Metal-free directed sp 2-C–H borylation

Article abstract of DOI:10.1038/s41586-019-1640-2

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials¹. The discovery of simpler, milder and more efficient approaches to organoborons can

Full text of DOI:10.1038/s41586-019-1640-2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Article
Metal-free directed sp2-C–H borylation
https://doi.org/10.1038/s41586-019-1640-2
Received: 9 July 2019
Jiahang Lv1,2,6, Xiangyang Chen3,6, Xiao-Song Xue3,4, Binlin Zhao1, Yong Liang1, Minyan Wang1,
Liqun Jin5, Yu Yuan2, Ying Han2, Yue Zhao1, Yi Lu1, Jing Zhao1, Wei-Yin Sun1, Kendall. N. Houk3*
& Zhuangzhi Shi1,2,4
*
Accepted: 4 September 2019
Published online: 30 September 2019
Organoboron reagents are important synthetic intermediates that have a key role in
the construction of natural products, pharmaceuticals and organic materials1. The
discovery of simpler, milder and more efcient approaches to organoborons can open
additional routes to diverse substances2–5. Here we show a general method for the
directed C–H borylation of arenes and heteroarenes without the use of metal
catalysts. C7- and C4-borylated indoles are produced by a mild approach that is
compatible with a broad range of functional groups. The mechanism, which is
established by density functional theory calculations, involves BBr3 acting as both a
reagent and a catalyst. The potential utility of this strategy is highlighted by the
downstream transformation of the formed boron species into natural products and
drug scafolds.
In order to achieve excellent site-selectivity, organoboron compounds conditions (including temperatures of up to 300ꢀ°C)12 and the use
have typically been synthesized by directed ortho-metalation (usually of aluminium salts13. Replacing the transition-metal-catalysed process
lithiation)6—a process that is not compatible with many sensitive func- by a mild metal-free strategy (Fig. 1c) offers an alternative pathway to
tional groups (Fig. 1a). During the past two decades, transition-metal- C–H borylation that is practical, inexpensive and environmentally
catalysed directed C–H activation7,8 has emerged as a powerful tool for benign15
.
the construction of C–B bonds9–11 (Fig. 1b). However, these reactions
The indole moiety is an important structural motif16,17. Several recent
rely mostly on precious-metal catalysts with ligands, which can be studies have reported indole C–H functionalization without the use of
a substantial limitation—particularly when considering large-scale transition metals (Fig. 1d), including a frustrated-Lewis-pair-catalysed
syntheses and the need to remove toxic trace metals in pharmaceuti- C–H borylation of indoles at the most electron-rich C3 position18 and a
cal products. Early studies involving directed C–H borylation without method to access C2-silylated indoles by KOtBu-catalysed C–H silyla-
transition-metal catalysts, assisted by strongly coordinating groups tion19. Installation of pivaloyl groups at the N1 or C3 positions of indoles
such as pyridine, have been reported12–14. Although very good levels of enables selective delivery of the boron species to the unfavourable C7
regioselectivity can be achieved, such reactions usually require harsh or C4 positions20–25 (Fig. 1d).
a
d
DG
H
DG
[B]
DG
Li
[B]
R-Li
Bpin
N
FLP
Directed
ortho-metalation
HBpin
N
O
b
H
H
Me
H
3
tBu
4
Ref. 18
Bpin
Bpin
5
DG
H
DG
DG
[B]
BX3
Then pinacol
tBu
TM catalyst
[B]
H
2
6
N
TM = Ir, Rh,
Pd, Ru...
O
TM
1
7
R
Directed C–H
transmetalation
KOtBu
HSiR3
c
R3Si
Boron
chemistry
DG
FG
DG
H
DG
Controlled by
Chelation effect
N
N
[B]
Ts
Me
Electronic effect
Metal-free
Ref. 19
This work
[B]
Directed C–H
borylation
C–C and C–Het
bond formation
Fig. 1 | Strategies for directed C–H bond borylation. a, Directed ortho-
metalation. b, Transition-metal-catalysed C–H borylation. c, Metal-free
directed C–H borylation. d, Transition-metal-free site-selective C–H
functionalization of indoles. DG, directing group; FG, functional group; FLP,
frustrated Lewis pair; Het, heteroatom; pin, pinacolate; TM, transition metal.
