuan Ye1, Seoung-Tae Kim2,3, Jinhoon Jeong2,3, Mu-Hyun Baik2,3*, Stephen L. Buchwald1*
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1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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2Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon, 34141, Korea
3Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon,
34141, Korea
Abstract: Enantioenriched molecules bearing indole-substituted stereocenters form a class
of privileged compounds in biological, medicinal, and organic chemistry. Thus, the
development of methods for asymmetric indole alkylation is highly valuable in organic
synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a
significant challenge, since there is an intrinsic preference for alkylation at C3, the most
nucleophilic position. Furthermore, selective and predictable access to either N- or C3-
alkylated chiral indoles using catalyst control has been a long-standing goal in indole
functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and
C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to
conventional alkylation reactions in which indoles are employed as nucleophiles, this
transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling
partners. N- or C3-alkylated indoles are prepared with high levels of regio- and
enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the
use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional
theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled
regiodivergence.
Introduction
Enantiomerically enriched indole derivatives are ubiquitous in biologically active natural
products, and widely recognized as privileged components in pharmacologically relevant
compounds (Figure 1a).1,2 Therefore, the development of techniques for the efficient
enantioselective synthesis of indoles is a prominent objective in organic synthesis. A few
powerful methods have been developed recently to access chiral alkylated indoles. In these
transformations, the indole derivatives generally serve as the nucleophilic coupling fragments,
reacting with a variety of electrophiles, including activated olefins, ketones, imines, allylic
alcohol derivatives, and alkynes.3-5 Most alkylation reactions take place largely or entirely at C3,
due to the higher nucleophilicity at this position (Figure 1b). 6,7
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The development of methods that generate enantioenriched N-alkylated indoles has been
an active area of research for the past few years. The majority of these processes involve the
enantioselective N-allylation of indoles with electron-withdrawing groups or with substituents
blocking the C3 position. In addition, two-step procedures including N-allylation/oxidation of
indolines and N-allylation/Fischer indolization of aryl hydrazines have been developed.8-13
Despite these notable advances, methods for highly enantioselective N-alkylation (non-allylic
alkylation) of indoles with broad substrate scope remain rare.14,15 The difficulty in controlling
regioselectivity in indole alkylation reactions originates from the nucleophilic character of the
indole, with the C3 position being much more nucleophilic than N or other positions. We
hypothesized that if the indole could be employed as an electrophile instead of as a nucleophile,
alkylation reactions could potentially occur at positions other than C3.
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During the past few years, CuH catalysis16-18 has emerged as an efficient method for the
enantioselective formation of C–N and C–C bonds. In these reactions, enantioenriched
alkylcopper(I) intermediates such as II (Figure 1c) are generated from the reaction of alkenes
and a CuH catalyst ligated by a chiral phosphine ligand.19,20 The alkylcopper(I) species can then
be efficiently trapped by electrophiles such as electrophilic amines,21-25 ketones,26-28 imines,29,30
allylic phosphate,31-33and other reagents.34-38 We felt that these alkylcopper(I) species could act
as nucleophiles toward appropriate indole electrophiles, providing alkylated indoles potentially
with high levels of enantioselectivity and chemoselectivity. Among a variety of possible classes
of electrophilic indoles,39 we considered N-hydroxyindole derivatives to be promising reagents
for our proposed transformation (Figure 1c, electrophilic indole). N-hydroxyindole derivatives
with a variety of leaving groups (e.g., OH, OMe, OBz, OTs) have been prepared and their
nucleophilic substitution reactions have been studied.40,41 The ability of these to react with
nucleophiles at N-,42 C2-,43 and C3-positions44 of indoles has been demonstrated, although not in
a catalytic, enantioselective manner. In order to be useful, the chosen electrophilic indole
reagents need to be stable under reductive reaction conditions in the presence of LCuH, but
reactive enough to productively interact with the alkylcopper(I) intermediate. By analogy to
previous CuH-catalyzed hydroamination reactions that use (benzoyloxy)amine derivatives as
aminating reagents,21 we postulated that N-(benzoyloxy)indole derivatives (e.g., Figure 1c,
electrophilic indoles, R = Bz) might be suitable coupling partners.
