Site-Selective C?S Bond Formation at C?Br over C?OTf and C?Cl Enabled by an Air-Stable, Easily Recoverable, and Recyclable Palladium(I) Catalyst

Article abstract of DOI:10.1002/anie.201806036

This report widens the repertoire of emerging Pd^I catalysis to carbon–heteroatom, that is, C?S bond formation. While Pd⁰-catalyzed protocols may suffer from the formation of poisonous sulfide-bound off-cycle intermediates and lack of selectivity, the mechanistically diverse Pd^I catalysis concept circumvents these challenges and allows for C?S bond formation (S–aryl and S–alkyl) of a wide range of aryl halides. Site-selective thiolations of C?Br sites in the presence of C?Cl and C?OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X-ray, and reactivity data support dinuclear Pd^I catalysis to be operative. Contrary to air-sensitive Pd⁰, the active Pd^I species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.

Full text of DOI:10.1002/anie.201806036

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Accepted Article
Title: Site-Selective C-S Bond Formation at C-Br over C-OTf and C-Cl
Enabled by an Air-Stable, Easy-to-Recover & Recyclable Pd(I)
Catalyst
Authors: Thomas Scattolin, Erdem Senol, Guoyin Yin, Qianqian Guo,
and Franziska Schoenebeck
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806036
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10.1002/anie.201806036
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Dinuclear Catalysis
Site-Selective C-S Bond Formation at C-Br over C-OTf and C-Cl
Enabled by an Air-Stable, Easy-to-Recover & Recyclable Pd(I) Catalyst
Thomas Scattolin, Erdem Senol, Guoyin Yin, Qianqian Guo and Franziska Schoenebeck*
Abstract: This report widens the repertoire of emerging Pd(I)
catalysis to carbon-heteroatom, i.e. C-S bond formation. While
Pd(0) catalyzed protocols may suffer from the formation of
poisonous sulfide bound off-cycle intermediates and lack of
selectivity, the mechanistically diverse Pd(I) catalysis concept
circumvents these challenges and allows for C-S bond formation
(S-Aryl and S-Alkyl) of a wide range of aryl halides. Site-selective
thiolations of C-Br sites in the presence of C-Cl and C-OTf were
achieved in a general and a priori predictable fashion.
Computational, spectroscopic, X-ray and reactivity data support
dinuclear Pd(I) catalysis to be operative. Contrary to air-sensitive
Pd(0), the active Pd(I) species was easily recovered in the open
atmosphere and subjected to multiple rounds of recycling.
relative mildness, functional group tolerance and generality.[11] Yet,
challenges still remain: aside from the above mentioned sustainability
aspects, surprisingly, site-selective thiolations of poly(pseudo)-
halogenated arenes, although being a powerful handle to increase
diversity and access densely functionalized arenes, has not been
accomplished for a broad set of substrates.[12] Moreover, traditional
Pd(0)/Pd(II) cycles may suffer from poisonous off-cycle Pd(II) ate
complexes that are assumed to form in the presence of thiolate
nucleophiles (Figure 1).[13] Since Pd(I) catalyzed transformations are
fundamentally different and rely on iodine/thiolate exchange at the
oxidation state (I) prior to oxidative addition to the aryl halide (see
Figure 1), we envisioned that we should be able to circumvent these
mechanistic limitations. Moreover, our previous work indicated that
the oxidation state (I) is rather privileged to achieve site-selective
transformations.[5a-b]
W
hile palladium-catalyzed coupling reactions have developed into
ubiquitous synthetic tools of significant industrial and societal
impact,[1] the vast majority of these coupling reactions rely on air-
sensitive mononuclear Pd catalysts that are either used directly under
inert conditions or formed in situ from suitable precursors.[1,2] As such,
the recovery of the active Pd species is frequently challenging under
routine laboratory conditions; ultimately resulting in the disposal of
the Pd. In this context, the emerging concept of dinuclear Pd(I)
catalysis has shown promise in displaying features of air-stability,
robustness and recoverability in applications employing the iodine-
bridged dinuclear Pd(I) complex 1 (see Figure 1).[3,4] In our previous
work, we developed Pd(I) dimer catalyzed Csp2-Csp2, Csp2-Csp3, C-
SeCF3 and C-SCF3 bond formations and provided mechanistic data in
support of dinuclear catalysis being operative.[3,5] Aside from the
mentioned specialized fluorinated examples, to date, carbon-
heteroatom bond formation is clearly underdeveloped in the Pd(I)
arena, but would benefit from widening of the repertoire. Thiolation
reactions (to make aryl or alkyl sulfides) are of importance in the
pharmaceutical and agrochemical arenas, as the C-S bond is widely
encountered in bioactive molecules.[6] To name a few, the thioether
motif is featured in agents to fight Alzheimer, Parkinson, HIV and
cancer,[ 7 ] but is also of importance in materials chemistry (e.g.
polymerization).[8] Thioethers are also key precursors in the synthesis
of highly relevant functional groups such as sulfoxide, sulfone,
sulfilimine and sulfoximine.[9] While catalytic methods involving Ni-
or Cu-catalysts can in principle be used for thiolations,[ 10 ] Pd(0)
catalyzed processes have become the method of choice owing to their
.
.
Air-sensitive
Strategies for recovery:
polyethylene-bound Pd
metal scavengers
specialized conditions (biphasic,
ionic liquids, supercritical CO2)
o
o
o
.
.
.
