Rapid Room-Temperature, Chemoselective Csp2?Csp2Coupling of Poly(pseudo)halogenated Arenes Enabled by Palladium(I) Catalysis in Air

Article abstract of DOI:10.1002/anie.201609635

While chemoselectivities in Pd⁰-catalyzed coupling reactions are frequently non-intuitive and a result of a complex interplay of ligand/catalyst, substrate, and reaction conditions, we herein report a general method based on Pd^Ithat allows for an a priori predictable chemoselective C_sp²?C C_sp²coupling at C?Br in preference to C?OTf and C?Cl bonds, regardless of the electronic or steric bias of the substrate. The C?C bond formations are extremely rapid (<5 min at RT) and are catalyzed by an air- and moisture-stable Pd^Idimer under open-flask conditions.

Full text of DOI:10.1002/anie.201609635

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201609635
German Edition: DOI: 10.1002/ange.201609635
Cross-Coupling
À
Rapid Room-Temperature, Chemoselective Csp2 Csp2 Coupling of
Poly(pseudo)halogenated Arenes Enabled by Palladium(I) Catalysis in
Air
Indrek Kalvet, Guillaume Magnin, and Franziska Schoenebeck*
Abstract: While chemoselectivities in Pd0-catalyzed coupling
reactions are frequently non-intuitive and a result of a complex
interplay of ligand/catalyst, substrate, and reaction conditions,
we herein report a general method based on PdI that allows for
À
À
an a priori predictable chemoselective Csp2 Csp2 coupling at C
À
À
Br in preference to C OTf and C Cl bonds, regardless of the
À
electronic or steric bias of the substrate. The C C bond
formations are extremely rapid (< 5 min at RT) and are
catalyzed by an air- and moisture-stable PdI dimer under open-
flask conditions.
T
he biaryl motif is not only present in numerous drug
molecules, but it is also a ubiquitous building block in
materials science and complex natural products. Its substitu-
tion pattern ultimately determines the function as pharma-
ceutical, agrochemical, electronic device, secondary metabo-
lite, or even privileged ligand.[1] Consequently, the develop-
ment of a synthetic repertoire to selectively access diversely
functionalized arenes is of considerable interest. Owing to the
relative mildness, palladium-catalyzed chemoselective cross-
coupling strategies of poly(pseudo)halogenated arenes rep-
resent a strategy of considerable interest.[2] In this context, the
oxidative addition step is generally selectivity-controlling.
Figure 1. Examples of divergent selectivities.[4,3] Tf =trifluoromethane-
sulfonyl.
While the relative ease of oxidative addition is frequently
[2]
À
À
À
À
referred to as C I > C OTf ꢀ C Br> C Cl, these rough
trends by no means allow an a priori prediction of favored
coupling site. Instead, it is a result of subtle interplay between
substrate (electronic/steric bias and bond strength), catalyst
(ligand/ligation state), solvent, and additive effects
(Figure 1).[2,3] For example, while [PdCl2{P(o-tol)3}2]-cata-
[5]
À
preferential coupling at the C OTf site for D. Although
progress has been made in the development of predictive
models[6] and in the mechanistic understanding of the factors
that dictate site selectivity,[2,3,7] selective couplings frequently
remain a result of rigorous screening activities. However,
modern research programs not only seek for greater sustain-
ability (i.e. less waste), but also frequently involve iterative,
programmable synthetic approaches to increase chemical
diversity.[8] As such, a general and predictive coupling
protocol would be highly desired, particularly if paired with
operational simplicity.
