Rh(I)/NHC*-Catalyzed site- and enantioselective functionalization of c(sp3)?H bonds toward chiral triarylmethanes

Article abstract of DOI:10.1021/acscatal.6b02392

The first Rh(I)-catalyzed asymmetric approach for the intermolecular functionalization of C(sp³)?H bonds is reported. For the first time, unsymmetrical N-heterocyclic carbenes (NHCs) were used for asymmetric catalysis that is capable of achieving not only high site-selectivity but also enantioselectivity. The Rh(I)/NHC* catalytic systems were applied to asymmetric direct C(sp³)?H arylation, which provides a synthetic route toward enantioenriched triarylmethanes.

Full text of DOI:10.1021/acscatal.6b02392

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Letter
Rh(I)/NHC*-Catalyzed Site- and Enantioselective Functionalization
of C(sp3)-H bonds Toward Chiral Triarylmethanes
Ju Hyun Kim, Steffen Greßies, Mélissa Boultadakis-Arapinis, Constantin Gabriel Daniliuc, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02392 • Publication Date (Web): 05 Oct 2016
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Rh(I)/NHC*-Catalyzed Site- and Enantioselective Functionali-
zation of C(sp3)–H bonds Toward Chiral Triarylmethanes
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Ju Hyun Kim, Steffen Greßies, Mélissa BoultadakisꢀArapinis, Constantin Daniliuc and Frank Glorius*
OrganischꢀChemisches Institut Westfälische WilhelmsꢀUniversität Münster Corrensstraße 40, 48149 Münster (Germany)
KEYWORDS: C(sp3)–H functionalization, asymmetric arylation, triarylmethane, Nꢀheterocyclic carbenes
approaches to the synthesis of racemic triarylmethanes have been
developed.[10] In recent years, a few asymmetric synthetic methods
have been successfully developed toward enantioenriched
triarylmethanes which are especially prominent in pharmaceutical
applications,[11] However, most of this work is focused on
stereospecific approaches.[12] In stark contrast, there are only a
handful of examples reported starting from racemic compounds
(Scheme 1A).[13]Further, these methods suffer from significant
disadvantages such as the requirement of multistep substrate
preparations, poor enantioselectivity and limited scope of subꢀ
strates. In consideration of the growing interest in green and
efficient process, a new approach through direct functionalization
of C(sp3)–H bonds would be highly desirable. Although Oshiꢀ
ma[14] and Walsh[15] reported the Pd catalyzed direct arylation of
diarylmethanes to form triarylmethanes, no enantioselective apꢀ
proach has been disclosed. The major obstacle possibly arises
from the difficulty in finding suitable ligands and catalysts.[13b,15a]
ABSTRACT: The first Rh(I)ꢀcatalyzed asymmetric approach for
the intermolecular functionalization of C(sp3)–H bonds is
reported. For the first time, unsymmetrical NHCs was used for
asymmetric catalysis that is capable of achieving not only high
siteꢀselectivity, but also enantioselectivity. The Rh(I)/NHC*
catalytic systems were applied to asymmetric direct C(sp3)–H
arylation, which provides syntheticroute towards enantioenriched
triarylmethanes.
KEYWORDS: C(sp3)–H functionalization, asymmetric arylation,
triarylmethane, Nꢀheterocyclic carbenes, rhodium
The development of transition metalꢀcatalyzed direct
functionalizations of C(sp3)–H bonds is one of the most important
subjects in modern organic chemistry in view of atomꢀ and stepꢀ
economy.[1] Despite the immense importance of this strategy, the
reactivity and selectivity issues, particularly controlling the siteꢀ
selectivity and enantioselectivity, remain a significant challenge.[2]
In the past few years, great progress has been made in the develꢀ
opment of catalytic asymmetric C(sp3)–H bond functionalizations
by using chiral versions of phosphoramidite, phosphine or amino
acid ligands.[3] However, the majority of these examples have
focused on intramolecular transformations under palladium
catalysis. On the other hand, very few examples of intermolecular
enantioselective functionalizations of C(sp3)–H bonds have been
reported.[4] Although Rh(II)ꢀcatalyzed asymmetric metal carbene
insertions into C(sp3)–H bonds have been well established,[5] to
the best of our knowledge, other rhodiumꢀcatalyzed asymmetric
methods for the intermolecular functionalization of C(sp3)–H
bonds have not been reported to date.
