2252
K. M. Boy, J. M. Guernon / Tetrahedron Letters 46 (2005) 2251–2252
Table 1. Yields of the Michael reaction of 4 to compounds 5a–i
study of these parameters could possibly improve yields
especially in the cases of more hindered amines. Reac-
tion with a primary amine (n-butylamine) with 4 gave
a mixture of secondary and tertiary amine products, as
was expected. A single attempt to modify the reaction
conditions by adding an ethanol solution of 4 dropwise
to an excess (10 equiv) of n-butylamine in ethanol pro-
vided, after the usual workup, exclusively the desired
secondary amine, although in surprisingly low yield
(11%).
Compound
number
HNR1R2
Yield (%)
5a
5b
5c
5d
5e
5f
Morpholine
63
79
71
47
73
55
69
24
11
N-Methyl ethanolamine
N,N0,N0-Trimethylethylenediamine
N-Methyl iso-propylamine
N-Methylhomopiperazine
N-Methylpiperazine
5g
5h
5i
4-Methoxyethyl piperazine
Thiomorpholine
n-Butylamine
The 2-vinylthiazole moiety has been shown to be a via-
ble Michael acceptor for a variety of amines. Future
studies will examine different classes (non-amine) of
nucleophiles. Additionally, saponification and further
derivatization of compounds 5, as well as results from
their biological evaluation will be reported in due
course.
modified from a literature procedure6 (93% yield). A
Pd(PPh3)4 catalyzed Stille cross coupling with tributyl-
(vinyl)tin provided the key compound 4 in modest yield
(42%).
Investigation of the Michael reaction with morpholine in
ethanol at room temperature provided the desired amino
adduct 5a (Table 1). Initial experiments conducted in
methanol were complicated by formation of methyl ester
products and amide side products. Presumably, the
amides arise from the trans-esterified methyl esters, since
the amide side-products are absent from reactions con-
ducted in ethanol.7 Products were conveniently isolated
by removal of solvent, followed by an acid/base extrac-
tion protocol. In most cases, the compounds so obtained
were analytically pure, although recourse to silica gel
chromatography was occasionally required.
Supplementary data
Supplementary data associated with this article can be
References and notes
1. You, S.-L.; Kelly, J. W. Chem. Eur. J. 2004, 10, 71–75.
2. Matsunaka, S.; Nakamura, H. Zasso Kenkyu 1972, 13, 29–
31.
Reaction scope was investigated with a variety of sec-
ondary amines. Acyclic amines and diamines (5b, 5c)
performed best, followed closely by unhindered cyclic
amines. Reaction efficiency was influenced by steric fac-
tors. Reaction of 4 with N-methyl isopropylamine pro-
vided product 5d in only modest yield (47%), whereas
diisopropylamine did not react at all. Likewise, the cyc-
lic amine cis-dimethylmorpholine reacted in low yield
(<8%). Less basic amines, exemplified by N-methylani-
line, did not react. Cyclic secondary amines with no
branching (5e–i) performed well, although thiomorpho-
line gave the desired product (5h) in unexpectedly low
yield. Reaction conditions were unoptimized for time,
temperature, and amount (1.2 equiv) of amine; further
3. Kelly, J.; Schraft, W. C.; Kutscher, A. H.; Tuoti, F.
Antibiot. Chemother. 1959, 9, 87–89.
4. Dondoni, A.; Merino, P. J. Org. Chem. 1991, 56, 5294–
5301.
5. A vinyl oxadiazole was reported as the presumed interme-
diate in the synthesis of 3-(aminoethyl)-1,2,4-oxadiazoles.
See: Macor, J. E.; Ordway, T.; Smith, R. L.; Verhoest, P.
R.; Mack, R. A. J. Org. Chem. 1996, 61, 3228–3229.
6. Lee, L. F.; Schleppnik, F. M.; Howe, R. K. J. Heterocycl.
Chem. 1985, 22, 1621–1630.
7. Amidation side-products were also circumvented by using
ethyl oxazole carboxylates over methyl oxazole carboxyl-
ates in the work of Hermitage et al. See Hermitage, S. A.;
Cardwell, K. S.; Chapman, T.; Cooke, J. W. B.; Newton, R.
Org. Process Res. Dev. 2001, 5, 37–44.