Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents

Article abstract of DOI:10.1021/acscatal.8b00641

High ortho selectivity for Ir-catalyzed C-H borylations (CHBs) of anilines results when B₂eg₂ (eg = ethylene glycolate) is used as the borylating reagent in lieu of B₂pin₂, which is known to give isomeric mixtures with anilines lacking a blocking group at the 4-position. With this modification, high selectivities and good yields are now possible for various anilines, including those with groups at the 2- and 3-positions. Experiments indicate that ArylN(H)Beg species are generated prior to CHB and support the improved ortho selectivity relative to B₂pin₂ reactions arising from smaller Beg ligands on the Ir catalyst. The lowest-energy transition states (TSs) from density functional theory computational analyses have N-H···O hydrogen-bonding interactions between PhN(H)Beg and O atoms in Beg ligands. Ir-catalyzed CHB of PhN(H)Me with B₂eg₂ is also highly ortho-selective. ¹H NMR experiments show that N-borylation fully generates PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs energy was the ortho TS, in which the Beg unit is oriented anti to the bipyridine ligand.

Full text of DOI:10.1021/acscatal.8b00641

Subscriber access provided by UNIVERSITY OF THE SUNSHINE COAST
Article
Achieving High Ortho Selectivity in Aniline C-
H Borylations by Modifying Boron Substituents
Milton R. Smith, Ranjana Bisht, Chabush Haldar, Gajanan Pandey, Jonathan E
Dannatt, Behnaz Ghaffari, Robert E. Maleczka, and Buddhadeb Chattopadhyay
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00641 • Publication Date (Web): 09 May 2018
Downloaded from http://pubs.acs.org on May 9, 2018
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 24
ACS Catalysis
1
2
3
4
5
6
7
8
9
Achieving High Ortho Selectivity in Aniline C–H
Borylations by Modifying Boron Substituents
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
Milton R. Smith, III,§,* Ranjana Bisht,†,‡ Chabush Haldar,† Gajanan Pandey,‡ Jonathan E.
Dannatt,§ Behnaz Ghaffari,§ Robert E. Maleczka, Jr.,§,* and Buddhadeb Chattopadhyay,†,*
§Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing,
Michigan 48824ꢀ1322 USA
†Division of Molecular Synthesis & Drug Discovery, Centre of BioꢀMedical Research (CBMR),
SGPGIMS Campus, Raebareli Road, Lucknow 226014, U.P., India
‡Department of Applied Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow
226025, U.P., India
KEYWORDS. C–H activation • hydrogen bonding • computational chemistry • aniline • ortho
functionalization
ABSTRACT. High ortho selectivity for Irꢀcatalyzed C–H borylations (CHBs) of anilines results
when B2eg2 (eg = ethylene glycolate) is used as the borylating reagent in lieu of B2pin2, which is
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 24
1
2
3
4
5
6
7
8
9
known to give isomeric mixtures with anilines lacking a blocking group at the 4ꢀposition. With
this modification, high selectivities and good yields are now possible for various anilines,
including those with groups at the 2 and 3ꢀpositions. Experiments indicate that ArylN(H)Beg
species are generated prior to CHB and support the improved ortho selectivity relative to B2pin2
reactions arising from smaller Beg ligands on the Ir catalyst. The lowest energy transition states
from DFT computational analyses have N–H···O hydrogen bonding interactions between
PhN(H)Beg and O atoms in Beg ligands. Irꢀcatalyzed CHB of PhN(H)Me with B2eg2 is also
highly ortho selective. 1H NMR experiments show that Nꢀborylation fully generates
PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs’ was the ortho TS where the Beg unit
is oriented anti to the bipyridine ligand.
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
INTRODUCTION. Anilines are chemicals with important dye, pharmaceutical, agrochemical,
and polymer applications.1 Aniline is commercially prepared by benzene nitration followed by
hydrogenation of the nitrobenzene intermediate. Most commercially available substituted
anilines are prepared by derivatizing aniline, often through electrophilic aromatic substitution
(EAS).2 The NH2 group is classified as a strong ortho/para director,3 even though traditional
nitration conditions give 32–49% metaꢀnitroaniline along with the major para isomer.4 The best
selectivities for EASs are typically C4 functionalizations, and most orthoꢀselective examples are
for anilines substituted at C4. For anilines that are unsubstituted at C4, EASs generate significant
quantities of para isomers even in some of the most orthoꢀselective methods.5 The best
traditional synthetic method for aniline ortho functionalization is directed ortho metalation
(DoM) of carbamate derivatives, followed by subsequent addition of an electrophile to the ortho
2
ACS Paragon Plus Environment