À
lyzed Kumada coupling of A gave selective C Br function-
À
alization, the introduction of two methyl groups ortho to C
Br (B) diminished selectivities, thus resulting in mixtures
under otherwise identical reaction conditions (Figure 1).[4]
A
similar substrate dependence was observed for [Pd(PPh3)4]-
À
catalyzed Suzuki couplings: while C Br was the favored
coupling site for C, analogous reaction conditions resulted in
Clearly, the ultimate site selectivity is strongly affected by
subtle changes in substrate, ligand, or reaction conditions in
the context of palladium(0) catalysis. This selectivity is likely
due to modifications of the electron-richness of the active
palladium(0) catalyst. Depending on the nature of the ligand
and reaction conditions, multiple potentially reactive species
may coexist, ranging from PdLn to anionic [PdLnX]À (n = 1 or
2)[3,7,9] and could in turn trigger divergent selectivities.[3d] We
therefore envisioned that utilizing a different oxidation state
(I), may be advantageous and potentially allow more
pronounced chemoselectivities. We recently showed that the
[*] I. Kalvet, 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 for this article can be found under:
http://dx.doi.org/10.1002/anie.201609635.
ꢀ 2016 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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iodine-bridged palladium(I) dimer 1 (shown in Table 1) is an
air- and moisture-stable, as well as thermally stable species
features an electronically deactivated (by ortho methoxy) and
À
sterically shielded (by ortho adamantyl) C Br site in com-
À
À
À
which functions as and efficient catalyst for C SCF3, C
petition with an accessible C OTf site. Despite these
À
SeCF3, and C Br bond formations with aryl iodides and
challenges, upon using an organozinc as the coupling partner
bromides.[10,11] Our mechanistic data indicated that the
catalysis proceeded by dinuclear palladium(I) cycles. In this
context, the cross-coupling partner was employed as a nucle-
ophile, which was incorporated as bridging unit in the PdI–PdI
framework and subsequently exchanged with an aryl halide to
give the functionalized arene. Whether carbon-based nucle-
ophiles, such as aryl Grignard or organozinc species, could
also function as bridges in dinuclear palladium(I) catalysis,
was unclear. Our initial studies on Kumada couplings
suggested that high reactvities could be achieved with
1 however.[12] Efficient Kumada and Negishi couplings of
aryl (pseudo)halides have otherwise been developed for
single coupling possibilities, using air-sensitive palladium(0)
[or nickel(0)] catalysis, with reaction times of several hours.[13]
Notably, Knochel and co-workers observed more rapid
Negishi and Kumada cross-coupling reactions under modified
palladium(0) catalysis conditions, which was ascribed to the
potential involvement of radicals.[14] A general method for the
realization of chemoselective couplings has not been
reported.[15] To test whether selective cross-couplings would
be possible, we subjected phenyl Grignard along with
2.5 mol% of the 1 in toluene to the densely functionalized
we observed strikingly rapid and selective C Br coupling. As
À
such, the bromo selectivity appears general for palladium(I)
catalysis, and is independent of both the steric and electronic
bias of the substrate, as well as the cross-coupling partner.
We subsequently investigated a wider range of substrates
for the preferred coupling selectivities, including pharma-
ceutically relevant heterocycles. Table 1 summarizes the
[a]
À
Table 1: C Br selective Kumada cross-couplings.
À
À
substrate 2, which has competitive possibilities for C Br, C
À
OTf, and C Cl couplings (Scheme 1a). All reagents were
handled in air and the reaction was performed in an open
À
flask. Pleasingly, we saw exclusive coupling at C Br. The
reaction was remarkably rapid and completed in less than
5 minutes at room temperature. In stark contrast, when we
subjected other air-stable complexes based on palladium(II),
we observed sluggish reactivity after 5–24 hours, thus obtain-
ing low conversion and no pronounced selectivity under open-
flask or inert reaction conditions (Scheme 1a).
We next focused on the sterically demanding aryl bromo
triflate 3 (Scheme 1b). This substrate is a stern test as it
[a] Reaction conditions: 1 (4.4 mg, 0.005 mmol), ArBr (0.2 mmol),
PhMgCl (2m in THF, 150 mL, 0.3 mmol), toluene (3.0 mL). Yield is that
of isolated product. [b] 5 mol% of 1 was used. [c] Used 1.8 equiv of
PhMgCl. [d] Used 2 equiv of PhMgCl. [e] Used 2.5 equiv of PhMgCl.
