Exploring a unique reactivity of N-heterocyclic carbenes (NHC) in rhodium(III)-catalyzed intermolecular C-H activation/annulation

Article abstract of DOI:10.1039/c4cc07170k

Disclosed herein is the unique conjugative role of N-heterocyclic carbene (NHC) ligands as a directing group in aromatic C-H activation, coupled with a facile NHC-alkenyl annulative reductive elimination which guided the Rh^III-catalyzed intermo

Full text of DOI:10.1039/c4cc07170k

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Exploring a unique reactivity of N-heterocyclic
carbenes (NHC) in rhodium(III)-catalyzed
intermolecular C–H activation/annulation†
Cite this:DOI: 10.1039/c4cc07170k
Received 11th September 2014,
Accepted 14th October 2014
Debasish Ghorai and Joyanta Choudhury*
DOI: 10.1039/c4cc07170k
www.rsc.org/chemcomm
Disclosed herein is the unique conjugative role of N-heterocyclic
carbene (NHC) ligands as a directing group in aromatic C–H
activation, coupled with a facile NHC–alkenyl annulative reductive
elimination which guided the RhIII-catalyzed intermolecular annula-
tions of imidazolium salts and alkynes under ambient conditions
leading to structurally important imidazo[1,2-a]quinolinium motifs.
The tremendous success of N-heterocyclic carbene (NHC) ligands
in homogeneous catalysis portrays a true reflection of their unique
stereoelectronic properties and strong metal–CNHC bonding, and
the excellent stability of their metal complexes toward heat, air and
moisture.1 The robust and inert metal–CNHC backbone is consid-
ered a key factor for providing the opportunity to explore catalytic
strong bond activation and oxidative functionalization without any
self-transformative side reactions. While these ideal spectator
Scheme 1 (a) Directing group (DG)-assisted C–H functionalization strategy
(FG = functionalizing group); and (b) NHC as a new directing group in a
catalytic C–H activation–alkyne insertion–annulation sequence.
ligand-like features of NHCs impart remarkable catalytic proper- catalytic intermolecular C–H functionalization–annulation reaction
ties to their transition metal complexes, the same features have using NHC motifs and leading to important organic molecules has
made them hitherto unknown to function as directing groups not been realized so far. Exploitation of non-NHC-based (hetero)-
(DGs) in very powerful and promising C–H functionalization arene substrates toward oxidative annulation via double C–H
strategies for C–C and C–heteroatom bond-forming catalysis activation has recently received growing attention.5 It is worth
(Scheme 1a),2 in spite of the fact that a few directed cyclometala- mentioning here that the imidazo/benzimidazo-fused quinolinium
tion (C–H activation) reactions were studied previously using the scaffolds are, similarly to other aza-fused heterocycles, important
NHC-platform.3 Addressing this challenge, herein, we report such structural motifs present in various biologically active compounds
an unprecedented reactivity of NHCs, where they participate and pharmaceuticals, and are hence in great synthetic demand.6
as directing groups in a RhIII-catalyzed C–H activation–alkyne These types of molecules have high affinities for DNA because of
insertion–annulation sequence to readily access imidazo[1,2-a]- their planar geometries and charged backbones, and they show
quinolinium salts from imidazolium salts and internal alkynes effective antitumor or anticancer activities.6 Additionally, these
at ambient temperature (Scheme 1b). In addition, although two molecules display fluorescence properties which might be useful
examples of catalytic intramolecular annulation reactions, involving in organic light-emitting diode (OLED) applications.7 Our new
a Ni0/NiII-based NHC–alkyl reductive elimination and a RhI-based finding exemplifies a novel approach for the easy synthesis of such
NHC–alkene insertion pathway, have been reported,4 a directed an important class of heterocyclic skeletons under ambient con-
ditions, in contrast to high-temperature (60–160 1C) or multistep
Organometallics & Smart Materials Laboratory, Department of Chemistry,
Indian Institute of Science Education and Research Bhopal, Bhopal 462 066, India.