Robust & air-stable
Straightforward recovery
Pd(I) catalysis cycles
vs.
 Challenge in Pd(0)/Pd(II) catalysis:
 Dinuclear catalysis concept:
Poisonous Pd ate complexes
No chemoselectivity in C-Br vs C-OTf
vs C-Cl
Avoidance of poisonous complexes from Pd(II)
I/SR exchange at oxidation state (I).
This work: Nu= S-Ar & S-Alkyl
Figure 1. Mononuclear Pd(0)/Pd(II) versus dinuclear Pd(I)-Pd(I) catalysis.
Our previous work in the area of Pd(I) catalysis indicated that the
key to efficient dinuclear Pd(I) catalysis is the effective displacement
of the iodine-bridge by the employed nucleophile along with the
ability of the nucleophile to function as a stabilizing unit of the
dinuclear entity.[3a-b] In this context, electron-rich nucleophiles could
potentially also compete in formally reducing the Pd(I) entity to
Pd(0),[14] and as such, alkyl and aryl thiolates present a significantly
greater challenge than the electron deficient SCF3 nucleophile. A
handful of dinuclear Pd(I) complexes with a single SR bridge have
been prepared and characterized to date,[ 15 ] but were never
investigated for their reactivity or catalytic potential. Thus, we first
set out to test whether a RS-bridged Pd(I) dimer could be prepared
[]
Mr. T. Scattolin, Mr. E. Senol, Dr. G. Yin, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University
Dr. Q. Guo
Institute of Inorganic Chemistry, X-ray Crystallography
Landoltweg 1, 52074 Aachen, Germany
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
1
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10.1002/anie.201806036
Angewandte Chemie International Edition
from 1. Pleasingly, when we treated Pd(I)-iodo dimer 1 with sodium
benzenethiolate in toluene at room temperature, we observed clean
exchange of the iodine bridges by SPh and formation of the new
[(PtBu3)Pd(I)(-SPh)]2 2. Our 31P NMR monitoring of the reaction at
the time points 0.5, 1 and 2 hours (see SI) showed the appearance of
two new signals at  = 101.3 and 97.4 ppm in addition to the peak
from the starting Pd(I) iodo dimer 1 (= 103.2 ppm) (see Scheme 1).
The two new signals are consistent with the expected intermediate
[I/SPh]-mixed dimer and the doubly bridged SPh dimer 2. After 2h,
def2TZVP.[18] In analogy to our previous detailed investigations in
this regard,[3a-b] we succeeded in the location of a transition state for
dinuclear oxidative addition by the Pd(I) dimer 3, bearing two SEt
bridging units to 4-iodoaniline.[19] Following the reaction pathway,
ultimately ArSEt will be formed along with the [I/SEt]-mixed Pd(I)
dimer, which can subsequently undergo another exchange reaction
with another molecule of ArI (TS is illustrated in Scheme 2, full
pathway in SI). We calculated a strong thermodynamic driving force
of Grxn = -28.3 kcal/mol for the process. Moreover, the mixed Pd(I)
species (with I and SEt bridge) is predicted to be more reactive in
oxidative addition than the bis-SEt bridged Pd(I) dimer 3 (by G‡ =
6.3 kcal/mol).
only species
2 remained which was further unambiguously
characterized by X-ray crystallographic analysis.[16] The two SPh
groups are oriented in an anti configuration to each other in the solid
state (see Scheme 1, middle). The collected data of the Pd-Pd bond
length of 2.553 Å is in the range of the previously reported Pd-Pd
single bonds.[17]
Table 1. Pd(I) catalyzed formation of thioethers ArSR from ArBr and ArI.a
Formation of 2 over time
t = 2h
t = 1h
t = 0.5h
103.2 ppm (X = Y = I) 1
101.3 ppm (X = I, Y = SPh) 2a
97.4 ppm
(X = Y = SPh) 2
31P NMR of the
crude mixture
Scheme 1. Formation and reactivity of the SPh-bridged Pd(I) dimer 2. 31P-NMR
analysis conducted with (EtO)3P=O as internal standard. Xray of 2 (thermal
ellipsoids are shown at 50% probability and hydrogen atoms have been omitted
for clarity).
Similarly, we found alkyl thiolates (such as sodium ethanethiolate)
to be equally effective in forming stable Pd(I) entities under these
conditions, displaying a characteristic signal of  = 100.6 ppm in 31P-
NMR for the fully SEt-bridged Pd(I) dimer 3. These newly formed
Pd(I) dimers were found to be completely stable to air and moisture
(time of examination: 12 months).
We subsequently assessed the ability of dimer 3 to undergo direct
reaction with an aryl iodide. To this end, we subjected
[(PtBu3)Pd(I)(SEt)]2 3 to 2 equivalents of 4-iodoaniline at 40°C for
1 h. We observed clean formation of the corresponding SEt-
functionalized aniline 4 in 84% yield relative to 2.0 equivalents of ArI
(see Scheme 1, bottom). Our 31P-NMR monitoring indicated that
clean SEt/I exchange had taken place with complete disappearance of
dimer 3 and concomitant appearance of Pd(I)-iodo dimer 1 (see SI).
Importantly, we did not observe Pd(0) nor Pd(II) species, indicating that
direct reactivity of the Pd(I) dimer 3 with the aryl iodide is likely.
