Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl Bromides

Article abstract of DOI:10.1016/j.chempr.2020.04.006

Although Ru-catalyzed meta-selective sp² C–H alkylation with secondary alkyl halides is well established, ortho selectivity has never been achieved. We demonstrate that the use of a cyclometalated Ru-complex, RuBnN, as the catalyst results in a complete switch of the inherent meta-selectivity to ortho selectivity in the Ru-catalyzed sp² C–H alkylation reaction with unactivated secondary alkyl halides. The high catalytic activity of RuBnN allows mild reaction conditions that result in a transformation of broad scope and versatility. Preliminary mechanistic studies suggest that a bis-cycloruthenated species is the key intermediate undergoing oxidative addition with the alkyl bromides, thus avoiding the more common SET pathway associated with meta-selectivity. Direct C–H functionalization is a powerful tool for milder and more environmentally friendly syntheses of biologically active compounds, as well as offering easy access to unexplored chemical space in drug discovery. However, major challenges remain for these methods to be widely applicable. The development of new catalysts with diverse and superior reactivity is key to address these challenges. Here, we show for the first time that cyclometalated Ru-complexes are able to catalyze the directed ortho-C–H alkylation of arenes with secondary alkyl bromides, enabling the late-stage functionalization and diversification of pharmaceuticals. The obtained regioselectivity is in stark contrast to that delivered by the commonly used arene-bound Ru-complexes, which afford exclusive meta-alkylation. Our work points a way to further rationally design next-generation Ru-catalysts with improved control over selectivity and reactivity, and a richer synthetic toolbox for chemists in the future. Here, we report the first ortho-selective sp² C–H bond alkylation with secondary alkyl bromides in the Ru catalytic platform, enabled by cyclometalated ruthenium(II) complex RuBnN. Mechanistic studies indicate that the formation of a bis-cycloruthenated intermediate enables an oxidative addition to occur, thus avoiding the single-electron transfer (SET) pathway associated with meta-selectivity in other Ru catalytic systems. The reaction is tolerant of a variety of medicinally relevant functional groups and has been used to modify existing pharmaceuticals.

Full text of DOI:10.1016/j.chempr.2020.04.006

ll
Article
Cyclometalated Ruthenium Catalyst Enables
Ortho-Selective C–H Alkylation with
Secondary Alkyl Bromides
Gang-Wei Wang, Matthew
Wheatley, Marco Simonetti,
Diego M. Cannas, Igor Larrosa
igor.larrosa@manchester.ac.uk
HIGHLIGHTS
Cyclometalated Ru-complex,
RuBnN, used as the catalyst
Complete switch of meta- to ortho
selectivity in sp2 C–H bond
alkylation
Bis-cycloruthenated intermediate
enables SN2-type oxidative
addition
Late-stage functionalization and
diversification of pharmaceutical
compounds
Here, we report the first ortho-selective sp2 C–H bond alkylation with secondary
alkyl bromides in the Ru catalytic platform, enabled by cyclometalated
ruthenium(II) complex RuBnN. Mechanistic studies indicate that the formation of a
bis-cycloruthenated intermediate enables an oxidative addition to occur, thus
avoiding the single-electron transfer (SET) pathway associated with meta-
selectivity in other Ru catalytic systems. The reaction is tolerant of a variety of
medicinally relevant functional groups and has been used to modify existing
pharmaceuticals.
Wang et al., Chem 6, 1–10
June 11, 2020 ª 2020 The Authors. Published by
Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.04.006

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Cyclometalated Ruthenium Catalyst
Enables Ortho-Selective C–H Alkylation
with Secondary Alkyl Bromides
Gang-Wei Wang,1,2 Matthew Wheatley,1,2 Marco Simonetti,1 Diego M. Cannas,1 and Igor Larrosa1,3,
*
SUMMARY
The Bigger Picture
Although Ru-catalyzed meta-selective sp2 C–H alkylation with sec-
ondary alkyl halides is well established, ortho selectivity has never
been achieved. We demonstrate that the use of a cyclometalated
Ru-complex, RuBnN, as the catalyst results in a complete switch of
the inherent meta-selectivity to ortho selectivity in the Ru-catalyzed
sp2 C–H alkylation reaction with unactivated secondary alkyl ha-
lides. The high catalytic activity of RuBnN allows mild reaction con-
ditions that result in a transformation of broad scope and versatility.
Preliminary mechanistic studies suggest that a bis-cycloruthenated
species is the key intermediate undergoing oxidative addition
with the alkyl bromides, thus avoiding the more common SET
pathway associated with meta-selectivity.
Direct C–H functionalization is a
powerful tool for milder and more
environmentally friendly
syntheses of biologically active
compounds, as well as offering
easy access to unexplored
chemical space in drug discovery.
However, major challenges
remain for these methods to be
widely applicable. The
development of new catalysts with
diverse and superior reactivity is
key to address these challenges.
