Microwave-assisted polymer-supported acylation of 15-membered azalides - A rapid and efficient procedure

Article abstract of DOI:10.1016/j.tetlet.2011.01.154

The application of microwave heating to a polymer-assisted solution phase synthesis technique has been used to develop a rapid and efficient protocol for the solution phase synthesis of amides from unprotected polyfunctional 15-membered azalides.

Full text of DOI:10.1016/j.tetlet.2011.01.154

Tetrahedron Letters 52 (2011) 1745–1748
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted polymer-supported acylation of 15-membered azalides—a
rapid and efficient procedure
⇑
´
ˇ ´
´
Antun Hutinec , Renata Rupcic, Irena Caleta, Mislav Oršulic
´
Galapagos Research Centre Zagreb Ltd, Prilaz baruna Filipovica 29, Zagreb HR-10000, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of microwave heating to a polymer-assisted solution phase synthesis technique has been
used to develop a rapid and efficient protocol for the solution phase synthesis of amides from unpro-
tected polyfunctional 15-membered azalides.
Received 7 December 2010
Revised 12 January 2011
Accepted 24 January 2011
Available online 26 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azalides
Amides
Microwave-assisted synthesis
Polymer-assisted reagent
Solution phase synthesis
The synthesis of amides from carboxylic acids is a common
transformation in organic chemistry.1 A wealth of methods have
been developed for this reaction which usually involves various
coupling reagents.2 These reagents activate the carboxylic acid
for nucleophilic substitution by derivatization into acid chlorides,
anhydrides, activated amides or esters, thus transforming the free
hydroxy into a good leaving group. Alternatively, carboxylic acids
can be condensed with amines in the presence of stoichiometric
activators such as arylboronic acids,3 bis[bis(trimethyl-
silyl)amino]tin(II),4 titanium tetrachloride,5 trimethylaluminum,6
Lawesson’s reagent,7 dimethyl phosphoryl chloride,8 tetrazoles,9
benzoxazoles10 and oxalates.11 Unfortunately, each of these re-
agents has their own disadvantages, being unstable, toxic, expen-
sive or commercially unavailable and require the removal of by-
products.
In our efforts to develop a robust, high-yielding, chemoselective
method which can be used for automated synthesis, we utilized
several reagents and protocols in which an amide bond is used to
functionalize the molecule. This search revealed polymer-sup-
ported carbodiimide (PS-CDI) as the reagent of choice.12
The use of polymer-supported reagents for the solution phase
synthesis of individual compounds or libraries has attracted atten-
tion, especially for the preparation of molecules of biological inter-
est.13 The most important advantages of these reagents are
simplification of the reaction work-up and product isolation, the
work-up being reduced to simple filtration. In a high-throughput
organic synthesis (HTOS) environment, polymer-assisted solution
phase synthesis is attractive since excess amounts of reagents
can be used to enhance chemoselectivity and to drive reactions
to completion. This results in compound libraries with higher puri-
ties, which is beneficial for the development of robust structure–
activity relationships (SARs) in medicinal chemistry studies. In
addition, when using polymer-supported reagents, reactions can
be monitored easily in real time by conventional methods. More-
over, a large number of commercially available polymer-supported
reagents are readily available for both synthesis and purification,14
making the technology more accessible.
In an ongoing synthetic project, we required a simple and fast
process for the selective acylation of unprotected polyfunctional
macrolide amines. Macrolides are natural or semi-synthetic prod-
ucts of polyketide origin with important biological activity and
pharmacological properties.15,16
An example of the conditions traditionally used in our laborato-
ries17 is shown in Table 1, Method A, as illustrated for the transfor-
mation of 1 into 3 (Scheme 1). With this method, chromatographic
purification has to be used in order to remove impurities from the
desired product. Overall more than 24–30 h are needed for the iso-
lation of the purified compound, which is too long for obtaining
reliable SAR in medicinal chemistry.
We started our investigation by changing the coupling reagent.
First, EDCꢀHCl was substituted with PS-CDI. Under the reaction
conditions of Method B (Table 1) the desired product was formed
in 37–75% yield with a large amount of unreacted macrolide 1
recovered. The yields were improved by increasing the amount of
carboxylic acid (Table 1, Method C), (54–99% yield). The reaction
⇑
Corresponding author. Tel.: +385 1 8886367; fax: +385 1 8886444.
E-mail address: Antun.Hutinec@glpg.com (A. Hutinec).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.154

