Ruthenium-catalyzed cross-dehydrogenative ortho-N-carbazolation of diarylamines: Versatile access to unsymmetrical diamines

Article abstract of DOI:10.1002/anie.201308601

The dehydrogenative C-N cross-coupling of unprotected, secondary anilines through ortho-N-carbazolation has been achieved using a Ru catalytic system with O₂ as the terminal oxidant. The reactions proceed in an intermolecular fashion, selectively in the ortho position. Implications for the field of organic synthesis are discussed. No-No-No: Amination of a non-acidic Ci￡H bond, no pre-activation of the coupling partners, no chelate-assisting directing group. Dehydrogenative C-N cross-coupling through the ortho-N-carbazolation of unprotected, secondary anilines has been achieved using a Ru catalyst with O₂ as the terminal oxidant. The reactions proceed in an intermolecular fashion, selectively in the ortho position.

Full text of DOI:10.1002/anie.201308601

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Chemie
DOI: 10.1002/anie.201308601
Dehydrogenative C–N Cross-Coupling
Ruthenium-Catalyzed Cross-Dehydrogenative ortho-N-Carbazolation
of Diarylamines: Versatile Access to Unsymmetrical Diamines**
Marie-Laure Louillat, Agostino Biafora, Fabien Legros, and Frederic W. Patureau*
Abstract: The dehydrogenative C–N cross-coupling of unpro-
tected, secondary anilines through ortho-N-carbazolation has
been achieved using a Ru catalytic system with O2 as the
terminal oxidant. The reactions proceed in an intermolecular
fashion, selectively in the ortho position. Implications for the
field of organic synthesis are discussed.
although unpractical, strongly coordinating directing groups
are often required.
T
he development of novel cross-coupling methods has
considerably expanded over the past decade, due to recent
À
exceptional discoveries in the field of metal-catalyzed C H
activation.[1] These methods are becoming very popular in the
field of chemistry as they usually allow useful and unprece-
dented reactivity. Those classified as cross-dehydrogenative
couplings (CDCs) are particularly attractive because they
typically do not require preactivation and/or preoxidation of
either coupling partners, and they are also more atom-
economical [Eq. (1)].[2] The formation of C N bonds is
immensely important for the construction of biologically
À
À
We recently reported promising C N bond-forming
reactivity in a Ru-catalyzed method for the intermolecular
homodimerization of carbazoles leading to an interesting
class of dicarbazole products: lauternazoles.[13] We now turn
À
our attention to the C H activation and CDC-amination of
relevant scaffolds.[3] Very few CDC-amination methods exist
highly ubiquitous diarylamines.[3] Initial investigations using
Ru as catalyst[14] rapidly established that diphenylamine can
be selectively ortho N-carbazolated to yield diamine 3a as an
exclusive cross-coupling product [Eq. (4), Scheme 1]. This
new reactivity is particularly synthetically relevant because:
1) it constitutes a rare case of intermolecular hetero CDC-
amination; 2) it is a surprisingly regioselective reaction with
however,[4] due to pKa incompatibility issues (C H activation
À
methods usually require acidic conditions),[5] but also ther-
modynamic limitations (the reductive elimination with for-
À
mation of the C N bond and/or the transmetalation step are
reputed to be energetically difficult).[6] In spite of these
challenges, inspiring seminal works from Yu and Che,[7] Su,[8]
Liu,[9] Nicholas,[10] Daugulis,[11] and others[12] have appeared
recently, showcasing the feasibility of the concept of inter-
molecular CDC-amination reactions [Eqs. (2) and (3)],
À
respect to the C H functionalization (diarylamine), as well as
the N H functionalization (carbazole), in spite of multiple
possibilities; 3) it does not require a conventional, strongly
coordinating, chelate-assisting directing group; 4) it utilizes
O2 as the terminal oxidant.
À
[*] M.-L. Louillat, A. Biafora, F. Legros, Prof. Dr. F. W. Patureau
FB Chemie, Technische Universitꢀt Kaiserslautern
Erwin Schrçdinger Strasse 52, Kaiserslautern (Germany)
E-mail: patureau@chemie.uni-kl.de
We optimized the reaction as follows. The carbazole
(1 mmol), the diarylamine (3 mmol), [{(p-cymene)RuCl2}2]
(5 mol%), anhydrous Cu(OAc)2 (2.2 equiv), cumene
(0.5 mL), tetrachloroethylene (TCE, 2 mL), and acetic acid
(0.5 mL) are united in a screw-cap vessel and flushed with O2.
The vessel is then sealed and heated at 1508C for 24 h.
Treatment with acetylacetonate (neutralization of metal salts)
followed by column chromatography affords the cross-
coupling products 3a–w in moderate to excellent yields
[Scheme 1, Scheme 2, Scheme 3, Eq. (5)].[15] For convenience,
Homepage: http://www.chemie.uni-kl.de/patureau
[**] This work was supported by the DFG-funded transregional collab-
orative research center SFB/TRR 88 “Cooperative effects in homo-
and heterometallic complexes (http://3MET.de)”. Corinna Nim-
phius is also acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308601.