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
2College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, China. 3Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA,
USA. 4State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin, China. 5College of Chemical Engineering, Zhejiang University of Technology,
Hangzhou, China. 6These authors contributed equally: Jiahang Lv, Xiangyang Chen. *e-mail: houk@chem.ucla.edu; shiz@nju.edu.cn
336 | Nature | Vol 575 | 14 November 2019

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Directed C–H borylation of indoles at the C7 position
H
a
Then pyridine,
pinacol, 0 °C–RT, 1 h
BBr3
H
N
N
N
DCM, RT, Ar, 1 h
78%
tBu
B
Br
Piv
Piv
O
H
BPin
Br
1a
1b
1c
Me
Ph
OMe
BPin
F
Me
OTBS
N
N
N
Me
N
N
N
N
Piv
Piv
Piv
BPin
BPin
BPin
Piv
Piv
Piv
Piv
BPin
BPin
BPin
3c, 78%
2c, 83%
4c, 85%
5c, 90%
6c, 56%
7c, 61%
8c, 91%
Ph
Cl
Br
I
N
N
N
F
Br
N
N
Piv
Piv
Piv
BPin
BPin
BPin
Piv
Piv
N
BPin
BPin
Piv
BPin
9c, 77%
10c, 72%
11c, 85%
12c, 67%
13c, 72%
14c, 78%
b
Directed C–H borylation of indoles at the C4 position
BPin
BPin
BPin
BPin
BPin
Ph
BPin
Piv
Piv
Piv
BPin
Piv
Piv
Piv
Piv
F
N
N
N
N
N
N
Me
N
H
Ts
Ts
Bn
Ts
Ts
Ts
OMe
15c, 88%
19c, 85%
BPin
Piv
20c, 71%
16c, 34%
17c, 48%
Piv
18c, 85%
21c, 93%
BPin
BPin
Br
Piv
BPin
BPin
BPin
Piv
Piv
Piv
Cl
Br
N
N
N
N
N
N
I
Ph
Ts
Ts
Ts
Ts
Ts
Ts
S
22c, 91%
23c, 77%
24c, 79%
25c, 55%
26c, 60%
27c, 87%
Directed C–H borylation of (hetero)arenes
c
H
N
tBu
H
N
tBu
NHPiv
BBr3
Then K2CO3,
O
pinacol, 0 °C–RT, 1 h
Cl
B
O
O
Cl
B
O
Cl
H
85%
DCM, RT, Ar, 1 h
Br
Br
Me
Me
Me
Me
28a
28b
28c
Me
Ph
NHPiv
BPin
NHPiv
BPin
Me
NHPiv
BPin
NHPiv Ph
BPin
NHPiv
NHPiv
NHPiv
BPin
NHPiv
BPin
tBu
BPin
33c, 80%
NHPiv
MeO
BPin
35c, 59%
NHPiv
TBSO
29c, 88%
NHPiv
30c, 96%
31c, 85%
32c, 94%
34c, 83%
36c, 70%
F
Cl
Br
NHPiv
BPin
NHPiv
BPin
NHPiv
BPin
NHPiv
BPin
NHPiv
EtOOC
F
BPin
37c, 95%a
Br
BPin
41c, 99%a
I
BPin
43c, 72%
BPin
40c, 99%a
Ph
39c, 99%a
42c, 99%a
38c, 71%
44c, 52%
NHPiv
CF3
NHPiv
BPin
NHPiv
NHPiv
BPin
NMePiv
BPin
OPiv
BPin
S
N
Piv
N
Piv
CF3
BPin
NC
BPin
47c, 49%b
BPin
50c, 99%a
BPin
51c, 99%a
48c, 54%
49c, 50%
52c, n.f.c
45c, 66%b
46c, 56%b
Fig. 2 | See next page for caption.
