Ni-Catalyzed Traceless, Directed C3-Selective C-H Borylation of Indoles

Article abstract of DOI:10.1021/jacs.0c05434

A highly efficient and general protocol for traceless, directed C3-selective C-H borylation of indoles with [Ni(IMes)2] as the catalyst is reported. Activation and borylation of N-H bonds by [Ni(IMes)2] is essential to install a Bpin moiety at the N-position as a traceless directing group, which enables the C3-selective borylation of C-H bonds. The N-Bpin group which is formed is easily converted in situ back to an N-H group by the oxidative addition product of [Ni(IMes)2] and in situ-generated HBpin. The catalytic reactions are operationally simple, allowing borylation of a variety of substituted indoles with B2pin2 in excellent yields and with high selectivity. The C-H borylation can be followed by Suzuki-Miyaura cross-coupling of the C-borylated indoles in an overall two-step, one-pot process providing an efficient method for synthesizing C3-functionalized heteroarenes.

Full text of DOI:10.1021/jacs.0c05434

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Article
Ni-catalyzed traceless, directed C3-selective C-H borylation of indoles
Ya-Ming Tian, Xiao-Ning Guo, Zhu Wu, Alexandra Friedrich, Stephen
Alan Westcott, Holger Braunschweig, Udo Radius, and Todd B. Marder
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Jun 2020
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Ni-catalyzed traceless, directed C3-selective C-H borylation of indoles
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Ya-Ming Tian,a Xiao-Ning Guo,a* Zhu Wu,a Alexandra Friedrich,a Stephen A. Westcott,b Holger
Braunschweig,a Udo Radius,a* and Todd B. Mardera*
a Institut für Anorganische Chemie, and Institute for Sustainable Chemistry & Catalysis with Boron,
Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
b Department of Chemistry and Biochemistry, Mount Allison University, Sackville, New Brunswick
E4L 1G8, Canada
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ABSTRACT: A highly efficient and general protocol for traceless, directed C3-selective C-H
borylation of indoles with [Ni(IMes)2] as the catalyst is reported. Activation and borylation of N-H
bonds by [Ni(IMes)2] is essential to install a Bpin moiety at the N-position as a traceless directing
group, which enables the C3-selective borylation of C-H bonds. The N-Bpin group which is formed
is easily converted in situ back to an N-H group by the oxidiative addition product of [Ni(IMes)2]
and in situ-generated HBpin. The catalytic reactions are operationally simple, allowing borylation of
a variety of substituted indoles with B2pin2 in excellent yields and with high selectivity. The C-H
borylation can be followed by Suzuki-Miyaura cross-coupling of the C-borylated indoles in an
overall two-step, one-pot process providing an efficient method for synthesizing C3-functionalized
heteroarenes.
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■ INTRODUCTION
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Indoles have important biological functions, and construction of the ring from other substrates or
direct functionalization of an existing indole are the usual approaches employed in synthesizing
substituted derivatives.1 Borylated indoles are of particular interest because they can serve as
versatile building blocks for the construction of functional molecules.2 Recently, transition
metal-catalyzed direct C-H borylation has emerged as a powerful tool for the construction of C-B
bonds due to its broad functional group tolerance and substrate scope allowing late-stage
functionalization without the use of protecting groups.2,3 The regioselectivity of the C-H
functionalization of unprotected indoles, which have seven different sites, is typically driven by
electronic effects. Therefore, C-H borylation reactions occur predominantly at the C2 position which
contains the most acidic and reactive C-H bond.4 However, the selectivity can be overridden by
steric factors. Many groups including Ishiyama and Miyaura,4 Hartwig,5 Ito,6 Marder,7 Tobisu and
Chatani,8 Chattopadhyay,9 Maleczka and Smith10 et al. have reported the selective borylation of
indoles using mainly Ir, but also Rh, Pt, Co, Ni and other catalysts.11 Metal-free catalytic C-H
borylation is also an attractive alternative as it offers a simple and cheap route to borylated indoles
under mild conditions.12
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Directing groups are usually employed to control regioselectivity in C-H functionalizations.13
For example, Maleczka and Smith et al. used tert-butoxycarbonyl (Boc) as a directing group in the
Ir-catalyzed C-H borylations of pyrroles, indoles, azaindoles, and pyrazoles ,and observed selective
functionalization of the N-Boc-protected heterocycles at positions β to the N atoms (Scheme 1A).10b
Hartwig and co-workers developed a one-pot protocol consisting of the Ru-catalyzed installation of a
silyl group at the indole N-atom, Ir-catalyzed borylation of the silylindole, and subsequent hydrolysis
of the N-silyl group to obtain C7-borylated indoles selectively (Scheme 1B).5b The groups of
Ingleson, Houk and Shi employed a pivaloyl moiety as an effective directing group at the N-position
to enable the C7 borylation of indoles and ortho-borylation of anilines simply by using BBr3.12j,l The
latter group also found that installation of pivaloyl groups at the C3 position of indoles enables
borylation at the unfavorable C4 position.12l
Although site-selective C-H functionalization can be efficiently achieved with the assistance of
directing groups, some difficult to remove or modify, thus limiting the practical application of this
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methodology. Therefore, employing traceless directing groups would be an attractive alternative to
the traditional methods. Krska, Maleczka, Smith et al. demonstrated that the (pinacolato)boryl (Bpin)
moiety can serve as a traceless directing group for selective Ir-catalyzed C-H borylation of indoles at
the C3 position (Scheme 1C).10d The addition of a tertiary amine base ensures the borylation of the
nitrogen atom. The N-Bpin moiety formed enables further Ir-catalyzed regioselective borylation of
C3-H bonds, and an aqueous workup was subsequently required to remove the N-bound Bpin group
to give the final 3-Bpin-indole product.
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Scheme 1. Examples of directed C-H borylation of indoles
(A) Boc-directed C3-H borylation of indoles
Boc
Boc
2) dtbpy (3 mol%)
[Ir(OMe)(COD)]2 (1.5 mol%)
H
H
3) 180 o
45 min
C
N
N
N
N
1) Boc2O
DMAP
HBpin (1.5 equiv)
hexane, 60 oC, 8 h
Bpin
Bpin
(B) Silyl-directed C7-H borylation of indoles
likely via
3) [Ir(COD)Cl]2 (0.25 mol%)
dtbpy (0.5 mol%), B2pin2 (1 equiv)
HBpin (5 mol%), 80 oC, THF
Bpin
Bpin
SiEt2
N
N
Bpin
1) [Ru(p-cymene)Cl2]2 (1 mol%)
H
H
N
N
N
Ir
Et2SiH2, PhMe, r.t.
