Poly(ethylene glycol) as solvent and polymer support in the microwave assisted parallel synthesis of aminoacid derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01067-4

A Schiff base protected glycine supported on a soluble polymer such as poly(ethylene glycol) reacted readily with various electrophiles in the presence of an inorganic base under microwave activation. It was shown in this study that the polymer support also serves as solvent in these reactions. Various α-aminoacids derivatives could be synthesized using this method. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01067-4

Tetrahedron Letters 41 (2000) 6371±6375
Poly(ethylene glycol) as solvent and polymer support in the
microwave assisted parallel synthesis of aminoacid derivatives
Berengere Sauvagnat, Frederic Lamaty,* Rene Lazaro and Jean Martinez
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Laboratoire des Aminoacides, Peptides et Proteines (LAPP), CNRS-Universites Montpellier 1 et 2,
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Place Eugene Bataillon, 34095 Montpellier, Cedex 5, France
Received 25 May 2000; accepted 23 June 2000
Abstract
A Schi€ base protected glycine supported on a soluble polymer such as poly(ethylene glycol) reacted
readily with various electrophiles in the presence of an inorganic base under microwave activation. It was
shown in this study that the polymer support also serves as solvent in these reactions. Various a-aminoacids
derivatives could be synthesized using this method. # 2000 Elsevier Science Ltd. All rights reserved.
Microwave-assisted organic synthesis has become an increasingly used technique for the
generation of new molecules.1 It usually leads to shorter reaction times and increased yields and
purity. Many solvent-free reactions using microwaves have been developed since it reduces the
risks of hazards by pressure build-up in the reaction vessel and the scale-up is made easier. One
particularly attractive ®eld is the coupling of microwave activation with the solvent-free phase-
transfer catalysis (PTC),2 where a reactant can also act as the organic phase. We report herein a
PTC reaction in which a polymer support serves also as the organic phase.
In an ongoing project dealing with the supported synthesis of a-aminoacids derivatives,3,4 we
developed a phase-transfer catalyzed alkylation of a Schi€ base glycine supported on a soluble
poly(ethylene glycol) polymer (PEG) (Scheme 1).3 Initially the reaction was carried out in
Scheme 1.
* Corresponding author. E-mail: frederic@crit.univ-montp2.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01067-4

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acetonitrile using an insoluble inorganic base such as K2CO3 or Cs2CO3 in the presence of
various electrophiles. We have shown that in such a reaction the soluble polymer could act as a
phase-transfer catalyst.3,4a
Since PEG of low molecular weight (400 to 800) have received attention as solvent in a wide
variety of reactions,5,6 we have decided to investigate the possibility of using a PEG simultaneously
as polymeric support and solvent. The PEG which we used has an average molecular weight of
3400 and was functionalized at both ends.3b A PEG supported molecule such as 2 is solid at room
temperature with a melting point of 45±47ꢀC. Therefore, we thought that a reaction could be
carried out in the absence of an extra solvent as long as the conditions would melt the poly-
meric molecule. Microwave heating was then considered to provide conditions for a solid±liquid
phase-transfer catalysis to occur.7,8
The reaction test which was chosen was the alkylation9 by benzyl bromide in the presence of
di€erent inorganic bases (K2CO3 or Cs2CO3) of two di€erent substrates, one in the absence of
PEG (1) and one supported on PEG (2). For the sake of comparison, reactions were performed
under microwave activation10 or in re¯uxing acetonitrile or with conventional heating without
extra solvent. The alkylation results are presented in Table 1.
Table 1
Reaction time for complete alkylation of 1 and 2 with benzyl bromidea
In all cases the reaction went to completion in a reasonable amount of time with both of the
inorganic bases, with reaction time being shorter with Cs2CO3 than with K2CO3. The reaction
performed on the PEG supported Schi€ base 2 was faster than the one performed on 1 in the
absence of PEG (entry 2 vs entry 1). This e€ect of PEG was con®rmed by running the reaction of
1 in the presence of PEG-OMe (entry 3). In this case the reactions were also accelerated. A
submolar amount of PEG (5 mol%) was also used but appeared to be less ecient (entry 4). In
these reactions the acceleration of the reaction kinetics could be interpreted by the fact that after
the PEG has melted at the temperature reached in the microwave oven, it provided a solvent
environment which could conduct the heat and di€use the chemicals. Moreover, this is a solvent
with special properties since it can chelate cations eciently and accelerate the alkylation as we
have shown before.3 Entry 2 clearly illustrates the fact that a poly(ethylene glycol) could be used
simultaneously as solvent and polymeric suppport.