Moreover, we measured a 1st order kinetic dependence in Pd(I) dimer
3. We also studied the feasibility of direct reactivity computationally,
using the M06L level of theory in combination with the implicit
solvation model CPCM (to account for toluene) and the basis set
[a] Conditions: Pd(I) dimer 1 (17.4 mg, 0.02 mmol), aryl halide (0.4 mmol), NaSR
(0.48 mmol) in toluene (1.5 mL). Isolated yields are given. [b] Reactions
performed at 40°C. [c] Reactions performed at 60°C.
With the stoichiometric reactivity and air-stability features of the
SR-bridged Pd(I) dimer established, we subsequently explored the
potential for catalytic applications. Pleasingly, using 5 mol% of the
air- and moisture stable Pd(I) iodo dimer 1 with alkyl and aryl thiolates
(1.2 equiv.) in toluene at respectively 40°C and 60°C, we successfully
coupled a range of aryl iodides and bromides to the corresponding
thioethers. Electron-rich and -deficient aryl halides were equally
2
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10.1002/anie.201806036
Angewandte Chemie International Edition
effective. Moreover, various substituents in ortho, meta and para
position to the site of C-S coupling were tolerated and the
corresponding products isolated in excellent yields. Notably, even
unprotected amines (primary amine and unprotected indole) did not
impede the efficiency of the transformation. The method proved
compatible with ether (11, 17, 22 and 24), ketone (29), aldehyde (7),
ester (9 and 10) and cyano (6 and 27) functional groups. Moreover,
pharmaceutically and agrochemically important heterocycles, such as
furan, thiophene, indole and pyrimidine gave rise to equally high
yields of the corresponding sulfide coupling products as standard
aromatic or polyaromatic substrates (7, 8, 21, 22 and 26) (see Table
1). For example, 33 is the final intermediate towards key bioactive
compounds, shown to have strong affinity for nicotinic acetylcholine
receptors with potential relevance in the treatment of Alzheimer’s
disease.[7]
most employed Pd(0)-derived thiolation catalyts, i.e. Pd2dba3
/DPEPhos,[21] showed functionalization at the C-OTf site (88%) in a
mixture with bisfunctionalized product (8%) and remaining starting
material (4%), when being challenged with 5-bromo-4-
methylpyridin-2-yl trifluoromethanesulfonate (see Scheme 3, entry 1,
bottom). When the air-sensitive and more labile Pd(I) bromo dimer
was employed using our conditions, poor conversion to the desired
product was observed (20%) with significant amount of starting
material remaining. This suggests that the Pd(I) bromo dimer might
behave as a precatalyst, releasing Pd(0) species in-situ which might
subsequently be trapped as Pd(II) ate complexes by the sulfur
nucleophile (see Scheme 3, entry 2, bottom) or alternatively
deactivated.[22] By contrast, employing Pd(I) iodo dimer 1 led to the
exclusive functionalization of the C-Br position in the presence of C-
OTf, regardless of the electronic or steric bias in the substrate (see
Scheme 3, entry 3). Notably, the complete selectivity for the C-Br
bond is also retained if excess of coupling partner is used, adding
practicability, as little care needs to be applied in weighing or
handling of the coupling partner. Standard Pd(0) based reactivity
trends usually refer to the relative reactivities of C-OTf vs. C-Br as
being roughly the same and highly dependent on the steric or
electronic influence by the substrate.[5b] By contrast, Pd(I) catalysis
proves to be completely Br-selective also for C-S bond formation, in
accord with our previous observations in C-C bond formations.[5a-b]
As such, the protocol is a priori predictable and completely substrate
independent. The selectivity was also independent of the nature of the
sulfide that was installed. Electron-rich and hindered StBu were just
as selective as the aromatic SPh nucleophile.
Computed
oxidative addition
and extension
2.32
2.77
2.31
G‡= 23.5 kcal.mol-1
[Yield of Ar-SPh]
1st cycle : 88 %
2nd cycle : 99 %
3rd cycle : 98 %
4th cycle : 97 %
5th cycle : 93 %
Scheme 2. Computed oxidative addition transition state of 4-iodoaniline
(hydrogen atoms on the PtBu3 ligands omitted for clarity) with extension (bond
distances in Å) (top) and demonstration of the recyclability of the Pd(I) dimer
species over 5 cycles (bottom).
To test whether the increasingly important demands for
sustainability can also be met to some extent with our protocol, we
next explored the ease of recoverability and recyclability of the Pd(I)
entity. Pleasingly, following the Pd(I) catalyzed reaction of 4-
iodoaniline with sodium benzenethiolate, we were able to recover
81% of dinuclear Pd(I) species (almost exclusively as the [I/SPh]-
mixed dimer 2a), using simple column chromatography on silica gel
under standard laboratory conditions in open atmosphere. Submission
of the isolated Pd(I) species to another transformation of 4-iodoaniline
was highly effective, which is in line with the computational data that
suggest the mixed [I/SPh] Pd(I) dimer to be more reactive. We
repeated the recovery/recycling cycle overall 5 times and saw no
decay in product yields or catalytic performance of the Pd(I) species
(see Scheme 2, bottom). The ease of recovery and recycling is due to
the exquisite feature of the Pd(I) dimer to be air- and moisture stable.