SiEt2
N
2) solvent removal
4) 3M aq. NaOAc
H
(C) Traceless-directed C3-H borylation of indoles
Bpin
Bpin
1) HBpin (2 equiv)
H
2) [Ir(OMe)(COD)]2
(0.25 mol%)
H
3) aqueous
workup
N
N
N
N
NEt3 (1 equiv)
80 oC, THF
10 min, - H2
dtbpy (1 mol%)
80 oC, 4 h
Bpin
Bpin
(D) This work: in situ traceless-directed C3-H borylation of indoles
Bpin
Bpin
[Ni(IMes)2] (10 mol%)
B2pin2 (1.5 equiv)
H
H
N
N
N
N
in situ via
and
hexane
60 oC, 4 h
Bpin
Bpin
N-Heterocyclic carbene (NHC) transition metal complexes have proven to be efficient for
homogeneous catalytic C-H activation.8,14 Nakao, Hartwig et al. demonstrated an anti-Markovnikov
addition of arenes and heteroarenes to alkenes catalyzed by a hindered Ni-NHC system.14b,h Tobisu,
Chatani et al. developed [Ni(ICy)2] (ICy = 1,3-dicyclohexylimidazolin-2-ylidene) which showed
excellent activity for the borylation of arenes and N-substituted heteroarenes with B2pin2.8a Selective
borylation of indoles was achieved at the reactive C2 position. Recently, Hahn et al. reported that
unsubstituted 2-halogenoazoles undergo N-H oxidative addition with [Ni(PEt3)2] forming a NiII
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hydride complex, rather than C-metalation of the C-Cl bond, at low temperature in THF.15 In light of
these findings and our long-standing interest in catalytic borylation reactions based on different
NHC-metal complexes,16 we report herein a highly selective traceless, directed C3-H borylation of
indoles that employs [Ni(IMes)2] (IMes = 1,3-dimesitylimidazoline-2-ylidene) as a catalyst without
an additional base or hydrolysis to achieve: 1) in situ installation of Bpin as a traceless directing
group at the indole N-position; 2) catalytic C3-H borylation; and 3) deprotection of the N-Bpin
moiety back to an N-H group to provide C3-borylated indoles with excellent activity and selectivity
(Scheme 1D).
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■ RESULTS AND DISCUSSION
Table 1. Control experiments for the directed C3-H borylation of different indoles
R1
H
N
N
Hexane (2 mL)
60 oC, 4 h
Boron source
0.3 mmol
+
R2
0.2 mmol
Bpin
1b
Boron
source
[Ni(IMes)2]
(10 mol%)
Entry
Substrate
Yield of 1b (%)a
√
ꓫ
√
ꓫ
√
ꓫ
√
ꓫ
√
ꓫ
√
ꓫ
1
2
R1 = H, R2 = H
R1 = H, R2 = H
R1 = H, R2 = H
R1 = H, R2 = H
B2pin2
B2pin2
HBpin
HBpin
B2pin2
B2pin2
HBpin
HBpin
B2pin2
B2pin2
HBpin
HBpin
89
-
3
7
4
-
5
R1 = Bpin, R2 = H
R1 = Bpin, R2 = H
R1 = Bpin, R2 = H
R1 = Bpin, R2 = H
R1 = Bpin, R2 = Bpin
R1 = Bpin, R2 = Bpin
R1 = Bpin, R2 = Bpin
R1 = Bpin, R2 = Bpin
91
6
-
7
traceb
8
-
trace
-
9
10
11
12
94
-
aYields are based on indoles and were determined by GC-MS analysis vs. a calibrated internal
standard and are averages of two runs. bThe yield of indole was ca. 50% apart from 1b.
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We first investigated the efficiency of the directed borylation reaction of indole (1a) with B2pin2
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using 10 mol % [Ni(IMes)2] as the catalyst and hexane as solvent at 60 C. This initial result gave
3-Bpin-indole (1b) in an excellent yield of 89% with high selectivity for the C3 position after 4 h
(Table 1, entry 1). A range of solvents was screened, with hexane proving to be optimal (Table S1).
The non-polar solvent methylcyclohexane gave almost the same yield of 1b as obtained in hexane,
but the reactivity was low in polar solvents. Dichloromethane and acetonitrile, respectively,
completely quench the reaction. The yield of 1b is higher at a reaction temperature of 60 °C than that
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at 30-50 C, but decreased significantly with decreasing number of equiv. of B2pin2 (Figure S1).
When HBpin was employed as the boron source instead of B2pin2, only a 7% yield of 1b was
achieved (Table 1, entry 3). It is important to note that no reaction occurred in the absence of the
[Ni(IMes)2] catalyst (Table 1, entries 2 and 4).
We further examined the scope of indoles for the directed borylation with [Ni(IMes)2] under the
optimized conditions, and the results are summarized in Table 2. Indoles with either
electron-donating (2a-9a) or electron-withdrawing (10a-13a) groups reacted smoothly to afford
corresponding C3-borylated indoles in good to excellent yields, suggesting the excellent functional
group tolerance of this method. The positions of Me and MeO substituents on the benzenoid unit of
indole did not significantly affect the catalytic activity; placing them at the C5 or C6 positions
resulted in slightly higher yields of products than when they were placed at the C4 or C7 positions
(2a-9a). Because fluorinated organic compounds have exceptional properties that are being exploited
in many applications,17 it is important to note that fluoroindoles underwent C3-H borylation with
fluoride moiety remaining intact under our conditions (10a-13a). Interestingly, 4-F-indole (10a) and
5-F-indole (11a) exhibited higher yields of products than 6-F-indole (12a) and 7-F-indole (13a)
revealed the lowest activity with only a 50% yield of 3-Bpin-7-F-indole (13b). The C3 selectivity of
the C-H borylation reported here was confirmed by the molecular structures of 1b, 3b-5b, 7b, and
9b-12b obtained by single-crystal X-ray diffraction.
Preliminary mechanistic studies were conducted to provide insight into the directed C3-H
borylation process with the [Ni(IMes)2] catalyst. First, we monitored the borylation of 1a by GC–MS
analysis. As shown in Table S2 (Supporting Information) and Figure 1, the yield of 1b increased
with longer reaction times. Importantly, the N-H monoborylation product 1-Bpin-indole (1c) and
diborylation product 1,3-(Bpin)2-indole (1d) were detected during the reaction. Compounds 1c and
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1d reached their maximum yields of 36% and 28% after 10 min and 30 min, respectively, and then
the yields decreased to trace amounts at 1.5 and 4 h, respectively. The above results suggest that the
N-borylated compound 1c and the bis N/C3-borylated compound 1d are important intermediates in
the formation of 1b.
