Microwave-assisted acylation of amines, alcohols, and phenols by the use of Solid-Supported Reagents (SSRs)

Article abstract of DOI:10.1021/jo048837q

A microwave-assisted synthesis of solid-supported reagents for the acylation of amines has been developed, and the same methodology has been successfully applied to the preparation of acylating agents anchored on different solid supports. Similarly, alcohols, phenols, and thiophenols have been easily acylated using these reagents under microwave irradiation.

Full text of DOI:10.1021/jo048837q

Microwave-Assisted Acylation of Amines, Alcohols, and Phenols by
the Use of Solid-Supported Reagents (SSRs)
Elena Petricci, Claudia Mugnaini, Marco Radi, Federico Corelli,* and Maurizio Botta*
Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy
botta@unisi.it
Received July 9, 2004
A microwave-assisted synthesis of solid-supported reagents for the acylation of amines has been
developed, and the same methodology has been successfully applied to the preparation of acylating
agents anchored on different solid supports. Similarly, alcohols, phenols, and thiophenols have
been easily acylated using these reagents under microwave irradiation.
Introduction
The amide bond is present in a very large number of
pharmacologically active compounds of either peptidic
or nonpeptidic nature.1-9 Therefore, the development of
new procedures for the easy, clean, and racemization-
free synthesis of amides is of topical interest in medicinal
chemistry.
Chemoselective acylation of amino groups is an im-
portant synthetic reaction and is often required in organic
synthesis. In general, the formation of carboxamides from
amines and carboxylic acids implies the activation of the
carboxy group by either the preventive conversion to a
more reactive acylating agent, such as acyl chloride,
mixed anhydride, acyl azide, or active ester, or in situ
activation by using coupling reagents, such as DDC,
EDC, HOBt, BOP, CDI, or HBTU. However, these
methods have some drawbacks such as exothermic reac-
tion, formation of byproducts, complicated conditions, and
low selectivity.
FIGURE 1. Acylating agents with a pyrimidinic structure.
tivity.10f In a recent communication,10a we have described
the synthesis on a solid support of 4-O-acylated pyrim-
idines 2 (Figure 1), which can be used as solid-supported
reagents (SSRs) for selective and high-yielding acylation
of amines.
Used since 1946, SSRs11 have been the subject of
several review articles,11a,b,12 and the advantages of their
use is presently widely recognized. Particular attention
is now devoted to the application of SSRs under micro-
wave irradiation. In fact, microwave activation as a
nonconventional energy source is becoming a very popu-
lar and useful technique in organic chemistry, as dem-
onstrated by the rapidly growing number of annual
publications on microwave-assisted organic synthesis,13
including microwave-assisted SSR strategies.14
During our studies on the synthesis of pyrimidinones
as antiviral compounds,10 4-O-acylated pyrimidines 1
(Figure 1) were found able to acylate amines, phenols,
and thiophenols in high yields and good chemoselec-
* To whom correspondence should be addressed. Tel: 0039-0577-
234306. Fax: 0039-0577-234306.
(1) Agwada, V. C. J. Chem. Eng. Data 1982, 27, 479-481.
(2) (a) Tsymbalov, S.; Hagen, T. J.; Moore, W. M.; Jerome, G. M.;
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Med. Chem. Lett. 2002, 12, 3337-3339. (b) Moormann, A. E.; Metz,
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P.; Hansen, D. W.; Pitzele, B. S.; Webber, R. K. Bioorg. Med. Chem.
Lett. 2001, 11, 2651-2653
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56, 369-377. (b) Saladino, R.; Crestini, C.; Palamara, A. T.; Danti, M.
C.; Manetti, F.; Corelli, F.; Garaci, E.; Botta, M. J. Med. Chem. 2001,
44, 4554-4562. (c) Botta, M.; Corelli, F.; Maga, G.; Manetti, F.;
Renzulli, M.; Spadari, S. Tetrahedron 2001, 57, 8357-8367. (d) Nizi,
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bacorta, A.; Nicoletti, R. Synth. Commun. 1985, 15, 27-34.
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10.1021/jo048837q CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/16/2004
7880
J. Org. Chem. 2004, 69, 7880-7887

Microwave-Assisted Acylation with SSRs
SCHEME 1. Microwave-Assisted Synthesis of SSRs 2(a-h) and Their Use for the Acylation of Benzylamine
The combination of solvent-free reaction conditions and
microwave irradiation leads to a remarkable reduction
in reaction time, enhancement in conversion, and some-
times in selectivity, with several advantages for the
ecofriendly approach, termed green chemistry.15,16
Very recently, we have also described17 the microwave-
assisted synthesis of a series of polymer-bound 4-acyl-
oxypyrimidines 2, which proved to be useful SSRs for the
efficient and selective acylation of amines. Used under
microwave irradiation, these compounds afforded the
corresponding amides in a few minutes and high yield
and purity.
