N-Acyl-4,5-dihydro-4,4-dimethyl-N-methyl-2-thiazolamine as a chemoselective acylating agent

Article abstract of DOI:10.1016/S0040-4039(02)02414-0

2-Methylamino-2-thiazoline reacted with alkyl acyl halides to produce N-acyl-2-methylamino-2-thiazolines, exo-acylated product regioselectively, which were found to be highly chemoselective acylating agents for primary amine in the presence of secondary amine and for the less sterically hindered of two different primary amines.

Full text of DOI:10.1016/S0040-4039(02)02414-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9553–9557
N-Acyl-4,5-dihydro-4,4-dimethyl-N-methyl-2-thiazolamine as a
chemoselective acylating agent
Taek Hyeon Kim* and Garp-Yeol Yang
Faculty of Applied Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 30 September 2002; revised 21 October 2002; accepted 25 October 2002
Abstract—2-Methylamino-2-thiazoline reacted with alkyl acyl halides to produce N-acyl-2-methylamino-2-thiazolines, exo-
acylated product regioselectively, which were found to be highly chemoselective acylating agents for primary amine in the presence
of secondary amine and for the less sterically hindered of two different primary amines. © 2002 Elsevier Science Ltd. All rights
reserved.
Chemoselective acylation of amines is one of the most
basic reactions for the protection or activation of func-
tional groups in organic synthesis.1 So far conventional
reagents have been developed by devising an appropri-
ate leaving group.2 Each reagent, however, has its
advantages and disadvantages and continuing efforts
have been made to develop an efficient chemoselective
reagent. Recently we reported synthetic route to 2-
methylamino-2-thiazolines by the selective S-cyclization
of N-(2-hydroxyethyl)-N%-methylthioureas.3 Heterocy-
cle system of 2-methylamino-2-thiazoline 1 is expected
to be a good leaving group for acylating reagent of
amines. In this paper we report that N-acyl-2-methyl-
amino-2-thiazolines 2 serve as a new reagent for the
selective acylation of a less hindered amines in the
presence of a more hindered amines.
2-methylamino-2-thiazoline in 83% yield by a one-
pot reaction using p-toluenesulfonyl chloride and
NaOH (Scheme 1).4 Acylation of the 2-methylamino-2-
thiazolines can conceivably proceed through an attack
upon acyl halide either by the exo-nitrogen to provide
N-acylated-2-methylamino-2-thiazolines or by the
endo-nitrogen to give N-acylated 2-methyliminothiazo-
lidine.5 Acylation of thiazolines 1 with acetic anhydride,
propionyl chloride, and trimethylacetyl chloride in the
presence of tert-BuOK gave only alkyl N-(4,5-dihydro-
4,4-dimethyl-2-thiazolyl)-N-methylamide which were
acylated to exo-nitrogen (Scheme 2). After column
chromatography 2a–d were obtained as air storable gel
or solid in good yield.6
To test the N-acyl transfer potentiality of 2a–d,
acylation of various amines was examined at room
temperature in CCl4. The results were summarized in
Table 1. At first to compare to the reactivity of 1a and
1b as a leaving group, acylation agent 2a and 2c was
chosen to give propionyl amides with various amines.
Compound 2c showed a little more reactivity over 2a
The synthesis of 2-methylamino-4,4-dimethyl-2-thiazo-
line was readily performed by the reaction of 1,2-
aminoalcohol with methyl isothiocyanate to give the
corresponding N-[(1,1-dimethylamino-2-hydroxy)ethyl]-
N%-methylthiourea, followed by the S-cyclization to the
Scheme 1.
* Corresponding author. E-mail: thkim@chonnam.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02414-0