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Table 2. Substrate scope for the C3-H borylation of indoles with [Ni(IMes)2]
H
N
H
N
[Ni(IMes)2] (10 mol%)
R
R
B2pin2
+
Hexane (2 mL)
60 oC, 4 h
Bpin
a
, 0.2 mmol
0.3 mmol
b
H
H
H
N
N
N
H3C
Bpin
Bpin
Bpin
CH3
a
b
3b
, 77% (68%)
1b
2b
5b
, 89% (78%)
, 62% (55%)
CH3
H
H
N
H
N
H3C
N
Bpin
Bpin
Bpin
OCH3
6b
, 64% (55%)
, 70% (60%)
4b
, 78% (69%)
OCH3
H
N
H
N
H
N
H3CO
H3CO
Bpin
Bpin
Bpin
7b
, 72% (63%)
9b
8b
, 67% (58%)
, 81% (72%)
H
N
H
N
H
N
F
F
Bpin
F
Bpin
Bpin
10b
, 85% (76%)
11b
12b
, 70% (62%)
, 88% (79%)
F
H
N
Bpin
13b
, 50% (42%)
aThe yields are based on indoles and were determined by GC-MS analysis vs. a calibrated internal
b
standard and are averages of two runs. Isolated yields based on 1 mmol indoles are given in
parentheses.
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Bpin
Bpin
H
H
N
N
N
N
[Ni(IMes)2] (10 mol%)
+
B2pin2
+
+
Hexane (2 mL), 60 o
C
Bpin
Bpin
7
8
1d
1b
1a
1c
, 0.2 mmol
0.3 mmol
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Figure 1. Yields of 1-Bpin-indole (1c), 1,3-(Bpin)2-indole (1d) and 3-Bpin-indole (1b) as a function
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of time. The yields are based on indoles and were determined by GC-MS analysis.
Figure 2. Molecular structures of [Ni(IMes)2(H)(N-indolyl)] (I1) and [Ni(IMes)2(H)(6F-N-indolyl)]
(I1-F) from single-crystal X-ray diffraction data at 100 K. Atomic displacement ellipsoids are drawn
at the 50% probability level, and some hydrogen atoms are omitted for clarity. Selected bond lengths
(Å) and angles (deg) for I1: Ni(1)-C(1) 1.9047(18), Ni(1)-C(2) 1.9047(18), Ni(1)-N(1) 1.954(3),
Ni(1)-H(1) 1.38(3); C(1)-Ni(1)-N(1) 100.3(2), C(1)-Ni(1)-H(1) 83.18(7), C(1)-Ni(1)-C(2) 166.3(1),
C(2)-Ni(1)-N(1) 93.3(2), C(2)-Ni(1)-H(1) 83.18(7), N(1)-Ni(1)-H(1) 172.3(1). Selected bond lengths
(Å) and angles (deg) for I1-F: Ni(2)-C(3) 1.906(3), Ni(2)-C(4) 1.906(3), Ni(2)-N(2) 1.951(5),
Ni(2)-H(2) 1.43(7); C(3)-Ni(2)-N(2) 100.7(2), C(3)-Ni(2)-H(2) 83.2(1), C(3)-Ni(2)-C(4) 166.3(2),
C(4)-Ni(2)-N(2) 92.8(2), C(4)-Ni(2)-H(2) 83.2(1), N(2)-Ni(2)-H(2) 170.7(1).
We also noted that the color of most [Ni(IMes)2]-catalyzed indole borylations changes from dark
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purple to orange-yellow very quickly. In situ 1H NMR spectra of the reaction 0.04 mmol of 1a with
0.5 equiv of B2pin2 in the presence of 0.5 equiv of [Ni(IMes)2] showed that the N-borylated
compound 1c was formed at the very beginning of the reaction (Figure S60). In addition, a resonance
at δ -21.18 ppm suggested the formation of a NiII hydride complex (Figure S60). After heating at
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60 C for 30 min, 1a was completely converted to 1c and the NiII hydride complex (Figures S61).
The reaction of 1 mmol of 1a and 1 mmol of 12a, respectively, with 1 equiv of [Ni(IMes)2] in
°
hexane (i.e., without B2pin2) was conducted at 60 C for 4 h, yielding 76% and 75% of the
corresponding NiII complexes [Ni(IMes)2(H)(N-indolyl)] (I1) and [Ni(IMes)2(H)(6F-N-indolyl)]
(I1-6F). After isolation, the NMR spectra (Figure S52-S56) and X-ray diffraction analysis (Figure 2)
confirmed the formation of NiII complexes I1 and I1-6F, which result from an oxidative addition of
the indole N-H bond to the Ni0 complex [Ni(IMes)2]. These results indicate that the facile activation
of the N-H bond by [Ni(IMes)2] generates intermediate I1, which then reacts with B2pin2 to give 1c.
Reaction of 1c with B2pin2 in the absence of [Ni(IMes)2] was not detected (Table 1, entry 6).
However, the reaction with 10 mol % [Ni(IMes)2] gave 1b in an excellent yield of 91% and a trace of
1d at 60 oC for 4 h (Table 1, entry 5), indicating that 1c requires the Ni-catalyst to form 1d. In situ 1H
NMR spectra of the reaction of 1c with [Ni(IMes)2] clearly showed that the oxidative addition of the
C3-H bond by the Ni0 complex formed [NiII(IMes)2(HC3)(1-Bpin-indole)] (I2, Figure S62).
Therefore, with [Ni(IMes)2] and B2pin2, the conversion of 1c to 1d appears to occur via formation of
intermediate I2. When HBpin was employed as the boron source instead of B2pin2 for the borylation
of 1c, there was no reaction without [Ni(IMes)2] (Table 1, entry 8). When [Ni(IMes)2] was present,
HBpin as the boron source led to only trace amounts of 1d; however, ca. half of 1c was converted to
1a (Table 1, entry 7). This suggests that the conversion of N-Bpin to N-H is achieved by reaction
with HBpin in the presence of [Ni(IMes)2]. When 1d was used as the substrate, it did not react with
either B2pin2 or HBpin in the absence of [Ni(IMes)2] (Table 1, entries 10 and 12). With [Ni(IMes)2],
B2pin2 as the boron source gave only a trace of 1b (Table 1, entry 9), whereas reaction of HBpin with
1d efficiently yielded 94% of 1b (Table 1, entry 11).
In light of these findings, a plausible mechanism for the C3-selective borylation of indoles with
[Ni(IMes)2] is shown in Scheme 2. First, the indoles undergo rapid N-H oxidative addition to
Ⅱ
[Ni(IMes)2] to give the Ni hydride complex I1, which further reacts with B2pin2 in situ to install
Bpin as a traceless directing group at the indole N-position to produce 1c and release [Ni(IMes)2].
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Then, the regenerated [Ni(IMes)2] catalyzes the C3-borylation of 1c; [Ni(IMes)2] thus inserts into the
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Ⅱ
C3-H bond of 1c to form the Ni hydride complex I2, which is converted with B2pin2 to the
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bis-N/C3-borylated indole 1d, a step which also regenerates the Ni0 complex [Ni(IMes)2]. Finally, it
appears that this, or another Ni-complex present in the reaction mixture, also catalyzes the removal
of the directing group, i.e., that the conversion of N-Bpin to N-H to form the final C3-borylated
indole 1b is achieved by the [Ni(IMes)2]-catalyzed reaction of 1d with a source of hydrogen atoms,
which we depict in Scheme 2 as in situ generated HBpin. While we do not observe HBpin by in situ
GC-MS during the course of the reactions, and do not yet know the intimate details of this final step
in the cycle, as the reaction proceed smoothly under an inert atmosphere and in carefully dried
solvents, it would appear that the hydrogen atom source must be generated in the N-H or C-H
activation steps.
