H. Yan et al.
Tetrahedron Letters 61 (2020) 152450
Fig. 1. NHCs with bulky aryl side chains.
corresponding 4-aminoindoles. In the Cu(I)-catalyzed carboxyla-
tion of arylboronic esters, selected ligands exhibited high levels
of performance comparable to the current best ligand IPr [17].
For comparison, unsymmetric imidazoliums with large anthra-
cyl side chains (6a and 6b) were also synthesized from 9-aminoan-
thracene (Ant-NH2).
Imidazoliums and imidazoliniums 3–6 could be converted to
the corresponding free NHCs under basic conditions. Trapping
the free NHC derived from imidazolinium 5b with sulfur [21]
yielded thiourea 8 (Scheme 2).
The synthesis of the corresponding (NHC)CuCl complexes [22]
was then carried out (Scheme 3). After several attempts, conditions
using Cu2O and KOtBu were established for reactions from imida-
zolium and imidazolinium chlorides (3 and 5), affording corre-
sponding complexes 9 and 11 in 30–77% yield. For the reactions
of imidazolium perchlorates (4 and 6), tetrabutylammonium chlo-
ride (TBAC) was found to be an effective chloride source. The nine
new complexes are air- and moisture-stable, and could be purified
by silica gel column chromatography.
The NMR spectra indicate that complex 9 is a single isomer,
although its precursor 3 is a mixture of trans-/cis-isomers. The
crystal structure of 9 (Fig. 3, CCDC 2008743) [23] confirmed the
trans-configuration of the NHC ligand, and also the linear two-
coordinate geometry, with a Cu-C(1) bond length of 1.873(4) Å
and a Cu-Cl bond length of 2.1073(11) Å. Density functional theory
(DFT) calculations at the B3LYP/6–311 + g(d, p) level suggest that
in the gas phase the trans isomer is 2.11 kcal/mol more stable than
the cis isomer. The computed Cu-C(1) and Cu-Cl bond lengths of
the trans isomer are 1.8939 and 2.1333 Å (Table 1), respectively.
These data are in good agreement and comparable to the corre-
sponding experimental results.
The electronic and steric properties of the obtained NHCs were
also evaluated by calculations (Table 1). The percent buried vol-
umes (%Vbur) of the ligands (36.5–41.1) are mostly between the
values of IPr (46.3) and IMes (36.7). The bond dissociation energies
(BDE) of the Cu-C(1) bonds exhibit the following trend:
IIn > SIIn > IAnt ꢀ IPr/IMes, indicating that introducing the indole
side chain indeed strengthens the coordination bonds, although
the bond lengths remain similar to the values of (IPr)CuCl [24]
and (IMes)CuCl. These results show that the properties of the
indole-substituted NHCs are different than phenyl-substituted IPr
and IMes.
Results and discussion
We started our investigation with the synthesis of 4-aminoin-
dole intermediates (1) (Scheme 1). Alkyl groups were installed at
the 1-, 2- and 3-positions to avoid undesired reactions, and
changes to the 5-substitution (H or Me) were introduced to adjust
the bulkiness of the side chain. From 2-methyl-5-nitroanilines (1a
and 1b), the corresponding 7-methyl-4-nitroindoles could be
obtained following a diazotization, reduction and Fischer cycliza-
tion sequence, and then converted to 4-aminoindoles 2 by methy-
lation and hydrogenation.
The synthesis of indole-substituted imidazolium and imida-
zolinium NHC precursors was then explored. Symmetric imida-
zolium 3, as a 7:3 mixture of trans-/cis-isomers, was obtained by
the condensation of 5-methyl-substituted 2a with glyoxal and then
paraformaldehyde. However, compound 2b, which has no sub-
stituent at the 5-position, failed to give the corresponding imida-
zolium chloride. Polymerization between 2a and glyoxal
presumably takes place in the reaction.
Unsymmetric imidazoliums 4 were prepared from 4-aminoin-
doles 2 and arylamine-derived 3-acetoxyoxazolinium perchlorates
A, according to a protocol developed by the Fürstner group [18]. 4-
Hydroxy imidazolinium intermediates are first obtained in the pro-
cedure, and then dehydrated in concentrated sulfuric acid to yield
the corresponding imidazoliums. Mesityl (Mes) and 2,6-diiso-
propylphenyl (Dipp) groups were used to adjust the overall bulki-
ness of the ligands.
With the same consideration, unsymmetric imidazoliniums 5
were prepared by a three-step procedure. 4-Aminoindoles 2 were
reacted with an excess amount of triethyl orthoformate to give
ethyl formimidates, which were then condensed with a second
arylamine to afford formamidines [19], followed by cyclization
with 1,2-dichloroethane (DCE) [20] to form the NHC precursors.
It is worth noting that in early trials of imidazoliniums synthesis,
we also tested 4-bromoindole intermediates (7, Fig. 2) which could
presumably couple with mono-protected ethylene diamine and be
used in further transformations. Unfortunately, the Buchwald-
Hartwig coupling of 7 was unsuccessful in our hands.
To evaluate the role of indole-substituted NHC ligands in Cu(I)-
catalyzed reactions, we selected the carboxylation of organoboro-
nic esters developed by the Hou group [17] as a model system
2