Herein, we report a CuH-catalyzed enantioselective alkylation of indoles using a polarity
reversal (umpolung) strategy.45 In this method, electrophilic indole derivatives (N-(2,4,6-
trimethylbenzoyloxy)indoles) are employed as starting materials. With a DTBM-SEGPHOS-
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modified CuH catalyst, N-alkylated indoles, which are difficult to access by other methods, can
be efficiently synthesized with high levels of regio- and enantioselectivity (Figure 1d, blue).
During the course of this study, we unexpectedly found that the regioselectivity (N/C3) of this
process is ligand-controlled. By switching the ligand from DTBM-SEGPHOS to Ph-BPE,
enantioenriched C3-alkylated indoles could be selectively accessed (Figure 1d, purple). Using
DFT calculations, we have proposed a model for the regioselectivity based on the structure of the
ligands in the regiochemistry-determining transition states.
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Figure 1. Design of a CuH-catalyzed indole alkylation reaction using electrophilic indole
reagents. a) Representative biologically active N- and C3-substituted α-chiral indoles. b)
Regioselectivity in conventional enantioselective indole alkylation reactions. c) Proposed
mechanistic pathway of enantioselective alkylation of electrophilic indoles. d) Ligand-controlled
regiodivergent alkylation of electrophilic indoles.
Results and discussion
Reaction development and optimization
We reasoned that the stability and reactivity of the electrophilic indole reagent could be
modulated by tuning the leaving group as we had seen before.46 Thus, N-(benzoyloxy)indole
derivatives with different benzoate substituents were prepared (Table 1, 2a, 2b, 2c, 2d). The
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feasibility of the alkylation process was then investigated using styrene as the pronucleophile,
copper(II) acetate as the precatalyst, and DTBM-SEGPHOS as the ligand. For all four
electrophiles evaluated, the corresponding N-alkylated indole was generated with excellent
regioselectivity (N:C3 > 20:1) and with good enantioselectivity (Table 1, entries 1-4). Among
the indole electrophiles tested, the use of N-(2,4,6-trimethylbenzoyl)indole (2d) provided the
best yield and the highest enantiometric excess. We hypothesized that the steric hindrance
provided by the two ortho-methyl groups on the benzoate slows direct reductive cleavage of the
N–O bond by LCuH, but still allows the reagent to undergo the desired C–N bond formation at
elevated temperatures.
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We found that the regioselectivity of this reaction was sensitive to the choice of ligand.
When DTBM-SEGPHOS was replaced with Ph-BPE, instead of, 3a, which arises from carbon-
nitrogen bond formation, 4a, resulting from carbon-carbon bond formation at C3 was the
predominant product. (Table 1, entries 5 and 6). Catalysts based on DuanPhos provided the
alkylated indoles in diminished yields and with poor selectivity (Table 1, entry 7). Other
phosphine ligands, such as a Josiphos derivative and MeO-BIPHEP, showed limited ability to
facilitate the reaction (Table 1, entries 8 and 9).
After further optimization of the reaction parameters (Table S1 and S2 in the Supporting
Information), chiral N-alkylated indole 3a could be accessed in 85% yield with 91% ee and
>20:1 regioselectivity using DTBM-SEGPHOS as the supporting ligand (Table 1, entry 10). C3-
alkylated indole 4a could be isolated in 71% yield with 76% ee and >5:1 regioselectivity using
Ph-BPE as the ligand (Table 1, entry 11). As we have previously seen, the inclusion of an
alcohol as an additive was found to improve the efficiency of both transformations.29
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Table 1. Optimization of CuH-catalyzed enantioselective N- and C3-alkylation of indole
derivatives.
