Meta-Selective C-H bond alkylation with secondary alkyl halides

Article abstract of DOI:10.1021/ja401466y

Ruthenium catalysts enabled C-H bond functionalizations on arenes with challenging secondary alkyl halides. Particularly, ruthenium(II) biscarboxylate complexes proved to be the key to success for direct alkylations with excellent levels of unusual meta-selectivity. The direct alkylations occurred under mild reaction conditions with ample scope and tolerated valuable functional groups. Detailed mechanistic studies were performed, including various competition experiments as well as reactions with isotopically labeled substrates. These studies provided strong support for an initial reversible cyclometalation. The cycloruthenation thereby activates the arene for a subsequent remote electrophilic-type substitution with the secondary alkyl halides. Independently prepared cycloruthenated complexes were found to be catalytically active provided that a carboxylate ligand was present, thereby highlighting the key importance of carboxylate assistance for effective meta-selective C-H bond alkylations.

Full text of DOI:10.1021/ja401466y

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Article
meta-Selective C–H Bond Alkylation with Secondary Alkyl Halides
Nora Hofmann, and Lutz Ackermann
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401466y • Publication Date (Web): 27 Mar 2013
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meta‐Selective C–H Bond Alkylation with Secondary Alkyl Halides
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Nora Hofmann, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, Georg‐August‐Universität, Tammannstrasse 2, 37077 Göttin‐
gen, Germany
ABSTRACT: Ruthenium catalysts enabled C–H bond functionalizations on arenes with challenging secondary alkyl ha‐
lides. Particularly, ruthenium(II) biscarboxylate complexes proved to be the key to success for direct alkylations with
excellent levels of unusual meta‐selectivity. The direct alkylations occurred under mild reaction conditions with ample
scope, and tolerated valuable functional groups. Detailed mechanistic studies were performed, including various competi‐
tion experiments as well as reactions with isotopically labeled substrates. These studies provided strong support for an
initial reversible cyclometalation. The cycloruthenation thereby activates the arene for a subsequent remote electrophilic‐
type substitution with the secondary alkyl halides. Independently prepared cycloruthenated complexes were found to be
catalytically active provided that a carboxylate ligand was present, thereby highlighting the key importance of carboxylate
assistance for effective meta‐selective C–H bond alkylations.
Scheme 1. Traditional Cross‐Coupling versus Direct
C–H Bond Alkylation
INTRODUCTION
Transition‐metal‐catalyzed cross‐coupling reactions are
among the most important tools for the selective assem‐
bly of substituted arenes.1‐4 Thus, catalytic coupling reac‐
tions between aryl halides and aromatic organometallic
reagents have found numerous applications in inter alia
natural product synthesis, medicinal chemistry, and ma‐
terial sciences. In contrast to the widely utilized C(sp2)–
C(sp2) bond forming processes, the corresponding trans‐
formations of unactivated alkyl halides are less developed,
with considerable recent progress being accomplished by
the research groups of Fu,5 Hu,6 Kambe,7 Knochel,8 and
Nakamura,9 among others.10 Particularly, secondary alkyl
halides have proven to be extremely challenging sub‐
strates, because these alkyl halides are more sterically
demanding and electron‐rich, thereby rendering the ele‐
mentary step of oxidative addition rather difficult.11 More
importantly, the formed metal alkyl intermediates have a
strong tendency to undergo β‐hydride elimination reac‐
tions, overall leading to undesired β‐eliminations of the
organic electrophiles.11, 12
In recent years, remarkable progress was accomplished
in metal‐catalyzed direct arylations and alkenylations,13, 14
whereas catalyzed C–H bond functionalizations with
unactivated, β‐hydrogen containing alkyl halides under
non‐acidic reaction conditions are scarce.15, 16 Yet, remark‐
able recent advances are constituted by ortho‐selective