Taking all these aspects into account, a new microwave-
assisted synthesis of the SSRs 2 (Scheme 1) was consid-
ered, together with their use for the microwave-assisted
acylation of a number of different substrates.
(12) (a) Baxendale, I. R.; Ley, S. Bioorg. Med. Chem. Lett. 2000, 10,
1983-1986. (b) Parlow, J. J.; Devraj, R. V.; South, M. S. Tetrahedron
1999, 55, 6785-6796. (c) Bleloch, A.; Johnson, B. F. G.; Ley, S. V.;
Price, A. J.; Shephard, D. S.; Thomas, A. W. Chem. Commun. 1999,
1907-1910. (d) Ley, S. V.; Thomas, A. W.; Finch, H. J. Chem. Soc.,
Perkin Trans. 1 1999, 669-699. (e) Flynn, D. L.; Devraj, R. V.; Parlow,
J. J. Curr. Opin. Drug Discovery Dev. 1998, 1, 41-50. (f) Flynn, D. L.;
Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner, J. J.; Yang, S. L. Med.
Chem. Res. 1998, 8, 219. (g) Hinzen, B.; Lenz, R.; Ley, S. V. Synthesis
1998, 977-992. (h) Hinez, B.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 1997, 1907-1921. (i) Shuttle-Worth, S. J.; Allin, S. M.; Sharma, P.
K. Synthesis 1997, 1217-1239. (j) Link, A.; van Calenbergh, S.;
Herdewijn, P. Tetrahedron Lett. 1998, 39, 5175-5176. (k) Hermkens,
P. H. H.; Otteheijm, H. C. J.; Rees, D. C. Tetrahedron 1997, 53, 5643-
5678. (l) Byun, J.-W.; Lee, D.-H.; Lee, Y.-S. Tetrahedron Lett. 2003,
44, 8063-8067.
(13) (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
(b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283. (c) Kabza, K. G.; Chapados, B. R.; Gestwicki, J.
E.; McGrath, J. L. J. Org. Chem. 2000, 65, 1210-1214. (d) Caddick,
S. Tetrahedron 1995, 51, 10403-10432. (e) Raner, K. D.; Strauss, C.
R.; Vyskoc, F.; Mokbel, L. J. Org. Chem. 1993, 58, 950-953. (f) Laurent,
R.; Laporterie, A.; Dubac, J.; Lefeuvre, S.; Audhuy, M. J. Org. Chem.
1992, 57, 7099-7102. (g) Blackwell, H. E. Org. Biomol. Chem. 2003,
1, 1251-1255.
(14) (a) Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 4, 154-161. (b)
Stadler, A.; Kappe, C. O. Tetrahedron 2001, 57, 3915-3920. (c)
Nicewonger, R. B.; Ditto, L.; Kerr, D.; Varady, L. Bioorg. Med. Chem.
Lett. 2002, 12, 1799-1802. (d) Sauer, D. R.; Kalvin, D.; Phelan, K. M.
Org. Lett. 2003, 5, 4721-4724.
(15) (a) Varma, R. S. Green Chem. 1999, 1, 43-55. (b) Perreux, L.;
Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155-2162.
(16) Loupy, A. C. R. Chim. 2004, 7, 103-112.
(17) Petricci, E.; Botta, M.; Corelli, F.; Mugnaini, C. Tetrahedron
Lett. 2002, 43, 6507-6509.
Results and Discussion
Preparation of Acylating Agents 2(a-h) and Study
of Their Reactivity toward Benzylamine. Consider-
ing the modest yields previously obtained for the syn-
thesis of the pyrimidine nucleus through a cyclization
reaction,10a we planned to accomplish the synthesis of the
fundamental intermediate 3 (Scheme 1) by nucleophilic
diplacement of bromine of 4 by commercially available
6-methyl-2-thiouracil.18 This reaction could be rapidly
and efficiently accomplished by the use of microwave
irradiation. Microwave-assisted reactions were performed
under controlled conditions in a safe and reproducible
procedure. Single-mode microwave irradiation was used
at a fixed temperature, pressure, and irradiation power
during the reaction time by an automatic power control.