open-flask Kumada cross-coupling reactions performed with
phenyl magnesium chloride at room temperature to test for
À
À
À
À
C Br versus C OTf and C Br versus C Cl selectivities. In all
À
cases, the coupling was completely selective for C Br, thus
allowing isolation of the coupling products in good to
excellent yields. This selectivity was once again found to be
independent of the respective relative positioning of the
potential leaving groups (ortho, meta, para to each other) or
the presence of additional (de)activating substituents or
heterocycles (3, 4, 6–9) (see Table 1). Notably, the pharma-
ceutically relevant quinoline 9 was previously reported to give
0
[16]
À
C Cl coupling under Pd /Xantphos catalysis. In our case,
Scheme 1. Stern tests: Palladium(I) dimer performance versus alterna-
tive air-stable palladium complexes in either Kumada or Negishi
couplings of challenging substrates.
À
orthogonal and exclusive C Br functionalization took place.
The coupling was also efficient with alternative aryl
2
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Grignards, thus allowing the installation of additional func-
and quinolone heterocycles were also studied, and the
[18]
À
À
À
tionality, such as either C Cl or C F using a Grignard
(Table 1, bottom).
analogous exclusive C Br selectivity was seen in all cases.
Alternative arenes (14 and 15) could also be introduced in an
To further test this methodology, we also undertook
a coupling reaction between PhMgCl and 2-bromophenyl
triflate (see Table 1) on a 1 gram scale (3.28 mmol) using
1 mol% 1 under otherwise identical open-flask reaction
conditions. The coupling reaction was found to be equally
equally efficient manner. As such, this catalytic system
À
provides consistent and predictable C Br selectivity, thus
offering orthogonal and programmable synthetic approaches
of high convenience (air-stable catalyst, room temperature,
rapid reaction speed, open flask).
À
rapid and completely selective for C Br. The corresponding
Intrigued by the observed reactivities, we subsequently
performed additional studies to shed light on the origins of
the selectivity and reactivity. There is the possibility that the
coupling proceeds by direct reactivity of the PdI dimer[10] or,
alternatively, 1 functions as a precatalyst to a highly reactive
monophosphine palladium(0) complex (Pd0PtBu3) upon acti-
vation by the nucleophilic organometallic coupling part-
ner.[12,11] While palladium(0)-based catalysis would generally
be incompatible with open-flask reaction conditions because
of oxidation of the catalyst/ligand, the impressive speed of the
present coupling reactions may simply exceed the rates of the
competing oxidation of any potentially released palladium(0)
species. Our in situ ReactIR monitoring showed that the
palladium(I)-dimer-catalyzed cross-coupling reaction of 4-
bromoaryl triflate with o-tolyl-MgCl reaches completion in
just over a minute (Figure 2), displaying a non-exponential
pseudo-first-order growth.[19] In contrast, when we subjected
[Pd0(PtBu3)2] to air for 30 minutes, we saw a significant
amount of [Pd0(PtBu3)2] remaining (as judged by 31P NMR
data; see the Supporting Information). Interestingly, upon
subsequent addition of (nBu4N)I along with PhMgCl (2 equiv
relative to Pd) to the latter mixture, we observed the
formation of 1 along with biphenyl.[20] To the best of our
knowledge, this is the first observation of an aerobically
induced oxidation of a palladium(0) complex to a palladium(I)
dimer.
coupling product was isolated in 95% yield after column
chromatography, thus showcasing that these coupling reac-
tions can also be performed under lower catalyst loadings or
significantly larger scale.[17]
We subsequently explored the generality for site-selective
Negishi cross-coupling and subjected a range of polysubsti-
tuted arenes and heterocycles to the catalyst 1 under open-
flask coupling conditions with ortho-tolyl zinc chloride in
toluene/THF. Table 2 summarizes the results. Once again, we
observed that the reactions were completed within 5 minutes
at room temperature. In analogy to the results in Table 1, also
for Negishi cross-coupling reactions, exclusive functionaliza-
tions of the C Br bonds were seen in competition with C Cl
and/or C OTf sites, regardless of the steric accessibility or
electronic bias imposed by the substrate. Several pharma-
ceutically and agrochemically relevant pyridine, thiophene,
À
À
À
[a]
À
Table 2: C Br selective Negishi cross-couplings.