Scheme 1. Synthesis of chiral triarylmethanes
(A) Previous work
Ar1
(1) Friedel–Crafts
alkylation
NHTs
(OTMS)
Ar1
Ar1
Ar2
R
Ar3-H
(3) C(sp2)-H
activation
N
H
Brønsted acid*
Ar3
ref. 13c, d
Ar1
N
Alkyl-B(OH)2
PdII/L*, [O]
ref. 13e
Ar1
OH
(2) Asymmetric
1,4-addition
NR2
(Ar3BO)3
Rh/L*
ref. 13a
Ar2
(B) This work: Rh(I)/NHC*-catalyzed site- and enantioselective arylation of C(sp3)–H bonds
Ar
ArBr
ArBr
Rh(I)
N
Ar
N
N
Rh(I)/NHC
R
R
R
To overcome the tremendous challenges faced in C(sp3)–H
bond functionalization, new ligands and catalytic systems need to
be developed. A number of papers have demonstrated that Nꢀ
heterocyclic carbenes (NHCs) can be used as efficient ligands for
the functionalization of C(sp3)–H bonds due to strong σꢀdonor
ability.[6] Additionally, a great advantage of employing NHC ligꢀ
ands is the ease of varying their steric and electronic properties.[7]
Given the precedent of using the attractive features of NHC ligꢀ
ands,[8] we envisioned that an intermolecular asymmetric funcꢀ
tionalization of C(sp3)–H bonds could be achieved by using chiral
NHC ligands. As a proof of concept, we first investigated a rhodiꢀ
umꢀcatalyzed intermolecular arylation. The employed Rh/NHC*
catalytic system controls the siteꢀ as well as enantioselectivity,
which provides efficient and easy access to chiral triarylmethanes.
Triarylmethanes are important molecular frameworks in
organic synthesis, medicinal chemistry, as well as in materials
such as dyes and fluorescent compounds.[9] Consequently, elegant
ref.17
Site-selective
C(sp2)–H o-Arylation
C(sp3)–H Arylation
Rh(I)/NHC* =
Ar1
Ar2
N
N
Ar1
Ar2Br
H
H
H
Rh(I)/NHC*
RhLn
N
N
F
Enantioselective
C–M rotation suppressed
Product
+ New access to chiral triarylmethanes
+ General coupling partners
+ Redox-neutral
Transformation
+ First Rh(I)-catalyzed asymmetric
functionalization of C(sp3)–H bonds
+ New chiral NHCs: No C2 symmetry
Herein, we report an operationally simple Rh(I)/NHC* catalytic
system which enables direct arylations of benzylic C(sp3)–H
bonds to give triarylmethanes. Significantly, the use of the
Rh(I)/NHC catalytic system can reverse the siteꢀselectivity of
pyridines under Rh(I) catalysis. Furthermore, the present catalytic
system can be applied to the enantioselective functionalization of
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C(sp3)–H bonds, thus providing
enantioenriched triarylmethanes (Scheme 1B).
a
novel route towards
critical for this transformation (Table S2), presumably to enable a
cyclometalation of the benzylic position of the NHC which leads
to a catalytically active species. Steric and electronic variations of
R3 did not improve either reactivity or enantioselectivity (entry 6ꢀ
8). Further improvement of the e.r. was achieved with variation of
R2 without affecting the yields (entry 2ꢀ5). The 4ꢀfluorophenyl
substituent on R2 proved to be the most effective one for this
reaction, affording a yield of 90% with 87:13 e.r. (entry
4).Finally, prolonging the reaction time at a lower temperature
(80°C) could slightly increase the e.r. while maintaining the yield
(entry 8). We also explored other rhodium precursors by using
NHC A* (entry 9ꢀ11). Both Rh(II) and Rh(III) precursors also
gave product 5a in similar yield but with lower enantioinduction
(entry 10ꢀ11).
