Meta-Selective C-H Borylation of Benzamides and Pyridines by an Iridium-Lewis Acid Bifunctional Catalyst

Article abstract of DOI:10.1021/jacs.9b03138

We report herein the iridium-catalyzed meta-selective C-H borylation of benzamides by using a newly designed 2,2′-bipyridine (bpy) ligand bearing an alkylaluminum biphenoxide moiety. We also demonstrate the iridium-catalyzed C3-selective C-H borylation of pyridine with a 1,10-phenanthroline (Phen) ligand bearing an alkylborane moiety. It is proposed that the Lewis acid-base interaction between the Lewis acid moiety and the aminocarbonyl group or the sp²-hybridized nitrogen atom accelerates the reaction and controls the site-selectivity.

Full text of DOI:10.1021/jacs.9b03138

Subscriber access provided by The University of Melbourne Libraries
Article
meta-Selective C-H Borylation of Benzamides and
Pyridines by an Iridium-Lewis Acid Bifunctional Catalyst
Lichen Yang, Nao Uemura, and Yoshiaki Nakao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03138 • Publication Date (Web): 21 Apr 2019
Downloaded from http://pubs.acs.org on April 21, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
meta-Selective C–H Borylation of Benzamides and Pyridines by an
Iridium–Lewis Acid Bifunctional Catalyst
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
Lichen Yang, Nao Uemura, and Yoshiaki Nakao*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
ABSTRACT: We report herein the iridium-catalyzed meta-selective C–H borylation of benzamides by using a newly designed
2,2’-bipyridine (bpy) ligand bearing an alkylaluminum biphenoxide moiety. We also demonstrate the iridium-catalyzed C3-
selective C–H borylation of pyridine with a 1,10-phenanthroline (Phen) ligand bearing an alkylborane moiety. It is proposed
that the Lewis acid–base interaction between the Lewis acid moiety and the aminocarbonyl group or the sp2-hybridized
nitrogen atom accelerates the reaction and controls the site-selectivity.
INTRODUCTION
Transition metal (TM)-catalyzed C–H functionalization is
one of the most efficient ways to construct C–C and C–
heteroatom bonds and is now becoming a powerful tool for
complex molecule synthesis.1 To develop practical C–H
functionalization methods, controlling the site-selectivity
among similar C–H bonds is one of the key challenges.2 In
nature, enzymes functionalize certain C–H bonds with excellent
site-selectivity through precise placing of substrates via non-
covalent interactions.3 Such an interaction4 has inspired the
development of artificial catalyst systems for site-selective
C(sp3)–H oxidation reactions, which are based on hydrophobic
interaction,5 Lewis acid–base interaction,6 or hydrogen-bonding
interaction.7
The non-covalent interaction strategies were extended to
iridium-catalyzed arene C–H borylation reactions8 in recent
years because of the broad utilities of the resulting arylboronic
esters.8g,9 For example, hydrogen-bonding has been employed
to control ortho-10 and meta-selective11 C–H borylation
Figure 1. Site-control of arene C–H borylation reactions using
reactions. And ion-pair interaction has been used to control
TM–LA bimetallic catalysts.
ortho-12 and meta-selective13 C–H borylation very recently.
Lewis acid (LA) catalysts,14 as well as Lewis acid–Lewis base
(LA–LB) bifunctional catalysts15 have been widely used to
control reaction selectivities. Recent researches of TM–LA
bifunctional catalysts,16 which contain TM and LA in one
catalyst molecule, have shown its potential to control the site-
selectivity of TM-catalyzed C–H functionalizations at the
remote positions.17 The application of TM–LA bifunctional
catalysts in site-selective arene C–H borylation, however, was
limited in a few reports, which included ortho-selective C–H
borylation of aryl sulfides by an Ir–B catalyst (Figure 1a),18
meta-selective C–H borylation of arylaldimines by an Ir–B
catalyst (Figure 1b),19 and para-selective C–H borylation of aryl
esters by an Ir–K catalyst (Figure 1c).20 Although great
progresses have been made so far, this strategy is still in its
infancy, and new TM–LA bimetallic catalyst systems are
desired for other substrate classes and/or complementary site-
selectivities.
We are interested in the site-control of C–H functionalization
by cooperative TM/LA catalysis for a decade.21 Recently, we
have developed the para-selective C–H borylation of
benzamides and pyridines by cooperative Ir/Al catalysis (Figure
2).22 We found the aluminum LA catalysts dramatically
accelerate the reaction by generating an LA–benzamide or –
pyridine adduct. This fact inspired us to design an Ir–LA
bifunctional catalyst for the meta-selective C–H borylation
reaction of benzamides and pyridines. Herein, we report a newly
designed LA-containing N-based bidentate ligands to realize
these transformations.24 The designed bifunctional catalyst
includes: (1) A bpy or phenanthroline moiety for ligating Ir; (2)
A linker which arranges the positions of the metal centers to
control the site-selectivity25; (3) A Lewis acidic alkylaluminum-
or alkylboron-based moiety to recognize aminocarbonyl groups
or sp2-hybridized nitrogen and accelerate the reactions through
electronic activation of the (hetero)arene substrates (Figure 2).22
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
bond than the C(4)–H. Our method could also be applied to
1
2
3
4
5
6
7
8
arylphosphonate 1m, which afforded a meta-C–H borylation
product with good yield and selectivity. Notably the hydrogen-
bonding strategy was not effective to control the site-selectivity
for 1m.11a Sunifiram(1n), which is an experimental antiamnesic
drug, was tested as a substrate. Our catalyst successfully
achieved the meta-C–H borylation with moderate yield and high
selectivity. Other functionalized arenes like arylketones,
benzoates and sulfonamides were not tolerated under these
conditions probably due presumably to their weaker Lewis
basicity (see Supporting Information). We indeed failed to
observe the interaction between L4–AlOct and 1a in NMR
experiments. We suggest that the alkylaluminum biphenoxide is
a weak LA but it could accelerate the reaction by stabilizing the
transition state of the meta-C–H activation.
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
Figure 2. Design of Ir–LA bifunctional catalysts for meta-selective
C–H borylation of benzamides.