E-mail: joyanta@iiserb.ac.in
methodologies.8
As imidazolium salts are well-known precursors for the synthesis
of transition-metal–NHC complexes via silver-transmetalation
routes, we first conducted a one-pot stoichiometric annulation
reaction to test the feasibility of our hypothesis on a directed
C–H activation–insertion–reductive elimination sequence using
† Electronic supplementary information (ESI) available: full experimental details;
NMR and mass spectra; CIFs of 4, 3a-PF6, 3a-OTf, 3f, 3m and 3p. CCDC 1020425–
1020430. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc07170k
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Table 1 Substrate scopea
Scheme 2 (a) A one-pot stoichiometric annulation reaction via a silver-
transmetalation route; and (b) optimized catalytic conditions (see ESI†).
the NHC–RhIII backbone. Accordingly, a successful annulation
reaction between 1-methyl-3-phenylimidazolium iodide (1a) and
diphenylacetylene (2a) in the presence of Ag2O and [Cp*RhIIICl2]2
with the use of KPF6 as an additive, affording the desired
annulated product 3a in a 75% yield (for full spectroscopic and
crystallographic characterization see ESI†), indicated that the
NHC–alkenyl annulative reductive elimination indeed proceeds
smoothly at room temperature (Scheme 2a).
Motivated by the above results, we initiated the catalytic
annulation studies, starting from 1a and 2a in the presence of
Ag2O and using [Cp*RhIIICl2]2 as the catalyst precursor in
dichloromethane at room temperature. Thus, the reaction of
1a (0.1 mmol) with 2a (0.12 mmol) was readily promoted by
[Cp*RhIIICl2]2 (5 mol%), Ag2O (0.055 mmol) and the oxidizing
agent AgOTf (0.2 mmol), affording the annulated product 3a in
a
Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), catalyst (0.005 mmol),
additives (as mentioned), CH2Cl2 (3.0 mL), N2 atm.
moderate yield (66%) after 24 h (entry 3; Table S1, ESI†). The Efforts towards the improvement of this by using alternative
silver-transmetalation and subsequent functionalization method- oxidants like Cu(II) or HOTf/O2 are in progress.
ology did not enhance the yield of the desired product sub-
This unique annulative reactivity of NHC ligands was further
stantially, even when increasing the amounts of Ag2O and explored by performing reactions with various types of imid-
AgOTf (Table S1, ESI†). We then endeavoured to couple another azolium salts having different wingtip substituents (N-substituents
popular method of metal–NHC bond formation from imid- in azoliums) with several internal alkynes to provide annulated
azolium salts, by using NaOAc as a base, with the ensuing products in moderate to good yields under optimized reaction
insertion–annulation cascade. Delightedly, the use of NaOAc conditions (Table 1). Like for the N-methyl substituent in 1a,
(0.4 mmol) proved to be beneficial and resulted in the for- the reaction was also successful with N-butyl and N-benzyl
mation of 3a in an 81% yield after 24 h with 5 mol% catalyst wingtip groups in the imidazolium substrates, providing good
and 0.3 mmol of AgOTf (Scheme 2b, and ESI†). A thorough yields of the corresponding products (3b and 3c). Modification
optimization study was performed to evaluate the importance of of the N-phenyl wingtip of the imidazolium moiety at the para
the appropriate catalyst precursor, coligand, halide abstractor position showed a direct effect on the reaction; a NO2 group
and metal oxidation state (see ESI†). It is significant to note that afforded 3d in excellent yield (up to 90%) whereas a OMe group
with 2 mol% catalyst, the yield of the product was found to be afforded only 29% of the corresponding product 3e. A benzimid-
76% under the same conditions (Scheme 2b). This result pro- azolium substrate provided an excellent yield of the annulated
vided a turn over number (TON) of 19 per Rh atom and a product 3f. Treatment of electron deficient alkynes, like dimethyl
turn over frequency (TOF) value of 0.79 hꢀ1, which are good acetylene dicarboxylate (DMAD), produces lower yields (39–49%)
results at room temperature conditions. Significantly high TON of the annulated products (3h–3i) compared with treatment of
(86 per Rh atom) and TOF (43 hꢀ1) values were obtained with a diphenyl acetylene with different imidazolium partners. On the
loading of 0.5 mol% catalyst under reflux conditions. These other hand, the reaction was found to be high-yielding with
TON and TOF values for the present catalytic system are superior to dialkyl acetylene, providing 90% and 74% yields for 3g and 3j
the majority of those for similar annulations catalysts (see ESI† for respectively. Interestingly, phenyl–alkyl unsymmetrical alkynes
details). However, this methodology suffers from the use of a large provided single regioisomers of 3k, 3l, and 3m in high yields.
amount of additives (3 equiv. of AgOTf and 4 equiv. of NaOAc). On the other hand, alkynes bearing two different aromatic
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rings produced regioisomeric pairs, in a 2 : 1 ratio for 3n (with a
NO2 group) and a 1 : 1.2 ratio for 3o (with a OMe group) in 66% and
35% combined yields, respectively. Notably, the reaction of two
equivalents of imidazolium salt 1a with a dialkyne moiety afforded
only mono annulated product 3p in 40% yield. Steric factors might
have played the main role in inhibiting double annulation.
