420
A. Manaka et al. / Tetrahedron Letters 46 (2005) 419–422
O
ylamine did not proceed and gave unidentified yellow
S
S
X
precipitates. At least 2 equiv of a-halocarbonyl reagent
were necessary for the reaction to proceed to comple-
tion. When the reaction was performed with 1 equiv of
a-halocarbonyl reagent, the reaction stopped when
about half of the acylthiourea was consumed.
R'
BzN
R
N
R
Bz
N
H
N
H
R'
alcohol
reflux
R, R' = Me, Ph
Scheme 2.
The variety of the substituents R1–R4 are summarized in
Table 1. With regard to R1, while aromatic derivatives
with both electron-withdrawing and -donating groups
were suitable for this reaction, alkyl derivatives were
not (entries 19 and 20). The reaction of acetyl isothiocya-
nate or phenylacetyl isothiocyanate with primary amines
gave the corresponding amides instead of acylthiourea
derivatives.
The efficient synthetic method for 3-alkyl-3H-thiazoline
is shown in Scheme 3. Thus, aroylisothiocyanates 5 pre-
pared from the corresponding acyl chlorides 4 and
ammonium thiocyanate5 reacted smoothly with various
amines to afford acylthioureas 6. Without isolation,
these intermediates were condensed with a-halocarbonyl
derivatives to construct a 3-alkyl-3H-thiazoline tem-
plate. The configuration of the acylimino moiety was
confirmed to be syn by direct comparison of its melting
point and spectral data with those of the authentic 3-n-
butyl derivative synthesized by the previous method.3
The syn selectivity in this reaction is likely due to the ste-
ric hindrance of the acyl group and the R2 group in the
isothiourea intermediates. As shown in Scheme 3,
elimination of hydrogen halide from sulfonium inter-
mediates 7 proceed via route A so as to avoid inter-
molecular steric hindrance (route B).
The introduction of an R2 group with primary amines
was widely tolerated. For example, 3-isopropyl-3H-
thiazoline derivatives, which required several days at
room temperature by alkylation of 2 (Scheme 1), were
obtained in yields of 77–92% with only a few hours
operation (entries 1, 12, 14). This procedure also made
it possible to introduce a cycloalkyl group (entries 4–
7), a phenyl group (entries 10 and 11) and a functional-
ized alkyl group (entries 7 and 8) as R2. However, intro-
duction of a methyl group failed due to the insolubility
of the intermediate thiourea derivative. Condensation of
the acylthiourea intermediate with 2-chloroacetylace-
tone, chloroacetone or diethyl 2-bromomalonate
smoothly gave the corresponding products, which
possessed an acetyl group, a hydrogen atom and an
ethoxycarbonyl group as R3, and methyl, and hydroxyl
groups as R4 (entries 16–18). In addition, the introduc-
tion of amino moieties to the R4 methyl group was
achieved by bromination with N-bromosuccinimide in
the presence of N,N-azobis(isobutyronitrile), followed
by treatment with amines.3
The reaction was performed in a non-polar solvent such
as benzene, toluene or xylene at reflux temperature with
water separator for the efficient removal of water and
hydrogen chloride generated by the reaction. For the
less soluble acylthiourea derivatives (e.g., R = Ph), ace-
tic acid was preferable for the solvent to accelerate the
reaction. In that case, the yield and purity of the product
were slightly decreased (entries 3 and 10). Contrary to
the description in the previous paper,4 reactions in etha-
nol or with a base such as potassium carbonate or trieth-
X
R3
R4
R3
O
O
R1
S
R2NH2
O
O
R1
S
NH4SCN
O
R1
R1
HN
R4
HN
NH
R2
acetone
reflux, 30 min
rt
to
reflux
Cl
N
C
S
NHO
R2
solvent, reflux
4
X
5
6
7
O
O
N
R3
R3
R1
_H2O
S
R1
S
N
N
R4
R4
NHO
R2
R2
route A
"syn"
8-25
_HX
R3
R3
R4
S
S
_H2O
route B
N
O
R4
N
R1
NHO
R2
R1
N
R2
O
"anti"
Scheme 3.