N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H tert-Alkylation with Removable Auxiliaries

Article abstract of DOI:10.1021/jacs.5b08435

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization.

Full text of DOI:10.1021/jacs.5b08435

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Article
N-Acyl Amino Acid Ligands for Ruthenium(II)-catalyzed
meta-C–H tert-Alkylation with Removable Auxiliaries
Jie Li, Svenja Warratz, Daniel Zell, Suman De Sarkar, Eloisa Eriko Ishikawa, and Lutz Ackermann
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08435 • Publication Date (Web): 29 Sep 2015
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N-Acyl Amino Acid Ligands for Ruthenium(II)-catalyzed meta-C–H
tert-Alkylation with Removable Auxiliaries
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Jie Li, Svenja Warratz, Daniel Zell, Suman De Sarkar, Eloisa Eriko Ishikawa, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstraße 2, 37077 Göttingen, Germany
ABSTRACT: Acylated amino acid ligands enabled ruthenium(II)-catalyzed C−H functionalizations with excellent levels of
meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from mono-protected amino
acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups.
Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline func-
tionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C−H trans-
formations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl- and pyrazolyl-substituted
arenes. Detailed mechanistic studies provided strong support for an initial reversible C−H ruthenation, followed by a SET-
type C−Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual
second order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the
exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumen-
tal for C−H activation chemistry beyond remote functionalization.
Introduction
The direct transformation of otherwise inert C−H
bonds as latent functional groups has received considera-
ble attention, because this approach avoids the use of
prefunctionalized starting materials.1 Since the substrates
of interest usually display numerous C−H bonds with
close dissociation energies, controlling the positional
selectivity represents the key challenge in intermolecular
C−H functionalizations.1,2 In this context, the recent years
have witnessed remarkable progress through the use of
Lewis-basic entities that allowed for proximity-induced
C−H transformations.3 Thus, site-selectivity ensuring
entities have been identified, which set the stage for en-
tropically favored C−H metalations by substrate pre-
coordination to the metal catalyst.1,3,4 Despite significant
recent advances, the vast majority of chelation-assisted
C−H activations provided solely access to a plethora of
ortho-functionalized products.1 In stark contrast, general
methods for meta-selective C−H functionalizations con-
tinue to be scarce.5 Notable exceptions include remote
C−H transformations that exploit the inherent steric or
electronic features of substrate-catalyst interactions (Fig-
ure 1a).6 As an alternative, rationally designed templates
were elegantly devised by among others Yu and cowork-
ers (1b).7 In order to avoid a stoichiometric template,
Figure 1. Strategies for meta-selective C‒H function-
transient covalent or secondary hydrogen-bonding inter-
alization. a, Steric interactions controlling site-
actions set very recently the stage for meta-selective C−H
functionalizations (1c), as elegantly devised by Yu,8 and
selectivity. b, Template-assisted transformation. c,
Norbornene as mediator. d, Remote σ-activation. e,
Dong9.10
Ruthenium(II)-MPAA-catalyzed meta-selective al-
kylation with removable directing groups; pym =
pyrimidyl.
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In contrast, ruthenium(II) complexes11 were recently
shown to facilitate meta-selective C−H functionalizations
by means of chelation-assisted cyclometalation (Figure
1d).12 While these reports indicated a unique strategy for
remote meta-C−H activation, the approach was thus far
significantly limited to strongly coordinating heteroaro-
matic pyridyl,12b-d pyrazolyl,12c imidazolyl,12c or pyrimidyl12c
directing groups, which are unfortunately very difficult to
remove13 or modify. Hence, ruthenium-catalyzed meta-
selective C−H functionalizations with removable directing
groups have as of yet unfortunately proven elusive. An-
other notable limitation was constituted in that rutheni-
um(II)-catalyzed meta-C−H functionalizations were thus
far not amenable to electron-rich arenes, such as syn-
thetically useful anilines. In consideration of the practical
importance of aniline derivatives in inter alia drug discov-
ery, crop protection and material sciences,14 we set out to
devise ruthenium catalysts for meta-selective C−H func-
tionalizations of N-(pyrimidine-2-yl)anilines15 − important
structural motifs of biologically active compounds of
relevance to pharmacologically active ingredients (Figure
2).16 As a result of our efforts, we herein17 report on a novel
ligand design for ruthenium-catalyzed C−H functionaliza-
tions that allowed for the challenging meta-C−H activa-
tion on electron-rich aniline derivatives. Thus, mono-
