C-N Cross-Couplings for Site-Selective Late-Stage Diversification via Aryl Sulfonium Salts

Article abstract of DOI:10.1021/jacs.9b07323

We report diverse C-N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C-H functionalization. The scope of N-nucleophiles ranges from primary and secondary alkyl and aryl amines to various N-containing hetero

Full text of DOI:10.1021/jacs.9b07323

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
C−N Cross-Couplings for Site-Selective Late-Stage Diversification via
Aryl Sulfonium Salts
‡
‡
́
́
̈
Pascal S. Engl, Andreas P. Haring, Florian Berger, Georg Berger, Alberto Perez-Bitrian,
and Tobias Ritter*
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm Platz 1, D-45470 Mulheim an der Ruhr, Germany
̈ ̈
S
* Supporting Information
Cross-coupling of aryl (pseudo)halides with various nitrogen
nucleophiles is a common and often reliable way of aryl C−N
bond construction (Scheme 1, top). Pd-catalyzed Buchwald−
ABSTRACT: We report diverse C−N cross-coupling
reactions of aryl thianthrenium salts that are formed site-
selectively by direct C−H functionalization. The scope of
N-nucleophiles ranges from primary and secondary alkyl
and aryl amines to various N-containing heterocycles, and
the overall transformation is applicable to late-stage
functionalization of complex, drug-like small molecules.
Scheme 1. Strategies for Aromatic C−N Bond Formation
itrogen-based functionalities can improve the pharmaco-
Nlogical profile of potential drug candidates due to
additional target interactions.1 Late-stage introduction of
amines and nitrogen-based heterocycles is desirable to avoid
protective group manipulations or interferences with other
synthetic steps, and to quickly generate molecular diversity in
the form of valuable pharmacophores. Aryl C−N bonds are
often formed conveniently via cross-coupling of prefunction-
alized arenes and nitrogen-based-nucleophiles, catalyzed by
transition metals like Pd2 or Cu.3 However, the need for
prefunctionalized arenes renders selective late-stage modifica-
tions by amination of complex small molecules difficult
because selective halogenation reactions, especially for
structurally complex molecules, are rare. Direct amination
reactions are promising in this regard but typically restricted to
a single or few nitrogen sources or quite limited with respect to
the arene substrate scope.4 Here we show for the first time that
aryl thianthrenium salts can be cross-coupled with N-
nucleophiles. Because aryl thianthrenium compounds can be
obtained selectively by direct functionalization of aryl C−H
bonds, even on densely functionalized small-molecule-arenes,
their coupling with N-nucleophiles enables selective late-stage
C−N bond formation that no other method can provide at
present. On the basis of nitrogen basicity and nucleophilicity,
as well as the limited tolerance of aryl thianthrenium salts
toward strong bases, we introduce four carefully chosen
methods that include both palladium catalysis and photoredox
catalysis in combination with copper-mediated C−N coupling.
The ability to employ several different methods for C−N
cross-coupling of aryl thianthrenium salts enables a remarkably
broad scope of nitrogen-based nucleophiles, including aliphatic
and aromatic amines, amides, and nitrogen-based heterocycles.
The combination of selective C−H functionalization with the
accessible diversity with respect to different cross-coupling
protocols sets this amination procedure conceptually apart
from all previously disclosed arene amination reactions.
Hartwig couplings2 have been substantially expanded in scope
through thoughtful ligand design.5 The Cu-catalyzed Ullmann-
type couplings6 exhibit a scope of N-nucleophiles often
complementary to that of Pd-catalysis.7 Cu-catalyzed Chan−
Lam couplings8 utilize arylboronic acids to oxidatively form
various anilines. All three approaches exhibit a broad scope
with respect to the nitrogen nucleophiles and have been
advanced to great synthetic utility.2,3,9 More recently, photo-
redox-10 and electrochemical11 methods, in combination with
redox active Ni-catalysts, have been used successfully for C−N
cross-coupling through high-valent Ni(III) intermediates, from
which C−N reductive elimination proceeds readily. All
methods require a functional group, for example a bromide
or a boronic acid, site-selective introduction of which is often
difficult,12−14 especially in complex small molecules with
monosubstituted arenes.
Over the past few years, several promising methodologies
have been developed for direct aryl C−N bond formation,
which do not require prefunctionalization (Scheme 1, middle).
In particular, addition of N-centered radicals such as aminium
radical cations,4a,t,v,w,aa imidyl radicals,4f,i,j,l−n and pyridinium
radical cations4ab proved to be viable for C−H amination.
Received: July 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b07323
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Coupling of Aryl Thianthreniums: Scope of N-nucleophiles
a
b
0.2−0.5 mmol scale; PC = photoredox catalyst. Three equiv. nBu4NN3, 20 mol % [Cu(MeCN)4]BF4.
