opening and rearrangement of vinyloxiranes. This process
provides an efficient synthetic procedure without formation
of an enolate or silyl enol ether, and we have demonstrated
that it can be applied to the rapid construction of nitrogen
containing six-membered heterocycles, e.g., 5-substituted
pipecolinic acid 4a.
Our approach began with N-benzhydryl-R-imino ester 2a
as an electrophilic reagent. In previous reports, Lewis acid
catalyzed Mannich-type additions to R-imino esters were
performed at low temperature (∼-100 °C) with reactive
nucleophiles such as enolates or silyl enol ethers.7,8 In
general, an R-imino ester is easily hydrolyzed to the
corresponding ketone and amine moieties in acidic media.
The N-benzhydrylimine has sufficient stability to allow
Mannich-type reactions with less reactive dienols at higher
temperatures using Sc(OTf)3 as a Lewis acid catalyst.
smoothly (entry 3, R ) 4-Cl-Ph, 3b: 70% yield), but ortho-
substituents were slightly less effective (entry 4 and 5, R )
2-Cl-Ph, 3d: 57% yield, R ) 2-CF3-Ph, 3e: 62% yield). A
phenyl (entry 2, R ) Ph, 3c: 50% yield) or 4-methoxyphenyl
(entry 6, R ) 4-MeO-Ph, 3f: 35% yield) aldimine gave
lower yields. A sterically hindered cyclohexyl R-imino ester
2g gave 3g in high yield (entry 7, 80% yield).9
A chiral analogue, (-)-8-phenylmenthol ester 2h provided
the corresponding amino aldehyde 3h in excellent yield and
diastereoselectivity (entry 8, 84% yield, S/R10 ) 11:1).
Amino aldehydes 3 are useful intermediates en route to
six-membered heterocycles by simple hydrogenation condi-
tions (Table 2). Treatment of 3a with Pd-C in MeOH under
Table 2. Efficient Transformation to Cyclic Unnatunal Amino
Acid Ester
Table 1. Lewis Acid Catalyzed Direct Vinylogous
Mannich-Type Reactions with in Situ Generated
â,γ-Unsaturated Aldehyde from Vinyloxirane 1
yieldb (%)
entry
solvent
time (h)
4a
84
trace
0
4b
4c
1
2
3
MeOH
Benzene
Benzene
4
24
1
0
0
5
53
entry
R
yielda (%)
77
trace
1
2
3
4
5
6
7
8
COOEt
Ph
4-Cl-Ph
2-Cl-Ph
2-CF3-Ph
4-MeO-Ph
a
b
c
d
e
f
74
50
70
57
62
35
80
84
a Diastereoselectivities were determined by 1H NMR spectroscopy.
b Isolated yield.
a H2 atmosphere gave 5-methylpipecolinic acid ethyl ester
COO-c-Hex
COO-(-)-8-Ph-Men
g
h
4a, an unnatural amino acid derivative, in excellent yield
S/R ) 11:1b
and diastereoselectivity (entry 1: 84% yield, cis/trans11
)
a Isolated yield. b Diastereoselectivity was determined by 1H NMR
spectroscopy.
>20:1).12 By changing the reaction solvent to a nonpolar
one such as benzene, the reaction proceeded more slowly
and 4b was obtained as the major product after 24 h
accompanied by a small amount of enamine 4c (entry 2: 4b,
77%; 4c, 5% yield). The synthetically useful enamine 4c was
formed as the main product by reaction for a short period of
time (entry 3: 1 h, 53% yield). Careful selection of the
solvent or reaction time during the hydrogenation process
made it possible to isolate 4b or 4c.
In Table 1, several types of N-benzhydrylimine could be
reacted with the less reactive dienol generated in situ from
2-methyl-2-vinyloxirane 1 leading to Mannich adducts 3. The
mixture of R-imino ester 2a and 1 (1.5 equiv) in THF was
treated with 10 mol % Sc(OTf)3 at 0 °C and allowed to warm
to 50 °C. After stirring for 10 min at the same temperature,
the corresponding amino-R,â-unsaturated aldehyde 3a was
obtained in 74% yield as a stable compound (entry 1). An
aromatic aldimine activated by a para-halogen reacted
(9) In the case of an R,â- or â,γ-unsaturated aldehyde as the nucleophilic
reagent under the same conditions: trans-2-methyl-2-butenal, 0% yield;
2-methyl-3-butenal, 67% yield. These facts indicate that a â,γ-unsaturated
aldehyde has to be used for the direct vinylogous Mannich-type reaction.
2-Methyl-3-butenal was prepared by the following literature using crotyl
bromide instead of allyl bromide: Crimmins, M. T.; Kirincich, S. J.; Wells,
A. J.; Choy, A. L. Synth. Commun. 1998, 28, 3675. Spectroscopic data:
see the Supporting Information.
(7) For recent examples of a Lewis acid-catalyzed Mannich-type reaction
using an R-imino ester as an electrophile: (a) Bernardi, L.; Gothelf, A. S.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583. (b)
Kobayashi, S.; Matubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J.
Am. Chem. Soc. 2003, 125, 2507. (c) Kobayashi, S.; Matsubara, R.;
Kitagawa, H. Org. Lett. 2002, 4, 143. (d) Ferraris, D.; Young, B.; Cox, C.;
Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J.
Am. Chem. Soc. 2002, 124, 67. (e) Ferraris, D.; Young, B.; Dudding, T.;
Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.
(8) Examples of direct Mannich-type reaction to an R-imino ester: (a)
Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (b) Co´rdova,
A.; Notz, Wolfgang.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1842. (c) Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 2995.
(10) The configuration was determined according to the following
literature procedure: Yamamoto, Y.; Kubota, Y.; Honda, Y.; Fukui, H.;
Asao, N.; Nemoto, H. J. Am. Chem. Soc. 1994, 116, 3161. See the
Supporting Information.
(11) The absolute configuration was determined by 13C NMR spectros-
copy based on the shift of the 5-Me substituent. See the Supporting
Information.
(12) Enantio- and/or diastereoselective synthesis of 5-substituted pipe-
colinic acid derivatives: (a) Cellier, M.; Mialhe, Y. G.; Husson, H. P.; Perrin,
B.; Remuson, R. Tetrahedron: Asymmetry 2000, 11, 3913. (b) Barluenga,
J.; Aznar, F.; Valde´s, C.; Ribas, C. J. Org. Chem. 1998, 63, 3918.
346
Org. Lett., Vol. 6, No. 3, 2004