Standard Pd(0) catalysts are not generally air-stable and usually
require specialized recovery techniques, such as polymer-bound
catalysts, use of metal scavengers or specialized reactions conditions
(biphasic, ionic liquids, supercritical CO2).[20]
Scheme 3. Demonstration of chemoselective coupling at C-Br bonds in presence
of competing C-Cl and C-OTf bonds (top) and comparison of reported efficient
catalytic system in thiolation reactions[23] (bottom). [a] Reactions performed at
80°C. [b] Reactions performed at 40°C [c] Remaining starting material: 4%. [d]
Remaining starting material: 80%. [e] Remaining starting material: 2%. Isolated
yield is given in parenthesis.
A remaining challenge in C-heteroatom bond formation, and metal
catalyzed transformations more generally, is to obtain site-selectivity
in couplings of poly(pseudo)halogenated arenes. While isolated
examples exist,[12] there is a lack of generality in substrate. Subtle
variations in steric or electronic features frequently lead to diminished
or abolished selectivities.[5b] In line with this, our test of one of the
3
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10.1002/anie.201806036
Angewandte Chemie International Edition
6879; d) I. Kalvet, K. J. Bonney, F. Schoenebeck, J. Org. Chem. 2014, 79,
12041; e) K. J. Bonney, F. Proutiere, F. Schoenebeck, Chem. Sci. 2013, 4,
4434.
To the best of our knowledge, this is the first general and a priori
predictable chemoselective C-S bond formation in the presence of
competing potentially reactive C-OTf and C-Cl sites (see Scheme 3).
Such chemoselective strategies are of considerable value in the build-
up of densely functionalized or complex molecules ranging from
pharmaceuticals to materials and a highly sought after strategy in the
demand for late-stage synthetic diversification.
[6] For examples, see: a) K. L. Dunbar, D. H. Scharf, A. Litomska, C.
Hertweck, Chem. Rev. 2017, 117, 5521; b) C.-F. Lee, Y.-C. Liu, S. S.
Badsara, Chem. Asian J. 2014, 9, 706.
[7] a) G. Liu, J. R. Huth, E. T. Olejniczak, R. Mendoza, P. DeVries, S. Leitza,
E. B. Reilly, G. F. Okasinski, S. W. Fesik, T. W. von Geldern, J. Med.
Chem. 2001, 44, 1202; b) S. F. Nielsen, E. Ø. Nielsen, G. M. Olsen, T.
Liljefors, D. Peters, J. Med. Chem. 2000, 43, 2217; c) E. De Gianni, C.
Fimognari, in The Enzymes, Vol. 37 (Eds.: S. Z. Bathaie, F. Tamanoi),
Academic Press, 2015; d) J. Yoo, N. Sanoj Rejinold, D. Lee, S. Jon, Y.-
C. Kim, J. Control. Release 2017, 264, 89.
[8] a) B. Hendriks, J. Waelkens, J. M. Winne, F. E. Du Prez, ACS Macro Lett.
2017, 6, 930; b) L. J. Mathias, G. Cei, R. A. Johnson, M. Yoneyama,
Polym. Bull. 1995, 34, 287.
[9] Advances in Sulfur Chemistry, Vol.2 (Ed.: C. M. Rayner), JAI Press,
Greenwich, CT, 2000.
[10] a) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400; b) I.
P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111, 1596-1636; c) Y.
Zhang, K. C. Ngeow, J. Y. Ying, Org. Lett. 2007, 9, 3495; d) G. T.
Venkanna, H. D. Arman, Z. J. Tonzetich, ACS Catalysis 2014, 4, 2941.
[11] a) M. Sayah, M. G. Organ, Chem. Eur. J. 2011, 17, 11719; b) J. L. Farmer,
M. Pompeo, A. J. Lough, M. G. Organ, Chem. Eur. J. 2014, 20, 15790; c)
M. A. Fernández-Rodríguez, Q. Shen, J. F. Hartwig, J. Am. Chem. Soc.
2006, 128, 2180; d) T. Itoh, T. Mase, Org. Lett. 2004, 6, 4587; e) J. F.
Hartwig, Acc. Chem. Res. 2008, 41, 1534; e) T. Kondo, T.-a. Mitsudo,
Chem. Rev. 2000, 100, 3205.
[12] To the best of our knowledge, there is no report on a site-selective C-S
coupling in which C-Br, C-Cl and C-OTf were in competition. For
examples where isolated selective couplings have been achieved, see: a)
M. A. Fernández-Rodríguez, J. F. Hartwig, J. Org. Chem. 2009, 74, 1663;
b) A. Rostami, A. Rostami, A. Ghaderi, M. A. Zolfigol, RSC Advances
2015, 5, 37060; c) Y. Liu, J. Kim, H. Seo, S. Park, J. Chae, Adv. Synth.
Catal. 2015, 357, 2205; d) B. A. Vara, X. Li, S. Berritt, C. R. Walters, E.
J. Petersson, G. A. Molander, Chem. Sci. 2018, 9, 336.
In summary, herein we demonstrated the versatility of the dinuclear
Pd(I) concept in C-S bond formation, allowing avoidance of poisonous
Pd ate complexes that may be encountered under Pd(0) catalysis. We
achieved thiolations of a wide range of aryl iodides and bromides,
even selectively in the presence of C-OTf and/or C-Cl for the first
time for a broad set of substrates. We provided X-ray, computational
and reactivity data in support of direct Pd(I)-Pd(I) catalysis. Due to
their air and moisture stability, the Pd(I) species generated were easily
recovered using standard laboratory purification methods
(chromatography on silica gel). In multiple rounds of recycling, there
was no loss in catalytic activity or efficiency.
