Site-Selective, Modular Diversification of Polyhalogenated Aryl Fluorosulfates (ArOSO2F) Enabled by an Air-Stable PdI Dimer

Article abstract of DOI:10.1002/anie.201911465

Since 2014, the interest in aryl fluorosulfates (ArOSO₂F) as well as their implementation in powerful applications has continuously grown. In this context, the enabling capability of ArOSO₂F will strongly depend on the substitution pattern of the arene, which ultimately dictates its overall function as drug candidate, material, or bio-linker. This report showcases the modular, substrate-independent, and fully predictable, selective functionalization of polysubstituted arenes bearing C?OSO₂F, C?Br, and C?Cl sites, which makes it possible to diversify the arene in the presence of OSO₂F or utilize OSO₂F as a triflate surrogate. Sequential and triply selective arylations and alkylations were realized within minutes at room temperature, using a single and air-stable Pd^I dimer.

Full text of DOI:10.1002/anie.201911465

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Accepted Article
Title: Site-Selective, Modular Diversification of Polyhalogenated Aryl
Fluorosulfates (ArOSO2F) enabled by an Air-Stable Pd(I) Dimer
Authors: Marvin Mendel, Indrek Kalvet, Daniel Hupperich, Guillaume
Magnin, and Franziska Schoenebeck
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911465
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DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Synthetic Methods
Site-Selective, Modular Diversification of Polyhalogenated Aryl
Fluorosulfates (ArOSO2F) enabled by an Air-Stable Pd(I) Dimer
Marvin Mendel, Indrek Kalvet, Daniel Hupperich, Guillaume Magnin and Franziska Schoenebeck*
(alkylation) or alternative carbon-heteroatom bond formation exists,
which would be highly attractive for the exploration of 3-dimensional
chemical space. Moreover, in terms of site-selective transformations,
there is only a single documentation by Sharpless, in which the
Suzuki-based arylation of C–Br vs. C–OSO2F vs. C–Cl in pyridines
has been showcased,[6g] employing relatively high catalyst loading
and requiring refluxing toluene over several hours. However, our
further examination of this protocol indicated that while effective for
pyridines, our attempts to couple other arenes resulted in
unpredictable and substrate-dependent functionalization of C–Br
and/or C–OSO2F (see supporting information Table S1). These
observations are in line with the general Pd(0)/Pd(II) catalysis reactivity
trends, which historically suffer from low predictability in the relative
selectivity of C–Br vs. C–Cl vs. C–OTf, as they are strongly
influenced by the catalyst, reaction conditions and, most importantly,
by the steric and electronic factors of the specific substrate.[11]
Consequently, even if an identified protocol was selective for a given
substrate, slight variations in sterics may change selectivity (as
observed above, see SI). By contrast, our group recently showcased
that the use of the air-stable, dinuclear [Pd(I)(μ-I)P(tBu)3]2 dimer 1
allows for extremely rapid, fully controlled and substrate-independent
coupling of C–Br vs. C–Cl vs. C–OTf in arenes (Figure 1).[12] As
such, we were keen to explore the potential of Pd(I) in realizing the
first general, substrate-independent and selective functionalization of
C–OSO2F vs. C–Br/C–Cl in arenes.
Abstract: Since 2014, the interest in aryl fluorosulfates
(ArOSO2F) as well as their implementation in powerful
applications has continuously grown. In this context, the enabling
capability of ArOSO2F will strongly depend on the substitution
pattern of the arene, which ultimately dictates the overall function
as drug candidate, material or bio-linker. This report showcases
the modular, substrate-independent and fully predictable,
selective functionalization of polysubstituted arenes bearing C–
OSO2F, C–Br and C–Cl sites, which allows to diversify the arene
in the presence of OSO2F or utilizing OSO2F as triflate surrogate.
Sequential and triply selective arylations and alkylations were
realized within minutes at room temperature, using a single and
air-stable Pd(I) dimer.
O
wing to the exceptional properties and specific reactivity features
of the S(VI)-F functionality[1] as well as its nowadays vastly improved
synthetic accessibility,[2] a wide variety of powerful applications have
recently been unlocked, harnessing aryl fluorosulfates as valuable
handle
for
selective
bioconjugation,[3]
polymerization,[4]
fluorination[5] or as pseudohalides in metal catalyzed cross-coupling
reactions.[6] Aside from their enabling utility in transformative
science, aryl fluorosulfates are also known for their bioactivity,
finding usage as irreversible enzyme inhibitors[7] and furthermore,
enabling “inverse” drug discovery strategies (see Figure 1).[8]
Consequently, a technology that is capable of selectively modifying
the arene unit in a highly modular, practical and general fashion,
while tolerating the pre-installed OSO2F functionality could enable
the rapid generation of a library of densely functionalized aryl
fluorosulfates which in turn would accelerate the identification of
novel bioactives, materials, bio-linkers and the discovery of new
function, as this is ultimately dependent on the substitution pattern.
