Regiospecificity in Ligand-Free Pd-Catalyzed C-H Arylation of Indoles: LiHMDS as Base and Transient Directing Group

Article abstract of DOI:10.1021/acscatal.9b04864

A highly efficient catalyst-base pair for the C-H arylation of free (NH)-indoles in the C-3 position is reported. Ligand-free palladium acetate coupled with lithium hexamethyldisilazide (LiHMDS) catalyzed the regiospecific, i.e. 100% regioselective, C-3 a

Full text of DOI:10.1021/acscatal.9b04864

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Article
Regiospecificity in Ligand-Free Pd-Catalyzed C-H Arylation
of Indoles: LiHMDS as Base and Transient Directing Group
Yorck Mohr, Marc Renom-Carrasco, Clement Demarcy, Elsje Alessandra Quadrelli,
Clément CAMP, Florian Michael Wisser, Eric Clot, Chloé Thieuleux, and Jerome Canivet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04864 • Publication Date (Web): 28 Jan 2020
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ACS Catalysis
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Regiospecificity in Ligand-Free Pd-Catalyzed C-H Arylation of
Indoles: LiHMDS as Base and Transient Directing Group
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Yorck Mohr,[a] Marc Renom-Carrasco,[b] Clément Demarcy,[b] Elsje Alessandra Quadrelli,[b] Clément
Camp,[b] Florian M. Wisser,[a] Eric Clot,[c] Chloé Thieuleux*[b] and Jérôme Canivet*[a]
[a]Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, IRCELYON - UMR 5256, 2 Av. Albert Einstein, 69626
Villeurbanne, France
[b]Univ. Lyon, Université Claude Bernard Lyon 1, CPE Lyon, CNRS, C2P2 - UMR 5265, 43 Bvd. du 11 Novembre 1918,
69616 Villeurbanne, France
[c]Institut Charles Gerhardt Montpellier, Université de Montpellier, UMR 5253 CNRS, ENSCM, 8 rue de l’Ecole Normale,
Montpellier 34296, France
ABSTRACT: A highly efficient catalyst-base pair for the C-H arylation of free (NH)-indoles in the C-3 position is reported. Ligand-
free palladium acetate coupled with lithium hexamethyldisilazide (LiHMDS) catalyzed the regiospecific, i.e. 100% regioselective,
C-3 arylation of indoles with high turnover numbers. This catalytic system has been successfully applied to a wide range of substrates
including various functional aryl halides and indolic cores. The unique role of LiHMDS as both a base and unexpected transient
directing group has been revealed experimentally and elucidated computationally, in line with a Heck-type insertion-elimination
mechanism.
KEYWORDS: cross-coupling, indole, C-H arylation, palladium, LiHMDS.
Heterobiaryls and in particular those containing indolic cores
are ubiquitous motifs in active pharmaceutical ingredients
(API) of marketed drugs.1–3 Their synthesis often involves at
least one catalytic step based on carbon-carbon coupling
reactions such as the Pd-catalyzed aryl boronate/aryl halide
Suzuki-Miyaura cross-coupling reaction.4 Only in the last
decade, the formidable challenge of activating aromatic C-H
bonds has led to reduced synthetic steps and improved atom
economy.5–10
procedure gave rise to almost exclusively C-3 arylation albeit
in moderate yields. Despite these synthetic limitations, C-3
arylated indoles are considered to be promising API, for
instance, as antimicrobial agents, enzyme inhibitors and
anticancer drugs (Scheme 1).35–41
O
R'
F
3
R
OMe
2
O
N
N
H
N
H
1
H
Heteroarene C-H arylation is reported to proceed following
three main pathways, often supported by DFT calculations:
electrophilic aromatic substitution,11 concerted metalation-
deprotonation12–16 or Heck-type carbo-metalation.17,18 The
reaction’s regioselectivity is often a key to discriminate
mechanisms for a given catalytic system and is mostly
explained on the basis of the substrate’s electronic or steric
properties, the directing effect of a ligand on the catalyst or the
presence of permanent or transient directing groups.18–24
R = H, Me, OMe
R' = H, o-Me, p-OMe
inhibitor of brassinin
glucosyltransferase
anticancer
(murrapanine)
antimicrobial
Scheme 1. API based on C-3 arylated free (NH)-indoles and their
biological activity.35–38
In this context, we report here the ligand-free palladium-
catalyzed regiospecific, i.e. 100% regioselective, C-3 arylation
of free (NH)-indole derivatives. Catalyzed by a standard
palladium salt, the reaction mechanism is driven by a specific
lithiated base whose dual role is crucial as demonstrated
experimentally and elucidated by DFT calculations.