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’.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: chemoselectivity • thiolation • dinuclear Pd(I) • DFT
calculation • homogeneous catalysis
[13] a) M. S. Oderinde, M. Frenette, D. W. Robbins, B. Aquila, J. W. Johannes,
J. Am. Chem. Soc. 2016, 138, 1760; b) C. Valente, M. Pompeo, M. Sayah,
M. G. Organ, Org. Process Res. Dev. 2014, 18, 180.
[1] a) Handbook of Organopalladium Chemistry for Organic Synthesis (Eds.:
E.-I. Negishi, A. de Meijere), Wiley, New York, 2002; b) Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: F. Diederich, A. de
Meijere), Wiley-VCH, Weinheim, 2004; c) J. F. Hartwig in
Organotransition Metal Chemistry-From Bonding to Catalysis,
University Science Books, Sausalito, CA, 2010; d) C. C. Johansson
Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew.Chem. Int.
Ed. 2012, 51, 5062; Angew. Chem. 2012, 124, 5150; e) T. Colacot, New
Trends in Cross Coupling:Theory and Applications, RSC, London, 2014.
[2] For examples of air-stable palladium catalysts, see: a) Q. Du, Y. Li,
Beilstein J. Org. Chem. 2011, 7, 378; b) A. Majumder, R. Gupta, M.
Mandal, M. Babu, D. Chakraborty, J. Organomet. Chem. 2015, 781, 23;
c) G. Y. Li, J. Org. Chem. 2002, 67, 3643; d) G. Y. Li, G. Zheng, A. F.
Noonan, J. Org. Chem. 2001, 66, 8677. On the air-sensitivity of
commonly used trialkylphosphine ligands, see: e) D. H. Valentine Jr, J. H.
Hillhouse, Synthesis 2003, 2003, 2437. For examples of air-stable
phosphine and phosphine oxide ligands, see: a) G. Y. Li, Angew. Chem.
Int. Ed. 2001, 40, 1513; b) L. Ackermann, R. Born, Angew. Chem. Int. Ed.
2005, 44, 2444; c) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27.
[3] a) M. Aufiero, T. Sperger, A. S. K. Tsang, F. Schoenebeck, Angew. Chem.
Int. Ed. 2015, 54, 10322; b) G. Yin, I. Kalvet, F. Schoenebeck, Angew.
Chem. Int. Ed. 2015, 54, 6809; c) T. Sperger, C. K. Stirner, F.
Schoenebeck, Synthesis 2017, 49, 115.
[14] a) M. Aufiero, T. Scattolin, F. Proutiere, F. Schoenebeck,
Organometallics 2015, 34, 5191; b) F. Proutiere, M. Aufiero, F.
Schoenebeck, J. Am. Chem. Soc. 2012, 134, 606. For applications of
labile Pd(I) complexes as precatalysts, see: a) T. Murahashi, H. Kurosawa,
Coord. Chem. Rev. 2002, 231, 207; b) D. P. Hruszkewycz, D. Balcells, L.
M. Guard, N. Hazari, M. Tilset, J. Am. Chem. Soc. 2014, 136, 7300; c) C.
Jimeno, U. Christmann, E. C. Escudero-Adan, R. Vilar, M. A. Pericas,
Chem. Eur. J. 2012, 18, 16510; d) T. Murahashi, K. Takase, M.-a. Oka,
S. Ogoshi, J. Am. Chem. Soc. 2011, 133, 14908; e) U. Christmann, D. A.
Pantazis, J. Benet-Buchholz, J. E. McGrady, F. Maseras, R. Vilar, J. Am.
Chem. Soc. 2006, 128, 6376; f) J. P. Stambuli, R. Kuwano, J. F. Hartwig,
Angew. Chem. Int. Ed. 2002, 41, 4746; g) M. Prashad, X. Y. Mak, Y. Liu,
O. Repič, J. Org. Chem. 2003, 68, 1163; h) T. J. Colacot, Platinum Met.
Rev. 2009, 53, 183; i) L. L. Hill, J. L. Crowell, S. L. Tutwiler, N. L.
Massie, C. C. Hines, S. T. Griffin, R. D. Rogers, K. H. Shaughnessy, G.
A. Grasa, C. C. C. J. Seechurn, H. Li, T. J. Colacot, J. Chou, C. J.
Woltermann, J. Org. Chem. 2010, 75, 6477.
[15] a) S. Lin, D. E. Herbert, A. Velian, M. W. Day, T. Agapie, J. Am. Chem.
Soc. 2013, 135, 15830; b) M. A. Jalil, T. Nagai, T. Murahashi, H.
Kurosawa, Organometallics 2002, 21, 3317; c) H. Werner, H.-J. Kraus, J.
Chem. Soc., Chem. Commun. 1979, 814; d) D. P. Hruszkewycz, J. Wu, N.
Hazari, C. D. Incarvito, J. Am. Chem. Soc. 2011, 133, 3280; e) S. Ogoshi,
K. Tsutsumi, M. Ooi, H. Kurosawa, J. Am. Chem. Soc. 1995, 117, 10415;
f) R. Usón, J. Forniés, J. Fernández Sanz, M. A. Usón, I. Usón, S. Herrero,
Inorg. Chem. 1997, 36, 1912.
[4] For a discussion of catalyst versus precatalyst, see: R. S. Paton, J. M.
Brown, Angew. Chem. Int. Ed. 2012, 51, 10448.