Starting from Merrifield’s resin 5 (Scheme 1), 1,4-
butandiol was first anchored on the solid support in order
to introduce a spacer with a free hydroxyl group that
could guarantee enhanced reactivity of the substrates
bound to the polymer.19 Bromination20 of 6 and subse-
(18) Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med Chem. 1998, 41,
191-198.
(19) Tietze, L. F.; Steinmetz, A. Angew Chem., Int. Ed. Engl. 1996,
35, 651-652.
(20) Ngu, K.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973-976.
J. Org. Chem, Vol. 69, No. 23, 2004 7881

Petricci et al.
SCHEME 2. Anchorage of 6-Methyl-2-thiouracil on Wang Resin
SCHEME 3. Anchorage of 6-Methyl-2-thiouracil on TentaGel S-NH2 Resin
TABLE 1. Results of the Acylation of Benzylamine
Using Different SSRs
SSRs 2d and 2g proved to be the most effective acylating
agent, giving the corresponding amides 7d and 7g in
100% and 85% yield, respectively. In this regard, the
scarce efficiency of 2e might be due to the steric hin-
drance exerted by the o-bromo substituent, and the scarce
reactivity of 2c has been explained considering electronic
effects.
compd
R
yield (%)
7a
7b
7c
7d
7e
7f
Me
Ph
47
75
p-tolyl
45
p-BrPh
o-BrPh
100
40
Use of Different Solid Supports. To show the
versatility of the methodology we had set up, we decided
to apply it to the synthesis of SSRs anchored on different
solid supports. In particular, the Wang resin and the
TentaGel S-NH2 resin were investigated for this purpose.
The Wang resin 8 (Scheme 2) was first brominated
under MW irradiation affording 9 and then 6-methyl-2-
thiouracil was anchored using the same conditions used
for the Merrifield to give 10.
PhCHdCH-
p-ClPh
50
7g
7h
85
p-NO2Ph
61
quent reaction with 6-methyl-2-thiouracil afforded the
supported pyrimidinone 3, which proved to be stable in
alkaline conditions, high temperatures (e100 °C), and
nucleophilic attack and which can be stored at 4 °C for
long times without degradation. Reaction of 3 with the
appropriate acyl chloride gave polymer-bound 4-acyloxy-
pyrimidines 2. Under microwave irradiation the synthe-
sis of the acylating agents 2 was accomplished in only
20 min rather than in a few days working in standard
conditions.
The acylating ability of pyrimidines 2 was then evalu-
ated by studing their reactivity with benzylamine (Scheme
1); the yields of the corresponding amides 6 are reported
in Table 1.
Cleavage with Oxone21 afforded 6-methyluracil in 80%
yield, thus showing a good loading.
On the other hand, TentaGel S-NH2 resin 11 (Scheme
3) was functionalized by reaction with 4-chloromethyl
benzoic acid, in the presence of HOBt22 and EDC as ac-
tivating agents. Reaction of 12 with 6-methyl-2-thioura-
cil under MW irradiation gave 13, which after cleavage
with Oxone afforded 6-methyluracil in 68%. In this case,
(21) Petricci, E.; Renzulli, M. L.; Radi, M.; Corelli, F.; Botta, M.
Tetrahedron Lett. 2002, 43, 9667-9670.
(22) Lorthioir, O.; McKeown, S. C.; Parr, N. J.; Washington, M.;
Watson, S. Tetrahedron Lett. 2002, 41, 8609-8613.
In all cases, acceptable to excellent yields were ob-
tained within a few minutes of microwave exposure (5
min at 80 °C). Among all the SSRs, the most electrophilic
7882 J. Org. Chem., Vol. 69, No. 23, 2004

Microwave-Assisted Acylation with SSRs
SCHEME 4. Acylation of Benzylamine by Use of Acylating Agents Anchored on Different Solid Supports
SCHEME 5. Microwave-Assisted Synthesis of Different Polymer-Bound Pyrimidinones
TABLE 2. Yields of Acylation Reaction of Benzylamine
Using Acylating Agents Anchored on Different Solid
Supports
TABLE 3. Loading of Different Polymer-Bound
Pyrimidinones and Yields of Their Acylating Reaction of
Benzylamine
yield (%)
cleavage with
formation of
linker
R
R1
oxone yield (%) amide yield (%)
acylating agent
7a
7b
7d
3
CH3
H
OH
OH
90
90
75
50
100
97
65
36
supported on Merrifield
supported on Wang
supported on Tentagel S-NH2
47
57
0
75
50
32
100
62
42
16a
16b
16c
CH2CH2CH3 OH
OH NH2
the low yield was explained considering the scarce sta-
bility of the resin in the conditions used for the cleavage.