Page 3 of 24
ACS Catalysis
1
2
3
4
5
carbanion.6 This approach requires conversion of the aniline to the carbamate, which is removed
after the reaction, if aniline products are desired.
6
7
8
9
Even though directed ortho metalation reactions are remarkably powerful,7 catalytic methods can
exhibit complementary selectivities and functional group tolerance.8 There are several examples
of catalytic ortho functionalizations of aniline. Most require the installation of a directing group
prior to C–H functionalization. Removal of the directing group is required to restore the nitrogen
functionality to that in the aniline starting material.9–11 While the NH2 group would be untouched
in ideal catalytic ortho functionalization of primary anilines, the next most desirable process is
one where there is no trace in the product of any in situ modification of the amino group during
catalysis.
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
The traceless Irꢀcatalyzed C–H borylation (CHB) of primary anilines has been described in the
literature.12 C–H borylation is a synthetic method where sp2, sp3, and sp C–H bonds are
converted to C–B bonds.13–15 With few exceptions,16,17 most examples require a catalyst, and
metalꢀcatalyzed CHBs have been reported for a number of transition metals.13,18–20 Some of the
earliest reports of metalꢀcatalyzed CHBs of arene C(sp2)–H bonds indicated that the least
hindered C–H bonds were generally more reactive.21–23 This feature became a hallmark of Irꢀ
catalyzed CHBs because regioselectivities generally complement those found in EAS and DoM,
as well as the regioselectivities in early examples of catalytic intraꢀ and intermolecular C–H
functionalizations that are orthoꢀselective.24,25
The first report of catalytic ortho CHBs relied on classic chelateꢀdirected mechanisms where a
substrate functional group binds to a vacant metal site.26–28 Directing effects of this type have
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 24
1
2
3
4
5
6
7
8
been branded as “innerꢀsphere”.29 Other inner–sphere approaches, like relayꢀdirected ortho
CHBs of silylated phenols and anilines, where reversible Si–H oxidative addition to Ir was
proposed to direct borylation, were also developed.30
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
Mechanisms for orthoꢀdirected CHBs have been proposed where the metal center is not a
directing element.31,32 In line with Taube’s definition, these are defined as “outerꢀsphere”
mechanisms.29,33 Examples of outer–sphere direction in ortho CHBs include Lewis acidꢀbase,34–
36
hydrogen bonding,12,33,37 electrostatic interactions,38 and an example where both innerꢀ and
outerꢀsphere mechanisms are plausible.39 The electrostatic mechanism is a more subtle variant of
the ionꢀpairing mechanisms proposed by Phipps and coꢀworkers in recently designed metaꢀ
selective CHBs,40 which complements other metaꢀselective CHBs where outer sphere
mechanisms are proposed to account for selectivity.34,37,41
Kanai and Kuninobu recently disclosed ortho CHBs of aniline and phenol derivatives (Scheme
1).36 The bipyridine with the best selectivity is not commercially available. It has an electronꢀ
withdrawing aryl group at the bipyridine 5ꢀposition and was synthesized from commercially
available precursors.42 To achieve ortho CHB of primary anilines thiomethyl methylene
(CH2SMe) and acyl groups must be attached to N. While this approach provides excellent ortho
selectivities, ligand synthesis and the additional synthetic steps to add and subsequently remove
functional groups at N are unappealing if orthoꢀborylated primary anilines are the desired
product.
4
ACS Paragon Plus Environment

Page 5 of 24
ACS Catalysis
1
2
3
4
Scheme 1. Comparison of the KanaiꢀKuninobu CHB of NꢀAcylated Anilines to This Work.36,43,44
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
The previously reported traceless CHBs of primary anilines built on an initial report of ortho
CHBs of NꢀBoc anilines.12,33 For these aryl carbamates, experiment and theory were consistent
with an outerꢀsphere mechanism involving N–H···O hydrogen bonding between the aniline
substrate and an Ir–Bpin ligand giving rise to the ortho selectivity.33 As shown in Figure 1,
previous CHBs required C4 substituents larger than H to achieve high ortho selectivity.12,33
Additionally, substitution at C2 was deleterious to ortho selectivity. Given that C–B bonds can
be readily converted to a host of functional groups, and the aforementioned limited scope of
previous orthoꢀdirected CHBs of anilines, a method overcoming these shortcomings would be
highly desirable.
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 24
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
Figure 1. Proposed transition states for ortho borylations of anilines and phenols.
Traceless, orthoꢀdirected CHB of phenols was also recently described.38 The initial CHB
substrates were phenol Oꢀboronate esters ArOBpin (pin = pinacolate). Experimental and
computational studies pointed to transition state stabilization arising from electrostatic
interactions between the bipyridine bound to Ir and OBpin of the phenol boronate ester. Like
previous aniline borylations, 4ꢀsubstituents larger than H were necessary to achieve synthetically
useful ortho selectivity.
An in silico redesign of the catalyst predicted that the ortho CHB transition state could be
significantly stabilized if the Bpin groups on Ir and the phenolboronate ester were replaced with
Beg (eg = ethylene glycolate). Indeed, this led to exquisite ortho selectivities for Irꢀcatalyzed
CHBs of phenols when the diboron reagent B2eg2 was used in lieu of HBpin. This raised the
question as to whether ortho selectivities for aniline CHBs could be similarly improved using
B2eg2. If ortho selectivities indeed improve, is transition state stabilization due to electrostatic
6
ACS Paragon Plus Environment