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dichlorocarbazole (3d,h,i,k isolated in 77, 77, 96, and 82%
yield, respectively) as well as 4,4’-diphenyldiarylamine (3j,k).
It is interesting to note that “perycarbazole” 1p, a compound
of industrial interest in high-performance semiconducting
devices,[17] undergoes our reaction, affording 3p in 50% yield
(Scheme 1). Intriguingly, diphenylamine is not effective as an
N-nucleophile (no homocoupling product 4). Neither are 2,3-
diphenylindole (electronically similar to carbazole, 5), 3,5-
trifluoromethylaniline (6), nor tosylamine (7).
Furthermore, sterics do not seem to alter reactivity. For
instance 2,7-dimethoxycarbazole still leads to 3m in 51%
yield. Even more illustrative, 1,3,5-dixylylamine still affords
3l,n,o in 67, 72, and 63% yield, respectively, in spite of
À
a methyl group ortho to the C H functionalization position.
Steric pressure could be utilized in order to induce regiose-
À
lective C N bond formation (product 3q, 5:1 in favor of the
À
less sterically hindered C H position, Scheme 2). Electronic
Scheme 2. Steering the regioselectivity by means of sterics and/or
electronics, reaction conditions: see Scheme 1. The ratio of regio-
isomers is given in parentheses.
effects are somewhat less efficient in inducing a regioselective
reaction, however, whether with electron-donating or with-
drawing substituents (3r and 3s, 2:1 and 1.5:1, respectively, in
favor of functionalization at the most electron-rich position).
Our method is also remarkably efficient for the prepara-
tion of unsymmetrical selectively isotopically labeled ortho
diamine compounds. For example, 3t (tertiary 15N, 98 +%),
and 3u (secondary 15N, 98 +%), were both readily prepared in
64% yield (Scheme 3).[15]
A biologically active carbazole could also be engaged:
Carprofen, a nonsteroidal antiinflammatory drug, notably
commercialized by Pfizer as a racemate under the trade name
Rimadyl.[18] The corresponding coupling product 3w could be
obtained with a promising 40% yield.[15,19] We expect that our
late-stage CDC-amination method could be used to generate
rapidly libraries of new drug candidates [Eq. (5)].
Scheme 1. Substrate scope, yields of isolated products. [a] All reactions
are carried out in a sealed reactor of circa 170 mL, on a 1 mmol scale
of N-coupling partner (carbazole), and 3 mmol of C-coupling partner
(diarylamine). [b] Those entries were carried out on 0.5 mmol scale, in
a circa 70 mL sealed reactor. [c] Entry 3p gives 50% NMR yield of the
expected product, but only 32% were isolated due to a difficult
separation.
we refer to this novel class of diamine compounds as
lauternamines. It should be noted that: 1) cumene is a signifi-
cantly better cosolvent than chlorobenzene, toluene, tert-
butylbenzene, or even para-cymene (the ligand on the Ru
precursor); 2) TCE is a necessary component of the reaction,
its omission typically leads to low conversion and/or decom-
position;[16] 3) O2 is the preferred oxidant, its replacement by
N2 (Cu(OAc)2 as sole oxidant) decreases the yield of 3a from
64 to 39%; 4) neither primary aniline nor acetanilide react
with carbazole, making diarylamines a privileged substrate
class in this reaction.
With these conditions in hand, we found this novel cross-
dehydrogenative amination reaction to tolerate a number of
functional groups, including halides such as Cl and Br (3c,d,g–
i,k). Selected substrates react with high efficiency, notably 3,6-
Surprisingly, engaging nonsymmetrical carbazoles system-
À
atically leads to chiral C N cross-coupling products, due to
À
constrained rotation about the C Ntert axis. We suspect that
À
the intramolecular N H···N hydrogen bond is partly respon-
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Scheme 3. Access to unsymmetrically semi-labeled 15N-14N ortho-
diamines, with absolute regio-isotopic control.
sible for this constraint.[20] For example, the racemic product
3 f, obtained from the condensation of simple 3-methoxycar-
bazole with diphenylamine, can be separated readily into its
enantiomers by analytical HPLC on a chiral stationary phase
(OD-H column, Figure 1). Likewise, product 3v, based on
Scheme 4. H–D scrambling experiments.
with [D1]-acetic acid, and initially without carbazole coupling
partner (for simplicity, Experiment A, Scheme 4).[15] As
expected, significant reversible metalation–deuteration
occurs in the ortho position (44% D), and in the para
position (46% D), with an overall average D incorporation of
À
25% (determined by MS). It is interesting to note that C H
metalation occurs at the most nucleophilic ortho and para
À
positions, but only the former reacts further to give the C N
cross-coupling product. We then performed the experiment in
the presence of carbazole (Experiment B, Scheme 4). The
unreacted diphenylamine was again found with a consistent
average deuterium incorporation of 28%. In other words, the
À
C H activation step is reversible under the reaction con-
À
Figure 1. OD-H HPLC profile of 3 f, flow: 1 mLminÀ1 in hexane/iPrOH
(97:3), detection 254 nm. Horizontal axis: retention time
(t=7.36 min., 50.8% of integration, first enantiomer, t=12.91 min.,
49.2% of integration, second enantiomer).