Conversely and in line with the ever increasing demand for
sustainability and practicability, the selective functionalization of
OSO2F would be equally powerful as a surrogate of the expensive
triflate group, which is associated with poorer atom economy,[9]
creating hazardous, expensive fluorocarbon waste.[10] While metal-
catalyzed aminations, arylations and carbonylations of aryl
fluorosulfates have been developed, to date, no Csp2–Csp3 coupling
[]
M. Mendel, I. Kalvet, D. Hupperich, G. Magnin, Prof. Dr. Franziska
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
Figure 1. Importance of aryl fluorosulfates in materials, biochemistry and
transformations (top), motivation for site-selective cross coupling in presence of
the OSO2F group and by using the OSO2F group (middle), and this work (bottom).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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Previous reports suggested on the basis of qualitative reactivity
comparisons, such as competition experiments, that aryl
fluorosulfates would react similarly as aryl triflates in cross
couplings.[6d,g] To get a more quantitative reactivity picture, we
initially computationally[13] assessed the activation free energy barrier
for oxidative addition to C–OSO2F (commonly abbreviated as C-
OFs) with Pd(0)P(tBu)3 as a model catalyst, relative to alternative C–
OR electrophiles, i.e. triflates, nonaflates, mesylates and tosylates.
Calculations at SMD (toluene) M06/def2-TZVP//ωB97XD/6-31G(d)
(SDD) level of theory suggested a 5-membered TS arrangement to be
favoured for C-OSO2F activation and predicted virtually identical
activation barriers as for triflates and nonaflates, reinforcing that OFs
should be excellent low-cost surrogate of these groups.
primary and secondary organozinc reagents proved to be equally
powerful for aryl fluorosulfates, functionalizing only C–Br and
leaving the C–OSO2F site (and alternative functionality) completely
untouched (11–14).[16][17] Moreover, with prolonged reaction times
and slightly elevated temperature, C–Br selective thiolations were
also possible (9, 10).[18] These are the first examples of selective
carbon-heteroatom bond formation and alkylations in the presence of
C-OSO2F.
Table 1. C–Br selective aryl-, alkyl- and thiolations in presence of the C-OSO2F
(= OFs) functionality and others.
Figure 2. Reactivity scale for oxidative addition to Ar–OSO2R derivatives,
involving 5-membered neutral transition states with Pd(0)P(tBu3). Free energies
are given relative to the TS of PhONf in kcal mol-1. [OFs = OSO2F]
We subsequently embarked on experimentally testing the
OSO2F (= OFs) group in C–Br selective C–C coupling under Pd(I)-
dimer 1 catalysis. Following our previous developments,[12a-d] we
added freshly prepared phenyl organozinc in excess and in one
portion to a solution of 4-bromo-3,5-dimethylphenyl fluorosulfate
and 2.5 mol % Pd(I)-dimer 1 in dry toluene in the presence of air. This
resulted in exclusive and extremely rapid functionalization of the C–
Br site to give compound 2 in less than 5 minutes at room temperature
and in air (see Table 1). The extreme speed and operational simplicity
of the transformation suggested that it could indeed have potential in
rapid aryl fluorosulfate diversification. As such, we next investigated
the generality of the method. Table 1 summarizes the results.
Pleasingly, we were able to perform selective arylations of the C–Br
site for a range of arenes and pharmaceutically and agrochemically
important heterocycles, irrespective of additional steric hindrance (2,
3) or the relative positioning of C–Br vs. C–OSO2F and C–Cl. Even
when the C–Br was ortho to C–OSO2F (5, 8) or the C–OSO2F site
was electronically more activated (4, 8), exclusive coupling at C–Br
was seen. Regardless of how many equivalents of cross-coupling
partner were added, there was no overcoupling. As such, the
functionalization appears to be a priori predictable for C–Br and
independent of the steric or electronic bias imposed by the substrate.
Given the importance of alkylations, we next investigated whether the
C–Br selectivity holds also for alkyl-based organometallic
nucleophiles. In Pd(0)/Pd(II) based alkylations of aryl halides, beta-
hydride elimination from Pd(II) intermediates as well as the inherent
driving force for metal halogen exchange from the alkyl
organometallic to the aryl halide are well known challenges.[14]
Despite significant progress in this field,[15] there are only two reports
of general and predictable site-selective alkylations of
Conditions: [a] 2.0–2.5 equiv of organozinc and fast addition, in air. [b] 1.5–
2.0 equiv of organozinc and slow addition over 10 min via syringe pump, argon
atmosphere. [c] Conditions: 1 (5 mol %), NaSR (1.5 equiv), ZnCl2 (1.6 equiv), LiCl
(1.6 equiv), toluene (1 mL), 40 °C, 6–8 h. [d] Yield determined by quantitative
19F NMR.