Page 7 of 24
ACS Catalysis
1
2
3
4
5
6
interactions or enhanced hydrogen bonding? This paper addresses these questions using
experiment and theory synergistically.
7
8
9
RESULTS AND DISCUSSION. Irꢀcatalyzed CHB of aniline with B2eg2 was used to optimize
reaction conditions. First, a THF solution of aniline, 0.5 equiv of B2eg2, and 0.5 mol %
[Ir(OMe)(cod)]2 was briefly heated to generate PhN(H)Beg, which was verified by 11B/1H NMR
spectroscopy. Then NEt3, dtbpy (dtbpy = 4,4´ꢀdiꢀtBuꢀ2,2´ꢀbipyridine), additional B2eg2 and
[Ir(OMe)(cod)]2 were added, and the resulting solution was heated at 80 °C until borylation
ceased. The best results were obtained with a 2.5 mol % loading of [Ir(OMe)(cod)]2, 5 mol %
dtbpy, 2.0 equiv B2eg2, and 2.0 equiv of NEt3. When CHB was complete, the eg group was
transesterified by treating the reaction mixture with 3.0 equiv of pinacol, and the more stable
Bpin product was purified and isolated in 67% yield. Conversion to products suffered at lower
catalyst loadings; however, high regioselectivity was achieved. The regioselectivities for aniline
CHBs with B2pin2 and B2eg2 are compared in Scheme 2. To avoid significant diborylation, the
control reaction used less B2pin2 and a shorter reaction time. Notably, the 2.7:1.8:1
ortho:meta:para isomer ratio for CHB with B2pin2 is similar to the ratio previously reported for
Irꢀcatalyzed aniline CHB with HBpin (ortho:meta:para = 2.3:1.5:1).12 While the major
regioisomer is the ortho product, which suggests some favorable interactions for ortho CHB with
B2pin2, substantial quantities of meta and para CHB products dampen the synthetic utility. In
contrast, B2eg2, which is easily prepared from commercially available (OH)2B–B(OH)2 and
ethylene glycol, provides exquisite ortho selectivity.
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
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 24
1
2
3
4
Scheme 2. Aniline CHBs with B2pin2 and B2eg2.
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
aAt 0.5 mmol scale 67% yield was obtained. At 5 mmol scale with 1 mol % loading of [Ir(OMe)(cod)]2, 0.25 mol % in step 1 and 0.75 mol % in step 2, the yield
increased to 75%.
We next assessed the substrate scope for ortho selectivity. Table 1 lists the results for twentyꢀ
four substrates. The catalyst loadings in Table 1 are (6 mol % Ir) higher than we usually use for
borylations because the reactions were run with 0.5 mmol of aniline substrates, using weighed
amounts of the [Ir(OMe)(cod)]2. When CHB of aniline was performed on a 5 mmol scale with
0.25 and 0.75 mol % of the precatalyst (2 mol % Ir) in steps 1 and 2 in Scheme 2, orthoꢀ
borylated product 2a was isolated in 75% yield. The average isolated yield is 71(±4)% for
substrates in Table 1. For substrate 1q, 20% diborylation contributed to the low yield of
monoborylated product. The only diborylated isomers detected were 2,6ꢀregioisomers. Substrate
1s had the lowest yield, but it is the first metalꢀcatalyzed CHB of a nitroꢀcontaining substrate that
gives more than trace quantities. In crude reaction mixtures, CHB was only detected at sites
ortho to NH2.
8
ACS Paragon Plus Environment

Page 9 of 24
ACS Catalysis
1
2
3
4
Table 1. Ortho Borylation of Substituted Anilines with B2eg2.a
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
aAll reactions were carried out on a 0.5 mmol scale, and yields are reported for isolated materials after column chromatographic separation. bThe other oꢀborylated
isomer was observed, but underwent rapid protoꢀdeboronation. c20% o,oꢀdiborylation was observed. dIsolated Yield: 20%; GC conversion: 50%.
Gratifyingly, CHBs of metaꢀsubstituted anilines 1jꢀ1m did not generate 5ꢀborylated products, as
had been found for Irꢀcatalyzed CHBs of anilines 1kꢀ1m with HBpin.12 The yields of orthoꢀ
9
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 24
1
2
3
4
5
6
7
8
9
borylated products from CHBs anilines 1k, 1l, and 1m increased over those previously reported
from CHBs with HBpin by 46%, 24%, and 55%, respectively. Furthermore, this methodology
outperforms previously reported CHB of NꢀBoc anilines. No CHBs of 2ꢀsubstituted NꢀBoc
anilines have been reported, and ortho selectivity eroded for substrates that lacked blocking
groups at the 4ꢀposition. For example, CHB of 3ꢀchloroꢀNꢀBocꢀaniline provided 92% yield but
exhibited an ortho:meta selectivity of only 2:1.33 In addition, this yield does not include removal
of the Boc group; however, substrate 1k provided only the ortho borylated product, 2k, and was
isolated in 88% yield. Substrates 1bꢀ i underwent CHB with B2eg2 at C6 exclusively, yielding
orthoꢀborylated products 2bꢀ2i. This stands in sharp contrast to previously reported CHBs of 2ꢀ
substituted anilines with HBpin, where ortho borylation was not observed.12 Borylation of
quinoline 1x proceeded smoothly providing the 7ꢀborylated product 2x in 71% isolated yield.
Indole CHB with either B2eg2 or B2pin2 gives the 2ꢀborylated products in comparable yields.45
Compounds 2cꢀi, 2r, and 2uꢀv are new. Of these, 2g is the only structure whose boronic acid has
been reported in the primary literature.46 Significantly, the transformations in Table 1 do not
require installing and removing a directing group and use dtbpy, the most commonly used ligand
in Irꢀcatalyzed CHBs.
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
The improved selectivity raises the interesting question as to whether their molecular origins
arise from ligand/substrate electrostatic interactions or hydrogen bonding (Scheme 2). To tackle
this question, we turned to theory. DFT calculations used the M06 functional with a 6ꢀ31G*
basis set for light atoms and an SDD basis set and core potential for Ir. The polarizable
continuum model was the selfꢀconsistent reaction field method applied for the THF solvent.
Compared to other systems that we have studied, transition state location was challenging. Low
10
ACS Paragon Plus Environment