Table 1. Ligand Optimization
RESULTS AND DISCUSSION
In the beginning, we designed L1, which has a 2-
hydroxyphenyl linker with a diisobutylaluminum LA moiety, as
a ligand for the Ir-catalyzed C–H borylation of benzamides. The
borylation reaction of 1a using dtbpy as a ligand gave a mixture
of meta- (2a) and para-borylation (5a) products including m,m’-
double borylation (3a) in an almost statistic ratio, suggesting
that the aminocarbonyl group served as an electronically neutral
substituent (entry 1 of Table 1).26 On the other hand, L1
dramatically increased the meta-selectivity (entry 2) though a
small amount of ortho-borylation product was also noted. L2
which has a longer and more flexible linker gave lower meta-
selectivity than L1 (entry 3). L3 bearing a 3-hydroxyphenyl
linker gave a much lower yield without any enhancement of
selectivity (entry 4). Finally, L4–AlOct was designed because
we thought the rigid aluminum-biphenoxide moiety would limit
the flexibility of the Al center and block the ortho-borylation.
To our delight, the combination of an Ir pre-catalyst and L4–
AlOct controlled the C–H borylation exclusively at the meta-
position with good reactivity (entry 5). The reaction using a
larger amount (0.30 mmol) of the borylating agent gave higher
yields (entry 6).
selectivitya
yield (%)a
entr
y
ligand
meta:ortho:para 2a 3a 4a 5a
1b
2b
3b
4b
5
dtbpy
L1
52:0:48
69:6:25
59:3:38
50:10:40
>99:0:0
>99:0:0
36 13 –– 23
11 ––
1
1
1
2
6
2
L2
18
5
1
––
3
L3
L4–AlOct
L4–AlOct
36
–– ––
By using L4-AlOct as a ligand, we applied our method to
ortho-mono-substituted benzamides. Generally, the reaction
proceeded at the C5 position. N,N-Diethyl-2-methylbenzamide
(1b) gave good yield and selectivity at 60 °C. 2-Phenyl-
substituted benzamide 1c gave good selectivity notably without
any borylation at the phenyl substituent. The catalyst-control
overrode the observed electronically induced site-selectivity by
a methoxy group, which accelerates the borylation at its meta-
position,26 to give 2d with good selectivity. 2-Halogenated
substrates 1e and 1f also gave good selectivity when hexane was
used as a solvent. The low reactivity and/or selectivity of these
reactions in THF/hexane could be ascribed to competitive
coordination of THF to Al. Electron-withdrawing substituents
like CF3 and OCF3 (1g and 1h) were also tolerated and gave
good yields and selectivities using hexane as a solvent. The
reaction of dicarbonyl substrate 1i exclusively proceeded at the
position meta to the aminocarbonyl group.
6c
46 49 –– ––
a Estimated by GC analysis of the reaction mixtures using n-
dodecane as an internal standard. Selectivity was calculated as
b
following: meta:ortho:para = [(2a+3a)/2]:(4a/2):5a.
4.0
c
mol% HB(pin) was used. B2(pin)2 (0.30 mmol) was used
under standard conditions.
To confirm the importance of the substrate–Al interaction for
the observed high meta-selectivity and reactivity, we conducted
the following experiments. The ligand L4 and L4-MOM, which
lack the Al moiety, gave a mixture of isomers as products
without selectivity (Table 3, entry 1 vs. entries 2 and 3). Unlike
the directed Ir–Al bifunctional catalyst (entry 1), the
combination of Ir–L1-MOM catalyst and Al(nOct)3 as LA
increased the ortho-selectivity with much lower yield (entry 4).
This result showed that the Al moiety located at an appropriate
distance to the Ir center is crucial for the high site-selectivity as
well as reactivity. Replacing the Al with K20,27 resulted in lower
selectivities and yields (entry 5). Finally, L4–AlOct showed the
highest catalytic activity compared with other conditions, which
indicated the acceleration effect of the Al LA catalyst (see
Supporting Information).
For meta-substituted benzamides, 3-fluoro-substituted
benzamide 1j, which gave a mixture of isomers under
conventional conditions, was borylated at the C5 position
exclusively by our method. Picolinamide 1k gave C4-borylation
product with good selectivity. The reaction of 1l proceeded at
the more steric hindered C5 position selectively probably
because of a more favored electronic property at the C(5)–H
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
Table 2. Scope of meta-Selective C–H Borylationa
1
2
3
4
5
6
7
8
2b,b 97% (>99:1) 2c, 77% (98:2)
(at 60 °C)
2d,c 98% (94:6)d; X =
2g,c 97% (>99:1); 2h,c,f 65% (90:10)
(68%, 22:78)e Clc: 2e, 99% (97:3) (92%, 58:42)e
(at 50 °C); (96%,
40:60)e
Brc:
2f,
89%
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
(>99:1) (at 80 °C);
(93%, 37:63)e
2i, 98% (95:5); 2j, 88% (>99:1); 2k, 83% (85:15); 2l, 95% (97:3); 2m, 84% (87:13)d; 2n, R = H, 24%;
(94%, 72:28)e
(56%, 56:44)e
(59%, 57:43)e
(>99%, 64:36)e
(87%, 18:82)
B(pin),
(93:7)g;
56:44)h
22%
(>99%,
a Reactions were performed with an arene substrate (0.20 mmol), B2(pin)2 (0.20 mmol), [Ir(cod)(OMe)]2 (1.0 mol%), and L4-AlOct (2.0
mol%) in THF (0.50 mL) and hexane (2.5 mL) at 30 C for 18 h. Yields were calculated by crude 1H NMR with 1,3,5-trimethoxybenzene
as an internal standard. Isolated yields shown in Supporting Information are generally lower than the NMR yields due to loss and/or partial
protodeboration of the products during purification. b Reaction run at 60 °C. c Reaction run using hexane (3.0 mL) as a solvent. d Selectivity
was estimated based on H NMR analysis of a crude product. e Reaction was performed under standard condition using dtbpy as ligand.
1
Yields and selectivities were calculated by crude 1H NMR with 1,3,5-trimethoxybenzene as an internal standard. f Reaction run at 50 °C.
g Reactions were performed with an arene substrate (1.0 mmol), B2(pin)2 (1.5 mmol), [Ir(cod)(OMe)]2 (1.0 mol%), and L4-AlOct (2.0
1
mol%) in THF (13 mL) at 60 C for 18 h. isolated yield. Selectivity was based on H NMR. h Reactions were performed with an arene
substrate (0.20 mmol), B2(pin)2 (0.30 mmol), [Ir(cod)(OMe)]2 (1.0 mol%), and dtbpy (2.0 mol%) in THF (2.5 mL) at 60 C for 18 h. Yield
and selectivity were based on 1H NMR with 1,3,5-trimethoxybenzene as an internal standard.
