C-H Borylation Catalysts that Distinguish between Similarly Sized Substituents like Fluorine and Hydrogen

Article abstract of DOI:10.1021/acs.orglett.9b02299

By modifying ligand steric and electronic profiles it is possible to C-H borylate ortho or meta to substituents in aromatic and heteroaromatic compounds, where steric differences between accessible C-H sites are small. Dramatic effects on selectivities between reactions using B₂pin₂ or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for the first time. Judicious ligand and borane combinations give highly regioselective C-H borylations on substrates where typical borylation protocols afford poor selectivities.

Full text of DOI:10.1021/acs.orglett.9b02299

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
C−H Borylation Catalysts that Distinguish Between Similarly Sized
Substituents Like Fluorine and Hydrogen
Susanne L. Miller, Ghayoor A. Chotana, Jonathan A. Fritz, Buddhadeb Chattopadhyay,
Robert E. Maleczka, Jr.,* and Milton R. Smith, III*
Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing 48824-1322, Michigan, United States
S
* Supporting Information
ABSTRACT: By modifying ligand steric and electronic profiles it is
possible to C−H borylate ortho or meta to substituents in aromatic and
heteroaromatic compounds, where steric differences between accessible C−
H sites are small. Dramatic effects on selectivities between reactions using
B2pin2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for
the first time. Judicious ligand and borane combinations give highly
regioselective C−H borylations on substrates where typical borylation
protocols afford poor selectivities.
−H borylation (CHB) has gained popularity,1 in part,
CHBs with a CoII precatalyst, where even C−F bonds are
cleaved.6
C
because the sterically directed regioselectivity observed
for arenes often complements that of electrophilic aromatic
substitution (EAS) and directed ortho metalations (DoM).2 As
shown in Scheme 1, CHBs of 1,3-substituted benzenes are
Given that C(sp2)−B bonds can be converted to a broad
range of functional groups, the ability to functionalize meta or
ortho to F in substrates bearing heavier C−halogen bonds
opens the cross-coupling “toolbox” for elaborating fluorinated
structures. Here we show that, through ligand design, good
regioselectivities are achieved for combinations of substrates,
substituents, and substitution patterns that are daunting for
standard CHBs and other C−H/X transformations.
3-Fluorochlorobenzene is illustrative of remaining challenges
in aromatic functionalization (Figure 1). While the 2-position
Scheme 1. Sterically Directed CHB Regioselectivities
highly meta selective when the substituents are sufficiently
large to block functionalization of the ortho positions. For 1,4-
substituted benzenes, regioselectivity can be achieved when
substituent sterics differ significantly.3 When these require-
ments are not met, selectivities erode.
Recent work demonstrated good to excellent selectivities for
CHB ortho to F.4 This underscores the challenge of selectively
borylating C−H bonds meta to F, where the intervening sp2 C
is H-substituted. Driess and co-workers reported a cobalt(II)
pincer complex that catalyzes CHB of fluoroarenes with the
best meta to F selectivities to date. CHBs of 2,3- and 3-
substituted fluorobenzenes were particularly good ranging
from more than 99:1 to 7:1.5
Figure 1. C−H functionalization of 3-fluorochlorobenzene.
can be selectively transformed via DoM,7 and EAS can be used
to functionalize the 6-position,8 selective derivatizations at the
4-position are limited to enzymatic9 and electrophilic10
processes. Moreover, only three reports, all C−H activations,
describe functionalization at the 5-position.10b,11 Given that
tens of thousands of 4- and 5-substituted analogues have been
reported, the dearth of direct routes12 from 1 is remarkable.
Ir-catalyzed CHB using the common ligand/precatalyst
combination of 4,4′-di-tert-butyl-2,2′dipyridyl/bis(1,5-cyclo-
This is a significant advance. However, Driess reported no
CHBs of fluorinated heterocycles, and aromatic substituents
besides F were limited to Me and CF3. Chirik’s Co CHB
catalysts do not tolerate heavier halogens,4d and we reported
Received: July 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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octadiene)-di-μ-methoxy-diiridium(I) (dtbpy/[Ir(OMe)cod]2,
cod = 1,5-cyclooctadiene) gives a 1:1.8 mixture of 4- and 5-
borylated products, respectively. Despite this low regioselec-
tivity, CHBs clearly provide opportunities to functionalize
these challenging positions. As electronic effects influence
CHB regioselectivities,13 borylations of 1 were performed
using 4,4′-disubstituted-2,2′-dipyridyl ligands (Scheme 2). The
their N(sp2) lone pairs have poorer overlap with Ir orbitals and
(ii) bozo and bnbozo are weaker σ-donors than dtbpy, since
Brønsted basicities of oxazoles are lower than pyridines.15 Bozo
is less sterically hindered than dtbpy, because its five-
membered oxazoline rings are smaller than the pyridine rings
in dtbpy. In contrast, the Ir center in five-coordinate trisboryl
bnbozo intermediates will be less accessible than for dtbpy and
bozo analogues, because the bnbozo benzyl groups will project
into the substrates’ path to the C−H cleaving transition state.