4
5
6
7
8
9
In order to address the challenge associate with siteꢀselectivity,
we began our investigations by examining the direct arylation of
2ꢀbenzylpyridine (1a) with bromobenzene (2a) as the model
substrates, where the reaction may occur at either an aromatic
C(sp2)ꢀH bond[16] or a benzylic C(sp3)–H bond. To our delight,
the desired product 3a was selectively obtained in 70% yield
when the reaction was carried out in the presence of Rh(PPh3)3Cl
(5 mol%), IMes·HCl (5 mol%) as a carbene precursor and
NaOtBu. After screening a variety of reaction conditions, it was
found that the choice of Nꢀsubstituent of the imidazolium salt
proved to be the most important factor for this transformation
(Table S1). The mesityl substituent on the NHC is crucial for the
activity, while other imidazolium salts (IPr·HCl, INpEt·HCl) did
not catalyze this transformation. Based on these results, we
designed new unsymmetrical imidazolium ligands containing one
mesityl substituent for the improvement of reaction efficiency.
With the newly developed unsymmetrical NHC A, the
corresponding product 3a could be isolated in better yield (82%).
Under the optimized reaction conditions, we have explored the
substrate scope of this reaction (Scheme 2). A number of aryl
halides 2 as well as diarylmethanes 1 smoothly underwent direct
arylation of C(sp3)–H bonds to afford the corresponding products
3aꢀ3g in good to excellent yields. With chiral NHC A*, the
reaction of 1a with 4ꢀbromotoluene (2b) which creates a new
stereogenic center was then conducted. However, unfortunately,
no enantioselectivity was observed, possibly due to the lack of
chiral induction or racemization of the products.
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Table 1. Screening of ligands and catalystsa
Yield
Entry
Catalyst
R1
R2
R3
e.rc
(%)b
1
2
3
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Me
Me
Me
Me
tꢀBu
tꢀBu
tꢀBu
80
90
43
82:18
87:13
86:14
2ꢀNp
4ꢀPy
pꢀF
C6H4
pꢀF
4
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Me
Me
tꢀBu
tꢀBu
90
87:13
89:11
87
5d
Scheme 2. Scope of 2-benzylpyridines and aryl bromidesa
C6H4
(85)e
6
7
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
[Rh(cod)Cl]2
Rh2(OAc)2
Rh(acac)3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
cPr
Ad
27
82
90
72
94
41
55:45
81:19
55:45
75:25
79:21
78:22
8
9f
10f
11f
Np
tꢀBu
tꢀBu
tꢀBu
aReaction conditions: 4a (0.1 mmol), phenylbromide (0.3 mmol),
catalyst (5 mol%), NHC (5 mol%) and NaOtBu (0.3 mmol) in
b
toluene (0.25 mL) for 4 h at 100 °C under Ar. GCꢀFID yield.
cDetermined by HPLC on a chiral stationary phase. dReaction was
e
carried out in 1,4ꢀdioxane (0.25 mL) for 12 h at 80°C. Isolated
yield. fReactions were performed with PCy3 (10 mol%).
Np=naphthyl, Py=pyrenyl, cPr=cyclopropyl, Ad=adamantyl.
aReaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), RhCl(PPh3)3 (5
mol%), NHC A (5 mol%) and NaOtBu (0.6 mmol) in toluene (0.5
mL) at 120°C under Ar, 12 h, isolated yield.
Having established reaction conditions for the enantioselective
C(sp3)–H arylations of 8ꢀ(4ꢀfluorobenzyl)quinoline (4a), we inꢀ
vestigated the scope of the reaction (Scheme 3). We were pleased
to observe that direct arylations of 8ꢀbenzyl quinoline (4b) with
aryl bromides bearing both electronꢀdonating groups (Me, OMe)
and F in para- position were wellꢀtolerated under the reaction
conditions, and afforded the corresponding products 5b–5d in
good yields with good e.r. ranging from 87:13 to 90:10. Next, the
influence of the electronic and steric nature of the substituents on
the diarylmethanes was investigated with bromobenzene(2a).
Electronꢀdonating substituents in metaꢀ and para- positions proꢀ
vided the corresponding products 5e and 5f in slightly lower yield
but with similar e.r. On the other hand, the reactions of electronꢀ
poor substrates with a wide range of aryl bromides proceeded
efficiently and afforded products 5gꢀ5l with better yield while
maintaining the e.r. value. Notably, 5ꢀbromobenzofurane is also
competent, affording 5m. [11b] Other electronꢀwithdrawing groups
(Cl, CF3)ꢀsubstituted substrates 4e, 4f as well as naphthylꢀ
For the development of an asymmetric version, we envisioned
that substrates that could make a more rigid metal complex would
be more likely to give asymmetric induction. To test our
hypothesis, 8ꢀbenzyl quinolines 4 were examined as substrates in
which the nitrogen on quinoline could coordinate to the rhodium
metal, resulting in a 5ꢀmembered metallacycle. To our delight, the
desired product 5a was obtained in 80% yield with 82:18 e.r.