We then turned our attention to the C3-selective borylation of
borylation of pyridines recently by cooperative Ir/Al catalysis,22
a C3-selective variant has been elusive.
pyridine. Substituted pyridines play an important role in
pharmaceuticals, natural products and functional materials.
Among various methods for their syntheses, direct
functionalization of a preformed pyridine core has an advantage
in terms of step- and atom-economy.28 C2-29 and C4-selective30
functionalization of pyridines has been studied extensively.
However, C3-selective functionalization of pyridines remains
challenging.
Table 3. Control Experiments to Study the Mechanism
C3-Selective C–H functionalization of pyridine has been
achieved by the aid of directed C–H metalation of pyridines.31
Only a few ideal catalyst-controlled C3-selective C–H function-
alization of pyridine have been developed. Yu and co-workers
reported Pd-catalyzed olefination32 and arylation.33 Itami and
co-workers reported Pd-catalyzed oxidative cross-coupling of
pyridines with heteroarenes.29m Shi and Li reported Ir-catalyzed
carbonyl addition.34 Oestreich reported Ru-catalyzed C5-
selective silylation of 2-arylpyridine.35 Oro reported NHC–
selectivitya
yield (%)a
entr
y
ligand
additive
(2a+3a)/4a/5a
2a
3a
Ir(III)-catalyzed
C5-selective
silylation
of
2-
1
2
3
4
5
L4–AlOct
L4
––
––
>99:0:0
56:0:44
36
14
3
arylpyridine.36Although these reactions show good yield and
site-selectivity, they suffer from a limited scope of pyridine
substrates and lack versatility.
––
––
63:3:34
23
<1
L4–MOM
L4–MOM
L4–Kb
Pyridylboronic esters have served as useful building blocks
in natural product synthesis.37 Nevertheless, the C–H borylation
of pyridine often suffers from poor site-selectivity,38 when
sterically less biased, and lower reactivity compared with
arenes.38a,b Although we have developed the C4-selective
AlOct3
––
7:89:4
9
6
––
––
82:0:18
a
Estimated by GC analysis of the reaction mixtures using n-
b
dodecane as an internal standard. L4-K was synthesized by
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
mixing L4 with the same amount of KOtBu in THF at rt for 10 min
and used as a solution.
carbonyl-substituted pyridines possibly because the competitive
non-selective undirected reaction pathway (see Supporting
Information).
1
2
3
4
5
6
7
8
9
At the onset, we studied the Ir-catalyzed borylation reaction
of 2-picoline. The reactions using conventional ligands such as
dtbpy or TMPhen gave a mixture of 4- and 5-boryl-2-picolines
(Table 4, entries 1 and 2). We thus examined L4-AlOct but poor
yield and site-selectivity resulted (entry 3). Al-tethered
phenanthroline ligand L5 gave a mixture in slightly higher yield
(entry 4). We reasoned that the low conversion and site-
selectivity with Al-tethered ligands might be ascribed to the
weak Lewis acidity and thus prepared L6, the B-based LA
moiety of which was introduced through hydroboration in situ.
Gratifyingly, L6 dramatically increased the C5-selectivity to
76% with a good yield (entry 5). Modification of the ligand by
introducing BCy2 as a LA unit further increased the selectivity
to 97% (entry 6). L8 bearing a BCy2-substituted 2-propylphenyl
side chain gave lower C5-selectivity compared with L7 (entry
7). After a series of further screenings of reaction solvents and
additives (see Supporting Information), we found that the
combination of [Ir(cod)(OMe)]2, L7, HB(pin) in a 1,4-dioxane
solvent gave the highest C5-selectivity as well as yield (entry
8).
Table 4. Ligand Optimization
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
yield
entry
ligand
solvent
7a/8aa
(%)a
71
1
2
dtbpy
TMPhen
hexane
hexane
1,4-
dioxane
1,4-
dioxane
hexane
hexane
hexane
1,4-
27:73
42:58
88
3
4
L4-AlOct
L5
35:65
46:54
8
By using L7 as a ligand, we investigated other pyridine
derivatives (Table 5). Pyridine gave a mixture of C3-borylation
and C3,C5-diborylation products with excellent overall C3-
selectivity (7b). 2-Ethylpyridine 6c also gave excellent site-
selectivity and high yield. While compatibility of Lewis basic
functionality with the LA co-catalysis was concerned, oxygen
and nitrogen-containing substituents as well as carbonyl, ether,
and amine functionalities were all tolerated to give the
respective functionalized pyridylboronates (7d–7i). 2-
Benzylpyridine (6j) gave C5-borylated product selectively by
using L7 without any borylation on the benzyl group. ortho-
Silyl group was also tolerated (7k). Our catalyst could also
borylate nicotine at the C5 position with a reaction rate much
faster than with dtpby (7l). Our method, however, failed to
control the site-selectivity of C2-halogen-, methoxy- or
29
5
6
7
L6
L7
L8
76:24
97:3
71:29
83
55
82
8b
L7
98:2
>99
dioxane
a
Estimated by GC analysis of the reaction mixtures using n-
dodecane as an internal standard. b Reaction run in the presence
of 4.0 mol% HB(pin) at rt for 2 h.
Table 5. Scope of C5(C3)-selective C–H Borylation of Pyridinesa
7a, 89% (97:3)
7g, 99% (94:6)
7b,b R = H, 60%; 7c, 96% (97:3)
B(pin), 16% (94:6)
7d, 98% (96:4)
7e, 99% (94:6)
7f, 97% (93:7)
7h, 92% (95:5)
7i, 99% (94:6)
7j, 99% (92:8); 7k, 99% (73:27)
7l, 99% (>99:1);
(87%, 27:73) d,e
(1%)d,e
7m,c R = H, 26%; 7n, >99% (60:40); 7o, 99% (76:24); 7p, 62% (>99:1)f
7q, 83% (71:29)e; (95%, 26:74)d,e
B(pin),
(>99:1)
24% (>99%, 2:98)d,e
(48%, 46:54)d,e
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
a Reactions were performed with a pyridine substrate (1.0 mmol), B2(pin)2 (1.0 mmol), [Ir(OMe)(cod)]2 (1.0 mol%), HB(pin) (4.0 mol%)
and L7 (2.0 mol%) in dioxane (15 mL) at 25 C for 18 h. Yields and site-selectivities were estimated by 1H NMR analysis of crude products
using dibromomethane as an internal standard. Isolated yields shown in Supporting Information are generally lower than the NMR yields
1
2
3
4
5
6
7
8
9
10
b
due to loss and/or partial protodeboration of the products during purification. Reaction run with 0.50 mmol B2(pin)2. c Reaction for 70
1
hours. d Reaction was performed under standard condition using dtbpy as a ligand. Yields and selectivities were calculated by crude H
NMR with 1,3,5-trimethoxybenzene as an internal standard. e Reaction run on a 0.20 mmol scale. f Reactions were performed with the
substrate (1.0 mmol), B2(pin)2 (3.0 mmol), [Ir(OMe)(cod)]2 (3.0 mol%), HB(pin) (12.0 mol%) and L7 (6.0 mol%) in dioxane (45 mL) at 60
C for 18 h. Isolated yield is shown.