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a) Reactions were conducted on 0.10 mmol scale. Yields were determined by gas
chromatography using dodecane as internal standard. b) The e.e. was determined by SFC
analysis. c) The regioselectivity (r.r.) was determined by GC analysis of the crude reaction
mixture. d) Conditions: 1 (0.10 mmol), 2 (0.10 mmol), Cu(OAc)2 (5.0 mol%), (R)-DTBM-
SEGPHOS (6.0 mol%), DEMS (4.0 equiv), THF (0.1 M), 90 ºC, 12 h. e) Conditions: 1 (0.15
mmol), 2 (0.10 mmol), Cu(OAc)2 (5.0 mol%), ligand (6.0 mol%), DEMS (4.0 equiv), THF (0.5
M), 50 ºC, 12 h. f) Conditions: 1 (0.10 mmol), 2 (0.15 mmol), Et3COH (0.02 mmol), Cu(OAc)2
(5.0 mol%), (R)-DTBM-SEGPHOS (6.0 mol%), DEMS (4.0 equiv), THF (0.1 M), 90 ºC, 20 h.
g) Isolated yield on a 0.50 mmol scale. h) Conditions: 1 (0.20 mmol), 2d (0.10 mmol), Et3COH
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(0.02 mmol), Cu(OAc)2 (1.0 mol%), (S,S)-Ph-BPE (1.2 mol%), DMMS (4.0 equiv), THF (0.5
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M), 40 ºC, 24 h. ND = Not determined. DEMS = (EtO)2MeSiH. DMMS = (MeO)2MeSiH.
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Substrate scope of the N-alkylation reaction.
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Using the optimized reaction conditions described above, we evaluated a range of
styrenes as substrates (Table 2). In all cases with DTBM-SEGPHOS as the supporting ligand, we
observed that the N-to-C3 selectivity was greater than 20:1. Styrenes bearing ortho- (3b, 3k),
meta- (3c, 3j, 3l), and para-substituents (3e) were all suitable, yielding the desired N-alkylated
indoles with high efficiency and high levels of enantioselectivity. Electron-withdrawing groups
on the aryl ring of the styrenes are tolerated (3c, 3j, 3k, 3l), while an electron-donating group
(3d) slowed down the reaction.47a trans-β-Substituted styrenes were also successfully
transformed using this protocol (3g, 3h). In particular, 3h, the derivative of an important
serotonin reuptake inhibitor, was efficiently prepared in a reaction that proceeded with excellent
levels of regio- and enantioselectivity. A more sterically hindered β,β-substituted styrene was
transformed to the desired product (3i) in moderate yield as a single diastereomer.
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Terminal aliphatic alkenes could also be employed as substrates (3o, 3p). In these cases,
the reaction exhibited a nearly complete change in regioisomeric preference toward the anti-
Markovnikov product. Monosubstituted C=C double bonds underwent the transformation
selectively (3q, 3r, 3s), in the presence of cis-disubstituted or trisubstituted olefins.
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Table 2. Substrate scope of CuH-catalyzed enantioselective N-alkylation.
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Conditions: 1 (0.50 mmol), 2 (0.75 mmol), Et3COH (0.10 mmol), Cu(OAc)2 (5.0 mol%), (R)-
DTBM-SEGPHOS (6.0 mol%), DEMS (4.0 equiv), THF (0.1 M), 90 ºC, 20 h. The e.e. was
determined by SFC analysis. The regioselectivity (r.r.) was determined by GC analysis of the
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crude reaction mixture. a) Conditions: 1 (0.75 mmol), 2 (0.50 mmol), KF (0.10 mmol),
Cu(OAc)2 (5.0 mol%), (R)-DTBM-SEGPHOS (6.0 mol%), DEMS (4.0 equiv), THF (0.1 M), 70
c
ºC, 20 h. b) Using 1,4-dioxane instead of THF. Conditions: 1 (0.50 mmol), 2 (1.5 mmol),
Et3COH (0.10 mmol), Cu(OAc)2 (5.0 mol%), (R)-DTBM-SEGPHOS (6.0 mol%), DEMS (4.0
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equiv), 1,4-dioxane (0.1 M), 90 ºC, 20 h. ND = Not determined. DEMS = (EtO)2MeSiH.