Here, we show for the first time
that cyclometalated Ru-
INTRODUCTION
The design of new catalysts exhibiting diverse and superior reactivity lies at the heart
of modern synthetic method development. Their discovery is pivotal for improving
both the efficiency and synthetic utility of existing chemical transformations, as well
as unlocking previously inaccessible reaction pathways toward difficult-to-make
compounds.1–3 In this context, the development of catalytic systems for C–C bond
formation through C–H functionalization has received significant attention over
the last two decades.4–8 Despite major advances in the formation of Csp2–Csp2
bonds through C–H activation,9–12 comparatively few methods have been devel-
oped for the more challenging C–H alkylation of arenes, particularly with secondary
alkyl halides.13–16 Over the last decade, significant advances on Pd,17 Ni,18–22 Co,23–
28 Mn,29 and Fe30–32 catalyzed directed alkylations with secondary alkyl halides have
been reported; however, important limitations still exist. For example, the majority
of methods are limited to the ortho-alkylation of benzamides, use a large bidentate
directing group, and require high temperatures (100ꢀC–160ꢀC). Those using Co,
Mn, and Fe generally require 3–4 equiv of alkyl Grignard as additives, heavily
reducing functional-group compatibility as well as in some cases leading to side
Grignard-alkylation products. Ru-catalyzed alkylations with unactivated secondary
alkyl halides have also been reported, displaying good compatibility with a wide va-
riety of directing groups.33–44 To date, every example of these Ru-catalyzed alkyl-
ations deliver exclusively the meta-alkylation product (Scheme 1A). This is in contrast
to Ru-catalyzed alkylations by using primary alkyl halides and benzyl halides, which
deliver ortho-alkylation.45–47 The origin of meta-selectivity in these reactions has
been attributed to a single-electron transfer (SET) process generating an alkyl radical
that preferentially adds para to a RuIII–C bond, rather than at the Ru center. Conse-
quently, ortho selectivity with unactivated secondary alkyl halides is currently un-
known on the Ru catalytic platform.
complexes are able to catalyze the
directed ortho-C–H alkylation of
arenes with secondary alkyl
bromides, enabling the late-stage
functionalization and
diversification of pharmaceuticals.
The obtained regioselectivity is in
stark contrast to that delivered by
the commonly used arene-bound
Ru-complexes, which afford
exclusive meta-alkylation. Our
work points a way to further
rationally design next-generation
Ru-catalysts with improved
control over selectivity and
reactivity, and a richer synthetic
toolbox for chemists in the future.
Chem 6, 1–10, June 11, 2020 ª 2020 The Authors. Published by Elsevier Inc.
1
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Scheme 1. Ru-Catalyzed C–H Meta-Alkylation with Secondary Alkyl Halides versus Proposed Ortho-Alkylation
Our group has recently reported mechanistic studies on the Ru-catalyzed C–H ary-
lation of arenes that revealed a previously unknown key catalytic intermediate in
these processes (Scheme 1B).48–50 Our studies demonstrated that two units of sub-
strate are needed in the active species, bis-cyclometalated Ru-intermediate IV,
before oxidative addition with the aryl halide can occur. This mechanistic insight
led to the development of a novel class of Ru-catalysts bearing a cyclometalated
ligand instead of the otherwise ubiquitous h6-coordinated para-cymene ligand.50
We showed that the cyclometalated Ru-complex RuBnN was able to outperform
the previous state-of-the-art catalysts in the arylation of arenes, realizing very mild
conditions for the late-stage arylation and diversification of a large number of
drug and drug-like molecules containing a breadth of delicate functionalities.
We envisaged that the coordinatively saturated nature of I was responsible for the
observed SET pathway leading to meta-selectivity with secondary alkyl halides
1Department of Chemistry, School of Natural
Sciences, University of Manchester, Oxford Road,
Manchester M13 9PL, UK
(Scheme 1A). Thus, we hypothesized that the highly electron-rich bis-cyclometalated
Ru-intermediates, such as IV, with labile neutral ligands might be able to undergo
oxidative addition at the Ru-center instead, leading to hitherto unachieved ortho-
alkylation selectivity (Scheme 1C). However, this process might be considerably
more difficult than the corresponding arylation because of the lower reactivity to-
ward oxidative addition of secondary alkyl halides, originating from their relatively
electron-rich C–X bond and increased steric bulk.51–55
2These authors contributed equally
3Lead Contact
*Correspondence:
igor.larrosa@manchester.ac.uk
https://doi.org/10.1016/j.chempr.2020.04.006
2
Chem 6, 1–10, June 11, 2020

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Scheme 2. Preliminary Studies
RESULTS AND DISCUSSION
In order to test this hypothesis, we performed stoichiometric experiments using the
cyclometalated ruthenium complex Ru(oMe-ppy) (Scheme 2A; Figures S1–S4).