protected amino acids (MPAA) – employed by Yu18 for
palladium-catalyzed transformations – proved to be the
best in class ligands for ruthenium(II)-catalyzed remote
C−H functionalizations. Notable features of our C−H
activation strategy are (i) an unprecedented high catalytic
activity in ruthenium-catalyzed meta-C−H-activation
through MPAA ligand acceleration, (ii) exceptionally high
levels of meta-selectivity, (iii) remote C−H functionaliza-
tions with synthetically useful removable auxiliaries, and
(iv) C−H transformations with challenging tertiary alkyl
halides (Figure 1e).19 With respect to the last point, nota-
ble progress has been made in metal-catalyzed cross-
coupling, including the development of nickel catalysts to
promote challenging coupling reactions of unactivated
tertiary alkyl halides by Fu and coworkers.20
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Figure 2. Representative Bioactive meta-Substituted N-
(Pyrimidine-2-yl)anilines
Results and Discussion
Aniline derivatives. Optimization: At the outset of our
studies, we probed reaction conditions that we had previ-
ously optimized for the ruthenium(II)-catalyzed meta-
alkylation of 2-phenylpyridines with secondary alkyl bro-
mides.12c To our delight, the desired meta-alkylated prod-
uct was obtained in 30% yield (table 1, entry 1). KOAc also
proved to be a competent ligand, albeit leading to a sig-
nificantly lower yield (entry 2). While the reaction did not
occur in the absence of an additive (entry 3), a considera-
bly improved catalytic efficacy proved viable with the
MPAA Piv-Phe-OH as the ligand (entry 4). While ruthe-
nium(II)-amino acid complexes are well established in the
literature,21 MPAAs have as of yet not been exploited for
ruthenium-catalyzed C–H functionalizations. Encouraged
by our initial lead, we examined differently substituted
MPAA ligands. Thus, among a representative set of
pivaloyl-protected amino acids, the valine derivative
turned out to be optimal (entries 4–6). In contrast, the
parent amino acid valine delivered the desired arene 3aa
only in an unsatisfactorily low yield, highlighting the
importance of the amide moiety and its N-substitution
pattern (entry 7). In agreement with this observation,
N,N-disubstituted valine bearing the amide motif proved
to be a competent ligand (entry 8). Further N-protected
MPAAs afforded the meta-alkylated product 3aa in com-
parable yields (entries 9–13). In order to unravel the na-
ture of the in-situ generated ruthenium catalyst we inde-
pendently prepared the ruthenium(II)-MPAA complex 4.
Intriguingly, the single-component ruthenium(II) species
4 was found to be catalytically active, despite of the de-
creased ligand loading (entry 14).
2
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Table 1: Optimization of meta-Selective tert-
Alkylation
ligand Ad-Ile-OH even enabled the direct meta-alkylation
1
2
3
4
5
6
7
8
of challenging ortho-substituted substrates, furnishing
the tert-alkylated products 3fa and 3ga through the exclu-
sive functionalization at the sterically more congested
meta-C−H bond. The 2,4-disubstituted aniline 1h was
smoothly alkylated at the 3-position within an intramo-
lecular competition, illustrating the excellent site-
selectivity of the approach. Subsequently, we tested a
variety of tertiary alkyl bromides 2 in the C−H transfor-
mation. Thus, cyclic tertiary bromide delivered the de-
sired product 3ab in 60% yield. Likewise, sterically more
hindered acyclic tertiary alkyl bromides 2 also afforded
the corresponding products. Aryl- and alkenyl-substituted
alkyl bromides 2e and 2f were well tolerated, thereby
providing a handle for further post-synthetic diversifica-
tions. It should be noted that the alkyl bromide 2g dis-
playing a primary alkyl chloride was chemo-selectively
converted at the more hindered site on the alkyl halide
(3ag). This observation clearly unravelled the relative
reactivity pattern within the ruthenium(II)-catalyzed C−H
alkylation process (vide infra).
Catalyst
Yield
(%)
Entry
Ligand
1
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
MesCO2H
KOAc
30
26
0
9
2
3
4
5
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8
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---
Piv-Phe-OH
Piv-Leu-OH
Piv-Val-OH
H-Val-OH
Boc2-Val-OH
50
58
66
18
54
MeO2C-Val-
OH
9
58
10
11
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
Boc-Val-OH
Ac-Val-OH
1-Ad-Val-OH
1-Ad-Ile-OH
--
55
47
62
65
56
Scheme 2: Scope of Ruthenium(II)-Catalyzed meta-
Alkylation of Anilines 1
12
13
[RuCl(Piv-Val-O)(p-cymene)]
(4)
14
a
Reaction Conditions: 1a (0.5 mmol), 2a (1.5 mmol), [RuCl2(p-
cymene)]2 (5.0 mol %), ligand (30 mol %), K2CO3 (1.0 mmol), 1,4-
dioxane (2 mL), 100 °C, 16 h; yields of isolated products.
Thereafter, we explored the dependence of the rutheni-
um(II)-catalyzed meta-C−H alkylation on the nature of
the aniline’s N-substitution pattern (Scheme 1). Interest-
ingly, the switch from the pyrimidyl to the more strongly-
coordinating22 pyridyl group resulted in a considerable
loss in catalytic efficacy. Moreover, a simple diarylaniline
failed to furnish the desired product, thereby highlighting
the relevance of chelation assistance.