Page 11 of 24
ACS Catalysis
1
2
3
4
energy imaginary frequencies associated with Me group rotations in dtbpy ligands plagued
5
6
t
calculations on the full system. Replacing bipyridine Bu with Me groups made the problem
7
8
9
more manageable, but Me rotations still generated multiple imaginary rotational frequencies
when software default values for step sizes and integration grids were used. Ultimately, TSs with
a single imaginary frequency corresponding to C–H scission were located. The maximum atom
displacement in all calculated TSs exceeded software convergence thresholds. In addition, the
RMS displacement exceeded the software convergence defaults in approximately half of the
calculated TSs. For two of these TSs, the maximum displacement was ten times greater than the
convergence default. We mention them only in passing (vide infra). Atomic Cartesian
coordinates and energies for these TSs are included in the SI.
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
Four transition states (TS1ꢀ4) were located for ortho borylation. Starting points for TS location
included syn and anti orientations of PhN(H)Beg moiety with respect to the bipyridine ligand
(Figure 2) and two additional geometries with close contacts between the aniline N–H and O
atoms of a Beg that is ligated to Ir. Figure 3 depicts the TSs and their relative Gibbs’ energies.
TS1 is analogous to the lowest energy transition state for phenol ortho borylation. In the other
three TSs the PhN(H)Beg H is hydrogen bonded to a Beg O. The H···O distances in TS2, TS3,
and TS4 are 2.07, 2.28, and 2.49 Å, respectively.
Figure 2. Proposed transition states for ortho borylations of anilines and phenols.
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 24
1
2
3
4
5
6
7
8
9
The ꢁꢁG‡ values for TS2ꢀ4 relative to TS1 are given as Grel in Figure 3. The hydrogenꢀbonded
TSs TS2, TS3, and TS4 are stabilized by 1.9, 2.6, and 1.7 kcal·mol–1, respectively, relative to
TS1. Notably, the starting geometry for TS4 was similar to that for TS1 except that the Beg
moiety was syn to the 4,4´ꢀdimethylpyridine ligand (Figure 2). The syn PhOBeg TS has short
(~3.0 Å) contacts between the Beg group and the bipyridine ligand that are reminiscent of πꢀ
stacking.38 The analogous TS was not found for PhN(H)Beg. Instead, the N(H)Beg group rotated
about the N–Cipso bond to engage in hydrogen bonding between the aniline proton and and an Ir–
Beg oxygen. A TS analogous to the syn geometry for PhOBeg was located for CHB of
PhN(Me)Beg (TS8, vide infra).
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
The highest energy hydrogenꢀbonded TS (TS4) has the longest H···O distance, but it is only 0.2
kcal·mol–1 less stable than TS2, where the H···O distance is 0.42 Å shorter. The number of
heavy atoms in TS1ꢀ4 is too large to apply the level of theory that is typically used to quantify
stabilization from hydrogen bonding.47 The νNꢀH values for N–H vibrations of the N(H)Beg
group in TS2 (3533 cm–1), TS4 (3541 cm–1), and TS3 (3557 cm–1) do not correlate with distance,
which is not surprising since Beg O lone pair interactions with the aniline H differ with Beg
ligand orientation. The νNꢀH values in TS2ꢀ4 are 62ꢀ38 cm–1 lower than that calculated for
PhN(H)Beg (νNꢀH = 3595 cm–1) at the same level of theory. Based on the infrared shift, H···O
distance, and NꢀH lengthening (see SI), the hydrogen bonding interaction is classified as a weak
hydrogen bond which are mostly electrostatic in nature.48
12
ACS Paragon Plus Environment

Page 13 of 24
ACS Catalysis
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
Figure 3. Computed transition states for Irꢀcatalyzed CHB of PhN(H)Beg with B2eg2. The N–H
hydrogen and the C–H hydrogen in the bond being cleaved are yellow. Dashed orange lines
indicate hydrogen bonding interactions. Grel and Hrel are ꢁꢁG‡ and ꢁꢁH‡ values relative to TS1.
DFT calculations were performed using the M06 functional and a split 6ꢀ31G*/SDD basis set for
light and Ir atoms. An SDD core potential was used for Ir.
The TS for para CHB (TS5) was also located. Its Gibbs’ energy was higher than all of the
hydrogenꢀbonding TSs, and was separated from the lowest energy TS (TS3) by 1.0 kcal·mol–1.
Attempts to locate the TS for meta CHB yielded a structure with one imaginary frequency
(TSmeta, p. S33ꢀS34 of the SI), but the respective RMS and maximum displacements were 10X
and 34X greater than software default convergence criteria. The theoretical ꢁꢁG‡ value of 1.0
kcal·mol–1 between TS3 and TS5 predicts an ortho:para ratio of 8.2:1. While the ortho:para ratio
of 26:1 predicted from calculated ꢁꢁH‡ values match experiment more closely, both ꢁꢁG‡ and
ꢁꢁH‡ predictions fall short of observed experimental selectivity. This is not uncommon in
combined experimental/computational studies.
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 24
1
2
3
4
5
6
7
8
9
The computational results predict that Beg outperforms Bpin because the N(H)Beg substituent
and Beg ligands can adopt optimal hydrogen bonding configurations with minimal steric
interference. CHBs of PhN(H)Bpin with B2eg2 and PhN(H)Beg with B2pin2 were performed as
an experimental test of this hypothesis (Scheme 3).
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
Scheme 3. Aniline CHBs of PhN(H)Bpin with B2eg2 and PhN(H)Beg with B2pin2.
CHB of PhN(H)Bpin exhibits the same high ortho selectivity when B2eg2 is the borylating agent
as is observed for CHB of aniline with B2eg2. When the NBeg in the structure of TS3 is
t
converted to NBpin and the syn bipyridine Me is converted to Bu, the closest C···C contact
(4.31 Å) is longer than the closest C···C contact (3.96 Å) in the crystal structure of
Ir(Bpin)3(dtbpy)(coe) (coe = cyclooctene).23 Consequently, retention of high ortho selectivity for
the NBpin/B2eg2 combination is not surprising.
In contrast, ortho selectivity erodes when PhN(H)Beg is borylated with B2pin2, although the
ortho:meta:para ratio of 11:1.2:1 is better than the 2.5:1.5:1 ratio for Irꢀcatalyzed CHB of aniline
with HBpin.12 The TSs for the PhN(H)Beg/Ir–Bpin structures are not calculated. However, it is
not unreasonable to expect that the calculated steric destabilization from changing Beg to Bpin in
14
ACS Paragon Plus Environment

