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atoms but is comparatively activated due to the adja-
cent C=O bond. This species can easily react with
a nucleophile to generate a reactive three-compo-
nent product that takes up the protons generated in
situ and undergoes deamination followed by aero-
bic/DMSO oxidation (Figure 2A). Our mechanism is
well supported by LC-MS results for the reaction be-
tween 1a and 3a, in which intermediate TN1 was de-
tected throughout till completion of the reaction
(Figure 2B; detailed LC-MS results are available in the
Supporting Information). Moreover, three control ex-
periments were performed to exclude the role of in-
termediate 14 in our reactions (Figure 2C). In experi-
ment a, the reaction of 1a and 3a in toluene at
room temperature failed to produce 14. However,
the same reaction at 808C resulted in 14 in 62%
yield (experiment b).[20] Treatment of compound 14
Table 3. Scope of aerobic iminium-mediated reactions towards various nucleophiles.[a]
13a, 3 h, 93% 13b, 2.5 h, 82% 13c, 2 h, 72%
13d, 2.5 h, 68% 13e, 2 h, 75%
13 f, 2 h, 62% 13g, 1.5 h, 78% 13h, 1.5 h, 67% 13i, 1.5 h, 72% 13j, 2.5 h, 68%
[a] 1 (0.75 mmol), 2 (0.895 mmol) in toluene (2 mL) at 608C for 1.5–3 h. Yields are
given for isolated products.
synthesized, but also promising structures such as a-ketoa-
mides were obtained by this method. Our method is not only
novel in terms of generating valuable structures, but also in ex-
ploring new modes of iminium-ion reactivity that can further
be extended in many directions.
(1 mmol) with 2a (20 mol%) failed to generate corresponding
1,2-dione 8a, even on heating to 808C for 24 h (experiment c).
On the basis of the above results, the only plausible route
for synthesis of diones can be proposed for two cases: 1) that,
in which DMSO acts as oxidant and 2) that, in which air acts as
oxidizing agent (Figure 3). In case of DMSO-promoted iminium
catalysis to give 8 or 9, the mechanism can be presumed to be
initiated by generation of iminium ion II, which undergoes nu-
cleophilic 1,2-addition with indolic or pyrrolic substrates (3 or
4, respectively) at C-3, resulting in formation of reactive three-
component intermediate TN1,which later abstracts H+ to pro-
mote elimination followed by addition of DMSO, which
through a concerted mechanism (Figure 3) results in loss of
DMS and H2O and leads to generation of the desired product.
On the other hand, when the same reaction is carried out in
toluene, TN1 undergoes self-deamination followed by aerobic
oxidation to the desired products 8 and 9. The advantage of
the latter reaction is the formation of ortho-coupled products
of phenols and b-naphthol (5 and 6, respectively), whereby the
same sort of reactive three-component intermediate TN2 is
generated by reaction of iminium ion II with a nucleophilic
carbon center of phenol/naphthol, and subsequent deamina-
tion followed by aerobic oxidation generates 10 and 11, re-
spectively. Generation of 12 can be explained by three-compo-
nent intermediate TN3, produced by attack of aryl nucleophile
(RÀ) on the iminium ion. The aryl nucleophile is generated by
the action of OHÀ on aryl boronic acid. The intermediate likely
abstracts a proton from H3BO3 generated in situ, and then
aerobic oxidation generates benzils. Finally, in accordance with
the LC-MS results obtained for two representative examples
(Supporting Information), it is well established that a-ketoa-
mide formation occurs through aerobic oxidation of iminium
ions generated by reaction of OA with secondary amines.
Methods reported earlier for most of these reactions are effi-
cient but generally involve the use of metals, ligands, oxidants,
additives, and bases under comparatively harsh conditions.
Our aerobic iminium method is an alternative mildest possible
approach for each class of reactions discussed.[17–19] For in-
stance, Li and co-workers obtained C-3 cross-coupled deriva-
tives of indole/substituted indoles 8 through transition metal
catalyzed a-arylation involving a copper salt and an oxidant
[CuCl/tert-butyl hydroperoxide (TBHP)].[17a] In contrast, our
method exploits the known tendency of iminium ions, gener-
ated in situ by reaction of an OA and a secondary amine 2, to
undergo cross-coupling reactions via an unprecedented
amino-catalyzed aerobic route to give desired products. Apply-
ing this reaction to pyrrole/substituted pyrroles 4 afforded
a method for the generation of C-3 coupled product 9 for the
first time. However, with phenols/substituted phenols 5, ortho-
coupled dione product 10 was obtained in moderate yields,
which was previously synthesized by Li et al. by using metal/
oxidant (Fe/TBHP) under refluxing conditions.[18] Furthermore,
application of our method to b-naphthol (6) generated the de-
sired product 11 for the first time in good yields. We also es-
tablished a high-yield method for generation of symmetrical/
unsymmetrical benzils through the reaction between 1 and 7,
which otherwise were obtained by Wu and co-workers through
Pd-based chemistry.[19]
To gain mechanistic insight into the unusual role of iminium
ions, we compared our reaction with reported reactions (Fig-
ure 2a). Evidently, the iminium ion generated from a secondary
amine and benzaldehydes undergoes 1,2-nucleophilic addition
with nucleophiles to give a three-component product that is
quite stable in an acidic environment. However, the three-com-
ponent intermediate produced from aldehydes having a-hy-
drogen atoms easily undergoes deamination to give an ole-
fin.[1d] In contrast, we presume that the reaction of an amine
with an OA generates an iminium ion that lacks a-hydrogen
Conclusion
We have established a novel aminocatalytic cross-coupling ap-
proach via iminium ions that results in the generation of 1,2-
diones with wide substrate scope. This difference in reactivity
of the iminium ion is attributed to the adjacent C=O bond.
Chem. Eur. J. 2014, 20, 1 – 8
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Mupparapu, Nagaraju