Scheme 1: Effect of the N-Substitution Pattern
a
Reaction Conditions:
1 (0.5 mmol), 2 (1.5 mmol), [RuCl2(p-
cymene)] (5.0 mol %), Piv-Val-OH (30 mol %), K2CO3 (1.0 mmol), 1,4-
o
dioxane (2.0 mL), 16 h, 120 C; yields of isolated products. b 1-Ad-Ile-
OH (30 mol %).
Intriguingly, the pyrimidyl group could be reliably cleaved
in a traceless fashion, providing meta-alkylated aniline
derivative 7aa in 84% yield (Scheme 3). Thereby, our
strategy offers a novel approach for the step-economical
synthesis of meta-substituted anilines 7, which are ex-
tremely difficult to access by other aniline functionaliza-
tion methods.
Scope and limitations. With the optimized rutheni-
um(II) catalytic system in hand, we explored its scope and
limitations in the meta-selective tert-alkylation (Scheme
2). We were pleased to observe that the ruthenium-MPAA
complex was broadly applicable. Thus, electron-rich as
well as functionalized arenes 1 bearing bromo or chloro
substituents were efficiently converted, furnishing the
desired meta-alkylated products 3ba−3ea. Notably, the
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a Reaction Conditions: 8a (0.5 mmol), 2a (1.5 mmol), [RuCl2(p-
Scheme 3: Removal of the Directing Group
1
2
3
cymene)]2 (5.0 mol %), ligand (30 mol %), K2CO3 (1.0 mmol),
1,4-dioxane (2 mL), 100 °C, 20 h, under N2; yield of isolated
products.
4
5
6
7
8
9
Scope and Limitations. After having optimized the
reaction conditions, we explored the generality of both
the in-situ formed ruthenium(II) catalytic system
(Scheme 4, conditions A) as well as of the single-
component complex 4 (conditions B). Generally, the in-
situ formed and the well-defined ruthenium(II)-MPAA
catalysts 4 furnished comparable results. Thus, the parent
unsubstituted 2-phenylpyridine (8b) as well as the para-
substituted derivatives 8a and 8c were efficiently convert-
ed under both reaction conditions (9ac−9ca). Phenylpyr-
idines 8c−8e bearing electron-withdrawing fluoro, acetyl
or ester groups in the para-position selectively delivered
the corresponding meta-alkylated products. It is notewor-
thy that C−H functionalizations of substrates 8a−8e at the
ortho-position of a weakly-coordinating directing ether,
halo, ketone, or ester in the presence of a strongly-
coordinating pyridine substituent are extremely difficult
to achieve. Different substituents in the 3, 4, or 5 position
on the pyridine moiety were well tolerated by the ruthe-
nium(II) catalyst (9fa−9ka), with electron-donating sub-
stituents slightly improving the performance. Given the
importance of heteroarenes as key motifs in various bio-
active compounds,24 we were delighted to observe that
the remote C−H tert-alkylation of substituted thiophene
9la proceeded with excellent positional selectivity. Like-
wise, ortho- and para-disubstituted arenes 8m and 8n
underwent the site-selective meta-C−H alkylation with
the ruthenium(II)-MPAA catalytic system. Subsequently,
the robustness of the ruthenium(II) catalyst was probed
with various unactivated tertiary alkyl bromides 2 under
otherwise identical reaction conditions. Thus, 1-
methylcyclohexyl bromide (2b) gave the C−H alkylated
products 9ab−9mb. Sterically more congested tertiary
alkyl bromides 2h, 2c and 2d afforded the desired prod-
ucts 9 as well. Tertiary alkyl bromides 2 bearing function-
al groups, such as an arene, an ether, an alkene, or the
chloro group were well tolerated (9ai−9ag). Intriguingly,
the meta-tert-alkylated product 9ag was not contaminat-
ed by the ortho-primary25 alkylated arene, again demon-
strating the useful chemo-selectivity. The versatile ruthe-
nium(II)-MPAA catalyst was not restricted to the strongly
coordinating pyridine derivatives. Indeed, the synthetical-
ly useful pyrazole and pyrimidine groups also served as
the site-selectivity ensuring entities for the C−H meta-
alkylation, affording the corresponding meta-alkylated
products 10aa−10ba and 11ae−11ba, respectively.
Heteroarenes. Optimization: Given the unique catalyt-
ic efficacy of the ruthenium-MPAA complex in the C−H
functionalization with aniline derivatives 3, we became
attracted by exploring its versatility with differently deco-
rated arenes. Hence, we tested various in-situ generated
ruthenium(II) catalysts in the direct functionalization of
pyridyl-substituted23 arene 8a (Table 2). The desired
reaction could not be achieved solely with [RuCl2(p-
cymene)]2 in the absence of any ligand (entry 1). Likewise,
the ligand KOAc furnished only an unsatisfactorily low
yield (entry 2), while Frost observed in very recent inde-
pendent studies high conversions with KOAc as the stoi-
chiometric base at an elevated reaction temperature of
120 °C.12d Among a set of representative amino acid deriva-
tives, Piv-Val-OH was again found to be the ligand of
choice (entries 3−11). It is noteworthy that the single com-
ponent ruthenium(II)-MPAA complex 4 delivered the
product 9aa in an improved yield of 80% at a significantly
reduced ligand loading (entry 12). Finally, a control exper-
iment confirmed that the ruthenium catalyst proved to be
essential (entry 13).
