Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective Alkylation of Aryl Bromides over Triflates and Chlorides in Air

Article abstract of DOI:10.1002/anie.201701691

Disclosed herein is the first general chemo- and site-selective alkylation of C?Br bonds in the presence of COTf, C?Cl and other potentially reactive functional groups, using the air-, moisture-, and thermally stable dinuclear Pd^I catalyst, [Pd(μ-I)PtBu₃]₂. The bromo-selectivity is independent of the substrate and the relative positioning of the competing reaction sites, and as such fully predictable. Primary and secondary alkyl chains were introduced with extremely high speed (<5 min reaction time) at room temperature and under open-flask reaction conditions.

Full text of DOI:10.1002/anie.201701691

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701691
German Edition: DOI: 10.1002/ange.201701691
Palladium Catalysis
Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective
Alkylation of Aryl Bromides over Triflates and Chlorides in Air
Indrek Kalvet, Theresa Sperger, Thomas Scattolin, Guillaume Magnin, and
Franziska Schoenebeck*
Abstract: Disclosed herein is the first general chemo-
À
and site-selective alkylation of C Br bonds in the
À
presence of COTf, C Cl and other potentially reactive
functional groups, using the air-, moisture-, and
thermally stable dinuclear PdI catalyst, [Pd(m-
I)PtBu3]2. The bromo-selectivity is independent of
the substrate and the relative positioning of the
competing reaction sites, and as such fully predictable.
Primary and secondary alkyl chains were introduced
with extremely high speed (< 5 min reaction time) at
room temperature and under open-flask reaction
conditions.
C
sp2–Csp3 cross-coupling reactions are key trans-
formations to access valuable feedstock material for
synthesis, materials, as well as for the pharmaceutical
and agrochemical arenas. Consequently, there has
been a tremendous interest in devising efficient
methodologies to achieve this feat.[1] While remark-
able progress has been made with transition-metal
catalysis,[2] Pd-based methodology frequently offers
superior generality and mildness—a prerequisite to
access richly functionalized building blocks for fur-
Figure 1. Key challenges in Pd-catalyzed alkylation reactions.
ther synthetic transformations.[3] Among the key challenges in
Pd-catalyzed alkylations is the possibility for b-hydride
elimination from [PdII]-alkyl intermediates and isomerization
of the coupling partner, resulting in product mixtures (Fig-
ure 1).[2a] Additionally, the nucleophilic/basic organometallic
cross-coupling partners that are generally employed (i.e.
RMgX or RZnX) are frequently unstable and may be
incompatible with additional functionalities in the substrate,
particularly under prolonged reaction times and/or elevated
temperatures.
While impressive progress has been made in minimizing
side-reactions,[4] as well as addressing the handling and
preparation of the cross-coupling partner,[5] to date, no
general
and
chemoselective
alkylation
of
poly-
(pseudo)halogenated arenes has been accomplished.[6] This
situation may be of little surprise, as even the more facile
Csp2–Csp2 coupling has until our recent report[8] been a long-
standing challenge; the overall site-selectivity in typical Pd0-
based methodology is substrate-, ligand-, and condition
dependent.[7]
We recently disclosed that the application of the air-,
moisture- and thermally stable iodide-bridged dinuclear PdI
catalyst 1 allows for a substrate-independent, chemoselective
arylation of poly(pseudo)-halogenated arenes.[8] Encouraged
by these findings, this report discloses our efforts to address
the greater challenge of site-selective alkylation, which would
be highly desired in the context of synthetic diversity and to
allow orthogonal, programmable, and sequential synthetic
approaches.[9]
Owing to their relative mildness, alkylzinc reagents are
the preferred coupling partners in Pd-catalyzed alkylations of
aryl (pseudo)halides.[2a] In this context, the commercially
available NHC (N-heterocyclic carbene)-based and biaryl
phosphine-based Pd-precatalysts developed by the groups of
Organ and Buchwald have been applied in versatile alkyla-
tions of aryl bromides, chlorides or triflates at room temper-
[*] M. Sc. I. Kalvet, M. Sc. T. Sperger, M. Sc. T. Scattolin,
M. Sc. G. Magnin, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701691.
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited, and is not used for commercial purposes.