Regarding free (NH)-indoles, their C-H arylation at the C-3
position combined with regiospecificity and high activity has
never been accomplished so far. The few reported systems
which show high selectivities for the C-3 arylated products
display only moderate TON values up to 81 (the catalysts in
these cases are mostly Pd- or Ir-based systems).25–32 Yields of
up to 76% for the C-3 arylated product (after 35 hours) were
obtained via a transition metal-free system developed by Chen
and Wu using four equivalents of potassium tert-butoxide and
an excess of indole.33 However, this system led to mixtures of
regioisomers. Another metal-free system for the arylation of
indoles was described by Ackermann et al. using substituted
diaryliodonium salts as reagents without any catalyst.34 This
After extensively screening reaction parameters (Scheme 2
and SI), we determined that palladium acetate, with a loading
as low as 0.05 mol%, efficiently catalyzed the phenylation of
1H-indole with 100% selectivity for the C-3 position using
lithium hexamethyldisilazide (LiHMDS) as base and
bromobenzene as the arylating agent, in toluene at 120°C. After
16 hours, the product was isolated with a yield of 90%,
corresponding to a TON of 1800 moles of isolated 3-phenyl-
1H-indole per mole of palladium. In toluene, classical inorganic
bases such as carbonates or acetates with lithium, potassium and
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ACS Catalysis
caesium as counter-cations, gave very poor yields. Organic
Page 2 of 8
toluene without affecting neither yield nor regiospecificity
(Table S7). To demonstrate the versatility of the present
catalytic system, different aryl electrophiles were evaluated
(Scheme 3). The C-3 indole arylation was found to proceed
efficiently using either iodo- (TON = 1900), bromo- (TON =
1
2
3
4
5
6
7
8
bases such as triethylamine (TEA), diisopropylethylamine
(DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were found to be
inefficient. Lithium and potassium tert-butoxide did not allow
the arylation to proceed in toluene, in contrast to the activity
reported by Chen and Wu in dimethylsulfoxide (DMSO).33
1800) or chlorobenzene (TON
Pd(OAc)2/LiHMDS catalytic system. High activity was also
achieved using p-iodoanisole (TON 1840) and p-
bromodimethylaniline (TON 1220). When N,N-
=
380) with the
=
H
Pd(OAc)2 (0.05 mol%)
LiHMDS (2.2 equiv.)
=
Br
bis(trimethylsilyl)-protected 4-bromo-aniline was used as
substrate, the coupling at the C-3 position also proceeded
efficiently (TON = 800). Using three equivalents of 1-bromo-
4-chlorobenzene as arylating agent gave rise to 3-(4-
chlorophenyl)-1H-indole with a TON of 700. Here the superior
reactivity of the bromide compared to the chloride moiety
allowed reaching 100% chemoselectivity. Further aromatic
systems, like naphthalene, benzothiophene and ferrocene could
be used efficiently as electrophiles with average to high activity
and full regioselectivity. Noteworthy, the Pd(OAc)2/LiHMDS
system allowed preparing 3-(o-tolyl)indole, which cannot be
obtained using the previously reported transition metal-free
system, since the latter operates via a benzyne intermediate.33
H
+
toluene (4 mL)
120°C, 16 h
9
N
H
H
N
H
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(0.5 mmol)
(1.2 equiv.)