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Table 2: Optimization for meta-Selective tert-
Alkylation of 2-Arylpyridine 8a
Entry
Catalyst
Ligand
Yield
(%)
1
2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
--
0
KOAc
50
55
48
53
76
19
3
Piv-Leu-OH
Piv-Gly-OH
Piv-Phe-OH
Piv-Val-OH
H-Val-OH
Boc2-Val-OH
MeO2C-Val-OH
Boc-Val-OH
Ad-Val-OH
--
4
5
6
7
8
9
10
11
12
46
58
61
55
80
[RuCl(Piv-Val-O)(p-cymene)]
(4)
13
--
Piv-Val-OH
0
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Scheme 5: Intermolecular Competition Experiments
Scheme 4: Scope of Heteroarene-Assisted meta-C−H
1
tert-Alkylation
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Furthermore, we conducted competition experiments
between tertiary alkyl halide 2a and primary or secondary
alkyl bromides 12a and 14a, respectively (Scheme 6). In-
terestingly, the relative reaction rates across these differ-
ent classes of electrophiles were similar. Furthermore, the
positional selectivity that was observed in single-
component reactions with individual electrophiles was
preserved in the competition experiments. Indeed, the
primary alkyl bromide furnished the ortho-substituted
product,25a while the secondary and tertiary electrophiles
delivered the meta-substitution pattern.
Scheme 6: Competition Between 3°, 2° and 1° Alkyl
Halides
a Reaction Conditions: A: [RuCl2(p-cymene)] (2.5 mol %), Piv-Val-
OH (30 mol %) or B: [RuCl(Piv-Val-O)(p-cymene)] (5.0 mol %); 8
(0.5 mmol), 2 (1.5 mmol), K2CO3 (1.0 mmol), 1,4-dioxane (2.0 mL),
Subsequently, we conducted C−H functionalization with
isotopically labelled compounds (Scheme 7). In the course
of the meta-alkylation of arene [D5]-8b, a significant D/H
exchange was observed, which was solely detected in the
ortho-position of the product [Dn]-9ba and the reisolated
substrate [Dn]-8b (Scheme 7a). This result provided
strong support for the C−H bond metalation step to pro-
ceed by an initial ortho-metalation in a reversible manner.
We also performed the standard meta-C−H alkylation in
the presence of D2O (Scheme 7b). Here, a significant
amount of deuterium incorporation in the ortho-positions
of both product [Dn]-9ca and the recovered starting ma-
terial [Dn]-8c was noted. To probe the mode of the meta-
C−H cleavage and the C−C formation, substrate [D3]-8b
was subjected to the optimized reaction conditions
b
20 h, 100 oC under N2 atmosphere; yield of isolated products.
[RuCl2(p-cymene)] (5.o mol %) or [RuCl(Piv-Val-O)(p-cymene)] (4,
10 mol %).
Mechanistic Studies. In consideration of the unique
catalytic activity of the ruthenium(II)-MPAA complexes,
we became intrigued by studying their mode of action. To
this end, we performed intermolecular competition ex-
periments between differently-substituted phenylpyri-
dines 8,26 which revealed electron-deficient arenes to be
inherently more reactive than their electron-neutral or
electron-rich counterparts (Scheme 5). This phenomenon
renders a simple electrophilic substitution-type mecha-
nism unlikely to be operative.
1
(Scheme 7c). Careful H NMR spectroscopic analysis did
not show any hydrogen incorporation in the meta-
position, neither in the product [D2]-9ba nor in the re-
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covered starting material [D3]-8b. These findings indicate Scheme 8: Kinetic Isotope Effect (KIE) Studies
Page 6 of 11
1
2
3
4
5
6
7
8
the meta-C−H cleavage and C−C forming elementary
steps likely to be irreversible in nature. It is interesting to
note that the C−H alkylation with isotopically labelled
alkyl bromide [D9]-2a resulted in a H/D exchange in the
ortho-positions of both the product [Dn]-9ca and the
recovered starting material [Dn]-8c (Scheme 7d). This
experiment revealed key information on the dual role of
the organic electrophile 2a, in that it not only served as
the electrophilic alkylating reagent, but also as the proton
source for the key elementary step of proto-demetalation.
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Scheme 7: Isotopic Labelling Studies
Given the key importance of the cycloruthenated com-
plexes as potential intermediates in the ruthenium(II)-
catalyzed meta-alkylation, we subsequently performed
reactions with well-defined complexes 16a and 17aa. No-
tably, the chloro-ruthenacycle 16a was not catalytically
competent. However, the presence of cocatalytic amounts
of the MPAA ligand Piv-Val-OH restored the catalytic
ability, affording the meta-alkylated 9da in an excellent
yield (Scheme 9a).26 These results clearly illustrate the
importance of carboxylate assistance28 for the rutheni-
um(II)-catalyzed C−H functionalization.29 Moreover, the
alkyl bromide t-BuBr (2a) was found to be indispensable
for releasing the desired product 9da from the cyclomet-
alated ruthenium(II) complex 17aa (Scheme 9b). This
observation illustrates the crucial relevance of the alkyl
halides 2 for the proto-demetalation step.
