An improved synthesis of solid-supported reagents (SSRs) for selective acylation of amines by microwave irradiation

Article abstract of DOI:10.1016/S0040-4039(02)01478-8

Microwave-assisted acylation of a solid-supported pyrimidine linker with different acyl chlorides gave polymer-bound 4-acyloxypyrimidines, which in turn were used as SSRs for rapid and selective acylation of amines under microwave irradiation.

Full text of DOI:10.1016/S0040-4039(02)01478-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6507–6509
An improved synthesis of solid-supported reagents (SSRs) for
selective acylation of amines by microwave irradiation
Elena Petricci, Maurizio Botta,* Federico Corelli* and Claudia Mugnaini
Dipartimento Farmaco Chimico Tecnologico, Universit a` degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Received 1 July 2002; accepted 18 July 2002
Abstract—Microwave-assisted acylation of a solid-supported pyrimidine linker with different acyl chlorides gave polymer-bound
4
©
-acyloxypyrimidines, which in turn were used as SSRs for rapid and selective acylation of amines under microwave irradiation.
2002 Elsevier Science Ltd. All rights reserved.
Recent reports indicate increasing efforts toward high
throughput solution synthesis using solid-supported
conversion and, sometimes, in selectivity with several
advantages for the eco-friendly approach, termed green
chemistry.
1
–5
27
reagents (SSRs).
Used since 1960, SSRs have been
6
–10
the subject of several review articles.
After the devel-
opment of combinatorial synthesis, the use of SSRs
became attractive and suitable for parallel synthesis
because of the possibility of having very clean, high-
yielding, and easily monitorable reactions. Moreover,
isolation of the reaction product simply involves filtra-
tion of the resin and evaporation of the solvent.
In a typical experiment, the solid-supported pyrimidi-
none derivative 1 (0.50 mmol), prepared in a few, high
yielding, steps from commercially available com-
11
pounds, the appropriate acyl chloride 2a–h (2 mmol)
and pyridine (3 mmol) were mixed in CH Cl (1 mL)
2
2
28
and irradiated by microwaves for 3 min at 200 watts
to give regioselectively the polymer-bound 4-
During our studies on the synthesis of pyrimidinones as
29
acyloxypyrimidines 3a–h. The resin was filtered and
1
1–18
antiviral compounds,
4-O-acylated pyrimidines
washed successively with CH Cl , toluene and Et O.
2
2
2
were found to be able to acylate amines, phenols and
The acylation reaction was repeated twice under the
same experimental conditions. The SSRs 3a–h (0.50
mmol) so prepared and amines 4a,b (0.50 mmol) were
mixed in CH Cl (1 mL) and irradiated by microwaves
1
6
thiophenols in high yields and good chemoselectivity.
11
In a recent communication we have described the
synthesis on a solid support of 4-O-acylated pyrimidi-
nes which can be used as solid-supported reagents
2
2
for 3 min at 200 watts. After filtration and evaporation
(
SSRs) for selective and high yielding acylation of
of the solvent, amides 5a–i were obtained as pure
amines. Considering the long reaction times (48–72 h)
required for both the preparation of our SSRs and the
subsequent amine acylation, the use of microwave irra-
diation as a means to enhance the rate of solid-phase
reactions was investigated. In fact, microwave activa-
tion as a non-conventional energy source is becoming a
very popular and useful technique in organic chemistry,
as demonstrated by the rapidly growing number of
annual publications on microwave-assisted organic syn-
30
crystalline solids in acceptable to excellent yield (40–
1
00%) (Scheme 1).
Resin 1, regenerated from the acylation reaction, could
be recycled and transformed again into the acylating
SSRs 3a–h at least twice with no decrease in the reac-
tion yield. The attempt to acylate 1 using acetic anhy-
dride in DMF under microwave irradiation for 1 min at
38
1
9–24
650 watts and to use it as acylating agent for 4a
thesis,
gies.
including microwave-assisted SSR strate-
The combination of solvent-free reaction
2
5,26
resulted in only 20% yield of the amide 5a.
conditions and microwave irradiation leads to a
remarkable reduction in reaction time, enhancement in
With the aim of exploring the dependence of the
acylating ability of these SSRs on their electronic prop-
erties, two new reagents 6 and 7, characterized by the
presence of a methyl group at both C-5 and C-6
positions or the absence of the C-6 substituent, respec-
*
Corresponding authors. Fax: 0039-0577-234333; e-mail: botta@
unisi.it
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01478-8

6
508
E. Petricci et al. / Tetrahedron Letters 43 (2002) 6507–6509
Scheme 1.
tively, were synthesized starting from the polymer-
assisted solid-phase synthesis. 3a–h proved to be
efficient and selective acylating reagents for amines
when used under microwave irradiation, affording the
corresponding amides in a few minutes and high purity.
Quite interestingly, the by-product of the acylation
reaction, i.e. the polymer-bound pyrimidinone 1, can be
recycled for several reaction runs. In addition, the
microwave-assisted acylating method we have described
11
bound pyrimidinones 8 and 9 (Scheme 2). Rather
surprisingly, neither 6 nor 7 showed better acylating
properties than 3b: in fact, when reacted with benzyl-
amine, they afforded the corresponding amide 5b in
only 35 and 70% yield, respectively. On the other hand,
the most electrophilic SSRs 3d and 3h proved to be the
most effective acylating agents, giving amides 5d and 5i
in 100 and 85% yield, respectively. In this regard, the
scarce efficiency of 3e might be due to the steric hin-
drance exerted by the ortho-bromo substituent. In
7
compares favourably with those developed so far, giv-
ing in most cases better results in terms of yield and
reaction times.
11
agreement with previous findings, when 4-aminobu-
tanol was used as nucleophile no O-acylated product
was detected, thus showing the complete chemoselectiv-
ity of the acylation reaction.
Acknowledgements
In conclusion, solid-supported reagents 3a–h have been
cheaply, rapidly and easily prepared by microwave-
Italian Research National Council (CNR) ‘Progetto
Finalizzato Biotecnologie’ (CNR Target Project on

E. Petricci et al. / Tetrahedron Letters 43 (2002) 6507–6509
6509
1
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