ditions, and is therefore not rate limiting. We assume the C N
bond-forming reductive elimination to be the most likely rate-
limiting step. Interestingly, in this experiment the unreacted
carbazole was measured with an average D incorporation of
26%. In other words, although carbazole acts as the N-
À
coupling partner, it is still significantly (reversibly) C H
(racemic) Carprofen, is characterized by NMR spectroscopy
as two diastereomers. It should be noted that increasing the
temperature to 1608C in [D6]-DMSO did not lead to internal
activated under the reaction conditions. It is also interesting
to note that Experiment A can still result in significant H–D
scrambling on diphenylamine (D incorporation of 36%) if
both Cu(OAc)2 and O2 are omitted, highlighting that those
À
rotation about the C Ntert axis on the NMR timescale. NMR
À
data at temperatures above 1608C could not be obtained for
compound 3v because of thermal decomposition.[15] In the
same spirit, chiral product 3o, bearing an enantiomerically
pure menthoxy auxiliary, was obtained in 63% yield as a 1:1
mixture of diastereomers. We expect that this new kind of
components do not operate at the C H activation stage, but
later on in the catalytic cycle.[21] This means the current
reaction mechanism is significantly different from the pre-
viously reported homodimerization of carbazoles.[13]
In summary, we have developed an efficient Ru-catalyzed
method to N-carbazolate diarylamines in the ortho position
by direct intermolecular CDC-amination, leading to unpre-
cedented unsymmetrical diamines. This intermolecular
hetero-CDC-amination method is exceptional because it
obviates the need for the preoxidation of either coupling
À
C Ntert axial chirality will find interesting future applications,
for example in ligands in metal-catalyzed enantioselective
transformations.
Initial mechanistic experiments were carried out by first
engaging diphenylamine under pseudo-reaction conditions,
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partners, and it operates without a chelate-assisting directing
group. We are now working on translating this new reactivity
À
to simple primary anilines, phenols, and other useful C H
activation substrates.[22] More in-depth mechanistic investiga-
tions are also underway.
Received: October 2, 2013
Revised: October 31, 2013
Published online: February 19, 2014
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Keywords: axial chirality · C–H activation ·
dehydrogenative cross-couplings · lauternamines ·
oxidative amination
.
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[15] See the Experimental Section in the Supporting Information.
[16] Replacement of TCE with any other standard chlorinated or
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benzene, dichloro- or dibromobenzenes, hexabromobenzene,
tribromoethylene, hexachlorobutadiene, etc.) typically leads to
significant loss of conversion. It should be noted that traces of
chlorination of the substrates or products were not detected. In
addition, omitting TCE while using a stoichiometric amount of
Ru salt leads to a significantly lower yield of 3a (19% instead of
64% under standard conditions). We therefore assume that TCE
is not specifically involved in the (re-)oxidation of the Ru
catalyst.
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À
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À
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[19] In Equation (5), the low yield of 3v (13%) can probably be
explained by competing decomposition pathways, perhaps
through undesired decarboxylation. The Carprofen starting
material (1v) could not be detected at all in the reaction
mixture due to heavy decomposition. Lowering the reaction
temperature did not improve the yield of 3v, however. Fortu-
nately, protecting the carboxylic acid in its methyl ester form
(1w) proved more effective, and the corresponding product 3w
was obtained in 40% yield.
[20] Chirality based on the slow or hindered pyramidal inversion of
the secondary NH atom was also considered but estimated to be
improbable. Supporting this point, no racemate separation was
evident when nonfunctionalized product 3a was analyzed by
HPLC on a chiral stationary phase (OD-H). Only a single sharp
peak was observed (see the Supporting Information).
expected product 3a was detected by GC–MS, suggesting that
the role of Cu is far more than just an acetate source.
[22] Phenoxazine and phenothiazine show promising reactivity, but
only in homocoupling reactions. Attempts at heterocoupling
with diarylamines typically lead to poorly useful mixture of
homo- and heterocoupling products. Optimized conditions for
homocouplings: Phenoxazine (1.0 mmol), [{(p-cymene)RuCl2}2]
(0.0125 mmol), Cu(OAc)2 (0.55 mmol), C2Cl4 (2 mL), cumene
(0.5 mL), and AcOH (0.125 mL) under otherwise standard
conditions. Phenothiazine (2.0 mmol), [{(p-cymene)RuCl2}2]
(0.025 mmol), Cu(OAc)2 (0.25 mmol), C2Cl4 (4 mL), cumene
(1 mL), and AcOH (0.250 mL) under otherwise standard con-
ditions.
[21] A control experiment in which the [{(p-cymene)RuCl2}2] pre-
catalyst is replaced by [(p-cymene)Ru(OAc)2] was carried out,
without any Cu salt. Only a very small nonisolable trace of
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