Regiodivergent C?H and Decarboxylative C?C Alkylation by Ruthenium Catalysis: ortho versus meta Position-Selectivity

Article abstract of DOI:10.1002/anie.202007144

Ruthenium(II)biscarboxylate complexes enabled the selective alkylation of C?H and C?C bonds at the ortho- or meta-position. ortho-C?H Alkylations were achieved with 4-, 5- as well as 6-membered halocycloalkanes. Furthermore, the judicious choice of the directing group allowed for a full control of ortho-/meta-selectivities. Detailed mechanistic studies by experiment and computation were performed and provided strong support for an oxidative addition/reductive elimination process for ortho-alkylations, while a homolytic C?X cleavage was operative for the meta-selective transformations.

Full text of DOI:10.1002/anie.202007144

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Accepted Article
Title: Regiodivergent C–H and C–C Alkylation by Ruthenium Catalysis:
ortho versus meta Position-Selectivity
Authors: Korkit Korvorapun, Marc Moselage, Julia Struwe, Torben
Rogge, Antonis Messinis, and Lutz Ackermann
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10.1002/anie.202007144
Angewandte Chemie International Edition
RESEARCH ARTICLE
Regiodivergent C–H and Decarboxylative Alkylation by
Ruthenium Catalysis: ortho versus meta Position-Selectivity
Korkit Korvorapun+, Marc Moselage+, Julia Struwe, Torben Rogge, Antonis M. Messinis, and Lutz
Ackermann*
Dedication ((optional))
Abstract: Ruthenium(II)biscarboxylate complexes enabled the
selective alkylation of C–H and C–C bonds at the ortho- or meta-
position. ortho-C–H Alkylations were achieved with 4-, 5- as well as 6-
membered halocycloalkanes. Furthermore, the judicious choice of the
directing group allowed for a full control of ortho-/meta-selectivities.
Detailed mechanistic studies by experiment and computation were
performed and provided strong support for an oxidative
addition/reductive elimination process for ortho-alkylations, while a
homolytic C–X cleavage was operative for the meta-selective
transformations.
Within our program on sustainable C–H activations,[12] we have
now unraveled ruthenium-catalyzed ortho- or meta-alkylations
through C–H or decarboxylative C–C/C–H activations (Scheme
1b). Notable feature of our strategy include (i) versatile ruthenium-
catalyzed meta- as well as ortho-alkylations with secondary alkyl
bromides, (ii) functionalization of synthetically useful pyrazoles
through C–H or decarboxylative C–C/C–H activations, (iii) detailed
mechanistic insights by experiment, and (iv) DFT studies for
ruthenium-catalyzed ortho-C–H alkylations.
Introduction
Methods for the direct modification of otherwise inert C–H bonds
gained enormous attention throughout the last decade.[1] For the
development of synthetically useful molecular transformations,
the full control of positional selectivity is of prime importance for
C–H functionalization reactions.[2] One important strategy for site-
selective C–H activations is the use of chelation-assistance
through the introduction of directing groups, thus allowing for
proximity-induced ortho-C–H metalation.[3] During the past years,
ruthenium catalysis was particularly recognized as an efficient
tool for C–H functionalizations and a plethora of ruthenium-
catalyzed C–H transformations was developed.[4] Especially, site-
selective ortho-,[5] meta-[6] as well as para-alkylations[7] of arenes
were devised by ruthenium catalysis, with major contributions by
the groups of Frost,[8] and Ackermann,[9] among others.[10]
Typically, secondary and tertiary alkyl halides result in C–H
alkylations at the meta- or para-position with excellent levels of
selectivity. In contrast, ortho-alkylated arenes were thus far
predominantly obtained with primary alkyl halides (Scheme 1a).
Likewise, ruthenium catalysis proved to be powerful for C–C bond
transformations, with notable progress by inter alia Dong and
Hartwig.[11] Inspired by the versatility and robustness of the
ruthenium catalyst, we became intrigued whether this C–C bond
functionalization could be exploited for alkylation with unactivated
alkyl halides.
Scheme 1. Ruthenium-catalyzed site-selective alkylations.