To obtain insight into the reaction mechanism, a series of
control experiments were performed. First and foremost, isola-
tion of the NHC-cyclometalated rhodium(III) intermediate 4 was
accomplished in excellent yield by using NaOAc as a base in the
reaction of 1a and [Cp*RhIIICl2]2 in CH2Cl2 at room tempera-
ture (Scheme 3a), followed by its full spectroscopic and crystallo-
graphic characterization (see ESI† for details). Interestingly, the
stoichiometric reaction of 4 with 2a at room temperature in the
presence of AgOTf easily afforded the annulated product 3a in
good yield (Scheme 3b). Furthermore, 4 was successfully utilized
Scheme 4 Postulated catalytic cycle.
On the basis of the above results and the reported directing-
as a catalyst in the reaction of 1a and 2a to form 3a in high yield group assisted C–H activation–annulation chemistry,2,5,8a–f
a
under the standardized conditions (Scheme 3c). The satisfactory plausible catalytic cycle is shown in Scheme 4. In the presence of
performance of the cyclometalated complex 4 in the above NaOAc, [Cp*RhIIICl2]2 forms the five-membered cyclometalated
stoichiometric as well as catalytic annulation reactions implied complex 4 from the substrate 1a, via ortho-C–H activation directed
that it is a tenable intermediate in the catalytic cycle. Moreover, the by the coordinated NHC ligand. After halide abstraction from 4 by
deuterium kinetic isotope effect (DKIE) value of B0.9 indicated AgOTf, the alkyne coordinates to generate intermediate I. Insertion
that the phenyl ortho-C–H cleavage was not involved in the rate- of the coordinated alkyne into the Rh–Caryl bond of I provides the
limiting step (Scheme 3d). In the H/D exchange experiment, seven-membered rhodacycle intermediate I0. The possibility of a
only 6.2% D incorporation into the ortho-C–H of the phenyl ring competitive NHC–alkyne insertion can not be ruled out, consider-
of the resulting product was achieved, and 3.5% deuteration at ing a few previous stoichiometric studies which show such a
the phenyl ortho-C–H of the unreacted substrate suggests that reactivity, albeit under a non-competitive environment.4b,9 Sub-
the phenyl C–H metalation is very weakly reversible. On the sequent reductive elimination from I0 affords the annulated pro-
other hand, a relatively moderate D incorporation (B23%) at duct 3 and a Cp*RhI species I00,8b which is oxidized by AgOTf to
the imidazolium C–H of the unreacted substrate indicates Cp*RhIII for further NHC-directed C–H activation of 1a to continue
a partially reversible imidazolium C–H metalation during the the catalytic cycle. Preliminary investigations by combined time-
1
catalysis (see ESI†).
dependent H NMR spectroscopy and ESI-MS analysis indicated
the generation of the postulated Cp*RhI intermediate I00 (Fig. S10,
ESI†).8b Detailed experimental and DFT studies are underway in
order to fully investigate the proposed intermediates and also the
NHC–alkyne insertion pathway for subsequent annulation.4b
In conclusion, we demonstrated a unique conjugative reactivity
of cyclometalated NHC ligands in rhodium(III)-catalyzed inter-
molecular annulation, leading to important imidazo[1,2-a]-
quinolinium structural motifs at room temperature. A series of
control studies suggested the proposed mechanistic sequence
involving NHC-directed C–H activation/insertion/annulative
reductive elimination/oxidative catalyst regeneration in the cata-
lytic cycle. Full investigations and further applications in other
reactions are currently ongoing in our laboratory.
This work was supported by IISER Bhopal (generous in-house
grant, and a postdoctoral fellowship to D.G.), DAE-BRNS and
DST (young scientist research grants). We sincerely thank the
reviewers for their helpful comments.
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