[5] a) I. Kalvet, T. Sperger, T. Scattolin, G. Magnin, F. Schoenebeck, Angew.
Chem. Int. Ed. 2017, 56, 7078; b) I. Kalvet, G. Magnin, F. Schoenebeck,
Angew. Chem. Int. Ed. 2017, 56, 1581; c) F. Proutiere, E. Lyngvi, M.
Aufiero, I. A. Sanhueza, F. Schoenebeck, Organometallics 2014, 33,
[16] Complete crystallographic data can be found in the Supporting
Information. Additional crystallographic information has been submitted
in CIF format and is available from the CCDC, deposition number
1841115.
4
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10.1002/anie.201806036
Angewandte Chemie International Edition
[17] R. Vilar, D. M. P. Mingos, C. J. Cardin, J. Chem. Soc., Dalton Trans. [21] a) T. H. Jepsen, M. Larsen, M. Jørgensen, K. A. Solanko, A. D. Bond, A.
1996, 4313.
Kadziola, M. B. Nielsen, Eur. J. Org. Chem. 2011, 2011, 53; b) B. Liu, R.
S. Shetty, K. K. Moffett, M. J. Kelly, Tetrahedron Lett. 2011, 52, 1680;
c) U. Schopfer, A. Schlapbach, Tetrahedron 2001, 57, 3069; d) A. Pueschl,
B. Bang-Andersen, M. Joergensen, K. Juhl, T. Ruhland, K. Andersen, J.
Kehler (Lundbeck & CO), WO2004087662, 2004; e) M. Sakurai, H.
Hamashima, K. Hattori (Fujisawa Pharmaceutical CO), US2004106653,
2004; f) E. Alvira, M. J. Graneto, L. M. Grapperhaus, K. Iyanar, M. T.
Maddux, W. M. Mahoney, A. M. Massa, K. R. Sample, A. M. Schmidt,
E. R. Seidel, G. J. Selbo, B. M. Tollefson, A. R. E. Vonder, M. G. Wagner,
S. S. Woodard (Pfizer Inc.), WO2009069044, 2009.
[18] The geometries were optimized at B3LYP/6-31G(d) with LANL2DZ for
Pd,I. Selected optimizations at ωB97XD (SDD for Pd, I) gave analogous
results in terms of overall activation barrier and driving force. 6-
311++G(d,p)/SDD basis set for single point energies was also tested and
gave similar results. The coordinates for the optimized structures together
with the energy diagram can be found in the Supporting Information.
[19] Calculations were conducted with Gaussian09, Revision E.01; Frisch M.
J. et al. See Supporting Information for full reference and further
computational details.
[20] a) E. Bergbreiter, P. L. Osburn, Y.-S. Liu, J. Am. Chem. Soc. 1999, 121, [22] If the strength of the nucleophile is lowered appropriately, higher
9531; b) S. Phillips, P. Kauppinen, Platinum Metals Rev. 2010, 54, 69; c)
H. Wong, C. J. Pink, F. C. Ferreira, A. G. Livingston Green Chem. 2006,
conversion to the product can be achieved. See: C. C. Eichman, J. P.
Stambuli, J. Org. Chem. 2009, 74, 4005.
8, 373; d) T. Welton, Chem. Rev. 1999, 99, 2071; e) P. G. Jessop, T. [23] For c) EtSH (1.0 equiv.) and KOtBu (1.1 equiv.). For d) and e) NaSEt (1.2
Ikariya, R. Noyori, Chem. Rev. 1999, 99, 475; f) W. Leitner, Acc. Chem. equiv.). See Supporting Information for more details.
Res. 2002, 35, 746; g) For an example of
recoverable Pd(I.I)
a
cyclometallated imine catalyst applied in Heck reactions, see: M. Ohff, A.
Ohff, D. Milstein, Chem. Commun. 1999, 357.
5
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Layout 2:
Dinuclear Catalysis
Pd(I) dimer catalysis
37 examples
up to 99%
 Wide applicability
and functional
T. Scattolin, E. Senol, G. Yin, Q. Guo, F.
group tolerance
 Recyclability
 Robust, air and
moisture stability
 C-Br selective
Schoenebeck* __________ Page – Page
Site-Selective C-S Bond Formation at
C-Br over C-OTf and C-Cl Enabled by
an Air-Stable, Easy-to-Recover &
Recyclable Pd(I) Catalyst
Chemoselective
Csp2 -S bond formation
[1] a) Handbook of Organopalladium Chemistry for Organic Synthesis (Eds.: E.-I. Negishi, A. de Meijere), Wiley
2
,
N
ew York
,
2002; b) Metal- Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: F. Diederich, A. de Meijere), Wiley-VCH, Weinheim
,
2004; c) J. F. Hartwig
I. Kalvet, F. Schoenebec k, Ange w. Chem. Int. Ed. 2015, 54, 6809; c) T. Sperger, C. K. Stirner, F. Schoenebeck, Synthesis 2017, 49, 115.
0448.
b) I. Kalvet, G. Magnin, F. Schoenebeck d. 2017, 56, 1581; c) F. Proutiere, E. Lyngvi, M. Auf iero, I. A. Sanhue za, F. Schoenebeck
in Organotransition Metal Chemistry-From Bonding to Catalysis, University Science Books, Sausalito, CA, 2010; d) C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Sniec kus, Angew.Chem. Int. Ed. 2012, 51, 5062; Ange w. Chem. 2012, 124, 5150; e) T. Colacot, Ne w Trends in Cross Coupling: Theory and Applications, RSC, London, 2014.