K. Korvorapun,[+] Dr. M. Moselage,[+] J. Struwe, Dr. T. Rogge, Dr. A.
M. Messinis, Prof. Dr. L. Ackermann
Results and Discussion
[*]
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
In orienting experiments, we first examined the C–H alkylation of
2-phenylpyridine (1) with bromocyclohexane (2a), which provided
the corresponding meta-alkylated product 4 in moderate yield
(Scheme 2a). However, ortho-C–H alkylated product 6aa was
obtained when pyrazole 5a was reacted with secondary alkyl
bromide 2a (Scheme 2b).
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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[a] Reaction conditions: 5a (0.5 mmol), 2a (1.5 mmol), [Ru] (5.0 mol %),
MesCO2H (30 mol %), K2CO3 (1.0 mmol), PhCMe3 (1.0 mL), 120 °C, 16 h,
yields of isolated products.
We next examined the effect of the halocycloalkane 2 ring size on
the site-selectivity of the C–H alkylation reaction (Scheme 3). The
reaction
of
unsubstituted
phenylpyrazole
5a
with
bromocyclobutane (2b) and bromocyclohexane (2a) afforded the
ortho-alkylated products 6aa and 6ab as the major product,
whereas bromocycloheptane (2d) and bromocyclooctane (2e)
preferentially furnished the meta-alkylated product 7 (Scheme 2a).
In contrast, bromocyclopentane (2c) yielded a mixture of the
ortho- and meta-alkylated products 6ac and 7ac. Then, we
probed the alkylation of arylpyrazoles 5 with primary as well as
secondary alkyl bromides 2 (Scheme 3b). The alkylation reaction
of arylpyrazoles 5 with exo-2-bromonorbornane (2f) or neopentyl
bromide (2i) afforded the ortho-alkylated products 6af, 6ai, and
6bi exclusively. Acyclic secondary alkyl bromides 2g and 2h were
smoothly converted into meta-alkylated products 7ag and 7ah
with excellent levels of positional selectivity.
Scheme 2. Site-selective C─H alkylations.
Intrigued by these unexpected results, we became interested in
investigating the C–H alkylation of arylpyrazole 5a. To this end,
different reaction conditions were probed for the ruthenium-
catalyzed C–H alkylation with bromocyclohexane (2a) (Table
[9f]
1).[13] PhCMe3 proved to be the optimal solvent (entries 1–2).
Furthermore, carboxylic acids[14] were found to be critical for
achieving high conversions (entry 3). Previously, we and Larrosa
had employed p-cymene-ligand-free ruthenium complexes for C–
H activation.[5a, 15] Cationic ruthenium(II) complexes could also
here be employed as catalysts (entries 4–8). In addition,
cyclohexyl chloride or iodide also afforded products 6aa and 7aa
with positional selectivity, albeit in somewhat reduced yield
(entries 9–10).
Table 1. Ruthenium-catalyzed C–H alkylation of pyrazole 5a
Entry
Deviation from the standard conditions
none
6aa [%]
60
7aa [%]
1
2
3
4
5
6
7
8
12
---
---
8
o-xylene instead of PhCMe3
without MesCO2H
50
28
[Ru(NCt-Bu)6][BF4]2 instead of 3
[Ru(NCt-Bu)6][PF6]2 instead of 3
[Ru(NCt-Bu)6][SbF6]2 instead of 3
[Ru(NCMe)6][PF6]2 instead of 3
60
62
10
9
63
65
12
---
[Ru(NCMe)6][PF6]2 instead of 3 and
---
without MesCO2H
9
Cy–Cl instead of 2a
Cy–I instead of 2a
38
53
5
7
10
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Scheme 4. Electronic effect on the site-selectivity of ruthenium-catalyzed C–H
alkylations of arylpyrazoles 5 with bromocyclohexane (2a). [a] The yield of meta-
alkylated product 7 is given in parentheses. [b] Dialkylated product was obtained
in 29% yield.
Scheme 3. (a) Site-selectivity of ruthenium-catalyzed C–H alkylations of
pyrazole 5a with various bromocycloalkanes 2, (b) scope for C–H alkylation of
pyrazoles 5. [a] The yield of meta-alkylated product 7 is given in parentheses.
[b] o-Xylene was used as solvent.
