Organic Letters
Letter
a b
,
Scheme 3. Scope of Tertiary α-Silylamines and (Het)aryl Bromides
a
b
All values correspond to isolated yields after purification. Unless otherwise noted, reactions were performed using aryl bromide (1 equiv, 0.3
mmol), α-silylamine (1.5 equiv, 0.45 mmol), 4CzIPN (3 mol %, 0.009 mmol), Ni(dtbbpy)Br2 (8 mol %, 0.024 mmol), K2CO3 (3 equiv, 0.9 mmol)
c
d
in THF (0.1 M) at rt for 20 h with blue LED (∼10 W) irradiation. Reactions were performed using aryl iodides. Reactions were performed using
two blue Kessil lamps (30 W) with a shortened reaction time (6 h). NMP (0.1 M) was used instead of THF (0.1 M).
e
(entry 5). Furthermore, control studies showcased that all
reaction parameters are necessary for effective aminomethyla-
tion (entries 6 to 8), and there is no erosion of the
details). Notably, neither starting material 1a nor product 2a
appears to undergo C−N coupling with aryl halide,
demonstrating the high chemoselectivity of this method.
Having established feasible cross-coupling conditions, the
substrate scope of this aminomethylation process was
evaluated (Scheme 2). The electron density on the aryl ring
was demonstrated to have little to no effect on the coupling
efficiency (2a−e), and meta- (2d) and ortho (2e)-substituted
substrates also exhibited good coupling efficiency. Meanwhile,
an unprotected alcohol group is well tolerated (2c), resisting
silylation during the reaction process.14 The scope of the
reaction with regard to heteroaryl halides was next explored,
permitting access to materials that otherwise would require use
of the less commercially available benzyl halides (for N-
alkylation approaches) or heteroaryl aldehydes (for reductive
amination). A wide variety of heteroaryl cores are incorporated
in good yields without the need of protection, including an
indazole (2i). Additionally, heteroaryl-based pharmacophores
(2m−p) including the antihistamine Loratadine (2m) and
GABA receptor antagonist Flumazenil (2o) display excellent
reactivity. Electron-rich heteroaryl systems (2f, 2g) serve as
competent substrates despite what must be a slower oxidative
addition.15 Notably, a primary sulfonamide (2k), which
contains a polar acidic group, is accommodated, showing
that multiple polar functional groups can be introduced by this
method. With respect to the scope of secondary α-silylamines,
amino acid based organosilanes including tyrosine (2s),
glutamate (2v), and N-Boc-lysine (2w) afford the desired
aminomethyl subunits without compromising yields. Further-
more, the oxidation-labile methionine residue (2r) is amenable
to this cross-coupling reaction. No protecting group is
necessary for the indole moiety of tryptophan (2q). The
scope has been further extended to more nucleophilic amines
(2x, 2y, 2aa). Because of the mild nature of Ni/photoredox
dual catalysis, the protocol is applicable to complex amine
systems including the dipeptide aspartame methyl ester (2z).
Finally, as part of our ongoing efforts to develop synthetic tools
to incorporate saccharide derivatives into complex molecular
fragments,16 this protocol was extended to the amino-
methylation of aryl bromides with a pyranose moiety (2aa),
prepared via reductive amination from the corresponding
glycosyl aldehyde and commercially available aminomethylsi-
lane.
With a broad scope based on a secondary α-amino radical,
we next applied the developed method to the construction of
tertiary amines. In fact, a significant improvement in reaction
efficiency and functional group tolerance was observed over
that of a protocol previously developed in the group (Scheme
3).7b Not only was a considerable improvement on yields
achieved, but substrates with polar functional groups including
amines (3i) and alcohols (3j, 3k) were successfully
accommodated. Additionally, instead of using (hetero)aryl
iodides, the less expensive and more readily available
(hetero)aryl bromides delivered the products in excellent
yields (3m−p). The scope of the α-silylamines was not limited
to aliphatic amines (3q, 3r), but could be extended to an
indole derivative as well (3s).
Another important feature of α-silylamine precursors is their
ease of modification. To demonstrate this, a streamlined
synthesis of dipeptide benzylamine 3t starting from proline-
derived organosilane 1l was carried out (Scheme 3c).12d
Deprotection of 1l with TFA followed by peptide coupling
afforded intermediate 1p with good efficiency. Under standard
arylation conditions, the corresponding tertiary amine 3t was
obtained without compromising the yield. As such, the
modular nature of this cross-coupling allows rapid access to
structurally diverse α-aminoalkyl radicals, delivering unique
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Org. Lett. 2021, 23, 4250−4255