For 4-substituted pyridines, the reaction of 4-picoline (6m)
took place with excellent C3-selectivity, while no reaction
proceeded when dtbpy was used as a ligand. This result
demonstrated a significant rate-acceleration induced by our
bifunctional Ir–B catalysis. Our catalyst could also direct the
borylation of 6n at the C6 position, while dtpby showed C7-
selectivity. The method could be used to functionalize the
pyridine-based polydentate ligands selectively at the C5
positions (7o and 7p). The novel C5-selective C–H borylation
reaction has been used to the late-stage functionalization of
brompheniramine 7q, which is an antihistamine drug. In sharp
contrast to the conventional dtbpy ligand (95%, C5:C4 = 26:74),
L7 showed the C5-selectivity (83%, C5:C4 = 71:29).
reaction temperature (entry 4), as well as Et3B as an additional
LA reagent (entry 5), which could accelerate the undirected
process, all decreased the site-selectivity; (3) The directed
reaction was important for selectivity control because the
combined use of L9 and 9 did not improve the site-selectivity
(entry 6). Finally, the interaction between pyridine or 3-
borylpyridine with L7 was confirmed by 1H NMR analysis (see
Supporting Information). We observed ligand exchange on the
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
1
B moiety of L7, which was more rapid than a H NMR time-
scale, suggesting that the turnover of LA catalysis was not the
rate-determine step of the reaction.
CONCLUSIONS
In summary, we have developed a new Ir–LA bifunctional
catalyst for the meta-selective C–H borylation of benzamides
and pyridines. The well-positioned Al or B recognizes the Lewis
basic aminocarbonyl or sp2-hybridized nitrogen to likely place
the Ir catalyst center close to the reacting C3-position. Our
method shows good tolerance toward a range of functional
groups including Lewis basic ones without loss of site-
selectivity. The unprecedented ligand design demonstrates the
potential of the Lewis acid–base interaction as a powerful tool
to control the site-selectivities of catalytic C–H
functionalization reactions at the remote positions, which is
potentially useful in other transition metal-catalyzed C–H
functionalizations.
Table 6. Control Experiments to Study the Mechanism
yield
entry
ligand
additive
7a/8aa
ASSOCIATED CONTENT
(%)a
>99
49
Supporting Information. Detailed experimental procedures
including spectroscopic and analytical data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
standard
L7
L9
L7
L7
L7
L7
L9
––
98:2
50:50
47:53
94:6
93:7
84:16
36:64
1
2
––
DMAP (2.0 mol%)
––
77
92
91
82
3b
4c
5
AUTHOR INFORMATION
––
BEt3 (0.20 mmol)
9 (2.0 mol%)
Corresponding Author
6
98
a Estimated by GC analysis of the reaction mixtures using n-
dodecane as an internal standard. b Reaction run using 1.0 mL
of 1,4-dioxane. c Reaction run at 60 °C.
nakao.yoshiaki.8n@kyoto-u.ac.jp
ACKNOWLEDGMENT
This work was supported by the “JST CREST program Grant
Number JPMJCR14L3 in Establishment of Molecular Technology
towards the Creation of New Functions”, the “JSPS KAKENHI
Grant Number JP15H05799 in Precisely Designed Catalysts with
Customized Scaffolding”
We performed the following control experiments to confirm
the designed directed pathway and the importance of Lewis
acid-base interaction (Table 6). We revealed the following
points: (1) Lewis acid-base interaction was essential for the site-
selectivity because ligand L9, which was similar to L7 in terms
of its bulkiness but lacking the B moiety, gave a mixture of
isomers as products (entry 1). The presence of a strong Lewis
base such as DMAP hampered the LA function that
dramatically decrease the site-selectivity and reactivity (entry 2
and Supporting Information); (2) Non-selective undirected
reaction might compete with the desired site-selective pathway
since increased concentration (entry 3) and/or increased
REFERENCES
(1) For recent reviews, see: (a) Yamaguchi, J.; Yamaguchi, A.
D.; Itami, K. C–H Bond Functionalization: Emerging
Synthetic Tools for Natural Products and Pharmaceuticals.
Angew. Chem. Int. Ed. 2012, 51, 8960. (b) Kuninobu, Y.;
Sueki, S. C–H Bond Transformations Leading to the
Synthesis of Organic Functional Materials. Synthesis 2015,
3823. (c) Bohra, H.; Wang, M. Direct C–H Arylation: a
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
“Greener” Approach towards Facile Synthesis of Organic
Amination Reaction Catalysed by a Supramolecular Rh(II)
1
2
3
4
5
6
7
8
Semiconducting Molecules and Polymers. J. Mater. Chem.
A 2017, 5, 11550.
Complex. Chem. Commun. 2013, 49, 8009. (d) Burg, F.;
Gicquel, M.; Breitenlechner, S.; Pöthig, A.; Bach, T. Site-
and Enantioselective C–H Oxygenation Catalyzed by a
Chiral Manganese Porphyrin Complex with a Remote
Binding Site. Angew. Chem Int. Ed. 2018, 57, 2953.
(2) For recent reviews, see: (a) Chen, Z.; Wang, B.; Zhang, J.;
Yu, W.; Liu, Z.; Zhang, Y. Transition Metal-catalyzed C–
H Bond Functionalizations by the Use of Diverse Directing
Groups. Org. Chem. Front. 2015, 2, 1107. (b) Dey, A.;
Maity, S.; Maiti, D. Reaching the South: Metal-catalyzed
Transformation of the Aromatic Para-position. Chem.