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We next surveyed the scope of indole electrophiles that could be used in the N-alkylation
reaction. It was found that a variety of functional groups were accommodated at different
positions on the benzene ring of the indole, including a 6-trifluoromethyl (3j), a 4-tert-butyl ester
(3k), and a 6-chloro (3s) substituent. Alkyl groups at the 2- and 4-position of the indole
electrophile were tolerated and the corresponding products were synthesized in good yield (3l,
3p) with excellent enantioselectivity in the case of (3l). An indole electrophile with a 2-
carbomethoxy substituent exhibited low reactivity under the standard reaction conditions (10%
conversion). However, by using an excess of the styrene substrate and employing dioxane as
solvent, the desired product was obtained in moderate yield (3m) although in racemic form.47b
Indole electrophiles bearing substituents at the 3-position were generally poor substrates in this
N-alkylation reaction. In the case shown in Table 2, the desired product was generated in low
yield with a low level of enantioselectivity (3n).48
Substrate scope of the C3-alkylation reaction.
Using the reaction conditions that favor carbon-carbon bond formation, (i.e., with Ph-
BPE) a number of C3-alkylated indoles were prepared in moderate-to-good yields and with
useful levels of enantiomeric excess (Table 3). Styrene bearing a 4-trifluoromethyl substituent
was found to be a suitable substrate in this transformation, providing the desired indole product
(4b) in moderate yield with a high level of regioselectivity. The lower enantioselectivity
observed compared to 4a can reasonably be ascribed to the relatively fast epimerization of the
electron-deficient alkylcopper species.20,49 In contrast, 1-tosyl-5-vinylindole, a relatively
electron-rich alkene, underwent the transformation with lower regioselectivity but higher
enantioselectivity (4c). A trans-β-substituted styrene was also effectively transformed by this
protocol (4d). To further demonstrate the synthetic utility of this method, chiral C3-alkylated
indoles derived from estrone and loratadine (a common antihistamine agent) were prepared with
good regio- and enantioselectivities (4e, 4f). In addition to styrenes, a terminal aliphatic olefin
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was used as the coupling partner, generating the corresponding product in a moderate yield with
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excellent regioselectivity (4g, >20:1).
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Table 3. Substrate scope of CuH-catalyzed enantioselective C3-alkylation.
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2d (1.0 equiv)
Cu(OAc)2 (1.0 mol%)
(S,S)-Ph-BPE (1.2 mol%)
DMMS (4.0 equiv)
N
R3
O
R1
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O
R2
Me
R1
Me
1
N
(1.5 equiv)
H
Et3COH (20 mol%)
2d
Me
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PMB
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Me
N
CF3
Me
Me
Me
Ts
N
N
N
N
H
H
H
H
4a
4b
4c
4d
71% yield, 76% e.e.
r.r. = 6:1
61% yield, 65% e.e.
r.r. = > 20:1
55% yield, 85% e.e.
r.r. = 3:1
61% yield, 67% e.e.
r.r. = 4:1
Me
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Me
Me
O
HN
N
H
O
H
H
4e
62% yield, 84% e.e.
r.r. = 5:1
N
N
O
OMe
OEt
F
N
H
4fa
4ga
41% yield, 81% e.e.
r.r = 5:1
32% yield
r.r. > 20:1
Crystal structure of 4e
Conditions: 1 (1.0 mmol), 2d (0.50 mmol), Et3COH (0.10 mmol), Cu(OAc)2 (1.0 mol%), (S,S)-
Ph-BPE (1.2 mol%), DMMS (4.0 equiv), THF (0.5 M), 40 ºC, 24 h. The e.e. was determined by
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SFC analysis. The regioselectivity (r.r.) was determined by H NMR analysis of the crude
reaction mixture. DMMS = (MeO)2MeSiH. a) Using 5.0 mol% Cu(OAc)2 and 6.0 mol% (S,S)-
Ph-BPE instead of 1.0 mol% Cu(OAc)2 and 1.2 mol% (S,S)-Ph-BPE.
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Mechanistic discussion
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DFT calculations were performed to construct a mechanistic model that explains the
regiodivergence observed in the reaction. Since the SEGPHOS ligand displays the same
regioselectivity as DTBM-SEGPHOS (>20:1 N:C3), we used SEGPHOS in the calculations to
reduce the computational cost. In addition, styrene and 2d were selected as model substrates. The
olefin insertion step, which is responsible for determining the enantioselectivity, is well-
understood24,27 and thus, we focused on subsequent steps in the mechanism to explain the
regioselectivity.50
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The alkylcopper(I) complex II can form either the N-indoyl copper(III) complex IIIN
(Figure 2a, N-oxidative addition) or the C3-indoyl copper(III) complex IIIC (Figure 2a, C3-
oxidative addition) through the oxidative addition transition states II-TS and II-TS’,
respectively. Subsequent reductive elimination affords the products 3a and 4a, respectively; in
the latter case after tautomerization of the initially formed intermediate 4a’. An intramolecular
interconversion between IIIN and IIIC through intermediate IV, which leads to decreased
regioselectivity, was also considered.