90% yield, 100% C-3 selectivity
other bases
other catalysts
none (< 1%)
Pd(bipy)(OAc)2 (86%)
Pd(bipy)Cl2 (86%)
Pd(PPh3)2(OAc)2 (21%)
Pd(PPh3)4 (20%)
Li2CO3, K2CO3, Cs2CO3, LiOAc, KOtBu, LiOtBu, KHMDS,
TEA, DIPEA, DABCO, DBU (< 5% in all cases)
other solvents
THF, dioxane, DMF, DMAc, DMSO (< 5% in all cases)
Scheme 2. The Pd(OAc)2/LiHMDS catalytic system for efficient
C-3 arylation of 1H-indole and overview of screened parameters.
Ar
Pd(OAc)2 (0.05 mol%)
LiHMDS (2.2 equiv.)
Ar-X
+
The scope of applicable functionalized indoles is presented in
Scheme 4. The C-3 arylation efficiently proceeded with both
phenyl iodide and bromide in most cases.
toluene (4 mL)
120°C, 16 h
N
H
N
H
(0.5 mmol)
(1.2 equiv.)
100% C-3 selectivity
Pd(OAc)2 (0.05 mol%)
LiHMDS (2.2 equiv.)
R
Product (TON; yield)
X
R
5
4
7
3
+
2
toluene (4 mL)
120°C, 16 h
N
H
6
N
1
H
(0.5 mmol)
(1.2 equiv.)
N
H
N
N
N
H
Product (TON; yield)
H
H
X = I (1900; 95%)
X = Br (1800; 90%)
X = Cl (380; 19%)
X = I (1680; 84%)
X = I (1700; 85%)
X = I (1000; 50%)
TMS
TMS
OMe
Cl
N
N
N
H
N
H
N
H
X = I (1800; 90%)
X = Br[](1760; 88%)[]
X = I (1200; 60%)
X = I (80; 4%)[b] X = Br (40; 2%)[b]
X = Br[](460; 23%)
(142; 71%)[a]
(38; 19%)[a,b]
(40; 80%)[c]
(18; 9%)[a,b]
N
H
N
H
N
H
N
H
X = Br[a] (700; 35%)
(184; 92%)[b]
X = Br (800; 40%)
(146; 73%)[b]
X = I (1840; 92%)
X = Br (1220; 61%)
Br
Cl
N
H
N
N
S
H
H
Fe
X = I (1440; 72%)
X = Br[](1320; 66%)[]
X = I (880; 44%)
(110; 55%)[a]
X = I (1560; 78%)
X = Br[](860; 43%)
(124; 62%)[a]
N
H
N
H
N
H
X = I (1780; 89%)
X = Br (520; 26%)
(110; 55%)[b]
X = Br (150; 8%)[c]
O
(52; 26%)[b]
F
MeO
B
O
N
H
N
H
N
Scheme 3. Scope of aryl halides. TON are calculated from isolated
yields if not otherwise stated. [a] 3 equivalents of 1-bromo-4-
chlorobenzene were used. [b] 0.5 mol% of Pd(OAc)2 used. [c] TON
calculated from GC-FID yield.
H
X = I (1120; 56%)
X = Br[](500; 25%)
(100; 50%)[a]
X = I (760; 38%)
(102; 51%)[a]
X = Br[](280; 14%)[b]
(92; 46%)[a]
X = I (620; 31%)
(94; 47%)[a]
X = Br[](120; 6%)[b]
(26; 13%)[a,b]
Using LiHMDS, solvents other than toluene and mesitylene,
such as tetrahydrofuran (THF), dioxane, dimethylformamide
(DMF), dimethylacetamide (DMAc) and DMSO, gave
essentially N-arylation or no reaction at all (see SI, Table S7).
In contrast to the work of Chen and Wu who noticed a change
in selectivity towards N-arylation in the presence of oxygen,33
here the standard reaction with bromobenzene and a metal
loading as low as 0.05 mol% did not require an anhydrous or
deoxygenated solvent but could be performed in technical grade
Scheme 4. Scope of functionalized indoles. TON are calculated
[a]
from isolated yields if not otherwise stated.
0.5 mol% of
Pd(OAc)2 used.[b] TON calculated from GC-FID yield. [c] 2.0 mol%
of Pd(OAc)2 used.
Indoles functionalized either at the C-5 or C-7 positions can
be efficiently arylated leading to a 100% regioselectivity in all
but one case. Only for 5-methyl-1H-indole, traces of a
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presumably N- or C-2 arylated product were detected with,
formation of traces of N-arylated indole were observed after
16 hours (Table 1, entry 10 and SI).
