Toward polynuclear Ru-Cu catalytic dehydrogenative C-N bond formation, on the reactivity of carbazoles

Article abstract of DOI:10.1021/ol303216u

The cooperative action of Ru and Cu catalysts enables direct polynuclear C-H and N-H activation for the dehydrogenative N-carbazolation of carbazoles, selectively at the C1 position. Initial mechanistic experiments are presented and discussed.

Full text of DOI:10.1021/ol303216u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Toward Polynuclear RuꢀCu Catalytic
Dehydrogenative CꢀN Bond Formation,
on the Reactivity of Carbazoles
Marie-Laure Louillat and Frederic W. Patureau*
€
Fachbereich Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger Strasse
€
Geb. 52, 67663 Kaiserslautern, Germany
patureau@chemie.uni-kl.de
Received November 21, 2012
ABSTRACT
The cooperative action of Ru and Cu catalysts enables direct polynuclear CꢀH and NꢀH activation for the dehydrogenative N-carbazolation of
carbazoles, selectively at the C1 position. Initial mechanistic experiments are presented and discussed.
Since 1905, and the founding works of Ullmann and
Goldberg (eq 1),1 the condensation of N-nucleophiles onto
aromatic positions has remained an intense field of re-
search, as many natural molecular structures and syn-
thetic targets contain nitrogen atoms.2 The celebrated Pd-
catalyzed version developed by Buchwald and Hartwig
(1995, eq 2)3 has allowed milder reaction conditions and a
broader amine scope, although preactivated substrates (aryl
halides) and elaborate ligand systems are often required.
Recently, Miura, Wing-Yiu Yu, and others have introduced
an alternative strategy, which relies on CꢀH activation4 in
combination with preactivated (and/or preoxidized) elec-
trophilic aminating reagents (eq 3).5
(1) (a) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 2211.
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r
10.1021/ol303216u
XXXX American Chemical Society

The latter still suffer however from an arguably tedious
preparation, and the low atom efficiency in the overall
coupling reaction. Thus, the development of direct cross-
dehydrogenative-coupling (CDC)6 amination methods by
double CꢀH/NꢀH activation still constitutes an immense
challenge (eq 4). In this emerging field, promising con-
tributions have been made recently by Buchwald,7 J.-Q.
Yu,8 and others,9 relying on Pd catalyzed CꢀH activation
techniques, in combination with often intramolecular and/
or protected substrates. Ru CꢀH activation catalysts,
however,10 have been underexploited in dehydrogenative
CꢀN bond forming reactions. We present here the outline
and potential of such technology.
Scheme 1. RuꢀCu Dehydrogenative CꢀN Carbazolation of
Carbazoles, Isolated Yieldsa
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We focused our initial efforts on carbazoles, because
they are ubiquitous heterocyclic cores in natural products
and, yet, have been underinvestigated as far as late-stage
CꢀH activation reactions are concerned.11 Furthermore,
carbazoles are an interesting study case because they
possess up to eight different and competing CꢀH posi-
tions, a substantial challenge in terms of CꢀH activation
regioselectivity.
We report here on the cooperative action of Ru and Cu
catalysts enabling direct CꢀH and NꢀH activation for the
dehydrogenative N-carbazolation of carbazoles, selec-
tively at the C1 position.12 After probing a series of typical
CꢀH activation methods,13 we identified the best con-
ditions as presented in Scheme 1 (2aꢀl). Long reaction
(11) For a recent review, see: Schmidt, A. W.; Reddy, K. R.;
€
Knolker, H.-J. Chem. Rev. 2012, 112, 3193.
(12) Fagnouhad previously found a similar byproduct (7% yield) in a
Pd catalyzed transformation; see: Liegault, B.; Lee, D.; Huestis, M. P.;
Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022.
(13) See Supporting Information for experimental details.
(14) Product 2l possesses two quaternary carbons displayed as
2
reciprocal dd (1J13C‑15N = 16 Hz, J13C15N = 1 Hz) in the 13C{1H} NMR,
thus confirming the ortho configuration of the two 15N centers. 1Hꢀ15N
HMBC (1H: 400 MHz, 15N: 41 MHz, CDCl3) δ (ref. CH3NO2, ppm): ꢀ276.5
(s, tertiary N), ꢀ291.7 (s, NH). For a representative survey of azole
derivatives, see: Nitrogen NMR; Witanowski, M., Webb, G. A., Eds.; Plenum
Publishing: 1973; ISBN 0-306-30734-0.
B
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for the formation of the true active species.16 In addition,
no deuteration was observed when the Cu or Ru salt was
respectively omitted (eqs 7 and 8). This indicates that both
Ru and Cu are required early on in the CꢀH activation
step.
Figure 1. X-ray structure: 2a (ORTEP view, 30% probability
level). Selected torsion angle (deg): C37ꢀN4ꢀC26ꢀC25 =
67.3(4).
times are helpful because of the chelate poisoning
effect of the products. Omission of either the Cu or
Ru salt shuts down the reactivity. For convenience in
referencing, we named this class of compounds Lau-
ternazole (Figure 1).14,15
Our initial mechanistic studies were very insightful for
understanding this intriguing reaction. We first engaged
carbazole 1a in the presence of deuterium-labeled acetic
acid-d1 (eq 5). Interestingly, the unreacted carbazole 1a
was isolated with an impressive deuterium grade, not only
at C1 (75% d-incorp.) but also at C2 (18% d-incorp.) and
especially C3 positions (44% d-incorp.), which is surpris-
ing as no coupling products were ever observed at C2 or
C3. This may indicate that (1) the catalyst approaches
the substrate from the top, through coordination to its
electron-rich π-aromatic system (hence CꢀH activation at
C2 and C3), and (2) the initial CꢀH activation is not rate-
limiting (because reversible). The final CꢀN reductive
elimination, an event known to be difficult, may be in fact
the rate-limiting step. Most surprising, however, was the
observation that running the deuterium scrambling experi-
ment under a strict N2 atmosphere completely suppresses
the CꢀH activation reactivity (11% d-incorp., at C1 only,
eq 6). Consequently, O2 not only is required as an oxidant
but also is probably a critical catalyst modifier, responsible
In its initial stage, the reaction is clearly first-ordered in
Ru, although with a slightly broken kinetic order of 0.7,
possiblydue tothe competing initialRu-dimerdissociation
process. There is however a clear zero kinetic order in
Cu, which is somewhat surprising at first, because Cu is
strictly required to effect reactivity. Nevertheless, we also
(15) It was found possible to gram-scale the reaction. 20 mmol of 1a
in a large sized reactor at 150 °C lead to 1.5 g of 2a; see exptl part.
(16) The importance of oxo-complexes in CꢀH activation reactivity:
Gunay, A.; Theopold, K. H. Chem. Rev. 2010, 110, 1060.
(17) For mixed Ru(II)ꢀCu(I) hetero-dinuclear complexes with in-
doles as, respectively, a π- and N-ligand, see for example: Chen, S.;
Carperos, V.; Noll, B.; Jeffrey Swope, R.; Rakowski DuBois, M.
Organometallics 1995, 14, 1221.
Figure 2. Initial reactivity Job plot. [Ru] þ [Cu] = 40% catalytic
loading; reaction time, 3 h, in otherwise standard conditions
(2 mmol scale).
Org. Lett., Vol. XX, No. XX, XXXX
C