a
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CuI
Me
Ph
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O
N
P
P
CuI
Ph
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II-TS
P
P
N
CuI
Ph
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II-TS’
Figure 2. DFT calculations on the mechanism of CuH-catalyzed alkylation of electrophilic
indoles. a) Proposed regiochemistry-determining reaction pathway. The mesitoate anion is
omitted for clarity in the many of the structures. b) Energy profiles of the oxidative addition and
reductive elimination steps with 2d and alkylcopper(I) complex II supported by SEGPHOS and
Ph-BPE, respectively. c) The optimized structures of II, II-TS, and II-TS’ with Ph-BPE and
SEGPHOS as the ligand, respectively. The phenyl group in the Ph-BPE ligand obscuring the
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copper center is displayed in green. (Subscripts S and P indicate SEGPHOS and Ph-BPE as the
supporting ligand, respectively)
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Figure 2b illustrates the most important portion of the reaction energy profiles for the
SEGPHOS and Ph-BPE ligands (subscripts S and P indicate SEGPHOS and Ph-BPE as the
supporting ligand, respectively). In good agreement with the experimental observation of
excellent regioselectivity of greater than 20:1 (N:C3), the alkylcopper(I) complex IIS bearing the
SEGPHOS ligand is predicted to prefer oxidative addition at N rather than at C3. These
processes proceed through the transition states IIS-TS and IIS-TS’ at 23.4 and 26.3 kcal/mol,
respectively (Figure 2b, SEGPHOS). In addition, the intramolecular interconversion from IIISN
to IIISC is predicted to be insignificant, since the barrier of 1,3-migration (from IIISN through the
transition states IIISN-TS’) was found to be 17.8 kcal/mol higher in energy than the reductive
elimination barrier (from IIISN through the transition states IIISN-TS).
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When the SEGPHOS ligand is replaced with Ph-BPE, oxidative addition is instead
slightly preferred at C3 rather than N: the transition state IIP-TS’ at 19.9 kcal/mol is lower in
energy than IIP-TS at 20.9 kcal/mol (Figure 2b, Ph-BPE). In this case, the barrier of 1,3-
migration from IIIPC to IIIPN is comparable with the reductive elimination barrier to generate 4a.
The small preference for the C3-alkylation regioisomer, and the competitive 1,3-migration are in
qualitative agreement with experimental results, which showed moderate levels of
regioselectivity (~5:1 C3:N).
We hoped to identify the origins of this ligand effect at a more fundamental level.
Therefore, we compared the structures of the alkylcopper(I) intermediates supported by Ph-BPE
(IIP) and SEGPHOS (IIS), respectively. As shown in Figure 2c, the phenyl group in the Ph-BPE
ligand, highlighted in green, rests above an open coordination site of the copper in IIP, whereas
the metal center in the intermediate IIS is relatively unhindered and freely accessible. During the
N-oxidative addition with Ph-BPE ligand (Figure 2c, IIP-TS), when catalyst IIP engages the
indole substrate at the N-position (blue), the benzoate ligand (red) is in close proximity to the
ligand phenyl group (green), which gives rise to unfavorable steric interactions. In contrast, C3-
oxidative addition can be accomplished without such steric crowding, because the benzoate
fragment can point away from the Ph-BPE ligand, as shown in the computed structure of IIP-
TS’.
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These steric considerations are less important in the SEGPHOS case. Thus the N–O
oxidative insertion, which appears to be favored by the intrinsic electrophilicity of the indole
electrophile, takes place (Figure 2c, IIS-TS vs. IIS-TS’). To confirm our hypotheses that the N-
oxidative addition transition state is destabilized by steric interactions when Ph-BPE is used
rather than SEGPHOS, an energy decomposition analysis (see the Supporting Information for
details) was used to compare transition states IIP-TS and IIP-TS’. The distortion energy on the
phosphine fragment is estimated to be ~5 kcal/mol higher in IIP-TS than in IIP-TS’. This
difference is more significant than the intrinsic energetic advantages of N-oxidative addition over
C3-oxidative addition, and steric effects are able to reverse this preference.