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T. H. Kim, G.-Y. Yang / Tetrahedron Letters 43 (2002) 9553–9557
benzylamine, a,a-dimethylbenzylamine, and N-methyl-
benzylamine (Table 1). Primary amine was predom-
inantly more reactive than secondary amine. With 2d
having a bulky acyl group, acylation of secondary
amine did not occur at room temperature for 28 h (entry
12). The observed difference in reactivity is attributed
to the differences in steric demand of primary
and secondary amines in accordance with aminoly-
sis of esters.7 Hindered primary amine needed more
reaction time than less hindered primary amine. Steri-
cally hindered a,a-dimethylbenzylamine was not
acylated at room temperature for 48 h (entry 10). Thus,
reaction rate was greatly affected by steric bulkiness in
the vicinity of the starting amine and the acylating
reagent. Treatment of 2a and 2c with hexylalcohol in
refluxing CCl4 did not provide the O-acylation product.
The leaving group, 2-methylamino-2-thiazoline 1 was
almost quantitatively recovered for recycling simply by
the neutralization of acidic aqueous solution after
extraction with CHCl3. The concentration of CHCl3
gave the amide product, which was purified by column
chromatography or recrystallization.
Scheme 2.
(entries 1–3 and 7–10). A difference in reaction time
depending on the bulkiness of amines occurred in both
2a and 2c. In addition, more convenient preparation
and higher yield in acylation reaction were observed in
reagent 1b.3,4 Thus reagent 1b was chosen as a leaving
group for chemoselective N-acylation. With 2b–d pre-
pared from 1b, the steric influence of substituents on
the amino group was clearly demonstrated by reaction
using various amines such as benzylamine, a-methyl-
Table 1. N-Acylation of various amines using 2a–d

T. H. Kim, G.-Y. Yang / Tetrahedron Letters 43 (2002) 9553–9557
9555
From the substantial difference in reaction rate between
hindered and less hindered amines, we expected that
chemoselective acylation of amine can be conveniently
achieved by simple mixing of the amine and a stoichio-
metric amount of 2a–d under neutral conditions at
room temperature. Thus, we now have turned to the
competitive acylation using 2a–d in the presence of a
1:1 mixture of benzylamine and N-methylbenzylamine
to examine selective acylation of amines. In comparison
with acid halide or anhydride all reagents 2a–d showed
excellent chemoselectivity (Table 2). Also, with a 1:1
mixture of a benzyl amine and an a-methylbenzylamine
the selectivity was investigated. The results are summa-
rized in Table 3. All reagents 2a–d gave high selectivity
to a less hindered primary amine. The chemoselective
acylation was performed with diamine system bearing
structurally diverse amino group in a molecule such as
N-propylethylene diamine and 2-methylpiperazine.
Products acylated at the less hindered nitrogen with
high regioselectivity were obtained in high yield (Table
4): acylation of these amines using acyl halide or acetic
anhydride afforded predominantly diacylated products.
In conclusion, N-acyl 2-methylamino-2-thiazoline is
very effective in chemoselective acylation of amines. We
believe that this novel acylating agent can be widely
used for the selective protection of various polyamine
compounds.
Acknowledgements
This work was supported by the grant No. (R05-2002-
000-00043-0) from the Basic Research Program of the
Korea Science and Engineering Foundation.
Table 2. Competitive acylation of a primary and secondary amine using 2a–d
Entry
Reagent
R%
Conditions
Yield (%)a 3+4
Selectivitya 3:4
1
2
3
4
5
6
7
2a
2c
Et
Et
Et
Me
Me
tert-Bu
tert-Bu
rt, 6 h
rt, 4 h
Et3N, rt, 1 h
rt, 2 h
Et3N, rt, 1 h
rt, 4 h
\99
\99
\99
\99
\99
\99
\99
100:0
100:0
46:54
83:17
50:50
100:0
66:34
EtCOCl
2b
(MeCO)2O
2d
tert-BuCOCl
Et3N, rt, 1 h
a Determined by 1H NMR.
Table 3. Competitive acylation of less hindered and more hindered primary amine using 2a–d
Entry
Reagent
R%
Conditions
Yield (%)a 3+5
Selectivitya 3:5
1
2
3
4
5
6
7
2a
2c
Et
Et
Et
Me
Me
tert-Bu
tert-Bu
rt, 6 h
rt, 4 h
Et3N, rt, 1 h
rt, 2 h
Et3N, rt, 1 h
rt, 4 h
\99
\99
\99
\99
\99
\99
\99
88:12
94:6
63:37
100:0
54:46
96:4
EtCOCl
2b
(MeCO)2O
2d
tert-BuCOCl
Et3N, rt, 1 h
60:40
a Determined by 1H NMR.

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T. H. Kim, G.-Y. Yang / Tetrahedron Letters 43 (2002) 9553–9557
Table 4. Chemoselective acylation of diamines using 2b–d
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9557
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