Taking into account the results obtained with both
Wang and TentaGel S-NH2 resin, we concluded that our
microwave-assisted synthesis can have a general ap-
plicability and can be efficiently used for the preparation
of pyrimidinones anchored on structurally different
polymers.
We thought therefore to investigate the acylation
reaction of the solid-supported pyrimidinones 10 and 13
(Scheme 4) using three acylating agents endowed with
decreasing electrophilicity: p-bromobenzoyl chloride,
benzoyl chloride, and acetyl chloride. Reaction with
benzylamine using the corresponding solid-supported
acylating agents 14 and 15 was used to estimate the
loading (Table 2).
The Wang resin showed to be endowed with an
intermediate reactivity and to give the best results among
all the solid supports with acetyl chloride (57% yield for
7a). The TentaGel S-NH2 resin was the less reactive and
was completely not reactive with acetyl chloride (0% yield
for 7a). Considering its good reactivity and its lower cost,
the Merrifield resin resulted to be the best resin for our
goals, and it was used for all the following studies.
Preparation of Different Polymer-Bound Acylat-
ing Agents. The reactivity of different polymer-bound
pyrimidinones was also investigated.
the solid support 4 (Scheme 5) following the usual
procedure under microwave irradiation (130 °C, 5 min)
affording the corresponding solid-supported pyrimidino-
nes 16(a-c). Cleavage with Oxone was used to calculate
the loading.
Acylation of 16(a-c) with p-bromobenzoyl chloride
gave the corresponding polymer-bound acylating agents,
which were used to acylate benzylamine. The yield of the
corresponding amides gives an idea of the acylating
ability of the synthesized SSRs (Table 3).
The results thus obtained showed that the substitution
in the 6 position with a bulky substituent (linker 16b)
determines a decrease in the reactivity of the system,
whereas the use of an unsubstituted system (linker 16a)
implies similar results. On the other hand, very poor
yields are obtained using structurally different linkers
such as the cytosinic 16c. These observations together
with the lower cost of 6-methyl-2-thiouracil prompted us
to use the 6-methyl-substituted linker 3 for all of the
following studies.
Acylation of a Series of Amines by the Use of 2d
and 2g. Taking into account the results obtained with
benzylamine, a series of reactions were carried out on
different amines 17 (Scheme 6) using the SSRs 2b, 2d,
and 2g, which had proved to be the best acylating agents,
to give the corresponding amides 18(a-k) (Table 4).
N-Pentylamine, an aliphatic primary amine, was first
acylated with 2d in CH2Cl2 for 48 h, and the reaction
To this aim 2-thiouracil, 6-propyl-2-thiouracil, and
6-amino-2-thiouracil, respectively, were anchored on
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Petricci et al.
SCHEME 6. Microwave-Assisted Synthesis of a Series of Amides by Use of SSR of Type 2
TABLE 4. Results of Acylation of a Series of Amines by Use of SSR of Type 2
was repeated under microwave irradiation in order to
underline the advantages of using the “nonconventional”
procedure. The corresponding amide 18a was obtained
in 75% and 70% yield, respectively, thus confirming the
validity of the microwave-assisted procedure. Modest
results were obtained when the reaction was performed
with different SSRs such as 2b and 2g: the correspond-
ing amides 18h and 18e were obtained in 36% and 30%
yield, respectively. When used to acylate the secondary
amine diallylamine, 2d, 2b, and 2g afforded analogous
results giving 18b in an excellent yield (99%) and 18f
and 18i in 30% and 38% yield, respectively, thus con-
firming the better acylating properties of 2d with re-
spect to those of 2b and 2g. Then enantiomerically pure
(R)-(+)-R-methylphenylamine was acylated to study the
problem of racemization under microwave irradiation.
The reaction was carried out using the traditional method
and under microwave irradiation, giving 18c in 98% and
90% yield, respectively. The measurement of [R]D and
comparison with the one obtained using traditional
methods showed the absence of racemization. When 2d
was used to acylate 1,2-phenylendiamine, the monoacy-
lated product 18d was obtained in 53% yield, while the
cyclodehydrated benzoimidazole,23 deriving from the in-
tramolecular nucleophilic attack of the amino group on
the amidic CdO, was isolated only in traces from the
reaction.