These data indicate that any palladium(0) released in the
reaction mixture could ultimately be reversibly transformed
back into the palladium(I) dimer. On the basis of these data,
neither palladium(0)- nor palladium(I)-based catalysis can be
excluded. Thus, we subsequently set out to computationally
À
study the chemoselectivities for oxidative additions at Ph Br
[a] 1 (8.7 mg, 0.01 mmol), ArBr (0.4 mmol), o-tolyl-MgCl (1m in THF,
600 mL, 0.6 mmol), ZnCl2 (1m in THF, 640 mL, 0.64 mmol), toluene
(1.5 mL). Yield is that of isolated product. [b] Used 1.1 equiv of ArMgCl
and 1.2 equiv of ZnCl2. [c] Used 1.3 equiv of ArMgCl and 1.4 equiv of
ZnCl2.
Figure 2. Top: ReactIR study of the Kumada coupling of 4-bromoaryl
triflate (Ar=o-tol) catalyzed by 1. Bottom: aerobic oxidation of Pd0 to
PdI–PdI.
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À
À
Coupling: Theory and Applications (Ed.: T. Colacot), RSC
Catalysis Series, Cambridge, UK, 2015.
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the method CPCM (toluene) M06/def2-TZVP//wB97XD/6-
31G(d)/SDD.[21] The computational data suggest a clear
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À
preference for oxidative addition at C Br for both, a mono-
ligated [Pd0PtBu3] and a PdI–PdI derived species (by DDG° ꢁ
6.8 kcalmolÀ1 for [Pd0PtBu3] and DDG° ꢁ 3.4 kcalmolÀ1 for
I
I
À
À
Pd -Pd relative to C Cl). C OTf addition is predicted to be
even less favored (see the Supporting Information). In
contrast, an anionic palladium(0) species [Pd0(PtBu3)XÀ]
with X = halogen or aryl, which may form under conditions
with nucleophilic additives,[2a,3a,f,9] particularly Grignard
reagents,[22] is predicted to add preferentially to C OTf (by
À
DDG° ꢁ 3.5 kcalmolÀ1 for X = Ph and 2.8 kcalmolÀ1 for X =
Cl). With monoligated [Pd0PtBu3] and PdI–PdI being formally
electron-deficient species (as opposed to PdLXÀ), selection
occurs for the coupling site with lowest distortion energies.[7b]
Key to overall high chemoselectivities therefore appears to be
the avoidance of co-existing reactive species, which are more
likely encountered under prolonged reaction times.
À
In summary, an a priori predictable chemoselective Csp2
Csp2 bond formation of poly(pseudo)halogenated arenes has
been developed. The coupling reactions are triggered by the
bench-stable dinuclear palladium(I) complex [{(PtBu3)PdI}2},
and are completed in less than 5 minutes at room temperature
in air.[17] Exclusive bromo selectivity was observed in the
presence of C OTf and C Cl sites, that is independent of any
electronic or steric bias imposed by the substrate. The method
proved to be compatible with heterocycles and functional
groups, thus tolerating C Cl, C OTf, C F, C CN, aldehydes,
esters, and sterically demanding groups (ortho-adamantyl) as
well as both, aryl zinc, and Grignard coupling partners. The
larger scale applicability of the present method was also
showcased (on 1 g scale with 1 mol% catalyst loading).
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À
À
À
À
À
À
[9] a) A. Jutand, A. Mosleh, Organometallics 1995, 14, 1810;
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Acknowledgements
We thank the RWTH Aachen, the MIWF NRW and the
European Research Council (ERC-637993) for funding.
Calculations were performed with computing resources
granted by JARA-HPC from RWTH Aachen University
under project “jara0091”.
[11] Labile PdI dimers have otherwise found applications as preca-
talysts: a) P. R. Melvin, A. Nova, D. Balcells, W. Dai, N. Hazari,
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Weissman, L. J. W. Shimon, D. Milstein, Organometallics 2004,
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Chem. 2003, 68, 1163; f) J. Stambuli, R. Kuwano, J. F. Hartwig,
Angew. Chem. Int. Ed. 2002, 41, 4746; Angew. Chem. 2002, 114,
4940.