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Scheme 2. Plausible mechanism for the traceless-directed C3-selective C-H borylation of
indoles with [Ni(IMes)2]
Bpin
N
H
1b
N
Ni(IMes)2
H
1a
"HBpin"
Step 3. Auto removal
of directing group
Ni(IMes)2
+
N
Bpin
MesI Ni IMes
H
Step 1. Auto installation
of directing group
I1
N
Bpin
B2pin2
1d
Step 2. Selective,
catalytic C3-H borylation
"HBpin"
"HBpin"
Bpin
N
N
B2pin2
+
Ni(IMes)2
Bpin
1c
MesI Ni IMes
H
I2
Scheme 3. A one-pot C3-H borylation/Suzuki-Miyaura cross-coupling sequence for synthesis of
C3-arylated indole
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H
N
X
COOMe
B2pin2 (1.5 mmol)
H
H
N
N
[Ni(IMes)2] (0.1 mmol)
(X = I or Cl, 1 mmol)
KOH (2 mmol)
hexane (5 mL)
60 oC, 4 h
[Pd2(dba)3] (0.1 mmol)
Bpin
1 mmol
1,4-dioxane/H2O (3.5/1.5 mL)
100 oC, 15 h
COOMe
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Not isolated
Isolated yield: 70% (X = I)
37% (X = Cl)
Arylindoles are key building blocks in many natural products and pharmaceuticals.18 C3-Arylated
indoles are particularly important because of their diverse biological activities such as antimicrobial,
anti-inflammatory, and anticancer activities.19 Thus, as a proof of principle, to demonstrate the
synthetic utility of our protocol, a one-pot C3-H borylation / Suzuki-Miyaura cross-coupling
sequence for the direct synthesis of C3-arylated indole was also investigated using the parent indole
1a (Part VI in the Supporting Information). The in situ formed 3-borylated indole 1b was directly
employed in one-pot cross-coupling reactions with methyl 4-iodobenzoate and methyl
4-chlorobenzoate, using [Pd2(dba)3] (dba = dibenzylideneacetone) as the catalyst precursor (Scheme
3). The product 3-(methyl-4-benzoate)-indole was obtained in 70% and 37% isolated yield,
respectively, demonstrating the potential for employing this C3-borylation methodology for the
tandem synthesis of C3-arylated indoles. Finally, and in response to queries of the referees, we note
that preliminary studies indicate that substrates such as pyrrole, a C2-substituted indole, and an
indole containing an ester functionality can be borylated under these conditions, but the current
corona virus situation and the resulting laboratory shut down has precluded more detailed studies of
these and additional substrates at the moment.
■ CONCLUSIONS
We have developed an efficient, traceless, directed C3-selective C-H borylation of indoles with
B2pin2 using [Ni(IMes)2] as the catalyst. The reaction proceeds without any base and under mild
conditions, displays broad scope and functional group tolerance, and furnishes borylated indoles in
good to excellent yields with high selectivity. Bpin, as a traceless directing, group is installed at the
N-position via activation of the N-H bond by [Ni(IMes)2]. The N-borylated indole formed undergoes
catalytic C3-selective C-H borylation with regenerated [Ni(IMes)2] to form the bis-N/C3-borylated
indole, which then generates the desired C3-borylated indole product by conversion of N-Bpin to
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N-H with [Ni(IMes)2] and in situ-generated HBpin. This protocol enables the in situ installation and
removal of the directing group without additional operations, using a first-row transition metal
catalyst, and can be followed, in the same pot, by a Suzuki-Miyaura cross-coupling with an aryl
halide.
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■ ASSOCIATED CONTENT
s.Details of synthetic methods, characterization (NMR and HRMS data) of products, and
investigation of the reaction mechanism are included in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Authors
Xiao-Ning Guo — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry &
Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg,
Germany; orchid.org/0000-0001-7626-1539; Email: guo.xiaoning@uni-wuerzburg.de
Udo Radius — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry &
Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg,
Germany; orchid.org/0000-0002-0759-1806; Email: u.radius@uni-wuerzburg.de
Todd B. Marder — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry &
Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg,
Germany; orchid.org/0000-0002-9990-0169;; Email: todd.marder@uni-wuerzburg.de
Authors
Ya-Ming Tian — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry &
Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg,
Germany; orchid.org/0000-0001-5083-137X
Zhu Wu — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis
with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany;
orchid.org/0000-0003-0500-7327
Alexandra Friedrich — Institute of Inorganic Chemistry and Institute for Sustainable Chemistry
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& Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074
Würzburg, Germany; orchid.org/0000-0002-1411-7336
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9
Stephen A. Westcott — Department of Chemistry and Biochemistry, Mount Allison University,
Sackville, New Brunswick E4L 1G8, Canada; orchid.org/0000-0002-5324-2295
Holger Braunschweig — Institute of Inorganic Chemistry and Institute for Sustainable
Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland,
97074 Würzburg, Germany; orchid.org/0000-0001-9264-1726
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Funding
This work was supported by funds from the Julius-Maximilians-Universität Würzburg, the
Deutsche Forschungsgemeinschaft DFG (RA 720/12-2; MA 4471/4-1) and the Natural Sciences and
Engineering Council of Canada. We are grateful to the China Scholarship Council for providing a
scholarship to Ya-Ming Tian and to the Alexander von Humboldt Foundation for providing a
postdoctoral fellowship to Xiao-Ning Guo. We thank AllyChem Co. Ltd. for a generous gift of
diboron(4) reagents.
Notes
The authors declare no competing financial interest.
■ REFERENCES
1. (a) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles. Chem.
Rev. 2006, 106, 2875-2911. (b) Sundberg, R. J. Indoles, Academic Press, San Diego, 1996. (c)
Bandini, M.; Eichholzer, A. Catalytic Functionalization of Indoles in a New Dimension. Angew.
Chem. Int. Ed. 2009, 48, 9608-9644. (d) Joucla, L.; Djakovitch, L. Transition Metal-Catalysed,
Direct and Site-Selective N1-, C2- or C3-Arylation of the Indole Nucleus: 20 Years of
Improvements. Adv. Synth. Catal. 2009, 351, 673-714. (e) Gribble, G. W.; Badenock, J. C.