In contrast to arylpyrazoles 5a–5f, the direct alkylation of
3,5-dimethyl-1-phenyl-1H-pyrazole (5g) with cyclic and acyclic
secondary alkyl bromides 2 exclusively provided the meta-
alkylated products 7 (Scheme 4). In addition, the alkylation with
neopentyl bromide (2i) selectively furnished the meta-alkylated
adduct 7gi, albeit in lower yield.
Next, the electronic effect on the site-selectivity was studied with
differently substituted arylpyrazoles 5 with cyclohexyl bromide
(2a) (Scheme 4). Electron-donating groups at the para-position
led to a mixture of ortho- and meta-alkylated products 6 and 7,
whereas electron-withdrawing groups exclusively afforded the
ortho-alkylated products (6da–6fa). The connectivity of product
6fa was unambiguously assigned by X-ray diffraction analysis.[16]
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Scheme 5. Ruthenium-catalyzed C–H alkylation of phenylpyrazole 5g. [a] The
yield of di-meta-alkylated product is given in parentheses.
To understand the nature of the reaction mechanism, the
alkylation reaction was conducted in the presence of typical
radical
scavengers
(Scheme
6a).
While
2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO) fully inhibited the catalytic
reaction, the use of 1,1-diphenylethylene significantly reduced the
yield of the corresponding product 6aa. The isolation of adduct 8
was supportive of a homolytic C–X bond cleavage. The reaction
mechanism was further elucidated by the use of
diastereomerically-pure electrophiles 2j and 2k (Scheme 6b). The
reaction with endo-2-bromobornane (endo-2j) provided ortho-
alkylated product endo-6fj as well as a diastereomeric mixture of
meta-alkylated products 7fj. Similarly, the stereochemistry of tert-
17]
butylcyclohexyl bromide cis-2k and trans-2k[9f,
translated
directly into the corresponding ortho-alkylated products cis-6fk
and trans-6fk, respectively. These findings thus provide strong
support for a concerted oxidative addition/reductive elimination
mechanism to be operative for the ortho-alkylation. In contrast,
the meta-functionalized product 7fk was obtained as cis- and
trans-isomers from the reaction with the single isomer cis-2k,
which is indicative of the formation of an alkyl radical via a single-
electron transfer (SET) process. The stereochemistry and site-
selectivity of products 6 and 7 were confirmed by X-ray
analysis.[16]
Scheme 6. Key mechanistic studies: (a) reaction in the presence of radical
scavengers, (b) C–H alkylations with diastereomerically pure alkyl bromides 2.
Furthermore,
we prepared
the well-defined
cationic
cyclometalated ruthenium complexes Ru I and Ru II,[13] which
showed high catalytic activity in the presence of MesCO2H
(Scheme 7a). In contrast to the standard condition, the reaction of
phenylpyrazole 5g in the absence of an acid additive resulted in
a mixture of ortho- and meta-alkylated products 6ga and 7ga. In
addition, a substantial amount of decoordinated p-cymene was
observed in the initial period of the alkylation reaction (Scheme
7b).
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Figure 1. Relative Gibbs free energy profile for the oxidative addition/reductive
elimination elementary step at the PW6B95-D3(BJ)/def2-TZVP+COSMO(o-
xylene)//TPSS-D3(BJ)/def2-TZVP level of theory.
A distortion energy analysis of TS2 with different directing groups
revealed a substantially increased distortion energy, when the
3,5-dimethylpyrazole was employed (Figure 2).[13]
(a)
Scheme 7. (a) Reactions with cyclometalated complex as catalyst, (b) detection
of free p-cymene. [a] The yield in parentheses was determined by 1H-NMR using
1,3,5-trimethoxybenzene as the internal standard.
(b)
Mechanistic studies by means of density functional theory (DFT)
calculations were next conducted at the PW6B95-D3(BJ)/def2-
TZVP+COSMO(o-xylene)//TPSS-D3(BJ)/def2-TZVP level of
theory.[18] These findings reveal a facile oxidative addition of
cyclohexyl bromide/reductive elimination process to occur on
biscyclometalated ruthenium(II) intermediates with an energy
barrier of only 17.6 kcal mol–1 (Figure 1). Calculations with various
substituted arylpyrazoles indicated a rather minor influence of the
substrate’s electronic properties on the energy barriers for the
oxidative addition/reductive elimination elementary steps.
Figure 2. Distortion energy (a) for reductive elimination with different
heterocycles, (b) for radical addition with N-heterocycles.