To test the selectivity of our SSR, 1,4-aminobutanol
was used as substrate for the acylation with 2g: the
corresponding amide 18g was obtained in 70% yield with
both methods, thus showing the chemoselectivity of the
acylating agent. A relatively modest yield was also
observed in the acylation of the cyclic amine morpholine
with 2b, which afforded the corresponding amide 18k in
42% yield.
Acylation of a Series of Alcohols, Phenols, and
Thiophenols. To study the applicability of the method-
ology we had set up, the acylation of a number of different
substrates, namely, alcohols, phenols, and thiophenols,
was then attempted.
In a first experiment, the SSR 2d was treated with dry
CH2Cl2, and benzylic alcohol was added to the suspen-
sion. After removal of the solvent under a stream of
nitrogen, the reaction mixture was irradiated for 5 min,
but no ester was detected at the end of the reaction. Only
(23) Matsushita, H.; Lee, S.-H.; Joung, M.; Clapham, B.; Janda, K.
D. Tetrahedron Lett. 2004, 45, 313-316.
7884 J. Org. Chem., Vol. 69, No. 23, 2004

Microwave-Assisted Acylation with SSRs
SCHEME 7. Microwave-Assisted Acylation of Alcohols, Phenols, and Thiophenols by Use of the SSR 2d
TABLE 5. Results of Acylation of a Number of Different
Substrates under Microwave Irradiation Using SSR 2d
• Enantiomerically pure alcohols do not undergo race-
mization after acylation.
• In the case of the acylation of 2-amino-thiophenol,
the more nucleophilic amino group is the first to react,
giving the corresponding amide 18k, which then under-
goes water elimination to give the corresponding cyclo-
dehydrated benzothiazole as the only product of the
reaction; this observation is in accordance with the
results recently reported by Janda et al., who has
described the possibility of preparing benzothiazoles
using polymer-bound esters in the presence of of a Lewis
acid in standard conditions (toluene as solvent, reflux
temperature).23
• The yields of the reactions were modest, and the
attempt to improve them by repeating the irradiation or
using an excess of the SSR was unsuccessful; in all cases,
unreacted starting material was recovered at the end of
the reaction with no evidence of byproducts.
• As a result of difficulties in the elimination of the
unreacted starting material with a simple workup or by
the use of solid-supported scavangers (sulfonyl chloride
polymer-bound,24 propionyl chloride functionalized silica
gel25), even after MW irradiation, purification of the
product by column chromatography is necessary.
• The use of MW irradiation was of primary importance
in this kind of transformation; in fact, the desired
products could be isolated from the reactions repeated
in standard conditions (DMAP, DMF, 80 °C, 24 h) only
in traces.
Conclusions
A number of SSRs able to acylate structurally dif-
ferent substrates have been rapidly and efficiently syn-
thesized using MW irradiation. They can be used to
acylate both primary and secondary amines and enan-
tiomerically pure amines without any racemization; the
corresponding amides can be obtained in high yields.
Appreciable yields can also be obtained in the acylation
of alcohols, phenols, and thiophenols with 2d in the
presence of DMAP. The byproduct of the acylation
reaction, the polymer-bound pyrimidinone 3, can be
recycled at least three times without observing variations
in the acylating ability of the corresponding solid-
supported acylating agent.
after the addition of 1 equiv of DMAP could the de-
sired product be obtained in a 50% acceptable yield
(Scheme 7).
The acylation of a series of substrates was then
investigated, and the results of the formation of the
corresponding esters or thioesters 19(a-k) are reported
in Table 5.
Analyzing the data reported in Table 5, a series of
comments can be made:
• Primary and secondary alcohols show almost the
same reactivity.
All of the reactions were performed under microwave
irradiation and afforded, after the cleavage step, pure
compounds without any need of purification except in the
case of the acylation of alcohols, when column chroma-
tography was used in order to obtain a pure compound.
(24) (a) Pirrung, M. C.; Tumey, L. N. J. Comb. Chem. 2000, 2, 675-
680. (b) Hu, J.; Zhao, G.; Yang, G.; Ding, Z. J. Org. Chem. 2001, 66,
303-304.
(25) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn,
P. J. Tetrahedron Lett. 1996, 40, 7193-7196.
• Phenols are generally more reactive than alcohols,
with the exception of ortho-substited ones as a result of
the steric hindrance.
J. Org. Chem, Vol. 69, No. 23, 2004 7885

Petricci et al.
followed to prepare 13 starting from 12. 3, 16a, and 16b: IR
(Nujol) 1645 cm-1. 16c: IR (Nujol) 3389, 1632 cm-1. 13: IR
(CHCl3) 1652 cm-1
The methodology we have developed, which proved to
be cheap, rapid, and efficient, is particularly interesting
for its applicability to the preparation of libraries of
structurally different amides.
