sponding imines under mild conditions.6 The second and third
points would be possible by generation of more electrophilic
imines that have an electron-withdrawing N-protecting group
such as the Cbz and Boc7 groups and by employing carbon
nucleophiles that show nucleophilicity under neutral condi-
tions, e.g., active methylene compounds. Thus, we planned
the one-pot oxidative Mannich reaction8 of N-protected
amines 2 that consisted of (i) oxidation (dehydrogenation)
of 2 to the corresponding imine 3 and (ii) trapping 3 with
carbon nucleophiles (Figure 1). We describe here the results
Table 1. One-Pot Oxidative Mannich Reaction of Various
N-Cbz Amines 4a-i with Diethyl Malonate
entry
R
product
yield (%)a
1
2
3
4
5
6b
7
8
9
Ph (4a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
92
92
86
82
88
73
87
92
89c
4-MeC6H4 (4b)
4-MeOC6H4 (4c)
Ph(CH2)2 (4d)
CH3(CH2)2 (4e)
(CH3)2CH (4f)
t-BuMe2SiOCH2CH2 (4g)
BnO(CH2)4 (4h)
CH2dCH (4i)
a Isolated yield. b The reaction mixture was stirred for 10 h after the
addition of diethyl malonate. c A mixture of 5i and 5i′ (5i/5i′ ) 30/70).
Figure 1. Oxidative generation of N-protected imines 3 from 2
and nucleophilic trapping.
a longer reaction time (10 h) (entry 6). These results suggest
that enolizable aliphatic N-Cbz aldimines were readily
formed by the oxidation with 1, and the N-Cbz aldimines
reacted with diethyl malonate efficiently under mild condi-
tions. Protecting groups such as TBS and benzyl groups were
not influenced in the oxidative Mannich reaction (entries 7
and 8). When N-Cbz allylamine (4i) was subjected to the
present oxidative Mannich reaction, 1,4-adduct 5i′ was
obtained as a major isomer along with 1,2-adduct 5i in 89%
combined yield (5i/5i′ ) 30/70, entry 9).
1,3-Dicarbonyl compounds other than diethyl malonate
were employed in the oxidative Mannich reaction of N-Cbz
p-methoxybenzylamine (4c) (Table 2). First, some diethyl
alkylmalonates (alkyl ) methyl, ethyl, allyl, and benzyl) were
used as a carbon nucleophile, and in each case, the Mannich
products 6-9 bearing a quaternary carbon center were
obtained in high yields (entries 1-4). Not only malonate
esters but also â-keto esters efficiently reacted with N-Cbz
imines: ethyl acetoacetate gave the adduct 10 in 89% yield
as a mixture of diastereomers (55/45, entry 5). On the other
hand, cyclic â-keto esters such as 2-carboethoxycyclopen-
tanone and 2-carboethoxycyclohexanone gave the Mannich
adducts 11 and 12 in 95 and 89% yields, respectively, as a
single diastereomer (entries 6 and 7). 1,3-Diketone, acetyl-
acetone, also reacted with N-Cbz aromatic imine to afford
13 in 92% yield (entry 8).
obtained in the oxidative Mannich reaction of N-carboben-
zyloxy (Cbz) amines with 1,3-dicarbonyl compounds such
as malonate esters, â-keto esters, and 1,3-diketones using
oxidation with 1.
First, N-Cbz benzylamine (4a) was oxidized by treating
lithiated 4a with 1 at -78 °C, and the resulting N-Cbz imine
was reacted with diethyl malonate in a one-pot manner. It
was found that the 1-mediated oxidation of 4a proceeded
smoothly at -78 °C, and diethyl malonate reacted with the
formed N-Cbz imine during warming to room temperature
to afford Mannich product 5a in 92% isolated yield (Table
1, entry 1). Oxidative Mannich reaction of other N-Cbz
benzylamine derivatives such as 4b and 4c also gave
Mannich adducts 5b and 5c in 92 and 86% yields, respec-
tively (entries 2 and 3). Interestingly, N-Cbz alkylamines such
as 4d-h gave the Mannich adducts 5d-h in good to high
yields (entries 4-7), though sterically hindered 4f required
(5) Rewiew: Matsuo, J.-i. J. Synth. Org. Chem. Jpn. 2004, 62, 574-
583.
(6) (a) Mukaiyama, T.; Kawana, A.; Fukuda, Y.; Matsuo, J.-i. Chem.
Lett. 2001, 390-391. (b) Matsuo, J.-i.; Kawana, A.; Fukuda, Y.; Mu-
kaiyama, T. Chem. Lett. 2001, 712-713. (c) Matsuo, J.-i.; Tanaki, Y.; Kido
A.; Ishibashi, H. Chem. Commun. 2006, 2896-2898.
(7) N-Boc imines were prepared in two steps: Kanazawa, A. M.; Denis,
J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238-1240.
(8) Catalytic oxidative Mannich reaction of tertiary amines: (a) Mura-
hashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003,
125, 15312-15313. (b) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173-
3176. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672-3673. (d)
Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem., Int. Ed. 2005, 44,
6931-6933.
Oxidative Mannich reaction of N-Cbz alkylamine with
various 1,3-dicarbonyl compounds was investigated using
N-Cbz butylamine (4e) as a model substrate (Table 3).
Similar to the results obtained in Mannich reaction of N-Cbz
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Org. Lett., Vol. 8, No. 19, 2006