6373
We then compared two di€erent mode of activation of 2, under microwave in the absence of
extra solvent (entry 1) and in re¯uxing acetonitrile (entry 5). For both of the bases the reaction
times were shorter under microwave activation, especially in the case of K2CO3. One might
question whether this e€ect was intrinsically produced by the microwave irradiation2 or whether
it was due only to the fact that a temperature higher than 85ꢀC was reached in the reaction vessel.
Another explanation could be that neat PEG was more ecient as a solvent and phase-transfer
catalyst than a mixture acetonitrile/PEG. We therefore chose to run the reaction under classical
thermal conditions without extra-solvent. The choice of the reaction temperature was then a
critical parameter for comparison. At this point we were reaching the limits of the microwave
oven we were using since it was dicult to measure the temperature reached at the end of the
reaction on the quantities of substrate we were using. Also, being a multimode oven, this
temperature might not be stable during the irradiation time. We ®nally chose to carry out the
reaction at 85ꢀC (temperature of the oil bath; entry 6), which would also provide for some
comparison with the re¯uxing acetonitrile conditions. In this case the reaction time was longer
than the one obtained under microwave (entry 2) but shorter than the one in re¯uxing acetonitrile
(entry 5). Microwave irradiation did not dramatically shorten the reaction times which seems to
con®rm that speci®c e€ects other than heating were not involved in this reaction. These
experiments also con®rmed that neat PEG was a better solvent than acetonitrile and could
strongly enhance the reactivity of the inorganic base by chelation of the countercation. Abribat et
al.6d have also noticed the increased catalytic eciency of PEG in the absence of a co-solvent in a
Williamson ether synthesis. Berdague et al.6a have defended the idea that activation generated by
a PEG could be modulated by adding a cosolvent: they described the bis O-alkylation of a
dihydroxybenzene carried out when PEG was used as the only solvent whereas selectivity could
be directed towards the mono O-alkylation when a co-solvent was added.
Finally, in all cases, reactions with K2CO3 were slower than with Cs2CO3 and also more
sensitive to the reaction conditions. Whereas the reaction times with Cs2CO3 were in the same
order of magnitude, large di€erences were met with K2CO3. The e€ects of PEG are more sensitive
with the potassium cation, most probably because of a more important chelation e€ect due to the
size of the cation.
Schi€ base 2 was then reacted with various electrophiles (Scheme 2) and the results are
presented in Table 2.
Scheme 2.
These examples showed that diverse electrophiles could be used in this reaction, including
acrylic acid derivatives.11 After alkylation, the aminoester was released from the polymer by trans-
esteri®cation with MeOH in the presence of Et3N.3b,12 This con®rmed the possibility of performing
microwave-assisted parallel synthesis of aminoacid derivatives supported on poly(ethylene glycol)
without extra solvent,13 and it could be extended to other small organic molecules. Microwave
assisted solid-phase synthesis of organic molecules has also been reported,14 but so far it seemed

6374
Table 2
Alkylation of 2 with various electrophiles
that an extra solvent was necessary and that sometimes degradation of the polymer support was
observed.14a
In summary we have shown that poly(ethylene glycol) with a molecular weight of 3400 could
serve as a solvent in microwave assisted reactions. These reactions can be performed when the
PEG also acts as the support. No speci®c microwave e€ects could be found but this technique
remains more practical than conventional heating and could be more widely applied to
combinatorial chemistry.
Acknowledgements
We thank the CNRS and the MENRT for ®nancial support.
References
1. (a) Caddick, S. Tetrahedron 1995, 51, 10403±10432. (b) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213±1234.
2. Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A. Tetrahedron 1999, 55, 10851±10870.
3. (a) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J. Tetrahedron Lett. 1998, 39, 821±824. (b) Sauvagnat, B.;
Lamaty, F.; Lazaro, R.; Martinez, J. J. Comb. Chem. 2000, 2, 134±142.
Â
4. (a) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J. C. R. Acad. Paris Serie IIc 1998, 1, 777±780. (b) Nouvet,
A.; Binard, M.; Lamaty, F.; Martinez, J.; Lazaro, R. Tetrahedron 1999, 55, 4685±4698. (c) Bouifraden, S.; Drouot,
C.; El Hadrami, M.; Guenoun, F.; Lecointe, L.; Mai, N.; Paris, M.; Pothion, C.; Sadoune, M.; Sauvagnat, B.;
Amblard, M.; Aubagnac, J. L.; Calmes, M.; Chevallet, P.; Daunis, J.; Enjalbal, C.; Fehrentz, J. A.; Lamaty, F.;
Lavergne, J. P.; Lazaro, R.; Rolland, V.; Roumestant, M. L.; Viallefont, P.; Vidal, Y.; Martinez, J. Amino Acids
1999, 16, 345±379.
5. For a review, see: (a) Totten, G. E.; Clinton, N. A. J. M. S. Rev. Macromol. Chem. Phys. 1988, C28, 293±337.
(b) Totten, G. E.; Clinton, N. A.; Matlock, P. L. J. M. S. Rev. Macromol. Chem. Phys. 1998, C38, 77±142.
6. For selected examples: (a) Berdague, P.; Perez, F.; Courtieu, J.; Bayle, J. P. Bull. Soc. Chim. Fr. 1993, 130, 475±
480. (b) Abribat, B.; Le Bigot, Y.; Gaset, A. Synth. Comm. 1994, 24, 1773±1779. (c) Abribat, B.; Le Bigot, Y.;