Moreover, the possibility to obtain, in a rapid and
efficient fashion, a family of compounds structurally
related to 3 having different substituents in 5 is particu-
larly interesting if we consider potential modifications
at different molecular sites26 or coupling with sugars to
afford solid-supported nucleosides.27
Polymer-Bound Chloride 12. TentaGel S-NH2 resin (1.0
g, 0.45 mol of functional group) was suspended in DMF (8 mL)
and swollen for 25 min. 4-Chloromethylbenzoic acid (153.5 mg,
0.9 mmol), HOBt (243.2 mg, 1.8 mmol), and EDC (258.8 mg,
1.35 mmol) were then added. The reaction mixture was stirred
at room temperature for 4 h. The polymer was filtered, washed
with water (3 × 10 mL), EtOH (3 × 10 mL), CH2Cl2 (3 × 10
mL), and Et2O (3 × 10 mL), and then dried in vacuo at 20 °C
for 4 h. IR (CHCl3) 3505, 1680 cm-1
General Procedure for Synthesis of Solid-Supported
Reagents 2(a-h). Compound 3 (500 mg, 0.5 mmol of func-
tional group) was dissolved in 3 mL of CH2Cl2 and swollen for
10 min. Then pyridine (243 µL) and the appropriate acyl
chloride (2 mmol) were added. After evaporation of the solvent
under a stream of nitrogen, the reaction mixture was irradi-
ated at 80 °C for 5 min. The resin was washed with CH2Cl2 (3
× 10 mL), toluene (3 × 10 mL), and Et2O (3 × 10 mL) and
then dried in vacuo at 20 °C for 4 h. The same procedure was
followed to prepare 14(a-c) and 15(a-c). 2a: IR (Nujol) 1774,
1269, 1145 cm-1. 2b: IR (Nujol) 1744, 1232, 1149 cm-1. 2c:
IR (Nujol) 1739, 1234, 1150 cm-1. 2d: IR (Nujol) 1719, 1234,
1148 cm-1. 2e: IR (Nujol) 1734, 1230, 1150 cm-1. 2f: IR (Nujol)
Experimental Section
General Considerations Reagents were obtained from
commercial suppliers and used without further purifications.
Merrifield’s peptide resin cross-linked 1% DVB, 200-400
mesh, 1.0-1.5 mmol Cl-/g; Wang resin cross-linked 1% DVB,
200-400 mesh, ∼1.0 mmol/g resin; and TentaGel S-NH2 resin
150-200 mesh, 0.45 mmol/g resin were used. Solvents were
dried before use (CH2Cl2 and CH3CN over CaH2).
Melting points are uncorrected. 1H NMR spectra were
measured at 200 MHz. Chemical shifts are reported relative
to TMS at 0.00 ppm. EI low-resolution MS spectra were
recorded with an electron beam of 70 eV.
1744, 1215, 1153 cm-1. 2g: IR (Nujol) 1747, 1234, 1162 cm-1
.
Microwave reactions were conducted using a machine
consisting of a continuous focused microwave power delivery
system with operator-selectable power output from 0 to 300
W. The reactions were performed in a round-bottom flask
equipped with a condenser. The temperature of the contents
of the vessel was monitored using a calibrated infrared
temperature control mounted under the reaction vessel. All
experiments were performed using a stirring option whereby
the contents of the vessel were stirred by means of a rotating
magnetic plate located below the floor of the microwave cavity
and a Teflon-coated magnetic stir bar in the vessel. These
reactions can also be conducted using a domestic microwave
oven with a maximum emitted power of 800 W. Using a
domestic oven, the temperature of the reaction mixture at the
end of microwave irradiation was found to be 70-100 °C.
Polymer-Bound Alcohol 6. t-BuOK (1.2 g, 10.8 mmol) was
dissolved in dry DMF (20 mL), and the solution was cooled to
0 °C. 1,4-Butanediol (957 µL, 10.8 mmol) was added, and the
reaction mixture was kept at 0 °C for 1 h. Addition of 5 (3.0 g,
3.6 mmol Cl) was followed by irradiation at 130 °C for 5 min.