Conflict of interest
The authors declare no conflict of interest.
Keywords: chemoselectivity · density-functional calculations ·
heterocycles · palladium · reaction mechanisms
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metallics 2015, 34, 5191.
[13] Selected examples: a) M. J. Iglesias, A. Prieto, M. C. Nicasio,
Org. Lett. 2012, 14, 4318; b) R. Martin, S. L. Buchwald, J. Am.
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Org. Chem. 2005, 70, 9364; f) N. Yoshikai, H. Mashima, E.
[1] For reviews, see: a) D. A. Horton, G. T. Bourne, M. L. Smythe,
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Metal-Catalyzed Couplings in Process Chemistry: Case Studies
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Dunetz), Wiley, Hoboken, 2013; d) New Trends in Cross-
4
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Nakamura, J. Am. Chem. Soc. 2005, 127, 17978; g) V. Bonnet, F.
atmosphere. The presence of O2 therefore does not appear
critical.
[18] Although the coupling was selective and complete, some loss of
material in purifications was experienced.
Mongin, F. Trecourt, G. Queguiner, P. Knochel, Tetrahedron
2002, 58, 4429; h) J. Huang, S. P. Nolan, J. Am. Chem. Soc. 1999,
121, 9889. For reviews, see: i) D. Haas, J. M. Hammann, R.
Greiner, P. Knochel, ACS Catal. 2016, 6, 1540.
[19] This could be indicative of reductive elimination being rate
determining, or a potentially autocatalytic scenario.
[14] a) M. Kienle, P. Knochel, Org. Lett. 2010, 12, 2702; b) G.
Manolikakes, P. Knochel, Angew. Chem. Int. Ed. 2009, 48, 205;
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[15] While a general protocol for chemoselective couplings of
poly(pseudo)-halogenated arenes have not been accomplished,
halogenated arenes could be introduced by the Grignard reagent
(Ref. [13b]).
[16] M. Weiss, E. F. Dimauro, T. Dineen, R. Graceffa, A. Guzman-
Perez, H. Huang, C. Kreisman, I. E. Marx, H. N. Nguyen, E.
Peterson, WO2014201173 A1, 2014.
[20] Subjecting [Pd0(PtBu3)2] to oxygen and (nBu4N)I did not yield
PdI dimer 1. However, mixing PhMgCl, [Pd0(PtBu3)2], and-
(nBu4N)I first under Ar (no change), followed by exposure to
air, gave PdI dimer 1.
[21] Gaussian09, RevisionD.01, M. J. Frisch, et al. [see SI for full
reference]. For appropriateness of the chosen computational
method, see: T. Sperger, I. A. Sanhueza, I. Kalvet, F. Schoene-
beck, Chem. Rev. 2015, 115, 9532.
[22] M. Kolter, K. Koszinowski, Chem. Eur. J. 2016, 22, 15744 – 15750.
[17] Note of safety: organozinc and Grignard reagents are moisture
sensitive and may react violently in air. In our tests with the
substrates 2 and 3 from Scheme 1 and substrate 4 from Table 2,
the couplings were equally efficient also under an argon
Manuscript received: October 1, 2016
Revised: November 4, 2016
Final Article published: && &&, &&&&
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Communications
Cross-Coupling
Open container: Reported herein is
a general method based on PdI for the
À
I. Kalvet, G. Magnin,
F. Schoenebeck*
predictable chemoselective Csp2 Csp2
À
À
&&&& — &&&&
coupling at C Br in preference to C OTf
À
and C Cl bonds, regardless of the elec-
tronic or steric bias of the substrate. The
Rapid Room-Temperature,
À
À
Chemoselective Csp2 Csp2 Coupling of
Poly(pseudo)halogenated Arenes
C C bond formations are rapid (<5 min
at RT) and can be conducted under open-
flask conditions.
Enabled by Palladium(I) Catalysis in Air
6
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