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Furthermore, the ruthenium(II)carboxylate catalysis was also
found to facilitate decarboxylative alkylation reactions. Here
various reaction conditions for the envisioned decarboxylative
alkylation reaction of acid 10a with bromocycloheptane (2d) were
tested first (Table 2).[13] Carboxylate assistance significantly
improved the catalytic efficacy, with MesCO2H being the optimal
acid additive (entry 1–4).[14b] The reaction without an acid additive
gave a reduced yield (entry 2), presumably because the substrate
10a can itself act as carboxylate ligand. Control experiments
verified the essential role of the ruthenium catalyst (entry 5).
Having identified the optimal reaction conditions, we tested the
versatility towards different alkyl bromides 2 (Scheme 8). With
primary alkyl bromides 2i–2m, the C–H alkylation took place at
the ortho-position with excellent levels of regioselectivity. It is
noteworthy that the reaction of acid 10i and neopentyl bromide
(2i) afforded 40% of the desired product 6ii and 37% of the
ortho-xylylated product 6ii’ as
a
side-product,[16] which
presumably forms via H-atom abstraction from the o-xylene
solvent followed by benzylation. Similar to the C–H alkylation
reaction (vide supra), the decarboxylative alkylation of
bromocyclohexane (2a) and exo-2-bromonorbornane (2f)
furnished the ortho-alkylated products 6aa, 6af, and 6if with
excellent levels of site-selectivity. In contrast, reactions with a
broad range of acyclic alkyl bromides as well as cyclic alkyl
bromides resulted in a preferred meta-alkylation.[16] Inspired by a
recent meta-selective alkylation with α-bromoesters from our
group,[9c] we probed whether this reaction can be combined with
a C–C cleavage step. Indeed, slightly modified reaction conditions
allowed for the formation of the products 7ap–7jp via C–C/C–H
activation in high yields. Moreover, tertiary alkyl bromides reacted
in the decarboxylative alkylation regime solely with meta-
selectivity.
Furthermore,
the
well-defined
complex
[Ru(O2CMes)2(p-cymene)][19] turned out to be a competent
catalyst (entry 6). To our delight, the reaction also proceeded
under arene-ligand-free conditions using ruthenium-nitrile
complexes (entries 7–8). Other ruthenium sources such as
Ru3(CO)12 and RuCl3·(H2O)n failed to facilitate any conversion
(entries 9–10). Moreover, no product formation was observed
when the reaction was attempted with palladium, rhodium, cobalt,
or nickel complexes.[13]
Table 2. Optimization of ruthenium-catalyzed decarboxylative C–C alkylation of
10a
Entry
Deviation from the standard conditions
Yield (%)
1
2
3
4
5
none
73
39
49
56
---
without MesCO2H
1-AdCO2H instead of MesCO2H
PivOH instead of MesCO2H
without 3
[Ru(O2CMes)2(p-cymene)] instead of 3 and without
MesCO2H
6
70
7
8
[Ru(NCt-Bu)6][BF4]2 instead of 3
[Ru(NCt-Bu)6][SbF6]2 instead of 3
RuCl3·(H2O)n instead of 3
60
49
---
---
9
10
Ru3(CO)12 instead of 3
Pd(OAc)2, [Cp*RhCl2]2, [Cp*Co(CO)I2] or [Ni(cod)2]
as catalysts
11
---
[a] Reaction conditions: 10a (0.5 mmol), 2d (1.5 mmol), [Ru] (5.0 mol %),
additive (30 mol %), K2CO3 (1.0 mmol), o-xylene (1.0 mL), 120 °C, 16 h,
yields of isolated products.
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Finally, ozonolysis[20] of the alkylated arenes 6 or 7 provided
access to synthetically useful meta-alkylated acetanilides 11 in
remarkably good yields, highlighting the versatility of the
ruthenium-catalyzed direct C–H alkylation (Scheme 9).[16]
Scheme 9. Product diversification by ozonolysis.
Given the broad applicability of this decarboxylative alkylation
reaction, we became interested in unraveling its mode of action.