Heterocyclic Scaffolds II: Reactions and Applications of Indoles, Springer, Berlin, 2010. (f)
Cacchi, S.; Fabrizi, G. Update 1 of: Synthesis and Functionalization of Indoles through
Palladium-Catalyzed Reactions. Chem. Rev. 2011, 111, PR215-PR283. (g) Lebrasseur, N.;
12
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Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Larrosa, I. Chapter 4-Recent Advances in the C2 and C3 Regioselective Direct Arylation of
Indoles. Adv. Heterocycl. Chem. 2012, 105, 309-351. (h) Sandtorv, A. H. Transition
Metal-Catalysed C-H Activation of Indoles. Adv. Synth. Catal. 2015, 357, 2403-2435. (i) Cheng,
H. G.; Chen, S. Q.; Chen, R. M.; Zhou, Q. H. Palladium(II)-Initiated Catellani-Type Reactions.
Angew. Chem. Int. Ed. 2019, 58, 5832-5844. (j) Qiu, X. D.; Wang, P. P.; Wang, D. Y.; Wang,
M. Y.; Yuan, Y.; Shi, Z. Z. PIII-Chelation-Assisted Indole C7-Arylation, Olefination,
Methylation, and Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis. Angew.
Chem. Int. Ed. 2019, 58, 1504-1508.
2. (a) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron
Compounds. Chem. Rev. 1995, 95, 2457-2483. (b) Hall, D. G. Boronic acids: Preparation and
Applications in Organic Synthesis Medicine and Materials, 2nd ed., Willey-VCH, Weinheim
2011. (c) Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B. Diboron(4)
Compounds: from Structural Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116,
9091-9161. (d) Cuenca, A. B.; Shishido, R.; Ito, H.; Fernández, E. Transition-Metal-Free B-B
and B-Interelement Reactions with Organic Molecules. Chem. Soc. Rev. 2017, 46, 415-430. (e)
Čubiňák, M.; Edlová, T.; Polák, P.; Tobrman, T. Indolylboronic Acids: Preparation and
Applications. Molecules 2019, 24, 3523.
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. (a) Iverson, C. N.; Smith, M. R., III. Stoichiometric and Catalytic B-C Bond Formation from
Unactivated Hydrocarbons and Boranes. J. Am. Chem. Soc. 1999, 121, 7696-7697. (b) Cho, J.
Y.; Iverson, C. N.; Smith, M. R., III. Steric and Chelate Directing Effects in Aromatic
Borylation. J. Am. Chem. Soc. 2000, 122, 12868-12869. (c) Cho, J. Y.; Tse, M. K.; Holmes, D.;
Maleczka, R. E., Jr.; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the
Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305-308. (d) Ishiyama, T.; Takagi, J.;
Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of
Arenes. High Turnover Numbers, Room Temperature Reactions and Isolation of a Potential
Intermediate. J. Am. Chem. Soc. 2002, 124, 390-391. (e) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B bonds.
Chem. Rev. 2010, 110, 890-931. (f) Hartwig, J. F. Regioselectivity of the Borylation of Alkanes
and Arenes. Chem. Soc. Rev. 2011, 40, 1992-2002. (g) Hartwig, J. F. Borylation and Silylation
of C-H Bonds: A Platform for Diverse C-H Bond Functionalizations. Acc. Chem. Res. 2012, 45,
13
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Page 14 of 21
1
2
3
4
5
6
7
8
9
864-873. (h) Tajuddin, H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.;
Cheung, M. S.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin, Z. Y.; Marder, T. B.;
Steel, P. G. Iridium-Catalyzed C-H Borylation of Quinolines and Unsymmetrical
1,2-Disubstituted Benzenes: Insights into Steric and Electronic Effects on Selectivity. Chem. Sci.
2012, 3, 3505-3515. (i) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.;
Maleczka, R. E., Jr; Smith, M. R., III. Outer-Sphere Direction in Iridium C-H Borylation. J. Am.
Chem. Soc. 2012, 134, 11350-11353. (j) Ros, A.; Fernandez, R.; Lassaletta, J. M. Functional
Group Directed C-H Borylation. Chem. Soc. Rev. 2014, 43, 3229-3243. (k) Larsen, M. A.;
Hartwig, J. F. Iridium-Catalyzed C-H Borylation of Heteroarenes: Scope, Regioselectivity,
Application to Late-Stage Functionalization, and Mechanism. J. Am. Chem. Soc. 2014, 136,
4287-4299. (l) Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore, D.; Marder, T. B.; Steel, P.
G. Multidirectional Synthesis of Substituted Indazoles via Iridium-Catalyzed C-H Borylation. J.
Org. Chem. 2015, 80, 5308-5314. (m) Wang, G. H.; Xu, L.; Li, P. F. Double N,B-Type
Bidentate Boryl Ligands Enabling a Highly Active Iridium Catalyst for C-H Borylation. J. Am.
Chem. Soc. 2015, 137, 8058-8061. (n) Xu, L.; Wang, G. H.; Zhang, S.; Wang, H.; Wang, L. H.;
Liu, L.; Jiao, J.; Li, P. F. Recent Advances in Catalytic C-H Borylation Reactions. Tetrahedron
2017, 73, 7123-7157. (o) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K.
A.; Maleczka, R. E., Jr; Singleton, D. A.; Smith, M. R., III. Ir-Catalyzed ortho-Borylation of
Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in
Silico Strategy for Optimizing Weak Interactions. J. Am. Chem. Soc. 2017, 139, 7864-7871; p)
Kanwal, S.; Ann, N.; Fatima, S.; Emwas, A. -H.; Alazmi, M.; Gao, X.; Ibrar, M.; Saleem, R. S.
Z.; Chotana, G. A. Facile synthesis of NH-free 5-(hetero)aryl-pyrrole-2-carboxylates by catalytic
C-H borylation and Suzuki coupling. Molecules 2020, 25, 2106.
10
11
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19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Iridium-Catalyzed C–H
Coupling Reaction of Heteroaromatic Compounds with Bis(pinacolato)diboron: Regioselective
Synthesis of Heteroarylboronates. Tetrahedron Lett. 2002, 43, 5649-5651. (b) Ishiyama, T.;
Takagi, J.; Hartwig, J. F.; Miyaura, N. A Stoichiometric Aromatic C-H Borylation Catalyzed by
Iridium(Ⅰ)/2,2’-Bipyridine Complexes at Room Temperature. Angew. Chem. Int. Ed. 2002, 41,
3056-3058.
5. (a) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F.
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2
3
4
5
6
7
8
9
10
11
12
13
Mechanism of the Mild Functionalization of Arenes by Diboron Reagents Catalyzed by Iridium
Complexes. Intermediacy and Chemistry of Bipyridine-Ligated Iridium Trisboryl Complexes. J.
Am. Chem. Soc. 2005, 127, 14263-14278. (b) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F.
Iridium-Catalyzed, Silyl-Directed Borylation of Nitrogen-Containing Heterocycles. J. Am. Chem.
Soc. 2010, 132, 4068-4069.
6. (a) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Enantioselective Borylative Dearomatization
of Indoles Through Copper(I) Catalysis. Angew. Chem. Int. Ed. 2015, 54, 8809-8813. (b) Pang,
Y.; Ishiyama, T. Kubota,; K.; Ito, H. Iridium(I)-Catalyzed C-H Borylation in Air by using
Mechanochemistry, Chem. Eur. J. 2019, 25, 4654-4659.