1
2
3
4
5
6
7
8
nonetheless, a selectivity of 99% for the C-3 arylated product
(Figure S3). 2-Methyl-1H-indole can also be C-3 arylated with,
however, a TON one order of magnitude lower than other
functionalized indoles. This lower activity is probably due to
steric hindrance resulting from the presence of the methyl
group. Similarly, the use of 2-phenylindole as substrate leads to
no reaction.
From a mechanistic point of view, since the use of LiHMDS
was key for both activity and selectivity, a series of experiments
was carried out to gain more insight into the role of the lithiated
base (Table 2). Under optimized conditions, we found that
reducing the amount of LiHMDS from 2.2 equiv. to 1.5 or 1.0
equiv. drastically lowered the yield of the reaction from 90% to
38% and 0.6%, respectively (Table 2, entries 1-3), thus
suggesting that two equivalents of LiHMDS are mandatory.
When using NaHMDS, KHMDS or Mg(HMDS)2 instead of
LiHMDS, very low arylation yields were observed (0.05 mol%
Pd, Table 2, entries 4-6). When 5 mol% Pd were used,
Mg(HMDS)2 was found to be capable to drive the reaction with
however a lower regioselectivity (33% yield, 96% selectivity,
Table S1 and S2), whereas KHMDS was not. It is noteworthy
that Sames and coworkers also reported in 2005 the use of
Mg(HMDS)2 as base for this reaction, among a series of Mg
salts, albeit with the formation of both C-2 and C-3 arylated
products and the nature of the magnesium salt of indole as well
as its role in the reaction mechanism not being elucidated.25
Overall, the Pd(OAc)2/LiHMDS catalytic system is tolerant
to various halide, methoxy, substituted amino, and boronate
substituents (Scheme 3 and 4), offering the possibility for
further functionalization of the 3-phenyl-1H-indole moiety.
Unfortunately, compounds bearing nitro or trifluoromethyl
groups, either at the electrophile or the indolic core, decompose
under the reaction conditions. Aryl halides based on pyridine or
with protic functional groups (-OH, -NH2) did not react with
1H-indole (see SI, Scheme S1).
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Following the concept of “homeopathic” catalysis introduced
by Beletskaya and Cheprakov42 and demonstrated by de Vries
and co-workers for ligand-free Pd-catalyzed C-C coupling
reactions,43,44 we tested the Pd(OAc)2/LiHMDS catalytic
system at Pd loadings as low as 5 ppm with respect to the
quantity of indole (i.e. 0.0005 mol%) and a TON of ca. 16000
was reached without affecting the selectivity for the C-3
arylated product (Table 1, entry 8). However, the yield
decreased significantly at such a low palladium loading.
The use of alternative lithiated bases such as lithium
diisopropylamide (LDA, pKa ~ 36), which is a stronger lithiated
base than LiHMDS (pKa ~ 26), or n-butyl lithium (BuLi, pKa
~ 50) gave rise to only 0.3% yield (Table 2, entry 7) or no
arylated product (Table 2, entry 8), respectively.
Table 1. Effect of lowering the palladium loading down to
the ppm level.[a]
Table 2. Evaluation of the effect of different lithiated and
different silazide bases on the catalytic performance.[a]
Entry
Pd loading
(mol%)
Time
(h)
Temperature
(°C)
C-3 yield
TON[c]
Entry
Base (equiv.)
C-3 yield (%)[b] TON[c]
(%)[b]
1
LiHMDS (2.2)
90
1800
750
11
8
1
0.05
0.05
0.05
0.05
0.01
0.002
0.002
0.0005
0
16
1
120
120
120
150
120
120
150
120
120
150
90
29
58
81
46
13
23
8
1800
570
2
LiHMDS (1.5)
38
2[d]
3[d]
4[d]
5
3
LiHMDS (1)
0.6
0.4
0.2
1.5
0.3
0
2
1200
1600
4600
6300
11400
15700
n.d.