Similar to the previous observations with aryl halide coupling partners,50 treatment
of this complex with 4-bromotetrahydropyran 2a revealed no formation of the alkyl-
ation product. Gratifyingly, upon addition of 1 equiv of 2-(o-tolyl)pyridine (1a), for-
mation of the desired ortho-alkylation product 4aa was observed, reaching 60%
yield in 4 h. Remarkably, no meta-alkylation product was observed, suggesting
that the SET pathway previously observed with other Ru-catalysts is not operative
with this class of catalysts. Addition of pyridine (1 equiv) instead of 1a did not afford
any product formation as it failed to form the bis-cyclometalated intermediate
(Scheme S3); this in turn, rules out the possibility that 2-(o-tolyl)pyridine (1a) only
acts as a pyridine-type ligand to promote the reaction. These results are consistent
with the hypothesized requirement for the formation of a bis-cycloruthenated com-
plex of the type IV (Scheme 1C) in order to facilitate oxidative addition. Encouraged
by the unprecedented formation of ortho-alkylation product 4aa, we explored the
development of a Ru-catalyzed alkylation process (Schemes 2B and S4). We were
pleased to observe, when 5 mol % Ru(oMe-ppy) was employed as the catalyst in
the alkylation of 1b with 2a, 67% of ortho-alkylation (4ba and 5ba) was obtained,
with no trace of meta-alkylation being formed (Scheme 2B, entry 1). However, a small
amount of alkylated 4aa was obtained as a by-product resulting from alkylation of
the ligand in the Ru-catalyst. To our delight, when RuBnN was used as the
catalyst, side-product formation was completely suppressed (Scheme 2B, entry 2).
It is noteworthy that [Ru(p-cymene)Cl2]2 has been reported to deliver exclusive
Chem 6, 1–10, June 11, 2020
3

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
meta-alkylation of 1a with secondary alkyl halides at 100ꢀC.34–39 However, under our
reaction conditions, no alkylation products of 1a were observed with p-cymene cat-
alysts (Scheme 2B, entries 3–5). To the best of our knowledge, this is the first
example of a meta-to-ortho selectivity switch of a C–H alkylation with unactivated
secondary alkyl halides by changing the ligand environment at Ru.56 RuBnN affords
simple and mild conditions for ortho-alkylation, operating at only 50ꢀC and using
K2CO3 as the base, without the requirement for a carboxylate co-catalyst (Tables
S2–S5).
With the optimized conditions in hand, we examined the substrate scope with
respect to the heteroarene unit (Schemes 3A and S1). Substrates bearing electron-
ically diverse substituents at different positions were efficiently transformed into
the corresponding ortho-alkylated products in good-to-excellent yields. In addition
to methyl esters and aryl chlorides, unprotected benzylic alcohols were tolerated
(4ga, 4ha, and 4ia). Where symmetrical substrates were used, minimal or trace
amounts of bis-ortho-alkylation product were obtained. Notably, the alkylation is
highly selective for mono-alkylation with substrates bearing meta-substituents,
and alkylation occurred exclusively at the less sterically hindered ortho-position
(4la and 4ma).57 Other heteroarenes, such as quinolines and pyrimidines, were
also found to be suitable directing groups, producing the corresponding ortho-alky-
lated products 4pa and 4qa in excellent yields.
After this, we investigated the scope of alkyl bromides (Schemes 3B and S2).
Different bromo-substituted carbocycles exhibited high reactivity and yielded the
products in excellent yield (4nb–4nc). Alkyl bromides bearing a wide variety of func-
tional groups and heteroarenes were compatible with our catalytic system. Piperi-
dine units are tolerated (4nd–4ah), a key structural motif in numerous natural prod-
ucts and pharmaceuticals.58,59 Although free N–H are not tolerated, amines
protected in the form of carbamate (4nd), benzyl amines (4ne), and amides (4nf–
4ah) were all compatible with the reaction conditions leading to good-to-excellent
yields of the corresponding products. Heteroaryls, such as furan (4nf), N-methyl-pyr-
role (4ng),60 and thiophene (4ah), were also supported motifs. Acyclic secondary
alkyl bromides were also tested. Interestingly, 2-bromopropane 2i led to ortho-alkyl-
ation product 4ni in 50% yield, and a small amount of meta-alkylation was observed
(Table S1), indicating a possible competition between oxidative addition to Ru and
SET pathways for these substrates. Gratifyingly, the meta-alkylation products were
suppressed when using meta-substituted phenyl pyridine substrates, leading to
good yields of the desired ortho-alkylated products with a range of acyclic alkylating
partners (4mi–4mk). It is noteworthy that in previously reported Ru-catalyzed C–H
alkylation with secondary alkyl halides, meta-substituted phenyl pyridines afforded
instead exclusively meta-alkylation or no reaction.34,37,38
Taking advantage of the mild reaction conditions of our new ortho-alkylation system, we
attempted the late-stage diversification of a series of pharmaceuticals and natural prod-
ucts (Scheme 3C). Accordingly, a series of alkyl bromides was prepared either through
conversion of an alcohol in the substrate or via amide coupling of a carboxylic acid with
4-bromopiperidine. The structurally complex cyclic alkyl bromides 2l and 2m, prepared
from epiandrosterone and cholesterol, respectively, reacted smoothly to the corre-
sponding ortho-alkylation products in good-to-excellent yields (4dl and 4am). Notably,
a single diastereoisomer was obtained in both cases (vide infra).