6375
Gaset, A. Synth. Comm. 1994, 24, 2091±2096. (d) Abribat, B.; Le Bigot, Y. Tetrahedron 1997, 53, 2119±2124. For
an example involving a PEG 6000, see: Neumann, R.; Sasson, Y. Tetrahedron 1983, 39, 3437±3440.
7. For an example of PEG supported synthesis using microwave with water as solvent see: Blettner, C. G.; Konig, W. A.;
Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64, 3885±3890.
8. For an example of microwave mediated esteri®cation on a soluble poly(styrene-co-allylalcohol)polymer: Vanden
Eynde, J.-J.; Rutot, D. Tetrahedron 1999, 55, 2687±2694.
9. Microwave activated alkylation of a benzaldehyde Schi€ base glycine has been described: Jiang, Y.; Wang, Y.;
Deng, R.; Mi, A. In Phase Transfer Catalysis, Mechanisms and Syntheses; Halpern, M. E., Ed.; ACS Symposium
Series 659:Washington DC, 1996; p. 203.
10. Microwave-assisted reactions were performed in an open pyrex glass vessel (beaker, 2 cm diameter, 2 mm thick
glass) with a Brandt MS 1100 Domestic Microwave oven at a frequency of 2450 Hz and a power of 850 W.
Caution: the inorganic base must be well distributed by previous mixing with the organic compounds in order to
avoid the destruction of the reaction vessel. A representation procedure for the synthesis of 4e is as follows:
Cinnamyl bromide (11.8 mg, 0.06 mmol) was added to poly(ethylene glycol) 3400 N-(diphenylmethylene) glycinate
(80 mg, 0.02 mmol) and Cs2CO3 (39 mg, 0.12 mmol). The mixture was heated under microwave for 45 min. After
cooling, the product was dissolved in CH2Cl2, then ®ltered. The ®ltrate was concentrated, dissolved in CH2Cl2,
®ltered, and then precipitated in Et2O. The product was ®ltered and dried in vacuo to yield 80 mg (98%) of the
title compound: IR (KBr) 2865 (m), 1736 (s), 1655 (s), 1459 (s), 1100 (m), 954 (m) cm^1; 1H NMR (CDCl3, Me4Si)
ꢀ 2.70±2.90 (m, 2H), 3.50±3.80 (s large, 310H), 4.05±4.15 (m, 1H), 4.20±4.30 (m, 2H), 5.90±6.15 (m, 1H), 6.30±6.45
(d, J=15.5 Hz, 1H), 7.10±7.40 (m, 13H), 7.55±7.70 (m, 2H); 13C NMR (CDCl3, Me4Si) ꢀ 37.48, 64.44, 65.78,
69.36, 126.40, 127.49, 128.27, 128.40, 128.83, 128.86, 129.03, 129.18, 130.73, 133.08, 136.72, 137.68, 139.85, 171.17,
171.99.
1
11. All new compounds have been characterized by IR, H NMR, 13C NMR and ESI mass spectrometry.
12. Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten, T. Synlett 1998, 295±297.
13. Conventional alkylation of Schi€ base protected glycine in the solid-phase has been described: (a) O'Donnell, M. J.;
Zhou, C.; Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070±6071. (b) O'Donnell, M. J.; Lugar, C. W.; Pottorf, R. S.;
Zhou, C. Tetrahedron Lett. 1997, 38, 7163±7166. (c) Domõnguez, E.; O'Donnell, M. J.; Scott, W. L. Tetrahedron
Lett. 1998, 39, 2167±2170. (d) O'Donnell, M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347±6362.
14. (a) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219±8222. (b) Chen, S. T.; Tseng, P. H.;
Yu, H. M.; Wu, C. Y.; Hsiao, K. F.; Wu, S. H.; Wang, K. T. J. Chin. Chem. Soc. 1997, 44, 169±182. (c) Hsieh, H. P.;
Chen, S. T.; Wang, K. T. J. Chin. Chem. Soc. 1997, 44, 597±600. (d) Yu, A. M.; Zhang, Z. P.; Yang, H. Z.; Zhang, C. X.;
Liu, Z. Synth. Commun. 1999, 29, 1595±1599. (e) Hoel, A. M. L.; Nielsen, J. Tetrahedron Lett. 1999, 40, 3941±
3944. (f) Chandrasekhar, S.; Padmaja, M. B.; Raza, A. Synlett 1999, 1597±1599.