4
NaHMDS (2.2)
KHMDS (2.2)
1
5
4
16
16
16
112
112
16
6
Mg(HMDS)2 (2.2)
LDA (2.2)
30
6
6
7[d]
7
8
BuLi (2.2)
n.d.
1680
6
8
9
BuLi (0.9) + LiHMDS (1.3)[d]
BuLi (0.9) + NaHMDS (1.3)[d]
84
9
10[d]
0
10
11
0.3
1.3
0
0
n.d.
LiHMDS (1.1) + NaHMDS
(1.1)[d]
26
[a]
Reaction conditions: 1H-indole (0.5 mmol), bromobenzene
(0.6 mmol), palladium acetate and LiHMDS (1.1 mmol) in toluene
[a]
Reaction conditions: 1H-indole (0.5 mmol), bromobenzene
[b]
(4 mL) at 120°C.
standard.
GC-FID yields with dodecane as internal
(0.6 mmol), palladium acetate (0.25 µmol) and base in toluene
[c]
Turnover number defined as (moles of
3-phenylindole)/(moles of palladium) (n.d.: not determined).
Reaction performed under microwave irradiation (300 W).
[b]
(4 mL) at 120°C for 16 h.
internal standard.
GC-FID yields with dodecane as
[d]
[c]
Turnover number defined as (moles of 3-
[d]
phenylindole)/(moles of palladium) (n.d.: not determined).
Indole and the two bases were stirred in toluene for 15 min prior to
the addition of bromobenzene and Pd(OAc)2.
We also investigated the use of microwave irradiation as
heating protocol.45–47 In the presence of 0.05 mol% of palladium
and under microwave irradiation, a TON of 1200 was reached
at 120°C after two hours and a TON of 1600 was obtained at
150°C after only one hour of reaction (Table 1, entries 3 and 4,
respectively). In the latter case, the turnover frequency (TOF),
defined as moles of 3-phenyl-1H-indole per mole of palladium
per hour, reaches a value of 1600 h-1, which represents one of
the highest TOF for metal-catalyzed C-H arylation reactions
reported so far.48,49 Furthermore, using only 20 ppm of
palladium acetate, the 3-phenyl-1H-indole was obtained with
full regioselectivity and a TON of 11400 (Table 1, entry 7). In
the absence of palladium, under microwave heating, only the
To further elucidate the role of both the lithium cation and the
hexamethyldisilazide anion (HMDS-) in the reaction, different
base combinations were evaluated. A mixture of BuLi and
LiHMDS gave comparable results to those found under
standard conditions (Table 2, entry 9). In contrast, when one
equivalent of Li was removed from the reaction mixture by
using either BuLi/NaHMDS or LiHMDS/NaHMDS, almost all
the activity was suppressed (Table 2, entries 10 and 11) similar
to when one equivalent of LiHMDS was employed (Table 2
entry 3). Thus, the palladium-based catalytic system requires
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two equivalents of base, at least one being HMDS-, and two
To get deeper insight into the possible reaction mechanism,
deuterium-labelling experiments were performed. When (2-
2H)-1H-indole was used as a substrate, the final product was
obtained with complete deuterium retention leading to 3-
phenyl-(2-2H)-1H-indole, which excludes any C-H activation at
the C-2 position. This is further supported by the fact that 2-
methyl-1H-indole could be C-3 arylated (Scheme 4 and section
4 of SI). As a blank experiment, we performed the reaction
using 3-methyl-1H-indole as substrate and the starting reagents
were quantitatively recovered showing that neither C-2 nor N-
arylation occurred as side reactions (Scheme S1). Using 1-
methyl-1H-indole, also no reaction was observed, highlighting
the importance of this position in the reaction mechanism
(Scheme S1).
When the reaction was carried out using (3-2H)-1H-indole
and 1H-indole as substrates in parallel reactions or in a 1:1
mixture for an intermolecular competition experiment, no
kinetic isotopic effect (KIE) was observed, kH/kD = 1 (Figure
S64-S66). Thus, the C-H cleavage at the C-3 position is not the
rate-determining step.55 The absence of any KIE makes a CMD
mechanism very unlikely, and thus is not considered any
further.18,56
equivalents of Li+ with respect to the substrate.