To this end, detailed mechanistic studies were performed
(Scheme 10). Reactions with radical scavengers led to a complete
or partial inhibition of the catalytic activity (Scheme 10a). In the
presence of TEMPO, the alkyl-TEMPO adduct 12 could be
detected and isolated, which is in line with a radical C–X bond
cleavage. Reactions in the presence of deuterated co-solvents
clearly indicated the organometallic character of the C–C
cleavage (Scheme 10b). In the absence of an alkyl bromide,
almost complete decarboxylation took place and significant
deuterium incorporation was observed at the ortho-position and
partly at the C3 and C5 position of the pyrazole, presumably due
to electrophilic activation. In the presence of alkyl bromide 2d, a
deuterium incorporation of 46% and 47% was observed at the
ortho-position of alkylated product [D]n-7ad. A considerable
decoordination of p-cymene was detected during the initial period
of the decarboxylative alkylation (Scheme 10c).
On the basis of our findings, a plausible catalytic cycle for the
ortho-selective alkylation commences by a carboxylate-assisted
C–H ruthenation and dissociation of p-cymene, thereby forming
the cyclometalated complex 14 (Scheme 11, left). A second
molecule of phenylpyrazole 5 coordinates to ruthenium complex
14 and undergoes C–H activation to form biscyclometalated
complex 15. The oxidative addition of alkyl bromide 2 to complex
15 generates the stable ruthenium(IV) intermediate 16/B (Figure
1). Finally, reductive elimination and ligand exchange deliver the
ortho-alkylated product 6 and ruthenacycle 14. In contrast, meta-
C–H alkylation occurs through a SET process from ruthenium(II)
complex 14 to alkyl bromide 2, forming ruthenium(III) intermediate
18 and a stabilized alkyl radical 19 (Scheme 11, right).
Subsequently, 19 preferentially attacks the position para to
Scheme 8. Ruthenium-catalyzed decarboxylative C–C alkylation. [a]
[RuCl2(p-cymene)]2 (5.0 mol %). [b] HCl adduct. [c] n-Octane instead of o-xylene
as solvent. [d] PPh3 (5.0 mol %), PhCMe3 instead of o-xylene.
ruthenium, thus leading to the formation of triplet ruthenium
9c]
intermediate 20.[9a,
Ligand-to-metal electron transfer and
rearomatization furnishes ruthenacycle 21, which undergoes
protodemetalation and C–H activation to furnish the desired meta-
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alkylated product 7 and regenerates the active ruthenium species
14.
Scheme 10. Key mechanistic findings: (a) reaction in the presence of radical
scavengers, (b) H/D scrambling experiments, (c) detection of free p-cymene.
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Scheme 11. Proposed catalytic cycle for ruthenium-catalyzed ortho- or meta-alkylation.
diastereomerically-pure alkyl bromdise unraveled an energetically
favorable novel mechanism for ortho-C–H secondary alkylations.
Conclusion
In summary, we have reported on a ruthenium-catalyzed C–H and
C–C activation allowing for ortho- and meta-alkylations of
synthetically useful pyrazoles. The steric properties of the
employed alkyl bromides and pyrazoles had a significant
influence on the position-selectivity of the alkylation reaction.
Mechanistic studies were suggestive of two distinct mechanisms,
an oxidative addition/reductive elimination event for the ortho-C–
H alkylation, while a SET pathway is proposed for meta-
functionalization. Moreover, an arene-ligand-free ruthenacycles
was identified as the key intermediate in this transformation.
Furthermore, computational studies and experiments with
Acknowledgements
Generous support by the DAAD (fellowship to K.K.) and the DFG
(SPP1807 and Gottfried-Wilhelm-Leibniz prize) is gratefully
acknowledged. We thank Dr. Christopher Golz (University
Göttingen) for the X-ray diffraction analysis.
Keywords: C–H activation • ruthenium • alkylation • C–C
activation • decarboxylation
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[1]
For selected reviews, see: a) S. Rej, Y. Ano, N. Chatani, Chem. Rev.
2020, 120, 1788–1887; b) P. Gandeepan, T. Müller, D. Zell, G. Cera,
S. Warratz, L. Ackermann, Chem. Rev. 2019, 119, 2192–2452; c)
C.-S. Wang, P. H. Dixneuf, J.-F. Soulé, Chem. Rev. 2018, 118,
7532–7585; d) C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer,
Chem. Rev. 2017, 117, 8908–8976; e) Y. Park, Y. Kim, S. Chang,
Chem. Rev. 2017, 117, 9247–9301; f) T. Gensch, M. N. Hopkinson,
F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 2016, 45, 2900–
2936; g) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102,
1731–1770.