Commun. 2016, 52, 12398. (c) Dey, A.; Agasti, S.; Maiti,
D. Palladium Catalysed Meta-C–H Functionalization
Reactions. Org. Biomol. Chem. 2016, 14, 5440. (d) 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.
(8) (a) Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.;
Marder, T. B. Synthesis and Structures of the First
Transition-metal
Tris(boryl)
Complexes:
Iridium
Complexes (6-arene)Ir(BO2C6H4)3. J. Am. Chem. Soc.
1993, 115, 9329. (b) Iverson, C. N.; Smith III, M. R.
Stoichiometric and Catalytic B–C Bond Formation from
Unactivated Hydrocarbons and Boranes. J. Am. Chem. Soc.
1999, 121, 7696. (c) 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. (d) Cho,
J. Y.; Tse, M. K.; Holmes, D.; Maleczka, Jr., R. E.
Remarkably Selective Iridium Catalysts for the Elaboration
of Aromatic C–H Bonds. Science 2002, 295, 305. (e)
Ishiyama, T.; Tagaki, 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. (f) Ishiyama, T.; Tagaki, 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. For reviews of C–H borylation reactions,
see: (g) 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.
(h) Ros, A.; Fernández, R.; Lassaletta, J. M. Functional
Group Directed C–H Borylation. Chem. Soc. Rev. 2014, 43,
3229. (i) Xu, L.; Wang, G.; Zhang, S.; Wang, H.; Wang,
L.; Liu, L.; Jiao, J.; Li, P. Recent Advances in Catalytic C–
H Borylation Reactions. Tetrahedron 2017, 73, 7123. For
recent works, see: (j) Li, H. L.; Kanai, M.; Kuninobu, Y.
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
(3) For recent reviews on natural and artificial enzymes-
catalyzed site-selective C–H functionalizations, see: (a)
Schnepel, C.; Sewald, N. Enzymatic Halogenation: a
Timely Strategy for Regioselective C–H Activation. Chem.
Eur. J. 2017, 23, 12064. (b) Upp, D. M.; Lewis, J. C.
Selective C–H Bond Functionalization Using Repurposed
or Artificial Metalloenzymes. Curr. Opin. Chem. Biol.
2017, 37, 48.
(4) For recent reviews on non-covalent interaction-controlled
selective catalytic reactions, see: (a) Das, S.; Brudvig, G.
W.; Crabtree, R. H. Molecular Recognition in
Homogeneous Transition Metal Catalysis: a Biomimetic
Strategy for High Selectivity. Chem. Commun. 2008, 413.
(b) Dydio, P.; Reek, J. N. H. Supramolecular Control of
Selectivity in Transition-metal Catalysis through Substrate
Preorganization. Chem. Sci. 2014, 5, 2135. (c) Davis, H. J.;
Phipps, R. J. Harnessing Non-covalent Interactions to
Exert Control over Regioselectivity and Site-selectivity in
Catalytic Reactions. Chem. Sci. 2017, 8, 864.
(5) (a) Groves, J. T.; Neumann, R. Enzymic Regioselectivity
in the Hydroxylation of Cholesterol Catalyzed by a
Membrane-spanning Metalloporphyrin. J. Org. Chem.
1988, 53, 3891. (b) Breslow, R.; Huang, Y.; Zhang, X.;
Yang, J. An Artificial Cytochrome P450 That
Hydroxylates Unactivated Carbons with Regio- and
Stereoselectivity and Useful CatalyticꢀTurnovers. Proc.
Natl. Acad. Sci. U. S. A. 1997, 94, 11156. (c) Breslow, R.;
Zhang, X.; Huang, Y. Selective Catalytic Hydroxylation of
a Steroid by an Artificial Cytochrome P-450 Enzyme. J.
Am. Chem. Soc. 1997, 119, 4535. (d) Yang, J.; Breslow, R.
Selective Hydroxylation of a Steroid at C-9 by an Artificial
Cytochrome P-450. Angew. Chem. Int. Ed. 2000, 39, 2692.
(e) Breslow, R.; Yang, J.; Yan, J. Biomimetic
Hydroxylation of Saturated Carbons with Artificial
Cytochrome P-450 Enzymes—Liberating Chemistry from
the Tyranny of Functional Groups. Tetrahedron 2002, 58,
653.
Iridium/Bipyridine-catalyzed
ortho-Selective
C–H
Borylation of Phenol and Aniline Derivatives. Org. Lett.
2017, 19, 5944. (k) Liu, L.; Wang, G.; Jiao, J.; Li, P. Sulfur-
directed Ligand-free C–H Borylation by Iridium Catalysis.
Org. Lett. 2017, 19, 6132.
(9) (a)
Darses,
S.;
Genet,
J.-P.
Potassium
Trifluoro(organo)borates: New Perspectives in Organic
Chemistry. Eur. J. Org. Chem. 2003, 4313. (b) Miyaura, N.
Metal-Catalyzed Reactions of Organoboronic Acids and
Esters. Bull. Chem. Soc. Jpn. 2008, 81, 1535. (c) Doucet,
H. Suzuki–Miyaura Cross-coupling Reactions of
Alkylboronic Acid Derivatives or Alkyltrifluoroborates
with Aryl, Alkenyl or Alkyl Halides and Triflates. Eur. J.
Org. Chem. 2008, 2013. (d) Roscales, S.; Csákÿ, A. G.
Transition-metal-free C–C Bond Forming Reactions of
Aryl, Alkenyl and Alkynylboronic Acids and Their
Derivatives. Chem. Soc. Rev. 2014, 43, 8215.
(6) Fang, Z.; Breslow, R. Metal Coordination-directed
Hydroxylation of Steroids with a Novel Artificial P-450
Catalyst. Org. Lett. 2006, 8, 251.
(10) (a) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.;
Singleton, D. A.; Maleczka, Jr., R. E.; Smith, III, M. R.
Outer-sphere Direction in Iridium C–H Borylation. J. Am.
Chem. Soc. 2012, 134, 11350. (b) Preshlock, S. M.; Plattner,
D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, Jr., R. E.;
Smith, III, M. R. A Traceless Directing Group for C–H
Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915.
(7) (a) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G.
W. Molecular Recognition in the Selective Oxygenation
of Saturated C–H Bonds by a Dimanganese Catalyst.