palladium‐, nickel‐, copper‐, and cobalt‐catalyzed direct
alkylations as reported by Yu,17 Daugulis,18, 19 Hu,20, 21 Mi‐
Generally, transition‐metal‐catalyzed cross‐coupling
reactions rely on the use of prefunctionalized nucleophilic
4
substrates (Scheme 1a).2, The preparation of the prere‐
quisite organometallic ‐ or main‐group element ‐ reagents
unfortunately involves time‐consuming reaction steps
that generate undesired waste. A significantly more atom‐
and step‐economical approach is, hence, represented by
the direct use of ubiquitous C–H bonds as latent func‐
tional groups (Scheme 1b).13
28
ura/Satoh,22‐24 Nakamura/Yoshikai,25‐27 and others.15,
We, on the contrary, recently devised reaction conditions
for versatile ruthenium(II)‐catalyzed direct alkylations of
arenes with primary alkyl29, 30 and benzyl31 halides.15
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One of the major challenges in developing methods for
Within our research program on sustainable C–H bond
synthetically useful C–H bond functionalizations is
represented by achieving site‐selectivity in intermolecular
transformations. Heteroarenes are electronically biased,
and can, hence, be functionalized in the α‐, β‐ or γ‐
position to the heteroatom with high levels of regiocon‐
trol, exploiting the heteroatoms as intramolecular direct‐
ing groups.32 On the contrary, controlling the site‐
selectivity of intermolecular direct C–H bond functionali‐
zation of mono‐substituted unactivated arenes is consi‐
derably more difficult, and was almost exclusively accom‐
plished in an ortho‐selective fashion by means of chela‐
tion assistance.33 Thus, only few C–H bond activation‐
based C–C bond forming reactions are thus far available
that provide access to meta‐disubstituted34 arenes.35‐37 In
pioneering studies, Yu elegantly devised palladium‐
catalyzed oxidative alkenylations with excellent levels of
meta‐selectivity.38‐40 Furthermore, two‐step alkylations of
arenes were very recently accomplished by Hartwig
through sterically controlled iridium‐catalyzed direct
borylations,41 while copper‐catalyzed meta‐selective direct
arylations proved viable with select aromatic sub‐
strates.42,43 Intriguingly, Frost disclosed ruthenium‐
catalyzed meta‐selective sulfonations through rate‐
determining C–H bond metalation employing sulfonyl
chlorides.44 In contrast, metal‐catalyzed meta‐selective C–
H bond alkylations under non‐acidic reaction conditions
have unfortunately as of yet proven elusive, irrespective of
the nature of the transition metal catalyst.
functionalizations for organic synthesis,52 we now devised
unprecedented direct C–H bond alkylations of arenes
with unactivated secondary alkyl halides under non‐
acidic reaction conditions (Scheme 2b). Herein, we wish
to disclose the development and scope of this first highly
meta‐selective direct C–H bond alkylation, along with
detailed mechanistic studies that provide strong support
for an initial remote ortho‐C–H activation with subse‐
quent meta‐functionalization (Figure 1).
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Figure 1. meta‐Functionalization through Remote
ortho‐C–H Bond Activation
RESULTS AND DISCUSSION
Optimization. At the outset of our studies, we tested the
effect of the stoichiometric base and the cocatalytic addi‐
tive on the desired direct alkylation with secondary alkyl
halide 2a (Table 1). Preliminary experiments indicated
that 1,4‐dioxane proved to be optimal among a variety of
solvents (NMP, m‐xylene, PhMe, n‐hexane, PivOH, t‐
AmOH, MeOH, MeCN, diglyme).53 Low conversions of
the arene 1a were unfortunately observed in the absence
of cocatalytic additives (entries 1–4). Likewise, the use of
trifluoroacetic acid or trifluorosulfonic acid led to unsatis‐
factory results (entries 5 and 6). Conversely, particularly
sterically hindered 1‐AdCO2H generated a highly active
ruthenium(II) catalyst, which interestingly led to C–H
bond functionalization at the meta‐position of substrate
1a.54 Among various carboxylic acids (entries 8–15), Mes‐
CO2H was found to be ideal both with respect to selectiv‐
ity and catalytic efficacy (entries 15 and 16). This reactivity
pattern can be rationalized in terms of steric interactions
and relative solubilities of the corresponding potassium
salts.