The polymer was filtered, washed successively with H2O (3 ×
10 mL), EtOH, (3 × 10 mL), CH2Cl2 (3 × 10 mL), and Et2O (3
× 10 mL), and then dried in vacuo at 20 °C for 4 h. IR (Nujol)
3429, 1054 cm-1
Polymer-Bound Bromide 4. Polymer-bound 6 (3.0 g, 3.6
mmol OH) was suspended in DMF (10 mL) and swollen for 10
min. Then PPh3 (3.6 g, 10.8 mmol) and CBr4 (2.8 g, 10.8 mmol)
were added, and the reaction mixture was irradiated at 130
°C for 5 min.The polymer was filtered, washed successively
with water (3 × 30 mL), EtOH (3 × 30 mL), CH2Cl2 (3 × 30
mL), and Et2O (3 × 30 mL), and then dried in vacuo at 20 °C
for 4 h. The same procedure was used to prepare 9, starting
from 8.
General Procedure for Synthesis of Linkers 3 and
16(a-c). Polymer-bound 4 (4.0 g, 4 mmol Br) was suspended
in DMF (10 mL) and swollen for 10 min. Then the appropriate
thiouracil or 6-hydroxythiocytosine (8 mmol) and K3CO3 (792
mg, 8 mmol) were added. The reaction mixture was then
irradiated at 130 °C for 5 min. The polymer was filtered,
washed successively with water (3 × 30 mL), EtOH (3 × 30
mL), CH2Cl2 (3 × 30 mL), and Et2O (3 × 30 mL), and then
dried in vacuo at 20 °C for 4 h. The same procedure was
2h: IR (Nujol) 1742, 1224, 1110 cm-1. 14a: IR (Nujol) 1774,
1269, 1145 cm-1. 14b: IR (Nujol) 1744, 1232, 1149 cm-1. 14c:
IR (Nujol) 1719, 1234, 1148 cm-1. 15a: IR (Nujol) 1770, 1674,
1146 cm-1. 15b: IR (Nujol) 1747, 1644, 1153 cm-1. 15c: IR
(Nujol) 1718, 1647, 1150 cm-1
General Procedure for Synthesis of Amides 7(a-h)
and 18(a-k). Polymer 2(a-h) (500 mg, 0.5 mmol of functional
group) was suspended in CH2Cl2 (3 mL) and swollen for 10
min. The appropriate amine (0.5 mmol) was added, the solvent
was evaporated under a stream of nitrogen, and the reaction
mixture was irradiated at 80 °C for 5 min. The polymer was
washed with CH2Cl2 (5 × 20 mL) and filtered. The organic
solution was washed with 1 N HCl, dried over anhydrous
Na2SO4, and filtered, and the solvent evaporated under
reduced pressure. The corresponding amides were obtained
pure without need of further purification. 7a, 7b, and 7d could
be obtained in a similar fashion starting from 14(a-c) or
15(a-c) in the presence of benzylamine. 18a: mp 94-96 °C;
1H NMR (CDCl3) δ 7.63-750 (m, 4H), 6.14 (s, 1H), 3.40 (q,
2H, J ) 6.7 Hz), 1.62-1.52 (m, 2H), 1.36-1.15 (m, 4H), 0.91-
0.89 (m, 3H); IR (CHCl3) 3001, 1659 cm-1. Anal. Calcd for
C12H16BrNO: C, 53.35; H, 5.97; N, 5.18. Found: C, 53.48; H,
5.97; N, 5.16. 18d: 1H NMR (CD3OD) δ 7.89-7.63 (m, 4H),
7.18-7.02 (m, 2H), 6.70-6.09 (m, 2H). Anal. Calcd for
C13H11BrN2O: C, 53.63; H, 3.81; N, 9.62. Found: C, 53.79; H,
1
3.81; N, 9.64. 18e: mp 60-61 °C; H NMR (CDCl3) δ 0.80-
0.97 (m, 3H), 1.23-1.37 (m, 4H), 1.56-1.63 (m, 2H), 3.35-
3.45 (m, 2H), 6.14 (s, 1H), 7.37 (d, 2H, J ) 8.4 Hz), 7.67 (d,
2H, J ) 8.4 Hz). Anal. Calcd for C12H16ClNO: C, 63.85; H,
7.14; N, 6.21. Found: C, 63.92; H, 7.10; N, 6.23.