This reaction tolerates various functional groups relevant to medicinal chemistry,
such as: amides; terminal, conjugated, and internal alkenes (4an, 4ao, and 4ap);
4
Chem 6, 1–10, June 11, 2020

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Scheme 3. Heteroarene-Directed Ortho-C–H Alkylation
Reactions carried out on a scale of 0.20 mmol of 1. Isolated yields of 4 and 5 are given. Reaction carried out at 30ꢀC. bReaction carried out for 72 h.
a
Chem 6, 1–10, June 11, 2020
5

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Scheme 4. Ketimine-Directed Ortho-C–H Alkylation
Reactions carried out on a scale of 0.20 mmol of 6. Isolated yields of 7 are given. aA small amount of meta-alkylation product was obtained. See
Supplemental Information for details.
sulfonamides (4nq and 4ar); aryl and alkyl ketones (4as and 4dl); oxazole (4at); and
N-Boc-proline (4au), and the desired ortho-alkylated products formed in moderate
to good yields. A pyrene61 containing bromoalkane was also a suitable alkylating
partner under our reaction conditions (4av). Furthermore, the late-stage functional-
ization of diazepam was achieved, leading to ortho-alkylated 4ra. This result further
demonstrated the applicability of our alkylation protocol and encouraged us to
investigate its application to the synthetically versatile ketimine directing group
(Scheme 4). Without any further optimization, ketimine-based substrate 6a reacted
smoothly with simple alkyl electrophiles, delivering the corresponding ortho-alky-
lated arylketones 7aa, 7ab, and 7ae in good yields, after an in situ hydrolysis. Sub-
sequently, different ketimines were examined in the reaction under the standard
conditions. Ortho-substitution had a significant negative effect on the reaction
(7bb), whereas meta-substitution could be tolerated (7cb). It is noteworthy that
ortho- and meta-substituted ketimines have not been shown to be competent in
Ru-catalyzed meta-alkylation manifolds.37 Notably, the reaction performed better
with ketimines bearing an electron-donating substituent at the para position, with
7eb and 7fb produced in 43% and 53% yields, respectively. However, lower yields
were delivered when electron withdrawing substitutions were introduced.62 Com-
plex alkyl bromide 2q was also successfully transformed into desired product 7aq
in the reaction, albeit in a lower yield.
Careful analysis of the stereochemical outcome of the alkylation reactions of deox-
ybromo-androsterone derivatives 3a-2l and 3b-2l revealed important differences
between our method and previous methods involving radical intermediates. Indeed,
when 3a-2l was submitted to the reaction conditions (Scheme 5A), 3b-4dl was ob-
tained as the only stereoisomer in excellent yield (83%). Conversely, previously re-
ported use of 2l in radical mediated C–C bond-forming processes led to varying ra-
tios from 1.4:1 to 6.7:1 of diastereomeric mixtures.63–67 The analysis of the
recovered starting material showed that 3b-2l, resulting from the epimerization of
3a-2l, was obtained in a significant amount. Intriguingly, when 3b-2l was used as
the coupling partner, the overall reaction was more sluggish but led to the formation
of the same equatorially substituted product 3b-4dl with epimerized 3a-2l detected
only in a trace amount. This observation is consistent with a more hindered SN2-
based oxidative addition on the equatorial C–Br bond of 3b-2l.68,69 Instead, we
found that 3b-2l can slowly epimerize under the reaction conditions to 3a-2l
(Schemes 5B and S5), which is then able to react smoothly to afford 3b-4dl. The
detection of only a trace amount of epimerized 3a-2l in the catalytic reaction not
only confirmed the slow epimerization of 3b-2l, but also indicated
a fast
6
Chem 6, 1–10, June 11, 2020

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
Scheme 5. Stereochemical Outcome of the Oxidative Addition Step
consumption of 3a-2l. These results, together with our preliminary stoichiometric ex-
periments (Scheme 2), are consistent with an SN2-type oxidative addition process,
with inversion of configuration, at the bis-cycloruthenated species IV.