1746
A. Hutinec et al. / Tetrahedron Letters 52 (2011) 1745–1748
Table 1
PS-CDI at room temperature proved to be sufficient to achieve
Effect of the polymer-supported reagent
complete conversion. With the addition of HOBt (Table 1, Method
D) we were able to achieve a higher conversion compared to that
with EDCꢀHCl. Unfortunately, HOBt-activated acid derivatives were
too reactive leading to 15–34% yields of diacyl derivatives 4,
Scheme 1. With this reagent combination, we were able to shorten
the overall procedure to about 12 h, but we could not improve the
yield of the desired products. Therefore, further optimizations
were necessary.
Acid
Product
Method/yield (%)
A
B
C
D
2a
3a
—
75
99
—
OH
O
O
OH
Almost all of the synthetic conditions reported to date have
been conducted at ambient temperature or on much simpler
systems.19
59a
72b
NC
2b
2c
3b
3c
—
45
37
62
54
O
An alternative to classical synthesis is the microwave-assisted
approach which has emerged as a powerful tool in combinatorial
chemistry and drug discovery.20 Microwave-assisted organic trans-
formations using polymer-supported reagents have been widely
exploited. The process involves rapid instantaneous heating. This
kind of flash heating is adapted to the overall stability of the poly-
mer backbone used and the supported species. The combination of
speed, control of reaction parameters, and automation makes this
technology ideally suited for a high-throughput environment in
which optimal reaction conditions are highly advantageous.
Bearing this in mind we decided to investigate the use of micro-
wave-assisted chemistry to enhance the speed of our transforma-
tion. For optimization studies we used the polyfunctional 15-
membered azalide 1 and p-cyanobenzoic acid (2b).
67
OH
O
Cl
O
2d
2e
3d
3e
74
84
49
57
67
78
58c
61d
OH
O
NO2
OH
Method A: EDCꢀHCl (3.6 equiv), acid (1.1 equiv), HOBt (1.8 equiv), Et3N (9 equiv),
CH2Cl2, rt, 24 h.
Method B: PS-CDI (2 equiv), acid (1.1 equiv), CH2Cl2, rt, 24 h.
Method C: PS-CDI (2 equiv), acid (1.5 equiv), CH2Cl2, rt, 24 h.
Method D: PS-CDI (2 equiv), acid (1.5 equiv), HOBt (1 equiv), CH2Cl2/DMF, rt, 12 h.
a
We again began by using PS-CDI alone, hoping that the elevated
temperature would be sufficient to bring the reaction to comple-
tion. However, even heating under microwave conditions at
100 °C for 30 min did not improve this conversion (Table 2, entry
2).21
Diacyl product formed in 32% yield.
Diacyl product formed in 15% yield.
Diacyl product formed in 34% yield.
diacyl product formed in 27% yield.
b
c
d
Adding HOBt (1 equiv) to the reaction dramatically changed the
outcome. No starting amine remained, but instead the diacyl prod-
uct 4 was formed in 21% yield. Despite the fact that it was reported
that CH2Cl2 is incompatible with the heated reaction environment
since it quantitatively alkylated HOBt when the reaction was con-
ducted at even slightly elevated temperatures (55 °C),19 we did not
detect the formation of such a product and, therefore, used CH2Cl2
as the solvent. In optimizing the reaction conditions we lowered
the amount of acid to 1 equiv to prevent ester formation at the
20-position of the sugar moiety. The formation of the desired amide
could be increased to more than 80% while the formation of 4 was
decreased to around 6% (Table 2, entry 6).22
with phenylacetic acid 2a yielded quantitative conversion into the
desired amide, but the reactions with benzoic acids, some contain-
ing electron-withdrawing groups, gave lower yields than those
using our initial conditions (Table 1, Method A). Here, we were
only able to improve the work-up procedure, but were not very
successful in speeding up the amide formation for the majority
of substrates.
The use of HOBt seems to be critical for reactions carried out at
ambient temperature as it significantly increases the amount of the
desired product. It has been reported that at ambient temperature,
HOBt (1.5 equiv) is required to drive the acylation reaction to com-
pletion,18 however, the use of HOBt (1 equiv) in combination with
R
R
O
O
NH2
NH
NH
N
R
N
N
N
O
R
OH
HO
HO
N
O
N
O
OH
OH
OH
+
+
O
O
HO
HO
HO
O
OH
OH
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
O
OH
OH
O
O
2
1
3
4
Scheme 1. Acylation of the 9a-(3-aminopropyl) derivative of azithromycin.