Scheme 9: Reactions with Cyclometalated Rutheni-
um(II) Complexes
The kinetic isotope effect (KIE) of the meta-C−H cleavage
was investigated by means of the initial rates for inde-
pendent reactions of substrates 8b and [D3]-8b, highlight-
ing a KIE of kH/kD ≈ 1.6 (Scheme 8). Intermolecular com-
petition experiment between the substrates 8b and [D3]-
8b established a KIE of 1.4 as an average of 2 independent
runs, which could be rationalized in terms of a kinetically
relevant meta-C−H cleavage step.27
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Thereafter, we became interested in understanding the
activation mode of the C−Br cleavage30 as well as the na-
Scheme 10: Investigation on the meta-C−C formation
1
2
ture of the meta-C−C forming step within the rutheni-
um(II)-catalyzed meta-alkylation with secondary and
tertiary alkyl bromides. In this context, it is noteworthy
that we12c and subsequently Frost12d had previously report-
ed the detrimental effect exerted by the radical scan-
venger TEMPO. The independently prepared alkyl pyri-
dinium salt 18 was not a competent alkylating reagent
(Scheme 10a). Moreover, the use of the alkene methylene-
cyclohexane (19a) did not afford the desired product 9ab,
which rendered a reaction sequence comprising of β-
elimination and a hydroarylation31 unlikely to be at play
(Scheme 10b). Thereafter, the stereochemically well-
defined cis- and trans-1-bromo-4-phenylcyclohexanes
(14b)32 were utilized as electrophiles in two independent
C−H functionalizations. Interestingly, both reactions
delivered the same diastereomeric product mixture. This
epimerization can be rationalized in terms of a homolytic
C−Br cleavage. In good agreement with these observa-
tions, experiments with the radical clock (3-bromo-3-
cyclopropylpropyl)benzene (14c) furnished the meta-
alkylated product 15ac with retention of the cyclopropane
ring as the major product, along with 9% of the meta-
homo-allylated arene 15ac’. Thus, a radical rebound
should feature a reaction rate being close to the one pre-
viously observed for the ring opening of the cyclopropyl-
methylene radical of 7.0 x 107 M-1 s-1.32 These findings are
in agreement with the inhibition of the meta-alkylation
by the radical scavenger TEMPO, as reported by us12cand
Frost.12d
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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41
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Finally, we performed a detailed kinetic analysis of the
ruthenium(II)-catalyzed meta-C−H alkylation.26 Hence,
the reaction displayed the a priori expected first order
kinetics with respect to the arene 8b. However, our stud-
ies revealed a second order dependence on the concentra-
tion of the ruthenium catalyst (Figure 3). This unusual
kinetic profile is suggestive of a second ruthenium com-
plex being involved in or before the rate-determining
step. Given the epimerization of the stereochemically
well-defined substrates 14b (vide supra), we thus propose
a second ruthenium complex to facilitate the homolytic34
C−Br cleavage within a homo-bimetallic35 catalysis re-
gime.36
Figure 3: Double logarithmic plot of the initial rate
versus the concentration of RuCl2(p-cymene)]2 and
the concentration of 2-Phenylpyridine (8b).
(a)
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Scheme 11: Plausible catalytic cycle.
Page 8 of 11
1
2
N
N
3
4
5
6
7
8
R2
R3
R4
H
H
+
R1
R2 R3
i-Pr
Me
O
H
Ru
N
8
9
t-Bu
X
O
proto-
demetalation
reversible
C−H ruthenation
K2CO3
H
H
O
R4
R3
R
X
4 (X = Cl, Br)
R2
KX + KHCO3
2
9
R
Me
i-Pr
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
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60
R
O
NHPiv
i-Pr
Me
Ru
N
O
NHPiv
Ru
O
N
O
17
R3
R1 R2
16
H
[Ru(II)], KHCO3, KX
R3
R2
R
.