In summary, we have demonstrated that cyclometalated ruthenium catalyst RuBnN
provides a distinct regiochemical outcome to previous non-cyclometalated (p-cym-
ene)Ru(II)-catalysts. This work provides a new platform for ortho-alkylation with un-
activated secondary alkyl bromides. Preliminary mechanistic studies are suggestive
of a SN2-type oxidative addition at a bis-cyclometalated Ru(II) intermediate. This is in
stark contrast to previous Ru(II)-catalyzed alkylations which are proposed to proceed
through an SET pathway and deliver meta-alkylated products. The transformation,
realized under mild conditions, exhibits a broad substrate scope and shows excel-
lent functional-group compatibility. Both heteroarenes and ketimines are suitable
directing groups and the synthetic utility of this new catalyst has been demonstrated
on the late-stage diversification and alkylation of pharmaceuticals and natural
products.
EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources and reagents should be directed to
and will be fulfilled by the Lead Contact, Igor Larrosa (igor.larrosa@manchester.
ac.uk).
Materials Availability
Unique and stable reagents generated in this study will be made available on
request, but we may require a payment and/or a completed Materials Transfer
Agreement if there is potential for commercial application.
Data and Code Availability
Metrical parameters for X-ray structures are available free of charge from the Cam-
bridge Crystallographic Data Centre (CCDC) under reference numbers 4ba:
1969096; 4ng: 1969097.
Representative Method for Ortho-Alkylation Process
In a glove box, an oven-dried crimp-cap microwave vial equipped with a magnetic
stirring bar was charged with RuBnN (5.44 mg, 0.01 mmol) and K2CO3 (82.8 mg,
Chem 6, 1–10, June 11, 2020
7

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
0.6 mmol), followed by addition of substrates 1a (33.8 mg, 0.20 mmol), 2a (34.2 mg,
0.21 mmol), and N-methyl-2-pyrrolidone (1.0 mL). The vial was then capped, taken
out of the glovebox, and stirred at 50ꢀC for 18 h. The reaction was then allowed to
cool to room temperature before being quenched with H2O (10 mL) and extracted
with Et2O (3 3 10 mL). The organic extracts were combined, washed with brine
(15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture
was purified by column chromatography (10% EtOAc/Hex) to yield the 4aa (41.7 mg,
82%) as a colorless solid.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.04.006.
ACKNOWLEDGMENTS
We gratefully acknowledge the Engineering and Physical Sciences Research Council
(EPSRC, EP/S02011X/1) for funding and the European Research Council for an
Advanced Grant (RuCat) to I.L. We are grateful to In˜ igo J. Vitorica-Yrezabal (UoM)
for X-ray crystallography.
AUTHOR CONTRIBUTIONS
M.S., D.M.C., and I.L. conceived the project. M.S. and D.M.C. carried out initial dis-
covery work. G.-W.W. and M.W. contributed equally to the design of experiments,
optimization of the methodology, and exemplification of the chemistry. I.L. secured
the funding and directed the work. The manuscript was prepared with contributions
from all authors.
DECLARATION OF INTERESTS
A patent protecting the findings disclosed in this manuscript has been filed by the
University of Manchester.
Received: February 21, 2020
Revised: March 23, 2020
Accepted: April 8, 2020
Published: May 4, 2020
REFERENCES
1. Freeze, J.G., Kelly, H.R., and Batista, V.S. (2019).
Search for catalysts by inverse design: artificial
intelligence, mountain climbers, and
6. Gandeepan, P., and Ackermann, L. (2018).
Transient directing groups for transformative
CÀH activation by synergistic metal catalysis.
Chem 4, 199–222.
11. Daugulis, O. (2010). Palladium and copper
catalysis in regioselective, intermolecular
coupling of C-H and C-Hal bonds. Top. Curr.
Chem. 292, 57–84.
alchemists. Chem. Rev. 119, 6595–6612.
7. Lyons, T.W., and Sanford, M.S. (2010).
Palladium-catalyzed ligand-directed CÀH
functionalization reactions. Chem. Rev. 110,
1147–1169.
12. Simonetti, M., Cannas, D.M., and Larrosa, I.
(2017). Biaryl synthesis via C–H bond activation:
strategies and methods. In Advances in
Organometallic Chemistry, P.J. Pe´ rez, ed.
(Elsevier), pp. 299–399.
2. Houk, K.N., and Cheong, P.H.-Y. (2008).
Computational prediction of small-molecule
catalysts. Nature 455, 309–313.
3. Ahn, S., Hong, M., Sundararajan, M., Ess, D.H.,
and Baik, M.-H. (2019). Design and
optimization of catalysts based on mechanistic
insights derived from quantum chemical
reaction modeling. Chem. Rev. 119, 6509–
6560.
8. He, J., Wasa, M., Chan, K.S.L., Shao, Q., and Yu,
J.-Q. (2017). Palladium-catalyzed
13. Evano, G., and Theunissen, C. (2019). Beyond
Friedel and Crafts: directed alkylation of CÀH
bonds in arenes. Angew. Chem. Int. Ed. 58,
7202–7236.
transformations of alkyl CÀH bonds. Chem.