Dipyridylmethane (dpm) intermediates differ from the
others, because the six-membered metallacyclic rings resulting
from κ2 coordination to Ir are puckered. Thus, the Ir center in
dpm intermediates will be less accessible than in dtbpy and
bozo analogues.
a
Scheme 2. Electronic Effects on Regioselectivity
The hypotheses in Figure 2 predict that ortho to F selectivity
for CHBs of 1 will increase in the order dpm < dtbpy < bozo,
and the meta to F CHB selectivity will follow the reverse order.
The positioning of bnbozo is difficult to predict a priori.
Gratifyingly, the experimental selectivities in Scheme 3
follow the predicted order for dpm, dtbpy, and bozo for
substrate 1. CHBs of 1 with bnbozo favor ortho to F product
2b.
a
0.5 equiv of B2pin2 equals 1 equiv of transferable Bpin groups.
remote substitution site on the bipyridine ligand ensures
electronically determined regioselectivities. Although selectiv-
ity changes are modest, Scheme 2 shows that 2a is favored with
the most electron-rich ligand, while 2b is major for the most
electron-poor ligand. On the basis of estimated pKa values of
halogenated benzenes, the C−H bond at the 4-position should
be more acidic than the C−H at the 5-position.14
Scheme 3. Ligand Selectivities for Borylation of 1
With the results in Scheme 2 and estimations of ligand steric
effects,3 the ligand design approach in Figure 2 was devised for
It is known that B2pin2 is more reactive than 4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (HBpin) in Ir CHB.16 Thus,
reactions with 0.5 equiv of B2pin2 proceed first via borylation
of the substrate, generating HBpin. Then, the second stage of
the reaction produces more borylated product and H2. For the
CHB of 1 with 0.5 equiv of B2pin2 catalyzed by dpm/
[Ir(OMe)cod]2, the selectivity for isomer 2a increased as the
reaction progressed. This suggested that the regioselectivities
with B2pin2 and HBpin differ.
This was confirmed by examining dpm/[Ir(OMe)(cod)]2
catalytic CHBs of 1 with 2 equiv of HBpin or B2pin2 under
conditions otherwise identical to those in Scheme 3. In
Scheme 4, CHB with B2pin2 lowered the 2a/2b ratio from
2.3:1 (Scheme 3) to 1:1. When CHB was performed with
HBpin the 2a/2b ratio rose to 5:1! This is the first time a
significant difference in selectivity between B2pin2 and HBpin has
been observed. For the other ligands in Scheme 3, the boron
reagent had little influence on 2a/2b ratios.
Figure 2. Bidentate nitrogen ligand properties.
selective functionalization at the 4- or 5-positions of 1.
Hindered, electron-rich ligands should favor isomer 2a, while
less encumbered, electron-poor ligands should select for
isomer 2b.
Scheme 4. Boron Reagent Effects on Regioselectivity of 1
When 4,4′-di-tert-butyl-2,2′dipyridyl (dtbpy), 2,2′-bis[(4S)-
4-benzyl-2-oxazoline] (bnbozo), and 2,2′-bis-2-oxazoline
(bozo) are κ2-bound to Ir, the resulting five-membered
metallacyclic structures are effectively coplanar. Both bozo
and bnbozo will be weaker donors relative to dtbpy, since (i)
B
DOI: 10.1021/acs.orglett.9b02299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Five- and Six-Membered Arene and Heteroarene Selectivities
a
See Supporting Information for variations to the standard conditions, which are as follows: 1 mmol of substrate, 1.5 mol % [Ir(OMe)(cod)]2, 3
mol % ligand, 1−3 equiv of HBpin, 3 mL of solvent. Reaction times vary from 1 to 72 h, isomer ratios were determined by gas chromatography−
1
flame ionization detector or H NMR, and isolated yields are in parentheses.