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. (a) Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P. G. Microwave-Accelerated
Iridium-Catalyzed Borylation of Aromatic C-H Bonds. Org. Lett. 2009, 11, 3586-3589. (b)
Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.; Howard, J. A. K.; Perutz, R.
N.; Marder, T. B. Ir-Catalyzed Borylation of C-H Bonds in N-Containing Heterocycles:
Regioselectivity in the Synthesis of Heteroaryl Boronate Esters. Angew. Chem. Int. Ed. 2006, 45,
489-491. (c) Sadler, S. A.; Tajuddin, H.; Mkhalid, I. A. I.; Batsanov, A. S.; Albesa-Jove, D.;
Cheung, M. S.; Maxwell, A. C.; Shukla, L.; Roberts, B.; Blakemore, D. C.; Lin, Z.; Marder, T.
B.; Steel, P. G. Iridium-Catalyzed C-H Borylation of Pyridines, Org. Biomol. Chem., 2014, 12,
7318-7327.
8. (a) Furukawa, T.; Tobisu, M.; Chatani, N. Nickel-Catalyzed Borylation of Arenes and Indoles
via C-H Bond Cleavage. Chem. Commun. 2015, 51, 6508-6511. (b) Furukawa, T.; Tobisu, M.;
Chatani, N. C-H Functionalization at Sterically Congested Positions by the Platinum-Catalyzed
Borylation of Arenes. J. Am. Chem. Soc. 2015, 137, 12211-12214.
9. (a) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in
Ir-Catalyzed C-H Activation: L‑Shaped Ligand for para-Selective Borylation of Aromatic Esters.
J. Am. Chem. Soc. 2017, 139, 7745-7748. (b) Smith, M. R., III; Bisht, R.; Haldar, C.; Pandey, G.;
Dannatt, J. E.; Ghaffari, B.; Maleczka, R. E., Jr.; Chattopadhyay, B. Achieving High ortho
Selectivity in Aniline C-H Borylations by Modifying Boron Substituents. ACS Catal. 2018, 8,
6216-6223.
10. (a) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.; Smith, M. R., III.
Ir-Catalyzed Functionalization of 2-Substituted Indoles at the 7-Position: Nitrogen-Directed
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Page 16 of 21
1
2
3
4
5
6
7
8
9
Aromatic Borylation. J. Am. Chem. Soc. 2006, 128, 15552-15553. (b) Kallepalli, V. A.; Shi, F.;
Paul, S.; Onyeozili, E. N.; Maleczka, R. E., Jr.; Smith, M. R., III. Boc Groups as Protectors and
Directors for Ir-Catalyzed C-H Borylation of Heterocycles. J. Org. Chem. 2009, 74, 9199-9201.
(c) Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka,
R. E., Jr.; Smith, M. R., III. Harnessing C-H Borylation/Deborylation for Selective Deuteration,
Synthesis of Boronate Esters, and Late Stage Functionalization. J. Org. Chem. 2015, 80,
8341-8353. (d) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E.,
Jr.; Smith, M. R., III. A Traceless Directing Group for C-H Borylation. Angew. Chem., Int. Ed.
2013, 52, 12915-12919. (e) Shen, F.; Tyagarajan, S.; Perera, D.; Krska, S. W. Maligres, P. E.;
Smith, M. R., III; Maleczka, R. E., Jr. Bismuth Acetate as a Catalyst for the Sequential
Protodeboronation of Di- and Triborylated Indoles. Org. Lett. 2016, 18, 1554-1557.
10
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59
60
11. (a) Mertins, K.; Zapf, A.; Beller, M. Catalytic Borylation of o-Xylene and Heteroarenes via C–H
Activation. J. Mol. Catal. A: Chem. 2004, 207, 21-25. (b) Lo, W. F.; Kaiser, H. M.;
Spannenberg, A.; Beller, M.; Tse, M. K. A Highly Selective Ir-Catalyzed Borylation of
2-Substituted Indoles: A New Access to 2,7- and 2,4,7-Substituted Indoles. Tetrahedron Lett.
2007, 48, 371-375. (c) Zhang, H.; Hagihara, S.; Itami, K. Aromatic C-H Borylation by Nickel
Catalysis. Chem. Lett. 2015, 44, 779-781. (d) Léonard, N. G.; Bezdek, M. J.; Chirik, P. J.
Cobalt-Catalyzed C(sp2)-H Borylation with an Air-stable, Readily Prepared Terpyridine
Cobalt(II) Bis(acetate) Precatalyst. Organometallics 2017, 36, 142-150. (e) Thongpaen, J.;
Schmid, T. E.; Toupet, L.; Dorcet, V.; Mauduit, M.; Baslé, O. Directed ortho C-H Borylation
Catalyzed using Cp*Rh(III)-NHC Complexes. Chem. Commun. 2018, 54, 8202-8205. (f) Das,
A.; Hota, P. K.; Mandal, S. K. Nickel-Catalyzed C(sp2)-H Borylation of Arenes.
Organometallics 2019, 38, 3286-3293. (g) Manguin, R.; Dorcet, V.; Vives, T.; Duhayon, C.;
Mauduit, M.; Baslé, O. Visible Light Induced Rhodium(I)-Catalyzed C−H Borylation. Angew.
Chem. Int. Ed. 2019, 58, 15244-15248.
12. (a) Bagutski, V.; Grosso, A. D.; Carrillo, J. A.; Cade, I. A.; Helm, M. D.; Lawson, J. R.;
Singleton, P. J.; Solomon, S. A.; Marcelli, T.; Ingleson, M. J. Mechanistic Studies into
Amine-Mediated Electrophilic Arene Borylation and Its Application in MIDA Boronate
Synthesis. J. Am. Chem. Soc. 2013, 135, 474-487. (b) Stahl, T.; Müther, K.; Ohki, Y.; Tatsumi,
K.; Oestreich, M. Catalytic Generation of Borenium Ions by Cooperative B-H Bond Activation:
16
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Page 17 of 21
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
The Elusive Direct Electrophilic Borylation of Nitrogen Heterocycles with Pinacolborane. J. Am.
Chem. Soc. 2013, 135, 10978-10981. (c) Légaré, M.-A.; Courtemanche, M.-A.; Rochette, É.;
Fontaine, F.-G. Metal-Free Catalytic C-H Bond Activation and Borylation of Heteroarenes.
Science 2015, 349, 513-516. (d) Bose, S. K.; Marder, T. B. Metal-free Catalytic Borylation of
Carbon-Hydrogen Bonds–A Leap Forward in C-H Functionalization. Science, 2015, 349,
473-474. (e) Lavergne, J. L.; Jayaraman, A.; Misal Castro, L. C.; Rochette, É.; Fontaine, F.-G.