Page 15 of 24
ACS Catalysis
1
2
3
4
5
6
7
8
9
phenol ortho CHB transition states would translate to aniline CHBs.38 The experiments in
Scheme 3 demonstrate that the B substituents on the boryl ligands, and thus the CHB reagent,
have the greater influence on ortho selectivity.
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
Meta and para CHB of Nꢀmethylaniline would further support the hypothesis that hydrogenꢀ
bonding is responsible for the high ortho selectivity of B2eg2 in aniline CHBs since PhN(Me)Beg
lacks an NH moiety. Remarkably, CHB on PhN(H)Me yields only the ortho isomer, albeit at
only 24% conversion. In operando NMR spectroscopy shows that PhN(H)Me is fully converted
to PhN(Me)Beg before CHB ensues (eq 1). Even though the conversion of PhN(Me)Beg to
borylated products is low, the ortho product is the only CHB isomer detected.
This surprising result raises an obvious question. Would calculations also favor ortho CHB when
hydrogen bonding is not an option? The calculated TS structures for meta CHB (TS6) and ortho
CHB with anti (TS7) and syn (TS8) dispositions of the Beg group relative to bipyridine ligand
are shown in Figure 4.
15
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 24
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
Figure 4. Computed transition states for Irꢀcatalyzed CHB of PhN(CH3)Beg with B2eg2. The
hydrogen in the C–H bond being cleaved is pale yellow. Grel and Hrel are ꢁꢁG‡ and ꢁꢁH‡ values
relative to TS6.
∠σ = 180 – ∠C4py – Npy – Ir
(2)
In line with phenol ortho CHBs, the Gibbs’ energy of the syn TS (TS8) is higher than the anti TS
(TS7). Other shared features of TS8 with the syn phenol TS include short contacts between the
NBeg, N, and, O atoms with the bipyridine N and flanking C atoms, and a distortion of the
pyridine Ir–N bond. This distortion reduces σꢀoverlap of the pyridine N lone pair with Ir and is
best quantified by ∠σ, which is defined in eq 2. When the Ir atom lies in the pyridine plane, σꢀ
overlap is maximized and ∠σ = 0. The Npy–BBeg distances, Cpy–O distances, and ∠σ values for the
phenol and aniline TSs are summarized in Table 2. The N–B and C–O distances in TS8 are 0.05ꢀ
0.13 Å longer than the corresponding values in phenol orthoꢀborylation TS. The negative charge
on the EBeg group (E = NMe, O) will be smaller for NMe than for O. Consequently, the
electrostatic interaction will be weaker, which is consistent with the elongation of the EBeg
16
ACS Paragon Plus Environment

Page 17 of 24
ACS Catalysis
1
2
3
4
5
6
7
8
9
contacts with the syn pyridine of the bipyridine ligand when E = N(Me)Beg. The 6.5° decrease
in ∠σ when E is switched from NMe to O also supports weakening of the electrostatic interaction
between N(Me)Beg and the syn pyridine.
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
Table 2. Structural comparisons between syn TSs in 4ꢀC6H4OBeg and C6H5NMe(Beg) CHBs.
aData from TS5-OBegsyn-dtbpy in Figure 3 of ref. 36
The Grel and Hrel values (ꢁꢁG‡ and ꢁꢁH‡ values relative to TS6) in Figure 4 predict that the
ortho CHB TS7, where the Beg group is anti to the bipyridine ligand, has the lowest energy. The
theoretical ꢁꢁG‡ value between of ꢀ0.3 kcal·mol–1 predicts an ortho:meta ratio of 1.5:1, and the
ꢁꢁH‡ value predicts a higher ortho:meta ratio of 4.1:1. Although the ortho isomer is predicted to
be the major one, the actual selectivity is much higher. While the trend in the computed ratio
correlates with the experimental results, future studies at a higher level of theory are warranted.
Overall, the experimental findings show that hydrogen bonding is not required for ortho
selectivity for Nꢀmethyl aniline when the CHB reagent is switched from B2pin2 to B2eg2.
In addition to removing previous limitations for ortho CHBs of anilines with B2pin2 and HBpin,
CHBs with B2eg2 can complement selectivities for aniline CHBs with commonly used boron
17
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 24
1
2
3
4
5
6
reagents. Scheme 4 shows two examples highlighting the most dramatic differences in CHB
selectivities.
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
18
ACS Paragon Plus Environment