A. Hutinec et al. / Tetrahedron Letters 52 (2011) 1745–1748
1747
Table 2
Effect of microwave heating and added HOBt on the polymer-assisted solution phase amidation of 1 and 2b to give 3ba
Entry
2b (equiv)
HOBt (equiv)
T (°C)
Reaction time (min)
1 (%)
3b (%)
4 (%)
1
2
3
4
5
6
1.5
1.5
1.5
1.5
1.3
1.1
—
—
—
1.0
1.0
1.0
100
100
120
100
100
100
5
30
5
5
5
42
39
32
—
—
—
46
43
51
68
76
83
—
—
—
21
18
6
5
a
Reaction conditions: 1 (0.015 mmol), PS-CDI (2 equiv), CH2Cl2 (0.4 mL), DMF (0.1 mL).
PS-trisamine (3 equiv) for three hours removed HOBt completely
resulting in the isolation of the product, after evaporation of the
solvent, in pure state.
Table 3
Effect of temperature, HOBt and PS-CDI
By combining the microwave-assisted polymer-supported solu-
tion phase chemistry with PS-trisamine scavenging, both the syn-
thesis and purification could be routinely accomplished in less
than 4 h at the bench. In addition, the products were isolated in
high yields and purities. The best reaction conditions for the acyl-
ation (Table 3, entry 3) yielded the desired product 3b in 92% yield
and in very good purity.
Entry
PS-CDI (equiv)
HOBt (equiv)
T (°C)
1 (%)
3b (%)
4 (%)
1
2
3
2.0
2.0
1.3
1.0
0.7
0.7
80
80
70
—
—
—
88
90
92
4
1
—
Reaction conditions: 1 (0.015 mmol), CH2Cl2 (0.4 mL), DMF (0.1 mL), 5 min.
With the above results in hand, we next pursued a variety of
target compounds (Table 4) using this microwave-assisted acyla-
tion protocol.23
The reaction conditions were further optimized by varying the
temperature, and the amounts of HOBt and the polymer-supported
reagent (PS-CDI) (Table 3).
In summary, we have described a rapid, convenient and high-
yielding protocol for the preparation of amides from polyfunctional
macrolide amines and carboxylic acids. The procedure utilizes
commercially available acids and equipment, and is suitable for
To remove the HOBt catalyst, which in many cases was the only
detectable impurity observed in the crude reaction mixture, the
use of scavenger resins is particularly well suited. In practice it
was found that treatment of the crude reaction mixtures with
Table 4
Substrate scope of the microwave-assisted polymer-supported amidation
Cl
O2N
O
N
H
3f
3g
3h
3i
3j
3k
R=
F
F
O
NO2
O
N
3l
3m
3n
3o
3p
3q
Product
Yield (%)
Purity (%)
Product
Yield (%)
Purity (%)
3f
96
91
94
95
96
96
93
98
93
90
89
92
3l
95
93
37b
96
95
97
90
92
91
89
91
90
3g
3h
3i
3j
3k
3m
3na
3o
3p
3q
a
Sodium salt of the acid was used.
After HPLC/MS purification.
b