Science 2006, 312, 1941. (b) Das, S.; Brudvig, G. W.;
Crabtree, R. H. High Turnover Remote Catalytic
Oxygenation of Alkyl Groups:ꢀ How Steric Exclusion of
Unbound Substrate Contributes to High Molecular
Recognition Selectivity. J. Am. Chem. Soc. 2008, 130,
1628. (c) Höke, T.; Herdtweck, E.; Bach, T. Hydrogen-
bond Mediated Regio- and Enantioselectivity in a C–H
(11) (a) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A meta-
Selective C–H Borylation Directed by a Secondary
Interaction Between Ligand and Substrate. Nat. Chem.
2015, 7, 712. (b) Davis, H. J.; Genov, G. R.; Phipps, R.
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
meta-Selective C−H Borylation of Benzylamine-,
Phenethylamine-, and Phenylpropylamine-derived Amides
Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed.
2017, 56. 13351. (c) Lu, X.; Yoshigoe, Y.; Ida, H.; Nishi,
M.; Kanai, M.; Kuninobu, Y. Hydrogen Bond-Accelerated
meta-Selective C−H Borylation of Aromatic Compounds
and Expression of Functional Group and Substrate
Specificities. ACS Catal. 2019, 9, 1705.
H Borylation. J. Am. Chem. Soc. 2017, 139, 17763. For
1
2
3
4
5
6
stoichiometric reactions, see: (d) Shih, W. C.; Ozerov, O.
V. Selective ortho C–H Activation of Pyridines Directed
by Lewis Acidic Boron of PBP Pincer Iridium Complexes.
J. Am. Chem. Soc. 2017, 139, 17297.
(18) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis Acid–Base
Interaction-controlled ortho-Selective C−H Borylation of
Aryl Sulfides. Angew. Chem. Int. Ed. 2017, 56, 1495.
7
8
9
(12) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I.
L.; Gore, K. A.; Maleczka, Jr., R. E.; Singleton, D. A.;
Smith, III, M. R. 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.
(19) Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-
enabled ortho and neta Borylation of Aromatic Aldehydes
via in situ-Generated Imines. J. Am. Chem. Soc. 2016, 138,
84.
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
(20) 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. (b)
During preparation of this manuscript, the same group has
reported the application of their system to meta-selective
borylation of benzamides. Bisht, R.; Hoque, M. E.;
Chattopadhyay, B. Amide Effect in C–H Activation: L-
Shaped Ligand for meta Borylation of Aromatic Amides
via Noncovalent Interaction. Angew. Chem. Int. Ed. 2018,
57, 15762.
(13) (a) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-
directed Regiocontrol in Transition-metal Catalysis: A
meta-Selective C–H Borylation of Aromatic Quaternary
Ammonium Salts. J. Am. Chem. Soc. 2016, 138. 12759. (b)
Mihai, M. T.; Phipps, R. J. Ion-pair-directed meta-
Selective C–H Borylation of Aromatic Quaternary
Ammonium Salts. Synlett 2017, 28, 1011.
(14) Saito, S.; Yamamoto, H. Designer Lewis Acid Catalysts—
Bulky Aluminium Reagents for Selective Organic
Synthesis. Chem. Commun. 1997, 1585.
(21) (a) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. A Strategy for
C–H Activation of Pyridines:ꢀ Direct C-2 Selective
Alkenylation of Pyridines by Nickel/Lewis Acid Catalysis.
J. Am. Chem. Soc. 2008, 130, 2448. (b) Nakao, Y.; Yamada,
Y.; Kashihara, N.; Hiyama, T. Selective C-4 Alkylation of
Pyridine by Nickel/Lewis Acid Catalysis. J. Am. Chem.
Soc. 2010, 132, 13666. (c) Okumura, S.; Tang, S.; Saito,
T.; Semba, K.; Sakaki, S.; Nakao, Y. para-Selective
Alkylation of Benzamides and Aromatic Ketones by
Cooperative Nickel/Aluminum Catalysis. J. Am. Chem.
Soc. 2016, 138, 14699. (d) Okumura, S.; Nakao, Y. para-
Selective Alkylation of Sulfonylarenes by Cooperative
Nickel/Aluminum Catalysis. Org. Lett. 2017, 19, 584. (e)
Inoue, F.; Saito, T.; Semba, K.; Nakao, Y. C3-Selective
Alkenylation of N-acylindoles with Unactivated Internal
Alkynes by Cooperative Nickel/aluminium Catalysis.
Chem. Commun. 2017, 53, 4497. (f) Okumura, S.; Komine,
T.; Shigeki, E.; Semba, K.; Nakao, Y. Site-selective Linear
Alkylation of Anilides by Cooperative Nickel/Aluminum
Catalysis. Angew. Chem. Int. Ed. 2018, 57, 929. (g) Hara,
N.; Saito, T.; Semba, K.; Kuriakose, N.; Zheng, H.; Sakaki,
S.; Nakao, Y. Rhodium Complexes Bearing PAlP Pincer
Ligands. J. Am. Chem. Soc. 2018, 140, 7070.
(15) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Power of
Cooperativity: Lewis Acid-Lewis Base Bifunctional
Asymmetric Catalysis. Synlett 2005, 1491.
(16) For selective reactions by TM–LA bifunctional catalysts,
see: (a) Bebbington, M. W. P.; Bontemps, S.; Bouhadir, G.;
Hanton, M. J.; Tooze, R. P.; van Rensburg, H.; Bourissou,
D.
Structure
A
1,1’-Ferrocenyl Phosphine-borane: Synthesis,
And Evaluation in Rh-catalyzed
Hydroformylation. New J. Chem. 2010, 34, 1556. (b) Shih,
W. C.; Chen, W. C.; Lai, Y. C.; Yu, M. S.; Ho, J. J.; Yap,
G. P. A.; Ong, T. G. The Regioselective Switch for Amino-
NHC Mediated C–H Activation of Benzimidazole via Ni–
Al Synergistic Catalysis. Org. Lett. 2012, 14, 2046. (c) Xu,
S.; Zhang, Y.; Li, B.; Liu, S.-Y. Site-selective and
Stereoselective trans-Hydroboration of 1,3-Enynes
Catalyzed by 1,4-Azaborine-based Phosphine–Pd
Complex. J. Am. Chem. Soc. 2016, 138. 14566. (d) Tseng,
K. N. T.; Kampf, J. W.; Szymczak, N. K. Modular
Attachment of Appended Boron Lewis Acids to a
Ruthenium Pincer Catalyst: Metal–Ligand Cooperativity
Enables Selective Alkyne Hydrogenation. J. Am. Chem.