Scheme 2. ortho‐Selective C–H Bond Functionaliza‐
tion versus meta‐Selective Direct Alkylation
Recently, we introduced carboxylates as key cocatalytic
additives for robust and reliable ruthenium(II)‐catalyzed
C–H bond arylations,45‐48 which also proved instrumental
for the development of ruthenium‐catalyzed oxidative
alkenylations49 and alkyne annulations.50,51 Ruthenium(II)
carboxylate catalysts further enabled direct C–H bond
alkylations with primary alkyl halides, which occurred
exclusively at the ortho‐position (Scheme 2a).29, 30
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Table 1. Optimization of meta‐Selective C–H Bond
Scheme 3. Variation of the Pyridine Substitution
Pattern
Alkylationa
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entry
1
additive
base
yield (%)
‐‐‐
19
‐‐‐
K2CO3
KOAc
CsOAc
KOPiv
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
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2
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3
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5
F3CCO2H
‐‐‐
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F3CSO3H
7
1‐AdCO2H
PhCO2H
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2,2’‐(C6H4CO2H)2
PhCH2CH2CO2H
2‐MeOC6H4CO2H
4‐MeOC6H4CO2H
4‐(F3C)C6H4CO2H
2‐(Ph2P)C6H4CO2H
MesCO2H
MesCO2H
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a
The corresponding di‐meta‐alkylated products were also isolated
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(see the SI).
‐‐‐
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‐‐‐
Thereafter, we tested different Lewis‐basic directing
groups for the direct alkylation with secondary alkyl bro‐
mide 2b (Scheme 4). It is noteworthy that the catalytic
system comprising [RuCl2(p‐cymene)]2 and MesCO2H was
not restricted to pyridine‐substituted arenes 1. Indeed,
direct C–H bond alkylations also proceeded meta‐
selectively with synthetically useful pyrazolyl‐, imida‐
zolyl‐, and benzimidazolyl‐substituted arenes 4, 6, and 8,
even when displaying a reactive free NH‐moiety (Scheme
4b). It is noteworthy that the direct functionalization of
substrate 6 solely furnished the mono‐meta‐substituted
product 7b, highlighting the excellent chemo‐ and site‐
selectivity of the optimized catalytic system.
16
a
Reaction conditions: 1a (0.50 mmol), 2a (1.50 mmol), base
(1.00 mmol), [RuCl2(p‐cymene)]2 (2.5 mol %), additive (30
mol %), 1,4‐dioxane (2.0 mL), 20 h, 100 °C.
Subsequently, we evaluated the effect exerted by the subs‐
tituents at the pyridine moiety onto the performance of
the ruthenium‐catalyzed meta‐selective C–H bond func‐
tionalization (Scheme 3). Pyridines bearing substituents
in the 4‐ or 5‐position did not furnish improved yields of
the desired products 3, while substrates displaying an
electron‐donating group in the 3‐position gave results
comparable to the one observed with the parent unsubsti‐
tuted compound 1a.
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Scheme 4. Azole‐Substituted Arenes as Substrates
Scheme 6. Scope of Ruthenium‐Catalyzed Direct
meta‐C–H Bond Alkylation
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Contrarily, the less electron‐rich pyrimidine derivative 10
delivered both the mono‐ as well as the di‐meta‐
substituted products 11b and 12b (Scheme 5).
Scheme 5. meta‐Selective Direct Alkylation with Py‐
rimidine Derivative 10
The remarkably high chemo‐selectivity of the ruthe‐
nium(II) catalyst was further highlighted by meta‐
selective C–H bond alkylations performed in water as a
nonflammable and nontoxic reaction medium55,56 as well
as by high yielding direct alkylations in the absence of
solvents (Scheme 7).
Scope and Limitations. Having identified the pyridyl‐
substituent as the most effective and most chemo‐
selective directing group, we subsequently explored the
scope and limitations of the meta‐selective arene alkyla‐
tion using secondary alkyl halides 2 (Scheme 6). The in‐
situ generated ruthenium(II) biscarboxylate catalyst was
found to be broadly applicable, as illustrated by the effi‐
cient conversion of various secondary alkyl halides 2, even
when being more sterically congested. Arenes 1 bearing
either electron‐donating or electron‐withdrawing substi‐
tuents in the para‐position selectively delivered the meta‐
substituted products 3.54 Furthermore, the optimized
catalyst displayed a synthetically useful chemo‐selectivity.