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air, yielding the same reaction outcome under inert
and open-flask conditions.[15]
Encouraged by this exceptional selectivity along
with high practicality, we subsequently explored the
À
generality of the observed C Br coupling preference.
À
We observed exclusive alkylation of the C Br bond,
independent of its relative positioning to the compet-
ing reaction sites or the nature of the alkylating
reagent (i.e. primary vs. secondary alkylzinc, see
Scheme 1). Selective functionalization of bromide
À
occurred in ortho, meta, and para positions to C
À
OTf, and also in the presence of C Cl (4a–4e,
Figure 2. Site-selectivity of Negishi alkylation with commercially available Pd
(pre-)catalysts[10] including 1.
Scheme 1), allowing the isolation of the corresponding
Csp –Csp coupled products in high yields. The C Br
coupling also proved to be equally selective and
2
3
À
À
efficient for more hindered C Br sites (entries 4o–
4r), as well as for pharmaceutically and agrochemically
ature or 608C in 0.5–2 hours.[4c,e,f] As there has not been any
report of a chemoselective alkylation method, we initially
assessed the performance of these highly successful catalyst
systems and conditions for their potential to site-selectively
À
relevant heterocycles. Selection for C Br occurred in all
À
À
cases, leaving the more activated C OTf and C Cl sites
untouched (entries 4h–4n). To our delight, the alkylation of
aromatic Csp2–Br bonds over competing Csp3–halogen sites
was also effective (entries 4 f and 4g). For some substrates
À
À
alkylate substrate 2a, which displays competing C Br, C Cl
À
and C OTf sites, with n-butylzinc chloride (Figure 2). Both
catalyst systems were unselective and generated bis-
alkylated products in mixtures with starting material.
Interestingly, while the biarylphosphine (CPhos)
system predominantly gave rise to the product
À
À
resulting from C OTf and C Br alkylation, the
À
NHC (IPent) system showed simultaneous C Br
[10]
À
and C Cl alkylation instead.
Both ligands are
generally presumed to form a low coordinate “Pd0L1”
active species, and would therefore be expected to
result in analogous site-selectivities.[11] This may hint
toward mixtures of different reactive species, for
example, through coordination of the nucleophilic
coupling partner to the Pd0 species to generate
anionic Pd0LXÀ,[12] which likely displays different
selectivity.[7e,g] Indeed, the majority of Csp2–Csp2
Kumada and Negishi couplings resulted in predom-
[7a]
À
À
inant coupling at C OTf over C Br.
We envisioned that a coupling concept based on
PdI could be advantageous in this context.[13] If the
alkyl coupling partner was incorporated as the
bridging unit via iodide/alkyl exchange in the dinu-
clear entity, the resulting transient alkyl-bridged PdI
dimer might selectively react and also allow us to
circumvent the intermediacy of [PdII]-alkyl species
and potential side reactions. Thus, we tested the air-
stable PdI dimer 1 (2.5 mol%) in the coupling of
substrate 2a with n-butylzinc chloride at room
temperature in toluene.[14] The reaction was
extremely rapid, having reached full conversion of
2a in less than 5 min reaction time (see Figure 2. To
our delight, the reaction proved to be completely
À
selective and yielded the product resulting from C Br
À
À
alkylation in 96% yield. Both the C Cl and C OTf
sites remained untouched. To the best of our knowl-
À
Scheme 1. Demonstration of site-selective alkylation of C Br bonds. Reaction
conditions: 2 (0.4 mmol), 3 (0.8 mmol in THF, prepared from 0.8 mmol of R-
MgX and 0.84 mmol of ZnCl2), 1 (0.01 mmol), toluene (1.5 mL), open flask, RT,
5 min. [a] Using R-MgX as 3. [b] 3 was added drop-wise.[16] [c] 0.6 mmol of 3.
[d] 0.72 mmol of 3. [e] 1.2 mmol of 3. [f] 1.0 mmol of 3.
edge, this is the first example of a selective Negishi
[6]
À
alkylation that does not react with the C OTf site.
Importantly, the transformation was also tolerant to
2
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Angewandte
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(e.g. more sterically hindered examples or those
bearing highly reactive functional groups), a slower
addition (over a 3–5 min interval) of the organome-
tallic coupling partner proved advantageous to ach-
ieve higher yields, regardless of whether the reaction
was performed in the presence or absence of air.