Cu order, we performed a reactivity-based Job plot experi-
ment where the two variables are [Ru] and [Cu]. The
highest initial rate was not obtained at the expected 1:1
ratio, but clearly at the optimal ratio of 1:2 (Ru/Cu, Figure 2).
Therefore, as much as one Ru center and two Cu centers
could be jointly involved in the rate-limiting step. Based
on these experiments and on polynuclear organometallic
literature precedents by Dubois,17 Murai,18 and Chang,19
we propose the initial mechanistic elements of Scheme 2.
These remain hypothetical at this stage but seem in accor-
dance with our kinetic data and the mentioned literature.
In summary, we expect that the surprising elements of
reactivity presented here will seed novel types of oxidative
amination reactions, particularly through synergic asso-
ciation of different metal catalysts.20
Scheme 2. Proposed and Initial Mechanistic Elements
Acknowledgment. We thank Dr. Harald Kelm (also of
the FB Chemie, TU Kaiserslautern) for the X-ray analysis
of 2a. This work was supported by the DFG-funded trans-
regional collaborative research center SFB/TRR 88 “Co-
operative effects in homo- and heterometallic complexes
(3MET)”.
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
performed a series of kinetic experiments at high Ru
loading, in which [Ru] > [Cu]. Under those conditions,
we measured the second-order kinetics for Cu (1.6) and,
reciprocally, zeroorderinRu. Therefore, itcan be assumed
that both Ru and Cu are involved in the rate-limiting
step(s) of the reaction. Surprised by the unexpectedly high
(19) Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
(18) For a polynuclear Ru catalyzed CꢀH activation reaction of
some azole derivatives, see: Fukuyama, T.; Chatani, N.; Tatsumi, J.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1998, 120, 11522.
(20) For the general dinuclear redox synergy aspect in CꢀH activa-
tion reactions, see also: (a) Powers, D. C.; Xiao, D. Y.; Geibel, M. A. L.;
Ritter, T. J. Am. Chem. Soc. 2010, 132, 14530. (b) Chuang, G. J.; Wang,
W.; Lee, E.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 1760. (c) Powers,
D. C.; Ritter, T. Top. Organomet. Chem. 2011, 35, 129. (d) Powers, D. C.;
Ritter, T. Acc. Chem. Res. 2012, 45, 840.
The authors declare no competing financial interest.
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