Indeed, the ruthenium(II) biscarboxylate proved tolerant
of electrophilic functional groups, such as a valuable ester
substituent, and allowed for the conversion of cyclic sec‐
ondary alkyl halides as well.
Scheme 7. Solvent Effect on Direct meta‐Alkylation
Arenes 1l–n displaying meta‐substituents also furnished
site‐selectively the meta‐alkylated products (Scheme 8),
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but were found to be considerably less reactive as com‐
formed detailed mechanistic studies to delineate its mode
of action. To this end, we conducted intermolecular com‐
petition studies with differently substituted arenes 1
(Scheme 10), which indicated the electron‐rich methoxy‐
substituted arene 1h to react preferentially, thereby being
suggestive of an electrophilic‐type activation manifold.
pared to the corresponding para‐substituted analogues
(Scheme 8 versus Scheme 6). These experimental findings
are particularly noteworthy, since steric interactions
would suggest an inverse order of reactivity (vide infra).
Scheme 8. meta‐Alkylation with meta‐Substituted
Arenes
Scheme 10. Intermolecular Competition Experiments
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Intramolecular competition experiments with ortho‐
substituted arenes 1 furnished the two corresponding
products of meta‐selective C–H bond functionalizations.
As to the catalysts working mode, it is particularly note‐
worthy that the more sterically congested arenes 3oa’’
and 3pa’’ were counterintuitively formed as the major
products (Scheme 9).
Intermolecular competition experiments between primary
and secondary alkyl halides 2a and 13a revealed that the
electrophiles were chemo‐specifically transformed into
the corresponding ortho‐ and meta‐alkylated products
3aa and 14a, respectively (Scheme 11). These experimental
findings can be rationalized with the varying steric inte‐
raction and the electrophilicities of primary and second‐
ary alkyl halides.57 Moreover, our experiments suggested
the ortho‐ and the meta‐alkylation to proceed with com‐
parable catalytic efficacies.
Scheme 9. Intramolecular Competition Experiments
with ortho‐Substituted Substrates
Scheme 11. Intermolecular Competition Experiments
between Primary and Secondary Alkyl Halides 2a and
13a
The direct meta‐alkylation with enantiomerically
enriched substrate (S)‐2a58 clearly showed that a racemi‐
Mechanistic Studies. Given the unique meta‐selectivity
of our ruthenium‐catalyzed direct alkylation, we per‐
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zation of the chiral organic electrophile occurred under
The initial formation of the cyclometalated complexes as
the reaction conditions (Scheme 12), which bears consi‐
derable potential for the future development of enanti‐
odivergent5 C–H bond functionalizations.
key intermediates directly explains the reduced efficacies
of the direct alkylation with meta‐substituted arenes
(Scheme 8) due to the considerable steric interactions
between the C‐3 substituent and the ruthenium fragment
in the ortho‐position (Figure 2a). Moreover, the a priori
unexpected formation of the more sterically hindered C‐3
alkylated products observed in the direct alkylations of
ortho‐substituted arenes is thus governed through a steric
shielding by the bulky ruthenium moiety (Figure 2b).