i-Pr
Me
(b)
R1
O
NHPiv
Ru
[Ru(III)]X, K2CO3
N
O
[Ru(III)]X
[Ru(II)]
single-electron
transfer
H
R3
R1
R2
18
R1
R3
X
R2
2
Conclusion
In summary, we have reported on the first ruthenium(II)-
catalyzed meta-selective C−H functionalization with syn-
thetically useful removable directing groups. Thus, N-acyl
amino acids were found to be the key to success for the
remote C−H tert-alkylation, which set the stage for the
first ruthenium(II)-catalyzed meta-functionalization of
electron-rich aniline derivatives. Thereby, our removable
auxiliary strategy provided a unique access to meta-
substituted anilines, which complements traditional ap-
proaches. The power of the ruthenium(II)-MPAA-
catalyzed remote C−H functionalization was reflected by
efficient couplings with secondary and sterically congest-
ed tertiary alkyl halides. Detailed experimental mechanis-
tic studies were conducted and provided strong support
for an initial reversible cyclometalation by a rutheni-
Based on our detailed mechanistic analysis we propose
the meta-C−H tert-alkylation to be initiated by the for-
mation of the ruthenium(II)-MPAA complex 4 (Scheme
11). The catalytically active complex 4 is initially undergo-
ing a reversible C−H ruthenation, thus leading to a H/D
exchange in the ortho-position of the arenes 1 / 8. Subse-
quently, a single-electron transfer-type activation of the
alkyl halides 2 leads to intermediate 18. The formation of
the radical intermediate hence rationalizes the previously
observed racemization of enantiomerically-enriched sec-
ondary alkyl halides as well as the inhibition by the radi-
cal scavenger TEMPO,12c and provided a rational for the
epimerization of the 1,4-disubstituted cyclohexane deriva-
tives as well as for the second order dependence on the
ruthenium concentration (Scheme 10c,d). Hydrogen atom
abstraction delivers cyclometalated intermediate 17,
which undergoes proto-demetalation with an additional
equivalent of the alkyl halide 2. Thereby, the desired me-
ta-substituted product 3 / 9 is liberated and the catalyti-
cally active complex 4 regenerated.
um(II)-MPAA complex. Thereafter,
a
ruthenium-
catalyzed homolytic C−Hal cleavage occurs, thus resulting
in an unusual second order dependence of the C−H func-
tionalization rate on the ruthenium concentration. In
more general terms, this report showcases, for the first
time, the power of ruthenium-MPAA complexes for cata-
lytic C−H functionalizations. Further, studies on the use
of ruthenium-MPAA complexes in C−H functionalization
are currently ongoing in our laboratories and will be re-
ported in due course.
ASSOCIATED CONTENT
Supporting Information.
1
Experimental procedures, characterization data, and H and
13C NMR spectra for new compounds. This material is availa-
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ble free of charge via the Internet at http://pubs.acs.org.
1976-1991. (f) Brückl, T.; Baxter, R. D.; Ishihara, Y.;
1
Baran, P. S. Acc. Chem. Res. 2011, 45, 826-839.
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
3.
Selected reviews: (a) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624-655. (b) Satoh,
T.; Miura, M. Top. Organomet. Chem. 2007, 24, 61-84.
(c) Ackermann, L. Top. Organomet. Chem. 2007, 24, 35-
60. (d) Omae, I. Coord. Chem. Rev. 2004, 248, 995-1023;
(e) Kalyani, D.; Sanford, M. S. Top. Organomet. Chem.
2007, 24, 85-116. See also: (f) Kuhl, N.; Hopkinson, M.
N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed.
2012, 124, 10382-10401.
Corresponding Author
Lutz.Ackermann@chemie.uni-goettingen.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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4.
5.
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-
1169.
Generous support by the European Research Council under
the European Community’s Seventh Framework Program
(FP7 2007–2013)/ERC Grant agreement no. 307535, the CSC
(fellowship to J.L.), the CaSuS PhD program, the CAPES
foundation, Ministry of Education of Brazil (fellowship to
EEI), and the Alexander von Humboldt Foundation (fellow-
ship to SDS) is gratefully acknowledged.
(a) Li, J.; De Sarkar, S.; Ackermann, L. Top. Organomet.
Chem. 2015, DOI: 10.1007/3418_2015_1130. (b) Yang, J.
Org. Biomol. Chem. 2015, 13, 1930-1941. (c) Li, J.;
Ackermann, L. Nat. Chem. 2015, 7, 686-687. (d) Julia-
Hernandez, F.; Simonetti, M.; Larrosa, I. Angew. Chem.
Int. Ed. 2013, 52, 11458-11460.
Selected examples: (a) Cho, J. Y.; Tse, M. K.; Holmes,
D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305-
308. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 390-391. (c) Phipps, R. J.; Gaunt, M. J. Science 2009,
323, 1593-1597. (d) Duong, H. A.; Gilligan, R. E.; Cooke,
M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem., Int. Ed.
2011, 50, 463-466. (e) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J.
Am. Chem. Soc. 2009, 131, 5072-5074. (f) Cheng, C.;
Hartwig, J. F. Science 2014, 343, 853-857, and references
cited therein.
(a) Leow, D.; Li, G.; Mei, T. S.; Yu, J.-Q. Nature 2012,
486, 518-522. (b) Yang, G.; Lindovska, P.; Zhu, D.; Kim,
J.; Wang, P.; Tang, R. Y.; Movassaghi, M.; Yu, J. Q. J.