Rev. 117, 8754–8786.
9. Alberico, D., Scott, M.E., and Lautens, M.
(2007). ArylÀaryl bond formation by transition-
metal-catalyzed direct arylation. Chem. Rev.
107, 174–238.
14. Evano, G., and Theunissen, C. (2019). Beyond
Friedel and crafts: innate alkylation of CÀH
bonds in arenes. Angew. Chem. Int. Ed. 58,
7558–7598.
4. Bergman, R.G. (2007). Organometallic
chemistry: C–H activation. Nature 446,
391–393.
10. McGlacken, G.P., and Bateman, L.M. (2009).
Recent advances in aryl–aryl bond formation by
direct arylation. Chem. Soc. Rev. 38, 2447–
2464.
5. Shilov, A.E., and Shul’pin, G.B. (1997).
Activation of C–H bonds by metal complexes.
Chem. Rev. 97, 2879–2932.
15. Chen, Z., Rong, M.-Y., Nie, J., Zhu, X.-F., Shi,
B.-F., and Ma, J.-A. (2019). Catalytic alkylation
of unactivated C(sp3)-H bonds for C(sp3)-C(sp3)
8
Chem 6, 1–10, June 11, 2020

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
bond formation. Chem. Soc. Rev. 48, 4921–
4942.
30. Fruchey, E.R., Monks, B.M., and Cook, S.P.
(2014). A unified strategy for iron-catalyzed
Ortho-alkylation of carboxamides. J. Am.
Chem. Soc. 136, 13130–13133.
the alkylarylation of alkenes. J. Am. Chem. Soc.
141, 13914–13922.
16. Ackermann, L. (2010). Metal-catalyzed direct
alkylations of (hetero)arenes via C–H bond
cleavages with unactivated alkyl halides.
Chem. Commun. (Camb.) 46, 4866–4877.
44. Li, G., Jia, C., Cai, X., Zhong, L., Zou, L.,
and Cui, X. (2019). Ruthenium-catalyzed
meta-C–H bond alkylation of aryl 2-pyridyl
ketones. Chem. Commun. (Camb.) 56,
293–296.
31. Ilies, L., Matsubara, T., Ichikawa, S., Asako, S.,
and Nakamura, E. (2014). Iron-catalyzed
directed alkylation of aromatic and olefinic
carboxamides with primary and secondary alkyl
tosylates, mesylates, and halides. J. Am. Chem.
Soc. 136, 13126–13129.
17. Zhang, S.-Y., Li, Q., He, G., Nack, W.A., and
Chen, G. (2015). Pd-catalyzed monoselective
ortho-CÀH alkylation of N-quinolyl
45. Ackermann, L., Nova´k, P., Vicente, R., and
Hofmann, N. (2009). Ruthenium-catalyzed
regioselective direct alkylation of arenes with
unactivated alkyl halides through CÀH bond
cleavage. Angew. Chem. Int. Ed. 48, 6045–
6048.
benzamides: evidence for stereoretentive
coupling of secondary alkyl iodides. J. Am.
Chem. Soc. 137, 531–539.
32. Cera, G., Haven, T., and Ackermann, L. (2016).
Expedient iron-catalyzed C-H allylation/
alkylation by triazole assistance with ample
scope. Angew. Chem. Int. Ed. 55, 1484–1488.
18. Song, W., Lackner, S., and Ackermann, L.
(2014). Nickel-catalyzed C–H alkylations: direct
secondary alkylations and trifluoroethylations
of arenes. Angew. Chem. Int. Ed. 53, 2477–
2480.
46. Ackermann, L., and Nova´k, P. (2009).
Regioselective ruthenium-catalyzed
direct benzylations of arenes through
CÀH bond cleavages. Org. Lett. 11, 4966–
4969.
33. Leitch, J.A., and Frost, C.G. (2017). Ruthenium-
catalysed s-activation for remote meta-
selective CÀH functionalisation. Chem. Soc.
Rev. 46, 7145–7153.
19. Ruan, Z., Lackner, S., and Ackermann, L. (2016).
A general strategy for the nickel-catalyzed C–H
alkylation of anilines. Angew. Chem. Int. Ed. 55,
3153–3157.
34. Hofmann, N., and Ackermann, L. (2013). meta-
Selective CÀH bond alkylation with secondary
alkyl halides. J. Am. Chem. Soc. 135, 5877–
5884.
47. Ackermann, L., Hofmann, N., and Vicente, R.
(2011). Carboxylate-assisted ruthenium-
catalyzed direct alkylations of ketimines. Org.
Lett. 13, 1875–1877.
20. Ghorai, D., Finger, L.H., Zanoni, G., and
Ackermann, L. (2018). Bimetallic nickel
complexes for aniline CÀH alkylations. ACS
Catal. 8, 11657–11662.