Scheme 12. Direct meta‐Alkylation with Substrate (S)‐
2a
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Figure 2. Sterically‐Controlled Reactivity and Selec‐
tivity with meta‐ and ortho‐Substituted Substrates
Moreover, we conducted experiments with isotopically
labeled substrates (Scheme 13). Thus, reactions performed
with the arene [D5]‐1a provided strong support for the C–
H bond metalation to initially proceed in the ortho‐
position of the arene (Scheme 13a). Moreover, the D/H‐
exchange by adventitious water in the stoichiometric base
and the additive MesCO2H indicated the ortho‐C–H bond
metalation to be reversible in nature. Subsequently, we
performed experiments with the partially deuterated
starting material [D3]‐1a, which was prepared by carbox‐
ylate‐assisted ruthenium(II)‐catalyzed D/H‐exchange46e
on compound [D5]‐1a in H2O. These studies were sugges‐
tive of the meta‐C–H bond cleavage not to be kinetically
relevant (Scheme 13b). This observation can be rationa‐
lized in terms of a SEAr‐type alkylative substitution in the
meta‐position. This electrophilic substitution is facilitated
by the strong activation as well as the ortho‐/para‐
directing effect induced by the Ru–C(sp2) σ‐bond.59‐61
Since our mechanistic studies indicated cycloruthenated
complexes to be key intermediates, we consequently be‐
came intrigued by probing the reactivity of well‐
characterized ruthenium(II) complexes, first evaluating
ruthenium(II) biscarboxylate 1529 (Scheme 14). Thus, the
isolated complex 15 selectively delivered the meta‐
alkylation product 3ha in a high isolated yield. Likewise,
the independently prepared cyclometalated complex 16
bearing a carboxylate ligand was found to be catalytically
competent (Scheme 14b). In stark contrast, the corres‐
ponding chloro‐ruthenacycle 17 did not furnish product
3ha. In this case, the catalytic activity could , however, be
restored by adding cocatalytic amounts of the carboxylic
acid MesCO2H (Scheme 14c), clearly highlighting the key
importance of carboxylate assistance.47
Scheme 13. Studies with Isotopically Labeled Com‐
pounds
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Scheme 14. Well‐Defined Ruthenium(II) Complexes
as the Catalysts
Scheme 15. Proposed Catalytic Cycle
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CONCLUSIONS
In summary, we have reported on the first metal‐
catalyzed meta‐selective direct alkylation reaction of
arenes with secondary alkyl halides under non‐acidic
reaction conditions. Thus, ruthenium(II) biscarboxylates
enabled C–H bond alkylations on various arenes with
ample scope. Detailed mechanistic studies were suppor‐
tive of an initial reversible cycloruthenation. This cyclo‐
metalation increases the reactivity of the arenes to under‐
go an electrophilic‐type substitution. The strong directing
group effect of the Ru–C(sp2) σ‐bond thereby overall al‐
lows for an efficient and site‐selective meta‐alkylation.
Experiments with independently prepared, well‐defined
ruthena(II)cycles clearly highlighted their key importance
as crucial intermediates, and provided strong evidence for
carboxylate assistance.
Based on our mechanistic studies we propose the catalytic
cycle to involve an initial reversible formation of the cyc‐
lometalated complex 16 (Scheme 15). This cyclometalation
activates the aromatic substrates 1 for a SEAr‐type alkyla‐
tion with the secondary alkyl halides 2 through the strong
directing group effect of the Ru–C(sp2) σ‐bond,61 thus
leading to a functionalization in the para‐ or ortho‐
position of the Ru–C(sp2) bond.62 Finally, proto‐
demetalation provides the desired meta‐substituted
product 3 and regenerates the catalytically active species
15.
ASSOCIATED CONTENT
Supporting Information.
1
Experimental procedures, characterization data, and H and
13C NMR spectra for new compounds. This material is availa‐
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Lutz.Ackermann@chemie.uni‐goettingen.de
ACKNOWLEDGMENT
Generous support by the CaSuS PhD program (fellowship to
N.H.), AstraZeneca, and the European Research Council
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under the European Community’s Seventh Framework Pro‐
kuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503‐4513. (f) Dau‐
gram (FP7 2007–2013)/ERC Grant agreement no. 307535 is
gratefully acknowledged. We furthermore thank Dr. Rubén
Vicente and M.Sc. Jie Li (Georg‐August‐Universität) for pre‐
liminary experiments, Dipl.‐Chem. R. Machinek for detailed
2D‐NMR experiments (Georg‐August‐Universität) and Dr. D.
S. Yufit (University of Durham) for two X‐ray diffraction
analyses.
gulis, O. Top. Curr. Chem. 2010, 292, 57‐84. (g) Livendahl, M.;
Echavarren, A. M. Isr. J. Chem. 2010, 50, 630‐651. (h) Satoh,
T.; Miura, M. Chem. Eur. J. 2010, 16, 11212‐11222. (i) Boutadla,
Y.; Davies, D. L.; Macgregor, S. A.; Poblador‐Bahamonde, A.
I. Dalton Trans. 2009, 5820‐5831. (j) Ackermann, L.; Vicente,
R.; Kapdi, A. Angew. Chem. Int. Ed. 2009, 48, 9792‐9826. (k)
Thansandote, P.; Lautens, M. Chem. Eur. J. 2009, 15, 5874‐
5883 and references cited therein.
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Table of Contents graphic:
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