For selected reviews, see: a) S. M. Khake, N. Chatani, Trends Chem.
2019, 1, 524–539; b) Y. Kommagalla, N. Chatani, Coord. Chem.
Rev. 2017, 350, 117–135; c) D. A. Colby, A. S. Tsai, R. G. Bergman,
J. A. Ellman, Acc. Chem. Res. 2012, 45, 814–825; d) S. R. Neufeldt,
M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946; e) D. A. Colby,
R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624–655; f) T.
W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169; g) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009,
48, 9792–9826.
For selected reviews on chelation-assisted C–H functionalization,
see: a) C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G.
Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord,
T. Besset, B. U. W. Maes, M. Schnürch, Chem. Soc. Rev. 2018, 47,
6603–6743; b) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang,
Org. Chem. Front. 2015, 2, 1107–1295; c) Z. Huang, H. N. Lim, F.
Mo, M. C. Young, G. Dong, Chem. Soc. Rev. 2015, 44, 7764–7786;
d) F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906–6919.
For selected reviews on ruthenium-catalyzed C–H functionalization,
see: a) C. Shan, L. Zhu, L.-B. Qu, R. Bai, Y. Lan, Chem. Soc. Rev.
2018, 47, 7552–7576; b) P. Nareddy, F. Jordan, M. Szostak, ACS
Catal. 2017, 7, 5721–5745; c) L. Ackermann, Acc. Chem. Res. 2014,
47, 281–295; d) S. De Sarkar, W. Liu, S. I. Kozhushkov, L.
Ackermann, Adv. Synth. Catal. 2014, 356, 1461–1479; e) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879–
5918; f) F. Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345,
1077–1101.
Gooßen, Org. Lett. 2019, 21, 6770–6773; c) J. Zhu, P.-h. Chen, G.
Lu, P. Liu, G. Dong, J. Am. Chem. Soc. 2019, 141, 18630–18640;
d) J. Zhu, J. Wang, G. Dong, Nat. Chem. 2019, 11, 45–51; e) L.
Deng, Y. Fu, S. Y. Lee, C. Wang, P. Liu, G. Dong, J. Am. Chem.
Soc. 2019, 141, 16260–16265; f) T. Sun, Y. Zhang, B. Qiu, Y. Wang,
Y. Qin, G. Dong, T. Xu, Angew. Chem. Int. Ed. 2018, 57, 2859–
2863; g) Z. Zhu, X. Li, S. Chen, P.-h. Chen, B. A. Billett, Z. Huang,
G. Dong, ACS Catal. 2018, 8, 845–849; h) H. Wang, I. Choi, T.
Rogge, N. Kaplaneris, L. Ackermann, Nat. Catal. 2018, 1, 993–
1001; i) M. Moselage, J. Li, F. Kramm, L. Ackermann, Angew. Chem.
Int. Ed. 2017, 56, 5341–5344; j) N. Y. P. Kumar, A. Bechtoldt, K.
Raghuvanshi, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
6929–6932; k) J. Zhang, R. Shrestha, J. F. Hartwig, P. Zhao, Nat.
Chem. 2016, 8, 1144–1151; l) L. Huang, A. Biafora, G. Zhang, V.
Bragoni, L. J. Gooßen, Angew. Chem. Int. Ed. 2016, 55, 6933–6937;
m) E. Ozkal, B. Cacherat, B. Morandi, ACS Catal. 2015, 5, 6458–
6462; n) N. Ishida, W. Ikemoto, M. Murakami, J. Am. Chem. Soc.
2014, 136, 5912–5915; o) L. Souillart, N. Cramer, Angew. Chem. Int.
Ed. 2014, 53, 9640–9644; p) T. Seiser, N. Cramer, J. Am. Chem.
Soc. 2010, 132, 5340−5341; q) T. Seiser, O. A. Roth, N. Cramer,
Angew. Chem. Int. Ed. 2009, 48, 6320–6323; r) N. Chatani, Y. Ie, F.
Kakiuchi, S. Murai, J. Am. Chem. Soc. 1999, 121, 8645–8646.
