Organic Letters
Moreover, the β-alkenyl β-alkyl acid derived from β-ionone
could be coupled with a furan-containing amine (3n). The
procedure for the β-(hetero)aryl,β-alkyl-substituted substrates
also worked well for β,β-diaryl substituted acids. In particular,
acids containing a bromoarene and a thiophene were efficiently
converted to the desired products (3o and 3p). However,
under these conditions, only low conversions were observed
for the reactions of more sterically hindered acids (see 3q and
SI for more structures), as well as using sterically hindered
amines such as diisopropylamine. We also examined substrates
with heteroatoms at the β-position. Silane 3r was obtained in
good yield from the corresponding Z-olefin, although with
diminished enantiopurity (75:25). In contrast, boronic ester 3s
and N-substituted indole 3t were obtained with excellent levels
of enantiomeric purity. In the cases of more complex
substrates, including nitrogen-rich heterocycles and functional
group containing amines, a 5 mol % catalyst loading was
employed to ensure full conversion of the unsaturated
carboxylic acids.
Figure 5. Two reaction pathways are considered after initial silylation
of the carboxylic acid.
Based on recent work of transition-metal-catalyzed reduction
combined. Full conversion to a mixture of silylated
intermediates 6a, 6b, and 6c (Figure 6A) in a ratio of 4:1:1
was observed after 60 h. Furthermore, neither 1,4-reduction of
the activated silyl esters nor interconversion between the
1
8
of amides to enamines and amines with hydrosilanes, we also
saw an opportunity to develop a one-pot synthesis of γ-chiral
Figure 4. One-pot synthesis of γ-chiral amines.
stereocenters in the γ-position are frequently encountered
19
structural components in bioactive molecules. However,
these remote stereocenters are in general challenging to form
directly and are usually installed in a stepwise process from a β-
14
chiral aldehyde followed by reductive amination reactions.
After a CuH-catalyzed reductive amidation reaction, 0.5 mol %
IrCl(CO)(PPh ) (Vaska’s complex) was added to the crude
3
2
reaction mixture, upon which the enamine 4a was efficiently
formed. Subsequent addition of methanesulfonic acid (MsOH)
induced further reduction, presumably via iminium ion
formation, delivering γ-chiral amine 5a in excellent yield and
enantiomeric ratio.
We next investigated some aspects of the mechanism of Cu
catalyzed reductive amidation of α,β-unsaturated acids (Figure
Figure 6. (A) Intermediary silyl ester intermediates identified and
characterized by NMR spectroscopy and high-resolution mass
spectrometry. (B) The CuH-catalyzed amidation was monitored by
H NMR-spectroscopy. (C) The CuH-catalyzed reduction of an
unsaturated amide is not efficient under the described conditions.
1
5
). Based on our previous investigations, we considered path A
as a possibility, in which the CuH-catalyzed 1,4-reduction of a
silyl ester delivers a copper enolate that could eliminate to a
ketene intermediate. Addition of the amine to the ketene
would then give the observed β-chiral amide product. An
alternative mechanism is illustrated as path B, involving the
Next, we monitored reactions using the conditions described
in Figure 3 (Figure 6B), using acid 1a and Et NH as model
2
substrates. Initially, the same silylated intermediates (6a, 6b,
6c) as observed previously were formed, although their
generation was accelerated (36 min vs 60 h), possibly by the
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direct amidation of the intermediate silyl ester, followed by
conjugate reduction of the resulting unsaturated amide.
Several experiments in THF-d8 were performed and
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presence of the basic amine. After complete consumption of
1
22
analyzed by H NMR spectroscopy. To identify and character-
the acid, first the more activated dimeric intermediate 6b is
ize the silyl ester intermediates, (E)-3-phenyl-but-2-enoic acid
converted to product 7, followed by the conversion of
monomer 6a. No other intermediates resulting from 1,4-
(1a), 0.5 mol % of (S)-CuCatMix, and 1 equiv of DMMS were
C
Org. Lett. XXXX, XXX, XXX−XXX