when the reaction of 8ꢀ(4ꢀfluorobenzyl)quinoline (4a) and
bromobenzene (2a) was carried out with chiral NHC A* (Table 1,
entry 1). This result suggestthat the preꢀcoordination of substrates
to the metal catalyst plays a significant role in asymmetric
induction. Inspired by this result, a series of unsymmetrical chiral
NHCs, which are accessible from readily available chiral amines
and anilines in one step,[17] were further investigated (Table 1). It
is noteworthy that an oꢀtolyl substituent (R1=Me) on the NHC is
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since the whole system is rigid, overcoming the possible rotation
substituted substrate 4g were also tolerated, providing the correꢀ
sponding products 5nꢀ5s in good yields with good e.r. The absoꢀ
lute configuration of 5c and 5n were determined by Xꢀray crystalꢀ
lographic analysis.[18] Recrystallization to enantiopurity was exꢀ
amined, with all selected samples isolated in excellent ee (5c,
>99%; 5n, >99%; 5p, 95%) and moderate yields (see SI).
around the metalꢀcarbon bond (I, Scheme 4).
1
To probe the order of events, H, 19F and 31P NMR analyses of
the stoichiometric reaction were conducted (see SI). The results
showed that preꢀformed rhodium complex does not interact with
the substrate 4b, while new signals appear readily even at room
temperature in the presence of 4ꢀbromoanisole 2c. Therefore, we
suggest that oxidative addition of arylbromide proceeded prior to
transmetalation of 4 (Scheme 4).
Scheme 3. Scope of 8-benzyl quinolines and aryl bromidesa
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Scheme 4. Proposed reaction mechanism
Recent papers report transition metalꢀfree coupling reactions
between haloarenes and arenes to form biaryls, triggered by alkali
metal tertꢀbutoxides with various additives.[19] These reactions are
known to involve the generation of aryl radical intermediates,
generated from potassium or sodium tertꢀbutoxide. In a similar
fashion, we considered that this reaction could proceed through a
radical intermediate. Addition of neither BHT nor 1,1ꢀ
diphenylethene to the reaction mixture decreased conversion to
the desired product 5a, suggesting that this reaction is not operatꢀ
ing via a radical mechanism.
aReaction conditions: 4 (0.2 mmol), 2 (0.6 mmol), RhCl(PPh3)3 (5
mol%), NHC B (5 mol%) and NaOtBu (0.6 mmol) in 1,4ꢀdioxane
(0.5 mL) at 80 oC under argon for 12 h, isolated yield.
To gain insights into the reaction mechanism, we conducted a
series of deuteriumꢀincorporation experiments. When 3 equivaꢀ
lents of NaOtBu was added to the substrate 4b in a mixture of
methanolꢀd4 and 1,4ꢀdioxane, 80% of deuterium was incorporated
to the benzylic C(sp3)–H bond of 4b in the absence of catalyst and
ligand. In contrast, no deuterium incorporation to the substrate
was observed upon running the reaction with Rh(PPh3)3Cl and
NHC B in the absence of base. These results indicate that the
reaction involves initial reversible deprotonation by the base. The
isolated product 5a was treated with the standard conditions. Deꢀ
spite basic conditions, no racemization of 5a could be observed,
retaining the same ee. The observation of relatively large KIE
value (kH/kD = 2.77) from parallel reactions suggests that the rate
determining step is probably the cleavage of C(sp3)–H bond.
In order to gain structural information on the reactive species,
we carried out a NMR study. When we mixed stoichiometric
amounts of RhCl(PPh3)3, NHC B and NaOtBu (3 equiv) in toluꢀ
eneꢀd8, the 1H NMR spectrum showed that one of the orthoꢀ
methyl C–H bonds on the aryl substituent of the NHC has been
activated leading to a Rh–C bond, which renders the metal center
highly electron rich presumably facilitating oxidative addition. In
addition, this species may play a central role in chiral induction
On the basis of above results and previous reports,[16,20] a plauꢀ
sible reaction mechanism is proposed in Scheme 4. The transforꢀ
mation is initiated by the coordination of in situ generated free
NHC to the Rh metal complex, followed by intramolecular C–H
bond activation of an aryl orthoꢀmethyl on the carbene to produce
reactive Rh(I)ꢀcomplex I. Then, oxidative addition of arylꢀhalide
into Rhꢀcomplex I is presumed to occur to give Rh(III)ꢀcomplex
II with concomitant loss of the associated ligands. Next, the
deprotonated substrate III, which is generated by excess amount
of NaOtBu, undergoes transmetalation leading to Rhꢀcomplex IV.