Nature | Vol 575 | 14 November 2019 | 337

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Article
Fig. 2 | Substrate scope of directed C–H borylation of (hetero)arenes. a, C7-
selective C–H borylation of indoles. b, C4-selective C–H borylation of indoles.
c, Ortho-selective C–H borylation of arenes. Reaction conditions: substrates
1–52a (0.20 mmol), BBr3 (0.22 mmol) in 1.0 ml of DCM at room temperature
(RT), 1–9 h, under Ar; then base (1–14a, pyridine; 15–27a, Et3N; 28–52a, K2CO3)
and pinacol were added to the mixture, and the temperature was increased
from 0ꢀ°C to room temperature over 1 h. aWithout further purification by
column chromatography on silica gel. bUsing BBr3 (2.0 mmol) in 0.1 ml of DCM.
cNot formed (n.f.). Piv, pivaloyl; Ts, 4-toluenesulfonyl. The B–O coordination
bonds in the products and all hydrogens in X-ray structures are omitted for
clarity.
The reaction of N-pivaloyl indole 1a (1.0 equiv.) with BBr3 (1.1 equiv.)26 examined the scope of the C7-selective C–H borylation of indoles
in dry dichloromethane (DCM) without any additive for 1 h at room (2–14a). Indoles bearing methyl (2c–4c), phenyl (5c), methoxy (6c),
temperature produced the dibromoborane product 1b, as confirmed OTBS (TBS, tert-butyldimethylsilyl; 7c), F, Cl, Br, and I (8–13c) sub-
by X-ray analysis (Fig. 2a). A C–B bond is formed at the indole C7 posi- stituents at the C4–C6 positions underwent borylation and gave the
tion, and the central B atom is tetrahedral and is chelated by O. In situ corresponding products in 56–91% yield. In addition, indole 14a—which
formation of the pinacol boronate ester was facile: product 1c was bears an alkenyl substituent—was also compatible. Next, we examined
isolated in 78% yield after reaction with pinacol using pyridine as a the scope of C3-pivaloyl indoles23 (15–27a) as coupling partners with
base (Supplementary Information, section 3). Indole C2- and C3-boryl- BBr3 (Fig. 2b), and found that they reacted with high regioselectivity
ation products were not detected. Using these conditions, we first to produce C4-borylated indoles. Treatment of the indole 15a—which
a
Ru-catalysed
N-hydrosilylation
NaBO3
N
N
H
N
H
Ir-catalysed
Piv
H
OH
C–H borylation
H
Previous strategy
1a
1a′
53, 77%
Me
H
Piv
OH
OH
Piv
O
N
H
Me
BBr3
TsOH
OH
glycol
N
NaBO3
N
N
Ts
N
H
Ts
Ts
15a
54, 85%
55, 81%
(S)-Pindolol
NHPiv
H
NHPiv
OH
DG
DG
TM catalyst
[O]
Oxidation
Directed C–H
transmetalation
H
TM
Hydroxylation
29a
56, 82%
Previous strategy
b
N
H
N
Piv
H
Me
Ph
N
Br
58, 61%
1a
MeOOC
O
NNHTs
BBr3
DCM, 1 h, RT
Alkylation
K2CO3
OMe
OMe
Ph
Me
OMe
57
OMe
60a
Pratosine
61a, 84%
Then K2CO3,
pinacol, 0 °C–RT, 1 h
Then H2O,
RT, 1 h
Pd catalyst
N
O
N
Arylation
N
H
Gram-scale
60%
88%
tBu
Piv
BO
B
Br
3
BPin
1e
Br
1d
1b
Br
MeOOC
Cu catalyst
NaN3
Azidation
N
O
O
O
60b
O
N
H
O
N3
59, 67%
Hippadine
61b, 70%
Fig. 3 | Applications of the metal-free directed C–H borylation strategy. a, Directed C–H hydroxylation mediated by boron species. b, Cascade C–H borylation/
C–C and C–Het bond formation.