Soc. 2016, 138, 10378. (e) Hirata, G.; Satomura, H.;
Kumagae, H.; Shimizu, A.; Onodera, G.; Kimura, M.
Direct Allylic Amination of Allylic Alcohol Catalyzed by
Palladium Complex Bearing Phosphine–Borane Ligand.
Org. Lett. 2017, 19. 6148. For recent reviews, see: (f)
Bouhadir, G.; Bourissou, D. Complexes of Ambiphilic
Ligands: Reactivity and Catalytic Applications. Chem. Soc.
Rev. 2016, 45, 1065.
(22) Yang, L.; Semba, K.; Nakao, Y. para-Selective C−H
Borylation
of
(Hetero)Arenes
by
Cooperative
Iridium/Aluminum Catalysis. Angew. Chem. Int. Ed. 2017,
56, 4853.
(23) For site-divergent C–H borylation reactions of
(hetero)arene carboxamides, see: (a) Hurst, T. E.; Macklin,
T. K.; Becker, M.; Hartmann, E.; Kügel, W.; Parisienne-
LaꢀSalle, J.-C.; Batsanov, A. S.; Marder, T. B.; Snieckus,
V. Iridium-catalyzed C–H Activation versus Directed
ortho Metalation: Complementary Borylation of Aromatics
and Heteroaromatics. Chem. Eur. J. 2010, 16, 8155. (b)
Sasaki, I.; Taguchi, J.; Hiraki, S.; Ito, H.; Ishiyama, T.
Catalyst-Controlled Regiodivergent C–H Borylation of
Multifunctionalized Heteroarenes by Using Iridium
Complexes. Chem. Eur. J. 2015, 21, 9236.
(17) For TM–LA bifunctional catalysis for site-selective C–H
functionalization reactions, see: (a) Tsai, C.-C.; Shih, W.-
C.; Fang, C.-H.; Li, C.-Y.; Ong, T.-G.; Yap, G. P. A.
Bimetallic Nickel Aluminun Mediated para-Selective
Alkenylation of Pyridine: Direct Observation of η2,η1-
Pyridine Ni(0)−Al(III) Intermediates Prior to C−H Bond
Activation. J. Am. Chem. Soc. 2010, 132, 11887. (b) Zhang,
Z.; Tanaka, K.; Yu, J.-Q. Remote Site-selective C–H
Activation Directed by a Catalytic Bifunctional Template.
Nature 2017, 543, 538. (c) Nakamura, T.; Suzuki, K.;
Yamashita, M. Aluminabenzene–Rh and –Ir Complexes:
Synthesis, Structure, and Application toward Catalytic C–
(24) A part of this work was presented at the 96th annual
meeting of the Chemical Society of Japan on March 2,
2016 (No. 2H7-03).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
(25) Lewis acid may abstract MeO from the Ir(I) precatalyst to
D. C–H Arylation of Pyridines: High Regioselectivity as a
1
2
3
4
5
6
7
8
generate a cationic Ir(I) complex, which has low catalytic
activity. See ref. 8e and Supporting Information.
Consequence of the Electronic Character of C–H Bonds
and Heteroarene Ring. J. Am. Chem. Soc. 2011, 133, 16338.
(b) Andou, T.; Saga, Y.; Komai, H.; Matsunaga, S.; Kanai,
M. Cobalt-catalyzed C4-Selective Direct Alkylation of
Pyridines. Angew. Chem. Int. Ed. 2013, 52, 3213. (c)
Mizumori, T.; Hata, T.; Urabe, H. Alkylation of Pyridines
at Their 4-Positions with Styrenes plus Yttrium Reagent or
Benzyl Grignard Reagents. Chem. Eur. J. 2015, 21, 422.
(d) Li, Y.; Deng, G.; Zeng, X. Chromium-catalyzed
(26) 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.; 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.
Regioselective
Organometallics 2016, 35, 747. (e) Nagase, M.; Kuninobu,
Y.; Kanai, M. 4-Position-selective C–H
Hydropyridination
of
Styrenes.
9
(27) Ohmura, T.; Torigoe, T.; Suginome, M. Iridium-catalysed
Borylation of Sterically Hindered C(sp3)–H Bonds:
Remarkable Rate Acceleration by a Catalytic Amount of
Potassium tert-Butoxide. Chem. Commun. 2014, 50, 6333.
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
Perfluoroalkylation and Perfluoroarylation of Six-
membered Heteroaromatic Compounds. J. Am. Chem.
Soc. 2016, 138, 6103. (f) Hilton, M. C.; Dolewski, R. D.;
McNally, A. Selective Functionalization of Pyridines via
Heterocyclic Phosphonium Salts. J. Am. Chem. Soc.
(28) For recent reviews on C–H functionalization of pyridine,
see: (a) Nakao, Y. Transition-metal-catalyzed C–H
Functionalization for the Synthesis of Substituted
Pyridines. Synthesis 2011, 3209. (b) Murakami, K.;
Yamada, S.; Kaneda, T.; Itami, K. C–H Functionalization
of Azines. Chem. Rev. 2017, 117, 9302.
2016, 138, 13806.
(g)
Zhang,
X.;
McNally,
A. Phosphonium Salts as Pseudohalides: Regioselective
Nickel-catalyzed Cross-coupling of Complex Pyridines
and Diazines. Angew. Chem. Int. Ed. 2017, 56, 9833. (h)
Dolewski, R. D.; Hilton, M. C.; McNally, A. 4-Selective
Pyridine Functionalization Reactions via Heterocyclic
Phosphonium Salts. Synlett 2018, 29, 8. (i) Koniarczyk, J.
L.; Hesk, D.; Overgard, A.; Davies, I. W.; McNally, A. A
General Strategy for Site-selective Incorporation of
Deuterium and Tritium into Pyridines, Diazines, and
Pharmaceuticals. J. Am. Chem. Soc. 2018, 140, 1990.
(29) For C2-selective C–H functionalization of pyridine, see ref
21a and: (a) Abramovitch, R. A.; Poulton. G. A. Direct
Evidence for an Intermediate Complex in a Nucleophilic
Aromatic Substitution. Chem. Commun. 1967, 274. (b)
McGill, C. K.; Rappa, A. Advances in the Chichibabin
Reaction. Adv. Heterocycl. Chem. 1988, 44, 1. (c) Jordan,
R. F.; Taylor, D. F. Zirconium-catalyzed Coupling of
Propene and -Picoline. J. Am. Chem. Soc. 1989, 111, 778.