L. Ackermann, Acc. Chem. Res. 2020, 53, 84–104.
For detailed information, see the Supporting Information.
a) D. L. Davies, S. A. Macgregor, C. L. McMullin, Chem. Rev. 2017,
117, 8649–8709; b) L. Ackermann, Chem. Rev. 2011, 111,
1315−1345.
a) T. Rogge, L. Ackermann, Angew. Chem. Int. Ed. 2019, 58,
15640–15645; b) M. Simonetti, D. M. Cannas, X. Just-Baringo, I. J.
Vitorica-Yrezabal, I. Larrosa, Nat. Chem. 2018, 10, 724–731; c) M.
Simonetti, D. M. Cannas, A. Panigrahi, S. Kujawa, M. Kryjewski, P.
Xie, I. Larrosa, Chem. Eur. J. 2017, 23, 549–553; d) L. Ackermann,
A. Althammer, R. Born, Tetrahedron 2008, 64, 6115–6124; e) L.
Ackermann, A. Althammer, R. Born, Synlett 2007, 2007, 2833–
2836; f) L. Ackermann, R. Born, P. Álvarez-Bercedo, Angew. Chem.
Int. Ed. 2007, 46, 6364–6367.
[2]
[3]
[4]
[12]
[13]
[14]
[15]
[5]
[6]
[7]
a) G.-W. Wang, M. Wheatley, M. Simonetti, D. M. Cannas, I. Larrosa,
Chem 2020, 6, 1459–1468; b) L. Ackermann, N. Hofmann, R.
Vicente, Org. Lett. 2011, 13, 1875–1877; c) L. Ackermann, P. Novák,
R. Vicente, N. Hofmann, Angew. Chem. Int. Ed. 2009, 48, 6045–
6048; d) L. Ackermann, P. Novák, Org. Lett. 2009, 11, 4966–4969.
For selected reviews on ruthenium-catalyzed meta-C–H
functionalization, see: a) M. T. Mihai, G. R. Genov, R. J. Phipps,
Chem. Soc. Rev. 2018, 47, 149–171; b) J. A. Leitch, C. G. Frost,
Chem. Soc. Rev. 2017, 46, 7145–7153; c) J. Li, S. De Sarkar, L.
Ackermann, Top. Organomet. Chem. 2016, 55, 217–257.
a) C. Yuan, L. Zhu, C. Chen, X. Chen, Y. Yang, Y. Lan, Y. Zhao,
Nat. Commun. 2018, 9, 1189; b) C. Yuan, L. Zhu, R. Zeng, Y. Lan,
Y. Zhao, Angew. Chem. Int. Ed. 2018, 57, 1277–1281; c) X.-G.
Wang, Y. Li, L.-L. Zhang, B.-S. Zhang, Q. Wang, J.-W. Ma, Y.-M.
Liang, Chem. Commun. 2018, 54, 9541–9544; d) J. A. Leitch, C. L.
McMullin, A. J. Paterson, M. F. Mahon, Y. Bhonoah, C. G. Frost,
Angew. Chem. Int. Ed. 2017, 56, 15131–15135.
[16]
CCDC 1979314 (6fa), 2016734 (endo-6fj), 2016645 (exo-7fj),
2016646 (endo-7fj), 2016647 (cis-6fk), 2016735 (trans-6fk),
1979319 (6ii'), 1979310 (7cd), and 1979311 (11a) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre.
[17]
[18]
G. Cera, T. Haven, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
1484–1488.
a) S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32,
1456–1465; b) S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem.
Phys. 2010, 132, 154104; c) S. Sinnecker, A. Rajendran, A. Klamt,
M. Diedenhofen, F. Neese, J. Phys. Chem. A 2006, 110, 2235–
2245; d) Y. Zhao, D. G. Truhlar, J. Phys. Chem. A 2005, 109, 5656–
5667; e) F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005,
7, 3297–3305; f) J. Tao, J. P. Perdew, V. N. Staroverov, G. E.
Scuseria, Phys. Rev. Lett. 2003, 91, 146401; g) A. Klamt, V. Jonas,
T. Bürger, J. C. W. Lohrenz, J. Phys. Chem. A 1998, 102, 5074–
5085; h) A. Klamt, J. Phys. Chem. 1995, 99, 2224–2235.