Metal-Free Borylation of Heteroarenes using Ambiphilic Aminoboranes: on the Importance of
Sterics in Frustrated Lewis Pair C-H Bond Activation. J. Am. Chem. Soc. 2017, 139,
14714-14723. (f) Lavergne, J. L.; Misal Castro, L. C.; Desrosiers, V.; Fontaine, F.-G. Metal-Free
Borylative Dearomatization of Indoles: Exploring the Divergent Reactivity of Aminoborane C–
H Borylation Catalysts. Chem. Sci. 2018, 9, 5057-5063. (g) Han, Y.; Zhang, S.; He, J.; Zhang, Y.
Switchable C-H Silylation of Indoles Catalyzed by a Thermally Induced Frustrated Lewis Pair.
ACS Catal. 2018, 8, 8765-8773. (h) Zhang, S.; Han Y.; He, J.; Zhang, Y. B(C6F5)3-Catalyzed
C3-Selective C-H Borylation of Indoles: Synthesis, Intermediates, and Reaction Mechanism. J.
Org. Chem. 2018, 83, 1377-1386. (i) Zhong, Q.; Qin, S.; Yin, Y.; Hu, J.; Zhang, H.
Boron(III)-Catalyzed C2-Selective C-H Borylation of Heteroarenes. Angew. Chem. Int. Ed. 2018,
57, 14891-14895. (j) Iqbal, S. A.; Cid, J.; Procter, R. J.; Uzelac, M.; Yuan, K.; Ingleson, M. J.
Acyl-Directed ortho-Borylation of Anilines and C7 Borylation of Indoles using just BBr3.
Angew. Chem. Int. Ed. 2019, 58, 15381-15385. (k) Rochette, É.; Desrosiers, V.; Soltani, Y.;
Fontaine, F.-G. Isodesmic C-H Borylation: Perspectives and Proof of Concept of Transfer
Borylation Catalysis. J. Am. Chem. Soc. 2019, 141, 12305-12311. (l) Lv, J.; Chen, X.; Xue,
X.-S.; Zhao, B.; Liang, Y.; Wang, M.; Jin, L.; Yuan, Y.; Han, Y.; Zhao, Y.; Lu, Y.; Zhao, J.; Sun,
W.-Y.; Houk, K. N.; Shi, Z. Metal-Free Directed sp2-C-H Borylation. Nature 2019, 575,
336-340.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
13. (a) Murai, S.; Kakiuchl, F.; Seklne, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.
Efficient Catalytic Addition of Aromatic Carbon-Hydrogen Bonds to Olefins. Nature 1993, 366,
529-531. (b) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed ortho-Borylation of
Arenes. A One-Pot ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc.
2008, 130, 7534-7535. (c) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. ortho-C-H
51
52
53
54
55
56
57
58
59
60
Borylation of Benzoate Esters with Bis(pinacolato)diboron Catalyzed by Iridium–Phosphine
17
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Journal of the American Chemical Society
Page 18 of 21
1
2
3
4
5
6
7
8
9
Complexes. Chem. Commun. 2010, 46, 159-161. (d) Kawamorita, S.; Ohmiya, H.; Hara, K.;
Fukuoka, A.; Sawamura, M. Directed ortho Borylation of Functionalized Arenes Catalyzed by a
Silica-Supported Compact Phosphine-Iridium System. J. Am. Chem. Soc. 2009, 131, 5058-5059.
(e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C-C Bond Formation via
Heteroatom-Directed C-H Bond Activation. Chem. Rev. 2010, 110, 624-655. (f) Kawamorita, S.;
Ohmiya, H.; Sawamura, M. Ester-Directed Regioselective Borylation of Heteroarenes Catalyzed
by a Silica-Supported Iridium Complex. J. Org. Chem. 2010, 75, 3855-3858. (g) Lyons, T. W.;
Sanford, M. S. Palladium-Catalyzed Ligand-Directed C-H Functionalization Reactions. Chem.
Rev. 2010, 110, 1147-1169. (h) Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.;
Fernández, R.; Lassaletta, J. M. Hydrazone as the Directing Group for Ir-Catalyzed Arene
Diborylations and Sequential Functionalizations. J. Am. Chem. Soc. 2012, 134, 4573-4576. (i)
Gulevich, A. V.; Melkonyan, F. S.; Sarkar, D.; Gevorgyan, V. Double-Fold C-H Oxygenation of
Arenes using PyrDipSi: A General and Efficient Traceless/Modifiable Silicon-Tethered
Directing Group. J. Am. Chem. Soc. 2012, 134, 5528-5531. (j) Zhang, F.; Spring, D. R. Arene
C-H Functionalisation using a Removable/Modifiable or a Traceless Directing Group Strategy.
Chem. Soc. Rev. 2014, 43, 6906-6919. (k) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S.
Transition Metal-Catalyzed Site- and Regio-Divergent C-H Bond Functionalization. Chem. Soc.
Rev. 2017, 46, 4299-4328.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14. (a) Zhao, H. T.; Dang, L.; Marder, T. B.; Lin, Z. Y. DFT Studies on the Mechanism of the
Diboration of Aldehydes Catalyzed by Copper(I) Boryl Complexes. J. Am. Chem. Soc. 2008,
130, 5586-5594. (b) Schramm, Y.; Takeuchi, M.; Semba, K.; Nakao, Y.; Hartwig, J. F.
Anti-Markovnikov Hydroheteroarylation of Unactivated Alkenes with Indoles, Pyrroles,
Benzofurans, and Furans Catalyzed by a Nickel-N-Heterocyclic Carbene System. J. Am. Chem.
Soc. 2015, 137, 12215-12218. (c) Parmelee, S. R.; Mazzacano, T. J.; Zhu, Y.; Mankad, N. P.;
Keith, J. A.; A Heterobimetallic Mechanism for C-H Borylation Elucidated from Experimental
and Computational Data. ACS Catal. 2015, 5, 3689-3699. (d) Tobisu, M.; Igarashi, T.; Chatani,
N. Iridium/N-Heterocyclic Carbene-Catalyzed C–H Borylation of Arenes by
Diisopropylaminoborane. Beilstein J. Org. Chem. 2016, 12, 654-661. (e) Procter, R. J.; Uzelac,
M.; Cid, J.; Rushworth, P. J.; Ingleson, M. J. Low-Coordinate NHC-Zinc Hydride Complexes
Catalyze Alkyne C-H Borylation and Hydroboration using Pinacolborane. ACS Catal. 2019, 9,
18
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Page 19 of 21
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5760-5771. (f) McGough, J. S.; Cid, J.; Ingleson, M. J. Catalytic Electrophilic C-H Borylation
using NHC·Boranes and Iodine Forms C2-, not C3-Borylated Indoles. Chem. Eur. J. 2017, 23,
8180-8184. (g) Jayasundara, C. R. K.; Sabasovs, D.; Staples, R. J.; Oppenheimer, J.; Smith, M.
