.
Angewandte
Communications
nate. Indeed, they were never envisioned for ACAs of
organometallic reagents and few reactions employing them
are described in literature. A report in 1998 described only
two examples of hetero-Diels–Alder reactions between a-
ketoamides and ethylvinylethers under bis(oxazoline)/cop-
per(II) catalysis.[8] Later, Rodriguez et al. described their use
in the synthesis of highly functionalized pyridines by a multi-
component reaction in the presence of ammonium acetate
and malonate derivatives.[9] Examples of quinoline[10] and
pyrazolinecarboxamide[11] syntheses were finally reported
using an a-ketoamide and m-N,N-dimethylamino aniline
and N-pentylhydrazine, respectively.
In the course of our studies on the ACA of organometallic
reagents, and with the aim of providing efficient access to g-
methyl-substituted carbonyls, we report herein the ACA of
AlMe3 to b,g-unsaturated a-ketoamides with excellent regio-
and enantioselectivities. If we consider the synthetic poten-
tiality of g-methyl-substituted a-ketoamides, we feel that this
method represents a new and powerful tool in organic
chemistry. To highlight it, we also describe the transformation
of the 1,4-adducts into chiral g-methyl-substituted building
blocks of interest.
perfect 1,4-regioselectivity (entry 3). Concerning the a-keto-
amides 1d and 1e, bearing phenyl and benzyl substituents,
respectively, on the nitrogen atom, the reactions had to be run
at room temperature for solubility reasons (entries 4 and 5).
Only 1d exclusively afforded the 1,4-adduct but with a lower
yield compared to that of 1c, and 1e gave a 1,4-adduct:1,2-
adduct ratio of 45:26. Finally, it appeared that the tert-butyl
group on the nitrogen atom was the substituent of choice for
a highly regioselective conjugate addition.
Having identified the best b,g-unsaturated a-ketoamide
structure, we next considered the use of various organome-
tallic reagents (Table 2). An asymmetric version was per-
formed using (R)-binap as a ligand. AlMe3 provided the
desired 1,4-adduct 2a exclusively in excellent yield (89%) and
99% ee (entry 1). Methylmagnesium bromide failed to
Table 2: Screening of organometallic reagents.
Entry[a] RM
Solvent T [8C] 2/3
Yield [%][b] ee [%][c]
Because of a structural similarity between ketoesters and
ketoamides, the same reaction conditions were first envi-
sioned: AlMe3 (2.0 equiv), copper thiophene carboxylate
(CuTC, 5 mol%), rac-binap (5 mol%) in THF. The optimi-
zation of the secondary amide moiety was first realized by
testing primary, secondary, and tertiary alkyl substituents as
well as p-methoxyphenyl and benzyl groups (Table 1). The
1
2
AlMe3
THF
MeMgBr Et2O
MeMgBr Et2O
MeMgBr THF
À78
À78
À78
À78
0
À20
À65
À65
99:1
1:99
1:99
1:99
89
85
88
92
–
99
rac.
rac.
rac.
–
–
24
rac.
3[d]
4
[e]
5
6
7
8
Me2Zn
Et2Zn
AlEt3
Et2O
Et2O
THF
Et2O
–
–
[f]
–
99:1
40:60
69
AlEt3
100[g]
Table 1: Optimization of the b,g-unsaturated a-ketoamide structure.
[a] Reaction done with a-ketoamide (0.416 mmol) and THF (1.5 mL.
[b] Yield of the isolated 1,4- or 1,2-adduct. [c] Determined by SFC using
a chiral stationary phase. [d] TMSCl (1.3 equiv) was used as additive.
[e] No reaction. [f] Complex reaction mixture. [g] Conversion.
provide 2a, but the racemic 1,2-adduct 3a was obtained
(entry 2). TMSCl was also tested as an additive as it is known
to promote conjugate addition on enals.[13] However, in the
case of ACAs to an b,g-unsaturated a-ketoamide, no traces of
2a were observed (entry 3). Dimethylzinc and diethylzinc
were not suitable for the reaction. With Me2Zn, no reaction
occurred and Et2Zn led to a complex reaction mixture
(entries 5 and 6). In the end, a triorganoaluminum reagent
proved to be the most efficient and so, we decided to
introduce an ethyl substituent by using Et3Al. The reaction
proceeded with perfect 1,4-regioselectivity, thus giving 2b in
69% yield (entry 7). Unfortunately, the ee value decreased
significantly to 24%.
Entry[a]
a-Ketoamide
T [8C]
t
1,4-adduct
[%][b]
1,2-adduct
[%][b]
1
2
3
4
5
1a
1b
1c
1d
1e
À78
À78
À78
25
30 min
3 h
3 h
30 min
1 h
46
68
89
63
45
32
16
–
–
26
25
[a] Reaction done with a-ketoamide (0.416 mmol) and THF (1.5 mL).
[b] Yield of isolated product. binap=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl.
These best reaction conditions were then applied to a wide
range of b,g-unsaturated a-ketoamides to evaluate the limits
of the methodology (Table 3). In all cases, reactions pro-
ceeded with perfect 1,4-regioselectivity as only 1,4-adducts
were recovered. First, if we considered para substituents
(alkyl, halide, or methoxy groups) on the aryl moiety had no
influence on regio- or enantioselectivity (entries 1–5). For
each a-ketoamide (S1–S5), the corresponding 1,4-adducts
A1–A5 were isolated in good to excellent yields (70–97%)
with excellent ee values (96–98.5%). Moreover, excellent
b,g-unsaturated a-ketoamides were easily synthesized by
a two-step procedure: a Passerini-like reaction gives a a-
hydroxyamide[12] followed by Dess–Martin periodinane oxi-
dation (see the Supporting Information). In the first attempt,
the n-butyl-substituted amide 1a gave a mixture of 1,4- and
1,2-adducts with a ratio of 46:32 (entry 1). By increasing steric
hindrance on the amide, exclusive formation of the conju-
gated adduct was possible. Indeed, the tert-butyl-substituted
amide 1c gave rise to the desired compound in 89% yield with
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 12701 –12704