General Procedure for Synthesis of Esters and Thio-
esters 19(a-j). Polymer 2d (500 mg, 0.5 mmol of functional
group) was suspended in CH2Cl2 (3 mL) and swollen for 10
min. Then DMAP (0.5 mmol) and the appropriate alcohol,
phenol, or thiophenol (0.5 mmol) were added. After evaporation
of the solvent under a stream of nitrogen, the reaction mixture
was irradiated at 80 °C for 5 min (2 × 3 min). The polymer
was washed with CH2Cl2 (5 × 20 mL). The organic solution
was dried over anhydrous Na2SO4 and filtered, and the solvent
was removed under vacuum. Purification by flash chromatog-
raphy afforded pure 19(a-j). 19b: 1H NMR (CDCl3) δ 8.06-
7.90 (m, 2H), 7.68-7.47 (m, 4H), 7.23-7.19 (m, 2H). Anal.
Calcd for C14H11BrO3: C, 54.75; H, 3.61. Found: C, 54.89; H,
3.62. 19c: 1H NMR (CDCl3) δ 7.93 (d, 2H, J ) 8.6 Hz), 7.57
(d, 2H, J ) 8.6 Hz), 7.40-7.27 (m, 5H), 5.89 (t, 1H, J ) 6.7
Hz), 2.02 (dq, 2H, J ) 7.2 Hz, J ) 6.7 Hz), 0.95 (t, 3H, J ) 7.2
(26) Petricci, E.; Radi, M.; Corelli, F.; Botta, M. Tetrahedron Lett.
2003, 44, 9181-9184.
(27) Rao, M. S.; Esho, N.; Sergeant, C.; Dembinski, R. J. Org. Chem.
2003, 68, 6788-6790.
7886 J. Org. Chem., Vol. 69, No. 23, 2004

Microwave-Assisted Acylation with SSRs
Hz); IR (CHCl3) 1716, 1271. Anal. Calcd for C16H15BrO2: C,
60.21; H, 4.74. Found: C, 60.32; H, 4.74. 19d: 1H NMR
(CDCl3) δ 7.90 (d, 2H, J ) 7.9 Hz), 7.56 (d, 2H, J ) 7.9 Hz),
6.08-5.95 (m, 1H), 5.43-5.25 (m, 2H), 4.81-4.78 (m, 2H).
Anal. Calcd for C10H9BrO2: C, 49.82; H, 3.76. Found: C, 49.98;
H, 3.75. 19e: 1H NMR (CDCl3) δ 7.87 (d, 2H, J ) 8.4 Hz),
7.55 (d, 2H, J ) 8.4 Hz), 5.12 (m, 1H), 1.90-1.50 (m, 2H),
1.39-1.19 (m, 11H), 0.91-0.87 (m, 3H). Anal. Calcd for
C15H21BrO2: C, 57.52; H, 6.76. Found: C, 57.44; H, 6.77. 19g:
1H NMR (CDCl3) δ 8.11 (d, 2H, J ) 8.4 Hz), 7.88-7.84 (m,
1H), 7.66 (d, 2H, J ) 8.4 Hz), 7.43-7.36 (m, 1H), 7.23-7.21
(m, 1H), 7.04-6.97 (m, 1H). Anal. Calcd for C13H8BrIO2: C,
38.74; H, 2.00. Found: C, 38.64; H, 2.00. 19h: mp 136-138
°C; 1H NMR (CDCl3) δ 8.04 (d, 2H, J ) 8.7 Hz), 7.86-7.65 (m,
NMR (CDCl3) δ 8.07 (d, 2H, J ) 8.7 Hz), 7.79 (d, 1H, J ) 2.1
Hz), 7.65 (d, 2H, J ) 8.7 Hz), 7.49 (dd, 1H, J ) 8.8 Hz, J ) 2.1
Hz), 7.15 (d, 1 H, J ) 8.8 Hz); IR (CHCl3) 1735 cm-1. Anal.
Calcd for C13H7Br3O2: C, 35.90; H, 1.62. Found: C, 35.82; H,
1.62.
Acknowledgment. The University of Siena (PAR
2001) is gratefully acknowledged. M.B. wishes to thank
the Merck Research Laboratories for the 2002 Academic
Development Program (ADP) Chemistry Award.
Supporting Information Available: Analytical data for
7(a-h), 18(b-c), 18(f-k), 19a, 19f, and 19j. This material
is available free of charge via the Internet at http://pubs.acs.org.
4H), 7.36 (d, 2H, J ) 8.7 Hz); IR (CHCl3) 2225, 1736 cm-1
.
Anal. Calcd for C14H8BrNO2: C, 55.66; H, 2.67; N, 4.64.
1
Found: C, 55.74; H, 2.68; N, 4.63. 19i: mp 163-164 °C; H
JO048837Q
J. Org. Chem, Vol. 69, No. 23, 2004 7887