35. Li, J., Warratz, S., Zell, D., De Sarkar, S.,
Ishikawa, E.E., and Ackermann, L. (2015). N-
Acyl amino acid ligands for ruthenium(II)-
catalyzed meta-CÀH tert-alkylation with
removable auxiliaries. J. Am. Chem. Soc. 137,
13894–13901.
48. Simonetti, M., Perry, G.J.P., Cambeiro, X.C.,
Julia´-Herna´ndez, F., Arokianathar, J.N., and
Larrosa, I. (2016). Ru-Catalyzed C–H arylation of
fluoroarenes with aryl halides. J. Am. Chem.
Soc. 138, 3596–3606.
21. Ruan, Z., Ghorai, D., Zanoni, G., and
Ackermann, L. (2017). Nickel-catalyzed C–H
activation of purine bases with alkyl
halides. Chem. Commun. (Camb.) 53, 9113–
9116.
49. Simonetti, M., Kuniyil, R., Macgregor, S.A., and
Larrosa, I. (2018). Benzoate cyclometalation
enables oxidative addition of haloarenes at a
Ru(II) center. J. Am. Chem. Soc. 140, 11836–
11847.
36. Li, G., Ma, X., Jia, C., Han, Q., Wang, Y., Wang,
J., et al. (2017). Ruthenium-catalyzed meta/
Ortho-selective CÀH alkylation of azoarenes
using alkyl bromides. Chem. Commun. (Camb.)
53, 1261–1264.
22. Soni, V., Jagtap, R.A., Gonnade, R.G., and
Punji, B. (2016). Unified strategy for nickel-
catalyzed C-2 alkylation of indoles
through chelation assistance. ACS Catal. 6,
5666–5672.
50. Simonetti, M., Cannas, D.M., Just-Baringo, X.,
Vitorica-Yrezabal, I.J., and Larrosa, I. (2018).
Cyclometallated ruthenium catalyst
enables late-stage directed
37. Li, J., Korvorapun, K., De Sarkar, S., Rogge, T.,
Burns, D.J., Warratz, S., et al. (2017).
Ruthenium(II)-catalysed remote CÀH
alkylations as a versatile platform to meta-
decorated arenes. Nat. Commun. 8, 15430.
23. Gao, K., and Yoshikai, N. (2013). Cobalt-
catalyzed Ortho alkylation of aromatic
imines with primary and secondary
alkyl halides. J. Am. Chem. Soc. 135, 9279–
9282.
arylation of pharmaceuticals. Nat. Chem. 10,
724–731.
38. Li, G., Gao, P., Lv, X., Qu, C., Yan, Q., Wang, Y.,
Yang, S., and Wang, J. (2017). Synthesis of m-
alkylphenols via a ruthenium-catalyzed CÀH
bond functionalization of phenol derivatives.
Org. Lett. 19, 2682–2685.
51. Rudolph, A., and Lautens, M. (2009). Secondary
alkyl halides in transition-metal-catalyzed
cross-coupling reactions. Angew. Chem. Int.
Ed. 48, 2656–2670.
24. Xu, W., and Yoshikai, N. (2017). Pivalophenone
imine as a benzonitrile surrogate for directed
C–H bond functionalization. Chem. Sci. 8,
5299–5304.
52. Ariafard, A., and Lin, Z. (2006). Understanding
the relative easiness of oxidative addition of
aryl and alkyl halides to palladium (0).
Organometallics 25, 4030–4033.
39. Paterson, A.J., Heron, C.J., McMullin, C.L.,
Mahon, M.F., Press, N.J., and Frost, C.G. (2017).
a-Halo carbonyls enable meta selective
primary, secondary and tertiary CÀH
alkylations by ruthenium catalysis. Org. Biomol.
Chem. 15, 5993–6000.
25. Chen, Q., Ilies, L., and Nakamura, E. (2011).
Cobalt-catalyzed Ortho-alkylation of
secondary benzamide with alkyl chloride
through directed C–H bond activation. J. Am.
Chem. Soc. 133, 428–429.
53. Luh, T.Y., Leung Mk, M.K., and Wong, K.T.
(2000). Transition metal-catalyzed activation
of aliphatic C-X bonds in carbon-
carbon bond formation. Chem. Rev. 100, 3187–
3204.
40. Korvorapun, K., Kaplaneris, N., Rogge, T.,
Warratz, S., Stuckl, A.C., and Ackermann, L.
¨
26. Mei, R., and Ackermann, L. (2016). Cobalt-
catalyzed C–H functionalizations by imidate
assistance with aryl and alkyl chlorides. Adv.
Synth. Catal. 358, 2443–2448.
(2018). Sequential meta-/ortho-C–H
functionalizations by one-pot ruthenium(II/III)
catalysis. ACS Catal. 8, 886–892.