[3] a) M. Aufiero, T. Sperger, A. S. K.
[4] For discussion of catalyst versus precatalyst, see: R. S. Paton, J. M. Brown
[5] a) I. Kalvet, T. Sperger, T. Scattolin, G. Magnin, F. Schoenebeck Angew. Chem. Int. Ed. 2017,
T
sang, F. Schoenebec
k
,
Ange w. Chem. Int. Ed. 2015, 54, 10322
;
b) G. Yin
,
a
,
Angew. Chem. Int. Ed. 2012, 51, 1
,
5
6, 7078
;
,
A
ngew. Chem. Int.
E
, Organometallics 2014, 33, 6879; d) I. Kalve t, K. J. Bonney, F. Schoenebeck, J. Org. Chem. 2014, 79, 12041; e) K. J. Bonney, F. Proutiere, F. Schoenebeck, Chem. Sci. 2013, 4, 4434.
[6] For
[7] a) G. Liu, J. R. Huth, E.
[8] a) B. Hendrik J. Wael
[9] Advances in Sulfu Chemistry, Vol.2 (Ed.: C. M. Rayner), JAI Press, Greenwich, CT, 2000.
[10] a) C. Arkaitz, C. Mónica, B. Carsten, Angew. Chem. Int Ed. 2008, 47, 2880; b) S. V. Ley
[11] a) M. Sayah, M. G. Organ, Chem. Eur. J. 011, 17, 11719 b) J. L. Farmer, M. Pompeo, A. J. Lough, M. G. Organ, Chem. Eur. J.
[12] For examples where single site selective coupling for
[13] a) M. S. Oderinde, M. Frenette, D. W. Robbins, B. Aquila, J. W. Johannes, J. Am. Chem. Soc. 2016, 138, 1760; b) C. Valente,
[14] a) M. Aufiero, T. Scattolin, F. Proutiere, F. Schoenebeck rganometallics 2015, 4, 5191 b) F. Proutiere, M. Aufiero, F. Schoenebeck
[15] a) S. Lin, D. E. Herbert, A. Velian, M. W. Day T. Agapie, J. Am. Chem. oc. 2013, 35, 15830; b) M. A. Jalil, T. Nagai, Murahashi,
[16] Complete crystallographic data can be found in the Supporting Information.
[17] R. Vilar, D. M. P. Mingos, C. J. Cardin, J. Chem. oc., Dalton Trans. 1996,
[18] The geometries were optimized at B3LYP level of theory The 6-311++G(d,p)/SDD basis set
[19] Calculations were conducted with Gaussian09, Revisio E.01; Frisch M. J. et al. See Supporting Information for full reference and further computational details.
m
olecules examples, see: K. L. Dunbar, D. H. Scharf, A. Litom
Olejnicza R. Mendoza, P. DeVries, S. Leitza, E. B. Reilly
ens, J. M. Winne, F. E. Du Prez, ACS Macro Lett. 2017, 6, 30; b) L. J. Mathias, G. Cei, R. A. Johnson, M. Yoneyama, Polym. Bull. 1995, 34, 287.
s
k
a, C. Hertweck
,
Chem. Rev. 2017,
1
17, 5521.
T
k
.
k,
,
G
.
F
.
O
k
a
s
i
n
s
ki, S. W. Fesi
k,
T
.
W. von Geldern, J. Med. Chem. 2001, 44, 1202; b) S. F. Nielsen,
E
.
Ø. Nielsen,
G
.
M.
O
lsen, T. Liljefors, D. Peters, J. Med. Chem. 2000, 43, 2217; c) E. De Gianni, C. Fimognari, in The Enzymes, Vol
.
37 (Eds.
:
S. Z. Bathaie, F. Tamanoi), Academic Press, 2015; d) J. Yoo, N. Sanoj Rejinold
,
D. Lee, S. Jon, Y.-C. Kim
,
J. Control
.
Release 2017, 264, 89
.
s
,
9
r
.
,
A. W. Thomas, Angew. Chem. Int. Ed.
2
2
003, 42, 5400; c) I. P. Belets
014, 20, 15790; c) M. A. Fernández-Rodr íguez,
k
aya, V. P. Ananikov
,
.
Chem. Rev. 2011, 111, 1596-1636; d) Y. Zhang, K. C. Ngeow, J. Y.
Shen, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128 2180 d) T. Itoh, T. Mase, Org
Advances 2015 5, 37060; c) Y. Liu, J. Kim
Y
ing, Org. Lett. 2007, 9, 3495; e) G. T. Ven
Lett. 2004 6, 4587; e) J. F. Hartwig,
H. Seo, S. Park Chae, Adv. Synth. Catal. 2015, 357, 2205; d) B. A. Vara, X. Li, S. Berritt, C. R. Walters, E. J. Petersson, G. A . Molander, Chem. Sci. 2018, 9, 336. To the best of our knowledge, no methodology on a site-selective coupling in which C-Br, C-Cl and C-OTf were in competition has been reported.
k
anna,
H
.
D. Arman, Z. J. Tonzetich, ACS Catalysi
s 2014 , 4, 2941.
2
;
Q
,
;
.