Furthermore, addition of N-nucleophiles to arenium radical
cations can provide C−N coupling products.4o Other methods
include insertion of nitrenoids,4r metal insertion,4e and
electrophilic aromatic substitution.15 While all of these
methodologies do not require functionalized arenes, they
typically afford mixtures of constitutional isomers in most cases
that must be separated to obtain analytically pure compounds
and are generally limited to a small selection of nitrogen-based
reaction components. For example, a rare case of a selective
C−H amination is limited to the introduction of the
piperazinyl group.4q Site-selective C−N bond formation by
direct C−H amination is achievable for specific cases if
coordinating directing groups are present;4b−d,g,s,x−z however,
the site-selective introduction of a variety of nitrogen-based
nucleophiles into functionalized arenes as we report here is
hitherto unknown.
As part of our program in aromatic C−H functionalization
chemistry, we reported on the site-selective functionalization to
aryl thianthrenium salts, i.e., the substitution of an aryl H by
the thianthrenyl moiety through reaction with commercially
available tetrafluorothianthrene-S-oxide or thianthrene-S-
oxide.14 Subsequent Pd-catalyzed C−C cross-coupling reac-
tions with conventional catalysts proceeded smoothly.
However, such reaction conditions could not be extended to
effective C−N cross-coupling. Conventionally, the use of
strong bases like NaOtBu is required for Pd-catalyzed C−N
cross-coupling of aryl halides, which are not compatible with
thianthrenium electrophiles due to benzyne formation.16
Following the seminal work of Buchwald that enables Pd-
catalyzed C−N cross-couplings with weaker bases,17 we
identified two Pd-catalyzed methods A and B (Scheme 2),
which enable C−N cross-coupling of aryl thianthrenium salts:
Cyclic and acyclic secondary amines gave high cross-coupling
yields with Cs2CO3 as base and RuPhos as best ligand (method
A),17 whereas aryl amines, amides, carbamates, and ureas
required 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in combi-
nation with AlPhos (method B).2h As an alternative to AlPhos,
tBuBrettPhos-Pd G3-catalyst can provide the same coupling
products but with slightly lower yields in some cases (e.g., yield
of 1i: AlPhos, 85%; tBuBrettPhos, 65%). To ensure solubility
of the aryl thianthrenium salts in tetrahydrofuran (THF), the
−
NTf2 counterion can be advantageous over the commonly
−
employed BF4 counterion.
Coupling with primary amines and N-heterocycles could not
be achieved effectively by Pd-catalysis. However, such amine
functionalities were successfully cross-coupled with photoredox
methods in combination with Cu(I). The higher reduction
potential of the aryl thianthrenium salts when compared to
B
DOI: 10.1021/jacs.9b07323
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Journal of the American Chemical Society
Communication
Table 1. C−N Cross-Coupling of Aryl Thianthreniums: Scope of Arenes
a
2-step yield (thianthrenation and acetalization).
more conventional leaving groups in cross-coupling chemistry
such as bromide, enables the efficient photoredox cycle with
appropriate redox chemistry on copper.14,18 We assume that
the reaction proceeds via single electron reduction of the aryl
thianthrenium, and subsequent generation of an aryl radical,
that can engage in Cu redox processes for subsequent C−N
reductive elimination from high-valent copper. After reaction
optimization (see Supporting Information), we identified two
methods, which reliably resulted in C−N bond formation with
azoles, imides, pyridones, and azide (method C) as well as
alkyl amines (method D). The lower nucleophilicity of N-
containing heterocycles in comparison to alkyl amines
necessitates deprotonation of the corresponding N-hetero-
cycles with Me4NOH or NaH to observe product formation
C
DOI: 10.1021/jacs.9b07323
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Journal of the American Chemical Society
Communication
using method C. A special case is the coupling of triazole,
which forms insoluble complexes with Cu(I). Therefore, the
success of the reaction depends on solubilizing the Cu-
triazolate complex, which was achieved via increasing the ratio
of triazolate to Cu to 3:1, and the use of a more polar solvent
(MeCN:DMSO 1:1 instead of pure MeCN). The introduction
of the azido group was accomplished using a catalytic amount
of Cu(I) (20 mol %, Scheme 2, 1s), while in all other cases a
stoichiometric amount was used. Taken together, the four
methods enable a remarkable broad substrate scope with
respect to the nitrogen nucleophile as shown in Scheme 2.
The Pd-catalyzed methods A and B can be applied to
sterically unhindered aryl thianthrenium salts (Table 1)
bearing various electrophilic functional groups like esters (2,
3), acetals (4), and amides (8a, 9); heteroarenes could also be
cross-coupled (7). Ortho-substituents are currently not well
tolerated, probably due to steric hindrance, and acidic
functional groups, e.g., alcohols, can be problematic. The
Cu-mediated methods C and D are less vulnerable to steric
hindrance, and tolerate ortho-substituents (e.g., 12, 13, 16).