With these excellent selectivities proven, we
subsequently tested this methodology for its potential
in large-scale applications. Addition of n-butylzinc
chloride to 1 g of 2-bromo-4-chlorophenyl triflate
(2a), along with 1 mol% of the PdI catalyst 1 under
otherwise identical open-flask reaction conditions,
À
yielded the C Br coupling product (4a) in 91% yield
in 5 min. Thus, these coupling reactions are also
equally selective and rapid under reduced catalyst
loadings and significantly larger scales. As such, our
methodology allows for fully predictable, robust and
À
substrate-independent C Br alkylation under highly
practical conditions.
Having demonstrated the exclusive bromo-selec-
À
À
tivity in competition with C OTf and C Cl sites, we
next investigated the general synthetic applicability
of this methodology for less activated arenes con-
taining only a single coupling site along with addi-
tional functional groups (Scheme 2). Heterocycles as
well as electrophilic functional groups (i.e. aldehyde
6e, nitriles 6k and 6s, ketones 6d, 6p, 6q, ester 6j)
are well tolerated. The reaction could also be
performed in the presence of nitro (6k), azido (6i)
functionalities.[17] Also boronic acid esters (i.e. BPin,
6c, 6l, and 6m), which can enable further orthogonal
coupling reactions and hence molecular diversity.
In terms of the scope of organometallic reagents
a variety of alkylzinc, as well as some alkylmagnesium
coupling partners could be utilized. Alkyl groups,
both with and without b-hydrogen atoms, all proved
compatible and underwent smooth Csp2–Csp3 cou-
plings (Scheme 2). Methylation (6a) proceeded most
efficiently under Kumada conditions. A range of
secondary alkyl zinc and magnesium reagents could
also be coupled efficiently. The desired products were
obtained in good yields for both acyclic (i-Pr, sec-butyl) as
well as cyclic (cyclopropyl, -pentyl, and -hexyl) alkyl groups.
Products arising from isomerization of the secondary alkyl
moiety were detected either in trace amounts (ꢀ 3% with
6m) or not at all (6l, 6p,q), and as such are competitive with
the current state-of-the-art.[4a–f]
To shed light on the potential mechanism of the trans-
formation and the origins of exclusive bromo-selectivity, we
conducted computational studies and examined the predicted
À
Scheme 2. Scope of C Br alkylation and functional group tolerance. Reaction
conditions: 2 (0.4 mmol), R-ZnX 3 (0.8 mmol in THF, prepared from 0.8 mmol
of R-MgX and 0.84 mmol of ZnCl2), 1 (0.01 mmol), toluene (1.5 mL), open flask,
RT, 5 min.[18] [a] Using R-MgX as 3. [b] 3 was added drop-wise. [c] Alkyl-ZnX was
prepared from Alkyl-X using Mg, LiCl and ZnCl2. See Supporting Information for
details. [d] 0.6 mmol of 3. [e] 0.72 mmol of 3. [f] 1.2 mmol of 3.
I
À
bridged Pd dimer, which indicated a clear C Br addition
À
À
preference. Both C Cl and C OTf are predicted to be
significantly disfavored (by DDG° = 5.8 and 2.8 kcalmolÀ1).
Alternatively, Pd0PtBu3 may be active and our computations
°
À
suggest preferential C Br addition (by DDG = 4.4 and
8.3 kcalmolÀ1 for Cl and OTf). Overall, these data suggest
0
I
I
À
that both Pd -based and Pd Pd -based reactivities are con-
sistent with the observed C Br selectivity. The NHC and
À
CPhos systems (as presented in Figure 2) are also generally
presumed to form mono-ligated active Pd0 species.[11] We also
calculated the predicted selectivities for these cases. Interest-
À
À
À
site-selectivity for C Br versus C Cl versus C OTf as
a function of active species.[19] The dinuclear PdI dimers may
either react directly with aryl halides or act as a precursor for
monophosphine Pd0. In short, the precise mode of reactivity is
highly dependent on whether the coupling partner can
function as a bridging unit in the dinuclear entity.[13,20] For
related dinuclear NiI complexes, there has been very recent
evidence that carbon-based bridges may in fact be possible.[21]
We calculated the predicted selectivities for an n-propyl-
ingly, these Pd0L1 species also show a clear preference for
°
À
oxidative addition at C Br (by DDG = 5.6 and 7.8 kcal
À1
À
À
mol , respectively, for C Cl and C OTf with L = IPent, and
3.0 and 9.5 kcalmolÀ1 with L = CPhos). These data contrast
the observed lack of selectivities and point toward more
complex reactivity scenarios. For example, there could be
alternative reactive species, or oxidative addition may not be
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however, on the basis of the collected data neither Pd0 nor
I
I
À
Pd Pd catalysis can be excluded in our case. Our future
studies are directed at gaining detailed mechanistic insight on
these and related processes.
In conclusion, a predictable, chemoselective alkylation of
À
À
À
C Br sites in the presence of C OTf, C Cl, and additional
functional groups was developed. The method is character-
ized by high speed (ꢀ 5 min reaction time) and operational
simplicity, being fully compatible with oxygen (open-flask
conditions) and employing an air-, moisture, and thermally
stable dinuclear PdI catalyst. Primary and secondary alkyl
groups were introduced for a wide range of substrates,
tolerating steric bulk and numerous functional groups,
including cyano, aldehyde, azide, nitro, ester, methoxy,
BPin, and silyl groups, as well as benzylic chlorides, alkyl
bromides, and heterocycles. Potential for large-scale applica-
tions was also showcased.
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À
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Acknowledgements
We thank the RWTH Aachen, the MIWF NRW, the Euro-
pean Research Council (ERC-637993) and Evonik (doctoral
scholarship to T.S.) for funding. Calculations were performed
with computing resources granted by JARA-HPC from
RWTH Aachen University under project “jara0091”.
[8] I. Kalvet, G. Magnin, F. Schoenebeck, Angew. Chem. Int. Ed.
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Conflict of interest
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Snieckus, Platinum Met. Rev. 2013, 57, 234.
The authors declare no conflict of interest.
Keywords: homogeneous catalysis · chemoselectivity · Csp2–
Csp3 coupling · dimers · palladium
[10] The other components are mainly the starting material or its
debromination product. With Pd-PEPPSI-IPent also 6% tri-
alkylated product was observed.
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4
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[15] Safety note: organometallic reagents are often moisture sensi-
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tive and may react violently in air. All necessary safety
precautions must be considered when operating under open-
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[16] Preparation of 4q required slow addition over 10 min.
[17] To date, there have been few reports of Negishi alkylation using
halonitroarenes. There have been no reports on alkyl halide and
azide functionalities. For Ni-catalyzed Kumada cross-coupling in
the presence of an alkyl bromide see: C. Lohre, T. Droege, C.
Wang, F. Glorius, Chem. Eur. J. 2011, 17, 6052.
[18] The organometallic reagents were obtained from commercial
sources, or prepared by the procedure from Ref. [5b] or by pre-
mixing the Grignard with ZnCl2 solution.
[21] For precedence of C-bridged NiI-dimer species, see: K. Matsu-
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2017, 36, 255.
[19] a) Gaussian09, RevisionE.01, M. J. Frisch, et al. [see Supporting
Information for full reference]. b) Calculations were performed
at the CPCM (toluene) M06L/def2TZVP//wB97XD/6-31G(d)
(LANL2DZ) level of theory. c) For appropriateness of method,
see: T. Sperger, I. A. Sanhueza, I. Kalvet, F. Schoenebeck, Chem.
Rev. 2015, 115, 9532.
Manuscript received: February 15, 2017
Revised: April 10, 2017
Final Article published: && &&, &&&&
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Communications
Palladium Catalysis
I. Kalvet, T. Sperger, T. Scattolin,
G. Magnin,
F. Schoenebeck*
&&&& — &&&&
Palladium(I) Dimer Enabled Extremely
Rapid and Chemoselective Alkylation of
Aryl Bromides over Triflates and
Chlorides in Air
À
À
Pick me! A method for cross-coupling
bromo groups with Grignard or organo-
zinc reagents mediated by a dinuclear PdI
catalyst was developed. The reactions
tolerant of both C OTf and C Cl func-
tionalities. The transformations pro-
ceeded under open-flask conditions at
room temperature, and were complete
within 5 min.
À
were highly selective for C Br and were
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!