Aside from functionalization in the presence of C–OSO2F, its
further conversion as triflate or nonaflate surrogate in cross-coupling
reactions would also be of interest. Moving to the polar solvent NMP
allowed the Csp2–Csp2 as well as Csp2–Csp3 coupling of the aryl
fluorosulfates (see Table 2).[12c] We speculate that the Pd(I)-dimer
converts under these conditions to a bisligated “ate” or NMP-
coordinated complex through rapid activation.[19][20] Notably, the
reaction was complete within 10 min at room temperature and fully
selective, tolerating the presence of C–Cl.[16] Once again, the site
selectivity was found to be independent of the electronic and steric
influence of the substrate and high yields of the corresponding
products were isolated. Aromatic and heterocyclic motifs (16, 17, 18)
as well as ortho substitution (21, 22) were well tolerated.[21] As such,
the first alkylation of the OSO2F group is presented, which is
characterized by high practicability, rapidness, mildness and
chemoselectivity.
poly(pseudo)halogenated arenes; both based on Pd(I) dimer catalysis
Owing to the ubiquitous abundance of polyfunctionalized arenes
as key motifs in pharmaceuticals, materials or natural products, a
developed by our group.[12b,
Pleasingly, the alkylation with
12c]
2
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10.1002/anie.201911465
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80 °C, argon atmosphere. [a] Additional aqueous work up was performed. For
detailed experimental procedure see supporting information.
straightforward, rapid and modular approach towards polysubstituted
arenes is in high demand. Given the exquisite selectivity observations
observed above, we next focused on performing sequential couplings
with minimal disruptions to the reaction set-up. To this end, we
initially undertook C–Br functionalization using substrate and Pd(I)
dimer 1 in toluene along with the cross-coupling partner. After an
additional 15 minutes of stirring, a mixture of the next organometallic
cross coupling partner in NMP was added to the mixture, which
resulted in selective OFs-functionalization. The products arising from
this one-pot, sequential double functionalization were subsequently
isolated in good to excellent yields (23–26, Table 3), requiring a total
of 35 minutes at room temperature for their generation without
intermediate work-ups or catalyst changes. In analogy to our previous
developments,[12c] we also executed the final step of C–Cl
functionalization at 80 °C within 10 min and using the same Pd(I)
dimer 1 to the trisubstituted aromatic compounds in excellent yield
over the three coupling steps (27, 28, Table 3).
In conclusion, the rapid, operationally simple, air-tolerant and
chemoselective Csp2–Csp2, Csp2–Csp3 and C–SR coupling of
poly(pseudo)halogenated arenes bearing C–Br, C–OSO2F and C–Cl
sites has been showcased, allowing for diversification in the presence
of the valuable C–OSO2F functionality, but also for selective
functionalization of C–OSO2F as low-cost and more atom-economic
surrogate for triflates. Key to this exquisite reactivity was the
employment of the air-stable Pd(I) dimer 1, which allowed for
selective couplings within minutes at room temperature. The modular
triply selective functionalization in the sequence C–Br, then C–OFs,
then C–Cl was also demonstrated. Given the generality, selectivity,
robustness and high speed, we anticipate widespread applications of
this methodology in academic and industrial research.
Acknowledgements
Table 2. C–OFs (= C-OSO2F) selective aryl- and alkylations.
We thank the RWTH Aachen University, the European Research
Council (ERC-637993) and the Fonds der Chemischen Industrie
(scholarship to D.H.) for funding. Calculations were performed with
computing resources granted by JARA-HPC from RWTH Aachen
University under project ‘jara0091’.
Conflict of interest
The authors declare no conflict of interests.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: chemoselectivity • aryl fluorosulfates • dinuclear Pd(I) •
DFT • catalysis
Conditions: slow addition of organozinc (1.2–2.0 equiv) over 10 min via syringe
pump, argon atmosphere. [a] Around 5–10% bicoupling detected by GCMS
reaction control. [b] Contains 10% of the linear isomer
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3
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[17] Our preliminary investigations to functionalize also C–Cl selectively
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[18] ZnCl2 and LiCl solutions were added and found to be beneficial for high
conversion.
[19] Our previous work showed that solvent polarity can impact the nature
of the active species and site-selectivity, with bisligated anionic ate
complexes favoring C–OTf activation over C-Cl addition. See: (i)
reference 11d; (ii) F. Proutiere, F. Schoenebeck, Synlett 2012, 5, 645;
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[20] Our calculations of the preference for oxidative addition by an assumed
anionic Pd(0) complex, [Pd0(PtBu3)Ph]¯, predicted ΔΔG⧧ = 6.3 kcal/mol
preference for C–OFs addition over C–Cl.
[21] The incorporation of sec-butyl (20) occurred with 10% of the linear
isomer as by-product.
4
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M. Mendel, I. Kalvet, D. Hupperich, G.
Magnin, F. Schoenebeck*
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Site-Selective, Modular Diversification
of Polyhalogenated Aryl Fluorosulfates
(ArOSO2F) enabled by an Air-Stable
Pd(I) Dimer
This report showcases the rapid, modular, substrate-independent and fully
predictable functionalization of polysubstituted arenes bearing C–OSO2F, C–Br and
C–Cl sites at room temperatures, which allows to diversify the arene in the presence
of a fluorosulfate functionality or utilizing it as triflate surrogate.
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