54. Frisch, A.C., and Beller, M. (2005). Catalysts for
cross-coupling reactions with non-activated
alkyl halides. Angew. Chem. Int. Ed. 44,
674–688.
41. Gandeepan, P., Koeller, J., Korvorapun, K.,
Mohr, J., and Ackermann, L. (2019). Visible-
light-enabled ruthenium-catalyzed meta-CÀH
alkylation at room temperature. Angew. Chem.
Int. Ed. 58, 9820–9825.
27. Gao, K., Yamakawa, T., and Yoshikai, N. (2014).
Cobalt-catalyzed chelation-assisted alkylation
of arenes with primary and secondary alkyl
halides. Synthesis 46, 2024–2039.
55. Fu, G.C. (2017). Transition-metal catalysis of
nucleophilic substitution reactions: a radical
alternative to SN1 and SN2 processes. ACS
Cent. Sci. 3, 692–700.
28. Punji, B., Song, W., Shevchenko, G.A., and
Ackermann, L. (2013). Cobalt-catalyzed C–H
bond functionalizations with aryl and
alkyl chlorides. Chem. Eur. J. 19, 10605–
10610.
42. Sagadevan, A., and Greaney, M.F. (2019).
meta-Selective C-H activation of arenes at
room temperature using visible light: dual
function ruthenium catalysis. Angew. Chem.
Int. Ed. 58, 9826–9830.
56. Ackermann and coworkers have recently
shown a regioselectivity switch using
primary benzyl halides as coupling partners.
see: Korvorapun, K., Kuniyil, R., and
Ackermann, L. (2020). Late-stage diversification
by selectivity switch in meta-C–H activation:
evidence for singlet stabilization ACS Catal. 10,
435–440.
29. Shen, Z., Huang, H., Zhu, C., Warratz, S., and
Ackermann, L. (2019). MnCl2-catalyzed C–H
alkylation on azine heterocycles. Org. Lett. 21,
571–574.
43. Wang, X.G., Li, Y., Liu, H.C., Zhang, B.S., Gou,
X.Y., Wang, Q., et al. (2019). Three-component
ruthenium-catalyzed direct meta-selective
CÀH activation of arenes: a new approach to
Chem 6, 1–10, June 11, 2020
9

Please cite this article in press as: Wang et al., Cyclometalated Ruthenium Catalyst Enables Ortho-Selective C–H Alkylation with Secondary Alkyl
Bromides, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.006
ll
Article
57. The Meta-OMe substituted
2-phenylpyridine derivative only yielded the
desired product in a very low yield (<10% NMR
yield).
63. Wang, C., and Dong, G. (2018). Direct
b-alkylation of ketones and aldehydes via Pd-
catalyzed redox cascade. J. Am. Chem. Soc.
140, 6057–6061.
alkyl bromides. J. Am. Chem. Soc. 135,
616–619.
67. Yan, X.B., Li, C.L., Jin, W.J., Guo, P., and Shu,
X.Z. (2018). Reductive coupling of benzyl
oxalates with highly functionalized alkyl
bromides by nickel catalysis. Chem. Sci. 9,
4529–4534.
64. Wang, G.Z., Shang, R., Cheng, W.M., and Fu, Y.
(2017). Irradiation-induced heck reaction
of unactivated alkyl halides at room
temperature. J. Am. Chem. Soc. 139, 18307–
18312.
58. Pinder, A.R. (1990). Pyrrolidine, piperidine,
and pyridine alkaloids. Nat. Prod. Rep. 7,
447–455.
59. O’Hagan, D. (2000). Pyrrole, pyrrolidine,
pyridine, piperidine and tropane alkaloids.
Nat. Prod. Rep. 17, 435–446.
68. Eliel, E.L., and Haber, R.G. (1959).
Conformational analysis. VII. Reaction of
alkylcyclohexyl bromides with thiophenolate.
The conformational equilibrium constant of
bromine. J. Am. Chem. Soc. 81, 1249–1254.
65. Sargent, B.T., and Alexanian, E.J. (2016).
Palladium-catalyzed alkoxycarbonylation
of unactivated secondary alkyl bromides
at low pressure. J. Am. Chem. Soc. 138, 7520–
7523.
60. CCDC number for 4ba: 1969096; CCDC
number for 4ng: 1969097.
69. Hartwig, J.F. (2010). Oxidative addition of
polar reagents. In Organotransition
Metal Chemistry – From Bonding to
Catalysis (University Science books),
pp. 301–320.
}
61. Figueira-Duarte, T.M., and Mullen, K. (2011).
66. Xiao, B., Liu, Z.J., Liu, L., and Fu, Y. (2013).
Palladium-catalyzed CÀH activation/
cross-coupling of pyridine
Pyrene-based materials for organic electronics.
Chem. Rev. 111, 7260–7314.
62. See Supplemental Information for details.
N-oxides with nonactivated secondary
10
Chem 6, 1–10, June 11, 2020