(d) Moore, E. J.; Pretzer,W. R.; O’onnell, T. J.; Harris, J.;
LaBounty, L.; Chou, L.; Grimmer, S. S. Catalytic and
Regioselective Acylation of Aromatic Heterocycles Using
Carbon Monoxide and Olefins. J. Am. Chem. Soc. 1992,
114, 5888. (e) Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
Rh(I)-Catalyzed Alkylation of Quinolines and Pyridines
via C–H Bond Activation. J. Am. Chem. Soc. 2007, 129,
5332. (f) Berman, A. M.; Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. Rh(I)-Catalyzed Direct Arylation of
Pyridines and Quinolines. J. Am. Chem. Soc. 2008, 130,
14926. (g) Tobisu, M.; Hyodo, I.; Chatani, N. Nickel-
Catalyzed Reaction of Arylzinc Reagents with N-Aromatic
Heterocycles: A Straightforward Approach to C−H Bond
(31) (a) Grigg, R.; Savic, V. Transition Metal Catalysed
Alkylation of Pyridines and Indoles. Tetrahedron Lett.
1997, 38, 5737. (b) Wada, M.; Worrell, B. T.; Yu, J.-Q.
Pd0/PR3-Catalyzed Arylation of Nicotinic and Isonicotinic
Acid Derivatives. Angew. Chem. Int. Ed. 2010, 49, 1275.
(32) Ye, M.; Gao G. L.; Yu, J.-Q. Ligand-Promoted C-3
Selective C–H Olefination of Pyridines with Pd Catalysts.
J. Am. Chem. Soc. 2011, 133, 6964.
(33) Ye, M.; Gao, G. L.; Edmunds, A. J. F.; Worthington, P. A.
J. A. Morris, Yu, J.-Q. Ligand-promoted C3-selective
Arylation of Pyridines with Pd Catalysts: Gram-Scale
Synthesis of (±)-Preclamol. J. Am. Chem. Soc. 2011, 133,
19090.
Arylation
of
Electron-deficient
Heteroaromatic
Compounds. J. Am. Chem. Soc. 2009, 131, 12070. (h) Wen,
J.; Qin, S.; Ma, L. F.; Dong, L.; Zhang, J.; Liu, S. S.; Duan,
Y. S.; Chen, S. Y.; Hu, C. W.; Yu, X. Q. Iron-mediated
Direct Suzuki−Miyaura Reaction: A New Method for the
ortho-Arylation of Pyrrole and Pyridine. Org. Lett. 2010,
12, 2694. (i) Guan, B.-T.; Hou, Z. Rare-earth-catalyzed C–
H Bond Addition of Pyridines to Olefins. J. Am. Chem. Soc.
2011, 133, 18086. (j) Frer, P. S.; Hartwig, J. F. Selective
C–H Fluorination of Pyridines and Diazines Inspired by a
Classic Amination Reaction. Science 2013, 342, 956. (k)
Fier, P. S.; Hartwig, J. F. Synthesis and Late-stage
Functionalization of Complex Molecules through C–H
Fluorination and Nucleophilic Aromatic Substitution. J.
Am. Chem. Soc. 2014, 136, 10139. (l) Yamada, S.;
Murakami, K.; Itami, K. Regiodivergent Cross-
dehydrogenative Coupling of Pyridines and Benzoxazoles:
Discovery of Organic Halides as Regio-Switching
Oxidants. Org. Lett. 2016, 18, 2415. (m) Fier, P. S. A
Bifunctional Reagent Designed for the Mild, Nucleophilic
Functionalization of Pyridines. J. Am. Chem. Soc. 2017,
139, 9499.
(34) Li, B.-J.; Shi, Z.-J. Ir-catalyzed Highly Selective Addition
of Pyridyl C–H Bonds to Aldehydes Promoted by
Triethylsilane. Chem. Sci. 2011, 2, 488.
(35) Wübbolt, S.; Oestreich, M. Catalytic Electrophilic C–H
Silylation of Pyridines Enabled by Temporary
Dearomatization. Angew. Chem. Int. Ed. 2015, 54, 15876.
(36) Rubio-Pérez, L.; Iglesias, M.; Munárriz, J.; Polo, V.;
Passarelli, V.; Pérez-Torrente, J. J.; Oro, L. A. A Well-
defined NHC–Ir(III) Catalyst for the Silylation of
Aromatic C–H Bonds: Substrate Survey and Mechanistic
Insights. Chem. Sci. 2017, 8, 4811.
(37) (a) Fischer, D. F.; Sarpong, R. Total Synthesis of (+)-
Complanadine A Using an Iridium-catalyzed Pyridine C−
H Functionalization. J. Am. Chem. Soc. 2010, 132, 5926.
(b) Newton, J. N.; Fischer, D. N.; Sarpong, R. Synthetic
Studies on Pseudo-dimeric Lycopodium Alkaloids: Total
Synthesis of ComplanadineꢁB. Angew. Chem. Int. Ed. 2013,
52, 1726. (c) Kim, S. H.; Sperry, J. Synthesis of Scalaridine
A. Tetrahedron Lett. 2015, 56, 5914.
(38) The site-selectivity of pyridine C–H borylation is usually
controlled by substituents and sterics, see ref 23a and: (a)
Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
(30) For C4-selective C–H functionalization of pyridine, see ref
17a, 21b and: (a) Guo, P.; Joo, J. M.; Rakshit, S.; Sames,
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
N. Iridium-catalyzed C–H Coupling Reaction of
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. (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. (e) Obligacion, J. V.;
Semproni, S. P.; Chirik, P. J. Cobalt-catalyzed C–H
Borylation. J. Am. Chem. Soc. 2014, 136, 4133.
1
2
3
4
5
6
7
8
Heteroaromatic Compounds with Bis(pinacolato)diboron:
Regioselective Synthesis of Heteroarylboronates.
Tetrahedron Lett. 2002, 43, 5649. (b) Mkhalide, I. A. I.;
Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.;
Howord, 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. (c) Sadler, S.
A.; Tajuddin, H.; Mkhalid, I. A. I.; Batsanov, A. S.;
Albesa-Jove, D.; Cheung, M. S.; Maxwell, A. C.; Shukla,
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
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
10
ACS Paragon Plus Environment