Page 19 of 24
ACS Catalysis
1
2
3
4
Scheme 4. Regiochemical consequences of Beg and Bpin reagents in aniline CHBs.
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
CONCLUSIONS. The important findings of this study are listed below.
● By changing the boron reagent from HBpin or B2pin2 to bisꢀ(ethyleneglycolato)diboron
(B2eg2), ortho CHBs can now be accomplished wide variety of anilines. Substrates whose
previously poor (or altered) regioselectivity is now overcome include (i) anilines with no
substituents at the 4ꢀposition, (ii) 2ꢀsubstituted anilines, (iii) 3ꢀsubstituted anilines, and
(iv) Nꢀmethylaniline.
● CHB ortho to NH2 in 2ꢀmethylquinolinꢀ6ꢀamine is possible.
● The substituents on the Ir boryl ligands have the greatest impact on selectivity.
● The orthoꢀborylated isomer is the only product observed in the Irꢀcatalyzed CHB of Nꢀ
1
methylaniline with B2eg2. H NMR studies show that PhN(H)Me is fully converted to
19
ACS Paragon Plus Environment

ACS Catalysis
Page 20 of 24
1
2
3
4
5
6
PhN(Beg)Me before CHB ensues. Thus, hydrogen bonding in the TS cannot account for
ortho selectivity.
7
8
9
● For Irꢀcatalyzed CHB of PhN(H)Beg, computational studies revealed three NH···O
hydrogen bonding transition states where the aniline N(Beg)H interacted with an IrꢀBeg
ligand. The NH···O TSs have lower Gibbs’ energies than an ortho CHB TS that lacks
hydrogen bonding.
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
● The three NH···O TSs Gibbs’ energies are also lower than that for para CHB TS of
PhN(H)Beg.
● Of three TSs calculated for Irꢀcatalyzed CHB of PhN(Me)Beg, the ortho TS where the
Beg moiety is anti to the bipyridine ligand has the lowest Gibbs’ energy. This TS closely
resembled the favored TS for CHB ortho to the OBeg of 4ꢀFꢀC6H4OBeg, where
selectivity is proposed to arise from electrostatic interactions between the OBeg unit and
the proximal pyridine ring of the bipyridine ligand.
In summary, the diboron reagent B2eg2 lifts the limitations seen in Irꢀcatalyzed CHBs of anilines
with HBpin. Experiment and theory are consistent with stabilization of hydrogen bonding TSs
when Bpin Ir boryl ligands are replaced by less sterically encumbered Beg ligands. Further
exploration of other diboron reagents and the synthetic utility of associated CHB products is
underway in our laboratories.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:xxxxxxxxxxxxx.
20
ACS Paragon Plus Environment

Page 21 of 24
ACS Catalysis
1
2
3
4
5
Experimental details, product characterizations, computational methods, energies, and
Cartesian coordinates (PDF)
6
7
AUTHOR INFORMATION
8
9
Corresponding Authors
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
*Eꢀmail for M.R.S: smithmil@msu.edu
*Eꢀmail for R.E.M: maleczka@chemistry.msu.edu
*Eꢀmail for B.C: buddhadeb.c@cbmr.res.in
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
R.E.M. and M.R.S. own a percentage of BoroPharm, Inc.
ACKNOWLEDGMENT
B.C. thanks DSTꢀSERB, New Delhi for Ramanujan Grant (SB/S2/RJNꢀ45/2013) and Young
Scientist Research Grant (SB/FT/CSꢀ141/2014) to execute this project, and the Director, CBMR
for providing research facilities. R.B. thank DSTꢀSERB, New Delhi for the SRF Fellowship
under the Ramanujan Grant and C.H. thanks the Young Scientist Research Grant for J.R.F.
R.E.M. and M.R.S thank the NIH (GM63188) for support, and the Institute for CyberꢀEnabled
Research (ICER) at MSU for computational resources. We also thank the teams in the NMR and
HRMS facilities at CBMR and MSU.
REFERENCES
(1) Travis, A. S. In The Chemistry of Anilines; John Wiley & Sons, Ltd, 2007; pp 715–782.
21
ACS Paragon Plus Environment