1
2
3
4
5
6
7
8
Further, the product of mixing 1H-indole with two
equivalents of LiHMDS was isolated as a white powder and
characterized by liquid and solid-state NMR spectroscopy as
1
well as ICP-OES and elemental analysis (see SI). H and 13C
liquid state NMR spectra of the isolated precipitate recorded at
105°C in toluene-d8 show the presence of indolide and HMDS-
in a 1:1 ratio (Figure S55 and S56). In addition, well-resolved
13C Cross-Polarization (CP) Magic Angle Spinning (MAS)
solid-state NMR spectra were obtained with chemical shifts in
good agreement to those obtained from liquid state 13C NMR
(Figure S56 and S59) spectroscopy. ICP-OES and elemental
analysis evidence the presence of two Li cations, which appear
as a single signal in both the liquid-state and the MAS solid-
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7
state Li NMR spectra at -1.5 ppm and -2.5 ppm, respectively
7
(Figure S57 and S60). In contrast, the Li NMR signal of
LiHMDS in toluene-d8 at 105°C is found at +1.4 ppm (Figure
S63), confirming a different chemical environment of Li in the
two compounds. Furthermore, 1H-1H NOESY experiments
display a correlation between the methyl groups of the HMDS-
moiety and several indole protons at 105°C in toluene-d8
(Figure S58).
Calculations performed at the DFT level allow to draw the
energy profile of the reaction between phenyl bromide and
indole catalyzed by Pd(II) in the presence of two equivalents of
LiHMDS (Figure 1). The calculations clearly show that a
mechanism based on the insertion of a Pd-aryl into the indole
C-2=C-3 bond (carbo-palladation) followed by a base-assisted
elimination in a Heck-type mechanism is much more favored
than an electrophilic aromatic substitution pathway (SEAr)
(Figure S72, see SI for detailed calculations). The Heck-type
mechanism represents here a new pathway since previously
proposed pathways for catalytic indole C-H arylation reactions
were of SEAr type.11,25 Noteworthy, the selectivity of the SEAr
reaction in the Mg(HMDS)2 catalyzed indole arylation was
explained so far only by steric effects. The use of a bulky
counter ion such as HMDS- was supposed to hinder the required
C-3 to C-2 migration of palladium, thus increasing the amount
of C-3 arylated indole.
These data strongly suggest that, as it is known for lithium
bis(silyl)amides,50–53 the lithiated compound is present
predominantly as a bis-lithium indolide hexamethyldisilazide
species with the general formula [indolide·Li2·HMDS]
(Scheme 5), the presence of larger aggregates being however
not excluded.54
Li
Si
H
Si
N
N
N
+
2
+
Li
N
Li
N
Si
Si
H
Si
Si
[indolide·Li2·HMDS]
Scheme 5. Postulated reactivity of 1H-indole with two equivalents
of LiHMDS leading to [indolide·Li2·HMDS] as a key intermediate.
When the deprotonation of indole is carried out in the
presence of two equivalents of Li+ and one equivalent of
HMDS- at room temperature, [indolide·Li2·HMDS] precipitates
in toluene but then dissolves back upon heating above 100°C.
In contrast, the use of other lithiated bases gave precipitates that
were not soluble even at 120°C in toluene (Figure S52). This
unique solubility of [indolide·Li2·HMDS] was confirmed by
in-situ liquid state NMR spectroscopy. Hexamethyldisilazane
Here, in the Heck-type insertion-elimination mechanism, the
overall energy barriers are very similar for both the C-2 and C-
3 arylation pathways. However, two key intermediates, both
implying the second LiHMDS molecule, favorably drive the
arylation to the C-3 position, namely D3 and D3’ (Figure 1).
First, in the insertion step, the D3 species is stabilized by
19.3 kcal/mol compared to the analogous D2 species due to the
interaction between one lithium atom and the bromide of the
palladium complex.
1
was the sole product observed in the H spectrum of a 1:2
mixture of 1H-indole and LiHMDS in toluene-d8 at room
temperature. Furthermore, no soluble Li species were detected,
i.e. no signal in the 7Li NMR spectrum. This evidences that at
room temperature all indole and Li species are insoluble. Upon
heating to 105°C the signals belonging to the
[indolide·Li2·HMDS] species become visible in both 1H and 7Li
NMR spectra (Figure S53 and S54).