338 | Nature | Vol 575 | 14 November 2019

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a
BBr3
Hα
ΔG (kcal mol–1
)
Br
α
β
–
BBr2
BBr4
+
Hα
O
BBr2
TSIIα
27.1
N
tBu
TSIIIα
25.8
O
tBu
N
N
Hβ
tBu
+
O
BBr2
Hβ
Hβ
BBr3
BBr2
Hα
N
–
BBr4
Br
20.9
TSIIIβ
20.7
TSI
19.4
tBu
Hα
TSIIβ
IN3β
17.7
O
O
N
tBu
BBr2
tBu
Hβ
N
IN2
Hβ
Br
BBr3
16.3
IN3α
O
+
BBr2
–
14.9
Hβ
–
BBr4
BBr2
Hα
BBr4
Hα
BBr3
tBu
O
Hα
N
N
BBr3
HBr
tBu
O
+
tBu
N
Hβ
+
BBr2
–
Hβ
O
BBr3
HBr
BBr4
Br
Br
Hβ
B
IN1
1.5
O
1a
Hα
N
tBu
0.0
tBu
N
Hβ
BBr3
O
Hα
1bα
Hβ
BBr3
tBu
–6.6
N
1bβ
O
B
–10.0
Br
Br
b
C
C
C
O
B
O
O
C7
B
B
C7
2.11
C2
2.09
TSIIβ
TSIIα
IN2 C–O–B = 135°
C–O–B = 131°
C–O–B = 118°
Fig. 4 | DFT calculations for the reaction of 1a with BBr3. a, Free energy profiles for the C–H borylation of indole 1a. b, Optimized structures of IN2, TSIIα
(292i cm−1) and TSIIβ (287i cm−1). Bond lengths are in Å.
bears an N–Ts group—with BBr3 resulted in an 88% isolated yield of taken place in the orthoposition of the amido group regardless of the
the desired C4-borylation product 15c. The N–Bn indole 16a gave a electronic properties of the substituent (30c, 34c, 38–40c). When the
much lower yield of the C4-borylation product. Notably, even the free pivanilide was substituted in the metaposition, C–H borylation occurs
indole 17a, bearing an N–H group, provided the desired product 17c in only at the less sterically hindered orthoposition (31c, 33c). Halogens
a modest yield. Various substituents—including methyl (18c), methoxy (37–42c) remain unaffected during the reaction. This system is toler-
(19c), phenyl (20c), F, Cl, Br, I (21–25c) and alkenyl (26c) groups—were ant of ester (43c) and alkynyl (44c) groups. Of particular note is the
tolerated. Substrate 27a, containing a dibenzothiophene moiety as an tolerance of this reaction to electron-withdrawing groups such as CF3
example of additional functionality, also underwent C–H borylation (45–46a) and CN (47a); these substrates also reacted and produced
at the C4-position of the indole motif.
ortho-borylated products 45–47c. The reaction is compatible with het-
The strategy is not restricted to indoles; other arenes are also viable erocyclic motifs such as thiophene (48c), and other amides including
substrates for the reaction (Fig. 2c). When N-pivaloyl aniline 28a was N-methylaniline (49c), indoline (50c) and tetrahydroquinoline (51c) are
used as a substrate, borylation proceeded at the ortho C–H bond. also tolerated. However, the phenyl pivalate 52a failed to react under
Pinacol was added to facilitate formation of the easily isolated pinacol the current reaction conditions.
boronic ester 28c in 85% yield. The intermediate 28b and product 28c
Our C–H borylation strategy therefore provides a simple way to
were confirmed by X-ray analysis. This approach has a good substrate construct various C–C and C–heteroatom bonds. As a key intermedi-
scope and is tolerant of a range of substituents in all positions of the ate for the synthesis of natural indolequinone, 7-hydroxyindole 5327
aromatic ring. For example, ortho-substituted pivanilides readily pro- could be rapidly prepared from indole 1a in 77% yield by a cascade C–H
duce multi-substituted aryl boronate esters, in which borylation has borylation–oxidation–directing-group-removal process, in which
Nature | Vol 575 | 14 November 2019 | 339