The transmetallation may be favored for one of the enantiomers
III, possibly due to steric interactions. The desired product 5 is
then produced by the reductive elimination of IV.
In summary, we have developed a novel Rh(I)/NHC catalytic
system for siteꢀ and enantioselective direct arylations of C(sp3)–H
bonds. The reactions were applied for the synthesis of chiral triꢀ
arylmethanes. Using Rh(PPh3)3Cl and newly designed chiral
NHCs, diverse triarylmethanes have been synthesized with good
enantioselelctivities and yields. The mechanistic studies demonꢀ
strate that the newly developed NHC* undergoes an intramolecuꢀ
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lar C(sp3)–H activation leading to a defined chiral environment
without the necessity of a C2 symmetric NHC. Further studies
regarding the detailed reaction mechanism and explorations of the
potential of newly developed chiral NHCs for other transforꢀ
mations are currently in progress.
(7) For selected review, see: (a) Hopkinson, M. N.; Richter, C.;
Schedler, M.; Glorius, F. Nature 2014, 510, 485ꢀ496; (b) Praetorius,
J. M.; Crudden, C. M. Dalton Trans 2008, 4079ꢀ4094.
(8) For the Pd/NHC*ꢀcatalyzed intramolecular asymmetric C(sp3)–H
arylations, see: (a) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig,
E. P. Angew. Chem. Int. Ed. 2011, 50, 7438ꢀ7441; (b) Larionov, E.;
Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P. Chem. Sci.
2013, 4, 1995ꢀ2005.
(9) For selected reviews and papers, see: (a) Mondal, S.; Panda, G.
RSC Adv. 2014, 4, 28317ꢀ28358; (b) Nair, V.; Thomas, S.; Mathew,
S. C.; Abhilash, K. G. Tetrahedron 2006, 62, 6731ꢀ6747; (c) Parai,
M. K.; Panda, G.; Chaturvedi, V.; Manju, Y. K.; Sinha, S. Bioorg.
Med. Chem. Lett. 2008, 18, 289ꢀ292.
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ASSOCIATED CONTENT
Supporting Information.
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Experimental procedure, characterization data, and copies of H
and 13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) For recent papers, see: (a) Nambo, M.; Crudden, C. M. ACS
Catal. 2015, 5, 4734ꢀ4742; (b) Nambo, M.; Ariki, Z. T.; Cansecoꢀ
Gonzalez, D.; Beattie, D. D.; Crudden, C. M. Org. Lett. 2016, 18,
2339ꢀ2342.
AUTHOR INFORMATION
Corresponding Author
(11) For selected papers, see: (a) Wood, P. M.; Woo, L. L.; Labrosse,
J.ꢀR.; Trusselle, M. N.; Abbate, S.; Longhi, G.; Castiglioni, E.;
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4238; (b) Asoh, K.; Kohchi, M.; Hyoudoh, I.; Ohtsuka, T.;
Masubuchi, M.; Kawasaki, K.; Ebiike, H.; Shiratori, Y.; Fukami, T.
A.; Kondoh, O.; Tsukaguchi, T.; Ishii, N.; Aoki, Y.; Shimma, N.;
Sakaitani, M. Bioorg. Med. Chem. Lett. 2009, 19, 1753ꢀ1757; (c)
Johnson, A. G.; Tranquilli, M. M.; Harris, M. R.; Jarvo, E. R.
Tetrahedron. Lett. 2015, 56, 3486ꢀ3488. (12) For selected papers,
see: (a) Taylor, B. L. H.; Harris, M. R.; Jarvo, E. R. Angew. Chem.
Int. Ed. 2012, 51, 7790ꢀ7793; (b) Harris, M. R.; Hanna, L. E.; Greene,
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3306; (c) Matthew, S. C.; Glasspoole, B. W.; Eisenberger, P.;
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Zhou, M.ꢀH.; Jiang, Y.ꢀJ.; Fan, Y.ꢀS.; Gao, Y.; Liu, S.; Zhang, S.
