.
Angewandte
Communications
[
12]
(
1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea) was found to
catalyze the addition of 4a to 2a to yield a modest amount of
[13]
3
a after 24 hours in toluene at 508C. Alternatively, when
hexafluoroisopropanol (HFIP) was employed as solvent
conditions B), no additional catalyst was necessary and 3a
was isolated in high yield (81%) after 24 hours at 508C in the
(
[
11]
presence of a pyridine additive.
After confirmation of the feasibility of metal-free
nitrimine-based carbon–carbon cross-coupling reactions, we
became interested in exploring their potential as reagents for
the preparation of active pharmaceutical ingredients. Indole-,
pyrrole-, and coumarin-containing therapeutic agents served
[14]
as the inspiration for our studies. For example, RU24969,
phenprocoumon, and tipranavir are attractive medicinal
targets which may benefit from nitrimine cross-coupling
chemistry (Figure 1). With these targets in mind, the scope of
reactions between various nitrimine electrophiles and
coupling partners was explored.
Scheme 3. Selected nitrogen heterocycles and nitrimine reagents toler-
ated in cross-coupling reactions. Unless otherwise noted, reactions
were conducted using conditions B: pyridine, 508C, 24 hours. Yields
determined from product isolated using silica gel chromatography.
[
a] Reactions conducted using conditions A: toluene, Schreiner’s urea,
08C, 24 hours. See the Supporting Information for experimental
details. [b] 48 hours reaction time. Nap=naphthalene.
5
5
3
7% yield as a 6:1 mixture of E:Z isomers, and the product
m was prepared in high yield with excellent diastereocontrol
Figure 1. Potential nitrimine-based disconnections in drug discovery.
over alkene geometry.
We were delighted to find that strategic monitoring of the
reaction conditions enabled excellent control over the final
alkene geometry of highly substituted alkenes (Scheme 4). At
slightly increased reaction temperatures (508C) and using an
excess of indole, the majority of nitrimine 2b was converted
into the E stereoisomer of 3n. On the other hand, when the
reaction was conducted at 238C in toluene with 1.2 equiv-
alents of indole, the Z stereoisomer of 3n was prepared in
63% yield.
In addition to nitrogen-based heterocycles, hydroxy-
coumarins participated in cross-coupling reactions with
a variety of nitrimines to afford products (6a–d) in high
yields using DMSO (dimethylsulfoxide) as solvent
(Scheme 5). For instance, the reaction of hydroxycoumarin
with nitrimines derived from 4-methoxyacetophenone and 4-
bromoacetophenone gave rise to the formation of disubsti-
tuted alkenes 6a and 6b in 60% and 94% yields, respectively.
Alkene 6c was isolated in 72% yield, and the reaction of the
acetophenone-derived nitrimine and 5 gave rise to the
formation of product 6d in a modest 57% yield.
Reactions between less sterically encumbered nitrimines
and nucleophiles were most efficient in pyridine at 508C in
the absence of HFIP (Scheme 3). A variety of acetophenone-
derived nitrimines and nucleophilic nitrogen heterocycles,
including indoles and pyrrole, were well tolerated in the
process. For instance, 2-methylindole and 5-bromoindole
coupled to acetophenone-derived nitrimines to generate 3b
and 3c in moderate yields (69% and 40%, respectively). Both
electron-rich and electron-poor nitrimines operated
smoothly, enabling the preparation of 3d–3g in high yields.
N-methylindole also proved to be a useful nucleophile, as
good yields of terminal alkenes 3h and 3i were obtained.
Interestingly, N-methylindole was a more efficient reagent
when using conditions A (that is, the urea catalyst in toluene).
In addition to enabling synthetic access to terminal, disub-
stituted alkenes, this process is useful for the direct con-
struction of sterically hindered trisubstituted olefins (3j–3m).
The reaction of 2-methylindole and the nitrimine derived
from deoxybenzoin gave rise to 3j in good yield as a 5:1 ratio
of E:Z alkene isomers. Vinyl bromide 3k was prepared in
moderate yield as a 1:1 mixture of stereoisomers. The reaction
of 2-methylindole with the nitrimine derived from propio-
phenone gave rise to the formation of 3l which was isolated in
Pleased with the array of products (3a–m and 6a–d)
accessible using our metal-free nitrimine coupling procedure,
we turned our attention toward applying the new method in
the synthesis of the active pharmaceutical ingredient
2
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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