ACS Catalysis
Page 22 of 24
1
2
3
4
5
6
7
8
9
(2) Berliner, E. Electrophilic Aromatic Substitution Reactions. Prog. Phys. Org. Chem. 1964, 2, 253.
(3) Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry; Oxford University Press, 2012.
(4) Holleman, A. F.; Hartogs, J. C.; Van der Linden, T. Quantitative Untersuchungen über Die
Nitrierung Des Anilins. Ber. Dtsch. Chem. Ges. 1911, 44, 704–728.
(5) Shen, H.; Vollhardt, K. P. C. Remarkable Switch in the Regiochemistry of the Iodination of Anilines
by NꢀIodosuccinimide: Synthesis of 1,2ꢀDichloroꢀ3,4ꢀDiiodobenzene. Synlett 2011, 2012, 208–214.
(6) Takagishi, S.; Katsoulos, G.; Schlosser, M. Fluorine and Trifluoromethyl Substituted Anilines: Site
Selective Metalation and Electrophilic Substitution. Synlett 2002, 1992, 360–362.
(7) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Beyond Thermodynamic Acidity: A Perspective
on the ComplexꢀInduced Proximity Effect (CIPE) in Deprotonation Reactions. Angew. Chem. Int. Ed
Engl. 2004, 43, 2206–2225.
(8) Hurst, T. E.; Macklin, T. K.; Becker, M.; Hartmann, E.; Kügel, W.; ParisienneꢀLa Salle, J.ꢀC.;
Batsanov, A. S.; Marder, T. B.; Snieckus, V. IridiumꢀCatalyzed CꢀH Activation versus Directed
Ortho Metalation: Complementary Borylation of Aromatics and Heteroaromatics. Chem. Eur. J.
2010, 16, 8155–8161.
(9) Tischler, M. O.; Tóth, M. B.; Novák, Z. Mild Palladium Catalyzed Ortho CꢀH Bond
Functionalizations of Aniline Derivatives. Chem. Rec. 2017, 17, 184–199.
(10) Fang, H.; Dou, Y.; Ge, J.; Chhabra, M.; Sun, H.; Zhang, P.; Zheng, Y.; Zhu, Q. Regioselective and
Direct Azidation of Anilines via Cu(II)ꢀCatalyzed CꢀH Functionalization in Water. J. Org. Chem.
2017, 82, 11212–11217.
(11) Allu, S.; Ravi, M.; Kumara Swamy, K. C. Rhodium(III)ꢀCatalysed Carbenoid C(sp2)–H
Functionalisation of Aniline Substrates with αꢀDiazo Esters: Formation of Oxindoles and
Characterisation/Utility of an IntermediateꢀLike Rhodacycle. Eur. J. Org. Chem. 2016, 2016, 5697–
5705.
(12) 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 CꢀH Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915–12919.
(13) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. CꢀH Activation for the
Construction of CꢀB Bonds. Chem. Rev. 2010, 110, 890–931.
(14) Hartwig, J. F. Borylation and Silylation of CꢀH Bonds: A Platform for Diverse CꢀH Bond
Functionalizations. Acc. Chem. Res. 2012, 45, 864–873.
(15) Lee, C.ꢀI.; Zhou, J.; Ozerov, O. V. Catalytic Dehydrogenative Borylation of Terminal Alkynes by a
SiNN Pincer Complex of Iridium. J. Am. Chem. Soc. 2013, 135, 3560–3566.
(16) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Pinacol Boronates by Direct Arene
Borylation with Borenium Cations. Angew. Chem. Int. Ed. 2011, 50, 2102–2106.
(17) Légaré, M.ꢀA.; Courtemanche, M.ꢀA.; Rochette, É.; Fontaine, F.ꢀG. MetalꢀFree Catalytic CꢀH Bond
Activation and Borylation of Heteroarenes. Science 2015, 349, 513–516.
(18) Mazzacano, T. J.; Mankad, N. P. Base Metal Catalysts for Photochemical CꢀH Borylation That
Utilize MetalꢀMetal Cooperativity. J. Am. Chem. Soc. 2013, 135, 17258–17261.
(19) Obligacion, J. V.; Semproni, S. P.; Chirik, P. J. CobaltꢀCatalyzed C–H Borylation. J. Am. Chem.
Soc. 2014, 136, 4133–4136.
(20) Furukawa, T.; Tobisu, M.; Chatani, N. NickelꢀCatalyzed Borylation of Arenes and Indoles via CꢀH
Bond Cleavage. Chem. Commun. 2015, 51, 6508–6511.
(21) 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.
(22) 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 CꢀH Bonds. Science 2002, 295, 305–308.
(23) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridiumꢀ
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
22
ACS Paragon Plus Environment