Am. Chem. Soc. 2014, 136, 10807-10813. (c) Tang, R. Y.;
Li, G.; Yu, J.-Q. Nature 2014, 507, 215-220. (d) Lee, S.;
Lee, H.; Tan, K. L. J. Am. Chem. Soc. 2013, 135, 18778-
18781. (e) Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D.
Angew. Chem., Int. Ed. 2015, 54, 8515-8519. See also: (f)
Bresolw, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc.
1997, 119, 4535-4536;.
6.
REFERENCES
1.
Representative recent reviews on C–H activation: (a)
Ye, B.; Cramer, N. Acc. Chem. Res. 2015, 48, 1308-1318.
(b) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015,
48, 1040-1052. (c) Daugulis, O.; Roane, J.; Tran, L. D.
Acc. Chem. Res. 2015, 48, 1053-1064. (d) Segawa, Y.;
Maekawa, T.; Itami, K. Angew. Chem., Int. Ed. 2015, 54,
66-81. (e) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.;
Su, W. Org. Chem. Front. 2014, 1, 843-895. (f) Kuhl, N.;
Schroeder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356,
1443-1460. (g) Mesganaw, T.; Ellman, J. A. Org. Process
Res. Dev. 2014, 18, 1097-1104. (h) Tani, S.; Uehara, T. N.;
Yamaguchi, J.; Itami, K. Chem. Sci. 2014, 5, 123-135. (i)
Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int.
Ed. 2014, 53, 74-100. (j) Ackermann, L. J. Org. Chem.
2014, 79, 8948-8954. (k) Nakamura, E.; Hatakeyama, T.;
Ito, S.; Ishizuka, K.; Ilies, L.; Nakamura, M. Org. React.
2014, 83, 1-209. (l) Gao, K.; Yoshikai, N. Acc. Chem. Soc.
2014, 47, 1208–1219. (m) Rouquet, G.; Chatani, N.
Angew. Chem., Int. Ed. 2013, 52, 11726-11743. (n) Wencel-
Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369-375. (o)
Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23, 1594-
1600. (p) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215-1292. (q) Nakao, Y. Chem. Rec. 2011, 11, 242-251. (r)
Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212-11222.
(s) Daugulis, O. Top. Curr. Chem. 2010, 292, 57-84. (t)
Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Chem. Soc. Rev. 2009, 38, 3242-3272. (u) Ackermann, L.;
Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48,
9792-9826. (v) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094-5115. (w)
Bergman, R. G. Nature 2007, 446, 391-393, and
references cited therein.
7.
8.
9.
Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.;
Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334-338.
Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137,
5887-5890.
10. See also: Das, S.; Incarvito, C. D.; Crabtree, R. H.;
Brudvig, G. W. Science 2006, 312, 1941-1943.
11.
For recent reviews on ruthenium(II)-catalyzed C−H
bond functionalizations, see: (a) Ackermann, L. Org.
Process Res. Dev. 2015, 18, 260-269. (b) De Sarkar, S.;
Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv. Synth.
Catal. 2014, 356, 1461-1479. (c) Thirunavukkarasu, V. S.;
Kozhushkov, S. I.; Ackermann, L. Chem. Commun. 2014,
50, 29-39. (d) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013,
42, 5744-5767. (e) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879-5918. (f)
Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211-229, and references cited therein.
2.
Representative reviews: (a) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960-
9009. (b) Chen, D. Y. K.; Youn, S. W. Chem. Eur. J. 2012,
18, 9452-9474. (c) Neufeldt, S. R.; Sanford, M. S. Acc.
Chem. Res. 2012, 45, 936-946. (d) McMurray, L.; O'Hara,
F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885-1898. (e)
Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
12. (a) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett.
2011, 13, 1875-1877. (b) Saidi, O.; Marafie, J.; Ledger, A.
E.; Liu, P. M.; Mahon, M. F.; Kociok-Kohn, G.;
Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011,
9
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Page 10 of 11
133, 19298-19301. (c) Hofmann, N.; Ackermann, L. J. Am.
23. During the preparation of our manuscript, we became
1
2
3
4
5
6
7
8
Chem. Soc. 2013, 135, 5877-5884. During the preparation
of our manuscript, we became aware of a very recent
independent report by Frost and coworkers: (d)
Paterson, A. J.; St John-Campbell, S.; Mahon, M. F.;
Press, N. J.; Frost, C. G. Chem. Commun. 2015, 51, 12807-
12810.
aware of a related independent report by Frost and
coworkers, see reference [12d].
24. (a) Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. Modern
Heterocyclic Chemistry. Wiley-VCH: Weinheim, 2011.
(b) Mei, T.-S.; Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q.
Synthesis 2012, 44, 1778-1791.
25. (a) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N.
Angew. Chem., Int. Ed. 2009, 48, 6045-6048. (b)
Ackermann, L. Chem. Commun. 2010, 46, 4866-4877.
26. For detailed information, see the Supporting
Information.
13. (a) Wang, C.; Huang, Y. Synlett 2013, 24, 145-149. (b)
Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50,
2450-2494.
14. Rappoport, Z. The Chemistry of Anilines. Wiley: New
York, 2007.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15. Song, W.; Ackermann, L. Chem. Commun. 2013, 49,
6638-6640.
27. Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed.
2012, 51, 3066-3072.
16. (a) Weisberg, E.; Manley, P.; Mestan, J.; Cowan-Jacob,
S.; Ray, A.; Griffin, J. D. Br. J. Cancer 2006, 94, 1765-
1769. (b) Baccarani, M.; Cortes, J.; Pane, F.;
Niederwieser, D.; Saglio, G.; Apperley, J.; Cervantes, F.;
Deininger, M.; Gratwohl, A.; Guilhot, F.; Hochhaus, A.;
Horowitz, M.; Hughes, T.; Kantarjian, H.; Larson, R.;
Radich, J.; Simonsson, B.; Silver, R. T.; Goldman, J.;
Hehlmann, R. J. Clin. Oncol. 2009, 27, 6041-6051. (c)
Owen, D. A.; Montana, J. G.; Keily, J. F.; Watson, R. J.;
Baxter, A. D. US Patent 6566384 B1, 2003. (d) Quintas-
Cardama, A.; Kantarjian, H.; Cortes, J. Nat. Rev. Drug
Discov. 2007, 6, 834-848.
17. For preliminary reports, see: (a) L. Ackermann, BASF
lecture, UC Berkeley, 11.03.2014. (b) J. Li, Doctoral
thesis, Georg-August-Universität Göttingen, 22.06.2015.
18. Representative references: (a) Engle, K. M.; Yu, J.-Q. J.
Org. Chem 2013, 78, 8927-8955. (b) Wang, D.-H.; Engle,
K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315-319. (c)
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 14137-14151.
19. Wu, X.; See, J. W. T.; Xu, K.; Hirao, H.; Roger, J.; Hierso,
J.-C.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 13573-
13577.
20. (a) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
10693-10697. (b) Zultanski, S. L.; Fu, G. C. J. Am. Chem.
Soc. 2013, 135, 624-627.
21. (a) Dersnah, D. F.; Baird, M. C. J. Organomet. Chem.
1977, 127, C55-C58. (b) Shinoda, S.; Inoue, N.; Takita, K.;
Saito, Y. Inorg. Chim. Acta 1982, 65, L21-L23. (c) Severin,
K.; Bergs, R.; Beck, W. Angew. Chem., Int. Ed. 1998, 37,
1635-1654.
28. Ackermann, L. Chem. Rev. 2011, 111, 1315-1345.
29. Ackermann, L. Acc. Chem. Res. 2014, 47, 281-295.
30. A recent contribution: Miloserdov, F. M.; McKay, D.;
Munoz, B. K.; Samouei, H.; MacGregor, S. A.; Grushin,
V. V. Angew. Chem., Int. Ed. 2015, 54, 8466-8470, and
references cited therein.
31. For recent reviews on catalytic hydroarylation
reactions, see: (a) Foley, N. A.; Lee, J. P.; Ke, Z.; Gunnoe,
T. B.; Cundari, T. R. Acc. Chem. Res. 2009, 42, 585-597.
(b) Bandini, M.; Emer, E.; Tommasi, S.; Umani-Ronchi,
A. Eur. J. Org. Chem. 2006, 3527–3544. (c) Nevado, C.;
Echavarren, A. M. Synthesis 2005, 167–182. (d) Liu, C.;
Bender, C. F.; Han, X.; Widenhoefer, R. A. Chem.
Commun. 2007, 3607–3618. (e) Kakiuchi, F.; Chatani, N.
Adv. Synth. Catal. 2003, 345, 1077–1101, and references
cited therein.
32. For the recent use of related alkyl iodides in palladium-
catalyzed reactions, see: Zhang, S.-Y.; Li, Q.; He, G.;
Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015, 137, 531–
539.
33. Bowry, V. W.; Lusztyk, J.; Ingold, K. U. J. Am. Chem.
Soc. 1991, 113, 5687-5698.
34. Kharasch, M.; Jensen, E.; Urry, W. Science 1945, 102, 128.
35. Recent reviews: (a) Perez-Temprano, M. H.; Casares, J.
A.; Espinet, P. Chem. Eur. J. 2012, 18, 1864-1884. (b)
Park, J.; Hong, S. Chem. Soc. Rev. 2012, 41, 6931-6943.
36. For recent examples of ruthenium-catalyzed atom
transfer radical additions, see: (a) Kiefer, G.; Ruiz, J.;
Solari, E.; Hilt, G.; Severin, K. Eur. J. Org. Chem. 2012,
77, 93-98. (b) Thommes, K.; Kiefer, G.; Scopelliti, R.;
Severin, K. Angew. Chem. Int. Ed. 2009, 48, 8115-8119. (c)
Richel, A.; Delfosse, S.; Cremasco, C.; Delaude, L.;
Demonceau, A.; Noels, A. F. Tetrahedron Lett. 2003, 44,
6011-6015; and references cited therein.
22. Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem.
Soc. 2008, 130, 13285-13293.
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