R., III; Maleczka, R. E. Jr. Cobalt-Catalyzed C-H Borylation of Alkyl Arenes and Heteroarenes
Including the First Selective Borylations of Secondary Benzylic C-H Bonds. Organometallics
2018, 37, 1567-1574. (h) Saper, N. I.; Ohgi, A.; Small, D. W.; Semba, K.; Nakao, Y.; Hartwig, J.
F. Nickel-Catalysed anti-Markovnikov Hydroarylation of Unactivated Alkenes with Unactivated
Arenes Facilitated by non-Covalent Interactions. Nat. Chem. 2020, 12, 276-283.
15. Das, R.; Blumenberg, J.; Daniliuc, C. G.; Schnieders, D.; Neugebauer, J.; Han, Y. F.; Hahn, F. E.
Regioselective N- and C‑Metalation of Neutral 2‑Halogenobenzimidazole Derivatives.
Organometallics 2019, 38, 3278-3285.
16. (a) Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.; Mix, A. C-F Activation of
Fluorinated Arenes using NHC-Stabilized Nickel(0) Complexes: Selectivity and Mechanistic
Investigations. J. Am. Chem. Soc. 2008, 130, 9304-9317. (b) Zhou, J.; Kuntze-Fechner, M. W.;
Bertermann, R.; Paul, U. S. D.; Berthel, J. H. J.; Friedrich, A.; Du, Z.; Marder, T. B.; Radius, U.
Preparing (Multi)fluoroarenes as Building Blocks for Synthesis: Nickel-Catalyzed Borylation of
Polyfluoroarenes via C-F Bond Cleavage, J. Am. Chem. Soc. 2016, 138, 5250-5253. (c) Bose, S.
K.; Fucke, K.; Liu, L.; Steel, P. G.; Marder, T. B. Zinc-Catalyzed Borylation of Primary,
Secondary and Tertiary Alkyl Halides with Alkoxy Diboron Reagents at Room Temperature,
Angew. Chem. Int. Ed. 2014, 53, 1799-1803. (d) Zhou, J.; Berthel, J. H. J.; Kuntze-Fechner, M.
W.; Friedrich, A.; Marder, T. B.; Radius, U. NHC Nickel-Catalyzed Suzuki-Miyaura
Cross-Coupling Reactions of Aryl Boronate Esters with Perfluorobenzenes. J. Org. Chem. 2016,
81, 5789-5794. (e) Bose, S. K.; Brand, S.; Omoregie, H. O.; Haehnel, M.; Maier, J.; Bringmann,
G.; Marder, T. B. Highly Efficient Synthesis of Alkylboronate Esters via Cu(II)-Catalyzed
Borylation of Unactivated Alkyl Bromides and Chlorides in Air. ACS Catal. 2016, 6, 8332-8335.
(f) Tian, Y. M.; Guo, X. N.; Kuntze-Fechner, M. W.; Krummenacher, I.; Braunschweig, H.;
Radius, U.; Steffen, A.; Marder, T. B. Selective Photocatalytic C-F Borylation of
Polyfluoroarenes by Rh/Ni Dual Catalysis Providing Valuable Fluorinated Arylboronate Esters.
J. Am. Chem. Soc. 2018, 140, 17612-17623. (g) Kuehn, L.; Jammal, D. G.; Lubitz, K.; Marder, T.
B.; Radius, U. Stoichiometric and Catalytic Aryl-Cl Activation and Borylation using
19
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 21
1
2
3
4
5
6
7
8
NHC-Stabilized Nickel(0) Complexes. Chem. Eur. J. 2019, 25, 9514-9521. (h) Kuehn, L.;
Huang, M.; Radius, U.; Marder, T. B. Copper-Catalysed Borylation of Aryl Chlorides. Org.
Biomol. Chem. 2019, 17, 6601-6606.
9
17. (a) Doherty, N. M.; Hoffmann, N. W. Transition-Metal Fluoro Compounds Containing
Carbonyl, Phosphine, Arsine, and Stibine Ligands, Chem. Rev. 1991, 91, 553-573. (b) Dolbier,
W. R. J. Fluorine Chemistry at the Millennium, Fluorine Chem. 2005, 126, 157-163. (c)
Uneyama, K. Organofluorine Chemistry; Wiley-Blackwell: Oxford, U.K., 2006. d) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry, Chem. Soc. Rev.
2008, 37, 320-330. (e) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky,
A. E.; Fustero, S.; Soloshonok, V. A.; Liu H. Fluorine in Pharmaceutical Industry:
Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011), Chem.
Rev. 2014, 114, 2432-2506.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18. (a) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles. Chem.
Rev. 2006, 106, 2875-2911. (b) Bandini, M.; Eichholzer, A. Catalytic Functionalization of
Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608-9644.
19. (a) Stuart, D. R.; Villemure, E.; Fagnou, K. Elements of Regiocontrol in Palladium-Catalyzed
Oxidative Arene Cross-Coupling. J. Am. Chem. Soc. 2007, 129, 12072-12073. (b) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles
under Mild Conditions. J. Am. Chem. Soc. 2008, 130, 8172-8174. (c) Roy, D.; Mom, S.; Royer,
S.; Lucas, D.; Hierso, J. -C.; Doucet, H. Palladium-Catalyzed Direct Arylation of
Heteroaromatics with Activated Aryl Chlorides Using
a
Sterically Relieved
Ferrocenyl-Diphosphane. ACS Catal. 2012, 2, 1033-1041. (d) Larsen M. A.; Hartwig, J. F.
Iridium-Catalyzed C-H Borylation of Heteroarenes: Scope, Regioselectivity, Application to
Late-Stage Functionalization, and Mechanism. J. Am. Chem. Soc. 2014, 136, 4287-4299. (e) Li,
X.; Gu, X. Y.; Li, Y. J.; Li, P. X. Aerobic Transition-Metal-Free Visible-Light Photoredox
Indole C‑3 Formylation Reaction. ACS Catal. 2014, 4, 1897-1900. (f) Jin, L. -K.; Wan, L.; Feng,
J.; Cai, C. Nickel-Catalyzed Regioselective Cross-Dehydrogenative Coupling of Inactive
C(sp3)-H Bonds with Indole Derivatives. Org. Lett. 2015, 17, 4726-4729. (g) Chen, J.; Wu, J.
Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides. Angew. Chem. Int. Ed. 2017,
56, 3951-3955. (h) Yamaguchi, M.; Suzuki, K.; Sato, Y.; Manabe, K. Palladium-Catalyzed
20
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Page 21 of 21
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Direct C3-Selective Arylation of N-Substituted Indoles with Aryl Chlorides and Triflates. Org.
Lett. 2017, 19, 5388-5391. (i) Mohr, Y.; Renom-Carrasco, M.; Demarcy, C.; Quadrelli, E. A.;
Camp, C.; Wisser, F. M.; Clot, E.; Thieuleux, C.; Canivet, J. Regiospecificity in Ligand-Free
Pd-Catalyzed C-H Arylation of Indoles: LiHMDS as Base and Transient Directing Group. ACS
Catal. 2020, 10, 2713-2719.
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