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Conclusion
In summary, we have developed an enantioselective CuH-catalyzed process to access
either N- or C3-alkylated indoles depending on the choice of ligand. In contrast to conventional
indole functionalizations in which indoles are used as nucleophiles, N-(benzoyloxy)indole
derivatives are employed as electrophiles in this method. When the DTBM-SEGPHOS is used as
the supporting ligand, N-alkylated indoles with a variety of functional groups are prepared in
good yields with high levels of regio- and enantioselectivity. When the Ph-BPE ligand is
employed, chiral C3-alkylated indoles can be accessed as well. We anticipate that the application
of this polarity reversal strategy is not limited to indole alkylation but may be further extended to
the catalytic functionalization of other important electron-rich nitrogen heterocycles.
Associated Content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental details and computational data (PDF)
Spectroscopic Data (PDF)
Author Information
Corresponding Author
*mbaik2805@kaist.ac.kr
*sbuchwal@mit.edu
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Notes
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The authors declare no competing financial interests.
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Acknowledgements
We are grateful to the National Institutes of Health (R35-GM122483), and the Institute for Basic
Science (IBS-R010-D1) in Korea. The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institute of Health. We thank Mr.
Richard Liu, Drs. Scott McCann, Christine Nguyen, and Andy Thomas for their advice on the
preparation of this manuscript. We acknowledge Drs. Peter Müller (MIT) and Charlene Tsay
(MIT) for X-ray crystallographic analysis of 4e. We thank Mr. Marek Domin (Boston College),
and Dr. Zhenxing Liu (Boston College) for the help with the High Resolution Mass
Spectrometry analysis. We thank National Institutes of Health for a supplemental grant for the
purchase of supercritical fluid chromatography (SFC) equipment (GM058160-17S1).
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and in turn facilitate the dissociation of the Cu–C bond of the corresponding benzyl copper
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intermediate at high temperature (90ºC). This would result in catalyst decomposition and might
be responsible for the low yield of 3d. (b) We speculate that the lower yield seen for 3m is due to
substrate chelation.
(48) In the case of 3-substituted indole electrophiles, we mainly observed the direct reduction of
the electrophile to the corresponding indole. Computational studies indicate that this process
begins with oxidative insertion of LCuH into the N–O bond of the indole electrophile, rather than
hydrocupration of the styrene double bond. See Figure S4 in the Supporting Information for
details.
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(49) (a) Lee, J.; Radomkit, S.; Torker, S.; del Pozo, J.; Hoveyda, A. H., Mechanism-Based
Enhancement of Scope and Enantioselectivity for Reactions Involving a Copper-Substituted
Stereogenic Carbon Centre. Nat. Chem. 2018, 10, 99–108. (b) Huang, Y.; del Pozo, J.; Torker,
S.; Hoveyda, A. H., Enantioselective Synthesis of Trisubstituted Allenyl–B(pin) Compounds by
Phosphine–Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity
of Cu–Allenyl Intermediates. J. Am. Chem. Soc. 2018, 140, 2643–2644.
(50) The absolute configurations of the products were assigned to be S in both C–N and C–C
formation reactions (see the Supporting Information for details). By comparison with previous
reactions involving irreversible, stereoselective hydrocupration of styrenes by DTBM-
SEGPHOS- and Ph-BPE-ligated copper hydride species, we conclude that the configuration of
the benzylic stereogenic center is most likely retained during the subsequent reaction with the
electrophilic indole reagent.
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R1
L*CuH, alkenes
N
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R3
L* = (R)-DTBM-SEGPHOS
R2
19 examples
N-Alkylation
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up to 85% yield, 99% e.e.
R1
N
R2
OR
R = COMes
R3
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R1
electrophile
L*CuH, alkenes
N
H
L* = (S,S)-Ph-BPE
7 examples
C3-Alkylation
up to 71% yield, 85% e.e.
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