Page 23 of 24
ACS Catalysis
1
2
3
4
5
6
7
8
9
Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and
Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390–391.
(24) Jones, W. D.; Kosar, W. P. CarbonꢀHydrogen Bond Activation by Ruthenium for the Catalytic
Synthesis of Indoles. J. Am. Chem. Soc. 1986, 108, 5640–5641.
(25) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Efficient
Catalytic Addition of Aromatic CarbonꢀHydrogen Bonds to Olefins. Nature 1993, 366, 529.
(26) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of
Functionalized Arenes Catalyzed by a SilicaꢀSupported Compact PhosphineꢀIridium System. J. Am.
Chem. Soc. 2009, 131, 5058–5059.
(27) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. OrthoꢀC–H Borylation of Benzoate Esters with
Bis(pinacolato)diboron Catalyzed by Iridium–phosphine Complexes. Chem. Commun. 2010, 46,
159–161.
(28) Ros, A.; Fernández, R.; Lassaletta, J. M. Functional Group Directed C–H Borylation. Chem. Soc.
Rev. 2014, 43, 3229–3243.
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
(29) Taube, H.; Posey, F. A. The Study of a System Involving Equilibrium Between Inner Sphere and
=
Outer Sphere Complex Ions ꢀ Co(NH3)5H2O+++ and SO4 . J. Am. Chem. Soc. 1953, 75, 1463–1467.
(30) Boebel, T. A.; Hartwig, J. F. SilylꢀDirected, IridiumꢀCatalyzed OrthoꢀBorylation of Arenes. A Oneꢀ
Pot OrthoꢀBorylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008, 130, 7534–
7535.
(31) Davis, H. J.; Phipps, R. J. Harnessing NonꢀCovalent Interactions to Exert Control over
Regioselectivity and SiteꢀSelectivity in Catalytic Reactions. Chem. Sci. 2017, 8, 864–877.
(32) Haldar, C.; Hoque, E.; Bisht, R.; Chattopadhyay, B. Concept of IrꢀCatalyzed CH Bond
Activation/borylation by Noncovalent Interaction. Tetrahedron Lett. 2018, 59, 1269–1277.
(33) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr; Smith, M.
R., III. OuterꢀSphere Direction in Iridium CꢀH Borylation. J. Am. Chem. Soc. 2012, 134, 11350–
11353.
(34) Bisht, R.; Chattopadhyay, B. Formal IrꢀCatalyzed LigandꢀEnabled Ortho and Meta Borylation of
Aromatic Aldehydes via in SituꢀGenerated Imines. J. Am. Chem. Soc. 2016, 138, 84–87.
(35) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis AcidꢀBase InteractionꢀControlled OrthoꢀSelective CꢀH
Borylation of Aryl Sulfides. Angew. Chem. Int. Ed Engl. 2017, 56, 1495–1499.
(36) Li, H.ꢀL.; Kanai, M.; Kuninobu, Y. Iridium/BipyridineꢀCatalyzed OrthoꢀSelective CꢀH Borylation of
Phenol and Aniline Derivatives. Org. Lett. 2017, 19, 5944–5947.
(37) Davis, H. J.; Genov, G. R.; Phipps, R. J. MetaꢀSelective C−H Borylation of Benzylamineꢀ,
Phenethylamineꢀ, and PhenylpropylamineꢀDerived Amides Enabled by a Single Anionic Ligand.
Angew. Chem. Int. Ed. 2017, 56, 13351–13355.
(38) Chattopadhyay, B.; Dannatt, J. E.; AndujarꢀDe Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr;
Singleton, D. A.; Smith, M. R., III. IrꢀCatalyzed OrthoꢀBorylation of Phenols Directed by Substrateꢀ
Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak
Interactions. J. Am. Chem. Soc. 2017, 139, 7864–7871.
(39) Yamamoto, T.; Ishibashi, A.; Suginome, M. Regioselective Synthesis of OꢀBenzenediboronic Acids
via IrꢀCatalyzed OꢀCꢀH Borylation Directed by a PyrazolylanilineꢀModified Boronyl Group. Org.
Lett. 2017, 19, 886–889.
(40) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion PairꢀDirected Regiocontrol in TransitionꢀMetal
Catalysis: A MetaꢀSelective CꢀH Borylation of Aromatic Quaternary Ammonium Salts. J. Am.
Chem. Soc. 2016, 138, 12759–12762.
(41) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A MetaꢀSelective CꢀH Borylation Directed by a
Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717.
23
ACS Paragon Plus Environment

ACS Catalysis
Page 24 of 24
1
2
3
4
5
6
7
8
9
(42) The ligand for the KanaiꢀKuninobu ortho CHB of aniline is prepared via a Suzuki crossꢀcoupling of
5ꢀbromoꢀ2,2´ꢀbipyridine ($14,000/mol) with 1ꢀBpinꢀ4ꢀ(trifluoromethyl)benzene ($870/mol) in 73%
yield. B2pin2 ($50/mol) is the borylating agent. Prices are the lowest per mole values of all
commercial sources listed by SciFinder Scholar on 02/01/18.
(43) The yields for deprotection are given in an endnote in ref. 35. The products are not specified and
experimental details were not reported. We presume that the deprotected compounds are Nꢀacylated
since all ArN(Ac)(CH2SMe) reactants were prepared from acylated anilines.
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
(44) The Ir ligand used in this work is dtbpy ($2,300/mol). B2eg2 is prepared from B2(OH)4 ($51/mol) and
ethylene glycol ($0.22/mol) in 91% Yield.
(45) Robbins, D. W.; Hartwig, J. F. A CꢀH Borylation Approach to SuzukiꢀMiyaura Coupling of
Typically Unstable 2ꢀHeteroaryl and Polyfluorophenyl Boronates. Org. Lett. 2012, 14, 4266–4269.
(46) Bartlett, R. K.; Turner, H. S.; Warne, R. J.; Young, M. A.; Lawrenson, I. J. The Reaction of Primary
Amines with Boron Halides. Part II. Arylamines. The Effect of OrthoꢀSubstitution: Formation of Diꢀ
BꢀHalogenoborazoles. J. Chem. Soc. A 1966, No. 0, 479–500.
(47) Thanthiriwatte, K. S.; Hohenstein, E. G.; Burns, L. A.; Sherrill, C. D. Assessment of the
Performance of DFT and DFTꢀD Methods for Describing Distance Dependence of Hydrogenꢀ
Bonded Interactions. J. Chem. Theory Comput. 2011, 7, 88–96.
(48) Parthasarathi, R.; Subramanian, V. Characterization of Hydrogen Bonding: From van Der Waals
Interactions to Covalency. In Hydrogen Bonding—New Insights; Grabowski, S. J., Ed.; Springer
Netherlands: Dordrecht, 2006; pp 1–50.
Table of Contents
24
ACS Paragon Plus Environment