To test the design principles built from CHBs of 1, several
five- and six-membered ring aromatic and heteroaromatic
compounds where CHBs with dtbpy/[Ir(OMe)cod]2 give
isomer mixtures were screened for CHB regioselectivities using
dpm, bnbozo, and bozo ligands and [Ir(OMe)cod]2. Each
parent substrate gives two primary regioisomers denoted as a
(sterically favored) and b (electronically favored). Results are
shown in Table 1, and ligands that gave the highest selectivities
for the respective major isomers are highlighted. Many
substrate/ligand combinations yielded more than 10:1
selectivity for isomer a. Significantly, dtbpy, the most common
Ir CHB ligand, never gave superior regioselectivity.
In keeping with trends illustrated in Figure 2, we sought to
further improve steric selectivity by design of a more basic
derivative of the dpm ligand. This was accomplished with
(4,4′-bis(dimethylamino)2,2′-dipyridyl)methane (dmadpm)
(Figure 3). Estimated pKa values15c,d for the parent 4-
dimethylamino monomer are significantly more basic than
the corresponding monomer estimates for dtbpy and dpm.
Thus, dmadpm tops the steric and basicity ranking.
Where dpm favored the sterically preferred product in Table 1,
dmadpm was tested under identical conditions. Improved
selectivity was seen for products 2a, 3a, 4a, 5a, 10a, and 15a.
For 5a, selectivity was sufficiently high that pure 5a was
obtained in a 95% yield with 0.25 mol % catalyst. Selectivity
worsened for 6a and 16a.
The utility of ligand-modulated selectivity that we developed
is showcased in Figure 4. C−H borylations are compared to
putative Miyaura C−X borylations (X = Br or I). Factors to be
considered in choosing between these routes are desired
regiochemistry and reactant price.17
For the synthesis of 2a, the low cost of the corresponding
aryl bromide substrate makes Miyaura borylation the route of
choice. In contrast, aryl and heteroaryl halides required for
Miyaura routes to 5a, 6a, or 12a range from being costly to
nonexistent. It is noteworthy that directed ortho metalations of
substrates where Y = H followed by trapping with boron
electrophiles will not give 5a or 6a as major isomers, and
bromothiophenes are known for halogen dance rearrange-
ments. Therefore, Ir CHB is the best option for making
isomers 5a, 6a, and 12a.
In summary, ligand modifications can dramatically improve
regioselectivity in Ir CHB of substrates, where the most
commonly used ligand, dtbpy, gives isomer mixtures that can
limit synthetic utility. We also showed that hindered, electron-
rich ligands can shift selectivity to steric products, whereas
unhindered electron-poor ligands shift selectivity toward
electronic products. Electron-poor oxazoline ligands such as
bnbozo facilitate high selectivity for activated, five-membered
With these results in hand, we set out to compare dpm
selectivity against the more electron-rich dmadpm (Scheme 5).
Figure 3. An electron-rich, hindered ligand for CHB.
C
DOI: 10.1021/acs.orglett.9b02299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
Scheme 5. Regioselectivities with dmadpm Versus dpm
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: smithmil@msu.edu. (M.R.S.)
*E-mail: maleczka@chemistry.msu.edu. (R.E.M.)
ORCID
Buddhadeb Chattopadhyay: 0000-0001-8473-2695
Robert E. Maleczka, Jr.: 0000-0002-1119-5160
Milton R. Smith, III: 0000-0002-8036-4503
Author Contributions
S.L.M., M.R.S., and R.E.M. wrote the manuscript. S.L.M.,
G.A.C., J.A.F., and B.C. performed research.
Notes
The authors declare the following competing financial
interest(s): S.L.M., M.R.S., and R.E.M. own a percentage of
BoroPharm, Inc.
ACKNOWLEDGMENTS
■
We thank Drs. D. Holmes and L. Xie in the Max. T. Rogers
NMR Facility, Dr. R. Staples in the MSU Center for
Crystallographic Research, and MSU RTSF Mass Spectrom-
etry Core for their assistance in compound characterization.
We thank the NIH (GM63188) for financial support and
BoroPharm, Inc. for a gift of B2pin2.
a
Isomer ratios determined by gas chromatography−flame ionization
b
detector or 1H NMR. Isolated yields in parentheses. See Supporting
Information for variations to the standard conditions.
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Experimental procedures and compound characteriza-
tion data (PDF)
Accession Codes
CCDC 1434792−1434794, 1436384, 1437270, and 1937214
contain the supplementary crystallographic data for this paper.
D
DOI: 10.1021/acs.orglett.9b02299
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DOI: 10.1021/acs.orglett.9b02299
Org. Lett. XXXX, XXX, XXX−XXX