L. Ackermann, R. Vicente, H. K. Potukuchi, V. Pirovano, Org. Lett.
2010, 12, 5032–5035.
[8]
[9]
a) A. J. Paterson, C. J. Heron, C. L. McMullin, M. F. Mahon, N. J.
Press, C. G. Frost, Org. Biomol. Chem. 2017, 15, 5993–6000; b) A.
J. Paterson, S. St John-Campbell, M. F. Mahon, N. J. Press, C. G.
Frost, Chem. Commun. 2015, 51, 12807–12810.
[19]
[20]
C. Kashima, S. Hibi, T. Maruyama, K. Harada, Y. Omote, J.
Heterocycl. Chem. 1987, 24, 637–639.
a) K. Korvorapun, R. Kuniyil, L. Ackermann, ACS Catal. 2020, 10,
435–440; b) P. Gandeepan, J. Koeller, K. Korvorapun, J. Mohr, L.
Ackermann, Angew. Chem. Int. Ed. 2019, 58, 9820–9825; c) K.
Korvorapun, N. Kaplaneris, T. Rogge, S. Warratz, A. C. Stückl, L.
Ackermann, ACS Catal. 2018, 8, 886–892; d) F. Fumagalli, S.
Warratz, S.-K. Zhang, T. Rogge, C. Zhu, A. C. Stückl, L. Ackermann,
Chem. Eur. J. 2018, 24, 3984–3988; e) Z. Ruan, S.-K. Zhang, C.
Zhu, P. N. Ruth, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed.
2017, 56, 2045–2049; f) J. Li, K. Korvorapun, S. De Sarkar, T.
Rogge, D. J. Burns, S. Warratz, L. Ackermann, Nat. Commun. 2017,
8, 15430; g) J. Li, S. Warratz, D. Zell, S. De Sarkar, E. E. Ishikawa,
L. Ackermann, J. Am. Chem. Soc. 2015, 137, 13894–13901; h) N.
Hofmann, L. Ackermann, J. Am. Chem. Soc. 2013, 135, 5877–5884.
a) G. Li, C. Jia, X. Cai, L. Zhong, L. Zou, X. Cui, Chem. Commun.
2020, 56, 293–296; b) C. Jia, S. Wang, X. Lv, G. Li, L. Zhong, L.
Zou, X. Cui, Eur. J. Org. Chem. 2020, 2020, 1992–1995; c) A.
Sagadevan, M. F. Greaney, Angew. Chem. Int. Ed. 2019, 58, 9826–
9830; d) B. Li, S.-L. Fang, D.-Y. Huang, B.-F. Shi, Org. Lett. 2017,
19, 3950–3953; e) G. Li, P. Gao, X. Lv, C. Qu, Q. Yan, Y. Wang, S.
Yang, J. Wang, Org. Lett. 2017, 19, 2682–2685; f) G. Li, D. Li, J.
Zhang, D.-Q. Shi, Y. Zhao, ACS Catal. 2017, 7, 4138–4143; g) G.
Li, X. Ma, C. Jia, Q. Han, Y. Wang, J. Wang, L. Yu, S. Yang, Chem.
Commun. 2017, 53, 1261–1264; h) Z.-Y. Li, L. Li, Q.-L. Li, K. Jing,
H. Xu, G.-W. Wang, Chem. Eur. J. 2017, 23, 3285–3290.
[10]
[11]
For selected examples of transition metal-catalyzed C–C activations,
see: a) S.-H. Hou, A. Y. Prichina, M. Zhang, G. Dong, Angew. Chem.
Int. Ed. 2020, 59, 7848–7856; b) Z. Hu, X.-Q. Hu, G. Zhang, L. J.
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10.1002/anie.202007144
Angewandte Chemie International Edition
RESEARCH ARTICLE
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RESEARCH ARTICLE
K. Korvorapun, M. Moselage, J. Struwe,
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Page No. – Page No.
Regiodivergent C–H and
Decarboxylative Alkylation by
Ruthenium Catalysis: ortho versus
meta Position-Selectivity
ortho vs meta control: C–H Alkylations of 1-arylpyrazoles were achieved through
ruthenium-catalyzed C–H or C–C activation. The site-selectivity of this
transformation was controlled by substituents on the pyrazole and the steric
hindrance of the alkyl moiety.
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