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He, Q.ꢀL.; You, S.ꢀL. Eur. J. Org. Chem. 2010, 47ꢀ50; (e) Shi, B.ꢀF.;
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glorius@uniꢀmuenster.de
ACKNOWLEDGMENT
This work was supported by the European Research Council unꢀ
der the European Community’s Seventh Framework Program
(FP7 2007ꢀ2013)/ERC Grant Agreement No. 25936. We thank
Dr. Daniel Paul for NMR experiments, Tobias Gensch, Suhelen
VásquezꢀCéspedes and Dr. Eric A. Standley (all WWU Münster)
for helpful discussions.
REFERENCES
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(2) For selected papers of siteꢀselective arylations, see: (a) Campeau,
L.ꢀC.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
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(3) For selected papers, see: (a) Pedroni, J.; Cramer, N. Angew.
Chem. Int. Ed. 2015, 54, 11826ꢀ11829; (b) Saget, T.; Cramer, N.
Angew. Chem. Int. Ed. 2012, 51, 12842ꢀ12845; (c) Saget, T.;
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Angew. Chem. Int. Ed. 2016, 55, 8723ꢀ8727.
(4) For selected papers of Pd catalyzed reactions, see: (a) Zhang, F.ꢀ
L.; Hong, K.; Li, T.ꢀJ.; Park, H.; Yu, J.ꢀQ. Science 2016, 351, 252ꢀ
256; (b) Chan, K. S. L.; Fu, H.ꢀY.; Yu, J.ꢀQ. J. Am. Chem.
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Jazzar, R.; Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem. Int.
Ed. 2010, 49, 7261ꢀ7265; For examples of Ir catalyzed reactions, see:
(d) Tahara, Y.ꢀK.; Michino, M.; Ito, M.; Kanyiva, K. S.; Shibata,
T. Chem. Commun. 2015, 51, 16660ꢀ16663; (e) Pan, S.; Matsuo, Y.;
Endo, K.; Shibata, T. Tetrahedron 2012, 68, 9009ꢀ9015.
(14) Niwa, T.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 2373ꢀ
2375.
(15) For selected papers, see: (a) Zhang, J.; Belloo, A.; Creamer, A.
D.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2012, 134, 13765ꢀ
13772; (b) Zhang, J.; Bellomo, A.; Trongsiriwat, N.; Jia, T.; Carroll,
P. J.; Dreher, S. D.; Tudge, M. T.; Yin, H.; Robinson, J. R.; Schelter,
E. J.; Walsh, P. J. J. Am. Chem. Soc. 2014, 136, 6276ꢀ6287.
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Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2010, 75, 7863ꢀ7868;
For the example of orthoꢀalkylation: (c) Song, G.; Wylie. W. N. O,
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(17) Queval, P.; Jahier, C.; Rouen, M.; Artur, I.; Legeay, J.ꢀC.;
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(18) CCDC 1498372 (5c) and CCDC 1487620 (5n) contain the
supplementary crystallographic data. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
(19) For selected papers, see: (a) Barham, J. P.; Coulthard, G.; Emery,
K. J.; Doni, E.; Cumine, F.; Nocera, G.; John, M. P.; Berlouis, L. E.
A.; McGuire, T.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2016,
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(20) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
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(5) For selected papers and review, see: (a) Liao, K.; Negretti, S.;
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234; (b) Fu, L.; Guptill, D. M.; Davies, H. M. L. J. Am. Chem.
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M.; Zhou, L. Chem. Rev. 2010, 110, 704ꢀ724.
(6) For the PdꢀNHC catalyzed C(sp3)–H functionalizations, see: (a)
Ye, S.; Yang, W.; Coon, T.; Fanning, D.; Neubert, T.; Stamos, D.;
Yu, J.ꢀQ. Chem. Eur. J. 2016, 22, 4748ꢀ4752; (b) Hsiao, C.ꢀC.; Lin,
Y.ꢀK.; Liu, C.ꢀJ.; Wu, T.ꢀC.; Wu, Y.ꢀT. Adv. Synth. Catal. 2010, 352,
3267ꢀ3274; For the NiꢀNHC catalyzed C(sp3)–H functionalization,
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