,
A
cc. Chem. Res. 2008, 1, 1534 e) T. Kondo, T.-a. Mitsudo, Chem. Rev. 2000,
4
;
100, 3205.
a
l
imited substrates has been achieve, see: a) M. A. Fernández- Rodrígue z, J. F. Hartwig, J. Org. Chem. 2009
Pompeo, M. Sayah, M. G. Organ, Org
J. Am. Chem. Soc. 2012, 134, 606. For applications of labile Pd(I) complexes as precatal
Kurosawa, Organometallics 2002, 21, 3317; c) H. Werner, H.-J. Kraus, J. Chem. Soc., Chem. Comm un. 1979, 814
,
74, 1663; b) A. Rostami, A. Rostami, A. Ghaderi, M. A. Zolfigol, RS
C
,
,
,
J
.
M
.
.
Process Res. Dev. 2014, 18, 80.
1
,
O
3
;
,
H
y
sts, see: a) T. Murahashi, H. Kurosawa, Coord. Chem. Rev. 2002
,
231,
2
07;
b
)
D. P. Hruszkewycz, D. Balcells, L. M.
G
uard, N. Hazari, M. Tilse t, J. Am. Chem. Soc. 2014, 136, 7300; c) C. Jimeno, U. Christmann, E. C. Escudero-Adan, R. Vilar, M. A. Pericas, Chem. Eur. J. 2012, 18, 16510
;
d) T. Murahashi, K. Ta kase, M.-a. O ka, S. Ogoshi, J. Am. Chem. Soc. 2011, 133, 14908; e) U. Christmann, D. A. Pantazis, J. Benet-Buchholz, J. E. McGrady, F. Maseras, R. Vilar, J. Am. Chem. Soc. 2006, 128, 6376; f) J. P. Stambuli, R. Kuwano, J. F. Hartwig, Angew. Chem. Int. Ed. 2002, 41, 4746; g) M. Prashad, X. Y. Ma k, Y. Liu, O. Repič, J. Org. Chem. 2003, 68, 1163; h) T. J. Colacot, Platinum Met. Rev. 2009, 53, 183; i) L. L. Hill, J. L. Crowell, S. L. Tutwiler, N. L. Massie, C. C. Hines, S. T. Griffin, R. D. Rogers, K. H . Shaughnessy, G. A. Grasa, C. C. C. J. Seechurn, H. Li, T. J. Colacot, J. Chou, C. J. Woltermann, J. Org. Chem. 2010, 75, 6477.
,
S
1
T
.
.
;
d) D. P. Hruszkewycz, J. Wu, N. Hazari, C. D. Incarvito, J. Am. Chem. Soc.
2
011, 133, 3280
;
e) S. Ogoshi,
K
.
Tsutsumi, M.
O
oi, H. Kurosawa, J. Am. Chem. Soc. 1995, 117, 10415; f) R. U són, J. Forniés,
J. Fernández Sanz, M. A. Usón, I. Usón, S. Herrero, Inorg. Chem. 1997, 36, 1912.
S
4313.
.
s
were employed and gave similar results. The coordinate for the optim
i
zed structures together with the energy diagram can be found in the Supporting Information.
n
[20] a) E. Bergbreiter, P. L. Osburn, Y.-S. Liu, J. Am. Chem. Soc. 1999, 121,
9
531; b) S. Phillips, P. Kauppinen,
P
latinum Metal
s
Rev. 2010,
5
4, 69; c) H. Wong, C. J. Pin
k,
F. C. Ferreira, A. G. Livingston Green Chem. 2006,
8
,
373; d) T. Welton, Chem. Rev. 1999, 99, 2071; e) P. G. Jessop
,
T.
I
kariya, R. No
y
ori, Chem. Rev. 1999, 99,
4
75; f) W. Leitner, Acc. Chem. Res. 2002,
3
5, 746; g) For an example of a recoverable Pd(II) cyclometallated imine catalyst applied in Hec kreactions, see: M. Ohff, A. Ohff, D. Milstein, Chem. Commun. 1999, 357.
[21] a) T. H. Jepsen, M. Larsen, M. Jørgensen, K. A. Solan
[22] If the strength of the nucleophile is lowered appropriately
[23] For c) EtSH (1.0 equiv.) and KOtBu (1.1 equiv.). For d) and e) NaSEt (1.2 equiv.). See Supporting Information for complete reaction conditions.
k
o, A. D. Bond, A. Kadziola, M. B. Nielsen,
E
ur. J. Org. Chem. 2011, 2011, 53; b) B.
L
iu, R. S. Shetty
,
K. K. Moffett, M. J. Kelly, Tetrahedron Lett. 2011, 52, 1680; c) U. Schopfer, A. Schlapbach, Tetrahedron 2001, 57, 3069; d) A. Pueschl, B. Bang-Andersen, M. Joergensen, K. Juhl, T. Ruhland, K. Andersen, J. Kehler (Lundbeck& CO), WO2004087662, 2004; e) M. Sa kurai, H. Hamashima, K. Hattori (Fujisawa Pharmaceutical CO), US2004106653, 2004; f) E. Alvira, M. J. Graneto, L. M. Grapperhaus, K. Iyanar, M. T. Maddux, W. M. Mahoney, A. M. Massa, K. R. Sample, A. M. Schmidt, E. R. Seidel, G. J. Selbo, B. M. Tollefson, A. R. E. V onder, M. G. Wagner, S. S. Woodard (Pfizer Inc.), WO2009069044, 2009.
005.
,
higher conversion to the product can be achieved. See: C. C. Eichman, J. P. Stambuli, J. Org. Chem. 2009, 74,
4
6
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