This stabilizing effect of LiHMDS is already present in the
coordination of Pd to C-2=C-3 as illustrated by the larger
stability of C3 compared to C2. The energy barrier to achieve
the base-assisted elimination at C-3 is composed of two
individual events: decoordination of LiHMDS from D3 to reach
a configuration (D3’) prone to effectively deprotonate the C-3
position, and actual base-assisted elimination through TS-D3.
Even though the transition state from D3 to D3’ could not be
located, the first step has an energy barrier of approximately
18.8 kcal/mol, whereas the second one has an energy barrier of
15.5 kcal/mol. In comparison, base-assisted elimination in the
C-2 pathway shows a direct transition from D2 to reach the
corresponding TS-D2 having a much higher energy barrier of
33.9 kcal/mol.
A catalytic test was carried out with the isolated precipitate
[indolide·Li2·HMDS] without adding any additional base under
standard conditions (see SI), giving 3-phenyl-1H-indole in 85%
yield. In light of these observations, only the combination of
indole with two equivalents of Li+ and one equivalent of
HMDS- gives rise to
a soluble reaction intermediate
[indolide·Li2·HMDS] which can be readily arylated by the
palladium catalyst.
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The calculations highlight that the transition between D3 and
Moreover, the computed structures confirm the experimental
evidence that the [indolide·Li2·HMDS], denoted B in Figure 1,
is the most stable species in a system of one molecule of 1H-
indole and two molecules of LiHMDS.
1
2
3
4
5
6
7
8
D3’ with the highest energy barrier (approximately
18.8 kcal/mol) should be the rate-determining step. This
supports the absence of a KIE observed experimentally, in line
with the “no KIE” scenario reported by Simmons and
Hartwig.55 Here the rate-determining step has to occur before
the cleavage of the C-H bond, e.g. the formation of a complex
undergoing subsequent deprotonation at the functionalized
carbon.
Based on experimental and computational findings, we
demonstrate herein for the first time the direct C-3 arylation of
indoles proceeding via a Heck-type mechanism. In this
insertion-elimination pathway LiHMDS acts not only as a base
but also as a unique transient directing group driving the
regiospecificity of the reaction towards the C-3 position.
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27
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40
41
42
43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
Figure 1. Schematic relative free energy profile for the reported reaction calculated at the DFT (PBE0-D3) level. Pathways towards C-2 or
C-3 arylated indole are shown in red and blue, respectively. Structures of calculated intermediates and transition states are represented.
All authors have given approval to the final version of the
manuscript.
In summary, we have uncovered a catalytic system able to
achieve the arylation of free (NH)-indoles with 100%
selectivity for the C-3 arylated product and remarkable turnover
numbers at the same time. Experimental findings combined
with DFT calculations highlight the key relevance of a bis-
lithium indolide hexamethyldisilazide [indolide·Li2·HMDS]
species as activated indole substrate. For the first time in indole
C-H arylation, the observed selectivity is explained by a Heck-
type mechanism in which LiHMDS uniquely plays the role of
both a base and transient directing group. In light of these
results, the use of LiHMDS opens new perspectives for the
transition metal catalyzed regiospecific C-H arylation of
heteroarenes.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data and computational
details. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
This work has been carried out within the H-CCAT project that has
received funding from the European Union’s Horizon 2020
research and innovation program under grant agreement No
720996. F.M.W. gratefully acknowledges financial support from
the Deutsche Forschungsgemeinschaft (DFG, Postdoctoral
Research Fellowship, grant number WI 4721/1-1) and from CNRS
through Momentum 2018 excellence grant. The authors are very
grateful to P. Mascunan for ICP-OES analysis, and to C. Lorentz
for solid-state NMR spectroscopy.
AUTHOR INFORMATION
Corresponding Author
*jerome.canivet@ircelyon.univ-lyon1.fr
*thieuleux@cpe.fr
Author Contributions
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(21) Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. Modulating
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500 to 5 ppm
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100% regioselective
25 examples
TON up to 16000
+
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