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A. Hutinec et al. / Tetrahedron Letters 52 (2011) 1745–1748
13. For examples, see: (a) Senten, K.; Danieels, L.; Van der Veken, P.; De Meester, I.;
Lambeir, A.-M.; Scharpe, S.; Haemers, A.; Augustyns, K. J. Comb. Chem. 2003, 5,
336–344; (b) South, M. S.; Dice, T. A.; Girard, T. J.; Lachance, R. M.; Stevens, A.
M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; Parlow, J. J. Bioorg. Med.
Chem. Lett. 2003, 13, 2363–2367; (c) South, M. S.; Case, B. L.; Wood, R. S.; Jones,
D. E.; Hayes, M. J.; Girard, T. J.; Lachance, R. M.; Nicholson, N. S.; Clare, M.;
Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; Parlow, J. J.
Bioorg. Med. Chem. Lett. 2003, 13, 2319–2325; (d) Jaunzems, J.; Hofer, E.;
Jesberger, M.; Sourkouni-Argirusi, G.; Kirschning, A. Angew. Chem., Int. Ed. 2003,
42, 1166–1170; (e) Vickerstaffe, E.; Warrington, B. H.; Ladlow, M.; Ley, S. V. Org.
Biomol. Chem. 2003, 1, 2419–2422; (f) Yun, Y. K.; Porco, J. A., Jr.; Labadie, J.
Synlett 2002, 739–742.
the preparation of individual analogues or automated library pro-
duction. This procedure has become the method of choice for pro-
ducing analogues for our High-Throughput Medicinal Chemistry
efforts and has been used to prepare thousands of analogues from
a variety of acid and amine cores. Further application of this meth-
odology for the synthesis of other amides from either macrolide
amines or macrolide acids will be described in due course.
Acknowledgements
14. (a) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner, J. J.; Yang, S. Med.
Chem. Res. 1998, 8, 219–243; (b) Flynn, D. L.; Devraj, R. V.; Parlow, J. J. Curr.
Opin. Drug Discov. Devel. 1998, 1, 41–50; (c) Weidner, J. J.; Parlow, J. J.; Flynn, D.
L. Tetrahedron Lett. 1999, 40, 239–242.
15. Macrolide Antibiotics; Schoenfeld, W., Kirst, H. A., Eds.; Birkhauser: Basel, 2002.
16. (a) Culic, O.; Erakovic, V.; Parnham, M. J. Eur. J. Pharmacol. 2001, 429, 209–229;
(b) Giamarellos-Bourboulis, E. J. Int. J. Antimicrob. Agents 2008, 31, 12–20.
17. Merc´ep, M., Mesic´, M., Tomaškovic, L., Markovic´, S. PCT Int. Appl. WO 04/
005309 A2, 2004; Chem. Abstr. 2004, 140, 111631.
The authors gratefully acknowledge the assistance of Bill
Leavans for high resolution mass spectroscopic (HRMS) analysis,
Zeljko Osman for LC/MS analysis and Biserka Metelko for NMR
ˇ
spectroscopy.
Supplementary data
18. Lannuzel, M.; Lamothe, M.; Perez, M. Tetrahedron Lett. 2001, 42, 6703–6705.
19. Sauer, D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003, 5, 4721.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.154.
20. (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4,
95–105; (b) Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314–320; (c) Dzierba, C.
D.; Combs, A. P. Annu. Rep. Med. Chem. 2002, 37, 247–256; (d) Santagada, V.;
Perissutti, E.; Caliendo, G. Curr. Med. Chem. 2002, 9, 1251–1283; (e) Blackwell,
H. E. Org. Biomol. Chem. 2003, 1, 1251–1255.
References and notes
21. All microwave reactions were performed using
a CEM Explorer (http://
1. Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.; Wiley: New York,
2001. and references cited therein.
2. (a) Larock, R. C. Comprehensive Organic Transformations; VCH: New York, 1989;
(b) Klausner, Y. S.; Bodansky, M. Synthesis 1972, 453.
www.cem.com) without the use of continuous cooling. The power was
automatically adjusted so as to maintain the desired temperature.
22. The diacylated product can be converted into the desired product by heating in
MeOH at 40 °C for 1–2 h.
3. Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196.
4. Burnell-Curty, C.; Roskamp, E. J. Tetrahedron Lett. 1993, 34, 5193.
5. Wilson, J. D.; Weingarten, H. Can. J. Chem. 1970, 48, 983.
6. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
7. Thorsen, M.; Andersen, T. P.; Pedersen, U.; Yde, B.; Lawesson, S. Tetrahedron
1985, 41, 5633.
8. Jászay, Z. M.; Petnecházy, I.; Töke, L. Synth. Commun. 1998, 28, 2761.
9. Schmidt, U.; Dietsche, M. Angew. Chem., Int. Ed. Engl. 1982, 21, 143. Angew.
Chem. 1982, 94, 145.
10. Ueda, M.; Oikawa, H.; Kawaharasaki, N.; Imai, Y. Bull. Chem. Soc. Jpn. 1983, 56,
2485.
11. Takeda, K.; Sawada, I.; Suzuki, A.; Ogura, H. Tetrahedron Lett. 1983, 24, 4451.
12. Argonaut Technologies, http://www.argotech.com.
23. General procedure for the preparation of amides via microwave heating and PS-
trisamine scavenging.
charged with PS-CDI (1.3 equiv, 1.24 mmol/g). A solution of carboxylic acid
(1 equiv) and HOBt (0.7 equiv), in mixture of CH2Cl2 (2 mL) and DMF
A dry reaction vessel equipped with a stir bar was
a
(0.15 mL) was added onto the dry resin followed by additional CH2Cl2 (1 mL).
The mixture was stirred at room temperature for 5 min, upon which the
macrolide amine 1 (40 mg, 0.05 mmol) dissolved in CH2Cl2 (2 mL) was added.
The reaction vessel was sealed and heated under microwave irradiation at
70 °C for 5 min in a CEM Explorer. After completion of the reaction, PS-
trisamine (3 equiv, 4.11 mmol/g) was added and the mixture was stirred for
3 h at room temperature. The product was separated from the resin by
filtration and the resin was washed with CH2Cl2 (3 ꢁ 1 mL), and the solvent
evaporated under reduced pressure to afford the desired amide.