Many functional groups do not interfere with the C−N
coupling including electrophiles like imides (10) and ketones
(20, 22). Esters (11), olefins (12), and aryl bromides (13, 22)
are tolerated. Photoredox methods fail to give isolable C−N
coupling products for very electron rich arenes like catechol-
derivatives. We assume that this result is due to oxidation and
subsequent decomposition of the initially formed coupling
product, whose reduction potential should be lower than the
substrate’s. Considering the general concept of photoredox
catalysis, overoxidation is a rather conceptual limitation than
one of the thianthrenium salts in particular.
All methods can be applied to aryl thianthrenium (TT) and
aryl tetrafluorothianthrenium (TFT) salts. In photoredox
catalysis, both derivatives perform similarly, while the Pd-
catalyzed methods afford higher yields with aryl thianthre-
niums as starting material. Use of aryl tetrafluorothianthrenium
salts in these cases may be problematic due to nucleophilic
aromatic substitution of the fluorine substituents. Moderate
yields for the Pd-catalyzed methods A and B correlate with
moderate conversion of the starting material. Methods C and
D gave full conversion in all cases. In some experiments,
hydrodefunctionalized starting material was observed as a side-
product, which can easily be removed by chromatography. The
same applies to the stoichiometric byproduct, thianthrene,
which can be recovered and recycled.14 Not all arenes can be
arbitrarily converted to either the thianthrenium or the
tetrafluorothianthrenium salt. For example, strychnine could
not be converted to a thianthrenium salt, but to a
tetrafluorothianthrenium salt. Conversely, indometacin methyl
ester reacted to its thianthrenium derivative, but not to its
tetrafluorothianthrenium analogue. Accordingly, the yield of
the Pd-catalyzed cross-coupling of the strychnine-derived
tetrafluorothianthrenium salt was 35% (Table 1, 9).
To showcase the potential of the thianthrenation−cross-
coupling approach for late-stage diversification, the flurbipro-
fen methyl ester-derived thianthrenium salt (TT-25) was
subjected to all four methods using a different N-nucleophile in
each case (Scheme 3). The products were isolated in yields
Scheme 3. Late-Stage Diversification of Flurbiprofen Methyl
a
Ester
a
(TT) Thianthrenation: 1 equiv. thianthrene-S-oxide, 3 equiv.
trifluoroacetic acid anhydride, 2 equiv. HBF4Et2O, MeCN, −40−25
°C, 15 h; (a) Method A; (b) Method B; (c) Method C; (d) Method
D.
between 55% and 77%. The transformations demonstrate how
the described methods complement one another to enable
cross-coupling of a broad variety of N-nucleophiles with aryl
thianthrenium salts and thereby provide a viable way for late-
stage diversification of complex small molecules in exquisite
selectivity and with straightforward purification.
In conclusion, we have developed the first C−N cross-
coupling reaction of aryl thianthrenium salts. A set of four
methods enables cross-coupling with a broad range of N-
nucleophiles, which includes alkyl and aryl amines, as well as
N-containing heterocycles. Although both approaches, Pd-
catalysis and photoredox catalysis, currently entail specific
restrictions with respect to the structure of the aryl electrophile
and the N-nucleophile, our work opens up a new opportunity
to achieve molecular diversity via selective late-stage C−N
bond formation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b07323.
■
S
In general, the Pd-based method A is best for the cross-
coupling of secondary amines. However, the photoredox
mediated amination (method D) can also be used to couple
secondary amines. For example, compounds 23 and 24 (Table
1), which are not accessible via Pd-catalysis due to their ortho-
substituents, could be synthesized via photoredox catalysis. In
direct comparison, the Pd-based method A affords higher
yields than method D for most other secondary amines; for
example, the yield of 2 is 92% with method A and 67% with
method D.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*ritter@kofo.mpg.de
■
ORCID
Tobias Ritter: 0000-0002-6957-450X
D
DOI: 10.1021/jacs.9b07323
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Journal of the American Chemical Society
Communication
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Author Contributions
‡P.S.E. and A.P.H. contributed equally.
Notes
The authors declare the following competing financial
interest(s): A patent application (number EP18204755.5,
Germany), dealing with the use of thianthrene and its
derivatives for C-H functionalization has been filed and F.B.
and T.R. may benefit from royalty payments.
ACKNOWLEDGMENTS
■
We thank the MPI fu
̈
r Kohlenforschung for funding and help
from the analytical departments. We thank Jiakun Li for help
with analytical data. This research was supported by the SNSF
through a grant to P.S.E. (P2EZP2_175112). A.P.-B. thanks
́
the Spanish Ministerio de Educacion, Cultura y Deporte for
financial support (FPU15/03940 and EST17/00459).
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DOI: 10.1021/jacs.9b07323
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX